First total synthesis of two new heterocyclic compounds: Bretschneiderazines A and B

Article abstract of DOI:10.1016/j.cclet.2010.11.036

Facile synthesis of the two new natural heterocyclic compounds bretschneiderazines A (2) and B (3), isolated from an extract of the stems of Bretschneidera sinensis, is reported. We employed the cyclization reaction of benzamide by directed lithiation and

Full text of DOI:10.1016/j.cclet.2010.11.036

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Chinese Chemical Letters 22 (2011) 801–803
www.elsevier.com/locate/cclet
First total synthesis of two new heterocyclic compounds:
Bretschneiderazines A and B
b
a
a
a
Qing Chao Liu a, , Tian Tian Guo , Zheng Fan , Dong Li , Wen Hong Li
*
a Department of Pharmaceutical Engineering, Northwest University, Xi’an 710069, China
b Department of Medical Science, Xi’an Creation College, Yanan University, Xi’an 710100, China
Received 8 October 2010
Available online 17 April 2011
Abstract
Facile synthesis of the two new natural heterocyclic compounds bretschneiderazines A (2) and B (3), isolated from an extract of
the stems of Bretschneidera sinensis, is reported. We employed the cyclization reaction of benzamide by directed lithiation and
sequential treatment with sulfur and phosgene as key steps. All new compounds have been fully characterized by means of IR, 1H
NMR, 13C NMR, and HRMS.
# 2010 Qing Chao Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Heterocyclic compounds; Bretschneiderazines; Directed lithiation; Synthesis
Natural compounds with the benzo[e][1,3]thiazine-2-thioxo-4-one ring system (1) exist rarely, and only some
synthesized compounds with such structure were reported [1–3]. Bretschneiderazines A (2) and B (3) (Fig. 1), two new
heterocyclic compounds with the benzo[e][1,3]thiazine-2-thioxo-4-one ring system, were first isolated from an extract
of the stems of Bretschneidera sinensis [4]. B. sinensis, a well-known Chinese folk medicine, is distributed only on the
southern bank of the Yangtse, China. Its bark has long been used to treat arthralgia and myalgia [5]. Besides,
bretschneiderazines A (2) showed moderate activity against the NCI-H446 cell line in vitro [4].
Attracted by the particular structure and potent biological properties of bretschneiderazines A (2) and B (3), We
report here the first total synthesis of bretschneiderazines A and B by a facile approach for thorough pharmacological
research and further SAR investigation.
The synthetic route toward bretschneiderazines A (2) and B (3) is depicted in Scheme 1. Firstly, isovanillin 4 was
converted to the intermediate 5 using tert-butyldimethylsilyl chloride (TBSCl) in the presence of imidazole in
anhydrous DMF with the yield of 95% [6]. Then, aldehyde 5 was oxidized by H2O2 and NaClO2 to the corresponding
carboxylic acid 6 in 63% yield [7], which was subjected to chlorination with thionyl chloride (SOCl2) in dry CH2Cl2
affording acyl chloride 7 in 89% yield. Compound 8 was obtained from 7 using CH3NH2 in EtOAc with the yield of
86% [8]. Benzamide 8 was treated by directed lithiation with n-butyllithium in THF, after which sulfur powder and
thiophosgene was added, affording the key intermediates 9 and 10 [3]. Because of the steric hindrance of TBS
protecting group, the formation of heterocyclic ring mainly occurred at C-6 of benzamide 8, which was supported by
* Corresponding author.
E-mail address: Liuqc21@nwu.edu.cn (Q.C. Liu).
1001-8417/$ – see front matter # 2010 Qing Chao Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.11.036

[()TD$FIG]
802
Q.C. Liu et al. / Chinese Chemical Letters 22 (2011) 801–803
OCH
3
1
8
5
S
S
H CO
3
S
S
H CO
S
S
3
7
6
N
N
N
R
HO
4
O
O
O
3
1
2
Fig. 1. The structures of bretschneiderazines A (2) and B (3).
[()TD$FIG]
HO
CHO
TBSO
CHO
TBSO
COOH
TBSO
COCl
a
b
c
H CO
3
H CO
3
H CO
3
H CO
3
6
7
5
4
d
OTBS
O
H CO
S
S
3
H CO
S
S
S
3
TBSO
e
NHCH
3
+
N
N
N
TBSO
H CO
3
O
O
S
10
9
2
8
f
f
H CO
3
OCH
3
OH
H CO
S
S
3
H CO
3
g
S
S
HO
N
N
O
O
O
3
11
Scheme 1. Reagents and conditions: (a) TBSCl, imidazole, DMF, 95%; (b) NaH2PO4, H2O2 (30%), NaClO2, MeCN, H2O, 10 8C, 63%; (c) SOCl2,
CH2Cl2, 89%; (d) MeNH2, Et3N, EtOAc, 86%; (e) n-BuLi, THF, À78 8C to 0 8C; S, 50 8C; Cl2C = S, 0 8C, 53% for 9, 7% for 10; (f) TBAF, THF,
89% for 2, 81% for 11; (g) K2CO3, MeI, CH3COCH3, 51%.
the ratio of 9 and 10 (53%:7%). Finally removal of TBS groups furnished bretschneiderazines A (2) and 11.
Compound 11 was subsequently methylated with MeI and K2CO3 to obtain bretschneiderazines B (3), whose
analytical data are identical in all respects to those reported in the literature [5,9].
In conclusion, we have developed a practical, highly efficient method for the preparation of bretschneiderazines A
(2) and B (3) employing the cyclization reaction of benzamide by directed lithiation and sequential treatment with
sulfur and phosgene as key steps. Further study on preparation and biological evaluation of derivatives is in progress
and will be reported in due course.
Acknowledgment
This work was financially supported by the Scientific Research Foundation of Northwest University (No.
PR10035).
References
[1] A.A. Magid, L. Voutquenne, D. Harakat, et al. Pharmazie 22 (1967) 611.
[2] M. Ukiya, T. Akihisa, Heterocycles 78 (2009) 2559.
[3] S.W. Wright, J. Heterocycl. Chem. 38 (2001) 723.
[4] C.M. Liu, B. Li, Y.H. Shen, et al. J. Nat. Prod. 73 (2010) 1582.
[5] W.C. Wang, Flora of China, vol. 34, Science Press, Beijing, 1990, p. 8.
[6] R.P. Tanpure, A.R. Harkrider, T.E. Hamel, et al. Bioorg. Med. Chem. 17 (2009) 6993.
[7] T. Harayama, T. Sato, Y. Nakano, et al. Heterocycles 59 (2003) 293.
[8] K. Bailey, E.W. Tan, Bioorg. Med. Chem. Lett. 13 (2005) 5740.

Q.C. Liu et al. / Chinese Chemical Letters 22 (2011) 801–803
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[9] Selected spectra data. Compound 9, IR (KBr) vmax 2930, 2895, 1735, 1374 cmÀ1; HRESIMS: m/z calcd. for C16H24NO3S2Si [M+H]+, 370.0961;
found, 370.0989; 1H NMR (500 MHz, acetone-d6): d 7.70 (s, 1H), 6.71 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR
(125 MHz, acetone-d6): d 191.0, 160.2, 151.3, 145.0, 129.1, 110.2, 113.8, 106.3, 54.3, 33.8, 25.7, 18.5, À4.7. Compound 10, IR (KBr) vmax 2927,
2897, 1741, 1374 cmÀ1; HRESIMS: m/z calcd. for C16H24NO3S2Si [M+H]+, 370.0961; found, 370.0976; 1H NMR (500 MHz, CDCl3): d 8.09
(d, 1H, J = 8.1 Hz), 7.02 (d, 1H, J = 8.0 Hz), 3.90 (s, 3H), 3.88 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (125 MHz, CDCl3): d 193.1, 160.1,
155.9, 135.6, 129.1, 128.0, 115.2, 111.2, 58.9, 34.3, 25.0, 18.5, À4.6. Compound 11, IR (KBr) vmax 3378, 2935, 2855, 1737, 1660, 1379 cmÀ1
;
HRESIMS: m/z calcd. for C10H8NO3S2 [MÀH]À, 253.9942; found, 253.9927; 1H NMR (500 MHz, CDCl3): d 8.11 (d, 1H, J = 8.0 Hz), 7.02 (d,
1H, J = 8.0 Hz), 3.95 (s, 3H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3): d 193.2, 160.1, 155.8, 138.9, 131.2, 128.5, 115.5, 111.3, 60.4, 34.8.
Compound 2, IR (KBr) vmax 3419, 2930, 2851, 1737, 1656, 1384 cmÀ1; HRESIMS: m/z calcd. for C10H8NO3S2 [MÀH]À, 253.9942; found,
253.9951; 1H NMR (500 MHz, acetone-d6): d 7.73 (s, 1H), 6.75 (s, 1H), 3.99 (s, 3H), 3.86 (s, 3H); 13C NMR (125 MHz, acetone-d6): d 191.3,
159.0, 152.2, 129.1, 114,2, 106.7, 55.0, 33.8. Compound 3, IR (KBr) vmax 2945, 2917, 1737, 1638, 1601, 1532 cmÀ1; HRESIMS: m/z calcd. for
C11H12NO3S2 [M+H]+, 270.0253; found, 270.0239; 1H NMR (500 MHz, CDCl3): d 8.09 (d, 1H, J = 8.1 Hz), 6.99 (d, 1H, J = 8.1 Hz), 3.96 (s,
3H), 3.92 (s, 3H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3): d 193.3, 160.3, 155.9, 139.3, 131.2, 128.6, 115.8, 111.6, 60.7, 56.3, 34.7.