Diastereomerically pure nucleoside‐5′‐O‐(2‐thio‐4,4‐pentamethylene‐1,3,2‐oxathiaphospholane)s—Substrates for synthesis of P‐chiral derivatives of nucleoside‐5′‐O‐phosphorothioates

Abstract

A method for stereocontrolled chemical synthesis of P-substituted nucleoside 5'-O-phosphorothioates has been elaborated. Selected 3'-O-acylated deoxyribonucleoside- and 2',3'-O,O-diacylated ribonucleoside-5'-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane)s were chromatographically separated into P-diastereomers. Their reaction with anions of phosphorus-containing acids was highly stereoselective (≥90%) and furnished corresponding P-chiral α-thiodiphosphates and their phosphonate analogs with satisfactory yield.

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

“…23 For the synthesis of stereodefined NXPαS, nucleoside-5'-Ooxathiaphospholane monomers (5'-OTP, 5, Y = protecting group, Chart 2) might be useful. 26 They were expected to be suitable for the stereocontrolled synthesis of NXPαS upon reaction with anions of phosphorus-containing acids. 24,25 Of course, the stereochemistry of these reactions could not be established, yet the expected reactivity was confirmed.…”

“…Unfortunately, chromatographic separation of P-diastereomers of many tested 5'-OTP could not be achieved for a long time, so a few P-chiral biophosphates, including NDPαS and NTPαS, were synthesized using unresolved monomers. 26 The reaction with anhydrous crystalline H 3 PO 4 in the presence of DBU, after deprotection, furnished the corresponding 5'-O-(α-thiodiphosphate) (2) with >90% stereoselectivity as assessed by 31 P nuclear magnetic resonance (NMR). Later on, several 3'-O-camphanoylated 2'deoxyribonucleoside-5'-O-(2-thio-4,4-pentamethylene-1,3,2oxathiaphospholane)s (5'-OTPs, 5, Y=(-)-camphanoyl) were synthesized and chromatographically separated into fastand slow-eluting P-diastereomers.…”

“…Later on, several 3'-O-camphanoylated 2'deoxyribonucleoside-5'-O-(2-thio-4,4-pentamethylene-1,3,2oxathiaphospholane)s (5'-OTPs, 5, Y=(-)-camphanoyl) were synthesized and chromatographically separated into fastand slow-eluting P-diastereomers. 26 They were expected to be suitable for the stereocontrolled synthesis of NXPαS upon reaction with anions of phosphorus-containing acids. To determine the stereochemistry of this type of reactions, diastereomerically enriched samples of 5 were used.…”

P-Stereodefined phosphorothioate analogs of glycol nucleic acids—synthesis and structural properties

“…35 In the presented example fast-12 was reacted with (S C + R C )-DMT-G A Bz (4b, prepared from racemic glycidol) to yield a pair of protected DMT-G A Bz PS T Camph (13b). By a routine two-step deprotection both isomers of 13b were converted into a pair of S C S P -and R C S P -11*b, but this time the absolute conguration at P-atoms (i.e.…”

Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and Application

“…Stereochemically defined synthesis was attempted using the oxathiaphospholane approach. For that purpose, selected 3'-O-acylated deoxyribonucleoside-and 2',3'-O,O-diacylated ribonucleoside-5'-O-(4,4-pentamethylene-2-thioxo-1,3,2-oxathiaphospholane)s, 36 and 37, respectively, carrying bulky acyl substituent(s) (1,1'-biphenyl-4-carbonyl, naphthalene-2-carbonyl, adamantane-1-carbonyl, or (À)-camphanoyl), were separated into P-diastereoisomers either by open column chromatography or semi-preparative HPLC on silica gel columns [127]. One of them, i.e., 3'-O-camphanoylthymidine-5'-O-(4,4-pentamethylene-2-thioxo-1,3,2-oxathiaphospholane) (36a; X¼ (À)-camphanoyl; Scheme 9) was reacted with three anions of P-containing acid, furnishing thymidine 5'-O-(athiodiphosphate) (TDP aS, 38), thymidine 5'-O-(b,g-methylene-a-thiotriphosphate) (39), and thymidine 5'-O-(benzylphosphono-a-thiophosphate) (40) in a highly stereoselective manner.…”