Enantioselective Synthesis of an HCV NS5a Antagonist

Abstract

A concise, enantioselective synthesis of the HCV NS5a inhibitor MK-8742 (1) is reported. The features of the synthesis include a highly enantioselective transfer hydrogenation of an NH imine and a dynamic diastereoselective transformation. The synthesis of this complex target requires simple starting materials and nine linear steps for completion.

Synthesis of Phenols: Organophotoredox/Nickel Dual Catalytic Hydroxylation of Aryl Halides with Water

“…Ak ey intermediate in the synthesis of elbasvir, [23] which has been approved for the treatment of hepatitis Cv irus (HCV) infection, the monohydroxylated product 43 was formed in 71 %yield with little loss of enantiomeric purity.I nt he case of the challenging N-heterocyclic substrate 44, [24] the desired phenol 45 was also formed in good yield. Ak ey intermediate in the synthesis of elbasvir, [23] which has been approved for the treatment of hepatitis Cv irus (HCV) infection, the monohydroxylated product 43 was formed in 71 %yield with little loss of enantiomeric purity.I nt he case of the challenging N-heterocyclic substrate 44, [24] the desired phenol 45 was also formed in good yield.…”

Aryl or heteroaryl substituted aminal derivatives of HCV NS5A inhibitor MK-8742

“…The rat PK profiles of several selected analogs are summarized in Table 3. The halogenated derivatives (13,14,17,18, and 21) bearing either one or two halogens demonstrated comparable pharmacokinetic profiles to each other. It seems that the halogen substitution on the phenyl group had minimum effect on the rat PK profiles as well.…”

“…12 The key intermediate dibromide 3 can be prepared either by reaction of dibromide 2 and indole 1 10,11 or from aldehyde 4 and indoline 5. 13 Compound 3 was then converted to bis-pinacol boronate ester 6 which was then treated, under Suzuki coupling conditions, with imidazole bromide 7 11 to afford the bisBoc intermediate. Treatment of the bis-Boc intermediate, under acid conditions, followed by HATUmediated amide coupling with methoxycarbonyl-L-valine generated a mixture of two diastereomers at the aminal carbon.…”

Hydrogen

“…93 Imine hydrogenation catalyzed by iridium or rhodium to give a primary amine was evaluated during the enantioselective synthesis of a hepatitis C NS5A antagonist, but due to challenges with imine hydrolysis, transfer hydrogenation using tethered Ru catalysts proven superior. 94 Phosphine-free asymmetric imine reductions have also been reported. Frustrated Lewis pairs have been shown to catalyze hydrogenation of the imines 32, 95 with an example shown in eq 37.…”