Dissertations / Theses on the topic 'Stereoselective synthesis'

This thesis begins in Chapter One with a discussion of the role of electrophilic cyclisation in the synthesis of tetrahydrofurans. Chapter Two begins with a discussion of the synthesis of iodo-olactones, by the iodolactonisation of β-silyloxy-δ-alkenoic acids (Scheme A). It will show how the potential of this chemistry has been expanded by proving the absolute stereochemistry at the iodine centre. Chapter Two goes on to consider the stereospecific synthesis of 2,3,5-trisubstituted iodo-tetrahydrofurans by the related iodo-etherification of homoallylic alcohols (Scheme B). This is facilitated by the use of anhydrous conditions. The synthesis of 2,3,5-trisubstituted iodo-tetrahydrofuranacetic acid esters and 2,3,5-trisubstituted hydroxy-tetrahydrofuranacetic acid esters by the iodocyclisation of geometrically pure (E)- and (Z)-β-hydroxy-δ-alkenoates was then developed and the stereochemical outcome of the reactions was proven (Scheme C). Targets were chosen which illustrated the utility of the key cyclisations of β-hydroxy-δ-alkenoates. Chapter Three discusses the synthesis of muscarine 93. It was chosen to synthesise muscarine from the cyclisation of the (Z)-β-hydroxy-δ-alkenoate 146. This synthesis is particularly versatile as it not only allows the preparation of muscarine itself, but also of various potentially highly biologically active analogues 146a. The second target selected was Goniofufurone 170. Approaches to this molecule will be discussed in Chapter Four. Model work in the synthesis of goniofufurone began with the cyclisation of the (E)-β-hydroxy-δ-alkenoate 53b, which indeed, led to the facile synthesis of the iodolactone 204. However, early attempts to incorporate the natural side chain met with limited success. Chapter Five discusses an approach to the 2-oxabicyclo-2.2.11-heptane ring system, which has been synthesised by the radical cyclisation of various β,y-unsaturated tetrahydrofurans of the general form shown in Scheme D.

The 2,6-diaryl-3,7-dioxabicyclo[3,3,0]octanes (or furofurans) belong to the lignan family of natural products. Lignans represent very attractive synthetic targets owing to their large range of biological properties including anticancer, antiviral and immunosuppressant activities. There is considerable structural variation in this series in both the nature and the stereochemistry of the aryl substituents. Since activity is dependent on stereochemistry, synthetic routes, which can provide controlled but tuneable access to one particular class, are very attractive. In this respect, we have been interested in developing efficient ways to synthesise the furofuran skeleton. Based on previous work in our group, the first synthesis of a natural endo-endo furofuran, Epiasarinin, has been achieved via a five step strategy. It included a Darzens condensation followed by a thermal rearrangement of vinyl epoxide to cis dihydrofuran, a Lewis acid promoted cyclisation of a dihydrofuryl alcohol and a reduction of a glycosidic bond. Variations of this methodology afforded the selective the thermal rearrangement has been explored and improvement of this step via different activation methods considered. Another aim of this thesis was to extend this existing method to generate aza analogues. Two strategies have been explored. Generation of furopyrroles can be achieved via the thermal rearrangement of vinyl aziridines or via the acid catalysed cyclisation of dihydrofuryl amines. In conclusion, this short and selective synthetic route leads to a large range of natural or unnatural furofurans and the extension to their aza analogues was also explored.

La Tesis que se presenta trata sobre el desarrollo de nuevos métodos selectivos de síntesis de carbohidratos. En la primera parte de la tesis se estudió la epoxidación de glicales utilizando catalizadores de Mo y ácido meta-cloroperbenzoico (MCPBA), en relación con la obtención de mano-oligosacáridos. En todos los casos estudiados, el epóxido formado se abría in situ para dar lugar al correspondiente diol o glicósido. Se observó un efecto director por parte de los hidroxilos libres, lo que permitía obtener derivados de manosa a partir de glucosa. En el caso del Mo, los resultados figuran entre los mejores descritos para epoxidación de glicales con catalizadores. Los resultados con MCPBA fueron excelentes, aplicándose este último procedimiento a la síntesis ortogonal de dadores de glicosilo. En la segunda parte, relacionado con la síntesis del cardiotónico digitoxina, se estudiaron dos metodologías sintéticas para obtener 2-desoxi-glicósidos mediante reacción de olefinación-ciclación-glicosilación y a través de síntesis asimétrica.
This thesis deals with two topics connected with carbohydrate chemistry. The first part presents epoxidation and dihydroxylation reactions of glycals using Mo-catalysts and m-chloroperbenzoic acid (MCPBA) towards the synthesis of manno oligosaccharides. The oxidation of glycals afforded in all cases the corresponding diols or glycosides, as a consequence of the in situ opening of the epoxides initially formed. Free hydroxyl groups were observed to direct the stereoselectivity of the epoxidation, and then manno derivatives were obtained from unprotected or partially protected glucals. The results using Mo-catalysts are among the best described for the catalytic epoxidation of glycals. The results using MCPBA were excellent, and this methodology was applied to the synthesis of orthogonally protected glycosyl donors. The second part is related to the synthesis of the cardiotonic digitoxin. Two different strategies were studied in order to obtain 2-deoxy-glycosides through olefination-cyclization-glycosylation reaction and using asymmetric synthesis.

Stereoselective Synthesis of 2-Deoxyoliogosaccharides
Autor: Omar Boutureira Martín


La tesi s'emmarca dins el camp de la síntesis de carbohidrats i glicoconjugats i mes concretament sobre la síntesi de 2-desoxi-glicòsids i oligosacàrids, que son unitats estructurals presents en substàncies biològicament actives i/o productes naturals com antitumorals, antibiòtics, agents antiparasitaris, cardiotònics...i a més a més són difícils d'obtenir a partir de carbohidrats naturals.
D'aquesta forma en aquesta tesi s'aborda la síntesis de 2-desoxi-2-iodo-1-tiopiranósids com a nous dadors de glicosil i la seva aplicació en la síntesis estereoselectiva d'oligosacàrids i glicòsids. Aquest dadors de glicosil es caracteritzen per la presència d'un grup fenilsulfanil com a grup sortint en la posició anomèrica (C1) i un grup iode en el C2 que actua com element de control en la reacció de glicosilació.
La memòria s'ha organitzat en una introducció general un capítol d'objectius, i quatre capítols on s'exposen i discuteixen els resultats obtinguts amb les seves corresponents conclusions.
La introducció (Capítol 1) tracta sobre els mètodes de síntesi de 2-desoxiglicòsids de configuracions  i ,. D'aquesta forma es fa una revisió dels mètodes desenvolupats fins avui per la síntesis d'aquest glicòsids. Lligat amb aquests mètodes anteriors, en els objectius (Capítol 2) es posa de manifest la necessitat d'arribar a un nou mètode de síntesis de 2-desoxicarbohidrats que permeti assolir totes les configuracions de piranòsids possibles.
En el Tercer capítol es desenvolupa el nou mètode d'obtenció de 2-desoxi-2 iodo-1-tioglicòsids que després es faran servir com a dadors de glicosil. A partir de pentoses de totes les configuracions i diferentment protegides es van estudiar diferent mètodes d'olefinació per tal d'obtenir polihidroxihexenilsulfurs. El mètode més eficaç en termes de rendiment i estereoselectivitat fou la olefinació amb òxid de fosfina (reacció de Wittig-Horner-WH). Aquests alquenols es van ciclar amb electròfils de iode, conduint de forma regioselectiva als 2-desoxi-2-iodo-1 tiopiranòsids. Aquest compostos es van utilitzar com dadors de glicosil i es van fer reaccionar amb colesterol com a model d'aglicona de diferents compostos bioactius i amb un glucòsid com a model de síntesi d'oligosacàrid.
Donat que la reacció de ciclació i la de glicolació eren activades per el mateix tipus de reactiu, es va pensar en realitzar la síntesi dels 2-desoxi-2-iode-glicòsids de forma consecutiva sense aïllar el tioglicòsid intermedi. Aquest procediment va resultar un èxit conduint al producte final con rendiments mol millors amb estereoselectivitats similars.
En el Quart capítol se estudia las mateixes reaccions que abans però emprant seleni en lloc de sofre i/o iode. Així, en primer lloc s'estudia la reacció de ciclació dels alquenols obtinguts en Capítol 3, però induïda per reactius electròfils de seleni. Se estudia com l'estructura del substrat afecta a la reacció. S'observa que en funció del substrat es formen principalment glicals o inclús selenoglicals. Solament s'obtenen els corresponents 2-desoxi-2-fenilselenenil-tioglicòsids quan existeixen grups protegits amb grups isopropilidé. En aquestos casos però els productes de ciclació amb seleni à la posició 2 son també excel.lents glicosil dadors, i el control de l'estereoselectivitat de la reacció es similar a quan s'utilitza iode.

En la segona part d'aquest Capítol s'estudien mètodes de síntesi de selenoalquens, concluint que la reacció es particularment difícil en el cas dels sucres i que també la reacció de W-H es la més apropiada.
En Capítol 5, aborda el estudi d'un nou mètode de síntesi de sulfanilalquens derivats de carbohidrats mitjançant la reacció de metatesi creuada amb catalitzadors de ruteni amb lligands carbè. La reacció es conegut que presenta elevada dificultat quan s'utilitzen alquens rics en densitat de càrrega com es el cas dels vinilèters o vinilsulfurs, però s'han aconseguit rendiments moderats dels compostos objectiu utilitzant microonas com font de calor i el ús de catalitzadors comercials.
En el Capítol 6 s'exposa la síntesi de glicals a partir del 1-tio-2-desoxi-2 iodo-piranosids. El glicals són compostos molt versàtils i útils en la síntesis de carbohidrats i amb el procediment desenvolupat en aquest capítol s'arribà a obtenir glicals de configuracions difícils d'obtenir per altres mètodes, com el D-allal i el D-gulal. A més, en una segona part del capítol tercer, aplicant un procediment de glicosilació estàndard per a com el de Gin ("dehydrative glycosylation") s'obtenen a partir de 2 iodolactols diversos compostos com a 2 iodoglicals, glicals o 1,1'-disacàrids.
En conjunt i com resultat del treball de recerca desenvolupat s'han posat a punt un nou mètode de síntesi de 2-desoxiglicòsids i 2-desoxi-oligosacàrids, compatible amb totes les configuracions dels sucres i que consta de tres reaccions olefinació de pentoses, ciclació intramolecular induïda per electròfils i glicosilació. Les dues ultimes etapes poden ser realitzades en un sol matràs de forma consecutiva.
El estudi d'aquest mètode ha suposat el posar a punt reaccions d'obtenció de sulfanil i selenenil alquens, els primer per dos procediments diferents (W-H i metatesi creuada), ciclació intramolecular regio i estereoselectiva induïda per electròfils de iode i seleni, y la glicosilació a partir de nous dadors de glicosil (2-deoxi-2-iodo-tioglicòsids i 2-desoxi-2-fenilselenenil-tioglicòsids).

Finalment, El sulfanil alquens preparats han estat utilitzats per posar a punt un nou mètode de síntesi de glicals que permet acce3dir a glicals de totes les configuracions. Els glicals per altra banda son intermedis de síntesi estratègics in síntesi orgànica. Així doncs es pot considerar que els objectius científics plantejats per aquesta Tesi ha sigut àmpliament assolits.
Stereoselective Synthesis of 2-Deoxyoliogosaccharides
Autor: Omar Boutureira Martín

The research described in this thesis aims to investigate a new method for the stereoselective synthesis of 2-deoxyglycosides and oligosaccharides based on a new access to 2-deoxy-2-iodo- and 2-deoxy-2-phenylselenenyl glycosyl donors that would not be limited by the availability of pyranoid glycals and by the stereoselective addition of electrophiles.
Chapter 3 describes our investigation into the application of the general procedure for the stereoselective synthesis of 2-deoxy-2 iodo-hexopyranosyl glycosides from furanoses. The procedure involves three reactions: Wittig-Horner olefination to give alkenyl sulfanyl derivatives, electrophilic iodine-induced cyclization to give phenyl 2-deoxy-2-iodo-1-thiopyranosides, a new type of glycosyl donor, and glycosylation. The olefination reaction afforded alkenyl sulfanyl derivatives in good to excellent yields, except in cases where the conformational freedom is constrained by cyclic protecting groups such as 3,4-O-isopropylidene. The cyclization reaction proceeds with complete regio- and stereoselectivity. The reaction proceeds exclusively as 6-endo cyclization to give phenyl 1-thiopyranoside derivatives. The stereochemistry of the iodine at C-2 is always cis to the neighboring alkoxy group, except for lyxo derivatives which lack cyclic protecting groups. This is a key point in the overall process because the iodine controls the stereoselectivity of the glycosylation reaction. The yield of the cyclization depends on the configuration of the starting material; it is very good for substrates with a ribo or xylo configuration, but more modest for those with an arabino or lyxo configuration. The glycosylation reaction proceeded with good yields and good to excellent stereoselectivities. The glycosidic bond created in the major isomers was always trans to the iodine at C-2. Although phenyl 2-deoxy-2-iodo-1-thioglycosyl donors of all configurations can be accessed using the proposed procedure, it is particularly effective in providing 2-deoxy-2 iodo-β-D-gulo- and -β-D-allo-glycosides. These glycosides are precursors of 2-deoxyglycosides of ribo and xylo configuration, which are difficult to obtain by the classical methodology starting from glycals.
Since 2-deoxy-2-iodo-1-thioglycosides are activated in conditions similar to those used to induce the cyclization, 2-deoxy-2-iodopyranosides were synthesized from sulfanyl alkenes using a "one pot" consecutive cyclization and glycosylation process. The "one pot" procedure has the advantage that it starts directly from the very stable acyclic alkenyl sulfide precursors and does not require isolation of the glycosyl donors. The overall strategy is fairly straightforward and operationally simple. Compared with the stepwise procedure, the "one pot" process gave significantly improved yields with similar or slightly lower selectivities. Furthermore, the "one pot" procedure was successfully applied to the synthesis of 2-deoxy- and 2,6-dideoxyglycosides.
Chapter 4 describes our investigation into the application of the general procedure for the stereoselective synthesis of 2-deoxy-2 phenylselenenyl-hexopyranosyl glycosides from furanoses. We developed 2-deoxy-2-phenylselenenyl-1-thioglycosides as a new class of glycosyl donors that provide access to 2-deoxyglycosides. The cyclization reaction proceeds with complete regio- and stereoselectivity enhanced by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group. We have also demonstrated that the glycosylation of 2-deoxy-2-phenylselenenyl-1-thioglycosides is highly substrate dependent. Although glycosylation products of all configurations can be accessed by employing the present methodology, it is particularly effective in providing 2-deoxy-2-phenylselenenyl--D-gulo- and --D-allo-glycosides. In particular, regardless of the nature of the solvent employed, the high β-selectivity observed in gulo (α/β ratio 1:14) and more modest in allo (α/β ratio 1:4) series is comparable to that previously observed for analogous glycosylation reactions of 2-deoxy-2-iodo-1-thio-D-gulo- (α/β ratio 1:16) and -D-allo-glycosyl donors (α/β ratio 1:6). Furthermore, the use of phenylselenenyl group at C-2 gave us some insight into the likely pathway of glycosylation reactions by using 2-deoxy-2-phenylselenenyl-1-thioglycosyl donors. Since the stereoselectivity observed is similar to that obtained using 2-deoxy-2-iodo-1-thioglycosides it can be concluded that this explanation is general for the different glycosylations assisted by chalcogens and halogens at C-2.
Since 2-deoxy-2-iodo- and 2-deoxy-2-phenylselenenyl-1-thioglycosides have been evaluated as a new class of glycosyl donors, we became interested in the preparation of other useful glycosyl donors such as 2-deoxy-2-iodo-1-selenoglycosides, and exploit their higher reactivity in developing milder and orthogonal stereoselective glycosylation protocols by using this methodology. Thus, carbohydrate-based vinyl selenides of arabino, ribo, and 2-deoxy-ribo configurations were prepared by Wittig-type reactions of various protected furanoses. Moderate yields were always obtained due to nature and reactivity of both carbohydrate lactols and selenium-based olefinating reagents under the conditions tested. The reaction with electrophiles proved to be challenging and no cyclization products were obtained. The preparation of vinyl selenides proved to be much more difficult than the related vinyl sulfides, which can be prepared in good yields using Wittig-Horner reaction.
Chapter 5 reports olefin cross metathesis reaction between carbohydrate-derived hydroxy alkenes and electron-rich olefinic partners with commercially available ruthenium-based catalysts. Microwave irradiation effectively accelerates the cross metathesis reaction of electron-rich olefins although some of the conversions remained low. Cross metathesis can only be achieved with hydroxy alkenes derived from 2-deoxysugars. In contrast, the hydroxy alkenes bearing an allylic alkoxy group neither isomerizes nor couples under similar conditions.
Chapter 6 reports a new method for accessing pyranoid glycals of different configurations by a short route that uses readily available starting materials, and conventional transformations. Our method is particularly valuable for the synthesis of non-readily accessible glycals such as D-allal and D-gulal that are valuable products to prepare some oligosaccharide molecules with biologically interesting properties.
A series of 2-deoxy-2-iodopyranoses were evaluated as precursors that provide access to pyranoid glycals and 2-iodoglycals from sulfanyl alkenes. This synthetic route involves consecutive cyclization and hydrolysis reactions followed by treatment of the resulting lactol under Gins' dehydrative glycosylation conditions. Despite the fact that this procedure has proved to be an efficient and general glycosylation method, its application to 2-deoxy-2-iodopyranoses did not afford the expected products. Although the observed product distribution (glycals, 2-iodoglycals, and 1,1'-disaccharides) revealed that this reaction is very sensitive to the configuration of the 2-deoxy-2-iodopyranose, 2-iodo pyranoid glycals can be almost exclusively obtained in good yields by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group.

The thesis describes the use of y,8-unsaturated alcohol in cyclisations with various aldehydes under acidic conditions to fonn monocyclic and bicyclic heterocycles with good stereocontrol. 6-Phenylhex-5-en-2-01136 was prepared in 3 steps and 55% yield and reacted with prop anal ill the presence of oxygen· and nitrogen nucleophiles to give tri-substituted tetrahydropyrans. Interestingly 229 and 230 have an equatorial C-3 side chain whereas 232 and 235 is in axial. Furthennore reaction of 6-phenylhex-5-en-2-01 136 with aldehydes possessing aryl, nitrogen and oxygen tethered nucleophiles suitably positioned to attack the secondary carbocation giving a range of bicyclic and tricyclic scaffolds with different ring sizes in a single pot. In chapter 3, the use ofhomoallylic alcohol 329 for the synthesis of blepharocalyxin D analogues with differing substitution at the C-7 is discussed. Homoallylic alcohol 329 was reacted with electron deficient and electron rich aromatic aldehydes to give lactones which were subjected to a Grignard addition/reduction protocol to give bicyclic tetrahydropyrans.

The work presented in this thesis is concerned with the design and development of chemical methods for the stereoselective synthesis of β-L-arabinofuranosides, in particular those which constitute the oligosaccharide fragments of the plant glycoprotein extensin. Previous methods intended for the preparation of 1,2-cis-glycofuranosides are reviewed. Relevant mechanistic and conformational studies are also discussed. Selected glycosylation methods are examined in preliminary experiments with the model secondary alcohols - isopropanol and cholesterol. Of the methods investigated, the most successful proved to be that involving 2, 3, 5-tri-O-benzyl-a-L-arabino-furanosyl chloride and promoters consisting of silver or thallium cations supported on molecular sieves. Good yields (60-90%) of the B-glycosides were obtained using stoichiometric amounts of reactants, in less than 4 hours at room temperature. The majority of these glycosylations proceeded with high (-9:1)B-stereoselectivity. However, with one promoter(based on thallium) a reversal of stereoselectivity was observed. The 1-0-trichloroacetimidate and 1-0-toluene-sulphonate derivatives of 2,3,5-tri-0-benzy1-L-arabinofuranose were also synthesised and studied as potential glycosylating agents. Four new derivatives of trans-4-hydroxy-L-proline have been synthesised, characterised, and used in glycosylation reactions with 2,3,5-tri-0-benzyl-arabinofuranosyl-oc-L-chloride and the molecular sieve-based promoters. The resulting B-arabino-furanosides were characterised, and each subsequently deblocked, to give the known component of extensin; 4-0-(B-L-arabinofuranosyl)-trans-oxy-L-proline. A number of other new derivatives were made and characterised during this work. These includeallyl-L-arabinofuranoside which provided an improved preparation of the known 2,3,5-tri-O-benzyl-L-arabinofuranose. An analogous synthesis of thecorresponding D-ribose derivative was also achieved. Throughout this work, extensive use has been made of and nmr spectroscopy in the identificationand characterisation of the new compounds. In particular, 13C nmr spectroscopy provided a veryconvenient means of establishing the ring sizes and anomeric configurations of the sugars.

The work presented in this thesis mainly describes the development of new reactions of β-lithiooxyphosphonium ylides to access stereodefined substituted alkenes in a highly convergent fashion. Firstly, β-lithiooxy ylides prepared from aldehydes and phosphonium ylides were shown to react with halogen electrophiles to provide a highly stereoselective route to E-alkenyl bromides and iodides. This methodology was successfully applied to the first total synthesis of naturally occurring (5E,9Z)-6-bromohexadeca-5,9-dienoic acid. Secondly, an experimentally straightforward method was developed for the stereocontrolled formation of trisubstituted Z-allylic esters by in situ trapping of β-lithiooxyphosphonium ylides with readily available halomethyl esters. The synthetic utility of this methodology was demonstrated with the synthesis of plaunotol [(2Z,6E)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-6-methylocta-2,6-diene-1,8-diol] and the first asymmetric synthesis of the naturally occurring geranylgeraniol-derived diterpene (6S,7R,Z)-7-hydroxy-2-((E)-6-hydroxy-4-methylhex-4-enylidene)-6,10-dimethylundec-9-enyl acetate. Furthermore, the chemistry of β-lithiooxyphosphonium ylides was expanded to access synthetically useful disubstituted Z-allylic esters. The synthetic utility of Z-allylic esters was also demonstrated in a versatile and diastereoselective Ireland-Claisen rearrangement to access γ,δ-unsaturated acids. Finally, the synthesis of the side-chain of the 6,7-dideoxysqualestatin H5 was also investigated. It was demonstrated that the side-chain of 6,7-dideoxysqualestatin H5 could be accessed by a convergent and stereoselective organozinc-based strategy.

Aquesta tesi doctoral s’emmarca dins un projecte dirigit a la síntesi de nous anàlegs de nucleòsids i la seva avaluació com a possibles agents antivírics. Concretament, la major part d’aquest treball es basa en la preparació d’anàlegs ciclobutànics de nucleòsids, utilitzant la reacció de fotocicloaddició [2+2] de 2(5H)-­‐furanones quirals a 1,1-­‐dietoxietilè com a pas clau de la seqüència sintètica per la construcció de l’anell de ciclobutà. Emprant aquesta metodologia, s’ha aconseguit la síntesi d’una nova família de nucleòsids conformacionalment restringits per la presència d’un anell de ciclobutà funcionalitzat. L’activitat biològica d’aquests nous compostos ha estat avaluada enfront de diferents virus, tot i que malauradament, cap ha mostrat activitat significativa. Precisament la manca d’activitat anti-­‐VIH tot i l’analogia estructural dels compostos sintetitzats amb fàrmacs que s’utilitzen per tractar aquesta malaltia (com el d4T), va promoure un estudi de docking del procés d’activació d’aquests nucleòsids així com de la seva interacció amb l’enzim transcriptasa inversa del VIH. A més a més, s’ha desenvolupat una nova ruta sintètica cap a anàlegs ciclobutànics de L-­‐nucleòsids, que ha permès la síntesi d’un nou grup d’aquests compostos. L’avaluació de la seva activitat biològica ha revelat una feble activitat anti-­‐influenza virus per un dels anàlegs, tot i que aquest nucleòsid també ha mostrat una elevada citotoxicitat. L’última part de la tesi recull la síntesi de double-­‐headed nucleosides, nucleòsids que presenten una nucleobase addicional en la seva estructura. Aquesta part de la tesi s’ha portat a terme durant una estada de tres mesos en el Nucleic Acid Center de la University of Southern Denmark.
This thesis is framed within a project that pursues the synthesis of novel nucleoside analogues and their evaluation as potential antiviral agents. Specifically, the main part of this work is devoted to the preparation of cyclobutane nucleoside analogues, using the [2+2] photocycloaddition reaction of chiral 2(5H)-­‐furanones to 1,1-­‐diethoxyethylene as a key step to construct the cyclobutane ring. Using this methodology, a new family of conformationally restricted nucleosides by the presence of a functionalized cyclobutane ring has been synthesized. The biological activity of these novel nucleosides against several viruses has been evaluated, although none of them showed significant activity. The lack of anti-­‐HIV activity of the newly synthesized compounds, despite their structural similarity with efficient drugs (e.g. d4T), prompted us to carry out a docking study to shed light on the activation process of these nucleosides as well as their binding with the enzyme reverse transcriptase from HIV. In addition, a new synthetic approach towards cyclobutane L-­‐nucleoside analogues has been developed, allowing the preparation of a new set of this class of compounds. These nucleosides have been screened for antiviral activity and although one compound exhibited weak activity against influeza viruses, it also showed significant cytotoxicity. The last part of the thesis is focused on the synthesis of double-­‐headed nucleosides, synthetic nucleosides featuring an additional nucleobase. This work has been carried out during a three-­‐month stay at the Nucleic Acid Center in the University of Southern Denmark (Odense).

Reported herein is a conceptually new synthetic route to 1’-aryl C-ribofuranosides and their 2’,3’-didehydro 2’,3’-dideoxy (D4) analogues. We have successfully implemented a divergent synthetic route capable to reach two important, biologically significant groups of compounds. The first two strategic transformations are common for both families of target compounds (asymmetric allylic substitution, and ring-closing metathesis). D4 C nucleoside analogues are synthesised in a three step procedure, and 1’-aryl ribofuranoses are constructed in a four step procedure. The target compounds were prepared in an excellent enantio and diastereopurity, in good overall yields. The yield in the synthesis of 1’-aryl-2’,3’-didehydro-1’,2’,3’-trideoxyribofunanoses is up to 46% over all the reaction steps. The overall yield of the 1’-arylribofuranoses is up to 42%. All the strategic transformations rely on catalytic oranometallic reactions employing group 8a transition metals. All the reactions have been optimized with a view of maximal atom efficiency and environmental impact. In summary, our new methodology is perfectly suitable for the synthesis of 1’ arylribofuranoses, and their D4 analogues, bearing non-ortho-substituted aromatics and hereroaromatics, lacking coordinating (nitrogen) substituents or heteroatoms. In this point of view the most promising target application is the synthesis of lipophilic isosters of ribonucleosides for the RNA studies.

The work described in this thesis deals with the development of catalytic methods for the stereoselective synthesis of 2-deoxyglycosides A thiourea has been successfully demonstrated as an efficient and mild catalyst for glycosylations of various protected galactals with a series of glycoside acceptors to afford 2- deoxy-a-D-galactosides, in yields of 72-98%. Complete a-selectivity was observed in all cases. The high a-selectivity is independent of the glycoside substitution pattern and reactivity profile. The method is tolerant of most common protecting groups and is orthogonal to thioglycosylation type reactions; this has allowed for a one-pot tandem glycosylation reaction to afford a trisaccharide in 58% yield with complete stereocontrol. Details of mechanistic investigations are described. Subjection of glucal substrates to the thiourea-catalysed conditions did not afford the same success, due to significant reactivity differences. Attempts to find a new, more active organocatalyst were also unsuccessful. The use of a cyclic protecting group on glucal substrates was found, under acid catalysis, to afford 2-deoxY-D-glucosides in high yields (81-89%), with high (20:1) to complete astereoselectivity. The 3,4-0-disiloxane cyclic protecting group was shown to work for a wide range of acceptors, which included monosaccharides, amino acids and a natural product. This protecting group was also shown to be successful for the synthesis of 2,6-dideoxY-Lglucosides in high yields (81-95%), with moderate (3.5:1) to good a-selectivity. Details of mechanistic and computational investigations are described. The activation of 2-nitro-o-galactals towards nucleophilic attack by alcohols via thiourea catalysis was found to be possible. Initial studies show that a thiourea bearing two cinchona alkaloid substituents is an effective catalyst; details of reaction optimisation will be described.

An intramolecular Michael-aldol reaction sequence has been developed for the stereocontrolled synthesis of pentacyclic steroids! with the new six-membered ring attached to the C(4) and C(6) positions. Cholesterol was converted into 3β-hydroxycholest-4-en-6-one by standard methods, and the corresponding 3α-isomer was obtained through Mitsunobu inversion. Acetoacetylation of the 3-alcohols afforded the corresponding 3β- and 3α-acetoacetoxycholest-4-en-6-ones, which served as substrates for an investigation of intramolecular condensation routes to the target ring systems. Base treatment of the 3β-ester resulted in an efficient and stereocontrolled intramolecular Michael addition to give (2R)-2-(3β-hydroxy- 6-oxo-5β-cholestan-4β-yl)-3-oxobutanoic acid 1,3'-lactone, and reaction conditions were developed to achieve sequential lactone cleavage, decarboxylation, and aldol closure, leading to 3β,6-dihydroxy- 4α,4',5β,6β-tetrahydrobenzo[4.5.6]cholestan-5'(6'H)-one. Although this product resisted base-mediated B-elimination, acid treatment resulted in dehydration to give the corresponding Δ⁶-compound. which underwent double bond isomerisation and 5-epimerisation. to give 3β-hydroxy- 4α,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. A similar series of reactions was performed on the 3α-acetoacetate, leading finally to formation of 3α-hydroxy-4β,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. Modification of foregoing reaction conditions, resulted in the design of a tandem Michael-aldol sequence, in which the 3-acetoacetates could be converted directly into the corresponding pentacyclic enones. These products were interrelated via base-mediated equ1llbration of their respective 3,6-diketones, leading to the thermodynamically favoured 4β,5α-isomer. Preliminary investigations into the stereoselective reduction of the olefinic bond in the 4α.5α-isomer, resulted in the formation of a new class of. hexahydrobenzo[4.5.6]cholestane derivatives. The structural and conformational properties of the condensation products were studied with the aid of ¹H NMR, ¹³C NMR, and IR spectroscopy.

RNA is recognised as an important biomolecule involved in many broad cellular functions such as transcription, translation regulation and protein synthesis. Most pathogenic viruses replicate their genome as RNA during some stages in their life cycle. There is an urgent need to develop new methods to treat numerous viral diseases by targeting RNA and to understand the processes by which RNA-protein complexation can be inhibited. Our study focuses on the interactions between the HIV-1 Rev Responsive Element RNA (RRE) with a series of aminoglycosides developed jointly between our group in Manchester and GSK (USA). Even though a number of novel aminoglycoside have been explored previously, they are complex, large molecular weight compounds with low specificity, which limits their use as RNA recognition ligands and anti-viral drugs. The key problem is to be able to synthesise precursors by short, direct routes, avoiding significant detours caused by traditional carbohydrate protecting group strategies, while still delivering sterocontrol and opportunities to diversify. In chapter II we describe our efforts to synthesize the 6-glucosamine moiety (A-ring). A flexible synthesis of 6-aminoglucosamine derivatives can be accomplished in 5 steps using a totally regioselective enzymatic hydrolysis, controlled oxidation to sensitive but manageable aldehydes (hitherto rarely accomplished with a C-4 OAc), and reductive amination technology that allow for unprecedented diversification. In a different approach stereocontrolled synthesis of a model compound was achieved in 4 steps including a novel TEMPO oxidation and a one-pot oxidation/imine-reduction for the complete synthesis of the molecule.Chapter III describes our attempts towards the development of a robust stereoselective O-glycosylation strategy using Lewis acids. In pursuance of an efficient synthesis of our designed RNA binder target compound the stereoselective formation of the glycosidic linkage connecting the A-ring with the 2-DOS ring is an important step. This chapter also gives a general overview of the challenges involved in glycosylation followed by the strategies we employed to overcome some of these issues. We discuss our unusual stereocontrolled glycosylation in which, despite a neighbouring “participatory” group at C-2, the α-glycoside is delivered in high yield. This result implies that the reaction does not occur through a conventional neighbouring group participation.

Thesis (Ph.D.) -- University of Maryland, College Park, 2004.
Thesis research directed by: Chemistry. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

The main topic of thesis is the use of organocatalysis to synthesize cyclobutanones derivatives. Cyclobutanone derivatives are useful molecular building blocks for the construction of complex molecular structures. Surprisingly, however, the use of organocatalysts to functionalize cyclobutanones is rare, especially when the substrate bears substituents. In this thesis, we present the enantioselective transformations and functionalizations of substituted cyclobutanones which employ readily-available amino acids (or derivatives) and thiourea derivatives as organocatalysts. - The first transformation involves the enantioselective aldol reaction between 2-hydroxy-cyclobutanone with a selection of aromatic aldehyde. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. - After, we synthesized 2,3-disubstituted cyclobutanones through direct aldol reactions involving 3-substituted cyclobutanones and aryl aldehydes catalyzed by N-phenylsulfonyl (S)-proline and via asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes catalyzed by thiourea derivatives. In the first case the relative aldol products were obtained with an unprecedented control of all three contiguous stereocenters in the latter the relatives γ-nitro cyclobutanones were obtained in good yield but in modest enantioselectivity. - The last case concerns the conversion of 3-substituted cyclobutanones into 4-substituted-5-hydroxy-γ-lactam using as electrophile nitrosobenzene and L-proline as catalysts. This reaction involves a ring-expanding O-nitroso-aldol-cyclization domino sequence. The synthetic protocol provides access to the five-membered ring system in good yield, and the formation of two new stereogenic centers is achieved with complete stereochemical control. Thus, the main topic of the first chapter is the organocatalysis, applications of the most common organocatalysts are discussed. The vast majority of organocatalytic reactions use chiral amine as catalysis (asymmetric aminocatalysis). Different types of organocatalysis involve the use of Br¿nsted acids and bases, Lewis acids, hydrogen bond-mediated catalysis, phase transfer and N-heterocyclic carbene catalysis. The second chapter deals with the reactivity of cyclobutanones. High electrophilicity and ring strain make the cyclobutanone and its derivatives a good substrate for ring transformation reactions. Characteristic reactions of functionalized cyclobutanones involve the ring opening, ring contraction and ring expansion reactions. In the third chapter, the synthesis of 2,2-disubstituted cyclobutanones via direct aldol reaction of 2-hydroxycyclobutanone with several aldehydes catalyzed by primary amines is presented. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. In the fourth chapter we describe the synthesis of 2,3-disubstituted cyclobutanones through direct aldol reactions of 3-substituted cyclobutanones and aryl aldehydes, catalyzed by N-phenylsulfonyl (S)-proline and through asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes, catalyzed by derivatives of thiourea. In this last chapter an organocatalyzed enantioselective desymmetrization reaction of 3-substituted cyclobutanones is presented using nitrosobenzene as an electrophile and proline derivatives as catalysts. This reaction give an original 5-hydroxy-γ-lactam in good yield and with the generation of two new stereogenic centers.

The diastereoselective synthesis of phosphorothioates and methylphosphonates has been investigated. It has been found that indole is a good leaving group, and that it can form a stable indolephosphorine and can be stereospecifically substituted by a nucleoside in the presence of DBU.
Chiral indole-oxazaphosphorines 31, 39, 44, 56 were synthesized and their reactivities were investigated. The cyano derivative 56 turned out to be a good chiral precursor in the diastereoselective synthesis of a T-T phosphorothioate dimer 65, with a diastereomeric excess larger than 96%. The reaction of cyano, monomer 63 on solid support was investigated. It was found that alkylphosphonate 64 was obtained as the major product, rather than the expected phosphorothioate 65.*
A novel internucleoside coupling reagent 87 was developed for the synthesis of methylphosphonates, in which the indole group can be replaced by a nucleoside within several minutes in the presence of DBU. Several chiral auxiliaries were tested for the stereoselective synthesis of methylphosphonates. A diastereomerically enriched monoester 104 (66% de) was synthesized.*
*Please refer to dissertation for diagrams.

A strategy for the stereocontrolled synthesis of polyene units was developed which centred around the chemistry of the vinyl boronate ester 4,4,6-trimethyl-2-vinyl-l,3,2- dioxaborinane 123. Reaction conditions have been developed to allow the Heck coupling of 123 with a range of aryl and alkenyl electrophiles. The reaction is promoted by cationic palladium species which can be generated through the addition of metal salts to the reaction mixture. Conversely conditions have also been developed which allows 123 to react exclusively at the boron functionality along the Suzuki-Miyaura pathway, the syntheses of a range of styrene and diene systems being demonstrated. Vinyl boronate 123 demonstrates complete chemoselectivity which is controlled by the reaction conditions employed. The alkenyl boronate esters, products of the Heck coupling of 123, can be converted to alkenyl iodides to produce the E- or Z-isomer with extremely high geometrical purity. This is done through an iododeboronation reaction involving ICI and NaOMe where the order of reagent addition determines the stereochemical outcome. Presented within is a detailed insight into the mechanistic intricacies of the transformations and the use of alternative and novel reagents such as pyridine-ICl for stereoselective iodo- and chlorodeboronation reactions is also demonstrated. This strategy was successfully applied to the syntheses of 1,6-diphenyl-1,3,5- . hexatrienes of varying alkene geometries 205-207, which were prepared from just iodobenzene and vinyl boronate 123 using those three key reactions. The use of this strategy also went some way to preparing the tetraene-containing natural product ixoric acid 124, although a total synthesis was not achieved during these studies. Research towards the first total synthesis of the natural product viridenomycin 125 was also conducted, especially towards the cyclopentenol core 246. An advanced intermediate cyclopentenone 248, was prepared from readily available starting materials along a succinct synthetic pathway to provide 248 in a good yield whilst expressing high diastereo- and enantioselectivity. Thus, a route was demonstrated which appears superior to those already existing in the literature.

Metal complexes have been used as catalysts for stereoselective syntheses in CC bond formation reactions, namely, alkyl- and allyl- additions to aldehydes. The enantiomeric alkylations involved reactions between Et₂Zn and arylaldehydes in the presence of chiral templates, e.g. zinc-, titanium- and boron-complexes of (S)-(-)-2-amino-3-(p-hydroxyphenyl)-1,1-diphenylpropanol. The reaction has been proved to be catalytic, using 3-5 mol% of the chiral ligand in the addition of Et₂Zn to p-tolualdehyde. Study of the substituent effects in arylaldehydes showed that p-tolualdehyde leads to the highest optical yield (83%ee) when a chiral Schiff base-zinc complex is formed. The in-situ produced chiral templates for the alkylations were studied by two different methods. Firstly, the alkyl metal itself; i.e. Et₂Zn, acts as the metal key atom. Secondly, other metal compounds; i.e. BH₃.THF and Ti(OPrⁱ)₄ formed chiral auxiliary complexes for the additions of Et₂Zn to arylaldehyde. The highest optical yield for 1-p-tolylpropanol [ca. 80%ee (S)] was obtained using the zinc- and boron-complexes. The chiral amino alcohol was also deposited onto silica gel to act as a heterogeneous catalyst. The asymmetric ethylations of p-tolualdehyde using the silica gel supported ligand have been tested with zinc-, titanium- and boron-complexes. Diethylzinc alone provides the best selectivity (53%ee), the values for the boron and the titanium systems are 16 and < 1%ee, respectively. On subsequent use of the solid catalyst, the optical yields fall off. Allylic additions of Bu₃SnCH₂CH=CH₂ to arylaldehydes have been examined in the presence of the chiral amino alcohol and titanium compounds. The optimum result was found to occur when TiCl₄ was reacted with the amino alcohol prior to the simultaneous addition of the reacting materials. However, the chiral allylic alcohol was obtained in low optical yield (31%ee).

Enzymes are biological catalysts capable of an enormous array of reactions. They demonstrate the ability to be reshaped and repurposed as synthetic tools by the process of enzyme engineering. Industrially, enzymes have been exploited for their ability to synthesise high value chiral molecules with excellent stereoselectivity. They are capable of functioning at low temperatures, near neutral pH and are completely biodegradable. Methods to harness the synthetic potential of enzymes have been extensively developed and applied over recent years. Directed evolution is one such approach that mimics natures evolution strategy but over a significantly shorter time frame. It involves iterative cycles of mutagenesis and screening until a required function is achieved. Advances in structural biology have enabled a huge number of enzyme structures to become available. These can help to implicate important catalytic residues in an enzyme, in turn, focussing engineering efforts to likely mutagenic hotspots. This can lead to greater chances of obtaining a desirable enzyme function if paired with an effective mutagenesis and screening strategy. In this thesis we use combinatorial active site saturation testing, a focused directed evolution method, to engineer a low-specificity L-threonine aldolase from Escherichia coli for improved stereoselectivity. We target the reversible retro-aldol cleavage reaction of phenylserine, an industrially interesting compound with four possible stereoisomers. Stereoselective variants are identified following the development of an effective high-throughput screen. Further, we use this screen to identify and produce rational combinations of variants. This achieves an enzyme that is 500-fold stereoselective for a single phenylserine stereoisomer. We also aim to provide insight into the poor stereoselectivity of the wild-type enzyme using molecular mechanics and quantum mechanics/molecular mechanics simulations. These are performed on an obtained 1.6 Å crystal structure of Escherichia coli threonine aldolase. We further propose plausible mechanisms for the stereogenic step of the aldol-condensation reaction.

The main topic of thesis is the use of organocatalysis to synthesize cyclobutanones derivatives. Cyclobutanone derivatives are useful molecular building blocks for the construction of complex molecular structures. Surprisingly, however, the use of organocatalysts to functionalize cyclobutanones is rare, especially when the substrate bears substituents. In this thesis, we present four enantioselective transformations of substituted cyclobutanones which employ readily-available amino acids (or derivatives) and thiourea derivatives as organocatalysts. - The first transformation involves enantioselective aldol reaction between 2-hydroxy-cyclobutanone with a selection of aromatic aldehyde. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. - After, we synthesized 2,3-disubstituted cyclobutanones through direct aldol reactions involving 3-substituted cyclobutanones and aryl aldehydes catalyzed by N-phenylsulfonyl (S)-proline and via asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes catalyzed by thiourea derivatives. In the first case the relative aldol products were obtained with an unprecedented control of all three contiguous stereocenters in the latter the relatives γ-nitro cyclobutanones were obtained in good yield but in modest enantioselectivity. - The last case concerns the conversion of 3-substituted cyclobutanones into 4-substituted-5-hydroxy-γ-lactam using L-proline-based catalysts. This reaction involves a ring-expanding O-nitroso-aldol–cyclization domino sequence. The synthetic protocol provides access to the five-membered ring system in good yield, and the formation of two new stereogenic centers is achieved with complete stereochemical control.

This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol.

The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain.

The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.

This thesis is concerned with the development and application of methods for the stereoselective cyclopropanation of allylic amines and derivatives. Firstly, a highly chemo- and stereoselective cyclopropanation of N,N-dibenzyl-protected allylic amines was developed using the highly reactive Shi’s carbenoid [CF₃CO₂ZnCH₂I]. Subsequent mechanistic studies revealed that the high diastereoselectivity of the reaction was likely to be due to coordination of the amine to the zinc carbenoid reagent. It is then shown that the reaction is general for a wide range of both cyclic and acyclic substrates giving the corresponding cyclopropanes in high yields and diastereoselectivities. Secondly, a novel stereodivergent cyclopropanation of allylic carbamates and amides was developed. It was found that reaction of cyclic allylic carbamates with the Wittig-Furukawa reagent [Zn(CH₂I)₂] typically gives the syn-diastereoisomer in high yields and diastereoselectivities, whilst treatment of the same substrates with Shi’s carbenoid [CF₃CO₂ZnCH₂I] gives the corresponding anti-diastereoisomers in high yields and diastereoselectivities. Mechanistic investigations suggested that reactions with the Wittig-Furukawa reagent proceed via a N-directed intramolecular cyclopropanation step whilst those with Shi’s carbenoid proceed via a sterically directed intermolecular cyclopropanation step. Unsuccessful investigations into an asymmetric variant of the cyclopropanation reaction utilising chiral carbamate protecting groups are then described. Finally, studies towards the total synthesis of the potential anti-obesity therapeutic trans-SCH-A and its epimer cis-SCH-A are described. A stereodivergent route towards the epimeric products was developed through the cyclopropanation of a common allylic carbamate intermediate with either the Wittig-Furukawa reagent or Shi’s carbenoid to give the corresponding trans-2-amino-5-arylbicyclo[3.10]hexane or cis-2-amino-5-arylbicyclo-[3.10]hexane intermediates respectively.