Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 5 125Entry Substrate R Time h C% Product Yield e.e. E1 (±)-60a H 4.5 47.3 (-)-(S)-60a 45.2 87.0 1002 H (-)-(R)-58a 30.5 97.03 (±)-60b 4Me 144 60.7 (-)-(S)-60b 57.3 99.5 354 4Me (-)-(R)-58b 33.8 64.85 (±)-60e 4C 52 67.8 (-)-(S)-60e 60.1 86.6 6N6 4CN(-)-(R)-58e 31.0 41.2Table 5.8: Enzymatic hydrolyses of arylpropargylic acetates (±)-60a,b,e.As reported in table 5.8, SAMII worked perfectly with the acetate(±)-60a which does not contain any substituent on the aromatic moiety,the corresponding E value was >100. For the two others esters having apara- substituent (Me for (±)-60b and CN for (±)-60e) the selectivitywas much lower ((±)-60b E=35, and (±)-60e E=6). In theseexperiments (2 mmoles of esters and 10% in weight of lipase Sam II) thesolubility of the substrates became a problem. (±)-60e was insoluble inthe phosphate buffer and appeared as a solid suspension in the reactionmixture. The inhomogeneity of the reaction mixture led tounreproducible results for the three sets of experiments. It is well knownthat the optimal reaction conditions for lipase catalysed reactions arethose in which the substrates are oil emulsions in buffer since the reactionoccurs at the interface between the two phases. For this reason it was triedto keep (±)-60e as an oil in the reaction mixture, however already afterfew minutes under stirring in the buffer it became solid. Theinhomogeneity of the reaction mixture could be one reason for the lowselectivity of the lipase during the hydrolysis. Therefore, the use of acosolvent was considered as a possible solution for this problem (Scheme5.10).OAcH OAcHO HSAM II, cosolventR PH=7; R.T.+R RH H H(±)-60a,b,e (-)-(S)-60a,b,e (-)-(R)-58a,b,eScheme 5.10: Effect of solvent on the enzymatic hydrolyses of (±)-60a,b,e.