A simple and efficient enantioselective route to 2,6-disubstituted piperidines: synthesis of (2R,6S)-isosolenopsin A and (2S,6R)-isosolenopsin

The enantioselective synthesis of 2,6-cis-disubstituted piperidine alkaloids, (2R,6S)-isosolenopsin A 2 and (2S,6R)-isosolenopsin 5 from fire ant venom is described. Starting from the dodecanal and decanal, the synthesis presents two key steps. The first step involves Keck allylation to afford the chiral homoallylalcohol with the required stereochemistry and the second key step consists of Grubbs olefin cross metathesis. The synthesis was achieved in five steps with 44% overall yield.     

Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H

The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids as (+)-(2R,5S) and (−)-(5S,2R).     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

Controlling stereoselectivity by enzymatic and chemical means to access enantiomerically pure (1S,3R)-1-benzyl-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline derivatives

A chemoenzymatic strategy for the synthesis of enantiomerically pure novel alkaloids (1S,3R)-1-benzyl-2,3-dimethyl-1,2,3,4-tetrahydroisoquinolines is presented. The key steps are the biocatalytic stereoselective reductive amination of substituted 1-phenylpropan-2-one derivatives to yield chiral amines employing microbial ω-transaminases, and the diastereoselective reduction of a Bischler–Napieralski imine intermediate by catalytic hydrogenation in the presence of palladium on charcoal, leading exclusively to the desired cis-isomer.     

Synthesis and biological activity of diastereoisomeric octahydro-1H-indole-5,6,7-triols,analogues of castanospermine

A straightforward stereoselective route towards (3aR,5R,6S,7R,7aR)- and (3aR,5R,6S,7R,7aR)-octahydro-1H-indole-5,6,7-triol, analogues of castanospermine, starting from the corresponding shikimic acid derivatives is described. The key transformations of this approach are the Overman rearrangement and ring-closing metathesis to form the diastereoisomeric cis-fused (5R,6S,7R)-octahydro-1H-indole-5,6,7-triols in good overall yields. Evaluation for in vitro cytotoxicity revealed for some prepared compounds significant antiproliferative activity and weak glycosidase inhibition.     

An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.     

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione^® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a′R,7a′S)-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.     

Synthesis of trihydroxy quinolizidine alkaloids: 1,3-addition reaction of allylmagnesium bromide to a sugar nitrone

The synthesis of (1R,2R,3S,9aR) and (1R,2R,3S,9aS) trihydroxy quinolizidine alkaloids 3a and 3b from d-glucose derived nitrone 4 is described. The key transformation involves the 1,3-addition of allylmagnesium bromide to nitrone 4 that afforded high diastereoselectivity in the presence of TMSOTf. The N-O bond reductive cleavage, N-Cbz protection, ozonolysis, Wittig olefination, lactum formation and reductive amination cascade afforded the target compounds 3a and 3b in good overall yield.     

First stereoselective synthesis of serinol-derived malyngamides and their 1′-epi-isomers

A stereoselective synthesis of 1a {N-[(1R)-2-hydroxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamide} has been accomplished in 10 steps from 1-tetradecanol for the first time in 28% overall yield. The key steps involved the coupling reaction of a chiral alkyne with a protected bromide in the presence of t-BuLi, as well as the amidation reaction of (4E,7S)-7-methoxyeicos-4-enoic acid with (R)-methoxyamino alcohol. Acetylation of 1a finished the preparation of 1b {N-[(1S)-2-acetyloxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamide}. Their 1′-epi-isomers have also been synthesized with a similar strategy.     

New asymmetric strategy for the total synthesis of naturally occurring (+)-alexine and (−)-7-epi-alexine

A novel and highly convenient process is described for the asymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids, (+)-alexine [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine] and (−)-7-epi-alexine [(1R,2R,3R,7R,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], as the potent glycosidase inhibitors by featuring the efficient and stereodefined elaboration of the functionalized pyrrolidine derivatives, which were, in turn, prepared via stereoselective manipulation of the homochiral allyl alcohol precursors derived from l-xylose.     

Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.     

Novel stereocontrolled synthesis of the tricyclic lactone (1R,3R,6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.03,9]nonane

The stereocontrolled synthesis of (1R,3R,6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.0^3,9]nonane 1 from (R)-(−)-carvone has been accomplished by application of a 13-step sequence with 12% overall yield. The absolute stereochemistry of the unsaturated acid 8a has been established by X-ray analysis of the chiral amide 8c.     

Two-directional synthesis of the non-adjacent bis(tetrahydrofuran) core of cis-sylvaticin

Synthesis of the C₂-symmetric, non-adjacent bis(tetrahydrofuran) core of cis-sylvaticin in seven steps and 24% overall yield from (2R,3S)-1,2-epoxy-4-penten-3-ol is reported. A strategy involving assembly of the central 1,4-diol unit by silicon-tethered ring-closing metathesis and subsequent two-directional functionalization, including establishment of the cis/threo stereochemical relationships of the tetrahydrofuran rings by Sharpless asymmetric dihydroxylation/S_N2 cyclization, is employed.     

Synthesis of the enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-octadecadiene,one of the major components of the sex pheromone of Ectropis oblique Prout

Both enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-octadecadiene, one of which is the major component of the sex pheromone of Ectropis oblique Prout, were synthesized in 23% overall yield for the (?)-(6S,7R)-enantiomer and 18% yield for the (+)-(6R,7S)-isomer. This protocol uses a sequential regioselective ring-opening strategy and provides a convenient and reliable access to other structurally related insect sex pheromones. Preliminary biological studies revealed that (?)-(6S,7R)-2a was roughly as active as the natural pheromone, while racemic (±)-2 was less bioactive and (+)-2b was much less bioactive.     

2,2′-Dihydroxy-3,3′-dimethoxy-5,5′-dimethyl-6,6′-dibromo-1,1′-biphenyl: preparation,resolution, structure and biological activity

The preparation and resolution of the titled conformationally stable biphenyl 1 has been performed in high chemical yield starting from creosol 2. Enantiopure biphenyls (aR)-(+)-1 and (aS)-(−)-1 were obtained by the corresponding menthylcarbonate diastereomer and successive reduction. The absolute configuration and specific rotation were correlated by X-ray analysis of the crystal structure of diastereopure menthylcarbonate (aS,1R,1′R,2S,2′S,5R,5′R)-(+)-16. Preliminary biological evaluation of both racemic enantiomers of 1 has been carried out on melanoma cell lines and significant and selective anticancer activity has been observed for the enantiomer (aS)-(−)-1.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

Synthetic approaches to imino sugar (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol from naturally occurring sugar and amino acid

Imino sugar compound 3 was prepared by two alternative routes starting from ribose and d-serine. From d-serine (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methylpyrrolidin-2-one was prepared in five steps in 50% overall yield, which was further converted into (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol in three steps in 23% overall yield.     

A concise synthetic pathway towards 5-substituted indolizidines

The total synthesis of 5-(2′-hydroxyethyl)indolizidine via 5-thioindolizidinone is described. The key step is the transformation of 5-thioindolizidinone via Eschenmoser’s sulfide contraction. The racemic mixture of 5R,9R- and 5S,9S-5-(2′-hydroxyethyl)indolizidine was obtained in seven steps in 17% overall yield from 2-allyl cyclopentanone.     

First total synthesis of (+)-Vedelianin, a potent antiproliferative agent

The total synthesis of (+)-vedelianin has been accomplished in 18 steps from vanillin. Preparation of a key intermediate in nonracemic form through a Shi epoxidation has allowed determination of the absolute stereochemistry of the natural product as the (2S,3R,4aR,9aR)-isomer.     

Asymmetric synthesis of (−)-(1R,7aS)-absouline

The most efficient and concise asymmetric synthesis of (?)-(1R,7aS)-absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)-amide to an enantiopure α,β-unsaturated ester derived from l-proline was employed as the key step. Subsequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant β-amino ester produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (?)-(1R,7aS)-absouline.