Permeable Self-Assembled Molecular Containers for Catalyst Isolation Enabling Two-Step Cascade Reactions

Article abstract of DOI:10.1021/jacs.7b02745

Establishment of a general one-pot cascade reaction protocol would dramatically reduce the effort of multistep organic synthesis. We demonstrate that the unique structure of M₁₂L₂₄ self-assembled complexes gives them the potential to serve as catalyst carriers for enabling continuous chemical transformations. A stereoselective cascade reaction (allylic oxidation followed by Diels-Alder cyclization) with two intrinsically incompatible catalysts was demonstrated. Our system is advantageous in terms of availability, scalability, and predictability.

Full text of DOI:10.1021/jacs.7b02745

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Communication
Permeable Self-assembled Molecular Containers for
Catalyst Isolation Enabling Two-Step Cascade Reactions
Yoshihiro Ueda, Hiroaki Ito, Daishi Fujita, and Makoto Fujita
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b02745 • Publication Date (Web): 12 Apr 2017
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Permeable Self-assembled Molecular Containers for Catalyst Isola-
tion Enabling Two-Step Cascade Reactions
Yoshihiro Ueda, Hiroaki Ito, Daishi Fujita, Makoto Fujita*
Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, 7ꢀ3ꢀ1 Hongo, Bunkyoꢀku,
Tokyo 113ꢀ8656, Japan
Supporting Information Placeholder
TEMPO for an oxidation reaction and MacMillan's cataꢀ
lyst for DielsꢀAlder (DA) chemistry. Without an approꢀ
priate carrier, the DA catalyst is promptly oxidized by
TEMPO, rendering each incompatible with the other. By
encapsulating each of them separately within the cavity
of an M12L24ꢀtype molecular capsule, the anticipated
cascade reaction proceeded smoothly, while the asymꢀ
metric catalyst retained its stereoꢀselectivity, an attribute
of the mechanism which was highly reproducible.
ABSTRACT: Establishment of a general oneꢀpot cascade
reaction protocol would dramatically reduce the effort of
multiꢀstep organic synthesis. We demonstrate that the
unique structure of M12L24 selfꢀassembled complexes
have a potential to serve as catalyst carriers for enabling
continuous chemical transformations. A stereoꢀselective
cascade reaction (allylic oxidation followed by Dielsꢀ
Alder cyclization) with two intrinsically incompatible
catalysts was demonstrated. Our system is advantageous
in terms of availability, scalability and predictability.
The M12L24 molecular capsule 2 is a palladium metal
complex quantitatively selfꢀassembled from 12 Pd(II)
ions (M) and 24 bent, ditopic ligands (1).186 This sphereꢀ
like structure possesses a rigid framework both with a
cavity large enough to house tens of catalytic centers,
and many apertures that are permeable to small molecule
substrates. As the capsule formation is based on a highꢀ
yielding selfꢀassembly mechanism, we anticipated that
encapsulation of the catalysts could be achieved by
simply covalently preꢀlinking the catalyst of interest to
Ideally, future laboratory organic synthesis should be a
simple oneꢀpot/oneꢀstep procedure.1,2 However, almost
all synthetic strategies today require a sequence of mulꢀ
tiple and stepwise chemical transformations. A methodꢀ
ology that enables continuous chemical transformation
in a manner reminiscent of biology’s metabolic systems
is one promising approach towards achieving this
goal.3,4 One important concept deeply related to mimꢀ
icking metabolism is catalytic site isolation.5 Enzymes
naturally possess this attribute by having the active cataꢀ
lytic site sterically isolated inside the proteins themꢀ
selves. There have been several developments in the
techniques required for synthetic siteꢀisolation of cataꢀ
lysts, which include the employment of semipermeable
films,6 multiꢀphase systems,7-11 soluble polyꢀ
mers/dendrimers12-,1513 and supramolecular164 architecꢀ
tures acting as the catalyst carrier. Although these techꢀ
niques were successfully applied, only limited transforꢀ
mations were reported and special instruments or elaboꢀ
rate procedures were necessary. Also, siteꢀisolated cataꢀ
lysts often show decreased reactivity and selectivity
compared to their nonꢀisolated counterparts as a result of
the difference in microenvironments surrounding the
catalysts.175
ligand
1.
Figure 1. Siteꢀisolation strategy for a new cascade reacꢀ
tion. TEMPO and MacMillan’s catalyst isolated in selfꢀ
assembled M12L24 spherical complexes work independently
and sideꢀbyꢀside, whereas they are incompatible when free
in solution.
Here, we report a stereoꢀcontrolled cascade reaction
exploiting the unique structure of a selfꢀassembled moꢀ
lecular capsule as the catalyst carrier for siteꢀisolation.
The two different catalysts employed in the synthesis are
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Figure 2. Oxidationꢀsphere 2a and DielsꢀAlderꢀsphere 2b. (a–c) NMR spectra measured at 300 K in CD3NO2 (a) 1H NMR of
ligand 1b; (b) H NMR of sphere 2b; (c) H DOSY NMR of sphere 2b. (d, e) CSIꢀMS spectra with assignment of the obꢀ
served species: (d) sphere 2a (e) sphere 2b.
1
1
In the past, this strategy has worked to afford a variety
of capsules with different functional groups197,2018 and
catalysts.2119,220 Also, the M12L24 complexes once
formed are remarkably stable in solution and ligand
exchange occurs only very slowly over weeks or
months.231 Thus, we envisaged at the outset that two
different M12L24 complexes should maintain their sepaꢀ
rate catalytic identities, preventing any mutual inhibiꢀ
tion of their functions brought about direct contact.
tween the pyridyl groups and PdII ions. The signal
broadening is indicative of the formation of a huge
molecular structure that tumbles slowly on the NMR
time scale (Figure 2a and 2b). Diffusionꢀordered NMR
spectroscopy (DOSY) also supported the quantitative
formation
of
a
large
structure
by
In order to demonstrate this strategy of catalytic siteꢀ
isolation, we chose a widely used oxidation catalyst,
TEMPO,242 and the chiral MacMillan’s catalyst, which
promotes various carbonylꢀrelated stereoꢀselective
chemical transformations.253,264 These catalysts are
typically incompatible in a twoꢀstep oneꢀpot synthesis,
because the oxoammonium species generated from
TEMPO oxidizes the free amines of MacMillan’s cataꢀ
lyst, rendering it inactive.275 To solve this problem, we
hypothesized that the poisoning of MacMillan’s cataꢀ
lyst by TEMPO could be prevented by isolating each
separately in the selfꢀassembled molecular cages, afꢀ
fording a novel oxidation and asymmetric DA286 casꢀ
cade reaction in the same solution.
Ligands tethered with TEMPO (1a) and MacMillan’s
catalyst (1b) were readily synthesized (see Supporting
Information). Each ligand was then selfꢀassembled
individually to M12L24 complex 2a and 2b, respectively
on treatment with [Pd(CH3CN)4](BF4)2 in CD3NO2
(room temperature for 30 min). We used NMR specꢀ
troscopy to monitor the formation of the M12L24 comꢀ
plexes, structures of which were then confirmed by
mass spectrometry. In the 1H NMR spectrum of 2b,
notable downfield shifts of the pyridine protons, parꢀ
ticularly the α proton (ꢁδ = 0.53 ppm), were observed.
The shifts are a result of the coordination bond beꢀ
Figure 3. Oxidation reaction profile catalyzed by sphere
2a. (a) oxidation reaction of 6 in the presence of 2a
(10/24 mol%) and PhI(OAc)2 (1.2 eq.) in CD3NO2 at
room temperature. (b) molecular modeling of sphere 2a.
c–e 1H NMR spectra measured at 300K in CD3NO2: (c)
ligand 1a; (d) sphere 2a; (e) reaction solution after 2 h.
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Table 1. Site-isolation effects on yields for catalysts encapsulated within M12L24 spherical complexes.
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the observation of a single band at logD = –10.20 (Figꢀ
ure 2c). In contrast, no significant 1H NMR signal was
detected for 2a due to the paramagnetic shifts derived
from the nitroxyl radical (Figure 3c and 3d).
Nevertheless, coldꢀspray ionization mass spectrometry
(CSIꢀMS)297 provided evidence for the formation of 2a
as well as 2b. The formation of 2a was successfully
confirmed by detection of prominent peaks for [M –
x(BF4)]x+ (x = 11ꢀ15) (Figure 2d). The highꢀresolution
mass spectra allowed the determination of the molecuꢀ
lar weight of 2a (15556.28 Da). The elemental compoꢀ
sition of sphere 2b was also determined (Figure 2e).
mol% based on TEMPO) and 1.2 equivalent of
PhI(OAc)2 as a coꢀoxidant, the oxidation reaction of 6
was completed within 1 hour to furnish aldehyde 7 in
96% yield (Figure 3a). In addition, kinetic monitoring
of the oxidation reaction revealed that TEMPO reꢀ
tained the same level of reactivity as that of the nonꢀ
isolated catalyst (TOFini of 2a = 23.6 h–1, TOFini of
TEMPO = 11.2 h–1, see Supporting Information). We
propose that the large, several nanometerꢀsized, interiꢀ
or space of the M12L24 cavity (Figure 3b) allows the
catalyst, substrate and solvent molecules to behave as
if in bulk solution.2308 Notably, the catalyst sphere 2a
is stable, and maintains its structure during the course
of the catalytic reaction and after its completion; by
comparing the 1H NMR spectra of 1a, 2a and the reacꢀ
tion solution, no signals for the dissociated ligand 1a
were detected in the reaction mixture (Figure 3c–e).
We then applied our new system to the designed oxiꢀ
dation and subsequent stereoselective DA cascade reꢀ
action (Scheme 1). To a preꢀmixed solution of 2a, 2b,
PhI(OAc)2, trifluoroacetic acid, and allylalcohol 3 were
added. First, substrate 3 was oxidized to the α,βꢀ
unsaturated aldehyde 4, followed by the intramolecular
DA cyclization. This twoꢀstep cascade successfully
converted 3 to the desired bicyclic compound 5 with
four adjacent stereogenic centers in high enantioꢀ and
diastereoselectivity (93% ee); this experimental result
indicated that both catalysts worked cooperatively as
designed. It is also noteworthy that stereoselectivity
(both enantioꢀ and diastereoselectivity) in the DA reacꢀ
tion is the same as the reported value in the case of the
nonꢀsiteꢀisolated system (93% ee).286 This comparable
reactivity provides evidence that this strategy of cataꢀ
lytic siteꢀisolation holds promise for fine chemical synꢀ
thesis by means of oneꢀpot cascade reactions.
Scheme 1. Oxidation and asymmetric DA cascade
reaction catalyzed by 2a and 2b.
Several control experiments verified that the selfꢀ
assembled catalyst carriers indeed served as vehicles
for siteꢀisolation, and were thus indispensable for the
cascade reaction (Table 1). When TEMPO was used
We first evaluated the oxidative catalytic activity of
2a by using the simple alcohol 6 as a model substrate
(Figure 3). In the presence of 10/24 mol% of 2a (= 10
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instead of sphere 2a, only oxidation to 4 proceeded,
Notes
and the yield of 5 dropped to 4% (entry 2). Similarly,
when MacMillan’s catalyst was used instead of sphere
2b, DielsꢀAlder product 5 was obtained only in 3%
yield (entry 3). Simple combination of TEMPO and
MacMillan’s catalyst also only yielded a trace amount
of 5 but provided aldehyde 4 in 90% yield (entry 4).
These experiments support the claim that MacMillan’s
catalyst is incompatible with the conditions for TEMꢀ
POꢀcatalyzed oxidation reaction. In addition, the presꢀ
ence of empty sphere 2c assembled from
[Pd(CH3CN)4](BF4)2 and ligand 1c did not improve the
yield of 5 (entry 5); apparently, neither the framework
alone nor its components participated directly in the
catalytic process. Only the combined use of both of the
caged catalysts (2a and 2b) allowed the desired casꢀ
cade reaction to proceed.
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This work was supported by GrantsꢀinꢀAid for Specially
Promoted Research (24000009) and JSTꢀACCEL.
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logical development for catalyst isolation by structures
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M12L24 spherical frameworks functioned as a stable
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ASSOCIATED CONTENT
Supporting Information.
Additional experiments, experimental procedures, and
physical properties. The Supporting Information is availꢀ
able free of charge on the ACS Publications website.
(PDF)
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*mfujita@appchem.t.uꢀtokyo.ac.jp
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