Synthesis of the glycoside moiety of Solaradixine, a glycoalkaloid
found in Solanum Laciniatum, using “super-armed” donors and
block synthesis strategies.
Angles d’Ortoli, T.; Widmalm, G.
Stockholm University, Sweden.
[email protected], [email protected].
Steroidal glycoalkaloids are glycosylated alkaloids found in a large number of the Solanum
species. Pharmacological effects of steroidal glycoalkaloids on human cells are dependent on
the chemical structures. Of all the modern structural methods for saponins related compounds,
NMR spectroscopy yields the most complete picture of the structure and the behavior in
solution. 1H and 13C NMR chemical shift data are used by the computer program CASPER to
predict chemical shifts of oligo- and polysaccharides. The enhancement of the quality of the
predictions can efficiently be achieved by focusing on carbohydrate structures of biochemical
significance.1 The main glycoalkaloid from roots of S. laciniatum was found to be O(3)-{α-LRhap-(1→2)-[β-D-Glcp-(1→2)-β-D-Glcp-(1→]3)-β-D-Galp}-solasodine.2
OH
OH
OH
O
O
HO
HO
O
OR
OH
O
H
O
HO
O
HO
OH
O
HO
R=Solasodine
HO
OH
The synthesis of the tetrasaccharide in this sequence was the target of this project. A so called
“super-armed” version of a disaccharide donor was synthesized as the first block.3
Meanwhile, another glycosylation procedure would provide the disaccharide acceptor needed
to obtain the targeted product. These strategies allowed a facile and rapid synthesis of the
target.
1. Rönnols, J.; Pendrill, R.; Fontana, C.; Hamark, C.; Angles d’Ortoli, T.; Engström, O.;
Ståhle, J.; Zaccheus, M. V.; Säwén, E.; Hahn, L.E.; Iqbal, S.; Widmalm, G. Carbohydrate
Research 2013, 340, 7-13.
2. Neszmelyi, A.; Machytka, D.; Shabana, M. M. Phytochemistry 1988, 27, 603-605.
3. Pedersen, M.C.; Marinescu, L.G.; Bols, M. C. R. Chimie 2011, 14, 17-43.
Synthesis of novel porphyrin-oligothiophene conjugates
Katriann Arja, Mathias Elgland and Peter Nilsson
Linköpings University, IFM – Department of Biology, Chemistry & Physics, SE-58183 LINKÖPING, Sweden
[email protected]
Porphyrins and porphyrin-related compounds have long been known for their interesting
optical, photophysical and biochemical properties. These include the ability to generate
singlet oxygen from molecular oxygen found in its surrounding. This property has found
application in photodynamic therapy (PDT) for combating cancer.1 We have previously
reported the synthesis of a new porphyrin-oligothiophene conjugate and its use as a
resourceful probe for visualizing protein aggregates, the pathological hallmark of Alzheimer’s
disease.2 Herein we report the synthesis of a set of novel porphyrin-oligothiophene conjugates
intended to be used as PDT-agents targeting distinct cancer-associated cells. In these
conjugates, a cationic thiophene pentamer is coupled to three different porphyrins bearing
either sugar moieties or sulfonic acid functionalities. The synthetic strategy for designing a
convenient and high-yielding route to the conjugates is described.
N
N
OAc
N
TsO
N
N
TsO
H
N
O
O
O
N
H
N
NH
HN
O
3
N
H
S
OH
R2
S
S
S
S
HO
O
O
H
N
S
N
N N
S
S
3
S
S
O
R1
OH
O
N
SO 3H
OAc
N
N
SO 3H
N
O
HN S
O
N
N
Zn
N
N
O
S NH
O
N N
N
O
HO
R1
SO 3H
O
OH
R
HO 2
O S O
HN
N
N N
HO
R1
O
glucose
R1 = H, R 2 = OH
galactose
R1 = OH, R 2 = H
O
OH
R
HO 2
Figure 1: Structures of porphyrin-oligothiophene conjugates.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
1
L. B. Josefsen, et al. Theranostics, 2(9): 916-966 (2012)
2
K. Arja, D. Sjölander, et al. Macromol. Rapid Commun., 34(9):723-30 (2013)
Iridium PC(sp3)P-type and Ruthenium Chiral Amino NHC
Complexes: Novel Avenues for Small Molecule Transformations
Dominic C. Babbini,† Vlad M. Iluc,† and Pher G. Andersson*
†
Univeristy of Notre Dame, Notre Dame, Indiana, USA
*
Stockholms Universitet, Stockholm, Sweden
Iridium and ruthenium organometallic complexes have been long known to exhibit
unique reactivity with respect to bond activation and molecular manipulation. Our attempt is
to engineer novel catalytic systems which allow for heightened reactivity and specific
selectivity with a focus on bond activation allowing for the functionalization of small
molecules. Herein we report a novel series of iridium organometallic complexes which
consist of a scaffold PC(sp3)P-type backbone as well as a proposed project utilizing a chiral
ruthenium amino N-heterocylic carbene (NHC) complex for chiral hydrogen transfer
reactions. The full synthesis and characterization of the PC(sp3)P-type ligand
bis(diisopropylphosphinophenyl)anisoylmethane, the complexes formed with iridium, and
their subsequent reactivities will be discussed along with the proposed synthetic formation of
the chiral NHC ligand and ruthenium complex as well as targeted catalytic transformations
utilizing this system.
Does the counterion influence the symmetry of the
three-center halogen bond in the solid state?
Michele Bedin, Alavi Karim, Marcus Reitti, Anna-Carin C. Carlsson, Jürgen
Gräfenstein, and Mate Erdelyi*
Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden
Halogen bonding is the attractive interaction between the electrophilic region of a
halogen atom in a molecular entity and a Lewis base.1 As the halogen bonding
phenomenon resembles hydrogen bonding in many aspects,2 it is predicted to have
high applicability in a wide variety of scientific fields, e.g. in governing molecular
recognition processes and the structure of supramolecular complexes. Three-center
halogen bonds are known to be remarkably strong and to possess very short
interatomic distances. A well-known example for such a halogen bonded complex is
the triiodide ion (III-), which is often cited to have a 180 kJ/mol secondary bond.2
For gaining an improved understanding of the properties of three-center halogen
bonds we have previously addressed its behavior in solutions,3-5 using
[bis(pyridine)iodine]+ and [bis(pyridine)bromine]+ model systems. These studies
revealed that these three-center halogen bonds are symmetric in solutions, in contrast
to the analogous three-center hydrogen bonds that are asymmetric.6
In this project we address the symmetry of the [bis(pyridine)iodine]+ model system in
complex with a variety of counterions in the solid state using X-ray diffraction
analysis, in collaboration with the group of Prof. Kari Rissanen at the University of
Jyväskylä in Finland. Crystals were obtained by cooling the complexes, prepared as
described previously,3-5 dissolved in a mixture of nonpolar solvents. The obtained
symmetry was then compared to that observed in solution by NMR and in silico by
DFT computations.
Figure 1. The X-ray structure of [bis(pyridine)iodine]+ nitrate and hexafluoroantimonate complexes.
References:
1
Desiraju, R. G. et al., Pure Appl. Chem. 2013, 85, 1711.
2
Metrangolo, P.; Neukirch, H.; Pilati T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386.
3
A.-C.C. Carlsson, et al., ChemCommun 2012, 48, 1458.
4
A.-C. C. Carlsson, et al., J. Am. Chem. Soc. 2012, 134, 5706.
5
A.-C. C. Carlsson, et al., CrystEngComm. 2013, 15, 3087.
6
Perrin, C. L. Pure Appl. Chem. 2009, 81, 571.
Design, synthesis and labeling with [11C]CO of benzovesamicolbased ligands as potential PET tracers for the Vesicular
Acetylcholine Transporter
Sara Bergman, Maria DeRosa, Hooman Hamdi, Luke Odell, Jonas Eriksson, Mats Larhed,
Gunnar Antoni*
Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Box 574, SE-751 23
Uppsala, Sweden. E-mail: [email protected]
*
Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Box 574, SE-751 23
Uppsala, Sweden.
The vesicular acetylcholine transporter (VAChT) is found in the axon terminal of cholinergic
neurons where it transports newly synthesized acetylcholine into synaptic vesicles.1 VAChT
has been acknowledged as a marker for the cholinergic system.2 As the impairment of
cognitive abilities and memory, the general hallmark of dementia diseases, has been
correlated to the loss of cholinergic neurons in cortex the study of VAChT could offer insight
into the disease progression and the effect of treatment as well as being a compliment in the
diagnosis of neurodegenerative diseases.3 With positron emission tomography (PET), VAChT
can be studied in both a quantitative and qualitative way.
In our research group, focus has been on synthesizing and labeling ligands for VAChT based
on a library approach. A common precursor and the same method are used for the labeling of
the ligands, thereby ensuring the possibility to incorporate a radioisotope in all ligands
without the need for unique precursors. Changing small details in the molecular structure
provides the possibility for facile fine tuning of the affinity and the pharmacokinetic
properties of the ligands.
Here, we present the design, synthesis and labeling of a library of ligands for VAChT based
on known allosteric inhibitor benzovesamicol. The ligands were synthesized with the aim of
exploring the 5-position of the fused benzocyclohexanol ring (figure 1).
Figure 1.
References
(1)
Erickson, J. D.; Varoqui, H.; Schäfer, M. K.; Modi, W.; Diebler, M. F.; Weihe, E.; Rand, J.; Eiden, L. E.;
Bonner, T. I.; Usdin, T. B. J. Biol. Chem. 1994, 269, 21929–21932.
(2)
Arvidsson, U. L. F.; Riedl, M.; Elde, R. 1997, 467, 454–467.
(3)
Terry, R. D.; Masliah, E.; Salmon, D. P.; Butters, N.; DeTeresa, R.; Hill, R.; Hansen, L. A.; Katzman, R.
Ann. Neurol. 1991, 30, 572–580.
NMR Spectroscopy Studies of the E. coli O91 O-antigen
Polysaccharide
Blasco P.1, Engström O.1, Widmalm G.*1
1
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Lipopolysaccharides (LPS) are vital to the function and structural integrity of the gramnegative bacteria (1), and are composed by a Lipid A, a core oligosaccharide, and an Oantigen (O-Ag) polysaccharide (PS). This O-Ag structure is composed by different number of
repeating units arranged into linear or branched structures (1). E. coli is the most common
bacteria isolated from patients with gastrointestinal diseases (1-2).
To understand the PS recognition, is essential to obtain information of the conformation of the
LPS at atomic resolution. In this study, we report NMR spectroscopy studies of the Oantigenic polysaccharide E. coli serotype O91, whose structure was previously reported (3,
See Figure). Various 1H,1H-NOESY experiments with different mixing times were performed
in order to obtain information of proton interresidual distances and their related NOE buildup
curves to gain insights into the global PS conformation in solution.
H 3C
O
Acyl
O
N
H
HO
O
OH
O
HO
HO
HN
OH
O
HO
O
O
O
HO
NHAc
Gly
O
OH
OH
O
HO
O
NHAc
4)αDQui3NAcyl(14)βDGal(14)βDGlcNAc(14)βDGlcA6NGly(13)βDGlcNAc(1
References:
(1) Erridge, C., Bennett-Guerrero, E., I.R. Poxton. Structure and function of
lipopolysaccharides. Microbes Infect. 2002, 4:837.
(2) Xu, H., Murdaugh, A., M.E. Núñez. Characterizing pilus-mediated adhesion of
biofilm-forming E. coli to chemically diverse surfaces using atomic force microscopy.
Langmuir. 2013, 29:3000.
(3) Kjellberg, A., Weintraub, A., Widmalm, G. Structural Determination and Biosynthetic
Studies of the O-Antigenic Polysaccharide from the Enterohemorrhagic Escherichia
coli O91 Using 13C-Enrichment and NMR Spectroscopy. Biochemistry. 1999,
38:12205.
Development of photoswitchable units for
structural modulation of peptidomimetics and
molecular tools
Magnus Blom1, Hao Huang2, Christoffer Karlsson2 and Adolf Gogoll1
1
Department of Chemistry BMC, Uppsala University, 2Nanotechnology and Functional Materials,
Department of Engineering Sciences, The Ångström Laboratory, Uppsala University
[email protected]
Photoswitchable compounds (photoswitches) that can be incorporated into larger
constructs, allow a manipulation of molecular structure by an external stimulus i.e. light. This
opens the opportunity to modulate a variety of molecular properties, such as enzymatic
activity, inibitory effect, and affinity.
hν
hν’
Figure 1. Photoisomerization of the switch changes the overall structure of our constructs
In previous work we have shown that incorporation of small, flexible photoswitchable
units based on the stilbene chromophore, into large peptidomimetics can be a viable concept
for photomodulation in biocatalytic systems. To achieve further improvements, our efforts
have recently been directed towards the development of a chromophore, with better
photochemical and structural characteristics.
The “stiff stilbene” chromophore offers two key advantages when compared to stilbene:
 Rigidity, for more pronounced differences between photoisomers
 More substantial difference between the absorption maxima of cis/trans isomers
Herein we present the design and synthesis of our stiff stilbene switch as well as its
incorporation into a bisporphyrin clip and a number of cyclic diesters.
References
[1] Photochemical Regulation of an Artificial Hydrolase by a Back-bone Incorporated
Tertiary Structure Switch. N. J. V. Lindgren, M. Varedian, and A. Gogoll, Chem. -Eur. J.
2009, 15, 501.
[2] Chemistry and Folding of Photomodulable Peptides - Stilbene and Thioaurone-type
Candidates for Conformational Switches. M. Erdélyi, M. Varedian, C. Sköld, I. B. Niklasson,
J. Nurbo, Å. Persson, J. Bergquist and A. Gogoll, Org.& Biomol. Chem. 2008, 6, 4356.
NMR evaluation of plant extracts used in traditional medicine
Hanna Buchholz, Mate Erdelyi*
Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden
Plant based traditional medicine is an essential component of health care for a vast part of the
world's population, predominantly in the third world, with very little modern medicine
available due to low accessibility and high prices. With minimal to none scientific evaluation
being done today regarding the safety or efficacy of these remedies, making forgery of
traditional medicine a huge problem, we herein report on a semi-automated method developed
to identify the natural product constituents of crude plant extracts. The method utilizes HSQC
NMR spectra, acquired on an 800 MHz spectrometer. The crude extracts of three traditional
medicinal plants were analyzed, and the results verified by conventional HPLC techniques.
Two of the analyzed plants, Pentas bussei and Pentas lanceolata, are used to treat malaria,
and the third, Millettia usaramensis, is an anticancer remedy in East Africa. Isolates of these
plants exhibited antimalarial activity, cytotoxicity or no significant bioactivity. Their rapid
identification in traditional medicines is therefore of high importance. The software used for
the method, MestReNova and MS Excel, are user friendly making the method easy-to-handle
and accessible. Our results indicate the ability of this approach to successfully identify single
components directly from crude plant extracts, avoiding time consuming and expensive
isolation. This opens up for a more efficient and a ground-up evaluation of traditional
medicine, facilitating increased patient safety in developing countries.
Figure 1. The HSQC NMR spectra of the crude extracts of P. bussei and M. usaramensis, used in East African
traditional medicine, indicate the presence of a series of secondary metabolites. These are rapidly identified by
the method developed in this study.
Chemical modification on biopolymers from trees
Mikaela Börjesson and Gunnar Westman
Organic Chemisrty, Department of Chemical and Biological Engineering,
Chalmers University of Technology, SE-412 96 Göteborg, Sweden
Email: [email protected]
Our nature produces several tons of biomass every year which could be used in many
different material and products within a wide range of application areas. Through several
different processes and methods, biobased polymers like cellulose and hemicelluloses can be
extracted from the trees or plants and used as a material itself or in a composite. By chemical
modification on biopolymers, new or improved functions will be obtained which in turn will
affect the functions of the final product. Addition of cellulose to polymeric materials will
enhance the profound strength and also reduce the need of fossil based polymers.
This study deals with two different types of chemical reactions, esterification and
etherification on the hydroxyl groups on cellulose and hemicelluloses. The main challenges in
both reactions are the use of “green chemistry” and the improvement from traditionally labscale reactions with a homogenous solution in a round bottom flask to a heterogeneous
reaction on larger scale (gram to kilogram).
One scalable method used is the spray technique with high temperature heating of cellulose in
solvent-free conditions1. The spray technique was used when forming an acrylic ester on
cellulose fibers, open up for further reactions. The reaction was studied with infrared analysis
(FTIR) and transmission electron microscopy (TEM) showing an esterification on the surface
on the cellulose fiber (see figure).
Figure. TEM picture of a cellulosic fibers (a) and an acrylic acid modified cellulose fiber (b).
The same etherification reaction described by de la Motte and Westman1 has also been
implemented on hemicelluloses (xylan from beech wood) but due to the differences in the two
biopolymers the challenge has been to find a similar reaction way to form an etherlinkage on
the water soluble hemicellulose. The chemically modified hemicelluloses in this study will be
used in foam materials made from the biobased polymers.
1. de la Motte, H. and Westman, G. (2012) Cellulose, 19, 1677-1688
Synthesis of an azide-functionalized β-mannosyl triflate:
An FDG precursor for PET imaging
Mathias Elgland , Peter Konradsson, Peter Nilsson*
Linköpings University, IFM – Department of Biology, Chemistry & Physics, SE-58183 LINKÖPING, Sweden
[email protected]
Molecular probes for selective imaging of protein aggregates are important to advance our
understanding of the molecular mechanisms underlying protein misfolding diseases. We have
previously reported how the fluorescent properties of specific thiophene based oligomeric
structures (Luminescent Conjugated Oligothiophenes, LCOs) can be used for the detection of
Aβ-amyloid aggregates related to Alzheimer’s disease1.
In this work, the synthesis of an azide-functionalized β-mannosyl triflate (azidoethyl 2-Otrifluoromethanesulfonyl-β-D-mannopyranoside) is described. The aim is to use the βmannosyl triflate as a “clickable” precursor to 2-fluoro[18]-2-deoxy-glucose (FDG), one of
the most frequently used radiotracers for in vivo PET imaging.
Concerning the synthesis, it has been shown that having a β-configuration of the glycosidic
bond is necessary in order to obtain a sufficient radiochemical yield during the 18F labelingstep2. Since β-mannosides are known to be difficult to obtain by direct glycosylation, a
synthetic strategy was devised where the β-glycosidic bond was formed through a 1,2orthoester rearrangement of a gluco-derivative that subsequently was epimerized to its
corresponding manno-derivative. The synthesized FDG-precursor will be conjugated to
alkyne functionalized LCOs, thus rendering amyloid specific PET tracers. However, the
FDG-precursor is not restricted to amyloid specific ligands, but may in principle be
conjugated to any suitable ligand having affinity for other biological targets.
References
1.Klingstedt, T., Aslund, A., Simon, R., Johansson, L., Mason, J., Nyström, S., Hammarström, P. & Nilsson, K.
(2011). Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral
assignment of protein aggregates. Organic & biomolecular chemistry doi:10.1039/c1ob05637a
2.Maschauer, S. & Prante, O. (2009). A series of 2-O-trifluoromethylsulfonyl-D-mannopyranosides as
precursors for concomitant 18F-labeling and glycosylation by click chemistry. Carbohydrate research 344, 753–
61
Iridium-Catalyzed 1,3-Hydrogen Shift / Bromination of Allylic
Alcohols: Synthesis of α-Bromocarbonyl Compounds
Elis Erbing, Antonio Bermejo Gómez, María Batuecas, Ana Vázquez-Romero, and Belén
Martín-Matute *
Organic Chemistry Department, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
α-Brominated ketones and aldehydes are highly valuable synthetic intermediates in organic
synthesis, with two adjacent electrophilic carbons. Their synthesis from unsymmetrical
ketones is very challenging, and current methods suffer from low selectivity. A new reliable
and efficient method for the synthesis of α-bromocarbonyl compounds in excellent yields and
with excellent selectivities will be presented.1 Starting from allylic alcohols as carbonyl
precursors, the combination of a 1,3-hydrogen shift catalyzed by iridium(III)2 with an
electrophilic bromination gives α-bromoketones and aldehydes in good to excellent yields.
The selectivity of the process is determined by the structure of the starting allylic alcohol, and
thus α-bromoketones formally derived from unsymmetrical ketones can be synthesized in a
straightforward and selective manner.
1,3$Hydrogen-shift-/-bromination-of-allylic-alcohols
R
H
OH
[(IrCp*) 2(OH) 3]OHcat
O
R
Br Br
O
O
H
Br
Acetone / H 2O
rt
√ Up#to#97%#isolated#yields
√ Single#constitutional#isomers
√ 18#examples#of#α;bromoketones#
####and#α;bromoaldehydes
1
A. Bermejo Gómez, E. Erbing, M. Batuecas, A. Vázquez-Romero, B. Martín-Matute, submitted for
publication.
2
a) N. Ahlsten, B. Martín-Matute, Chem. Commun. 2011, 47, 8331-8333. b) N. Ahlsten, A. Bartoszewicz, S.
Agrawal, B. Martín-Matute, Synthesis, 2011, 16, 2600-2608. c) N. Ahlsten, A. Bermejo Gómez, B. MartínMatute, Angew. Chem. 2013, 125, 6393-6396; Angew. Chem. Int. Ed. 2013, 52, 6273-6276.
Mechanistic studies on the N-alkylation of amines with alcohols
catalyzed by a bifunctional iridium complex
Greco González Miera, Agnieszka Bartoszewicz, Rocío Marcos, Per-Ola Norrby and Belén
Martín-Matute*
Organic Chemistry Department and Berzelii Center EXSELENT on Porous Materials Arrhenius Laboratory,
Stockholm University, SE-106 91 Stockholm, Sweden.
The mechanism of the N-alkylation of amines with alcohols 1,2 catalyzed by an iridium
complex 3,4 containing an N-heterocyclic carbene (NHC) ligand with a tethered alcohol /
alkoxide functionality has been investigated by both experimental computational methods: 5
The mechanism of the reaction consists of three main steps: i) oxidation of the alcohol
substrate to form an aldehyde with concomitant formation of an iridium hydride, ii)
condensation of the aldehyde with the amine substrate to form an imine intermediate, and iii)
reduction of the imine intermediate by the iridium hydride.
Here we will present insights into the mechanism obtained from Hammett studies and isotopic
labeling experiments under competitive and non-competitive conditions, as well as from
kinetic investigations. 6
1
For recent reviews and perspective articles, see: (a) Guillena, G.; Ramón, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611-1641. (b) Dobereiner,
G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681-703. (c) Watson, A. J. A.; Williams, J. M. J. Science, 2010, 329, 635-636. (d) Bähn, S.;
Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller, M. ChemCatChem 2011, 3, 1853-1864. (e) Pan, S.; Shibata, T. ACS Cat. 2013, 3,
704-712.
2
Bacells, D.; Nova, A.; Clot, E.; Gnanamgari, D.; Crabtree, R. H.; Eisenstein, O. Organometallics 2008, 27, 2529-2535.
3
Schley, N. D.; Halbert, S.; Raynaud, C.; Eisenstein, O.; Crabtree, R. H. Inorganic Chemistry 2012, 51, 12313-12323.
4
Fristrup, P.; Tursky, M.; Madsen, R. Org. Biomol. Chem. 2012, 10, 2569-2577.
5
Bartoszewicz, A.; Marcos, R.; Miera, G. G.: Norrby, P.-O.; Martín-Matute, B., 2014, submitted.
6
Bartoszewicz, A.; Marcos, R.; Sahoo, S.; Inge, A. K.; Zou, X.; Martín-Matute, B. Chem. Eur. J. 2012, 18, 14510-14519.
Transition Metal-Catalyzed Alkenylation of Enolates
Michael Grigalunas, Tobias Ankner, Per-Ola Norrby†, Olaf Wiest* and Paul Helquist*
†
Pharmaceutical Development, Global Medicines Development, AstraZeneca, Sweden
* Department of Chemistry and Biochemistry, University of Notre Dame, USA
-unsaturated carbonyl functionalities are structural features in a number of
biologically important molecules. From a synthetic chemist’s perspective, the numerous
manipulations to the carbonyl and alkene moiety present a platform for easy access to
complex structures. Transition metal-catalyzed methods have proved to be an effective route
to synthesize these -alkenylated compounds.1 However, compared to the similar -arylation
reactions, -alkenylations have remained at an early stage of development. Opportunities for
this reaction include developing mild conditions and procedures that use alternative transition
metals as well as a further understanding of the reaction through mechanistic studies,
ultimately resulting in ligand design for enantioselective synthesis.
References:
(1) Ankner, T.; Cosner, C. C.; Helquist, P. Chem. Eur. J. 2013, 19, 1858–1871.
Chemoenzymatic Dynamic Kinetic Resolution of Primary Amines using a
Recyclable Palladium nanoparticle catalyst together with Lipases
Karl P. J. Gustafson, Richard Lihammar, Oscar Verho, Karin Engström and Jan-Erling
Bäckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden.
A powerful technique for producing enantiomerically enriched compounds is to utilize an
enzyme in a kinetic resolution. In this process the enzyme catalyzes the transformation of one
enantiomer faster than the second, resulting in two products of opposite stereochemistry with
a maximum yield of 50% of each. One way of avoiding this limitation is to carry out the
kinetic resolution in parallel with an in situ racemization catalyst, thus making it into a
dynamic kinetic resolution (DKR), which theoretically could increase the yield up to 100% of
a single enantiomer. Herein, we report on a heterogonous palladium nanocatalyst (Pd-AmPMCF) utilized as a racemization catalyst in the chemoenzymatic DKR of benzylic amines into
their corresponding amides in high yields and excellent ee’s. The protocol allowed reaction
temperatures more suitable for enzymes, a feature demonstrated by subjecting 1phenylethylamine to a DKR using two commercially available enzymes. CALB (Candida
antartica Lipase B) and the Lipase PS (lipase from Burkholderia Cepacia) were used, where
the latter lipase has previously not been reported in the DKR of amines, due to its low
stability at temperatures over 60 °C. A few analogues of 1-phenylethylamine were also
evaluated in the DKR protocol. The stability of the heterogeneous Pd-AmP-MCF was further
shown by recycling the catalyst, where it was shown that the nanocatalyst could be used up to
five times.
Acknowledgement: Financial support from the Berzelius Center EXSELENT, the European
Research Council (ERC AdG 247014), the Knut and Alice Wallenberg Foundation, and the
Swedish Research Council are gratefully acknowledged.
Heterogeneous acid and lipase catalysed tandem synthesis of
cyclic allylic alcohol derivatives
Chicco Manzuna Sapu, Tamás Görbe, Richard Lihammar, Jan-Erling Bäckvall and Jan
Deska*
*Department für Chemie, Universität zu Köln, Cologne, Germany
e-mail: [email protected]
The chiral cyclic allylic alcohols are important building blocks as intermediates of
pharmaceuticals, agrochemicals and natural products. The general protocols to synthesize
these enantiopure alcohols are asymmetric reduction of vinyl ketones by using chiral
catalysts, enantioselective addition of alkenyl metal reagents to aldehydes and kinetic
resolution (KR) or dynamic kinetic resolution (DKR) of allylic alcohols. One of the most
interesting and environmentally friendly way is to utilize an enzyme as the chiral catalyst.
A tandem reaction is a series of reactions in one-pot. These processes are usually more
efficient and show higher atom economy. In our project the substrate, a tertiary alcohol, can
be rearranged to an allylic secondary alcohol by the acid catalysis. In this step of the reaction
we produce in situ our substrate for the next step of the tandem reaction, which is the DKR.
The lipase catalyzed KR is a highly chemo- and stereoselective method for the preparation of
enantiomerically pure alcohols and esters. As a drawback of the reaction, only one of the
enantiomers is converted into the product, therefore the reaction will stop at 50% conversion.
This limitation can be circumvented by using an in situ racemization catalyst, this extension
of the process is called a DKR.
Migratory DKR
DKR
HO
R1
R2
acid
R1
R2
water
n
acid
acyl donor
CALB
R1
R2
water / i-octane
n
OH
n
O
O
R3
In the literature it is published that the acidic resin materials with sulfonyl groups are good
racemization catalysts for the secondary alcohols. In our research we extent their protocol and
developed a two phase tandem reaction for transformation of racemic cyclic tertiary alcohols
to enantiomerically pure allylic esters. The acidic polymer was used as a catalyst in two steps
of the reaction, it was catalysing the rearrangement of the tertiary alcohol to allylic secondary
alcohol. This alcohol could then also be racemized using the acidic resin and the CALB was
highly selective in the enzymatic transesterification reaction. The recyclability of the
heterogenous material was also studied.
Synthesis and biology of bishydroxylated naphthoxylosides
Karin Holmqvist,a Andrea Persson,b Anna Siegbahna and Ulf Ellervika*
a
Center for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 22100 Lund, Sweden
b
Department of Experimental Medicinal Science, Lund University, BMC A13, SE-221 84 Lund, Sweden
Xylose is a very unusual carbohydrate in mammalian cells, acting as a linker between a
protein and glycosaminoglycan (GAG) chains in proteoglycans (PG), which are
macromolecules that are involved in many functions, such as regulation of growth factors,
cell-cell interactions, and uptake of biomolecules. PG and GAG are also involved in the
pathobiology of cancer progression by regulating cancer cell proliferation, tumor invasion,
metastasis, and angiogenesis. It has long been known that xylosides carrying a hydrophobic
aglycon can enter cells and act as primers for GAG synthesis, independent on the core
protein.1 The structure of the aglycon affects the structure of the GAG chains and thus the
biological activity. Previously, we have reported that 2-(6-hydroxynaphthyl) β-Dxylopyranoside (XylNapOH), in contrast to 2-naphthol β-D-xylopyranoside (XylNap),
selectively inhibited tumor growth both in vitro and in vivo as well as reduced the level of
acetylation of histone H3 selectively in cancer cells.2 To further investigate the underlying
cause of this selectivity exhibited by XylNapOH, bishydroxylated analogs and related
compounds have been synthesized and their biology tested. The key step in the synthesis is
the regionselective introduction of a second hydroxyl group in the aromatic system.
HO
HO
O
O
OH
HO
HO
O
O
OH
OH
XylNap
1
2
XylNapOH
Schwartz, N. B.; Galligani, L.; Ho, P.-L.; Dorfman, A., Proc. Nat. Acad. Sci. USA 1974, 71, 4047-4051.
Nilsson, U.; Johnsson, R.; Fransson, L.-A.; Ellervik, U.; Mani, K. Cancer Res. 2010, 70, 3771-3779.
Quinone Functionalized Pyrrole For Organic Energy Storage
Hao Huang, Christoffer Karlsson, Maria Strømme, Martin Sjödin and Adolf Gogoll*
Nanotechnology and Functional Materials, Department of Engineering Sciences, The Ångström Laboratory,
Uppsala University, Box 534, SE-751 21 Uppsala, Sweden
* Department of Chemistry - BMC, Biomedical Centre, Uppsala University, Box 576, SE-751 23 Uppsala,
Sweden
Quinones have been suggested as alternative cathode materials in lithium ion batteries for
their well-defined redox potential.1 However, most of them suffer from low conductivity, poor
redox kinetics and dissolution problems.2 To compensate for these problems, we attach
quinones as pending moieties onto a conducting polypyrrole backbone, rendering them
insoluble, while increasing conductivity and preserving redox activity.3 In this work, a series
of monomeric compounds with hydroquinone substituted pyrroles with various linkers
between the subunits has been synthesized. Suzuki and Sonogashira reactions were employed
to couple these two subunits, which allows for synthetic flexibility in combining
hydroquinone and pyrrole derivatives, as well as in the choice of interconnecting linkers.
Studies of electrochemical measurements and spectroscopical characterization on these
compound have been performed to understand the influence of linker units on the
electrochemical properties. Monomers were polymerized electrochemically and the polymers
exhibited high capacities and conductivities.
References
1. Liang, Y.; Tao, Z.; Chen, J., Adv. Energy Mater. 2(2012) 742-769.
2. Pud, A. A. Synth. Met. 66(1994) 1−18.
3. Karlsson, C.; Huang, H.; Strømme, M.; Gogoll, A.; Sjödin, M. J. Phys. Chem. C, 117
(2013) 23558-23567.
Novel n-type Thiophene-based Terephthalate Redox Polymer for
Energy Storage
Li Yang1, Xiao Huang2, Martin Sjödin1, Adolf Gogoll2, Maria Strømme1
1
Uppsala University, Nanotechnology and Functional Materials, Department of Engineering Sciences,
Box 534, 751 21 Uppsala, Sweden
2
Uppsala University, Synthetic Organic Chemistry, Department of Chemistry - BMC, Box 576, 751 23
Uppsala, Sweden
[email protected]; [email protected]
Conjugated polymers such as poly-thiophene, pyrrole and aniline provide attractive components in
organic matter based electrode materials due to their environmental friendliness, eco-efficient
production process, as well as readily accessible resources. Thiophene-based conducting polymers
display both n-doping and p-doping properties, good mechanical and cycling stability, and this
type of material has been used in batteries, capacitors and other electrical devices [1-3]. The
polythiophene can be n-doped as low as about 1.0V vs Li/Li+ and introduces a potential
application as anode material for electrical energy storage. However, the charge storage capacity
of polythiophene by itself is inferior to current commercial anode materials used in rechargeable
batteries. A thiophene-based polymer with a capacity-carrying terephthalate pending group has
been successfully synthesized in this study. This material was inspired by the electrochemistry
studies of both polythiophene and single molecule terephthalate. The pended terephthalate group
on polythiophene was expected to give a fast redox conversion in the polymer conducting region
as a “charge tank”. The redox potential matching of the pendant and polymer chain has been
supported by recent computational studies, and the experimental cyclic voltammetry of this redox
polymer shows that the terephthalate group can be reversibly cycled at high rates.
[1] F. Rosciano, M.M. Salamone, Riccardo Ruffo, M. Sassi, L. Beverina, J. Electrochem. Soc. 160 (2013)
A1094-A1098.
[2] T.F. Otero, J. Arias-Pardilla, H. Herrera, J.L. Segura, C. Seoane, Phys. Chem. Chem. Phys. 13 (2011) 16513–
16515.
[3] C.Y. Wang, A.M. Ballantyne, S.B. Hall, C.O. Too, D.L. Officer, G.G. Wallace, J. Power Sources 156 (2006)
610–614.
Synthesis of crystal mimicking 1,3-diphenylisobenzofuran
Fredrik Johansson, Bo Albinsson and Jeker Mårtensson
Department of Chemical and Biological Engieneering, Chalmers University of Techology
The potential of solar energy is enormous and might be one of the few energy sources viable
in a long term perspective for large scale energy production. However, the viability of solar
energy harvesting devices are hampered by high production costs and limited efficiencies.
The most significant of the efficiency limiting factors in solar cells is spectrum losses. The
incoming light might either possess too little energy to participate in power production or
have an excess of energy in which the surplus is dissipated as heat. In single junction silicon
based solar cells these energy mismatches constitutes for a 50 % energy loss.1 One potential
strategy to diminish the energy loss due to dissipation of excess energy is to use systems able
to support singlet fission. These are multi-chromophore systems in which an organic
chromophore in its singlet excited stated shares the excitation energy with a neighboring
ground state chromophore, resulting in the formation of two triplet excited compounds. The
characteristics of the systems needed to support this process are exotic. Molecular architecture
capable of sustaining singlet fission are found in slip-stacked crystalline structures made of a
limited number of compounds with specific electronic properties.2
Systems able to self-assemble 1,3-diphenylisobenzofuran chromophores in a slip-stack
manner is targeted within this work. The chromophore is constructed via a Suzuki-Miyaura
type coupling between 2-benzoylbenzaldehyde and a bromo-aryl that carries the linker and
the anchor group functionality. The synthesis is designed to accommodate variations of the
linker and anchor group, as well as being mild enough to ensure stability of the otherwise
sensitive 1,3-diphenylisobenzofuran (See Figure 1).
Figure 1: The targeted slip-stacked self-assembled structure is shown to the left and the schematic outline of the
synthetic pathway is shown to the right.
References
[1] Archer, M.D., Bolton, J.R. J. Phys. Chem . 1990, 94, 8028-8036
[2] Smith, M.B., Michl, J. Chem Rev. 2010, 110, 6891-6936.
13
C solid state NMR investigations of graphite oxide
Dan Johnels*, Mattias Hedenström*, Guillame Mercier** and Alexandr Talyzin**
*Department of Chemistry, Umeå University, SE 901 87 Umeå Sweden
** Department of Physics, Umeå University, SE 901 87 Umeå Sweden
Graphite oxide was produced in the previous millennium by oxidation of graphite by fuming
nitric acid or KMnO4. There has been a renewed interest in graphite oxide in connection to
the hype around graphene. Graphite oxide is still produced by the same methods, but the
structure and properties of the formed material depends on the oxidation method. We have
investigated material produced by these methods by 13C solid state NMR spectroscopy. It
turns out that the differences between these materials are more pronounced than previously
noted. The results will be presented in the poster.
The nature of [N-Cl-N]+ and [N-F-N]+ halogen bonds in solution
Alavi Karim, Marcus Reitti, Anna-Carin C. Carlsson, Jürgen Gräfenstein, Mate Erdelyi*
Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden
E-mail: [email protected]
Three-center-four-electron interactions are common in nature and have been the matter of
discussion since decades.1 While hydrogen bond symmetry in [N-H-N]+ type systems have
been studied extensively, the analogous [N-X-N]+ type halogen bonded complexes are yet to
be explored. It is especially relevant as the three-center [N-I-N]+ BF4- complex has found
application in synthetic organic chemistry as electrophilic halogenating, cross-coupling and
oxidizing agent, for example.2
Previously, we have characterized 3c4e systems comprising of [N−I−N]+ and [N−Br−N]+
halogen bonds in solution to be static, symmetric geometries. However, the nature of the
highly reactive, lighter halogens including [N-Cl-N]+ and [N-F-N]+ type complexes in
solution are yet to be defined. Stabilization of halonium ions by attachment to two nitrogen
atoms, instead of carbons, is as challenging as impactful. Recently, we ventured towards the
synthesis of a bis(pyridine)chloronium and bis(pyridine)fluoronium complexes where an
electropositive chlorine(I) or fluorine(I) is incorporated between two nitrogenous electron
donors. The geometrical arrangement of the [N-Cl-N]+ and [N-F-N]+ systems concluded from
solution NMR measurements were confirmed by DFT calculations. In line with fluorine being
a poor halogen bond donor,3 the [N+−F···N] system shows a different behavior as compared
to the heavier halogens.
In addition to the theoretical value of an improved understanding of three-center halogen
bonds, the rapidly growing awareness of electrophilic halogenating agent’s wide synthetic
applicability provides the practical importance of the above study.4
Figure 1. The sigma hole of the halogens (I to F from left) of the studied systems.
References
1
G. C. Pimentel, J. Chem. Phys. 1951, 19, 446.
2
J. Barluenga, Pure Appl Chem 1999, 71, 431-436.
3
P.Metrangolo, G. Resnati, Science 2008, 321, 918-919.
4
R.S. Brown, A.A. Neverov, C.T. Liu, C. I. Maxwell Acs Sym Ser 2007, 965, 458-476.
Ring-fused 2-pyridones inactivate the virulence regulator PrfA in
Listeria monocytogenes
Martina Kulén1,2,, James A. D. Good1,2,, Christopher Andersson2,3,4,, Jessica Wall2,3,4,, Sabine
Hansen2,3,4,#, K. Syam Krishnan1,2,#, Christin Grundström1,2, Moritz S. Niemiec1, Karolis
Vaitkevicius2,3,4, Erik Chorell1,2, Uwe H. Sauer1,2, Pernilla Wittung-Stafshede1, Elisabeth Sauer–
Eriksson1,2,4, Fredrik Almqvist1,2,* and Jörgen Johansson2,3,4,*
1
Department of Chemistry, 2Umeå Centre for Microbial Research, 3Department of Molecular Biology, 4Molecular Infection
Medicine, Sweden (MIMS), Umeå University, 901 87 Umeå, Sweden.
*Umeå University, Department of Chemistry, 901 87 Umeå, Sweden; Umeå Centre for Microbial
Research, Umeå University, 901 87 Umeå, Sweden; E-mail: [email protected].
The rapid emergence of bacterial resistance to antibiotics is a serious global problem and new
therapeutic options to treat severe bacterial infections are urgently required.1 The bacterium
Listeria monocytogenes is a Gram-positive saprophyte which is responsible for the disease
listeriosis in humans upon ingestion. Due to its ability to grow at low temperatures, high salt
and low oxygen conditions, it is one of the most problematic foodborne pathogens known.2 We
have identified several ring-fused 2-pyridone molecules that attenuate L. monocytogenes
infectivity by reducing the expression of virulence genes, without compromising bacterial
growth. The inhibitors bind to and prevent activation of PrfA, the central transcriptional
virulence regulator in L. monocytogenes. One of the identified inhibitors binds to PrfA with a
KD ≈ 1 µM according to ITC measurements. The structural basis for inhibition was elucidated
by the co-crystal of PrfA with this inhibitor. This represents the first structurally resolved
complex between an inhibitor and a Crp family transcriptional regulator. Here, we will present
the background to this discovery and initial structure activity relationships generated within the
project. The PrfA·inhibitor crystal structure provides an excellent platform for structure-based
drug design and synthesis of improved inhibitors.
1
Davies, J. & Davies, D. Origins and Evolution of Antibiotic Resistance. Microbiology and
Molecular Biology Reviews 74, 417-433 (2010).
2
Vázquez-Boland, J.A. et al. Listeria Pathogenesis and Molecular Virulence Determinants. Clinical
Microbiology Reviews 14, 584-640 (2001).
Molecular solar-thermal energy storage
Anders Lennartson, Victor Gray, Karl Börjesson, and Kasper Moth-Poulsen
Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
In a future society with limited access to fossil fuels, technologies for efficient delivery of
renewable energy are highly desirable. In this regard, methods that allow for solar energy
storage and on demand solar driven power generation are particularly relevant since the sun is
the most abundant energy source.
Compounds undergoing reversible photoinduced isomerisation can be used for storage of
solar energy: energy is absorbed upon irradiation and is released by the photoisomer by
applying heat or a catalyst; this principle is called molecular solar-thermal (MOST) energy
storage. Here we will present our recent progress based on two systems: tetracarbonyl
fulvalene diruthenium compounds1 and substituted norbornadiens.2 Norbornadiene itself
undergoes photoisomerisation to metastable quadricyclane, but this system suffers from the
fact that only UV-radiation can induce isomerisation and sun light therefor has little effect.
We have prepared a series of substituted norbornadienes with red-shifted absorption spectra
without compromising half-lives of the corresponding quadricyclanes.2 While the ruthenium
system absorbs visible light, a major problem has been the low isomerisation quantum yields.
We have successfully increased the quantum yields by introducing sterical hindrance at the
central C−C bond.3
1. a. M. R. Harpham, S. C. Nguyen, Z. Hou, J. C. Grossman, C. B. Harris, M. W. Mara, A. B. Stickrath, Y.
Kanai, A. M. Kolpak, D. Lee, D.-J. Liu, J. P. Lomont, K. Moth-Poulsen, N. Vinokurov, L. X. Chen, K. P. C.
Vollhardt, Angew. Chem. Int. Ed., 2012, 51, 7692. b. K. Moth-Poulsen, D. Coso, K. Börjesson, N. Vinokurov, S.
K. Meier, A. Majumdar, K. P. C. Vollhardt, R. A. Segalman, Energy Environ. Sci., 2012, 5, 8534. c. K.
Börjesson, A. Lennartson, K. Moth-Poulsen, J. Fluorine Chem., 2014, accepted. d. K. Börjesson, D. Dzebo, B.
Albinsson and K. Moth-Poulsen J. Mater. Chem. A. 2013, 1, 8521.
2. V. Gray, A. Lennartson, P. Ratanalert, K. Börjesson and K. Moth-Poulsen, Chem. Commun. 2013. DOI:
10.1039/c3cc47517d
3. A. Lennartson, K. Börjesson, V. Gray, P.-O. Norrby and K. Moth-Poulsen. Manuscript in preparation.
Terpenoid responses from methyl jasmonate treatment of Pinus
sylvestris and Picea abies
Lina Lundborg and Anna-Karin Borg-Karlson
Ecological chemistry group, Division of Organic Chemistry, Royal Institute of Technology, Stockholm, Sweden
The pine weevil Hylobius abietis (L.) is a pest to young conifers in Europe, and in Sweden
annual cost amounts to millions of SEK. The chemical protection of insecticides is to be
phased out against ecological alternatives. Exogenous application of methyl jasmonate, a
plant hormone involved in herbivore damage signaling and plant induced responses, causes
terpenoid defense responses that may increase conifer resistance against weevil attack. In field
trials, treated seedlings of Scots pine (Pinus sylvestris) and Norway spruce (Picea abies) were
evaluated for damage and mortality in an area of naturally occurring weevils1 . Random
seedlings were freeze stored at -80°C, to make possible for chemical analysis of the treatment
group (strength and timing) that induced superior protection. The volatile terpenoid fraction
was analyzed using two dimensional GC-MS with a chiral column in the second GC, using
instrumental setup as described by Moreira et al 20132 . In phloem of treated conifer juveniles,
induction of 1,8-cineole and (-)-β-pinene was observed. In space-repellency tests with
weevils, both components mask the attraction of Scots pine host odor. Female and male
weevils reacted differently to induced achiral components terpinolene and β-myrcene. The
chemical data will be presented using multivariate statistics and discussed in a biological
context.
1
Zas, R., Björklund, N., Nordlander, G., Cendán, C., Hellqvist, C. & Sampedro, L. 2014. Exploiting jasmonateinduced responses for field protection of conifer seedlings against a major forest pest, Hylobius abietis. Forest
Ecology and Management 313: 212-223.
2
Moreira, X., Lundborg, L., Zas, R., Carrillo-Gavilán, A., Borg-Karlson, A-K. & Sampedro, L. 2013.
Inducibility of chemical defences by two chewing insect herbivores in pine trees is specific to targeted plant
tissue, particular herbivore and defensive trait. Phytochemistry 94: 113-122.
The functionalization of C-H bonds by molecular imprinted Nheterocyclic carbene- palladium catalysts
Maitham H. Majeed, Payam Shayesteh, Lei Ye, Joachim Schnadt, Ola F. Wendt*
Department of Chemistry, Lund University, SE-221 00 Lund, Sweden
and
Department of Physics, Lund University, SE-221 00 Lund, Sweden
The selective oxidation of unactivated C-H bonds is a significant research goal because of its
importance in synthesis and the chemical industry.[1] Transition metals, particularly
palladium(II) and platinum(II), have played an important role as catalysts in these
transformations. Acetoxylation of simple arenes is one such examples (Fig. 1).[2,3]
OAc
Catalyst [Pd II]
Oxidant
AcOH/Ac2O (9:1)
100 oC
Figure 1. Example of Pd catalyst activity for benzene C−H acetoxylation
The success of this strategy (C−H activation) is constrained by the necessity of using specific
types of reactants and specific conditions. To lift these restrictions and to synthesize a catalyst
for substrates without directing groups, we have designed a molecular catalyst imprinted in a
polymer matrix, with the aim of combining the advantages of both homogeneous and
heterogeneous catalysts. This methodology is based on the template-directed assembly of a
metal catalyst in molecularly imprinted cavities, where high efficiency C-H activation will be
provided by N-heterocyclic carbene-palladium complexes and the selectivity will be
controlled by the shape of the molecular binding cavity.
To characterize these systems, we used solid state NMR, FTIR, TG, ICP, SEM and X-ray
spectroscopy. XPS and XAS techniques will be used as a characterizing tools to investigate
the geometry of the molecularly imprinted N-heterocyclic carbene-palladium polymers on the
surfaces and to determine the catalytic mechanism.
References:
1. R. Giri, et al., Angew. Chem. Int. Ed., 2005, 44, 7420-7424.
2. A. Maleckis, J. W. Kampf, and M. S. Sanford, J. Am. Chem. Soc., 2013, 135, 6618-6625.
3. J. B. Gary, A. K. Cook, and M. S. Sanford, ACS Catal., 2013, 3, 700-703.
Synthesis of a tetrasaccharide corresponding to the inner part of
N-Linked glycoproteins
Hani Mobarak, Jerk Rönnols and Göran Widmalm
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
E-mail: [email protected]
The tetrasaccharide β-D-Manp-(1→4)-β-D-GlcpNAc-(1→4)[α-L-fucp-(1→3)]-β-D-GlcpNAc
is a partial structure of N-glycans. These glycoconjucatees are widely spread in biological
systems where they have different fucosylation patterns. The synthesis of this molecule with a
limited number of protecting groups in the building blocks will also result an efficient
synthetic scheme for larger N-glycans. The β-(1→4)-linkage was formed in a regioselective
manner with a 3,4-dihydroxy acceptor having an azido group in the anomeric position (which
later can be transformed to different anomeric analogues), followed by two successive cisglycosylations, namely, α-fucosylation and β-mannosylation.
References
(1)
Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985, 54, 631–664.
(2)
Zhu, T.; Boons, G. J. Chemistry 2001, 7, 2382–2389.
(3)
Söderman, P.; Larsson, E. A.; Widmalm, G. European J. Org. Chem. 2002, 2002, 1614–1618.
(4)
Crich, D. Acc. Chem. Res. 2010, 43, 1144–1153.
(5)
Wang, A.; Auzanneau, F.-I. Carbohydr. Res. 2010, 345, 1216–1221.
Few-layer graphene on polymer substrates
Michael Nordlund,[1] Sumanta Bhandary,[2] Biplab Sanyal,[2]
Torbjörn Löfqvist,[3] Helena Grennberg[1]
[1] Department of Chemistry – BMC, Uppsala University
[2] Department of Physics and Astronomy, Uppsala University
[3] EISLAB, Department of Computer Science, Electrical and Space Engineering,
Luleå University of Technology
In order for graphene to be used in applications it has to be on a substrate. Flexible and
transparent polymers are particularly attractive but very challenging. The main aim of this
project is to study different aspects of deposition of few-layer graphene (FLG) flakes on
PVDF films.
A simple and efficient method of exfoliating natural graphite into solvents to produce flakes
of FLG is used to generate a graphene suspension.[1] The deposition from suspension is then
followed using spectroscopic techniques and compared with the computations on model
molecules.
[1]
E. Widenkvist, D. W. Boukhvalov, S. Rubino, S. Akhtar, J. Lu, R. A. Quinlan, M. I.
Katsnelson, K. Leifer, H. Grennberg, U. Jansson, J. Phys. D-Applied Phys. 2009, 42.
Bitopic porphyrin host-guest systems for stereochemical
characterization
Sandra Olsson, Sara Norrehed, Helena Grennberg, Adolf Gogoll,
Uppsala University, Department of Biochemistry and Organic Chemistry
Box 576, SE-751 23 Uppsala
A challenge with stereochemical characterisation of flexible molecules by NMR spectroscopy
in solution is their rapid change of conformation. The measured chemical shifts, NOE:s and
coupling constants will be population-weighted averages of all present conformers. To reduce
the conformational space, we have developed molecular tweezers [1]. These tweezers, in
combination with NMR Analysis of Molecular Flexibility in Solution (NAMFIS), facilitate
stereochemical characterisation of diamines with multiple stereogenic centres [2]. We now
intend to extend this method from diamines to diols and other compounds with N, O, S or P
containing functional groups. The main challenge so far is to redesign the tweezers to bind, e.
g. -alcohols as well as amines.
Figure 1. Molecular tweezers binding a
guest molecule.
Figure 2. J-based analysis is not sufficient to distinguish the alditol
congeners represented by their Newman projections [2].
References
[1] Norrehed, S.; Polavarapu, P.; Yang, W.; Gogoll, A.; Grennberg, H. Tetrahedron 2013, 69,
[2]
7131–7138.
Norrehed, S.; Johansson, H.; Gogoll, A.; Grennberg, H. Chem. Eur. J. 2013, 43, 14631–14638.
Lanthanide-based luminescent probes for the detection of
enzymatic activity
Elias Pershagen, Eszter Borbas*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 10691, Stockholm, Sweden,
and *Department of Chemistry - BMC, Uppsala University, 751 23 Uppsala, Sweden.
The synthesis and photophysical characterization of four different luminescent probes for
enzymatic activity is described. The probes are based on the lanthanide emitters Eu ,Tb and
Sm and are constructed from the same framework. Ratiometric as well as simultaneous
detection of multiple enzymatic activities is possible using the probes.
Aryl sulfonates in inversions at galactose C3: a new and improved
route towards 3-azido-β-D-galactopyranosides
Kristoffer Petersona, Alex Weymouth-Wilsonb and Ulf J. Nilssona
a
b
Centre for Analysis and Synthesis, Lund University, POB 124, 22100 Lund (Sweden)
Dextra Laboratories Ltd, Science & Technology Centre, Earley Gate, Whiteknights Rd, Reading, RG6 6BZ
(UK)
3-azido-β-D-galactopyranosides is a key intermediate in the synthesis of some of the most
potent galectin-3 inhibitors1. Its synthesis has previously been described in our group2 through
a double inversion at C3 with triflate as leaving group in both inversions. A novel and
improved route in which the triflate leaving group is replaced with more stable aryl sulfonates
is described herein, which facilitates scale up and improve reproducibility.
In the first inversion we employed arylsulfonates described by Muramatsu3 and for the
second inversion an imidazolate shown by Vatéle and Hanessian4. All intermediates in the
new route were stable and the 3-azido-β-D-galactopyranosides was obtained in satisfactory
yields. The nucleophiles explored in the second inversion were sodium azide and
tetrabutylammonium azide, but other nucleophiles could be studied to determine what
functionalities can be introduced at galactose C3 via this route.
1
a) B. A. Salameh, I. Cumpstey, A. Sundin, H. Leffler, U. J. Nilsson, Bioorg. Med. Chem., 2010, 18, 53675378; b) I. Cumpstey, E. Salomonsson, A. Sundin, H. Leffler, U. J. Nilsson, Chem. Eur. J., 2008, 14, 4233-4245;
c) P. Sörme, P. Arnoux, B. Kahl-Knutsson, H. Leffler, J. M. Rini, U. J.Nilsson, J. Am. Chem. Soc., 2005, 127,
1737-1743; d) I. Cumpstey, A. Sundin, H. Leffler, U. J. Nilsson, Angew. Chem. Int. Ed., 2005, 44, 5110-5112.
2
C. T. Öberg, A-L. Noresson, T. Delaine, A. Larumbe, J. Tejler, H. von Wachenfeldt, U. J. Nilsson,
Carbohydrate research, 2009, 344, 1282-1284.
3
W. Muramatsu, J. Org. Chem., 2012, 77, 8083-8091.
4
J. Vatéle, S. Hanessian, Tetrahedron, 1996, 52, 10557-10568.
Quantum chemical studies of the iodonium-centered three-center
halogen bond
Marcus Reitti, Jürgen Gräfenstein,* and Máté Erdélyi*
Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Gothenburg, Sweden
Halogen bonding (XB) is a noncovalent interaction where halogens accept electron pairs from
Lewis bases. XB resembles hydrogen bonding (HB) but tends to surpass HB in terms of
strength, specificity, and directionality so it may open up new paths e.g. in crystal engineering
and medicinal chemistry.
A reliable computational description of XB complexes is non-trivial. In this work, we present
an extensive test of different wave-function and density-functional theory (DFT) methods for
the description of geometric and NMR properties of the HB complex 1 that contains an
iodonium ion bound between two nitrogen atoms.1,2 The three-center four-electron bond in 1
is particularly challenging to describe with DFT because of (i) the considerable non-dynamic
electron correlations in this bond and (ii) the electron delocalization and, consequently, the
potentially large self-interaction error.3 Similar studies have been done earlier for neutral twocenter halogen bonds4-6 but only in restricted form7 for three-center halogen bonds.
Figure 1. 1 optimized using the M06-2X functional (left). 2D-depiction of the studied system (right).
References
1.
2.
3.
4.
5.
6.
7.
Carlsson, A.-C. C.; Gräfenstein, J.; Laurila, J. L.; Bergquist, J.; Erdélyi, M. Chem. Commun.
2012, 48, 1458.
Carlsson, A.-C. C.; Uhrbom, M.; Karim, A.; Brath, U.; Gräfenstein, J.; Erdélyi, M.
CrystEngComm 2013, 15, 3087.
Gräfenstein, J.; Cremer, D. Theor Chem Acc 2009, 123, 171.
Jorgensen, W. L.; Schyman, P. J. Chem. Theor. Comput. 2012, 8, 3895.
Chudzinski, M. G.; Taylor, M. S. J. Org. Chem. 2012, 77, 3483.
Kozuch, S.; Martin, J. M. L. J. Chem. Theor. Comput. 2013, 9, 1918.
Georgiou, D. C; Butler, P.; Browne, E. C.; Wilson, D. J. D.; Dutton, J. L. Aust. J. Chem. 2013,
66, 1179.
Microwave-absorbing Silicon Carbide continuous-flow reactors
Vivek Konda, Jonas Rydfjord, Jean-Baptiste Véron, Jonas Sävmarker and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University
*Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University
We have recently introduced a continuous-flow (CF) setup (Figure 1) using a semiconductor
based microwave system for heating.[1–4] The reactants are pumped through a tubular
borosilicate glass reactor which is placed in a microwave field. As the borosilicate glass is
practically transparent to microwaves this will result in direct heating of the reaction mixture
by microwaves.
A complimentary reactor material is silicon carbide
(SiC) which can be described as a completely
microwave absorbing material. A reactor made out of
SiC placed in a microwave field will thus be directly
heated, and no microwave heating of the reaction
mixture will occur.
Our interest in this ceramic reactor material began
with a phenomenon that many chemists have
Figure 1: CF setup (left: pump; middle: reactor,
microwave generator; right: fraction collector
observed when running palladium-catalyzed reactions
(in our case Mizoroki-Heck reactions in CF), namely
the formation of palladium deposits. Usually this would be nothing but a small nuisance in the
workup/purification - unless the deposits are present on a microwave transparent reactor in a
microwave field. Extreme heating of the deposits then occur (and did in our model reaction),
causing rupture of the reactor.
With the construction of SiC reactors we have now been able to develop CF-protocols for the
Mizoroki-Heck reaction as well as the Suzuki-Miyaura cross-coupling using the microwave
CF system, completely avoiding problems with reactor failure due to palladium precipitation.
References
[1]
[2]
[3]
[4]
P. Öhrngren, A. Fardost, F. Russo, J.-S. Schanche, M. Fagrell, M. Larhed, Org. Process Res. Dev. 2012, 16, 1053–
1063.
A. Fardost, F. Russo, M. Larhed, Chim Oggi 2012, 30, 14–16.
J. Rydfjord, F. Svensson, M. Fagrell, J. Sävmarker, M. Thulin, M. Larhed, Beilstein J. Org. Chem. 2013, 9, 2079–
2087.
J. Rydfjord, F. Svensson, A. Trejos, P. J. R. Sjöberg, C. Sköld, J. Sävmarker, L. R. Odell, M. Larhed, Chem. Eur. J.
2013, 19, 13803–13810.
Glycerol derivatives in the hydrogen autotransfer reaction
Anna Said Stålsmeden,a Kim van Weerdenburg,a Per-Ola Norrbyb and Nina Kanna,*
a
Department of Chemical and Biological Engineering, Organic Chemistry. Chalmers University of Technology,
SE-41296 Gothenburg, Sweden
b
Department of Chemistry and Molecular Biology, University of Gothenburg. SE-41296 Gothenburg, Sweden
Hydrogen autotransfer is a catalytic method that allows for the direct substitution of alcohols
with a variety of nucleophiles to form new carbon-carbon and carbon-heteroatom bonds.1
Glycerol (1,2,3-propanetriol) is obtained as a byproduct in the biodiesel industry.2 The
growing interest for such fuel has resulted in an increasing surplus of glycerol. Thus, glycerol
is an interesting candidate in the quest for more sustainable starting materials for organic
synthesis. As glycerol is dense in alcohol functionalities, we have aimed at developing
hydrogen autotransfer procedures employing amine and enolate nucleophiles using different
glycerol derivatives as electrophiles.
1,3-Propanediol, obtained from glycerol via hydrogenolysis,3 can be used as an alkylation
agent in iridium-mediated hydrogen autotransfer reactions. We have explored these reactions
using enolate nucleophiles such as aceteophenone and we here disclose our results, giving
over-reduced products (Scheme 1).
Scheme 1. Reaction of 1,3-propanediol with acetophenone using hydrogen autotransfer methodology.
Moreover, high selectivity in the substitution on the three glycerol carbons is greatly desirable
and protected glycerol derivatives are promising candidates in achieving such selectivity.
Herein, we discuss our outcomes from investigating the amination of these substrates using
hydrogen autotransfer methodology (Scheme 2).
Scheme 2. Selective amination of glycerol.
1. (a) Guillena, G.; Ramón, D. J.; Yus, M., Alcohols as Electrophiles in C-C Bond-Forming Reactions: The
Hydrogen Autotransfer Process. Angew. Chem. Int. Ed. 2007, 46, 2358-2364; (b) Nixon, T. D.; Whittlesey, M.
K.; Williams, J. M. J., Transition metal catalysed reactions of alcohols using borrowing hydrogen methodology.
Dalton Trans. 2009, 753-762.
2. Pagliaro, M.; Rossi, M., The Future of Glycerol. 2 ed.; Royal Society of Chemistry: Cambridge, UK, 2010.
3. (a) Behr, A.; Eilting, J.; Irawadi, K.; Leschinski, J.; Lindner, F., Improved utilisation of renewable resources:
New important derivatives of glycerol. Green Chem. 2008, 10, 13-30; (b) Zhou, C.-H.; Beltramini, J. N.; Fan,
Y.-X.; Lu, G. Q., Chemoselective catalytic conversion of glycerol as a biorenewable source to valuable
commodity chemicals. Chem. Soc. Rev. 2008, 37, 527-549.
Synthesis and evaluation of chroman-4-one-based SIRT2 inhibitors
Tina Seifert,a Marcus Malo,a Tarja Kokkola,b Karin Engen,a Maria Fridén-Saxin,a Elina Jarho,b
and Kristina Luthmana,*
a,*
Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-412 96
Göteborg, Sweden. bSchool of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Sirtuins (silent information regulator human type protein) are an enzyme family consisting of
seven human isoforms (SIRT1–SIRT7) which function as NAD+-dependent lysine deacetylases.1
Beside histones (H1, H3, H4) also tumor suppressors, transcription factors, and proteins involved
in insulin signaling, metabolism and aging have been shown to be deacetylated by SIRTs.2 As the
enzymes are implicated to be important in certain diseases such as cancer, neurodegeneration,
and diabetes,3 the development of SIRT modulating agents has become highly interesting.4
Our group has a long-term interest in the chemistry and biological activities of chromone and
chroman-4-one derivatives.5 We have recently shown that trisubstituted chroman-4-ones can
selectively inhibit SIRT2 with IC50 values in the low micromolar range (Figure 1).6 A set of
chroman-4-ones based on this lead compound has been synthesized to explore the structureactivity relationship and improve the physicochemical properties. Two potent inhibitors were
chosen for investigation of their anti-cancer effects and both showed antiproliferative effects in
lung and breast cancer cell lines.
Figure 1. The most potent SIRT2 inhibitor with an IC50 value of 1.5 M.
[1]
[2]
[3]
[4]
[5]
Imai, S.; Armstrong, C. M.; Kaeberlein, M.; Guarente, L. Nature 2000, 403, 795–800.
Sinclair, D.; Michan, S. Biochem. J. 2007, 404, 1–13.
Morris, B. J. Free Radical Biol. Med. 2013, 56, 133–171.
Sanchez-Fidalgo S.; Villegas I.; Sanchez-Hidalgo M.; de la Lastra C. A. Curr Med Chem. 2012, 19, 2414–2441.
Friden-Saxin, M.; Pemberton, N.; Andersson, K. D.; Dyrager, C.; Friberg, A.; Grötli, M.; Luthman, K. J. Org.
Chem. 2009, 74, 2755–2759.
[6] Fridén-Saxin, M.; Seifert, T.; Rydén Landergren, M.; Suuronen, T.; Lahtela-Kakkonen M.; Jarho, E. M.;
Luthman, K. J. Med. Chem. 2012, 55, 7104–7113.
Asymmetric transfer hydrogenation of propargylic ketones
by a pseudo-dipeptide based ruthenium catalyst
Helena Lundberg, Andrey Shatskiy, Fredrik Tinnis and Hans Adolfsson*
Department of Organic Chemistry, Stockholm University, SE-106 91, Stockholm, Sweden
Mail: [email protected]; Mail*: [email protected]
Homochiral propargylic alcohols are important multifunctional synthons which are used in
synthesis of various organic compounds including natural products. 1 The most widely used
synthetic rout for their synthesis is an asymmetric reduction of propargylic ketones, which is
usually done by the use of monotosylated 1,2-diamine–based ruthenium complexes. 2 These
complexes can operate under both hydrogenation and transfer hydrogenation conditions and
give generally good to excellent yields with an excellent enantioselectivities for a wide variety
of substrates.
During the previous decade our group was focused on the development of efficient and
enantioselective amino acid–derived catalysts for asymmetric transfer hydrogenation (ATH)
of ketones. Screening of a big number of pseudo-dipeptide ligands derived from Bocprotected amino acids and amino alcohols revealed a particularly promising ligand, derived
from L-alanine and (S)-1-amino-2-propanol.3 Complex of this ligand with ruthenium was used
for ATH of various aryl and heteroaryl alkyl ketones and gave generally good to excellent
yields and enantioselectivities.4 The current work aimed at broadening the substrate scope of
this catalytic system to propargylic ketones. A number of alkylethynyl and arylethynyl alkyl
ketones as well as TIPS-protected propargylic ketone were reduced to corresponding alcohols
under optimized conditions with generally good yield (70–98 %) and excellent
enantioselectivity (96 to >99 % ee).
O
Boc
O
R2
R1
NH
N
H
, 2.2 mol %
OH
[RuCl2(p-cymene)]2, 1 mol %
LiCl, 10 mol %
K Ot-Bu, 10 mol %
i -PrOH:toluene, rt, 10–30 min
R1 = Alk, Ar, 2-thiophene, SiR3 ; R2 = Alk
OH
R2
R
1
70–98 %
96 to >99 % ee
1) Drug Discovery and Development, Volume 2: Drug Development, Edited by Mukund S. Chorghade, 2007,
John Wiley & Sons, Inc.
2) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563;
Arai, N.; Satoh, H.; Utsumi, N.; Murata, K.; Tsutsumi, K.; Ohkuma, T. Org. Lett. 2013, 15, 3030–3033;
Fang, Z.; Wills, M. J. Org. Chem. 2013, 78, 8594–8605
3) Bøgevig, A.; Pastor, I. M.; Adolfsson., H. Chem. Eur. J. 2004, 10, 294–302
4) Wettergren, J.; Buitrago, E.; Ryberg, P.; Adolfsson, H. Chem. Eur. J. 2009, 15, 5709–5718; Buitrago, E.;
Lundberg, H.; Andersson, H.; Ryberg, P.; Adolfsson, H. ChemCatChem 2012, 4, 2082–2089
Utilizing photothermal organic dyes to selectively enhance
reaction catalysis
Gillian Karen Shawa, Graeme T. Spencea, Bradley D. Smitha* and Jan-E Bäckvallb*
a
b
* University of Notre Dame, Notre Dame IN 46656
* Stockholm University, Universitetsvägen 10, 114 18 Stockholm
The use of modified ruthenium catalysts in combination with enzymes for dynamic
kinetic resolution (DKR) has been studied heavily by the Bäckvall group. However,
current production is limited by temperature incompatibilities; Catalytic activity requires
increased temperatures but enzymes exhibit decomposition under these conditions. The
use of local nanoscale heating may solve this problem by utilizing photothermal
chromophores developed by the Smith group. Conjugation of a heat-generating nearinfrared chromophore to the metal catalyst should produce local nanoscale heating,
without bulk temperature increase. Synthesis, characterization, and initial catalytic
activity of these new photoactive metal catalysts are described.
Probing the β4GalT7 Active Site
Anna Siegbahna, Sophie Mannera, Emil Tykessonb and Ulf Ellervika*
a
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00 Lund, Sweden
b
Department of Experimental Medical Science, Lund University, BMC D12, SE-221 00 Lund, Sweden
E-mail: [email protected]
Mammalian cells produce proteoglycans (PG), which consist of a core protein with one or
several glycosaminoglycan (GAG) chains attached. PG is a class of widely distributed cellsurface macromolecules that are important for a diverse set of biological functions such as
blood coagulation, wound repair, angiogenesis and developmental processes. They are also
important in the pathobiology of all stages of cancer progression, such as cancer cell
proliferation, cancer stem cell differentiation, tumor invasion, and metastasis.
The biosynthesis of GAG chains is initiated by xylosylation of a serine residue in the core
protein. The xylosylated protein is then stepwise galactosylated by two galactosyl transferases
(β4GalT7 and β3GalT6) and glucuronated to form a linker tetrasaccharide, see figure 1, which
is later elongated to form a GAG chain. However, the biosynthesis can also be initiated by
exogenously added xylosides with hydrophobic aglycons. These compounds can act as
acceptors in the first galactosylation step (i.e. β4GalT7).
O
GAG
O
HO
OH
COOH
O
OH
OH
O
O
OH
GlcAT-I
HN
OH
O
O
HO
O
OH
OH
β4GalT7
β3GalT6
O
O
OH
O
NH
XylT-I
Figure 1. The tetrasaccharide linker and and enzymes involved in the biosynthesis.
In order to determine the structural requirements of β4GalT7, we have synthesized a number
of 2-naphthyl β-D-xylosides with modifications in the xylose moiety. The abilities of these
xylosides, including previously synthesized analogs1, to act as substrates (see figure 2) or
inhibitors of β4GalT7 have been investigated in a cell free assay. From these enzymatic
studies and molecular modeling using the crystal structure2, we conclude that the binding
pocket of β4GalT7 is very narrow, with a precise set of important hydrogen bonds.
UDP-Gal
HO
HO
O
ONap
OH
XylNap
β4GalT7
GalXylNap
Figure 2. Galactosylation of 2-naphthyl β-D-xyloside.
(1) Siegbahn, A.; Aili, U.; Ochocinska, A.; Olofsson, M.; Rönnols, J.; Mani, K.; Widmalm, G.; Ellervik, U.
Bioorg. Med. Chem. 2011, 19, 4114.
(2) Tsutsui, Y.; Ramakrishnan, B.; Qasba, P. K. J. Biol. Chem. 2013, 288, 31963.
Synthesis of sulfinic acids using DABSO as a bench-stable, gas-free
alternative to SO2
Bobo Skillinghaug, Jonas Rydfjord, and Luke Odell
Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala University, Sweden
Graphical abstract:
Aryl sulfinic acids have received relatively little attention in the literature but can be used
successfully as precursors in palladium catalysed reactions. The synthesis of sulfinic acids from
the corresponding sulfonyl chloride is generally convenient which affords the product as the more
stable sodium salt.1 However, some aryl sulfinic acids are easily oxidized and mixtures of the aryl
sulfinic acid and the corresponding aryl sulfonic acid are obtained. Another synthetic strategy is
to use SO2 gas and Grignard reagents for the production of sulfinic acids. The main problems
with this approach are that the handling of gaseous regents requires special equipment and that
SO2 is toxic. To avoid the use of toxic gas, solid sources may be used for in situ generation of the
desired reactant. This approach has been successful in carbonylation reactions where Mo(CO)6
and Wo(CO)6 have been used as solid sources of toxic CO gas. Recently the use of 1,4diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) for the synthesis of aryl sulfones
via an aryl sulfinic acid intermediate was reported.2 Through reactions of Grignard reagents and
DABSO sulfinic acids can be obtained in a two-step one pot protocol. Sulfinic acids are generally
prone to oxidize in air and isolation as the corresponding sodium salt is preferred. Following
purification by extraction, the salt can be prepared for storage.
Initially, conventional Grignard methods were compared to the “turbo Grignard” using
isopropylmagnesium chloride lithium chloride for the two-step one pot synthesis of benzene
sulfinic acid from bromobenzene and DABSO. The use of either method results in satisfying
yield. The influence of the halide was investigated by employing chloro- and iodo-benzene in the
two-step protocol. Not surprisingly a clear trend was observed where iodobenzene is much more
reactive than the other halides and gives very good yield. The use of bromobenzene results in fair
yield while chlorobenzene results in poor yield.
A new protocol for the synthesis of sulfinic acids has been developed and different aryl and alkyl
bromides and iodides have been employed, resulting in moderate to very good yields of the
desired products.
References
(1)
Curti, C.; Laget, M.; Carle, a O.; Gellis, a; Vanelle, P. Eur. J. Med. Chem. 2007, 42, 880–
4.
(2)
Richards-Taylor, C. S.; Blakemore, D. C.; Willis, M. C. Chem. Sci. 2014, 5, 222.
Aminocarbonylation of (Hetero)Aryl Iodides using Solid-Phase
Bound Amino Acid Nucleophiles and in situ Generated CO gas
†
Anna Skogh, ‡Troels Skrydstrup and †Anja Sandström.
†
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University, Sweden.
E-mail: [email protected]
‡
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry, Interdisciplinary Nanoscience
Center, Aarhus University, Denmark.
The three-component Pd-catalyzed coupling of a (hetero)aryl halide and an amine in the presence of CO is a well-established synthetic method for the installation of amides. This group
represents a common constituent of many pharmaceuticals, attached to a variety of heteroaromatic ring structures. We recently demonstrated the use of a Buchwald Pd-precatalyst for
promoting aminocarbonylations at low temperature.1 In our efforts to develop a versatile
method for introducing various end capping groups to a peptide chain for the synthesis of
pseudopeptides and peptidomimetic, we examined the possibility of combining such a methodology with Fmoc-Solid-Phase Peptide Synthesis (SPPS) chemistry.
The overall aim of the study is to implement the Pd-catalyzed aminocarbonylation of (hetero)aryl iodides to solid-phase chemistry, and in particular, solid phase peptide synthesis, by
applying an in situ generated CO from a solid silacarboxylic acid CO precursor.2 Herein, we
describe a low temperature aminocarbonylation of (hetero)aryl iodides using resin-bound
amino acids nucleophiles and it’s application for the introduction of end capping groups in
Fmoc-SPPS.
1. N. C. Bruno et al., J. Org. Chem. 2014, ASAP, DOI: 10.1021/jo500355k, S. D. Friis et al., Manuscript submitted.
2. S. D. Friis et al., J. Am. Chem. Soc. 2011, 133, 18114–18117.
Asymmetric transfer hydrogenation of allylic alcohols in a
tandem isomerization/reduction catalyzed by a pseudodipeptide ruthenium complex
Tove Slagbrand, Helena Lundberg and Hans Adolfsson*
Dept. of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 16091 Stockholm (Sweden)
*E-mail: [email protected]
Catalysis is the best alternative for formation of many chemical compounds since it
is manageable to obtain mild reaction conditions and high selectivity. Furthermore, it is possible
to avoid large amounts of waste and by-products, which makes the transformations
environmentally friendly.i Catalytic protocols are therefore a very good target for research,
especially if many reaction steps can occur subsequently (tandem reactions). These
transformations are challenging and the benefits are formation of complex products that usually
require many separate steps and lower amounts of formed waste.
We have recently developed an efficient protocol for the subsequent isomerization
and asymmetric reduction of allylic alcohols into saturated and asymmetric alcohols in one step
catalyzed by ruthenium. Both transformations; isomerization and transfer hydrogenation, are well
studied but little has been reported on the combination of these two steps in a tandem reaction.
Previously published protocols required high temperatures and long reaction times with little or
no enantioselectivity.ii,iii,iv,v One exception with good enantiomeric excess was published, but the
stereogenic center was located on another carbon than the alcohol carbon.vi In our work, the
transformation was investigated with the use of an active catalyst, which can perform both
transformations at milder reaction conditions and yields much higher enantioselectivity on the
alcohol carbon than previously reported. Currently, the optimization of the reaction conditions is
complete and further work will be focused on finishing the substrate scope and studying the
mechanism of the transformation. The methodology is still under development and a manuscript
is under preparation.
i
Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998,
p.30.
ii
Cadierno, V.; Francos, J.; Gimeno, J.; Nebra, N. Chem. Commun., 2007, 24, 2536-2538.
iii
Cadierno, V.; Crochet, P.; Francos, J.; García-Garrido, S. E.; Gimeno, J.; Nebra, N. Green Chem., 2009, 11,
1992-2000.
iv
Díaz-Álvarez, A.; Crochet, P.; Cadierno, V. Cat. Commun., 2011, 13, 91-96.
v
Maytum, H.C.; Francos, J.; Whatrup, D. J.; Williams, J. M. J. Chem. Asian J., 2010, 5, 538-542.
vi
Wu, R.; Beauchamps, M. G.; Laquidara, J. M.; Sowa Jr., J. R. Angew. Chem. Int. Ed., 2012, 51, 2106-2110. Ethenolysis on electron poor, biobased enoic acids
J. Spekreijse, J. Le Nôtre, E. L. Scott and J. P. M. Sanders.
Wageningen University, P.O. Box 17, 6700 AA, Wageningen, The Netherlands
[email protected]
The current fossil based industry brings issues involving depleting fossil resources, global
warming and geopolitical instability. The alternative to this outdated system is a biobased
economy, where biomass is refined to be used for food, chemicals, feed, fuels and energy.
Current systems involve rest streams that still contain potential carbon sources that can be
converted into chemicals. Many of these carbon sources allow access to small enoic acids
with electron poor double bonds. One enoic acid can be converted into two biobased bulk
chemicals in a single atom efficient ethenolysis step. Bioethanol can be used as a source of
ethylene to obtain a purely biobased product. The ethenolysis of several enoic acids has been
successfully performed in our lab resulting in the conversion of low reactive double bonds.
Conversion of 30% to 50% to the desired products is reached with careful selection of the
reaction conditions using Hoveyda-Grubbs 2nd generation catalyst.
Scheme 1 Synthesis of biobased polymers from rest streams using ethenolysis
1
J. P. M. Sanders, J. v. Haveren, E. Scott, D. S. v. Es, J. Le Nôtre and J. Spekreijse, WO Pat., 002 284, 2011.
2
J. Spekreijse, J. Le Nôtre, J. van Haveren, E. L. Scott, J. P. M. Sanders, Green Chem., 2012, 14, 2747.
Synthesis of Arylsulfonyl Azides via Diazotransfer Using an
Imidazole-1-Sulfonyl Azide Salt: Scope and 15N NMR Labelling
Experiments
Marc Y. Stevens, Rajiv T. Sawant and Luke R. Odell *
Organic Pharmaceutical Chemistry, BMC, Uppsala
*[email protected]
We hereby present imidazole-1-sulfonyl azide hydrogen sulfate as an efficient reagent for the
synthesis of arylsulfonyl azides from aryl sulfonamides. The described method is
experimentally simple and high-yielding and does not require the addition of copper salts.
Furthermore, 15N NMR labelling studies show the reaction proceeds via a diazotransfer
mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable over
existing diazotransfer reagents in terms of cost, safety and ease of handling.
Development of ECODAB into a relational database for
Escherichia coli O-antigens and other bacterial polysaccharides
Jonas Ståhle1, Miguel A. Rojas-Macias, Thomas Lütteke and Göran Widmalm1
1
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
E-mail: [email protected]
1
ECODAB is a web-based application to support the collection of O-antigen structures,
polymerase and flippase amino acids sequences, NMR chemical shift data of O-antigens as
well as information on glycosyltransferases (GTs) involved in the assembly of O-antigen
repeating units.
The latest iteration of the database includes a migration to a relational database2 and the
increased flexibility and performance when handling the data has allowed the processes of
retrieving, predicting and presenting information to be completely automated. As such, the
system has evolved from being just a repository to generate data on its own. GT specificity is
suggested through sequence comparison to GTs whose function is known. In order to further
increase the accuracy of the predictions of GT functions, the scope of the database has been
extended so that polysaccharide structure and related information from other bacteria
subsequently could be added, e.g. from S. pneumoniae.
ECODAB is freely available at http://www.casper.organ.su.se/ECODAB/. Currently, data on
171 E. coli unique O-antigen forms, 119 structures with NMR data and 338
glycosyltransferases is covered.
(1)
Lundborg, M.; Modhukur, V.; Widmalm, G. Glycobiology 2010, 20, 366–368.
(2)
Rojas-Macias MA.; Lütteke T.; Widmalm G. International Carbohydrate Symposium 26 2012, P236
Ionic liquids as precatalysts in the highly stereoselective conjugate addition
of α,β-unsaturated aldehydes to chalcones.
Linda Ta, Anton Axelsson, Joachim Bijl and Henrik Sundén*
Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96
Email: [email protected]
During the last decade Ionic Liquids (ILs) have gained widespread attention in both academia
and the industry owing to their non-volatility and adjustable properties. ILs are composed of
cations and anions which are liquid at room temperature. Imidazolium based ILs are
particulary interesting as they upon deprotonation can form N-heterocyclic carbenes
(NHCs).1,2
The NHCs offers a powerful strategy in order to generate organic substrates by way of
umpolung. For example, α,β-aldehydes which are normally regarded as Michael acceptors
can, in combination with an NHC become Michael donors (homoenolates) reactive towards a
large number of electrophiles.3-5
Herein we report our studies of the catalytic properties of ILs which has led us to the
discovery of a highly diastereoselective and chemoselective addition of cinnamaldehydes to
substituted chalcones forming 1,6-diketoesters (Scheme 1). The active NHC is generated
through the deprotonation of base that activates the α,β-unsaturated aldehyde (1) creating a
homoenolate. The enolate makes a nucleophilic attack on the unsaturated ketone (2) which
forms the 1,6-diketoester (3) together with methanol.
Scheme 1. Synthesis of 1,6-diketoesters using ionic liquids.
By using the inherent catalytic properties of ILs several important benefits relating to green
chemistry can be gained; replacement of volatile solvents, easy separation of the products
from the reaction mixtures and recovery and reuse of both solvent and the catalyst.
Furthermore, the highly functionalized 1,6-diketoesters offer a range of synthetic utility as
they can be transformed into a wide variety of organic compounds.
(1) Henrique Teles, J.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer, E.; Harder, W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. Helv.
Chim. Acta 1996, 79, 61.
(2) Liu, D.; Zhang, Y.; Chen, E. Y. X. Green. Chem. 2012, 14, 2738.
(3) Glorius, F. Top. Organomet. Chem. 2007, 21, 1.
(4) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182.
(5) Bode, J. W. Nat. Chem. 2013, 5, 813.
Design of chiral cofactor-controlled ligands for asymmetric
catalysis
Laure Théveau, Christina Moberg*
KTH Royal Institute of Technology
Department of Chemistry, Organic Chemistry, 100 44 Stockholm (Sweden)
[email protected]
Supramolecular catalysis is currently an attractive strategy for the development of regio
and/or stereoselectively controlled reactions.1 It is based on the specific non-covalent
assembly of several interacting components to find an efficient catalyst instead of the tedious
structural modification of small privileged ligands that is usually used in conventional
screening methods. Notably, host-guest binding involving week hydrogen interactions is one
of the fundamental concepts for this strategy.2 In this way, the 7,7’-diamido-2,2’diindolylmethane building block has been shown to be a very efficient and selective
carboxylate anion receptor3 which, after appropriate decoration with phosphines for transition
metal binding, was used by Reek’s group as an efficient catalytic pocket for the
enantioselective rhodium-catalyzed hydrogenations of alkenes by the use of amino acid
derivative guests as chiral anionic cofactors.4
Our group has been involved since several years in the study of conformationally flexible
ligands to design new catalysts able to adapt their conformation to different kinds of
substrates. Especially, published studies have focused on the palladium-catalyzed asymmetric
allylic alkylation reactions using phosphepine and diazepine ligands.5 As part of collaboration
with professor J. N. H. Reek, we present here the design of a new achiral diindolylmethanebased ligand possessing two flexible phosphite moieties for potential application in chiral
cofactor-controlled palladium-catalyzed asymmetric allylic alkylation reactions.6 Moreover,
interested in extending our research thematics, we also designed other achiral
diindolylmethane-based ligands possessing salen or pyridylamide moieties to study the chiral
cofactor-controlled enantioselective Lewis acid/Lewis base-catalyzed acylcyanation of
aldehyde and the molybdenum-catalyzed asymmetric allylic alkylation, respectively. 7,8
1
Meeuwissen, J.; Reek, J. N. H. Nature Chem. 2010, 2, 615.
Supramolecular Chemsitry, 2nd ed. (Eds.: J. W. Steed, J. L. Atwood), Wiley, New York, 2009.
3
Dydio, P.; Lichosyt, D.; Zieliński, T.; Jurczak, J. Chem. Eur. J. 2012, 18, 13686.
4
Dydio, P.; Rubay, C.; Gadzikwa, T.; Lutz, M.; Reek, J. N. H. J. Am. Chem. Soc. 2011, 133, 17176.
5
Zalubovski, R.; Bouet, A.; Fjellander, E.; Constant, S.; Linder, D.; Fischer, A.; Lacour, J.; Privalov, T.;
Moberg, C. J. Am. Chem. Soc. 2008, 130, 1845.
6
Initial work performed by Dr. R. Bellini, A. Laurell Nash, A. van der Werf and R. Afshin Sander.
7
Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc. 2005, 127, 11592.
8
Belda, O.; Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Hallberg, A.; Moberg, C. J. Org. Chem. 2000, 65, 5868.
2
Protein active site comparison tool for optimizing drug selectivity
Ivana Uzelac, Thomas Olsson, Johan Gottfries
Department of Chemistry and Molecular Biology, University of Gothenburg
Attaining selectivity of a drug towards one target is oftentimes a hard but nonetheless a
crucial task when working in drug design. The challenge with selectivity can depend on how
unique the target protein in itself is. If the target compared to other proteins has a
considerably large structural difference it may be easier to obtain selectivity rather than if
there are structurally related or even homologues proteins existing. We have constructed an
easily adaptable model for comparing and differentiating between closely related proteins. By
combining PCA and OPLS discriminant methods the data could be described in an easily
interpretable fashion. The present method can be applied to optimize lead structures, analyze
target interaction, or simply as a protein comparison tool.
Determination of stereochemistry of 6,10,14-trimethylpentadecan2-ol and the corresponding ketone in 17 Bicyclus species
Erika A. Wallin, Jimmy Andersson, Joakim Bång and Erik Hedenström
Eco-chemistry, Department of Chemical Engineering, Mid Sweden University, SE-85170 Sundsvall, Sweden
The African butterfly, genus Bicyclus, is spread throughout the African continent and
consists of more than 80 species which live in overlapping regions[1]. One of the components
of the male sexual pheromone for the model species Bicyclus anynana is 6,10,14trimethylpentadecan-2-ol and the active stereoisomer has been identified as (2R,6R,10R)6,10,14-trimethylpentadecan-2-ol[2], the corresponding ketone has also been found in several
species. By synthesising a mixture of 6,10,14-trimethylpentadecan-2-ol with known
stereoisomeric ratio, the mixture was derivatised and separation of all eight stereoisomers on
GC-MS was obtained (Figure 1.). The identification of the stereoisomer of the ketone was
possible by reducing the ketone and perform the same derivatisation as for the alcohol.
Figure 1. Chromatogram of 6,10,14-trimethylpentadecan-2-ol (known mixture) derivative.
1.
2.
Larsen, T.B., Butterflies of West Africa: text volume. 2005: Apollo Books.
Nieberding, C.M., et al., Cracking the olfactory code of a butterfly: the scent of
ageing. Ecology Letters, 2012. 15(5): p. 415-424.
Mild and selective hydrogenation of nitro compounds using
palladium nanoparticles supported on amino-functionalized
mesocellular foam
Oscar Verhoa*, Karl P. J. Gustafsona, Anuja Nagendirana, Cheuk-Wai Taib, Jan-E. Bäckvalla*
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden
b
Department of Materials and Environmental Chemistry, and Berzelii Center EXSELENT on Porous Material,
Stockholm University, Arrhenius Laboratory, S-106 91 Stockholm, Sweden
Aromatic and heterocyclic amines constitute important building blocks in industrial-scale
organic chemistry, as they are common intermediates for the synthesis of various dyes,
pharmaceuticals, pigments, and polymers.[1] These amines are primarily accessed by the use
of catalytic hydrogenation of the corresponding nitro compounds, employing classical
heterogeneous catalysts such as Pd/C, Pt/C and Raney Ni.[2] Although, these heterogeneous
catalysts generally exhibit good performance in this transformation, they are unfortunately
also associated with chemoselectivity issues when other reducible groups are present in the
substrate. Thus, significant attention has lately been dedicated to the design of new catalytic
hydrogenation systems that show higher selectivity towards the reduction of the nitro
functionality.
In our group, we have recently developed a heteregeneous catalyst comprised of Pd
nanoparticles immobilized on amino-functionalized siliceous mesocellular foam (Pd0-AmPMCF).[3] The Pd0-AmP-MCF was found to be a highly efficient and selective catalyst for the
hydrogenation of a wide range of aliphatic, aromatic and heterocyclic nitro compounds to the
corresponding amines under an ambient pressure of hydrogen gas at room temperature.
Moreover, the Pd nanocatalyst displayed excellent recyclability, low leaching and straightforward integration into a continious flow reactor, which makes it an attractive and economic
catalytic system for nitro compound reduction on a large scale.
[1] a) The Nitro Group in Organic Synthesis (Ed.: N. Ono), Wiley-VCH, New York, 2001; b) R. S. Downing,
P. J. Kunkeler, H. van Bekkum, Catal. Today 1997, 37, 121-136; c) Heterogeneous Catalysis and Fine
Chemicals, Vol. 4 (Eds.: H.-U. Blaser, E. Schmidt), Elsevier, Amsterdam, 1997.
[2] H. –U. Blaser, H. Steiner, M. Studer, ChemCatChem 2009, 1, 210-221.
[3] a) E. V. Johnston, O. Verho, M. D. Kärkäs, M. Shakeri, C. –W. Tai, P. Palmgren, K. Eriksson, S.
Oscarsson, J. –E. Bäckvall, Chem. Eur. J. 2012, 18, 12202-12206; b) M. Shakeri, C. –W. Tai, E. Göthelid,
S. Oscarsson, J. –E. Bäckvall, Chem. Eur. J. 2011, 17, 13269-13273.
3-O-Arylmethyl derivatives of p-methoxyphenyl β-Dgalactopyranoside as galectin inhibitors
Prashant Ranjan Vermaa, Hakon Lefflerb, Ulf J. Nilssona*
a
b
Center for Analysis and Synthesis, Lund University, PO Box 124, SE-221 00 Lund, Sweden
Section MIG, Department of Laboratory Medicine, Lund University, Sölvegatan 23, SE-223 62 Lund, Sweden.
Galectins are a family of carbohydrate binding proteins (i.e. lectins) known by their
affinity for β-galactoside.1,2 They play important roles in cell–cell communication, cell-matrix
adhesion, cell growth regulation, intracellular processes, inflammation, fibrosis and immunity
as well as cancer.
OH
OH
O
O
O
A
ryl
OH
O
Figure 1: Structure of the 3-O-arylmethyl galactoside
Figure 2: Computer model of the galectin-3:lacNAc complex
with an extended binding groove near HO3 indicated with
a blue arrow.
Natural small ligands of the galectins, such as N-acetyl lactosamine (LacNAc) and
lactose, show low inhibition potency3 and the development of new inhibitors with a higher
affinity for galectins has therefore emerged as a new field of research. The crystal structure of
a LacNAc: galectin-3 complex shows a possible extended binding groove close to HO-3(Gal)
and inhibitors exploiting this groove have been reported previously by us.4 This presentation
describes the exploration of the extended binding groove with 3-O-arylmethyl derivatives of
p-methoxyphenyl β-D-galactopyranoside towards novel high-affinity galectins inhibitors.
Several synthesized inhibitors (Fig. 1) display greatly enhanced affinity for galectins over the
parent p-methoxyphenyl β-D-galactopyranoside.
References:
[1] D. Houzelstein, I. R. Goncalves, A. J. Fadden, S. S. Sidhu, D. N. Cooper, K. Drickamer,
H. Leffler, F. Poirier, Mol. Biol Evol. 2004, 21, 1177.
[2] H. Leffler, S. Carlsson, M. Hedlund, Y. Qian, F. Poirier, Introduction to galectins,
Glycoconj. J. 2004, 19, 433–440.
[3] H. Leffler, S. H. Barondes, J.Biol.Chem. 1986, 22, 10119.
[4] (a) B. A. Salameh, I. Cumpstey, A. Sundin, H. Leffler, U. J. Nilsson, Bioorg. Med. Chem.
2010, 18, 5367-5378; (b) T. Delaine, I. Cumpstey, L. Ingrassia, M. Le Mercier, P.
Okechukwu, H. Leffler, R. Kiss, U. J. Nilsson, J. Med. Chem. 2008, 51, 8109–8114; (c) I.
Cumpstey, A. Sundin, H. Leffler, U. J. Nilsson, Angew. Chem. Int. Ed. 2005, 44, 5110 –5112;
(d) I. Cumpstey, E. Salomonsson, A. Sundin, H. Leffler, U. J. Nilsson, Chem. Eur. J. 2008,
14, 4233 – 4245; (e) P. Sörme, P. Arnoux, B. K. -Knutsson, H. Leffler, J. M. Rini, U. J.
Nilsson, J. Am. Chem. Soc. 2005, 127, 1737-1743.
Protein-driven Retro-Diels-Alder Reaction
Priya Verma* and Ulf J. Nilsson
Centre of Analysis and Synthesis, Lund University, P O Box 124, Lund, Sweden
Cycloaddition reactions constitute a general class of organic transformations that are
particularly amenable for execution in aqueous environment and even in biological systems.1
Diels-Alder reaction rates can be accelerated by acid-catalysis. Rate accelerations have also
been observed by molecules that provide an environment with optimal shape complementarity
to the Diels-Alder adduct and/or stabilizing the transition state (i.e. true catalysis).
The galectins are a family of soluble proteins defined by affinity for β-galactosides.
Galectin-1 is an important member of galectin family and has been attributed to many
functions as immunomodulatory effects and tumour formation. This makes galectin-1 as an
interesting target for cancer chemotherapy.2
We herein present the synthesis of thiodigalactoside-based high affinity (low nM) galectin
ligands that are Diels Alder adducts and evaluation of their retro-Diels-Alder reactivity in the
presence of galectin-1. The hypothesis is that a strongly galectin-bound Diels Alder adduct
will be sequestered from the media and its formation thus favored.
In designing novel thiodigalactosides based ligands containing Diels-Alder adducts that are
de-stabilized by galectin-1 binding, a dibenzobarrelene 9-carboxamide moiety is introduced.
Upon a possible retro-Diels-Alder reaction, the dibenzobarrelene 9-carboxamide moiety will
form a flat aromatic anthracene 9-carboxamide that will posses near to perfect surface
complementarity with a flat π-system constructed by galectin-1 arg-glu in-plane ion-pairing.
In this presentation we demonstrate that strong binding of the diene product (anthracene-9carboxamide) to galectin-1 will enhance retro-Diels-Alder reaction rates. Hence, productprotein shape complementarity significantly enhances product formation.
1. Rideout, D. C. et al. J. Am. Chem. Soc. 1980, 102, 7817-7818.
2. L. Astorgues-Xerri et al., Cancer Treatment Reviews 2014, 40, 307–319.
Synthetic tools for drug design in the treatment of cancer
Laura Woods, Kevin Vaughan*, and Richard Taylor
Department of Chemistry and Biochemistry, *Department of Biological Sciences,
University of Notre Dame, IN, USA
Synthesis is an important tool for the development of new drugs for human diseases. Taxol®,
Ixempra®, Istodax®, and Gleevec® are examples of natural products and small molecules
currently used in the treatment of various cancers. Synthetic design is important not only for
access to medicinally relevant compounds, but also for understanding the mechanisms in
which the disease state is compromised. This is where analogue design can be used to modify
existing drugs to enhance their bioactivity and reduce toxicity. Two projects will be presented
which utilize synthetic chemistry to develop biologically active compounds for cancer
therapy.
Apicularen A is a polyketide natural product first isolated from the myxobacteria
genus Chondromyces in 1998 by Jansen and co-workers. It has been shown to have highly
cytostatic activity with IC50 values in the range of 0.3 to 3.0 ng/mL in nine different human
cancer cell lines, including the multi-drug resistant line KB-V1. Access to apicularen A from
nature is limited by challenges associated with production and isolation of the native host. A
well-designed synthetic route allows access to significant amounts of the material for
biological testing, while also providing a platform for modification of the chemical entities.
Efforts towards an efficient total synthesis of apicularen A will be presented. This will
facilitate the determination of the solution conformation using NMR based methods.
Modification of the synthetic route will be utilized to access conformational analogues.
The microtubule stabilizing agents Taxol® and Ixempra® are used as chemotherapy
agents in breast, ovarian, and lung cancer. Despite the clinical success of these drugs, patients
often suffer from side effects including cellular resistance and neuropathy. To overcome these
side effects, we will present our synthetic efforts towards the design of a conjugate; an
epothilone B analogue bound by an alkyl linker to a modified aurora kinase B inhibitor. The
covalent combination of two biologically active components provides a localized, dual target
approach to drug design.
Asymmetric Synthesis of Oxazolidin-2-one Derivatives
through Lipase-Catalyzed Kinetic Resolution
Yan Zhang, Yang Zhang and Olof Ramström*
KTH Royal Institute of Technology, Department of Chemistry,
Teknikringen 30, S-10044 Stockholm, Sweden
[email protected]
2-oxazolidinone derivatives have shown some pharmacologically activities, such as
antibacterial effects against Gram-positive and Gram-negative pathogens. In the
present work, asymmetric synthesis of 2-oxazolidinone derivatives has been
established through a novel lipase-catalyzed kinetic resolution protocol.
The method proceeds through biocatalyzed, sequential acylation/cyclization in a
one-pot procedure involving the use of carbonates as acyl donors. The method proved
efficient for a range of substrates, generally resulting in good yields, and with
enantiopurities up to >99% ee.
OH
R
H
N
Lipase
R' R''OCOOR''
O
O
R ∗
N
R' Regio- and stereoselective palladium(II)-catalyzed oxidative Heck
reactions with vinyl ether boronic acid pinacol esters
Linda Åkerbladh, Mats Larhed
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574,
SE-751 23 Uppsala, Sweden.
Palladium(II)-catalyzed oxidative Heck coupling of vinylboron compounds with olefins
provide a new and convenient route to 1,3-dienes. In this study we aim to investigate the
reaction of (E)- and (Z)-ethoxyvinylboronic acid pinacol esters with various olefins. Our
preliminary results using the stable dmphen (2,9-dimethyl-1,10-phenanthroline) ligand
suggest that electron-poor olefins such as butyl acrylate and acrylonitrile give terminally
substituted dienes with retained stereochemistry of the vinyl ether coupling partner. In
contrast, the electron-rich olefin butyl vinyl ether gives exclusively internal coupling under
these cationic conditions. Subsequent hydrolysis-isomerization of the resulting vinyl ether
intermediate provides formyl substituted olefins. This type of compound may be further
manipulated e.g. in radical cycloadditions. In summary, our preliminary results indicate that
the oxidative Heck coupling of (E)- and (Z)-ethoxyvinylboronic acid pinacol esters has the
potential to selectively deliver a number of useful building blocks for organic, medicinal and
polymer chemistry.

宇野 文二 - 岐阜大学

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