This project aims to exploit the Broad Institute CMLD's chemical methodology efforts to drive small-molecule library development using a strategy that evolved from the Broad Institute CMLD community. We will use the simple yet powerful build/couple/pair (B/C/P) strategy to develop two exceptionally short, modular and stereoselective pathways yielding compounds having, relative to Project 1, high sp[2] content in the atoms that define the heterocyclic skeletons of the products. We note that this descriptor is characteristic of many FDA-approved small-molecule drugs or small molecules currently being investigated in the pharmaceutical industry. These pathways illustrate a new approach to synthesizing stereoisomers of such compounds;stereoisomers of drug-like compounds in screening collections such as the Molecular Libraries Small-Molecule Repository (MLSMR) for use by the Molecular Libraries Probe-Production Centers Network ((MLPCN) provide valuable insights into structure/activity relationships not otherwise available from a primary small-molecule screen. Based on recent progress from the Jacobsen laboratory component of the Broad Institute CMLD, we have conceived of a pathway that exploits both highly selective chiral catalysts for the Pictet-Spengler-like reaction and the B/C/P strategy. We will evaluate the role of catalyst and substrate structure on Pictet-Spengler reaction stereochemistry by constructing a range of hydroxylactams as precursors.
We aim to prepare all possible stereoisomers of each skeletal type. The outcomes of reactions using this high level of substrate diversity should lead to a far greater understanding of the asymmetric Pictet-Spengler-like reactions developed in the course of our chemical methodology efforts, especially its generality and value in the context of challenging library syntheses. In addition, the studies are expected to yield a rich collection of stereochemically and skeletally diverse heterocyclic compounds suitable for small-molecule screening. We will also explore a second pathway that builds on the principles of the first pathway and that aims to yield a heterocyclic compounds having multiple skeletons, including ones not yet represented in small-molecule screening collections. Based on progress in a current CMLD project on chemical methodology from the Schreiber laboratory, we have conceived of a B/C/P pathway that exploits a cationic gold(l)/silver(l)-mediated isomerization and nucleophilic trapping of easily synthesized substrates having two neighboring acetylenes yielding novel and complex yield a-pyrones, among others. This pathway exploits this new method for a-pyrone synthesis and a new method for intramolecular, functional group-pairing reactions that incorporate nitriles in order to synthesize a library of small molecules having diverse heterocyclic skeletons, including complex pyridine rings. A unifying theme of the two pathways is the application of the B/C/P strategy to synthesize in high yield, and using very few steps, small molecules that possess (relative to Project 1) high sp[2]/sp[3] ratios in ring atoms, a feature reminiscent of many heterocyclic, small-molecule probes and drugs.
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