Reagent and process for protecting active groups
AssigneesIsis Pharmaceuticals, Inc., The Regents of the University of California
InventorsYogesh S. Sanghvi, Emmanuel A. Theodorakis, Ke Wen
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Abstract
Silylating reagents having a group other than a divalent oxygen separating two silyl groups provide regioselective protection of reactive groups under robust conditions, such as basic conditions used in alkylation, acylation and deoxygenation. In particular, silylating reagents having a group other than oxygen separating two silyl groups are useful for protecting two hydroxy groups of a ribonucleic or deoxyribonucleic acid. Alkylation of a 2′-hydroxy group of a ribonucleoside protected with the inventive silylating agents in the presence of an excess of a mild hindered base such as sodium HMDS may be carried out without protecting the exocyclic amine and oxo functionalities of nucleobases.
Claims178
A process of protecting the 5′- and 3′-positions of a precursor, said precursor being a nucleic acid having the formula:
- 68
- wherein Bx is a nucleobase,
- said process comprising contacting said compound with a silylating reagent of the formula:
- 69
- wherein R1, R2, R3 and R4 are independently alkyl, each of L1 and L2 is independently a leaving group, and A is a moiety other than O,
- for a time and under conditions suitable to protect the 5′- and 3′-positions of the nucleic acid, whereby a protected intermediate is formed, said protected intermediate having the formula:
- 70
A process of protecting the 5′- and 3′-positions of a precursor, said precursor being a nucleic acid having the formula:
- 76
- wherein Bx is a nucleobase,
- said process comprising contacting said compound with a silylating reagent of the formula:
- 77
- wherein each of R1 and R2 is independently an alkyl group, each of L1 and L2 is independently a leaving group, and A is phenylene or naphthylene,
- for a time and under conditions suitable to protect the 5′- and 3′-positions of the nucleic acid, whereby a protected intermediate is formed, said protected intermediate having the formula:
- 78
A compound having the formula:
- 79
- wherein R1, R2, R3 and R4 are independently alkyl, A is a moiety other than O, and Bx is a nucleobase.
A compound having the formula:
- 80
- wherein R1, R2, R3 and R4 are independently alkyl, A is a moiety other than O, Bx is a nucleobase and Z is alkyl, substituted alkyl, acyl or substituted acyl.
A compound having the formula:
- 81
- wherein R1, R2, R3 and R4 are independently alkyl, A is a moiety other than O, Bx is a nucleobase and Z is alky, substituted alkyl, acyl or substituted acyl.
A compound having the formula:
- 82
- wherein R1 and R2 are independently alkyl, A is a moiety other than O and Bx is a nucleobase.
A compound having the formula:
- 83
- wherein R1 and R2 are independently alkyl, A is a moiety other than O and Bx is a nucleobase.
A compound having the formula:
- 84
- wherein R1 and R2 are independently alkyl, A is a moiety other than O, Bx is a nucleobase and Z is alkyl, substituted alkyl, acyl or substituted acyl.
A compound having the following formula:
- 85
- wherein A is a moiety other than O, R1, R2, R3 and R4 are each independently alkyl or substituted alkyl, Bx is a nucleobase and X2 is selected from the group consisting of O, S, NH, NR5, CH2, CHR6 or CR7R8, wherein R5 is alkyl, R6 is alkyl, and R7 and R8 are alkyl or are taken together to form a carbocyclic ring.
A compound having the formula:
- 88
- wherein A is a moiety other than O, R1 and R2 are each independently alkyl or substituted alkyl, and Bx is a nucleobase.
A compound having the following formula:
- 89
- wherein A is a moiety other than O, R1, R2, R3 and R4 are each independently alkyl or substituted alkyl and Bx is a nucleobase.
A compound having the formula:
- 92
- wherein A is a moiety other than O, R1 and R2 are each independently alkyl or substituted alkyl and Bx is a nucleobase.
A compound having the formula:
- 93
- wherein A is a moiety other than O, R1, R2, R3 and R4 are each independently alkyl or substituted alkyl and Bx is a nucleobase.
A compound having the formula:
- 96
- wherein A is a moiety other than O, R1 and R2 are each independently alkyl or substituted alkyl and Bx is a nucleobase.
A compound having the formula:
- 97
- wherein A is a moiety other than O, R1 and R2 are each independently alkyl or substituted alkyl, Bx is a nucleobase, and Y is H, —OH, —O-alkyl, substituted —O-alkyl, —O-acyl or substituted —O-acyl.
A compound having the formula:
- 98
- wherein A is a moiety other than O, R1 and R2 are each independently alkyl or substituted alkyl, Bx is a nucleobase and Y is H, —OH, —O-alkyl, substituted —O-alkyl, —O-acyl or substituted —O-acyl.
A compound having the formula:
- 99
- wherein W is H, OH, OAk, or OAkOAk, wherein each Ak is alkyl.
A compound having the formula:
- 100
- wherein W is H, OH, OAk, or OAkOAk, wherein each Ak is alkyl.
A compound having the formula:
- 101
- wherein each of R1, R2, R3 and R4 is independently an alkyl group, each of L1 and L2 is independently halo, excluding compounds in which each of R1, R2, R3 and R4 is methyl when L1 and L2 are both chloro, both L1 and L2 are bromo, or both L1 and L2 are fluoro.
A process of making a compound having the formula:
- 102
- wherein each of R1, R2, R3 and R4 is independently an alkyl group and each of L1 and L2 is independently halo, said process comprising:
- providing a compound having the formula:
- 103
- and reacting said compound with a source of leaving group moiety in the presence of PdCl2 catalyst.
A process of alkylating a protected precursor having the formula:
- 104
- wherein each of R1, R2, R3 and R4 is alkyl or substituted alkyl, A is a moiety joining the two Si atoms, and Bx is a nucleobase,
- the process comprising reacting the precursor with a compound having the formula:
- Z-L3, wherein L3 is a leaving group and Z is alkyl, substituted alkyl, acyl or substituted acyl, in the presence of a mild hindered base to form a compound having the formula:
- 105
A process of introducing a 2′O—CH3 moiety on a nucleoside, the process comprising the steps of reacting 3′,5′-diprotected nucleoside with an electrophile under conditions sufficient to introduce the CH3 group on the 2′-O, wherein said electrophile is methyl chloride.
Dependencies are inferred from the claim text.