An Asymmetric Route to the Conanine BCDE Ring System. A Formal Total Synthesis of (+)-Conessine

Abstract

The first enantioselective synthesis of the known (+)-conessine precursor (+)-benzohydrindan 23 from the chiral nonracemic bicyclic lactam 1 is described. The key transformation was the highly diastereoselective (3 + 2) cycloaddition of azomethine ylide 11a to lactam 7 in order to construct the pyrrolidine E ring system at any early stage in the synthesis. The requisite pyrrolidine methyl group at C-21 was stereoselectively installed late in the synthesis by lithiation of N-Boc-pyrrolidine intermediate 20 with sec-BuLi/TMEDA followed by quenching at −90 °C with iodomethane, furnishing the tetracyclic pyrrolidine 21. Reduction of t-Boc 21 with lithium aluminum hydride affords (+)-N-methyl tetracycle 23 in a concise 13-step synthesis from 1.

Highly Enantioselective Construction of Fused Pyrrolidine Systems That Contain a Quaternary Stereocenter: Concise Formal Synthesis of (+)‐Conessine

“…Reduction with sodium triacetoxyl borohydride then provided (+)-21 as a single isomer in 93 % yield ([a] 25 D = + +51 (c = 0.21, benzene)). The optical rotation of the product was in agreement with that reported by Meyers and co-workers for the same compound, [4] and the configuration of the product was further confirmed by X-ray crystallographic analysis. [13] The steric hindrance at the concave a face of the tetracyclic molecule 20 may explain the excellent stereoselectivity observed.…”

“…The key transformation was a diastereoselective [3+2] cycloaddition with an azomethine ylide under pressure to construct the pyrrolidine ring system, followed by intramolecular addition of an aryl lithium and an aldol reaction to afford the tetracyclic cyclopentenone skeleton of the tetracyclic pyrrolidine enantioselectively. [4] Based on our recent studies towards the convergent assembly of the cyclopenta[c]proline ring system in an efficient and stereoselective manner by an intramolecular Pauson-Khand reaction of a chiral enyne amino acid, [5] it was envisaged that the tetracyclic pyrrolidine 21 of (+)-conessine could be accessed by an asymmetric Pauson-Khand reaction in a single step. The installation of the stereogenic quaternary carbon center would also be possible if the substrates possessed a dihydronaphthalenyl group (Scheme 1).…”

Combination of RCM and the Pauson–Khand Reaction: One‐Step Synthesis of Tricyclic Structures

“…This natural product, which has significant biological activity against dysentery, [14] has been synthesized by Meyers [15] and other groups. [16] In particular, Meyers and co-workers described a nonracemic synthesis of Conessine in which polycyclic enone 33 was obtained as an intermediate, although with benzyl as a protecting group.…”

Alkaloids

“…The structure of conanine (412) was confirmed by X-ray analysis of its N-oxide derivative [379]. A formal total synthesis of (+)-connecine (410) was reported by Meyers [380].…”