Diastereoselective strategies for the synthesis of glutamate-containing natural products: Total synthesis of (S)-(+)-lycoperdic acid and studies toward the total synthesis of (-)-dysiherbaine and the design and synthesis of a scaffold for glutamate receptor ligands using a natural product-based library approach.

摘要

Chapter 1 of this dissertation reviews the recent use of pyroglutamic acid as a chiral building block for asymmetric natural product synthesis. The synthetic examples illustrated in this chapter provide a foundation for the research projects described in the remainder of this dissertation, which investigate the diastereoselective reactions of pyroglutamic acid derivatives for the synthesis of glutamate-containing natural products and analogs.; The three synthesis projects described in this dissertation were inspired by the unique architectures and impressive biological profiles of the structurally related glutamate-containing natural products (-)-dysiherbaine, neodysiherbaine, and (S)-(+)-lycoperdic acid. Chapter 2 of this dissertation describes the development of an efficient method for the diastereoselective annulation of an oxolane ring onto a pyroglutamate scaffold to produce glutamate-appended oxolane rings in high yields. The successful implementation of this pyroglutamate ring annulation methodology was demonstrated in a stereocontrolled synthesis of (S)-lycoperdic acid.; Chapter 3 of this dissertation describes our investigations toward a second-generation total synthesis of dysiherbaine featuring a pyroglutamate ring annulation to assemble the glutamate-appended oxolane ring of the bicyclic skeleton. This chapter details four approaches for the enantioselective synthesis of the dysiherbaine tetrahydropyran core, a key intermediate containing four contiguous syn stereocenters and a 2-amino-1,3-diol motif. Three of the four strategies employed trichloroacetimidate cyclizations to install the C-8 amino group, while the remaining strategy utilized Donohoe's tethered aminohydroxylation methodology to construct the syn amino diol of dysiherbaine.; Chapter 4 of this dissertation implements a new strategy for the discovery of glutamate receptor ligands by applying a natural product-based library paradigm. This chapter details the evolution of a synthesis plan for the generation of a focused library of glutamate receptor ligands based a scaffold that emulates the glutamate-containing natural products. Critical information that guided the design of the dihydrobenzofuran library scaffold was revealed through molecular modeling studies and verified by biological evaluation. The synthesis of the library scaffold was achieved by expanding the substrate scope of the pyroglutamate ring annulation methodology, ultimately allowing the glutamate-containing natural products and related analogs to be prepared by a common stereocontrolled approach.