Chemoselective and Stereoselective Alcoholysis of Binaphthyl Phosphonothioates: Straightforward Access to Both Stereoisomers of Biologically Relevant P-Stereogenic Phosphonothioates

Abstract

P-Stereogenic phosphonothioates have attracted great attention due to their potent biological activities as analogues of phosphoric acids and phosphorothioates. We demonstrate here straightforward access to P-stereogenic phosphonothioates through the use of binaphthyl phosphonothioates as a chiral template. The first-step alcoholysis of binaphthyl phosphonothioates proceeded via a transfer of the axial chirality of a binaphthyl group to the central chirality of a phosphorus atom to give only monoalcohol adducts with moderate to excellent diastereoselectivities. Further alcoholysis of the obtained products in the presence of a small excess of alcohol and base proceeded with complete elimination of a binaphthyl group to give the corresponding P-stereogenic phosphonothioates with high enantiomeric excess. A DFT study of the reaction mechanisms in first-step alcoholysis indicated that the coordination of a sulfur atom to a sodium cation is the key factor in controlling the diastereoselectivities. This method can be applied to prepare both stereoisomers of a G6P analogue with high diastereomeric purity.

Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters

“…Recently, the Baran group reported a highly versatile chiral P(V) reagent: PSI (ψ), derived from limonene, for the diastereoselective synthesis of phosphorothioate oligonucleotides and of cyclic dinucleotides (CDNs). 13 Building upon previous chiral auxiliary approaches, [14][15][16][17][18] this work was also expanded towards the synthesis of P-chiral phosphines, as well as methylphosphonate oligonucleotides (MPOs). 19 3 While these elegant processes towards P-chiral compounds are effective, they remain diastereoselective, where chirality at the phosphorous centre is installed either through a matched combination of catalyst and a carefully tailored starting material or by employing a stoichiometric chiral leaving group.…”

“…Such changes were broadly tolerated with aryl (12), methyl (13), higher alkyl (14-15) and β-branched ( 16) substituents maintaining high reaction efficiency and enantioselectivities. Benzyl substituents (17)(18)(19) were also tolerated, despite a slight decrease in selectivity. Finally, we were pleased to find that thiophene (20) and (thio)ether (21,22) substituted prochiral phosphorous electrophiles were also competent substrates for our methodology.…”

Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters

“…Recently, the Baran group reported a highly versatile chiral P(V) reagent: PSI (ψ), derived from limonene, for the diastereoselective synthesis of phosphorothioate oligonucleotides and of cyclic dinucleotides (CDNs). 13 Building upon previous chiral auxiliary approaches, [14][15][16][17][18] this work was also expanded towards the synthesis of P-chiral phosphines, as well as methylphosphonate oligonucleotides (MPOs). 19 While these elegant processes towards P-chiral compounds are effective, they remain diastereoselective, where chirality at the phosphorous centre is installed either through a matched combination of catalyst and a carefully tailored starting material or by employing a stoichiometric chiral leaving group.…”

“…Such changes were broadly tolerated with aryl (12), methyl (13), higher alkyl (14-15) and β-branched (16) substituents maintaining high reaction efficiency and enantioselectivities. Benzyl substituents (17)(18)(19) were also tolerated, despite a slight decrease in selectivity. Finally, we were pleased to find that thiophene (20) and (thio)ether (21,22) substituted prochiral phosphorous electrophiles were also competent substrates for our methodology.…”

“…Finally, TBS protected phosphonate ester 6 was deprotected with TFA and cyclised with t-BuMgCl to give CycloSal derivative 34 in 67% yield and 92% es over 2 steps. Upon recrystallisation to enantiopurity and single crystal X-ray diffraction analysis (see SI for details), the absolute configuration of 34 was determined to be (R) showing inversion of configuration 18,[42][43][44] with respect to the starting material. [a] 3 eq of t-BuMgCl were used.…”