2282 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Ashwood et al.
7.25-7.34 (10H, m, arom), 7.59 (1H, d, arom, J ) 8.0 Hz); νmax
1717, 1483, 1412, 1335, 1274, 751 cm-1; m/z 557 (MH+, 100%);
[R]D +9.6° (c ) 0.75, MeOH). Anal. (C32H32N2O7) C, H, N.
(2H, dd, CH2O, J ) 12.0, 14.8 Hz), 5.75 (2H, m, dCH, NH),
7.14 (1H, t, arom, J ) 8.0 Hz), 7.28-7.47 (13H, m, arom), 8.15
(1H, bd, arom, J ) 6.4 Hz); νmax 3418, 3352, 1736, 1501, 1456,
20
1399, 1250, 1087, 749 cm-1; m/z 557 (MH+, 100%); [R]D
20
(2S,3aS,8aR)-2-Dim eth ylam in om eth yl-2,3,3a,8a-tetr ah y-
d r o-p yr r olo[2,3-b]in d ole-1,2,8-tr ica r boxylic Acid 2-Allyl
Ester 1,8-Diben zyl Ester (6e). Procedure as for the prepara-
tion of compound 6a to give a clear oil (1.90, 76%): δH 2.23
(6H, s, 2 × CH3), 2.40 (1H, d, IndCHH, J ) 13.2 Hz), 2.66
(1H, d, CHHN, J ) 14.4 Hz); 3.00 (1H, dd, IndCHH, J ) 8.2,
13.4 Hz), 3.29 (1H, bs, CHHN), 3.69 (1H, dddd, OCHH, J )
1.6, 2.9, 5.8, 13.3 Hz), 3.94 (1H, t, CH, J ) 7.0 Hz), 4.11 (1H,
bs, CHHN), 4.93-5.33 (7H, m, 2 × CH2O, dCH, dCH2), 6.40
(1H, d, CH, J ) 6.4 Hz), 6.99 (1H, t, arom, J ) 7.4 Hz), 7.06
(1H, d, arom, J ) 7.6 Hz), 7.18 (1H, t, arom, J ) 7.6 Hz), 7.26-
7.37 (10H, m, arom), 7.58 (1H, bs, arom); νmax 2947, 1717, 1483,
1412, 1331, 1267, 1043, 1020, 750 cm-1; HRMS for C33H36N3O6
+13.0° (c ) 0.67, MeOH).
3-((S)-Allyloxyca r bon yl-ben zyloxyca r bon yla m in o-(d i-
m eth yla m in o)-p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl
Ester (7e). A solution of compound 6 (5.82 g, 10.2 mmol) in
methanol (20 mL) was treated with a mixture of cH2SO4/H2O
(23/18 mL), and the resultant mixture was stirred at room
temperature for 24 h. This solution was added dropwise to a
mixture of saturated NaHCO3 and ice, the product was
extracted with EtOAc, and the organics were washed with
saturated NaHCO3 and brine and dried (MgSO4). The material
was purified by chromatography (10-25% EtOAc in heptane)
to give a straw colored gum (3.46 g, 59%): δH 2.26 (6H, s, 2 ×
CH3), 2.83 (1H, d, CHHN, J ) 13.6 Hz), 3.23 (1H, d, IndCHH,
J ) 14.4 Hz), 3.32 (1H, d, CHHN, J ) 13.6 Hz), 3.64 (1H, dd,
IndCHH, J ) 14.4 Hz), 4.49 (1H, d, CHHO, J ) 13.2 Hz), 4.59
(1H, d, CHHO, J ) 6.0 Hz), 5.08 (2H, dd, CH2O, J ) 12.4,
27.6 Hz), 5.23 (1H, d, dCHH, J ) 10.4 Hz), 5.34 (1H, d, d
CHH, J ) 14.4 Hz), 5.41 (2H, s, CH2O), 5.85 (1H, m, dCH),
6.00 (1H, s, NH), 7.14 (2H, m, arom), 7.25-7.48 (12 H, m,
arom), 8.15 (1H, bd, arom, J ) 6.4 Hz); νmax 3418, 1736, 1456,
19
requires 570.2604, found 570.2604 (MH+, 100%); [R]D -0.4°
(c ) 0.49, MeOH).
3-((R)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
bu tyl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (7a ). TFA
(2 mL) was added to a solution of compound 6a (1.66 g, 3.07
mmol) in dichloromethane (10 mL), and the resulting solution
was stirred at room temperature for 24 h. The solvent was
removed, and the residue was diluted with EtOAc, the organics
were washed with saturated NaHCO3 and brine and dried
(MgSO4). The product was purified by chromatography (15%
EtOAc in heptane) to yield a clear gum (1.14 g, 69%): δH 0.82
(3H, t, CH2CH3, J ) 7.4 Hz), 1.99, 2.60 (2H, 2 × m, CH2CH3),
3.23 (1H, d, IndCHH, J ) 10.4 Hz), 3.74 (2H, d, IndCHH, J )
10.4 Hz), 4.46 (1H, d, OCHH, J ) 6.0 Hz), 4.57 (1H, d, CHHO,
J ) 12.8 Hz), 5.09 (2H, dd, CH2O, J ) 12.4, 18.4 Hz), 5.21
(1H, d, dCHH, J ) 14.4 Hz), 5.30 (1H, d, dCHH, J ) 10.4
Hz), 5.41 (2H, dd, CHHO, J ) 12.4, 16.8 Hz), 5.74 (1H, s, NH),
5.80 (1H, m, dCH), 7.11 (1H, t, arom, J ) 7.6 Hz), 7.25-7.47
(13H, m, arom), 8.17 (1H, bd, arom, J ) 5.6 Hz); νmax 3419,
1736, 1500, 14456, 1399, 1250, 1085 cm-1; HRMS for C32H33N2-
O6 requires 541.234, found 541.234 (MH+, 100%); [R]D20 +8.1°
(c ) 0.57, MeOH).
3-((R)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
p en t-4-en yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (7b).
Procedure as for the preparation of compound 7a to give an
oil (0.48 g, 92%): δΗ 2.66-2.72 (1H, m, CHHCd), 3.26 (1H, d,
CHHind, J ) 14.4 Hz), 3.27-3.35 (1H, m, CHHCd), 3.77 (1H,
d, CHHind, J ) 14.4 Hz), 4.43-4.48 (1H, m, OCHH), 4.55 (1H,
dd, OCHH, J ) 5.7, 13.1 Hz), 5.03-5.12 (4H, m, OCH2, dCH2),
5.20 (1H, d, dCH, J ) 10.3 Hz), 5.29 (1H, d, dCHH, J ) 17.1
Hz), 5.37-45 (2H, m, CH2Ph), 5.57-5.67 (1H, m, dCH), 5.72
(1H, s, NH), 7.12 (1H, t, arom, J ) 7.6 Hz) 7.26-7.48 (13H,
m, arom), 8.12 (1H, bd, arom, J ) 4.9 Hz); νmax 3416, 1736,
1455, 1249, 1083, 748 cm-1; MS (ES+) 575.29 (M+ + Na, 63%),
553.32 (M+ + H, 100%).
3-((R)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
4-m eth yl-p en t-4-en yl)-in d ole-1-ca r boxylic Acid Ben zyl
Ester (7c). Procedure as for the preparation of compound 7a
to give an oil (0.33 g, 79%): δΗ 1.63 (3H, s, CH3), 2.70 (1H, d,
CHHCdC, J ) 13.9 Hz), 3.23 (1H, d, CHHind, J ) 14.4 Hz),
3.41 (1H, d, CHHCdC, J ) 13.8 Hz), 3.87 (1H, d, CHHind, J
) 14.4 Hz), 4.41-4.53 (2H, m, OCH2), 4.70 (1H, s, CHHdC),
4.80 (1H, s, CHHdC), 5.02 (1H, d, CHHPh, J ) 12.2 Hz), 5.11
(1H, d, CHHPh, J ) 12.2 Hz), 5.30 (1H, d, dCHH, J ) 17.7
Hz), 5.41 (2H, dd, CH2Ph, J ) 12.2, 15.9 Hz), 5.78-5.86 (2H,
m, NH, dCH), 7.12 (1H, t, arom, J ) 7.4 Hz) 7.25-7.49 (13H,
m, arom), 8.13 (1H, bs, arom); νmax 3418, 2946, 1722, 1498,
1455, 1398, 1358, 1249, 1083, 1048, 747 cm-1; MS (ES+) 589
(M+ + Na, 100%), 567 (M+ + H, 43%).
1248, 1084, 1037, 748 cm-1; m/z 570 (MH+, 100%); [R]D
-12.6° (c ) 0.27, MeOH).
19
3-((R)-2-Ben zyloxyca r bon yla m in o-2-ca r boxy-bu tyl)-in -
d ole-1-ca r b oxylic Acid Ben zyl E st er (8a ). Tetrakis(tri-
phenylphosphine)palladium (0) (50 mg, 43 µmol) was added
to a solution of compound 7a (1.14 g, 2.11 mmol) in THF (10
mL). After 5 min, morpholine (1.84 g, 21.1 mmol) was added,
and the mixture stirred at room temperature for 30 min.
EtOAc was added, and the organics were washed with 10%
HCl and brine and dried (MgSO4). After removal of the solvent
in vacuo, a clear glass was obtained (1.01 g, 95%): δH 0.86
(3H, t, CH2CH3, J ) 7.6 Hz), 1.99 (1H, m, CHHCH3), 2.51 (1H,
m, CHHCH3), 3.30 (1H, d, IndCHH, J ) 14.9 Hz), 3.71 (1H, d,
IndCHH, J ) 14.4 Hz), 5.07 (2H, dd, CH2O, J ) 12.4, 19.2
Hz), 5.40 (2H, s, CH2O), 5.60 (1H, s, NH), 7.10 (1H, t, arom, J
) 7.4 Hz), 7.24-7.52 (13H, m, arom), 8.10 (1H, bs, arom); νmax
3409, 1732, 1455, 1400, 1250, 1086, 745 cm-1; HRMS for
C
29H29N2O6 requires 501.2026, found 501.2026 (MH+).
3-((R)-2-Ben zyloxyca r b on yla m in o-2-ca r b oxy-p en t -4-
en yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8b). Proce-
dure as for the preparation of compound 8a to give a solid (0.44
g, 98%): δΗ 2.67-2.73 (1H, m, CHHCHd), 3.20-3.26 (1H, m,
CHHCHd), 3.32 (1H, d, CHHInd, J ) 14.7 Hz), 3.73 (1H, d,
CHHind, J ) 14.4 Hz), 5.03-5.12 (4H, m, 2 × OCH2, 2 × d
CH2), 5.39 (2H, s, OCH2Ph), 5.61-5.68 (2H, s, NH, CHd), 7.10
(1H, t, arom, J ) 7.6 Hz), 7.23-7.65 (13H, m, arom), 8.11 (1H,
br s, arom); νmax 3405, 1731, 1455, 1399, 1249, 1084, 747 cm-1
MS (ES-) 511 (M- - H, 100%).
;
3-((R)-2-Ben zyloxyca r bon yla m in o-2-ca r boxy-4-m eth yl-
p en t-4-en yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8c).
Procedure as for the preparation of compound 8a to give a solid
(0.28 g, quantitative): δΗ 1.65 (3H, s, CH3), 2.71 (1H, d,
CHHCHd, J ) 13.7 Hz), 3.27 (1H, d, CHHind, J ) 14.9 Hz),
3.35 (1H, d, CHHCd, J ) 13.9 Hz), 3.84 (1H, d, CHHind, J )
14.9 Hz), 4.74 (1H, s, CdCHH), 4.80 (1H, s, CdCHH), 5.02
(1H, d, OCHHPh, J ) 12.2 Hz), 5.11 (1H, d, OCHHPh, J )
12.5 Hz), 5.39 (2H, s, OCH2Ph), 5.79 (1H, s, NH), 7.09 (1H, t,
arom, J ) 7.3 Hz), 7.23-7.65 (13H, m, arom), 8.11 (1H, br s,
arom); νmax 3408, 3033, 2948, 1731, 1500, 1455, 1399, 1358,
1248, 1083, 747 cm-1; MS (ES-) 526 (M-, 33%), 525 (M- - H,
100%).
3-((S)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
3-m eth oxy-p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl Es-
ter (7d ). Procedure as for the preparation of compound 6a to
give a clear oil (1.19 g, 72%): δH 3.32 (3H, s, OCH3), 3.24 (1H,
d, IndCHH, J ) 14.4 Hz), 3.60 (1H, d, IndCHH, J ) 14.4 Hz),
3.77 (1H, d, CHHO, J ) 9.2 Hz), 4.13 (1H, d, CHHO, J ) 9.2
Hz), 4.49 (1H, dd, OCHH, J ) 4.8, 12.8 Hz), 4.61 (1H, dd,
OCHH, J ) 5.2, 12.8 Hz), 5.09 (2H, s, CH2O), 5.11 (1H, d, d
CHH, J ) 10.8 Hz), 5.28 (1H, d, dCHH, J ) 17.2 Hz), 5.41
3-((S)-2-Ben zyloxycar bon ylam in o-2-car boxy-3-m eth oxy-
p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8d ). Pro-
cedure as for the preparation of 8a to give a clear glass (1.11
g, 100%): δH 3.33 (1H, d, IndCHH, J ) 14.7 Hz), 3.37 (3H, s,
OCH3), 3.60 (1H, d, IndCHH, J ) 14.4 Hz), 3.84 (1H, d, CHHO,
J ) 9.3 Hz), 3.99 (1H, d, CHHO, J ) 8.8 Hz), 5.09 (2H, s,
CH2O), 5.40 (2H, s, CH2O), 5.71 (1H, s, NH), 7.14 (1H, t, arom,
J ) 7.6 Hz), 7.27-7.52 (13H, m, arom), 8.18 (1H, dd, arom, J
) 6.8 Hz); νmax 3411, 1732, 1456, 1399, 1250, 1086, 748 cm-1
.