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.     

Synthesis of versatile chiral intermediates by enantioselective conjugate addition of alkenyl Grignard reagents to enamides deriving from (R)-(−)- or (S)-(+)-2-aminobutan-1-ol

Conjugate addition of but-3-enylmagnesium bromide to the chiral crotonamide (R)-(+)- and (S)-(−)-3, followed by hydrolysis and oxidation, afforded enantiopure (R)-(+)- and (S)-(−)-3-methyladipic acids 8, respectively. Conjugate addition of vinylmagnesium chloride to the chiral crotonamide and cinnamamides (R)-(+)-3–5, followed by hydrolysis, gave the alkenoic acids (S)-12–14, respectively. Iodolactonization of the latter led to the 5-iodomethyllactones (+)-15–17, which were reduced by means of n-Bu₃SnH into the trans-disubstituted 5-methyllactones (+)-19–21, respectively. Treatment of the iodomethyllactone (+)-16 with LiMe₂Cu or n-Bu₂CuLi furnished the trans-5-alkyl-4-phenyllactones (−)-22 or (+)-23.     

Synthesis of chiral 2-(2′-pyrrolidinyl)pyridines from (S)- and (R)-proline: potential ligands of the neuronal nicotinic acetylcholine receptors

A new strategy for a straightforward synthesis of novel optically active nicotine analogues starting from (S)- and (R)-proline is reported utilizing as the key steps the inverse electron demand Diels–Alder reaction of, hitherto unknown, chiral 5-(2′-pyrrolidinyl)-1,2,4-triazines (S)- and (R)-16. These serve as appropriate precursors for the preparation of different, highly enantiomerically enriched 2-(2′-pyrrolidinyl)pyridines, modifications of natural (−)-nornicotine and (−)-nicotine and potential ligands of the neuronal nicotinic acetylcholine receptors. The multistep syntheses proceed under mild conditions, with good overall yields and with stereochemical integrity of the original stereogenic centers.     

Synthesis of decalin type chiral synthons based on enzymatic functionalisation and their application to the synthesis of (−)-ambrox and (+)-zonarol

Stereoselective syntheses of (−)-ambrox 2 and (+)-zonarol 3 were achieved based on the enzymatic syntheses of (8aS)- and (8aR)-decalin-type 1,3-diols 1, respectively. Non-racemic intermediates such as (8aS)-1 and (8aR)-1 were obtained based on the enantioselective hydrolyses of the phenolic acetal derivative (±)-7 by acylase I.     

Synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones

A synthesis of the enamine (−)-(1′S)-5-ethyl-1-(1′-phenylethyl)-1,2,3,4-tetrahydropyridine 4 and its application in a synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones 5 and 6 is described. In addition, an X-ray study of 6 is reported. Finally, the preparation of (+)-(4aS,8aR)-4a-ethyl-octahydroquinolin-7-one 7 is described.     

Synthesis of optically active dihydrocarveol via a stepwise or one-pot enzymatic reduction of (R)- and (S)-carvone

A recombinant enoate reductase LacER from Lactobacillus casei catalyzed the reduction of (R)-carvone and (S)-carvone to give (2R,5R)-dihydrocarvone and (2R,5S)-dihydrocarvone with 99% and 86% de, respectively, which were further reduced to dihydrocarveols by a carbonyl reductase from Sporobolomyces salmonicolor SSCR or Candida magnolia CMCR. For (R)-carvone, (1S,2R,5R)-dihydrocarveol was produced as the sole product with >99% conversion, while (1S,2R,5S)-dihydrocarveol was obtained as the major product, but with a lower de when (S)-carvone was used as the substrate. The one-pot reduction was performed at a 0.1 M substrate concentration, indicating that it might provide an effective synthetic route to this type of chiral compound.     

New methodology for the synthesis of enantiopure (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]-pyridin-5-one: a synthesis of (S)-(+)-coniine

A new and efficient methodology for the enantiopure synthesis of (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one 3 starting from (1′R)-(−)-1-(2′-hydroxy-1′-phenyl-ethyl)-(1H)-pyridin-2-one 1 is described. In addition, the enantiospecific synthesis of (S)-(+)-coniine hydrochloride 6 in good yield from 3 is reported.     

Chemoenzymatic synthesis of (S)-2-cyanopiperidine,a key intermediate in the route to (S)-pipecolic acid and 2-substituted piperidine alkaloids

The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2-substituted piperidines. This synthesis is based on an enantioselective (R)-oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2-hydroxyhexanenitrile 1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(−)-coniine 10 and (S)-(−)-pipecolic acid 13 is also described.     

Microbial reduction of 2-(6-m-methoxyphenyl-3-oxohexyl)-2,4-dimethylcyclopenta-1,3-dione with Schizosaccharomyces pombe (NRRL Y-164)

A mixture of cis- and trans-2-(6-m-methoxyphenyl-3-oxohexyl)-2,4-dimethylcyclopenta-1,3-dione (±)-10 was synthesized and incubated with Schizosaccharomyces pombe (NRRL Y-164) to give (+)-11, (+)-12, (−)-13, and (−)-14 in 19, 13, 22, and 16% yields, respectively. Chromic acid oxidation of these microbiologically reduced products gave (−)-10a, (+)-10b, (+)-10a, and (−)-10b, respectively.     

Studies on Wittig rearrangement of furfuryl ethers in steroidal side chain synthesis

Wittig rearrangement of 17(20)-ethylidene-16-furfuryloxy steroids 5-8 was examined. Reaction of 17E(20)-ethylidene-16α-furfuryloxy steroid 5 with t-BuLi in THF afforded (20S,22S)- and (20S,22R)-22-hydroxy steroids 9, 10 and 17Z(20)-ethylidene-16α-(2-furyl)hydroxymethyl steroid 11 in 61, 28, and 9% yields, respectively. Base treatment of 17E(20)-ethylidene-16β-furfuryloxy steroid 7 gave (20R,22R)-22-hydroxy steroid 13 and 17Z(20)-ethylidene-16β-(2-furyl) hydroxymethyl steroid 14 in 60 and 17% yields. In contrast, 17Z(20)-ethylidene-16-furfuryloxy steroids 6, 8 led to the corresponding 2,3-rearranged products in low yields (25% for (20R,22S)-22-hydroxy steroid 12; 31% for (20S,22R)-22-hydroxy steroid 10). Both (20S,22S)- and (20S,22R)-22-hydroxy steroids 9, 10 were converted by catalytic hydrogenation into known compounds 16, 17, key intermediates for the synthesis of biologically active steroids.     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

Asymmetric [2,3] Wittig rearrangement of crotyl furfuryl ethers

Asymmetric Wittig rearrangement of crotyl furfuryl ethers was investigated in diastereo- and enantioselective manners. Both (2S,3Z)- and (2S,3E)-3-penten-2-yl furfuryl ethers 3 and 9 rearranged with complete chirality transfer to give the syn- and anti-isomers 4 and 10, respectively. Enantioselective Wittig rearrangement of both (Z)-and (E)-crotyl furfuryl ethers 15 and 17 using butyllithium and (−)-sparteine was examined to afford (1S,2R)-1-(2-furyl)-2-methyl-3-buten-ol 16 in up to 43% ee.     

Chemoenzymatic synthesis of enantiopure geminally dimethylated cyclopropane-based C2- and pseudo-C2-symmetric diamines

Enantiopure (−)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxamide 2 and (+)-(1R,3R)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylic acid 3 were easily obtained from a multigram scale biotransformation of racemic amide or nitrile in the presence of Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions. Coupled with efficient and convenient chemical manipulations, comprising mainly of the Curtius rearrangement, oxidation, and reduction reactions, chiral C₂-symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine 6 and ((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methanamine 8 and pseudo-C₂-symmetric (1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine 11 were prepared. These were also transformed into the corresponding chiral salen derivatives 12, 13, and 14, respectively, in almost quantitative yields.     

Enantioselective acylation of 2-hydroxymethyl-2,3-dihydrobenzofurans catalysed by lipase from Pseudomonas cepacia (Amano PS) and total stereoselective synthesis of (−)-(R)-MEM-protected arthrographol

Lipase Amano PS catalysed acylation of (±)-2-hydroxymethyl-2,3-dihydrobenzofurans using vinyl acetate as the acyl donor in n-hexane gave (−)-(R)-2-acetoxymethyl-2,3-dihydrobenzofurans and (+)-(S)-2-hydroxymethyl-2,3-dihydrobenzofurans in high enantiomeric excess. (−)-(R)-Acetate 18j is converted to (−)-(R)-MEM-protected arthrographol 22.     

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.     

Lipase-mediated partial resolution of 1,2-diol and 2-alkanol derivatives: towards chiral building-blocks for pheromone synthesis

1,2-Propanediol 5, 1-chloro-2-propanol 8 and its related 2-O-acetate 9 were partially resolved by chemoenzymatic acetylation and deacetylation, in the presence of Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-(−)-1-acetoxy-2-propanol 6, (R)-(+)-2-acetoxy-1-chloropropane 9 and (R)-(−)-1-chloro-2-propanol 8, respectively. On the other hand, treatment of (2RS)-2 with vinyl acetate in ether and Chirazyme^® L-2 gave 2-O-acetyl-1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-manno-non-5-ulo-5,9-pyranose 1 and 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-gluco-non-5-ulo-5,9-pyranose 11, respectively. Compound 10 was subsequently deacylated to 12. Both alcohols 11 and 12 were treated with Me₂CO/H⁺ to cause their rearrangement to (2S,5R,8R,9R,10S)-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3 and its (2R)-epimer 4, which closely matched the skeleton of the odour bouquet minor components of Paravespula vulgaris (L.).     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

(S)-(−)-α-Methylbenzylamine as an efficient chiral auxiliary in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine

(S)-(−)-α-Methylbenzylamine 2 was used as a chiral auxiliary in the enantiodivergent synthesis of simple isoquinoline alkaloids. The prochiral imine moiety in compound 4 was reduced with different reagents, giving diastereomeric amines 5a or 5b, which subsequently were transformed to either (S)-(−)-N-acetylcalycotomine 6 or (R)-(+)-N-acetylcalycotomine ent-6 in good enantiomeric excess. ¹⁹F NMR of its Mosher's acid ester was used to establish the purities of final compounds.     

A new route for the preparation of the 22,23-dioxocholestane side chain from diosgenin and its application to the stereocontrolled construction of the 22R,23S-diol function

The new (22R,23S,25R)-3β,16β,26-triacetoxy-cholest-5-ene-22,23-diol (11a) was synthesized from diosgenin (3) through a synthetic route based on chemoselective RuO₄ oxidation of (25R)-3β,16β-diacetoxy-23-ethyl-23¹,26-epoxycholesta-5,23(23¹)-dien-22-one (9) that afforded (20S,25R)-3β,16β,26-triacetoxycholest-5-ene-22,23-dione (10) which was stereoselectively reduced using NaBH₄. Compound 9 was obtained from the known isomeric 22,26-epoxycholest-5-ene steroidal skeleton 8b by treatment with p-TsOH in toluene, amberlyst-15 or directly from diosgenin by treatment with BF₃·OEt₂/Ac₂O. Chemoselective reduction of the 23-keto group of 10, was attained using NaBH₄/ZnCl₂ at −70 °C to give 23S-14. The NMR spectra of all compounds were unambiguously assigned based on one and two dimensional experiments and the C-22 and C-23 stereochemistry in the diacetate derivative 11b, as well as the structure of epoxycholestene 9 were further established by X-ray diffraction analyses. The new route for the functionalization of the side chain of diosgenin can find application in the synthesis of norbrassinosteroid analogues.