Two chiral catalysts in action: insights into cooperativity and stereoselectivity in proline and cinchona-thiourea dual organocatalysis.

Increasing use of two chiral catalysts in cooperative asymmetric catalysis in recent years raises some fundamental questions on chiral compatibility between the catalysts, modes of activation, and relative disposition of substrates within the chiral environment of the catalysts for effective asymmetric induction. We present molecular insights into a one-pot catalytic Michael reaction cascade between a dicarbonyl compound (7-oxo-7-phenylhept-5-enal) and nitrostyrene, catalyzed by two chiral organocatalysts (proline and cinchona-thiourea), leading to a densely functionalized tetra-substituted cyclohexane product. The density functional theory (SMD_(toluene)/M06-2X/6-31G**) computations helped us identify the role of the organocatalytic catalytic dyad in providing a lower energy pathway. The covalent activation of the aldehydic end by (S)-proline results in an enamine, which then adds to the noncovalently activated nitrostyrene in the first Michael addition to give a nitronate anion. The configuration at two of the four chiral centers of the product gets fixed in this step whereas that of the remaining two is determined by intramolecular cyclization between the nitronate and the enone. Important mechanistic features such as (a) a lower energy pathway as compared to a proline-only route for the formation of the syn-enamine and its participation in the first Michael addition and (b) the origin of the preferred prochiral faces in the C-C bond formation are traced to the active involvement of the cinchona-thiourea catalyst in conjunction with proline in each step of the reaction. The true cooperative action by both the catalysts is identified as enabled by a network of hydrogen bonding, and π···π stacking between the aryl ring of the cinchona-thiourea catalyst as well as other noncovalent interactions between the catalysts themselves, and that between the catalysts and substrate.