94 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Eich et al.
was stirred for 0.5 h, and a solution of 2-butenolide (0.71 mL,
10 mmol) dissolved in dry THF (2 mL) was added. The
reaction mixture was stirred for a further 2.5 h at -78 °C and
then treated dropwise with a solution of 3-(benzyloxy)benzyl
bromide (2.8 g, 10 mmol) and HMPA (1.8 mL, 10 mmol) in
dry THF (5 mL). The reaction mixture was allowed to warm
to room temperature overnight, an then the reaction was
quenched with water. The mixture was extracted with EtOAc,
and the EtOAc, and the extracts were washed with water and
dried over Na2SO4. Evaporation of the solvent left a gum
which was purified by column chromatography (silica gel,
cyclohexane-EtOAc, 95:5) to give 36 as crystals after crystal-
lization from acetone-diisopropyl ether (3.0 g, 58%, mp 125
°C): 1H NMR (CDCl3) δ 6.63-7.46 (12 ArH, m), 6.00 (1 H, s,
OCH2O), 5.98 (1 H, s, OCH2O), 5.00 (2 H, s, PhCH2O), 4.58 (1
H, dd, J ) 10.0, 5.0 Hz), 3.88 (1 H, dd, J ) 10.0, 8.6 Hz), 3.14
(1 H, m), 2.95 (1 H, dd, J ) 14.0, 6.0 Hz), 2.60-2.75 (6 H, m),
1.93 (2 H, m); HRMS m/ z calcd for C29H28O5S2 (M+) 520.1378,
obsd 520.1375. Anal. (C29H28O5S2) C, H.
(()-2-Ben zyl-3-[r,r-(1,3-dith iopr opylen e)-3,4-dim eth ox-
yben zyl]bu tyr ola cton e (30): crystals from acetone; mp 101
°C; 1H NMR (CDCl3) δ 7.49 (1 H, dd, J ) 8.5, 2.3 Hz), 7.36 (1
H, d, J ) 2.3 Hz), 7.21 (3 H, m), 6.95 (2 H, m), 6.87 (1 H, d, J
) 8.5 Hz), 4.59 (1 H, dd, J ) 10.0, 5.0 Hz), 3.93 (3 H, s, OCH3),
3.87 (1 H, t, overlapping), 3.84 (3 H, s, OCH3), 3.19 (1 H, m),
2.98 (1 H, dd, J ) 14.0, 6.0 Hz), 2.61-2.74 (5 H, m), 2.53 (1 H,
dd, J ) 14.0, 6.0 Hz), 1.92 (2 H, m); HRMS m/ z calcd for
C23H26O4S2 (M+) 430.1273, obsd 430.1272. Anal. (C23H26O4S2)
C, H.
(()-2-[4′-(Ben zyloxy)b en zyl]-3-[r,r-(1,3-d it h iop r op y-
len e)-3′′,4′′-d im eth oxyben zyl]bu tyr ola cton e (31): crystals
from acetone; mp 68 °C; 1H NMR (CDCl3) δ 6.79-7.50 (12 ArH,
m), 5.03 (2 H, s, PhCH2O), 4.58 (1 H, dd, J ) 10.0, 5.0 Hz),
3.92 (3 H, s, OCH3), 3.87 (1 H, t, overlapping), 3.85 (3 H, s,
OCH3), 3.14 (1 H, m), 2.94 (1 H, dd, J ) 14.0, 5.5 Hz), 2.62-
2.75 (5 H, m), 2.44 (1 H, dd, J ) 14.0, 5.5 Hz), 1.92 (2 H, m);
HRMS m/ z calcd for C30H32O5S2 (M+) 536.1691, obsd 536.1696.
Anal. (C30H32O5S2‚0.5H2O) C, H.
(()-2-[3′,4′,′5-Tr is(ben zyloxy)ben zyl]-3-[r,r-(1,3-d ith io-
p r op ylen e)-3′′,4′′-d im eth oxyben zyl]bu tyr ola cton e (33):
1H NMR (CDCl3) δ 7.24-7.45 (17 ArH, m), 6.83 (1 H, d, J )
8.5 Hz), 6.29 (2 H, s), 5.02 (6 H, s, 3 PhCH2O), 4.53 (1 H, dd,
J ) 9.8, 5.4 Hz), 3.86 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 3.77
(1 H, t, J ) 9.3 Hz), 3.13 (1 H, m), 2.93 (1 H, dd, J ) 14.0, 5.0
Hz), 2.67 (5 H, m), 2.39 (1 H, dd, J ) 14.0, 5.5 Hz), 1.93 (2 H,
m); HRMS m/ z calcd for C44H44O7S2 (M+) 748.2528, obsd
748.2521. Anal. (C44H44O7S2) C, H.
dd, J ) 9.0, 7.0 Hz, H-4b), 3.85 (1 H, dd, J ) 9.0, 7.5 Hz, H-4a),
3.01 (1 H, dd, J ) 14.0, 5.0 Hz, H-7′b), 2.89 (1 H, dd, J ) 14.0,
7.0 Hz, H-7′a) 2.58 (2 H, m, H-2, H-7′′b), 2.47 (2 H, H-3, H-7′′a);
HRMS m/ z calcd for C19H18O5 (M+) 326.1154, obsd 326.1158.
(()-tr a n s-2-Ben zyl-3-(3,4-d im eth oxyben zyl)bu tyr ola c-
1
ton e (37): H NMR (CDCl3) δ 7.16-7.33 (5 ArH, m), 6.76 (1
H, d, J ) 8.0 Hz, H-5′′), 6.56 (1 H, dd, J ) 8.0, 1.9 Hz, H-6′′),
6.44 (1 H, d, J ) 1.9 Hz, H-2′′), 4.12 (1 H, dd, J ) 9.2, 6.8 Hz,
H-4b), 3.88 (1 H, m, overlapping, H-4a), 3.86 (3 H, s, OCH3),
3.81 (3 H, s, OCH3), 3.09 (1 H, dd, J ) 14.0, 5.0 Hz, H-7′b),
2.94 (1 H, dd, J ) 14.0, 7.0 Hz, H-7′a), 2.58 (2 H, H-2, H-7′′b),
2.49 (2 H, m, H-3, H-7′′a); HRMS m/ z calcd for C20H22O4 (M+)
326.1518, obsd 326.1515.
(()-tr a n s-2-(4′-Hyd r oxyben zyl)-3-(3′′,4′′-d im eth oxyben -
zyl)bu tyr ola cton e (38): 1H NMR (CDCl3) δ 7.01 (2 H, d, J )
8.5 Hz, H-2′, H-6′), 6.78 (1 H, d, J ) 8.0 Hz, H-5′′), 6.76 (2 H,
d, J ) 8.5 Hz, H-3′, H-5′), 6.58 (1 H, dd, J ) 8.0, 1.9 Hz, H-6′′),
6.46 (1 H, d, J ) 1.9 Hz, H-2′′), 5.22 (1 H, s, OH), 4.13 (1 H,
dd, J ) 9.0, 7.0 Hz, H-4b), 3.89 (1 H, m, overlapping, H-4a),
3.86 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 2.98 (1 H, dd, J )
14.0, 5.0 Hz, H-7′b), 2.86 (1 H, dd, J ) 14.0, 7.0 Hz, H-7′a),
2.59 (2 H, m, H-2, H-7′′b), 2.52 (2 H, m, H-3, H-7′′a); HRMS
m/ z calcd for C20H22O5 (M+) 342.1467, obsd 342.1465.
(()-tr a n s-2-(3′-Hyd r oxyben zyl)-3-(3′′,4′′-d im eth oxyben -
zyl)bu tyr ola cton e (39): 1H NMR (CDCl3) δ 7.14 (1 H, t, J )
8.0 Hz), 6.64-6.78 (4 ArH, m), 6.56 (1 H, dd, J ) 8.0, 1.8 Hz,
H-6′′), 6.48 (1 H, d, J ) 1.8 Hz, H-2′′), 5.93 (1 H, s, OH), 4.14
(1 H, dd, J ) 9.0, 7.0 Hz, H-4b), 3.88 (1 H, m, overlapping,
H-4a), 3.85 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 2.99 (1 H, dd,
J ) 14.0, 5.0 Hz, H-7′b), 2.90 (1 H, dd, J ) 14.0, 7.0 Hz, H-7′a),
2.60 (2 H, m, H-2, H-7′′b), 2.50 (2 H, m, H-3, H-7′′a); HRMS
m/ z calcd for C20H22O5 (M+) 342.1467, obsd 342.1465.
(()-tr a n s-2-(3′,4′,5′-Tr ih ydr oxyben zyl)-3-(3′′,4′′-dim eth ox-
1
yben zyl)bu tyr ola cton e (40): H NMR (DMSO-d6) δ 8.74 (2
H, s, 2 OH), 6.95 (1 H, s, OH), 6.81 (1 H, d, J ) 8.0 Hz, H-5′′),
6.63 (1 H, br s, H-2′′), 6.60 (1 H, d, J ) 8.0 Hz, H-6′′), 6.15 (2
H, br s, H-2′, H-6′), 4.00 (1 H, m, H-4b), 3.87 (1 H, m, H-4a),
3.72 (3 H, s, OCH3), 3.70 (3 H, s, OCH3), 2.66 (2 H, m, H-7′a,
H-7′b), 2.55 (2 H, m, H-2, H-7′′b), 2.41 (2 H, m, H-3, H-7′′a);
HRMS m/ z calcd for C20H22O7 (M+) 374.1366, obsd 374.1362.
(()-tr a n s-2-Ben zyl-3-[3,3-(m eth ylen d ioxy)ben zyl]bu ty-
r ola cton e (41): 1H NMR (CDCl3) δ 7.30-7.42 (5 ArH, m), 6.77
(1 H, d, J ) 8.2 Hz, H-5′′), 6.50 (2 ArH, m), 6.77 (1 H, d, J )
8.2 Hz, H-5′′), 6.50 (2 ArH, m), 5.93 (2 H, s, OCH2O), 4.09 (1
H, dd, J ) 9.0, 6.85 Hz, H-4b), 3.92 (1 H, dd, J ) 9.9, 7.3 Hz,
H-4a), 3.20 (1 H, dd, J ) 14.0, 5.0 Hz, H-7′b), 2.98 (1 H, dd, J
) 14.0, 7.0 Hz, H-7′a), 2.57 (2 H, m, H-2, H-7′′b), 2.43 (2 H, m,
H-3, H-7′′a); HRMS m/ z calcd for C19H18O4 (M+) 310.1205,
obsd 310.1205.
(()-2-Ben zyl-3-[r,r-(1,3d it h iop r op ylen e)-3,4-(m et h yl-
en ed ioxy)ben zyl]bu tyr ola cton e (34): crystals from acetone;
mp 178 °C; 1H NMR (CDCl3) δ 7.44 (1 H, dd, J ) 8.2, 2.0 Hz),
7.36 (1 H, d, J ) 2.0 Hz), 7.0-7.26 (5 ArH, m), 6.82 (1 H, d, J
) 8.2 Hz), 6.02 (2 H, s, OCH2O), 4.53 (1 H, dd, J ) 10.0, 5.0
Hz), 3.82 (1 H, dd, J ) 10.0, 9.0 Hz), 3.18 (1 H, m), 3.00 (1 H,
dd, J ) 14.0, 6.0 Hz), 2.61-2.72 (6 H, m), 1.93 (2 H, m); HRMS
m/ z calcd for C22H22O4S2 (M+) 414.0960, obsd 414.0968. Anal.
(C22H22O4S2) C, H.
(()-tr a n s-2-(4′-Hydr oxyben zyl)-3-[3′′,4′′-(m eth ylen dioxy)-
ben zyl]bu tyr ola cton e (42): 1H NMR (CDCl3) δ 7.04 (2 H, d,
J ) 8.4 Hz, H-2′, H-6′), 6.76 (2 H, d, J ) 8.4 Hz, H-3′, H-5′),
6.72 (1 H, d, J ) 8.3 Hz, H-5′′), 6.48 (2 H, m), 5.94 (2 H, s,
OCH2O), 5.06 (1 H, s, OH), 4.09 (1 H, dd, J ) 9.0, 7.0 Hz, H-4b),
3.85 (1 H, dd, J ) 7.0 Hz, H-4a), 3.00 (1 H, dd, J ) 14.0, 5.0
Hz, H-7′b), 2.89 (1 H, dd, J ) 14.0, 7.0 Hz, H-7′a), 2.57 (2 H,
m, H-2, H-7′′b), 2.45 (2 H, m, H-3, H-7′′a): HRMS m/ z calcd
for C19H18O5 (M+) 326.1154, obsd 326.1151.
(()-2-[4′-(Ben zyloxy)-3′-m eth oxyben zyl]-3-[r,r-(1,3-dith i-
opr opylen e)-3′′,4′′-dim eth oxyben zyl]cyclopen tan on e (44).
Dithiane 44 was prepared by the method described for
compounds 30-36 using 2-cyclopentenone instead of
2-butenolide: HRMS m/ z calcd for C32H36O5S2 (M+) 564.2004,
obsd 564.2007.
(()-tr a n s-2-(4′-H yd r oxy-3′-m e t h oxyb e n zyl)-3-(3′′,4′′-
d im eth oxyben zyl)cyclop en ta n on e (45). 45 was prepared
from 44 by the method described for compounds 37-43: 1H
NMR (DMSO-d6) δ 8.75 (1 H, s, OH, D2O exchangeable), 6.53-
6.84 (6 ArH, m), 3.69 (9 H, br s, 3 OCH3), 2.76 (2 H, m), 2.67
(1 H, dd, J ) 13.0, 4.0 Hz), 2.32 (2 H, m), 2.16 (1 H, m), 1.82-
1.97 (3 H, m), 1.44 (1 H, m); 13C NMR (DMSO-d6, 75.50 MHz)
δ 219.38 (C-1), 54.94 (C-2), 42.12 (C-3), 26.20 (C-4), 40.26 (C-
5), 37.23 (C-7′), 32.99 (C-7′′), 132.49 (C-1′), 112.60 (C-2′), 144.68
(C-3′), 146.97 (C-4′), 115.11 (C-5′), 121.35 (C-6′), 130.09 (C-
1′′), 113.24 (C-2′′), 147.22 (C-3′′), 148.41 (C-4′′), 111.68 (C-5′′),
120.55 (C-6′′), 55.24 (OCH3), 55.39 (OCH3), 55.42 (OCH3);
HRMS m/ z calcd for C22H26O5 (M+) 370.1780, obsd 370.1786.
(()-2-[4′-(Ben zyloxy)b en zyl]-3-[r,r-(1,3-d it h iop r op y-
len e)-3′′,4′′-(m eth ylen ed ioxy)ben zyl]bu tyr ola cton e (35):
1
crystals froma acetone; mp 132 °C; H NMR (CDCl3) δ 6.87-
7.43 (12 ArH, m), 6.01 (1 H, s, OCH2O), 5.98 (1 H, s, OCH2O),
5.02 (2 H, s, PhCH2O), 4.56 (1 H, dd, J ) 10.0, 5.0 Hz), 3.85 (1
H, t, J ) 10.0 Hz), 3.11 (1 H, m), 2.92 (1 H, dd, J ) 14.0, 6.0
Hz), 2.54-2.76 (6 H, m), 1.93 (2 H, m); HRMS m/ z calcd for
C29H28O5S2 (M+) 520.1378, obsd 520.1372. Anal. (C29H28O5S2)
C, H.
Gen er a l P r oced u r e for th e P r ep a r a tion of Hyd r oxy-
lated tr a n s-2,3-Diben zylbu tyr olacton es 37-43. (()-tr a n s-
2-(3′-Hyd r oxyben zyl)-3-[3′′,4′′-(m eth ylen ed ioxy)ben zyl]-
bu tyr ola cton e (43). 36 (2.5 g, 4.8 mmol) was heated with a
suspension of W-2 Raney nickel (25 g) in ethanol for 2 h. The
catalyzator was removed by filtration and the solution evapo-
rated to dryness. The crude product was purified by thin-layer
chromatography (silica gel 60 PF254 with CaSO4, CH2Cl2:
cyclohexane:CH3OH, 100:20:2) using the technique of radial
development (Chromatotron) to give 43 as a gum (1.41 g,
90%): 1H NMR (CDCl3) δ 7.17 (1 H, t, J ) 7.8 Hz), 6.47-6.75
(6 ArH, m), 5.93 (2 H, s, OCH2O), 5.65 (1 H, s, OH), 4.10 (1 H,