Enantioselective synthesis of functionalized 1-benzoxepines by phenoxide ion mediated 7-endo-tet carbocyclization of cyclic sulfates

Article abstract of DOI:10.1002/ejoc.200800661

A new asymmetric synthesis of 2,3-disubstituted 1-benzoxepines is described. Key steps include Sharpless asymmetric dihydroxylation of trans-α,β-unsaturated esters and phenoxide ion mediated intramolecular 7-endo-tet carbocyclization of syn-2,3-dihydroxy ester derived cyclic sulfates. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200800661

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800661
Enantioselective Synthesis of Functionalized 1-Benzoxepines by Phenoxide Ion
Mediated 7-endo-tet Carbocyclization of Cyclic Sulfates[‡]
Sajal Kumar Das,[a] Subal Kumar Dinda,[a] and Gautam Panda*[a]
Dedicated to Professor Goverdhan Mehta on his 65th birthday
Keywords: 1-Benzoxepine / Sharpless asymmetric dihydroxylation / Cyclic sulfate
A new asymmetric synthesis of 2,3-disubstituted 1-benzoxep- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ines is described. Key steps include Sharpless asymmetric Germany, 2009)
dihydroxylation of trans-α,β-unsaturated esters and phenox-
ide ion mediated intramolecular 7-endo-tet carbocyclization
of syn-2,3-dihydroxy ester derived cyclic sulfates.
clic molecules including natural and natural-product-like
Introduction
molecules.[4] As part of our research programme in this
1-Benzoxepine is an important benzo-fused medium-
field, we sought to develop a synthetic route that could pro-
sized heterocycle, because there are numerous biologically
vide enantiomerically pure natural-product-like small mole-
active natural products[1] and synthetic molecules,[2] which
cules of general structure 6 containing the 1-benzoxepine
contain this structural framework. Thus, synthesis of 1-
framework (Figure 1).
benzoxepine derivatives constitutes an important objective
in modern organic synthesis.[3] Following our interest in the
field of enantioselective synthesis of biologically important
heterocycles, we recently employed naturally occurring α-
Results and Discussion
In a recent paper[4b] we have reported that asymmetric
synthesis of 2,3-disubstituted 1-benzoxepine derivative 8
could not be achieved by a phenoxide ion mediated intra-
molecular SN2 displacement of the tosyloxy group of a β-
hydroxy-α-tosyloxy ester derivative possibly due to an en-
tropy factor (Scheme 1). This unsuccessful synthesis of 2,3-
disubstituted 1-benzoxepine derivatives prompted us to
search for an alternative synthetic route.
amino acids and Sharpless asymmetric dihydroxylation as
the sources of chirality to generate a large array of heterocy-
Figure 1. Selected natural products 1–5 and our designed target
molecules 6 containing the 1-benzoxepine ring system.
[‡] CDRI communication number 7471.
[a] Medicinal and Process Chemistry Division, Central Drug
Research Institute,
Scheme 1. Unsuccessful synthesis of 2-substituted 1-benzoxepine
derivative.
Lucknow 226001, UP, India
Cyclic sulfates have been known for a long time, and the
use of these compounds has been the subject of several re-
views.[5] They are like epoxides but have a higher reactiv-
ity.[6] The high reactivity of these compounds as nucleophile
Fax: +91-5222623405
E-mail: gautam_panda@cdri.res.in
gautam.panda@gmail.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Enantioselective Synthesis of Functionalized 1-Benzoxepines
acceptors is well known. Whereas several synthetic utiliza- chloride and triethylamine in CH2Cl2 gave the respective
tions of cyclic sulfates are known, their use for the enantio- cyclic sulfites, which were further oxidized with NaIO4 and
selective preparation of heterocycles has not been explored a catalytic amount of ruthenium trichloride to furnish the
in depth. For example, cyclic sulfates have only been used corresponding cyclic sulfates 15a–c in good yields.
as intramolecular O-alkylation substrates for the construc-
tion of tetrahydrofuran and tetrahydropyran rings.[7] Al-
though it is well known that the intramolecular cyclization
of a tetrahedral system generally proceeds by an exo cycli-
zation pathway,[8] the pioneering report[7e] by Sharpless et
al. suggested that the relatively unstrained cyclic sulfate
could permit endo cyclization in preference to exo cycliza-
tion. Taking into account of all these facts and our interest
in the asymmetric synthesis of benzo-annulated heterocy-
cles,[4] we describe in this commuinication our preliminary
results that illustrate a new asymmetric synthesis of 2,3-di-
substituted 1-benzoxepines utilizing phenoxide ion medi-
ated intramolecular 7-endo-tet SN2 carbocyclization of syn-
2,3-dihydroxy ester derived cyclic sulfates as the key step.
In our study, commercially available 2-hydroxy-5-meth-
oxybenzaldehyde (9a), 2-hydroxy-3-methoxybenzaldehyde
(9b) and 2-hydroxybenzaldehyde (9c) were selected as model
starting materials. Compounds 9a–c were converted into
the corresponding phenol-protected and two-carbon-ho-
mologated aldehydes 12a–c by essentially applying the steps
as depicted in Scheme 2. Thus, Wittig olefination of 9a–
c with (ethoxycarbonylmethylene)triphenylphosphorane in
dry CH2Cl2 at room temparature furnished the correspond-
ing (E)-cinnamate esters 10a–c in very high yields. Next,
hydrogenation of 10a–c in the presence of 10% Pd/C fol-
lowed by benzylation of the resulting hydroxy esters with
benzyl bromide and anhydrous K2CO3 in dry acetone under
reflux condition yielded 11a–c in high yields. DIBAL-H re-
duction of 11a–c in dry toluene at –78 °C furnished the cor-
responding aldehydes 12a–c in very high yield.
Scheme 3. Reagents and conditions: (a) Ph3P=CHCO2Et, CH2Cl2,
room temp., overnight, 13a (80%), 13b (82%) and 13c (77%). (b)
AD-mix-β, MeSO2NH2, tBuOH/H2O (1:1), 0 °C, 24 h, 14a (95%),
14b (94%) and 14c (88%). (c) (i) SOCl2, Et3N, CH2Cl2, 0 °C,
20 min, (ii) RuCl3, NaIO4, MeCN/H2O (1:9), 0 °C, 10 h, 15a (84%),
15b (87%) and 15c (85%) for combined two steps.
With cyclic sulfates 15a–c in hand, we turned our atten-
tion to the phenoxide ion directed intramolecular cyclic sul-
fate ring opening reaction (Scheme 4). Accordingly, 15a–c
were first debenzylated under hydrogen in the presence of
10% Pd/C to furnish the corresponding phenol derivatives,
which, without further purification, were treated with anhy-
drous K2CO3 in dry acetone and subsequently with 20%
H2SO4 in THF.[10] After extensive NMR studies (1H, 13C,
COSY, HMBC, HSQC), we were very delighted to observe
that cyclic sulfates 15a–b furnished the respective cyclic
products 16a and 18b, which contain the 1-benzoxepine
skeleton. It is important to mention that in the deben-
zylation/cyclization reaction sequence, cyclic sulfates 15a,b
did not provide the corresponding products 17a and 19b
with the 1-benzopyran ring system. However, cyclic sulfate
15c furnished the major cyclic product 20c containing a 1-
benzoxepine skeleton (60%) and the minor product 21c
(15%) with a benzopyran ring system. To the best of our
knowledge this is the first use of α,β-dihydroxy ester cyclic
sulfates in benzo-fused heterocycle synthesis.
Scheme 2. Reagents and conditions: (a) Ph3P=CHCO2Et, CH2Cl2,
room temp., 1 h, 10a (96%), 10b (95%) and 10c (95%). (b) (i) H2,
10% Pd/C, EtOAc, 8 h, (ii) BnBr, anhyd. K2CO3, dry acetone, re-
flux, 4 h, 11a (90%), 11b (87%) and 11c (91%) for combined two
steps. (c) DIBAL-H, dry toluene, –78 °C, 1 h, 12a (95%), 12b (94%)
and 12c (95%).
With the ready availability of aldehydes 12a–c, attention
was turned to their elaboration into cyclic sulfate deriva-
tives (Scheme 3). Towards that objective, 12a–c were treated
with (ethoxycarbonylmethylene)triphenylphosphorane in
dry CH2Cl2 at room temperature to obtain the correspond-
ing (E)-unsaturated esters 13a–c. Subjection of 13a–c to
Sharpless asymmetric dihydroxylation[9] with AD-mix-β in
tBuOH/H2O (1:1) at 0 °C for 24 h furnished enantiopure
Scheme 4. Reagents and conditions: (a) (i) H2, 10% Pd/C, EtOAc,
8 h, 89%, (ii) anhyd. K2CO3, dry acetone, room temp., 8 h, (iii)
20% H2SO4, THF, room temp., overnight, 16a (70%), 18b (72%)
and 20c (60%) and 21c (15%) for combined three steps.
1
The H NMR spectrum of 16a showed the presence of
dihydroxy derivatives 14a–c in good yields and high enan- two multiplets at δ = 2.34–2.25 and 1.65–1.52 ppm attribut-
tiomeric excess (90%, ee Ͼ99%; determined by chiral able to the protons 4-Ha and 4-Hb and another multiplet at
HPLC analysis). Treatment of diols 14a–c with thionyl δ = 2.89–2.65 ppm due to two 5-H protons; 3-H appeared
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S. K. Das, S. K. Dinda, G. Panda
SHORT COMMUNICATION
as a multiplet at δ = 4.18–4.11 ppm, whereas the proton 2-
H showed a doublet at δ = 3.85 (J = 9.2 Hz). The presence
of the OH group was indicated by a broad singlet at δ =
3.11 ppm. The above assignment of various protons was
done by incisive analysis of a COSY spectrum of 16a. Based
on the coupling observed in the HSQC spectrum of 16a,
signals of ring carbon atoms appearing at δ = 83.9, 71.9,
33.4 and 28.0 ppm were attributed to C-2, C-3, C-4 and C-
5, respectively. Similarly, the signals at δ = 61.6, 55.4, and
14.0 ppm were assigned to OCH2CH3, OCH3 and
OCH2CH3, respectively.
Finally, six signals at δ = 156.0, 151.9, 135.6, 121.8,
115.0, and 112.1 ppm were assigned to the aromatic carbon
atoms C-7, C-10, C-11, C-8, C-6 and C-9. In the HMBC
spectrum of 16a, 2-H [δ = 3.85 (J = 9.2 Hz)] showed coup-
ling with C=O (δ = 170.7 ppm), C-3 (δ = 71.9 ppm), C-4 (δ
= 33.4 ppm) and C-10 (δ = 151.9 ppm) (Figure 2). The
long-range coupling of 2-H with C-10 confirmed our hy-
pothesis of 1-benzoxepine ring formation over 1-benzopy-
ran ring formation, as this coupling would not be possible
in the case of 17a. Again, had the cyclic product been 17a,
the 2-H [δ = 4.18–4.11 (m, 1 H) ppm] would have shown a
long-range coupling with the aromatic carbon atom C-9 (δ
= 151.9 ppm in structure 17a), which is completely absent
in the HMBC spectrum. Thus, the 1-benzoxepine structure
16a was confirmed. The structures of other isolated cyclic
products 18b, 20c and 21c were similarly assigned.
Scheme 5. Reagents and conditions: (a) MeMgI, dry THF, 0 °C to
reflux, 3 h, 22a (88%), 22b (90%) and 22c (94%).
Conclusions
In the present communication we describe an asymmetric
synthesis of 2,3-disubstituted 1-benzoxepines by an easy
and high-yielding reaction sequence. Key steps include
Sharpless asymmetric dihydroxylation reaction on suitable
α,β-unsaturated esters and construction of the 1-benzoxep-
ine ring by phenoxide ion directed intramolecular 7-endo-
tet carbocyclization of syn-2,3-dihydroxy ester derived cy-
clic sulfates. The presence of methoxy groups ortho and
para to the phenol functionality on the phenyl ring rendered
the cyclization reaction completely regioselective producing
1-benzoxepine derivatives only. In the absence of a methoxy
group on the phenyl ring, the reaction furnished both 1-
benzoxepine and 1-benzopyran derivatives, with the former
being the major one. A systematic study of the effect of
different substituents at different positions of the phenyl
ring on the key cyclization reaction and the utilization of
the same reaction in the synthesis of other benzo-fused oxa-
heterocycles of different ring size is underway in our labora-
tory and will be reported in due course with complete struc-
ture–reactivity relationships.
Figure 2. Coupling of 2-H in the HMBC spectrum of 16a.
It is a well known fact that due to the presence of an
ester group, the α-carbon atom of an α,β-dihydroxy ester
derived cyclic sulfate possesses a higher reactivity than the
β-carbon atom, and hence nucleophilic attack occurs at the
α-carbon atom almost exclusively.[5b] Thus, formation of 1-
benzoxepine derivatives 16a, 18b and 20c (by 7-endo-tet cy-
clization) might be explained on the basis of the high reac-
tivity at the α-carbon atom. At the same time, 1-benzopyran
derivatives 17a, 19b and 21c (formed by 6-exo-tet cycliza-
tion) might be considered as entropically favoruable. Since
Experimental Section
Ethyl (2R,3R)-3-Hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzo[b]ox-
epine-2-carboxylate (16a): To a stirred solution of 15a (0.9 g,
2.06 mmol) in ethyl acetate (20 mL) was added 10% Pd/C (50 mg).
After stirring at room temperature under the pressure of a hydro-
gen balloon for 3 h, the reaction mixture was filtered through a
pad of Celite®, and the filtrate was concentrated under reduced
the presence of methoxy groups ortho and para to a phenol pressure to yield the corresponding debenzylated product (0.64 g)
as a colorless semi-solid which was used for the next step without
further purification. To a stirred solution of the above debenzylated
product in dry acetone (20 mL), was added anhyd. K2CO3 (0.4 g,
2.89 mmol), and the mixture was stirred at room temperature for
5 h. After removal of the acetone from the raction mixture under
reduced pressure, the residue was stirred with 20% aq. H2SO4
(20 mL) and THF (10 mL) for 16 h. The resultant solution was
then neutralised with aq. saturated NaHCO3 solution and ex-
tracted with ethyl acetate. The combined organic phases were
washed with water, brine, dried (Na2SO4), and concentrated. Purifi-
cation of the crude product by silica gel column chromatography
functionality on a phenyl ring increases the nucleophilicity
of the corresponding phenoxide ion, cyclic sulfates 15a–b
gave only 1-benzoxepine derivatives 16a, 18b and 20c. In
the absence of a methoxy group, the nucleophilicity of a
phenoxide ion is reduced. Thus, cyclic sulfate 15c furnished
1-benzoxepine derivative 20c along with a minor amount of
1-benzopyran derivative 21c.
Finally, treatment of 16a, 18b and 20c with an excess of
methylmagnesium iodide furnished the corresponding terti-
ary alcohols 22a–c in high yields (Scheme 5).
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Enantioselective Synthesis of Functionalized 1-Benzoxepines
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4.11, CHCl ). IR (KBr): ν = 3434, 2923, 2358, 1648, 1511, 1218,
˜
3
768 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.01–6.98 (m, 1 H),
6.67–6.64 (m, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 4.18–4.11 (m, 1 H),
3.85 (d, J = 9.2 Hz, 1 H), 3.75 (s, 3 H), 3.11 (br. s, 1 H), 2.89–2.65
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Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and analytical data of se-
lected compounds.
Acknowledgments
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This research project was supported by the Department of Science
and Technology, New Delhi, India (SR/S1/OC-23/2005). S. K. Das
and S. K. Dinda thank the CSIR, New Delhi, for providing fellow-
ships.
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Received: July 3, 2008
Published Online: December 2, 2008
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