عنوان

Hydrolase-catalyzed resolutions of enantiomers

Number

TLpq230607824

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

Hydrolase-catalyzed resolutions of enantiomers

General Material Designation

[Thesis]

First Statement of Responsibility

A. N. Serreqi

Name of Publisher, Distributor, etc.

McGill University (Canada)

Date of Publication, Distribution, etc.

1995

Specific Material Designation and Extent of Item

155

Dissertation or thesis details and type of degree

Ph.D.

Body granting the degree

McGill University (Canada)

Text preceding or following the note

1995

Text of Note

Enantiomerically-pure compounds are becoming increasingly important particularly to the pharmaceutical industry. Enzymes are useful tools in the synthesis of such compounds. To better understand how lipases discriminate between enantiomers of chiral secondary alcohols we obtained x-ray crystal structures of covalent complexes of Candida rugosa lipase with the transition-state analogs (1R)-menthyl hexylphosphonate and (1S)-menthyl hexylphosphonate. These compounds are transition-state analogs for the hydrolysis of menthyl esters. We observed that the transition-state analog of the unfavored (1S)-enantiomer of menthol disrupted the hydrogen bond between Nusd\varepsilonusd2 of histidine 449 and the menthol oxygen. His 449 is part of the catalytic triad in CRL. This may account for the slower reaction of the (1S)-enantiomer of menthol. The crystal structures also identified binding site regions for secondary alcohols in CRL. These regions are common among many lipases and esterases and account for their common enantiopreference toward secondary alcohols. Lipases and esterases can resolve compounds with phosphorus and sulfur stereocenters by hydrolysis of a pendant acetoxy group. Both CRL and cholesterol esterase have high selectivity for (2-acetoxy-1-naphthyl)methylphenylphosphine oxide. They resolved this substrate with and E of 81 and 32 respectively. A synthetic scale resolution of this substrate with subsequent recrystallization and chemical transformation followed by stereospecific reduction gave both enantiomers of (2-methoxy-1-naphthyl)methylphenyl-phosphine with 96-97% ee. This chiral phosphine is potentially useful in asymmetric syntheses. CE is the most selective enzyme for the sulfur substrates tested but these enantioselectivities were moderate, E's ranged from 5 to 25. From the CE resolution of the phosphorus and sulfur compounds and others we propose an empirical model that predicts which enatiomer reacts faster. The model is based on the size of the substituents and their conformational preferences. Crude Aspergillus niger resolves esters of pipecolic acid with an E of 20 4. A simple partial purification of ANL by fractional precipitation with ammonium sulfate increased the enantioselectivity to >100. The partially purified ANL can be used in a synthetic scale resolution of ()-n-octyl pipecolate to give (S)-()-pipecolic acid (93% ee) and (R)-(+)-pipecolic acid (97% ee).

Pharmacology

Pure sciences

A. N. Serreqi

Electronic name

p

[Thesis]

276903

a

Y