A Concise Enantioselective Total Synthesis of (−)‐Deoxoapodine

Abstract

We have established a highly convergent 10-step route for the total synthesis of (À)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C À H palladation/alkylation cascade at the indole 2position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.

The application of C–H bond functionalization in the total syntheses of indole natural products

“…2.5 Enantioselective total synthesis of (−)-deoxoapodine (Tokuyama, 2020) 36 (−)-Deoxoapodine ( 16) was isolated from Tabernae armeniaca and Hazunta modesta, respectively. 37 This indole alkaloid has a characteristic tetrahydrofuran ring fused to the aspidosperma skeleton.…”

“…The unique structure of (−)-deoxoapodine ( 16) has attracted great interest from synthetic chemists globally over the past three decades. Successful syntheses have been achieved by the groups of Overman, 38a Boger, 38b Movassaghi, 38c Peng, 38d and Tokuyama, 36 respectively. Notably, in the 2020 report by Tokuyama and co-workers, a concise total synthesis of (−)-deoxoapodine ( 16) within a 10-step linear sequence was disclosed.…”

“…The Mannich reaction of 90 and N-Boc-6-bromoindolylacetonitrile gave products 91 and 92 as a Scheme 8 The total synthesis of (−)-deoxoapodine by Tokuyama. 36 (PDP = bis(2-pyridinylmethyl)-2,2'-bipyrrolidine).…”

Total Synthesis of (–)-Voacinol and (–)-Voacandimine C

“…Alkaloids 1 and 2 have significant structural similarities with (-)-deoxoapodine (4), 27,28 a hexacyclic alkaloid isolated from Tabernae armeniaca in 1975, exhibiting a C2-vinylogous urethane along with C21-oxygenation. 1 Inspired by our observations concerning the reactivity of a transiently formed D-ring iminium ion 29 en route to (-)-deoxoapodine (4), [30][31][32][33] we hypothesized that alkaloids 1 and 2 may be biogenetically accessed by derivatization of (-)-deoxoapodine (4). Given prior isolation of natural alkaloids comprised of simpler aspidosperma alkaloids adjoined by a methylene, such as (-)-methylenebismehranine (6), 34,35 we posited that (-)methylenebisdeoxoapodine (3) may be of interest as a congener of alkaloids 1 and 2.…”