Kinetic resolution, nucleophilic substitution

The classical kinetic resolution of racemic substrate precursors allows only access to a theoretical 50% yield of the chiral ladone product, while the antipodal starting material remains unchanged in enantiomerically pure form. The regioseledivity for the enzymatic oxidation correlates to the chemical readion with preferred and exclusive migration of the more nucleophilic center (usually the higher substituted a-carbon). The majority of cydoketone converting BVMOs (in particular CHMOAdneto)... 

Historically, the thermal transesterification of (-)-ethyl p-toluene-sulfinate 224 with n-butanol affording (+)-n-butyl p-toluenesulfinate 225 described by Phillips in 1925 (100) is the first nucleophilic substitution reaction at chiral sulfur involving a Walden-type inversion. The evidence for inversion of configuration in this reaction was based on the assumption that both (-)-esters 224 and 225 obtained from the kinetic resolution have the same configuration. 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Basically, two different routes are conceivable for their asymmetric construction 1) nucleophilic substitution reaction with a fluoride anion and 2) electrophilic addition of fluoronium cations to activated or masked carbanions. First attempts on enantioselective nucleophilic fluorination date back to the pioneering work of Hann and Sampson [3]. In an ambitious dehydroxylation/fluorination sequence the authors reacted a racemic a-trimethylsiloxy ester with a half molar equivalent of an enantiomerically pure proline-derived aminofluorosulphurane in hope to achieve a kinetic resolution. Unfortunately, the fluorinated product was obtained without significant enantiomeric excess. 

Stereocontrol in nucleophilic acyl substitution might at first appear to be not an issue, since the carbonyl carbon is achiral. However, if the incoming nucleophile or the leaving group are chiral, then the TS and intermediates could be diasterotopic, and selectivity can occur (see Scheme 6.5). Houk and Birman address this in a computational study of kinetic resolution of carboxylic acids. They found that the Felkin-Anh model applies, extending its applicability to the nucleophilic acyl substitution. 

Fig. 7 (a) Similar equatorially substituted environment about the 4- and 6-hydroxyls of myoinositol derivative 62. (b) P(III) transfer, catalyzed by a tetrazole sidechain and inspired from previous efforts using Pmh sidechains as nucleophilic catalysts for P(V) transfer among several other transformations, (c) Hit Atz-containing peptide 64, derived from a library inspired by 1,3-desymmetrization catalyst 5. (d) Enantioselective preparation of myo-inositol-6-phosphate precursor 65 by means of enantioselective phosphitylation followed by a phosphate-directed P (III) transfer that operates as a kinetic resolution ( 1 65 66 35). (i) Et2NP(OBn)2, 5 mol% peptide 64, 10 A M.S., CHCI3,4°C. (ii) 30% (aq.) H2O2, 0°C, 1 h. 71% yield for 1st pass to yield 85 15 er 74% yield of 65 in second pass as kinetic resolution with peptide 64 [114]... 

When a racemic allylic substrate is employed in an enantioselective substitution reaction, one of the two substrate enantiomers may react more quickly than the other. This effect is a kinetic resolution and has been noted reasonably often in enantioselective allylic substitution reactions. Several studies on kinetic resolution have been reported, - and a few highlight reactions are noted in Scheme 45. These include recovery of unreacted cy-clohexenyl acetate 92, as well as the tetraacetate 225. Kinetic resolution has also been observed in allylic snbstitution using a snlfinate nucleophile (Li02STlu) with allyl acetate... 

An enantioselective method in which a chiral catalyst is responsible of a desymmetrizing nucleophilic aromatic substitution through discrimination in the displacement of an enantiotopic leaving group has been reported very recently in the heterocyclic series. Under PTC conditions, the chiral counterion 113 (10% mol) directs the substitution of prochiral dichloropyrimidine 112 by PhSKby a tandem desymmetrization/kinetic resolution mechanism, leading to the chiral product 114 (Scheme 8.23) [87]. 

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