Conformationally stable peptide macrocycles assembled using the Petasis borono-Mannich reaction.

Macrocyclization of linear peptide precursors using the Petasis borono-Mannich reaction affords a diverse range of macrocycles with an endocyclic amine. Analysis of the corresponding macrocyclic structures underscores that the hydrogen bond between an endocyclic amine and the adjacent amide NH is a powerful control element for conformationally homogenous peptide macrocycles.

Enantioselective synthesis of 2,2-disubstituted terminal epoxides via catalytic asymmetric Corey-Chaykovsky epoxidation of ketones.

Catalytic asymmetric Corey-Chaykovsky epoxidation of various ketones with dimethyloxosulfonium methylide using a heterobimetallic La-Li(3)-BINOL complex (LLB) is described. The reaction proceeded smoothly at room temperature in the presence of achiral phosphine oxide additives, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (97%-91% ee) and yield ( > 99%-88%) from a broad range of methyl ketones with 1-5 mol% catalyst loading. Enantioselectivity was strongly dependent on the steric hindrance, and other ketones, such as ethyl ketones and propyl ketones resulted in slightly lower enantioselectivity (88%-67% ee).

Catalytic asymmetric synthesis of alpha-alkylidene-beta-hydroxy esters via dynamic kinetic asymmetric transformation involving Ba-catalyzed direct aldol reaction.

A Ba-catalyzed dynamic kinetic asymmetric transformation (DYKAT) involving a direct aldol/retro-aldol reaction of beta,gamma-unsaturated ester donors is described. A Ba(O-iPr)(2)/BINOL complex promoted the direct aldol reaction/isomerization sequence, and alpha-alkylidene-beta-hydroxy esters were obtained from aryl, heteroaryl, alkenyl, and alkyl aldehydes under simple proton-transfer conditions with 99-87% ee and >20:1 to 15:1 alpha/gamma selectivity.

Catalytic asymmetric synthesis of 2,2-disubstituted terminal epoxides via dimethyloxosulfonium methylide addition to ketones.

Catalytic asymmetric Corey-Chaykovsky epoxidation of ketones with dimethyloxosulfonium methylide 2 using an LLB 1a + Ar3P O complex proceeded smoothly at room temperature, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (91-97%) and yield (>88-99%) from a broad range of methyl ketones with 1-5 mol % catalyst loading. The use of achiral additive Ar3P O 5i was important to achieve high enantioselectivity.

Direct catalytic asymmetric Mannich-type reactions of gamma-butenolides: effectiveness of Brønsted acid in chiral metal catalysis.

Direct catalytic asymmetric Mannich-type reactions of gamma-butenolides are described. A chiral Lewis acid/amine base/Brønsted acid combination was used to catalyze a gamma-addition of gamma-butenolides to N-diphenylphosphinoyl imines, affording the products in up to >99% yield, anti/syn = >97:3, and 84% ee. The use of a catalytic amount of TfOH in addition to La(OTf)3/Me-PyBox/TMEDA was important for improving yield and stereoselectivity.

Ba-catalyzed direct Mannich-type reactions of a beta,gamma-unsaturated ester providing beta-methyl aza-Morita-Baylis-Hillman-type products.

Barium-catalyzed direct Mannich-type reactions of a beta,gamma-unsaturated ester are described. The Ba-catalyst not only promoted the Mannich-type reactions, but also isomerized Mannich adducts to afford beta-methyl aza-Morita-Baylis-Hillman-type products in 61-88% yield from various aryl, heteroaryl, and alkyl imines. Preliminary trials on enantioselective variants with a chiral biaryldiol ligand gave products in up to 80% ee.

syn-selective direct catalytic asymmetric Mannich-type reactions of hydroxyketones using Y{N(SiMe3)2}3/linked-BINOL complexes.

[reaction, structure: see text] Chiral Y{N(SiMe3)2}3/linked-BINOL catalyst generated Y-enolate in situ from various hydroxyketones (R2 = aryl, heteroaryl). Beta-amino-alpha-hydroxy ketones (R1 = aryl, heteroaryl, alkenyl) were obtained syn-selectively (up to 96/4) in high ee (up to 98%) and good yield (up to 98% yield).