Total Synthesis of (-)-Stemoamide

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

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

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

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

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

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

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

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

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

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.