J. F. Sanz-Cervera et al. / Bioorg. Med. Chem. 8 (2000) 2407±2415
2413
ddd, J=8.8, 8.8, 12.1 Hz), 4.23 (1H, ddd, J=4.0, 4.0,
.6 Hz), 5.92 (1H, bs), 7.04 (1H, d, J=2.2 Hz), 7.11 (1H,
ddd, J=1.1, 8.0, 8.0 Hz), 7.18 (1H, ddd, J=1.1, 8.0,
130.16 (s, C-3a*), 126.16 (d, C-2), 124.73 (d, C-6),
122.58 (d, C-5), 119.64 (d, C-4), 115.01 (d, C-7), 113.71,
(s, C-3), 84.07 (s, C-19), 83.73 (s, C-24), 60.53 (d, C-12),
60.21 (d, C-9), 44.73 (t, C-15), 28.89 (t, C-8), 28.89 (t, C-
13, q, C-20, C-21, C-22***), 27.59 (q, C-25, C-26, C-
27***), 20.57 (t, C-14) (*assignments for signals with
the same superscript may be interchanged) minor rota-
mer: d 167.25 (s, C-17*), 164.95 (s, C-11*), 150.11 (s, C-
18**), 149.35 (s, C-23**), 135.38 (s, C-7a*), 129.90 (s,
C-3a*), 125.25 (d, C-2), 124.81 (d, C-6), 122.73 (d, C-5),
6
8
8
3
1
2
.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=8.0 Hz),
1
3
.17 (1H, bs). C NMR (75 MHz, CDCl ): d 21.6, 29.0,
3
0.8, 45.1, 57.9, 58.4, 109.4, 111.2, 118.8, 119.9, 122.5,
24.1, 126.9, 136.1, 165.3, 169.3. I.R. (NaCl neat) 3260,
�
1
924, 2884, 1651, 1455, 1338, 1302, 1104, 1010, 743 cm
ꢀ
.
[a]D25=+50.9 (c 0.23, CH Cl ). HRMS (FAB+) calcd
2
2
for C H N O : 284.1399; found 284.1389.
1
6
18
3
2
1
18.94 (d, C-4), 115.27 (d, C-7), 114.29, (s, C-3), 84.34
0
15
N,N -Di-Boc-cyclo-L-tryptophan-L-proline (8). Crystal-
line cyclo-l-Trp-l-Pro (brevianamide F, 6) (1.5 g,
(s, C-19), 83.96 (s, C-24), 61.13 (d, C-9), 59.20 (d, C-12),
45.18 (t, C-15), 29.16 (t, C-13), 28.09 (q, C-20, C-21, C-
22***), 27.95 (t, C-8), 27.65 (q, C-25, C-26, C-27***),
21.95 (t, C-14) (*assignments for signals with the same
superscript may be interchanged).
5
.298 mmol) was suspended in 10 mL of dry CH Cl
2 2
under an Ar atmosphere. To this suspension, dimethyla-
minopyridine (DMAP) (64.7 mg, 0.53 mmol, 0.1 equiv)
and triethylamine (1.072 g, 10.60 mmol, 1.48 mL,
ꢀ
15
2
equiv) were added. The mixture was cooled to � 18 C
N-Boc-cyclo-L-tryptophan-L-proline (9). To a stirred
0
(
(
ice-salt bath), and di-tert-butyldicarbonate ((Boc) O)
2
suspension of N,N -di-Boc-cyclo-l-Trp-l-Pro (8) (2.00 g,
2.312 g, 10.60 mmol, 2 equiv) was added in one portion.
4.135mmol) in 100 mL of MeCN under an Ar atmo-
sphere was added dimethylamine (40% aq soln, 3.0 mL).
The solution was heated to re¯ux for 90 min. The solvent
was removed under reduced pressure and the residue
was separated by means of silica gel column chromato-
graphy, using hexane:EtOAc:MeOH (4:5:1) as eluent to
give 1.48 g of 9 as a colorless glass (93% yield). This
fraction was further puri®ed using column chromato-
graphy, with CH Cl :MeOH 25:1 as eluent to give
The mixture was stirred at that temperature for 30 min
for 2 h at 0 C and 2 h at rt. The reaction was diluted
ꢀ
with 100 mL of dichloromethane and washed with 1%
aq KHSO soln (2Â50 mL), then with 5% NaHCO aq
4
3
soln (50 mL) and dried over anhydrous MgSO .
4
Removal of the solvent under reduced pressure gave
2.63 g of crude reaction product, which was separated
by silica gel column chromatography, using toluene:
EtOAc 2:1 as eluent to give 2.30 g of 8 as a viscous col-
orless oil (90% yield).
2
2
1.39 g of pure 9 as a colorless glass (87% yield).
Optical rotation: [a] =+4.45 (CH Cl , c 0.88). 1H
d
2
2
[
a] =+77.21 (CH Cl , c 1.18). IR (neat, NaCl): 2980,
NMR (CDCl , 400 MHz): d 8.05 (1H, br d, J=8.0 Hz,
d
934, 2878, 1777, 1731, 1667, 1457, 1455, 1369, 1323,
2
2
3
2
1
7
4
H-7), 7.51 (1H, d, J=7.6 Hz, H-4), 7.44 (1H, s, H-2),
7.25 (1H, ddd, J=7.6, 7.6, 1.2 Hz H-6), 7.17 (1H, ddd,
J=7.6, 7.6, 1.2 Hz, H-5), 7.11 (1H, brs, H-10 (N-H)),
4.19 (1H, ddd, J=6.4, 4.4, 4.4 Hz, H-9), 3.51 (1H, ddd,
J=8.8, 8.8, 12.0 Hz, H-15), 3.15±3.25 (3H, m, H-8, H-
292, 1257, 1155, 1084, 1018, 965, 917, 852, 768, 748,
�
1
32 cm . HRMS (FAB+) calcd for C H N O :
3
2
6
33
6
83.2369; found 483.2368 (M+).
ꢀ
0
0
In DMSO-d6 at 80 C, this compound appears as a
mixture of two predominant rotamers in a ꢁ2:1 pro-
portion that interconvert slowly on the NMR time
scale. For that reason, both H and C spectra include
the signals for both major and minor rotamers.
NMR (CDCl , 25 C, 400 MHz): major rotamer: d 8.08
(
7
(
12, H-15 ), 3.13 (1H, dd, J=14.8, 4.8 Hz, H-8 ), 2.09
(1H, ddd, J=6.4, 6.4, 11.8 Hz, H-13), 1.83 (1H, m, H-
0
14), 1.71 (1H, m, H-13 ), 1.58 (9H, s, H-20, H-21, H-22),
0
1
13
13
1.51 (1H, m, H-14 ). C NMR (CDCl , 100 MHz): d
3
16 1
H
169.44 (s, C-17*), 165.56 (s, C-11*), 149.68 (s, C-18),
135.57 (s, C-7a*), 130.05 (s, C-3a*), 125.48 (d, C-2),
124.90 (d, C-6), 122.89 (d, C-5), 119.30 (d, C-4), 115.39
(d, C-7), 114.71, (s, C-3), 84.16 (s, C-19), 58.16 (d, C-9),
57.97 (d, C-12), 45.45 (t, C-15), 30.49 (t, C-13), 29.10 (q,
C-20, C-21, C-22), 28.34 (t, C-8), 21.86 (t, C-14)
(assignments for signals with the same superscript may
be interchanged). IR (neat, NaCl): 3236, 2979, 2927,
2876, 1732, 1664, 1452, 1370, 1332, 1308, 1256, 1228,
ꢀ
3
1H, d, J=7.9 Hz, H-7), 7.47 (1H, d, J=7.9 Hz, H-4),
.27 (1H, t, J=7.0 Hz, H-6) 7.25 (1H, bs, H-2), 7.19
1H, t, J=7.3 Hz, H-5), 4.93 (1H, dd, J=2.6, 4.7 Hz, H-
9
1
), 3.84 (1H, dd, J=6.2, 11.1 Hz, H-12), 3.59 (1H, m, H-
5), 3.56 (1H, dd, J=2.9, 14.7 Hz, H-8), 3.46 (1H, dd,
0
0.3 Hz, H-15 ), 1.77 (1H, m, H-13), 1.63 (9H, s, H-20,
J=5.0, 14.7 Hz, H-8 ) 3.09 (1H, ddd, J=4.4, 1,.3,
1
0
H-21, H-22), 1.56 (9H, s, H-25, H-26, H-27), 1.48 (1H,
m, H-14), 1.25 (1H, m, H-14 ). 0.11 (1H, m, H-13 );
�
1
1159, 1109, 1085, 1017, 865, 765, 747, 729, 699 cm
HRMS (FAB+) calcd for C H N O : 383.1845;
.
0
0
21
25
3
4
minor rotamer: d 8.10 (1H, d, J=7.9 Hz, H-7), 7.52
found 383.1842 (M+).
(
ddd, J=1.2, 7.3, 7.3 Hz, H-6), 7.22 (1H, ddd, J=0.9,
1H, d, J=7.6 Hz, H-4), 7.57 (1H, bs, H-2), 7.29 (1H,
0
15
stirred solution of compound 9 (925 mg, 2.412 mmol) in
4 mL of dry DMF under an Ar atmosphere at 0 C,
N-Boc-N -prenyl-cyclo-L-tryptophan-L-proline.
To
a
7
3
.3, 7.3 Hz, H-5), 5.03 (1H, dd, J=5.6, 5.6 Hz, H-9),
0
0
ꢀ
NaH was added (58 mg of a 60% oil suspension,
.48 (1H, m, H-15), 3.31 (3H, m, H-8, H-8 , H-15 ), 3.13
(
5
1H, dd, J=6.5, 9.4 Hz, H-12), 2.11 (1H, ddd, J=5.9,
0
s, H-20, H-21, H-22), 1.45(1H, m, H-14 ), 1.40 (9H, s, H-
ꢀ
for 30 min and prenyl bromide (719 mg, 4.83 mmol,
.9, 10.9 Hz, H-13), 1.84 (2H, m, H-13 , H-14), 1.64 (9H,
0
5, H-26, H-27). C NMR (CDCl , 25 C, 100 MHz):
2.412 mmol, 1 equiv). The mixture was stirred at 0 C
1
3
ꢀ
2
2 equiv, 502 mL) was added. The reaction mixture was
stirred for 1 h at 0 C and then 2 h at rt. The reaction
3
ꢀ
was then quenched with 5% aqueous NaHCO (50 mL)
major rotamer: d 165.85 (s, C-17*), 164.02 (s, C-11*),
50.98 (s, C-18**), 149.30 (s, C-23**), 134.14 (s, C-7a*),
1
3