The catalytic asymmetric synthesis of both α-substituted and α,α-disubstituted (quaternary) β-tetralones through direct α-functionalization of the corresponding β-tetralone precursor remains elusive. A designed Brønsted base-squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α-monosubstituted β-tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α-carbon atom of the β-tetralone exclusively, but adducts including all-carbon quaternary centers are also formed in highly diastereo- and enantioselective manner.

In this study, the unique capacity of bifunctional Brønsted bases to generate α‐branched ketone dienolates and control both site‐ and stereoselectivity of their addition reactions to representative classes of carbon electrophiles (i.e., vinyl sulfones, nitroolefins, formaldehyde) is documented. We demonstrate that by using selected chiral tertiary amine/squaramide catalysts, the reactions of β,γ‐unsaturated cycloalkanones proceed through the dienolate Cα almost exclusively and provide all‐carbon quaternary cyclic ketone adducts in good yields with very high enantioselectivities. A minor amount (<5 %) of γ‐addition is observed when nitroolefins are used as electrophiles. The parent acyclic ketone dienolates proved to be less reactive under these conditions, and thus still constitute a challenging class of substrates. Quantum chemical calculations correctly predict these differences in reactivity and explain the observed site‐specificity and enantioselectivity.

The catalytic asymmetric synthesis of both a-substituted and a,a-disubstituted (quaternary) b-tetralones through direct a-functionalization of the corresponding b-tetralone precursor remains elusive.Adesigned Brønsted base-squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or a-monosubstituted b-tetralones to nitroalkenes.U nder these reaction conditions, not only enolization, and thus functionalization, occurs at the a-carbon atom of the b-tetralone exclusively,b ut adducts including all-carbon quaternary centers are also formed in highly diastereo-and enantioselective manner.Syntheses of many bioactive compounds with polycyclic structures,i ncluding homoerythrina alkaloids, [1] morphan derivatives, [2] glucocorticoid receptors, [3] and stradiols, [4] among others, [5] have employed b-tetralones.H owever, this interest did not translate into avariety of approaches for the asymmetric synthesis of substituted b-tetralones.M ost approaches for the a/a'-functionalization of b-tetralones so far documented exploit the idea of Stork et al. [6] which involves condensation with ac hiral amine and subsequent C-alkylation of the resulting enamine,typically by addition to aMichael acceptor. [7] One complication, for any nonsymmetric cycloalkanone,ist hat enolization may occur at either the a or a' site.Inthis context, Blarer and Seebach [8] reported that the reaction with nitrostyrenes of the enamine derived from (S)-2-methoxymethylpyrrolidine,a nd the respective b-tetralone produced in moderate yields the a'-adduct predominantly (a/a' from 1:4t o1 :20) with generally good diastereoand enantioselectivity after hydrolysis of the resulting iminium species (Scheme 1a). Alternatively,t he groups of Pfau and dAngelo reported the condensation of b-tetralones with (S)-1-phenylethylamine and subsequent Michael reaction to afford the a-substituted adducts preferentially, [9] but with exceptions. [9a] Apart from these stoichiometric multistep approaches,we are unaware of catalytic methods for the enantioselective a-functionalization of b-tetralones leading to an all-carbon quaternary stereocenter. [10] Chen and co-workers have reported direct reaction of b-tetralones with a,b-unsaturated aldehydes by iminium activation, [11] but stereogenicity at C a is lost upon spontaneous hemiketal formation. Herein we report the direct site-, diastereo-, and enantioselective C a -alkylation of b-tetralones by conjugate addition reaction enabled by newly designed Brønsted base catalysts.The new C À Cbond is formed at the a-carbon atom exclusively,a nd adducts, including those with an a-quaternary center, are formed in ahighly stereoselective manner.Our consideration was that the fused aromatic ring in b-tetralones might induce preferential enolization at C a rather than C a ',a nd that in the presence of aB rønsted base relatively high concentrations of the enolic form would be expected, thus eventually driving the catalytic process forward. Nonetheless,t his assumption was accompanied by asecond significant...