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Epoxide Hydrolase‐Catalysed Kinetic Resolution of a Spiroepoxide, a Key Building Block of Various 11‐Heterosteroids
Author(s) -
Bottalla AnneLise,
IbrahimOuali Malika,
Santelli Maurice,
Furstoss Roland,
Archelas Alain
Publication year - 2007
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.200600535
Subject(s) - chemistry , enantiopure drug , kinetic resolution , enantiomer , substrate (aquarium) , regioselectivity , stereochemistry , enantiomeric excess , epoxide , hydrolysis , enantioselective synthesis , organic chemistry , catalysis , oceanography , geology
Two microbial epoxide hydrolases – i.e., Aspergillus niger ( An EH) and Rhodococcus erythropolis (the so‐called “Limonene EH”: LEH) were used to achieve, for the first time, the biocatalysed hydrolytic kinetic resolution (BHKR) of spiroepoxide rac ‐ 1 . This compound is a strategic key building block allowing the synthesis of 11‐heterosteroids. Interestingly enough, the two enzymes exhibited opposite and therefore complementary enantioselectivity allowing us to isolate the residual ( R,R )‐ 1 (from An EH) and the residual ( S,S )‐ 1 (from LEH) in nearly enantiopure forms (>98 %). Their absolute configurations were determined by X‐ray crystallography. An opposite regioselectivity of the oxirane ring opening for both enantiomers of substrate 1 , determined using H 2 18 O labelling and chiral GC‐MS analysis, was also observed, corresponding to an attack at the less substituted carbon atom using An EH, and at the most substituted carbon atom using LEH. A chemical process‐improving methodology was also developed. This allowed us to obtain both enantiomers of the substrate in high enantiomeric purity (99 %) and optimised quantity. In the case of the An EH, the use of a biphasic (water/isooctane) reaction medium allowed us to increase the global substrate concentration up to 200 g/ L. The preparation of both enantiomers of 1 clearly paves the way to the preparative scale synthesis and biochemical evaluation of the corresponding 11‐heterosteroid enantiomers.