Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

Vinigrol is a structurally unique diterpenoid natural product featuring a tricyclo[4.4.4.0.4a,8a]tetradecene carbon skeleton containing eight contiguous stereocenters and a challenging oxygenation pattern. Vinigrol has been demonstrated to possess a wide array of biological activities including tumor necrosis factor (TNF) antagonism, antihypertensive activity, and platelet aggregation inhibitory activity. Our first-generation plan for the synthesis of vinigrol utilized a cascade reaction sequence involving: (1) diastereoselective alkylation of an α-alkenyl-β-ketoester, (2) retro-aldol-aldol equilibration (3) anion-accelerated oxy-Cope rearrangement, and (4) transannular Dieckmann condensation to afford the bicyclo[5.3.1]undecene ring system of vinigrol in a single operation. Discoveries concerning the limitations of this process are disclosed. Our second-generation approach to vinigrol employed a cis-decalin substrate in an alternative cascade reaction sequence, which was expected to deliver the complete tricyclo[4.4.4.0.4a,8a]tetradecene carbon skeleton of vinigrol in one step. An unexpected deviation from the envisioned reaction pathway instead afforded an alternative tricyclic enol silane. / Chemistry and Chemical Biology

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.