Biomedical subjects
Publications and source records attributed to Artem Melman.
This review is devoted to the problem of chemoselective formation of ester functions in polyfunctional molecules. The review covers most typical approaches to chemoselective acylation of hydroxy groups in molecules containing an amino, mercapto, or another hydroxy functionality as well as chemoselective esterification of di- and polycarboxylic acids.
Esterification of carboxylic acids capable of forming ketene intermediates upon treatment with carbodiimides permits the selective acylation of alcohols in the presence of phenols lacking strong electron-withdrawing groups. The selectivity of acylations involving highly acidic phenols could be reversed through the addition of catalytic amount of acid. Esterification of other carboxylic acids was found to proceed through the formation of symmetric anhydrides and provide the opposite chemoselectivity. In both cases the relative acylation rates of substituted phenols are consistent with a reaction mechanism involving an attack of phenolate anions on electrophilic intermediates such as ketenes and symmetric anhydrides, with the carbodiimides serving both as an activating reagent and as a basic catalyst.
Carboxylic acids possessing a strong electron-withdrawing group in the alpha-position undergo facile dehydration upon reaction with carbodiimides to form the corresponding substituted ketenes that can react in situ with alcohols providing esters in a high yield. The ketene formed by the treatment of ethyl 2-methylmalonate with DCC was trapped in situ by a [4+2] cycloaddition with a second DCC molecule. The chemoselectivity of the acylation through the ketene intermediates was found to be substantially different from that of conventional acylation reagents showing a very low sensitivity toward the steric bulk of alcohols. A comparison of the sensitivity of the acylation to the steric bulk of alcohols supports the presence of a pseudopericyclic pathway for the nucleophilic addition of alcohols to ketenes derived from ethyl malonic and diethylphosphonoacetic acid.
Zirconacycles 1, obtained from diethyl 1-alkynylphosphonates, insert either acyl chlorides or nitriles to provide, after acidic workup, (E)-3-oxo-1-alkenylphosphonates, 2, in isolated yields of 55-83%. Insertion produces only one regio- and stereoisomer. The reaction is quite general and proceeds well with both aliphatic and aromatic acyl chlorides. Acetonitrile and p-methoxybenzonitrile also inserted efficiently. Insertion of isobutyl chloroformate produced the vinylphosphonocarboxylate, 2c, the first representative of this class of compounds.
Thiol-mediated free radical isomerization of a deliberately substituted but-3-enyl isocyanide 12a, and n-Bu(3)SnH/AIBN-mediated free radical cyclization of a deliberately substituted but-3-enyl isothiocyanate 22, afforded, respectively, the (ethylthio)pyrroline 13a and the thiopyroglutamates 5 and 23. Reduction, protection, and deprotection of these heterocyclic compounds afforded proline derivatives 6 and 25 which contain all the structural elements of alpha-kainic acid (1) except the C-2 acetic acid moiety. These intermediates were stereospecifically converted into (+/-)-alpha-kainic acid using a new method of temporary sulfur connection. Accordingly, CH(2)CO(2)Me is linked to the chiral isopropenyl anchor and then intramolecularly connected to the pyrrolidine ring and eventually disconnected from its anchor by a sequential reductive double elimination process in which the isopropenyl double bond is restored.