Active immunization with a glycolipid transition state analogue protects against endotoxic shock

Article abstract of DOI:10.1002/1521-3773(20021115)41:22<4289::AID-ANIE4289>3.0.CO;2-4

Septic shock may be treated by this new immunomodulatory approach: Active immunization of mice (three strains) with synthetic lipid X bisphosphonate glycoconjugates 1 and 2 resulted in significant protection (up to 94%) against a sublethal challenge of li

Full text of DOI:10.1002/1521-3773(20021115)41:22<4289::AID-ANIE4289>3.0.CO;2-4

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anisotropy may be controlled by their aspect ratio, which gives
rise to ferromagnetic nanomaterials at room temperature. The
rods grow after the initial formation of spherical nano-
particles; the exact mechanism of this process is not known
but we note that the initial formation of nanoparticles,
followed by formation of nanorods or nanowires either
through coalescence of the initial particles[21] or upon using
the particles as nuclei for an anisotropic growth process, have
been very recently reported.[22] Further work will be necessary
to determine the exact mechanism that operates in our case.
In conclusion, we describe in this report a new and simple
method for the preparation of cobalt nanoparticles, nanorods,
and nanowires of uniform diameter that does not require a
special procedure or size selection. The magnetic nanowires
have no equivalent, whereas the rods differ from those
previously described by their uniformity of diameter, their
thermodynamic stability, and the possibility of fine tuning of
their aspect ratio. We further demonstrate that, under these
conditions, the nanomaterials maintain a magnetization at
saturation similar to bulk cobalt. This results from the choice
of ligands that do not display p-accepting behavior, which is in
agreement with previous research work from our group. All of
these aspects emphasize the role of an organometallic
approach in the design of precursors and ligands. Finally,
these objects may find use in many practical applications such
as, for example, in data storage.
Generation of Reactivity from Typically Stable
ꢀ
Ligands: C C Bond-Forming Reductive
Elimination from Aryl Palladium(ii) Complexes
of Malonate Anions**
Joanna P. Wolkowski and John F. Hartwig*
Anions of 1,3-dicarbonyl compounds are some of the most
common ligands in transition-metal chemistry.[1,2] They typi-
cally bind in an h2-O,O fashion,[3] have delocalized charge, and
donate electron density more weakly to a metal center than
alkyls or alkoxides. They are usually supporting ligands that
are ancillary to the site of reaction. Anions of 1,3-dicarbonyl
compounds are also common nucleophiles in metal-catalyzed
6]
allylic substitution,[4 but the facility of this chemistry relies
on external attack of the anion without coordination to the
metal center. If metal fragments could induce reactivity from
coordinated versions of these anions, then complexes of these
common ligands could serve as intermediates in catalytic
processes.
Complexes of malonate anions are likely intermediates in
recently developed palladium-catalyzed arylations of malo-
nates.[7 11] Although palladium complexes of malonate anions
16]
have been isolated previously,[12
their reactivity has been
limited.[17 20] We report here reductive elimination of arylmal-
onate and acetylarylacetone from isolated aryl palladium
complexes of malonate and acetylacetone anions, respective-
ly. Our results suggest that the propensity of these complexes
to undergo reductive elimination depends critically on the
steric properties of the ancillary phosphane ligand.
Received: July 10, 2002
Revised: September 3, 2002 [Z19713]
[1] D. Weller, A. Moser, IEEE Trans. Magn. 1999, 35, 4423.
[2] Y. M. Kim, D. Choi, K. H. Kim, S. H. Han, H. J. Kim, IEEE Trans.
Magn. 2001, 37, 2288.
[3] M. Dumm, M. Zˆlfl, R. Moosb¸hler, M. Brockmann, T. Schmidt, G.
Bayreuther, J. Appl. Phys. 2000, 87, 5457.
[4] H. Cao, Z. Xu, H. Sang, D. Sheng, C. Tie, Adv. Mater. 2001, 13, 121.
[5] S. Sun, C. B. Murray, J. Appl. Phys. 1999, 85, 4325.
[6] V. F. Puntes, K. M. Krishnan, A. P. Alivisatos, Appl. Phys. Lett. 2001,
78, 2187.
[7] S. Sun, C. B. Murray, D. Weller, L. Folks, A. Moser, Science 2000, 287,
1989.
Our synthesis of aryl palladium malonates is summarized in
Scheme 1. Addition of dimethyl malonate or diethyl phenyl-
malonate to the basic PPh3-ligated palladium hydroxide
dimers 1a[21,22] and 1b generated the O,O’-bound palladium
dimethyl malonate complexes 2a c. Complexes 2a and 2c
were characterized by X-ray diffraction (Figure 1). No
unusual angles at the palladium center were found in 2a or
[8] J. Legrand, A. T. Ngo, C. Petit, M. P. Pileni, Adv. Mater. 2001, 13, 58.
[9] L. S. Li, J. Hu, W. Yang, A. P. Alivisatos, Nano Lett. 2001, 1, 349.
[10] V. F. Puntes, K. M. Krishnan, A. P. Alivisatos, Science 2001, 291, 2115.
[11] J. Park-Sang, K. Seungsoo, S. Lee, Z. G. Khim, K. Char, T. Hyeon, J.
Am. Chem. Soc. 2000, 122, 8581.
[12] T. Ould Ely, C. Amiens, B. Chaudret, E. Snoeck, M. Verelst, M.
Respaud, J. M. Broto, Chem. Mater. 1999, 11, 526.
[13] M. Verelst, T. Ould Ely, C. Amiens, E. Snoeck, P. Lecante, A. Mosset,
M. Respaud, J. M. Broto, B. Chaudret, Chem. Mater. 1999, 11, 2702.
[14] M. Respaud, J. M. Broto, H. Rakoto, A. R. Fert, L. Thomas, B.
Barbara, M. Verelst, E. Snoeck, P. Lecante, A. Mosset, J. Osuna, T.
Ould Ely, C. Amiens, B. Chaudret, Phys. Rev. B 1998, 57, 2925.
[15] C. Pan, K. Pelzer, K. Philippot, B. Chaudret, F. Dassenoy, P. Lecante,
M. J. Casanove, J. Am. Chem. Soc. 2001, 123, 7584.
Scheme 1. Synthesis of aryl palladium malonates.
[16] K. Soulantica, A. Maisonnat, F. Senocq, M. C. Fromen, M. J.
Casanove, B. Chaudret, Angew. Chem. 2001, 113, 3071; Angew. Chem.
Int. Ed. 2001, 40, 2983.
[17] N. Cordente, M. Respaud, F. Senocq, M. J. Casanove, C. Amiens, B.
Chaudret, Nano Lett. 2001, 1, 565.
[18] S. Otsuka, M. Rossi, J. Chem. Soc. A 1968, 2630.
[19] Z. A. Peng, X. Peng, J. Am. Chem. Soc. 2001, 123, 1389.
[20] J. S. Bradley, B. Tesche, W. Busser, M. Maase, M. Reetz, J. Am. Chem.
Soc. 2000, 122, 4631.
[*] Prof. J. F. Hartwig, J. P. Wolkowski
Department of Chemistry
Yale University
P.O. Box 208107, New Haven, CT 06520-8107 (USA)
Fax : (þ 1)203-432-3917
E-mail: john.hartwig@yale.edu
[**] We thank the National Institutes of Health for support of this work
(GM-58108) and Johnson-Matthey for a gift of palladium salts.
[21] Z. Tang, N. A. Kotov, M. Giersig, Science 2002, 297, 237.
[22] Z. A. Peng, X. Peng, J. Am. Chem. Soc. 2002, 124, 3343.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 22
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To generate complexes that could be in-
duced to undergo reductive elimination be-
cause of increased steric hindrance, we pre-
pared complexes ligated by di-tert-butylphos-
phanylferrocene (FcPtBu2) (4)[23] (Scheme 1).
Metathetical exchange between the anion of
dimethyl malonate and the halide of dimeric
aryl palladium bromide complexes 5 ligated by
4 occurred readily to form the desired palla-
dium malonate complexes 6a and 6b in high
yield. Reaction with the sodium anion of
diethyl-2-phenylmalonate occurred similarly.
Complexes 6a c were isolated and fully
characterized by spectroscopic and microana-
lytical methods, and the diethyl malonate
complex 6b was characterized by X-ray dif-
fraction (Figure 1). Complex 6b displays the same h2-O,O-
coordination mode as 2a and 2c, but the geometry is
Figure 1. ORTEP plot of 2a (left) and 6b (right).
ꢀ
2c. The Pd O bonds located trans to the phenyl ligand in 2a
and 2c are longer than those trans to the phosphane
(2.113(2) ä vs. 2.088(2) ä for 2a; 2.097(2) ä vs. 2.070(2) ä
ꢀ
distorted. The Pd O distances are much longer than those
ꢀ
ꢀ
for 2c). The Pd O distances in 2c are shorter than those in 2a,
of 2a and 2c. For example, the Pd O bond trans to the aryl
but addition of diethyl phenylmalonate to 2a or visa versa
indicated an equilibrium constant for the exchange that is
close to unity and, therefore, equivalent thermodynamic
stabilities for the two malonate complexes.
group (2.189(3) ä) is nearly 0.1 ä longer than that in complex
2c. Moreover, the P1-Pd1-O2 angle is larger (100.4(1)8), and
the O1-Pd1-C1 is smaller (82.6(2)8) than the ideal 908. These
ꢀ
distorted angles and long metal ligand bond distances
Coordination of two phosphorus donors generated C-
bound isomers. For example, addition of 1,2-bis(diphenyl-
phosphanyl)ethane (dppe) to 2a generated the C-bound
palladium dimethyl malonate 3 (Scheme 1). However, addi-
tion of excess PPh3 to 2a did not generate a stable
diphosphane complex. Instead, exchange of free and coordi-
nated phosphane occurred on the NMR timescale. A single
broad 31P NMR resonance was observed for the free and
presumably arise from the steric demands of the hindered
phosphane.
Warming of malonate complexes 6a and 6b to 60 1058C in
the presence of 4 to trap the Pd0 product formed dimethyl and
diethyl o-tolylmalonate in 86% and 91% yield, respectively
(by 1H NMR spectroscopy with an internal standard,
Scheme 2). Heating of the phenylmalonate complex 6c
formed the diarylmalonate from reductive elimination in less
than 10% yield. This difference in reactivity between 6a,b and
6c is consistent with the high selectivity for monoarylation
observed from the palladium-catalyzed reaction of aryl
halides with malonates.[7]
Heating of the PPh3-ligated 2a at 808C in the presence of 3
15 equivalents of the bulky ligand 4 also led to reductive
elimination of arylmalonate in 75 90% yield. This reaction
was nearly complete after 45 min when conducted with
15 equivalents of added 4. In contrast, it occurred to about
50% conversion after this time when 3 equivalents of 4 were
added. The same reaction required roughly 12 h for comple-
tion at 1108C and formed only 65% yield of arylmalonate
when conducted in the presence of 3 equivalents of 4 and
1 equivalent of PPh3. dppe-ligated 3 did not form arylmalo-
nate when heated in the presence of added 4. Thus, reductive
elimination from 2a most likely occurs after exchange of 4 for
PPh3, and the increased steric hindrance of the FcPtBu2 ligand
triggers the reductive elimination. Most important, this steric
hindrance dominates the electronic and structural properties
of the malonate anion that are unfavorable for reductive
elimination.
1
coordinated PPh3, and the same H NMR resonance for the
central malonate proton was observed in the presence and
absence of added PPh3.
Heating of 2a or 2b for 48 h at 1108C in THF or C6D6 in the
presence of added PPh3 to trap the Pd0 product fully
converted the starting complex into a PPh3-ligated Pd0
species, but arylmalonate was formed in only 20% yield
(Scheme 2) from 2a and in < 5% yield from 2b. Biaryls
from the phosphane and palladium-bound aryl group,
along with free malonate (25%), were the major organic
products formed. Heating of 3 for 15 h at 708C fully converted
it to PPh3- and dppe-ligated Pd0 complex, but free dimethyl
malonate, toluene, and products from self-condensation
of dimethyl malonate were the major organic products.
In contrast to the slow and low-yielding reductive elimina-
tion from these complexes, aryl palladium methyl com-
plexes undergo facile reductive elimination.[21,22] Thus,
the electron-withdrawing property of the two carbonyl groups
dramatically increases the barrier for reductive elimina-
tion.
Aryl palladium acetylacetonate complex 7 ligated by
phosphane 4 was prepared by addition of the sodium salt of
2,4-pentanedione to aryl palladium halide 5. Complex 7 was
much more stable than the malonate complexes. Complete
consumption of 7 in the presence of ligand 4 required 36 h at
1408C, instead of the similar times at 1108C for the analogous
Scheme 2. Reductive elimination of malonates.
4290
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malonate complex 6b. Complex 7 did form the corresponding
2-aryl 1,3-diketone during this thermolysis, but in only 22%
yield.
A Five-Component Synthesis of
Hexasubstituted Benzene**
One would expect that rearrangement of the h2-O,O-bound
complexes to their C-bound tautomers would precede reduc-
tive elimination. Indeed, complexes of 1,3-dicarbonyl anions
that we could not observe as a C-bound isomer did not
undergo reductive elimination in high yield. For example,
arylmalonate anions 2c and 6c, and acetylacetonate 7
produced Pd0 complexes and free malonate or acetylacetone
upon addition of the chelating ligands dppe, dppbz ¼ 1,2-
bis(diphenylphospnanyl)benzene (dppbz), 2,2’-bis(diphenyl-
phosphanyl)-1,1’-binaphthyl (binap), and 1,1’-bis(diphenyl-
phosphanyl)ferrocene (dppf). No complex of a C-bound
anion was detected.
Pierre Janvier, Hugues Bienaymÿ, and Jieping Zhu*
Bis(indolyl)maleimides and indolo[2,3-a]carbazole alka-
loids constitute a rapidly growing family of natural products
with diverse biological activities.[1] Thus, rebeccamycin (1)[2]
and staurosporine (2)[3] are potent topoisomerase I and
MeO
OH
HO
H
O
O
N
N
HN
HO
HN
O
NHMe
OMe
N
In summary, the greater steric hindrance of FcPtBu2 (4),
relative to that of phenylphosphanes, induces reductive
elimination from complexes of typically unreactive ligands
derived from malonate and actylacetonate anions. This steric
effect overrides the stabilizing effect of the h2-O,O-coordina-
tion mode and the electron-withdrawing groups on the central
carbon atom of the malonate anion. Studies on the mechanism
of these new reductive eliminations and the synthesis of
complexes with related stabilized anions are in progress.
O
Me
NH
O
1
2
protein kinase C inhibitors, respectively. Structurally, this
class of compounds is characterized by an hexasubstituted
benzene ring with a fused indolo (forming an indolocarbazole
entity) and a fused lactam or an imide ring with a pendant
sugar moiety. The novelty of the structures combined with
their interesting biological profile have stimulated numerous
synthetic efforts from both academic and industrial research-
ers.[4]
Received: July 22, 2002 [Z19785]
[1] S. Kawaguchi, Coord. Chem. Rev. 1986, 70, 51.
[2] F. A. Cotton, G. Wilkinson, Advanced Inorganic Chemistry, 5th ed.,
Wiley, New York, 1988.
Transition-metal-mediated cyclization of appropriately
functionalized enynes[5] and Diels Alder cycloaddition of
furan[6] are two main strategies used for the synthesis of
hexasubstituted benzenes.[7] Although high level of structural
complexity can be generated from these two key transforma-
tions, the overall efficiency is often counter-balanced by
efforts associated with the synthesis of linear precursors. In
connection with our continued interest in the development of
highly efficient synthesis of druglike polyheterocycles,[8] we
report herein a conceptually new strategy for the synthesis of
hexasubstituted benzenes 3 based on a novel one-pot five-
component domino process.[9,10]
[3] D. F. Shriver, P. W. Atkins, Inorganic Chemistry, 3rd ed., Freeman,
New York, 1999.
[4] J. Tsuji, Acc. Chem. Res. 1969, 2, 144.
[5] B. M. Trost, Tetrahedron 1977, 33, 2615.
[6] A. Pfaltz, M. Lautens, Allylic substitution reactions in Comprehensive
Asymmetric Catalysis I III, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Berlin, 1999, pp. 833 884.
[7] N. A. Beare, J. F. Hartwig, J. Org. Chem. 2002, 67, 541.
[8] M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 1473.
[9] J. M. Fox, X. Huang, A. Chieffi, S. L. Buchwald, J. Am. Chem. Soc.
2000, 122, 1360.
[10] L. Djakovitch, K. Kohler, J. Organomet. Chem. 2000, 606, 101.
[11] M. A. Aramendia, V. Borau, C. Jimenez, J. M. Marinas, J. R. Ruiz, F. J.
Urbano, Tetrahedron Lett. 2002, 43, 2847.
The underlying principle of our synthesis is shown in
Scheme 1. A recently developed three-component reaction
based on Ugi chemistry pioneered by Ugi and co-workers[9]
provides the 5-aminooxazole 7,[11] Reaction of the latter with
acyl chloride 8 (X ¼ Cl) should give 5,6-dihydrofuro[2,3-c]-
pyrrol-4-one 10 following a sequence of acylation, intra-
molecular Diels Alder cycloaddition and retro-Diels Alder
cycloreversion.[12] Addition of a second dienophile 11 to the
reaction mixture should initiate an intermolecular Diels
Alder reaction of furan[6,7e] to give, after directed fragmenta-
[12] K. Hiraki, M. Onishi, H. Matsuo, J. Organomet. Chem. 1980, 185, 111.
[13] P. J. Chung, H. Suzuki, Y. Moro-oka, T. Ikawa, Chem. Lett. 1980, 63.
[14] G. R. Newkome, T. Kawato, D. K. Kohli, W. E. Puckett, B. D. Olivier,
G. Chiari, F. R. Fronczek, W. A. Deutsch, J. Am. Chem. Soc. 1981, 103,
3423.
[15] B. F. Straub, F. Rominger, P. Hofmann, Inorg. Chem. Commun. 2000,
3, 358.
[16] J. Ruiz, V. Rodriguez, N. Cutillas, M. Pardo, J. Perez, G. Lopez, P.
Chaloner, P. B. Hitchcock, Organometallics 2001, 20, 1973.
[17] G. R. Newkome, V. K. Gupta, Inorg. Chim. Acta 1982, 65, L165.
[18] G. R. Newkome, V. K. Gupta, H. C. R. Taylor, F. R. Fronczek,
Organometallics 1984, 3, 1549.
[19] T. Kawato, T. Uechi, H. Koyama, H. Kanatomi, Y. Kawanami, Inorg.
Chem. 1984, 23, 764.
[*] Dr. J. Zhu, P. Janvier
[20] H. Kurosawa, K. Ishii, Y. Kawasaki, S. Murai, Organometallics 1989, 8,
1756.
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-
Yvette (France)
[21] V. V. Grushin, H. Alper, Organometallics 1993, 12, 1890.
[22] M. S. Driver, J. F. Hartwig, Organometallics 1997, 16, 5706.
[23] G. Mann, C. Incarvito, A. L. Rheingold, J. F. Hartwig, J. Am. Chem.
Soc. 1999, 121, 3224.
Fax : (þ 33)1-69077247
E-mail: zhu@icsn.cnrs-gif.fr
Dr. H. Bienaymÿ
Chrysalon, 11 Avenue Albert Einstein, 69100 Villeurbanne (France)
[**] Financial support from the CNRS and a doctoral fellowship from
Rhodia (PJ) is gratefully acknowledged.
Angew. Chem. Int. Ed. 2002, 41, No. 22
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4291