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. 2012 Sep 19;134(37):15237-40.
doi: 10.1021/ja306362m. Epub 2012 Sep 7.

Synthesis of alkaloid (-)-205B via stereoselective reductive cross-coupling and intramolecular [3+2] cycloaddition

Dexi Yang  1 , Glenn C Micalizio
Affiliations

Synthesis of alkaloid (-)-205B via stereoselective reductive cross-coupling and intramolecular [3+2] cycloaddition

Dexi Yang et al. J Am Chem Soc. .

Abstract

An asymmetric synthesis of alkaloid (-)-205B, a tricyclic member of the architecturally diverse family of natural products isolated from the skin of neotropical poison frogs, is described that proceeds through two recently developed stereoselective synthetic methods: (1) Ti-mediated allylic alcohol-imine reductive cross-coupling and (2) intramolecular [3+2] cycloaddition of a glyoxylate-based homoallylic nitrone. The utility of this latter cycloaddition process for the assembly of the stereochemically dense piperidine core of 205B is noteworthy, as this method enables direct [3+2] cycloaddition of an intermediate homoallylic (E)-nitrone via a pathway that is stereochemically unscathed by competitive [3,3]-sigmatropic rearrangement processes. Overall, the synthesis is asymmetric, concise, and highly stereoselective-features which point to the potential future utility of these chemical methods in natural product synthesis and medicinal chemistry.

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Figures

Figure 1
Figure 1
Structurally diverse alkaloids from the skin of the neotropical poison-frog Dendrobates pumilio.
Figure 2
Figure 2
Strategic considerations and retrosynthesis of (−)-205B.
Figure 3
Figure 3
Asymmetric synthesis of (−)-205B via Ti-mediated reductive cross-coupling and stereoselective intramolecular [3+2] cycloaddition.
Figure 4
Figure 4
Stereochemical course of the reductive cross-coupling reaction between aldehyde 7 and allylic alcohol 8.
Figure 5
Figure 5
Success of the cationic annulation may reflect an increased rate for aza-Sakurai vs. [3,3] rearrangement and resulting competitive fragmentation and epimerization pathways.
See this image and copyright information in PMC

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