Asymmetric Synthesis of an N-Acylpyrrolidine for Inhibition of HCV Polymerase
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- 作者：Armel A. Agbodjan ; Bob E. Cooley ; Royston C. B. Copley ; John A. Corfield ; Roy C. Flanagan ; Bobby N. Glover ; Rossella Guidetti ; David Haigh ; Peter D. Howes ; Mary M. Jackson ; Richard T. Matsuoka ; Katrin
- 刊名：Journal of Organic Chemistry
- 出版年：2008
- 出版时间：April 18, 2008
- 年：2008
- 卷：73
- 期：8
- 页码：3094 - 3102
- 全文大小：191K
- 年卷期：v.73,no.8(April 18, 2008)
- ISSN：1520-6904
文摘
A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale isdescribed. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methylacrylate and an imino ester prepared from L-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and acinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87%enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethineylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical elementfor the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinylketone, providing access to either 
- or 
-epimers of 4-acetylpyrrolidine depending on the reactionconditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation,and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achievesexcellent chemoselectivity but also avoids formation of the undesired but thermodynamically favoredepimer. The highly functionalized target is synthesized in seven linear steps from L-leucine t-butyl esterhydrochloride with all three isolated intermediates being highly crystalline.
- or -epimers of 4-acetylpyrrolidine depending on the reactionconditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation,and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achievesexcellent chemoselectivity but also avoids formation of the undesired but thermodynamically favoredepimer. The highly functionalized target is synthesized in seven linear steps from L-leucine t-butyl esterhydrochloride with all three isolated intermediates being highly crystalline.