Straightforward organocatalytic enantioselective protonation of silyl enolates by means of cinchona alkaloids and carboxylic acids

Article abstract of DOI:10.1055/s-2008-1078260

The combination of cinchona alkaloids and carboxylic acids provides a very simple chiral proton source. By using this system, enantioselective protonation of silyl enolates was achieved affording the corresponding ketones in high yields and in up to 75% e

Full text of DOI:10.1055/s-2008-1078260

LETTER
2447
Straightforward Organocatalytic Enantioselective Protonation of Silyl
Enolates by Means of Cinchona Alkaloids and Carboxylic Acids
O
rganocatalytic
h
E
nantiosele
o
ctive Protona
m
tionof Silyl Enola
ta
es s Poisson,a Sylvain Oudeyer,a Vincent Dalla,b Francis Marsais,a Vincent Levacher*a
a
Institut de Recherche en Chimie Organique Fine (IRCOF) associé au CNRS (UMR-6014), INSA-Université de Rouen, Rue Tesnières,
76130 Mont-Saint-Aignan, France
Fax +33(235)522962; E-mail: vincent.levacher@insa-rouen.fr
Laboratiore de Chimie, URCOM, EA 3221, Faculté des Sciences et Techniques, Université du Havre,
25 Rue Philippe Lebon, BP 540, 76058 Le Havre, France
b
Received 5 June 2008
handy proton source such as a simple carboxylic acid
(Figure 1b).
Abstract: The combination of cinchona alkaloids and carboxylic
acids provides a very simple chiral proton source. By using this sys-
tem, enantioselective protonation of silyl enolates was achieved af-
fording the corresponding ketones in high yields and in up to 75%
ee.
According to this new scenario, the protonation of a tertia-
ry amine 1 by a carboxylic acid would generate the corre-
sponding hydrogen carboxylate salt 1-RCO2H. This
species should be a better protonating agent than the rath-
er more acidic carboxylic acid itself, due to the coopera-
tive activation of the silyl enolate 2 by the carboxylate
Key words: organocatalysis, enantioselective protonation, silyl
enolates, cinchona alkaloids
–
counterion (Figure 1c; X = RCO2 ) through generation of
either an enolate or a hypervalent silicate.4 Considering
this cooperative activation mode as a prerequisite for
achieving high levels of stereoinduction,3 the question
then arose whether the carboxylate counter-anion would
be capable to enhance the silyl enol ether nucleophilicity
with similar efficiency as the fluoride ion did in our previ-
ous approach. Actually, the capacity of carboxylate an-
ions to serve such an effective Lewis base catalyst has
recently been proven by reports from the Fu5 and
Mukaiyama6 groups dealing with the C-acylation of silyl
ketene acetals and the catalytic Mannich-type reaction be-
tween trimethylsilyl enol ethers and aldimines, respec-
tively.
The enantioselective protonation of prochiral enol deriva-
tives has emerged as a helpful tool to achieve optically en-
riched carbonyl compounds possessing
a tertiary
stereogenic carbon center at the a-position.1 The success-
ful development of various catalytic deracemization pro-
cesses over the last fifteen years made this approach more
synthetically useful and quite complementary to the cata-
lytic enantioselective alkylation technology, generating
nowadays increasing interest amongst the synthetic chem-
istry community.2
We have recently reported the first organocatalytic enan-
tioselective protonation of silyl enolates 2 by means of
cinchona alkaloids and a ‘latent source of HF’.3 This or-
ganocatalytic approach offers unprecedented mild, neu-
tral and metal-free conditions with excellent yields and
high enantioselectivities of up to 92% (Figure 1a).3 Mech-
anistically, the strategy relies on the in situ catalytic gen-
eration of a hydrogen fluoride salt 1-HF through the
reaction between an acid fluoride and an alcohol in the
presence of a chiral tertiary amine 1. As a result of the
high silicon–fluoride affinity, the active catalytic species
1-HF can exert a specific silyl enolate activation mode
(Figure 1c; X = F–) to promote the protonation of silyl
enolate 2 along with the regeneration of the precatalyst 1.
(a)
(b)
This work
RCO2H
"latent source of HF"
RCOOR'
RCOF +
R'OH
RCHO2–
H
H
F–
R* N +
R* N
R* N
R* N +
1
1
1-HF
1-RCO2H
O
OTMS
O
OTMS
R
Within our continuing interest to develop a more straight-
forward and general approach for the organocatalytic
enantioselective protonation of silyl enol ethers, we que-
ried whether our methodology could be rendered more
atom economic and operationally simpler by replacing the
two-component, naked source of HF with a more readily
R
R
H
R
H
H
H
2
3
2
3
+ RCO2TMS
+ TMSF
(c)
O
X–
SiMe3
–
= F–, RCO2
R
X–
H
N+
SYNLETT 2008, No. 16, pp 2447–2450
Advanced online publication: 22.08.2008
x
x
.x
x
.2
0
0
8
*R
DOI: 10.1055/s-2008-1078260; Art ID: G19108ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Proposed organocatalytic mechanism for the protonation:
(a) using a ‘latent source of HF’,3 and (b) using a carboxylic acid; (c)
specific enolate activation mode of silyl enolate 2 by means of fluo-
ride or carboxylate anion.

2448
T. Poisson et al.
LETTER
Encouraged by these literature precedents, we started ex- ment of the enantioselectivity (entries 5 and 6). Finally, it
amining the protonation of 2-methyl-1-tetralone-derived could be concluded that the biscinchona alkaloid
trimethylsilyl enolate 2a7 with various carboxylic acid (DHQ)2AQN (1a) initially selected emerged as the best
sources under the previously optimized reaction condi- candidate amongst those evaluated to achieve this enanti-
tions,3 i.e., in the presence of the biscinchona alkaloid hy- oselective proton transfer. It is noteworthy that the enan-
droquinine anthraquinone-1,4-diyl diether [(DHQ)2AQN tioselective performance of the process was slightly
(1a); 10 mol%] in DMF at room temperature (Table 1). affected by lowering (DHQ)2AQN (1a) loading from 10
Under these initial conditions, the reaction occurred with mol% to 2 mol% (entry 1).
excellent conversion after stirring overnight. The use of
benzoic acid and acetic acid as protonating agents provid-
Table 1 Protonating Agent Screeninga
OTMS
O
ed tetralone 3a with modest enantioselectivities of 32%
and 36%, respectively (entries 1 and 2). Attempts to opti-
mize these preliminary results by lowering the tempera-
ture to –20 °C furnished tetralone 3a with up to 51% ee
(entry 2). The use of Boc-glycine, Boc-L-proline and pi-
colinic acid afforded slightly higher enantioselectivities at
room temperature (entries 3–5), reaching 68% ee with
Boc-L-proline when the protonation was conducted at
–20 °C. The use of other chiral proton sources such as tar-
taric acid, mandelic acid and lactic acid did not lead to
substantial improvement of the enantioselectivity (entries
6–8). At this point, we also examined the influence of the
chirality within the carboxylate anion on the stereochem-
ical outcome of the protonation. A significant match/mis-
match effect was observed between the chiral ammonium
cation and the chiral carboxylate anion as revealed by the
experiments conducted with D-tartaric acid or Boc-D-pro-
line and their respective enantiomers (entries 4 and 6).8
Me
Me
RCOOH, DMF
+
RCOOTMS
(DHQ)2AQN (10 mol%)
2a
(S)-3a
Entry RCOOH
equiv
1.05
Temp (°C)
Time (h)b eec
1
2
PhCOOH
AcOH
20
8
32
1.05
1.05
1.05
20
0
–20
8
12
120
36
45
51
3
4
Boc-glycine
1.05
20
8
44
Boc-L-proline
1.05
1.05
1.05
20
–20
20
8
28
8
56
68
25
Boc-D-proline
picolinic acid
5
6
1.05
1.05
20
–10
8
28
48
55
The best result was finally recorded with citric acid, which
afforded tetralone 3a in 71% ee by conducting the proto-
nation at –10 °C. Remarkably, using only 0.35 equivalent
of citric acid was sufficient to complete the reaction, while
maintaining the enantioselectivity to its optimal level.
However, the reagent economy occurred at the expense of
time, since 72 hours were required to achieve complete
conversion (entry 10). Importantly, in the absence of cat-
alyst 1a, the uncatalyzed background protonation of 2a
proved to be rather slow affording tetralone 3a with less
than 10% of conversion under the preselected optimized
conditions (DMF, –10 °C, 24 h, 1.05 equiv of citric acid).
The poor reactivity displayed by citric acid in the absence
of cinchona alkaloid 1a strongly supports our cooperative
carboxylate-silicon activation mode event. A brief solvent
screen indicated that DMSO could be used as well as
DMF to give comparable enantioinduction (entry 10),
while 2a was quantitatively recovered when the reaction
was carried out in acetonitrile, dichloromethane, THF and
dioxane, most likely due to the poor solubility of citric
acid in those solvents.
L-tartaric acid
D-tartaric acid
1.05
0.50
1.05
20
20
20
8
8
8
32
36
43
7
8
9
DL-mandelic acid 1.05
20
20
8
8
43
46
L-lactic acid
citric acid
1.05
1.05
1.05
0.50
0.50
0.35
0.35
20
–10
20
–10
20
8
24
8
38
8
66
71
63
72
65
73
–10
72
10d citric acid
1.05
20
10
66
a Reaction was performed with silyl enolate 2a (0.5 mmol) in the pres-
ence of (DHQ)2AQN (0.05 mmol) and the protonating agent in DMF
(1 mL).
b Time after which complete conversion of 2a into 3a was observed
from GC analysis.
c Determined by HPLC.3 In all cases, the absolute configuration of 3a
was assigned as S by comparison with literature data.2m
d Reaction was carried out in DMSO.
We then turned our attention to the survey of other readily
accessible cinchona alcaloids 1a–f (Table 2). The two
commercially available biscinchona alkaloids hydroqui-
nine 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2-
Pyr (1b)] and hydroquinidine 1,4-phthalazinediyl diether
[(DHQD)2PHAL (1c)] furnished tetralone 3a in 55% and
32% ee values, respectively (entries 2 and 3). Whereas
quinine 1d proved to be poorly efficient (entry 4), deriva-
tization of the 9-OH group led to a significant improve-
This result compares very favorably with our previously
reported process where a dramatic drop in enantioselec-
tivity was observed when attempting to reduce the catalyst
loading. Another striking difference between the two
methods stands in the clear-cut positive effect on the
enantioselectivity exerted herein by lowering the temper-
ature while a constant temperature–enantioselectivity pro-
file had been observed previously.3
Synlett 2008, No. 16, 2447–2450 © Thieme Stuttgart · New York

LETTER
Organocatalytic Enantioselective Protonation of Silyl Enolates
2449
counterparts,3 this modified process offers remarkable ad-
vantages in terms of practical simplicity, environmental
concerns and cost. These attributes make this organocata-
lytic approach probably one of the most appealing derace-
mization process for further development at an industrial
scale. Further exploration of the scope and limitation of
this promising technology is underway in our laboratory
and will be reported in due course.
Table 2 Catalyst Screeninga
1a: (DHQ)2AQN
H
1b: (DHQ)2PYR
1c: (DHQD)2PHAL
N
N
R1O
R2O
H
MeO
MeO
1d: R1 = H (quinine)
1e: R1 = Ac
N
N
1f: R2 = 9-phenanthryl
Acknowledgment
OTMS
O
We are grateful for financial support of this work by the MRT and
the région Haute-Normandie. T.P. thanks the MRT for a grant.
citric acid
(1.05 equiv)
Me
Me
+
RCO2TMS
1a–f (2–10 mol%)
DMF, r.t.
References and Notes
2a
(S)-3a
(1) For reviews, see: (a) Duhamel, L.; Duhamel, P.; Plaquevent,
J. C. Tetrahedron: Asymmetry 2004, 15, 3653. (b) Fehr, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2566.
Entry
1
Catalyst 1
mol (%)
Time (h)b
eec
1a
10
5
2
10
14
17
66
60
57
(2) For catalytic enantioselective protonation, see: (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.
(g) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 11179. (h) Ishihara, K.; Nakamura, S.;
Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,
12854. (i) Sugiura, M.; Nakai, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2366. (j) Nakamura, S.; Kaneeda, M.;
Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
8120. (k) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 24.
2
3
4
5
6
1b
1c
1d
1e
1f
10
10
10
10
10
12
12
12
12
12
55
32
25
40
45
a Reaction was performed with silyl enolate 2a (0.5 mmol) in the pres-
ence of the catalyst 1 and citric acid (0.525 mmol) in DMF (1 mL) at
r.t.
b Time after which complete conversion of 2a into 3a was observed
from GC analysis.
c Determined by HPLC.3 In all cases, the absolute configuration of 3a
was assigned as S by comparison with literature data.2m
(l) Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem. Int.
Ed. 2005, 44, 1546. (m) Mohr, J. T.; Nishimata, T.;
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128,
11348.
Having identified an optimal catalyst/proton donor com-
bination, we next studied the generality of the protonation
using various silyl enolates 2a–i under the optimized con-
ditions (Table 3).9 In all cases, ketones 3a–i were obtained
with excellent isolated yields ranging from 91% to 98%
after flash chromatography. In tetralone series, moderate
to good enantioselectivities from 58% to 75% ee were ob-
tained, with the exception of the fluorinated silyl enolate
2f which afforded 2-fluoro-1-tetralone 3f10 in only 34% ee
(entry 1). In the indanone series, silyl enolates 2g,h af-
forded somewhat lower ee values of 43% and 45%, re-
spectively (entry 2). Lastly, protonation of silyl enolate 2i
returned the corresponding chromanone 3i11 with a decent
enantioselectivity of 68% (entry 3).
(3) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.;
Levacher, V. Angew. Chem. Int. Ed. 2007, 46, 7090.
(4) For recent authoritative reviews on this topic, see:
(a) Oestreich, M.; Rendler, S. Synthesis 2005, 1727.
(b) Orito, Y.; Nakajima, M. Synthesis 2006, 1391.
(5) (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 4050. (b) Mermerian, A. H.; Fu, G. C. J. Am. Chem.
Soc. 2005, 127, 5604.
(6) Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem. Eur. J.
2006, 12, 5082.
(7) General Procedure for the Preparation of Silyl Enolates
2a–i: To a solution of (i-Pr)2NH (1.19 mL, 8.4 mmol) at –78
°C in anhyd THF (50 mL) was added n-BuLi (2.5 M solution
in hexanes, 3.22 mL, 8.05 mmol). The solution was stirred
for 1 h at this temperature, after which the ketone 3 (7.0
mmol) was slowly added. After stirring for 1 h at –78 °C,
freshly distilled TMSCl (0.98 mL, 7.7 mmol) was dropwise
added and the resultant solution was allowed to reach r.t.
before being stirred for an additional 2 h. A solution of
NaHCO3 (20 mL) was added and the mixture was extracted
with Et2O (3 × 50 mL). The combined organic layers were
washed with brine and dried (MgSO4). The solvent was
removed under vacuum and the residue was purified by flash
chromatography on silica gel (Et2O–cyclohexane, 5:95)
affording the pure silyl enol ether 2. All spectral data of silyl
In summary, we have reported on the first investigation on
the combined use of cinchona alkaloids and carboxylic ac-
ids, leading to chiral ammonium carboxylate salts 1-
RCO2H as active catalytic species in the enantioselective
protonation of silyl enolates. This straightforward organo-
catalytic approach provided the corresponding ketones
with enantioinduction up to 75%. Although chiral ammo-
nium carboxylate salts 1-RCO2H display somewhat lower
enantioselective performances than their fluorinated
Synlett 2008, No. 16, 2447–2450 © Thieme Stuttgart · New York

2450
T. Poisson et al.
LETTER
Table 3 Scope of the Reactiona
OTMS
R1
O
R1
*
citric acid (1.05 equiv)
RCO2TMS
+
(DHQ)2AQN (10 mol%)
DMF, –10 °C
2a–i
3a–i
Entry
Substrate
Yield (%)b
ee (%)c
1
2a: R1 = Me; R2 = H
2b: R1 = Et; R2 = H
2c: R1 = Bn; R2 = H
3a (95)
3b (93)
3c (97)
3d (98)
3e (92)
3f (91)
70 (S)
58 (S)
60 (R)
75 (n.d.)
74 (n.d.)
34 (S)
OTMS
R1
2d: R1 = Me; R2 = OMe
2e: R1 = Bn; R2 = OMe
2f: R1 = F; R2 = H
R2
2
3
2g: R1 = Me
2h: R1 = Bn
3g (97)
3h (94)
43 (S)
45 (n.d.)
OTMS
R1
2i
3i (95)
68 (S)
OTMS
Ph
O
a Reaction was performed with silyl enolates 2a–i (0.5 mmol) in the presence of (DHQ)2AQN (10 mol%) and citric acid (0.525 mmol) in DMF
(1 mL) at –10 °C for 24 h.
b Isolated yield after chromatographic purification.
c Determined by HPLC. The absolute configuration of 3a–e and 3g,h were assigned by comparison with literature data.3 The absolute config-
uration of 3i was assigned by comparison with literature data.12
enolates 2a–e and 2g,h are reported in ref. 3. All spectral
data of silyl enoalte 2f are reported in ref. 13. 2i: 1H NMR
(300 MHz, CDCl3): d = 0.23 (s, 9 H), 3.56 (s, 2 H), 4.57 (s,
2 H), 6.77 (dd, J = 1.1, 8.05 Hz, 1 H), 6.92 (dt, J = 1.3, 7.5
Hz, 1 H), 7.11 (dt, J = 1.6, 7.7 Hz, 1 H), 7.17–7.32 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 1.01, 33.87, 68.89, 112.85,
115.74, 121.25, 122.81, 123.24, 126.66, 128.88 (2), 129.06,
138.73, 141.35, 155.11.
(10) Preparation of 2-Fluoro-1-tetralone 3f: To a solution of 2-
(ethoxycarbonyl)tetralone 13 (1.107 g, 5 mmol) in MeCN
(40 mL) was added TiCl4 (0.15 mL, 0.75 mmol) at r.t. After
5 min SelectfluorTM (2.157 g, 6.1 mmol) was added and the
resulting mixture was stirred at r.t for an additional 3 h. The
reaction was carefully quenched with NaHCO3 (50 mL) and
extracted with Et2O (4 × 40 mL). The combined organic
layers were washed with brine (50 mL), dried over MgSO4
and concentrated. The residue was purified by flash
chromatography (SiO2, 20% Et2O in cyclohexane) to afford
2-fluoro-2-(ethoxycarbonyl)tetralone in 98% yield as a pale
yellow oil. All spectral data were consistent with those
previously reported.2m
(8) For a preceding example of matched/mismatched catalyst-
ion pair combination, see: Martin, N. J. A.; List, B. J. Am.
Chem. Soc. 2006, 128, 13368.
(9) General Procedure for the Enantioselective Protonation
of Silyl Enolates 2a–i: To a solution of silyl enol ether 2 (0.5
mmol) and (DHQ)2AQN (43 mg, 0.05 mmol) in DMF (0.5
mL) at –10 °C was added citric acid (0.100 g, 0.525 mmol)
as a solution in DMF (0.5 mL). The reaction was stirred at
–10 °C until complete disappearance of the starting material
(monitored by GC). The solution was diluted with Et2O (10
mL), washed with NaHCO3 (10 mL), brine (3 × 10 mL),
dried over MgSO4 and concentrated. The residue was
filtered through a short pad of silica gel (Et2O as eluent) to
give the pure ketone 3 which was analyzed by chiral HPLC.
Chromatographic conditions for enantioseparation of
ketones 3a–e and 3g–h are reported in ref. 3. HPLC
conditions for enantioseparation of ketone 3f: Daicel
Chiralcel OJ-H, heptane–i-PrOH, 95:5, flow rate: 1 mL/min,
tR =15.30 min (major), tR = 17.09 min (minor). HPLC
conditions for enantioseparation of ketone 3i: Daicel
Chiralcel OJ-H, heptane–i-PrOH, 90:10, flow rate: 1 mL/
min, tR = 14.21 min (major), tR = 18.68 min (minor).
To a solution of2-fluoro-2-(ethoxycarbonyl)tetralone (1.157
g, 4.9 mmol) dissolved in EtOH–H2O (5:1, 30 mL) was
added KOH (0.825 g, 14.7 mmol). The resulting mixture was
refluxed for 1.5 h, cooled to r.t., quenched with a sat. aq
NH4Cl solution (25 mL) and extracted with Et2O (5 × 30
mL). The combined organic layers were washed with brine
(100 mL), dried over MgSO4 and concentrated. The residue
was purified by flash chromatography on silica gel (Et2O–
cyclohexane, 2:8) to afford 2-fluoro-1-tetralone 3f in 76%
yield as a pale yellow oil. All spectral data were consistent
with those previously reported.2m
(11) For the preparation of chromanone 3i, see: Kirkiacharian, B.
S.; Gomis, M. Synth. Commun. 2005, 35, 563.
(12) Kawasaki, M.; Toyooka, N.; Matsui, Y.; Tanaka, A.; Goto,
M.; Kakuda, H.; Kawabata, S.; Kometani, T. Heterocycles
2005, 65, 761.
(13) Bélanger, E.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin,
J.-F. J. Am. Chem. Soc. 2007, 129, 1034.
Synlett 2008, No. 16, 2447–2450 © Thieme Stuttgart · New York