Synthesis of Optically Active Vicinal Fluorohydrins by Lipase-Catalyzed Deracemization

Abstract

Three microbial lipases have been used to deracemize trans-2-fluorocycloalkanols 2 both by hydrolysis of the corresponding acetates 3 or chloroacetates 4 and by esterification of the fluorohydrins 2 using vinyl acetate and vinyl chloroacetate, respectively. Pseudomonas cepacia lipase was the most selective for the six- and the seven-membered-ring compounds, while the lipase from Candida rugosa was most useful for the eight-membered-ring compounds. Both lipases transform the (R)-enantiomers preferentially. In contrast the lipase from Candida antarctica hydrolyzed the esters of trans-2-fluorocyclohexanol 2a and esterified the fluorohydrin itself with very low enantiopreference for the (R)-isomers. The seven- and the eight-membered ring esters and the corresponding fluorohydrins were also transformed with low, but reverse, enantioselectivity.

Ab initio calculations for the optical rotations of conformationally flexible molecules: A case study on six‐, seven‐, and eight‐membered fluorinated cycloalkanol esters

“…8 The absolute configuration of (−)−1, (−)−3, and (+)−4 was determined by application of the octant rule to the CD spectra. 8 In addition, the absolute configuration of a crystalline derivative of 1 was determined by X-ray structural analysis. 9 The optical rotations were measured in CHCl 3 (concentration about 1g/100 ml) of samples having >87% ee.…”

Regio- and stereoselective synthesis of vicinal fluorohydrins

“…Hydrolyses of the corresponding acetates or chloroacetates with the lipases mentioned showed the same enantiopreference and almost equal selectivity [110].…”

“…Furthermore, ring opening of cyclooctene oxide with Et 3 NÁ3HF gave exclusively trans-2-fluoro-cyclooctanol [110] after heating at 155 8C for 5 h. In contrast treatment of this epoxide with Olah's reagent at RT for 20 h gave a 5:60:30 mixture of the trans-1,2-fluorohydrin, the cis-1,4-fluorohydrin and cyclooct-4-enol (Scheme 34) [111].…”

“…In contrast, the lipase from C. antarctica (CAL) esterified trans-fluorocyclohexanol with very low enantiopreference for the (R)-enantiomer. The seven-and the eight membered fluorohydrins were also transformed with quite low, but reverse, enantioselectivity (Scheme 68) [110].…”

Synthesis of new ligands for targeting the S1P1 receptor

“…An enzyme-catalyzed kinetic resolution of the racemic allylic alcohols using Candida antarctica lipase provided the enantiomerically enriched (R)-alcohols. 17 After esterification with Boc-glycine the chelate ester enolate Claisen rearrangement proceeded with complete chirality transfer from C-3 of the allylic esters 8 and 9 to C-2 of the amino acids 10 and 11 due to the preferred lowest energy chair-like, six-membered transition state. 15 Thus, starting from the (R)-alcohols, the amino function is obtained in the correct configuration as compared to sphingosine.…”