Enantioselective synthesis of bicyclo[3.1.0]hexane carbocyclic nucleosides via a lipase-catalyzed asymmetric acetylation. Characterization of an unusual acetal byproduct

Yuichi Yoshimura, Hyung R. Moon, Yongseok Choi, Victor E. Marquez

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The bicyclo[3.1.0]hexane scaffold can lock the conformation of a carbocyclic nucleoside into one of the two antipodal (north or south) conformations typical of conventional nucleosides that normally exist in a rapid, two-state equilibrium in solution. In a recent brief communication, we reported a practical method to access the requisite bicyclo[3.1.0]hexane pseudosugar for the north antipode via an intramolecular olefin-ketocarbene cycloaddition. The most attractive features of this synthesis was that a relatively complex synthon was obtained from simple and inexpensive starting materials and that the resulting racemic mixtures of purine nucleosides could be successfully resolved by adenosine deaminase (ADA) hydrolysis. In this work, we describe the development of a more general, lipase-catalyzed double-acetylation reaction, which could successfully resolve an earlier precursor, 4-(tert-butyldiphenylsilamethoxy)-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-ol [(±)7], into enantiomerically pure (+)-diacetate 8 and (-)-monoacetate 9. The former diacetate was converted to the conformationally locked (north)-carbocyclic guanosine (+)-17 identical to the one obtained previously by ADA resolution. The present method represents a more general and efficient process applicable to the synthesis of all classes of (north) bicyclo[3.1.0]hexane nucleosides, including pyrimidine analogues. During the lipase-catalyzed resolution, we were able to demonstrate the presence of an unusual acetal-forming reaction that consumed small amounts of the unreactive monoacetate (-)-9. This side reaction was also enzyme-catalyzed and was triggered by the byproduct acetaldehyde generated during the reaction.

Original languageEnglish
Pages (from-to)5938-5945
Number of pages8
JournalJournal of Organic Chemistry
Volume67
Issue number17
DOIs
Publication statusPublished - 2002 Aug 23
Externally publishedYes

Fingerprint

Acetylation
Acetals
Lipase
Nucleosides
Byproducts
Adenosine Deaminase
Carbasugars
Conformations
Pyrimidine Nucleosides
Purine Nucleosides
Cycloaddition
Acetaldehyde
Guanosine
Cycloaddition Reaction
Alkenes
Scaffolds
Hydrolysis
Communication
Enzymes
bicyclo(3.1.0)hexane

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Enantioselective synthesis of bicyclo[3.1.0]hexane carbocyclic nucleosides via a lipase-catalyzed asymmetric acetylation. Characterization of an unusual acetal byproduct. / Yoshimura, Yuichi; Moon, Hyung R.; Choi, Yongseok; Marquez, Victor E.

In: Journal of Organic Chemistry, Vol. 67, No. 17, 23.08.2002, p. 5938-5945.

Research output: Contribution to journalArticle

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