Synergistic One-pot Tandem Combination of Cu and Proline Catalysis: Stereodivergent Synthesis of Chiral Aldols from Primary Alcohols

A new stereodivergent one-pot tandem protocol, whichgranted diastereo- and enantioselective access to chiral aldolsby starting from simple primary alcohols, is presented as aproof-of-concept. The synergistic combination of a chemo-selective Cu(II)-catalyzed oxidation of primary alcohols into thecorresponding aldehydes (without the expected overoxidationinto the corresponding carboxylic acids and using simple aerialO2 as co-oxidant), followed by a concomitant organocatalyzedenantioselective aldol coupling promoted by the system (S)-proline/HTBD-BF4 [TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene],was achieved after fine-tuning and compatibilizing the con-ditions required for the successful performance of both catalyticsystems. Here, we demonstrated that selection and pairing of both catalysts needs to be extremely judicious to avoidorthogonality, kinetic, concentration or reciprocal poisoningissues. Refinement of the overall tandem protocol allowed us todesign a synergistic and stereodivergent protocol which affordscomparable or even better diastereoselective results than theorganocatalytic system by itself. Finally, the following keyfactors (from a sustainable point of view) should be highlighted:i) no external VOC solvents are needed during our one-pottandem synthetic protocol (by working under neat conditions);and ii) isolation/purification of any intermediate is not required,thus reducing the chemical waste and energy/time costs,simplifying the practical aspects of our synthetic methodology.