Unexpected Loss of Stereoselectivity in Ring‐Opening Reaction of 2‐Alkoxy‐2‐Thio‐1,3,2‐Oxathiaphospholanes With a Pyrophosphate Anion

Abstract

A reaction of DBU promoted ring opening in nucleoside-3'-O- and nucleoside-5'-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane) monomers with a pyrophosphate or a methylenediphosphonate anion proceeds with substantial loss of stereoselectivity. Depending on the absolute configuration of the phosphorus atom, so far widely accepted the stereoretentive mechanism of condensation is accompanied by a stereoinvertive one, most likely employing an intramolecular ligand-ligand exchange in an uncharged intermediate.

Practical Stereocontrolled Access to Thioisosteres of Essential Signaling Molecules and Building Blocks for Life: Nucleoside Di- and Triphosphates

“…In terms of reaction choreography, it was known from Stec's studies that the loading of a nucleoside followed by displacement with phosphate-type nucleophiles leads to extensive epimerization. 20,24 In our hands, using Ψ-loaded nucleosides, [26][27][28][29] no α-thiodiphosphate products were observed (presumably due to the increased steric hindrance of our reagents). Thus, the only viable alternative was to create a chiral α-thiodiphosphate transfer reagent in situ, that could be appended to a nucleoside of interest.…”

“…With regards to P2Y14, a combination of 2-thio and RP-αthiophosphate modifications was synergistic resulting in very high (EC50 = 37 nM) affinity of a UTP derivative 24 (100 fold increase in activity compared to natural substrates UDP and UDP-glucose) (Figure 2A-2 and 2A-3). Remarkably, the P2Y6 receptor stereochemical preference is reversed with SP-αthiophosphates showing higher affinity than RP isomers.…”

“…20,24 However, the final coupling step proceeds with substantial PS epimerization via an intramolecular ligand-ligand exchange mechanism. 24 Stereopure α-thioNDPs and NTPs have been only prepared using enzymatic methods which are highly substratespecific and usually provide access to only one PS-stereoisomer. Applying such an approach to unnatural nucleotides requires systematic enzyme evolution, thereby limiting utility for a medicinal chemistry program.…”

“…Such an approach had never been pursued before, despite obvious advantages of such a convergent path, due to expected stability challenges of such a reagent, the phosphate itself acting as a leaving group, and epimerization during coupling step. 24 Herein, a stereo-controlled, modular, and scalable method for the synthesis of these valuable structures is enabled through the invention of new chiral P(V)-α-thio-di-and triphosphate transfer reagents 4 and 5, prepared in situ and easily appended to a library of nucleoside donors (Figure 1C). These reagents are derived from easy-to-handle, bench-stable solids, available on decagram scale.…”

“…18 Finally, Stec's oxathiophospholane (OTP) approach (1c) begins with a P(III)-OTP loading reaction, followed by oxidative sulfurization to furnish a chiral P(V)-OTP auxiliary; this stable intermediate can then be coupled with pyrophosphate to form the final α-thioNTP using simple base activation (DBU). 20,24 However, the final coupling step proceeds with substantial PS epimerization via an intramolecular ligand-ligand exchange mechanism. 24 Stereopure α-thioNDPs and NTPs have been only prepared using enzymatic methods which are highly substratespecific and usually provide access to only one PS-stereoisomer.…”