Enantioselective Protonation of Silyl Enol Ethers Catalyzed by a Chiral Pentacarboxycyclopentadiene-Based Bronsted Acid

Article abstract of DOI:10.1055/s-0037-1611849

The enantioselective protonation of silyl enol ethers was realized in the presence of a pentacarboxycyclopenta-1,3-diene-based chiral Bronsted acid catalyst with water as an achiral proton source to give the corresponding α-aryl ketones in good yields and up to 75percent ee.

Full text of DOI:10.1055/s-0037-1611849

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
J. Li et al.
Letter
Synlett
Enantioselective Protonation of Silyl Enol Ethers Catalyzed by a
Chiral Pentacarboxycyclopentadiene-Based Brønsted Acid
Jun Li
*RO
O
OTMS
OH
COOR*
COOR*
PCCP catalyst
10 mol%
PCCP catalyst
Shaoyu An
Chao Yuan
Pingfan Li*
Ar
Ar
*ROOC
*ROOC
R*=
1.1 equiv H2O
xylenes
n
n
10 examples
89–99% yield
67–75% ee
n = 1, 2
Department of Organic Chemistry, Faculty of Science,
Beijing University of Chemical Technology, Beijing
100029, P. R. of China
lipf@mail.buct.edu.cn
Received: 14.04.2019
Accepted after revision: 13.05.2019
Published online: 29.05.2019
such approach involves the asymmetric protonation of lith-
ium enolates.1 Another strategy is based on the protonation
of silyl enol ethers with an excess of an achiral source of
protons in the presence of a chiral Lewis acid or Brønsted
acid catalyst.2,3 Compared with the first method, the
prochiral intermediate silyl enol ethers in the second meth-
od are more stable and can be isolated; consequently, this
has attracted much study in this field. In 1994, Yamamoto
and co-workers reported the first protonation reaction of a
silyl enol ether by a Lewis acid-activated Brønsted acid
(LBA) by using tin tetrachloride and a chiral binaphthol as
the proton source to achieve a series of asymmetric proton-
ation reactions.2a In 1996, they modified the structure of
the chiral binaphthol and they successfully achieved an
DOI: 10.1055/s-0037-1611849; Art ID: st-2019-k0209-l
Abstract The enantioselective protonation of silyl enol ethers was re-
alized in the presence of a pentacarboxycyclopenta-1,3-diene-based
chiral Brønsted acid catalyst with water as an achiral proton source to
give the corresponding -aryl ketones in good yields and up to 75% ee.
Key words protonation, Brønsted acids, asymmetric catalysis, organo-
catalysis, carbonyl compounds, silyl enol ethers
The asymmetric protonation of prochiral enolate com-
pounds is a simple and straightforward way to prepare op-
tically active -substituted carbonyl compounds.1–3 One
Yamamoto's Work:
Ar
5 mol%
phosphoramide
O
OTMS
O
S
Ph
Ph
P
toluene, r.t.
NHTf
O
1.1 equiv PhOH
n
n
Ar
Ar = 4-(t-Bu)-2,6-(i-Pr)2C6H2
99% yield 82% ee
phosphoramide
Ar
10 mol%
phosphoric acid
O
O
O
OTMS
P
toluene, r.t.
Ph
Ph
OH
O
1.1 equiv
2,4,6-t-BuC6H2CO2H
n
n
Ar
Ar = 2,4,6-(i-Pr)3C6H2
no reaction
phosphoric acid
This Work:
HO
O
OR*
OR*
10 mol%
PCCP catalyst
O
OTMS
*RO
*RO
Ph
Ph
xylenes, –10 °C
R*=
O
1.1 equiv H2O
OR*
O
n
n
O
PCCP catalyst
99% yield 74% ee
Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
J. Li et al.
Letter
Synlett
asymmetric protonation of silyl enol ethers with an excess
of an achiral source of protons in the presence of a catalytic
amount of an LBA.2b A series of LBA-catalyzed reactions
have since been reported.2
zation of epoxides.5–8 Here, we report an asymmetric pro-
tonation reaction of silyl enol ethers by using a PCCP-based
catalyst derived from chiral (–)-borneol, with water as a
proton source.
Compared with LBA catalysts, chiral phosphoric acids,
the most commonly used Brønsted acids, are usually less
acidic3a,4 and do not, therefore, readily catalyze the proton-
ation of silyl enol ethers. In 2008, Cheon and Yamamoto re-
ported the first Brønsted acid-catalyzed asymmetric pro-
tonation reaction of silyl enol ethers. They showed that chi-
ral phosphoric acids are unable to catalyze such reactions
and they identified N-[2,6-bis(4-tert-butyl-2,6-diisopropyl-
phenyl)-4-sulfidodinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphos-
phepin-4-yl]-1,1,1-trifluoromethanesulfonamide as a good
catalyst and obtained the product in 82% ee.3a (Scheme 1)
In 2016, Lambert and co-workers5 reported a novel chi-
ral catalyst based on pentacarboxycyclopenta-1,3-diene
(PCCP) that could be easily prepared from readily available
pentamethyl cyclopenta-1,3-dienepentacarboxylate and
chiral (–)-menthol in one transesterification step. The Lam-
bert catalyst is more acidic and less expensive than most
chiral phosphoric acids, and a number of catalytic enanti-
oselective reactions using this catalyst have been reported,
including a Mannich reaction, a Diels–Alder reaction of sa-
licylaldehyde acetals with vinyl ethers, and a desymmetri-
First, five optically active PCCP-type catalysts 1a–e (Ta-
ble 1), based on Lambert’s work, were prepared from natu-
ral chiral alcohols. Next, we examined the protonation reac-
tion of silyl enol ether 2a with ten equivalents of methanol
as a proton source with a 5 mol% loading of the PCCP cata-
lysts 1a–e in dichloromethane at room temperature for 12
hours as a model reaction. When 5 mol% PCCP catalyst 1b
derived from (–)-borneol was used (Table 1, entry 2), (2R)-
2-phenylcyclohexane (3a) was obtained in 88% isolated
yield and 28% ee. The other catalysts all gave 3a with less
than 10% ee. We therefore focused on screening the reac-
tion conditions for catalyst 1b.
To further enhance the stereoselectivity of the reaction,
we then screened a number of reaction conditions, includ-
ing the proton source, solvent, temperature, and catalyst
loading (Table 2). When phenols were used as proton sourc-
es, we found either the yield or the enantioselectivity was
low, indicating that phenols were unsuitable for use in the
reaction (Table 2, entries 1–3). When 10 equivalents of an
alcohol were used as the proton source at room tempera-
ture, the protonation product 3a was obtained with low en-
antioselectivity (entries 4–9). The enantioselectivity was
greatly improved by reducing the number of equivalents of
the proton source and lowering the reaction temperature
(entries 9–11). We also found that steric hindrance of the
achiral proton affected the enantiomeric excess of the prod-
uct. The effects of propan-2-ol and ethanol as proton sourc-
es were worse than that of MeOH (entries 8 versus entries 4
and 5). The best result (67% ee) was obtained when H2O
was used as the proton source (entries 12–21).
Table 1 Optimization of the PCCP Catalyst
HO
O
O
OR*
OR*
O
OTMS
*RO
*RO
Ph
Ph 5 mol% catalyst
10 equiv MeOH
O
OR*
CH2Cl2, r.t.
O
3a
2a
PCCP catalyst
With the optimized proton source in hand, we screened
a number of solvents and the loading of the catalyst for this
reaction (Table 2, entries 14 and 16–20). The best result
(74% ee) was obtained when xylenes were used as the sol-
vent at –20 or –10 °C with a 10 mol% loading of 1b (entries
19 and 20). (For more solvent optimization, see the Sup-
porting Information.) Next, we attempted enhance the se-
lectivity by lowering the reaction temperature; however,
the enantioselectivity decreased to 62% ee at –40 °C and to
68% ee at –30°C (entries 15 and 21), suggesting that the en-
ergy gap for the transition states for the stereodetermining
step might be different at different temperatures.
Entry
1
Catalysta
R*
Yieldb (%)
ee (%)
9
1a
1b
59
88
2
3
28
5
1c
97
Ph
Finally, we explored the substrate scope by using 10
mol% of catalyst 1b and 1.1 equivalents of water in xylenes
at –10 °C (Table 3).9 Several 2-aryl-substituted cyclic ke-
tones substituted in the ortho and meta positions were ob-
tained with similar ee values, and ketones bearing electron-
donating or electron-withdrawing para-substituents were
tolerated (Table 3, entries 1–7). A substrate with a seven-
membered ring and naphthyl-substituted substrates gave
comparable results (entries 8–10).
4
5
1d
1e
NRc
47
–
8
a Catalysts 1a–e were derived from chiral (–)-menthol, (–)-borneol, (–)-8-
phenylmenthol, (–)-isopinocampheol, and (+)-norborneol, respectively.
b Isolated yield for 0.2 mmol scale reaction.
c No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
J. Li et al.
Letter
Synlett
Table 2 Optimization of the Reaction Conditions
Table 3 Substrate Scope
O
OTMS
O
OTMS
Ar
10 mol% 1b
–10 °C, xylenesa
8–12 h
5 mol% 1b
Ph
Ph
Ar
1.1 equiv H2O, 6–8 h
n
n
2a
3a
3a–j
2a–j
Entry Achiral Brønsted acid
(equiv)
Solvent
Temp Time
(°C) (h)
Yielda ee
(%) (%)
Entry
n
Ar
Yieldb (%)
ee (%)
1
2
1
1
1
1
1
1
1
1
1
2
Ph
99
99
95
89
98
93
95
96
89
92
74
69
74
73
75
67
75
68
69
70
1
2
2,6-Dimethylphenol (2) CH2Cl2
2,6-Diphenylphenol (2) CH2Cl2
25
24
trace
–
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
2-naphthyl
1-naphthyl
Ph
25
25
24
24
12
12
12
12
12
12
12
8
trace
51
74
37
trace
34
88
74
29
91
43
94
94
77
91
86
94
94
99
99
–
3
3
PhOH (2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCl
0b
4c
5c
6
4
EtOH (10)
i-PrOH (10)
t-BuOH (10)
F3CCH2OH (10)
MeOH (10)
MeOH (10)
MeOH (1.1)
MeOH (1.1)
H2O (1.1)
25
16
5
25
7
6
25
–
7
7
25
0b
8
8
25
28
9c
10
9
25
34
39
62
60
66
67
62
69
66
71
74
74
68
10
11
12
13
14
15
16
25
a Commercial mixture of xylenes and ethylbenzene.
b Isolated yield from a 0.2 mmol scale reaction.
c 15 mol% catalyst loading.
–20
25
12
8
H2O (1.1)
0
H2O (1.1)
–20
–40
–20
–20
–20
–20
–10
–30
8
Funding Information
H2O (1.1)
10
8
H2O (1.1)
Fundamental Research Funds for the Central Universities,
(Grant/Award Number: XK-1802-6, 12060093063); National Natural
Science Foundation of China, (Grant/Award Number: 21402005).
17c H2O (1.1)
18d H2O (1.1)
19d H2O (1.1)
20d H2O (1.1)
21f H2O (1.1)
PhCl
12
8
F
u
n
d
a
m
e
ntalResearc
h
F
u
n
dsforth
e
C
e
ntarlU
n
i
v
ersities(XK-1
8
0
2-6
,
1
2
0
6
0
0
9
3
0
6
3)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
4
0
2
0
0
5)
PhCl
xylenese
xylenes
xylenes
8
Supporting Information
8
12
Supporting information for this article is available online at
a Isolated yield from 0.2 mmol scale reaction.
b Racemic product.
https://doi.org/10.1055/s-0037-1611849.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
c 2.5 mol% catalyst loading.
d 10 mol% catalyst loading.
References and Notes
e Commercial mixture of xylenes and ethylbenzene.
f 15 mol% catalyst loading.
(1) (a) Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem. Int. Ed. Engl.
1993, 32, 1044. (b) Fehr, C.; Galindo, J. Angew. Chem. Int. Ed.
Engl. 1994, 33, 1888. (c) Yanagisawa, A.; Kikuchi, T.; Watanabe,
T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372. (d) Vedejs,
E.; Kruger, A. W. J. Org. Chem. 1998, 63, 2792. (e) Yamashita, Y.;
Emura, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 2000, 41,
209. (f) Mitsuhashi, K.; Ito, R.; Arai, T.; Yanagisawa, A. Org. Lett.
2006, 8, 1721.
(2) (a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc.
1994, 116, 11179. (b) Ishihara, K.; Nakamura, S.; Kaneeda, M.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854.
(c) Nakashima, D.; Yamamoto, H. Synlett 2006, 150. (d) Cheon,
C. H.; Imahori, T.; Yamamoto, H. Chem. Commun. 2010, 46, 6980.
(e) Cheon, C. H.; Yamamoto, H.; Toste, F. D. J. Am. Chem. Soc.
2011, 133, 13248.
In summary, we have found that the chiral PCCP catalyst
1b, prepared from (–)-borneol, could by successfully used
in the asymmetric protonation of silyl enol ethers with wa-
ter as the proton source. This reaction gave up to 99% yield
and 75% ee, whereas Yamamoto et al. achieved up to 90% ee
for this reaction by using a chiral N-triflylthiophosphora-
mide as a catalyst;3a conventional chiral phosphoric acids
were found to have no catalytic activity. We have therefore
demonstrated the advantages of a chiral pentacarboxy-
cyclopenta-1,3-diene-based Brønsted acid as a cheap and
readily accessible alternative to chiral N-triflylthiophos-
phoramide-type strong acids.
(3) (a) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
9246. (b) Beck, E. M.; Hyde, A. M.; Jacobsen, E. N. Org. Lett. 2011,
13, 4260. (c) Das, A.; Ayad, S.; Hanson, K. Org. Lett. 2016, 18,
5416.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
J. Li et al.
Letter
Synlett
(4) (a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047. (b) Parmar, D.; Sugiono, E.; Raja, S.; Rueping,
M. Chem. Rev. 2017, 117, 10608.
(5) Gheewala, C. D.; Collins, B. E.; Lambert, T. H. Science 2016, 351,
961.
(6) Gheewala, C. D.; Hirschi, J. S.; Lee, W.-H.; Paley, D. W.; Vetticatt,
M. J.; Lambert, T. H. J. Am. Chem. Soc. 2018, 140, 3523.
(7) Yuan, C.; Li, J.; Li, P. ACS Omega 2018, 3, 6820.
(8) (a) Qiao, X.; El-Shahat, M.; Ullah, B.; Bao, Z.; Xing, H.; Xiao, L.;
Ren, Q.; Zhang, Z. Tetrahedron Lett. 2017, 58, 2050. (b) Sui, Y.;
Cui, P.; Liu, S.; Zhou, Y.; Du, P.; Zhou, H. Eur. J. Org. Chem. 2018,
215. (c) Zhao, X.; Xiao, J.; Tang, W. Synthesis 2017, 49, 3157.
(9) (2R)-2-Phenylcyclohexanone (3a); Typical Procedure
PCCP catalyst 1b (19.3 mg, 0.02 mmol, 10 mol%) was weighed
into a cryogenic vial. The vial was cooled to –10 °C, and H2O (4
L 1.1 equiv) and anhyd xylenes (2 mL) were added. After 15
min at –10 °C, silyl enol ether 2a (49 mg, 0.2 mmol, 1.0 equiv)
was added dropwise to the stirred mixture. After 8 h, the reac-
tion was quenched by the addition of sat. aq NaHCO3 (3 mL) and
the mixture was extracted with CH2Cl2 (25 mL). The organic
layer was washed with brine (5 mL), dried (NaSO4), filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography [silica gel, hexanes–EtOAc (100:1 to
10:1)] to give a white solid; yield: 35 mg (99%, 74% ee);
[]D25 +50.7 (c = 0.4, CHCl3).
HPLC: Chiralpak Lux 5u cellulose-1 [hexanes–i-ProH (99:1),
flow rate = 1.0 mL/min;  = 215 nm], tR (minor, S) = 14.8 min; tR
(major, R) = 16.2 min. 1H NMR (400 MHz, CDCl3):  = 7.33 (t, J =
7.4 Hz, 2 H), 7.25 (t, J = 7.4 Hz, 1 H), 7.14 (d, J = 7.4 Hz, 2 H), 3.60
(dd, J = 12.1, 5.4 Hz, 1 H), 2.63–2.36 (m, 2 H), 2.26–2.30 (m, 1 H),
2.21–2.09 (m, 1 H), 2.09–1.90 (m, 2 H), 1.90–1.71 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D