Stereoselective synthesis of trisubstituted (E,E)-1,3-dienes by the site-selective reductive cross-coupling of internal alkynes with terminal alkynes: A fragment coupling reaction for natural product synthesis

Lark J. Perez, Heidi L. Shimp, Glenn C. Micalizio

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Abstract

(Chemical Equation Presented) A highly selective convergent coupling reaction is described between alkynes for the synthesis of stereodefined trisubstituted (E,E)-1,3-dienes-structural motifs commonly found embedded in the skeletons of bioactive polyketide-derived natural products. While numerous multistep processes for the synthesis of this stereodefined functional group exist, the current method represents a significant advance as it does not require stereodefined olefinic coupling partners (vinyl halide or vinyl organometallic); it proceeds by a single convergent C-C bond-forming event (avoiding multistep methods based on carbonyl olefination) and is tolerant of a diverse array of functional groups including free hydroxyls. Through a systematic study of titanium-mediated reductive cross-coupling reactions of internal alkynes with terminal alkynes, a fragment coupling reaction of great utility in natural product synthesis has emerged. Here, use of a proximal hydroxy group to control regioselection in the functionalization of a preformed titanacyclopropene has led to the establishment of a highly selective bimolecular coupling process, where C-C bond formation occurs in concert with the establishment of two stereodefined alkenes. Compared to the body of literature known for related metal-mediated coupling reactions, the current work defines a powerful advance, achieving site-selective bimolecular C-C bond formation without the need for using TMS-alkynes or conjugated alkynes. Overall, complex 1,3-dienes relevant for the synthesis of polyketide-derived natural products of varying stereochemistry were prepared with typically ≥20:1 selectivity, defining the important role of an alkoxide directing group located δ to preformed titanacyclopropenes.

Original languageEnglish (US)
Pages (from-to)7211-7219
Number of pages9
JournalJournal of Organic Chemistry
Volume74
Issue number19
DOIs
StatePublished - Oct 2 2009

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All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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