Concise asymmetric synthesis of fully substituted isoxazoline-N-Oxide through lewis base catalyzed nitroalkene activation

Article abstract of DOI:10.1002/chem.201001237

(Figure Presented) Transforming isoxazoline-N-oxides: A concise asymmetric synthesis of isoxazoline-N-oxides is reported through secondary amine Lewis base catalyzed nitroalkene activation and sequential intermolecular condensation with aldehydes and ylides. Application of camphor-derived chiral sulfur ylides gave the enantiomeric-enriched isoxazolineN-oxides in excellent yields and stereoselectivity. Simple transformations of isoxazoline-N-oxide led to the gramscale synthesis of a (-)-clausenamide analogue in four steps, with excellent stereochemistry control (see scheme).

Full text of DOI:10.1002/chem.201001237

COMMUNICATION
DOI: 10.1002/chem.201001237
Concise Asymmetric Synthesis of Fully Substituted Isoxazoline-N-Oxide
through Lewis Base Catalyzed Nitroalkene Activation
Cheng Zhong, Lekh Nath S. Gautam, Jeffrey L. Petersen, Novruz G. Akhmedov, and
Xiaodong Shi*[a]
Structurally unique heterocycles are of great importance
in chemical and biological related research.[1] The isoxazo-
line-N-oxide and its derivatives are an interesting class of
compounds in this family[2] and have been applied as biolog-
ically active compounds[3] and drug candidates[4] in many re-
search areas. Moreover, with the unique functionality-en-
riched structures, isoxazoline-N-oxides have also been rec-
ognized as versatile synthetic building blocks that could be
readily converted into useful intermediates for complex mol-
ecules[5] and natural product syntheses.[6]
The conventional strategies for the preparation of isoxa-
zoline frameworks include the intramolecular 5-exo-tet cycli-
zation of nitro compounds[7] and intermolecular [3+2] cy-
Scheme 1. Tandem isoxazoline-N-oxide synthesis through Lewis base cat-
alyzed, nitroalkene activation.
cloaddition.[8] However, both approaches suffered from lim-
ited substrate scope and low overall efficiency.[9] In addition,
efficient asymmetric synthesis of isoxazoline-N-oxides is
rare.[10,11] Thus, the practical synthesis of isoxazoline-N-
oxides remains big challenge and new efficient methodolo-
gies are highly desirable.
lowed the preparation of isoxazoline-N-oxide without the
challenging nitronate intermediate synthesis. However, this
method possessed three limitations: 1) the C-4 position was
limited to aliphatic groups, 2) two identical vinyl groups on
C-3 and C-5 positions, and 3) poor enantioselectivity
(<15% ee was observed in all cases with different chiral
amines).
Owing to the unique mechanism and strong desire for ef-
fective synthesis of enantiomerically enriched isoxazolines,
we investigated the asymmetric synthesis of these fully sub-
stituted isoxazoline-N-oxides. Herein, we report a simple al-
dehyde condensation with amine-activated nitroalkene for
the formation of diene intermediates and chemoselective
condensation with chiral sulfide ylides, forming fully substi-
tuted isoxazoline-N-oxides in one-pot with excellent yields
and stereoselectivity. Moreover, from the functional-group-
enriched products, simple transformations gave the (À)-clau-
senamide analogue in four steps with good yield and excel-
lent stereochemistry control.
Recently, our group reported the amine-catalyzed b-alkyl
nitroalkene activation as a new approach in promoting com-
plex-molecule cascade synthesis. Based on this strategy, sev-
eral cascade processes have been successfully devel-
oped.[12,13] All of these new methods were carried out in a
one-pot fashion, providing complex products with high effi-
ciency and good stereoselectivity. Among these new meth-
ods, one particularly interesting reaction was the synthesis
of isoxazoline-N-oxide through nitroalkene and vinyl ester
condensation (Scheme 1).[14]
This cascade approach revealed an efficient strategy in
producing active diene intermediate A in-situ, which al-
[a] Dr. C. Zhong, L. N. S. Gautam, Prof. Dr. J. L. Petersen,
Dr. N. G. Akhmedov, Prof. Dr. X. Shi
C. Eugene Bennett Department of Chemistry
West Virginia University, Morgantown, WV 26506 (USA)
Fax : (+1)304-293-4904
First, we postulated that the diene intermediate A, be-
sides the nitroalkene/vinyl ester condensation, could also be
achieved through the Lewis based mediated Henry reaction
between a nitroalkene and an aldehyde. Thus, the isoxazo-
E-mail: Xiaodong.Shi@mail.wvu.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001237.
Chem. Eur. J. 2010, 16, 8605 – 8609
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8605

Table 1. Substrate screening for three-component condensation in the
line-N-oxide could be prepared through a more general pro-
cess with broader substrate scopes on the C-4 position. The
reactions between nitroalkene 1a and benzaldehyde 2a
were then performed. As expected, isoxazoline-N-oxide 3a
was obtained with excellent yields (Scheme 2).[15]
synthesis of hetero-isoxazoline-N-oxide.[a]
Nu-LG
Product[b]
3a [%]
5 [%]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4 f
76
85
58
74
<5
<5
<5
<5
35
18
91[c]
92[c]
[a] Reaction conditions: 1a (1.2 equiv), 2a (1.0 equiv, 0.5m), 4 (1.1 equiv)
and catalysts were mixed in solvent. [b] NMR yield with 1,3,5-trimeth-
Scheme 2. Tandem nitroalkene/aldehyde condensation.
AHCTUNGTREGoNNUN xybenzene as internal standard. [c] Isolated yield.
Encouraged by this result, we then moved toward the dis-
covery of effective strategy for introducing different substi-
tuted groups on the C-3 and C-5 positions. Based on the re-
action mechanism, we envisioned that functional molecules
with both nucleophilic site and leaving groups (Nu-LG)
could also be of possible reagents to give the hetero-isoxa-
zoline-N-oxide (Scheme 3).
amines did not provide good stereochemistry control,[16,17]
we wondered whether chiral sulfur ylides could serve as aux-
iliaries to deliver the chirality. Several readily available cam-
phor-derived sulfur ylides[18] were investigated to evaluate
the stereoselectivity of these auxiliaries in this cascade pro-
cess (Table 2).
Table 2. Reaction condition screening of chiral auxiliaries for asymmetric
isoxazoline-N-oxide synthesis.[a]
Scheme 3. Proposed alternative synthesis of C-3,C-5-unsymmetric isoxa-
zoline-N-oxides.
Solvent LB
(20%)
Base
(1.0 equiv)
Aux.
T
t
yield [%][b]
ACHTUNGTRENNUNG
(ee [%])[c]
G
[oC] [h]
The key for the success of this process is to identify an ef-
fective third component (Nu-LG) to compete with the addi-
tion of intermediate B, which gives the undesired homo-iso-
xazoline-N-oxide 3a. Based on this hypothesis, compounds
with Nu-LG functionality were employed to react with ni-
troalkene 1a and aldehyde 2a (Table 1).
Application of 4a and 4b, under previously developed op-
timal conditions, produced only the homo-isoxazoline-N-
oxide 3a, which was likely due to the low reactivity of the
nucleophiles (entries 1 and 2). The phosphonium bromide
4c and ammonium bromide 4d did generate the desired
product 5. However, the reaction suffered from significant
competition of homocondensation (entries 3 and 4). To our
pleasure, application of sulfonium salts 4e and 4 f gave com-
pound 5 as the dominant product in excellent yields (en-
tries 5 and 6). Only a trace amount of 3a was detected.
At this stage, we then moved on to further investigate the
enantioselective synthesis. Since all the chiral secondary
1
2
3
4
5
6
7
8
9
DMSO l-proline
DMSO l-proline
acetone l-proline
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
6a
6b
6b
6b
6b
6c
6d
6e
6c
6c
6c
6c
6c
6c
RT
RT
RT
RT
RT
RT
RT
RT
RT
À25 48
À40 60
À25 48
À25 48
À25 48
12
6
<5 (n.d.)[d]
19 (n.d.)[d]
16 (n.d.)
13 (n.d.)
60[e] (36)
81[e] (75)
23 (40)
6
THF
l-proline
24
6
MeOH l-proline
MeOH l-proline
MeOH l-proline
MeOH l-proline
MeOH l-proline
6
6
6
6
43 (59)
54 (76)
10 MeOH l-proline
11 MeOH l-proline
12 MeOH d-proline
13 MeOH pyrrolidine Cs2CO3
14 MeOH N-Me-Gly Cs2CO3
87[e] (82)
62[e] (82)
90[e] (86)
86[e] (91)
51[e] (89)
[a] General reaction conditions: 1a (1.2 equiv), 2a (1.0 equiv, 0.15m) and
auxiliary 6 (1.1 equiv). Ester exchange happened in MeOH, and only the
methyl ester was detected. [b] NMR yield with 1,3,5-trimethACTHNUGRTNEUNGoxybenzene
as internal standard. [c] Determined by HPLC on chiral stationary
phases. [d] Major products were homo-isoxazoline 3a and the epoxide.
[e] Isolated yield.
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Asymmetric Synthesis
COMMUNICATION
Table 3. Asymmetric synthesis of substituted isoxazoline-N-oxides.[a]
The ketone ylide 6a[19] did not promote the heterocou-
pling reaction (entry 1), giving the homocoupling product
3a (>85% yield) and epoxide product,[20] which was likely
caused by the relatively low nucleophilicity associated with
the more hindered chiral ylide in a polar solvent (compared
to the simple ketone ylide 4e). The ester-modified ylide 6b
produced the heterocoupling product 7 though with poor
yield (entry 2). Solvent screening indicated that MeOH was
the best solvent (entries 3–5). Further modification on the
ylides revealed 6c (R1 =Me and R2 =H) as the optimal aux-
iliary (entry 6) and Cs2CO3 as the preferred choice of base
under lower temperature (entry 10), producing the desired
product in excellent yield. Interestingly, the secondary
amine Lewis base catalyst also influenced the stereochemis-
try of the products. With either l- or d-proline, the absolute
stereochemistry of product 7 was identical (entries 10 and
12), which indicated that the ylide auxiliary dominated the
stereochemistry control in the diene nucleophilic addition.
However, to our surprise, slightly improved stereoselectivity
was observed when d-proline was used as the catalyst
(entry 12). Further investigation revealed that achiral secon-
dary amine pyrrolidine gave improved stereoselectivity,
without sacrificing much of the reactivity (entry 13, 86%
yield and 91% ee). Application of N-methylglycine gave the
similarly good enantioselectivity with moderate yield
(entry 14). Notably, >50% of the camphor auxiliary was re-
covered during the purification. With the optimal conditions,
various nitroalkenes 1 and aldehydes 2 were applied to in-
vestigate the reaction substrate scope.
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
C6H5
7a
7b
7c
7d
7e
7 f
7g
7h
7i
86
82
89
90
71
86
63
92
82
84
79
91
94
91
80
90
96
88
81
70
88
92
p-OMe-C6H4
p-Me-C6H4
2-Py
2-furanyl
1-naphthyl
nPr
p-NO2-C6H4
2-NO2-C6H4
2-OMe-C6H4
2,4-di-Me-C6H3
10
11
7j
7k
12
13
14
15
2-furanyl
7l
81
88
81
91
76
81
92
93
2-OMe-C6H4
p-OMe-C6H4
1-naphthyl
7m
7n
7o
16
17
18
2-OMe-C6H4
1-naphthyl
C6H5
7p
7q
7r
75
70
80
81
93
85
19
20
21
p-Me-C6H4
1-naphthyl
p-NO2-C6H4
7s
7t
7u
80
85
93
90
91
65
[a] General reaction conditions: 1 (1.2 equiv), 2 (1.0 equiv, 0.15m) and
auxiliary 6c (1.1 equiv). Ester exchange happened in MeOH and only the
methyl ester was detected. [b] Isolated yield. [c] ee was determined by
HPLC on chiral stationary phases.
The reaction tolerates various nitroalkenes, including aryl,
alkyl and cyclic structures (Table 3). Moreover, various alde-
hydes (aromatic, aliphatic and heteroaromatic) were suitable
for this transformation. Compared to the nitroalkenes, the
aldehyde substrates have stronger influence on the overall
yield and stereoselectivity. With electron-deficient aldehydes
(i.e., 7h), excellent yields were obtained. However, the
enantioselectivity was slightly decreased. This could be ex-
plained by the higher reactivity of the diene intermediate,
which gave the lower efficiency in the stereoselectivity. Ster-
ically hindered aldehydes (i.e.,
cules with high efficiency and good stereoselectivity. One
great example is its application in the synthesis of all-cis g-
lactam, towards the synthesis of clausenamide derivatives
(Scheme 4).[21]
The clausenamide derivatives 8e was prepared in five
steps from nitroalkene 1a with 38% overall yield, on a
gram scale. The synthesis involved neither exotic reagents
nor protecting groups, giving high atomic efficiency. More-
over, excellent stereochemistry control was achieved in this
7 f), on the other hand, promot-
ed the stereoselectivity by pro-
viding better spatial control,
and therefore led to the ob-
served high enantioselectivity.
Similar steric and electronic ef-
fects of the aldehyde were ob-
served for all the other sub-
strates that were tested.
This new enantioselective iso-
xazoline-N-oxides synthesis lit
up our interest in its application
towards the total synthesis of
biological active, structurally
unique natural products. Simple
transformations would allow
easy synthesis of complex mole- Scheme 4. Gram-scale synthesis of clausenamide derivatives.
Chem. Eur. J. 2010, 16, 8605 – 8609
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www.chemeurj.org
8607

X. Shi et al.
transformation, and 8e was prepared in 85% ee (>99% ee
after one recrystallization). The reduction of 8d was highly
diastereoselective to give 8e.[22] Notably, 8e was one of the
most challenging isomers in the clausenamide family, since
it possesses all-cis-substitution on the g-lactam ring. With
the reported synthetic route, preparation of different clause-
namide derivatives, including different substitute groups on
C-4 and C-5 positions and different stereoisomers at all four
stereogenic centers, is feasible with simple modifications.
In conclusion, a one-pot asymmetric synthesis of fully sub-
stituted isoxazoline-N-oxides was developed. The methodol-
ogy was based on a Lewis base catalyzed, multicomponent
condensation, which allowed easy derivatization to achieve
various substitutions at selected positions. Excellent yields
and enantioselectivity were obtained. With the high efficien-
cy and excellent chemo- and enantioselectivity, the reported
method provides a new protocol for the preparation of iso-
xazoline derivatives, which could be applied both for the dis-
covery of new drug candidates and for the construction of
complex building blocks. Successful transformation of isoxa-
zoline-N-oxide 7a into a g-lactam in a highly stereoselective
fashion and gram-scale synthesis of clausenamide derivative
9e, further highlights the advantages of the reported
method as a powerful approach for the preparation of com-
plex molecules with high atom efficiency and good stereose-
lectivity.
Keywords: asymmetric
enantioselectivity · isoxazoline-N-oxides · Lewis bases
synthesis
·
clausenamide
·
[1] For selected recent reviews, see: a) S. Perreault, T. Rovis, Chem.
Soc. Rev. 2009, 38, 3149–3159; b) C. A. Carson, M. A. Kerr, Chem.
Soc. Rev. 2009, 38, 3051–3060; c) V. Polshettiwar, R. S. Varma, Curr.
Opin. Drug Discovery Dev. 2007, 10, 723–737; d) D. M. D’Souza,
T. J. J. Muller, Chem. Soc. Rev. 2007, 36, 1095–1108; e) P. A. Tem-
pest, Curr. Opin. Drug Discovery Dev. 2005, 8, 776–788.
[2] For selected reviews, see: a) M. O. F. Khan, H. J. Lee, Chem. Rev.
2008, 108, 5131–5145; b) T. Pinho e Melo, Curr. Org. Chem. 2005, 9,
925–958; c) A. P. Kozikowski, Acc. Chem. Res. 1984, 17, 410–416.
[3] For selected recent examples, see: a) V. Varshney, N. N. Mishra,
P. K. Shukla, D. P. Sahu, Bioorg. Med. Chem. Lett. 2009, 19, 3573–
3576; b) P. P. Shao, F. Ye, A. E. Weber, X. H. Li, K. A. Lyons, W. H.
Parsons, M. L. Garcia, B. T. Priest, M. M. Smith, J. P. Felix, B. S. Wil-
liams, G. J. Kaczorowski, E. McGowan, C. Abbadie, W. J. Martin,
D. R. McMasters, Y. D. Gao, Bioorg. Med. Chem. Lett. 2009, 19,
5329–5333; c) J. Kaffy, R. Pontikis, D. Carrez, A. Croisy, C. Monner-
et, J. C. Florent, Bioorg. Med. Chem. 2006, 14, 4067–4077; d) Z.
Mincheva, M. Courtois, J. Creche, M. Rideau, M. C. Viaud-Mas-
suard, Bioorg. Med. Chem. 2004, 12, 191–197; e) A. P. Kozikowski,
K. Sato, A. Basu, J. S. Lazo, J. Am. Chem. Soc. 1989, 111, 6228–
6234.
[4] For selected recent example, see: a) K. Karthikeyan, T. V. Seelan,
K. G. Lalitha, P. T. Perumal, Bioorg. Med. Chem. Lett. 2009, 19,
3370–3373; b) M. Benltifa, J. M. Hayes, S. Vidal, D. Gueyrard, P. G.
Goekjian, J. P. Praly, G. Kizilis, C. Tiraidis, K. M. Alexacou, E. D.
Chrysina, S. E. Zographos, D. D. Leonidas, G. Archontis, N. G. Oi-
konomakos, Bioorg. Med. Chem. 2009, 17, 7368–7380; c) R.
Maurya, P. Gupta, G. Ahmad, D. K. Yadav, K. Chand, A. B. Singh,
A. K. Tamrakar, A. K. Srivastava, Med. Chem. Res. 2008, 17, 123–
136; d) M. C. Pirrung, L. N. Tumey, C. R. H. Raetz, J. E. Jackman,
K. Snehalatha, A. L. McClerren, C. A. Fierke, S. L. Gantt, K. M.
Rusche, J. Med. Chem. 2002, 45, 4359–4370.
[5] For selected examples: a) A. L. Smith, E. N. Pitsinos, C. K. Hwang,
Y. Mizuno, H. Saimoto, G. R. Scarlato, T. Suzuki, K. C. Nicolaou, J.
Am. Chem. Soc. 1993, 115, 7612–7624; b) B. M. Trost, L. Li, S. D.
Guile, J. Am. Chem. Soc. 1992, 114, 8745–8747.
[6] For selected reviews: a) R. Y. Baiazitov, S. Nguyen, S. E. Denmark,
Heterocycles 2008, 76, 143–154; b) H. M. I. Osborn, N. Gemmell,
L. M. Harwood, J. Chem. Soc. Perkin Trans. 1 2002, 2419–2438;
c) S. E. Denmark, D. S. Middleton, J. Org. Chem. 1998, 63, 1604–
1618.
[7] For selected samples: a) R. A. Kunetsky, A. D. Dilman, S. L. Ioffe,
M. I. Struchkova, Y. A. Strelenko, V. A. Tartakovsky, Org. Lett.
2003, 5, 4907–4909; b) N. Scardovi, A. Casalini, P. Francesca, P.
Righi, Org. Lett. 2002, 4, 965–968; c) C. Galli, E. Marotta, P. Righi,
G. Rosini, J. Org. Chem. 1995, 60, 6624–6626.
[8] For selected examples of nitro compound [3+2] reactions: a) S. E.
Denmark, M. Seierstad, B. Herbert, J. Org. Chem. 1999, 64, 884–
901; b) A. Voituriez, J. Moulinas, C. Kouklovsky, Y. Langlois, Syn-
thesis 2003, 1419–1426; c) P. Y. Roger, A. C. Durand, J. Rodriguez,
J. P. Dulcere, Org. Lett. 2004, 6, 2027–2029; d) A. Arrieta, D. Otae-
gui, A. Zubia, F. P. Cossio, A. Diaz-Ortiz, A. de La Hoz, M. A. Her-
rero, P. Prieto, C. Foces-Foces, J. L. Pizarro, M. I. Arriortua, J. Org.
Chem. 2007, 72, 4313–4322; C. Foces-Foces, J. L. Pizarro, M. I. Ar-
riortua, J. Org. Chem. 2007, 72, 4313–4322.
Experimental Section
General procedure for the synthesis of isoxazoline-N-oxide 3a: The ni-
troalkene 1a (176 mg, 1.1 mmol, 1.1 equiv) was added to a solution of al-
dehyde 2a (0.5 mmol, 1.0 equiv), l-proline (25 mg, 0.22 mmol, 0.2 equiv),
and K2CO3 (35 mg, 0.25 mmol, 0.5 equiv) in DMSO (5.5 mL), with alde-
hyde concentration as 0.1m. The resulting mixture was stirred at room
temperature for 3 h. The mixture was diluted with EtOAc (100 mL). The
organic phase was washed with HCl (1.0m), saturated NaHCO3 (aq.),
and brine, and then dried over anhydrous Na2SO4. Flash silica gel chro-
matography was then applied to give 3a (169 mg, 92%) as clear oil.
General procedure for preparation of three-component isoxazoline-N-
oxide 7a: The nitroalkene 1a (114 mg, 0.7 mmol, 1.4 equiv) was added to
a solution of the sulfur ylide 4d (219 mg, 0.6 mmol, 1.2 equiv) in MeOH
(0.4m for nitroalkene), till the ylide dissolved. The mixture was cooled
down to À258C. Pyrrolidine (7 mg, 0.1 mmol, 0.2 equiv) and K2CO3
(35 mg, 0.25 mmol, 0.5 equiv) were then added and the resulting mixture
was stirred for 30 min. The aldehyde 2a (0.5 mmol, 1.0 equiv) in MeOH
(4.6 mL) was added dropwise over a period of 10 min. The resulting reac-
tion mixture was stirred at À258C for 48 h. The mixture was then diluted
with EtOAc (20 mL) and the water phase was extracted with EtOAc
(20 mLꢁ3). The organic phase was washed with HCl (1.0m), saturated
NaHCO3 (aq.), and brine, and then dried over anhydrous Na2SO4. Flash
silica gel chromatography was then applied to give the product 7a
(144 mg, 89%) as clear oil.
For explicit experimental data, including spectroscopic data, see the Sup-
porting Information.
[9] K. S. Huang, E. H. Lee, M. M. Olmstead, M. J. Kurth, J. Org. Chem.
2000, 65, 499–503.
[10] a) C.-Y. Zhu, X.-M. Deng, X.-L. Sun, J.-C. Zheng, Y. Tang, Chem.
Commun. 2008, 738–740; b) C.-Y. Zhu, X.-M. Sun, X.-M. Deng, J.-
C. Zheng, Y. Tang, Tetrahedron 2008, 64, 5583–5589.
[11] H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V. Marcos, K. A. Jør-
gensen, Angew. Chem. 2009, 121, 6976–6980; Angew. Chem. Int. Ed.
2009, 48, 6844–6848.
Acknowledgements
We thank NSF Career (CHE-0844602), ACS-PRF-47843-G1 and DOE
(DE-FC26-04NT42136) for financial support.
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Asymmetric Synthesis
COMMUNICATION
[12] a) X. Sun, S. Sengupta, J. L. Petersen, H. Wang, J. P. Lewis, X. Shi,
Org. Lett. 2007, 9, 4495–4498; b) C. Zhong, Y. Chen, J. L. Petersen,
N. Akhmedov, X. Shi, Angew. Chem. 2009, 121, 1305–1308; Angew.
Chem. Int. Ed. 2009, 48, 1279–1282; c) S. Sengupta, H. Duan, W.
Lu, J. L. Petersen, X. Shi, Org. Lett. 2008, 10, 1493–1494; d) Y.
Chen, Y. Liu, J. L. Petersen, X. Shi, Chem. Commun. 2008, 3254–
3256; e) Y. Liu, W. Yan, Y. Chen, J. L. Petersen, X. Shi, Org. Lett.
2008, 10, 5389–5392; f) H. Duan, W. Yan, S. Sengupta, X. Shi,
Bioorg. Med. Chem. Lett. 2009, 19, 3899–3902.
[19] The single-crystal X-ray structure of 6a revealed the formation of a
hydrogen bond for improved stereochemistry control.
[13] a) Y. Chen, C. Zhong, X. Sun, N. Akhmedov, J. L. Petersen, X. Shi,
Org. Lett. 2009, 11, 2333–2336; b) Y. Chen, C. Zhong, X. Sun, N.
Akhmedov, J. L. Petersen, X. Shi, Chem. Commun. 2009, 5150–
5152; c) C. Zhong, T. Liao, O. Tuguldur, X. Shi, Org. Lett. 2010, 12,
2064–2067.
[14] H. Duan, X. Sun, W. Liao, J. L. Petersen, X. Shi, Org. Lett. 2008, 10,
4113–4116.
[15] See the Supporting Information for the detailed screening condi-
tions.
[16] The detailed mechanistic study of the interaction between chiral sec-
ondary amine Lewis base and the nitro alkene or the intermediate is
currently under investigation.
[17] For recent successful selective addition of sulfur ylides to mono-sub-
stituted nitroalkenes, see: L.-Q. Lu, Y.-J. Cao, X.-P. Liu, J. An, C.-J.
Yao, Z.-H. Ming, W.-J. Xiao, J. Am. Chem. Soc. 2008, 130, 6946–
6948.
[18] For the synthesis of chiral sulfur ylides, see: a) J.-C. Zheng, C.-Y.
Zhu, X.-L. Sun, Y. Tang, L.-X. Dai, J. Org. Chem. 2008, 73, 6909–
6912; for related studies in asymmetric chiral sulfur ylide auxiliaries,
see: b) X.-L. Sun, Y. Tang, Acc. Chem. Res. 2008, 41, 937–948;
c) Q.-G. Wang, X.-M. Deng, B.-H. Zhu, L.-W. Ye, X.-L. Sun, C.-Y.
Li, C.-Y. Zhu, Q. Shen, Y. Tang, J. Am. Chem. Soc. 2008, 130, 5408–
5409; d) X.-M. Deng, P. Cai, S. Ye, X.-L. Sun, W.-W. Liao, K. Li, Y.
Tang, Y.-D. Wu, L.-X. Dai, J. Am. Chem. Soc. 2006, 128, 9730–9740;
e) S. Ye, Z.-Z. Huang, C.-A. Xia, Y. Tang, L.-X. Dai, J. Am. Chem.
Soc. 2002, 124, 2432–2433.
[20] a) E. Borredon, M. Delmas, A. Gaset, Tetrahedron 1987, 43, 3945–
3954; b) E. Borredon, F. Clavellinas, M. Delmas, A. Gaset, J. V. Sin-
isterrat, J. Org. Chem. 1990, 55, 501–504. For further related studies,
see: c) V. K. Aggarwal, J. N. Harvey, J. Richardson, J. Am. Chem.
Soc. 2002, 124, 5747–5756; d) V. K. Aggarwal, G. Hynd, W. Picoul,
J. Vasse, J. Am. Chem. Soc. 2002, 124, 9964–9965.
[21] For the bioactivity of Clausenamide: a) X. Y. Wang, J. T. Zhang, J.
Asian. Nat. Prod. Res. 2003, 5, 1–4; b) X. Y. Wang, J. T. Zhang, Acta
Pharmacol. Sin. 2001, 22, 1099–1102; c) L. Xu, S. L. Liu, J. T.
Zhang, Chirality 2005, 17, 239–244. For the synthesis of Clausena-
mide: d) L. Yang, G. Deng, C. X. Wang, Z. T. Huang, J. P. Zhu,
M. X. Wang, Org. lett. 2007, 9, 1387–1390; e) T. Yakura, Y. Matsu-
mura, M. Ikeda, Synlett 1991, 343–344.
[22] 2D NMR studies and the X-ray structure for 8e are provided in the
Supporting Information, and indicated the all-cis configuration of
the g-lectam.
Received: May 7, 2010
Published online: July 6, 2010
Chem. Eur. J. 2010, 16, 8605 – 8609
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8609