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1. A process for the preparation of phosphorothiotriesters of structure IIIa comprising the steps of:
i) reacting an H-phosphonate of structure Ia with an silylating reagent to provide a silyloxyphosphonate; and ii) reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa to provide a phosphorothiotriester of structure IIIa;wherein,the H-phosphonate of structure Ia has the following structure:wherein,
W is independently selected from O, S, NH, or CH2; R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa or —SRc; Y1 is O, NRd, S, or Se; Ra is a blocking group; Rc is a blocking group; each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re); each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1; Y2 is O, NRd, or S; each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group; each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase; R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; and n is between 1 and about 200; andthe thiosulfonate reagent of structure IIa has the following structure:wherein,
X is alkyl, cycloalkyl, or heteroaryl; R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R1-R2; R1 is selected from —S-alkenylene-, —S-alkylene-, —S-alkylene-aryl-alkylene-, —S—CO-aryl-alkylene-, or —S—CO-alkylene-aryl-alkylene-; R2 is selected from heterocyclo-alkylene-S—, heterocyclo-alkenylene-S—, aminoalkyl-S—, or (alkyl)4N-alkylene-S—;and the phosphorothiotriester of structure IIIa has the following structure:wherein,
W is independently selected from O, S, NH, or CH2; R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R1-R2; R1 is selected from —S-alkenylene-, —S-alkylene-, —S-alkylene-aryl-alkylene-, —S—CO-aryl-alkylene-, or —S—CO-alkylene-aryl-alkylene-; R2 is selected from heterocyclo-alkylene-S—, heterocyclo-alkenylene-S—, aminoalkyl-S—, or (alkyl)4N-alkylene-S—; R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —HP(O)(Re), —ORa or —SRc; Y1 is O, NRd, S, or Se; Ra is a blocking group; Rc is a blocking group; each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re); each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1; Y2 is O, NRd, or S; each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group; each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase; R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; and n is between 1 and about 200. |
