Claims
- 1. A method for the synthesis of chirally pure nucleoside dimers of chosen sense of P-chirality of the formula: ##STR2## wherein (a) R.sub.2 is a protecting group;
- (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 12 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms;
- (c) B is an independently selected optionally protected nucleoside base;
- (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; and
- (e) R.sub.X is an aroyl protecting group, acyl protecting group, alkoxycarbonyl protecting group, benzenesulfonyl or ring-substituted benzenesulfonyl protecting group, a coupling group, a silyl protecting group, a 5'-O-nucleotide analog or a 5'-O-oligonucleotide analog or an alkyl protecting group;
- which comprises
- (i) separating a racemic mixture of the compound of formula (II) ##STR3## into diastereomers of chosen and unchosen sense of P-chirality, wherein X is sulfur or selenium, Ar is phenyl optionally substituted with 1 to 5 substitutients independently selected from halogen, nitro, cyano and lower alkyl;
- (ii)
- (a) contacting the diastereomer of the chosen sense of P-chirality with a strong non-nucleophilic base and carbon dioxide to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate;
- (b) contacting the transient intermediate of step (ii)(a) with an alkylating agent of the formula R.sub.3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesitylate, triisopropyl benzenesulfonyl or benzenesulfonyl and R.sub.3 is -Q.sub.1 to give a chirally pure diastereomer of the chosen sense of P-chirality of the formula (III) ##STR4## (iii) contacting the diastereomer of the unchosen sense of P-chirality from step (i) with an oxygen transferring oxidizing agent to form an intermediate nucleoside of the unchosen sense of P-chirality of the formula (IV) ##STR5## (iv) (a) contacting the intermediate nucleoside of step (iii) with a strong non-nucleophilic base and CX.sub.2 to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate; and
- (b) contacting the transient intermediate of step (iv)(a) with an alkylating agent of the formula R.sub.3 W to give a diastereomer of the chosen sense of P-chirality of formula (III); and
- (v) coupling the diastereomer of formula (III) with a nucleoside of formula (V) ##STR6## under stereospecific coupling conditions including DBU and a Lithium halide to give the chirally pure dimer of chosen sense of P-chirality of formula I.
- 2. A method according to claim 1 wherein said oxygen transferring oxidizing reagent is selected from the group consisting of oxone, hydroperoxide, alkylhydroperoxides, arylhydroperoxide, perbenzoic acids, and perphthalates.
- 3. A method for the synthesis of chirally pure nucleoside monomer synthons of chosen sense of P-chirality of the formula III: ##STR7## wherein (a) R.sub.1 is a protecting group;
- (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 12 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms;
- (c) B is an independently selected optionally protected nucleoside base;
- (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl;
- (e) R.sub.3 is -Q.sub.1 ; and
- (f) X is selenium or sulfur;
- which comprises
- (i) separating a racemic mixture of the compound of formula (II) ##STR8## into diasteromers of chosen and unchosen sense of P-chirality, wherein Ar is phenyl optionally substituted with 1 to 5 substitutients independently selected from halogen, nitro, cyano and lower alkyl;
- (ii)
- (a) contacting the diastereomer of the chosen sense of P-chirality with a strong non-nucleophilic base and carbon dioxide to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate;
- (b) contacting the transient intermediate of step (ii)(a) with an alkylating agent of the formula R.sub.3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesitylate, triisopropyl benzenesulfonyl or benzenesulfonyl to give a chirally pure diastereomer of the chosen sense of P-chirality of the formula (III) ##STR9## (iii) contacting the diastereomer of the unchosen sense of P-chirality from step (i) with an oxygen transferring oxidizing agent to form an intermediate nucleoside of the unchosen sense of P-chirality of the formula (IV) ##STR10## (iv) (a) contacting the intermediate nucleoside of step (iii) with a strong non-nucleophilic base and CX.sub.2 to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate; and
- (b) contacting the transient intermediate of step (iv) (a) with an alkylating agent of the formula R.sub.3 W to give a chirally pure diastereomer of the chosen sense of P-chirality of formula (III ).
- 4. A method according to claim 3 wherein said oxygen transferring oxidizing agent is selected from the group consisting of oxone, hydroperoxides, alkylhydroperoxides, arylhydroperoxides, perbenzoic acids and perphthalates.
- 5. A method for the synthesis of chirally pure nucleoside monomer synthons of chosen sense of P-chirality of the formula III: ##STR11## wherein (a) R.sub.1 is a protecting group;
- (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms;
- (c) B is an independently selected optionally protected nucleoside base;
- (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl;
- (e) R.sub.3 is -Q.sub.1 ; and
- (f) X is selenium or sulfur; which comprises
- (i) separating a racemic mixture of the compound of formula (II) ##STR12## into diastereomers of chosen and unchosen sense of P-chirality, wherein Ar is phenyl optionally substituted with 1 to 5 substitutients independently selected from halogen, nitro, cyano and lower alkyl;
- (ii)
- (a) contacting the diastereomer of the chosen sense of P-chirality a strong non-nucleophilic and carbon dioxide to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate; and
- (b) contacting the transient intermediate of step (ii)(a) with an alkylating agent of the formula R.sub.3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesylate, triisopropyl benzenesulfonyl or benzenesulfonyl to give a chirally pure diastereomer of the chosen sense of P-chirality of the formula (III) ##STR13##
- 6. A method for the synthesis of chirally pure nucleoside monomer synthons of chosen sense of P-chirality of the formula III: ##STR14## wherein (a) R.sub.1 is a protecting group;
- (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms;
- (c) B is an independently selected optionally protected nucleoside base;
- (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl;
- (e) R.sub.3 is -Q.sub.1 ; and
- (f) X is selenium or sulfur; which comprises
- (i) separating a racemic mixture of the compound of formula (II) ##STR15## into diasteromers of chosen and unchosen sense of P-chirality, wherein X is sulfur or selenium, Ar is phenyl optionally substituted with 1 to 5 substitutients independently selected from halogen, nitro, cyano and lower alkyl;
- (ii) contacting the diastereomer of the unchosen sense of P-chirality from step (i) with an oxygen transferring oxidizing agent to form an intermediate nucleoside of the unchosen sense of P-chirality of the formula (IV) ##STR16## (iii) (a) contacting the intermediate nucleoside of step (ii) with a strong non-nucleophilic base and CX.sub.2 to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate; and
- (b) contacting the transient intermediate of step (iii)(a) with an alkylating agent of the formula R.sub.3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesitylate, triisopropyl benzenesulfonyl, or benzenesulfonyl to give a chirally pure diastereomer of the chosen sense of P-chirality of formula (III).
- 7. A method according to claim 6 wherein said oxygen transferring oxidizing agent is selected from the group consisting of oxone, hydroperoxide, alkylhydroperoxides, arylperoxides, perbenzoic acids and perphthalates.
- 8. A method of converting a nucleoside monomer intermediate of unchosen sense of P-chirality of formula (II) to a nucleoside monomer synthon of chosen sense of P-chirality of the formula (III) ##STR17## wherein (a) R.sub.1 is a protecting group;
- (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms;
- (c) B is an independently selected optionally protected nucleoside base;
- (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; and
- (e) R.sub.3 is -Q.sub.1 ; and
- (f) X is selenium or sulfur;
- which comprises
- (i) contacting a diastereomer of the unchosen sense of P-chirality of formula II ##STR18## wherein X is sulfur or selenium and Ar is phenyl optionally substituted with 1 to 5 substitutients independently selected from halogen, nitro, cyano and lower alkyl with an oxygen transferring oxidizing agent to form a second intermediate nucleoside of the unchosen sense of P-chirality of the formula (IV) ##STR19## (ii) (a) contacting the intermediate nucleoside of step (i) with strong non-nucleophilic base and CX.sub.2 to give a transient nucleoside 3'-O-(Z-substituted) phosphonoselenoic or phosphonothioic acid intermediate; and
- (b) contacting the transient intermediate of step (ii)(a) with an alkylating agent of the formula R.sub.3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesitylate, triisoprophylbenzenesulfonyl or benzenesulfonyl, to give a diastereomer of the chosen sense of P-chirality of formula (III).
- 9. A method according to claim 8 wherein said oxygen transferring oxidizing agent is selected from the group consisting of oxone, hydroperoxide, alkylhydroperoxides, arylperoxides, perbenzoic acids and perphthalates.
- 10. A method according to any one of claims 1, 3, 5, 6 or 8 wherein said strong non-nucleophilic base is selected from sodium hydride and DBU.
- 11. A compound of the formula II ##STR20## wherein (a) R.sub.1 is a protecting group, (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or flouroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, axido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q, -OQ.sub.1, -SQ.sub.1 or NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 atoms, and alkynyl of 3 to 12 carbon atoms; (c) B is an independently selected optionally protected nucleoside base; (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; (e) X is sulfur or selenium; and (f) Ar is phenyl optionally substituted with 1 to 5 substututients independently selected from halogen, nitro, and lower alkyl of 1 to 6 carbon atoms, with the proviso that when R.sub.2 is hydrogen, optionally protected hydroxyl or methoxy, then Ar is not unsubstituted phenyl.
- 12. A compound of the formula III ##STR21## wherein (a) R.sub.1 is a protecting group, (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms, cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms; (c) B is an independently selected optionally protected nucleoside base; (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; (e) R.sub.3 is -Q.sub.1 ; and (f) X is selenium or sulfur, with the proviso that when R.sub.2 is hydrogen, optionally protected hydroxyl or methoxy then R.sub.3 is not methyl, benzyl or nitrobenzyl.
- 13. A compound of the formula IV: ##STR22## wherein (a) R.sub.1 is a protecting group; (b) each R.sub.2 is independently selected from hydrogen, optionally protected hydroxy, halogen, chloroalkyl or fluoroalkyl of 1 to 4 carbon atoms and 1 to 9 chlorine or fluorine atoms , cyano, azido, optionally protected amino, perfluoroalkyl of 1 to 4 carbon atoms, perfluoroalkoxy of 1 to 4 carbon atoms, alkoxyalkyl, vinyl, ethynyl -Q.sub.1, -OQ.sub.1, -SQ.sub.1 or -NHQ.sub.1 wherein Q.sub.1 is alkyl of 1 to 12 carbon atoms, aryl of 1 to 12 carbon atoms, aralkyl of 2 to 15 carbon atoms, alkaryl of 2 to 15 carbon atoms, alkenyl of 3 to 12 carbon atoms, and alkynyl of 3 to 12 carbon atoms; (c) B is an independently selected optionally protected nucleoside base; (d) Z is independently selected from -Q.sub.1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; and (e) Ar is phenyl optionally substituted with 1 to 5 substitutents independently selected from halogen, nitro, cyano and lower alkyl of 1 to 6 carbon atoms.
- 14. A compound of any one of claims 11, 12 or 13 wherein Z is selected from lower alkyl of 1 to 4 carbon atoms, optionally protected aminomethyl or optionaly protected aminoethyl.
- 15. A compound according to claim 14 wherein R.sub.2 is selected from hydrogen, optionally protected hydroxyl, halogen, optionally protected amino, azido, cyano, alkoxyalkyl, vinyl, -Q.sub.1, -OQ.sub.1, -SQ.sub.1, or -NHQ.sub.1, wherein Q.sub.1 is lower alkyl of 1 to 4 carbon atoms or alkenyl of 3 to 4 carbon atoms.
- 16. A compound according to claim 12 wherein X is sulfur.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Ser. No. 08/653,204 filed May 26, 1996 and claims priority from the following Polish patent applications: Polish patent application Serial No. P-310248 filed Aug. 31, 1995 and Polish patent application Serial No. P-312934 filed Feb. 26, 1996.
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Continuation in Parts (1)
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Number |
Date |
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Parent |
653204 |
May 1996 |
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