22530-09-2Relevant articles and documents
Regioselective reductive opening of substituted phthalans: synthetic applications
García, Daniel,Foubelo, Francisco,Yus, Miguel
, p. 4275 - 4286 (2008/09/20)
The reductive opening of substituted phthalans 6, 11, 12, 20, 21 and 28 with lithium and a catalytic amount of DTBB leads to the formation of corresponding functionalised organolithium intermediates 8, 15, 16, 23, 25 and 29+30 in a regioselective manner. The further reaction of these dianions with different electrophiles, mainly carbonyl compounds, gives the expected functionalised benzylic alcohols 9, 17, 18, 24, 26 and 31+32. The observed stereochemistry can be easily explained taking into account the values of the electron densities deduced by semiempirical PM3 calculations.
Regiochemistry in the reductive opening of phthalan derivatives
Foubelo, Francisco,García, Daniel,Moreno, Benjamín,Yus, Miguel
, p. 3379 - 3383 (2008/02/12)
The lithiation of phthalan derivatives 4, 9 and 12 with an excess of lithium in the presence of a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB) in THF at -78 °C gives dianionic intermediates 5, 10 and 13, respectively, which by reaction with different electrophiles [H2O, t-BuCHO, Me2CO, (EtO)2CO] at the same temperature, followed by hydrolysis, leads to regioselective functionalised naphthalenes 7, and biphenyls 11 and 14. The reductive opening takes place with high or total regioselectivity and can be explained considering the electron density in the dianion or in the radical anion, which are formed previous to the carbon-oxygen bond excision. The lithiation of the dihydrofurophthalan derivative 18 with the same reaction mixture but at higher temperature (0 °C) leads to intermediates 19 and 20, resulting from a single and a double reductive cleavage, respectively, which after addition of H2O and benzaldehyde as electrophiles gives a mixture of compounds 21 and 22.
Synthesis and structure-activity relationships of phenylenebis(methylene)- linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker
Bridger,Skerlj,Thornton,Padmanabhan,Martellucci,Henson,Abrams,Yamamoto,De Vreese,Pauwels,De Clercq
, p. 366 - 378 (2007/10/02)
We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11- tetraazamacrocyclic(cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p- phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (III(B)) and HIV-2 (ROD) at EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 μM. In order to identify the structural features of bis- tetraazamacrocycles required for potent activity, we have prepared a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depending upon the substitution of the phenylenebis-(methylene) linker (para or meta), sub- micromolar anti-HIV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4 cells. Furthermore, while we found that identical macrocyclic rings are not required for activity, substituting an acyclic polyamine equivalent for one of the cyclam rings in 19a resulted in a substantial reduction in anti-HIV potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transition metal complexes of 19a were also prepared and evaluated. Complexes of low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of bicyclam analogs appears to be insensitive to the electron-withdrawing or - donating properties of substituents introduced onto the linker, but sterically hindering groups such as phenyl markedly reduced activity. As a result, several analogs with anti-HIV potency comparable to that of 19a have been identified.
