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Synfacts 2018; 14(04): 0335
DOI: 10.1055/s-0037-1609119
DOI: 10.1055/s-0037-1609119
Synthesis of Natural Products and Potential Drugs
Synthesis of Histone Acetyltransferase Inhibitor A-485
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
Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.
ACS Med. Chem. Lett. 2018;
9: 28-33
Further Information
Publication History
Publication Date:
15 March 2018 (online)
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.
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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).
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