Deuterium labelling carbonyl reduction

The mechanism of the reduction remains uncertain. The work of E. D. Williams, K. A. Krieger and A. R. Day (1953) using deuterium-labelled aluminium isopropoxide, shows that hydrogen atoms are transferred predominantly from the central carbon atom of an isopropoxide group to the carbon atom of the carbonyl group undergoing reduction, the process probably involving a cyclic complex ... 

As corroborated by deuterium labeling studies, the catalytic mechanism likely involves oxidative dimerization of acetylene to form a rhodacyclopen-tadiene [113] followed by carbonyl insertion [114,115]. Protonolytic cleavage of the resulting oxarhodacycloheptadiene by the Bronsted acid co-catalyst gives rise to a vinyl rhodium carboxylate, which upon hydrogenolysis through a six-centered transition structure and subsequent C - H reductive elimina-... 

Although a cobalt-catalyzed intermolecular reductive aldol reaction (generation of cobalt enolates by hydrometal-lation of acrylic acid derivatives and subsequent reactions with carbonyl compounds) was first described in 1989, low diastereoselectivity has been problematic.3 6 However, the intramolecular version of this process was found to show high diastereoselectivity (Equation (37)).377,377a 378 A Co(i)-Co(m) catalytic cycle is suggested on the basis of deuterium-labeling studies and the chemistry of Co(ll) complexes (Scheme 81). Cobalt(m) hydride 182, which is... 

The asymmetric reduction of raeso-epoxides with hydrogen or hydrides has been scarcely explored, despite the synthetic utility of the chiral secondary alcohol products. The lone example has been provided by Chan, who treated the disodium salt of epoxysuccinic acid with H2 or MeOH as the reducing agent in the presence of a chiral rhodium catalyst (Scheme 13) [27]. Deuterium labeling experiments established that the reduction proceeded through direct cleavage of the epoxide C-O bond, rather than isomerization to the ketone followed by carbonyl reduction. 

Three different methods have been discussed previously (sections III-C,III-D and IV-A) for the replacement of a carbonyl oxygen by two deuteriums. However, in the conversion of a 3-keto steroid into the corresponding 3,3-d2 labeled analog, two of the three methods, electrochemical reduction (section ni-C) and Raney nickel desulfurization of mercaptal derivatives (section IV-A), lead to extensive deuterium scrambling and the third method, Clemmensen reduction (section III-D), yields a 2,2,3,3,4,4-dg derivative. 

The Clemmensen reduction was accompanied by D/H exchange via acid-catalysed enolization of the carbonyl group, resulting in the production of deuteriated compounds 57 and 58 with various numbers of deuterium atoms. The mixture of the compound 59 obtained by the Wolf-Kishner reduction was predominantly labelled at position 2. This has been proved by the 13C-NMR spectrum. Isotope shift and loss intensivity on substituted C(2) carbon signals have been observed54,55. 

Reduction of activated carbonyl groups of a-keto esters, benzils, cyclohexane-1,2-dione, and o -ketophosphonates by alkylphosphines afforded the corresponding cr-hydroxy esters or ketones in good to excellent yields. A mechanism has been suggested on the basis of deuterium and 180 labelling experiments.380... 

This reduction almost certainly proceeds via the activation of the aldehyde carbonyl both by bond polarization in the ground-state and by stabilization of bonding interactions in the transition state. Although deuterium isotope labeling experiments show that hydrogen transfer is direct, comparison of kinetic isotope effects with isotope discrimination studies (23) suggest that the transition state of this reaction may not be a simple transfer of hydride ion (see Section IV—2). 

Asymmetric reduction of carbonyl compounds and production of isotopically labelled species has been achieved. A system based on deuterated formate and formate dehydrogenase provides the best system for the introduction of deuterium through nicotinamide-cofactor catalysed process (Table 2). 

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