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. 2017 Dec 15;82(24):13656-13662.
doi: 10.1021/acs.joc.7b02403. Epub 2017 Nov 27.

Further Investigation of the Intermolecular Diels-Alder Cycloaddition for the Synthesis of Bicyclo[2.2.2]diazaoctane Alkaloids

Jonathan C Perkins  1 , Xiye Wang  1 , Robert D Pike  1 , Jonathan R Scheerer  1
Affiliations

Further Investigation of the Intermolecular Diels-Alder Cycloaddition for the Synthesis of Bicyclo[2.2.2]diazaoctane Alkaloids

Jonathan C Perkins et al. J Org Chem. .

Abstract

The convergent synthesis of bicyclo[2.2.2]diazaoctane structures using an intermolecular Diels-Alder cycloaddition between a pyrazinone and commercially available fumarate or maleate precursors is reported. High reactivity and stereoselection is observed with both dienophile substrates. Structure validation was achieved by conversion of cycloadducts into known [2.2.2]diazabicyclic compounds or into crystalline derivatives suitable for X-ray analysis. The cycloadduct derived from reaction of pyrazinone and maleic anhydride underwent selective anhydride ring opening and intersected an established precursor in the synthesis of brevianamide B.

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Figures

Figure 1.
Figure 1.
Representative bicyclo[2.2.2]diazaoctane metabolites with anti or syn configuration.
Scheme 1.
Scheme 1.
Intermolecular Cycloaddition of Pyrazinone Precursors with Electron-Deficient Dienophiles
Scheme 2.
Scheme 2.
Structure Validation of Cycloadducts and Formal Synthesis of Brevianamide B
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