Guanidine-Based γ-Peptide Nucleic Acids
for another 20 min. The solvent was evaporated. The crude product
was purified by column chromatography and dried to afford a light
yellow colored liquid (1.7 g, 3.1 mmol); yield 76%. 1H NMR
(CDCl3) δ 8.28 (br s, NH), 7.38-7.25 (m, 10 H), 5.15 (s, 2H),
5.10 (s, 2H), 4.15 (q, J ) 7.2 Hz, 2H), 3.70-3.50 (m, 1H),
3.50-3.25 (m, 4H), 2.60 (2ABq, J1 ) 12.2 Hz, J2 ) 10.4 Hz, 2H),
1.56-1.4 (m, 7H), 1.41 (s, 9H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR
(CDCl3) δ 14.2, 23.2, 28.4, 28.8, 32.8, 40.8, 50.3, 50.9, 52.9, 60.7,
67.1, 68.0, 79.0, 127.8, 128.1, 128.3, 128.4, 128.6, 128.7, 134.6,
136.8, 153.8, 155.8, 156.0, 163.7, 172.4; LRMS: 628.13; HRMS:
(ESI-MS m/z) Mcalc for C32H46N5O8 628.3347, found 628.3323.
Boc-Lys(Guanidine-Di-Cbz)-PNA-Thyamine Monomer Ethyl
Ester (7a). To a stirred solution of thymine acetic acid (0.48 g,
2.64 mmol) in dry DMF (15 mL) was added DCC (0.54 g, 2.64
mmol) and DhbtOH (0.42 g, 2.64 mmol). The resulting mixture
was stirred at room temperature for another 1 h. Compound 6
(1.2 g, 2.2 mmol) dissolved in dry DMF (10 mL) was added to
the reaction mixture and stirred at 40 °C for another 24 h. The
solvent was removed under reduced pressure and the residue
was diluted with ethyl acetate (100 mL). The ethyl acetate layer
was washed with saturated solution of NaHCO3 (100 mL),
followed by 10% KHSO4 (100 mL). The organic layer was
washed with brine (50 mL) and dried over anhydrous Na2SO4,
and the solvent was removed in Vacuo. The crude product was
further purified by column chromatography and dried to afford
J1 ) 9.2 Hz, J2 ) 8.0 Hz, 1H], 5.18 (s, 2H), 5.17 (s, 2H),
4.94-4.49 [2ABq (Rot1, 2), J1 ) J2 ) 16.3 Hz, 2H], 4.40-2.84
(m, 9H), 1.77-1.41 (m, 4H), 1.33 [d (Rot 1,2), J ) 3.8 Hz, 9H],
1.21 (t, J ) 7.1 Hz, 2H), 1.14 (t, J ) 7.1 Hz, 3H); 13C NMR
(DMSO d6) δ 14.4, 23.2, 23.4, 28.6, 31.5, 48.6, 49.3, 49.8, 52.2,
60.9, 61.6, 66.8, 66.9, 68.0, 78.4, 94.3, 128.3, 128.5, 128.7,
128.9, 129.0, 131.8, 132.0, 135.6, 136.4, 137.4, 150.9, 153.7,
155.3, 155.5, 156.0, 163.5, 167.8, 168.2, 169.2, 169.6; LRMS:
935.39; HRMS: (ESI-MS m/z) Mcalc for C46H56N8O12Na 935.3915,
found 935.3884.
Boc-Lys (Guanidine-Di-Cbz)-PNA-Thyamine Monomer Acid
(8a). To a stirred solution of 7a (0.5 g, 6.3 mmol) in THF (10
mL), 2N NaOH (10 mL) was added dropwise at 0 °C over a
period of 15 min. The resulting mixture was stirred at same
temperature for another 0.5 h. At the end of the reaction, as
monitored by TLC, H2O (20 mL) was added. The reaction
mixture was extracted with ethyl acetate (2 × 25 mL). The
combined aqueous layers were acidified with 5% HCl (to pH 4)
at 0 °C and then extracted with ethyl acetate (4 × 25 mL). The
combined organic layers were dried over Na2SO4 (anhd.) and
the solvent was evaporated in Vacuo. The crude product was
purified by column chromatography and dried to afford a
colorless solid (0.35 g, 4.5 mmol); yield 72%. 1H NMR (DMSO
d6) δ 8.42-8.39 (m, 1H), 7.43-7.23 (m, 10 H), 7.18 (br s, 1H),
6.80-6.60 [2d (Rot1,2), J1 ) 8.2 Hz, J2 ) 7.4 Hz, 1H], 5.18 (s,
2H), 5.00 (s, 2H), 4.71-4.31 [ABq (Rot1, J ) 17.2 Hz), m (Rot
2), 2H], 3.94-2.60 (m, 7H), 1.7 (s, 3H), 1.55-1.36 (m, 3H),
1.32 (s, 9H), 1.29-1.10 (m, 3H); 13C NMR (DMSO d6) δ 12.4,
23.4, 28.7, 31.9, 48.1, 48.9, 49.2, 51.7, 52.2, 66.8, 68.0, 77.9,
78.2, 108.4, 128.2, 128.4, 128.7, 129.0, 135.6, 137.3, 142.6,
151.5, 153.1, 155.4, 156.0, 163.4, 164.8, 168.3; LRMS 766.27;
HRMS: (ESI-MS m/z) Mcalc for C37H48N7O11 766.3412, found
766.3429.
1
a white solid (1.5 g, 1.88 mmol); yield 82%. H NMR (DMSO
d6) δ 8.38 (br s, 1H), 7.44-7.23 (m, 10H), 7.21 (br s, 1H),
6.81-6.56 [2d (Rotamer1, 2),* J1 ) J2 ) 9.2 Hz, 1H], 5.19 (s,
2H), 5.01 (s, 2H), 4.80-4.40 [ABq (Rot1, J ) 16.2 Hz), m (Rot2),
2H], 4.39-2.88 (m, 9H), 1.73 (s, 3H), 1.58-1.39 (m, 4H), 1.33
[d (Rot1, 2), J ) 3.5 Hz, 9H], 1.15 (t, J ) 7.1 Hz, 3H); 13C NMR
(DMSO d6) δ 23. 2, 28.4, 28.8, 31.0, 40.7, 52.6, 65.7, 67.2,
68.2, 79.6, 127.9, 128.2, 128.4, 128.7, 128.8, 134.6, 136.7, 153.9,
156.0, 156.4, 163.7; LRMS: 794.04; HRMS: (ESI-MS m/z) Mcalc
for C39H52N7O11 794.3725, found 794.3682.
PNA monomer Adenine (Cbz) acid (8b), Guanine ester(Cbz)
acid (8c) and Cytosine (Cbz) acid (8d) were prepared and
isolated following the same procedure as outlined in the
preparation of (8a) above.
*Because of the carbonyl group in the bridge, two rotamers
were formed for the monomers and the ester precursorsseach
with different chemical shift. Adenine ester (7b), Guanine ester
(7c), Cytosine ester (7d) were prepared and isolated following
the same procedure as outlined in the preparation of (7a).
Boc-Lys(Guanidine-Di-Cbz)-PNA-Adenine (Cbz) Monomer Eth-
yl Ester (7b); Yield 85%. 1H NMR (DMSO d6) δ 8.60-8.56 [ 2d
(Rot1, 2), J1 ) 2.1 Hz, J2 ) 1.6 Hz, 1H], 8.47-8.32 (m, 1H),
8.31-8.19 [2d (Rot1,2), J1 ) 1.1, J2 ) 2.5 Hz, 1H], 7.65-7.25
(m, 15H), 6.95-6.56 [2d (Rot1,2), J1 ) J2 ) 9.1 Hz, 1H],
5.42-4.90 (m, 8H), 4.60-3.70 (m, 6H), 3.56-3.37 (m, 2H),
3.07-2.91 (m, 1H), 1.59-1.41 (m, 4H), 1.35 [d (Rot1, 2), J )
Boc-Lys (Guanidine-Di-Cbz)-PNA-Adenine (Cbz) Monomer
1
Acid (8b); Yield 75%. H NMR (DMSO d6) δ 8.55 [d (Rot1, 2),
J ) 5.2 Hz, 1H], 8.42-8.37 (m, 1H), 8.23 [d (Rot1,2) J ) 11.8
Hz, 1H], 7.47-7.21 (m, 15 H), 6.96-6.61 [2d (Rot1, 2) J1 ) 9.5
Hz, J2 ) 7.9 Hz, 1H], 5.30-4.90 (m, 9H), 4.04-2.68 (m, 7H),
1.55-1.37 (m, 3H), 1.28 (s, 9H), 1.26-1.16 (m, 3H); 13C NMR
(DMSO d6) δ 23.4, 28.7, 31.9, 44.5, 49.3, 51.9, 63.3, 66.7, 66.8,
68.0, 77.9, 123.3, 126.8, 127.0, 128.3, 128.4, 128.7, 128.8, 129.0,
135.6, 136.8, 137.4, 145.7, 149.7, 151.7, 152.6, 153.1, 155.4,
155.9, 163.4, 166.5, 167.6; LRMS: 909.00; HRMS: (ESI-MS
m/z) Mcalc for C45H53N10O11 909.3895, found 909.3897.
2.8 Hz, 9H], 1.29-1.22 (m, 2H), 1.37 [2t (Rot 2), J1 ) J2 )
1,
7.04, 3H]; 13C NMR (DMSO d6) δ 14.4, 23.4, 28.6, 29.7, 31.5,
32.1, 44.3, 48.5, 49.2, 52.3, 60.8, 61.7, 65.6, 66.7, 66.8, 68.0,
78.4, 123.4, 128.2, 128.4, 128.7, 128.8, 129.0, 131.9, 132.0,
135.6, 136.8, 137.3, 145.4, 149.8; LRMS: 937.13; HRMS: (ESI-
MS m/z) Mcalc for C47H57N10O11 937.4208, found 937.4132.
Boc-Lys (Guanidine-Di-Cbz)-PNA-Guanine (Cbz) Monomer
Boc-Lys (Guanidine-Di-Cbz)-PNA-Guanine (Cbz) Monomer
1
Acid (8c); Yield 68%. H NMR (DMSO d6) δ 8.42-8.39 (m,
1H), 7.72 [d (Rot1,2) J ) 5.2 Hz, 1H], 7.43-7.26 (m, 15H),
6.91-6.61 [2d (Rot1,2), J1 ) 9.8 Hz, J2 ) 8.0 Hz, 1H], 5.22 (s,
2H), 5.15-4.78 (m, 4H), 4.19-2.85 (m, 7H), 1.58-1.37 (m,
3H), 1.31 [d (Rot1, 2), J ) 6.1 Hz, 9H], 1.25-1.12 (m, 3H); 13C
NMR (DMSO d6) δ 23.3, 23.4, 28.6, 28.7, 31.7, 44.2, 49.1, 66.8,
67.5, 67.6, 68.0, 78.0, 78.5, 119.5, 119.6, 128.2, 128.3, 128.6,
128.7, 128.8, 135.6, 135.9, 136.0, 137.3, 147.6, 147.7, 150.0,
153.2, 154.9, 155.0, 155.5, 155.6, 156.1, 163.4, 166.9, 167.6;
LRMS: 925.13; HRMS: (ESI-MS m/z) Mcalc for C45H53N10O12
925.3845, found 925.3860.
1
Ethyl Ester (7c); Yield 80%. H NMR (DMSO d6) δ 8.42-8.31
(m, 1H), 7.69 [d (Rot1, 2), J ) 6.5 Hz, 1H], 7.60-7.09 (m, 15 H),
6.89-6.58 [2d (Rot 1,2), J1 ) 9.5 Hz, J2 ) 8.3 Hz, 1H], 5.34-4.78
(m, 8H), 4.44-2.87 (m, 9H), 1.89-1.47 (m, 4H), 1.31 [d (Rot1, 2),
J ) 9.8 Hz, 9H], 1.22 (t, J ) 7.0 Hz, 2H), 1.13 (t, J ) 7.0 Hz,
3H); 13C NMR (DMSO d6) δ 14.4, 23.4, 24.9, 28.6, 28.7, 31.7,
33.8, 44.1, 48.0, 48.5, 49.3, 52.2, 60.9, 61.7, 66.8, 67.6, 68.0, 78.6,
119.5, 128.5, 128.8, 128.9, 129.0, 135.6, 136.0, 137.3, 140.5, 148.1,
150.1, 153.2, 155.5, 155.7, 156.1, 163.5, 167.2, 167.7, 169.3, 169.8;
LRMS: 975.27; HRMS: (ESI-MS m/z) Mcalc for C47H56N10O12Na
975.3977, found 975.3817.
Boc-Lys (Guanidine-Di-Cbz)-PNA-Cytosine (Cbz) Monomer
Acid (8d); Yield 70%. 1H NMR (DMSO d6) 8.38 (br s, 1H), 7.80
(d, J ) 7.5 Hz, 1H), 7.47-7.21 (m, 15 H), 6.97 (d, J ) 7.3 Hz,
1H), 6.85-6.60 [2d (Rot1,2), J1 ) 11.1 Hz, J2 ) 6.4 Hz, 1H],
5.17 (br s, 4H), 5.00 (s, 2H), 4.88-4.89 [ ABq (Rot1, J ) 16.3
Hz), m (Rot2), 2H], 3.98-2.68 (m, 7H), 1.56-1.36 (m, 3H),
1.32 (s, 9H), 1.29-1.10 (m, 3H); 13C NMR (DMSO d6) 23.4,
28.7, 31.9, 41.0, 49.0, 49.4, 50.1, 51.7, 52.3, 66.8, 66.9, 68.0,
77.9, 78.3, 94.4, 128.2, 128.3, 128.4, 128.6, 128.7, 128.9, 129.0,
Boc-Lys (Guanidine-Di-Cbz)-PNA-Cytosine (Cbz) Monomer
Ethyl Ester (7d); Yield 80%. 1H NMR (DMSO d6) δ 8.45-8.38
(m, 1H), 7.87-7.74 [2d (Rot 1,2), J1 ) J2 ) 7.5 Hz, 1H],
7.65-7.48 (m, 1H), 7.43-7.19 (m, 15 H), 7.06-6.91 [2d (Rot1,2),
J. Org. Chem. Vol. 74, No. 4, 2009 1515