Novel Asymmetric Synthesis of Atropisomeric 6-Aryl Pyrazinones via an Unusual Chirality Transfer Process.

Cyclization of (S,S)-alpha-[(1-phenylethyl)amino]-alpha-(2-iodophenyl)acetonitrile with (COCl)(2) in toluene or chlorobenzene afforded the atropisomeric pyrazinone (aS,S) 6-(2-alpha-iodophenyl)-3,5-dichloro-1-(1-phenylethyl)-2(1H)-pyrazinone in 57% yield. With smaller ortho substituents (F, Cl, CH(3), CF(3), OCH(3)) on the aromatic ring, mixtures of atropisomers were obtained from the cyclization reaction. All of the individual atropisomers prepared were stable at room temperature. All but the o-fluoro-substituted atropisomers were stable at elevated temperatures. This paper describes a stereoselective synthesis of pyrazinones and suggests a mechanism for formation via an interesting transfer of chirality.

Microbiological Oxygenation of Bridgehead Azabicycloalkanes.

A series of N-substituted bridgehead azabicycloalkanes has been prepared and examined as substrates for microbiological oxygenation using the fungi Beauveria bassiana, Rhizopus nigricans, Aspergillus ochraceus, and Rhizopus arrhizus. Oxygenation using B. bassiana of N-tosyl-7-azabicyclo[2.2.1]heptane gave N-[p-(hydroxymethyl)benzenesulfonyl]-7-azabicyclo[2.2.1]heptane (56% yield), of N-(phenyloxycarbonyl)-7-azabicyclo[2.2.1]heptane gave the 2-endo-ol (56% yield, 51% ee), of N-BOC-7-azabicyclo[2.2.1]heptane gave the 2-endo-ol (10% yield), of N-Cbz-7-azabicyclo[2.2.1]heptane gave the 2-endo-ol (28%), of N-(phenyloxycarbonyl)-8-azabicyclo[3.2.1]octane gave the 3-endo-ol, and of N-(phenyloxycarbonyl)-9-azabicyclo[3.3.1]nonane gave the 3-exo-ol (30%) and 3-one (16%). Oxygenation using R. nigricans of N-BOC-7-azabicyclo[2.2.1]heptane gave the 2-endo-ol (62% yield, 28% ee) and the 2-exo-ol (27% yield, 42% ee). Oxidation of the N-BOC-7-azabicyclo[2.2.1]heptan-2-ols gives the 2-ketone, a synthetic intermediate useful for conversion to the natural product, epibatidine. Oxygenation of N-(phenyloxycarbonyl)-7-azabicyclo[2.2.1]heptane using R. arrhizus gives the 2-endo-ol (5% yield, 31% ee) and the 2-exo-ol (18% yield, 22% ee). Oxygenation of N-(phenyloxycarbonyl)-8-azabicyclo[3.2.1]octane using A. ochraceous gives the 3-endo-ol (36%) and the 3-one (4%).

Synthesis of an Azasteroid Using an Acyl Iminium Ion-Initiated Tandem Cyclization.

An acyl iminium ion-initiated tandem cyclization gave an unexpected dienone product, a seco-azasteroid (2). The factors governing the formation of 2 were investigated in an attempt to optimize its formation. The reaction was applied to a more elaborate system, resulting in the synthesis of the full steroid skeleton of 13-azaandrosta-1,4-diene-3,17-dione (3), which contains the unusual substitution of a chlorine atom for the axial 19-methyl.

Cyclopentene Synthesis from 1,3-Dienes via Base-Induced Ring Contraction of 3,6-Dihydro-2H-thiopyrans: Studies on Diastereoselection and Mechanism.

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the alpha-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.