Enantioselective Aminohydroxylation of Styrenyl Olefins Catalyzed by an Engineered Hemoprotein

Article abstract of DOI:10.1002/anie.201812968

Chiral 1,2-amino alcohols are widely represented in biologically active compounds from neurotransmitters to antivirals. While many synthetic methods have been developed for accessing amino alcohols, the direct aminohydroxylation of alkenes to unprotected, enantioenriched amino alcohols remains a challenge. Using directed evolution, we have engineered a hemoprotein biocatalyst based on a thermostable cytochrome c that directly transforms alkenes to amino alcohols with high enantioselectivity (up to 2500 TTN and 90 % ee) under anaerobic conditions with O-pivaloylhydroxylamine as an aminating reagent. The reaction is proposed to proceed via a reactive iron-nitrogen species generated in the enzyme active site, enabling tuning of the catalyst's activity and selectivity by protein engineering.

Full text of DOI:10.1002/anie.201812968

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Enantioselective Aminohydroxylation of Styrenyl Olefins
Catalyzed by an Engineered Hemoprotein
Authors: Inha Cho, Christopher K. Prier, Zhi-Jun Jia, Ruijie K. Zhang,
Tamás Görbe, and Frances H. Arnold
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812968
Angew. Chem. 10.1002/ange.201812968
Link to VoR: http://dx.doi.org/10.1002/anie.201812968
http://dx.doi.org/10.1002/ange.201812968

10.1002/anie.201812968
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Aminohydroxylation of Styrenyl Olefins
Catalyzed by an Engineered Hemoprotein
Inha Cho[a], Christopher K. Prier[b], Zhi-Jun Jia[a], Ruijie K. Zhang[a], Tamás Görbe [c], and Frances H.
Arnold*[a]
Abstract: Chiral 1,2-amino alcohols are widely represented in
biologically active compounds from neurotransmitters to antivirals.
While many synthetic methods have been developed for accessing
amino alcohols, the direct aminohydroxylation of alkenes to
unprotected, enantioenriched amino alcohols remains a challenge.
introduce a nitrogen in a protected form.[7]
Amination methods that directly transfer a simple NH unit to
olefins have been developed only recently. In 2014, Kürti and
coworkers developed rhodium-based catalysts and an aryl
hydroxylamine precursor for the synthesis of NH-aziridines.[8]
Morandi and coworkers subsequently reported the synthesis of
2-amino-1-arylethanols from styrenes, using iron phthalocyanine
(FePc) as the catalyst and O-pivaloylhydroxylamine triflic acid (1)
as the nitrogen source (Figure 1A).[9] While further work by
these laboratories and others has introduced other
hydroxylamine-based reagents for the direct installation of
unprotected amines,[10] enantioselective versions have not been
reported. Given the prevalence of the amino alcohol motif in
medicinal agents, methods that can directly access this
structural unit in an enantioselective fashion from abundant
olefins are highly desirable.
Using directed evolution, we have engineered
a hemoprotein
biocatalyst based on a thermostable cytochrome c that directly
transforms alkenes to amino alcohols with high enantioselectivity (up
to 2500 TTN and 90% ee) under anaerobic conditions with O-
pivaloylhydroxylamine as an aminating reagent. The reaction is
proposed to proceed via a reactive iron-nitrogen species generated
in the enzyme active site, enabling tuning of the catalyst's activity
and selectivity by protein engineering.
The 1,2-amino alcohol motif is a privileged scaffold present
in numerous bioactive compounds, drugs, and natural products
such as neurotransmitters, β-blockers, anti-malarial and anti-HIV
drugs, and antibiotics.[1] Optically active amino alcohols serve
other important roles as chiral auxiliaries, ligands, bases, and
catalysts in asymmetric reactions.[2] Multiple enzymatic routes
have been developed to access chiral amino alcohols from diols,
ketones, and esters,[3] or through multistep enzyme cascades
from styrenyl olefins.[4] To enable single-step enantioselective
synthesis of amino alcohols from olefins,[5] several methods,
Our group and others have engineered iron hemoproteins to
perform nitrene transfer reactions using sulfonyl azides as
nitrene precursors, demonstrating that enzymes have the ability
to perform and control the selectivity of challenging non-
biological amination processes.[11] Fasan and coworkers also
reported enzymatic generation of nitrenes from azidoformates,[12]
and Hartwig and coworkers reported the use of sulfonyl azides
for
nitrene
transfer
with
artificial
iridium-containing
such
as
the
pioneering
Sharpless
asymmetric
metalloenzymes.[13] In all of these cases, however, nitrene
transfer with engineered hemoproteins produces protected
amine products. Furthermore, the use of azide-based reagents
may pose safety concerns for large-scale synthesis.
aminohydroxylation of alkenes,[6] have been developed. These
chemical methods unfortunately suffer from various drawbacks
related to their scope, selectivity, or the use of toxic metals.
Furthermore, all of these methods install a nitrogen atom
bearing a protecting group, necessitating further steps to reveal
the free amine functionality. Aminooxidation can also be
In a remarkable recent report, Tsutsumi and coworkers
identified a wild-type cytochrome P450 that performs nitrene
achieved by the aziridination of alkenes followed by ring opening, transfer in benzastatin biosynthesis through the cleavage of an
but the majority of asymmetric aziridination reactions also
N-O bond, demonstrating that hydroxylamines can function as
nitrene precursors in biological systems (Figure 1B).[14] Inspired
by nature’s chemistry and Morandi’s FePc catalyst system, we
aimed to develop a hemoprotein catalyst for one-step production
[a]
I.Cho, Z-J.Jia, R.K.Zhang, and F.H.Arnold.
Division of Chemistry and Chemical Engineering MC 210-41
California Institute of Technology
1200 East California Blvd, Pasadena, CA 91125, USA.
Corresponding author e-mail: frances@cheme.caltech.edu
C.K.Prier.
Current address: Merck Research Laboratories, Merck & Co.
P.O. Box 2000, Rahway, NJ 07065, USA.
T.Görbe.
Current address: School of Engineering Sciences in Chemistry,
Biotechnology, and Health
of chiral unprotected amino alcohols from olefins,
a
transformation not known in biology. We thought to discover
such a reaction using nitrene source 1 as the precursor to a
putative unprotected iron-nitrenoid intermediate 2 (Figure 1C).
We anticipated that intermediate 2 could react with an olefin,
adding a nitrogen from the reagent and an oxygen from water to
form a 1,2-amino alcohol product. In this work, we present the
directed evolution of an enzyme based on the highly
thermostable Rhodothermus marinus (Rma) cytochrome c that
generates and transfers the unprotected iron-nitrenoid for the
efficient synthesis of chiral amino alcohols from olefins.
[b]
[c]
KTH Royal Institute of Technology, Science for Life Laboratory 23
Tomtebodavägen, Solna 171 65, Sweden.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812968
Angewandte Chemie International Edition
COMMUNICATION
conditions and remarkably provided 4 with 32% ee. This result
indicated that the configuration at the newly formed stereocenter
is controlled by the protein, suggesting that highly
enantioselective synthesis of amino alcohols could be achieved
through protein engineering.
Rma cytochrome c was used as the template for directed
evolution to improve activity and enantioselectivity. Starting from
the distal ligand M100, the closest residues facing the iron of the
heme cofactor were targeted for sequential site-saturation
mutagenesis in order to create an active site tailored for the
putative iron-nitrenoid intermediate and the olefin substrates.
Nearby residues that do not directly face the heme cofactor were
also subjected to site-saturation mutagenesis with the
hypothesis that these residues could impact substrate binding.
For each round of mutagenesis, beneficial mutations were
identified by screening for increased product yield and
enantioselectivity using reverse phase LC-MS and normal phase
HPLC, respectively. Focusing initially on improving product
formation, four consecutive rounds of site-saturation
mutagenesis at residues closest to the heme yielded Rma
cytochrome c M99V M100S T101P M103G, which produces
amino alcohol 4 with 360 TTN, a nine-fold improvement over the
wild-type Rma cytochrome c, and 70% ee (Figure 2A). We then
selected mutations that provided the greatest improvements in
enantioselectivity in subsequent rounds. Two additional site
saturation libraries targeting residues T98 and M76 yielded a
further 5-fold increase in turnovers (1,800 TTN) and an increase
in ee to 85%. The final round of site-saturation mutagenesis and
screening introduced the Y44T mutation. This final variant, Rma
cytochrome c TQL, provided the product with 2,500 turnovers
and 90% ee under optimal conditions.
The crystal structure of Rma wild-type cytochrome c (Figure
2B) shows the heme iron is coordinated by the distal ligand
M100, the heme cofactor, and the axial ligand H49, leaving
neither a free coordination site nor space for substrate binding,
at least according to the static structure. Nonetheless, the wild
type protein catalyzes the reaction with 40 TTN. Mutation of
M100 to serine presumably weakens coordination to iron and
promotes nitrenoid formation. Residues M99 and M103 in the
same loop as M100 were also mutated to smaller residues (99V
and 103G), which may increase the flexibility of the distal loop.
This may promote alternative conformations of the distal loop,
potentially allowing new binding poses for the substrates, as
Figure 1. (A) FePc-catalyzed aminohydroxylation of olefins delivers racemic
amino alcohol products.[9] (B) The biosynthesis of benzastatins proceeds via
BezE-catalyzed nitrene formation from an N-acetoxy species, followed by
intramolecular aziridination.[14] (C) Proposed enzymatic, enantioselective
aminohydroxylation of alkenes.
observed previously in computational studies on
a Rma
cytochrome c catalyst evolved for carbene Si-H insertion.[16]
Residue Y44 is farther from the heme center but is among the
residues that surround the active site opening to the aqueous
environment. Mutation to threonine at this position may improve
substrate access to the active site.
Various catalysts were evaluated for aminohydroxylation
activity, including cytochrome P450 monooxygenase from
Bacillus megaterium (P450BM3), P450BM3 variants having the
Cys400 axial ligand replaced with Ser (P411‘s), the reduced
heme cofactor alone, iron phthalocyanine (FePc), protoglobins,
and cytochrome c variants (Supplementary Tables 1 and 2).
Whereas FePc catalyzes aminohydroxylation of olefins as
reported,[7] the reduced heme cofactor as well as most of the
tested hemoproteins showed no or trace activity. The wild-type
Rhodothermus marinus (Rma) cytochrome c, an extremely
thermostable (Tm = 106 °C) and small (124 aa) protein which
coordinates heme using distal methionine and proximal histidine
ligands in a small solvent-accessible pocket,[15] converted 4-
vinylanisole (3) to aminoalcohol 4 with 4% yield under anaerobic
This article is protected by copyright. All rights reserved.

10.1002/anie.201812968
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Substrate scope of aminohydroxylation catalyzed by Rma
cytochrome c TQL variant. Aminoalcohols
4 – 14 are synthesized from
substituted styrenes, 15 is synthesized from p-isopropenylanisole, and 16 is
from trans-anethole. Absolute configuration of 4 and 9 is the R-enantiomer,
and the configuration of other products is assigned by analogy. The major
diastereomer of product 16 is threo-16 based on NMR.
Our working mechanistic hypothesis for styrenyl olefin
aminohydroxylation involves formation of a reactive complex
between iron and the nitrogen reagent, which may be either the
nitrene 2 or the corresponding nitrene radical.[18] At this point,
nitrene transfer to the styrene could proceed to give an aziridine
intermediate. To test whether this aziridine is a viable reaction
intermediate, we synthesized racemic 2-phenylaziridine and
separated the enantiomers via chiral HPLC. Incubating each
enantiomer in aqueous buffer either with or without the purified
TQL variant resulted in enantiospecific hydrolysis with inversion
of configuration at the benzylic center (Scheme 2A). These
results demonstrate that the aziridine may be a species en route
to the amino alcohol, with any enantioselectivity conferred by the
enzyme in the aziridination step persisting in the product.
Alternatively, the putative nitrene or nitrene radical may engage
the styrene to produce an iron-bound carbocation intermediate,
which could be intercepted by water to provide the amino
alcohol without the intermediacy of an aziridine (Supplementary
Figure 1).[9] The aminohydroxylation of trans-anethole supports
such a scenario, as the observed major threo diastereomer is
Figure 2. (A) Directed evolution of Rma cytochrome c from wild type to the
TQL variant. (B) Crystal structure of wild-type Rma cytochrome c (PDB ID:
3CP5),[17] with mutated residues marked.
Testing a variety of styrenyl olefin substrates, we found that
cytochrome c TQL tolerates a range of substitutions on the
aromatic ring (Scheme 1). Styrenes bearing electron-donating
as well as -withdrawing substituents at the para position are
accepted as substrates, undergoing aminohydroxylation with
hundreds of turnovers in several examples. Meta- and ortho-
substitutions are also tolerated, although these styrenes are
converted with reduced turnovers and enantioselectivities. The
TQL variant was also found to be active on - or -substituted
styrenes to generate amino alcohols 15 and 16. Interestingly,
examples of activity on internal olefins are rare in both the FePc-
catalyzed aminohydroxylation[9] and hemoprotein-catalyzed
aziridination with sulfonyl azides.[11d] Aminohydroxylation of
trans-anethole yielded amino alcohol 16, an analog of the
neurotransmitter β-hydroxyamphetamine, with 87:13 dr and 95%
ee. Less activated olefins are challenging substrates, with 4-
phenyl-1-butene and 1-octene providing only trace amounts of
aminohydroxylation products. We next investigated whether
inconsistent with
a
mechanism involving stereospecific
aziridination and hydrolysis. Further study will be required to
delineate the exact reaction pathway and characterize the
reactive iron-nitrogen species.
aminohydroxylation using TQL could be achieved on
a
We also performed aminohydroxylation of olefin 3 with a
preparative scale. A 2.0-mmol scale aminohydroxylation of olefin
3 using whole cells in phosphate buffer under anaerobic
conditions furnished product 4 in 61% (204 mg) isolated yield
and 85% ee. Aminohydroxylation of trans-anethole was
performed on 1.0-mmol scale and yielded 95 mg of product 16
(see Supporting Information for details). The reaction can also
be performed with purified cytochrome c TQL, proceeding to
1500 TTN and 85% ee over 24 hours.
different
nitrene
precursor,
O-(tert-butoxycarbonyl)-
hydroxylamine (17). When the reaction was performed using
catalyst-harboring E. coli whole cells, aminohydroxylation of 3
with reagent 17 yielded amino alcohol 4 with 1,500 TTN with
93% ee (Scheme 2B). This demonstrates that hemoproteins
can utilize different reagents to access the putative unprotected
nitrenoid intermediate. The effect of the nitrene precursor on the
This article is protected by copyright. All rights reserved.

10.1002/anie.201812968
Angewandte Chemie International Edition
COMMUNICATION
reaction may provide an additional handle for reaction
engineering.
2013, 52, 6772-6775; b) J. Rehdorf, M. D. Mihovilovic, U. T.
Bornscheuer, Angew. Chem. Int. Ed. 2010, 49, 4506-4508; c) G.
Hasnaoui-Dijoux, M. M. Elenkov, J. H. L. Spelberg, B. Hauer, D. B.
Janssen, Chem. Bio. Chem. 2008, 9, 1048-1051.
[4]
[5]
S. Wu, Y. Zhou, T. Wang, H-P. Too, D. I. C. Wang, Z. Li, Nat. Commun.
2016, 7, 11917-11929.
a) T. J. Donohoe, C. K. A. Callens, A. Flores, A. R. Lacy, A. H. Rathi.
Chem. Eur. J. 2011, 17, 58-76; b) P. H. Fuller, J-W. Kim, S. R. Chemler,
J. Am. Chem. Soc. 2008, 130, 17638-17639; c) D. J. Michaelis, K. S.
Williamson, T. P. Yoon, Tetrahedron 2009, 65, 5118-5124; d) K. S.
Williamson, T. P. Yoon, J. Am. Chem. Soc. 2012, 134, 12370-12373; e)
U. Farid, T. Wirth, Angew. Chem. Int. Ed. 2012, 51, 3462-3465; f) G.-S.
Liu, Y.-Q. Zhang, Y.-A. Yuan, H. Xu, J. Am. Chem. Soc. 2013, 135,
3343-3346; g) D.-F. Lu, C.-L. Zhu, Z.-X. Jia, H. Xu, J. Am. Chem. Soc.
2014, 136, 13186-13189.
[6]
[7]
a) K. B. Sharpless, D. W. Patrick, L. K. Truesdale, S. A. Biller, J. Am.
Chem. Soc. 1975, 97, 2305; b) G. Li, H. T. Chang, K. B. Sharpless,
Angew. Chem. Int. Ed. 1996, 35, 451-453; c) J. A. Bodkin, M. D.
McLeod, J. Chem. Soc. Perkin Trans. 1, 2002, 2733-2746; d) D. Nilov,
O. Reiser, Adv. Synth. Catal. 2002, 1169-1173.
Scheme 2. (A) Enantiospecific hydrolysis of 2-phenylaziridine occurs in both
the presence and absence of the TQL cytochrome c variant, indicating that the
aziridine is a viable intermediate en route to enantioenriched products. (B) An
alternative nitrene source 17 also provides the amino alcohol product 4.
a) R. Vyas, G-Y. Gao, J. D. Harden, X. P. Zhang, Org. Lett. 2004, 6,
1907-1910; b) Y. Zhu, Q. Wang, R. G. Cornwall, Y. Shi, Chem. Rev.
2014, 114, 8199-8256; c) L. Degennaro, P. Trinchera, R. Luisi, Chem.
Rev. 2014, 114, 7881-7929; d) P. Müller, C. Fruit, Chem. Rev. 2003,
103, 2905-2919.
Wild-type Rma cytochrome c displayed a limited ability to
catalyze the amination of styrenyl olefins with hydroxylamine
reagent 1. Directed evolution improved this promiscuous
function, delivering the cytochrome c TQL variant, an efficient
catalyst for the synthesis of unprotected amino alcohols directly
from alkenes. The heme cofactor of TQL is based on the most
widely available transition metal in the Earth’s crust, iron, and
the enzyme exhibits levels of activity and selectivity toward
aminohydroxylation that have been difficult to achieve with
diverse synthetic methods. As the catalyst is fully genetically
encoded, it can be tuned by directed evolution and produced
and used in bacteria. This approach also provides a path to
taming and utilizing an unusual and synthetically valuable
unprotected nitrene equivalent, potentially enabling biocatalytic
solutions to further challenges in direct amination chemistry.
[8]
[9]
J. L. Jat, M. P. Paudyal, H. Gao, Q. L. Xu, M. Yousufuddin, D.
Devarajan, D. H. Ess, L. Kürti, J. R. Falck, Science 2014, 343, 61-65.
L. Legnani, B. Morandi, Angew. Chem. Int. Ed. 2016, 55, 2248-2253.
[10] a) Z. Ma, Z. Zhou, L. Kürti, Angew. Chem. Int. Ed. 2017, 56, 9886-9890;
b) L. Legnani, G. P. Cerai, B. Morandi, ACS Catal. 2016, 6, 8162-8165;
c) S. Sabir, G. Kumar, J. L. Jat, Org. Biomol. Chem. 2018, 16, 3314-
3327; d) L. Legnani, G. Prina-Cerai, T. Delcaillau, S. Willems, B.
Morandi, Science, 2018, 362, 434-439.
[11] a) J. A. McIntosh, P. S. Coelho, C. C. Farwell, Z. J. Wang, J. C. Lewis,
T. R. Brown, F. H. Arnold, Angew. Chem. Int. Ed. 2013, 52, 9309-9312;
b) C. K. Prier, R. K. Zhang, A. R. Buller, S. Brinkmann-Chen, F. H.
Arnold, Nature Chem. 2017, 9, 629-634; c) T. K. Hyster, C. C. Farwell,
A. R. Buller, J. A. McIntosh, F. H. Arnold, J. Am. Chem. Soc. 2014, 136,
15505-15508; d) C. C. Farwell, R. K. Zhang, J. A. McIntosh, T. K.
Hyster, F. H. Arnold. ACS Cent. Sci. 2015, 1, 89-93; e) R. Singh, M.
Bordeaux, R. Fasan. ACS Catal. 2014, 4, 546-552; f) M. Bordeaux, R.
Singh, R. Fasan. Bioorg. Med. Chem. 2014, 22, 5697-5704.
[12] R. Singh, J. N. Kolev, P. A. Sutera, R. Fasan, ACS Catal. 2015, 5,
1685-1691.
Acknowledgments
[13] P. Dydio, H. M. Key, H. Hayashi, D. S. Clark, J. F. Hartwig, J. Am.
Chem. Soc. 2017, 139, 1750-1753.
We thank Kai Chen and Dr. Xiongyi Huang for helpful
discussions and assistance with ee determination. We also
thank X. H. And Dr. Sabine Brinkmann-Chen for proofreading
the manuscript. We acknowledge the National Science
Foundation, Division of Molecular and Cellular Biosciences
(grant MCB-1513007) for supporting this work. C. K. P. thanks
the Resnick Sustainability Institute for a postdoctoral fellowship.
R. K. Z. was supported by a National Science Foundation
Graduate Research Fellowship, the Caltech Biotechnology
Leadership Program, and the Donna and Benjamin M. Rosen
Bioengineering Center. Z.-J. J. is supported by the Deutsche
Forschungsgemeinschaft. T.G. thanks for the financial support
of the Stiftelsen Olle Engkvist Byggmästare and the Kungl.
Skogs- och Lantbruksakademien.
[14] H. Tsutsumi, Y. Katsuyama, M. Izumikawa, M. Takagi, M. Fujie, N.
Satoh, K. Syin-ya, Y. Ohnishi, J. Am. Chem. Soc. 2018, 140, 6631-
6639.
[15] S. B. J. Kan, R. D. Lewis, K. Chen, F. H. Arnold, Science 2016, 354,
1048-1051.
[16] R. D. Lewis, M. Garcia-Borràs, M. J. Chalkley, A. R. Buller, K. N. Houk,
S. B. J. Kan, F. H. Arnold, Proc. Nat. Acad. Sci. USA. 2018, 115, 7308-
7313.
[17] M. Stelter, A. M. P. Melo, M. M. Pereira, C. M. Gomes, G. O.
Hreggvidsson, S. Hjorleifsdottir, L. M. Saraiva, M. Teixeira, M. Archer,
Biochemistry 2008, 47, 11953-11963.
[18] a) A. I. O. Suarez, V. Lyaskovskyy, J. N. H. Reek, J. I. van der Vlugt, B.
de Bruin, Angew. Chem. Int. Ed. 2013, 52, 12510-12529; b) M.
Goswami, V. Lyaskovskyy, S. R. Domingos, W. J. Buma, S. Woutersen,
O. Troeppner, I. Ivanović-Burmazović, H. Lu, X. Cui, X. P. Zhang, E. J.
Reijerse, S. DeBeer, M. M. van Schooneveld, F. F. Pfaff, K. Ray, B. de
Bruin, J. Am. Chem. Soc. 2015, 137, 5468-5479; c) E. T. Hennessy, T.
A. Betley, Science 2013, 340, 591-595.
Keywords: Biocatalysis • Heme proteins • Directed evolution •
Amino alcohols • Alkenes • Nitrenes
[1]
[2]
[3]
S. C. Bergmeier, Tetrahedron, 2000, 2561-2576.
D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835-876.
a) T. Sehl, H. C. Hailes, J. M. Ward, R. Wardenga, E. Von Lieres, H.
Offermann, R. Westphal, M. Pohl, D. Rother, Angew. Chem. Int. Ed.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812968
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A hemoprotein catalyst was
engineered to transform alkenes
directly to amino alcohols with high
enantioselectivity. Derived by directed
evolution from a thermostable
cytochrome c, the protein catalyst
uses O-pivaloylhydroxylamine to
generate a reactive iron-nitrogen
species.
I. Cho, C. K. Prier, Z-J. Jia, R. K. Zhang,
T. Görbe, F. H. Arnold*
Page No. – Page No.
Enantioselective Aminohydroxylation
of Styrenyl Olefins Catalyzed by an
Engineered Hemoprotein
This article is protected by copyright. All rights reserved.