Organocatalytic, Enantioselective, intramolecular oxa-michael reaction of alkoxyboronate: A new strategy for enantioenriched 1-substituted 1,3-Dihydroisobenzofurans

Article abstract of DOI:10.1021/ol502614n

An unprecedented strategy for the synthesis of enantioenriched 1-substituted 1,3-dihydroisobenzofurans via an enantioselective oxa-Michael reaction of o-alkoxyboronate containing chalcone (II) has been accomplished employing cinchona alkaloid based squara

Full text of DOI:10.1021/ol502614n

Letter
pubs.acs.org/OrgLett
Organocatalytic, Enantioselective, Intramolecular Oxa-Michael
Reaction of Alkoxyboronate: A New Strategy for Enantioenriched
1‑Substituted 1,3-Dihydroisobenzofurans
Barnala Ravindra, Braja Gopal Das, and Prasanta Ghorai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal 462066, India
S
* Supporting Information
ABSTRACT: An unprecedented strategy for the synthesis of
enantioenriched 1-substituted 1,3-dihydroisobenzofurans via
an enantioselective oxa-Michael reaction of o-alkoxyboronate
containing chalcone (II) has been accomplished employing
cinchona alkaloid based squaramide bifunctional organo-
catalyst in the presence of proton source. The corresponding
alkoxyboronate intermediates have been readily prepared in
situ from o-formyl chalcones using neutral borane as hydride source and a tertiary amine moiety which is a counterpart of the
catalyst.
Scheme 1. Strategies for Synthesis of Enantiomerically
Enriched 1-Substituted 1,3-Dihydroisobenzofurans
hiral 1-substituted 1,3-dihydroisobenzofurans are impor-
Ctant scaffolds that are commonly found in many molecular
targets, including the natural product pestacin1 as well as
molecules of fascinating pharmaceutical relevance such as
citalopram2 and synthetic A (Figure 1).3 Despite their
importance, to the best of our knowledge, the enantioselective
synthesis via catalytic pathways has not been achieved and still
remains a major challenge.
unsuccessful because of its rapid cyclization to the corresponding
racemic isobenzofuran ( )-3e.6
To suppress such rapid cyclization, we hypothesized a
transiently generated alkoxyboronate intermediate (II, Scheme
1) by which the alcohol counterpart could be potentially masked
and would be released only upon further activation. Inspired by
the recent success of push/pull-type bifunctional organocatalysis
using catalysts bearing a H-bond donor moiety and a tertiary
amino group on a chiral scaffold,7,8 we were interested in
pursuing our current interest, the asymmetric intramolecular
oxa-Michael addition process of intermediate II using such
catalysts derived from cinchona alkaloid. We assumed that the
tertiary amine part of the catalyst could activate the
alkoxyboronate counterpart (the push); on the other hand, the
H-bonding counterpart could activate the enone moiety (the
pull) (TS-I, Scheme 2, second step). Furthermore, such a
coordination also preorganized the intermediate to a well-
defined orientation, an important prerequisite for asymmetric
induction. To achieve the alkoxyboronate intermediate (II), the
Figure 1. 1-Substituted 1,3-dihydroisobenzofurans structural motif in
drugs and natural products.
The oxa-Michael addition reaction is one of the most powerful
tools to construct carbon−oxygen bonds.4 In particular, the
intramolecular variants are the most straightforward route to
oxoheterocycles. However, the development of asymmetric
variants of such an intramolecular oxa-Michael addition still
remains significantly challenging because of its rapidity and
reversibility.4b,g In recent times, chiral bifunctional catalysts have
been utilized to surmount such a barrier to achieve highly
enantioselective intramolecular oxa-Michael reactions.5
Inspired by these elegant reports, we envisaged that
enantioenriched 1-substituted 1,3-dihydroisobenzofurans could
easily be accessed through an intramolecular asymmetric oxa-
Michael reaction of o-hydroxymethyl-containing chalcones (I)
(Scheme 1) using bifunctional catalysts. However, the synthesis
of o-hydroxymethyl-containing chalcone (I, Scheme 1) remained
Received: September 3, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
TLC), the oxa-Michael addition was found to be feasible and
provided the desired 3a with moderate enantioselectivity. The
screening of other chiral thiourea (2a,b)9 as well as squaramide
(2c−f)11 catalysts (entry 2−7) in iPrOH revealed that 2c is the
best catalyst to provide 3a in terms of high enantioselectivity
(91% ee, entry 4). Further, screening of a mixture of iPrOH and
Scheme 2. Concept of the New Catalytic Mode of Action
i
aprotic solvents (1:4 v/v) revealed that a PrOH and MeNO2
solvent mixture in 1:4 ratio was the best combination with
respect to enantioselectivity (entry 8). To our delight, further
increases in the overall reaction yields were observed by
increasing the reaction temperature to 45 °C (entry 9) with
reduced reaction time. Using H2O as protic solvent instead of
iPrOH resulted in minor reduction of the enantioselectivity
(entry 10). The lowering of the catalyst loading from 10 mol %
resulted in decreased reactivity as well as selectivity. The use of
only iPrOH or MeNO2 as solvent at 45 °C was also not effective.
Other hydride sources such as NaBH4, NaB(CN)H3, BH3−
SMe2, and catecholborane were found to be ineffective for such
reactions with respect to yields and enantioselectivities.6
reduction of aldehyde via neutral borane activation catalyzed by
tertiary amine (part of the catalyst) has been adopted (Scheme 2,
first step).8
To materialize this strategy, the reduction of o-formyl chalcone
1a using pinacolborane as hydride source was investigated using
10 mol % of chiral thiourea-based catalyst (2a)9 derived from
cinchona alkaloid (Table 1). In anhydrous aprotic solvents such
Table 1. Optimization of the Reaction Conditions
With the optimized reaction conditions in hand, the scope of
the external aryl group has been briefly investigated (Table 2).
a
Table 2. Substrate Scope: 1,3-Dihydroisobenzofurans
b
c
temp
(°C)
time
(h)
yield
ee
entry
2
solvent
(%)
(%)
a
1
2
2a
2a
2b
2c
aprotic solvents
iPrOH
iPrOH
rt
rt
12
12
12
12
12
12
12
12
5
<5
25
nd
81
nd
91
87
81
82
93
94
92
3
rt
>5
25
4
iPrOH
rt
5
2d iPrOH
rt
39
6
2e
2f
iPrOH
iPrOH
rt
21
7
rt
35
d
8
2c
2c
2c
iPrOH/MeNO2
iPrOH/MeNO2
rt
77
d
9
45
rt
100
100
d
10
H2O/MeNO2
12
a
Aprotic solvents such as toluene, EtOAc, CHCl3, CH2Cl2, MeCN,
b
and MeNO2. The conversion was calculated based on 1NMR
spectroscopy of the crude reaction mixture using anisole as internal
standard. Enantiomeric excess was determined by HPLC analysis on a
c
d
chiral stationary phase. Ratio was 1:4 (v/v).
as toluene, EtOAc, CHCl3, CH2Cl2, MeCN, and MeNO2, the
hydroboration was completed within 45 min to provide the
corresponding alkoxyboronate intermediate IIa,10 which was
supported by NMR and mass spectroscopic studies, whereas the
oxa-Michael addition step of IIa remained nearly unachievable in
these solvents (entry 1, Table 1). Further, we investigated the
feasibility of the reaction in protic solvents (for details, see the
Supporting Information).6 We observed that in case of MeOH,
the side reaction to provide the corresponding acetal prohibited
a
Reaction conditions: 1 (0.225 mmol), pinBH (0.34 mmol, 1.5 equiv),
2c (0.0225 mmol, 10 mol %) in iPrOH/CH3NO2 (1:4, 0.111 M) at 0
°C for 45 min then 45 °C for 2−6 h. Yields shown are based on
isolated products. Enantiomeric excess were determined by HPLC
analysis on a chiral stationary phase. The yields and % ee after
recrystallization are shown in parentheses. The reduction was carried
out at 0 °C for 2 h.. Catalyst 2e was used instead of 2c.
b
c
d
i
e
the reduction step itself. Interestingly, in EtOH and PrOH,
although the reduction step remained partially completed (by
f
B
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Organic Letters
Letter
Aryls with electron-withdrawing substituents (F−, di-F−, O2N−,
F3C−, EtO2C−, NC−, amide) and electron-donating sub-
stituents (Me−, MeO−, Me2N−) gave the corresponding
isobenzofurans 3a−o in good yields and with high enantiose-
lectivities (81−97% ee). Notably, many of the above-mentioned
functional groups such as O2N−, NC−, ester, amide, and amine,
which are generally sensitive toward borane, are found to
produce the desired oxa-Michael products under such mild
reaction conditions. Heteroaromatics such as 2-furan and 2-
thiophene (entries 17 and 18, Table 2) provided high yields and
enantioselectivity (94% ee in each case). Furthermore, the use of
α-naphthyl ring resulted in decreased yield and enantioselectivity
(entry 19). Interestingly, most of these products are crystalline
compounds; optically pure products (>99% ee) could be
obtained after recrystallization (entries 1, 4, 5, and 10−12). In
addition, when the reaction of 1e was scaled 14-fold (1g, 3.2
mmol) with similar catalyst loading under similar reaction
conditions, even better results were obtained (entry 6).
Moreover, the optical antipode (for example, 3f instead of 3e,
entry 7) could also be obtained with high enantioselectivity using
catalyst 2e instead of 2c.
Scheme 4. Benzylic Oxidation of Chiral 1-Substituted
Isobenzofurans to 1-Substituted Phthalide
The quantitative kinetic isotopic effect (KIE, kH/kD = 3.84) for
ortho-cyclization of alkoxyboronate was also calculated on the
basis of 1H NMR studies in the presence of H2O and D2O.6 This
indicates the crucial role of the proton source in the rate-
determining step.
On the basis of the above observations, a plausible mechanism
for the oxa-Michael addition of alkoxyboronate II is depicted in
Scheme 5.14 In the absence of a protic solvent, the catalyst alone
Scheme 5. Proposed Mechanism
To expand the substrate scope, our further examination
focused on the substitution of the internal aryl group
(summarized in Scheme 3). Good yields and high enantiose-
Scheme 3. Substrate Scope: 1-Substituted 1,3-
a c
−
Dihydroisobenzofurans
may not be able to push the oxa-Michael addition to occur to
provide the intermediate D.15,16 In the presence of a protic
solvent, the decomposition of the alkoxyboronate to correspond-
ing alcohol C, via intermediate B, followed by alcohol cyclization
could occur to provide the desired product 3. An alternative
pathway in which the direct cyclization of the intermediate B
could also be possible. However, such requirement of an alcohol
in addition to a Lewis base catalyst have already been realized for
the activation of diborane.17
A transition state similar to those previously proposed for the
squaramide/thiourea catalysts in the oxa-Michael reaction of
enone7,8 may be invoked to explain the observed absolute
stereochemistry of product (Scheme 6).
a
b
The reaction conditions were same as those in Table 2. Isolated
c
yield. Enantiomeric excess were determined by HPLC analysis on a
chiral stationary phase. After recrystallization. For absolute
configuration, see the literature value (ref 3).
d
e
lectivities were achieved in the reductive oxa-Michael addition of
a variety of substituted o-formyl chalcones (1r−za). The
presence of either electron-donating or electron-withdrawing
substituents on the internal aryl moiety (3s−zb) were found to
be equally effective. In the cases of 3zb and 3t, reduced
enantioselectivity (82% and 74% ee, respectively) was observed.
Notably, compounds 3u,v are synthetic precursors for several
5HT receptor agonists (A, in Figure 1).3
In summary, a highly enantioselective intramolecular oxa-
Michael reaction of alkoxyboronate has been achieved employing
a chiral bifunctional organocatalyst. Alkoxyboronates are
generated in situ by the reduction of corresponding aldehyde
Scheme 6. Proposed Model for the Enantioselectivity-
Determining Step
Inspired by the importance of the 1-substituted phthalide
(isobenzofuran-1(3H)-ones) moiety in natural products such as
isopestacin and cryphonectric acid possessing significant bio-
logical activities,12 we intended to convert our synthesized chiral
substituted isobenzofurans to the phthalide moiety by benzylic
oxidation as shown in Scheme 4. A decrease in enantioselectivity
was observed, probably due to the reversible oxa-Michael
addition of 3a under basic conditions as well as the formation
of a benzylic radical under such oxidation conditions.13
C
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Letter
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catalyst. The current methodology leads to highly enantiose-
lective synthesis of 1-substituted 1,3-dihydroisobenzofurans with
a broad substrate scope. Further studies to clearly understand the
reaction mechanism and further synthetic applications are
ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
(6) See the Supporting Information for details.
■
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pghorai@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been funded by the Council of Scientific and
Industrial Research (CSIR), New Delhi, and IISER Bhopal. B.R.
and B.G.D. thank CSIR for doctoral fellowships. We are thankful
to Dr. Deepak Chopra, Dr. Abhijit Patra, and Dr. Joyanta
Choudhury, Assistant Professors, IISER Bhopal, for helpful
discussions.
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1
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