Enantiopure building blocks for the synthesis of 3-methyl-2-alkanols. Diastereoselective methylmetal addition to a chiral 2-methylaldehyde followed by lipase catalysed esterification

• The racemic synthetic building block (2R*,3R*)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R*,3R*)-2 was obtained in a high diastereomeric ratio [95:5, (2R*,3R*)/(2R*,3S*)-ratio] by Lewis acid catalysed dimethylzinc addition to racemic 2-methyl-3-(phenylsulfanyl)propanal (rac-1). Two consecutive acylations with vinyl acetate catalysed by Chirazyme L-2 (immobilised Candida antarctica lipase 13, CAL-B) led to preferential esterification of three of the four stereoisomers leaving (2S,3S)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2S,3S)-2 of 98:2 dr and 98% ee. The stereoisomerically impure acetate of (2R,3R)-3-methyl-4-(phenyisulfanyl)butan-2-ol (2R,3R)-2, obtained in the first CAL-B-catalysed acylation step, was hydrolysed and reesterified using CAL-A (immobilised Novozyme SP 525) as the catalyst, which left (2R,3R)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R,3R)-2 of 98:2 dr and 99% ee as the remaining substrate. The individual enantiomers of 2-methyl-3-(phenylsulfanyl)propanal 1 were prepared from readily available (S)- and (R)-3-hydroxy-2-methylpropanoic acid methyl ester and reacted with dimethylzinc to give both enantiomers of (2R*,3R*)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R, 3R)- or (2S,3S)-2 of both high dr and ee. These products were purified by lipase catalysed acylation to give the enantiomerically and diastereomerically highly pure enantiomers (>99.5:0.5 dr, >99.9% ee). Pure (2S,3S)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2S,3S)-2 was transformed into a potential pheromone precursor isolated from some pine sawflies of the genus Gilpinia, (2S,3R)-3-methylpentadecan-2-ol in 54% yield over eight steps.

Subject headings

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

TEKNIK OCH TEKNOLOGIER  -- Industriell bioteknik (hsv//swe)

ENGINEERING AND TECHNOLOGY  -- Industrial Biotechnology (hsv//eng)

Keyword

hypophosphite combination system

enantioselective total synthesis

candida-antarctica lipase

sex-pheromone

secondary alcohols

raney-nickel

reductive desulfurization

macrodiprion-nemoralis

microdiprion-pallipes

neodiprion-sertifer

Chemistry

Kemi

Bioengineering

Publication and Content Type

ref (subject category)

art (subject category)