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Alkyne Hydrofunctionalization and Dehomologative Olefin Synthesis

  • Author(s): Cruz, Faben
  • Advisor(s): Dong, Vy M
  • et al.
Abstract

The dehydroformylation of aldehydes to generate olefins occurs during the biosynthesis of various sterols, including cholesterol in humans. A mild and chemoselective synthetic version has been developed that features the transfer of a formyl group and hydride from an aldehyde substrate to a strained olefin acceptor. A Rh(Xantphos)(benzoate) catalyst activates aldehyde C–H bonds with high chemoselectivity to trigger C–C bond cleavage and generate olefins at low loadings (0.3 to 2 mol%) and temperatures (22 to 80 °C). This mild protocol is tolerant of several functional groups and can be applied to various natural products, including a deoxycholic acid derivative.

Previous efforts to directly transform alcohols to olefins via dehomologation have been limited to isolated examples and/or occur at harsh conditions (>380 ºC). This same Rh(Xantphos)(benzoate) catalyst enables access to olefins from primary alcohols by a C–C bond cleavage that results in dehomologation. This functional group interconversion proceeds by an oxidation-dehydroformylation enabled by N,N-dimethylacrylamide as a sacrificial acceptor of hydrogen gas. Alcohols with diverse functionality and structure undergo oxidative dehydroxymethylation to access the corresponding olefins. This catalyst protocol enables a two-step semi-synthesis of (+)-yohimbenone and dehomologation of feedstock olefins. Under mild conditions, the olefin remains intact without further reduction or isomerization.

Hydrofunctionalization is an attractive method for transforming alkynes that addresses the need for atom-economic, green, and sustainable processes. Alkyne hydrofunctionalizations typically generate achiral poly-substituted olefins. We envisioned that using metal-hydride catalysis would enable novel alkyne activation and functionalization. We have developed metal-hydride catalysts that isomerize alkynes to generate metal-allyl species which are then coupled with a variety of partners to generate new alkyne hydrofunctionalization motifs bearing a chiral center and terminal olefin. By careful choice of metal-hydride catalyst, we can control the polarity of the generated metal-allyl species (nucleophilic vs. electrophilic) and engage with an appropriate coupling partner to achieve (1) alkyne hydroacylation with unprecedented regiocontrol via Ru–H catalysis, (2) decarboxylative alkyne hydroalkylation with β-keto acids via Rh–H catalysis, (3) stereodivergent alkyne hydroalkylation with aldehydes via synergistic Rh–H/enamine catalysis, and (4) enantioselective alkyne hydroheteroarylation via Rh–H catalysis. Ultimately, we hope that this new mode of alkyne functionalization would enable chemists to use alkynes as an alternative synthetic disconnection.

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