Enantioselective total synthesis of (+)-ibophyllidine via an asymmetric phosphine-catalyzed [3 + 2] annulation

Abstract

In this study we performed the total synthesis of the terpene indole alkaloid (+)-ibophyllidine through a pathway involving asymmetric phosphine catalysis, with our novel l-4-hydroxyproline-derived chiral phosphine mediating the key [3 + 2] annulation. Hydrogenation of the [3 + 2] adduct allowed the rapid formation of the stereochemically dense pyrrolidine ring of (+)-ibophyllidine in excellent yield with exceptionally high levels of both diastereo- and enantioselectivity. We constructed the remainder of the pentacyclic skeleton through an intramolecular alkylation and an intramolecular aza-Morita-Baylis-Hillman reaction.

Figure 1

Representative ibophyllidines and the aspidospermine/pseudoaspidospermidine alkaloid skeleton

Scheme 1

Summary of strategies that have been used to synthesize ibophyllidine and our unique approach

Scheme 2

Retrosynthetic analysis of (+)-ibophyllidine based on a phosphine-catalyzed [3 + 2] annulation

Scheme 3

Synthesis of the key pyrrolidine 11: (a) p-toluenesulfonamide, TiCl₄, Et₃N, CH₂Cl₂, 0 °C to rt, 90%; (b) allenoate 10, 10 mol% chiral phosphine 12, benzene, 93%, 99% ee; (c) Raney Ni, THF, H₂ (200 psi), 80%.

Scheme 4

Elaboration of the pyrrolidine 11 to the cyclization precursor 14: (a) LiAlH₄, THF, 0 °C to rt; (b) Mg powder, THF/MeOH (9:1), sonication; (c) chloroacetyl chloride, THF, Et₃N, 0 °C, 78% (three steps); (d) oxalyl chloride, DMSO, −78 °C, then Et₃N, 98%; (e) methyl diethylphosphonoacetate, NaHMDS, THF, −78 °C, 76%; (f) SiO₂, toluene, reflux; (g) NaI, acetone, reflux, 94% (2 steps).

Scheme 5

Completing the synthesis of (+)-ibophyllidine: (a) AgOTf, Et₃N, toluene, 0 °C to room temp.; (b) Me₃P, benzene/MeOH (14:1), 80% (two steps); (c) Lawesson’s reagent, benzene, reflux; (d) Raney Ni, THF, H₂ (200 psi), 90% (two steps); (e) Dess–Martin periodinane, CH₂Cl₂, 51%.