The first project in this dissertation describes the total synthesis of yaku’amide A analogues. Natural product yaku’amide A possesses potent anticancer activity and exhibits a novel mode of action. However, due to its complex asymmetrical isoleucine dehydroamino acids, the synthesis of this polypeptide poses a unique challenge. Despite the efficient synthesis developed in our lab, the total synthesis of this natural product remains lengthy. In order to simplify the overall synthesis, symmetrical dehydroamino acids were incorporated to replace the dehydroisoleucine residues yielding two analogues of yaku’amide A that closely resembles the conformation of the natural product. Biological testing of the simplified analogues disclosed similar potency to that of yaku’amide A. The second part of this dissertation focuses on the influence that dehydroamino acids have on secondary structures. Peptides have an important role in medicine despite their limitations due to poor bioavailability and stability. Therapeutic use of peptides can be enhanced by designing new strategies to improve the proteolytic stability of these compounds. Attempts to increase peptide stability using trisubstituted and tetrasubstituted dehydroamino acids (ΔAAs) have been reported. Similarly, modified ΔAAs should also help tune the electronic and steric properties of peptides, while improving proteolytic stability. However, studies of peptides containing modified ΔAAs and are scarce. This project describes the synthesis and studies of incipient 310 helical tetrapeptides containing dehydroamino acids. Bulky and cyclic ΔAAs were demonstrated to alter the conformation of these tetrapeptides and impart greater stability against proteolysis and thiol additions. We believe these results can be a powerful tool to design peptide drug candidates with high proteolytic resistance and stability. tetrasubstituted dehydroamino acids (ΔAAs) have been reported. Similarly, modified ΔAAs should also help tune the electronic and steric properties of peptides, while improving proteolytic stability. However, studies of peptides containing modified ΔAAs and are scarce. This project describes the synthesis and studies of incipient 310 helical tetrapeptides containing dehydroamino acids. Bulky and cyclic ΔAAs were demonstrated to alter the conformation of these tetrapeptides and impart greater stability against proteolysis and thiol additions. We believe these results can be a powerful tool to design peptide drug candidates with high proteolytic resistance and stability.

The first project in this dissertation endeavors to outline the total synthesis of yaku'amide A and its analogs. Yaku'amide A is a natural product comprised of dehydroamino acids, including E-dehydro isoleucine, and unprecedented Z-dehydro isoleucine. These amino acids present a significant challenge to their synthesis owing to their unsymmetrical nature. To simplify the synthesis process, we synthesized analogs by substituting the E and Z dehydroamino acids with symmetrical subunits. This substitution facilitated the synthesis process and enabled us to obtain a similar three-dimensional structure to that of the natural product. Furthermore, biological testing of the simplified analogs revealed potency similar to yaku'amide A. The second part of this project describes the synthesis of the bicycle core of virosinine A, commencing with an enantioselective Evans glycolate aldol reaction. Following a series of transformations, an oxime phenyl ether is generated, which, upon microwave irradiation, triggers an iminyl radical cascade reaction. The iminium formed in the microwave reactor is reduced with red-Al, obtaining the desired diastereomer.

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.