Curtin-Hammett versus non-Curtin-Hammett frameworks is optimizing the enantioselective binolam/titanium(IV)-catalyzed cyanobenzoylation of aldehydes: Part 2

Extensive experimental and computational studies have been carried out on the enantioselective titanium(IV)-catalyzed cyanobenzoylation of aldehydes using 1:n Binolam:Ti(OiPr)4 mixtures as precatalysts, with the purpose of identifying the key mechanistic aspects governing enantioselectivity. HCN and isopropyl benzoate were detected in the reacting mixtures. This, as well as the reaction’s response to the presence of an exogenous base, and the failure to react in the presence of Binol:Ti(OiPr)4 mixtures, led us to propose not a direct cyanobenzoylation but an indirect process involving enantioselective hydrocyanation followed by O-benzoylation. Computational work provided positive evidence for the intervention of both indirect and direct cyanobenzoylation routes, the former being faster. However, the standard Curtin–Hammett-based optimization search ended with unsatisfactory results. Experimental and computational DFT studies (B3LYP/6-31G*) led us to conclude that: (1) the overall cyanobenzoylation of aldehydes catalyzed by 1:n Binolam:Ti(OiPr)4 mixtures involves an enantioselective hydrocyanation followed by an stereochemically inert O-benzoylation; (2) the initial complexes prevailing in a 1:1 Binolam:Ti(OiPr)4 mixture are the solvated mononuclear monomer 5·2(iPrOH) and solvated dinuclear dimer 9·2(iPrOH), whereas 9·2(iPrOH) is the major component in a 1:2 or higher 1:n mixture; (3) since the slowest step is that of benzoylation of ligated iPrOH which yields the actual catalysts 5–9, the catalytic system fits into a non-Curtin–Hammett framework, the final products deriving from a kinetic quench of the competing routes; and (4) accordingly, catalysis by 1:1 Binolam:Ti(OiPr)4 mixtures should involve cyanobenzoylations promoted by mononuclear 5, contaminated with those promoted by some dinuclear open dimer 9, whereas cyanobenzoylations catalyzed by a 1:2 and higher 1:n mixtures should be the result of catalysis promoted by the large amounts of dinuclear open dimer 9.

Copper-Catalyzed Asymmetric Alkylation of β-Keto Esters with Xanthydrols

The copper(II) triflate-tert-butyl-bisoxazoline [Cu(OTf)2-t-Bu-BOX]-catalyzed asymmetric alkylation of β-keto esters using free benzylic alcohols such as xanthydrols, as alkylating agents, is herein described for the first time. This green protocol renders in general the corresponding products with good results in terms of both yields and enantioselectivities using different keto esters, even when quaternary stereocenters were created. The scope, limitations and mechanistic aspects of the process are also discussed.