Design and Synthesis of Chiral Diene Ligands for Rh^I‐Catalyzed Enantioselective Arylation of N‐DPP‐protected Aldimines: Synthesis of the Antifungal Agent Bifonazole

Abstract

Herein we describe the design and synthesis of a novel family of bifunctional, chiral bicyclo[2.2.1]heptadiene ligands bearing aryl and secondary amido groups, and demonstrate their usefulness in the Rh -catalyzed enantioselective addition reaction of arylboronic acids to N-diphenylphosphinyl (N-DPP)-protected aldimines. Unlike the analogous Rh -catalysts comprising diene ligands substituted with aryl and carboxylic ester groups, or only with aryl groups, the addition reaction proceeded with high stereoselectivity. The protocol tolerated a range of N-DPP-aldimines and arylboronic acids, producing the desired optically active N-DPP-protected amines with yields between 31-99 % and with ee values up to 91-99 %. The synthetic utility of the method was demonstrated by the conversion of N-DPP-protected amine 3 ae into the antifungal agent, bifonazole (13).

Chiral Diene Ligands in Asymmetric Catalysis

“…The diketone 7 was subjected to the bistriflation, followed by the palladium-catalyzed cross-coupling of ditriflate 8 with arylboronic acids, to give the corresponding 2,5-diarylated bicyclo[2.2.1]­heptadienes L4a–d , which are different from dienes L2 in that they bear three methyl groups, one of which is at the bridgehead. Those substituted with a carbonyl group ( L4e–g ) were also synthesized, where the palladium-catalyzed carbonylation of alkenyl triflate was one of the key steps …”

Rh-Catalyzed Enantioselective Allylation of N-Tosyl- and N-Nosylaldimines: Total Synthesis of (−)-Crispine A

“…In our previous studies, Rh­(I) catalysts derived from chiral bicyclo[2.2.1]­heptadiene ligands L1 have demonstrated their high catalytic capability (TON up to 2000 with excellent enantioselectivity) in the asymmetric 1,4-addition reactions with a broad scope of substrates . Furthermore, this catalytic system imparted high efficiency in the synthesis of optically active diarylmethyl and allylic amines . With the prior successful 1,2-arylation and 1,2-alkenylation of N -Ts- and N -Ns-aldimines catalyzed by Rh/ L1 , herein, we report the preparation of homoallylic amines with high stereocontrol based on Rh-catalyzed 1,2-allylation of N -Ts- and N -Ns-imines.…”

Application of Rh(I)/Bicyclo[2.2.1]heptadiene Catalysts to the Enantioselective Synthesis of Chiral Amines

“…For this aim, the asymmetric addition reaction of p-tolylboronic acid 5 a with the Ndiphenylphosphinoyl (N-DPP) aldimine 10 a [14] derived from benzaldehyde was performed in the presence of rhodium catalysts comprised of chiral diene ligands L1 (Scheme 4). [15] The observed chemical yield and enantioselectivity of the adduct 11 aa, however, was only moderate, thus stimulating us to redesign and synthesize the chiral diene ligands L2 bearing a phenyl group and one secondary amido group, in the hopes to achieve high reactivities and asymmetric induction, as was found for those analogous chiral bicyclo[2.2.2]octadiene ligands. [16] The diketone 2 was first, treated with KHMDS and Comins' reagent (1.1 equiv.…”