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Chiral Recognition of -Amino Acid Derivatives with a Homooxacalix[3]arene Construction of a Pseudo-C2-Symmetrical Compound from a C3-Symmetrical Macrocycle.

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ethyl acetate and methanol: 40-30% methanol). Further purification was achieved
by semipreparative HPLC (70-85% yield). After lyophilization the triesters 3 and
4 were isolated as colorless solids.
Received: June 30, 1995
Revised version: September 29, 1995 [Z 8150 IE]
German version: Angew. Chem. 1996, 108, 77--79
Keywords: AIDS . chemotherapy . phosphotriesters . prodrugs
. thymidine derivatives
[I] Chem. Eng. N e w 1994, 72(4), 22.
[2] R. J. Jones, N. Bischofberger, Antiviral Res. 1995, 27, 1-17.
[3] Several nucleoside phosphotriesters have been studied previously which should
liberate nucleoside monophosphates by nonenzymatic [3 a] or enzymatic
[3 b-d] hydrolysis: a) U. Nillroth, L. Vrang, G. Ahlsen, Y Besidsky, J. Chattopadhyaya, I. Ugi, U. H. Danielson, Antiviral Chem. Chemother. 199.5,6,50-64
and references therein; b) D. Farquhar, R. Chen, S. Khan, J. Med. Chem. 1995,
38, 488-495; c) C. Perigaud, A.-M. Aubertin, S. Benzaria. H. Pelicano, G.
Gosselin, A. Kirn, J. L. Imbach, Biochem. Pharmacol. 1994, 48, 11-14; d) W.
Thomson, D. Nicholls, W. J. Irwin, J. S. Al-Mushadani, S . Freeman, A. Karpas, J. Petrik, N. Mahmood, A. J. Hay, J. Chem. SOC.Perkin Trans. 1 1993,
1239-1245; see also ref. [2].
[4] a) C. Meier, Angew. Chem. 1993, 105, 1854-1856; Angews. Chem. I n l . Ed. EngI.
1993,32,1704-1706; b) C. Meier, L. Habel, W. H. G. Laux, J. Balzarini, E. De
Clercq, Nucleosides Nucleotides 1995, 14, 759-762; c) C. Meier, R. Mauritz,
ibid. 1995, 14, 803-804.
[5] Prodrugs for ddT 1: S. I. Shimizu. J. Balzarini, E. De Clercq, R. T. Walker,
Nucleosides Nucleotides 1992, If, 583-594; ref. [4a]. Prodrugs for d4T 2: C.
McGuigan, H. M. Sheeka, N. Mahmood, A. Hay, Bioorg. Med. Chem. Lett.
1993, 3, 1203-1206; C. Sergheraert, C. Pierlot, A. Tartar, Y Henin, M.
Lemaitre, J. Med. Chem. 1993, 36, 826-830.
[6] S. N. Farrow, A. S. Jones, A. Kumar, R. T. Walker, J. Balzarini, E. De Clercq,
J. Med. Chem. 1990,33, 1400-1406.
IMed. Chem. 1982, 20, 907-911.
[7] J. W. Engels, E.-J. Schlager, .
[XI C. Meier. L. Habel, J. Balzarini, E. De Clercq, Liebigs Ann. Chem. 1995, in
press; L. Habel, Diploma thesis, Universitlt Frankfurt, 1994.
[9] Two different mechanisms of benzylester hydrolysis are discussed: 1) a spontaneous heterolytic bond breakage leading to a henzyl cation and a phosphate
ester; 2) a nucleophilic attack of water at the benzylic methylene group: a) J. W.
Engels, Z . Nuturjorsch. B 1977, 32, 807-809; h) A. G. Mitchell, D. Nicholls,
Chem. Soc. Perkin Trans. 2 1992, 1145- 1150.
W. J. Irwin, S . Freeman, .
[lo] C. Meier, unpublished results.
[ll] A. Wissner, M. L. Carroll, .
IMed. Chem. 1992,35, 1650-1662.
[I21 The ”P NMR shifts of the diastereomers correlate with their CD properties as
well as with their eluting properties during chromatography: the “fast”-eluting
diastereomer (semipreparative reversed-phase silica gel HPLC-column)
showed an upfield shift in the 31PNMR spectrum and a positive Cotton-effect
at 225 nm in the CD spectrum as compared to the “slow”-eluting diastereomer.
[I31 J. Balzarini. J. M. Cools, E. De Clercq, Biochem. Biophys. Res. Commun. 1989,
[I41 The hydrolysis studies were carried out as described before, see ref. [4a].
[I 51 It should be mentioned that at pH < 7 no or only a very slow hydrolysis of 3
or 4 was observed, whereas at pH > 7 a pH-dependent hydrolysis occurred.
Chiral Recognition of a-Amino Acid Derivatives
with a Homooxacalix[3]arene : Construction
of a Pseudo-C,-Symmetrical Compound from
a C,-Symmetrical Macrocycle
Koji Araki, Kousuke Inada, and Seiji Shinkai*
The NH: moiety of primary alkylammonium ions (RNH:)
possesses C , symmetry, and therefore complementary hosts
might best possess C, symmetry as well. In chiral molecules with
two complexing faces, the importance of having the two faces
related by C , symmetry has been emphasized.[’] A chiral guest
molecule interacts identically with the homotopic faces of this
Prof. S. Shinkai. K. Araki, K. Inada
Department of Chemical Science and Technology
Faculty of Engineering, Kyushu University, Fukuoka 812 (Japan)
0 VCH Erlagsgesellschafi mbH, 0-69451
Weinheim, 1996
type of chiral host. Therefore, for the enantioselective recognition of primary alkylammonium ions, it is desirable for a chiral
host molecule to possess a C , axis perpendicular to a local C ,
symmetry element. Satisfying these requirements is quite diffcult. [IS]Crown-6 is one of the few compounds that has these
two local symmetry elements-at least when it binds K + or
RNH: ions in the solid state. In fact, several chiral[18]crown-6
derivatives are known to bind racemic substrates containing
NH: centers with high enantioselectivity.[’] Here we describe
how such a host molecule for chiral recognition can be prepared
from a homooxacalix[3]arene.
As the starting material we chose 7,15,23-tri-tert-butyl-
25,26,27-trihydroxy-2,3,10,11,18,19-hexahomo-3,11,19-trioxacalix[3]arene (IH,) ,[’I which possesses C, symmetryr4] and
shows high affinity for primary alkylammonium ions.[’’ When
two hydroxyl groups in lH, are converted into ethers (R’) with
bulky alkyl groups, which can suppress rotation of the
phenylene group, and the third hydroxyl group is transformed
into an ether (R) having a small alkyl group, the product, anriIRR;, is optically active. It behaves like a C,-symmetrical
macrocycle as a result of the free rotation of the phenylene
group having the less bulky ether group (Scheme 1). A guest
Scheme 1 . Schematic representation of the binding of an RNH: ion ( R ’ - N + ) to
a pseudo-C,-symmetric host.
molecule meets the “same chiral face” of anti-1RR2 regardless
of the direction from which it approaches. For this reason we
consider anti-IRR, to have “pseudo-C,-symmetry”.
It is known that rotation of the phenylene groups in IH, can
be suppressed when the substituent on the 0 atom is bulkier
than an n-propyl group.[5a1In this study we used n-butyl groups
(R’ = Bu) to fix the conformation. The reaction of IH, and
n-butyl iodide in the presence of NaH gave anti-lHBu, in 48 YO
yield (Scheme 2). Although the unmodified OH group can still
pass through the ring, this calix[3]arene is already optically active. As the smaller R group, which can also pass through the
annulus, we chose the methyl group. The OH group in antiIHBu, was methylated with methyl iodide and NaH to give
anti-IMeBu, in 70% yield. The IR spectrum and elemental
analysis data were in satisfactory agreement with expected values. X-ray crystallographic analysis of anti-lMeBu, shows that
one of the OBu groups is directed upward and the second downward, and that the OMe group points downward (Fig. 1).[6,71
However, the ‘H NMR spectra of anti-lMeBu, are characteristic of a C,-symmetrical structure: two singlets are observed for
the tBu protons with a 1:2 integral intensity ratio, and these
signals did not split into doublets even at -85°C.The results
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Angew. Chem. Int. Ed. Engl. 1996, 35, No. 1
optical resolution
Scheme 2. Synthesis of the pseudo-C2-symmetrical macrocycle unti-lMeBu, starting from the C,-symmetrical compound IH,.
To obtain further insight into the complex structure we
measured NOE spectra of the
complex of IMeBu, and
neopentylammonium picrate.
When the resonance frequency of the tert-butyl protons in
the neopentyl group was irradiated, the difference NOE
signal for the ArH protons in
the OMe-substituted phenylene unit was larger than that
for those in the OBu-substituted phenylene unit (Fig. 2).
This result clearly shows that
the alkyl group Of this guest is
Fig, 2, NOE s',gnal intensities of the
located in the cavity formed
ArH Drotons on irradiation of the resoby an OMe-substituted and
.zinc, frequency of the IBU protons in
one OBu-substituted phenylthe unti-lMeBu,jneopentylammonium complex (5.0 x lo-' moldm-',
ene ring.
25 ' C . CDCI,/CD,CN (311)).
anti-lMeBu, was optically
resolved by HPLC method
(Chiralpak OP( +), n-hexane/2-propanol (lil)). The first fraction (( -)-anti-IMeBu,) and the second fraction ((+)-antiIMeBu,) gave symmetrical CD spectra with A, = 232 nm and
Om,, = 20200 degcm' dmol-' (Fig. 3).
(+)-anti-1 MeBu,
Fig. 1 . X-ray crystal structure of anti-lMeBu,; only one of the two molecules in the
unit cell ia shown.
can be explained by two possibilities: either the OMe group lies
in the plane of the homooxacalix[3]arene resulting in C, symmetry, or in solution the OMe group rotates rapidly on the NMR
time scale to give pseudo-C,-symmetry. However, judging from
CPK molecular models and MM3 computations, the first possibility is not likely.'81
We measured 'H NMR spectra of anti-IMeBu, in the presence of r>-phenylalanineethyl ester hydrochloride (25 "C, CDCI,/CD,CN (311). 250 MHz). Most of the signals split into
pairs, indicating that anti-lMeBu, is a pair of enantiomers. This
compound can bind primary alkylammonium ions through hydrogen-bonding interactions with three oxygen atoms. Judging
from the chemical shift changes of lMeBu,, at least two phenolic oxygens and possibly an oxygen atom from a CH,OCH,
group may be involved. CPK molecular models indicate that it
is sterically impossible for the oxygen atoms from three
CH,0CH2 groups to form hydrogen bonds with RNH: ions.
Aiigr,w <'/im~Int. Ed. EngI. 1996, 35. N o . I
Fig. 3. CD spectra of (-)- and (+)-unti-lMeBu, ( 1 . 0 ~
1 0 ~ 3 m o l d m ~235,° C
The association constants (KaJ for a-amino acid ethyl ester
picrates and 1-arylethylammonium picrates were determined at
25 "C in chloroform/THF (99/1) by monitoring the change
in the absorption spectrum ([picrate] = 1.00 x
m ~ l d m - ~ R,,,(picrates)
[anti-IMeBu,] = (0.2-14) x
345 nm, l.,,,(complexes) = 380 nm ; Table I) .191 Plots of the absorption A380 versus [anti-lMeBu,] give an inflection point at
[unti-lMeBu,]/[picrate] = 1.O, indicating that the complexes
have a 1 :1 stoichiometry. The association constants for the
L-configurated isomers are greater with (-)-anfi-IMeBu, than
with ( + )-anti-lMeBu, . The largest chiral discrimination
(74% ee) was observed for the picrate salt of t-phenylalanine
ethyl ester.
Verlugsgesrllschu/rmbH, 0-69451 Weinheim,1996
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Table 1. Association constants K,,, [dm3mol-'] for the complexes of anti-IMeBu,
and picrate salts of @-aminoacid ethyl esters and 1-arylethylamines (25 -C, chloroformiTHF (99/1)).
Picrate salt
L-alanine ethyl ester picrate
L-phenylalanine ethyl ester picrate
(R)-1-naphthylethylamine picrate
The foregoing results prove that the molecular design concept
proposed in this paper, a pseudo-C,-symmetrical compound
based on a C,-symmetrical skeleton, is very effective for chiral
recognition of optically active primary alkylammonium ions.
We believe that the chiral discrimination ability of anti-lRR;
can be further enhanced by elaborating the bulkiness and polarity of the substituents R and R'.
Received: June 16. 1995
Revised version: October 16. 1995 [Z8110IE]
German version: Angen. Chem. 1996, 108. 92-94
Keywords: calixarenes . chiral recognition . host- guest chemistry . macrocycles
[l] a) T. Mizutani. T. Ema, T. Tomita. Y. Kuroda. H. Ogoshi, J. A m . Chew. Soc.
1994,116,4240: b) E. N. Jacobsen. W. Zhang. A. R. Muci. J. R. Ecker. L. Deng.
ibid. 1991, 113.7063; c) A. Miyashita, A. Yasuda, H. Tdkaya, K. Toriumi, T. Ito.
T. Souchi, R. Noyori. ibid. 1980. 102, 7932; d) T. Katsuki. K. B. Sharpless, ;bid.
1980, 102. 5974; e) T. J. van Bergen. R. M. Kellogg, ibicl. 1977, 99. 3882.
[2] a) J.-M. Lehn, Angrn. Chmi. 1988. 100. 91 : Angel1 . Chem. Jnr. Ed. D i g / . 1988.
27,89. and references cited therein; b) D. J. Cram. ibid. 1988.100.1041 and ibid.
1988. 27. 1009. and references cited therein.
[3] a) Y. Mukoyama. T. Tanno, Org. Coat. Plust. Cltem. 1979, 40, 894; b) B.
Dhawan, C. D. Gutsche, J. Org. Chem. 1983,48, 1536: c) P. Zerr. M. Mussrabi,
J. Vicens, Tetrahedron Lett. 1991, 32, 1879.
[4] Strictly speaking, l H , may not be C,-symmetrical since the direction of OH
groups (above, below the annulus) and the conformation ofthe ArCH,OCH,Ar
groups may be in constant flux. However, the complementarity of lH, with
C,-symmetrical RNH: ions described here indicates that this molecule can be
considered to be C,-symmetrical.
a) K. Araki. K. Inada, H. Otsuka. S. Shinkai, Tetrahedron 1993.49. 9465: b) K .
Araki, N. Hashimato. H. Otsuka. S. Shinkai. J. Org. Chem. 1993. 58, 5958.
Further details of the crystal structure investigation may be obtained from the
Director of the Cambridge Crystallographic Data Centre, 12 Union Road, GBCambridge CB2lEZ (UK), on quoting the full journal citation.
"Upward" and "downward" have been defined by Gutsche et al. (S. Kanamathareddy, C. D. Gutsche J . Am. Chem. Soc. 1993, 115. 6572).
This structure is difficult to construct with CPK molecular models, because the
bulky OMe group must be included in the cavity of the homooxacalix[3]arene.
MM3(92) calcnlations also predict that the most stable conformations of
lMeBu, are cone and partial-cone, whereas the structure in which the M e 0
group is lies in the plane of the ring is much less stable (by at least 1.5 kcal).
The K,,, values were evaluated by the Benesi-Hildebrand method: H. Benesi.
J. H. Hildebrand. J. A m . Clirrn. Soc. 1949. 71, 2703.
A Convergent, Enantioselective Total Synthesis
of Hapalosin : A Drug with Multidrug-Resistance
Reversing Activity**
Arun K. Ghosh,* Wenming Liu, Yibo Xu, and
Zhidong Chen
Hapalosin (l), a novel cyclodepsipeptide isolated recently"]
from the blue-green alga Hapalosiphon welwitschii, has shown
important multidrug-resistance reversing activity."] The term
multidrug-resistance (MDR), is defined as the ability of tumor
cells exposed to one drug to develop cross resistance to seemingly unrelated drugs. This phenomenon is apparently caused by an
overexpression of P-glycoprotein. a 170- 200 kDa transmembrane protein that acts as an ATP-dependent drug efflux
pump.'31 As a consequence, chemotherapy very often becomes
ineffective. Thus, the agents that are capable of reversing this
P-glycoprotein-induced MDR effect, may have therapeutic potential for patients undergoing cancer chemotherapy. Preliminary biological studies indicated that hapalosin inhibits the Pglycoprotein efflux pump."] Also, hapalosin has already been
shown to have better MDR-reversing activity than verapamil
which is currently under active investigation to test the MDRreversing hypothesis in the clinic.[41The structure of hapalosin
was assigned by Moore et a].['] through spectroscopic and
degradation studies. Besides important MDR-reversing activity, one of the intriguing features of hapalosin is that the molecule exists as a mixture of two conformers, as shown by 'H and
13C NMR spectroscopy. Perhaps, only one of these conformers
is responsible for the potent MDR-reversing activity. In order to
study the structure-function relationships as well as to gain
information regarding the bioactive conformation, we sought a
flexible, enantioselective synthesis of hapalosin. We describe
here a convergent and stereocontrolled first total synthesis of
The synthesis of (3R,4S-4-(N-benzyloxycarbonyl-N-methylamino)-3-methoxymethoxy-5-phenylpentanoicacid 5 was carried out stereoselectively starting from Weinreb amide 2
(Fig. I ) .['I Treatment of 2 with allylmagnesium bromide
(2.2 equiv) in T H F at - 20 "C afforded the corresponding ketone, which was subsequently reduced with sodium borohydride
in propanol at 0 "C to provide the alcohol 3 as a mixture (5:1)
of diastereomers in 73 % yield.[61The isomers were separated by
chromatography (silica gel, 15 % ethyl acetate/hexane). Protection of the major isomer 3 as a methoxymethyl (MOM) ether
followed by N-methylation with sodium hydride (2 equiv) and
methyl iodide (3 equiv) in a mixture of THF/DMF (10:l) at
23 "C afforded the protected amino alcohol 4 in 68 % yield after
silica gel chromatography.['] The cleavage of the double bond in
4 with ruthenium trichloride and excess of sodium periodate in
a mixture of acetonitrile, carbon tetrachloride, and water at
23 "C for 12 h provided the acid 5 in 84 YOyield.[*1
The protected 8-hydroxy acid 7 was conveniently prepared by
an asymmetric aldol reaction utilizing an (1S,2R)-aminoindan2-01 derived chiral auxiliary.[g1Thus, reaction of n-octanaldehyde and the corresponding chiral propionimide using di-nbutylboryl trifluoromethanesulfonate and triethylamine at
- 78 "C furnished the aldol product 6 in 90 % yield after silica
VerIagsgeseNsrhaft mbH, 0-69451 Weinheiin. 1996
Prof. A. K . Ghosh. W. Liu, Y Xu. Z. Chen
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Chicago. IL 60607 (USA)
Fax: Int. code f ( 3 1 2 ) 996-0431
We thank Prof. Robert Moriarty for helpful discussions. Financial support of
this project was provided by the University of Illinois at Chicago and Merck
Research Laboratories.
U57O-OX33/96/3501-0074$ lO.UU+ .25/0
Angew. Chem. Jnt. Ed. Engl. 1996, 35, N o . 1
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