title: An efficient approach to Aspidosperma alkaloids via [4 + 2] cycloadditions of aminosiloxydienes: stereocontrolled total synthesis of (+/-)-tabersonine. Gram-scale catalytic asymmetric syntheses of (+)-tabersonine and (+)-16-methoxytabersonine. Asymmetric syntheses of (+)-aspidospermidine and (-)-quebrachamine.
abstract: Described is a concise, highly stereocontrolled strategy to the Aspidosperma family of indole alkaloids, one that is readily adapted to the asymmetric synthesis of these compounds. The strategy is demonstrated by the total synthesis of (+/-)-tabersonine (rac-1), proceeding through a 12-step sequence. The basis for this approach was provided by a highly regio- and stereoselective [4 + 2] cycloaddition of 2-ethylacrolein with 1-amino-3-siloxydiene developed in our laboratory. Subsequent elaboration of the initial adduct into the hexahydroquinoline DE ring system was accomplished efficiently by a ring-closing olefin metathesis reaction. A novel ortho nitrophenylation of an enol silyl ether with (o-nitrophenyl)phenyliodonium fluoride was developed to achieve an efficient, regioselective introduction of the requisite indole moiety. The final high-yielding conversion of the ABDE tetracycle into pentacyclic target rac-1 relied on intramolecular indole alkylation and regioselective C-carbomethoxylation. Our approach differs strategically from previous routes and contains built-in flexibility necessary to access many other members of the Aspidosperma family of indole alkaloids. The versatility of the synthetic strategy was illustrated through the asymmetric syntheses of the following Aspidosperma alkaloids: (+)-aspidospermidine, (-)-quebrachamine, (-)-dehydroquebrachamine, (+)-tabersonine, and (+)-16-methoxytabersonine. Of these, (+)-tabersonine and (+)-16-methoxytabersonine were synthesized in greater than 1-g quantities and in enantiomerically enriched form ( approximately 95% ee). The pivotal asymmetry-introducing step was a catalyzed enantioselective Diels-Alder reaction, which proceeded to afford the cycloadducts in up to 95% ee. Significantly, the synthetic sequence was easy to execute and required only four purifications over the 12-step synthetic route.
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozmin
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Iwama
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Viresh H
authors.initials: VH
authors.lastname: Rawal
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D030009:Aspidosperma / Q000737:chemistry*; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis; D011804:Quinolines; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C409672:aspidospermidine; C009373:tabersonine; C091897:quebrachamine