Development of Anti-Selective Aldol Additions and a Convergent Assembly of Polycyclic Ethers: Synthesis of the ABCDE Fragment of Brevetoxin A

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  • March 20, 2019
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  • Mcdougall, Patrick J.
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Anti-selective aldol additions between the titanium enolates of N-glycolyl oxazolidinethiones and simple aldehydes are described. Variation to the Lewis acid stoichiometry of known syn aldol conditions led to a reversal of stereoselectivity favoring formation of one anti diastereomer. Highest selectivity and yield were observed using alpha,beta-allyloxy glycolylimides and aliphatic, unbranched aldehydes. Other suitably protected imides and alpa,beta-unsaturated or aromatic aldehydes were also viable reacting partners. Application of the anti glycolate aldol additions toward the stereoselective synthesis of the BCDE fragment of the potent red tide neurotoxin brevetoxin A is also described. Synthesis of the B ring began with an anti aldol addition to set the C3 and C4 stereogenic centers. Further elaboration using glycolate alkylation and ring-closing metathesis reactions provided the B ring core. The E ring fragment likewise utilized anti aldol methodology to rapidly access a diene fragment needed to close the nine-membered ring. A novel convergent coupling strategy was developed for the synthesis of the completed trans-fused BCDE tetracycle from the individual B and E units. This approach relied on a Horner-Wadsworth-Emmons reaction to join the two complex fragments. Enone reduction and subsequent cyclodehydration generated an intermediate endocyclic enol ether representing the B, C, and E rings. Elaboration of the enol ether intermediate via oxidation, cyclization of the D ring, and ketal reduction then provided the completed BCDE fragment. A revised synthesis of this molecule was subsequently developed to provide the onecarbon homologated version needed for eventual completion of the natural product. The E ring revision is highlighted by a novel glycolate alkylation using bromoacetonitrile and several protecting group alterations. Significant improvements to the convergent assembly were realized during the revision, providing the BCDE fragment in significantly higher yield from the individual rings and in fewer synthetic steps. Finally, the A ring lactone was formed, providing the complete ABCDE pentacycle.
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  • In Copyright
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  • Crimmins, Michael T.
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  • October 19, 2010

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