Carbanions isotopic label

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

Because of the localization of electron density and negative charge, carbanions are both bases and nucleophiles. As a base, a carbanion can abstract a proton from any substance with a pKa smaller than that of the protonated carbanion, and the use of isotopically labeled proton donors affords a useful synthesis of labeled compounds. For example, abstraction of a proton from the methyl group of exo-3-acetyl-endo-tricyclo[3.2.1.0 ]octane (88) gave an enolate ion that could abstract a deuterium ion from the solvent to produce a monodeuterated compound. Repeated exchange of the methyl protons led to a nearly quantitative yield of trideuterio product 89 (equation... 

This reaction was confirmed by isotopic labelling. When cyclo-butanecarbonitrile was in excess, the product, even under mild conditions, was dicyclobutyl ketone (v =q 1700 cm l) formed by a rapid reaction of carbanion with the CN group (Thorpe-Ziegler reaction). 

Extension of this research was then delayed until two of us had returned to New Zealand. One of the first jobs of Tasker, a PhD student from Brisbane, was to use 3H-labeling methods to examine epimerization. At that time we were under the impression that reprotonation of carbanion intermediates would be diffusion controlled, as was subsequently reported for phenylglycine in phosphate buffers (18), so that no isotopic discrimination against 3H would be present. But then Wautier et al. reported (6) the complete loss of chirality in [Co(tren)(AA-(S)-AA OMe)]3+, prepared by treating [Co(tren)((S)-AAOMe)]3+ (AA = Ala, Leu) generated in situ in MeOH with (S)-AA OMe (AA = Leu, His, Ala, Val), although their reaction times and temperatures (1-15 h sometimes 35-50°C) and other experimental conditions ([Co(III)] —0.1 M L/V-ethylmorpholine salt of p-toluene sul-... 

Kuo and Rose showed that the proton that is removed is retained by the enzyme (67). Stubbe and Abeles prepared an alternative substrate in which fluoride elimination competes with carboxylation 68, 69). Neither result defines the mechanism, but they do show that it is likely that the carbanion derived from the substrate is generated as an intermediate and therefore the reaction is not concerted. Definitive results come from double-isotope fraction studies by O Keefe and Knowles (70) and by Cleland and co-woricers (71). As described for Claisen enzymes, this methodology tests whether processes occur in one or two steps. Labeling of the carboxyl to be transferred with carbon-13 and the proton to be transferred as deuterium provided the means to do this test. The results indicate clearly that proton removal from the substrate to generate the carbanion and transfer of the carboxyl occurs in distinct steps. The resulting attack of the carb-... 

Possibly the measurement of the chlorine isotope effect for a series of suitably substituted substrates may help to decide whether or not greater stereospecificity is associated with decreased carbanion character of the transition state for elimination from alkenes. Of course, such studies must be accompanied by labelling experiments to exclude the possibility that alkynes arise by an apparent alpha-elimination (Section 5.1) involving formation of a carbanion at the alpha carbon, which subsequently eliminates alpha halogen simultaneously with migration of a substituent from the beta carbon. Results with alcoholic media, however, tend to indicate this alternative mechanism is unimportant if a normal beta-elimination is possible. 

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