312732-09-5Relevant articles and documents
Application of ring-closing metathesis to the formal total synthesis of (+)-FR900482
Fellows, Ingrid M.,Kaelin Jr., David E.,Martin, Stephen F.
, p. 10781 - 10787 (2007/10/03)
A formal, enantioselective synthesis of the antitumor antibiotic (+)-FR900482 (1) has been completed using an approach that featured the ring-closing metathesis of the diene 37 to give the key intermediate benzazocine 38. Although several initial protecting-group strategies unexpectedly failed at various stages of the endeavor, the successful approach to 1 involved the conversion of commercially available 5-nitrovanillin (10) into the prochiral diol 24. The manipulations of the residues on the aromatic ring of 10 were straightforward, and the diol array in 24 was introduced by the hydride reduction of the malonate 23, which was in turn prepared by a nucleophilic substitution of the triflate 12. Adjustment of alcohol-protecting groups to give 27 and refunctionalization of the aromatic nitro group led to the protected N-allylamine 36. Elaboration of the diol array via a highly stereoselective Grignard addition furnished the diene 37. Ring-closing metathesis of 37 using the Grubbs catalyst 34 cleanly afforded the benzazocine 38. A tactic originally conceived for preparing 42 by introduction of the aziridine ring onto 38 was impractical because the iodo cyclization of the allylic tosylcarbamate 39 was neither efficient nor selective to give 40. Hence, 38 was transformed into 49, which was a key intermediate in Fukuyama's elegant synthesis of racemic FR900482, thereby completing a formal synthesis of the alkaloid. The prochiral diol 24 was enzymatically desymmetrized using Pseudomonas species lipase to give 25 in 94% enantiomeric excess. Inasmuch as subsequent adjustment of the alcohol-protecting groups gave the intermediate 26 (cf the racemic analogue 27) in enantiomerically pure form, an enantioselective synthesis of (+)-FR900482 has also been completed in a formal sense.
