Chiral sulfinamide/achiral sulfonic acid cocatalyzed enantioselective protonation of enol silanes

Article abstract of DOI:10.1021/ol201608a

The application of chiral sulfinamides and achiral sulfonic acids as a cocatalyst system for enantioselective protonation reactions is described. Structurally simple, easily accessible sulfinamides were found to induce moderate-to-high ee's in the formation of 2-aryl-substituted cycloalkanones from the corresponding trimethylsilyl enol ethers.

Full text of DOI:10.1021/ol201608a

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4260–4263
Chiral Sulfinamide/Achiral Sulfonic Acid
Cocatalyzed Enantioselective Protonation
of Enol Silanes
Elizabeth M. Beck, Alan M. Hyde, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, United States
jacobsen@chemistry.harvard.edu
Received June 15, 2011
ABSTRACT
The application of chiral sulfinamides and achiral sulfonic acids as a cocatalyst system for enantioselective protonation reactions is described.
Structurally simple, easily accessible sulfinamides were found to induce moderate-to-high ee’s in the formation of 2-aryl-substituted
cycloalkanones from the corresponding trimethylsilyl enol ethers.
Weak-to-moderately strong chiral Brønsted acids, ran-
ging from diols to phosphoric acids, have been applied in a
variety of catalytic enantioselective transformations. Par-
ticular success has been achieved in catalysis of addition
reactions to relatively basic electrophiles such as imines.1
More recently, some effort has been directed toward
accessing and utilizing stronger Brønsted acids, enabling
expansion of the scope to the activation of carbonyl groups
and certain olefins.2
We became interested in exploring the potential of the
conjugate acids of chiral sulfinamides as a novel class of
strong, chiral Brønsted acid catalysts. While sulfinamides
find extensive use as chiral auxiliaries and ligands in
asymmetric synthesis,3 applications of these privileged
chiral structures as organocatalysts are less common.4,5
Our design was inspired by recent studies with sulfinamideꢀ
urea catalyst 1a, which revealed that the highly enantiose-
lective addition of electron-rich alkenes to protioiminium
ions can be achieved through a network of noncovalent
interactions between the electrophile and the chiral urea-
bound counteranion.5 In particular, spectroscopic and
computational evidence was obtained for a hydrogen-
bond interaction between the sulfinamide group of the
catalyst and the NꢀH proton of the iminium ion inter-
mediate (Figure 1A). We hypothesized that, in the absence
of the Lewis basic imine, the combination of a sulfonic acid
and sulfinamide urea catalyst 1a could produce a chiral
acidic species capable of effecting enantioselective proto-
nation reactions (Figure 1B). The proximity of the stereo-
genic sulfur to the proton would potentially enable high
levels of stereochemical communication. Here we describe
the development of this new approach for catalysis and its
application to the enantioselective catalytic protonation of
(1) For general reviews on chiral Brønsted acids as organocatalysts,
see: (a) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2010,
291, 395. (b) Terada, M. Synthesis 2010, 12, 1929. (c) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(2) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626. (b) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara,
K. J. Am. Chem. Soc. 2008, 130, 16858. (c) Garcıa-Garcıa, P.; Lay, F.;
Garcıa- Garcıa, P.; Rabalakos, C.; List, B. Angew. Chem., Int. Ed. 2009,
48, 4363. (d) Uragguachi, D.; Nakashima, D.; Ooi, T. J. Am. Chem. Soc.
2009, 131, 7242. (e) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu,
J.; Toste, F. D. Nature 2011, 470, 245.
(3) For a recent, comprehensive review of the synthesis and applica-
tions of tert-butanesulfinamide, see: (a) Robak, M. T.; Herbage, M. A.;
Ellman, J. A. Chem. Rev. 2010, 110, 3600. For p-tolylsulfinamide, see:
(b) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(4) For examples of sulfinamides as organocatalysts, see: (a) Pei, D.;
Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006, 8, 5913. (b) Tan,
K. L.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315. (c) Wang,
C.; Wu, X.; Zhou, L.; Sun, J. Chem.;Eur. J. 2008, 14, 8789. (d) Pei, D.;
Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv. Synth. Catal. 2008, 350, 619.
(e) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 15110. (f) Kimmel, K. L.; Robak, M. T.; Ellman, J. A. J. Am. Chem.
Soc. 2009, 131, 8754.
(5) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Science 2010, 327, 986.
r
10.1021/ol201608a
Published on Web 07/25/2011
2011 American Chemical Society

prochiral enol silanes as a method for the preparation of
chiral, R-branched ketones.6,7
functional groups such as sulfonamides (1d) or tertiary
amines (1e) led to much less effective catalysts for the
protonation of 5a with 2,4-diNBSA and that urea deriva-
tives such as 2, lacking a basic ancillary group, were com-
pletely unreactive (Scheme 1).
Scheme 1. Evaluation of Catalyst Structuresa
Figure 1. (A) Schematic representation of the geometry and
energy-minimized lowest energy transition structure for sulfi-
namideꢀurea/TfOH cocatalyzed Povarov reaction (from ref 5).
(B) Schematic representation of the energy-minimized lowest
energy ground state structure for the sulfinamideꢀurea 1a/
TfOH ‘chiral acid’ complex. Structures calculated at the
B3LYP/6-31G(d) level of density functional theory. Ar = 3,5-
bis(CF3)C6H3.
a Yield determined by 1H NMR on a 0.05 mmol scale. Enantioselec-
tivity determined by chiral HPLC.
Silyl enol ether 5a, derived from 2-phenylcyclohexa-
none, was selected as the model substrate (Scheme 1). A
suitable achiral stoichiometric proton source was sought
that would effect protonation of the sulfinamide catalyst
scaffold without promoting a background racemic proto-
nation pathway. It was found that 2,4-dinitrobenzene
sulfonic acid (2,4-diNBSA) was well suited, as it is com-
pletely insoluble in toluene at ꢀ40 °C and, consequently,
unreactive toward 5a under these conditions. However, in
the presence of catalytic levels of sulfinamideꢀurea 1a,
substrate protonation occurred to generate the corre-
sponding ketone 6a in 67% ee. No reactivity toward 5a
was displayed by 1a alone under these conditions. Ketone
6a was found to be configurationally stable under the
catalytic conditions.
Examination of simple sulfinamide 3, which lacks a urea
moiety, revealed that it was also catalytically active in the
protonation of 5a, affording ketone 6a in >95% yield and
41% ee. The enantioselectivity observed with 3, while
moderate, revealed that enantioselective catalysis could
be achieved with compounds bearing only the sulfinamide
moiety. The synthetic accessibility of these simple struc-
tures allowed for the rapid preparation and screening of a
large array of substituted sulfinamide derivatives.8 Testing
analogues of 3 demonstrated that branching at the carbon
center adjacent to the sulfinamide nitrogen was delete-
rious to both reactivity and enantioselectivity, so efforts
were focused on simple primary sulfinamide derivatives
(Scheme 1, 4aꢀf). Interestingly, both simple alkyl- and
benzyl-substituted catalysts performed comparably (4a vs
4d). For both, however, a significant increase in enantios-
electivity was observed with analogues bearing additional
electron-withdrawing groups. This effect was especially
pronounced with fluorinated analogues (4a vs 4b and 4c;
4d vs 4e and 4f).
Systematic variation of the catalyst structure revealed
that replacement of the sulfinamide group with other basic
(6) For previous examples of enantioselective protonation as a route
to R-aryl cyclohexanones, see: (a) Ishihara, K.; Nakamura, S.; Kaneeda,
M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854. (b) Nakamura,
S.; Kaneeda, M.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000,
122, 8120. (c) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H.
J. Am. Chem. Soc. 2003, 125, 24. (d) Yanagisawa, A.; Touge, T.; Arai, T.
Angew. Chem., Int. Ed. 2005, 44, 1546. (e) Cheon, C. H.; Yamamoto, H.
J. Am. Chem. Soc. 2008, 130, 9246.
(7) For enantioselective protonation of other silyl enol ether sub-
strate classes, see: (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, 2447. (c) Sugiura, M.; Nakai, T. Angew. Chem., Int. Ed. 1997, 36,
2366. (d) Morita, M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858. (e)
Uraguchi, D.; Kinoshita, N.; Ooi, T. J. Am. Chem. Soc. 2010, 132,
12240.
The enantioselectivity was also found to be responsive to
the identity of the sulfonic acid, even though none of the
sulfonic acid derivatives examined displayed any back-
ground reactivity in the absence of catalyst 4c (Table 1,
(8) For additional details of other sulfinamide structures and asso-
ciated selectivities in the enantioselective protonation reaction, see
Supporting Information.
Org. Lett., Vol. 13, No. 16, 2011
4261

entries 2ꢀ5). Reactions with 2,4-dinitrobenzene sulfonic
acid as a strong acid source afforded the highest ee’s.
Further, it was observed that it is possible to use a catalytic
quantity of the sulfonic acid as long a stoichiometric
proton source such as water or a phenol is introduced
(entries 6ꢀ8). In particular, reactions with hindered phe-
nols such as 2,6-di-tert-butylphenol afforded product 6a
with high enantioselectivity (entry 8). Addition of a desic-
cant such as sodium sulfate to remove residual water
associated with the hygroscopic sulfonic acids had a
beneficial effect on both yield and ee (entries 1 vs 2, and
8 vs9). Underoptimal conditions, product6awasobtained
in 86% ee using 4c as the catalyst with 0.2 equiv of 2,4-
diNBSA, 1.1 equiv of 2,6-di-tert-butylphenol, and 2.0
equiv of Na2SO4 in toluene at ꢀ50 °C (Table 2, entry 9).
Table 2. Substrate Scopea
enol
yieldb
(%)
eec
entry
silane
n
R
ketone
(%)
1
2
3
4
5
6
7
8
9
10
5a
5b
5c
5d
5e
5f
1
1
1
1
1
1
1
1
1
2
C6H5
6a
6b
6c
6d
6e
6f
91
92
90
89
88
84
92
91
93
88
86
88
84
89
81
78
84
85
82
73
4-MeC6H4
4-OMeC6H4
4-ClC6H4
4-FC6H4
4-CO2MeC6H4
3-MeC6H4
2-MeC6H4
2-Naphthyl
C6H5
5g
5h
5i
6g
6h
6i
Table 1. Effect of the Proton Source on Enantioselectivitya
5j
6j
a Reactions were carried out on 0.15 mmol scale. Silyl enol ether and
4c were added as a solution in toluene to 2,4-diNBSA, 2,6-di-tert-butyl
phenol and Na2SO4 in toluene at ꢀ78 °C. b Isolated yield based on silyl
enol ether. c Determined by HPLC using commercial chiral columns.
conversionc eed
for stereoinduction in these reactions is intriguing and not
at all apparent. As outlined below, our preliminary me-
chanistic investigation suggests several interesting possibi-
lities for how a catalyst as simple as 4c might participate in
cooperative stabilizing interactions in the selectivity-deter-
mining transition structure.
A linear dependence of reaction enantioselectivity on the
enantiopurity of 4c was observed, indicating the sulfina-
mide catalyst maintains a monomeric structure in the
ground state and in the ee-determining transition state.
Accordingly, our analyses considered only pathways in-
volving one chiral catalyst molecule.
In principle, either proton transfer or silyl transfer may
be rate- and enantiodetermining in the protonation of silyl
enol ethers catalyzed by 4c.10 Both scenarios were evalu-
ated computationally in the reaction of silyl enol ether 5a
with protonated sulfinamide catalyst CF3CH2NHS(O)t-
Bu (4g) (Figure 2). Given the structural and functional
group simplicity of the chiral catalyst, we were especially
interested in whether attractive noncovalent interactions
might play a role in organizing the transition structures
into energetically well-defined geometries.11
Preliminary calculations indicated that proton transfer
should occur from the oxygen atom of the sulfinamide, as
NH-to-C proton transfer was significantly higher in en-
ergy. We examined a series of transition structures incor-
porating NHꢀπ, CHꢀπ, or hydrogen bonding interactions,
as well as others lacking secondary noncovalent interactions.
equiv of
ArSO3H
entry
R
Hþ source
(%)
(%)
1
2,4-(NO2)2
2,4-(NO2)2
2-NO2
1.0
1.2
1.2
1.2
1.2
0.1
0.1
0.1
0.2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
>95
>95
>95
>95
>95
43
76
85
69
55
58
69
76
83
86
2b
3b
4b
5b
6
3-NO2
2,4,5-Cl3
2,4-(NO2)2
2,4-(NO2)2
2,4-(NO2)2
2,4-(NO2)2
H2O
7
PhOH
>95
70
8
9b
2,6-(t-Bu)C6H3OH
2,6-(t-Bu)C6H3OH
78
a Reactions were carried out on 0.05 mmol scale. b 2 equiv Na2SO4
included. c Determined by 1H NMR. d Determined by HPLC using
commercial chiral columns.
A variety of silyl enol ethers were examined under these
conditions in the enantioselective protonation reaction
(Table 2). Several 2-aryl-substituted cyclic ketones bearing
electron-donating or -withdrawing para substituents could
be obtained in high yield and withee’s between 78and 89%
(entries 1ꢀ6). Substituents in the ortho and meta positions
were also tolerated (entries 7ꢀ9). The cycloheptanone
derivative 5j, however, underwent protonation with mea-
surably lower enantioselectivity (entry 10).
While the sulfinamide appears to promote the protona-
tion reaction by functioning as a solid-to-solution phase
transfer catalyst for the insoluble 2,4-diNBSA,9 the basis
(9) The complexation behavior of the sulfinamide catalysts with 2,4-
diNBSA was investigated by 1H NMR. Peak integration of mixtures in
C6D6 revealed that bifunctional catalysts 1aꢀe form a 1:1 complex with
2,4-diNBSA. In contrast, no dissolution of 2,4-diNBSA was observed
with the simple urea 2. Simple sulfinamides 4c and 4f, lacking a urea
component, also induced solubilization of the sulfonic acid. These data
point to a role of the sulfinamides as solid-to-solution phase transfer
catalysts.
(10) For an example in which rate-limiting desilylation is proposed,
see ref 6e.
(11) Accurately reproducing noncovalent interactions is a challenge
for many density functional theory methods. We utilized Truhlar’s M05-
2X functional, which has been shown to be suitable in this respect: Zhou,
Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
4262
Org. Lett., Vol. 13, No. 16, 2011

Of these, the lowest energy structures were those that
included CHꢀπ interactions from the electron-deficient
CH2 side chain ofthe catalysttothe substratearylring (one
representative structure is shown in Figure 2A). In this
structure the distance from the closest hydrogen of the
catalyst to the centroid of the arene is 2.47 A. Since the
existence of a weak noncovalent interaction cannot be
inferred from atomic distance only, analysis of the electron
density and its derivatives was carried out using the
NCIPLOT program recently developed by Yang and co-
workers.12 This approach allows for the generation of
gradient isosurfaces that indicate the location and strength
of noncovalent interactions of all types.
Transition structures for silyl transfer from a C-proto-
nated silyl enol ether intermediate to the sulfinamide
oxygenwerealsomodeled. Inone suchstructure, hydrogen
bonding from the NH of 4g to the incipient carbonyl and
also to the arene is observed to provide a rigidifying
framework (Figure 2B).
The identity of the sulfonate counterion has a measur-
able influence on enantioselectivity (Table 1). Modeling
the proton transfer step with a benzene sulfonate counter-
ion included (Figure 2C) also revealed a network of
potential attractive interactions. In the most energetically
accessible structures, the sulfonate appears to be held in
place by hydrogen bonding to the sulfinamide NH. How-
ever, NCI analysis points to electrostatic attraction with
the CO bond developing a positive charge as the dominant
force that positions the sulfonate.
At this stage, development of a rigorous stereochemical
model is beyond the scope of this analysis and would likely
require a dynamic approach that considers an ensemble of
structures. Nevertheless, intriguing possibilities have been
identified for how the structurally simple sulfinamide
catalysts might engage in noncovalent, attractive inter-
actions that can play a critical role in transition state
organization.
In summary, simple chiral sulfinamide derivatives used
in conjunction with a strong achiral sulfonic acid are
effective catalysts for enantioselective protonation of
prochiral silyl enol ethers. The use of these sulfinamide
catalysts as acid shuttles introduces a new role for these
readily accessible compounds, and we anticipate an
extension of this reactivity principle to other types of
synthetically interesting enantioselective protonation
reactions.
Figure 2. NCI (noncovalent interaction) analysis of calculated
transition states. Gradient isosurfaces for noncovalent interac-
tions are diplayed. The surfaces are colored according to the
strength of the NCI which increase from green to blue with red
signifying destabilizing nonbonded overlap. (A) Proton transfer
from sulfinamide to substrate; (B) silyl transfer from substrate
to sulfinamide; (C) proton transfer with a sulfonate counterion
included. Structures fully optimized at the M05-2X/6-31þg(d,p)
level of theory.
Acknowledgment. This work was supported by the
NIGMS (PO1 GM-69721 and RO1 GM-43214) and by a
Mary Fieser Postdoctoral Fellowship to E.M.B. from Harvard
University and an NIH postdoctoral fellowship to A.M.H. We
thank Amanda Turek for catalyst synthesis and Stephan
Zeund for providing the calculated structure in Figure 1B.
Supporting Information Available. Full experimental
procedures, syntheses of substrates and catalysts, char-
acterization data for all new compounds, NMR spectra
and HPLC traces for protonation products, additional
optimization with details of additional sulfinamide scaf-
folds, methods for computational anaylsis, Cartesian
coordinates for calculated structures, and NCIPLOT
structures. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
(12) (a) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; Contreras-
Garcıa, J.; Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498. (b)
Contreras-Garcıa, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal,
J.-P.; Beratan, D. N.; Yang, W. J. Chem. Theory Comput. 2011, 7, 625.
Org. Lett., Vol. 13, No. 16, 2011
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