Syntéza derivátů adamantanu

Undirected functionalization of adamantane by electrophilic oxidation proceeds mainly at the tertiary positions, owing to the higher reactivity of its C-H bonds and stability of electron deficient species, relative to the secondary positions. Ring contraction and expansion methods have been shown as a powerful tool to prepare such derivatives avoiding the reactivity constraints of undirected electrophilic oxidation reactions. Previous ring contraction methods proceeded under harsh conditions limiting their scope to simple alkyl substituents. In this work a new ring contraction method for the preparation of noradamantane derivatives from adamantane under mild conditions has been developed, enabling the presence of additional functional groups during the process. The new method utilizes the commercially available Burgess reagent for mild dehydration conditions of the starting material leading to 1,3- and 3,7-disubstituted (3-noradamantyl)methylene aldehydes, that were previously hard to obtain, if not unobtainable, and post functionalized to their corresponding protected amino-alcohols and diols. The method was also applied for the synthesis of protoadaman-4-one that is mainly synthesized through the deamination of 2-aminoadamantan-1-ol. The deamination method was also optimized for the preparation...Substituce adamantanu neřízenou elektrofilní oxidací probíhá především na terciárních polohách v důsledku vyšší reaktivity jejich C-H vazeb a stabilitě elektronově chudých intermediátů, relativně vůči jeho sekundárním polohám. Metody založené na kontrakci a expanzi adamantanového skeletu se ukázaly jako silný nástroj, který obchází omezení kladené neřízenou elektrofilní substitucí a umožňuje tak přístup k poly-substituovaným derivátům v méně reaktivních polohách. Předchozí metody pro kontrakci adamantanového skeletu probíhaly za náročných podmínek, které omezily jejich aplikaci na substráty s jednoduchými alkylovými substituenty. V této práci byla vyvinuta jednoduchá metoda pro syntézu derivátů noradamantanu s využitím komerčně dostupného Burgessova činidla, která probíhá za jemných podmínek. Umožňuje tak přítomnost dalších funkčních skupin vedoucí tak k přípravě 1,3- a 3,7-disubstituovaných (3-noradamantyl)methylen aldehydů, které byly v minulosti obtížně připravitelné, ne-li nedostupné. Připravené deriváty byly dále modifikovány na jejich příslušné ochráněné amino-alkoholy nebo dioly. Nová metoda byla také aplikována pro přípravu protoadamantane-4-onu, který je syntetizován především deaminací 2-aminoadamantan-1-olu. Deaminační metoda byla optimalizována také pro přípravu (3-noradamantyl)methylen...Department of Organic ChemistryKatedra organické chemieFaculty of SciencePřírodovědecká fakult

Concise enantioselective synthesis of (+)-FR66070 and (+)-FR900482 and the synthesis and biochemical studies of a photo-triggered FR900482 mitosene progenitor

2003 Summer.Includes bibliographical references.The total synthesis of the natural products (+)-FR66979 and (+)-FR900482 is presented. The synthesis features a novel dimethyldioxirane-mediated reaction for construction of the hydroxylamine hemiketal functionality and represents the shortest total synthesis reported to date. The synthesis of a photo-triggered mitosene progenitor based on the natural products (+)-FR66979 and (+)-FR900482 has also been described. Biochemical studies demonstrate the capacity of the mitosene progenitor to form DNA interstrand cross-links upon photo-activation. Furthermore, the cross-links have been shown to share the identical sequence specificity as the natural products

Development of New Methods Involving Strained Heterocycles

Four-membered heterocycles such as oxetanes and azetidines represent a unique class of small, strained rings. These scaffolds are found in a variety of biologically active natural products and also function as important structural building blocks in pharmaceutical products due to their desirable pharmacokinetic properties. However, from a synthetic standpoint, four-membered heterocycles are often considered the most difficult to access in comparison to their smaller, three-membered, as well as their larger, five- and six-membered analogs. Thus, there is a strong demand for the development of new synthetic methods that allow for the synthesis of four-membered heterocycles in an efficient and practical fashion. The synthetic challenges in accessing four-membered rings are commonly associated with their high ring-strain, yet this inherent property provides these scaffolds with unique reactivity that can also be harvested in catalytic transformations. This dissertation discusses the development of new methods for the synthesis of azetidines relying on visible light photocatalysis, as well as investigations into the Lewis acid-catalyzed carbonyl–olefin metathesis reaction that utilizes oxetanes as reactive intermediates. The first chapter of this dissertation studies the divergent reactivity in Lewis acid-mediated transformations between carbonyls and olefins. Herein, it is demonstrated that relatively simple metal salts can achieve remarkable selectivity, resulting in either carbonyl–olefin metathesis or carbonyl–ene reaction products. Furthermore, parametrization of relevant reaction intermediates through DFT calculations allowed for the development of predictive statistical models that provide important insights into the observed divergent reactivity. The second and third chapter of this dissertation discuss the development of new methods for the synthesis of azetidines via visible light-mediated [2+2] cycloadditions. This strategy is advantageous over traditional approaches as it utilizes readily available oxime and alkene precursors that are reacted in a single, highly atom-economic transformation. A method for the synthesis of azetidines via an intramolecular [2+2] cycloaddition is reported herein that proceeds via triplet energy transfer from a commercially available iridium photocatalyst. This reaction utilizes substrates containing styrenes, which possess low triplet energies and are amenable to activation via energy transfer. This intramolecular strategy readily affords highly functionalized azetidine products, yet it cannot be translated into an intermolecular variant due to the limited excited state lifetime of styrenes. Therefore, a new method is presented that relies on 2-isoxazoline-3-carboxylates as a previously unexplored imine reagent. This class of compound can be activated via triplet energy transfer from an iridium photocatalyst to react with unactivated alkenes with high efficiency. This new intermolecular strategy complements the limitations of previous methods for the synthesis of azetidines, and provides facile access to previously inaccessible azetidine scaffolds.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/168091/1/marcrb_1.pd

Synthesis of Novel Sultam Scaffolds: Method and Library Development

The development of methods to produce diverse set of small molecules to be utilized as chemical probes in chemical biology is a continuing emerging area critical in the pursuit of broadening the understanding of biological pathways and search for new therapeutics and biological probes to improve human health. In particular, sultams as non-natural lactam surrogates have recently gained attention as a novel class of compounds with extensive chemical and biological profiles that will be further discussed in introduction to Chapter 1. The virtues of diversity-oriented synthesis (DOS) paired with “Click, Click, Cyclize” paradigm in designing methods and libraries for the production of novel and unique sultam compounds provide a facile and efficient pathway in achieving this goal. Despite these attributes, methodologies for the synthesis of sultams and their corresponding libraries are limited in literature relative to lactam surrogates. A more in detail analysis of this gap will be introduced in the introduction of each chapter. It is the purpose of this dissertation to develop novel methods and production of libraries based on scaffolds generated from these methods. Through these methods and libraries, we aim to produce various sultam compounds that present opportunities in accessing underexplored and underrepresented regions of chemical space with potentials for serving as chemical probes in search for unknown biological activities. An outline of the following chapters of this thesis is shown in Figure A.1. The goal of Chapter 1 is to introduce methods and library development previously reported from the Hanson group. The introduction reviews the libraries that utilize Click “3+2” Huisgen cycloaddition reaction and/or intermolecular nucleophilic aromatic substitution (SNAr) for peripheral diversification. Then efforts on production of two novel sultam libraries based on one-pot Click-aza-Michael of RCM-derived sultam scaffolds and one-pot Click-SNAr of “4+4” derived scaffolds. Chapter 2 introduces a review of recent advances in synthesis of molecules containing triazole motifs via one-pot multicomponent Click reactions (MCR). This review is categorized into three sections, including 2-, 3-component MCR, 4-, 5-, 6-component MCR, and development of novel catalysts for Cu-catalyzed azide–alkyne coupling (CuAAC) reactions. This review will be then followed by studies towards application of one-pot, sequential, multicomponent reaction strategy for the facilitated synthesis of “4+4” dibenzofused 8-membered sultam scaffolds and their analogs produced from 3-, 4-, 5-component reactions. Lastly, Chapter 3 discusses recent advances in the synthesis of various biologically active tetramic acids and their analogs. The review is divided into three sections: synthesis of tetramic acids via Dieckmann reaction, via methods other than Dieckmann condensation, and modification of existing tetramic acids for diversification and studies towards reactivity profile of tetramic acids. Subsequent section of this chapter includes our recent work on synthesis of sultam analogs of tetramic acids via intramolecular sulfa-Dieckmann cyclization. Further diversifications utilizing condensation with isocyanates to produce 3-carboxamide substituted sultam analogs of tetramic acids are reported

Synthesis of polycyclic aromatic hydrocarbon containing cyclophanes: new and improved methodologies

Cyclophanes are a vast class of compounds that can be defined as any system containing an aromatic system bridged by at least one n-membered bridge (n≥0). This description encompasses a large number of compounds, but relatively few examples in which the aromatic system is more complex than benzene exist. This is largely due to the increase is synthetic difficulty and a lack of universal methodologies. The work described in this thesis includes improvements in the synthesis of pyrenophanes and the introduction of new methodology for cyclophane formation in which the aromatic unit is peropyrene. Chapter 1 serves as an introduction to the concept of non-planarity in aromatic systems and the strategies for incorporating such morphologies into structures. Focus has been placed primarily on cyclophanes containing one aromatic system and one bridge and their advantages in structural modulation. Chapter 2 contains a review of the history of pyrenophanes and strategies towards their preparation. Improvements to the synthesis of the 1,n-dioxa-[n](2,7)pyrenophanes and [n](2,7)pyrenophanes are discussed in detail. Additionally, the reactivity of these systems is briefly discussed. Chapter 3 introduces peropyrene and discusses its properties and limited synthetic accessibility. The synthesis of a series of new cyclophanes is discussed which takes advantage of the dimerization of phenalenlyl radicals generated phenalene. Characterization of resulting [n](2,6)peropyrenophanes is briefly discussed

Chemical Symmetry Breaking

This book entitled “Chemical Symmetry Breaking” is a collective volume of state-of-the-art reports on unique nonlinear chemical and physical symmetry-breaking phenomena that were experimentally observed upon a thermally or photochemically induced phase transition in various organic condensed phases, such as metastable liquid crystals, crystals, amorphous solids, and colloidal polymer materials, only under nonequilibrium conditions. Each author summarizes the introductory section in simple terms but in detail for beginners in this field. We wish that many readers familiarize themselves with the general concepts and features of nonlinear and nonequilibrium (or out of equilibrium) complexity theory, which govern a variety of unique dynamic behaviors observed in chemistry, physics, life science and other fields, so that they may discover novel symmetry-breaking phenomena in their own research areas

More than a memoir

This autobiography was written originally as a test of memory, as a means of diminishing piles of stored papers and file folders, and in an effort to record events as they actually happened. It had been my experience as a child, hearing oral histories presented by adult family members, that there was great variance in their perceptions. Perhaps I could set down the "facts" of a life and leave interpretations up to any readers. Each of the chapters was distributed to my four children, Kenneth, Marcia, James and David. Inasmuch as they read the sporadic mailings, I incorporated their corrections and tried to answer any questions they raised. I relied upon friends to check specific chapters against their memories and upon Peggy Phelps to offer penetrating criticism where she discerned opinion masquerading as fact. Diane Orona deciphered my handwriting sufficiently to produce a handsome, typed manuscript, and I thank her for her patience and her aim at perfection. Who will read such a manuscript? Who among the grandchildren or children has the time for it? With the completion of the story, can I hope that others may find it of interest? The very personal nature may decide against that. The diverse nature of the subject matter would guide toward selective readings: organic chemistry with some biochemistry and plant physiology; music, but mainly singing; bi-continental living and romance; family; travel; universities; extraneous material about foundations, research support, national and international organizations, even some talks (in the appendix). However, there is a whole to it -- the story of a sample life in the twentieth century and a bit into the twenty-first. I have found life's journey exciting and rewarding. I have been fantastically lucky. NJ