Intramolecular hydroalkoxylation catalyzed inside a self-assembled cavity of an enzyme-like host structure

Article abstract of DOI:10.1039/c4cc08211g

Self-assembled resorcin[4]arene hexamer catalyzes the intramolecular hydroalkoxylation of unsaturated alcohols to the corresponding cyclic ethers under mild conditions. The mode of catalysis and encapsulation-based substrate selectivity of the host efficiently mimic the basic principle of operation observed in enzymes.

Full text of DOI:10.1039/c4cc08211g

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Intramolecular hydroalkoxylation catalyzed inside
a self-assembled cavity of an enzyme-like host
structure†
Cite this:DOI: 10.1039/c4cc08211g
Received 16th October 2014,
Accepted 20th November 2014
L. Catti and K. Tiefenbacher*
DOI: 10.1039/c4cc08211g
www.rsc.org/chemcomm
Self-assembled resorcin[4]arene hexamer catalyzes the intramolecular
hydroalkoxylation of unsaturated alcohols to the corresponding cyclic
ethers under mild conditions. The mode of catalysis and encapsulation-
based substrate selectivity of the host efficiently mimic the basic
principle of operation observed in enzymes.
Supramolecular catalysis aims to mimic the functions of enzymes
without copying the complexity of their evolutionarily derived
three-dimensional structure. Key features of enzyme catalysis
comprise the selection of suitable substrates inside a hydrophobic
reaction pocket, the altering of substrate orientation and/or
conformation and the stabilization of the transition state of the
reaction.1 In the last two decades, research in the field of
supramolecular chemistry has led to the preparation of a variety
of self-assembled hosts bearing an internal cavity, which provides
a defined chemical environment distinct from the bulk solvent.1,2
Application of a subset of noncovalently self-assembled structures
to catalysis was successfully investigated by several groups.1,2d, f,3
However, the use of hydrogen bond-based assemblies in catalysis
is limited to only five examples reported in literature.3f,4
Fig. 1 (a) Structure of resorcin[4]arene 1; (b) schematic representation of
the hexameric resorcin[4]arene capsule I, emphasizing the octahedral
cavity space (blue); alkyl groups have been omitted for clarity; (c) compe-
titive inhibitor tetrabutylammonium bromide (Bu4NBr) (2).
The resorcin[4]arene hexamer I (Fig. 1) represents one of the charged compounds like quaternary ammonium ions (e.g. 2) display
largest hydrogen bond-based self-assembled hosts and has been a high affinity for the capsule interior.9 Other suitable guests like
studied intensively due to its ready accessibility.5 It spontaneously alcohols and carboxylic acids rely on their ability to form hydrogen
forms in apolar solvents like chloroform and benzene from six bonds with the hexameric host and, depending on their size, are
resorcin[4]arene units 1, which are easily prepared in multigram coencapsulated with residual solvent molecules.7,10 Besides the
scale in a single step. In addition to the six monomer units, eight capability of reversible guest encapsulation, the resorcin[4]arene
water molecules participate in the formation of the hexamer,6 hexamer acts as relatively strong phenol-based Brønsted acid
which explains the excessive use of water-saturated solvents in (pKa E 5.5–6), as recently reported by our group,3f making it an
resorcin[4]arene chemistry.2a,7 The capsule-like structure, held appropriate choice for the study of enzyme-like acid catalysis.
together by 60 hydrogen bonds, forms an octahedral-shaped cavity
Being aware of the good uptake of certain alcohol molecules,10b
of about 1375 Å3.5a In chloroform solution, this cavity is occupied we set out to explore the potential use of I as an acid catalyst in the
by six solvent molecules in the absence of suitable guests.8 Due to intramolecular hydroalkoxylation of unactivated hydroxy olefins.
extended cation–p interactions with the aromatic cavity, positive Intramolecular hydroalkoxylation offers a direct, atom-economical
access to cyclic ethers, which represent important core structures
frequently found in polyether antibiotics, marine macrocycles and
¨
¨
Department Chemie, Technische Universitat Munchen, Lichtenbergstraße 4,
flavor compounds.11 Although the cationic intramolecular hydro-
alkoxylation of unsaturated alcohols has been reported to be
catalyzed by strong Brønsted acids like triflic acid (TfOH),12
D-85747 Garching, Germany. E-mail: konrad.tiefenbacher@tum.de
† Electronic supplementary information (ESI) available: Experimental details,
characterization data and NMR spectra. See DOI: 10.1039/c4cc08211g
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poor functional group compatibility, acid induced side reactions in the region of 0.5 to À0.6 ppm in the H NMR spectrum of the
and the overall harsh reaction conditions limit the scope of these reaction mixture, caused by the anisotropy of the capsule walls,
protocols. The application of weaker acids on the other hand often indicated encapsulation of substrate 3a. Reaction monitoring via
requires the use of over-stoichiometric amounts.13 Alternative NMR spectroscopy and GC and finally isolation confirmed selective
catalytic approaches include the utilization of Lewis super-acids conversion to cyclic ether 4a. A subsequent optimization of the
like Al(OTf)3 and Ca(NTf2)2,15 transition metals,16 zeolites17 reaction conditions revealed the influence of water content and
14
and Amberlyst H-15.18 In the context of supramolecular catalysis, substrate concentration on the reaction rate. Reducing the water
Bergman, Raymond and Toste investigated the intramolecular content of the reaction mixture from 30 equiv. to 11 equiv. of water
1
hydroalkoxylation of activated hydroxy olefins inside a supra- per hexamer I (determined via H NMR spectroscopy) by utilizing
molecular host using an encapsulated gold catalyst.19
regular CDCl3 instead of water-saturated CDCl3 resulted in a signifi-
We began our investigation by adding 10 equiv. of hydroxy cant increase in the reaction rate. It seems likely that the water
olefin 3a (Table 1) to a solution of I (1 equiv.) in water-saturated molecules compete with the substrate for the protons of the catalyst.
CDCl3 (3.3 mM). The appearance of new upfield-shifted signals High substrate concentration on the other hand lead to a drastic
decrease of the reaction rate, since the hydroxyl group of the substrate
can interact with the monomer units and thereby reduce the
Table 1 Intramolecular hydroalkoxylation of unactivated hydroxy olefinsa
equilibrium concentration of operational catalyst.9 Applying the
Background Yieldb (%)
conv.b (%) (Time (d))
optimized conditions, full conversion of substrate 3a was achieved
after about 3.5 d at 30 1C. In a control experiment, a small excess of
the high affinity guest Bu4NBr (2) (1.5 equiv.) was added to the
catalyst solution prior to substrate addition. When catalyst I was
blocked in this manner, the hydroalkoxylation of alcohol 3a was
efficiently slowed down, giving only a weak background conversion of
7%. A second control experiment without added catalyst was per-
formed to rule out a background reaction catalyzed by trace amounts
of HCl/DCl, potentially formed by photodegradation of CDCl3. In this
case, no detectable conversion was observed after 7 d. These results
demonstrated that a catalytic conversion is indeed possible with I and
that the reaction takes place inside the cavity after initial protonation
of the substrate. The observed catalytic effect imparted by hexamer I
is believed to result from the stabilization of cationic intermediates
and transitions states by cation–p interactions with the aromatic
cavity. The catalytic cycle is finally completed by release of the cyclic
ether, which does not bind strongly to the cavity.
In order to evaluate the scope of the hexamer I-catalyzed
intramolecular hydroalkoxylation, we next investigated the formation
of differently substituted tetrahydropyran and oxepane derivatives as
summarized in Table 1. In general, the reactions proceeded to
completion in 0.7 to 6 d at 30 1C using a 10 mol% catalyst loading.
Conversion of g,d-unsaturated monoalcohols gave the corresponding
tetrahydropyran derivatives in good yields (Table 1, entries 1–4).
When employing substrates bearing two hydroxyl groups, full con-
version was achieved within 16 h, owing to the high affinity of diols to
the capsule interior (Table 1, entries 5 and 6). In the case of substrate
3g, a reduced yield was obtained, presumably due to an oligomeriza-
tion side reaction, as implied by broad signals in the 1H NMR
spectrum. Meanwhile, the formation of oxepane 4h proceeded in
good yield. However, when a terminal olefin was used, the reaction
proceeded much slower with GC indicating intermediary formation
of the corresponding trisubstituted and hydrated olefin (Table 1,
entry 9). The spirobicyclic ether 4j was obtained in 63%. The reduced
yield is based on an equilibrium between starting material and
cyclization product, as proven by subjecting the isolated ether to
standard reaction conditions. All performed hydroalkoxylations
occurred with Markovnikov selectivity. Furthermore, all substrates
were tested with Bu4NBr (2)-inhibited catalyst, giving only a weak
background reaction in each case (Table 1). Catalyst I was also
Entry
1
Substrate
Product
96c
(3.5)
7c
98
(1.5)
2
3
4
5
8
91
(1.8)
3
84
(3.4)
8
88
(0.7)
6
93
(0.7)
6
7
8
45
(5.5)
6
94
(1.9)
8
9
4
91
(5.0)
10
63
(5.0)
10
4
a
Reaction conditions: hydroxy olefin (33 mM), catalyst I (3.3 mM),
b
c
CDCl3, 30 1C, 0.7–6 d. Determined via 1H NMR. Determined via GC
(response factor-corrected).
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Furthermore, we thank Dr Thomas Magauer and MSc Klaus
Speck for help with HRMS measurements.
Notes and references
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This project was supported by the ‘‘Bayerische Akademie der
Wissenschaften’’ (Junges Kolleg), ‘‘Fonds der Chemischen 19 Z. J. Wang, C. J. Brown, R. G. Bergman, K. N. Raymond and
F. D. Toste, J. Am. Chem. Soc., 2011, 133, 7358–7360.
20 E. Raamat, K. Kaupmees, G. Ovsjannikov, A. Trummal, A. Ku¨tt,
Industrie’’ (Sachkostenzuschuss), the TUM Junior Fellow Fund
and the ‘‘Dr-Ing. Leonhard-Lorenz-Stiftung’’. The help of MSc
J. Saame, I. Koppel, I. Kaljurand, L. Lipping, T. Rodima, V. Pihl,
Johannes Richers with graphical design is greatly acknowledged.
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