Enantioselective intramolecular cyclization of alkynyl esters catalyzed by a chiral Br?nsted base

Article abstract of DOI:10.1039/c6cc01690a

An enantioselective intramolecular cyclization reaction of alkynyl esters was developed, which employs a Br?nsted base catalyst generated in situ from a chiral Schiff base and t-BuOK. This reaction is a rare example of the enantioselective intramolecular addition of simple ester enolates to alkynes under Br?nsted base catalysis.

Full text of DOI:10.1039/c6cc01690a

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DOI: 10.1039/C6CC01690A
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Enantioselective Intramolecular Cyclization of Alkynyl Esters
Catalyzed by Chiral Brønsted Base
Azusa Kondoh,a Hoa Thi Quynh Tran,b Kyoko Kimura,b and Masahiro Terada*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An enantioselective intramolecular cyclization reaction of alkynyl limited to substrates with relatively high acidity, such as
esters was developed, which employs a Brønsted base catalyst nitroalkanes and active methine compounds. Meanwhile, in an
generated in situ from a chiral Schiff base and t-BuOK. This effort to come up with an efficient cyclization of substrates having a
reaction is a rare example of the enantioselective intramolecular less acidic pro-nucleophilic site, we recently developed an
addition of simple ester enolates to alkynes under Brønsted base intramolecular cyclization of ortho-alkynylphenyl benzyl ethers and
catalysis.
alkynyl esters using phosphazenes as the Brønsted base catalyst.8 In
our continuous studies of Brønsted base catalysis, we envisioned to
develop an enantioselective method for the intramolecular
cyclization of less acidic substrates, that is, the activation of a less
acidic pro-nucleophile by a chiral Brønsted base. In particular, we
focused our attention on chiral alkoxides as potential chiral
Brønsted base catalysts that facilitate the deprotonation of less
acidic pro-nucleophiles because of their high basicity. Herein we
report an enantioselective cyclization of alkynyl esters catalyzed by
a chiral Brønsted base that was generated in situ from a readily
available and structurally modifiable chiral Schiff base and t-BuOK
(Scheme 1).9 The method provides a facile route to enantiomerically
enriched dihydrobenzofuran derivatives possessing a quaternary
stereogenic center.
The intramolecular addition of enols or enolates to alkynes is an
important method for the construction of cyclic frameworks.1
Generally, this transformation takes place via the activation of an
electrophilic site, that is, a C-C triple bond. A variety of π-acidic
transition metal complexes as well as Lewis acids are employed as
the catalyst, and the catalyst-activated nucleophilic addition to an
alkyne affords cyclic compounds.2 Whereas many useful reactions,
including enantioselective variants,3 have been developed to date,
the substrates are limited to easily enolizable pro-nucleophiles
having a relatively acidic proton at the α-position, such as 1,3-
dicarbonyl compounds.4 In order to overcome this intrinsic
limitation, alkynyl silyl enol ethers have been utilized.5 In this case,
however, cumbersome pre-functionalization of carbonyl
compounds is required and therefore, more straightforward
methods applicable to substrates bearing less acidic pro-
nucleophilic groups, such as simple esters, are desired . In addition,
the enantioselective variants of the intramolecular cyclization are
limited.6 In contrast, an alternative approach to the intramolecular
cyclization has emerged, which is based on the activation of a
nucleophilic site by a Brønsted base. Typically, strong alkali metal
bases are employed as the catalyst.7 This approach is, in principle,
capable of activating less acidic pro-nucleophilic groups and thus
would overcome the intrinsic limitation of the approach that is
based on the activation of an electrophilic site. However, even with
this methodology, the reactions developed to date are mainly
Our investigation commenced with a screening for the reaction
conditions using alkynyl ester 2a as the substrate (Table 1). The
initial experiment involved treating 2a with a catalyst generated in
situ from 5.0 mol% chiral Schiff base 110 and 10 mol% t-BuOK in
toluene at room temperature for 6 h.11 As a result, desired product
3
was obtained with good
Z selectivity and moderate
enantioselectivity, albeit in low yield (entry 1).12 In this reaction, the
R3
cat. 1
R3
cat. t-BuOK
R1
R1
CO2Et
t-Bu
R2
O
CO2Et
O
R2
2
3
t-Bu
N
OH
1
OH
Scheme 1 Enantioselective intramolecular cyclization of alkynyl esters catalyzed
by chiral Brønsted base
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Table 1. Screening for reaction conditionsa
such as an ethoxycarbonyl group and a trifluoromethyl group,
underwent the reaction smoothly to provide 3b and 3c in high
yields albeit with modest enantioselectivities. In contrast, the
reaction of 2d, which possesses an electron-donating group at the
para position, was very sluggish at -40 °C (<10%). For this substrate,
improvement of the yield was achieved by increasing the reaction
temperature to -20 °C, and 3d was obtained in 81% yield with 86%
ee. The reaction of substrates having a para-bromophenyl group
and a meta-methoxyphenyl group proceeded smoothly to afford 3e
and 3f in good yields with high enantioselectivities, respectively.
Sterically demanding ortho-substituted substrate 2g underwent the
reaction without any problem to provide 3g in good yield with good
enantioselectivity. Next, the substituents on the benzene ring at the
linker moiety were explored. Both an electron-donating group and
an electron-withdrawing group at the para position of the alkyne
moiety were examined. In these cases, the electronic effect of the
substituents was less significant than that of the substituents at the
alkyne terminus, and both 3h and 3i were obtained in good yields
with good enantioselectivities. The reaction of substrate 2k having a
naphthyl group at the linker moiety proceeded without any
problem to afford 3k in high yield with high enantioselectivity. The
substituents at the α-position of the ester moiety were then
investigated. The reaction of 2l having a phenyl group proceeded
cat. 1
cat. Base
cat. Additive
Solvent, Temp.,Time
CO2Et
O
O
CO2Et
2a
3a
1
Base
(mol%)
Temp. Time Yieldb
% ee
Entry
Solvent
Z/Ec
(mol%)
(°C)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
(h)
6
(%)
4
of Zd
1
2
5
5
5
5
5
5
5
5
5
5
5
t-BuOK (10) Toluene
t-BuOK (15) Toluene
t-BuOK (20) Toluene
t-BuONa (20) Toluene
t-BuOLi (20) Toluene
KHMDS (20) Toluene
t-BuOK (20) CH2Cl2
t-BuOK (20) Et2O
80/20 31
6
78 >95/5 52
84 >95/5 57
3
2
4
2
0
0
-
-
-
-
5
2
6
2
21 90/10 28
78 >95/5 45
86 >95/5 34
7
2
8
2
9
t-BuOK (20) THF
2
81
92/8
5
3
10
11
12
13
14
15e
16f
17g
t-BuOK (20) CH3CN
t-BuOK (20) Toluene
24
24
24
24
24
24
24
24
68 >95/5
54 80/20 69
87 >95/5 75
86 >95/5 81
93 >95/5 86
94 >95/5 87
93 >95/5 88
90 >95/5 92
10 t-BuOK (30) Toluene
0
10 t-BuOK (30) Toluene —20
10 t-BuOK (30) Toluene —40
10 t-BuOK (30) Toluene —40
10 t-BuOK (30) Toluene —40
10 t-BuOK (30) Toluene —40
Table 2. Substrate scopea
a Reaction conditions: 1a (0.010-0.020 mmol), 2a (0.20 mmol), base (0.030-0.060
mmol), solvent (1.0 mL). b Determined by 1H NMR analysis after column
chromatography. 1,3-Benzodioxole was used as the internal standard. c
Determined by 1H NMR analysis after column chromatography. d Determined by
chiral stationary phase HPLC analysis. e 0.020 mmol t-BuOH (10 mol%) was used
as an additive. f 0.020 mmol 4a (10 mol%) was used as additive. g 0.020 mmol 4b
(10 mol%) was used as additive.
1 (10 mol%)
R3
t-BuOK (30 mol%)
R3
4b (10 mol%)
R1
R1
Toluene, 40 °C, 24 h
−
CO2Et
R2
O
CO2Et
O
R2
2
3
CO2Et
CF3
OMe
CO2Et
CO2Et
3c
CO2Et
3db,c
O
O
O
ratio of 1 to t-BuOK was very important. The combination of 5.0
mol% 1 and 15 mol% or 20 mol% t-BuOK dramatically improved
chemical yield, Z/E selectivity, and enantioselectivity (entries 2 and
3). The choice of inorganic base was also critical: The use of t-
BuONa and t-BuOLi resulted in no reaction (entries 4 and 5). In
contrast, the use of KHMDS provided a product in low yield with
low enantioselectivity (entry 6). Screening for the solvent revealed
that toluene was the solvent of choice (entries 7-10).
Enantioselectivity was improved by decreasing the reaction
temperature. When the reaction was performed at 0 °C, the
enantiomeric excess was improved to 69% although the yield was
decreased (entry 11). Modification of catalyst loading, that is, 10
3b
90% yield, 33% ee
90% yield, 53% ee
81% yield, 86% ee
Z/E =89/11
Z/E = >95/5
Z/E = >95/5
Br
OMe
CO2Et
O
CO2Et
CO2Et
O
3gb
O
3e
3f
91% yield, 85% ee
Z/E = >95/5
80% yield, 87% ee
79% yield, 81% ee
Z/E = >95/5
Z/E =95/5
Br
CO2Et
CO2Et
CO2Et
O
O
O
F3C
MeO
MeO
3h
3ib
3j
mol%
1 with 30 mol% t-BuOK, improved both yield and
86% yield, 79% ee
80% yield, 89% ee
90% yield, 92% ee
Z/E = >95/5
Z/E = >95/5
Z/E = >95/5
enantioselectivity (entry 12). An investigation of the reaction
temperature revealed that -40 °C was the optimum temperature
(entry 14). Finally, use of tertiary alcohol as additive further
improved enantioselectivity (entries 15-17). In particular, by using
10 mol% alcohol 4b, desired product 3a was obtained in 90% yield
with 92% ee (entry 17).12
Ph
Bn
OTBS
CO2Et
O
CO2Et
CO2Et
CO2Et
O
3nb
O
3lb
O
3k
3md
97% yield, 93% ee
Z/E = >95/5
82% yield, 48% ee
96% yield, 84% ee
85% yield, 80% ee
Z/E = 88/12
Z/E = >95/5
Z/E =95/5
With the optimum conditions in hand, the screening for the
substrate was carried out. At first, the substituents on the benzene
ring at the alkyne terminus were investigated. Substrates
possessing an electron-withdrawing group at the para position,
a Reaction conditions: 1a (0.020 mmol), t-BuOK (0.060 mmol), 2 (0.20 mmol), 4b
(0.020 mmol), toluene (1.0 mL). The enantiomeric excess was determined for Z
isomers. b The reaction was conducted without 4b. c The reaction was conducted
at -20 °C. d 0.020 mmol 4a (10 mol%) was used instead of 4b.
2 | J. Name., 2012, 00, 1-3
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smoothly but the enantioselectivity was moderate. Benzyl-
substituted 2m provided 3m in high yield with good
enantioselectivity. The siloxy group on the alkyl chain well tolerated
under the reaction conditions and could therefore serve as a handle
for further manipulation (vide infra).
Notes and references
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Finally, the transformation of products
3 by altering the
functionalities was carried out (Scheme 2). The reduction of the
ester moiety of 3 proceeded by treating with an excess amount of
NaBH4 to provide corresponding alcohols 5 in high yields (Scheme
2a). Hydrogenation of the C-C double bond catalyzed by Pd/C
proceeded in a highly diastereoselective manner to afford product
6a having two contiguous quaternary- and tertiary stereogenic
centers in high yield (Scheme 2b).13 Treatment of 3n, which has a
siloxy moiety, with TBAF provided enantio-enriched spirocyclic
compound 7 in good yield without loss of enantiomeric purity.
In conclusion, we have successfully developed an enantioselective
intramolecular cyclization of alkynyl esters that uses a chiral
Brønsted base catalyst generated in situ from a chiral Schiff base
and t-BuOK, providing dihydrobenzofuran derivatives bearing a
quaternary stereogenic center. This novel catalyst system, in which
the readily available and structurally modifiable chiral Schiff base is
utilized as an efficient chiral platform for the Brønsted base
catalysis, is a rare example of the enantioselective intramolecular
addition of simple ester enolates to alkynes. Further investigations
are in progress, focusing on the utilization of the catalyst system in
other Brønsted-base-catalyzed reactions and mechanistic studies.
This work was partially supported by a Grant-in-Aid for Scientific
3
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Scheme 2. Transformation of products
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11 Screening of chiral Schiff bases were also conducted. See the
Electronic Supplementary Information for details.
12 (Z) configuration was initially determined by NOE analysis of
3a. In addition, it was unambiguously determined by X-ray
crystallographic analysis of 5e. At the same time, the
absolute configuration of
3 was determined to be S. See the
Electronic Supplementary Information for details. CCDC No.
1431742 contains the supplementary crystallographic data.
These data can be obtained free of charge from The
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
13 The relative configuration of 6a was determined by NOE
Crystallographic
Data
Centre
via
analysis. See the Electronic Supplementary Information for
details.
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