Stereoselective synthesis of tilivalline

Article abstract of DOI:10.1021/jo972158g

Tilivalline 1, a metabolite from Klebsiella pneumoniae var. ocytoca, was easily synthesized in five steps from (S)-proline and 3-(benzyloxy)isatoic anhydride 4g. This synthesis is based on modified Curtius reactions of 3- substituted phthalic anhydrides 11 to 3-substituted isatoic anhydrides 4, conversion of lactams 6 to the acyliminium precursors 7 and stereoselective introduction of indole from the less hindered side of 7.

Full text of DOI:10.1021/jo972158g

J . Org. Chem. 1998, 63, 6797-6801
6797
Ster eoselective Syn th esis of Tiliva llin e1
Tatsuo Nagasaka* and Yuji Koseki
Tokyo University of Pharmacy and Life Science, School of Pharmacy, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, J apan
Received November 25, 1997 (Revised Manuscript Received J uly 21, 1998)
Tilivalline 1, a metabolite from Klebsiella pneumoniae var. ocytoca, was easily synthesized in five
steps from (S)-proline and 3-(benzyloxy)isatoic anhydride 4g. This synthesis is based on modified
Curtius reactions of 3-substituted phthalic anhydrides 11 to 3-substituted isatoic anhydrides 4,
conversion of lactams 6 to the acyliminium precursors 7 and stereoselective introduction of indole
from the less hindered side of 7.
Sch em e 1
In tr od u ction
Tilivalline 1, a metabolite, was isolated by Mohr and
Budzikiewicz2 from Klebsiella pneumoniae var. oxytoca.
Its pyrrolo[2,1-c][1,4]benzodiazepine skeleton is similar
to those of anthramycin (2) antibiotics.3 The first syn-
thesis2 of 1 has been reported in 1982, but was considered
unsatisfactory since the formation ratio of 1 to its 11-
epimer 3 was 8:92. In 1986, a brilliant stereoselective
synthesis of 1 was carried out by Shioiri et al.4 via a new
type of Mannich reaction. Tilivalline 1 and its analogues
have since been found to possess strong cytotoxicity
toward mouse leukemia L12105 and thus are of value.
5,11- dione skeleton,6 and thus it is necessary to establish
how to synthesize 3-substituted isatoic anhydrides as
starting materials in this research. The key step in
Scheme 1 is the enantioselective introduction of indole
at the C-11 position from the less hindered side, because
there is a possibility of epimerization5a at the C-11 due
to cleavage-recyclization of the N(10)-C(11) bond or
racemization at the C-11a via acyliminium-enamine
equilibration. Activation of lactam carbonyl groups by
introducing alkoxycarbonyl groups at N-positions fol-
lowed by reduction of amide carbonyl groups with sodium
borohydride and substitution by various functional groups
at R-positions via N-acyliminium ions have been exam-
ined in detail.7 A model experiment on the reaction of
2-ethoxy-1-(ethoxycarbonyl)hexahydroazepine with in-
dole was carried out to give the desired 1-(ethoxycarbo-
nyl)-2-(3′-indolyl)hexahydroazepine in 55% yield.8
We reported an alternative stereoselective synthesis1
of 1 in 1989. The results are presented in this paper.
The strategy for 1 is shown in Scheme 1. The reaction
of isatoic anhydride (2H-3,1- benzoxazine-2,4(1H)-dione)
with (S)-proline gives the pyrrolo[2,1-c][1,4]benzoazepin-
Resu lts a n d Discu ssion
The approach in the present synthesis is based on use
of readily available enantiopure lactams, whose conver-
sion to benzodiazepines possessing indole at the â-side
(1) This work has been presented as a brief communication: Na-
gasaka, T.; Koseki, Y.; Hamaguchi, F. Tetrahedron Lett. 1989, 30, 1871.
(2) Mohr, N.; Budzikiewicz, H. Tetrahedron 1982, 38, 147.
(3) For anthramycin antibiotics, see (a) Hurley, L. H. J . Antibiot.
1977, 30, 349. (b) Hurley, L. H.; Thurston, D. E. Pharm. Res. 1984,
52. (c) Remers, W. A. The Chemistry of Antitumor Antibiotics J ohn
Wiley & Sons: New York, 1988; Vol. 2, pp 28-92.
(6) Wright, W. B. J r.; Brabander, H. J .; Greenblatt, E. N.; Day, I.
P.; Hardy, R. A., J r. J . Med. Chem. 1978, 21, 1087.
(4) Mori, S.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1986, 27, 6111.
(5) (a) Aoyama, T.; Shioiri, T. Yakugaku Zasshi 1995, 115, 446. (b)
Shioiri, T.; Aoyama, T.; Yamagami, N.; Shimizu, N.; Mori, N.; Kohda,
K. Anti-Cancer Drug Design 1995, 10, 167. (c) Kohda, K.; Yamagami,
N.; Kasamatsu, T.; Aoyama, T.; Shioiri, T. Biochem. Pharmacol. 1995,
49, 1063.
(7) For conversion of lactams to R-substituted cyclic amines, see (a)
Nagasaka, T.; Abe, M.; Ozawa, N.; Kosugi, Y.; Hamaguchi, F. Hetero-
cycles 1983, 20, 985. (b) Nagasaka, T.; Tamano, H.; Maekawa, T.;
Hamaguchi, F. Heterocycles 1987, 26, 617.
(8) Nagasaka, T.; Koseki, Y.; Hayashi, H.; Yasuda, Y.; Hamaguchi,
F. Yakugaku Zasshi 1989, 109, 823.
S0022-3263(97)02158-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/11/1998

6798 J . Org. Chem., Vol. 63, No. 20, 1998
Nagasaka and Koseki
Ta ble 2. 1H NMR Sp ectr a of 1, 3 (epi-1), a n d 9
Sch em e 2
compd
11-H
11a-H
1
3
9
4.92 (d, J ) 9 Hz)
5.30 (d, J ) 3 Hz)
4.74 (d, J ) 9 Hz)
4.43 (m)
4.32 (m)
4.32 (m)
romethane failed to make the reaction at 0 °C (run 2)
but, at room temperature, increased the yield (62%) of
7a along with the undesired byproduct 10 (17%) (run 3).
The best results were obtained using tetrahydrofuran
(THF) near 0 °C (run 4), in which only alcohol 7a formed
in 69% yield. Generally acidic conditions in ethanol
should afford not R-hydroxy- but R-ethoxyamines via
acyliminium ion.9 That the corresponding R-ethoxyamine
of 7a was not detected means that 7a may form directly
by attack of borohydride at the less hindered â-side and
possibly may have a hydroxy group on the R-side. The
condensation of 7a with indole did not proceed at room
temperature or under reflux conditions in various sol-
vents, but heat application at 150 °C in acetic acid in a
sealed tube produced 8a in 50% yield as the sole product.
Stereoselectivity for this reaction was reasonable if the
nucleophile (indole) be considered to attack on the less
hindered side4 of the acyliminium intermediate9 formed
from alcohol 7a . The catalytic hydrogenetion of 8a gave
1
9 in 93% yield.10 On the basis of H NMR spectra of 1,
3 (11-epimer of 1),2 and 9 (Table 2), the protons of C-11
and C-11a of 9 were concluded to have a trans configu-
ration as tilivallin 1.
Ta ble 1. Red u ction of 6a w ith Sod iu m Bor oh yd r id e
Tilivalline 1 was synthesized by the above route
(Scheme 2), but under refined conditions. Washburne
et al.11 reported the reaction of phthalic anhydride 11a
with trimethylsilyl azide (TMSA) (modified Curtius reac-
tion) to give isatoic anhydride 4a , via an equilibrium
mixture of trimethylsilyl 2-isocyanatobenzoate and N-
(trimethylsilyl)isatoic anhydride, in total yield of 76%.
The reaction of 3-nitrophthalic anhydride 11b with
sodium azide has been reported by Caronna12 to give
3-nitroisatoic anhydride 4b exclusively. To obtain start-
ing materials (3-substituted isatoic anhydrides 4) of 1,
the modified Curtius reaction of various 3-substituted
phthalic anhydrides 11 with TMSA was examined, and
the results are shown in Table 3. Reactions of 3-amino-
and 3-acetaminophthalic anhydrides, 11d and 11e, gave
6-amino- and 3-acetaminoisatoic anhydrides, 12d and 4e,
respectively. Reactions of isatoic anhydrides possessing
oxygen functional groups at the 3-position, 11c, 11f, and
11g, gave a mixture of 3- and 6-substituted isatoic
anhydrides, 4c and 12c, 4f and 12f, and 4g and 12g.
Regioselectivity by attack of azide ion should be explained
product (yield, %)
NaBH4 temp. timea
run
(equiv)
(°C)
(h)
solvent
7a
10
1
2
3
4
1.1
1.1
2.1
1.1
-5-0
-5-0
rt
2
2
2
2
EtOH
CH2Cl2
CH2Cl2
THF
50
45
no reaction
62
69
17
-
-5-0
a
A few drops of ethanol solution containing a small amount of
hydrogen chloride were added every 10 min during the reactions.
(10) Optimum conditions were not determined in the model experi-
ments for 9. Compound 13 N-protected by an ethoxycarbonyl group
was initially prepared. Removal of the protecting group (CO2Et) of 13
using HBr-AcOH failed to give 9, but the crystalline material, mp
188-190 °C, having the same molecular formula of 13 (C23H23N3O3)
was obtained in 57% yield. The structure and formation mechanism
of this product will appear in a separate paper.
of the 11-position appears promising.4 Initially, as a
model experiment, the synthesis of deoxytilivalline 9 was
carried out as shown in Scheme 2.
Treatment of pyrrolobenzodiazepine 5a , obtained in
high yield from isatoic anhydride 4a and (S)-proline by
a known method,6 with benzyl chloroformate in the
presence of n-BuLi gave N-benzyloxycarbonyl compound
6a in 62% yield. The controlled reduction9 of 6a with
sodium borohydride was examined in detail, and some
of results are shown in Table 1. Ordinary conditions
using ethanol near 0 °C afforded a mixture of alcohol 7a
(50%) and cleavage product 10 (45%) (run 1). Dichlo-
(11) Washburne, S. S.; Peterson, W. R., J r.; Berman, D. A. J . Org.
Chem. 1972, 37, 1738.
(12) Caronna, G. Gazz. Chim. Ital. 1941, 71, 470.
(9) Nagasaka, T.; Tamano, H.; Hamaguchi, F. Heterocycles 1986,
24, 1231.

Stereoselective Synthesis of Tilivalline
J . Org. Chem., Vol. 63, No. 20, 1998 6799
Ta ble 3. Rea ction s of 3-Su bstitu ted P h th a lic
An h yd r id es w ith Tr im eth ylsilyl Azid e
Exp er im en ta l Section
All melting points were determined on a hot stage apparatus
without correction. Optical rotaion was measured at 589 nm.
1H (90 and 400 MHz) and 13C NMR (100 MHz) spectra were
recorded in CDCl3 with TMS or CDCl3, respectively, as the
internal reference. Elemental analyses were performed by
Central Analytical Laboratory, Tokyo University of Pharmacy
and Life Sciences.
Phthalic anhydride 11a and 3-nitrophthalic anhydride 11b
were obtained from commercial sources (Tokyo Kasei). 3-Ac-
etoxyphthalic anhydride 11c was prepared by the method of
Cava et al.14 from 2-acetoxyfuran derived from furan by the
method of Clauson and Elming.15 3-Amino- and 3-acetami-
nophthalic anhydrides 11d and 11e were prepared by catalytic
hydrogenation (5% Pd-C) of 11b in EtOAc and acetic anhy-
dride, respectively. 3-Methoxyphthalic anhydride 11f was
prepared from 2-methoxyfuran by the method of Rao et al.16
3-(Benzyloxy)phthalic anhydride 11g was prepared by the
method of Menard et al.17 from 3-hydroxyphthalic acid, which
was derived from 3-nitrophthalic acid by the method of
Gisvold.18 Compound 5a was prepared by the method of
Wright.6
product (yield, %)
run
11a -g
X
solvent
4a -g
12a -g
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
11g
H
benzene
benzene
benzene
THF
benzene
benzene
benzene
4a (76)
4b (75)
4c (12)
4d (0)
4e (74)
4f (55)
4g (68)
-
NO2
OAc
NH2
NHAc
OMe
12b (0)
12c (41)
12d (85)
12e (0)
12f (6)
OCH2Ph
12g (9)
based on further study, but 3-(benzyloxy)isatoic anhy-
dride 4g, the most suitable starting material, was
predominantly obtained. The structures of 3- and 6-sub-
stituted isatoic anhydrides 4 and 12 were determined
based on comparison of 1H NMR spectra of 4 with those
of 12. Signals of aromatic protons of 4 appear in lower
field than those of 12. Furthermore, some compounds
were converted to those identical to authentic samples.
The hydrolysis of 4b and 4f afforded 3-substituted
anthranilic acids, respectively, whose melting points were
identical with authentic samples, respectively. Hydro-
genation of 4b over Pd-C under hydrogen atmosphere
gave 3-aminoisatoic anhydride 4d in 90% yield which is
quite different from 6-aminoisatoic anhydride 12d .
(+)-(11a S)-1,2,3,10,11,11a -H exa h yd r o-10-(b en zyloxy-
ca r b on yl)-5H -p yr r olo[2,1-c][1,4]b en zod ia zep in -5,11-d i-
on e (6a ). To a solution of 5a (7.5 g, 0.034 mol) in absolute
THF (300 mL) was added dropwise at 0 °C a 1.6 M solution of
n-BuLi in hexane (21.2 mL) under argon. A 30% solution of
benzyl chloroformate in toluene (21 mL) was added at 0 °C to
this mixture, which was then stirred for 2 h at this temper-
ature. Saturated NH4Cl solution was added to terminate the
reaction, and the mixture was extracted with CHCl3. The
combined extract was washed with brine, dried over MgSO4,
and evaporated under reduced pressure to give a solid, which
was chromatographed by elution with hexane-acetone (6:1)
to afford 7.3 g (60%) of a colorless amorphous solid. Recrys-
tallization from benzene-petroleum ether gave colorless pow-
der, mp 109-119 °C. IR (KBr) 1780, 1735, 1615 cm-1; 1H NMR
(90 MHz, CDCl3) δ 2.11 (m, 3H), 2.68 (m, 1H), 3.67 (m, 2H),
4.05 (m, 1H), 5.23 (ABq, J AB ) 12 Hz, 2H), 7.08-7.58 (m, 8H),
Condensation of 4g with (S)-proline gave diazepine 5b
in 84% yield. Carbamate 6b could not be obtained at all
under the same reaction conditions using n-BuLi as
described for the preparation of 6a . This compound was
obtained in 88% yield using lithium hexamethyldisilazide
(LHMDS) instead of n-BuLi. The reaction of 5a with
benzyl chloroformate using LHMDS caused no increase
in yield, and many byproducts were formed. The con-
trolled reduction9 of compound 6b with sodium borohy-
dride in THF provided only alcohol 7b in 76% yield. In
this case, ethanol solvent gave a mixture of the desired
product 7b and a cleavage amide-ester like 10-analogue
in a ratio of 1:1. Alcohol 7b, via acyliminium ion,
condensed with indole to afford 8b exclusively in 93%
yield. The catalytic hydrogenation of 8b gave tilivalline
1 in 82% yield. This tilivalline 1 was found to have mp
180-185 °C and [R]D +210° (c ) 1.01 MeOH), different
from mp 168 °C (Mohr and Budzikiewicz)2 and 242-245
°C (Shioiri)4 and [R]D +126.8 (MeOH) (Mohr and Budz-
ikiewicz)2 and +245° (Shioiri),4 respectively. However,
the purity of the present tilivalline 1 was comfirmed pure
(>98% ee) by HPLC using a chiral column.13 The spectral
7.93 (m, 1H); MS m/z 350 (M+), 215 (M+ - COOCH2Ph). [R]25
D
+84.3 (c 1.05, MeOH); HRMS (FAB) calcd for C20H18N2O4
350.1265, found 350.1284.
(+)-(11a S)-1,2,3,10,11,11a -H exa h yd r o-10-(b en zyloxy-
ca r bon yl)-11-h yd r oxy- 5H-p yr r olo[2,1-c][1,4]ben zod ia ze-
p in -5-on e (7a ). To a solution of 6a (600 mg, 1.7 mmol) in
absolute THF (80 mL) under ice-cooling was added NaBH4 (71
mg, 1.8 mmol). The reaction mixture was stirred for 2 h at 0
°C while adding a few drops of the HCl-EtOH solution,
prepared by diluting saturated HCl-EtOH solution with 10
times volume of EtOH, at intervals of 10 min19 followed by
acidfication with the same diluted HCl-EtOH solution so that
pH was 3-4 at the end of the reaction. Finally, the system
was neutralized with alkali solution of 0.5 N KOH-EtOH. The
reaction mixture was evaporated under reduced pressure to
give a white mass, which was extracted with CHCl3. The
CHCl3 extract was filtered and evaporated under reduced
pressure to afford an oil. Chromatography of this oil by elution
with hexane-acetone (6:1) afforded 413 mg (69%) of a white
1
amorphous solid. IR (KBr) 3400, 1720, 1630 cm-1; H NMR
(400 MHz, CDCl3) δ 2.01 (m, 2H), 2.12 (m, 2H), 3.45 (m, 1H),
3.56 (m, 1H), 3.73 (m, 1H), 4.96 (ABq, J AB ) 12.5 Hz, 2H),
data (IR, H- and 13C NMR, mass, and UV) of tilivalline
produced here showed complete agreement with those of
an authentic sample provided through the courtesy of
Prof. Shioiri.
1
(14) Cava, M. P.; Wilson, C. L.; Williams, C. J ., J r. J . Am. Chem.
Soc. 1956, 78, 2303.
(15) Clauson-Kass, N.; Ellming, N. Acta Chem. Scand. 1952, 6, 535.
(16) Rao, A. V. R.; Chanda, B. M.; Wadekar, A. V. Indian J . Chem.
1981, 20B, 248.
(17) Menard, M.; Erichomovitch, L.; Brooy, M. L. Canadian J . Chem.
1963, 41, 1722.
(13) Column (Chiralcel OJ , Daicel Chem. Ind. Ltd.), 25 × 0.46 (i.d)
cm stainless tube packed with cellulose esters coated on silica gel; flow
(18) Gisvold, O. J . Am. Pharm. Assoc. 1942, 31, 202 [Chem Abstr.
1942, 36, 54708].
i
rate, 0.5 mL/min at 20 °C; solvent, PrOH-n-hexane (1:1); detector, a
UV-detector at 254 nm; rt, 26.4 min. A trace of (-)-enantiomer (<1%)
of tilivalline 1, probably due to the impurity of the starting (S)-proline,
was detected; rt, 30.9 min. These chromatograms were carefully
checked by (()- and (+)-tilivallines, prepared from (()- and (S)-(-)-
prolines, respectively.
(19) The general method9 needs the addition of a catalytic amount
of ethanol solution containing hydrogen chloride at regular intervals.
Reduction of 6a and 6b with sodium borohydride in ethanol and
tetrahydrofuran, however, could be also accomplished without addition
of acid.

6800 J . Org. Chem., Vol. 63, No. 20, 1998
Nagasaka and Koseki
5.65 (d, J ) 8.8 Hz, 1H), 7.15-7.51 (m, 9H), 7.77 (dd, J ) 1.8,
7.4 Hz, 1H); MS m/z 352 (M+), 217 (M+ - COOCH2Ph).
(+)-(11S,11a S)-1,2,3,10,11,11a -H exa h yd r o-10-(b en zyl-
oxyca r b on yl)-11-(3′-in d olyl)-5H -p yr r olo[2,1-c][1,4]b en -
zod ia zep in -5-on e (8a ). A mixture of 7a (160 mg, 0.45 mmol),
indole (69 mg, 0.58 mmol), and acetic acid (6 mL) was heated
for 5 h at 150-160 °C in a sealed tube. The reaction mixture
was evaporated under reduced pressure, and the residue was
chromatographed by elution with CH2Cl2-MeOH (40:1) to give
crystals which were recrystallized from acetone to colorless
prisms. Yield 50%, mp 223-225 °C. IR (KBr) 3460, 1690,
(M+ - CO2 - COCH3). Anal. Calcd for C10H7NO5: C, 54.30;
H, 3.19; N, 6.33. Found: C, 54.34; H, 3.21; N, 6.12.
6-Am in oisa toic An h yd r id e (12d ). Yellow prisms (147
mg, 85%) of 12d were obtained using 3-aminophthalic anhy-
dride (11d , 190 mg, 1.17 mmol), TMS-N3 (0.32 mL, 2.4 mmol)
and absolute THF (3 mL), under the conditions for 4b, followed
by recrystallization from isopropyl alcohol: mp 267-270 °C.
1
IR (KBr) 3480, 3330. 1760, 1700, 1610, 1600 cm-1; H NMR
(90 MHz, d6-DMSO + CDCl3) δ 6.18 (d, J ) 7.2 Hz, 1H), 6.43
(d, J ) 7.2 Hz, 1H), 6.99 (br, 2H), 7.23 (t, J ) 7.2 Hz, 1H),
11.20 (br, 1H); MS m/z 178 (M+), 134 (M+ - CO2), 107 (M+
-
1
1620 cm-1; H NMR (400 MHz, CDCl3) δ 1.76 (m, 1H), 1.98
COOCO). Anal. Calcd for C8H6O3N2: C, 53.93; H, 3.40; N,
15.73. Found: C, 53.85; H, 3.38; N, 15.67.
(m, 2H), 2.15 (m, 1H), 3.65 (m, 1H), 3.84 (m, 1H), 4.11 (m,
1H), 5.02 (ABq, J AB ) 12.7 Hz, 2H), 5.78 (d, J ) 11.5 Hz, 1H),
6.91 (d, J ) 7.9 Hz, 1H), 7.00 (d, J ) 2.5 Hz, 1H), 7.05 (m,
3H), 7.20 (m, 4H), 7.36 (m, 2H), 7.45 (m, 2H), 7.86 (dd, J )
3-Aceta m in oisa toic An h yd r id e (4e). Using 3-acetami-
nophthalic anhydride (11e, 200 mg, 0.98 mmol), TMS-N3 (0.26
mL, 1.96 mmol), and absolute C6H6 (4.5 mL), colorless prisms
(160 mg, 74%) of 4e were prepared under the conditions as
for 4b, followed by recrystallization from EtOAC: mp 252-
1.7, 7.6 Hz, 1H) 8.40 (br, 1H); MS m/z 451 (M+). [R]25 +107°
D
(c 0.4, CHCl3). Anal. Calcd for C28H25N3O3: C, 74.78; H, 5.58;
N, 9.31. Found: C, 74.64; H, 5.61; N, 9.26. Any product such
as the epimer of 8a was not detected.
253 °C. IR (KBr) 3150, 1770, 1740, 1700, 1610, 1600 cm-1
;
1H NMR (90 MHz, d6-DMSO + CDCl3) δ 2.20 (s, 3H), 6.83 (d,
J ) 8.0 Hz, 1H), 7.56 (t, J ) 8.0 Hz, 1H), 8.36 (d, J ) 8.0 Hz,
1H), 10.40 (br, 1H), 11.38 (br, 1H); MS m/z 220 (M+), 177 (M+
- CH3CO), 176 (M+ - CO2), 134 (M+ - CO2-CH3CO). Anal.
Calcd for C10H8N2O4: C, 54.55; H, 3.66; N, 12.72. Found: C,
54.62; H, 3.66; N, 12.74.
9-Deoxytilivallin e: (+)-(11S,11a S)-1,2,3,10,11,11a-Hexa-
h yd r o-11-(3′-in d olyl)- 5H-p yr r olo-[2,1-c][1,4]ben zod ia ze-
p in -5-on e (9). Catalytic hydrogenation (H2 2 atm, 5% Pd-C
50 mg) of 8a (75 mg, 0.17 mmol) in a solution of THF-MeOH
(1:1) (5 mL) was carried out for 1 h. The catalyst was filtered
off, and the filtrate was evaporated under reduced pressure
to give an oil which was chromatographed by elution with
CHCl3-MeOH (30:1) to give a crude powder which, by recrys-
tallization from CH2Cl2-hexane afforded 49 mg (93%) of yellow
powder: mp 219-224 °C. IR (KBr) 3500, 1610, 1360 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.67 (m, 1H), 1.80 (m, 2H), 1.94 (m,
1H), 3.77 (m, 1H), 3.91 (m, 1H), 4.32 (m, 1H), 4.74 (d, J ) 9.0
Hz, 1H), 6.54 (d, J ) 8.0 Hz, 1H), 6.89 (t, J ) 7.5 Hz, 1H),
7.08 (t, J ) 7.5 Hz, 1H), 7.14 (br, 1H), 7.21 (m, 3H), 7.41 (d, J
) 8.0 Hz, 1H), 7.49 (d, J ) 8.0 Hz, 1H), 7.97 (d, J ) 8.0 Hz,
1H), 8.99 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 22.8, 30.7,
47.9, 59.9, 62.5, 111.8, 117.1, 119.1, 119.5, 120.0, 121.5, 121.6,
122.6, 122.7, 125.2, 131.6, 132.3, 136.8, 145.0, 167.9; MS m/z
3-Meth oxyisa toic An h yd r id e (4f) a n d 6-Meth oxyisa -
toic An h yd r id e (12f). Reaction of 3-methoxyphthalic anhy-
dride (11f, 250 mg, 1.4 mmol) with TMS-N3 (0.19 mL, 2.8
mmol) in absolute C6H6 (4.5 mL), under the conditions as for
4b, gave crude crystals which were chromatographed by
elution with CH2Cl2-hexane-acetone, (30:1:1) followed by
recrystallization from EtOAc to give colorless prisms (116 mg,
43%) of 4f from the first fractions and colorless prisms (15 mg,
6%) of 12f from the second fractions; 4f: mp 255-260 °C. IR
(KBr) 1800, 1700, 1620, 1610 cm-1 1H NMR (90 MHz,
;
d6-DMSO + CDCl3) δ 3.95 (s, 3H), 7.17 (t, J ) 8.1 Hz, 1H),
7.39 (dd, J ) 1.8, 8.1 Hz, 1H), 7.48 (dd, J ) 1.8, 8.1 Hz, 1H);
MS m/z 193 (M+), 149 (M+ - CO2), 121 (M+ - COOCO). Anal.
Calcd for C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C,
55.90; H, 3.65; N, 7.31. 12f: mp 258-261 °C. IR (KBr) 3250,
1780, 1730, 1620 cm-1; 1H NMR (90 MHz, d6-DMSO + CDCl3)
δ 3.88 (s, 3H), 6.70 (d, J ) 8.1 Hz, 1H), 6.76 (d, J ) 8.1 Hz,
317 (M+). [R]25 +58.7 (c 1.01, CHCl3). HRMS (FAB) calcd
D
for C20H19N3O 317.1527, found 317.1513.
3-Nitr oisa toic An h yd r id e (4b). A mixture of 3-nitro-
phthalic anhydride (11b, 350 mg, 1.8 mmol), TMS-N3 (2.7
mmol, 0.35 mL) and absolute C6H6 (5 mL) was refluxed for 3
h and concentrated under reduced pressure to a viscous oil
containing a small amount of benzene which was further
heated for 16 h at 100 °C (bath temperature) and evaporated
completely under reduced pressure. Absolute EtOH (3 mL)
was added to the residue and immediately evaporated under
reduced pressure to give crude crystals, which were then
recrystallized from C6H6 to give 280 mg (75%) of yellow
prisms: mp 169-170 °C. IR (KBr) 1800, 1730, 1620, 1480
1H), 7.59 (t, J ) 8.1 Hz, 1H); MS m/z 193 (M+), 149 (M+
CO2), 121 (M+ - COOCO).
-
3-(Ben zyloxy)isa t oic An h yd r id e (4g) a n d 6-(Ben zyl-
oxy)isa toic An h yd r id e (12g). Colorless prisms (269 mg,
68%) of 4g were prepared under the conditions as for 4b,
followed by recrystallization from EtOAc, using 3-(benzyloxy)-
phthalic anhydride (11g, 370 mg, 1.46 mmol), TMS-N3 (0.39
mL, 2.92 mmol), and absolute C6H6 (6 mL). The filtrate left
from the recrystallization of 4g was evaporated to a solid which
was chromatographed by elution with CH2Cl2-acetone (20:
1), followed by recrystallization from EtOAc to give colorless
prisms (34 mg, 9%) of 12g. 4g: mp 204-206 °C. IR (KBr)
3200, 1800, 1730, 1620, 1610 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.17 (s, 2H), 7.18 (t, J ) 8.0, 1H), 7.25 (dd, J ) 1.5, 8.0 Hz,
1H), 7.40-7.46 (m, 5H), 7.67 (dd, J ) 1.5, 8.0 Hz, 1H), 8.15
(br, 1H); MS m/z 269 (M+), 196 (M+ - COOCO), 92. Anal.
Calcd for C15H11NO4: C, 66.91; H, 4.12; N, 5.20. Found: C,
66.75; H, 4.10; N, 5.19. 12 g: mp 224-229 °C. IR (KBr) 1790,
1720, 1620, 1600 cm-1; 1H NMR (90 MHz, d6-DMSO + CDCl3)
δ 5.26 (s, 2H), 6.69 (d, J ) 8.4 Hz, 1H), 6.73 (d, J ) 8.2 Hz,
1H), 7.37 (m, 4H), 7.51 (dd, J ) 8.2, 8.4 Hz, 1H), 7.54 (m, 1H),
1
cm-1; H NMR (90 MHz, d6-DMSO + CDCl3) δ 7.45 (dd, J )
7.9, 8.3 Hz, 1H), 8.48 (dd, J ) 1.5, 7.9 Hz, 1H), 8.64 (dd, J )
1.5, 8.3 Hz, 1H), 10.6 (br, 1H); MS m/z 208 (M+), 164 (M+
CO2). Anal. Calcd for C8H4N2O5: C,46.16; H, 1.94; N, 13.46.
Found: C, 46.30; H, 1.98; N, 13.21.
-
6-Acetoxyisa toic An h yd r id e (12c) a n d 3-Acetoxyisa -
toic An h yd r id e (4c). Colorless prisms (107 mg, 41%) of 12c
were obtained from a mixture of 3-acetoxyphthalic anhydride
(11c, 240 mg, 1.17 mmol), TMS-N3 (0.23 mL, 1.75 mmol), and
C6H6 (5.5 mL), under the same conditions as for 4b, followed
by recrystallization from EtOAc: mp 242-247 °C. IR (KBr)
3250, 1760, 1700, 1620, 1600 cm-1 1H NMR (90 MHz,
;
d6-DMSO + CDCl3) δ 2.35 (s, 3H), 6.83 (d, J ) 8.1 Hz, 1H),
7.05 (d, J ) 8.1 Hz, 1H), 7.62 (t, J ) 8.1 Hz, 1H), 11.72 (br,
1H); MS m/z 221 (M+), 179 (M+ - COCH3), 135 (M+ - CO2-
COCH3). Anal. Calcd for C10H7NO5 C, 54.30; H, 3.19; N, 6.33.
Found C, 54.39; H, 3.46; N, 6.53. The filtrate left from the
recrystallization of 12c was evaporated under reduced pres-
sure, and the residue was chromatographed by elution with
CH2Cl2-acetone (10:1) to give colorless prisms (30 mg, 12%)
11.31 (br, 1H); MS m/z 269 (M+), 92. Anal. Calcd for C15H11
-
NO4: C, 66.91; H, 4.12; N, 5.20. Found: C, 66.93; H, 4.19; N,
5.17.
3-Am in oisa toic An h yd r id e (4d ). The catalytic hydroge-
nation (H2 2 atm, 5% Pd-C 89 mg) of 3-nitroisatoic anhydride
(4b, 150 mg, 7.21 mmol) in THF (15 mL) was carried out for
1 h, followed by removal of the catalyst by filtration, evapora-
tion of the filtrate, and recrystallization of the residue from
THF to give a colorless powder (116 mg, 90%) of 4d : mp over
of 4c: mp 222-224 °C. IR (KBr) 1800, 1780, 1740, 1630 cm-1
;
1H NMR (90 MHz, d6-DMSO + CDCl3) δ 2.35 (s, 3H), 7.21 (t,
J ) 7.5 Hz, 1H), 7.44 (dd, J ) 1.5, 7.5 Hz, 1H), 7.85 (dd, J )
1.5, 7.5 Hz, 1H); MS m/z 221 (M+), 179 (M+ - COCH3), 135
1
280 °C. IR (KBr) 3200, 1700, 1610 cm-1; H NMR (90 MHz,
d6-DMSO + CDCl3) δ 6.93 (t, J ) 8.1 Hz, 1H), 7.09 (dd, J )

Stereoselective Synthesis of Tilivalline
J . Org. Chem., Vol. 63, No. 20, 1998 6801
1.5, 8.1 Hz, 1H), 7.45 (dd, J ) 1.5, 8.1 Hz, 1H), 9.84 (br, 1H),
10.75 (br, 1H); MS m/z 178 (M+), 106 (M+ - CO2).
(130 mg, 3.51 mmol). Stirring was continued at 0 °C for 2 h
while adding a few drops of diluted HCl-EtOH solution at
intervals of 10 min.19 The reaction mixture was evaporated
under reduced pressure to give a white mass which was
extracted with CHCl3. The extract was evaporated under
reduced pressure to the residue which was chromatographed
by elution with CH2Cl2-hexane-acetone (6:6:1) to give color-
less prisms (1.09 g, 76%) of 7b, recrystallized from EtOAc; mp
Hyd r olysis of Isa toic An h yd r id es: 3-Nitr oa n th r a n ilic
Acid . A solution of 4b (150 mg, 0.72 mmol) in concd HCl (3
mL) was refluxed for 1 h, followed by evaporation and
recrystallization of the residue from C6H6 to give yellow prisms
(90 mg, 69%) of mp 203-204 °C. IR (KBr) 3460, 3340, 3100-
2800, 1680, 1250 cm-1; 1H NMR (90 MHz, d6-DMSO + CDCl3)
δ 6.68 (t, J ) 7.8 Hz, 1H), 8.23 (d, J ) 7.8 Hz, 1H), 8.31 (d, J
) 7.8 Hz, 1H); MS m/z 164 (M+).
1
193-196 °C. IR (KBr) 3240, 1720, 1620 cm-1; H NMR (400
MHz, CDCl3) δ 2.05 (m, 4H), 3.47 (m, 1H), 3.55 (m, 1H), 3,75
3-Nitr oa n th r a n ilic a cid : mp 202-203 °C (lit.20).
(m, 1H), 4.90 (ABq, J AB ) 11.96 Hz, 2H), 4.99 (ABq, J AB
)
6-Nitr oa n th r a n ilic a cid : mp 184 °C (lit.20).
12.6 Hz, 2H), 5.63 (dd, J ) 3.4, 9.6 Hz, 1H), 7.00-7.38 (m,
13H); MS m/z 458 (M+). [R]25 +129° (c 0.99, CHCl3). Anal.
3-Meth oxya n th r a n ilic Acid . Colorless prisms (10 mg,
34%) of mp 173-174 °C were prepared from 4f (34 mg, 0.18
mmol) under the conditions above. IR (KBr) 3500, 3390,
D
Calcd for C27H26N2O5: C, 70.73; H, 5.72; N, 6.11. Found: C,
70.68; H, 5.77; N, 5.91.
1
3100-2600, 1670 cm-1; H NMR (90 MHz, CDCl3) δ 3.83 (s,
(+)-(11S,11aS)-1,2,3,10,11,11a-Hexah ydr o-9-(ben zyloxy)-
10-ca r boben zyloxy- 11-(3′-in d olyl)-5H-p yr r olo[2,1-c][1,4]-
ben zod ia zep in -5-on e (8b). A mixture of 7b (200 mg, 0.43
mmol), indole (102 mg, 0.87 mmol), and glacial AcOH (7 mL)
was heated at 150 °C for 5 h in a sealed tube. The solvent
was evaporated under reduced pressure to give a solid which
was purified by chromatography with CH2Cl2-hexane-
acetone (5:5:1) elution to give 228 mg (94%) of colorless prisms,
recrystallized from EtOH, mp 260-265 °C. IR (KBr) 3200,
1H), 6.55 (t, J ) 8.1 Hz, 1H), 6.83 (dd, J ) 1.5, 8.1 Hz, 1H),
7.49 (dd, J ) 1.5, 8.1 Hz, 1H). Mp and spectra (IR and 1H
NMR) agreed with the data for 3-methoxyanthranilic acid.21
(+)-(11a S)-1,2,3,10,11,11a -H exa h yd r o-9-(b en zyloxy)-
5H-p yr r olo[2,1-c][1,4]ben zod ia zep in -5,11-d ion e (5b).
A
solution of 4g (2.64 g, 9.8 mmol) and (S)-proline (1.35 g, 11.7
mmol) in absolute DMSO (7 mL) was heated at 100 °C for 5
h. After the reaction mixture was cooled, ice-water was
added, and the crystals that formed were separated by
filtration, washed with brine and dried. Recrystallization from
C6H6 afforded colorless prisms (2.65 g, 84%); mp 178-182 °C.
1
1700, 1610 cm-1; H NMR (400 MHz, CDCl3) δ 1.78 (m, 1H),
1.97 (m, 2H), 2.14 (m, 1H), 3.67 (m, 1H), 3.87 (m, 1H), 4.30
(m, 1H), 4.35 (ABq, J AB ) 11.8 Hz, 2H), 4.90 (ABq, J AB ) 12.8
Hz, 2H), 5.68 (d, J ) 8.0 Hz, 1H), 6.91-7.28 (m, 16H), 7.40 (d,
J ) 7.9 Hz, 1H), 7.44 (dd, J ) 1.1, 7.7 Hz, 1H), 8.14 (br, 1H);
MS m/z 557 (M+), 466 (M+ - CH2Ph), 422 (M+ - COOCH2-
Ph), 353 (M+ - indole - CH2Ph). [R]25D +267 (c 1.37, CHCl3).
Anal. Calcd for C35H31N3O4: C, 75.38; H, 5.60; N, 7.54.
Found: C, 75.56; H, 5.63; N, 7.59.
IR (KBr) 2970, 2850, 1690, 1600 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 2.01 (m, 3H), 2.75 (m, 1H), 3.60 (m, 1H), 3.79 (m,
1H), 4.02 (m, 1H), 5.12 (s, 2H), 7.10 (d, J ) 8.0 Hz, 1H), 7.17
(t, J ) 8.0 Hz, 1H), 7.38 (m, 5H), 7.58 (d, J ) 8.0 Hz, 1H),
7.97 (br, 1H); MS m/z 322 (M+), 231 (M+ - CH2Ph), 91. [R]25
D
+350° (c 1.00, CHCl3). Anal. Calcd for C19H18N2O3: C, 70.79;
Tiliva llin e (1). Catalytic hydrogenation (H2 1 atm, 5%
Pd-C 110 mg) of 8b (180 mg, 0.32 mmol) in THF-MeOH (1:
1) (10 mL) was carried out for 10 h, followed by filtration,
evaporation under reduced pressure, and chromatography of
the residue by elution with CHCl3-MeOH (40:1 to 20:1) to give
a solid which was recrystallized from acetonitrile to afford a
yellow amorphous mass (88 mg, 82%) of 1; mp 180-185 °C.
IR (THF) 3500, 3350, 1620, 760 cm-1; 1H NMR (400 MHz, d5-
pyridine) δ 1.61 (m, 1H), 1.71 (m, 2H), 1.79 (m, 1H), 3.84 (m,
1H), 4.08 (m, 1H), 4.50 (m, 1H), 4.99 (d, J ) 8.8 Hz, 1H), 5.92
(br, 1H), 6.90 (t, J ) 7.7 Hz, 1H), 7.22 (m, 2H), 7.31 (t, J ) 7.7
Hz, 1H), 7.57 (m, 2H), 7.86 (d, J ) 7.6 Hz, 1H), 8.11 (d, J )
7.9 Hz, 1H), 11.97 (br, 1H), 12.19 (br, 1H); 13C NMR (100 MHz,
d5-pyridine) δ 22.8, 31.2, 48.4, 60.8, 62.1, 112.4, 116.0, 117.1,
117.6, 119.9, 120.0, 121.1, 122.3, 123.2, 124.2, 126.3, 136.7,
H, 5.63; N, 8.69. Found: C, 71.08; H, 5.57; N, 8.53.
(11aS)-1,2,3,10,11,11a-Tetr ah ydr o-9-(ben zyloxy)-10-(ben -
zyloxyca r bon yl)-5H- p yr r olo[2,1-c][1,4]ben zod ia zep in -5,-
11-d ion e (6b). A solution of LHMDS (lithium hexamethyl-
disilazide, 3 mL, 3.1 mmol) in hexane was added dropwise at
room temperature to 5b (1 g, 3.1 mmol) in absolute THF (60
mL). After the reaction mixture was stirred at the same
temperature for 50 min, a solution of 30% benzyl chloroformate
(2.64 g, 4.65 mmol) in toluene was added, and stirring was
continued for 2 h. The reaction was terminated by adding
saturated NH4Cl solution and extracted with CHCl3. The
extract was washed with brine, dried over MgSO4, and
evaporated under reduced pressure to give an oil which was
chromatographed by elution with hexane-CH2Cl2-acetone
(15:15:1) to give yellow amorphous (1.25 g, 88%). Recrystal-
lization from ether gave 1.13 g (80%) of a colorless amorphous
138.0, 146.8, 167.8; MS m/z 333 (M+). [R]25 +210° (c 1.01,
D
1
solid. IR (KBr) 1790, 1730, 1640 cm-1; H NMR (400 MHz,
MeOH). HRMS (FAB) calcd for C20H19N3O2: 333.1476, found
333.1479.
CDCl3) δ 1.95 (m, 2H), 2.11 (m, 1H), 2.67 (m, 1H), 3.51 (m,
1H), 3.79 (m, 1H), 3.92 (d, J ) 7.5 Hz, 1H), 4.95 (ABq, J AB
)
Ack n ow led gm en t. The authors are grateful to
Professor T. Shioiri of Nagoya City University for kindly
providing spectral data and a sample of tilivalline.
4.0 Hz, 2H), 4.97 (ABq, J AB ) 12.0 Hz, 2H), 7.09-7.49 (m,
12H), 7.50 (d, J ) 7.7 Hz); MS m/z 456 (M+), 365 (M+ - CH2-
Ph), 321 (M+ - COOCH2Ph).
1
(+)-(11a S)-1,2,3,10,11,11a -Hexa h yd r o-9-(ben zyloxy)-10-
(ben zyloxyca r bon yl)- 11-h yd r oxy-5H-p yr r olo[2,1-c][1,4]-
ben zoa zep in -5-on e (7b). To a solution of 6b (1.43 g, 3.13
mmol) in absolute THF (200 mL) was added at 0 °C NaBH4
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for compounds 1, 4d , 6a , 6b, 7a , 9, 13C NMR spectra
for compounds 1, 9, and mass spectra of 1 (9 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
(20) Huntress, E. H.; Gladding, J . V. K. J . Am. Chem. Soc. 1942,
64, 2644; Nagai, U.; Chem. Pharm. Bull. 1975, 23, 1841.
(21) Tsunakawa, M.; Kamei, H.; Konishi, M.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J . Antibiotics 1988, 1366.
J O972158G