Reduction of the two carboxyl functionalities completed the synthesis of alcyopterosin O in a much improved five steps from 3. The key (4 + 2) cycloaddition/SO 2 extrusion step again proceeded smoothly using furan 5, giving 2,2-dimethylindane core 14 with the methyl group “transposed” to the C6 position. Reduction of the exocyclic C–S bond using PdCl 2/Et 3SiH, followed by oxidation to the bicyclic thiophene S,S-dioxide 12, proceeded in high yield (74% over two steps).
Treatment of 3 with carbon disulfide under basic conditions, followed by the addition of ethyl bromoacetate, led to thiophene 13. Thiophene S,S-dioxide 12 ( Scheme 2) was therefore targeted, the synthesis of which again commenced with 3,3-dimethylcyclopentanone 3. A different approach involves “rotating” the orientation of the thiophene relative to its fused cyclopentane ring to enable the direct introduction of all arene substituents with suitable degrees of oxygenation. Comparison of alcyopterosin O with riparol B reveals the structural source of the problem─namely, the transposition of the arene methyl and hydroxymethyl substituents between the two targets, which necessitated multiple post-cycloaddition manipulations. (11)Īlthough alcyopterosin O could be accessed using this route, we questioned whether an alternative approach could be devised with a lower step count. (8,10) Simple intermolecular cycloadditions with alkynes, alkenes, and furans are known in a methodological context but have mainly employed (poly)halogenated or symmetric thiophenes. (9) Far less studied are thiophene S,S-dioxides: to the best of our knowledge, only a single use of these motifs in natural product synthesis exists in an elegant formal synthesis of dictyodendrins B, C, and E by Kabuki and Yamaguchi, involving intramolecular cycloaddition of an electron-rich ynamide with a thiophene S,S-dioxide ( Figure 1c). In the case of SO 2 extrusion, the majority of research has exploited the ability of sulfolenes (2,5-dihydrothiophenes) to reveal dienes by the loss of SO 2, which subsequently engage with a dienophile. (7) Single-atom variants such as SO 2 or CO (i.e., cheletropic extrusions) are also possible but have been surprisingly little used in target-oriented synthesis. It does not store any personal data.A different approach to benzene synthesis involves the Diels–Alder cycloaddition/retro-cycloaddition of dienes equipped with “leaving groups” such as N 2, nitriles, and CO 2. The cookie is set by the GDPR Cookie Consent plugin and is used to store whether or not user has consented to the use of cookies. The cookie is used to store the user consent for the cookies in the category "Performance". This cookie is set by GDPR Cookie Consent plugin. The cookies is used to store the user consent for the cookies in the category "Necessary".
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