Hydrogen-bonding activation stereochemistry

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. 

A number of 7V-carboxyalkyl and A-phosphonoalkyl substituted substrate analogue inhibitors have been examined [161,204-208]. These derivatives contain both the acidic carboxylate (or phosphonate) and basic amine functionalities in the vicinity of the scissile bond. Thus, they are capable both of electrostatic interaction with the active site Zn(II) and hydrogen bonding interactions with other active site residues. They are, however, only moderately potent collagenase inhibitors Table 8.18). The stereochemistry at the carbon atom to which the carboxylate moiety is bonded markedly influences the inhibitory potency of these derivatives ((197) vs. (198)). The phosphonate analogues of this class of derivatives have also been evaluated Table 8.18), but are not substantially better inhibitors than the carboxyl-ates. 

As shown in Fig. 3, Lewis acids (i.e., metal ions and hydrogen bond donors) display syn or anti stereochemistry as they interact with the carboxylate anion. However, in a study of enzyme active sites. Candour (1981) first noticed that hydrogen bond donors to the carboxylates of aspartate and glutamate residues preferentially occur with syn stereochemistry. As a carboxylate-hydrogen bond donor interaction COg-H... 

Fig. 27. Optimal hydrogen bond stereochemistry in the active site of carbonic anhydrase II. Lone electron pairs are represented by stippled dumbbells.

Derivatives with a C-14 hydroxyl group such as oxymorphone (5.89, 7, 8-dihydro-14-hydroxymorphine-6-one) show increased potency (up to five times that of morphine), probably as a result of the introduction of an additional hydrogen-bonding substituent. The stereochemistry of this hydroxyl is of considerable importance in terms of activity. 

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