Two different research projects are described in this dissertation. The first one focuses on microwave-promoted iminyl radical cyclization for the formation of azaheterocycles which are embedded within numerous pharmaceuticals and biologically active natural products (such as clindamycin, eletriptan, moxiflaxin, etc.). We are quite interested in this project because of the significance of nitrogen-containing heterocycles as pharmaceuticals and organocatalysts combined with the need for safe, simple, and economical means of constructing them. We have successfully developed an efficient one-step synthesis of 2-acylpyrroles and diastereoselective dihydropyrroles from readily available oxime ether substrates. This remarkably efficient and environmentally friendly methodology should be useful for rapid and easy preparation of potent drugs containing pyrrolidine ring systems. The second project focuses on the total synthesis of yaku'amide A. The natural compound, isolated from a marine sponge in 2010, is a medium-sized peptide that contains bulky dehydroamino acids. It has an excellent IC50 value (14 ng/mL) against leukemia cells, making it a promising anticancer agent. Because of the unique anticancer profile, potent bioactivity, and limited supply, the natural product was attractive to us for an efficient synthesis and mechanistic investigation. We have devised more efficient strategies compared to Inoue's methods for the synthesis of bulky ∆AAs and their incorporation into peptides, which are innovative and will allow us to synthesize yaku'amide A rapidly and conveniently. A one-pot sequence consisting Martin sulfurane mediated anti dehydration, azide reduction, and O→N acyl transfer was developed for the construction of E- and Z-dehydroisoleucine-containing peptides. We also developed a three-step synthesis of N-terminal acyl group involving a one-pot indium-catalyzed cross-Claisen condensation/reduction from a known compound. The most hindered coupling reaction of pentapeptide acid and nanapeptide amine in the late stage is accomplished. Our total synthesis of yaku'amide A can be completed in 19 longest linear steps and 66 total steps. Further identification of yaku'amide A for elucidation of its biological target and mode of action will be explored, which will open up new avenues in the fight against cancer.

The first project in this dissertation describes the use of microwave-promoted iminyl radical fragmentations to form functionalized nitriles. Nitrogen-centered radical chemistry is a useful tool to construct valuable C-N bonds commonly found in pharmaceuticals and biologically active molecules. Classically, these reactions require the use of toxic initiators and propagators. Iminyl radical chemistry has been gaining momentum as a means of avoiding these harsh conditions. This project utilizes the fragmentation of cyclic iminyl radicals via irradiation of O-phenyl oxime ethers to produce a synthetically useful nitrile tethered to an alkyl radical in the absence of metal catalysts and redox chemistry. The efficacy of this synthetic method was demonstrated by the diverse functionalization of estrone. We believe this useful chemistry can be a powerful tool when applied to both early and late-stage synthetic endeavors. The latter half of this dissertation focuses on the total synthesis of yaku'amide A, a natural product isolated from a marine sponge. This peptide contains potent anticancer activity and exhibits a novel, unique mode of action. Due to its scarcity in nature, comprehensive biological studies have remained elusive. The structure of yaku'amide A contains complex, unsymmetrical bulky dehydroamino acids such as E- and Z- dehydroisoleucine which pose a synthetic challenge. Despite the efficient strategy developed in our lab, the synthesis remains lengthy. Simpler symmetrical dehydroamino acids dehydrovaline and dehydroethylnorvaline were substituted in place to prepare two analogues of yaku'amide A that closely resemble the conformation of the natural peptide. Activity profile of the simplified analogues showed comparable potency to that of yaku'amide A.

Yaku'amide A shows a unique inhibitory profile against a series of 39 human cancer cell lines (JFCR39). In our efforts to synthesize yaku'amide A, we have optimized our regioselective base-free aminohydroxylation method with a series of nitrogen sources, developed a chiral reagent-mediated aminohydroxylation strategy and chemoselective deprotections of the resulting aminohydroxylation product, and explored a stereospecific E2 dehydration and O-N acyl transfer sequence. In addition, we have prepared the right-hand tetrapeptide and the NTA subunit. For our bulky α,β-dehydroamino acids project, we have developed strategies to incorporate α,β-dehydroamino acids such as ΔVal and ΔEnv into small synthetic peptides via Solid Phase Peptide Synthesis (SPPS). We have also prepared two analogues of a monomeric helical peptide with 13 residues.

The synthetic progress towards yaku'amide A is described. The study leads to development of new synthetic methodologies. Base-free regioselective aminohydroxylation is convenient to deliver β-tert-hydroxyamino acids. A sequence consisting of alkylative esterification, Martin sulfurane mediated anti dehydration, a tandem azide reduction-O→N acyl transfer allows the rapid access of E- and Z-dehydroisoleucine-containing peptides from β-tert-hydroxyisoleucine derivatives. Those methods are effective in constructing complicated peptides and advanced subunits of yaku'amide A.