Conformationally-preorganized, miniPEG-containing gamma-peptide nucleic acids
The present invention relates to γ-PNA monomers according to Formula I where substituent groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , B and P are defined as set forth in the specification. The invention also provides methodology for synthesizing compounds according to Formula I and methodology for synthesizing PNA oligomers that incorporate one or more Formula I monomers.
1. A compound according to Formula VIII
wherein,
P is selected from the group consisting of hydrogen (H), 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 1 and R 2 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 1 and R 2 is selected from the group consisting of
each of R 3 and R 4 is independently selected from the group consisting of hydrogen (H),
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;
R 7 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )aryl, and (C 1 -C 6 )alkylene;
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 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 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
R 1 is —CH 2 —O[(CH 2 ) 2 —O—] X R 8 ; each of R 2 , R 3 and R 4 is hydrogen (H); wherein x is an integer from 1 to 4 inclusive;
R 5 is selected from the group consisting of hydrogen (H) and methyl;
R 7 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl; and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl.
3. The compound of claim 2 , wherein R 5 is hydrogen (H); R 7 is methyl, ethyl or t-butyl; R 8 is methyl, ethyl, or t-butyl and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).
4. The compound of claim 3 having the formula VIIIa-1:
wherein, x is 1, 2 or 3; R 7 is methyl, ethyl or t-butyl, and R 8 is methyl, ethyl or t-butyl.
5. The compound of claim 4 having the formula VIIIa-2 or VIIIa-3:
wherein R 7 is methyl, ethyl or t-butyl.
6. The compound of claim 5 , having an optical purity of at least 99% enantomeric excess (ee).
7. The compound of claim 3 having the formula VIIIa-1T:
wherein, x is 1, 2 or 3; R 7 is methyl or ethyl and R 8 is methyl or ethyl.
8. The compound of claim 7 having the formula VIIIa-2T or VIIIa-3T:
wherein R 7 is methyl or ethyl.
9. The compound of claim 8 , having an optical purity of at least 99% enantomeric excess (ee).
10. The compound of claim 1 , wherein
R 2 is —CH 2 —O[(CH 2 ) 2 —O—] X R 8 ; each of R 1 , R 3 and R 4 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;
R 7 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl; and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl.
11. The compound of claim 10 , wherein R 5 is hydrogen (H); R 7 is methyl, ethyl or t-butyl; R 8 is methyl, ethyl or t-butyl, and P is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc).
12. The compound of claim 11 , having the formula VIIIa-4:
wherein, x is 1, 2 or 3; R 7 is methyl, ethyl or t-butyl, and R 8 is selected from methyl, ethyl or t-butyl.
13. The compound of claim 12 , having the formula VIIIa-5 or VIIIa-6:
wherein R 7 is methyl, ethyl or t-butyl.
14. The compound of claim 13 , having an optical purity of at least 99% enantomeric excess (ee).
15. The compound of claim 11 having the formula VIIIa-4T:
wherein, x is 1, 2 or 3; R 7 is methyl or ethyl and R 8 is selected from methyl or ethyl.
16. The compound of claim 15 having the formula VIIIa-5T or VIIIa-6T:
wherein R 7 is methyl or ethyl.
17. The compound of claim 16 , having an optical purity of at least 99% enantomeric excess (ee).