Michelelides MR.
*
Kesicki EA.
* et al. AbbVie, Inc., North Chicago and Acylin Therapeutics, Inc., Seattle, USA;
BioDuro, Bejing, P. R. of China
Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors
of p300/CBP Histone Acetyltransferases.
ACS Med. Chem. Lett. 2018;
9: 28-33
Key words
A-485 - asymmetric cyanosilylation - catalytic double activation - Buchwald–Hartwig
reaction - oxazolidinediones
Significance
A-485 is a histone acetyltransferase (HAT) domain inhibitor. The key step in the synthesis
depicted is the construction of the stereogenic center in G by catalytic asymmetric cyanosilylation. Intermediate G was initially obtained in only 77% ee. Enhancement of the ee required a combination
of trituration, chromatography, and crystallization (2×) to give G in 59% yield (>99% ee) from D.
Comment
The asymmetric cyanosilylation entails a catalytic double-activation in which a chiral
aluminium Lewis acid derived from B (2 mol%) activates the electrophile and an achiral Lewis base (N-oxide C, 1 mol%) activates the nucleophile (X. M. Feng et al. Chem. Eur. J. 2004,10, 4790).
