Conformationally-preorganized, miniPEG-containing gamma-peptide nucleic acids

1. A compound according to Formula IIIa

wherein,

Z is selected from the group consisting of hydroxyl (OH), iodine (I), 4-toluenesulfonate and methanesulfonate;

R 5 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;

P is selected from the group consisting of: 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), benzhydryloxycarbonyl (Bhoc), O-nitroveratryloxycarbonyl (Nvoc), 1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);

each of R 11 and R 12 is independently selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene,

provided that at least one of R 11 and R 12 is selected from the group consisting of

P 2 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);

P 3 selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;

x is an integer from 1 to 10, inclusive; and

y is an integer from 1 to 9, inclusive.

2. The compound of claim 1 , wherein

Z is selected from the group consisting of iodine and hydroxyl;

R 11 is —CH 2 —[O(CH 2 ) 2 ] x —OR 8 and R 12 is H, wherein x is an integer from 1 to 4 inclusive;

R 5 is selected from the group consisting of hydrogen (H) and methyl; and

R 8 is selected from the group consisting of hydrogen, methyl, ethyl, and t-butyl.

3. The compound of claim 2 , wherein Z is hydroxyl, R 5 is hydrogen, R 12 is hydrogen and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).

4. The compound of claim 3 having the formula IIIa-1:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

5. The compound of claim 4 having the formula IIIa-2 or IIIa-3:

6. The compound of claim 5 , having an optical purity of at least 99% enantiomeric excess (ee).

7. The compound of claim 1 , wherein

Z is selected from the group consisting of iodine and hydroxyl;

R 11 is H and R 12 is —CH 2 —[O(CH 2 ) 2 ] x —OR 8 , wherein x is an integer from 1 to 4 inclusive;

R 5 is selected from the group consisting of hydrogen (H) and methyl; and

R 8 is selected from the group consisting of hydrogen, methyl, ethyl, and t-butyl.

8. The compound of claim 7 , wherein Z is hydroxyl, R 5 is hydrogen, R 11 is hydrogen and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).

9. The compound of claim 8 , having the formula IIIa-4:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

10. The compound of claim 9 , having the formula IIIa-5 or IIIa-6:

11. The compound of claim 10 , having an optical purity of at least 99% enantiomeric excess (ee).

12. The compound of claim 1 , wherein Z is hydroxyl (—OH).

13. The compound of claim 1 , wherein Z is iodine (I), 4-toluenesulfonate or methanesulfonate.

14. A method comprising: a) contacting a compound of formula X:

wherein, P is selected from the group consisting of: 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT); R 5 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;

one of R 1 and R 2 is —CH 2 —OH and the other of R 1 and R 2 is H with a compound of formula: P 3 —(O—CH 2 —CH 2 —) x OX, wherein X is CH 3 S(O) 2 —, P 3 is methyl, ethyl, or t-butyl; and x is a number from 1 to 10, inclusive, to thereby obtain a compound of formula XI:

wherein one of R 11 and R 12 is —CH 2 —O—(CH 2 —CH 2 —O)x-P 3 and the other of R 11 and R 12 is H; and

b) reducing the carboxylic acid of formula XI to an alcohol to thereby produce a compound of formula

15. The method of claim 14 , further comprising:

c) contacting said compound of formula with a reagent selected from the group consisting of: methanesulfonyl chloride, 4-toluenesulfonyl chloride and sodium iodide.

16. The method of claim 14 , wherein the compound of formula IIIa-7 has the formula IIIa-1:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

17. The method of claim 16 , wherein the compound of formula IIIa-1 has the formula IIIa-2 or IIIa-3:

18. The method of claim 14 , wherein the compound of formula IIIa-7 has the formula IIIa-4:

wherein, P 3 is selected from methyl, ethyl and t-butyl.

19. The method of claim 18 , wherein the compound of formula IIIa-4 has the formula IIIa-5 or IIIa-6: