Synthesis of novel chiral bipyrimidine diphosphine and aminoalcohol ligands and their application in asymmetric catalysis

Abstract

Palladium-catalyzed asymmetric allylic alkylation (AAA) is one of the most powerful tools for the sterically controlled introduction of carbon-carbon and carbon-heteroatom bond formation. In this thesis work, a novel chiral atropisomeric diphosphine ligand, 5,5'-bis(diphenylphosphino)- 1,1',3,3'-tetramethyl-4,4'- bipyrimidine-2,2',6,6'-( 1H, 1'H,3H,3'H)-tetrone (PM-Phos) was developed, whose palladium complex exhibited good to excellent enantioselectivity in catalytic asymmetric allylic alkylation. PM-Phos is the first bipyrimidine-type diphosphine ligand. The synthetic highlight includes an interesting "halogen-dance" reaction, a crucially modified Ullmann coupling procedure and an unexpected methyl group rearrangement. With the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with malonates as a model reaction, the asymmetric induction properties of PM-Phos was preliminarily tested. In this reaction, the optimal nucleophile was dimethyl malonate, the optimal solvent was CH2Cl2 and the optimal base was NaOAc. The catalytic activity of the PM-Phos palladium complex was excellent especially at room temperature. The enantioselectivity was fair at room temperature, but good at 0 oC and almost excellent at a lower temperature (up to 95% ee at -40 oC). Another part of this thesis work is the synthesis of novel chiral amino alcohol ligands. With L-valine as starting material, new amino alcohol ligands with two stereogenic centers, i.e., 1R- [2'-(6'-methoxynaphthyl)] -2S-amino-3 -methylbutan-1-ol (4-6a) and 1R- [2'-(6'-methoxynaphthyl)] -2S-pyrrolidinyl-3 -methylbutan-1-ol (4-8), were synthesized. The enantioselective borane reduction of acetophenone catalyzed by the amino alcohols 4-6a provided high ee's (up to 97%). The enantioselective diethylzinc addition to aldehydes catalyzed by the N,N-cycloalkylated amino alcohol 4-8 also afforded the corresponding chiral secondary alcohols with good to excellent ee's (up to 98%). The third part of this thesis work is based on chiral ruthenium-complex catalysts recycled by ion exchangers and their application in asymmetric hydrogenation. The ruthenium complex of P-Phos was an excellent catalyst for the asymmetric hydrogenation of b-ketoesters. After the reaction, the catalyst was separated easily by a column packed with silica gel-based ion exchanger and was used in the subsequent recycling runs of the reaction with a slight loss of enantioselectivity and activity. This result indicates that the special nitrogen-containing feature of P-Phos favors the stability and recyclability of its ruthenium complex catalyst in asymmetric hydrogenation.