Total production of (R)-3,5-bistrifluoromethylphenyl ethanol by asymmetric reduction of 3,5-bis(trifluoromethyl)-acetophenone in the submerged culture of Penicillium expansum isolate

A total of 82 fungal isolates were screened for their ability to reduce 3,5-bis(trifluoromethyl)-acetophenone 1. Penicillium expansum was found to successfully reduce ketone 1 in the submerged culture. A second screening was performed on the active P. expansum strains identified by the first screening. A number of strains of P. expansum were found to produce (R)-3,5-bistrifluoromethylphenyl ethanol 2 with over 99% enantiomeric excess (ee) from ketone 1. The most productive strain was identified as P. expansum EBK-9, and this strain was selected for further experiments. The total production of 2 was carried out by P. expansum EBK-9 in a laboratory-scale bioreactor employing optimized conditions as determined by our experiments. P. expansum EBK-9 gave 2 with ee >99% and 76% yield. On a large scale, a total of 3.35 g/L of 2 was produced from 1 after 56 h.     

Scalable,efficient process for the synthesis of (R)-3,5-bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex

(R)-3,5-Bistrifluoromethylphenyl ethanol 2, a key building block in the synthesis of aprepitant, has been synthesized from ketone 5 via catalytic asymmetric transfer hydrogenation using a simplified catalyst generation procedure. The process uses (1S,2R)-cis-1-aminoindan-2-ol 10 and dichloro(p-cymene)Ru(II)dimer 9 as the chiral ligand and metal source for the reduction. While the reduction provides 2 in 90–92% ee, an isolation of 2 as a 2:1 inclusion complex with DABCO was developed to allow for the upgrade of the enantiomeric excess to >99%.     

(-)-(S)-Nakinadine B: first asymmetric synthesis

(-)-(S)-Nakinadine B has been synthesized for the first time (in 9 steps and 17% overall yield from commercially available atropic acid) using the conjugate addition of lithium dibenzyl-amide to an N-α-phenylacryloyl SuperQuat derivative with in situ diastereoselective enolate protonation as the key step.     

Enantioselective synthesis of (S)-salmeterol via asymmetric reduction of azidoketone by Pichia angusta

An efficient enantioselective route to (S)-salmeterol involving asymmetric reduction of an azidoketone intermediate to an azido alcohol by Pichia angusta is described.     

Concise asymmetric synthesis of (5S, 6S)- aeginetolide and (5S)- dihydroactinidiolide

An asymmetric deprotonation reaction allows for short syntheses of the lactones (5S, 6S)- Aeginetolide (1) and (5S)-Dihydroactinidiolide (2).     

Simultaneous enzymatic synthesis of (S)-3-fluoroalanine and (R)-3-fluorolactic acid

A coupled enzymatic system for the simultaneous synthesis of (S)-3-fluoroalanine (1a) and (R)-3-fluorolactic acid (3) with l-alanine dehydrogenase (l-AlaDH) from Bacillus subtilis and rabbit muscle l-lactate dehydrogenase (l-LDH) using rac-1 and NAD⁺ is described. Analysis of isolated products of the laboratory preparative scale process revealed 1a in 60% yield and 88% ee and 3 in 80% yield and over 99% ee. The compounds 1a and 3 represent chiral building blocks for the synthesis of several products with pharmacological activity.     

Total synthesis of (-)-alpha-kainic acid by (-)-sparteine-mediated asymmetric deprotonation-cycloalkylation

[reaction: see text] We report a new enantioselective synthesis of (-)-alpha-kainic acid from d-serine methyl ester hydrochloride, based on a (-)-sparteine-mediated asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti S(N)'S(E)' intramolecular cycloalkylation, leads to the pyrrolidine ring precursor of (-)-alpha-kainic acid, in high yield and diastereoselectivity. The intermediate pyrrolidine was further transformed to (-)-alpha-kainic acid in three steps.     

First chemoenzymatic synthesis of (R)- and (S)-1-(9H-fluoren-9-yl)ethanol

A simple chemoenzymatic synthesis of 1-(9H-fluoren-9-yl)ethanol stereoisomers is described. The enantiomers were resolved by a kinetically controlled transesterification with vinyl acetate in the presence of commercially available lipases. High-throughput screening and subsequent exhaustive investigation of the utility of the lipases in a stereoselective process of introducing chirality have been carried out. Lipase A from Candida antarctica as a cross-linked aggregate (CAL-A-CLEA) was the most efficient enzyme for the resolution of the title compound providing (S)-1-(9H-fluoren-9-yl)ethanol and its (R)-acetate in enantiopure form (>99% ee). Under mild reaction conditions, excellent enantioselectivity (E = 407), and good isolated yields of the products were obtained.     

Photomediated asymmetric synthesis of (-)-cuparene

Generation of a benzylic quaternary stereocentre via the photomediated cyclisation of a chiral alpha-(aminobutyl)styrene followed by a microwave-assisted Cope elimination has led to a total synthesis of the sesquiterpene (-)-cuparene.     

Concise asymmetric synthesis of (-)-sparteine

A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an alpha,beta-unsaturated amino ester.     

Improved chemoenzymatic asymmetric synthesis of (S)-Rivastigmine

(S)-Rivastigmine [(S)-1] was obtained via a four-step synthesis using an asymmetric enzymatic transamination protocol as the key step. An early introduction of the carbamate pharmacophore side chain avoided the use of protective group strategies and hence led to a considerable shortcut. This strategy required a novel ω-transaminase from Paracoccus denitrificans, which could transform the highly polar key substrate 3-acetylphenyl ethyl(methyl)carbamate (4) to the corresponding amine (S)-5 in 99% ee and >80% conversion.     

Improved asymmetric synthesis of aziridine 2-phosphonates using (S)-(+)-2,4,6-trimethylphenylsulfinamide

The aza-Darzens reaction of lithium diethyl iodomethylphosphonate with enantiopure N-(2,4,6-trimethylphenylsulfinyl)imines affords a single diastereomeric N-sulfinylaziridine 2-phosphonate which, on treatment with MeMgBr, gives the corresponding NH-aziridine 2-phosphonate chiral building blocks. An improved asymmetric synthesis of (S)-(+)-2,4,6-trimethylphenylsulfinamide is also given.     

A novel synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by sharpless asymmetric epoxidation method

Synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by the Sharpless asymmetric epoxidation reaction has been achieved. 2,4,5-Trifluorobenzaldehyde with methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate gave methyl (E)-3-(2,4,5-trifluorophenyl)acrylate in 83% yield. The reduction of ester group with DibalH followed by Sharpless asymmetric epoxidation gave ((2R,3R)-3-(2,4,5-trifluorophenyl)oxiran-2-yl)methanol. Pd/C-catalyzed hydrogenation of epoxy alcohol furnished (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >90% ee and 71% yield.     

Biomimetic synthesis of (+/-)-galanthamine and asymmetric synthesis of (-)-galanthamine using remote asymmetric induction

(+/-)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol coupling of N-(4-hydroxy)phenethyl-N-(3',4',5'-trialkoxy)benzyl formamide (15b) as a key step. Because of the symmetrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole coupling product except for volatile components from the oxidizing agent. On the basis of the successful results of the above strategy, (-)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction, where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C-N bond of the tri-O-alkylated gallyl amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry for the synthesis of (-)-1.     

A concise asymmetric synthesis of (-)-rasfonin

A very efficient total synthesis of the apoptosis inducer (-)-rasfonin has been developed using CuBr/JosiPhos catalyzed iterative asymmetric conjugate addition of MeMgBr and Feringa's butenolide.     

Divergent asymmetric synthesis of 3,5-disubstituted piperidines

A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently obtained from N-benzylglycinate in five steps by the use of chemoenzymatic methods. In the subsequent enzyme- and Ru-catalyzed reaction, the rac/meso diol mixture was efficiently transformed to the cis-(3R,5S)-diacetate with excellent diastereoselectivity and in high yield. Further transformations of the cis-diacetate selectively delivered the cis-piperidine diol and the cis-(3R,5S)-hydroxy acetate. Alternatively, the DYKAT could be stopped at the monoacetate stage to give the trans-(3R,5R)-hydroxy acetate.     

Microbial and homogenous asymmetric catalysis in the reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone

Two complementary approaches for the enantioselective reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone 1 are described and compared: microbial versus asymmetric reduction of ketones through asymmetric hydrogen transfer. Among the various microorganisms screened, Lactobacillus kefir and Aspergillus niger reduced ketone 1 to the corresponding (R)-alcohol (R)-2. The (S)-alcohol (S)-2 was obtained by reduction of 1 using homogenous asymmetric catalysis. The configuration of the alcohol in both the biocatalysis and hydrogen transfer approaches was controlled by the choice of the enzyme and by the configuration of ligands, respectively. Both enantiomers were obtained in high yield and ee.     

Short asymmetric synthesis of (-)- and (+)-cis-lauthisan

The asymmetric synthesis of both enantiomers of cis-lauthisan (3) is achieved in only six steps from diethyl pimelate (4), the key steps being the diastereodivergent reduction of beta-ketosulfoxide 7 and the highly cis-stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization of enantiopure hydroxy sulfinyl ketones (S)-14 and (R)-14.     

An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.