acetate), mp 130–133 ЊC (Found: C, 71.0; H, 4.8; N, 12.2.
C47H39N7O6 requires C, 70.8; H, 4.9; N, 12.3%); δH (200
MHz; CDCl3) 2.58 and 2.83 [2 H, 2 × m, CH2(3Ј)], 3.78–4.40
[m, unresolved CH2(5Ј), Gly CH2, Fmoc aliphatic CH and
CH2], 4.78 [1 H, m, CH(2Ј)], 5.05 and 5.28 [1 H, 2 × m, CH(4Ј)
rotamers], 6.13 (1 H, br t, Gly NH), 6.76 (1 H, 2 × s, CHPh2
rotamers), 7.20–7.75 (m, benzoyl m- and p-H, phenyl and Fmoc
aromatic CH), 7.96–8.00 (2 H, d, J 7.1, benzoyl o-H), 8.23 [1 H,
s, CH(8)], 8.70 [1 H, s, CH(2)] and 9.48 (1 H, br s, benzamide
NH); δC(50.28 MHz; CDCl3) 33.5 [CH2(3Ј)], 43.3 (Gly CH2),
47.0 (Fmoc aliphatic CH), 49.4 [CH2(5Ј)], 53.2 [CH(4Ј)], 57.8
[CH(2Ј)], 67.1 (Fmoc CH2), 78.6 (CHPh2), 120.1 (Fmoc aro-
matic CH), 123.5 [C(5)], 125.2–128.9 and 133.0 (aromatic CH),
133.8, 139.4 and 141.4 (aromatic C), 142.0 [CH(8)], 144.1
(aromatic C), 150.0 [C(4)], 152.1 [C(6)], 152.7 [CH(2)], 156.9
(Fmoc CO), 165.4 (benzoyl CO), 168.6 (Gly CO) and 170.4
(ester CO); m/z (ES-MS) 798 (M + H+, 100%); νmax(KBr)/cmϪ1
1718 (C᎐O) and 1668 (C᎐O); [α]22 +18.6 (c 0.21, CHCl3).
1 h. The volatiles were evaporated under reduced pressure, the
residue was triturated with diethyl ether and then washed with
methanol–diethyl ether.
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-cis-4-(thymin-1-
yl)--proline 9a was obtained as a solid (50%, starting from 2.5
mmol of substrate 8a). Recrystallisation from ethanol–water
gave a solid, mp >200 ЊC (Found: C, 62.5; H, 5.1; N, 10.6.
C27H26N4O7 requires C, 62.5; H, 5.1; N, 10.8%); δH [200 MHz;
(CD3)2SO] 1.75 (3 H, br s, thymine CH3), 2.00–2.35 [2 H, br m,
CH2(3Ј) rotamers], 3.30–4.00 [br m, CH2(5Ј) and Gly CH2
obscured by the water signal], 4.15–4.30 (3 H, br m, Fmoc ali-
phatic CH and CH2), 4.50–4.65 [1 H, br m, CH(2Ј) rotamers],
4.80–4.85 and 4.95–5.05 [1 H, br m, CH(4Ј) rotamers], 7.25–
7.45 (4 H, m, Fmoc aromatic CH), 7.52 [1 H, br s, CH(6)
rotamers], 7.70 and 7.85 (4 H, 2 × d, J 7.1, Fmoc aromatic CH);
m/z (FAB) 541 (M + Na+, 9%), 179 {[(C H ) C᎐CH + H]+,
᎐
6
4
2
2
81}, 165 (32), 119 (30), 103 (44), 85 (83), 77 (32), 59 (85) and
47 (100); νmax(KBr)/cmϪ1 1731 (C᎐O), 1703s (C᎐O) and 1678
᎐
᎐
᎐
᎐
D
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-cis-4-(N4-
(C᎐O); [α]23 Ϫ4.13 (c 0.63, DMF).
᎐
D
benzoylcytosin-1-yl)--proline diphenylmethyl ester 16 was
obtained as a foam (70%, starting from 1.12 mmol of substrate
15) after column chromatography [SiO2; ethyl acetate–methanol
(20:1)]. Recrystallisation from ethanol gave a solid, mp 131–
133 ЊC (Found: C, 71.2; H, 4.9; N, 9.0. C46H39N5O7 requires C,
71.4; H, 5.1; N, 9.0%); δH (200 MHz; CDCl3) 2.20 and 2.85 [2 H,
2 × m, CH2(3Ј)], 3.61–4.40 [m, unresolved CH2(5Ј), Gly CH2,
Fmoc aliphatic CH and CH2], 4.76–4.81 [1 H, m, CH(2Ј) rotam-
ers], 5.22 and 5.41 [1 H, 2 × m, CH(4Ј) rotamers], 6.03 and 6.12
(1 H, 2 × br t, Gly NH rotamers), 6.78 (1 H, br s, CHPh2),
7.05–8.00 [m, CH(5), CH(6), benzoyl, phenyl and Fmoc aro-
matic CH] and 9.32 (1 H, br s, benzamide NH); δC(50.28 MHz;
CDCl3) 33.2 [CH2(3Ј)], 43.5 (Gly CH2), 47.0 (Fmoc aliphatic
CH), 49.2 [CH2(5Ј)], 55.5 [CH(4Ј)], 57.8 [CH(2Ј)], 67.1 (Fmoc
CH2), 78.6 (CHPh2), 97.3 [CH(5)], 120.1 (Fmoc aromatic CH),
125.4–129.1 and 133.1 (aromatic CH), 133.3, 139.4 and 141.1
(aromatic C), 144.1 (aromatic C), 145.6 [CH(6)], 155.8 [C(2)],
156.7 (Fmoc CO), 162.6 and 163.0 [C(4) rotamers], 167.1 (ben-
zoyl CO), 168.6 (Gly CO) and 170.6 (ester CO); m/z (ES-MS)
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-trans-4-(thymin-
1-yl)--proline 9b was obtained as a solid (57%, starting
from 5.3 mmol of substrate 8b), mp >200 ЊC; δH [200 MHz;
(CD3)2SO] 1.70 (3 H, br s, thymine CH3), 2.05–2.15 and 2.40–
2.60 [br m, CH2(3Ј) rotamers, obscured by the Me2SO (DMSO)
signal], 3.50–4.00 [br m, CH2(5Ј) and Gly CH2], 4.15–4.30 (3 H,
br m, Fmoc aliphatic CH and CH2), 4.35–4.45 and 4.75–4.85 [1
H, br m, CH(2Ј) rotamers], 4.90–5.00 and 5.05–5.10 [1 H, m,
CH(4Ј) rotamers], 7.25–7.45 (4 H, m, Fmoc aromatic CH), 7.55
[1 H, br s, CH(6)], 7.68 (4 H, 2 × d, J 7.1, Fmoc aromatic CH);
m/z (FAB) 519 (M + H+, 6%), 179 {[(C H ) C᎐CH + H]+, 34},
᎐
6
4
2
2
85 (100), 59 (23) and 47 (32).
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-cis-4-(thymin-
1-yl)--proline 9c was obtained as a solid (42%, starting from
6.8 mmol of substrate 8c), mp >200 ЊC; δH [200 MHz;
(CD3)2SO] 1.75 (3 H, br s, thymine CH3), 2.11 and 2.52 [2 H,
2 × br m, CH2(3Ј) rotamers], 3.50–4.00 [br m, CH2(5Ј) and Gly
CH2], 4.18–4.30 [4 H, br m, CH(2Ј) and Fmoc aliphatic CH and
CH2], 4.73 and 4.98 [1 H, 2 × br m, CH(4Ј) rotamers], 7.28–7.41
(4 H, m, Fmoc aromatic CH), 7.51 (1 H, m, Gly NH), 7.54 [1 H,
br s, CH(6) rotamers] and 7.72 and 7.88 (4 H, 2 × d, J 7.1,
Fmoc aromatic CH); m/z (FAB) 541 (M + Na+, 2%), 519
(M + H+, 5), 179 (33), 103 (17), 85 (100), 77 (18), 59 (43) and
47 (45); [α]2D3 +4.26 (c 0.61, DMF).
774 (M + H+, 100%); νmax(KBr)/cmϪ1 1750–1665br (C᎐O);
᎐
[α]2D2 +20.9 (c 0.21, CHCl3).
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-cis-4-(N2-
isobutyrylguanin-9-yl)--proline diphenylmethyl ester 19 was
obtained as a solid (52%, starting from 0.73 mmol of substrate
18) after column chromatography (SiO2; 10% methanol in ethyl
acetate). Recrystallisation from ethyl acetate–light petroleum
(40–60 ЊC) gave a crystalline solid, mp 145–150 ЊC (Found: C,
68.0; H, 5.2; N, 12.6. C44H41N7O7 requires C, 67.8; H, 5.3; N,
12.6%); δH (200 MHz; CDCl3) 1.18 and 1.21 [6 H, d, J 6.7,
(CH3)2CH], 2.31 (1 H, br m) and 2.61–2.79 (2 H, br m) [CH2(3Ј)
and (CH3)2CH], 3.89–4.20 [m, unresolved CH2(5Ј), Gly CH2
and Fmoc aliphatic CH], 4.37 (2 H, d, J 6.7, Fmoc CH2), 4.63 [1
H, m, CH(2Ј)], 4.82 [1 H, m, CH(4Ј)], 6.10 (1 H, br m, Gly NH),
6.77 (1 H, s, CHPh2), 7.12–7.36 (m, phenyl and Fmoc aromatic
CH), 7.49–7.57 [3 H, m, Fmoc aromatic CH and CH(8)], 7.69–
7.73 (2 H, d, J 7.4, Fmoc aromatic CH) and 9.83 (1 H, br s,
isobutyramide NH); δC(50.28 MHz; CDCl3) 18.9 [(CH3)2CH],
35.7 [CH2(3Ј)], 42.9 (Gly CH2), 46.5 (Fmoc CH), 49.0 [CH2(5Ј)],
52.9 [CH(4Ј)], 57.7 [CH(2Ј)], 66.9 (Fmoc CH2), 78.3 (CHPh2),
120.1 (Fmoc aromatic CH), 120.9 [C(5)], 125.2–128.8 (Fmoc
aromatic CH), 137.5 [CH(8)], 139.4 and 139.6 (aromatic C),
144.0 (aromatic C), 148.3 and 148.8 [C(2)/C(6)], 155.8 [C(4)],
157.2 (Fmoc CO), 169.0 (Gly CO), 170.2 (ester CO) and 180.6
(isobutyramide CO); m/z (ES-MS) 780 (M + H+, 100%);
λmax(CHCl3)/nm 270sh (ε/dm3 molϪ1 cmϪ1 11.9 × 104); [α]2D3
+36.7 (c 0.645, CHCl3).
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-4-(thymin-1-
yl)proline pentafluorophenyl esters 10a–c
A suspension of the Fmoc-dipeptide (9a, 9b or 9c) (1.0 mmol),
pentafluorophenol (1.1 mmol) and DCCI (1.1 mmol) in
dichloromethane (5 ml) was stirred at room temperature for 2–
3 h. The precipitated DCU was filtered off and washed with
dichloromethane. Evaporation of the filtrate followed by
column chromatography (SiO2; ethyl acetate) gave the product
as a foam which in most cases could be made crystalline by tri-
turation with diethyl ether–light petroleum, then being filtered
and air dried.
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-cis-4-(thymin-
1-yl)--proline pentafluorophenyl ester 10a was obtained from
substrate 9a as a solid (0.574 g, 84%), mp 124–126 ЊC; δH (200
MHz; CDCl3) 1.94 (3 H, s, thymine CH3), 2.26–2.42 and 2.85–
3.00 [2 H, m, CH2(3Ј)], 3.66–3.75 and 3.95–4.26 [m, unresolved
CH2(5Ј), Gly CH2, Fmoc aliphatic CH], 4.38–4.42 (2 H, d, J
7.1, Fmoc CH2), 4.85–4.93 [1 H, m, CH(2Ј)], 5.34–5.42 [1 H, m,
CH(4Ј)], 5.80–5.82 (1 H, br t, Gly NH), 7.10 [1 H, s, CH(6)],
7.31–7.44, 7.60–7.63 and 7.75–7.79 (8 H, m, Fmoc aromatic
CH) and 9.50 (1 H, s, thymine NH); δF (235.35 MHz; CDCl3)
Ϫ162.0 (dd, J 18.1 and 21.4) and Ϫ161.2 (t, J 19.6) (m-F major
and minor rotamers), Ϫ157.0 (t, J 21.8) and Ϫ156.2 (t, J 21.7)
(p-F major and minor rotamers) and Ϫ153.1 (d, J 18.5) and
Ϫ152.8 (d, J 17.7) (o-F minor and major rotamers). The ratio
of major :minor rotamers was ~15:1; m/z (ES-MS) 685.1
N-[N-(Fluoren-9-ylmethoxycarbonyl)glycyl]-4-(thymin-1-yl)-
prolines 9a–c
The protected dipeptide (8a, 8b or 8c) was treated with 10%
HBr in acetic acid (5–10 ml mmolϪ1) at room temperature for
J. Chem. Soc., Perkin Trans. 1, 1997
553