Synthesis of a chiral receptor molecule with converging amidinium and hydroxy groups

Article abstract of DOI:10.1055/s-1999-3095

The axially chiral amidinium ion 1 was synthesized by Suzuki cross coupling and by base induced cyclization of an amino nitrile intermediate. Receptor 1 may interact with guest molecules by three converging H-bond donors.

Full text of DOI:10.1055/s-1999-3095

966
LETTER
Synthesis of a Chiral Receptor Molecule with Converging Amidinium and
Hydroxy Groups
Tilmann Schuster, Michael W. Göbel*
Institut für Organische Chemie der Johann Wolfgang Goethe-Universität, Marie-Curie-Strasse 11, D-60439 Frankfurt am Main, Germany
Fax +49(69)7982 9464; E-mail: M.Goebel@chemie.uni-frankfurt.de
Received 28 January 1999
Abstract: The axially chiral amidinium ion 1 was synthesized by
Suzuki cross coupling and by base induced cyclization of an amino
nitrile intermediate. Receptor 1 may interact with guest molecules
by three converging H-bond donors.
Key words: chiral axis, guanidine, hydrogen bond, molecular
recognition, Suzuki reaction
Figure 2 Recognition of anionic and neutral guests by three
converging hydrogen bond donors
Amidinium and guanidinium ions have been successfully
applied to the construction of anion receptors1 which
cleave RNA2 and undergo rapid transphosphorylation
chemistry.3 Chiral anion receptors are used for enantiose-
Inspection of molecular models finally led to the target
lective complexation of guest molecules. In addition,
structure 1. Due to the symmetric resorcinol subunit,
since they can stabilize anionic transition states, the catal-
rotation around the biaryl axis of compound 1 cannot re-
ysis of many useful reactions by such receptors may be
move the hydroxy group from the binding site. This mo-
envisioned. In consequence, several syntheses of chiral
tion will only allow a fine tuning in host-guest structures
guanidines appeared in the literature.4 We have developed
of the receptor molecule which is completely rigid in the
a general method for the preparation of chiral amidines
remaining parts.
(e.g. 2) based on a diastereoselective cyclization of amino
nitriles.5 We reasoned that additional hydrogen bonds be-
tween host and guest should further improve complex sta-
bility and stereoselectivity of guest recognition (Figure 2).
The terarylic skeleton of 1 was established by palladium
catalyzed cross coupling. In the first Suzuki reaction,6 we
employed boronic acid 5 which could be prepared from
MEM protected resorcinol 4 in 65 % yield (Scheme 1).
Naphthalene building block 7 was accessible via perbro-
mination of 2-hydroxynaphthalene and reduction (6),7 fol-
lowed by silylation of the hydroxyl group (90 %, Scheme
2). The sterically demanding TBDPS group proved to be
essential for the selectivity of the Suzuki coupling. Using
standard conditions, a clean reaction was observed
leading to 70 % of biaryl 8. In contrast, THP protected
analogues of 7 produced mixtures in the coupling
step. After conversion of 8 into the tetrahydropyranyl
ether (9, 98 %), a boronic acid was prepared from the
Figure 1 Molecular models of amidinium ions 1 and 2
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LETTER
Synthesis of a Chiral Receptor Molecule
967
groups, it was of critical importance not to remove MEM
from compound 15. When BOC was used instead of
TEOC, selective N-deprotection could not be achieved. In
the base induced cyclization of amino nitrile 15, preorga-
nization of the aromatic skeleton favors the formation of
the ten-membered ring. For steric reasons, ring closure
can only occur when the methyl group adopts an equato-
rial position in the product (see Figure 1). By this mecha-
nism, the chirality is efficiently transferred from the
amino side chain to the chiral axes of the amidine.9 Final-
ly, acid induced removal of MEM and crystallization of
the picrate salt 1a completed the synthesis of receptor
molecule 1 (48 % from 15).10 The corresponding chloride
1b and tetrakis(3,5-bistrifluoromethylphenyl)-borate salts
1c were prepared by ion exchange.
Preliminary complexation experiments were carried out
with the yellow diketone 16. According to its achiral
structure, the CD spectra of 16 did not show any bands.
However, upon addition of amidinium salt 1c, the yellow
color became more intense and a broad CD band around
400 nm was induced: coordination of 16 to the receptor re-
sulted in a chiral perturbation of its chromophore (room
bromo naphthalene 9. Cross coupling of the non-purified
reagent with 8-iodonaphthalene-1-carbonitrile 8 then led
to 72 % of teraryl 10. Treatment with oxalic acid in meth-
anol allowed a selective deprotection of the naphthol moi-
ety (11, 72 %).
As shown in Scheme 3, the side chain was prepared from temperature; CH2Cl2; [1c] = 10 mM, [16] = 12 mM).
(S)-2-amino-1-propanol 12 by N-protection with TEOC When cyclic phosphate 17 was added in slight excess,
(2-trimethylsilylethyl carbamate; 13, 98 %) and activation both effects were completely reversed. Phosphate 17 is
as a mesylate (14, 99 %). Alkylation of naphthol 11 by a better ligand for amidinium ion 1 than compound
mesylate 14 in the presence of Cs2CO3 and selective 16. The use of receptor 1 as a stereoselective catalyst in
cleavage of TEOC led to amino nitrile 15 (63 %, Scheme chirogenic11 reactions of diketone 16 is the topic of
4). Since the final cyclization was blocked by hydroxy present work.
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T. Schuster, M. W. Göbel
LETTER
2051; d) Schlama, T.; Gouverneur, V.; Valleix, A.; Greiner,
A.; Toupet, L.; Mioskowski, C. ibid. 1997, 62, 4200;
e) Alcazar, V.; Segura, M.; Prados, P.; de Mendoza, J. Tetra-
hedron Lett. 1998, 39, 1033; chiral amidines: f) Dobashi, Y.;
Kobayashi, K.; Dobashi, A. ibid. 1998, 39, 93; g) Dobashi, Y.;
Kobayashi, K.; Sato, N.; Dobashi, A. ibid. 1998, 39, 2985.
(5) Lehr, S.; Schütz, K.; Bauch, M.; Göbel, M.W. Angew. Chem.
1994, 106, 1041; ibid. Int. Ed. Engl., 1994, 33, 984.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Fries, K.; Schimmelschmidt, K. Liebigs Ann. Chem. 1930,
484, 245.
Acknowledgement
Financial support by the Fonds der Chemischen Industrie and by
the Schweizerischer Nationalfonds zur Förderung der wissen-
schaftlichen Forschung is gratefully acknowledged.
(8) Müller, G.; Dürner, G.; Bats, J. W.; Göbel, M. W. Liebigs Ann.
Chem. 1994, 1075.
(9) For a detailed explanation see (5).
(10) Selected physical data of amidinium picrate 1a: M.p. 202 –
204°C (ethanol / water). [α]D20 = + 147.6° (c = 0.27, metha-
nol). 1H NMR (270 MHz, d6-DMSO): d = 1.17 (d, 3 H, J = 6.7
Hz, Me), 3.58 - 3.76 (m, 1 H, CHN), 4.13 (dd, 1 H, J = 12.4,
3.7 Hz, Heq), 4.47 (dd, 1 H, J = 12.3, 10.7 Hz, Hax), 6.43 (d, 2
H, J = 8.1 Hz, H-C(3''), H-C(5'')), 6.95 (t, 1 H, J = 8.1 Hz, H-
C(4'')), 7.47 (dd, 1 H, J = 8.5, 1.6 Hz, H-C(7')), 7.53 (dd, 1 H,
J = 7.1, 1.2 Hz, H-C(7)), 7.62 (dd, 1 H, J = 7.0, 1.2 Hz, H-
C(2)), 7.68 (s, 1 H, H-C(1')), 7.73 (t, 1 H, J = 7.6 Hz, H-C(3)),
7.74 (t, 1 H, J = 7.7 Hz, H-C(6)), 7.80 (s, 1 H, H-C(5')), 7.82
(s, 1 H, H-C(4')), 7.83 (d, 1 H, J = 8.5 Hz, H-C(8')), 8.11 (s, 1
H, NHax), 8.18 (dd, 1 H, J = 8.4, 1.1 Hz, H-C(5)), 8.33 (dd, 1
H, J = 8.3, 1.1 Hz, H-C(4)), 8.59 (s, 2 H, picrate), 8.96 (s, 1 H,
NHeq), 9.16 (s, 2 H, OH), 9.18 (d, 1 H, J about 10 Hz, NHax).
Anal. calc for C36H27N5O10 · 2 EtOH (781.77): C 61.45, H
5.03, N 8.96; found: C 61.66, H 4.82, N 9.02.
References and Notes
(1) For an early example of anion complexation by lipophilic
amidines see: Heinzer, F.; Soukup, M.; Eschenmoser, A. Helv.
Chim. Acta 1978, 61, 2851.
(2) a) Smith, J.; Ariga, K.; Anslyn, E. V. J. Am. Chem. Soc. 1993,
115, 362; b) Kurz, K.; Göbel, M. W. Helv. Chim. Acta 1996,
79, 1967.
(3) a) Jubian, V.; Dixon, R. P.; Hamilton, A. D. J. Am. Chem. Soc.
1992, 114, 1120; b) Jubian, V.; Veronese, A.; Dixon, R. P.;
Hamilton, A. D. Angew. Chem. 1995, 107, 1343; ibid. Int. Ed.
Engl. 1995, 34, 1237; c) Muche, M.-S.; Göbel, M. W. ibid.
1996, 108, 2263; ibid. Int. Ed. Engl. 1996, 35, 2126;
d) Muche, M.-S.; Kamalaprija, P.; Göbel, M. W. Tetrahedron
Lett. 1997, 38, 2923; e) Oost, T.; Kalesse, M. Tetrahedron
1997, 53, 8421; f) Oost, T.; Filippazzi, A.; Kalesse, M. Liebigs
Ann. Recl. 1997, 1005.
(11) Drenkard, S.; Ferris, J.; Eschenmoser, A. Helv. Chim. Acta
1990, 73, 1373.
(4) Recent articles (see also references cited in (5)): a) Metzger,
A.; Peschke, W.; Schmidtchen, F. P. Synthesis 1995, 566;
b) Peschke, W.; Schiessl, P.; Schmidtchen, F. P.; Bissinger,
P.; Schier, A. J. Org. Chem. 1995, 60, 1039; c) Metzger, A.;
Gloe, K.; Stephan, H.; Schmidtchen, F. P. ibid. 1996, 61,
Article Identifier:
1437-2096,E;1999,0,S1,0966,0968,ftx,en;W03899ST.pdf
Synlett 1999, S1, 966–968 ISSN 0936-5214 © Thieme Stuttgart · New York