SYNTHESIS OF A FAMILY OF FINE-TUNABLE NEW CHIRAL LIGANDS FOR CATALYTIC ASYMMETRIC-SYNTHESIS - LIGAND OPTIMIZATION THROUGH THE ENANTIOSELECTIVE ADDITION OF DIETHYLZINC TO ALDEHYDES

A family of enantiomerically pure R)-1-(dialkylamino)-1-phenyl-3-(R-ox y)-2-propanols (4) has been synthesized from (2S,3S)-2,3-epoxy-3-pheny lpropanol (la), arising from the Sharpless epoxydation of cinnamyl alc ohol, by two alternative sequences involving either the regioselective ring opening of the epoxide by a secondary amine (C-3 attack) and sub sequent chemoselective protection of the primary hydroxy group or the reverse of these operations. A total of 19 different derivatives 4 hav e been prepared in an iterative process aimed at the optimization of t heir catalytic properties in the enantioselective addition of diethylz inc to benzaldehyde. In doing this, the steric bulk of the R-oxy group and the choice of the dialkylamino substituent as a nitrogen-containi ng six-membered ring have been identified as the key structural parame ters for high catalytic activity and enantioselectivity in 4. Two opti mized ligands fulfilling these structural requirements, 4d-Tr (R-oxy = trityloxy, dialkylamino = piperidino) and 4i-Tr (R-oxy = trityloxy, d ialkylamino = 4-methylpiperazin-1-yl), depict a convenient activity an d selectivity profile in the addition of Et-2-Zn to a structurally div erse family of aldehydes. These results show how chiral ligands based on non-natural starting materials can accommodate subtle variations of the steric/electronic characteristics key to the fine tuning of catal ytic properties and thus represent a convenient alternative to ligands based on natural products.