Molecules 2012, 17, 1-14; doi:10.

3390/molecules17010001
OPEN ACCESS

molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article

Facile Preparation of the Tosylhydrazone Derivatives of a Series
of Racemic trans-3,4-Substituted Cyclopentanones
Kamal H. Bouhadir 1,*, Bilal Abou Aleiwe 1 and Fares A. Fares 1,2
1
2

Department of Chemistry, American University of Beirut, Beirut 11-0236, Lebanon
Department of Chemistry, Lebanese University, Hadath 6573-14, Lebanon

* Author to whom correspondence should be addressed; E-Mail: kb05@aub.edu.lb;
Tel.: +961-01-350-000; Fax: +961-01-365-217.
Received: 14 November 2011; in revised form: 19 December 2011 / Accepted: 19 December 2011 /
Published: 22 December 2011

Abstract: We report the synthesis and characterization of a variety of trans-3,4-substituted
cyclopentanones and the corresponding tosylhydrazone derivatives starting with diethyl
fumarate. Protection of the keto group followed by selective monohydrolysis of esters was
achieved, resulting in cyclopentanones with different substituents at positions 3 and 4. The
tosylhydrazone derivative of each cyclopentanone intermediate was prepared in moderate to
good yields. These compounds are potential precursors for functionalized methanofullerenes.
Keywords: tosyl hydrazone; cyclopentanone; ethylene ketal; monohydrolysis

1. Introduction
Over the past two decades there has been an increasing interest in functionalized methanofullerenes [1,2].
These molecules have been utilized to couple proteins, oligonucleotides [3,4], and other macromolecules
as well [5]. The reason behind this interest is the potential utility of this class of compounds in
biomedical applications [6]. Fullerene derivatives such as fulleropyrrolidines are active against HIV-1
and HIV-2 and amino acid derivatives of fullerenes inhibit HIV and human cytomegalovirus
replication [7,8]. In addition, water-soluble photoactive fullerenes have been investigated as potential
photosensitizers for photodynamic therapy [9]. Several synthetic routes leading to methanofullerenes
have been well established over the last two decades including the thermal addition of diazocompounds
and carbenes to C60 [10]. We have previously reported the addition of tosylhydrazone salts to C60

ii. KMnO4.4-substituted cyclopentanone is an interesting entry to the formation of fuctionalized methanofullerenes and carbon nanotubes as well. 125 °C. 0 °C. However. Ac2O.4-bis(carboethoxy) cyclopentanone [(±)4] in 70% yield. Compound (±)3 was allowed to react continuously with acetic anhydride (thus forming the mixed anhydride) followed by sodium acetate whereby it underwent a Dieckmann condensation to form rac-trans-3. H2O:THF (8:2). Intermediate (±)2 was oxidized with potassium permanganate to yield the rac-trans-3. or a mixture of both. rac-trans-3. HCl. EtOH. stirring compound (±)4 for two hours under these conditions formed racemic trans-3. Preparation of intermediates 5 and 9. vi.4-substituted cyclopentanones and the corresponding tosylhydrazone derivatives as potential adducts for the preparation of methanofullerenes.5-bis(hydroxy-methyl) cyclohexene [(±)6] in 72% yield (Scheme 1) [21].4-bis(carboethoxy)cyclopentanone (±)4 was synthesized following a reported procedure (Scheme 1) [12]. In contrast. we either isolated the starting diester (±)4. Scheme 1. iii. NaOAc. Results and Discussion The first cyclopentanone derivative. The desired monohydrolysis product was procured following a different route. Compound (±)6 was then acylated with acetic anhydride to form racemic trans-4. Ac2O. iv. 2. Butadiene sulfone. THF (b) HCl.5-bis(acetoxymethyl)cyclohexene [(±)7] in 83% yield. We attempted at this point to selectively hydrolyze one of the ester groups in compound (±)4 under alkaline conditions utilizing sodium hydroxide in aqueous tetrahydrofuran (20% v/v THF:H2O) at 0 °C [11].4bis(carboethoxy)hexanedioic acid [(±)3] in 87% yield. pyridine. 17 2 resulting in the formation of methanofullerenes [11]. We report herein the facile preparation of a series of trans-3. as shown later on in this paper (Scheme 3). Intermediate . The synthesis of the second cyclopentanone derivative was initiated with the reduction of compound (±)2 in a stirred suspension of LAH in dry THF to form the racemic trans-4.4-bis(carboxy)cyclopentanone [(±)5] in 70% yield [13-15].5-bis(carboethoxy)-cyclohexene [(±)2] in 89% yield [8]. (a) LAH. CO2Et CO2Et i EtO2C ii HO2C HO2C CO2Et 1 CO2Et 2 (89%) EtO2C CO2Et iii CO2Et iv O 3 (87%) CO2H HO2C O 4 (70%) 5 (50%) v OH OAc vi ii OAc OH 6 (72%) OAc 7 (83%) HO2C AcO OAc iii HO2C OAc 8 (57%) O 9 (90%) Reagents and conditions: i. 2 hours (b) aq. The Diels-Alder reaction between butadiene sulfone and diethylfumarate (1) was utilized to form rac-trans-4. 24 hours. The tosylhydrazone derivative of 3.Molecules 2012. v. (a) NaOH. H2O. diacid (±)5.

(±)19. Intermediate (±)4 was converted to the corresponding ethylene ketal (±)10 in 92% yield (Scheme 2).4-bis(hydroxymethyl)cyclopentanone ethylene ketal [(±)14] in 97% yield. ii. 16 and 17. (±)22.N-dibenzylaminomethyl)cyclopentanone [(±)13] in 79% yield. DCC. Compound (±)19 was then reduced with LAH to form the ethylene ketal intermediate (±)20 in 96% yield.4-bis(N. 63%. 58%. 10% oxalic acid. Following this. Scheme 2. Reduction of intermediate (±)12 in a stirred suspension of LAH in dry THF formed the ethylene ketal derivative of racemic trans-3. silica gel. and 65% respectively (Scheme 2) [17]. Deketalization of compounds (±)12. 0 °C (b) HCl. and 90% respectively (Scheme 3). 17 3 (±)7 was oxidized with potassium permanganate to form racemic trans-3. Preparation of intermediates 15. and (±)15 in 70%.4-bis(acetoxymethyl)cyclopentanone [(±)9] in 90% yield (Scheme 1) [11]. HOBt. reflux. Hydrolysis of the ester groups in compound (±)10 was performed in alkaline aqueous tetrahydrofuran (80% v/v THF:H2O) at 0 °C to afford intermediate (±)11 in 65% yield [16]. v. NH(Bn)2. The free carboxylic acid groups were then coupled to dibenzylamine with dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) to form the corresponding amide (±)12 in 93% yield. THF:H2O (8:2). The free carboxylic acid group of compound (±)18 was coupled to dibenzylamine with DCC and HOBt to form the corresponding amide (±)19 in 87% yield. iv. 0 °C iii. The ethylene ketal derivatives (±)18. and (±)23 in 72%. . compound (±)10 was reduced with LAH to afford 3. (±)17. (±)13. and (±)14 was accomplished by stirring each compound in an aqueous suspension of oxalic acid (10% w/v) over silica gel for 24 hours at room temperature to afford the corresponding compounds (±)16.4-bis(acetoxy-methyl) hexanedioic acid [(±)8] in 57% yield. and (±)20. compound (±)8 was allowed to react with acetic anhydride and sodium acetate to undergo the a Dieckmann condensation and form racemic trans-3. In addition. were separately hydrolyzed as before by stirring over 10% aqueous oxalic acid and silica gel for 24 hours at room temperature to afford compounds (±)21.Molecules 2012. ethylene glycol. THF. The selective monohydrolysis of compound (±)10 was achieved with sodium hydroxide in aqueous dioxane (50:50 H2O/dioxane) at room temperature to form intermediate (±)18 in 81% yield (Scheme 3) [18]. (a) LAH. NaOH. 24 hours. CO2Et EtO2C CO2H CO2Et HO2C EtO2C i ii O O 4 10 (92%) O NBn2 NBn2 Bn2N iv O O 11 (65%) O O 12 (93%) O 13 (79%) v iv OH HO O iii O O Bn2N OH HO Bn2N O O v NBn2 NBn2 Bn2N v O O 14 (97%) O O 15 (65%) 16 (70%) O 17 (63%) Reagents and conditions: i. p-TsOH.

THF (b) HCl. Table 1.p. iii. iv. . dioxane. Scheme 4.4-substituted cyclopentanone intermediates was prepared following the classical method via the addition of each cyclopentanone derivative to a hot ethanolic solution of p-toluenesulfonyl hydrazide (Scheme 4) [19]. NH(Bn)2. silica gel. Entry R1 R2 Yield (%) a M. 24 hours. Experimental yields of the tosyl hydrazone derivatives 24a–i as shown in Scheme 4. Preparation of compounds 21. The tosylhydrazone derivative of each of the trans-3. b Compound decomposed. EtOH. The detailed experimental protocol for the preparation of the reported derivative 24a is included in this manuscript. 24 hours. Preparation of the tosylhydrazone derivatives 24a–i. (°C) 1 -CO2CH2CH3 -CO2CH2CH3 24a (64) 163–164 2 -CH2OCOCH3 -CH2OCOCH3 24b (81) ND c 3 -CO2H -CO2H 24c (59) 202–203 b 4 -CH2OH -CH2OH 24d (50) ND c 5 -CON(Bn)2 -CON(Bn)2 24e (54) 219–220 6 -CH2N(Bn)2 -CH2N(Bn)2 24f (52) 143–144 7 -CO2H -CO2CH2CH3 24g (64) 199-200 b 8 -CON(Bn)2 -CO2CH2CH3 24h (46) 177–178 9 -CH2N(Bn)2 -CH2OH 24i (66) 261–262 b a Yields refer to isolated products. c Not determined (hygroscopic). HOBt. Reagents and conditions: TsNHNH2.Molecules 2012. 17 4 Scheme 3. (a) LAH. 10% oxalic acid. The purified and isolated yield of each derivative varied between 46% for (±)24h (entry 8) and 81% for (±)24b (entry 2) as shown in Table 1. O CO2Et EtO2C CO2H EtO2C i O NBn2 EtO2C ii O O 10 O 18 (81%) iii O CO2H O 21 (72%) O O 19 (87%) iv EtO2C NBn2 HO O 20 (96%) iv iv O EtO2C O 22 (58%) NBn2 NBn2 HO O 23 (90%) Reagents and conditions: i. DCC. 22 and 23. reflux. NaOH. ii.

15 (q.735. ACROS Chemicals (Belgium). 100 mL) and with cold water (2 × 50 mL). 1H-NMR (DMSO-d6)  1.4-bis(methoxycarbonyl)cyclohexene (2. 2. 2. 0. 4. and were used as received. 1.57 mol) in water (350 mL) was slowly added.4. 2. The mixture was stirred vigorously and a solution of sodium carbonate (60 g.037. 33.3.51 mol). Chemical shifts are reported in ppm () downfield relative to TMS. 13C-NMR (DMSO-d6)  13. 174. The reaction was stirred for 3 hours at room temperature. The mixture was stirred for an additional 20 minutes.937. NJ. Reagents used in the syntheses were purchased from the Aldrich Chemical Company (Milwaukee.6. 2H).5 g. 0. Thin layer chromatography (TLC) was performed on polygram Sil G/UV254 silica gel sheets. 2H). 2.657. Petroleum ether (200 mL) was added and the mixture was stirred for about 10 minutes at a rate sufficient to achieve homogenization. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate and dried under reduced pressure to afford the product (38. The organic layer was separated and the aqueous layer was extracted with petroleum ether (2 × 100 mL). diethyl fumarate (86 g. 13C-NMR (CDCl3)  14. 41.82 (s). 2. The spectroscopic data were in good agreement with those reported in the literature [6].83 (m. 12. A pressure vessel was charged with butadiene sulfone (60 g. 4H). 5. rac-trans-3. 125. 2H). 6H). The organic layers were combined. The solvent was removed under reduced pressure and the product was purified by vacuum distillation (115 °C.4-bis(Ethoxycarbonyl)cyclohexene (2). 2H). The reaction was then carefully acidified (pH 2) with concentrated HCl and the clear solution was extracted with EtOAc:THF 1:1 (2 × 200 mL).42 (d). and hydroquinone (1 g. 2H). Preparative thin layer chromatography employed ALLTECH silica gel 60 F254 plates.69 (t.02 (t. Absolute ethanol (90 mL) was added and the mixture was stirred until most of the solid was dissolved.1 (d). 2. USA). 150.2 g. NMR spectra were determined in deuterated solvents with TMS as the internal standard on a Bruker AM 300 NMR spectrometer. Fisher Scientific Company (Fair Lawn.82 (q). Infrared spectra were recorded as KBr pellets using a Nicolet AVATAR 360 FTIR ESP spectrometer with a Hewlett Packard Desk jet 840C plotter.16 (t. and filtered.981.4-bis(Ethoxycarbonyl)hexanedioic acid (3). 2H). dried over anhydrous MgSO4. 34 g. 87%).25 (t. The mixture was cooled in an ice-water bath and a solution of rac-trans-3. 60. The vessel was sealed and heated slowly at 125 °C for 24 hours.44 (d.5. 2H). Experimental Melting points were determined on a Fisher-Johns apparatus and were uncorrected. 82 mL.038.58 (t). 1.6.19 (q). Sodium bisulfite was added (75 g) and the reaction was stirred for an extra 20 minutes. 200–400 mesh). 89%). Preparative column chromatography employed ACROS silica gel (60 Å.5 mol). Melting point: 170 °C (d). 27. and the yellowish mixture was transferred into an Erlenmeyer flask. 0.75 mmol) and water (365 mL) was stirred at room temperature for one hour.2. rac-trans-3. . 2H). WI.21 (m. 6H). 1H-NMR (CDCl3)  1.38 (d. FTIR (cm−1) 1. The vessel was allowed to cool down to room temperature. The organic layers were combined and washed with aqueous sodium carbonate (5%. 1.40 (m.2.18 (br s.92 (t). A solution of potassium permanganate (75 g. 9 mmol). 2.073.180. 4 mmHg) to yield an oil (99. 1.3 mmol) in acetone (40 mL) was added drop-wise while maintaining the temperature below 10 °C. 3. The IR bands are reported in wavenumbers (cm−1). 17 5 3.Molecules 2012. 4. The organic layer was dried over anhydrous MgSO4 and filtered.29 (t). 1. USA).

5.87 (s). The reaction was stirred for about 3 hours. 5. A solution of rac-trans-4.05 (t). 2H). 19 mL). 1. 10 mmHg) to afford the product (9 g.71 (s.8. Methanol (75 mL) was carefully added to decompose the excess acetic anhydride followed by water (150 mL).Molecules 2012. The combined organic layers were dried over anhydrous MgSO4 and filtered. Tetrahydrofuran (400 mL) was added to the solution and then decomposition of LAH was continued by the addition of aqueous KOH (15% w/v. 125. 72%): 1H-NMR (CDCl3) δ 1.65 (m.728.10 (q). 1. 6H). The spectroscopic data were in good agreement with those reported in the literature [11]. 1.62 (s).8. 0. 13C-NMR (CDCl3) δ 27. 171. 1. rac-trans-3.62 (m. 172.2.01 (d). 2. 1. 4H).01 (d). rac-trans-3. 2H).3.655. Sodium bicarbonate (5 g) was carefully added portion-wise and the mixture was stirred in an ice-water bath until bubbles ceased to evolve.7. 1.36 (m. FTIR (cm−1) 2.2.235. 20 g. Stirring was continued for 10 minutes and the white solid was filtered and washed with diethyl ether (2 × 100 mL).735. Sodium hydroxide (100 mL. 4. The reaction was saturated with sodium chloride and the solution was extracted with ethyl acetate (3 × 50 mL). The spectroscopic data were in good agreement with those reported in the literature [17].708. 65. 3.8 g.86 (m.962.084. 13C-NMR (DMSO-d6)  40. 0. Sodium acetate (3. 0.983. .3. 4-Oxocyclopentane-1. 4.890. 1.54–3.52 (s). and water (19 mL).11 (t). Excess LAH was decomposed by the addition of water (19 mL). 4H). 13C-NMR (CDCl3)  14.9 (br). 1. rac-cis-3.209. 1. 4H).91 (d).5 hours then refluxed for 14 hours.21 (m. FTIR (cm−1) 3.99–2. The filtrate was dried over anhydrous MgSO4 and filtered.5 hours.7 mmol) and acetic anhydride (75 mL) mixed and heated at 130 °C for 1. The solvent was evaporated under reduced pressure and the product was purified by vacuum distillation (180 °C.4. 1H-NMR (CDCl3)  2.68–1.4-bis(Ethoxycarbonyl)hexanedioic acid (3.054. 1.2. 172. 76%).353. 41.28 (t.5.294.26 (s).69 (t). The solution was extracted with CH−2Cl2 (3 × 75 mL). 50%). 43. The solvent was removed under reduced pressure to yield the product (12 g.04 (m. 213. 15 g.4. Melting point: 194–195 (d). 2H).18 (q.5-bis(Hydroxymethyl)cyclohexene (6). 2.181.37–2. 1H-NMR (DMSO-d6)  3.25 N) was added drop-wise during one hour at room temperature.4-bis(Ethoxycarbonyl)cyclopentanone (4. The spectroscopic data were in good agreement with those reported in the literature [20]. 212.282. 51. and then dipped in an ice-water bath. The reaction was acidified to pH 2 using aqueous hydrochloric acid (1 N). 1. The solvent was evaporated under reduced pressure to yield a solid (0.9.7. 17 6 42.1. 43.48 (s).753.27 mol) was added to dry THF (300 mL) under a nitrogen atmosphere at 0 °C. and the combined organic layers were dried over anhydrous MgSO4 and filtered. FTIR (cm−1) 2.8.2-dicarboxylic acid (5). The flask was cooled down to room temperature and immersed in an ice-water bath.92 (d). 61.75 g) was added in one portion and stirred at 130 °C until carbon dioxide ceased to evolve (20 minutes). Lithium aluminum hydride (10 g. 1.94 (t).41 (t). 4H). 3. rac-trans-4.52 (m. 174. 1.5.983.98 (t).019. The mixture was stirred at room temperature for 1. The mixture was cooled to room temperature.4-bis(Ethoxycarbonyl)cyclopentanone (4). 3.5-bis (ethoxycarbonyl)cyclohexene (2.5 mmol) was dissolved in THF (7 mL) and water (50 mL) was added. 39. 88. FTIR (cm−1) 2.5 mmol) in tetrahydrofuran (200 mL) was added drop-wise to the mixture. 2H).3 g. 60. The mixture was stirred for about one hour at room temperature.74 (d. 1.033. 4H). 1. 1.4.83 (s). 2H).14 (d).

6.10 (s). 5. 170. The flask was cooled to room temperature and immersed in an ice-water bath.30 (t). The solvent was evaporated under reduced pressure to afford the product (2. rac-trans-3.73 g.12 mL.43–2. 176. .31–2.34–4.99 (m. The reaction mixture was washed with a saturated solution of sodium bicarbonate (90 mL). The mixture was transferred to a separatory funnel and CH2Cl2 (40 mL) was added.6 (t). (6. rac-trans-3.7.694 g. 21.12 g) was added and stirring was continued for 5 minutes. 4H). 20.80 (t). 90%): 1H-NMR (CDCl3)  2.247.5 hours. 11 mmol) in acetone (5 mL) was added dropwise to a solution of potassium permanganate (5 g. 28. 2 × 25 mL).12–2. 21 mmol) was added in one portion and the reaction was stirred at 130 °C until carbon dioxide ceased to evolve (1 hour).4-bis(Ethoxy-carbonyl) cyclopentanone (4. The solution was then carefully acidified (pH 2) with concentrated HCl.5-bis(Hydroxymethyl)cyclohexene. rac-trans-4. The solution was extracted with CH2Cl2 (3 × 60 mL) and the organic layers were combined.9 (q). 20. 13C-NMR (CDCl3) δ 26.87 (d). 1. The mixture was refluxed for 20 hours. The mixture was cooled down to room temperature followed by the addition of ice-cold water (30 mL) was added.34 g.37 (m. FTIR (cm−1) 2. The organic layer was separated and washed with an aqueous solution of sodium hydroxide (10% w/v.34 (t.13 (m. 254 mmol) was added portion-wise and the mixture was stirred in an ice-water bath until the bubbling ceased to evolve. 2. 1. 2H).366. 1.69 g.01 (q).Molecules 2012.85 (s).118.68 (q).239.7.5 g. 13C-NMR (CDCl3)  41. 85%): 1H-NMR (DMSO-d6) δ 2.05 (s.732. 4H). The organic layers were combined.59–2. 33.22 g. Sodium acetate (1.48 (m. Sodium metabisulfite (5. 66.89 g. 64.91 (s). 1.00 (m. 171.9. Sodium bicarbonate (0.2. 3.19 mmol) and water (31 mL) while maintaining the temperature below 10 °C.63 (d.6 g. 3.239. 2H). 4H). The organic layer was dried over anhydrous MgSO4 and filtered. FTIR (cm−1) 1.4-bis(Acetoxymethyl)hexanedioic acid (8). 4.7 mmol) and acetic anhydride (26 mL) were mixed and heated at 130 °C for 1. 2.4-bis(Ethoxycarbonyl)cyclopentanone ethylene ketal (10).16 (d.69 (s).4-bis(Acetoxymethyl)hexanedioic acid (8. 4H).3 mmol) was added to a solution of ethylene glycol (60 mL) and p-toluenesulfonic acid monohydrate (0.10 (d). The mixture was stirred at room temperature for 20 hours. 1.95–3.658. rac-trans-3. Methanol (30 mL) was carefully added to decompose the excess acetic anhydride. 2. 6H). 37.739. The mixture was refluxed for 0.035. dried over anhydrous MgSO4.308. 1.8.6.5 hours.589 g.87 mmol) and sodium acetate (0. The clear solution was extracted with EtOAc-THF 1:1 (2 × 31 mL). FTIR (cm−1) 3.308. A solution of rac-trans-4. 1. 17 7 rac-trans-4. 2. 2H).5-bis(Acetoxymethyl)cyclohexene (7). 171.2 g) in toluene (270 mL). 2H). The solvent was removed under reduced pressure to yield an oil (6. dried over anhydrous MgSO4. and the solvent was evaporated under reduced pressure to afford the product (4.60 (t). filtered.95–2. and filtered. 64. Water (60 mL) was then added to the solution.8. 2. 13C-NMR (DMSO-d6) δ 33.2 mmol). 6 g. 125. 2H).82 (d).6. Sodium bicarbonate (21. 35.60 (s. 25. 1.8.048 (s. 33. The solution was extracted with CH2Cl2 (2 × 34 mL) and the combined organic layers were dried over anhydrous MgSO4. 26. 4. 20. 83%): 1H-NMR (CDCl3) δ 1. 2H).4 g.035. 6 g. 6H).17 (m.17 (d.5-bis(acetoxymethyl) cyclohexene (7. 2. 1. 4. 7. rac-trans-3.739.49 (t).05–4. 1.7.4-bis(Acetoxymethyl)cyclopentanone (9).9 mmol) was added to a mixture of acetic anhydride (6. 1. and filtered.2. 92%). 4H). rac-trans-3.904.4 mmol) was added and the mixture was stirred for 30 minutes.6. The solvent was removed under reduced pressure to yield the product (4.4 (d).80 (s). 215.

22–1. 3. 4H).9 mmol) was added to dry THF (8 mL) under a nitrogen atmosphere. 128. 4H).21–7. FTIR (cm−1) 3.71 (s).19 (m.81 mmol) in DMF (50 mL) at 0 °C and stirred for 90 minutes at room temperature.47 (s). 20H). aqueous KOH (15% w/v. The combined filtrate and organic washes were dried over anhydrous MgSO4 and filtered.090. 1.4-bis(ethoxycarbonyl)cyclopentanone ethylene ketal (10 g.260. 1. 48. Lithium aluminum hydride (0. 7. 128. A mixture of rac-trans-3.83 (d). 13 C-NMR (CDCl3)  42. 40. 3. 65%).33 (m. 2H). 1. 1.82 (t). 4H). 64. 59.34 (m.30–4. 139.19 (q). 8H). A solution of compound 12 (0. 1.06 (t). 3.3. 4.97 g.01 (m.77 (t). C-NMR (CDCl3)  14. 1. 127.77 (d).2-dicarboxylic acid ethylene ketal (11). 213. 116.88 (s). 1. 4 mmol) was dissolved in THF (10 mL) and water (80 mL). 4H). 2H). 36.6. and water (6 mL). 1.6.3–2. 173. 1. Lithium aluminum hydride (5.7 g.82 (s. FTIR (cm−1) 2. 4H).4-bis(hydroxymethyl)cyclopentanone (14). rac-trans-3. 2H). 4H). The reaction mixture was immersed in an ice-water bath and cooled down to 0 °C.21 (t). 2H). 128.2. The solvent was evaporated under reduced pressure to yield a solid (0. 4H). 2H).8 g.179. 95%. 2H). 13C-NMR (CDCl3)  30.87 (t).4.3 g. 1. 698.36 (m. 3.48 (d).76 (m. 815. 7. 2. 0.8. 1.28–3.310.80–3. 20H). 2. 44. 1.87 (d). 43. 115. 17 8 1 H-NMR (CDCl3)  1. The mixture was dried over anhydrous MgSO4 and filtered.1–4. 2.4.2-dicarboxylic acid 11 (1 g. 8 mmol) and 4-oxo-cyclopentane-1. 7. 1H-NMR (DMSO-d6)  1. The urea was filtered off and the filtrates were added to a solution of dibenzyl amine (1. 13 4-Oxocyclopentane-1. 127.157.52 g.22 mmol) in dry THF (6 mL) was added to the mixture dropwise. 39. The reaction was carefully quenched with water (10 mL). 114.52 (d).93 (m. The reaction mixture was saturated with NaCl and the product was extracted with ethyl acetate (3 × 60 mL). 3.05 (d). 2H). 174.377.16 (d).4-bis(Ethoxycarbonyl) cyclopentanone ethylene ketal (10.08 (t).05 mmol) was added to dry THF (180 mL) under a nitrogen atmosphere at 0 °C. 3.93 (t). The solvent was evaporated under reduced pressure to yield an oil (2.07 (m.1 g.33 (m.5. 1H-NMR (CDCl3)  1.8.066.26 (m. 4. 5.88 g. 3. 2H). 4-Oxo-cyclopentane-1.39 (t). 2. 3. 128. The solution was filtered and the solid washed with diethyl ether. 136. 1.92 (t). 551.53 (m.68–3.22 (m.325. The mixture was stirred overnight and the solvent was removed under reduced pressure. 60.96 (d). 6 mL).13 (m.735.66 (s).38 mmol) was added to a stirred solution of HOBT (1 g.43 (d).14–7.635. 58.41 (d). The combined organic layers were dried over anhydrous MgSO4 and filtered. 13C-NMR (DMSO-d6)  39.387. Dicyclohexylcarbodiimide (4 g. The solvent was evaporated under reduced pressure to form an oily residue that was triturated with hexane to yield a solid (0. and then acidified with aqueous HCl (1 N).8 (s). 1.90 (m. 4.15 (s).25 (t. The solid residue was dissolved in ethyl acetate and washed with a saturated solution of NaHCO3.59 (t).4.33 (m. 63. 49. 2H). 39.85 (s). 136.39 (s). 42. 126. 6H).61 (d).93 (t).1 (m. 78%).12 (d). 147.Molecules 2012.76 mmol) and . The mixture was refluxed overnight then cooled down to 0 °C in an ice-water bath.52 (s).25 N) was added drop-wise with stirring during one hour and the reaction was stirred at the same temperature for an additional hour.4-bis-(Dibenzylaminomethyl)cyclopentanone ethylene ketal (13). 129. 4H).41 (d).4 (m. 126. 63. The ethylene ketal of rac-trans-3. 19. 173. mmol) in DMF (50 mL).33.56 g.13 (q. 2H).28 (s). 3.58 (t). 93%).13 (t). 1H-NMR (CDCl3)  2.83 (m.036.982.14 (m.2-dicarboxylic acid bis-dibenzylamide ethylene ketal (12).4. Aqueous sodium hydroxide (100 mL.

4.9. Sodium bicarbonate (0.47–1.98 (d).79–1. 4.95–2.91 (m.5 g) was added to neutralize the mixture.10 (s). An aqueous solution of oxalic acid (10% w/v.83 mmol) in dichloromethane (10 mL) was added and the mixture was stirred for one day.21–7. 3.28 (s).88–2.69–3. 128.95 (t). 17 9 tetrahydrofuran (115 mL) was added dropwise and the mixture was stirred at room temperature for 0. 64.384. 3.73 (m. 4H). 70%).931. 1.6 (m.7.75 mL.59 (d.12 (t). A solution of compound 12 (0. 4. 1.2-dicarboxylic acid monoethyl ester ethylene ketal (18). 49. 2H).32 g.5 g) was added to neutralize the mixture. 173. 48. 136.4 (m. 2H). 12.82 (d).48 (d). The mixture was filtered and the silica gel was washed with ethyl acetate (2 × 20 mL) to remove any adsorbed product. 2H).90 (s.85 (s).16 (d).82 (m. 127.56 (q.888.4-bis-(Dibenzylaminomethyl)cyclopentanone (17).8. 20 drops) was added to a stirred suspension of silica gel (5 g) and CH2Cl2 (20 mL). 4. 4-Oxocyclopentane-1. 1. 2H). 4-Oxocyclopentane-1.55–3.01 (d. 139. 13C-NMR (CDCl3) δ 41.12 (t). 3.84 (d). 20 drops) was added to a stirred suspension of silica gel (3 g) and CH2Cl2 (20 mL).67 (d).52 (d).26 (d). 37. 4H).4-bis(Hydroxymethyl)cyclopentanone (15).80–3. 1. 949. aqueous KOH (15% w/v 12 mL). 3. 2. 4H).15 (s).371. Sodium bicarbonate (0.87 (t). rac-trans-3.92 (t).012. 57.83 (m. 13C-NMR (CDCl3)  28. rac-trans-3.83 (m.13 (m. 1.58 (s).35 (m. 6 mmol) was dissolved in water/dioxane .36 (m. 2.70–3. 2. 4.11(d).31 (s).99–2. 0. 1H-NMR (CDCl3)  2.3–2. 4H). 44. 126. After adsorption of the aqueous phase on the silica gel surface. 127. 3.49 (m. 128.74 (s. 2H).79 (s.084.638 g.2 (d). FTIR (cm−1) 3.41 (d). 21.5.13 (t).34 (m. 43.734. FTIR (cm−1) 1.Molecules 2012.46 (m. 2.58 g. 20H). The organic layers were combined and the solvent was removed under reduced pressure to yield an oily product (0. 13C-NMR (CDCl3)  42. The mixture was filtered and the silica gel was washed with ethyl acetate (2 × 20 mL) to remove any adsorbed product.14–7.85 (t). 58.36%): 1H-NMR (CDCl3) δ 1. Stirring was continued for 10 minutes and the white solid was filtered and washed with diethyl ether (2 × 50 mL). The organic washes were combined and the solvent was removed under reduced pressure to yield an oil (2 g. 2H). 217. 13C-NMR (CDCl3) δ 39. 4H). 3. and water (12 mL). An aqueous solution of oxalic acid (10% w/v.83 (d). 4H).4-bis(hydroxymethyl) cyclopentanone ethylene ketal (4 g.30–4. 4H).43–3.05 (d).7 g. An aqueous solution of oxalic acid (10% w/v. 55 drops) was added to a stirred suspension of silica gel (12 g) and methylene chloride (16 mL).4.95 mmol) was added to neutralize the mixture and the silica gel was filtered out and washed with ethyl acetate (70 mL). 2H). Sodium bicarbonate (0. 20H).4-bis (Ethoxycarbonyl)cyclopentanone ethylene ketal (10. 127. 65. The combined washes and filtrates were dried over anhydrous MgSO4. The organic layers were combined and the solvent was removed under reduced pressure to yield an oil (0.048. 3.5 g. 64. 5. rac-trans-3. 2H). 1. 213.98 (m.18 (m.2-dicarboxylic acid bis-dibenzylamide (16). 129. 4H). 136.38 (d. The reaction mixture was cooled to 0 °C using an ice-water bath. 65.1. A solution of compound 13 (1 g. 2H). 4H).5 hours and refluxed overnight. Excess LAH was decomposed by successive additions of water (12 mL).1.5 g.93 (t). 115. 3.8.1–4. 63%). 1H-NMR (CDCl3)  0. and filtered. 1.90 (t). 1.61 (t). 7. 128. 97%): 1H-NMR (CDCl3) δ 3.27 (s). The solvent was removed under reduced pressure to yield the product (6.41 (d). 4H). 4H). 129.87 mmol) in dichloromethane (10 mL) was added and the mixture was stirred for one day. 3. 7. 42.21 (d). 219. 43.2 mmol) was added and the mixture was stirred for 3 days.39 (s).

115. 64. 1H-NMR (CDCl3)  1. 0.6 (br). 3. 49.89 (m. 2H).25 (t. 6 mL) and water (6 mL).7.202. 42.2 g of an oily product (81%).47 (d).406.52 (s).6 g 1.22 (t. 39. The solvent was evaporated under reduced pressure and the residue was dissolved in water (30 mL).128. 38.93 (s). The organic layer was dried over anhydrous MgSO4 and filtered. 86%). The aqueous layer was acidified (pH 2) with aqueous HCl (1 N).63 (s). The aqueous layer was washed with chloroform (2 × 30 mL). 1H-NMR (CDCl3)  1. 41. 1. 47. 1.7. 128. 38.91 (s.4 mmol) was added to a stirred solution of HOBt (0.3. 1. 64.7. 173.4 mmol) in dry DMF (2 mL). 3-Dibenzylaminomethyl-4-hydroxymethylcyclopentanone ethylene ketal (20). 13C-NMR (CDCl3)  14.29–3. 48.54 mmol) was added to dry THF (25 mL) under a nitrogen atmosphere at 0 °C. 173. 3H).12 (q).20 (d). 1.86 (t). 2H).1.156.91 (d). 3. 10H). The crude was dissolved in ethyl acetate (10 mL) and washed with saturated solution of NaHCO3 and brine. 60. sodium hydroxide (50 mL.40 (m. 126.09 (d).80 (m.55 (t). 2.11 (t).5 g of an oily product (96%). 1. 3.187. 39.7. aqueous KOH (10% w/v.500.25 (m.81 (d). The reaction was refluxed overnight then cooled down in an ice-water bath .1 g.1 g. 2H). 10 mL) followed by aqueous NaOH (5% w/v.2-dicarboxylic acid monoethyl ester ethylene ketal (18.Molecules 2012. 58.84 (t).67 (t).25 (t). 547. 10 mL).9.20 (q).37 (d).31 (t). 2H).11 (dd. 178. 129. 2. Dicyclohexylcarbodiimide (0.34 (d). 0.41–1.44 (s).8.73 (d). 1H). 2H).715. 1. 2. 13C-NMR (CDCl3)  39. 3.644. 10. 2H). The reaction mixture was then stirred for an additional hour at room temperature. 137. 3. 58.79 (t).62 (m.71 (t). Lithium aluminum hydride (0. 0. 2H).66 (m.19–7. 2H).12 (t). 127.60 (d). 7.66 (d).4 mmol) and 4-oxocyclopentane-1.728. 1H). 1.7.495. 17 10 1:1 (30 mL).29 (m. The solution was filtered and the solid washed with diethyl ether. 2H).68 (s).67 (s).10 (d). 3.03 (d).341. 128.21–7. 4.59 (d).33 (d). 66.35 (m. 2. 115. The combined organic washes were dried over anhydrous MgSO4 and filtered. 3.029. 127. 115. 43. 136. 0. 3H). 7. 127.96 (t).030.17 (q. 13C-NMR (CDCl3)  14. 67.70 (d). 3. 4H).90 (d). 2. 4. 1.8.25 N) was added drop-wise during one hour.4 mmol) in dry DMF (2 mL) at 0 °C and stirred for 90 minutes.16 (s).15 g. 1. FTIR (cm−1) 3.01 (m.054 g. 2H).4 (m.99 (t). 4H).98 (m.23 (dt. 95%.21 (dd.9. 126.193. 4H). 2.33 (t).71 (s). 1. 128. 64. 128. 128.88 (s). After stirring overnight the solvent was evaporated under reduced pressure.75 (d). 1. . 4H).979. 41. 64. 2-Dibenzylcarbamoyl-4-oxo-cyclopentanecarboxylic acid ethyl ester ethylene ketal (19). 2H).24 (t). The organic layer was washed with aqueous HCl (1 N.418 mmol) in dry THF (25 mL) was added drop-wise and the mixture was stirred for 30 minutes. A solution of compound 19 (0.8. 10H). 44.64 (t).44 (d).442. FTIR (cm−1) 3. 0.15–4.25–1.024. The solution was extracted with chloroform (3 × 50 mL) and the organic layer was evaporated under reduced pressure to give 1. The solvent was evaporated under reduced pressure to yield 0.17 (t).46 (m. 1H-NMR (CDCl3)  1.63 (m. 126.85 (m. 173.22 (s). 0.0786 g.451.60 (t). 136. 44. 4. The solvent was evaporated under reduced pressure to give the product which was loaded on a silica gel column chromatography and eluted first with methylene chloride isolating the excess DCU and then with ethyl acetate to yield an oil after the evaporation of the solvent (0.71 (t). After stirring 30 minutes at room temperature DCU was filtered and the filtrate was added to a solution of dibenzyl amine (0. 60. 1.74 (d).16 (q. 1.The reaction was carefully quenched with water (10 mL).7. After stirring for 10 minutes at room temperature aqueous.4 g. 1. 3. 2H).

3. 3-(Dibenzylaminomethyl)-4-(hydroxymethyl)cyclopentanone (23).41–7.06 (d).97 (t).38 (s. The organic layers were combined and the solvent was removed under reduced pressure to yield an oily product (0. 42.34 (d.95 (t).7.451.20 (m. 128.69 (d). 1H-NMR (CDCl3)  1. filtered.363.07 (d).26 (m. 40. 4H). 42.57 g. 2-Dibenzylcarbamoyl-4-oxo-cyclopentanecarboxylic acid ethyl ester (22). 20 drops) was added to a stirred suspension of silica gel (3 g) and CH2Cl2 (20 mL). The silica gel was washed with ethyl acetate (2 × 30 mL) to remove any adsorbed product.56 (t). 128.14 (d).3.01 (s). 40. Sodium bicarbonate (0.1. 213. 1H-NMR (DMSO-d6) δ 1. 127. 216. 13C-NMR (CDCl3)  14.24 (d).37 (t). 128. 2H). 129.03–1.64 (d).2-dicarboxylic acid monoethyl ester (21).25 (m. 3. 2H).41 (m.52 g. 58%). 3.28 (t.75 (dd.41 (t).17 (t. 7. 1. 62.69 (d. 701.38 (t). 2H). 17 11 4-Oxocyclopentane-1.37 (dd. 1.05 (t). 3.80 (s).67 (m. 2H).61 (d).57 (d).07 (q.728.55 (d). 44.029.58 (d).90 (m.7.62 (d). 2H). 4. 71%). 10H).57 (m.91 (s). 3H).16–3. The mixture was filtered and the silica gel was washed with ethyl acetate (20 mL) to remove any adsorbed product. 1.48 (m.36 mmol) in dichloromethane (15 mL) was added and the mixture was stirred for one day. A solution of compound 18 (1 g. 2H). 129.09 (s). 20.82 (d).13 (m. 57.91 (q). 1. 2.1. 61. 48. The mixture was filtered and the silica gel was washed with ethyl acetate (2 × 30 mL) to remove any adsorbed product. rac-trans-3.06 (s). 2. 2.030. 35. 50. 6H). 161.62 mmol) in dichloromethane (15 mL) was added and the mixture was stirred for one day.39–3. 31.9. 2H). 7.57 (m. 172. Sodium bicarbonate (1 g) was added to neutralize the mixture and the mixture was filtered. The organic layers were combined and the solvent was removed under reduced pressure to yield the product (0.38 (t).52 (d). 43.40 (t). 10H).05 (t). 40.1. 5. 126. 136. 2H). 2H).2.69 (t).24–1.47 (s). 127.4-bis(Ethoxycarbonyl)cyclopentanone p-tosylhydrazone (24a).87 (q).85 (d). 55.13 (q). 127.62 (m. 2. 61.50 (d). General Protocol for the Preparation of the Tosyl Hydrazone Derivatives 24a–i p-Toluenesulfonyl hydrazide (1. 7. 43.643.9.19 (m.38 mmol) was added followed by water (1 mL) and the hot mixture was allowed to stand at room temperature for 30 minutes. 3.80 (t).4 g. 4. 4. 127. The organic layers were combined and the solvent was removed under reduced pressure to yield an oily product (0. 2H). 1.74 (t). 1H-NMR (CDCl3)  1. 173. 44.85 (m. 4H).77 (d).187. 177.36 (m. 2. 3. 20 drops) was added to a stirred suspension of silica gel (3 g) and CH2Cl2 (20 mL). 2H). 4. 44. 4.29 (s). The desired cyclopentanone (4. 13C-NMR (DMSO-d6)  39. 13C-NMR (CDCl3)  14. FTIR (cm−1) 3.52 (t). 4H).38 (m. 2. 4. 2. 43.979.08 (q). 4H). 2H).817 (t).8. A solution of compound 20 (0. A solution of compound 19 (1 g. 1. An aqueous solution of oxalic acid (10% w/v.22 (q. 173. 40. 4. 20 drops) was added to a stirred suspension of silica gel (3 g) and CH2Cl2 (5 mL).187. 3H). 2. 2H). 3. A white solid precipitated. 2H). 40. 2H). 90%). 1.62 (s).35 .5 g) in dichloromethane (10 mL) was added and the mixture was stirred for one day.48 mmol) was dissolved in hot ethanol (13 mL).02 g. 1. 213. and recrystallized from ethanol to yield the corresponding p-tosylhydrazone derivative 24a–i.93 (t). Sodium bicarbonate (1 g) was added to neutralize the mixture. An aqueous solution of oxalic acid (10% w/v.46 (s). An aqueous solution of oxalic acid (10% w/v. 13 C-NMR (DMSO-d6) δ 13.442.7. 3H).14–7. 61.91 (t).71 (m.08 (m. 7.Molecules 2012. 1H-NMR (DMSO-d6)  1.57 (s). 60. 136. 2H).37 (d).41 (d). 127.5 g) was added to neutralize the mixture.

38 (s. 1.3. 12H).00 (d). 128. 128.81 (m. 4-Oxocyclopentane-1. 49.38 (s.093. 161.165.597.37–7.2. .76 (s). 1.453.14 (s. 1H). 2H).2-dicarboxylic acid monoethyl ester p-tosylhydrazone (24g).9.23–7. 4. 35. FTIR (cm−1) 3.92 (q).1 (s).21 (t). 173.410.35 (d). 142.9. 1.086.22 (s). 4H). 173.4.734.8. 136. 2H). 4H).960.288.1. 2. 4H). 127.42 (m.5. 1.51 (t). 4. 143. 43. 2.52 (t). 1. 143.635.71 (d).2.307. 13C-NMR (DMSO-d6) δ 20.337. 41.70 (d.40 (m.45 (m. 57.021.86 (q).73 (m.022.90 (m. 1.57(d).04 (s).12 (t).6. 39. 40.409. 1.45 (t).2. 2H). 2. 129.475.39 (m.19 (d). 2H). 129.45 (m. 1H).450.349.2. 1.156. 2.59 (t).72 (s). 3.73 (d.597.36 (t).733.64–3.59 (s). 8H). 127.092.31 (t).37 (s. 127. 1. 2. 7. FTIR (cm−1) 3. 1. 967.3.94 (m.923.42 (m. 1. 13C-NMR (DMSO-d6) δ 13. 2. 136.70–7.70 (m.55 (d. 1.50 (s).4. 1. 2.19 (s).19 (d). 2.17 (s. 7.9. 2H). 129.60 (dd. 136 (s).21 (m. 918.69 (t).71 (t).17–137.9. 126.52 (d). 2.97 (d).72 (d).33 (t). 128.64 (d).288.70 (s). 50.307.67 (d).46 (t). 129.67 (d. 13C-NMR (DMSO-d6) δ 20.598.65 (m.3. 3. 2H). 3H). 7. 129. 17 12 (d). 2H).701. 137. 1. 3H). 1. 8H).33 (d). 2.1.4.50–129.56 (t).7.93 (d).07 (q. 923. 1H-NMR (DMSO-d6) δ: 1. 7. 2H).6.78–7. 1.21 (s).91 (m. 125. 3H). 144. 143.65 (s).598. 172.9. 4.51 (m. 1H).61 (t).96 (s). 4-Oxocyclopentane-1. 127.21 (m.5.62–7.55 (m.23 (d). 129. 126.36–4. 10. 44. 815. 2. 1.66 (t). 48. 2.12 (q.61 (q). 127. 1.10 (s).2. 4. 2H).40 (d). 60.2.923.38 (d).01. 7.10 (d). 3-(Dibenzylaminomethyl)-4-(hydroxymethyl)cyclopentanone p-tosylhydrazone (24i).349. 45. 3.52 (s). 1H). 2. 2. 2H).42 (s.37 (s. 37. 172. 127.38 (d). 162.20 (s). 162. 3.162.81(d).2.99–4. 2H).6. 2H).032. 2H). 1. 2H). 2H). 1. 127.5.33 (d).6. 1.11 (s). FTIR (cm−1) 3. 7. 2.200.598.1. 136.494. 37. 1. 1. 1H). 39. 60. 127.23 (d). 1. 2. 50.59 (d).200. 1H-NMR (DMSO-d6) δ 2.7. 2H).09 (d. 129. 3H). 1.62 (d). 1. 1.15 (t.35 (d). 2H).338. 1. 13C-NMR (DMSO-d6) δ: 13.37 (d). 31.200.83 (s). 3.093. 2H). 124.53 (d). 172. 13C-NMR (CDCl3) δ 21.10–7. 4.91 (q).61–2.219.75 (d). 22H).8. 136. 1. 31. 62.91 (q).94 (s). 162. 49.162. 126. 20.5. 128. 1H). 1. 1.9. FTIR (cm−1) 3. 1H). 39.32–7.64 (s). 2.40 (s).165.46(d).2. 1H-NMR (DMSO-d6) δ 1.926.76 (t). 2H).23 (s).338. 143. 44. 10. 1.2.6. 3. 4H). 2. 1. 7. 7.7. 4H).028.029.4-bis-(Dibenzylaminomethyl)cyclopentanone p-tosylhydrazone (24f).37 (d).18 (m.1.258.88 (t).4. 2H).378.701. 7.021.2.92 (d).44 (d). 7.85 (q). FTIR (cm−1) 3.71 (s). 2H). 1H-NMR (DMSO-d6) δ 2.80 (m. 2-Dibenzylcarbamoyl-4-oxo-cyclopentanecarboxylic acid ethyl ester p-tosylhydrazone (24h).91 (m.5.410. 172.8. 136. 3H). 2H).2. 3. 136. 1. 1.49 (s). 3. 4-Oxocyclopentane-1.18 (s).493.387.633. 1. 1. 164.12–7. 1.27 (d). 141.08 (s).21 (s).9. 127. 1. 7. 3.51 (d). 2.6. 32. 30.2.92 (d).32 (m. 4.10 (d).409.7.28 (m.74 (d. 44. 44.95 (dd. 129. 57.33 (d.24 (t).156.28 (m. 39.85 (m. FTIR (cm−1) 3. 7. 136. 129. 3. 20H).91 (q).21 (s).40 (d. 38. 172. 1.60 (d).51 (t).2-dicarboxylic acid p-tosylhydrazone (24c).441. 126.Molecules 2012.81 (m. 1H-NMR (CDCl3) δ 2.33 (s). 174.5. 129.8.41(d). 3H).812.49 (t).56 (m. 127. 7.2-dicarboxylic acid bis-dibenzylamide p-tosylhydrazone (24e). 2. 2. 13C-NMR (DMSO-d6) δ 39.21 (m.13 (d). 2H).1. 3H).68 (d).1. 174. 918. 44.2.35–4. 1. 1. 162.6.17 (s). 128. 3. 3.75 (s).63 (d). 1.13 (t).60–4. 20.36 (d).06 (m.984.85 (d).40 (s.4.9.91 (d). 4H). 1. 10H).90 (d). 1H-NMR (DMSO-d6) δ 1. 128.092. 2H).9. 49. 48. 1H). 1.37 (m.63 (d.66 (t). 4.

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