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 language | English |
|---|---|
| Pages (from-to) | 5938-5945 |
| Number of pages | 8 |
| Journal | Journal of Organic Chemistry |
| Volume | 67 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - 2002 Aug 23 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Enantioselective synthesis of bicyclo[3.1.0]hexane carbocyclic nucleosides via a lipase-catalyzed asymmetric acetylation. Characterization of an unusual acetal byproduct
AU - Yoshimura, Yuichi
AU - Moon, Hyung R.
AU - Choi, Yongseok
AU - Marquez, Victor E.
PY - 2002/8/23
Y1 - 2002/8/23
N2 - 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.
AB - 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.
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U2 - 10.1021/jo020249u
DO - 10.1021/jo020249u
M3 - Article
VL - 67
SP - 5938
EP - 5945
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
SN - 0022-3263
IS - 17
ER -