Hydrometallation-asymmetric conjugate addition: application to complex molecule synthesis

Abstract

Copper catalysis allows alkyl zirconium species, generated in situ from alkenes, to undergo conjugate addition reactions. A hydrometallation-catalytic asymmetric 1,4-addition was used to synthesize either enantiomer of a natural product in one step from commercially available materials. Hydrometallation-addition sequences applied to steroids containing a cross-conjugated dienone or 1,6-acceptor give highly functionalized products.

Formation of Quaternary Centers by Copper‐Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

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Alkenes are among the most readily available organic molecules, and are feedstocks for the preparation of many commodity chemicals. We recently reported [2] that alkenes can be used as the equivalents to premade alkyl metal species in coppercatalyzed asymmetric conjugate additions (ACA). We recently reported [2] that alkenes can be used as the equivalents to premade alkyl metal species in coppercatalyzed asymmetric conjugate additions (ACA).

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“…We recently reported [2] that alkenes can be used as the equivalents to premade alkyl metal species in coppercatalyzed asymmetric conjugate additions (ACA). [2] Herein we report that this approach can be used to form quaternary centers. These processes are currently limited to the formation of tertiary centers from ACA to unsubstituted cyclic enones.…”

Asymmetric Conjugate Additions and Allylic Alkylations Using Nucleophiles Generated by Hydro‐ or Carbometallation

“…[61,62] This generally gives high enantioselectivity in additions to cyclic enones at room temperature, and as shown in Scheme 24, tolerates ar ange of functional groups.T he procedure is generally compatible with different solvents and additives, and can be used on ag ram scale with no loss of enantioselectivity or yield. [63] Additionally,w er ecently demonstrated the use of internal alkenes as precursors for terminal alkylzirconium nucleophiles, generated by hydrometallation of the internal olefin followed by thermal iso-Scheme15. [63] Additionally,w er ecently demonstrated the use of internal alkenes as precursors for terminal alkylzirconium nucleophiles, generated by hydrometallation of the internal olefin followed by thermal iso-Scheme15.…”

Copper-catalyzed steroid reactions

“…The formation of by-products by reductive dehalogenation was not observed at all, in contrast to the amination of substrate 73. In 2013 Fletcher et al 37 examined a hydrometallation-addition sequence with unsaturated steroids and found that copper catalyzed conjugate addition reactions readily occur, and functional groups are tolerated (Scheme 24). 1,4-Androstadiene-3,17-dione 84 is a cross-conjugated dienone capable of 1,4-addition reactions, 1,2-additions to the dienone and ketone moieties, as well as other possibilities, such as rearrangement.…”