Direct one-pot synthesis of luotonin F and analogues via rational logical design

Article abstract of DOI:10.1021/ol303331g

An efficient one-pot synthetic protocol has been proposed for the synthesis of luntonin F from easily available starting materials. Through a rational logical design, multifundamental reactions (iodination, Kornblum oxidation, and annulation) were assembled in one-pot. The developed approach can efficiently synthesize luntonin F and a diversity of analogues.

Full text of DOI:10.1021/ol303331g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct One-Pot Synthesis of Luotonin F
and Analogues via Rational Logical
Design
Yan-ping Zhu, Zhuan Fei, Mei-cai Liu, Feng-cheng Jia, and An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Hubei, Wuhan 430079, P. R. China
chwuax@mail.ccnu.edu.cn
Received December 5, 2012
ABSTRACT
An efficient one-pot synthetic protocol has been proposed for the synthesis of luntonin F from easily available starting materials. Through a
rational logical design, multifundamental reactions (iodination, Kornblum oxidation, and annulation) were assembled in one-pot. The developed
approach can efficiently synthesize luntonin F and a diversity of analogues.
Maximizing synthetic efficiency while at the same time
minimizing unnecessary synthetic steps is a very important
but difficult achievement in the total synthesis of natural
Scheme 1. Structure of Luotonins AÀF
products.1 In recent years, the one-pot synthetic strategy
has been proposed and employed in the synthesis of
natural products.2 Chu and co-workers previously demon-
strated a graceful self-directed one-pot synthesis of luotonin
A and analogues.2a This approach allowed concomitant
construction of multiple rings through a multiple reaction
sequence. Liu and co-workers also proposed an elegant
one-pot total synthesis of glyantrypine, fumiquinazoline F,
nigellastrum Bunge, which has a long history in Chinese
and fiscalin B through a microwave-promoted three-
medicine for the treatment of rheumatism, inflammation,
component reaction.2b Many impressive results have been
abscesses, and other maladies.3 Due to their biological and
attained in this area, yet it is clear that a strategy for one-
pharmaceutical activities, extensive synthetic methods
pot synthesis for natural product is still in its infancy.
have been developed for the synthesis of luotonins
Luotonins A, B, C, D, E and F are novel alkaloids that
(Scheme 1).4 However, the methodology for the synthesis
have been isolated from the aerial parts of the Peganum
of luotonin F still remains very limited.
In 1999, Nomura and co-workers were the first to
achieve the total synthesis of luotonin F by a six-step
(1) Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis;
Wiley: New York, 1995; pp 1À16. (b) Tietze, L. F.; Brasche, G.; Gericke,
K. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2006. (c) Trost, B. M. Science 1991, 254, 1471. (d) Nicolaou,
K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 44. (e) Nicolaou, K. C.; Hale, C. R. H.; Nilewski, C.;
Ioannidou, H. A. Chem. Soc. Rev. 2012, 41, 5185.
(2) (a) Tseng, M. C.; Chu, Y. W.; Tsai, H. P.; Lin, C. M.; Hwang, J.;
Chu, Y. H. Org. Lett. 2011, 13, 920. (b) Liu, J. F.; Ye, P.; Zhang, B. L.;
Bi, G.; Sargent, K.; Yu, L. B.; Yohannes, D.; Baldino, C. M. J. Org.
Chem. 2005, 70, 6339. (c) Foley, P.; Eghbali, N.; Anastas, P. T. J. Nat.
Prod. 2010, 73, 811.
(3) (a) Xiao, X. H.; Qiu, G. L.; Wang, H. L.; Liu, L. S.; Zheng, R. L.;
Jia, Z. J.; Deng, Z. B. Chin. J. Pharmacol. Toxicol. 1988, 2, 232. (b) Ma,
Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Heterocycles 1997, 46, 541.
(c) Osborne, D.; Stevenson, P. J. Tetrahedron Lett. 2002, 43, 5469.
(d) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M. J.
Am. Chem. Soc. 2003, 125, 13628. (e) Ma, Z.; Hano, Y.; Nomura, T.;
Chen, Y. Bioorg. Med. Chem. Lett. 2004, 14, 1193. (f) Cagir, A.; Jones,
S. H.; Eisenhauer, B. M.; Gao, R.; Hecht, S. M. Bioorg. Med. Chem.
Lett. 2004, 14, 2051.
r
10.1021/ol303331g
XXXX American Chemical Society

reaction with nearly a 5.6% overall yield from 3-fomylqui-
noline and isatoic anhydride (Scheme 2a).5 In 2002, Ar-
gade and co-workers described a three-step biogenetic type
synthesis of luotonin F with an ensuing overall yield of
38% from the natural product pegamine and 2-aminoben-
zaldehyde (Scheme 2b).6 In 2004, Ma and co-workers
demonstrated a two-step synthesis of luotonin F from
3-quinolinenitrile isatoic anhydride with 37% overall yield
(Scheme 2c).7 However, all of the above methods still
utilized the step-by-step synthetic strategy. Therefore, the
development of a practical and efficient, one-pot protocol
to access luotonin F is both desirable and valuable; it could
also have significance in directing further research for one-
pot synthesis of other natural products.
while 4 could be furnished from the R-haloge ketone 5
through Kornblum oxidation.9 It was also thought that 5
could easily be prepared from 3-acetylquinoline 1k
through a halogenation process.10 The synthetic process
is depicted in Scheme 3b. It is thought to consist of a
R-halogenation, Kornblum oxidation, intermolecular con-
densation, and aromatization reaction sequence. Based on
the draft (Scheme 3aÀb), we wanted to test whether it
would be possible to develop a one-pot protocol for the
synthesis of luotonin F from 3-acetylquinoline 1k and
2-aminobenzamide 2a via a rational logical design, in
which multiple reactions would self-sequentially take place
in one-pot (Scheme 3c).
Scheme 3. Retrosynthetic Analysis and the Protocols for One-
Pot Synthesis of Luotonin F
Scheme 2. Methods for the Synthesis of Luotonin F
Retrosynthetically (Scheme 3a), it was envisioned that
luotonin F could be obtained from 2-oxo-2-(quinolin-3-yl)-
acetaldehyde 4 and 2-aminobenzamide 2a through an
intermolecular condensation and aromatization process,8
(4) (a) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Phytochemistry
2000, 53, 1075. (b) Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe, H.;
Takeuchi, Y. Synlett 2003, 847. (c) Twin, H.; Batey, R. A. Org. Lett.
2004, 6, 4913. (d) Ju, Y.; Lu, F., F.; Li, C. Org. Lett. 2009, 11, 3582.
(e) Liang, Y.; Jiang, X.; Yu, Z. X. Org. Lett. 2009, 11, 5302. (f) Huang,
W. P.; Liu, J. L.; Wang, C. L. Chin. J. Org. Chem. 2009, 29, 1533.
(g) Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913. (h) Zhou, H. B.; Liu,
G. S.; Yao, Z. J. J. Org. Chem. 2007, 72, 6270. (i) Mason, J. J.; Bergman,
J. Org. Biomol. Chem. 2007, 5, 2486. (j) Liu, F.; Li, C. J. Org. Chem. 2009,
74, 5699. (k) Liang, J. L.; Cha, H. C.; Jahng, Y. Molecules 2011, 16, 4861
and references therein.
(5) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Heterocycles 1999,
51, 1883.
(6) Mhaske, S. B.; Argade, N. P. Synthesis 2002, 323.
(7) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J. Bioorg. Med. Chem.
Lett. 2004, 14, 1193.
(8) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153.
(9) (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.;
Larson, H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79,
6562. (b) Zhu, Y. P.; Liu, M. C.; Jia, F. C.; Yuan, J. J.; Gao, Q. H.; Lian,
M.; Wu, A. X. Org. Lett. 2012, 14, 3392. (c) Zhu, Y. P.; Jia, F. C.; Liu,
M. C.; Wu, L. M.; Cai, Q.; Gao, Y.; Wu, A. X. Org. Lett. 2012, 14, 5378.
(d) Zhu, Y. P.; Jia, F. C.; Liu, M. C.; Wu, A. X. Org. Lett. 2012, 14, 4414.
(e) Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.; Gao, Q. H.;
Wu, A. X. Chem. Commun. 2012, 48, 9086. (f) Jiang, H. F.; Huang,
H. W.; Cao, H.; Qi, C. R. Org. Lett. 2010, 12, 5561.
(10) (a) Yin, G. D.; Gao, M.; She, N. F.; Hu, S. L.; Wu, A. X.; Pan,
Y. J. Synthesis 2007, 3113. (b) Wang, Z. H.; Yin, G. D.; Qin, J.; Gao, M.;
Cao, L. P.; Wu, A. X. Synthesis 2008, 3675. (c) Zhu, Y. P.; Gao, Q. H.;
Lian, M.; Yuan, J. J.; Liu, M. C.; Zhao, Q.; Yang, Y.; Wu, A. X. Chem.
Commun. 2011, 47, 12700. (d) Barluenga, J.; Marco-Arias, M.;
With this idea in mind, we optimized the reaction con-
ditions using acetophenone 1a and 2-aminobenzamide 2a
as model substrates (Table 1). Initially, the reaction was
carried outwithI2 (1.1 equiv) in DMSO at 110 °C (entry 1).
This afforded a 73% combined yield of 3aa and 3af (with a
ratio of 1.2:1). To improve the chemoselectivity of the pro-
ducts, various catalysts, additives, and oxidants were inves-
tigated in further detail in DMSO. First, a series of Brønsted
acids, such as HCl, HOAc, MeSO3H, CF3SO3H, and L-
proline, were screened for the reaction. However, the pro-
ducts 3aa and 3af were still only produced with a ratio of 1:1
(entries 2À6). Even when various metal salts and bases, such
as CuO, CuBr, NaOH, PPh3, pyridine, DABCO, DBU, and
K3PO4ÀH2O were added, the reaction efficiency was still
showed no improvement (entries 7À14). Moreover, neither
additives (NIS and TBAI) nor oxidant (TBHP) led to any
further improvement in the reaction efficiency (entries
15À18). However, to our delight, the reaction efficiency
was greatly improved when 2-aminobenzamide 2a in 2 mL
DMSO was added dropwise to a mixture of acetophenone
1a (1.0 mmol) and I2 (1.1 mmol) in 3 mL DMSO at 110 °C
(entry 19). The desired product 3aa was obtained in 75%
yield; while the product 3af was hardly observed at all.
Subsequent increases and decreases in the temperature did
not enhance the reaction yield any further (entries 20À23).
ꢀ
ꢀ
Gonzalez-Bobes, F.; Ballesteros, A.; Gonzalez, J. M. Chem. Commun.
2004, 2614. (e) Pavlinac, J.; Stavber, S.; Zupan, M. J. Org. Chem. 2006,
71, 1027.
B
Org. Lett., Vol. XX, No. XX, XXXX

corresponding products (Scheme 5). The substrates with
electron-donating groups and halogen on aryl ring, such as
4-Me, 4-OMe, 3,4-OCH2CH2O, and 4-Cl, exhibited good
reactivity (3baÀ3fa). However, when the strong electron-
withdrawing group NO2 was situated in the para position,
the aromatic ketone 1g was converted into the desired
product 3ga with a yield of just 48%. It is notable that
heterocycles, such as 2-acetylfuran 1h, 2-acetylthiophen 1i,
3-acetylthiophen 1j, and 3-acetylquinoline 1k, were also
found to be suitable for the reaction and gave the corre-
sponding products 3haÀ3ka in good yields (72À81%). In
addition, the sterically hindered 2-acetylnaphthalene 1l
and 1-acetylnaphthalene 1m also furnished the desired
products 3la and 3ma smoothly in 80 and 78% yields,
respectively.
Table 1. Optimization Studiesa
additive
temp.
yield 3aa/3af
entry
(mol %)
cat.
oxidate (°C)
(%)b
1
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (80)
110
110
110
110
110
110
110
110
110
110
110
110
110
110
40/33
35/27
30/25
20/30
25/30
38/28
30/23
36/25
37/27
35/20
33/26
28/38
28/39
26/38
35/15
33/13
35/13
0/0
2
HCl
3
HOAc
4
CF3SO3H
CH3SO3H
L-proline
CuO
5
6
7
8
CuBr
9
NaOH
Scheme 5. Scope of Aromatic Ketones
10
11
12
13
14
15
16
17
18
19c
20c
21c
22c
23c
PPh3
Pyridine
DABCO
DBU
K3PO43H2O
TBHP
TBHP
TBHP
TBHP
110
110
110
110
110
90
I2 (50)
NIS (50)
TBAI (50)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
I2 (110)
75/<5
40/<10
62/<10
73/<5
70/<5
100
120
130
a Reaction conditions: a mixture of acetophenone 1a (1.0 mmol),
2-aminobenzamide 2a (1.0 mmol), I2 (1.1 mmol), catalyst (50 mol %),
oxidant (1.0 mmol), were heated in DMSO (3 mL). b Ratio of products
was determined by 1H NMR. c 2-Aminobenzamide 2a (1.0 mmol in 2 mL
DMSO) was added dropwise to a mixture of acetophenone 1a (1.0
mmol) and I2 (1.1 mmol) in DMSO (3 mL) upon stirred at 110 °C for 2 h.
With the optimal conditions established, we applied
them to synthesize luotonin F in one-pot. To our delight,
the reaction of 3-acetylquinoline 1k with 2-aminobenza-
mide 2a occurred smoothly to afford the desired luotonin
F in 72% yield in the presence of I2 in DMSO at 110 °C for
1 h (Scheme 4). Compared with the previous reports, this
method not only provided high yields, butalsoprovidedan
efficient method achieved in just one step.
Wewent ontofurther expand the scope of 2-aminobenz-
amides 2. The results are subsequently displayed in
Scheme 6. Various substituted 2-aminobenzamides 2 were
found to be tolerant in the reaction. For example, 2-
aminobenzamides bearing electron-rich (2bÀ2d) and elec-
tron-deficient (2eÀ2g) substituents on aryl ring underwent
the reaction smoothly to afford the corresponding pro-
ducts in good yields. When 2-amino-5-iodobenzamide 2f
was used as a substrate, the reaction afforded an 84%
combined yield of 3af and 3aa (with a ratio of 4.6:1). More
importantly, the phenylethynyl group attached to the
phenyl ring of 2-aminobenzamides did not affect the over-
all reaction efficiency and the corresponding product 3ah
was still furnished in 75% yield. Meanwhile, 2-amino-
N-methylbenzamide 2i was also found to react efficiently
with a variety of aromatic ketones to provide the corre-
sponding products in 40À65% yields (3aiÀ3li). Further-
more, the target compound 3ca was further determined by
X-ray crystallographic analysis (Figure S1).
Scheme 4. One-Pot Synthesis of Luotonin F
Inspired by the above results, the scope of aromatic
ketones was further investigated and the results are subse-
quently listed in Scheme 5. A wide array of aromatic
ketones were examined in the reaction with 2-aminoben-
zamide 2a; moderate to good yields were achieved in the
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 6. Scope of 2-Aminobenzamides
Scheme 7. Control Experiments
Scheme 8. Proposed Mechanism
To elucidate the mechanism, some control experiments
were performed. Under an argon atmosphere, the reaction
of R-iodo ketone 1aa with 2-aminobenzamide 2a per-
formed very well to give the product 3aa in good yield
both with I2 (50 mol %) and without I2 (Scheme 7a). The
reaction between phenylglyoxal (1ab) and 2-aminobenza-
mide 2a was also investigated under an argon atmosphere.
In the presence of I2 (50 mol %) the product 3aa was
obtained in excellent yield in 30 min (Scheme 7b). How-
ever, 3aa was not observed in 30 min without I2. When the
reaction time was extended to 12 h, the product 3aa was
afforded in 73% yield (Scheme 7c). The results shown in
Scheme 7bÀc suggest that I2 was very important in the
conversion of 1ab with 2a into 3aa. These results clearly
confirm the intermediacy of phenacyl iodine 1aa and
phenylglyoxal 1ab in the transformation.
In accordance with the results, a possible mechanism for
the present reaction is depicted in Scheme 8. It is suggested
that acetophenone 1a with I2 initially undertook a halo-
genation reaction to afford the intermediate R-iodo ketone
1aa, which further transformed into phenylglyoxal (1ab)
via Kornblum oxidation.11 This step was likely followed
by condensation and addition with 2-aminobenzamide
2a to yield intermediate B. Finally, it is proposed that
intermediate B underwent oxidation and aromatization to
provide the desired product 3aa in the presence of I2.12
In conclusion, we have developed an efficient one-pot
protocol for the synthesis of the naturalproduct luotonin F
and derivatives from simple and readily available aromatic
ketones and 2-aminobenzamides. Through a rational lo-
gical design, multiple fundamental reactions (iodination,
Kornblum oxidation, condensation, addition, and aroma-
tization) were self-sequentially assembled in a single reac-
tor. This efficient strategy could have significance for
directing further research into one-pot synthesis of many
natural products. Further studies on the applications of
this strategy will be reported in due course.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Grant
21032001 and 21272085) and PCSIRT (No. IRT0953).
We would also like to thank Dr. Chuanqi Zhou, Hebei
University, for analytical support.
(11) Halogenation reaction and Kornblum oxidation processes are
well investigated in our previous studies. See refs 9bÀ9e and 10aÀ10c.
(12) (a) Ishihara, M.; Togo, H. Synlett 2006, 227. (b) Xu, W.; Jin,
Y. B.; Liu, H. X.; Jiang, Y. Y.; Fu, H. Org. Lett. 2011, 13, 1274. (c) Yan,
Y. Z.; Wang, Z. Y. Chem. Commun. 2011, 47, 9513. (d) Zhou, J. G.;
Fang, J. J. Org. Chem. 2011, 76, 7730. (e) Hikawa, H.; Ino, Y.; Suzuki,
H.; Yokoyama, Y. J. Org. Chem. 2012, 77, 7046. (f) Guggenheim, K. G.;
Toru, H.; Kurth, M. J. Org. Lett. 2012, 14, 3732.
Supporting Information Available. Spectrascopic data
and general procedure. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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