Remote chiral induction in vinyl sulfonium salt-mediated ring expansion of hemiaminals into epoxide-fused azepines

Article abstract of DOI:10.1002/asia.201000817

The planet of the azepines: Epoxy-fused azepines have been synthesized in a highly selective reaction with hemiaminals and vinyl sulfonium salts. Stereochemistry is controlled by the substituent at the four- or five-position of the hemiaminal. The key step involves ring-opening of the hemiaminal, conjugate addition onto a vinyl sulfonium salt, and epoxidation of the aldehyde by the in situ formed sulfur ylide. Copyright

Full text of DOI:10.1002/asia.201000817

COMMUNICATION
DOI: 10.1002/asia.201000817
Remote Chiral Induction in Vinyl Sulfonium Salt-Mediated Ring Expansion
of Hemiaminals into Epoxide-Fused Azepines
Muhammad Yar, Matthew G. Unthank, Eoghan M. McGarrigle,* and
Varinder K. Aggarwal*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Perhydroazepines,[1] seven-membered ring nitrogen het-
erocycles, have attracted considerable attention from the
synthetic community due to their significant biological activ-
ity. In particular, the discovery that (À)-balanol 1 was a
potent protein kinase C inhibitor acted as a springboard to a
broader study of related analogues.[2–5] For example, the
seven-substituted azepine SB-462795 2[3,4] was found to be a
potent cathepsin K inhibitor and so has potential application
in the treatment of osteoporosis. Thus, there is considerable
interest in the synthesis of substituted perhydroazepines
bearing suitable functionality for further manipulation.[1,3–5]
As part of our ongoing research on the chemistry of vinyl
sulfonium salts,[6,7] we recently reported a new route to per-
hydroazepines, which involves ring expansion of a hemiami-
nal (Scheme 1).[6a,8] The process involves ring opening of the
Scheme 1. Proposed pathway for a vinyl sulfonium salt mediated annula-
tion reaction for the synthesis of epoxide-fused N-heterocycles from hem-
iaminals.
hemiaminal 3 to the aminoaldehyde 4, conjugate addition of
the amide to the vinyl sulfonium salt 5 to form a sulfur ylide
6, followed by ring-closure to the betaine 7, and finally cycli-
zation to the epoxide. Due to the significant interest in sub-
stituted azepines, we investigated the effect of substituents
on the hemiaminal ring on the course of the reaction. In this
paper, we report that sterically encumbered substituents can
lead to very high diastereocontrol in the formation of substi-
tuted epoxy azepines, thereby providing a rapid entry into
substituted and functionalized azepines.
We began our studies with the 5-methyl-substituted hemi-
aminal 3a, which was synthesized from commercially avail-
able 5-methyl-2-pyrrolidone in two steps.[9] The 5-methyl
hemiaminal 3a was then treated with an excess of diphenyl
vinyl sulfonium salt 5 in the presence of 1,8-diazabicyclo-
[a] Dr. M. Yar,+ Dr. M. G. Unthank, Dr. E. M. McGarrigle,
Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantockꢀs Close, Bristol BS8 1TS (UK)
Fax : (+44)117-925-1295
E-mail: V.Aggarwal@bristol.ac.uk
[+] Current address:
Department of Chemistry
King Fahd University of Petroleum & Minerals
P.O. Box 1347, Dhahran 31261 (Saudi Arabia)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000817.
AHCTUNGTREG[NNNU 5.4.0]undec-7-ene (DBU) in a range of solvents, from non-
372
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Chem. Asian J. 2011, 6, 372 – 375

polar toluene to highly polar N,N-dimethylformamide
(DMF), as shown in Table 1. The best diastereoselectivity
was obtained using DMF as solvent, which produced the
isomer was found to be the major azepine and no epimeriza-
tion of the carbon bearing the ester substituent was detect-
ed. The absolute stereochemistry of both 8c and 8d was
confirmed by X-ray crystallography (see Supporting Infor-
mation for X-ray data).
Table 1. The optimization of reaction conditions for the synthesis of
To explore the effect of substituents at C-4 on the diaste-
reoselectivity, the hemiaminal 3e bearing a tert-butyldime-
thylsilyl (TBS)-ether substituent was prepared from com-
mercially available pyrrolidin-2-one. Hemiaminal 3e afford-
ed the azepine 8e/9e in good diastereoselectivity (4:1) and
good yield (70%; Table 2, entry 4). Once again the cis epox-
ide 8e was the major diastereoisomer.
fused epoxy azepines 8a and 9a.
The factors affecting diastereocontrol in this reaction are
worthy of further consideration. If betaine formation is re-
versible, the diastereoselectivity will be dependent on the
relative stability of the anti-betaines 10 and 11 that lead to
cis- and trans-azepines, and their relative rates of ring clo-
sure to form the corresponding epoxides (Scheme 2). How-
Entry
Solvent
cis/trans[a]
Yield [%][b]
1
2
3
4
5
6
DMF
THF
CH3CN
CHCl3
CH2Cl2
toluene
6:1
2:1
2:1
1.2:1
3:1
2:1
61
54
70
51
50
31
[a] d.r. was measured by GC on crude samples before purification-see the
Supporting Information for details. [b] Isolated yields after column chro-
matography.
epoxy azepine with good diastereoselectivity (6:1) and in
good yield (60%). The two diastereoisomers were separable
and it was determined by X-ray crystallography that the cis-
isomer 8a was the major product (see the Supporting Infor-
mation for X-ray data). Dichloromethane, tetrahydrofuran
(THF), acetonitrile, and toluene gave moderate diastereose-
lectivity (cis/trans, 3:1 to 2:1), while chloroform showed
poor diastereoselectivity (cis/trans, 1.2:1).
Scheme 2. Pathways for epoxide formation in the azepine synthesis.
Under the optimized conditions, a range of substituted
hemiaminals were explored bearing different groups at both
the four- and five-position (Table 2). The methoxyester-sub-
stituted hemiaminal 3b gave the azepines 8b/9b in good
diastereoselectivity 4:1 and 62% yield (Table 2, entry 1). To
our delight, the tert-butoxyester-substituted hemiaminal 3c
and tert-butyldiphenylsilyl (TBDPS)-substituted hemiaminal
3d[10] generated the azepines 8c and 8d, respectively, with
essentially complete diastereoselectivity and good yield (61–
69%; Table 2, entries 2 and 3). In all cases the cis diastereo-
ever, betaine formation is not usually considered to be re-
versible for nonstabilized ylides.
If betaine formation is nonreversible (which is suspected
as a nonstabilized ylide is involved), the diastereoselectivity
will be determined in the betaine formation step. Reaction
of the ylide with the aldehyde can lead to betaines 12 and
13 (Scheme 3). Electrostatic interactions between the sulfo-
nium group and the developing alkoxide group are expected
to lower the energy of the transition states, thus leading to
conformers 12A and 13A.[11] We propose that formation of
betaine 12A is favored over 13A as the transition state
leading to the latter betaine will suffer from a steric clash
between the pseudo-equatorial R substituent and the bulky
tosyl group. Similarly, conformer 13B would suffer from a
clash between the pseudo-axial R substituent and the sulfo-
nium groups. We propose that conformer 12B is formed
from 12A and leads to epoxide 8 by ring closure. Based on
this proposal, one would expect that the larger the substitu-
ent, the greater the steric clash and hence the higher the
diastereoselectivity. A similar line of argument can be ad-
vanced for the formation of 8e as the major product from
3e. In this case, the tert-butyldimethylsiloxy (TBSO)-group
Table 2. Synthesis of azepines using diphenyl vinyl sulfonium salt 5.
Entry
R1
R2
cis/trans
Yield [%][a]
1
2
3
4
b
c
d
e
MeCO2
tBuCO2
TBDPSOCH2
H
H
H
H
TBSO
4:1
62
>19:1
>19:1
4:1
61
69[b]
70[b]
[a] Isolated yields after column chromatography. [b] 3 equiv of DBU and
4 equiv of 5 were used. TBDPS=tert-butyldiphenylsilyl.
Chem. Asian J. 2011, 6, 372 – 375
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373

V. K. Aggarwal et al.
COMMUNICATION
Experimental Section
The supporting information (SI) for this paper provides full experimental
details, characterization data, and NMR spectra. CCDC 800707,
CCDC 800708, CCDC 800709, CCDC 800710 contain the supplementary
crystallographic data for 8a, 9a, 8c, and 8d in this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
M.Y. thanks the Higher Education Commission of Pakistan and the Uni-
versity of Bristol for support of a studentship. M.U. thanks GlaxoSmithK-
line and the EPSRC for financial support. V.K. A. thanks the Royal Soci-
ety for a Wolfson Research Merit Award, the EPSRC for a Senior Re-
search Fellowship, and Merck for research support. We thank Ms. Saowa-
nit Saithong and Dr. Mairi Haddow for solving the X-ray crystal struc-
tures of 8a, 9a, 8c, and 8d.
Scheme 3. Proposed rationale for the selectivity observed in azepine syn-
thesis.
can sit in either a pseudo-equatorial (12A) or pseudo-axial
(12B) position depending on which betaine is formed.
Lower selectivity is observed as there is no steric clash with
the tosyl (Ts) group.
Keywords: azepine
compounds · nitrogen heterocycles · sulfur ylide
·
epoxidation
·
medium-ring
The synthetic utility of the products is further illustrated
by a completely regioselective ring opening of the epoxy
azepine 8c with NaN3.[2j,k,3,4c,12] The regiochemistry was es-
tablished from the 2D NMR spectra of the product, and is
in line with expectations based on reports on the ring open-
ing of the parent (unsubstituted) epoxy azepine with a range
of nucleophiles.[2j,k] Tanner and co-workers attributed the ex-
cellent regioselectivity to a combination of charge and con-
formational effects.
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Scheme 4
Scheme 4. Regioselective ring-opening of epoxide 8c.
In conclusion, the synthesis of seven-membered epoxide-
fused azepines has been achieved from hemiaminals and the
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and position of substituents play an important role in con-
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sulfonium salt furnished the ep-
oxides with high ee (86–99%).
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Received: November 15, 2010
Published online: December 23, 2010
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