Asymmetric aldol reaction catalyzed by a chiral phosphine-silver complex

Article abstract of DOI:10.1002/ejoc.201402351

A catalytic asymmetric aldol reaction of alkenyl trihaloacetates or a γ,δ-unsaturated δ-lactone with aldehydes or an α-keto ester was achieved by using a 2,2′-bis(diphenylphosphino)-1,1′- binaphthyl·silver trifluoromethanesulfonate complex as the chiral p

Full text of DOI:10.1002/ejoc.201402351

Job/Unit: O42351
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Date: 03-06-14 11:16:06
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402351
Asymmetric Aldol Reaction Catalyzed by a Chiral Phosphine–Silver Complex
Akira Yanagisawa,*[a] Ryoji Miyake,[a] and Kazuhiro Yoshida[a]
Keywords: Synthetic methods / Asymmetric catalysis / Aldol reactions / Silver / Aldehydes
A catalytic asymmetric aldol reaction of alkenyl trihaloacet- as the base precatalyst in the presence of methanol. Optically
ates or a γ,δ-unsaturated δ-lactone with aldehydes or an α-
keto ester was achieved by using a 2,2Ј-bis(diphenylphos-
active α-alkyl β-hydroxy ketones with enantioselectivities of
up to 95%ee were diastereoselectively obtained in moderate
phino)-1,1Ј-binaphthyl·silver trifluoromethanesulfonate com- to high yields through the in situ generated chiral silver enol-
plex as the chiral precatalyst and N,N-diisopropylethylamine
ates.
asymmetric aldol reaction of alkenyl trihaloacetates with
aldehydes or an α-keto ester by using a BINAP·AgOTf
complex as the chiral precatalyst and N,N-diisopropylethyl-
amine as the base precatalyst (Scheme 1).
Introduction
The β-hydroxy carbonyl moiety is a key synthon for nat-
ural products and biologically active organic compounds.
Various synthetic methods have been developed for the con-
struction of this functional group. Among them, the aldol
reaction is undoubtedly the most efficient and convenient.[1]
Many catalytic asymmetric aldol processes have been re-
ported; however, most of them are chiral Lewis acid or chi-
ral Lewis base catalyzed Mukaiyama-type aldol reactions
that use silyl enolates as nucleophiles[2,3] or direct aldol re-
actions involving organocatalysts,[4] and there are no exam-
ples of reactions that employ alkenyl esters as latent enol-
ates. We reported that alkenyl trichloroacetates react with
dibutyltin dimethoxide to furnish the corresponding tin
enolates that have sufficient reactivity toward aldehydes. In
addition, in the presence of a catalytic amount of dibutyltin
dimethoxide and a stoichiometric amount of methanol, the
aldol reaction occurs smoothly to give the desired prod-
ucts.[5] An asymmetric version of the catalytic aldol process
has been accomplished as well, which involves the addition
of a 2,2Ј-bis(diphenylphosphino)-1,1Ј-binaphthyl·silver tri-
fluoromethanesulfonate (BINAP·AgOTf) catalyst.[6] More-
over, not only diverse aldehydes, including α,β-unsaturated
aldehydes and aliphatic aldehydes, but also ketones, such
as α-keto esters, have shown remarkable reactivity in the
reaction.[7] Although the transformation provides a benefi-
cial route to nonracemic β-hydroxy ketones, it has a disad-
vantage in that the use of a toxic organotin compound is
indispensable. To solve the problem, we explored the poten-
tial of chiral silver(I)-catalyzed asymmetric aldol synthesis
in the absence of organotin reagents.[8] We report herein the
Scheme 1. Enantioselective aldol reaction of alkenyl trihaloacetates
with carbonyl compounds catalyzed by the (S)-BINAP·AgOTf
complex.
Results and Discussion
As previously mentioned, dibutyltin dimethoxide acts as
a catalyst in the aldol reaction of alkenyl trichloroacetates
with aldehydes.[5] The reaction takes place via a tin enolate,
and the tin dimethoxide is regenerated with the assistance
of MeOH. We envisaged that if a BINAP·AgOMe complex
could be formed from a BINAP·AgOTf complex and
MeOH, the chiral silver(I)-catalyzed asymmetric aldol reac-
tion of alkenyl trichloroacetates without an organotin com-
pound would be possible. Thus, we initially attempted to
generate the BINAP·AgOMe complex in the reaction of
1-trichloroacetoxycyclohexene (1a)[9] with benzaldehyde.
Upon treating a 1.5:1 mixture of 1a and benzaldehyde with
(S)-BINAP (8 mol-%) and AgOTf (16 mol-%) in the pres-
ence of MeOH (5 equiv.) and 3 Å molecular sieves in THF
at –20 °C for 24 h, desired 2-[hydroxy(phenyl)methyl]cyclo-
hexanone (2aa) was not obtained at all (Table 1, entry 2),
even though the corresponding reaction with Bu2Sn-
(OMe)2 (6 mol-%) produced 2aa in 98% yield with an
anti/syn ratio of 86:14. The anti isomer had 92%ee and its
absolute configuration was determined to be (2R,1ЈS) by
comparison with reported HPLC analytical data (Table 1,
entry 1).[6] Then, we examined the utility of a tertiary amine
[a] Department of Chemistry, Graduate School of Science, Chiba
University,
Inage, Chiba 263-8522, Japan
E-mail: ayanagi@faculty.chiba-u.jp
http://org.chem.chiba-u.jp/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402351.
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A. Yanagisawa, R. Miyake, K. Yoshida
SHORT COMMUNICATION
as an additive to facilitate the deprotonation of methanol entry 1). However, there was no further improvement in the
and increase its nucleophilicity. As a consequence, we found enantioselectivity if the reaction was performed at –60 °C
that target product 2aa was obtained in 66% yield in the (Table 2, entry 8). A significant deceleration of the reaction
presence of 40 mol-% of N,N-diisopropylethylamine was observed for the reaction at –78 °C (Table 2, entry 9).
(Table 1, entry 3). Even more significant was that the terti-
ary amine gave the anti product with good diastereoselectiv- Table 2. Enantioselective aldol reaction of alkenyl trichloroacetate
1a with benzaldehyde catalyzed by chiral phosphine·AgOTf.[a]
ity (anti/syn = 78:22) and remarkable enantioselectivity
(80%ee). To attain better results, we further tried to opti-
mize the reaction conditions. Consequently, it turned out
that the 3 Å molecular sieves were not necessary for the
present asymmetric aldol reaction. In fact, the reaction in
the absence of 3 Å molecular sieves at –20 °C for 1 h af-
forded the desired aldol adduct in 99% yield with high dia-
stereoselectivity (anti/syn = 89:11) and satisfactory enantio-
selectivity (90%ee; Table 1, entry 4).
Table 1. Enantioselective aldol reaction of alkenyl trichloroacetate
1a with benzaldehyde catalyzed by (S)-BINAP·AgOTf.[a]
[a] Unless otherwise specified, the reaction was performed with chi-
[a] Unless otherwise specified, the reaction was performed with (S)-
BINAP (8 mol-%), silver triflate (16 mol-%), alkenyl trichloroacet-
ate 1a (1.5 equiv.), benzaldehyde (1 equiv.), N,N-diisopropylethyl-
amine, methanol (5 equiv.), and 3 Å molecular sieves in THF at
ral phosphine (8 mol-%), silver triflate (16 mol-%), alkenyl tri-
chloroacetate 1a (1.5 equiv.), benzaldehyde (1 equiv.), N,N-diiso-
propylethylamine (40 mol-%), methanol (5 equiv.), and additive in
a specified solvent. [b] Yield of isolated product. [c] Determined by
1H NMR spectroscopy. [d] The value corresponds to the major dia-
stereomer. Determined by HPLC analysis.
1
–20 °C. [b] Yield of isolated product. [c] Determined by H NMR
spectroscopy. [d] The value corresponds to the anti isomer. Deter-
mined by HPLC analysis. The absolute configuration is shown in
parentheses. [e] The reaction was performed in the presence of
Bu2Sn(OMe)2 (6 mol-%).[6] [f] The reaction was performed without
3 Å molecular sieves.
With the optimum reaction conditions (entry 7 in
Table 2) in hand, we performed the chiral silver(I)-catalyzed
asymmetric aldol reaction by using various combinations
Subsequently, we examined the asymmetric induction of alkenyl trihaloacetates and aldehydes (Table 3). The in-
ability of chiral phosphines other than BINAP and recon- troduction of an electron-donating group at the para or or-
firmed that BINAP was the chiral ligand of choice (Table 2, tho position of benzaldehyde (R3 = 4-MeOC6H4 or 2-Me-
entry 1 vs. entries 2–4).[10] Tol-BINAP and SEGPHOS were OC6H4) promoted the reaction with 1-trichloroacetoxycy-
also promising chiral ligands in terms of anti selectivity and clohexene (1a) to yield anti adduct 2ab or 2ac predomi-
enantioselectivity (Table 2, entries 2 and 3). In contrast, the nantly with 91 or 89%ee, respectively, without decreasing
use of tBu-QuinoxP* led to the opposite diastereoselectiv- the yield of the isolated product (Table 3, entries 2 and 3).
ity, and the syn aldol adduct was predominantly obtained In addition, we executed the reaction of 4-CF3C6H4CHO
with unsatisfactory optical purity (Table 2, entry 4). Then, and found that the electron-deficient aromatic aldehyde also
we investigated the reaction conditions, specifically the opti- showed remarkable stereoselectivity although the yield of
mum solvent and temperature. First, we checked the suit- isolated product 2ad was moderate (Table 3, entry 4). α,β-
ability of dichloromethane and toluene as solvents instead Unsaturated aldehydes undergo 1,2-addition, and in fact,
of THF because less polar solvents were anticipated to be the reaction of (E)-cinnamaldehyde with 1a gave 2-[(E)-1-
more favorable for realizing a rigid transition-state struc- hydroxy-3-phenylallyl]cyclohexanone (2af) almost exclu-
ture; however, we found that those less polar solvents were sively (Table 3, entry 6). We also examined the reaction be-
inferior in terms of enantioselectivity, anti/syn selectivity, tween alkenyl ester 1a and hydrocinnamaldehyde at –20 °C
and yield of the product (Table 2, entries 5 and 6 vs. en- for 24 h; however, we obtained desired adduct 2ag in only
try 1). Lowering the reaction temperature to –40 °C raised 16% yield probably as a result of the low reactivity of the
the enantiomeric excess of 2aa to 94% (Table 2, entry 7 vs. aliphatic aldehyde (Table 3, entry 7). The above-mentioned
2
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Ag-Catalyzed Asymmetric Aldol Reaction
Table 3. Enantioselective aldol reaction of alkenyl trihaloacetates 1 with aldehydes catalyzed by (S)-BINAP·AgOTf.[a]
[a] Unless otherwise specified, the reaction was performed with (S)-BINAP (8 mol-%), silver triflate (16 mol-%), alkenyl trihaloacetate 1
(1.5 equiv.), aldehyde (1 equiv.), N,N-diisopropylethylamine (40 mol-%), and methanol (5 equiv.) in THF. [b] Yield of isolated product.
1
[c] Determined by H NMR spectroscopy. [d] The value corresponds to the major diastereomer. Determined by HPLC analysis.
results further encouraged us to employ the alkenyl trifluoro- good electrophiles for the BINAP·AgOTf-catalyzed asym-
acetates of other cyclic ketones in the asymmetric aldol metric aldol reaction of alkenyl trichloroacetates in the
reaction. 1-Tetralone derivative 1b afforded target products presence of a catalytic amount of Bu2Sn(OMe)2.[7] Treat-
2ba and 2bb with good optical purities (75–80%ee) and ment of methyl benzoylformate with 1-trichloroacetoxy cy-
predominant anti selectivities (anti/syn = 92:8–93:7) in the clohexene (1a) in the presence of (S)-BINAP (8 mol-%),
reaction with benzaldehyde and p-anisaldehyde (Table 3, AgOTf (16 mol-%), N,N-diisopropylethylamine (40 mol-%),
entries 8 and 9). Then, we examined the ability of alkenyl and MeOH (5 equiv.) in dry THF at –40 °C for 4 h gave a
trifluoroacetates to generate chiral silver enolates. Alkenyl 57:43 diastereomeric mixture of optically active aldol ad-
esters have been shown to be superior substrates for an duct 3a in almost quantitative yield (Table 4, entry 1). The
asymmetric protonation that used a cinchona alkaloid as major diastereomer had 70%ee. The utility of the present
the chiral catalyst.[11] By performing the enantioselective (S)-BINAP·AgOTf-catalyzed asymmetric aldol reaction of
aldol reaction of 1-tetralone-derived alkenyl trifluoroacet- methyl benzoylformate was further demonstrated by using
ate 1bЈ with benzaldehyde and p-anisaldehyde at a low tem- alkenyl trifluoroacetates prepared from diverse ketones
perature (–78 °C) for 3 h, we acquired aldol adducts 2ba (Table 4, entries 2 and 3). In addition to cyclic substrate 1bЈ,
and 2bb in high yields with improved enantiomeric excess acyclic substrate 1c was also allowed to react with the α-
values (Table 3, entries 10 and 11). The reaction of acyclic keto ester enantioselectively, although a long reaction time
alkenyl trifluoroacetate 1c (E/Z = 8:92) with benzaldehyde was necessary for the latter substrate to give a satisfactory
at –78 °C provided aldol product 2ca in a satisfactory yield yield (Table 4, entry 3). Worthy of note was that the reac-
but with opposite syn selectivity. The optical purity of the tion with acyclic substrate 1c exhibited nearly exclusive dia-
syn isomer was 89%ee (Table 3, entry 12). Remarkable syn stereoselectivity although the enantioselectivity was moder-
selectivity was also noted in the reaction between 1c and p- ate (57%ee; Table 4, entry 3). In contrast, the reaction with
anisaldehyde (Table 3, entry 13).
The above-mentioned results prompted us to use a better enantioselectivity (82%ee; Table 4, entry 2).
ketone as an electrophile for the chiral silver(I)-catalyzed γ,δ-Unsaturated δ-lactones can be used in place of alk-
aldol reaction. We previously showed that α-keto esters are enyl trihaloacetate 1 in the present chiral silver(I)-catalyzed
alkenyl trifluoroacetate of α-tetralone 1bЈ proceeded with
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A. Yanagisawa, R. Miyake, K. Yoshida
SHORT COMMUNICATION
Table 4. Enantioselective aldol reaction of alkenyl trihaloacetates 1 presence of N,N-diisopropylethylamine to afford the corre-
with an α-keto ester catalyzed by (S)-BINAP·AgOTf.[a]
sponding (S)-BINAP·AgOMe, which is the true catalyst in
the present asymmetric aldol reaction. Next, the thus-gen-
erated chiral silver methoxide attacks alkenyl trihaloacetate
1 to yield chiral silver enolate 7. The following addition
reaction of chiral silver enolate 7 with carbonyl compound
8 provides chiral silver alkoxide of aldol adduct 9. Finally,
the protonation of 9 with MeOH results in the formation
of optically active β-hydroxy ketone 2 or 3 with regenera-
tion of the chiral silver methoxide. The rapid methanolysis
of silver alkoxide 9 advances the catalytic cycle efficiently.
[a] Unless otherwise specified, the reaction was performed with (S)-
BINAP (8 mol-%), silver triflate (16 mol-%), alkenyl trihaloacetate
1 (1.5 equiv.), α-keto ester (1 equiv.), N,N-diisopropylethylamine
(40 mol-%), and methanol (5 equiv.) in THF. [b] Yield of isolated
product. [c] Determined by 1H NMR spectroscopy. [d] The value
corresponds to the major diastereomer. Determined by HPLC
analysis.
asymmetric aldol reaction. In fact, the reaction of γ,δ-un-
saturated δ-lactone 4 with benzaldehyde provided target
aldol adduct 5 in 81% yield. The major diastereomer of
5 had 63%ee (Scheme 2). The γ,δ-unsaturated δ-lactone-
derived chiral silver enolate also showed satisfactory reac-
tivity toward an α-keto ester. Upon treating methyl benzo-
ylformate with 4 under the same reaction conditions for
Figure 1. Plausible catalytic cycle for the asymmetric aldol reaction
catalyzed by chiral silver methoxide.
24 h, aldol product 6 having a tertiary alcohol moiety was
formed in 57% yield as a single diastereomer (65%ee,
Scheme 2).
The results in Table 3 are evidence that the diastereo-
selectivity depends on the geometry of a BINAP-coordi-
nated silver enolate and that cyclic transition-state struc-
tures (i.e., A and B) described in Figure 2 are the proposed
models. Thus, from the (E)-silver enolate, the anti-aldol ad-
duct can be obtained via cyclic transition state model A,
and model B connects the (Z)-silver enolate to the syn-aldol
adduct.[12]
Scheme 2. Enantioselective aldol reaction of γ,δ-unsaturated δ-lact-
one 4 with benzaldehyde and an α-keto ester catalyzed by (S)-
BINAP·AgOTf.
A plausible catalytic mechanism is shown in Figure 1.
Initially, (S)-BINAP·AgOTf reacts with methanol in the Figure 2. Proposed cyclic transition state structures.
4
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Ag-Catalyzed Asymmetric Aldol Reaction
meric ratio of the major diastereomer was determined by HPLC
analysis.
A hypothesis for the enantioface discrimination between
an aldehyde and a silver enolate in the present asymmetric
aldol reaction catalyzed by (S)-BINAP·AgOTf is displayed
in Figure 3. An aldehyde approaches the α carbon atom of
a chiral silver enolate while avoiding steric repulsion from a
phenyl group of the chiral phosphine ligand. Thus, carbon–
carbon bond formation occurs selectively between the Si
face of the silver enolate and the Si face of the aldehyde to
yield the (2R,1ЈS)-β-hydroxy ketone.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and copies of
1
the H NMR and 13C NMR spectra and HPLC traces.
Acknowledgments
This work was supported by the Japanese Ministry of Education,
Culture, Sports, Science and Technology, MEXT/JSPS KAKENHI
(grant number 25410107), the Naito Foundation and the Chiba
University (COE Start-up Program led by Professor Takayoshi
Arai). The authors gratefully acknowledge a generous gift of (R)-
SEGPHOS from Takasago International Corporation and (R,R)-
tBu-QuinoxP* from Nippon Chemical Industrial Co., Ltd.
[1] For reviews, see: a) C. H. Heathcock, Comprehensive Organic
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Figure 3. A hypothesis for enantioface discrimination between an
aldehyde and a silver enolate.
Conclusions
In summary, we demonstrated a novel example of an
asymmetric aldol reaction of alkenyl trihaloacetates or a
γ,δ-unsaturated δ-lactone with carbonyl compounds
through in situ generated chiral silver enolates catalyzed by
BINAP·AgOTf and N,N-diisopropylethylamine. The pro-
cedure is operationally simple, employs readily available
chemicals, and produces various optically active α-alkyl-β-
hydroxy ketones with enantioselectivities up to 95%ee not
only from aromatic and α,β-unsaturated aldehydes but also
from an α-keto ester. This process is environmentally benign
because toxic organotin compounds are not required. Fur-
ther work is in progress on the asymmetric reaction.
Experimental Section
General Experimental Procedure for the Asymmetric Aldol Reaction
Catalyzed by the (S)-BINAP·AgOTf Complex and iPr2NEt: A mix-
ture of AgOTf (20.6 mg, 0.08 mmol) and (S)-BINAP (24.9 mg,
0.04 mmol) was dissolved in dry THF (3 mL) under an argon at-
mosphere and with direct light excluded, and the mixture was
stirred at room temperature for 20 min. CH3OH (101 μL,
2.5 mmol) and iPr2NEt (34 μL, 0.20 mmol) were successively added
to the resulting solution at the specified temperature (–20, –40, or
–78 °C). The mixture was stirred at the specified temperature for
5 min. Then, alkenyl trihaloacetate 1 or γ,δ-unsaturated δ-lactone
4 (0.75 mmol) and aldehyde or α-keto ester (0.5 mmol) were suc-
cessively added drop by drop to the resulting solution at the speci-
fied temperature. After stirring for 2–50 h at that temperature, the
mixture was treated with MeOH (2 mL). Then, the mixture was
filtered with a glass filter funnel filled with Celite and washed with
diethyl ether, and the combined filtrate and washes were concen-
trated in vacuo. The residual crude product was purified by column
chromatography on silica gel to give corresponding β-hydroxy
ketones 2, 3, 5, or 6 (see Tables 3 and 4 and Scheme 2). The anti/syn
ratio was determined by 1H NMR spectroscopy and the enantio-
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SHORT COMMUNICATION
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[7]
[8]
A. Yanagisawa, Y. Terajima, K. Sugita, K. Yoshida, Adv.
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Quite recently, we found that a chiral phosphine·silver(I) com-
plex catalyzed asymmetric Mannich-type reaction of alkenyl
trichloroacetates with imines takes place in the presence of a
substoichiometric amount of N,N-diisopropylethylamine with-
out dibutyltin dimethoxide: A. Yanagisawa, Y. Lin, R. Miyake,
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[9]
J. Libman, M. Sprecher, Y. Mazur, Tetrahedron 1969, 25, 1679.
[10] Employment of SEGPHOS or tBu-QuinoxP* in place of
BINAP resulted in a deceleration of the aldol reaction probably
because of ligand bite angle effects, which might affect the tran-
sition-state structure, see: P. W. N. M. van Leeuwen, P. C. J.
Kamer, J. N. H. Reek, P. Dierkes, Chem. Rev. 2000, 100, 2741.
[11] a) J. Gil, M. Medio-Simon, G. Mancha, G. Asensio, Eur. J.
Org. Chem. 2005, 1561; b) A. Claraz, J. Leroy, S. Oudeyer, V.
Levacher, J. Org. Chem. 2011, 76, 6457.
[12] In addition to the latter pathway, the syn-aldol adduct can be
formed from the (E)-silver enolate through another cyclic tran-
sition-state structure in which the R3 group of the aldehyde is
directed to the axial position. Therefore, the size of the R3
group also affects the anti/syn ratio of the aldol products.
Received: April 3, 2014
[5] a) A. Yanagisawa, T. Sekiguchi, Tetrahedron Lett. 2003, 44,
7163; b) A. Yanagisawa, R. Goudu, T. Arai, Org. Lett. 2004,
6, 4281.
[6] a) S. E. Denmark, R. A. Stavenger, K.-T. Wong, X. Su, J. Am.
Chem. Soc. 1999, 121, 4982; b) A. Yanagisawa, T. Ichikawa, T.
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Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42351
/KAP1
Date: 03-06-14 11:16:06
Pages: 7
Ag-Catalyzed Asymmetric Aldol Reaction
Asymmetric Catalysis
A. Yanagisawa,* R. Miyake,
K. Yoshida ........................................ 1–7
Asymmetric Aldol Reaction Catalyzed by
a Chiral Phosphine–Silver Complex
An efficient catalytic enantioselective aldol
reaction between alkenyl trihaloacetates
and aldehydes or an α-keto ester is de-
scribed. The use of in situ generated chiral
silver methoxide as the chiral catalyst al-
lows the synthesis of various nonracemic α-
alkyl β-hydroxy ketones with enantioselec-
tivities of up to 95%ee.
Keywords: Synthetic methods / Asymmetric
catalysis / Aldol reactions / Silver / Alde-
hydes
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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