Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins

Abstract

Carbon-carbon bonds, including those between sp³-hybridized carbon atoms (alkyl-alkyl bonds), typically comprise much of the framework of organic molecules. In the case of sp³-hybridized carbon, the carbon can be stereogenic and the particular stereochemistry can have implications for structure and function^1-3. As a consequence, the development of methods that simultaneously construct alkyl-alkyl bonds and control stereochemistry is important, although challenging. Here we describe a strategy for enantioselective alkyl-alkyl bond formation, in which a racemic alkyl electrophile is coupled with an olefin in the presence of a hydrosilane, rather than via a traditional electrophile-nucleophile cross-coupling, through the action of a chiral nickel catalyst. We demonstrate that families of racemic alkyl halides-including secondary and tertiary electrophiles, which have not previously been shown to be suitable for enantioconvergent coupling with alkyl metal nucleophiles-cross-couple with olefins with good enantioselectivity and yield under very mild reaction conditions. Given the ready availability of olefins, our approach opens the door to developing more general methods for enantioconvergent alkyl-alkyl coupling.

Figure 1|. Transition-metal-catalyzed enantioconvergent alkyl-alkyl cross-coupling reactions of racemic alkyl electrophiles.

R = carbon substituent; X = leaving group; M = metal; Y = R or H; ee = enantiomeric excess.

Figure 2|. Enantioconvergent alkyl-alkyl cross-couplings of racemic secondary alkyl electrophiles with olefins.

a, Secondary α-halocarbonyl compounds as electrophiles. b, Transformation into other families of enantioenriched compounds. c, Other families of electrophiles. d, Chain-walking and “directed” alkylation. e, Alkynes as coupling partners. ^aIodide as the leaving group. ^bReaction run in toluene at room temperature. ^cReaction run in toluene. ^dReaction run with 2 equiv NaI. ^eReaction run with 0.5 equiv (n-Bu)₄NI.

Figure 3|. Enantioconvergent alkyl-alkyl cross-couplings of racemic tertiary alkyl electrophiles with olefins.

a, Couplings. b, Transformation into other families of enantioenriched compounds.

Figure 4|. Mechanism.

a, Evidence against a conventional cross-coupling mechanism. b, Possible mechanism for enantioconvergent electrophile/olefin cross-coupling (for the sake of simplicity, all steps are drawn as irreversible; H-Si(OEt)₃ represents the hydrosilane activated by K₃PO₄•H₂O). c, Synthesis of proposed intermediates A and C. d, Competence of complexes A and C as catalysts. e, Chemical competence of complex C. f, Support for β-migratory insertion. g, Identification and quantification of the likely resting state via UV-vis spectroscopy (coupling partners illustrated in d, using10% NiBr₂•glyme/12% (R,R)-L*, at ∼25% conversion).