Part I: Palladium-mediated aromatic decarboxylation. Part II: Formation of alpha,alpha-disubstituted alpha-amino acids via three component coupling of alpha-iminoesters

Part I. A mild palladium-mediated decarboxylation protocol was developed for the decarboxylation of advanced biaryl intermediates. This methodology has facilitated the completion of the total syntheses of both hypocrellin A and ent-calphostin D. Kinetic studies directed towards the elucidation of the reaction mechanism of the decarboxylation were undertaken.*;Application of transition state theory (a.k.a. activated complex theory) to the kinetic results allowed the activation parameters (DeltaH ‡, DeltaS‡, and DeltaG‡ 298) for both steps of the decarboxylation reaction (decarboxylative palladation and protodepalladation) to be determined. The rate-determining protodepalladation step has been proposed to occur through an electrophilic aromatic substitution type mechanism. A Hammett study provides additional support for this hypothesis. Based on the mechanistic and kinetic studies, a palladium-catalyzed aromatic decarboxylation reaction was developed and the scope of the reaction was delineated.*;Part II. A three-component coupling of alpha-iminoesters has been developed for the synthesis of complex and novel alpha-amino acid and alpha,alpha-disubstituted alpha-amino acid derivatives. The reaction proceeds through an initial umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting tetra-substituted enolate intermediates react with electrophiles (aldehydes, imines, conjugate acceptors, alkyl halides, and acyl cyanides) to form the desired quaternary amino acid derivatives.*;Tethering of the organometallic nucleophile with an electrophile in a solvent triggered reaction provides an intramolecular three-component coupling reaction to yield cyclic alpha,alpha-disubstituted alpha-amino acid derivatives. Further derivatization of the alpha-amino acid derivatives was achieved through oxidative cleavage of the para-methoxyphenyl nitrogen-protecting group with ceric(IV) ammonium nitrate. Also, the three-component coupling methodology has been extended to the asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids through the use of pi-allyl palladium chemistry.;*Please refer to dissertation for diagrams.