1048 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
(d, 1 H, J ) 10.5 Hz), 5.14 (d, 1 H, J ) 17.8 Hz), 5.05-4.95
(m, 1 H), 4.81 (d, 1 H, J ) 7.4 Hz), 4.77-4.67 (m, 1 H), 4.65-
4.58 (m, 2 H), 4.56 (t, 1 H, J ) 5.0 Hz), 4.38-4.30 (m, 1 H),
4.30-4.20 (m, 1 H), 3.84 (dd, 1 H, J ) 2.2, 9.3 Hz), 3.70 (dd,
1 H, J ) 8.7, 11.0 Hz), 3.53-3.43 (m, 2 H), 3.40-3.20 (m, 3
H), 2.96 (dd, 1 H, J ) 3.3, 13.7 Hz), 2.68-2.55 (m, 1 H), 2.48-
2.38 (m, 1 H), 2.13-1.97 (m, 1 H), 1.97-1.75 (m, 2 H), 1.52 (s,
3 H), 1.41 (s, 3 H), 1.28 (s, 3 H), 1.25 (s, 3 H), 1.21-1.10 (m, 2
H), 1.07 (d, 3 H, J ) 6.5 Hz), 1.00-0.82 (m, 9 H); 1H NMR
(500 MHz) δ 8.03 (d, 1 H, J ) 5.4 Hz), 7.98 (t, 2 H, J ) 4.6
Hz), 7.52 (d, 1 H, J ) 7.1 Hz), 7.22-7.15 (m, 3 H), 7.03-6.98
(m, 2 H), 6.11 (d, 1 H, J ) 10.1 Hz), 5.95 (dd, 1 H, J ) 10.8,
17.6 Hz), 5.75 (dd, 1 H, J ) 11.0, 17.4 Hz), 5.30 (d, 1 H, J )
17.6 Hz), 5.26 (d, 1 H, J ) 10.8 Hz), 5.15 (d, 1 H, J ) 10.7 Hz),
5.14 (d, 1 H, J ) 17.7 Hz), 5.06-5.00 (m, 1 H), 4.82 (d, 1 H, J
) 7.8 Hz), 4.75 (t, 1 H, J ) 6.8 Hz), 4.72-4.60 (m, 2 H), 4.56
(t, 1 H, J ) 5.0 Hz), 4.40-4.30 (m, 1 H), 4.30-4.22 (m, 1 H),
3.85 (dd, 1 H, J ) 2.4, 9.4 Hz), 3.71 (dd, 1 H, J ) 8.7, 11.1
Hz), 3.58 (dd, 1 H, J ) 3.3, 9.4 Hz), 3.52 (dd, 1 H, J ) 9.9,
17.1 Hz), 3.43-3.25 (m, 3 H), 2.96 (dd, 1 H, J ) 3.3, 13.7 Hz),
2.70-2.62 (m, 1 H), 2.50-2.40 (m, 1 H), 2.10-2.02 (m, 1 H),
2.00-1.90 (m, 1 H), 1.88-1.78 (m, 1 H), 1.52 (s, 3 H), 1.41 (s,
3 H), 1.28 (s, 3 H), 1.26 (s, 3 H), 1.26-1.16 (m, 2 H), 1.08 (d,
3 H, J ) 6.4 Hz), 1.02-0.90 (m, 9 H); 13C NMR δ 173.8, 172.9,
170.5, 170.3, 142.8, 142.4, 136.0, 129.9, 128.0, 127.0, 115.9,
115.1, 79.2, 78.4, 76.0, 66.4, 61.7, 60.5, 57.4, 57.2, 57.0, 53.8,
47.4, 46.9, 39.0, 36.5, 35.8, 27.9, 26.4, 25.8, 25.6, 25.5, 25.2,
24.4, 19.5, 18.4, 16.4, 12.5; MS (FAB) m/z (rel intensity) 860
([M + Na]+, 48), 838 ([M + H]+, 55), 770 (35), 702 (100); HRMS
(FAB) m/z calcd for C43H63N7O8NaS (M + Na), 860.4357, found
860.4412.
colorless solid: mp 154-156 °C; [R]D -8.0 (c 0.50, CHCl3, 22
1
°C); IR (film) 3378, 3315, 1668 cm-1; H NMR δ 8.57 (d, 1 H,
J ) 9.0 Hz), 7.75 (d, 1 H, J ) 7.6 Hz), 7.38 (d, 1 H, J ) 5.7
Hz), 7.30-7.20 (m, 5 H), 7.06 (d, 1 H, J ) 8.8 Hz), 6.95 (d, 1
H, J ) 8.6 Hz), 6.57 (d, 1 H, J ) 9.3 Hz), 5.85 (dd, 1 H, J )
10.8, 17.4 Hz), 5.75 (dd, 1 H, J ) 10.9, 17.5 Hz), 5.26 (d, 1 H,
J ) 10.7 Hz), 5.24 (d, 1 H, J ) 17.4 Hz), 5.18 (d, 1 H, J ) 10.8
Hz), 5.15 (d, 1 H, J ) 17.6 Hz), 5.02-4.90 (m, 1 H), 4.87-4.78
(m, 1 H), 4.68 (dd, 1 H, J ) 5.5, 8.5 Hz), 4.55-4.40 (m, 3 H),
4.17-4.05 (m, 2 H), 3.90-3.75 (m, 2 H), 3.70-3.50 (m, 2 H),
3.48-3.37 (m, 3 H), 2.93 (dd, 1 H, J ) 10.3, 14.0 Hz), 2.45-
2.10 (m, 2 H), 1.90-1.78 (m, 2 H), 1.75-1.60 (m, 1 H), 1.60-
1.42 (m, 1 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.29 (s, 3 H), 1.27 (s,
3 H), 1.26 (d, 3 H, J ) 5.5 Hz), 1.06 (d, 3 H, J ) 6.3 Hz), 1.00-
0.93 (m, 6 H), 0.90-0.80 (m, 2 H); 13C NMR δ 172.3, 171.8,
171.3, 170.7, 170.1, 142.4, 142.2, 137.3, 129.4, 128.7, 127.1,
116.2, 115.5, 67.5, 63.8, 62.0, 60.8, 58.1, 57.1, 55.9, 55.6, 54.4,
47.9, 47.7, 38.4, 36.3, 29.3, 26.9, 26.5, 26.1, 25.7, 25.5, 23.9,
19.7, 17.3, 16.5, 12.1; HRMS (FAB) m/z calcd for C43H66N7O10
(M + H) 840.4871, found 840.4911.
Cyclo[Ala -P r o-D-P h e -D-Se r (oxa z)-Th r (r p r e n yl)-Se r -
(r p r en yl)-Ile]. According to general procedure G, 40 (34.6 mg,
41.2 µmol) provided 20.8 mg (61%) of cyclo[Ala-Pro-D-Phe-D-
Ser(oxaz)-Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless glass:
[R]D -27.1 (c 0.93, CHCl3, 22 °C); IR (film) 3338, 1666 cm-1
;
1H NMR δ 8.18 (d, 1 H, J ) 6.1 Hz), 8.03 (d, 1 H, J ) 4.3 Hz),
7.87 (d, 1 H, J ) 3.9 Hz), 7.68 (d, 1 H, J ) 8.1 Hz), 7.20-7.05
(m, 5 H), 6.00 (d, 1 H, J ) 10.6 Hz), 5.93 (dd, 1 H, J ) 17.6,
10.8 Hz), 5.78 (dd,1 H, J ) 17.7, 10.7 Hz), 5.28 (d, 1 H, J )
17.7 Hz), 5.24 (1 H, J ) 10.8 Hz), 5.16 (d, 1 H, J ) 17.0 Hz),
5.16 (d, 1 H, J ) 11.5 Hz), 5.07-4.97 (m, 1 H), 4.95-4.85 (m,
1 H), 4.75-4.60 (m, 2 H), 4.55-4.30 (m, 5 H), 4.25-4.15 (m, 1
H), 3.87 (dd, 1 H, J ) 2.8, 9.4 Hz), 3.62 (dd, 1 H, J ) 3.3, 9.3
Hz), 3.55-3.35 (m, 2 H), 3.12 (dd, 1 H, J ) 4.6, 14.0 Hz), 2.91
(dd, 1 H, J ) 7.6, 13.9 Hz), 2.50-2.35 (m, 2 H), 2.10-1.85 (m,
2 H), 1.77-1.60 (m, 1 H), 1.51 (s, 3 H), 1.39 (s, 3 H), 1.35-
1.10 (m, 11 H), 1.03 (d, 3 H, J ) 6.4 Hz), 0.98-0.82 (m, 6 H);
13C NMR δ 172.4, 171.5, 170.5, 170.2, 170.1, 169.8, 168.8,
142.9, 142.4, 136.6, 129.4, 128.6, 126.7, 115.9, 115.1, 79.1, 78.3,
76.0, 70.4, 68.5, 65.6, 61.7, 59.4, 57.5, 57.3, 48.6, 47.2, 46.7,
39.3, 35.8, 27.9, 25.7, 25.5, 24.3, 20.0, 18.0, 16.4, 12.5; HRMS
(FAB) m/z calcd for C43H63N7O9Na (M + Na) 844.4585, found
844.4594.
F m oc-Ala -P r o-D-P h e-D-Ser (TBS)-OBn (38). According to
general procedure D, 37 (2.15 g, 3.88 mmol) and D-Ser(TBS)-
OBn (1.20 g, 3.88 mmol) provided 1.59 g (81%) of 38 as a
colorless foam: [R]D -43.8 (c 0.26, CHCl3, 22 °C); IR (film)
1
3418, 3300, 1724, 1658 cm-1; H NMR (benzene-d6) δ 7.60-
7.35 (m, 5 H), 7.28-6.95 (m, 15 H), 5.95 (d, 1 H, J ) 8.0 Hz),
5.05-4.78 (m, 4 H), 4.53-4.36 (m, 3 H), 4.30-4.22 (m, 1 H),
4.15-4.10 (m, 1 H), 3.92 (dd, 1 H, J ) 3.2, 10.0 Hz), 3.80 (dd,
1 H, J ) 3.8, 10.0 Hz), 3.23 (dd, 1 H, J ) 5.3, 14.0 Hz), 3.11
(dd, 1 H, J ) 8.1, 13.9 Hz), 3.05-2.92 (m, 1 H), 2.90-2.80 (m,
1 H), 2.05-1.95 (m, 1 H), 1.72-1.55 (m, 1 H), 1.33 (d, 3 H, J
) 6.8 Hz), 1.25-1.10 (m, 2 H), 0.87 (s, 9 H), -0.03 (s, 3 H),
-0.05 (s, 3 H); 13C NMR (benzene-d6) δ 173.2, 171.5, 171.4,
170.8, 156.3, 144.9, 144.8, 142.1, 138.0, 136.3, 130.2, 129.5,
128.9, 127.7, 127.3, 125.9, 120.6, 67.4, 64.1, 60.5, 55.7, 55.5,
49.1, 48.0, 47.2, 38.7, 27.5, 26.4, 25.3, 18.9, -5.0, -5.1; HRMS
(FAB) m/z calcd for C48H59N4O8Si (M + H) 847.4102, found
847.4132.
Cyclo[Ala -P r o-D-P h eΨ{(CdS)NH}-D-Ser -Th r (r p r en yl)-
Ser (r p r en yl)-Ile]. According to general procedure H, cyclo-
[Ala-Pro-D-Phe-D-Ser(oxaz)-Thr(rprenyl)-Ser(rprenyl)-Ile] (19.5
mg, 23.8 µmol) provided 16 mg (79%) of cyclo[Ala-Pro-D-PheΨ-
{(CdS)NH}-D-Ser-Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless
solid: mp 140-142 °C; [R]D +25.7 (c 0.23, CHCl3, 22 °C); IR
1
F m oc-Ala -P r o-D-P h e -D-Se r (TBS)-Th r (r p r e n yl)-Se r -
(r p r en yl)-Ile-OMe (39). According to general procedure I,
benzyl ester deprotection of 38 (0.768 g, 0.917 mmol) in EtOAc/
EtOH (10:1, 8 mL) and the condensation with the amine 25
(30.8 mg, 65.8 µmol) provided 55.1 mg (54% over two steps) of
39 as a colorless foam: [R]D -4.4 (c 0.18, CHCl3, 22 °C); IR
(film) 3314, 1670 cm-1; H NMR δ 9.79 (d, 1 H, J ) 7.8 Hz),
7.83 (d, 1 H, J ) 7.6 Hz), 7.38 (d, 2 H, J ) 5.9 Hz), 7.35-7.20
(m, 5 H), 6.65 (d, 1 H, J ) 8.9 Hz), 6.52 (d, 1 H, J ) 9.4 Hz),
5.85 (dd, 1 H, J ) 10.9, 17.3 Hz), 5.75 (dd, 1 H, J ) 10.9, 17.5
Hz), 5.45-5.40 (m, 1 H), 5.25 (d, 1 H, J ) 10.6 Hz), 5.23 (d, 1
H, J ) 17.5 Hz), 5.19 (d, 1 H, J ) 10.5 Hz), 5.15 (d, 1 H, J )
17.6 Hz), 4.74 (dd, 1 H, J ) 5.4, 8.6 Hz), 4.65-4.32 (m, 4 H),
4.22-4.10 (m, 2 H), 3.93-3.68 (m, 4 H), 3.59 (dd, 1 H, J )
4.7, 9.3 Hz), 3.40-3.25 (m, 2 H), 2.90 (dd, 1 H, J ) 10.8, 13.9
Hz), 2.47-2.30 (m, 1 H), 1.85-1.70 (m, 2 H), 1.70-1.48 (m, 2
H), 1.39 (s, 3 H), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.27 (s, 3 H), 1.25
(d, 3 H, J ) 6.7 Hz), 1.25-1.00 (m, 3 H), 1.03 (d, 3 H, J ) 6.3
Hz), 1.00-0.83 (m, 6 H); 13C NMR δ 205.2, 171.8, 171.3, 171.0,
170.4, 170.1, 170.0, 142.3, 142.1, 137.5, 129.3, 128.7, 127.1,
116.3, 115.6, 76.5, 67.5, 63.0, 61.9, 60.5, 58.0, 57.2, 55.7, 47.9,
47.7, 41.9, 36.4, 29.1, 26.8, 26.5, 26.0, 25.7, 25.4, 23.7, 19.8,
17.2, 16.5, 12.1; HRMS (FAB) m/z calcd for C43H66N7O9S (M
+ H) 856.4643, found 856.4669.
1
(film) 3315, 1719, 1644 cm-1; H NMR δ 7.77 (d, 2 H, J ) 7.4
Hz), 7.65-7.55 (m, 2 H), 7.41 (t, 4 H, J ) 7.2 Hz), 7.34-7.20
(m, 9 H), 7.06 (d, 2 H, J ) 8.5 Hz), 6.90 (d, 1 H, J ) 6.9 Hz),
5.94 (dd, 1 H, J ) 10.7, 17.6 Hz), 5.87-5.75 (m, 2 H), 5.32-
5.04 (m, 4 H), 4.70-4.45 (m, 4 H), 4.36 (d, 3 H, J ) 7.4 Hz),
4.25-4.18 (m, 1 H), 4.05-3.95 (m, 1 H), 3.90-3.80 (m, 2 H),
3.75-3.55 (m, 2 H), 3.70 (s, 3 H), 3.34 (t, 1 H, J ) 7.4 Hz),
3.20-3.00 (m, 3 H), 2.25-2.18 (m, 1 H), 2.20-1.75 (m, 4 H),
1.45 (s, 3 H), 1.36 (s, 3 H), 1.35-1.10 (m, 5 H), 1.29 (s, 6 H),
1.03 (d, 3 H, J ) 6.4 Hz), 0.98-0.83 (m, 6 H), 0.87 (s, 9 H),
0.06 (2s, 6 H); 13C NMR δ 172.8, 172.1, 171.4, 171.0, 170.3,
169.8, 168.8, 155.9, 144.0, 142.8, 141.4, 136.8, 136.5, 129.5,
128.8, 128.5, 127.9, 127.2, 125.3, 120.1, 115.1, 114.9, 76.2, 67.2,
63.0, 62.5, 60.4, 58.0, 56.9, 55.3, 54.6, 53.4, 52.1, 48.7, 47.3,
37.8, 27.6, 26.0, 25.7, 25.3, 25.2, 18.4, 18.2, 17.5, 15.7, 11.6,
-5.2; MS (FAB) m/z (rel intensity) 1247 ([M + K]+, 100), 1231
([M + Na]+, 75).
Cyclo[Ala -P r o-D-P h e-D-Ser (t h ia z)-Th r (r p r en yl)-Ser -
(r p r en yl)-Ile] (41). According to general procedure G, cyclo-
[Ala-Pro-D-PheΨ{(CdS)NH}-D-Ser-Thr(rprenyl)-Ser(rprenyl)-
Ile] (6.4 mg, 8.1 µmol) provided 4.9 mg (79%) of 41 as a
colorless amorphous solid: [R]D -28.0 (c 0.49, CHCl3, 22 °C);
IR (film) 3345, 1667 cm-1; 1H NMR δ 8.30-8.20 (m, 2 H), 8.13
(d, 1 H, J ) 4.8 Hz), 7.58 (d, 1 H, J ) 7.8 Hz), 7.27-7.10 (m,
5 H), 6.05 (d, 1 H, J ) 10.4 Hz), 5.95 (dd, 1 H, J ) 10.8, 17.6
Cyclo[Ala -P r o-D-P h e-D-Ser -Th r (r p r en yl)-Ser (r p r en yl)-
Ile] (40). According to general procedure F, 39 (119 mg, 92.7
µmol) provided 27.9 mg (36% over four steps) of 40 as a