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

Factor XI (FXI) is a key enzyme in the coagulation pathway and an attractive target for the development of anticoagulant drugs. A small number of high-resolution crystal structures of FXIa in complex with small synthetic inhibitors have been published to date. All of these ligands have a basic P1 group and bind exclusively in the nonprime side of the active site of FXIa. Here, two structures of FXIa in complex with nonbasic inhibitors that occupy both the prime and nonprime sides of the active site are presented. These new structures could be valuable in the design and optimization of new FXIa synthethic inhibitors.

The E/Z-selectivity in the formation of silylketene acetals derived from phenylacetate esters, mediated by LiHMDS, has been studied by in situ NMR techniques. The formation is seen to be highly E-selective with use of the newly developed protocol. Isolated aryl-substituted silylketene acetals are now attainable with high levels of E-geometrical purity in excellent yield.

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time-and dose-dependent downregulation of a proximal biomarker could be shown.

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)...