A bronsted acid catalyst for the enantioselective protonation reaction

Article abstract of DOI:10.1021/ja8041542

A highly reactive and robust chiral Bronsted acid catalyst, chiral N-triflyl thiophosphoramide, was developed. The first metal-free Bronsted acid catalyzed enantioselective protonation reaction of silyl enol ethers was demonstrated using this chiral Bronsted acid catalyst. The catalyst loading could be reduced to 0.05 mol % without any deleterious effect on the enantioselectivity. Copyright

Full text of DOI:10.1021/ja8041542

Published on Web 06/27/2008
A Brønsted Acid Catalyst for the Enantioselective Protonation Reaction
Cheol Hong Cheon and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received June 2, 2008; E-mail: yamamoto@uchicago.edu
Table 1. Reactivity for the Protonation Reactions
Metal-free chiral Brønsted acid catalysis has been a growing area
of research for the past decade. Several chiral Brønsted acids such as
urea/thiourea and TADDOL have been reported as an activator of
electrophiles via hydrogen bonding.1,2 In 2004, the research groups
of Akiyama3 and Terada4 independently reported a different type of
activation of electrophiles by way of protonation with moderately
strong phosphoric acids derived from chiral BINOLs. Following these
seminal studies, it soon became clear that chiral phosphoric acids
possessed tremendous potential for application in the development of
novel asymmetric processes.5 However, due to the relatively low
acidity of phosphoric acids, their utility has been limited to more basic
nitrogen-based electrophiles such as imines or aziridines. The activation
of aldehydes and ketones by chiral phosphoric acids has been very
rare. Our group reported the first activation of carbonyl compounds
with chiral phosphoric acids by introducing the N-trifluoromethane-
sulfonyl (NTf) group into phosphoric acid.6,7 Continuing efforts to
make the utility of chiral phosphoric acid catalysts more general in
organic synthesis require the design of a new chiral Brønsted acid with
higher acidity. In general, acidity increases as it descends in a column
of the periodic table due to better stabilization of the conjugate base
in a larger size atom. For example, the pKa values of PhOH, PhSH,
and PhSeH in DMSO are 18.0, 10.3, and 7.1, respectively.8 With this
in mind, we expected that substitution of the oxygen in the PdO bond
in an N-triflyl phosphoramide with sulfur or selenium would increase
the reactivity of the Brønsted acid.9
Enantioselective protonation of prochiral enol derivatives is an
attractive route for the preparation of optically active R-carbonyl
compounds.10 However, it is difficult to control the enantioselectivity
in an acidic condition because of the bonding flexibility between the
proton and its chiral counterion and the orientational flexibility of the
proton. Our group overcame these difficulties with the Lewis acid
assisted chiral Brønsted acid (LBA) system.11,12 Although the LBA
provided an excellent solution for asymmetric protonation reactions
of silyl enol ethers, to the best of our knowledge, metal-free chiral
Brønsted acid catalyzed enantioselective protonations of silyl enol
ethers have never been reported.13 This is probably due to the
unavailability of chiral Brønsted acids with suitable acidity. Herein
we describe the preparation of a new designer chiral Brønsted acid
and its application to the enantioselective protonation reaction of silyl
enol ethers.
entry catalyst time (h) % yielda erb entry catalyst time (h) % yielda
erb
1
2
1
2
96 NR
ND
3
4
5
3
4c
5
4.5 >99 (98) 77:23 (S)
3.5 >99 (97) 89:11 (S)
3.5 >99 (97) 86:14 (S)
96 trace ND
a Yield was measured by 1H NMR analysis, and the isolated yields
are shown in parentheses. b Enantiomeric ratio (er) was determined by
HPLC analysis. NR and ND mean no reaction and not determined,
respectively.
(CH3)3C6H2CO2H as an achiral proton source. The results are sum-
marized in Table 1. Although 2 was slightly more reactive than 1,
almost no reaction was observed with 1 and/or 2 even after long
reaction times (entries 1 and 2). However, 3-5 gave the desired product
with quantitative yield and moderate to good enantioselectivity (entries
3-5). These results again supported our previous hypothesis that
introduction of a )NTf group into the phosphoryl group could improve
reactivity.6,7 Gratifyingly, we found that substitution of the oxygen
with sulfur or selenium in the phosphoramide improved enantioselec-
tivity as well as reactivity (entries 3-5).
Next, we optimized the reaction conditions for the enantioselective
protonation reaction with 4c.14 Among various reaction parameters,
we found that reactivities and enantioselectivities of protonation
reactions catalyzed by 4c are strongly dependent on the achiral proton
sources. Higher enantioselectivity could be achieved with nonhindered
phenol and carboxylic acid derivatives as achiral proton sources. Under
these optimized conditions, several N-triflyl thiophosphoramides 4a-e
with varying substituents at the 3,3′-positions of the binaphthyl scaffold
were tested. We found that alkyl substituents at 2,6-positions of
aromatic substituents at 3,3′-positions of the binaphthyl scaffold are
crucial for enantioselectivity. Enantioselectivity as high as 91:9
enantiomeric ratio (er) could be obtained using 4d as the catalyst.
Using these optimized conditions with catalyst 4d, various silyl enol
ethers were studied in the enantioselective protonation reaction. The
results are summarized in Table 2. Various 2-aryl-substituted cyclic
ketones, bearing either electron-donating or electron-withdrawing
substituents, could be obtained in quantitative yields and high enan-
tioselectivities (entries 1-4). However, the enantioselectivity showed
a slight dependence on the size of R-substituents of the cyclic ketones.
A bulky substituent gave slightly better enantioselectivity (entry 5),
while the aryl substituent carrying o-substitution had a deleterious effect
on the enantioselectivity (entry 6). In addition, the ring size of the
cyclic ketone affected enantioselectivity: the seven-membered ring
ketone had better enantioselectivity than six-membered ring ketones
(entries 1, 5, 7, and 9). It should be noted that the catalyst loading
Chiral N-triflyl thio- or selenophosphoramides 4a-e and 5 were
synthesized from the optically active BINOL derivatives by thio- or
selenophosphorylation with PSCl3 or PCl3 followed by oxidation with
selenium powder and amidation of the resultant thio- or selenophos-
phoryl chlorides by NH2Tf.14 X-ray crystallography revealed, as
suggested in the molecular structure of 4c (Table 1), 4c has a PdS
double bond rather than a PdN double bond, which implies the proton
is located on the nitrogen atom, instead of the sulfur atom bonded to
the phosphorus atom.14
To compare the catalytic reactivity of various chiral Brønsted acids
1-5, the enantioselective protonations of the silyl enol ether 6a were
investigated in the presence of a stoichiometric amount of 2,4,6-
9
9246 J. AM. CHEM. SOC. 2008, 130, 9246–9247
10.1021/ja8041542 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope
Scheme 1. Proposed Mechanism of Brønsted Acid Catalyzed
Asymmetric Protonations of Silyl Enol Ethers
entry
n
Ar
time (h)
% yielda
erb (config)
1
2
3
4
1
1
1
1
1
1
2
2
2
2
1
1
Ph (6a)
8
6
>99 (97) 91:9 (S)
>99 (96) 93:7 (S)
>99 (98) 92:8 (S)
>99 (95) 92:8
>99 (99) 93:7 (S)
>99 (97) 86:14
>99 (99) 94:6 (S)
4-MeC6H4 (6b)
4-MeOC6H4 (6c)
4-ClC6H4 (6d)
2-Naphthyl (6e)
2-MeOC6H4 (6f)
Ph (6g)
12
12
12
40
6
24
6
22
8
Without PhOH, the desilylation was very slow because the affinity
of the resultant conjugate base [A]- to the silicon is quite low.
However, in the presence of PhOH with enough affinity to silicon
desilylation could be accelerated.17
5
6c
7
8c
9
Ph (6g)
>99
95:5 (S)
2-naphthyl (6h)
2-naphthyl (6h)
-CH2Ph (6i) (94:6)d
-cyclohexyl (6j) (96:4)d
>99 (97) 95:5
In conclusion, we have reported the first metal-free Brønsted acid
catalyzed asymmetric protonation reactions of silyl enol ethers using
a chiral Brønsted acid catalyst in the presence of achiral Brønsted
acid media. In addition, the reactivity of this Brønsted acid is especially
appealing for chiral phosphoric acid catalysis in that the catalyst loading
for this reaction could be decreased up to 0.05 mol % without any
significant loss of enantioselectivity.
10c
11
12
>99
94:6
>99 (97) 77:23 (S) (79:21)e
>99 (96) 82:18 (S) (84:16)e
8
a Yield was measured by 1H NMR analysis, and the isolated yields
are shown in parentheses. b Enantiomeric ratio was determined by HPLC
or GC analysis. c 1 mol % of catalyst was used. d The value in
parentheses indicates the regioisomeric ratio of the starting silyl enol
ethers. e Corrected value based on the regioisomeric ratio of the starting
silyl enol ethers.
Acknowledgment. This work was partially supported by NSF
(Grant No. 0412060), NIH (Grant No. RO1 GMo74639-01), and
Merck. Special thanks to Dr. Ian Steele for X-ray crystallographic
analysis.
could be reduced to 1 mol % without any detrimental effect on the
selectivity, although longer reaction times were needed (entries 7-10).
In addition, asymmetric protonations of the silyl enol ethers of 2-alkyl-
substituted cyclic ketones were achieved using this catalytic system
in quantitative yields, even though the enantioselectivities were
moderate (entries 11 and 12).
Supporting Information Available: Experimental procedures and
spectroscopic data of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
With these successful results in terms of catalyst activity and
enantioselectivity, we wanted to test the reactivity and robustness of
the Brønsted acid by decreasing the catalyst loading. The protonated
product of 6g was quantitatively obtained in 94:6 er with a catalyst
loading of only 0.1 mol %. Even the smallest substrate/catalyst ratio,
namely S/C 2000 at room temperature, provided excellent yield and
good enantioselectivity. This was an unprecedented example of chiral
phosphoric acid catalysis with such a low catalyst loading, which
proves its remarkable catalytic efficiency.15
References
(1) For a review of enantioselective organocatalysis, see: Pihko, P. M.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 2062, and see Supporting Information
for more references.
(2) For a review of hydrogen bond organic catalysis, see: Doyle, A. G.; Jacobsen,
E. N. Chem. ReV. 2007, 107, 5713, and see Supporting Information for
more references.
(3) Akiyama, T.; Itoh, J.; Yokota, D.; Fuchibe, K. Angew. Chem., Int. Ed. 2004,
43, 1566.
(4) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(5) For a review of chiral phosphoric acid catalysis, see: Akiyama, T Chem. ReV.
2007, 107, 5744, and see Supporting Information for more references.
(6) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626. (b)
Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47,
2411.
(7) After our publication of N-triflyl phosphamide, two other examples of carbonyl
activation with this reagent were published; see: (a) Rueping, M.; Ieawsuwan,
D.; Antonchick, A. P.; Nachtsheim, B. J. Angew. Chem., Int. Ed. 2007, 46,
2097. (b) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew.
Chem., Int. Ed. 2008, 47, 593.
(8) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(9) Similar acidity enhancement by substitution of the oxygen with sulfur was
observed in the urea/thiourea catalyst. See ref 2 and Robak, M. T.; Trincado,
M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110.
(10) For a review of enantioselective protonation, see: Duhamel, L.; Duhamel, P.;
Plaquevent, J. C. Tetrahedron: Asymmetry 2004, 15, 3653, and see
Supporting information for more references.
(11) For the asymmetric protonation with LBA, see: Nakashima, D.; Yamamoto,
H. Synlett 2006, 150, and see Supporting Information for more references.
(12) For another example of asymmetric protonation of silyl enol ether with
Binap ·AgF complex, see: Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem.,
Int. Ed. 2005, 44, 1546.
(13) For another excellent organocatalytic asymmetric protonation of silyl enol ethers
in different systems was reported, see: Poisson, T.; Dalla, V.; Marsais, F.;
Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090.
(14) See Supporting Information for more detailed experimental results.
(15) For another excellent example of high S/C ratio with phosphoric acid, see:
Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45,
2254.
Preliminary studies into the mechanism of the Brønsted acid
catalyzed asymmetric protonation reaction of silyl enol ethers indicate
that achiral proton sources play an important role in determining
reactivity.14 In the absence of an achiral proton source, even though a
stoichiometric amount of chiral Brønsted acid was used, no reaction
was observed even after 2 days. However, when the same reaction
was carried out in the presence of stoichiometric amount of CH3CO2H
as an achiral proton source, the reaction was completed within 2 h
with almost the same enantioselectivity as the catalytic one.
These results suggest that the protonation reaction proceeds through
a two-step sequence (Scheme 1): initially, the protonation takes place
enantioselectively from the chiral Brønsted acid HA or achiral oxonium
ion pair [PhOH2]+ ·A-, generated by rapid proton transfer between
HA and the achiral proton source PhOH, to the silyl enol ether a to
form an intermediary chiral ion pair [aH]+ ·[A]-.16 This is followed
by the desilylation with PhOH to form the corresponding ketone b,
the silylated achiral proton source Ph-OTMS, and the regenerated HA.
(16) For a concept of asymmetric counteranion-directed catalysis, see: (a) Mayer,
S.; List, B. Angew. Chem., Int. Ed. 2005, 45, 4193. (b) Hamilton, G. L.;
Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
(17) Similar reaction rate enhancement of phosphoric acid catalysis in alcoholic
solvents: Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631.
JA8041542
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