Stereoselective synthesis of C19–C27 fragment of bryostatin 11

A convergent synthesis of C19–C27 fragment (2) of bryostatin-11 is described. The key steps involved in this approach are kinetic resolution, Grignard reaction, and Sharpless dihydroxylation. AIBN catalyzed radical cyclization strategy has been used for the first time to construct the six-membered pyran system.     

Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2-phenylethyl)oxirane

A short and efficient enantioselective synthesis of the HIV protease inhibitor amprenavir 1 (99% ee) as well as a formal synthesis of saquinavir 3 have been achieved in high enantiomeric purity starting from commercially available materials. Our strategy mainly comprises a Co-catalyzed two-stereocentred hydrolytic kinetic resolution (HKR) of racemic 2-(1-azido-2-phenylethyl)oxirane as the chirality inducing step. Also presented is a concise synthesis of (S)-3-hydroxytetrahydrofuran 4, the key structural feature, in high enantiomeric purity (98% ee).     

Enantioselective synthesis of (R)- and (S)-curcumene and curcuphenol: an efficient chemoenzymatic route

An efficient enantioselective synthesis of curcumene and curcuphenol is described. The key intermediates, substituted butanoates 7a and 7b and their acids 8a and 8b are obtained in high enantiopurity (>99% ee) by a lipase-catalyzed kinetic resolution process. The enantiopure intermediates thus obtained were utilized for the total synthesis of the target compounds.     

Chemoenzymatic synthesis of deoxy analogues of the DNA topoisomerase II inhibitor eleutherin and the 3C-protease inhibitor thysanone

The asymmetric synthesis of (−)-9-demethoxyeleutherin 6, (+)-9-demethoxyeleutherin 7 and (+)-7,9-deoxythysanone 8 has been achieved using a microwave assisted kinetic resolution of racemic alcohol 11 with Novozyme 435^® as the key step.     

Asymmetric synthesis of 1-hydroxyindolizidines, biosynthetic precursors to the toxic indolizidine alkaloids slaframine and swainsonine

An enantioselective synthesis of 1-hydroxyindolizidines (1 and 2) from racemic N-benzyloxycarbonyl-3-hydroxy-4-pentenylamine (3) by following the Sharpless kinetic resolution, intramolecular amidomercuration, and radical Michael addition as key steps is described.     

Studies on the chemoenzymatic synthesis of 3-phenyl-GABA and 4-phenyl-pyrrolid-2-one: the influence of donor of the alkoxy group on enantioselective esterification

A new chemoenzymatic method for the synthesis of enantiomerically pure 3-phenyl-γ-aminobutyric acid 1 and 4-phenyl-pyrrolid-2-one 9 based on the enzymatic kinetic resolution of 3-phenyl-4-pentenoic acid 2 is described herein. Enzymatic resolution of the racemic substrate provided products with good enantioselectivity upon esterification. In these reactions, a new class of alkoxy group donor—orthoesters, acetals and ketals were used. The best results of the enzymatic kinetic resolution were obtained for triethyl orthoacetate in toluene solvent.     

Stereocontrolled synthesis of the enantiomers of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one

The asymmetric synthesis of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one 1 is described. Enantiomers of compound 1 were obtained using the Sharpless asymmetric dihydroxylation (AD) or hydrolytic kinetic resolution (HKR) methods. The enantiomers of compound 1, which were obtained by HKR had higher enantiomeric excesses than those which were synthesized by AD and epoxidation. The enantiomeric purity of the synthesized compounds was determinated by capillary electrophoresis.     

Enantio- and diastereo-convergent synthesis of (2R,5R)- and (2R,5S)-Pityol through enzyme-triggered ring closure

A short chemoenzymatic synthesis of the (2R,5S)- and (2R,5R)-stereoisomer of the bark beetle pheromone Pityol 1 was achieved from (±)-Sulcatol 2 in an enantio- and diastereo-convergent fashion without the formation of any ‘unwanted’ stereoisomer. The key steps include: (i) lipase-catalyzed deracemization of (±)-2 using kinetic resolution coupled to an in-situ inversion or, alternatively, dynamic resolution using combined lipase- and Ru-catalysis; and (ii) creation of the second stereogenic center by an epoxide hydrolase-catalyzed diastereo-convergent hydrolysis of a haloalkyl oxirane, followed by spontaneous ring closure to form 1 in a stereoselective fashion.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Asymmetric dehydration of β-hydroxy esters via kinetic resolution

Catalytic asymmetric dehydration of β-hydroxy esters via kinetic resolution has been investigated. The kinetic resolution of rac-β-hydroxy esters in the presence of prolinol chiral ligand 2a and BrZnCH₂CO₂t-Bu can provide highly enantioenriched β-hydroxy esters 3 and 5-11 with selectivity factors ranging from 15 to 42.     

A short synthesis of (+) and (−)-falcarinol

A short, practical synthesis of the bis-acetylenic natural product falcarinol 1 is reported. This method relies on the alternate functionalisation of bis-trimethylsilylbutadiyne 10. This may be achieved in one-pot, however, better yields were obtained more conventionally. Lipase mediated enzymatic kinetic resolution of the racemic adduct in an organic solvent afforded (+)-1 in 97% enantiomeric excess. The analogous process performed with racemic 3-acetoxy falcarinol 11 under aqueous conditions gave (−)-1. Oxidation of 1 with Dess-Martin periodinane gave falcarinone 2.     

Unified approach to the sesquiterpenoids,lauranes and cyclolauranes: Total synthesis of (±)-isolaurene

A general approach to the total synthesis of sesquiterpene, isolaurene (1a) and cyclolaurene (2a) is featured from commercially available 3-methyl cyclopenten-2-one. The strategy includes a Stork-Danheiser sequence concomitant with a Ni(II)-catalyzed conjugate addition of methyl group onto 3-aryl 2-methyl cyclopenten-2-one to afford the advanced intermediate 11. A methyllithium addition onto compound 11 with an eventual dehydration completed the total synthesis of isolaurene (1a) in 5 steps (58.3% overall yields).     

Enantioselective synthesis of (R)- and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution: application to the synthesis of reboxetine analogs

The (R)- and (S)-N-Boc-morpholine-2-carboxylic acids 9 and 10 were prepared using an enantioselective synthesis employing a highly selective enzyme-catalyzed kinetic resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (11) as the key step. Acids 9 and 10 were then converted efficiently and stereoselectively to reboxetine analogs 3 and 4.     

Enantioselective addition of diethylzinc to aldehydes using novel axially chiral 2-aminomethyl-1-(2′-hydroxyphenyl)naphthalene catalysts

The synthesis of atropo-enantiomerically pure aminomethyl and hydroxymethyl substituted biaryls derivatives M-2 and M-3 (and, optionally, their enantiomers), by dynamic kinetic resolution of a racemic lactone precursor, is described. Their application as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes leads to excellent enantiomeric ratios of up to 99:1 and high chemical yields.     

Chemoenzymatic synthesis of piperoxan,prosympal, dibozane,and doxazosin

The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (±)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee ～99%, E = 535) at 258 mmol (50 g/L) substrate concentration.     

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to α-ketoxime-ether acetal 9 bearing chiral auxiliary on the α-carbonyl function gave benzyloxyamine 11 major in 83% yield with 82% de, which was converted to the corresponding amino ketone 12. However, the reaction of 2-chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an alternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance, was designed in which the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cyanate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1 with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy.     

Stereoselective synthesis of 5′-hydroxyzearalenone

A first stereoselective total synthesis of 14-memebered β-resorcylic macrolactone 5′-hydroxyzearalenone (1) has been achieved. The key steps are Jocobsen hydrolytic kinetic resolution, Sharpless asymmetric dihydroxylation, Vilsmeier-Haack reaction, Mitsunobu esterification and ring-closing metathesis.     

Synthesis and biocatalytic resolution of a new atropisomeric thiobiphenyl: (2,2′,6,6′-tetramethoxybiphenyl-3,3′-diyl)dimethanethiol

Both atropisomers of racemic thiobiphenyl (±)-1 were obtained in enantiopure form using lipase catalysed procedures. The esterification reaction of (±)-1 in the presence of vinyl acetate gave in a one-pot reaction (+)-1 and (−)-1 via a lipase assisted dynamic kinetic resolution of epimerizing hemithioacetal intermediates. The alcoholysis of the diacetylthioester, (±)-5, is an alternative strategy for access to the enantiomers of 1 with high enantiomeric excess.     

Synthesis of 8-deoxypumiliotoxin 193H and 9-deoxyhomopumiliotoxin 207O

The asymmetric synthesis of 8-deoxypumiliotoxin 193H and 9-deoxyhomopumiliotoxin 207O has been achieved, starting from both enantiomers of (+)- and (?)-10. Enantiomerically pure alcohols (+)- and (?)-10 were obtained by lipase-mediated kinetic resolution of racemic 10, which was prepared in 3 steps from new lactam-type building block (?)-8 in a highly stereoselective manner.     

Stereoselective synthesis of 4-hydroxy-2-phenylproline framework

Highly diastereoselective (>20:1) bromo-lactonization of N-sulfonyl-2-allyl-2-phenylglycine methyl ester (11) was observed. Successive treatment of the chiral lactone with MeONa gave the desired (2S,4R)-4-hydroxy-2-phenylproline derivative in high yield without erosion of the diastereoselectivity. The starting chiral non-racemic compound (5) was prepared from the racemic 2-phenylglycine using a classical kinetic resolution (crystallization), an asymmetric phase transfer alkylation, and an enzyme-catalyzed kinetic resolution.