Ring Expansion of Epoxides under Br?nsted Base Catalysis: Formal [3+2] Cycloaddition of β,γ-Epoxy Esters with Imines Providing 2,4,5-Trisubstituted 1,3-Oxazolidines

Article abstract of DOI:10.1002/anie.201505893

A novel ring-expansion reaction of epoxides under Br?nsted base catalysis was developed. The formal [3+2] cycloaddition reaction of β,γ-epoxy esters with imines proceeds in the presence of triazabicyclodecene (TBD) as a superior Br?nsted base catalyst to afford 2,4,5-trisubstituted 1,3-oxazolidines in a highly diastereoselective manner. This reaction involves the ring opening of the epoxides with the aid of the Br?nsted base catalyst to generate α,β-unsaturated esters having an alkoxide at the allylic position, which would formally serve as a synthetic equivalent of the 1,3-dipole, followed by a cycloaddition reaction with imines in a stepwise fashion. This methodology enables the facile synthesis of enantioenriched 1,3-oxazolidines from easily accessible enantioenriched epoxides.

Full text of DOI:10.1002/anie.201505893

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Angewandte
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International Edition: DOI: 10.1002/anie.201505893
German Edition: DOI: 10.1002/ange.201505893
Asymmetric Synthesis
Ring Expansion of Epoxides under Brønsted Base Catalysis: Formal
[3+2] Cycloaddition of b,g-Epoxy Esters with Imines Providing 2,4,5-
Trisubstituted 1,3-Oxazolidines
Azusa Kondoh, Kenta Odaira, and Masahiro Terada*
Abstract: A novel ring-expansion reaction of epoxides under
Brønsted base catalysis was developed. The formal [3+2]
cycloaddition reaction of b,g-epoxy esters with imines proceeds
in the presence of triazabicyclodecene (TBD) as a superior
Brønsted base catalyst to afford 2,4,5-trisubstituted 1,3-oxazo-
lidines in a highly diastereoselective manner. This reaction
involves the ring opening of the epoxides with the aid of the
Brønsted base catalyst to generate a,b-unsaturated esters
having an alkoxide at the allylic position, which would
formally serve as a synthetic equivalent of the 1,3-dipole,
followed by a cycloaddition reaction with imines in a stepwise
fashion. This methodology enables the facile synthesis of
enantioenriched 1,3-oxazolidines from easily accessible enan-
tioenriched epoxides.
the 1,3-dipole from epoxides with the aid of a Brønsted base
catalyst is the key to the development of the stereoselective
cycloaddition reactions. To this end, we envisioned epoxides
A possessing an EWG (electron-withdrawing group)-substi-
tuted methyl group as the possible precursor of the synthetic
equivalent of the 1,3-dipole. Our reaction design is shown in
Scheme 1.
T
he ring expansion of strained ring compounds has attracted
a great deal of attention as a useful method for the
construction of polysubstituted cyclic frameworks.[1] In par-
ticular, the formal [3+2] cycloaddition reaction of epoxides
with unsaturated compounds has been intensively investi-
gated as a powerful tool for the synthesis of five-membered
heterocyclic compounds containing oxygen. Generally, in
catalytic reactions, transition metals[2] as well as Lewis acids[3]
are utilized as the catalyst. In addition, the combination of
Lewis acidic metals and halides is employed in some cases.[4]
In each case, epoxides formally serve as the synthetic
equivalent of the 1,3-dipole under the influence of those
catalysts, and thus the [3+2] cycloaddition successfully
proceeds with various types of unsaturated compounds to
provide a variety of heterocyclic compounds. However, there
still remains the issue of the limitation of the substituents on
the epoxides and therefore the development of novel
methodologies is highly anticipated. In this context, we
envisioned employing a conceptually different approach,
that is, Brønsted base catalysis, which has rarely been utilized
in the ring expansion of strained-ring compounds. We
considered that the generation of the synthetic equivalent of
Scheme 1. Reaction design.
Treatment of A with a Brønsted base would result in
deprotonation at the position a to the EWG group followed
by epoxide opening, for which the release of ring strain would
serve as a driving force for the generation of electron-
deficient alkenes C having an alkoxide at the allylic position.
This intermediate would then formally serve as the synthetic
equivalent of the 1,3-dipole, and the cycloaddition reaction
with unsaturated compounds (X = Y) would proceed in
a stepwise fashion, that is, the addition of the alkoxide
moiety to the unsaturated compounds followed by cyclization
of the resulting anion to the electron-deficient alkene moiety,
to provide five-membered ring compound E.[5,6] In our
investigation, imines were chosen as a potential partner of
the formal 1,3-dipole in light of the synthetic value of the
adduct, 2,4,5-trisubstituted 1,3-oxazolidines. 1,3-Oxazolidines
can be utilized as versatile intermediates in organic synthesis,
as chiral auxiliaries in asymmetric synthesis,[7] and as ligands
in transition metal catalysis.[8] They are also found in many
natural products as well as bioactive compounds.[9] Whereas
several catalytic [3+2] cycloaddition reactions of epoxides
with imines have been developed,[10] the synthesis of 2,4,5-
trisubstituted 1,3-oxazolidines is rather limited because of the
difficulty of using 2,3-disubstituted epoxides in most cases.
Furthermore, diastereocontrol in multisubstituted 1,3-oxazo-
lidine formation, particularly the formation of trisubstituted
1,3-oxazolidines, represents a great challenge. We envisaged
that in our reaction system, the diastereocontrol would be
[*] Dr. A. Kondoh, Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
K. Odaira, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505893.
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Table 1: Initial screening for reaction conditions.[a]
Entry Base
Solvent Yield [%][b]
3aa[c]
d.r. of 3aa[d] 4a
5a
6aa
1
2
3
4
5
6
7
8
DBU
TBD
MTBD
THF
THF
THF
13 94:6 <1
35 51
Scheme 2. Diastereocontrol in 2,4,5-trisubstituted 1,3-oxazolidine for-
mation under Brønsted base catalysis.
67 97:3
49 95:5
<1
2
12 10
29 16
10 16
22 51
P1-tBu THF
P2-tBu THF
tBuOK THF
Cs2CO3 THF
TBD
TBD
TBD
TBD
TBD
8
3
97:3
99:1
30
1
achieved by substrate control in cooperation with the
reversibility of the hemiaminal ether formation through
addition of the alkoxide to the imine (Scheme 2). If one of
the diastereomers of the hemiaminal ether undergoes sub-
strate-controlled cyclization whereas the other reverses to the
alkoxide in preference to the cyclization, one of the four
diastereomers would be formed selectively. To establish the
proposed stereo-controlling system, a conceptually novel
approach, i.e., the use of a Brønsted base catalyst, is crucial
because of adopting the equilibrium process prior to the
cyclization. Herein we report a formal [3+2] cycloaddition
reaction of b,g-epoxy esters with imines under Brønsted base
catalysis, which provides 2,4,5-trisubstituted 1,3-oxazolidines
in a highly diastereoselective manner. By adopting this
methodology, we achieved the facile synthesis of enantioen-
riched 2,4,5-trisubstituted 1,3-oxazolidines from easily acces-
sible enantioenriched epoxides.
24 94:6
36 95:5
73 95:5
84 95:5
81 97:3
51 98:2
22
26
2
4
8
1
1
6
2
4
2
3
4
1
2
Et2O
9
toluene
CH3CN
DMF
10
11
12[e]
2
12 27
<1 1
CH3CN 91 (84) 97:3
1
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.30 mmol), base
(0.025 mmol), solvent (2.0 mL), rt, 24 h. [b] Yields were determined by
1H NMR measurement. CHBr3 was used as the internal standard. The
yield of isolated product is shown in parenthesis. [c] Yields of the major
diastereomer of 3aa. [d] The ratio of the major diastereomer to the sum
of the other three diastereomers as determined by 1H NMR analysis of
the crude mixture. [e] 2.0 equivalents of 2a was used.
To ascertain the viability of the designed reaction, b,g-
epoxy ester 1a was chosen as the initial substrate and treated
with tosyl imine 2a in the presence of a catalytic amount of
DBU in THF for 24 h. As a result, 1a was completely
consumed and the desired oxazolidine 3aa was formed in
a highly diastereoselective manner albeit in low yield
(Table 1, entry 1). Various by-products, such as alcohol 4a,
g-ketoester 5a, and the diastereomers of 6aa were detected.
5a would be formed by isomerization of the carbon–carbon
double bond of 4a, and 6aa is the adduct of 5a and 2a. A
screening of Brønsted bases showed that the choice of base
was critical for the formation of the desired product 3aa
(entries 1–7). Among the bases tested, guanidines were
superior and 3aa was obtained in moderate yield (entries 2
and 3). In particular, TBD gave the best result (entry 2). The
difference between the results obtained when TBD was used
as the base and those obtained when MTBD was used
indicates that the two hydrogen donor sites of the conjugated
acid of TBD may play a key role in accelerating the [3+2]
cycloaddition. Weak bases, such as tertiary amines, resulted in
no reaction (not shown) whereas strong bases, including
phosphazene bases, provided 3aa only in low yield along with
a significant amount of by-products (entries 4 and 5).
Inorganic bases, such as tBuOK and Cs2CO3, were less
effective, and unreacted 1a (39% and 25%, respectively) as
well as alcohol 4a was intact even after 24 h (entries 6 and 7).
With regard to the diastereoselectivity, the choice of the base
had minimal influence, and 3aa was obtained with a high
diastereoselectivity in all cases, indicating that substrate
control is operative, as expected. Next, solvents were
screened with TBD as the Brønsted base catalyst (entries 8–
11). Among the solvents tested, acetonitrile was the solvent of
choice from the point of view of both yield and diastereose-
lectivity. Employment of a higher amount of tosyl imine 2a
suppressed the formation of by-products, and the major
diastereomer of 3aa was obtained in 91% yield (entry 12).
The relative configuration of the major diastereomer was
determined by single-crystal X-ray diffraction analysis.[11] The
control experiments suggested the involvement of the alk-
oxide of 4a in the reaction.[12] The reaction of 4a with 2a
provided an almost identical result as the reaction of 1a with
2a. In addition, treatment of 1a or 4a in the absence of 2
generated 5a smoothly. These results indicate that the
presence of imines is essential for the formation of the
desired product during the course of generating the alkoxides
from epoxy esters.
With the optimum conditions in hand, the scope of imines
and substituents on the epoxide was investigated (Table 2). At
first, the effect of the substituents on imines was examined
(entries 1–3). Both electron-donating and the electron-with-
drawing groups on the benzene ring affected the reaction. The
reaction with electron-rich imine 2b proceeded smoothly to
provide the product in good yield, but substantial amounts of
by-products 5a and 6ab were formed (entry 1). In contrast,
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Table 2: Scope of b,g-epoxy esters and imines.[a]
Scheme 3. Gram-scale synthesis of 3aa.
Entry R1
R2
3
Yield [%][b]
3[c] d.r. of 3[d]
4
5
6
1
Ph
4-MeO-
C6H4
3ab 68 96:4
3
6
7
2
3
4
Ph
Ph
4-MeO-
C6H4
4-Cl-C6H4
2-Me-C6H4 Ph
2-naphthyl
Bn
iPr
4-Cl-C6H4
2-Me-C6H4 3ad 67 96:4
Ph
3ac 78 97:3
2
7
<1
10
2
5
3ba 93 97:3
<1 <1 <1
5[e]
6
7
8
9
Ph
3ca 79 97:3
3da 79 91:9
3ea 81 96:4
3 fa 80 90:10
3ga 72 98:2
1
2
2
7
Scheme 4. Reaction of b,g-epoxy sulfones. [a] Yield of the major
diastereomer as determined by 1H NMR spectroscopy after column
chromatography. [b] The ratio of the major diastereomer to the sum of
the other three diastereomers.
<1 <1
Ph
Ph
Ph
<1 <1
2
4
5
<1 <1
<1 <1
[a] Reaction conditions: 1 (0.25 mmol), 2 (0.50 mmol), TBD
(0.025 mmol), CH3CN (2.0 mL), rt, 24 h. [b] Determined by 1H NMR
measurement after column chromatography. See the Supporting
Information for details. [c] Yields of the major diastereomer of 3. [d] Ratio
of the major diastereomer to the sum of the other three diastereomers as
determined by H NMR analysis of the crude mixture. [e] The reaction
was performed for 48 h.
for further manipulation, in high yields with high diastereo-
selectivities. It is worth noting that no by-products were
detected in the reaction of the epoxy sulfones in contrast to
the reactions with epoxy esters.
1
In this reaction, cleavage of the carbon–oxygen bond of
the unsymmetrical 2,3-disubstituted epoxides proceeds regio-
selectively, and thus the stereochemistry of one of the carbon
centers of the epoxide is retained throughout the reaction,
enabling the synthesis of enantioenriched 2,4,5-trisubstituted
1,3-oxazolidine derivatives from enantioenriched epoxides.
Indeed, the reaction of enantioenriched epoxides was
attempted (Scheme 5). Enantioenriched epoxides 1a and 1 f,
which have an aryl and an alkyl substituent, respectively, were
easily synthesized by Shiꢀs protocol.[14] The thus synthesized
enantioenriched epoxides were subjected to the reaction
conditions, and the corresponding enantioenriched 2,4,5-
trisubstituted 1,3-oxazolidines were formed without erosion
of the enantiomeric purity. Whereas in principle, from
a mechanistic point of view, the reaction of enantioenriched
alcohols 4 with imines 2 would also allow the synthesis of the
same compounds, this methodology has an advantage due to
the high accessibility of enantioenriched epoxides 1 as sub-
strates compared to the corresponding enantioenriched
alcohols 4.[15]
the reaction with electron-poor imine 2c was slow compared
to the reactions with 2a and 2b, and 9% of 1a remained even
after 24 h (entry 2). The reaction with sterically congested
aryl imine 2d provided the product in good yield but starting
material 1a (4%) and considerable amounts of by-products
4a, 5a, and 6ad were detected (entry 3). In all cases, the
diastereoselectivity was as good as that with 2a.[13] The tosyl
group on the nitrogen was essential for this reaction. Imines
with other substituents, such as Boc and the diphenylphos-
phoryl group, provided a complex mixture of products. Next,
the scope of substituents on the epoxide was examined
(entries 4–9). The substrate with a para-methoxyphenyl group
provided the product in high yield (entry 4). The reaction with
the para-chlorophenyl-substituted substrate required a long
time (entry 5). The ortho-tolyl-substituted substrate furnished
the product in good yield, but the diastereoselectivity was
slightly lower (entry 6). 2-Naphthyl-substituted epoxide 1d
underwent the reaction without any problem (entry 7). In this
reaction, aliphatic substituents were also applicable. Primary
and secondary alkyl-substituted substrates 1 f and 1g afforded
the corresponding products in good yields (entries 8 and 9).
This reaction was sufficiently reliable to permit the
synthesis of 3 in gram scale, and 1.54 g of the single
diastereomer of 3aa was isolated after recrystallization
(Scheme 3). This methodology was further extended to the
reaction of b,g-epoxy sulfones 7 (Scheme 4). Both aryl- and
alkyl-substituted substrates underwent the reaction to pro-
vide the corresponding 1,3-oxazolidines 8 possessing a sulfo-
nylmethyl group, which can potentially function as a handle
Scheme 5. Reactions of enantioenriched b,g-epoxy esters. [a] NMR
yields of the major diastereomer.
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Scheme 6. Transformation of 3aa.
Finally, the transformation of 1,3-oxazolidine 3aa was
performed (Scheme 6). The reduction of the ester moiety of
3aa with LiAlH4 followed by treatment with trifluoroacetic
acid in a mixed solvent of 1,4-dioxane and H2O provided the
2-aminobutane-1,4-diol derivative in good yield (Scheme 6a).
The removal of the hemiaminal ether moiety followed by
lactonization afforded lactone 11 in good yield (Scheme 6b).
In conclusion, a novel ring expansion reaction of epoxides
under Brønsted base catalysis was developed. The formal
[3+2] cycloaddition reaction of b,g-epoxy esters with imines
proceeded in the presence of TBD as a superior Brønsted
base catalyst to afford 2,4,5-trisubstitued 1,3-oxazolidines in
a highly diastereoselective manner. This reaction involves the
regioselective cleavage of the carbon–oxygen bond of unsym-
metrical 2,3-disubstituted epoxides to generate a formal
synthetic equivalent of the 1,3-dipole, followed by the cyclo-
addition reaction with imines in a stepwise fashion. The
operationally simple reaction enables the facile synthesis of
enantioenriched 2,4,5-trisubstitued 1,3-oxazolidines from
easily accessible enantioenriched epoxides. Further investi-
gations to expand the scope of this methodology are in
progress.
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Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molec-
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(Japan) and a Grant-in-Aid for Scientific Research from the
JSPS.
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Keywords: asymmetric synthesis · brønsted base ·
cycloaddition · organocatalyst · ring expansion
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11240–11244
Angew. Chem. 2015, 127, 11392–11396
[11] CCDC 1062825. See the Supporting Information for details.
[12] See the Supporting Information for details.
[13] An aliphatic imine, such as cyclohexyl-substituted imine, and
a heteroaromatic imine, such as 2-furyl-substituted imine, were
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also tested. However, the reaction with those imines provided
the corresponding 1,3-oxazolidines only in moderate yields and
a significant amount of the starting material 1 was recovered. In
both cases, the diastereoselectivity was as high as those in the
reaction with other imines (> 95:5).
[15] Generally, the synthesis of enantioenriched g-hydroxy-a,b-
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Received: June 26, 2015
Revised: July 17, 2015
Published online: August 12, 2015
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