Graduate Thesis Or Dissertation
 

Analysis of the mechanism of sulfoxide-lithium exchange and the reactive intermediate in stereospecific reagent-controlled homologation (StReCH)

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  • The stereospecific reagent-controlled homologation (StReCH) of boronic esters with enantioenriched carbenoid species generated in situ by the addition of organolithium initiators to stereodefined α-chloroalkyl aryl sulfoxides was previously reported. The reaction of an organolithium with an α-chloroalkyl aryl sulfoxide ostensibly generates an α-chloroalkyllithium via sulfoxide-lithium exchange; however, the true nature of the chain-extending carbenoid intermediate in chlorosulfoxide-based StReCH is not certain. It may be: an α-chloroalkyllithium, a sulfurane intermediate en route to the α-chloroalkyllithium, or a complex of closely-associated α-choroalkyllithium and the sulfoxide by-product of sulfoxide-lithium exchange. To elucidate which of these scenarios is most relevant under the reaction conditions of StReCH, the homologation of variously B-substituted racemic (±)-(4R*,5R*)-4,5-diphenyl-1,3,2-dioxaborolanes [RB[O(CHPh)₂O], R = CH₂CH₂Bn, c-C₆H₁₁, and Ph) with enantioenriched (S[subscript S])-chloromethyl phenyl sulfoxide was investigated in THF solvent (at –78 °C) using three different organolithium initiators (n-BuLi, t-BuLi, and PhLi). Observation of kinetic resolution in such an experiment would indicate that the active carbenoid is not simply chloromethyllithium (an achiral species) but instead a chiral entity such as a sulfurane or a complex of chloromethyllithium and a chiral ligand (e.g., a chiral sulfoxide). In the event, only one of the reaction variants investigated proved wholly amenable to the type of analysis required. Thus, addition of n-BuLi to a mixture of racemic B-cyclohexyl (4R*,5R*)-4,5-diphenyl-1,3,2-dioxaborolane and (S[subscript S])-chloromethyl phenyl sulfoxide (%ee > 95%) in THF at –78 °C, followed by warming to rt, resulted in 5-10% conversion to the corresponding B-cyclohexylmethylboronate. The unreacted boronate starting material and its homologated congener were separated by chromatography (using an achiral stationary phase) and 1,2-diphenylethan-1,2-diol liberated from each by hydrolysis was separately analyzed by HPLC on a chiral stationary phase. Both samples of diol were found to be effectively racemic (%ee < 2%). This finding supports the hypothesis that the active carbenoid reagents in chlorosulfoxide-based StReCH are truly α-chloroalkyllithiums; however, the possibility that the experiment described involved a chiral carbenoid species incapable of efficient kinetic resolution of the racemic boronate starting material cannot be discounted.
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