1972 J . Org. Chem., Vol. 63, No. 6, 1998
Faul et al.
4.35-4.03 (m, 4H), 3.76-3.66 (m, 1H), 3.60-3.50 (m, 1H),
3.42-3.31 (m, 1H), 3.09 (d, 2H, J ) 4.4 Hz), 2.19-1.91 (m,
2H); 13C NMR (75 MHz, DMSO-d6) δ 165.4, 143.5, 135.7, 132.5,
132.1, 132.0, 131.9, 131.8, 131.7, 131.4, 128.1, 127.9, 127.8,
127.7, 127.1, 127.0, 126.0, 125.9, 121.9, 121.4, 121.1, 120.7,
110.3, 102.2, 102.1, 86.3, 76.3, 66.0, 63.8, 45.8, 42.5, 31.5; IR
(CHCl3) ν 1752, 1527, 1490, 1471, 1449, 1393, 1360, 1321,
(ꢀ 4586), 281 nm (ꢀ 11 567), 233 nm (ꢀ 45 031), 205 nm (ꢀ
47 341); MS (FD) m/z calcd for C26H23N3O4 441, found 441
(100). Anal. Calcd for C26H23N3O4; C, 70.74; H, 5.25; N, 9.52.
Found: C, 70.91; H, 5.38; N, 9.81.
(S)-6,7,10,11-Tetr ah ydr o-9-[[(m eth ylsu lfon yl)oxy]m eth -
yl]-9H,18H-5,21:12,17-d im eth en od iben zo[e,k]p yr r olo[3,4-
h ][1,4,13]oxadiazacycloh exadecin e-18, 20(19H)-dion e (39).
To a suspension of 35 (329.5 g, 0.74 mol, 1.0 equiv) in THF
(6.6 L) was added pyridine (177 mL, 2.24 mol) and methane-
sulfonic anhydride (268 g, 1.49 mol). The reaction was heated
at reflux for 1 h and then cooled to room temperature and
diluted with THF (3 L). To the reaction solution was added 1
N HCl (3.3 L) and the mixture stirred for 15-20 min. The
layers were separated and the aqueous layer re-extracted with
EtOAc (2 L). The combined organic layers were concentrated
in vacuo until mainly water was distilling. The product 39,
which crystallized from solution, was filtered and rinsed with
deionized water. The solids were dried to afford 391 g (100%)
of 39 as a purple solid: 1H NMR (300 MHz, DMSO-d6) δ 10.96
(s, 1H), 7.84 (d, 1H, J ) 7.7 Hz), 7.69 (d, 1H, J ) 7.5 Hz), 7.50
(m, 4H), 7.20 (t, 2H, J ) 6.99 Hz, J ) 8.1 Hz), 7.12 (t, 2H, J
) 7.7 Hz), 4.41-4.37 (m, 2H), 4.28-4.11 (m, 4H), 3.95-3.86
(m, 1H), 3.68-3.57 (m, 2H), 3.17 (s, 3H), 2.19-1.92 (m, 2H);
13C NMR (75 MHz, DMSO-d6) δ 172.2, 135.6, 135.5, 132.2,
131.3, 126.6, 126.5, 121.6, 121.5, 121.3, 120.2, 120.1, 110.1,
109.9, 103.3, 103.2, 74.8, 69.1, 66.5, 45.5, 42.5, 36.4, 31.1; IR
(CHCl3) ν 3869, 3610, 3441, 3026, 2978, 1765, 1723, 1624,
1603, 1538, 1523, 1472, 1393, 1365, 1340, 1220, 1197, 1177,
1111, 1071, 1094, 994, 963 cm-1; UV (EtOH) λmax 495 nm (ꢀ
4228), 380 nm (ꢀ 4096), 281 nm (ꢀ 10 598), 232 nm (ꢀ 40 337),
206 nm (ꢀ 41 098); MS (FD) m/z calcd for C27H25N3O6S1 519,
found 519 (100). Anal. Calcd for C27H25N3O6S1 C, 62.42; H,
4.85; N, 8.09. Found C, 62.26; H 4.88; N, 7.96. [R]20D -22.40°
(c 1.0, MeOH).
1264, 1195, 1159, 1103, 1067, 1019, 915, 738, 701, 631 cm-1
;
UV (EtOH) λmax 527 nm (ꢀ 2059), 514 nm (ꢀ 2091), 393 nm (ꢀ
1906), 332 nm (ꢀ 423), 288 nm (ꢀ 4638), 229 (ꢀ 18 963), 208 (ꢀ
20 123); MS (FD) m/z alcd for C45H36N2O5 684, found 684 (100).
Anal. Calcd for C45H36N2O5: C, 78.93; H, 5.30; N, 4.09.
Found: C, 78.67; H, 5.49; N, 4.25.
(S)-6,7,10,11-Tetr ah ydr o-9-[(tr iph en ylm eth oxy)m eth yl]-
9H ,18H ,-5,21:12,17-d im et h en od ib en zo[e,k ]-p yr r olo[3,4-
h ][1,4,13]oxadiazacycloh exadecin e-18,20(19H)-dion e (34).
To a solution of 33 (47.0 g, 0.07 mol) in DMF (470 mL) was
added a premixed solution of HMDS (110.9 g, 0.69 mol, 145
mL) and MeOH (14 mL). The reaction was heated to 80 °C
and monitored by HPLC for approximately 7 h. Upon comple-
tion, the reaction was cooled to room temperature and diluted
with CH2Cl2 (470 mL). The solution was then cooled to 0-5
°C and quenched with 1 N HCl (470 mL), maintaining the
temperature at 0-5 °C. The organic layer was removed and
diluted with EtOH (470 mL). The solvent was removed until
10 volumes of the distillate remained, at which time the
product crystallized out of solution. The reaction was cooled
to 0-5 °C and stirred for 1 h. The solids were filtered and
rinsed with cold EtOH (235 mL). The product was dried to a
constant weight in a vacuum oven to afford 45.7 g (97%) of 34
as a purple solid: [R]20 -0.58° (c 0.98, MeOH): 1H NMR (300
D
MHz, DMSO-d6) δ 10.96 (s, 1H), 7.83 (d, 1H, J ) 7.4 Hz), 7.75
(d, 1H, J ) 7.7 Hz), 7.47 (d, 1H, J ) 13.6 Hz), 7.41-7.06 (m,
22H), 4.25-3.96 (m, 4H), 3.73-3.63 (m, 1H), 3.57-3.46 (m,
1H), 3.31-3.21 (m, 1H), 3.08-2.95 (m, 2H), 2.16-1.91 (m, 2H);
13C NMR (75 MHz, DMSO-d6) δ 172.2, 143.5, 135.5, 132.2,
131.4, 131.3, 131.1, 131.0, 128.1, 127.8, 126.9, 126.6, 126.5,
121.6, 121.5, 121.2, 120.0, 110.0, 109.9, 103.3, 86.3, 76.0, 66.7,
63.7, 45.7, 42.2, 31.3; IR (CHCl3) ν 1762, 1719, 1534, 1490,
1470, 1449, 1391, 1335, 1196, 1156, 1106, 1069, 1016, 988, 743,
706, 633 cm-1; UV (EtOH) λmax 494 nm (ꢀ 4277), 382 nm (ꢀ
4320), 281 nm (ꢀ 11 034), 228 nm (ꢀ 49 353), 208 nm (ꢀ 70483);
MS (FD) m/z calcd for C45H37N3O4 683, found 683 (100). Anal.
Calcd for C45H37N3O4: C, 79.04; H, 5.45; N, 6.14. Found: C,
78.99; H, 5.50; N, 6.26.
(S)-6,7,10,11-Tet r a h yd r o-9-[(d im et h yla m in o)m et h yl]-
9H,18H-5,21:12,17-d im eth en od iben zo[e,k]p yr r olo[3,4-h ]-
[1,4,13]oxa d ia za cycloh exa d ecin e-18,20(19H)-d ion e (1). A
10 gal stainless steel reactor was charged with 39 (770 g, 1.48
mol) and 18.7 L of a 2 M solution of dimethylamine (37 mol,
25 equiv) in DMF. The reactor was sealed and heated at 65
°C for 17 h. The reaction was then cooled to room temperature
and the DMF removed in vacuo to 5-7 volumes. MeOH (40
volumes) was added at 60 °C and the mixture stirred at 60 °C
for 45 min, during which time 1 crystallized out of solution as
a
red solid. The reaction was allowed to cool to room
temperature and stir overnight. The slurry was then cooled
to 0-5 °C for an additional 4 h and filtered. The product was
rinsed with 4 × 1 L of cold MeOH and dried to afford 585 g
(84%) of 1: 1H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H),
7.82 (d, 1H, J ) 4.8 Hz), 7.78 (d, 1H, J ) 4.8 Hz), 7.46-7.41
(m, 4H), 7.24-7.06 (m, 4H), 4.38-4.05 (m, 4H), 3.93-3.82 (m,
1H), 3.47-3.40 (m, 1H), 3.37 (t, 2H, J ) 7.2 Hz), 3.24 (t, 2H,
J ) 6.9 Hz), 2.47-2.32 (m, 1H), 2.23-2.09 (m, 1H), 2.00-1.88
(m, 2H), 1,0.84b (q, 2H, J ) 6.6 Hz), 1.76 (q, 2H, J ) 6.9 Hz);
13C NMR (75 MHz, DMSO-d6) δ 172.2, 136.0, 135.7, 132.0,
131.9, 131.0, 130.9, 126.6, 126.3, 121.7, 121.6, 121.5, 121.4,
120.2, 120.1, 110.0, 103.6, 74.1, 67.3, 57.3, 45.5, 43.3, 43.0, 41.7,
31.5; IR (CHCl3) ν 3440, 2976, 2947, 2870, 2827, 2776, 1763,
1720, 1536, 1521, 1470, 1391, 1364, 1337, 1098, 1045, 1016,
986 cm-1; UV (EtOH) λmax 493 nm (ꢀ 3944), 382 nm (ꢀ 3796),
282 nm (ꢀ 9946), 232 nm (ꢀ 38 382), 204 nm (ꢀ 43 887); MS
(FD) m/z calcd for C28H28N4O3 468, found 468 (100). Anal.
Calcd for C28H28N4O3: C, 71.78; H, 6.02; N, 11.96. Found: C,
71.53; H, 6.19; N, 11.72.
(S)-6,7,10,11-Tet r a h yd r o-9-(p yr r olid in om et h yl)-9H ,-
18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]-
oxa d ia za cycloh exa d ecin e-18,20(19H)-dion e (2). To a solu-
tion of 39 (1.5 g, 2.89 mmol) in 30 mL of N,N-dimethylacetamide
was added pyrrolidine (6.02 mL, 72.20 mmol, 25 equiv) and
the reaction heated at 65 °C for 17 h and then cooled to room
temperature. To the red slurry was added 12 N NaOH (0.24
mL) and the mixture stirred for 30 min. The reaction was
then extracted into CH2Cl2 (125 mL) and washed with 10%
aqueous ammonium chloride (125 mL) and 5% aqueous LiCl
solution (125 mL). The CH2Cl2 was removed in vacuo and the
(S)-6,7,10,11-Tet r a h yd r o-9-(h yd r oxym et h yl)-9H ,18H -
5,21:12,17-d im et h en od ib en zo[e,k ]p yr r olo[3,4-h ][1,4,13]-
oxa d ia za cycloh exa d ecin e-18,20(19H)-d ion e (35). A sus-
pension of 34 (40.6 g, 0.06 mol) in EtOH (400 mL) and 6 N
HCl (400 mL) was heated at reflux for 2 h. The resulting
slurry was cooled to room temperature, filtered, and rinsed
with CH2Cl2 (80 mL). The isolated 35 was reslurried in CH2Cl2
(50 mL) at room temperature for 2 h to remove residual
tritylated impurities. The solids were filtered and dried to
afford 24.86 g (95%, >98% ee)38 of 35 as a purple solid: [R]20
D
-11.26° (c 0.99, MeOH). 1H NMR (300 MHz, DMSO-d6) δ
10.96 (s, 1H), 7.84 (d, 1H, J ) 8.1 Hz), 7.80 (d, 1H, J ) 8.1
Hz), 7.52 (d, 1H, J ) 8.7 Hz), 7.51 (s, 1H), 7.45 (d, 1H, J ) 8.7
Hz), 7.43 (s, 1H), 7.24-7.07 (m, 4H), 4.40-4.28 (m, 1H), 4.26-
4.08 (m, 3H), 3.95-3.83 (m, 1H), 3.67-3.56 (m, 1H), 3.56-
3.47 (dd, 1H, J ) 11.4 Hz, J ) 4.8 Hz), 3.44-3.36 (dd, 1H, J
) 11.4 Hz, J ) 3.6 Hz), 3.36-3.26 (m, 2H), 2.16-2.03 (m, 1H),
2.03-1.89 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 172.2,
135.6, 135.5, 132.1, 131.5, 131.4, 131.4, 131.3, 131.2, 131.1,
126.5, 121.6, 121.5, 121.3, 120.0, 110.1, 109.9, 103.2, 103.0,
77.4, 66.1, 61.2, 49.5, 45.7, 42.6, 31.3; IR (CHCl3) ν 3449, 1761,
1703, 1528, 1471, 1448, 1392, 1365, 1341, 1199, 1102, 1033,
801, 749, 744 cm-1; UV (EtOH) λmax 500 nm (ꢀ 4826), 377 nm
(38) The enantiomeric excess of 35 was determined by chiral
HPLC: A 2 mg sample was placed in a 5 mL volumetric flask and
diluted with 5 mL of MeOH. Column: SS Whelk 01 (Regis Chemical
Co.). Wavelength: 233 nm. Flow rate: 0.5 mL/min. Injection volume:
20 µL. Isocratic mobile phase: MeOH. (R)-isomer tR ) 21.1 min. (S)-
isomer tR ) 22.7 min.