Chiral Pyridinium Phosphoramide as a Dual Br?nsted Acid Catalyst for Enantioselective Diels-Alder Reaction

Article abstract of DOI:10.1021/acs.orglett.6b00608

Chiral pyridinium phosphoramide 1·HX was designed to be a new class of chiral Br?nsted acid catalyst in which both the pyridinium proton and the adjacent imide-like proton activated by the electron-withdrawing pyridinium moiety could work cooperatively as strong dual proton donors. The potential of 1·HX was shown in the enantioselective Diels-Alder reactions of 1-amino dienes with various dienophiles including N-unsubstituted maleimide, which has yet to be successfully used in an asymmetric Diels-Alder reaction.

Full text of DOI:10.1021/acs.orglett.6b00608

Letter
pubs.acs.org/OrgLett
Chiral Pyridinium Phosphoramide as a Dual Brønsted Acid Catalyst
for Enantioselective Diels−Alder Reaction
Yasuhiro Nishikawa,*,† Saki Nakano,† Yuu Tahira,† Kanako Terazawa,† Ken Yamazaki,†
Chitoshi Kitamura,‡ and Osamu Hara*,†
†Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan
‡Department of Materials Science, School of Engineering, The University of Shiga Prefecture, 2500 Hassaka-cho, Hikone, Shiga
522-8533, Japan
S
* Supporting Information
ABSTRACT: Chiral pyridinium phosphoramide 1·HX was
designed to be a new class of chiral Brønsted acid catalyst in
which both the pyridinium proton and the adjacent imide-like
proton activated by the electron-withdrawing pyridinium
moiety could work cooperatively as strong dual proton donors.
The potential of 1·HX was shown in the enantioselective
Diels−Alder reactions of 1-amino dienes with various
dienophiles including N-unsubstituted maleimide, which has
yet to be successfully used in an asymmetric Diels−Alder
reaction.
ual hydrogen bonding (DHB) catalysts have received
1
Dmuch attention in the area of enantioselective synthesis.
The tight complexes formed by DHB donors and Lewis basic
substrates through secondary interactions can contribute to
higher reactivities and stereoselectivities compared to single
hydrogen bonding (HB) catalysts with similar acidity. Having
identified thioureas as one of the most promising scaffolds in
neutral DHB catalysis, much effort has been dedicated to
exploring alternative motifs, which address some of its
drawbacks such as reactivity, selectivity, and the scope of
reactions.2 As a result, several scaffolds such as guanidines,3
squaramides,4 and silanediols5 were identified, yielding better
results than thioureas in some cases (Figure 1). In parallel with
the development of Brønsted acid catalysts,6,7 other approaches
to expand the potential of DHB catalysis have centered around
ionic HB donors such as guanidinium,8 aminopyridinium,9
(amino)quinolinium,10,11 and phosphonium.12 The enhanced
acidity of a DHB donor or dual Brønsted acid in ionic catalysts
is expected to result in higher reactivity while maintaining the
stereoselectivity of their bidentate nature.
In this context, we focused our attention on the possibility of
Figure 1. Neutral and ionic dual hydrogen bonding catalysts in
pyridinium amide 1′·HX as a highly acidic dual Brønsted acid
asymmetric synthesis.
catalyst that could be produced by protonation of 2-
aminopyridine 1′ bearing an electron-withdrawing group
(EWG) on the amino group (Figure 1). In the structure of
mind, chiral pyridinium phosphoramide 1·HX was designed.
1′·HX, we envisioned that the pyridinium moiety should
Herein, we report newly designed ionic Brønsted acid catalysts
and their application to an enantioselective Diels−Alder
reaction.
function as an additional EWG for the adjacent amino group
based on its cationic character, generating an acidic N-H proton
between two EWG, like an imide. Subsequently, the imide-like
proton cooperating with the pyridinium proton in 1′·HX could
result in a strong dual proton donor compared to N-
alkylaminopyridinium derivatives.13 With this concept in
Received: March 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In preliminary screening of catalysis by pyridinium
phosphoramide 1·HX consisting of pyridyl phosphoramide
114 and strong Brønsted acid (HX), we found 1a·TfOH
catalyzed a Diels−Alder reaction of N-Cbz-1-amidodiene 2a
and N-H maleimide 3a to afford endoadduct 4a in good yield
and excellent diastereoselectivity as well as moderate
enantioselectivity (Table1, entry 1).15 Interestingly, addition
indicated that the stability of the resulting ionic complex due to
acid−base interaction is related to stereoselectivity in this
reaction (entry 13). At this stage, we speculated that a proton
of the ionic Brønsted acid catalyst could dissociate to the basic
component in the reaction such as a counteranion or imide
carbonyl group, which would produce an achiral strong
Brønsted acid causing undesired racemization (Figure 2).16
a
Table 1. Optimization of the Reaction Conditions
Figure 2. Plausible equilibrium of ionic Brønsted acids.
The increased enantioselectivity by addition of pyridine
derivatives 1a or 1e can be explained as due to the pyridine
moiety inhibiting racemization by recovery of a proton from the
achiral Brønsted acid (entries 1 and 2, 6 and 10).
Encouraged by the preliminary results, we next investigated
the function of the pyridinium phosphoramido moiety bearing
two acidic protons as follows (Scheme 1, R1). Using the same
reaction conditions as 1e·TfOH, a corresponding chiral
phosphoric acid (R1 = OH) afforded no cyclized product.
Removal of TfOH from 1e·TfOH resulted in unreactive and
4a
b
c
entry
1·HX (mol %)
1 (mol %)
% yield
% ee
1
1a·TfOH (10)
1a·TfOH (10)
1b·TfOH (10)
1c·TfOH (10)
1d·TfOH (10)
1e·TfOH (10)
1f·TfOH (10)
1g·TfOH (10)
1h·TfOH (10)
1e·TfOH (10)
1e·TfOH (7.5)
1e·Tf2NH (10)
1e·MsOH (10)
0
5
70
66
31
44
67
67
99
77
92
100
94
47
40
50
67
0
2
3
5
4
5
29
80
84
70
72
79
90
72
80
23
5
5
Scheme 1. Optimization of Aminopyridine Moiety in
Catalyst 1
6
5
7
5
8
5
9
5
10
11
12
10
7.5
5
c
13
5
a
Reactions were performed with 0.4 mmol of 2a, 0.2 mmol of 3a and
toluene (1 mL) in the presence of catalyst as shown. See the
b
Supporting Information for details. Isolated yield as single
c
diastereomer. Determined by chiral HPLC.
of 0.5 equiv of pyridylphosphoramide 1a relative to 1a·TfOH
increased the enantioselectivity (entry 2). To further improve
enantioselectivity, a variety of derivatives of chiral phosphor-
amide 1 having different Ar groups on the 3,3′-position of the
binaphthyl backbone were tested. Ortho- or meta-substituted
phenyl rings on the 3,3′-position dramatically reduced reactivity
and enantioselectivity (entries 3 and 4). On the other hand,
para substitution by a tert-butyl group resulted in increased
enantioselectivity (entry 5). After various catalysts bearing para-
substituted phenyl groups were tested (entry 5−9), we
identified 1e·TfOH as having the highest enantioselectivity
(entry 6). Increasing the amount of pyridylphosphoramide 1e
improved both reactivity and selectivity, though 20 mol % of
chiral catalyst in total must be used (entry 10). Unfortunately,
decreasing the amount of 1e·TfOH and 1e to 7.5 mol % gave
inferior selectivity relative to both entry 6 and 10 (entry 11).
Furthermore, we confirmed that the catalyst counteranion,
derived from achiral Brønsted acid, affected the reaction
efficiency (entries 6, 12, and 13). The more basic mesylate
anion had a deleterious effect on enantioselectivity, which
a
b
Isolated yield as single diastereomer. 1i·TfOH was prepared in situ.
See the Supporting Information for details.
B
DOI: 10.1021/acs.orglett.6b00608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unselective catalyst 1e. Notably, pyridinium phosphoric ester 1i
bearing one pyridinium proton and no phosphoramido N-H
showed almost no enantioselectivity. These results clearly
suggest that the simultaneous presence of both protons in
pyridinium phosphoramide 1·HX is necessary for high yield
and enantioselectivity in this reaction. Toward further
optimization of the catalyst structure, the basicity of the
pyridine moiety in the catalyst was modified by introducing
electron-donating groups on the pyridine ring to prevent
dissociation of the proton from the ionic complex (Figure 2).
To our delight, improvements in both reaction yield and
enantioselectivity were observed when catalyst 1k·TfOH or
1m·TfOH17 was used in place of 1e·TfOH, whereas the use of
1j·TfOH having a methyl group at the 6-position on the
pyridine ring led to a poor result. Introduction of a strong
electron-donating group such as a dimethylamino group was
ineffective, implying a balance of the stability and acidity of the
resulting pyridinium phosphoramide is crucial.
Scheme 2. Substrate Range of the Diels−Alder Reaction
While N-Ar or N-bulky alkylmaleimides have been utilized in
asymmetric Diels−Alder reactions to exploit enhanced
reactivity as well as to easily discriminate their prochiral faces
due to N-substituents, to the best of our knowledge, a catalytic
method for the highly enantioselective Diels−Alder reaction of
N-H maleimide was still lacking.18 Having expected flexible
utility of Diels−Alder adducts from N-H maleimide without
cleavage of unnecessary N-substituent bonds in some cases, we
examined the scope of the Diels−Alder reaction of various N-
Cbz-1-amidodienes and N-H maleimides with 1m·TfOH
(Scheme 2). 3-Alkyl-substituted 1-amidodienes reacted with
3a in a similar fashion, furnishing highly enantioenriched
products 4b and 4c. 4-Alkyl-substituted 1-amidodienes were
successfully employed to afford 4d and 4e with four contiguous
stereocenters in diastereo- and enantioselective manners. In
turn, the reaction with N-methylmaleimide 3b bearing no acidic
imide proton proceeded efficiently to give 5a−c in higher
enantioselectivity than the corresponding products 4a, 4b, and
4d from 3a. However, the presence of a bulkier benzyl group
on maleimide led to lower enantioselectivity for 5d. Not only
maleimides but also benzoquinones could be employed in this
Diels−Alder reaction with 1e·TfOH, as chiral tetrahydronaph-
thalene 6a and 6b were obtained in excellent yields and
enantioselectivities after acetylation of the unstable Diels−Alder
adducts. When phenyl benzoquinone was used as a substrate,
the catalyst could control enantioselectivity as well as
regioselectivity of the double bond to afford one regioisomer
6c preferably.
a
3a: N-H maleimide, 3b: N-Me maleimide, 3c: 1,4-benzoquinone, 3d:
b
2-phenyl-1,4-benzoquinone, 3e: N-Bn maleimide. Isolated yields as
c
single diastereomers. 1e·TfOH (10 mol %) and 1e (5 mol %) were
used as catalyst at −78 °C. The product was obtained after acetylation.
d
Regioisomer substituted with phenyl group at 2-position was also
obtained (3-Ph:2-Ph = 4:1).
Scheme 3. Transformation of Optically Active Diels−Alder
Adducts
The utility of chiral Diels−Alder adducts was demonstrated
as shown in Scheme 3. The two imide carbonyl groups in 4a
were successfully differentiated by reduction with DIBAL-H to
furnish hemiaminal 4ab as a mixture of stereoisomers. Further
reduction of 4ab by triethylsilane in the presence of BF3·OEt2
afforded the pyrrolidinone derivative 4ac with all other
functional moieties in 4a remaining intact. The Cbz group
could be removed by hydrogenolysis to give 4ad, which was
directly converted to Mosher amide 4ae to determine the
absolute configuration of 4a.19 Moreover, stereoselective
epoxidation of the double bond in 5c produced the unusual
compound 5ca having six contiguous all-syn asymmetric centers
on the cyclohexane ring constructed by the Diels−Alder
reaction.
withdrawing group. Careful optimization of the structure of the
catalysts enabled the first successful use of N-unsubstituted
maleimide in highly enantioselective Diels−Alder reactions
using various Cbz-protected 1-aminodienes. Through catalyst
screening, it was shown that the characteristic two acidic
In conclusion, we have developed chiral pyridinium
phosphoramides as dual Brønsted acid catalysts based on the
concept that a cationic heterocycle functions as an electron-
C
DOI: 10.1021/acs.orglett.6b00608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) For recent reviews on chiral Brønsted acid catalysis, see:
(a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014,
114, 9047. (b) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev.
2011, 40, 4539. (c) Terada, M. Curr. Org. Chem. 2011, 15, 2227.
(8) For selected examples, see: (a) Yu, K.; Liu, X.; Lin, X.; Lin, L.;
Feng, X. Chem. Commun. 2015, 51, 14897. (b) Dong, S.; Liu, X.; Zhu,
Y.; He, P.; Lin, L. J. Am. Chem. Soc. 2013, 135, 10026. (c) Dong, S.;
Liu, X.; Zhang, Y.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 5060.
(d) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062.
(e) Fu, X.; Loh, W. T.; Zhang, Y.; Chen, T.; Ma, T.; Liu, H.; Wang, J.;
Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 7387. (f) Uyeda, C.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228.
protons in pyridinium phosphoramide are essential for its
catalytic reactivity and stereoselectivity. Future work in our
laboratory will involve investigation of possible alternative acids
for 1·HX and extending the range of applications of the
catalysts.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00608.
(9) (a) Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.;
Chandrakumar, A. J. Am. Chem. Soc. 2010, 132, 4536. (b) Narcis, M. J.;
Sprague, D. J.; Captain, B.; Takenaka, N. Org. Biomol. Chem. 2012, 10,
9134.
Experimental procedures and spectroscopic data of all
new compounds (PDF)
X-ray crystal structural data for rac-1m·TfOH (CIF)
(10) For selected examples, see: (a) Sprague, D. J.; Nugent, B. M.;
Yoder, R. A.; Vara, B. A.; Johnston, J. N. Org. Lett. 2015, 17, 880.
(b) Vara, B. A.; Struble, T. J.; Wang, W.; Dobish, M. C.; Johnston, J.
N. J. Am. Chem. Soc. 2015, 137, 7302. (c) Schwieter, K. E.; Johnston, J.
N. ACS Catal. 2015, 5, 6559. (d) Toda, Y.; Pink, M.; Johnston, J. N. J.
Am. Chem. Soc. 2014, 136, 14734. (e) Singh, A.; Yoder, R. A.; Shen, B.;
Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466. (f) Nugent, B. M.;
Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418.
(11) Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
(12) (a) Uraguchi, D.; Kinoshita, N.; Kizu, T.; Ooi, T. J. Am. Chem.
Soc. 2015, 137, 13768. (b) Uraguchi, D.; Kizu, T.; Ohira, Y.; Ooi, T.
Chem. Commun. 2014, 50, 13489. (c) Uraguchi, D.; Kinoshita, N.;
Nakashima, D.; Ooi, T. Chem. Sci. 2012, 3, 3161. (d) Uraguchi, D.;
Kinoshita, N.; Ooi, T. J. Am. Chem. Soc. 2010, 132, 12240.
(e) Uraguchi, D.; Nakashima, D.; Ooi, T. J. Am. Chem. Soc. 2009,
131, 7242.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yasuhiro@meijo-u.ac.jp.
*E-mail: oshara@meijo-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Young Scientists (B) (26810063) from the Japan Society for
the Promotion of Science (JSPS).
(13) For a review of Brønsted acid assisted Brønsted acids, see:
Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924.
(14) Wakchaure, V. N.; List, B. Angew. Chem., Int. Ed. 2010, 49, 4136.
(15) For selected examples of catalytic asymmetric Diels−Alder
reactions employing 1-amido dienes, see: (a) Hatano, M.; Goto, Y.;
Izumiseki, A.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2015, 137,
13472. (b) Pous, J.; Courant, T.; Bernadat, G.; Iorga, B. I.; Blanchard,
F.; Masson, G. J. Am. Chem. Soc. 2015, 137, 11950. (c) Kong, L.; Han,
X.; Jiao, P. Chem. Commun. 2014, 50, 14113. (d) Kohari, Y.; Okuyama,
Y.; Kwon, E.; Furuyama, T.; Kobayashi, N.; Otuki, T.; Kumagai, J.;
Seki, C.; Uwai, K.; Dai, G.; Iwasa, T.; Nakano, H. J. Org. Chem. 2014,
79, 9500. (e) Ishihara, K.; Yamada, H.; Akakura, M. Chem. Commun.
2014, 50, 6357. (f) Momiyama, N.; Konno, T.; Furiya, Y.; Iwamoto,
T.; Terada, M. J. Am. Chem. Soc. 2011, 133, 19294. (g) Huang, Y.;
Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.
(h) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci.
U. S. A. 2004, 101, 5846.
REFERENCES
■
(1) For recent reviews on hydrogen bonding donor catalysis, see: (a)
Asymmetric Organocatalysis 2.Science of Synthesis; Maruoka, K., Ed.;
Georg Thime Verlag KG: Stuttgart, 2012. (b) Auvil, T. J.; Schafer, A.
G.; Mattson, A. E. Eur. J. Org. Chem. 2014, 2014, 2633. (c) Takemoto,
Y. Chem. Pharm. Bull. 2010, 58, 593. (d) Zhang, Z.; Schreiner, P. R.
Chem. Soc. Rev. 2009, 38, 1187. (e) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713.
(2) For seminal works in asymmetric synthesis, see: (a) Sigman, M.
S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b) Okino, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
(3) For selected examples, see: (a) Kobayashi, Y.; Taniguchi, Y.;
Hayama, N.; Inokuma, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2013,
52, 11114. (b) Inokuma, T.; Furukawa, M.; Uno, T.; Suzuki, Y.;
Yoshida, K.; Yano, Y.; Matsuzaki, K.; Takemoto, Y. Chem. - Eur. J.
2011, 17, 10470. (c) Almasi
Najera, C. J. Org. Chem. 2009, 74, 6163. (d) Zhang, L.; Lee, M.-M.;
Lee, S.-M.; Lee, J.; Cheng, M.; Jeong, B.-S.; Park, H.-G.; Jew, S.-S. Adv.
Synth. Catal. 2009, 351, 3063.
́
̧ , D.; Alonso, D. A.; Gomez-Bengoa, E.;
(16) The acidity of 1e·TfOH, which can be regarded as pyridinium
bearing a phosphoramide moiety at the 2-position, in CH3CN is
estimated to be higher than that of aminopyridinium (pKa 14.47),
pyridinium (pKa 12.53), and several chiral phosphoric acids (pKa
12.5−14); see: (a) Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping,
M.; Leito, I. Angew. Chem., Int. Ed. 2013, 52, 11569. (b) Kaljurand, I.;
́
(4) For selected examples, see: (a) Isı̧ k, M.; Unver, M. Y.; Tanyeli, C.
J. Org. Chem. 2015, 80, 828. (b) Tungen, J. E.; Nolsøe, J. M. J.;
Hansen, T. V. Org. Lett. 2012, 14, 5884. (c) Konishi, H.; Lam, T. Y.;
Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028. (d) Jiang, H.;
Kutt, A.; Soovali, L.; Rodima, T.; Maemets, V.; Leito, I.; Koppel, I. A. J.
̈
̈
̈
Org. Chem. 2005, 70, 1019.
Paixao, M. W.; Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010,
̃
(17) The three-dimensional structure of rac-1m·TfOH was verified
by X-ray crystallographic analysis.
132, 2775. (e) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int.
Ed. 2010, 49, 153. (f) Dai, L.; Wang, S.-X.; Chen, F.-E. Adv. Synth.
Catal. 2010, 352, 2137. (g) Xu, D. Q.; Wang, Y.-F.; Zhang, W.; Luo, S.
P.; Zhong, A. G.; Xia, A. B.; Xu, Z. Y. Chem. - Eur. J. 2010, 16, 4177.
(h) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008,
130, 14416.
(18) N-H maleimide is known as a difficult substrate in which to
induce high enantioselectivity because of its symmetric structure
around the carbonyl group and its acidic imide proton potentially
hindering favorable HB interactions; see: (a) Gioia, C.; Hauville, A.;
Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236.
(b) Corey, E. J.; Sarshar, S.; Lee, D.-H. J. Am. Chem. Soc. 1994, 116,
12089.
(5) Schafer, A. G.; Wieting, J. M.; Fisher, T. J.; Mattson, A. E. Angew.
Chem., Int. Ed. 2013, 52, 11321−11324.
(6) For seminal works on chiral Brønsted acid catalysis, see:
(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.
(19) Kusumi, T.; Fukushima, T.; Ohtani, I.; Kakisawa, H. Tetrahedron
Lett. 1991, 32, 2939 See the Supporting Information for details..
D
DOI: 10.1021/acs.orglett.6b00608
Org. Lett. XXXX, XXX, XXX−XXX