A new set of structurally related enantiopure polypyrazolyl ligands of varying rotational symmetry: Synthesis, metal complexation, and comparison of asymmetric induction

A new family of enantiomerically pure pyrazoles with a variety of substitutions on a key stereogenic center was synthesized from (R)-(+)-pulegone by a straightforward, large-scale route involving initial construction of the pyrazole ring via formylation/dehydration with hydrazine followed by ozonolysis to yield a readily functionalized ketone (5). Alkylation of 5 with a variety of Grignard reagents, dehydration, hydrogenation, and recrystallization afforded the set of new chiral pyrazoles (7a-c). Cis and/or trans diastereomers of one of these pyrazoles having a phenyl substituent (7a) were elaborated into enantiopure, multidentate Ci-symmetric bis(pyrazolyl)diphenylborate (Tl[cis-Ph₂Bp^pm]), C₂-symmetric bis-(pyrazolyl)methane (cis- and trans-X^pm), and C₃-symmetric tris(pyrazolyl)phosphine oxide (cis- and trans-OP^pm) and tris(pyrazolyl)hydroborate (K[trans-Tp^pm]) ligands. Interestingly, epimerization of the benzylic stereogenic center occurred during the synthesis of K[trans-Tp^pm], as determined by comparison of 2D NMR spectral and X-ray crystal structural data for the starting cis-pyrazole (cis-7a) and the copper complex (trans-Tp^pm)Cu(CH₃CN). Comparison of the abilities of copper complexes of the various [Ph₂Bp^pm]^-, X^pm, OP^pm, and Tp^pm ligands to catalyze the cyclopropanation of styrene by ethyldiazoacetate revealed significantly enhanced enantioselectivity for the Tp^pm case. This result represents the first example of a high degree of enantiocontrol in a catalytic reaction of any complex of a Tp ligand and provides experimental support for the possible efficacy of higher order rotational . symmetry in metal-mediated stereoselective reactions.