An Efficient and Enantioselective Approach to the Azaspirocyclic Core of Alkaloids:  Formal Synthesis of Halichlorine and Pinnaic Acid

• Published in: Journal of organic chemistry 2005-06, Vol.70 (13), p.4954-4961
• Main Authors: Zhang, Hong-Lu, Zhao, Gang, Ding, Yu, Wu, Bin
• Format: Article
• Language: English
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Catalysis; Chemistry; Combinatorial Chemistry Techniques; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Indicators and Reagents; Molecular Structure; Organic chemistry; Preparations and properties; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo047882v

A novel, highly stereoselective synthesis of an azaspirocyclic core, which contains four stereogenic carbons consistent with structures of natural halichlorine and pinnaic acid, is presented. Lipase PS-catalyzed selective acylation, asymmetric methylation on the α-methylene of the bicyclic lactone, and an asymmetric Michael addition of the tertiary nitro cyclopentane were concisely used to conquer the challenging problem of successfully constructing the C9 quarternary carbon center with complete stereocontrol. The spiropiperidine ring was formed by reduction of the δ-nitroketone, intramolecular condensation, and then highly stereoselective reduction of the cyclic nitrone with NaBH4. This spirocyclic core is a key intermediate in Danishefsky's synthesis of pinnaic acid and halichlorine.