aquetación 1 - La Fundación Lilly

Transcription

Index
5
Introduction
7
From Supramolecular Chemistry to Constitutional
Dynamic Chemistry
Jean-Marie Lehn. Nobel Laureate in Chemistry 1987
8
Catenanes, Rotaxanes and Molecular Machines
Jean-Pierre Sauvage
10
Fluorous Mixture Synthesis Approaches to Natural
Product Stereoisomer Libraries
Dennis Curran
12
The Awesome Power of Metathesis
Alois Fürstner
14
New Approaches for the Synthesis of Complex
Peptides
Fernando Albericio
17
Domino and Multiple Pd-Catalyzed Reactions for the
Efficient Synthesis of Natural Products and Materials
Lutz F. Tietze
19
DNA Charge Transport for DNA Damage and Repair
Jacqueline K. Barton
22
Streamlining Synthesis via C-H Oxidation
M. Christina White
23
Recent Studies in Alkaloid Total Synthesis
Larry E. Overman
24
The Catalytic Cycle of Discovery in Total Synthesis
Phil S. Baran
26
Palladium -and Nickel- Catalyzed Coupling
Reactions
Gregory C. Fu
27
New Developments of Organometallic Catalysts in
Organic Synthesis
Jean-Pierre Genet
31
New Applications of Quinones and Quinols in
Asymmetric Synthesis
M. Carmen Carreño
34
Stereoselective Transformations of Allylamines
Steve G. Davies
36
The Evolution of Lilly Oncology, from Targeted
Cytotoxic Agent (Alimta®) to Kinase Inhibitors
Joe Shih
39
Lilly Distinguished Career Award. Chemistry 2008
41
Speakers & Chairpersons
PROMOTER/SPONSOR
3
13th LILLY FOUNDATION
SCIENTIFIC SYMPOSIUM
13ª FUNDACIÓN LILLY
SIMPOSIO CIENTÍFICO
Chemistry:
Science at the
Frontier
Química,
Ciencia en la
frontera
Chemistry is, often called the central science,
because of its role in connecting “hard” sciences
such as physics with the “soft” sciences such as
biology or medicine, producing the more exciting
advances in the frontier with other scientific
areas. It is in that way chemistry is producing
seminal contributions to biomedicine, helping the
creation of new drugs.
A la química con frecuencia se la denomina “la
ciencia central”, debido a su papel como puente
entre ciencias "duras" como la física, y ciencias
"blandas" como la biología o la medicina,
favoreciendo los avances mas interesantes en la
fronteras con otras áreas científicas. De esta
manera la química está contribuyendo a abrir
nuevas perspectivas a la biomedicina, ayudando
a la creación de nuevos fármacos.
Inventing and developing a new drug is a long,
complex, costly and risky process that has few
peers in the industry world. Historically, as its
today, creation of a new drug rides much
–although not only- over the wave of new
synthetic technologies. The new synthetic
methods, by which scientists can create
increasingly complex molecules, are often in the
basis of the new, and more efficient molecular
entities recently developed. In addition, present
miniaturization and automation of testing
techniques is producing a parallel effort in
improvement of synthetic methodology.
The Thirteenth Lilly Foundation Scientific
Symposium “Chemistry: Science at the Frontier”
had tried to mix scientists with different views and
cultures in their approach to creation of new
molecules, from the use of parallel fluorous
techniques to obtain libraries of natural products,
to organometallic chemistry in all his present
possibilities, expanding the available synthetic
methods as never seen before; from new
approaches to the synthesis of alkaloids, to the
synthesis of complex peptides; from catalysis in
their last approaches, to enantioselective
synthesis; from purely medicinal chemistry
directed to precisely chosen targets, to chemical
biology related to DNA chemistry; from
supramolecular chemistry developments, to the
chemistry of catenanes, rotaxanes and molecular
machines.
In all these lectures an equilibrium was always
intended between two philosophies: one takes in
nature its inspiration, while the other uses new
tools and processes which science is putting in
our hands, and in our labs. This combination of
lectures would make and exciting offer about
modern chemistry.
In previous symposia, a mixture of well
established masters with young emerging
La invención y desarrollo de un nuevo fármaco
es un proceso largo, complejo, costoso y
arriesgado que tiene pocos ejemplos similares en
el mundo industrial. Históricamente, como en la
actualidad, la creación de un nuevo fármaco ha
cabalgado sobre todo –aunque no solamentesobre la onda de las nuevas metodologías de
síntesis. Los nuevos métodos de síntesis, a
través de los cuales los científicos pueden crear
moléculas cada vez más complejas, se
encuentran con frecuencia en la base de las
nuevas y cada vez más eficaces entidades
moleculares desarrolladas. De forma adicional, la
actual miniaturización y automatización de las
técnicas de ensayo biológico está produciendo
un avance paralelo en la mejora de la
metodología de síntesis.
El decimotercero Simposio Científico de la
Fundación Lilly “Química, Ciencia en la Frontera”
ha intentado reunir científicos con diferentes
puntos de vista y culturas en la creación de
nuevas moléculas. Desde el uso de técnicas
fluorosas en paralelo para obtener productos
naturales hasta la química organometálica, con
todas sus posibilidades actuales, que está
produciendo la expansión y disponibilidad de
nuevos métodos sintéticos como nunca se había
visto anteriormente; desde la catálisis en sus
últimas aproximaciones hasta la síntesis
enantioselectiva; desde la química médica
dirigida con precisión a dianas escogidas hasta
la biología química relacionada con la química
del ADN; desde los desarrollos de la química
supramolecular hasta la química de los
catenanos, rotaxanos y máquinas moleculares.
Hemos pretendido en todas las conferencias el
equilibrio entre dos filosofías: una, que toma de
la naturaleza su fuente de inspiración, y otra que
hace uso de nuevas herramientas que la ciencia
5
CHEMISTRY: SCIENCE AT THE FRONTIER
specialists has been sought by the committee, in the
expectation that this would create an inspiring and
unique atmosphere useful to all participants in the
Symposium.
Scientific Organizing Committee
va poniendo en nuestras manos y en nuestros
laboratorios. Esperamos que de esta combinación
de enfoques resulte una oferta atractiva para la
química moderna.
Como en simposios anteriores, el Comité Científico
ha pretendido una mezcla de maestros reconocidos
con jóvenes investigadores, esperando con ello
crear una atmósfera única e inspiradora, para todos
los participantes en el Simposio.
Comité Científico Organizador
6
13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
From
Supramolecular
Chemistry to
Constitutional
Dynamic
Chemistry
Supramolecular chemistry is actively exploring
systems undergoing self-organization, i.e. systems
capable of spontaneously generating well-defined
functional supramolecular architectures by selfassembly from their components, on the basis of the
molecular information stored in the covalent
framework of the components and read out at the
supramolecular level through specific interactional
algorithms, thus behaving as programmed chemical
systems.
Supramolecular chemistry is intrinsically a dynamic
chemistry in view of the lability of the interactions
connecting the molecular components of a
supramolecular entity and the resulting ability of
supramolecular species to exchange their
constituents. The same holds for molecular
chemistry when the molecular entity contains
covalent bonds that may form and break reversibility,
so as to allow a continuous change in constitution by
reorganization and exchange of building blocks.
These features define a Constitutional Dynamic
Chemistry (CDC) on both the molecular and
supramolecular levels.
Jean-Marie Lehn
ISIS, Université Louis Pasteur, Strasbourg
and Collège de France, Paris, France
References
1] Lehn, J.-M., Supramolecular Chemistry: Concepts and
[1
5.
Perspectives, VCH Weinheim, 1995
[2
2] Lehn, J.-M., Dynamic combinatorial chemistry and
9, 5, 2455.
virtual combinatorial libraries, Chem. Eur. J., 1999
[3
3] Lehn, J.-M., Programmed chemical systems: Multiple
subprograms and multiple processing/expression of
000, 6, 2097.
molecular information, Chem. Eur. J., 20
[ 4] Lehn, J.-M., Toward complex matter: Supramolecular
chemistry and self-organization, Proc. Natl. Acad. Sci. USA,
2002, 99, 4763.
[5
5] Lehn, J.-M., Toward self-organization and complex
02, 295, 2400.
matter, Science, 200
[6
6] Lehn, J.-M., Dynamers : Dynamic molecular and
005, 30, 814.
supramolecular polymers, Prog. Polym. Sci., 20
[7
7] Lehn, J.-M., From supramolecular chemistry
towards constitutional dynamic chemistry and adaptive
chemistry, Chem. Soc. Rev., 2007, 36, 151.
CDC introduces a paradigm shift with respect to
constitutionally static chemistry. The latter relies on
design for the generation of a target entity, whereas
CDC takes advantage of dynamic diversity to allow
variation and selection. The implementation of
selection in chemistry introduces a fundamental
change in outlook. Whereas self-organization by
design strives to achieve full control over the output
molecular or supramolecular entity by explicit
programming, self-organization with selection
operates on dynamic constitutional diversity in
response to either internal or external factors to
achieve adaptation.
Applications of this approach in biological systems
as well as in materials science will be described.
The merging of the features: - information and
programmability, - dynamics and reversibility, constitution and structural diversity, points towards
the emergence of adaptive chemistry.
7
Catenanes,
Rotaxanes
and Molecular
Machines
Jean-Pierre Sauvage
Institut de Chimie, Laboratoire de Chimie
Organo-Minérale, Université Louis Pasteur
CNRS/UMR 7177, Strasbourg, France
The field of catenanes and rotaxanes [1] is
particularly active, mostly in relation to the novel
properties that these compounds may exhibit
(electron transfer, controlled motions, mechanical
properties, etc…). In addition, catenanes represent
attractive synthetic challenges in molecular
chemistry. The creation of such complex functional
molecules as well as related compounds of the
rotaxane family demonstrates that synthetic
chemistry is now powerful enough to tackle problems
whose complexity is sometimes reminiscent of
biology, although the elaboration of molecular
ensembles displaying properties as complex as
biological assemblies is still a long-term challenge.
The most efficient strategies for making such
compounds are based on template effects. The first
templated synthesis [2] relied on copper(I). The use
of Cu(I) as template allows to entangle two organic
fragments around the metal centre before
incorporating them in the desired catenane
backbone. Organic templates assembled via
formation of aromatic acceptor-donor complexes
or/and hydrogen bonds have also been very
successful. Nowadays, numerous template
strategies are available which have led to the
preparation of a myriad of catenanes and rotaxanes
incorporating various organic or inorganic fragments
and displaying a multitude of chemical or physical
functions.
A particularly promising area is that of synthetic
molecular machines and motors [3]. In recent years,
several spectacular examples of molecular machines
leading to real devices have been proposed, based
either on interlocking systems or on non interlocking
molecules [4]. In parallel, more and more
sophisticated molecular machines have been
reported, frequently based on multicomponent
rotaxanes. Particularly noteworthy are the musclelike compounds reported by two groups [5,6], a
molecular elevator [7], illustrating the complexity that
dynamic threaded systems can reach.
One of the prototypical systems is a bistable
catenane whose motions are triggered by an
electrochemical signal. The compound and its
various forms are represented in Figure 1 [4a].
Copper is particularly well adapted to the design of
molecular machines since its two oxidation states
have distinct stereo-electronic requirements:
whereas copper(I) is fully satisfied in a 4-coordinate
(tetrahedral) geometry, copper(II) requires more
ligands in its coordination sphere. A5-coordinate
situation is more adapted to the divalent state, as
illustrated on Figure 1, Cu(II) being coordinated to
both a 1,10-phenanthroline ligand and a 2,2’,2’’,6’’terpyridine.
Figure 1. The prototypical bistable copper-complexed
catenane. The compound undergoes a complete
metamorphosis by oxidising Cu(I) or reducing Cu(II). The
process is quantitative but slow.
In the course of the last 12 years, the response
times of the various molecular machines made in
Strasbourg have been considerably shortened. The
fastest system is a rotaxane, able to undergo a
“pirouetting” motion under the action of the same
redox signal as for the catenane (CuII/CuI) and
whose axis incorporates a non sterically hindering
chelate of the 2,2’-bipyridine type. Now, the motions
take place on the micro- to milli-second timescale [8].
In recent years, our group has also proposed
transition metal-based strategies for making twodimensional interlocking and threaded arrays [9].
Large cyclic assemblies containing several copper(I)
centres could be prepared which open the gate to
controlled dynamic two-dimensional systems and
membrane-like structures consisting of multiple
catenanes and rotaxanes. Two examples are
presented in Figure 2.
8
lead to applications in a short term prospective,
although spectacular results have been obtained in
the course of the last few years in relation to
information storage and processing at the molecular
level [11]. From a purely scientific viewpoint, the field
of molecular machines is particularly challenging and
motivating: the fabrication of dynamic molecular
systems, with precisely designed dynamic properties,
is still in its infancy and will certainly experience a
rapid development during the next decades.
References
Figure 2. 2-dimensional interlocking arrays built via
the copper(I)-template strategy. The "gathering and
threading effect "of Cu(I) leads to the quantitative
formation of the rotaxane tetramers (A) or (B) from the
corresponding organic fragments and stoichiometric
amounts of copper(I) [ref. [9a] and [9b] respectively].
The X-ray structure of a compound similar to (B) was
recently solved by the group of Kari Rissanen
(Finland). It is shown in Figure 3.
Figure 3. X-ray structure of the [2]rotaxane tetramer. The
black dots of the Scheme (right) represent the 4 copper(I)
atoms.
Finally, in the course of the last four years, we have
been much interested in endocyclic but non sterically
hindering chelates [10]. These compounds are based
on carefully designed 3,3'-biisoquinoline (biiq)
derivatives. Some of them have even been
incorporated into macrocyclic compounds. A
particularly efficient and fast moving molecular
"shuttle" based on such a chelate has been made
and investigated as well as three-component
molecular entanglements constructed by assembling
three such ligands around an octahedral metal
centre. These biisoquinoline-based compounds are
particularly promising in relation to fast-responding
controlled dynamic systems and novel topologies. An
X-ray structure of a biiq-incorporating ring is
presented in Figure 4 as well as that of an iron(II)
complex containing three such ligands and thus
leading to the formation of a three-component
entanglement.
[1] a) For early work, see: G. Schill, Catenanes, Rotaxanes
and Knots, Academic Press, New York and London, 1971;
b) C. O. Dietrich-Buchecker, J.-P. Sauvage, Chem. Rev.
1987, 87, 795-810; c) D. B. Amabilino, J. F. Stoddart, Chem.
Rev. 1995, 95, 2725-2828; d) J.-P. Sauvage, C. DietrichBuchecker, Molecular Catenanes, Rotaxanes and Knots,
Wiley-VCH, Weinheim, 1999.
[2] C.O. Dietrich-Buchecker, J.-P. Sauvage, J.-P. Kintzinger,
Tet. Letters, 1983, 24, 5095-5098. C.O. Dietrich-Buchecker,
J.-P. Sauvage, J.-M. Kern, J. Am. Chem. Soc., 1984, 106,
3043-3044.
[3] a) Acc. Chem. Res. 2001, 34, 409-522 (Special Issue on
Molecular Machines) and references therein; b) J.-P.
Sauvage, Ed., Structure and Bonding – Molecular Machines
and Motors, Springer, Berlin, Heidelberg, 2001; c) V. Balzani,
M. Venturi, A. Credi, Molecular Devices and Machines – A
Journey Through the Nanoworld, Wiley-VCH, Weinheim,
2003; d) E. R. Kay, D. A. Leigh, F. Zerbetto, Angew. Chem.
2007, 119, 72-196; Angew. Chem. Int. Ed. 2007, 46, 72-191.
[4] a) A. Livoreil, C.O. Dietrich-Buchecker, J.-P. Sauvage,
J. Am. Chem. Soc. 1994, 116, 9399-9400; b) N. Koumura,
R. W. J. Zijistra, R. A. van Delden, N. Harada, B. L. Feringa,
Nature 1999, 401, 152-155; c) C. P. Collier, G. Mattersteig,
E. W. Wong, Y. Luo, K. Beverly, J. Sampaio, F. M. Raymo,
J. F. Stoddart, J. R. Heath, Science 2000, 289, 1172-1175;
d) D. A. Leigh, J. K. Y. Wong, F. Dehez, F. Zerbetto, Nature
2003, 424, 174-179; e) B. Korybut-Daszkiewicz,
A. Wieçkowska, R. Bilewicz, S. Domagata, K. Wozniak,
Angew. Chem. 2004, 116, 1700-1704; Angew. Chem. Int.
Ed. 2004, 43, 1668-1672; f) L. Fabbrizzi, F. Foti, S. Patroni,
P. Pallavicini, A. Taglietti, Angew. Chem. 2004, 116, 51835186; Angew. Chem. Int. Ed. 2004, 43, 5073-5077.
[5] a) M. C. Jiménez, C. Dietrich-Buchecker, J.-P. Sauvage,
Angew. Chem. Int. Ed. 2000, 39, 3284-3287; b) M. C.
Jiménez-Molero, C. Dietrich-Buchecker, J.-P. Sauvage,
Chem. Eur. J. 2003, 8, 1456-1466.
[6] Y. Liu, A. H. Flood, P. A. Bonvallet, S. A. Vignon, B. H.
Northrop, J. O. Jeppesen, T. J. Huang, B. Brough, M. Baller,
S. N. Magonov, S. D. Solares, W. A. Goddard, C.-M. Ho, J.
F. Stoddart, J. Am. Chem. Soc. 2005, 127, 9745-9759.
[7] J. D. Badjic, V. Balzani, A. Credi, S. Serena, J. F.
Stoddart, Science 2004, 303, 1845-1849.
[8] U. Létinois-Halbes, D. Hanss, J. Beierle, J.-P. Collin, J.P. Sauvage, Org. Lett. 2005, 7, 5753.
[9] a) T. Kraus, M. Budesinsky, J. Cvacka, J.-P. Sauvage,
Angew. Chem. Int. Ed. 2006, 45, 258-261. b) J.-P. Collin, J.
Frey, V. Heitz, E. Sakellariou, J.-P. Sauvage, C. Tock, New
J. Chem. 2006, 30, 1386-1389.
[10] a) F. Durola, L. Russo, J.-P. Sauvage, K. Rissanen, O.
S. Wenger, Chem. Eur. J. 2007, 13, 8749-8753. b) F.
Durola, J.-P. Sauvage, Angew. Chem. Int. Ed. 2007, 46,
3537-340.
[11] J. E. Green, J. W Choi, A. B., Y. Bunimovich, E.
Johnston-Halperin, E. DeIonno, Y. Luo, B. A. Sheriff, K. Xu,
Y. S. Shin, H.-R. Tseng, J. F. Stoddart, J. R. Heath, Nature,
2007, 445, 415-417
Figure 4. Endo topic but sterically non hindering ligands are
used to construct fast moving molecular shuttles and threecomponent entanglements [9].
To conclude, It is still not sure whether the fields of
catenanes, rotaxanes and molecular machines will
9
Fluorous Mixture
Synthesis of
Natural Product
Stereoisomer
Libraries
Dennis P. Curran
Much current work in the field of fluorous chemistry
relies on the use of fluorous stationary phases for
separation. Following the introduction of fluorous
tagging in 1996, [1] we soon introduced the
technique of fluorous solid phase extraction (FSPE)
[2]. The FSPE separation (Figure 1) allows the use of
smaller (and therefore lighter) fluorous tags, and the
method is especially useful for small scale discovery
chemistry and library applications in drug discovery
and other areas [3]. A recent review of FSPE
features almost one hundred papers that have used
the technique [4]. Scores of light fluorous reagents,
reactants, catalysts, scavengers and protecting
groups are now commercially available from Aldrich,
Waco and Fluorous Technologies, Inc.[5]
Our studies on FSPE soon led us to fluorous HPLC
experiments, and this in turn led to the introduction
of “fluorous mixture synthesis”,[6] a technique that we
have since used in many new guises. The underlying
concepts behind fluorous mixture synthesis, Figure
2, are those of solution phase mixture synthesis with
separation and identification tagging. Briefly, a series
of substrates is tagged with a homologous series of
fluorous tags. The resulting tagged substrates are
mixed and then taken through a multistep synthesis
to provide a mixture of tagged products. During this
mixture synthesis phase, effort is saved proportional
to the number of compounds that are mixed. Finally,
the last mixture is demixed by fluorous HPLC to
provide the individual tagged products, which are
then detagged (deprotected) to provide the final
target compounds The concepts of solution phase
mixture synthesis are general, and Craig Wilcox
introduced a new class of oligoethylene (OEG)
tags[7].
Department of Chemistry,
University of Pittsburgh, Pittsburgh, PA, USA
Fii g urr e 2. Concepts of Fluorous Mixture Synthesis:
Substrates are tagged and mixed. Mixture synthesis then
precedes demixing and detagging.
Figure 1. Fluorous Solid Phase Extraction: Separates
tagged compounds (orange fraction) from untagged ones
(blue fraction) by a generic filtration-like process.
Soon after the introduction fluorous quasiracemic
synthesis [8], we introduced the concept of complete
stereoisomer libraries [9] (made by fluorous mixture
synthesis), a concept that has been featured in much
of our natural products work since then. We later
united fluorous and OEG tags in the technique of
double mixture synthesis [10]. These techniques
have gone well beyond “proof-of-principle”; the
derived products (see Figure 3) have been used to
solve structure problems and provide importance
biological information[11,12].
10
Figure 3. Natural Products Made by FMS or Double Mixture
Synthesis
All these applications are driven by the favorable
features of fluorous tagging in reactions,
identification and analysis, and separation. Most
recently, these features have begun to be recognized
by the chemical biology community, and a new wave
of fluorous chemistry appears to be on the horizon.
I warmly thank an excellent cadre of collaborators
and coworkers for their intellectual and experimental
contributions as well as for their support and
friendship. I thank the Institute of General Medical
Sciences of the National Institutes of Health for
sustained funding of our work in fluorous chemistry
over more than a decade.
References
1] Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.;
[1
Wipf, P.; Curran, D. P. Science 1997, 275, 823-826.
[2
2] Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997
7,
62, 6714-6715.
[3
3] Curran, D. P. Aldrichim. Acta 200
06, 39, 3-9.
4] Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837[4
11865.
[ 5] DPC owns an equity interest in this company.
[6
6] Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P.
Science 2001, 291, 1766-1769.
[7
7] Wilcox, C. S.; Turkyilmaz, S. Tetrahedron Lett. 2005, 46,
1827-1829.
[8
8] Zhang, Q. S.; Curran, D. P. Chem. Eur. J. 200
05, 11,
4866-4880.
[9
9] Dandapani, S.; Jeske, M.; Curran, D. P. Proc. Nat. Acad.
Sci. 2004, 101, 12008-12012.
[1
10] Wilcox, C. S.; Gudipati, V.; Lu, H. J.; Turkyilmaz, S.;
Curran, D. P. Angew. Chem. Int. Ed. 2005, 44, 6938-6940.
[1
11] Short review: Zhang, W., Arkivoc 2004, 101-109.
[1
12] (a) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org.
Chem. 2005, 70, 9447-9462. (b) Zhang, W.; Luo, Z.; Chen,
C. H. T.; Curran, D. P. J. Am. Chem. Soc. 2002, 124,
10443-10450. (c) Fukui, Y.; Brueckner, A. M.; Shin, Y.;
Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett. 2006,
8, 301-304. (d) Curran, D. P.; Zhang, Q. S.; Richard, C.; Lu,
H. J.; Gudipati, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006,
128, 9561-9573. (e) Curran, D. P.; Moura-Letts, G.;
6, 45, 2423-2426.
Pohlman, M. Angew. Chem. Int. Ed. 2006
(f) Yang, F.; Newsome, J. J.; Curran, D. P. J. Am. Chem.
6, 128
8, 14200-14205.
Soc. 2006
11
The Awesome
Power of
Metathesis
Alois Fürstner
Max-Planck-Institut für Kohlenforschung,
Mülheim an der Ruhr, Germany
Although olefin metathesis had already been
discovered during early studies on Ziegler
polymerization and had found industrial applications
shortly thereafter, it was not until the 1990th that this
transformation gained real significance for advanced
organic synthesis. The last decade, however, has
seen an explosive growth of interest in metathetic
conversions in general, making clear that this
reaction is one of the most fascinating and versatile
processes in the realm of homogeneous catalysis.
Scheme 1. Basic catalytic cycle of RCM.
Alkene metathesis refers to the redistribution of the
alkylidene moieties of a pair of olefins effected by
catalysts that are able to cleave and to form C-Cdouble bonds under the chosen reaction conditions.
This mutual alkylidene exchange occurs via a
sequence of formal [2+2] ycloadditions/cycloreversions
(Chauvin mechanism)[1] involving metal alkylidene
and metallacyclobutane species as the catalytically
competent intermediates. Among the many possible
uses of metathesis, the ring closing olefin metathesis
(RCM) of dienes to cycloalkenes depicted in Scheme
1 remains particularly popular.
It was the development of well defined metal
alkylidene complexes combining high catalytic
activity with an excellent tolerance towards polar
functional groups that has triggered this avalanche of
interest. The most prominent and versatile ones are
molybdenum alkylidenes developed by Schrock[2]
and five coordinate ruthenium carbene complexes
introduced by Grubbs (Scheme 1)[33]. These
commercially available complexes define the
standard in the field and have reached an immense
popularity as witnessed by a truly prolific number of
successful applications. They also serve as “lead
structures” for the development of even more
powerful “second generation” catalysts bearing Nheterocyclic carbenes as ancillary ligands. The latter
effect even the formation of
tetrasubstituted cycloalkenes and are
sufficiently reactive to activate electron
deficient? as well as certain electron
rich alkenes that were beyond reach of
the parent Grubbs catalyst.
RCM is essentially driven by entropy;
the ensuing equilibrium is constantly
shifted towards the cycloalkene by
loss of ethylene (or another volatile
olefin) formed as the by-product (cf.
Scheme 1). The inherent competition
between cyclization of a given diene
and its polymerization via acyclic diene
metathesis (ADMET) strongly depends
on the ring size formed as well as on
pre-existing conformational constraints
and can be influenced to some extent
by adjusting the dilution. While five to sevenmembered carbo- and heterocycles usually form
without incident, medium- and large rings are more
delicate and deserve careful consideration during
retrosynthetic planning. It is known that chelation of
the metal carbene intermediates by the polar
substitutents in the substrates plays a decisive role
for productive macrocyclization [ 4]; hence, proper
analysis of the donor strength of the heteroatoms,
their distance and relative orientation towards the
alkene groups allows for reliable planning even of
complex target molecules of virtually any ring size. A
few recent examples of bioactive compounds formed
by RCM-based total synthesis protocols by our group
are shown in Scheme 2 [ 5]] .
A major advantage of RCM over more conventional
approaches stems from the exceptional
chemoselectivity of the available metathesis
12
catalysts for the activation of olefins in the presence
of most other functional groups. This, in turn, allows
to avoid lengthy protecting group manipulations, thus
rendering many metathesis based approaches
unprecedentedly short and economic in the overall
number of steps. As a consequence modern
metathesis chemistry has a profound impact on the
logic of synthesis. Its enormous relevance is further
increased by the fact that the modern catalysts are
fully operative under aqueous conditions as well as
in unconventional media such as ionic liquids or
supercritical CO2.
Despite this highly attractive overall profile and the
maturity reached in recent years, several problems
remain yet to be solved. One of the major challenges
is the missing control over the geometry of the
emerging double bond during RCM-based formations
of macrocycles as well as in many cross metathesis
reactions. One way to tackle this problem takes
recourse to ring closing alkyne metathesis (RCAM)
followed by semi-reduction of the cycloalkynes thus
formed (Scheme 3) [6] . This approach has been
successfully implemented into various total
syntheses, including a fully selective and high
yielding route to the promising anti-cancer agent
epothilone A [7].
Sch
h eme
e 3. Ring Closing Alkyne Metathesis RCAM)/SemiReduction – Selected Examples of Natural Products
prepared by this Methodology
References
[1
1] Y. Chauvin, Angew. Chem. Int. Ed. 2006
6, 45, 3740
(Nobel lecture).
[2
2] R. R. Schrock, Angew. Chem. Int. Ed. 2006, 45, 3748
(Nobel lecture).
[ 3] R. H. Grubbs, Angew. Chem. Int. Ed. 2006, 45, 3760
(Nobel lecture).
[4
4] a) A. Fürstner, K. Langemann, J. Org. Chem. 19
996, 61,
3942; b) A. Fürstner, O. R. Thiel, C. W. Lehmann,
2, 21, 331.
Organometallics 2002
[5
5] A. Fürstner, Angew. Chem. Int. Ed. 2000
0, 39, 3013.
[6
6] A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. Engl.
19
998, 37, 1734.
[7
7] A. Fürstner, P. W. Davies, Chem. Commun. 20
005, 2307.
Scheme 2. Natural products prepared by our group via RCM.
13
Nuevas
Estrategias
para la Síntesis
de Péptidos
Complejos
Fernando Albericio
Institute for Research in Biomedicine,
Barcelona Science Park,
University of Barcelona, Spain
New Approaches for the
Synthesis of Complex
Peptides
Abstract
Recent years have witnessed a revival in the field of
peptides. Success in the field of peptide research is
partly attributable to the fact that it is now possible to
synthesize almost any peptide on both small and
large scales. In this communication, several topics
will be discussed. First of all, we will present a short
overview of the use of peptides in medicine. Next,
the most used synthetic strategies, which involve
solid-phase, a combination of solid-phase solution,
and chemical ligation, will be discussed for the
synthesis of complex peptides from marine origin.
Introducción
Durante los últimos años se ha visto un aumento
importante en el número de péptidos como APIs
(ingredientes farmacéuticos activos). Así, hasta el
inicio de los años 90 únicamente estaban en el
mercado los análogos de LH-RH (leuprolide,
goserelin, gonadorelin…), los análogos de
somatostatina y las diferentes calcitoninas. A finales
de los 90 e inicios de los 2000, el mercado
experimentó un crecimiento reducido, pero a partir
del año 2004 se ha experimentado un crecimiento
mucho más importante, con nuevas entidades
químicas (NCE) introducidas. Así, en el año 2004,
el volumen de negocio fue de 5.9 billones de US $
y en el 2006 de 7.94 billones de US $, lo que
representa un crecimiento anual de dos dígitos.
Aunque la oncología continúa siendo la principal
indicación terapéutica para los péptidos, los NCE
recientemente introducidos han ampliado sus
indicaciones terapéuticas. Así, tenemos péptidos
para inmunología (glatiramer), diabetes (exenatide
y pramlintide), afecciones cardiovasculares
(bivalirudin, eptifibatide), infecciones (enfuvirtide y
thymalfasin), reproducción (atosigan), sistema
nervioso central (ziconotide y taltirelin), y
enfermedades óseas (teriparatide). Asimismo en el
año 2006, había 136 péptidos en fases clínicas,
mientras que en el 2004, eran únicamente 70.
Cuáles son las razones para este renacimiento de
los péptidos como fármacos. En primer lugar, un
fracaso relativo de las llamadas “small molecules”
(pequeñas moléculas), luego una relativa facilidad
para desarrollar los programa de química médica
basados en péptidos (facilidad para alcanzar fases
clínicas, necesidad de menor número de
investigadores para alcanzar los hitos), todo ello
acompañado del enorme impulso que se ha dado a
las nuevas formulaciones de “drug delivery”
(administración de fármacos).
Otro hecho interesante es la evolución que ha
sufrido la propia estructura de los péptidos en el
mercado o en fase clínicas. En la últimas decadas,
eran péptidos basados en secuencias naturales, de
relativo bajo peso molecular. En estos momentos,
las moléculas son más sofisticadas, con secuencias
más largas, más estructurados, conteniendo
aminoácidos no naturales y partes no peptídicas
(ciclos, péptidos pegilados, con ácidos grasos, con
carbohidratos, con cadenas múltiples…).
Un factor importante en este “boom” de los péptidos
como fármacos lo podemos encontrar en el
desarrollo extraordinario que ha sufrido la fase sólida
como estrategia de síntesis. Así, los nuevos
soportes sólidos, grupos protectores y agentes de
acoplamiento permiten sintetizar a escala de
multiquilogramos casi cualquier estructura. En
nuestra presentación se discutió algunas de las
metodologías desarrolladas en nuestro laboratorio,
tales como la utilización de soportes sólidos de
polietilenglicol, reactivos de acoplamiento/protección
basados en la hexafluoroacetona (HFA), el
p-nitrobenciloxicarbonilo (pNZ) como grupo protector
ortogonal, y la síntesis de una molécula compleja
como es la oxatiocoralina.
Resinas de polietilenglicol
Recientemente y en colaboración con Côté [1],
hemos desarrollado una resina totalmente de PEG
(ChemMatrix). Las propiedades óptimas de PEG son
debidas a las distribuciones vecinal de enlaces
carbono-oxígeno en la cadena, las cuales provocan
que PEG adopte una estructura helicoidal con
interacciones gauche entre los enlaces polarizados.
PEG puede exhibir tres organizaciones helicoidales
distintas, la primera, enormemente hidrofóbica, la
segunda, de hidrofobicidad intermedia, y la tercera,
hidrofílica. La naturaleza amfifílica de PEG hace que
la resina solvate bien en disolventes polares y no
polares.
14
Es t r u c t u r a Qu ím i c a d e r es i n a Ch em Mat r i x .
Se ha utilizado la resina ChemMatrix para la síntesis de
péptidos complejos y también de pequeñas proteínas (> 60
aa) mediante una síntesis secuencial. Como ejemplo,
podemos citar la proteína asociada al virus del SIDA.
Química basada en la HFA
La química de la hexafluoroacetona (HFA), que es
un reactivo bidentado para la protección y la
activación de los ácidos carboxílicos a-funcionalizados
se ha desarrollado y adaptado a la fase sólida. Las
lactonas formadas a partir de a-hidroxiácidos
representan ésteres activos, que pueden sufrir un
ataque nucleófilo y rendir derivados de ácido
carboxílico. Se han utilizado los derivados de HFA
para la preparación de aminoácidos no-naturales,
que a su vez se han incorporado en péptidos con
actividad biológica [3] . Esta química se puede aplicar
a la síntesis de péptidos con arquitectura compleja,
como son lo péptidos siameses que comparten
algún enlace.
agentes antitumorales aislados de organismos
marinos el micromonospora sp. Posee varios
motivos communes con una familia de péptidos
antibióticos antitumorales, que incluye BE-22179,
Triostin A, y Echinomycin. Este grupo de peptidos
poseen: a) estructure bicíclica; b) una simetría C2;
c) una unidad cromófora de intercalación; d) una
unión ester o tioester en la parte terminal de la
cadena peptídica; e) un puente disulfuro o un
análogo en el medio de la cadena peptídica; f) la
presencia de varios N-metil amino ácidos; y g) un
aminoácido no natural de configuración D. Así, la
función amino N-terminal de la tiocoralina está
terminada con ácido 3-hidroxiquináldico, cuya unidad
actúa grupo cromóforo intercalador; las dos cadenas
peptídicas son puentes con uniones tioester y
disulfuro de resíduos Cys, siendo los dos que
proporcionan el puente disulfuro N-metilado y D
configuración asi como los dos resíduos Cys(Me).
Todas estas características permiten a esta familia
de péptidos capacidad de enlazarse con DNA por
bisintercalación, y además alterar el ciclo celular
vital. La tiocoralina inhibe la elongación de DNA por
DNA a polimerasa a concentraciones que inhiben la
progresión del ciclo celular y la clonogenicidad. Sin
embargo, una desventaja para el uso clínico de
tiocoralina es su baja solubilidad en todos los
medios utilizados para su administración. Una
alternativa consiste en la preparación de
compuestos que mantengan una topología similar,
presentando distinto patrón de solubilidad. Así, se ha
sintetizado el derivado oxa de tiocoralina, donde los
enlaces tioester se han sustituido por esteres (esto
desde el punto de vista de building blocks implica la
utilización de resíduos de Ser en lugar de Cys).
Aplicaciones de los sistema de protección/activación de la
HFA
pNZ, Grupo Protector Ortogonal.
El grupo p-nitrobenciloxicarbonilo (pNZ) se ha
utilizado como grupo protector temporal para la
función a-amino en SPPS. El pNZ, que es ortogonal
con la mayor parte de grupos protectores utilizados
en química de péptidos, se elimina mediante
condiciones neutras en presencia de cantidades
catalíticas de ácido. La utilización del pNZ en
química Fmoc ha permitido obviar reacciones
secundarias típicas asociadas con la piperidina,
tales como la formación de dicetopiperacinas y
aspartiimidas. Asímismo, nos ha permitido
desarrollar nuevas estrategias de química ortogonal
y convergente, para la síntesis de péptidos que
están en fase clínica como la Kahalalide F. [4]
Mecanismo de eliminación del pNZ
Síntesis de la Oxatiocoralina
La tiocoralina es uno de los nuevos potentes
Estructura de la Oxatiocoralina
La síntesis se ha llevado a cabo en fase sólida
utilizando una resina tipo Wang, cinco diferentes
grupos protectores [Fmoc para la Gly; Fmoc también
para la introducción de la D-Ser, pero se intercambia
por el Boc; Trt para la cadena lateral de la Ser; Alloc
para la NMe-Cys(Me); y pNZ para la NMeCys(Acm)]; cuatro diferentes métodos de
acoplamiento (HATU/DIEA para la incorporación
sobre los aminoácidos N-metilados; DIPCDI/DMAP
para la esterificación; PyBOP/HOAt/DIEA para la
macrolactamización; EDC·HCl, HOSu para la
incorporación del cromóforo). La formación del
puente disulfuro, que se ha realizado en fase sólida,
confiere a la molécula una restricción
conformacional que permite evitar totalmente la
formación de dicetopiperacinas, que es la principal
reacción secundaria que tiene lugar con péptidos
N-metilados [55] . La oxatiocoralina presenta actividad
antitumoral en tres líneas celulares.
15
Conclusiones
El desarrollo de métodos sintéticos debe ser
clave en el proceso de descubrimiento de nuevos
fármacos. Muchos de ellos estarán inspirados en
la naturaleza, puesto que la dificultad sintética
que presentan muchos de los productos, podrá
ser vencida gracias a las nuevas estrategias
sintetizadas. En este sentido, se augura que cada
vez más péptidos entrarán en fases clínicas y al
mercado.
Referencias
[1] García-Martín, F.; Quintanar-Audelo, M.; GarcíaRamos, Y.; Cruz, L.J.; Gravel, C.; Furic, R.; Côté, S.;
Tulla-Puche, J.; Albericio, F. ChemMatrix®, a
Polyethylene glycol (PEG)-based Support for the SolidPhase Synthesis of Complex Peptides. J. Comb. Chem.,
8, 213-220 (2006).
[2] Frutos, S.; Tulla-Puche, J.; Albericio, F.; Giralt, E.
Chemical Synthesis of 19F-labeled HIV-1 Protease
Using Fmoc-Chemistry and ChemMatrix Resin. Int.
J. Peptide Res. Therapeutics, 13, 221-227 (2007).
[3] Spengler, J.; Böttcher, C.; Albericio, F.; Burger, K.
Hexafluoroacetone as Protecting and Activating
Reagent: New Routes to Amino, Hydroxy and Mercapto
Acids and their Application for Peptide, Glyco- and
Depsipeptide Modification. Chem Rev., 106, 4728-4746
(2006).
[ 4] Gracia, C.; Isidro-Llobet, A.; Cruz, L.J.; Acosta, O.;
Álvarez, M.; Cuevas, C.; Giralt, E.; Albericio, F.
Convergent Approaches for the Synthesis of the
Antitumoral Peptide, Kahalalide F. Investigation of
Orthogonal Protecting Groups. J. Org. Chem., 71, 71967204 (2006).
[5] Tulla-Puche, J.; Bayó-Puxan, N.; Moreno, J.A.;
Francesch, A.M.; Cuevas, C.; Álvarez, M.; Albericio, F.
Solid-Phase Synthesis of Oxathiocoraline by a Key
Intermolecular Disulfide Dimer. J. Am. Chem. Soc., 129,
5322-5323 (2007).
16
Domino and
Multiple
Pd-Catalyzed
Reactions for
the Efficient
synthesis of
Natural Products
and Materials
Lutz F. Tietze
The development of efficient syntheses of bioactive
compounds such as natural products and analogues,
drugs, diagnostics, agrochemicals in academia and
industry is a very important issue of modern
chemistry [1]. In this respect, complex multistep
syntheses have to be avoided since they are neither
economically nor ecologically justifiable. Modern
syntheses must deal carefully with our resources and
our time, must reduce the amount of waste formed,
should use catalytic transformations and finally must
avoid all toxic reagents and solvents. In addition,
synthetic methodology must be designed in a way
that it allows access to diversified substance libraries
in an automatized way.
It consists of a Knoevenagel condensation [ 3] of
generally an aldehyde with a 1,3-dicarbonyl
compound in the presence of catalytic amounts of a
weak base such as ethylene diammonium diacetate
(EDDA) or piperidinium acetate. In the reaction a 1oxa-1,3-butadiene is formed as intermediate which
can undergo a hetero-Diels-Alder reaction [ 4]] either
with an enol ether or an alkene.
A general way to improve synthetic efficiency and in
addition also to give access to a multitude of
diversified molecules is the development of domino
reactions which allow the formation of complex
compounds starting from simple substrates in a
single transformation consisting of several steps [1].
We have defined domino reactions as processes of
two or more bond forming reactions under identical
conditions, in which the subsequent transformations
take place at the functionalities obtained in the
former transformations. The quality and importance
of a domino reaction can be correlated to the
number of bonds generated in such a process and
the increase of complexity, for which we have
created the expression "bond forming efficiency".
Domino reactions can be performed as single-, twoand multicomponent transformations. Thus, most of
the known multicomponent processes [2] can be
defined as a subgroup of domino reactions.
Domino reactions can be classified according to the
mechanism of the single steps which may be of the
same or of different kind. As mechanistical
differentiation we have included cationic, anionic,
radical, pericyclic, transition metal-catalyzed and
redox transformations.
Institute of Organic and Biomolecular Chemistry,
University of Göttingen, Göttingen, Germany
The procedure has been used by us among others
for the synthesis of several alkaloids (Scheme 1).
Sch
h eme
e 1. Enantiopure alkaloids synthesized by a three or
four component domino-Knoevenagel-hetero-Diels-Alder
reaction
Another highly fruitful approach consisting of a Pdcatalyzed nucleophilic substitution of an allyl acetate
followed by a Pd-catalyzed arylation of an alkene
was used in the synthesis of (–)-cephalotaxine. The
starting material for this process was obtained via an
enantioselective CBS-reduction of the corresponding
2 bromocyclopentenone; moreover, the reaction
proceeds with high diastereoselectivity forming only
one diastereomer.
A combination of mechanistically different reactions
is the domino-Knoevenagel-hetero-Diels-Alder
reaction, which was developed in my group and
which has emerged as a powerful process which not
only allows the efficient synthesis of complex
compounds such as natural products starting from
simple substrates but also permits the preparation of
highly diversified molecules.
Sch
h eme
e 2. Synthesis of (–)-cephalotaxine
17
In a similar way steroids such as estradiol and the
contraceptiva desogestrel were synthesized in an
enantioselective way using a Pd-catalyzed vinylation
and arylation to allow a highly efficient construction
of the tetracyclic core of steroids [ 5].. An especially
effective procedure is the combination of an
enantioselective Wacker-oxidation and a vinylation
using a phenol containing an alkene moiety in the
presence of an alkene with electron withdrawing
groups such as acrylate or methyl vinyl ketone. In
this process first an intramolecular formation of an
ether takes place which is followed by an
intermolecular C-C-bond formation.
Scheme 3. Synthesis of a-tocopherol
This domino reaction has been used for the
enantioselective synthesis of a-tocopherol (Vitamin E)
[6] and several other compounds containing a
chroman moiety [7].
References
[1] (a) L.F. Tietze, G. Brasche, K. Gericke, Domino
Reactions in Organic Synthesis, Wiley VCH, Weinheim
2006; (b) L.F. Tietze, A. Modi, Medicinal Research Reviews
2000, 20, 4, 304–322; (c) L.F. Tietze, Chem. Rev. 1996
6, 96,
93,
115–136; (d) L.F. Tietze, U. Beifuss Angew. Chem. 199
93, 32,
105, 137–170; Angew. Chem. Int. Ed. Engl. 199
131–163.
[2] (a) J. Zhu, Eur. J. Org. Chem. 200
03, 1133–1144, cited
00, 112,
lit.; (b) A. Dömling, I. Ugi, Angew. Chem. 200
000, 39, 3168–3210;
3300–3344, Angew. Chem. Int. Ed. 20
(c) L.F. Tietze, A. Steinmetz, F. Balkenhohl, Bioorganic and
Medicinal Chemistry Letters , 1997, 7, 1303–1306.
[3] (a) L.F. Tietze, U. Beifuss, In Comprehensive Organic
91;
Synthesis; B.M. Trost, Ed.; Pergamon Press: Oxford, 199
Vol. 2, p 341.
[4] (a) L.F. Tietze, G. Kettschau, J.A. Gewert, A.
Schuffenhauer, Curr. Org. Chem. 1998, 2, 19–62; (b) L.F.
97,
Tietze, G. Kettschau, Topics in Current Chemistry 199
189, 1–120.
[5] L.F. Tietze, I. Krimmelbein, Chem. Eur. J. 20
008, 14,
1541–1551.
[6] L.F. Tietze F. Stecker, J. Zinngrebe, K.M. Sommer,
Chem. Eur. J. 2006, 12, 8770–8776.
[7] (a) L.F. Tietze, K.F. Wilckens, S. Yilmaz, F. Stecker, J.
Zinngrebe, Heterocycles 2006, 70, 309–319; (b) L.F. Tietze,
007,
J. Zinngrebe, D.A. Spiegl, F. Stecker, Heterocycles 20
74, 473–489.
18
DNA Charge
Transport
Chemistry and
Biology
Our laboratory has been interested in exploring both
the fundamentals of how electrons and holes migrate
through the base pair stack as well as the biological
implications of this chemistry with respect to how
DNA may be damaged and repaired. From our
laboratory and others it has by now been
demonstrated in a range of different experiments that
double helical DNA does indeed mediate the efficient
transport of charge, both electrons and holes, on
timescales as short as picoseconds. [ 1] Moreover,
recently our laboratory has focused studies on
determining how the cell may harnass this chemistry
to facilitate redox signaling among proteins bound to
DNA, to funnel damage to specific sites and activate
repair of damage to DNA. [2]
This analogy between DNA and solid state p-systems
is useful in considering DNA charge transport: the
interactions between the p-electrons of the DNA
base pairs provide the electronic coupling necessary
for DNA charge transport to occur. But it is important
to consider also the differences between DNA, a pstacked macromolecular assembly in solution, and
solid state p-stacks.
The ability of DNA to serve as a medium for the
transport of charge is intrinsic to its p-stacked
structure. The B-DNA double helix is an array of
heterocyclic aromatic base pairs, stacked at a
distance of 3.4 Å, wrapped within a negatively
charged sugar phosphate backbone. (Figure 1)
Figure 1. An illustration of the stacked base pairs in DNA
looking across the helix (above) and down the helix axis
(below).
It is no surprise that shortly after the double helical
structure was proposed by Watson and Crick,
scientists asked whether inherent in the structure of
stacked base pairs there might be another functional
property of DNA. Given the similarity to one
dimensional aromatic crystals, it was proposed that
the DNA p-stack might be a conduit for rapid and
efficient charge migration. [3]
Division of Chemistry and Chemical Engineering.
California Institute of Technology. Pasadena, CA, USA
In contrast to solid state p-stacks, DNA is
conformationally dynamic, a property that is key to
all of its biological functions. Conformational
rearrangements of the DNA bases on the ps to ms
time scale modulate base stacking interactions,
redox potentials, and electronic coupling between
the DNA bases. Thus the sequence-dependent
dynamical motions of DNA both facilitate and inhibit
long range charge transport through the base pair
stack. [ 4] Charge transport through the base pair
stack is gated by the motions of the DNA bases.
Using electrochemical, biochemical, and biophysical
measurements, we have now characterized some of
the important features of DNA charge transport
chemistry. [55] Importantly, we have found that charge
transport through DNA can occur over very large
molecular distances, > 200 Å. [66,7] In DNA
assemblies containing a pendant photooxidant, we
have shown that hole transport through the DNA
duplex can promote oxidative damage to guanine
doublets far from the site of the pendant oxidant.
(Figure 2) Moreover this chemistry is independent of
the oxidant utilized. It is a property of the DNA base
pair stack.
Figu
u re
e 2. As schematically illustrated, in a DNA assembly
with tethered photooxidant (red), oxidative damage to
guanine doublets (yellow) can be promoted over long
distances through DNA charge transport.
This property is interesting to consider in the context
of reactions within the cell. Indeed, we have also
shown that DNA hole transport can proceed in the
nucleosome core particle to effect damage to DNA
from a distance. [ 8] Hence while DNA may be
19
packaged into chromatin, protecting the DNA library
from the onslaught of harmful agents, this chromatin
structure cannot protect the DNA from long range
oxidative damage through DNA charge transport.
Perhaps instead Nature funnels damage to particular
sites, protecting others. [2]
It is interesting also to note that we have
demonstrated not only damage to DNA promoted
from a distance but also the oxidation of DNA-bound
proteins from a distance. [9] In particular, p53, a
critically important cell cycle regulatory protein,
bound to some promoters but not others can be
oxidized from a distance leading to its dissociation
from the DNA. We have proposed that this long
range chemistry may provide a global signaling of
oxidative stress within the cell, yielding the
dissociation of p53 from some promoters but not
others so as to activate the cell to respond to the
conditions of oxidative stress.
While DNA charge transport can proceed over long
molecular distances, another critical characteristic of
this chemistry is the exquisite sensitivity to
perturbations in the intervening base stack. Single
base pair mismatches, base lesions, and the
structural changes associated with protein binding all
lead to an inhibition of DNA charge transport. [55]
(Figure 3)
Figure 3. Illustrations of perturbations that inhibit long range
charge transport through DNA: (left) DNA bulges; (center)
DNA mismatches; (right) protein binding that kinks the DNA.
We have demonstrated this sensitivity in not only
through experiments monitoring an attenuation in
long range oxidative damage but also in DNA
electrochemistry experiments that monitor the
attenuation in redox signal as a function of
intervening perturbations in the base pair stack.
[10,11] (Figure 4) This sensitivity in DNA charge
transport to p-stacking perturbations has led to the
development of novel biosensors capable of the
detection of single base mismatches, lesions and
DNA-protein interactions.
Given this remarkable sensitivity of DNA charge
transport in detecting DNA lesions, we have also
asked whether Nature may harnass this chemistry
also in the first steps of DNA repair, where base
lesions are first detected. [12,14] Within cells there is
an extraordinary repair machinery, the
base excision repair enzymes, which constantly
monitor the genome for base damage, and once
Fi g u r e 4. DNA-mediated electrochemistry to a redox probe
(blue). This electrochemistry is, however, inhibited by an
intervening mismatch (red).
found, excise the damage, repairing the genome.
Interestingly, biquitous to a subset of these base
excision repair enzymes are 4Fe-4S clusters, a
common redox cofactor in biology. Although these
clusters are not redox-active in the absence of DNA,
we have demonstrated using DNA-modified
electrodes that, in the presence of DNA, their
potentials are shifted to a physiologically relevant
range. [ 12,,15] DNA binding thus facilitates oxidation
of the clusters in a DNAmediated reaction. We have
furthermore demonstrated that this potential shift is
general to a range of DNA repair proteins that
contain the 4Fe-4S clusters, and we have proposed
DNA-mediated signaling among different repair
proteins bound to DNA in detecting base lesions.
Essentially analogous to telephone repairmen
looking for a break in the telephone line, proteins can
carry out DNAmediated electron transfer reactions
with one another as long as the intervening DNA is
intact; these electron transfers facilitate protein
dissociation and a search of the genome. However, if
there is an intervening lesion, DNA-mediated charge
transport is inhibited, the proteins do not dissociate,
and instead remain in the vicinity to repair the lesion.
Hence this chemistry provides a means to
redistribute the repair proteins where they are
needed in the vicinity of the DNA lesion.
We are now focused on delineating how DNA charge
chemistry plays a role in the activity of base excision
repair proteins as well as asking whether other DNAbinding proteins that contain redox cofactors may
similarly employ DNA-mediated charge transport for
long range signaling. Certainly this chemistry is
unique in that the chemistry can occur with control
over long molecular distances but with a remarkable
sensitivity to intervening perturbations. There is
20
Figure 5. An illustration of DNA-mediated electron transfer
between two repair proteins (blue and gray).
much to be unraveled still with respect to this rich
DNA chemistry.
Acknowledgments
I am grateful to the NIH for their support of this
research as well as to my coworkers and
collaborators for their ideas and hard work.
References
[1] Topics in Current Chemistry, 236: 67-115, ed. Schuster
GB, Springer Verlag (2004).
[2] “Biological Contexts for DNA Charge Transport
Chemistry,” E. J. Merino, A. K. Boal, and J. K. Barton,
Current Opinion in Chemical Biology, 12, 229 (2008).
[ 3] “Semiconductivity of organic substances. IX. Nucleic
acid in the dry state,” D. D. Eley and D. I. Spivey, Trans.
Faraday Soc. 58, 411 (1962).
[4] “2-Aminopurine: A Probe of Structural Dynamics and
Charge Transfer in DNA and DNA:RNA Hybrids,”M. A.
O’Neill and J. K. Barton, Journal of the American Chemical
Society, 124, 13053 (2002).
[5] “Sequence-dependent DNA Dynamics: The Regulator of
DNA-mediated Charge Transport,” M. A. O’Neill and J. K.
Barton, in Charge Transfer in DNA: From Mechanism to
Application, ed. H.-A. Wagenknecht, Wiley-VCH, 27-75
(2005).
[6] "Oxidative DNA Damage through Long Range Electron
Transfer," D. B. Hall, R. E. Holmlin, and J. K. Barton,
Nature, 382, 731 (1996).
[7] “Long-Range Oxidative Damage to DNA: Effects of
Distance and Sequence,”M. E. Nunez, D. B. Hall and J. K.
Barton, Chemistry & Biology, 6, 85 (1999).
[8] “Evidence for DNA Charge Transport in the Nucleus,
”M. E. Nunez, G. P. Holmquist and J. K. Barton,
Biochemistry, 40, 12465 (2001).
[9] “A Role for DNA-mediated Charge Transport in
Regulating p53: Oxidation of the DNA-bound Protein from a
Distance,” K. E. Augustyn, E. J. Merino and J. K. Barton,
Proceedings of the National Academy of Science, USA,
104, 18907 (2007).
[10] “Electrochemical DNA Sensors,” T. G. Drummond, M.
G. Hill and J. K. Barton, Nature Biotechnology, 21, 1193
(2003).
[11] “An Electrical Probe of Protein-DNA Interactions on
DNA-Modified Surfaces,”E. M. Boon, J. W. Salas, and J. K.
Barton, Nature Biotechnology, 20, 282 (2002).
[12] “DNA-bound Redox Activity of DNA Repair
Glycosylases Containing [4Fe-4S] Clusters,” A. K. Boal, E.
Yavin, O. A. Lukianova, V. L. O’Shea, S. S. David, and J. K.
Barton, Biochemistry, 44, 8397 (2005).
[13] “DNA Repair Glycosylases with a [4Fe-4S] Cluster: A
Redox Cofactor for DNA-mediated Charge Transport?,”A. K.
Boal, E. Yavin and J. K. Barton, Journal of Inorganic
Biochemistry, 101, 1913 (2007).
[14] “Protein-DNA Charge Transport: Redox Activation of a
DNA Repair Protein by Guanine Radical,” E. Yavin, A. K.
Boal, E. D. A. Stemp, E. M. Boon, A. L. Livingston, V. L.
O’Shea, S. S. David, and J. K. Barton, Proceedings of the
National Academy of Sciences, USA, 102, 3546 (2005).
[15] “Direct Electrochemistry of Endonuclease III in the
Presence and Absence of DNA,” A. A. Gorodetsky, A. K.
Boal and J. K.
21
Streamlining
Synthesis via
C—H Oxidation
M. Christina White
Department of Chemistry, Roger Adams Laboratory,
University of Illinois, Urbana, IL, USA
Among the frontier challenges in chemistry in the
21st century are (1) increasing control of chemical
reactivity and (2) synthesizing complex molecules
with higher levels of efficiency. Although it has been
well demonstrated that given ample time and
resources, highly complex molecules can be
synthesized in the laboratory, too often current
methods do not allow chemists to match the
efficiency achieved in Nature. This is particularly
relevant for molecules with non-polypropionate-like
oxidation patterns (e.g. Taxol). Traditional organic
methods for installing oxidized functionality rely
heavily on acid-base reactions that require extensive
functional group manipulations (FGMs) including
wasteful protection-deprotection sequences. Due to
their ubiquity in complex molecules and inertness to
most organic transformation, C—H bonds have
typically been ignored in the context of methods
development for total synthesis. Highly selective
oxidation methods, similar to those found in Nature,
for the direct installation of oxygen, nitrogen and
carbon functionalities into allylic and aliphatic C—H
bonds of complex molecules and their intermediates
will be discussed. Unlike Nature which uses
elaborate enzyme active sites, we rely on the subtle
electronic and steric interactions between C—H
bonds and small molecule transition metal
complexes to achieve high selectivities. Our current
understanding of these interactions gained through
mechanistic studies will be discussed. Novel
strategies for streamlining the process of complex
molecule synthesis enabled by these methods will be
presented. Collectively, we aim to change the way
that complex molecules are constructed by
redefining the reactivity principles of C—H bonds in
complex molecule settings.
References
A lii p h at i c C—H Ox i da
at ion
n
[ 1] Chen, M.S.; White, M.C. “A Predictably Selective
Aliphatic C—H Oxidation Reaction for Complex Molecule
07, 318, 783-787.
Synthesis.” Science, 200
A lll y l i c C—H
H Ox i d at i on
n
[ 2] Delcamp, J.H.; White, M.C. “Sequential Hydrocarbon
Functionalization: Allylic C—H Oxidation/Vinylic C—H
Arylation.” J. Am. Chem. Soc. 2006, 128, 15076-15077.
[ 3] Fraunhoffer, K.J.; Prabagaran, N.; Sirios, L.E.; White,
M.C. “Macrolactonization via Hydrocarbon Oxidation.”
006, 128, 9032-9033.
J. Am. Chem. Soc. 20
[ 4] Chen, M.S.; Prabagaran, N.; Labenz, N.; White, M.C.
“Serial Ligand Catalysis: A Highly Selective Allylic C-H
Oxidation.” J. Am. Chem. Soc. 2005, 127, 6970-6971.
[ 5] Chen, M.S.; White, M.C. “A Sulfoxide-Promoted,
Catalytic Method for the Regioselective Synthesis of Allylic
Acetates from Monosubstituted Olefins via C-H Oxidation.”
004, 126, 1346-1347.
J. Am. Chem. Soc. 20
A lll y l i c C—H
H A mii n at i o n
[ 6] Reed, S.A.; White, M.C. “Catalytic Intermolecular Linear
Allylic C—H Amination via Heterobimetallic Catalysis.”
J. Am. Chem. Soc., 2008, 130, 3316-3318.
[ 7] Fraunhoffer, K.J.; White, M.C. “syn-1,2-Amino Alcohols
via Diastereoselective Allylic C—H Amination.” J. Am.
7, 129, 7274-7276.
Chem. Soc. 2007
Strr eam
m linii n g Sy n th
h es i s Stt ra
at eg
g i es
[ 8] Covell, D.J.; Vermeulen, N.A.; Labenz, N.A.; White, M.C.
“Polyol Synthesis via Hydrocarbon Oxidation: De Novo
Synthesis of L-Galactose.” Angew. Chem., Int. Ed. Engl.
2006, 45, 8217-8220.
[ 9] Fraunhoffer, K. J.; Bachovchin, D.A.; White, M.C.
“Hydrocarbon Oxidation vs. C-C Bond Forming Approaches
for Efficient Syntheses of Oxygenated Molecules.” Org. Lett.
2005, 7, 223-226.
22
Recent Studies
in Alkaloid Total
Synthesis
An important objective in chemical synthesis is the
development of new transformations that rapidly
evolve molecular complexity in a stereocontrolled
fashion. One approach toward this goal is to
combine two or more distinct reactions into a single
transformation, producing a process often referred to
as a sequential, tandem, cascade, or domino
reaction. In this lecture, I discuss the implementation
of several cascade processes as the key strategic
element in the total synthesis of heterocyclic natural
products. One illustrative example is described in
this brief summary.
A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9Hcarbazole is a central structural feature of the
Strychnos alkaloid minfiensine , and akuammiline
alkaloids such as vincorine and echitamine (Figure
1). Extracts containing akuammiline alkaloids are
used throughout the world in the practice of
traditional medicine [1].
Larry E. Overman
Department of Chemistry, 1102 Natural Sciences II,
University of California, Irvine, CA, USA
(iminoethano)-9H-carbazoles in high enantiomeric
purity (Figure 2).
Fii g urr e 2. Cascade asymmetric Heck /iminium ion
cyclizations for forming 1,2,3,4-tetrahydro-9a,4a(iminoethano)-9H-carbazoles.
The use of this cascade sequence to complete an
efficient catalytic asymmetric total synthesis of (+)minfiensine is dsummarized in Figure 3 [ 2] .
Figure 1. Representative alkaloids containing a 1,2,3,4tetrahydro-9a,4a-(iminoethano)-9H-carbazole.
Dihydro-9a,4a-(iminoethano)-9H-carbazoles having a
1,2- or 2,3-double bond could serve as versatile
platforms for constructing alkaloids of the types
illustrated in Figure 1. Stitching an ethylideneethano
unit between the pyrrolidine nitrogen and C3 of such
a precursor would generate the ring system of
minfiensine, whereas inserting such a unit between
the pyrrolidine nitrogen and C2 would generate the
ring system of vincorine and congeners. A cascade
catalytic-asymmetric Heck–iminium cyclization was
developed that rapidly provides 3,4-dihydro-9a,4a-
Figure 3. Catalytic asymmetric total synthesis of (+)minfiensine.
References
[1]] Ramirez, A.; Garcia-Rubio, S. Current. Med. Chem.
200
03, 10, 1891–1915.
[2]] Dounay, A. B.; Humphreys, P. G.; Overman, L. E.;
8, 130, 5368–5377
Wrobleski, A. D. J. Am. Chem. Soc. 2008
23
Phil S. Baran
Chemistry Department, The Scripps Research Institute,
La Jolla, California, USA
El Ciclo Catalítico
del Descubrimiento
en Síntesis Total
The Catalytic Cycle
of Discovery in Total
Synthesis
Abstract
Many would argue that the field of organic synthesis
has made such phenomenal advances over the past
five decades that given unlimited resources, the
synthesis of almost any molecule is now possible. As
such, total synthesis is becoming increasingly
focused on preparing natural products in the most
innovative and efficient manner possible. Selected
studies from our lab will be presented on the total
synthesis of complex natural products (see Figure
below for selected targets).
Desde la penicilina hasta el Taxol, los productos
naturales no tienen competencia en la mejora de la
salud mundial. De hecho, nueve de los veinte
fármacos más vendidos por la industria farmaceútica
están inspirados o derivan de productos naturales.
Incluso el fármaco más vendido de todos los
tiempos, Lipitor, está basado en un producto natural.
El arte y ciencia de recrear estas entidades en el
laboratorio, o síntesis total, invariablemente da lugar
a descubrimientos fundamentales tanto en el ámbito
de la química, como en el de la biología o la
medicina. Nuestro grupo de investigación tiene
como objetivo resolver interesantes retos en la
síntesis de productos naturales y en acortar las
distancias entre el punto de partida y el objetivo
mediante el descubrimiento de nuevas reacciones
químicas. De esta forma, estamos más interesados
en hacer contribuciones esenciales para la química.
La creación, descubrimiento y diseño de nuevos
métodos que van surgiendo en el camino hasta un
producto natural, es lo que promueve nuestro
entusiasmo. A partir de una cuidadosa selección de
las dianas y un análisis retrosintético creativo, el
esfuerzo de la síntesis total se convierte en una
máquina de descubrir que conduce al campo de la
química orgánica hacia un nuevo nivel de
sofisticación y pragmatismo.
En la Figura 1 se muestran recientes síntesis
totales, de las cuales todas ellas requieren de
nuevas estrategias químicas. En un ejemplo
representativo, la síntesis total de ‘welwitindolinone’
y otros alcaloides relacionados llevó a explorar la
formación oxidativa del enlace C-C mediante
heteroacoplamiento de enolatos. De esta forma se
obtienen importantes ventajas en cuestión de
eficiencia (ausencia de grupos protectores,
halógenos, grupos funcionales desechables),
pragmatismo (secuencias extremadamente
concisas), estereocontrol (completa
distereoselectividad a menudo observada) y
conservación del estado de oxidación (el estado de
oxidación aumenta de manera lineal en una síntesis
mediante el uso de funcionalidad innata) cuando la
formación oxidativa del enlace C-C se emplea
estratégicamente. Tal y como se muestra en la
Figura 2, la síntesis total de ‘welwitindolinone A’ hace
uso de la formación oxidativa del enace C-C en su
etapa clave. Esta síntesis ilustra de manera clara y
concisa las ventajas mencionadas anteriormente, ya
que en únicamente ocho pasos de síntesis, reactivos
sencillos, ausencia de grupos protectores y diez días
de trabajo con un solo estudiante de doctorado, son
suficientes para construir este complejo producto
natural marino de una forma enantioselectiva. A
pesar de que la eliminación de grupos protectores
en la síntesis de moléculas complejas ha sido
siempre un objetivo a largo plazo, esta síntesis
parece ser el primer ejemplo hasta la fecha en
alcanzar esta meta.
En esta presentación, se discutirán los ejemplos
más recientes de síntesis totales alcanzadas con
éxito, incluyendo moléculas tales como ‘cortistatin A’,
psycotrimine’, ‘axinellamines A y B’ y ‘vinigrol’.
Fi g u r a 1. Selección de síntesis totales completadas con
éxito (2004-2008).
24
Fi g u r a 2. Sencillo ejemplo de síntesis total enantioselectiva
de productos naturales complejos mediante formación
oxidativa del enlace C-C.
Referencias
[ 1] Chen, K.; Richter, J. M.; Baran, P. S. 1,3-Diol Synthesis
via Controlled, Radical Mediated C–H Functionalization,
J. Am. Chem. Soc., 2008, in press.
[ 2] Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.; Baran, P.
S. Synthesis of (+)-Cortistatin A, J. Am. Chem. Soc. 2008,
in press.
[3] O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple, I. B.;
Baran, P. S. Total Synthesis of (±)-Axinellamines A and B,
Angew. Chem. Int. Ed. 2008, 47, 3581 – 3583.
[4] Yamaguchi, J.; Seiple, I. B.; Young, I. S.; O’Malley, D. P.;
Maue, M.; Baran, P. S. Synthesis of 1,9-Dideoxy-preaxinellamine, Angew. Chem. Int. Ed. 2008, 47, 3578 – 3580.
[5] Maimone, T. J.; Voica, A.-F.; Baran, P. S. A Concise
Approach to Vinigrol, Angew. Chem. Int. Ed. 2008, 47, 3054
– 3056.
[6] Burns, N. Z; Baran, P. S. On the Origin of the Haouamine
Alkaloids, Angew. Chem. Int. Ed. 2008, 47, 205 – 208.
[7] Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.;
Castroviejo, P.; Baran, P. S. Scope and Mechanism of the
Direct Indole Coupling Adjacent to Carbonyl Compounds:
Total Synthesis of Acremoauxin A and Oxazinin 3, J. Am.
Chem. Soc. 2007, 129, 12857-12869.
[8] Grube, A.; Immel, S.; Baran, P. S.; Köck, M. Massadine
Chloride: a Biosynthetic Precursor of Massadine and
Stylissadine, Angew. Chem. Int. Ed. 2007, 46, 6721-6724.
[9] Köck, M.; Grube, A.; Seiple, I.; Baran, P. S. The Pursuit
of Palau’amine, Angew. Chem. Int. Ed. 2007, 46, 6586-6594
[10] Maimone, T. J.; Baran, P. S. Modern Synthetic
Approaches to Terpenes, Nature Chem. Bio. 2007, 3, 396 –
407.
[11] O’Malley, D.P.; Li, K.; Maue, M.; Zografos, A.L.; Baran,
P. S. Total Synthesis of Dimeric Pyrrole-Imidazole Alkaloids:
Sceptrin, Ageliferin, Nagelamide E, Oxysceptrin, Nakamuric
Acid, and the Axinellamine Carbon Skeleton, J. Am. Chem.
Soc. 2007, 129, 4762 – 4775.
[12] Baran, P. S.; Maimone, T. J.; Richter, J. M. Total
Synthesis of Marine Natural Products Without Using
Protecting Groups, Nature 2007, 446, 404-408.
[13] Baran, P. S.; Shenvi, R. A. Total Synthesis of
(±)–Chartelline C, J. Am. Chem. Soc. 2006, 128, 14028 –
14029.
[14] Baran, P. S.; DeMartino, M. P. Intermolecular Enolate
Heterocoupling, Angew. Chem. Int. Ed. 2006, 45, 7083–7086.
[15] Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.;
Guerrero, C. A.; Gallagher, J. Enantioselective Total
Synthesis of Avrainvillamide and the Stephacidins, J. Am.
Chem. Soc. 2006, 128, 8678-8693.
25
Palladium -and
Nickel- Catalyzed
Coupling
Reactions
Gregory C. Fu
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, MA, USA
Despite the tremendous accomplishments that have
been described in the development of palladium-and
nickel-catalyzed carbon–carbon bond-forming
processes, it is nevertheless true that many
significant opportunities remain. For example, to
date the overwhelming majority of studies have
focused on couplings between two sp2-hybridized
reaction sites (e.g., an aryl metal with an aryl halide;
Figure 1). Although biaryl and related linkages are
certainly a common feature in many organic
compounds, so, too, are Csp2–Csp3 and Csp3–Csp3
linkages.
Fi g u r e 2. Asymmetric Negishi reactions of allylic halides.
Fi g u r e 3. Asymmetric Hiyama reactions of _-halocarbonyl
compounds.
Figure 1. Some carbon–carbon bond-forming processes of
interest.
As of 2001, there were few examples of palladium-or
nickel-catalyzed coupling reactions of alkyl
electrophiles. Slow oxidative addition of alkyl
halides/sulfonates and facile ‚-hydride elimination are
two likely causes for this paucity of success. Indeed,
nearly all of the successful couplings that had been
described by 2001 involved specialized electrophiles
that circumvent these impediments by being
activated toward oxidative addition and by lacking ‚
hydrogens (e.g., benzyl halides).
Fi g u r e 4. Asymmetric Suzuki reactions of homobenzylic
halides.
During the past several years, we have pursued the
discovery of palladium-and nickel-based catalysts for
coupling activated and unactivated primary and
secondary alkyl electrophiles that bear ‚ hydrogens.
Our recent efforts to develop broadly applicable
methods, including enantioselective processes, will
be discussed.
26
New Developments
of Organometallic
Catalysts in
Organic Synthesis
Despite the tremendous accomplishments that have
been described in the development of palladium-and
nickel-catalyzed carbon–carbon bond-forming
processes, it is nevertheless true that many
significant opportunitieHomogeneous asymmetric
catalysis is undoubtedly a powerful synthetic tool of
the organic chemist, both on laboratory and
production scale. Effective homogeneous
asymmetric catalysts are organometallic complexes
that consist of one or more chiral ligand coordinated
to a metal center. The choice of the chiral ligand is
decisive both for catalytic activity and for achieving
high level of chiral induction.
Atropisomeric biaryl diphosphines
Noyori discovered the BINAP ligand in 1980, which
resulted in an extraordinary expansion of the scope
of asymmetric hydrogenation. [1] The elaboration of
new ligand families such as the MeO-BIPHEP
(Roche) or the SEGPHOS (Takasago) is significant
of the new current challenges of chemists in the field
of asymmetric catalysis (Figure 1). Licensing policies
compel companies to synthesize their own original
ligand families, displaying high activity and selectivity
and the broadest possible scope in terms of
substrates. Following our continuous interest in
ligand design [2] , we have reported the synthesis of
two original atropisomeric diphosphines SYNPHOS®
[3] , and DIFLUORPHOS® [4] , with stereo
electronically complementary backbones, based
respectively on bi(benzodioxane) and
bi(difluorobenzodioxole) moieties (Figure 1). We also
propose detailed structural profiling [5] of these
ligands and catalytic evaluation in asymmetric
Ru-mediated hydrogenation compared to other
leading atropisomeric diphosphines such as BINAP
and MeO-BIPHEP.
Figure 1. Rhodium-catalyzed reactions for carbon-carbon
bounds formation.
Asymmetric Pauson-Khand reaction
In recent years, a great deal of research has been
Jean Pierre Genet
Laboratoire de Synthèse Sélective Organique
et Produits Naturels - UMR 7573, CNRS
Ecole Nationale Supérieure de Chimie de Paris,
Paris, France
devoted to asymmetric catalytic Pauson-Khand
reaction (denoted as PKR reaction hereafter), which
is characterized as transition metal mediated [2+2+1]
cycloaddition of an alkyne, an alkene and CO. Many
years ago , Jeong introduced the first rhodium
catalyzed enantioselective PKR under CO
atmosphere in the presence of an atropisomeric
ligand.These early results were promising in terms of
enantioselectivity, but they also exhibited some
limitations with certain class of substrates. We have
demonstrated that enantioselectivity and reaction
yield were influenced by the electronic density on
phosphorus, the dihedral angle of ligands and the
electronic density of the alkyne substrate. Ligands
bearing a narrower dihedral angle than BINAP, such
as SYNPHOS and DIFLUORPHOS, were found to
increase substantially the enantioselectivity of the
reaction, compared to BINAP-type ligands.
DIFLUORPHOS deshielded phosphine provided
better enantioselectivity than BINAP, especially with
electron-poor alkyne substrates (Scheme 1).[ 6]
Sch
h eme
e 1. Potassium organotrifluoroborates in organic
synthesis
Since the discovery of the Suzuki-Miyaura reaction,
organoboranes have emerged as the reagents of
choice in transition metal-catalyzed reactions. The
main interesting feature of organoboron reagents is
their low toxicity as well as for the by-product
generated, making these compound environmentally
friendly compared to other organometallic reagents
and particularly organostannanes.
However many trivalent organoboranes are not
highly stable, particularly alkyl- and alkynylboranes.
The lack of stability of organoboranes is due to the
vacant orbital on boron, which can be attacked by
27
oxygen or water, resulting in the decomposition of
the reagent. Efficient preparations of the highly
stable potassium aryl, alkenyl and alkynyl
trifluoroborates, which does not require the use of
purified organoboronic acids, are now available [ 7] .
Five years ago only a limited papers were published
on these emerging compounds, to day an increased
number of publications and patents on that topic
have been reported in the literature.[7]]
Potassium trifluoro(organo) borates rhodium
catalyzed reactions
The 1,2- and 1,4- additions of organometallic
reagents to unsaturated compounds are some of the
most versatile reactions in organic synthesis. We
have developed an efficient system using rhodium
catalyst [RhCl(C2H4)]2 3 mol %, P(tBu)3, 3 mol%. In
the presence of an electron-rich phosphine such as
PBu3 and water (toluene/H2O) the reaction proved to
be general, allowing the production of highly
hindered diaryl carbinols and aliphatic aldehydes
were also reactive under these conditions.[8]]
Interestingly, the same catalyst system in the
absence of water allows a direct access to ketones
from aldehydes via rhodium-catalyzed cross-coupling
reaction with potassium trifluoro (organo) borates [ 9a] .
We also have described for the first time a
straightforward preparation to congested
benzophenones frameworks from aryl aldehydes
and potassium aryltriffluoroborates. This reaction
occurring under neutral conditions, allows formation
of di-,tri- and even tetra-ortho substituted
benzophenones thanks to the use of stable
phosphonium salt of P(t-Bu)3.(Scheme 2) .[ 9b]]
and selectively to enones (Scheme 3). [7] The
reaction has been applied to a,b unsaturated
amides, ester and lactones.
Sc h em e 3
N-protected amidoacrylates
The tandem -1,4 addition enantioselective
protonation of N-protected amidoacrylates would
provide a new and efficient route to enantiomerically
enriched a-amino acids derivatives. We have shown
that choosing a suitable proton source could control
the · chiral center. Indeed the conjugate addition of
potassium aryl and alkenyl-trifluoroborates to Nacylamidoacrylates mediated by a chiral rhodium
complex in the presence of achiral phenol derivatives
furnishes a variety of _-amino acid derivatives with
good enantioselectivities up to 89.5% ee using RhBINAP catalyst.[ 100] The best proton source was
found to be inexpensive and non-toxic 2methoxyphenol or guaiacol. The influence of steric
hindrance from methyl to isopropyl and t-butyl ester
improved the enantioselectivity ee up to 95%.[11]
Fi g u r e 2
However lower yields were generally achieved using
t-butyl ester a good compromise is the use of
isopropyl ester.
Scheme 2.
Asymmetric conjugate addition of potassium
trifluoro (organo) borates to Michael acceptors
Enones
The asymmetric 1,4-addition of potassium
organotrifluoroborates turned out to be trickier than
the racemic version. Most rhodium catalysts
described earlier by Batey, Miyaura, Hayashi
underwent poor conversions and/or low enantiomeric
excesses. We have reported, after careful
optimization of the reaction system including ligand,
solvent, temperature, that [Rh (cod)2]PF6 associated
to chiral phosphine BINAP, JOSIPHOS and MeOBIPHEP that the presence of water is also crucial for
this reaction: in its absence, the reaction was very
slow and the asymmetric induction too. On the other
hand, an excess of water slows the reaction down
and in pure water no asymmetric induction was
observed. Indeed, for practical purposes, one should
therefore use an excess of water compared to boron
reagent (typically 10:1 mixture of toluene/water).
Potassium trifluoro (organo) borates react efficiently
Reaction pathway of the tandem 1,4
enantioselective Rh-catalyzed reaction
Initially we believed that this reaction proceeded
through an oxa p-allyl rhodium intermediate as
established by Hayashi. Actually, it appears that the
presence of a free N-H bond in a position to the
Michael acceptor was essential in order to achieve
high level of enantioselectivity. Deuterium labeling
studies show new interesting aspects of this
rhodium-catalyzed -1,4 addition. The catalyst cycle
involves (a) transmetallation of the aryl group from
boron to rhodium (b) insertion of the olefin into the
aryl-rhodium bond forming a rhodium alkyl species
(c) ?-elimination giving a Rh-imino complex (d) 1,3
hydrogen shift from rhodium to carbon forming the
Rh-NP intermediate and (e) its cleavage with
guaiacol giving the addition product.
The potential energy profiles have been studied by
DFT calculations. The computed sequence of the
elementary steps, relative intermediates and
28
transitions states agrees with the previous proposal
step (c) is endothermic with an energy barrier of 27.8
kcal/mol (Figure 2).[11]
This step being the rate-determining step. Thus, we
anticipated that a more p acceptor than BINAP
should facilitate th _-elimination and improve the
selectivity. Having developed DIFLUORPHOS an
original atropisomeric ligand with original steric and
electronic properties [4,5]. We were pleased to find
that under optimized conditions both yields and
enantioselectivies were significantly increased using
Rh- DIFLUORPHOS catalyst (Scheme 4) [11].
Scheme 4. Ruthenium-mediated asymmetric hydrogenation
reactions. Chiral Ruthenium catalysts
The first mononuclear hexacoordinate ruthenium
complex bearing BINAP a ligand has been reported
by Noyori [ 1] . In the last two decades we focused
some efforts on the design of new, general and mild
syntheses of chiral ruthenium complexes. Our
methods are based on the easy availability of
Ru(COD)(h3-methylallyl)2 from [RuCl2(COD)] n by
treatment with methallyl Grignard [2] . Interestingly, in
situ generated catalysts Ru(P*P)X2 have been
synthesized from Ru(COD)(h3-methylallyl)2 and the
appropriate chiral diphosphine by treatment with HX
(X= Cl, Br, I) at room temperature, giving rise to a
wide range of chiral catalysts (Scheme 5).In the
course of collaboration with Firmenich, an industrial
product-oriented project, a new type of catalyst with
high reactivity was discovered by treatment of
Ru (COD)(h3-methylallyl)2 and various ligands P*P
(BINAP, DuPHOS, JOSIPHOS) in weakly coordinating
solvent (CH2Cl2) with HBF2 (Scheme 5) [13] .
enantiomers of 3-hydroxy-2-methylpropanoic acid
t-Butyl with high enantioselectivity (up to 96% ee)
(Scheme 6).. [113]
Sc h em e 6
The Dolabelides contain a 22- or 24- membered ring,
including eleven stereogenic centers (Figure 3).
Eight of them are hydroxyl or acetyl functions. Those
challenging molecules and especially their syn and
anti 1,3-diol sequences constitute an excellent target
for our ongoing program on the use of rutheniummediated asymmetric hydrogenation for the
preparation of biologically relevant natural products.[ 2]
The synthesis of the C1-C13 fragment of Dolabelides
was performed for the first time using catalytic
asymmetric hydrogenation of b-keto esters and
b-hydroxy ketones to install the hydroxyl groups at
C3, C7, C9 and C11 stereocenters [ 14a]] . This flexible
strategy is also currently used for the preparation of
Discodermolide (potent antimitotic agent). Thus, the
synthesis of C1-C7,C9-C14 and C15-C24 key fragments
of Discodermolide were achieved from a common
intermediate. [114b]]
Figu
u re
e3
Scheme 5
Applications in organic synthesis
3-hydroxy-2-methylpropionic acid methyl ester known
as Roche ester represents a significant building
block in organic synthesis and is present in a
substantial number of both naturally occurring and
synthetic biologically relevant molecules.
We found that a generation of cationic chiral
Ru-catalyst developed earlier in our group for the
paradisone synthesis was highly efficient catalyst.
The in situ generated Ru-SYNPHOS catalyst was
prepared by treating a mixture of
Ru (COD)(h3-methylallyl)2 and SYNPHOS [3] in
dichloromethane by addition of 1 or 2eq of HBF4.
This cationic Ru-SYNPHOS complex was the best
catalyst for the hydrogenation reaction providing both
29
References
[1] Ohkuma, T.; Kitamura, M.; Noyori, R. Asymmetric
Hydrogenation in Catalytic Asymmetric Synthesis, 2nd
000, 1-110.
edition, Ojima, I. Ed. Wiley, New York, 20
[2] Genet, J.P. Acc. Chem. Res., 2003
3, 36, 908-918.
[3] (a) Duprat de Paule, S.; Jeulin, S.; RatovelomananaVidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Tetrahedron
Lett. 2003, 44, 823-826. (b) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Genêt, J.P.; Champion, N.;
Dellis, P. Eur. J. Org. Chem. 2003, 1931-1941. Both
antipodes of SYNPHOS® and DIFLURPHOS® are
commercially available from Strem Chemicals.
[4] Jeulin, S.; Duprat de Paule S.;Vidal V.; Genet J.P.;
Champion, N.; Dellis P. Angew. Chem. Int. Ed. 2004, 43,
320-325.
[ 5] Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal,
V.; Genet, J.P.; Champion, N.; Dellis P. Proc.Natl.Acd.Sci.
USA 2004, 101, 5799–5804.
[ 6] Kim,O.E.;Choi,C.;Kim,I.S.;Jeong,N.; Jeulin S.; Vidal V.;
Genet, J.P. Adv. Synth. Cat 2007, 349, 1999-2006.
[ 7] Darses S.; Genet J.P. Chem.Rev. 2008, 108, 288-325
and references cited therein.
[8] (a)Pucheault M.; Darses S.; Genet J.P. Chem.
Commun., 2005, 4714-4716;(b) Navarre L., Darses S.,
Genet J.P. Adv. Synth. Catal. 2006 348, 317-322.
[9] Pucheault M.; Darses S.; Genet, J.P. J. Am. Chem. Soc.
2004, 126, 15356-15359 ; b) Chuzel O.; Roesch A.; Genet
J.P.;Darses S. J. Org. Chem. 2008 in press
[10] Navarre,L.; Darses, S.; Genet, J.P. Angew. Chem. Int.
Ed., 2004, 43, 719-721.
[11] Navarre,L.; Martinez,R.; Darses, S.; Genet, J.P. J. Am.
Chem. Soc. 2008, 130,6159-6169.
[12] Jeulin S.;Vidal V.; Genet J.P.; Ayad, T, Adv. Synth. Cat,
2007, 349,1592-1596
[13] Dobbs, D.A.; Vanhessche, K.P.M.; Brazi, E.;
Rautenstrauch, V.; Lenoir, J.Y.; Genet, J.P.; Wiles, J.;
000, 39, 1992-1995.
Bergens, S.H. Angew. Chem. Int. Ed. 20
[14] (a) Dolabelides: Le Roux R.; Desroy N.; Phansavath P.;
Genet J.P. Org. Lett. 2008 in press ;(b) Discodermolide :
Roche, C.; Le Roux R.; Desroy N.; Phansavath P.; Genet J.P.
30
New Applications
of Quinones
and Quinols in
Asymmetric
Synthesis
M. Carmen Carreño
Quinone Diels-Alder reactions have been extensively
used in organic synthesis for the stereoselective
construction of polycyclic skeletons from which
complex natural products were later synthesized [1] .
Until recently, resolution of racemic adducts was the
only way of access to enantiopure derivatives.
Nowadays, some efficient chiral catalysts allow a
direct synthesis of the enantiopure adducts [ 2] .
Applications of quinones in asymmetric synthesis
have been rarely based on the use of simple
quinonic systems bearing a chiral auxilliary directly
linked to the dienophilic bond.
In order to apply this domino sequence to the
synthesis of polycyclic targets, we focused on
helicenes. These are well known representative of
polycyclic aromatic compounds bearing a series of
ortho-condensed aromatic rings that exist in a chiral
non_planar helical disposition due to the steric
hindrance of the external rings and their substituents
[ 5] . The helical structures can be resolved into their
enantiomers if the interconversion barrier between
them is high enough. These artificial molecules
present excellent properties of huge interest in the
field of new materials, which are inherently
associated to their enantiopurity.
Enantiopure 2-p-tolylsulfinylquinones turned out to
be powerful dienophiles opening an enantioselective
access to different groups of complex structures
using an asymmetric Diels-Alder reaction as key
step. The sulfoxide was shown to play several
important roles in the reactions of these dienophiles.
This group was able to control the regiochemistry of
sulfinylquinone cycloadditions with a range of
substituted dienes [3] . High endo and p-facial
diatereoselective reactions were always achieved
due to an efficient differentiation of the diastereotopic
faces of the quinone by the sulfoxide. Moreover,
once the adduct was formed, elimination of
p-toluenesulfenic acid occurred spontaneously
allowing to recover the quinone skeleton in a single
step. As a consequence of this domino process,
enantiopure sulfinylquinones could act as homochiral
synthetic equivalents of the unknown triple bonded
quinones. The results shown in Scheme 1 illustrate
the one-step synthesis of enantiopure 5-methyl5,8¬dihydro-1,4-naphthoquinone (SS)-4 by reaction
between (SS)-2-p-tolylsulfinyl-p_benzoquinone 3 and
piperylene. The sulfinyl quinone was readily
accessible in two steps from 1,4-dimethoxybenzene
1 by sequential reaction with n-BuLi and (–)-menthylp_toluene sulfinate (SS)-2, followed by oxidative
demethylation of the intermediate diaromatic
sulfoxide with CAN4.
Organic Chemistry Department (C-I), Autonoma University
of Madrid, Cantoblanco, Madrid, Spain
The smaller systems, [4]helicenes, have
racemisation barriers which are highly dependent on
the particular structure. Using our asymmetric DielsAlder reaction we could synthesize 12-alkyl-and 12methoxy-substituted 7,8-dihydro[4]helicenequinones
(P)-9 from (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone
(SS)-3 and 3-vinyl-1,2¬dihydronaphthalenes 7 to
further evaluate their configurational stability. 6 The
dienes 7 were accessible from 7-methoxy-1-tetralone
4 by addition of a Grignard reagent (R1MgBr)
followed by sequential aromatization of the
dihydroaromatic ring, reductive dearomatization of
the 2-methoxy substituted ring and transformation of
the C-2 carbonyl into the enol triflate 6. This key
intermediate was transformed into the vinyl
substituted derivatives 7 by Stille coupling. Upon
reaction with an excess of the sulfinylquinone (SS)-3,
these dienes gave the dihydro [4]helicenequinones
(P)-9 in a one-pot process where the domino
Diels–Alder reaction/pyrolytic sulfoxide elimination
sequence was followed by the oxidation of the B ring
of the intermediate (12bR,P)-8 . This aromatization
occurred in situ by the action of the excess of the
quinone which was acting as an oxidant. The
configurational stability of these [4]helicenequinones
was highly dependent on the size of the R1
substituent at C-12 being the tert-butylsubstituted
derivatives the only [4]helicenequinones that were
indefinitely stable at room temperature. The values
of the racemisation barriers, calculated from
computations, confirmed the main role of the steric
effects in the configurational integrity of these helical
quinones.
Scheme 1
31
Scheme 2
The higher analogues, [5] and [7]helicenequinones,
could also be synthesized in enantiomerically pure
form from (SS)-3, by applying a similar strategy. The
choice of the diene allowed the access to the
bisquinones. Thus, reaction of vinyl
dihydrophenantrene 10 with (SS)-3, afforded
enantiopure [5]helicenequinone [77] (P)-11 which
could be oxidized to the bisquinone (P)-12.
cycloaddition occurred with resolution of the diene in
a double asymmetric induction process where the
matched pair corresponded to the endo-cycloaddition
of (SS)-15 approaching in an anti fashion to the
(3R,5R) enantiomer of trans-3-hydroxy-5-methyl-1vinylciclohexene 16. Aromatization of the new
generated ring of 17, deprotection of the OTBDMS
group and photochemical oxidation led to rubiginone
B2. Ochromycinone [ 8b ] and deoxytetrangomycin [8b]
were also synthesized by applying this strategy.
Sch
h eme
e5
Scheme 3
Using a bisdiene such as 13, a domino process
including the asymmetric Diels-Alder
reaction/pyrolytic elimination of the sulfoxide and
aromatization, in the presence of an excess of the
quinone, took place twice, leading directly to the
enantiopure [7]helicenequinone (M)-14 (Scheme 4).
The vinyl and divinyl phenantrene derivatives 10 and
13 were available from the corresponding
phenantrenone or phenantrenedione, using a Stille
coupling to introduce the vinyl groups on the
enoltriflate intermediate.
Scheme 4
Starting from (SS)-2-p-tolylsulfinyl-1,4naphthoquinones, we could synthesize some
angucyclinones,[8] a group of natural tetracyclic
quinones showing antibiotic and antitumoral
properties. The tetracyclic skeleton of rubiginone B2
(Scheme 5) was assembled by reaction between 5methoxy-2-p-tolylsulfinylnaphthoquinone (SS)-15 and
the diene 16, which was used racemic. The
Within the angucyclinone family, some members,
such as Rubiginones A2 and C2 (Scheme 6) have an
additional oxygenated function at C-4 of the
hydroaroamatic A ring. The Diels-Alder strategy
based on the resolution of the diene could not be
applied in this case. We then considered the
construction of the tetracyclic skeleton starting from
an enantiopure vinylcyclohexene such as 25 [9]
which could be synthesized from
(SS)-[(p-tolylsulfinyl)methyl]-p-quinol 20. The
p-quinols bearing a CH2SOpTol substituent at C-4 of
the cyclohexadienone moiety had been previously
synthesized by us [110]. A methodologic study had
evidenced that AlMe3 reacted with such p-quinols in
a highly chemo-and diastereoselective manner
leading to only one out of the four possible
diastereomers resulting from conjugate addition. The
process led to the efficient desimmetrization of the
prochiral cyclohexadienone moiety of 20. As shown
in Scheme 6, the synthesis of (SS)-20 was achieved
in two steps from p-benzoquinone dimethylketal 19,
by addition of the lithium anion derived from
enantiopure (SS)-methyl p-tolyl sulfoxide to the
carbonyl group followed by hydrolysis of the ketal
group. p-Quinol 20 reacted with AlMe3 leading to
derivative 21, which has the R configuration at the
new C5 stereogenic center. The sulfoxide of 21 was
oxidized into the sulfone to afford, after
stereoselective reduction of th C=O and protection of
the secondary carbinol, the _-hydroxy sulfone 22.
32
Previously, we had shown that after oxidation of the
sulfoxide to a sulfone, compounds such as 21
suffered the elimination of methyl p_tolylsulfone by a
Cs2CO3-promoted retrocondensation, allowing to
recover a carbonyl group at C-4 [11] . Thus, ketone
23 was obtained in 86% yield, showing that the initial‚
_hydroxy sulfoxide can be considered as a chiral
protecting group of a cyclohexanone.
Treatment of 23 with Br2 and Et3N promoted an
addition elimination process leading to an
intermediate _-bromo enone, which was
stereoselectively reduced and esterified to 24. This
was the immediate precursor of the enantiopure vinyl
cyclohexene 25, available after a Stille coupling in 78
% yield.
Scheme 6
We then proceeded to the construction of the
tetracyclic skeleton through the Diels–Alder reaction
between the enantiopure vinyl cyclohexene 25 and
2-(p_tolylsulfinyl)-juglone methyl ether 26, which was
used in racemic form since the role of the sulfoxide
in this case was limited to the regiochemical control
of the cycloaddition and to facilitate the recovery of
the quinone structure from the initial adduct, by
spontaneous elimination of p-tolylsulfenic acid
(Scheme 6). Rubiginone C2 was finally obtained
upon exposure of 27 to sunlight in the presence of
air under solvent-free conditions. This unprecedented
photoinduced one-pot transformation implied a
domino sequence of three reactions: aromatization of
the B ring, deprotection of the silyl ether and
oxidation of the C-1 position into a carbonyl group.
The other natural product, rubiginone A2, resulted
from rubiginone C2, by methanolysis of the C-4 ester.
The 11_methoxy regioisomers of both natural
products were synthesized in a similar manner using
racemic 3-p-tolylsulfinyl juglone methyl ether as
dienophile [9a] . Other synthetic applications of
sulfoxide bearing p-quinols, focused on natural
polyoxygenated cyclohexanes and cyclohexenes
from compounds 22 and 23, easily transfromed into
the natural targets by sterereoselective processes
occurring on the rigid cyclic systems. [12]
References
[1
1] Review: Nicolaou, K. C.; Snyder, S. A. ; Montagnon, T.;
Vassilikogiannakis, G.; Angew. Chem. Int. Ed. 2002, 41,
1668-1698.
[2
2] For recent examples see: a) Pingfan Li.; Payette, J. N.;
007, 129, 9536-9537. b)
Yamamoto, H. J. Am. Chem. Soc. 20
7,
Liu, D., Canales, E., Corey, E. J. J. Am. Chem. Soc. 2007
129, 1498-1499. c) Jarvo, E. R.; Lawrence, B. M.; Jacobsen
005, 44, 6043-6046.
E. N. Angew. Chem. Int. Ed. 20
[ 3] Carreño, M. C.; García Ruano, J. L.; Toledo, M. A.;
Urbano, A.; Remor, C. Z.; Stefani, V.; Fischer, J. J.
Org.Chem. 1996, 61, 503-509.
[4
4] Carreño, M. C.; García Ruano, J. L.; Urbano, A.
Synthesis, 1992, 651-653.
[5
5] Vögtle, F. Fascinating Molecules in Organic Chemistry,
Wiley and Sons, New York, 1992, 156-180.
[ 6] a) Carreño, M. C.; Enríquez. A. L.; García-Cerrada, S.;
Sanz-Cuesta, M. J.; Urbano, A.; Maseras, F.; Novell-Canals,
A. Chem. Eur. J. 2008, 14, 603-620. b) Carreño, M. C.;
García-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. Chem.
Commun. 2001, 1452 – 1453.
[7
7] a) Carreño, M. C.; García-Cerrada, S.; Urbano,
A. Chem. Eur. J. 2003, 9, 4118 –4131. b) Carreño, M. C.;
02,
García-Cerrada, S.; Urbano, A. Chem. Commun. 200
1412 – 1413; c) Carreño, M. C.; García-Cerrada, S.;
01, 123, 7929 –7930.
Urbano, A. J. Am. Chem. Soc. 200
8] a)Carreño, M. C.; Urbano, A. ; Di Vitta, C. Chem. Eur. J.
[8
20
000, 6, 906 –913. b) Carreño, M. C.; Urbano, A. ; Di Vitta,
C. Chem. Commun. 1999, 817 –818. c) Carreño, M. C.;
97, 109, 1695 –
Fischer, J.; Urbano, A. Angew. Chem. 199
1697. Angew. Chem. Int. Ed. Engl. 1997, 36, 1621 –1623.
[ 9] a) Carreño, M. C.; Ribagorda, M.; Somoza, A.; Urbano,
A. Chem. Eur. J. 2007, 13, 879 – 890. b) Carreño, M. C.;
Ribagorda, M.; Somoza, A.; Urbano, A. Angew. Chem.
2002, 114, 2879 –2881. Angew. Chem. Int. Ed. 2002, 41,
2755 –2757.
[1
10] Carreño, M. C.; Pérez González, M.; Ribagorda, M.;
98, 63, 3687-3693.
Houk, K. N. J. Org. Chem. 199
[1
11] a) Carreño, M. C.; Merino, E.; Ribagorda, M.; Somoza,
05, 7, 1419-1422. b) Carreño, M.
A.; Urbano, A. Org, Lett. 200
C.; Pérez González, M.; Ribagorda, M.; Somoza, A.;
02, 63, 3052-3053.
Urbano, A. Chem. Comm. 200
[1
12] Carreño, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.;
Urbano, A. Chem. Eur. J. 2007, 13, 1064-1077.
Acknowledgments
I am grateful to all my co-workers, especially Drs.
Ribagorda and Urbano, for their contribution to the
group’s research results. Financial support from the
Ministerio de Educación y Ciencia (Spain) and
Comunidad de Madrid is greatly acknowledged.
33
Stereoselective
Synthesis of
Amino Diols
Stephen G. Davies
Department of Chemistry,
University of Oxford, Oxford, UK
The amino diol motif is a recurring structural
component in a diverse range of biologically active
natural products and synthetic molecules. The
asymmetric synthesis of a range of natural products
[1,2] and other highly functionalised molecular
architectures containing the amino diol unit utilising a
variety of synthetic methodology including asymmetric
conjugate addition of nitrogen nucleophiles,[ 3] novel
cyclisation strategies[ 4] and ammonium-directed
dihydroxylation is delineated.[ 4]
in the presence of NaHCO3 gave a 19:81 mixture of
C(5)-epimeric N-benzyl pyrrolidines with in situ loss
of the _-methylbenzyl cation, from which the major
diastereoisomer was isolated in 63% yield in >98%
de. In this process, ring-closure to the pyrrolidine and
chemoselective N-deprotection had been affected in
a single step. Subsequent manipulation of the
primary iodide by displacement with AgOAc, and
deprotection, gave the polyhydroxylated pyrrolidine
as a single stereoisomer in good yield.[ 4]
The conjugate addition of lithium (S)-N-benzyl-N-(_methylbenzyl)amide to a _-silyloxy-_-‚ _-unsaturated
ester with in situ enolate oxidation with (+)-CSO
gives ready access to the corresponding _-hydroxy_-amino esters as a single diastereoisomer in good
yield. This methodology had been utilised in the
synthesis of a range of natural products including
sphingosine and jaspine B.[2]
Oxidation of an allylic primary, secondary or tertiary
amine with a peracid is known to occur preferentially
at the nitrogen atom, giving the corresponding
N-oxide. Recent investigations have shown that the
in situ protection of the nitrogen atom of an allylic
amine by protonation allows chemoselective
oxidation of the double bond syn to the amino
fragment, under hydrogen-bond controlled delivery
We have recently developed a novel iodinemediated ring-closure/debenzylation protocol of a
tertiary, unsaturated amine. The utility of this
exquisite transformation has been demonstrated via
the synthesis of polyhydroxylated pyrrolidines. Thus,
conjugate addition of lithium (S)-N-benzyl-N-(_methylbenzyl)amide to a D-ribose-derived _‚ _unsaturated ester gave the corresponding_-amino
ester. Treatment of this_-amino ester with I2 in MeCN
by the adjacent ammonium ion. Thus, treatment of
3-N,N-dibenzylamino-cyclohexene with
trichloroacetic acid, followed by subsequent,
sequential treatment with mCPBA gives 1,2-anti-2,3syn-3-amino-1,2-in quantitative yield and >90% de.
This metal-free methodology has been successfully
applied to the synthesis of all four possible
diastereoisomers of 3-amino-cyclohexane-1,2-diol in
>98% de.[ 5]]
34
This work has recently been extended to encompass
the chemo- and stereoselective cyclopropanation of
a range of allylic amines, and a stereodivergent
protocol for the preparation of 2-aminobicyclo[4.1.0]heptane derivatives has been
developed.[6]
References
[1] S. G. Davies and O. Ichihara, Tetrahedron Letters, 1999,
40, 9313; S. G. Davies, R. J. Kelly and A. J. Price-Mortimer,
Chem. Comm., 2003, 2132; S. G. Davies and O. Ichihara,
Tetrahedron Asymmetry, 1996, 7, 1919.
[2] E. Abraham, J. I. Candela-Lena, S. G. Davies, M.
Georgiou, R. L. Nicholson, P. M. Roberts, A. J. Russell, E.
M. Sánchez-Fernández, A. D. Smith and J. E. Thomson,
Tetrahedron: Asymmetry, 2007, 18, 2510; E. Abraham, S. G.
Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts and A.
D. Smith, Org. Biomol. Chem., 2008, 6, 1655; Abraham, E.
A. Brock, J. I. Candela-Lena, S. G. Davies, M. Georgiou, R.
L. Nicholson, P. M. Roberts, A. J. Russell, E. M. SánchezFernández, P. M. Scott, A. D. Smith and J. E. Thomson,
Org. Biomol. Chem., 2008, 6, 1665; E. Abraham, S. G.
Davies, P. M. Roberts, A. J. Russell, J. E. Thomson,
Tetrahedron: Asymmetry, 2008, 19, 1027.
[ 3] S. G. Davies, P. D. Price and A. D. Smith, Tetrahedron:
Asymmetry, 2005, 16, 2833; S. G. Davies, N. M. Garrido, D.
Kruchinin, O. Ichihara, L. J. Kotchie, P. D. Price, A. J. Price
Mortimer, A. J. Russell and A. D. Smith, Tetrahedron:
Asymmetry, 2006, 17, 1793.
[4] S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Roberts
and A. D. Smith, Synlett, 2004, 901.
[5] S. G. Davies, M. J. C. Long and A. D. Smith, Chem.
Commun., 2005, 4536.
[6] S. G. Davies, K. B. Ling, P. M. Roberts, A. J. Russell
and J. E. Thomson, Chem. Commun., 2007
35
The Evolution of
Lilly Oncology:
From Targeted
Cytotoxic Agents
(Alimta®) to
Kinase Inhibitors
Joe Shih
Discovery Chemistry Research and Technologies,
Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, USA
The anticancer drug discovery effort at Lilly can be
traced back to the early 1960s and 1970s. Using
cytotoxicity-based cell screen as the primary strategy
for lead identification, the Lilly team then led by Dr.
Irving Johnson uncovered potent cytotoxic Vinca
alkaloids in the extracts prepared from the leaves of
Madagascar periwinkle (Vinca Rosea Linn G. Don).
Through careful chemical structure elucidation and
investigation of the pharmacological actions of these
cytotoxic alkaloids, Vincristine and Vinblastine were
successfully developed as the first class of anti-tubulin
chemotherapeutic agents for the treatment of various
leukemia (ALL, ML), Hodgkin/non-Hodgkin lymphoma
and germ cell malignancies. Vincas (Vindesine was
discovered and added later to the arsenal of Vincabased chemotherapeutic agents) have since become
widely used to treat various type of cancers either as
single agent or in combination with other
chemotherapeutic agents.
The success of Vincas stimulated considerable
amount of interest at Lilly to continue investigate
novel approaches in discovering effective agents in
particular for the treatment of solid tumors (breast,
lung, colon, pancreas and prostate cancers for
example). In early 1980s, the anticancer program
under the direction of Dr. Gerald Grindey decided to
shift to the use of solid-tumor human tumor xenograft
screening as way to identify broad-spectrum antitumor
agents for difficult to treat human solid tumors.
Under this initiative, two novel anti-metabolites,
Gemzar (Gemcitabine) and Alimta (Pemetrexed)
were discovered and put into clinical development in
late 1980s and 1990s and eventually each received
US FDA approval for marketing (Gemzar first in1996
for pancreatic cancer and Alimta in 2004 received
the first approval for malignant pleural mesothelioma).
Gemcitabine is a prodrug that requires enzymatic
conversion to its bioactive diphosphate and
triphosphate forms. The diphosphate form of
gemcitabine inhibits the ribonucleotide reductase
and the triphosphate form of gemcitabine can act as
a DNA chain terminator once it was incorporated into
the DNA. Gemzar is an effective anticancer agent for
treating various forms of human cancers. In addition
as the gold standard for the treatment of pancreatic
cancer, Gemzar is also now approved for the
treatment of non-small cell lung cancer (1st line in
combination with cisplatin), bladder cancer,
metastatic breast, ovarian and pediatric cancer.
Alimta on the other hand is a novel pyrrole-pyrimidine
based “classical” antifolate. It is derived from the
successful 10-year antifolate drug discovery
collaboration program between Lilly and the Princeton
University (key collaborator: Professor Edward Taylor
of the Chemistry Department, now retired). Three
clinical candidates (Lometrexol, Alimta and GARFTII)
were identified during the decade long collaboration
and Alimta was identified through an active SAR
program attempting originally in removing the chirality
at the C-6 asymmetric center (thus simplify the
separation issue of the two diastereomers) of the
tetrahydropyridine-pyrimidine region of the GARFT
(glycinamide ribonucleotide formyltransferase)
inhibitor, Lometrexol. Replacement of the
tetrahydropyridine ring with pyrrole led to the
discovery Alimta. Alimta can be effectively prepared
by using the palladium-based Sognagesia coupling
between the 2-pivaloyl-5-iodo-pyrrolopyrimidine and
the 4-ethynyl-diethylbenzoyl-Lglutamate, followed by
hydrogenation and removal of the ester and amide
protection groups. While the chemical modification of
Lometrexol to Alimta seems straight forward, however,
the mode of action of Alimta turned out to be very
different and unique from its predecessor, Lometrexol.
Through various careful cell-based cytotoxicity
reversal studies and evaluation of polyglutamated
form of Alimta against isolated human folate enzymes,
it was concluded that Alimta can potently inhibit
several key folate enzymes in the folate biochemical
pathway involved in both the purine and the
pyrimidine biosynthesis. These enzymes include
GARFT, TS (thymidylate synthase) and DHFR
(dihydrofolate reductase). For example, it was found
that the pentaglutamate derivative of Alimta (AlimtaGlu5) can potently inhibit hTS (IC50= 1.3 nM),
dDHFR (IC50= 7.2 nM) and GARFT (IC50= 65 nM).
In addition to these three enzymes, Alimta
polyglutamates also inhibit AICARFT
(aminoimidazolecarboxamide ribonucleotide
formyltransferase, IC50= 260 nM) and C-1
tetrahydofolate synthase.[ 1] Alimta was found to be
an excellent substrate for the enzyme
folylpolyglutamate synthetase (FPGS), through both
36
enzyme kinetic and cellular uptake studies it was
found Alimta can be rapidly (<2h) converted into the
polyglutamated forms (usually up to penta- and
hexaglutamates) when incubated in the CCRF-CEM
leukemia cells. The excellent polyglutamation profile
coupled with the fact that Alimta can be efficiently
transported into the cells by the active transport
system, Reduced Folate Carrier (RFC), makes
Alimta a very novel classical antifolate that can be
effectively taken up into the tumor cells and affecting
the cellular de novo DNA and RNA synthesis (which
are essential for the rapidly dividing malignant
cancerous cells) by simultaneously inhibiting several
key folate-requiring enzymes of the folate pathway
(Figure 1).
Figure 1. Mechanism of action of ALIMTA®
Alimta went into phase I clinical development in the
early 1990s for safety assessment. The 21-day
schedule of Pemetrexed administered at 600 mg/m2
on day 1 as a 10-minute intravenous infusion was
carried into phase II trials. As a single agent,
interesting activity was observed in mesothelioma,
breast, gastrointestinal and NSCLC (non-small cell
lung cancer), with myelosuppression as the major
dose-limiting toxicity. Alimta’s first registration trial
was focused on malignant pleural mesothelioma
(MPM) in combination with cisplatin since exciting
responses were observed from the earlier phase II
studies for Alimta/cisplatin against MPM. With the
critical introduction of daily supplement of oral folic
acid (300-1000 ug) and vitamin B12 (1000 ug q9w)
to mitigate grade 3 and 4 drug-related toxicities
(bone marrow), it was found Alimta plus cisplatin can
significantly increase the median survival time (MST)
(13.3 month vs. 10.0 month) than patients on
cisplatin only.[2] The lung functions of the MPM
patients who received Alimta and cisplatin also
improved significantly. Alimta was approved by US
FDA in February 2004 as the first line therapy (in
combination with cisplatin) for malignant pleural
mesothelioma. Alimta was also found to be an
effective antitumor agent for non-small cell lung
cancer. It received US FDA approval as a 2nd line
treatment (single agent) on October 2004 for
NSCLC. Recently (April 2008), it has also received
EU EMEA’s approval as a 1st line treatment (in
combination with cisplatin) for NSCLC. Four years
since the first approval for MPM in 2004, Alimta has
now emerged as a major targeted-cytotoxic agent for
the management of thoracic cancer with quite
acceptable safety profile and manageable toxicity.
Gemzar and Alimta have now become the
cornerstones of the Lilly oncology franchise with total
annual sales of more than 2.3 billion dollars (2007).
With this success, the Lilly oncology program
continues to evolve focusing on bringing more novel
and effective agents for the management and
treatment of various forms of cancer. Beginning in
the late 1990s, with the success deciphering of
human genome and advancement of molecular and
cellular biology in understanding of the control of
cell-signaling pathway, Lilly
Oncology has shifted the focus
and strategy once again into
the area of kinase drug
discovery.
To tackle the challenging task
of targeting kinase genome for
drug discovery, we have built
extensive infrastructures and
capabilities at Lilly Research
Laboratories for rapidly
identifying hits and leads for
various kinase targets. For
example, we have used
various approaches including
targeted kinase compound
cassette MTS (medium
throughput screen), PLS
(platform library science), high throughput SBDD
(structure-based drug design), bioinformatics, kinase
panel profiling (at Upstate) and phenotypic drug
screening as novel tools for assisting rapid
identification and iteration/optimization of novel
actives into hits and leads. To illustrate this
integrated approach for kinase drug discovery, a
rapid SBDD effort in identifying potent p38a MAP
kinase inhibitor for oncology indication is shown.
p38a MAP kinase plays an important role in the
signal transduction pathway and the activation of this
kinase in macrophages and tumors can lead to the
production of cytokines (TNFa, IL-1b) as well as the
stimulation of various angiogenic factors (VEGF,
bFGF, EGF, IGF1 and HGF) that could lead to
angiogenesis and the development of tumors. For
example, by using structure-based design approach
in carefully analyzing the active site (ATP) of p38a
MAP kinase, we have successfully converted a
relatively no so potent benzimidazole aryl ketone hit
(uM potency identified from c-Raf kinase screen) into
a potent series of triarylimidazole class of p38a MAP
kinase inhibitors (LSN 479754, IC50 ~ 5 nM). The
N3 and 2-NH2 groups on the benzimidazole ring can
serve each as the hydrogen bond acceptor and
donor interacting pairs with the hinge region amide
bonds.
The larger benzimidazole warhead was nicely
accommodated in the p38a MAP kinase active site
since it was observed that the hinge of p38a MAP
kinase is quite flexible and can move outward
37
(compared to other p38a MAK kinase structures with
smaller warhead inhibitor, SB203580 for example) to
tolerate bigger structure element such as
benzimidazole. The binding mode of the solved
inhibitor/enzyme complex of LSN470754 is exactly
identical to what was predicted based on the original
SBDD design.
References
[ 1] C. Shih, V. J. Chen, L. S. Gossett, S. B. Gates, W. C.
MacKellar, L. L. Habeck, K. A. Shackelford, L. G.
Mendelsohn, D. J. Soose, V. F. Patel, S. L. Andis, J. R.
Bewley, E. A. Rayl, B. A. Morrison, G. P. Beardsley, W.
Kohler, R. Ratnam and R. M. Schultz, LY231514, A
Pyrrolo[2,3-d]pyrimidine Based Antifolate That Inhibits
Multiple Folate Requiring Enzymes. Cancer Research, 57,
1116-1123 (1997)
[ 2] H Pass, N. Vogelzang, S. Hahn, M. Carbone. Malignant
pleural mesothelioma. Curr Probl Cancer. MayJun;28(3):93-174 (2004)
--
Figure 2. p38aMAP kinase/inhibitor co-crystal structures
Green: LSN 479754, Yellow: SB203580
(Noticed the movement of the hinge region, Met109 Gyl110
to accommodate the larger benzimidazole warhead)
Further modification of the LSN 479754 series
quickly led to the identification of LSN2322600 which
demonstrated potent effects both in vitro as well as
p38a MAP kinase target inhibition in vivo (in either
peripheral blood monocytes or in B-16F10
melanoma, TMED50=3.6 mg/kg). Compound LSN
2322600 also demonstrated good antitumor effects
(tumor growth delay) in U87MG glioma (in
combination with Temodar) or as a single agent in
A549 lung xenograft. Excellent anti-inflammatory
effect in collagen-induced arthritis (CIA) model (rat)
was also observed for LSN2322600 (with both paw
swelling and histology scores TMED50 = 1.5 mg/kg).
The Phase I first human dose of LSN2322600 is
scheduled to begin in Q2, 2008.
In conclusion, Lilly Oncology has evolved
successfully in the past 50 years, starting from the
natural products based approach that led to the
identification of novel chemotherapeutic agents such
as Vinca alkaloid (Vincristine, Vinblastine and
Vindesine). This was then followed by using the
solid-tumor screening in xenografts to identify
broadly active antimetabolite agents (Gemzar and
Alimta) for human solid tumors. Gemzar and Alimta
are excellent examples of the power of this
approach; both drugs have now become one of the
most important chemotherapeutic agents/arsenals in
modern day clinical oncology for the front line
treatment and management of various forms of
cancer, including lung, pancreatic, bladder, ovarian,
breast and mesothelioma cancer. Lilly Oncology is
now actively involved in the discovery and
development of an array of novel targeted agents
including various kinase inhibitors as a way to show
our continued commitment in bringing patients and
physician the most effective drugs in the war against
cancer.
38
Lilly
Distinguished
Career Award.
Chemistry
2008
As part of the actions of promotion of R&D in
Biomedicine in Spain, the Scientific Advisory Council
of the Lilly Foundation proposed the creation of the
Lilly Distinguished Career Award, deliverable in each
Lilly Foundation Scientific Symposium, that seeks to
recognize the scientific trajectory of the Spanish
scientists, working either in Spain or abroad, that,
once fulfilled its career, they have fertilized its area of
knowledge, contributing to increase its scientific
level, and to generate vocations among its
collaborators.
The concession of these prizes will be made with the
collaboration of the Spanish Scientific Society
corresponding to the area of knowledge of the
Symposium, through a protocol agreed by the two
parts.
In the 13th Lilly Foundation Scientific Symposium
“Chemistry: Science at the Frontier”, the Lilly
Foundation with the collaboration of the Royal
Spanish Society of Chemistry, granted the Lilly
Distinguished Career Award to Prof. José Elguero
Bertolini, of the Institute of Medicinal Chemistry
(CSIC) of Madrid, for his influence in connection with
the improvement of the level of the Spanish organic
chemistry, specially for his contributions in
heterociclic, medicinal chemistry and physical
organic chemistry, as well as for his influence on the
younger generations of scientists.
39
Como parte de las acciones de promoción de la
I+D en Biomedicina en España, el Consejo
Científico Asesor de la Fundación Lilly propuso la
creación del Lilly Distinguished Career Award, que
se entregará en cada edición del Simposio
Científico de la Fundación Lilly. El premio pretende
reconocer la trayectoria investigadora de los
científicos españoles que trabajan en España o en
el extranjero que, una vez cumplida su carrera
científica, han fertilizado su área de conocimiento,
contribuyendo a aumentar su nivel científico, y a
generar vocaciones entre sus colaboradores.
La concesión de estos premios, que constarán de
un diploma y un trofeo diseñado al afecto, se hará
con la colaboración de la sociedad –o en su caso
sociedades- científica española correspondiente al
área de conocimiento del Simposio, mediante un
protocolo acordado por las dos partes.
En el 13º Simposio Científico de la Fundación Lilly
“Química, Ciencia en la Frontera”, el premio Lilly
Distinguished Career Award se ha concedido al
Prof. José Elguero Bertolini, del Instituto de
Química Médica (CSIC) de Madrid, por su
influencia en el avance del nivel de la química
orgánica española, especialmente por sus
contribuciones en la química de heterociclos,
química médica y química orgánica física, así
como por su magisterio sobre los investigadores
de las generaciones mas jóvenes.
Chairpersons
& Speakers
Chairmen
Jean-Marie P. Lehn -Nobel LaureateProfessor at the Collège de France
Laboratoire de Chimie Supramoléculaire,
Université Louis Pasteur. Paris, France
[email protected]
Arthur & Marian Hanisch Memorial Professor of Chemistry
Division of Chemistry and Chemical Engineering
California Institute of Technology. California, USA
[email protected]
Jean-Pierre Sauvage
CNRS Director of Research
Institut de Chimie, Laboratoire de Chimie Organo-Minérale,
Université Louis Pasteur CNRS/UMR 7177
Strasbourg, France
[email protected]
Joe Shih
Distinguished Lilly Scholar
Lilly Research Laboratories, Eli Lilly. Indianapolis, USA
[email protected]
Phil S. Baran
Associate Professor
Department of Chemistry, The Scripps Research Institute
La Jolla, California, USA
[email protected]
Dennis Curran
Distinguished Service Professor and Bayer
Professor of Chemistry
Department of Chemistry, Chevron Science Center
Pittsburgh, USA
[email protected]
Gregory C. Fu
Professor
Massachusetts Institute of Technology
Cambridge, MA, USA
[email protected]
Alois Fürstner
Director
Max-Planck-Institut für Kohlenforschung
Mülheim an der Ruhr, Germany
[email protected]
Jean-Pierre Genet
Professor
Laboratoire de Synthèse Sélective Organique et Produits
Naturels, Ecole Nationale Supérieure de Chimie de Paris
Paris, France
[email protected]
Fernando Albericio
Full Profesor
Institute for Research in Biomedicine, Barcelona Science
Park, University of Barcelona. Barcelona, Spain
[email protected]
María del Carmen Carreño García
Full Professor
Departamento de Química Orgánica, Facultad de Ciencias,
Universidad Autónoma de Madrid. Madrid, Spain
[email protected]
Stephen G. Davies
Professor
Chemistry Research Laboratory, Department of Chemistry,
Oxford University. Oxford, UK
[email protected]
Julio Álvarez-Builla
Jesús Ezquerra
Miguel Yus
M. Christina White
Assistant Professor
Department of Chemistry, University of Illinois
Urbana, IL, USA
[email protected]
Larry E. Overman
Distinguished Professor of Chemistry
University of California. Irvine, CA, USA
[email protected]
Full Professor
Organic Chemistry Department, Pharmacy School,
University of Alcalá de Henares. Madrid, Spain
[email protected]
Miguel A.Yus
Full Professor
Organic Chemistry Department, Sciences School,
University of Alicante. Alicante, Spain
[email protected]
Jesús Ezquerra
European Discovery Chemist Director
Lilly Research Laboratories. Alcobendas, Madrid, Spain
[email protected]
María Ángeles Martínez-Grau
Lilly Research Laboratories. Alcobendas, Madrid, Spain
[email protected]
Rafael Suau
Full Profesor
Organic Chemistry Department, Sciences School,
University of Málaga. Málaga, Spain
[email protected]
José A. Gutiérrez-Fuentes
Director Fundación Lilly
Madrid, Spain
[email protected]
SCIENTIFIC COMMITTEE
Miguel Yus
Jesús Ezquerra
José A Gutiérrez-Fuentes
Lutz F. Tietze
Professor
Institut für Organische und Biomolekulare Chemie,
Universität Göttingen. Göttingen, Germany
[email protected]
41
13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM CHEMISTRY: SCIENCE AT THE FRONTIER

aquetación 1 - La Fundación Lilly

Transcription

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