Ionic nucleophilic catalysis of chiral ammonium betaines for highly stereoselective aldol reaction from oxindole-derived vinylic carbonates

Article abstract of DOI:10.1021/ja3022939

A new strategy for developing stereoselective bond-forming reactions is introduced; it takes advantage of the ionic nucleophilic catalysis of chiral ammonium betaines to utilize vinylic esters simultaneously as the enolate precursor and the acylating agent for coupling with electrophiles. Its synthetic utility is clearly demonstrated by the realization of a highly diastereo- and enantioselective aldol reaction from oxindole-derived vinylic carbonates.

Full text of DOI:10.1021/ja3022939

Communication
pubs.acs.org/JACS
Ionic Nucleophilic Catalysis of Chiral Ammonium Betaines for Highly
Stereoselective Aldol Reaction from Oxindole-Derived Vinylic
Carbonates
Daisuke Uraguchi, Kyohei Koshimoto, and Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan
S
* Supporting Information
the simultaneous utilization of the acyl and enolate moieties of
substrates such as 5-oxazolyl carbonates (Figure 1 middle).8−10
ABSTRACT: A new strategy for developing stereo-
selective bond-forming reactions is introduced; it takes
advantage of the ionic nucleophilic catalysis of chiral
ammonium betaines to utilize vinylic esters simultaneously
as the enolate precursor and the acylating agent for
coupling with electrophiles. Its synthetic utility is clearly
demonstrated by the realization of a highly diastereo- and
enantioselective aldol reaction from oxindole-derived
vinylic carbonates.
These reactions involve the generation of chiral enolate i
through the attack of the catalyst (Nu*) on vinylic esters
(carbonates) and subsequent stereoselective acyl transfer within
the ion pair i. Recently, Seidel and co-workers discovered that
use of a nucleophilic reaction partner such as isoquinoline for
the generation of i from an azlactone-derived vinylic carbonate
under the influence of a chiral hydrogen-bonding catalyst
enabled the stereoselective introduction of the nucleophile
framework into the product (Figure 1 top).9 On the other
hand, if external electrophiles (CX) such as carbonyl
compounds or electron-deficient olefins could be inserted
into i to forge two new bonds in a sequential manner, the
potential utility of the asymmetric nucleophilic catalysis would
be greatly expanded (Figure 1 bottom). However, this
possibility remains unexplored, probably because of the
difficulties associated with precise control of the reactivity of i
and the stereochemistry of the initial C−C bond formation by
the catalyst.11 Herein we report our own approach to address
this problem using the characteristic features of chiral
ammonium betaines 1 as ionic nucleophilic catalysts,8h,12
leading to the development of a highly diastereo- and
enantioselective aldol reaction from oxindole-derived vinylic
carbonates. The key for establishing this new system is the
appropriate structure and reactivity of aryl carbonates of type I
possessing an ammonium enolate (Figure 2), which enables
selective enolate addition to the aldehyde and subsequent acyl
transfer. Thus, the stereochemically homogeneous product is
derivatized with judicious incorporation of the two functional
groups originating from the vinylic carbonate.
inylic esters (carbonates) represent one of the universal
V
structural motifs encountered in natural products and are
important, reactive synthetic intermediates.1−3 The primary
structure of a vinylic ester comprises activated ester and
electron-rich olefin moieties (Figure 1). While the activated
As illustrated in Figure 2, the reaction of chiral ammonium
betaine 1 with vinylic ester 2 smoothly generates the
intermediate I, and the following pseudo-intramolecular attack
of this transient enolate on the aryl ester moiety of the pairing
ammonium ion gives the usual Steglich product (path A).
However, considering the moderate acyl transfer ability of the
ammonium ion, we envisaged that ammonium enolate I could
react with an external electrophile such as aldehyde 3 to afford
the corresponding ammonium alkoxide II (path B), which
would rapidly be O-acylated to furnish the fully protected aldol
adduct 4 with regeneration of the betaine catalyst 1. We further
expected that this unique catalytic pathway involving
Figure 1. Working hypothesis (G = alkyl, alkoxy).
ester component of vinylic esters has been widely used as a
mild and efficient acylating reagent,2 the olefin component has
been comparatively underutilized in organic synthesis except
for use as a monomer in the preparation of several polymers
and copolymers in academia and industry.3 In the arena of
asymmetric catalysis, the latent reactivity of the olefin
component has been harnessed for the effective utilization of
vinylic esters as enolate precursors or surrogates in facilitating
otherwise difficult stereoselective bond-forming reactions.4−7
Among the synthetically valuable transformations based on this
strategy, chiral nucleophilic catalyst-mediated, enantioselective
Steglich-type rearrangements are unique in regard to realizing
Received: March 8, 2012
Published: April 6, 2012
© 2012 American Chemical Society
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Communication
relatively unstable under basic conditions and are prone to
retro-aldol reactions. In fact, Bencivenni and co-workers
recently pointed out this problem and introduced an O-
protection procedure for ease of analysis and eventual product
manipulations.14d In this respect, our approach would be
intrinsically advantageous for the in situ derivatization of the
desired aldol adduct in a stable form.
The actual investigation was initiated by carrying out the
reaction of O-trichloroethoxycarbonyl enolate 2a with
benzaldehyde (3a) in the presence of chiral ammonium betaine
1a and 4A molecular sieves (MS4A) in toluene.15 Nearly
complete consumption of the starting 2a was observed within
30 min, and the desired aldol adduct 4a was obtained as a 6:1
mixture of diastereomers in 77% yield with concomitant yet
considerable formation of the Steglich product 5a (4a:5a =
8:1). The enantiomeric excess of the major isomer of 4a was
determined to be 34% ee (Table 1, entry 1). As anticipated,
structural modification of the catalyst had a beneficial impact on
the product distribution as well as on the stereoselectivity, and
interestingly, installation of the 3,5-disubstituted benzyl group
on the nitrogen atom of 1 dramatically enhanced the
production of 4a over 5a with promising diastereo- and
enantioselectivities (entries 3 and 4). The aromatic substituent
on the binaphthyl backbone (Ar) also affected each selectivity,
and the 2,6-xylyl group was found to be optimal (entry 5).16 In
addition, we reasoned that the structure of the carbonate
substituent of 2 (R3) would be critical for the improvement of
the reaction profile because the parent structure of 1 is
modified by the acyl transfer from 2 to serve as a chiral
component of the ammonium enolate in the C−C bond-
forming stage (Figure 2, I → II). Indeed, the incorporation of
the benzyl group (2b) improved the enantioselectivity to 92%
ee, albeit with a decrease in the catalyst turnover (entry 6).
Additional electronic tuning by the introduction of a
trifluoromethyl substituent (2c) delivered sufficient reaction
efficiency and even higher selectivities (entry 7). Eventually, the
use of 3,5-bis(trifluoromethyl)benzyl-substituted 2d in combi-
nation with the catalyst 1e led to virtually complete
discrimination of the reaction pathway with excellent levels of
stereoselectivity (entry 8). Importantly, the attempted reaction
Figure 2. Structures of chiral ammonium betaines 1 and the
mechanism of their catalysis with vinylic esters.
intermolecular C−C bond formation could be selectively
guided by the appropriate structural modification of 1. To
examine this hypothesis, 3-substituted oxindole-derived vinylic
carbonate 2 was selected as a model substrate. Although the
oxindole core and the related structural frameworks, particularly
those having a quaternary carbon stereocenter, are commonly
found in biologically relevant molecules,13 the catalytic
asymmetric aldol reaction of oxindoles has been poorly studied,
and only a few protocols using highly reactive carbonyl
compounds as requisite electrophiles have been developed.14
This is probably because the aldol adducts of oxindoles are
Table 1. Optimization of the Conditions for the Aldol Reaction of Vinylic Carbonates 2 with Benzaldehyde (3a) Catalyzed by
a
Chiral Ammonium Betaines 1
b
c
c
d
entry
1
R3
2
yield (%)
dr
4:5
ee (%)
4
1
2
3
4
5
1a
1b
1c
1d
1e
1e
1e
1e
Cl3CCH2
Cl3CCH2
Cl3CCH2
Cl3CCH2
Cl3CCH2
PhCH2
2a
2a
2a
2a
2a
2b
2c
2d
77
67
79
82
86
51
88
89
6:1
7:1
8:1
4:1
34
39
71
78
89
92
93
95
4a
4a
4a
4a
4a
4b
4c
4d
15:1
15:1
15:1
11:1
≥20:1
≥20:1
≥20:1
≥20:1
13:1
e
6
≥20:1
≥20:1
≥20:1
7
8
4-CF3−C6H4CH2
3,5-(CF3)2−C6H3CH2
a
Unless otherwise noted, reactions were performed on a 0.1 mmol scale with 2.0 equiv of 3a and 5 mol % 1 in toluene (2.0 mL) for 0.5 h at rt.
b
c
d
Isolated yields. The diastereomeric ratios and product distributions were determined by 1H NMR (400 MHz) analysis of crude aliquots. Shown is
the enantiomeric excess of the major isomer as determined by chiral stationary phase HPLC. The absolute configurations of 4a−d were assigned by
e
analogy to 4e (Scheme 1). The reaction time was 12 h.
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Communication
of 2d with 4-dimethylaminopyridine (DMAP) (5 mol %) as a
representative nucleophilic catalyst under otherwise identical
conditions exclusively yielded the corresponding Steglich
product 5d (12 h, 96% yield), illustrating the distinct feature
of the ionic nucleophilic catalysis of chiral ammonium betaines
of type 1.17
Scheme 1. Determination of the Absolute Configuration of
4e and the ORTEP Diagram of 7 (H Atoms except Those
Attached to the Stereogenic Carbon Have Been Omitted for
Clarity)
With the optimized conditions in hand, further experiments
were conducted to explore the scope of this new stereoselective
aldol reaction of oxindoles catalyzed by 1e. As shown by the
representative results summarized in Table 2, the present
a
Table 2. Substrate Generality [Cbzf = 3,5-(CF3)2-C6H3CH2]
hexane/EtOH solvent system at room temperature (see the
ORTEP diagram in Scheme 1).
b
c
d
entry
2
Ar2 (3)
yield (%)
dr
ee (%)
4
1
2
2d
2d
2d
2d
2d
2d
2d
2e
2f
4-ClC6H4 (3b)
4-MeC6H4 (3c)
3-BrC6H4 (3d)
3-MeOC6H4 (3e)
1-naphthyl (3f)
3-pyridyl (3g)
2-thienyl (3h)
3a
96
87
95
90
73
92
91
90
87
89
87
94
≥20:1
≥20:1
14:1
91
96
90
93
95
92
96
96
94
92
92
93
4e
4f
In conclusion, we have introduced a new strategy for
developing stereoselective carbon−carbon bond-forming re-
actions that exploits the salient features of chiral ammonium
betaines as ionic nucleophilic catalysts to utilize the binary
reactivity of vinylic esters (carbonates) for coupling with
electrophiles. This enables a highly stereoselective aldol
reaction of oxindole-derived vinylic carbonates with simple
aldehydes. The present approach significantly expands the
scope of asymmetric ionic nucleophilic catalysis of chiral
ammonium betaines and also offers an unprecedented
opportunity to utilize both of the reactive subunits of vinylic
esters in reaction development.
3
4g
4h
4i
4
≥20:1
≥20:1
10:1
5
6
4j
7
≥20:1
≥20:1
≥20:1
18:1
4k
4l
8
9
3a
4m
4n
4o
4p
10
11
12
2g
2h
2i
3a
3a
18:1
3a
≥20:1
a
Reactions were performed on a 0.1 mmol scale with 2.0 equiv of 3
and 5 mol % 1e in toluene (2.0 mL) for 0.5 h at rt. Isolated yields.
The diastereomeric ratios were determined by H NMR (400 MHz)
analysis of crude aliquots. Shown is the enantiomeric excess of the
major isomer as determined by chiral HPLC analysis. The absolute
configuration of 4e was determined by X-ray crystallographic analysis
of its derivative (Scheme 1; see the Supporting Information for
details). Absolute configurations of 4f−p were assigned by analogy to
4e.
b
ASSOCIATED CONTENT
* Supporting Information
■
c
1
S
d
Representative experimental procedures, physical data for all
new compounds, details of X-ray analysis, and crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tooi@apchem.nagoya-u.ac.jp
■
system nicely accommodated a range of simple aromatic
aldehydes, and the corresponding aldol adducts were obtained
uniformly with excellent diastereo- and enantioselectivities
(entries 1−5). Moreover, heteroaromatic aldehydes appeared
to be good candidates for an electrophilic partner (entries 6 and
7). The structure of vinylic carbonates 2 could also be varied
with regard to the C(5) and C(3) substituents without loss of
stereocontrol (entries 8−11). It should be noted that
comparable reactivity and selectivity were observed in the
reaction with vinylic carbonate 2i bearing a p-methoxyphenyl
group on the nitrogen atom (entry 12).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NEXT program, the Global
COE Program in Chemistry of Nagoya University, the Program
for Leading Graduate Schools “Integrative Graduate Education
and Research Program in Green Natural Sciences” at Nagoya
University, and Grants for Scientific Research from JSPS. K.K.
acknowledges financial support from JSPS.
The absolute configuration of 4e was determined by X-ray
crystallographic analysis after it was converted into the
corresponding indoline derivative 7 (Scheme 1). Reduction
of the carbonyl moiety of 4e by treatment with BH3·SMe2 in
THF followed by hydrolysis using LiOOH afforded secondary
alcohol 6. Subsequent acylation with 4-bromobenzoyl chloride
furnished a good yield of 7, which was recrystallized from an n-
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