Journal Article Reading (B)Log

A Pd(0)-Catalyzed Diamination of Terminal Olefins at Allylic and Homoallylic Carbons via Formal C-H Activation under Solvent-Free Conditions

2007-05-24T21:40:00.000-05:00

Link: JACS ASAP

Haifeng Du, Weicheng Yuan, Baoguo Zhao, and Yian Shi*

Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523

This is a new method di-amidation of terminal alkenes at the allylic and homoallylic positions using di-tert-butyldiaziridinone (2). A similar method was reported before with conjugated diene 1. In this method, terminal alkene 4 was used to give similar product.

The reaction is applicable to a variety of alkenes, affording products with trans-stereochemistry in modest to excellent yields.

The products of the current reaction is useful in further transforming to give 1,2-diamines such as 6.

In addition to mono alkenes, the reaction was also applied to bis-terminal alkenes. In case of 7, the products were formed as a mixture of 8a and 8b in a 1:1 ratio. In case of 9, while 11 was formed, both 10a and 10b were isolated and are believed to be intermediates in the reaction. Both 10a and 10b when subjected to Pd(PPh3)4 transformed give 11.

The mechanism of the reaction was proposed to be as followed:

Essentially, the reaction probably goes through intermediate diene 15 formed in situ. A more detailed mechanistic study is needed.

Substituted Diarylmethylamines by Stereospecific Intramolecular Electrophilic Arylation of Lithiated Ureas

2007-05-24T21:03:00.000-05:00

Link: JACS ASAP

Jonathan Clayden,* Jérémy Dufour, Damian M. Grainger, and Madeleine Helliwell

School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom

This is a neat and remarkable methodology for the synthesis of diarylmethylamines. The reaction starts with N-aryl-N'-methylaryl-urea. Upon treatment with sec-BuLi, the bezylic position is deprotonated. This benzylic lithium then adds across the urea carbonyl to the ipso-position of the other aryl group on the other nitrogen. The complex formed then rearranges to give the aryl-migrated product, ie 3. This product can serve as a precursor to diarylmethylamine 4 upon reduction or hydrolysis.

The reaction was found to be stereosepcific, that is the configuration of the benzylic position in the SM is retained in the product. The reaction was found to be widely applicable regardless of electronic character of the aryl ring being transferred.

And as mentioned above, the reaction is stereospecific. In case of chiral SM, the configuration of the stereogenic center is retained. This is summarized in the table below.

The stereospecificity of the reaction was further demonstrated in the synthesis of chiral 7.

The reaction was found to be intramolecular as proven by the absence of cross-over products in a cross-over experiment. The intermediate of the reaction was found to be 9 as proven by the isolations of 10o and 10p upon exposure of the intermediates to dry air, thus fully proving the mechanism of the reaction. In this reaction, DMPU was added to help promote the dearomatization reaction for the formation of intermediate 9 (both DMPU and HMPA are known to promote such reaction).

This is a neat reaction which can provide a ready access to racemic or enantio-enriched diarylmethylamines.

The First Sequential Reaction Promoted by Manganese: Complete Stereoselective Synthesis of (E)-alpha,beta-Unsaturated Esters from 2,2-Dichloroesters

2007-05-20T00:14:00.000-05:00

Link: JOC ASAP

José M. Concellón,* Humberto Rodríguez-Solla, Pamela Díaz, and Ricardo Llavona

Departamento de Química Orgnica e Inorgnica, Facultad de Química, Universidad de Oviedo, Julin Clavería 8, 33071 Oviedo, Spain

Mn has increasingly received much interest as a reagent/catalyst in organic transformation with its reactivity profile similar to SmI2 and CrCl2 but much less toxic and less expensive. In this current paper, activated Mn (Mn*) was used in refluxing THF to effect the following transformation with high stereoselectivity giving products in high yields.

Importantly, the Mn* system was able to transform inexpensive dichloroacetate ester derivatives in the presence of aldehydes to give both di- and trisubstituted alpha,beta-unsaturated esters in refluxing THF. The system also worked with dibromoacetate ester derivatives at rt. However, the dibromoacetate ester derivatives are generally more expensive than the dicholo-counterparts. Enolizable aldehydes could be used to effectively form the desired ester product without problem. However, when ketone was used in place of aldehyde, mixture of unidentifiable products was formed.

For the transformation below, activated Mn* was prepared by treatment of mixture of MnCl2 (13 mmol) and LiCl (26 mmol) with a slurry of lithium powder (26 mmol) at rt.

In comparative studies, some of these transformations to disubstituted products were compared with results using SmI2 and CrCl2 and Mn* was found to be superior in most cases as shown in Table 1.

To show versatility of this reaction, trisubstituted products could also be made. And these results are summarized in Table 2.

All products, both di- and trisubstituted enoates, were formed stereoselectively to yield only E-enoates. All of these transformations were believed to be a sequential processes starting from aldol reaction, followed by beta-elimination, all in one step. Selectivity of the reaction was believed to stem from TS-I where bulky R1 was placed in the pseudo-equatorial position. This is also illustrated in Fisher projection of TS-II. Scheme 2 demonstrates the proposed mechanism and transition states.

Rhodium-Catalyzed Aryl Transfer from Trisubstituted Aryl Methanols to alpha,beta-Unsaturated Carbonyl Compounds

2007-05-19T23:59:00.000-05:00

Link: ACIEE EarlyView

Takahiro Nishimura,*, Taisuke Katoh, Tamio Hayashi*

Department of Chemistry, Graduate School of Science, Sakyo, Kyoto 606-8502, Japan

The method shown in the paper demonstrated the use of Rh to transfer aryl group from tertiray substituted methanol to alpha,beta-ketones and ester.

The Rh-Aryl bond is formed via beta-elimination of the tertiary alcohol. This transformation also paralleled to methods known previously using other metals.

In effecting this transformation, alcohol 1 was used as the source of aryl group. Other aryl sources were also studied (4m-8m for Ph, Scheme 3) but 1 was found to give the best result, yielding the desired 1,4-adduct 9 and ketone 2 as a byproduct.

The results using 1m-u are summarized in Table 1.

Additionally, the reaction could be conducted with stereoselectivity when (S,S)-Bn-bod* was used in place of cod on the Rh catalyst. This is demonstrated in the reaction between 3a and 1p in Scheme 4.

The mechanism was proposed as shown in Scheme 6.

Synthesis of the Tricyclic Core of Colchicine via a Dienyne Tandem Ring-Closing Metathesis Reaction

2007-05-19T23:43:00.000-05:00

Link: Org Lett ASAP

François-Didier Boyer and Issam Hanna*

Unité de Chimie Biologique, AgroParisTech, INRA, F-78026 Versailles, and Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France

This paper presented a very neat use of RCM and quite clever strategy to construct the 7,7-fused core of colchicine. For the first time, the 7,7-fused bicyclic system could be accessed very quickly in a single step. This main strategy is summarized in the retrosynthetic analysis below.

Therefore, substrate 4 was needed for the RCM step and it was constructed according to the following scheme.

The key reactions were formylation of 6 mediated by SnCl4 to give 7 and the synthesis of propargylic alcohol 14 which was achieved in three steps from 5, using the Ohira-Bestman reagent in the last step.

Next, sequential RCM reactions were performed on 14 using Grubbs' second generation catalyst (15) after the protection of the OH group with TMS. The reaction proved to be very efficient, providing the desired 16 in 74% yield from 14.

This intermediate 16 was further elaborated as shown in Scheme 4 via oxidative rearrangement. Compound 18 could be obtained in high yield. However, going along a more well-known route of previous total syntheses of colchicine, intermediate 19 could be obtained in modest yield, along with 20, from 17. This latter route effectively constituted a formal synthesis of colchicine. The final completion of this molecule by a novel sequence is currently under investigation.

Overall, the double RCM (enyne RCM and RCM) in constructing the 7,7-core of colchicine presented in this paper is quite ingenius.

Ring-Closing Reaction of Allenic/Propargylic Anions Generated by Base Treatment of Sulfonylallenes

2007-05-19T23:40:00.000-05:00

Link: Org Lett ASAP

Shinji Kitagaki, Satoshi Teramoto, and Chisato Mukai*

Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan

This is a report of a very neat and novel ring closing reaction. The reaction involves the allenic moiety substituted with an EWG and a strategically placed electrophile tethered to the allene.

The EWG could be sulfone, ketone and ester and electrophile could be halide, aldehyde and alpha,beta-unsat ester. The reaction conditions were quite mild and even TBAF could be used as a base, as well as a more potent base such as NaH. When EWG was sulfone, and the electrophile was either OTs group or I, the reactions proceeded to give the expected cyclic propargylic sulfone as shown in Table 1.

But when electrophile was an aldehyde, product of type 9 could be obtained in good yields, except in entry 14 of Table 2 where 10, instead of the expected 9, was also obtained in 26% presumably via addition of enolate of the aldehyde to the allene in the endo-mode.

In addition, when electrophile was alpha,beta-unsat ester and the base used was KOt-Bu, the expected product (12) was obtained in good yields.

Finally, when EWG was something else other than a sulfone, and the elctrophile was a terminal iodide, the reaction proceeded to give the ring-closing product of type 14 in modest to excellent yields (except 14c).

Asymmetric Amine-Intercepted Nazarov Cyclization

2007-05-19T23:33:00.000-05:00

Link: JACS ASAP

Francis Dhoro, Tor E. Kristensen, Vegar Stockmann, Glenn P. A. Yap, and Marcus A. Tius*

Department of Chemistry, 2545 The Mall, University of Hawaii, Honolulu, Hawaii 96822, and Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716

This is a work on amine-intercepted Nazarov cyclization. The reaction yielded alpha'-amino-, alpha, beta-unstaturated cyclobutenone. Initial result is as shown in Scheme 1.

In this paper, a camphor-derived derivative of 1 was used in the studies as shown in Scheme 2.

Subsequently, the following substrates were used in the study, all were made from addition of the organolithium to the corresponding morpholine amide.

The reaction conditions were very mild, essentially on exposure to activated silica gel, alumina, or florisil. For 12, reaction did not work well and mixture of unidentifiable products were obtained. Otherwise, the products obtained from other substrates are summarized in Table 1.

The structures of these products were assigned based on the x-ray crystal structure of the picrate salt of 20. Streochemistry observed was the result of conrotatory electrocyclic ring closure.

Additionally, the intermediate of type 8 as in Scheme 2 could be trapped intramolecularly by a tethered amino group as in 26 to give a unique compound 27 in good yield. Interestingly, due to the steric constraint, trapping of nitrogen occurred on the same face of the cyclopentenone (which is different from other intermolecular trapping cases, see Table 1).

The products from this reaction could be further utilized. The TIPS group and chiral auxiliary are easily cleaved from the products. Exposure of 23 to tetra-n-butylammonium fluoride in THF led to rapid cleavage of the TIPS group (28, 92% yield). Subsequent exposure of the product to chlorotrimethylsilane in methanol at 0 °C led to cleavage of the chiral auxiliary (29, 93% yield). (See the paper and the Supporting Information for details.)

Amine-Catalyzed Direct Aldol Addition

2007-05-19T23:32:00.000-05:00

Link: JACS ASAP

Morris Markert, Michael Mulzer, Bernd Schetter, and Rainer Mahrwald*

Institut für Chemie der Humboldt-Universität zu Berlin, Brook-Taylor Strasse 2, 12 489 Berlin, Germany

A new method emerged for tertiary amine-catalyzed cross aldol reaction between aldehydes and hydroxyl acetone. This method is different from previous method where tertiary amine was used in conjunction with LiClO4. The initial results are as seen in Scheme 1 of the reactions catalyzed by DBU.In the subsequent scheme, further utilities of the reaction is illustrated, using Hunig's base as catalyst. In some of these reactions, cyclic acetal was obtained along with the expected aldol adduct.As is readily seen, the reaction predominantly afforded syn-aldol product. The selectivity was probably stemed from the effect of hydrogen-bonding - a welcome complement to the previously known anti-selectivity.

The method is applicable to enolizable aldehyde. The reaction is also regioselective with regards to enolate counterpart, namely only alpha-carbon bearing OH group was observed to add to the aldehyde. In the scheme below, the method was used effectively in the synthesis of furanose 8 and sorbose 9.In addition to DBU and Hunig's base, alkaloid such as cinchonine was also found to be an effective catalyst as demonstrated in the example below.

Enantioselective Organocatalytic Singly Occupied Molecular Orbital Activation: The Enantioselective alpha-Enolation of Aldehydes

2007-05-19T14:14:00.000-05:00

Link: JACS ASAP

Hye-Young Jang, Jun-Bae Hong, and David W. C. MacMillan*

Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

In continuing their investigation in the newly discovered mode of organocatalysis - the singly occupied molecular orbital, or SOMO activation - MacMillan group presented a new reaction. In the original contribution, alpha-allylation of aldehyde using allylsilane was recently reported.

This time alpha-enolation of aldehyde and enolsilane using the same catalyst system was reported for the first time. The mode of activation is through a single-electron activation with CAN, as shown in the scheme below, to give the corresponding electron-deficient radical cation.

Based on a DFT calculation, the enolsilane or the "SOMOphile" would approach the "SOMO-catalyst" on the si-face to avoid the bulky t-Bu group of 1, establishing the enantioselectivity of the reaction.

Thus, using enolsilane 3 as a somophile, reactions with various aldehydes proceeded in good yields and ees as shown in Table 1.

In addition, several somophiles were used to react with octanal to give the expected products in good to excellent yields and excellent ees (Table 2).

In addition, the reaction was found to be very mild and chemoselective as illustrated in Eqs 5 and 6. In a normally difficult-to-control intramolecular radical cyclization of 4, when reaction was conducted in the presence of enolsilane, the corresponding alpha-enolation product was obtained selectively in excellent yield and ee.

SOMO-activation has become more important in the field of organocatalysis. One could expect to see much more of this in the near future.

Direct, Catalytic Hydroaminoalkylation of Unactivated Olefins with N-Alkyl Arylamines

2007-05-15T18:59:00.000-05:00

Link: JACS ASAP

Seth B. Herzon and John F. Hartwig*

Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801

A new reaction which will probably become a name reaction: the Hartwig Hydroaminoalkylation.

This was based on the work done over two decades by Maspero and Nugent, according the scheme below.

The reaction essentially added aminoalkyl group across the double bond of an olefin. The aminoalkyl group is part of the N-methylaniline and. The catalyst was screened as presented in Table 1 and Ta[N(CH3)2]5 was found to be most optimal.

The reaction was found to work well with a variety of terminal olefins, which in most cases, providing methyl-branched products in good yields (except entry 2 below where a mixture of products was obtained).

A variety of arylamine partners could also be utilized as shown in Table 3.

The mechanism of the reaction is largely under investigation. Nonetheless, this is a neat reaction.

Highly Selective Thiiranation of 1,2-Allenyl Sulfones with Br2 and Na2S2O3: Mechanism and Asymmetric Synthesis of Alkylidenethiiranes

2007-05-15T14:49:00.000-05:00

Link: ACIEE EarlyView

Chao Zhou (1), Chunling Fu (1),* Shengming Ma (1,2)*

(1)Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou, 310027, Zhejiang, P.R. China

(2)Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P.R. China

A method for thiirane synthesis from allene, using bromine and sodium thiosulfate. The reaction goes through a neat mechanism, via the isolated five-membered intermediate 5l for the formation of (E)-3l.

The reaction is also stereospecific as shown in Table 3.

The reaction was found to be widely applicable to a variety of substrates as shown in Table 2.

Finally, the reaction mechanism was proposed to be as shown in Scheme 2 - quite neat.

Cinchona Alkaloid-Catalyzed Enantioselective Monofluoromethylation Reaction Based on Fluorobis(phenylsulfonyl)methane Chemistry Combined with a Mannic

2007-05-13T10:36:00.000-05:00

Cinchona Alkaloid-Catalyzed Enantioselective Monofluoromethylation Reaction Based on Fluorobis(phenylsulfonyl)methane Chemistry Combined with a Mannich-type Reaction

Link: JACS ASAP

Satoshi Mizuta, Norio Shibata,* Yosuke Goto, Tatsuya Furukawa, Shuichi Nakamura, and Takeshi Toru*

Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan

A new method for the overall alpha-monofluoromethylation of alpha-amino sulfone. After desulfonation, enantio-enriched compound of type 4 was obtained.

First, the catalysts were screened as shown in Table 1. The most optimal conditions were found to be in runs 10 and 11.

After the optimal conditions were identified, the reaction was screened with different substrates and results are summarized in Table 2 with yields of compounds of type 3.

The compounds of type 3 could be desulfonated under a variety of conditions. All of these conditions are summarized in Table 3, giving the final monofluoromethyl compounds of type 4 in excellent yields.

This is a quite nice two-step protocol to install monofluoromethyl group to alpha-amino sulfone in a quite good to excellent enantioselective manner using 1 effectively as a monofluoromethyl transferring reagent.

Total Synthesis of (-)-Stemoamide

2007-04-24T21:26:00.000-05:00

Link: JOC Note ASAP

Staffan Torssell, Emil Wanngren, and Peter Somfai*

KTH Chemical Science and Engineering, Department of Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden

This is a rather short synthesis of (-)-stemoamide (1), the simplest member of various alkaloids present in Stemona tuberosa. Traditionally, the root extracts of this plant have been employed in Chinese and Japanese folk medicine for respiratory disorders and also as an antihelminthic.The synthesis started with lactam alcohol 4. Following routine reactions, beta,gamma-ester 2 was rapidly constructed. The reaction sequence featured N-alkylation of 6, one-carbon homologation from aldehyde to alkyne using Ohira-Bestmann diazophosphonate 8, iodoboration of 5 to give 3, Pd-catalyzed Negishi cross-coupling of 3 with Reformatsky reagent 9 which required DMPU a co-solvent, and finally RCM with Grubbs' 2nd generation catalyst.The installation of the lactone ring was first planned through hydroboration-oxidation followed by lactonization. However, several hydoration conditions tried either did not give any product or caused decomposition (9-BBN/THF or BH3-THF at both low and high temperatures). Thinking that failure was caused by the ester group, it was reduced to alcohol, but the reaction still failed.The lactonization was finally realized through lactonization-bromination of the carboxylic acid generated from ester 2, followed by in situ elimination of HBr to give 12. The synthesis was completed when 12 was subjected to 1,4-reduction to give 13 stereoselectively (NiCl2/NaBH4) via more accessible beta face, followed by a previously reported protocol of alpha-methylation. This also constituted an efficient strategy to install a C8-C9 trans-ring junction.The reaction was completed stereoselectively in only 12 steps from commercially available (S)-pyroglutaminol (4).

Pt(II)-Catalyzed Synthesis of 1,2-Dihydropyridines from Aziridinyl Propargylic Esters

2007-04-24T18:14:00.000-05:00

Link: Org Lett ASAP

Massoud Motamed, Eric M. Bunnelle, Surendra W. Singaram, and Richmond Sarpong*

Department of Chemistry, University of California, Berkeley, California 94720

A neat reaction of aziridine, tethered to propargylic acetate, with PtCl2 catalyst as a way to access 1,2-dihydropyridines.

The reaction mechanism was proposed to be as shown below.

The authors explored this chemistry in continuation from their earlier work of a similar reaction with the epoxide derivative as shown.

The reactions were found to proceed well. Scope of the reaction was studied and illustrated in the table below.

Cases where the Ts group aziridine nitrogen was substituted with acyl group were also studied. In these cases although desired pyridine products were formed in good yields, byproducts of type 18 (as shown) were also formed.

This byproduct was formed by participation of acyl C=O group as proposed in the mechanism below.

As shown in Scheme 4, the dihydropyridine 5b could be used as a precursor to pyridine 20 demonstrating the utility of the products.The reaction was also shown to be stereospecific, that is the stereochemistry in the starting material was effectively transferred to the product as shown in the scheme where stereochemistry of carbon bearing the phenyl group in 1a was retained in product 5a.

A Concise Synthesis of Butylcycloheptylprodigiosin

2007-04-22T17:39:00.000-05:00

Link: Org Lett ASAP

Jonathan T. Reeves*

Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877

A total synthesis in racemic form of butylcycloheptylprodigiosin in a very short sequence by a single author.

The key reaction was installation of the 2-formyl pyrrole ring in 4 based on previously reported method as shown below.

The synthesis started with enone 6. A sequence of 1,4-addition to 6 and trapping with oxazole 7 led to 5. Treatment of 5 based on previous method afforded 4 in good yield.

The rate of cyclization of enone type B in Figure 3 was tested. Dehydration of 5 led to 6:1 mixture of E-8 and Z-8 which could be separated by chromatography. E-8 was found to convert to 4 faster than Z-8 probably because of torsional strain of the enone in Z-8 which prevented optimal conjugation and thus rendering C-2 of oxazole ring less reactive towards hydrolysis in with base.

The total synthesis was completed according to the following sequence. Installation of triflate group, for Suzuki-Miyaura cross-coupling, was pretty cool. The conversion of 3 to 1 followed the Furstner protocol of the total synthesis of the same molecule accomplished previously.

The current total synthesis was accomplished in 5 steps from 6, which compared favorably with Furstner's 16 linear steps from 1,4-cyclononadien-3-one.

A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Me

2007-04-22T16:53:00.000-05:00

A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Mediated Intramolecular Cyclopropanation of (R)-1,2-Epoxyhex-5-ene

Link: Org Proc & Dev ASAP

Anthony D. Alorati, Matthew M. Bio, Karel M. J. Brands, Ed Cleator,* Antony J. Davies, Robert D. Wilson, and Chris S. Wise

Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, EN11 9BU, UK

The method is pretty unique in obtaining fused 3,5-bicyclic system as shown in 1.

This was achieved by treatment of epoxide 2 with LiTMP. The hindered base would deprotonate the alpha-carbon of epoxide trans- to the beta-alkyl side chain. Then stereospecific cyclization of the carbenoid species would follow to give bicyclic alcohol 4. The reaction could be conducted with catalytic amount of TMP (with slight excess of n-BuLi). The rate of n-BuLi addition (not too fast) was crucial in a successful catalytic reaction.

Compound 4 was found to be acid-sensitive. Compound 4 can be utilized in further transformations. TEMPO/NaOCl treatment of 4 successfully led to 1 in greater than 99.5% ee. This reaction sequence was demonstrated to be amenable to preparing 1 on a 7.5 kg scale. pH of the oxidation step had to be carefully controlled. If the pH was too low (5-8), oxidation was incomplete. If pH was too high (>11), dibrominated compound 12 was formed as a sginificant byproduct.

[4+1]/[2+1] Cycloaddition Reactions of Fischer Carbene Complexes with alpha,beta-Unsaturated Ketones and Aldehydes

2007-04-21T13:29:00.000-05:00

Link: ACIEE EarlyView

José Barluenga,* Hugo Fanlo, Salomé López, Josefa Flórez

Instituto Universitario de Química Organometálica, Enrique Moles, Unidad Asociada al CSIC, Universidad de Oviedo, Julián Clavería 8, 33006 Oviedo, Spain

Group 6 Fisher carbenes are know to transfer carbene to electro-deficient alkenes. However, reactions with alpha,beta-unsaturated ketones and aldehydes (enones and enals) are generally poor. The article presented a new development in a successful use of Chromium-based Fisher carbene as a carbene transfer reagent to enones and enals.

First, reaction was invetigated with carbenes 1a and 1b with enone 2a.Reactions were found to proceed to give dihydrofurans in a formal [4+1] cycloaddition reaction. Products 3a and 3b were found to easily aromatize to furans 4a and 4b.

Next, the effect of solvents was studied.THF was found to be optimal for the reaction either at 80 C or 100 C or especially efficient in microwave. The scope the reaction was then studied with a large variety of enones, enals with various Fisher carbenes. The table showed the scope of the reaction. This is a large table, so it may appear illegible. Look at the article for the actual table.In general, enones react faster than enals. Some of these dihydrofurans had to be purified by deactivated silica gel to prevent aromatization to form furans and ring-opening to form 1,4-dicarbonyl compounds.

Additionally, the authors also proved that the formal [4+1] to give dihydrofurans went through a [2+1] carbene transfer to yield cyclopropane follow by rearrangements.

Subsequently, the authors showed that simple treatment of resulting dihydrofurans with HBF4 in Et2O and then SiO2 can cleanly provide aromatized products.

Furthermore, dihydrofurans of type 3 when treated with HCl in THF could ring-open to give 1,4-diketones, which is a product equivalent to acyl anion undergoing 1,4-addition (umpolung reactivity). As for 3i where aromatization was not possible, simple treatment with SiO2 also led to 1,4-diketone 6i.

Efficient Removal of Ruthenium Byproducts from Olefin Metathesis Products by Simple Aqueous Extraction

2007-04-15T19:28:00.000-05:00

Link: Org Lett ASAP

Soon Hyeok Hong and Robert H. Grubbs*

The Arnold and Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

The article presents a new way for removal of Ru-catalyst from an RCM reaction. Catalysts 3 and 4 were used to perform RCM reaction of 5 to give 6 and then level of Ru was measured against other known methods for removal of ruthenium. Catalyst 2 was also used in comparison of reactivity for substrate 5.

Catalyst 4 was the modified version of 3 where NHC part of the species was supported by poly(ethylene glycol) (PEG). Possessing PEG-bound NHC, 4 became soluble in water in addition to being soluble in typical RCM solvents such as toluene and CH2Cl2, while it was insoluble in other organic solvents such as ethers, isopropyl alcohol, and hexanes. This provided the basis for aqueous extraction to be more effective in removal of catalyst from product.

Before proceeding, reactivity of catalysts 2-4 was tested with diene 5 to make sure that having PEG-bound NHC in 4 would not affect the reactivity in RCM. Ans this was found to be the case, that all catalysts performed RCM in comparable capacities.

RCM of 5 was then performed with both catalysts 3 and 4 and the level of Ru in 6 was measured. The results are summarized below.

As seen in Table 1, entry 5, after RCM of 5 using 4, the use of aqueous washes alone removed Ru better than any other known methods. When aqueous washes were used in conjunction with tris(hydroxymethyl)phosphine (THMP) or activated carbon, level of Ru was effectively reduced to a small trace (entries 6 and 7). The use of PEG separately in the aquoues washes in RCM of 5 using catalyst 3 did not reduce level of Ru, indicating that PEG-bound NHC of 4 remained intact after the reaction and was crucial in assisting the removal of the catalyst.

The workup was very simple, after the RCM was complete, the reaction mixture was taken up in ether which was simply washed with water to give clear ether layer and brown aqueous layer. The crude product was further treated with other removal techniques to further reduce the trace of ruthenium species.

A Vaulted Biaryl Phosphoric Acid-Catalyzed Reduction of alpha-Imino Esters: The Highly Enantioselective Preparation of alpha-Amino Esters

2007-04-15T18:59:00.000-05:00

Link: JACS ASAP

Guilong Li, Yuxue Liang, and Jon C. Antilla*

Department of Chemistry, University of South Florida, 4202 East Fowler Avenue CHE205A, Tampa, Florida 33620

This is a new organocatalytic method for enantioselective reduction of acyclic alpha-imino esters to form the corresponding alpha-amino esters (and subsequently alpha-amino acids). The method employed sterically hindrance chiral biaryl phosphoric acid as a ligand and Hantzsche ester as hydrogen source in a transfer hydrogenation process. Several biaryl phosphoric acids were initally considered.

In the initial studies, imino esters 2a-c were screened in the reaction using using phosphoric acid (PA) 1e to investigate the effect of solvents and it was found that non-polar, non-coordinating solvents such as benzene and toluene gave the best results, especially with imino ester 2a-b while ester 2c did not work too well presumably due to its steric hindrance.

Next, all PAs in Figure 1 were screened using 2a as a test substrate and PA 1e was found to be the most optimal acid for the reaction.

Generality of the reaction was established in the following table, where several alpha-imino esters were subjected to the optimal reaction conditions. In all cases, the reactions proceeded in excellent yields to give products in excellent ees.

In general, the imino esters were pre-formed before subjecting to the reactions. When the imino esters were formed in situ before the reductions, yields were lower (10-20%). However, in the cases of the alkyl-substituted imino esters (Table 3, entries 9-11), yields were found to be good to excellent, indicating that this reduction could be performed with an alpha-imino ester generated in situ in one pot.

Chiral Calcium Complexes as Brnsted Base Catalysts for Asymmetric Addition of -Amino Acid Derivatives to ,-Unsaturated Carbonyl Compounds

2007-04-15T15:04:00.000-05:00

Link: JACS ASAP

Susumu Saito, Tetsu Tsubogo, and Sh Kobayashi*

Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO, Japan Science Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

This paper presented a novel metal catalyst system in conducting a 1,4-addition of glycine derivative to alpha,beta-unsaturated carboxylic acid derivative to give glutamic acid derivative as a product. The novel catalyst being used in the reaction was Ca2+ salt in conjunction with chiral ligand.

Initially, reaction was screened to find the most optimal conditions. This included the screening of metal salts and ligands and the results are summarized as followed.

In the end, ligand 4 was found to be the most optimal ligand along with Ca(Oi-Pr)2 salt. Upon identifying the best conditions, the scope of the reaction was investigated. The reactions with various substrates were mostly found to proceed in great yields and stereoselectivity as seen in Table 2.

Next, the reaction was screened with crotyl carboxylic acid derivatives. It was surprisingly found that instead of the 1,4-addition addition product, pyrrolidine derivative 7 was obtained in a formal [3+2] cycloaddition reaction. Several substrates were then explored and the results are summarized below. In most cases, the reactions proceeded in excellent yields and diastereo- and enantioselectivities.

The catalytic cycle was proposed to be as followed.

In a regular 1,4-addition, intermediate 10 was protonated to give product 6. But when the amide derivative was used as the Michael acceptor, the intermediate 10 became more reactive and intramolecular cyclization occurred to give pyrrolidine 7. However, from both Tables 1 and 2, this distinction was not very clear as the only difference in conditions between the two reactions seemed to be the reaction time. Therefore (in my opinion), it is more likely that the reaction intramolecularly cyclized faster (in 3 h). But when the reaction was allowed to react longer (12 h), retrocyclization occurred and the initial pyrrolidine derivative product (formal [3+2]) was transformed to the glutamic derivative product (1,4-addition).

Ligand 4 was suspected to be an anionic ligand as when structurally-related ligand 8 (which was expected to form a neutral complex) was used instead of 4 in a reaction between methyl acrylate and 1a, the reaction proceeded in only 31% and provided the product in racemic form.

An Alkoxide-Directed Intermolecular [2+2+1] Annulation

2007-04-15T14:06:00.000-05:00

An Alkoxide-Directed Intermolecular [2+2+1] Annulation: A Three-Component Coupling Reaction for the Synthesis of Tetrasubstituted alpha,beta-Unsaturated gamma-Lactams

Link: ACIEE EarlyView

Martin McLaughlin, Masayuki Takahashi, Glenn C. Micalizio*

Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520-8107, USA

This is a method to make 1,5-unsaturated amino alcohol and alpha,beta-unsaturated gamma-lactams employing [2+2+1] annulation catalyzed by titanium complex. The type of coupling is presented in the general scheme below.

The coupling relied on the ability of the homopropagylic hydroxyl group of alkyne to coordinate to titanium and direct the addition of the alkyne to the imine partner. This methodology was found to work well as illustrated with the alkyne substrates in Table 1.

It should be noted in entry 4 that the coupling of internal alkyne substituted with TMS group occurred at the alpha carbon. This was in contrast to a typical coupling of TMS-substituted alkynes where the TMS group directed the reaction to occur at the beta carbon. This effect was only possible because of the directing effect of the hydroxyl group on the titanium center which overrode the effect of the TMS group.

In a Pauson-Khand type coupling in the presence of CO2, alpha,beta-unsaturated gamma lactams could be synthesized as illustrated between various alkyne and imine substrates in Table 2.

It should be noted in entry 5 that when ortho-substituted aromatic group of imine 21 was used, the reaction occurred diastereoselectively to give a 4:1 atropisomeric mixture.

When the imine coupling partner carried a stereogenic center, the reaction was also found to occur stereoselectively both in the syntheses of 1,5-amino alcohols and gamma-lactam (Scheme 2). As for the synthesis of the amino alcohols 28 and 29, the diastereoselectivity seemed to depend on the size of the R group on the alkyne coupling partners.

Design of Chiral Auxiliaries for the Allene Ether Nazarov Cyclization

2007-04-14T15:07:00.000-05:00

Link: JACS ASAP

April R. Banaag and Marcus A. Tius*

Department of Chemistry, University of Hawaii, 2545 The Mall, Honolulu, Hawaii 96822, and Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813

This is an interesting article describing a cool experimental result and identifying a key factor influencing enantioselectivity of a Nazarov cyclization of lithium allene species. This led to a basis for designing a chiral auxiliary on the allene moiety based on stereochemistry of the sugar molecules.

The premise of the studies was based on the following Nazarov cyclization to form alpha-methylene cyclopentenone (eq 1).

Following deprotonation with alkyllithium, allenyl lithium 1 could add to enamide 2. After a mild acid-induced Nazarov cyclization, cyclopentenone 4 could be obtained. If a chiral sugar molecule (a pyranose) was attached as an R1 group in 1, this could lead intermediate 3 to a selective conrotation to give 4 enantioselectively, and pyrilium cation as a by-product.

Keith A. Woerpel has demonstrated that the C-3 and C-4 substituents exert a large influence on the conformation of the tetrahydropyran oxocarbenium ions relative to their uncharged precursors (a) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521-15528. b) Shenoy, S. R.; Woerpel, K. A. Org. Lett. 2005, 7, 1157-1160.) Specifically, C-3 and C-4 alkoxy groups have pseudoaxial preference in the oxocarbenium ion.

In testing this principle, lithium species 5 was treated with enamide 6 to give intermediate 7, which upon acid-workup gave R-(9) in high yield (84%) and er (93/7).

As seen from Scheme 1, the presence of C-4 axial group in transition state 8 blocked the back face of developing cyclopentenone and induced counterclockwise conratation to give 9 in good er. The criteria for the model to be valid are the 3,4,5-triaxial conformation of the pyran ring in 7 must be energetically accessible and one must assume a late transition state for the cyclization.

The model was further tested based on the ground of three hypotheses/predictions: 1) C-3 OTBS group is not important in the outcome, 2) C-4 OTBS is needed to effect the selectivity, and 3) locking C-4 OTBS group in equatorial position in the pyran ring will erode the selectivity.

As seen below, when 11 (missing C-3 OTBS) was reacted with enamide 6, R-(9) was obtained in good yield and unaffected er. In this case, 11 was also used to prove that oxygen atom in the pyran ring was needed to transfer the stereochemical information from the auxiliary to the product as its cyclohexyl derivative (without oxygen in the ring) delivered R-(9) in low yield and low er (55.5/44.5).

When 12 (missing C-4 OTBS) was treated with 6, lower yield and er of 9 were obtained.

When C-4 alkoxy was locked in equatorial position as in 13, 9 was obtained in lower er.

Because 1,3-diaxial interaction was required, therefore even though the conformation of C-4 was locked in the equatorial position in 14, by placing C-3 axial OTBS group, 9 could still be delivered in high er.

The stereochemistry of product could be inverted by inverting the sterechemistry of the anomeric C-1 allene from alpha- to beta-position. This allowed both enantiomers of cyclopentenone to be made from the D-sugar. The C-3 and C-5 substituents in this series were cis in relationship and it was expected that when the pyran ring was inverted in the transition state, these two groups would become cis diaxial to influence stereochemical outcome of the product.

But when both 15 and 16 were treated with enamide 6, S-(9) was obtained with the results as shown below. It was concluded that in this series, the pyran ring was not inverted in the transition state or the stereochemical outcomes would have been more similar. The reason for this difference in conformational preference between the alpha- and the beta-series was not known but it was suspected that the 1,3-diaxial interaction in the alpha-series may have affected the ring inversion in the transition state. This destabilizing 1,3-diaxial interaction was not present in the beta-series.

The stereochemical outcome of this series could be predicted using transition state 17 in Scheme 2. Therefore, the electron pair donation from oxygen in the pyran ring restricted the conformation of the transition state, bringing the cyclization intermediate closer to the C-4 OTBS group. This led the conrotation of 17 to occur in the counterclockwise fashion leading to S-(9).

Enamide 6 was by no means the best substrate for 5, or 14 and 16. Compound 5 was screened with 6 and other eight 2,3-disub morpholine enamides with good to excellent ers. More screening results will be reported in the future. In this work, one key factor, among many others, had been identified as contributing to the stereoselectivity of Nazarov cyclization. This would lay groud work for future studies in designing effective chiral auxiliary.

Cu2(OTf)2-Catalyzed and Microwave-Controlled Preparation of Tetrazoles from Nitriles and Organic Azides under Mild, Safe Conditions

2007-04-14T11:39:00.000-05:00

Link: ACIEE EarlyView

Lluís Bosch, Jaume Vilarrasa*

Departament de Química Orgànica, Universitat de Barcelona, Av. Diagonal 647, 08028 Barcelona, Spain

A copper-catalyzed dipolar cycloaddition between organic azide and EWG-nitrile was reported. The report was dedicated to Profs. Rolf Huisgen and K. Barry Sharpless. Dipolar cycloaddition is also generally known as the Huisgen reaction.

Organic azide can react with organic nitrile attached to an electron withdrawing group to give an important class of compounds of pharmaceutical interest: tetrazole. The preparation of this class of compound, however, can be marred with danger of explosion due to high reactivity in organic azide starting materials and in tetrazole product.

The studies were commenced by investigation of a vast number of metal salt additives to probe the improvement of the reaction. The results are summarized in the table below. In addition to the salts shown in the table, several other additives were also tested, such as Cu powder, AgSbF6, AgBF4, AgF, AgOAc, AuCl3, Au(OTf)3, Ru/C, RuCl3, [Ru(C5Me5)(PPh3)2]Cl2, [Pd2(dba)3]·CHCl3, PdCl2, Pt/C, PtCl2, PtCl4, Sc(OTf)3, and LaCl3), none of which provided any product. Of all the additives tested, only some copper salts were found to promote the reaction led to lower reaction temperature, namely Cu2(OTf)2-Tol and Cu2(OTf)2-C6H6. These reactions were conducted under the homogeneous conditions.

The effect of triflic acid (HOTf) which may be present in commercial copper(I) triflate salt was ruled out (entry 12). Combinations of a few common organic nitriles and azides were explored and the results are presented below.

In these cases, mild conditions were employed. As seen in some cases, a microwave technology could also be applied to the reaction to reduce the reaction time. As seen in entries 7-12 in the table, 1,4-regioisomers (8a-11a) emerged when larger amount of copper salt was used (50-100 mol%) under the heterogeneous conditions. This is in contrast to the purely thermal conditions or with lower loading of copper catalyst (10 mol%) where only 1,5-regioisomers were observed. Thus when more copper salt was used, products 8a-11a could override and become the exclusive products.

As shown in entries 11 and 12, Bs-CN (Bs = benzenesulfonyl) and Ts-CN (Ts = toluenesulfonyl)could be used as H-CN equivalent in the cycloaddition as the sulfonyl group in the products could be easily reduced to hydrogen. The reaction could be carried out neat. But when a solvent is necessary to dissipate heat (to reduce the risk of explosion), CH2Cl2 was found to be superior (in term of yield) when tested in the synthesis of 5 (CH2Cl2 (85%), toluene (76%), THF (56%), CH3CN (0%; the solvent itself does not react), DMF (0%), and absolute EtOH (0%)).

The mechanism that explained the results is presented below.

As seen in the scheme, when more copper(I) was used, the copper species also coordinate to the azide at the internal nitrogen, thus changing the regiochemistry of the product (top right vs. bottom right). This method was then applied to a more sterically hindered aliphatic azide in the synthesis of 3’-azido-3’-deoxythymidine (AZT/zidovudine) derivative as shown below (yields were reported as excellent without numeric values). In this case, even when more copper salt was used in the synthesis of 12 (up to 200 mol%), only 1,5-regioisomer was obtained, demonstrating the inability of copper to coordinate to the internal nitrogen of the azide due to the steric hindrance (the bottom right species in Scheme 2).

A Practical Buchwald-Hartwig Amination of 2-Bromopyridines with Volatile Amines

2007-04-10T21:59:00.000-05:00

Link: JOC ASAP

Jie Jack Li,* Zhi Wang, and Lorna H. Mitchell

Department of Chemistry, Michigan Laboratories, Pfizer Global Research & Development, Ann Arbor, Michigan 48105

This is a quick-read paper on a method to improve Buchwald-Hartwig amination using volatile amines as coupling partners.

The authors stated that in order to conduct an amination reaction of 2-bromopyridine using volatile amine such as methylamine (bp, -6.2 C), the process would have to utilize methyl benzylamine for amination and debenzylation of the coupling product (Scheme 1), which sometimes destroys that integrity of the molecule.

Another available method is to use methylamine-HCl salt as a precursor to the amine, as illustrated in Scheme 2. However, the process employs large excess of NaOt-Bu and cannot be applied to free amines.

The answer to these problems was to conduct the reaction in a sealed tube. Thus substrate, such as 1 was added with excess of volatile amine via condensation at -78 C, followed by addition of NaOt-Bu, Pd-catalyst and phosphine bidentate ligand in toluene. The tube was sealed and heated at 80 C overnight to give the desired product in 77% yield.

The volatilities of amines at 80 C in term of vapor pressure are as followed: methylamine, 20 atm; dimethylamine, 10 atm; ethylamine, 7.5 atm; and 3.5 atm for propylamine and cyclopropylamine.

The results of cross-couplings for other substrates are summarized in Table 1. In general, secondary amines gave better results than primary amines, presumably because the tertiary amines products were less readily to undergo further side-reactions, such as further cross-coulping, or N-oxidation with light.

And as seen in entry 10, 2-chloropyridine derivative did not work as well as the bromo counterpart in previous entries. The authors also noted that the current method did not yield any product with 2-chloropyridine and 2-bromopyridine.

Synthesis of Biaryls via Decarboxylative Pd-Catalyzed Cross-Coupling Reaction

2007-04-10T21:35:00.000-05:00

Link: Org Lett ASAP

Jean-Michel Becht,* Cédric Catala, Claude Le Drian, and Alain Wagner*

Université de Haute-Alsace, Ecole Nationale Supérieure de Chimie de Mulhouse, Laboratoire de Chimie Organique et Bioorganique, UMR-CNRS 7015, 3 rue Alfred Werner, 68093 Mulhouse Cedex, France, and Novalyst Discovery, Bioparc, Boulevard Sébastien Brant BP 30170, 67405 Illkirch Cedex, France

An alternative way to synthesize biaryl compounds other than the standard Suzuki-Miyaura coupling which could be expensive with commercially available boronic acid or ester coupling partners. This was conducted using aryl iodide and carboxylic acid coupling partner. Presumably, the carboxylic acid undergoes decarboxylation under the reaction conditions.

First, the system was optimized to find the best conditions (as seen in the table bel0w). PdCl2 was found to be the most optimal catalyst while solvent and base additive were found to be DMSO and Ag2CO3, respectively. In addition, the best ligand was discovered to be AsPh3, which was superior to other phosphines or stibines.

In contrast to other decarboxylative methods described previously, the current method worked well with both electron-rich and electron-poor systems as shown in the table below. In addition, this method could also be applied to the synthesis of 2,2',6-substituted hindered biaryls (entries 10, 13, 17, and 18) in good yields.

Further more, cross-coupling between heterocycle, such as a benzofuran carboxylic acid derivative, with aryl iodide 2 and between carboxylic acid 1 and 1-iodo-naphthalene (Scheme 1) were also possible and gave products in good yields.

Synthesis of the Otteliones A and B: Use of a Cyclopropyl Group as Both a Steric Shield and a Vinyl Equivalent

2007-04-08T20:49:00.000-05:00

Link: ACIEE EarlyView

Derrick L. J. Clive*, Dazhan Liu

Chemistry Department, University of Alberta, Edmonton, AB T6G 2G2, Canada

A total synthesis of two related systems: otteliones A and B, which are stereochemically-related as cis- and trans-5,6-fused bicycles, respectively.

These two compounds are potent anticancer agents against various cancer cell lines with in vitro GI-50 values in the nanomolar to picomolar range.

In previous syntheses, ottelione A was first synthesized and ottelione B was then prepared by epimerization of C3a of ottelione A to afford the material in variable yields. The current synthesis served to prepare these two natural products independently from a common precursor. Key features of this synthesis are the use of the chiral cyclopropane 3, as a stereo-bias group to install other functionalities, and regioselective RCM reaction of tetraene 4 to give the requisite core structure of both natural products.

First, cyclopropane 3 was prepared using the carbohydrate route starting from methyl 2,3-O-isopropylidene-D-ribofuranosides to give 6 via a known procedure. The chiral acetonide group in 6 led to stereoselective introduction of cyclopropane by sulfonium reagent and DBU. Following deprotection of diol, dimesylation/hydrogenation/hydrogenolysis sequence was achieved to give the desired 3.

Routine chemical operations in Scheme 3 then led to alpha,beta-unsaturated aldehyde 17. The key features in this sequence included introduction of CH2-Ar group opposite to the cyclopropane ring, and SmI2-mediated demasking of cyclopropane to give required vinyl group at C1. Thus, the cyclopropane moiety had served as both stereochemical anchor for subsequent functionalizations and precursor to the vinyl group.

Next, 17 was subjected to a series of routine reactions to tetraene 4 as a mixture of isomers epimeric at C4 alcohol. It should be noted that 1,4-addition of diene occurred anti to the vinyl group at C1 and reprotonation of the resulting enolate at C3a occurred on the opposite face to substituent at C3. Then, the key RCM reaction was conducted using Grubbs' generation I catalyst regioselective and efficiently to give the core bicycle 20 in consistently excellent yield. More routine operations ensued and 1 was completed upon deprotection of TBS group on the aryl ring with TBAF.

As for completion of 2, triene 18 was epimerized at C3a with DBU to give the desired trans- isomer (>10:1 trans-:cis-). Aldehyde 22 was then subjected to a practically identical series of reactions as Scheme 4 above to give the desired 2.

Diazo Preparation via Dehydrogenation of Hydrazones with "Activated" DMSO

2007-04-08T15:12:00.000-05:00

Link: Org Lett ASAP

Muhammad I. Javed and Matthias Brewer*

The University of Vermont, Department of Chemistry, 82 University Place, Burlington, Vermont 05405

This is a nice and convenient method of preparing diazo compound from hydrazones. Dehydrogenation of hydrazones is usually achieved by toxic heavy-metal salts such as HgO or Pb(OAc)4. Now it can be achieved under mild condition using Et3N and DMSO activated with oxalyl chloride (to give Me2SCl2). Ammonium chloride salt by-product could be removed by filtration and solution of diazo compounds could be used directly in next reaction.

Initial study using hydrazone 1 in CH2Cl2 was found to give desired diazo derivative. But in trapping the diazo compound with benzoic acid, significant amount of 4 was formed. This was due to higher solubility of ammonium chloride salt in CH2Cl2 which reacted with the diazo intermediate. The solvent was switched to THF and this gave better yield of trapping product 3 because ammonium chloride was less solution in THF and it was crashed out more completely.

Therefore, several hydrazones were studied. Yields of diazo products were determined by amount of nitrogen gas evolution (in THF) and by trapping with benzoic acid (in CH2Cl2) as seen in Tables 1 and 2, respectively.

In both experiments, the trend is clear that aryl hydrazones gave better and more consistent yields of diazo compounds than aliphatic hydrazones. In some cases, when the resulting diazo products were stable, they were separated by filtration and could be directly characterized, e.g. diazo 6.

For hydrazone 7, in addition to ester 11, trapping of the corresponding diazo compound also gave by-product ester 12 formed from participation of THF in trapping the stable benzylic cation species 9. This problem could be circumvented by using a mixture of 9:1 Et2O:CH2Cl2, which allowed most, if not all, ammonium chloride salt to be removed while limiting solvent participation as seen in Table 2 that yield of 11 (as well as 13) was vastly improved.

Highly Diastereoselective Synthesis of Homoallylic Alcohols Bearing Adjacent Quaternary Centers Using Substituted Allylic Zinc Reagents

2007-04-07T17:24:00.000-05:00

Link: JACS ASAP

Hongjun Ren, Guillaume Dunet, Peter Mayer, and Paul Knochel*

Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München, Germany

A recent report from the Knochel lab. The paper reported an improved method in generating allylzinc chloride reagents from corresponding allyl chlorides through zinc dust insertion upon activation with LiCl. This is an improvement over previous method of generating allylzinc species from the corresponding allyl bromides as that method does not allow efficient generation of reagents with substitutions on allylic systems due to extensive formation of homocoupling by-products.

In this improved system, several allylzinc chloride reagents could be prepared in good yield with only moderate homocoupling observed, thus allowing efficient generation of allylzinc species not possible to prepare by other means (Scheme 1).

As for the cinnamyl system, both allyl chloride and allyl phosphate could be used to prepare the corresponding allylzinc species readily (1e and 1f).

Allylzinc reagents thus generated were used in several nucleophilic additions to demonstrate their utilities as seen in Table 1. All additions to carbonyl compounds happened under very mild conditions to afford the homoallylic alcohols in excellent yields. The reaction was also found to be highly diatereoselective furnishing products in excellent dr in all cases.

Besides high diastereoselectivities, the reaction was also chemoselective as demonstrated in entries 6 and 7 when allylzinc reagent added to carbonyl group in the presence of chloride and azide group alpha to the carbonyl. In addition, the reagent also added to an aldehyde in the presence of free NH2 without problem (entry 3).

Additionally, in cases of substituted allylzinc reagent (1c), it added regiospecifically to provide homoallylic alcohols containing two contiguous quarternary stereocenters in excellent yields and diastereoselectivities (entries 9 and 10).

Reagent 1e containing cinnamyl system was found to participate in highly diastereoselective and regiospecific additions to methyl ketone furnishing products (4a-e) in excellent yields and drs.

Mechanism of addition was proposed to follow a zinc-chelated 6-membered chair-like transition state as seen below.

In the cases of products 4a, 4c, and 4d, the structures were readily established by comparison to literature precedents. As for products 4b and 4e whose structures were not possible to assess directly, these compounds were converted to tetrahydrofuran derivatives 5 and 6 which therefore confirmed the generality cyclic transition state 7.

Highly Stereoselective Formal [3 + 3] Cycloaddition of Enals and Azomethine Imines Catalyzed by N-Heterocyclic Carbenes

2007-04-07T13:01:00.000-05:00

Link: JACS ASAP

Audrey Chan and Karl A. Scheidt*

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208

A method for polarity reversal (umpolung) applied to alpha,beta-unsaturated aldehydes (1) using NHC catalyst and reaction of the resulting intermediate with azomethine imines (2) in a formal [3+3] cycloaddition to form pyridazinones (3). NHC catalyst effectively generated homoenolate species in the process.The mechanism was proposed to involve addition of NHC to aldehyde to form the extended Breslow intermediate I, followed by reaction of this intemediate with azomethine imine to give intermediate II. This intermediate then tautomerized to give III which intramolecularly acylated to give product 3.

Initial studies were conducted between aldehyde 1a and imine 2a to give bicycle 4. Three NHC precursors, A, B, and C, were screened and results are in the table below.

From the table, one could conclude that catalyst C containing a single mesitylene group worked best (entry 8). In all cases, products were obtained in high diastereoselectivity having all syn substituents.

Having identified optimal reaction parameters, scope of the reaction was explored with various aldehydes and azomethine imines. The results are summarized below.The reaction tolerated various R groups on aldehyde including aliphatic (entry 6) and extended olefin (entry 7). However, when R group was eletron-withdrawing group-substituted phenyl ring, the reaction did not yield any product (entry 8).

In term of variation in R1 groups, the reaction tolerated well with both electron-donating and electron-withdrawing aryl groups (entries 9-14), although yield was lower in a more electron-rich system (entry 14). When R1 contained an enolizable alpha-carbon such as entry 15, the reaction was shut down.

The nature of an all-syn selectivity was proposed to be a hydrogen-bond-directed addition of 'homoenolate' to the imine away from phenyl group as shown in the scheme below.Further transformations of pyridazinone 4 were found to be facile both with MeOH and BnNH2 to give the corresponding ester 19 and amide 20 in almost quantitative yields.

Concise Total Synthesis of (-)-Calycanthine, (+)-Chimonanthine, and (+)-Folicanthine

2007-04-06T23:22:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114207298/ABSTRACT

Mohammad Movassaghi* and Michael A. Schmidt

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

This is quite an intriguing paper on total synthesis of three related natural products (ACIEE EarlyView). The methods used in these syntheses are also very interesting and efficient. The three target natural products are (+)-chimonanthine (1), (+)-folicanthine (2), and (-)-calycanthine (3).

The retrosynthesis analysis of these compounds consisted of the key disconnection of the 3a-3a' bond of a key common intermediate to arrive at monomeric radical 6 and subsequently bromide precursor 7, which should be available in a short number of steps from commercially available methyl ester of L-tryptophan 8.

Therefore, 8 was subjected to neat phosphoric acid, followed N-sulfonylation to give hexahydropyrroloindole (+)-9 in multigram scale in >99% de, and >99% ee. Upon obtaining 9, it was subjected to a sequence of hydrolysis, acyl chloride formation, and radical decarboxylation using tris(TMS) silane and AIBN to give 10 in excellent yield and ee (see below).

Next, 10 was brominated. Unfortunately, ee deteriorated during this process. This was believed to be due to tautomerization to tryptamine during the reaction (ring opening) in the presence of trace acid. Using acid scavenger in this step did not improve outcome. Therefore, the endo-methyl ester group at C2 was kept to be cleaved later as it was believed that the presence of this group increase stability of the compound.

Therefore, subjecting 9 to benzylic bromination directly afforded (+)-11 in good yield while maintaining excellent ee. The key radical dimerization step was first attempted through activation with Mn(CO)5 generated by photolytic cleavage of Mn2(CO)10. The reaction did not work very well both with 0.5 and 1.0 equiv of the reagent.

From what could be gathered in the paper, it sounded that dimerization of these radicals was expected to be a second-order process whose success largely depended on high concentration of the monomeric radical. Therefore, monomeric radical needed to be generated faster in the reaction to accrue high enough concentration. This was finally achieved using a more reactive reducing agent, [CoCl(PPh3)3]. Upon further adjustment with solvents and concentrations, the most optimal conditions were found to be in acetone (0.1 M) at rt for 15 min, which could give the desired dimeric compound in 60% yield with greater than 99% ee on a 3-gram scale!

This mechanism of this process was proposed to be either abstraction of bromine atom to give the radical which then combined outside of the solvent cage or oxidative addition of Co(I) to give Co(III) species, followed by homodimerization, C-Co bonds fragmentation and a C-C bond formation within the solvent cage.

After smooth procession of dimerization, 14 was decarboxylated using the same sequence as above (hydrolysis, acid chloride formation, and reduction with silane). The next step, desulfonylation of nitrogen, was tricky as both photolytic cleavage and strong reductive conditions failed. This was finally achieved with mild sodium amalgam and sodium phosphate dibasic in excellent yield and ee. The next and last step to give (+)-1 involved reduction of bis methyl ester with Red-Al.

Equilibration study of 1 in NMR tube using acetic acid-d4 and D2O was found that 1 was in equilibrium with 3 as a 85:15 mixture (3:1). Later 3 was isolated in 54% yield. This equilibrium was confirmed by subjecting pure 3 to equilibration conditions and the same mixture was obtained. Subsequently, 1 was converted to 2 via reductive amination using aq formaldehyde and NaBH(OAc)3 in quantitative yield.

Equilibration of 1 to 3 in acidic conditions (heating in acetic acid/water) still baffles me. Formally, it looks like a sigma-bond metathesis process happening across the C3a-C3a' bond, although this is not likely. This could be a good mechanism problem.

A commendable synthesis!

Cross Metathesis of alpha-Methylene Lactones II: gamma- and delta-Lactones

2007-04-05T21:27:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070574+.html

Ravinder Raju, Laura J. Allen, Tri Le, Christopher D. Taylor, and Amy R. Howell*

Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060

This is the other paper that was published online the same day as the Prof. Cossy's paper on cross metathesis (CM) reaction of alpha-methylene lactone and alkenes (previous post). The Howell group previously reported studies on CM reaction of alpha-methylene-beta-lactones with alkenes using Grubbs' 2nd generation catalyst (3) which was found to proceed to give cross products favoring Z-stereochemistry exclusively.

Therefore in commencing the current studies, catalyst 3 was initially used. However, it was found that when alpha-methylene-gamma-butyrolactone 5 was subjected to 3 and 1-acetoxy-9-decene, only alkene isomerization product 6 was obtained. This is in contrast to the Cossy group's result that the reaction was incomplete giving a mixture of both cross product and isomerization product, although the alkene cross partner in that study was 4-methyl-1-pentene. (See the previous post, Table 1, entry 3). Because catalyst 3 did not perform the desired transformation, catalyst 4 was explored. The results are summarized in the table below.

To suppress the formation of 6, 2,6-dichlorobenzoquinone was added as an additive along with catalyst 4. The combination of the two reagents were found to give excellent yield of the desired product (5) when 0.10 equiv of benzoquinone was used coupled with successive addition of the catalyst in two portions in the total of 10 mol %, while formation of 6 was completely suppressed (entry 8). When only 5 mol % of catalyst 4 was used, the reaction would not go to completion (entry 7) and this is in agreement with the results from the French group.

Next, a couple of alkenes were looked at using the optimal condition with catalyst 4 and additive 7.

In general, reactions proceeded as expected giving cross products favoring E-stereochemistry. For entries 5 and 6, yields were lower mainly because reactions did not proceed to completion.

The attention was then turned to CM reaction of delta-lactone 2. It was found that CM reaction using both catalysts 3 and 4 did not afford any desired product 9. When the reaction was conducted at higher temperater (toluene), only isomerized product 10 was obtained. Additive of additive 7 did suppress the formation of 10 but still did not produce any 9.

Thinking that substrate may complex with the catalyst to form unreactive species, Lewis acid Ti(Oi-Pr)4 (11) was added to reaction in toluene, complete consumption of SM giving only 10 resulted. When HOAc was used as additive, 54% of 9 was produced while 10 was suppressed. But this was not efficient as 10 mol % of catalyst was needed and reaction only proceeded to the maximum of 54% after 36 h. Although, efficient conversion of lactone 2 to 9 failed, the results seem to suggest that there may be an optimal combinations of additives and catalysts to be found. And this warranted more future studies of these systems.

Cross-Metathesis between alpha-Methylene-gamma-butyrolactone and Olefins: A Dramatic Additive Effect

2007-04-05T18:31:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0703940.html

Joëlle Moïse, Stellios Arseniyadis,* and Janine Cossy*

Laboratoire de Chimie Organique, ESPCI, CNRS, 10 rue Vauquelin, F-75231 Paris Cedex 05, France

There are two papers being published online this week in Org Lett ASAP on exactly the same topic. The first one is from prof. Janine Cossy's group on their work studying cross metathesis (CM) between alpha-methylene-gamma-lactone. The other one will follow this post.

Several Grubbs' catalysts (all three below) were investigated, but not the Schrock's catalyst.

In the initial study, parent gamma-lactone 4 was subjected to reaction with alkene 5a in refluxing CD2Cl2 to prevent loss of compounds due to their volatility, and the results of which could be monitored directly by NMR. The results are summarized in the Table 1.

It was found that [Ru]-I and III did not provide any conversion while [Ru]-II produced some desired CM product 6a along with alkene isomerization product 7 in variable amounts via a well-documented mode of Ru-catalyzed reaction of alkene. It is well known that through chelation of substrate and ruthenium carbene, CM process could be shut down due to the formation of unreactive catalyst species.

In order to prevent formation of 7 and increase conversion of 4, several additives were studied, the results of which are included in Table 2.

Several points could be made from the table. Cy2PCl and Ph2PCl gave opposite results in term of ratio of 6a and 7 (entries 2 and 6). The best additive for substrate 4 was 2,6-dichlorobenzoquinone (entry 7) which entirely suppressed formation of 7 although conversion of 4 was incomplete. The other drawback of this benzoquinone additive was its inconsisitent performance, ie. it seemed to be substrate-dependent.

In addition to the benzoquinone additive, chlorocatecholborane produced quite satisfactory result. Besides, it performed more consistently with other substrates. Therefore, this catecholborane was used to investigate the scope of the reaction of lactone 4 with various alkenes as summarized in Table 3.

All CM products could be produced in moderate to excellent yields while formations of isomerized products were largely suppressed. All cross products were formed in favor of E stereochemistry. As seen in table, in some cases, namely olefins 5c, 5h, and 5k-m conversion with 2.5 mol % of [Ru]-II catalyst and 5.0 mol % of chlorocatecholborane (the general protocol) remained low. As a result, the procedure for these olefins were modified to be the successive treatments of [Ru]-II (2 x 2.5 mol %) separated by a 7 h period.

Stereocontrolled Total Synthesis of (-)-Kainic Acid

2007-04-03T20:45:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0631197.html

From Prof. Tohru Fukuyama's group at University of Tokyo, Tokyo, Japan

A new stereoselective synthesis of (-)-kainic acid appeared in Org Lett ASAP. This time it came from Prof. Tohru Fukuyama in Japan. Kainic acid is a parent member of the kainoid family. Kainoids display potent anthelmintic properties and neurotransmitting activities in the mammalian central nervous system, and kainic acid in particular has been widely used as a tool in neuropharmacology for stimulation of nerve cells and the mimicry of disease states such as epilepsy, Alzheimer’s disease, and Huntington’s chorea.

The general plan for the forward direction is as followed.

In the retro, kainic acid (1) was traced back to oxazolone 6, through a series of transformations including the key 1,4-addition of enolate to enone lactone, which was to be built by RCM.

Therefore the synthesis commenced with construction of RCM precursor 13. The key reaction included crotyl aldol reaction of 8 to give 9 using Evan's aldol auxiliary, and Mitsunobu reaction to form 12.

But Mitsunobu reaction was not practical for larger scale synthesis to install the glycine fragment, a new route was devised. In this new route, the glycine fragment was installed using intermediate aminal 15 via reductive amination.

The low yielding step to make 16 (Scheme 3), was improved by starting with chiral auxiliary 17. Fragment 16 was further manipulated using the same sequence in Scheme 2 to give RCM precursor 13.

Hoveyda-Grubbs catalyst was chosen and conditions were screened for the best one. The reaction proceeded most optimally in dichloroethane with only 0.8 mol% catalyst loading (entry 10). The loading could be decreased to 0.5 mol% while maintaining relatively high RCM yield (entry 11).

The same enone 21 could be constructed using a different route in attempts to avoid the use of expensive RCM catalyst. The key steps in this sequence were constructions of enone fragment 23 and 24. Enone 23, obtained in 83:17 ratio of the desired Z-isomer, could cyclize directly to 21 in two steps. But for E-enone 24, the double bond was temporarily removed to facilitate cyclization before it was re-installed in the last step by oxidation of sulfide 25 to intermediate sulfone with ozone, followed by heating to eliminate sulfonic acid to give 21 in the total of three steps (Scheme 5).

The next key step was the 1,4-addition. In order to control the stereochemistry of the 2-position of pyrrolidine ring, several conditions were screened. It was found that LiHMDS in DMF worked best to give the best ratio of 26a/26b in excellent yield (Table 2 entries 5, 6, and 7). It should be noted that even though when R=tert-butyl group gave the best yield and ratio of 26a, the construction of t-Butyl derivative of ester 16 from 19 proceeded in very poor yield (see Scheme 4).

Fragment 26 was then subjected to methanolysis to give 27, followed by TPAP/NMO oxidation to ketone 28. The next key step was olefination of methyl ketone under non-basic conditions to prevent epimerization at C4 position (of the pyrrolidine ring) to give 29. Two further routine steps then afforded (-)-kainic acid.

Isoxazole-Directed Pinacol Rearrangement: Stereocontrolled Approach to Angular Stereogenic Centers

2007-04-02T23:47:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114201809/ABSTRACT

From Prof. Keisuke Suzuki's group at Tokyo Institute of Technology, Tokyo, Japan with collaboration with Prof. Jeffrey W. Bode at University of California, Santa Barbara, CA

The work in this ACIEE EarlyView article stemmed from synthetic studies toward some polyketide-derived natural products, such as seragakinone A (1) and the antibiotic BE-43472A (2). A general method for installing quaternary stereogenic centers at the angular position of these natural products was required.

A general approach to solve this problem involved a pinacol type alkyl shift as shown in Scheme 2.

However, this approach had some issues that needed addressing. First, I needed to be generated stereoselectively. Second, since both carbinol carbons are tertiary, the OH at the angular position had to be the only leaving group to facilitate migration of R group. A successful two-step process was reported in this article, employing a substrate of type 3, incorporating oxazole ring in the tricyclic core. (R)-3 can be readily prepared in enantio-pure form. General strategy is summarized in Scheme 3.

It was found that starting with (R)-3, addition of an alkyl group proceeded stereoselectively to give cis-diol without the loss of ee, as seen in Scheme 4 in the case of vinyl addition. Pleasingly, treatment of 4a afforded enantio-enriched (S)-5a in high yield and high ee (no loss of ee from chiral 3).

When reaction started with starting material trans-diol 6, it was surprising to find that enantiomeric (R)-5a was obtained in excellent yield and high ee.

This result illustrated the amazing carbocation-stabilizing ability of the oxazole ring. This concept was and illustrated again in separate racemization experiments as shown in equations 2 and 3.

As shown in Eq 2 and 3, when chiral (R)-3 was subjected to protic acid conditions, 3 was recovered with only 60% ee in 94% yield. And when (R)-3 was subjected to Lewis acid-promoted allylsilane addition, 5e was afforded in racemic form. These two experiments showed that racemization occurred in the generation of carbocation at the carbinol carbon, stabilized by oxazole. This is particularly impressive provided that this carbocation was situated alpha to a carbonyl.

The overall mechanism of the process was proposed and summarized in Scheme 5. Basically, exposure of cis-diol to Lewis acid could lead to intermediate A, which led to enantio-enriched product C, or racemization intermediate B, which ultimately led to ent-C.

Having established the method, several substrates were investigated for scope of the reaction. All pinacol rearrangement substrates were synthesized in excellent yields and stereoselectivities to provide only cis-diol (4b-f). On treatment of 4b-e with BF3-OEt2, pinacol products 5b-e were obtained in excellent yields and ees.

The only exception was 4f where the alkynyl group could not migrate fast enough, and this led to racemization intermediate B (Scheme 5, vide supra), which ultimately led to loss in ee in 5f. This problem could be gotten around by complexing the alkynyl group of 4f with Co2(CO)6 before subjecting to Lewis acid conditions. Using this solution, after decomplexation, 5f was afforded in high yield over three steps, and in high ee.

After the method was well-established, it was tested in natural product synthetic studies. Isoprenoid-containing natural product, such as 1 was looked at.

Prenyl group installation was performed on (R)-3 using prenylbarium reagent, followed by treatment with BF3-OEt2. The reaction sequence proceeded smoothly, and stereo- and regioselectively to provide 8 in both excellent yield and ee (Scheme 6).

Stereoselective Synthesis of 2,4,6-Trisubstituted Tetrahydropyrans by the Use of Cyclopropanols as Homoenols

2007-04-02T21:27:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114201814/ABSTRACT

From Prof. Jin Kun Cha's group at Wayne State University, Detroit, MI

An ACIEE EarlyView paper from Prof. Cha involving with diastereo- and enantioselective construction of 2,4,6-trisubstituted tetrahydropyran (THP). The methodology described is based on trapping of oxocarbenium intermediate by proximal R3SiOTf-promoted cyclopropanol ring openning. Scheme shows the general reaction method and partners involved.

Cyclopropanol moiety of type 1 (see below) could be installed through titanium-mediated hydroxycyclopropanation of homoallylic alcohols, a method reported previously by authors (Kulinkovich reaction). As seen in Scheme 2, several aldehydes could react with compound of type 1 in presence of TMSOTf to afford THP 4 with all cis stereochemistry.

The reaction proceeded through cyclic acetal intermediate A, followed by Lewis acid-promoted cyclopropanol ring openning concurrently with trapping of the nascent oxocarbenium species (I and II). It was later found that step-wise operation to form cyclic acetal, followed by oxocarbenium formation was not necessary. The entire sequence could be performed in one step by treatment of substrate 1 with 2.5 equiv of TMSOTf.

In preparation toward natural product synthesis, the coupling of two related segments 6 and 7 was performed. Under reaction conditions, however, the desired product 9 was obtained along with undesired elimination product 10.

In an effort to optimize this step, cyclic acetal 8 was pre-formed and then subjected to silyl triflates. The acceptable result was obtained with TIPSOTf. During this optimization, it was discovered that this required process was actually promoted by triflic acid, generated from silyl triflate as evidenced from the fact that the reaction could be shut down in presence of base.

By starting from chiral alcohol 11, both chiral 6 and 12 could be prepared. Coupling of this two fragments gave rise to enantio-pure all cis THP product, such as 13 (see below). Further manipulations afforded the bis-THP system 15 in good enantioselectivity with THP rings in all cis arrangement.

In another illustration of the utility of this method is shown in the rapid synthesis of (+)-18 starting with all enantio-pure starting materials.

When the relationship of cyclopropane and the OR in the tethered chain were trans as in 19, reaction with 3b afforded product 21 selectively over 22 (10:1) via the intermediacy of III as shown below.

This method has shown a lot of potential to be applied to syntheses of natural products, especially with the readily available enantio-pure starting materials, enantio- and diastero-pure THP products could be formed in good to excellent yields and selectivities due to the reaction's high stereospecificity.

Fischer Carbene Catalysis of Alkynol Cycloisomerization: Application to the Synthesis of the Altromycin B Disaccharide

2007-04-02T19:24:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070435s.html

From Prof. Frank E. McDonald's group at Emory University, Atlanta, GA.

This article appeared in Org Lett ASAP demonstrates the utility of Fischer carbene and its novel non-photochemical method of activation for use in catalytic alkynyl alcohol cycloisomerization.

The general concept of this catalyst is shown in the following figure.

As seen in the figure, in the presence of catalytic amount of tungsten complex, alkynyl alcohol 1 is expected to cycloisomerize to give dihydropyran derivative 2. As for the tungsten complex, the conventional method of generating this catalyst involves photolysis of W(CO)6 in presence of Et3N. However, the tungsten Fischer carbene 3 could also be activated by Et3N to generating the reactive catalyst. Thus a stable and easily-prepared tungsten Fischer carbene 3 served a the pre-catalyst for the reaction.

Upon obtaining the optimal conditions for generating the catalyst, a number of substrates were screen in cycloisomerization and the results are summarized in the table below.

As seen in the table, a variety of cyclic enol ether products could be prepared using this method in good to excellent yields. However, further optimizations were needed for substrates possessing C3- and C4-oxygen substituents (such as 20, vide infra) as this substrate, under the current conditions, cycloisomerized to give a mixture of endo and exo cyclic products, 21 and 22, respectively. This is in contrast to using DABCO under photochemical conditions which gave better results with this substrate. The optimizations are shown in the table below.

The selectivity between endo and exo cyclization was found to depend on the steric bulk of C3-OSiR3 group. According to the proposed mechanism below, by having small SiR3 group on C3, coordination of tungsten to alkyne functioned as Lewis acid activation for the substrate to cyclize in the endo fashion. However, by increasing steric bulk of OSiR3, this pathway became less favored (see steric interaction in 25) while the eta-2 cooridnation of tungsten became more prominent. This action led to formation of the desired tungsten vinylidene, intermediate which further led to the desired endo cyclization product (ie. 23 -> 24 -> 26 -> 21). (Compare entries 3 and 6 in Table 2).

Finally, the utility of this method was shown in the successful synthesis of altromycin disaccharide as shown in the scheme below.

Asymmetric Synthesis of 2H-Azirine 3-Carboxylates

2007-04-01T23:06:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070365p.html

From Prof. Franklin A. Davis' group at Temple University, Philadelphia, PA

This recent Org Lett ASAP article illustrates a method for the synthesis of chiral 2H-azirine-3-carboxylates and their use in endo-selective Diels-Alder reactions.

As shown in Scheme 1, racemic azirine 1 was prepared before, as well as chiral azirine 2 where chirality resided in the R group. Chiral azirine 2 was also used in Lewis acid-promoted Diels-Alder reaction to give bi- and tri-cyclic compounds in good yield and selecitivity. In 2002, the authors of this article also successfully prepared chiral azirine phosphonate 3 using Swern oxidation of NH-aziridine-2-phosphonates and have shown their utility as new chiral aza dienophiles. In this paper, the authors detailed their synthesis of chiral 4 from dechlorination of 5.

As shown in Scheme 2, the synthesis started with reaction of known sulfinimine 6 with dichloro enolate 7. Attempts to convert chiral esters 8 to azirines 9 were successul with KH treatment. However, only 9b and 9c were produced. In case of 9a, only starting sulinimine 6 was obtained instead. Retro-Mannich of sulfinimine-derived sulfinamide products are usually rare because the N-sulfinyl group stabilizes anions at nitrogen. But in 8a the combination of steric inhibition to chloride displacement and the stability of the dichloro enolate 7 apparently favors the retro-Mannich fragmentation.

9b was oxidized to sulfone 10. Attempt to reduce sulfone group in 10 with subsequent dechlorination to azirine, however, failed. Instead Raney nickel directly reduced chlorine to hydrogen to give 11. In addition, reduction/ring-opening product 12 was also afforded.

The next attempt was by desulfinylation with Grignard reagent. However, treatment of 9 with MeMgBr only provided 14 as a single isomer. The stereochemistry of 14 was confirmed by comparison with desulfinylation product of 15, a known compound. The formation of 14 confirmed intermediacy of 13, followed by addition of MeMgBr to the less-hindered face (Scheme 4).

Therefore, it seemed that a new way to remove sulfinyl group under different conditions was required to avoid exposing this sensitive compound to acids, or bases, or protic solvents under reaction conditions. The solution to this was photodesulfinylation. Although, photodesulphonylation is well-known, this was the first example of photodesulfinylation.

As seen in Scheme 5, photolysis of 9b in ether degassed with argon for 10 h generated chloroaziridine 16 in 70% after chromatography. This was the first stable example of an N-unprotected-alpha-halo-alpha-amino ester. The reluctance of 16 to eliminate HCl was likely due to added strain energy in the installation of double bond in three-membered aziridine ring.

Subsequently, it was found that it was more efficient to conduct aza Diels-Alder of crude 16. Therefore following photolysis of 9, the crude reaction mixture was treated with large excess (100 equiv) of appropriate alkenes and a few drops of Hunig base. After 8 h, bi- and tricyclic products (-)-17, (-)-18, and (-)-19 were isolated as single isomers 46-74% yield for the two steps after chromatography. The structures assigned to these aziridines were based on endo addition of the 2H-azirine-3-carboxylated aza dienophile (S)-13 as reported previously.

Highly Efficient Ruthenium Catalysts for the Formation of Tetrasubstituted Olefins via Ring-Closing Metathesis

2007-04-01T21:34:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0705144.html

From Prof. Robert H. Grubbs' group at Cal Tech

This is another paper in the series studies on RCM to form tetrasubstituted-alkene-containing ring appeared recently in Org Lett ASAP. This is a second paper in March, following the other one that became a blog entry here. The authors continued to explore the effect on the ortho-substituents in NHCs group in Ru-center.

RCM reactions to form disub olefin work well using phosphine-based catalyst (ie. Grubbs I) and to form trisub olefin work well with NHC-based (ie. Grubbs II, 1). But for the tetrasub, it is still difficult.

In this paper, the authors continued discussion on the variations of substitution on o-position of aryl groups on NHC. Contrast to previous paper (as mentioned in previous post), the studies were conducted with mono substitution of the o-position on NHCs. As a result 5a-c and 6a-c were studied. The catalysts were subsequently screened with dienes 7 and 9.

The results of the screening with 7 are summarized in table and chart below. It was found that conversions with catalyst 5a-c were faster than 6a-c. And 5a and 6a performed better than other alkyl derivatives. NMR studies of 5a found a rapid initiation than 6a but quickly decomposed. This was thought to be due to build-up of ethylene in the system which deteriorated the catalyst by reacting with PCy3. In contrast, 6a initiated more slowly, but was longer-lived. However, when reaction of 9 using 6a was heated to 60 C (to assist initiation of the catalyst), it proceeded very efficiently to give 10 in less than 30 min. Subsequently, loading of 6a could be lowered to 2.5 mol% to accomplish RCM of 9 in >95% in 1 h.

X-ray structure of 6a was determined and was found to contain 91:9 mixture of syn- to trans-conformation of methyl groups in the o-positions of aryl groups. But it was not clear which was more reactive in RCM.

6a was then used to screen a number of substrates and was found to perform very well with all dienes, except 16 and 17.

In conclusion, 6a was discovered to be very reactive in RCM to form tetrasub-cycloalkene. 6a initiates more slowly than 5a but is more stable because of the lack of PCy3. However, initiation of 6a could be accelerated by heating reaction mixture. The mono o-substituted aryl groups on NHC open up the Ru center to facilitate the reaction more than the older generation of catalysts, making it more reactive to form tetrasub-alkene rings.

Enantioselective Total Synthesis of (+)-Neosymbioimine

2007-04-01T20:18:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070049a.html

From Prof. Martin E. Maier's group at Institut für Organische Chemie, Universität Tübingen, Tübingen, Germany

This was a recent Org Lett ASAP paper detailing the first enantioselective total synthesis of (+)-Neosymbioimine. Another entry in this blog was entered last month on an enantioselective total synthesis or a related molecule (+)-Symbioimine. The key step of the current synthesis involved an employment of intramolecular Diels-Alder reaction of a diene generated from HWE olefination.

The retro is as shown below. The plan traced back to citronellol which is commercially available in 92% ee.

The iminium installation was to be accessed via nitrile. Before that, several routine installations of functional groups were planned including the use of protected-TBS ether (4), as a directing group in controlling the enantioselectivity of the IMDA. Secondary alcohol precursor of 4 was to be installed using MacMillan's organocatalytic protocol for enantioselective alpha-hydroxylation of an aldehyde.

The forward direction of the synthesis proceeded as followed. Due to limitations in posting pictures on blogspot, detailed descriptions of reaction conditions were omitted.

The key installation of diene using HWE olefination proceeded in good enantioselectivity to provide a 1:1 mixture of diene 12 and cycloadduct 13. Heating this mixture turned all 12 into 13 with about 5% of uncyclized material present as seen in 1H NMR. This uncyclized material was soon discovered to be epimeric C-sp3 methyl group, which was originally present in commercial (-)-S-citronellol 5. In fact, some impurities (5%) attributed to 5 were observed in NMR of all intermediates 7-13. The cycloadduct was formed as a single diastereomer. The 5% uncyclized material was postulated to arise from the inability of the epimer to overcome the steric hindrance in the transition state of IMDA (Scheme 2).

The other notable step was an unexpected diastereoselectivity observed in methylation alpha to nitrile group (14 to 3). This was attributed to the steric bulk of OTBS group, therefore the approach of MeI from above the aryl ring. Structure of 3 was confirmed by x-ray crystallography.

In the last sequence of reactions, resorcinol was globally sulfated with SO3, followed by selective hydrolysis with water/methanol. The monosulfate natural product 1 was found to hydrolyze slowly. This was attributed to stabilizing effect of inner salt on the remaining sulfate group (Scheme 3).

(+)-Neosymbioimine (1) obtained from selective hydrolysis (as inner salt) could be routinely purified by flash column chromatography on silica gel using CHCl3/MeOH as eluent.

Stereo- and Regiochemical Divergence in the Substitution of a Lithiated Alk-1-en-3-yn-2-yl Carbamate: Synthesis of Highly Enantioenriched Vinylallenes

2007-03-28T23:05:00.000-05:00

Stereo- and Regiochemical Divergence in the Substitution of a Lithiated Alk-1-en-3-yn-2-yl Carbamate: Synthesis of Highly Enantioenriched Vinylallenes or Alk-3-en-5-yn-1-ols

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114190082/ABSTRACT

From Prof. Dieter Hoppe's group at Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

I think this is some interesting and intriguing chemistry presented in ACIEE EarlyView regarding the reactivity of organolithium in the presence of (-)-sparteine. It has been reported previously by the same research group that gamma-deprotonation of alkene carbamate of type 1, possessing negative-charge stabilizing group W (such as aryl, triorganosilyl, and 1-alkenyl groups), using n-BuLi in the presence of (-)-sparteine (2), a stereo-defined alkyllithium (3) could be generated which could add stereoselectively to electrophile to afford 4.

In the new development, when the W group was changed to an alkynyl group, the reactivity of the alkyllithium changed. That is when enyne 7 was deprotonated using n-BuLi/2 system, H(R) was selectively deprotonated and (S)-8 was produced.

When treated with acetone, (S)-8 added in an anti-SE' fashion to give allene (-)-(aR,E)-9a selectively (Method A). However, if (S)-8 was allowed to equilibrate over a longer period (15h), (R)-8 was produced and it added to acetone in the same anti-SE' fashion to give (+)-(aS,E)-9a instead (Method B). Method A was confirmed again with 4,4'-dibromobenzophenone to give (-)-(aR,E)-9b.

When (S)-8 was treated with ClTi(OiPr)3, lithium-titanium occurred that also inverted the C-metal center. The resulted organotitanium (S)-10 then added to acetone in the syn fashion at the allylic position to give homoallylic alcohol (S,Z)-11a (Method C). The TS for this addition was proposed to be 6-membered chairlike Zimmerman-Traxler transition state. As (R)-8, lithium-titanium exchange led to (R)-10, which afforded (R,Z)-11a upon addition to acetone (Method D).

Finally, two other experiments were performed to confirm the mechanisms of both organolithium and organotitanium. In the first experiment, (R)-8 was trapped with Ph3SnCl to give allene 9c, structure of which was confirmed by x-ray. Because previous study of stannylation of propargyllithium/2 system showed the mechanism to be anti-SE', thus this result showed that the configuration of 8 was R.

The kinetic organolithium (S)-8 was transmetalated with titanium to form (S)-10 which reacted with chiral aldehyde 12 to give 11b, the structure of which was confirmed by x-ray. Because it is known that chiral alpha-(carbamoyloxy)allyltitanium compounds react with chiral aldehydes with strict chirality transfer from the Zimmerman–Traxler transition state. Therefore, configuration shown in 11 must be generated from (S)-10, which in turn was obtained by inversion of configuration of (S)-8.

Reaction of 8 with other electrophiles were also reported as summarized in the table below.

Conclusion for the current system:

1) Organolithium ---> anti-SE' addition to give allenyl alcohols
2) Lithium-titanium exchange ---> inversion of configuration
3) Organotitanium ---> syn addition via Zimmerman-Traxler transition state to give homoallylic alcohol
4) Organolithium was generated stereoselectively with n-BuLi/(-)-sparteine system. This kinetic organolithium can epimerize to give the opposite configuration upon prolonged reaction time.

Enesulfonamides as Nucleophiles in Catalytic Asymmetric Reactions

2007-03-28T18:42:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114190087/ABSTRACT

From Prof. Shu Kobayashi's group at The University of Tokyo, Tokyo, Japan

The recent article in ACIEE EarlyView from the lab of Prof. Kobayashi detailed a novel reaction of enesulfonamide as a nucleophile in nucleophilic addition catalyzed by copper-based Lewis acid in the presence of chiral ligand. Comparison was made with enecarbamate that enesulfonamide is more convenient to make than the enecarbamate the reactions demonstrated here were efficient. The product generated from the addition is sulfonylimine, which could be reduced to either 1,3-amino alcohol or sulfonamide, both of which are medicinally important.

Enesulfonamide can be simply made from condensation of a ketone and a sulfonamide. E- and Z-alkene isomers could be separated by column chromatography.

Most of the examples of enesulfonamide were made from aromatic ketones. But aliphatic ketones were also shown to be feasible to make and to be employed in the reaction. The early example from the study was the addition of p-methoxyphenyl-substituted enesulfonamide, generate from condensation of p-methoxysulfonamide and phenyl ethyl ketone, to ethyl glyoxylate. The product, sulfonylimine, could be hydrolyzed to give ketone. Several hydrolysis conditions were investigated as shown in Table 1.

From the table, the use of too little acid led to decrese in yield and diastereoselectivity of keto ester 7a (entry 1). However, increasing the amount of acid, as in entry 2, both yield and diastereoselectivity improved significantly. Increase in the amount of acid probably prevented formation of enesulfonamide 8a which led to epimerization.

The optimal reaction conditions were screened with different enesulfonamide using ethyl glyoxylate as the reaction partner. General trend: electron-rich aryl substituent on the sulfonyl group is more reactive than electron-poor aryl substituent. The reaction is also stereospecific: Z-enesulfonamide afforded syn-product, and E-enesulfonamide afforded anti-product.

As mentioned before, the sulfonylimine product could be reduced stereoselectively to give a sulfonamide alcohol, as represented in Scheme 2.

Enesulfonamide also added to azodicarboxylate as shown in Equation 2 between sulfonamide (E)-4b and diisopropyl azodicarboxylate. In this case, diamine 11 was used as the chiral ligand.

In summary, a novel method copper-catalyzed enesulfonamide addition to glyoxylate has been developed. The reactions proceeded in high yield and high diastereo- and enantioselectivities, even with catalyst loading as low as 0.2 mol%.

Rearrangement of Alkynyl Sulfoxides Catalyzed by Gold(I) Complexes

2007-03-27T11:51:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070789e.html

From Prof. F. Dean Toste's group at University of California, Berkeley, CA

This article appeared recently in JACS ASAP from Prof. Toste's group at UC, Berkeley, demonstrating the utility of gold(I) complex as a catalyst for formation of gold-carbenoid species from alkynes and their subsequent reactions. The reaction was proposed to start with an activation of an alkyne with gold(I) catalyst, followed by an attack from a nucleophile (attached to a leaving group). Electron from gold species then moved in to form a carbenoid species concurrently with the expulsion of the leaving group.

In this paper, the nucleophile employed was sulfoxide which would generate sulfonium ion as a leaving group upon attacking gold-activated alkyne. It was found that under the reaction conditions, Friedel-Craft type reaction occurred to give ketone 3 as shown in Equation 2 above. Initially, several ligands were screened. The best result was found in an NHC ligand carrying mesitylene groups (IMes).

The reaction was screened with a variety of substrates. All reactions proceeded well, for instance, electron-rich as well as electro-poor aryl systems tolerated well. In addition, substitutions at both propargylic and homopropargylic positions proceeded without problem. Notably, in entry 5 one diastereomer (as shown) was more reactive than the other.

A marked difference was seen between entries 6, and 7 and entry 8. When substituent of alkyne is non-aliphatic (entries 6, 7), 5-exo-dig mode of cyclization was observed. But when the substituent was aliphatic group, as an ethyl group in 18, 6-endo-dig cyclization prevailed. These modes of mechanism are summarized in the scheme below.

With this mode of reaction with aliphatic substituent, complex furan 22 could be prepared in one step from diyne 20 in 56% yield.

Additional experiment with sulfimine 27 to generate N-tosyl enamine 28 confirmed that the oxygen atom was delivered intramolecularly from sulfur.

Gold(I) complexes were also found to catalyze the conversion of propargyl sulfoxides to alpha-thioenones in high yields as shown in equations below.

In this case, (dimethylsulfide)gold(I) chloride proved to be a better catalyst and the reaction afforded enones 31 from propargyl sulfoxides 29 with excellent tolerance for substitution on the alkyne and the sulfoxide. Additionally, secondary and tertiary propargyl sulfoxides react under these conditions to provide trisubstituted (eq 6) and tetrasubstituted alkenes. For example, sulfide 33 was obtained from sulfoxide 32 in preference to cycloisomerization of 1,5-enyne.

In analogy to the mechanism described in Scheme 1, this rearrangement is postulated to proceed through gold(I)-promoted sequential 5-endo-dig cyclization/cleavage of the S-O bond leading to gold(I)-carbenoid intermediate 30 which undergoes a 1,2-sulfide shift. In a separate cross-over experiment, the intramolecular 1,2-sulfide shift process was confirmed as there was no cross-over product observed as shown in the equation below. Note that the SMs should be 29b and 29c and the products should be 31b and 31c, respectively.

This paper has presented an important aspect of reactivity of gold catalyst with alkynes and provided a method for an efficient generation of gold-carbenoid species.

Aminomethylations via Cross-Coupling of Potassium Organotrifluoroborates with Aryl Bromides

2007-03-26T20:01:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070543e.html

From Prof. Gary A. Molander's group at University of Pennsylvania, Philadelphia, PA

The paper recently appeared in Org Lett ASAP presented a novel Suzuki-Miyaura cross-coupling reaction using potassium organotrifluoroborate salt as an aminomethyl transfering reagent in cross-coupling with aryl halide.

Prior to this work, only one example of aminomethyl transfer is known using organotin reagent as shown below. The use of tin reagent is naturally objectionable as tin is toxic and purification is usually not simple. Plus, the tin reagent sometimes requires a tedious synthesis of its own.

The use of potassium organotrifluoroborate salt as a coupling partner in Suzuki-Miyaura reaction is attractive because this reagent is nontoxic, and air- and moisture-stable. The studies were first conducted using potassium N-(trifluoroboratomethyl)piperidine, which could be conveniently prepared based on a known procedure. The reaction was screen with different aryl bromides. The results are summarized in the table below. Note: XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

As seen in the table, the reaction tolerated well with various aryl bromide derivatives, whether it was electron-rich, or electron-deficient. Steric hindrance in proximity of the coupling site was also well-tolerated. Some of the reactions were found to give higher yields when they were conducted in cyclopentyl methyl ether (CPME)/water mixture (10:1), possibly because reactions could be heated at higher temperature than THF/water.

The reaction of the same borate salt was expanded to react with a variety of heteroaromatic systems. (Table 2).Again, the reactions proceeded well with all heteroaromatic coupling partners examined. In these cases, the reactions were found to work better (higher yields) with the original THF/water system.

Next, different aminomethyl reagents were examined. Various aminomethyltrifluoroborate salts were prepared from potassium trifluoroboratomethyl bromide with stoichiometric amines and the results are summarized below.

As can be seen, in all cases tertiary amine borate salts could be prepared in good yields with great structural diversities. These salts were subjected to the standard coupling conditions in THF/water with 4-bromoanisole to afford coupling products in good to excellent yields (Table 4), with only exceptions of 5e and 5f where there was no reaction both in CPME/water and THF/water systems.

Enantioselective Organocatalytic Double Michael Addition Reactions

2007-03-26T08:40:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070581y.html

From Prof. Wei Wang's group at the University of New Mexico, Albuquerque, NM

The method presented in this paper recently published in Org Lett ASAP detailed the using of chiral organo catalyst in performing domino double Michael additions to form chiral tetrahydrothiophene derivatives.

The reaction seemed to be quite simple to conduct. First, several catalysts (I-IV) were screened for reactivity in the representative reaction using enal 1a. However, the reaction only proceeded and stopped after the first Michael addition to give aldehyde 3. The authors reasoned that the steric hindrance of the benzene ring in the thiophenol framework perhaps prevented the second addition of the enamine intermediate to the ester.

Therefore, the thiol reacting partner was switched to thiol ester 4 and the reaction was screened again with all four organocatalysts and the results are summarized below.

This time, the reaction worked very well with catalysts I-III, while catalyst IV did not give any desired product. The reactions between 1a and 4 were found to be extremely efficient both in terms of yields and selectivities. After optimal conditions were found, the several substrates were screened for scope of the reaction and the results are summarized in Table 2.

The reactions were found to telerate well in a variety of substrates 1, whether it be electron-rich (entries 8 and 9) or electron-deficient aromatic rings (entries 2-7), or both (entry 10). In 2-substituted aromatic rings (entries 3, 7, and 9), the reaction also tolerated well with steric hindrance. Entry 11 demonstrated the tolerance of the reaction with heteroaromatic. Entry 12 showed that extended conjugation in aromatic ring also worked well, as well as with alkyl-substituted enal (entry 13).

A nice method, which can be used to build complex tetrahydrothiophene derivatives quickly with good to excellent yields and excellent enantio- and diastereoselectivities.

Kinetic Resolution of Hydroperoxides with Enantiopure Phosphines: Preparation of Enantioenriched Tertiary Hydroperoxides

2007-03-25T16:44:00.001-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070482f.html

From Prof. Keith A. Woerpel's group at the University of California, Irvine

A new method for reductive kinetic resolution of tertiary hydroperoxide employing cyclophane diphosphine as a selective reducing agent was recently published in JACS ASAP.

Several phosphines were investigated as shown.
The test substrate was chosen as tertiary benzyl hydroperoxide 11. The results of the initial screening for the appropriate phosphine are shown in Table 1. As seen in the table, cyclophane-derived phosphine 10 showed the most promising result (entry 9). This commercially available phosphine was used to investigate the scope of the reaction with several benxyl tertiary hydroperoxides as shown in Table 2.
This phosphine worked well with all substrates, including secondary hydroperoxides (entries 7-10). Functionalized hydroperoxide (entry 6) could be resolved well, although selectivity was lower. In all cases, (R)-10 reduced the (-)-(S)-hydroperoxide preferentially, and the enantiomer, (S)-10, had the opposite selectivity.

Selectivities diminished with increasing length of the alkyl linker in the resolutions of non-benzylic hydroperoxides 23 and 24 with (R)-10 (Scheme 1). Presumably, as the tether length increases, the steric differentiation decreases at the reactive center.

Preparative-scale resolution was also possible. For instance, one gram of hydroperoxide (+/-)-11 was subjected to resolution conditions with commercially available phosphine (R)-10 (71% conversion, Scheme 2). The resulting enantiopure hydroperoxide (+)-(R)-11 and enriched alcohol (-)-(S)-12 could not be separated by physical means, but a strategy was developed to facilitate purification. When the mixture of hydroperoxide (+)-(R)-11 and alcohol (-)-(S)-12 was treated with Et3SiCl, the hydroperoxide was protected selectively, and the resulting silylperoxy ether could be separated from the alcohol by column chromatography. Subsequent desilylation provided enantiopure (>99% ee) hydroperoxide (+)-(R)-11 in 24% overall yield. This route also allows access to enantiopure tertiary alcohol (+)-(R)-12 by reduction with triphenyl phosphine (Scheme 2).

Preliminary mechanistic studies reveal that the two phosphines of xylyl-PHANEPHOS (10) operate independently. The supposed intermediate, mono(phosphine oxide) (R)-25, was isolated from the reaction of phosphine (R)-10 and 1 equiv of hydroperoxide 17. Utilizing this compound in the resolution of hydroperoxide 11 afforded starting material with 84% ee at 51% conversion (krel = 25, Scheme 3). This experiment demonstrates that the monophosphine intermediate (R)-25 reduces hydroperoxides with a similar selectivity to that of xylyl-PHANEPHOS. It also suggests that less complex monophosphines may also be useful for this type of resolution.

In conclusion, the authors have described a method for the stoichiometric kinetic resolution of hydroperoxides employing commercially available phosphines. The reaction provides access to enantiopure hydroperoxides and, therefore, the corresponding alcohols as well. In addition, the resulting bis(phosphine oxide) can be converted back to the phosphine in high yield (the bis(phosphine oxide) isolated from the resolution reaction can be reduced with HSiCl3 in >90% yield.)

General Strategy for the Construction of Enantiopure Pyrrolidine-Based Alkaloids. Total Synthesis of (-)-Monomorine

2007-03-25T15:05:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/asap/abs/jo062532p.htm

From Prof. Mark L. Trudell's group at the University of New Orleans, LA

This is a JOC Note ASAP article detailing the use of natural cocaine as a starting material in synthesizing a chiral building block which could be useful for further manipulation. The utility was proven in their total synthesis of (-)-monomorine alkaloid natural product.

I guess the major problem in working with cocaines is how to access to the substance since it is illegal to possess. This is what the authors had to say:

"Although not commercially available,confiscated grade cocaine can be obtained from the National Institute on Drug Abuse with appropriate DEA licensing in sufficient quantities to provide useful amounts of chiral building blocks."

So it is possible to get some. This is good information. What embedded in cocaine is the cis-dialkyl substituent on the pyrrolidine ring as in 2 through a series of chemical degradation. This cis-relationship was also found in some indolizidine-type natural products, as in 1.

As was reported earlier by the authors, cocaine could be easily converted to (+)-2-tropinone and so this is where they started.

Starting with (+)-2-tropinone 4, demethylation followed by Cbz installation afforded 6. The process was conducted to decrease the basicity of nitrogen and to protect nitrogen from being oxizided in the subsequent step. Usual chemical operations ensued to provide protected pyrrolidine 8 in good overall yield (Scheme 2). It was found that compound 8 existed as a mixture of rotomers which made it difficult to be properly characterized.

Onto the synthesis of (-)-monomorine, the synthetic sequence is illustrated in the scheme below.

The usual synthetic operations led from compound 8 to 11. The double bonds were then hedrogenated and at the same time with the deprotection of N-Cbz group. The free nitrogen then cyclized with the ketone carbonyl to form the intermediate imine which was hydrogenated under the reaction conditions to give the desired product 12 in 87% as a single enantiomer. This was in agreement with previous report (Conchon, E.; Gelas-Mialhe, Y.; Remuson, R. Tetrahedron: Asymmetry 2006, 17, 1253.) that in hydrogenation of imine double bond, hydrogen is delivered from the face syn to the hyfrogen at the 8a position on the ring.

Thus the paper demonstrated the successful and convenient way of generating cis-2,5-dialkylpyrrolidine from cocaine. The article also illustrated the utility of this useful chiral building block in a successful total synthesis of (-)-monomorine.

N-Heterocyclic Carbene Ligands in Cobalt-Catalyzed Sequential Cyclization/Cross-Coupling Reactions of 6-Halo-1-hexene Derivatives with Grignard Reagen

2007-03-25T14:03:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070392f.html

From Prof. Koichiro Oshima's group at Kyoto University, Japan

Another paper utilizing NHCs as ligands appeared in this month's Org Lett ASAP. This is the paper describing intramolecular cyclization of alkyl iodide and tethered alkene, followed by cross-coupling with Grignard reagents. The reaction is catalyzed by Co-catalyst.

Several NHC ligands were excamined. These are shown below.

In the initial studies, NHC ligand 1 and allyldimethylsilylmethylmagnesium chloride were subjected to react with alkene 5 to give coupling product 6 in good yield. The allyldimethylsilyl group in the product could be oxidized smoothly via Tamao-Flemming oxidation to alcohol 7. This initial result showed that the method could be used in a sequential operation to obtain a cyclic alcohol of type 7.

A number of imidazolium salts other than 1 were screened. Salts 2 and 3 showed moderate reactivity giving product 6 36% and 54% yields, respectively. The use of phosphine and diamine ligands resulted in much lower yield. The scope of the reaction is as shown below.

In a related example, secondary iodide 18 could be subjected to the reaction conditions to give 19, followed by Tamao-Flemming oxidation to give diol 20 in good overall yield.

In addition, the authors also found that the reaction conditions could be used in a normal cross-coupling reaction (without cyclization) of primary alkyl iodide and Grignard reagent. For example, treatment of isobutyl iodide (0.5 mmol) with allyldimethylsilylmethylmagnesium chloride (1.5 mmol, 1 M ether solution) in dioxane (2 mL) in the presence of 1 (0.025 mmol) and CoCl2 (0.025 mmol) for 30 min at 25 °C afforded the corresponding coupling product in 79% yield.

Next, the cyclization-coupling process was examined for the cross-coupling reaction with alkynyl Grignard. Recently, the authors obtained promising result with trimethylsilyl-substituted alkynyl Grignard, but not with alkyl-substituted ones. However, for the cyclization-cross coupling process it was discovered that NHC ligand 2 proved to be effective. As shown in Scheme 3, cyclization-cross coupling sequence of various alkyl-substituted alkynyl Grignard reagents (21a-c) proceeded smoothly with CoCl2 in the presence of ligand 2 to give the coupling products 22a-c in good yields.

21a also underwent cyclization-cross coupling process with 9, and after Jones oxidation, provided lactone 23 in good yield over two steps.

The mechanism of this process is proposed to be:

1) generation of primary radical of the iodide via single electron transfer (SET) process
2) radical cyclization to give Co-carbocycle
3) transmetallation of Grignard reagent with Co species
4) reductive cyclization

Synthesis of the Tricyclic Core of Vinigrol via an Intramolecular Diels-Alder Reaction

2007-03-24T11:09:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0702977.html

From Prof. Louis Barriault's group at the University of Ottawa, Ottawa, Canada

A recent article in Org Lett ASAP detailing a partial total synthesis of vinigrol (1), particularly the tricyclic core structure of the natural product. The natural product shows antihypertensive and platelet aggregation-inhibiting properties.

The authros planned to use intramolecualr Diels-Alder reaction to construct this core. The planned cycloaddition looked quite funky as the orientation of the dienophile seemed quite strained in order to have a good interaction with the diene, not to mention that the orientation of diene had to cooperate. Nonetheless, the strategy seemed ambitious. In their retrosyn, they were led back to aldehyde 10 as the simpler building block.

Another aspect of the cycloaddition that required attention was the different approach of the dienophile to give a regioisomeric product 13 as shown in Scheme 3. Although the transition state leading to cycloadduct 13 seemed unlikely, this partial synthesis would also serve as a confirmation of this hypothesis.

In the forward direction, the synthesis started with aldehyde 10 as shown below.

Takai elefination of aldehyde 10 gave vinyl iodide 15. Buchwald's coupling protocol of 15 with 16 gave the ether 17. The care with temperature had to be taken as slightly higher temperature than 90 C would increase the amount of aldehyde 18 with epimerization at the alpha carbon. After ether 17 was obtained, it was subjected to i-Bu3Al as the Lewis acid to promote stereocontrol [3,3] sigmatropic rearrangement followed by immediate reduction to alcohol 19. Silylation then afforded 20.

Alkene 20 was subjected to conditions in scheme below. A more direct synthesis of the nitrile 22 would be to use of Grubbs' catalyst to perform cross metathesis with acrylonitrile followed by hydrogenation. But this did not work; only SM was returned. So it was resorted to KCN displacement of OTs group obtained from hydroboration-oxidation and then tosylation of alkene 20.

Then alkyne 24 was synthesis from the corresponding aldehyde of 23 using modified Ohira's protocol ((a) Roth, G. J.; Muller, S.; Bestmann, H. J. Synthesis 2004, 59. (b) Ohira, S. Synth. Commun. 1989, 19, 561.) as the aldehyde is sensitive to epimerization. The Wittig olefination of aldehyde 25 to alkene 26 was performed using Conia conditions (Conia, J.-M.; Limasset, J.-C. Bull. Soc. Chim. Fr. 1967, 114, 1936.)

An always-cool enyne ring-closing metathesis using Grubbs' second generation catalyst then afforded diene 27. Attempts to directly convert nitrile to corresponding enone 11 using Grignard reagents and various additives failed. Therefore, it was resorted to step-wise operations as shown.

BF3-OEt2-catalyzed Diels-Alder reaction then afforded the desired cycloadduct 12 in almost quantitative yield (as the only regioisomer). This result was not surprising as DFT calculations using Khon-Sham DFT at the B3LYP19 level of theory with a 6-31G** basis set also confirmed that the transition state leading to regioisomer 13 was 10.7 kcal/mol higher than the one leading to 12 (Scheme 7).

An ok partial synthesis overall with the exception of some noteworthy steps. The synthesis was also a little too linear.

Ruthenium-Catalyzed Cycloisomerization-6-Cyclization: A Novel Route to Pyridines

2007-03-23T21:06:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070163t.html

From Prof. Barry M. Trost's group at Stanford University

Recently appeared in Org Lett ASAP, the article presented a novel method for the synthesis of pyridine derivative.

Following metal-catalyzed [2+2+2] cyclotrimerization methodology for the synthesis of 6-membered N-heterocycles (equation 1), it was reasoned that a similar 6-pi electrocyclization of 1-aza-1,3,5-triene may provide access to pyridine derivatives.

In addition, recently the authors had disclosed a ruthenium-catalyzed cycloisomerization in the formation of alpha,beta,gamma,delta-dienones and dienals from compound of type 2 (equation 2). It was perhaps possible to use the product from this reaction to produce the required 1-aza-1,3,5-triene for the electrocyclization.

It seemed that 1-aza-triene could be formed by condensation of the carbonyl in 3 with hydroxylamine to form an oxime 4 which could electrocyclize to give pyridine 6 upon dehydration of 5 (Scheme 1).

This idea seemed to work well with compound 2a. Although pyridine 6a was not formed on prolonged refluxing in toluene, it could be obtained efficiently with microwave irradiation (Scheme 2).

Therefore, 2b was chosen to screen for optimal reaction conditions. In this substrate, pyridine 6b could be synthesized efficiently when aldehyde 3b was heated with hydroxylamine and NaOAc in ethanol.

From this initial result, more conditions were explored and the results are summarized in the table below.

The reaction was found to proceed more rapidly when the reaction was heated at higher temerpature and especially very efficient under microwave irradiation (entry 3).

After having found the optimal conditions, the scope of the method was explored and results are summarized in the table below.

The heteroatom-tethered substrates tolerated well and proceeded to give the desired products in good yields (entries 3-5). Mixture of E and Z isomers of alkene were also found to proceed without the need to separate them before the reactions (entries 5-9). Mehtyl ketones also worked quite well (entries 4, 5, 9, 10).

In the case of terminal alkene as in 3d, the reaction also worked well. Aldehyde 3d was obtained as a mixture with ketone 7 in the reaction from primary alcohol 2d.

In addition, the reaction could be run in one pot. For example, pyridine 6h could be made in 54% overall yield from alcohol 2h. The key operation in this case was that after the first step, acetone (which could cause problem with hydroxylamine in the second step) had to be removed from the reaction. The crude material could then be subjected to the second step as shown in Scheme 5.

Competitive Cationic Pathways and the Asymmetric Synthesis of Aryl-Substituted Cyclopropanes

2007-03-22T23:35:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol063026p.html

From Prof. Richard E. Taylor's group at the University of Notre Dame, Notre Dame, IN

A new cyclopropanation method specifically for the construction of phenyl vinyl cyclopropane was reported in Org lett ASAP.

The method relied on the cyclization homoallylic alcohol allylic trimethylsilane. The authors previously reported a similar method for cyclopropane formation of alkyl homoallyic alcohol allylic silane in high diasteroeselectivity (trans) on the basis of cationic cyclization pathways with the proposed transitions states as shown in the figures below.

In the current study, a substrate where R group is a simple phenyl group (5d) was first tested. Therefore, the substrate was constructed from benzaldehyde. Brown's asymmetric allylation of aldehyde 3d afforded the homoallylic alcohol 4d in good yield and excellent er (95:5).

Cross-metathesis with allyltrimethylsilane afforded the allylsilane in 86% with modest 66:34 selectivity for the E isomer. The geometry of the double bond does not matter for the selectivity in the cyclopropanation, and therefore the E/Z mixture was used directly. Treatment of 5d with mesyl anhydride furnished cyclopropane 6d in good yield and diastereoselectivity (9:1 trans/cis isomer). The er was determined by conversion of the alkene via a two-step process to the alcohol and the er was measured using 19F NMR of the Mosher ester of the alcohol 8d.

In the cyclopropanation step, it was found necessary to use Ms2O in place of Tf2O (which the authors used in their previous studies) to prevent silyl migration from allylsilane to OH to form Si-O bond, which essentially shut down the cyclopropanation. Scope of the reaction was studied and several phenyl vinyl cyclopropanes could be prepared in good yields, diastereoselectivity, and enantioselectivity. The cyclization substrates 5a-g were prepared in similar fashion to 5d.

The cyclization process was stereospecific - the sterechemistry of the alcohol determined the outcome in the stereochemistry of the cyclopropane, thus the er of the product. Two different cationic pathways are shown below.

In general, the reaction proceeds through the enantiospecific pathway. But when the phenyl group contained a strongly electron-donating group, the ionization of the mesylate to form a more stable benzyl cation could take precedent leading to increase in racemization in products. This problem could be overcome by installing the electron-donating group after cyclopropanation through cross-coupling reaction. The bromophenyl derivative was found to be appropriate.

For example, 9 could be prepared in good yield and diastereo- and enantioselectivities (entry 5 in the table above). This phenyl bromide underwent smooth Kumada coupling and after deprotection with TBAF afforded 8a in virtually identical er to 9. Compare to entry 1 in the table, 8a was obtained in increased er, though through longer number of steps.

Similarly, bromide 9 underwent Hartwig's Pd-catalyzed amination with diethylamine to give the aniline derivative 10 after deprotection with TBAF in good yield and in almost identical er to 9. Although longer number of steps, electron-rich phenyl cyclopropane could be obtained in high overall yield and diastereo- and enantioselectivities.

Cobalt-Catalyzed Diastereoselective Reductive [3 + 2] Cycloaddition of Allenes and Enones

2007-03-22T22:41:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja0710196.html

From Prof. Chien-Hong Cheng's group at National Tsing Hua University, Taiwan

This is quite an interesting and intriguing chemistry. The new Co-mediated [3+2] cycloaddition of an allene and alpha,beta-unsaturated ketone was recently reported in JACS ASAP. The method is highly diasteroeselective and seems efficient in generating a variety of 3-methylene-cyclopentanols.

The catalyst system consisted of CoI2(dppe), Zn, ZnI2, and water in CH3CN. ZnI2 was crucial for the reaction to proceed, without which there was no reaction. The reaction partners were heated with the catalyst and co-catalyst at 80 C for several hours. The products were obtained in good yields. In the case where the allene partner was the phenyl allene, the enone partner, which reacted as the three-carbon partners, cycloadded to the internal double bond of the allene to give the desired cyclopentanol as a single diastereomer.

As seen in entries 10-12, when the allene partner was naphthalene and ortho-methylphenyl allene, the products were obtained as diastereomeric mixtures, still in excellent selectivity. This method complements well with the existing [3+2] method where the allene reacts as the three-carbon partner and the enone as the two-carbon component.

When the allene partner contained an ester functionality, the initial cyclopantanol adduct readily cyclized to give fused lactone products.

In probing the mechanism of the reaction and the role of water, D2O was used in placed of H2O and it was found that deuterium was incorporated to the 5-position of the carbocycle as well as on the oxygen of the alcohol.

Thus, initially, the mechanism was proposed as followed. The cobalt inserted into the internal double bond of allene and the double bond of the enone to form cobaltocycle 4. This intermediate is expected to be in equilibrium with the enolate derivative which then got quenched with D2O or H2O. The resulting carbonyl in 5 was added nucleophilically with the Co-C bond and thus formed the Co-O bond, which picked up another deuterium or proton from D2O or H2O, respectively.

This is quite cool chemistry and is expected to find numerous uses as a tool in total synthesis of natural products.

A General Synthesis of Substituted Formylpyrroles from Ketones and 4-Formyloxazole

2007-03-22T15:37:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070340q.html

From Jonathan T. Reeves at Boehringer Ingelheim Pharmaceuticals, Inc. in Ridgefield, CT

The report in Org Lett ASAP detailed a method for the synthesis of 4-formyloxazole.

Based on the Cornforth's finding in 1949 that various 2-substituted 4-formyloxazoles underwent alkaline hydrolysis to give N-acylated aminomalondialdehydes, it was reasoned that the vinylogous extension of the Cornforth's reaction could be applicable for the synthesis of 2-formylpyrroles.

Therefore the idea was tested with enone 3, which was prepared from commercially available oxazole ester 1 in two steps.

Gratifyingly, treatment of 3 with aqueous NaOH afforded pyrrole 4 in 82% yield. Later, it was found that compound 3 could be prepared by aldol reaction followed by elimination of the mesylate (scheme below). It was necessary that the mesylate formation from aldol 6 was complete before the addition of NaOH for the synthesis of pyrrole 4 in one pot to be effective. In this manner, the elimination of the mesylate with NaOH to form the enone occurred quickly compared to using Et3N.

After the optimal conditions for the 2-formylpyrrole synthesis were established, the scope of the reaction was explored and the results are summarized below.

Extension of the methodology to beta-(4-thiazolyl)-enone was explored. It was planned that if the reaction pattern is the same as the oxazole, then 2-thioformylpyrrole could be prepared. However, it was found that the reaction did not proceed when 26 was subjected to the same reaction conditions (recovered SM).

It was suspected that thiazolium salt may be necessary for the hydrolysis with NaOH to occur. Therefore, the thiazole was alkylated with benzyl bromide before being subjected to the NaOH hydrolysis. However, only complex mixture of products was obtained. It was suspected that the intermediate A was not stable under the reaction conditions. Thus, MeI was added to trap A as sulfide B. Under the reaction conditions, the intermediate B underwent an exchange with OH to give intermediate C which eventually underwent the same reaction pathway to give pyrrole 28 in 64%.

Although the reaction of thiazole 26 failed to give the anticipated 2-thioformylpyrrole, it provided an effective route to N-benzyl-2-formylpyrrole.

Enantioselective Total Synthesis of the Osteoclastogenesis Inhibitor (+)-Symbioimine

2007-03-22T12:39:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114188062/ABSTRACT

From Prof. Regan J. Thomson's group at Northwestern University, Evanston, IL

A short synthesis of (+)-Symbioimine (1) was recently reported in ACIEE EarlyView. The synthesis an unusual intramolecular Diels-Alder reaction of conjugated cyclic iminium ion intermediate. Compound 1 is believed to find potential uses in preventative treatment of osteroporosis and possibly as an anti-inflammatory therapeutic agent.

In their retro, it was thought that the allylic methyl group in 3 would impose a poor facial selectivity for an exo [4+2] cycloaddition; not enough to drive the reaction to the desired stereochemistry. However, the cyclic iminium species 4 with its stereo-defined allylic methyl group was believed to impose a stronger preference for an endo cycloaddition to provide cycloadducut 5 with good desired stereochemistry. This cycloadduct then could undergo an epimerization to adjust its stereochemistry to an all trans ring junction of 1.

Diene 13 was identified as the needed Diels-Alder precursor and the synthetic route was devised as shown in the scheme below.

Starting from aldehyde 6, HWE olefination proceeded with good yield to provide 7 with excellent E/Z selectivity (>11:1). Conversion to methyl ketone 8 could be performed through Weinreb amide in one step for a small scale or a two-step protocol is necessary for a larger scale synthesis. Mukaiyama aldol of enol ether 9 with acetal 11, followed by the Staudinger-aza-Wittig reaction sequence then provided the key compound 13 in excellent yield.

Heating 13 with TFA effected the formation of 14 followed by cycloaddition-epimerization allowed a rapid access to the imine 16. Treatment of 16 with TFAA then afforded 17 in good overall yield as a single diastereomer. The structure of 17 was characterized with nOe experiments, and could be converted back to 16 under mild reaction conditions by treatment with K2CO3/MeOH.

Treatment of 16 with BBr3 (global demethylation), followed by selective sulfation finally afforded the natural product 1. This synthesis has showcased the use of the dihydropyridinium species (14) in a rare Diels-Alder reaction, which could find more uses in the future. The lower yield of the cycloaddition was probably due to the generation of other unavoidable pyridine derivatives. However, this Diels-Alder reaction may provide a direct support in the biosynthesis of 1. Overall, this is a very nice and short synthesis that could provide rapid access to 1 and its analogs.

Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent

2007-03-21T22:49:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114179538/ABSTRACT

From Prof. Erick M. Carreira's group at ETH Zürich, Zürich, Switzerland

A report in ACIEE EarlyVIew presents a new and intriguing method of converting allylic alcohol directly to allylic amine. The features of this method includes a direct conversion of the allylic alcohol to the allylic amine without prior manipulation of the alcohol, the use of sulfamic acid as the NH2 group equivalent leading to the product as primary ammonium salt and the use of iridium phosphoramidite catalyst.

Ligands L1 to L4 were screened with substrates 1-3 as test models. Low conversions were observed with substrates 1 and 2. However, it was discovered by accident that substrate 3 as the free alcohol could be converted to the corresponding allylic amine.

The iridium catalyst used in the process was [{Ir(cod)Cl}2] (1.5 mole%). When ligand L3 was used (3 mol%) with the Ir-catalyst in DMF as the solvent of choice, substrate 3 could be converted to the corresponding allylic amine in the presence of sulfamic acid in >99% conversion after 24 h at 23 C. The double bond in ligand L3 was crucial as the comparison studie using ligand L4 (missing double bond) only led to 20% conversion. Ligand L3 could be accessed easily from reaction of 2,2'-BINOL, PCl3 and 5H-dibenzo-[b,f]azepine in one step. This was an early example of sulfamic acid being utilized as amino-group equivalent in organic synthesis.

The scope of the reaction was studied and the results are summarized below.

From the table, besides obtaining the products as the free amine salts, it could also be obtained as N-Bz, N-Boc or N-amide protected amino group (entries 2-4).

In proton NMR experiments using DMF-d7 as the solvent, the allylic alcohol 3 was quickly converted to the corresponding allylic amine 4 very quickly (after two hours). However, when the excess sulfamic acid was used and when the reaction was allowed to react longer, the expected product 5 was formed.

Based on the spectroscopic observations, the following conclusions were made:

- When an excess of sulfamic acid was employed in the Ir-catalyzed process, the amine 4 initially produced underwent partial sulfamation with the second equivalent of sulfamic acid to form 6. This sulfamation only began after 3 had been entirely transformed into 4
- Throughout the course of the Ir-catalyzed process, no signals corresponding to the sulfate ester 5 were observed. Given the long reaction time required to perform the sulfation with sulfamic acid (eight hours), it is unlikely that the sulfate ester 5 serves as activated intermediate in the Ir-catalyzed reaction
- The absence of signals corresponding to 6 leads the authors to suspect that sulfamic acid does not act as a nucleophile in the catalytic process

The mechanism of the process was proposed as followed. It is believed that the Vilsmeier-type intermediate 7 was formed from DMF and sulfamic acid. This intermediate then reacted with the allylic alcohol to give the intermediate 8, which underwent oxidative addition with Ir-catalyst. This pi-allyl iridium complex 9 then reacted with ammonia in the reaction to form the desired product.

Besides the achiral version of the reaction, the process was also shown to undergo asymmetric catalysis process to produce chiral allylic amine. That is when ligand L5 was used with the iridium catalyst system, the cyclohexyl allylic alcohol was converted to the corresponding allylic ammonium chloride salt in 70% yield and 70% ee, demonstrating the utility of this method in asymmetric catalysis. This was also the first asymmetric example of the process.

An Azomethine Ylide Approach to Complex Alkaloid-like Heterocycles

2007-03-21T00:26:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/asap/abs/jo062579a.html

From William V. Murray at Johnson and Johnson Pharmaceutical Research and Development LLC, Cranbury, New Jersey

The report in JOC Note ASAP detailed the reaction sequence leading to the formation of alkaloid-like tricyclic pyrrole via an intermolecular [3+2] dipolar cycloaddition between nitrone and alkyne.

In their early studies of the intramolecular Diels-Alder reaction of 1, it was found that instead of obtaining enamine 2, they obtained nitrone 3. According to their calculation, 3 is 11 kcal more stable than 2.

When nitrone 3 was subjected to dipolar cycloaddition to alkyne as a dipolarophile in toluene at 60-80 C, isoxazole 4 was obtained. However, in subsequent studies when nitrone 3a was subjected to DMAD and the reaction was heated in toluene at reflux, instead of obtaining isoxazole 4a as expected, a different product was obtained. After careful spectral analysis and x-ray crystallography, the new product was found to be the pyrrole 5a.

The product 5a was later found to the thermal rearrangement product of 4a when the reaction mixture was heated at higher temperature (refluxing toluene).

The scope of this cycloaddition-thermal rearrangement sequence was studied with different nitrones and dipolarophiles and the results are summarized in the table below.

Along with the scope of the reaction, a reaction mechanism of the transformation from 4 to 5 was also proposed as illustrated below.

This is believed to be the working mechanism as it fits well with the result of the reaction between nitrone 3b and the dipolarophile where X is a phenyl group. In this case, the reaction took longer (110 C/5 h) than other entries because of the inherent stability of phenyl ketone which made it less prone to cyclization by enamine addition (vide supra). The featured transformation (4 to 5) is an interesting reaction and can make a good reaction mechanism question.

Double Insertion of Isocyanides into Dihydropyridines: Direct Access to Substituted Benzimidazolium Salts

2007-03-20T23:19:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114182360/ABSTRACT

From Prof. Rodolfo Lavilla's group at Institute for Research in Biomedicine, Barcelona Science Park, and University of Barcelona, Barcelona, Spain

This paper in ACIEE EarlyView deals with the use of isocyanide in a novel reaction. This is the type of reaction which could be a good mechanism question. Basically, dihydropyridines or DHPs could react with isocyanide in the presence of Br2 or I2 to give new products, depending on the halogens employed.

The reaction of interest in this paper is the case where I2 is used in the reaction. This is because the reaction led to the formation of the benzimidazolium salt, for example 4a in the scheme above. This is significant as imidazolium salts are a precursor of N-heterocyclic carbenes (NHCs), which have found increasing applications as ligands in transition metal catalysis process. Additionally, imidazolium salts may find uses as ionic liquids in various processes. By using a series of C13- and H2-isotopic studies, the mechanism of this process, even though not fully established, has been proposed to be as followed.

The authors suggested the followings:

"The subtle distinction between the nucleophilicity and nucleofugacity of bromide and iodide may account for the different stabilization of the nitrilium intermediates, as well as the capacity to promote the ring opening and recyclization from intermediates C and D, respectively."

The established method was applied to various combinations of DHP and isocyanide derivatives, which gave access to several benzimidazolium salts 4. The results on scope of the reaction are summarized in Table 1. It is noteworthy that when the amide and formyl derivatives of DHP were used (entries 11 and 12), no desired product was formed. This was contributed to the oxidative interferences of the amido and formyl groups during the oxidation process.

Although several yields are not that great, nonetheless, this paper still presented a unique way of accessing benzimidazolium salts 4, an increasingly important class of compounds through a quite novel reaction pathway.

A Concise Total Synthesis of the Notoamides C and D

2007-03-20T20:40:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114123310/ABSTRACT

From Prof. Robret M. Williams' group at Colorado State University

This paper came out a while back in ACIEE EarlyView and now is in print. It details the research aiming at total synthesis and biosynthesis of fungi metabolites notoamides C and D and their related prenylated indole alkaloid cousins, namely the notoamides A and B, norgeamides A, B, C, and D and Stephacidin A. For Stephacidin A, its total synthesis and biomimetic synthesis had been written about before in an early entry of this blog.

As seen in the scheme that follows, it is thought that indole 11 is the common biosynthetic intermediate of all the alkaloids mentioned. In the biosynthesis of notoamides C (3) and D (4), oxidation of the C2-C3 bond in the indole ring is involved, after which, the intermediate epoxide takes different reaction paths.

For the formation of 4, epoxidation of indole C2-C3 bond is followed by openning-trapping with nitrogen of tryptophyl amide to form the pyrroloindole system. As for 3, after oxidation of C2-C3 bond, pinacol-type rearrangement follows to give the oxindole system.

After the intermediate 11 was identified, the synthesis of this intermediate could be traced back to the simpler fragments of glycine, (S)-proline and the gramine derivative 13.

Indole 11 could then be put together as shown in the scheme below.

Indole 18 could be separated from 11 by chromatography. When 11 was subjected to oxidation with oxaziridine 19, notoamides C, and D and the 3-epi-notoamide C were isolated in the combined yields of about 86% (3 (28 %), 20 (48%), 4, and 2,3-epi-notoamide (10% combined)).

The conversion of the oxidized intermediate was proposed to occur as followed.

Notoamide C should arise from the oxidation from the alpha-face of 11 and notoamide D would arise from beta-face oxidation. The fact that the oxindole species of 3 is usually isolated in a more dominant amount than N-tryptophyl trapping of 4 may imply that besides the role of nitrogen of indole in the ring openning of epoxide, oxygen atom in the pyranyl ring may also assist in the ring openning. The authors were not able to use modeling to rationalize the occurance of oxindole in higher amount.

However, the hypothesis of the pyranyl ring participation was tested by replacing the pyran ring with BocO group at the 6-position of the indole nucleus. The electron-withdrawing Boc group should attenuate the electronic effect of oxygen into the ring. This should change the outcome in term of products distribution of the reaction (more N-trapping and less pinacol-type rearrangement to oxindole).

This indeed was the case as shown in the scheme below.

Compound 29 failed to be oxidized by oxaziridine 19. But when 29 was exposed to oxygen in the presence of methylene blue, only products 30 and 31 were obtained as a result of trapping the intermediates (both alpha-face and beta-face oxidations) with tryptophyl amide nitrogen and no oxindole was detected. Therefore, by changing the electronic property of the indole ring (ie, oxygen at the 6-position), the pathway of the reaction can be controlled and/or altered.

The oxidation-pinacol rearrangement sequence of indole to give oxindole in this synthesis is believed to be the first example of the transformation where the oxindole was obtained directely from indole after oxidation. This represents a more convenient way in accessing oxindole nucleus from indole than the traditional multi-step method, which typically consists of chlorination at C3 with hypochlorite, followed by hydration to form 2-hydroxy-3-chloro-indoline (chlorohydrin), then pinacol-type migration of hydride concurrent with dechlorination.

These are pretty nice total syntheses and biomimetic systhetic studies.

Readily Accessible, Modular, and Tuneable BINOL 3,3'-Perfluoroalkylsulfones: Highly Efficient Catalysts for Enantioselective In-Mediated Imine Allylat

2007-03-19T23:45:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070742t.html

From Prof. Gregory R. Cook's and Guy C. Lloyd-Jones' groups at North Dakota State University, USA and University of Bristol, UK, respectively

A collaborative effort of the groups at ND State Univ and Univ of Bristol resulted in a new method for the allylation of imine N-acyl hydrazones mediated by indium, which was reported in JACS ASAP this month. The method was capable to produce indium-mediated allylated products in high yield and enantioselectively. In fact, this is the highest ee-yielding method to date in indium-mediated allylation.

Following their initial report of indium-mediated allylation of imine hydrazones using ligand 3a and 3b, they have found that the yield and enantioselectivity could be markedly improved using new BINOL ligands which were even more electron-deficient.

Therefore, new ligands were synthesized employing thia-Fries rearragement of BINOL to give fluoro- and perfluorosulfone derivatives. This also represendted the first examples of the rearrangement of higher perfluoralkylsulfonates. The syntheses of these BINOL are illustrated in Scheme 2.

Comparing to ligands 3a-b, ligands 4a-c were found to be supeior as shown in Table 1.

The presence of two SO2R(F) [R(F) = fluoroalkyl or perfluoroalkyl group)] in the new ligands was found to be crucial in term of selectivity. As a result, BINOL 4d and 4e were inferior to 4a-c, whereas ligands 5a and 5b (with one SO2R(F) group) were least effective.

Scope of ligand bis-SO2R(F) BINOL 4a was established in Table 2. The ligand was found to be very effective with aryl imine. Ligand 4a was even more effective when the aryl ring is substituted at the 6-position (compare entries 6-11), so much so that the loading of the ligand could be reduced to 2-3 mol%.

The only cases where this method did not work as well was when the R group is aliphatic. This is probably because when R is aliphatic, the substrate becomes more reactive. Even with this problem, substrate 1l (entry 17) still gave product 2l with up to 74% ee using ligand 4a, which compares favorably with lignad 3a, which afforded 2l in only 34% ee. This catalyst system is the highest ee-yielding to date. The ligand is easily recovered by silica gel chromatography and can be recycled up to 3 times without loss of reactivity or selectivity.

Palladium-Catalyzed Formal [4+2] Cycloaddtion of o-Xylylenes with Olefins

2007-03-19T22:31:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070012l.html

From Prof. Ryoichi Kuwano's group at Kyushu University, Japan

A report on formal Diels-Alder reaction of compound of type 1 with alpha,beta-unsaturated carbonyl compounds and derivatives which is catalyzed by Pd complex recently appeared in JACS ASAP.

The reaction was proposed to proceed either through intermediate A (path a) or B (path b) (Scheme 1).

In the initial reaction conditions screening using compound 1a and 2a to obtain 3a, it was found that the reaction proceeded best using Lewis basic solvent (DMSO and DMF), and diphosphine ligand (dppe) (Table 1).

When 1a was heated under the optimal reaction conditions without 2a, only trace of 4 was detected but 5 was not observed, indicating that the 0-xylylene was not formed.

The scope of reaction was explored with several trans-disubstituted and geminal-disubstitued alkenes. The reaction was found to be stereospecific in trans-alkenes. The reaction also worked with acrylonitrile (entry 5) and styrene (entry 6) (Table 2). The reaction failed to proceed in the cases of strongly electron-deficient olefins, such as maleate, and fumarate, as well as cyclic olefins.

When substrates with substituents in the aryl rings (1b-e) were used, regioisomeric mixtures of products were obtained. These results indicated that most likely intermediate A (palldacycle) was involved in the cycloaddition process with alkenes because if it were intermediate B, products would have been afforded with perfect regioselectivity (through 1,4-addition of the anion to the olefin, followed by displacement of Pd with the nascent enolate).

Palladium-Catalyzed Coupling of Ammonia and Hydroxide with Aryl Halides: The Direct Synthesis of Primary Anilines and Phenols

2007-03-19T21:29:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114179535/ABSTRACT

From Prof. Michael C. Willis at University of Oxford, UK

This is a recent highlights in ACIEE EarlyView detailing the recent developments in direct coupling technology of amino (NH2) and hydroxyl (OH) with aryl halides to form aniline and phenol. The methodologies were recently reported by the two research groups, namely the Hartwig group and the Buchwald group. The methodologies developed were both based on Pd-catalyst.

In the background of these couplings, the challenges exist in the formation of aniline directly from ammonia and phenol directly from water. The challenges in using ammonia directly for the formation of aniline are:

- ammonia is an excellent ligand for many metals and will often bind to the metal in preference to the ligands needed to form active catalyst systems

- the stability of amido–metal complexes also makes the key reductive elimination, leading to C-N bond formation, a difficult process

- if a successful amination with ammonia could be achieved, the product of the reaction, a primary amine such as 1 (see below), is very likely to be an excellent coupling partner itself, leading to the formation of di- and triaryl amines

The challenges in using water as a direct coupling partner for phenol formation are also similar.

Recently, the Hartwig group has shown that selective coupling reactions between aryl halides and ammonia can be achieved if catalysts incorporating the bulky ferrocene-based ligand A are employed (Scheme 2). For example, the reaction between unhindered aryl bromide 3 and ammonia (80 psi) at 90 C using 1 mol% of [APdCl2] and the strong base NaOt-Bu delivered aniline 4 in 86% yield. Importantly, only a few percent of the diaryl amine was observed (17:1 ratio of mono-/dicoupled material).

The Hartwig group has shown that solid lithium amide can also be conveniently used in these coupling reactions, although the selectivity for mono- over diarylation was sometimes lower in these modified reactions but still synthetically useful. The selectivity ranges from 8:1 to >50:1, with the more hindered aryl halide substrates being most selective.

The major factor in the success of these reactions is the hindered, tightly bound chelated intermediates generated from the use of the sterically demanding diphosphine ligand.

The Buchwald group has developed a series of bulky electron-rich monophosphines that generate efficient catalysts for the coupling reactions between aryl halides and phenols. They have very recently shown that these ligands are effective for the coupling of potassium hydroxide with aryl halides. For example, the use of a catalyst featuring the sterically demanding biphenyl ligand B allowed the conversion of aryl bromide 5 to phenol 6 in 96%yield after 6 h (Scheme 3).The reactions were conducted in 1:1 water/dioxane at 100 C. As the second example in Scheme 3 illustrates, the process was amenable to aryl chloride substrates. The latter example featured the bulkier ligand C, which was found to generate more stable catalysts and thus allow lower catalyst loadings. The reductive elimination step of the mechanism, responsible for C-O bond formation, was identified as the key step of the process. By matching the ligand, either B or C, with the substrate under investigation, the authors were able to effectively convert a wide range of aryl bromides and chlorides to their corresponding phenol derivatives.

Although the ability to halt both the ammonia and hydroxide coupling reactions at the monoarylation stage was one of the chief difficulties to be overcome,the capacity to utilize these monoarylation products directly in controlled and synthetically useful second transformations presents many exciting possibilities for reaction development.

Both groups have already seized this opportunity. The Hartwig group has demonstrated that the use of dibromobiphenyl substrate 7 allows the direct formation of carbazole 8 in 64% yield by way of a tandem amination process (Scheme 4).

The Buchwald group has developed a tandem process based on an initial hydroxide coupling, followed by the alkylation with an alkyl halide. In the overall transformation an aryl halide is converted to an alkyl aryl ether. For example (Scheme 4), reaction of aryl halide 9 with potassium hydroxide leads to phenoxide intermediate 10. Introduction of a secondary alkyl halide in combination with the phase-transfer catalyst cetyltrimethylammonium bromide, then provides alkyl aryl ether 11 in an overall yield of 84%. This new approach to alkyl aryl ether synthesis avoids the problem of unwanted beta-hydride elimination often encountered with secondary alcohols in palladium-catalyzed etherification reactions of aryl halides.

A second cascade sequence based on an initial hydroxide coupling was also developed. Coupling of potassium hydroxide with (2-chloroaryl) alkynes delivered phenol intermediates that cyclized under the reaction conditions to generate benzofuran products.

The methodology for a direct coupling of aryl halides with H2S may be on the way(?).

Chromium-Catalyzed Arylmagnesiation of Alkynes

2007-03-18T01:13:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0703938.html

From Prof. Hideki Yorimitsu's and Koichiro Oshima's group at Kyoto University, Japan

Another Org Lett ASAP this month. This one deals with chromium-catalyzed arylmagnesiation of alkynes.

During the screening process for the optimal reaction conditions using 1 and 2, protic additive was found to be essential. For this purpose, carboxylic acid was found to work best. The bulkiness of the acid was crucial for a successful reaction and thus tBuCOOH was identified as an optimal additive. This acid additive could catalyze the reaction to a much faster rate while improving yield and E/Z selectivity.

The scope of the reaction was investigated and the results are summarized below. A variety of arylmagnesium bromide could couple stereoselectively with various alkynes to give, after quenching with water, desired alkenes.

In addition, the new intermediate alkenylmagnesium bromide, such as 4, was shown to undergo various typical trapping/subsequent reactions of Grignard reagents to provide a variety of products in good to excellent yields and selectivities (Scheme 1).

Low-Valent Niobium-Catalyzed Reduction of alpha,alpha,alpha-Trifluorotoluenes

2007-03-18T00:12:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070249m.html

From Prof. Takahiko Akiyama's group at Gakushuin University, Tokyo, Japan

Recent work in Org Lett ASAP focused on the use of NbCl5 together with LAH in reducing CF3 group on an aromatic ring to CH3 group.

The reaction appeared to be applicable to a wide range of substrates as shown in the table below (with conditions).

The reduction is selective to the benzylic C-F bonds as apparent in entries 5 and 6 where only the benzylic C-F bond was reduced while the aryl C-F bond remained unaffected. This is in contrast to entries 9 and 10, where both aryl C-Cl and benzylic C-F bonds were reduced completely. The biaryl substrate 11 could also be reduced completely to give 2c.

The presence of NbCl5 in the reaction is critical for a complete reduction of fluorine as the comparison studies below demonstrates.It was also found that by lowering the amount of LAH employed as in the case of 1k, one of the CF3 groups could be completely reduced while leaving the other one intact providing 1d in good yield. When higher equiv of LAH was used, complete reduction resulted.

The result of the comparison experiments above (with 3 equiv LAH) seemed to show that the reduction occurred in the step-wise fashion. And that when one fluorine is replaced by a hydrogen, the resulting CHF2 group became more prone to the reduction than the other CF3 group, thus reacting faster to give CH2F group. This group was reduced faster still than the CF3 group and underwent another reduction to give CH3 group while the other CF3 group largely remained untouched.

Morita–Baylis–Hillman Cyclizations of Arene–Ruthenium-Functionalized Acrylamides

2007-03-16T23:41:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114182375/ABSTRACT?CRETRY=1&SRETRY=0

From Prof. F. Christopher Pigge's group at University of Iowa

I have read it, although not that thoroughly. From what I saw, this was a strange chemistry, but neat, nonetheless. The paper recently appeared in ACIEE EarlyView. The chemistry involved the Morita-Baylis-Hillman (MBH) reaction performed intramolecularly on acrylamides which are normally difficult substrates to participate in MBH. The enolate intermediate then cyclized to the activated aryl ring by CpRu complex to form a spiroamide-Ru intermediate. Following base-promoted elimination of the alpha-proton and extrusion of the nucleophile promoter, a spiroamide-RuCp complex was obtained. The CpRu could be demetalated to give the highly-functionalized spirolactams. These transformations represent the first examples of direct metal–arene participation in MBH-type reactions.

The first successful reaction conditions is shown in the formation of spiroamide-Ru complex 4.

The choice of solvent was critical and dimethoxyehtane (DME) was found to do the best job. Acetonitrile (MeCN) will also promote the reaction although it gave a lower yield. The nucleophile promoters that worked well were found to be Bu3P and DMAP.

A variety of substrates worked well, even in the aryls containing ortho-substituent. Both electron-rich and -deficient aryl rings also worked well in the reaction. In addition, acrylamides containing beta-substituent, which are normally difficult to react in MBH reaction, reacted smoothly to give the desired products in moderate yields. Substrate containing benzyl substituent was also tolerated.

Next, the substrates containing beta,beta-disubstituted acrylamide were explored as shown in Scheme 3. Dimethyl acrylamide (19a-c) and cyclopentylidene acrylamide (22) readily reacted under the standard MBH conditions to provide the desired products in good yields. In cases of 19a and 19b, the products were obtained as inseparable mixture of alkene isomers. And in case of 22, the elimination in intermediate 24 occurred at H-gamma.

In addition to the 5-membered spirolactam ring, the 6-membered was briefly investigated and two examples were shown to proceed in good to excellent yields (Scheme 4).

The metal complex product could be easily oxidized to yield metal-free organic materials. In the case where an OMe group is present in the para-position, the complex could be demetalated to provide an quinone-like compound.

However, when the OMe group is not present in the periphery, such as compound (S)-16, an oxidation with CuBr2 in water/THF could proceed to afford compound (-)-29 in good yield, with recovery of CpRu fragment.

Pd-Catalyzed Kumada-Corriu Cross-Coupling Reactions at Low Temperatures Allow the Use of Knochel-type Grignard Reagents

2007-03-16T22:40:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070830d.html

From Prof. Stephen L. Buchwald's group at MIT

A new method from the Buchwald group at MIT, exploring the use of Knochel-type Grignard reagents in Pd-catalyzed cross-coupling with aryl halides. The method presented a new way to do cross-coupling with reactive Grignard reagents at lower temperature (-20 to -65 °C) while tolerating a wide range of functionaly groups in both partners.

In the first step, screening for the optimal reaction conditions, including the search for the right ligand. As shown in Table 1, ligand L3 was found to give the best result with aryl trfilate. However, it was later discovered that the reaction could perform much better when the coupling partner was switched to aryl iodide.

Next, the scope of the coupling reaction was explored using aryl iodide and various functionalized Grignard reagents prepared by the method of Knochel's (Mg/I exchange method). The coupling results and the conditions for each coupling are summarized in Table 2.

As shown, their version of the Pd-catalyzed Kumada-Corriu cross-coupling reaction manifests a broad substrate scope:

- Ortho-, meta- and para-substituted biaryls could all be efficiently prepared.

- In addition, a variety of functional groups were tolerated, including nitriles (entries 1 and 2), amines (entries 3 and 10), esters (entries 5 and 7), heterocycles (entries 6 and 7), and a benzylic acetal (entry 6).

- This process could also be employed for challenging cross-coupling reactions at -50 °C (entries 2 and 9) or at -65 °C (entry 3), as well as for the construction of a triortho-substituted biaryl (entry 4). To the best of their knowledge, no other Pd-catalyzed biaryl-forming reactions have been accomplished at such temperatures.

- Moreover, the process showed excellent chemoselectivity toward aryl halide substituents, as chlorides (entries 2, 3, and 8), fluorides (entry 10), and even bromides (entry 8) were tolerated, making them available, in many instances, for further functionalization via conventional cross-coupling techniques.

Table 3 demonstrates the utility of this method in cross-coupling of a variety of heteroaryl Grignard reagents. In these cases, catalyst L2 was found to perform better than L3 while other reaction conditions are essentially identical.

In electron-deficient arylboronic acid such as ortho-fluoro derivatives are often poor substrate due to their low reactivity in the transmetalation process and higher tendency to homocouple. It was expected that the higher reactivity of Grignard reagents would overcome the difficulty of the transmetalation step, even though these organometallic species are unstable at ambient temperatures, decomposing via benzyne and other pathways.

However, as shown in Table 4, the fears were not warranted as highly electron-deficient aryl Grignard reagents cross-coupled smoothly with aryl iodides providing various 2-fluoro and, especially, 2,6-difluoro biaryls, which have been quite difficult to make, in good to excellent yields. In addition, a variety of functional groups were well-tolerated in these reactions.

A Highly Enantioselective Intramolecular Michael Reaction Catalyzed by N-Heterocyclic Carbenes

2007-03-16T07:23:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114188063/ABSTRACT?CRETRY=1&SRETRY=0

From Prof. Karl A. Scheidt's group at Northwestern University

I have only skimmed through the paper. But I think this is a neat method demonstrating the use of N-heterocyclic carbenes or NHCs in a basic organic reaction for the formation carbocycles (1 to 2).

The mechanism of this process is proposed as followed.

The reaction conditions were screened with four different NHC compounds. The screening results are summarized below.

Triazolium salt D was found to be the most effective in term of both yield and ee of product 3. The scope of the reaction was explored and the results are in Table 2.

- The use of methanol to quench the reaction avoids the propensity for several of the bicyclic products to undergo hydrolysis when purified on silica gel.

- The optimized reaction conditions allowed both electron-withdrawing and -donating groups on the enone (entries 1–3).

- Additionally, electron-withdrawing and -donating substituents could be placed on the aromatic tether (entries 6 and 7).

- The alpha,beta-unsaturated methyl ketone 1d provided a moderate yield of the cyclopentane product with excellent enantioselectivity (entry 4).

- The bisaldehyde 1e underwent an interesting desymmetrization reaction in which one aldehyde became the nucleophile when exposed to an NHC while the other unsaturated moiety became the conjugate acceptor (entry 5).

- The cyclization of the aliphatic substrate 13 (entry 8) proceeded in good yield after ten hours with a catalyst loading of 20 mol%.

- When the tether length was increased to access six-membered rings, cyclohexene products were afforded but with reduced enantioselectivity and yield (62%ee, 52%; entry 9). Interestingly, product 16 did not open after the addition of methanol, unlike the cyclopentane compound.

The method also allows access to amide-substituted carbocycles when amines, instead of metahnol, were used to open the ring.

Nice chemistry which seems to have practical uses. NHCs have become an efficient and popular tool in organic synthesis. And chemists have started to explore the use of this class of compounds in reactions, other than only as ligands for Grubbs or Hoveyday-Grubbs metathesis catalysts. In fact, recently a book on NHCs in organic synthesis has been published by Wiley.

Generation and Reactions of Pentacyclo[4.3.0.02,4.03,8.05,7]non-4-ene

2007-03-15T23:19:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/asap/abs/jo0626313.html

From Prof. Mark A. Forman's group at Saint Joseph's University, Philadelphia

I have to admit that I have not read this article closely, only skimmed through it and thought some of the materials worth blogging about, especially the novelty of the synthesis and some of the chemistries performed on the pentacycle. Also, the schemes and charts should be easily understood. This article recently appeared in JOC ASAP.

The highly pyramidalized alkene, pentacycle 9 was synthesized and its reactivities were studied. The plan was to make diiodide 12, then perform Li-halogen exchange and LiI should eliminate to give 9. The synthesis started with norbonadiene, see the scheme below.

Key of Reactions: (a) dimethylacetylene dicarboxylate, MeOH, heat, 73%; (b) KOH, MeOH, H2O then 10% HCl, 97%; (c) light, diethylether, 25%; (d) DCC, THF; (e) NaOMe, MeOH, 98% 2 steps; (f) (i) (COCl)2, CH2Cl2, DMF, (ii) 2-mercaptopyridine-N-oxide sodium salt, benzene, 2-iodo-1,1,1-trifluoroiodoethane, DMAP, 66%; (g) KOH, MeOH, H2O then 10% HCl, 94%; (h) (i) (COCl)2, CH2Cl2, DMF, (ii) 2-mercaptopyridine-N-oxide sodium salt, benzene, 2-iodo-1,1,1-trifluoro-iodoethane, DMAP, 53%.

After diiodide 12 was successfully synthesized, it was subjected to several different reactions as shown below. First, the treatment of 9 with 10.

Treatment of 9 with n-BuLi.

Compound 9 could also be trapped with 1,3-diphenylisobenzofuran (DPIBF) to give 27.

The diiodide 12 could also be treated with t-BuLi to generate 9.

In this case, t-BuLi did not add across the double bond in 9, like in the case of n-BuLi. Alkene 9, generated by t-BuLi was also trapped with other dienes.

The saturated derivative of 9 was also synthesized from a similar route to give 33.Later on, the molecular calculation of alkene 9 was conducted and several characteristic numbers from the calculation, including the calculation parameters, are shown in the following figure.

Synthesis of Carbamates and Ureas Using Zr(IV)-Catalyzed Exchange Processes

2007-03-15T22:46:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0702728.html

From Prof. John A. Porco, Jr's group at Boston University

A report appeared in Org Lett ASAP on the synthesis of carbamates and ureas from dialkyl carbonates by exchange reaction catalyzed by Zr(IV) catalyst.

In their study of the exchange process for the formation of carbobates from dialkyl carbonates with amines. Zr(Ot-Bu)4 was chosen as the catalyst. In their synthesis of carbamates, an additive was required and they found 2-hydroxypyridine (or HYP) to be optimal. The following table shows the scope of the reaction.

In this series of reaction, it was found that the reaction could not be accelerated with microwave. The typical reaction conditions are: performed neat with 1.0 equiv of amine and 1.5 equiv of dialkyl carbonate in the presence of 5 mol % Zr(Ot-Bu)4 and 10 mol % HYP at 80 °C (12 h). The reaction was found to perform well both with aliphatic and aromatic amines.

Next, the optimal conditions for the carbamate-urea exchange (for the synthesis of ureas) were screened. In the model reactions between 3,4-dimethoxyphenethylamine and N-ethyl urethane
to give urea 9, 4-methyl-2-hydroxyquinoline (Me-HYQ) was found to be an optimal additive.

The scope of the urea formation was then studied and the results are summarized in the table below.

In contrast to the carbamate formation, the carbamate-urea exchange process can be accelerated using microwave. Some of the ureas can also be synthesized in one pot from dialkyl carbonate.

Rhenium-Catalyzed C-H and C-C Bond Activation

2007-03-15T13:21:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114130502/ABSTRACT

From Prof. Yoshikazu Horino at University of Toyama, Japan

This work appeared recently in ACIEE Highlights as a minireview on a specific type of reaction in the field of C-H and C-C bond activations using Rhenium and Ruthenium catalysts. The work featured in this minireview is the work being done by other leaders in the field, such as Kuninobu and Takai.The first catalyst being discussed is [{ReBr(CO)3(thf)}2] which was found to work well in the reaction with aldimine 1 as shown in Scheme 1 above. The mechanism was proposed as the activation of the aryl C-H bond ortho to the aldimine group resulting in the C-Re bond formation, where the metal center is coordinated by the proximal N group of the aldimine. Thus, it is required that the metal center lost a CO in order for this coordination to occur. This CO-loss hypothesis was later confirmed by other experiments. Also, the nitrogen had to be present to coordinate to the metal and thus stabilized the intermediate.

Another point worth mentioning is the reverse of product composition with different phenyl acetylene derivative was used without significant loss of yield. (compare ratio of 5 and 6 in the scheme above).

The reaction with aldimne 1 with a ruthenium catalyst was found to take a different course of action. When [Ru3(CO)12] was used as a catalyst, no metal migratory insertion on the aldimine occurred following insertion of ruthenium to acetylene, and the reaction stopped at product 9 (Scheme 2).

The same rhenium catalyst as above was also used in a reaction to form indene derivatives from aromatic ketones with alpha,beta-unsaturated esters. In this case, p-anisidine was needed as a co-catalyst for the reaction to proceed via the intermediacy of the ketimine 11, of which the nitrogen of the ketimine then directed the activation of C-H bond by the metal center followed by cyclization with unsaturated ester (Scheme 3).

The same rhenium complex was also found to facilitate the vinylation of 1,3-diketones and beta-keto esters with acetylenes as illustrated in the scheme below.

Kuninobu and Takai also found that their rhenium complex in the presence of an isocyanide as a ligand can also catalyze a ring expansion reaction of cyclic 1,3-dicarbonyl compounds with acetylenes as demonstrated in Scheme 5 below. It is important that isocyanide is used as a ligand. In the absence of an isocyanide, only alpha-vinylated product was obtained.

As shown in the scheme above, the retro-aldol (path A) and the deMayo-type reaction (path B) were proposed as a possible reaction mechanism of this process. Although experimental data to differentiate between the two proposed mechanisms has not been discussed, mechanistic studies on a related ruthenium-catalyzed [2+2] cycloaddition reactions of olefins with acetylenes are consistent with the deMayo reaction (path B). While [ReBr(CO)5] and [MnBr(CO)5] also catalyze the synthesis of 35 in modest yield (45% and 59%, respectively), neither [Ru3(CO)12], [RuH2(CO)(PPh3)3], PtCl2, AuCl3, nor GaCl3 promote formation of 35 under identical reaction
conditions.

This paper gave a good reactivity profile of the rhenium catalyst and the recent technology on its effect on C-H and C-C activation reactions, in comparison with other metal catalyst. This is a good place to come back to consult with when this type of reaction/activation is desired.

Highly Efficient Copper-Catalyzed N-Arylation of Nitrogen-Containing Heterocycles with Aryl and Heteroaryl Halides

2007-03-13T23:42:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/asap/abs/jo062059f.html

From Prof. Jingsong You's group at Sichuan University, Chengdu, P.R. China

Another new method of Copper-catalyzed Ullman-type coupling of N-heterocycles with aryl and heteroaryl halides. The methodology employed proline-derived ligands in the reaction. Ligands were synthesized according to the follwing scheme.

The catalyst CuI and ligands were then screened for the best conditions using 5a and 6a as test coupling partners.

The most optimal conditions for coupling reaction of 5a and 6a were found to be the catalyst system generated in situ from 5 mol % of CuI and 10 mol % of 4a (see ligand synthesis above) in the presence of 2 equiv of Cs2CO3 in DMF at 110 °C under N2. These conditions were used to explore the scope of the reaction in coupling of imidazole with various aryl and heteroaryl halides (see table below).

(a) Reaction conditions: 5 (1.2 mmol), 6a (1.0 mmol), 2.0 mmol of Cs2CO3 in the presence of 10 mol % of ligand 4a and 5 mol % of CuI in 2.0 mL of DMF at 110 °C under N2 atmosphere for 24 h. (b) Isolated yields (average of two runs) based on 6a. (c) 48 h at 110 °C.

The scope was further investigated in the coupling reactions of bromobenzene (5a) and iodobenzene (5v) with various heteroaryl partners as shown below.

A very extensive paper.

Novel Formal Synthesis of Cephalotaxine via a Facile Friedel-Crafts Cyclization

2007-03-13T20:27:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070024b.html

From Prof. Wei-Dong Z. Li's group at Lanzhou University, and Nankai University, P.R. China

A recent report in Org Lett ASAP highlights a synthetic study conducted toward a formal synthesis of cephalotaxine (CET) showcasing a new tactic used in the closure of the B-ring. Cephalotaxine and its naturally occurring ester derivatives (harringtonine and homo- harringtonine) possess antitumor therapeutic potentials.

Although, the tactic employed in closing the B-ring is novel, the synthetic interest in the CET-type structure is hardly new. Because of its antitumor property and its unique spirocyclic alkaloid core structure, it has attracted numerous attention from synthetic chemists in the past.

Several strategic approaches have been explored in the formation of the B-ring and this article could also be treated as a summary of these past strategems. The past approches include:

1) Lewis acid or protic acid mediated Friedel-Crafts-type cyclization as employed by the Kuehne, Royer, Sha, and Mori groups.

(4) Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer, T. D.; Blount, J. F.; Zubieta, J. J. Org. Chem. 1988, 53, 3439.
(5) Planas, L.; Perard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69, 3087.
(6) Sha, C. K.; Young, J. J.; Yeh, C. P.; Chang, S. C.; Wang, S. L. J. Org. Chem. 1991, 56, 2694.
(7) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115.

2) Pd(0)-catalyzed Heck-type coupling of an unsaturated spirocyclic aryl halide precursor as exemplified by the Tietze, Ikeda, Suga-Yoshida, and Hayes groups.(9) (a) Tietze, L. F.; Shirok, H. Angew. Chem., Int. Ed. 1997, 36, 1124. (b) Tietze, L. F.; Shirok, H. J. Am. Chem. Soc. 1999, 121, 10264.
(10) (a) Ikeda, M.; Hirose, K.; El Bialy, S. A. A.; Sato, T.; Yakura, T.; Bayomi, S. M. M. Chem. Pharm. Bull. 1998, 46, 1084. (b) Ikeda, M.; El Bialy, S. A. A.; Hirose, K.; Kotake, M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.; Abdelal, A. M.; Gad, L. M.; Yakura, T. Chem. Pharm. Bull. 1999, 47, 983.
(11) Suga, S.; Watanabe, M.; Yoshida, J. I. J. Am. Chem. Soc. 2002, 124, 14824.
(12) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011.

3) radical cyclization approaches as used by the Semmelheck and Taniguchi groups.

(13) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507.
(14) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.; Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922.

The current synthesis commenced with synthesis of cyclization substrate 4a and 4b and also 8a and 8b.

It should be noted that both 4a and 8a (where the R groups are the methylenedioxy group) did not cyclize to give any desired product, whereas the dimethoxy derivatives 4b and 8b cyclized smoothly. This stereoelectronic effect of methylenedioxy group on the aryl system, which precludes the acid-promoted Friedel-Craft cyclization, was first noticed by Sha and co-workers.

The current acid-catalyzed cyclization strategy was also tested with other spirocyclic systems 10-13. Here, again, the stereoelectronic of methylenedioxy group precluded the cyclization even under forcing conditions, while dimethoxy derivatives underwent smooth cyclization (compare 10b and 11b).

Upon standing in mild acidic conditions, compound 9b could undergo skeletal rearrangement to give isomers 9b' and 14, where 9b' is more stable than 9b.

A similar skeletal rearragement was also previously observed by Dolby and co-workers where the Dolby-Weinreb enamine alkylation product 15 underwent a facile reorganization through a proposed pathway as shown in the scheme. At the end, 14a was the sole isolable product. Upon acid treatment, 14a easily converted to 14b. The alpha-ethoxy carbonyl group in the cyclopentanone ring and the methylenedioxy substituent on the aryl ring of 15 may have influenced this facile isomerization process.

(24) Dolby, L. J.; Nelson, S. J.; Senkovich, D. J. Org. Chem. 1972, 37, 3691.

Rhodium-Catalyzed Intramolecular Alkyne-carbodiimide Pauson-Khand-Type Reaction

2007-03-13T18:26:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol063123i.html

From Prof. Takao Saito's group at Tokyo University of Science, Tokyo, Japan

This is a method which applies the Pauson-Khand cyclization strategy to a different system using a different metal catalyst, rather than the usual C02(CO)8. The substrate being studied in this report (Org Lett ASAP) is the a system consisting of carbodiimide moiety (as referred to as heterocumulenic portion) tethered to an alkynic system, which cyclizes intramolecularly in the presence of CO in a [2+2+1] fashion.

In their earlier findings, it was discovered that this Pauson-Khand-type process could be accomplished using Mo(CO)6 in the presence of DMSO as the promoter in the reaction conducted in toluene, albeit stoichiometric molybdenum compound was required.

However in their latest findings using substrate 1a during the screening, they found that this process could be catalyzed by a Rh-catalyst. The catalyst of choice was found to be [RhCl(CO)dppp]2 (5 mol %), generated in situ by mixing [RhCl(COD)]2 and 1,3-bis(diphenylphosphino)propane (dppp, 11 mol %). This marks the first known Rh-catalyst system able to catalyze Pauson-Khand-type reaction of carbodiimide and alkyne. Other results from catalyst screening are summarized in the following table.

It should be noted that dppp is more superior than other ligands studied and the Rh catalyst could be lowered to 2.5 mol % and still afforded 58% of 2a (compare entries 10 and 11).

Next, the scope of this new catalyst system was explored in a series of substrates and the results are included in the following table.

In general, the catalyst seems to function well across the table giving the desired products in moderate to good yields, except in substrates 1b and 1g (entries 2 and 7) where the R2 group being cyclohexyl group, where the yields were lower. This may be due to the steric hindrance during the cyclization.

The scope of the catalyst was explored further in its application to the substrate where the carbodiimide is tethered through ethylene (CH2-CH2) group to the alkyne (3a-g), Table 3. The Rh catalyst was still able to function well, yielding the desired products in acceptable yields in most cases. The only exception was 3a where the subtituent R2 on the carbodiimide is less bulky (n-Pr group), which made it prone to dimerize or deteriorate under the harsh reaction conditions.

Tetrasubstituted Pyrrolidines via a Tandem Aza-Payne/Hydroamination Reaction

2007-03-12T22:36:00.000-05:00

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja068077w.html

From Prof. Babak Borhan's group at Michigan State University in East Lansing, MI

The work involves a new and mild methodology in intramolecular hydroamination of alkynes. The process is activated by the formation of an epoxide in the molecule following an openning of the N-protected aziridine ring through an aza-Payne rearrangement process. The reaction then resulted in the exocyclic methylene epoxy pyrrolidine, i.e. 5.

The reaction sequence is catalytic in the formation of the pyrrolidine ring. However, the aza-Payne rearrangement requires stoichimetric amount (2-4 equiv) of base. The aziridinol starting materials 2 are preapred by Grignard reaction of aziridinyl aldehydes and ketones. The diastereoselectivity of the Grignard addition is crucial in the success of the latter cyclization process as only the syn-isomer of the aziridinol will produce the epoxide intermediate with nitrogen nucleophile in the right orientation to cyclize (Scheme 2).Different starting materials were prepared as shown in the table below.Notes for the results in Table 1:

- The presence of an R group syn to the carbonyl eroded the diastereoselectivity (1a and 1o)while the use of a trans disubstituted aziridine aldehyde gave only moderate dr (1b and 1c).

- However, the use of 2,2,3-trisubstituted aziridine aldehydes gave the syn-aziridinols as the sole detectable product (1d-1m).

- Also of note was the excellent diastereoselectivity obtained in the generation of quaternary hydroxyl centers from aziridine ketones (1j and 1k).

The process could proceed in one pot providing that excess base, dimethylsulfoxonium methylide, (2-4 equiv) is employed at rt. The following table summarizes the results of this process.

Notes for the results in Table 2:

- For 2a and 2c, the desired syn-aziridinol substrate could not be cleanly separated from the anti-isomer. Therefore 2a and 2c were treated with NaH in THF to give mixtures of the epoxy amines, which were separated by column chromatography before the desired diastereomer was subjected to hydroamination conditions.

- Alternatively, the hydroamination could be run on the mixture of syn/anti compounds, and the epoxy amine (resulting from reaction of the anti diastereomer) was separated from the desired pyrrolidine (2o).

- The remaining substrates (2b, 2d-2n) contained only the syn-aziridinol, and the majority underwent hydroamination smoothly. The exceptions were alkynes substituted with alkyl or silyl groups (2h, 2l, and 2m) as it may be necessary for terminally substituted alkynes to contain a group capable of stabilizing a developing negative charge on the carbon adjacent to the newly forming C-N bond.

- The TMS-substituted alkyne 2l did deliver the desilylated product 5d, presumably as a result of initial deprotection of the TMS group.

- The Z-stereochemistry of the enamides obtained from aryl-substituted alkynes (2i and 2k) may result from prior coordination of the sulfoxonium to the opposite face of the alkyne, thus leading to rapid proton transfer and the observed stereochemistry.

- A 64% yield of 5d was obtained from the epoxy amine 4d using 0.2 equiv of ylide, confirming that the hydroamination reaction is catalytic in base.

As mentioned before, the facile hydroamination was suspected to be aided by the preorientation of the nitrogen and the alkyne on the same side of the epoxide by the aza-Payne rearrangement (Scheme 2). This hypothesis was tested by subjecting an unfunctionalized amino alkyne (8) to several different hydroamination conditions (Scheme 3), but no pyrrolidine product was obtained, implying a decrease in activation entropy of the cyclization is the underlying reason for the favorable hydroamination reaction.

Synthesis of 1,2-Disubstituted Benzimidazoles by a Cu-Catalyzed Cascade Aryl Amination/Condensation Process

2007-03-11T22:17:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114177283/ABSTRACT?CRETRY=1&SRETRY=0

From: Prof. Dawei Ma's group at Shanghai Institute of Organic Chemistry, Shanghai, P.R. China

A new cascaded method in synthesizing 1,2-disubstitued benzimidazoles starting from 2-haloacetanilides, catalyzed by CuI/L-proline catalyst system. This is a copper-catalyzed amination process or aryl iodide or bromide, which attaches an primary amine to the aryl ring, followed by a ring closure of the 2-acetanilide group in one pot. The amination process is promoted by the ortho-NHCOR group in substrate since the simple amination of iodobenzene does not provide any amination product.

This is the kind of work which summarized results in tables speak better than words. So here they are.

For the aryl iodide substrates,
For the aryl bromide substrates,

The aryl bromide results are not ideal to view in this blog. For best viewing, look at the actual article.

Lithiation-Induced Migrations from Nitrogen to Carbon in Terminal Aziridines

2007-03-11T18:09:00.000-05:00

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114122819/ABSTRACT

From Prof. David M. Hodgson's group at University of Oxford, UK

A nice method involving a 1,2-anionic migration of Boc and phosphonate groups upon deprotonation with LiTMP of terminal N-Boc and N-phosphonate aziridines, respectively, was recently reported in ACIEE. This was done in comparison to their earlier study of deprotonation and trapping with external electrophile of the terminal N-Bus (Bus = tert-butylsulfonyl) aziridine.

In comparison, when the N-Bus aziridine was deprotonated and quenched with CD3OD, aziridine 3 was obtained. But when N-Boc aziridine was employed, only 4a was isolated along with 50% of recovered SM without deuterium incorporation.

The reaction was investigated further and a satisfying condition set was identified (3 equiv of LiTMP at -78 C). The scope of the methodology was then investigated and the results are summarized below.

From the table, the followings are the notable points:

- Complications were not observed from potential allylic deprotonation, cyclopropanation, or benzylic deprotonation (entries 2 and 3)

- X-ray crystallographic analysis of 4c supported the assigned trans stereochemistry

- Distal and proximal protected alcohols were tolerated (entries 4 and 5)

- A potentially eliminable primary chloride was also tolerated (entry 6)

- A 2,2,3-trisubstituted aziridinylester could also be accessed (entry 7), although in this case warming to 0 C was required for reaction to occur.
- No degradation of ee was observed under the reaction conditions (entry 8, determined by chiral HPLC analysis of the 2,4-dinitrobenzoyl derivatives)

Also, attempted reaction of a 2,3-disubstituted aziridine (N-Boc aziridine of cyclohexene) only led to return of starting material, presumably owing to unfavorable steric interactions. When the latter reaction mixture was allowed to warm from -78 C to 0 C, a mixture of starting material and decomposed material was obtained, whereas warming to room temperature resulted in only decomposition.

A crossover experiment was conducted and the anionic migration was found to occur in the intramolecular fashion (hence 1,2-migration).

One of the products obtained from the 1,2-migration of Boc group was further utilized in a number of useful subsequent transformations. These include:

- Regioselective hydrogenolysis of 4b to give protected beta-amino acid 8
- Oxidative cycloamination of the tethered olefin of 4b with NBS to give azabicycle 9, followed by subsequent elimination using DBU to give enamine 10
- Regioselective Swern oxidation of 4b, which occurred in a completely regioselective manner to give azirine 11

The utility of this methodology was further demonstrated in the scheme below in a concise asymmetric synthesis of a stable ester of the unstable antibiotic natural product azirinomycin 12. Note that compound 13 was obtained in more than 99% ee.

1,2-Phosphonate migration of terminal N-phosphonate aziridine was then investigated and a new condition set was established for this substrate (5 equiv LiTMP at -78 C, high dilution). The scope of this reaction was subsequently studied and the results are summarized in the table below. It should be noted that the 1,2-N-to-C migration reaction of N-phosphonate aziridine derivatives shows a similar selectivity profile to that of the N-Boc derivatives.

Utility of one of the phosphonate products was further demonstrated in the hydrogenolytic ring cleavage of (-)-19h to give beta-aminophosphonate (+)-20 in 68% yield. Beta-Amino-phosphonates and the corresponding phosphonic acids have attracted considerable interest as replacements for natural amino acids in various targets of medicinal interest.