General and Stereocontrolled Approach to the Chemical Synthesis of Naturally Occurring Cyanogenic Glucosides

Article abstract of DOI:10.1021/acs.jnatprod.5b01121

An effective method for the chemical synthesis of cyanogenic glucosides has been developed as demonstrated by the synthesis of dhurrin, taxiphyllin, prunasin, sambunigrin, heterodendrin, and epiheterodendrin. O-Trimethylsilylated cyanohydrins were prepared and subjected directly to glucosylation using a fully acetylated glucopyranosyl fluoride donor with boron trifluoride-diethyl etherate as promoter to afford a chromatographically separable epimeric mixture of the corresponding acetylated cyanogenic glucosides. The isolated epimers were deprotected using a triflic acid/MeOH/ion-exchange resin system without any epimerization of the cyanohydrin function. The method is stereocontrolled and provides an efficient approach to chemical synthesis of other naturally occurring cyanogenic glucosides including those with a more complex aglycone structure.

Full text of DOI:10.1021/acs.jnatprod.5b01121

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General and Stereocontrolled Approach to the Chemical Synthesis of
Naturally Occurring Cyanogenic Glucosides
Birger L. Møller,†,‡,§,⊥ Carl E. Olsen,†,‡,§ and Mohammed S. Motawia*,†,‡,§
†Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, ‡VILLUM Research Center “Plant Plasticity”, and
§Center for Synthetic Biology “bioSYNergy”, University of Copenhagen, 40 Thorvaldsensvej, DK-1871 Frederiksberg C,
Copenhagen, Denmark
⊥Carlsberg Laboratory, 10 Gamle Carlsberg Vej, 1799 Copenhagen V, Denmark
S
* Supporting Information
ABSTRACT: An effective method for the chemical synthesis
of cyanogenic glucosides has been developed as demonstrated
by the synthesis of dhurrin, taxiphyllin, prunasin, sambunigrin,
heterodendrin, and epiheterodendrin. O-Trimethylsilylated
cyanohydrins were prepared and subjected directly to
glucosylation using a fully acetylated glucopyranosyl fluoride
donor with boron trifluoride−diethyl etherate as promoter to
afford a chromatographically separable epimeric mixture of the
corresponding acetylated cyanogenic glucosides. The isolated
epimers were deprotected using a triflic acid/MeOH/ion-
exchange resin system without any epimerization of the
cyanohydrin function. The method is stereocontrolled and
provides an efficient approach to chemical synthesis of other naturally occurring cyanogenic glucosides including those with a
more complex aglycone structure.
the CGs dhurrin, prunasin, heterodendrin, and their related
epimers taxiphyllin, sambunigrin, and epiheterodendrin, as
shown in Figure 2.
yanogenic glucosides (CGs) are widely distributed in the
Cplant kingdom, and more than 2650 different plant
species have been reported to contain cyanogenic glucosides
including ferns, gymnosperms, and angiosperms.1 Some
arthropods, e.g., species within the millipedes and butterflies,
are also able to de novo synthesize CGs.2 In nature, CGs are
derived from only six amino acids, namely, L-valine, L-
isoleucine, L-leucine, L-phenylalanine, L-tyrosine, and the
nonprotein amino acid cyclopentenylglycine.1 Chemically,
CGs are defined as O-β-glycosidic derivatives of α-hydroxyni-
triles (cyanohydrins) as shown in Figure 1. The absolute
configuration of the cyanohydrin function may be R or S, but a
single plant species will contain only a single diastereoisomer.
In the present study, the efficient and fully stereocontrolled
chemical synthesis of cyanogenic glycosides is demonstrated.
The method is general and exemplified by chemical synthesis of
The labile cyanohydrin function is stabilized by glycosylation.
The sugar moiety directly bound to the cyanohydrin function
(e.g., in cyanogenic monoglycosides) is always D-glucose. Other
CGs may harbor additional sugar residues including other
hexoses as well as pentoses linked in different configurations,
giving rise to the large number of different CGs found in nature
such as the cyanogenic disaccharides (R)-amygdalin, (R)-
vicianin, and linustatin and the structurally highly complex
cyanogenic trisaccharide xeranthin.1a,3
The L-tyrosine-derived cyanogenic glucoside dhurrin [(S)-4-
hydroxymandelonitrile-β-D-glucopyranoside] present in sor-
ghum (Sorghum bicolor) has been developed as an experimental
model system for studying the biosynthesis and endogenous
turnover of cyanogenic glucosides.3a,4 The biosynthetic path-
way is catalyzed by two cytochrome P450s (CYP79A1 and
CYP71E1) and the glucosyltransferase UGT85B1 with electron
transfer provided by NADPH P450 oxidoreductase.4,5 In
synthetic biology approaches, the dhurrin pathway has been
used to demonstrate the possibility to transfer entire
cytochrome P450-catalyzed pathways into chloroplasts and
drive the catalytic cycle of the P450s with direct electron
Received: December 17, 2015
Figure 1. General chemical structure of cyanogenic glycosides.
© XXXX American Chemical Society and
American Society of Pharmacognosy
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hydroxybenzyl halides and related compounds was proposed10
(Figure 4).
These concomitant base sensitivity properties of CGs as well
as the inherent instability of their aglycones (cyanohydrins) to
hydrolysis have precluded exploration of stereocontrolled
chemical synthesis for construction of pure cyanogenic
glycosides. Only a few approaches toward chemical synthesis
of CGs have been reported. In 1917, chemical synthesis of an
epimeric mixture of prunasin and sambunigrin involving a five-
step reaction sequence and an overall yield of less than 2% was
reported.11 The only attempt to synthesize dhurrin and
taxiphyllin was reported12 in 1966 and afforded an epimeric
mixture of the pentaacetates of dhurrin and taxiphyllin in 5.9%
yield. No information on how to obtain each of the target
molecules by deprotection was provided. Synthesis of
heterodendrin was attempted13 by Koenigs−Knorr condensa-
tion of acetobromoglucose and 2-hydroxy-3-methylbutaneni-
trile. In spite of numerous variations of the reaction conditions,
the yield of the tetraacetates of heterodendrin and its epimer
epiheterodendrin was low (3% total yield). Again, no attempts
to obtain the target molecules by deprotection were reported.
An improved route to chemical synthesis of the cyanogenic
glucosides prunasin, linamarin, and heterodendrin has been
reported8b in which the final step involved removal of the O-
acetyl protecting groups using different basic catalysts (NH3,
K2CO3, hydrazine, and KCN) in alcoholic medium, which
resulted in epimeric mixtures.8b
Figure 2. Structures of the synthetic cyanogenic glucosides: dhurrin,
taxiplyllin, prunasin, sambunigrin, heterodendrin, and epiheteroden-
drin.
To overcome the base sensitivity issues related to stereo-
controlled synthesis of pure cyanogenic glucosides, a novel
synthetic approach avoiding any basic treatment has developed.
The approach is based on (1) initial stabilization of the
aglycone (cyanohydrin) by conversion of its OH group into an
O-trimethylsilyl derivative, which at the same time serves to
enhance the nucleophilicity of the OH group, and (2)
performing the glucosylation and the deprotection reactions
under acidic conditions. On the basis of these principles we
succeeded in designing a general and efficient route toward the
chemical synthesis of cyanogenic glucosides without epimeriza-
tion.
transfer from photosystem I without the involvement of
NADPH.6
Under basic conditions and due to the acidity of the α-H of
CGs, all CGs are susceptible toward basic media and prone to
epimerization (isomerization) even in the presence of small
amounts of base.7 The isomerization proceeds via a carbanion
after elimination of the cyanohydrin proton,7a,8 as shown in
Figure 3.
In 1965, dhurrin was reported to be extremely labile to alkali
while showing no special instability toward acids.9 The phenolic
hydroxy group of dhurrin was proposed as responsible for the
observed sensitivity to alkali, and a reaction sequence based on
the mechanism for base-catalyzed decomposition of the p-
Glycosyl fluorides have become important in glycosylation
reactions due to their enhanced stability, ease of handling, and
high stereoselectivity compared with other glycosyl halides and
activation using mild reaction conditions.14 The synthesis of
Figure 3. Mechanism for epimerization of cyanogenic glycosides.
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Note
Figure 4. Mechanism of alkaline hydrolysis of dhurrin and/or its epimer taxiphyllin.9
glycosyl fluorides can be achieved by various approaches15 with
Scheme 1. Synthesis of the Glucosyl Donor
diethylaminosulfur trifluoride (DAST)16 as the preferred
fluorinating reagent of 1-glycoses. Recently, an efficient method
for the synthesis of 2,3,4,6-tetra-O-acetyl-D-13C6/14C6-glucopyr-
anosyl fluoride starting from commercially available D-
glucose-13C6 mixed with commercially available D-glucose-14C6
in desired ratios using DAST as the fluorinating agent was
reported.17 On the basis of this approach, the chemical
synthesis of the glucosyl donor 2,3,4,6-tetra-O-acetyl-D-
glucopyranosyl fluoride (3) was accomplished starting with
the commercially available 1,2,3,4,6-penta-O-acetyl-β-D-gluco-
pyranose (1) as outlined in Scheme 1.
The strategy for the synthesis of a target cyanogenic
glucoside is described in Scheme 2.
Compound 1 was deprotected regionselectively at the
anomeric position by treatment with a solution of ethylenedi-
amine/HOAc (1:1)18 in THF to obtain 2,3,4,6-tetra-O-acetyl-
D-glucopyranose (2) (α/β = 3:1) in 92% yield. Fluorination of
2 by reaction with DAST in dichloromethane19 afforded the
glucosyl fluoride 3 as an anomeric mixture (α/β = 2:8). The α-
and β-anomers were separated by silica gel chromatography (n-
pentane/Et2O, 1:1 v/v) to afford pure α- and β-anomers of 3 in
The commercially available aldehydes 4-O-acetylbenzalde-
hyde (4), benzaldehyde (5), and isobutyraldehyde (6) were
used as starting materials. Aldehydes 4−6 were reacted with
trimethysilyl cyanide (TMS-CN) in the presence of LiClO4
under solvent-free conditions21 to afford the corresponding O-
trimethylsilylated cyanohydrins 7−9 in quantitative yields.
Compounds 7−9 were glucosylated by reaction with 3 in the
presence of BF3·Et2O as catalyst22 in CH2Cl2 at rt (Scheme 2)
to afford the acetylated cyanogenic glycoside-epimeric mixtures
1
93% overall yield. Both H and 13C NMR data were in full
agreement with reported data.20
C
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Note
Scheme 2. Synthesis of the Cyanogenic Glucosides
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were carried
out under an atmosphere of argon in oven-dried glassware with
magnetic stirring. Unless otherwise indicated, commercially available
starting materials, reagents, solvents, and dry solvents were purchased
from Sigma-Aldrich Chemicals (Copenhagen, Denmark) and were
used without further treatment. All commercial materials were used as
received unless otherwise noted. All reactions were monitored by TLC
on aluminum sheets coated with silica gel 60F254 (0.2 mm thickness,
E. Merck, Darmstadt, Germany) using UV light as a visualizing agent,
and the components were detected by charring with 10% H2SO4 in
MeOH. Column chromatographies were carried out using silica gel 60
(particle size 0.040−0.063 mm, 230−400 mesh ASTM, E. Merck).
Solvent extracts were dried over anhydrous MgSO4 unless otherwise
1
specified. The H and 13C NMR spectra were recorded on a Bruker
Avance 400 spectrometer at 400 and 101 MHz, respectively; δ-values
are relative to internal TMS; coupling constants (J) are given in Hz.
HRESIMS data were recorded on a Bruker micrOTOF-Q mass
spectrometer.
Synthesis of 2,3,4,6-Tetra-O-acetyl-D-glucopyranosyl Fluo-
ride, 3 (Scheme 1). Glacial HOAc (1.2 mL, 21 mmol) was added
dropwise with stirring to a solution of ethylenediamine/HOAc (EDA)
(1.2 mL, 18 mmol) in THF (150 mL), resulting in the immediate
formation of a precipitate, which remained present until aqueous
workup. The peracetate 1 (6.0 g, 15.4 mmol) in THF (50 mL) was
added, and the mixture was stirred at rt for 24 h, after which TLC
(silica gel 60 F254 plates Merck, n-pentane/acetone, 8:2 v/v) showed
complete absence of 1. Water (100 mL) was added, and the mixture
was extracted with CH2Cl2 (3 × 50 mL). The organic phase was
washed sequentially with dilute HCl, NaHCO3(aq), and H2O and
dried. The solvent was evaporated and coevaporated with 96% EtOH
(3 × 50 mL) to obtain a chromatographically pure sample of 2 (α/β =
3:1, 4.9 g, 14.1 mmol, 92% yield) as a colorless syrup, which was used
for the next synthetic step without further purification. Diethylami-
nosulfur trifluoride (2.0 mL, 15.15 mmol) was added to a stirred
solution of 2 (4.6 g, 13.2 mmol) in dry CH2Cl2 (100 mL) at −15 °C
under Ar. Stirring was continued, and the temperature allowed to rise
to rt during a 45 min period. The mixture was diluted with CH2Cl2
(50 mL) and filtered through silica gel. The silica gel was washed
several times with CH2Cl2 (5 × 25 mL), and the collected filtrate was
washed with saturated NaHCO3(aq) (2 × 100 mL), water (3 × 100
mL), and brine (100 mL) and dried (MgSO4). The solvent was
evaporated to dryness to obtain a colorless syrup corresponding to
glucopyranosyl fluoride 3 as an anomeric mixture. α- and β-anomers
were separated by silica gel chromatography (n-pentane/ether, 1:1 v/
v) to afford pure α- and β-anomers of 3 (4.3 g in total, 12.3 mmol,
93% yield). (For NMR spectroscopic data see Supporting
Information.)
10−12 and 13−15 in 80−85% yield. Separation of the (S)-
epimers 10−12 from the corresponding (R)-epimers 13−15
and isolation of the pure stereoisomers were achieved using
silica gel chromatography and recrystallization.
Conventionally, removal of O-acetyl groups is performed
under base catalysis. Only a few examples of acid-catalyzed
removal of O-acetyl groups have been reported,23 typically
using HCl/MeOH as standard reagent in connection with a
demand for selective removal of O-acetyl groups in the
presence of O-benzoyl groups.23a−c In all acid-catalyzed
reactions, a base is required to neutralize the excess acid at
the end of the reaction. This should be avoided in order to
prevent epimerization of the synthetic cyanogenic glucosides.
When we applied these acid catalysts, only slow and partial
deacetylation was observed.
General Procedure for Synthesis of Compounds 10−15
(Scheme 2). A mixture of aldehydes 4−6 (2.5 mmol), solid LiClO4
(0.27 g, 2.5 mmol), and TMS-CN (0.38 mL, 3.0 mmol) was stirred at
rt for 30 min. Then CH2Cl2 (30 mL) was added to the mixture, and
the LiClO4 was removed by filtration. The organic layer was washed
with H2O (15 mL) and dried. The solvent was removed in a rotary
evaporator to obtain the corresponding crude O-trimethylsilyl
cyanohydrins 7−9 (quantitative), which were used directly for the
next step. BF3·Et2O (1.04 mL, 8.4 mmol) was added in one portion at
rt to a stirred solution of the crude O-(trimethylsilyl) cyanohydrins 7−
9 and the glucosyl fluoride 3 (0.71 g, 2 mmol) in dry CH2Cl2 (30 mL)
under Ar. Stirring was continued at rt for 2 h. The mixture was basified
by careful addition of saturated NaHCO3(aq) and diluted with CH2Cl2
(100 mL). The organic phase was washed with H2O (3 × 5 mL) and
brine (50 mL) and dried, and the CH2Cl2 evaporated. The residue was
purified by chromatography on silica gel to afford compounds 10−15
as stereochemically pure compounds. (For NMR spectroscopic data
see Supporting Information.)
Trifluoromethanesulfonic acid (triflic acid) is one of the
strongest Brøndsted−Lowry acids.24 Triflic acid and its
derivatives constitute a versatile family of useful reagents for
organic synthesis.24,25 When using it in MeOH as an acid
catalyst for deprotection of compounds 10−15, the removal of
the O-acetyl groups proceeded smoothly and efficiently within
3 h at rt. At this time, triflic acid was exchanged with HOAc
using an anion ion-exchange resin (HcO−) (Scheme 2) instead
of neutralization using a base as conventionally used. The
deprotection step proceeded smoothly without any epimeriza-
tion and afforded the target molecules 16−21 in 80−90% yield
after chromatographic purification on silica gel using 10%
MeOH in CH2Cl2 (v/v). The identity and purity of the
synthetic compounds were assessed by ESIMS and 1H and 13
C
Preparation of Amberlyst A26 (CH3COO− Form). Amberlyst
A26 hydroxide form (commercially available from Sigma-Aldrich,
542571 Aldrich) was added to an excess of 1 N HOAc(aq) and
magnetically stirred for 1 h at room temperature. The resin was filtered
NMR data analyses. All NMR spectroscopic data of the
synthetic compounds were in full agreement with those
reported in the literature (Supporting Information).
D
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Note
off and washed with deionized H2O until the pH was neutral, then
washed with acetone (3 × 100 mL) and MeOH (3 × 100 mL), air-
dried, and used as such. The used resin can be readily regenerated with
1 N NaOH to its hydroxide form and reused.
General Procedure for Synthesis of Compounds 16−21
(Scheme 2). Trifluoromethanesulfonic acid (triflic acid: TfOH) (0.65
mL, 7.34 mmol) was added in one portion at rt to a stirred solution of
10−15 (1.18 mmol) in dry MeOH (5 mL) under Ar. Stirring was
continued at rt for 3 h, and the reaction mixture was diluted with
MeOH (25 mL), neutralized with Amberlyst-A26 (CH3COO− form)
resin, filtered, and evaporated to dryness. The residue was chromato-
graphed on silica gel with 10% MeOH/CH2Cl2 as eluent to afford
compounds 16−21 in 80−85% yield. (For NMR spectroscopic data
see the Supporting Information).
(4) Tattersall, D. B.; Bak, S.; Jones, P. R.; Olsen, C. E.; Nielsen, J. K.;
Hansen, M. L.; Høj, P. B.; Møller, B. L. Science 2001, 293, 1826−1828.
(5) (a) Kahn, R. A.; Bak, S.; Svendsen, I.; Halkier, B. H.; Møller, B. L.
Plant Physiol. 1997, 115, 1661−1670. (b) Busk, P. K.; Møller, B. L.
Plant Physiol. 2002, 129, 1222−1231. (c) Sibbesen, O.; Koch, B.;
Møller, B. L. J. Biol. Chem. 1995, 270, 3506−3511. (d) Nielsen, K. A.;
Tattersall, D. B.; Jones, P. R.; Møller, B. L. Phytochemistry 2008, 69,
88−98. (e) Bak, S.; Olsen, C. E.; Halkier, B. A.; Møller, B. L. Plant
Physiol. 2000, 123, 1437−1448.
(6) (a) Møller, B. L. The Royal Society of Chemistry, Specialist
Periodical Reports. Synthetic Biology; Ryadnov, M.; Brunsveld, L.; Suga,
H., Eds.; 2014; Vol. 1, pp 330−359. (b) Lassen, L. M.; Nielsen, A. Z.;
Ziersen, B.; Gnanasekaran, T.; Møller, B. L.; Jensen, P. E. ACS Synth.
Biol. 2014, 3, 1−12.
In conclusion, we have developed an effective method for the
chemical synthesis of dhurrin, prunasin, heterodendrin, and their
related epimers taxiphyllin, sambunigrin, and epiheterodendrin. The
method is stereocontrolled and provides an efficient approach to the
chemical synthesis of other cyanogenic glycosides including those that
have more complex glycone structures. The method also provides for
the synthesis of cyanogenic glucosides where the glycone is labeled
with radioactive or stable isotopes.17 In general, the synthetic strategy
offers unique insights into the synthesis of base-sensitive glucosides.
The availability of synthetic pure cyanogenic glucosides will advance
biochemical studies on the yet uncharacterized enzymes involved in
endogenous turnover of cyanogenic glucosides in plants and their role
as storage compounds of reduced nitrogen.3a Studies on sequestering,
metabolism, and excretion of cyanogenic glucosides in insects feeding
on cyanogenic plants will also benefit especially from access to
isotopically labeled cyanogenic glucosides.17,26
(7) (a) Nahrstedt, A. Arch. Pharm. 1975, 308, 903−910. (b) Ettlinger,
M.; Jaroszewski, J. W.; Jenson, S. R.; Nielsen, B. J.; Nartey, F. J. J.
Chem. Soc., Chem. Commun. 1977, 952−953.
(8) (a) Turczan, J. W.; Medwick, T. H. Ass. Off. Anal. Chem. 1979,
62, 190−196. (b) Nakajima, N.; Ubukata, M. Biosci., Biotechnol.,
Biochem. 1998, 62, 453−458. (c) Sendker, J.; Nahrstedt, A. Phytochem.
Anal. 2010, 21, 575−581.
(9) Mao, C.-H.; Anderson, L. J. Org. Chem. 1965, 30, 603−607.
(10) Filar, L. J.; Winatein, S. Tetrahedron Lett. 1960, 25, 9−16.
(11) Fischer, E.; Bergman, M. Ber. Dtsch. Chem. Ges. 1917, 50, 1047−
1069.
(12) Kofod, H.; Eyjolfss, R. Tetrahedron Lett. 1966, 5249−5251.
(13) Jaroszewski, J. W. J. Nat. Prod. 1986, 49, 927−928.
(14) Toshima, K. Carbohydr. Res. 2000, 327, 15−26.
(15) Shimizu, M.; Togo, H.; Yokoyama, M. Synthesis 1998, 1998,
799−822.
(16) (a) Posner, G. H.; Haines, S. R. Tetrahedron Lett. 1985, 26, 5−8.
(b) Rosenbrook, W.; Riley, D. A.; Lartey, P. A. Tetrahedron Lett. 1985,
26, 3−4.
(17) Zagrobelny, M.; Olsen, C. E.; Pentzold, S.; Furstenberg-Hagg, J.;
Jørgensen, K.; Bak, S.; Møller, B. L.; Motawia, M. S. Insect Biochem.
Mol. Biol. 2014, 44, 44−53.
(18) Zhang, J.; Kovacs, P. J. Carbohydr. Chem. 1999, 18, 461−469.
(19) Middleton, W. J. J. Org. Chem. 1975, 40, 574−578.
(20) Griffith, M. H. E.; Hindsgaul, O. Carbohydr. Res. 1991, 211,
163−166.
(21) Azizi, N.; Saidi, M. R. J. Organomet. Chem. 2003, 688, 283−285.
(22) Kunz, H.; Sager, W. Helv. Chim. Acta 1985, 68, 283−287.
(23) (a) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; mioskowsli,
C.; Samuelsson, B.; Hmmarstron, C. J. Am. Chem. Soc. 1980, 102,
1436−1439. (b) Byramova, N. E.; Ovchinnikov, M. V.; Backinowsky,
L. V.; Kochetkov, N. K. Carbohydr. Res. 1983, 124, C8−C11.
(c) Petrakova, E.; Schraml. Collect. Czech. Chem. Commun. 1983, 48,
877−888. (d) Askin, D.; Angst, C.; Danishefsky, S. J. Org. Chem. 1987,
52, 622−635. (e) Pozsgay, V.; Coxon, B. Carbohydr. Res. 1993, 257,
189−215.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.5b01121.
Experimental procedures and 1H and 13C NMR
1
spectroscopic data; copies of H and 13C NMR spectra
of all synthesized compounds 2−21 (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mosm@plen.ku.dk (M. S. Motawia). Phone: (+45)
35333305.
■
Notes
The authors declare no competing financial interest.
(24) Howells, R. D.; McCown, J. D. Chem. Rev. 1977, 77, 69−92.
(25) (a) Rakita, P. E. Chem. Today 2004, 48−50. (b) Sbramanian, L.
R.; Martinez, A. G.; Hanack, M.; Prakash, G. K. S.; Hu, J. Encyclopedia
of Reagents for Organic Synthesis: Trifluoromethanesulfonic Acid; John
Wiley & Sons: New York, 2006.
(26) Pentzold, S.; Zagrobelny, M.; Khakimov, B.; Engelsen, S. B.;
Cluasen, H.; Petersen, B. L.; Borch, J.; Møller, B. L.; Bak, S. Sci. Rep.
2015, in press.
ACKNOWLEDGMENTS
■
This work was supported by the VILLUM Research Center
“Plant Plasticity” and by the Center for Synthetic Biology
“bioSYNergy” supported by the UCPH Excellence Program for
Interdisciplinary Research.
REFERENCES
■
(1) (a) Møller, B. L. Curr. Opin. Plant Biol. 2010, 13, 338−347.
(b) Gleadow, R. M.; Møller, B. L. Annu. Rev. Plant Biol. 2014, 65,
155−185.
(2) Larsen, M. Z.; Møller, B. L. Phytochemistry 2011, 72, 1585−1592.
(3) (a) Picmanova, M.; Neilson, E. H.; Motawia, M. S.; Olsen, C. E.;
Agerbirk, A.; Gray, C. J.; Flitsch, S.; Silvestro, D.; Jørgensen, K.;
Sanchez-Perez, R.; Møller, B. L.; Bjarnholt, N. Biochem. J. 2015, 469,
375−389. (b) Neilson, E. H.; Goodger, J. Q. D.; Motawia, M. S.;
Bjarnholt, N.; Frisch, T.; Olsen, C. E.; Møller, B. L.; Woodrow, J. E.
Phytochemistry 2011, 72, 2325−2334. (c) Schwind, P.; Nahrstedt, A.;
Wray, V. Planta Med. 1989, 55, 600.
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