Scientific Publications

An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors.

Publication TypeJournal Article
AuthorsMarcaurelle, LA, Comer E., Dandapani S., Duvall JR, Gerard B., Kesavan S., Lee MD 4th, Liu H., Lowe JT, Marie JC, Mulrooney CA, Pandya BA, Rowley A., Ryba TD, Suh BC, Wei J., Young DW, Akella LB, Ross NT, Zhang YL, Fass DM, Reis SA, Zhao WN, Haggarty SJ, Palmer M., and Foley MA
AbstractAn 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 γ-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 (S(N)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.
Year of Publication2010
JournalJournal of the American Chemical Society
Volume132
Issue47
Pages16962-76
Date Published (YYYY/MM/DD)2010/12/01
ISSN Number0002-7863
DOI10.1021/ja105119r
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/21067169?dopt=Abstract