Over the past several years, highly effective methods for enantioselective aldol additions catalyzed by Lewis acids have been developed.1 Analogous alkylations of imines, however, have not been nearly as well studied nor as successful.2 R-Imino esters are almost unstudied in Lewis acid-catalyzed reactions,3 but are especially attractive imine substrates for the efficient syntheses of natural product precursors,4 pharmaceutically active compounds,5 and nonnatural amino acids;6 the last category has recently received much attention as peptidomimetics7 and in sitedirected mutagenesis studies.8 In a recent report, we demonstrated that select late transition metals can catalyze the cis-trans isomerization of prolyl peptides through simultaneous coordination of the metal to the amide nitrogen (Na) and the side chain carbonyl group (Figure 1, a).9 Catalysis fails to occur on simple amides that do not contain an additional binding site. These results prompted us to investigate whether analogous coordination of a transition metal to the nitrogen of a functionalized imine and a chelating carbonyl group could activate the substrate toward a highly enantioselective addition of nucleophiles (Figure 1, b). From our point of view, activated R-imino esters 1 seemed ideal substrates for Lewis acid catalyzed asymmetric alkylations for several reasons: (1) alkylation occurs readily at the imine carbon with a variety of nucleophiles, (2) the electron-withdrawing R-ester group provides additional activation of the imino group to nucleophilic attack, (3) the imine N and carbonyl O can form a stable five-membered chelate ring with a chiral Lewis acid catalyst (eq 1),10 providing additional rigidity to an activated complex and potentially enhanced product selectivity, and (4) alkylation of imine derivatives 1 with enol silane nucleophiles can lead to substituted γ-oxo R-amino acids (aspartic acid analogues) that comprise a class of interesting and useful biologically active natural compounds.11 We report herein a means to alkylate R-imino esters enantioselectively in up to 98% ee and in high chemical yields with enol silanes using chiral catalytic late transition metal phosphine complexes selected from Ag(I), Cu(I), Ni(II), and Pd(II) (eq 2).
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Apr 1, 2019
D N Gorbunov + 5
Open Access