Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates.
Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.
Hamashima
Yoshitaka
Y
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Miyagi, Japan. yhamashima@riken.jp
D002021:Buffers; D002384:Catalysis; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism
D002021:Buffers; D009942:Organometallic Compounds; D010165:Palladium