An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors Lisa A. Marcaurelle Eamon Comer Sivaraman Dandapani Jeremy R. Duvall Baudouin Gerard Sarathy Kesavan Maurice D. Lee Haibo Liu Jason T. Lowe Jean-Charles Marie Carol A. Mulrooney Bhaumik A. Pandya Ann Rowley Troy D. Ryba Byung-Chul Suh Jingqiang Wei Damian W. Young Lakshmi B. Akella Nathan T. Ross Yan-Ling Zhang Daniel M. Fass Surya A. Reis Wen-Ning Zhao Stephen J. Haggarty Michelle Palmer Michael A. Foley 10.1021/ja105119r.s003 https://acs.figshare.com/articles/dataset/An_Aldol_Based_Build_Couple_Pair_Strategy_for_the_Synthesis_of_Medium_and_Large_Sized_Rings_Discovery_of_Macrocyclic_Histone_Deacetylase_Inhibitors/2709319 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 <i>build</i> phase, a series of asymmetric <i>syn-</i> and <i>anti-</i>aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of <i>O</i>-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the <i>couple</i> 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 <i>pair</i> phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S<sub>N</sub>Ar), 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. 2010-12-01 00:00:00 histone deacetylase inhibitors stereoisomeric amides couple step chiral acid membered 16 stereoisomers stereochemical dependencies chiral amine enzyme inhibition strategy RCM pairing reaction macrolactam pair phase novel class mouse neuron culture amine building blocks