Facile air-oxidation of N-homopiperonyl-5,6-dimethoxyhomophthalimide: simple and efficient access to nuevamine

Article abstract of DOI:10.1016/j.tet.2007.11.104

A facile six-step synthesis of naturally occurring (±)-nuevamine with 55% overall yield has been described, starting from methyl 2-(6-formyl-2,3-dimethoxyphenyl)acetate via the quantitative benzylic air-oxidation of the corresponding N-homopiperonyl-5,6-d

Full text of DOI:10.1016/j.tet.2007.11.104

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Tetrahedron 64 (2008) 1786e1791
www.elsevier.com/locate/tet
Facile air-oxidation of N-homopiperonyl-5,6-dimethoxyhomophthalimide:
simple and efficient access to nuevamine
Prasad B. Wakchaure a, Srinivasan Easwar a, Vedavati G. Puranik b, Narshinha P. Argade a,
*
a Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
Received 31 August 2007; received in revised form 16 November 2007; accepted 29 November 2007
Available online 3 December 2007
Abstract
A facile six-step synthesis of naturally occurring (ꢀ)-nuevamine with 55% overall yield has been described, starting from methyl 2-
(6-formyl-2,3-dimethoxyphenyl)acetate via the quantitative benzylic air-oxidation of the corresponding N-homopiperonyl-5,6-dimethoxy-
homophthalimide to N-homopiperonyl-5,6-dimethoxyisoquinoline-1,3,4-trione as the key reaction, followed by base catalyzed regioselective
alcoholysis of the trione with ring contraction, acid catalyzed dehydrative ring closure of the formed lactamol and decarboxylation pathway.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
homopiperonyl amine (2)7 we prepared the homophthalimide
48 in 92% yield (Scheme 1). We attempted a NaBH4 reduction
of homophthalimide 4 in methanol at room temperature with
the aim of regioselectively reducing the more reactive uncon-
jugated imide carbonyl group for the further enzymatic resolu-
tion and synthesis of gusanlung D. In the above reaction, we
observed the formation of a new product in 70% yield but to
The naturally occurring (ꢀ)-nuevamine (1)1,2 from the
Berberis darwini Hook species1 is the first eminent member of
the isoindolo[1,2-a]isoquinolinone family.2 On the basis of syn-
thesis,2 the structure of nuevamine (1) has been reestablished
with the alteration in the positions of two methoxy groups.
Several general approaches for the synthesis of isoindoloiso-
quinoline skeleton are known in the literature.3 Very recently,
Couture and co-workers have reported two elegant approaches
to 1 by using an aryne-mediated intramolecular cyclization
and a Parham cyclization as the key reactions.4 In the course
of our studies on the total synthesis of gusanlung D,5 we ob-
served the facile air-oxidation of the benzylic methylene
groups of the intermediate homophthalimides and taking ad-
vantage of the same, we now herein report a new simple and
efficient access to the nuevamine (Schemes 1 and 2).
1
our surprise, the H NMR spectrum of the product revealed
the absence of both the benzylic protons from the starting ma-
terial 4. Careful analysis of both the analytical and spectral
data of the product indicated the formation of an isoindole 5
with a net oxidative ring contraction. Since we did not observe
the formation of our originally desired reduced product, we
presumed that a catalytic amount of NaBH4 got converted
into sodium methoxide in situ and thus, we proposed a facile
air-oxidation of the benzylic carbon in the imide 4, followed
by very fast regioselective methanolysis (catalyzed by the
methoxide) and an intramolecular ring closure pathway for
the formation of a-hydroxy ester 5. Our hypothesis was justi-
fied when we carried out the reaction of imide 4 in methanol
using triethylamine as the base catalyst and obtained the same
a-hydroxy ester 5 in 76% yield. Our literature search, then
revealed that such type of serendipitous air oxidation of methyl-
ated homophthalimide, under the basic conditions, to the
corresponding tertiary alcohol intermediate is known.9,10 The
lactamol 5 on treatment with catalytic amount of sulfuric
2. Results and discussion
In continuation of our studies on cyclic anhydrides chemi-
stry,6 starting from homophthalic anhydride (3) and
* Corresponding author. Tel.: þ91 20 25902333; fax: þ91 20 25902624.
E-mail address: np.argade@ncl.res.in (N.P. Argade).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.104

P.B. Wakchaure et al. / Tetrahedron 64 (2008) 1786e1791
1787
O
O
O
O
O
N
O
N
O
O
O
O
i
ii/iii
O
HO
MeOOC
+
NH2
O
5
4
Homopiperonyl amine (2)
Homophthalic
anhydride (3)
iv
O
O
O
O
N
N
N
O
O
O
O
O
v
vi
MeOOC
HO
7
6
8
ORTEP Diagram of 6
Scheme 1. Synthesis of isoindoloisoquinoline. Reagents, conditions, and yields: (i) o-dichlorobenzene, reflux, 3 h (92%); (ii) NaBH4, MeOH, rt, 20 h (70%); (iii)
MeOH, NEt3, rt, 12 h (76%); (iv) 6 M H2SO4þAcOH (1:2), rt, 2 h (84%); (v) NaCl, H2O, DMSO, 175 ꢁC, 30 min (79%); (vi) NaBH4, TFA, rt, 5 h (85%).
acid in acetic acid at room temperature, underwent an expedi-
tious intramolecular dehydrative ring closure to yield the iso-
indoloisoquinoline 6 with an angular carbomethoxy function in
84% yield. Finally, the structure of compound 6 was confirmed
by using X-ray crystallographic analysis. The compound 6 on
decarboxylation furnished the isoindoloisoquinoline 7 in 79%
yield, with an angular hydroxyl function, as a result of the re-
action of the formed intermediate carbanionic species with the
dissolved oxygen. The compound 7 on NaBH4eTFA reduc-
tion3f furnished via the corresponding iminium intermediate,
the desired isoindoloisoquinoline 8 in 85% yield.
methyl 2-(6-formyl-2,3-dimethoxyphenyl)acetate (9) in six
steps using the known procedure.11 The aldehyde 9 on Jones
oxidation gave the desired 3,4-dimethoxyhomophthalic acid
mono-ester 10 in 98% yield. The N-ethyl-N0-(3-dimethylamino-
propyl)carbodimide hydrochloride (EDCI) induced intermole-
cular dehydrative coupling reaction of 10 with homopiperonyl
amine gave the homophthalamic acid methyl ester 11 in 83%
yield. The solution of ester 11 in methanol, on treatment with
catalytic amount of triethylamine at room temperature immedi-
ately furnished the white precipitate of homophthalimide 12 in
quantitative yield. Herein, the homophthalimide 12 was practi-
cally insoluble in methanol and we did not observe formation of
any further air-oxidized product. However, the solution of imide
12 in DMSOþMeOH mixture (4:1), on treatment with catalytic
amount of triethylamine under the oxygen atmosphere at room
All the results summarized in Scheme 1, prompted us to
launch a program toward the synthesis of nuevamine (Scheme
2). We started the synthesis of required 3,4-dimethoxyhomoph-
thalic acid from the isovanillin and obtained the corresponding
O
O
O
O
CHO
COOH
HN
O
MeOOC
MeOOC
N
O
O
i
ii
iii
MeOOC
MeO
(98%)
(83%)
(99%)
MeO
MeO
12
OMe
9
OMe
10
MeO
iv
OMe
OMe
11
15
(98%)
(99%)
v
O
O
O
O
O
O
O
N
N
HN
O
O
O
HO
MeOOC
vi
(99%)
MeOOCOC
O
MeO
MeO
MeO
13
[14]
OMe
15
MeO
OMe
O
vii (81%)
O
O
N
N
O
O
O
viii
MeOOC
MeO
(86%)
MeO
MeO
( )-Nuevamine (1)
(+)-Nuevamine (9%, 98% ee)
MeO
16
ORTEP Diagram of 1
ix
Scheme 2. Synthesis of nuevamine. Reagents, conditions, and yields: (i) Jones reagent, acetone, rt, 5 h (98%); (ii) N-ethyl-N0-(3-dimethylaminopropyl)carbodimide
hydrochloride (EDCI), HOBt, DMF, homopiperonyl amine, rt, 3 h (83%); (iii) MeOH, NEt3, rt, 20 min (99%); (iv) DMSOþMeOH (4:1), NEt3, oxygen atmo-
sphere, rt, 24 h (98%); (v) DMSO, oxygen atmosphere, rt, 48 h (99%); (vi) MeOH, NEt3, rt, 3 h (99%); (vii) TFA, rt, 2 h (81%); (viii) NaCl, DMSO, H2O,
185 ꢁC, 30 min (86%); (ix) CHCl3þEtOAc (1:3), four recrystallizations of conglomerate, each 24 h (9%, 98% ee).

1788
P.B. Wakchaure et al. / Tetrahedron 64 (2008) 1786e1791
temperature for 24 h furnished the desired product 15 in 98%
yield via the requisite facile air-oxidation pathway. At this stage,
we decided to isolate and characterize the proposed intermediate
trione 13. In a control experiment, we stirred the solution of
imide 12 in DMSO under the oxygen atmosphere for 48 h at
the room temperature, specifically under the neutral conditions
and noticed the facile air-oxidation of methylene group in 12 to
the corresponding carbonyl group to form the trione 13 [both by
the change in color of the reaction mixture (colorless to yellow)
and thin layer chromatography (TLC)]. We could actually iso-
late the reactive trione 13 in 99% yield and its structure was es-
tablished on the basis of analytical and spectral data. The
isolated pure trione 13 was fairly stable at room temperature
for 48 h plus time and then started undergoing the slow decom-
position process. The freshly isolated trione on treatment with
methanoletriethylamine at room temperature, again furnished
the expected product 15 in quantitative yield via the unisolable
intermediate keto-ester 14. As expected, the lactamol 15 on acid
catalyzed intramolecular dehydrative cyclization furnished the
isoindoloisoquinoline 16 in 81% yield. Finally, the decarboxyl-
ation of the angular carbomethoxy function in 16 in the complete
absence of oxygen, gave the desired natural product (ꢀ)-nuev-
amine (1) in 86% yield. Starting from aldehyde 9, the nuevamine
was obtained in six steps with 55% overall yield. The obtained
analytical and spectral data for 1 were in complete agreement
with the reported data4 and the structure of nuevamine was fur-
ther confirmed on the basis of X-ray crystallographic analysis.
The single crystal X-ray data indicated that the crystalline nuev-
amine racemate is a rare conglomerate. As expected, the four
successive recrystallizations of (ꢀ)-1 from chloroformeethyl
acetate mixture (1:3) led to the spontaneous resolution to furnish
the enantiomerically pure (þ)-nuevamine in 9% recrystalliza-
tion yield with 98% ee (by chiral HPLC).
N-ethyl-N0-(3-dimethylaminopropyl)carbodimide hydrochlo-
ride (EDCI), 1-hydroxybenzotriazole (HOBt), piperonal, homo-
phthalic anhydride, acetic anhydride, and nitromethane were
used.
4.2. 2-(2-Benzo[1,3]dioxol-5-yl-ethyl)-4H-isoquinoline-
1,3-dione (4)
A stirred solution of homopiperonyl amine (1.00 g,
6.06 mmol) and homophthalic anhydride (980 mg, 6.06 mmol)
was heated at reflux in o-dichlorobenzene (20 mL) for 3 h. After
cooling the reaction mixture, it was loaded on silica gel column
and initially the column was eluted with petroleum ether for the
removal of o-dichlorobenzene and then it was eluted with petro-
leum ethereethyl acetate mixture (6:4) to obtain pure compound
4 as a crystalline yellow solid (1.72 g, 92% yield). Mp 158 ꢁC
(lit.8 156e157 ꢁC); IR (CHCl3) nmax 1709, 1662, 1607, 1352,
1246 cmꢂ1; 1H NMR (CDCl3, 200 MHz) d 2.75e2.90 (m, 2H),
4.02 (s, 2H), 4.05e4.25 (m, 2H), 5.92 (s, 2H), 6.73 (s, 2H), 6.81
(s, 1H), 7.28(d, J¼8 Hz, 1H), 7.45(t, J¼8 Hz, 1H), 7.60(dt, J¼8
and 2 Hz, 1H), 8.22 (d, J¼8 Hz, 1H); 13C NMR (CDCl3,
50 MHz) d 33.7, 36.3, 41.6, 100.7, 108.1, 109.3, 121.7, 125.2,
127.0, 127.6, 129.0, 132.2, 133.5, 134.0, 146.0, 147.5, 164.6,
169.7. Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53.
Found: C, 70.02; H, 4.81; N, 4.59.
4.3. 2-(2-Benzo[1,3]dioxol-5-yl-ethyl)-1-hydroxy-3-oxo-
2,3-dihydro-1H-isoindole-1-carboxylic acid methyl ester
(5)
Method A: to a solution of imide 4 (400 mg, 1.29 mmol) in
MeOH (15 mL) was added NaBH4 (123 mg, 3.22 mmol) and
the reaction mixture was stirred for 20 h at room temperature.
After addition of water (20 mL) to the reaction mixture, it was
extracted with ethyl acetate (20 mLꢃ3). The combined organic
layer was washed with water, brine, and dried over Na2SO4.
Concentration of the organic layer in vacuo followed by silica
gel column chromatographic purification of the residue using
petroleum ethereethyl acetate mixture (85:15) as an eluent fur-
nished 5 as a crystalline solid (321 mg, 70% yield). Method B: to
a solution of imide 4 (400 mg, 1.29 mmol) in MeOH (15 mL)
was added NEt3 (0.50 mL) and the reaction mixture was stirred
for 12 h at room temperature. Reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate (20 mLꢃ3). The
combined organic layer was washed with water, brine, and dried
over Na2SO4. Concentration of the organic layer in vacuo fol-
lowed by silica gel column chromatographic purification of
the residue using petroleum ethereethyl acetate mixture
(85:15) as an eluent furnished 5 as a crystalline solid (349 mg,
76% yield). Mp 162e164 ꢁC; IR (CHCl3) nmax 3431, 1749,
3. Conclusions
In summary, we have demonstrated a noteworthy total
synthesis of nuevamine by taking the advantage of facile air-
oxidation propensity of the active methylene group in homo-
phthalimide to the corresponding carbonyl group. We feel that
the observed air-oxidation process is general in nature and
would be useful to design the congeners of nuevamine and sev-
eral other types of natural and unnatural carbocycles and
heterocycles.
4. Experimental
4.1. General
1
Melting points are uncorrected. H NMR spectra were re-
corded in CDCl3 using TMS as an internal standard on Brucker
AC 200 spectrometer (200 MHz). 13C NMR spectra were re-
corded on Brucker ACF 200, ACF 400, and DRX 500 NMR
spectrometers (50, 100, and 125 MHz, respectively). FTIR spec-
tra were recorded on a FT-IR-8300 Shimadzu spectrometer.
Column chromatographic separations were done on silica gel
(60e120 mesh). Commercially available NaBH4, Jones reagent,
1707, 1502, 1491, 1439, 1215 cmꢂ1 1H NMR (CDCl3,
;
200 MHz) d 2.75e3.05 (m, 2H), 3.20e3.45 (m, 1H), 3.65e3.85
(m, 1H), 3.72 (s, 3H), 4.69 (br s, 1H), 5.92 (s, 2H), 6.65e6.80 (m,
3H), 7.40e7.50 (m, 1H), 7.50e7.65 (m, 2H), 7.75e7.90
(m, 1H); 13C NMR (CDCl3, 50 MHz) d 34.6, 41.9, 54.1, 88.3,
100.8, 108.3, 109.3, 121.7 (2 carbons), 123.6, 130.4, 131.5,
132.5, 132.6, 143.2, 146.1, 147.6, 167.9, 171.5. Anal. Calcd

P.B. Wakchaure et al. / Tetrahedron 64 (2008) 1786e1791
1789
for C19H17NO6: C, 64.22; H, 4.82; N, 3.94. Found: C, 64.13; H,
5.00; N, 4.06.
reaction mixture was stirred at room temperature for 3 h. The re-
action mixturewas diluted with water (5 mL) and extracted with
ethyl acetate (20 mLꢃ3). The combined organic layer was
washed with 5% aqueous solution of NaHCO3, brine, and dried
over Na2SO4. Concentration of organic layer in vacuo followed
by silica gel column chromatographic purification using petro-
leum ethereethyl acetate mixture (1:1) as an eluent furnished
pure compound 8 as a crystalline solid (160 mg, 85% yield).
4.4. Methyl 7-oxo-5,6-dihydro-7H-1,3-dioxa-6a-aza-
indeno[5,6-c]fluorene-11b-carboxylate (6)
To a solution of 5 (600 mg, 1.69 mmol) in acetic acid (6 mL)
was added sulfuric acid (6 M, 3 mL) and the reaction mix-
turewasstirredfor2 hatroomtemperature. Thereactionmixture
was diluted with water (20 mL) and extracted with ethyl acetate
(25 mLꢃ3). The combined organic layer was successively
washed with water, 5% aqueous NaHCO3 solution, brine, and
dried over Na2SO4. Concentration of the organic layer in vacuo
followed by silica gel column chromatographic purification of
the residue using petroleum ethereethyl acetate mixture (8:2)
as an eluent furnished 6 as a crystalline solid (478 mg, 84%
yield). Mp 185e187 ꢁC; IR (CHCl3) nmax 1736, 1697, 1614,
Mp 179e180 ꢁC; IR (CHCl3) nmax 1686, 1618 cmꢂ1 1H
;
NMR (CDCl3, 200 MHz) d 2.70e2.85 (m, 1H), 2.90e3.09
(m, 1H), 3.45 (ddd, J¼12, 9, and 4 Hz, 1H), 4.38 (dt, J¼12
and 6 Hz, 1H), 5.56 (s, 1H), 5.93 (d, J¼16 Hz, 2H), 6.65 (s,
1H), 7.08 (s, 1H), 7.50 (t, J¼8 Hz, 1H), 7.61 (t, J¼8 Hz, 1H),
7.81 (d, J¼8 Hz, 1H), 7.88 (d, J¼8 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) d 29.3, 38.1, 59.0, 101.0, 105.4, 109.0,
123.2, 123.8, 127.1, 128.1, 128.4, 131.4, 132.6, 144.1, 146.4,
146.7, 167.8. Anal. Calcd for C17H13NO3: C, 73.10; H, 4.69;
N, 5.01. Found: C, 73.22; H, 4.83; N, 5.16.
1504, 1487, 1391, 1246, 1231 cmꢂ1 1H NMR (CDCl3,
;
200 MHz) d 2.65e3.10 (m, 2H), 3.60e3.80 (m, 1H), 3.74
(s, 3H), 4.35e4.55 (m, 1H), 5.93 (d, J¼12 Hz, 1H), 5.94 (d,
J¼12 Hz, 1H), 6.61 (s, 1H), 7.44 (s, 1H), 7.53 (dt, J¼8 and
1 Hz, 1H), 7.65 (dt, J¼8 and 1 Hz, 1H), 7.86 (d, J¼8 Hz, 1H),
8.04 (d, J¼8 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d 28.7, 36.9,
53.4, 69.3, 101.2, 107.3, 108.8, 123.9, 124.2, 126.3, 128.5,
129.4, 131.7, 132.0, 143.4, 146.4, 147.6, 167.5, 170.1. Anal.
Calcd for C19H15NO5: C, 67.65; H, 4.48; N, 4.15. Found: C,
67.75; H, 4.63; N, 4.08.
4.7. 3,4-Dimethoxy-2-(2-methoxy-2-oxoethyl)benzoic
acid (10)
To a stirred solution of compound 9 (700 mg, 2.94 mmol) in
acetone (20 mL) was added Jones reagent (6 mL) in dropwise
fashion at room temperature and the reaction mixturewas stirred
for 4 h. The excess of reagent was quenched by addition of
i-PrOH. The reaction mixture was diluted with water (10 mL)
and extracted with ethyl acetate (25 mLꢃ3). The organic layer
was washed with water, brine, and dried over Na2SO4. Concen-
tration of organic layer in vacuo gave pure compound 10 as
a crystalline solid (732 mg, 98% yield). Mp 128e130 ꢁC; IR
4.5. 11b-Hydroxy-5,11b-dihydro-6H-1,3-dioxa-6a-aza-
indeno[5,6-c]fluoren-7-one (7)
To a stirred solution of compound 6 (400 mg, 1.18 mmol) in
a mixture of DMSO (20 mL) and water (1 mL) was added NaCl
(76 mg, 1.30 mmol) and the reaction mixture was heated for
30 min at 175 ꢁC. The reaction mixture was allowed to cool to
room temperature and extracted with ethyl acetate
(20 mLꢃ3). The combined organic layer was washed with wa-
ter, brine, and dried over Na2SO4. Concentration of organic layer
in vacuo followed by silica gel column chromatographic purifi-
cation using petroleum ethereethyl acetate mixture (1:1) as an
eluent gave compound 7 as a crystalline solid (276 mg, 79%
yield). Mp 175e176 ꢁC; IR (Nujol) nmax 3250, 1678, 1462,
(CHCl3) nmax 1734, 1686, 1597 cmꢂ1 1H NMR (CDCl3,
;
200 MHz) d 3.70 (s, 3H), 3.81 (s, 3H), 3.94 (s, 3H), 4.18
(s, 2H), 6.91 (d, J¼8 Hz, 1H), 7.96 (d, J¼10 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) d 32.5, 51.8, 55.8, 60.8, 110.2, 121.0, 129.0,
131.7, 147.8, 156.8, 172.0, 172.3. Anal. Calcd for C12H14O6:
C, 56.69; H, 5.54. Found: C, 56.64; H, 5.55.
4.8. Methyl 2-(6-(2-(benzo[d][1,3]dioxol-5-yl)ethyl
carbamoyl)-2,3-dimethoxyphenyl)acetate (11)
To a stirred solution of compound 10 (650 mg, 2.55 mmol) in
DMF (15 mL) at 0 ꢁC were slowly added HOBt (413 mg,
3.06 mmol) and N-ethyl-N0-(3-dimethylaminopropyl)carbod-
imide hydrochloride (EDCI, 535 mg, 2.80 mmol). The reaction
mixture was stirred under inert atmosphere for 20 min. Homopi-
peronyl amine (420 mg, 2.55 mmol) in DMF (7 mL) was added
to the above reaction mixture in a dropwise fashion over 10 min
and it was further stirred for 4 h at room temperature. The reac-
tion mixture was diluted with water (50 mL) and extracted with
ethyl acetate (25 mLꢃ3). The organic layer was washed with
water, brine, and dried over Na2SO4. Concentration of the or-
ganic layer in vacuo followed by silica gel column chromato-
graphic purification of the obtained residue using petroleum
ethereethyl acetate mixture (4:6) as an eluent gave 11 as a
white crystalline solid (851 mg, 83% yield). Mp 120e121 ꢁC;
1456 cmꢂ1 1H NMR (CDCl3, 200 MHz) d 2.60e2.74 (m,
;
1H), 2.76e2.96 (m, 1H), 3.35 (ddd, J¼13, 11, and 4 Hz, 1H),
4.08 (ddd, J¼13, 5, and 2 Hz, 1H), 5.92 (dd, J¼10 and 2 Hz,
2H), 6.55 (s, 1H), 7.38 (s, 1H), 7.46 (t, J¼8 Hz, 1H), 7.63
(t, J¼8 Hz, 1H), 7.65 (d, J¼6 Hz, 1H), 7.97 (dd, J¼8 and
2 Hz, 1H); 13C NMR (DMSO-d6, 50 MHz) d 29.2, 34.6, 85.9,
101.3, 108.0, 108.5, 122.7, 124.2, 128.5, 129.5, 130.5, 130.7,
132.7, 146.3, 147.2, 148.9, 166.3. Anal. Calcd for C17H13NO4:
C, 69.14; H, 4.43; N, 4.74. Found: C, 69.02; H, 4.52; N, 4.55.
4.6. 5,11b-Dihydro-6H-1,3-dioxa-6a-aza-indeno[5,6-c]-
fluoren-7-one (8)
To a stirred solution of the compound 7 (200 mg, 0.67 mmol)
in TFA (7 mL) was added NaBH4 (26 mg, 0.70 mmol) and the
1
IR (CHCl3) nmax 1734, 1710, 1630 cmꢂ1; H NMR (CDCl3,

1790
P.B. Wakchaure et al. / Tetrahedron 64 (2008) 1786e1791
200 MHz) d 2.81 (t, J¼8 Hz, 2H), 3.62 (q, J¼6 Hz, 2H), 3.70 (s,
3H), 3.78 (s, 3H), 3.83 (s, 2H), 3.87 (s, 3H), 5.93 (s, 2H), 6.43 (t,
J¼6 Hz, 1H), 6.62e6.78 (m, 3H), 6.83 (d, J¼8 Hz, 1H), 7.17 (d,
J¼8 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d 32.4, 35.2, 41.1,
52.1, 55.7, 60.5, 100.8, 108.3, 109.0, 110.9, 121.6, 123.6,
127.0, 130.0, 132.6, 146.1, 147.6, 147.8, 153.9, 168.9, 173.7.
Anal. Calcd for C21H23NO7: C, 62.83; H, 5.77; N, 3.49. Found:
C, 63.02; H, 5.80; N, 3.61.
1.35 mmol) inmixture ofDMSO (20 mL) and MeOH (5 mL) was
added NEt3 (0.5 mL) and the reaction mixture was stirred under
theoxygenatmosphereatroomtemperaturefor24 h.Thereaction
mixture was diluted with ethyl acetate (50 mL) and the organic
layer was washed with water, brine, and dried over Na2SO4. Con-
centration of organic layer invacuo followed by silica gel column
chromatographic purification of the obtained residue using petro-
leum ethereethyl acetate mixture (4:6) as an eluent furnished
compound 15 as a faint brown solid (548 mg, 98% yield). Mp
4.9. 2-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5,6-dimethoxy-
145e146 ꢁC; IR (CHCl3) nmax 3483, 1742, 1701, 1618 cmꢂ1
;
isoquinoline-1,3(2H,4H)-dione (12)
1H NMR (CDCl3, 200 MHz) d 2.68e2.97 (m, 2H), 3.30e3.48
(m, 1H), 3.51e3.70 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93
(s, 3H), 4.81 (s, 1H), 5.92 (s, 2H), 6.65e6.78 (m, 3H), 7.04 (d,
J¼8 Hz, 1H), 7.53 (d, J¼8 Hz, 1H); 13C NMR (CDCl3,
50 MHz) d 34.6, 41.3, 53.9, 56.1, 61.0, 86.3, 100.8, 108.2,
109.2, 114.1, 119.6, 121.6, 124.4, 132.5, 136.1, 143.6, 146.0,
147.5, 156.1, 167.5, 171.5. Anal. Calcd for C21H21NO8: C,
60.71; H, 5.09; N, 3.37. Found: C, 60.52; H, 5.00; N, 3.44.
To a stirred solution of compound 11 (750 mg, 2.03 mmol)
in MeOH (20 mL) at room temperature was added catalytic
amount of NEt3 (1 drop) and the reaction mixture was stirred
for 30 min. The obtained white precipitate was filtered out and
washed with MeOH (5 mL) and dried in vacuo to provide pure
compound 12 as a snow-white crystalline solid (683 mg, 99%
yield). Mp 216e217 ꢁC; IR (Nujol) nmax 1705, 1666,
1597 cmꢂ1
;
1H NMR (CDCl3, 200 MHz) d 2.76e2.81 (m,
4.12. 10,11-Dimethoxy-7-oxo-5,6-dihydro-7H-1,3-dioxa-
6a-aza-indeno[5,6-c]fluorene-11b-carboxylic acid
methyl ester (16)
2H), 3.88 (s, 3H), 3.96 (s, 5H), 4.07e4.19 (m, 2H), 5.93
(s, 2H), 6.74 (s, 2H), 6.82 (s, 1H), 7.02 (d, J¼8 Hz, 1H), 7.99
(d, J¼10 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d 32.0, 33.9,
41.5, 55.9, 60.3, 100.8, 108.2, 109.4, 111.5, 118.4, 121.8,
125.9, 128.2, 132.5, 144.6, 146.1, 147.6, 156.6, 164.3, 169.9.
Anal. Calcd for C20H19NO6: C, 65.03; H, 5.18; N, 3.79.
Found: C, 64.90; H, 5.01; N, 3.53.
The solution of compound 15 (400 mg, 0.96 mmol) in TFA
(10 mL) was stirred at room temperature for 2 h. To the reaction
mixture was added ethyl acetate (30 mL) and organic layer was
washed with 5% aqueous solution of NaHCO3, water, brine, and
dried over Na2SO4. Concentration of organic layer in vacuo fol-
lowed by silica gel column chromatographic purification of the
obtained residue using petroleum ethereethyl acetate mixture
(3:7) as an eluent gave compound 16 as a crystalline solid
(309 mg, 81% yield). Mp 233e235 ꢁC; IR (CHCl3) nmax 1742,
4.10. 2-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-5,6-
dimethoxyisoquinoline-1,3,4(2H)-trione (13)
The solution of compound 12 (100 mg, 0.27 mmol) in
DMSO (5 mL) was stirred under the oxygen atmosphere for
24 h at room temperature. To the formed yellow colored reaction
mixture was added ethyl acetate (20 mL) and the total organic
layer was washed with water, brine, and dried over Na2SO4.
Concentration of organic layer in vacuo gave pure compound
13 as a yellow solid (102 mg, 99% yield). Mp 155e157 ꢁC;
1
1686, 1612 cmꢂ1; H NMR (CDCl3, 200 MHz) d 2.71 (dt,
J¼16 and 6 Hz, 1H), 3.01 (ddd, J¼16, 8, and 6 Hz, 1H), 3.40
(ddd, J¼14, 9, and 6 Hz, 1H), 3.73 (s, 3H), 3.92 (s, 3H), 3.96
(s, 3H), 4.30 (ddd, J¼12, 7, and 4 Hz, 1H), 5.90 (dd, J¼9 and
2 Hz, 2H), 6.58 (s, 1H), 7.08 (d, J¼8 Hz, 1H), 7.58
(d, J¼10 Hz, 1H), 7.67 (s, 1H); 13C NMR (CDCl3, 125 MHz)
d 28.5, 37.0, 53.3, 56.2, 60.2, 70.0, 101.0, 108.4, 109.4, 113.8,
119.8, 125.2, 127.6, 128.3, 137.3, 143.9, 146.3, 147.3, 156.1,
167.7, 170.6. Anal. Calcd for C21H19NO7: C, 63.47; H, 4.81;
N, 3.54. Found: C, 63.32; H, 4.71; N, 3.59.
IR (CHCl3) nmax 1724, 1707, 1676 cmꢂ1; H NMR (CDCl3,
1
200 MHz) d 2.81e2.93 (m, 2H), 3.97 (s, 3H), 4.01 (s, 3H),
4.12e4.23 (m, 2H), 5.93 (s, 2H), 6.73 (s, 2H), 6.80 (s, 1H), 7.35
(d, J¼10 Hz, 1H), 8.15 (d, J¼10 Hz, 1H); 13C NMR (CDCl3,
100 MHz) d 33.1, 41.8, 56.7, 60.8, 101.0, 108.5, 109.2, 118.1,
121.7, 122.5, 124.8, 126.4, 132.6, 145.9, 147.5, 149.3, 157.5,
157.9, 162.2, 173.0. Anal. Calcd for C20H17NO7: C, 62.66; H,
4.47; N, 3.65. Found: C, 62.57; H, 4.61; N, 3.58.
4.13. 10,11-Dimethoxy-5,11b-dihydro-6H-1,3-dioxa-6a-
aza-indeno[5,6-c]fluoren-7-one [Nuevamine (ꢀ)-1]
To the stirred solution of compound 16 (200 mg, 0.50 mmol)
in the mixture of DMSO (7 mL) and H2O (1 mL) was added
NaCl (32 mg, 0.55 mmol). The reaction mixture was deoxygen-
ated by bubbling excess of nitrogen gas for 3 h and it was heated
for 30 min at 185 ꢁC. The reaction mixture was allowed to cool
to room temperature and diluted with ethyl acetate (20 mL). The
organic layer was washed with water, brine, and dried over
Na2SO4. Concentration of organic layer in vacuo followed by
silica gel column chromatographic purification of the obtained
residue by using petroleum ethereethyl acetate mixture (3:7)
as an eluent furnished the desired compound 1 as a crystalline
4.11. Methyl 2-(2-(benzo[d][1,3]dioxyl-5-yl)ethyl)-1-
hydroxy-6,7-dimethoxy-3-oxoisoindoline-1-carboxylate
(15)
Method A: to the stirred solution of compound 13 (50 mg,
0.13 mmol) in MeOH (5 mL) was added catalytic amount of
NEt3 (1 drop) at room temperature and the reaction mixture was
further stirred for 3 h. Concentration of the reaction mixture inva-
cuodirectlyfurnishedcompound15asafaintbrownsolid(53 mg,
99% yield). Method B: to the solution of compound 12 (500 mg,

P.B. Wakchaure et al. / Tetrahedron 64 (2008) 1786e1791
1791
solid (146 mg, 86% yield). Mp 214e215 ꢁC (ethyl acetate) (lit.1
Acknowledgements
1
212 ꢁC); IR (CHCl3) nmax 1680, 1651, 1620 cmꢂ1; H NMR
(CDCl3, 200 MHz) d 2.78e3.12 (m, 2H), 3.57 (dt, J¼12 and
6 Hz, 1H), 3.98 (s, 3H), 4.00 (s, 3H), 3.95e4.15 (m, 1H), 5.63
(s, 1H), 5.90 (dd, J¼12 and 2 Hz, 2H), 6.67 (s, 1H), 7.07
(d, J¼8 Hz, 1H), 7.32 (s, 1H), 7.59 (d, J¼8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 28.8, 38.7, 56.2, 58.3, 60.5, 100.9, 107.4,
108.4, 113.2, 119.7, 126.6, 128.4, 128.8, 136.1, 144.3, 146.4,
146.7, 155.4, 167.5. Anal. Calcd for C19H17NO5: C, 67.24; H,
5.04; N, 4.12. Found: C, 67.09; H, 5.11; N, 4.15.
P.B.W. thanks CSIR, New Delhi and S.E. thanks UGC, New
Delhi, for the awards of research fellowships. We thank Mrs.
S.S. Kunte from NCL, Pune for the chiral HPLC data.
References and notes
1. Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett.
1984, 25, 599.
2. Alonso, R.; Castedo, L.; Dominguez, D. Tetrahedron Lett. 1985, 26, 2925.
3. (a) Winn, M.; Zaugg, H. E. J. Org. Chem. 1969, 34, 249; (b) Walker,
G. N.; Kempton, R. J. J. Org. Chem. 1971, 36, 1413; (c) Moniot, J. L.;
Hindenlang, D. M.; Shamma, M. J. Org. Chem. 1979, 44, 4347; (d)
Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E.
J. Org. Chem. 1997, 62, 2080; (e) Katritzky, A. R.; Mehta, S.; He, H.-Y.
J. Org. Chem. 2001, 66, 148; (f) Osante, I.; Lete, E.; Sotomayor, N.
Tetrahedron Lett. 2004, 45, 1253 and references cited therein.
4. (a) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.
Tetrahedron 2004, 60, 6169; (b) Moreau, A.; Couture, A.; Deniau, E.;
Grandclaudon, P. Eur. J. Org. Chem. 2005, 3437 and references cited
therein.
4.14. (þ)-Nuevamine
The conglomerate (ꢀ)-nuevamine (120 mg) on four succes-
sive recrystallizations from the chloroformeethyl acetate mix-
ture (1:3, 1 mL/20 mg) with 24 h as the each recrystallization
time furnished the enantiomerically pure (þ)-nuevamine
(11 mg, 9% recrystallizations yield, 98% ee by chiral HPLC).
Mp 215 ꢁC; [a]D20 þ185 (c 1.0, CHCl3). HPLC details: column:
chiralcel OD (250ꢃ4.6 mm), mobile phase: isopropyl alcohole
hexane (20:80), wavelength: 254 nm, flow rate: 1 mL/min,
retention time: 17.6 min (þ)-isomer, 23.4 min (ꢂ)-isomer.
5. Chrzanowska, M.; Dreas, A.; Rozwadowska, M. D. Tetrahedron: Asym-
metry 2004, 15, 1113 and references cited therein.
6. (a) Patel, R. M.; Argade, N. P. J. Org. Chem. 2007, 72, 4900; (b) Mondal,
M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72, 2068; (c) Baag,
M. M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72, 1009 and
references cited therein.
4.15. Supporting information
7. Batra, S.; Sabnis, Y. A.; Rosenthal, P. J.; Avery, M. A. Bioorg. Med. Chem.
2003, 11, 2293.
8. Haworth, R. D.; Pinder, A. R. J. Chem. Soc. 1950, 1776.
9. Heaney, H.; Taha, M. O.; Slawin, A. M. Z. Tetrahedron Lett. 1997, 38,
3051 and references cited therein.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 659028 and 659029. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: þ44-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
10. For the recently reported serendipitous air-oxidation of a carbocyclic
system, please see: Liu, H.; Siegel, D. R.; Danishefsky, S. J. Org. Lett.
2006, 8, 423 and references cited therein.
11. Queffelec, C.; Bailly, F.; Cotelle, P. Synthesis 2006, 768.