Chapter one: Stereoselective total synthesis of the racemic and natural enantiomer of the marine tunicate alkaloid lepadiformine. Chapter two: Studies directed towards a total synthesis of chartelline A

Chapter one. Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (14) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. To introduce the hydroxymethyl group at C-13 of the racemic spirocycle 68, our methodology for radical-based oxidative remote functionalization of o-aminobenzamides 76 was utilized, followed by copper-catalyzed addition of Grignard reagent 82 to the N-acyliminium ion intermediate 83 derived from 81. Subsequent Tamao oxidation of silane 85 then afforded the requisite hydroxymethyl compound 67, which was converted to the dimethyl acetal 86 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 86 and subsequent protection of the primary alcohol gave benzyl ether 102. The synthesis was concluded from 102 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (+/-)-lepadiformine (14).; The enantioselective total synthesis of 14 started from known enantiomerically pure bromide 122, derived from ( S)-pyroglutamic acid, and followed a similar sequence to the racemic series involving the key spirocyclization of N-acyliminium ion 127. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R), 5( S),10(S),13(S).; Chapter two. In work directed towards a total synthesis of chartelline A, several strategies were investigated to construct the ten-membered macrocyclic ring of this natural alkaloid.; The first approach involved an intramolecular aldehyde/beta-lactam cyclocondensation strategy to form the macrocyclic enamide. Therefore, tribromooxindole beta-lactam 68 was synthesized from commercially available 5-nitroisatin ( 48) in 7 steps and 30% overall yield via a Staudinger ketene-imine cycloaddition strategy. The requisite 2-bromoimidazole subunit 124 bearing a terminal alkyne and a masked aldehyde was efficiently prepared from the known imidazole ester 54 through functional group manipulations in 10 steps. With both advanced intermediates available, we next investigated the addition of the lithium alkynilide generated from 2-bromoimidazole subunit 124 to the gamma-lactam of tribromooxindole 98, affording the desired N-Boc aminal 146. Hydrolysis of the acetonide moiety of 146 followed by oxidative cleavage of the resulting diol gave the aldehyde 148. Unfortunately, treatment of the aldehyde 148 under acidic conditions did not give the desired ten-membered macrocyclic Z-enamide 152, but rather the highly unsaturated seven-membered ring compound 150. (Abstract shortened by UMI.)...