Total synthesis of +/-lysergic acid: A new Diels-Alder pyridine synthesis

Struck by the extent of redundancy in past syntheses of lysergic acid, we developed a non-redundant, efficient synthesis plan quite different from those. Our plan was based on the dissection of the target structure into two simple halves corresponding to indole and nicotinic acid, with only two skeletal bonds (a and b) to construct (Scheme 9).; Of the two orders for joining these units we examined (b + a) first by acylating indole with 6-chlorocarbonyl-nicotinic ester (Chapter 1) or their halogenated derivatives (Chapter 2). Our attempted cyclizations to close bond a with several cyclizing transition state.; Turning to the other variation (b + a) we first created bond a via Suzuki coupling of 4-halo-indoles with 5-chloro-6-carboxy-nicotinic diester (Chapter 3). Conversion of the 6-carboxyl to aldehyde afforded successful cyclization of bond b. The synthesis was finished by N-methylation and pyridine ring reduction.; In conjunction with this synthesis we also developed a new synthesis of substituted pyridines by the Diels-Alder reaction of tosyl cyanide with various α-pyrones, catalyzed by TiCl₄ (Chapter 4). The reaction is driven by pyridine aromatization and extrusion of CO₂ and affords good yields. The α-tosyl substituent on the product pyridines may be replaced by common nucleophiles.