Unexpected Alkene Isomerization during Iterative Cross-Coupling To Form Hindered, Electron-Deficient Trienes

Abstract

An iterative cross-coupling approach to conjugated trienes was explored as part of a planned stereoselective synthesis of bicyclic terpenes. Using a bifunctional bromoboronate building block, sequential Suzuki coupling reactions were employed to provide a conjugated trienone target containing a tetrasubstituted alkene. During the final cross-coupling step, an unexpected alkene isomerization was observed to give less hindered trans products. Examination of different substrates determined that conjugation to a ketone withdrawing group was responsible for isomerization, rather than steric hindrance of the tetrasubstituted alkene.

Synthesis of an electrophilic keto-tetraene 15-oxo-Lipoxin A4 methyl ester via a MIDA boronate

“…However, a general instability of the tetraenone frequently led to impurities in the post-oxidation steps, and products from 14 on were thus treated with minimal heating and stored as methanol solutions, cold, in reduced-light conditions and under argon or nitrogen to minimize intermolecular reaction. Indeed, a prior synthesis of 5-oxoETE noted 42, 43 the facile cis - trans isomerization of the keto-diene, and a recent report 44 on a keto-triene described the inherent instability of an analogous Z -isomer in an electron deficient polyene as being an electronic rather than steric effect. This relative configurational stability may be further investigated as additional electrophilic polyenes are synthesized.…”

Ligand-dependent stereoselective Suzuki–Miyaura cross-coupling reactions of β-enamido triflates

“…In the last decade, only a few reports describing isomerization of the double bond of vinyl (pseudo)halides during the Suzuki coupling have been published [25][26][27][28][29]. Typically, inversion of configuration occurs on substrates containing a double bond in conjugation with an electron-withdrawing group, such as the carbonyl group in enones [27,30].…”