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).

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.

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

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.

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

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!

Stereocontrolled Total Synthesis of (-)-Kainic Acid

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.

Enantioselective Total Synthesis of (+)-Neosymbioimine

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.

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

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.

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

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.

A Concise Total Synthesis of the Notoamides C and D

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.