Synthesis of Suaveoline and Related Alkaloids Using Intramolecular Diels–Alder Reaction of Oxazoles

Abstract

Suaveoline (1) and norsuaveoline (2), Rauwolfia alkaloids possessing a 9-azabicyclo[3.3.1]nonane skeleton fused by indole and pyridine rings, have been synthesized through a route starting from L-tryptophan methyl ester (3) and exploiting an intramolecular oxazole-olefin Diels–Alder reaction. On treatment with α-lithiated methyl isocyanide −78°C, the ester 3 protected by the Boc group was converted into the oxazole 4. The stereoselective formation of the 1,3-cis-tetrahydro-β-carboline moiety from 4 via Bischler–Napieralski cyclization followed by catalytic hydrogenation and subsequent introduction of the olefinic dienophile afforded the oxazole-olefin 5. The intramolecular Diels–Alder reaction of 5 proceeded smoothly in boiling xylene in the presence of DBN to provide the pyridine 6, which was then converted into 1 and 2 by the conventional method.