A Sequential Umpolung/Enzymatic Dynamic Kinetic Resolution Strategy for the Synthesis of γ-Lactones

Article abstract of DOI:10.1002/chem.202000747

Combining biological and small-molecule catalysts under a chemoenzymatic manifold presents a series of significant advantages to the synthetic community. We report herein the successful development of a two-step/single flask synthesis of γ-lactones through the merger of Umpolung catalysis with a ketoreductase-catalyzed dynamic kinetic resolution, reduction, and cyclization. This combined approach delivers highly enantio- and diastereoenriched heterocycles and demonstrates the feasibility of integrating NHC catalysis with enzymatic processes.

Full text of DOI:10.1002/chem.202000747

A Journal of
Accepted Article
Title: A Sequential Umpolung/Enzymatic Dynamic Kinetic Resolution
Strategy for the Synthesis of g-Lactones
Authors: Karl Scheidt, Mark Maskeri, and Malte Schrader
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202000747
Link to VoR: http://dx.doi.org/10.1002/chem.202000747
Supported by

10.1002/chem.202000747
Chemistry - A European Journal
COMMUNICATION
A Sequential Umpolung/Enzymatic Dynamic Kinetic Resolution
g
Strategy for the Synthesis of -Lactones
Mark A. Maskeri,[a] Malte L. Schrader,[a] and Karl A. Scheidt*[a]
Abstract: Combining biological and small-molecule catalysts under a
chemoenzymatic manifold presents a series of significant advantages
to the synthetic community. We report herein the successful
development of a two-step/single flask synthesis of γ-lactones through
the merger of Umpolung catalysis with a ketoreductase-catalyzed
dynamic kinetic resolution, reduction, and cyclization. This combined
approach delivers highly enantio- and diastereoenriched heterocycles
and demonstrates the feasibility of integrating NHC catalysis with
enzymatic processes.
alcohols.[5h] Similarly, the Hyster and Hartwig labs have reported
photocatalytic cooperativity with enzymatic processes for
enantioselective deacetoxylation and access to a–substituted
succinic esters and related species, respectively.[5c, 5d] Despite
these impressive reports, intermolecular reactions, particularly
carbon-carbon bond forming reactions, have received less
attention in chemoenzymatic catalysis.
Our research group has long been driven by the synthetic
utility found in leveraging the Umpolung, or reversal of polarity, of
functional groups to facilitate valuable carbon-carbon bond-
forming reactions.[6] Of particular use has been N-heterocyclic
carbenes (NHCs) as organocatalysts due to their ability to induce
the Umpolung of carbonyl species (e.g., classical reactions such
as the Stetter reaction, Fig. 1A), as well as recent exploration of
photochemically-enabled Umpolung of unsaturated malonate
species.[7] We envisioned a chemoenzymatic sequence[8] that
leveraged the powerful carbon-carbon bond-forming capabilities
of NHC- or acyl radical chemistries[9] with the selectivity and
specificity of engineered enzymes[10] (e.g., Fig. 1B) would present
convenient and rapid access to a variety of scaffolds, notably γ-
lactones, from readily-available commercial chemicals.
Natural biological systems utilize a wide variety of chemical
reactions catalyzed by enzymes. Poly-enzyme cascades
harmoniously exchange substrates, sequestering otherwise
incompatible chemical transformations to permit the synthesis of
complex molecular scaffolds from simple building blocks.[1]
Seeking to mimic these advantages, synthetic chemists have
devised multi-catalyst systems to conduct cooperative, domino,
and tandem catalytic processes that, ideally, shepherd a
substrate through multiple chemical transformations.[2] These
reactions are often challenging to develop, as conditions
amenable for all catalysts and transformations may be elusive
and/or fully incompatible.[3] Such a challenge is especially
apparent in the case of paired chemical and enzymatic systems,
since traditional reaction conditions suitable for small-molecule
catalysts are characteristically incompatible with enzymes (e.g.,
solvent, pH, temperature). The challenges inherent in designing
such processes notwithstanding, these systems remain attractive
for reasons beyond the powerful bond transformations they
enable, such as reduced intermediate purification and isolation
requirements, decreased operation and production costs, and
diminished waste generation.[3a]
A. Carbonyl Umpolung (e.g., Stetter)
O
acyl anion equivalent
O
NHC
OH
O
R
Ph
O
“
”
+
Ph
N
R1
≡
R1
R1
H
Ph
R1
Ph
S
O
B. KREDs enantioenriched alcohols (e.g., Codexis)
O
OH
KRED
R
R
montelukast
(Singulair)
Ar
Ar
> 99% ee
Previous studies to merge chemical and biological catalysts
have traditionally focused on chemoenzymatic dynamic kinetic
resolutions (DKRs) of racemic alcohols and amines.[4] Only
recently have examples of merging organocatalysis, transition-
metal catalysis, and photocatalysis with enzymatic catalysis and
cascades emerged.[5] Recent work from Garg demonstrated
cooperative nickel-catalyzed Suzuki-Miyaura coupling with
enzymatic reduction for access to enantioenriched diaryl tertiary
C. Dynamic kinetic resolutions by hydrogenation (e.g., Noyori)
O
O
O
OH
Ru*
H
H
98:2 dr
94% ee
O
Me
O
Me
H2
racemic
D. This work: chemoenzymatic sequence
O
O
O
O
H
O
NHC
KRED
R1
R1
OR
OR
H
R1
+
[a]
M. A. Maskeri, M. L. Schrader, and Prof. Dr. K. A. Scheidt*
Department of Chemistry, Center for Molecular Innovation and Drug
Discovery, Northwestern University
(±)
RO2C
O
CO2R
O
RO
small-molecule catalysis
C–C bond formation
enzymatic catalysis
DKR and reduction
Silverman Hall, Evanston, Illinois 60208
*scheidt@northwestern.edu
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Existing strategies and proposed combined catalysis strategy
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10.1002/chem.202000747
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COMMUNICATION
The γ-lactone is found present in nearly 10% of natural
products, and methods for the enantio- and diastereoselective
construction of this privileged heterocycle are much desired.[11]
From a reaction design standpoint, the 1,4-dicarbonyl products of
an NHC-facilitated Stetter reaction could be intercepted by a
ketoreductase enzyme, furnishing the desired lactone by catalytic
yields, establishing 1:3:6 isopropanol:1-chlorododecane:0.1 M tris
buffer at pH = 9 as the optimal solvent conditions for the
enzymatic DKR/reduction.
With optimized conditions for the enzymatic DKR/reduction
portion of the chemoenzymatic process established, we set out to
explore the capabilities of the reaction (Table 1). All products
reported herein were observed in >20:1 dr as determined from 1H
NMR spectral analysis of the unpurified reaction mixtures. This
observation, together with the high stereochemical fidelity of the
resulting products, strongly validates our DKR/reduction
approach to γ-lactones. Aryl substrates bearing electron-neutral
to electron-poor substituents produced products in good-to-
excellent yield and excellent er (2a-2i), though rigid scaffolds of
high steric bulk (2j) induced a reduction in yield and minor erosion
in enantioselectivity. Heterocycles (2k) were well tolerated, as
were alkyl substrates (2l, 2m) in good to excellent yield and
enantioselectivity. Electron-rich substrates (e.g., 4-OMe, not
shown) were largely unreactive under this manifold, requiring
extended reaction times with poor yield and selectivity. This
discrepancy may be due to cation-π interactions of the electron-
rich arene in the enzyme active site.[14] Crystals of 2a suitable for
X-ray crystallographic analysis confirm both the absolute and
relative trans stereochemical relationship of the lactone
substituents.
reduction
and
intramolecular
cyclization.[12]
Strategic
implementation of this process would permit the enzyme to set
multiple stereogenic centers through a dynamic kinetic resolution,
obviating NHC catalyst stereocontrol (Fig. 1C; Fig. 1D).
Given the challenges inherent to the development of
chemoenzymatic processes, we initially decoupled and optimized
each component of the two-step process, affecting a sequential
chemoenzymatic process. Due to the sensitivity of enzymes to
traditional small-molecule catalysis conditions, we sought
especially robust operating conditions for the DKR/reduction
portion of the overall reaction. We therefore initiated our enzyme
studies by surveying a panel of commercially available KREDs
from Codexis Inc. against ketone 1a for reduction and DKR
activity (see electronic Supporting Information [SI] for screening
details). The enzyme KRED-P2-C02 handily afforded γ-lactone
2a and was subsequently subjected to a broader selection of
biphasic solvent conditions (Figure 1).[13] Scale-up of the
screening hits found, with minor additional optimization, biphasic
solvent conditions with a clear partition between organic and
aqueous phases predominated. Such biphasic conditions are
synthetically tractable for enzymatic catalysis due to the capability
of the organic solvent to overcome the low water solubility of many
organic compounds and mitigate substrate/product enzyme
inhibition.
O
O
KRED P2-C02 (10 wt %)
NADP (10 wt %)
CO2Me
CO2Me
O
R
biphasic solventa
40 °C
R
1
2
OMe
O
R =
O
O
≡
KRED P2-C02 (5 wt %)
NADP (1 wt %)
CO2Me
F
F
Cl
Br
O
Ph
2a, 72%
>99:1 er
>20:1 dr
2b, 79%
99:1 er
>20:1 dr
2c, 90%
98:2 er
>20:1 dr
2d, 75%
99:1 er
>20:1 dr
biphasic solventa
40 °C
Ph
2a
X-ray
CO2Me
1a
OMe
50% solvent
Me
O
5% solvent
15% solvent
30% solvent
PO4 TRIS ETA PO4 TRIS ETA PO4 TRIS ETA PO4 TRIS ETA
Me
CF3
F
1
2
3
4
5
6
7
8
9
10
11 12
2e, 77%
>99:1 er
>20:1 dr
2f, 78%
99:1 er
>20:1 dr
2g, 74%
>99:1 er
>20:1 dr
2h, 52%
98:2 er
>20:1 dr
2i, 55%
99:1 er
>20:1 dr
O
MTBE
A
B
C
D
E
F
2-Me THF
THF
O
BnO
Ph
N
Ph
2j, 22%
93:7 er
>20:1 dr
2k, 44%
94:6 er
>20:1 dr
2l, 73%
99:1 er
>20:1 dr
2m, 76%
>99:1 er
>20:1 dr
CPME
O
O
diethyl ether
1,4 dioxane
DME
2n, 51%
>99:1 er
>20:1 dr
G
H
Table 1. Substrate scope of enzymatic reduction. See SI for reaction protocol
and details. Yields reported are isolated; er determined by chiral-phase
SFC/HPLC analysis; dr determined from unpurified 1H NMR spectra. Absolute
stereochemistry of 2a determined by X-ray crystallographic analysis;
stereochemistry of all other lactone products assigned by analogy. bSolvent:
1:3:6 isopropanol:1-chlorododecane:tris buffer (0.1 M, pH = 9).
1-Cl-dodecane
low conversion
high conversion
Figure 1. Solvent and buffer screening for the enzymatic DKR/reduction and
cyclization. a”Biphasic solvent” is composed of X% organic solvent (5, 15, 30,
50%) with the remaining balance occupied by aqueous buffer (phosphate [PO4],
TRIS, triethanolamine [ETA]) and 10% IPA. See SI for screening details.
This enzymatic DKR/reduction and cyclization also permitted
access to differentially-protected lactones such as 2n in high
selectivity and moderate yield. Together with methyl ester lactone
2a, these products were further processed through amidation (3),
yielding a densely-functionalized β-hydroxy ester, and palladium-
catalyzed deprotection (4). Such a strategy permits differential
access to both the ester and lactone functionality, enabling further
Our screening analysis identified that the enzymatic reaction
proceeded with high levels of efficiency in
a 10:45:45
isopropanol:aqueous buffer:organic solvent mixture with
particular efficacy in clearly-defined phase separation. Scale-up
efforts generally ruled out ethereal solvents due to diminished
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10.1002/chem.202000747
Chemistry - A European Journal
COMMUNICATION
transformations. For example, scaffolds such as 4 present useful
functionality for elaboration through classical two-electron and
radical decarboxylative pathways.[15]
Stetter reaction were introduced to the enzyme portion of the
process revealed the use of potassium bases entirely inhibited
enzyme activity, an outcome not well documented to date or
anticipated (see SI). However, substituting potassium carbonate
with sodium carbonate and magnesium carbonate basic—metal
counterions amenable to KRED catalysis—restored activity, albeit
in diminished yield (54%). With the identification of a Stetter
reaction to produce the substrates for enzymatic reduction, we
successfully realized a two-step chemoenzymatic process for the
synthesis of diastereo- and enantioenriched γ-lactones.
Additionally, the utilization of an NHC catalyst in this synthesis of
γ-lactones represents access to substrates previously
inaccessible in the NHC catalytic domain. Though NHC-catalyzed
syntheses of γ-lactones are known to the literature, these
preparations both preferentially produce the cis product and are
not extendable to the ester-substituted class of compounds 2. The
oxobutanoate substrate required for this bond disconnection
O
OH
H
MeO
Ph
H
N
4-BrBnNH2 (1.2 equiv)
3, 65%
Ar = 4-BrPh
O
THF, 50 °C
R = Me
O
O
Ar
O
Ph
Pd(Ph3P)4 (3 mol %)
HCO2H (4 equiv)
OR
O
O
4, 60%
THF, rt
R = allyl
Ph
OH
O
With efficacious conditions for the enzymatic portion of our
chemoenzymatic process identified, we turned our attention to the
Umpolung reaction sequence. Despite the widespread use of
NHCs in organocatalysis, the usage of such catalysts under
reaction conditions suitable for enzymatic catalysis is
comparatively rare.[16] Also surprisingly atypical are Stetter
reactions conducted on the α,β-unsaturated ester substrates
preferentially
undergoes
NHC-catalyzed
β-protonation/
dimerization through the enolate pathway to afford 5, not the
expected homoenolate product
6
in the presence of
benzaldehyde (see SI, references). [7a, 20]
considered precursors for the desired acetylated ketones 1.[17]
A
reaction traditionally performed neat, in ethanol, or DMF at
elevated temperatures, the Stetter reaction and other NHC-
catalyzed reactions can be made more amenable to conditions
favorable to enzymes.[12a, 12b, 18] We have previously demonstrated
the viability of a decarboxylation-enabled Stetter reaction under
buffered aqueous conditions, though the elevated temperatures
required for the generation of the Breslow intermediate would be
deleterious to paired enzymes.[16a] Indeed, we observed
significant drop-off in enzyme activity with prolonged exposure to
temperatures above 50 °C, which validates the sequential
approach to this chemistry. However, an approach utilizing
Glorius’s Isa-NHC catalyst[19] proved fruitful, furnishing desired
acetylated β-ketoesters 1 in good to excellent yields over a variety
of substrates (Table 2).[12c]
BF4
Mes
N
N
N
(10 mol %)
iPrEt2N (10 mol %)
PhCHO (1 equiv)
O
O
O
O
H
EtO2C
EtO2C
O
THF (0.1 M), rt
Ph
EtO2C
CO2Et
5 (dimer)
observed, NMR
6
not observed
Given the comparatively mild conditions we identified for the
Stetter reaction producing species 1, we conducted the full
chemoenzymatic cascade in
a single operation. Directly
combining the Stetter reaction with KRED catalysis furnished a
modest yield of 27% of the desired lactone with full consumption
of the starting 4-chlorobenzaldehyde and the intermediate ketone
1c (Scheme 2A). Analysis of the unpurified reaction indicates the
presence of multiple species containing the 4-chlorophenyl
moiety, suggesting unproductive side reactions of both the NHC
and KRED. Significantly more success was identified under a
solvent-swap manifold, whereby the Stetter reaction was run to
completion in THF before replacement with the optimized
biphasic solvent conditions. This one-pot chemoenzymatic
procedure produced 75% yield of the desired lactone product with
a single purification and minimal handling.
ClO4
Mes
N
O
O
O
(15 mol %)
S
O
R
OMe
OMe
dimethyl fumarate (1.5 equiv)
K2CO3 (80 mol %)
THF, 50 °C, 5 h
R
H
F
1 (±)
R =
Me
Cl
Me
1a, 85%
1b, 78%a
1c, 95%
1e, 87%
1h, 75%
O
O
A.
dimethyl fumarate (1.5 equiv)
Isa-NHC (15 mol %)
base (0.8 equiv)
O
O
O
KRED P2-C02 (10 wt %)
NADP (10 wt %)
O
N
O
H
1k, 69%a
1l, 54%
1n, 74%a
40 °C, 1:3:6
IPA:Cl-dodecane:tris
O
Cl
CO2Me
Cl
2c
Table 2. Scope of NHC-catalyzed Stetter reaction of aldehydes and fumarates.
aReaction conducted under air atmosphere.
75% (solvent swapa)
27% (one stepb)
B.
[Ir] (1 mol %)
O
O
NADPNa (1 wt %)
then
O
O
KRED P2-C02 (5 wt %)
OMe
OMe
This Stetter reaction proved modestly efficient under air and
in 1:1 THF:0.1 M tris @ pH = 9. Additionally, the reaction was
operable at enzyme-friendly temperatures (40 °C), though with
reduced reaction rate. Slight reductions in yield were noted when
THF was replaced by the enzyme-optimal biphasic solvent
conditions (see SI). Control reactions wherein elements of the
ONa
Ph
buffer:Novec 7000:IPA
(4.5:4.5:1)
O
CO2Me
2a
O
73% (sequentialc)
49% (one stepb)
[Ir] = (Ir[dF(CF3)ppy]2(dtbpy))PF6
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10.1002/chem.202000747
Chemistry - A European Journal
COMMUNICATION
aFumarate+NHC+K2CO3, THF, then solvent swap then enzyme; see SI for
reaction details. bAll components present at start of reaction. cPhotoredox
catalysis then enzyme addition in the same flask; see SI for reaction details.
Scheme 2. One-pot chemoenzymatic
syntheses
of γ-lactones.
361, 1733-1755; e) F. Romiti, J. Del Pozo, P. H. S. Paioti,
S. A. Gonsales, X. Li, F. W. W. Hartrampf, A. H. Hoveyda,
J. Am. Chem. Soc. 2019, 141, 17952-17961.
a) F. Rudroff, M. D. Mihovilovic, H. Gröger, R. Snajdrova,
H. Iding, U. T. Bornscheuer, Nat. Catal. 2018, 1, 12-22; b)
S. Schmidt, K. Castiglione, R. Kourist, Chem. Eur. J. 2018,
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M. P. Thompson, M. D. Truppo, N. J. Turner, Nat. Rev.
Chem. 2018, 2, 409-421.
For reviews of enzymatic DKR for the production of
stereoenriched alcohols and amines, see: a) O. Verho, J. E.
Backvall, J. Am. Chem. Soc. 2015, 137, 3996-4009; b) C.
Aranda, G. Oksdath-Mansilla, F. Bisogno, G. de Gonzalo,
Adv. Synth. Catal. 2019; For reviews of DKR, see: c) B. M.
Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921-2944; d)
H. Pellissier, Tetrahedron 2011, 67, 3769-3802; e) H.
Pellissier, Tetrahedron 2016, 72, 3133-3150; Selected
examples of metal- and small molecule-catalyzed DKR: f)
R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H.
Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109,
5856-5858; g) M. Kitamura, T. Ohkuma, M. Tokunaga, R.
Noyori, Tetrahedron: Asymmetry 1990, 1, 1-4; h) V.
Jurkauskas, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124,
2892-2893; i) S. Hoffmann, M. Nicoletti, B. List, J. Am.
Chem. Soc. 2006, 128, 13074-13075; j) K. M. Steward, E.
C. Gentry, J. S. Johnson, J. Am. Chem. Soc. 2012, 134,
7329-7332.
[3]
[4]
In parallel with our exploration of Stetter reactivity for the
generation of β-ketoesters 1, we examined the possibility of
pairing our enzymatic DKR/reduction with a photocatalytic
generation of 1 (Scheme 2B). The combination of photocatalysis
with enzymatic catalysis is appealing: photocatalytic reactions
typically occur at or near ambient temperature and proceed
through water- and protein-stable reactive intermediates.
Accordingly, accessing acyl radicals by way of photoredox-
induced decarboxylation enables
a Giese-type addition to
dimethyl maleate, producing 1a on way to the desired lactone in
49% one-pot yield.[16a, 21] By delaying the addition of enzyme until
the photochemical reaction is complete the yield of the desire
lactone increases to 73%. However, attempts to generalize the
substrate scope of this process has not been realized yet and
efforts are ongoing to realize this process.
We have developed an efficient, mild, and highly selective
two-step-one-pot chemoenzymatic protocol to access densely
functionalized γ-lactones inaccessible to date with established
NHC catalysis. The process, accomplished through the
concomitant application of a compatible Stetter reaction and
KRED-catalyzed DKR/reduction, permits rapid access to these
privileged heterocycles from simple building blocks. Given the
synthetic ease and high selectivity of this approach, we anticipate
such processes merging the synthetic breadth of small-molecule
catalytic manifolds with highly-selective biocatalysts represent the
future of synthetic catalysis.
[5]
For reviews of cooperative chemo/biocatalytic processes,
see: a) C. A. Denard, J. F. Hartwig, H. Zhao, ACS Catal.
2013, 3, 2856-2864; b) M. Hönig, P. Sondermann, N. J.
Turner, E. M. Carreira, Angew. Chem. Int. Ed. 2017, 56,
8942-8973;
Selected
examples
of
cooperative
chemo/biocatalytic processes: c) Z. C. Litman, Y. Wang, H.
Zhao, J. F. Hartwig, Nature 2018, 560, 355-359; d) K. F.
Biegasiewicz, S. J. Cooper, M. A. Emmanuel, D. C. Miller,
T. K. Hyster, Nat. Chem. 2018, 10, 770-775; e) E. Burda,
W. Hummel, H. Gröger, Angew. Chem. Int. Ed. 2008, 47,
9551-9554; f) E. V. Johnston, K. Bogár, J. E. Backväll, J.
Org. Chem. 2010, 75, 4596-4599; g) A. M. Sarkale, V.
Maurya, S. Giri, C. Appayee, Org. Lett. 2019, 21, 4266-
4270; h) J. E. Dander, M. Giroud, S. Racine, E. R. Darzi, O.
Alvizo, D. Entwistle, N. K. Garg, Commun. Chem. 2019, 2,
82.
a) R. B. Lettan, T. E. Reynolds, C. V. Galliford, K. A. Scheidt,
J. Am. Chem. Soc. 2006, 128, 15566-15567; b) T. E.
Reynolds, C. A. Stern, K. A. Scheidt, Org. Lett. 2007, 9,
2581-2584; c) A. Chan, K. A. Scheidt, J. Am. Chem. Soc.
2007, 129, 5334-5335; d) T. E. Reynolds, M. S. Binkley, K.
A. Scheidt, Org. Lett. 2008, 10, 5227-5230; e) R. B. Lettan,
C. C. Woodward, K. A. Scheidt, Angew. Chem. Int. Ed.
2008, 47, 2294-2297; f) R. B. Lettan, C. V. Galliford, C. C.
Woodward, K. A. Scheidt, J. Am. Chem. Soc. 2009, 131,
8805-8814.
Acknowledgements
[6]
We thank Northwestern and the National Institute of General
Medical Sciences (GM073072 and GM131431) for support of this
work. The authors thank Keegan Fitzpatrick and Charlotte Stern
(NU) for X-ray crystallography assistance, Ada Kwong (NU) for
high-resolution mass spectrometry assistance, and Dr. Adam
Csakai for helpful early discussions.
[7]
For recent reviews on NHCs and NHC cooperative
catalysis, see: a) M. N. Hopkinson, C. Richter, M. Schedler,
F. Glorius, Nature 2014, 510, 485-496; b) M. H. Wang, K.
A. Scheidt, Angew. Chem. Int. Ed. 2016, 55, 14912-14922;
c) K. J. R. Murauski, A. A. Jaworski, K. A. Scheidt, Chem.
Soc. Rev. 2018, 47, 1773-1782; Selected NHC-catalyzed
processes from our group: d) A. E. Mattson, A. R.
Bharadwaj, K. A. Scheidt, J. Am. Chem. Soc. 2004, 126,
2314-2315; e) M. T. Hovey, D. T. Cohen, D. M. Walden, P.
H. Cheong, K. A. Scheidt, Angew. Chem. Int. Ed. 2017, 56,
9864-9867; f) K. J. R. Murauski, D. M. Walden, P. H.
Cheong, K. A. Scheidt, Adv. Synth. Catal. 2017, 359, 3713-
3719; g) A. Lee, J. L. Zhu, T. Feoktistova, A. C. Brueckner,
P. H. Cheong, K. A. Scheidt, Angew. Chem. Int. Ed. 2019,
58, 5941-5945; Selected photocatalytic Umpolung
processes from our group: h) B. R. McDonald, K. A. Scheidt,
Org. Lett. 2018, 20, 6877-6881; i) R. C. Betori, K. A. Scheidt,
ACS Catal. 2019, 9, 10350-10357.
Keywords: chemoenzymatic catalysis • sequential catalysis •
ketoreductase enzyme • N-heterocyclic carbene catalysis •
photoredox catalysis
References:
[1]
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2019, 58, 6846-6879; For recent reviews on artificial
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COMMUNICATION
COMMUNICATION
Maskeri, Mark A., Schrader, Malte L.,
Scheidt, Karl A.*
O
O
O
O
O
small-molecule catalysis
C–C bond formation
O
NHC
KRED
R1
OR
OR
H
R1
+
R1
+
enzymatic catalysis
DKR and reduction
Page No. – Page No.
(±)
RO2C
O
CO2R
RO
high-value
heterocycles
Title
readily-available
starting materials
Herein we report the development of a two-step-one-pot synthesis of γ-lactones
through the unification of a robust NHC-catalyzed Stetter reaction with a
ketoreductase-catalyzed dynamic kinetic resolution, reduction, and cyclization. The
process sets two stereogenic centers and provides rapid access to densely-
functionalized privileged heterocycles.
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