Cavitand templated catalysis of acetylcholine

Article abstract of DOI:10.1039/b515558d

A Zn-salen-modified cavitand templates the catalytic formation of acetylcholine from choline and acetic anhydride. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b515558d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Cavitand templated catalysis of acetylcholine{
Felix H. Zelder and Julius Rebek, Jr.*
Received (in Colombia, MO, USA) 4th November 2005, Accepted 17th November 2005
First published as an Advance Article on the web 11th January 2006
DOI: 10.1039/b515558d
derivatives3,4,5b and Zn complexes catalyze the acylation of
A Zn–salen-modified cavitand templates the catalytic formation
of acetylcholine from choline and acetic anhydride.
alcohols,1e,2 it was expected that Zn–1 may template the catalytic
formation of ACh from Ch and acetic anhydride (4) (Scheme 1,
left). Herein, we report the esterification of Ch with anhydrides in
the presence of Zn–1.
The catalytic esterification of alcohols by enzymes or chemocata-
lysts plays a key role in biological systems, organic synthesis and
industry. Despite the long history of this reaction, progress in the
kinetic resolution of racemic alcohols with chiral, non-enzymatic
acylation catalysts has only recently attracted attention.1
Moreover, little is known about substrate-selective acylation
involving alcohols differing in size and shape.2
An energy-minimized structure of the host–guest complex
ACh@Zn–1 indicates that binding through cation–p-interactions
and Zn2+–carbonyl coordination can take place simultaneously
(Scheme 1, right). To ensure the solubility of all components and
enable weak binding for the desired catalytic turnover, the
acylation of choline was carried out in DMSO-d6 and monitored
Cavitands derived from resorcinarenes are supramolecular hosts
that selectively bind suitable guests.3 Specifically, guests bearing a
trimethylammonium ‘‘knob’’ are well positioned deep within the
cavity. Recently, we demonstrated how the Zn–salen monofunc-
tionalised complex cavitand Zn–1 (Fig. 1) can accelerate the
hydrolysis of the bound guest para-nitro phenyl choline carbonate
(PNPCC).4 Other examples of catalyst-modified calixarenes or
cavitands have been applied in this context, but all of these
examples report the catalytic cleavage of activated choline
derivatives.4,5
1
by H-NMR spectroscopy (Table 1).
In the absence of catalyst, the acylation with 4 is very slow
(Table 1, entry 1), whereas the reaction is significantly accelerated
in the presence of Zn–1 (Table 1, entries 2–5).{
In the presence of 0.4 mol% of Zn–1, the acylation is accelerated
320 times, and when 2 mol% of Zn–1 is added, the reaction takes
place 1900 times faster than the background reaction (Table 1,
entries 2 and 5). Compared to the reaction catalyzed by Zn–1
(Table 1, entry 5), the reaction is up to 23 times slower when the
metal complex Zn–2 is not covalently attached to the cavitand 3
(Table 1, entry 10) or used without any additional binding pocket
(Table 1, entry 6).
Acetylcholine (ACh) is a neurotransmitter generated from
choline (Ch) and acetyl coenzyme A. Since cavitands bind choline
No reaction is observed with 3 alone (Table 1, entry 9). It is
puzzling that a catalytic amount of the non-functionalized
cavitand 3 slows down the reaction (Table 1, entry 9 vs. 1), and
we observed this effect in almost all other control experiments
(Table 1, entries 10, 14 and 15).
When the bulkier TCh is used as a substrate, the Zn–1-catalyzed
acylation is 6 times slower (Table 1, entry 8), whereas almost no
Fig. 1 Compounds used in the esterification reactions.
The Skaggs Institute for Chemical Biology and The Department of
Chemistry, The Scripps Research Institute, MB-26, 10550 North Torrey
Pines Road, La Jolla, California, 92037, USA.
E-mail: jrebek@scripps.edu; Fax: (+1) 858-784-2876;
Tel: (+1) 858-784-2250
{ Electronic Supplementary Information (ESI) available: Correlation of
kob vs. Zn–1; representative 1H-NMR spectra; experimental details,
binding of Ch@Zn–1 and ACh@Zn–1; preparation of the chloride salt
of TCh. See DOI: 10.1039/b515558d
Scheme 1 Left: Catalytic formation of ACh from Ch and 4, triggered by
Zn–1. Right: Energy-minimized structure (CaChe 4.9E) of the complex
between Zn–1 (stick) and ACh (CPK); the front wall and the hydrogens
have been omitted for clarity.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 753–754 | 753

View Article Online
entries 12–15; Fig. 1). Sterically more demanding anhydrides
experienced slower kinetics during the course of the reaction. The
relative reactivity of anhydrides 4–6, tested in the Zn–1-catalyzed
acylation of Ch, were as follows: 4 : 6 : 5 = 15 : 2 : 1.{
In summary, metal complex-modified cavitands are supramo-
lecular catalysts for the synthesis of biologically-relevant ACh from
Ch and 4. Their ability to discriminate and accelerate the
esterification of choline has been demonstrated. Additionally, the
activity and selectivity of the metal catalyst is unequivocally
enhanced when the metal complex is well positioned at the
periphery of the binding pocket.
Table 1 Acetylation of choline Ch and triethylcholine TCh in the
presence of acetic anhydridea
Catalyst
Entry (Quantity)/mol% Substrate kob/6 1024 min21 kob/kuncat
b
1
2
3
4
5
6
7
8
9
—
Ch
Ch
Ch
Ch
Ch
Ch
TCh
TCh
Ch
0.1
32
46
72
190
14
11
32
1
Zn–1 (0.4)
Zn–1 (0.6)
Zn–1 (1.0)
Zn–1 (2.0)
Zn–2 (2.0)
Zn–2 (2.0)
Zn–1 (2.0)
3 (2.0)
320
460
720
1900
140
110
320
—
—
We are grateful to the Skaggs Foundation and the National
Institute of Health (GM 27932) for financial support, to Dr. Laura
B. Pasternack for advice with the 1H-NMR experiments, and
Sebastien Richeter for a sample of Zn–1. We thank the DFG for a
postdoctoral fellowship to F. H. Z.
10
11
12
13
14
15
a
Zn–2/3 (2.0)
Zn–2/3 (2.0)
DMAP (2.0)
DMAP (2.0)
DMAP/3 (2.0)
DMAP/3 (2.0)
Ch
TCh
Ch
TCh
Ch
TCh
8
11
180
200
140
170
80
110
1800
2000
1400
1700
Conditions: Ch, TCh (50 mM), 4 (50 mM); DMSO-d6, 25 ¡ 2 uC.
Detection method: Error limit: 20%.
1H-NMR.
rate
rate(entry 1)
Notes and references
b
kob
~
; kuncat~
{ As an undesired side reaction, hydrolysis of the anhydride occurred from
residual water (6–11% after ca. 100 min).
½Chꢀ
½Chꢀ
§ The signals of the host are strongly broadened by dynamic effects,
probably involving exchange equilibration with the alternative ‘‘kite’’
conformation. Therefore, the binding constant was calculated only from
the trimethylammonium ‘‘knob’’ signals of the guests (Dd = 3.6 ppm). This
precludes the accurate determination of the binding constant.
1 (a) E. Vedejs and X. Chen, J. Am. Chem. Soc., 1996, 118, 1809–1810; (b)
E. Vedejs, O. Daugulis, J. A. MacKay and E. Rozners, Synlett, 2001,
1499–1505; (c) J. C. Ruble, J. Tweddell and G. C. Fu, J. Org. Chem.,
1998, 63, 2794–2795; (d) J. C. Ruble, H. A. Latham and G. C. Fu, J. Am.
Chem. Soc., 1997, 119, 1492–1493; (e) B. M. Trost and T. Mito, J. Am.
Chem. Soc., 2003, 125, 2410–2411.
Fig. 2 Selectivity (S) of the acylation of Ch vs. TCh (kob(Ch)/kob(TCh)).
2 (a) N. C. Gianneschi, S. T. Nguyen and C. A. Mirkin, J. Am. Chem. Soc.,
2005, 127, 1644–1645; (b) L. G. Mackay, R. S. Wylie and J. K.
M. Sanders, J. Am. Chem. Soc., 1994, 116, 3141–3142.
3 (a) D. J. Cram, Science, 1983, 219, 1177–1183; (b) E. Dalcanale,
P. Soncini, G. Bacchilega and F. Ugozzoli, J. Chem. Soc., Chem.
Commun., 1989, 500–502; (c) P. Soncini, S. Bonsignore, E. Dalcanale and
F. Ugozzoli, J. Org. Chem., 1992, 57, 4608–4612; (d) J. L. Atwood and
A. Szumna, J. Am. Chem. Soc., 2002, 124, 10646–10647; (e) P. Ballester,
A. Shivanyuk, A. R. Far and J. Rebek, Jr., J. Am. Chem. Soc., 2002, 124,
14014–14016.
4 S. Richeter and J. Rebek, Jr., J. Am. Chem. Soc., 2004, 126,
16280–16281.
5 (a) F. Cuevas, S. Di Stefano, J. O. Magrans, P. Prados, L. Mandolini and
J. de Mendoza, Chem.–Eur. J., 2000, 6, 3228–3234; (b) A. Gissot and
J. Rebek, Jr., J. Am. Chem. Soc., 2004, 126, 7424–7425.
selectivity (S) (kob(Ch)/kob(TCh)) is observed with the metal complex
Zn–2 (Table 1, entries 6 and 7; Fig. 2).
We assume that weak binding of Ch and ACh within Zn–1 (Ka =
10 and 20 M21, respectively){§ is responsible, since product
inhibition has not been observed.{ In contrast to Ch, the bulkier
TCh showed no inclusion within the cavity.
The Zn–1-templated acylation of Ch with 4 is in the range of the
same reaction catalyzed by dimethylaminopyridine (DMAP), one
of the best organic acylation catalysts. DMAP, or the combination
of DMAP with cavitand 3, showed, as expected, no selectivity
between the electronically equivalent guests Ch and TCh (Table 1,
754 | Chem. Commun., 2006, 753–754
This journal is ß The Royal Society of Chemistry 2006