Novel polymeric carbonylhaloruthenium(I) polyanions: Rational design and self-reorganization in the presence of CO2 and H2O

Article abstract of DOI:10.1002/(SICI)1521-3773(19991216)38:24<3707::AID-ANIE3707>3.0.CO;2-E

We just need to mix [Ru(CO)₃Cl₂(thf)] with methanolic NEt₄OH - nature will do the rest: The unsaturated fragments thus generated spontaneously polymerize with production of CO₂ and H₂O, which combine

Full text of DOI:10.1002/(SICI)1521-3773(19991216)38:24<3707::AID-ANIE3707>3.0.CO;2-E

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unstable ªacidº[4] hydrido intermediate. Though elusive, the
latter is prone to insertion reactions in the presence of olefins
or alkynes.[1, 5, 6] Upon simply replacing KOH by [NEt4][OH]
with the aim to obtain highly concentrated solutions of the
hydroxy-carbonyl adduct for a 13C NMR investigation, we
were surprised to observe that CO2 evolution was becoming
significant at room temperature, and occurred at rates
apparently depending both on the nature of the counterion
and the concentration.
[3] P. Welzel in Antibiotics and Antiviral CompoundsÐChemical Syn-
thesis and Modifications (Eds.: K. Krohn, H. Kirst, H. Maas), VCH,
Weinheim, 1993, pp. 373 ± 378, and references therein.
[4] N. El-Abadla, M. Lampilas, L. Hennig, M. Findeisen, P. Welzel, D.
Müller, A. Markus, J. van Heijenoort, Tetrahedron 1999, 55, 699 ± 722.
[5] O. Ritzeler, L. Hennig, M. Findeisen, P. Welzel, D. Müller, A. Markus,
G. Lemoine, M. Lampilas, J. van Heijenoort, Tetrahedron 1997, 53,
1675 ± 1694.
[6] S. Marzian, M. Happel, U. Wagner, D. Müller, P. Welzel, H.-W.
Fehlhaber, A. Stärk, H.-J. Schütz, A. Markus, M. Limbert, Y.
van Heijenoort, J. van Heijenoort, Tetrahedron 1994, 50, 5299 ± 5308.
[7] U. Kempin, L. Hennig, P. Welzel, S. Marzian, D. Müller, H.-W.
Fehlhaber, A. Markus, Y. van Heijenoort, J. van Heijenoort, Tetrahe-
dron 1995, 51, 8471 ± 8482, and references therein.
[8] H. Heerklotz, A. Donnerstag, G. Klose, P. Welzel, A. Markus, A. Giel,
unpublished results.
[9] U. Kempin, L. Hennig, D. Müller, A. Markus, P. Welzel, Tetrahedron
Lett. 1996, 37, 5087 ± 5090; U. Kempin, L. Hennig, D. Knoll, P. Welzel,
D. Müller, A. Markus, J. van Heijenoort, Tetrahedron 1997, 53,
17669 ± 17690.
[10] 8 was prepared by the following route: a) reaction of 7-diethylamino-
4-methyl-coumarin with the diazonium salt obtained from N-(4-
aminophenyl)-acetamide, b) hydrolysis of the amide, c) reaction with
thiophosgene.
[11] See: J. R. Silvius, R. Leventis, P. M. Brown, M. Zuckermann,
Biochemistry 1987, 26, 4279 ± 4287.
[12] G. Lantzsch, H. Binder, H. Heerklotz, P. Welzel, G. Klose, Langmuir
1998, 14, 4095 ± 4104.
[13] J. Silvius, R. Leventis, Biochemistry 1993, 32, 13318 ± 13326.
Typically, when one equivalent of a concentrated metha-
nolic solution of [NEt4][OH] (1 mL, 1.5m) was added to a
solid sample of 1 (500 mg, 1.5 mmol) at 258C, rapid dissolu-
tion of the complex was observed within seconds along with
1
gas evolution (strong n(CO2) IR absorption at 2338 cm ) and
development of an intense red color. This was rapidly
followed by nearly quantitative precipitation of a red-orange
microcrystalline product. High-quality homogeneous single
crystals of this product were obtained from slightly modified
experiments where 1 was dissolved in a minimum amount of
ethanol or methanol (1 ± 2 mL) prior to the addition of the
hydroxide. This complex, recovered in 90 ± 95% yield, was
formulated as 2 (Scheme 2) on the basis of an X-ray structure
analysis revealing its polymeric nature (Figure 1).[7]
Novel Polymeric Carbonylhaloruthenium(i)
Polyanions: Rational Design and Self-
Reorganization in the Presence of CO2 and
H2O**
Luc Maurette, Bruno Donnadieu, and Guy Lavigne*
Â
Dedicated to Professor Rene Poilblanc
on the occasion of his 65th birthday
We recently reported that RuII is readily reduced to Ru0 by
simple treatment of [Ru(CO)3Cl2(thf)] (1) with KOH fol-
lowed by thermally induced decarboxylation of the incipient
hydroxy-carbonyl adduct at 858C under CO (1 atm) to
produce [Ru3(CO)12] (Scheme 1).[1] The reaction is under-
stood in terms of a reductive elimination of HCl[2, 3] from an
Scheme 2. Synthesis of the polymeric polyanion 2. The square represents a
vacant coordiation site.
The structure of 2 is based on the discrete association of
identical monoanionic dimeric units. The basic motive is a
face-sharing bioctahedron in which two ruthenium centers are
connected through two bridging halides and one bridging
carbonyl group. Each ruthenium atom bears two terminal
carbonyl groups in a fac arrangement with the bridging one.
The third halide (trans to the bridging CO) serves as a
symmetric bridge between neighboring units of the polymeric
chain. Though the metal ± metal separation within the dimer is
2.964(1) Š, an electron count reveals that, formally, there is
no metal ± metal bond.
O
C
HO
O
C
C
O
O
KOH, 25°C
CO, 85°C
C
Cl
Cl
Cl
Cl
Ru
Ru
[Ru3(CO)12
]
C
C
O
O
– CO2, – HCl
thf
1
Scheme 1. Reaction of 1 with KOH.
Complex 2 appears to be the first representative of the
family of binary halo-carbonyl RuI species. Indeed, the
relevant edge double-bridged RuI prototype [Ru2X2(CO)6]
recently identified by Fachinetti, Funaioli et al.[8] for X ˆ tri-
fluoroacetate, is still unknown for X ˆ halide,[9] though a
number of phosphane-substituted derivatives have been
prepared from other precursors.[10, 11]
[*] Dr. G. Lavigne, Dipl.-Chem. L. Maurette, Dr. B. Donnadieu
Laboratoire de Chimie de Coordination du CNRS
205 route de Narbonne, F-31077 Toulouse, Cedex 4 (France)
Fax: (‡33)5-61-55-30-03
E-mail: lavigne@lcc-toulouse.fr
[**] We thank Dr NoeÈl Lugan, Prof. Giuseppe Fachinetti, and Dr Tiziana
Funaioli for helpful discussions. This work was supported by the
CNRS.
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On several occasions, beautiful yellow crystals of a minor
1
species exhibiting an IR absorption at 1532 cm
were
obtained from the filtrate of the reaction in Equation (1)
after a few days. Their electrospray mass spectrum revealed a
puzzling pattern, consisting of three multiplets at high m/z,
namely, 1816.3, 1757.4, and 1651.1. A single-crystal X-ray
analysis provided the clue to this phenomenon (see the
Experimental Section) and allowed unambiguous formulation
of the compound as the tetraanionic cluster 3 containing
carbonate ligands (Scheme 4, Figure 2).[7b, 13]
[NEt4]Na2[Ru8(m-CO3)4(m-Cl)4(CO)16]
3
Cl
O
(OC)2Ru
Ru(CO)2
Ru(CO)2
(OC)2Ru
O
O
O
O
O
Cl
Cl
O
O
O
O
O
(OC)2Ru
Ru(CO)2
O
Cl
(OC)2Ru
Ru(CO)2
Figure 1. Perspective view of two consecutive units of the polymeric
polyanion 2. Selected interatomic distances [Š] and angles [8]: Ru1 Ru1*
2.964(1), Ru1 C1 1.842(6), Ru1 C2 1.838(6), Ru1 C3 2.031(6), Ru1 Cl1
2.499(2), Ru1 Cl2 2.489(2), Ru1 Cl3 2.614(2); Ru1-Cl3-Ru1* 113.24(8),
Cl1-Ru1-Cl2 84.81(6), Cl1-Ru1-Cl3 88.64(6), Cl2-Ru1-Cl3 87.30(4), C1-
Ru1-C2 87.9(2), C1-Ru1-C3 93.5(3), C2-Ru1-C3 90.7(2).
Scheme 4. The tetraanionic unit of the carbonato cluster 3.
Why do we get RuI here? Indeed, reductive elimination of
HCl from a RuI precursor should normally give Ru0, as
previously observed[1] when the decarboxylation of K[Ru-
{C(O)OH}Cl2(CO)2] is thermally induced under CO atmos-
phere (Scheme 1). We propose that both the high concen-
tration and the absence of a strongly coordinating solvent
favor intermolecular association of the incipient unsaturated
mononuclear hydroxy-carbonyl adduct as a dimer involving
either bridging hydroxy-carbonyl groups[12] or bridging halides
(Scheme 3).
2–
O
C
HO
O
C
Cl
HO
C
C
O
O
C
O
Cl
Cl
Cl
Ru
Ru
Cl
Ru
C
O
Cl
C
O
C
OH
O
C
O
Figure 2. Perspective view of one of the two identical independent
tetraanionic units of the carbonato cluster complex 3. Selected interatomic
distances [Š]: Ru1 Ru2 2.648(1), Ru3 Ru4 2.645(1), Ru5 Ru6 2.637(1),
Ru7 Ru8 2.639(1), Ru1 O1 2.138(5), Ru8 O1 2.130(5), Ru1 Cl1
2.552(2), Ru8 Cl1 2.526(2), Ru1 O2A 2.108(5), Ru8 O4B 2.120(5),
C1 O1 1.32(1), C1 O1A 1.26(1), C1 O1B 1.262(9), Ru1 C11 1.811(8),
Ru1 C12 1.804(9), C11 O11 1.16(1), C12 O12 1.16(1).
1
–CO2
2–
O
C
O
O
C
O
Cl
HO
C
C
C
O
O
O
–H2O
–Cl–
Cl
C
C
O
C
C
Ru
Ru
Ru
Cl
Ru
H
Cl
Cl
Cl
O
Cl
C
O
The tetraanionic ensemble is based on the fusion of four
identical metal ± metal-bonded dimeric units ªRu2(CO)4º
assembled together into a ring by four bridging halides and
four bridging carbonate moieties. The carbonate groups are
the principal building blocks responsible for the observed
annulation: Each one holds two consecutive Ru dimers by
acting 1) as a bridging ligand connecting these dimers through
a m2-oxygen atom spanning the same open Ru ´´´ Ru edge as
the m-halide, and 2) as a doubly chelating ligand supporting
the two Ru Ru-bonded edges. Though carbonate ligands are
rarely seen in ruthenium carbonyl complexes, there is some
precedent with other metals.[14] A close examination of the
2
Scheme 3. Proposed mechanism for the formation of 2.
At room temperature, the molecule loses only one CO2 per
dimeric unit to form a transient bimetallic hydrido-hydroxy-
carbonyl complex. Intramolecular neutralization between the
ªacidº hydride and the OH of the remaining hydroxy-
carbonyl group will lead directly to the unsaturated building
block of the polymer [Eq. (1)].
2n[Ru(CO)3Cl2(thf)] ‡ 2nNEt4OH
!
(1)
{[NEt4][Ru2(CO)5Cl3]}n ‡ nCO2 ‡ nH2O ‡ nNEt4Cl
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packing[7b] reveals that the sodium cations are located on both
sides of the crown, along its virtual fourfold symmetry axis,
and in close contact with the carbonate oxygen atoms.
Let us confess that the source of sodium ions in the original
preparation giving the first crystals of 3 was incidental: We
believe they came from our glassware which had been cleaned
by immersion into an ethanolic NaOH bath and might have
been insufficiently rinsed. It is amazing that such traces of
sodium ions were selectively removed from the solution by
the multiply charged anion just acting as a crown ether.
Of course, the carbonate ligand originates from the reaction
products, namely, CO2 and H2O. Evidence for this dual origin
could be obtained by simple modifications of the experimen-
tal conditions: First, when the released CO2 was evacuated
under reduced pressure, the minor product obtained in
addition to 2 was no longer 3, but the known oxo species 4
(Scheme 5),[15, 16] the oxygen atom of which comes from the
water released in the reaction [see Eq. (1)]. The oxo
compound even became the major product when more water
was added. Second, we found that improved yields of 3 can be
obtained when the reaction is carried out in the presence of
NaHCO3 (see the Experimental Section).
philes, demonstrate the ability of halides or pseudohalides to
mediate an interplay between low oxidation states of ruthe-
nium, with possible relevance for their role as promoters in
many catalytic systems.[6, 18]
We have recently observed that treatment of 1 with
[NEt4][OH] at 258C in the presence of various unsaturated
incoming substrates (e.g., olefins, alkynes, formate esters)
does not yield the polymer 2, but new trappable adducts
between these substrates and the unsaturated fragments thus
generated.
Experimental Section
2: A solid sample of 1[1] (500 mg, 1.5 mmol) was dissolved in ethanol (ca. 1 ±
2 mL) and stirred in a small Schlenk flask under nitrogen. A 1.5m solution
of NEt4OH in methanol (1 mL) was added dropwise. Magnetic stirring was
stopped after 2 min. Homogeneous large crystals of 2 suitable for X-ray
diffraction were obtained within 2 h. The mother liquor was then
cannulated into another tube and kept separately. Slower crystallization
of the minor product 3 was then observed after a few days; a direct
synthesis of 3 was also devised (see below). Crystals of 2 were washed with
dichloromethane and alcohol, and isolated (420 mg, 95% yield). IR (KBr
pellets from single crystals): nÄ ˆ 2052(s), 2043(s), 2021(s), 1984(s), 1962(s),
1
1944(sh), 1928(sh), 1728(s), 1723(s) cm (n(CO)). The crystals are only
soluble in CH3CN, which, however, causes disruption of the polymer as
indicated by 1) the disappearance of the absorption for the bridging CO
group (IR (CH3CN): nÄ ˆ 2047(s), 2021(s), 1982(s), 1964(s) cm) and 2) the
detection of the ion [Ru2(CO)4Cl3] (m/z 422.6) in the electrospray mass
spectrum.
[NEt4]2[Ru4(m-O)(m-Cl)4(CO)10]
4
(CO)2
3: Complex 1 (500 mg, 1.5 mmol) and NaHCO3 (126 mg, 1.5 mmol) were
dissolved in ethanol (10 mL). After addition of a 1.5m solution of NEt4OH
in methanol (1 mL), the solution was heated at 858C for 5 min, during
which the orange color intensified. After addition of acetone (2 mL), the
solution was allowed to crystallize at room temperature.[13] Crystals of 3
suitable for X-ray diffraction appeared on the walls of the glassware over a
period of 5 d. They were isolated by filtration and washed with ethanol
(70 mg, 19% yield). IR (KBr pellets from single crystals): nÄ ˆ 2028(vs),
Ru
O
Cl
C
Cl
O
Ru(CO)2
C
(OC)2Ru
Cl
Ru
(CO)2
O
Cl
Scheme 5. The dianionic unit of the oxo cluster 4.
1
1953(m), 2021(s), 1948(s, br), 1910(m) (n(CO)), 1532(s) cm (n(OCO)).
13C{1H} NMR (100 MHz, CD3CN) d ˆ 204.8, 204.6 (CO), 169.5 (CO3), 52.5
Thus, the addition of [NEt4][OH] to 1 at 258C in concen-
trated solution appears to be a simple, rapid, and mild
procedure to generate unsaturated ruthenium carbonyl halide
fragments in a low oxidation state. Such fragments are prone
to either polymerization in the absence of donor ligand or
capturing any potentially coordinating molecule (including
those produced in situ, as observed here). Consequently, we
should be able to quench the polymerization process by any
incoming donor ligand.[17] Effectively, if we saturate the
solution and the atmosphere of the Schlenk flask with CO
prior to the addition of [NEt4][OH] to 1 at 258C, we do not
generate the polymer 2. Instead, a 1/1 mixture of [Ru3(CO)12]
and [NEt4][Ru(CO)3Cl3] is recovered after a few hours. A
glance at the basic unit of 2 allows an understanding of this
phenomenon: The relative oxidation states of the two metal
centers within the dimeric unit depend formally on how the
bridging halides share their three electrons. Thus, the RuI ±
RuI dimer can be alternatively viewed as a Ru0 ± RuII dimer in
which we can even visualize the preformed ligand environ-
ment of the RuII center, ª[Ru(CO)3Cl3] º. Disruption of the
chain by CO leads to a net differentiation between Ru0 and
RuII centers.
‡
‡
(N(CH2CH3)4 ), 14 (N(CH2CH3)4 ); ES-MS (CH3CN): m/z: 843
([Na2(Ru8(CO3)4Cl4(CO)16)]2 ), 1816 ([Na2(NEt4)(Ru8(CO3)4Cl4(CO)16)] ),
1758 ([Na(NEt4)(Ru8(CO3)4Cl3(CO)16)] ), 1651 ([Na2(Ru8(CO3)4Cl3-
(CO)16)] ).
Received: August 6, 1999 [Z13839IE]
German version: Angew. Chem. 1999, 111, 3919 ± 3922
Keywords: carbonyl complexes ´ cluster compounds ´ hal-
ogens ´ polyanions ´ ruthenium
[1] M. Faure, L. Maurette, B. Donnadieu, G. Lavigne, Angew. Chem.
1999, 111, 539 ± 542; Angew. Chem. Int. Ed. 1999, 38, 518 ± 522.
[2] V. V. Grushin, Acc. Chem. Res. 1993, 26, 279 ± 286.
[3] D. Huang, R. Folting, K. G. Caulton, Inorg. Chem. 1996, 35, 7035± 7040
[4] B. M. Trost, Chem. Eur. J. 1998, 4, 2405 ± 2412.
[5] G. Lavigne, Eur. J. Chem. 1999, 917 ± 930.
[6] For an example of a RuII hydride exhibiting parallel reactivity, see T.
Funaioli, C. Cavazza, F. Marchetti, G. Fachinetti, Inorg. Chem. 1999,
38, 3361 ± 3368.
[7] a) Crystallographic data for 2: orthorhombic, space group Cmca; a ˆ
11.721(2), b ˆ 19.580(2), c ˆ 17.686(2) Š; Vˆ 4058.9(9) Š3; R ˆ 0.026,
Rw ˆ 0.057. b) Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tions nos. CCDC-133106 (2) and 133107 (3). Copies of the data can be
obtained free of charge on application to CCDC, 12 Union road,
Cambridge, CB2 1EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@
ccdc.cam.ac.uk).
The present observation is reminiscent of the CO-induced
disproportionation of [Ru2X2(CO)6] (X ˆ CF3COO) in the
presence of an excess of X .[8] Our concordant findings,
probably generalizable to a range of other anionic nucleo-
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[8] G. Fachinetti, T. Funaioli, L. Lecci, F. Marchetti, Inorg. Chem. 1996,
35, 7217 ± 7224.
[9] To date, only the osmium analogue [Os2X2(CO)6] (X ˆ I) has been
reported: G. L. Geoffroy, S. Rosenberg, A. W. Herlinger, A. L.
Rheingold, Inorg. Chem. 1986, 25, 2916 ± 2919.
[10] a) R. Mason, K. M. Thomas, D. F. Gill, B. L. Shaw, J. Organomet.
Chem. 1972, 40, C67 ± C69; b) D. F. Jones, P. H. Dixneuf, A. Benoit,
J. Y. Le Marouille, Inorg. Chem. 1983, 22, 29 ± 33; c) J. S. Field, R. J.
Haines, C. N. Sampson, J. Sundermeyer, J. Organomet. Chem. 1986,
2/Neu-protooncogene (also called erbB-2). This receptor is
vastly overexpressed in about 30% of primary breast, ovary,
and gastric carcinomas.[1, 3, 4] Amplification is closely corre-
lated with the clinical behavior of these neoplasms, such that
tumors with Her-2 amplification are more agressive and
associated with reduced patient survival. Therefore, com-
pounds that can selectively block Her-2 activity are of
paramount importance for the development of new anti-
cancer drugs;[1, 2, 5] a monoclonal antibody against Her-2 has
already been introduced by Genentech into the clinic as a new
revolutionary treatment for breast cancer. In addition, such
drugs are likely to be useful in dissecting signalling path-
ways.[2, 6, 7] Until today only a few natural products with
intrinsic tyrosine kinase inhibiting activity per se were isolated
and, in particular, a natural product that inhibits Her-2 has not
been synthesized.[2, 6] Recently, however, the nakijiquinones
1a ± d (see Scheme 1) were identified as selective inhibitors of
the Her-2/Neu kinase, displaying pronounced cytotoxicity
against L 1210 murine leukemia cells and KB human
epidermoid carcinoma cells.[8] We now disclose the first
enantioselective total synthesis of the nakijiquinones.
The nakijiquinones embody three basic structural elements,
an amino acid, a central p-quinoid unit, and a diterpenoid
system. To reach a high degree of convergency, the nakijiqui-
nones were first, dissected in a retrosynthetic sense into
isospongiaquinone (2), an interesting natural product in its
own right[9] and an amino acid that can be introduced in the
last step by conjugate addition to the vinylogous methyl ester
present[8] (Scheme 1). It was further planned to generate the
selectively functionalized quinoid system by oxidation of a
tetramethoxy-substituted aromatic precursor 3 to a 1,4-
dicarbonyl compound and subsequent selective saponification
Â
310, C42 ± C46; d) A. Colombie, G. Lavigne, J.-J. Bonnet, J. Chem.
Soc. Dalton Trans. 1986, 899 ± 901.
[11] Review: R. J. Haines in Comprehensive Organometallic Chemistry II,
Vol. 7 (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon
Elsevier, Oxford, 1996, Chap. II, p. 625.
[12] A related methoxycarbonyl-bridged species is known: G. Süss-Fink, J.-
Â
M. Soulie, G. Rheinwald, H. Stoeckli-Evans, Y. Sazaki, Organo-
metallics 1996, 15, 3416 ± 3422.
[13] The first crystals of 3 were obtained from methanol/ethanol in a
systematically twinned crystalline form (orthorhombic, space group
Immm, a ˆ 14.919(1), b ˆ 20.006(2), c ˆ 22.279(3) Š). Acetone/etha-
nol mixtures gave single crystals of a different form, albeit containing
solvent molecules: [NEt4]2Na2[Ru8(m-CO3)4(m-Cl)4(CO)16] ´ 2EtOH ´
0.5(CH3)2CO ´ 1.5H2O: triclinic, space group P1, a ˆ 16.405(3), b ˆ
19.109(4), c ˆ 23.073(8) Š; a ˆ 85.26(3), b ˆ 85.64(3), g ˆ 72.97(2);
Vˆ 6882(3) Š3; R ˆ 0.035, Rw ˆ 0.079 (refinement on F 2).[7b]
[14] a) P. Süsse, Acta Crystallogr. 1967, 22, 146 ± 149; b) M.-C. Suen, G.-W.
Tseng, J.-D. Chen, T.-C. Keng, J.-C. Wang, Chem. Commun. 1999,
1185± 1186; c) E. G. Lundquist, K. Foltig, J. C. Huffman, K. G. Caulton,
Inorg. Chem. 1987, 26, 205 ± 208.
‡
[15] For the [(Ph3P)2N] (PPN) salt of 4 (obtained by different routes), see:
Â
a) G. Lavigne, N. Lugan, P. Kalck, J.-M. Soulie, O. Lerouge, J.-Y.
Saillard, J.-F. Halet, J. Am. Chem. Soc. 1992, 114, 10669 ± 10670; b) N.
Â
Lugan, G. Lavigne, J.-M. Soulie, P. Kalck, J.-Y. Saillard, J.-F. Halet,
Organometallics 1995, 14, 1713 ± 1731.
[16] Crystal data for the tetraethylammonium salt of 4: monoclinic, space
group C2/c; a ˆ 23.862(2), b ˆ 24.107(2), c ˆ 19.045(2) Š; b ˆ
128.2(1)8; Z ˆ 8.
[17] The soluble anionic building block of the polymer 2 can be generated
and kept in acetonitrile as a ªlightly stabilizedº species that is still
incompletely formulated.
[18] T. Naota, H. Takaya, S.-I. Murahashi, Chem. Rev. 1998, 98, 2599 ±
2660.
R
OMe
OH
HN
COOH
O
O
O
H
O
H
1
13OH
9
Asymmetric Synthesis of the NakijiquinonesÐ
Selective Inhibitors of the Her-2/Neu
Protooncogene**
8
3
4
1
2
1a: R = H: Nakijiquinone A
1b: R = iPr: Nakijiquinone B
Petra Stahl and Herbert Waldmann*
1c: R = CH2OH: Nakijiquinone C
1d: R = CH(CH3)OH: Nakijiquinone D
Extracellular growth-promoting signals are recognized in
many cases by transmembrane receptors with tyrosine kinase
activity. These proteins trigger numerous intracellular signal-
ling cascades by which cell growth, proliferation, and other
genetic programs are regulated.[1] Dysregulation of these
signal sequences may contribute to or cause many diseases.
For instance, enhanced activity of receptor tyrosine kinases
can promote tumor growth and has been implicated in
carcinogenesis.[2] A particularly relevant example is the Her-
OMe
MeO
OMe
OMe
MeO
OMe
Hal
OMe
OMe
H
5
+
O
O
[*] Prof. H. Waldmann, Dipl.-Chem. P. Stahl
Max-Planck-Institut für molekulare Physiologie
Otto-Hahn-Strasse 11, D-44227 Dortmund (Germany)
Fax: (‡49)231-133-2499
3
O
O
4
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
[**] This research was supported by the Fonds der Chemischen Industrie.
Scheme 1. Retrosynthetic analysis of the nakijiquinones 1.
3710
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3824-3710 $ 17.50+.50/0 Angew. Chem. Int. Ed. 1999, 38, No. 24