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Antibiotics and Much More.

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Meeting Reviews
Antibiotics and Much More**
Karsten Krohn*
The
synthesis of biologically active
natural and synthetic compounds is
without doubt a topical field of activity.
A forum for the exchange of the most
recent results in this area was provided
by the 9th International Conference on
the Chemistry of Antibiotics and Other
Bioactive Compounds (ICCA-9), organized by St$phane Quideau (University
of Bordeaux), which took place in
Arcachon
(France)
during
September 25–29, 2005. A feature of this
series of conferences is the participation
of researchers from both academia and
industry: This year, industrial chemists
represented about a third of the 140
participants.
The focus of the conference was
bioactive compounds—not just antibiotics, which were discussed in only about
a third of the lectures. Nevertheless, the
increasingly observed resistance of bacteria to antibiotics has lent an urgency to
research into antibiotics. Who better to
introduce this topic than C. Walsh
(Harvard Medical School),[1] who
recently appeared as the editor of a
whole volume of Chemical Reviews[2] on
this theme? Indeed, the theme of the
development of resistance stood at the
center of his plenary lecture “Antibiotics: Past, Present, Future”. On the basis
of the most recent results on the mechanisms of action of antibiotics, Walsh
stated that the development of resistance is unavoidable and a further rapid
proliferation of multidrug resistance has
to be expected. Even today, about 30 %
of enterococci are resistant towards
vancomycin, leading to a mortality rate
of around 25 % in infected, immunedeficient patients. Added to this, the
large gap in the development of new
antibiotics that after almost 40 years was
interrupted with the oxazolidinones
(2000) and daptomycin (2003) appears
critical. The upshot of his lecture was the
requirement for increased research
efforts in this area to find new targets,
new molecules, and a greater level of
success in the discovery of antibiotics
that are active against resistant pathogens.
Closely associated with the synthesis
of natural products is the continued
development of synthetic methods. A
prime example of this was given at the
beginning by J. Mulzer (University of
Vienna, Austria), who presented the
most recent results on two difficult
problems: control of the E/Z geometry
of the double bond (e.g. in epothilones)
and stereocontrol of radical processes in
conjunction with isoprostane syntheses.
As an example, the metathesis reaction
in the Danishefsky epothilone synthesis
gives only a 1:1 ratio of the E/Z
isomers;[3] however, the selectivity is
improved by a new concept that involves
the fragmentation of b-hydroxy esters
(simultaneous elimination of CO2 and
HOR) starting from cyclic precursors
(Scheme 1).
The control of stereochemistry and
the development of new synthetic strategies was discussed in the plenary lecture by B. M. Trost (Stanford Univer-
sity). The “taming” of radical cyclizations for a stereoselective outcome was
introduced with the example of the
synthesis of siccanin. The efficiency
and the diversity of substrates controlled by palladium- or ruthenium-catalyzed allylations with the assistance of
C2-symmetric amidophosphines 1 a, 1 b,
and 2 was demonstrated impressively
with many examples of natural product
syntheses.
The synthesis of active antitumor
polyketides (mostly macrolides) remains a challenge in synthetic chemistry
owing to their low natural abundance.
These polyketides also include modulators of apoptosis such as ( )-rasfonin or
( )-apoptolidin (3), the synthetic
approaches of which were described by
R. K. Boeckman, Jr (University of
Rochester, USA). From the point of
view of methodology, oxazaborilidines
or aluminum-ate complexes have been
[*] Prof. Dr. K. Krohn
Department of Chemistry
University of Paderborn
Warburgerstrasse 100
33098 Paderborn (Germany)
Fax: (+ 49) 525-1603-245
E-mail: karsten.krohn@uni-paderborn.de
[**] 9th International Conference on the
Chemistry of Antibiotics and Other Bioactive Compounds, Arcachon, France, September 25–29, 2005.
536
Scheme 1. anti-Elimination of CO2H and MsOH to Z-dienes. Ms = methanesulfonyl; TBS = tertbutyldimethylsilyl.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 536 – 539
Angewandte
Chemie
demonstrates its
analogy to discodermolide
(5),
whose
synthesis
has
recently
become interesting
from an industrial
point of view.[8]
The
newly
assigned
stereochemistry of dictyostatin was confirmed completely
by synthesis and
moreover
also
agreed with the
results obtained in parallel by Curran
and co-workers.[9] The stereochemical
structure of spirastrellolid A was also
revised by Paterson and co-workers with
the aid of spectroscopic techniques and
synthesis.
The synthesis of natural products of
polyketide origin was described by M.
Miyashita
(Hokkaido
University,
Japan). During the course of the synthesis of zincophorin, new reagents were
developed that display remarkable
regio- and stereoselectivity on openchain systems. One example is illustrated by the opening of the unsaturated
epoxide 6, which is transformed into the
allyl alcohol 7 with high regio- and
stereoselectivity (Scheme 2). Miyashita
also described the synthesis of zoanthamine and norzoanthamine, both highly
complex biologically active compounds
with anti-osteoporotic and analgesic
activity, which was carried out in
41 steps with a remarkable overall
yield of 3.5 %.[10]
A general solution for the construction of conjugated Z-dienols, which
occur in many biologically active natural
products such as dictyostatin, discodermolide, or mycothiazole, was described
by J. Cossy (ESPCI, Paris, France). The
efficiency of the method was demonstrated with a series of total syntheses
including that of mycothiazole. After
deprotonation, the sultone 8, which was
prepared by metathesis, was converted
with ICH2MgCl into 9, which in turn
fragmented to the conjugated Z-dienol
10 by expulsion of SO2 (Scheme 3).
Somewhat smaller molecules also
represent a challenge, as discussed by
L. Chabaud (Y. LandaisN group; University of Bordeaux, France). The synthesis
of the hydroxylated pyrrolizidine alkaloid 3-epi-hyacinthacine A1 was achieved by carboazidation of chiral allylsilanes in only 13 steps in 8 % overall
yield.[11] The trend towards simplified
developed as enantioselective catalysts
for Mukaiyama-type reactions. Chiral
auxiliaries such as Oppolzer lactams or
chiral starting materials such as the
chiral bisepoxide of butadiene also
offer further opportunities for innovation in the bidirectional construction of
unsymmetric 1,2-diols.
G. A. Sulikowski (Vanderbilt University, USA) presented a new total
synthesis of the complex apoptolidinone, which was previously synthesized
by the groups of Nicolaou,[4] Koert,[5]
and Crimmins[6] . The synthesis comprised only 14 steps in the longest
linear sequence and covered many
aspects of modern stereoselective synthetic chemistry. Once again, the metathesis reaction played a key role and was
applied several times both intermolecularly and intramolecularly. The principles of ring-rearrangement metathesis
(RRM) and diastereoselective double
RRM was subsequently demonstrated
by S. Blechert (Technical University of
Berlin, Germany), with new examples of
the efficient synthesis of nitrogen-containing heterocycles.
The synthesis of antitumor macrolides from marine sponges has been
developed to perfection by I. Paterson
(Cambridge University, UK) and coworkers. The importance of synthesis for
Scheme 2. Opening of the unsaturated epoxide 6, which is transformed into the allyl alcohol 7.
both structural elucidation and to supply Bn = benzyl.
material for biological testing was highlighted with the example of dictyostatin,
which was isolated by Petitt et al. in
1994 (only 1.35 mg from over 400 kg
sponge).[7] In the nanomolecular range,
dictyostatin inhibits the proliferation of
taxol-resistant mammary, ovarian, and
colon cancer cells. At the same time, the
revised structure of dictyostatin (4) Scheme 3. Synthesis of the conjugated Z-dienol 10 from intermediate 9 with expulsion of SO2.
Angew. Chem. Int. Ed. 2006, 45, 536 – 539
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
537
Meeting Reviews
structures and the determination of the
structural features essential for biological activity were discussed by M. E.
Maier (University of TObingen, Germany) in his talk “Synthetic Strategies
Towards Benzolactone Collections”. The
most well-known example of these benzolactones of high biological activity is
perhaps the salicylihalamide family. He
showed that indeed such benzolactones
can be constructed with relative ease
from epichlorohydrin by a sequence of
standard reactions such as the Mitsunobu reaction, the ring-closing metathesis reactions, or transition-metal-catalyzed couplings. A similar concept in
the search for structural features essential for biological activity also resounded
in the lecture by M. Braun (University
of DOsseldorf, Germany), who described the systematic synthesis of arylindanyl ketones as new peptidyl-prolyl
cis/trans-isomerase inhibitors that catalyze the cis and trans isomerization of
peptidyl-prolyl bonds.
Besides polypropionates, aromatic
or quinoid polyketides are often characterized by interesting biological activity. Particularly interesting currently are
the angularly constructed ring systems
of the angucyclins, gilvocarcins, and
kinamycins, to which six lectures of the
symposium were devoted. A particular
highlight was the lecture by K. Suzuki
(Tokyo Institute of Technology, Japan),
who described the total syntheses of
benanomicin B (11),[12] TAN-1065, and
ravidomycin (12). The enantioselective
construction of the diol in benanomicin B was achieved by chirality transfer
of axial to central chirality. The key step
in the construction of C-glycosides, such
as in ravidomycin (12), was the rearrangement of O- to C-glycosides catalyzed by the hard Lewis acids of the
early transition metals such as
538
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[(Cp)2Hf]Cl(ClO4). This reaction is of
fundamental importance for the synthesis of many bioactive C-glycosides.
Kinamycin (13), derived biosynthetically from angucyclinen, is active at
50 nm concentrations against Gram-positive bacteria such as Staphylococcus
aureus. Detailed mechanistic investigations into the role and reactivity of the
diazo group, which is rarely found in
natural products, was discussed by K.
Feldmann (Pennsylvania State University, USA).
The
naphthopyran
antibiotics
nanaomycin, kalafungin, and medermycin, also fall within the group of aromatic polyketides, and their comprehensive syntheses were described by K.
Tatsuta (Waseda University, Japan).
Rhamnose was used as a chiral template
by Tatsuta in the synthesis of the chiral
part of the naphthopyran antibiotics.
That this “ex chiral pool” approach
remains topical in asymmetric synthesis
was illustrated by the discussions of M.
Chmielewski (Polish Academy of Science, Poland), J. Thiem (University of
Hamburg, Germany), and K. Krohn
(University of Paderborn, Germany).
This approach is useful not only in
preparing unusual structures such as
oxo analogues of the penicillins and
cephalosporins or seven- and eightmembered cyclitol mimetics, but it also
has potential in the preparation of
building blocks for the synthesis of
macrolides.
Another part of the conference was
devoted specifically to different aspects
of special antitumor activity. F. Roussi
(ICSN, Gif-sur-Yvette, France) demonstrated that a number of steroid-like
choline derivatives could imitate the
action of taxols with respect to the
organization of microtubuli. J. Dubois
(also ICSN, France) reported on the
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
synthesis of protein farnesyl transferase
inhibitors. Although ene-diynes have
found no entry into therapy owing to
their high toxicity, they remain of interest as substrates for the investigation of
the Bergman cyclization, as discussed by
A. Basak (Indian Institute of Technology, India). T. Sunazuka (Kitasato University, Japan) reported the first total
synthesis of madindolines, which have
attracted interest as selective interleukin 6 inhibitors.
A considerable problem in chemotherapy of tumors is systemic toxicity,
and the development of selective preparations is urgently needed. In his lecture “New Prodrugs of Cytotoxic Antibiotics for a Selective Treatment of
Cancer”, L. F. Tietze (University of
GPttingen, Germany) described a concept based on the selective transformation of a precursor (“prodrug”) into the
active cytotoxic compound by a conjugated enzyme that releases the cyctotoxic compound and a monoclonic antibody that binds to the tumor-associated
antigens.[13] The success of the concept is
associated with a series of conditions
such as, in particular, a large difference
between the toxicity of the “prodrug”
and the active principle (ratio of ED50
values greater than 1000). Through an
extensive program of synthesis, many
highly promising new products such as
15 that are derived from the natural
product duocarmycin were isolated.
Angew. Chem. Int. Ed. 2006, 45, 536 – 539
Angewandte
Chemie
The ICCA series of conferences has
established itself at the highest level as a
forum for the presentation of the most
recent syntheses in the area of active
natural and synthetic products (not just
antibiotics). The next symposium in the
USA (Nashville, TN) is already awaited
with anticipation.
[5]
[6]
[1] C. Walsh, Antibiotics: Actions, Origins,
Resistance, ASM, Washington, DC,
2003.
[2] C. Walsh, G. D. Wright (Guest Editors),
Chem. Rev. 2005, 105, 391 – 774.
[3] D. Meng, P. Bertinato, A. Balog, D.-S.
Su, T. Kamanecka, E. J. Sorensen, S. J.
Danishefsky, J. Am. Chem. Soc. 1997,
119, 10 073 – 10 092.
[4] K. C. Nicolaou, Y. Li, K. Sugita, H.
Monenschein, P. Guntupalli, H. J.
Angew. Chem. Int. Ed. 2006, 45, 536 – 539
[7]
[8]
Mitchell, K. C. Fylaktakidou, D. Vourloumis, P. Giannakakou, A. ONBrate, J.
Am. Chem. Soc. 2003, 125, 15 443—
15 454.
H. Wehlan, M. Dauber, M.-T. Mujica
Fernaud, J. Schuppan, R. Mahrwald, B.
Ziemer, M.-E. Juarez Garcia, U. Koert,
Angew. Chem. 2004, 116, 4698 – 4702;
Angew. Chem. Int. Ed. 2004, 43, 4597 –
4601.
M. T. Crimmins, H. S. Christie, K.
Chaudhary, A. Long, J. Am. Chem.
Soc. 2005, 127, 13 810 – 13 812.
G. R. Pettit, Z. A. Cichacz, F. Gao,
M. R. Boyd, J. M. Schmidt, J. Chem.
Soc. Chem. Commun. 1994, 1111 – 1112.
S. J. Mickel, G. H. Sedelmeier, D. Niederer, R. Daeffler, A. Osmani, K.
Schreiner, M. Seeger-Weibel, B. B$rod,
K. Schaer, R. Gamboni, Org. Process
[9]
[10]
[11]
[12]
[13]
Res. Dev. 2004, 8, 92 – 100, and four
subsequent reports in the same issue.
Y. Shin, J.-H. Fournier, Y. Fukui, A. M.
BrOckner, D. P. Curran, Angew. Chem.
2004, 116, 4734 – 4737; Angew. Chem.
Int. Ed. 2004, 43, 4634 – 4637.
M. Miyashita, M. Sakai, I. Hattori, M.
Sasaki, K. Tanino, Science 2004, 305,
495 – 499.
L. Chabaud, Y. Landais, P. Renaud, Org.
Lett. 2005, 7, 2587 – 2590.
K. Ohmori, M. Tamiya, M. Kitamura, H.
Kato, M. Oorui, K. Suzuki, Angew.
Chem. 2005, 117, 3939-3942; Angew.
Chem. Int. Ed. 2005, 44, 3871 – 3874.
Review: L. F. Tietze, T. Feuerstein, Curr.
Pharm. Des. 2003, 9, 2155 – 2175.
DOI: 10.1002/anie.200504256
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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