To help organic chemists use enzymes as synthetic reagents, guidelines are needed to help them choose an appropriate enzyme. / We proposed reliable empirical substrate rules that predict the stereochemical outcome of reactions catalyzed by hydrolases. These rules, developed through a combination of substrate screening and literature surveys, are based on the difference in size of the substituents at the stereocenter of substrates. One proposed rule predicts the enantiopreference of cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugosa towards secondary alcohols and their esters. / A similar rule is proposed to predict the enantiopreference of subtilisins towards isosteric primary amines of the type NH2CHRR' . The enantiopreference of lipases towards primary amines and of subtilisins toward secondary alcohols is reviewed. Lipases and subtilisins have opposing enantiopreferences towards both secondary alcohols and primary amines. We also observed that the regioselectivity of subtilisin is opposite to that of lipases. We offer a rationalization to explain these opposing selectivities, based on known crystal structures of lipases and subtilisin. / A similar rule is also found to predict the enantiopreference of lipase from Pseudomonas cepacia towards primary alcohols; this rule excludes substrates having an oxygen atom directly attached to the stereocenter. The favored enantiomer of primary alcohols is opposite to the favored enantiomer of secondary alcohols. Experiments conducted on substrates with two stereocenters and molecular modeling studies suggest that both classes of alcohols bind in the same regions of the active site. / We proposed a method to enhance enantioselectivity of lipases and esterases towards secondary alcohols. This technique, based on increasing the difference in size of the substituents at the stereocenter, was successfully applied to the preparation of two useful chiral synthons: (S)-(-)-4-acetoxy-2-cyclohexen-1-one and esters of (R)-lactic acid. / Using a similar approach, we designed a synthetic scheme for the preparation of both enantiomers of a useful C2-symmetric synthon. The key step is an acylation reaction catalyzed by lipase from Candida rugosa. (1R,4R)- and (1S,2 S)-bicyclo[2.2.1]heptan-2,5-diones were obtained with high optical purity.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37601 |
| Date | January 1999 |
| Creators | Weissfloch, Alexandra N. E. |
| Contributors | Kazlauskas, R. J. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Chemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001747902, proquestno: NQ64691, Theses scanned by UMI/ProQuest. |
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