Compartmentalization and Photoregulating Pathways for Incompatible Tandem Catalysis

Article abstract of DOI:10.1021/jacs.1c00257

This contribution describes an advanced compartmentalized micellar nanoreactor that possesses a reversible photoresponsive feature and its application toward photoregulating reaction pathways for incompatible tandem catalysis under aqueous conditions. The

Full text of DOI:10.1021/jacs.1c00257

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Compartmentalization and Photoregulating Pathways for
Incompatible Tandem Catalysis
Peiyuan Qu, Michael Kuepfert, Maryam Hashmi, and Marcus Weck*
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ABSTRACT: This contribution describes an advanced compart-
mentalized micellar nanoreactor that possesses a reversible photo-
responsive feature and its application toward photoregulating
reaction pathways for incompatible tandem catalysis under aqueous
conditions. The smart nanoreactor is based on multifunctional
amphiphilic poly(2-oxazoline)s and covalently cross-linked with
spiropyran upon micelle formation in water. It responds to light
irradiation in a wavelength-selective manner switching its morphol-
ogy as confirmed by dynamic light scattering and cryo-transition
electron microscopy. The compartmental structure renders distinct
nanoconfinements for two incompatible enantioselective trans-
formations: a rhodium−diene complex-catalyzed asymmetric 1,4-
addition occurs in the hydrophilic corona, while a Rh-TsDPEN-catalyzed asymmetric transfer hydrogenation proceeds in the
hydrophobic core. Control experiments and kinetic studies showed that the gated behavior induced by the phototriggered reversible
spiropyran to merocyanine transition in the cross-linking layer is key to discriminate among substrates/reagents during the catalysis.
The smart nanoreactor realized photoregulation to direct the reaction pathway to give a multichiral product with high conversions
and perfect enantioselectivities in aqueous media. Our SCM catalytic system, on a basic level, mimics the concepts of
compartmentalization and responsiveness Nature uses to coordinate thousands of incompatible chemical transformations into
streamlined metabolic processes.
works fabricated from these materials have realized compart-
mentalization for multiple active catalytic sites, as epitomized
by the cell, and enabled multistep nonorthogonal trans-
formations.12−14,18−23 Incorporating responsive elements into
the support structures has rendered them “smart”, i.e., allowing
for reversible alterations of the physical and chemical
properties in response to external stimuli such as temper-
ature,24,25 pH,26 light,27,28 or enzymes.29,30 The properties of
the resulting smart materials impart an additional bioinspired
control over single-step catalytic transformations.24,31−35
Manipulation of multicatalytic tandem sequences, however,
remains challenging and restricted to the regulation of
reactivities via temperature actuation.36,37 This limitation
significantly affects the choice of catalysts and limits the
feasibility of performing one-pot tandem catalysis at arbitrary
temperature ranges. To date, no “smart” catalytic system can
use or control different switchable states to tune and activate a
INTRODUCTION
■
Multistep synthesis via a one-pot procedure is of great
importance in modern organic synthesis due to economic
and environmental considerations.1−4 It often involves two or
more chemical transformations that are carried out in a single
reaction vessel and mediated by multiple catalysts. Combining
multiple discrete catalysts in a single reaction vessel generally
engenders catalyst deactivation.5 Additionally, successful
execution of a multistep synthesis relies on programming the
reaction sequence as well as controlling selectivity between
multiple competitive reaction pathways since undesired
pathways will lead to side products and lower yields.6 The
fundamental design strategies of Nature overcome such
catalyst incompatibility and reaction sequencing by positionally
assembling active species inside subcellular compartments,
separated by membranes.7−9 The cell performs metabolic
processes via the most efficient pathway by tuning membrane
permeability in response to regulatory signals, which governs
the transportation of molecules for catalysis and orchestrates
thousands of incompatible transformations into a streamlined
biosynthetic route.10,11
Received: January 8, 2021
Published: March 16, 2021
Scientists have developed multicompartmental catalytic
systems based on various strategies including the use of sol−
gels,12 Pickering emulsion droplets,13 supramolecular metal
complex architectures,14,15 and polymers.16,17 Catalytic frame-
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Figure 1. Rational design of “smart” SCMs nanoreactors for photoregulating incompatible tandem catalysis. (a) Targeted two-step tandem
catalysis, Pathway-1, to synthesize the secondary alcohol-b from an enone. The competitive pathway, Pathway-2, generates ketone-c and the
secondary alcohol-d. (b) Design and structural motifs of the polymeric scaffold: assembly of amphiphilic ABC-triblock copolymers with orthogonal
functional groups at various locations into core−shell micelles followed by the cross-linking with spiropyran (SP) to yield the target SCM.
Reversible photochromism between SP-SCM and the zitterionic merocyanine (MC)-SCM form accompanied by switchable permeability of the
micelle shell. (c) Compartmentalization of two incompatible metal catalysts in distinct microenvironments (hydrophobic core and hydrophilic
shell) on the SCM support. (d) Access to microenvironments can be phototriggered enabling molecular discrimination and suppression of
competitive steps.
desired synthetic pathway among many possible ones during a
multistep synthesis.
transformations: the Rh-diene-catalyzed asymmetric 1,4-
addition of enones and the rhodium-N-tosylated 1,2-
diphenyl-1,2-ethylenediamine (Rh-TsDPEN) catalyzed asym-
metric transfer hydrogenation (ATH). Light exposure directs
the tandem catalysis toward the desired reaction pathway and
results in a diastereomeric product with excellent conversions
and stereoselectivities.
Among artificial materials, polymers have attracted increas-
ing attention as catalyst supports, such as polymersomes for
multistep enzymatic cascade catalysis38−40 and star polymers
for acid−base tandem catalysis.41,42 In particular, shell cross-
linked micelles (SCMs) are an attractive scaffold for supported
catalysis due to their robustness, tenability, and potential for
functionalization in multiple domains.43 The unique hydro-
phobic pocket and the intramicellar diffusion of substrates
within the nanostructure can facilitate tandem catalysis in
aqueous media.44−46 We have used SCMs as compartmental-
ized nanoreactors for nonorthogonal tandem catalysis.45−48 To
realize a cell-like microenvironment for catalysis, the
incorporation of both compartmentalization and responsive-
ness into a single support structure is key. By engineering
responsive units within traditional SCMs, we take a significant
step toward this goal. Herein, we report such a “smart”
catalytic system that includes a morphology switch to realize
orthogonal modulation of different catalysts/catalytic pro-
cesses. Our photoresponsive SCM nanoreactor operates in
water and is designed for two nonorthogonal enantioselective
RESULTS AND DISCUSSION
■
The primary target of our tandem catalysis is to synthesize the
secondary alcohol-b with two chiral centers (Figure 1a). The
Rh-catalyzed 1,4-addition of arylboronic acids to commercially
available enones was used to form the corresponding β-
arylated carbonyl compounds that were subsequently trans-
formed by the Rh-catalyzed ATH into the chiral secondary
alcohols. Rhodium−chiral diene complexes have been reported
to efficiently catalyze the asymmetric 1,4-addition of enones to
the corresponding β-arylated carbonyl compounds with
excellent yields and enantioselectivities under mild reaction
conditions.49,50 ATH mediated by transition-metal complexes
with N-tosylated 1,2-diphenyl-1,2-ethylenediamine (TsDPEN)
derivatives as ligands is a powerful method to prepare
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Scheme 1. Fabrication of Smart SCM Nanoreactors
enantioenriched chiral alcohols from ketones.51−53 In one pot,
both catalytic transformations proceed simultaneously from
the onset and cannot be orchestrated into a proper sequence of
events (Figure 1a). As a result, the native reactivity profile of
the tandem catalysis has two reaction pathways that are
mutually competitive, which is not conducive to generate the
desired product in high yields. The intermediates and the final
product secondary alcohol-d from the competitive pathway are
side products and complicate the desired product isolation.
Our strategy is to compartmentalize the two incompatible
catalysts to avoid mutual interference between multiple
transformations and to photoregulate and ultimately direct
the tandem catalysis toward the desired reaction pathway.
A critical design element of the smart SCM nanoreactor is
the introduction of multiple orthogonal functionalities at
various locations on the polymer scaffold, e.g., the side chains
and the termini of the main chain (Figure 1b). The
straightforward yet efficient self-assembly of well-defined
amphiphilic block copolymers in selective solvents enables a
high degree of control over morphology and the positions of
multifold functions throughout three dimensions, which is
pivotal for precisely cross-linking the micelles or attaching
catalysts.43 Covalent cross-linking of dynamic micellar
structures affords stable self-assembled nanostructures.43
Spiropyran (SP), a photochromic molecule,54,55 was used to
covalently cross-link the micelles. Light is chosen as the
external trigger due to its facile operation, noninvasiveness, and
precise spatiotemporal control. Spiropyran responds to light
irradiation in a wavelength-selective manner and reversibly
isomerizes between the hydrophobic SP form and the
hydrophilic zwitterionic merocyanine (MC). We hypothesized
that this SP to MC photochromic transition can be translated
into the cross-linking layer leading to a light-induced gating
behavior of the shell accompanied by tunable permeability
(Figure 1b).
The chiral rhodium diene complex was immobilized in the
hydrophilic corona, while the Rh-TsDPEN catalyst was
sequestered into the hydrophobic core (Figure 1c). This
spatial arrangement implements nature’s fundamental com-
partmentalization principles to site-isolate active catalytic sites.
For aqueous-based tandem catalysis, the diffusion of hydro-
phobic substrates from the aqueous bulk solution into the core
is a major driving force for conversion inside micellar
nanoreactors.44,48 Therefore, the spatial positioning of each
catalyst inside the SCM nanoreactor corresponds to the
diffusion pathway. Rh−diene complex-catalyzed asymmetric
1,4-addition of arylboronic acids to enones was reported with
water as the best solvent,50 and thus, the hydrophilic corona
serves as a preferred nanodomain for immobilization of the
chiral Rh−diene complexes.
Rh-TsDPEN is anchored in the micelle core surrounded by
a photoswitchable shell. The gating behavior of the micellar
shell provides a spatiotemporal modulation of mass transport
and regulates the catalysis of the ATH. Prior to UV exposure,
the hydrophobic SP cross-linked layer prevents the water-
soluble HCOONa, the hydrogen donor, from diffusing into the
core, thereby suppressing ATH catalysis. Upon UV light
irradiation, the phototriggered transition from SP to MC
increases the permeability of the shell and enables the diffusion
of HCOONa between compartments to continue the tandem
catalysis (Figure 1d).
The SCM nanoreactor was formed from the assembly of
amphiphilic poly(2-oxazoline)-based ABC-triblock copolymers
(Scheme 1). By using functional initiators, monomers, and
terminators, poly(2-oxazoline)s with high functionality fidelity
can be synthesized through living cationic ring-opening
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polymerization (CROP).56−58 The triblock copolymers are
comprised of a carboxylic acid salt-based hydrophilic block, a
cross-linkable middle block containing a terminal alkyne, and a
hydrophobic block containing an alkyl tail and a terminal
allylamine as the functional handle for postpolymerization
modification in the micellar core. The carboxylic acid salts can
be transformed into the corresponding carboxylic acids
providing a functional handle for the attachment of the
hydroxy-functionalized chiral Rh−diene complexes. Spiropyran
has been reported to be pH responsive.55 A neutral or basic
corona can stabilize the photoresponsive shell and increase the
responsiveness of the light trigger. The Rh-catalyzed
asymmetric 1,4-addition reaction prefers neutral or basic
conditions, and therefore, the corona of lithium carboxylic
salts is a suitable nanodomain for the catalytic 1,4-addition.49,50
We synthesized the poly(2-oxazoline) triblock copolymers
through CROP with methyl triflate as the initiator.57 The
1
polymerization process was monitored by H NMR spectros-
copy. After completion, the final triblock copolymer 1 was
analyzed by 1H NMR spectroscopy and gel-permeation
chromatography (GPC) (for details, see the Supporting
Information). The apparent molecular weight (Mnapp) and
dispersity (D̵) were 5.4 kDa and 1.30, respectively. Hydrolysis
of the ester block generated copolymer 2 with a carboxylate
block (for details, see the Supporting Information). We
dissolved copolymer 2 in water at 1.0 mg mL−1 and
characterized the self-assembled micelles by dynamic light
scattering (DLS) (Figure S17, left). No nanostructure
formation was observed if the assembly was performed in an
organic solvent such as methanol (Figure S17, right). The
micelles in water were cross-linked using copper(I)-catalyzed
alkyne−azide cycloaddition (CuAAC) between the alkyne
moiety and bifunctionalized spiropyran (N3-SP-N3) (see the
Supporting Information for the synthesis and character-
izations) to afford SCM 3. The covalent cross-linking was
confirmed by NMR and FT-IR spectroscopies by observing the
disappearance of the characteristic alkyne signals at 1.98 ppm
in the 1H NMR spectrum, 84.7 and 71.0 ppm in the 13C NMR
spectrum, and 3278.6 cm−1 in the FT-IR spectrum and the
presence of the aromatic SP signals in the 1H NMR spectrum,
13C NMR spectrum, and IR spectrum (Figures S18−S20). The
observation of the nanostructure via DLS after cross-linking
and changing the solvent to methanol also indicated the
successful covalent cross-linking of the micelles (Figure S21).
A core−shell phase separated structure of the SCM domains
was observed by cryogenic TEM (Cryo-TEM) imaging (Figure
2a).
Next, we investigated the photoresponsiveness of SCM 3 by
DLS and Cryo-TEM. SCM 3 was dispersed in water at 0.5 mg/
mL for DLS analysis and at 0.05 mg/mL for Cryo-TEM. The
micelle solution was exposed to visible light (λ = 550 nm) for
15 min and then switched to UV irradiation (λ = 350 nm) for
15 min. The pink color of the micelle solution changed to dark
purple while switching from visible to UV light. Once the first
cycle was completed, the same UV/vis sequence was repeated
for five consecutive UV/vis cycles. DLS measurements of SCM
3 showed hydrodynamic diameters (Dh) under visible light of
105 5 nm. Upon irradiation with UV light, the Dh fluctuated
between 58 and 70 nm, demonstrating a significant change in
micelle morphology (Figure 2b). Similarly, reversible photo-
switchability was observed when SCM 3 was dispersed in
methanol accompanied by a color transition from dark yellow
(under visible light) to dark red (under UV light) (Figure
Figure 2. Morphological investigations of SCM 3. (a) Cryo-TEM
image of the phase separation of the SCM domains. A core−shell
structure was observed. Scale bar = 50 nm. (b) Dh distributions of five
consecutive cycles determined by DLS. The micelle solution turned
pink after exposure to visible light for 15 min (I) and dark purple (II)
after UV light irradiation for 15 min. (c) Cryo-TEM images of SCM 3
during visible light (left) and UV light (right) switching. Scale bar =
50 nm. (d) Statistical size distribution of SCM 3 under visible light
(left) and UV-light (right) exposure based on 120 micelles from
Cryo-TEM images. .
S21). Statistical size distribution is based on a sample size of at
least 120 micelles in the Cryo-TEM (Figure 2c,d). The z-
average diameter for the micelles, calculated from the
distribution, was 74 nm under visible light and 51 nm under
UV irradiation. These results indicate that our smart SCMs
have a photoinduced “breathing” feature.
With the photoswitchable SCM 3 in hand, the two chiral Rh
catalysts were immobilized in two separate nanoenvironments
via orthogonal chemistries. We first reacted the alkene
functionalities in the core with a multivalent tetrathiol linker
through thiol−ene click chemistry (Scheme 1). A ratio of 1:1
of alkene to tetradentate thiol linker was chosen, leaving an
average of three free thiols per polymer chain for further
functionalization with the alkene-functionalized Rh-TsDPEN
through a second thiol−ene click addition to produce SCM 4.
A rhodium loading of 0.934% was determined by inductively
coupled plasma-mass spectrometry (ICP-MS), corresponding
to 1.63 Rh-TsDPEN catalysts per polymer chain for SCM 4.
After acidifying the corona domain, the hydroxy-functionalized
Rh−diene complex was attached along the side-chains of the
hydrophilic corona via o-(benzotriazol-1-yl)-N,N,N′,N′-tetra-
methyluronium tetrafluoroborate (TBTU)/N,N-diisopropyle-
thylamine (DIPEA)-mediated coupling. The corona domain of
the resulting polymer was subsequently basified to obtain the
final bifunctional SCM 5. The rhodium content of the
bifunctionalized SCM 5 was determined by ICP-MS to be
2.02%, corresponding to 1.86 Rh−diene complexes and 1.63
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Table 1. Unsupported Catalytic Tests of Single- and Multistep Reactions
a
b
c
c
entry
transformation
catalyst
cat. loading (mol %)
time (h)
conversion (%)
ee (%)
dr (%)
d
1
I
I
II
II
III
III
Rh−diene
Rh−diene
Rh−TsDPEN
Rh−TsDPEN
Rh−diene + Rh−TsDPEN
Rh−diene + Rh−TsDPEN
6
6
5
5
6/5
6/5
15
15
20
20
25
25
99
80
72
15
48 (47)
73 (24)
96
96
99
nd
nd
nd
e
2
e
3
96:4
nd
nd
d
4
e
f
5
d
f
6
nd
a
Reaction conditions: all reactions were performed on a 0.02 mmol substrate scale in 3 mL of water at 40 °C. For transformation I, the reactions
were performed with phenyl boronic acid (2.0 equiv) under an argon atmosphere. For transformation II, the reactions were performed with
HCOONa (10 equiv) in open air. For transformation III, the reactions were performed with phenyl boronic acid (2.0 equiv) and HCOONa (10
b
1
equiv) under an argon atmosphere. Conversions of final products for each transformation were determined by H NMR spectroscopy using
c
d
e
mesitylene as an internal standard. Determined by chiral HPLC analyses. KOH (0.5 equiv) was added to the reaction. KOH was not added to
the reaction. The conversion in bracket is for (R)-1-phenylbutan-1-ol.
f
Table 2. Micelle-Supported Catalytic Tests of Single- and Multistep Reactions
a
b
c
c
entry
transformation
catalyst
cat. loading (mol %)
time (h)
conversion (%)
ee (%)
dr (%)
1
2
3
I
II
II
III
III
III
SCM 5
SCM 4
SCM 4
SCM 5
SCM 5
SCM 5
6
5
5
6/5
6/5
6/5
15
20
20
30
30
30
99
trace
98
96
d
99
99
99
99
96:4
96:4
96:4
96:4
4
92
f
5
f
90
91
e
6
a
Reaction conditions: all reactions were performed on a 0.02 mmol substrate scale in 3 mL of water at 40 °C. (I) The reaction was performed with
SCM 5 (9 mg, containing 1.3 μmol Rh−diene), phenyl boronic acid (2 equiv), and KOH (0.5 equiv) under an argon atmosphere. II: The reactions
were performed with SCM 4 (9 mg, containing 1 μmol Rh−TsDPEN), HCOONa (10 equiv) in open air. III: The reactions were performed with
SCM 5 (9 mg, containing 1.3 μmol of Rh−diene and 1 μmol of Rh−TsDPEN), phenyl boronic acid (2.0 equiv), KOH (0.5 equiv), and HCOONa
b
(10 equiv) under an argon atmosphere. UV-light irradiation was applied after 15 h. Conversions were determined by 1H NMR spectroscopy using
c
d
e
mesitylene as the internal standard. Determined by Chiral HPLC analyses. The reaction was performed under UV light irradiation. The
f
conversion was for the catalysis using recycled nanoreactors. The tandem reaction was performed on a 50 mg (0.34 mmol) substrate scale in 50
mL of water and the conversion was based on the isolated product.
Rh−TsDPEN complexes per polymer chain. DLS of SCM 5
confirmed that the reversible photoswitchable behavior was
retained after catalyst immobilizations (Figure S22).
reaction are highly pH-dependent.51−53 In the presence of
KOH (0.5 equiv), the conversion of the ATH was only 15%
(Table 1, entry 4), which is due to the basification of the
reaction mixture (pH = 11.5) through the addition of KOH
causing deactivation of the Rh-TsDPEN. Attempting the
tandem reaction by combining the two catalysts without
adding KOH resulted in 48% of (1R,3S)-1,3-diphenyl-1-
butanol, the desired product from Pathway-1 and 47% of
(R)-1-phenylbutan-1-ol, the side product from Pathway-2
(Figure 1a and Table 1, entry 5). This result confirmed the
competitiveness of the two possible pathways (Figure 1a).
Interestingly, in the presence of KOH (0.5 equiv), the tandem
reaction yielded 73% of the desired (1R,3S)-1,3-diphenyl-1-
butanol and 24% of (R)-1-phenylbutan-1-ol (Table 1, entry 6).
The rationales behind the difference between entries 5 and 6 in
Table 1 are as follows. (1) KOH facilitated the Rh-catalyzed
1,4-addition. As a result, more intermediate Ketone-1 was
generated in entry 6, which resulted in a higher amount of
(1R,3S)-1,3-diphenyl-1-butanol. (2) The mixture of phenyl
boronic acid (pKa = 8.83) and KOH turned the reaction
Before using the micelle-supported catalytic system, we
investigated the catalytic activity of both unsupported catalysts
independently of each other and in the tandem transformation.
In the presence of KOH (0.5 equiv), the unsupported Rh−
diene catalyzed the asymmetric 1,4-addition of phenylboronic
acids to trans-1-phenyl-2-buten-1-one quantitatively at 40 °C
over 15 h with excellent enantioselectivities (96% ee) (Table 1,
entry 1). Without the presence of KOH, the conversion
dropped to 80% (96% ee) (Table 1, entry 2), which indicated
that the addition of KOH enhances the catalytic activity to
promote the Rh-catalyzed 1,4-addition.49 Unsupported hetero-
geneous Rh-TsDPEN catalyzed the ATH of the hydrophobic
and sterically hindered substrate (S)-1,3-diphenylbutan-1-one
in water with 72% conversion over 20 h and excellent
enantioselectivity (99% ee, 96:4 dr) (Table 1, entry 3). The
enantioselectivity, activity, and recyclability of transition-metal
complexes based on TsDPEN or its derivatives in the ATH
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slightly basic, which decreased the activity of the Rh-TsDPEN
catalyst, compared to Table 1, entry 3. Entry 6 (Figure S37) of
Table 1 shows the formation of multiple intermediates, the
desired product and side products, during tandem catalysis
confirmed the competitiveness between the two pathways. The
unsupported catalytic tests of the single and tandem trans-
formations demonstrated the incompatibility between two Rh
catalysts and the existence of two competitive tandem reaction
pathways. We reasoned that this tandem reaction presents a
perfect testbed to investigate whether our strategy can
circumvent catalyst incompatibility and photoregulate the
reaction pathway to improve the overall synthetic efficiency.
We investigated the catalytic activity of the SCM for each
single step transformation. SCM 5 catalyzed the asymmetric
1,4-addition of phenylboronic acids to trans-1-phenyl-2-buten-
1-one quantitatively and with excellent enantioselectivities
(96% ee) under the same conditions as the unsupported
rhodium catalyst, which shows the hydrophilic corona is a
suitable catalytic environment for this transformation (Table 2,
entry 1). The ATH mediated with SCM 4 can be suppressed
or accelerated according to the type of stimulus applied
(Figure 3). Under visible light, the ATH with SCM 4 yielded
Next, we investigated whether our smart SCM nanoreactors
SCM 5 can facilitate two incompatible catalytic steps and
photoregulate the reaction pathways. In the presence of KOH,
SCM 5 catalyzed the asymmetric 1,4-addition of phenyl-
boronic acids to trans-1-phenyl-2-buten-1-one to generate the
only intermediate (S)-1,3-diphenylbutan-1-one (Ketone-1)
(Figure 4). After 15 h, UV irradiation was applied resulting
Figure 4. Time course of the tandem catalysis (Table 2, entry 4):
Under visible light irradiation, SCM 5 catalyzed the asymmetric 1,4-
addition of phenylboronic acids to trans-1-phenyl-2-buten-1-one to
generate the only observed intermediate (S)-1,3-diphenylbutan-1-one
accompanied by the complete consumption of starting material trans-
1-phenyl-2-buten-1-one. After 15 h, UV irradiation was turned on to
initiate the ATH to yield the desired and only product (1R,3S)-1,3-
diphenyl-1-butanol (black squares, trans-1-phenyl-2-buten-1-one; red
solid circles, (S)-1,3-diphenylbutan-1-one; purple rhombus, (1R,3S)-
1,3-diphenyl-1-butanol; butyrophenone and (R)-1-phenylbutan-1-ol
were not observed). Reaction conditions: 0.02 mmol of substrate
scale in 3 mL of water at 40 °C with SCM 5 (9 mg, containing 1.3
μmol of Rh-Diene and 1 μmol of Rh-TsDPEN), phenyl boronic acid
(2.0 equiv), KOH (0.5 equiv), and HCOONa (10 equiv) under an
argon atmosphere and the UV irradiation was applied after 15 h.
in the activation of the ATH to yield the desired product
(1R,3S)-1,3-diphenyl-1-butanol in 92% conversion with
excellent enantioselectivities (99% ee, >96:4 dr) (Table 2,
entries 4 and 5). These results indicated that the SCM 5
circumvented the incompatibility of the two catalysts via
compartmentalization and that one reaction pathway can be
selected over competing ones based on the external light
stimulus (compare Table 2, entry 4, and Table 1, entries 5 and
6). The SCMs can be easily recovered via dialysis and recycled
without major loss of reactivity (Table 2, entry 6).
Figure 3. Conversion vs time for Table 1, entry 3, and Table 2, entries
2 and 3. Rh-TsDPEN-catalyzed ATH of (S)-1,3-diphenylbutan-1-one:
purple circles represent the reaction with SCM 4 under UV light
irradiation; black squares represent the reaction with unsupported Rh-
TsDPEN; pink triangles represent the reaction SCM 4 under visible
light. All reactions were performed on a 0.02 mmol substrate scale in
3 mL of water at 40 °C with 5 mol % Rh catalyst loading and
HCOONa (10 equiv).
A limited substrate screen was performed using SCM 5
(Table 3). Aromatic boronic acids, substituted with either
electron-withdrawing or -donating groups, can be converted in
high yields and ee and dr values (Table 3, entries 1−3).
Aliphatic enone also underwent micellar tandem catalysis with
high conversions (98%) and enantioselectivities (99% ee, 5:1
dr). In contrast, the unsupported one-pot tandem catalysis
only yielded 48% desired product under the same reaction
conditions (Table 3, entry 4).
trace amounts of product in 20 h (Table 2, entry 3). Under UV
irradiation, however, the ATH with SCM 4 was slightly
accelerated in comparison to the unsupported Rh−TsDPEN
catalyst with quantitative conversion and excellent enantiose-
lectivities (99% ee, >96:4 dr) (Figure 3 and Table 2, entry 3).
We hypothesize that under visible light the hydrophobic SP
cross-linking layer prevents the diffusion of the hydrogen
donor HCOONa into the core resulting in the suppression of
the ATH. Under UV-light irradiation, the SP isomerizes to MC
resulting in an increase in hydrophilicity of the cross-linking
layer and ultimately an increase in permeability for HCOONa.
The kinetic data (Figure 3) and the catalytic tests of the ATH
(Table 2, entries 2 and 3) demonstrate that the phototriggered
reversible spiropyran to merocyanine transition results in the
gated behavior to SCMs, which is key to discriminating
between substrates/reagents during catalysis; photomodulating
the diffusion of HCOONa and providing an On/Off control
over ATH catalysis.
CONCLUSION
■
In summary, we realized the concept of compartmentalization
and responsiveness with an artificial multicatalytic system that
can photoregulate an efficient synthetic pathway for non-
orthogonal tandem catalysis in water. The key design is a
responsive cross-linking layer between the two compartments
in a core−shell micellar nanostructure. The smart nanostruc-
ture responds to light irradiation in a wavelength-selective
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Table 3. Substrate Scope for Micelle-Supported One-Pot Tandem Catalysis
a
Reaction conditions unless otherwise indicated: SCM 5 (9 mg, containing 1.3 μmol of Rh-Diene and 1 μmol of Rh-TsDPEN), 0.02 mmol of
enone (1.0 equiv), boronic acid (2.0 equiv), KOH (0.5 equiv), HCOONa (10 equiv) in 3 mL of water at 40 °C for 30 h under an argon
b
atmosphere. UV-light irradiation was applied after 15 h. Conversions were determined by 1H NMR spectroscopy using mesitylene as an internal
c
d
standard. Determined by chiral HPLC analyses. The conversion in parenteses was using unsupported catalysts under the same conditions.
Authors
manner. Two incompatible catalysts were spatially isolated in
the hydrophilic corona and the hydrophobic core. The gated
behavior induced by the phototriggered reversible spiropyran
to merocyanine transition in the cross-linking layer is essential
to discriminate among substrates/reagents during the catalysis.
The smart SCM nanoreactor can circumvent incompatibility
between the catalysts via compartmentalization and allows for
the photoregulation of the desired reaction pathway. The smart
SCM nanoreactors, on a basic level, mimic how cells use
compartmentalization and responsiveness to coordinate
thousands of incompatible chemical transformations into a
streamlined metabolic process. Future research in our group
will focus on preparing smart compartmentalized nanoreactors
with more than two nanodomains and that can respond to
multiple stimuli to regulate otherwise incompatible tandem
reactions.
Peiyuan Qu − Molecular Design Institute and Department of
Chemistry, New York University, New York 10003, United
States
Michael Kuepfert − Molecular Design Institute and
Department of Chemistry, New York University, New York
10003, United States
Maryam Hashmi − Molecular Design Institute and
Department of Chemistry, New York University, New York
10003, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00257
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding provided by the U.S. Department of Energy, Office of
Basic Energy Sciences, through Catalysis Science Contract DE-
FG02-03ER15459, is gratefully acknowledged. We thank
Kristen Dancel-Manning from the OCS Microscopy Core
and William J. Rice and Bing Wang from the Cryo-Electron
Microscopy Laboratory at New York University Langone
Medical Center for obtaining the Cryo-TEM images.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00257.
Materials, synthetic procedures, characterizations of
small molecules and macromolecules, and general
procedures for micelle-supported single-and multistep
catalysis (PDF)
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