Enantioselective Steglich Rearrangement of Oxindole Derivatives by Easily Accessible Chiral N,N-4-(Dimethylamino)pyridine Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b02089

Chiral N,N-4-(dimethylamino)pyridine (DMAP) derivatives, which can be readily prepared by the Ugi multicomponent reaction in a one-pot manner, have been efficiently applied to the enantioselective Steglich rearrangement of oxindole derivatives to give the

Full text of DOI:10.1021/acs.orglett.5b02089

Letter
pubs.acs.org/OrgLett
Enantioselective Steglich Rearrangement of Oxindole Derivatives by
Easily Accessible Chiral N,N‑4-(Dimethylamino)pyridine Derivatives
Hiroki Mandai,*,† Takuma Fujiwara,† Katsuaki Noda,† Kazuki Fujii,† Koichi Mitsudo,†
Toshinobu Korenaga,‡ and Seiji Suga*,†,§,∥
†Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka,
Kita-ku, Okayama 700-8530, Japan
‡Faculty of Engineering, Department of Chemistry and Bioengineering, Iwate University, Morioka, Iwate 020-8551, Japan
§Research Center of New Functional Materials for Energy Production, Storage and Transport, Okayama University, 3-1-1
Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
∥Japan Science and Technology Agency, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: Chiral N,N-4-(dimethylamino)pyridine
(DMAP) derivatives, which can be readily prepared by the
Ugi multicomponent reaction in a one-pot manner, have been
efficiently applied to the enantioselective Steglich rearrange-
ment of oxindole derivatives to give the desired products
bearing a quaternary carbon center in high yield (>98% yield)
and with high enantioselectivity (up to 99:1 er).
ver the past two decades, the development of chiral
nucleophilic catalysts has become one of the most
to the kinetic resolution of secondary alcohols.11 To the best of
our knowledge, this is the first example in which chiral DMAP
derivatives were synthesized by a multicomponent reaction in a
one-step procedure and then applied to an enantioselective
acylation reaction. However, the reaction with the minor
diastereomer of the Ugi product 1a′ showed a higher selectivity
factor (s factor) than that with the major diastereomer 1a under
the optimal conditions. Application of the major diastereomer 1a
to other important classes of enantioselective transformations is
of particular interest. As a result of our extensive screening of
acyl-transfer reactions with 1a, we found that 1a showed high
catalytic activity and enantioselectivity in the Steglich rearrange-
ment12 of O-acylated oxindole derivatives. In this paper, we
report the details of the optimization of the reaction conditions
with 1a, the substrate scope, and computational studies to
elucidate the reaction mechanism.
Initially, the Steglich rearrangement of oxindole 2a was carried
out in the presence of 10 mol % of diastereomerically and
enantiomerically pure catalyst 1a with an L-valine scaffold, a
major diastereomer of the Ugi product, in various solvents at 0
°C for 12 h (Table 1). The reaction in common organic solvents
(0.1 M) afforded the product 3a in low to moderate conversion
(10−79% conv) with an acceptable enantioselectivity (89:11 to
92:8 er, entries 1−7). The use of a protic solvent, tert-amyl
alcohol, significantly suppressed the reaction efficiency (entry 7).
According to the solvent screening, the reaction in THF was
found to be optimal at 0 °C with respect to both product
conversion and enantioselectivity (78% conv; 92:8 er; entry 3).
O
important areas in organic synthesis.1 Chiral catalysts with
DMAP or 4-pyrrolidinopyridine (PPY) scaffolds are widely
studied in response to pioneering studies by Vedejs2 and Fu,3
particularly with regard to their application to various
enantioselective transformations, such as the kinetic resolution
of racemic alcohols4 or amines,5 desymmetrization of meso-
compounds,6 Steglich rearrangements,7 and many others.
However, most chiral DMAP and PPY derivatives have required
a longer linear synthetic route as well as the optical resolution of a
racemic intermediate or the final catalyst form.1e Thus, chiral
DMAP derivatives that can be easily synthesized from a readily
available chiral source in short steps (<5 steps) without
cumbersome operations (e.g., optical resolution or HPLC
separation) are highly attractive. Very recently, we developed a
method for the synthesis of chiral DMAP derivatives starting
from an α-amino acid8,9 as a chiral source using a
diastereoselective Ugi multicomponent reaction, and the
protocol allowed us to access a variety of chiral catalysts in a
one-step and one-pot manner.10 For example, an L-valine-based
chiral DMAP derivative was synthesized in 55% yield as a mixture
of two diastereomers (1a/1a′ = 92:8, eq 1) and could be applied
Received: July 21, 2015
© XXXX American Chemical Society
A
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Letter
a
the corresponding products 12a (50% conv; 91:9 er; entry 7) and
13a (>98% conv; 68:32 er; entry 8), respectively. An electron-
donating group substituted phenyl carbonate 9a dramatically
decreased the reaction conversion with an identical enantiose-
lectivity. On the other hand, 10a with an electron-withdrawing
group resulted in moderate enantioselectivity of the product 13a
(entry 8). The reaction of 2a at a higher concentration delivered
the desired product 3a in >98% conversion with 92:8 er after 12 h
(entry 9).
To identify an L-amino acid moiety of the catalyst that could
influence the enantioselectivity, the Steglich rearrangement of
oxindole 2a was carried out with 10 mol % of selected catalysts
1a−d in THF (0.4 M) at 0 °C for 12 h (Table 3). The reaction
Table 1. Screening of the Solvent and Reaction Temperature
b
c
entry
solvent
CH2Cl2
temp (°C)
conv (%)
er of 3a
1
2
3
4
5
6
7
8
9
0
0
54
70
92:8
91:9
92:8
91:9
89:11
91:9
92:8
90:10
85:15
toluene
THF
0
78
Et2O
0
79
i-Pr2O
CPME
t-amyl alcohol
THF
0
71
0
73
a
Table 3. Screening of Selected Catalysts
0
10
rt
>98
76
THF
−20
a
Reactions were performed on a 0.1 mmol scale in solvent (0.1 M)
under an argon atmosphere. Conversions were determined by H
NMR analysis of the unpurified reaction mixture. Enantioselectivities
b
1
c
were determined by HPLC analysis.
b
c
entry
1
catalyst
conv (%)
er of 3a
The effect of the reaction temperature was also examined (entries
8 and 9). At room temperature, the reaction proceeded smoothly
(>98% conv), but the enantioselectivity was slightly decreased
(90:10 er; entry 8 vs 92:8 er; entry 3). While the same
conversions (76% conv) were seen at a lower temperature of −20
°C, the enantiomeric ratio was significantly decreased compared
to that at 0 °C (85:15 er; entry 9 vs 92:8 er; entry 3). According
to these results, the reaction in THF (0.1 M) at 0 °C was optimal
in the enantioselective Steglich rearrangement of oxindoles with
catalyst 1a.
1a
>98
>98
>98
>98
>98
92:8
80:20
91:9
95:5
91:9
d
2
1a + 1a′
1b
3
4
5
1c
1d
a
Reactions were performed on a 0.1 mmol scale in THF (0.4 M)
b
1
under an argon atmosphere. Conversions were determined by H
NMR analysis of the unpurified reaction mixture. Enantioselectivities
were determined by HPLC analysis. Diastereomeric mixture of
catalyst (1a + 1a′, 92:8 dr) was used in the reaction.
c
d
Next, we examined the effects of carbonate and carbamate
moieties on the reaction conversion and the enantioselectivity of
the product (Table 2). The use of alkyl-substituted carbonates
4a−7a resulted in no reaction (<2% conv) at all (entries 2−5).
Benzyl-substituted carbonate 8a slightly facilitated the trans-
formation (10% conv to 11a; 88:12 er; entry 6). On the other
hand, aryl-substituted carbonates 9a and 10a were converted to
with a mixture of the diastereomers 1a and 1a′ (92:8 dr)
decreased the enantioselectivity of 3a compared to that with
diastereomerically pure 1a (80:20 er; entry 2 vs 92:8 er; entry 1).
Compound 1a′ should act as a pseudoenantiomer of 1a, and
diastereomerically pure catalyst should be used in the reaction.
The sense of enantioselectivity for the reaction may mainly be
determined by the absolute configuration of the stereogenic
center immediately adjacent to the DMAP skeleton. The L-
isoleucine-derived catalyst 1b slightly decreased the enantiose-
lectivity of 3a (91:9 er, entry 3), whereas the more sterically
demanding L-tert-leucine-derived catalyst 1c afforded the desired
product 3a in 95:5 er (entry 4). L-Methionine-based DMAP
derivative 1d was slightly inferior to catalyst 1a and 1c in terms of
enantioselectivity (91:9 er, entry 5). According to these results,
we selected 1c as well as 1a containing inexpensive L-valine as
optimal catalyst candidates.13
Table 2. Effects of Carbonate and Carbamate Moieties on the
a
Reaction Conversion and Enantioselectivity
b
c
entry
R
substrate product conv (%) er of product
1
2
3
4
5
6
7
8
Ph
2a
4a
5a
6a
7a
8a
9a
10a
2a
3a
78
<2
92:8
Under the optimal conditions, we carried out a preparative-
scale reaction and tested the recovery of catalyst 1a. As shown in
eq 2, the reaction of 2a (502.7 mg, 1.3 mmol) with catalyst 1a
Me
Et
<2
i-Pr
i-Bu
Bn
<2
<2
11a
12a
13a
3a
10
88:12
91:9
4-MeOC6H4
4-FC6H4
Ph
50
>98
>98
68:32
92:8
d
9
a
Reactions were performed on a 0.1 mmol scale in THF (0.1 M)
b
1
under an argon atmosphere. Conversions were determined by H
NMR analysis of the unpurified reaction mixture. Enantioselectivities
were determined by HPLC analysis. The concentration of substrate
c
d
was 0.4 M.
B
DOI: 10.1021/acs.orglett.5b02089
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Letter
proceeded smoothly to afford the desired product in >98% yield
with 92:8 er, and 1a was recovered in 98% yield. Furthermore,
the recovered catalyst 1a could catalyze another batch of reaction
(0.2 mmol scale) without any loss of catalytic activity and
enantioselectivity (see the Supporting Information for details),
indicating the robust nature of 1a.
The enantioselective Steglich rearrangement of an array of
substrates 2b−n was carried out with 10 mol % 1a or 1c in THF
(0.4 M) at 0 °C for 12 h (Figure 1). 3-Alkyl-, allyl-, and propargyl-
92:8 to 99:1 er. In addition, the reaction of 3-aromatic- or 3-
heteroaromatic-substituted oxindole derivatives 2i−l gave good
to excellent enantioselectivity. Catalysts 1a and 1c could be
applied to not only 3-alkyl-substituted oxindoles but also to a 3-
aromatic- or 3-heteroaromatic-substituted substrate with good to
high enantioselectivity. Substrate 2m with a bromo substituent at
the benzene ring could be used in this reaction with an acceptable
level of enantioselectivity (90.5:9.5 er with catalyst 1a, and 91:9
er with catalyst 1c). However, the reaction of O-acylated
oxindole derivatives with an N-Me protecting group 2n did not
proceed at all, suggesting that an N-acyl moiety is required for the
reaction. According to these results, catalysts 1a and 1c can be
applied to a wide range of substrates including 3-alkyl-, -allyl-, and
-propargyl-substituted oxindoles. These findings allow us to
access various synthetically valuable 3,3′-disubstituted oxindole
derivatives with a quaternary stereogenic center.
The Steglich rearrangement of substrate 2c using catalyst 1a is
believed to proceed through the formation of ion-pair
intermediate, pyridinium cation I and enolate II (Figure
2),7b,14 followed by C−C bond formation to give product 3c.
Figure 2. Ion-pair intermediate in the Steglich rearrangement.
The transition states of C−C bond formation for the reaction
system of 2c using 1a were calculated at the B3LYP/6-31G(d)
level. We identified 12 structures as candidates for the transition
states: six structures, TSS series, gave an S-product and six, TSR
series, gave an R-product (see the Supporting Information).
Among the possible transition structures, TsS(COA_CCO)
and TsR(COA_CCO) showed the lowest energies in the TSS
and TSR series, respectively (Figure 3).
Figure 1. Enantioselective Steglich rearrangement of various O-acylated
oxindole derivatives with catalyst 1a or 1c.
Figure 3. Schematic representation models and 3D models of
energetically favorable TsS(COA_CCO) and TsR(COA_CCO).
The ion-pair structures of I and II in the 3D models are represented as
“tube” and “ball & bond type” models, respectively. The relative free
energies (kcal/mol) of single-point energy calculations with the SCRF
method based on CPCM (THF) are shown, and values in parentheses
are the relative energies (kcal/mol).
substituted O-acylated oxindole derivatives 3b−e were efficiently
obtained in >98% yields with moderate to excellent enantiose-
lectivities (up to 99:1 er). The reaction of 3-alkyl substrates
having a functional group (−CH2CH2NHCO2Me,
−CH2CH2OTBS, or −CH2CN) 2f−h also proceeded efficiently,
and the desired products 3f−h were obtained in >98% yield with
C
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(4) (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc.
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Single-point energy calculations with the self-consistent
reaction field (SCRF) calculation based on the polarizable
continuum model (CPCM, THF) were carried out at the 6-
311+g** level for both cases. The gap in relative energies
between the two transition states was ΔG = 2.99 kcal/mol (ΔE =
1.83 kcal/mol), which is consistent with the experimental
enantioselectivity of 3c using 1a (99:1 er). In both TS structures,
the enolate fragment (CC−O−) in II and the reactive carbonyl
group in I are oriented in an anti-conformation (Figure 3). In the
case of TsR(COA_CCO), a phenylene group of II is located
close to the t-Bu group of the catalyst, which would cause
destabilization. In contrast, the tert-butyl group of the catalyst in
TsS(COA_CCO) is far from an adjacent group (Bn) of II. We
could not obtain any evidence of positive interaction (e.g.,
cation−π) in these transition states.
(5) (a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed.
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14264.
In conclusion, we have developed an enantioselective Steglich
rearrangement of O-acylated oxindoles to give the desired
products possessing a quaternary stereogenic center in >98%
yield with up to 99:1 er. The reaction proceeded smoothly in the
presence of 10 mol % of 1a or 1c, which can be readily prepared
by the diastereoselective Ugi reaction in a one-step and one-pot
manner. Such easy-to-prepare catalysts in the enantioselective
Steglich rearrangement of O-acylated oxindole derivatives have
not been reported previously. The application of such a catalyst
scaffold to other important classes of enantioselective trans-
formations is now underway.
(6) (a) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R.
L. J. Org. Chem. 2003, 68, 7379. (b) Schedel, H.; Kan, K.; Ueda, Y.;
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(d) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J.
Am. Chem. Soc. 2006, 128, 925.
(8) Initial report on peptide-based organocatalyst: Miller, S. J.;
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am.
Chem. Soc. 1998, 120, 1629.
(9) For a review on synthetic peptides in asymmetric catalysis see:
Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107,
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(10) Mandai, H.; Irie, S.; Mitsudo, K.; Suga, S. Molecules 2011, 16,
8815.
(11) Mandai, H.; Irie, S.; Akehi, M.; Yuri, K.; Yoden, M.; Mitsudo, K.;
Suga, S. Heterocycles 2013, 87, 329.
(12) Initial report on Steglich rearrangement with achiral DMAP, see:
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02089.
■
S
Experimental procedures and copies of 1H and 13C NMR
spectra for substrates and products (PDF)
Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981.
̈
(13) We also investigated the effect of catalyst loading, and found that
10 mol % catalyst was required for full conversion within 12 h.
(14) Joannesse, C.; Johnston, C. P.; Morrill, L. C.; Woods, P. A.;
Kieffer, M.; Nigst, T. A.; Mayr, H.; Lebl, T.; Philp, D.; Bragg, R. A.;
Smith, A. D. Chem. - Eur. J. 2012, 18, 2398.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mandai@cc.okayama-u.ac.jp.
*E-mail: suga@cc.okayama-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (Japan). The
authors gratefully thank the Division of Instrumental Analysis,
Department of Instrumental Analysis & Cryogenics, Advanced
Science Research Center, Okayama University, for NMR and
high-resolution mass spectrometry measurements (FAB).
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DOI: 10.1021/acs.orglett.5b02089
Org. Lett. XXXX, XXX, XXX−XXX