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Experimental and Computation Studies on Candida antarctica Lipase B‐Catalyzed Enantioselective Alcoholysis of 4‐Bromomethyl‐β‐lactone Leading to Enantiopure 4‐Bromo‐3‐hydroxybutanoate
Author(s) -
Lim Jung Yun,
Jeon Nan Young,
Park AReum,
Min Bora,
Kim Bum Tae,
Park Seongsoon,
Lee Hyuk
Publication year - 2013
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201200901
Subject(s) - chemistry , enantiopure drug , candida antarctica , lactone , steric effects , enantioselective synthesis , kinetic resolution , stereochemistry , enantiomer , stereocenter , substituent , lipase , organic chemistry , catalysis , enzyme
Both enantiomers of optically pure 4‐bromo‐3‐hydroxybutanoate, which is an important chiral building block in the syntheses of various biologically active compounds including statins, were synthesized from rac ‐4‐bromomethyl‐β‐lactone through kinetic resolution. Candida antarctica lipase B (CAL‐B) enantioselectively catalyzes the ring opening of the β‐lactone with ethanol to yield ethyl ( R )‐4‐bromo‐3‐hydroxybutanoate with high enantioselectivity ( E >200). The unreacted ( S )‐4‐bromomethyl‐β‐lactone was converted to ethyl ( S )‐4‐bromo‐3‐hydroxybutanoate (>99% ee ), which can be further transformed to ethyl ( R )‐4‐cyano‐3‐hydroxybutanoate, through an acid‐catalyzed ring opening in ethanol. Molecular modeling revealed that the stereocenter of the fast‐reacting enantiomer, ( R )‐bromomethyl‐β‐lactone, is ∼2 Å from the reacting carbonyl carbon. In addition, the slow‐reacting enantiomer, ( S )‐4‐bromomethyl‐β‐lactone, encounters steric hindrance between the bromo substituent and the side chain of the Leu278 residue, while the fast‐reacting enantiomer does not have any steric clash.