Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-Friendly and Asymmetric Synthesis

Article abstract of DOI:10.1021/acscatal.6b01031

Organic synthesis is in general performed using stepwise transformations where isolation and purification of key intermediates is often required prior to further reactions. Herein we disclose the concept of integrated heterogeneous metal/enzymatic multiple relay catalysis for eco-friendly and asymmetric synthesis of valuable molecules (e.g., amines and amides) in one-pot using a combination of heterogeneous metal and enzyme catalysts. Here reagents, catalysts, and different conditions can be introduced throughout the one-pot procedure involving multistep catalytic tandem operations. Several novel cocatalytic relay sequences (reductive amination/amidation, aerobic oxidation/reductive amination/amidation, reductive amination/kinetic resolution and reductive amination/dynamic kinetic resolution) were developed. They were next applied to the direct synthesis of various biologically and optically active amines or amides in one-pot from simple aldehydes, ketones, or alcohols, respectively.

Full text of DOI:10.1021/acscatal.6b01031

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Letter
Integrated Heterogeneous Metal/Enzymatic Multiple Relay
Catalysis for Eco-friendly and Asymmetric Synthesis
Carlos Palo-Nieto, Samson Afewerki, Mattias Anderson, Cheuk-Wai Tai, Per Berglund, and Armando Cordova
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01031 • Publication Date (Web): 16 May 2016
Downloaded from http://pubs.acs.org on May 18, 2016
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Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-
Friendly and Asymmetric Synthesis
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Carlos Palo-Nieto,1 Samson Afewerki,1 Mattias Anderson,3 Cheuk-Wai Tai,2 Per Berglund3
Armando Córdova*1,2
&
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1. Mid Sweden University, Department of Natural Sciences, Holmgatan 10, 85170,
Sundsvall (Sweden)
2. Berzelii Centre EXSELENT on Porous Materials, Department of Materials and
Environmental Chemistry, Stockholm University, 10691 Stockholm (Sweden)
3. KTH Royal Institute of Technology, Division of Industrial Biotechnology, School of
Biotechnology, Alba Nova University Center, SE-106 91 Stockholm, Sweden
Correspondence and requests for materials should be addressed to A.C. (email:
armando.cordova@miun.se).
Abstract. Organic synthesis is in general performed using stepwise transformations
where isolation and purification of key intermediates is often required prior to further
reactions. Herein we disclose the concept of integrated heterogeneous metal/enzymatic
multiple relay catalysis for eco-friendly and asymmetric synthesis of valuable molecules
(e.g. amines and amides) in one-pot using a combination of heterogeneous metal and
enzyme catalysts. Here reagents, catalysts and different conditions can be introduced
along the one-pot procedure involving multi-step catalytic tandem operations. Several
novel co-catalytic relay sequences (reductive amination/amidation, aerobic
oxidation/reductive amination/amidation, reductive amination/kinetic resolution and
reductive amination/dynamic kinetic resolution) were developed. They were next
applied to the direct synthesis of various biologically and optically active amines or
amides in one-pot from simple aldehydes, ketones or alcohols, respectively.
Keywords: Heterogeneous metal, enzyme, reductive amination, relay catalysis, heterogeneous catalysis,
tandem reactions, kinetic resolution, dynamic kinetic resolution
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One-pot operations such as multi-component, domino, cascade and tandem reactions are
of immense significance in Nature and chemical research.1 In fact, the biochemistry of
the cell is based on multi-enzymatic relay catalysis (or sequential catalysis) of
ingeniously linked transformations in “one-pot”. In chemical synthesis, these
transformations, which include important “green chemistry parameters” (e.g. reduction
of steps, waste and solvents, etc.) are becoming a new tool for the synthetic chemist.2
However, when catalyzing these cascade or tandem sequences using different types of
catalysts (i.e. metal catalyst, organocatalyst or enzyme catalyst) compatibility and
inactivation problems can occur. Thus, there is a significant need for the development of
new concepts that unify different types of catalysts. Here, homogeneous relay catalysis,
which combines the use of organometallic and organocatalysts, was recently
disclosed.3,4 A one-pot relay catalytic tandem operation describes a process where
substrate 1 (S1) is converted to intermediate 1 (I1) by catalyst system 1 followed by
conversion of I1 to the final product (P) by reacting it with another substrate using
another catalyst system 2. Here additional substrates and catalyst can be introduced
during the reaction pathway. While homogeneous relay catalysis has begun to be
exploited as means for accomplishing transformations, which are not possible using the
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catalysts individually in one-pot, the reports of multi-catalyst systems for relay catalysis
involving heterogeneous catalysts are very few.5-7 The inclusion of heterogeneous
catalysis is highly desirable since it would allow for different reactivity not possible
using homogeneous organometallic catalysts (e.g reductions and oxidations) and allow
for facile removal and recycling of the transition metals.8 It can also be implemented in
flow-chemistry processes.9 Recently, a multiple relay catalysis strategy for eco-friendly
asymmetric synthesis, which employs a combination of heterogeneous metal and amine
catalysts was disclosed.7 In this approach, the heterogeneous metal catalyst takes part in
several steps of the catalytic relay sequence and can operate in cooperation with the
amine catalyst.7 However, a heterogeneous metal/enzyme multiple relay catalysis
strategy applied to asymmetric synthesis has so far not been reported. In this approach,
the heterogeneous metal catalysts would also as described vide supra take part in
several consecutive reaction steps (Fig. 1), which could be asymmetric and open up for
a plethora of enzyme catalyzed10 reactions (e.g. kinetic resolution (kr, Fig. 1b) or
dynamic kinetic resolution (dkr, Fig. 1c).11-13
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Figure 1. (a) One-pot combined heterogeneous metal/enzyme relay catalysis strategy.
(b) One-pot catalytic kr relay sequence. (c) One-pot catalytic dkr relay sequence. M =
Heterogeneous metal. E = Enzyme catalyst. S = substrate, I = Intermediate. P = product.
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The proposed heterogeneous metal/enzyme multiple relay catalysis strategy contributes
to the significant need for expansion of eco-friendly and asymmetric synthesis from
simple feedstock chemicals. It also has the possibility of providing new transformations
and allow for synthesis of small molecules from starting materials, which are not
accepted as substrates by the enzymatic catalyst.14-16 Here methodology for the
assembly of biologically and optically active amines or amides is of immense
importance. Thus, we decided to investigate the assembly of these valuable compounds
by a heterogeneous metal/enzyme relay catalysis strategy (Figure 1, Scheme. 1). For
example, the integration of heterogeneous metal catalysis with heterogeneous enzymatic
catalysis could create a novel co-catalytic one-pot reductive amination/direct amidation
relay sequence to give amides 3 from aldehydes 1 and HCO2NH4 via amines 2 using
acids 4 as acyl donors for the enzyme (Scheme 1). Here a lipase-catalyzed amidation
would make the reaction irreversible. Moreover, the catalytic relay sequence may also
be further expanded to include an initial catalytic aerobic oxidation reaction of an
alcohol 5. In this context, the direct conversion of alcohols to amines 2 and amides 3 is
a very difficult task in organic chemistry.17
Scheme 1. One-pot reductive amination/direct amidation relay sequence.
However, key for its success would be the discovery of a highly chemoselective
heterogeneous metal-catalyzed reductive amination transformation,18,19 which employs
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ammonium formate as both the amine and hydrogen source (Leuckart reaction). Here
we present a novel integrated heterogeneous metal/enzymatic multiple relay catalysis
strategy for the sustainable and enantioselective tandem synthesis of valuable and
biologically active amines and/or amides starting from an aldehyde, ketone or an
alcohol, respectively.
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Combined heterogeneous metal/enzyme relay catalysis strategy. We began to
investigate a heterogeneous metal-catalyzed reductive amination transformation. Here
the Leuckart reaction is a classical process for the reductive amination of aldehydes or
ketones by formamide, ammonium formate, or formic acid with formamide.20 However,
it suffers from several drawbacks such as requirement of high temperatures (150-240
°C), which leads to high consumption of energy and increased production costs, the
formation of N-formyl derivatives, low chemoselectivity in the synthesis of primary
amines and long reaction times. Thus, most of the current reductive amination
procedures for the synthesis of primary amines are performed in two steps (e.g. separate
imine-type formation and reduction reactions). However, these two-step procedures take
as much time as the traditional Leuckart reaction. Therefore, it is evident that there is a
compelling need for fast and inexpensive methods for this classical reaction preferably
under eco-friendly conditions. Transition metal catalysts such as Rh, Ru and Ir have
been used for the synthesis of primary amines under the Leuckart-type conditions.21
However, the use of Pd/C as the catalyst leads to reduction of the carbonyl substrate to
the corresponding methylene derivative.22,23 Thus, there are serious chemoselectivity
issues to take into consideration when performing a possible Pd-nanoparticle-catalyzed
mild direct synthesis of primary amines starting from aldehydes/ketones using
ammonium formate as amino donor and hydrogen source (Scheme 2) For example,
aldehydes 1 can be reduced either to the desired amines 2, dialkyl amine 2’, alcohols 5
or alkanes 6. Furthermore, the aldehyde substrates can oligomerize and polymerize.
Scheme 2. Chemo-selectivity issues for a Pd-catalyzed reaction between HCO2NH4 and carbonyl
compounds.
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Despite these drawbacks, palladium is arguably one of the most powerful and versatile
transition-metal catalysts, which can be used for a variety of organic transformations
and immobilized on various heterogeneous supports.24 This could also lead to efficient
recycling with consequent economic and environmental advantages. Heterogeneous
palladium catalysts can also be efficiently combined with simple chiral amine co-
catalysts without loss of their reactivity.25 Hence, there might be a chance of discovering
a highly chemoselective reductive amination using ammonium formate and a
heterogeneous palladium catalyst. Next, this novel transformation could be integrated
with a heterogeneous/enzyme multiple relay catalysis strategy as described vide supra
(Figure 1, Scheme 1). The initial screening studies were performed using vanillin 1a,
which can be produced from the renewable resource lignin, as the model substrate, solid
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HCO2NH4 as the amine donor and reducing agent in the presence of different palladium
catalysts (Table 1).
Table 1. Condition screening.
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Entry
Catalyst
HCO2NH4 Temp (°C) Time (h)
(Equiv)
Conv(%)[a] Ratio
(2a:6a:5a)[a]
Pd(0)-AmP-MCF
-
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3
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22
80
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12
90
38:62:0
24
2.5
2.5
7
<1
-
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Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
Pd(PPh3)4
3
>99
>99
>99
<1
88:12:0
94:6:0
86:14:0
-
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24
2.5
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7[c]
8
>95
>95
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>99
>99
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>99
81:15:4
79:14:7
55:45:0
34:60:6
39:38:23
42:5:53
46:54:0
Pd(0)-AmP-CPG
Pd(0)-AmP-CPG
Pd(OH)2/C
9
Pd/C
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11
12[b]
13[d]
Pd(OAC)2
Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
[a] Determined by 1H-NMR analysis of the crude reaction mixture. [b] The reaction was
run with Ms 4Å. [c] 6.6 mol% cat. [d] 1 mol% cat.
For example, aldehyde 1a was converted to the desired amine 2a in poor
chemoselectivity together with significant amounts of 6a in the presence of
palladium(0)-aminopropyl-mesocellular foam (Pd0-AmP-MCF,24a,b 5 mol%) in toluene
at room temperature (entry 1). Increasing the temperature significantly accelerated the
reaction as well as switched the chemoselectivity towards amine 2a formation (entries
3-5). This was also the case when employing palladium(0)-aminopropyl-controlled pore
glass (Pd0-AmP-CPG)25b as the catalyst (entry 7). The use of other commercially
available heterogeneous and homogeneous Pd catalysts resulted in low chemoselectivity
(entries 9-11). Moreover, the same relay sequence using homogeneous Pd(PPh3)4 as
catalyst or performing the reaction in the absence of a palladium source did not deliver
amine 2a (only starting material was detected, entries 2 and 6). With these results in
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hand, we decided to probe the scope of the catalytic amination of a range of aldehydes
using Pd0-Amp-MCF or Pd0-Amp-CPG (6.6 mol%) as the heterogeneous catalysts and
HCO2NH4 (3 equiv) at 80 oC in toluene (Table 2).
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Table 2. Aldehyde 1 substrate scope.
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Entry
1
Pd(0) cat.
R
Time (h)
2.5
Prod.
Yield (%)[a]
87
2a
Pd(0)-AmP-MCF
2
2.5
2a
78
Pd(0)-AmP-CPG
3
4
3
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2b
2c
85
Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
92[b]
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n-Pent
n-Pent
n-Octyl
4
2d
2d
2e
2f
91[b]
87[b]
78
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Pd(0)-AmP-CPG[c]
Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
3.5
4
4
85
Pd(0)-AmP-CPG[c]
9
2f
76
10
11
3
3
2g
2h
90
Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
71[b]
12
3
2i
72
Pd(0)-AmP-MCF
13
14
Et
3
2j
93[b]
63
Pd(0)-AmP-MCF
Pd(0)-AmP-MCF
3.5
2k
15
CO2Et
3
2l
55[d]
Pd(0)-AmP-MCF
1
[a] Isolated yield of pure 2. [b] H-NMR yield using mesitylene as internal standard. [c] 6.6
mol% cat. [d] 1 (0.4 mmol).
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The reactions were highly chemoselective and a variety of aldehydes were converted to
the corresponding amines 2a-2k and glycine derivative 2l. (55-93 % yield, Table 2).
Notably, the transformation was chemospecific towards amine 2-formation when
aliphatic aldehydes were used as substrates. The total synthesis of natural products is a
highly desirable aim. Here, nonivamide 3a and capsaicin 3b are pungent amides that
have been a part of the human diet of the Americas since minimum 7500 BC (chili
pepper, Fig. 2).26,27 They activate the TRPV1 receptor and a wide variety of
physiological and biological activities induced by them have recently been reported.26-28
According to Eq. 1 they should be possible to assemble via a heterogeneous
metal/enzyme reductive amination/amidation or aerobic oxidation/reductive
amination/amidation sequence.
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Figure 2. Examples of biologically active Capsaicinoids.
Thus, we embarked on development of a one-pot co-catalytic reaction between aldehyde
1a, HCO2NH4 and nonanoic acid 4a using commercially available Candida antarctica
lipase B (Novozyme-435, CALB) immobilized on a macroporous resin as the co-
catalyst (Scheme 1, See SI). CALB was chosen as the catalyst for its ability to amidate
2a.6 The one-pot co-catalytic relay sequence gave nonivamide 3a in high yield (74%)
using a Pd(0)-nanoparticle and enzyme catalyst system. However, no amide 3a was
formed if either the enzyme or the Pd catalyst was absent. Thus, the enzyme and the Pd-
catalyst operated synergistically during the in situ amidation step. The scope of the co-
catalytic one-pot cascade transformation sequence and the total synthesis of capsaicin
3b and “phenylcapsaicin”28 3c were next investigated (Table 3).
Table 3. Reductive amination/amidation catalytic relay.
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Entry
1
R
R1
Prod.
3a
Yield[a]
74
2[b]
3[c]
4
74
73
78
3a
3b
3c
5
6
62
76
3d
3e
n-Prop
7
8
n-Pent
n-Pent
40[d]
70
3f
3g
9
71
3h
[a] Isolated yield of pure product 6. [b] Pd0-AmP-CPG (6.6 mol%) as catalyst. [c]
Starting acid 4b (Z:E = 85:15). [d] 100% conv. to 2d and 3f (50:50 ratio).
The co-catalytic one-pot total syntheses were highly chemoselective and gave
the corresponding valuable 3b and 3c after one-step purification in 73 and 78% overall
yield, respectively. Moreover, the synergistically heterogeneous Pd and lipase-catalyzed
in situ amidation step tolerated aromatic, heterocyclic and aliphatic substituents with
respect to the aldehyde component as well as functional acids to give 3a-3d mostly in
good to high overall yields (two in situ steps). Here, a clear substrate specificity of
CALB with respect towards both the in situ generated amine substrate and the acid
substrates was observed. For example, acid 4a was a better donor for the intermediate
vanillyl amine 2a as compared to n-hexyl amine 2d (entries 1 and 7). The long-chain
alkyne functionalized fatty acid 4b turned out to be a very good donor for the enzyme.
Moreover, we observed that the excess ammonia also could serve as a nucleophile for
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the enzyme-catalyzed amidation of the acyl donors. Performing the co-catalytic one-pot
reductive amination/amidation cascade reaction at a 0.5g scale of 1a provided 3a in
good yield (51%, 0.5g). We also designed a co-catalytic aerobic oxidation/reductive
amination/amidation sequence starting from an alcohol substrate 5a (Scheme 3).
Notably, alcohol 5a was converted to nonivamide 3a in one-pot (49% yield) using a
multi-catalyst system.
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Scheme 3. Catalytic aerobic oxidation/reductive amination/amidation relay sequence.
Combined heterogeneous metal/enzyme asymmetric relay catalysis. We first had to
develop a heterogeneously Pd(0)-nanoparticle catalyzed reductive amination of ketones
1 with HCO2NH4 to give chiral primary amines. The extensive condition screening
revealed that the Pd0-Amp-MCF-catalyzed reductive amination of acetophenone 1m
gave the corresponding alcohol 5m as the major product in toluene (See SI). To our
delight, the chemoselectivity switched to 2m when the transformation was performed in
MeOH with a decreased and optimized catalyst loading (Table 4). Thus, the scope of the
catalytic reductive amination of ketones 1 was investigated using this condition (Table
4).
Table 4. Ketone 1 substrate scope.
Entry
1
Ketone
Amine
Ratio
Time
(h)
Conv.
(%)[a]
Yield
of
2:5[a]
3
(%)[b]
74
88:12
1.5
>99
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[a] Determined by HNMR analysis of the crude reaction mixture. [b] Isolated yield of pure
racemic 3.
The catalytic transformation exhibited high chemoselectivity and the corresponding
racemic amides 3 were isolated in high yields after in situ amidation of amines 2. We
could now begin to test the heterogeneous metal/enzyme asymmetric relay catalysis
strategy. The heterogeneous metal/enzyme co-catalyzed reductive amination/kr relay
sequence was first investigated (Fig. 1b and Scheme 4).
Scheme 4. Heterogeneous metal/enzyme co-catalyzed reductive amination/kr relay sequence.
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Here ester 7 was employed as the acyl donor since it has been previously been shown to
improve the rate of the irreversible acylation of amines by hydrogen bond-activation in
the active site of CALB.29 The use of Pd-nanoparticles in combination with CALB as
co-catalysts for the dkr of secondary amines has recently been reported.12 Thus, if the
metal catalyst could take active part in the racemization of the intermediate amine 2
during the lipase-catalyzed amidation step a dkr would occur and the yield would be >
50%. If not, the yield would be lower (kr). The catalytic relay sequence was performed
in one-pot converting ketones 1m and 1n to the corresponding amides (R)-3m and (R)-
3n in 36% and 25% overall isolated yield with 97 and 92% ee, respectively. While
>76% of the ketone 1m was converted to 2m, it was next converted in around 50% to
amide (R)-3m by the co-catalytic amidation. Thus, the final transformation of the
catalytic relay sequence had performed according to a kinetic resolution step. Formic
acid is an inhibitor of CALB, however, the Pd0-Amp-MCF-catalyzed the conversion of
the excess formic acid to H2, CO2 and H2O as described vide supra so that catalytic
amidation could occur. We next turned our focus on developing a heterogeneous
metal/enzyme co-catalyzed reductive amination/dkr relay sequence (Fig. 1c and Scheme
5). It is known from the literature that the addition of H2 gas can promote the
racemization of amines 2 during a dynamic kinetic resolution step.12b,c We therefore
increased the Pd catalyst loading as well as added H2 after the catalytic reductive
amination to 2 had been completed (Scheme 5). The co-catalytic reaction sequences
assembled the corresponding amides (R)-3 in good overall yields with high ee’s from
ketones 1.
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Scheme 5. Heterogeneous metal/enzyme co-catalyzed reductive amination/dkr relay sequence. (a)
Isolated overall yield from 1. (b) Na2CO3 instead of Mol Sieve (4Å).
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We also investigated a heterogeneous metal/enzyme co-catalyzed reductive
amination/kinetic resolution relay sequence using a combination of Pd0-Amp-MCF and
transaminase (ATA, EC 2.6.1.18)30 as catalysts (Scheme 6). ATA enzymes were chosen
since they have been shown to be very important catalysts for industrial production of
biologically active amines.30b,c The one-pot catalytic relay sequence was successful and
the corresponding amines (S)-2 or (R)-2 were assembled from ketones 1 and ammonium
formate with high ees, respectively. The (R)-enantiomer of amine 2m was obtained with
an enantiomeric excess of 87% using ATA113 or 85% using Cv-ATA, respectively. No
conversion of the (R)-enantiomer was detected in these reactions, but the (S)-enantiomer
was not fully converted thus resulting in lower ee values as compared to the excellent
ones (>99%) obtained using ATA117.
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Scheme 6. Heterogeneous metal/enzyme co-catalyzed reductive amination/kinetic resolution relay
sequence. (a) Yield based on reacted ketone based on chiral-phase HPLC analysis.
Recycling. The recycling and life-time of heterogeneous catalysts are significant issues
for practical applications. Thus, we investigated the possibility of recycling both the
Pd0-Amp-MCF and Pd0-Amp-CPG after the reductive amination reactions of 1d and
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ketone 1m, respectively (see SI). Both catalysts displayed excellent recyclability and
chemoselectivity and no leaching was observed. To determine the Pd species in our
catalytic reductive amination system a hot filtration tests was performed. Thus, the Pd0-
AmP-MCF catalyst was filtered off after 20% conversion to 2a and the solid free filtrate
was allowed to stir for 3 h under identical reaction conditions. Analysis of the catalyst
free reaction by NMR analysis determined that no further conversion of the substrate
had occurred.
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Based on our experiments and the literature, the Pd catalyst is proposed to
accelerate: (1) The transfer hydrogenation of the in situ generated imine intermediates,
which are derived by condensation between 1 and HCO2NH4, to form 2. Here the
presence of iminium intermediates prior to formation of 2 was confirmed by HRMS
analysis of the reactions. (2) The decomposition of formate/formic acid to H2, H2O and
CO2. These catalytic processes allowed for the significant lower temperature and faster
rates than normally required for the Leuckart reactions. Notably, the latter process is
essential for the synergistically catalyzed one-pot transformation, since remaining
HCO2NH4 after the in situ formation of the amine 2 intermediate inhibited the catalytic
activity of CALB.
In summary, we have designed a novel concept for eco-friendly and asymmetric
synthesis based on highly chemo- and enantioselective heterogeneous metal/enzyme
relay catalysis. Here catalytic relay sequences were designed for the chemo- and
enantioselective synthesis of amines and amides in one-pot using heterogeneous multi-
catalyst systems. We began our investigation by the development of a mild and efficient
Pd-catalyzed direct synthesis of primary amines from aldehydes or ketones using
HCO2NH4 as amine source and reducing agent. The catalytic reaction was highly
chemoselective towards amine-formation and represents a heterogeneous, recyclable
and environmentally benign protocol for the simple one-step synthesis of a wide variety
of primary amines and glycine esters in high to excellent yields. Integration with
enzyme catalysis allowed for direct one-pot amide formation and one-step total
syntheses of biologically active capsaicinoids starting from an aldehyde or alcohol
substrate. The heterogeneous metal/enzyme catalysis strategy was also applied to the
direct on-pot asymmetric synthesis of amines and amides (up to >99% ee) when using
ketones as substrates. In all of the investigated catalytic relay sequences, the
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heterogeneous metal and enzyme operated in synergy during the in situ amidations and
the corresponding amides were mostly isolated in good to high overall yields. Future
application of heterogeneous metal-catalyzed reductive aminations, mechanistic and
medicinal studies as well as development of co-catalytic multi-component reactions are
ongoing and will be disclosed in due course.
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Experimental methods
Catalytic reductive amination of aldehydes. A microwave-vial containing a solution of 1 (0.2
mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-
MFC, 13.4 mg, 0.01 mmol, 8 wt%, 5 mol%) or (Pd0-AmP-CPG, 569Å, 74.0 mg, 2 wt%, 6.6
mol%) in toluene (1 mL) was stirred at 80 oC under N2 atmosphere for the time shown in Table
2. Next, the crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent,
concentrated and the crude amide 3 was purified by silica gel flash column chromatography.
Reductive amination/amidation catalytic relay. A microwave-vial containing a solution of 1
(0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd0-nanocatalyst (Pd0-
AmP-MFC, 13.4 mg, 0.01 mmol, 8 wt%, 5 mol%) or (Pd0-AmP-CPG, 569Å, 74.0 mg, 2 wt%,
o
6.6 mol%) in toluene (1 mL) was stirred at 80 C under N2 atmosphere for the time shown in
Table 2. Next, molecular sieves 4Å, acid 5 (0.2 mmol, 1.0 equiv.) and Novozyme-435
immobilized on a macroporous anionic resin (120 mg/mmol) were added. After 36 h of stirring
o
at at 80 C, the crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as
eluent, concentrated and the crude amide 3 was purified by silica gel flash column
chromatography.
Aerobic oxidation/reductive amination/amidation catalytic realy: To a microwave-vial
containing a solution of alcohol 5a (0.2 mmol, 1.0 equiv.) and Pd0-AmP-CPG (10.1 mg, 0.002
mmol, 1 mol %) in dry toluene(0.25 mL) was connected a O2 balloon. After stirring the reaction
mixture for 16h at 80 oC, HCO2NH4 (37.8 mg, 0.6 mmol, 3.0 equiv.), Pd0-AmP-MFC (10.8 mg,
0.008 mmol, 8 wt%, 4 mol%) and toluene (0.75 mL) were added under N2 conditions and the
o
reaction mixture was stirred at 80 C for 2.5 h. Next, molecular sieves 4Å, acid 4a (0.2 mmol,
1.0 equiv.) and lipase (120 mg/mmol) were added to the reaction mixture, which was stirred at
80 oC for 40h. The crude reaction mixture was filtrated through Celite using CHCl3 (10 mL) as
eluent and next concentrated under reduced pressure. The crude material was purified by silica
gel flash column chromatography.
Catalytic reductive amination of ketones. A vial containing a solution of 1 (0.2 mmol, 1.0
equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68
mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC
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for the time shown in table 4. Next, the solvent was evaporated and a solution of DIPEA (0.052
mL, 0.3 mmol, 1.5 equiv.) in dry dichloromethane (2.0 mL) followed by the addition of
methoxy acetylchloride (0.4 mL, 0.51 mmol/mL, 1 equiv.) were added to the vial, which was
flushed with Ar. After stirring overnight at room temperature, reaction mixture was filtered
through Celite with CH2Cl2 (2.5 mL) and the solvent was removed under reduced pressure. The
racemic α-methoxy-acetamides 3 were next isolated by silica gel flash column chromatography.
Reductive amination/kr catalytic relay. A vial containing a solution of 1 (0.2 mmol, 1.0
equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68
mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC
for the time shown in table 4. Next, the solvent was evaporated and Pd0- Pd0-AmP-MFC (5.4
mg, 0.008 mmol, 8 wt%, 2 mol%), Novozyme-435 (50 mg/mmol) and Mol. sieves (4 Å, 100
mg) were added to the vial with amine product. The vial was evacuated three times and refilled
with H2. Dry toluene (0.6 mL) was added to the vial and the mixture was heated 70 oC followed
by addition of ethyl methoxyacetate (47 µL, 0.4 mmol) and stirred for 6h. Next, the crude
reaction mixture was filtrated through Celite using CHCl3 (10 mL) as eluent and evaporated.
The crude material was purified by silica gel flash column chromatography.
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Reductive amination/dkr catalytic relay. A vial containing a solution of 1 (0.2 mmol, 1.0
equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68
mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC
for the time shown in table 4. Next, the solvent was evaporated and Pd0-Nanocatalyst (Pd0-
AmP-MFC, 10.72 mg, 0.008 mmol, 8 wt%, 4 mol%), Novozyme-435 (50 mg/mmol) and
additive (mol. siev. 4 Å (100 mg) or dry Na2CO3 (20 mg)] were added to the vial with amine
product. The vial was evacuated three times and refilled with H2. Dry toluene (0.6 mL) was
added to the vial, and a balloon containing H2 was connected to the vial. The mixture was
heated 70 oC followed by addition of ethyl methoxyacetate (47 µL, 0.4 mmol) and stirred for the
time shown in the Scheme 5. Next, the crude reaction mixture was filtrated through Celite using
CHCl3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash
column chromatography.
Reductive amination/kr catalytic relay. A vial containing a solution of 1 (0.2 mmol, 1.0
equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd0-nanocatalyst (Pd0-AmP-MFC, 2.68
mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70 oC
for the time shown in table 4. Next, the vial was put on ice and methanol (0.367 mL) was added,
followed by 6 mL of an aqueous buffer solution (50 mM HEPES, pH 8.2) containing amine
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transaminase (ATA) and 2-5 equivalents sodium pyruvate (1 equiv. = 0.2 mmol, 22 mg). The
tubes were put in darkness and room temperature for 24 hours with gentle mixing on an orbital
shaker. Enantiomeric excess (ee) was determined by HPLC analysis (triplicate samples).
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Supporting Information Available: Full experimental procedures, data and spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgements. Dedicated to Prof. Karl Hult on the occasion of his 70th birthday. We gratefully
acknowledge financial support from the European Union and Mid Sweden University. The Knut
and Alice Wallenberg Foundation is acknowledged for an equipment grant for the electron
microscopy facilities at Stockholm University. KTH Royal Institute of Technology is
acknowledged for the award of a PhD student excellence position to M. A.
References
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115-136. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem. Int. Ed. 2006, 45, 7134-7186. (c)”Cascade Biocatalysis – Integrating Stereoselective and
Environmentally Friendly Reactions”, Fessner, W.-D.; Riva, S. (Eds.), Wiley-VCH, Weinheim, Germany,
2014. (d) Cioc, R. C.; Ruijer, E.; Orru, R. V. A. Green. Chem. 2014, 16, 2958-2975. (e) Ramón, D. J.;
Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602-1634. (f) O’Reilly, E.; Turner, N. J. Perspectives in
Science 2015, 4, 55-61.
(2) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press,
New York, 2000. (b) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007, 9, 438-440.
(3) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745–2755.
(4) (a) Ibrahem, I.; Córdova, A. Angew, Chem Int. Ed. 2006, 45, 1952-1956. (b) Silvero, D. L.; Torker, S.;
Pilyugina, T.; Vieira, E. M.; Snapper, M. L., Haeffner, F.; Hoveyda, A. H. Nature 2013, 494, 216-221. (c)
Ibrahem, I.; Samec, J. S. M.; Bäckvall, J.-E.; Córdova, A. Tetrahedron Lett. 2005, 46, 3965-3968. (d)
Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008, 130, 14452-14453. (e) Han, Z.-Y.; Xiao, H.; Chen,
X.-H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182-9183. (f) Allen, A. E.; MacMillan, D. W. C.
Chem. Sci. 2012, 3, 633-658. (g) Rueping, M.; Dufour, J.; Maji, M. S. Chem. Commun. 2012, 48, 3406-
3408. (h) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365-2377. (i)
Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745−2755. (j) Zhong, C.; Shi, X. Eur. J. Chem. 2010,
2999−3025. (k) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012, 10, 211−224. (l) Du, Z.;
Shao, Z. Chem. Soc. Rev. 2013, 42, 1337−1378.
(5) Leyva-Perez, A.; Garcia-Garcia, P.; Corma, A. Angew. Chem. Int. Ed. 2014, 53, 8687-8690.
(6) Anderson, M.; Afewerki, S.; Berglund, P.; Córdova, A. Adv. Synth. Catal. 2014, 356, 2113-2118.
(7) Deiana, L.; Jiang, Y.; Palo-Nieto, C.; Afewerki, S.; Incerti-Pradillos, C. A.; Verho, O.; Tai, C-W.;
Johnston, E. V.; Córdova A. Angew. Chem. Int. Ed. 2014, 53, 3447-3451.
18
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2
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5
6
7
8
9
(8) (a) Thomas, J. M. Design and applications of single-site heterogeneous catalysts – contributions to
green chemistry, clean technology and sustainability; Imperial college press, London, 2012. (b) Corma,
A.; Garcia, H. Top. Catal. 2008, 48, 8–31. (c) Heterogenized homogeneous catalysts for fine chemical
production; Barbaro, P.; Liguori, F. eds., Springer, Dordrecht-Heidelberg-London-New York, Vol. 33,
2010.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Tsubogo, T.; Oyamada, H.; Kobayashi, S. Nature 2015, 520, 329-332.
(10) Mayer, S. F.; Kroutil, W.; Faber, K. Chem. Soc. Rev. 2001, 30, 332-339.
(11) (a) Pàmies, O.; Bäckvall, J.-E.. Chem. Rev. 2003, 103, 3247-3262. (b) Verho, O.; Bäckvall, J. -E. J.
Am. Chem. Soc. 2015, 137, 3996-4009.
(12) For examples of heterogeneous metal/enzyme co-catalyzed dkr of racemic amines see: (a)
Parvulescu, A.; De Vos, D.; Jacobs, P. Chem. Commun. 2005, 5307-5309. (c) Kim, M.-J.; Kim, W.-H.;
Han, K.; Choi, Y. K.; Park, J. Org. Lett., 207, 9, 1157-1159. (d) Gustafson, K. P.; Lihammar, R.; Verho,
O.; Engström, K.; Bäckvall, J.-E. J. Org. Chem. 2014, 79, 3747-3751.
(13) For examples of DKR of primary amines using an organometallic Ir complex as co-catalyst see: (a)
Blacker, A. J.; Stirling, M. J.; Page, M. I. Org. Process Res. Dev. 2007, 11, 642-648. a mercapto-radical
co-catalyzed see: (b) Poulhes, F.; Vanthunye, N.; Bertrand, M. P.; Gastaldi, S.; Gil, G. J. Org. Chem.
2011, 76, 7281-7286.
(14) Denard, C. A., Hartwig, J. F.; Zhao, H. ACS Catalysis, 2013, 3, 2856-2864.
(15) Sato, H.; Hummel, W.; Gröger, H. Angew. Chem. Int. Ed. 2015, 54, 4488-4492.
(16) For examples of combinations of metal/enzyme using compartmentalization using sol-gel
encapsulation to protect the enzyme from the transition metal co-catalyst see: (a) Gelman, F.; Blum, J.;
Avnir, D. J. Am. Chem. Soc. 2002, 124, 14460-14463. (b) Gelman, F.; Blum, J.; Avnir, New J. Chem.
2003, 27, 205-207. (c) Heidlinmann, M.; Rulli, G.; Berkessel, A.; Hummel, W.; Gröger, H. ACS Catal.
2014, 4, 1099-11103.
(17) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790-792.
(18) (a) Rylander, P. N. Hydrogenation Methods, Academic Press, NewYork, 1985. (b) Gomez, S.;
Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002, 344, 1037-1057. (c) Tarasevich, V. A.; Kozlov, N.
G. Russ. Chem. Rev. 1999, 68, 55-72. (d) Emerson, W. S. 1984, 4, 174-244.
(19) (a) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002, 344, 1037-1057. (b) Tararov,
V. I.; Börner, A. Synlett 2005, 203-211. (c) Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res. Dev.
2006, 10, 971-1031. (d) Antos, J. M.; Francis, M. B. Curr. Opin. Chem. Biol. 2006, 10, 253-262.
(20) (a) Leuckart, R. Ber. Dtsch. Chem. Ges. 1885, 18, 2341-2344. (b) Wallach, O. Ber. Dtsch. Chem.
Ges. 1891, 24, 3992-3993. (c) Pollard, C. B.; Young, D. C. J. Org. Chem. 1951, 16, 661-672. (d) Webers,
V. J.; Bruce, W. F. J. Am. Chem. Soc. 1948, 70, 1422-1424. (e) Moore, M. L. The Leuckart Reaction, In
Organic Reactions, Adams, R. Ed., John Wiley and Sons, New York, 1949, Vol. 5, pp 301-330.
(21) (a) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem, 2002, 67, 8685-
8687. (b) Wang, C.; Pettman, A.; Bacsa, J.; Xiao, J. Angew. Chem. Int. Ed. 2010, 49, 7548-7552. (c)
Kadyrov, R.; Riermeier, T. H. Angew. Chem. Int. Ed. 2003, 42, 5472-5474.
(22) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1988, 29, 3741-3744.
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3
4
(23) Hanson, R. W. J. Chem. Ed. 1997, 74, 430-431.
5
6
7
8
(24) (a) Lunxiang, Y.; Liebscher, J. Chem. Rev. 2007, 107, 133-173. (b) Ping, E.W.; Wallace, R.; Pierson,
J.; Fuller, T. F.; Jones, C. W. Microporous Mesoporous Mater. 2010, 132, 174-180. (c) Shakeri, M.; Tai,
C.-W.; Göthelid, E.; Oscarsson, S.; Bäckvall, J. E. Chem. Eur. J. 2011, 17, 13269-13273. (d) Johnston, E.
V.; Verho, O.; Kärkäs, M. D.; Shakeri, M.; Tai, C.-W.; Palmgren, P.; Eriksson, K.; Oscarsson, S.;
Bäckvall, J.-E. Chem. Eur. J. 2012, 18, 12202-12206. (e) Long, W.; Brunelli, N. A.; Didas, S. A.; Ping, E.
W.; Jones, C. W. ACS Catal. 2013, 3, 1700-1708. (f) Engström, K.; Johnston, E. V.; Verho, O.;
Gustafson, K. P. J.; Shakeri, M.; Tai, C.-W.; Bäckvall, J. E. Angew. Chem. 2013, 125, 14256-14260. (g)
Verho, O.; Nagendiran, A.; Johnston, E. V.; Tai, C. W.; Bäckvall, J.-E. ChemCatChem, 2013, 5, 612-618.
(h) Verho, O.; Gustafson, K. P.; Nagendiran, A.; Tai, C.-W.; Bäckvall, J.-E. ChemCatChem, 2014, 6,
3153-3159. (i) Bagal, D. B.; Watile, R. A.; Khedkar, M. V.; Dhake, K. P.; Bhanage, B. M. Catal. Sci.
Technol. 2012, 2, 354-358.
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(25) (a) Deiana, L.; Afewerki, S.; Palo-Nieto, C.; Verho, O.; Johnston, E. V.; Córdova, A. Sci. Rep. 2012,
2, 851-857. (b) Deiana, L.; Ghisu, L.; Córdova, O.; Afewerki, S.; Zhang, R.; Córdova, A. Synthesis 2014,
46, 1303-1310. (c) Deiana, L.; Ghisu, L.; Afewerki, S.; Verho, O.; Johnston, E. V.; Hedin, N.; Bacsik, Z.;
Córdova, A. Adv. Synth. Catal. 2014, 356, 2485-2492. (d) Córdova, A. Pure Appl. Chem. 2015, 87, 1011-
1019.
(26). Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.; Julius, D. Nature
1997, 389, 816-824.
(27). Lv, J.; Qi, L.; Yu, C.; Yang, L.; Guo, Y.; Chen, Y.; Bian, Z.; Sun, D.; Du, J. Ge, P.; Tang, Z.; Hou,
W.; Li, Y.; Chen, J.; Chen, Z.; Li, L. BMJ 2015, 351:h3942.
(28). Phenylcapcaisin 6c is biologically active and is used as a microorganism repellant agent. See: T.
Helsing, E. Bakstad, Int. Pat. PCT/NO2004/000270.
(29). Veld, M. A. J.; Hult, K.; Palmans, A. R. A.; Meijer, E. W. Eur. J. Org. Chem. 2007, 5416-5421.
(30) (a) Berglund, P.; Humble, M. S.; Branneby, C.; in: Comprehensive Chirality, Carreira, E. M.,
Yamamoto, H., Eds. Elsevier, Amsterdam, 2012, Vol 7. 390. (b) Savile, C. K.; Janey, J. M.; Mundorff, E.
C.; Moore, J. C.; Tam, S.;Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P.
N.; Huisman, G. W. Hughes, G. J. Science 2010, 239, 305-309. (c) Bornscheuer, U. T.; Huisman, G. W.;
Kazlauskas, R. J., Lutz, S.; Moore, J. C., Robins, K. Nature 2012, 485, 185-194.
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Scheme1
52x17mm (300 x 300 DPI)
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ACS Catalysis
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scheme2
39x10mm (300 x 300 DPI)
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ACS Catalysis
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Scheme3
32x5mm (300 x 300 DPI)
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ACS Catalysis
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Scheme4
43x8mm (300 x 300 DPI)
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scheme5
68x20mm (300 x 300 DPI)
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ACS Catalysis
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Table1
165x165mm (300 x 300 DPI)
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Scheme6
137x93mm (300 x 300 DPI)
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ACS Catalysis
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Table2
166x199mm (300 x 300 DPI)
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Table3
212x288mm (300 x 300 DPI)
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