Source: Dissertation Abstracts International, Volume: 75-05(E), Section: B.

Adviser: Seth Herzan.

The hasubanan and acutumine alkaloids are a large family of botanical metabolites that all share a common tetracyclic propellane carbon scaffold. Alkaloids within these families display a wide range of biological activities including affinities to both delta- and mu-opioid receptors, inhibition of human T-cell proliferation, and antimicrobial, anti-HIV and anti-hepatitis B activities. This thesis details the evolution and development of our synthetic route that has culminated in the enantioselective synthesis of four hasubanan and two acutumine alkaloids.

Our syntheses of the hasubanan and acutumine alkaloids begin with a diastereoselective addition of various lithium acetylide nucleophiles to the N-methyl iminium ion 120, derived from the imine 119 (e.g., 120→121, 54-94%). The imine 119 is prepared in three steps, 93% ee, and 37% overall yield from 5-(2-azidoethyl)-1,2,3-trimethoxybenzene (101). The silylcyclopentene substituent is removed by mild thermolysis (e.g., 121→113, 135°C, 85-99%). The key C-8--C-9 bonds of the hasubanan and acutumine alkaloids were formed by Friedel-Crafts ( e.g., 125→126, 72-89%) and Hosomi--Sakurai (e.g., 195→196, 32-37%) cyclizations, respectively. Our synthesis of (--)-acutumine (9) incorporates a [3,3]-sigmatropic rearrangement (220→221) and a substrate directed hydrogenation of a hindered vinyl chloride (224→9, 57% yield at 30% conversion of 224).*

We have established the utility of 5-trimethylsilylcyclopentadiene ( 116) as a stabilizing, directing, and easily removable functionality in organic synthesis. Through X-ray analysis we have demonstrated that the trimethylsilyl group present in Diels--Alder adducts of 5-trimethylsilylcyclopentadiene shields the olefin of the cyclopentene fragment thereby allowing for the site-selective functionalization [e.g., hydrogenation (152→228, 50%), hydrosilylation (152→230, 76%), hydrostannylation (152→232, 78%)] of unsaturated carbon-carbon bonds in the presence of an otherwise highly reactive norbornene substructure.

*Please refer to dissertation for diagrams.