Highly enantioselective synthesis of chiral 7-ring O- and N-heterocycles by a one-pot nitro-Michael-cyclization tandem reaction

Article abstract of DOI:10.1039/c3cc47397j

A concise enantioselective approach to synthesise medium-sized 7-ring O- and N-heterocycles has been developed. The synthetic strategy relies on an organocatalytic nitro-Michael-nitrile oxide cycloaddition tandem reaction, leading to the corresponding chiral benzoxe- and benzazepine derivatives containing an additional fused dihydroisoxazoline ring in good yields and excellent enantioselectivities (up to 97% ee).

Full text of DOI:10.1039/c3cc47397j

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Highly enantioselective synthesis of chiral
7-ring O- and N-heterocycles by a one-pot
nitro-Michael–cyclization tandem reaction†
Cite this: Chem. Commun., 2013,
49, 11665
Received 27th September 2013,
Accepted 17th October 2013
Renate Rohlmann, Constantin-Gabriel Daniliuc and Olga Garc´ıa Manchen˜o*
DOI: 10.1039/c3cc47397j
www.rsc.org/chemcomm
A concise enantioselective approach to synthesise medium-sized 7-ring
O- and N-heterocycles has been developed. The synthetic strategy relies
on an organocatalytic nitro-Michael–nitrile oxide cycloaddition tandem
reaction, leading to the corresponding chiral benzoxe- and benzazepine
derivatives containing an additional fused dihydroisoxazoline ring
in good yields and excellent enantioselectivities (up to 97% ee).
Oxygen and nitrogen containing medium-sized heterocycles are
important common structural motifs found in numerous biologically
active and natural products.1 Much attention has been paid to the
construction of 7-ring systems such as benzoxe- and benzazepines
due to their interesting and broad range of biological applications2 as
antibacterial compounds,2b diverse receptor agonists,2c,d or regulators
of metabolic disorders like insulin secretion.2e Some examples of
such natural and bioactive derivatives are shown in Fig. 1.
Despite their structural significance, the development of efficient
enantioselective methodologies for the synthesis of such 7-ring
heterocycles remains a big challenge.3 Although important advances
have already been made using asymmetric strategies based on
transition-metal-catalysis, such as Pd (e.g. Heck),4 Rh (e.g. olefin
hydroacylation),5 Mo (e.g. ring closing metathesis (RCM))6 or Ir/Ru
(e.g. allylic amination–RCM sequence)7 catalysis, organocatalytic
processes are still quite rare.8
Fig. 1 Some selected bioactive 1-benzoxe- and benzazepines.
as a model substrate and methylmalonate 3a in the presence of
10 mol% of bifunctional thiourea–cinchona catalyst 1a in o-xylene
was first carried out.12 The corresponding addition product 4a was
obtained in excellent yield and enantioselectivity (99%, 96% ee).
Next, 4a was subjected to the reaction with Boc2O in the presence of
20 mol% of DMAP as a base at 90 1C for 3.5 h in the same solvent
(o-xylene) used in the first step.12,13 Under these conditions the
corresponding nitrile oxide intermediate is generated in situ and
can further be cyclized with the olefin present in the side chain
of the molecule to form the desired 7-ring, along with a fused
Herein, we report an easy and alternative metal-free one-pot
procedure for the synthesis of various chiral benzoxa- and
benzazepine derivatives. Our synthetic design involved an
asymmetric organocatalyzed nitro-Michael addition9,10 followed
by an in situ nitrile oxide generation–intramolecular cycloaddition
tandem reaction (Scheme 1).11
Initially, the two steps involved in the synthetic sequence
were studied independently. Thus, the enantioselective nitro-
Michael addition reaction between b-nitro styrene derivative 2a
¨
Organisch-Chemisches Institut, Munster University, Corrensstrasse 40,
¨
48149 Munster, Germany. E-mail: olga.garcia@uni-muenster.de;
Fax: +49 251 83 33202; Tel: +49 251 83 33239
† Electronic supplementary information (ESI) available: Optimization studies, experi-
mental procedures, characterization, NMR spectra of compounds, HPLC (4a and 5),
and X-ray ORTREP and the CIF-file for (3aR,10R)-5a. CCDC 961434. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc47397j
Scheme 1 Approach to synthesise chiral benzoxe- and benzazepines.
Chem. Commun., 2013, 49, 11665--11667 11665
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a good 60% yield. Moreover, the absolute configuration of 5a was
determined to be (3aR,10R) by X-ray crystallographic analysis
(Scheme 2).14 Assuming that the initial enantioselective addition
occurs in the Re-face of the olefin and the nitrile oxide cycloaddi-
tion reaction takes place with retention of the chiral information at
C10, the configuration of all further synthesized derivatives 5 was
accordingly assigned by analogy. Having proved the feasibility of
the two steps involved in the sequence, the one-pot synthesis was
carried out (Table 1). Similar results were obtained for compound
5a (96% ee, 61%/2-step yield), showing the compatibility of these
transformations in a one-pot fashion. It is also important to note
that the enantiomer ent-5a can also be attained in 97% ee when
using the pseudo-enantiomer catalyst 1b derived from quinine
Scheme 2 X-Ray structure of the major diastereoisomer of 5a.
dihydroisoxazoline 5-ring. The desired product 5a was then formed instead of quinidine. The scope of the one-pot reaction was then
in 75% NMR-yield as a 3 : 1 diastereomeric mixture. To our delight, explored. Besides 3a, different activated methylene compounds 3
the cyclization reaction proceeded without erosion of the enantio- such as ethyl or iso-propyl substituted malonates and a b-diketone
selectivity (96% ee, for both diastereomers), and 5a was isolated in were also efficiently employed as nucleophiles. They led to similar
Table 1 One-pot synthesis of chiral benzoxapine and benzazepine derivatives 5a,b
a
Catalyst 1a (10 mol%), 2 (0.2 mmol) and 3 (0.24 mmol) in o-xylene (0.2 M) at 10 1C for 4–7d; then DMAP (20 mol%) and Boc2O (2.5 equiv.) in
b
c
d
o-xylene at 90 1C for 3.5 h. Isolated yields and ee determined for the final products by chiral HPLC. Same ee for both diastereoisomers. Use of the
pseudoenantiomer catalyst 1b prepared from quinine. A nitrile side-product 6 was also obtained (see ESI).
e
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Notes and references
1 Reviews on medium-sized rings in natural products: (a) L. Yet,
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D. Marona-Lewicka, N. V. Cozzi, D. L. Nelsont and D. E. Nichols,
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H. Miyamoto, K. Nakaya, H. Ogawa, M. Tanaka, M. Tominaga,
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3 Review on metal-mediated synthesis of medium-sized rings: L. Yet,
Chem. Rev., 2000, 100, 2963. For some selected examples, see Pd-
catalyzed: (a) M. Lautens, J.-F. Paquin and S. Piguel, J. Org. Chem.,
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Scheme 3 Synthetic application of the methodology.
excellent enantioselectivities (90–96% ee) and good overall yields
(46–75%) on the corresponding benzoxepines 5b–d (Table 1, first
row). Moreover, the reaction showed a broad scope and substitu-
tion tolerance of the aryl moiety. Thus, both electron donating
(2e–i) and withdrawing (2k and 2l) groups at the b-nitrostyrenes
provided high enantioselectivities (92–96% ee). However, the reac-
tion was significantly affected by steric hindrance. Accordingly,
precursors possessing two ortho substituents on the arene, such as
2j and 2m, led to a slight decrease in the enantioselectivity (81 and
80% ee, 5j and 5m respectively). Lastly, the one-pot nitro-Michael–
cycloaddition reaction with the nitrogen-containing substrates 1n
and 1o and the O-propargyl (1p–s) instead of the O-allyl unit
[Table 1, last row] was carried out. The N-COPh 5n and N-Ts 5o
substituted benzazepines were formed within 95 and 97% ee and
in 60 and 57% yield, respectively. The benzoxapine–isoxazoles 5p–s
were also obtained in homogenous high enantioselectivity and
good to excellent overall yields (55–95%).
After demonstrating the scope of this approach, the synthesis of
the biologically active benzoxepine ent-82e was pursued (Scheme 3).
To achieve this goal the squarimide-cinchona 1e0 was employed as
catalyst. Thus, the cyclic product ent-5t could be obtained in an
excellent 97% ee.15,16 Finally, ent-5t was subjected to a Suzuki
coupling with 4-trifluoromethylphenylboronic acid and in situ
decarboxylation reaction to directly build the desired product
ent-8 in 99% yield and 90% ee.
´
´
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12 For more details on the optimization see the ESI†.
13 See for example: Y. Basel and A. Hassner, Synthesis, 1997, 309.
14 CCDC 961434 ((3aR,10R)-5a).
15 In this particular case, the isolation of the addition intermediate
ent-4t was necessary to avoid the erosion of enantioselectivity
during the cyclization process in the presence of the remaining
starting materials.
16 The highly demanding benzoxepines 5t and ent-5t were obtained
in a moderate 70% ee and low 33–34% yields under the standard
one-pot conditions using 1a and 1b as catalysts, respectively. The
2 step approach provided the Michael adduct in 35% yield and
95% ee (in DCM) and the benzoxepine in 94% ee (21% overall
yield). To improve the conversion of the nitro-Michael step,
the squarimide catalyst 1e0 was employed at r.t. in DCM for 7 days
(ent-4t: 60%, 97% ee).
In conclusion, we have developed a highly enantioselective
one-pot method for the synthesis of a variety of optically active
seven-membered O- and N-heterocycles. The presented approach
is based on a one-pot enantioselective organocatalytic nitro-Michael
addition–nitrile oxide cycloaddition sequence. The corresponding
heterocyclic derivatives, 1-benzoxe- and benzazepines, were obtained
in moderate to good yields and excellent enantioselectivities. Finally,
the applicability of this methodology was demonstrated by the
straightforward synthesis of ent-8, which is an efficient deriva-
tive for the treatment of metabolic disorders.
The Fonds der Chemischen Industrie, the Deutsche For-
schungsgemeinschaft, and Prof. Frank Glorius are acknowledged
for generous support. R.R. thanks Mu¨nster University within the
Bonusprogram for a predoctoral contract.
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Chem. Commun., 2013, 49, 11665--11667 11667