title: Biomimetic entry to the sarpagan family of indole alkaloids: total synthesis of +-geissoschizine and +-N-methylvellosimine.
abstract: A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from d-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-N(a)-methylvellosimine (5). The approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5, by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common intermediate 27 was then converted via a straightforward sequence of reactions into the alpha-amino nitrile 39. The derived silyl enol ether 40 underwent ionization upon exposure to BF(3).OEt(2) to give the intermediate iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver (+)-N(a)-methylvellosimine (5). This transformation provides experimental support for the involvement of such a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Deiters
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: C Todd
authors.initials: CT
authors.lastname: Eary
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Martin
mesh_terms: D040761:Biomimetic Materials / Q000138:chemical synthesis*; D002243:Carbolines / Q000138:chemical synthesis*; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D002243:Carbolines; D026121:Indole Alkaloids; C474539:n-methylvellosimine; C410326:geissoschizine