Stereoselective synthesis of (+)-isoindolo-β-carboline

Article abstract of DOI:10.1016/j.tetasy.2009.01.001

Starting from homophthalic anhydride and (S)-tryptophan, the stereoselective synthesis of (+)-isoindolo-β-carboline has been described via the corresponding homophthalimide, its chemoselective oxidative ring contraction, and the intramolecular dehydrative

Full text of DOI:10.1016/j.tetasy.2009.01.001

Tetrahedron: Asymmetry 20 (2009) 220–224
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (+)-isoindolo-b-carboline
Prasad B. Wakchaure a, Vedavati G. Puranik b, Narshinha P. Argade a,
*
a Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from homophthalic anhydride and (S)-tryptophan, the stereoselective synthesis of (+)-isoindolo-
b-carboline has been described via the corresponding homophthalimide, its chemoselective oxidative
ring contraction, and the intramolecular dehydrative ring closure followed by a geometry-specific
demethoxycarbonylation.
Received 25 November 2008
Accepted 9 January 2009
Available online 31 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The b-carboline nucleus is present in very important bioactive
natural products, such as reserpine, yohimbine, rutacarpine, and
ajmalicine.1 Both natural and unnatural b-carboline compounds,
as well as their analogues and congeners, are of high synthetic
interest as important hypotensive agents.1,2 An important target
is the isoindolo-b-carboline system, for which several racemic syn-
theses, starting from 3-hydroxyphthalide or phthalimide deriva-
We started the synthesis of (+)-1 from the isomeric acids 2/3
and (S)-tryptophan via the requisite precursor, imide 6. Homoph-
thalic anhydride upon treatment with methanol in the presence
of boron trifluoride diethyl etherate (BF3ꢀEt2O) underwent a highly
regioselective methanolysis at the more reactive unconjugated car-
bonyl group and furnished the mono-ester 2 in quantitative yiel-
d.8a On the other hand, the reaction of homophthalic acid with
one equivalent of diazomethane in diethyl ether furnished the
opposite mono-ester 38b in 95% yield via the reaction of the more
acidic aromatic carboxylic group. The N-ethyl-N0-(3-dimethylami-
nopropyl)carbodimide hydrochloride (EDCI) induced dehydrative
coupling reactions of isomeric acids 2 and 3 with (S)-tryptophan
furnished the corresponding homophthalamic esters 5 and 4,
respectively, in high yields. Both 5 and 4 upon treatment with tri-
ethylamine furnished the corresponding imide 6. As anticipated,
the intramolecular cyclization of 5, involving the non-conjugated
ester unit, to form 6 was faster and more efficient (89% yield)
than the cyclization of 4 to 6 involving an aromatic ester unit
(46% yield). Treatment of any of the three precursors 4/5/6 with
triethylamine in methanol furnished directly a mixture of diaste-
reomeric lactamols 7a/b, not separable by silica-gel column chro-
matography, in a 2:3 ratio (by 1H NMR) with 71%/92%/88% yields,
respectively. In the case of 4/5, the entire transformation occurs
in one-pot. The sequence consists of an initial conversion of 4/5
to the imide 6, followed by a facile in situ chemoselective air-
oxidation of the methylene group in homophthalimide 6 to the
corresponding reactive trione intermediate. This subsequently
undergoes regioselective methanolysis at the unconjugated imide
carbonyl group and then an intramolecular ring closure to yield
the oxidative ring-contracted product. Herein, the possibility of at-
tack of methanol on the more reactive newly generated benzylic
carbonyl group followed by an in situ facile intramolecular 1,2-
shift of the methoxy group to form the corresponding un-isolable
keto-ester intermediate leading to the intramolecular cyclization
tives, and one stereoselective approach affording
a
20%
diastereomeric excess, are known in the literature.3,4 Recently, a
stereoselective approach to isoindolo-b-carbolines has been re-
ported, which takes advantage of a palladium-catalyzed carbonyl-
ation process, but with an observed partial racemization.5 The
above-mentioned studies revealed that starting from the (S)-tryp-
tophan and pre-reduced 3-hydroxyphthalide, the stereoselectivity
obtained during the course of intramolecular cyclization was
weak.4 On the other hand, in the case of requisite phthalimide as
a starting material, the chemoselective reduction of an imide car-
bonyl group in the presence of a methoxycarbonyl unit without
any racemization at the sensitive stereogenic center would be a
difficult task. During our extensive studies on cyclic anhydrides
and their use in the construction of structurally interesting and
biologically important natural/unnatural products,6 we have re-
cently witnessed a facile air-oxidation of the active methylene
group in homophthalimide to the corresponding carbonyl group;
this strategy was successfully used for the synthesis of the natural
product nuevamine.7 Hence, we envisaged homophthalic anhy-
dride and (S)-tryptophan as suitable building blocks for the
synthesis of enantiomerically and diastereomerically pure isoindo-
lo-b-carbolines. Herein, we report another application of such a pro-
pensity of homophthalimides to undergo air-oxidation to complete
the stereoselective synthesis of isoindolo-b-carboline (Scheme 1).
* Corresponding author. Tel.: +91 20 25902333; fax: +91 20 25902629.
E-mail address: np.argade@ncl.res.in (N.P. Argade).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.001

P. B. Wakchaure et al. / Tetrahedron: Asymmetry 20 (2009) 220–224
221
COOH
COOMe
COOMe
COOH
3
2
i
(94%)
(93%)
O
i
COOMe
COOMe
O
NH
NH
COOMe
N
COOMe
N
H
H
ii
iiia
(71%)
(89%)
5
4
iiib
(92%)
ii
(46%)
COOMe
COOMe
O
iv
HO
O
N
O
N
N
H
(88%)
N
H
MeOOC
6
7a
7b
(α-OH): (β-OH) = 2:3
v
(71%)
COOMe
O
N
N
H
MeOOC
8a
8b
(α-COOMe): (β-COOMe) = 4:1
vi
(72%)
COOMe
O
N
N
-
H
9a
COOMe
O
COOMe
O
N
N
N
H
N
H
-
H
9b
1
( )-
Scheme 1. Reagents, conditions, and yields: (i) 2/3, N-ethyl-N0-(3-dimethylaminopropyl)carbodimide hydrochloride (EDCI), (S)-tryptophan methyl ester hydrochloride,
DMAP, DCM, NEt3, rt, 6 h (94/93%); (ii) 4/5, NEt3, MeOH, rt, 24/4 h (46/89%); (iii) (a) NEt3, MeOH, rt, 48 h, (71%), (b) NEt3, MeOH, oxygen atmosphere, rt, 18 h, (92%); (iv) NEt3,
MeOH, rt, 12 h, (88%); (v) AcOH, cat. H+/H2SO4, rt, 6 h (8a: 57%, ꢁ100% ee, 8b: 14%); (vi) 8a, NaCl, DMSO, H2O, AcOH, 210 °C, 2 h (72%, 98% ee).
with the net formation of lactamols 7a/b also exists. We could also
enhance the rates of these air-oxidation reactions by carrying them
out under an oxygen atmosphere. The 1H NMR spectrum of the
mixture of 7a/b (2:3) revealed that in 7b, the signal for the methyl
ester of the tryptophan subunit was shielded due to the intramo-
lecular influence of the free b-hydroxyl group, present on the same

222
P. B. Wakchaure et al. / Tetrahedron: Asymmetry 20 (2009) 220–224
face, on an ester moiety. Initially, we were unhappy with the 20%
diastereomeric excess obtained in the formation of 7a/b; however,
in the next transformation of 7a/b to 8a/b, it was possible to gain
some diastereoselectivity. The above mixture of 7a/b on treatment
with trifluoroacetic acid at room temperature furnished 8a exclu-
sively, but with only 21% yield. When a catalytic amount of sulfuric
acid in acetic acid was used to carry out the same reaction, a sep-
arable mixture of intramolecular dehydrative cyclization products
8a/b was obtained in a 4:1 ratio (by 1H NMR), but with an im-
proved yield of 71%. We presume that the present acid-catalyzed
cyclization takes place via an SN1 mechanism, and in the conver-
sion of 7a/b (20% de) to 8a/b (60% de), the cyclization of a transient
N-acyliminium ion9 takes place with the predominant formation of
the trans-isomer 8a. In the event of an SN2 mechanism being in
operation, we feel that a dynamic kinetic resolution of the sub-
strate 7a could be occurring via the partial racemization of 7b
through the ring-chain tautomerism. Unfortunately, all our at-
tempts to further improve the diastereomeric excess met with fail-
ure, as the rate of cyclization was plausibly faster than the rate of
formation of N-acyliminium ion/racemization of 7b. We separated
the diastereomeric mixture of 8a and 8b by silica-gel column chro-
matography and further confirmed the structure as well as the
enantiomeric purity of the major isomer 8a from X-ray crystallo-
graphic data and chiral HPLC (ꢁ100% ee), respectively. In the 1H
NMR spectrum of 8a, we noticed a considerable geometry-depen-
mization at the asymmetric angular position, is already known
in the literature.11
3. Conclusion
In summary, we have demonstrated the first stereoselective
approach to enantiomerically pure (+)-isoindolo-b-carboline by
taking advantage of a facile chemoselective air-oxidation of hom-
ophthalimide and gain in the diastereoselectivity during the intra-
molecular dehydrative cyclization process. We feel that the highly
stereoselective geometry-dependent demethoxycarbonylation in
the present approach is also noteworthy.
4. Experimental
4.1. General
Melting points are uncorrected. 1H NMR spectra were recorded
in CDCl3 and DMSO-d using TMS as an internal standard on 200
and 400 MHz spectrometers. 13C NMR spectra were recorded on
200, 400, and 500 NMR spectrometers (50, 100, and 125 MHz,
respectively). IR spectra were recorded on a FT-IR spectrometer.
Column chromatographic separations were done on silica gel
(60–120, 230–300 mesh). Commercially available homophthalic
anhydride, N-ethyl-N0-(3-dimethylaminopropyl)carbodimide hydro-
chloride (EDCI), and (S)-tryptophan were used.
dent shielding of the a-methine proton. In 8a/b, the angular carbo-
methoxy group is attached to the carbon, which is both allylic and
benzylic with an adjacent tertiary amide nitrogen atom. Hence, we
systematically studied the demethoxycarbonylation of both 8a and
8b under the Krapcho and Lovey conditions, suitable for geminal
4.2. (S)-Methyl 2-(2-(3-(1H-indol-3-yl)-1-methoxy-1-oxopro-
pan-2-ylamino)-2-oxoethyl)benzoate 4
diesters, b-ketoesters, and
a
-cyano esters.10 The reaction of the
To a stirred slurry of acid 3 (300 mg, 1.54 mmol) in DCM (20
mL) were added N-ethyl-N0-(3-dimethylaminopropyl)carbodimide
hydrochloride (EDCI, 590 mg, 3.09 mmol), (S)-tryptophan methyl
ester hydrochloride (391 mg, 1.54 mmol), and cat. DMAP under a
nitrogen atmosphere. The reaction mixture was cooled to 0 °C,
and NEt3 (0.20 mL, 1.54 mmol) was added slowly, and the reaction
mixture was stirred at room temperature for further 6 h. DCM was
removed in vacuo, and to the reaction mixture was added water
(30 mL), and then it was extracted with ethyl acetate (3 ꢃ 20
mL). The combined organic layer was washed with 1 M HCl, brine,
and dried over Na2SO4. Concentration of the organic layer in vacuo
followed by silica-gel column chromatographic purification of the
residue obtained using petroleum ether–ethyl acetate (2:3) as an
major isomer 8a with sodium chloride in moist dimethyl sulfoxide
at 210 °C furnished ꢁ100% diastereomerically pure 1 in 72% yield.
Plausibly, this proceeds via the regioselective decarbomethoxyla-
tion of the angular
a-ester moiety, followed by inversion of the
formed -carbanion 9a to the b-carbanion 9b and subsequent
a
abstraction of a proton from the same b-face. At this stage, we felt
that the possible escaping of methyl chloroformate/hydrochloric
acid formed during the course of the reaction at 210 °C can result
in in situ formation of sodium hydroxide, causing the excessive
racemization of the asymmetric center present in the tryptophan
subunit. The synthesis of ( )-1 and the comparison of chiral HPLC
data of the racemic mixture with (+)-1 revealed that our concern
about the racemization of (+)-1 was indeed correct and it was ob-
tained with only 66% ee. We reasoned that, it should be possible to
stop such a racemization of (+)-1 by carrying out the decarbometh-
oxylation in the presence of acetic acid, which would then generate
only the weak base sodium acetate in situ. Thus, we repeated the
decarbomethoxylation of (ꢂ)-8a in the presence of acetic acid
and obtained (+)-1 with a similar yield of 72%, but this time with
98% ee (by chiral HPLC). Thus, starting from homophthalic anhy-
dride, enantiomerically pure (+)-isoindolo-b-carboline 1 was ob-
tained in five steps with 35% overall yield. The analytical and
spectroscopic data obtained for (+)-1 were in complete agree-
ment with the reported data;5 the structure of (+)-1 was also
confirmed from the X-ray crystallographic data. Pure 8b or 8b
in the mixture of 8a/b (4:1) on treatment with sodium chloride
in moist dimethyl sulfoxide at 210 °C remained completely unre-
acted, and we were unable to force the decarbomethoxylation of
the angular ester moiety in 8b. On the basis of a manually pre-
pared flexible molecular model, we feel that in the case of com-
pound 8b, the negatively charged chloride ion is unable to access
the carbonyl group of the angular ester moiety because of the
eluent gave compound
¼ þ29:6 (c 2.8, CHCl3); IR (CHCl3) mmax 3477, 3422, 1740,
1717, 1665 cmꢂ1 1H NMR (CDCl3, 400 MHz) d 3.24 (d, J = 4 Hz,
4 as a thick oil (566 mg, 93%).
½ ꢄ
a 2D0
;
2H), 3.62 (s, 3H), 3.74 (s, 3H), 3.82 (d, J = 16 Hz, 1H), 3.92 (d,
J = 16 Hz, 1H), 4.83–4.91 (m, 1H), 6.77 (d, J = 4 Hz, 1H), 6.84 (br
d, J = 8 Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 7.28–
7.38 (m, 3H), 7.42–7.48 (m, 2H), 7.91 (d, J = 8 Hz, 1H), 8.02 (br s,
1H); 13C NMR (CDCl3, 100 MHz) d 27.3, 41.8, 51.9, 52.0, 52.9,
109.1, 111.2, 118.1, 119.1, 121.5, 122.9, 127.1, 127.2, 129.0,
130.8, 131.9, 132.4, 136.0, 136.2, 167.7, 170.7, 172.2. Anal. Calcd
for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10. Found: C, 67.09; H,
5.53; N, 7.22.
4.3. (S)-Methyl 3-(1H-indol-3-yl)-2-(2-(2-methoxy-2-oxoethyl)
benzamido)propanoate 5
To a stirred slurry of acid 2 (1.50 g, 7.73 mmol) in DCM (50 mL)
were added N-ethyl-N0-(3-dimethylaminopropyl)carbodimide
hydrochloride (EDCI, 2.95 g, 15.46 mmol), (S)-tryptophan methyl
ester hydrochloride (1.96 g, 7.73 mmol), and cat. DMAP under a
nitrogen atmosphere. The reaction mixture was cooled to 0 °C,
and NEt3 (1.10 mL, 7.78 mmol) was added slowly, and the reaction
internal steric crowding and also repulsive
p-cloud interactions
reasons. Further, decarbomethoxylation of the second carbome-
thoxy group on compounds of the type (+)-1, without any race-

P. B. Wakchaure et al. / Tetrahedron: Asymmetry 20 (2009) 220–224
223
mixture was stirred at room temperature for further 6 h. DCM was
removed in vacuo, and to the reaction mixture was added water
(50 mL), and then it was extracted with ethyl acetate (3 ꢃ 30
mL). The combined organic layer was washed with 1 M HCl, brine,
and dried over Na2SO4. Concentration of the organic layer in vacuo
followed by silica-gel column chromatographic purification of the
residue obtained using petroleum ether–ethyl acetate (2:3) as an
3.69 (s, 1.20H), 3.75 (s, 1.80H), 3.96 (dd, J = 14 and 10 Hz, 0.60H),
4.09 (br s, 0.40H), 4.49 (br s, 0.60H), 4.71 (dd, J = 10 and 6 Hz,
0.60H), 4.93 (dd, J = 10 and 6 Hz, 0.40H), 7.04–7.21 (m, 3H),
7.27–7.43 (m, 2H), 7.50–7.58 (m, 2H), 7.59–7.70 (m, 1H), 7.77–
7.90 (m, 1H), 8.08 (br s, 1H); 13C NMR (CDCl3, 125 MHz) d 24.70,
25.63, 52.47, 52.69, 52.97, 53.47, 54.13, 56.40, 87.53, 88.69,
110.70, 110.92, 111.16, 111.23, 118.31, 118.35, 119.30, 119.32,
121.67, 121.82, 121.93, 122.21, 123.09, 123.55 (2-carbons),
124.00, 126.95, 127.04, 130.26 (2-carbons), 130.76, 130.81,
132.76 (2-carbons), 135.96, 136.09, 143.74, 143.93, 167.88,
168.65, 169.18, 170.26, 171.17, 171.86. Anal. Calcd for
C22H20N2O6: C, 64.70; H, 4.94; N, 6.86. Found: C, 64.57; H, 5.06;
N, 6.99.
Method B: To a stirred solution of amide 4 (100 mg, 0.253 mmol)
in methanol (10 mL) at room temperature was added NEt3 (two
drops), and the reaction mixture was stirred for 48 h under atmo-
spheric conditions. The reaction mixture was concentrated in va-
cuo, and the obtained residue was purified by silica-gel column
chromatography using petroleum ether–ethyl acetate (1:1) as an
eluent to obtain a mixture of compounds 7a/b (2:3, 73 mg, 71%).
Method C: To a stirred solution of imide 6 (200 mg, 0.55 mmol)
in methanol (15 mL) at room temperature was added NEt3 (two
drops), and the reaction mixture was stirred for 12 h under atmo-
spheric conditions. The reaction mixture was concentrated in va-
cuo, and the obtained residue was purified by silica-gel column
chromatography using petroleum ether–ethyl acetate (1:1) as an
eluent to obtain a mixture of compounds 7a/b (2:3, 198 mg, 88%).
eluent provided compound
¼ þ41:1 (c 2.0, CHCl3); IR (CHCl3) mmax 3477, 3422, 1736,
1655 cmꢂ1 1H NMR (CDCl3, 400 MHz) d 3.33–3.45 (m, 2H), 3.59
5 as a thick oil (2.86 g, 94%).
½ ꢄ
a 2D0
;
(s, 3H), 3.72 (s, 3H), 3.81 (d, J = 16 Hz, 1H), 3.88 (d, J = 16 Hz, 1H),
5.07–5.14 (m, 1H), 7.02 (br d, J = 8 Hz, 1H), 7.07 (br s, 1H), 7.10
(d, J = 8 Hz, 1H), 7.17 (t, J = 8 Hz, 1H), 7.20–7.28 (m, 2H), 7.31–
7.42 (m, 3H), 7.56 (d, J = 8 Hz, 1H), 8.19 (br s, 1H); 13C NMR (CDCl3,
100 MHz) d 27.5, 38.6, 52.0, 52.3, 53.2, 109.5, 111.3, 118.3, 119.3,
121.9, 123.1, 127.3, 127.4, 127.8, 130.4, 131.2, 132.4, 135.7,
136.1, 168.9, 172.4, 172.7. Anal. Calcd for C22H22N2O5: C, 66.99;
H, 5.62; N, 7.10. Found: C, 67.11; H, 5.54; N, 7.17.
4.4. (S)-Methyl 2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-
3-(1H-indol-3-yl)propanoate 6
Method A: To a stirred solution of compound 5 (300 mg, 0.76
mmol) in methanol (20 mL) at room temperature was added
NEt3 (two drops), and the reaction mixture was stirred for further
4 h under argon atmosphere. The reaction mixture was concen-
trated in vacuo, and the obtained residue was purified by silica-
gel column chromatography using petroleum ether–ethyl acetate
(3:2) as an eluent to obtain compound 6 as a thick oil (245 mg,
4.6. (S)-Methyl 5,7,8,13b-tetrahydro-5-oxo-13H-13b-methoxy-
carbonyl-(S)-indolo[2,3-c]isoindolo[2,1-a] pyridine-7-carboxy-
late 8a and (R)-methyl 5,7,8,13b-tetrahydro-5-oxo-13H-13b-
methoxycarbonyl-(S)-indolo[2,3-c]isoindolo[2,
89%). ½a 2D0
ꢄ
¼ ꢂ131:0 (c 2.0, CHCl3); IR (CHCl3) mmax 3477, 1744,
1720, 1674 cmꢂ1
;
1H NMR (CDCl3, 400 MHz) d 3.53–3.79 (m,
3H), 3.74 (s, 3H), 3.85 (d, J = 24 Hz, 1H), 5.87 (dd, J = 8 and 8 Hz,
1H), 6.99 (t, J = 8 Hz, 1H), 7.03 (s, 1H), 7.09 (t, J = 8 Hz, 1H), 7.15
(d, J = 8 Hz, 1H), 7.25 (d, J = 8 Hz, 1H), 7.39 (t, J = 8 Hz, 1H), 7.54
(t, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.97 (bs, 1H), 8.12 (d, J = 8
Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 24.3, 36.0, 52.3, 53.7,
111.0, 111.1, 118.3, 119.1, 121.6, 123.0, 124.7, 126.9, 127.3,
127.5, 128.9, 133.6, 133.9, 135.9, 164.4, 169.5, 170.3. Anal. Calcd
for C21H18N2O4: C, 69.60; H, 5.01; N, 7.73. Found: C, 69.47; H,
4.94; N, 7.74.
Method B: To a stirred solution of compound 4 (400 mg, 1.01
mmol) in methanol (15 mL) at room temperature was added
NEt3 (two drops), and the reaction mixture was stirred for a further
24 h under an argon atmosphere. The reaction mixture was con-
centrated in vacuo, and the residue obtained was purified by sil-
ica-gel column chromatography using petroleum ether–ethyl
acetate (3:2) as an eluent to obtain compound 6 as a thick oil
(170 mg, 46%).
1-a] pyridine-7-carboxylate 8b
To a stirred solution of mixture of 7a/b (1.70 g, 4.16 mmol) in
AcOH (15 mL) at 10 °C was added concd H2SO4 (two drops), and
the reaction mixture was stirred at room temperature for 6 h. The
reaction mixture was diluted with ethyl acetate (30 mL), and the or-
ganic layer was washed with 5% aqueous NaHCO3 solution, brine,
and dried over Na2SO4. Concentration of the organic layer in vacuo
followed by silica gel (230–400 mesh) column chromatographic
purification of the residue obtained using petroleum ether–ethyl
acetate (7:3) as an eluent furnished compound 8a (920 mg, 57%)
and 8b (230 mg, 14%) as crystalline solids with a total yield of 71%.
Compound 8a: Mp 189–191 °C; ½a D20
¼ ꢂ43:6 (c 1.0, CHCl3);
ꢄ
ꢁ100% ee by chiral HPLC; IR (CHCl3) mmax 3248, 1755, 1749, 1684
cmꢂ1 1H NMR (CDCl3, 200 MHz) d 3.16 (dd, J = 16 and 4 Hz, 1H),
;
3.36 (dd, J = 16 and 8 Hz, 1H), 3.89 (s, 3H), 3.97 (s, 3H), 4.54 (dd,
J = 12 and 4 Hz, 1H), 7.11 (dt, J = 8 and 2 Hz, 1H), 7.22 (dt, J = 8
and 2 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.52
(dt, J = 8 and 2 Hz, 1H), 7.66 (dt, J = 8 and 2 Hz, 1H), 7.82 (dd,
J = 8 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 8.68 (br s, 1H); 13C NMR (CDCl3,
50 MHz) d 23.3, 52.2, 53.3, 53.9, 68.8, 108.5, 111.9, 118.9, 119.5,
122.7, 123.8, 124.2, 125.5, 129.5, 130.1, 130.3, 133.3, 137.1,
143.1, 167.7, 168.3, 169.6. Anal. Calcd for C22H18N2O5: C, 67.69;
H, 4.65; N, 7.18. Found: C, 67.65; H, 4.80; N, 7.12. HPLC details: Col-
umn: chiralcel ODH (250 ꢃ 4.6 mm), mobile phase: Ethanol/n-hex-
ane (15:85), wavelength: 240 nm, flow rate: 0.5 mL/min, retention
time: 25.4 min (ꢂ)-isomer, 27.5 min (+)-isomer.
4.5. (R)-Methyl 2-((S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopro-
pan-2-yl)-1-hydroxy-3-oxoisoindoline-1-carboxylate (7a) and
(S)-methyl 2-((S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-
2-yl)-1-hydroxy-3-oxoisoindoline-1-carboxylate 7b
Method A: To a stirred solution of amide 5 (2.00 g, 5.07 mmol) in
methanol (50 mL) at room temperature was added NEt3 (1 mL),
and the reaction mixture was stirred for a further 6 h at room tem-
perature. The reaction mixture was oxygenated by bubbling excess
of oxygen gas for 6 h and stirred for further 6 h. The reaction mix-
ture was concentrated in vacuo, and the obtained residue was puri-
fied by silica-gel column chromatography using petroleum ether–
ethyl acetate (1:1) as an eluent to obtain the mixture of com-
pounds 7a/b inseparable by column chromatography (2:3, 1.90 g,
Compound 8b: Mp 120–122 °C; ½a D20
ꢄ
¼ þ63:5 (c 2.4, CHCl3); IR
(CHCl3) mmax 3454, 1742, 1740, 1701 cmꢂ1
;
1H NMR (CDCl3, 200
MHz) d 3.17 (dd, J = 16 and 6 Hz, 1H), 3.31 (dd, J = 16 and 2 Hz, 1H),
3.67 (s, 3H), 3.73 (s, 3H), 5.86 (dd, J = 8 and 2 Hz, 1H), 7.04–7.24
(m, 2H), 7.36–7.66 (m, 4H), 7.80–7.95 (m, 2H), 9.06 (br s, 1H); 13C
NMR (CDCl3, 50 MHz) d 24.9, 51.0, 52.4, 53.3, 66.9, 107.7, 111.5,
118.7, 119.9, 121.9, 123.0, 124.8, 126.1, 128.2, 129.7, 130.2, 133.0,
92%). Mp 72–74 °C; ½a D20
ꢄ
¼ ꢂ98:0 (c 0.2, CHCl3); IR (CHCl3) mmax
3476, 3398, 1744, 1736, 1709, 1701 cmꢂ1
;
1H NMR (CDCl3, 200
MHz) d 2.78 (s, 1.80H), 3.38 (s, 1.20H), 3.44–3.75 (m, 1.40H),

224
P. B. Wakchaure et al. / Tetrahedron: Asymmetry 20 (2009) 220–224
137.3, 144.7, 170.1, 170.8, 171.0. Anal. Calcd for C22H18N2O5: C,
67.69; H, 4.65; N, 7.18. Found: C, 67.72; H, 4.56; N, 7.07.
graphic Data Center as supplementary publication numbers CCDC
710301 and 710302. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.7. (S)-7-Oxo-6,7,11b,12-tetrahydro-5H-6a,12-diaza-(R)-indeno
[1,2-a]fluorene-6-carboxylic acid Methyl ester 1
Acknowledgements
To a stirred solution of compound 8a (700 mg, 1.79 mmol) in a
mixture of DMSO (20 mL), water (1 mL), and acetic acid (1 mL) was
added NaCl (100 mg, 1.79 mmol). The reaction mixture was deoxy-
genated by bubbling an excess of nitrogen gas for 12 h. Then, it
was heated at 210 °C for 2 h. The reaction mixture was then cooled
to room temperature and diluted with ethyl acetate (25 mL). The
organic layer was washed with brine and driedover Na2SO4. Concen-
tration of the organic layer in vacuo followed by silica gel (100–200
mesh) column chromatographic purification of the residue obtained
using petroleum ether–ethyl acetate (4:1) as an eluent gave com-
pound 1 as a white crystalline solid (429 mg, 72%). Mp 238–240 °C
P.B.W. thanks CSIR, New Delhi for the award of research fellow-
ship. We thank Mrs. S. S. Kunte from NCL, Pune for the chiral HPLC
data.
References
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(ethyl acetate) (lit.5 166–168 °C); ½a D20
¼ þ101:6 (c 1.0, CHCl3), 98%
ꢄ
ee by chiral HPLC; IR (CHCl3) mmax 3470, 1742, 1739, 1686 cmꢂ1
;
1H NMR (CDCl3, 200 MHz) d 3.20 (ddd, J = 16, 8 and 2 Hz, 1H), 3.47
(td, J = 16 and 2 Hz, 1H), 3.72 (s, 3H), 5.78 (d, J = 6 Hz, 1H), 6.24 (s,
1H), 7.06–7.23 (m, 2H), 7.36 (dd, J = 8 Hz, 1H), 7.49 (d, J = 8 Hz,
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50 MHz) d 24.5, 50.3, 52.6, 55.5, 106.2, 111.2, 118.4, 119.8, 122.5,
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C, 72.09; H, 4.68; N, 8.43. HPLC details: Column: chiralcel ODH
(250 ꢃ 4.6 mm), mobile phase: isopropyl alcohol/Pet Ether
(30:70), wavelength: 254 nm, flow rate: 0.5 mL/min, retention time:
11.2 min (+)-isomer, 12.7 min (ꢂ)-isomer.
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4.8. Crystallographic data
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Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge Crystallo-