Organocatalytic enantioselective protonation of silyl enolates mediated by cinchona alkaloids and a latent source of HF

Article abstract of DOI:10.1002/anie.200701683

Hidden benefits: The enantioselective organocatalytic protonation of silyl enolates has been achieved by using readily available cinchona alkaloid catalysts (1) and a latent source of HF that delivers "at will" the active catalytic hydrogen fluoride salt

Full text of DOI:10.1002/anie.200701683

Communications
DOI: 10.1002/anie.200701683
Organocatalysis
Organocatalytic Enantioselective Protonation of Silyl Enolates
Mediated by Cinchona Alkaloids and a Latent Source of HF**
Thomas Poisson, Vincent Dalla, Francis Marsais, Georges Dupas, Sylvain Oudeyer, and
Vincent Levacher*
The enantioselective protonation of enolates, as pioneered by
Duhamel and Plaquevent,[1] and then intensively pursued by
several other research groups,[2] is arguably one of the
simplest and most straightforward way to access a wide
range of optically active a-substituted carbonyl compounds.
Of the existing strategies towards effecting this deracemiza-
tion process, only a few proceed catalytically,[3] which
seriously limits the synthetic utility of this methodology in
modern organic synthesis.The rare examples of catalytic
processes broadly fall into two main categories.The first one
is based on the protonation of lithium enolates in the presence
of a substoichiometric chiral source of protons and an excess
of an achiral source of protons.[3a–f] A second strategy involves
the catalytic protonation of silyl enolates by making use of a
chiral Lewis acid catalyst to activate the proton source.[3g–l]
Despite the great advances in this field, further development
remains to be accomplished, in particular with regard to the
design of new organocatalytic processes capable of promoting
high enantioselective protonation under mild and more
environmentally benign conditions.In this context, we
demonstrate herein the first organocatalytic enantioselective
protonation of silyl enolates by means of hydrogen fluoride
salts of tertiary amines derived from cinchona alkaloids.[4]
Quaternary cinchonium fluoride and hydrogen difluoride
salts were previously reported to be catalysts for a variety of
asymmetric addition reactions of silicon-based nucleo-
philes.[5–8] Accordingly, the use of the hydrogen fluoride
salts (1-HF) of cinchona alkaloids seems to be a very simple
and attractive chiral source of protons for the enantioselective
protonation of silyl enolates.By taking advantage of the high
affinity of silicon for the fluoride anion, we anticipated that
such salts would be very active chiral sources of protons, with
the resultant specific enolate-activation mode being expected
to confine the proton source and C-protonation site of the
silyl enolate 2 in proximity.According
to this ideal scenario, the asymmetric
transfer of a proton should be facili-
tated through both entropic and
enthalpic activations (Figure 1).
Quite surprisingly, such an event
has so far been completely ignored,
Figure 1. Specific acti-
vation of silyl enolates
2 by means of a hydro-
gen fluoride salt of a
tertiary amine (1-HF).
most likely because of the difficulties
in preparing and storing dry hydrogen
fluoride salts (1-HF).Our organoca-
talytic approach, which is depicted in
Scheme 1, overrides this practical
limitation.In the presence of
chiral tertiary amine catalyst,
a
a
latent source of HF resulting from the unusual combination
of an acid fluoride and an alcohol delivers “at will” a catalytic
amount of the key hydrogen fluoride salt 1-HF.Besides
providing an elegant solution to thwart the tricky preparation
and storage of hydrogen fluoride salts 1-HF, this approach
offers a unique opportunity to design the first organocatalytic
enantioselective protonation of silyl enolates.
Scheme 1. Enantioselective protonation of silyl enolates 2 catalyzedby
hydrogen fluoride salts of a chiral amine (1-HF) generatedfrom a
latent source of HF. TMS=trimethylsilyl.
[*] T. Poisson, Prof. F. Marsais, Prof. G. Dupas, Dr. S. Oudeyer,
Dr. V. Levacher
Institut de Recherche en Chimie Organique Fine (IRCOF)
associØ au CNRS (UMR-6014)
INSA-UniversitØ de Rouen
Rue Tesni›res, 76130 Mont-Saint-Aignan (France)
Fax: (+33)2-35-52-24
E-mail: vincent.levacher@insa-rouen.fr
Initial experiments were conducted in the presence of
10 mol% quinuclidine in THF at room temperature using a
combination of benzoyl fluoride and ethanol as the latent
source of HF, as well as silyl enolate 2a as a standard substrate
(Scheme 2).The protonation proceeded very smoothly, and
afforded tetralone 3a in quantitative yields within 3 h.A
labeling experiment conducted in the presence of [D1]ethanol
provided tetralone [D1]-3a with a high level of deuterium
incorporation, thus illustrating that ethanol is the sole proton
source responsible for the protonation of silyl enol ether 2a.
In the absence of the tertiary amine, no reaction took place,
even after prolonged reaction times, thus demonstrating the
full compatibility between the silyl enolate 2a and the latent
Dr. V. Dalla
Laboratiore de Chimie
URCOM, EA 3221, FacultØ des Sciences et Techniques
UniversitØ du Havre
25, Rue Philippe Lebon, BP 540, 76058 Le Havre (France)
[**] T.P. thanks the MRT for a grant.
Supporting information for this article (including full experimental
details) is available on the WWW under http://www.angewandte.org
or from the author.
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Chemie
A selection of the most representative results is summar-
ized in Table 2.We first examined the influence of the solvent
on the stereochemical outcome of the reaction.While less
Table 2: Optimization of the reaction conditions: Enantioselective
organocatalytic protonation of silyl enol ether 2a by means of
(DHQ)2AQN (1 f).[a]
Scheme 2. Organocatalytic protonation of silyl enol ether 2a mediated
by PhCOF andEtOH as a latent source of HF in the presence of
quinuclidine as a catalyst.
source of HF while providing strong evidence for the
proposed organocatalytic mechanism illustrated in Scheme 1.
The good catalytic performance exhibited by quinuclidine
prompted us to select commercially available cinchona
alkaloids 1a–f as appealing candidates to tackle the challeng-
ing task of controlling the stereoselectivity of this organo-
catalytic proton transfer (Table 1).A first set of experiments
Entry Solvent 1 f [%] EtOH [equiv] PhCOX [1.05 equiv] ee [%][b]
1
2
3
4
5
6
THF
toluene 10
CHCl3 10
dioxane 10
CH3CN 10
10
2
2
2
2
2
2
PhCOF
PhCOF
PhCOF
PhCOF
PhCOF
PhCOF
42
26
19
45
68
78
78[d]
78
84
50
30
81
71
45
Table 1: Cinchona alkaloids screening: Enantioselective protonation of
silyl enol ether 2a.[a]
DMF
10
7
8
9
10
11
12
13
NMP
10
2
2
2
2
1
4
2
PhCOF
PhCOF
PhCOF
PhCOF
PhCOF
PhCOF
(PhCO)2O
DMSO[c] 10
DMF
DMF
DMF
DMF
DMF
5
2
10
10
10
[a] Unless otherwise noted, the reaction was carried out at room
temperature with silyl enol ether 2a (1 mmol), EtOH (2 mmol), PhCOX
(1.05 mmol), and 1 f (10 mol%). [b] Determinedby HPLC; see the
Supporting Information. [c] Some O-benzoylation of silyl enolate 2a was
observed, see Ref. [9]. [d] Reaction performed at À208C.
Entry Cinchona alkaloid 1 Solvent Conv. [%][b] ee [%][c] Abs. conf.[d]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
THF
THF
THF
THF
THF
THF
100
100
100
100
100
100
20
26
21
39
36
42
S
S
R
S
S
S
polar solvents proved to be less effective (Table 2, entries 1–
3), we were pleased to notice a considerable improvement of
the enantioselectivity in more polar solvents, with values of
78% ee being reached in DMF and N-methylpyrrolidone
(NMP; Table 2, entries 6 and 7).At lower temperature, the
reaction rate is considerably reduced, but without any
improvement in the enantioselectivity (Table 2, entry 6).
This result is of particular interest with respect to the few
existing catalytic processes which usually need to be con-
ducted at À788C to reach optimum enantioselectivity.[3]
Although DMSO furnished somewhat higher ee values, its
use was severely hampered by the formation of a side product
resulting from O-benzoylation of 2a with benzoyl fluoride
(Table 2, entry 8).[9] The conclusions drawn from this set of
experiments resulted in DMF being the solvent of choice for
obtaining the best balance between good enantioselectivity
and clean conversion into the desired tetralone 3a.Attempts
to reduce the amount of catalyst resulted in a drop in the
enantioselectivity, although without any noticeable lowering
of the reaction rate (Table 2, entries 9 and 10).The influence
of the EtOH/PhCOF ratio was then examined: this study
showed that both the reaction rate and stereochemical
outcome of the protonation remained unaffected by changing
this ratio from 2:1 to 1:1 (Table 2, entries 6 and 11).Some
[a] Unless otherwise noted, the reaction was carried out in anhydrous
THF (2 mL) at room temperature with silyl enol ether 2a (1 mmol), EtOH
(2.0 mmol), PhCOF (1.05 mmol), and 1 (10 mol%). [b] Determinedby
GC/MS. [c] Determinedby HPLC, see the Supporting Information.
[d] Assigned by comparison of the sign of the optical rotation with
literature data. (DHQ)2PYR=hydroquinine 2,5-diphenyl-4,6-pyrimidine-
diyl diether, (DHQD)2PHAL=hydroquinidine 2,5-diphenyl-4,6-pyrimidi-
nediyl diether, (DHQ)2AQN=hydroquinine anthraquinone-1,4-diyl
diether.
were performed with 10 mol% of the cinchona alkaloids in
THF at room temperature for 12 h.All the cinchona alkaloids
(1a–f) provided tetralone 3a in 100% conversion, but with
moderate ee values that ranged from 20 to 42%, with the best
results being obtained with biscinchona alkaloids 1d–f
(Table 1, entries 4–6).It is interesting to note that cinchona
alkaloid 1c gave rise to tetralone 3a with opposite enantio-
selectivity, and indicates that the quinoline moiety is respon-
sible for this enantio-inversion (Table 1, entry 3).On the basis
of these results, (DHQ)2AQN (1 f) was finally selected as the
best candidate for further optimization of the reaction
conditions.
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erosion of the enantioselectivity was, however, observed
available cinchona alkaloid catalysts and a latent source of
HF.High enantioselectivities of up to 92% were obtained
under mild, neutral, and metal-free conditions.The method-
ology reported in this study adds to the repertoires of
asymmetric catalytic protonation, organocatalyzed reactions,
and of reactions that can be catalyzed by cinchona alkaloid
derivatives, in particular those building on the enantioselec-
tive activation of silicon-based nucleophiles by a cinchonium
fluoride ion.Further investigations of this innovative organo-
catalytic approach, including exploration of new chiral
tertiary amines, a detailed mechanism, and expanded sub-
strate scope, are underway.
when this ratio was increased to 4:1 (Table 2, entry 12).[10]
Interestingly, whereas benzoyl fluoride afforded tetralone 3a
in 78% ee, a serious diminution of the enantioselectivity was
evident with benzoic anhydride, which furnished tetralone 3a
with only 45% ee (Table 2, entries 6 and 13).The superiority
of benzoyl fluoride over benzoic anhydride in regard to chiral
induction illustrated that the nature of the counteranion in the
catalytic active species 1 f-HX (XÀ = FÀ, PhCOOÀ) is an
important parameter in this organocatalytic approach.
With this optimized catalytic process in hand (Table 2,
entry 11), the reaction scope was investigated using various
silyl enolates 2b–j (Table 3).We were pleased to find that silyl
enolates 2a–j afforded the corresponding tetralones 3a–j with
Experimental Section
Typical procedure for enantioselective protonation of silyl enolate
2a: A solution of 1 f (73 mg, 0.085 mmol) in DMF (0.5 mL), EtOH
(0.05 mL, 0.89 mmol), and benzoyl fluoride (110 mg, 0.89 mmol) were
Table 3: Reaction scope: Enantioselective organocatalytic protonation of
various silyl enol ether 2a–i by means of (DHQ)2AQN (1 f).[a]
added successively to
a solution of silyl enolate 2a (0.197 g,
0.85 mmol) in dry DMF (1.2 mL). The solution was stirred at room
temperature until all the starting material had completely disap-
peared (monitored by GC/MS).The solution was diluted with Et O
2
(10 mL), washed with saturated aqueous NaHCO3 (10 mL), and the
aqueous solution was extracted with Et2O (3 ” 10 mL).The combined
organic layers were washed with saturated brine (3 ” 25 mL) and
dried (MgSO4).After evaporation of the solvent under vacuum, the
residue was purified by flash chromatography on silica gel (Et2O/
cyclohexane 3:97) to afford the pure tetralone 3a, which was analyzed
by chiral HPLC.
Entry Silyl enolates 2
Yield[%] [b] ee [%][c] Configuration[d]
1
2
3
2a: n=2, R1 =Me, R2 =H 88
81
78
85
S
S
R
2b: n=2, R1 =Et, R2 =H 70
2c: n=2, R1 =Bn, R2 =H 84
2d: n=2, R1 =
4
91
74
nd[f]
Received: April 17, 2007
Revised: June 19, 2007
Published online: August 9, 2007
5
6
2e: n=2, R1 =Me,
R2 =OMe
98
81
nd
nd
2 f: n=2, R1 =Bn,
R2 =OMe
86
92
Keywords: alkaloids · enantioselectivity · hydrogen fluoride ·
7
8
9
2g: n=1, R1 =Me, R2 =H 78
2h: n=1, R1 =Et, R2 =H 76
2i: n=1, R1 =Bn, R2 =H 78
2j
71
74
64
S
S
nd
.
ketones · organocatalysis
10
98
30
S
[1] a) L.Duhamel, C. R. Acad. Sci. 1976, 282, 125; b) L.Duhamel,
J.C.Plaquevent, Tetrahedron Lett. 1977, 18, 2285; c) L.Duha-
mel, J.C.Plaquevent, J. Am. Chem. Soc. 1978, 100, 7415.
[2] For reviews on enantioselective protonation, see a) L.Duhamel,
P.Duhamel, J.C.Plaquevent, Tetrahedron: Asymmetry 2004, 15,
3653; b) C.Fehr, Angew. Chem. 1996, 108, 2726; Angew. Chem.
Int. Ed. Engl. 1996, 35, 2566.
[3] For catalytic enantioselective protonation, see a) C.Fehr, I.
Stempf, J.Galindo, Angew. Chem. 1993, 105, 1093; Angew.
Chem. Int. Ed. Engl. 1993, 32, 1044; b) C.Fehr, J.Galindo,
Angew. Chem. 1994, 106, 1967; Angew. Chem. Int. Ed. Engl.
1994, 33, 1888; c) A.Yanagisawa, T.Kikuchi, T.Watanabe, T.
Kuribayashi, H.Yamamoto, Synlett 1995, 372; d) E.Vedejs,
A.W.Kruger, J. Org. Chem. 1998, 63, 2792; e) Y.Ymashita, Y.
Emura, K.Odashima, K.Koga, Tetrahedron Lett. 2000, 41, 209;
f) K.Mitsuhashi, R.Ito, T.Arai, A.Yanagisawa, Org. Lett. 2006,
95
58[e]
[a] Unless otherwise noted, the reaction was carried out in DMF(2 mL) at
room temperature for 12 h with silyl enol ether 2 (1 mmol), EtOH
(1.05 mmol), PhCOF (1.05 mmol), and 1 f (10 mol%). [b] Yieldof
isolatedproduct. [c] Determinedby HPLC, see the Supporting Informa-
tion. [d] Assigned by comparison with literature data. [e] Reaction
conducted at À108C. [f] nd=not determined.
satisfactory to good enantioselectivities of up to 92% ee
(Table 3, entries 1–6).While still acceptable, somewhat lower
enantioselectivities ranging from 64% to 74% ee were
obtained in the indanone series from silyl enolates 2g–i
(Table 3, entries 7–9).The more reactive silyl enolate 2j
afforded the corresponding cyclohexanone 3j with a rather
modest 30% ee, which, however, could be significantly
improved by conducting the reaction at À108C (Table 3,
entry 10).In all cases, ketones 3a–i were isolated in excellent
yields (70–98%).
8, 1721; g) K.Ishihara, M.Kaneeda, H.Yamamoto,
J. Am.
Chem. Soc. 1994, 116, 11179; h) K.Ishihara, S.Nakamura, M.
Kaneeda, H.Yamamoto, J. Am. Chem. Soc. 1996, 118, 12854;
i) M.Sugiura, T.Nakai, Angew. Chem. 1997, 109, 2462; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2366; j) S.Nakamura, M.
Kaneeda, K.Ishihara, H.Yamamoto, J. Am. Chem. Soc. 2000,
122, 8120; k) K.Ishihara, D.Nakashima, Y.Hiraiwa, H.
Yamamoto, J. Am. Chem. Soc. 2003, 125, 24; l) A.Yanagisawa,
T.Touge, T.Arai, Angew. Chem. 2005, 117, 1570; Angew. Chem.
Int. Ed. 2005, 44, 1546.
In summary, we have developed the first organocatalytic
enantioselective protonation of silyl enolates by using readily
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Chemie
[4] Enantioselective decarboxylation/re-protonation of malonate
derivatives was reported previously by means of cinchona
Z.Ye, J.F.Cannon, Org. Lett. 2005, 7, 3861; Nitroaldol reaction
f) T.Ooi, K.Doda, K.Maruoka, J. Am. Chem. Soc. 2003, 125,
2054.
alkaloids, and represent
a further example of metal-free
enantioselective protonation, see a) H.Brunner, P.Schmidt,
Eur. J. Org. Chem. 2000, 2119; b) L.M.A.Rogers, J.Rouden, L.
Lecomte, M.C. Lasne, Tetrahedron Lett. 2003, 44, 3047; c) T.
Seitz, J.Baudoux, H.Bekolo, D.Cahard, J.C.Plaquevent, M.C.
Lasne, J.Rouden, Tetrahedron 2006, 62, 6155.
[7] Trifluoromethylation of carbonyl electrophiles: a) K.Iseki, T.
Nagai, Y.Kobayashi, Tetrahedron Lett. 1994, 35, 3137; b) S.
Caron, N.M.Do, P.Arpin, A.LarivØe, Synthesis 2003, 1693.
[8] Mukaiyama Michael processes: T.Ooi, K.Doda, K.Maruoka, J.
Am. Chem. Soc. 2003, 125, 9022.
[5] For a recent review on this topic, see K.Maruoka, T.Ooi, Acc.
Chem. Res. 2004, 37, 526.
[9] We recently reported such O-silyl/O-benzoyl interconversions
catalyzed by 4-dimethylaminopyridine (DMAP), see: T.Poisson,
V.Dalla, C.Papamical, G.Dupas, F.Marsais, V.Levacher,
Synlett 2007, 381.
[10] Under identical conditions as those reported in Table 3, entry 6,
the use of other alcohols in place of EtOH led to diminished
enantioselectivities.
[6] Aldol reaction a) A.Ando, T.Miura, T.Tamematsu, T.Shiori,
Tetrahedron Lett. 1993, 34, 1507; b) M.Horikawa, J.Busch-
Petersen, E.J.Corey, Tetrahedron Lett. 1999, 40, 3843; c) T.Ooi,
K.Doda, K.Maruoka, Org. Lett. 2001, 3, 1273; d) G.Bluet, J.M.
Campagne, J. Org. Chem. 2001, 66, 4293; e) M.B.Andrus, J.Liu,
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