Palladium catalyzed synthesis of quinazolino [1,4] benzodiazepine alkaloids and analogous

Article abstract of DOI:10.1016/j.tet.2011.12.032

A concise synthesis of enantiopure quinazolino [1,4] benzodiazepine was accomplished by palladium-catalyzed N-arylation of amidines with o-bromobenzoates followed by intra molecular cyclization. The strategy was successfully applied to the total synthesis of pyrrolo quinazolino [1,4] benzodiazepine alkaloids such as circumdatin H, J and other analogues.

Full text of DOI:10.1016/j.tet.2011.12.032

Tetrahedron 68 (2012) 2001e2006
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium catalyzed synthesis of quinazolino [1,4] benzodiazepine alkaloids
and analogous
a
,
b
,
, K. Mukkanti , Srinivas Pusuluri a
b
*
Kumaraswamy Sorra
a
Chemistry Services, GVK Biosciences Private Limited, Plot No.5C, IDA Uppal, Hyderabad 500 039, AP, India
Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of enantiopure quinazolino [1,4] benzodiazepine was accomplished by palladium-
catalyzed N-arylation of amidines with o-bromobenzoates followed by intra molecular cyclization. The
strategy was successfully applied to the total synthesis of pyrrolo quinazolino [1,4] benzodiazepine
alkaloids such as circumdatin H, J and other analogues.
Received 15 September 2011
Received in revised form 24 November 2011
Accepted 13 December 2011
Available online 19 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Quinazolinobenzodiazepine
Circumdatin
BuchwaldeHartwig amination
Palladium
Lawesson’s reagent
1. Introduction
Circumdatins, a sub-group of fused quinazolinobenzodiaze-
pine alkaloids (Fig. 1), were first isolated by Rahbæk et al. from
3
e7
Benzodiazepines are an important class of compounds’ repre-
senting as a member of the family of privileged scaffold. A large
a marine fungus Aspergillus ochraceus (subgenus Circumdati).
1
They possess antitumour, antifungal, insecticide, antibiotic
4
e6,8
9
number of structurally interesting and biologically important nat-
activities,
cholescystokinin antagonism, inhibition of sub-
2
3d
10
ural and synthetic benzodiazepines are known in the literature.
stance P3 and mitochondrial NADH oxidase. The quinazoli-
nobenzodiazepine moiety has received much attention in the
synthetic community due to it’s structural and biological attrib-
uted features.
Benzodiazepine with fused quinazoline system appears in a num-
ber of naturally occurring alkaloids, such as circumdatins, benzo-
3e7
malvins, asperlicin, sclerotigenin (Fig. 1).
In the total synthesis of quinazolinobenzodiazepine alkaloids,
various methods have been developed for the synthesis of qui-
nazolino [1,4] benzodiazepine moiety in their skeleton. Primarily,
the cyclization has been done via the aza-Wittig reaction, known
11,12
as the Eguchi protocol.
Though, it provided a direct route to
heterocyclic natural products; this approach has a down side of
using explosive 2-azidobenzoic acids. Witt and Bergman synthe-
sized circumdatin F via iminobenzoxazine intermediate by the
MazurkiewiczeGanesan protocol, but it requires longer synthetic
13
sequences. Bock’s group afforded the asperlicins C and E by
regioselective annulation of benzodiazepinedione with anthra-
14
nilic acid. Liu and co-workers synthesized racemic quinazoli-
15
nobenzodiazepine by means of a one-pot synthesis. And also,
lately progress has been made using metal triflate catalyzed
16
Fig. 1. Structures of known quinazolinobenzodiazepine alkaloids.
dehydrocyclization of tripeptide-anthranilate and reductive cy-
17
clization of the 2-nitrobenzamides affords the quinazolinone.
Most recently, copper-catalyzed N-arylation of a quinazolinone
*
Corresponding author. Tel.: þ91 40 67126600; fax: þ91 40 27208866; e-mail
18
address: kumaraswamy.s@gvkbio.com (K. Sorra).
led to the benzodiazepine ring system.
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.032

2002
K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
In this communication, we report a concise and preferably
Table 1
Optimization chart of palladium catalyzed conditions for quinazolino [1,4]
benzodiazepine
convergent route for the synthesis of highly enantiopure pyrrolo
quinazolino [1,4] benzodiazepine-2,5-diones via amination/cycli-
zation domino reaction of amidines with o-bromobenzoates under
BuchwaldeHartwig conditions. The present work represents
a considerably improved synthesis and we envisioned that this
reaction would make possible a short synthesis of enantiopure
pentacyclic circumdatin H, J and their analogues.
19
2
. Results and discussion
Palladium catalyzed amination and followed by intramolecular
cyclization involving in the tandem carbonenitrogen bond forma-
tion were preformed on the amidine 4a,b, which can be synthe-
Temperature ( C) Time Yield of 6a (%)
ꢀ
Entry Pd source
Ligand
Xantphos Cs
Xantphos NaO-t-Bu 130
Base
1
2
Pd
Pd
2
(dba)
(dba)
3
3
2
CO
3
100e
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
12 h
12 h
12 h
24 h
(NR)b
sized in three steps from the commercially available
isatoic anhydrides (Scheme 1). The cyclocondensation of equimolar
of naturally occurring -proline with isatoic anhydride (1a) and
methoxy isatoic anhydride (1b) in DMF at 150 C for 5 h provided
L-Proline and
e
e
(NR)b
2
b
3
4
Pd2 (dba)3
Pd (dba)
BINAP
Aphos
Cs CO3
Cs CO
2 3
2
100
(NR)
100e
(NR)b
10
L
2
3
e
ꢀ
5
P
d
(
d
p
p
f
)
C
l
X
a
n
t
p
h
o
s
C
s
C
O
100
2
2
3
2
0
17
6
Pd (dppf) Cl
2
BINAP
2 3
Cs CO
130e
8
30
corresponding products 2a and 2b in 85e90% yields. The
dilactam compound 2a,b subsequently converted to mono thio-
lactams 3a,b using 0.5 equiv Lawesson’s reagent in toluene at 70 C
e
7
8
Pd (PPh
Pd (PPh
3
)
)
4
4
Xantphos NaO-t-Bu 100
BINAP
Xantphos NaO-t-Bu 100
NaO-t-Bu 100e
e
3
32
65
53
75
ꢀ
c
9
Pd (OAc)2
2
0
NaO-t-Bu 100e
c
for 6 h. The thiolactam 3a,b was reacted with anhydrous NH
3
and
10
11
Pd (OAc)
Pd (OAc)
Pd (OAc)
Pd (OAc)
2
2
2
2
BINAP
d
21
Xantphos Cs
Xantphos Cs
Xantphos Cs
2
2
2
CO
3
CO
3
CO
3
100e
HgCl
2
afforded the amidine 4a,b in 90% yield, which were chosen
f
d
1
1
2
3
100
55
as key precursors for the quinazolinone ring formation.
g
d
100
15 min 78
a
All reactions were run with 4a (0.23 mmol), 5a (0.23 mmol), base (0.46 mmol,
2
equiv), Pd catalyst (5 mol %) and ligand (10 mol %) in 1,4-dioxane (2 mL) under Ar.
Isolated yields.
b
No reaction.
c
70% ee.
d
e
f
>99% ee.
The reaction was performed in sealed tube under oil-bath heating.
The reaction was performed under conventional oil-bath heating.
The reaction was performed under microwave irradiation.
g
different bases (NaO-t-Bu/Cs
which prove to be incapable of amination (entries 1e4). As an al-
ternate palladium source, the use of Pd (dppf) Cl under the same
2 3 3 4
CO /K PO ) at elevated temperatures,
2
reaction conditions gave compound 6 in 8e10% yield. The results
encouraged us to examine various catalysts, in the due course
Pd(PPh
and Pd(OAc)
cyclized compound. Finally, cyclization of compound 6 has been
achieved in 75% yield (>99% ee) with 5 mol % of Pd(OAc) and
0 mol % Xantphos in the presence of 2 equiv of Cs CO in 1,4-
dioxane at 100 C (entry 11). The analytical and spectral data for
3
)
4
eXantphos/(ꢁ)-BINAP gave a moderate yield (entries 7, 8)
2
eXantphos has demonstrated more effective to get the
2
1
2
3
ꢀ
2
2
compound 6 were in complete agreement with the reported data.
While Buchwald’s amination using Pd(OAc) eXantphos in the
presence of NaO-t-Bu gave us a disappointing enantiomeric purity
70% ee) (entries 9, 10). For further optimization of the reaction
conditions using Pd(OAc) /Xantphos/Cs CO in 1,4-dioxane, we
2
(
2
2
3
continued to examine reactions at various temperatures and re-
action duration. The reaction has taken 24 h for completion under
ꢀ
conventional heating at 100 C resulted in moderate yield (55%)
(
entry 12), but in sealed tube it was completed in 12 h with good
Scheme 1. Palladium catalyzed N-arylation and followed by intramolecular cycliza-
yield (entry 11). The time duration tremendously reduced under
microwave heating, microwave exposure to 5 min at 100 C resulted
low yield (35%) due to the incompletion of the reaction, the best
yield was obtained when the reaction was run at 100 C for 15 min
tion: synthesis of circumdatin H,
J
and analogues. Reagents and conditions: (a)
ꢀ
ꢀ
ꢀ
L-proline, DMF, 140 C, 5 h, 85% yield (b) Lawesson’s reagent, toluene, 70 C, 5 h, 85%
ꢀ
yield (c) NH
3
, HgCl
2
, THF, 60 C, 1 h, 90e95% yield (d) Pd (OAc)
2
, Xantphos, Cs
2 3
CO , 1,4-
ꢀ
ꢀ
dioxane, 100 C, sealed tube, 12 h or MW, 15 min. 70e85% yield.
provided the desired compound 6 in 78% yield (entry 13). De-
lightfully, the chiral integrity was preserved in all the cases. The
enantiomeric purity was determined by the chiral HPLC area
method with a comparison of racemic compound 6, which was
synthesized similarly from the DL-proline.
Palladium catalyzed annulation of model substrate 4a with 5a
has been extensively investigated resulting in a substantial opti-
mization. The formation of the quinazolinone ring, while preserving
the chiral integrity has been studied by changing the reaction pa-
rameters (Table 1). Our studies began with Pd
phosphine ligands (Xantphos/(ꢁ)-BINAP/Aphos) in the presence of
2
(dba)
3
with various
Subsequently, functionalized cyclic amidine and o-bromo-
benzoates were investigated under the above optimized conditions

K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
2003
to achieve the total syntheses of natural pyrrolo quinazolino [1,4]
benzodiazepine-2,5-dione alkaloids (Scheme 1). Circumdatin H (7),
which contains an additional methoxy substituent, the synthesis
was preceded uneventfully from compound 4a and 5-methoxy-2-
bromo benzoate 5b. Circumdatin J (8), which contains methoxy
substituent on both benzodiazepine and quinazolino rings was
afforded from compound 4b and compound 5b. Both the circum-
datin H and J were synthesized in 75% yield with >99% ee. The
analytical and spectral data for the (ꢂ)-circumdatins H (7) and J (8)
The proposed mechanistic way for quinazolinone cyclization is
depicted in Scheme 3. In the first stage, the amination of AreBr (5a)
with 4a via BuchwaldeHartwig approach of the palladium complex
containing the chelating phosphine ligand produce the uncyclized
19,23
aminated compound (17).
In the next stage, the base catalyzed
medium could trigger the intramolecular cyclization with the
proximate nitrogen to lead the quinazolinobenzodiazepine ring
system.
10,17,22
were in complete agreement with the reported data.
The
3. Conclusion
natural products circumdatin E and circumdatin D contains hy-
droxy functionality on quinazolinone ring along with the methoxy
substituents, here we have synthesized the methoxy derivative of
the circumdatin D (9) and E (10) in 72e75% yield with >99% ee and
for our convenience we named them as methoxy circumdatin D and
E, respectively.
Most of the natural circumdatins have electron rich sub-
stituents, such as hydroxy and methoxy groups; herein we
employed the optimized conditions on various substituted systems
including both activating and deactivating groups to examine the
competence of the ring substituents on the reaction conditions
We have developed a highly efficient and concise synthetic
strategy for the total synthesis of enantiopure circumdatin alkaloids
under palladium-catalyzed conditions. It features a quinazolino ring
cyclization process as a key synthetic step with preserving the chiral
integrity. This efficient strategy should allow easy access to a variety
of quinazolino [1,4] benzodiazepine alkaloids and their analogues.
4
4
. Experimental
.1. General
(Scheme 2). Compound 4a was reacted with the substituted 2-
bromo benzoates 5dei under the above described conditions to
afford compound 11e16, respectively, significantly the reaction was
completed much faster (8 h) and obtained >80% yield with the
electron-withdrawing substitutes rather than donating sub-
stituents. These results envisaged that the reaction conditions are
well tolerated by both electron-withdrawing and electron-
donating substituents in the Csp2 donors.
All reactions dealing with Palladium catalyst were conducted
under an atmosphere of argon. The solvents were purified
according to standard procedures prior to use, Pd catalysts, ligands
and Cs
chemicals were used as received. For thin-layer chromatography
TLC) analysis, Merck precoated Plates (silica gel 60 F254) were used
2 3
CO were purchased from Aldrich and all commercial
(
and eluting solvents are indicated in the procedures. Merck silica
gel 60 (230e400 mesh) was used for flash column chromatography.
Melting point (mp) determinations were performed by using Mel-
1
13
temp apparatus and are uncorrected. H and C NMR spectra were
recorded on a Varian Unity instrument at rt at 400 MHz. Chemical
shifts are reported in
d parts per million (ppm) downfield from
tetramethylsilane (TMS) with reference to internal solvent and
coupling constants in hertz. Mass spectra were obtained on
Micromass QuattroMicroÔAPI-autospectrometer using APCI tech-
nique. HRMS TOF ES mass spectra were recorded on a Waters-
Alliance 2695 Separation Module/Q-TOF Micromass. Infrared (IR)
spectra were recorded on a PerkineElmer FT-IR spectrometer. Op-
Scheme 2. Synthesis of quinazolino [1,4] benzodiazepines from deactivated and ac-
tivated aromatic rings.
tical rotations ([
a
]D) were measured on a JASCO P-1030 polarimeter
temp, concentration (c g/
and data are reported as follows: [
a]
D
Scheme 3. Mechanistic proposal for the Pd catalyzed amination and intramolecular cyclization.

2004
K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
þ
þ
þ
1
(
00 mL) and solvent. Liquid chromatography-mass spectrometry
LCMS) on a Waters Acquity UPLC photodiode array detector sys-
tem using ESI technique under the following conditions: column
, Mobile Phase: A:
COOH in acetonitrile, T/%B:
/15, 3/95, 4/95, 4.1/15; flow rate: 0.4 mL/min, diluent: acetonitrile;
23.3; MS (APCI) m/z 216 (MH ); HRMS (TOF ES ): MH , found
216.1129. C12 O requires 216.1137.
14 3
H N
used: Acquity-UPLC BEH-C18 (2.1ꢃ50 mm) 1.7
m
4.1.4. (S)-11-Aminio-7-methoxy-2,3-dihydro-1H-benzo[e]
[1,2-a][1,4]diazepine-5 (11aH)-one (4b). Thiolactam 3b (2.5 g,
9.54 mmol) was converted to 4b using the procedure for the
pyrrolo
0
0
.025% aqueous CF
3
COOH, B:0.025% CF
3
UV: max-plot. Enantiomeric excess (ee) was determined by HPLC
, hexane/
ethanol (1:1) with 0.1% isopropyl amine at 1.0 mL/min. All isolated
compounds had purity greater than 99% (area percent) as judged by
HPLC analysis area method.
preparation of 4a. This gave off white solid, 90% yield; R
f
(15%
ꢀ
26
D
analysis using Chiralpak IA column (250ꢃ4.6 mm), 5
m
MeOH/CHCl
n
3
) 0.40; mp 189e190 C; ½
a
ꢄ
þ615.9 (c 1.05, DMSO);
max (KBr) 3389, 3325, 3206, 1609, 1488, 1437, 1405, 1267, 1228,
ꢂ1
1034, 834, 762 cm
NH
.77 (3H, s, OCH
2.12e2.08 (1H, m, CH
H 6
; d (400 MHz, DMSO-d ) 7.40e7.20 (3H, br,
2
and ArH), 71.2e7.06 (2H, m, ArH), 4.13 (1H, d, J¼7.2 Hz, NCH),
), 3.67e3.62 (1H, m, CH ), 3.40e3.36 (2H, m, CH ),
), 2.05e1.96 (2H, m, CH ); (100 MHz,
3
3
2
2
4.1.1. (11aS)-11-Thioxo-1,2,3,10,11,11a-hexahydro-5H pyrrolo [2,1-c]
2
2
d
C
[
1,4]benzodiazepin-5-one (3a). To a suspension of dilactam com-
DMSO-d
6
) 164.5, 161.3, 154.7, 127.6, 126.4, 123.0, 119.2, 112.4, 55.3,
þ
pound 2a (1.0 g, 4.62 mmol) in 100 mL toluene was added Law-
esson’s reagent (0.94 g, 2.31 mmol). The yellow suspension was
heated to 70 C for 5 h. After this time a yellow solid has pre-
54.0, 46.4, 26.0, 23.3; MS (APCI) m/z 246 (MH ).
ꢀ
cipitated, which was recrystallized from ethanol to yield pure 3a
4.2. General procedure for the Pd catalyzed synthesis of
quinazolinone [1,4] benzodiazepine
(
0
3
923 mg, 86% yield) as yellow crystals. R
f
(50% EtOAc/pet ether)
ꢀ
27
D
.50; mp 291e292 C; ½
a
ꢄ
þ729.1 (c 1.08, DMSO); max (KBr) 3446,
n
171, 2943, 1616, 1605, 1521. 1417, 1374, 1270, 1141, 1030, 886, 832,
Method A: A sealed tube was charged with compound 4a,b
ꢂ1
8
(
13, 753, 695 cm
1H, d, J¼8.0 Hz, ArH), 7.53e7.49 (1H, m, ArH), 7.37e7.33 (1H, m,
ArH), 7.05 (1H, d, J¼8.4 Hz, ArH), 4.22 (1H, d, J¼7.6 Hz, NCH),
.80e3.77 (1H, m, CH ), 3.64e3.57 (1H, m, CH ), 3.13e3.08 (1H, m,
CH ), 2.31e2.22 (1H, m, CH ), 2.18e2.08 (1H, m, CH ), 2.03e1.97
1H, m, CH ); (100 MHz, DMSO-d ) 201.9, 164.1, 136.4, 132.1,
30.2, 127.7, 125.6, 121.8, 59.7, 46.8, 28.9, 22.6; MS (APCI) m/z 233
;
d
H
(400 MHz, CDCl
3
) 9.73 (1H, br, NH), 8.04
(0.93 mmol), 5aee (0.93 mmol), 5 mol % of Pd(OAc)
2
, 10 mol % of
Xantphos, 2 equiv of Cs CO (1.86 mmol) and 10 mL of 1,4-dioxane.
2
3
The mixture was degassed and backfilled with argon, the reaction
ꢀ
3
2
2
vessel was sealed with a Teflon tap and heated at 100 C for 12 h.
2
2
2
The reaction mixture was cooled to rt and concentrated in vacuo.
The residue was dissolved in chloroform, washed with 10% citric
(
1
2
d
C
6
acid solution, brine solution, dried over anhydrous Na
2 4
SO and
þ
þ
þ
(
MH ); HRMS (TOF ES ): MH , found 233.0738. C12
13 2
H N OS
concentrated. The crude compound was purified by flash column
requires 233.0749.
3
chromatography using 3e5% of MeOH/CHCl as an eluent to give
the title cyclized compound.
4
.1.2. (11aS)-7-Methoxy-11-thioxo-1,2,3,10,11,11a-hexahydro-5Hpyr-
rolo[2,1-c][1,4]benzodiazepin-5-one (3b). Dilactam compound 2b
3 g, 12.19 mmol) was converted to 3b using the procedure for the
Method B: To a thick-well borosilicate glass vial (5 mL) was
added compound 4a,b (0.23 mmol), compound 5aee (0.23 mmol),
5 mol % of Pd(OAc) , 10 mol % of Xantphos, 2 equiv Cs CO
2 2 3
(
preparation of 3a. This gave yellow solid; 85% yield; R
f
(50% EtOAc/
(0.46 mmol) and 1,4-dioxane (2 mL). The mixture was degassed
and the reaction vial was sealed and placed in the CEM-DISCOVER
microwave reactor and irradiated at 100 C for 15 min. After cooled
ꢀ
26
D
pet ether) 0.50; mp 196e197 C; ½
a
ꢄ
þ 632 (c 1.02, MeOH);
n
max
ꢀ
(
KBr) 3467, 3247, 2958, 1627, 1606, 1497, 1434, 1385, 1301, 1245,
164, 1095, 1026, 872, 820, 788, 630 cm
ꢂ1
1
9
3
3
3
;
d
H
(400 MHz, CDCl
3
)
to rt, the product was isolated as above described in method A.
.65 (1H, br, NH), 7.50 (1H, d, J¼2.8 Hz, ArH), 7.06 (1H, dd, J¼8.8,
.2 Hz, ArH), 7.0 (1H, d, J¼8.8 Hz, ArH), 4.19 (1H, d, J¼7.2 Hz, NCH),
4.2.1. (S)-(ꢂ)-Desmethoxy circumdatin H (6). Pale yellow solid;
.93 (3H, s, OCH
.12e3.08 (1H, m, CH
); (100 MHz, CDCl
3
), 3.84e3.76 (1H, m, CH
2
), 3.63e3.56 (1H, m, CH
2
),
method A: 75% yield, method B: 78% yield; R
f
(10% MeOH/CHCl
3
)
ꢀ
27
D
2
), 2.32e2.23 (1H, m, CH
2
), 2.16e1.96 (2H, m,
0.60; mp 251e252 C; ½
a
ꢄ
ꢂ123.5 (c 0.54, MeOH);
nmax (KBr) 3435,
CH
2
d
C
3
) 200.8, 164.9, 157.6, 129.6, 129.2, 122.5,
3067, 2972, 2879, 1690. 1643, 1615, 1473, 1450, 1417, 1362, 1295,
þ
ꢂ1
1
20.1, 113.5, 60.1, 55.8, 47.3, 29.5, 22.9; MS (APCI) m/z 263 (MH );
1251, 1215, 1115, 1021, 973, 897, 782, 778, 764, 704 cm
(400 MHz, DMSO-d
; d
H
þ
þ
HRMS (TOF ES ): MH , found 263.0875. C13
H
15
N
2
O
2
S requires
6
) 8.18 (1H, d, J¼8.0 Hz, ArH), 7.89 (1H, t,
2
63.0854.
J¼7.2 Hz, ArH), 7.83 (1H, d, J¼7.6 Hz, ArH), 7.74 (1H, d, J¼8.4 Hz,
ArH), 7.67e7.56 (4H, m, ArH), 4.64 (1H, d, J¼6.4 Hz, NCH),
4
.1.3. (S)-11-Aminio-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a] [1,4]
3.63e3.59 (1H, m, CH
CH
CDCl
128.6, 128.3, 127.6, 127.5, 127.4, 121.4, 58.8, 46.4, 26.9, 23.6; MS
2
), 3.49e3.42 (1H, m, CH
2
), 2.94e2.93 (1H, m,
); (100 MHz,
3
) 164.4, 161.7, 153.6, 146.1, 134.1, 133.2, 132.3, 130.7, 129.9,
diazepine-5 (11aH)-one (4a). A suspension of 3a (2.5 g,
2
), 2.16e2.08 (2H, m, CH
2
), 1.99e1.98 (1H, m, CH
2
d
C
1
0.77 mmol) and mercuric chloride (3.5 g, 12.93 mmol, 1.2 equiv)
ꢀ
in dry THF (125 mL) was warmed to 60 C and an ammonia stream
þ
þ
þ
was bubbled into the solution. After 1 h, the solution became black
(APCI) m/z 318 (MH ); HRMS (TOF ES ): MH , found 318.1205.
requires 318.1243.
(
formation of mercuric sulfide), the stream of ammonia was
19 16 3 2
C H N O
stopped and the reaction mixture was stirred for 1 h. The reaction
mixture was filtered through Celite, washed with a mixture of
methanol/THF, the combined filtrate was concentrated, the solid
4.2.2. (S)-(ꢂ)-Circumdatin H (7). Pale yellow solid; method A: 75%
yield, method B: 79% yield; R
f
3
(10%MeOH/CHCl ) 0.55; mp
ꢀ
29
D
residue was washed with acetone and Et
amidine 4a as pale yellow solid. 95% yield; R
2
O and dried to give the
(15% MeOH/CHCl
max (KBr)
216e217 C; ½
a
ꢄ
ꢂ106 (c 0.82, MeOH);
n
max (KBr) 3435, 3065,
f
3
)
2972, 1692, 1646, 1619, 1491, 1456,1423, 1361, 1278, 1235,1022, 875,
832, 789, 761, 707 cm
ꢀ
26
D
ꢂ1
0
3
.40; mp 314e315 C; ½
a
ꢄ
þ582.3 (c 1.04, DMSO);
n
;
d
H
(400 MHz, CDCl
3
) 7.99 (1H, d, J¼7.2 Hz,
541, 3365, 3128. 1673, 1616, 1580, 1453, 1403, 1257, 1239, 1149,
ArH), 7.67 (1H, d, J¼2.8 Hz, ArH), 7.64 (1H, d, J¼8.8 Hz, ArH),
ꢂ1
762, 702 cm
;
d
H
(400 MHz, DMSO-d
6
) 7.75 (1H, d, J¼8.0 Hz,
), 7.12 (1H,
t, J¼8.4 Hz, ArH), 7.06 (1H, d, J¼7.6 Hz, ArH), 4.06 (1H, d, J¼6.8 Hz,
NCH), 3.66e3.61 (1H, m, CH ), 3.41e3.34 (2H, m, CH ), 2.13e2.05
1H, m, CH ), 1.98e1.91 (2H, m, CH ); (100 MHz, DMSO-d
64.8, 161.9, 143.6, 129.9, 126.7, 126.5, 124.9, 122.5, 54.1, 46.4, 26.0,
7.58e7.50 (3H, m, ArH), 7.38 (1H, dd, J¼8.8, 2.8 Hz, ArH), 4.54 (1H,
ArH), 7.44 (1H, t, J¼7.6 Hz, ArH), 7.40e7.20 (2H, m, NH
2
d, J¼8.0 Hz, NCH), 3.93 (3H, s, OCH
3
), 3.82e3.77 (1H, m, NCH
2
),
), 2.32e2.30 (1H, m,
), 2.10e2.05 (1H, m, CH ); (100 MHz,
) 164.4, 161.6, 158.9, 151.5, 140.5, 133.4, 132.4, 130.7, 129.9,
129.1,128.6,128.3,124.8,122.3,106.9, 58.7, 55.8, 46.5, 26.9, 23.7; MS
3.64e3.57 (1H, m, CH
CH ), 2.17e2.12 (1H, m, CH
CDCl
2 2
), 3.18e3.14 (1H, m, CH
2
2
2
2
2
d
C
(
2
2
d
C
6
)
3
1

K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
2005
þ
þ
þ
(
APCI) m/z 348 (MH ); HRMS (TOF ES ): MH , found 348.1338.
requires 348.1348.
ArH), 7.59e7.50 (3H, m, ArH), 7.38 (1H, dd, J¼10.0, 2.4 Hz, ArH), 7.23
(1H, dd, J¼8.4, 2.4 Hz, ArH), 4.54 (1H, d, J¼7.2 Hz, NCH), 3.82e3.77
20 18 3 3
C H N O
(
1H, m, CH
2.31e2.29 (1H, m, CH
CDCl ) 168.0, 165.4, 164.3, 160.9, 154.9, 148.4, 148.2, 132.6, 138.8,
130.5, 130.1, 128.5, 118.2, 116.3, 113.2, 58.9, 46.5, 26.9, 23.6; MS
2
), 3.64e3.59 (1H, m, CH
2
), 3.17e3.12 (1H, m, CH
2
),
4
.2.3. (S)-(ꢂ)-Circumdatin J (8). Pale yellow solid; method A: 75%
), 2.18e2.06 (2H, m, CH ); d (100 MHz,
2 2 C
ꢀ
29
D
yield; R
1
1
d
f
(10% MeOH/CHCl
Cl );
3
) 0.50; mp 189e191 C; ½
a
ꢄ
ꢂ63.2 (c
3
.19, 1:1 MeOH/CH
2
2
n
max (KBr) 3436, 2936, 2875, 1687, 1633,
ꢂ1
þ
þ
þ
617, 1491, 1465, 1439, 1368, 1282, 1238, 1029, 869, 835, 771 cm
;
(APCI) m/z 336 (MH ); HRMS (TOF ES ): MH , found 336.1110.
19 15 3 2
C H N O F requires 336.1148.
H
(400 MHz, CDCl
3
) 7.67 (1H, d, J¼2.8 Hz, ArH), 7.63 (1H, d,
J¼8.8 Hz, ArH), 7.47 (1H, d, J¼8.8 Hz, ArH), 7.46 (1H, d, J¼2.0 Hz,
ArH), 7.37 (1H, dd, J¼8.8, 2.8 Hz, ArH), 7.11 (1H, dd, J¼9.2, 3.2 Hz,
4.2.8. Compound (13). White solid; method A: 80% yield; R
f
(10%
);
ꢀ
28
D
ArH), 4.56 (1H, d, J¼4.2 Hz, ArH), 3.92 (3H, s, OCH
3
), 3.91 (3H, s,
), 3.18e3.13
), 2.17e2.12 (1H, m, CH ),
(100 MHz, CDCl ) 164.3, 161.7, 159.1,
MeOH/CHCl
n
3
) 0.60; mp 197e200 C; ½
a
ꢄ
ꢂ77.56 (c 0.52, CHCl
3
OCH
(
2
1
3
), 3.80e3.75 (1H, m, NCH), 3.64e3.58 (1H, m, CH
1H, m, CH ), 2.32e2.29 (1H, m, CH
.11e2.05 (1H, m, CH );
2
max (KBr) 3434, 3053, 2925, 1697, 1648, 1615, 1466, 1418, 1363,
ꢂ1
2
2
2
1276, 1074, 829, 721 cm
H 3
; d (400 MHz, CDCl ) 8.27 (1H, m, ArH),
2
d
C
3
8.0 (1H, d, J¼8.0 Hz, ArH), 7.74e7.73 (1H, m, ArH), 7.72 (1H, m, ArH),
58.9, 151.6, 140.6, 133.5, 129.7, 129.1, 126.2, 124.7, 122.3, 117.9, 112.9,
06.8, 58.8, 55.8, 55.7, 46.5, 26.9, 23.6; MS (APCI) m/z 378 (MH );
HRMS (TOF ES ): MH , found 378.1469. C21
7.67e7.26 (3H, m, ArH), 4.54 (1H, d, J¼7.6 Hz, NCH), 3.83e3.77 (1H,
þ
1
m, CH
(3H, m, CH
133.6, 133.1, 132.5, 131.0, 130.2, 129.4, 129.0, 128.4, 126.9, 122.8, 59.0,
2
), 3.64e3.57 (1H, m, CH
2 2
), 3.17e3.12 (1H, m, CH ), 2.31e2.05
þ
þ
H
20
N
3
O
4
requires
2
);
C 3
d (100 MHz, CDCl ) 164.5, 160.9, 154.1, 144.8, 135.3,
3
78.1454.
þ
þ
þ
4
6.7, 27.2, 23.8; MS (APCI) m/z 352 (MH ); HRMS (TOF ES ): MH ,
4
.2.4. (S)-(ꢂ)-Methoxy circumdatin E (9). Off white solid; method
found 352.0878. C19 Cl requires 352.0853.
15 3 2
H N O
ꢀ
A and B: 75% yield; R
f
(10%MeOH/CHCl
3
) 0.50; mp 263e264 C;
2
8
½
a
1
ꢄ
ꢂ145 (c 0.38, 1:1 MeOH/CHCl
3
);
n
max (KBr) 3432, 2924, 2851,
4.2.9. Compound (14). Yellow solid; method A: 82% yield; R
f
(10%
D
ꢂ1
ꢀ
28
D
647, 1457, 1375, 1260, 1214, 1099, 1048, 1020, 836, 789, 669 cm
(400 MHz, DMSO-d
m, ArH), 7.13 (1H, d, J¼2.4 Hz, ArH), 7.01 (1H, d, J¼2.8 Hz, ArH), 4.60
1H, d, J¼6.0 Hz, NCH), 3.94 (3H, s, OCH ), 3.87 (3H, s, OCH ),
.57e3.55 (1H, m, CH ), 3.48e3.46 (1H, m, CH ), 3.0e2.95 (1H, m,
CH ), 2.18e2.11 (2H, m, CH ), 2.01e1.95 (1H, m, CH ); (100 MHz,
CDCl ) 164.5, 161.5, 159.5, 156.0, 150.6, 133.4, 132.3, 131.7, 130.7,
29.8, 128.6, 128.3, 123.2, 106.0, 98.1, 58.9, 56.5, 55.8, 46.5, 27.0,
;
MeOH/CHCl
MeOH/CHCl
3
) 0.60; mp 267e269 C; ½
a
ꢄ
ꢂ79.85 (c 0.51, 1:1
d
H
6
) 7.83 (1H, d, J¼6.4 Hz, ArH), 7.64e7.57 (3H,
3
);
n
max (KBr) 3435, 3047, 2926, 2229, 1700, 1686, 1644,
ꢂ1
H
; d (400 MHz,
1609, 1594, 1484, 1417, 1364, 1248, 1217, 839 cm
CDCl ) 8.63 (1H, s, ArH), 8.03e8.97 (2H, m, ArH), 7.81 (1H, d,
J¼8.4 Hz, ArH), 7.64e7.54 (3H, m, ArH), 4.57 (1H, d, J¼6.8 Hz, NCH),
3.83e3.79 (1H m, CH ), 3.64e3.57 (1H, m, CH ), 3.17e3.12 (1H, m,
CH ), 2.32e2.09 (3H, m, CH ); (100 MHz, CDCl ) 164.1, 160.2,
(
3
3
3
3
2
2
2
2
2
d
C
2
2
3
2
2
d
C
3
1
2
156.5, 148.7, 136.6, 132.7, 132.4, 132.2, 130.9, 130.1, 129.2, 128.9,
þ
þ
þ
3.8; MS (APCI) m/z 378 (MH ); HRMS (TOF ES ): MH , found
requires 378.1454.
127.9, 122.1, 117.7, 111.1, 58.9, 46.6, 27.0, 23.6; MS (APCI) m/z 343
þ
þ
þ
378.1469. C21
20
H N
3
O
4
(MH ); HRMS (TOF ES ): MH , found 343.1181. C20
15 4 2
H N O re-
quires 343.1195.
4
.2.5. (S)-(ꢂ)-Methoxy circumdatin
D
(10). Pale yellow solid;
ꢀ
method B: 72% yield; R
f
(10% MeOH/CHCl
);
3
) 0.50; mp 171e173 C;
4.2.10. Compound (15). Off white solid; method A: 72% yield; R
f
2
8
ꢀ
26
D
½
a
1
ꢄ
ꢂ98.6 (c 0.53, CHCl
3
n
max (KBr) 3435, 2925, 2857, 1636, 1615,
(10%MeOH/CHCl
3
) 0.30; mp 297e299 C; ½
a
ꢄ
ꢂ111.99 (c 0.52,
D
ꢂ1
457, 1377, 1282, 1236, 1214, 1160, 1057, 1040, 842, 772, 669 cm
;
DMSO);
n
max (KBr) 3435, 3305, 3070, 2926, 1690, 1616, 1543, 1492,
ꢂ1
d
H
(400 MHz, DMSO-d
6
) 7.50 (1H, d, J¼9.2 Hz, ArH), 7.27 (1H, d,
1457, 1420, 1361, 1312, 1251, 1163, 1011, 897, 845, 710 cm
(400 MHz, DMSO-d
(1H, d, J¼8.8 Hz, ArH), 7.82 (1H, d, J¼7.6 Hz, ArH), 7.71e7.55 (4H, m,
ArH), 4.62 (1H, d, J¼6.8 Hz, NCH), 3.60e3.58 (1H, m, CH ),
3.48e3.41 (1H, m, CH ), 2.90 (1H, m, CH ), 2.15e2.01 (5H, m, CH
COCH ), 1.97 (1H, m, CH ); (100 MHz, DMSO-d ) 168.6, 163.4,
; d
H
J¼2.4 Hz, ArH), 7.20 (1H, dd, J¼8.8, 3.2 Hz, ArH), 7.12e7.10 (1H, m,
ArH), 7.01 (1H, d, J¼2.4 Hz, ArH), 4.62 (1H, d, J¼5.6 Hz, NCH), 3.94
6
) 10.35 (1H, s, AceNH), 8.47 (1H, s, ArH), 8.02
(
3
3H, s, OCH
.0e2.95 (1H, m, CH
CH ); (100 MHz, CDCl
33.4, 131.7, 129.6, 126.2, 123.2, 117.9, 112.8, 105.9, 98.0, 58.9, 56.5,
3
), 3.78 (6H, s, OCH
3
, OCH
), 2.15e2.10 (2H, m, CH
) 164.4, 161.7, 159.4, 159.1, 155.9, 150.7,
3
), 3.55e3.46 (2H, m, CH
2
),
2
2
2
), 2.01e1.95 (1H, m,
2
2
2
,
2
d
C
3
3
2
d
C
6
1
161.1, 152.9, 141.3, 138.5, 133.1, 132.1, 130.5, 129.0, 128.4, 127.9, 126.2,
þ
5
5.8, 55.7, 46.5, 27.0, 23.8; MS (APCI) m/z 408 (MH ); HRMS (TOF
121.3, 114.8, 58.4, 46.0, 26.36, 23.98, 23.18; MS (APCI) m/z 375
þ
þ
þ
þ
þ
ES ): MH , found 408.1543. C22
22
H N
3
O
5
requires 408.1559.
(MH ); HRMS (TOF ES ): MH , found 375.1445. C21
quires 375.1457.
19 4 3
H N O re-
4
.2.6. Compound (11). Yellow solid; method A: 82% yield,
ꢀ
method B: 70% yield; R
f
(10% MeOH/CHCl
3
) 0.60; mp 239e240 C;
4.2.11. Compound (16). Off white solid; method A: 78% yield; R
f
2
7
ꢀ
26
D
½
a
1
ꢄ
ꢂ18.3 (c 0.76, CHCl
3
); max (KBr) 3447, 3082, 2957, 2883, 1699,
n
(10%MeOH/CHCl
MeOH/CHCl );
3
) 0.50; mp 276e278 C; ½
a
ꢄ
ꢂ123.83 (c 0.51, 1:1
D
683,1654,1611,1577,1523,1454,1412,1344,1278,1242,1183,1122,
3
n
max (KBr) 3447, 2957, 2929, 1682, 1651, 1609, 1500,
ꢂ1
ꢂ1
1
090, 849, 824, 787, 750, 717, 694 cm
1H, d, J¼2.8 Hz, ArH), 8.59 (1H, dd, J¼8.8, 2.8 Hz, ArH), 8.03 (1H, d,
J¼8.0 Hz, ArH), 7.86 (1H, d, J¼8.8 Hz, ArH), 7.64e7.55 (3H, m, ArH),
.59 (1H, d, J¼7.6 Hz, NCH), 3.83e3.80 (1H, m, CH ), 3.63e3.61 (1H,
m, CH ), 3.18e3.14 (1H, m, CH ), 2.32e2.30 (1H, m, CH ), 2.20e2.10
2H, m, CH ); (100 MHz, CDCl ) 164.1, 160.5, 156.9, 150.2, 146.2,
32.3, 132.2, 131.0, 131.2, 129.3, 129.2, 128.9, 127.9, 123.9, 121.1, 58.9,
;
d
H
(400 MHz, CDCl
3
) 9.17
1458, 1394, 1359, 1302, 1242, 1202, 1155, 1001, 870 cm
(400 MHz, CDCl
7.58e7.49 (3H, m, ArH), 7.11 (1H, s, ArH), 4.53 (1H, d, J¼8.0 Hz,
NCH), 4.05 (3H, s, OCH ), 4.0 (3H, s, OCH ), 3.82e3.77 (1H, m, CH ),
3.65e3.58 (1H, m, CH ), 3.17e3.12 (1H, m, CH ), 2.35e2.28 (1H, m,
CH ), 2.20e2.04 (2H, m, CH ); (100 MHz, CDCl ) 164.5, 161.0,
; d
H
(
3
) 7.99 (1H, d, J¼7.6 Hz, ArH), 7.63 (1H, s, ArH),
4
2
3
3
2
2
2
2
2
2
(
1
4
2
d
C
3
2
2
d
C
3
155.2, 152.5, 149.5, 142.3, 133.4, 132.3, 130.5, 129.8, 128.5, 128.4,
þ
þ
þ
6.6, 27.0, 23.6; MS (APCI) m/z 363 (MH ); HRMS (TOF ES ): MH ,
requires 363.1093.
114.8, 108.1, 106.4, 58.7, 56.4, 56.3, 46.4, 26.9, 23.7; MS (APCI) m/z
þ
þ
þ
found 363.1091. C19
H
15
N
4
O
4
378 (MH ); HRMS (TOF ES ): MH , found 378.1412. C21
requires 378.1412.
20 3 4
H N O
4
.2.7. Compound (12). Pale yellow solid; method A: 76% yield,
ꢀ
method B: 85% yield; R
f
(10% MeOH/CHCl
3
) 0.50; mp 264e265 C;
Acknowledgements
2
6
½
a
1
ꢄ
ꢂ75.1 (c 0.69, MeOH);
n
max (KBr) 3436, 3088, 2954, 1703, 1646,
D
ꢂ1
610, 1476, 1457, 1365, 1273, 1159, 1102, 978, 869, 781, 706 cm
;
d
H
The authors are grateful to the GVK Biosciences management for
(
400 MHz, CDCl
3
) 8.34e8.30 (1H, m, ArH), 8.0 (1H, d, J¼7.2 Hz,
the financial support and encouragement. We are thankful to

2006
K. Sorra et al. / Tetrahedron 68 (2012) 2001e2006
Dr. Srinivasa Rao Alapati and Dr. Balaram Patro for their valuable
suggestions and support.
10. Lopez-Gresa, M. P.; Gonzalez, M. C.; Primo, J.; Moya, P.; Romero, V.; Estornell, E.
J. Antibiot. 2005, 58, 416e419.
1
1. (a) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep. Proced. Int. 1992, 24,
11; (b) Eguchi, S.; Okano, T. J. Synth. Org. Chem. Jpn. 1993, 51, 203; (c)
Wamhoff, H.; Richard, G.; Stoelben, S. Adv. Heterocycl. Chem. 1995, 64,
59e249; (d) Molina, P.; Viliplana, M. J. Synthesis 1994, 1197e1218; (e) Gusar,
2
Supplementary data
1
The 1H NMR and 13C NMR copies of all compounds were at-
N. I. Russ. Chem. Rev. 1991, 60, 146; (f) Ming-Wu, D.; Zhao-Jie, L. Chin. J. Org.
Chem. 2001, 21, 1; (g) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57,
tached. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2011.12.032. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
3
301e3307; (h) Tseng, M. C.; Lai, C.-Y.; Chu, Y.-W.; Chu, Y. H. Chem. Commun.
2009, 445e447.
2. (a) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417e6418;
b) Sugimori, T.; Okawa, T.; Eguchi, S.; Kakehu, A.; Yashima, E.; Okamoto, Y.
Tetrahedron 1998, 54, 7997e8008.
3. Witt, A.; Bergman, J. J. Org. Chem. 2001, 66, 2784e2788.
1
(
1
References and notes
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