Abstract
A strategy for DNA-compatible, palladium-catalyzed hydroxycarbonylation of (hetero)aryl halides on DNA–chemical conjugates has been developed. This method generally provided the corresponding carboxylic acids in moderate to very good conversions for (hetero)aryl iodides and bromides, and in poor to moderate conversions for (hetero)aryl chlorides. These conditions were further validated by application within a DNA-encoded chemical library synthesis and subsequent discovery of enriched features from the library in selection experiments against two protein targets.
Highlights
DNA-encoded chemical libraries (DECLs) are collections of small molecules connected to a unique DNA sequence that serves as a barcode for the small molecule structure.[1−3] Due to the high fidelity of DNA amplification and high-throughput sequencing, multibillion member DECL pools may be used in affinity-based protein target screening campaigns to enrich small molecule binders whose identifying DNA tags may be amplified/decoded at subfemtomole scales.[4−6] many types of DNA-compatible chemical transformations for solution-phase small molecule synthesis have been disclosed,[7−15] a survey of reported DECLs show the majority are constructed with at least one amidation reaction,[16] likely due to the inherent stability of amide bonds to aqueous conditions,[17] the broad substrate scope of amidations on oligonucleotide−chemical conjugates,[18,19] and the wide commercial availability of amines and carboxylic acids.[20]
Amidation substrates in DECL synthesis are typically prepared through attachment of a building block already containing the required functional group, such as a bifunctional protected amine (e.g., N-Fmoc, N-Boc, nitro21), bifunctional protected acid, or by addition of an amino acid.[22,23]
These conditions were used on a portion of the pooled cycle 2 material from a three-cycle, “split-and-pool” type DECL synthesis we described previously (Scheme 5).[21]
Summary
DNA-encoded chemical libraries (DECLs) are collections of small molecules connected to a unique DNA sequence that serves as a barcode for the small molecule structure.[1−3] Due to the high fidelity of DNA amplification and high-throughput sequencing, multibillion member DECL pools may be used in affinity-based protein target screening campaigns to enrich small molecule binders whose identifying DNA tags may be amplified/decoded at subfemtomole scales.[4−6] many types of DNA-compatible chemical transformations for solution-phase small molecule synthesis have been disclosed,[7−15] a survey of reported DECLs show the majority are constructed with at least one amidation reaction,[16] likely due to the inherent stability of amide bonds to aqueous conditions,[17] the broad substrate scope of amidations on oligonucleotide−chemical conjugates,[18,19] and the wide commercial availability of amines and carboxylic acids.[20] Amidation substrates in DECL synthesis are typically prepared through attachment of a building block already containing the required functional group, such as a bifunctional protected amine (e.g., N-Fmoc, N-Boc, nitro21), bifunctional protected acid (e.g., ester), or by addition of an amino acid.[22,23] many of such bifunctional building blocks are commercially available or known, an alternative paradigm would be to install the amino or carboxyl group through conversion of a DNAattached functional group. Several methods to generate carbon monoxide in situ from reagent decomposition in the reaction medium have been reported, including the use of N-formyl saccharin,[42] molybdenum hexacarbonyl,[43] and formyl acetates.[36−38] Based upon our work[27] and that of others[8,14,28] on DNA-compatible Suzuki coupling using hydroxide base, we hypothesized that similar conditions utilizing an internal carbon monoxide source could yield (hetero)aromatic carboxylic acids from the corresponding (hetero)aromatic halides (Scheme 1b)
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