On-DNA Alkyne Iodination and Acetylenic Coupling as a Useful Tool for DEL Synthesis

Abstract

1-Iodoalkynes and 1,3-diynes are versatile chemical intermediates and pharmaceutically valuable ingredients. In this study, copper mediated on-DNA alkyne iodination and Cadiot-Chodkiewicz coupling are developed for the first time. This generates diverse, systematic, and unprecedented topographic structural features, which could be invaluable as molecular recognition agents for drug discovery in DEL screening.

Development of On‐DNA Thiophene Synthesis for DEL Construction

“…As a general trend, this focus on aliphatic DNA-conjugates supplements quite rationally our seminal study. [30] Indeed, the reaction showed a broad tolerance for various linker's lengths (3 b, 3 d-f, and 3 h), or presence of functionalizing moieties on the aliphatic chain (3 a, 3 g, 3 k, and 3 p). Also, inversion of the amide bond didn't influence the reaction outcome much (3 d vs 3 h).…”

“…Additionally, we recently reported the synthesis of 1,3diynes from alkyne-bearing DNA-conjugates using an iodination and Cadiot-Chodkiewicz coupling cascade. [30] Considering the robustness of this approach, the wide availability of involved building blocks, we set our course on the development of an heterocyclization strategy for on-DNA thiophene generation and application to DEL synthesis. We herein present the results of this endeavor.…”

“…[31][32][33] The latter approach was proved to be efficient in our previous work. [30] Next, syntheses of 1,3-diynes were carried out using a Cadiot-Chodkiewicz coupling between a variety of iodoalkyne DNA-conjugates and terminal alkynes (Table 1). In past studies, the constraints of performing reactions on DNA naturally led to an enrichment of sp 2 -rich structures and peptidomimetics in published libraries, as Prof. Schreiber summarized.…”

Constructive On-DNA Abramov Reaction and Pudovik Reaction for DEL Synthesis

“…DNA-encoded library technology (DELT) is a compelling pharmaceutical tool for drug discovery. − The method allows for the screening of billions of potential drug-like molecules against a target protein. − The rapid development of DNA-compatible chemistries has considerably expanded the chemical space available for drug discovery to identify the initial hit compounds. As a matter of fact, in recent years, there has been a significant emphasis on developing DNA-compatible chemistries to form a comprehensive chemical toolbox for DEL design, which increases the structural diversity of small molecule library members in DELs. − Our team also took part of this endeavor, and our most recent work on-DNA reactions for α-hydroxyphosphonate synthesis is documented here, which illustrates particularly well our will to explore new chemical space or novel DEL synthetic strategy. − …”

Development of the Inverse Sonogashira Reaction for DEL Synthesis

“…Nevertheless, the synthesis of DELs is currently impeded by the limited availability of effective and DNA-compatible reactions applicable to a wide variety of substrates with high conversion rates and without compromising DNA integrity . Along with a plethora of other DELT practitioners, we have worked on DNA-compatible chemical reactions, particularly those with the potential for DEL synthesis to explore new chemical space or develop innovative DEL synthetic strategies . The palladium-catalyzed carbon–carbon cross-coupling of organometallic nucleophiles with organoelectrophiles plays an important role in contemporary organic synthesis .…”