Synthetic study of (+)-anthramycin using ring-closing enyne metathesis and cross-metathesis

Article abstract of DOI:10.1016/j.tet.2004.07.040

Synthesis of (+)-anthramycin was examined. A pyrrolobenzodiazepine skeleton could be synthesized by reductive cyclization of pyrrolidine derivative, which was obtained by enyne metathesis. The conjugated enamide ester part of (+)-anthramycin derivative was constructed by cross-metathesis. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.07.040

Tetrahedron 60 (2004) 9649–9657
Synthetic study of (C)-anthramycin using ring-closing enyne
metathesis and cross-metathesis
*
Tsuyoshi Kitamura, Yoshihiro Sato and Miwako Mori
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 18 June 2004; revised 5 July 2004; accepted 7 July 2004
Available online 28 August 2004
Abstract—Synthesis of (C)-anthramycin was examined. A pyrrolobenzodiazepine skeleton could be synthesized by reductive cyclization
of pyrrolidine derivative, which was obtained by enyne metathesis. The conjugated enamide ester part of (C)-anthramycin derivative was
constructed by cross-metathesis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
amine with the carbobenzyloxy group gave 4. Conversion
of sulfide 4 into sulfoxide 5 by treatment with NaIO4
smoothly proceeded, and b-hydrogen elimination of the
sulfoxymethyl group of 5 gave the desired enyne 3a
(Scheme 2).
(C)-Anthramycin, which has an antitumor activity, was
isolated by Leimgruber1a,b in 1965, and the total synthesis of
anthramycin was achieved by the same group1c and later by
Stille.1d The remarkable structural feature of this skeleton is
that it possesses a pyrrolobenzodiazepine skeleton and a
dienamide group conjugated with nitrogen in a pyrrolidine
ring. Since we have been interested in the structure of the
dienamide group conjugated with nitrogen in a pyrrolidine
ring, the total synthesis of (C)-anthramycin was planned
because this structure would be constructed by ring-closing
enyne metathesis2,3 (RCM) and cross-metathesis4 (CM)
followed by isomerization of the resulting double bond
(Fig. 1).
To construct the pyrrolidine ring, enyne metathesis was
carried out. When a CH2Cl2 solution of enyne 3a and
5 mol% of first-generation of ruthenium carbene complex
6a was stirred at room temperature under ethylene gas5d for
24 h, the desired pyrrolidine derivative 7 was obtained in
76% yield (Scheme 3).
Deprotection of the benzyloxy group of 7 with TMSCl in the
presence of NaI7 followed by condensation of o-nitro-
benzoyl chloride 8a gave 2a in 76% yield. Construction of a
pyrrolobenzodiazepine skeleton was carried out by treat-
ment of 2a with zinc-acetic acid8 in CH2Cl2 and treatment
of the resultant crude product with dil. HCl in THF to give
1a in 86% yield via aniline derivative 9a. Thus, a novel
procedure for synthesis of a pyrrolobenzodiazepine skeleton
could be developed (Scheme 4).
Our retrosynthetic analysis is shown in Scheme 1. The
conjugated amide part of (C)-anthramycin should be
formed by cross-metathesis with an alkene part of the
diene moiety in pyrrolobenzodiazepine derivative 1 fol-
lowed by olefin isomerization. A pyrrolobenzodiazepine
skeleton of 1 should be constructed by reductive cyclization
of a nitro group and an ester group of pyrrolidine derivative
2, which should be obtained by enyne metathesis5 of 3. The
starting enyne 3 would be obtained from L-methionine.
Subsequently, elongation of the carbon one-unit to the
alkene part in 1a was examined by cross-metathesis. When a
CH2Cl2 solution of 1a, (Z)-1,4-diacetoxy-but-2-ene 10
(10 equiv) and 15 mol% of second-generation ruthenium
2. Construction of a pyrrolobenzodiazepine skeleton
Esterification of L-methionine followed by alkylation6 with
propargyl bromide and then protection of the secondary
Keywords: (C)-Anthramycin; Pyrrolobenzodiazepine skeleton;
Deprotection.
* Corresponding author. Tel./fax: C81-11-706-4982;
e-mail: mori@pharm.hokudai.ac.jp
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.040

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T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
Scheme 1. Retrosynthetic analysis of anthramycin.
carbene complex 6b was refluxed for 2 h, the desired cross-
metathesis product 11a was obtained in 89% yield
(Scheme 5).
Thus, the carbon framework of anthramycin was con-
structed using RCM and CM as key steps.
3. Synthetic study of anthramycin
Since a pyrrolobenzodiazepine skeleton was constructed
from L-methionine, the total synthesis of anthramycin was
examined. Deprotection of the benzyloxy group of 7
followed by condensation with 2-nitro-3-benzyloxy-4-
methyl-benzoyl chloride 8b afforded compound 2b, which
was treated in a similar manner to give 1b in high yield. The
[a]D value C334.3 of this compound indicated that an
optically active benzodiazepine derivative was produced in
these processes. Cross metathesis of 1b with 10 using 6b
smoothly proceeded to give 11b in 91% yield. Then the ally
alcohol part was converted into an ester group. Deprotection
of the acetoxy group followed by treatment with MnO2 gave
aldehyde 12, which was converted into ester 13a in the usual
manner (Scheme 6).
Scheme 2. Synthesis of substrates.
Further study of cross-metathesis was carried out to shorten
the steps. When a CH2Cl2 solution of 1b, 10 mol% of 6b and
methyl acrylate (10 equiv) was refluxed for 24 h, the
desired compound 13a was obtained in 41% yield.
Furthermore, compound 1b was treated with 6c developed
by Blechert9 at room temperature to give 13a in 63% yield
(Scheme 7).
Scheme 3. Synthesis of a pyrrolidine derivative using enyne metathesis.
Scheme 4. Synthesis of a benzodiazepine derivative.
Scheme 5. Cross-metathesis.

T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
9651
Scheme 6. Synthesis of an anthramycine derivative.
Isomerization of the double bond in a pyrrolidine ring was
carried out. When a toluene solution of 13a was refluxed in
the presence of a catalytic amount of RuHCl(CO)(PPh3)3 for
8 h, further isomerized pyrrole derivative 14 was obtained in
66% yield. On the other hand, when an EtOH solution of
13a and RhCl3$3H2O10 was heated at 110 8C in a sealed
tube, the desired isomerization product 15a was obtained
along with the corresponding ethyl ester 15b. Thus, 13b was
prepared from 1b and ethyl acrylate using 6c and was
treated with RhCl3$3H2O in EtOH at 110 8C to give 15b in
50% yield (Scheme 8).
Stille has succeeded in the total synthesis of (C)-
anthramycin.2 In his total synthesis, the aminal part of 17
was constructed by treatment of 16 with NaBH4 and
deprotection of 17 gave (C)-anthramycin (Scheme 9).
Thus, debenzylation of 15b was carried out by treatment
with CF3CO2H and BF3$Et2O followed by protection of the
phenol and the amide nitrogen as a benzylidene acetal to
give 19, which was treated with NaBH4 to give aminal 20
(Scheme 10).
Thus, we succeeded in the synthesis of an anthramycin
derivative 20 having the desired functional groups from
commercially available L-methionine using ring-closing
enyne metathesis and cross-metathesis as the key steps.
Coversion of the ester group into an amide group for the
total synthesis of (C)-anthramycin is further investigated.
Scheme 7. Cross-metathesis.

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T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
Scheme 8. Isomerization of the double bond.
Scheme 9. Stille’s synthesis of anthramycin.
Scheme 10. Conversion of 15b into aminal 20.

T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
9653
4. Experimental
276, 261, 244, 200, 170, 91; HRMS Calcd for C17H21NO4S
(MC) 335.1191, found 335.1185. Anal. Calcd for
C17H21NO4S: C, 60.87; H, 6.31; N, 4.18. Found: C, 60.79;
H, 6.39; N, 4.23. [a]2D3.4ZK50.9 (c 1.00, CHCl3).
4.1. General
All manipulations were carried out under an atmosphere of
argon unless otherwise mentioned. Ethylene gas was
purified by passage through the aqueous CuCl solution
(2 g of CuCl in 180 mL of saturated NH4Cl aqueous) and
concentrated H2SO4 and then KOH tubes. Ruthenium
complexes 6a and 6b were purchased from Strem
Chemicals. Ruthenium complex 6c was prepared according
to the literature procedure.9 All other solvents and reagents
were purified when necessary using standard procedure.
4.1.3. (S)-2-(Benzyloxycarbonyl-prop-2-ynyl-amino)-4-
methanesulfinyl-butyric acid methyl ester (5). To a
solution of 4 (4.38 g, 13.0 mmol) in MeOH/H2O (1/1,
64 mL) was added NaIO4 (2.9 mL, 13.6 mmol) slowly, and
the solution was stirred at 0 8C for 4 h. After the solution
was filtered through celite, the filtrate was washed with
brine, dried over MgSO4. The solvent was removed and the
residue was purified by flash column chromatography on
silica gel (MeOH/ethyl acetate 1:10) to yield 5 (4.56 g,
quant.) as colorless oil. IR (neat) n 3282, 2953, 1740, 1700,
1456, 1413, 1257, 1048 cmK1; 1H NMR (400 MHz, CDCl3)
d two diastereomers (ratio 3:2) 2.29 (t, JZ2.4 Hz, 1H), 2.37
(br, 1H), 2.47–2.61 (m, 4H), 2.76–2.83 (m, 2H), 3.60 (s,
1.2H), 3.73 (s, 1.8H), 4.06–4.25 (m, 2H), 4.53 (m, 0.4H),
4.74 (m, 0.6H), 5.09–5.20 (m, 2H), 7.34–7.38 (m, 5H); 13C
NMR (100 MHz, CDCl3) d two diastereomers 22.2 (CH2),
22.6 (CH2), 22.9 (CH2), 23.6 (CH2), 35.4 (CH2), 35.6 (CH2),
36.4 (CH2), 36.7 (CH2), 38.1 (CH3), 38.6 (CH3), 50.3 (CH2),
50.5 (CH2), 50.9 (CH2), 52.3 (CH3), 58.1 (CH), 58.4 (CH),
67.7 (CH2), 72.5 (CH), 72.8 (CH), 78.8 (C), 79.0 (C), 127.4
(CH), 127.8 (CH), 128.1 (CH), 128.2 (CH), 128.2 (CH),
135.4 (C), 135.6 (C), 155.4 (C), 155.3 (C), 170.1 (C); LRMS
m/z 351 (MC), 320, 288, 261, 228, 152, 91; HRMS Calcd
for C17H21NO5S (MC) 351.1140, found 351.1128. Anal.
Calcd for C17H21NO5S: C, 58.10; H, 6.02; N, 3.99. Found:
C, 57.88; H, 6.03; N, 4.06.
4.1.1. (S)-4-Methylsulfanyl-2-prop-2-ynylamino-butyric
˚
acid methyl ester (A). To a solution of activated MS 4 A
(13 g) in DMF (50 mL) was added LiOH$H2O (2.26 g,
53.8 mmol), and the suspension was stirred at 0 8C for
20 min. To this mixture was added L-methionine methyl
ester hydrochloride (5 g, 25 mmol), and the suspension was
stirred at 0 8C for 45 min. To this mixture was added
propargyl bromide (2.3 mL, 25 mmol), and the mixture was
stirred at room temperature for 28 h. After the solution was
filtered through celite, the filtrate was washed with brine,
dried over Na2SO4. The solvent was removed and the
residue was purified by flash column chromatography on
silica gel (hexane/ethyl acetate 9:1) to yield title compound
A (3.1 g, 62%) as a colorless oil. IR (neat) n 3287, 2950,
2917, 2840, 1732, 1435, 1204, 1168, 1129 cmK1; 1H NMR
(400 MHz, CDCl3) d 1.85–2.03 (m, 2H), 2.10 (s, 3H), 2.23
(dd, JZ2.4, 2.4 Hz, 1H), 2.36 (br, 1H), 2.60 (m, 2H), 3.42
(dd, JZ2.4, 17.2 Hz, 1H), 3.48 (dd, JZ2.4, 17.2 Hz, 1H),
3.59 (dd, JZ7.6, 5.6 Hz, 1H), 3.75 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 15.3 (CH3), 30.2 (CH2), 32.4 (CH2),
36.8 (CH2), 51.8 (CH3), 58.7 (CH), 71.6 (CH), 81.1 (C),
174.6 (C); LRMS m/z 201 (MC), 186, 162, 154, 142, 127,
114, 94; HRMS Calcd for C9H15NO2S (MC) 201.0823,
found 201.0803. Anal. Calcd for C9H15NO2S: C, 53.70; H,
7.51; N, 6.96. Found: C, 53.72; H, 7.47; N, 6.99.
[a]2D3.9ZK14.2 (c 1.00, CHCl3).
4.1.4. (S)-2-(Benzyloxycarbonyl-prop-2-ynyl-amino)-
but-3-enoic acid methyl ester (3a). A solution of 5 (13 g)
in xylene (50 mL) was refluxed at 140 8C for 60 h. To this
solution was added ethyl acetate and the solution was
washed with 3% H2O2 aq., brine, and dried over Na2SO4.
After the solvent was removed, the residue was purified by
flash column chromatography on silica gel (hexane/ethyl
acetate 9:1) to yield 3a (3.1 g, 37%) as colorless oil, and 5
(5 g, 41%) was recovered. IR (neat) n 3288, 2953, 2122,
1746, 1710, 1560, 1449, 1409, 1255 cmK1 1H NMR
;
4.1.2. (S)-2-(Benzyloxycarbonyl-prop-2-ynyl-amino)-4-
methylsulfanyl-butyric acid methyl ester (4). To a
solution of A (2.86 g, 14.2 mmol) and KHCO3 (7.1 g,
71 mmol) in EtOAc/H2O (1/1, 140 mL) was added CbzCl
(3.0 mL, 21 mmol), and the solution was stirred at 0 8C for
14 h. The organic layer was washed with 10% HCl aq.,
brine, and dried over Na2SO4. After the solvent was
removed, the residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate 4:1) to
yield 4 (4.76 g, quant.) as colorless oil. IR (neat) n 3285,
2952, 2917, 2120, 1740, 1704, 1455, 1410, 1318, 1257,
(400 MHz, CDCl3) d two rotamers 2.24 (br, 1H), 3.60 (br,
2H), 3.75 (br, 3H), 4.20 (br, 1H), 5.20 (br, 2H), 5.38 (m,
2H), 6.14 (ddd, JZ6.2, 10.3, 17.0 Hz, 1H), 7.34–7.36 (m,
5H); 13C NMR (100 MHz, CDCl3) two rotamers d 35.3
(CH2), 36.3 (CH2), 52.2 (CH3), 61.2 (CH), 67.7 (CH2), 71.7
(CH), 72.2 (CH), 79.0 (C), 79.5, (C), 119.6 (CH2), 120.0
(CH2), 127.5 (CH), 127.9 (CH!2), 128.2 (CH!2), 130.5
(CH), 130.8 (CH), 135.7 (C), 135.9 (C), 154.8 (C), 155.2
(C), 170.1 (C); LRMS m/z 287 (MC), 272, 255, 228, 196,
184, 152, 91; HRMS Calcd for C14H14NO2 (MCKCO2Me)
228.1024, found 228.1034. Anal. Calcd for C16H17NO4: C,
66.89; H, 5.96; N, 4.88. Found: C, 66.81; H, 6.08; N, 4.90.
[a]2D4.8ZK13.6 (c 0.25, CHCl3).
1
1119 cmK1; H NMR (400 MHz, CDCl3) d two rotamers
2.06 (s, 1.5H), 2.11 (s, 1.5H), 2.17–2.34 (m, 2H), 2.26 (br,
1H), 2.55–2.71 (m, 2H), 3.60 (s, 1.5H), 3.72 (s, 1.5H), 4.00–
4.25 (m, 2H), 4.65 (m, 0.5H), 4.82 (m, 0.5H), 5.11–5.24 (m,
2H), 7.30–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) d two
rotamers 15.3 (CH3), 28.9 (CH2), 29.2 (CH2), 30.8 (CH2),
35.5 (CH2), 36.5 (CH2), 52.2 (CH3), 52.3 (CH3), 57.9 (CH),
58.2 (CH), 67.7 (CH2), 67.8 (CH2), 72.0 (CH), 72.3 (CH),
79.1 (C), 79.4 (C), 127.5 (CH), 127.9 (CH), 128.0 (CH),
128.1 (CH), 128.3 (CH), 135.8 (C), 136.0 (C), 155.4 (C),
155.5 (C), 171.2 (C), 171.3 (C); LRMS m/z 335 (MC), 304,
4.1.5. (S)-4-Vinyl-2,5-dihydro-pyrrole-1,2-dicarboxylic
acid 1-benzyl ester 2-methyl ester (7). To a solution of
3a (1.1 g, 3.8 mmol) in CH2Cl2 (77 mL, 0.05 M) was added
6a (158 mg, 191 mmol, 5 mol%), and the solution was
stirred under an atmosphere of ethylene for 24 h. To this
solution was added an excess of ethyl vinyl ether. After the
solvent was removed, the residue was purified by flash

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T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
column chromatography on silica gel (hexane/ethyl acetate
4:1) to yield 7 (840 mg, 76%) as a colorless crystal. Mp 58–
60 8C; IR (film) n 3065, 2952, 2868, 1754, 1713, 1645,
was filtered through celite. The filtrate was washed with
saturated NaHCO3 aq., brine, and dried over Na2SO4. After
the solvent was removed, the crude aniline 9a was dissolved
in THF (5 mL) and 0.2% HCl aq. (5 mL). The whole
solution was stirred at room temperature for 12 h. The
aqueous layer was extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and evaporated.
The residue was purified by flash column chromatography
on silica gel (hexane/ethyl acetate 1:1) to yield 1a (31 mg,
86%, 2 steps) as a colorless crystal. Mp 210 8C (dec.); IR
(nujol) n 3223, 2855, 1693, 1655, 1614, 1484, 1457, 1376,
1252, 1215 cmK1; 1H NMR (400 MHz, CDCl3) d 4.52 (dd,
JZ2.4, 15.2 Hz, 1H), 4.72 (d, JZ15.2 Hz, 1H), 4.94 (br,
1H), 5.29 (d, JZ17.6 Hz, 1H), 5.35 (d, JZ10.8 Hz, 1H),
5.93 (br, 1H), 6.59 (dd, JZ17.6, 10.8 Hz, 1H), 6.98 (d, JZ
8.4 Hz, 1H), 7.31 (dd, JZ8.4, 8.0 Hz, 1H), 7.51 (ddd, JZ
1.6, 8.0, 8.0 Hz, 1H), 7.77 (br, 1H), 8.05 (dd, JZ8.0, 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 53.0 (CH2), 63.9 (CH),
118.5 (CH2), 120.8 (CH), 121.1 (CH), 125.2 (CH), 126.1
(C), 129.7 (CH), 131.3 (CH), 132.6 (CH), 135.0 (C), 139.8
(C), 164.9 (C), 171.0 (C); LRMS m/z 240 (MC), 211, 120;
HRMS Calcd for C14H12N2O2 (MC) 240,0899, found
240,0894. [a]D23.9ZC499.1 (c 1.00, CHCl3).
1
1596, 1416, 1355, 1205, 1117 cmK1; H NMR (400 MHz,
CDCl3) d two rotamers 3.59 (s, 1.5H), 3.75 (s, 1.5H), 4.34–
4.45 (m, 2H), 5.06–5.29 (m, 5H), 5.64 (s, 0.5H), 5.69 (s,
0.5H), 6.42 (dd, JZ17.6, 10.8 Hz, 0.5H), 6.43 (dd, JZ17.6,
11.2 Hz, 0.5H), 7.29–7.41 (m, 5H); 13C NMR (100 MHz,
CDCl3) d two rotamers 52.1 (CH2), 52.3 (CH3), 52.4 (CH3),
52.6 (CH2), 66.5 (CH), 66.8 (CH), 67.1 (CH2), 67.2 (CH2),
117.9 (CH2), 118.3 (CH2), 121.6 (CH), 121.8 (CH), 127.7
(CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.3 (CH),
128.4 (CH), 129.5 (CH), 129.6 (CH), 136.3 (C), 136.3 (C),
140.5 (C), 140.6 (C), 153.7 (C), 154.2 (C), 170.0 (C), 170.3
(C); LRMS m/z 287 (MC), 256, 243, 228, 196, 184, 152, 91;
HRMS Calcd for C16H17NO4 (MC) 287.1158, found
287.1144. Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96;
N, 4.88. Found: C, 66.83; H, 5.95; N, 4.89. [a]2D0.8ZK241.1
(c 1.00, CHCl3).
4.1.6. (S)-1-(2-Nitro-benzoyl)-4-vinyl-2,5-dihydro-1H-
pyrrole-2-carboxylic acid methyl ester (2a). To a solution
of 7 (92 mg, 0.32 mmol) in CH3CN (3 mL) was added NaI
(330 mg, 2.2 mmol) and TMSCl (0.26 mL, 2 mmol) at 0 8C
and the solution was stirred at room temperature for 10 h. To
this solution was added MeOH (1 mL) at 0 8C. After the
solvent was removed, the residue was dissolved in CH2Cl2
(1 mL). To this solution was added Et3N (1 mL) and
o-nitrobenzoyl chloride (107 mg, 0.6 mmol) in CH2Cl2
(4 mL) at 0 8C. The whole solution was stirred at 0 8C for
8 h. To this solution were added MeOH and saturated
Na2S2O3 aq., and the aqueous layer was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na2SO4, and evaporated. The residue was purified by
column chromatography on silica gel (hexane/ether 2:1) to
yield 2a (73.5 mg, 76%, 2 steps) as pale yellow oil. IR (neat)
n 1742, 1659, 1595, 1531, 1485, 1424, 1348, 1265, 1207,
4.1.8. (11aS, E)-Acetic acid 3-(5,11-dioxo-5,10,11,11a-
tetrahydro-3H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-
yl)-allyl ester (11a). To a solution of 1a (4.3 mg, 18 mmol)
and 10 (29 mL, 0.18 mmol) in CH2Cl2 (0.5 mL) was added
6b (2.4 mg, 3 mmol, 15 mol%), and the solution was
degassed through freeze–pump–thaw cycle. The whole
solution was refluxed 50 8C for 2 h. After the solvent was
removed, the residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate 3:1–
1:1) to yield 11a (5 mg, 89%) as a colorless crystal. Mp
185 8C (dec.); IR (film) n 3240, 1745, 1688, 1640, 1264,
734, 699 cmK1; 1H NMR (400 MHz, CDCl3) d 2.10 (s, 3H),
4.49 (dd, JZ3.2, 16.0 Hz, 1H), 4.68 (d, JZ6.0 Hz, 2H),
4.72 (m, 1H), 4.94 (br, 1H), 5.80 (dt, JZ15.6, 6.0 Hz, 1H),
5.97 (br, 1H), 6.52 (d, JZ15.6 Hz, 1H), 7.04 (d, JZ8.0 Hz,
1H), 7.51 (ddd, JZ1.6, 8.0, 8.0 Hz, 1H), 8.04 (dd, JZ1.6,
8.0 Hz, 1H), 8.47 (br, 1H); 13C NMR (100 MHz, CDCl3) d
20.9 (CH3), 53.1 (CH2), 63.9 (CH2), 64.1 (CH), 121.1 (CH),
121.6 (CH), 125.3 (CH), 125.9 (C), 126.1 (CH), 127.9 (CH),
131.3 (CH), 132.7 (CH), 135.0 (C), 138.5 (C), 164.8 (C),
170.5 (C), 170.8 (C); LRMS m/z 312 (MC), 281, 252, 224,
191, 133, 120; HRMS Calcd for C17H16N2O4 (MC)
312.1110, found 312.1106. [a]2D0.7ZC402.0 (c 0.93,
CHCl3).
1
1004 cmK1; H NMR (400 MHz, CDCl3) d (two rotamers,
major/minor 3/1) major rotamer 3.81 (s, 3H), 4.09 (d, JZ
16.0 Hz, 1H), 4.23–4.27 (m, 1H), 4.93 (d, JZ17.6 Hz, 1H),
5.18 (d, JZ10.8 Hz, 1H), 5.49 (br, 1H), 5.81 (br, 1H), 6.41
(dd, JZ17.6, 10.8 Hz, 1H), 7.56–7.71 (m, 2H), 7.77 (m,
1H), 8.22 (d, JZ8.0 Hz, 1H), minor rotamer 3.54 (s, 3H),
4.53–4.58 (m, 1H), 4.79 (m, 1H), 4.86 (d, JZ15.2 Hz, 1H),
5.31 (d, JZ17.6 Hz, 1H), 5.35 (d, JZ10.8 Hz, 1H), 5.61
(br, 1H), 6.47 (dd, JZ17.6, 10.8 Hz, 1H), 7.45 (d, JZ
7.6 Hz, 1H), 7.56–7.71 (m, 2H), 8.19 (d, JZ8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) d major rotamer 52.7 (CH3),
53.6 (CH2), 66.1 (CH), 118.0 (CH2), 121.9 (CH), 124.6
(CH), 128.4 (CH), 129.4 (CH), 130.2 (CH), 132.5 (C), 134.6
(CH), 139.7 (C), 144.8 (C), 165.9 (C), 169.4 (C), minor
rotamer 52.5 (CH3), 53.6 (CH2), 67.7 (CH), 119.1 (CH2),
120.8 (CH), 124.7 (CH), 129.1 (CH), 129.3 (CH), 130.3
(CH), 131.8 (C), 134.1 (CH), 140.4 (C), 144.7 (C), 166.4
(C), 169.7 (C); LRMS m/z 303 (MCC1), 270, 243, 150, 93;
HRMS Calcd for C13H11N2O3 (MCKCO2Me) 243.0769,
found 243.0765. [a]2D1.2ZK200.6 (c 0.59, CHCl3).
4.1.9. (2S)-1-(3-Benzyloxy-4-methyl-2-nitro-benzoyl)-4-
vinyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl
ester (2b). To a solution of 7 (70 mg, 0.24 mmol) in CH3CN
(2 mL) was added NaI (298 mg, 2 mmol) and TMSCl
(0.26 mL, 2 mmol) at 0 8C and the solution was stirred at
room temperature for 5 h. To this solution was added MeOH
(1 mL) at 0 8C. After the solvent was removed, the residue
was dissolved in CH2Cl2 (1 mL). To this solution was added
Et3N (1 mL) and o-nitrobenzoyl chloride 8b (83 mg,
0.29 mmol) in CH2Cl2 (4 mL) at 0 8C. The whole solution
was stirred at 0 8C for 12 h. To this solution was added
MeOH (1 mL) and saturated Na2S2O3 aq., and the aqueous
layer was extracted with ethyl acetate. The organic layer
was washed with brine, dried over Na2SO4, and evaporated.
4.1.7. (S)-2-Vinyl-3,11a-dihydro-10H-benzo[e]pyrrolo
[1,2-a][1,4]diazepine-5,11-dione (1a). To a solution of 2a
(46 mg, 0.15 mmol) and Zn dust (400 mg) in CH2Cl2 (2 mL)
was slowly added AcOH (0.1 mL) at 0 8C. The solution was
stirred at room temperature for 30 min and then the solution

T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
9655
The residue was purified by column chromatography on
silica gel (hexane/ether 1:1) to yield 2b (93 mg, 93%) as
pale yellow oil. IR (neat) n 1748, 1658, 1641, 1563, 1538,
of 1b (115 mg, 0.32 mmol) and 10 (0.5 mL, 0.3 mmol) in
CH2Cl2 (6.4 mL) was added 6b (13.5 mg, 16 mmol,
5 mol%), and the solution was degassed through freeze–
pump–thaw cycle. The whole solution was refluxed for 12 h.
After the solvent was removed, the residue was purified by
flash column chromatography on silica gel (hexane/ethyl
acetate 3:1–1:1) to yield 11b (126 mg, 91%) as a colorless
crystal. Mp 138–140 8C; IR (CHCl3) n 3242, 1737, 1692,
1637, 1568, 1500, 1462, 1425, 1361, 1229, 1074 cmK1; 1H
NMR (400 MHz, CDCl3) d 2.10 (s, 3H), 2.43 (s, 3H), 4.41
(dd, JZ3.2, 15.6 Hz, 1H), 4.51 (br, 1H), 4.63 (d, JZ
15.6 Hz, 1H), 4.66 (d, JZ5.6 Hz, 2H), 4.88 (d, JZ11.2 Hz,
1H), 4.96 (d, JZ11.2 Hz, 1H), 5.77 (dt, JZ16.0, 5.6 Hz,
1H), 5.85 (s, 1H), 6.49 (d, JZ16.0 Hz, 1H), 7.12 (d, JZ
8.0 Hz, 1H), 7.31–7.37 (m, 5H), 7.70 (d, JZ8.0 Hz, 1H),
7.81 (br, 1H); 13C NMR (100 MHz, CDCl3) d 16.7 (CH3),
20.9 (CH3), 53.0 (CH2), 63.6 (CH), 64.0 (CH2) 75.3 (CH2),
121.6 (CH), 124.3 (C), 126.1 (CH), 126.3 (CH), 127.3 (CH),
127.8 (CH), 128.7 (CH!2), 128.7 (CH), 128.9 (CH!2),
129.6 (C), 135.3 (C), 138.3 (C), 145.6 (C), 164.4 (C), 169.5
(C) 170.4 (C); LRMS m/z 432 (MC), 372, 341, 281, 91;
HRMS Calcd for C25H24N2O5 (MC) 432.1685, found
432.1675. [a]D19.8ZC331.7 (c 1.00, CHCl3).
1493, 1429, 1364, 1265, 1209, 1181, 1056, 1030, 1002 cmK1
;
1H NMR (400 MHz, CDCl3) d (two rotamers, major/minor
3/1) major rotamer 2.42 (s, 3H), 3.78 (s, 3H), 4.27 (d, JZ
13.6 Hz, 1H), 4.39–4.44 (m, 1H), 4.99 (d, JZ10.4 Hz, 1H),
5.02 (d, JZ17.6 Hz, 1H), 5.12 (d, JZ10.4 Hz, 1H), 5.23 (d,
JZ10.8 Hz, 1H), 5.42 (br, 1H), 5.79 (s, 1H), 6.43 (dd, JZ
17.6, 10.8 Hz, 1H), 7.24 (d, JZ8.0 Hz, 1H), 7.34–7.45 (m,
6H), minor rotamer d 2.37 (s, 3H), 3.64 (s, 3H), 4.46–4.51
(m, 1H), 4.74 (d, JZ15.6 Hz, 1H), 4.94–5.11 (blind, 3H),
5.28 (d, JZ17.6 Hz, 1H), 5.34 (d, JZ10.8 Hz, 1H), 5.66 (s,
1H), 6.56 (blind, 1H), 7.06 (d, JZ8.0 Hz, 1H), 7.34–7.45
(m, 6H); 13C NMR (100 MHz, CDCl3) major rotamer d 16.4
(CH3), 52.5 (CH3), 53.9 (CH2), 66.1 (CH), 76.5 (CH2),
117.9 (CH2), 121.6 (CH), 121.7 (CH), 122.2 (CH), 128.1
(CH!2), 128.4 (CH!2), 129.3 (CH), 129.5 (C), 133.9
(CH), 135.6 (C), 135.9 (C), 139.7 (C), 143.1 (C), 149.2 (C),
164.8 (C), 169.1 (C), minor rotamer d 16.4 (CH3), 52.3
(CH2), 52.5 (CH3), 67.9 (CH), 76.5 (CH2), 118.9 (CH2),
121.0 (CH), 121.0 (CH), 122.4 (CH), 128.2 (CH!2), 128.4
(CH!2), 129.1 (C), 129.2 (CH), 133.7 (CH), 135.5 (C),
135.9 (C), 140.2 (C), 142.8 (C), 149.1 (C), 165.2 (C), 169.8
(C); LRMS m/z 422 (MC), 363, 270, 91; HRMS Calcd
for C23H22N2O6 (MC) 422.1477, found 422.1489.
[a]2D2.1ZK230.4 (c 0.90, CHCl3).
4.1.12. (11aS)-3-(9-Benzyloxy-8-methyl-5,11-dioxo-
5,10,11,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-a][1,4]
diazepin-2-yl)-acrylic acid methyl ester (13a). A solution
of 11b (22 mg, 51 mmol) in MeOH (2 mL) was added
K2CO3 (12 mg, 87 mmol) at 0 8C and the solution was
stirred at 0 8C for 9 h. To this solution was added saturated
NH4Cl aq. and the aqueous layer was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na2SO4, and evaporated to yield crude alcohol (21 mg) as a
colorless crystal. To the solution of crude alcohol (21 mg) in
CH2Cl2 (2 mL) was added MnO2 (70 mg) and the whole
suspension was stirred at room temperature for 3 days. The
solution was filtered through celite and the filtrate was
concentrated to give crude aldehyde 12 (20.5 mg), which
was dissolved in t-BuOH/H2O (1 mL, 3.5/1). To this solu-
tion was added KH2CO3 (73 mg, 0.5 mmol), 2-methyl-2-
butene (0.2 mL, 2 mmol), and NaClO2 (23 mg, 0.25 mmol)
and the solution was stirred at room temperature for 3 h. To
this solution was added saturated Na2S2O3 aq. and the
aqueous layer was extracted with CH2Cl2. The organic layer
was washed with brine, dried over Na2SO4, and evaporated
to yield carboxylic acid (25 mg) as a colorless solid. A
solution of crude carboxylic acid (25 mg) in MeOH (2 mL)
was added SOCl2 (10 drops) at 0 8C and the solution was
stirred at room temperature for 18 h. After the solvent was
removed, the residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate 1:1) to
yield 13a (11 mg, 52%, 4 steps) as a colorless crystal. Mp
189–191 8C; IR (nujol) n 3215, 3065, 2854, 1722, 1699,
1645, 1623, 1565, 1499, 1462, 1376, 1315, 1261, 1225,
4.1.10. (11aS)-9-Benzyloxy-8-methyl-2-vinyl-3,11a-
dihydro-10H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11-
dione (1b). To a solution of 2b (570 mg, 1.35 mmol) and Zn
dust (6.0 g) in CH2Cl2 (15 mL) was slowly added AcOH
(1.2 mL) at 5 8C and the solution was stirred at room
temperature for 20 min and was filtered through celite. The
filtrate was washed with brine, and dried over Na2SO4. After
the solvent was removed, the crude aniline was dissolved in
THF (10 mL) and 0.2% HCl aq. (30 mL). The whole
solution was stirred at room temperature for 24 h. The
aqueous layer was extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and evaporated.
The residue was purified by flash column chromatography
on silica gel (hexane/ethyl acetate 2:1) to yield 1b (451 mg,
93%, 2 steps) as a colorless crystal. IR (nujol) n 2924, 2854,
1703, 1654, 1622, 1606, 1566, 1497, 1461, 1428, 1376,
1
1262, 1211, 1070 cmK1; H NMR (400 MHz, CDCl3) d
2.43 (s, 3H), 4.43 (dd, JZ4.0, 16.0 Hz, 1H), 4.50 (br, 1H),
4.65 (d, JZ16.0 Hz, 1H), 4.88 (d, JZ10.8 Hz, 1H), 4.96 (d,
JZ10.8 Hz, 1H), 5.24 (d, JZ17.6 Hz, 1H), 5.31 (d, JZ
10.8 Hz, 1H), 5.81 (s, 1H), 6.55 (dd, JZ17.6, 10.8 Hz, 1H),
7.12 (d, JZ8.0 Hz, 1H), 7.31–7.37 (m, 5H), 7.70 (d, JZ
8.0 Hz, 1H), 7.83 (br, 1H); 13C NMR (100 MHz, CDCl3) d
16.6 (CH3), 52.8 (CH2), 63.6 (CH), 75.2 (CH2), 118.2
(CH2), 120.7 (CH), 124.7 (C), 126.2 (CH), 127.2 (CH),
128.5 (CH), 128.6 (CH), 128.9 (C), 129.6 (C), 129.7 (CH),
135.3 (C), 135.4 (C), 139.6 (C), 145.6 (C), 164.4 (C), 169.7
(C); LRMS m/z 360 (MC), 269, 241, 91; HRMS Calcd for
C22H20N2O3 (MC) 360.1474, found 360.1472. Anal. Calcd
for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C,
73.19; H, 5.69; N, 7.86. [a]2D3.0ZC334.3 (c 1.00, CHCl3).
1
1174, 1072, 1001 cmK1; H NMR (400 MHz, CDCl3) d
2.45 (s, 3H), 3.79 (s, 3H), 4.45 (dd, JZ3.6, 16.0 Hz, 1H),
4.55 (m, 1H), 4.66 (d, JZ16.0 Hz, 1H), 4.69 (d, JZ11.2 Hz,
1H), 4.98 (d, JZ11.2 Hz, 1H), 5.89 (d, JZ15.6 Hz, 1H),
6.21 (br, 1H), 7.14 (d, JZ8.0 Hz, 1H), 7.31–7.38 (m, 5H),
7.47 (d, JZ15.6 Hz, 1H), 7.70 (d, JZ8.0 Hz, 1H), 7.76 (br,
1H); 13C NMR (100 MHz, CDCl3) d 16.7 (CH3), 51.9
(CH3), 52.7 (CH2), 63.9 (CH), 75.4 (CH2) 121.9 (CH), 124.1
(C), 126.4 (CH), 127.5 (CH), 128.6 (CH), 128.7 (CH!2),
4.1.11. (11aS,E)-Acetic acid 3-(9-benzyloxy-8-methyl-
5,11-dioxo-5,10,11,11a-tetrahydro-3H-benzo[e]pyrrolo
[1,2-a][1,4]diazepin-2-yl)-allyl ester (11b). To a solution

9656
T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
128.8 (CH), 129.0 (CH!2), 129.6 (C), 135.3 (C), 135.7 (C),
136.2 (CH), 137.6 (C), 145.7 (C), 164.5 (C), 166.5 (C) 169.1
(C); LRMS m/z 418 (MC), 327, 91; HRMS Calcd for
C24H22N2O5 (MC) 418.1528, found 418.1529. [a]D20.5Z
C313.4 (c 1.00, CHCl3).
15 mol%) and degassed EtOH (0.5 mL) was added in a
sealed tube and was stirred at 110 8C for 24 h. After the
solvent was removed, the residue was purified by flash
column chromatography on silica gel (hexane/ethyl acetate
3:1–1:1) to yield 15b (5 mg, 50%) as a colorless crystal. IR
(film) n 3247, 2980, 2931, 1698, 1621, 1569, 1499 cmK1
;
1H NMR (500 MHz, CDCl3) d 1.31 (t, JZ7.3 Hz, 3H), 2.46
(s, 3H), 2.85 (dd, JZ11.7, 16.1 Hz, 1H), 3.65 (dd, JZ3.3,
16.1 Hz, 1H), 4.14 (dd, JZ3.3, 11.7 Hz, 1H), 4.23 (q, JZ
7.3 Hz, 2H), 4.88 (d, JZ11.3 Hz, 1H), 4.98 (d, JZ11.3 Hz,
1H), 5.81 (d, JZ15.6 Hz, 1H), 7.15 (d, JZ8.1 Hz, 1H), 7.27
(s, 1H), 7.28–7.31 (m, 2H), 7.36–7.37 (m, 3H), 7.47 (d, JZ
15.6 Hz, 1H), 7.68 (d, JZ8.1 Hz, 1H), 7.74 (br, 1H); 13C
NMR (125 MHz, CDCl3) d 14.3 (CH3), 16.7 (CH3), 29.2
(CH2), 56.7 (CH), 60.4 (CH2), 75.5 (CH2) 118.7 (CH), 122.9
(C), 123.9 (C), 126.8 (CH), 127.8 (CH), 128.8 (CH!2),
128.9 (CH), 129.2 (CH!2), 129.6 (C), 132.0 (CH), 135.3
(C), 136.5 (C), 137.1 (CH), 146.0 (C), 162.1 (C), 166.8 (C)
167.5 (C); LRMS m/z 432 (MC), 387, 341, 295, 176, 120,
91; HRMS Calcd for C25H24N2O5 (MC) 432.1685, found
432.1689. [a]D24.1ZC244.0 (c 0.58, CHCl3).
4.1.13. (11aS)-3-(9-Benzyloxy-8-methyl-5,11-dioxo-
5,10,11,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-a][1,4]
diazepin-2-yl)-acrylic acid methyl ester (13a). To a
solution of 1b (19 mg, 50 mmol) and methyl acrylate
(0.05 mL, 0.5 mmol) in degassed CH2Cl2 (1 mL) was
added 6c (5.0 mg, 7 mmol, 13 mol%), and the solution
refluxed for 17 h. After the solvent was removed, the residue
was purified by flash column chromatography on silica gel
(hexane/ethyl acetate 2:1–1:1) to yield 13a (13.8 mg, 63%)
as a colorless crystal.
4.1.14. (11aS)-3-(9-Benzyloxy-8-methyl-5,11-dioxo-
5,10,11,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-a][1,4]
diazepin-2-yl)-acrylic acid ethyl ester (13b). To a solution
of 1b (105 mg, 0.29 mmol) and ethyl acrylate (0.3 mL,
2.9 mmol) in degassed CH2Cl2 (2.8 mL) was added a
solution of 6c (21 mg, 30 mmol, 10 mol%) in degassed
CH2Cl2 (3 mL), and the solution was stirred at room
temperature for 17 h. After the solvent was removed, the
residue was purified by flash column chromatography on
silica gel (hexane/ethyl acetate 1:1) to yield 13b (75.3 mg,
60%) as an amorphous solid. IR (CHCl3) n 1702, 1630,
1570, 1500, 1463, 1423, 1370, 1313, 1230, 1210, 1207,
4.1.17.
(11aS)-3-(9-Hydroxy-8-methyl-5,11-dioxo-
5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]
diazepin-2-yl)-acrylic acid ethyl ester (18). A mixture of
crude 15b (17 mg), TFA (1 mL), and BF3$Et2O (0.05 mL)
was stirred at room temperature for 10 min. To this solution
were added MeOH and H2O, and the aqueous layer was
extracted with CH2Cl2. The organic layer was washed with
brine, dried over Na2SO4, and evaporated to yield crude 18
(17 mg) as a colorless crystal. 1H NMR (400 MHz, CDCl3)
d 1.32 (t, JZ6.8 Hz, 3H), 2.36 (s, 3H), 2.97 (dd, JZ11.2,
15.6 Hz, 1H), 3.76 (dd, JZ15.6, 3.6 Hz, 1H), 4.23 (q, JZ
6.8 Hz, 2H), 4.63 (dd, JZ11.2, 3.6 Hz, 1H), 5.83 (d, JZ
16.0 Hz, 1H), 7.07 (d, JZ8.4 Hz, 1H), 7.34 (s, 1H), 7.37 (br,
1H), 7.50 (d, JZ16.0 Hz, 1H), 7.51 (d, JZ8.4 Hz, 1H), 8.36
(br s, 1H); LRMS m/z 342 (MC), 313, 297, 268, 176, 149,
120, 92.
1
1183, 1073 cmK1; H NMR (500 MHz, CDCl3) d 1.32 (t,
JZ7.1 Hz, 3H), 2.44 (s, 3H), 4.24 (q, JZ7.3 Hz, 2H), 4.44
(dd, JZ3.6, 15.7 Hz, 1H), 4.56 (m, 1H), 4.66 (d, JZ
15.7 Hz, 1 H), 4.89 (d, JZ11.2 Hz, 1H), 4.97 (d, JZ
11.2 Hz, 1H), 5.89 (d, JZ16.0 Hz, 1H), 6.20 (s, 1H), 7.13
(d, JZ8.2 Hz, 1H), 7.31–7.33 (m, 2H), 7.36–7.38 (m, 3H),
7.45 (d, JZ16.0 Hz, 1H), 7.70 (d, JZ8.2 Hz, 1H), 7.78 (br,
1H); 13C NMR (125 MHz, CDCl3) d 14.1 (CH3), 16.6
(CH3), 52.7 (CH2), 60.7 (CH2), 63.8 (CH), 75.4 (CH2) 122.4
(CH), 124.2 (C), 126.4 (CH), 127.5 (CH), 128.5 (CH), 128.7
(CH!2), 128.8 (CH), 129.0 (CH!2), 129.7 (C), 135.4
(CH), 135.7 (C), 135.9 (CH), 137.7 (C), 145.8 (C), 164.5
(C), 166.1 (C) 169.2 (C); LRMS m/z 432 (MC), 360, 341,
269, 91; HRMS Calcd for C25H24N2O5 (MC) 432.1685,
found 432.1683. [a]2D3.5ZC312.1 (c 1.00, CHCl3).
4.1.18. Benzylidene acetal (19). A mixture of crude 18
(17 mg), benzaldehyde dimethylacetal (0.5 mL), and p-TsOH
(1.7 mg) was warmed to 100 8C for 40 h. To this solution
was added brine and EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and evaporated. The residue
was purified by flash column chromatography on silica gel
(hexane/ethyl acetate 2:1) to yield 19 (9 mg, 53%) as a
colorless crystal. IR (CHCl3) n 1698, 1650, 1593, 1499,
4.1.15.
3-(9-Benzyloxy-8-methyl-5,11-dioxo-10,11-
dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl)-
propionic acid methyl ester (14). To a solution of 13a
(3 mg, 18 mmol) in toluene (1 mL) was added RuHCl(CO)
(PPh3)3 (1 mg), and the solution was stirred at 120 8C for
8 h. After the solvent was removed, the residue was purified
by flash column chromatography on silica gel (hexane/ethyl
acetate 1:1) to yield 14 (2 mg, 66%) as a colorless crystal.
1H NMR (270 MHz, CDCl3) d 2.40 (s, 3H), 2.65 (t, JZ
7.6 Hz, 2H), 2.89 (t, JZ7.6 Hz, 2H), 3.70 (s, 3H), 4.91 (s,
2H), 7.08 (d, JZ8.6 Hz, 1H), 7.40–7.50 (m, 6H), 7.92 (m,
1H), 8.16 (d, JZ8.6 Hz, 1H), 8.75 (brs, 1H); LRMS m/z 418
(MC), 387, 344, 327, 299, 243, 176, 148, 120.
1457, 1398, 1259, 1223, 1177, 1143 cmK1 1H NMR
;
(400 MHz, CDCl3) d 1.32 (t, JZ6.8 Hz, 3H), 2.40 (s, 3H),
2.91 (dd, JZ11.2, 15.2 Hz, 1H), 3.76 (dd, JZ15.2, 4.0 Hz,
1H), 4.23 (q, JZ6.8 Hz, 2H), 4.41 (dd, JZ11.2, 4.0 Hz,
1H), 5.84 (d, JZ16.0 Hz, 1H), 7.16 (d, JZ8.0 Hz, 1H),
7.34–7.56 (m, 8H), 7.72 (d, JZ8.0 Hz, 1H); LRMS m/z 430
(MC), 401, 385, 373, 356, 266, 236, 209, 121, 91; HRMS
Calcd for C25H22N2O5 (MC) 430.1528, found 430.1543.
4.1.19. Aminal (20). To a solution of 19 (2 mg) in MeOH
(1 mL) was added NaBH4 (4.4 mg) at 0 8C and the solution
was stirred at 0 8C for 4 h. To this solution was added H2O,
and the aqueous layer was extracted with ethyl acetate. The
organic layer was washed with brine, dried over Na2SO4,
and evaporated. The residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate 1:1) to
4.1.16. (11aS,E)-3-(9-Benzyloxy-8-methyl-5,11-dioxo-
5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]
diazepin-2-yl)-acrylic acid ethyl ester (15b). A solution of
13b (4.3 mg, 18 mmol), RhCl3$3H2O (2.4 mg, 3 mmol,

T. Kitamura et al. / Tetrahedron 60 (2004) 9649–9657
9657
1
(k) Mori, M. Top. Organomet. Chem. 1998, 1, 133.
(l) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1.
yield 20 (1.7 mg, 84%) as a colorless crystal. H NMR
(500 MHz, CDCl3) d 1.30 (t, JZ7.1 Hz, 3H), 2.08 (d, JZ
8.4 Hz, 1H), 2.19 (s, 3H), 2.92 (dd, JZ15.6, 4.9 Hz, 1H),
3.13 (dd, JZ11.4, 3.7 Hz, 1H), 4.22 (q, JZ7.1 Hz, 2H),
4.29 (dd, JZ11.2, 4.8 Hz, 1H), 4.84 (d, JZ8.6 Hz, 1H),
5.63 (d, JZ15.6 Hz, 1H), 6.55 (s, 1H), 6.66 (d, JZ8.5 Hz,
1H), 7.35 (d, JZ8.5 Hz, 1H), 7.43–7.53 (m, 7H); LRMS m/z
432 (MC), 414, 385, 356, 266, 238, 209; HRMS Calcd for
C25H24N2O5 (MC) 432.1685, found 432.1680.
4. Review for cross-metathesis: (a) Connnon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900. For examples:
(b) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed.
2002, 41, 3171. (c) Choi, T.-L.; Lee, C. W.; Chatterjee,
A. K.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 10417.
(d) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed.
2002, 41, 3171, and references cited therein.
5. For reports from our laboratory: (a) Kinoshita, A.; Mori, M.
Synlett 1994, 1020. (b) Kinoshita, A.; Mori, M. J. Org. Chem.
1996, 61, 8356. (c) Kinoshita, A.; Mori, M. Heterocycles 1997,
46, 287. (d) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org.
Chem. 1998, 63, 6082. (e) Kinoshita, A.; Sakakibara, N.; Mori,
M. J. Am. Chem. Soc. 1997, 119, 12388. (f) Kinoshita, A.;
Sakakibara, N.; Mori, M. Tetrahedron 1999, 55, 8155.
(g) Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org.
Lett. 2000, 2, 543. (h) Mori, M.; Kitamura, T.; Sato, Y.
Synthesis 2001, 654. (i) Kitamura, T.; Mori, M. Org. Lett.
2001, 3, 1161. (j) Mori, M.; Kuzuba, Y.; Kitamura, T.; Sato, Y.
Org. Lett. 2002, 4, 3855. (k) Kitamura, T.; Sato, Y.; Mori, M.
Chem. Commun. 2001, 1258. (l) Kitamura, T.; Sato, Y.; Mori,
M. Adv. Synth. Catal. 2002, 344, 678. (m) Mori, M.; Tonogaki,
K.; Nishiguchi, N. J. Org. Chem. 2002, 67, 224. (n) Saito, N.;
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References and notes
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V.; Schenker, F.; Karr, A.; Berger, J. J. Am. Chem. Soc. 1965,
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J. Am. Chem. Soc. 1965, 87, 5793. Total syntheses:
(c) Leimgruber, W.; Batcho, A. D.; Czajkowski, R. C.
J. Am. Chem. Soc. 1968, 90, 5641. (d) Pena, M. R.; Stille,
J. K. J. Am. Chem. Soc. 1989, 111, 5417.
2. (a) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: New
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Chemistry; Springer: Berlin Heidelberg, 1998; Vol. 1.
3. Recent reviews for olefin metathesis: (a) Grubbs, R. H.; Miller,
S. J. Acc. Chem. Res. 1995, 28, 446. (b) Schuster, M.; Blechert,
S. Angew. Chem., Int. Ed. 1997, 36, 2036. (c) Schmalz, H.-G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (d) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (e) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (f) Phillips,
A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75. (g) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3013. (h) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(i) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592. (j) Connnon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900. Review for enyne metathesis:
6. Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273.
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J. Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.;
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