Enzymes Desymmetrisation

Kielbasinski, P., Rachwalski, M., Mikolajczyk, M. et al. (2007) Enzyme-promoted desymmetrisation of prochiral bis(cyanomethyl) sulfoxide. Advanced Synthesis and Catalysis, 349, 1387-1392. 

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. 

Allan, G., Camell, A.J., Escudero Hernandez, M.L. and Pettman, A., Desymmetrisation of 4,4-disubstituted cyclohexanones by enzyme-catalysed resolution of their enol acetates. J. Chem. Soc. Perkin Trans. 1, 2000, 3382. 

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. 

Kinetic resolution with racemisation Enzymes versus whole organisms Desymmetrisation with lipases Immobilised enzymes in desymmetrisation Polymer-supported reagents and enzymes Effects of amines on lipases and esterases Other acylating enzymes Enzymatic Oxidation... 

Waste products None with an enzyme, lots with a yeast but at least they are environmentally friendly. Desymmetrisation with lipases... 

Now the acetyl cholinesterase from the electric eel (EEAC) efficiently desymmetrises the diacetate to give the enantiomerically pure monoester 36. The enzyme can be used as a lyophilised powder or is available (from Sigma) immobilised on agarose beads. This form is easy to use and easy to isolate after the reaction. Other cyclic examples work well as does the most impressive open chain example 38 with an Zi-alkene.14... 

We end this section with two examples of the effects amines may have on esterase activity. The aggressive nitrogen nucleophile can obviously interfere with ester formation or hydrolysis. In designing a synthesis based on these enzymes we must find a symmetrical intermediate that might be desymmetrised. In the synthesis of the simple P-lactam 48, simple disconnections led to the symmetrical amino-diester 50, with the nitrogen atom protected. 

Synthesis of a suitable substrate from citric acid 51 was straightforward17 and Ohno18 found that the Cbz-protected dimethyl ester 53 could be desymmetrised efficiently with pig liver esterase (PLE) or with even higher enantioselectivity, with the microbial enzyme from Flavobacterium lutescens (98% ee). The P-lactam 48 could be closed by the dipyridine-disulfide/Ph3P method. 

Whole cells of engineered E. coli BL21(DE3)(pMM4) desymmetrise cyclohexanones with substituents in the 4-position with variable results.36 Simple mono-substitution 118 and 120 gives good results but the enzyme is very sensitive to hydroxyl groups giving a lower yield with the tertiary alcohol 122 and poor ee with the secondary alcohol 124. 

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