First total synthesis of (-)-Circumdatin H, a novel mitochondrial NADH Oxidase inhibitor

Article abstract of DOI:10.1055/s-0029-1218606

An efficient and highly convergent synthesis of the mitochondrial NADH oxidase inhibitor (-)-circumdatin H is described. The strategy employs the intramolecular Eguchi aza-Wittig protocol as a key step to install the crucial central core BC ring system, leading to the first total synthesis of the target molecule. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218606

PAPER
643
First Total Synthesis of (–)-Circumdatin H, a Novel Mitochondrial NADH
Oxidase Inhibitor
First
Total
S
ynthes
.
is of (–)-Circ
S
umdatin
H
ubhas Bose,* M. Venu Chary
Organic Chemistry Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India
Fax +91(40)27160387; E-mail: dsb@iict.res.in; E-mail: bose_iict@yahoo.co.in
Received 6 October 2009; revised 20 October 2009
O
O
Abstract: An efficient and highly convergent synthesis of the mito-
chondrial NADH oxidase inhibitor (–)-circumdatin H is described.
The strategy employs the intramolecular Eguchi aza-Wittig proto-
col as a key step to install the crucial central core BC ring system,
leading to the first total synthesis of the target molecule.
R1
R3
NR2
N
N
R1
B
A
H
H
N
N
N
C
O
O
R2
D
Key words: benzodiazepine alkaloids, circumdatin H, mitochon-
drial NADH oxidase, intramolecular aza-Wittig reaction, Eguchi
protocol, quinazolin-4(3H)-ones
MeO
1: R1 = R2 = R3 = H (sclerotigenin)
5: R1 = OMe, R2 = OH (circumdatin D)
6: R1 = H, R2 = OH (circumdatin E)
7: R1 = H, R2 = H (circumdatin H)
8: R1 = OMe, R2 = H (circumdatin J)
2: R1 = Bn, R2 = Me, R3 = H (benzomalvin A)
3: R1 = Me, R2 = H, R3 = OH (circumdatin C)
4: R1 = Me, R2 = R3 = H (circumdatin F)
Benzodiazepine-fused quinazolinone alkaloids occupy an
important place in the realm of natural and synthetic or-
ganic chemistry because of their therapeutic and pharma-
cological properties.1 Naturally occurring alkaloids
belonging to this class include compounds such as scle-
rotigenin (1), which was isolated from organic extracts of
sclerotia of Penicillium sclerotigenum (NRRL 3461)2 and
shows promising antiinsectan activity, asperlicin, which
is produced by Aspergillus alliaceus and is a potent chole-
cystokinin antagonist,3 and benzomalvin A (2), which was
isolated from a fungal culture of Penicillium sp. and
shows inhibitory activity against human neurokinin NK1
receptors.4 Related alkaloids have been isolated from a
terrestrial isolate of the fungus Aspergillus ochraceus.
Circumdatin C (3)5 and circumdatin F (4)6 are prototypi-
cal members, while other members such as circumdatin D
(5),6 circumdatin E (6)6 and circumdatin H (7)7 have an
additional tetrahydropyrrole ring (Figure 1). The com-
pounds of this group are considered to be useful chemo-
taxonomic markers. Among these compounds,
circumdatin H (7) and circumdatin E (6) are able to inhibit
the mitochondrial respiratory chain in submitochondrial
particles from beef heart, presumably by interfering with
NADH oxidase activity (IC50 1.5 mM and 2.5 mM, respec-
tively). Similar molecules, circumdatins A–H, have re-
cently been reported by Kusumi and co-workers from the
marine-derived fungus Aspergillus ostianus strain
01F313, together with a new compound, named circum-
datin J (8), and a revision of the structures of circumdatin
A and B from the previously reported betaine structures to
unique oxepinones based on X-ray crystallography.8
These alkaloids are often biosynthetically derived from
two appropriately substituted anthranilic acid units and
chiral amino acids, and as a result contain a chiral center
Figure 1 Chemical structures of circumdatins and related natural
products
in the a-position of the 2-substituent on the quinazolin-4-
one.
Due to their interesting biological activity, limited avail-
ability from natural sources and fascinating molecular ar-
chitecture, these compounds have attracted immediate
attention and have become attractive synthetic targets. To
the best of our knowledge, however, the synthesis of cir-
cumdatins 5–8 is not known. In this communication, we
report the first efficient and convergent synthesis of 7, fea-
turing the construction of the pentacyclic ring system,
which can be easily adopted for the synthesis of various
analogues.
Our synthetic plan for the synthesis of (–)-circumdatin H
(7) is outlined in Scheme 1. Two adaptable and useful
strategies for the present purpose were explored: i) syn-
thesis of the substituted quinazoline ring system 11 either
by cyclodehydration of benzoxazinone 10 or the tripep-
tide precursor 9 and ii) an exceptionally mild route via in-
tramolecular aza-Wittig cyclization (Eguchi protocol) of
precursor 12 to form the imine functionality while pre-
serving the neighboring chiral center as a critical step in
the synthesis.
In an effort to develop a more widely applicable method-
ology for 11, we chose to evaluate one of the most com-
monly employed synthetic strategies via benzoxazinone
10 as an intermediate9 (Scheme 2). Our synthesis started
with the condensation of methyl anthranilate (13) with N-
(tert-butoxycarbonyl)-L-proline (14) under standard cou-
pling
conditions,10
N,N¢-dicyclohexylcarbodiimide
(DCC) and N-hydroxybenzotriazole (HOBt), which re-
sulted in a 73% yield of the corresponding amide 15a. Se-
lective hydrolysis of the ester functionality under mild
conditions using lithium hydroxide yielded the acid 15b in
SYNTHESIS 2010, No. 4, pp 0643–0650
x
x
.
x
x
.2
0
1
0
Advanced online publication: 16.12.2009
DOI: 10.1055/s-0029-1218606; Art ID: Z20909SS
© Georg Thieme Verlag Stuttgart · New York

644
D. S. Bose, M. V. Chary
PAPER
membered ring. Based on the literature reports,9 a mixture
of benzoxazinone 10 and methyl anthranilate (13) was re-
fluxed in pyridine or in the presence of zinc chloride for
the transformation to the target molecule circumdatin;
however, this procedure led to a complex mixture of prod-
ucts, necessitating chromatographic separation. In order
to circumvent this problem, the reactants 10 and 13 were
heated under solvent-free conditions using molten tet-
rabutylammonium bromide at 160 °C, which afforded the
expected pentacyclic 13-desmethoxycircumdatin H (16)
along with the tricyclic dilactam 17 in 62% and 12% iso-
lated yield, respectively, after separation on silica gel
(Scheme 2). To our surprise, enantiomeric erosion was
encountered during the course of the reaction12b–d and re-
sulted in the racemic form ( )-16. To overcome the draw-
back of racemization, a new approach for 7 was
formulated which is disclosed below.
O
R
O
O
R
N
N
CO2Me
H
O
22
19
10: R = H
N
N
1
N
4
5
H
21
20
Boc
11: R = H
2
N
3
Boc
A
B
O
N
18
9
N
10
8
H
6
7
R
17
N
C
Eguchi
aza-Wittig
O
H
O
16
O
11
CO2Me
15
14
N
H
D
12
N
H
N
13
Boc
R
H
O
N3
N
O
R
7: R = OMe
7a: R = H
9: R = H
12a: R = H
12b: R = OMe
Scheme 1 Retrosynthetic analysis of (–)-circumdatin H
94% yield. To find a rapid and elegant method for the for-
mation of benzoxazinone 10, intramolecular cyclodehy-
dration of 15b was carried out under various reaction
conditions.11 Of the commonly available coupling agents
screened for the cyclization (DCC/HOBt, Boc2O), the use
of 1,1¢-carbonyldiimidazole (CDI) in tetrahydrofuran at
room temperature was found to be most suitable for this
reaction in terms of yield (95%), reaction time and work-
up.
In this new approach, N-sulfinylanthraniloyl chloride
(18),13 prepared from anthranilic acid and thionyl chlo-
ride, was treated with methyl anthranilate (13) to yield
methyl
2-(2-aminobenzoylamino)benzoate
(19)14
(Scheme 3). Treatment of the latter with N-(tert-butoxy-
carbonyl)-L-proline (14) using DCC and HOBt afforded
the tripeptide 9 in 65% yield. Recently, intramolecular
dehydrative cyclization of diamides to various quinazoli-
none scaffolds by employing 1,1,1,3,3,3-hexamethyldisi-
lazane with iodine under mild conditions has been
reported.15 When similar conditions were applied for the
cyclization of 9 with the hope of obtaining quinazolinone
11, however, the sole product was identified as the N-Boc-
deprotected tripeptide 20, which may be due to the steri-
cally hindered cyclic nature of L-prolinamide. Hence, we
devised an alternative route.
Reaction of benzoxazin-4-ones with anilines containing a
reactive functional group at the ortho position adds anoth-
er dimension to the basic transformation, in that further
cyclization to more complex heterocyclic systems is pos-
sible.12a We considered this strategy would be useful for
the synthesis of circumdatin H (7), to induce cyclization
involving one six-membered ring and one seven-
CO2Me
CO2H
O
CO2Me
O
H
LiOH, THF
DCC, HOBt
+
CO2H
H2O–MeOH
THF
N
NH2
N
N
Boc
14
H
H
H
H
13
15a
15b
N
N
Boc
Boc
N
O
O
O
N
13, TBAB,160 °C
O
CDI, THF
+
H
H
N
N
N
H
N
H
O
10
BocN
O
(
)-17
(
)-16
Scheme 2 Preparation of ( )-13-desmethoxycircumdatin H (16)
O
O
14, DCC, HOBt,
COCl
13, toluene,
N
N
THF
r.t.
H
H
O
CO2Me
CO2Me
N
H
N=S=O
NH2
18
19
9
H
N
Boc
O
O
N
HMDS, I2,
N
CH2Cl2, r.t.
H
O
CO2Me
X
CO2Me
N
H
N
H
H
HN
11
N
20
Boc
Scheme 3
Synthesis 2010, No. 4, 643–650 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of (–)-Circumdatin H
645
As we were searching for an alternative, more efficient nished a single compound, the expected imine 7. All of the
strategy, our attention was drawn towards the tandem in- spectroscopic data for the synthetic compound (–)-7 were
tramolecular aza-Wittig reaction (Eguchi protocol),16 in good agreement with the literature data7 for natural (–)-
which is devoid of a protection and deprotection sequence circumdatin H. The specific optical rotation of the syn-
of reactions (Scheme 4). As part of our ongoing efforts thetic circumdatin H {[a]D20 –35.4 (c 0.1, MeOH)} differs
20
devoted to the development of novel pyrrolobenzodiaz- from the reported value for natural circumdatin H {[a]D
epine DNA-interactive ligands,17 we explored the oppor- –26.33 (c 0.078, MeOH)}. Since there is no ambiguity
tunity to utilize dilactam 23 for the synthesis of about the structure of the synthetic compound, we assume
circumdatin H (7).
that the optical rotation of the natural product was lowered
by minor impurities. Although the melting point of natural
circumdatin H (7) was not determined due to the small
amount of material isolated, the melting point of the syn-
thetic circumdatin H is 218–219 °C.
O
O
R
CO2H
NH2
N
EtOCOCl,
Et3N
O
L-proline
or
H
DMSO,
120 °C
N
H
O
N
(Cl3CO)2CO
21
H
O
The preparation and transformation of azide 12a was car-
ried out under an identical sequence of reactions as de-
scribed above for 12b in order to obtain synthetic
pentacyclic (–)-13-desmethoxycircumdatin H (7a) whose
23
22
a: R = H
b: R = OMe
R
COCl
N3
R
CO2H
SOCl2
DMAP,
Et3N,
THF
i) NaNO2, HCl,
Urea
N3
ii) NaN3
20
specific rotation was observed as [a]D –124.60 (c 0.5,
25
24
MeOH), which is very close to other natural circumdatins.
O
O
N
N
In summary, we have accomplished a highly efficient syn-
thesis of (–)-circumdatin H in four steps and 46% overall
yield starting from anthranilic acid. Notable features of
our synthetic approach include an efficient intramolecular
aza-Wittig cyclization of a highly strained tetracyclic de-
rivative and no protection and deprotection sequence of
reactions. This effort also documents the first enantiospe-
cific total synthesis of the pentacyclic circumdatin H. The
convergent approach reported here provides a foundation
for the future synthesis of other natural quinazolinobenzo-
diazepine alkaloids and synthetic analogues of circumda-
tin H for SAR studies and lead optimization, which will be
reported in due course.
Bu3P, 60 °C,
benzene
H
H
(–)-7 (R = OMe)
(–)-7a (R = H)
N
N
O
O
O
O
N3
N=PBu3
R
R
Iminophosphorane
12a: R = H
12b: R = OMe
Scheme 4 Intramolecular aza-Wittig reaction to form (–)-circumda-
tin H (7)
Reaction of anthranilic acid (21a) with either ethyl chlo-
roformate and triethylamine at room temperature for 18
hours followed by reflux for 4 hours or triphosgene at
room temperature generated isatoic anhydride (22)18 in
78% and 90% yield, respectively. Treatment of the latter
with L-proline in dimethyl sulfoxide at 120 °C afforded
dilactam 23.19 2-Azido-5-methoxybenzoyl chloride (25b)
is an important intermediate which was required for the
construction of the quinazolinone system (C and D rings).
Thus, 25b was prepared from 2-amino-5-methoxybenzoic
acid (21b) via a sequence which involved diazotization
(NaNO2, HCl, –5 to 0 °C; liberated excess nitrous acid
was destroyed by adding urea), nucleophilic substitution
with sodium azide to give 24b and, finally, treatment with
thionyl chloride. The next step was the acylation of dilac-
tam 23 with the 2-azidobenzoyl chloride 25b, in the pres-
ence of 4-(dimethylamino)pyridine and triethylamine in
tetrahydrofuran, to give 12b in quantitative yield. Having
useful quantities of tetracyclic precursor 12b in hand, the
All moisture-sensitive reactions were carried out under N2 atmo-
sphere in flame-dried glassware sealed by rubber septa. Unless oth-
erwise specified, materials were obtained from commercial sources
and used without purification. All solvents were dried according to
standard procedures and purified by distillation prior to use. Addi-
tion of chemicals was performed using disposable plastic syringes.
Column chromatography was performed using Acme silica gel (60–
120 mesh). Solvents for chromatography (n-hexane, CH2Cl2,
EtOAc) were distilled prior to use. For analytical TLC, Merck pre-
coated silica gel 60 F-254 plates were used with UV light (254 nm)
as visualizing agent. Melting points were obtained using a Veego
VMP-DS precision digital melting point apparatus and are uncor-
rected. Optical rotations were measured on a Jasco P-1030 polarim-
eter. IR spectra were recorded on a Thermo Nicolet Nexus 670 FT-
1
IR spectrophotometer. H and 13C NMR spectra were recorded in
CDCl3 on either a Bruker Avance 300 (300.132 MHz for 1H, 75.473
MHz for 13C) or a Varian FT-200 MHz (Gemini) spectrometer.
Chemicals shifts are reported in parts per million (d) relative to tet-
stage was then set for the investigation of the crucial ring- ramethylsilane (d = 0.0) as an internal standard. Elemental analyses
closure reaction to establish the pentacyclic framework of
circumdatin H (7). To this end, Staudinger reaction of the
aryl azide 12b with tributylphosphine in benzene at 60 °C
were performed on an Elementar Vario EL microanalyzer. Low-
resolution mass spectra (ESI-MS) and HRMS were recorded on
Micromass Quattro LC and Applied Biosystems QSTAR XL spec-
trometers, respectively.
for one hour generated the corresponding iminophospho-
rane intermediate (N3 → N=PBu3), and concomitant aza-
Wittig cyclization with the imide carbonyl functionality
Methyl Anthranilate (Methyl 2-Aminobenzoate, 13)
A mixture of anthranilic acid (21a; 10.0 g, 72.99 mmol), dimethyl
afforded circumdatin H [(–)-7] in high yield. We were de- sulfate (9.20 g, 72.99 mmol) and K2CO3 (25.22 g, 182.48 mmol) in
anhyd acetone (200 mL) was heated under reflux for 3 h. After com-
lighted to note that 12b was smoothly cyclized and fur-
Synthesis 2010, No. 4, 643–650 © Thieme Stuttgart · New York

646
D. S. Bose, M. V. Chary
PAPER
pletion of the reaction, H2O (300 mL) was added and the mixture
was extracted with EtOAc (3 × 100 mL). The combined organic
phases were washed with brine (2 × 25 mL), dried (Na2SO4) and fil-
tered, and the solvent was evaporated under reduced pressure to
give the crude product, which was purified by column chromatog-
raphy on silica gel (hexane–EtOAc, 7:3) to give 13 as a thick syrup;
yield: 8.476 g (77%).
1H NMR (300 MHz, CDCl3): d = 3.85 (s, 3 H, CO2CH3), 5.70 (br s,
2 H, NH2), 6.55–6.62 (m, 2 H, H-5,6), 7.18–7.26 (m, 1 H, H-4), 7.80
(dd, J = 2.26, 1.51 Hz, 1 H, H-3).
2-{[N-(tert-Butoxycarbonyl)-L-prolyl]amino}benzoic Acid (15b)
To a stirred soln of methyl 2-{[N-(tert-butoxycarbonyl)-L-pro-
lyl]amino}benzoate (15a; 4.50 g, 12.9 mmol) in a 2:1 mixture of
MeOH (65 mL) and THF (32 mL) at r.t. was added 10% aq LiOH
(8.13 mL), and the reaction mixture was maintained at r.t. for 4 h.
After completion of the reaction, the mixture was diluted with H2O
(100 mL) and acidified with 10% aq KHSO4 to pH 2–3 at 5 °C . The
mixture was extracted with EtOAc (3 × 100 mL). The combined ex-
tracts were washed with brine (2 × 50 mL), dried (Na2SO4) and con-
centrated under reduced pressure to afford a solid residue, which
was purified by silica gel column chromatography (hexane–EtOAc,
1:1) to give 15b as a syrup; yield: 4.1 g (94%).
ESI-MS: m/z = 152 [M+ + H].
Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00. Found: C, 63.61; H,
5.92.
IR (KBr): 3195, 2979, 2621 (acid), 1686, 1646 (amide), 1585, 1521,
1451 (aromatic C=C), 1411, 1366, 1303, 1257, 1236, 1161, 1133,
890, 852, 795, 758 cm–1.
N-(tert-Butoxycarbonyl)-L-proline (14)
1H NMR (300 MHz, CDCl3): d = 1.35–1.49 [br s,
9 H,
L-Proline (3.45 g, 30 mmol) was suspended in THF–H2O (2:1, 45
mL), and then 10% aq NaOH (15 mL) was added. To the resultant
biphasic mixture was added Boc2O (6.54 g, 30 mmol) in THF–H2O
(2:1, 45 mL). The reaction was stirred at r.t. overnight, and then the
THF was removed by evaporation under reduced pressure. The re-
sidual aqueous solution was adjusted to pH 2 by the addition of 10%
aq KHSO4 (ca. 50 mL). The acidic solution was extracted with
EtOAc (2 × 40 mL). The combined organic extracts were washed
with H2O (30 mL) and brine (30 mL), and then dried (Na2SO4). Re-
moval of the desiccant and evaporation of the solvent under reduced
pressure afforded a solid residue (7.25 g), which was recrystallized
(EtOAc) to give 4.52 g of 14. An additional 0.65 g (total yield: 80%)
was recovered from the filtrate in two crops; mp 133–135 °C (dec
with effervescence).
CO2C(CH3)3], 1.92–2.41 (m, 4 H, H-3¢,4¢), 3.32–3.90 (m, 2 H, H-
5¢), 4.28–4.62 (m, 1 H, H-2¢), 6.74 (br s, 1 H, CO2H), 7.10 (t,
Jortho = 7.5 Hz, 1 H), 7.53 (t, Jortho = 8.3 Hz, 1 H), 8.12 (d, J = 7.5
Hz, 1 H), 8.74 (dd, J = 7.5, 8.3 Hz, 1 H), 11.52 and 11.76 (2 × s, 1
H, CONH).
ESI-MS: m/z = 335 [M+ + H].
Anal. Calcd for C17H22N2O5: C, 61.07; H, 6.63. Found: C, 61.15; H,
6.67.
2-[(2S)-N-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-4H-3,1-benz-
oxazin-4-one (10)
CDI (0.485 g, 3 mmol) was added to a stirred soln of 2-{[N-(tert-
butoxycarbonyl)-L-prolyl]amino}benzoic acid (15b; 1.0 g, 3 mmol)
in anhyd THF (28 mL) under N2 atmosphere at r.t. The mixture was
stirred at the same temperature for 1 h. After completion of the re-
action, the solvent was evaporated and the crude product was puri-
fied by silica gel column chromatography (hexane–EtOAc, 9:1) to
give 10 as a syrup; yield: 0.886 g (94%).
[a]D20 –59.7 (c 1.0, AcOH) {Lit.10 [a]D20 –61 (c 1.0, AcOH)}.
1H NMR (200 MHz, CDCl3): d = 1.38–1.54 [br s,
9 H,
CO2C(CH3)3], 1.83–2.38 (m, 4 H, H-3,4), 3.30–3.62 (m, 2 H, H-5),
4.18–4.39 (m, 1 H, H-2).
ESI-MS: m/z = 216 [M+ + H].
[a]D20 –130.77 (c 1.3, CHCl3) {Lit.11a [a]D20 –131.3 (c 1.3, CHCl3)}.
Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96. Found: C, 55.88; H,
7.90.
1H NMR (300 MHz, CDCl3): d = 1.42–1.50 [br s,
9 H,
CO2C(CH3)3], 1.89–2.50 (m, 4 H, H-3¢,4¢), 3.45–3.79 (m, 2 H, H-
5¢), 4.23–4.52 (m, 1 H, H-2¢), 7.42–7.60 (m, 2 H, H-7,8), 7.78–7.80
(m, 1 H, H-6), 8.05–8.20 (m, 1 H, H-5).
Methyl 2-{[N-(tert-Butoxycarbonyl)-L-prolyl]amino}benzoate
(15a)
To a stirred soln of methyl anthranilate (13; 3.00 g, 19.86 mmol),
HOBt (3.22 g, 23.84 mmol) and N-(tert-butoxycarbonyl)-L-proline
(14; 4.27 g, 19.86 mmol) in anhyd THF (60 mL) at 0 °C under N2
atmosphere was added DCC (4.91 g, 23.84 mmol), and the mixture
was maintained at 0 °C for 1 h and at r.t. overnight. After comple-
tion of the reaction, the separated N,N¢-dicyclohexylurea was fil-
tered off and the filtrate was concentrated under reduced pressure.
The resulting residue was dissolved in a mixture of EtOAc (300
mL) and 10% aq NaHCO3 (150 mL). The organic layer was sepa-
rated and washed with 10% aq citric acid (150 mL), followed by
10% aq NaHCO3 (150 mL) and H2O (150 mL). Then, the organic
layer was dried (Na2SO4) and concentrated under reduced pressure
to obtain 15a as a syrup; yield: 5.1 g (73%).
ESI-MS: m/z = 317 [M+ + H].
Anal. Calcd for C17H20N2O4: C, 64.54; H, 6.37. Found: C, 64.61; H,
6.40.
( )-13-Desmethoxycircumdatin H (16)
To freshly prepared 2-[(2S)-N-(tert-butoxycarbonyl)pyrrolidin-2-
yl]-4H-3,1-benzoxazin-4-one (10; 0.452 g, 1.45 mmol) and methyl
anthranilate (13; 0.218 g, 1.45 mmol) under N2 atmosphere was
added TBAB (0.466 g, 1.45 mmol), and the mixture was stirred at
120 °C for 3 h and at 160 °C for 3 h. After completion of the reac-
tion (based on TLC), the mixture was cooled, dissolved in EtOAc
(2 × 50 mL), and washed with 2% aq NaOH (2 × 50 mL), followed
by H2O (2 × 50 mL) and brine (25 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure to afford a solid
residue, which was purified by silica gel column chromatography
(hexane–EtOAc, 7:3). A higher Rf spot of the target 13-desmethoxy-
circumdatin H (16) was isolated as a pale yellow solid; yield: 0.283
g (62%); mp 283–284 °C.
1H NMR (300 MHz, CDCl3): d = 1.25–1.58 [br s,
9 H,
CO2C(CH3)3], 1.95–1.98 (m, 2 H, H-3¢), 2.06–2.22 (m, 2 H, H-4¢),
3.40–3.78 (m, 2 H, H-5¢), 3.94 (s, 3 H, CO2CH3), 4.20–4.42 (m, 1
H, H-2¢), 6.99–7.06 (m, 1 H), 7.49–7.52 (m, 1 H), 7.88–8.01 (m, 1
H), 8.75–8.78 (m, 1 H), 11.44 (br s, 1 H, CONH).
ESI-MS: m/z = 349 [M+ + H].
[a]D20 –1.00 (c 0.1, MeOH).
Anal. Calcd for C18H24N2O5: C, 62.05; H, 6.94. Found: C, 62.12; H,
7.04.
1H NMR (300 MHz, CDCl3): d = 2.03–2.45 (m, 3 H, H-
20b,21a,21b), 3.18–3.20 (m, 1 H, H-20a), 3.53–3.86 (m, 2 H, H-
22a,22b), 4.58 (d, J = 5.9 Hz, 1 H, H-19), 7.47–7.58 (m, 4 H, H-
5,6,7,14), 7.65–7.81 (m, 2 H, H-13,15), 8.00 (d, J = 6.6 Hz, 1 H, H-
12), 8.31 (d, J = 8.1 Hz, 1 H, H-4).
Synthesis 2010, No. 4, 643–650 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of (–)-Circumdatin H
647
ESI-MS: m/z = 318 [M+ + H].
10% aq NaHCO3 (50 mL). The organic layer was separated and
washed with 10% aq citric acid (50 mL), followed by 10% aq
NaHCO3 (50 mL) and H2O (50 mL), then dried (Na2SO4), concen-
trated and purified by column chromatography on silica gel (hex-
ane–EtOAc, 8:2) to give 9 as a syrup; yield: 0.733 g (65%).
Anal. Calcd for C19H15N3O2: C, 71.91; H, 4.76. Found: C, 71.85; H,
4.70.
Upon further elution (hexane–EtOAc, 6:4), a lower Rf spot of the
homocoupled compound ( )-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-
a][1,4]diazepine-5,11(10H,11aH)-dione (17) was isolated as a
cream-white solid; yield: 0.037 g (12%); mp 244–246 °C.
[a]D20 –101.36 (c 2.43, CHCl3).
IR (KBr): 3262 (amide NH), 2975, 1702 (amide), 1585, 1520, 1438
(aromatic C=C), 1384, 1266, 1163, 1128, 1049, 957, 894, 756, 696,
665 cm–1.
[a]D20 +2.00 (c 0.30, MeOH).
IR (KBr): 3438, 3248 (amide NH), 2975, 2945, 1677, 1629 (amide),
1481, 1444, 1414 (aromatic C=C), 1392, 1287, 1264, 846, 798, 759,
700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98–2.04 (m, 3 H), 2.75–2.77 (m,
1 H), 3.60–3.82 (m, 2 H), 4.07 (d, J = 6.0 Hz, 1 H), 7.03 (d, J = 8.3
Hz, 1 H), 7.27 (t, J = 8.3 Hz, 1 H), 7.46 (t, J = 9.1 Hz, 1 H), 7.98 (d,
J = 8.3 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.30–1.46 [br s,
9 H,
CO2C(CH3)3], 1.82–2.40 (m, 4 H, H-3¢,4¢), 3.42–3.62 (m, 1 H, H-
5¢), 3.76–3.78 (m, 1 H, H-5¢), 3.98 (s, 3 H, CO2CH3), 4.21–4.43 (m,
1 H, H-2¢), 7.18–7.21 (m, 2 H), 7.50–7.70 (m, 2 H), 7.84–7.86 (m,
1 H), 8.08 (d, J = 7.5 Hz, 1 H), 8.73–8.96 (m, 2 H), 11.80 (s, 1 H,
NH), 12.10 (br s, 1 H, NH).
ESI-MS: m/z = 468 [M+ + H].
ESI-MS: m/z = 217 [M+ + H].
Anal. Calcd for C25H29N3O6: C, 64.23; H, 6.25. Found: C, 64.15; H,
6.18.
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59. Found: C, 66.61; H,
5.63.
Methyl 2-[2-(L-Prolylamino)benzoylamino]benzoate (20)
N-Sulfinylanthraniloyl Chloride (18)
To a stirred soln of methyl 2-(2-{[N-(tert-butoxycarbonyl)-L-pro-
lyl]amino}benzoylamino)benzoate (9; 0.234 g, 0.5 mmol) in anhyd
CH2Cl2 (10 mL) was added I2 (0.380 g, 1.5 mmol), followed by
HMDS (0.242 g, 1.5 mmol, 3.0 equiv), under N2 atmosphere at r.t.
The reaction mixture was stirred at the same temperature for 48 h.
After completion of the reaction, the mixture was diluted with
CH2Cl2 (50 mL) and the organic layer was washed with 5% aq
Na2S2O3·5H2O (3 × 25 mL), followed by H2O (25 mL) and brine
(25 mL), and then dried (Na2SO4). Then, the organic layer was con-
centrated under reduced pressure and the resulting residue was pu-
rified by silica gel column chromatography (EtOAc) to give 20 as a
brownish yellow solid; yield: 0.168 g (90%); mp 119–120 °C. (The
expected quinazolinone derivative 11, however, was not obtained.)
To a stirred suspension of anthranilic acid (21a; 4.11 g, 30 mmol)
in anhyd toluene (60 mL) under N2 atmosphere was added freshly
distilled SOCl2 (8.75 mL, 120 mmol), and the mixture was refluxed
for 3 h. The excess SOCl2 and toluene were distilled off by codistil-
lation with toluene (10 mL) and the resulting residue (6.027 g) of
compound 18 was dissolved in toluene and was immediately used
in the next step.
Methyl 2-(2-Aminobenzoylamino)benzoate (19)
To a stirred soln of freshly prepared N-sulfinylanthraniloyl chloride
(18; 6.027 g, 30 mmol) in toluene (60 mL) at r.t. under N2 atmo-
sphere was added methyl anthranilate (13; 3.48 g, 23.1 mmol) in
toluene (60 mL) dropwise over 10 min, and the mixture was main-
tained at r.t. for 48 h. After completion of the reaction, the mixture
was diluted with cold H2O (150 mL) and extracted with CH2Cl2
(2 × 150 mL). The combined organic phases were washed with 10%
aq NaHCO3 (2 × 75 mL), followed by H2O (50 mL) and brine (30
mL), dried (Na2SO4) and concentrated under reduced pressure to af-
ford a solid residue, which was purified by column chromatography
on silica gel (hexane–EtOAc, 98:2) to give 19 as a light yellow sol-
id; yield: 3.241 g (40%); mp 115–116 °C (Lit.11b 116–117 °C).
IR (KBr): 3317, 3264, 3211 (amide NH), 2947, 2869, 1693, 1664
(amide), 1584, 1509, 1437 (aromatic C=C), 1296, 1268, 747, 691,
660 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.69–1.85 (m, 2 H, H-3¢), 2.00–
2.24 (m, 2 H, H-4¢), 3.12–3.14 (m, 2 H, H-5¢), 3.84–3.87 (m, 1 H,
H-2¢), 3.95 (s, 3 H, CO2CH3), 7.09–7.20 (m, 2 H), 7.50 (t, J = 8.3
Hz, 1 H), 7.60 (t, J = 9.1 Hz, 1 H), 7.81 (dd, J = 6.0, 1.5 Hz, 1 H),
8.06 (dd, J = 6.0, 1.5 Hz, 1 H), 8.70 (d, J = 8.3 Hz, 1 H), 8.87 (d,
J = 8.3 Hz, 1 H), 11.96 (br s, 2 H).
IR (KBr): 3472, 3356 (amine), 3028, 2940, 1727, 1668 (amide),
1582, 1520, 1444 (aromatic C=C), 1301, 1258, 1164, 1095, 968,
899, 753, 651 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.95 (s, 3 H, CO2CH3), 5.78 (br s,
2 H, NH2), 6.63–6.75 (m, 2 H), 6.98–7.05 (m, 1 H), 7.17–7.24 (m,
1 H), 7.53–7.59 (m, 1 H), 7.68–7.71 (dd, J = 1.5, 1.5 Hz, 1 H), 8.01–
8.04 (dd, J = 1.5, 1.5 Hz, 1 H), 8.24–8.87 (dd, J = 1.5, 1.5 Hz, 1 H),
11.83 (s, 1 H, CONH).
13C NMR (75 MHz, CDCl3): d = 26.06, 31.11, 47.32, 52.48, 61.69,
99.93, 120.52, 121.66, 122.85, 123.26, 127.12, 130.93, 132.57,
134.63, 139.17, 141.38, 167.21, 174.69, 175.07.
ESI-MS: m/z = 368 [M+ + H].
Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76. Found: C, 65.45; H,
5.84.
ESI-MS: m/z = 271 [M+ + H].
Isatoic Anhydride (22)
To a stirred suspension of anthranilic acid (21a; 5.0 g, 36.5 mmol)
in ethyl chloroformate (35.181 mL, 368.28 mmol), Et3N (5.09 mL,
36.50 mmol) was added dropwise over 10 min at r.t. The reaction
mixture was stirred at the same temperature for 18 h and then re-
fluxed at 100 °C for 4 h. After completion of the reaction, the mix-
ture was cooled and the clear solution was diluted with benzene (30
mL). The separated solid was collected by filtration and recrystal-
lized (EtOH, 40 mL) to afford 22 as a white solid; yield: 4.643 g
(78%); mp 232–233 °C (Lit.18a 233 °C).
Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22. Found: C, 66.68; H,
5.18.
Methyl 2-(2-{[N-(tert-Butoxycarbonyl)-L-prolyl]amino}ben-
zoylamino)benzoate (9)
To a stirred soln of methyl 2-(2-aminobenzoylamino)benzoate (19;
0.650 g, 2.41 mmol), HOBt (0.390 g, 2.89 mmol) and N-(tert-but-
oxycarbonyl)-L-proline (14; 0.517 g, 2.41 mmol) in anhyd THF (25
mL) at 0 °C under N2 atmosphere was added DCC (0.596 g, 2.89
mmol), and the mixture was maintained at 0 °C for 1 h and at r.t. for
8 h. After completion of the reaction, the separated N,N¢-dicyclo-
hexylurea was filtered off and the filtrate was concentrated. The re-
sulting residue was dissolved in a mixture of EtOAc (100 mL) and
1H NMR (200 MHz, CDCl3 + DMSO-d6): d = 7.18 (t, J = 8.0 Hz, 2
H), 7.61 (t, J = 7.3 Hz, 1 H), 7.95 (dd, J = 6.5, 1.4 Hz, 1 H), 11.67
(br s, 1 H, NH).
ESI-MS: m/z = 164 [M+ + H].
Synthesis 2010, No. 4, 643–650 © Thieme Stuttgart · New York

648
D. S. Bose, M. V. Chary
PAPER
Anal. Calcd for C8H5NO3: C, 58.90; H, 3.09. Found: C, 58.82; H,
3.15.
h. To the reaction mixture was added 2-azido-5-methoxybenzoyl
chloride (25b; 1.093 g, 5.18 mmol, 1.25 equiv), which was prepared
from 2-azido-5-methoxybenzoic acid (24b; 1.0 g, 5.18 mmol) and
SOCl2 (3.16 mL, 43.4 mmol) at 80 °C for 2 h, in THF (5 mL) at
0 °C. The mixture was stirred at the same temperature for 30 min
and then at r.t. for 1 h. The solvent was evaporated and the resulting
residue was dissolved in CH2Cl2 (100 mL). The organic layer was
washed with H2O (2 × 60 mL), dried (Na2SO4) and concentrated un-
der reduced pressure to give 12b (1.793 g) as a gummy brownish
yellow syrup, which was dissolved in anhyd benzene (25 mL) and
immediately used for the next step.
(+)-2,3-Dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-
5,11(10H,11aH)-dione (23)
A mixture of isatoic anhydride (22; 2.0 g, 12.26 mmol) and L-pro-
line (1.552 g, 13.49 mmol) in DMSO (6.5 mL) was heated in an oil
bath at 120 °C for 4 h. After completion of the reaction, the clear
mixture was cooled to r.t. and diluted with H2O (200 mL). The sep-
arated solid was collected by filtration and washed with H2O (2 × 10
mL) to give 23 as a cream white solid; yield: 2.171 g (82%); mp
220–222 °C (Lit.19 220–222 °C).
Rf = 0.61 (CH2Cl2–EtOAc, 5:1).
[a]D20 +524.10 (c 1.0, MeOH) {Lit.19 [a]D +523.00 (c 1.0, MeOH)}.
(5bS)-2-Methoxy-5b,6,7,8-tetrahydro-10H,16H-pyrrolo[2,1-
c]quinazolino[3,2-a][1,4]benzodiazepine-10,16-dione [(S)-(–)-
Circumdatin H, 7]
Rf = 0.50 (CH2Cl2–EtOAc, 5:1).
IR (KBr): 3438, 3248 (amide NH), 2975, 2945, 2870, 1677, 1629
(amide), 1481, 1444, 1414 (aromatic C=C), 1392, 1287, 1264, 846,
798, 759, 700, 663 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01–2.04 (m, 3 H), 2.75–2.77 (m,
1 H), 3.60–3.82 (m, 2 H), 4.07 (d, J = 6.0 Hz, 1 H), 7.05 (d, J = 8.3
Hz, 1 H), 7.29–7.31 (m, J = 8.3 Hz, 1 H), 7.49 (t, J = 9.1 Hz, 1 H),
8.01 (d, J = 8.3 Hz, 1 H), 9.00 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 23.42, 26.16, 47.23, 56.64, 121.08,
124.85, 126.97, 130.96, 132.31, 135.44, 165.40, 171.38.
ESI-MS: m/z = 217 [M+ + H].
To a stirred soln of imide derivative 12b (1.793 g) in anhyd benzene
(25 mL) was added Bu3P (0.889 g, 4.397 mmol) in one portion un-
der N2 atmosphere at r.t. The mixture was refluxed at 60 °C for 1 h
and then left at r.t. overnight. After completion of the reaction, the
solvent was evaporated and the resulting residue was dissolved in
CH2Cl2 (150 mL). The organic layer was washed with 0.5 N aq HCl
(3 × 60 mL) followed by brine (2 × 30 mL), and then dried
(Na2SO4) and concentrated under reduced pressure to afford a solid
residue, which was purified by silica gel column chromatography
(CH2Cl2–EtOAc, 5:1) to give (–)-7 as a cream white solid; yield:
1.047 g (73% over two steps starting from 23); mp 218–219 °C.
HRMS (ESI): m/z calcd for C12H13N2O2: 217.0977 [M+ + H],
C12H12N2NaO2: 239.0796 [M+ + Na]; found: 217.0972 [M+ + H],
239.0788 [M+ + Na].
[a]D20 –35.4 (c 0.1, MeOH) {Lit.7 [a]D20 –26.33 (c 0.078, MeOH)}.
Rf = 0.56 (CH2Cl2–EtOAc, 5:1).
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59. Found: C, 66.72; H,
5.68.
IR (KBr): 3066, 2972, 1690, 1648, 1617 (amide), 1491, 1457, 1420
(aromatic C=C), 1361, 1275, 1235 (ether), 1023, 875, 832, 785,
759, 705 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98–2.40 (m, 3 H, H-
20b,21a,21b), 3.14–3.16 (m, 1 H, H-20a), 3.60–3.62 (m, 1 H, H-
22a), 3.77–3.79 (m, 1 H, H-22b), 3.93 (s, 3 H, OCH3), 4.50 (d,
J = 6.2 Hz, 1 H, H-19), 7.32 (dd, J = 6.2, 2.3 Hz, 1 H, H-14), 7.46–
7.58 (m, 4 H, H-5,6,7,15), 7.61 (d, J = 3.1 Hz, 1 H, H-12), 7.98 (d,
J = 6.2 Hz, 1 H, H-4).
13C NMR (75 MHz, CDCl3): d = 23.62 (C-21), 26.93 (C-20), 46.42
(C-22), 55.77 (OCH3), 58.71 (C-19), 106.88 (C-12), 122.25 (C-11),
124.70 (C-14), 128.34 (C-7), 128.53 (C-5), 129.09 (C-15), 129.82
(C-4), 130.61 (C-6), 132.36 (C-3), 133.33 (C-8), 140.49 (C-16),
151.43 (C-18), 158.89 (C-13), 161.54 (C-10), 164.42 (C-2).
DEPT-13C NMR (75 MHz, CDCl3): d = 23.62 (CH2-21), 26.93
(CH2-20), 46.42 (CH2-22) (below the base line), 55.77 (OCH3),
58.71 (CH-19), 106.88 (CH-12), 124.70 (CH-14), 128.34 (CH-7),
128.53 (CH-5), 129.09 (CH-15), 130.61 (CH-6) (above the base
line).
2-Azido-5-methoxybenzoic Acid (24b)
To a stirred suspension of 2-amino-5-methoxybenzoic acid (21b;
1.00 g, 5.98 mmol) in a mixture of concd HCl (1.25 mL) and H2O
(5 mL) at –5 °C was added a precooled soln of NaNO2 (0.450 g,
6.52 mmol) in H2O (1.2 mL) dropwise over 5 min. The mixture was
stirred at –5 to 0 °C for 30 min, and then urea (0.450 g, 7.5 mmol)
was added to destroy the excess nitrous acid. After 3 min at 0 °C, a
precooled soln of NaN3 (0.460 g, 7.08 mmol) in H2O (1.25 mL) was
added dropwise over 5 min at –5 to 0 °C. After 10 min at –5 to 0 °C,
stirring of the clear reaction mixture was continued at r.t. overnight.
The precipitated solid was collected by filtration, washed with cold
H2O (2 × 5 mL) and dried to give 24b as a cream white solid; yield:
1.095 g (95%); mp 107–108 °C.
IR (KBr): 2943, 2658 (acid), 2125 (azide), 2086, 1703, 1672, 1610
(acid), 1571, 1499, 1449 (aromatic C=C), 1301, 1272, 1228 (ether),
1074, 1034, 913, 881, 814, 750, 658 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.86 (s, 3 H, OCH3), 7.10–7.19
(m, 2 H, H-3,4), 7.58 (d, Jmeta = 2.26 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = 55.73 (OCH3), 116.60 (C-2),
120.81, 121.40, 132.48, 156.60, 168.23 (CO2H).
EI-MS: m/z (%) = 193 (4.3) [M+], 165 (20.43), 149 (9.67), 134
(6.45), 121 (60.21), 106 (100), 85 (9.67), 78 (38.70), 63 (23.65), 43
(96.77), 41 (27.95), 40 (10.75).
EI-MS: m/z (%) = 347 (93.54) [M+], 322 (3.22), 306 (3.22), 280
(21.50), 279 (100), 263 (16.12), 236 (8.60), 221 (3.22), 207 (11.82),
179 (8.60), 160 (2.68), 149 (13.97), 139 (25.80), 120 (10.75), 102
(15.05), 90 (10.75), 77 (16.66), 63 (16.13), 45 (32.25), 41 (23.11),
40 (3.76).
ESI-MS: m/z = 348 [M+ + H].
HRMS (ESI): m/z calcd for C20H18N3O3: 348.1348 [M+ + H],
C20H17N3NaO3: 370.1168 [M+ + Na]; found: 348.1328 [M+ + H],
370.1150 [M+ + Na].
Anal. Calcd for C8H7N3O3: C, 49.74; H, 3.65. Found: C, 49.66; H,
3.72.
10-(2-Azido-5-methoxybenzoyl)-2,3-dihydro-1H-benzo[e]pyr-
rolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (12b)
To a soln of Et3N (0.524 g, 5.18 mmol, 1.25 equiv) and DMAP
(0.354 g, 2.90 mmol, 0.7 equiv) in anhyd THF (8.0 mL) was slowly
added dilactam 23 (0.895 g, 4.14 mmol, 1.0 equiv) at 0 °C under N2
atmosphere. The mixture was stirred at the same temperature for 1
Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93. Found: C, 69.08; H,
4.97.
2-Azidobenzoic Acid (24a)
To a stirred suspension of anthranilic acid (21a; 5.0 g, 36.5 mmol)
in a 1:1 mixture of H2O (63 mL) and concd HCl (63 mL) at –5 °C
Synthesis 2010, No. 4, 643–650 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of (–)-Circumdatin H
649
was added a precooled soln of NaNO2 (2.375 g, 34.42 mmol) in
H2O (32 mL) dropwise over 5 min, and the mixture was maintained
at –5 to 0 °C for 15 min. The cold reaction mixture was filtered on
a precooled Büchner funnel at –10 °C and the clear filtrate was add-
ed to a magnetically stirred soln of NaN3 (2.10 g, 32.30 mmol) and
NaOAc·3H2O (52.5 g, 385.8 mmol) in H2O (63 mL) at –5 °C over
5 min. After 10 min at –5 °C, the reaction mixture was allowed to
attain r.t. over 90 min and the separated solid was collected by fil-
tration, washed with H2O (2 × 25 mL) and dried to give 24a as a
white solid; yield: 4.57 g (77%); mp 144–145 °C.
13C NMR (75 MHz, CDCl3): d = 23.61, 29.57, 46.42, 58.82 (C-19),
121.42, 127.32, 127.44, 127.53, 128.29, 129.83, 130.64, 132.30,
133.14, 134.66, 146.04, 153.53 (C-18), 161.59 (C-2), 164.30 (C-
10).
ESI-MS: m/z = 318 [M+ + H].
HRMS (ESI): m/z calcd for C19H16N3O2: 318.1243 [M+ + H],
C19H15N3NaO2: 340.1062 [M+ + Na]; found: 318.1247 [M+ + H],
340.1037 [M+ + Na].
Anal. Calcd for C19H15N3O2: C, 71.91; H, 4.76. Found: C, 71.85; H,
4.82.
IR (KBr): 2962, 2821, 2646 (acid), 2105 (azide), 1696 (acid), 1595,
1574, 1485, 1454, 1410 (aromatic C=C), 1268, 1074, 918, 748, 688
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21–7.25 (m, 2 H), 7.58 (t,
J = 7.3 Hz, 1 H), 8.08 (d, J = 7.3 Hz, 1 H).
EI-MS: m/z (%) = 163 (2.68) [M+], 149 (2.15), 135 (19.35), 119
(6.98), 107 (16.12), 90 (9.67), 79 (100), 63 (45.16), 52 (67.74), 40
(6.98).
Acknowledgment
One of the authors (M.V.C.) thanks CSIR, New Delhi for financial
support.
References
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(10) Bodanszky, M.; Bodanszky, A. The Practice of Peptide
Synthesis; Springer-Verlag: Berlin, 1994.
(11) (a) Mohapatra, D. K.; Datta, A. Bioorg. Med. Chem. Lett.
1997, 7, 2527. (b) Witt, A.; Bergman, J. J. Org. Chem. 2001,
66, 2784.
(12) (a) Ozaki, K.; Yamada, Y.; Oine, T. Chem. Pharm. Bull.
1984, 32, 2160. (b) Zhichkin, P.; Kesicki, E.; Treiberg, J.;
Bourdon, L.; Ronsheim, M.; Ooi, H. C.; White, S.; Judkins,
A.; Fairfax, D. Org. Lett. 2007, 9, 1415. (c) Liu, J.-F.;
Kaselj, M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi, G.;
Yohannes, D.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005,
70, 10488. (d) Taher, D.; Ishtaiwi, Z. N.; Al-Said, N. H.
ARKIVOC 2008, (xvi), 154.
10-(2-Azidobenzoyl)-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-
a][1,4]diazepine-5,11(10H,11aH)-dione (12a)
To a soln of Et3N (0.585 g, 5.79 mmol, 1.25 equiv) and DMAP
(0.395 g, 3.24 mmol, 0.7 equiv) in anhyd THF (8.0 mL) was slowly
added dilactam 23 (1.0 g, 4.63 mmol, 1.0 equiv) at 0 °C under N2
atmosphere. The mixture was stirred at the same temperature for 1
h. To the reaction mixture was added 2-azidobenzoyl chloride (25a;
1.05 g, 5.79 mmol, 1.25 equiv), which was prepared from 2-azido-
benzoic acid (24a; 0.943 g, 5.79 mmol) and SOCl2 (3.536 mL,
48.48 mmol) at 80 °C for 2 h, in THF (5 mL) at 0 °C. The mixture
was stirred at the same temperature for 30 min and then at r.t. for 1
h. The solvent was evaporated and the resulting residue was dis-
solved in CH2Cl2 (100 mL). The organic layer was washed with
H2O (2 × 60 mL), dried (Na2SO4) and concentrated under reduced
pressure to give 12a (1.80 g) as a gummy brownish yellow syrup,
which was dissolved in anhyd benzene (25 mL) and immediately
used for the next step.
Rf = 0.61 (CH2Cl2–EtOAc, 5:1).
(S)-(–)-13-Desmethoxycircumdatin H (7a)
To a stirred soln of imide derivative 12a (1.803 g) in anhyd benzene
(25 mL) was added Bu3P (0.889 g, 4.397 mmol) in one portion un-
der N2 atmosphere at r.t. The mixture was refluxed at 60 °C for 1 h
and then left at r.t. overnight. After completion of the reaction, the
solvent was evaporated and the resulting residue was dissolved in
CH2Cl2 (150 mL). The organic layer was washed with 0.5 N aq HCl
(3 × 40 mL) followed by brine (2 × 25 mL), and then dried
(Na2SO4) and concentrated under reduced pressure to afford a solid
residue, which was purified by silica gel column chromatography
(CH2Cl2–EtOAc, 5:1) to give (–)-7a as a cream white solid; yield:
1.139 g (78% over two steps starting from 23); mp 250–251 °C.
[a]D20 –124.60 (c 0.5, MeOH).
Rf = 0.55 (CH2Cl2–EtOAc, 5:1).
IR (KBr): 2924, 2878, 1689, 1641, 1610 (amide), 1448, 1410 (aro-
matic C=C), 1360, 1334, 1293, 1210, 1154, 1112, 1082, 1082,
1020, 966, 876, 827, 780, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98–2.45 (m, 3 H, H-
20b,21a,21b), 3.12–3.15 (m, 1 H, H-20a), 3.50–3.86 (m, 2 H, H-
22a,22b), 4.53 (d, J = 5.9 Hz, 1 H, H-19), 7.46–7.59 (m, 4 H, H-
5,6,7,14), 7.74–7.80 (m, 2 H, H-13,15), 7.98 (d, J = 6.6 Hz, 1 H, H-
12), 8.29 (d, J = 8.1 Hz, 1 H, H-4).
(13) Garin, J.; Merino, P.; Orduna, J.; Tejero, T.; Uriel, S.
Tetrahedron Lett. 1991, 32, 3263.
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D. S. Bose, M. V. Chary
PAPER
(14) Kamat, V. P.; Kirtany, J. K. Org. Prep. Proced. Int. 1994,
26, 494.
(15) Kshirsagar, U. A.; Mhaske, S. B.; Argade, N. P. Tetrahedron
Lett. 2007, 48, 3243.
(17) (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
(b) Bose, D. S.; Srinivas, P.; Gurjar, M. K. Tetrahedron Lett.
1997, 38, 5839. (c) Kothakonda, K. K.; Bose, D. S. Bioorg.
Med. Chem. Lett. 2004, 14, 4371.
(16) The intramolecular version of the tandem Staudinger/aza-
Wittig reaction is often referred to as the Eguchi aza-Wittig
protocol; see: (a) Eguchi, S.; Matsushita, Y.; Yamashita, K.
Org. Prep. Proced. Int. 1992, 24, 209. (b) Mollina, P.;
Vilaplaza, M. J. Synthesis 1994, 1197. (c) Eguchi, S.
ARKIVOC 2005, (ii), 98. (d) Grieder, A.; Thomas, A. W.
Synthesis 2003, 1707.
(18) (a) Coppola, G. M. Synthesis 1980, 505. (b) Scherrer, R. A.
US Patent 3233201, 1966; Chem. Abstr. 1966, 64, 17614.
(19) Write, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.;
Hardy, R. A. Jr. J. Med. Chem. 1978, 21, 1087.
Synthesis 2010, No. 4, 643–650 © Thieme Stuttgart · New York