Enantioselective total synthesis of (-)-acutumine

Abstract

An account of the total synthesis of the tetracyclic alkaloid (-)-acutumine is presented. A first-generation approach to the spirocyclic subunit was unsuccessful as a result of incorrect regioselectivity in a radical cyclization. However, this work spawned a second-generation strategy in which the spirocycle was fashioned via a radical-polar crossover reaction. This process merged an intramolecular radical conjugate addition with an enolate hydroxylation and created two stereocenters with excellent diastereoselectivity. The reaction was promoted by irradiation with a sunlamp, and a ditin reagent was required for aryl radical formation. These facts suggest that the substrate may function as a sensitizer, thereby facilitating homolytic cleavage of the ditin reagent. The propellane motif of the target was then installed via annulation of a pyrrolidine ring onto the spirocycle. The sequence of reactions used included a phenolic oxidation, an asymmetric ketone allylation mediated by Nakamura's chiral allylzinc reagent, an anionic oxy-Cope rearrangement, a one-pot ozonolysis-reductive amination, and a Lewis acid promoted cyclization of an amine onto an alpha,beta-unsaturated dimethyl ketal. Further studies of the asymmetric ketone allylation demonstrated the ability of the Nakamura reagent to function well in a mismatched situation. A TiCl(4)-catalyzed regioselective methyl enol etherification of a 1,3-diketone completed the synthesis.

Figure 1

Acutumine (1) and related alkaloids.

Figure 2

Proposed stereocontrol in enolate hydroxylation.

Figure 3

Diagnostic NOE enhancements.

Figure 4

Proposed transition state for allylation of 38.

Scheme 1

First-Generation Retrosynthetic Analysis

Scheme 2

Synthesis of Weinreb Amide 11 and Vinyl Iodide 12

Scheme 3

Preparation and 6-endo Radical Cyclization of 10

Scheme 4

Second-Generation Retrosynthetic Analysis

Scheme 5

Synthesis of Vinyl Iodide 21

Scheme 6

Synthesis of Enone 20

Scheme 7

Asymmetric Nozaki–Hiyama–Kishi Coupling

Scheme 8

Conversion of Byproduct 32 into 19

Scheme 9

Synthesis of Phenol 36

Scheme 10

Preparation of Amine 42

Scheme 11

Completion of the Total Synthesis of 1