Synthesis of new optically active bis-pyridino-and bis pyridono-18-crown-6 type ligands containing four lipophilic chains attached to the chiral centers by “ two-to-two ” type macrocyclization 1

Three new optically active bis-pyridino-18-crown-6 type ligands containing four lipophilic chains at the chiral centers [(S,S,S,S)-10, (R,R,R,R)-11 and (S,S,S,S)-12] were prepared by sodium ion template effect assisted “two-to-two” type macrocyclizations. The benzyloxysubstituted (R,R,R,R)-11 and (S,S,S,S)-12 were transformed to the new pyridone analogues (R,R,R,R)-13 and (S,S,S,S)-14 by catalytic hydrogenation.

Two procedures for the preparation of (S,S,S,S)-3 have been reported.Bradshaw and coworkers prepared it 4 in one step from (2R,3R)-butane-2,3-diol and 2,6bis(tosyloxymethyl)pyridine by a so called "two-to-two" type sodium ion template assisted cyclization 11 in 15% yield.Kobayashi and coworkers 5 in turn used the same starting materials, but to avoid the low yield of the above method, applied a five-step procedure resulting in an only slightly better overall yield (18%).The latter authors extended their procedure to the preparation of the analogues (R,R,R,R)-4 to (R,R,R,R)-8 (see Figure 1) which they obtained in overall yields of 6, 1, 20, 19 and 9%, respectively. 5ur longstanding endeavor has been to prepare optically active lipophilic bis-pyridinoand bis-pyridono-18-crown-6 type macrocycles that would enable the study of the selective transport of metal ions in an aqueous source phase/organic membrane /aqueous receiving phase system 12 or potentiometric sensing when incorporated into an electrode membrane. 13It is known that natural ionophores, such as valinomycin, lasalocid, monensin, etc. also contain several chiral centers and their chirality contributes to the selectivity in complexation and transport of metal ions through biological membranes. 14,15Several studies have shown that the stereostructure of chiral synthetic ligands has also a great influence on binding, solvent extraction, and transport of metal ions. 15,16,17,18oncerning bis-pyridono-18-crown-6 type macrocycles, to our best knowledge only a mixture of racemic-and meso-bis-pyridono-bis-cyclohexano-18-crown-6 ligands 9 (see Figure 1) has been reported. 19It was prepared by sodium ion template assisted "two-to-two" type cyclization from racemic trans-cyclohexane-1,2-diol and 4-(tetrahydro-2-pyranyloxy)-2,6-bis(tosyloxymethyl)pyridine using sodium hydride in tetrahydrofuran, followed by removal of the protecting group by acid.The overall yield was 8%.
In our search for optically pure chiral macrocycles with enhanced selectivity for metal ions in complexation, solvent extraction, membrane transport and potentiometric studies we prepared a series of new highly lipophilic bis-pyridino ligands, namely (S,S,S,S)-10, the bisp-benzyloxy-substituted crown ethers (R,R,R,R)-11 and (S,S,S,S)-12 by the "two-to-two" type cyclization method.Removal of the benzyl groups from (R,R,R,R)-11 or (S,S,S,S)-12 gave bispyridono ligands (R,R,R,R)-13 and (S,S,S,S)-14 (see.Figure 2).In this paper we also describe the synthesis of the new tetrabutoxymethyl-substituted-18crown-6 ether (S,S,S,S)-15 which was performed by the usual "one-to-one" method.We intend to compare the properties of the latter ligand to those containing pyridine, pbenzyloxypyridine and pyridone subcyclic units.
The above mentioned studies of the new ligands and also their applicability in stereoselective reactions will be published in the future, here we present only the synthetic work.

Results and Discussion
The "two-to-two" type cyclization to (S,S,S,S)-10, (R,R,R,R)-11, and (S,S,S,S)-12 was carried out by forming the disodium salts of the diols (S,S)-16 20 and (R,R)-17, 21 respectively with sodium hydride in THF followed by the addition of the ditosylates 18 or 19.The template effect of the sodium ion 11 allowed access to the macrocyclic compounds in yields of 19, 22, and 18% for (S,S,S,S)-10, (R,R,R,R)-11 and (S,S,S,S)-12, respectively.These yields can be considered as satisfactory for template assisted "two-to-two" type cyclizations. 2,3,4,19reparation of the optically active diols (S,S)-16 20 and (R,R)-17, 21 and of the di-p-tosylates 18, 22 and 19 22 was performed as reported.

Inc Experimental Section General Procedures.
13frared spectra were recorded on a Zeiss Specord IR 75 spectrometer.Optical rotations were taken on a Perkin-Elmer 241 polarimeter that was calibrated by measuring the optical rotations of both enantiomers of menthol. 1 H (500 MHz) and13C (125 MHz) NMR spectra were taken on a Bruker DRX-500 Avance spectrometer.Elemental analyses were performed in the Microanalytical Laboratory of the Department of Organic Chemistry, L. Eötvös University, Budapest, Hungary.Molecular weights were determined by a VG-ZAB-2 SEQ reverse geometry mass spectrometer.Melting points were taken on a Boetius micro melting point apparatus and were uncorrected.Starting materials were purchased from Aldrich Chemical Company unless otherwise noted.Silica gel 60 F 254 (Merck) and aluminum oxide 60 F 254 neutral type E (Merck) plates were used for TLC.Aluminum oxide (neutral, activated, Brockman I) and silica gel 60 (70-230 mesh, Merck) were used for column chromatography.Romil Ltd. (Cambridge UK) Super Purity Solvent grade THF stored under argon was used in all reactions.Solvents were dried and purified according to the well established methods.Evaporations were carried out under reduced pressure.