Amidation of rac-N-Boc amino acid thioesters under DKR conditions

Amide bond formation is a labour intensive process often involved in the synthesis of fine chemicals; esters and thioesters aminolysis is a practical method of amide synthesis avoiding inconvenient carboxylate activation. In recent evaluations of chemical processes trying to comply to the rule of GMF and green chemistry, amide bond formation was identified as one of the most utilized and problematic synthetic step in the pharmaceutical industry. From a detailed study it was found that N-acylation reactions for amide formation were used in more than 50% of current synthesis of drug candidates. We have recently developed an efficient methodology for the hydrolysis of N-protected amino acid thioesters under Dynamic Kinetic Resolution (DKR) conditions, where the relatively high acidity of the α-hydrogen was exploited in a base-catalysed substrate racemization occurring in the same pot with a selective, protease-mediated, hydrolysis. As a result, several amino acid derivatives have been obtained with high conversions and enantiomeric excesses. We now report on a similar procedure aimed at the deracemization of a group of rac-N-Boc-Aas-thioesters with N-protected amino acid amides formation. Starting with the relative thioester, in presence of a racemizing strong organic base (DBU) and a nitrogen nucleophile in t-ButOH with controlled water activity, ammoniolysis or aminolysis catalyzed by CLEA AlcalaseTM yield the corresponding amide with high optical purity and high chemical yields. The reaction is carried out under kinetic control, and a number of parameters (amine concentration, base ratio, water content, enzyme amount) are critical for the successful DKR process. Here we present some results so far obtained employing this methodology.