Catalytic Enantioselective Synthesis of 1,4-Benzodioxepines

Article abstract of DOI:10.1021/acs.orglett.9b04244

An efficient organocatalytic enantioselective synthesis of chiral 1,4-benzodioxepines is described. By proper incorporation of an intramolecular oxetane desymmetrization process, a range of benzylic alcohols bearing an internal oxetane reacted in the pres

Full text of DOI:10.1021/acs.orglett.9b04244

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Synthesis of 1,4-Benzodioxepines
Xi Zou,† Guangwu Sun,† Hai Huang,∥ Jinping Wang,*,† Wen Yang,*,† and Jianwei Sun*,‡
†College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P.R. China
‡Department of Chemistry and Shenzhen Research Institute, The Hong Kong University of Science and Technology, Clear Water
Bay, Kowloon, Hong Kong SAR, P.R. China
∥Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou
University, Changzhou 213164, P.R. China
S
* Supporting Information
ABSTRACT: An efficient organocatalytic enantioselective
synthesis of chiral 1,4-benzodioxepines is described. By proper
incorporation of an intramolecular oxetane desymmetrization
process, a range of benzylic alcohols bearing an internal
oxetane reacted in the presence of a suitable chiral phosphoric
acid catalyst to form chiral 1,4-benzodioxepines with high
enantioselectivity. This process provides a new catalytic
asymmetric example of direct synthesis of seven-membered heterocycles with good stereocontrol.
1,4-Benzodioxepines are useful substructures of a range of
natural products and biologically important molecules.1 As a
result, strategies for the assembly of such motifs are highly
desirable, particularly in the context of asymmetric synthesis.
While various approaches have been known for the synthesis of
these benzene-fused seven-membered heterocycles, essentially
all of them are racemic or achiral.2 It is worth noting that there
have been very few catalytic asymmetric strategies to directly
assemble such cyclic structures and concomitantly establish a
stereogenic center.
Seven-membered ring formation with simultaneous stereo-
control is not a trivial task.3,4 Compared with a six-membered
ring, seven-membered ring formation experiences both
unfavorable kinetics and thermodynamics. Moreover, the
ring-closing transition state is much less ordered than that of
six-membered ring, which is particularly detrimental to the
effective stereocontrol. Therefore, it is a challenge to develop a
catalytic asymmetric approach for such a cyclization event.
In continuation of our interests in asymmetric opening
reactions of strained rings,5 we envisioned that benzyl alcohol
1 bearing an ortho-tethered oxetane moiety may undergo an
intramolecular ring-opening reaction, which could directly
deliver 1,4-benzodioxepine 2 (Scheme 1).6,7 It was also
expected to induce chirality in this desymmetrization process
with a chiral catalyst, though it could be challenging. It is worth
noting that the incorporation of an oxygen atom between the
arene and oxetane makes these substrates easily accessible and
thus renders this process a highly expedient approach for the
synthesis of chiral 1,4-benzodioxepine and their analogues.
We began our study with 1a as the model substrate. Chiral
phosphoric acids were employed as catalysts for this process in
view of their demonstrated success for the oxetane
desymmetrization.5,8 However, in the presence of 10 mol %
of A1, almost no conversion of 1a was observed in toluene for
48 h (Table 1, entry 1). It indicated that the barrier of this
reaction is relatively high, which further corroborates the
elusive transition state when compared with 5- and 6-
membered ring formation. Next, a higher reaction temperature
was evaluated. Fortunately, at 80 °C, the reaction successfully
afforded the desired product 2a, albeit with moderate
conversion and very low enantioselectivity (entry 2). Further
screening of various chiral phosphoric acids with different
chiral backbones and 3,3′-substituents indicated that the
SPINOL-based catalyst B1 showed higher enantioselectivity
but lower catalytic activity (entry 6). In contrast, catalyst B4
showed much higher catalytic activity while maintaining
reasonably good stereocontrol. Thus, B4 was used for further
optimization. Indeed, with B4, the same transformation could
go to completion at room temperature with only 5 mol % of
catalyst (entry 10). As mentioned above, the stereodetermin-
ing transition state for 7-membered ring formation might be
loose and not well-ordered. To further restrict the freedom of
this transition state, we employed tertiary alcohol 1b. To our
surprise, the same conditions resulted in immediate increase of
the enantioselectivity to 90% ee (entry 11). This dramatic
change in the outcome might be attributed to the Thorpe−
Ingold effect.9 Next, other parameters, such as solvents,
concentration, and temperature, were optimized. Other
Scheme 1. Reaction Design
Received: November 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04244
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Reaction Scope
b
c
entry
1
cat.
solvent
T (°C) t (h) conv (%) ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
A1
A1
A2
A3
A4
B1
B2
B3
B4
B4
B4
B4
B4
B4
B4
B4
B4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
rt
48
36
24
24
24
36
12
12
6
24
24
24
24
24
24
48
36
trace
72
100
100
100
45
100
100
100
100
100
98
80
80
80
80
80
80
80
80
rt
rt
rt
rt
rt
13
10
8
26
69
51
44
62
69
90
82
83
d
d
d
d
16
<5
16
74
d
14
15
16
17
THF
d
MeCN
toluene
toluene
rt
0
rt
74
91
92
d
de
,
100
a
Unless noted otherwise, reactions were performed with oxetane 1a
or 1b (0.05 mmol), catalyst (10 mol %), and solvent (0.5 mL).
b
Determined by 1H NMR analysis with CH2Br2 as an internal
standard. The converted material is fully transformed to the desired
c
d
e
product. Determined by HPLC analysis. 5 mol % B4 was used. c =
0.05 M.
a
Isolated yield.
this mild reaction. Oxetanes 1l−s tethered with different
benzylic tertiary alcohols were all suitable substrates, furnishing
the corresponding products with good to excellent efficiency
and enantioselectivities (90−98% ee). Generally, the increased
steric hindrance of the alcohol unit could lead to increased
enantioselectivity but decreased reactivity. Notably, the use of
cyclic alcohols provided easy access to the construction of
spiro heterocycles (2n−s). The absolute configuration of
enantiopure 2e was confirmed to be R by single-crystal X-ray
crystallography (Figure 1), and those of other products were
assigned by analogy based on the transition-state model.
The substrate scope was further investigated for the
synthesis of other heterocycles. Sulfur-tethered oxetane 1b-S
solvents did not improve the outcome (entries 12−15).
Decreasing the temperature to 0 °C slightly improved the
enantioselectivity but compromised the reaction efficiency
(entry 16). However, at a low concentration (0.05 M), both
excellent efficiency and high enantioselectivity could be
achieved (entry 17). Notably, substrates 1 could be easily
prepared in two steps, including nucleophilic substitution of
the commercially available p-tosylate of oxetan-3-ol with a
phenol bearing an o-carbonyl substituent followed by
nucleophilic addition of the carbonyl group. These steps
were straightforward and high yielding.
With the optimized conditions in hand, we next explored the
substrate scope of the intramolecular oxetane desymmetriza-
tion reaction (Scheme 2). A range of substrates 1b−k with
different electron-withdrawing and -donating substituents on
the aromatic ring all proceeded smoothly to form the desired
1,4-benzodioxepines 2b−k with excellent efficiency and high
enantioselectivities (87−93% ee). The electronic property and
position of substituents showed minor influence on the
reaction outcomes. Various functional groups, such as
halogens, ethers, alkenes, and alkynes, are well-tolerated in
Figure 1. X-ray crystal structure of 2e.
B
DOI: 10.1021/acs.orglett.9b04244
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
also worked well, providing the desired 1,4-oxathiepine 2b-S in
97% yield with 90% ee (eq 1). In addition to benzene-fused
Scheme 3. Product Transformations
a
Conditions: (a) CBr4, PPh3, CH2Cl2, 0 °C to rt; (b) DMP, CH2Cl2,
rt; (c) TsCl, Et3N, DMAP, CH2Cl2, rt; (d) NaN3, DMSO, 80 °C; (e)
potassium phthalimide, DMF, 80 °C; (f) AcSK, DMF, rt; (g) 4-
MePhSH, Cs2CO3, DMF, 80 °C; (h) 4-NO2C6H4OH, K2CO3, DMF,
80 °C.
substrates, we also investigated those without a benzene ring.
For example, oxetane 3 provided the desired 1,4-dioxepine 4
with good efficiency but moderate enantioselectivity (69% ee,
eq 2). The diminished enantioselectivity might be due to the
more flexible aliphatic side chain and, thus, the less organized
ring-closing transition state. Interestingly, oxetane 5 underwent
a ring-opening/lactonization cascade reaction to afford the
corresponding spiro-heterocycle 6 with moderate efficiency
and high enantioselectivity (91% ee). Subsequent ring-opening
with benzylamine took places smoothly to give 1,4-oxathiepane
7 in quantitative yield (eq 3). This result indicated that the
construction of a quaternary stereocenter in this process is
feasible. Finally, to demonstrate the robustness of this protocol,
a scale-up synthesis of 2n was carried out. In the presence of 3
mol % of (S)-B4, the reaction of 1n on 3.6 mmol scale
proceeded smoothly at 35 °C to afford the desired product 2n
without obvious erosion in yield or enantioselectivity (98%,
95% ee, eq 4).
The 1,4-benzodioxepine products formed in our reaction
could serve as precursors for the synthesis of other useful chiral
molecules. For example, bromination of 2n with triphenyl-
phosphine and carbon tetrabromide afforded the correspond-
ing bromide 8. After oxidation by Dess−Martin periodinane,
aldehyde 9 could be formed with high efficiency. Tosylation of
2n followed by SN2 substitution reactions with various
nucleophiles readily delivered the desired compounds 11−15
with good to excellent efficiency. In all of these trans-
formations, the high enantiopurity essentially remained intact
(Scheme 3).
In conclusion, we have developed an efficient catalytic
enantioselective synthesis of chiral 1,4-benzodioxepines, which
are important structures lacking efficient asymmetric access. In
particular, catalytic asymmetric synthesis of such seven-
membered ring structures involves a poorly ordered transition
state, making stereocontrol illusive. The present reaction was
able to overcome this challenge by incorporating an intra-
molecular oxetane desymmetrization on properly designed
substrates. With the suitable chiral phosphoric acid catalyst,
this process proceeded efficiently to form a wide range of chiral
1,4-benzodioxepines with high enantioselectivity. This catalytic
process features mild reaction conditions and good functional
group compatibility. It is also expected to extend to the
synthesis of other chiral heterocycles.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04244.
1
Experimental details, copies of H and 13C spectra of
A simplified transition-state model is depicted to rationalize
the possible interactions involved in this catalytic reaction. We
believe that the chiral phosphoric acid serves as a bifunctional
catalyst. The acid functionality provides the primary activation
of the oxetane unit by hydrogen bonding. In the meanwhile,
the phosphoryl oxygen provides a secondary hydrogen
bonding with the nucleophile hydroxyl group, which increases
its nucleophilicity. With these two interactions, the transition
state is relatively rigid, which explains the observed good
asymmetric induction.
new compounds, and HPLC chromatograms (PDF)
Accession Codes
CCDC 1967687 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.9b04244
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
55, 6954. (f) Zhang, R.; Guo, W.; Duan, M.; Houk, K. N.; Sun, J.
Angew. Chem., Int. Ed. 2019, 58, 18055.
(6) For reviews on oxetane chemistry, see: (a) Burkhard, J. A.;
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sunjw@ust.hk.
*E-mail: yangwen@hnu.edu.cn.
*E-mail: jinpingwang1985@126.com.
Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew.
̈
Chem., Int. Ed. 2010, 49, 9052. (b) Wang, Z.; Chen, Z.; Sun, J. Org.
Biomol. Chem. 2014, 12, 6028. (c) Malapit, C. A.; Howell, A. R. J. Org.
Chem. 2015, 80, 8489. (d) Bull, J. A.; Croft, R. A.; Davis, O. A.;
Doran, R.; Morgan, K. F. Chem. Rev. 2016, 116, 12150.
(7) (a) Mizuno, M.; Kanai, M.; Iida, A.; Tomioka, K. Tetrahedron:
Asymmetry 1996, 7, 2483. (b) Loy, R. N.; Jacobsen, E. N. J. Am. Chem.
Soc. 2009, 131, 2786.
ORCID
Wen Yang: 0000-0002-3166-4171
Jianwei Sun: 0000-0002-2470-1077
Notes
(8) Reviews of CPA catalysis: (a) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (c) Nakashima, D.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626. (d) Parmar, D.;
Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047.
(e) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115, 9277.
(9) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21702055) and Shenzhen
Science and Technology Innovation Committee
(JCYJ20170818113708560).
REFERENCES
■
(1) (a) Tanaka, N.; Murakami, T.; Wada, H.; Gutierrez, A. B.; Saiki,
Y.; Chen, C. Chem. Pharm. Bull. 1985, 33, 5231. (b) Zhao, Z.; Ruan,
J.; Jin, J.; Zou, J.; Zhou, D.; Fang, W.; Zeng, F. J. Nat. Prod. 2006, 69,
265. (c) Zhao, Z.; Jin, J.; Ruan, J.; Zhu, C.; Lin, C.; Fang, W.; Cai, Y.
́
́
J. Nat. Prod. 2007, 70, 1683. (d) Marchal, J. A.; Nun
̃
ez, M. C.; Suarez,
́
́
I.; Díaz-Gavilan, M.; Gomez-Vidal, J. A.; Boulaiz, H.; Rodríguez-
́
Serrano, F.; Gallo, M. A.; Espinosa, A.; Aranega, A.; Campos, J. M.
Breast Cancer Res. Treat. 2007, 105, 237. (e) Conejo-García, A.; Gallo,
M. A.; Espinosa, A.; Campos, J. M. Expert Opin. Ther. Pat. 2008, 18,
211. (f) Saniger, E.; Campos, J. n. M.; Entrena, A.; Marchal, J. A.;
́
́
́
́
Suarez, I.; Aranega, A.; Choquesillo, D.; Niclos, J.; Gallo, M. A.;
́
̃
Espinosa, A. Tetrahedron 2003, 59, 5457. (g) del Carmen Nunez, M.;
Entrena, A.; Rodríguez-Serrano, F.; Marchal, J. A.; Aranega, A.; Gallo,
́
́
M. A.; Espinosa, A.; Campos, J. M. Tetrahedron 2005, 61, 10363.
(2) Synthesis of 1,4-denzodioxepine and 1,4-benzooxathiepines:
(a) Saniger, E.; Campos, J. n. M.; Entrena, A.; Marchal, J. A.; Boulaiz,
́
́
H.; Aranega, A.; Gallo, M. A.; Espinosa, A. Tetrahedron 2003, 59,
́
8017. (b) Nunez, M. C.; Rodríguez-Serrano, F.; Marchal, J. A.; Caba,
̃
́
O.; Aranega, A.; Gallo, M. A.; Espinosa, A.; Campos, J. M.
Tetrahedron 2007, 63, 183. (c) Dai, L.-Z.; Shi, M. Eur. J. Org.
Chem. 2009, 2009, 3129. (d) Nagarjuna Reddy, M.; Kumara Swamy,
K. C. Org. Biomol. Chem. 2013, 11, 7350. (e) Zhao, J.-J.; Tang, M.;
Zhang, H.-H.; Xu, M.-M.; Shi, F. Chem. Commun. 2016, 52, 5953.
(f) Gharpure, S. J.; Anuradha, D. Org. Lett. 2017, 19, 6136.
(3) Selected reviews on the synthesis of seven-membered oxa-
heterocycles: (a) Hoberg, J. O. Tetrahedron 1998, 54, 12631.
(b) Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron
2006, 62, 9301. (c) Meyer, A. G.; Bissember, A. C.; Hyland, C. J. T.;
Williams, C. C.; Szabo, M.; Abel, S.-A. G.; Bird, M. J.; Hyland, I. K.;
Pham, H. In Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J.
A., Eds.; Elsevier, 2018; Vol. 30, pp 493−550.
(4) Selceted recent examples of catalytic enantioselective synthesis
of seven-membered heterocycles: (a) Zhu, S.-Y.; Zhang, Y.; Wang,
W.; Hui, X.-P. Org. Lett. 2017, 19, 5380. (b) Schafroth, M. A.;
Rummelt, S. M.; Sarlah, D.; Carreira, E. M. Org. Lett. 2017, 19, 3235.
(c) Fang, C.; Lu, T.; Zhu, J.; Sun, K.; Du, D. Org. Lett. 2017, 19, 3470.
(d) Fukata, Y.; Yao, K.; Miyaji, R.; Asano, K.; Matsubara, S. J. Org.
Chem. 2017, 82, 12655. (e) Denmark, S. E.; Kornfilt, D. J. P. J. Org.
Chem. 2017, 82, 3192. (f) Ota, Y.; Kondoh, A.; Terada, M. Angew.
Chem., Int. Ed. 2018, 57, 13917. (g) Jiang, F.; Yuan, F.-R.; Jin, L.-W.;
Mei, G.-J.; Shi, F. ACS Catal. 2018, 8, 10234. (h) Feng, J.-J.; Zhang, J.
ACS Catal. 2017, 7, 1533−1542.
(5) (a) Wang, Z.; Chen, Z.; Sun, J. Angew. Chem., Int. Ed. 2013, 52,
6685. (b) Chen, Z.; Wang, Z.; Sun, J. Chem. - Eur. J. 2013, 19, 8426.
(c) Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Angew. Chem., Int.
Ed. 2013, 52, 2027. (d) Yang, W.; Sun, J. Angew. Chem., Int. Ed. 2016,
55, 1868. (e) Yang, W.; Wang, Z.; Sun, J. Angew. Chem., Int. Ed. 2016,
D
DOI: 10.1021/acs.orglett.9b04244
Org. Lett. XXXX, XXX, XXX−XXX