1,3,5‐Triaza‐7‐phosphaadamantane (PTA) Derived Caged Phosphines for Palladium‐Catalyzed Selective Functionalization of Nucleosides and Heteroarenes

Abstract

Phosphines have, in combination with transition metals, played a pivotal role in the rapid development of efficient catalytic processes. Caged phosphines constitute a class of three‐dimensional scaffolds providing unique control over steric and electronic properties. The versatility of the caged phosphine ligands has been demonstrated elegantly by the groups of Verkade, Gonzalvi as well as Stradiotto. Our research group has also been working extensively for the past several years in the development of 1,3,5‐triaza‐7‐phosphaadamantane‐based caged ligands and in this personal note we have summarized these applications pertaining to the modification of biologically useful nucleosides and heteroarenes.

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding

“…In our previous reports, we have provided evidence for the involvement of Cu(II)/PTABS remaining unchanged throughout the catalytic reaction (no change in oxidation state confirmed by ESR studies) and yet providing very high yields of the amination products in aqueous media at ambient temperature. 11 A plausible mechanism depicting the same was also put forth (Figure 7), which suggests the presence of a catalytically active [Cu II ] species generated via the coordination of Cu(OAc) 2 and the PTABS ligand. The exact nature of this species has been unknown until now, and in this report, we would like to provide further insights into the nature of the catalytically active [Cu II ] species prevalent in the given reaction.…”

“…Our research group has contributed significantly in the past decade to the functionalization of chloroheteroarenes using a variety of nucleophiles (including amines) at ambient or low temperatures owing to the identification of a unique Cu(II)/PTABS (KapdiPhos)promoted S N Ar. 11,12 The entire experience of working with our catalytic system and understanding the reactivity observed especially with heteroarenes (such as pyrimidine) provides us with an opportunity to address the site selectivity issue, and we therefore present herein our results for the efficient siteselective amination of polychlorinated pyrimidines using Cu(II)/PTABS catalytic system and assisted by DFT analysis of the bond dissociation energies (BDEs) of the different C− Cl bonds. The difference in the BDE of regioisomeric C−Cl bonds (calculated by DFT) was exploited as the Cu/PTABS catalytic system via electronic and steric effects, which were able to enhance the reactivity of certain positions.…”

Palladium-Catalyzed Cyanation of Nucleobases: Total Synthesis of Toyocamycin, Sangivamycin, and a Mycalisine A Precursor

“…Our previous reports on the Pd-catalyzed Suzuki-Miyaura crosscoupling of 5-iodo-2'-deoxyuridine (1a) using [Pd(imidate)2(PTA)2] and Pd/PTABS (Kapdiphos) catalytic systems were a good starting point. [17][18][19] Several metal-based cyanide sources (KCN, NaCN, Zn(CN)2) as well as organic substrates acting as in-situ sources of CNare known in literature. [13,20] The possible interference of organic substrates (as sources of CN -) with the catalytic cycle and their interaction with the nucleoside scaffold restricts their applicability, while the hazardous nature of KCN or NaCN (currently available under Synlett Letter / Cluster / New Tools Template for SYNLETT Thieme restrictions) further limit the choice of cyanide reagents for performing the desired transformation.…”

“…Our previous reports on the Pd-catalyzed Suzuki-Miyaura cross-coupling of 5-iodo-2′-deoxyuridine (1a) by using [Pd(imidate) 2 (PTA) 2 ] and Pd/PTABS (Kapdiphos) catalytic systems were a good starting point. [17][18][19] Several metal-…”

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

“…1). The Pd/PTABS system allows Suzuki‐Miyaura coupling of all four nucleobase structures in unprotected 2′‐deoxynucleosides to be modified in water as the sole reaction solvent (Bhilare, Murthy Bandaru, Schulzke, & Kapdi, 2021; Shet, Bhilare, Sanghvi, & Kapdi, 2020). Similarly, the Heck coupling reaction can also be performed efficiently (Kapdi, Ardhapure, & Sanghvi, 2015), albeit in organic solvents due to the poor solubility of the coupling partners.…”