Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine, and Related Aspidosperma Alkaloids

Abstract

We report an efficient and highly stereoselective synthetic strategy for the synthesis of aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent level of diastereoselection due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the aspidosperma alkaloids (−)-mehranine and (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine. A late-stage scandium trifluoromethanesulfonate-mediated dimerization of (−)-mehranine enabled the first total synthesis of (−)-methylenebismehranine.

Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction

“…This iminium ion bears close resemblance to a fully characterized complex iminium ion from our earlier studies. 17a Specifically, characteristic values in the IR (1670 cm −1 ), 19 F NMR (−78.6 ppm), and 13 C NMR (192.0 ppm) spectra of the hexacyclic iminium trifluoromethanesulfonate previously isolated are in accordance with the values we observed for spiroindoline iminium ion (±)- 13 . Importantly, the isolation and full characterization of spiroindoline iminium ion (±)- 13 is significant as it provides a bridge between final products such as tetracycle (±)- 12 and intermediates that are too fragile for isolation such as diiminium ion (±)- 11 .…”

“…This allowed for the identification of the lowest temperature for efficient tertiary lactam activation and a reference for the influence of base additives. We began our studies with tertiary, six-membered ring lactams 1a and 1b (Scheme 2A) because they possess important characteristics of the lactam substrates we have utilized in our total synthesis efforts, 17 but lack functional groups that would obscure the region of interest in the IR spectra. Lactams 1a (1625 cm −1 ) and 1b (1621 cm −1 ) both react with Tf 2 O at −78 °C to form the corresponding O -trifluoromethanesulfonyloxyiminium trifluoromethanesulfonates 3a (1692 cm −1 ) and 3b (1664 cm −1 ), respectively.…”

“…14,15 Recently, we have applied this amide activation chemistry to access spirocyclic indolines via the interruption of the Bischler–Napieralski reaction, 16 and applied this strategy to the total synthesis of various members of the aspidosperma alkaloids. 17 While new applications of this amide activation chemistry continue to offer unique and versatile synthetic transformations, the paucity of detailed studies concerning the identity and reactivity of crucial intermediates prompted our investigation of sensitive and electrophilic compounds involved in this chemistry. Herein, we report the first direct monitoring of the electrophilic amide activation of tertiary lactams and the subsequent observation of the resulting O -trifluoromethanesulfonyloxyiminium ions, mono- and diiminium spiroindolines, and diiminium ethers through the use of in situ reaction monitoring techniques.…”

Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings

“…For instance, the 3-oxo derivative of catharanthine could be epoxidized with m -chloroperoxybenzoic acid [23]. Another example, mehranine, the 14,15-epoxi derivative of aspidospermidine, was isolated from Tabernaemontana bovina and its total synthesis was recently presented [24]. …”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…249) [654], hippocasine and a diastereomer [655], and sedridine [656]; (8) six-membered ring β,γ-unsaturated lactams [657], including those employed in total syntheses of mehranine and methylenebismehranine and related alkaloids (e.g. 250) [658]; (9) quinolizin-4-ones (e.g. 252) via RCM and oxidation of the dihydroaromatic system (e.g.…”