DNA-encoded combinatorial libraries are increasingly being used as tools for the discovery of small organic binding molecules to proteins of biological or pharmaceutical interest. In the majority of cases, synthetic procedures for the formation of DNA-encoded combinatorial libraries incorporate at least one step of amide bond formation between amino modified DNA and a carboxylic acid. We investigated reaction conditions and established a methodology by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-hydroxy-7-azabenzotriazole and N,N′-diisopropylethylamine (EDC/HOAt/DIPEA) in combination, which provided conversions greater than 75% for 423/543 (78%) of the carboxylic acids tested. These reaction conditions were efficient with a variety of primary and secondary amines, as well as with various types of aminomodified oligonucleotides. The reaction conditions, which also worked efficiently over a broad range of DNA concentrations and reaction scales, should facilitate the synthesis of novel DNAencoded combinatorial libraries. KeywordsDNA-encoded chemical libraries; amide bond formation; synthesis; bioconjugation DNA-encoded combinatorial libraries (DECLs) are collections of organic compounds, individually coupled to distinct DNA fragments, serving as identification barcodes.1-4 Since DNA can be efficiently amplified by the polymerase chain reaction (PCR) and read by highthroughput DNA sequencing methods, the encoding of combinatorial libraries with DNA barcodes allows both the facile identification of specific ligands to protein targets immobilized on a solid support and the convenient handling of the libraries as mixtures of compounds. Compared to High-Throughput Screening, which relies on expensive compound Various chemical strategies have been developed for the generation of large combinatorial DECLs, including DNA-templated synthesis,10,11 DNA-encoded routing,12 hybridizationbased chemical assembling 13-17and DNA-encoded solid-phase synthesis.18 In addition, the iterative assembly of sets of building blocks in a "split-and-pool" methodology, accompanied by the stepwise addition of DNA barcodes (which unambiguously identify the chemical identity of the nascent molecules), is the most generally used strategy for DECLs construction. This strategy facilitates the preparation of DECLs containing millions or even billions of compounds, starting from just few hundred building blocks and oligonucleotides. 19,20,21 In the majority of DECLs disclosed so far, at least one synthesis step involved the formation of an amide bond.4 More than 20'000 carboxylic acids can be purchased from commercial sources at moderate costs (less than $150/g). 22 The acylation of DNA-attached amines with carboxylic acids can be performed on protected DNA structures linked to Controlled Pore Glass (CPG) supports 6 or in solution, 23 followed by deprotection and HPLC purification of the individual conjugates at early stages of library construction. Additionally, for unprotected DNA-attached amines, acylation can be performed either...

A new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Brønsted base/Lewis acid catalysts in the asymmetric aldol reaction of isocyanoacetate nucleophiles. Under optimal conditions, high diastereoselectivities (up to 98%) and enantioselectivities (up to 98%) were obtained.

An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting selectivity in substrates with multiple alcohols is given.

A mutually compatible and cooperative combination of copper(I) triflate and bifunctional 9-amino-9-deoxyepicinchona-derived urea compounds for the enantioselective Conia-ene cyclization of alkyne-tethered beta-ketoester substrates is reported. The reaction is efficient, broad in scope, and easy to perform and allows access to chiral methylenecyclopentane products with high enantiocontrol. The transformation illustrates the concept of combining inactive precatalysts with inactive transition-metal-ion complexes in situ to reversibly create a catalytically active combination of the two.

We report a novel prosthetic group based on a heterocyclic methylsulfone derivative for the rapid, stable, and chemoselective (18)F-labeling of thiol-containing (bio)molecules under mild aqueous reaction conditions. Compared to established maleimide approaches, the new methodology displays some clear advantages for imaging probe development.