A convenient synthesis of chiral 2-methylenebenzo[e][1,4]diazepin-5-ones via a one-pot reductive cyclodehydration with retention of chirality

Article abstract of DOI:10.1016/j.tetlet.2016.09.060

Total synthesis of optically pure (+)-Fuligocandin A from L-proline has been achieved in 29% overall yield. The key step, one-pot reductive cyclodehydration of the chiral 2-nitrophenyl-1,3-dicarbonyl compound, proceeds with >98% retention of configuration

Full text of DOI:10.1016/j.tetlet.2016.09.060

Accepted Manuscript
A convenient synthesis of chiral 2-methylenebenzo[e][1,4]diazepin-5-ones via
a one-pot reductive cyclodehydration with retention of chirality
Kumaraswamy Sorra, Chin-Hung Lai, Chun-Yen Feng, Yang-Chang Wu,
Srinivas Pusuluri, Khagga Mukkanti, Ta-Hsien Chuang
PII:
S0040-4039(16)31229-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.060
TETL 48130
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 June 2016
11 September 2016
18 September 2016
Please cite this article as: Sorra, K., Lai, C-H., Feng, C-Y., Wu, Y-C., Pusuluri, S., Mukkanti, K., Chuang, T-H., A
convenient synthesis of chiral 2-methylenebenzo[e][1,4]diazepin-5-ones via a one-pot reductive cyclodehydration
with retention of chirality, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.09.060
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A convenient synthesis of chiral 2-methylenebenzo
[e][1,4]diazepin-5-ones via a one-pot reductive
Leave this area blank for abstract info.
cyclodehydration with retention of chirality
Kumaraswamy Sorra, Chin-Hung Lai, Chun-Yen Feng, Yang-Chang Wu, Srinivas Pusuluri, Khagga Mukkanti,
Ta-Hsien Chuang*
O
O
reductive
cyclodehydration
O
Bn
O
(CH2)n
N
(S)
N
(S)
N
(S)
R
N
Zn
(S)
H
H
N
H
AcOH
N
H
N
H
NO2
O
CH2Cl2
rt, 16 h
O
O
O
OCH3
17b: R = CH3
17c: R = CH(CH3)2 17d: R = Bn
OCH3
CH3
O
CH3
17a: R = H
13a: n = 1
13b: n = 2
(+)-fuligocandin A

1
Tetrahedron Letters
journal homepage: www.els evier.com
A convenient synthesis of chiral 2-methylenebenzo[e][1,4]diazepin-5-ones via a one-
pot reductive cyclodehydration with retention of chirality
Kumaraswamy Sorra a,b, Chin-Hung Lai c,d, Chun-Yen Feng e, Yang-Chang Wu f,g, Srinivas Pusuluri a,
Khagga Mukkanti b, Ta-Hsien Chuang f,g,
*
a Medicinal Chemistry Division, GVK Biosciences Private Limited, Plot No. 28 A, Industrial Development Area Nacharam, Hyderabad 500076, India
b Department of Chemistry, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, India
c Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40201, Taiwan
d Department of Medical Education, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
e Department of Medical Laboratory Science and Biotechnology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
f School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
g Research Center for Chinese Herbal Medicine, China Medical University, Taichung 40402, Taiwan
ARTICLE INFO
ABSTRACT
Total synthesis of optically pure (+)-Fuligocandin A from L-proline has been achieved in 29%
overall yield. The key step, one-pot reductive cyclodehydration of the chiral 2-nitrophenyl-1,3-
dicarbonyl compound, proceeds with >98% retention of configuration. This method represents a
convenient approach to the synthesis of 2-methylenebenzo[e][1,4]diazepin-5-ones containing
one chiral center. A series of benzo[e][1,4]diazepin-5-one derivatives have been successfully
Article history:
Received
Received in revised form
Accepted
Available online
synthesized with retention of chirality by the one-pot reaction developed in this work.
possible reductive cyclodehydration mechanism was also proposed.
A
Keywords:
(+)-Fuligocandin
2-Methylenebenzo[e][1,4]diazepin-5-one
Vinylogous amide
2016 Elsevier Ltd. All rights reserved.
One-pot reductive cyclodehydration
six steps.4 The key step in this method is the reaction of optically
pure azido-1,3-diketone 4 with PPh3 to construct the seven-
membered ring; however, no optical purity of 1 was reported.
Later, the Meyer–Schuster rearrangement of propargylic alcohol
5 gave only the Z-isomer of 1, with high selectivity resulting
from the formation of an intramolecular hydrogen bond. An
enantiomeric excess (ee) of 70% was obtained under acidic
conditions at temperatures as low as -20 °C.5 Finally, the
Eschenmoser episulfide contraction was used in the synthesis of
racemic Fuligocandin A from monothione 6.6,7 The last two
routes were concise; however, compound 1 was obtained as a
racemic mixture with a low ee value. Although the total synthesis
of (+)-Fuligocandin A had been reported by More,4 a short and
highly enantioselective synthesis method for (+)-fuligocandin A
is still needed.
Introduction
(+)-Fuligocandin A (1), a benzo[e]pyrrolo[1,2-a][1,4]diazepin-
5-one containing a vinylogous amide moiety, has previously been
isolated from field-collected fruit bodies of the myxomycete
Fuligo candida.1 Compound 1 may be a natural product
contained in the myxomycete organism, but it more likely results
from the decarboxylation of Fuligocandin
C (2). This
decarboxylation may occur during or after extraction, or it may
proceed biogenetically or spontaneously inside the organism’s
body before extraction.2 Although the possibility that compound
1 is an artificial product cannot be excluded, treatment of
cycloanthranilylproline (3) with acetone does not afford (+)-
Fuligocandin A (1).3 Notably, compounds 1 and 3 have shown
significant cytotoxic activity against murine leukemia P388 cells,
having IC50 values of 13.0 µg/mL and 2.9 µg/mL, respectively.1
O
O
O
O
O
O
N
O
N
N
N
N
N
H
H
OH
N
3
N
H
N
H
H
S
N
H
N
H
N
H
Boc
O
O
O
O
5
6
4
Cycloanthranilylproline (3)
Fuligocandin A (1)
O
OH
Fuligocandin C (2)
β-Enaminocarbonyl compounds are versatile synthetic
intermediates in organic synthesis.8 Moreover, the β-
enaminocarbonyl functionality in these alkaloids is worth
exploring in relation to active natural products for medicinal
In the last decade, three methodologies have been used to
obtain Fuligocandin A. The aza-Wittig method enabled the first
total synthesis of (+)-Fuligocandin A (1) from anthranilic acid in

2
Tetrahedron Letters
methylenebenzo[e][1,4]diazepin-5-one core of these alkaloids
could be a major limiting factor in the synthesis of
was in agreement with that reported previously, [α]26D = +657° (c
1.4, MeOH).1 Complete assignment of the H and 13C NMR
1
benzodiazopine alkaloid derivatives. Herein, we disclose a
concise strategy for the synthesis of optically pure (+)-
Fuligocandin A, 11-alkenyl substituted cycloanthranilylprolines,
and benzo[e][1,4]diazepin-5-one derivatives, retaining chirality
via a one-pot reductive cyclodehydration of chiral 2-nitrophenyl-
1,3-dicarbonyl compounds.
signals of (+)-1 were obtained from 2D-NMR spectra, including
COSY, HMQC, HMBC, and NOESY. The NOE correlations
were observed between H-1 and H-12, indicating that the double
bond between C-11 and C-12 was Z-configured.
Scheme 2. Synthesis of (+)-Fuligocandin A (1)
For the retrosynthetic analysis of chiral Fuligocandin A,
cycloanthranilylproline derivatives, and benzo[e][1,4]diazepin-5-
ones with exocyclic β-enamino esters, a one-pot intramolecular
reduction/cyclodehydration cascade sequence starting from 2-
nitrophenyl-1,3-dicarbonyl precursors A could be a useful
strategy to quickly construct the seven member ring system.
Moreover, acetylacetone derivatives A1 could be easily prepared
from 2-nitrobenzamide-amino acids D via diazotization, followed
by condensation with acetaldehyde. Alternatively, methyl
acetoacetate derivatives A2 could also be obtained by the
acylation of D with Meldrum’s acid, followed by pericyclic
reaction and electrophilic addition with methanol (Scheme 1).
O
O
ethyl chloroformate
o
1)
7
Et N
3
N
O
N
O
Et N, THF, - 20 C
3
+
THF-H O
2
8
NO
NO
2) TMSCHN , rt, 16 h
2
2
2
OH
rt, 4 h
N
2
9a (78%)
10 (64%)
O
O
Zn, AcOH
CH Cl
N
11a
CH CHO
3
N
1
2
2
11 H
SnCl , CH Cl
2
2
2
NO
N
H
2
rt, 16 h
12
O
rt, 3 h
O
O
11
(+)-1 (59%)
Scheme 1. Retrosynthesis of Fuligocandin A Derivatives
Based on the above results, we anticipated that the optical
purity of the 11-alkenyl-substituted cycloanthranilylprolines 13a
and 13b could be readily determined by using carboxylic acids
9a and 9b, obtained by the amide coupling of 7 with L-
homoproline in 73% yield. Then, acids 9a and 9b were coupled
with Meldrum’s acid using N,N'-dicyclohexylcarbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP) as a coupling agent. The
mixture was then treated with methanol to afford β-keto methyl
esters 12a and 12b in good yields (74% and 73%, respectively).
The exocyclic β-enamino esters 13a and 13b were then obtained
in 75% and 72% yields, respectively, with >98% enantiomeric
purity (see the Supporting Information) and in the Z-
configuration only, by using the developed one-pot reductive
cyclodehydration (Scheme 3).
O
O
O
R'
R'
R'
reduction/
cyclodehydration
N
N
N
condensation
R
R
R
NO2
N
H
NO2
O
H
O
+
O
N2
O
A1: R" = CH3
R"
O
CH3
R"
B
A2: R" = OCH3
electrophilic
addition
diazotization
+
CH3OH
O
O
O
R'
R'
R'
pericylic
reaction
N
N
N
acylation
R
R
O
R
NO2
NO2
O
NO2
- acetone
- CO2
O
OH
O
O
O
O
C
O
+
O
O
O
O
D
C
ketene
Scheme 3. Synthesis of Exocyclic β-Enamino Esters 13
Results and discussion
O
O
O
1) Meldrum's acid,
(CH )
2 n
(CH )
2
N
(CH )
DCC, DMAP,
n
N
O
2 n
N
(+)-Fuligocandin A (1) was chosen as the initial target in order
to examine the optical purity of 1 after the key one-pot reductive
cyclodehydration under mild acidic conditions. First, the amide
coupling of commercially available 2-nitrobenzoyl chloride (7)
with naturally occurring L-proline (8) in the presence of triethyl
amine (Et3N) afforded (S)-1-(2-nitrobenzoyl) pyrrolidine-2-
carboxylic acid (9a) in 78% yield. Because α-diazoketones B are
good precursors of β-diketones A1,9 activated carboxylic acid 9a
was converted to the corresponding diazoketone 10 in 64% yield,
by the reaction of 9a with ethyl chloroformate in the presence of
Et3N, followed by treatment with (trimethylsilyl)diazomethane
(TMSCHN2). Subsequently, diazoketone 10 was reacted with
acetaldehyde in the presence of tin(II) chloride to give diketone
11. We observed that compound 11 was unstable during the
isolation and purification process. Therefore, after the reaction
and the work-up process were complete, the CH2Cl2 extract of 11
was treated with acetic acid followed by treatment with zinc
powder. (+)-Fuligocandin A (1) could then be produced in 59%
yield by the one-pot reductive cyclodehydration of the chiral 2-
nitrophenyl-1,3-dicarbonyl compound 11 (Scheme 2).
Zn
CH Cl , rt, 16 h
2
2
H
NO
N
NO
2
2
AcOH,
O
CH Cl ,
OH
2) MeOH, reflux,
4 h
H
2
2
O
O
rt, 16 h
OCH
H CO
3
3
9a: n = 1
9b: n = 2 (73% from L-homoproline)
13a: n = 1 (75%)
13b: n = 2 (72%)
12a: n = 1 (74%)
12b: n = 2 (73%)
Following the synthesis of (+)-Fuligocandin A (1) and 11-
alkenyl substituted cycloanthranilylprolines 13, the general
applicability
of
the
developed
one-pot
reductive
cyclodehydration was investigated via the synthesis of
benzo[e][1,4]diazepin-5-ones with exocyclic β-enamino esters 17
from β-keto methyl esters 16 (Scheme 4). These N-benzyl (Bn)
protected precursors 16a–d were obtained from the
corresponding amino acids 14a–d by the same protocol (for the
detailed experimental procedures of these reactions see the
Supporting Information). The one-pot reductive cyclodehydration
of 16a–d produced the corresponding (Z)-exocyclic β-enamino
esters 17a–d in 66–78% yield with highly enantiomeric purity
(see the Supporting Information).
Moreover, the unprotected amido acid 9c was produced by the
amide coupling of 2-nitrobenzoyl chloride (7) with L-valine in
68% yield. Unfortunately, attempts to synthesize an unprotected
β-keto methyl ester from amido acid 9c by the Meldrum’s acid
coupling/alcoholysis protocol were unsuccessful, but lactam
derivative 18 was obtained in 50% yield (eq 1). Other
To our delight, the one-pot reductive β-enamino cyclization
proceeded with the retention of chirality at C-11a, as determined
by comparison of the optical rotation of the synthesized (+)-
Fuligocandin A (1). The ee was measured to be >98% on chiral
HPLC (Lux Cellulose-2 column, see the Supporting Information).
The optical rotation of (S)-(+)-1, [α]25 = +685° (c 1.4, MeOH)
D

3
modifications using Fuligocandin A as a template are being
studied in our laboratories. We hope to obtain 2-
methylenebenzo[e][1,4]diazepin-5-one derivatives with strong
cytotoxicity against leukemia cells in the near future.
Conclusion
In conclusion, we have accomplished concise, highly efficient,
and convergent total synthesis of enantiopure (+)-Fuligocandin A
(1),
cycloanthranilylproline
derivatives
13,
and
benzo[e][1,4]diazepin-5-ones with exocyclic β-enamino esters 17,
using one-pot reductive cyclodehydration as the key step. This
one-pot reductive cyclodehydration is a useful strategy to obtain
2-methylenebenzo[e][1,4]diazepin-5-one derivatives with the
retention of chirality and exclusive Z-configuration.
Scheme 4. Synthesis of Benzo[e][1,4]diazepin-5-ones with
Exocyclic β-Enamino Esters 17
O
O
Bn
R
N
R
Et3N
Bn
OH
Cl
NO2
N
+
H
O
NO
THF-H2O
rt, 4 h
2O
OH
Acknowledgments
14a: R = H
15a: R = H (72%)
7
14b: R = CH3
15b: R = CH3 (70%)
15c: R = CH(CH3)2 (75%)
15d: R = Bn (82%)
The authors would like to thank GVK Biosciences, the
Ministry of Science and Technology, Taiwan (MOST 105-2113-
M-039-002), and the Chinese Medicine Research Center, China
Medical University (the Ministry of Education, the Aim for the
Top University Plan) for their financial support.
14c: R = CH(CH3)2
14d: R = Bn
O
Bn
N
R
O
Bn
1) Meldrum's acid,
DCC, DMAP,
N
R
Zn, AcOH,
CH2Cl2, rt, 16 h
N
H
NO
2O
CH2Cl2,
rt, 16 h
References and notes
2) MeOH, reflux,
4 h
O
O
OCH3
OCH3
1.
Nakatani, S.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.;
Ishibashi, M. Chem. Pharm. Bull. 2004, 52, 368.
Ishibashi, M.; Arai, M. A. Heterocycles 2012, 85, 1299.
Ishibashi, M. Med. Chem. 2005, 1, 575.
17a: R = H (76%)
16a: R = H (55%)
16b: R = CH3 (60%)
17b: R = CH3 (70%)
17c: R = CH(CH3)2 (66%)
17d: R = Bn (78%)
2.
3.
4.
16c: R = CH(CH3)2 (61%)
16d: R = Bn (71%)
More, S. S.; Shanmughapriya, D.; Lingam, Y.; Patel, N. B. Synth.
Commun. 2009, 39, 2058.
1) Meldrum's acid,
DCC, DMAP,
O
H
5.
Arai, M. A.; Seto, J.; Ahmed, F.; Uchiyama, K.; Ishibashi, M.
Synlett 2010, 2498.
O
O
N
CH Cl , rt, 16 h
2 2
N
6.
Pettersson, B.; Hasimbegovic, V.; Bergman, J. Tetrahedron Lett.
2010, 51, 238.
(1)
NO
2
2) MeOH, reflux,
4 h
O
OH
NO
O
2
7.
Pettersson, B.; Hasimbegovic, V.; Bergman, J. J. Org. Chem. 2011,
76, 1554.
9c (68% from L-valine)
18 (50%)
8.
Kuckländer, V. In The Chemistry of Enamines; Rappoport, Z., Ed.;
John Wiley & Sons: New York, 1994; Part 1, pp 525–639.
Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J. Org. Chem.
1990, 55, 5297.
A possible mechanism for the reductive cyclodehydration is
shown in Scheme 5. First, the reduction of nitro compounds 11,
12, and 16 with zinc under acidic conditions afforded the
corresponding phenyl amines E.10,11 Then, the intramolecular
nucleophilic addition of arylamine to the β-carbonyl group of
1,3-dicarbonyl compound E furnished a cyclic carbinolamine F.
Finally, E1-like loss of water under acidic conditions produced
conjugated β-enaminocarbonyl compounds 1, 13, and 17. These
final products were predominantly in the Z-form, probably due to
the formation of an intramolecular hydrogen bond.
9.
10.
11.
Barlaam, B.; Boivin, J.; Zard, S. Z. Tetrahedron Lett. 1993, 34,
1023.
Brady, E. D.; Clark, D. L.; Keogh, D. W.; Scott, B. L.; Watkin, J.
G. J. Am. Chem. Soc. 2002, 124, 7007.
Supplementary Material
Copies of the 1H and 13C NMR spectra of compounds 1, 9a–c,
10, 12a–b, 13a–b, 15a–d, 16a–d, 17a–d, and 18 can be found
in the online version of this paper.
Scheme 5. Possible Reductive Cyclodehydration Mechanism
3 Zn2+
3 Zn
O
O
R'
R'
N
N
Click here to remove instruction text...
R
R
6 e- + 6H+
NH2
NO2
O
- 2H2O
O
reduction
O
R"
O
R"
11, 12, and 16
E
intramolecular
nucleophilic addition
O
O
R'
R'
N
N
R
R
+ H+
OH
H
N
H
N
H
O
- H2O, -H+
H
dehydration
O
R"
R"
1, 13, and 17
F

4
Tetrahedron Letters
Highlights
•Total synthesis of optically pure (+)-fuligocandin
A from L-proline.
•A one-pot reductive β-enamino cyclodehydration
proceeds with retention of chirality.
•Easy access to chiral 2-
methylenebenzo[e][1,4]diazepin-5-ones by one-pot
reaction.