Highly efficient and stereoselective N-vinylation of oxiranecarboxamides and unprecedented 8-endo-epoxy-arene cyclization: Expedient and biomimetic synthesis of some clausena alkaloids

Article abstract of DOI:10.1021/ol070292+

Figure presented Catalyzed by Cul/N,N-dimethylglycine, oxiranecarboxamides underwent a highly efficient and stereoselective N-vinylation reaction with (Z)-1-aryl-2-bromoethenes to afford the corresponding enamides. The method has been applied to a straigh

Full text of DOI:10.1021/ol070292+

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1387-1390
Highly Efficient and Stereoselective
N-Vinylation of Oxiranecarboxamides
and Unprecedented 8-endo-Epoxy-arene
Cyclization: Expedient and Biomimetic
Synthesis of Some Clausena Alkaloids
Luo Yang,† Gang Deng,† De-Xian Wang,† Zhi-Tang Huang,† Jie-Ping Zhu,‡ and
Mei-Xiang Wang*,†
Beijing National Laboratory for Molecular Sciences, Laboratory of Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China, and
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Gif-sur-YVette, France
mxwang@iccas.ac.cn
Received February 5, 2007
ABSTRACT
Catalyzed by CuI/N,N-dimethylglycine, oxiranecarboxamides underwent a highly efficient and stereoselective N-vinylation reaction with (Z)-1-
aryl-2-bromoethenes to afford the corresponding enamides. The method has been applied to a straightforward synthesis of ( )-(2R,3S)-
SB204900, the enantiomer of the natural product. Following a hypothetic biomimetic pathway, both ( )-(5R,6S)- -Clausenamide and ( )-
−
+
ê
−
(5R,6S)-balasubramide have been efficiently synthesized for the first time through the unprecedented intramolecular 8-endo-epoxy-arene cyclization
of (Z)-N-(phenylvinyl)oxiranecarboxamides.
Rutaceae Clausena lansium (Lour.) Skeels is a fruit tree
widely distributed in southern China, and its fruits and leaves
are used for the treatment of influenza, gastrointestinal
disorders, viral hepatitis, and dermatological diseases in folk
medicine. The investigation of the hot-water extract of the
leaves in the mid 1980s resulted in the isolation of a number
of natural products,1a-d and among them, the (()-ê-Clause-
namide 1 is especially intriguing because of its eight-
membered lactam structure and efficacious liver-protecting
and antiamnesia effects.1b-e About 10 years ago, another
eight-membered lactam-containing alkaloid (+)-balasubra-
mide 2 was isolated from Clausena indica which grows in
the central montane rainforests in Sri Lanka,2 whereas (Z)-
N-methyl-N-phenylvinyl-3-phenyloxirane-2-carboxamide (+)-
(1) (a) Chen, Y.-R.; Yang, M.-H.; Huang, L.; Liu, G.-T.; Benz, U. Ger.
Offen. DE 3,431,257, 1986; Chem. Abstr. 1986, 105, 7269r. (b) Yang, M.-
H.; Chen, Y.-Y.; Huang, L. Phytochemistry 1988, 27, 445. (c) Yang, M.-
H.; Chen, Y.-Y.; Huang, L. Chin. Chem. Lett. 1991, 2, 291. (d) Ji, X.; ver
der Helm, D. Acta Cryst. 1992, C48, 1082. (e) Yang, M.-H.; Chen, Y.-R.;
Liu, G.-T.; Huang, L. Ger. Offen. DE 3,700,706, 1987; Chem. Abstr. 1988,
108, 37514v.
† Chinese Academy of Sciences.
‡ Institut de Chimie des Substances Naturelles.
(2) Riemer, B.; Hofer, O.; Greger, H. Phytochemistry 1997, 45, 337.
10.1021/ol070292+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/03/2007

SB204900 33 was isolated from a hexane extract of the
Clausena lansium leaves. Surprisingly, the synthesis of 1-3
(Figure 1) has been largely unexplored.4 Our recent study5
ring. The use of ligands such as N,N′-dimethylethylenedi-
amine (A), trans-N,N′-dimethylcyclohexyldiamine (B), and
proline (C) that have been successfully employed in C-N
bond-forming reactions8 gave desired enamide 6aa only in
very low yields, along with the formation of an epoxide ring-
opening byproduct (entries 1-5, Table 1). Further reaction
Table 1. CuI-Catalyzed N-Vinylation of 4a with 5a
Figure 1. Structures of SB204900, ê-Clausenamide, and bala-
subramide
ligandb (0.8 mmol)/
base (2 mmol)/
solvent/temp, time (h)
6aa+7aa
entry 4a/5aa
(%)c
6aa/7aa
of nitrile biotransformations for the preparation of enan-
tiopure oxiranecarboxamides led us to address the synthesis
of optically active SB204900, ê-Clausenamide, and bala-
subramide. We envisioned that, in nature, ê-Clausenamide
1 is most likely constructed from SB204900 3 via an
intramolecular epoxide-arene cyclization, whereas enamide
3 might be synthesized from cross-coupling reaction of trans-
3-phenyloxirane-2-carboxamide with a vinyl halide.
A number of methods have been reported6 for the
preparation of enamides; however, they are not compatible
with epoxide-containing molecules such as 3. Having
considered the easy availability of enantiomerically pure
oxiranecarboxamides from both nitrile biotransformations5
and asymmetric syntheses7 and the emerging powerful cross-
coupling reactions between amides and vinyl halides,8 we
decided to explore the vinylation of oxiranecarboxamides
with a vinyl halide.
1
2
3
4
5
6
7
8
9
1:1 A/Cs2CO3/dioxane/rt, 20
1.2:1 A/Cs2CO3/dioxane/60 °C, 20
1:3 A/Cs2CO3/dioxane/reflux, 3
1:3 B/Cs2CO3/dioxane/60 °C, 4
1:3 C/K2CO3/DMSO/100 °C, 22
1:1 D/Cs2CO3/dioxane/reflux, 5
2:1 D/Cs2CO3/dioxane/reflux, 8
2:1 D/Cs2CO3/dioxane/reflux, 20
2:1 D/Cs2CO3/toluene/reflux, 8
2:1 D/tBuOK/dioxane/reflux, 8
1:2 D/Cs2CO3/dioxane/reflux, 5
1:3 D/Cs2CO3/dioxane/reflux, 5
3
100/-
ndd
ndd
ndd
ndd
92:8
ndd
ndd
-
12
15
trace
trace
21
38
32
-
10
11
12
-
58
82
-
ndd
93:7
Molar ratio (mmol/mmol). b Ligand: A, N,N′-dimethylethylenediamine;
B, trans-N,N′-dimethylcyclohexyldiamine; C, proline; D, N,N-dimethyl-
glycine hydrochloride. Determined by H NMR. nd ) not determined.
a
c
1
d
screenings revealed that the combination of CuI and N,N-
dimethylglycine (D) was effective to catalyze the vinylation
of 4a with 5a (entries 6-12, Table 1). As indicated by Table
1, under the optimal conditions, such as refluxing 4a with
an excess amount of 5a in 1,4-dioxane using Cs2CO3 as a
base, an efficient CuI-N,N-dimethylglycine-catalyzed cross-
coupling reaction yielded 82% of enamide product (entry
12, Table 1). Importantly, the reaction proceeded in a highly
stereoselective manner, giving Z-isomer 6aa and E-isomer
7aa in a ratio of 93:7.
As summarized in Table 2, the cross-coupling reaction was
generally applicable to oxiranecarboxamides 4 and vinyl
bromides 5 that contain either an electron-donating or an
electron-withdrawing group. All reactions proceeded ef-
ficiently to afford enamide products in 49-82% yield (entries
1-8, Table 2). Tri- and tetrasubstituted oxiranecarboxamides
4d and 4e reacted equally well with 5a to furnish the
corresponding enamides in 91% and 79% yield, respectively
As we expected, the CuI-catalyzed cross-coupling reaction
of trans-3-phenyloxirane-2-carboxamide 4a with (Z)-2-
bromo-1-phenylethene 5a appeared challenging because of
the low reactivity of amide 4a and the lability of the epoxide
(3) Milner, P. H.; Coates, N. J.; Gilpin, M. L.; Spear, S. R. J. Nat. Prod.
1996, 59, 400.
(4) (a) The synthesis of racemic SB-204900 was reported from the
epoxidation of Lansiumamide. Stefanuti, B. I.; Smith, S. A.; Taylor, R. J.
K. Tetrahedron Lett. 2000, 41, 3735. (b) In a communication, synthesis of
racemic ê-clausenamide in 21.6% yield was reported from BF3‚Et2O-
mediated reaction of an enamide. Ma, N. C.; Wu, K. M.; Huang, L. Chin.
Chem. Lett. 1996, 7, 706.
(5) (a) Wang, M.-X.; Lin, S.-J.; Liu, C.-S.; Zheng, Q.-Y.; Li, J.-S. J.
Org. Chem. 2003, 68, 4570. (b) Wang, M.-X.; Deng, G.; Wang, D.-X.;
Zheng, Q.-Y. J. Org. Chem. 2005, 70, 2439.
(6) (a) Boeckman, R. K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am.
Chem. Soc. 1988, 110, 8250. (b) Hosokawa, T.; Takano, M.; Kuroki, Y.;
Murahashi, S.-I. Tetrahedron Lett. 1992, 33, 6643. (c) Zezza, C. A.; Smith,
M. B. Synth. Commun. 1987, 17, 729. (d) Kiefel, M. J.; Maddock, J.;
Pattenden, G. Tetrahedron Lett. 1992, 33, 3227. (e) Kondo, T.; Tanaka,
A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc., Chem. Commun. 1995, 413.
(f) Brettle, R.; Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1 1988, 2185.
(g) Cuevas, J.-C.; Patil, P.; Snieckus, V. Tetrahedron Lett. 1989, 30, 5841.
(h) Palomo, C.; Aizpurua, J. M.; Legido, M.; Picard, J. P.; Dunogues, J.;
Constantieux, T. Tetrahedron Lett. 1992, 33, 3903. (i) Couture, A.; Deniau,
E.; Grandclaudon, P. Tetrahedron Lett. 1993, 34, 1479.
(7) (a) Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.-y.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544. (b) Kakei, H.;
Nemoto, T.; Ohshima, T.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43,
417; Angew. Chem. 2004, 116, 321. (c) Tosaki, S.-y.; Tsuji, R.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 2147. (d) Ohshima, T.;
Nemoto, T.; Tosaki, S.-y.; Kakei, H.; Gnanadesikan, V.; Shibasaki, M.
Tetrahedron 2003, 59, 10485.
(8) For leading references, see: (a) Ogawa, T.; Kiji, T.; Hayami, K.;
Suzuki, H. Chem. Lett. 1991, 1443. (b) Shen, R.; Porco, J. A., Jr. Org.
Lett. 2000, 2, 1333. (c) Shen, R.; Lin, C. T.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2002, 124, 5650. (d) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc.
2003, 125, 6040. (e) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43,
111. (f) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667. (g) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6,
27. (h) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577. (i) Pan, X.; Cai,
Q.; Ma, D. Org. Lett. 2004, 6, 1809. (j) Nishikawa, T.; Kajii, S.; Isobe, M.;
Chem. Lett. 2004, 33, 440. (k) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035.
1388
Org. Lett., Vol. 9, No. 7, 2007

Scheme 1. Synthesis of (-)-(2R,3S)-11 and
(+)-(5R,6S)-ê-Clausenamide 12
Table 2. Stereoselective N-Vinylation of Oxanecarboxamides 4
with (Z)-1-Aryl-2-bromoethenes 5
6+7
entry
1
4
Ar1
5
Ar2
R1 R2 (%)
6/7
4a C6H5
4a C6H5
4a C6H5
4a C6H5
4a C6H5
4a C6H5
5a C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
82 6aa/7aa
(93:7)
64 6ab/7ab
2
3
5b 4-Cl-C6H4
5c 4-CF3-C6H4
5d 4-Me-C6H4
5e 3-Me-C6H4
5f 2-Me-C6H4
(84:16)
62 6ac/7ac
(78:22)
54 6ad/7ad
5
(88:12)
4
62 6ae/7ae
(92:8)
49 6af/7af
6
(84:16)
7
4b 4-Cl-C6H4 5a C6H5
4c 4-Me-C6H4 5a C6H5
54 6ba/7ba
(93:7)
74 6ca/7ca
8
(87:13)
9
4d C6H5
4e C6H5
5a C6H5
5a C6H5
Me 91 6da/7da
exclusively in high yield (entry 5). The use of a smaller
amount of p-TSA (entries 6 and 7) and of trifluoroacetic
acid (entry 9) can also promote the reaction to give (()-1
after a longer period of time. Acetic acid, however, was
proved not to be effective at all in the transformation of (()-
11 into (()-1 (entry 8). Applying the optimal conditions for
intramolecular aryl-epoxide cyclization to SB204900 (-)-
(2R,3S)-11 led to the highly efficient synthesis of enantiopure
(+)-(5R,6S)-ê-Clausenamide 12 as the sole product in 86%
yield (Scheme 1).
The highly efficient and stereospecific 8-endo- rather than
7-exo-epoxy-arene cyclization of 11 is remarkable. Though
epoxy-arene cyclizations to yield six- and seven-membered
rings have been well documented, to our knowledge, the
formation of an eight-membered ring is not known.9 The
exclusive formation of 12 is most probably due to the
(87:13)a
10
Me Me 79 6ea/7ea
(95:5)b
a
Reaction time was 8 h. b Reflux for 6 h. When the reaction was stopped
after 10 h, a quantitative yield was obtained with the ratio of 6fa/7fa being
53:47.
(entries 9 and 10, Table 2). The stereoselectivity of the
reaction was good to excellent with the ratio of Z-isomer
over E-isomer ranging roughly from 85:15 to 95:5, except
trifluoromentyl-substituted vinyl bromide 5f which gave a
decreased selectivity (entry 3, Table 2).
The successful coupling reaction established for oxirane-
carboxamides allowed us to attempt the synthesis of natural
products 1-3. Starting with enantiopure 2R,3S-3-phenyl-
oxirane-2-carboxamide 9, obtained from the biotransforma-
tion of racemic trans-3-phenyloxirane-carbonitrile 8 using
a Rhodococcus erythropolis AJ270 whole-cell catalyst,5a
catalytic N-vinylation with 5a led to 10 in 76% yield.
Treatment of 10 with methyl iodide in the presence of a
strong base afforded an almost quantitative yield of 11 with
Table 3. 8-endo-Aryl-epoxide Cyclization of Racemic
SB204900
20
[R]D -14.2° (Scheme 1). Because product 11 has an
25
opposite optical rotation to 2 ([R]D +14°),3 compound 11
is therefore the enantiomer of the natural product, and the
absolute configuration of (+)-SB204900 2 was assigned as
2S,3R.
entry
acid (equiv)
solvent, temp, time (h)
yield (%)a
To test our hypothetical synthetic pathway of ê-Clause-
namide 1 from enamide 2, the 8-endo-aryl-epoxide cycliza-
tion reaction of the racemic SB204900 (()-11 was investi-
gated under a variety of conditions (Table 3). Lewis acids
such as SnCl4 and BF3·Et2O did not promote intramolecular
cyclization reaction. Instead, a mixture of epoxide ring-
opening products by halides were formed (entries 1 and 2).
Amberlyst and p-toluenesulfonic acid (p-TSA) were found
to effect the desired reaction in refluxing dichloromethane,
albeit in low yields (entries 3 and 4). When (()-11 was
treated with 2 equiv of p-TSA in acetonitrile at ambient
temperature, racemic ê-Clausenamide (()-1 was produced
1
2
3
4
5
6
7
8
9
SnCl4 (2)
CH2Cl2, reflux, 3
CH2Cl2, reflux, 12
CH2Cl2, reflux, 12
CH2Cl2, reflux, 18
CH3CN, rt, 2
CH3CN, rt, 24
CH3CN, rt, 24
CH3CN, rt, 24
CH3CN, rt, 24
0b
0b
BF3·Et2O (2)
amberlyst (2)
p-TSA (2)
p-TSA (2)
p-TSA (0.2)
p-TSA (1)
37
44
86
46c
76
0d
CH3CO2H (2)
CF3CO2H (2)
80
a
Isolated yield. b Ring-opening product was formed. c Starting material
d
was recovered. No reaction was observed.
Org. Lett., Vol. 9, No. 7, 2007
1389

synergetic electronic and steric effects, i.e., the conjugation
of an enamide with a benzene ring and the folded conforma-
tion of 11.3 In other words, both the delocalization of enamide
electrons into the benzene ring and the perfectly predisposed
conformational structure of 11 dictate the 8-endo-epoxy-arene
cyclization.
an almost quantitative yield of (-)-(5R,6S)-balasubramide
16 (Scheme 3).
Scheme 3. Synthesis of (-)-(5R,6S)-Balasubramide 16
Using the same strategy that comprises the cross-coupling
reaction followed by the biomimetic 8-endo-epoxide-arene
cyclization reaction, (-)-(5R,6S)-balasubramide 16, the
enantiomer of the natural balasubramide (+)-3, was synthe-
sized very efficiently (Scheme 3). Thus, the reaction of
enantiopure 2R,3S-3-phenyloxirane-2-carboxamide 9 with
(Z)-3-(2-bromovinyl)-1-tosyl-1H-indole 13, the synthesis of
which was depicted in Scheme 2, afforded enamide inter-
Scheme 2. Synthesis of
(Z)-3-(2-Bromovinyl)-1-tosyl-1H-indole 13
In summary, we have developed a highly efficient and
stereoselective CuI-catalyzed N-vinylation of trans-3-aryl-
oxirane-2-carboxamides with (Z)-1-aryl-2-bromoethenes for
the synthesis of functionalized enamides. With the use of
an enantiopure 2R,3S-3-phenyloxirane-2-carboxamide, the
method has been utilized for a straightforward synthesis of
(-)-(2R,3S)-SB204900, the enantiomer of natural product
(+)-SB204900. Following a hypothetic biomimetic intramo-
lecular 8-endo-epoxide-arene cyclization reaction, we have
achieved highly efficient synthesis of enantiopure (+)-
(5R,6S)-ê-Clausenamide and (-)-(5R,6S)-balasubramide for
the first time. The easy availability of oxiranecarboxamides
and vinyl bromides and the efficient cross-coupling reaction
and biomimetic intramolecular epoxide-arene cyclization
reaction should render the present protocols attractive for
the synthesis of libraries of natural product-like compounds.
mediate 14 in 55-63% yield. N-Methylation using methyl
iodide in the presence of sodium hydride and, without
isolation and purification of the N-methylated intermediate,
p-TSA-promoted 8-endo-indole-epoxide cyclization gave
indole-fused eight-membered lactam 15 in 50-62% yield.
Deprotection of the tosyl group in the presence of magnesium
turnings followed by catalytic hydrogenation of 15 yielded
Acknowledgment. We thank the Ministry of Science and
Technology (2003CB716005, 2006CB806106), the National
Natural Science Foundation of China, and the Chinese
Academy of Sciences for financial support.
Supporting Information Available: Detailed experi-
mental procedures, full characterization of all products, and
X-ray molecular structure of racemic ê-Clausenamide (()-
1. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) (a) For a review of epoxy-arene cyclizations, see: Taylor, S. K. Org.
Prep. Proceed. Int. 1992, 24, 245. For recent examples, see: (b) Islas-
Gonza´lez, G.; Benet-Buchholz, J.; Maestro, M. A.; Riera, A.; Perica`s, M.
A. J. Org. Chem. 2006, 71, 1537. (c) Kraus, G. A.; Kim, I. Org. Lett. 2003,
5, 1191. (d) Nagumo, S.; Miyoshi, I.; Akita, H.; Kawahara, N. Tetrahedron
Lett. 2002, 43, 2223.
OL070292+
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Org. Lett., Vol. 9, No. 7, 2007