New methodologies for the asymmetric synthesis of alkaloids using chiral vinylic sulfoxides: I. An enantioselective synthesis of the aspidosperma skelton and II. A novel approach to pyrrolidines and pyrrolizidines.
Rubio, Maria Belen
2000
Abstract
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, (1<italic>E</italic>,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(<italic>t</italic>-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.Subjects
Alkaloids Alkaloidsusing Andpyrrolizidines Approach Aspidosperma Skeleton Asymmetric Synthesis Chiral Enantioselective Synthesis Ii Methodologies New Novel Ofthe Pyrrolidines Pyrrolizidines Skelton Vinylic Sulfoxides
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