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Stereochemistry at Brgenstock Chemical Biology and Organic Synthesis in Focus.

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Meeting Reviews
Stereochemistry at Brgenstock:
Chemical Biology and Organic
Synthesis in Focus**
Christian P. R. Hackenberger, Hermann A. Wegner,
and Andreas Zumbuehl
“Have you heard who is
presenting?”
Upon arrival and registration, all the
participants of the 43rd conference on
Stereochemistry at Brgenstock probably did the same thing: taking an excited
look at the scientific program to see who
was going to present a talk at this
prestigious meeting. But this secret
line-up of plenary speakers is only one
of the traditional rules that add to the
myth and appreciation of this conference in the chemical community. Other
rules dictate that scientists can give only
one plenary presentation in their lifetime, that all of the circa 100 participants
are required to attend the whole meeting, and that the participants should be
from both academia and industry. Furthermore, the participants must include
established as well as young scientists,
the latter being supported by the junior
scientists program JSP. And finally,
there is a guest of honor present at the
meeting, who this year was Dieter
Seebach (ETH Zrich).
[*] Dr. C. P. R. Hackenberger
Freie Universit/t Berlin
Institut f2r Chemie und Biochemie
Takustr. 3, 14195 Berlin (Germany)
Fax: (+ 49) 308-385-2551
Dr. H. A. Wegner
Department of Organic Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+ 41) 61 267 09 76
Dr. A. Zumbuehl
Department of Organic Chemistry
University of Geneva
30, quai E. Ansermet, 1211 GenCve 4
(Switzerland)
Fax: (+ 41) 22 379 32 15
[**] 43rd EUCHEM Conference on Stereochemistry in B2rgenstock, April 12–18,
2008. The authors would like to thank the
Junior Scientists Participation Program for
the generous financial support.
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The conference committee, in
which Fran2ois Diederich (ETH
Zrich), E. Peter Kndig (University of Geneva) and Klaus
Mller (Hoffmann-La Roche)
acted for the last time after
many years of duties, was presided by Don Hilvert (ETH
Zrich), who attracted an exceptional line-up of prominent
speakers. The scientific program,
which was well-balanced in its
diversity, spanned all areas of
organic chemistry, including
topics from organic synthesis,
organometallic and organocatalysis, biological chemistry, and
polymer science.
Scheme 1. First copolymerization of vinyl acetate with
carbon monoxide by Nozaki et al. (top) and catalytic
double carbonylation of epoxides to succinic anhydrides by Coates et al. (bottom). Ar = o-MeOC6H4,
ClTPP = meso-tetra(4-chlorophenyl)porphyrinato.
Polymer Synthesis and Materials
Science
Kyoko Nozaki (Tokyo University)
added her last name to Brgenstock:s
speakers: list for a second time—but
without breaking the conference rules:
It was actually her father who gave a
lecture in 1979. She presented her
classical work on stereoselective olefinCO copolymerization employing PdII(R,S)-binaphos as a catalyst, which
propagates by a stepwise chain elongation, as elucidated by a combination of
theoretical calculations and experimental data. Using a different Pd/phosphine–sulfonic acid
ligand/catalyst
system, she demonstrated the first coordination polymerization of vinyl acetates (Scheme 1, top).[1]
In the same session, Geoffrey W. Coates
(Cornell University) presented his
research on stereoselective polymerization, highlighting a new trend of
environmentally
benign
polymers
based on the use of renewable feedstocks, such as CO2. In his system, both
zinc and cobalt catalysts were employed
to deliver poly(propylene)carbonates.
2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Another fascinating reaction, the insertion of CO into epoxides giving raise to
lactones and succinic anhydrides
(Scheme 1, bottom), was discovered
during his studies on poly(b-hydroxybutyrates).[2]
Bioorganic Chemistry and
Chemical Biology
A major focus of the conference was on
topics from the area of chemical biology.
Ben G. Davis (University of Oxford)
presented new orthogonal strategies to
attach various glycan architectures of
high complexity to proteins. The combination of two distinct conjugation techniques, the copper(I)-catalyzed click
reaction to form a triazole linkage and
the generation of a disulfide-linked
glycan, allowed the selective attachment
of two different glycan side chains,
thereby introducing another impressive
example for a “bioorthogonal” reaction.[3] In a very recent study, different
phosphorus(III) reagents were used to
convert the disulfide-linked glycoproteins into stable glycosyl thioether linkages.[4] Moreover, dehydroalanine-containing proteins were obtained by conversion of a surface-exposed Cys in a
Angew. Chem. Int. Ed. 2008, 47, 5496 – 5499
Angewandte
Chemie
protein by treatment with o-mesitylenesulfonylhydroxylamine (MSH). These
protein derivatives allowed a straightforward chemoselective incorporation
of various functional groups, including
phosphates, into the protein backbone
to mimic natural occurring posttranslationally modified proteins (Scheme 2).[5]
Orthogonality was also addressed in the
presentation by Kai Johnsson (EPF
Lausanne) who described a combination
of fusion proteins that allow the study of
protein–protein interactions. Specifically, such a fusion protein assay
employed an O6-alkylguanine DNA
alkyltransferase for the attachment of
various biophysical probes onto a protein tag, which has been introduced as
SNAP tag technology and has found
widespread application in biotechnology.[6] In an orthogonal strategy, a
CLIP tag was engineered which allowed
protein–protein interactions to be studied by the introduction of specific labels
to monitor the interplay between p53
and Mdm2.[7]
In a session on crystallography, Lorena S. Beese (Duke University Medical
Center) presented her cocrystallization
technique that provides snapshots of
DNA polymerase I in different states,
and provides information on nature:s
proofreading mechanisms by studying
the dynamics of the actual nucleotide
incorporation.[8] This approach was also
applied to the investigation of DNA
lesions, which can be caused by alkylation of DNA.[9] These studies illustrated
the resulting DNA topology (and carcinogenicity) and consequently the need
for a specific proofreading mechanism.
Another application of crystallization as
a tool in chemical biology was demonstrated in combination with a pH jump
experiment: this technique allowed a
kinetic analysis of the enzymes involved
in DNA repair mechanisms.
Mohamed A. Marahiel (Philipps University Marburg) followed with an
inspiring presentation covering the distinct features of nonribosomal peptide
synthesis, which allows the incorporation of a large number of modified
amino acid building blocks in peptides
of often complex architectures, including cyclic or crosslinked topologies and/
or postsynthetically modified elements.[10] The biosynthesis of this class
of natural products was illustrated by
characterizing
individual
domains
within the complete nonribosomal
assembly line, including the condensation domain which contains two active
sites, a donor and an acceptor site, to
allow the formation of an amide bond
between two amino acid building blocks.
Moreover, the concept of a “non-ribosomal” code was presented, which
allows a prediction of a certain amino
acid which is incorporated into the
peptidic product.
The next speakers showed that biological machines can be reprogrammed in
the hands of chemists. Homme W. Hellinga (Duke University) showed impressive examples of theoretical approaches
for the conceptual alteration of protein
function.[11] In his presentation he illustrated the re-engineering of binding
sites in proteins, as demonstrated for
the artificial zinc(II) binding sites into
the enzyme thioredoxin or into the F1ATPase, which resulted in an ATPdriven nanomotor.[12] Other examples
described biosensors that were incorporated into tobacco plants that, for example, change color upon detecting TNT.
Frances H. Arnold (California Institute
of Technology) was able to decouple a
cytochrome P450 heme monooxygenase
from its natural function. In its natural
form, this enzyme is involved in the
subterminal oxidation of unsaturated
fatty acids. Using molecular directed
evolution, a technique which was developed in her own laboratory and which
has become a standard technique in
biochemical and bioengineering science,[13] she was able to alter the protein:s function to the oxidation of propane to propanol using air as oxidant
(Scheme 3).[14] Improving the turnover
Scheme 3. Oxidation of propane to propanol
with a P450 mutant obtained by domainbased directed evolution.
numbers (TTN) for this catalytic process
is not the only constraint in this
research, as the overall stability of the
protein has to be taken into account as
well. Additionally, other chemical reactions, such as the selective deprotection
of permethylated sugars, were also achieved by this technique.
Appreciated by everyone was a very
special presentation, garnished with various scent samples, by Roman Kaiser
(Givaudan) about capturing the scents
of the vanishing flora that he has tracked
down for over 30 years in some of the
planet:s remotest places.[15]
Organic Synthesis and Catalysis
Scheme 2. Chemoselective strategies for protein functionalization in the synthesis of dehydroalanine-containing proteins (left) and S-linked glycoproteins (right). MSH = O-mesitylenesulfonylhydroxylamine.
Angew. Chem. Int. Ed. 2008, 47, 5496 – 5499
All the above-mentioned topics were
“framed” by lectures on organic synthesis: On the first day of talks, JKrLme
Lacour (University of Geneva) pre-
2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5497
Meeting Reviews
sented chiral anions and their impact on
catalysis. The chiral environment created by the TRISPHAT counterion
allowed the first enantioselective 1,2Stevens rearrangement. Additionally,
highly selective catalysts for the asymmetric Carroll rearrangement of allylic
b-ketoesters
were
designed
(Scheme 4).[16] The catalysts used were
easily separable by column chromatography on silica gel. The theme was then
complemented by Ben List (Max Planck
Institute Mlheim), who introduced the
concept of asymmetric counteriondirected catalysis (ACDC), which was
showcased by an asymmetric epoxidation reaction (Scheme 5).[17] In only a
few years, the List group has developed
asymmetric catalytic versions of a variety of classic systems, such as Aldol,
Mannich, and Michael reactions. In the
case of transannular Aldol condensations, they recently reported on an
organocatalytic asymmetric version,
featured in the shortest asymmetric synthesis of (+)-Hirsutene.[18]
The last day of the conference focused
again on organic synthesis, which was
represented by Goverdhan Mehta
(Indian Institute of Science, Bangalore).
He highlighted his contribution on the
synthesis of polyprenylated acylphloroglucins (PPAPs). Starting from simple
cyclohexadiones, he accessed a number
of members of the PPAPs in an elegant
and efficient way.[19] Another class of
neurotrophically active compounds are
the seco prezizaane sesquiterpenes, of
which the Mehta group prepared, for
example, Merrilactone A in 26 linear
steps.[20] They also developed a global
route to epoxyquinones which was used
to prepare 22 different natural products
in just 4 years.
Justin du Bois (Stanford University)
focused his presentation on the amination reaction of C H bonds he has
developed. Carbamates and sulfonamides are both suitable substrates for
this insertion reaction catalyzed by a
rhodium catalyst. The products obtained
are useful building blocks for a variety
of functionalities (e.g., diamines) as well
as starting materials for further reactions (e.g., cross-coupling reactions).
Furthermore, he presented a meticulous
Scheme 4. Air-, moisture-, and microwave-stable catalysts used in the Carroll rearrangement of
allyl-b-ketoesters.
Scheme 5. An ACDC salt catalyst for the epoxidation of (E)-cinnamaldehyde.
5498
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2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
study on the mechanism of this reaction.[21] From those results he was able to
greatly improve the catalyst, regarding
its stability, reactivity, and selectivity. He
could even present first results towards
an asymmetric version of the reaction.
Organometallic Reactions with
Biochemical Screening Techniques
In the last presentation, David R. Liu
(Harvard University) summarized his
work, and perhaps the tenor of the
whole meeting, by combining chemical
biology and organic synthesis in his talk
on DNA-templated chemistry.[22] In this
strategy, two reactive sites are brought
into close proximity by oligonucleotide
pairing of conjugated DNA strands,
thereby inducing a high effective molarity for reactions between the active sites.
One of the most fascinating applications
of this approach is the identification of
novel reactions between the active sites
in a combinatorial fashion, which was
even demonstrated for organometallic
reactions.[23] Another focus of this presentation was the analysis of naturally
occurring RNA conjugates to probe the
occurrence of the RNA-templated
(bio)synthesis of natural products.
It will be hard for the next president
(Ben L. Feringa, University of Groningen) and the next organizing committee
of the Brgenstock Conference 2009 to
match the quality of the preceding
symposium, but this challenge is just
another tradition that comes up year
after year…
[1] T. Kochi, A. Nakamura, H. Ida, K.
Nozaki, J. Am. Chem. Soc. 2007, 129,
7770 – 7771.
[2] J. M. Rowley, E. B. Lobkovsky, G. W.
Coates, J. Am. Chem. Soc. 2007, 129,
4948 – 4960.
[3] S. I. van Kasteren, H. B. Kramer, H. H.
Jensen, S. J. Campbell, J. Kirkpatrick,
N. J. Oldham, D. C. Anthony, B. G.
Davis, Nature 2007, 446, 1105 – 1109.
[4] G. J. L. Bernardes, E. L. Grayson, S.
Thompson, J. M. Chalker, J. C. Errey,
F. E. Oualid, T. D. W. Claridge, B. G.
Davis, Angew. Chem. 2008, 120, 2276 –
2279; Angew. Chem. Int. Ed. 2008, 47,
2244 – 2247.
[5] G. J. L. Bernardes, J. M. Chalker, J. C.
Errey, B. G. Davis, J. Am. Chem. Soc.
2008, 130, 5052 – 5053.
Angew. Chem. Int. Ed. 2008, 47, 5496 – 5499
Angewandte
Chemie
[6] A. Keppler, S. Gendreizig, T. Gronemeyer, H. Pick, H. Vogel, K. Johnsson,
Nat. Biotechnol. 2003, 21, 86 – 89.
[7] A. Gautier, A. Juillerat, C. Heinis, I.
Reis CorrÞa Jr. , M. Kindermann, F.
Beaufils, K. Johnsson, Chem. Biol. 2008,
15, 128 – 132.
[8] J. R. Kiefer, C. Mao, J. C. Braman, L. S.
Beese, Nature 1998, 391, 304 – 307.
[9] J. J. Warren, L. J. Forsberg, L. S. Beese,
Proc. Natl. Acad. Sci. USA 2006, 103,
19701 – 19706.
[10] a) S. A. Sieber, M. A. Marahiel, Chem.
Rev. 2005, 105, 715 – 738; b) F. Kopp,
M. A. Marahiel, Curr. Opin. Biotechnol.
2007, 18, 513 – 520.
[11] L. L. Looger, M. A: Dwyer, J. J. Smith,
H. W. Hellinga, Nature 2003, 423, 185 –
190.
[12] a) M. S. Wisz, C. Z. Garrett, H. W. Hellinga, Biochemistry 1998, 37, 8269 –
Angew. Chem. Int. Ed. 2008, 47, 5496 – 5499
[13]
[14]
[15]
[16]
[17]
[18]
8277; b) H. Liu, J. J. Schmidt, G. D.
Bachand, S. S. Rizk, L. L. Looger,
H. W. Hellinga, C. D. Montemagno,
Nat. Mater. 2002, 1, 173 – 177.
E. T. Farinas, T. Bulter, F. H. Arnold,
Curr. Opin. Biotechnol. 2001, 12, 545 –
551.
R. Fasan, M. M. Chen, N. C. Crook,
F. H. Arnold, Angew. Chem. 2007, 119,
8566 – 8570; Angew. Chem. Int. Ed.
2007, 46, 8414 – 8415.
R. Kaiser, Science 2006, 311, 806 – 807.
S. Constant, S. Tortoioli, J. Mueller, D.
Linder, F. Buron, J. Lacour, Angew.
Chem. 2007, 119, 9137 – 9140; Angew.
Chem. Int. Ed. 2007, 46, 8979 – 8982.
X. Wang, B. List, Angew. Chem. 2008,
120, 1135 – 1138; Angew. Chem. Int. Ed.
2008, 47, 1119 – 1122.
C. L. Chandler, B. List, J. Am. Chem.
Soc. 2008, 130, 6737 – 6739.
[19] For a recent example, see: G. Metha,
M. K. Bera, S Chatterjee, Tetrahedron
Lett. 2008, 49, 1121 – 1124.
[20] G. Metha, S. R. Singh, Tetrahedron Lett.
2005, 46, 2079 – 2082.
[21] K. W. Fiori, J. du Bois, J. Am. Chem. Soc.
2007, 129, 562 – 568.
[22] a) X. Li, D. R. Liu, Angew. Chem. 2004,
116, 4956 – 4979; Angew. Chem. Int. Ed.
2004, 43, 4848 – 4870; b) M. M. Rozenman, B. R. McNaughton, D. R. Liu,
Curr. Opin. Chem. Biol. 2007, 11, 259 –
268.
[23] N. Momiyama, M. W. Kanan, D. R. Liu,
J. Am. Chem. Soc. 2007, 129, 2230 –
2231.
DOI: 10.1002/anie.200802643
2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5499
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