Ternary enantioselective complexes from α-amino acids, 18-crown-6 ether and a macrocyclic xanthone-based receptor

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  Ternary enantioselective complexes from α-amino acids, 18-crown-6 ether and a macrocyclic xanthone-based receptor
  Ternary enantioselective complexes from  a -amino acids,18-crown-6 ether and a macrocyclic xanthone-based receptor q Jos  e V. Hern  andez, Ana I. Oliva, Luis Sim  on, Francisco M. Mu ~ niz, Manuel Grandeand Joaqu  ın R. Mor  an * Departamento de Qu  ımica Org   a nica, Plaza de los Ca  ıdos 1-5, Universidad de Salamanca, Salamanca E-37008, Spain Received 5 April 2004; revised 27 April 2004; accepted 28 April 2004Available online 18 May 2004 Abstract—  A macrocyclic receptor shaped by two xanthone units bonded to binaphthyl is able to extract zwitterionic amino acidsenantioselectively from water to chloroform in the presence of 18-crown-6 ether. Based on  1 H NMR and circular dichroism spectra,the most stable associate of receptor  1  with alanine is assigned to the ( M  , S  ) configuration while the opposite configuration inphenylglycine yields the strong associate ( M  , R ).   2004 Elsevier Ltd. All rights reserved. Amino acid chiral recognition 1 is of current interest dueto the huge biological and technical importance of thesecompounds. Receptors able to resolve their racemicmixtures have been widely sought. 2 Here we reportreceptor  1 , which was prepared as shown in Scheme 1with the binaphthol derivative  2  and compound  3 3 asstarting materials. This receptor was initially designed toassociate organic carboxylates. However, the acidity of its sulfonamide protons prevents the association of acetate-like anions, since proton transfer takes place.The field effect in amino acids provides fewer basiccarboxylates and, in this case, association with receptor 1  seems to be possible.While racemic receptor  1  alone was unable to extractenantiomerically pure zwitterionic amino acids fromwater to chloroform, adding 18-crown-6 ether to thebiphasic system resulted in a splitting and shift of the re-ceptor  1  1 H NMR signals. The combined effect of thereceptor as a hydrogen bonding donor and the crownether as the acceptor for the ammonium group makesthe extraction of amino acids into the organic phase Scheme 1.  Preparation of receptor  1 . Keywords : Macrocyclic receptor; Xanthone; Anions; Zwitterionic amino acids; Chiral recognition; Enantioselectivity. q Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2004.04.168* Corresponding author. Tel.: +34-923294481; fax: +34-923294574; e-mail: romoran@usal.es0040-4039/$ - see front matter    2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.tetlet.2004.04.168Tetrahedron Letters 45 (2004) 4831–4833 TetrahedronLetters  possible. The signals of amino acids, like phenylglycine,show strong anisotropic shifts in the complex (Fig. 1)but, in general, protons of the amino acid in  1 H NMRspectra are difficult to assign in the chloroform solution.Therefore the classic ninhydrin test 4 was used to assessthe amount of amino acid extracted. Table 1 shows theresults.Hydrophilic amino acids such as histidine, tyrosine,aspartic and glutamic acids or their primary amides werenot extracted at all. However, lipophilic compoundssuch as alanine (Ala), phenylalanine (Phe) or phenyl-glycine (Phy) were completely extracted. In order toassess the enantioselectivity for receptor  1 , competitiveexperiments were carried out by adding small portionsof 18-crown-6 ether to the biphasic system of water/deuterochloroform with the racemic receptor  1  and  1 HNMR spectra were recorded. Graphic plotting of themovement of the receptor protons usually allows cal-culation of the chiral recognition, 5 but not in this case.The self-association of receptor  1  probably provides acomplex system with more than one equilibrium, fromwhich different chiral recognitions can be obtaineddepending on the proton that is monitored. 6 Therefore,a different procedure was used to assess the enantio-selectivity of the receptor.Extraction of a racemic amino acid with the racemicreceptor  1  afforded an  1 H NMR spectrum in which nosplitting of the receptor signals took place. Once thechemical shift of a certain proton is known for thestrong and weak complexes, the new chemical shift ( d  x )obtained in the previous experiment can be easily relatedto the relative amount of both complexes making use of Eq. 1. Since all the receptor is forming the complexes,receptor self-association does not take place in solutionand therefore it cannot interfere in the  K  rel  measurement.The results are shown in Table 2, in which it may be seenthat alanine and phenylglycine are the best enantio-selectively complexed substrates. An explanation of theobserved selectivity will be delayed until the geometry of the complexes is discussed.  K  rel  ¼ ½ strong complex ½ weak complex  ¼  d  x    d weak complex d strong complex    d x ð 1 Þ The resolution of the racemic receptor  1  was done bychromatography using its supramolecular properties. 7 Thus, preparative silicagel TLC plates were preparedwith an 1% aqueous solution of ( LL )-alanine and thestoichiometric amount of the crown ether. After elutionwith CHCl 3 /diethyl ether 9/1, receptor  1  was split intotwo spots with  R f   ¼ 0.6 and 0.4. No elution was observedin a blank experiment on a TLC plate without the aminoacid, so complex formation is probably responsible forthe elution and therefore the strong complex has thelarger  R f  . The complexes were scraped from the TLCplate, placed in a short-path silicagel column, and elutedwith CH 2 Cl 2 /MeOH 1/1, affording the enantiomericallypure receptors { ½ a  20D  +146 ( c  0.9, CHCl 3 ) for the enan-tiomer that forms the strong complex with ( LL )-alanineand  ½ a  20D  ) 145 ( c  1.1, CHCl 3 ) for the enantiomer thatforms the weak complex with ( LL )-alanine}.Since phenylglycine showed the best recognition, thisamino acid was used to establish the geometry of thecomplexes. Figure 1 shows the configuration assigned tothe strong complex, including the anisotropic shifts andNOE effects obtained from the  1 H NMR spectra. Themost stable associate ( M  , R ), corresponding to the  M  binaphthyl configuration, showed the smallest sterichindrance between the phenylglycine aromatic ring andthe binaphthyl aromatic sheet.The circular dichroism spectrum of receptor (+)  1  wasalso in agreement with the proposed configuration.Apart from the presence of some maxima above 255nmrelated to the absorption bands of the xanthone ligands,the CD spectrum of receptor  1  showed a strong bisig- Figure 1.  Strong complex of receptor  1  with phenylglycine with con-figuration ( M  , R ). Table 2.  Chiral recognition of several amino acids and receptor  1  (4.0 · 10  4 M) in the biphasic system chloroform/water in the presence of 18-crown-6 ether (8.0 · 10  4 M) (the aqueous phase was saturated with the amino acid)Guest Ala Ser Phe Trp Leu Val Phy  K  rela 7 6 3 2 1 2 9 a Ratio between the two association constants of both diastereomeric complexes. Table 1.  Extraction of several amino acids from water to chloroformin the presence of receptor  1  (4.0 · 10  4 M) and 18-crown-6 ether(8.0 · 10  4 M) established by the ninhydrin test (the aqueous phase wassaturated with the amino acid)Amino acid Extraction a (%)Phe 100Phy 100Ala 100Gly 83Trp 45Thr 27 a Extraction percentage is given respect to receptor  1 .4832  J. V. Hern  a ndez et al. / Tetrahedron Letters 45 (2004) 4831–4833  nate Cotton effect (Davidov splitting), 8 with maxima at241nm ( D e , +1390) and 227nm ( D e ,  ) 1200). Thereceptor had two aromatic systems that could srcinatethe couplet: the naphthalene rings of the binaphthyl andthe xanthone groups. The (+) chirality of the xanthoneligands and the ( ) ) chirality for the binaphthyl moiety(see Supplementary information) allow us to concludethat the (+)  1  receptor should have  M   helicity ( ¼  R a absolute configuration) for the binaphthyl, as shown inFigure 1.To our surprise, other amino acids such as alanineshowed the opposite configuration in the strong com-plex. The unexpected selectivities shown in Table 2 canbe explained taking into account that amino acids withsmall substituents, such as alanine, preferred the ( M  , S  )configuration; while larger groups, such as phenylala-nine, showed only small selectivities; greater hindranceclose to the amino acid  a  carbon, as in valine, changedthe preferred configuration, and the even larger aro-matic ring of phenylglycine showed the best recognition.In an experiment in which aqueous racemic phenylgly-cine was extracted with a chloroform solution of theenantiomerically pure receptor  1  and 18-crown-6 ether,the organic phase essentially showed only the signalscorresponding to the strong complex. The protons of thephenylglycine in the weak complex were broad and verysmall and hence integration of these signals was difficult.An estimation of the chiral discrimination was achievedfrom the chemical shift of H-6, a proton that showedup at 8.850ppm, between the respective absorptionsignals in the pure strong complex ( d ¼ 8.843ppm) andthe weak complex ( d ¼ 8.911ppm) (see Supplementaryinformation), suggesting a ninefold higher concentrationof the strong complex as compared to the weak one. Inour opinion, this is a very good result for a singleextraction experiment. A ‘Cram Machine’ 9 could besuitable for large-scale resolution of zwitterionic aminoacids since chiral receptors are not consumed during theprocess. Acknowledgements We thank Anna Lithgow for the 400MHz NMR spectraand C  esar Raposo for the mass spectra. We alsothank the ‘Direcci  on General de Investigaci  on Cient  ıficay T  ecnica’ (DGICYT Grant BQU-2002-00676) and JCL(SA 053/03) for their support of this work. The MEC isacknowledged for three fellowships (A.I.O., L.S.,F.M.M.). References and notes 1. (a) Kyne, G. M.; Light, M. E.; Hursthouse, M. B.; deMendoza, J.; Kilburn, J. D.  J. Chem. Soc., Perkin Trans. 1 2001 , 1258–1263; (b) Tye, H.; Eldred, C.; Wills, M.  J.Chem. Soc., Perkin Trans. 1  1998 , 457–465; (c) Chin, J.;Lee, S. S.; Lee, K. J.; Park, S.; Kim, D. H.  Nature  1999 , 401 , 254–257; (d) Lawless, L. J.; Blackburn, A. G.; Ayling,A. J.; P  erez-Pay  an, M. N.; Davis, A. P.  J. Chem. Soc.,Perkin Trans. 1  2001 , 1329–1341; (e) Schmuck, C.  Chem.Eur. J.  2000 ,  6  , 709–718; (f) Hayashida, O.; Sebo, L.;Rebeck, J., Jr.  J. Org. Chem.  2002 ,  67  , 8291–8298; (g)Kim, H. J.; Asif, R.; Chung, D. S.; Hong, J. I.  TetrahedronLett.  2003 ,  44 , 4335–4338; (h) Oliva, A. I.; Sim  on, L.;Mu ~ niz, F. M.; Sanz, F.; Mor  an, J. R.  Tetrahedron  2004 ,  60 ,3755–3762.2. (a) Pirkle, W. H.; Pochapsky, T. C.  Chem. Rev.  1989 ,  89 ,347–362; (b) Baraga ~ na, B.; Blackburn, A. G.; Breccia, P.;Davis, A. D.; de Mendoza, J.; Padr  on-Carrillo, J. M.;Prados, P.; Riedner, J.; de Vries, J. G.  Chem. Eur. J.  2002 , 8 , 2931–2936; (c) Breccia, P.; Van Gool, M.; P  erez-Fern  andez, R.; Mart  ın-Santamar  ıa, S.; Gago, F.; Prados,P.; de Mendoza, J.  J. Am. Chem. Soc.  2003 ,  125 , 8270– 8284.3. Hern  andez, J. V.; Mu ~ niz, F. M.; Oliva, A. I.; Sim  on, L.;P  erez, E.; Mor  an, J. R.  Tetrahedron Lett.  2003 ,  44 , 6983– 6985.4. Weyl, H. In  Methoden der Organischen Chemie ; M € uller, E.,Ed.; Georg Thieme: Stuggart, 1958; Vol. 11/2, pp 324–326.5. (a) Fielding, L.  Tetrahedron  2000 ,  56  , 6151–6170; (b)Witlock, B. J.; Witlock, H. W.  J. Am. Chem. Soc.  1990 , 112 , 3910–3915.6. Crego, M.; Partearroyo, A.; Raposo, C.; Mussons, M. L.;L  opez, J. L.; Alc  azar, V.; Mor  an, J. R.  Tetrahedron Lett. 1994 ,  35 , 1435–1438.7. Mart  ın, M.; Raposo, C.; Almaraz, M.; Crego, M.; Cabal-lero, M. C.; Grande, M.; Mor  an, J. M.  Angew. Chem., Int.Ed.  1996 ,  35 , 2386–2388.8. Nakanishi, K.; Beroya, N. In  Circular Dichroism. Principlesand Applications ; Nakanishi, K., Beroya, N., Woody, R.W., Eds.; VCH: New York, 1994. Chapter 13, pp 361–398.9. Cram, D. J.  Angew. Chem., Int. Ed. Engl.  1988 ,  27  , 1009– 1020. J. V. Hern  a ndez et al. / Tetrahedron Letters 45 (2004) 4831–4833  4833
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