We report a concise,
stereocontrolled synthesis of the neurotoxic
sesquiterpenoid (−)-picrotoxinin (1, PXN). The
brevity of the route is due to regio- and stereoselective formation
of the [4.3.0] bicyclic core by incorporation of a symmetrizing geminal
dimethyl group at C5. Dimethylation then enables selective C–O
bond formation in multiple intermediates. A series of strong bond
(C–C and C–H) cleavages convert the C5 gem-dimethyl group to the C15 lactone of PXN.
The strength of the weak: An L‐tert‐leucine‐derived amine–thiourea catalyst (see scheme, green box) promotes the asymmetric vinylogous conjugate addition reaction between γ‐aryl‐ and alkyl‐substituted butenolides with the butenamides and enoates shown. Computational studies show the preference for the observed stereochemistry is a result of favourable weak non‐bonding interactions, which stabilize the transition state.
The fruitful advancement in synthetic chemistry of the title families of complex diterpenes has stimulated and enjoyed strategic balance between building the skeletons and installing the functional groups.
Using a strategy featuring rapid assembly of the tricyclic core and highly stereocontrolled establishment of the dense functionality and a cyclopropane ring, Li and co-workers have accomplished a concise and highly modular synthesis of prostratin. The chemical synthesis of this natural diterpene poses a significant challenge but can be crucial for developing adjuvant drugs for elimination of latent HIV reservoir as well as anti-cancer drugs, thus providing a chemical foundation for drug development based on related natural products.
An appropriately functionalized [5-7-6] tricyclic framework of tigliane and daphnane diterpenes containing seven contiguous stereocenters has been prepared in 10 steps from very simple building blocks in a modular and stereocontrolled fashion. The key features of this approach involve an efficient visible light-induced singlet oxygen oxidative dearomatization and an array of substrate-controlled highly diastereoselective transformations. This work provides a model strategy for rapid and diverted synthesis of natural and unnatural molecules sharing the common skeleton.
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