Convergent and stereospecific synthesis of complex skipped polyenes and polyunsaturated fatty acids

Abstract

Skipped polyenes (i.e. 1,4-dienes and higher homologues) are stereodefined components of a vast array of biologically important natural products, including polyunsaturated fatty acids. While widespread in nature, these architectures are generally considered to represent significant barriers to efficient chemical synthesis. While partial reduction of skipped poly-ynes provides a pathway to a subset of such structures, general chemical methods for the preparation of skipped polyenes that contain varied stereochemistries and substitution patterns are lacking. Here, we describe a metal-promoted reductive cross-coupling reaction between vinylcyclopropanes and alkynes (or vinylsilanes) that provides stereoselective access to a diverse array of skipped polyenes through a process that establishes one C–C bond, generates up to three stereodefined alkenes, and can be used to introduce stereogenic centers at the central positions of the skipped polyene motif. We also demonstrate the significance of the present bond construction by preparing substituted and stereodefined polyunsaturated synthetic fatty acids.

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

“…Oxidation of the C-Si bond then delivers the primary carbinol products that possess stereodefined skipped dienes. 144 Notably, these studies described the utility of vinylcyclopropanes in alkene-alkyne-coupling chemistry, defining convergent coupling reactions that deliver skipped trienes in a highly stereoselective fashion (not depicted).…”

A reductive coupling strategy towards ripostatin A

“…Braddock has demonstrated that the internal 3,4- E olefin is obtained exclusively in Prins reactions terminated by cyclopropylmethylsilane (Scheme 3, reaction 3), which may be explained by the participation of a carbocation that is stabilized by the adjacent cyclopropane ring in the bisected conformation where (CHOR)R′ is oriented anti to the cyclopropane [28–30]. Finally, Micalizio has described a titanium-mediated, alkoxide-directed fragment coupling reaction between vinylcylopropanes and vinyldimethylchlorosilane (Scheme 3, reaction 4) in which the stereochemical outcome of the rearrangement is orchestrated by the adjacent alkoxide, which is believed to direct formation of a tricyclic titanacyclopentane that subsequently fragments in a stereospecific manner [31]. …”

Palladium‐Catalyzed Completely Linear‐Selective Negishi Cross‐Coupling of Allylzinc Halides with Aryl and Vinyl Electrophiles

“…The current Negishi coupling protocol successfully addressed these problems. Vinyl bromides and triflates were converted to the corresponding “skipped dienes”, which represent key structural motifs in a number of biologically active natural products, [19] in a completely regioselective manner (Scheme 3). Notably, mono- ( 8a ), di- ( 8b – 8d ) and trisubstituted ( 8e – 8f ) vinyl electrophiles could all be applied in this reaction without noticeable erosion of regioselectivity.…”