Chemoenzymatic synthesis of enantiopure 1,4-dihydropyridine derivatives

• Main Author: Sobolev, A.
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: 2003
• Subjects: derivatives; enantiomers; enzyme activity; pyridines; synthesis; derivaten; enantiomeren; enzymactiviteit; synthese; Antarc*; Antarctica
• Online Access: https://research.wur.nl/en/publications/chemoenzymatic-synthesis-of-enantiopure-14-dihydropyridine-deriva

Chirality is important for the activity of many biologically active compounds, since differences in biological properties of stereoisomers occur frequently. The exact stereochemical composition of each new chiral compound as well as toxicological and pharmacological data for racemic and enantiomerically pure compounds are required for their approval as new chiral medicines in the EU.The research described in this thesis deals with the chemoenzymatic synthesis of 1,4-dihydropyridine derivatives (1,4-DHPs) in enantiopure form as the key intermediates for chiral analogues of symmetrical biologically active compounds. The use of enzymes is an advantageous alternative to classical chemical methods, as enzymes are efficient catalysts with high chemo-, regio- and stereoselectivity under mild conditions.In Chapter 1, a literature review is given about the synthesis of 1,4-dihydropyridine derivatives, and their biological activities. Synthesis of 1,4-DHPs by cyclocondensation reactions and reduction of pyridines are described whereby special attention is paid to stereoselective chemical and biotechnological methods for the synthesis of enantiopure 1,4-DHPs.Derivatives of bis(ethoxycarbonylmethyl) 1,4-dihydropyridine-3,5-dicarboxylates have shown antimetastatic activities as well as activities against the Herpes simplex virus. The first objective of the current research is the enzyme-catalysed hydrolysis of these compounds as described in Chapter 2.Prochiral bis(ethoxycarbonylmethyl) substituted 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates 1a-f are hydrolysed enantioselectively by Candida antarctica lipase B (Novozym 435 ®) (Scheme 1). The enantiomeric excesses range from 68 to 97%, depending on the substituent at position 4. In some cases, the e.e. can be significantly increased by changing the solvent system.Scheme 1Cerebrocrast (2,6-dimethyl-3,5-bis[2-(propoxy)ethoxycarbonyl]-4-[2-(difluoromethoxy)phenyl]-1,4-dihydropyridine) is a highly active neuroprotector. This compound has been found active in the treatment of ...