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1
Case-Green, S. C. "Double asymmetric synthesis". Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293361.
Testo completo
2
Ridge, Katerina. "Absolute asymmetric synthesis". Thesis, University of Surrey, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493053.
Testo completoAbstract (sommario):
One possible way of achieving absolute asymmetric synthesis is by "freezing" the chirality of a molecule by crystaUisation. This work is a study of the synthesis of :ertain imides which have potential for axial chirality and are likely to undergo spontaneous resolution on crystallisation. The synthesis starts from achiral compounds and therefore, if it does yield chiral crystals by spontaneous resolution, it can be classified as absolute asymmetric synthesis.
3
Lewis, Neil. "Asymmetric piperidine synthesis". Thesis, University of Nottingham, 1995. http://eprints.nottingham.ac.uk/13293/.
Testo completoAbstract (sommario):
It has been demonstrated that bakers' yeast reduction of 1-tert-butyl-2-methyl 3-oxo-piperidine-1,2-dicarboxylate gives (2R, 3S), 1-tert-butyl-2-methyl 3-hydroxy-piperidine-1,2-dicarboxylate in 80% chemical yield with >99% d.e. and >97% e.e. Also bakers' yeast reduction of 1-tert-butyl-3-ethyl 4-oxo-piperidine-1,3-dicarboxylate gives (3R, 4S), 1-tert-butyl-3-ethyl4-hydroxy-piperidine-1,3-dicarboxylate in 74% chemical yield with >99% d.e. and >93% e.e. The optical purity and absolute configurations of the hydroxy-ester derivatives were determined by conversion into the corresponding chiral bis-tosylate derivatives of 2- and 3-piperidinemethanol respectively. It has also been shown that bakers' yeast reduction of 1-tert-butyl-4-methyl 3-oxo-piperidine-1,4-dicarboxylate gives (3R, 4R)-1-tert-butyl-4-methyl 3-hydroxypiperidine-dicarboxylate in 81% chemical yield with >99% d.e. and 87% e.e. The optical purity and absolute configuration of the hydroxy-ester derivative were determined by utilisation of the compound in the total synthesis of (R)-3-quinuclidinol via chain elongation at C-4 of the piperidine followed by cyclisation to produce the bicyclic structure. Further work is reported on the diastereoselective synthesis of polyhydroxylated indolizidine alkaloids. 1-Acetoxy-2-hydroxy-3-(hydroxymethyl)-indolizidine has been synthesised as a single diastereomer from 2-piperidinemethanol via attack of an amine onto an epoxide functionality thus producing the bicyclic system.
4
Pedersen, Daniel Sejer. "Asymmetric cyclopropane synthesis". Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613762.
Testo completo
5
Harris, Matthew Eben. "Asymmetric lactam synthesis". Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/58635/.
Testo completoAbstract (sommario):
Broad-Spectrum Chemokine Inhibitors (BSCIs) are a novel type of antiinflammatory drug, discovered by Fox and colleagues. We have shown that the syntheses of C-substituted γ-thialactams are possible via a modular approach starting from the simple amino acid cystine. These compounds are a new class of GPCR ligand, showing BSCI activity comparable to their non-sulfur counterparts. Initial migratory data suggests that these lactams are inhibitors of leukocyte migration and comparable to the analogous BSCI lactams at μM concentrations, with decreased activity at the nM scale. Efforts have been made to the synthesis of substituted piperidinones, as well as employing Jocic-Reeve-Corey-Link chemistry to the general synthesis of lactams, ultimately looking to the synthesis of C-substituted lactams. Attempting to utilise trichloromethyl carbinol chemistry for these purposes has led to the synthesis of stereochemically-pure heterocycles containing up to 3 stereocentres. α- Trichloromethyl carbinols and asymmetric transfer hydrogenation chemistry are used from simple starting materials. Developments of this type of chemistry will undoubtedly lay the foundations to produce further non-racemic substituted heterocycles which will be important both synthetically and biologically.
6
Ravindran, Swarnam Shanthi. "Studies in asymmetric synthesis". Thesis, Rhodes University, 1994. http://hdl.handle.net/10962/d1005017.
Testo completoAbstract (sommario):
The stereoselectivity of TiCI₄-catalysed Mukaiyama reactions of a camphor acetal-derived chiral silyl enol ether with a range of substituted aromatic aldehydes has been examined. The enantiomeric excess in each of the resulting ß-hydroxy ketones, determined by ¹H NMR spectroscopy using the lanthanide chiral shift reagent Pr(Etcf₃), ranged between 9 and 13%. The stereo-directing potential of the camphor acetal as a chiral auxiliary in the α-benzylation of carboxylate esters has been studied; the acids were chosen to illustrate substituent effects on asymmetric induction. The observed diastereoselectivity increased with increasing steric bulk of the ester group and α-benzylation of the tert-butylacetate derivative proceeded with 48% diastereoselectivity. It is proposed that the enolate adopts an endo-s-trans conformation in the transition state and preferential attack by the electrophile at the somewhat less hindered Si-face is supported by both the optical rotation data and computer modelling studies. Reductive cleavage and hydrolysis of one of the benzylated esters furnished known products from whose optical rotation the configuration of the major diastereomer was established. In order to improve the steric advantage of Si-facial attack, methods of increasing the steric bulk of the blocking group were explored. A novel 2,2-propylenedioxy hydroxycamphor acetal and its 3,3-propylenedioxy analogue were prepared. Selected carboxylate esters of these propylenedioxy acetals were subjected to α-benzylation and the 2,2-(propylenedioxy)-3-exo-tert-butylacetate derivative showed a diastereoselectivity of 57% during a-benzylation. Hydrolysis of the abenzylated phenylacetate analogue offered the known 2,3-diphenylpropanoic acid whose optical rotation indicated the preferred configuration at the new chiral centre to be (R), a result which is consistent with the proposed approach of the electrophile to the less hindered Re-face of theendo-s-trans enolate moiety and reflects an inversion of the configurational bias observed with 2-v exo-carboxylate analogues. Attempts to prepare the monocatechol acetal of the hydroxy camphor derivative although unsuccessful, led to the isolation of two novel dibornyl ethers whose structures were established by 1- and 2-D NMR spectroscopy. A study of novel applications of camphor-derived auxiliaries in the asymmetric synthesis of α-amino acids has been initiated. The several approaches tried led to the preparation of three novel dural glycine derivatives in good yield
7
Wang, Ziyu, e 汪子玉. "Organocatalytic asymmetric synthesis of dihydrodibenzofurans and asymmetric aziridination of α-nitroalkenes". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/193388.
Testo completoAbstract (sommario):
The synthesis of useful chiral skeletons from simple achiral starting materials is always the dream of organic chemists. In the past decades, organocatalysis has been rapidly developed and has become one of the most important methods in asymmetric catalysis. The aim of this thesis is to develop asymmetric methods for the construction of useful chiral skeletons based on organocatalytic chemistry.
Many natural products and biologically important compounds contain the hydrogenated dibenzofuran (Figure 1) as a common sub-structure. In the first part of this thesis, the first amine-catalysed asymmetric synthesis of a dihydrodibenzofuran species from bisenal substrates has been demonstrated.
After a systematic screening of various reaction parameters, the optimal conditions have been found to be as follows: 0.1 M of substrate in solution with toluene with 0.2 equiv of (S)-di(2-naphthyl)pyrrolinol TMS ether (C2.8) and 0.2 equiv of 2-nitrobenzoic acid at 50 ℃ for 7 h under an argon atmosphere (Scheme 1). The first step product, an aldehyde, can be reduced in one pot to an alcohol by NaBH4. This two-step protocol gives exclusive cis selectivity. Many chiral cis-dihydrodibenzofuran species have been synthesized from the corresponding bisenal substrates in moderate to good yield with good to excellent ee (Scheme 1). The resulting cis-dihydrodibenzofuran species have promising synthetic applications. As shown in Scheme 2, the less hindered face of the newly formed C ring is more reactive and highly regioselective functionalizations of the C ring have been achieved.
In the second part of this thesis, the first asymmetric aziridination of trans-α-nitroalkenes via a phase-transfer catalysis strategy has been systematically studied. The chiral phase-transfer catalysts screened are derivatives of the cinchona alkaloids. The new cinchonidine-derived phase-transfer catalyst CD17 has been found to be optimal for the aziridination (Figure 2). Addition of a small amount of water is crucial to achieve complete conversion of the reaction. Both trans-1-nitro-2-arylalkenes and trans-1-nitro-2-alkylalkenes are suitable substrates (Scheme 3). The reaction can be run on the gram-scale without significant loss of efficiency and ee. Mechanistic studies have revealed that the aziridination proceeds through an aza-Michael addition followed by an intramolecular SN 2 type three-membered ring formation (Scheme 4).published_or_final_version
Chemistry
Doctoral
Doctor of Philosophy
8
White, Rachael A. "Asymmetric Synthesis of Prostaglandins". Digital WPI, 2005. https://digitalcommons.wpi.edu/etd-theses/735.
Testo completoAbstract (sommario):
Prostaglandins (PGs) are medicinally interesting because of the wide variety of roles they play in the body. PGs are ubiquitous and can be found in the reproductive system, the nervous system, the cardiovascular system, and the immune system. Accordingly, PGs are an important therapeutic target for pharmaceutical companies, and an efficient synthesis is highly desirable. Past research indicates that an approach to prostaglandins via a chiral acetylenic ester or amide provides a promising method for control of C-15 geometry. This project seeks to validate a key stereospecific reduction of an enantiomerically pure cyclopentenone intermediate. This is in turn available from a chiral acetylenic ester or amide via a formal [3+2] cycloaddition step. Several methods have been investigated for asymmetric synthesis of the requisite chiral acetylenic acid derivative including asymmetric conjugate addition, CBS-oxazaborolidine reduction of a ketone, and the separation of diastereomers of a chiral amide. With the optically pure cyclopentenone in hand, we will investigate hydroxyl directed conjugate reduction of the cyclopentenone double bond.
9
Ambler, P. W. "Asymmetric synthesis of cyclopropanes". Thesis, University of Oxford, 1988. https://ora.ox.ac.uk/objects/uuid:958e77c2-d15e-4d8f-af84-36dca36e4215.
Testo completoAbstract (sommario):
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.
10
Dixon, Darren J. "Asymmetric synthesis of andrimid". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337813.
Testo completo
11
Santos, Soraia Patricia Pinto dos. "Asymmetric synthesis of Tetrahydropyrans". Thesis, University of York, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489203.
Testo completoAbstract (sommario):
Tetrahydropyrans (THP) are important building blocks in organic synthesis, present in a variety of natural products with significant biological activity. The synthesis of these units has been achieved, first in a racemic manner where a one pot procedure was developed.
12
Innes, J. F. "Dispiroketals in asymmetric synthesis". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604937.
Testo completoAbstract (sommario):
This thesis is divided into five Chapters. The first consists of an introduction to dispiroketals and an overview of what has been achieved through their application in organic synthesis. The second Chapter describes the use of (2S,2'S)-2,2'-diphenyl-6,6'-bi-3,4-dihydro-2H-pyran to achieve the asymmetric synthesis of (+)-D-conduritol B. The synthesis proceeds in nine steps from DL-1-0,2-0:4-O,5-O-dicyclohexylidene-myo-inositol and the key step is the simultaneous protection and resolution of a racemic diol via dispiroketal methodology. The optical rotation of the final product, (+)-1D-Conduritol B, was found to differ significantly from literature reports, but the optical purity of our synthetic material was proved to be >98% using chiral gas chromatography. The third Chapter concerns work towards the synthesis of unsymmetrical bis-enol ethers and their use in dispiroketalisations. The synthetic approach to these compounds is a palladium-catalysed coupling of enol triflates with vinyl stannanes. Unusually, homocoupling of both partners was observed in addition to the desired heterocoupling but optimisation of conditions led to reasonable yields. The few dispiroketals possessing unsymmetrical alkyl substitution on the pyran rings are prepared. The fourth Chapter describes studies towards the development of an asymmetric reagent based on dispiroketals. A lithium aluminium hydride reduction modified with an enantioenriched dispiroketal-based diol gave a modest enantiomeric excess of product. A synthetic route to a dispiroketal-based secondary amine was developed in the racemic series, with a view to application of an enantioenriched version as a homochiral lithium amide base.
13
Goddard, Euan. "Asymmetric Synthesis of Alkaloids". Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489446.
Testo completo
14
Storer, N. P. "Asymmetric synthesis of lignans". Thesis, Swansea University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.639120.
Testo completoAbstract (sommario):
An introduction to lignans, including classification, occurrrence, biological activity, the role of lignans and their biosynthesis, is described in chapter 1. Chapter 2 presents a review of the conjugate addition reaction, with particular emphasis on chiral conjugate additions. This chapter also reviews the synthesis of lignans via conjugate additions to both chiral and achiral acceptors. Chapter 3 describes an attempt to synthesize lignans via tandem conjugate additions to a chiral crotonate ester. The project was, however, unsuccessful, due to problems associated with the synthesis of the chiral ester. A number of protected derivatives of ethyl 4-hydroxycrotonate were, however synthesized, as were various mono-protected derivatives of (Z)-1,4-dihydroxybut-2-ene. Chapter 4 describes the synthesis of lignans via tandem conjugate addition to chiral (-)-5-(1-menthyloxy)furan-2(5H)-one. Conjugate addition utilizing diphenyl thioacetals as acyl anion equivalents, followed by in situ trapping with aromatic aldehydes or acid chlorides afforded the adducts in good yields. Desulphurisation and dementhylation yielded (-)-epipodorhizol, which on oxidation afforded (-)-podorhizon. This was successfully cyclised to (-)-γ-apopicropodophyllin, thereby constituting a formal total synthesis of chiral deoxypodophyllotoxin. Chapter 5 describes the use of O-tert-butyldimethysilyl protected cyanohydrins as acyl anion equivalents in the conjugate addition to the chiral butenolide. It has been shown that conjugate additions proceed to afford a single isomer, while tandem conjugate additions afford the adduct as a mixture of two isomers. Ketone regeneration from the cyanohydrin causes isomerisation to occur, to afford a single isomer. A novel dementhylation reaction utilizing sodium borohydride, which occurs with concurrent stereoselective reduction of ther benzylic ketone, is discussed. This methodology has realised the chiral synthesis of a member of the retrolignan series, and the potential for the synthesis of chiral 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans is discussed.
15
Sirit, A. "Asymmetric synthesis of butenolides". Thesis, Swansea University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.639047.
Testo completoAbstract (sommario):
Optically active butenolides have been prepared from the reaction of chiral 1,3-dioxolans and 1,3-oxazolidines with the silyl enol ethers 2-trimethylsilyloxyfuran and 2-trimethylsilyoxy-4-methoxyfuran. Chiral 1,3-dioxolans were prepared in high yields (80-96%) by the exchange reaction of diisopropyl L-tartrate with triethyl orthoformate, triethyl orthoacetate and triethyl orthobenzoate. These were reacted with 2-trimethylsilyoxyfuran (TMSOF) under Lewis acid conditions to give optically active butenolides. The stereoselectivity and yield were not very good. (-)-(R)-Phenyl glycinol and (-)-(1R,2R)-norpseudoephedrine, as their N-tosyl derivatives were reacted with trimethyl orthobenzoate to furnish the chiral 1,3-oxazolidines in high yields (79-85%). Their reaction with TMSOF and 2-trimethylsilyoxy-4-methoxyfuran in the presence of BF3.Et2O afforded the optically active butenolides. Moderate yield, but high stereoselectivity, were obtained. Conjugate addition of lithium organocuprates and sulphur stabilized carbanions to the chiral butenolides gave γ-lactones with high stereoselectivity.
16
Sparey, Tim. "Asymmetric synthesis using sulfimides". Thesis, University of Warwick, 1995. http://wrap.warwick.ac.uk/55816/.
Testo completoAbstract (sommario):
Asymmetric synthesis, the synthesis of chiral molecules, has developed into one of the most important areas of chemistry. Numerous methods are used to prepare chiral compounds, one of which involves using chiral acyl anion equivalents. The potential of imides of cyclic sulfimides 148 as chiral acyl anion equivalents was found to be limited to simple alkylations using sodium hydride and an alkyl iodide in DMF. Alkylated adducts 154,158 and 159 were prepared with good diastereoselectivity, with the anti and anti-anti geometries being preferred for 154 and 158, and 159, respectively. The conformations of the parent sulfimides 148 were investigated. We found that cyclic sulfimides (1,3,4-oxathiazines) 132 were inaccessible, which precluded our investigation into the potential of this new class of compound as chiral acyl anion equivalents. In the course of this work, the BPTM group was developed as a replacement for the troublesome PTM group as a protecting group for primary, secondary and benzylic alcohols. Vinyl sulfimides 186 were prepared using a modified Wadsworth-Emmons reaction, with good E selectivity. Additions of alcohols to give adducts 185 proceeded with good diastereoselectivity. The attempted deprotection of adduct 185b using hydrogenolysis resulted in reduction of the sulfimide group to yield protected ß-hydroxy sulfide 192. Radical additions to vinyl sulfimides 186 resulted in 2-vinyl oxa-heterocycles 202 and 210, with THE and THP as solvent, respectively. A radical addition mechanism has been proposed, but uncertainty still exists as this mechanism can not explain both triethylborane and benzoyl peroxide mediated reactions as the E/Z selectivities are different. At this stage, an ionic mechanism can not be ruled out. 2-Vinyl oxa-heterocycles 202 and 210 have been converted, using Taylor's variant of the Malherbe-Bellus reaction, into 9- and 10-membered lactones 220 and 221, respectively, which are closely related to a number of important natural products. Considerable progress has been made in developing a new asymmetric sulfimidation procedure. Promising enantioselectivites have been observed using a copper-catalysed decompsition of tosyl azide or PhI=NTs 224 into nitrenes. Interception of the nitrenes by sulfide within the chiral influence of C-2 symmetric chiral ligands 225 or 231 yielded sulfimide 65. A discrete copper-nitrene species is thought to be an intermediate in the catalytic cycle.
17
Simpson, Carol Jane. "Towards enzymatic asymmetric synthesis". Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398495.
Testo completo
18
Baird, Charlotte. "Sulfimide-mediated asymmetric synthesis". Thesis, University of Warwick, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338708.
Testo completo
19
Xu, Youli. "Asymmetric synthesis involving silicon". Thesis, Open University, 1996. http://oro.open.ac.uk/57654/.
Testo completoAbstract (sommario):
Several different types of optically active, synthetically useful, silylated diols (17 pairs) have been prepared by asymmetric dihydroxylation of the corresponding allyl and vinylsilanes using Sharpless catalysts. Chiral analysis of these silyl diols was carried out by 1H NMR methods in the presence of Eu(hfc)3. Enantiomeric purity of some of these silyl diols is greater than 90% e. e. Synthetically more useful, optically active trimethylsilylepoxides, trimethylsilyl amino alcohols and aziridines have been isolated by a multi-stage chirality transfer from their precursor diol involving no racemization. The main routes for these chirality transfers were via silylated cyclic sulphite or sulphate intermediates and via silylated cyclic ortho esters and halohydrin derivatives. The reactions of these silylated species can be very regioselective, such as the ring opening of epoxysilanes by azide ion, leading exclusively to a single regioisomer. Similarly, the deoxygenation of vicinal silyl diols has been observed without loss of the silyl group. Chiral analysis of trimethylsilyl amino alcohols and aziridines (with enantiomeric excesses of up to 95%)h aveb eenc arriedo ut by 13CN MR methodsi n the presenceo f Eu(hfc)3 Asymmetric epoxidation of allyl and vinylsilanes without polar groups have been investigated using manganese (III) salen complexes as a catalyst. A number of axial ligands of the salen complexes has been studied and some of these axial ligands were very effective to influence the reactivity of the catalyst, cis / trans ratio of the silyl epoxides and enantioselectivity of the epoxidation. Several different types of allyl and vinylsilanes have been epoxidized enantiomerically using this catalytic method. Enantiomeric excesses of epoxides were determined by Chiradex G-PN column. Some of these silyl epoxides had e. e. of greater than 95%.
20
Yoshizawa, Akina. "Azetidines for asymmetric synthesis". Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8719/.
Testo completoAbstract (sommario):
The creation of asymmetric ligands with lower environmental impact is important, as such chiral N,N' ligands attract some attention. A new method for the synthesis of 1,2,4-trisubstituted amino azetidines with \(cis\) relative configuration across its two stereogenic centres was reported in 2013. Due to this \(cis\) conformation, the azetidine compounds are expected to be good chiral ligands for asymmetric catalysis. The nitro aldol (Henry) reaction is an established method for producing new carbon-carbon bonds and is a key reaction in the synthesis of many important compounds. Enantioselective Henry reactions generate carbon-carbon bonds and our azetidines are probed as ligands for that reaction. In this work, new azetidines and their palladium and platinum complexes were prepared and characterised by techniques including X-ray diffraction, confirming retention of the \(cis\) conformation. Furthermore, enantiopure \(cis\)-azetidines were used as chiral ligands for a range of transition metals including the use of Cu-azetidine complexes as catalysts for the Henry reaction, in up to >99.5% ee. New enantiopure amino azetidines and their transition metal complexes are demonstrated as asymmetric catalysts for the asymmetric Henry reaction.
21
Reignier, Serge. "Sulfur in asymmetric synthesis". Thesis, Loughborough University, 2002. https://dspace.lboro.ac.uk/2134/33720.
Testo completoAbstract (sommario):
This thesis is divided into three chapters. The first chapter is a review of the literature methods utilised to date in the synthesis of non-racemic chiral sulfoxides, including resolution, stereospecific nucleophilic substitution at sulfur, asymmetric oxidation and enzymatic methods Also, this first chapter introduces briefly the palladium-catalysed allylic nucleophilic substitution reaction. It covers the nature of different factors which can influence on the enantiomeric excess. The second section deals with our approaches to the synthesis of potentially chelating sulfoxides of high enantiomeric purity and their subsequent application, mainly in the process of palladium-catalysed allylic nucleophilic substitution reactions as chiral ligands, but also their application as chiral auxiliaries in the synthesis of chiral α-hydroxy or α-amino ketones. This second chapter also deals with the design of a new class of chiral ammo-sulfides as ligand in the palladium-catalysed allylic nucleophilic substitution reaction. The most successful ligand synthesised enantiomerically pure N-(1,1-dimethylethyl)-N-(1S,2S)-2-[(1,1-dimethylethyl)thio]-1-methyl-2-phenylethyl-N-methylamine was applied successfully to the palladium-catalysed allylic nucleophilic substitution reaction, furnishing the product in up to 89% ee. The third part of this thesis deals with the experimental procedures undertaken in this work.
22
Learmonth, Robin Alec. "Studies in asymmetric synthesis". Thesis, Rhodes University, 1991. http://hdl.handle.net/10962/d1005018.
Testo completoAbstract (sommario):
The concept of combining two well established areas of organic chemistry, viz., organosilicon chemistry and the use of chiral auxiliaries, into a viable, alternative method of asymmetric synthesis has only very recently begun to receive attention. At the outset of this investigation, no asymmetric reactions of silyl enol ethers, chiral by virtue of optically active substituents on the silicon, had been reported. A range of novel chiral silyl enol ethers have thus been prepared from a variety of ketones, including pinacolone, cyclohexanone, and α-tetralone, and employing menthol, borneol, and cholesterol as chiral auxiliaries. These preparations have been achieved via several distinct routes, including a novel convergent approach involving the isolation of either the chloro(menthyloxy)dimethylsilane or the (bornyloxy)chlorodimethylsilane. The MS and NMR spectra of these silyl enol ethers were examined in detail and, in the case of the crystalline cholesteryloxy silyl enol ether, the X-ray structure has been determined. The potential of chloroalkoxysilanes to act as general, chiral derivatizing agents has been established by the preparation of diastereomeric silyl acetal mixtures of racemic secondary alcohols (e.g. I-phenylethanol and 2-octanol). The experimental diastereomeric ratios, obtained by GLC and ¹H NMR spectroscopy, approached the expected value of unity, confirming the potential of the alkoxychlorosilanes as chiral probes. The chiral silyl enol ethers have been successfully oxidized to the corresponding α-siloxy ketones employing MCPBA, MMPP, and 2-(phenylsulphonyl)-3-phenyloxaziridine as oxidizing agents and the diastereomeric excesses obtained, which varied from 0 to 16%, indicated some potential for stereochemical control. Alkylation and hydroxyalkylation reactions of the silyl enol ethers have yielded the expected α-iert-butyl and β-hydroxy ketones in good to excellent material yields, with the enantiomeric excesses, as determined by chiral shift reagent studies, reaching 14%. To improve the stereo control in these reactions, attempts have been made to prepare chiral silyl enol ethers with auxiliaries possessing the potential for transition state complex co-ordination in the reactions under consideration. The preparation of such silyl enol ethers, incorporating the proline-derived auxiliaries, N-methyl-2-hydroxymethylpyrrolidine and 2-methoxymethylpyrrolidine met with only limited success. In an alternative approach, three derivatives of 2,3-dihydroxybornane have been prepared. However, two of these auxiliaries, viz., 3-exo-benzyloxy-2-exo-hydroxybornane and 3-exo-(1-methoxyethoxy)-2-exo-hydroxybornane failed to form silyl enol ethers, even under considerably more vigorous conditions than normally employed. The third derivative, 3,3-ethylenedioxy-2-hydroxybornane has been successfully utilized in the preparation of a pinacolone-derived chiral silyl enol ether. Hydroxyalkylation of this compound with benzaldehyde has yielded the β-hydroxyketone with significantly improved enantiomeric excess (26%) and a transition state complex has been proposed to rationalize this improvement.
23
Donovan, Anthony Richard. "Aids in asymmetric synthesis". Thesis, Donovan, Anthony Richard (1998) Aids in asymmetric synthesis. PhD thesis, Murdoch University, 1998. https://researchrepository.murdoch.edu.au/id/eprint/51636/.
Testo completoAbstract (sommario):
The aims of this investigation were twofold. 1) Development of a practical diagnostic NMR reagent. 2) Novel C2 symmetric ligands for asymmetric synthesis.
1) Naturally occurring (+)-camphor was chosen as the basis for this programme ie the synthesis of homochiral isocyanates for use as NMR diagnostic reagents.
Isocyanates 11, 39, 46 and 56 were synthesised via a wide range of synthetic techniques and these novel compounds and their precursors treated to comprehensive In addition all were subjected to reaction with suitable However, although these structural characterisation. alcohols to determine the enantio-diagnostic value, compounds reacted in the desired manner, none have exhibited the desired diagnostic ability.
2) (R,R)- and (S,S)-l,3-Diphenyl-l,3-propanediol 86 are useful C2 chiral auxiliaries.
A number of oxidative and catalytic techniques were employed in an attempt to synthesise these compounds. Kinetic resolution via Sharpless epoxidation finally served as the key step in our successful synthesis. The cyclohexyl analogues of these enantiomerically pure diols, as well as a number of novel and interesting phosphorus and nitrogen derivatives, were also prepared. These compounds present themselves as a promising range of ligands for future exploitation in catalytic asymmetric synthesis.
*compound diagrams of (1) & (2) can be seen on page x
24
Razzino, Pasquale. "Asymmetric [alpha]-amino acid synthesis /". Title page, contents and abstract only, 1991. http://web4.library.adelaide.edu.au/theses/09PH/09phr279.pdf.
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25
Bentley, Scott Alexander. "Asymmetric conjugate addition reactions". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:9e619a66-6277-48c2-8a2e-24f8206e52b3.
Testo completoAbstract (sommario):
This thesis is concerned with the asymmetric conjugate addition reactions of a range of chiral nucloeophiles. Chapter 1 introduces the conjugate addition reaction as a valuable carbon-carbon and carbon-heteroatom bond forming reaction in organic chemistry, and explores the asymmet- ric conjugate addition of a range of chiral and achiral carbon and nitrogen nucleophiles to a range of acceptors. Chapter 2 explores the use of the N-benzyl-N-(α-methylbenzyl)amino group as a chi- ral auxiliary, by employing the attempted conjugate additions of both N-benzyl-N-(α- methylbenzyl)hydrazine and N -benzyl-N -(α-methylbenzyl)hydroxylamine as chiral ammo- nia and water equivalents respectively. Chapter 3 describes the asymmetric and stereoselective preparation of a range of 4,4- disubstituted isoxazolidin-5-ones from the conjugate addition of lithium (S)-N-tert-butyl- dimethylsilyloxy-N -(α-methylbenzyl)amide. The isoxazolidin-5-ones are then globally de- protected via hydrogenolysis, giving rise to the corresponding β2,2,3-amino acids. Chapter 4 focuses on the development of a protocol to effect the conjugate addition of a chiral aniline equivalent. The scope of the reaction is delineated by varying both the nu- cleophile and the α,β-unsaturated ester. Finally, cyclisation of the β-N-arylamino esters to the corresponding tetrahydroquinolines is explored, and an application to the synthesis of the natural product (−)-angustureine is presented. Chapter 5 contains full experimental procedures and characterisation data for all com- pounds synthesised in Chapters 2, 3 and 4.
26
Harrison, Michael John. "Asymmetric synthesis using chiral amines". Thesis, University of York, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280371.
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27
Rustenhoven, Job Jesse. "Asymmetric synthesis of novel anthracyclinones". Thesis, University of Auckland, 1995. http://hdl.handle.net/2292/1903.
Testo completoAbstract (sommario):
The synthesis of novel C9-halogenated anthracyclinones by Lewis acid promoted cyclisations of ortho-methallyl anthraquinonyl chiral dioxanes has been investigated. Tin tetrachloride-N,N-dimethylformamide promoted cyclisation of the dioxane (30) proceeded with excellent stereoselectivity to give an 82% yield of the diastereomerically pure chlorotetracycle (78). Stronger Lewis acids gave poorer selectivity and boron trifluoride etherate reacted slowly with (30) but with high selectivity to give the diastereomerically pure fluorotetracycle (91) in 58% yield. The presence of a β-methoxy group in the substrate leads to decreased stereoselectivity due to competition between chelation and non-chelation controlled pathways. Stereochemistry was assigned to the products using a combination of X-ray crystallography, conformational analysis, nuclear Overhauser enhancements and chemical degradation. Attempts were made to extend the highly selective acetal cyclisation methodology to the intramolecular reaction of the allylsilane (121), cyclisation of which was expected to provide enantioselective access to the alkene (146). The synthesis of (121) was achieved despite its instability, but attempted cyclisations with Lewis acids or fluoride ions were unsuccessful. The racemic alkene (146) was prepared by an ene cyclisation and subjected to asymmetric dihydroxylation (AD). The products from the AD reactions are of considerable biological interest and have been characterized. Their stereochemistry has been assigned by 1H nmr comparisons with the parent diphenols, which have resulted in revisions of assignments made by earlier workers.
28
Stratford, Peter William. "Asymmetric synthesis in heterogeneous systems". Thesis, Lancaster University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305943.
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29
Black, Antonia. "Catalytic asymmetric synthesis via organoboranes". Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410615.
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30
Smethurst, Chris. "Asymmetric synthesis of cyclic amines". Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298718.
Testo completo
31
McKenna, Jeffrey M. "Asymmetric synthesis of #beta#-lactams". Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240681.
Testo completo
32
Nicholson, Rebecca. "The asymmetric synthesis of hexoses". Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270229.
Testo completo
33
Roger-Evans, Tania. "Asymmetric #alpha#-amino acid synthesis". Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279903.
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34
Kelly, Richard J. "Asymmetric synthesis of sperabillin D". Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300798.
Testo completo
35
Yin, Jingda. "Enantiorecognition phenomena in asymmetric synthesis". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:89838860-52f1-4cdb-94e9-112d5bf0ef4b.
Testo completoAbstract (sommario):
This thesis is concerned with investigations into applications of double asymmetric induction and parallel kinetic resolution in asymmetric synthesis. Chapter 1 introduces enantiorecognition phenomena as a significant field in asymmetric synthesis. The main approaches in this field are described: double asymmetric induction, kinetic resolution, parallel kinetic resolution and dynamic kinetic resolution. Chapter 2 describes investigations into the use of double asymmetric induction as a mechanistic probe to elucidate the reactive conformation of enantiopure α,β-unsaturated esters (derived from Corey’s 8-phenylmenthol auxiliary) and hydroxamates [derived from (S)-N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine] upon conjugate addition. Chapter 3 describes investigations into the doubly diastereoselective organocatalytic intramolecular Michael cyclization of enantiopure enamides (derived from a 4-substituted-5,5-dimethyl-oxazolidin-2-one auxiliary) and α,β-unsaturated esters (derived from Corey’s 8-phenylmenthol auxiliary) using α-methylbenzylamine and its derivatives as the chiral catalysts. Chapter 4 describes investigations into parallel kinetic resolution of acyclic γ-amino-α,β-unsaturated esters utilising a 50:50 pseudoenantiomeric mixture of lithium amides. To highlight the synthetic utility of the resultant β,γ-diamino esters, their elaboration to a range of 5-substituted-4-amino-pyrrolidin-2-ones is demonstrated and a concise synthesis of natural product (±)-absouline is performed. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.
36
Najah, Zaid. "Asymmetric synthesis using anthracene auxiliaries". Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555128.
Testo completoAbstract (sommario):
Diels-Alder reaction conditions of the chiral anthracene auxiliary, 9-(l-methoxyethyl) anthracene and 2-cyclopenten-I-one were optimised using the microwave irradiation to give three regioisomers in 80: 12:8 ratio. Flash chromatography purification afforded the desired adduct in 45% yield. Subsequent asymmetric transformations on the major cycloadduct were performed in good yield with excellent levels of diastereoselectivity. Alkylation-reduction reactions sequence on the ketone cycloadduct furnished the desired ketones in 65-75% yield and up to 92:8 diastereoselectivity. Corresponding alcohols were also prepared in 57-82% yield and up to 99 % diastereoselectivity. A retro Diels-Alder reaction of the methylated ketone applying flash vacuum pyrolysis furnished the desired 5- alkyl cyclopentenone in good yield but no enantioselectivity was observed. In contrast, the retro Diels-Alder reaction of the alkylated alcohols afforded enantiomerically pure 5-alkyl cyclopentenols in 80-85% yield and high enantioselectivity (83-99%). Dehydrogenation of the ketone adducts using IBX followed by conjugate addition afforded alkylated products in 60-70% yield, the subsequent cycloreversion reaction furnished desired enones but in racemic form. The observed racemisation was proposed to be caused by the high temperatures involved. Reduction of the alkylated ketones gave the analogous alcohols In 60-70% yield. The following cycloreversion reactions produced enantiornerically pure 4-alkyl cyclopentenols in excellent yield and enantioselectivity (68- 83%,99% ee). Baeyer- Villiger oxidation of the nonalkylated ketone adducts (Diels-Alder reaction products) provide the desired lactones in excellent regioselectivity (up to 90: I 0) and moderate yield. Moving to alkylated ketones, poor yield and regioselectivity were noticed which made the cycloreversion reaction impractical. As an alternative route, alkylation of the lactones adducts followed by retro Diels-Alder reaction furnished an alkylated pyranone in 77% yield and 62% ee.
37
Treacy, Alan Bernard. "Nitrogen heterocycles in asymmetric synthesis". Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361310.
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38
Cobb, Alexander John Andre. "Chiral diamines in asymmetric synthesis". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395035.
Testo completo
39
Devlin, Edward Charles. "New ligands for asymmetric synthesis". Thesis, University of Liverpool, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428366.
Testo completo
40
Morfitt, Charles Neil. "Diazo compounds in asymmetric synthesis". Thesis, University of Exeter, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286531.
Testo completo
41
Buck, Richard Tony. "Rhodium carbenoids in asymmetric synthesis". Thesis, University of Exeter, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267219.
Testo completo
42
Parr, Nigel. "Asymmetric #alpha#-amino acid synthesis". Thesis, University of Sussex, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302251.
Testo completo
43
Thomas, Stephen Patrick. "Phosphorus mediated asymmetric cyclopropane synthesis". Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613118.
Testo completo
44
Foster, Emma Marie. "Asymmetric synthesis of amino polyols". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:3393ed50-d465-491b-9270-c5f5228572ec.
Testo completoAbstract (sommario):
This thesis is concerned with the development of methodology for the asymmetric synthesis of a range of amino polyol containing compounds. Chapter 1 highlights the abundance of the amino polyol motif in nature, the wide range of biological activities displayed by amino polyol containing compounds, and their occurrence in drug molecules. A variety of different methods for the synthesis of stereodefined amino polyols is then discussed. Chapter 2 details a full investigation into the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to enantiopurealpha,beta-unsaturated esters which contain a dioxolane unit. The “matched” conjugate addition reactions were further coupled with a highly diastereoselective in situ enolate oxidation using camphorsulfonyloxaziridine for the synthesis of keyalpha-hydroxy-beta-amino ester intermediates. Subsequent cyclisation and further elaboration allowed access to a range of amino polyol containing compounds including imino sugars, amino sugars, and amino acids. Chapter 3 extends the investigation into the doubly diastereoselective lithium amide conjugate addition reaction to enantiopure alpha,beta-unsaturated esters which contain two dioxolane units. A full assessment into the conjugate addition of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a series of D-pentose derived alpha,beta-unsaturated esters is reported. Subsequent elaboration of thebeta-amino ester products of these conjugate addition reactions resulted in the synthesis of (2'S,3'S,4'R)-dihydroxyhomoproline and (2'S,3'R,4'S)-dihydroxyhomoproline. Chapter 4 describes the asymmetric syntheses of protected forms of APTO and AETD, the 2,4,5-trihydroxy substitutedbeta-amino acid residues found within the hexapeptide marine natural products microsclerodermins C, D and E. The optimised synthetic routes to APTO and AETD involved three key steps: a diastereoselective aminohydroxylation [via conjugate addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to an achiralalpha,beta-unsaturated ester followed by in situ enolate oxidation with camphorsulfonyloxaziridine], a diastereoselective dihydroxylation, and an olefination. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.
45
Ho, Wen-Bin. "The asymmetric synthesis of (-)-quinocarcin". Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1056475181.
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46
Brown, Richard Alan. "Asymmetric synthesis in neoteric solvents /". For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2003. http://uclibs.org/PID/11984.
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47
Suzuka, Toshimasa. "Asymmetric Synthesis of Cyclopentadiene Derivatives". 京都大学 (Kyoto University), 2003. http://hdl.handle.net/2433/149096.
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48
Lu, Chin-Wei. "Synthesis of Asymmetric Phthalocyanine Derivatives". Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/312651.
Testo completoAbstract (sommario):
The work in this dissertation describes improved methods of asymmetrically substituted Pc derivative synthesis addressing some currently encountered problems including: (1) the need for facile synthesis of asymmetric Pc/Nc hybrids; (2) a lack of general methods for producing asymmetric Pc materials with structural diversity. Chapter 1 provides a concise review on Pc and Pc/perylenediimide (PDI) derivatives that have been reported as a part of architecture in monochromophoric or multichromophoric molecules for energy and charge transfer studies. In addition, the intrinsic electronic and photophysical properties suitable for OPV applications, such as charge transfer rate, lifetime of charge separated state, and transfer pathway are also discussed. Chapter 2 details the use of ROMP-Capture-Release to synthesize a small library of asymmetric Pc/Nc hybrids and study of chemical and physical properties of these structurally related asymmetric chromophores and the corresponding symmetric Pc and Nc in both metalated (Zn) and unmetallated form. The extension of the Pc aromatic core as well as the asymmetry afforded by the unique quadrant can result in modulated physical properties, particularly bathochromic shifted electronic absorption spectra. Further modification of the pendent hydroxyl group on the molecule demonstrated the possibility for covalently grafting Pcs onto inorganic contacts such as ITO and TiO₂. Chapter 3 reports the investigation of using an asymmetric Pc as the platform for the preparation of a small library of zinc hexatriazolyl-monohydroxyphthalocyanines via Cu-catalyzed azide-alkyne cycloaddition (CuAAC). The modification of peripheral substituents was demonstrated using azides bearing hydrophobic, photo-crosslinkable, and electroactive moieties. Monitoring the click chemistry by both UV-Vis and FT-IR spectroscopies was performed to provide insight into the role of azide equivalent, reaction time, and catalyst on reaction progress. Chapter 4 describes the synthesis and characterization of a novel series of Pc-PDI dyads with different perylene bay-functional groups (H, thioether, and sulfonyl), as well as phosphonic acid as an anchoring group connected to the perylene moieties, for the studies of molecular-level heterojunction on transparent conductive oxides. The developed model system for further electrochemical analysis was proved to firmly attach to the ITO surface by ATR-UV/Vis spectroscopy.
49
Tye, Heather. "Novel diazaphospholidines for asymmetric synthesis". Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320431.
Testo completo
50
Foust, Benjamin John. "Synthesis of asymmetric phosphonate prodrugs". Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6734.
Testo completoAbstract (sommario):
The isoprenoid biosynthetic pathway is an essential metabolic system that is responsible for the production of one of the largest and most diverse ranges of biomolecules ever identified. The termini of this pathway include: fat-soluble vitamins, cholesterol, reproductive hormones, and components of cellular signal transduction and electron transport pathways. With such a diverse set of biologically important metabolites, it has become one of the most targeted pathways for study in human pathology. Earlier pharmaceutical development has yielded clinically relevant classes of compounds that impact specific enzymatically catalyzed stages along the mevalonate pathway. Possibly the most commonly recognizable class would be the statins, which were developed to constrain the production of cholesterol and other sterols via the inhibition of an early stage enzyme HMG-CoA reductase, making them useful in the treatment of cardiovascular disease. Another important class of inhibitors would be nitrogenous bisphosphonates such as Pamidronate and Zoledronate, which have been shown to disrupt the more downstream enzyme farnesyl diphosphate synthase (FDPS). The bisphosphonate core of these compounds helps to impart a high affinity for bone mineral, making them useful in the treatment of bone diseases such as osteoporosis and multiple myeloma.
Noting the success of bisphosphonates in the treatment of certain bone diseases via action on isoprenoid biosynthesis, more recent research has yielded compounds that selectively inhibit the later stage enzyme geranylgeranyl diphosphate synthase (GGDPS). One promising compound is digeranyl bisphosphonate (DGBP) which has been shown to induce apoptosis in some cancer cell lines. Crystallographic data for GGDPS aided in the determination of important structural features that lead to the activity and selectivity of DGBP. The bisphosphonate head group likely coordinates with magnesium cations in the active site of GGDPS, and the long nonpolar side chains can occupy hydrophobic channels which normally allow the binding of the natural substrates. These data appear to suggest DGBP’s selective binding arises from its capacity to form a ‘V-shaped’ inhibitor with the geranyl groups at the alpha position extending into the hydrophobic regions within the enzyme and the bisphosphonate functionality establishing a strong electrostatic interaction with the magnesium ions.
Noting these features, the development of novel compounds that retain the seemingly important structural features of known inhibitors while modifying certain aspects intended to enhance the biological activity of the resulting compounds was undertaken. These novel compounds were envisioned through a synthetic approach that would incorporate one isoprenoid chain at the α-carbon of the bisphosphonate and a second as a phosphonic ester. The previously studied phosphonate salts also were modified to the corresponding pivaloyl oxymethyl (POM) protected esters. The resulting motif was intended to allow for the liberation of a highly anionic species within a cell, which could more closely resemble the charge of the naturally occurring pyrophosphate substrates while retaining more desirable ADMET properties in the prodrug form. After intracellular formation of the active salt, the isoprenoid chains in the new motif could adopt a structure with more gradual curvature through the central portion making the structure more closely resemble a ‘U-shaped’ inhibitor.
A short synthetic sequence for the production of these new bisphosphonate inhibitors was developed. Each of the triPOM species formed was tested for the ability to disrupt the action of GGDPS in multiple myeloma cells. The compounds showed rather potent activity in cellular bioassays, in the hands of our collaborators in the research group of Dr. Sarah A. Holstein, with EC50 values in the single digit micromolar range. These compounds confirmed that the use of POM ester functionality can act as a viable prodrug strategy for the intracellular delivery of these compounds to the myeloma cells. These studies also demonstrate that the incorporation of a methyl group at the α-carbon results in the enhanced ability of these bisphosphonates to inhibit GGDPS. In general, the low µM range of concentrations required for these compounds to express meaningful cytotoxic biological activity makes them unattractive candidates for further investigation. However, the recognition of improved activity through the use of POM prodrug functionality and alpha methylation led to the development of other compounds that display these features. This has resulted in the synthesis of the most active inhibitors of GGDPS yet reported.
Another focus of research in the Wiemer group is the generation of novel phosphoantigens. Phosphoantigens are small phosphorus containing compounds that are recognized by certain immune cells and stimulate proliferation. The development of drugs that can regulate immune function via immunostimulatory activity is of great interest. The specific target for these phosphoantigens (γδ T cells) has recently been shown to play an important role in native cancer immunosurveillance. Currently the most potent natural phosphoantigen known, (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), is found in the non-mevalonate isoprenoid biosynthetic pathway of bacterial cells, which may help explain the development of its immunostimulatory effect. However, the inherent lack of metabolic stability of HMBPP, which translates to a short in vivo lifetime, provides a significant challenge to clinical utility. The mechanism for phosphoantigen stimulation of T cell production is not fully characterized, but recent work has demonstrated the importance of intracellular delivery of phosphoantigens that bind to an intracellular domain of the butyrophilin 3A1 protein necessary to induce proliferation.
Noting the potent activity of HMBPP, we have advanced the design and synthesis of structurally similar compounds with potentially enhanced metabolic stability and cellular permeability. Some more recent contributions to this project include the synthesis of tris-pivaloyloxymethyl prodrug phosphinophosphonates. These phosphinophosphonates were found to produce a strong immunostimulatory cellular response, while demonstrating greater metabolic stability by virtue of the –C-P-C-P linkage replacing the anhydride –O-P-O-P arrangement in HMBPP. The POM prodrug functionality appeared to provide improved cell permeability as reflected in a significant increase in T cell proliferation.
Efforts to develop phosphoantigens with activity that matches or surpasses that of HMBPP, while exhibiting more desirable ADMET properties, are ongoing. The most recently developed compounds vary by the introduction of aryl phosphonic esters. The success of phosphorous-containing prodrugs that incorporate phenolic acid esters such as Sofosbuvir has supported our interest in this area. Preliminary T cell data for the lead compounds show great promise with significant proliferation at nanomolar concentrations. Biological assays for the phosphoantigens developed herein were performed by Dr. Andrew Wiemer and coworkers, and most of the tested compounds were found to be exceptionally active for the stimulated proliferation of Vγ9Vδ2 T cells. Studies are currently being conducted to form novel phosphoantigen prodrugs that express potent activity and desirable pharmacokinetic properties and will no doubt lead to the development of interesting and potentially therapeutically relevant compounds.