Enantiospecific total synthesis of ($-$)-podophyllotoxin and related lignans.
Deering, Carl Francis
1988
Abstract
The recently discovered reaction of optically pure vinyl sulfoxides with haloketenes has led to a wide variety of optically active $\gamma$-thio substituted $\gamma$-butyrolactones. As part of an effort to develop new applications of our new methodology, directed towards the syntheses of novel lactone systems, the syntheses of optically pure $\beta$-benzylvinyl sulfoxides and highly functionalized benzylchloroketenes were studied. The synthesis of the new optically active sulfoxides, $\beta$-bromovinyl sulfoxide 117, $\beta$-benzylvinyl sulfoxide 114, and $\beta$-($\alpha$-silyloxybenzyl)vinyl sulfoxide 122a, are discussed. The enantiospecific total synthesis of the naturally occurring lignan Hinokinin is described. The key step involves the formation of an optically pure $\gamma$-arylthio-$\beta$-benzyl-$\alpha$, $\alpha$-dichlorobutyrolactone 125 from the reaction of optically pure $\beta$-benzylvinyl sulfoxide 114 with dichloroketene. Dechlorination and desulfurization of this lactone provides the chiral $\beta$-benzyl-$\gamma$-butyrolactone 20 with the correct absolute stereochemistry at the $\beta$-carbon of the lactone. Alkylation of this lactone with piperonyl bromide affords optically pure Hinokinin. The enantiospecific total syntheses of the naturally occurring lignan Podophyllotoxin and two novel isomers, Epiisopodophyllotoxin and Isopodophyllotoxin, are described. A key step in these syntheses is the selective formation of two epimeric chiral $\gamma$-arylthio-$\beta$-($\alpha$-silyloxybenzyl)-$\alpha$,$\alpha$-dichlorobutyrolactones 130a, from the reaction of the two epimeric chiral $\beta$-($\alpha$-silyloxy)benzylvinyl sulfoxides 122a with dichloroketene. Dechlorination and desulfurization of this lactone, followed by separation of the epimers, provides the optically pure $\beta$-($\alpha$-silyloxy)benzyl-$\gamma$-butyrolactones 136a and 136b. Alkylation of these lactones with a 4-hydroxy-protected benzyl bromide, followed by deprotection, affords the optically pure trans-$\alpha$-(4-hydroxybenzyl)-$\beta$-($\alpha$-silyloxy)benzyl-$\gamma$-butyrolactones 138a and 138b. Attempts at effecting intramolecular phenolic oxidative coupling of these compounds with diphenylselenoxide(bis)trifluoroacetate is discussed. Condensation of the chiral $\beta$-($\alpha$-silyloxy)benzyl-$\gamma$-butyrolactones 136a and 136b with 3,4,5-trimethoxybenzaldehyde provides the chiral benzyl alcohols 141a and 141b as mixtures of diastereomers. The corresponding epimeric benzyl chlorides from 141a are cyclized with silver triflate, without affecting the crucial trans-stereochemistry of the lactone, and deprotected to afford the novel compound Epiisopodophyllotoxin. Similarly the corresponding epimeric benzyl chlorides derived from 141b are cyclized with silver triflate, to give Podophyllotoxin as the minor product and the novel compound Isopodophyllotoxin as the major product, after deprotection.Subjects
Enantiospecific Lignans Podophyllotoxin Related Synthesis Total
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