Recent Development of Ring Closing Metathesis Approach to Bioactive Heterocycles: Synthesis of Nakadomarin A, Quinolines, and Indoles

Abstract

Asymmetric total synthesis of marine natural product, nakadomarin A, is described and as further extension, a novel synthesis of quinoline and indole ring system by ring closing metathesis is also described. We have been interested in the synthesis of nakadomarin A 1 [2] , which belongs to manzamine alkaloids [3] by two different routes (Routes A and B). We envisioned that if functional group conversions of the key intermediate 1 for manzamine A to the new tricyclic system 2 followed by oxidative cleavage of the double bond could take place, then the resulting dialdehyde most probably undergoes aldol cyclization to form unsaturated aldehyde 3. From 3 the furan ring could be constructed to give ABCD ring, an advanced key intermediate for nakadomarin A. Subsequent construction of both 8-and 15-membered azacycles could be performed by ring-closing metathesis (RCM) (Scheme 10.1). The key chiral intermediate 4 , highly functionalized hydroisoquinoline, was obtained by a Diels-Alder reaction between siloxydiene 5 and chiral dienophile 6 which was prepared from L-serine [4]. Ruche reduction of enone 4 gave allyl alco