Catalytic Enantioselective Synthesis of 2,5-Dihydrooxepines

Article abstract of DOI:10.1002/anie.201700890

A Michael addition initiated cyclopropanation/retro-Claisen rearrangement tandem reaction was developed for the enantioselective synthesis of highly functionalized 2,5-dihydrooxepines. In the presence of a chiral oxazaborolidinium ion (COBI) catalyst, the reaction proceeds to give good yields and high enantioselectivity.

Full text of DOI:10.1002/anie.201700890

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700890
German Edition: DOI: 10.1002/ange.201700890
Heterocycles Very Important Paper
Catalytic Enantioselective Synthesis of 2,5-Dihydrooxepines
Su Yong Shim, Soo Min Cho, Anipireddy Venkateswarlu, and Do Hyun Ryu*
Abstract: A Michael addition initiated cyclopropanation/
retro-Claisen rearrangement tandem reaction was developed
for the enantioselective synthesis of highly functionalized 2,5-
dihydrooxepines. In the presence of a chiral oxazaborolidi-
nium ion (COBI) catalyst, the reaction proceeds to give good
yields and high enantioselectivity.
tion are rare.[4c] Indeed, using this approach for the formation
of oxepine derivatives is discouraged due to the multiple steps
required to prepare chiral cis-1-formyl-2-vinylcyclopropanes
(FVCs) for such a rearrangement reactions.[6]
Recently, our group has reported highly enantioselective
catalytic Michael addition initiated cyclopropanations[7] using
diazoesters as ylides with the chiral oxazaborolidinium ion[8]
(COBI) as a Lewis acid catalyst. We envisioned that the
reaction of substituted acroleins with vinyldiazoester would
generate chiral cis-1-formyl-2-vinylcyclopropanes (FVCs; 1),
which are ideally substituted for subsequent retro-Claisen
rearrangement to provide highly functionalized 2,5-dihy-
drooxepines (2; Scheme 1).
Oxepine and hydrooxepine derivatives form the structural
core of numerous naturally occurring biologically active
compounds and present interesting challenges as potential
synthetic targets (Figure 1).[1] While a variety of synthetic
Scheme 1. Asymmetric tandem cyclopropanation/retro-Claisen rear-
rangement to provide 2,5-dihydrooxepines.
Figure 1. Natural products containing oxepine and hydrooxepine sub-
structures.
Although cis-FVCs 1 and 2,5-dihydrooxepines 2 are
known to be in equilibrium that generally favors 1, the
equilibrium could be controlled to favor 2 by using p-
stabilizing substituents such as the COR4 or R1 groups
(Scheme 1).[4c,6a–b,9] To the best of our knowledge, a catalytic
asymmetric synthetic method to prepare dihydrooxepine
derivatives has not been reported to date. In this communi-
cation, we describe the first example of a catalytic asymmetric
formation of 2,5-dihydrooxepines through tandem cyclopro-
panation/retro-Claisen rearrangement from the simple start-
ing materials acrolein derivatives and vinyldiazo com-
pounds.[10]
methods have been developed through the years for their
synthesis,[2–6] few approaches exist for the preparation of
enantioenriched hydrooxepines from achiral starting materi-
als.[4] The development of new stereoselective methods to
access substituted hydrooxepines from simple, achiral starting
materials is thus highly desirable. [3,3]-Sigmatropic rear-
rangement is an efficient strategy to access dihydrooxepines
in a stereospecific manner.[5,6] Cope rearrangement of 1,2-
divinyl epoxides provides 4,5-dihydrooxepine derivatives.[5]
similar transformation with cyclopropane derivatives where
A
=
one of the vinyl groups is replaced with a C O group, known
Enantioselective formation of 2,5-dihydrooxepine was
first examined with a-bromoacrolein and g-methyl-a-vinyl
diazoester in the presence of COBI catalyst 3a. When the
reaction was carried out at À788C in propionitrile, chiral 2,5-
dihydrooxepine 2a was formed in 50% yield with 58% ee
(Table 1, entry 1). At the same time, 48% of trans-FVC 1a
was isolated, which was confirmed by 1D NOE experiments
as having a trans relationship between the aldehyde and olefin
(path b). Interestingly, while there are some reports that high
temperature is required for retro-Claisen rearrangement,[4c]
otherwise mixtures of cis-FVC and 2,5-dihydrooxepine
form,[6b–c,9b–c] cis-FVC 1a was not observed with these reaction
conditions. It appeared that all of the cis-FVC 1a was
as the retro-Claisen rearrangement, leads to 2,5-dihydroox-
epine derivatives through an analogous mechanism.[6] While
retro-Claisen rearrangements of this type are quite common
for 2,5-dihydrooxepines, asymmetric examples of this reac-
[*] S. Y. Shim, S. M. Cho, A. Venkateswarlu, Prof. Dr. D. H. Ryu
Department of Chemistry, Sungkyunkwan University
Suwon 440-746 (Korea)
E-mail: dhryu@skku.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201700890.
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Table 1: Optimization of enantioselective 2,5-dihydrooxepine forma-
Table 2: Enantioselective 2,5-dihydrooxepine formation from a-bro-
moacrolein and various a-vinyldiazoesters.[a]
tion.[a]
Entry
2
R
X
Yield[b] [%]
ee[c] [%]
1
2
3
4
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Me
Me
Et
Bn
n-Hex
i-Pr
t-Bu
Ph
3-ClPh
3-MePh
4-FPh
4-BrPh
OtBu
NMe(OMe)
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
82
72
84
78
64
80
56
75
80
85
86
73
96
95
95
93
90
98
93[e]
97
91
90[e]
99
98
5[d]
6
Entry
Solvent
Cat.
2a/trans-1a[b]
Yield[c] [%]
ee[d] [%]
7
8[d]
9[f]
10[f]
11[f]
12[d]
1
2
3
4
5
6
EtCN
EtCN
EtCN
CH2Cl2
PhMe
EtCN
3a
3b
3c
3c
3c
3d
1:1
1.6:1
1.7:1
1.7:1
1:1
50
60
62
63
51
82
58
86
97
92
85
96
2j
2k
2l
OtBu
OtBu
OtBu
[a] Except for entries 1–3, the reactions of a-vinyldiazoesters (0.2 mmol)
with a-bromoacrolein (0.3 mmol) were performed in the presence of
catalyst 3d (20 mol%) in 1.0 mL of solvent at À788C for 2 h. [b] Yield of
isolated 2,5-dihydrooxepine; 5–10% of the trans-cyclopropane was also
isolated. [c] ee determined by chiral HPLC. [d] 0.5m diazo solution was
used. [e] ee determined by chiral HPLC after reduction of the ester to the
corresponding aldehyde with DIBAL-H. [f] 30 mol% catalyst was used.
9:1
[a] The reactions of g-methyl-a-vinyldiazoester (0.3 mmol) with a-
bromoacrolein (0.2 mmol) were performed in the presence of catalyst 3
(20 mol%) in 1.0 mL of solvent at À788C for 2 h. [b] Determined by
1H NMR analysis of the crude reaction mixture. [c] Yield of isolated
product 2a. [d] ee of 2a determined by chiral HPLC.
immediately transformed into 2,5-dihydrooxepine 2a through
retro-Claisen rearrangement at low temperature (path a). To
improve the yield and ee of 2a, we optimized the catalyst
structure and solvent. The effect of changing the boracycle
catalyst substituents was investigated. Gratifyingly, using
catalyst 3b, which has an o-tolyl substituent at the boron
center, greatly improved the enantioselectivity to 86% with
a small increase in yield (entry 2). When a 3,5-dimethylphenyl
Ar substituent was used, the desired product was obtained
with 97% ee albeit in moderate yield (entry 3). Use of
dichloromethane or toluene as the solvent was found to be
less effective than using propionitrile (entries 4–5). The
sterically hindered catalyst system 3d, which has a 3,5-
dimethylphenyl Ar substituent and an isopropyl R substitu-
ent, gave the best result (entry 6). The yield of 2,5-dihydroox-
epine 2a was dramatically improved to 82% with an excellent
96% ee.
After optimization of the enantioselective formation of
2,5-dihydrooxepine 2a, we then evaluated the scope of this
reaction using various g-substituted a-vinyldiazo compounds
(Table 2). Various g-alkyl-a-vinyl diazo compounds were
successfully applied, resulting in high yields and excellent
enantioselectivity (entries 1–7). Considering other the possi-
ble reaction pathways, such as 1,2-hydride shift,[8d,11] 1,3-
dipolar cycloaddition[12] and Roskamp reaction,[8a–c,13] the
yields obtained for the 2,5-dihydrooxepines are remarkable.
This catalytic system was also successfully applied to the
reaction of a-vinyl a-diazo Weinreb amide to furnish highly
optically active 2,5-dihydrooxepine 2b in 72% yield and 95%
ee (entry 2). Notably, diazo compounds with a long alkyl chain
or a sterically hindered alkyl group successfully reacted with
a-bromoacrolein to provide the corresponding 2,5-dihydroox-
epine products in moderate to high yield and excellent ee
(entries 5–7). While the reactivity of g-aryl-a-vinyldiazoesters
was lower than that of g-alkyl-a-vinyldiazoesters, enantiose-
lective formation of chiral 2,5-dihydrooxepines with aryl
substituents proceeded with high yields and excellent enan-
tioselectivity up to 99% (entries 8–12).
Encouraged by the good results illustrated in Table 2, we
next investigated the scope with respect to a- or a,b-
substituted acrolein compounds (Table 3). Regardless of the
electronic or steric properties of the a-substituents on the
acrolein, highly optically active 2,5-dihydrooxepines 2 were
obtained in moderate to good yields (entries 1–7). Among the
a-halogen-substituted compounds, a-bromoacrolein was the
best substrate, providing 2,5-dihydrooxepine 2a in 82% yield
with 96% ee (Table 3, entries 1–4). Asymmetric 2,5-dihy-
drooxepine formation with alkyl or phenyl groups also
proceeded with good enantiocontrol, although the yields
were not as high (entries 5–8).[7a] Interestingly, some a-
alkylacroleins required higher temperature for the retro-
Claisen rearrangement of the cis-FVC 1 to the 2,5-dihydroox-
epine 2 (entries 5–6). The catalytic asymmetric reaction with
a,b-disubstituted acroleins was attempted in order to obtain
highly functionalized chiral 2,5-dihydrooxepines containing
two stereogenic centers. Remarkably, the reaction with a-
bromo-b-methylacrolein proceeded well to give 6-bromo-2,5-
dimethyl-2,5-dihydrooxepine (2t) in good yield with com-
plete control of the enantio- and diastereoselectivity (Table 3,
entry 9). The relative and absolute configurations of 2t were
unambiguously established by X-ray crystallographic analysis
(Figure 2), and the configurations for all other products are
based on this assignment by analogy. Under the optimized
2
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Table 3: Enantioselective 2,5-dihydrooxepine formation from g-methyl-a-
vinyldiazoester and various substituted acroleins.[a]
Entry
2
X
Y
Yield[b] [%]
ee[c] [%]
1
2
2a
2m
2n
2o
2p
2q
2r
2s
2t
2u
Br
Cl
Cl
I
Me
Bn
n-Pen
Ph
Br
H
H
H
H
H
H
H
H
Me
Et
82
67
71
74
60
52
63
58
82
65
96
97
>99
93
95
87
94
76
>99
96
3[d]
4
5[e]
6[f]
7
Figure 3. Transition-state model for the enantioselective formation of
2,5-dihydrooxepines as catalyzed by 3d.
8
9[g]
10[g]
Br
[a] The reactions of g-methyl-a-vinyldiazoester (0.3 mmol) with acroleins
(0.2 mmol) were performed in the presence of catalyst 3d (20 mol%) in
1.0 mL of solvent at À788C for 2 h. [b] Yield of isolated 2,5-dihydroox-
epine; 5–10% of the trans-cyclopropane was also isolated. [c] ee
determined by chiral HPLC. [d] g-phenyl-a-vinyldiazoester was used.
[e] Reaction temperature was allowed to warm to 08C over 4 h and kept
for another 1 h. [f] Reaction temperature was allowed to warm to room
temperature over 4 h and kept for another 1 h. [g] d.r. determined by
1H NMR analysis of the crude reaction mixture; a single diastereomer
was obtained.
conditions, the reaction with a-bromo-b-ethylacrolein pro-
vided the corresponding 2,5-dihydrooxepine 2u with excel-
lent enantio- and diastereoselectivity, although in moderate
yield (Table 3, entry 10).
Scheme 2. Derivatization of 2,5-dihydrooxepines.
The observed stereochemistry for the enantioselective
formation of 2,5-dihydrooxepine with COBI catalyst 3d can
be rationalized on the basis of the transition-state model
shown in Figure 3. The coordination mode of the acrolein to
catalyst 3d is the same as that previously observed for
enantioselective cyclopropanation reactions.[7] After asym-
metric cyclopropanation between the a-bromoacrolein and a-
vinyldiazo compound, the resulting cyclopropane 1 shows cis
geometry between the aldehyde and olefin groups. The
intermediate cyclopropane cis-FVC 1 is immediately con-
verted into cis-(2S,5R)-2,5-dihydrooxepine as the major
enantiomer for 2t. The absolute configuration of cis-
Scheme 2. Stille coupling reaction of 2a with the correspond-
ing tin reagents successfully introduced alkynyl (5a) and
heteroaromatic (5b) groups in high yields without an obvious
loss of enantiopurity. Suzuki coupling with vinylboronic acid
pinacol ester and Pd(OAc)2 produced 6 in 71% yield. In
addition, chemoselective conjugate reduction with a carbene-
copper complex[15] provided tetrahydrooxepine 7 with one
additional chiral center as a 1.7:1 mixture of diastereomers in
high yield.
In summary, the first example of a highly enantiocon-
trolled catalytic formation of 2,5-dihydrooxepine has been
developed. This tandem cyclopropanation/retro-Claisen rear-
rangement reaction gives highly functionalized 2,5-dihy-
drooxepines in a single step with excellent enantioselectivity.
The resulting 6-bromo-2,5-dihydrooxepines can easily be
converted into various hydrooxepine derivatives with
alkyne, heteroaromatic, and vinyl functional groups without
loss of optical purity. We believe that the resulting chiral 2,5-
dihydrooxepines could be highly valuable intermediates for
the synthesis of useful complex molecules.
(2S,5R)-6-bromo-2,5-dimethyl-2,5-dihydrooxepine
(2t;
Table 3, entry 9) supports the rearrangement proceeding in
a concerted manner via boat-like transition state 4, as several
DFT calculations have reported.[6c,14]
Further chemical transformations of the resulting opti-
cally active 6-bromo-2,5-dihydrooxepine are illustrated in
Acknowledgements
This work was supported by the National Research Founda-
tion of Korea (NRF) grants funded by the Korean govern-
ment (MSIP) (No. NRF-2016R1A2B3007119, No.
2016R1A4A1011451).
Figure 2. X-ray structure of 2t.
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33, 438 – 439; g) W.-N. Chou, J. B. White, W. B. Smith, J. Am.
Chem. Soc. 1992, 114, 4658 – 4667; h) D. L. Clark, W.-N. Chou,
J. B. White, J. Org. Chem. 1990, 55, 3975 – 3977; i) R. A. Aitken,
J. I. G. Cadogan, I. Gosney, B. J. Hamill, L. M. McLaughlin, J.
Chem. Soc. Chem. Commun. 1982, 1164 – 1165; j) J. C. Pomme-
let, N. Manisse, J. Chuche, Tetrahedron 1972, 28, 3929 – 3941;
k) E. L. Stogryn, M. H. Hianni, A. J. Passannante, J. Org. Chem.
1964, 29, 1275 – 1276.
Conflict of interest
The authors declare no conflict of interest.
Keywords: enantioselectivity · heterocycles · hydrooxepines ·
Lewis acids · rearrangement reactions
[6] a) B. Hofmann, H.-U. Reissig, Chem. Ber. 1994, 127, 2327 – 2335;
b) R. K. Boeckman, Jr., M. D. Shair, J. R. Vargas, L. A. Stolz, J.
Org. Chem. 1993, 58, 1295 – 1297; c) B. Hofmann, H.-U. Reissig,
Synlett 1993, 27 – 29.
[7] a) S. Y. Shim, J. Y. Kim, M. Nam, G.-S. Hwang, D. H. Ryu, Org.
Lett. 2016, 18, 160 – 163; b) L. Gao, G.-S. Hwang, D. H. Ryu, J.
Am. Chem. Soc. 2011, 133, 20708 – 20711.
[8] Selected recent examples for asymmetric reactions with COBI
catalysts: a) B. C. Kang, D. G. Nam, G.-S. Hwang, D. H. Ryu,
Org. Lett. 2015, 17, 4810 – 4813; b) S. H. Shin, E. H. Baek, G.-S.
Hwang, D. H. Ryu, Org. Lett. 2015, 17, 4746 – 4749; c) L. Gao,
B. C. Kang, D. H. Ryu, J. Am. Chem. Soc. 2013, 135, 14556 –
14559; d) S. I. Lee, G.-S. Hwang, D. H. Ryu, J. Am. Chem. Soc.
2013, 135, 7126 – 7129; e) L. Gao, B. C. Kang, G.-S. Hwang, D. H.
Ryu, Angew. Chem. Int. Ed. 2012, 51, 8322 – 8325; Angew. Chem.
2012, 124, 8447 – 8450; f) B. K. Senapati, G.-S. Hwang, S. I. Lee,
D. H. Ryu, Angew. Chem. Int. Ed. 2009, 48, 4398 – 4401; Angew.
Chem. 2009, 121, 4462 – 4465; g) E. J. Corey, Angew. Chem. Int.
Ed. 2009, 48, 2100 – 2117; Angew. Chem. 2009, 121, 2134 – 2151;
h) E. J. Corey, T. Shibata, T. W. Lee, J. Am. Chem. Soc. 2002, 124,
3808 – 3809; i) D. H. Ryu, T. W. Lee, E. J. Corey, J. Am. Chem.
Soc. 2002, 124, 9992 – 9993.
[1] Reviews on the synthesis, properties, reactivity, and natural
occurrences of oxepine and dihydrooxepine derivatives: a) J. J.
Vaquero, A. M. Cuadro, B. Herradꢀn, Modern Heterocyclic
Chemistry, Wiley-VCH, Weinheim, 2011, pp. 1865 – 1988; b) L. I.
Belenꢁkii, Comprehensive Heterocyclic Chemistry III, Vol. 13
(Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor), Elsevier, Oxford, 2008, pp. 45 – 95; c) D. L. Riley,
W. A. L. van Otterlo, Heterocycles in Natural Product Synthesis
(Eds.: K. C. Majumdar, S. K. Chattopadhyay), Wiley-VCH,
Weinheim, 2011, pp. 537 – 549; d) D. J. Faulkner, Nat. Prod.
Rep. 1987, 4, 539 – 576.
[2] Reviews on the synthesis of oxepine and dihydrooxepine
derivatives: a) J. O. Hoberg, Tetrahedron 1998, 54, 12631 –
12670; b) N. L. Snyder, H. M. Haines, M. W. Peczuh, Tetrahe-
dron 2006, 62, 9301 – 9320; c) L. Yet, Chem. Rev. 2000, 100,
2963 – 3007; d) S. K. Chattopadhyay, S. Karmakar, T. Biswas,
K. C. Majumdar, H. Rahaman, B. Roy, Tetrahedron 2007, 63,
3919 – 3952.
[3] Recent selected examples for the synthesis of oxepine and
dihydrooxepine derivatives: a) S. Hosseyni, L. Wojtas, M. Li, X.
Shi, J. Am. Chem. Soc. 2016, 138, 3994 – 3997; b) K. C. Nicolaou,
R. Yu, L. Shi, Q. Cai, M. Lu, P. Heretsch, Org. Lett. 2013, 15,
1994 – 1997; c) H. Fujiwara, T. Kurogi, S. Okaya, K. Okano, H.
Tokuyama, Angew. Chem. Int. Ed. 2012, 51, 13062 – 13065;
Angew. Chem. 2012, 124, 13239 – 13242; d) B. P. Machin, B. L.
Pagenkopf, Synlett 2011, 2799 – 2802; e) A. Varela-Fernꢂndez,
C. G. -Yebra, J. A. Varela, M. A. Esteruelas, C. Saꢂ, Angew.
Chem. Int. Ed. 2010, 49, 4278 – 4281; Angew. Chem. 2010, 122,
4374 – 4377; f) U. Gross, M. Nieger, S. Brꢃse, Chem. Eur. J. 2010,
16, 11624 – 11631; g) M. Bruder, P. L. Haseler, M. Muscarella, W.
Lewis, C. J. Moody, J. Org. Chem. 2010, 75, 353 – 358; h) S.
Yamaguchi, Heterocycles 2009, 79, 243 – 263; i) J. Peng, D. L. J.
Clive, Org. Lett. 2007, 9, 2939 – 2941; j) A. J. Leyhane, M. L.
Snapper, Org. Lett. 2006, 8, 5183 – 5186; k) A. Seoane, N.
Casanova, N. QuiÇones, J. L. MascareÇas, M. Gulꢄas, J. Am.
Chem. Soc. 2014, 136, 834 – 837.
[4] a) X.-G. Song, S.-F. Zhu, X.-L. Xie, Q.-L. Zhou, Angew. Chem.
Int. Ed. 2013, 52, 2555 – 2558; Angew. Chem. 2013, 125, 2615 –
2618; b) J. A. Codelli, A. L. A. Puchlopek, S. E. Reisman, J. Am.
Chem. Soc. 2012, 134, 1930 – 1933; c) C. G. Nasveschuk, T. Rovis,
Angew. Chem. Int. Ed. 2005, 44, 3264 – 3267; Angew. Chem. 2005,
117, 3328 – 3331.
[5] a) A. Cameron, B. Fisher, N. Fisk, J. Hummel, J. M. White, E. H.
Krenske, M. A. Rizzacasa, Org. Lett. 2015, 17, 5998 – 6001; b) S.
Krꢅger, T. Gaich, Beilstein J. Org. Chem. 2014, 10, 163 – 193;
c) X. Xu, W.-H. Hu, P. Y. Zavalij, M. P. Doyle, Angew. Chem. Int.
Ed. 2011, 50, 11152 – 11155; Angew. Chem. 2011, 123, 11348 –
11351; d) K. C. Nicolaou, M. Lu, S. Totokotsopoulos, P.
Heretsch, D. Giguꢆre, Y.-P. Sun, D. Sarlah, T. H. Nguyen, I. C.
Wolf, D. F. Smee, C. W. Day, S. Bopp, E. A. Winzeler, J. Am.
Chem. Soc. 2012, 134, 17320 – 17332; e) M. Shimizu, T. Fujimoto,
X. Liu, Y. Takeda, T. Hiyama, Heterocycles 2008, 76, 329 – 351;
f) M. Shimizu, T. Fujimoto, X. Liu, T. Hiyama, Chem. Lett. 2004,
[9] Equilibrium between cis-FVC (1) and 2,5-dihydrooxepine 2 has
been studied for decades: a) S. J. Rhoade, N. R. Raulins, Org.
React. 1975, 22, 1; b) D. Sperling, H.-U. Reissig, J. Fabian, Eur. J.
Org. Chem. 1999, 1107 – 1114; c) D. Sperling, H.-U. Reissig, J.
Fabian, Liebigs Ann./Recueil 1997, 2443 – 2449; d) S. J. Rhoads,
R. D. Cockroft, J. Am. Chem. Soc. 1969, 91, 2815 – 2816.
[10] a-vinyldiazo compounds exhibit reasonable stability and have
been used as starting material for years: a) G. Xu, C. Zhu, W. Gu,
J. Li, J. Sun, Angew. Chem. Int. Ed. 2015, 54, 883 – 887; Angew.
Chem. 2015, 127, 897 – 901; b) C. Qin, H. M. L. Davies, J. Am.
Chem. Soc. 2013, 135, 14516 – 14519; c) Z. Li, B. T. Parr, H. M. L.
Davies, J. Am. Chem. Soc. 2012, 134, 10942 – 10946; d) H. M. L.
Davies, A. M. Walji, Angew. Chem. Int. Ed. 2005, 44, 1733 –
1735; Angew. Chem. 2005, 117, 1761 – 1763; e) H. M. L. Davies,
B. Xiang, N. Kong, D. G. Stafford, J. Am. Chem. Soc. 2001, 123,
7461 – 7462.
[11] a) S. I. Lee, B. C. Kang, G.-S. Hwang, D. H. Ryu, Org. Lett. 2013,
15, 1428 – 1431; b) T. Hashimoto, Y. Naganawa, T. Kano, K.
Maruoka, Chem. Commun. 2007, 5143 – 5145.
[12] a) T. Kano, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2006,
128, 2174 – 2175; b) L. Gao, G.-S. Hwang, M. Y. Lee, D. H. Ryu,
Chem. Commun. 2009, 5460 – 5462; c) S. I. Lee, K. E. Kim, G.-S.
Hwang, D. H. Ryu, Org. Biomol. Chem. 2015, 13, 2745 – 2749;
d) M. P. Sibi, L. M. Stanley, T. Soeta, Org. Lett. 2007, 9, 1553 –
1556.
[13] W. Li, J. Wang, X. Hu, K. Shen, W. Wang, Y. Chu, L. Lin, X. Liu,
X. Feng, J. Am. Chem. Soc. 2010, 132, 8532 – 8533.
˙
[14] a) M. Zora, J. Org. Chem. 2005, 70, 6018 – 6026; b) I. ꢇzkan, M.
Zora, J. Org. Chem. 2003, 68, 9635 – 9642.
[15] J. Yun, D. Kim, H. Yun, Chem. Commun. 2005, 5181 – 5183.
Manuscript received: January 25, 2017
Final Article published: && &&, &&&&
4
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Heterocycles
S. Y. Shim, S. M. Cho, A. Venkateswarlu,
D. H. Ryu*
&&&& — &&&&
Catalytic Enantioselective Synthesis of
2,5-Dihydrooxepines
I get a round: A Michael addition initiated
cyclopropanation/retro-Claisen rear-
rangement tandem reaction was devel-
oped for the enantioselective synthesis of
highly functionalized 2,5-dihydrooxe-
pines. In the presence of a chiral oxaza-
borolidinium ion (COBI) catalyst, the
reaction proceeds to give good yields and
high enantioselectivity.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!