Combining Rh-Catalyzed Diazocoupling and Enzymatic Reduction to Efficiently Synthesize Enantioenriched 2-Substituted Succinate Derivatives

Article abstract of DOI:10.1021/acscatal.7b00254

We report the development of a modular, one-pot, sequential chemoenzymatic system for the formal enantioselective construction of the C-C bond in 2-aryl 1,4-dicarbonyl compounds. This sequence comprises a rhodium-catalyzed diazocoupling that provides >9:1

Full text of DOI:10.1021/acscatal.7b00254

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Letter
Combining Rh-catalyzed diazocoupling and enzymatic reduction to
efficiently synthesize enantioenriched 2-substituted succinate derivatives
Yajie Wang, Mark J. Bartlett, Carl A. Denard, John F. Hartwig, and Huimin Zhao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00254 • Publication Date (Web): 08 Mar 2017
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ACS Catalysis
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Combining Rh-catalyzed diazocoupling and enzymatic reduction to
efficiently synthesize enantioenriched 2-substituted succinate deriv-
atives
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Yajie Wang,a Mark J. Bartlett,b Carl A. Denard,a John F. Hartwig*,b and Huimin Zhao*,a,c
aDepartment of Chemical and Biomolecular Engineering, University of Illinois at UrbanaꢀChampaign, Urbana, IL 61801
bDepartment of Chemistry, University of CaliforniaꢀBerkeley, Berkeley CA 94720
cDepartments of Chemistry, Biochemistry, and Bioengineering, Carl R. Woese Institute for Genomic Biology, University of
Illinois at UrbanaꢀChampaign, Urbana, IL 61801
KEYWORDS: Chemo-enzymatic catalysis, biocatalysis, transition metal catalysis, diazocoupling, alkene reduction, one-pot
ABSTRACT: We report the development of a modular, oneꢀpot, sequential chemoenzymatic system for the formal enantioselecꢀ
tive construction of the CꢀC bond in 2ꢀaryl 1,4ꢀdicarbonyl compounds. This sequence comprises a rhodiumꢀcatalyzed diazocoupling
that provides >9:1 selectivity for heterocoupling of two diazoesters and a reduction mediated by an eneꢀreductase (ER), which ocꢀ
curs in up to 99% enantiomeric excess (ee). The high yield and enantioselectivity of this system result from the preferential generaꢀ
tion of an (E)ꢀalkene from the diazo coupling reaction and selective reduction of the (E)ꢀalkene in a mixture of (E) and (Z) isomers
by the ER. Screening of a panel of ERs revealed that OPR1 from Lycopersicum esculentum catalyzes the reduction of bulky tertꢀ
butyl or benzyl esters to afford chiral diesters that are poised for orthogonal reactions at the two distinct ester units of the product.
Overall, this work demonstrates the benefit of combining organometallic and enzymatic catalysis to create unusual overall transꢀ
formations that do not require the isolation and purification of intermediates.
ic (E) and maleic (Z) acid derivatives remains challenging.7
The increasing demand for chiral building blocks, particuꢀ
larly those used for the preparation of biologically active comꢀ
pounds, has motivated the development of novel strategies for
enantioselective synthesis. To this end, systems that catalyze
enantioselective carbonꢀcarbon bond formation have been
studied intensively.1 Biocatalysts are increasingly employed to
provide levels of chemoꢀ, regioꢀ and stereoselectivity that are
challenging to achieve with a smallꢀmolecule catalyst, but
applications of biocatalysts for carbonꢀcarbon bond formation
are limited.2 The combination of chemical and biological cataꢀ
lysts in oneꢀpot could enable transformations that cannot be
Only recently did Pfaltz and coworkers report an enantioselecꢀ
tive Irꢀcatalyzed hydrogenation of 2ꢀarylꢀsubstituted fumarates
and maleates (Figure 1b).7a However, the hydrogenation reacꢀ
tions were limited to symmetric diesters and required high
catalyst loadings and hydrogen pressure.
Alternative methods to prepare enantioenriched 2ꢀaryl sucꢀ
cinic derivatives include Rhꢀcatalyzed 1,4ꢀadditions of arylꢀ
boronic acids to fumarate derivatives (Figure 1c),8 Cinchona
alkaloidꢀcatalyzed parallel kinetic resolution of monosubstiꢀ
tuted succinic anhydrides (Figure 1d),9 or enantioselective Nꢀ
heterocyclic carbene (NHC)ꢀcatalyzed βꢀprotonation through
the orchestration of three distinct organocatalysts: triazolium
salt, thiourea (HDB), and DMAP (Figure 1e).10 However, each
reaction has its limitations, such as requiring diꢀtertꢀbutyl
fumarates for high enantioseletivity, forming inseparable mixꢀ
tures of constitutional isomers from fumarates bearing two
different ester functional groups, having a maximum yield of
50%, and forming product with lower ee at higher conversion.
achieved by either of the two catalysts alone 2a, 3
and we conꢀ
,
sidered that formal, enantioselective CꢀC bond formation
could be achieved by combining a chemical catalyst that forms
a CꢀC bond and an enzyme that can set a stereogenic center at
one of the carbons of the new bond.
Asymmetric 2ꢀsubstituted succinic acid derivatives are
versatile building blocks for the preparation of biologically
active compounds,4 particularly natural products containing
the γꢀbutyrolactoneꢀunit.5 Rhodiumꢀcatalyzed asymmetric
hydrogenation of itaconic acid derivatives (Figure 1a) has
been widely used to prepare enantiomerically enriched 2ꢀ
subsituted succinic acid derivatives, but these methods are not
applicable to the synthesis of 2ꢀaryl substituted succinic acid
derivatives.6 Meanwhile, the synthesis of 2ꢀaryl succinic acid
derivatives via organocatalytic and transition metalꢀcatalyzed
asymmetric hydrogenation of prochiral arylꢀsubstituted fumarꢀ
Enzymatic C=C bond reduction was once coupled with oleꢀ
fin synthesis to prepare nonꢀchiral products.11 Here we report a
twoꢀstep, oneꢀpot sequential chemoenzymatic transformation
to prepare enantioenriched 2ꢀaryl 1,4ꢀdicarbonyl compounds
with good yield and excellent enantioselectivity. This transꢀ
formation combines a Rh(II)ꢀcatalyzed diazo coupling reaction
with an enzymatic reduction into oneꢀpot catalytic sequence
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unsymmetrical 2ꢀarylꢀsubstituted, alkenes containing carbonyl
that occurs in greater efficiency than the two individual steps,
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3
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7
8
while avoiding purification of the alkene intermediates (Figure
1). This process constitutes a novel chemoenzymatic carbonꢀ
carbon bond formation with control of the absolute configuraꢀ
tion of the new stereogenic center at one of the two carbons,
while addressing limitations of the prior syntheses of 2ꢀaryl
succinic acid derivatives.
groups at the 1 and 4 positions of the alkene. Davies and coꢀ
workers reported the [Rh2(OPiv)4]ꢀcatalyzed crossꢀcoupling of
diazo compounds to form 2ꢀarylꢀfumarate derivatives with
high chemoꢀ and stereoselectivity,1c and we tested reactions
catalyzed by both [Rh2(OPiv)4] and the commercially availaꢀ
ble rhodium(II) octanoate dimer [Rh2(Oct)4]. As shown in
Table 1, crossꢀcoupling of aryldiazo compounds 1 with diazoꢀ
acetate derivatives 2 affords predominantly the dicarbonyl
compounds 3a and 3b with only trace amounts (<5%) of hoꢀ
modimerization product 4. Importantly, the reaction catalyzed
by [Rh2(OPiv)4] occurs with high selectivity for formation of
E alkenes (100% stereoselectivity favoring the (E)ꢀdiester,
>10:1 stereoselectivity favoring (E)ꢀketoneꢀester, except entry
8). The reactions catalyzed by [Rh2(Oct)4] occur with yields,
chemoselectivity and stereoselectivity that are similar to those
of reactions catalyzed by [Rh2(OPiv)4]. With improved methꢀ
ods for preparation of diazoꢀcompounds,12 Rh(II)ꢀcatalyzed
carbenoidꢀinduced crossꢀcoupling of diazo compounds serves
as an attractive convergent method for the synthesis of unꢀ
symmetrical alkenes.
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To achieve the proposed enantioselective chemoenꢀ
zymatic formation of the CꢀC bond in 1,4ꢀdicarbonyl comꢀ
pounds, an appropriate enzyme is needed to reduce the 2,3ꢀ
unsaturated 1,4ꢀdicarbonyl compounds resulting from the diꢀ
azo coupling. Eneꢀreductases (ERs) have been shown to be
efficient, sustainable and costꢀeffective catalysts for reducing
activated α,βꢀunsaturated ketones, aldehydes, nitroalkenes,
13
carboxylic acids, and carboxylic acid derivatives,2a, and a
few enantioselective reductions of 2ꢀsubstituted fumaric acid
derivatives have been reported.13a, 14 However, our efforts were
focused on the synthesis and reduction of fumarate derivatives
containing two different carbonyl groups with orthogonal reꢀ
activity and, therefore, greater synthetic utility than symmetric
fumarate derivatives.
Figure 1. Synthesis of 2ꢀaryl succinate derivatives using sequenꢀ
tial rhodiumꢀ and enzyme catalysis (GDH: Glucose dehydrogenꢀ
ase, rt: room temperature).
To create a modular, enantioselective route to 2ꢀarylꢀ
fumarate derivatives, we first investigated the synthesis of
Table 1. Synthesis of asymmetric 2-aryl-sbustitued dicarbonyl alkenes by Rh-catalyzed cross-coupling of diazo compounds
[Rh2(Oct)4]
[Rh2(OPiv)4]
Entry
Ar
R1
R2
3aa
3ba
3aa
3bb
1
2
3
4
5
6
7
8
Ph
Ph
OMe
OMe
OMe
OtBu
Me
OEt
OtBu
OBn
OEt
44%
57%
44%
39%
64%
68%
47%
32%
ꢀ
67%
74%
67%
N.A.
57%
64%
46%
20%
ꢀ
ꢀ
ꢀ
Ph
6%
ꢀ
ꢀ
Ph
N.A.
5%
4%
3%
3%
4ꢀFꢀPh
4ꢀClꢀPh
3ꢀCF3ꢀPh
Ph
OEt
7%
7%
10%
4%c
Me
OEt
Me
OEt
OMe
4ꢀFꢀPh
aIsolated yield. bYield determined by GC analysis.
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ERs containing flavin mononucleotides (FMN) require
distinct esters that allow orthogonal reactivity at each termiꢀ
nus.10 None of the enzymes catalyzed the reduction of the subꢀ
strate containing a bulky ester group and aryl group on the
same alkene carbon (Entry 4).
1
2
3
4
5
6
7
8
NADPH or NADH as coꢀfactors to catalyze asymmetric reꢀ
duction. In this study, glucose dehydrogenase (GDH) from
Bacillus megaterium was used to recycle NADPH continuousꢀ
ly by reduction of NADP+ with concomitant conversion of
glucose to gluconic acid. We tested the reduction of the 2ꢀaryl
fumaric and maleic acid derivatives with a series of ERs origiꢀ
nating from different organisms, including Old Yellow Enꢀ
zymes OYE1, OYE2 and OYE3 from Saccharomyces cere-
visiae, OYE4 from Achromobacter sp., 1, 2ꢀoxophytodienoate
reductases OPR1 and OPR3 from Lycopersicum esculentum,
alkene reductase YersER from Yersinia bercovieri; thermoꢀ
philic ‘ene’ꢀreductase TOYE from Thermoanaerobacter pseu-
dethanolicus, LacER from Lactobacillus casei, XenA and
XenB from Pseudomonas putida, and NADPH dehydrogenase
EBP1 from Candida albicans.
Compared to metalꢀcatalyzed hydrogenation of dimethyl
2ꢀphenylmaleates,7a the enzymatic reduction offers several
advantages. The turnover numbers for the enzymatic reduction
were seventy times higher than those obtained with current
catalysts, and the process occurred with excellent enantioseꢀ
lectivity (>99%) at room temperature, in phosphate buffer
under atmospheric pressure. Furthermore, YersER tolerates
both water miscible organic solvents, such as DMSO and ethꢀ
ylene glycol, and immiscible organic solvents such as hexane
and toluene.13b This tolerance toward organic solvents enhancꢀ
es the potential use of ERs for reactions of less waterꢀsoluble
substrates.
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Most of the ERs catalyzed the reduction of the E isomers
(3a) of 2ꢀarylꢀsubstitued, 1,4ꢀdicarbonyl alkenes generated
from the crossꢀcoupling reactions of the diazo compounds, but
some of them resulted in products with poor ee (Table S1).
None of the ERs we tested reduced the trace amount of Z isoꢀ
mers 3b (<5%), based on GC evaluation. Table 2 shows the
asymmetric reduction of (E)ꢀ2ꢀarylꢀsubstitued, 1,4ꢀdicarbonyl
alkenes by the ERs that gave the product in 65%ꢀ85% yield. In
general, ERs catalyzed the reduction of the alkenes containing
two esters with excellent enantioselectivity (>99%) (Entries
1&2) and the reduction of alkenes containing one ketone and
one ester with good to excellent enantioselectivity (85%ꢀ99%)
(Entry 5ꢀ8). OPR1 is the only enzyme we tested that reduced
the unsaturated 1,4ꢀdicarbonyl compounds containing bulky
ester groups at the carbon β to the aryl group (Entries 2&3) to
form enantioenriched 2ꢀaryl succinate derivatives bearing two
Having identified an ER that reduces the substrates of the Rhꢀ
catalyzed coupling of diazocompounds, we sought to develop
conditions to conduct the two reactions in one pot without
purification of the intermediates. After conducting the diazo
coupling reaction, we evaporated the DCM, added all reagents
and the ER for the reduction step into the crude mixture. The
oneꢀpot process formed the enantioenriched succinate derivaꢀ
tives in >70% yield by completely converting the (E)ꢀalkenes,
the major product from crossꢀcoupling reaction (Table 3), and
leaving the (Z)ꢀalkene unreacted. Similar yield and enantioseꢀ
lectivity were observed with purified samples of the alkene
(Table 2), suggesting that the ERs are compatible with the
Rhodium(II) catalyst and trace amounts of chemical impurities
contained in the crude crossꢀcoupling reaction.
Table 2. Enzymatic reduction of (E)-2-aryl-sbustitued, 1,4-dicarbonyl alkenes by ene-reductases
Large scale
isolated yieldb
Most selective
ER
Entry
1
Ar
Ph
R1
R2
Yielda 4
%ee
TONe
91%
71%f
76%
86%
ꢀ
455
7071f
650
430
ꢀ
OMe
OEt
>99%c
YersER
84%
2
3
4
5
6
7
8
Ph
Ph
OMe
OMe
OtBu
Me
OtBu
OBn
OEt
>99% c
>99% c
ꢀ
87% c
85%d
85% d
>99% d
>99% d
93% d
OPR1
OPR1
ꢀ
65%
80%
ꢀ
Ph
4ꢀFꢀPh
4ꢀClꢀPh
3ꢀCF3ꢀPh
Ph
OEt
80%
85%
78%
87%
74%
93%
YersER
YersER
YersER
OYE2
YersER
OPR1
75%
78%
70%
80%
69%
85%
375
423
322
460
370
465
Me
OEt
Me
OEt
OMe
4ꢀFꢀPh
aGC yield. blargeꢀscale (0.2 mmol) reactions and isolated yield. cee determined by chiral SFC. dee determined by chiꢀ
ral HPLC. eTurn over number (TON) is defined as the number of moles of substrate that a mole of catalyst can conꢀ
vert before becoming inactivated. KPi: sodium phosphate buffer. fReaction with 0.01mol% enzyme loading
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1
2
Table 3. Two-step sequential reaction to synthesize enantioenriched 2-aryl-substituted succinate derivatives
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4
5
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Yielda
Isolated yield
Ar
R1
R2
%eed
TON
over two stepse
3ab
3bb
0%
0%
4%
4%
4c
Entry
1
2
3
4
Ph
Ph
OMe
OMe
OMe
Me
OEt
OBn
78%
72%
38%
56%
93%
88%
90%
82%
>99%
>99%
>99%
89%
62%
54%
26%
37%
465
440
450
410
Ph
4ꢀFꢀPh
OEt
3ꢀCF3ꢀPh
aDetermined by GC analysis. bTrace amount of reaction mixture was taken after the diazocoupling reaction and evaluated by
GC analysis. cCalculated based on the starting materials for enzymatic reaction. dee determined by chiral HPLC. eCalculated
based on the starting materials of the crossꢀcoupling reaction.
Figure 2. Docking of A) 4ꢀethyl 1ꢀmethyl 2ꢀ phenylfumarate, B) 4ꢀethyl 1ꢀmethyl 2ꢀ phenylmaleate, and C) 4ꢀ(tertꢀbutyl) 1ꢀmethyl 2ꢀ
phenylfumarate within the active site of OPR1. D) the surface representation of the active site view of OPR1 with 4ꢀ(tertꢀbutyl) 1ꢀmethyl
2ꢀphenylfumarate docked at active site. In the stick models, substrates shown in green, FMN shown in yellow, protein residues shown in
grey.
To provide possible explanations of the origin of the seꢀ
lectivity of ERs for (E)ꢀalkenes over (Z)ꢀalkenes, we conductꢀ
ed computational docking studies. Docking of 4ꢀethyl 1ꢀ
methyl 2ꢀphenylfumarate and 4ꢀethyl 1ꢀmethyl 2ꢀ
phenylmaleate into the active site of OPR1 was conducted
using the crystal structure of OPR1 (Figure S1) containing pꢀ
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hydroxybenzoic acid (PHB) bound to the active site. As shown
Author Contributions
1
2
3
4
5
6
7
8
in Figure 2A, the carbonyl oxygen of 4ꢀethyl 1ꢀmethyl 2ꢀ
phenylfumarate is hydrogen bonded to Hisꢀ187 Nϵ2 and Hisꢀ
190 Nδ1 with distances of 3.2 Å and 2.8 Å respectively. The
distance between the N(5) of FMNH2 (transferring a hydride)
and the carbon of the alkene that is β to the aryl group (βꢀ
carbon) of the substrate is 4.0 Å, and the distance between the
Tyr 192 (a proton donor) and αꢀcarbon of the substrate is 3.9
Å. The (Z)ꢀalkene 4ꢀethyl 1ꢀmethyl 2ꢀphenylmaleate binds to
the same site of OPR1 (Figure 2B). However the distance beꢀ
tween N(5) of FMNH2 and the β carbon is more than 5.0 Å.
This distance would be too large for the reaction to occur. In
addition, the more hindered 4ꢀ(tertꢀbutyl) 1ꢀmethyl 2ꢀ
phenylfumarate did not dock into most of the ERs (data are
not shown), but it did dock into OPR1. As shown in Figure
2C, the distance between the N(5) of FMNH2 and the βꢀcarbon
of 4ꢀ(tertꢀbutyl) 1ꢀmethyl 2ꢀphenylfumarate, and the distance
between Tyr 192 and αꢀcarbon of 4ꢀ(tertꢀbutyl) 1ꢀmethyl 2ꢀ
phenylfumarate are both 4.0 Å. These distances are comparaꢀ
ble to those between the proton and hydride donors of OPR1
to 4ꢀethyl 1ꢀmethyl 2ꢀphenylfumarate. A pocket formed by
Tyrꢀ78, Lysꢀ79 and Tyrꢀ358 at the entrance of active site acꢀ
commodates the phenyl ring, while the relatively open active
site entrance may tolerate the bulky tertꢀbutyl group (Figure
2D).
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manuꢀ
script.
Funding Sources
This work was supported by the NSF under the CCI Center for
Enabling New Technologies through Catalysis (CENTC) Phase II
Renewal, CHEꢀ1205189.
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ACKNOWLEDGMENT
Prof. Kurt Faber is acknowledged for the gift of plasmid pET21aꢀ
OPR1, pET21aꢀOPR3 and pET22a_EBP1. Prof. Uwe T.
Bornscheuer is acknowledged for the gift of plasmid pGastonꢀ
XenA and pGastonꢀXenB. Prof. Nigel S. Scrutton is acknowlꢀ
edged for the gift of plasmid pET21b_TOYE. Prof. Zhongliu Wu
is acknowledged for the gift of plasmid pET28a_OYE4. We also
thank Metabolomics Center of UIUC for GCꢀMS facilities and
Dr. Alexander Vladimirovich Ulanov’s suggestions on GC analyꢀ
sis. Part of NMR data was collected in the IGB Core on a 600
MHz NMR funded by NIH grant number S10ꢀRR028833. We
thank Dr. Xudong Guan’s assistance with NMR data acquisition.
ABBREVIATIONS
ER, eneꢀreductase; GDH, glucose dehydrogenase, OYE, old yelꢀ
low enzyme; FMN, flavin mononucleotides; ee, enantiomeric
excess; rt, room temperature; GC, gas chromatography; HPLC,
high performance liquid chromatography; SFC, supercritical fluid
chromatography; PHB, pꢀhydroxybenzoic acid.
In summary, we have developed a oneꢀpot, sequential
catalytic system for the synthesis of 2ꢀarylꢀsuccinate derivaꢀ
tives by formal asymmetric CꢀC bond formation created by
integrating a transitionꢀmetal catalyst with an enzyme, whereꢀ
by a Rhꢀcatalyzed crossꢀcoupling of carbene units is followed
by an ERꢀcatalyzed enantioselective reduction of (E)ꢀ2ꢀarylꢀ
substituted dicarbonyl alkenes among a mixture of the E and Z
isomers. With this system, 2ꢀarylꢀsubstituted succinate derivaꢀ
tives are generated from two different diazaoesters or ketones
and reducing equivalents in high yield and excellent ee withꢀ
out purification of the alkene intermediates or separation of E
and Z isomers. Evaluation of a panel of ERs as catalyst led to
the identification of OPR1, which reacts with substrates conꢀ
taining bulky tertꢀbutyl esters and produces enantioenriched,
chiral unsymmetrical diesters that have great potential as synꢀ
thetic intermediates.
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Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Supplemental tables and figures, and additional information of
experimental procedures and methods, characterization data, and
NMR spectra of organic products.
AUTHOR INFORMATION
Corresponding Author
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Huimin Zhao: zhao5@illinois.edu
John F. Hartwig: jhartwig@berkeley.edu
Present Addresses
Carl Denard: University of TexasꢀAustin, Chemistry Department,
2500 Speedway, Austin Texas, 78712
Mark J. Bartlett: Gilead Sciences, Inc., 333 Lakeside Dr., Foster
City, CA 94404
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