An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

被引:179
作者
Marcaurelle, Lisa A. [1 ]
Comer, Eamon
Dandapani, Sivaraman
Duvall, Jeremy R.
Gerard, Baudouin
Kesavan, Sarathy
Lee, Maurice D.
Liu, Haibo
Lowe, Jason T.
Marie, Jean-Charles
Mulrooney, Carol A.
Pandya, Bhaumik A.
Rowley, Ann
Ryba, Troy D.
Suh, Byung-Chul
Wei, Jingqiang
Young, Damian W.
Akella, Lakshmi B.
Ross, Nathan T.
Zhang, Yan-Ling [1 ]
Fass, Daniel M. [1 ,2 ]
Reis, Surya A. [1 ,2 ]
Zhao, Wen-Ning [1 ,2 ]
Haggarty, Stephen J. [1 ,2 ]
Palmer, Michelle
Foley, Michael A.
机构
[1] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA
[2] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
基金
美国国家科学基金会;
关键词
RUTHENIUM-CATALYZED CYCLOADDITION; DIVERSITY-ORIENTED SYNTHESIS; CLOSING METATHESIS REACTION; AZIDE-ALKYNE CYCLOADDITION; SKELETAL DIVERSITY; NATURAL-PRODUCTS; SELECTIVE REDUCTIONS; ORGANIC-COMPOUNDS; MOLECULES; LIBRARY;
D O I
10.1021/ja105119r
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected gamma-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (SNAr), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8-to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.
引用
收藏
页码:16962 / 16976
页数:15
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