Dissertation

Radical-based syntheses of the Amaryllidaceae alkaloids lycoricidine, narciclasine and 7-deoxypancratistatin

Wager, Travis T

1998

Overview

The total syntheses of the naturally occurring Amaryllidaceae alkaloids (+)-lycoricidine, (+)-narciclasine, (+)-7-deoxypancratistatin, and a synthesis of unnatural lycoricidine are described. The key strategic element of the approach utilized in the synthesis of lycoricidine was an intermolecular radical addition-cyclization sequence. Thiyl radical addition to a disubstituted alkyne generated a vinyl radical that underwent a stereoselective 6-exo cyclization onto an oxime ether. This process was high yielding when thiyl radical was used, but fails when stannyl radical was used. Pivotal to the completion of this synthesis was the use of SmI2 in a reduction-cyclization sequence to form the lactam ring and reductive removal of the vinyl sulfide moiety. The synthesis described affords (−)-lycoricidine in 13 linear steps from D-lyxose in an 8% overall yield. The syntheses of (+)-lycoricidine and (+)-narciclasine both use a radical addition-cyclization sequence to construct the C-ring. The synthesis of (+)-lycoricidine proceeds in nine linear steps with a 41% overall yield from isopropylidine-D-gulonolactone. The aryl ring contained in narciclasine was synthesized from piperonal using an ortho metallation strategy. Removal of the N,N-dimethylamide ortho directing group was accomplished using trimethyloxonium tetrafluoroborate. The use of the electron withdrawing phenolic protecting group, tosylate, was critical to obtain high yields in the palladium-mediated coupling and in the radical addition-cyclization sequence. Pivotal to the completion of the synthesis was the use of SmI2 in the reduction of the N-O and reductive removal of the vinyl sulfide. High yields for these processes were obtained only after the closure of the lactam ring. The synthesis described is 12 steps from a D-gulonolactone derivative and proceeds in 22% overall yield. A tandem radical cyclization approach was used to construct 7-deoxypancratistan. The route described utilizes a 6-exo radical cyclization of an aryl radical onto an aziridinyl imine, followed by generation of a new radical that underwent a second 6-exo radical cyclization to an oxime ether to establish the trans-phenanthridone ring junction. The synthesis described is 13 linear steps from 6-iodopiperonol and affords a 21% overall yield.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biochemistry / Chemistry / Organic chemistry / Physical chemistry
• ISBN: 9780599096578, 0599096578