Phosphinoamidite carboxylates and analogs thereof in the synthesis of oligonucleotides having reduced internucleotide charge

1. A compound having the formula (III)

wherein:

A is hydrogen, hydroxyl, halogen, lower alkoxy, lower alkoxy-substituted lower alkoxy, SH, NH 2 , azide or DL wherein D is O, S or NH and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;

B is a nucleobase; and

one of R 11 and R 12 is a blocking group and the other has the formula (IV)

in which

R 1 is hydrogen, a protecting group removable by an elimination reaction, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;

n is zero or 1;

W is NR 2 R 3 or DL wherein R 2 and R 3 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl, or R 2 and R 3 are linked to form a substituted or unsubstituted, five- or six-membered nitrogen-containing heterocycle, D is O, S or NH, and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;

X is O, S, NH, or NR 7 wherein R 7 is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;

Y is —(Y′) m —(CR 8 R 9 )— wherein m is zero or 1, Y′ is hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene, wherein R 8 and R 9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl and with the proviso that P is directly attached to at least one carbon atom; and

Z is O, S, NH or NR 10 wherein R 10 is as defined for R 7 ;

wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.

2. A compound having the formula (III)

wherein:

A is hydrogen, hydroxyl, or protected hydroxyl;

B is a nucleobase; and

one of R 11 and R 12 is a blocking group and the other has the formula (IV)

in which

R 1 is hydrogen, a protecting group removable by an elimination reaction, or an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl;

W is NR 2 R 3 or DL wherein R 2 and R 3 are unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moieties selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl, or R 2 and R 3 are linked to form a substituted or unsubstituted, five- or six-membered nitrogen-containing heterocycle, D is O, S or NH, and L is a heteroatom-protecting group removable by an elimination reaction;

n is zero or 1;

X is O or S;

Y is —(Y′) m —(CR 8 R 9 )— wherein m is zero or 1, Y′ is an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkylene, arylene, aralkylene, alkarylene, cycloalkylene, cycloalkylalkylene, cycloalkylarylene, alkenylene, cycloalkenylene, alkynylene and aralkynylene, wherein R 8 and R 9 are independently selected from hydrogen and unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moieties selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl, and with the proviso that P is directly attached to at least one carbon atom; and

Z is O or S;

wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.

3. The compound of claim 2 , wherein n is zero.

4. The compound of claim 2 , wherein n is 1.

5. The compound of claim 4 , wherein m is zero.

6. The compound of claim 4 , wherein m is 1.

7. The compound of claim 2 , wherein Z is O.

8. The compound of claim 7 , wherein X is O.

9. The compound of claim 2 , wherein R 1 is a protecting group removable by an elimination reaction.

10. The compound of claim 9 , wherein R 1 is selected from the group comprised of β-cyanoethyl, methyl-β-cyanoethyl, dimethyl-β-cyanoethyl, phenylsulfonylethyl, methyl-sulfonylethyl, p-nitrophenylsulfonylethyl, 2,2,2-trichloro-1,1-dimethylethyl, 2-(4-pyridyl)ethyl, 2-(2-pyridyl)ethyl, allyl, 4-methylene-1-acetylphenol, β-thiobenzoylethyl, 1,1,1,3,3,3-hexafluoro-2-propyl, 2,2,2-trichloroethyl, p-nitrophenylethyl, p-cyanophenylethyl, 9-fluorenylmethyl, 1,3-dithianyl-2-methyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, -methylcinnamyl, and 8-quinolyl.

11. The compound of claim 2 , wherein R 1 is hydrogen.

12. The compound of claim 2 , wherein NR 2 R 3 is selected from the group consisting of dimethylamino, diethylamino, diisopropylamino, dibutylamino, methylpropylamino, methylhexylamino, methylcyclohexylamino, ethylcyclopropylamino, ethylchloroethylamino, methylbenzylamino, methylphenylamino, thiomorpholino, methyltoluylamino, methyl-p-chlorophenylamino, methylcyclohexylamino, bromobutylcyclohexylamino, methyl-p-cyanophenylamino, ethyl-β-cyanoethylamino, piperidino, 2,6,-dimethylpiperidino, pyrrolidino, piperazino, isopropylcyclohexylamino, and morpholino.

13. The compound of claim 12 , wherein R 2 and R 3 are isopropyl.

14. A compound having the formula (III)

wherein:

A is hydrogen, hydroxyl, or protected hydroxyl;

B is a nucleobase; and

one of R 11 and R 12 is a blocking group and the other has the formula (IV)

wherein:

R 1 is hydrogen, lower alkyl, or a hydroxyl-protecting group removable by an elimination reaction;

R 2 and R 3 are lower alkyl, or R 2 and R 3 are linked to form a piperidino, piperazino or morpholino ring;

n is zero or 1; and

Y is —(Y′) m —(CH 2 )— wherein m is zero or 1 and Y′ is lower alkylene.

15. A compound having the formula (III)

wherein:

A is hydrogen, hydroxyl, halogen, lower alkoxy, lower alkoxy-substituted lower alkoxy, SH, NH 2 , azide or DL wherein D is O, S, or N, and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;

B is a nucleobase; and

one of R 11 and R 12 is a blocking group and the other has the formula (VI)

in which

R 1 is hydrogen, a protecting group removable by an elimination reaction, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;

n is zero or 1;

X is O, S, NH, or NR 7 wherein R 7 is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;

Y is —(Y′) m —(CR 8 R 9 )— wherein m is zero or 1, Y′ is hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene, wherein R 8 and R 9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl, and with the priviso that P is attached to at least one carbon atom; and

each Z is independently O, S, NH or NR 10 wherein R 10 is as defined for R 7 ;

wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.

16. A compound having the formula (III)

wherein:

A is hydrogen, hydroxyl, or protected hydroxyl;

B is a nucleobase; and

one of R 11 and R 12 is a blocking group and the other has the formula (VI)

in which

R 1 is hydrogen, a protecting group removable by an elimination reaction, or an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl;

n is zero or 1;

X is O or S;

Y is —(Y′) m —(CR 8 R 9 )— wherein m is zero or 1, Y′ is an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkylene, arylene, aralkylene, alkarylene, cycloalkylene, cycloalkylalkylene, cycloalkylarylene, alkenylene, cycloalkenylene, alkynylene and aralkynylene, wherein R 8 and R 9 are independently selected from hydrogen and unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moieties selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl, and with the proviso that P is directly attached to at least one carbon atom; and

each Z is independently O or S;

wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.

17. The compound of claim 16 , wherein n is zero.

18. The compound of claim 16 , wherein n is 1.

19. The compound of claim 16 , wherein m is zero.

20. The compound of claim 16 , wherein m is 1.

21. The compound of claim 20 , wherein R 1 is a protecting group removable by an elimination reaction.

22. The compound of claim 21 , wherein R 1 is selected from the group comprised of β-cyanoethyl, methyl-β-cyanoethyl, dimethyl-β-cyanoethyl, phenylsulfonylethyl, methylsulfonylethyl, p-nitrophenylsulfonylethyl, 2,2,2-trichloro-1,1-dimethylethyl, 2-(4-pyridyl)ethyl, 2-(2-pyridyl)ethyl, allyl, 4-methylene-1-acetylphenol, β-thiobenzoylethyl, 1,1,1,3,3,3-hexafluoro-2-propyl, 2,2,2-trichloroethyl, p-nitrophenylethyl, p-cyanophenylethyl, 9-fluorenylmethyl, 1,3-dithionyl-2-methyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, -methylcinnamyl, and 8-quinolyl.

23. The compound of claim 20 , wherein R 1 is hydrogen.

24. A compound having the formula (III)

wherein:

A is hydrogen, hydroxyl, or protected hydroxyl;

B is a nucleobase; and

one of R 11 and R 12 is a blocking group and the other has the formula (VII)

wherein:

R 1 is hydrogen, lower alkyl, or a hydroxyl-protecting group;

n is zero or 1; and

Y is —(Y′) m —(CH 2 )— wherein m is zero or 1 and Y′ is lower alkylene.

25. The compound of claim 24 , wherein R 11 is a blocking group and R 12 has the formula (VII)

26. The compound of claim 25 , wherein R 12 is a blocking group and R 11 has the formula (VII)