Kizhakethil M. Sadhu

Chloromethyl) lithium in an efficient conversion of carbonyl compounds to chlorohydrins or oxiranes

Abstract (Chloromethyl)lithium has been generated and captured in nearly quantitative yields by addition of n -butyllithium or methyllithium to mixtures of chloroiodomethane with aldehydes or ketones in THF at −78 °C. Immediate acidification yields chlorohydrins, delayed workup yields epoxides.

Benzamidomethaneboronic acid: Synthesis and inhibition of chymotrypsin

Benzamidomethaneboronic acid (2) has been synthesized unambiguously from the reaction of dibutyl iodomethaneboronate and N-lithiohexamethyldisilazane to form dibutyl [bis(trimethylsilyl)amino]methaneboronate (4), which was desilylated, benzoylated, and hydrolyzed to 2. It has been shown that 2 is a strong competitive inhibitor of alpha-chymotrypsin (Ki = 8.1 X 10(-6) M, pH 7.5). The reaction product from dibutyl iodomethaneboronate and sodiobenzamide, previously shown to be a potent inhibitor of chymotrypsin, was shown by this work to be O-linked isomer, benzimidoxy-methaneboronic acid (3). The pH-Ki profile over the pH range 6.5-9.5 was consistent with the formation of an enzyme-inhibitor complex which resembled the metastable tetrahedral reaction intermediates occurring during acylation and deacylation of chymotrypsin-catalyzed hydrolysis.

Directed asymmetric synthesis with boronic esters

Our recent work on asymmetric synthesis is reviewed. Boronic esters with (dichloromethyl)lithium at −100°C form borate complexes which rearrange at 0–25°C, preferably in the presence of zinc chloride, to form α-chloro boronic esters. (+)-Pinanediol boronic esters routinely yield (αS)-α-chloro boronic esters which are > 99% this single diastereomer, and which readily undergo displacement of the chloride by nucleophilic reagents such as Grignard reagents or alkoxides to yield chiral boronic esters. The sequence may be repeated to install adjacent chiral centers. Since (−)-pinanediol is also readily available, this process provides a useful method for absolute control of stereochemistry. An alternative chiral directing group, (R,R)2,3-butanediol, yields 95% (αS)-α-chloro boronic esters and is useful for several practical purposes. Our ultimate products have been chiral alcohols formed from peroxidic cleavage of the boronic ester group, including examples of insect pheromones containing paired chiral centers. We have also prepared several α-acetamido boronic esters, which are inhibitors of serine protease enzymes.