An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors.
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 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.
Chemical Biology Platform, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States. lisa@broadinstitute.org
Lisa A
LA
Marcaurelle
Eamon
E
Comer
Sivaraman
S
Dandapani
Jeremy R
JR
Duvall
Baudouin
B
Gerard
Sarathy
S
Kesavan
Maurice D
MD
Lee
Haibo
H
Liu
Jason T
JT
Lowe
Jean-Charles
JC
Marie
Carol A
CA
Mulrooney
Bhaumik A
BA
Pandya
Ann
A
Rowley
Troy D
TD
Ryba
Byung-Chul
BC
Suh
Jingqiang
J
Wei
Damian W
DW
Young
Lakshmi B
LB
Akella
Nathan T
NT
Ross
Yan-Ling
YL
Zhang
Daniel M
DM
Fass
Surya A
SA
Reis
Wen-Ning
WN
Zhao
Stephen J
SJ
Haggarty
Michelle
M
Palmer
Michael A
MA
Foley
D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013379:Substrate Specificity
D000447:Aldehydes; D001688:Biological Products; D056572:Histone Deacetylase Inhibitors; D047028:Macrocyclic Compounds; C116609:3-hydroxybutanal; D006655:Histone Deacetylases