| In conjunction with our continuing interest in the synthesis of indoline alkaloids, a new approach to the synthesis of the pentacyclic skeleton of the Aspidosperma skeleton [ABCDE] has been developed. The asymmetry was introduced by the use of the optically active beta,beta-disubstituted vinylic sulfoxide, (3E,Rs)-2-[3-(2-(N-t-butoxycarbonylamino)-phenyl)-4-(p-tolylsulfinyl)-but-3-enyl]-2-propyl-[1,3]dioxolane, prepared by ortholithiation of N-boc-aniline [A ring], transmetalation to the cuprate and cis addition to the optically active alkynyl sulfoxide, 2-propyl-2-(4-(Ss)-p-tolylsulfinyl-but-3-ynyl)-[1,3]dioxolane. The chirality was transferred from the sulfur to a quaternary carbon by reaction of the optically active vinylic sulfoxide, (1E,Rs)-2-[3-(2-(N,N-bis-t-butoxycarbonylamino)-phenyl)-4-(p-tolylsulfinyl)-but-3-enyl]-2-propyl-[1,3]dioxolane, with dichloroketene to afford after dechlorination and deketalization the gamma-thiogamma-butyrolactone, (4S,5R)-4-[2-(N,N-bis-t-butoxycarbonylamino)-phenyl]-3dichloro-4-[2-(2-propyl-[1,3]dioxolan-2-yl)-ethyl]-5-p-tolylsulfanyl-dihydro-furan-2-one. The gamma-position of the lactone is synthetically equivalent to an aldehyde. Thus opening of the lactone with pyrrolidine generated the aldehyde, 3-[2-N,N-bis(t-butoxycarbonylamino)-phenyl]-3-formyl-6-oxo-N-pyrrolidinyl-nonylanlide. Then intramolecular aldol reaction, followed by amidation with 3-chloropropyl amine generated the 4,4 disubstituted cyclohexenone, 2-[1-(2-N,N-bis(t-butoxycarbonyl)amino-phenyl)-3-ethyl-4-oxo-cyclohexene-2-enyl]-N-(3-chloropropyl)-acetamide [C ring]. A tandem reaction by intramolecular Michael addition of the amide nitrogen to the unsaturated ketone, followed by intramolecular alkylation of the enolate onto the alkyl chloride chain, afforded the tricyclic core [CDE], 9a-[2-N,N-bis(t-butoxycarbonylamino)-phenyl]-6a-ethyl-octahydro-pyrrolo[3,2,1-ij]quinolin-2,7-dione. Thus two more rings and two more stereocenters were generated with this reaction. The last ring [B ring] and the last stereocenter were achieved after unsaturation of the ketone to afford 9a-(2-N,N-bis(t-butoxycarbonylamino)-phenyl)-6a-ethyl-4,5,6,6a,9a,9b-hexahydro-1H-pyrrolo[3,2,1-ij]quinolin-8-en-2,7-dione. Then, deprotection of the amine functionality under acidic conditions with concomitant Michael addition, gave 4,10-dioxoaspidospermidine and completed the formation of the Aspidosperma skeleton.; Application of the use of vinylic sulfoxides to the synthesis of pyrrolidine and pyrrolizidine alkaloids has also been explored. For the synthesis of pyrrolidines the corresponding alpha-substituted vinylic sulfoxides were prepared by condensation of different protected S-phenylalaninals with alpha-lithiated vinylic sulfoxides. Deprotection of the amine functionality, followed by 5-endo-trig cyclization gave pyrrolidines. As proof of stereochemistry the antifungal pyrrolidine alkaloid (+)-Preussin was prepared. For the synthesis of pyrrolizidines the corresponding alpha-substituted vinylic sulfoxides were prepared from N-(t-Butoxycarbonyl)-(S)-prolinal. To extend the methodology and check the role of the sulfoxide analogous vinylic sulfones were prepared by reaction of the amino aldehydes with alpha-lithiated vinylic sulfides, followed by oxidation to the sulfone. |
