Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

Sodium bicarbonate-catalyzed stereoselective isomerizations of electron-deficient propargylic alcohols to (Z)-enones.

Redox isomerization is a synthetically important process because it creates two new functional groups in the product, among which is the isomerization of propargylic alcohols to conjugated enones. Although E-enones have been prepared by this approach, Z-enones could not be accessed. We previously reported DABCO-catalyzed E-selective isomerization of electron-deficient propargylic alcohols to enones and its mechanism.

Base-catalyzed stereoselective isomerization of electron-deficient propargylic alcohols to E-enones.

We have developed highly stereoselective methods to isomerize electron-deficient propargylic alcohols to E-enones under mild conditions (EWG = electron-withdrawing group). Among weak bases we screened, catalytic (10-20 mol %) 1,4-diazabicyclo[2.2.

On the mechanism of DABCO-catalyzed isomerization of gamma-hydroxy-alpha,beta-alkynoates to gamma-oxo-alpha,beta-(E)-alkenoates.

[reaction: see text] Since the discovery of organic base-catalyzed isomerization of gamma-hydroxy-alpha,beta-acetylenic esters to gamma-oxo-alpha,beta-trans-alkenyl esters in 1949, the mechanism has not been elucidated. This study shows that the mechanism involves cumulene formation, protonation with the conjugate acid of the amine, and protonation of the resulting allenol with water.