Cinchona hydrophosphonylation

Based on prior results where Ricci used Cinchona alkaloids as phase-transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48], Employing the chiral tertiary amine as a Brpnsted base, a-amino phosphonates products were synthesized in high yields and good selectivities. 

The first catalytic enantioselective hydrophosphonylations of ketimines (363) using commercially available cinchona alkaloids (364) and (365) have been reported by Nakamura et al. (Scheme 83). ... 

Organocatalytic asymmetric hydrophosphonylation/Mannich reactions using thiourea, cinchona and Bronsted acid catalysts 12SL1108. Organocatalytic asymmetric transformations of modified Morita—Bayhs— HiUman adducts 12CSR4101. 

In 2009, Feng et al. reported the asymmetric hydrophosphonylation of a-keto esters catalysed for the first time by cinchona-derived thiourea organocatalysts. Thus, a series of aromatic and heteroaromatic a-keto esters reacted with dimethyl phosphite to afford the corresponding a-hydroxy phosphonates in high yields and enantioselectivities of up to 91% ee (Scheme 2.53). 

The mechanism and stereochemistry of hydrophosphonylation of a-ketoesters by dimethylphosphonate [H-P(=0)(0Me)2l has been studied theoretically by the ONIOM method, for catalysis by cinchona-thioureas. Deprotonation of the phosphonate 0 is rate determining. It is followed by C-P bond formation (the stereo-controlhng step) via nucleophilic addition, and then reprotonation (regenerating the catalyst). Multiple hydrogen bonds activate the substrates, facilitate charge transfer and stabihze transition states. 

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