(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: a wingless beta-catenin agonist that increases bone formation rate.

A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.

1-substituted beta-carbolines by a Pictet-Spengler cyclization with thioortho esters and carbon-carbon bond formation via N-sulfonyl iminium ions generated from N,S-sulfonyl acetals.

The reaction of N-tosyltryptamines with thioortho esters, leading to 1-thiosubstituted tetrahydro-beta-carbolines under modified Pictet-Spengler conditions, is described. The 1-heterosubstituted beta-carbolines furnished 1-substituted beta-carbolines upon reaction with Grignard reagents and silyl derivatives under Lewis acid promotion. [reaction: see text]

Stereoselective Suzuki-Miyaura cross-coupling reactions of potassium alkenyltrifluoroborates with alkenyl bromides.

[reaction: see text] The stereoselective synthesis of conjugated dienes using air-stable potassium alkenyltrifluoroborates as coupling partners is described. The palladium-catalyzed cross-coupling reaction of potassium (E)- and (Z)-alkenyltrifluoroborates with either (E)- or (Z)-alkenyl bromides proceeds readily with moderate to excellent yields to give the corresponding (E,E)-, (E,Z)-, (Z,E)-, or (Z,Z)-conjugated dienes stereospecifically. The cross-coupling can generally be effected using 5 mol % of Pd(OAc)2, 10 mol % of PPh3, and 3 equiv of Cs2CO3 in THF-H2O (10:1).