1204
K. C. Nicolaou et al./Bioorg. Med. Chem. 6 (1998) 1185±1208
J=1.5, 7.0, 7.0 Hz, 1H, naphthyl), 7.12 (d, J=9.0 Hz,
1H, Ar), 6.69 (t, J=5.5 Hz, 1H, CH2NH(C=O)), 5.89
(d, J=8.0 Hz, 1H, NHSO2), 4.03 (ddd, J=4.0, 8.0,
8.5 Hz, 1H, CHCH2), 3.85 (ddd, J=4.0, 6.0, 14.0 Hz,
1H, CHCHH), 3.70 (bdt, J=5.5, 5.5 Hz, 2H, NHCH2),
3.61±3.50 (m, 3H, CHCHH, CH2NH(C=N)), 1.52 (s,
9H, Bu), 1.47 (s, 9H, Bu), 1.18 (s, 9H, Bu); 13C NMR
(125 MHz, CDCl3): d 168.5, 165.6, 156.6, 153.2, 146.9,
136.0, 134.8, 134.6, 132.0, 131.3, 129.6, 129.2, 128.9,
128.6, 127.8, 127.6, 126.0, 122.2, 120.8, 114.3, 83.8, 83.6,
56.4, 42.4, 42.2, 39.1, 28.3, 28.0, 27.6; FAB-HRMS
(M+Cs+) calcd 932.2265, found 932.2285.
(2Âbddd, superimposed, 2H, naphthyl), 7.13 (bm, 1H,
NH(C=O)), 6.98 (d, J=9.0 Hz, 1H, Ar), 4.01 (ddd,
J=3.5, 8.0, 9.0 Hz, 1H, CHCH2), 3.88 (ddd, J=4.0, 6.0,
13.5 Hz, 1H, CHCHH), 3.73 (bm, 4H, NCH2), 3.55
(ddd, J=5.5, 8.5, 13.5 Hz, 1 H CHCHH), 3.18 (bm, 4H,
NCH2), 1.48 (s, 18 H, tBu), 1.15 (s, 9H, tBu); 13C NMR
(125 MHz, CDCl3): d 168.6, 165.1, 155.2, 147.3, 140.9,
135.6, 134.9, 132.0, 129.6, 129.2, 129.0, 128.7, 127.8,
127.7, 126.2, 126.0, 122.1, 119.8, 119.7, 83.9, 56.1, 50.3,
42.2, 28.2, 28.0, 27.3; FAB-HRMS (M+Cs+) calcd
958.2422, found 958.2458.
t
t
t
Compound 19. Compound 19 was prepared by the same
procedure as for 11. Yield (31.9 mg, 93%) as a yellowish
solid. tR=11.1 min; IR (KBr): Vmax 3401, 3297, 3251,
2996, 2928, 1659, 1613, 1523, 1451, 1385, 1323, 1199,
Compound 18. Compound 18 was prepared by the
same procedure as 11. Yield (81.7 mg, 90%) as an
orange yellow solid. tR=12.4 min; IR (KBr): Vmax
3364, 1676, 1624, 1556, 1520, 1426, 1315, 1241, 1200,
1
1157, 1138, 1078, 992, 808, 753, 720, 660, 549 cm 1; H
1158, 1133, 1076, 1025, 999, 824, 757, 719, 660, 549,
;
1H NMR (500 MHz, methanol-d4): d 8.17
NMR (500 MHz, methanol-d4): d 8.19 (bs, 1H, naph-
thyl), 7.93 (d, J=2.0 Hz, 1H, Ar), 7.76 (bd, J=9.0 Hz,
1H, naphthyl), 7.71±7.61 (m, superimposed, 3H, naph-
thyl, Ar), 7.55 (dd, J=2.0 Hz, 8.8 Hz, 1H, naphthyl),
7.44±7.36 (2Âddd, superimposed, 2H, naphthyl), 6.91
(d, J=8.5 Hz, 1H, Ar), 4.21 (dd, J=4.5, 9.5 Hz, 1H,
CHCH2), 3.61 (dd, J=4.5, 13.5 Hz, 1H, CHCHH), 3.55
(m, 4H, NCH2), 3.29 (dd, J=9.5, 13.5 Hz, 1H,
CHCHH), 3.15±3.09 (m, 4H, NCH2); 13C NMR
(125 MHz, methanol-d4): d 167.6, 158.5, 148.2, 142.1,
139.4, 136.0, 133.5, 133.3, 130.4, 130.3, 129.7, 128.9,
128.5, 127.3, 126.7, 123.6, 121.2, 50.9, 49.6, 48.6,
46.4; FAB-HRMS (M+Cs+) calcd 702.0747, found
702.0784.
1
479 cm
(bs, 1H, naphthyl), 8.14 (d, J=2.0 Hz, 1H, Ar), 7.72
(d, J=8.0 Hz, 1H, naphthyl), 7.68±7.65 (m, 2H, naph-
thyl), 7.57 (bd, superimposed, J=9.5 Hz, 1H, naph-
thyl), 7.55 (dd, superimposed, J=2.0, 9.0 Hz, 1H, Ar),
7.41 (ddd, J=1.5, 7.0, 8.0 Hz, 1H, naphthyl), 7.36
(ddd, J=1.5, 7.0, 8.0 Hz, 1H, naphthyl), 6.74 (d,
J=9.0 Hz, 1H, Ar), 4.25 (dd, J=4.5, 10.0 Hz, 1H,
CHCH2), 3.62 (dd, J=4.5, 14.0 Hz, 1H, CHCHH),
3.52 (t, J=6.0 Hz, 2H, NHCH2), 3.41 (t, J=6.0 Hz,
2H, NHCH2), 3.30 (dd, J=10.0, 14.0 Hz, 1H,
CHCHH); 13C NMR (125 MHz, methanol-d4): d 173.0,
167.8, 147.8, 139.5, 135.9, 135.3, 133.4, 130.3, 130.2,
129.3, 128.7, 128.6, 128.3, 127.2, 123.5, 121.5, 114.5,
57.0, 42.9, 42.5, 41.5; FAB-HRMS (M+Na+) calcd
566.1434, found 566.1453.
Preparation of compounds 20 and 21
Compound 67. To a solution of 57 (0.10 g, 0.20 mmol) in
DMF (8 mL) was added 55 (0.038 g, 0.22 mmol) and
triethylamine (0.06 mL, 0.44 mmol) at room tempera-
ture. After stirring at 25 ꢀC for 16 h, the reaction mix-
ture was diluted with ethyl acetate (10 mL) and water
(10 mL). The layers were seperated and the aqueous
layer was extracted with ethyl acetate (2Â10 mL). The
organic extracts were collected and washed with water
(2Â10 mL) and brine (20 mL) and dried over Na2SO4.
After ®ltration and evaporation under reduced pressure
the residue was puri®ed by ¯ash chromatography (silica,
ethyl acetate) to give 67 as a yellowish solid (110 mg,
92%). Rf=0.43 (silica, ethyl acetate); 1H NMR
(500 MHz, methanol-d4): d 8.57 (d, J=2.0 Hz, 1H, Ar),
7.96 (bm, 1H, Ar), 7.83 (dd, J=2.0, 9.0 Hz, 1H, Ar),
7.80±7.78 (m, 2H, Ar), 7.48±7.39 (m, 4H, Ar), 7.18 (dd,
J=4.0, 6.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 1H, Ar), 4.12
(dd, J=6.0, 8.0 Hz, 1H, CH2CH), 3.89 (t, J=7.0 Hz,
2H, CH2Ar), 3.65 (dd, J=6.0, 14.0 Hz, 1H, CHHCH),
3.46 (dd, J=8.0, 14.0 Hz, 1H, CHHCH), 3.26 (t,
Compound 66. To a solution of 59 (150 mg, 0.29 mmol)
in DMF (5 mL) was added 52 (190 mg, 0.58 mmol) at
room temperature. After 20 h, the reaction mixture was
diluted with water (25 mL) and ethyl acetate. After
phase seperation, the aqueous phase extracted with
ethyl acetate (3Â30 mL). The combined organic extracts
were washed succesively with water (2Â20 mL) and
brine (20 mL) and dried over MgSO4. After ®ltration
and evaporation under reduced pressure the residue was
puri®ed by ¯ash column chromatography (silica gel,
40% ethyl acetate in hexanes) to give 66 as a yellow
solid (240 mg, 99%). Rf=0.33 (silica gel, 50% ethyl
acetate in hexanes); IR (KBr): Vmax 3397, 2979, 2933,
1741, 1610, 1524, 1454, 1367, 1303, 1239, 1157, 1015,
1
975, 834, 752, 661, 615, 552, 477 cm
;
1H NMR
(500 MHz, CDCl3): d 11.49 (bs, 1H, (C=N)NH(C=O),
8.38 (bs, 1H, naphthyl), 8.24 (d, J=2.0 Hz, 1H, Ar),
7.90 (bd, J=7.5 Hz, 1H, naphthyl), 7.87 (bd, J=9.0 Hz,
1H, naphthyl), 7.83 (dd, superimposed, J=2.0, 8.5 Hz,
1H, Ar), 7.82 (d, superimposed, J=8.0 Hz, 1H, naph-
thyl), 7.79 (dd, J=2.0, 8.5 Hz, 1H, naphthyl), 7.64±7.55
t
J=7.0 Hz, 2H, CH2NH), 1.22 (s, 9H, Bu); 13C NMR
(125 MHz, methanol-d4): d 170.4, 168.1, 164.8, 153.6,