This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1. It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family.

Marine natural products have continued to be a source of compounds with interesting structures and biological activities. Two such compounds are maculalactone A and haterumalide NA. In the process of exploring a route to the synthesis of haterumalide NA, the novel ring system, spiroepoxy-b-lactones were discovered. Spiroepoxy-b-lactones were synthesized by the oxidation of ketene-homo dimers with dimethyldioxirane (DMDO). After a synthetic route to this ring system was obtained we next explored the varied reactivity of spiroepoxy-b-lactones, and it was apparent that they might be applied to the synthesis of maculalactone A. Also with the aim of the total synthesis of the haterumalides, a palladium catalyzed cross coupling was developed. This reaction couples a 1,1-dichloroolefin with an alkyl zinc reagent. It was found that this reaction necessitates a heteroatom on the zinc reagent in order to proceed.

Marine sponges produce a series of complex polycyclic diamine alkaloids which appear to have a common biogenesis from simple bis-pyridine macrocycles. These structurally novel secondary metabolites are presumably biosynthetically produced by the controlled ionic coupling of macrocyclic 3-alkyl piperidines leading to 3,4??-linked bis-piperidines (ii). Included among these diamine marine alkaloids is haliclonacyclamine C (i) which serves as our synthetic target. Chapter I in this thesis provides background information describing biological activity and proposed biosynthetic pathways to these important diamine marine alkaloids. Chapter II details progress towards the total synthesis of haliclonacyclamine C. The focus of Chapter II will be on our successful construction of the 3,4??-linked bispiperidine central core (ii) highlighted by the use of palladium-mediated C-C bond forming processes. The stereoselective hydrogenation of a coupled product will also be discussed.

This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1. It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family.

Master of Science / Department of Chemistry / Ryan Rafferty / The lagunamides are group of natural products derived from cyanobacterium. Lagunamides A, B, and C have shown impressive cytoxicity towards a panel of cancer and malarial cell lines. Each of the lagunamide family members share structural similarities within their polypeptide backbone, but the polyketide units with A/B differ from C by an additional methylene insertion. The total synthesis of lagunamide A and an analog of lagunamide B have been reported by Dai and Pal’s groups, respectively. The synthesis of lagunamide A was completed first by Dai and proved that the original structural elucidation was incorrect. With this inaccurate stereochemical assignment, it was suspected that this inaccuracy also appeared in the structural elucidation of Lagunamide B that was completed by Pal. It is alleged that these inaccuracies have occurred in the stereochemical assignments of the isolated structure of lagunamide C. In addition to the stereochemical inaccuracies, a new synthetic route is necessary to synthesize lagunamide C. The structures of lagunamides A and C are nearly identical, except for the addition of one carbon in the polyketide portion of lagunamide C. This additional carbon disallows the use of same synthetic methods applied on lagunamide A to be employed on the synthesis of the polyketide portion of lagunamide C. This work will discuss a modular approach towards the synthesis of lagunamide C. Model systems were employed to test the validity and success of the proposed route. Key steps of the proposed synthetic route include a titanium mediated mixed aldol reaction, cyclopropanation, and Charette cyclopropane ring-opening. The current synthetic route is shown to be scalable and possessing optimizable transformations. These steps have proven to be successful with the model systems and have laid the groundwork for the synthesis of the target compound, lagunamide C.

This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1. It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family. / Science, Faculty of / Chemistry, Department of / Graduate

Thesis advisor: James P. Morken / This dissertation will present three main projects focusing on the transition metal-catalyzed enantioselective synthesis of secondary organoboronic esters and progress towards the total synthesis of sarcodictyins. In the first project, a palladium-catalyzed enantioselective conjunctive cross-coupling reaction with propargylic electrophiles will be described. The tetra-substituted allenes are isolated with good yield and enantioselectivity and the beneficial effects of alcohol additives are investigated. The second project describes the enantioselective synthesis of ɑ-boryl zinc reagents by a nickel-catalyzed carbozincation reaction. The in situ generated ɑ-boryl zinc intermediate can be trapped by copper-mediated allylations, palladium-catalyzed Negishi cross-couplings, and cerium-mediated halogenation reactions to construct various chiral organoboranes. The synthetic utility of this methodology is showcased by the synthesis of natural products, including bruguierol A, (-)-aphanorphine, and (-)-enterolactone. The mechanism is studied with the assistance of EPR and deuterium-labeling experiments and a catalytic cycle through a Ni(I) intermediate is proposed. The third project depicts a synthetic route to essential precursors in the progress of the total synthesis of sarcodictyins. Various attempts to construct the ten-membered ring core of sarcodictyin have been made, including Sonogashira reaction, Dieckmann condensation, and lithium—halogen exchange process. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The penostatins are a family of polycyclic natural products isolated from marine bacteria. They exhibit unique biological activity and have garnered interest from synthetic organic chemists due to their complex structure. In particular, the complex oxidation pattern combined with either a fused tricyclic or bridged bicyclic core presents significant challenges to synthesis. The lack of a completed total synthesis of the bridged bicyclic congener penostatin F has motivated the pursuit of a strategy for its synthesis based on a Diels-Alder reaction /Claisen rearrangement sequence. In this work, progress and limitations of this approach are presented. A hydroxy-directed Diels-Alder/Claisen Rearrangement cascade was envisioned and explored however a series of roadblocks prevented the elaboration of bridged bicycle intermediates. Through this process, a novel degradation of hydroxy-dienes was uncovered as well as the isolation of a bridged bicycle containing a cyclic anti-Bredt alkene. The challenges uncovered led to a pivot away from this strategy and ultimately to a new approach for the synthesis of penostatin natural products. In this strategy, a hydroxyl group is used as a tether for an intramolecular Michael addition. Following the optimization of this reaction, an unexpected retro-Dieckman rearrangement of the product forced the development of an alternative route to an initially envisioned decarboxylation. This approach was employed to yield 5-deoxypenostatin B. Finally, progress towards integrating the cyclopentanol ring of penostatin B as part of this strategy via a Tamao-Fleming reaction is described.

The use of a Nazarov cyclization for the diastereoselective synthesis of rocaglamide was studied. Chapter 1 discusses the biological activity of the rocaglamide family of natural products and details the previous synthetic work on these compounds. Chapter 2 discusses the approaches taken in the Magnus group for the total synthesis of rocaglamide. Several approaches to the natural product were undertaken. Using a novel acid bromide induced Nazarov cyclization, construction of the C-ring of the natural product was achieved. Attempts to construct the remainder of rocaglamide were ultimately unsuccessful. / text

The hasubanan alkaloid cepharatine A, was efficiently synthesized in 8 steps from commercially available starting materials in overall 16% yield. Highlighted in this synthesis, is a tandem phenolic alkylation – annulation which formed both a quaternary center as well as an unsaturated ring. This key step allowed for rapid construction of the core of the molecule. Subsequent reductive amination and acid catalyzed cyclization afforded the title compound. / text