Synthesis of the first mixed-donor spiro-linked macrocyclic tetralactams

A synthesis of spiro-linked macrocyclic tetraamides 1 and 2 was accomplished by the reaction of pentaerythrityl tetrabromide 13 with two moles of the appropriate dipotassium salts 5a and 5b in refluxing DMF. Treatment of 1 and 2 with Lawesson`s reagent in refluxing toluene afforded the novel spiro-linked macrocyclic tetrathiotetraamides 14 and 15 , respectively.


Introduction
The pioneering work of Pedersen, 1 Lehn, 2 and Cram 3 on the syntheses of macrocyclic and macropolycyclic host systems such as crown ethers, azacrown ethers, cryptands and spherands, has generated a great amount of interest in host-guest chemistry.These macrocycles have been shown to exhibit important applications including selective ion separation and detection, molecular recognition, catalysis, biological applications as well as many other interesting applications in diverse fields of supramolecular chemistry. 4Of particular interest are crown ethers incorporating amide groups.It was reported that such groups modify the binding properties of the crown compounds with respect to alkali metal ions. 5Furthermore, macrocyclic amides are precursors in the preparation of azacrown ethers and cryptands. 4Some diamidecontaining macrocycles have been utilized as new catalysts. 6Moreover, special interest has been directed in recent years, toward the synthesis of bis(macrocycles) as well as multi-site crown compounds which are capable of binding simultaneously to two or more metal ions. 7Ligands capable of simultaneously being involved in two binding interactions are attracting current interest due to their applications in molecular recognition. 8A number of such compounds has been observed to act as anti-HIV agents, which exhibited low cytotoxicity. 9Bifunctional ligands may also have versatile properties in stereoselective catalysis due to their ability to be engaged in secondary interactions with the substrate undergoing reaction. 10n continuation of the above studies, we report here on the first synthesis of spiro-linked macrocycles tetraamides 1 and 2 which are expected to have ability to bind more than one metal ion.
It is noteworthy to mention that Weber 11 and Inoue et al 12 pioneered the synthesis of the first spiro crown ethers 3 starting from pentaerythritol using stepwise cyclization techniques.Previously, we reported the synthesis of dibenzo-and tribenzosubstituted macrocyclic diamides 7 by the reaction of the potassium salts 5a and 5b (obtained upon treatment of the appropriate bis(phenols) 4a and 4b with ethanolic KOH) with the corresponding dihalo compounds 6 in refluxing DMF under conventional heating methods as well as under microwave irradiation conditions (Scheme 1).Monocrown of type 7 prefer sizes of metal ions, depending on the ring size of the macrocycle.It had been reported 14 that the bis-crown effect occurs when two crown ether rings in one molecule bind a cation in a sandwich-type structure, and it enables the molecules to bind a cation that is larger than the ideal size for particular crown ether unit.To improve the cation binding abilities of the macrocycles 7, we have recently reported the synthesis of macrocyclic diamide with pendant hydroxyl group 8 which can be successfully utilized as a key intermediate for the synthesis of the bis (macrocyclic diamides) 9. 15

Results and Discussion
As part of our continuing effort in this area we investigated two strategies for the synthesis of the target compounds 1 and 2. In the first strategy, we studied the synthesis of the dihydroxy macrocycles 11 which should then undergo bromination with PBr 3 to give the dibromo compounds 12. Subsequent reaction with another equivalent of 5a and 5b should give the target spiro macrocycles 1 and 2, respectively (Scheme 2).Unfortunately, we were not able to isolate a pure sample of the corresponding dihydroxy derivatives 11 by the reaction of 2,2-bis(bromomethyl)-1,3-propanediol 10 with one equivalent of the appropriate potassium salt 5a and 5b in refluxing DMF.

Scheme 2
In the second strategy (Scheme 3) we applied one-step synthesis of 1 and 2 utilizing pentaerythrityl tetrabromide 13 as a starting material.reaction of 13 with two moles of the appropriate dipotassium salts 5a and 5b in refluxing DMF afforded the corresponding spirolinked macrocycles 1 and 2 in 52 % and 44 % yields, respectively.Physical measurements ( 1 H and 13 C-NMR, mass spectra) as well as elemental analyses were in accordance with the structure proposed for the latter compounds.The novel spiro macrocyclic tetraamides, now available, prompted us to study their possible transformation to their corresponding tetrathiotetraamide derivatives.Thus, the novel macrocycles 14 and 15 were prepared in 55 % and 52 % yields, respectively, upon treatment of each of the macrocyclic tetraamides 1 and 2 with Lawesson`s reagent in refluxing toluene for 6h.Thioamides are known to be weaker hydrogen-bond acceptors and stronger acids than amides. 16or these reasons, thioamides are attractive groups for the construction of anion hosts.The 1 H NMR and 13 C NMR data of the spiro macrocycles 1, 2, 14, and 15, showed magnetic equivalence of the OCH 2 and NCH 2 protons which indicates rapid exchange in these macrocycles.

Conclusions
We prepared the first spiro-linked macrocyclic tetraamides 1 and 2 as well as their corresponding spiro-linked macrocyclic tetrathiotetraamides 14 and 15.The new synthesized macrocycles offer an advantage of their easy synthesis in a simple one step procedure from inexpensive starting materials.In addition, the presence of the thioamide groups allows of the new macrocycles to produce side armed ligands which permit a more dynamic complexation of metal ions.We believe that these new series of compounds should exhibit useful analytical uses on account of their abilities to bind more than one metal ion.Comparison of the binding abilities of the new macrocycles with their corresponding single-ring derivatives 7 as well as the bis macrocycle 9, in which two macrocyclic dilactam units are connected by a flexible bridge, is still underway.

Experimental Section
General Procedures.Melting points are uncorrected.IR spectra (KBr) were recorded on a Perkin-Elmer 1430 spectrophotometer.NMR spectra were measured with a Varian Mercury 300 (300 MHz 1 H NMR, 75 MHz 13 C NMR) spectrophotometer and chemical shifts are given in ppm from TMS. Mass spectra were recorded on a GC MS-QP1000 EX (70 eV) or MS 5988 (15 eV) spectrometers.Elemental analyses were carried out at the Microanalytical Centre, Cairo University.

Preparation of the potassium salts (5a and 5b)
To a solution of KOH (1.14 g, 10 mmol) in methanol (10 ml) was added the bis-phenol 4a,b (5 mmol).The mixture was stirred at room temperature for 10 min.The solvent was then removed in vacuo.The remaining solid was triturated with dry ether, collected, dried, and used in the next step without further purification.