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

1. An oligonucleotide containing at least one internucleotide linkage having the structure of formula (VIII)

wherein:

R 1 is hydrogen, a protecting group removable by an elimination reaction, 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;

n is zero or 1;

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

Z is O, S, NH or NR 10 wherein R 10 is as defined for R 7 , wherein in any substituted hydrocarbyl, substituted heteroatom-containing hydrocarbyl, substituted hydrocarbylene, and substituted heteroatom-containing hydrocarbylene at least one hydrogen atom bound to a carbon atom is replaced by at least one of the following: hydroxyl, alkoxy, thio, thioester, halo, amino, nitrile, nitro, sulfonyl, phosphoro, carboxyl and thienyl.

2. An oligonucleotide containing at least one internucleotide linkage having the structure of formula (VIII)

wherein:

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;

X is O or S;

n is zero or 1;

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

Z is O or S, wherein in any substituted heteroatom-containing moiety, at least one hydrogen atom bound to a carbon atom is replaced by at least one of the following: hydroxyl, alkoxy, thio, thioester, halo, amino, nitrile, nitro, sulfonyl, phosphoro, carboxyl, carbonyl and thienyl.

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

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

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

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

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

8. The oligonucleotide of claim 7 , 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-cyanophenyl-ethyl, 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, α-methylcinnamyl, and 8-quinolyl.

9. The oligonucleotide of claim 2 , wherein R 1 is hydrogen.

10. An oligonucleotide containing at least one internucleotide linkage having the structure of formula (IX)

wherein:

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

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

11. An oligonucleotide containing at least one internucleotide linkage having the structure of formula (X)

wherein:

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;

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

n is zero or 1;

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

Z is O, S, NH or NR 10 wherein R 10 is as defined for R 7 , and wherein the internucleotide linkage forms a link between a first nucleotide and a second nucleotide wherein at least one of the first nucleotide and the second nucleotide comprises a nitrogenous base that is A, C, G, or U and, wherein in any substituted or substituted heteroatom-containing moiety, at least one hydrogen atom is replaced by at least one of the following: hydroxyl, alkoxy, thio, thioester, halo, amino, nitrile, nitro, sulfonyl, phosphoro, carboxyl, carbonyl and thienyl.

12. An oligonucleotide containing at least one internucleotide linkage having the structure of formula (X)

wherein:

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;

X is O or S;

n is zero or 1; 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

Z is O or S, and wherein the internucleotide linkage forms a link between a first nucleotide and a second nucleotide wherein at least one of the first nucleotide and the second nucleotide comprises a nitrogenous base that is A, C, G, U and, wherein in any substituted or substituted heteroatom-containing moiety, at least one hydrogen atom bound to a carbon atom is replaced by at least one of the following moieties: hydroxyl, alkoxy, thio, thioester, halo, amino, nitrile, nitro, sulfonyl, phosphoro, carboxyl, carbonyl and thienyl.

13. The oligonucleotide of claim 12 , wherein n is zero.

14. The oligonucleotide of claim 12 , wherein n is 1.

15. The oligonucleotide of claim 14 , wherein m is zero.

16. The oligonucleotide of claim 12 , wherein m is 1.

17. The oligonucleotide of claim 12 , wherein R 1 is a protecting group removable by an elimination reaction.

18. The oligonucleotide of claim 17 , 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-cyanophenyl-ethyl, 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, β-methylcinnamyl, and 8-quinolyl.

19. The oligonucleotide of claim 12 , wherein R 1 is hydrogen.

20. An oligonucleotide containing at least one internucleotide linkage having the structure of formula (XI)

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

n is zero or 1; and

Y is —(Y′) m —(CH 2 )— wherein m is zero or 1 and Y′ is lower alkylene, and wherein the internucleotide linkage forms a link between a first nucleotide and a second nucleotide wherein at least one of the first nucleotide and a second nucleotide wherein at least one of the first nucleotide and the second nucleotide comprises a nitrogenous base that is A, C, G, or U.