Aspects of the radial chemistry of the thiocarbonyl function and a new synthesis of olefins via Alpha-nitro-Beta-trithiothionocarbonates

Abstract

The dibenzofuran-based amino acid residue, 4-(2-arninoethyl)-6-dibenzofuranpropanoic acid (1), was studied to evaluate its efficacy in nucleating antiparallel,8-sheet structure in a series of thirteen residue peptides related to and including the K-V-K-V-K-V-1-V-K-VK-V-K-NH2 sequence. Spectroscopic studies indicate these peptides are able to adopt a #-sheet structure in aqueous solution. Residue I nucleates #-sheet structure in aqueous solution through the formation of an intramolecularly hydrogen bonded hydrophobic cluster resulting from interactions between the dibenzofuran skeleton in residue I and the hydrophobic side chains of the a-amino acids flanking residue 1. The hydrophobic cluster acts as a nucleation site which is poised to facilitate [ ]sheet folding once the charge density in the polycationic tridecapeptide sequence is lowered by adjusting the solution pH or increasing the ionic strength of the solution. Analytical equilibrium ultracentrifugation studies reveal that the intramolecularly folded,6-sheet tridecapeptides undergo further self-assembly mediated by intermolecular lateral hydrogen bonding of the pepfide backbone. This association ultimately yields a quaternary [ ]sheet structure which can be visualized by from electron microscopy studies. The incorporation of N-methylated amino acids into the peptide sequence serves to block the lateral hydrogen bonding network and has shown promise towards preventing p-sheet association. The potential for the formation of the cisisomer about the N-methyl amide, however, can produce unwanted peptide backbone conformations. Circular dichroism, NMR and analytical equilibrium ultracentrifugation studies reveal that the N-methylated peptides are monomeric and adopt p-sheet structure, although not as well-defined as the associated #-sheets. The [ ]sheet structure present in these N-methylated peptides can be further stabilized by increasing the temperature or by addition of trifluoroethanol. Relative and absolute reaction rates were determined in a systematic study of reagents and derivatives for the Barton-McCombie deoxygenation reaction. Derivatives (S-methyldithiothionocarbonate, phenylthionocarbonate, 4-chlorophenylthionocarbonate, 4-fluorophenylthionocarbonate, 2,4,6-trichlorophenylthionocarbonate, 2,3,4,5,6 pentafluorophenylthionocarbonate, S-(2,4-ditnitrophenyl) dithiothionocarbonate, and N,N-(diethyl)-thionocarbamate) of model alcohols (cyclododecanol and cholesterol) were synthesized and reacted under standard conditions (100 'C or I 10 'C, AEBN initiator) with tributyltin hydride. Rate data were obtained by quantitative IH-NMR. In nearly every case, Barton-McCombie deoxygenation was much faster than expected -literature methods generally advised reaction times of three hours or more. Furthermore, there was little appreciable difference in reaction rates for most of the derivatives (first half-lives were about 0.5 - 1.0 min). The xanthate (S-methyldithiothionocarbonate) reacted somewhat faster than any of the arylthionocarbonate derivatives - among these, a decreased reaction rate was noted for derivatives with greater electronegative substitution on the phenyl ring. Exceptions were noted in reactions of the S-(2,4-dinitrophenyl) dithiothionocarbonate and NN-(diethyl)-thionocarbamate derivatives. The NN-(diethyl)-thionocarbamate derivative remained essentially unchanged even after prolonged reaction times, while the S-(2,4-dinitrophenyl) dithiothionocarbonate derivative reacted to give 2,4-dinitrobenzene and the starting alcohol instead of the expected deoxygenation product. Reaction rates were also obtained for the synthesis of several arylthionoformate derivatives of cholesterol (model alcohol). The model alcohol was treated with pyridine and an arylchlorothionoformates (phenyl chlorothionoformate, 4-chlorophenyl chlorothionoformate, 4-fluorophenyl chlorothionoformate, 2,4,6-trichlorophenyl chlorothionoformate, and 2,3,4,5,6-pentafluorophenyl chlorothionoformate). Rates for the acylation were measured under standard conditions (25 'C, CDC13 soln) using quantitative I H-NMR. Acylation using 2,4,6-trichlorophenyl chlorothionoformate was much slower than with any of the other reagents (first half-life = 27 min). Rates for the remaining reagents tended to increase with greater electronegative substitution on the phenyl ring. First half-lives for these ranged from 0.5 - 3.5 min, with 2,3,4,5,6-pentafluorophenyl chlorothionoformate reacting more than twice as fast as any of the other reagents. A new method for the synthesis of olefins from nitroolefins or (X-nitro alcohols was developed. The reactions involved are quite mild. and the use of undesirable tributyltin hydride is avoided. A pivotal step is nucleophilic Michael addition of S-ethyl trithiothionocarbonate to non-hindered vinylic nitroolefins. The novel (x-nitro trithiothionocarbonate derivatives can generally be obtained in near quantitative yield without purification. Radical-induced (visible light photolysis of 1-2 eq of N-(2-methylpropionyloxy)-pyridine-2-thione as radical source) elimination of the ethyltrithiothionocarbonate and nitro moieties gave olefins (mixture of E and Z) in good to high yields. Olefins were prepared using several simple model compounds. This method was also applied in the synthesis of 7,8-dideoxy-1,2:3,4-di-0-isopropylidene-(X-D-galacto-oct-6-ene-1,5pyranose.