Fluoride Anions in Self-Assembled Chiral Cage for the Enantioselective Protonation of Silyl Enol Ethers

Article abstract of DOI:10.1021/acs.orglett.7b01429

The potential of Song's chiral oligoethylene glycols (oligoEGs) as catalysts was explored in the enantioselective protonation of trimethylsilyl enol ethers in combination with alkali metal fluoride (KF and CsF) and in the presence of a proton source. Highly enantioselective protonations of various silyl enol ethers of α-substituted tetralones were achieved, producing chiral α-substituted tetralones in full conversion and with up to 99% ee. The established protocol was successfully extended to the synthesis of biologically relevant chiral α-substituted chromanone and thiochromanone derivatives.

Full text of DOI:10.1021/acs.orglett.7b01429

Letter
pubs.acs.org/OrgLett
Fluoride Anions in Self-Assembled Chiral Cage for the
Enantioselective Protonation of Silyl Enol Ethers
Sushovan Paladhi,†,§ Yidong Liu,‡,§ B. Senthil Kumar,†,§ Min-Jung Jung,† Sang Yeon Park,†
Hailong Yan,*,‡ and Choong Eui Song*,†
†Department of Chemistry, Sungkyunkwan University, Suwon, 440-746, Korea
‡Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China
S
* Supporting Information
ABSTRACT: The potential of Song’s chiral oligoethylene glycols (oligoEGs) as catalysts was explored in the enantioselective
protonation of trimethylsilyl enol ethers in combination with alkali metal fluoride (KF and CsF) and in the presence of a proton
source. Highly enantioselective protonations of various silyl enol ethers of α-substituted tetralones were achieved, producing
chiral α-substituted tetralones in full conversion and with up to 99% ee. The established protocol was successfully extended to
the synthesis of biologically relevant chiral α-substituted chromanone and thiochromanone derivatives.
he proton is the smallest constituent in organic synthesis,
and it is extremely challenging to control it in terms of
T
enantioselectivity. Nevertheless, in nature, enzymes such as
esterases and decarboxylases catalyze the enantioselective
protonation of prochiral enolates for the construction of
optically active α-tertiary carbonyl compounds.1 Consequently,
chiral α-carbonyl tertiary carbon stereocenters are common
functionalities present in huge numbers of bioactive natural
products. In contrast, the enantioselective introduction of
protons into carbanions via synthetic routes is still challenging
due to the small size of the proton. Furthermore, protonation
reactions are among the most rapid, often diffusion-controlled
reactions.1,2
During the past decade, several research groups have
developed a number of strategies, especially catalytic methods,
for the enantioselective protonation of enolate derivatives.1−4
A
significant number of organocatalytic methods5 were developed
for the asymmetric protonation of silyl enol ethers.4 However,
successful applications of chiral fluoride ions for enantiose-
lective protonation reaction have been rare,4a,c possibly because
of the high reactivity of such nascent fluoride ions, resulting in
product racemization.2a
Figure 1. (A) Song’s oligoEG catalysts. (B) Hypothesis for the
mechanism of enantioselective protonation of silyl enol ethers
catalyzed by Song’s chiral oligoEGs.
Recently, we reported easily accessible Song’s chiral oligoEGs
(Figure 1A), which bear phenols and polyether units, as
organocatalysts for asymmetric cation-binding catalysis.6,7 The
ether oxygens act as a Lewis base to coordinate alkali metal
fluorides, such as KF and CsF, thus generating a soluble
fluoride anion in a confined chiral space. The terminal phenol
groups are capable of simultaneously activating the electrophile
via hydrogen bonding interaction, resulting in a well-organized
transitions state leading to excellent stereoinduction in
asymmetric catalysis.
Received: May 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
We envisioned that our cation-binding catalyst system would
be ideally suited for the enantioselective protonation reaction of
silyl enol ethers 2. As shown in Figure 1B, the soluble chiral
fluoride anion was generated in situ upon the activation of MF
by the chiral cation-binding catalyst. Subsequently, it can
promote desilylation of silyl enol ethers, producing the enol
intermediate, which can then be protonated enantiomerically
by the phenolic proton of the catalyst, affording the desired
enantio-enriched α-substituted ketone product. The metal salt
of the catalyst can then be regenerated by means of an
additional proton source. The chiral cage, in situ formed by the
incorporation of alkali metal fluoride salt, creates an ideal active
site architecture, in which the reactive fluoride and the silyl enol
ether can be brought into proximity, consequently enhancing
the reactivity as well as efficiently transferring the stereo-
chemical information (Figure 1B).
Here, we report highly enantioselective organocatalytic
protonation of trimethylsilyl enol ethers of cyclic ketones
using cesium fluoride and Song’s chiral oligoEGs as a cation-
binding catalyst in the presence of a suitable proton source.
In general, enantioselective protonation is a kinetically
controlled process, which requires a balance of acidity between
the chiral protonating catalyst, the stoichiometric proton
source, and the substrate.2a This must be achieved in order
to obtain an optimized rate of protonation through the
catalyzed pathway by avoiding undesired background reactions.
The desired protonation is required to be as complete as
possible, as otherwise nonselective protonation reactions will
occur during workup. With this in mind, we have conducted a
systematic study by carefully choosing catalysts as well as
proton sources in order to find optimal conditions for the
enantioselective protonation reaction of silyl enol ether 2a as
the model substrate. The catalytic results are summarized in
Table 1.
As shown in Table 1, the ether chain length is critical for the
catalytic performance in this reaction (entries 1−5 vs entries 6−
13). Although the catalyst (R)-1a in combination with KF
showed promising enantioselectivity (up to 94% ee), the
observed activity was unsatisfactory, regardless of the type of
proton source (9−75% conversion even after 100 h) (entries
1−5). These observed slow reaction rates can be attributed to
the low concentration of soluble fluoride anion in the reaction
mixture. However, to our delight, the same reaction using (R)-
1b in combination with more soluble cesium fluoride
proceeded much faster (>99% conversion) than those observed
with 1a and KF (entries 6−13). In particular, when using 4-
nitrocatechol or (R)-3,3′-diiodo-BINOL as the proton source
(see Supporting Information for more detailed proton source
screening), almost full conversion even at 0 °C and quantitative
enantioselectivity were observed. These results indicate that the
proper combination of chiral cage size, fluoride source, and
proton source is critical for effective catalytic performance. In
further experiments performed with (R)-1b as the optimal
catalyst and 4-nitrocatechol as the proton source, different
solvents were examined (see Supporting Information for
solvent screening).
Table 1. Optimization of Reaction Conditions
time
(h)
conversion
(%)
ee
b
c
entry condition
proton source
catechol
(%)
1
2
3
4
5
6
7
8
9
A
A
A
A
A
B
B
B
B
B
B
48
100
100
72
75
39
84
70
91
94
93
90
90
96
92
94
94
4-nitro-catechol
Amberlite CG 50
rac-BINOL
65
55
(S)-3,3′-I2-BINOL
catechol
72
9
72
92
4-nitro-catechol
4-nitro-catechol
Amberlite CG 50
(S)-3,3′-I2-BINOL
24
>99
99
d
96
96
92
10
11
48
80
(R)-3,3′-I2-
48
>99
BINOL
d
12
B
B
(R)-3,3′-I2-
48
99
99
BINOL
de
,
13
no proton source
12
>99
99
a
Condition A: 2a (0.05 mmol), (R)-1a (10 mol %), KF (0.1 mmol),
and the proton source (0.06 mmol) in CH2Cl2 (0.05 M) at 20 °C.
Condition B: 2a (0.05 mmol), (R)-1b (10 mol %), CsF (0.1 mmol),
and the proton source (0.06 mmol) in CH2Cl2 (0.05 M) at 20 °C.
Conversion was determined by H NMR analysis of the unpurified
reaction mixture. Enantiomeric excess was determined by HPLC
analysis using a chiral stationary phase. Reaction was performed at 0
°C. Using 100 mol % (R)-1b. (S)/(R)-3,3′-I2-BINOL: (S)/(R)-3,3′-
b
1
c
d
e
diiodo-1,1′-bi-2-naphthol.
amount of catalyst (R)-1b in the absence of an additional
proton source, where catalyst regeneration is not required
(entry 13, Table 1). As expected, full conversion of 2a (>99%)
was observed within 12 h, affording 3a with 99% ee.
Having optimized the reaction conditions (entry 12, Table
1), we then examined the generality of the reaction by
subjecting various silyl enol ethers (2a−2p) derived from cyclic
ketones, which are summarized in Scheme 1. Silyl enol ethers of
tetralones (2a−2l) with different substituted alkyl and benzyl
chains were smoothly protonated to the corresponding chiral α-
substituted tetralones (3a−3l) in high chemical yields and
excellent enantioselectivities (up to 99% yield and 99% ee).8
Using commercially available 4-nitrocatechol as a proton
source, similar conversions were obtained, albeit with slightly
lower enantioselectivity (3a, 3d, and 3i). To our delight, the
present reaction conditions for the enantioselective protonation
are also applicable to the synthesis of chiral α-substituted
chromanone and thiochromanone derivatives 3m−3p, which
constitute the basic structure of natural products9 possessing
diverse biological activities such as antimutagenic10 and anti-
inflammatory11 properties. The palladium-catalyzed enantiose-
lective decarboxylative protonation was also applied to the
synthesis of 3-substituted 4-chromanones by Muzart and co-
workers. However, very low enantioselectivities were obtained
(22−60% ee).12
However, all tested solvents, nonpolar and polar, led to lower
yields and asymmetric induction (see Supporting Information).
In summary, the combination of catalyst 1b, CsF as fluoride
source, (R)-3,3′-diiodo-BINOL as proton donor, and CH2Cl2
as solvent provided the best result.
To further support our hypothesized reaction mechanism, we
performed the reaction of 2a with CsF using a stoichiometric
This method was also suitable for the synthesis of chiral α-
allyl and ethyl acetate substituted tetralones, chromanones, and
thiochromanone derivatives 2q−2z with excellent yields and
enantioselectivities (up to 99% yield and 97% ee, Scheme 2).
Chiral α-allyl and ethyl acetate substituted tetralones,
chromanones, and thiochromanone derivatives were previously
B
DOI: 10.1021/acs.orglett.7b01429
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Organic Letters
Letter
Scheme 1. Enantioselective Protonation of Trimethylsilyl
Scheme 2. Enantioselective Synthesis of α-Allyl and α-Ethyl
Enol Ethers of α-Alkyl Substituted Tetralones, Chromanone,
acetate Tetralones, Chromanones, and Thiochromanones by
a
a
and Thiochromanones
Organocatalytic Enantioselective Protonation
a
Unless otherwise indicated, the reactions were performed with 2
(0.05 mmol), (R)-1b (10 mol %), CsF (0.1 mmol), and (R)-3,3′-
diiodo BINOL (0.06 mmol) as proton source in CH2Cl2 (0.05 M) at 0
°C.
substituted acyclic ketone system is currently underway in our
laboratory.
a
Unless otherwise indicated, the reactions were performed with 2
(0.05 mmol), (R)-1b (10 mol %), CsF (0.1 mmol), and (R)-3,3′-
diiodo BINOL (0.06 mmol) as proton source in CH2Cl2 (0.05 M) at 0
°C. The reaction was carried out on 1 mmol scale. Using 4-
nitrocatechol (0.06 mmol) as the proton source.
b
c
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01429.
prepared by a palladium catalyzed decarboxylative asymmetric
allylic alkylation reaction13 and N-heterocyclic carbene-
catalyzed enantioselective intramolecular Stetter reaction,14
respectively.
Experimental details, analytical data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
In summary, we developed a method for the highly
enantioselective protonation of trimethylsilyl enol ethers of
cyclic ketones by using a highly accessible Song’s chiral
oligoethylene glycol (oligoEG) as the cation binding catalyst
and CsF as the base in the presence of a proton source.
Excellent enantioselectivities were obtained with a variety of α-
substituted tetralones. This protocol was also successfully
extended to the synthesis of biologically relevant chiral α-
substituted chromanone and thiochromanone derivatives. The
salient features of this process include (a) a transition-metal-
free and operationally simple procedure, (b) a broad substrate
scope, and (c) excellent enantioselectivity with up to 99% ee.
The extension of this strategy to an extremely challenging α-
*E-mail: s1673@skku.edu.
*E-mail: yhl198151@cqu.edu.cn.
ORCID
Hailong Yan: 0000-0003-3378-0237
Choong Eui Song: 0000-0001-9221-6789
Author Contributions
§S.P., Y.L., and B.S.K. contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b01429
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Organic Letters
Letter
Song, C. E. Nat. Commun. 2017, 8, 14877. (j) Tan, Y.; Luo, S.; Li, D.;
Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H. J. Am. Chem.
Soc. 2017, 139, 6431. (k) Duan, M.; Liu, Y.; Ao, J.; Xue, L.; Luo, S.;
Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Org. Lett. 2017, 19, 2298.
(8) We also examined other types of α-substituted cyclic ketones
(e.g., 2-methylindanone, 2-methylbenzocycloheptan-1-one, 2-benzyl-1-
cyclohexanone, and 1-methyl-2-tetralone) as well as acyclic ketones
(e.g., 2-methylbutyrophenone and 2-methyl-1,3-diphenylpropan-1-
one). However, unfortunately, only low to moderate enantioselectiv-
ities were obtained. For details, see Supporting Information.
(9) (a) Adinolfi, M.; Aquila, T.; Barone, G.; Lanzetta, R.; Parrilli, M.
Phytochemistry 1989, 28, 3244. (b) Corsaro, M. M.; Lanzetta, R.;
Mancino, A.; Parrilli, M. Phytochemistry 1992, 31, 1395.
ACKNOWLEDGMENTS
■
This study was supported by the Fundamental Research Funds
for the Central Universities in China (Grant No.
0236015205004), the Scientific Research Foundation of
China (Grant No. 0236011104404), Graduate Scientific
Research and Innovation Foundation of Chongqing, China
(CYB16032) and the Ministry of Science, ICT, and Future
Planning in Korea (Grant Nos. NRF-2014R1A2A1A01005794
and NRF-2016R1A4A1011451).
REFERENCES
■
(10) Wall, M. E.; Wani, M. C.; Manikumar, G.; Taylor, H.;
McGivney, R. J. Nat. Prod. 1989, 52, 774.
(11) Loggia, R.; Del Negro, P.; Tubaro, A.; Barone, G.; Parrilli, M.
Planta Med. 1989, 55, 587.
(1) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359.
(2) (a) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566.
(b) Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 1997,
411. (c) Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12,
1. (d) Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron:
Asymmetry 2004, 15, 3653. (e) Claraz, A.; Oudeyer, S.; Levacher, V.
Curr. Org. Chem. 2012, 16, 2192. (f) Oudeyer, S.; Briere, J.-F.;
̀
Levacher, V. Eur. J. Org. Chem. 2014, 2014, 6103. (g) Legros, F.;
Oudeyer, S.; Levacher, V. Chem. Rec. 2017, 17, 429.
(3) (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J.
Am. Chem. Soc. 1996, 118, 12854. (b) Yanagisawa, A.; Kikuchi, T.;
Kuribayashi, T.; Yamamoto, H. Tetrahedron 1998, 54, 10253.
(c) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am.
Chem. Soc. 2000, 122, 8120. (d) Ishihara, K.; Nakashima, D.; Hiraiwa,
Y.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 24. (e) Yanagisawa, A.;
Touge, T.; Arai, T. Angew. Chem., Int. Ed. 2005, 44, 1546.
(f) Mitsuhashi, K.; Ito, R.; Arai, T.; Yanagisawa, A. Org. Lett. 2006,
8, 1721. (g) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
9246. (h) Morita, M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858.
(i) Uraguchi, D.; Kinoshita, N.; Ooi, T. J. Am. Chem. Soc. 2010,
132, 12240. (j) Cheon, C. H.; Imahori, T.; Yamamoto, H. Chem.
Commun. 2010, 46, 6980. (k) Cheon, C. H.; Kanno, O.; Toste, F. D. J.
Am. Chem. Soc. 2011, 133, 13248. (l) Yanagisawa, A.; Sugita, T.;
Yoshida, K. Chem. - Eur. J. 2013, 19, 16200.
(12) Roy, O.; Loiseau, F.; Riahi, A.; Hen
2003, 59, 9641.
́
in, F.; Muzart, J. Tetrahedron
(13) (a) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846.
(b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131,
18343.
(14) For selected examples on an enantioselective intramolecular
Stetter reaction using chiral triazolium salts, see: (a) Kerr, M. S.; de
Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (b) Kerr, M.
S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (c) de Alaniz, J. R.;
Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. (d) Mennen, S. M.; Blank,
́
J. T.; Tran-Dube, M. B.; Imbriglio, J. E.; Miller, S. J. Chem. Commun.
2005, 195. (e) de Alaniz, J. R.; Kerr, M. S.; Moore, J. L.; Rovis, T. J.
Org. Chem. 2008, 73, 2033. (f) Moore, J. L.; Silvestri, A. P.; de Alaniz,
J. R.; DiRocco, D. A.; Rovis, T. Org. Lett. 2011, 13, 1742. (g) Rafin
́
ski,
Z.; Kozakiewicz, A.; Rafinska, K. ACS Catal. 2014, 4, 1404.
́
(4) (a) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.;
Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090. (b) Poisson, T.;
Oudeyer, S.; Dalla, V.; Marsais, F.; Levacher, V. Synlett 2008, 2008,
2447. (c) Poisson, T.; Gembus, V.; Dalla, V.; Oudeyer, S.; Levacher, V.
J. Org. Chem. 2010, 75, 7704. (d) Claraz, A.; Leroy, J.; Oudeyer, S.;
Levacher, V. J. Org. Chem. 2011, 76, 6457. (e) Beck, E. M.; Hyde, A.
M.; Jacobsen, E. N. Org. Lett. 2011, 13, 4260. (f) Yamamoto, E.;
Gokuden, D.; Nagai, A.; Kamachi, T.; Yoshizawa, K.; Hamasaki, A.;
Ishida, T.; Tokunaga, M. Org. Lett. 2012, 14, 6178. (g) Claraz, A.;
Landelle, G.; Oudeyer, S.; Levacher, V. Eur. J. Org. Chem. 2013, 2013,
7693. (h) Guin, J.; Varseev, G.; List, B. J. Am. Chem. Soc. 2013, 135,
2100.
(5) (a) Dalko, P. I.; Moisan, L. Angew. Chem. 2001, 113, 3840;
Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Yanagisawa, A. In
Comprehensive Asymmetric Catalysis, Supplement 2; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 2004; p 125.
(c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(6) Oliveira, M. T.; Lee, J.- W. ChemCatChem 2017, 9, 377 and
references therein.
(7) (a) Yan, H.; Jang, H. B.; Lee, J. W.; Kim, H. K.; Lee, S. W.; Yang,
J.; Song, C. E. Angew. Chem., Int. Ed. 2010, 49, 8915. (b) Yan, H.; Oh,
J. S.; Lee, J. W.; Song, C. E. Nat. Commun. 2012, 3, 1212. (c) Park, S.
Y.; Lee, J. W.; Song, C. E. Nat. Commun. 2015, 6, 7512. (d) Li, L.; Liu,
Y.; Peng, Y.; Yu, L.; Wu, X.; Yan, H. Angew. Chem., Int. Ed. 2016, 55,
331. (e) Liu, Y.; Ao, J.; Paladhi, S.; Song, C. E.; Yan, H. J. Am. Chem.
Soc. 2016, 138, 16486. (f) Vaithiyanathan, V.; Kim, M. J.; Liu, Y.; Yan,
H.; Song, C. E. Chem. - Eur. J. 2017, 23, 1268. (g) Kim, M. J.; Xue, L.;
Liu, Y.; Paladhi, S.; Park, S. J.; Yan, H.; Song, C. E. Adv. Synth. Catal.
2017, 359, 811. (h) Yu, L.; Wu, X.; Kim, M. J.; Vaithiyanathan, V.; Liu,
Y.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Adv. Synth. Catal. 2017,
DOI: 10.1002/adsc.201700015. (i) Park, S. Y.; Hwang, I. S.; Lee, H. J.;
D
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