The marine natural product cyclocinamide A was isolated from a Psammocinia sponge found in the waters of Papua New Guinea. The very similar natural product cyclocinamide B was isolated from the sponge Cortium sp. in Fijian waters. The cyclic tetrapeptide core of both natural products consist of two -amino acids (5-bromotryptophan and asparagine) and two - amino acids (1,2-diaminopropionic acid and isoserine). Both have a glycine chlorinated N-methyl pyrrole dipeptide side chain. The isolation and two previous total synthetic efforts are discussed in chapter 1. Original research resulting in the total synthesis of (4S,7R,11S,14R) cyclocinamide A and B is presented in chapters 2 and 3. Cyclocinamide is disconnected into three dipeptides: glycyl-4,5-dichloro-N-methylpyrrole, isoseryl-5-bromotryptophan and diaminopropionyl-(cyclo)asparagine. The synthesis of these three dipeptides is highlighted in chapter 2. The formation of the cyclic core and completion of the synthesis of the 4R,7S,11R,14S isomer of cyclocinamide A and B is detailed in chapter 3. The full NMR analysis in chapter 4 of the 4R,7S,11R,14S, 4S,7S,11S,14S and 4S,7S,11R,14S reveals that the assignment of both cyclocinamide A and B to be incorrect and further experimentation is needed to determine the actual stereochemistry of the natural products.

1. Compound NSC-670224, previously shown to be toxic to Saccharomyces cerevisiae at low micromolar concentrations, potentially acts via a mechanism of action related to that of tamoxifen (NSC 180973), a widely utilized breast cancer drug. The structure of NSC-670224, previously thought to be a 2,4-dichloro arene, was established as the 3,4-dichloro arene, and a focused library of analogues were synthesized and biologically evaluated in conjunction with the UCSC Chemical Screening Center. The synthesis of a biotinylated affinity probe was also completed in order to extract the protein target(s) of NSC-670224 from yeast and human cell lines in collaboration with the Hartzog lab (UCSC MCD Biology)

2. Stabilization of ruthenium nanoparticles (Ru NPs) through carbene bound ligands has led to a simple and effective means to generate new materials with unique optoelectronic properties. The affinity of freshly prepared Ru NPs to diazo compounds, specifically octyl diazoacetate (ODA), provides a robust nanostructure that can be further functionalized via metathesis of terminal olefins to generate these unique materials. Carbene-stabilized Ru NPs have provided insights into the nature of extended conjugation and intraparticle charge delocalization through covalently bound probes (e.g., ferrocene and pyrene). The growing interest to study electronic communication through Ru NPs has lead to collaborative, multidisciplinary efforts between analytical (Shaowei Chen lab, UCSC), theoretical (Haobin Wang Lab, NMSU), and synthetic organic chemists (Konopelski Lab, UCSC). With this powerful collaboration, new methods to generate stabilized Ru NPs, testing theory with experiment, and efficient means to functionalize NPs have been investigated. The syntheses of custom ligands and their applications to nanoparticle-mediated electronic communication are reported.

The beta-lactam synthon method is an established technique utilizing beta-lactams in natural product synthesis. Through application of our previously described novel beta-lactam preparation, we describe the C3 functionalization and application of previously described and novel β-lactams towards the synthesis of pactamycin--a densely functionalized cyclopentane natural product--and non-natural analogs of salinosporamide A--a proteasome inhibitor currently in clinical trials for treatment of multiple myeloma.

Additionally, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds towards development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.

Finally, we report the application of this "split-pool" synthetic library approach towards the extension of known physical models of passive membrane permeation--in particular, the barrier domain model--to larger molecular weight chemical space. We show that the membrane permeability of macrocycles is governed by lipophilicity and solubility and that the window between the two narrows with increasing molecular size. We recognize this brings into question again the origin of intrinsic permeability of natural membrane-permeable macrocycles such as cyclosporin A.