Chiral Auxiliaries and Chirogenesis

This Reprint Book highlights and overviews the most important and novel aspects of chiral auxiliary and chirogenesis in different natural/physical sciences and in modern technologies. In particular, some newly emerging classes of molecules used for these purposes are described. This book consists of four review articles and one research paper and is of interest for general chemistry readership, including graduate and postgraduate students, and for researchers specializing in the fields of chirality and stereochemistr

Cannogenol and Related Cardiotonic Steroids: Concise Synthesis and their Anticancer Activity Evaluation

Small molecules that are approved as drugs are largely the result of extensive synthetic efforts. A robust synthetic method is required to access the natural products and their analogs to study their biological activities. This thesis largely focuses on the synthesis of cardiotonic steroids, the steroids that are known for the treatment of heart conditions and more recently has shown promising prospect in anticancer studies against various human cancer cell lines. Furthermore, the anti-cancer activities of the molecules of this class were studied and substantial data on structure-activity relationship (SAR) were obtained. In addition, this thesis also presents an anion binding catalysis, the process by which anions are selectively transported between membranes in human body, of a new class of catalyst thiophosphoramide that showed promising ability to bind with anions. The first chapter describes the utility of three hydrogen-bond donor, thiophosphoramide-based catalyst anion binding catalysis. The study illustrates that the thiophosphoramide-based HBDs could significantly accelerate Cu(II)-catalyzed reactions of potassium carboxylates with diaryliodonium salts. The scope of counterion on both the diaryliodonium salt and the copper salt is explored, followed by the application of this method in a wide-variety of carboxylic acid including some naturally available carboxylic acid. The second chapter introduces cardiotonic steroids and the discusses the relevant prior synthesis. Impressive synthesis of digitoxigenin by Yoshii and Nakada followed by the synthesis of strophanthidin by Yoshii and Kočovsky are discussed in detail. The total synthesis of cannogenol-3-O-α-L-rhamnoside that will be discussed in following chapter is inspired by the work previously published by Nagorny and coworkers on enantioselective synthesis of oxygenated steroids by copper-catalyzed Michael reaction followed by double aldol reaction and the utilization of this method in the total synthesis of 19-hydroxysermentogenin and trewianin aglycone are discussed in this chaper. The third chapter describes the development of a robust and divergent synthetic pathway to access natural product of the class called cardiotonic steroids. The chapter highlights the first enantioselective total synthesis of two cardiotonic steroids that have been recently of interest because of their anti-cancer activities: 1) cannogenol 2) cannogenol-3-O-α-L-rhamnoside. The challenges during the development of this method, that could provide analogs with different heterocycles and sugar moieties with minimum deviations, are described in detail. Finally, the fourth chapter focuses on the generation of natural products and analogs using the method developed in chapter 3. Another natural product cannogenol-3-O-glucopyranoside and an analog of cannogenol-3-O-α-L-rhamnoside with alkyne incorporation in the sugar moiety for the target identification studies were synthesized. In addition to the molecules synthesized in our group, other commercial steroids of diverse functional group at different part of the molecule were collected. The collaboration with Dr. Yimon Aye’s group at Cornell University presented us with significant structure-activity relationship (SAR) data. In addition, an analog of strophanthidin with amine incorporation instead of alcohol at C19 was synthesized by reductive amination of aldehyde.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147616/1/btbhat_1.pd

Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry

The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described

THE EXPLORATION OF NOVEL SYNTHETIC METHODS OF BIOLOGICALLY RELEVANT NITROGEN AND HALOGEN CONTAINING MOLECULES

Visible light has become a highly useful, and regarded, tool to the organic chemist. The additions and transformations of an abundance of molecules can be achieved with the use of visible light and photocatalysts, when appropriate. More specifically compounds that contain nitrogen, halogens, or both are highly useful structures in nearly every chemical industry. They are elements found in naturally occurring molecules and have the capacity to mimic biologically active and relevant structures. This makes them useful targets for pharmaceutical compounds. Bromine and chlorine can act as leaving groups; this property makes molecules with these elements reactive and thus able produce desirable effects in vivo. Nitrogen can be found within and outside of cyclic structures and is one of the most commonly functionalized elements in pharmaceuticals. The element can be found in nearly every class of pharmaceuticals ranging from chemotherapeutic to antifungal agents. Herein is reported the methodological development of synthetic nitrogen and halogen placement through a wide variety of chemical moieties. This work shows that visible light and photocatalysts can be used to furnish small heteroatomic compounds and halogenated products. These works highlight the value of substituted hydroxylamines for their nitrogen transfer capability; metal-halogen compounds in visible light transformations will also be highlighted

Exploiting the mechanical bond for molecular recognition and sensing of charged species

The unique properties of the mechanical bond have been increasingly used for the purpose of molecular recognition. The recent progress in the development of cation and anion template strategies for the construction of mechanically interlocked molecules (MIMs) have resulted in a variety of ion binding catenane and rotaxane host structures. The appropriate integration of reporting redox- and photo-active centres into their structural frameworks can result in prototype molecular sensors for targeting charged species and molecular switches for potential nanotechnological applications. This review presents progress in the field of MIM hosts for ion recognition and sensing since 2014, focusing on the synthetic approaches employed and mechanisms of host–guest binding and detection

Novel methods for stereocontrolled cycloaddition/dearomatization reactions under catalytic conditions

292 p.Los alcaloides son, en general, una familia de compuestos heterocíclicos de origen vegetal que incorporan átomos de nitrógeno en su compleja estructura. Su interés recae en las interesantes actividades biológicas que presentan, y por ello son extensamente empleados por la industria farmacéutica. En concreto, los anillos de pirrolidina y piperidina se encuentran como base fundamental en un elevado número de este tipo de estructuras. Por otro lado, uno de los principales objetivos de la química sintética es el de obtener este tipo de moléculas de una manera asimétrica. Entre otros, la catálisis metálica ha resultado de gran utilidad para tal objetivo. Por ejemplo, los ligandos tipo ferrocenilo previamente desarrollados en nuestro grupodio lugar a pirrolidinas enantiopuras densamente funcionalizadas. Así mismo, este tipo de ligandos han sido evaluados en diferentes tipos de reacciones de cicloadición, que han resultado en la formación de manera asimétrica de estructuras tricíclicas de interés biológico. Por el contrario, se ha desarrollado una síntesis racémica colectiva de compuestos tetracíclicos de la familia Securinega. Esta síntesis permite acceder a diferentes productos naturales de la familia debido a la versatilidad que presenta el intermedio bicíclico lactona

Synthesis of 3-heterocyclic phenyl N-alkyl carbamates and their activity as FAAH inhibitors

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide (AEA) to arachidonic acid and ethanolamine. FAAH also hydrolyze another important endocannabinoid, 2-arachidonoylglycerol (2-AG), although the main enzyme responsible for hydrolysis of 2-AG is MGL. Inhibition of FAAH or MGL enzymatic activity potentially leads to beneficial effects in many physiological disorders such as pain, inflammation and anxiety, due to increased endocannabinoid induced activation of cannabinoid receptors CB1 and CB2. In the present study a total of 101 compounds were designed, synthesized, characterized and tested against FAAH and MGL enzyme activity. Altogether 47 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC50) between 0.74 and 100 nM. All potent compounds belong to the structural family of carbamates. Other carbonyl-containing compounds were prepared for comparison and they were found not to inhibit either FAAH or MGL. The synthesized carbamate derivatives were found to be selective for FAAH as the inhibition of MGL enzyme by these compounds was negligible. From the library of phenyl N-alkyl carbamates the most potent FAAH inhibitors were meta-substituted N-cyclohexylcarbamates. 4,5-Dihydrooxazol-2-yl (221), oxazol-2-yl (242), 2-methyltetrazol-5-yl (273a), imidazol-4-yl (252) and 1,2,3-thiadiazol-4-yl (314) were found to be the best heterocycle substituents of phenolic N-alkyl carbamate. Methyl ester (276) was the best acyclic substituent. These compounds inhibited FAAH with IC50 values between 0.74-3.9 nM. Various synthesis methods were used to achieve the desired compounds. Microwave assisted novel or little known reactions applied in synthesis including condensation of acids and 2-aminophenol/2-amino-3-hydroxypyridine to prepare corresponding fused 2-oxazoles, oxazole formation via condensation of bromoketones and amides, and cleavage of benzyl and methyl ethers using ionic liquids. In conclusion, the results of this work provide useful structure-activity relationship (SAR) information of carbamate compounds as FAAH inhibitors which can be utilized in further developments in this area