title: General approach for the synthesis of 12-methoxy-substituted sarpagine indole alkaloids including (-)-12-methoxy-N(b)-methylvoachalotine, (+)-12-methoxy-N(a)-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline.
abstract: [structures: see text] The enantiospecific synthesis of 7-methoxy-D-tryptophan ethyl ester was completed by combination of the Larock heteroannulation process with a Schöllkopf-based chiral auxiliary in good yield. This ester was then employed in the first regiospecific, stereospecific total synthesis of (+)-12-methoxy-N(a)-methylvellosimine, (+)-12-methoxyaffinisine, (-)-fuchsiaefoline, and 12-methoxy-N(b)-methylvoachalotine in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed cross-coupling processes served as key steps. The quaternary center at C16 of 12-methoxy-N(b)-methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-N(a)-methylvellosimine and formaldehyde to form diol 17. The two prochiral primary alcohols in diol 17 were differentiated by the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of 17 with the benzylic postion at [C6] to form a cyclic ether [C6-O17]. After oxidative formation of the alpha-ester at C16, the ether bond was reductively cleaved with TFA/Et3SiH in high yield. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps in order to provide a versatile entry into the voachalotine alkaloids.
authors.affiliation: Department of Chemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Xuebin
authors.initials: X
authors.lastname: Liao
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Yin
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D004988:Ethers, Cyclic / Q000737:chemistry; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism; D014364:Tryptophan / Q000737:chemistry
chemical_list: C459453:12-methoxy-N(a)-methylvellosimine; C511845:12-methoxy-N(b)-methylvoachalotine; C459455:12-methoxyaffinisine; D004988:Ethers, Cyclic; D026121:Indole Alkaloids; D007659:Ketones; C511846:fuchsiaefoline; D014364:Tryptophan; C475809:sarpagine