Mendeleev Communications Electronic Version, Issue 1, 2001 (pp. 1.42) Synthesis of closo-monocarbon carborane-substituted natural porphyrins Valentina A. Ol¡�shevskaya,*a Rima P. Evstigneeva,b Valentina N. Luzgina,b Maya A. Gyul¡�malieva,b Pavel V. Petrovskii,a John H. Morrisc and Leonid I. Zakharkina a A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation.Fax: + 7 095 135 5085; e-mail: olshevsk@ineos.ac.ru b M. V. Lomonosov Moscow State Academy of Fine Chemical Technology, 117571 Moscow, Russian Federation. Fax: + 7 095 434 8711; e-mail: evstigneeva@httos.mitht.msk.ru c Department of Pure and Applied Chemistry, Strathclyde University, Glasgow, G1 1XL, UK 10.1070/MC2001v011n01ABEH001383 Previously unknown 1,3,5,8-tetramethyl-6,7-di[2'-(closo-monocarbon carborane-1''-yl caesium)methoxycarbonylethyl]porphyrin and 1,3,5,8-tetramethyl-2,4-divinyl-6,7-di[2'-(closo-monocarbon carborane-1''-yl caesium)methoxycarbonylethyl]porphyrin were synthesised in the reactions of deuteroporphyrin IX and protoporphyrin IX, respectively, with (1-hydroxymethyl-closomonocarbon carborane)caesium.Currently, considerable attention is paid to the synthesis of carboranyl-substituted heterocycles for the use as pharmaceuticals for the boron neutron-capture therapy (BNCT) of cancer.1 Among these compounds are carboranylporphyrins, which were synthesised more than two decades ago.2 Interest in the synthesis of boronated porphyrins is caused by the ability of these compounds to accumulate selectively and to persist in tumour cells for a long time.Previously,3.5 we described the syntheses of carboranyl-substituted porphyrins, in which the carborane polyhedron is bound to the porphyrin ring through the boron atom of carborane, which allows further functionalization at carbon atoms of the carborane polyhedron in order to decrease the lipophilicity of carborane substituents.Current progress in the carborane chemistry provides an opportunity to prepare new functionalised organic derivatives of monocarbon carborane,6 which are convenient synthons for the synthesis of a new type of monocarbon carborane-substituted porphyrins for BCNT. This work is devoted to the synthesis of novel monocarbon carborane-substituted porphyrins. Using natural deuteroporphyrin IX 1a, protoporphyrin IX 1b and (1-hydroxymethyl-closomonocarbon carborane)caesium 2, we obtained anionic monocarbon carborane derivatives of deuteroporphyrin IX 3a and protoporphyrin IX 3b, in which the closo-monocarbon carborane substituent is bound to the carboxylic groups of porphyrins 1a,b through the carbon atom of the closo-monocarbon carborane polyhedron (Scheme 1).¢Ó The reactions were performed in a methylene chloride.pyridine (1:1) mixture. Upon activation of carboxylic groups of porphyrins 1a,b with di-tert-butylpyrocarbonate (Boc2O) in the 1:2 ratio, compounds 3a and 3b were obtained as dark claret substances in 52 and 50% yields, respectively. Note that, although they are salts, compounds 3a and 3b are, nevertheless, poorly soluble in hydroxy-containing solvents.At the same time, they are readily soluble in THF, DMSO, DMF, MeCN and C5H5N. It is believed that the use of Na+, K+ or lipophilic organic cations instead of the Cs+ cation increases the water solubility of these compounds. The structures of 3a and 3b were confirmed by mass spectrometry and electronic absorption, IR and 1H NMR spectroscopy.¢Ô C HO NH N N HN Me R Me Me Me R HOOC COOH Cs+ Py.CH2Cl2 Boc2O DMAP 20 ¡ÆC NH N N HN Me R Me Me Me R O O C O O C 2 2Cs+ 1a,b 2 3a,b a R = H b R = CH=CH2 Scheme 1 ¢Ó General procedure for the synthesis of porphyrins 3a,b.To a solution of porphyrin 1a or 1b (0.196 mmol) in a mixture of 5 ml C5H5N and 5 ml CH2Cl2, Boc2O (0.22 mmol) was added, and the mixture was stirred for 10 min at 0 ¡ÆC.Then, compound 2 (0.392 mmol) and 4-dimethylaminopyridine (15 mg) were added, and the mixtiure was stirred for 1 h at 20 ¡ÆC. The reaction was monitored by TLC [Silufol plates, CHCl3. MeOH (9:1) as an eluent]. After completion of the reaction, the solvents were removed in vacuo, CHCl3 (5 ml) was added to the residue, and crystals of precipitated porphyrins 3a or 3b precipitated were filtered off.Recrystallisation from a DMSO.water mixture gave porphyrins 3a and 3b in 52 and 50% yields, respectively. ¢Ô Electronic absorption spectra were recorded on a Varian MAT 731 instrument. IR spectra were recorded on a UR-20 spectrometer as KBr pellets. 1H NMR spectra were recorded on a Bruker AMX-400 spectrometer at 400.13 MHz in [2H6]DMSO with TMS as a standard. 1,3,5,8-Tetramethyl-6,7-di[2'-(closo-monocarbon carborane-1''-yl caesium)methoxycarbonylethyl]porphyrin 3a: yield 52%. 1H NMR, d: 10.82 (s, 1H, meso-H), 10.31 (s, 1H, meso-H), 10.27 (s, 2H, meso-H), 9.33 (s, 1H, ¥â-pyrrole), 9.32 (s, 1H, ¥â-pyrrole), 4.35 (s, 4H, OCH2), 3.76 (s, 6H, Me), 3.73 (s, 6H, Me), 3.60 (m, 4H, CH2CH2CO), 2.92 (m, 4H, CH2CH2CO), .4.06 (br. s, 2H, NH). MS, m/z: 1086.45 (M+).Electronic spectrum, lmax/nm (e¡¿10.3) (DMSO): 399.4 (43.71), 496.8 (9.66), 528.4 (5.97), 564.8 (4.78), 618.8 (2.5). IR (n/cm.1): 3320 (NH), 2527 (BH), 1723 (C=O). Found (%): C, 37.93; H, 4.86; N, 5.27. Calc. for C34H54B22Cs2N4O4 (%): C, 37.58; H, 4.97; N, 5.16. 1,3,5,8-Tetramethyl-2,4-divinyl-6,7-di[2'-(closo-monocarbon carborane- 1''-yl caesium)methoxycarbonylethyl]porphyrin 3b: yield 50%. 1HNMR, d: 10.22 (s, 1H, meso-H), 10.12 (s, 2H, meso-H), 10.09 (s, 1H, meso-H), 8.42 (br. s, 1H, CH=CH2), 6.40 (d, 1H, =CHH, 3Jtrans 17.2 Hz), 6.19 (d, 1H, =CHH, 3Jcis 10.4 Hz), 4.29 (s, 4H, OCH2), 3.56 (m, 4H, CH2CH2CO), 3.08 (m, 4H, CH2CH2CO), 2.50 (s, 12H, Me), .4.23 (br. s, 1H, NH), .4.30 (br. s, 1H, NH). MS, m/z: 1138.53 (M+). Electronic spectrum, lmax/nm (e¡¿10.3) (DMSO): 397.8 (65.40), 495.6 (11.85), 527.6 (6.92), 563.8 (5.57), 617.8 (2.09).IR (n/cm.1): 3327 (NH), 2532 (BH), 1714 (C=O), 1657 (C=C). Found (%): C, 40.37; H, 4.98; N, 5.07. Calc. for C38H58B22Cs2N4O4 (%): C, 40.09; H, 5.10; N, 4.92.Mendeleev Communications Electronic Version, Issue 1, 2001 (pp. 1–42) Thus, the anionic nature of the compounds synthesised, as well as the effect of the cation, makes them more promising than the currently known carboranyl-substituted porphyrins for the preparation of water-soluble pharmaceuticals for BNCT.This work was supported by the Russian Foundation for Basic Research (grant nos. 00-03-3287-2a and 00-15-97866). References 1 A. H. Soloway, W. Tjarks. B. A. Barnum, F.-G. Rong, R. F. Barth, I. M. Codogni and J.G. Wilson, Chem. Rev., 1998, 98, 1515. 2 R. C. Hausholter and R. W. Rudolph, J. Am. Chem. Soc., 1978, 100, 4628. 3 R. P. Evstigneeva, V. N. Luzgina, V. A. Ol’shevskaya and L. I. Zakharkin, Dokl. Ross. Akad. Nauk, 1997, 357, 637 (Dokl. Chem., 1997, 357, 299). 4 L. I. Zakharkin, V. A. Ol’shevskaya, R. P. Evstigneeva, V. N. Luzgina, L. E. Vinogradova and P. V. Petrovskii, Izv. Akad. Nauk, Ser. Khim., 1998, 347 (Russ. Chem. Bull., 1998, 47, 340). 5 L. I. Zakharkin, V. A. Ol’shevskaya, S. Yu. Panfilova, P. V. Petrovskii, V. N. Luzgina and R. P. Evstigneeva, Izv. Akad. Nauk, Ser. Khim., 1999, 2337 (Russ. Chem. Bull., 1999, 48, 2312). 6 L. I. Zakharkin, V. A. Ol’shevskaya, P. V. Petrovskii and J. H. Morris, Mendeleev Commun., 2000, 71. Received: 13th October 2000; Com. 00/