Academic literature on the topic 'Synthesis of cyclopropanes'

This thesis is concerned with the asymmetric synthesis of cyclopropyl derivatives via the use of chiral iron acyl complexes of the type (η⁵-C₅H₅)Fe(CO)(PPh₃)(COCH=CR'R), Chapter 1 reviews previous routes to optically active cyclopropyl derivatives and reviews the use of the chiral auxiliary (η⁵-C₅H₅)Fe(CO)(PPh₃) for asymmetric synthesis. Chapter 2 describes the synthesis of the complexes (η⁵-C₅H₅)Fe(CO)(PPh₃)(COCH=CRR') and presents a conformational analysis of the α, β-unsaturated acyl ligand. Chapter 3 describes the diastereoselective synthesis of cis- substituted cyclopropyl complexes via the reaction of Z-α, β-unsaturated iron acyl complexes with electrophilic alkylidene species. Decomplexation, to give the corresponding cyclopropyl esters, occurred without epimerisation of the cyclopropane ring. By the use of homochiral iron acyl complexes the enantioselective synthesis of cyclopropyl derivatives was achieved. Section A describes methylene addition and Section B isopropylidene addition reactions. Section C describes attempts to synthesise pyrethroid insecticide precursors which occurred with good diastereoselectivity but poor regioselectivity. Section D describes electrophilic ethylidene addition reactions in which the chiral auxiliary exerts good stereochemical control over three new chiral centres. Chapter 4 describes the diastereoselective synthesis of trans- substituted cyclopropyl complexes via the reaction of E-α, β-unsaturated iron acyl complexes with nucleophilic alkylidene transfer reagents. Section A describes methylene transfer reagents. Whilst α-lithiosulphides and α-lithiosulphoxides were of limited use, iodomethyllithium (generated in situ) resulted in highly diastereoselective syntheses of the cyclopropyl complexes. Decomplexation, to give the corresponding cyclopropyl esters, occurred without epimerisation of the cyclopropane ring. By the use of homochiral iron acyl complexes the enantioselective synthesis of cyclopropyl derivatives was achieved. Section B describes the generation of 1-iodoethyllithium and 1-iodobutyllithium and their reactions as nucleophilic alkylidene transfer reagents. The stereo- chemistry at two of the new chiral centres is controlled by the iron chiral auxiliary, whilst that at a third is controlled by a number of factors.

Activated cyclopropanes have been extensively used in synthetic chemistry as precursors for cycloaddition reactions. The rationale behind this is their ability to undergo ring-opening when activated by a Lewis acid, this can be enhanced further by the presence of a carbocation stabilising group like electron-rich aromatics. The stabilised dipole formed after ring opening can be trapped with suitable electrophiles such as imines and aldehydes via a [3+2] cycloaddition reaction. This results in the synthesis of pyrrolidines and tetrahydrofurans in excellent yields but moderate diastereoselectivity. Similarly, 6-membered heterocycles can be formed via a [3+3] cycloaddition reaction of activated cyclopropanes with nitrones. Now to extend the scope of the methodology, a [3+3] dipolar cycloaddition has been developed using activated 2,3 disubstituted cyclopropane diesters to access a range of highly functionalised oxazines in moderate to good yields (50-75%) and with reasonable diastereoselectivity. The use of activated symmetrical disubstituted cyclopropanes afforded the desired oxazines in a regio- and diastereocontrolled manner, while the use of unsymmetrical cyclopropanes significantly reduced the diastereoselectivity of the reaction. The stereochemistry outcome of the reaction developed was determined by nOe analyses and X-ray diffraction structures could be recorded in some examples. A new methodology has also been developed to gain access to novel N-heterocyclic- and phenol- substituted cyclopropanes in one step from the corresponding cyclopropene via a conjugated addition.

Multi-substituted optically pure cyclopropanes are important motifs present in many agrochemicals, pharmaceuticals and materials employed in manifold applications. Their synthesis is challenging due to both the strained conformation and the need to control both the relative and absolute stereochemistry. This thesis describes an investigation of the scope of the Wadsworth-Emmons cyclopropanation, highlighting it as a potential efficient methodology for diastereoselective and enantiospecific synthesis of these valuable ring systems. Chapter 1 is an introduction to the cyclopropanation protocols and is split in two subsections. The first is a description of the currently most exploited synthetic pathways to cyclopropanes, with analysis of their substrate scope and critical analysis of their limitations as compared to potential of the Wadsworth-Emmons cyclopropanation (Sections 1.1 to 1.3). The latter section consists of a review on the history and the evolution of this procedure and introduces the preconditions for the development of the project (Sections 1.4 to 1.17). Chapter 2 describes the results and discussion, introducing the use of novel alkyl-substituted triethyl phosphonoacetates to yield cyclopropyl-esters containing quaternary stereocentres. The high yields and the excellent trans-diastereoselectivity values obtained (proved by X-ray crystallography) allowed the proposal of a suggested reaction mechanism, which is supported by the subsequent experiments carried out in the presence of other functional groups, e.g. other carbonyls, nitriles, hetero-aromatics, substituted phenyl rings. This study was further extended to examine the effect of fluorine atom, due to its importance in biologically active environments. The study on the stereochemistry of the Wadsworth-Emmons cyclopropanation has been strongly supported by a range of X-ray crystal structures of the cyclopropane products. The chapter ends with an empirical set of guidelines, helpful for the design of successful cyclopropanations. Chapter 3, describes the experimental methods in full as well as full characterisation of the products obtained. Literature references, noted throughout the thesis, are listed in the final chapter.

On treatment with base, diphenylphosphinoyl esters 3 (X=O) give cyclopropanes 4 <i>via</i> a series of steps including intramolecular acyl and phosphinoyl transfer processes. β-Substituted esters have been shown to give cyclopropanes with high diastereoselectivity. This thesis describes the synthesis of optically active β-substituted esters using Evans’ alkylation methodology and their use in the stereocontrolled synthesis of substituted cyclopropanes. It was found that that phosphine oxide 1 (X=O) is unstable in the conditions of the alkylation reaction and the corresponding phosphine borane 1 (X=BH₃) was employed with greater success. The thesis also describes investigations into the potential formation of cyclopropanes 4 from esters 3 (X= BH₃/S) without prior conversion to the phosphine oxide 3 (X=O). It has been proposed that a phosphine ester is a key intermediate in the formation of cyclopropanes 4 from diphenylphosphinoyl esters 3 (X=O). Detailed in this thesis, is an investigation into the synthesis of optically active cyclopropanes 8 from phosphonate esters 7 prepared by an Evans’ alkylation route. Also included in this thesis are studies into the relative rates of deprotonation and the palladium-catalysed hydrogenation reactions of allyl phosphine oxides, boranes and sulfides. Phosphine oxides have also been used in the synthesis of cyclopropanes <i>via</i> a route analogous to that of the Wadsworth-Emmons cyclopropanation reaction.

Ce manuscrit décrit la synthèse énantiosélective de cyclopropanes trifluorométhylés, difluorométhylés et mono-halométhylés hautement fonctionnalisés. Cette synthèse repose sur la cyclopropanation d’alcènes. De plus, la synthèse d’alcools tertiaires difluorométhylés à partir des oléfines fluorées correspondantes suivant un processus de dihydroxylation asymétrique est décrite. Ce manuscrit se découpe en 3 chapitres. Le premier chapitre décrit la première synthèse catalytique asymétrique de cyclopropanes difluorométhylés en utilisant le Rh₂((S)-BTPCP)₄ comme catalyseur pour la réaction de cyclopropanation d’oléfines α,α-difluoromethylées avec des composés diazoïques di-accepteurs. Un large éventail de cyclopropanes a été obtenu avec de très bon rendements et d’excellentes diastéréosélectivités et énantiosélectivités (&gt;20:1 et jusqu’à 99% ee). Le second chapitre illustre la synthèse de cyclopropanes trifluorométhylés suivant une stratégie similaire. Ces derniers ont été obtenus avec des très bons rendements et d’excellentes diastéréosélectivités et énantiosélectivités (&gt;20:1 et jusqu’à 99% ee). Ces travaux ont également permis une extension aux dérivés mono-halométhylés. Dans un troisième chapitre, l’époxydation asymétrique de styrenes α,α-difluoromethylés a été étudiée. Malheureusement, tous les essais métallo- ou organocatalysés se sont avérés infructueux. Par la suite la réaction de dihydroxylation asymétrique de ces styrenes α,α-difluorométhylés a été développée pour conduire aux alcools tertiaires difluorométhylés énantioenrichis. L’utilisation d’AD-mix-α et AD-mix-β comme catalyseurs a permis d’obtenir les produits désirés avec de très bons rendements et d’excellentes énantiosélectivités. De plus, cette réaction a été étendue aux styrenes α,α-difluorométhylés, α-monofluorométhylés, β-difluoromethylé et β-trifluorométhylé<br>This thesis presents the enantioselective synthesis of functionalized trifluoromethyl, difluoromethyl and monohalomethyl cyclopropanes based on the cyclopropanation reaction of alkenes bearing various fluorinated groups. In addition, the synthesis of enantioenriched fluorinated tertiary alcohols resulting from the dihydroxylation of fluorinated olefins is discussed. This thesis is divided into three chapters. In the first chapter, we reported the first example of catalytic asymmetric synthesis of difluoromethyl cyclopropanes, which is achieved by using Rh₂((S)-BTPCP)₄ as a catalyst to perform the cyclopropanation reaction of α,α-difluoromethyl olefins with donor-acceptor diazo compounds and di-acceptor diazo compounds. This methodology allows the access to a broad range of cyclopropanes in high yields with excellent diastereo- and enantioselectivities (up to &gt;20:1 and up to 99% ee). In the second chapter, a practical and efficient asymmetric synthesis of trifluoromethyl cyclopropane derivatives was described and a series of functionalized cyclopropanes were obtained in excellent diastereoselectivities with excellent enantioselectivities (up to &gt;20:1 and 99% ee). These investigations also extended to the synthesis of highly enantioselective monohalomethyl cyclopropanes. In the third chapter, the initial propose aimed at exploring the asymmetric epoxidation of α,α-difluoromethyl styrenes. The reaction was performed in the presence of a metal-catalyst or an organic catalyst, unfortunately, none of the result was positive. Therefore, we turned our attention to the asymmetric synthesis of α,α difluoromethylated tertiary alcohols. To this propose, the use of commercially available reagents AD-mix-α and AD-mix-β as the best catalysts, allowed the reaction with α,α-difluoromethyl styrenes to construct the corresponding α,α-difluoromethylated tertiary alcohols in good to high yields with excellent enantioselectivities (up to 99% ee). In addition, this transformation could be applied to a broad range of substrates, including variety of α,α-difluoromethyl styrenes, α-monofluoromethyl styrenes, β-difluoromethyl styrene and β-trifluoromethyl styrene

Thesis (M.A. in Chemistry)--University of Texas at Austin, May 1992.<br>"May 1992." Description based on title screen as viewed on April 8, 2009. Includes bibliographical references (p. 94-101). Also available in print.

Organofluorine compounds constitute a large part of all the drugs, crop protection agents and advanced materials produced nowadays. Therefore, there is a great interest in developing the new methods of synthesis of organofluorine compounds. In this thesis we report a novel method of synthesis of monofluorinated cyclopropanes based on the Michael-initiating ring closure (MIRC) reaction. Our method allows obtaining polysubstituted monofluorinated cyclopropanes from ethyl dibromofluoroacetate and various Michael acceptors. We have also implemented the asymetric version of cyclopropanation using a novel oxazolodinone-derived chiral fluorinated reagent. In the final part of this thesis we report the synthesis of a fluorinated analog of L-FAP4, a potent agonist of group II metabotropic glutamate receptors (mGluR II). Incorporation of a fluorine atom is expected to increase the biological activity and bioavailabiblity of this compound.