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Compositions and methods for the synthesis of chirally pure organophosphorus nucleoside derivatives

  • US 5,856,465 A
  • Filed: 08/29/1996
  • Issued: 01/05/1999
  • Est. Priority Date: 05/24/1996
  • Status: Expired due to Fees
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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