Homogeneous and Functional Group Tolerant Ring-Closing Metathesis for DNA-Encoded Chemical Libraries
Publication Date
2-10-2020
Journal
ACS Combinatorial Science
DOI
10.1021/acscombsci.9b00199
PMID
31913011
PMCID
PMC7014401
PubMedCentral® Posted Date
1-8-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Buffers, Catalysis, Cyclization, DNA, Gene Library, Peptides, Small Molecule Libraries
Abstract
Reaction heterogeneity, poor pH control, and catalyst decomposition in the ring-closing metathesis (RCM) of DNA–chemical conjugates lead to poor yields of the cyclized products. Herein we address these issues with a RCM reaction system that includes a novel aqueous solvent combination to enable reaction homogeneity, an acidic buffer system which masks traditionally problematic functional groups, and a decomposition-resistant catalyst which maximizes conversion to the cyclized product. Additionally, we provide a systematic study of the substrate scope of the on-DNA RCM reaction, a demonstration of its applicability to a single-substrate DNA-encoded chemical library that includes sequencing analysis, and the first successful stapling of an unprotected on-DNA [i, i+4] peptide.
Graphical Abstract
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