Compositions and methods for the synthesis of chirally pure organophosphorus nucleoside derivatives
First Claim
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1. A method for the synthesis of chirally pure nucleoside dimers of chosen sense of P-chirality of the formula:
- ##STR2## wherein (a) R2 is a protecting group;
(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; and
(e) RX 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 R3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesitylate, triisopropyl benzenesulfonyl or benzenesulfonyl and R3 is -Q1 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 CX2 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 R3 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.
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Abstract
Methods for the stereospecific synthesis of chirally pure organophosphorus dinucleotide derivatives and nucleoside monomer synthons used in their synthesis are provided. These methods allow for conversion of nucleoside intermediates of unchosen sense of P-chirality to nucleoside monomer synthons of chosen sense of P-chirality. Also provided are novel nucleoside intermediates useful in such methods.
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16 Claims
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1. A method for the synthesis of chirally pure nucleoside dimers of chosen sense of P-chirality of the formula:
- ##STR2## wherein (a) R2 is a protecting group;
(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; and (e) RX 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 R3 W wherein W is chloro, bromo, iodo, alkanesulfonyl, perfluoroalkanesulfonyl, triflate, tosylate, mesitylate, triisopropyl benzenesulfonyl or benzenesulfonyl and R3 is -Q1 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 CX2 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 R3 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. - View Dependent Claims (2, 10)
- ##STR2## wherein (a) R2 is a protecting group;
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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) R1 is a protecting group;
(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; (e) R3 is -Q1 ; 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 R3 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 CX2 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 R3 W to give a chirally pure diastereomer of the chosen sense of P-chirality of formula (III ). - View Dependent Claims (4)
- ##STR7## wherein (a) R1 is a protecting group;
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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) R1 is a protecting group;
(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; (e) R3 is -Q1 ; 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 R3 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##
- ##STR11## wherein (a) R1 is a protecting group;
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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) R1 is a protecting group;
(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; (e) R3 is -Q1 ; 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 CX2 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 R3 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). - View Dependent Claims (7)
- ##STR14## wherein (a) R1 is a protecting group;
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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) R1 is a protecting group;
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(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl; and (e) R3 is -Q1 ; 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 CX2 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 R3 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). - View Dependent Claims (9)
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11. A compound of the formula II ##STR20## wherein (a) R1 is a protecting group, (b) each R2 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, -OQ1, -SQ1 or NHQ1 wherein Q1 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 -Q1, 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 R2 is hydrogen, optionally protected hydroxyl or methoxy, then Ar is not unsubstituted phenyl. - View Dependent Claims (14, 15)
- (c) B is an independently selected optionally protected nucleoside base;
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12. A compound of the formula III ##STR21## wherein (a) R1 is a protecting group, (b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, vinyl, ethynyl, optionally protected aminomethyl and optionally protected aminoethyl;
(e) R3 is -Q1 ; and
(f) X is selenium or sulfur, with the proviso that when R2 is hydrogen, optionally protected hydroxyl or methoxy then R3 is not methyl, benzyl or nitrobenzyl. - View Dependent Claims (16)
- (c) B is an independently selected optionally protected nucleoside base;
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13. A compound of the formula IV:
- ##STR22## wherein (a) R1 is a protecting group;
(b) each R2 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 -Q1, -OQ1, -SQ1 or -NHQ1 wherein Q1 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 -Q1, 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.
- ##STR22## wherein (a) R1 is a protecting group;
Specification