title: Development of a Diastereoselective Phosphorylation of a Complex Nucleoside via Dynamic Kinetic Resolution.
abstract: The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a ∼7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1).
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Kristy
authors.initials: K
authors.lastname: Tran
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beutner
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Jacob
authors.initials: J
authors.lastname: Janey
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Rosso
authors.affiliation: Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Eastgate
mesh_terms: D000577:Amides / Q000737:chemistry*; D000840:Anisoles / Q000737:chemistry; D003460:Crystallization; D007700:Kinetics; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D010756:Phosphoric Acids / Q000737:chemistry*; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000577:Amides; D000840:Anisoles; D009705:Nucleosides; D010756:Phosphoric Acids; D011355:Prodrugs; C011067:phosphoramidic acid