Chiral Phosphoric Acid-Catalyzed Kinetic Resolution via Amide Bond Formation

Article abstract of DOI:10.1021/jacs.7b03592

We describe the kinetic resolution of a readily available 2-pyridyl ester via an amide bond formation catalyzed by a chiral Br?nsted acid. A chiral phosphoric acid bearing a 2,4,6-trimethyl-3,5-dinitrophenyl group at the 3,3′-position enabled this transformation with high selectivities. We also found that the addition of Lewis acid increased both the reactivity and selectivity in the substrate with a methoxy group.

Full text of DOI:10.1021/jacs.7b03592

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Communication
Chiral Phosphoric Acid-Catalyzed Kinetic
Resolution via Amide-Bond Formation
Yasushi Shimoda, and Hisashi Yamamoto
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 May 2017
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Chiral Phosphoric Acid-Catalyzed Kinetic Resolution via Amide-
Bond Formation
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Yasushi Shimoda* and Hisashi Yamamoto*
Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan
Supporting Information Placeholder
lution (KR) of racemic substrates, affording enantio-
merically pure compounds.4 It is also well established
that racemic carboxylic acids can be separated into a
diastereomeric salt by recrystallization in the presence of
a stoichiometric or excess amount of a chiral amine.
However, these methods are not always useful and re-
quire an excess amount of reagents, leading to poor atom
economy. In contrast, catalytic KR reactions allow the
separation of racemic compounds without use of stoi-
chiometric amount of reagents. Although various cata-
lytic KR methods of amines via an amide bond for-
mation5 or other transformations6 have been developed,
the catalytic KR of carboxylic acid or its derivatives is
still a challenging research subject. Pioneering works on
catalytic KR of carboxylic acids using esterification
have been developed by Ishihara7 and Shiina8. Their
methods show high selectivities with various substrate
scopes but requires pre-activation of carboxylic acids.
ABSTRACT: We describe a kinetic resolution of readily
available 2-pyridyl ester via an amide-bond formation
catalyzed by a chiral Brønsted acid. A chiral phosphoric
acid bearing 2,4,6-trimethyl-3,5-dinitrophenyl group at
3,3’-position enabled this transformation with high se-
lectivities. Additionally, We also found that the addition
of Lewis acid increased both the reactivity and selectivi-
ty in the substrate with methoxy group.
Optically active carboxylic acid derivatives are highly
important and fundamental motifs found in a wide varie-
ty of natural products, biologically active and pharma-
ceutically useful compounds (Figure 1).1 As a conse-
quence, the preparation of chiral carboxylic acid deriva-
tives has received much attention in organic chemistry.
Although asymmetric hydrogenation of α,β-unsaturated
carboxylic acids2 or asymmetric alkylation of achiral
carboxylic acids3 is known to be the direct method for
the preparation of such chiral carboxylic acids with an
α-stereogenic center, they sometimes require the com-
plicated preparation of starting materials or catalysts.
We present herein a new strategy for the kinetic resolu-
tion of carboxylic acid derivatives catalyzed by chiral
phosphoric acid. We envisioned that esters bearing pyri-
dine moiety could interact with a proton from chiral
Brønsted acid to form a chiral ion pair,9 which enables
kinetic resolution of racemic esters through an amide-
bond formation reaction10 with an amine as a nucleo-
phile (Figure 2). It is known that pyridyl esters can be
used as an active ester11 for amide bond formation reac-
tions,12 however, to the best of our knowledge, there are
no examples of its application to asymmetric synthesis.
Figure 1. Examples of pharmaceutical compounds bearing
carboxylic acid or its derivatives with α-stereogenic center
On the other hand, separation of racemic chiral car-
boxylic acids can be a straightforward route to afford the
optically pure carboxylic acids. It has been well studied
that the enzymes are generally used for the kinetic reso-
Figure 2. Working hypothesis of KR reaction
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tution at the 3-position increased the selectivities. The
1
We commenced our studies on the KR reaction of 2-
pyridyl ester 1 with p-toluidine (2) as a nucleophile in
toluene using a chiral phosphoric acid 3a (Table 1, entry
1). With non-substituted pyridyl ester, the reaction pro-
ceeded smoothly but only a low s factor was detected
(entry 1). To improve the selectivity, we introduced a
methyl group onto the pyridine ring and found that sub-
stituent on the 6-position increased the selectivity (entry
3). The reaction did not proceed in the substrate with
phenyl group at the 6-position probably due to its steric
hindrance (entry 4). Subsequently, various phosphoric
acid catalysts (entries 3, 5-8) were evaluated. Among the
catalysts tested, the phosphoric acid bearing 2,4,6-
trimethyl-3,5-dinitrophenyl group at 3,3’-position,
which was developed by our group,13 was found to be
efficient catalyst for this KR reaction (entry 8, s factor =
20). Stronger Brønsted acids, such as phosphoramide 3c
or thiophosphoramide 3d, gave almost racemic products
because of its high acidity (entries 6 and 7). Other sol-
vents did not improve the reactivity and selectivity (en-
tries 9 and 10). The catalyst loading could be reduced to
5 mol% without loss of reactivity and selectivity (entry
11).
carboxylic acid analogues of 1j and 1k are well known
to be medicinal drugs (Figure 1). These substrates also
could be separated by our KR method to afford corre-
sponding amide products 4j and 4k with good s factors.
Notably, substitution of the methyl group to the bulkier
alkyl group (4l-4n) showed the influence to the selectivi-
ty. An extremely high s factor (s = 397) was observed
with compound bearing isopropyl group 4n. This KR
method also separated the heteroatom-containing car-
boxylic acid derivatives at the α-position. After prelimi-
nary screening of the protecting group, both oxygen and
nitrogen-containing substrate showed good s factor (4o
and 4p).
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Scheme 1. Examples of substrates in the KR reac-
tiona)
Table 1. Screening of reaction conditionsa)
entry R’
catalyst solvent
conv. (%)
s
1
2
H
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
30
39
30
NR
30
26
24
48
12
10
3
2
3a
3a
3a
3a
3b
3c
3d
3e
3e
3e
3e
3-Me
6-Me
6-Ph
6-Me
6-Me
6-Me
6-Me
6-Me
6-Me
6-Me
3
12
-
4
5
2
6
0
7
0
8
20
1
9
10
11b)
CH2Cl2
toluene
0
47
20
1
a) ee, conv., and s factor were determined by H NMR and
a)
ee, conv., and s factor were determined by 1H NMR and HPLC.
HPLC. b) Reaction was performed with 5 mol% of catalyst.
With the optimal conditions in hand, we applied this
KR reaction to a wide variety of substrates (Scheme 1).
Although the substituent at the 2-position on the benzene
ring decreased the selectivity, various substrates showed
the similar reactivities and selectivities (4a-4k). Substi-
Additionally, this KR reaction is also successful when
we use esters with quaternary stereogenic center, which
is difficult to have optical active one using such as hy-
drogenation methods. The corresponding products were
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obtained with good selectivities under slightly modified
conditions (Scheme 2).
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Scheme 2. A kinetic resolution of substrates with qua-
ternary stereogenic center
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Interestingly, we found that the addition of Lewis
acid13 improved both the reactivity and selectivity in the
substrate bearing methoxy group (Table 2). Although
only the low conversion and s factor are observed with-
out Lewis acid additive, the use of Lewis acid improved
both the reactivity and selectivity. Among the Lewis
acids tested15, tantalum (V) chloride16 showed efficient
catalytic activity to furnish the amide product 4s with
high selectivity (s = 30). We assumed that Lewis acid
coordinates to the oxygen atom of the methoxy group to
activate the carbonyl group.
The hydroxy pyridyl group in the ester compound 1a
could be removed easily to afford carboxylic acid 5
without loss of enantioselectivity (Scheme 4). More im-
portantly, pyridyl esters are known to be activated car-
bonyl compounds. Benzylamine reacted smoothly to
afford amide compound 6 in high chemical yield. After
treatment with DIBAL-H, the corresponding alcohol 7
was obtained in a high chemical yield.
Table 2. Additive effect of Lewis acidsa)
Scheme 4. Derivatization of pyridyl ester
entry
additive
conv. (%)
s
1
2
3
4
5
6
7
none
Mg(OTf)2
NiBr2
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31
22
48
3
13
11
11
14
8
La(OTf)3
Hf(OTf)4
NbCl5
In conclusion, we have developed an enantioselective
catalytic KR reaction of pyridyl esters using a chiral
Brønsted acid catalyst bearing the 2,4,6-trimethyl-3,5-
dinitrophenyl group. This KR protocol shows broad sub-
strate scopes including heteroatom-containing substrate
or substrates with quaternary stereogenic center. In addi-
tion, the hydroxy pyridyl group can be converted to oth-
er derivatives in a simple way. Further studies including
the investing of mechanistic studies and application to
other transformation are in progress in our laboratory.
TaCl5
30
1
a) ee, conv., and s factor were determined by H NMR and
HPLC.
Enantiomerically pure esters could be obtained by us-
ing the KR method with a slightly excess amount of
amines (Scheme 3). The reaction of 1a with 70 mol% of
2 affords an amide product with 65% conversion. Grati-
fyingly, 99% ee was observed in recovered starting ma-
terial. Similarly, almost optically pure α-hydroxy ester
derivative 1o could be obtained.
ASSOCIATED CONTENT
Supporting Information
Scheme 3. Reaction for the enantiomerically pure
esters
The Supporting Information is available free of charge on
the ACS Publications website.
Corresponding Author
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2014, 136, 11783-11791. (i) Mittal, N.; Lippert, K. M.; De, C. K.;
Klauber, E. G.; Emge, T. J.; Schreiner, P. R.; Seidel, D. J. Am. Chem.
Soc. 2015, 137, 5748-5758.
yshimoda@isc.chubu.ac.jp
hyamamoto@isc.chubu.ac.jp
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(6) (a) Kitagawa, O.; Yotsumoto, K.; Kohriyama, M.; Dobashi, Y.;
Taguchi, T. Org. Lett. 2004, 6, 3605-3607. (b) Hoffmann, S.; Ni-
coletti, M.; List, B. J. Am. Chem. Soc. 2006, 128, 13074-13075.(c)
Hou, X. L.; Zheng, B. H. Org. Lett. 2009, 11, 1789-1791. (d) Das, S.;
Majumdar, N.; Kanta De, C.; Kundu, D. S.; Döhring, A.; Garczynski,
A.; List, B. J. Am. Chem. Soc. 2017, 139, 1357-1359.
(7) (a) Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org.
Lett. 2008, 10, 3191-3194. (b) Sakakura, A.; Umemura, S.; Ishihara,
K. Synlett, 2009, 10, 1647-1650.
Notes
No competing financial interests have been declared.
ACKNOWLEDGMENT
This work was supported by JST, ACT-C Grant Number
JPMJCR12ZD, Japan.
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(8) (a) Shiina, I.; Nakata, K.; Ono, K.; Onda, Y.; Itagaki, M. J. Am.
Chem. Soc. 2010, 132, 11629-11641. (b) Nakata, K.; Onda, Y.; Ono,
K.; Shiina, I. Tetrahedron Lett. 2010, 51, 5666-5669.
(9) For reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744-
5758. (b) Seayad, J.; List, B. Org. Biomol. Chem., 2005, 3, 719-724.
(c) Terada, M. Chem. Commun. 2008, 44, 4097-4112. (d) Terada, M.
Synthesis 2010, 1929-1982. (f) Rueping, M.; Kuenkel, A.; Atodiresei,
I. Chem. Soc. Rev. 2011, 40, 4539-4549. (h) Parmer, D.; Sugiono, E.;
Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047-9153. (i) Akiyama,
T.; Mori, K. Chem. Rev. 2015, 115, 9277-9306.
REFERENCES
(1) (a) Ghose, A K.; Viswanadham, V. N.; Wendoloski, J. J. J.
Comb. Chem. 1999, 1, 55-68. (b) von Nussbaum, F.; Brands, M.;
Hinzen, B.; Weigand, S.; Habich, D. Angew. Chem., Int. Ed. 2006, 45,
5072-5129.
(2) (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J.
Org. Chem., 1987, 52, 3174-3176. (b) Ohta, T.; Takaya, H.; Noyori,
R. Tetrahedron Lett. 1990, 31, 7189-7192. (c) Li, S.; Zhu, S.-F.;
Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2008, 130,
8584-8585.
(3) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737-1739. (b) Myers, A. G.; Yang, B. H.; Chen, H.;
Mckinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496-6511. (c) Jew, S.; Lee, Y.-J.; Lee, J.; Kang, M.-J.; Jeong,
B.-S.; Lee, J.-H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.; Ku, J.-M.; Park,
H. Angew. Chem. Int. Ed. 2004, 43, 2382-2385. (d) Liu, X.; Hartwig,
J. F. J. Am. Chem. Soc. 2004, 126, 5182-5191. (e) Kitamura, M.;
Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed. 2005, 44, 1549-
1551.
(4) For reviews, see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
Adv. Synth. Catal. 2001, 343, 5-26. (b) Huerta, F. Minidisa, A. B.
E.; Bäckvall, J. B. Chem. Soc. Rev. 2001, 30, 331-341. (c) Robinson,
D. E. J.; Bull, S. D. Tetrahedron: Asymmetry, 2003, 14, 1407-1446.
(d) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613-1666. (e)
Rachwalski, M.; Vermue, N.; Rutjes, F. P. J. T. Chem. Soc. Rev.
2013, 42, 9268-9282.
(5) (a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem.
Int. Ed. 2001, 40, 234-236. (b) Arp, F. O.; Fu, G. C. J. Am. Chem.
Soc. 2006, 128, 14264-14265. (c) Arnord, K.; Davies, B.; Hérault
D.;O Whiting, A. Angew. Chem. Int. Ed. 2008, 47, 2673-2676. (d)
De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131,
17060-17061. (e) Klauber, E. G.; De, C. K.; Shah, T. K.; Seidel, D. J.
Am. Chem. Soc. 2010, 132, 13624-13626. (f) Fowler, B. S.; Mikochik,
P. J.; Miller, S. J. Am. Chem. Soc. 2011, 133, 2870-2871. (g) Wanner,
B.; Kreituse, I.; Gutierrez, O.; Kozlowski, M. C.; Bode, J. W. J. Am .
Chem. Soc. 2015, 137, 11491-11497. (h) Allen, S. E.; Hsleh, S.-Y.;
Gutierrez, O.; Bode, J. W.; Kozlowski, M. C. J. Am . Chem. Soc.
(10) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem.
Soc. Rev. 2014, 43, 2714-2742.
(11) Recently, Yamada, Takasu et al reported chiral Brønsted acid
catalyzed activation of trichloroacetimidate as leaving group: see, a)
Kuroda, Y.; Harada, S.; Oonishi, A.; Yamaoka, Y.; Yamada, K.; Ta-
kasu, K. Angew. Chem. Int. Ed. 2015, 54, 8263-8266. b) Kuroda, Y.;
Harada, S.; Oonishi, A.; Kiyama, H.: Yamaoka, Y.; Yamada,K.; Ta-
kasu, K. Angew. Chem. Int. Ed. 2016, 55, 13137-13141.
(12) (a) Kim, S.; Lee, I.-J.; Ko, K.-K. Tetrahedron Lett. 1984, 43,
4943-4946. (b) Saitoh, K.; Shiina, I.; Mukaiyama, T. Chem. Lett.
1998, 27, 679-680. (b) Shiina, I.; Suenaga, Y.; Nakano, M.; Mukai-
yama, T. Bull. Chem. Soc. Jpn., 2000, 73, 2811-2818.
(13) Zhou, F.; Yamamoto, H. Angew. Chem., Int. Ed. 2016, 55,
8970-8974.
(14) For the references of the reactions catalyzed by Lewis acid-
assisted Brønsted acid, see: (a) Ishihara, K.; Kaneeda, M.; Yamamoto,
H. J. Am. Chem. Soc. 1994, 116, 11179-11180. (b) Nakamura, S.;
Ishihara, K.; Yamamoto, H J. Am. Chem. Soc. 2000, 122, 8131-8140.
(c) Lv, J.; Zhang, L.; Zhou, Y.; Nie, Z.; Luo, S.; Cheng, J.-P. Angew.
Chem. Int. Ed. 2011, 50, 6610-6614. (d) Hatano, M.; Goto, Y.;
Izumiseki, A.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2015, 137,
13472-13475. (d) Thirupathi, B.; Breitler, S.; Mahender, B.; Reddy, K.
M.; Corey, E. J. J. Am. Chem. Soc. 2016, 138, 10842-10845. (e) Sibi,
M. P. Private communication.
(15) For details, see Supporting Information.
(16) Our group has reported tantalum alkoxide-catalyzed amidation
reaction of carboxylic acid bearing hydroxy group, see; Tsuji, H.;
Yamamoto, H. J. Am. Chem. Soc. 2016, 138, 14218-14221.
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