Tryprostatin B & Demethoxyfumitremorgin C Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1583
0.46, MeOH); IR νmax (KBr): 3261, 1661, 1637, 1461 cm-1; 1H
NMR δ 8.41 (br s, 1H), 7.65 (d, 1H, J ) 7.8 Hz), 7.41-7.25 (m,
6H), 7.17 (t, 1H, J ) 7.2 Hz), 7.09 (t, 1H, J ) 7.8 Hz), 6.93 (d,
1H, J ) 2.2 Hz), 6.69 (d, 1H, J ) 15.8 Hz, PhCHd), 6.20 (ddd,
1H, J ) 15.8, 8.5, 5.2 Hz, PhCHdCH-), 5.12 (dd, 1H, J ) 14.8,
3.7 Hz), 4.44 (br s, 1H), 3.81-3.65 (m, 3H), 3.48-3.38 (m, 1H),
3.31 (dd, 1H, J ) 14.8, 4.6 Hz), 2.95 (td, 1H, J ) 11.0, 4.7 Hz),
1.79-1.65 (m, 1H), 1.32 (m, 1H), 0.74 (m, 1H), -0.16 (quintet,
1H, J ) 10.8 Hz); 13C NMR δ 166.2, 164.4, 136.0, 135.7 (s),
134.9, 128.7, 128.2, 127.4 (d), 126.5 (s), 123.9, 122.7, 122.5,
119.7, 119.7, 110.9 (d), 108.5 (s), 59.9, 59.3 (d), 45.1, 44.5, 28.3,
26.9, 20.6 (t); MS (ESI) m/ z calcd for M + H 400.2, found
400.2. Anal. (C25H25N3O2‚1/4H2O) C, H, N.
[5a S,12S,14a S]-1,2,3,5a ,6,11,12,14a -Oct a h yd r o-12-(2-
m eth ylp r op yl)-5H,14H-p yr r olo[1′′,2′′:4′,5′]p yr a zin o[1′,2′:
1,6]p yr id o[3,4-b]in d ole-5,14-d ion e (cis-6a ) a n d [5a S,12R,-
14aS]-1,2,3,5a,6,11,12,14a-Octah ydr o-12-(2-m eth ylpr opyl)-
5H ,14H -p yr r olo[1′′,2′′:4′,5′]p yr a zin o[1′,2′:1,6]p yr id o[3,4-
b]in d ole-5,14-d ion e (tr a n s-6a ). These two compounds were
prepared in quantitative yields from cis-11a and trans-11a ,
respectively. Their NMR spectra were identical to those
reported.17
[5a S,12S,14a S]-1,2,3,5a ,6,11,12,14a -Octa h yd r o-12-p h en -
yl-5H,14H-p yr r olo[1′′,2′′:4′,5′]p yr a zin o[1′,2′:1,6]p yr id o[3,4-
b]in d ole-5,14-d ion e (cis-6b): yield 91% from cis-11b; white
solid; [R]22D ) -5.0 (c 0.077, MeOH); IR νmax (KBr) 3285, 1663,
1456, 1396 cm-1; 1H NMR (DMSO-d6) δ 11.23 (br s, 1H, NH),
7.56 (d, 1H, J ) 7.7 Hz), 7.32 (d, 1H, J ) 7.9 Hz), 7.29-7.24
(m, 4H, PhH), 7.19-7.15 (m, 1H, PhH), 7.07 (td, 1H, J ) 7.0,
1.2 Hz), 7.00 (t, 1H, J ) 7.4 Hz), 6.32 (s, 1H, Ph-CHN), 4.55
(dd, 1H, J ) 11.6, 5.0 Hz, Trp-CHN), 4.37 (t, 1H, J ) 7.8 Hz,
Pro-CHN), 3.54-3.45 (m, 2H, Pro-NCH2), 3.43 (dd, 1H, J )
15.8, 5.2 Hz, Trp-CH2), 2.99 (dd, 1H, J ) 15.7, 11.7 Hz, Trp-
CH2), 2.22 (m, 1H), 1.95-1.84 (m, 3H); 13C NMR (DMSO-d6) δ
169.8, 165.3, 142.7, 135.9, 133.9 (s), 128.4, 126.8, 125.6 (d),
125.6 (s), 121.1, 118.8, 118.0, 111.3 (d), 104.4 (s), 58.3 (Pro-
CHN), 56.2 (Trp-CHN), 54.8 (PhCHN), 44.8, 27.8, 22.5, 21.4
(t); NOE (DMSO-d6) δ 6.32 (11.23, 7.29-7.24, 4.55), 4.55 (6.23);
MS (ESI) m/ z calcd for M + H 372.2, found 372.2. Anal.
(C23H21N3O2‚1/5H2O) C, H, N.
(q), 53.9 (d), 44.9 (t), 27.7 (t), 22.9 (t), 20.9 (t); 1H-13C HMQC
(DMSO-d6) δH (δC) 6.31 (53.9), 4.56 (55.9); MS (ESI) m/ z calcd
for M + H 448.2, found 448.0. Anal. (C25H25N3O5‚4/3H2O) C,
N; H: calcd, 5.91; found, 5.17. HPLC purity (retention time):
solvent system A, 100.0% (10.19 min); solvent system B, 98.0%
(11.23 min).
[5a S,12R,14a S]-1,2,3,5a ,6,11,12,14a -Octa h yd r o-12-(4-h y-
d r oxy-3,5-d im eth oxyp h en yl)-5H,14H-p yr r olo[1′′,2′′:4′,5′]-
p yr a zin o[1′,2′:1,6]p yr id o[3,4-b]in d ole-5,14-d ion e (tr a n s-
6c): yield 100% from trans-11c; white solid; mp 270 °C; IR
νmax (KBr) 3320, 1657, 1595, 1516, 1459 cm-1 1H NMR
;
(DMSO-d6) δ 10.91 (br s, 1H), 8.49 (br s, 1H), 7.51 (d, 1H, J )
7.8 Hz), 7.30 (d, 1H, J ) 8.0 Hz), 7.09 (t, 1H, J ) 7.5 Hz), 7.01
(t, 1H, J ) 7.4 Hz), 6.76 (s, 1H, Ar-CHN), 6.50 (s, 2H, ArH),
4.48 (dd, 1H, J ) 10.7, 4.7 Hz), 4.20 (dd, 1H, J ) 10.4, 6.0
Hz), 3.68 (overlapped, 1H), 3.66 (s, 6H, 2×OCH3), 3.47 (dd,
1H, J ) 15.7, 4.6 Hz), 3.28 (overlapped, 1H), 2.87 (dd, 1H, J )
15.6, 10.9 Hz), 2.23 (m, 1H), 1.90-1.80 (m, 3H); 13C NMR
(DMSO-d6) δ 164.9, 163.6, 147.8, 136.4, 135.8, 130.9, 129.9,
125.8 (s), 121.4 (d), 118.6 (d), 118.0 (d), 111.2 (s), 106.5 (s),
105.7 (d), 58.5 (d), 56.0 (q), 53.1 (d), 52.0 (d), 44.5 (t), 29.2 (t),
27.1 (t), 21.1 (t); 1H-13C HMQC (DMSO-d6) δH (δC) 6.76 (52.3),
4.48 (53.3); MS (ESI) m/ z calcd for M + H 448.2, found 448.0.
Anal. (C25H25N3O5‚1/5H2O) C, H, N.
[5a S,12S,14a S]-1,2,3,5a ,6,11,12,14a -Octa h yd r o-12-(3,4,5-
tr im eth oxyp h en yl)-5H,14H-p yr r olo[1′′,2′′:4′,5′]p yr a zin o-
[1′,2′:1,6]p yr id o[3,4-b]in d ole-5,14-d ion e (cis-6d ): yield 94%
from cis-11d ; white solid; mp >270 °C; [R]25 ) -36.9 (c 0.20,
D
MeOH); IR νmax (KBr) 3312, 1656, 1593, 1507, 1456, 1418 cm-1
;
1H NMR (DMSO-d6) δ 11.32 (br s, 1H, NH), 7.54 (d, 1H, J )
7.8 Hz), 7.36 (d, 1H, J ) 7.9 Hz), 7.08 (t, 1H, J ) 7.5 Hz), 7.00
(t, 1H, J ) 7.4 Hz), 6.56 (s, 2H, ArH), 6.33 (s, 1H, Ar-CHN),
4.59 (dd, 1H, J ) 11.4, 5.5 Hz, Trp-CHN), 4.41 (t, 1H, J ) 7.8
Hz, Pro-CHN), 3.69 (s, 6H, 2×OCH3), 3.56 (s, 3H, OCH3), 3.51
(m, 2H, Pro-NCH2), 3.45-3.40 (overlapped, 1H, Trp-CH2), 3.02
(dd, 1H, J ) 15.7, 11.7 Hz, Trp-CH2), 2.22 (m, 1H), 2.02 (m,
1H), 1.92-1.84 (m, 2H); 13C NMR δ 170.6, 166.4, 153.3, 137.6,
137.1, 136.7, 133.3, 126.0 (s), 122.1, 119.7, 118.4, 111.7 (d),
105.1 (s), 103.5 (d), 60.8 (q), 59.5 (Pro-CHN), 57.3 (Trp-CHN),
1
56.1 (2×OCH3), 56.1 (ArCHN), 45.6, 28.6, 23.3, 22.0 (t); H-
13C HMQC (DMSO-d6) δH (δC) 6.33 (54.0), 4.59 (55.9); NOE
(DMSO-d6) δ 6.33 (4.59, 4.41, 6.56), 4.59 (6.33, 4.41); MS (EI)
m/ z (relative intensity %) 461 (M+, 88), 278 (100). Anal.
(C26H27N3O5) C, H, N.
[5a S,12R,14a S]-1,2,3,5a ,6,11,12,14a -Octa h yd r o-12-p h en -
yl-5H,14H-p yr r olo[1′′,2′′:4′,5′]p yr a zin o[1′,2′:1,6]p yr id o[3,4-
b]in d ole-5,14-d ion e (tr a n s-6b): yield 89% from trans-11b;
white solid; mp >250 °C dec; [R]22 ) -18.9 (c 0.016, MeOH);
D
IR νmax (KBr) 3345, 1657, 1627, 1424 cm-1; H NMR (DMSO-
[5a S,12R,14a S]-1,2,3,5a ,6,11,12,14a -Octa h ydr o-12-(3,4,5-
tr im eth oxyp h en yl)-5H,14H-p yr r olo[1′′,2′′:4′,5′]p yr a zin o-
[1′,2′:1,6]p yr id o[3,4-b]in d ole-5,14-d ion e (tr a n s-6d ): yield
1
d6) δ 10.97 (br s, 1H, NH), 7.52 (d, 1H, J ) 7.7 Hz), 7.37-7.27
(m, 6H), 7.09 (td, 1H, J ) 7.6, 1.1 Hz), 7.02 (td, 1H, J ) 7.4,
0.9 Hz), 6.88 (s, 1H), 4.38 (dd, 1H, J ) 10.3, 4.6 Hz, Trp-CHN),
4.20 (dd, 1H, J ) 9.0, 6.2 Hz, Pro-CHN), 3.69 (dt, 1H, Pro-
NCH2), 3.44 (dd, 1H, J ) 15.8, 4.9 Hz, Trp-CH2), 3.34-3.26
(overlapped, 1H, Pro-NCH2), 2.92 (dd, 1H, J ) 15.3, 11.2 Hz,
Trp-CH2), 2.24 (m, 1H), 1.91-1.77 (m, 3H); 13C NMR (DMSO-
d6) δ 165.0, 163.4, 139.7, 136.3, 130.5 (s), 128.5, 128.0, 127.8
(d), 125.8 (s), 121.4 (d), 118.7, 118.0, 111.2 (d), 106.5 (s), 58.5
(Pro-CHN), 53.0 (Trp-CHN), 51.6 (PhCHN), 44.5, 29.1, 26.9,
21.0 (t); MS (ESI) m/ z calcd for M + H 372.2, found 372.1.
Anal. (C23H21N3O2‚4H2O) C, N; H: calcd, 6.59; found, 5.27.
HPLC purity (retention time): solvent system A, 100.0% (13.29
min); solvent system B, 97.6% (15.86 min).
89% from trans-11d ; white solid; mp 158-160 °C; [R]25
)
D
-238 (c 0.24, MeOH); IR νmax (KBr) 3311, 1654, 1591, 1506,
1457, 1327 cm-1; 1H NMR (DMSO-d6) δ 10.88 (br s, 1H), 7.52
(d, 1H, J ) 7.7 Hz), 7.31 (d, 1H, J ) 8.0 Hz), 7.09 (td, 1H, J )
7.5, 1.1 Hz), 7.01 (td, 1H, J ) 7.4, 0.9 Hz), 6.74 (br s, 1H, Ar-
CHN), 6.57 (br s, 2H, ArH), 4.56 (dd, 1H, J ) 10.6, 4.7 Hz,
Trp-CHN), 4.24 (dd, 1H, J ) 8.7, 6.4 Hz, Pro-CHN), 3.70 (s,
6H, OMe×2), 3.67 (overlapped, 1H, Pro-NCH2), 3.63 (s, 3H,
OMe), 3.48 (dd, 1H, J ) 15.8, 4.9 Hz, Trp-CH2), 3.30 (over-
lapped, 1H, Pro-NCH2), 2.89 (dd, 1H, J ) 15.8, 10.7 Hz), 2.23
(m, 1H), 1.93-1.80 (m, 3H); 13C NMR δ 164.6, 164.3, 153.2,
138.0, 136.7, 134.9, 129.7, 126.2, 122.5, 119.8, 118.5, 111.2,
108.6, 105.7, 60.7, 59.4, 56.1, 53.8, 52.6, 45.0, 30.2, 28.7, 21.5;
1H-13C HMQC (DMSO-d6) δH (δC) 6.74 (52.3), 4.56 (53.7); NOE
(DMSO-d6) no NOE between δ 6.74 and 4.56 was observed;
MS (EI) m/ z (relative intensity %) 461 (M+, 100). Anal.
(C26H27N3O5‚H2O) C, H, N.
[5a S,12S,14a S]-1,2,3,5a ,6,11,12,14a -Octa h yd r o-12-(4-h y-
d r oxy-3,5-d im eth oxyp h en yl)-5H,14H-p yr r olo[1′′,2′′:4′,5′]-
p yr a zin o[1′,2′:1,6]p yr id o[3,4-b]in d ole-5,14-d ion e (cis-6c):
yield 100% from crude cis-11c; white solid; mp 261 °C dec; IR
νmax (KBr) 3256, 1671, 1656, 1516, 1460 cm-1 1H NMR
;
(DMSO-d6) δ 11.28 (br s, 1H), 8.28 (s, 1H), 7.54 (d, 1H, J )
7.7 Hz), 7.35 (d, 1H, J ) 8.0 Hz), 7.07 (td, 1H, J ) 7.1, 1.0
Hz), 7.00 (td, 1H, J ) 7.2, 0.6 Hz), 6.49 (s, 2H, ArH), 6.31 (s,
1H, Ar-CHN), 4.56 (dd, 1H, J ) 11.5, 5.5 Hz, Trp-CHN), 4.39
(t, 1H, J ) 7.8 Hz, Pro-CHN), 3.66 (s, 6H, 2×OCH3), 3.53-
3.45 (m, 2H), 3.40 (dd, 1H, J ) 15.8, 5.7 Hz, Trp-CH2), 3.01
(dd, 1H, J ) 15.7, 11.7 Hz, Trp-CH2), 2.21 (m, 1H), 2.01 (m,
1H), 1.87 (m, 2H); 13C NMR (DMSO-d6) δ 169.5 (s), 165.8 (s),-
147.7 (s), 135.7, 134.3, 134.1, 132.5, 125.6 (s), 121.0 (d), 118.8
(d), 118.0 (d), 111.3 (s), 103.9 (s), 102.6 (d), 58.4, 55.8 (d), 55.8
[6S,12a S]-2,3,6,7,12,12a -H exa h yd r o-6-(4-h yd r oxy-3,5-
d im eth oxyp h en yl)p yr a zin o[1′,2′:1,6]p yr id o[3,4-b]in d ole-
1,4-d ion e (cis-15c): yield 94% from crude cis-14c in two steps;
white solid; mp 227-229 °C; IR νmax (KBr) 1668, 1616, 1517,
1462, 1427, 1322, 1217, 1113 cm-1; 1H NMR (DMSO-d6) δ 11.17
(br s, 1H), 8.43 (d, 1H, J ) 4.2 Hz, Gly-NH), 8.27 (s, 1H), 7.53
(d, 1H, J ) 7.6 Hz), 7.33 (d, 1H, J ) 7.8 Hz), 7.06 (t, 1H, J )
7.3 Hz), 6.99 (t, 1H, J ) 7.2 Hz), 6.57 (s, 2H, ArH), 6.20 (s,
1H, Ar-CHN), 4.42 (dd, 1H, J ) 11.5, 4.9 Hz, Trp-CHN), 4.06
(d, 1H, J ) 16.8 Hz), 3.73 (dd, 1H, J ) 17.0, 4.5 Hz), 3.69 (s,