Kinetic Resolution of Tertiary Alcohols by Chiral DMAP Derivatives: Enantioselective Access to 3-Hydroxy-3-substituted 2-Oxindoles

Article abstract of DOI:10.1021/acs.orglett.0c03956

We developed an efficient acylative kinetic resolution of 3-hydroxy-3-substituted 2-oxindoles by a chiral DMAP derivative having a 1,1′-binaphthyl with two tert-alcohols units. A wide range of 3-hydroxy-3-substituted oxindoles having various functional groups were efficiently resolved (14 examples, up to s = 60) in the presence of 1 mol % of catalyst within 3-9 h. Multigram-scale reactions (10 g) also proceeded with a high s-factor (s = 43) within 5 h.

Full text of DOI:10.1021/acs.orglett.0c03956

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Letter
Kinetic Resolution of Tertiary Alcohols by Chiral DMAP Derivatives:
Enantioselective Access to 3‑Hydroxy-3-substituted 2‑Oxindoles
Hiroki Mandai,* Ryuhei Shiomoto, Kazuki Fujii, Koichi Mitsudo, and Seiji Suga*
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ABSTRACT: We developed an efficient acylative kinetic resolution of 3-hydroxy-3-substituted 2-oxindoles by a chiral DMAP
derivative having a 1,1′-binaphthyl with two tert-alcohols units. A wide range of 3-hydroxy-3-substituted oxindoles having various
functional groups were efficiently resolved (14 examples, up to s = 60) in the presence of 1 mol % of catalyst within 3−9 h.
Multigram-scale reactions (10 g) also proceeded with a high s-factor (s = 43) within 5 h.
in advance, which could not be achieved by the aldol reaction
or Friedel−Crafts reaction.
he optically active 3-hydroxy-3-substituted 2-oxindole
1
Tskeleton
is frequently found in natural products and
biologically active molecules. To construct the structure in an
enantioselective fashion, various synthetic methods have been
extensively studied.2 For example, the aldol reaction,3 Friedel−
Crafts reaction,4 the addition of aryl boronic acids,5 and
Morita−Baylis−Hillman reactions of 1,2-unsaturated carbon-
yls6 using isatin and other methods7 have been widely
employed. However, limited types of nucleophiles (e.g.,
enolizable carbonyl compounds for an aldol reaction or
electron-rich aromatic compounds for the Friedel−Crafts
reaction) could be used in each reaction. Enantioselective
hydroxylation of 3-substituted 2-oxindoles8 and the kinetic
resolution of 3-hydroxy-3-substituted 2-oxindoles have also
been reported. Regarding the latter case, there are only a few
reports on organocatalytic approaches to obtain enantioen-
riched 3-hydroxy-3-substituted 2-oxindoles. Zhao and co-
workers reported the NHC-catalyzed acylative kinetic
resolution of 3-hydroxy-3-substituted 2-oxindoles with high s-
factors.9 Very recently, Smith and co-workers reported the
acylative kinetic resolution of 3-hydroxy-3-substituted 2-
oxindoles by 1−10 mol % of hyperBTM catalyst, which gave
an array of enantioenriched products with high s-factors.10
Extensive experimental and mechanistic studies revealed that
CO···isothiouronium interaction is important for the
enantiodiscrimination of tertiary alcohols. Such kinetic
resolution approaches are attractive options to access an
array of enantioenriched 3-hydroxy-3-substituted 2-oxindoles
from the racemate because various substituents (alkyl, aryl, and
carbonyl groups) can be incorporated into the starting material
Our research interests involve the development of chiral
nucleophilic catalysts11 for acyl-transfer reactions.12 Among
these, we developed binaphthyl-based chiral N,N-dimethyl-4-
aminopyridine (DMAP) derivatives, which showed drastic rate
enhancement and high enantioselectivity in the Steglich-type
rearrangement of O-acylated oxindoles11e and furanyl carbo-
nates,11k kinetic resolution of carbinols11f and d,l-1,2-diols,11g
desymmetrization of meso-1,2-diols11h and 1,3-diols,11j,l and
dynamic kinetic resolution of azlactone.11i According to our
extensive studies on acyl transfer reactions, a polar functional
group (tert-alcohol or amide) in the catalyst structure is
needed to achieve high catalytic activity and high enantiose-
lectivity. To further explore the utility of the catalyst, we
selected the kinetic resolution of a sterically congested tertiary
alcohol, which is a challenging enantioselective transformation.
Our scenario is inspired by the favored transition state revealed
by DFT studies in the Steglich-type rearrangement with
binaphthyl-based catalyst having two tert-alcohol units (Figure
1a).11e We expected that the kinetic resolution of 3-hydroxy-3-
substituted 2-oxindoles (similar in structure to enolate in
Figure 1a) might proceed smoothly with a high s-factor
Received: November 30, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03956
© 2020 American Chemical Society
Org. Lett. 2021, 23, 1169−1174
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Figure 2. Catalyst screening for the kinetic resolution of rac-2a.
Table 1. Effect of Solvent in the Kinetic Resolution of rac-
a
2a
Figure 1. (a) Favored transition state in Steglich-type rearrangement
of 2-O acylated oxindole derivatives (b) General scheme of the
current study.
associated with some sort of hydrogen-bonding interactions
between the catalyst and substrate, directly or indirectly
(Figure 1b), and raises alternative possibilities to access 3-
hydroxy-3-substituted 2-oxindoles in a highly enantioselective
fashion.
Herein, we report on the acylative kinetic resolution of
various 3-hydroxy-3-substituted 2-oxindoles by using as little as
1 mol % of a chiral DMAP derivative having a 1,1′-binaphthyl
with two tert-alcohols units. Several control experiments
involving the structure of a reaction substrate and a catalyst
were also conducted to understand these processes.
We began by identifying the optimal catalyst from a selected
library 1a−f for the kinetic resolution of 3-allyl-3-hydroxy 2-
oxindoles 2a in 1,2-dichloroethane (C2H4Cl2) at 0 °C for 15 h
(Figure 2). As a general tendency, the reactions with 1 mol %
of catalysts 1d−f having tert-alcohols with 3,5-di- or 3,4,5-
trisubstituted aryl group apparently showed higher selectivity
factors (s = 33−43) than those from catalysts 1a−c (s = 15−
16). Based on these results, we selected catalyst 1f [Ar = 3,5-(t-
Bu)2-4-MeOC6H2] as an optimal catalyst for further
optimization of the reaction conditions.
Next, the effects of solvent were investigated in the kinetic
resolution process (Table 1). The reactions in common
organic solvents (CH2Cl2, Et2O, t-BuOMe, and toluene,
entries 2−5) proceeded in 49−50% conversion but showed
less efficient s-factors (s = 6−30) compared to that obtained in
1,2-dichloroethane (s = 40, entry 1). Surprisingly, the use of
tert-amyl alcohol did not significantly reduce the s-factor (s =
18, entry 6). According to our previous observations,11f−j the
protic solvent showed a poor s-factor because that should
prevent the formation of an effective hydrogen bonding
network between the catalyst and the substrate,13 which is
undoubtedly responsible for the high enantioselectivity.
Furthermore, the reaction in the optimal solvent (C2H4Cl2)
with more concentrated conditions (0.1−0.5 M, entries 7−9)
showed somewhat lower s-factor (s = 32−35). After
b
conc
(M)
conv
(%)
er of
c
c
d
entry
1
solvent
3a
er of 2a
s
C2H4Cl2 (1,2-
dichloroethane)
CH2Cl2
0.05
55
90:10
99:1
40
2
3
4
5
6
7
8
9
0.05
0.05
0.05
0.05
0.05
0.1
50
51
50
51
49
48
49
56
92:8
91.5:8.5
90:10
90:10
79:21
87:13
90:10
92:8
30
20
22
6
18
32
35
33
Et2O
89:11
90:10
78:22
89:11
93:7
t-BuOMe
toluene
t-amyl alcohol
C2H4Cl2
C2H4Cl2
C2H4Cl2
0.3
0.5
93:7
88:12
>99:1
a
Reactions were performed on a 0.1 mmol scale in solvent (0.2 M)
under an argon atmosphere. Conversion was determined by
enantiomeric excess (ee) of 2a and 3a. Enantioselectivities were
determined by HPLC analysis. s-Factors were calculated by Kagan’s
b
c
d
equation.14
considering these results and extensive screening of the
reaction conditions (see the Supporting Information for
details), we selected the following optimal reaction conditions:
1 mol % of 1f, 0.5 equiv of (i-PrCO)2O, and 0.5 equiv of Et3N
in C2H4Cl2 at 0 °C.
With the optimal reaction conditions in hand, the kinetic
resolution of various 3-hydroxy-3-substituted 2-oxindoles 2a−
n was examined (Figure 3). The reactions of alkyl-, vinyl-, or
alkynyl-substituted substrates 2a, 2b, 2e, and 2f could be
efficiently resolved with high s-factors (s = 41−60), but the s-
factors were still acceptable when 2c or 2d having a sterically
demanding substituent (R = i-Pr or Cy) was used (s = 27 and
17, respectively). On the other hand, the reaction of aryl- or
heteroaryl-substituted substrates 2g−j showed higher s-factors
(s = 49−60) compared to those of 2a−f (s = 17−60). With 2h
or 2i, an electron-donating or -withdrawing substituent on the
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Scheme 1. Kinetic Resolution of rac-2a in a Multigram-Scale
Reaction and Deprotection of Recovered 2a for
Determination of Absolute Configuration
significantly (2a vs 2o, from s = 41 to 25) while maintaining
its reactivity (∼50% conv within 5 h) (Figure 4). On the other
Figure 3. Kinetic resolution of various 3-hydroxy-3-substituted 2-
oxindoles with 1 mol % of catalyst 1f.15
aryl group did not significantly affect the s-factor (2h [s = 63, 5
h] vs 2i [s = 60, 5 h]). A polar functional group within the
substrate could be tolerated. The use of 2k having a silyl ether
showed an excellent s-factor (s = 60), and 2l having a β-
hydroxy ketone (aldol adduct) showed a good s-factor (s =
30). In the latter case, we expected dynamic kinetic resolution
of 2l via retro-aldol reaction, but kinetic resolution only
proceeded (s = 30). 5-Cl- and 5-MeO-substituted substrates
2m and 2n also showed good to excellent s-factors (s = 60 and
31, respectively). According to these experiments, the current
kinetic resolution process allowed us to access various
enantioenriched 3-hydroxy-3-substituted 2-oxindoles having
an N-methoxycarbonyl group with s = 17−60 within 3−9 h.
We also conducted a multigram-scale reaction with 2a to
test the scalability of this reaction (Scheme 1). With only 19.2
mg (1 mol %) of catalyst 1f, 10.0 g of rac-2a was smoothly
resolved to give monoacylate 3a (6.7 g, 93:7 er) and recovered
2a (4.7 g, 95:5 er) with excellent selectivity (51% conv, s = 43)
at 0 °C for 5 h. The N-methoxycarbonyl group of recovered 2a
was successfully removed by Krapcho-type decarboxylation
under mild conditions (NaCl and H2O in DMSO) to give 4a,
the absolute configuration of which was determined to be R by
comparison to the reported value for the specific optical
rotation of (S)-4a.16 Other recovered alcohols 2b−n were also
assigned R by analogy.
Figure 4. Kinetic resolution of various N-protected 3-hydroxy-3-
substituted 2-oxindoles 2o−q with 1 mol % of catalyst 1f.
hand, the use of N-alkyl substrates 2p and 2q, an N-methyl or
benzyl group, required a longer reaction time (30 h) for
achieving ∼50% conv and resulted in a significant decrease in
the s-factor (s = 16 for 2p, s = 21 for 2q, respectively). These
results suggested that the electron-withdrawing group attached
to the nitrogen atom is required for acceleration of the
reaction.
One possible explanation for this effect is that the electron-
withdrawing group at the N-position might increase the acidity
of a hydroxy group, which was easily deprotonated by
carboxylate ion (−OCOi-Pr) fixed by a hydrogen-bonding
network (see Figure 6), which accelerates the rate of the
reaction. Furthermore, 3-hydroxy-3-substituted 2-benzofura-
none was also subjected to kinetic resolution [eq 1]. Thus, the
kinetic resolution of 2r showed a reasonably good s-factor (s =
28 within 9 h). Compared to N-methoxycarbonyl variant 2b,
almost the same reactivity was observed (48% conv for 9 h
with 2b in Figure 3, and 46% conv for 9 h with 2r). The
relatively strong electronegativity of oxygen atom maintains the
acidity of the hydroxyl group, which is important for
acceleration of the reaction. Finally, the importance of the
five-membered moiety was also confirmed (eq 2). The reaction
of 2s, where the five-membered ring is deconstructed, resulted
in poor conversion and a low s-factor within 26 h (5% conv, s =
2) compared to 2a having a five-membered structure. Overall,
Next, several control experiments regarding substrate
structure were carried out to obtain further insight into these
reactions. Change of the N-protecting group from methox-
ycarbonyl to tert-butoxycarbonyl decreased the s-factor
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the electronic properties and steric rigidity of the substrate
strongly affected the efficiency of the reaction.
Next, we focused our attention on the importance of the tert-
alcohol unit(s) of the catalyst. The kinetic resolution of rac-2a
was carried out using pseudo-C2-symmetric catalyst 1f′
(lacking one hydroxy group), C2-symmetric catalyst 1f″
(lacking two hydroxy groups), and 1g (elimination of two
tert-alcohol units) under the optimal conditions for 1f (Figure
5). The catalyst 1f′ showed lower conversion and s-factor
Figure 6. Plausible transition states.
anion11f,17,19,20 fixed by both a tert-alcohol unit and ortho-
proton of pyridine, followed by acylation to give (S)-3a and
recovered alcohol (R)-2a. At this stage, the electron-with-
drawing N-methoxycarbonyl group is responsible for the high
acidity of a hydroxy group, accelerating the rate of the reaction
(see also Figure 4). In the disfavored transition state (Figure 6,
bottom), steric repulsion between the substituent (drawn as R)
and the isopropyl group of N-acylpyridinium ion might be
dominant.
In summary, we have demonstrated that a small amount of
catalyst 1f efficiently promoted the kinetic resolution of 3-
hydroxy-3-substituted 2-oxindoles with a high s-factor. These
transformations required as little as 1 mol % of catalyst 1f and
were relatively faster than previously reported methods.9a,10 An
array of functional groups within the substrate were tolerated
and a variety of reactions proceeded with excellent
enantioselectivity (14 examples, up to s = 60). A multigram-
scale reaction (10 g) could be easily conducted within 5 h with
1 mol % of the catalyst 1f, and deprotection of an N-
methoxycarbonyl group of recovered alcohol 2a was also
successively achieved in 74% isolated yield by Krapcho-type
decarboxylation. Several control experiments on the substrate
structure (N-protecting group) and the catalyst structure
revealed that the substrate with N-methoxycarbonyl group is
for achieving a high s-factor. With regard to the catalyst
structure, the catalyst required two tert-alcohol units to achieve
high enantioselectivity and acceleration of the reaction rate.
Further elucidation of the mechanism of the current reaction
involving transition states (computational calculations) and
application of these products to the synthesis of biologically
important molecules are now in progress.
Figure 5. Kinetic resolution of rac-2a in the presence of catalyst with
or without hydroxy group(s) or tert-alcohol unit(s).
(41% conv, s = 27) but 1f″ and 1g showed no catalytic activity
or enantioselectivity. Interestingly, two sterically demanding
−CHAr2 units of 1f″ completely shut down its catalytic activity
(4% conv). Accordingly, the hydroxy group of the catalyst
enables hydrogen bonding-assisted kinetic resolution, and
significantly accelerates the reaction efficiency (1f″ vs 1f′ or
1f). Such phenomena were also observed in our previous
studies.11e−h Based on these observations, and after consider-
ing models provided by Spivey and Zipse et al.,17 Zipse,18 and
Yamanaka and Kawabata et al.,19 as well as our previous
transition states models,11e−g we speculated that N-methox-
ycarbonyl group of the substrate is located at far from catalyst
to avoid steric repulsion against the catalyst in plausible
transition states (Figure 6). The appropriate hydrogen bonding
network in the favored transition state should be responsible to
the deprotonation of the hydroxy group of the substrate
(Figure 6, top). It is deprotonated by a carboxylate
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03956.
Experimental procedures and copies of 1H and 13C
NMR spectra for substrates and products (PDF)
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F.; Wu, X.-Y. Direct enantioselective vinylogous aldol−cyclization
cascade reaction of allyl pyrazoleamides with isatins: asymmetric
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AUTHOR INFORMATION
Corresponding Authors
■
Hiroki Mandai − Department of Pharmacy, Faculty of
Pharmacy, Gifu University of Medical Science, Gifu 509-
0293, Japan; orcid.org/0000-0001-9121-3850;
Email: hmandai@u-gifu-ms.ac.jp
Seiji Suga − Division of Applied Chemistry, Graduate School
of Natural Science and Technology, Okayama University,
Okayama 700-8530, Japan; orcid.org/0000-0003-0635-
2077; Email: suga@cc.okayama-u.ac.jp
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catalytic Enantioselective Friedel-Crafts Reaction of Indoles with
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Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K. Catalytic
asymmetric synthesis of substituted 3-hydroxy-2-oxindoles. Angew.
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Authors
Ryuhei Shiomoto − Division of Applied Chemistry, Graduate
School of Natural Science and Technology, Okayama
University, Okayama 700-8530, Japan
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Asymmetric Addition of Aryl- and Alkenylboronic Acids to Isatins.
Angew. Chem., Int. Ed. 2006, 45, 3353−3356. (b) Toullec, P. Y.; Jagt,
R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Rhodium-
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W.; Cheng, C.; Wang, M.; Chen, B.; Zhou, Z.; Pang, J.; Qiu, L.
Synthesis of a Class of Chiral-Bridged Phosphoramidite Ligands and
Their Applications in the First Iridium-Catalyzed Asymmetric
Addition of Arylboronic Acids to Isatins. J. Org. Chem. 2015, 80,
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Kazuki Fujii − Division of Applied Chemistry, Graduate
School of Natural Science and Technology, Okayama
University, Okayama 700-8530, Japan
Koichi Mitsudo − Division of Applied Chemistry, Graduate
School of Natural Science and Technology, Okayama
University, Okayama 700-8530, Japan; orcid.org/0000-
0002-6744-7136
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03956
Notes
The authors declare no competing financial interest.
(6) (a) Guan, X. Y.; Wei, Y.; Shi, M. Construction of Chiral
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Organocatalytic Asymmetric Synthesis of Substituted 3-Hydroxy-2-
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2010, 132, 15176−15178. (c) Dong, Z.; Yan, C.; Gao, Y.; Dong, C.;
Qiu, G.; Zhou, H.-B. Tunable Bifunctional Phosphine-Squaramide
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Zhan, G.; Du, W.; Chen, Y. C. Application of 7-azaisatins in
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Enantioselective cyanoethoxycarbonylation of isatins promoted by a
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ACKNOWLEDGMENTS
■
This research was partially supported by JSPS Kakenhi Grant
No. JP19K05456.
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