a colorless oil in 85% yield: dH (500 MHz, d4-methanol) 1.68 (1H,
m), 1.90 (1H, m), 2.53 (1H, t, J 7.5), 2.68 (1H, t, J 7.5), 2.79–2.95
(2H, m), 3.55 (0.5H, dt, J 10.0 and 6.0), 3.86 (0.5H, dt, J 10.5
and 6.5), 4.05 (1H, m), 4.64–4.85 (3H, m), 5.73 (0.5H, d, J 6.0),
5.95 (0.5H, d, J 6.0), 6.25 (0.5H, d, J 6.0), 6.36 (0.5H, d, J 6.0),
6.98–7.20 (5H, m), 7.24 (1H, s), 7.42 (0.5H, s), 7.45 (1H, s), 8.74
(1H, s), 8.76 (1H, s); m/z (FAB) 421.1987 (M+ + 1, C22H25N6O3
requires 421.1988).
39.5, 42.9, 43.6, 46.8, 56.1, 60.3, 128.3, 129.1, 129.6, 129.9, 129.9,
131.2, 131.3, 135.4, 139.1, 158.7, 169.9, 181.1; m/z (FAB) 442.2455
(M+ + 1, C23H32N5O4 requires 442.2454).
Syntheses of compounds 69 and 70
Compounds 11c were synthesized using conditions similar to that
described for the synthesis of compound 11a, and were purified
using the same chromatographic condition. Using Cbz-p-fluoro-
L-phenylalanine, compound 11c was obtained as a white solid in
Syntheses of compounds 44 and 45
◦
95% yield: mp 118–119 C; dH (500 MHz, CDCl3) 3.01 (2H, m),
Alkylation of compound 12a with 4-chloromethyl-5-methyl-1-
tritylimidazole25 (9) using conditions similar to that described for
the synthesis of compound 13a2, afforded compound 13a4 as a
colorless oil in 70% yield: dH (500 MHz, d4-methanol) 1.40 (3H,
s), 2.76 (2H, m), 4.44 (1.5H, m), 4.55 (0.5H, d, J 15.0), 4.59 (0.5H,
d, J 15.0), 4.77 (0.5H, m), 4.84 (0.5H, d, J 12.0), 4.87 (0.5H, m),
4.93 (0.5H, d, J 15.0), 5.02 (0.5H, d, J 15.0), 5.63 (0.5H, d, J 5.8),
5.83 (0.5H, d, J 5.8), 6.19 (0.5H, d, J 5.8), 6.31 (0.5H, d, J 5.8),
6.76 (1H, s), 6.96–7.40 (21H, m); m/z (FAB) 659.3025 (M+ + 1,
C43H39N4O3 requires 659.3022).
Compound 14a4 was obtained as a colorless oil in 98% yield
by hydrogenation of compound 14a3, using similar conditions
described previously: dH (500 MHz, d4-methanol) 1.42 (3H, s),
2.10 (1H, br), 2.77 (2H, m), 3.00 (1H, dt, J 12.5 and 4.0), 3.32
(2H, m), 3.38 (1H, dd, J 13.5 and 3.2), 3.53 (1H, dd, J 10.0
and 3.3), 4.35 (1H, d, J 14.5), 4.60 (1H, d, J 14.5), 7.00–7.34
(21H, m); m/z (FAB) 527.2812 (M+ + 1, C35H35N4O requires
527.2811).
Scaffold 14a4 was coupled to the L-leucine methyl ester iso-
cyanate following he previously described general procedures to
give trityl-protected 44 as a colorless oil in 85% yield: dH (500 MHz,
d4-methanol) 0.81 (3H, d, J 6.0), 0.82 (3H, d, J 6.0), 1.02 (1H, m),
1.27 (2H, m), 1.46 (3H, s), 2.91 (1H, ddd, J 13.5, 10.5 and 3.5),
3.03 (1H, dd, J 14.0 and 8.8), 3.15 (1H, dt, J 12.0 and 3.0), 3.33
(1H, dd, J 13.5 and 3.5), 3.39 (1H, ddd, J 11.7, 11.7 and 4.0),
3.64 (3H, s), 4.00 (1H, br d, J 8.0), 4.04 (1H, br d, J 13.5), 4.22
(1H, dt, J 8.3 and 5.0), 4.41 (1H, d, J 14.5), 4.42 (1H, br s), 4.58
(1H, d, J 14.5), 7.06–7.35 (21H, m); m/z (FAB) 698.3706 (M+ +
1, C43H48N5O4 requires 698.3706).
Deprotection of the above mentioned compound following the
general procedure described previously afforded 44 as a colorless
oil in 88% yield: dH (500 MHz, d4-methanol) 0.81 (3H, d, J 6.0),
0.82 (3H, d, J 6.0), 1.10 (1H, m), 1.30 (2H, m), 2.36 (3H, s), 3.06
(2H, m), 3.28 (1H, J 13.5 and 3.8), 3.45 (1H, ddd, J 12.0, 12.0 and
4.5), 3.63 (3H, s), 4.08 (1H, br d, J 13.5), 4.20 (1H, m), 4.54 (4H,
m), 7.13–7.25 (5H, m), 8.43 (1H, s); dC (100 MHz, d4-methanol)
9.5, 22.1, 23.0, 24.8, 37.7, 37.9, 40.4, 41.7, 47.0, 52.4, 52.5, 60.6,
124.6, 127.6, 128.6, 129.2, 129.2, 129.9, 129.9,132.8, 137.6, 156.7,
168.5, 174.6; m/z (FAB) 456.2612 (M+ + 1, C24H34N5O4 requires
456.2611).
3.28 (1H, s), 3.29 (1H, s), 4.19 (1H, t, J 5.0), 4.33 (1H, m), 5.07 (2H,
br s), 5.29 (1H, m), 5.78 (1H, m), 6.95 (2H, t, J 8.7), 7.13 (2H, m),
7.28–7.36 (5H, m); m/z (FAB) 405.1825 (M+ + 1, C21H26N2O5F
requires 405.1826).
Compound 12c was synthesized using conditions similar to that
described for the synthesis of compound 12a. Compound 12c was
obtained in 85% yield as a colorless solid: dH (500 MHz, CDCl3)
2.85–3.06 (2H, m), 4.65 (0.5H, d, J 12.0), 4.87 (0.5H, t, J 6.5),
4.96 (0.5H, d, J 12.0), 5.03 (1.0H, m), 5.14 (0.5H, d, J 12.0), 5.40
(0.25H, d, J 5.5), 5.41 (0.25H, d, J 5.5), 5.64 (0.25H, d, J 5.5),
5.65 (0.25H, d, J 5.5), 6.16 (0.5H, d, J 6.0), 6.37 (0.5H, d, J 6.0),
6.83–7.40 (10H, m); m/z (FAB) 341.1302 (M+ + 1, C19H18N2O3F
requires 341.1301).
Alkylation of compound 12c with 4-chloromethyl-5-methyl-1-
tritylimidazole27 (9) using conditions similar to that described
for the synthesis of compound 13a2, afforded compounds 13c
as colorless oils in 65% yield: dH (500 MHz, CDCl3) 1.44 (1.5H,
s), 1.45 (1.5H, s), 2.75–2.92 (2H, m), 4.46 (0.5H, d, J 12.0), 4.48
(0.5H, d, J 12.0), 4.58 (0.5H, d, J 12.0), 4.64 (0.5H, d, J = 14.5),
4.73 (0.5H, d, J 14.5), 4.85 (0.5H, t, J 6.5), 4.91 (0.5H, d, J 12.0),
4.98 (0.5H, d, J 12.0), 5.00 (0.5H, t, J 6.5), 5.10 (0.5H, d, J 2.0),
5.76 (0.5H, d, J 6.0), 5.91 (0.5H, d, J 6.0), 6.14 (0.5H, d, J 6.0),
6.34 (0.5H, d, J 6.0), 7.04–7.35 (25H, m); m/z (FAB) 677.2928
(M+ + 1, C43H38N4O3F requires 677.2928).
Compounds 14c were obtained in 95% yields by hydrogenation
of compound 13c, using similar conditions described previously,
as a colorless oil: dH (500 MHz, CDCl3) 1.41 (3H, s), 2.80 (2H, m),
3.00 (1H, dt, J 12.5 and 4.0), 3.28–3.33 (3H, m), 3.50 (1H, dd, J
10.0 and 3.5), 4.36 (1H, d, J 14.5), 4.58 (1H, d, J 14.5), 6.86–7.40
(20H, m); m/z (FAB) 545.2717 (M+ + 1, C35H34N4OF requires
545.2717).
Scaffold 14c was coupled to L-leucine methyl ester isocyanate
following the previously described general procedures to give
trityl-protected 69 as colorless oil in 87% yield: dH (500 MHz,
d4-methanol) 0.80 (6H, d, J 6.0), 1.09 (1H, m), 1.30 (2H, m),
1.49 (3H, s), 2.78 (1H, ddd, J 13.5, 10.5 and 3.5), 3.01 (1H, dd,
J 14.0 and 8.5), 3.08 (1H, dt, J 12.0 and 3.0), 3.22 (1H, dd, J
14.0 and 4.0), 3.33 (1H, ddd, J 12.5, 11.0 and 4.5), 3.61 (3H,
s), 3.94 (1H, br d, J 14.0), 4.11 (1H, br d, J 8.0), 4.24 (1H, m),
4.34 (1H, d, J 14.5), 4.39 (1H, m), 4.55 (1H, d, J 14.5), 6.85–7.34
(20H, m); m/z (FAB) 716.3609 (M+ + 1, C43H47N5O4F requires
716.3612).
Saponification of 44 following the general procedure described
previously afforded 45 as a colorless oil in 85% yield: dH (500 MHz,
d4-methanol) 0.68 (3H, d, J 6.0), 0.70 (3H, d, J 6.0), 1.21 (1H, m),
1.31 (2H, m), 2.08 (3H, s), 2.66 (1H, ddd, J 13.5, 10.0 and 3.7),
2.75 (1H, dd, J 12.3 and 3.2), 3.00–3.15 (3H, m), 3.66 (1H, br
d, J 13.5), 3.95 (1H, dd, J 10.0 and 4.5), 4.28 (1H, d, J 14.8),
4.38 (1H, d, J 14.8), 4.60 (1H, t, J 5.5), 6.95–7.04 (5H, m), 7.42
(1H, s); dC (125 MHz, d4-methanol) 10.4, 22.6, 24.1, 26.3, 38.8,
Deprotection of the above mentioned compound following the
general procedure described previously afforded 69 as a colorless
oil in 85% yield: dH (CDCl3, 500 MHz) 0.79 (d, J = 6.2, 3H), 0.82
(d, J = 6.2, 3H), 1.17 (m, 1H), 1.28 (m, 1H), 1.34 (m, 1H), 2.31
(s, 3H), 3.03 (m, 2H), 3.20 (br d, J = 10.0, 1H), 3.42 (m,1H), 3.61
(s, 3H), 4.06 (br d, J = 11.5, 1H), 4.18 (m, 1H), 4.47 (d, J = 15.0,
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1768–1784 | 1781
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