Ketone desymmetrisation

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

Camell, A.J., Barkely, J. and Singh, A., Desymmetrisation of prochiral ketones by catal3ftic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997, 38, 7781-7784 Allan, G.R., Carnell, A.J. and Kroutil, W., One-pot deracemisation of an enol acetate derived from a prochiral cyclohexanone. Tetrahedron Lett., 2001, 42, 5959-5962. 

Camell, A.J., Barkley, J. and Singh, A., Desymmetrisation of prochiral ketones by catalytic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997,38,7781. 

A lot of work has to be done. A carbon atom needs to be added and the ketone moved round to allow addition of a d1 reagent. But this is an attractive strategy because tropinone is achiral and enolate formation desymmetrises the molecule. It was not easy to find the right base. In the end the C2-symmetric double base 148 gave the silyl enol ether 149 in good yield, and, as we shall see later, good ee. 

Hydrogenation of 170 gives the achiral saturated ketone 171 that can be desymmetrised by a chiral base. The lithiated diamine 172 gives mostly the lithium enolate 173 and hence, by addition of selenium and oxidative elimination, the enone (R)-170. Different bases give the other enantiomer.26... 

Also, the Schreiner group published in 2009 a desymmetrisation approach of meso-(cyclo)alkane-l,2-diols applying the lipophilic peptide catalyst 7 (Scheme 13.8) already successfully used in kinetic resolution processes (Scheme 13.5) as previously described. The desymmetrisation step was combined in one pot with a direct TEMPO oxidation to the corresponding ot-aceto)y ketone in order to avoid racemisation of the monoacelylated intermediate. 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

Intramolecular desymmetrising aldol reaction catalysed by QNA and QDA, transition-state structure with QNA and the two enantiomers of celery ketone. 

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