Stereodivergent Synthesis of β,γ-Fused Bicyclic γ-Lactones via a Multicomponent Ring-Expansion Cascade

Ettore J. Rastelli, Andrew A. Bolinger, Don M. Coltart

Research output: Contribution to journalArticlepeer-review

Abstract

The 3-alkoxy-1-N-toluenesulfonyl azopropene structural motif has been known in the context of the Eschenmoser-Tanabe fragmentation for over 50 years. It is derived from α-epoxy N-toluenesulfonyl hydrazones by deprotonation and epoxide ring opening. A very interesting yet unreported feature of these intermediates is their putative 1,3-dipolar nature and the potential to use them in reactions with complimentary dipoles to enable novel ring-expansion methods for the synthesis of saturated and partially saturated oxygen heterocycles. Herein, we describe such a transformation that requires the simple combination of an ester or acyl pyrrole, an α-epoxy 2-nitrophenyl hydrazone, and a commercially available base (KHMDS or LiHMDS) and leads to the highly (up to >25:1) diastereoselective synthesis of β,γ-fused bicyclic γ-lactones (an important class of chiral oxygen heterocycles), including those with quaternary centers. Conveniently, both syn- and anti-fused bicyclic systems can be generated stereoselectively through a simple modification of the reaction conditions. Heterocycles are among the most prevalent structural motifs present in pharmaceutical compounds. Remarkably, relatively few of these compounds contain chiral heterocycles, a limitation that is due in part to a lack of effective and broadly applicable methods for their preparation. As drug development moves away from the use of unsaturated (flat), structurally simple heterocyclic structures and seeks out more stereochemically sophisticated chiral compounds with higher degrees of saturation, the need for methods for the synthesis of chiral heterocycles has become increasingly important. We have developed a stereocontrolled synthetic approach to β,γ-fused bicyclic-γ-lactones (an important class of chiral oxygen heterocycles) through the simple combination of an α-epoxy hydrazone and an enolate. The lactone products, including those with quaternary centers, are produced with typically very high (>25:1) diastereoselectivity across a range of substrates. A method for the synthesis of β,γ-fused bicyclic-γ-lactones, an important class of chiral oxygen heterocycles, has been developed. This was achieved via 1,3-dipole reactivity of 3-alkoxy-1-azopropenes, intermediates well known in Eschemoser-Tanabe fragmentation. The lactone products, including those with quaternary centers, were produced with typically very high (>25:1) diastereoselectivity across a range of substrates. In addition, both the syn- and anti-fused bicycles were accessible by a simple modification of the reaction conditions.

Original languageEnglish (US)
Pages (from-to)2228-2238
Number of pages11
JournalChem
Volume4
Issue number9
DOIs
StatePublished - Sep 13 2018
Externally publishedYes

Keywords

  • SDG3: Good health and well-being
  • cascading ring expansion
  • stereoselective synthetic method
  • synthesis of chiral oxygen heterocycles

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Environmental Chemistry
  • Chemical Engineering(all)
  • Biochemistry, medical
  • Materials Chemistry

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