Kinetic resolution of tertiary alcohols: Highly enantioselective access to 3-hydroxy-3-substituted oxindoles

Article abstract of DOI:10.1002/anie.201209043

Enantioselective: The first highly enantioselective kinetic resolution of 3-hydroxy-3-substituted oxindoles has been developed through oxidative esterification catalyzed by a N-heterocyclic carbene (see picture). This method uses a simple procedure and provides 3-hydroxy-oxindoles with various substituents at the 3-position in excellent enantiopurity. S=selectivity. Copyright

Full text of DOI:10.1002/anie.201209043

Angewandte
Chemie
DOI: 10.1002/anie.201209043
Asymmetric Catalysis
Kinetic Resolution of Tertiary Alcohols: Highly Enantioselective
Access to 3-Hydroxy-3-Substituted Oxindoles**
Shenci Lu, Si Bei Poh, Woon-Yew Siau, and Yu Zhao*
In contrast to the well-established kinetic resolution of
secondary alcohols,[1] use of the tertiary alcohol kinetic
resolution has remained limited with only a handful of
systems reported in the literature including enzymatic and
chemical methods.[2] During our studies, we became inter-
ested in the synthesis of 3-hydroxy-3-substituted oxindoles (I,
Scheme 1), which represent the core structure of a large
halo aldehydes)[9] or from simple aldehydes under oxidative
conditions,[10] has added a powerful dimension to NHC
catalysis. Application of these new concepts to enantioselec-
À
tive C C bond formation has met with great success; the use
of the chiral acyl azolium to induce asymmetric induction of
the alcohol counterpart, however, has lagged behind. In fact,
only a few isolated examples for the secondary alcohol kinetic
resolution (selectivity S up to 7.3)[9e,10g] or diol desymmetriza-
tion (up to 83% ee)[9b,10b] were reported in the literature.[11]
Simple tertiary alcohols (e.g., tert-butanol), on the other hand,
showed no reactivity towards the acyl azolium species.
Asymmetric induction for tertiary alcohols using NHC
catalysis, to the best of our knowledge, is not known.
We initiated our studies by examining the reaction of
racemic 1a with a,b-unsaturated aldehydes catalyzed by
triazolium-based NHCs in the absence of an external oxidant
(Scheme 1). After extensive experimentation, no significant
conversion to the desired saturated ester was obtained and
the selectivity remained low (S < 5). When MnO2 was
included in the reaction between 1a and cinnamaldehyde
catalyzed by NHC derived from azolium 3,[12] 32% conver-
sion to ester 2a and a good level of selectivity (S = 21) were
obtained (entry 1, Table 1). The identity and equivalent of the
base turned out to be essential for the reaction (entries 2–4),
with 1.0 equiv DBU being the optimal choice (S = 30). The
screening of different NHC precursors proved azolium 3 as
the optimum (entries 2 and 5–7). When quinone 7 was used as
the oxidant instead of MnO2,[10f–j] low levels of selectivity and
reactivity were obtained (entry 8). Other aldehydes including
benzaldehyde and hydrocinnamaldehyde were also tested,
which proved less efficient and less selective for the reaction
as compared to cinnamaldehyde.
We then focused our attention on improving the reaction
rate to recover the unreacted alcohol in high enantiopurity.
Solvent screening showed that tetrahydrofuran (THF) was
the optimal choice in terms of enantioselectivity, whereas the
reaction rate in CH3CN was higher, which turned out to be
important for less reactive substrates later on (see Table 3 and
the Supporting Information for details). A higher concen-
tration led to a slight improvement in both reactivity and
selectivity (entry 1, Table 2 vs. entry 2, Table 1). Inspired by
the recent reports on cooperative catalysis by NHC and Lewis
acid pioneered by the Scheidt research group,[10i,13] we
reasoned that the a-hydroxy carbonyl moiety of our sub-
strates may be well-suited for Lewis acid activation. To our
satisfaction, although the addition of Sc(OTf)3 proved futile
(entry 2, Table 2), the combination of Mg(OTf)2 and NHC led
to improvement on both selectivity and reaction rate
(entry 3). Interestingly, the introduction of NaBF4 as additi-
ve[10h] further drove the reaction to a higher selectivity (S =
Scheme 1. Kinetic resolution of 3-hydroxy-3-substituted oxindoles by
NHC-catalyzed esterification.
number of biologically significant natural products and are
themselves important targets in medicinal chemistry.[3] It is
shown that the identity of the substituent at the 3-position has
significant influence on the biological activity of these natural
products.[4] Not surprisingly, extensive efforts have been
focused on their asymmetric synthesis and many successful
systems have been developed.[5] One general catalytic asym-
metric method that can tolerate a wide range of 3-substitu-
ents, however, remains elusive. We hope to address this issue
using an unprecedented and alternative approach, namely the
catalytic kinetic resolution of this important class of tertiary
alcohols that are readily available in racemic form.[6]
Considering the strategies applicable to our goal, we were
particularly attracted to asymmetric esterification of alcohols
employing chiral acyl azolium species (II, Scheme 1)[7]
generated from aldehydes catalyzed by a N-heterocyclic
carbene (NHC).[8] This novel catalytic generation of activated
carboxylates, either from internal redox reactions of func-
tionalized aldehydes (such as a,b-unsaturated aldehydes or a-
[*] Dr. S. Lu, S. B. Poh, W.-Y. Siau, Prof. Y. Zhao
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: zhaoyu@nus.edu.sg
Homepage: http://zhaoyu.science.nus.edu.sg
[**] We are grateful for the generous financial support from Singapore
National Research Foundation (NRF Fellowship) and National
University of Singapore. We thank Dr. Hailong Yan for helpful
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209043.
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Table 1: Optimization of the kinetic resolution of the tertiary alcohol 1a.
Table 3: Scope of the kinetic resolution of 3-hydroxy-3-substituted
oxindoles.[a]
Conv.[c] S[c]
[a]
[a,b]
Entry Azolium Base
Oxidant ee2a ee1a
1
2
3
3
3
3
0.5 equiv DBU
1.0 equiv DBU
1.0 equiv
MnO2
MnO2
MnO2
87
88
–
40
63
–
32
42
0
21
30
–
Entry Recovered 1
t [h];
Yield2 [%]; Yield1 [%];
S
DIPEA[d]
Conversion [%] ee2 [%]
ee1 [%]
4
5
6
7
8
3
4
5
6
3
1.0 equiv K2CO3 MnO2
–
–
0
–
21
4
8
3
1.0 equiv DBU
1.0 equiv DBU
1.0 equiv DBU
1.0 equiv DBU
MnO2
MnO2
MnO2
7
81
45
70
52
73
50
40
7
47
44
36
12
1
24;53
52;87
45;98
70
[a] Determined by HPLC. [b] The absolute configuration of the recovered
1a was assigned by comparison of the measured optical rotation with
the reported value. [c] Conversions and selectivity values were calculated
by the methods of Kagan and Fiaud (Ref. [6a]): Conv.=ee1/(ee1+ee2).
S=ln[(1ÀConv.)(1Àee1)]/ln[(1ÀConv.)(1+ee1)]. See the Supporting
Information for details. [d] DIPEA=diisopropylethylamine.
2[b]
3[b]
4
24;55
24;56
24;46
24;27
36;57
52;80
53;78
43;92
24;95
53;72
39;99
40;99
52;80
69;35
42;98
46
41
59
56
27
5
6
Table 2: Cooperative effect of a Lewis acid and NaBF4 for the kinetic
resolution of 1a.
7
24;63
59;58
35;99
18
8[b]
48;60
36;39
36;53
57;64
34;86
53;80
32;98
52;55
44;92
20
23
29
[a]
[a,b]
Entry Lewis acid
NaBF4
ee2a
ee1a
Conv.[c] S[c]
1
2
3
4
none
10 mol% Sc(OTf)3
10 mol% Mg(OTf)2 none
10 mol% Mg(OTf)2 50 mol% 88
none
none
87
90
89
78
47
85
98
47
34
49
53
36
32
48
70
9
[a–c] See Table 1.
10[b]
70) as well as over 50% conversion (entry 4). Under these
optimal conditions, unreacted 1a could be recovered in 45%
yield with 98% ee (entry 1, Table 3).
11
48;34
30;83
60;43
16
The substrate scope of this catalytic system turned out to
be remarkably broad (Table 3). The same set of reaction
conditions can be used for the successful kinetic resolution of
a wide range of 3-hydroxy-3-substituted oxindoles. The
selectivities for the 3-alkyl-substituted substrates are uni-
formly high (S > 40, entries 1–5), whereas the selectivities for
the alkenyl, alkynyl, and aryl-substituted tertiary alcohols
(entries 6–11) are also in a synthetically useful range (S > 16).
In most cases, the unreacted tertiary alcohols were recovered
in high to excellent enantiopurity. As a general trend,
increased steric bulk in the 3-substituent led to a reduced
[a] Unless stated otherwise, all reactions were carried out in THF for the
period of time as indicated. All reagents were used as received from
commercial supplier without purification. [b] Reactions were run in
CH3CN. See the Supporting Information for comparing data in THF.
reaction rate. The choice of THF routinely provided the
highest level of stereoselectivity. However, for some less
reactive substrates reactions in CH3CN were more efficient as
they allowed the reaction to proceed to > 50% conversion so
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that the unreacted tertiary alcohols could be recovered in
excellent enantiopurity (entries 2, 3, 8 & 10, Table 3). For
example, the kinetic resolution of 1b in THF proceeded to
50% conversion after 24 h with S = 54, under which condi-
tions both ester product 2b and unreacted 1b were isolated
with 90% ee. The reaction in CH3CN, in contrast, proceeded
to 55% conversion with S = 46 under otherwise identical
conditions and 1b was recovered with an excellent 99% ee
(entry 2; see the Supporting Information for more data on
comparison of THF and CH3CN).
In addition to a wide range of 3-substituents, different
substitutions on the oxindole backbone are also well tolerated
by our catalytic system (entries 1–3, Table 4). Substrates
bearing both electron-donating and electron-withdrawing
groups on the oxindole ring underwent esterification
smoothly to produce the recovered starting alcohols in high
1q provided a synthetically useful level of selectivity (S = 17,
entry 6), albeit with low reaction rate.
The catalytic kinetic resolution is simple to perform at
ambient temperature using a readily available catalyst. All
the reagents (cinnamaldehyde, DBU, MnO2, Mg(OTf)2 and
NaBF4) are used as received without further purification.
Our approach to access enantiopure 3-hydroxy-3-substi-
tuted oxindoles complements previous asymmetric syntheses
of these molecules nicely. The enantiopurity of the products
from a catalytic synthetic method can be easily boosted up to
nearly perfect if it is coupled with our kinetic resolution.[14]
This sequential asymmetric catalysis in turn results in an
overall more efficient process to access the target compounds.
As shown in Scheme 2, following the procedures disclosed by
the Hayashi research group[15] on the Rh-catalyzed arylation
of related isatins using the commercially available ligand (R)-
Table 4: Scope of the kinetic resolution of 3-hydroxy-3-substituted
oxindoles.
Entry Recovered 1
t [h];
Yield2 [%]; Yield1 [%];
S
Conversion [%] ee2 [%]
ee1 [%]
Scheme 2. Sequential catalysis for more efficient synthesis.
a) 2.5 mol% [RhCl(C2H4)2]2, 5 mol% (R)-MeO-MOP, 2 equiv
PhB(OH)2, 15 mol% KOH, THF/H2O, 508C, 24 h. b) 3 equiv allyltribu-
tyltin, 5 mol% Sc(OTf)3, 5 mol% inda-PyBOX, 0.2m in CH2Cl2, 4 ꢀ MS,
238C, 16 h.
1
2
3
4
5
72;52
72;52
72;54
55;52
55;28
55;29
51;91
51;83
52;81
50;89
24;80
26;85
46;98
78
34
35
68
12
45;92
44;95
47;97
70;31
67;35
MeO-MOP and the Franz research group[16] on allylation of
N-methyl isatins catalyzed by Sc(OTf)3-inda-PyBOX com-
plex, respectively, alcohols 1h and ent-1o were obtained in
good yields with moderate ee of 75% and 54% (see the
Supporting Information for more details). The kinetic reso-
lution of these moderately enantioenriched compounds
following the conditions listed in Tables 3 and 4 then provided
the alcohols in nearly enantiopure form, and more impor-
tantly, with 71 and 74% isolated yields, which compared
favorably with the < 50% yield in the kinetic resolution of the
corresponding racemates. Alcohol ent-1o has served as a key
intermediate for the preparation of the natural product CPC-
1, which was previously reported with only 85% ee.[17]
The proposed reaction pathway is illustrated in Scheme 3.
The formation of acyl azolium II under oxidative NHC
catalysis and its conformation were well-documented.[7,10]
The tertiary alcohol presumably attacks II from the opposite
side of the catalyst chiral backbone. The Lewis acid additive
may activate the substrate in a cooperative fashion. Secon-
dary interactions between the aryl ring of the substrate and
the styrenyl moiety on II may be involved to secure the
substrate conformation during the esterification.
6
17
enantioselectivity. We have also tested the effect of protecting
groups on the nitrogen (entries 4–6). PMB-containing sub-
strate 1o worked as well as the Bn protected 1a, whereas
methyl containing 1p proved a less reactive and less selective
substrate. Interestingly, the unprotected oxindole derivative
Preliminary studies on substrate modification suggested
that the oxindole structure is important for this system to
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Received: November 12, 2012
Revised: December 6, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · enantioselectivity ·
.
kinetic resolution · oxindoles
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Communications
Asymmetric Catalysis
S. Lu, S. B. Poh, W.-Y. Siau,
Y. Zhao*
&&& — &&&
Kinetic Resolution of Tertiary Alcohols:
Highly Enantioselective Access to 3-
Hydroxy-3-Substituted Oxindoles
Enantioselective: The first highly enan-
tioselective kinetic resolution of 3-hy-
droxy-3-substituted oxindoles has been
developed through oxidative esterifica-
tion catalyzed by a N-heterocyclic carbene
(see picture). This method uses a simple
procedure and provides 3-hydroxy-oxin-
doles with various substituents at the 3-
position in excellent enantiopurity.
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These are not the final page numbers!