Abstract
The thesis consists of two chapters. The first chapter describes a detailed synthetic study of perhydroindole. We have identified 2-cyclohexen-1-one 43 as starting material, which underwent sequential Johnson iodination, Luche reduction, Mitsunobu reaction and anionic cyclization to give perhydroindole 58 in 52% overall yield. Thus we have developed an efficient methodology for the synthesis perhydroindole 58. The perhydroindole 58, which is otherwise difficult to prepare, can serve as an important intermediate for the total syntheses of (-)-brunsvigine (3) and (-)-pancracine (73) of montanine-type alkaloids.The second chapter deals with a new approach toward the syntheses of montanine-type alkaloids. In this approach, the key starting material perhydroindole 58 was synthesized as disclosed in the previous chapter. Compound 58 was then reduced with NaBH4 in the presence of CeCl3˙7H2O, followed by esterification to form allylic pivalate 151. Regioselective alkylation of allylic pivalate 151 gave an inseparable mixture of 149 and 150 in 1:1 ratio. Cleavage of sulfonamide in 149 and 150 with sodium naphthalenide followed by conventional Pictet-Spengler cyclization afforded the 5,11-methanomorphanthridine 161. The molecule 161 obtained by our methodology is identical to that previously reported by Overman and Shim. Thus we have completed the formal synthesis of (+)-pancracine (73). These results stimulated us to synthesize optically active (-)-brunsvigine (3). For this purpose, we have selected optically pure enone 162 as starting material which was prepared from commercially available D-(-)-quinic acid in four chemical operations. The transformation of enone 162 to enantiomerically pure perhydroindole 164 was carried out according to the synthetic sequence discribed in the previous chapter. Treatment of compound 164 with NaBH4 in the presence of CeCl3˙7H2O, followed by subsequent esterification with pivaloyl chloride in pyridine, furnished the allylic pivalate 180. The structure of compound 180, containing the correct stereogenic centers required for (-)-brunsvigine (3), was confirmed by X-ray analysis. Regioseletive alkylation of allylic pivalate 180 with 3,4-(methylenedioxy)phenylmagnesium bromide in the presence of 10% CuI obtained the main product 166 in 76% yield. Treatment of 166 with sodium naphthalenide in 1,2-dimethoxyethane gave the secondary amine 185. Compound 185 was cyclized with Eschenmoser's salt to afford 5,11-methanomorphanthridine 186 in 62% yield. Finally, deprotection of acetonide 186 with HCl in THF and methanol finished the synthesis of (-)-brunsvigine (3). The total synthesis of (-)-brunsvigine (3) has been achieved in ten chemical operations in 12% overall yield from optically pure enone 162.In order to synthesize (-)-pancracine (73), the key compound 166 was hydrolyzed with HCl to give diol 191. Regioselective monobenzylation of diol 191 with benzaldehyde dimethyl acetal in the presence of catalyst CSA, followed by reduction with DIBALH provided the monobenzyl ether 192 in 95% yield. Inversion of configuration at the carbon atom attached hydroxy moiety of 192 was achieved by the treatment of trifluoromethanesulfonic anhydride and pyridine in CH2Cl2 to give the unstable triflate 193. Reaction of 193 with cesium acetate and 18-crown-6 in toluene produced acetate 188. Further efforts have to be made to utilize the compound 188 for the total synthesis of (-)-pancracine (73).