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.

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…The synthesis involved the preparation of a dihydrocarboline iminium salt followed by a highly selective attack at C-3 of a vinyl ketene acetal from the face opposite to the carboxyl group at C-5 (Scheme 5) [36,37].…”

Chemistry of β‐Carbolines as Synthetic Intermediates

“…Selective reduction of the lactam in 11 to afford 12, followed by removal of the 5-carboxylic acid group by radical decarbonylation and then by formylation, gave (+)-geissoschizine (Scheme 19). [31] Scheme 19.…”

Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Indolemonoterpene Alkaloids

“…Indeed, the conversion of 54 into strychnine (2) can be achieved through the intermediacies of the dihydro-derivative 55 and Wieland-Gümlich aldehyde (56), according to standard procedures (Scheme 3.12) [29]. More recently, the same type of intermediates also permitted a biomimetic entry to the sarpagan alkaloids [30]. …”