Browsing by Subject "Total Synthesis"

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    2,5-Cyclohexadienones as a Useful Launching Point for the Synthesis of the Briarane Diterpenoids and A Hypervalent Iodine-Mediated Synthesis of Oxazolines
    (2015-05) Moon, Nicholas
    The briarane diterpenoids are a large class of natural products derived from gorgonians and other corals from throughout the world. Despite the extremely large number of briaranes that have been isolated, along with the potent and diverse range of biological activities that have been observed, the total synthesis of the briaranes remains underexplored. A facile synthetic route to the briarane diterpenoids will aid in the further exploration of these molecules. Herein, we will describe a number of synthetic approaches that were evaluated to access a key fragment of the briarane diterpenoids. A key feature of all routes involves the use of 2,5-cyclohexadienone substrates as a diverse platform for the launching of the synthesis. Chapter 1 will provide background information on 2,5-cyclohexadienones. Methods for their synthesis, a survey of their diverse reactivity, and selected examples of their use in natural product synthesis will all be described. Emphasis will be given to reactivity patterns which aided us in our research. Chapter 2 will provide a brief survey of the briarane diterpenoids as well as some of the major biologically active families. Previous synthetic efforts used to access these molecules will also be described. Chapter 3 will describe our efforts to synthesize a key fragment of the briarane diterpenoids (referred to as the briarane stereotetrad) utilizing intermediates containing a bicyclic lactone. Chapter 4 will describe our successful efforts to access the briarane stereotetrad using monocyclic intermediates. The important influence of torsional strain in key steps, as well as a successful route to access the briarane stereotetrad will be described. Chapter 5 will report the results of a separate research project in which an iodine(III) promoted cyclization of N-allylamides to form oxazolines was studied. The development of optimum reaction conditions and the evaluation of the substrate scope will be described. Key results that suggest novel mechanistic details for this electrophilic oxidative cyclization will also be described.
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    Macrocyclization Through Ene-Yne Cross-Coupling/Alkyne Reduction Tandem Reaction And Its Application In Natural Product Synthesis
    (2015-09) Li, Wei
    Chapter 1 — Macrocyclization Through Copper-Catalyzed Castro–Stephens Coupling/Alkyne Reduction Tandem Reaction Macrocycles, incorporating conjugated polyene subunits within the ring, are structural features found in a number of natural products that exhibit diverse and potent biological activities. Existing methods for the construction of such structures are limited and in many cases inefficient. We discovered an unprecedented copper-mediated reductive ene–yne macrocyclization reaction during our pursuit of the total synthesis of oximidine II. The reaction selectively generates an endocyclic Z-double bond through an intramolecular coupling of a vinyl iodide and a terminal alkyne fragment followed by in situ alkyne reduction. We developed this transformation as a general method for the preparation of polyunsaturated macrocycles. The reaction conditions were optimized and the scope of the reaction was extensively explored. It was found that the alkyne reduction step is driven by the release of the ring strain. Thus, the reaction is particularly efficient for suitably strained 11- to 13-membered E,Z-1,3-diene macrocycles. A complementary stepwise procedure was employed for the synthesis of larger rings. Finally, a plausible reaction mechanism was proposed based on experimental findings. HASH(0x7f87dd8493f8) Chapter 2 — Formal Total Synthesis of Lactimidomycin Lactimidomycin is a macrocyclic natural product that possesses potent in vitro and in vivo anti-tumor activities. We accomplished a facile, 9-step synthesis of an advanced intermediate for the total synthesis of lactimidomycin. The crucial 12-membered polyene lactone core structure was constructed employing our newly developed Castro–Stephens coupling/alkyne reduction tandem reaction. The stereocenters were established via asymmetric a vinylogous aldol reaction and a Marshall’s propargylation reaction. Chapter 3 — Synthesis and Biological Evaluation of Oximidine II Analogues Oximidine II belongs to a family of benzolactone enamide natural products that exert their cytotoxic effects through inhibition of V-ATPases. Unlike other members of this family, the structure-activity relationship (SAR) of oximidines has not been extensively investigated. Guided by computational analysis and previous studies in our group, we designed and synthesized two oximidine II analogues with simplified scaffold. The simplified benzolactone core was accessed through a ring-closing metathesis (RCM) reaction and the enamide side chain was installed via a copper-mediated C–N coupling reaction. The analogues were evaluated for their biological activity. The results revealed that these molecules were weakly cytotoxic to a number of cancer cell lines.