Organocatalysis in a synthetic receptor with an inwardly directed carboxylic acid

Article abstract of DOI:10.1021/ja801107r

A cavitand functionalized with a Kemp-s triacid derivative was used to catalyze the epoxide ring-opening cyclizations of 1,5-epoxyalcohols. A deep, cylindrical cavity containing electron-rich aromatic walls and an inwardly directed carboxylic acid displayed the necessary characteristics to bind different 1,5-epoxyalcohols and initiate their cyclization reactions. The reactions inside this synthetic receptor occurred in a catalytic and regioselective manner. These results highlight that the arrangement of functionality and unique solvation provided by the structured interiors of natural enzymes can be incorporated into synthetic systems having useful physical and chemical properties. Copyright

Full text of DOI:10.1021/ja801107r

Published on Web 04/08/2008
Organocatalysis In a Synthetic Receptor with an Inwardly
Directed Carboxylic Acid
Siddhartha R. Shenoy, Fernando R. Pinacho Criso´stomo, Tetsuo Iwasawa, and
Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received February 13, 2008; E-mail: jrebek@scripps.edu
The intramolecular ring-opening reaction of epoxides con-
tinues to raise issues in physical organic and bioorganic
chemistry. Early studies of this reaction were used to define
the stereoelectronic effects governing cyclization processes.1–4
Current efforts are revealing the effects of solvation on this
reaction in solution5–7 and in the hydrophobic interiors of
enzymes.8–11 Of specific interest are the factors directing the
course of the reaction to afford either five- or six-membered
ring products (Figure 1). We report here the epoxide ring-
opening cyclization reaction of epoxyalcohols within the
structured environment of a cavitand. The results from our study
highlight the special reactivity provided by cage structures12–16
bearing functional groups on their concave surfaces.17–20
Figure 1. The 5-exo versus 6-endo modes of cyclization for epoxide ring-
opening reactions.
Cavitand 1 is a deep, open-ended receptor built up from a
resorcinarene scaffold18,21,22 and functionalized with a Kemp’s
triacid derivative (Figure 2).23 The cavitand can fold around suitable
guest molecules, isolate them from the bulk solution, and present
them with an inwardly directed carboxylic acid. This vase-like
conformation is stabilized by a seam of hydrogen bonds conferred
by a cyclic array of secondary amides around the rim of the
receptor. These amides make up a polar region in the receptor and,
together with the inwardly directed acid, can participate in
host-guest hydrogen bonding interactions. Likewise, the receptor’s
eight aromatic walls may be regarded as immobilized benzenes
that offer an electron-rich π-surface to bound substrates. Taken
together, these features provide bound guests with a unique
solvation and an arrangement of organic functionality that are
otherwise unavailable in solution. In this study, we investigated
the reaction of 1,5-epoxyalcohols 3-5 in the synthetic receptor 1
and in solution using model acid 2 (Figure 3).
Figure 2. Cavitand 1 represented in its folded vase-like conformation (left)
and as its detailed Lewis structure (right).
Upon adding epoxyalcohol 3 to a solution of 1 in mesitylene-
d12, we observed immediate host-guest complexation as indicated
by the characteristic signals in the upfield region of the 1H NMR
spectrum (Figure 4a).24 The conversion of epoxide 3 into ether 6
was monitored by the disappearance of the starting material
resonances at 2.43 ppm and the appearance of product resonances
at 3.52 ppm (in bulk solution). The five-membered ring (THF)
ether 6 was the exclusiVe product of the reaction. In contrast, the
solution-phase reaction of epoxyalcohol 3 with camphorsulfonic
acid afforded an 87:13 ratio of the THF to tetrahydropyran (THP)
products.25 The synthetic receptor 1 provided a >50-fold rate
acceleration over the reaction using acid 2 as the comparator
(t1/2cavitand1 ) 7.2 h, t1/2acid2 ) 16 days).26
Figure 3. Model acid 2 and the 1,5-epoxyalcohols 3-5 used in this study.
the model acid 2 (t1/2cavitand1 ) 8.9 h, t1/2acid2 ) 114 days). The
upfield chemical shifts of the guest resonances in the complexes
of 4 and 1 were not as pronounced as those in the case of
epoxyalcohol 3 (Figure 4a).25 This indicated that the guest was
not bound as deeply within the receptor or was not positioned
as close to its aromatic walls.28
Regiocontrol over the cyclization reaction was restored in the
case of alcohol 5. Cavitand 1 catalyzed the formation of the THF
product 8 as the exclusive product.29 In this case, the epoxyalcohol
5 was closely associated with the aromatic walls of the receptor 1
as indicated by the large upfield shift of guest resonances in the
1H NMR spectrum (Figure 3c).28 Moreover, the 5-exo-tet cycliza-
tion of epoxide 5 inside cavitand 1 corresponded to >100-fold rate
Cavitand 1 also catalyzed the cyclization reaction of alcohol
4. In this case, the reaction provided a 1:1 mixture of THF and
THP products (7a and 7b, Figure 4b).27 Although no regiose-
lectivity was observed in this reaction, the cavitand provided a
>300-fold rate acceleration over the analogous reaction using
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5658 J. AM. CHEM. SOC. 2008, 130, 5658–5659
10.1021/ja801107r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
directed carboxylic acid functionality initiates the cyclization
of these substrates to afford the five- and six-membered ring
products 6-8. This synthetic system incorporates the arrange-
ment of functionality and the unique solvation provided within
the structured interiors of natural enzymes. In contrast to flexible
receptors for selective recognition,34 these cavitands catalyze
the regiocontrolled transformation of epoxyalcohols into cyclic
ethers. A full account of the kinetic and mechanistic studies of
this system will be reported in due course.
Acknowledgment. We are grateful to the Skaggs Institute
for Research, and the National Institutes of Health (GM 27932)
for financial support. S.R.S. thanks the San Diego Foundation
Blasker Science and Technology Fellowship for financial
support. S.R.S. and F.P.C. thank Prof. Dr. Yoshiki Morimoto
for helpful correspondence on structural determinations, and Dr.
Laura B. Pasternack for assistance with NMR spectroscopy.
Supporting Information Available: Detailed experimental
procedures and kinetic study data. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
(2) Baldwin, J. E.; Reiss, J. A. J. Chem. Soc., Chem. Commun. 1977, 77.
(3) Stork, G.; Cama, L. D.; Coulson, D. R. J. Am. Chem. Soc. 1974, 96, 5268–
5270.
(4) Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270–5272.
(5) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189–1192.
(6) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873–8874.
(7) Fish, P. V.; Sudhakar, A. R.; Johnson, W. S. Tetrahedron Lett. 1993, 34,
7849–7852.
1
Figure 4. Sections of the H NMR spectra of the reactions of alcohols 3
(a), 4 (b), and 5 (c) inside introverted acid cavitand 1. Regions of the spectra
corresponding to the starting epoxides are marked with blue squares. Regions
of the spectra corresponding to the product ethers are marked with either
red circles and/or green diamonds.
(8) de la Torre, M. C.; Sierra, M. A. Angew. Chem., Int. Ed. 2004, 43, 160–181.
(9) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int.
Ed. 2000, 39, 2812–2833.
(10) Cane, D. E.; Celmer, W. D.; Westley, J. W. J. Am. Chem. Soc. 1983, 105,
3594–3600.
enhancement over the control reaction with using model acid 2
(t1/2cavitand1 ) 5.3 h, t1/2acid2 ) 27 days).
(11) Nakanishi, K. Toxicon 1985, 23, 473–479.
(12) Nishioka, Y.; Yamaguchi, T.; Yoshizawa, M.; Fujita, M. J. Am. Chem.
Soc. 2007, 129, 7000–7001.
Several factors may be responsible for the rate enhancement
observed in this system. First, molecular recognition is involved
(as it is in any bimolecular reaction), but the substrate is more
or less surrounded by the catalyst of finite capacity. Second,
complexation exposes the epoxyalcohol substrates to a high local
concentration of a Brønsted acid.18 Third, CH-π contacts
between the concave π-surface of the host and the alkyl
backbone of the guest induce the coiling of the substrate inside
the cavitand.30–32 Such coiling brings the reactive centers of
the epoxyalcohols in close proximity, folding the substrates into
conformations resembling the transition-state structures of the
cyclization reactions.
(13) (a) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc.
2007, 129, 11459–11467. (b) Grotzfeld, R. M.; Branda, N.; Rebek, J., Jr.
Science 1996, 271, 487–489. (c) Brody, M.; Schalley, C. A.; Rudkevich,
D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed. 1999, 38, 1640–1644.
(14) Makeiff, D. A.; Vishnumurthy, K.; Sherman, J. C. J. Am. Chem. Soc. 2003,
125, 9558–9559.
(15) Natarajan, A.; Kaanumalle, L. S.; Jockusch, S.; Gibb, C. L. D.; Gibb, B. C.;
Turro, N. J.; Ramamurthy, V. J. Am. Chem. Soc. 2007, 129, 4132–4133.
(16) (a) Chen, J.; Rebek, J., Jr. Org. Lett. 2002, 4, 327–329. (b) Shivanyuk, A.;
Rebek, J., Jr. Chem. Commun. 2001, 2374–2375.
(17) Hooley, R. J.; Iwasawa, T.; Rebek, J., Jr. J. Am. Chem. Soc. 2007, 129,
15330–15339.
(18) Purse, B. W.; Ballester, P.; Rebek, J., Jr. J. Am. Chem. Soc. 2003, 125,
14682–14683.
(19) Butterfield, S.; M.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 15366–15367.
(20) Lutter, H.-D.; Diederich, F. Angew. Chem., Int. Ed. Engl. 1986, 25, 1125–
1127.
The coiling of substrates inside the cavitand can also explain
the regioselectivity observed in this reaction.30–32 The aromatic
walls of cavitand 1 form multiple CH-π contacts with the geminal
methyl groups at the alcohol terminus of substrates 3 and 5. These
interactions are believed to impose strong conformational control
over these acyclic epoxyalcohols. Such binding limits the confor-
mational flexibility of these guests within the cavitand and directs
the reactions to proceed via the compressed five-membered-ring
transition-state structures leading to THF products. Primary alcohol
4 garners fewer CH-π contacts33 with the aromatic walls of the
receptor and is consequently less conformationally constrained. For
this reason, the acyclic alcohol 4 enjoys greater flexibility within
the cavitand and undergoes reaction through both the compressed
five-membered ring and the more extended six-membered ring
transition-state structures leading to both THF and THP products
7a and 7b.
(21) Hoegberg, A. G. S. J. Am. Chem. Soc. 1980, 102, 6046–6050.
(22) Renslo, A. R.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2000, 39, 3281–3283.
(23) Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140–5143.
(24) Rudkevich, D.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998,
120, 12216–12225.
(25) Morimoto, Y.; Nishikawa, Y.; Ueba, C.; Tanaka, T. Angew. Chem., Int.
Ed. 2006, 45, 810–812.
(26) The reaction of epoxyalcohol 3 with acid 2 provided an 87:13 ratio of
THF:THP products.
(27) The reaction of epoxyalcohol 4 with camphorsulfonic acid and acid 2
provided a 30:70 ratio of THF:THP products 7a and 7b.
(28) Ajami, D.; Iwasawa, T.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8934–8936.
(29) The reaction of epoxyalcohol 5 with camphorsulfonic acid or acid 2
provided a 60:40 ratio of THF:THP products.
(30) Purse, B. W.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 2530–-
2534.
(31) Scarso, A.; Trembleau, L.; Rebek, J., Jr. J. Am. Chem. Soc. 2004, 126,
13512–13518.
(32) Trembleau, L.; Rebek, J., Jr. Science 2003, 301, 1219–1221.
(33) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003,
42, 1210–1250.
(34) Gala´n, A.; de Mendoza, J.; Toiron, C.; Bruix, M.; Deslongchamps, G.;
Rebek, J., Jr. J. Am. Chem. Soc. 1991, 113, 9424–9425.
In conclusion, the synthetic receptor 1 binds and controls the
conformation of 1,5-epoxyalcohol substrates 3-5. The inwardly
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