A novel method for the construction of a fused cyclohexadiene ring on C60 based on a nickel-promoted [2+2+2] cycloaddition of 1,6-diynes is described. Treatment of C60 with terminal 1,6-diynes (HC⋮CCH2)2X) in the presence of NiCl2(PPh3)2, Zn, and PPh3 at 90 °C in toluene afforded [2+2+2] bicyclic hexadiene derivatives (X = C(CO2Me)2 (2a), C(CO2Et)2 (2b), C(COMe)2 (2c), CH2 (2d), O (2e), NSO2-p-C6H5CH3 (2f), C(SO2Ph)2 (2g), and (2h) in good yields. Spectral data for products 2a − h indicated that the cycloaddition of diynes to C60 occurs across a 6,6-ring junction on the fullerene. On the basis of the established chemistry of metal-mediated [2+2+2] cycloaddition, a mechanism is proposed to account for the present nickel-mediated reaction. All the hexadiene derivatives 2a−h in solution are readily oxidized by molecular oxygen in the presence of light at ambient temperature. The oxidation process of compound 2a in chloroform-d was monitored by 1H NMR spectroscopy, and the results showed that 2a first reacted with molecular oxygen to form peroxide 3 and was subsequently converted to dialdehyde 4 and C60-containing polymeric material. Photochemical properties of some cyclohexadiene derivatives were then investigated. Upon irradiation (350 nm), compounds 2a−c, 2f, and 2h readily underwent [4+4] cycloaddition to give the corresponding bisfulleroids 5a−c, 5f, and 5h in excellent yields.
A unique method to introduce phosphorus substituents onto C(60) is based on the reaction of phosphines with acetylenes and C(60). Treatment of C(60) with phosphines (PR(3)) and electron-deficient acetylenes (A) in toluene at ambient temperature gave fullerene derivatives (1, R = C(6)H(5) and A = MeO(2)CC&tbd1;CCO(2)Me; 2, R = C(6)D(5) and A = MeO(2)CC&tbd1;CCO(2)Me; 3, R = C(6)H(5) and A = EtO(2)CC&tbd1;CCO(2)Et; 4, R = p-CH(3)C(6)H(5) and A = MeO(2)CC&tbd1;CCO(2)Me; 6, R = C(6)H(5) and A = trans-MeO(2)CC&tbd1;CCH=CHCO(2)Me) consisting of a phosphorus ylide group and a cyclopropane ring on the fullerene moiety in good to excellent yields. The structures of these ylide derivatives are determined on the basis of their spectral data and single-crystal X-ray diffraction measurements. All these ylides show temperature-dependent NMR spectra that can be rationalized on the basis of interchange between two Z,E isomers and restricted rotation of the substituents on the fullerene moiety. Based on the known chemistry of phosphines and acetylenes, we propose a mechanism to account for the formation of these ylide derivatives. Phosphine ylides 1 and 4 readily undergo protonation and decarboxylation in the presence of acid to give phosphonium salts 7 and 8, respectively.
Treatment of phosphites (P(OR)(3)) and MeO(2)CCCCO(2)Me with C(60) affords the corresponding fullerene derivatives (1, R = Me; 2, R = Et; 3, R = n-Bu) consisting of a phosphite ylide group and a cyclopropane ring on the fullerene moiety in high yields. NMR data indicate that all phosphite ylides 1-3 exist as mixtures of E and Z isomers. Under similar reaction conditions, the reaction of phosphinite PPh(2)(OMe) and MeO(2)CCCCO(2)Me with C(60) gives ylide 4. Ylides 1-3 readily undergo hydrolysis with HBr to give corresponding phosphonates 5-7 in excellent yields, while ylide 4 reacts with hydrobromic acid to afford phosphine oxide 8. A mechanism is proposed to account for the formation of these phosphonate derivatives. Further treatment of phosphonate derivative 5 with trimethylsilyl iodide followed by water gave phosphonic acid derivative 9 in 83% yield.
Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6--12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.
An alpha-carbonyl radical cyclization approach toward synthesis of angular triquinanes is described. As a model study, conjugate addition of 4-(trimethylsilyl)-3-butynylmagnesium chloride to enone 7 followed by trapping of the enolate with chlorotrimethylsilane gave trimethysilyl enol ether 8. Iodination of 8 with a mixture of NaI and m-CPBA afforded iodo ketone 6. Radical cyclization of 6 effected by Bu(3)SnH and AIBN gave 5. Epoxidation of 5 with m-CPBA yielded epoxy ketone 9. Desilylation and rearrangement of 9 by formic acid gave aldehyde 4. Aldol condensation and dehydration furnished angular triquinane skeleton 3. Total synthesis of (-)-5-oxosilphiperfol-6-ene (1) was accomplished in 12 steps starting from keto ester 14 based on this route. Conjugate addition of 3-hexynylmagnesium bromide to chiral ester 13 followed by treatment with chlorotrimethylsilane gave intermediate 15. Iodination of 15 with a mixture of NaI and m-CPBA gave alpha-iodo ester 12. Intramolecular radical cyclization of 12 gave ester 11. Reduction of 11 by LiAlH(4) yielded alcohol 16. On treatment with m-CPBA, alcohol 16 was converted to the corresponding epoxide 17, which was subjected to the epoxy-ketone rearrangement using BF(3) etherate as a catalyst to give ethyl ketone 18. Subsequent oxidation of 18 with PCC afforded aldehyde 10. Intramolecular aldol condensation of 10 yielded tricyclic compound 19. Methylation of 19 gave 20. Conjugate addition of lithium dimethylcuprate to 20 followed by trapping of the resulting enolate with chlorotrimethylsilane gave 21. Oxidation of 21 by DDQ afforded enantiomerically pure (-)-5-oxosilphiperfol-6-ene (1). Racemic (+/-)-1was also synthesized in the same manner in order to determine the optical purity of chiral product (-)-1. The gas chromatographic analysis with a chiral column proved that 1 has high enantiomeric purity. A single-crystal X-ray analysis of 2,4-dinitrophenylhydrazone 22 was performed to unambiguously confirm the stereochemistry of 19.
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