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Efficient Synthesis of New 2-Cycloalk(en)ylpropanoic Acid DerivativesЧMedium and Large Rings as Bioisosteres of Alkylphenyl Moieties.

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BNPP is reduced from approximately 75 years[’*] to as little as
8 min (with Eu:+ - 4 a t 50 “C and p H 7.0); that ofdouble-stranded DNA from approximately 2 0 0 0 y e a r ~to~ 50min
~ ~ ~ (with
Pr:’.4 at 37 ‘ C and pH 7.0).
Received: September 25, 1995
Revised version: December 29, 1995 [Z8424IE]
German version: Angel$. Chem. 1996. 108. 1314-1316
Keywords: DNA cleavage . hydrolyses . phosphorus compounds
supramolecular chemistry . lanthanide compounds
[ l ] R. Breslow. D -L. Hudng, PI-oc. N;fl. Acud Sci. U S A 1991,88, 4080.
[?I a) M. Komiyama. K. MatSdmUrd, Y. Matsumoto, J. Chem. Sor. Chem. Comnnm 1992, 640: b) M. Komiyama, N. Takeda, Y Takahashi. H. Uchida, T.
Shiiba. T. Kodama, M Yashiro, J. Chixm. Sue. Perkm Truns. 2 1995,269, and
references therein
[3] J. 1.Morrow. L A Buttrey. V. M. Shelton. K. A. Berback. J. Am C / ~ e mSoc.
1992. 114. 1903.
[4] D. Wahnon. R. C. Hynes, J. Chin, J. Chem. Soc. Chem. Commun. 1994, 1441.
[j] Lanthanides were used to catalyze the hydrolysis of phosphate esters decades
ago without recognition of their full potential. For a review see E. Bamann, H.
Trapman, A h , . En;ymol. Relul. Suhj Biochrm. 1959. 21, 169.
161 a ) H -J. Schneider. J. Rammo. R. Hettich. Angew Chem. 1993. 105. 1773;
A n p i ’ Chi,m. Inf. Ed. Engl. 1993.32.1716: b) J. Rammo, R. Hettich, A. Roigk,
H.-J. Schneider. J Cheni. Soc. Chem. Commun. 1996. 105-107.
[7] For a review on the use of binucledr metal complexes as catalysts for different
hydrolysis reactions see. M. W. Gobel, Angew. Chern. 1994, 106, 1201. Angew.
Chenr.I n f . Ed. E I I ~ I1994,
33, 1141
[8] W. H. Chapman. Jr.. R. Breslow, J. Am. Chem. Sue. 1995. 117, 5851.
[9] As the factor F‘chardcterizing the efficiency of a ligand we use the ratio kM2,/kM
for the reaction with the complex [M,L] and with the corresponding metal M
alone at the same concentration as with the ligand L.
[lo] 8. K. Takasaki. J Chin. J. Am. Chem. Soc.1995, 117, 8582.
[I I ] M Yashiro. A Ishikubo, M. Komiyama. J. Chem. Soc. Chem. Commun. 1995,
[12] A. Tsubouchi. T. C. Bruice. J. Am. Chem. Soc.1995, 117, 7399.
[13] E.A Kesicki. M. A. DeRosch, L. H. Freeman, C. L. Wdlton, D. F. Harvey.
W. C. Trogler, lnorg. Chim. 1993, 32, 5851
[14] a) D. Chen. A. E. Martell, Tefruhedron 1991.47,6895 for 1 and 3; b) R Menif.
A. E Martell. P. J. Squattrito, A. Clearfield. Inorg. Chem. 1990,29,4723 for 2 ;
c) R. Menif. D. Chen, A. E. Martell, [hid. 1989, 26, 4633 for 4
[lS] R. B King. R Heckley, J. An7. Chem. So?. 1974. 96, 3118.
1991. 24, 145.
[16] J. Chin. A<? < ‘ I r ~ ~ i r iRc~s.
[17] The rate constant observed for the 1 : 1 complex of ligand 4 and P r 3 + prepared
in buffer solution by equilibriating 1 mM 4 and 1 mM Pr3+ for 8 h at 25°C and
30 min at 50 C wds only 4.1 x lo-’ min-l, and that for the complex prepared
in methanol (dried over Mg(OMe),) by mlxing the ligdnd and the metal in 1 :1
ratio and warming the solution to 40’C to remove methanol was
9 1 x lo-’ min
The van? Hoff plot for the hydrolysis of BNPP by the complexes ofligdnd 4 and various amounts of Pr”, prepared directly in the buffer
solution. gave a slope of only 1.2. When the ligdnd 4 and Pr3’ in the ratio 2: 1
were warmed in anhydrous methanol, catalysis with the resulting complex was
even slower than with free Pr” alone. This could be due to formation of the
2: 1 sandwich complex. in which the metal is shielded against reaction with the
ester and/or u ater.
[I81 J. R. Morrou. L. A. Buttrey, V. M. Shelton, K. A. Berback, J. Am. Chem. Sor.
1992, 114. 1903.
1191 A. J. Kirby. M. Younas. J. Chem. Soc. B 1970, 510.
1201 JLL. Sagripanti. K. H. Kraemer, J. M u / . Biol. 1989, 264, 1729.
1211 .I.Eigner. H. Boedtker, G. Michaels. 5joch1m. Bioph.vs. Arm. 1961, Sl, 165.
[22j J. Chin. M Banaszczyk. V. Jubian. X. 20%J. Am. Chem. Soc. 1989, 111, 186.
Efficient Synthesis of New
2-Cycloalk(en)ylpropanoic Acid DerivativesMedium and Large Rings as Bioisosteres
of Alkylphenyl Moieties?**
Bjorn Greve, Peter Imming,* and Stefan Laufer
Dedicated to Professor Gunther Seitz
on the occasion of his 60th birthday
Ring systems with 9-12 (or 7-14) members are classed as
medium-sized rings. They occur less frequently and are more
difficult to prepare than five- and six-membered and large rings,
and their applicability is restricted.“] In an evaluation of two
standard encyclopedias of chemistry and pharmacyi2]we found
only 132 compounds with a n eight-, 23 with a nine-, 26 with a
ten-, 12 with an eleven-, 28 with a twelve-, and 6 with a thirteenmembered ring. Of these, 81 % are natural products and 73 %
are heterocycles. In medicinal chemistry particular 9- 12-membered lactams are of current interest as mimics of fi-turn~.[~I
this paper we introduce a new approach to the use of medium
and large ring systems.
Medium-sized carbocycles can be seen as lipophilic “clusters”
and should be bioisosteric to alkylphenyl moieties. In comparison to these they will bind more weakly to electrophilic protein
side chains, but because of their conformative flexibility
they should display better adaptation to binding domains of
protein^.'^] Medium-sized carbocycles also provide a far more
versatile framework than phenyl and “normal” rings (five- and
six-membered rings) for the regio- and stereodefined attachment
of substituents.
To test our concept we prepared compounds that are structurally derived from both arachidonic acid (1) (the physiological
substrate of cyclo- (COX) and lipoxygenases (LOX)) and inhibitors of these enzymes[51like 2-(alkylphenyl)propanoic acids
(for example ibuprofen (2)). In the active site of the enzyme[61
and in solution[71arachidonic acid adopts a bent conformation
as shown. A substrate with a medium-sized ring should at least
partly mimic the conformation of 1.
We have developed a synthetic route to 2-cycloalk(en)ylpropanoic acids of the general formula 3 (MR = medio-/macro-
[*] Priv.-Doz. Dr. P. Imming, DiplLChem. B. Greve
Institut fur Pharmazeutische Chemie der Universitdt
D-35032 Marburg (Germany)
Fax: h i . code +(6421)287052
e-mail . imming(a
Anges. Clremr. Int Ed Engl
1996, 35, No. 1I
Dr. S . Laufer
Merckle GmbH
Postfach 1161. D-89135 Blaubeuren (Germany)
This work was supported by the Fonds der Chemischen Industrie and the
Bundesministerium fur Forschung und Technologie. We thank Hiils AG
(Marl) and Firmenich S A . (Genf) for financial and material support.
8 V C H Verlu~sgesell.~chu~i
m h H . 0-69451
Weinhelm, 1996
OS70-0833/96~3Sl1-1221$ 1S.OOf . 3 ~ 0
cycle), which leads to the desired compounds in excellent overall
yield (Scheme 1). In the first step we treated cycloalkanones 4
with a modified Reformatsky reagent prepared from 5. (This
new type of reagent was developed several years ago.@')
Table 1. Pharmacological activities of some compounds with medium-sized rings in
comparison to known drugs [a].
in hi bi t ion
at 10 i l M
at 1 0 p M
< 10%
at 10 pM
not determined
45 Yo
at 10 p M
< 10%)
at 10 pM
48 9
at 1opM
< 10%
at 10pM
Scheme 1 Synthetic route to 2-cycloalk(enjylpropanoic acid derivatives with
I ) Zn, T H F : CuCN. LiCI; 01 - 5010'C 2) T H F ; -78 C t o room
temperature, 12 h 3)p-TsOH. toluene; reflux; 48 h. 4) K0H;MeOH: room temperature; 24 h. 5 ) H, (3 bar). 10% Pd,C; 55 C; 6 h.
n = 4-12, 14
Organozinc compounds, which had not been treated with medium-sized and larger cycloalkanones previously, were found to
have excellent reactivity towards these ketones. Analogous reactions with other organometallic reagents, including organocerium compounds (where one has to use the more expensive alkyl
iodides)[" were not as satisfactory.
The subsequent water elimination proceeded almost regioselectively in the case of the medium-sized rings, yielding the endocyclic, nonconjugated olefins 8. The introduction of two sp2
centers in the ring is energetically more favorable than conjugation with the ester group. Through this, our study proves the
applicability of H. C. Brown's I-strain (internal strain) concept,["] which had been supported theoretically by a force-field
analysis."0b1 After hydrolysis we isolated the pure ( E )esters 11,
and after the final hydrogenation the carboxylic acids 13.
Pharmacological tests" 'I showed interesting differences in activities depending on ring size. Table 1 summarizes the test results.
We did not measure significant activities up to a ring size of ten.
The derivatives of cycloundecane, cyclododecene, and cyclopentadecene (13a, llb, and l l c , respectively) inhibit COX-I with
about twice the activity of aspirin. In contrast to the cyclodododecene derivative 1 lb, the cycloundecene and cyclododecatriene
derivatives, l l a and 15, respectively, inhibit 5-LOX more effectively than COX-I. (In the synthesis of 15 from 14['21we obtained
mhH. 0-69451 Weinheim, I996
acetylsalicylic acid
nordihydrogudiaric acid
In vitro tests. IC,,, in p ~ .
the (E,E,E) isomer with loo%&.) The almost equal inhibition
of both enzymes by the saturated 11-membered and olefinic
15-membered rings 13a and l l c makes them promising candidates for the development of "dual action" antirheumatics, a
very recent research strategy for the reduction of the gastrointestinal side effects of these drugs.['3] According to present knowledge, a further simultaneous inhibition of COX-2 would be
advantageous though not sufficient for the suppression of the
symptoms.['41We thus regard our cyclopentadecene derivative
l l c to be a promising lead for the development of a mimic of
arachidonic acid with a (medium) large ring that will have the
desired activity profile.
We also prepared the derivatives 16 and 17, which have a
methylsulfonyl instead of a carboxyl function, in a similar
Fashion. The starting materials were dimethyl sulfone and cyclododeca(die)none. The methylsulfonyl group typical of COX-2
inhibitor^"^"] led in our case to a strong decrease in activity
towards 5-LOX and COX-1.
In summary, OUT work has shown for the first time that a
differentiated inhibition of enzymes is possible with medium
rings of various sizes and degrees of saturation. We propose that
unsaturated medium-sized and larger carbocycles are bioisos-
0570-OX33!96~3511-1222$15 OO+ .25)0
A n p r Clicwl Int.
Ed. Engl. 1996. 35. No. 11
teric to alkylphenyl moieties. This opens up extensive synthetic
possibilities and offers a new approach to the rational application of medium-sized and larger carbocycles beyond medicinal
Esprrinirntal Procedure
All neu compounds gave correct analyses or high-resolutaion mass spectra.
6 ( 1 1 = I I ) : To a suspension of 6.5 g (100 mmol) of zinc (activated with SiMe,CI and
dibromoethane) in 30 mL of anhydrous T H F was added dropwise 9.1 g (SO mmol)
o f 5 at 0 C The ice bath was removed. After excesszinc had settled, the supernatant
was transferred dropwise into a solution of CuCN-2LiCl (50 mmol) in 100 mL of
T H F at - 50 C. The mixture was warmed to 0 C, stirred for 30 min. and cooled to
- 78 C. Then X.2 g (45 mmol) o f 4 ( n = 11) was added The mixture was allowed to
warm to room temperature overnight and was worked up as described [8]to yield
12.6 g (98%) of a uhite solid. which was of sufficient purity for further transformations. 'H NMR (400 MHz, CDCI,): 6 = 4.10-4.04 (m, 2 H ) , 3.18 (s, 1 H). 2.372.32(m.2H). 1.62 1.53(m.2H). 1.34-1.10(m,24H): "C('Hi NMR(125 MHz,
CDCI,). d = I 7 8 3. 75 3. 61.0, 45.9. 35.0. 30.9. 27.0. 26.9, 26 6. 23.1, 23.0. 22.62.
22.56. 20.0. 19.6. 14.7. 12 3.
[ l l ] COX-1 tests were performed with thrombocyrec from Iic\li Iiuinm blood.
5-LOX tests with polymorphnuclear leukocytes from fresh human blood (K.
Stolingwa, S. Baur, Diploma Theses. Fachhochschule Isny. 1995).COX-? tests
with isolated recombinant enzyme (J. A. Mitchell. P. 4karasereenont. C.
Thiemermann, R. J Flower, J. R. Vane. P r u c Nut(. Ai.ud. Sci. U S A 1993. YO,
[12] G. Wilke (Studiengesellschaft Kohle mbH), DBP 1058987. 1959 [Chem. Ahrr
1961, 55. 114351: G. Wilke, P. W. Borner (Studiengesellscliaft Kohle mbH),
DBP 1075601, 1960 [Chent. Abstr. 1961, 55, 133401.
1131 S. Laufer. J. Augustin. G. Dannhardt. W. Kiefer. J Med. Clrivn 1994, 37, 1894,
and references therein.
[I41 a) D. J. Pinto, W. J. Pitts, R. A. Copeband. M. B. Covington. J Trzaskos, R.
Magolda. Mcd. Chrm. Res. 1995,5,394, and references therein: b) J. L. Masferrer. B. S. Zweifel. P T. Manning, S. D. Hauser. K. M. Leahy. W. G. Smith.
P. C. Isakson, K. Seibert. Pruc. Nuti Acud. Sci. U S A 1994, 91, 3228, and
references therein.
7.'8!9 (11 = 1 1 ) - A solution of 6 (17 = l l ) in toluene was heated to reflux with a
catalytic amount of 4-~oluenesulfonicacid for 48 h After vacuum distillation (104Torr) we obtained the isomeric olefins in 9 3 % yield. They were
106 C 1.8 x
purified by chromatography on silica gel eluting with pentane/diethyl ether (812). 8:
'HNMR(4O0MHz.CDCI3):b = 5.21 (t. J = 8 H z . lH).4.08-3.96(m,2H),2.98
(9. J = 7 Hz. I H ) . 2.13-1 91 (m. 4 H ) , 1.48-1.10 (m.22H); I3C('Hj N M R
Gregory S. Girolami,* Christopher L. Hein, and
( ~ ~ ~ M H L . C D C~=,1273.599,,26.3,,
Kenneth S. Suslick*
24.5. 24.2. 3 . 8 . 22.5. 22.1. 16.6. 13.9.
l l h (I? = I I ) . We obtained the compound in 74% yield after vacuum distillation
(I00 C'1.Xx 1K'Torr). bystirring18mmolofSin 18mLofmethanolwith30mL
The development of our understanding of the chemical and
of a 3 M methanol~cKOH solution for 24 h; m.p. 69-70-C (pentane). ' H NMR
physical properties of the photosynthetic reaction center (RC)
has been greatly assisted by studies of synthetic analogs. For
1 H ) . 2 I ? 1.91 (ii1.5H). 1.50-1.12(m,18H);i3C('H}NMR(125MHz,CDCI,):
example, remarkably long-lived charge-separated states have
d =lXl.X. 137.8. 128 1.43.9. 27.0. 26.7. 25.4, 24.93. 24.88. 24.87, 22.7.
16 7.
been observed in synthetic porphyrin-quinone tetrads and pen-
A Zirconium Bis(porphyrinate) Sandwich
Complex with an Appended Quinone**
13b (17 = 1 I ). A I M solution of l l h in ethyl acetate was hydrogenated for 6 h at 3 bar
and 55 C with 1O"h PdiC catalyst. We isolated a 9 4 % yield of a white solid. m.p.
46-48 C . ' H N M R (400MHz. CDCI,): 6=11.04 (s. 1 H ) . 2.45-2.28 (m. 1 H ) .
1 7 9 - 1.77 (m. 1 HI. 1 39-1 18 (m. 22H). 1.03 (d, J = 7 Hz. 3 H ) ; I3C('H: NMR
(lXMH~.CDCl,).i'j=1834.42.3,366.27 1.2S.,
22.3, 21.3. 13.4
Received: September 7. 1995
Revised version: March 1, 1996 [283741E]
German version: Angetv. Chrm. 1996. 108. 1312-1314
Keywords: cycloalkanones
medium-sized rings - zinc compounds
See for example M. Braun, Nuchr. Chen?. Tech. Lob. 1985. 33. 1066; B. Dietrich. P. Viout. J:M. Lehn. Macrocwlic Cumpounds Chemisrrj, VCH. Weinheim. 1993; E. L Eliel. S. H. Wilen. Stereochemotr? uf Organic Compounds.
Wiley. New York. 1994, p. 762ff.
a ) S. Budavari, The Merck 1nde.x Merck & Co.. Rahway. NJ, USA. 1989;
b) J. Falbe, M . Regitz. RBmpp Cliemie Lexikon, Thieme, Stuttgart. 19891992.
See for example a ) G. Holzemann, Konfaktr (Merck) 1991 (1). 3-12; ;hid.
1991 (2). 55-63. b) A Giannis. T. Kolter, Angew. Chem. 1993, 105. 1303;
Angor. Chenr. h i . Ed. Engi. 1993. 32, 1244: c) J. Gante. ibid 1994. 106, 1780
and 1994.33. 1699.
a ) Tt~rruhtv/ruii1993, 49, 3433ff. (Symposia-in-print No. 50); b) G. J. Moore,
Tr.rnd\ Phorniocoi Sci 1994, 15. 124.
For COX and LOX inhibitors see J. Vane, Nature 1994. 367, 215.
D. Picot. P. J. Loll. R. M. Garavito. Nuture 1994, 367. 243.
a ) P. Gund. T. Y. Shen. J. Med. Chenr. 1977.20. 1146; b) S. R. Wilson, W. Cui.
J. W. Moskobitz. K . E. Schmidt, Tetrahedron Lett. 1988, 29, 4373; c) A. R.
Leach. K. Prout. J. Cmrpcti. Chrin. 1990. I / . 1193.
P. Knochel. R. D Singer, Clirm. Rev 1993. 93, 2117, and references
Ce. T. lmamoto. K . Kusumoto, Y. Tawarayama. Y. Sugiura. T. Mita. Y.
Hatanaka. M Yokoyama. J Org. Chem. 1984, 49. 3904; Li/Mg (including a
discussion of contradictory reports): L. I. Zakharkin. I. M. Churilova, P. V
Petrovskii. RZI.\.S.
Chem. Bull. 1993,42,863; see also P. Ballester, A. Costa, A.
Garcia-Raso. R. Mestres, J. Cliem. Suc. Perkin Trans. 1 1989. 21
a ) H. C. Brown. M. Gerstein. J. Am. Cl7em. Sue. 1950, 72. 2926; b) H.-J.
Schneider. G. Schmidt. F. Thomas. ihid. 1980. 105. 3556, c) E. L. Eliel. S. H.
Wilen. Sieri,.ochcmi.slri. of Organic Compounds, Wiley. New York. 1994.
D. 7hYK
.4ngeu. C'hi~n~.
lni Ed EnKI. 1996. 35. No. I 1
tads, and the physiological significance of chromophore orientation and donor-acceptor energetics in reaction centers has
been addressed through studies of gable porphyrin dimers and
porphyrin -quinone complexes, respectively.['' The distinctive
structura1 feature of the RC, however, is the closeIy stacked
"special pair" of bacteriochlorophylls that act as the primary
photoelectron donor; unfortunately, no model compounds to
date feature such a closely spaced cofacial porphyrin dimer as
the primary electron donor. Stacked porphyrin macrocycles
constrained by rigid organic tethers d o not closely resemble the
special pair because their mean porphyrin -porphyrin separation is relatively targe, typically 5
Much better building
blocks for synthetic analogues of the RC are bis(porphyrin)
metal sandwich complexes in which the porphyrin -porphyrin
separations are about 3 8\.L3] We now describe the first compounds that combine two key structural features present in the
reaction center of photosynthetic organisms: a donor consisting
of a cofacial arrangement of two porphyrinic macrocycles held
about 3 8, apart, and a quinone electron acceptor.
We have previously developed a method to convert the sandwich complex [Zr(TTP),] 1 (TTP = 5,10,15,20-tetra(p-tolyl)porphyrinato dianion) to the amine-substituted bis(porphyrin)
zirconium species [Zr(TTP)(TTP-NH,)] 2, in which the amine
group is attached to a a-pyrrole site on one of the porphyrin
rings.[4, In such bis(porphyrin) zirconium species, the two porphyrin rings are cofacial with an N, mean plane separation of
[*] Prof. Dr. G. S. Girobami, Prof. Dr. K. S. Suslick. C L. Hein
School of Chemical Sciences
The University of Illinois at Urbana-Champaign
Urbana. IL 61801 (USA)
Fax: Int. code +(217)333-2685
e-mail :
This work was supported by the U. S. National Institutes of Health (PHS
5ROl-HL25934). We thank Dr. Alex I. Smimov, Illinois. for the EPR spec-
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acid, efficiency, synthesis, large, ylpropanoic, derivativesчmedium, alkylphenyl, ring, bioisosteres, new, cycloalk, moieties
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