Stereoselective vinylogous Mannich reactions [1] are of significant utility in organic synthesis.[2] Through diastereoselective addition of vinylogous enol equivalents to enantiomerically enriched imines, a,b-unsaturated, d-amino carbonyls have been synthesized and used as chiral building blocks. A catalytic asymmetric vinylogous Mannich (AVM) process would constitute a more efficient strategy, one that does not require pre-existing chirality.[3] As illustrated in Equation (1) (PG = protecting group), a catalytic AVM involving a siloxyfuran can deliver synthetically versatile, enantiomerically enriched products that bear two stereogenic centers appended to a g-butenolide.In 1999, Martin and Lopez reported a method (Ticatalyzed) for addition of siloxyfurans to 2-aminophenolderived imines; reactions proceeded in 40-92 % de but in only up to 54 % ee.[4] Terada and co-workers have outlined an enantioselective (up to 97 % ee) protocol for Brønsted acid catalyzed Friedel-Crafts reactions of N-Boc aldimines with 2-methoxyfuran. Enantiomerically enriched furan-2-ylamines may be oxidized to afford alkylamine-substituted g-butenolides [Eq. (1)] by a two-step sequence that generates the carbinol stereogenic center with moderate diastereoselectivity (70 % de).[5]Herein we report the first highly diastereo-and enantioselective protocol for catalytic AVM reactions. Ag-catalyzed transformations [6] proceed in > 98 % de, in 79 to > 98 % ee and 60-98 % isolated yield. The catalytic method is practical: transformations are carried out in air with undistilled solvent and undistilled additive, in the presence of 1-15 mol % commercially available AgOAc (not purified) and an easily accessible chiral phosphine (three steps, 50 % yield). Siloxyfurans are commercially available and/or readily prepared (one step, 90 % yield).As the data summarized in entry 1 of Table 1 illustrate, in the presence of 1 mol % 1 a, [6b-d] 1 mol % AgOAc, 1.1 equivalents iPrOH, in undistilled THF and in air, reaction of aldimine 2 a and commercial siloxyfuran 3 affords g-butenolide 4 a in > 98 % de, 95% ee, [7] and 82 % yield. When 1 b, bearing a tLeu (vs. iLeu) unit (entry 2) or ligand 1 c, containing the less expensive Val (entry 3) is used, similar reactivity and selectivity is observed.[8] The efficient reaction with 3 is especially noteworthy and was somewhat surprising, since we had previously established that silylketene acetals do not participate (< 2 % conv.) in this class of catalytic Mannich reactions.[6d] It is likely that this change in reactivity, in spite of somewhat lower nucleophilicity of siloxyfurans (vs. ketene acetals) [9] is the result of reduced steric hinderance at the reacting carbon. As represented by catalytic AVM in entries 4-5 (Table 1), one of the chiral phosphines (1 a, 1 b, or 1 c) can deliver slightly higher efficiency (90 % vs. 85 % conv.) and enantioselectivity (97 % vs. 93 % ee); others are shown in entries 12-13 and 15-16. Reactions proceed readily and with high enantioselectivity with electron-rich (entries 4-5 and 15-16)...

[reaction: see text] A readily available iso-leucine-based phosphine ligand is used to promote Ag-catalyzed Mannich reactions between silylketene acetals and various alkynyl imines. Reactions can be effected in the presence of 5 mol % catalyst, without the need for rigorous exclusion of air, and with commercially available solvents (without purification) to afford the desired beta-alkynyl-beta-amino esters in 84-94% ee and 61-91% isolated yield.

ABSTRACT:We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

A readily accessible small-molecule phosphine, derived from commercially available starting materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based chiral complex that can be prepared and used in situ to promote a variety of enantioselective vinylogous Mannich (EVM) reactions that involve siloxypyrroles as reaction partners. Transformations with unsubstituted nucleophilic components proceed efficiently and with exceptional site- (γ vs α-addition), diastereo- and enantioselectivity [up to 98% yield, generally >98:2 γ/α and diastereomeric ratio (dr) and up to 99:1 enantiomeric ratio (er)]. The first examples of efficient, diastereo- and enantioselective vinylogous Mannich additions with 5-methyl-substituted siloxyfuran, resulting in the formation of O-substituted quaternary carbon stereogenic centers are presented as well. Appreciable efficiency and diastereo- and enantioselectivity (up to >98:2 dr and >99:1 er) is accompanied by formation of α-addition products that can be oxidatively removed