Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C–N Coupling with Chiral Bisphosphine Mono-oxides

Abstract

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions

“…9 Treatment of ArBr 3 with L*(O) and Pd[P(( o -tolyl) 3 ) 2 ] also afforded a single pair of characteristic 31 P NMR resonances at δ 48.6 and 34.9 ppm that correspond to the phosphine oxide and phosphine moieties of the BPMO, respectively (see ESI†). Gratifyingly, the isolated complex D allowed the growth of X-ray quality single crystals by slow evaporation from toluene.…”

“…More significantly, L*(O) was synthesized from the free ligand L* in a 3-step sequence with an overall 67% isolated yield. 9 Therefore, any advantage gained in catalytic performance from the oxidative addition complex C would be offset by its tedious preparation.…”

“…We recently reported 9 a novel, enantioselective hemiaminal synthesis via a palladium-catalyzed C–N coupling using chiral bis-phosphine ligands (Scheme 1) that has been used in the preparation of ruzasvir, a clinically relevant hepatitis C virus NS5A inhibitor. 10 …”

Controlling Regioselectivity in the Enantioselective N‐Alkylation of Indole Analogues Catalyzed by Dinuclear Zinc‐ProPhenol

“…Indeed, its stability is such that the synthetic intermediate 2 can be synthesized asymmetrically using a novel C-N coupling. 3 Indeed, this method extended to form the cyclic aminal 3 asymmetrically. Also there are many methods available for the synthesis of N,O -aminals and utilized for several organic transformations.…”

Pd-catalyzed enantioselective C–H arylation of phosphinamides with boronic acids for the synthesis of P-stereogenic compounds

“…In contrast, P-stereogenic compounds have been largely unexplored because of their synthetic challenge. A number of reports [13][14][15][16][17][18][19][20][21][22][23] have demonstrated that P-stereogenic compounds exhibit superior enantioselectivity due to the proximity of their chiral environments to the reactive center.…”