Suzuki‐Miyaura Coupling, Heck Alkenylation, and Amidation of DMTr‐Protected 5‐Iodo‐2′‐Deoxyuridine via Palladium‐catalyzed Reactions

Abstract

Modification of nucleosides via cross-coupling processes has been carried out extensively on unprotected halonucleosides to produce functionalized nucleosides that are often developed for incorporation into oligonucleotides or used as fluorescent probes. This approach requires protection of the 5 -OH with the 4,4 -dimethoxytrityl (DMTr) group, which is complicated and a common cause of reaction failure. Here we report a method for direct functionalization of 5 -O-DMTr-5-iodo-2 -deoxyuridine via Suzuki-Miyaura cross-coupling, Heck alkenylation, and carboamidation. This approach facilitates rapid synthesis of a variety of C5-substituted 5 -O-DMTr-2 -deoxyuridine derivatives. © 2022 Wiley Periodicals LLC. BasicProtocol 1: Synthesis of the SerrKap palladacycle complex Basic Protocol 2: Suzuki-Miyaura coupling of 5 -O-DMTr-5-iodo-2deoxyuridine using SerrKap palladacycle Basic Protocol 3: Heck coupling of 5 -O-DMTr-5-iodo-2 -deoxyuridine using SerrKap palladacycle Basic Protocol 4: Heck coupling of 5 -O-DMTr-5-iodo-2 -deoxyuridine with Ruth linker using Pd(OAc) 2 /PTABS Basic Protocol 5: Carbonylative amidation of 5 -O-DMTr-5-iodo-2deoxyuridine using Pd(OAc) 2 /PTABS

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

“…A typical catalytic protocol for the coupling of 5-iodo-2'-deoxycytidine (I-dC) with arlyboronic acid proceeds with relatively lower reactivity compared to its uridine counterpart partly due to the more electron-rich nature of the heterocyclic ring that resists the attack of the nucleophile as a part of the catalytic coupling pathway. We have in recent years demonstrated the capability of several of our catalytic systems to efficiently couple I-dC with different arylboronic acids [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. However, the reaction has been relatively slower than uridine coupling processes (up to 24 hrs).…”

“…We have also been active in the development of several catalytic systems (palladium-based) allowing efficient cross-coupling [23][24][25][26][27][28][29][30]. Starting with [Pd(imidate) 2 (PTA) 2 ] [ [31][32][33] allowing the Suzuki-Miyaura cross-coupling of all four nucleosides, PTABS (KapdiPhos) [34][35][36][37][38][39][40][41][42][43][44][45] in combination with Pd(II) precursor allowing the isolation via column-free procedure (as well as catalyst recyclability), SerrKap palladacycle [46,47] as a phosphine-free catalyst and recently, [Pd(sacc) 2 (THPEN)] [48] another example of water-soluble phosphine-free catalyst promoting the coupling to take place at ambient temperature (Scheme 1).…”

Water‐Soluble Pd‐Imidate Complexes as Versatile Catalysts for the Modification of Unprotected Halonucleosides

“…SerrKap palladacycle (3 c), which had worked efficiently for the unprotected version of the nucleosides, was successfully tested in both reactions. [66] Thus Suzuki-Miyaura cross-coupling of 5'-O-DMT-5-iodo-2'-deoxyuridine was catalyzed by 3 c with several aryl and heteroarylboronic acids, as displayed in Scheme 10. Although the reaction was initially tried in water, the scarce solubility of the starting DMT-protected 5-iodo-2'-deoxyuridine in it prompted us to use DMF as a solvent instead, obtaining the corresponding C5 substituted 2'-deoxyuridines in good yields.…”