Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis

Article abstract of DOI:10.1002/anie.201810059

A chemobiocatalytic strategy for the highly stereoselective synthesis of nitrile-substituted cyclopropanes is reported. The present approach relies on an asymmetric olefin cyclopropanation reaction catalyzed by an engineered myoglobin in the presence of ex situ generated diazoacetonitrile within a compartmentalized reaction system. This method enabled the efficient transformation of a broad range of olefin substrates at a preparative scale with up to 99.9 % de and ee and up to 5600 turnovers. The enzymatic product could be further elaborated to afford a variety of functionalized chiral cyclopropanes. This work expands the range of synthetically valuable, abiotic transformations accessible through biocatalysis and paves the way to the practical and safe exploitation of diazoacetonitrile in biocatalytic carbene transfer reactions.

Full text of DOI:10.1002/anie.201810059

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Accepted Article
Title: Highly diastereo- and enantioselective synthesis of nitrile-
substituted cyclopropanes via myoglobin-mediated carbene
transfer catalysis
Authors: Rudi Fasan and Ajay L. Chandgude
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810059
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10.1002/anie.201810059
Angewandte Chemie International Edition
COMMUNICATION
Highly Diastereo- and Enantioselective Synthesis of Nitrile-
Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer
Catalysis
Ajay L. Chandgude and Rudi Fasan*[a]
Abstract: A chemobiocatalytic strategy for the highly stereoselective
synthesis of nitrile-substituted cyclopropanes is reported. The present
approach relies on an asymmetric olefin cyclopropanation reaction
catalyzed by an engineered myoglobin in the presence of ex situ
generated diazoacetonitrile within a compartmentalized reaction
system. This method enabled the efficient transformation of a broad
range of olefin substrates at the preparative scale with up to 99.9%
de and ee and up to 5,600 turnovers. The enzymatic product could be
strategy for the highly stereoselective synthesis of nitrile-
substituted cyclopropanes via myoglobin-catalyzed olefin
functionalization with diazoacetonitrile. This method provides a
rather general, efficient, and scalable route to enantiopure
cyclopropanes incorporating a cyano group, which can be readily
elaborated to afford variously functionalized chiral cyclopropanes.
further elaborated to afford
a variety of functionalized chiral
cyclopropanes. This work expands the range of synthetically valuable,
abiotic transformations accessible through biocatalysis and it paves
the way to the practical and safe exploitation of diazoacetonitrile in
biocatalytic carbene transfer reactions.
The catalytic asymmetric cyclopropanation of alkenes with
diazo compounds constitutes a convenient and direct strategy for
the construction of optically active cyclopropanes,[1] which are key
structural motifs in numerous natural products and
pharmaceuticals[2] Within this structural class, cyano-substituted
cyclopropanes represent particularly attractive building blocks
owing to the versatility of the cyano group toward its
interconversion to a variety of functional groups.[3] Moreover,
cyano-functionalized cyclopropanes have been incorporated into
pharmacologically active molecules, including the potent
cathepsin K inhibitor odanacatib.[4] Notable contributions from the
Davies, Charette, and Zhang group have recently introduced
chemocatalytic protocols for the asymmetric synthesis of cyano-
substituted cyclopropanes starting from donor-acceptor or
acceptor-acceptor diazo compounds.[5] In stark contrast, viable
methods for the asymmetric synthesis of cyano-substituted
Scheme 1. Methods for synthesis of nitrile-substituted cyclopropanes using
diazoacetonitrile.
Heme-containing proteins[9] as well as engineered/artificial
metalloenzymes[10] have been recently identified as viable
biocatalysts for promoting olefin cyclopropanations in the
presence of diazo reagents. In particular, we previously reported
the ability of engineered variants of myoglobin (Mb) to catalyze
the cyclopropanation of vinylstyrenes with ethyl α-diazoacetate
(EDA) with a high degree of diastereo- and enantioselectivity.[9c,
cyclopropanes
using
the
acceptor-only diazo
reagent diazoacetonitrile (N2CHCN) have been largely missing.
As an isolated effort in this direction, chiral Ru-porphyrins were
reported to catalyze the cyclopropanation of styrene derivatives
in the presence of pre-formed diazoacetonitrile (1a), but only with
moderate diastereoselectivity (20-50% de) and enantioselectivity
(41-71% ee) (Scheme 1).[6] More recently, the Koenigs group has
reported the iron-catalyzed cyclopropanation of vinylarenes in the
presence of in situ generated[7] diazoacetonitrile.[8] While offering
good yields and scalability, this method provides only moderate
diastereoselectivity (2:1 to 7:1 dr) and no enantioselectivity in the
cyclopropanation reaction (Scheme 1).[8] Motivated by the
shortcomings of current methodologies for this transformation, we
have pursued and report herein the development of a biocatalytic
9d]
Despite this progress, the scope of biocatalytic
cyclopropanations has been largely restricted to α-diazoacetates,
limiting the types of functionalized cyclopropanes accessible
using these systems. To overcome these limitations, our attention
was drawn to diazoacetonitrile, a largely underutilized reagent in
organic chemistry.[11] The application of diazoacetonitrile in
carbene transfer manifolds presents important challenges since
this reagent cannot be easily handled, due to its high volatility,
toxicity, and explosive nature.[12] While protocols for in situ
generation of diazoacetonitrile through diazotization of 2-amino-
acetonitrile[11, 13]—a shelf-stable, readily available, and
inexpensive reagent—, are incompatible with protein stability and
function, our recent success in engaging gaseous 2-diazo-
trifluoroethane (DTE) in myoglobin catalysis[9g] prompted us to
apply an analogous compartmentalized reaction system for
testing the ability of myoglobin to accept diazoacetonitrile as a
carbene donor for olefin cyclopropanation. Accordingly, we tested
a reaction system in which diazoacetonitrile (1a) generated in situ
[a]
Dr. A. L. Chandgude, Prof. Dr. R. Fasan
Department of Chemistry, University of Rochester
120 Trustee Road, Rochester, NY 14627 (USA)
E-mail: rfasan@ur.rochester.edu
Supporting information for this article is given via a link at the end of
the document.
via diazotization of 2-amino-acetonitrile (1b) in
a ‘reagent
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10.1002/anie.201810059
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Mb(H64V,V68A)-catalyzed cyclopropanation of p-chlorostyrene
with ex situ generated diazoacetonitrile.[a]
generation chamber’, is carried through a ‘reaction chamber’
containing the biocatalyst and a model olefin substrate (p-chloro-
styrene, 2a) via a continuous flow of inert gas (Ar) (Table 1 and
Figure S1). The myoglobin variant Mb(H64V,V68A) was selected
as the catalyst in reason of its high stereoselectivity in olefin
cyclopropanations with EDA.[9c, 9d] Gratifyingly, a reaction system
involving Mb(H64V,V68A)-containing whole cells (OD600: 80) and
ex situ generated diazoacetonitrile resulted in the accumulation of
the desired nitrile-substituted cyclopropane product, 3a, in good
conversion (44%; Table 1, Entry 2). A similar reaction with purified
protein did not yield any product (Table 1, Entry 1), indicating that
the whole cell system protects the biocatalyst from inactivation by
the gas flow. Importantly, the Mb(H64V,V68A)-catalyzed reaction
was found to proceed also with excellent diastereo- and
equiv
1[b]
5
Conv.
(Yield)[c]
0
%
de
-
Entry
Cat.
OD600
TON
-
% ee
1
2
protein
cells
cells
cells
cells
cells
cells
cells
-
-
80
40
20
10
5
5
5
44%
43%
55%
50%
46%
40%
230
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
99.9
enantioselectivity (99.9% de and ee), producing
a single
3
465
930
stereoisomer with trans-(1S,2S) absolute configuration as
established by X-ray crystallography (Table 1; Figure S3). These
results thus showed that diazoacetonitrile can be effectively
utilized as carbene donor by the Mb-based carbene transferase.
In addition, the chiral induction imposed by Mb(H64V,V68A) in the
cyclopropanation reaction with diazoacetonitrile mirrors that
4
5
5
5
1,700
3,110
675
6
5
7[d]
8[e]
20
20
10
5
72%
87%[f]
86%[f]
(81%)[f]
1,500
9[e,g]
cells
20
5
5,600
99.9
99.9
observed in styrene cyclopropanation with EDA[9c] and DTE[9g]
,
highlighting the conserved stereoselectivity of this biocatalyst
across these acceptor-only carbene donors. Further experiments
showed that other hemoproteins can catalyze this reaction, but
only with lower activity and/or stereoselectivity compared to
Mb(H64V,V68A) (Table S2).
[a] Reaction conditions: 10 mM 4-chloro-styrene (2a), purified Mb variant
(20 μM) or Mb(H64V,V68A)-expressing E. coli (BL21(DE3)) cells in KPi 50
mM (pH 7), at 20 mL-scale, RT, 5 hours. NaNO2 was slowly added over 30
min.[22] [b] Relative to olefin. [c] Product conversion as determined by SFC.
Isolated yields are reported in brackets. Errors are within 10%. [d] Slow
addition of NaNO2 over 4h.[e]2-Aminoacetonitrile in 2 mL of 1:1 H2O:toluene
mixture. [f] Reaction time: 15 hours. [g] 2a at 30 mM.
Based on the promise of these initial results, the
Mb(H64V,V68A)-catalyzed reaction was further optimized. A
decrease in catalyst loading (i.e., cell density (OD600) from 80 to
5) showed a progressive increase in the catalytic turnovers (TON)
supported by the hemoprotein (230 → 3,110), while providing
similar or higher product conversions (44-55%) and maintaining
excellent stereoselectivity (Table 1, Entries 3-6). Because of its
superior efficiency, a cell density (OD600) of 20 was thus chosen
for the subsequent studies. Upon observing that a larger excess
of carbene precursor (10 vs. 5 equiv. of 1b) generated over a
longer time period (4 vs. 0.5 hours) did not lead to noticeable
improvements in product conversion (Entry 7), we surmised that
only part of the diazo compound produced in the ‘reagent
generation chamber’ is made available to the biocatalyst. We
attributed this phenomenon to the high solubility of
diazoacetonitrile in water, which would hamper its effective
transfer to the reaction chamber. Upon optimization of the reagent
generation reaction using different solvent systems (Table S3),
we found that a water:toluene (1:1) mixture proved to be optimal
for maximizing both formation of the diazo reagent and its mass
transfer to the reaction chamber, leading to improved product
conversions of 72% and 87% over 5 and 15 hours, respectively,
with no impact on diastereo- and enantioselectivity (Table 1, entry
8). Importantly, the reaction could be readily scaled up (from 10
to 30 mM p-chlorostyrene), enabling the isolation of 86 mg of
enantiopure 3a (99.9% de and ee) in 81% yield (Table 1, entry 9).
Under these conditions, the Mb(H64V,V68A) catalyzes 5,600
turnovers, which corresponds to an approximately 50-to 100-fold
higher catalytic activity than reported with chemocatalytic systems
(~50-100 TON).[6, 8]
Mb(H64V,V68A)-catalyzed
cyclopropanation
with α-
diazoacetonitrile under the optimized conditions described above
and at the preparative scale (0.6 mmol olefin) (Table 2). These
experiments showed that styrene (2b) as well as various styrene
derivatives carrying para, meta and ortho substituents (2c-2i) are
efficiently processed by the Mb(H64V,V68A) variant, leading to
the corresponding cyclopropanation product 3b-3i in good to
excellent conversion (50-99%) and isolated yields (44-84%)
(Table 2; Entries 1-2;4-8). Both electrondonating (3f-i) and
electronwithdrawing substituents (3c, 3e) on the benzene ring of
the olefin were equally well tolerated, although lower yields were
obtained for 3d due to its volatility. Importantly, excellent levels of
diastereo- and enantioselectivity (98 - >99% de and ee) were
maintained across these styrenyl substrates. In addition, different
vinylarenes such as naphtyl-, pyridyl-, and thiophenyl-substituted
olefins could be also efficiently transformed by the
Mb(H64V,V68A) biocatalyst to give the corresponding
cyclopropane products 3j, 3l, and 3m in good yields (48-87%) and
with high stereoselectivity (84-99% de and ee) (Table 2; Entries
9, 11-12). Along with 3l and 3m, the efficient synthesis of 3k in
high enantiopurity further demonstrated the substrate scope of
the Mb(H64V,V68A) across α,α-disubstituted olefins (Entry 10) as
well as substrates incorporating N- and S-containing heterocycles,
which find widespread use in medicinal chemistry.
The high catalytic activity of Mb(H64V,V68A) across these
substrates (1,520-4,960 TON; Table 2) prompted us to investigate
challenging substrates such as β-methyl-styrene, which has
previously eluded Mb-catalyzed cyclopropanation with EDA[9c]
.
To explore the scope of this reaction, a diverse panel of
styrene derivatives and vinylarenes were subjected to
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10.1002/anie.201810059
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COMMUNICATION
Table 1. Substrate scope of Mb(H64V,V68A)-mediated olefin cyclopropanation
with diazoacetonitrile.[a]
enzyme containing a highly reactive[14] iridium-porphyrin (20-310
TON).[10d] Altogether, the results summarized in Table 2 denoted
the broad substrate scope of Mb(H64V,V68A)-mediated olefin
cyclopropanation with diazoacetonitrile. Remarkably, this
biocatalyst maintains high trans-(1S,2S) stereoselectivity across
the diverse arylarenes, as judged based on crystallographic
analysis of 3c, 3d, and 3i (Figure S4-6) and the similar
chromatographic behavior of the other products in chiral SFC or
GC compared to that of the structurally characterized enantiopure
products (Table S5-S8).
Conv.
Motivated by the positive results with the α,β-disubstituted
alkenes, we further probed the capability of the method to enable
the transformation of alkenes other than aryl-substituted olefins,
Entry
Product
(Yield)
TON
% de
% ee
[b]
50%
(44%)
1
2
2080
4960
>99
97
96
96
whose successful cyclopropanation with diazoacetonitrile was not
8]
previously reported.[6,
This group included unactivated
99%
(74%)
substrates such as alkyl-substituted (5a-b) and electrondeficient
olefins (5e-f). To our delight, all the reactions afforded the desired
nitrile-substituted cyclopropane products 5a-f with modest to
excellent diastereo- and enantioselectivity (Scheme 2).
32%
(31%)
3
4
5
2420
3820
3820
>99
>99
98
>99
>99
97
77%
(50%)
77%
(66%)
98%
(84%)
6
7
4880
3730
2760
2550
3540
3810
>99
>99
99
99
>99
97
75%
(66%)
65%
(61%)
8
63%
(61%)
9
84
85
87%
(73%)
10
11
>99
>99
99
96%
(61%)
76
Scheme 2. Methods for synthesis of nitrile-substituted cyclopropanes using
diazoacetonitrile. *Enantiomers could not be resolved using chiral SFC or GC.
90%
(71%)
Notably, the biocatalyst displayed over 4,700 TON in the
conversion of the acrylamide substrate 4f to 5f. These results
further highlighted the generality of Mb(H64V,V68A)-catalyzed
cyclopropanation reaction with diazoacetonitrile as well as its
expanded scope compared to Mb-catalyzed cyclopropanation
with α-diazoesters.[9c, 9d]
12
13
3590
110
>99
69
85
2%
(nd)
>99
5%
(nd)
14
380
17
46
While biocatalytic cyclopropanation reactions have so far
9h, 9i, 10, 15]
remained largely confined to α-diazo esters,[9a-f,
we
envisioned that a key advantage of the present strategy would lie
in the possibility to access diverse cyclopropane structures by
leveraging the versatile reactivity of the cyano group.[3] Illustrating
this point, the enzymatically produced compound 3a could be
further processed to access a panel of functionally diversified
cyclopropanes (Scheme 3). Specifically, alkaline hydrolysis of 3a
readily produced the carboxy- and the carboxyamide-
functionalized cyclopropanes 6 and 7, respectively, in 51-84%
yield in a single step. On the other hand, reduction of 3a with
DIBAL furnished the formyl-substituted cyclopropane 8 in 83%
yield, whereas its reduction with LAH followed by N-benzylation
afforded the methylamino derivative 9 in 63% yield over two steps.
[a] Reaction conditions: 30 mM olefin, Mb(H64V,V68A)-expressing E. coli
(OD600 = 20) in KPi buffer (50 mM, pH 7), 20 mL-scale, RT, 5-12 hours. NaNO2
was slowly added over 30 min. [b] Product conversion as determined by SFC.
Isolated yields are reported in brackets. Errors are within 15%.
Albeit in low yields, 3n and 3o could be obtained in
enantioenriched form (73-98% ee), demonstrating the feasibility
of the present methodology to access tri-substituted
cyclopropanes (Table 2; Entries 13 and 14). Notably, the catalytic
activity of the iron-based Mb(H64V,V68A) in this reaction (110-
380 TON) compares well with that reported for the
cyclopropanation of β-methyl-styrene with EDA using an artificial
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10.1002/anie.201810059
Angewandte Chemie International Edition
COMMUNICATION
2007, 36, 1109-1119; d) H. Pellissier, Tetrahedron 2008, 64, 7041-
7095.
T. T. Talele, J. Med. Chem. 2016, 59, 8712-8756.
Of note, methylamino-cyclopropanes constitute the core structure
of marketed drugs such as tasimelteon[16] and levomilcipran.[17]
Finally, a zinc-catalyzed [2+3] cycloaddition reaction of 3a with
NaN3[18] gave the tetrazole-substituted cyclopropane 10, whereas
a reaction with aminoethanol and zinc chloride[19] afforded the
oxazoline-functionalized cyclopropane 11 in good yields (39-84%).
In most cases, the transformation of the nitrile group occurred with
no erosion of enantiopurity (>99% ee, Scheme 3).
[2]
[3]
a) A. J. Fatiadi, Preparation and Synthetic Applications of Cyano
Compounds, Wiley-VCH, New York, 1983; b) F. C. Schaefer, The
Chemistry of the Cyano Group: Nitrile Reactivity, Interscience, New
York, 1970.
a) J. Y. Gauthier, N. Chauret, W. Cromlish, S. Desmarais, L. T.
Duong, J. P. Falgueyret, D. B. Kimmel, S. Lamontagne, S. Leger, T.
LeRiche, C. S. Li, F. Masse, et al., Bioorg. Med. Chem. Lett. 2008,
18, 923-928; b) J. Pedersen, C. Lauritzen, 2012, WO 2012/130299.
a) J. R. Denton, K. Cheng, H. M. L. Davies, Chem. Commun. 2008,
1238-1240; b) W. Lin, A. B. Charette, Adv. Synth. Catal. 2005, 347,
1547-1552; c) D. Marcoux, S. Azzi, A. B. Charette, J. Am. Chem.
Soc. 2009, 131, 6970-+; d) S. F. Zhu, X. Xu, J. A. Perman, X. P.
Zhang, J. Am. Chem. Soc. 2010, 132, 12796-12799.
[4]
[5]
[6]
[7]
Y. Ferrand, P. Le Maux, G. Simonneaux, Tetrahedron-Asymmetr.
2005, 16, 3829-3836.
a) R. P. Wurz, A. B. Charette, Org. Lett. 2002, 4, 4531-4533; b) B.
Morandi, E. M. Carreira, Angew. Chem. Int. Ed. 2010, 49, 938-941;
c) B. Morandi, B. Mariampillai, E. M. Carreira, Angew. Chem. Int. Ed.
2011, 50, 1101-1104.
[8]
[9]
K. J. Hock, R. Spitzner, R. M. Koenigs, Green Chem. 2017, 19,
2118-2122.
a) P. S. Coelho, E. M. Brustad, A. Kannan, F. H. Arnold, Science
2013, 339, 307-310; b) P. S. Coelho, Z. J. Wang, M. E. Ener, S. A.
Baril, A. Kannan, F. H. Arnold, E. M. Brustad, Nat. Chem. Biol. 2013,
9, 485-487; c) M. Bordeaux, V. Tyagi, R. Fasan, Angew. Chem. Int.
Ed. 2015, 54, 1744–1748; d) P. Bajaj, G. Sreenilayam, V. Tyagi, R.
Fasan, Angew. Chem. Int. Ed. 2016, 55, 16110–16114; e) J. G.
Gober, A. E. Rydeen, E. J. Gibson-O'Grady, J. B. Leuthaeuser, J.
S. Fetrow, E. M. Brustad, Chembiochem 2016, 17, 394-397; f) J. G.
Gober, S. V. Ghodge, J. W. Bogart, W. J. Wever, R. R. Watkins, E.
M. Brustad, A. A. Bowers, ACS Chem. Biol. 2017, 2, 1726–1731; g)
A. Tinoco, V. Steck, V. Tyagi, R. Fasan, J. Am. Chem. Soc. 2017,
139, 5293-5296; h) A. M. Knight, S. B. J. Kan, R. D. Lewis, O. F.
Brandenberg, K. Chen, F. H. Arnold, ACS Central Sci. 2018, 4, 372-
377; i) O. F. Brandenberg, C. K. Prier, K. Chen, A. M. Knight, Z. Wu,
F. H. Arnold, ACS Catal. 2018, 8, 2629-2634.
Scheme 3. Diversification of biocatalytically produced nitrile-substituted
cyclopropane.
In summary, we have developed an efficient biocatalytic
method for the highly diastereo- and enantioselective synthesis of
nitrile-substituted cyclopropanes through the activation of
diazoacetonitrile. The present strategy offers unprecedented
degrees of stereocontrol compared to previous chemocatalytic
strategies (Scheme 1), along with high TON, scalability, and a
[10]
a) P. Srivastava, H. Yang, K. Ellis-Guardiola, J. C. Lewis, Nat.
Commun. 2015, 6, 7789; b) G. Sreenilayam, E. J. Moore, V. Steck,
R. Fasan, Adv. Synth. Cat. 2017, 359, 2076–2089; c) G.
Sreenilayam, E. J. Moore, V. Steck, R. Fasan, ACS Catal. 2017, 7,
7629-7633; d) H. M. Key, P. Dydio, D. S. Clark, J. F. Hartwig, Nature
2016, 534, 534-537; e) H. M. Key, P. Dydio, Z. N. Liu, J. Y. E. Rha,
A. Nazarenko, V. Seyedkazemi, D. S. Cark, J. F. Hartwig, ACS
Central Sci. 2017, 3, 302-308; f) M. W. Wolf, D. A. Vargas, N.
Lehnert, Inorg. Chem. 2017, 56, 5623-5635; g) K. Ohora, H. Meichin,
L. M. Zhao, M. W. Wolf, A. Nakayama, J. Hasegawa, N. Lehnert, T.
Hayashi, J. Am. Chem. Soc. 2017, 139, 17265-17268; h) H. Yang,
A. M. Swartz, H. J. Park, P. Srivastava, K. Ellis-Guardiola, D. M. Upp,
G. Lee, K. Belsare, Y. F. Gu, C. Zhang, R. E. Moellering, J. C. Lewis,
Nat. Chem. 2018, 10, 318-324; i) L. Villarino, K. E. Splan, E.
Reddem, L. Alonso-Cotchico, C. Gutiérrez de Souza, A. Lledós, J.-
D. Maréchal, A.-M. W. H. Thunnissen, G. Roelfes, Angew. Chem.
Int. Ed. 2018, in press (doi: 10.1002/anie.201802946).
P. K. Mykhailiuk, Eur. J. Org. Chem. 2015, 7235-7239.
a) D. D. Phillips, W. C. Champion, J. Am. Chem. Soc. 1956, 78,
5452-5452; b) M. J. S. Dewar, R. Pettit, J. Chem. Soc. 1956, 2026-
2029.
K. J. Hock, L. Mertens, R. Hommelsheim, R. Spitzner, R. M. Koenigs,
Chem. Commun. 2017, 53, 6577-6580.
B. J. Anding, A. Ellern, L. K. Woo, Organometallics 2012, 31, 3628-
3635.
E. W. Reynolds, T. D. Schwochert, M. W. McHenry, J. W. Watters,
E. M. Brustad, Chembiochem 2017, 18, 2380-2384.
J. Catt, G. Johnson, D. Keavy, R. Mattson, M. Parker, K. Takaki, J.
Yevich, Vol. U.S. Pat. 5,981,571 (Ed.: B.-M. Squibb), 1999.
R. Mago, R. Mahajan, M. E. Thase, Expert Rev. Clin. Phar. 2014, 7,
137-145.
broad substrate scope that extends beyond that of Mb-catalyzed
9d]
cyclopropanations with α-diazoesters.[9c,
The latter feature
may stem from
a higher reactivity of the heme-carbene
intermediate[20] generated from acetonitrile, an aspect that will be
addressed in future studies. As the first example of a biocatalytic
reaction involving diazoacetonitrile, this study paves the way to
the application of this reagent in the context of other
metalloprotein-catalyzed carbene transfer reactions. This
capability combined with the versatility of the cyano functional
group as exemplified by Scheme 2 is expected to expand
opportunities toward the exploitation of biocatalysis for
asymmetric synthesis of pharmaceuticals and other high-value
compounds.[21]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
Acknowledgements
This work was supported by the U.S. National Institute of Health
grant GM098628. The authors are grateful to Dr. William
Brennessel for assistance with crystallographic analyses. MS and
X-ray instrumentation are supported by U.S. National Science
Foundation grants CHE-0946653 and CHE-1725028.
[18]
[19]
Z. P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945-7950.
K. Qiao, X. Yuan, L. Wan, M. W. Zheng, D. Zhang, B. B. Fan, Z. C.
Di, Z. Fang, K. Guo, Green Chemistry 2017, 19, 5789-5793.
Y. Wei, A. Tinoco, V. Steck, R. Fasan, Y. Zhang, J. Am. Chem. Soc.
2018, 140, 1649-1662.
a) U. T. Bornscheuer, G. W. Huisman, R. J. Kazlauskas, S. Lutz, J.
C. Moore, K. Robins, Nature 2012, 485, 185-194; b) M. Honig, P.
Sondermann, N. J. Turner, E. M. Carreira, Angew. Chem. Int. Ed.
2017, 56, 8942-8973; c) M. T. Reetz, J. Am. Chem. Soc. 2013, 135,
12480-12496; d) M. Honig, P. Sondermann, N. J. Turner, E. M.
Carreira, Angew. Chem. Int. Ed. 2017, 56, 8942-8973.
Cambridge Crystallographic Data Centre (CCDC) entry: 1872015.
[20]
[21]
References
[1]
a) M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911-936; b) H.
Lebel, J. F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003,
103, 977-1050; c) H. M. L. Davies, S. J. Hedley, Chem. Soc. Rev.
[22]
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