Synthesis of pyrazines, carbocycles, and substituted piperidines.

摘要

Aromatic heterocycles such as pyrazines are core moieties in a variety of natural products, flavorings, and pharmaceuticals. Before this work, there was no general method to prepare unsymmetrical 2,3,5,6 tetraalkylated pyrazines. An approach was established based upon the opening of epoxides with unprotected vicinal amino alcohols. Swern oxidation followed by condensation with hydroxylamine hydrochloride led directly to the product pyrazines in moderate yields. This provided a succinct entry to tri- and tetraalkylpyrazines in a regiocontrolled fashion.;Polycarbocyclic systems, priviledged structures in biological and medicinal chemistry, are common in natural products. Because of this, it is necessary to develop toolsets for polycarbocyclic construction so pharma space can be more thoroughly explored. One such tool in our lab is the UV-promoted, Fe(CO) 5-mediated cyclocarbonylation of alkenyl cyclopropanes. Birch reduction of m-xylene gave a symmetrical diene that was monocyclopropanated with ethyl diazoacetate and Cu-bronze catalyst. The ester was then homolgated to an olefin providing an alkenyl cyclopropane substrate for the cyclocarbonylation chemistry. Iron-mediated cyclocarbonylation proceeded smoothly delivering an angularly methylated cis-octalone ring system which could be epimerized trans by acid-catalyzed conjugate addition of thiophenol. Oxidation of resulting thioether gave a crystalline sulfone suitable for elaboration to polycarbocyclic targets.;(-)-N-tosyl norcitronellamine was synthesized by Curtius inversion of (-)-citronellic acid. Ozonolysis of (-)-N-tosyl norcitronellamine gave an aminal that dehydrated to a cyclic 5-methyl N-tosyl enamine. Diastereoselective bromohydrin formation gave a crystalline bromohydrin. Treatment of the bromohydrin with KH generated an epoxide in situ that was opened with crotyl Grignard delivering two diastereomers in a 1:1 ratio. The one diastereomer possessed the requisite stereochemistry for the piperidine ring of Veratrum alkaloids.;Conversely, treatment of the crystalline bromohydrin with (P )-1-tributystannyl-1,2-butadiene and BF3-O(Et)2 gave a cis-2,5 disubstituted pyridine with a stereochemical configuration matching that of Nuphar alkaloids.