Catalytic and Enantioselective Diels-Alder Reactions of (E)-4-Oxopent-2-enoates

Article abstract of DOI:10.1021/acs.orglett.7b01692

Novel oxazaborolidines activated by the strong acid triflimide or AlBr₃ form cationic chiral catalysts. These are effective catalysts for highly regio- and enantioselective Diels-Alder reactions using substituted (E)-4-oxopent-2-enoates as dienophiles.

Full text of DOI:10.1021/acs.orglett.7b01692

Letter
pubs.acs.org/OrgLett
Catalytic and Enantioselective Diels−Alder Reactions of (E)‑4-
Oxopent-2-enoates
Su-Lei Zhang,†,‡,∥ Yong Lu,‡,∥ Yuan-He Li,‡ Kuang-Yu Wang,‡ Jia-Hua Chen,*,‡ and Zhen Yang*,‡,§
†Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing National Laboratory for
Molecular Science, College of Chemistry and Molecular Engineering, and Peking-Tsinghua Center for Life Sciences, Peking
University, Beijing 100871, China
§Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: Novel oxazaborolidines activated by the strong
acid triflimide or AlBr3 form cationic chiral catalysts. These are
effective catalysts for highly regio- and enantioselective Diels−
Alder reactions using substituted (E)-4-oxopent-2-enoates as
dienophiles.
1,2-Disubstituted dienophiles with two different electron-
withdrawing groups1 are good partners in the Diels−Alder
reaction because of their LUMO-lowering properties.2 In this
context, substituted (E)-4-oxopent-2-enoates (A in Figure 1) are
control, which presents a challenge in the development of a
catalytic asymmetric variant of Diels−Alder reaction. Herein, we
describe the development of an enantioselective Diels−Alder
reaction of (E)-4-oxopent-2-enoates (A) using modified
oxazaborolidine-based catalysts.
We recently reported that Hayashi’s ligand E was an effective
catalyst in the enantioselective synthesis of aldehyde 3 (eq 1 in
Scheme 1), which was then converted to ketone 4, a key
intermediate in our asymmetric total synthesis of the natural
product propindilactone G.5 However, the process would be
more attractive if ketone 4 could be directly constructed from
diene 1 and (E)-4-oxopent-2-enoate-based dienophile 5. We,
therefore, began to explore this concise synthesis.
Cationic chiral oxazaborolidiniums 7, 8, and 9 (eq 2 in Scheme
1) are the most versatile and electrophilic chiral catalysts, which
are obtained by activation of the (R)-oxazaborolidine 6 with
either triflic acid, triflimide, or AlBr3.6,4b Because these catalysts
are effective in a variety of Diels−Alder reactions with high
enantio- and diastereoselectivities,7 we initially investigated the
enantioselective synthesis of 4 from diene 1 and dienophile 5
using catalysts 7−9.
Table 1 shows the results. When catalysts 7 and 8 were used,
both reactions proceeded in the presence of catalyst (10 mol %)
in CH2Cl2 at 0 °C to give product 4 in 85% yield with 63% ee and
88% yield with 54% ee, respectively (Table 1, entries 1 and 2).
When 9 was used as the catalyst, the reaction at −78 °C gave 4 in
94% yield with 57% ee (entry 3), indicating that catalyst 9 was
more potent than catalysts 7 and 8. Although catalyst 9 afforded
the desired product in high yield, its enantioselectivity was
Figure 1. Diels−Alder reactions of (E)-4-oxopent-2-enoates.
unique because they can coordinate with Lewis acids. This
increases the reactivity of the dienophiles and induces
enantioselectivity in the presence of asymmetric catalysts in the
Diels−Alder reactions.
However, the usefulness of (E)-4-oxopent-2-enoates in the
asymmetric synthesis via Diels−Alder reactions is diminished
both by the low site selectivity of coordination of its two carbonyl
groups to Lewis acids3 (eq 1 in Figure 1) and by the lower
selectivity of Lewis acid coordination with its ketone moiety
because the ketone is positioned in a similar steric environment4
(eq 2 in Figure 1).
Both these issues arise in the Lewis acid association step, an
organizational event that is essential for stereo- and regioselective
Received: June 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01692
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Organic Letters
Letter
Information (SI). To evaluate the effect of the methyl group on
the C ring of ligand 10 on the outcome of the Diels−Alder
reaction, we also made the ligand 10a (eq 3 in Scheme 1) by
replacing this methyl group with a hydrogen.
Scheme 1. Diels−Alder Reactions and Cationic Chiral
Oxazaborolidines
We then performed the Diels−Alder reactions. First, ligand 10
and AlBr3 were mixed in CH2Cl2 at −25 °C, which was then
cooled to −78 °C. To this solution was added a solution of diene
1 and dienophile 5 in CH2Cl2 in a dropwise manner at −78 °C,
and the resultant mixture was then stirred at −78 °C for 1.5 h.
The reaction was then quenched by addition of Et3N (0.2 mL).
The desired product 4 was obtained in 80% yield with 90% ee
(Table 2, entry 1). We also ran the same reactions under the
Table 2. CF3-Derived Oxazaborolidines As Catalysts in the
Diels−Alder Reaction of Diene 1 and Ketoester 5
entry
catalyst
time (h)
yield (%)
ee (%)
1
2
10
1.5
5.5
80
80
90
94
10a
identical conditions in the presence of ligand 10a for comparison.
The data in Table 2 show that 10a catalyzed the Diels−Alder
reaction to give 4 in 80% yield with 94% ee.
The absolute stereochemistry of 4 was confirmed by
comparison of its NMR spectrum and optical rotation with
those of compound 4 derived from the Hayashi-ligand-catalyzed
Diels−Alder reaction, which is a key intermediate in our
asymmetric total synthesis of propindilactone G.5
Table 1. Corey’s Oxazaborolidine-Based Catalysts in the
Diels−Alder Reaction of Diene 1 and Ketoester 5
a
bc
,
Mechanistically, the optimal structure of ketone-binding
substrate−oxazaborolidinium complex A shown in Figure 2
entry activator catalyst
temp
0 °C
0 °C
time (h) yield (%) ee (%)
1
2
3
TfOH
Tf2NH
AlBr3
7
8
9
7
85
88
94
63
54
57
5
−78 °C
1.5
a
Reagents and conditions: to a solution of catalyst in CH2Cl2 prepared
by mixing ligand (1.25 equiv) and activator (1.0 equiv) was added the
solution of diene 1 (2 equiv) and dienophile 5 (1 equiv) in CH2Cl2 at
the given temperature, and the reaction was carried out under the
b
conditions listed above. Product ratios determined by chiral HPLC.
c
Absolute configuration of product 4 was determined by chemical
correlation to a known compound.
unsatisfactory. We, therefore, decided to initiate a program to
identify more efficient catalysts that give high yields and high
enantioselectivities in the proposed Diels−Alder reaction.
Recently, Corey and co-workers reported that the fluorine
substituents in the chiral oxazaborolidinium ligands can lead to
more potent chiral oxazaborolidinium cationic catalysts.8 The
effectiveness of Hayashi’s ligand, which bears four trifluor-
omethyl groups on its two phenyl rings, in the Diels−Alder
reaction for the synthesis of 3 from diene 1 and dienophile 2
inspired us to prepare a modified oxazaborolidine ligand 10 (eq 3
in Scheme 1). We expected that this type of ligand would be
effective in the enantioselective synthesis of ketone 4 from diene
1 and dienophile 5 because the four electron-deficient
trifluoromethyl groups would significantly reduce the electron
density on the gem-biaryl rings. This would enhance coordination
of the boron atom in catalyst 10 with the carbonyl group in
dienophile 5.
Figure 2. Optimal conformations of the substrate−oxazaborolidinium
complex (A) and favored transition state structure (B).11
exhibits characters similar to previous studies:4b,10 (1) the ketone
favors coordinating to the boron atom from the less congested
convex face of the fused 5/5 ring system; (2) in the complex, the
coordinating CO double bond favors an s-trans configuration
relative to the CC double bond; (3) the remaining lone pair on
the carbonyl oxygen adopts a trans-planar conformation relative
to B−O bond, probably due to secondary orbital interaction; and
(4) for the nonclassical C−H···O hydrogen bond, the O···H
distance and C(−H)···O distance are short, at around 230 and
285 pm, respectively, although the C−H···O angle is relatively
sharp, at around 110°.
The favorable substrate−oxazaborolidinium complex A has a
coordinate site from its convex face, which led the diene 1 to
attack A from its less hindered direction. The reaction of the
resulting borane complex A with diene 1 would proceed via
To test our proposal, ligand 10 was prepared according to the
reported protocol,9 and the details are given in the Supporting
B
DOI: 10.1021/acs.orglett.7b01692
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Organic Letters
Letter
transition state B in which the bonding is principally between the
β-carbon of the binding carbonyl group in the dienophile 5 and
C(1) of diene 1. The enhanced enantioselectivities of ligands 10
and 10a indicate that electron-deficient groups (CF3−) on the
oxazaborolidine scaffold could benefit the asymmetric synthesis
of product 4.
carbonyl groups of dienophile 15 to the catalysts caused by
reducing the electron density on the ester group.
With this chemistry in mind, we then began to synthesize
carbocycles 18a−18e using catalysts derived from 10, 12, and 13.
As shown in Table 5, all the selected substrates could afford the
To support this analysis, ligands 11, 12, and 13 (eq 3 in
Scheme 1) were synthesized accordingly. Ligand 11 was made by
replacement of the C ring of ligand 10 by a 2,5-difluoro-phenyl
group,8 and ligands 12 and 13 were prepared by replacement of
the C ring of ligand 10 by a 2-(trifluoromethyl)phenyl group and
a 2-(trifluoromethoxy)phenyl group, respectively. With these
ligands in hand, we then carried out their Diels−Alder reactions
of diene 1 with dienophile 5. As illustrated Table 3, all the
reactions could afford the desired product 4, and the catalyst
derived from ligand 12 gave both the highest yield and ee (Table
3, entry 2).
Table 5. Enantioselective Synthesis of Carbocycles 18a−18e
Table 3. Diels−Alder Reactions Catalyzed by
Oxazaborolidines 11−13 Derived Catalysts
entry
catalyst
time (h)
yield (%)
ee (%)
1
2
3
11
12
13
4
4
87
97
85
88
97
79
36
In an attempt to decipher the enhanced enantioselectivity, we
then carried out computational experiments. Our results reveal a
general trend that the bonding between the carbonyl oxygen and
oxazaborolidinium boron atom is strengthened by the electron-
withdrawing aryl groups on the oxazaborolidinium. As a result,
the bond distance between the carbonyl oxygen of dienophile
and the boron atom of oxazaborolidinium is shortened, which
coincides with the observed increase of enantioselectivity (details
in SI).11,12
To examine the electronic effect of the ester in dienophile on
the outcome of Diels−Alder reaction, we prepared dienophile 15
bearing a trifluoroethyl ester13 and ran its Diels−Alder reaction
with diene 1 in the presence of the catalysts derived from 11, 12,
and 13; the results are given in Table 4. When the catalyst derived
a
b
The reaction was conducted at −60 °C. The reaction was conducted
c
at −70 °C. The ratio of endo/exo for the product 18e is >99:1.
expected annulated products in good yields with good ee values.
It is worthwhile to mention that different substrates need
different catalyst and various combinations of catalyst loadings
and reaction times to achieve better results.
To extend the reaction scope, we used the developed method
for the enantioselective synthesis of carbocycle 20, which is a key
intermediate in our asymmetric total synthesis of naturally
occurring complex triterpenoid lancifodilactone G.14 A pre-
cooled solution of diene 1 and dienophile 19 was added to the
freshly prepared catalyst, either 10, 10a, 12, or 13, and the
reaction was run under the conditions listed in Table 6. The
results show that the catalysts derived from ligands 12 and 13
(entries 3 and 4) afforded the desired product 20 in excellent
Table 4. Diels−Alder Reactions with Dienophile 15
entry
catalyst
time (h)
yield (%)
ee (%)
1
2
3
11
12
13
5
4
80
42
77
73
89
75
Table 6. Enantioselective Synthesis of Carbocycle 20
18
from 11 was used in the Diels−Alder reaction, 16 was formed in
80% yield with 73% ee. In the case of the catalyst derived from 12,
the yield of adduct 16 decreased significantly, and the ee was
slightly higher (Table 4, entry 2). However, moderated yield and
ee of adduct 16 were obtained when ligand 13 was used in the
reaction (Table 4, entry 3). The observed results are presumably
because of the low site selectivity of the coordination of its two
entry
catalyst
time (h)
yield (%)
ee (%)
1
2
3
4
10
10a
12
6
2
1
1
87
85
97
95
87
92
94
96
13
C
DOI: 10.1021/acs.orglett.7b01692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Alder reaction using substituted (E)-4-oxopent-2-enoates as
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Corey’s oxazaborolidinium cations. The developed method was
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ASSOCIATED CONTENT
* Supporting Information
■
(5) You, L.; Liang, X.-T.; Xu, L.-M.; Wang, Y.-F.; Zhang, J.-J.; Su, Q.; Li,
Y.-H.; Zhang, B.; Yang, S.-L.; Chen, J.-H.; Yang, Z. J. Am. Chem. Soc.
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01692.
Experimental procedures, spectral, and other character-
ization data (PDF)
(7) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808.
(8) Reddy, K. M.; Bhimireddy, E.; Thirupathi, B.; Breitler, S.; Yu, S.;
Corey, E. J. J. Am. Chem. Soc. 2016, 138, 2443.
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AUTHOR INFORMATION
Corresponding Authors
■
(10) (a) Johnston, R. C.; Cheong, P. H. Org. Biomol. Chem. 2013, 11,
5057. and references therein. (b) Paddon-Row, M.; Kwan, L. C.; Willis,
A. C.; Sherburn, M. S. Angew. Chem., Int. Ed. 2008, 47, 7013.
(11) Computations are carried out at the PWPB95-D3/def2-TZVP//
B3LYP- D3/def2-SV(P)+LANL08(d) level (LANL08(d) basis set and
corresponding pseudopotential were used for Br atoms and def2-SV(P)
basis sets for all the other atoms during optimization), and solvation
effect in CH2Cl2 was considered with SMD solvation model at the M05-
2X/6-31G(d) level. The calculations were performed with the Gaussian
09 program package and ORCA 3.0.3 program at the given level. Details
of complexation preference, transition state structures, and energies are
discussed in SI. For references of the programs, see: (a) Frisch, M.;
Trucks, J.; Schlegel, H.; et al. Gaussian 09, Revision D.01; Gaussian, Inc.:
Wallingford CT, 2013 (see Supporting Information for full reference).
(b) Neese, F. WIREs Comput. Mol. Sci. 2012, 2, 73. for references of the
methods and basis sets see: (c) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
(d) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297.
(e) Goerigk, L.; Grimme, S. J. Chem. Theory Comput. 2011, 7, 291.
(f) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comput. Chem. 2011, 32, 1456.
(g) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Chem. Phys. 2009,
356, 98. (h) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem.
B 2009, 113, 6378.
*E-mail: jhchen@pku.edu.cn
*E-mail: zyang@pku.edu.cn
ORCID
Zhen Yang: 0000-0001-8036-934X
Author Contributions
∥S.-L.Z. and Y.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Lian-Suo Zu and Prof. Jian Wang (School of
Pharmaceutical Sciences, Tsinghua University) for assistance in
chiral HPLC analysis. This work is financially supported by
Natural Science Foundation of China (Grant Nos. 21372016,
21572009, and 21472006).
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D
DOI: 10.1021/acs.orglett.7b01692
Org. Lett. XXXX, XXX, XXX−XXX