Synthesis of the ABC Ring System of Manzamine A

• Published in: Journal of organic chemistry 2002-08, Vol.67 (17), p.6181-6187
• Main Authors: Coldham, Iain, Crapnell, Katherine M, Fernàndez, Joan-Carles, Moseley, Jonathan D, Rabot, Rémi
• Format: Article
• Language: English
• Subjects: Arecoline - chemistry; Carbazoles; Catalysis; Chemistry; Chemistry, Organic - methods; Crystallography, X-Ray; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Indole Alkaloids - chemical synthesis; Indoles - chemical synthesis; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Organic chemistry; Preparations and properties; Pyrroles - chemical synthesis; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo016376s

A synthesis of the core ABC ring system of the manzamine alkaloids is described, starting from arecoline. The key steps involve a Claisen rearrangement to set up a 4-substituted-3-methylenepiperidine and a stereoselective azomethine ylide dipolar cycloaddition reaction. Condensation of the aldehyde 6 and sarcosine ethyl ester hydrochloride salt gives an intermediate azomethine ylide, which undergoes an intramolecular cycloaddition reaction to set up two new rings and three new chiral centers stereoselectively. The aldehyde 6 was not a suitable substrate for related azomethine ylide cycloaddition reactions with other amines. However, the related dimethyl acetal 26 could be condensed with a variety of amines to give the desired tricyclic products. The cycloaddition reaction with N-methyl or N-allyl glycine ethyl ester gave almost exclusively the exo adduct, whereas cycloaddition with glycine ethyl ester gave the endo adduct.