Aminopolyols from Carbohydrates: Amination of Sugars and Sugar-Derived Tetrahydrofurans with Transaminases

Article abstract of DOI:10.1002/anie.201813712

Carbohydrates are the major component of biomass and have unique potential as a sustainable source of building blocks for chemicals, materials, and biofuels because of their low cost, ready availability, and stereochemical diversity. With a view to upgrading carbohydrates to access valuable nitrogen-containing sugar-like compounds such as aminopolyols, biocatalytic aminations using transaminase enzymes (TAms) have been investigated as a sustainable alternative to traditional synthetic strategies. Demonstrated here is the reaction of TAms with sugar-derived tetrahydrofuran (THF) aldehydes, obtained from the regioselective dehydration of biomass-derived sugars, to provide access to cyclic aminodiols in high yields. In a preliminary study we have also established the direct transamination of sugars to give acyclic aminopolyols. Notably, the reaction of the ketose d-fructose proceeds with complete stereoselectivity to yield valuable aminosugars in high purity.

Full text of DOI:10.1002/anie.201813712

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Aminopolyols from carbohydrates: the amination of sugars and
sugar-derived tetrahydrofurans with transaminases
Authors: Helen Claire Hailes, Fabiana Subrizi, Laure Benhamou, John
Ward, and Tom Sheppard
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.201813712
Angew. Chem. 10.1002/ange.201813712
Link to VoR: http://dx.doi.org/10.1002/anie.201813712
http://dx.doi.org/10.1002/ange.201813712

10.1002/anie.201813712
Angewandte Chemie International Edition
COMMUNICATION
Aminopolyols from carbohydrates: the amination of sugars and
sugar-derived tetrahydrofurans with transaminases
Fabiana Subrizi,[a] Laure Benhamou,[a] John M. Ward,[b] Tom D. Sheppard,[a] and Helen C. Hailes*[a]
compounds,[6,23] hydroxyketones,[24] and dihydroxyketones,[25,26]
and are used industrially, e.g. in the synthesis of Sitagliptin.[27]
Abstract: Carbohydrates are the major component of biomass and
have unique potential as a sustainable source of building blocks for
Many transaminases have been developed for the synthesis of
lipophilic amines, but very few have been described to accept
polyhydroxylated ketones[25] or aldehydes, and to the best of our
knowledge, none have been reported in the literature to accept
reducing sugars. A further challenge is that sugars are present
almost entirely in the hemiacetal form in solution, with very little
free carbonyl present to undergo reaction with the enzyme
(Scheme 1). As a consequence, in this work we initially explored
the reaction of TAm enzymes with sugar-derived tetrahydrofuran
(THF) aldehydes, generated via the regioselective dehydration of
biomass-derived sugars,[28] to provide access to cyclic
aminopolyols (Scheme 1A). These were found to be excellent
chemicals, materials and biofuels due to their low cost, ready
availability and stereochemical diversity. With a view to upgrading
carbohydrates to access valuable nitrogen containing sugar-like
compounds such as aminopolyols, biocatalytic aminations using
transaminase enzymes (TAms) have been investigated as
a
sustainable alternative to traditional synthetic strategies. Here we
demonstrate the reaction of TAms with sugar-derived tetrahydrofuran
(THF) aldehydes, obtained from the regioselective dehydration of
biomass-derived sugars, to provide access to cyclic aminodiols in high
yields. In a preliminary study we have also established the direct
transamination of sugars to give acyclic aminopolyols. Notably, the
reaction of the ketose D-fructose proceeds with complete
stereoselectivity to yield valuable aminosugars in high purity.
substrates for
a
variety of TAm enzymes, giving the
corresponding amines in excellent yields. Subsequently, in a
preliminary study we have also demonstrated the direct
transamination of several sugars to give acyclic aminopolyols,
which were obtained with excellent diastereoselectivities from a
keto-sugar (Scheme 1B).
Aminated carbohydrates such as aminosugars, iminocyclitols,
and other linear or cyclic polyhydroxylated amines are of
particular interest as carbohydrate mimetics for the treatment of
diabetes and viral infections, as anti-tumor or immunosuppressive
agents[1–3] and as monomers in biopolymer formation.[1,2,4] Chiral
aminopolyols therefore represent an interesting class of higher
value products that could be accessed from renewable
carbohydrate feedstocks such as sugar beet pulp.[5–7] The
amination of highly functionalized carbohydrates via traditional
synthetic strategies typically requires regioselective control using
complex chemical strategies[3] and protection-deprotection steps
which decrease the overall atom economy.[1,2,8] Furthermore,
using traditional reductive amination methods, alkylation events
typically occur, resulting in the formation of undesired secondary
or tertiary amine products.[9,10] As an alternative approach,
biocatalytic methods could be used such as transaminases
(TAms),[11,12] imine reductases,[13–16] or amine dehydrogenases.[17]
Biocatalytic aminations can be significantly more sustainable than
chemical approaches, but to date, the biocatalytic amination of
sugars to provide access to aminopolyols has not been reported.
TAms were selected as suitable enzymes as they have been
reported to accept a wide range of substrates including cyclic
ketones,[18] aromatic ketones,[19–21] steroids,[22] heterocyclic
Concept
sugar-derived THFs
and sugars
cyclic and acyclic
aminopolyols
O
OH
OH
OH
O
HO
H
HO
OH OH
OH
L-arabinose + 3 more examples
<1% aldehyde
ref [28]
This work
OH
O
O
*
TAm, PLP
*
A
OH
NH2
amine
co-product
HO
OH
HO
OH
donor
2a
sugar-derived THFs
3a
cyclic aminopolyols
This work
sugars
TAm, PLP
L-arabinose
B
acyclic aminopolyols
D-xylose
D-fructose
amine
donor
co-product
+ 7 more examples
Scheme 1. Previous approach to sugar-derived THFs from sugars (e.g. 2a).
This work using: A TAms to generate amine-THFs (e.g. 3a); B TAms to
generate acyclic aminopolyols.
[a]
[b]
Dr. F. Subrizi, Dr. L. Benhamou, Prof. T. D. Sheppard, Prof. H. C.
Hailes
Department of Chemistry
University College London
20 Gordon Street, London WC1H 0AJ
E-mail: h.c.hailes@ucl.ac.uk
Prof. J. M. Ward
Department of Biochemical Engineering
University College London
The preparation of amine 3a, via catalytic hydrogenation of
the corresponding dimethylhydrazone gave the Boc-derivative in
a moderate 60% yield.[28] While this is a useful method to access
the aminodiol, significant problems were encountered on scaling
up the chemistry. We therefore elected to study a more
sustainable approach by exploring the reaction of TAm enzymes
with the cyclic aldehydes 2a-2d, prepared from L-arabinose, D-
ribose, D-xylose and L-rhamnose, respectively.[28] This three-step
synthesis was efficient with overall yields ranging from 77-91%,
Bernard Katz Building, London WC1E 6BT
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.201813712
Angewandte Chemie International Edition
COMMUNICATION
with the diastereomeric ratio (due to C-2 isomers) varying
considerably between the different sugar-derivatives.
OH
1a L-arabinose
1b D-ribose
1c D-xylose
O
3 steps
OH
1d D-rhamnose
HO
OH
2a-2d
OH
OH
OH
OH
OH
OH
O
O
O
O
*
*
*
*
OH
OH
HO
OH
OH
HO
OH
HO
OH
HO
2a
dr 80:20
2d
dr 70:30
2c
dr 60:40
2b
dr 90:10
Scheme 2. Aldehydes prepared: 2a, 77% from L-arabinose; 2b, 79% from D-
ribose; 2c, 91% from D-xylose; 2d, 81% from L-rhamnose. Major isomer shown
at C-2 (starred*).
Initially, 11 TAms were selected from our library at UCL,
based upon high activities previously observed in other screening
programmes. The preliminary experiments was carried out using
crude cell lysates and a colorimetric assay with the amine donor
2-(4-nitrophenyl)ethan-1-amine 5, which gives a red precipitate in
successful amination reactions (Figure 2A).[29] The colorimetric
assay, initially conducted on compound 2a, showed good activity
for eight of the TAms selected from our library (SI, Figure S4).
From this initial screen three were selected for further study, two
(S)-selective TAms as they have been shown to be versatile
enzymes for many substrates, Chromobacterium violaceum TAm
(Cv-TAm)[30] and Rhodobacter sphaeroides TAm (Rh-TAm),[25]
and the (R)-selective Mycobacterium vanbaalenii TAm (Mv-
TAm),[31] due to its complementary stereoselectivity. These three
TAms were then screened against 2a-d and a strong red
coloration was observed with all enzymes indicating good levels
of substrate acceptance (Figure 2B).
Figure 2. Colorimetric assay on compounds 2a-d (10 mM) using 5 as the amine
donor (25 mM). Pyruvate was used as a positive control (+) and buffer solution
as a negative control (-).
Activity of the three TAms towards 2a-d was also confirmed
using (R)- or (S)- α-methylbenzylamine (MBA) as the amine donor.
The best results were obtained with Cv-TAm and Rh-TAm on 2a
and 2b which gave conversion yields of 60-63% using (S)-MBA
while up to 27% yield was achieved with Mv-TAm under the same
reaction conditions with (R)-MBA (Figure 3). Moreover, the
reaction seemed to be complete within 3 h for Cv-TAm and Rh-
TAm with 2a and 2b, while reactions with substrates 2c and 2d
showed slower kinetics (SI, Figure S5) and lower yields ranging
from 40-50%. Notably, conversion yields with Mv-TAm were
similar for all compounds 2a-d. With the aim of enhancing yields
further, an alternative amine donor isopropylamine (IPA, 6) was
used (Table 1). With both Rh-TAm and Cv-TAm the yields
improved significantly (up to 91% for 2b). These conditions also
gave improved yields with Mv-TAm, with all the substrates giving
yields of between 60% and 81%.
Figure 3. Assays using 20 mM (S)-MBA (Cv-TAm and Rh-TAm) or (R)-MBA
(Mv-TAm) as amine donor with the three selected TAms towards 2a-2d (5 mM).
Pyruvate was used as a positive control (+) and buffer solution as a negative
control (-).
For both 2a and 2b all the selected TAms appeared to
preferentially accept the major anti-isomer while the syn-isomer
was converted more slowly into the corresponding amine leading
to product yields of up to 91% and diastereomeric ratios of up to
95:5. In the same way Rh-TAm more readily accepted the anti-
isomer of 2c (dr 60:40) producing 3c with an enhanced dr (70:30).
Interestingly Cv-TAm more readily accepted the minor syn-isomer
of 2c which was almost all converted in the first 30 minutes as
shown in time course experiments following the reaction either by
HPLC or NMR (SI, Figures S6, S7). However, anti-2c is also
converted into the corresponding amine product anti-3c which is
the major product at the end of the reaction. By comparison, Mv-
TAm had a clear preference for converting the minor isomer syn-
2c (20:80 dr after 4 h), although after 24 h the ratio was 35:65 (SI,
Figure S6). In contrast, in the case of the rhamnose-derived THF
2d the two isomers were converted at similar rates with all three
This article is protected by copyright. All rights reserved.

10.1002/anie.201813712
Angewandte Chemie International Edition
COMMUNICATION
enzymes, to give the amines 3d in a similar isomeric ratio to the
starting material in 75-84% yield. The THF-amines 3a-d are
valuable biomass-derived synthons and biocatalytic syntheses
were investigated on an enzyme preparative scale (50 mM) using
either Cv-TAm or Rh-TAm. Under these conditions, compounds
2a-c were converted quantitatively and only traces of the starting
material were detected in the case of 2d. The aminated products
were isolated via derivatization with di-tert-butyl dicarbonate
(Boc2O), to give the corresponding derivatives in 58-76% isolated
yield (Table 1). After deprotection, amines 3a-d were
quantitatively recovered as the hydrochloride salt in high purity.
generally better accepted than L-arabinose, whilst D-xylose and
L-rhamnose were accepted only by Rh-TAm and the enzyme
encoded by pQR2191 respectively. Notably, D-fructose, a
ketosugar, was accepted by Mv-TAm and the TAm encoded by
pQR2191 using 5 as the amine donor.
Table 1. Yields for the TAm reactions using 6 (10 equiv.) and 2a-d (25 mM),
to give 3a-d at 37 °C and 24 h unless indicated otherwise. The major product
is indicated with the yield and diastereomeric ratio (dr anti:syn) calculated by
HPLC analysis after derivatization with Fmoc-Cl.
Figure 4. Assays of TAm enzymes using 5 (25 mM) with a selection of sugar
substrates (5 mM) at 30 °C, pyruvate (+) was used as a positive control and
buffer (-) as a negative control. Pseudomonas putida TAm (Pp1-TAm pQR427)
and Klebsiella pneumoniae TAm (Kp-TAm)[25] were representative of many of
the TAms which showed no activities towards the sugar substrates. Enzymes
encoded by pQR2189, pQR2191 and pQR2208 have been reported
previously.[33]
The variation in sugar-conversions could reflect the fact that
certain stereochemistries are not accepted in the TAm active site.
However, they will also be significantly influenced by the equilibria
between acyclic, pyranose and furanose forms in water. Sugar
mutarotation is also influenced by temperature and pH.[34] On this
basis we explored the effect of these parameters on the
conversion of selected sugars using Cv-TAm and Rh-TAm. The
results suggested improved activity at more basic pHs and at
higher temperatures. This finding was consistent with the
observation that the proportion of the acyclic form of the sugar
typically increases with temperature.[34] It has also been reported
that when in DMSO the pyranose-furanose equilibria change and
for some sugars such as arabinose and fructose, a higher
proportion of the furanose form exists.[35] Indeed, the yield
doubled to 15% with D-ribose ((S)-MBA and Cv-TAm) when the
assay was conducted in the presence of 5% of DMSO at 30 °C
and pH 8. This suggested that robust thermostable TAms able to
tolerate high proportions of DMSO may give enhanced reactivities.
In particular, three of the selected TAms (namely those encoded
by pQR2189, pQR2191, and pQR2208) have been reported to
have excellent tolerances towards DMSO and higher
temperatures, and these enzymes were therefore used in up to
40% v/v DMSO. Satisfyingly, two of the three TAms selected,
encoded by pQR2189 and pQR2191, showed good activity
towards almost all the aldose sugars tested with DMSO as co-
solvent at 45 °C (SI, Figures S8, S9). With these improved
conditions we extended the screen to other sugars including D-
galacturonic acid (D-GalAc) and ketose sugars with different
chain lengths (e.g. D-ribulose, L-sorbose and D-tagatose, and L-
glucoheptulose ; Table 2, SI Figure S10). The latter was efficiently
prepared via a one-step reaction, catalysed by a mutant
transketolase enzyme starting from L-arabinose.[36,37]
Starting
material
2a
(80:20)
2b
(90:10)
2c
(60:40)
2d
(70:30)
Cv-TAm
Rh-TAm
Mv-TAm
anti-3a
84% (90:10)
anti-3b
91% (95:5)
76%[a]
anti-3c
anti-3d
74% (65:35) 81% (75:25)
58%[a]
anti-3a
75% (90:10)
71%[a]
anti-3b
85% (95:5)
anti-3c
67%(70:30) 84% (65:35)
69%[a]
anti-3d
anti-3a
56% (85:15)
anti-3b
47% (95:5)[b]
70% (95:5)
syn-3c
anti-3d
31% (20:80)[b] 75% (70:30)
60% (35:65)
[a] Isolated yield of the Boc protected amine obtained on a preparative scale (50
mM); [b] reaction time 4 h.
Having successfully demonstrated the amination of sugar-
derived THFs to access cyclic aminopolyols, the amination of
reducing sugars using TAms was also explored. In preliminary
screens, class-VI and class-III TAms from our UCL library were
selected. Class-VI TAms, known as sugar aminotransferases,
largely use the amine donor L-glutamate and accept activated
keto-hexoses, while class-III TAms such as Cv-TAm are
characterized by their broad substrate acceptance.[32] More than
30 TAms (including three from a metagenomic study)[33] were
screened as crude cell lysates against L-arabinose using 5 as the
amine donor. No hits were identified with the class-VI TAms,
perhaps reflecting that another amine-donor was required or that
they typically convert a cyclic non anomeric ketone. However,
several TAms, notably Rh-TAm and the enzyme encoded by
pQR2191 accepted L-arabinose using 5 as the amine donor
(Figure 4). Other sugars were also tested, and D-ribose was
This article is protected by copyright. All rights reserved.

10.1002/anie.201813712
Angewandte Chemie International Edition
COMMUNICATION
Table 2. TAm catalysed reactions of sugars using 5, and (S)- or (R)-MBA as amine donors. Reaction conditions: amine
donor 5 (25 mM) or MBA (20 mM), sugar (10 mM or 5 mM), KPi buffer pH 8 (50 mM) and clarified cell extract, 45 °C, 400
rpm, 24 h. Buffer was used as a negative control (-) and pyruvate as a positive control (+).
[a]Reaction at 30 °C; [b]Reaction in the presence of 25% of DMSO.
Quantification of the TAm reactions was carried out using
MBA and acetophenone detection by HPLC. This indicated
conversion yields of up 54% for D-ribose, 29% D-GalAc and L-
sorbose, 28% D-xylose and ~23% D-tagatose and L-
glucoheptulose. Notably, Mv-TAm showed a conversion yield of
40% with D-fructose at 45 °C when (R)-MBA was used as the
amine donor. Generally, the ketosugars were well accepted by
Mv-TAm and the TAm encoded by pQR2191, although L-
glucoheptulose was only accepted by pQR2191. Use of the co-
solvent DMSO also seemed to be less relevant when a keto sugar
was used as the substrate as high conversions could still be
obtained in its absence. The acceptance of D-GalAc (Table 2) was
interesting as this produces an ω-aminoacid with potential as a
monomer for the preparation of polyhydroxy polyamides as
analogues of Nylon-6.[38] Upon cyclization, it would also provide
report of the direct amination of reducing sugars using TAm
enzymes to give access to potentially valuable aminopolyols on a
D-fructose
L-arabinose
OH
Rh-TAm
NH2
O
pQR2191
Mv-TAm
HO
OH NH2
OH
OH
OH
HO
HO
7, 42%
OH
OH
OH OH
OH NH2
D-xylose
Rh-TAm
OH
HO
HO
OH
OH OH
OH OH
9, 40%
NH2
8, 79%
epi-9, 21%
OH OH
preparative scale.
Scheme 3. Synthesis of aminopolyols from L-arabinose, D-xylose and D-
fructose using TAms and 6 or MBA as amine donors.
an advanced precursor for the preparation of
polyhydroxyazepane glycosidase inhibitor.[39]
a potent
In summary, the transamination of sugar-derived THFs and
sugars available from biomass has been achieved in high yield,
providing access to valuable cyclic and acyclic aminopolyols.
Several TAms were identified to readily accept the sugar-derived
THF-aldehydes, and using IPA as an amine donor, isolated yields
of 58-76% were obtained. Moreover, the direct transamination of
reducing sugars has been achieved, with transamination
conversions for some sugar substrates increasing at higher
temperatures and with the addition of DMSO. The first preparative
scale transaminase reactions of reducing sugars has also been
achieved, with the amination of D-xylose and L-arabinose. D-
fructose was also converted stereoselectively into either 9 or epi-
9 using enantiocomplementary TAms. Aminopolyol 9 is an
ingredient in cosmetic formulations, and an advanced precursor
for the preparation of the potent α-glycosidase inhibitor 1-
deoxynojirimycin.[42]
Linear aminopolyols are valuable products and direct
syntheses from sugars using TAm were therefore investigated on
a biocatalytic preparative scale and isolated using a Dowex
50WX8 ion exchange resin.[8] Rh-TAm in reactions with L-
arabinose and D-xylose (at 25 mM) and IPA (see SI), gave 7[8] in
42% isolated yield and 8 in 79% isolated yield, respectively
(Scheme 3). The reaction of D-fructose with Mv-TAm was scaled
up using either (R)-MBA or IPA as the amine donor to a 25 mM
1
scale at 45 °C. H NMR analysis indicated a 50% yield of the
corresponding aminopolyol as a single diastereoisomer, in both
cases demonstrating complete stereoselectivity in the TAm
reaction. The product 9 was isolated in 40% yield. The
configuration of the new stereogenic centre was assigned as R in
agreement with reported data,[40] which is consistent with the
known selectivity of the Mv-TAm. With the aim of isolating the
epimer at C-2 we also scaled up the reaction with D-fructose and
the enantiocomplementary TAm encoded by pQR2191 and (S)-
MBA. Again, the reaction was highly stereoselective and epi-9
was isolated in 21% yield.[41] These reactions constitute the first
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/anie.201813712
Angewandte Chemie International Edition
COMMUNICATION
Asymmetry 2013, 24, 1495–1501.
The authors would like to thank the UK Engineering and Physical
Sciences Research Council (EPSRC) for financial support of this
work to F. S. (EP/K014897/1) as part of their Sustainable
Chemical Feedstocks programme. Input and advice from the
project Industrial Advisory Board is also acknowledged. We also
thank the EPSRC for financial support to L.B. via the UCL Impact
Acceleration Account (EP/K503745/1). Furthermore, we gratefully
acknowledge the UCL Mass Spectrometry and NMR Facilities in
the Department of Chemistry UCL and the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
[20]
C. E. Paul, M. Rodríguez-Mata, E. Busto, I. Lavandera, V. Gotor-
Fernꢀndez, V. Gotor, S. García-Cerrada, J. Mendiola, O. de Frutos,
Org. Process Res. Dev. 2014, 18, 788–792.
[21]
[22]
[23]
[24]
M. S. Weiß, I. V Pavlidis, P. Spurr, S. P. Hanlon, B. Wirz, H. Iding, U.
T. Bornscheuer, Org. Biomol. Chem. 2016, 14, 10249–10254.
N. Richter, R. C. Simon, W. Kroutil, J. M. Ward, H. C. Hailes, Chem.
Commun. 2014, 50, 6098–6101.
E. O. Reilly, C. Iglesias, D. Ghislieri, J. Hopwood, J. L. Galman, R. C.
Lloyd, N. J. Turner, Angew. Chem Int. Ed. 2014, 53, 2447–2450.
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.
2013, 52, 6772–6775.
Keywords: Biocatalysis • biomass waste • transaminases •
sugars • aminopolyols
[25]
[26]
[27]
M. F. Villegas-Torres, R. J. Martinez-Torres, A. Cazeres-Korner, H.
Hailes, F. Baganz, J. Ward, Enzyme Microb. Technol. 2015, 81, 23–
30.
[1]
M. Ávalos, R. Babiano, P. Cintas, A. Gómez-Carretero, J. L. Jiménez,
M. Lozano, A. L. Ortiz, J. C. Palacios, A. Pinazo, Chem. - A Eur. J.
2008, 14, 5656–5669.
P. Gruber, F. Carvalho, M. P. C. Marques, B. O‘Sullivan, F. Subrizi,
D. Dobrijevic, J. Ward, H. C. Hailes, P. Fernandes, R. Wohlgemuth,
F. Baganz, N. Szita, Biotechnol. Bioeng. 2018, 115, 586–596.
C. K. Savile, J. M. Janey, E. C. Mundorff, J. C. Moore, S. Tam, W. R.
Jarvis, J. C. Colbeck, A. Krebber, F. J. Fleitz, J. Brands, P. N. Devine,
G. W. Huisman, G. J. Hughes, Science 2010, 329, 305–310.
R. W. Foster, C. J. Tame, D. K. Bučar, H. C. Hailes, T. D. Sheppard,
Chem. - A Eur. J. 2015, 21, 15947–15950.
[2]
[3]
R. V. Gómez, O. Varela, Macromolecules 2009, 42, 8112–8117.
T. Ishikawa, T. Kudo, K. Shigemori, S. Saito, J. Am. Chem. Soc. 2000,
122, 7633–7637.
[4]
[5]
S. A. Sanchez-Vazquez, H. C. Hailes, J. R. G. Evans, Polym. Rev.
2013, 53, 627–694.
[28]
[29]
[30]
[31]
M. Cárdenas-Fernández, M. Bawn, C. Hamley-Bennett, P. K. V.
Bharat, F. Subrizi, N. Suhaili, D. P. Ward, S. Bourdin, P. A. Dalby, H.
C. Hailes, P. Hewiston, S. Ignatova, C. Kontoravdi, D. J. Leak, N.
Shah, T. D. Sheppard, J. M. Ward, G. J. Lye, Faraday Discuss. 2017,
202, 415–431.
D. Baud, N. Ladkau, T. S. Moody, J. M. Ward, H. C. Hailes, Chem.
Commun. 2015, 51, 17225–17228.
U. Kaulmann, K. Smithies, M. E. B. Smith, H. C. Hailes, J. M. Ward,
Enzyme Microb. Technol. 2007, 41, 628–637.
M. Höhne, S. Schätzle, H. Jochens, K. Robins, U. T. Bornscheuer,
Nat. Chem. Biol. 2010, 6, 807–813.
[6]
[7]
[8]
A. Dunbabin, F. Subrizi, J. M. Ward, T. D. Sheppard, H. C. Hailes,
Green Chem. 2017, 19, 397–404.
[32]
[33]
J. Ward, R. Wohlgemuth, Curr. Org. Chem. 2010, 14, 1914–1927.
L. Leipold, D. Dobrjevic, J. W. E. Jeffries, M. Bawn, T. S. Moody, J.
M. Ward, H. C. Hailes, Green Chem. 2019, 21, 75–86.
V. A. Yaylayan, A. A. Ismail, S. Mandeville, Carbohydr. Res. 1993,
248, 355–360.
G. Righi, A. Ferrara, A. Mari, P. Bovicelli, Synth. Commun. 2010, 40,
1650–1657.
E. M. Dangerfield, C. H. Plunkett, A. L. Win-Mason, B. L. Stocker, M.
S. M. Timmer, J. Org. Chem. 2010, 75, 5470–5477.
N. Kise, N. Ueda, Tetrahedron Lett. 2001, 42, 2365–2368.
F. Lehmann, M. Scobie, Synthesis 2008, 1679–1681.
F. Guo, P. Berglund, Green Chem. 2017, 19, 333–360.
J. Ward, R. Wohlgemuth, Curr. Org. Chem. 2010, 14, 1914–1927.
P. N. Scheller, M. Lenz, S. C. Hammer, B. Hauer, B. M. Nestl,
ChemCatChem 2015, 7, 3239–3242.
[34]
[9]
[35]
[36]
W. Mackie, A. S. Perlin, Can. J. Chem. 1966, 44, 2039–2049.
F. Subrizi, M. Cárdenas-Fernández, G. J. Lye, J. M. Ward, P. A.
Dalby, T. D. Sheppard, H. C. Hailes, Green Chem. 2016, 18, 3158–
3165.
[10]
[11]
[12]
[13]
[37]
[38]
[39]
M. Bawn, F. Subrizi, G. J. Lye, T. D. Sheppard, H. C. Hailes, J. M.
Ward, Enzyme Microb. Technol. 2018, 116, 16–22.
[14]
M. Lenz, P. N. Scheller, S. M. Richter, B. Hauer, B. M. Nestl, Protein
Expr. Purif. 2016, 133, 199–204.
J. A. Galbis, M. D. G. García-Martín, M. V. De Paz, E. Galbis, Chem.
Rev. 2016, 1600–1636.
[15]
[16]
P. Matzel, M. Gand, M. Höhne, Green Chem. 2017, 19, 385–389.
J. Mangas-Sanchez, S. P. France, S. L. Montgomery, G. A. Aleku, H.
Man, M. Sharma, J. I. Ramsden, G. Grogan, N. J. Turner, Curr. Opin.
Chem. Biol. 2017, 37, 19–25.
H. Li, Y. Blériot, C. Chantereau, J. M. Mallet, M. Sollogoub, Y. Zhang,
E. Rodríguez-García, P. Vogel, J. Jiménez-Barbero, P. Sinaÿ, Org.
Biomol. Chem. 2004, 2, 1492–1499.
[40]
[41]
Y. Wu, J. Arciola, N. Horenstein, Protein Pept. Lett. 2014, 21, 10–14.
I. N. Krasikova, V. I. Gorbach, V. V. Isakov, T. F. Solov’eva, Y. S.
Ovodov, Eur. J. Biochem. 1982, 126, 349–351.
[17]
[18]
T. Knaus, W. Böhmer, F. G. Mutti, Green Chem. 2017, 19, 453–463.
N. Richter, R. C. Simon, H. Lechner, W. Kroutil, J. M. Ward, H. C.
Hailes, Org. Biomol. Chem. 2015, 13, 8843–8851.
J. S. Reis, R. C. Simon, W. Kroutil, L. H. Andrade, Tetrahedron:
[42]
S. Onose, R. Ikeda, K. Nakagawa, T. Kimura, K. Yamagishi, O.
Higuchi, T. Miyazawa, Food Chem. 2013, 138, 516–523.
[19]
This article is protected by copyright. All rights reserved.

10.1002/anie.201813712
Angewandte Chemie International Edition
COMMUNICATION
This article is protected by copyright. All rights reserved.