Shair, Matthew DavidMilgram, Benjamin Charles2014-02-252014-02-252013Milgram, Benjamin Charles. 2013. Progress Toward the Total Synthesis of Vinigrol and Hibarimicin B. Doctoral dissertation, Harvard University.http://dissertations.umi.com/gsas.harvard:11220http://nrs.harvard.edu/urn-3:HUL.InstRepos:11744417Vinigrol 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.en-USOrganic chemistryAngelmicinHibarimicinNatural ProductTotal SynthesisVinigrolThesis or Dissertation2015-02-04