Catalytic asymmetric construction of spiro(γ-butyrolactam-γ- butyrolactone) moieties through sequential reactions of cyclic imino esters with Morita-Baylis-Hillman bromides

Article abstract of DOI:10.1002/chem.201201475

Spiro(γ-butyrolactam-γ-butyrolactone): A route to enantioenriched spiro(γ-butyrolactam-γ-butyrolactone) compounds, a valuable motif for drug discovery, was developed by use of a highly efficient copper(I)/TF-BiphamPhos-catalyzed tandem Michael addition-elimination of homoserine lactone derived cyclic imino esters with Morita-Baylis-Hillman (MBH) bromides, followed by treatment with para-toluenesulfonic acid (see scheme). Copyright

Full text of DOI:10.1002/chem.201201475

COMMUNICATION
DOI: 10.1002/chem.201201475
Catalytic Asymmetric Construction of Spiro(g-butyrolactam-g-
butyrolactone) Moieties through Sequential Reactions of Cyclic Imino Esters
with Morita–Baylis–Hillman Bromides
Huai-Long Teng,[a] He Huang,[a] and Chun-Jiang Wang*[a, b]
Spirocycles containing g-butyrolactam and g-butyrolac-
tone moieties are prevalent scaffolds in biologically active
molecules and natural products.[1–5] Some representative ex-
amples are shown in Figure 1. The privileged cyclic g-butyr-
olactam and g-butyrolactone skeletons have high potential
lactone) compounds containing consecutive spiro quaternary
and tertiary stereocenters through a CuI-catalyzed tandem
Michael addition–eliminaton of homoserine lactone derived
cyclic imino esters with Morita–Baylis–Hillman bromides,
followed by a deprotection/lactamization reaction.
The Morita–Baylis–Hillman reaction is one of the most
popular atom-economic carbon–carbon bond-forming reac-
tions. This reaction straightforwardly provides densely func-
tionalized molecules, and has recently received considerable
attention.[8] Multifunctionalized Morita–Baylis–Hillman ad-
ducts have been employed successfully as valuable starting
materials for the synthesis of heterocycles and many biologi-
cally active molecules.[9] Among these, Morita–Baylis–Hill-
man carbonates are the most commonly used substrates for
a large number of asymmetric transition-metal-catalyzed
and organocatalyzed transformations.[10] As part of our con-
tinuing interest in the application of Morita–Baylis–Hillman
adducts in asymmetric catalysis,[11] we recently reported a
catalytic asymmetric method for the rapid construction of
pyroglutamate derivatives containing the g-butyrolactam
moiety and a quaternary stereogenic center through CuI/
2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP)-cata-
lyzed tandem Michael addition–elimination of a-substituted
aldimino esters with Morita–Baylis–Hillman (MBH) carbo-
nates, followed by a simple deprotection/lactamization pro-
tocol (Scheme 1a).[11b] Along this research pathway, it occur-
red to us that with the appropriate Morita–Baylis–Hillman-
type adducts as nucleophilic acceptors, such a sequential
protocol might be applicable for facile access to enantioen-
riched spiro(g-butyrolactam-g-butyrolactone) skeletons, fea-
turing adjacent spiro quaternary and tertiary stereogenic
centers. However, as outlined in Scheme 1b, the expected
tandem Michael addition–elimination reaction did not pro-
ceed when the less reactive (Z)- or (E)-trisubstituted MBH-
type acetates[12] were initially employed, which was probably
caused by the unfavorable steric congestion. Considering
that a bromo group at the allylic position of MBH reagents
is also a suitable leaving group,[13,14] we envisaged that the
sterically less bulky MBH bromides might be employed as
an efficient nucleophilic acceptor, and hence facilitate the
tandem transformation through regioselective g-position at-
tack,[14e] leading to the key adduct containing two adjacent
stereogenic centers.
Figure 1. Representative bioactive spiro(g-butyrolactam)s and spiro(g-bu-
tyrolactone)s containing a quaternary stereogenic center.
as core elements for the development of related compounds
that lead to medicinal agents.[5] Therefore, the spiro(g-butyr-
olactam-g-butyrolactone) motif, that is, the combination of
the two key units through a spiro quaternary carbon atom,[6]
may introduce some unprecedented benefits and is expected
to find valuable applications in medicinal chemistry.
In sharp contrast to the well-documented approaches to
either g-butyrolactam- or g-butyrolactone-containing com-
pounds, an effective method for the construction of the
spiro(g-butyrolactam-g-butyrolactone) skeleton remains elu-
sive. To our knowledge, there have been no reports on the
catalytic asymmetric synthesis of spiro(g-butyrolactam-g-bu-
tyrolactone) moieties so far.[7] Herein, we report the first
asymmetric construction of spiro(g-butyrolactam-g-butyro-
[a] H.-L. Teng, H. Huang, Prof. Dr. C.-J. Wang
College of Chemistry and Molecular Sciences
Wuhan University, 430072 (P.R. China)
Fax : (+86)27-68754067
E-mail: cjwang@whu.edu.cn
[b] Prof. Dr. C.-J. Wang
State Key Laboratory of Elemento-organic Chemistry
Nankai University
Tianjin, 300071 (P.R. China)
To test our hypothesis, we first decided to study the race-
mic reaction of MBH bromide (Z)-2-(bromomethyl)-3-phe-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201475.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Table 1. Optimization of the catalytic asymmetric tandem Michael addi-
tion–elimination reaction of homoserine lactone derived cyclic imino
ester 1 with MBH bromide 2a.[a]
Entry
L
[M]
Solvent
3a/3a’[b]
Yield[c]
[%]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[e]
L1
L1
L2
L2
L3
L3
L4
L4
L4
L4
L4
L4
L4
L4
AgOAc
CuBF4
AgOAc
CuBF4
AgOAc
CuBF4
AgOAc
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
Et2O
CH3CN
CHCl3
CH2Cl2
2:1
–
–
42
–
–
15
–
–
2:1
30
70
69
74
85
25
92
60
68
47
45
26
40
54
86
92
20
74
89
73
89
94
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Scheme 1. Asymmetric construction of pyroglutamate (a) and spiro(g-bu-
tyrolactam-g-butyrolactone) compounds containing one spiro quaternary
and one tertiary stereogenic center (b and c).
nylprop-2-enoate 2a[15] with the homoserine lactone derived
cyclic imino ester 1 to probe the possible reaction pathway.
To our delight, we found that the expected tandem Michael
addition–elimination reaction was efficiently promoted by a
catalytic amount of the CuI/PPh3 complex, and the expected
Michael addition–elimination product 3a was isolated as a
stable compound through exclusively g-attack,[16] in high
yield with excellent diastereoselectivity (d.r.>20:1;
Scheme 2).
[a] All reactions were carried out with 2a (0.24 mmol) and 1 (0.20 mmol)
in a solvent (2 mL) for 36 h. CuBF4 =CuACTHNUTRGNEUNG(CH3CN)4BF4. [b] The ratio of
3a/3a’ was determined from the crude 1H NMR spectrum. [c] Yield of
the isolated product. [d] The ee was determined by chiral HPLC analysis.
[e] Carried at 08C for 72 h.
for Morita–Baylis–Hillman carbonates (Table 1, entry 2).[11b]
However, with the AgI/(S)-BINAP complex as the catalyst
and K2CO3 as the base, the reaction proceeded at room tem-
perature, although a-[16] and g-attack products were formed
in an unsatisfactory ratio with a pretty low ee for the major
isomer (Table 1, entry 1). If combined with (S)-Monophos
(L2), AgOAc hardly promotes this reaction, whereas the
CuACHTUNRTGNEUN(G CH3CN)4BF4 salt directs the g-attack pathway exclusive-
ly, albeit with low reactivity and enantioselectivity (Table 1,
entries 3 and 4). Next, the chiral ligands TF-BiphamPhos,
developed in this laboratory,[17] were screened to identify a
more efficient catalyst system. In general, TF-BiphamPhos
ligands exhibited the best results in terms of reactivity and
regioselectivity, and copper salts gave better enantioselectiv-
ity than silver salts (Table 1, entries 5–8). By using the Cu-
Scheme 2. CuBF4/PPh3-catalyzed tandem Michael addition–elimination
reaction of homoserine lactone derived cyclic imino ester 1 with MBH
bromide 2a.
Encouraged by this promising result and inspired by our
recent finding that the CuI/(S)-BINAP complex exhibits ex-
cellent results in the catalytic asymmetric tandem Michael
addition–elimination of Morita–Baylis–Hillman carbonates,
we began chiral-ligand screening with the bisphosphine
BINAP. Unfortunately, no reaction occurred between the
Morita–Baylis–Hillman bromide 2a and cyclic imino ester 1
under the previously reported optimal reaction conditions
AHCTNUGTER(GNNNU CH3CN)4BF4/TF-BiphamPhos L3 complex as the catalyst,
the g-attack adduct 3a was exclusively obtained with good
yield, excellent diastereoselectivity and moderate enantiose-
lectivity (54% ee; Table 1, entry 6). TF-BiphamPhos L4,
containing two bromine atoms in the 3,3’-positions of the
TF-BIPHAM backbone was revealed to be the most promis-
&
2
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Spiro(g-butyrolactam-g-butyrolactone) Compounds
COMMUNICATION
Table 2. Substrate scope of the CuI-catalyzed asymmetric tandem Mi-
chael addition–elimination reaction of homoserine lactone derived cyclic
imino ester 1 with MBH bromides 2.[a]
ing ligand, providing 3a in 85% yield and 92% ee (Table 1,
entry 8), which demonstrates the significant role that the
ortho-substituted biphenyl skeleton (TF-BIPHAM) plays in
this process, and similar improvements in enantioselectivity
have also been noticed in other asymmetric catalysis reac-
tions.[18] Subsequently, a study of the reaction with CuI/TF-
BiphamPhos L4 at room temperature in various solvents
identified diethyl ether and chloroform to be suitable alter-
natives to dichloromethane (Table 1, entries 8–13). Reducing
the reaction temperature from RT to 08C led to a small in-
crease in the enantioselectivity, but the reaction rate drop-
ped significantly, providing only a moderate yield even after
an extended reaction time (Table 1, entry 14). Thus, the op-
timized reaction conditions were established to be the
CuBF4/L4 complex (10 mol%) and K2CO3 as the base in
CH2Cl2 at room temperature.
Next, the scope and generality of this novel tandem Mi-
chael addition–elimination reaction of the cyclic imino ester
1 with a series of MBH bromides 2 were investigated under
the optimized experimental conditions. As shown in Table 2,
a wide array of MBH bromides derived from aromatic alde-
hydes reacted smoothly with cyclic imino ester 1 through
the exclusively g-attack reaction pathway, providing the de-
sired tandem Michael addition–elimination adducts in excel-
lent diastereoselectivities and high enantioselectivities
(Table 2, entries 1–11). It appears that the position and elec-
tronic properties of the substituents on the aromatic ring
have a very limited effect on the stereoselectivity. The con-
sistently excellent diastereo- and enantioselectivities ob-
tained with the sterically hindered ortho-methoxyl- and
ortho-chloro-substituted MBH bromides 2b and 2 f is note-
worthy (Table 2, entries 2 and 6). Additionally, polycyclic ar-
omatic 2-naphthylaldehyde-derived imino ester 2l was
found to be a viable substrate for this process, producing the
corresponding product 3l in
Entry
R
Product
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph (2a)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
85
78
83
78
75
75
87
83
88
86
75
88
68
92
92
93
94
92
94
87
89
92
90
91
82
90
o-MeOPh (2b)
p-MeOPh (2c)
m-MeOPh (2d)
p-MeOPh (2e)
o-ClPh (2 f)
m-ClPh (2g)
p-ClPh (2h)
p-FPh (2i)
p-BrPh (2j)
p-CF3Ph
2-naphthyl (2l)
Et (2m)
3j
3k
3l
(2k)
3m
[a] The reactions were carried out with 2 (0.24 mmol) and 1 (0.20 mmol)
in CH2Cl2 (2 mL) for 36 h. [b] Yield of the isolated product. [c] Deter-
mined by HPLC analysis.
of the imino protecting group and subsequent lactamization,
providing the corresponding spiro(g-butyrolactam-g-butyro-
lactone) compounds containing adjacent spiro quaternary
and tertiary stereogenic centers without a reduction in dia-
stereomeric ratio or enantiomeric excess. An X-ray crystal-
lographic analysis of a crystal of tert-butoxycarbonyl (Boc)-
protected compound 5 revealed a (4R,5R) configuration[19]
for the two consecutive stereogenic centers and therefore
also for the corresponding moiety in 3j and 4j. Direct hy-
88% yield with >20:1 d.r. and
82% ee (Table 2, entry 12). Re-
markably, MBH bromide 2m,
derived from an aliphatic alde-
hyde, also worked well in this
tandem reaction, providing the
desired g-attack adduct exclu-
sively with excellent diastereo-
and enantioselectivity (Table 2,
entry 13).
The regioselective tandem
Michael
addition–elimination
reaction can then be applied for
facile access to spiro(g-butyro-
lactam-g-butyrolactone) com-
pounds with high molecular
complexity, as exemplified in
Scheme 3. Simple treatment of
adducts 3a and 3j with TsOH
(Ts=para-toluenesulfonyl) in
THF/H2O (1:1) at room tem-
Scheme 3. Facile access to spiro(g-butyrolactam-g-butyrolactone) compounds with high molecular complexity.
perature achieved the cleavage Compound (4R,5R)-5: Ellipsoids were drawn at the 30% probability level.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

C.-J. Wang et al.
bromide 2 (0.24 mmol) were added sequentially. The mixture was stirred
at room temperature until full consumption of 1 had occurred (monitored
by TLC analysis). Then, the residue was purified by flash column chro-
matography on silica gel to give the corresponding product 3 as a color-
less oil, which was then directly analyzed by chiral HPLC to determine
the enantiomeric excess.
drogenation of the a-methylene group in spirocyclic com-
pound 4a in the presence of Pd/C delivered compound 6,
containing three consecutive stereogenic centers, and the ad-
ditional tertiary stereogenic center was efficiently generated
in a remarkably diastereoselective manner.
Prompted by these results for the homoserine lactone de-
rived cyclic imino esters, we then investigated the reaction
of glycine-derived imino ester 7, which contains no substitu-
tion at the a-position, from which two adjacent tertiary ster-
eogenic centers would be generated in the corresponding
adduct (Scheme 4). To our delight, the reaction occurred
Acknowledgements
This work is supported by the National Natural Science Foundation of
China (20972117, 21172176), the Program for New Century Excellent
Talents in University (NCET-10–0649), the Program for Changjiang
Scholars and Innovative Research Team in University of the Ministry of
Education (IRT1030), the 973 program (2011CB808600), the Fundamen-
tal Research Funds for the Central Universities, and the Large-scale In-
strument and Equipment Sharing Foundation of Wuhan University. We
thank Prof. Hua Li at Wuhan University for solving the crystal structure.
Keywords: asymmetric
catalysis
·
bromides
·
diastereoselectivity · enantioselectivity · imino esters · spiro
compounds
Scheme 4. Results of the tandem Michael addition–elimination of an
imino ester derived from glycine (7) with MBH bromide 2a and the syn-
thetic transformation.
[1] a) C.-P. Chung, C.-Y. Hsu, J.-H. Lin, Y.-H. Kuo, W. Chiang, Y.-L.
Lin, J. Argic. Food. Chem. 2011, 59, 1185–1194; b) H.-C. Lo, R. En-
twistle, C.-J. Guo, M. Ahuja, E. Szewczyk, J.-H. Hung, Y.-M. Ching,
B. R. Oakley, C. C. Wang, J. Am. Chem. Soc. 2012, 134, 4709–4720;
c) S. K. Panday, J. Prasad, D. K. Dikshit, Tetrahedron: Asymmetry
2009, 20, 1581–1632; d) R. H. Feling, G. O. Buchanan, T. J. Mincer,
C. A. Kauffman, P. R. Jensen, W. Fenical, Angew. Chem. 2003, 115,
369–371; Angew. Chem. Int. Ed. 2003, 42, 355–357; e) W. Chu, J. H.
Perlman, M. C. Gershengorn, K. D. Moeller, Bioorg. Med. Chem.
Lett. 1998, 8, 3093–3096; f) M. B. Smith, Alkaloids Chem. Biol. Per-
spect. 1998, 12, 229–287; g) R. Benoit, C. Pascal, F. Dominique, S.
Francois, Trends Heterocycl. Chem. 1991, 2, 155–204.
[2] J.-H. Jang, Y. Asami, J.-P. Jang, S.-O. Kim, D. O. Moon, K.-S. Shin,
D. Hashizume, M. Muroi, T. Saito, H. Oh, B. Y. Kim, H. Osada, J. S.
Ahn, J. Am. Chem. Soc. 2011, 133, 6865–6867.
[3] T. J. Simpson, A. J. Bartlett, E. OꢁBrien, J. S. E. Holker, J. Chem.
Soc. Perkin Trans. 1 1982, 2687–2691.
[4] a) O. Mꢂrquez-Fernꢂndez, A. Trigos, J. L. Ramos-Balderas, G. Vin-
iegra-Gonzꢂlez, H. B. Deising, J. Aguirre, Eukaryotic Cell 2007, 6,
710–720; b) E. Szewczyk, Y. M. Chiang, C. E. Oakley, A. D. David-
son, C. C. C. Wang, B. R. Oakley, Appl. Environ. Microbiol. 2008,
74, 7607–7612.
[5] a) T. Mori, K. Takahashi, M. Kashiwabara, D. Uemura, Tetrahedron
Lett. 1985, 26, 1073–1076; b) S. Omura, T. Fujimoto, K. Otoguro, K.
Matsuzaki, R. Moriguchi, H. Tanaka, Y. Sasaki, J. Antibiot. 1991, 44,
113–116; c) S. Omura, K. Matsuzaki, T. Fujimoto, K. Kosuge, T.
Furuya, S. Fujita, A. Nakagawa, J. Antibiot. 1991, 44, 117–118;
d) M. G. Moloney, P. C. Trippier, M. Yaqoob, Z. Wang, Curr. Drug
Discovery Technol. 2004, 1, 181–199.
[6] a) Quaternary Stereocenters: Challenges and Solution for Organic
Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH, Weinheim,
2005; b) J. Christoffers, A. Mann, Angew. Chem. 2001, 113, 4725–
4732; Angew. Chem. Int. Ed. 2001, 40, 4591–4597; c) J. Christoffers,
A. Baro, Angew. Chem. 2003, 115, 1726–1728; Angew. Chem. Int.
Ed. 2003, 42, 1688–1690; d) B. M. Trost, C. Jiang, Synthesis 2006,
369–396; e) C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci.
USA 2004, 101, 5363–5367.
successfully with the CuI/TF-BiphamPhos L4 complex to
give pyroglutamate 8 highly diastereo-/enantioselectively
through tandem Michael addition–elimination (by g-attack),
followed by the aforementioned deprotection/lactamization
protocol.
In conclusion, we have successfully developed the first ex-
ample of the catalytic asymmetric construction of highly
functionalized spiro(g-butyrolactam-g-butyrolactone) com-
pounds, a valuable structural motif for drug discovery,
through the CuI-catalyzed tandem Michael addition–elimi-
nation reaction of homoserine lactone derived cyclic aldimi-
no esters, followed by a deprotection/lactamization protocol.
The success of this methodology relies on the logical design
and rational optimization that led to utilizing Morita–
Baylis–Hillman bromides as the key nucleophilic acceptors.
The highly efficient CuI/TF-BiphamPhos catalytic system ex-
hibited excellent performance, providing enantioenriched
spiro(g-butyrolactam-g-butyrolactone) derivatives contain-
ing adjacent spiro quaternary and tertiary stereogenic cen-
ters in a regioselective manner, with excellent diastereose-
lectivity (>20:1) and high enantioselectivity (82–94% ee).
Further investigations into the scope and synthetic applica-
tions of this methodology are ongoing, and the results will
be reported in due course.
Experimental Section
[7] For recent examples of the catalytic asymmetric synthesis of biologi-
cally active spiro compounds, see: a) X.-H. Chen, Q. Wei, S.-W. Luo,
H. Xiao, L. Z. Gong, J. Am. Chem. Soc. 2009, 131, 13819–13825;
b) Q. Wei, L.-Z. Gong, Org. Lett. 2010, 12, 1008–1011; c) X. X.
Jiang, Y. M. Cao, Y. Q. Wang, L. P. Liu, F. F. Shen, R. Wang, J. Am.
General procedure: Under an argon atmosphere, CuACTHNUTRGNE(UNG CH3CN)4BF4
(6.3 mg, 0.020 mmol) and (S)-TF-BiphamPhos L4 (17.5 mg, 0.022 mmol)
were dissolved in CH2Cl2 (2 mL), and stirred at room temperature for
1 h. Then, cyclic imino ester 1 (0.20 mmol), K2CO3 (0.4 mmol), and MBH
&
4
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Spiro(g-butyrolactam-g-butyrolactone) Compounds
COMMUNICATION
Chem. Soc. 2010, 132, 15328–15333; d) Q. Cai, C. Zheng, J.-W.
Zhang, S.-L. You, Angew. Chem. 2011, 123, 8824–8828; Angew.
Chem. Int. Ed. 2011, 50, 8665–8669; e) Q.-F. Wu, W.-B. Liu, C.-X.
Zhuo, Z.-Q. Rong, K.-Y. Ye, S.-L. You, Angew. Chem. 2011, 123,
4547–4550; Angew. Chem. Int. Ed. 2011, 50, 4455–4458; f) Q.-F.
Wu, C. Zheng, S.-L. You, Angew. Chem. 2012, 124, 1712–1715;
Angew. Chem. Int. Ed. 2012, 51, 1680–1683; g) B. M. Trost, N.
Cramer, S. M. Silverman, J. Am. Chem. Soc. 2007, 129, 12396–
12397; h) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F.
Pesciaioli, M.-P. Song, G. Bartoli, P. Melchiorre, Angew. Chem.
2009, 121, 7336–7339; Angew. Chem. Int. Ed. 2009, 48, 7200–7203;
i) B. Tan, N. R. Candeias, C. F. Barbas III, J. Am. Chem. Soc. 2011,
133, 4672–4675; j) B. Tan, G. Hernꢂndez-Torres, C. F. Barbas III, J.
Am. Chem. Soc. 2011, 133, 12354–12357; k) A. P. Antonchick, C.
Gerding-Reimers, M. Catarinella, M. Schꢃrmann, H. Preut, S. Zie-
gler, D. Rauh, H. Waldmann, Nat. Chem. 2010, 2, 735–740; l) T.-L.
Liu, Z.-Y. Xue, H.-Y. Tao, C.-J. Wang, Org. Biomol. Chem. 2011, 9,
1980–1986; m) T.-L. Liu, Z.-L. He, H.-Y. Tao, Y.-P. Cai, C.-J. Wang,
Chem. Commun. 2011, 47, 2616–2618; n) T.-L. Liu, Z.-L. He, Q.-H.
Li, H.-Y. Tao, C.-J. Wang, Adv. Synth. Catal. 2011, 353, 1713–1719;
o) T.-L. Liu, Z.-L. He, C.-J. Wang, Chem. Commun. 2011, 47, 9600–
9602.
13, 6082–6085; p) W. S. Sun, H. Hong, C. X. Liu, R. Wang, Org.
Lett. 2010, 12, 3914–3917; q) L. Hong, W. S. Sun, C. X. Liu, D. P.
Zhao, R. Wang, Chem. Commun. 2010, 46, 2856–2858; r) C.-G.
Chen, X.-L. Hou, L. Pu, Org. Lett. 2009, 11, 2073–2075;
s) D. J. V. C. van Steenis, T. Marcelli, M. Lutz, A. L. Spek, J. H. van
Maarseveen, H. Hiemstra, Adv. Synth. Catal. 2007, 349, 281–286;
t) P. V. Ramachandran, S. Madhi, L. Bland-Berry, M. V. R. Reddy,
M. J. OꢁDonnell, J. Am. Chem. Soc. 2005, 127, 13450–13451; u) R. J.
Reddy, K. Chen, Org. Lett. 2011, 13, 1458–1461.
[11] a) H.-L. Teng, H. Huang, H.-Y. Tao, C.-J. Wang, Chem. Commun.
2011, 47, 5494–5496; b) H.-L. Teng, F.-L. Luo, H.-Y. Tao, C.-J.
Wang, Org. Lett. 2011, 13, 5600–5603.
[12] J. M. Kim, K. H. Kim, T. H. Kim, J. N. Kim, Tetrahedron Lett. 2008,
49, 3248–3251.
[13] P. Singh, S. Singh, V. K. Rai, L. D. S. Yadav, Synlett 2010, 2649–
2653.
[14] a) A. Novak, M. J. Calhorda, P. J. Costa, S. Woodward, Eur. J. Org.
Chem. 2009, 898–903; b) A. Novak, R. Fryatt, S. Woodward, C. R.
Chim. 2007, 10, 206–212; c) E. Gꢄmez-Bengoa, A. Landa, A. Lizar-
raga, A. Mielgo, M. Oiarbide, C. Palomo, Chem. Sci. 2011, 2, 353–
357; d) G. Martelli, M. Orena, S. Rinaldi, Eur. J. Org. Chem. 2011,
7199–7206; for the definition of a-and g-attack to the leaving group
in allylic halides or acetates, see: e) C. Bçrner, J. Gimeno, S. Gladia-
li, P. J. Goldsmith, D. Ramazzottic, S. Woodward, Chem. Commun.
2000, 2433–2434.
[15] a) H. M. Huang, X. C. Liu, J. Deng, M. Qiu, Z. Zheng, Org. Lett.
2006, 8, 3359–3362; b) B. Das, K. Damodar, N. Bhunia, B. Shashi-
kanth, Tetrahedron Lett. 2009, 50, 2072–2074.
[16] The exclusively a-attack product 3a’ could be formed instead
through a AgOAc/PPh3-catalyzed tandem Michael addition–elimina-
tion reaction of the homoserine lactone derived cyclic imino ester
with the Morita–Baylis–Hillman (MBH) carbonate (ref. [11b]):
[8] a) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43, 1005–1018; b) D. Basa-
vaiah, B. S. Reddy, S. S. Badsara, Chem. Rev. 2010, 110, 5447–5674;
c) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev. 2009, 109, 1–48;
d) E. Ciganek in Organic Reactions, Vol. 51 (Ed.: L. A. Paquette),
Wiley, New York, 1997, pp. 201–350.
[9] a) Z. Qiao, Z. Shafiq, L. Liu, Z.-B. Yu, Q.-Y. Zheng, D. Wang, Y.-J.
Chen, Angew. Chem. 2010, 122, 7452–7456; Angew. Chem. Int. Ed.
2010, 49, 7294–7298; b) Y. H. Du, X. Y. Lu, C. M. Zhang, Angew.
Chem. 2003, 115, 1065–1067; Angew. Chem. Int. Ed. 2003, 42, 1035–
1037; c) Y. Wang, Z. Shafiq, L. Liu, D. Wang, Y.-J. Chen, J. Hetero-
cycl. Chem. 2010, 47, 373–378; d) V. K. Aggarwal, A. Patin, S. Tis-
serand, Org. Lett. 2005, 7, 2555–2557; e) P. Wasnaire, M. Wiaux, R.
Touillaux, I. E. Marko, Tetrahedron Lett. 2006, 47, 985–989; f) K. Y.
Lee, S. Gowrisankar, J. N. Kim, Tetrahedron Lett. 2005, 46, 5387–
5391; g) J. E. Yeo, X. Yang, H. J. Kim, S. Koo, Chem. Commun.
2004, 236–237; h) K. Y. Lee, S. Gowrisankar, N. Kim, Bull. Korean
Chem. Soc. 2005, 26, 1481–1490; i) S. Tekkam, M. A. Alam, S. C.
Jonnalagadda, V. R. Mereddy, Chem. Commun. 2011, 47, 3219–
3221; j) J. Q. Feng, X. Y. Lu, A. Kong, X. L. Han, Tetrahedron 2007,
63, 6035–6041; k) D. Basavaiah, S. Roy, Org. Lett. 2008, 10, 1819–
1822; l) L.-W. Ye, X. Han, X.-L. Sun, Y. Tang, Tetrahedron 2008, 64,
1487–1493; m) P. H. Mason, N. D. Emslie, Tetrahedron 1994, 50,
12001–12008.
[10] a) Y.-Q. Jiang, Y.-L. Shi, M. Shi, J. Am. Chem. Soc. 2008, 130, 7202–
7203; b) H.-P. Deng, Y. Wei, M. Shi, Adv. Synth. Catal. 2012, 354,
783–789; c) Y.-L. Yang, C.-K. Pei, M. Shi, Org. Biomol. Chem.
2011, 9, 3349–3358; d) L. Jiang, Q. Lei, X. Huang, H. L. Cui, X.
Zhou, Y.-C. Chun, Chem. Eur. J. 2011, 17, 9489–9493; e) X. Feng,
Y.-Q. Yuan, H.-L. Cui, K. Jiang, Y.-C. Chen, Org. Biomol. Chem.
2009, 7, 3660–3662; f) K. Jiang, J. Peng, H.-L. Cui, Y.-C. Chen,
Chem. Commun. 2009, 3955–3957; g) H.-L. Cui, X. Feng, J. Peng, J.
Lei, K. Jiang, Y.-C. Chen, Angew. Chem. 2009, 121, 5847–5850;
Angew. Chem. Int. Ed. 2009, 48, 5737–5740; h) J. Peng, X. Huang,
H.-L. Cui, Y.-C. Chen, Org. Lett. 2010, 12, 4260–4263; i) H.-L. Cui,
J. Peng, X. Feng, W. Du, K. Jiang, Y.-C. Chen, Chem. Eur. J. 2009,
15, 1574–1577; j) H.-L. Cui, J.-R. Huang, J. Lei, Z.-F. Wang, S.
Chen, L. Wu, Y.-C. Chen, Org. Lett. 2010, 12, 720–723; k) A. J. Lin,
H. B. Mao, X. Zhu, H. M. Ge, R. X. Tan, C. J. Zhu, Y. X. Cheng,
Chem. Eur. J. 2011, 17, 13676–13679; l) W. G. Yang, X. L. Wei,
Y. H. Pan, R. Lee, B. Zhu, H. J. Liu, L. Yan, K.-W. Huang, Z. Y.
Jiang, C.-H. Tan, Chem. Eur. J. 2011, 17, 8066–8070; m) F. R.
Zhong, X. Y. Han, Y. Q. Wang, Y. X. Lu, Angew. Chem. 2011, 123,
7983–7987; Angew. Chem. Int. Ed. 2011, 50, 7837–7841; n) G.-Y.
Chen, F. R. Zhong, Y. X. Lu, Org. Lett. 2011, 13, 6070–6073; o) Y.
Li, F. Liang, Q. Li, Y.-C. Xu, Q.-R. Wang, L. Jiang, Org. Lett. 2011,
[17] a) C.-J. Wang, G. Liang, Z.-Y. Xue, F. Gao, J. Am. Chem. Soc. 2008,
130, 17250–17251; b) C.-J. Wang, Z.-Y. Xue, G. Liang, Z. Lu, Chem.
Commun. 2009, 2905–2907; c) G. Liang, M.-C. Tong, C.-J. Wang,
Adv. Synth. Catal. 2009, 351, 3101–3106; d) Z.-Y. Xue, T.-L. Liu, Z.
Lu, H. Huang, H.-Y. Tao, C.-J. Wang, Chem. Commun. 2010, 46,
1727–1729; e) G. Liang, M.-C. Tong, H.-Y. Tao, C.-J. Wang, Adv.
Synth. Catal. 2010, 352, 1851–1855; f) Z.-Y. Xue, Q.-H. Li, H.-Y.
Tao, C.-J. Wang, J. Am. Chem. Soc. 2011, 133, 11757–11765; g) M.-
C. Tong, J. Li, H.-Y. Tao, Y.-X. Li, C.-J. Wang, Chem. Eur. J. 2011,
17, 12922–12927.
[18] a) J. M. Brunel, Chem. Rev. 2005, 105, 857 and J. M. Brunel, Chem.
Rev. 2007, 107, PR1; b) T. Akiyama, Chem. Rev. 2007, 107, 5744;
c) M. Terada, Chem. Commun. 2008, 4097.
[19] Crystal data for spiro-(4R,5R)-5: C19H20BrNO5, Mr =422.27, T=
293 K, monoclinic, space group P2(1), a=11.886(3), b=6.4413(17),
c=12.608(3) ꢅ, V=953.2(4) ꢅ3, Z=2, 3488 unique reflections, final
R1 =0.0340 and wR2 =0.1210 for 2555 observed [I>2s(I)] reflec-
tions, Flack c=0.015(12). CCDC-873311 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: April 28, 2012
Revised: June 16, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

C.-J. Wang et al.
Domino Reactions
H.-L. Teng, H. Huang,
C.-J. Wang* ................... &&&& — &&&&
Catalytic Asymmetric Construction of
Spiro(g-butyrolactam-g-butyrolactone)
Moieties through Sequential Reactions
of Cyclic Imino Esters with Morita–
Baylis–Hillman Bromides
Spiro(g-butyrolactam-g-butyrolac-
tone): A route to enantioenriched
spiro(g-butyrolactam-g-butyrolactone)
compounds, a valuable motif for drug
discovery, was developed by use of a
highly efficient copper(I)/TF-Bipham-
Phos-catalyzed tandem Michael addi-
tion–elimination of homoserine lactone
derived cyclic imino esters with
Morita–Baylis–Hillman (MBH) bro-
mides, followed by treatment with
para-toluenesulfonic acid (see
scheme).
&
6
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!