Calyciphylline B-type Alkaloids: Evolution of a Synthetic Strategy to (-)-Daphlongamine H.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B

Biodiesel and green diesel generation: An overview

First, second, third, and fourth-generation biofuels are continuously evolving as a promising substitute to petrodiesel catalyzed by energy depletion, economic and environmental considerations. Bio-diesel can be synthesized from various biomass sources, which are commonly divided into FAME and renewable biodiesel. FAME biodiesel is generally produced by the transesterification of vegetable oils and fats while renewable diesel is produced by hydro-deoxygenation of vegetable and waste oils and fats. The different generation, processing technologies and standards for FAME and renewable biodiesel are reviewed. Finally, the life cycle analysis and production cost of conventional and renewable biodiesel are described

Current Technologies and Future Perspectives in Immunotherapy towards a Clinical Oncology Approach

Immunotherapy is now established as a potent therapeutic paradigm engendering antitumor immune response against a wide range of malignancies and other diseases by modulating the immune system either through the stimulation or suppression of immune components such as CD4+ T cells, CD8+ T cells, B cells, monocytes, macrophages, dendritic cells, and natural killer cells. By targeting several immune checkpoint inhibitors or blockers (e.g., PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM-3) expressed on the surface of immune cells, several monoclonal antibodies and polyclonal antibodies have been developed and already translated clinically. In addition, natural killer cell-based, dendritic cell-based, and CAR T cell therapies have been also shown to be promising and effective immunotherapeutic approaches. In particular, CAR T cell therapy has benefited from advancements in CRISPR-Cas9 genome editing technology, allowing the generation of several modified CAR T cells with enhanced antitumor immunity. However, the emerging SARS-CoV-2 infection could hijack a patient’s immune system by releasing pro-inflammatory interleukins and cytokines such as IL-1β, IL-2, IL-6, and IL-10, and IFN-γ and TNF-α, respectively, which can further promote neutrophil extravasation and the vasodilation of blood vessels. Despite the significant development of advanced immunotherapeutic technologies, after a certain period of treatment, cancer relapses due to the development of resistance to immunotherapy. Resistance may be primary (where tumor cells do not respond to the treatment), or secondary or acquired immune resistance (where tumor cells develop resistance gradually to ICIs therapy). In this context, this review aims to address the existing immunotherapeutic technologies against cancer and the resistance mechanisms against immunotherapeutic drugs, and explain the impact of COVID-19 on cancer treatment. In addition, we will discuss what will be the future implementation of these strategies against cancer drug resistance. Finally, we will emphasize the practical steps to lay the groundwork for enlightened policy for intervention and resource allocation to care for cancer patients

Part I. Synthesis of delavatine A, incarviatone A, and fascaplysin natural products. Part II. Total synthesis of calyciphylline B-type alkaloids

This dissertation details work in two categories: (1) development of novel annulation strategies enabled by regioselective ring-opening of 2-pyrone derivatives and showcasing the utility of such transformations in total synthesis (Chapters 1–4). (2) total synthesis of calyciphylline B-type alkaloids and evolution of a novel methodology to access oxazaborinine heterocycles (Chapters 5–6). Chapter 1 is an introduction to known annulation reactions employing the versatile reactivity of 2-pyrone derivatives. This chapter provides a comprehensive summary of such strategies to highlight the key areas where further development is needed.Chapter 2 describes the evolution of our symmetry-inspired unified strategy for the synthesis of delavatine A and incarviatone A. Key features of our final synthetic route include an electrocyclization cascade sequence involving five transformations occurring in a single pot. This sequence was initiated by a regioselective 1,6-ring opening of a 2-pyrone derivative, which was synthesized by employing site-selective cross-couplings of 3,5-dibromo-2-pyrone. Chapter 3 details experimental and computational studies conducted to gain insight into the mechanism of the observed site-selective cross-coupling of 3,5-dibromo-2-pyrone. These insights may prove valuable in developing a more general understanding of the effects of solvents and additives on site-selective cross-coupling of other polyhalogenated heterocycles.Chapter 4 describes an extension of our interest in exploiting annulation strategies enabled by the regioselective ring-opening of 2-pyrone derivatives. Specifically, this chapter discusses the development of an annulation strategy that relies on 1,2-ring opening of N-heterocycle–pyrone adducts. The scope of this strategy was extended to access diverse N-fused heterocycles including pyrido[1,2-a]indoles. Additionally, the utility of this methodology was demonstrated in a concise formal synthesis of three fascaplysin congeners. Chapter 5 focuses on our early approach toward the synthesis of calyciphylline B-type natural products, a subfamily of the polycyclic Daphniphyllum alkaloids. While this strategy did not prove fruitful to access the target molecules, the approach revealed a wealth of interesting reactivity surrounding oxazaborinine heterocycles.Chapter 6 highlights our successful route to access calyciphylline B-type alkaloids. Specifically, the synthetic studies culminated in the first total synthesis of daphlongamine H, gave access to isodaphlongamine H, and also led to revision of the reported structure of deoxyisocalyciphylline B

Part I. Synthesis of delavatine A, incarviatone A, and fascaplysin natural products. Part II. Total synthesis of calyciphylline B-type alkaloids

This dissertation details work in two categories: (1) development of novel annulation strategies enabled by regioselective ring-opening of 2-pyrone derivatives and showcasing the utility of such transformations in total synthesis (Chapters 1–4). (2) total synthesis of calyciphylline B-type alkaloids and evolution of a novel methodology to access oxazaborinine heterocycles (Chapters 5–6). Chapter 1 is an introduction to known annulation reactions employing the versatile reactivity of 2-pyrone derivatives. This chapter provides a comprehensive summary of such strategies to highlight the key areas where further development is needed.Chapter 2 describes the evolution of our symmetry-inspired unified strategy for the synthesis of delavatine A and incarviatone A. Key features of our final synthetic route include an electrocyclization cascade sequence involving five transformations occurring in a single pot. This sequence was initiated by a regioselective 1,6-ring opening of a 2-pyrone derivative, which was synthesized by employing site-selective cross-couplings of 3,5-dibromo-2-pyrone. Chapter 3 details experimental and computational studies conducted to gain insight into the mechanism of the observed site-selective cross-coupling of 3,5-dibromo-2-pyrone. These insights may prove valuable in developing a more general understanding of the effects of solvents and additives on site-selective cross-coupling of other polyhalogenated heterocycles.Chapter 4 describes an extension of our interest in exploiting annulation strategies enabled by the regioselective ring-opening of 2-pyrone derivatives. Specifically, this chapter discusses the development of an annulation strategy that relies on 1,2-ring opening of N-heterocycle–pyrone adducts. The scope of this strategy was extended to access diverse N-fused heterocycles including pyrido[1,2-a]indoles. Additionally, the utility of this methodology was demonstrated in a concise formal synthesis of three fascaplysin congeners. Chapter 5 focuses on our early approach toward the synthesis of calyciphylline B-type natural products, a subfamily of the polycyclic Daphniphyllum alkaloids. While this strategy did not prove fruitful to access the target molecules, the approach revealed a wealth of interesting reactivity surrounding oxazaborinine heterocycles.Chapter 6 highlights our successful route to access calyciphylline B-type alkaloids. Specifically, the synthetic studies culminated in the first total synthesis of daphlongamine H, gave access to isodaphlongamine H, and also led to revision of the reported structure of deoxyisocalyciphylline B

Catalytic, contra-Thermodynamic Alkene Isomerization

The positional isomerization of C–C double bonds is a powerful strategy for the interconversion of alkene regioisomers. However, existing methods provide access to thermodynamically more stable isomers from less stable starting materials. Here we report the discovery of a dual catalyst system that promotes contra-thermodynamic positional alkene isomerization under photochemical irradiation, providing access to terminal alkene isomers directly from conjugated, internal alkene starting materials. The utility of the method is demonstrated in the deconjugation of diverse electron rich/poor alkenes and through strategic application to natural product synthesis. Mechanistic studies are consistent with a regiospecific bimolecular homolytic substitution (SH2\u27) mechanism proceeding through an allyl-cobaloxime intermediate

The Calyciphylline B-type Alkaloids: Total Syntheses of (–)-Daphlongamine H and (–)-Isodaphlongamine H

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (–)-daphlongamine H in enantioenriched form has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson–Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (–)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B, which resulted in the proposal of a modified biosynthetic pathway to the calyciphylline B-type alkaloids

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes