Deracemisation of β-hydroxy esters using immobilised whole cells of Candida parapsilosis ATCC 7330: substrate specificity and mechanistic investigation

Deracemisation of aryl substituted β-hydroxy esters by immobilised whole cells of Candida parapsilosis ATCC 7330 gave >99% ee and up to 75% yield of their corresponding (S)-enantiomers. Mechanistic investigation of the deracemisation reaction carried out using a deuterated substrate, ethyl 3-deutero-3-hydroxy-3-phenyl propanoate revealed that while the (S)-enantiomer remains unreacted the (R)-enantiomer undergoes enantioselective oxidation to its corresponding ketoester, which on complementary enantiospecific reduction gives the (S)-enantiomer in high yield and % ee.     

Enzymatic resolution of (RS)-1-phenylalkyl β-d-glucosides to (R)-1-phenylalkyl β-primeverosides and (S)-1-phenylalkyl β-d-glucosides via plant xylosyltransferase

The stereoselective xylosylation of (RS)-1-phenylalkyl β-d-glucosides was investigated using plant xylosyltransferase isolated from cultured Catharanthus roseus cells. Enzymatic xylosylation of (RS)-1-phenylethyl β-d-glucoside afforded (R)-1-phenylethyl β-primeveroside and (S)-1-phenylethyl β-d-glucoside. The (R)-selective xylosylation of (RS)-1-phenylbutyl β-d-glucoside also occurred to give (R)-1-phenylbutyl β-primeveroside and recovered (S)-1-phenylbutyl β-d-glucoside.     

Mechanistic investigation of the Candida albicans CCT 0776 stereoinversion system and application to obtain enantiopure secondary alcohols

Phenylethanol deracemization with Candida albicans CCT 0776 whole cells yields the (R)-enantiomer in over 99% enantiomeric excess and 98% yield. The deracemization process involves, in the first step, a fast, highly (S)-selective oxidation (NADP and O₂ dependent) and, in the second step, a slower partially (S)-selective reduction (NADH dependent) of the intermediate ketone. The process was extended to other 2-alkanols, 1,2-diols and 1,3-diols and, with the exception of 1,3-diol (unreactive), the enantiomeric excess and yield of the deracemization were about 99% and 62–98%, respectively.     

A biocatalytic one-pot oxidation/reduction sequence for the deracemisation of a sec-alcohol

Biocatalytic deracemisation via inversion of rac-2-decanol was accomplished by a combined oxidation/reduction sequence using the same ‘single’ catalyst for both steps. Overall, the (R)-alcohol was inverted to the corresponding (S)-alcohol. Lyophilised cells of various Rhodococci spp. were tested for the unselective oxidation of the racemic sec-alcohol using acetone as the hydrogen acceptor in the first step. For the second step, the stereoselective asymmetric reduction of the corresponding ketone, 2-propanol was employed as the hydrogen donor. Employing lyophilised cells of Rhodococcus sp. CBS 717.73 racemic 2-decanol was transformed to (S)-2-decanol with excellent enantiomeric excess (92% ee) and yield (82% isolated yield) in the combined one-pot oxidation/reduction sequence.     

Synthesis of some new tertiary amines and their application as co-catalysts in combination with l-proline in enantioselective Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone

A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl l-prolinate hydrochloride. Diastereomeric (1R,2R,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3a and (1S,2S,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-α-phenylethylamine and cyclohexene oxide via ring-opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazin 5 was synthesized from methyl l-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of l-proline. The corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.     

Stereoselective chemoenzymatic synthesis of sitophilate: a natural pheromone

The aggregation pheromone of the granary weevil Sitophilus granarius, (2S,3R)-1-ethylpropyl 3-hydroxy-2-methylpentanoate, has been synthesized in 63% total isolated yield and high chemical and enantiomeric purity (98% de, >99% ee) from readily available methyl 3-oxopentanoate. A stereoselective ketone reduction followed by an ester hydrolysis, were the two key steps of the synthesis and were both performed by commercially available enzymes.     

Towards enantiomeric 2,3-epoxypropylphosphonates

Hydrolysis of diethyl 2,3-epoxypropylphosphonate in the presence of (R,R)-salen–Co(III)-OAc after 19 h afforded a mixture of (S)-epoxide (82% ee) and diethyl (R)-2,3-dihydroxypropylphosphonate (98% ee). Improved enantiomeric excess (93%) of the (S)-epoxide was obtained in the 72 h hydrolytic kinetic resolution experiment. Acid-catalyzed hydrolysis of (S)-epoxide (91% ee) gave (S)-diol (72% ee) due to low C-3 regioselectivity of the reaction.     

Resolution approaches to enantiomers of 4-formyl[2.2]paracyclophane

Three techniques for the resolution of 4-formyl[2.2]paracyclophane were examined with the separation of the diastereomeric derivatives with (R)- and (S)-2-hydrazino-2-oxo-N-(1-phenylethyl)acetamide followed by their hydrolysis being found to be the most efficient, allowing (Rp)- and (Sp)-4-formyl[2.2]paracyclophanes to be obtained with 99.5% and 98.7% ee, respectively.     

Synthesis of four enantiomers of 2-acetamido-1-hydroxypropylphosphonates

Enantiomerically pure diethyl 2-acetamido-1-hydroxypropylphosphonates were synthesised from N-[(R)-(1-phenylethyl)]aziridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes via phosphonylation followed by acetylation of the hydroxy groups and the simultaneous hydrogenolytic cleavage of the aziridine rings and the removal of the chiral auxiliaries. In addition, enantiomerically pure diethyl (1S,2R)- and (1R,2S)-2-amino-1-hydroxypropylphosphonates (the phosphonate analogues of isothreonine) were separated.     

A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions

A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N¹-n-pentyl, N¹-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-β-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively.     

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).     

Synthesis of (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol,the aggregation pheromone of the ambrosia beetle Platypus quercivorus,its racemate, (1R,4R)- and (1S,4S)-isomers

(S)-Perillyl alcohol was converted to (R)-cryptone (91.5–93% ee) in six steps, which was then treated with methyllithium to give (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol, the aggregation pheromone of the ambrosia beetle Platypus quercivorus. The racemic pheromone was also prepared by methylation of (±)-cryptone. Both (1R,4R)- and (1S,4S)-isomers (98% ee) of the pheromone were synthesized from the enantiomers of dihydrolimonene oxide.     

Organocatalysis of asymmetric aldol reaction in water: comparison of catalytic properties of (S)-valine and (S)-proline amides

(S)-Valine amides containing (S)- or (R)-α-phenylethyl substituents at N¹ atom efficiently catalyze asymmetric aldol reactions between cyclic (heterocyclic) ketones and aromatic aldehydes in water, predominantly giving rise to the aldol anti-diastereomers in high yields (up to 98%) and enantiomeric excess (up to 94%).     

Microbial Baeyer–Villiger oxidation applied to the synthesis of the N-protected (1R,5R)-Geisman–Waiss lactone

Using whole cell Baeyer–Villiger biooxidation as a key step and depending on the choice of the biocatalyst {E. coli TOP10[pQR239] or Acinetobacter TD63}, the synthesis of nearly enantiopure N-protected (1R,5R)-(−)-Geisman–Waiss lactone (92% ee) or its (1R,5S)-(−) regioisomer (98% ee) be performed.     

Enantioselective enzymatic acylation of 1-(3′-bromophenyl)ethylamine

An efficient biocatalytic process has been developed for the resolution of 1-(3′-bromophenyl)ethylamine (RS)-1 by way of enantioselective lipase-mediated (R)-selective acylation with ethyl 2-methoxyacetate to afford (S)-amine (S)-1 and (R)-2″-methoxyacetamide ((R)-2) in 91–95% and 90–92% isolated yield, respectively, and both with >99% ee.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

Practical and highly stereoselective method for the preparation of several chiral arylsulfinamides and arylsulfinates based on the spontaneous crystallization of diastereomerically pure N-benzyl-N-(1-phenylethyl)-arylsulfinamides

A novel and simple process for the preparation of enantiomerically pure (S_S)-benzenesulfinamide (S_S)-3a, (S_S)-p-toluenesulfinamide (S_S)-3b, (S_S)-p-chloro-benzenesulfinamide (S_S)-3c and (S_S)-p-fluorobenzenesulfinamide (S_S)-3d has been developed. The treatment of arylsulfinyl chlorides with (R)-N-benzyl-1-phenylethanamine in the presence of excess triethylamine gave diastereomeric mixtures of N-benzyl-N-(1-phenylethyl)-arylsulfinamides 1, which underwent spontaneous crystallization to furnish diastereomerically pure (R,S_S)-N-benzyl-N-(1-phenylethyl)-arylsulfinamides (R,S_S)-1a-1d in 28%, 29%, 27% and 31% yields, respectively. The diastereomerically pure compounds (R,S_S)-1 were then converted into four enantiopure (R_S)-methyl arylsulfinates (R_S)-2, and finally into four enantiopure (S_S)-arylsulfinamides (S_S)-3 in good yields.     

Dithiophosphorylation of racemic and enantiomerically pure 1-phenylethanamines

N,N′-Bis[(RS)-, (S)-, and (R)-1-phenylethyl]phosphorodiamidodithioic acids were synthesized by reactions of racemic and enantiomerically pure 1-phenylethanamines with tetraphosphorus decasulfide.     

Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines

An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (±)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively.