title: Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy.
abstract: Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (+/-)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park 16802, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Sun
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Sun
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weinreb
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001685:Biological Factors / Q000737:chemistry; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D018360:Crystallography, X-Ray; D003500:Cyclization; D007202:Indicators and Reagents; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014561:Urochordata / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D001685:Biological Factors; D007202:Indicators and Reagents; C431548:lepadiformine; D011761:Pyrrolidonecarboxylic Acid