Executive Summary : | γ-Alkylideneutenolides are very important frameworks found in many natural products, and they also display promising biological activities. These are also very useful synthetic intermediates in the total synthesis of natural compounds. Over the years many γ-alkylidenebutenolides natural products were isolated from natural sources having exocyclic γ-δ unsaturation. A close structural inspection revealed that structural variations arise from the C6 appendage in the general class of γ-Z or E alkylidenebutenolides. Topologically γ-alkylideneutenolides have been classified into four different types: The presence of an extra ring (with the suitable functional group) connecting C4-C5 and C6 of the core butenolide belongs to the class-I topology. Piptocarphin A, Lupeol acetate,Chochinolide are few representative examples. γ-Alkylidenebutenolides having an extra ring at C3-C4 belongs to class-II topology, Z and E ligustilide (anticholinergic, antispasmodic, smooth muscle relaxant activity), and (Z)-6,6´,7,3´α-diligustilide (antihyperglycemic) are two representative examples. Most of the naturally occurring and topologically distinct γ- alkylidenebutenolides belong to class-IIIa topology, in which a cyclic ring is situated at the C6 part of the alkylidenebutenolide core. Few representative examples are eremolactone, leocosceptroid K (antifeedant), pestaloliolactone B, pandamarilactonines, to name a few. Whereas rhodocoranes (I and H) belong to class IIIb topology and contain a spirocyclic ring at the C6 position. It is clear that topology or cyclic connectivity played an important role in the structural classification of several naturally occurring and biologically active γ-alkylidenebutenolides. Total synthesis of such complex natural products through a strategy-driven approach should be of paramount importance, as it will allow us to access those molecules in reasonable quantity for further biological study. In this current proposal, our main focus will be to develop efficient, sustainable, and atom-economical strategies for the total synthesis of topologically distinct γ-alkylidenebutenolides. Most of the natural products shown in the proposal are not synthesized yet. In general, our synthetic strategies will be centered on the powerful hetero PK-reaction for accessing the core butenolide core belonging to class I topology. In addition, Pd-Au bimetallic cascade cyclization will also be employed for the construction of “Z-γ-alkylidenebutenolides”. Ru-based thermal isomerization reaction or adventitious photo-isomerization will then be adapted to access “E-γ-alkylidenebutenolides” natural products (belonging to class II and IIIa topology). Finally, the construction of γ-alkylidenebutenolides belonging to class IIIb topology is planned through intercepting the vinyl-gold/copper intermediate (ene-yne activation through Au, or “Pd-Cu” bimetallic cascade method) with proper electrophile in an intramolecular fashion. |