Transfer of Chirality in the Rhodium-Catalyzed Intramolecular Formal Hetero-[5 + 2] Cycloaddition of Vinyl Aziridines and Alkynes: Stereoselective Synthesis of Fused Azepine Derivatives

Article abstract of DOI:10.1021/jacs.5b01305

By taking advantage of vinyl aziridines as a heteroatom-containing five-atom component in rhodium-catalyzed intramolecular formal hetero-[5 + 2] cycloaddition reactions with alkynes, a highly efficient method for the synthesis of fused azepine derivatives

Full text of DOI:10.1021/jacs.5b01305

Communication
pubs.acs.org/JACS
Transfer of Chirality in the Rhodium-Catalyzed Intramolecular Formal
Hetero-[5 + 2] Cycloaddition of Vinyl Aziridines and Alkynes:
Stereoselective Synthesis of Fused Azepine Derivatives
Jian-Jun Feng, Tao-Yan Lin, Hai-Hong Wu, and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P. R. China
S
* Supporting Information
ABSTRACT: By taking advantage of vinyl aziridines as a
heteroatom-containing five-atom component in rhodium-
catalyzed intramolecular formal hetero-[5 + 2] cyclo-
addition reactions with alkynes, a highly efficient method
for the synthesis of fused azepine derivatives at 30 °C was
developed. The reaction has broad substrate scope and
tolerates a wide range of functional groups. The chirality of
vinyl aziridine-alkyne substrates can be completely trans-
ferred to the cycloadducts, representing an atom-economic
and enantiospecific protocol for the construction of fused
2,5-dihydroazepines for the first time.
Figure 1. Natural products featuring ring-fused azepines.
2,5-dihydroazepines in racemic form (Scheme 1a). However,
there are no examples of enantioselective cycloaddition for the
Scheme 1. Rhodium-Catalyzed Cycloaddition Strategy for
Constructing Fused Azepines
he cycloaddition reaction is one of the most powerful and
T
straightforward synthetic tools for the atom-economical
construction of cyclic skeletons in modern organic chemistry.1
However, as compared to those well-established cycloadditions
for synthesis of five- and six-membered ring systems, the
development of cycloadditions leading to seven-membered rings,
particularly seven-membered heterocycles such as azepine
derivatives, are still highly desirable, mainly due to the
unfavorable enthalpic and entropic reasons.2,3 Despite the
obstacles and challenges in this field, the almost continuous
identification of bioactive natural products that contain a seven-
membered azaheterocycle in the core structure has driven recent
interest.4 Therefore, a number of methodologies have been
developed for the synthesis of these azepine rings.5 For example,
the research group of Wender has done pioneering works on the
rhodium-catalyzed hetero-[5 + 2] cycloaddition of cyclopropyl
imines with electron-deficient alkyne, leading to a new route to
dihydroazepines.6 Subsequently, the groups of Li,7a Fiksdahl,7b
and France7c have realized some other novel formal [5 + 2]
cycloadditions of various precursors by using different transition-
metal catalysts. Alternatively, the formation of azepine products
by [4 + 3]8 and [3 + 2 + 2]9 cycloadditions have also been
developed, but only a few approaches exist for the preparation of
their ring-fused analogues, which represent a privileged structural
motif in many biologically active azepines such as fawcettimine,
tetrapetalone A, stemoamide, and akagerine (Figure 1).4 Thus,
the development of new cycloaddition reactions to access
polysubstituted, ring-fused azepines from readily available acyclic
precursors remains highly desirable. Of note, Sarpong8a and
Tang8b have independently demonstrated an elegant Rh(II)-
catalyzed formal [4 + 3] cycloaddition of dienyltriazoles through
the carbene intermediate, providing an efficient access to fused
construction of chiral azepines. Consequently, the synthesis of
enantiomerically pure azepines is in great demand in both
organic and medicinal chemistry. Herein, we report a new Rh(I)-
catalyzed intramolecular formal hetero-[5 + 2] cycloaddition of
optically pure vinyl aziridine-alkyne substrates for synthesis of
enantioenriched fused 2,5-dihydroazepines with high ee in
moderate to good yield through chirality transfer strategy
(Scheme 1b).
As a part of our continual program in the discovery of
rhodium-catalyzed cycloaddition reactions,10 we became inter-
ested in whether readily available optically pure vinyl aziridines11
could be employed in formal hetero-[5 + 2] cycloaddition with
unactivated alkynes. If this approach is successful, it will provide
an atom-economic and enantiospecific protocol access to
valuable chiral fused 2,5-dihydroazepines through chirality
transfer strategy. However, this hypothesis may face considerable
challenges such as (1) vinyl aziridines are commonly used as
three-atom components in [3 + 2] cycloadditions,12 and the
Received: February 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b01305
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
example of vinyl aziridines as five-atom components in [5 + 2]
cycloaddition with unactivated alkynes is extremely rare.13 (2)
vinyl aziridines easily undergo rearrangement14a and isomer-
ization14b to corresponding 3-pyrrolines and ketimines in the
presence of transition-metal catalysts.
To examine the above hypothesis, substrate (S)-1a was
selected as the model substrate, which can be easily prepared in
90% ee from commercially available D-serine methyl ester
hydrochloride. Initially, (S)-1a was treated with [Rh(CO)2Cl]2
in DCE at 80 °C for 15 h, resulting in the decomposition of
starting material (Table 1, entry 1). After several attempts, we
mmol), 5 mol % [Rh(NBD)2] BF4, 1,2-dichloroethane (DCE),
30 °C, and 3 h.
With the optimal reaction conditions in hand, we next
examined the scope of this cycloaddition by variation of the
substitution patterns on alkynes and aziridines moieties (Table
2). The alkyne substitution could be an aryl (2a-2c), heteroaryl
ab
,
Table 2. Exploration of Substrate Scope
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
[Rh(CO)2Cl]2
time (h) yield (%)
ee (%)
c
1
15
15
15
15
15
5
f
2
[Rh(η6-C10H8)(COD)] SbF6
[Rh(dnCOT)(MeCN)2] SbF6
RhCl(IPr)(COD)/AgSbF6
[Rh(NBD)dppe] BF4
[Rh(NBD)Cl]2/AgSbF6
[Rh(NBD)Cl]2/AgOTf
[Rh(NBD)Cl]2/AgPF6
[Rh(NBD)Cl]2/AgClO4
[Rh(NBD)Cl]2/C3F7CO2Ag
[Rh(NBD)2] BF4
92
40
92
56
99
99
92
88
47
99
99
99(90)
90
87
83
84
88
90
90
90
90
70
91
90
90
90
3
4
5
6
7
5
8
5
9
5
10
5
c
11
5
d
12
[Rh(NBD)2] BF4
3
e
13
[Rh(NBD)2] BF4
3
e
14
[Rh(COD)2] BF4
3
a
All reactions were carried out with 0.2 mmol of 1a and 5 mol % of
catalyst (Rh to AgSbF6 = 1:1) in 3.0 mL of 1,2-dichloroethane (DCE)
b
at 80 °C. NMR yield with CH2Br2 as an internal standard; values in
c
the parentheses are isolated yield. Ten mole percent of catalyst was
d
e
used. Reaction was run at 60 °C. Reaction was run at 30 °C.
f
Complex mixture.
were pleased to find that product (R)-2a could be obtained in
92% NMR yield and 87% ee in the presence of cationic [Rh(η6-
C10H8)(COD)]SbF6 catalyst (Table 1, entry 2). Subsequently, a
number of other cationic catalysts derived from weak counter-
anion, including [Rh(dnCOT)(MeCN)2]SbF6,3c [Rh(IPr)-
(COD)]SbF6, and [Rh(NBD)dppe]BF4 were tested, but leading
to lower ee values and yields (Table 1, entries 3−5). Gratifyingly,
we found that [Rh(NBD)Cl]2/AgSbF6 affords the desired
dihydroazepine in 99% NMR yield without loss of chirality
information (Table 1, entry 6). Different silver salts, such as
AgOTf, AgPF6, AgClO4, and C3F7CO2Ag were investigated
(Table 1, entries 7−10). Similar results were obtained with
[Rh(NBD)Cl]2/AgOTf and [Rh(NBD)Cl]2/AgPF6 catalysts
(Table 1, entries 7 and 8). Treatment of 1a with [Rh(NBD)Cl]2/
AgClO4 afford the product with lower yield (Table 1, entry 9).
Remarkably, the use of [Rh(NBD)Cl]2/C3F7CO2Ag bearing a
a
Standard conditions: [Rh(NBD)2]+BF4− (5 mol %), DCE (0.067 M),
b
30 °C, 3 h. Average isolated yield of the reactions from (S)-1 and its
enantiomer. The reaction was run at 80 °C for 4 h with 10 mol %
catalyst. The ee value of 1q can not be determined by HPLC analysis
c
d
using a chiral stationary phase.
(2d), alkyl (2e−2f), or cyclohexenyl group (2i). The hydroxyl
group in 2h was tolerated under the reaction conditions (2g
versus 2h). Notably, both internal and terminal alkynes were
compatible to afford the corresponding substituted fused 2,5-
dihydroazepine scaffolds (2j−2l), which is complementary to
Sarpong and Tang’s method.8a,b The structure and absolute
configuration of the product (S, R)-2l were established by X-ray
crystallographic analysis.15 The stereochemistry of other azepine
products was then assigned accordingly. A substrate (2k) bearing
two methyl groups at the propargylic position was also
successfully converted to the desired product. The reaction
remained efficient when the aziridines moiety was changed from
−
more nucleophilic counteranion C3F7CO2 resulted in both
lower yield and lower ee (Table 1, entry 10). Given that the
commercially available [Rh(NBD)2]BF4 showed the same good
performance as [Rh(NBD)Cl]2/AgSbF6 and the reaction
temperature can be reduced to 30 °C (Table 1, entries 11−
14), the final reaction conditions are described as follows: 1 (0.2
B
DOI: 10.1021/jacs.5b01305
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
methyl to n-propyl (2m and 2n), whereas substrate 1o
possessing isopropyl group on aziridine moiety afforded the
corresponding product 20 in moderate yield, but required
increased catalyst loading and reaction temperature. Importantly,
substrate 1p with trisubstituted alkene moiety reacted smoothly
at 80 °C to afford cycloadduct 2p without any detectable amount
of olefin isomerization. Substrates with a geminal diester or
oxygen tether in the 1,6-enyne yielded the corresponding
azepines successfully (2q−2t). It should be noted that
enantiomerically enriched substrate (+)-1 and (−)-1 was easily
prepared from the corresponding chiral aziridine aldehydes; its
absolute stereochemistry was determined by comparison with
known intermediates. Moderate to high yield and complete
chirality transfer could be achieved for substrate (+)-1 and (−)-1
respectively, under the standard conditions.
Scheme 3. Proposed Mechanism
Moreover, this stereospecific cycloaddition is easy to scale-up.
A gram-scale reaction of 1.2 g of (S, S)-1m (95% ee) was
subjected to the current reaction conditions with a reduced
catalyst loading (2 mol % Rh), delivering the corresponding
(S,R)-2m in 92% yield and 93% ee (Scheme 2a). To demonstrate
Scheme 2. Gram-Scale Reaction and Synthetic
Transformations
requires a syn alignment of the protons Hb and Hc along the C−C
bond, which is achieved through rotation around this bond to
give A-III and B−III. However, only the conformation of A-III
allow the C−N bond in the aziridine moiety to properly overlap
with the C−Rh bond as required for concerted ring expansion to
afford the species A-IV. Finally, reductive elimination from this
species produces the fused 2,5-dihydroazepine (R)-2a and
regenerates the rhodium catalyst. The observed highly efficient
chirality transfer is thus a consequence of the reversibility of the
initial mechanistic steps and the influence of the substituent on a
later step, putatively involving irreversible cleavage of the
aziridine. The stereospecificity with respect to (S)-1u is in
agreement with the model outlined in Scheme 3.
In summary, we have demonstrated that the chirality of vinyl
aziridine-alkyne substrates, which are readily available in optically
pure form, can be efficiently transferred to the fused 2,5-
dihydroazepine products of a formal hetero-[5 + 2] cyclo-
addition. This method provides strategically novel, atom-
economic, and mild access to the azepine architectures with
both excellent functional-group compatibility and high enantio-
selectivity (up to >99% ee). Moreover, the further trans-
formations of the products and mechanistic study have also
been carried out. The salient features of this transformation
include mild reaction conditions, readily available starting
materials, ease of scale-up, stereospecificity, general substrate
scope, and commercially available rhodium catalyst. Further
synthetic applications of this efficient transformation to the
synthesis of natural products and pharmaceutical agents are
currently in progress.
potential synthetic utilities of this protocol, the diastereoselective
dihydroxylation was realized with K2OsO4-2H2O/NMO, provid-
ing the corresponding (+)-4 and (−)-4 in 72% yield with 98% ee
and 93% ee, respectively. Alternatively, the disubstituted double
bond could be selectively hydrogenated to produce the
corresponding 3 in 91% yield with complete chirality transfer
(Scheme 2b).
To gain further insights into the reaction mechanism, we
prepared substrate (S)-1u with a Z-alkene moiety. However,
substrate (S)-1u was far less reactive than its E-siomer (S)-1a (eq
1). What’s more surprising, treatment of (S)-1u (97% ee) with 20
mol % [Rh(NBD)2] BF4 in DCE for 8 h at 80 °C gave (S)-2a
rather than (R)-2a in 38% NMR yield with 90% ee. On the basis
of the above chirality transfer experiment, we proposed a
plausible mechanism to account for this rhodium-catalyzed
stereospecific formal hetero-[5 + 2] cycloaddition (Scheme 3).
First, both the re-face and si-face of the carbon−carbon double
bond in (S)-1a could coordinate to the rhodium complex, which
lead to diastereomeric metallacyclopentenes A-II or B−II
formed by oxidative cyclometalation of the 1,6-enyne moiety.
The subsequent formation of a Z-olefin in A-IV and B−IV
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data for the substrates
and products (PDF), and crystallographic data (CIF) for (S,R)-
2l. This material is available free of charge via the Internet at
http://pubs.acs.org.
C
DOI: 10.1021/jacs.5b01305
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(d) Seto, M.; Aikawa, K.; Miyamoto, N.; Aramaki, Y.; Kanzaki, N.;
Takashima, K.; Kuze, Y.; Iizawa, Y.; Baba, M.; Shiraishi, M. J. Med. Chem.
2006, 49, 2037. For ring-closing metathesis, see: (e) Maier, M. E. Angew.
Chem., Int. Ed. 2000, 39, 2037. (f) Jakubec, P.; Hawkins, A.; Felzmann,
W.; Dixon, D. J. J. Am. Chem. Soc. 2012, 134, 17482. For ring-expansion
reactions through nitrogen transfer, see: (g) Bergen, T. J. V.; Kellogg, R.
M. J. Org. Chem. 1971, 36, 978. For condensation reaction, see:
(h) Finch, N.; Blanchard, L.; Werner, L. H. J. Org. Chem. 1977, 42, 3933.
For Heck coupling, see: (i) Qadir, M.; Cobb, J.; Sheldrake, P. W.;
Whittall, N.; White, A. J. P.; Hill, K. K.; Horton, P. N.; Hursthouse, M. B.
. J. Org. Chem. 2005, 70, 1545. For some related cycloprocesses, see:
(j) Shi, Z.; Grohmann, C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52,
5393. (k) Wang, L.; Huang, J.; Peng, S.; Liu, H.; Jiang, X.; Wang, J.
Angew. Chem., Int. Ed. 2013, 52, 1768. (l) Baktharaman, S.; Afagh, N.;
Vandersteen, A.; Yudin, A. K. Org. Lett. 2010, 12, 240. (m) Yin, G.; Zhu,
Y.; Lu, P.; Wang, Y. J. Org. Chem. 2011, 76, 8922.
(6) (a) Wender, P. A.; Pedersen, T. M.; Scanio, M. J. C. J. Am. Chem.
Soc. 2002, 124, 15154. (b) Merced Montero-Campillo, M.; Cabaleiro-
Lago, E. M.; Rodríguez-Otero, J. J. Phys. Chem. A 2008, 112, 9068.
(7) (a) Zhou, M.-B.; Song, R.-J.; Wang, C.-Y.; Li, J.-H. Angew. Chem.,
Int. Ed. 2013, 52, 10805. (b) Iqbal, N.; Fiksdahl, A. J. Org. Chem. 2013,
78, 7885. (c) Shenje, R.; Martin, M. C.; France, S. Angew. Chem., Int. Ed.
2014, 53, 13907.
(8) For selected papers on [4 + 3] cycloaddition routes to azepines,
see: (a) Schultz, E. E.; Lindsay, V. N. G.; Sarpong, R. Angew. Chem., Int.
Ed. 2014, 53, 9904. (b) Tian, Y.; Wang, Y.; Shang, H.; Xu, X.; Tang, Y.
Org. Biomol. Chem. 2015, 13, 612. (c) Shang, H.; Wang, Y.; Tian, Y.;
Fang, J.; Tang, Y. Angew. Chem., Int. Ed. 2014, 53, 5662. (d) Shapiro, N.
D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244. (e) Jeffrey, C. S.;
Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J. Am. Chem. Soc. 2011, 133,
7688. (f) Liu, K.; Teng, H.-L.; Wang, C.-J. Org. Lett. 2014, 16, 4508.
(9) Zhou, M.-B.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2014, 53,
4196.
(10) (a) Fan, L.; Zhao, W.; Jiang, W.; Zhang, J. Chem.Eur. J. 2008,
14, 9139. (b) Zhang, Y.; Chen, Z.; Xiao, Y.; Zhang, J. Chem.Eur. J.
2009, 15, 5208. (c) Zhao, W.; Zhang, J. Chem. Commun. 2010, 46, 7816.
(d) Zhao, W.; Zhang, J. Org. Lett. 2011, 13, 688. (e) Wang, T.; Wang, C.-
H.; Zhang, J. Chem. Commun. 2011, 47, 5578. (f) Feng, J.-J.; Zhang, J. J.
Am. Chem. Soc. 2011, 133, 7304.
(11) (a) Yudin, A. K., Ed. Aziridines and Epoxides in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2005. (b) Ohno, H. Chem. Rev.
2014, 114, 7784. (c) Mack, D. J.; Njardarson, J. T. ACS Catal. 2013, 3,
272.
(12) For examples of [3 + 2] cycloaddition reactions of vinyl aziridines
with alkenes, see: (a) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org.
Chem. 2002, 67, 5977. (b) Lowe, M. A.; Ostovar, M.; Ferrini, S.; Chen,
C. C.; Lawrence, P. G.; Fontana, F.; Calabrese, A. A.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2011, 50, 6370. (c) Hirner, J. J.; Roth, K. E.; Shi,
Y.; Blum, S. A. Organometallics 2012, 31, 6843. (d) Xu, C.-F.; Zheng, B.-
H.; Suo, J.-J.; Ding, C.-H.; Hou, X.-L. Angew. Chem., Int. Ed. 2015, 54,
1604.
(13) For two examples of N-unsubstituted 2-vinylaziridines with
activated electron-deficient alkyne to afford the azepines through a
tandem addition/aza-[3,3]-Claisen rearrangement reaction, see:
(a) Stogryn, E. L.; Brois, S. J. J. Am. Chem. Soc. 1967, 89, 605.
(b) Hassner, A.; D’Costa, R.; McPhail, A. T.; Butler, W. Tetrahedron Lett.
1981, 22, 3691.
AUTHOR INFORMATION
Corresponding Author
*jlzhang@chem.ecnu.edu.cn
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the funding support of Science and
Technology Commission of Shanghai Municipality
(15YF1403600), NSFC (21172074, 21373088, 21425205),
973 Program (2011CB808600), and the Program of Eastern
Scholar at Shanghai Institutions of Higher Learning.
REFERENCES
■
(1) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev.
1996, 96, 635. (b) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96,
49. (c) Yet, L. Chem. Rev. 2000, 100, 2963. (d) Aubert, C.; Buisine, O.;
Malacria, M. Chem. Rev. 2002, 102, 813. (e) Nakamura, I.; Yamamoto, Y.
Chem. Rev. 2004, 104, 2127. (f) Tanaka, K. Heterocycles 2012, 85, 1017.
(2) For special reviews on the cycloaddition reactions for the synthesis
of seven-membered carbocyclic rings, see: (a) Wender, P. A.; Bi, F. C.;
Gamber, G. G.; Gosselin, F.; Hubbard, R. D.; Scanio, M. J. C.; Sun, R.;
Williams, T. J.; Zhang, L. Pure Appl. Chem. 2002, 74, 25. (b) Pellissier, H.
Adv. Synth. Catal. 2011, 353, 189. (c) Ylijoki, K. E. O.; Stryker, J. M.
Chem. Rev. 2013, 113, 2244. (d) Harmata, M. Chem. Commun. 2010, 46,
8904. (e) Harmata, M. Chem. Commun. 2010, 46, 8886. (f) Battiste, M.
A.; Pelphrey, P. M.; Wright, D. L. Chem.Eur. J. 2006, 12, 3438.
(g) Butenschon, H. Angew. Chem., Int. Ed. 2008, 47, 5287. (h) Evans, P.
̈
A., Ed. Modern Rhodium-Catalyzed Organic Reactions; Wiley-VCH:
Weinheim, Germany, 2005. (i) Schienebeck, C. M.; Li, X.; Shu, X.-z.;
Tang, W. Pure Appl. Chem. 2014, 86, 409.
(3) For selected examples for discovery of new five-carbon synthons in
transition-metal catalyzed [5 + 2] cycloadditions, see: (a) Wender, P. A.;
Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720.
(b) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998, 120,
10976. (c) Wender, P. A.; Lesser, A. B.; Sirois, L. E. Angew. Chem., Int.
Ed. 2012, 51, 2736. (d) Wender, P. A.; Fournogerakis, D. N.; Jeffreys, M.
S.; Quiroz, R. V.; Inagaki, F.; Pfaffenbach, M. Nat. Chem. 2014, 6, 448.
(e) Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089. (f) Trost, B.
M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379. (g) Trost,
B. M.; Shen, H. C. Angew. Chem., Int. Ed. 2001, 40, 2313. (h) Trost, B.
M.; Shen, H. C.; Horne, D. B.; Toste, F. D.; Steinmetz, B. G.; Koradin, C.
Chem.Eur. J. 2005, 11, 2577. (i) Hong, X.; Trost, B. M.; Houk, K. N. J.
Am. Chem. Soc. 2013, 135, 6588. (j) Zuo, G.; Louie, J. J. Am. Chem. Soc.
2005, 127, 5798. (k) Furstner, A.; Majima, K.; Martin, R.; Krause, H.;
̈
Kattnig, E.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130,
1992. (l) Jiao, L.; Ye, S.; Yu, Z.-X. J. Am. Chem. Soc. 2008, 130, 7178.
(m) Jiao, L.; Yu, Z.-X. J. Org. Chem. 2013, 78, 6842. (n) Shu, X.-z.;
Huang, S.; Shu, D.; Guzei, I. A.; Tang, W. Angew. Chem., Int. Ed. 2011,
50, 8153. (o) Shu, X.-z.; Schienebeck, C. M.; Song, W.; Guzei, I. A.;
Tang, W. Angew. Chem., Int. Ed. 2013, 52, 13601. (p) Shu, X.-z.; Li, X.;
Shu, D.; Huang, S.; Schienebeck, C. M.; Zhou, Xin.; Robichaux, P. J.;
Tang, W. J. Am. Chem. Soc. 2012, 134, 5211. (q) Xu, X.; Liu, P.; Shu, X.-
z.; Tang, W.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 9271.
́
(4) (a) Vaquero, J. J.; Cuadro, A. M.; Herradon, B. Modern Heterocyclic
(14) (a) Ilardi, E. A.; Njardarson, J. T. J. Org. Chem. 2013, 78, 9533.
(b) Wolfe, J. P.; Ney, J. E. Org. Lett. 2003, 5, 4607.
(15) CCDC 1047219 ((S,R)-2l).
Chemistry; Wiley-VCH: Weinheim, Germany, 2011. (b) Renfroe, B.;
Harrington, C.; Proctor, G. R. Heterocyclic Compounds: Azepines; Wiley
& Interscience: New York, 1984. (c) Sakata, K.; Aoki, K.; Chang, C.-F.;
Sakurai, A.; Tamura, S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457.
̀
(d) Habermann, J.; Capito, E.; Ferreira, M. d. R. R.; Koch, U.; Narjes, F.
Bioorg. Med. Chem. Lett. 2009, 19, 633.
(5) Representative classical methods for azepine synthesis: for radical
addition, see: (a) Yet, L. Tetrahedron 1999, 55, 9349. (b) Masse, C. E.;
Morgan, A. J.; Panek, J. S. Org. Lett. 2000, 2, 2571. For nitrene insertion
or diene-conjugated nitrile ylide cyclization, see: (c) Katritzky, A. R., II,
Ed. Comprehensive Heterocyclic Chemistry; Pergamon: New York, 1996;
Vol. 9, p 21. For intramolecular Clasien−Schmidt cyclization, see:.
D
DOI: 10.1021/jacs.5b01305
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX