Application of a novel stereospecific imino ene reaction of allenyl silanes to the enantioselective total synthesis of the marine alkaloid papuamine

A concise enantioselective total synthesis of the recently isolated antifungal marine alkaloid papuamine (1) is described. The key feature of the synthesis includes the development and subsequent implementation of a novel pericyclic imino ene reaction. Enantiomerically pure allenyl silane N-benzyl imines 334 and 337, generated in situ from aldehydes 332a/b undergo concerted stereospecific imino ene reactions to afford silyl acetylenes 335 and 338, respectively. These reactions were found to be promoted thermally and at lower temperatures through the use of Lewis acid catalysis. Desilylation of compounds 335 and 338 afforded terminal alkynes 336 and 339, respectively, whose structures and stereochemistry were unambiguously established by X-ray crystal structure analysis of the corresponding HCl salts.; In a more highly convergent approach to 1, aldehyde allenyl silane 332b was treated with 1,3-diaminopropane in refluxing toluene to afford homopropargylic diamine 368 as one stereoisomer via a double imino ene reaction, which effectively established the remaining four of eight stereogenic centers of papuamine in one operation.; To complete the route to papuamine an unprecedented Pd(II) catalyzed macrocyclization of bis-E-vinyl silane 403 was effected in moderate yield. The absolute configuration of papuamine was determined by the synthesis to be as shown in structure 1 by comparison of the optical rotations of synthetic and natural material.; During an initial attempt at the synthesis of papuamine, CrCl{dollar}sb2{dollar} and SmI{dollar}sb2{dollar} was found to promote cyclizations of N-sulfonyl imine allyl bromide 305, to yield bicyclic sulfonamides 306a-c. The yields and stereoselectivities for this transformation, however, were modest at best. A generally useful nitrogen protecting group, {dollar}beta{dollar}-tosylethylamine (372) was also developed during the synthesis. This compound 372 can be used as an ammonia synthon or benzyl amine substitute and was successfully used to prepare N-protected amido compounds 374b-e.