This thesis describes the development of chiral auxiliary based methodologies for the asymmetric synthesis of hydroxylated !-lactones and "-lactones containing multiple contiguous stereocentres. The first chapter introduces the concept of chirality and provides a general overview of the range of strategies available for the preparation of chiral molecules in enantiomerically pure forms. The second chapter critically reviews the range of synthetic methodology that is currently available for the asymmetric synthesis of chiral #-lactones that are either natural products or useful chiral building blocks for synthesis. The third chapter describes the development of novel methodology for the epoxidation/lactonisation of a range of $-vinyl-syn-aldols to directly afford !-lactones containing up to four contiguous stereocentres in high de. These reactions were shown to proceed via a mechanism whereby hydroxyl-directed diastereoselective epoxidation is followed by intramolecular attack of their !-acyl-oxazolidin-2- one fragment, to directly afford the desired chiral !-lactone. The ‘self-cleavage’ aspect of these reactions was exploited to enable this methodology to be transferred to polymer-support using an immobilised Evans’-oxazolidin-2-one for asymmetric synthesis. Chapter 4 describes the development of a complementary methodology for the asymmetric synthesis of this type of hydroxylated !-lactone based on a strategy involving dihydroxylation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols using catalytic amounts of osmium tetroxide. This methodology was developed as part of a reinvestigation of previously reported dihydroxylation reactions by Dias and coworkers, where we have clearly shown that the stereochemistry of thelactones reported in their paper have been incorrectly assigned. This diastereoselective dihydroxylation methodology has been successfully applied to the asymmetric synthesis of the natural product deoxyribonolactone. Finally, Chapter 5 describes the development of methodology for the asymmetric synthesis of chiral "-lactones containing four contiguous stereocentres of use as potential chiral building blocks for the synthesis of polyketide natural products. In this approach, cyclopropanation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols occurs under the sterodirecting effect of the $- hydroxyl group to afford cyclopropyl-aldols in very high de. These cyclopropyl-aldols are then ring opened in the presence of mercuric ions, with their N-acyl-oxazolidin-2-one fragment acting as an internal nucleophile, to afford highly functionalised alkyl-mercury species that may be subsequently reduced to afford their corresponding "-lactones in high de.

<div>Biomass-derived fuels have long been considered as a possible replacement for traditional liquid fuels derived from petroleum. However, biomass as a feedstock requires significant refinement prior to application as a liquid fuel. The H2Bioil process has previously been proposed in which biomass is pyrolyzed and the resulting vapors are passed over a catalyst bed for upgrading to hydrocarbon products in a hydrogen environment [1]. A PtMo catalyst has been developed for the complete hydrodeoxygenation (HDO) of biomass pyrolysis vapors to hydrocarbons [2]. However, the product hydrocarbons contain a large fraction of molecules smaller than C4 which would not be suitable as liquid fuels. In fast hydropyrolysis of poplar followed by hydrodeoxygenation over a PtMo/MWCNT catalyst at 25 bar H2 and 300oC, only 32.1% of carbon is captured in C4 – C8 products; 21.7% of carbon is captured in C1 – C3 hydrocarbons [2]. Here, approaches are examined to increase selectivity of H2Bioil to desired products. Aldol condensation catalysts could be used prior to the HDO catalyst in order to increase the carbon number of products. These products would then be hydrodeoxygenated to hydrocarbons of greater average carbon number than with an HDO catalyst alone. Application of a 2% Cu/TiO2 catalyst to a classic aldehyde model compound, butanal, shows high selectivity towards aldol condensation products at low H2 pressures. In more complex systems which more closely resemble biomass pyrolysis vapors, this catalyst also shows significant yields to aldol condensation products, but substantial carbon losses presumed to be due to coke formation are observed. Both glycolaldehyde, a significant product of biomass pyrolysis, and cellulose, a component polymer of biomass, have been pyrolyzed and passed through aldol condensation followed by hydrodeoxygenation in a pulsed fixed-bed microreactor. Glycolaldehyde aldol condensation resulted in the formation of products in the C2-C¬9 range, while the major aldol condensation products observed from cellulose were C7 and C8 products. Carbon losses in glycolaldehyde aldol condensation were reduced under operation at increased hydrogen partial pressures, supporting the hypothesis that increasing selectivity to hydrogenation products can reduce coke formation from primary aldol condensation products. </div><div>The use of feeds which have undergone genetic modification and/or pretreatment by other catalytic processes may also lead to improvements in overall product selectivity. The influence of genetic modifications to poplar lignin on the pyrolysis plus HDO process are investigated, and it is found that these materials have no effect on the final product distribution. The product distribution from a poplar sample which has had lignin catalytically removed is also examined, with the conclusion that the product distribution strongly resembles that of cellulose, however the lignin-removed sample shows high selectivity towards char which is not seen from cellulose. </div><div><br></div>

Monoterpenoid derivatives are some of the most effective asymmetric controllers used in organic synthesis. They are also precursors in target syntheses, especially in synthesis of natural products with useful biological properties. However, there are still significant opportunities to develop new structural synthetic modifications. This project target focuses on employing commercially available chiral pool cyclic ketones, such as R-(-)-carvone, (+)-isomenthone, and (-)-isopinocamphone to create new potential substrates for biocatalytic modifications, via terpenone enolate alkylations, aldol additions, and formation of alkylidenes. Evaluation of these substrates has been carried out using isolated enzymes as biocatalysts to reduce the double bond and/or carbonyl group, as well expansion of six membered rings by Baeyer-Villiger monooxygenase to generate lactone derivatives, consequently resulting in new high-value terpenone, terpenol and lactone derivatives. Bioreduction of R-(-)-carvone substituted (with Me or OH) at C6 and/or C3 via OYEs afforded with highly diastereoselectivity in most cases with varied yields; and there was no activity observed toward substrates with substituents bigger than Me. Biooxidation of dihydrocarvone substituted (Me) at C6 or C3 via cyclohexanone monooxygenase (CHMO_Phi1) was selective, and oxidised only one diastereomer. For instance, (2R,3R,6R)-methyldihydrocarvone was completely converted to lactone with high regio- and enantioselectivity, while for the (2S,3R,6R)-diastereomer no lactone was produced, and starting material was recovered. (+)-Isomenthone, R-(-)-carvone, (-)-isopinocamphone and their derivatives were treated with carbonyl reductase, and only (+)-isomenthone, R-(-)-carvone and anti (5S,6S)-hydroxycarvone showed reaction, with varied yields and selectivities. The bioreduction and oxidation of substrates were scaled up to 50-100 mg as part of chemo-enzymatic reactions. The simulation of substrates with PETNR enzyme was studied, and docking was modelled.

En la presente memoria se describe la síntesis y aplicaciones de nuevos organocatalizadores derivados de B1NAM y prolina en reacciones aldólicas. Se ha puesto a punto la síntesis de las diferentes prolinamidas derivadas de BINAM y prolina, discutiendo su estructura, relación entre ellas, así como su recuperación. Se ha estudiado la actividad catalítica de los nuevos catalizadores BINAM-prolinamidas en condensación aldólica directa entre aldehidos y cetonas alifáticas, en diferentes disolventes comparando con L-Pro. Las prolinamidas han sido recuperadas por técnicas de extracción sencillas, pudiendo ser reutilizadas. Además, se describe el estudio del control de la regio-, diastereo-, y enantioselectividad en reacciones aldólicas directas organocatalizadas por L-prolina y BINAM-prolinamidas utilizando la a-hidroxi ó a-alcoxiacetonas como donores lo cual ha permitido sintetizar mayoritariamente los correspondientes dioles anti. Los tiempos de reacción se han reducido cuando se usa como cocatalizador un ácido carboxílico en medios acuosos. Se ha observado que en presencia de ácido benzoico además de que los tiempos de reacción son mucho más cortos, se mantiene e incluso se mejora la regio-, diastereo-, y enantioselectividad en la mayoría de los casos. Se ha llevado a cabo la síntesis enantio- y diastereoselectiva de a,B-epoxicetonas llevando a cabo la reacción aldólica de a-cloroacetona con diferentes aldehidos seguido de ciclación intramolecular de los a-cloroaldoles. Se describe también el estudio de la reacción aldólica directa organocatalizada por (Sa-BINAM-L-prolinamida y ácido benzoico en ausencia de disolventes, bajo estas condiciones se ha podido disminuir la cantidad de cetona utilizada y mejorar los tiempos de reacción, así como la regio-, diastereo-, y enantioselectividad. También se ha estudiado el posible mecanismo de reacción para la reacción aldólica organocatalizada por (Sa)-BINAM-L-prolinamida utilizando la técnica de espectrometría de masas mediante ionización por electrospray. De estos estudios se puede deducir que aunque se forma la doble enamina, solamente una unidad de prolinamida lleva a cabo la reacción aldólica. / In this work, the synthesis and applications of new organocatalysts derived of BINAM and proline are described in aldol reactions. The catalyts synthesis are described, explaining their structure, the relationship between them and as well as, the conditions for its recovery. Applications of the new catalysts BINAM-prolinamides in direct aldol condensations between aldehydes and aliphatic ketones are described in several solvents. In addition, comparison studies with L-Pro and the recovery of the catalyst after the reaction by simple extractive techniques are performed. Reaction conditions are studied in order to control the regio-, diastereo-, and enantioselectivities of aldol direct reactions organocatalyzed by L-proline and BINAM-prolinamides between aldehydes and oc-hydroxy or a-alcoxyacetones to the anti aldols. The rection times were reduced for aldol direct reactions using (Sa-BINAM-L-prolinamide and carboxilic acids as cocatalysts in aqueous media giving similar regio-, diastereo- and enantioselectivities. The enantio- and diastereoselective synthesis of a,B-epoxyketones by the aldol reaction of the a-chloroacetone with several aldehydes followed by intramolecular cyclization of the a-chloroaldols is described. Studies on the aldol direct reaction organocatalyzed by (Sa)-BINAM-L-prolinamide and benzoic acid in absence of solvent are described, as well as, the decreasing in the amount of ketone used, trying to improve the reaction times, the regio-, diastereo- and enantioselectivities. Finally, studies on the mechanism of the aldol direct reaction organocatalyzed by (Sa)-BINAM-L-prolinamide are described, using ionization electrospray mass spectroscopy techniques. From these mechanistic studies it can be deduced that in spite of the formation of double enamine, only one enamine is working in the aldol direct reaction.

<p>The direct addition of enolizable aldehydes and sulfonyl imines to &alpha;-halo thioesters to produce &beta;-hydroxy/amino thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high <italic>syn</italic>-selectivity, which is the opposite of that produced for the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that not only contain acidic &alpha;-protons, but also towards electrophiles containing other acidic protons and base-sensitive functional groups. Moreover, excellent diastereoselectivity is achieved when a chiral non-racemic &alpha;-hydroxy aldehyde derivative is used. Using MgI₂ and Ph₃P, this method gives a wide range of aldol and Mannich products in good yields with high <italic>syn</italic>-diastereoselectivity. The products obtained from the reductive aldol and Mannich reactions are synthetically important intermediates in both polyketide and &beta;-lactam synthesis, respectively, and can be readily derivatized to form many carbonyl derivatives through known manipulation of the thioester moiety.</p><p><p>Also, herein the asymmetric synthesis of (+)-mefloquine, a potent anti-malarial compound, is described. The synthesis is based on a key enantioselective Darzens reaction between a chiral &alpha;-chloro-N-amino cyclic carbamate (ACC) hydrazone and a quinoline-based aldehyde. This is a novel methodology developed by our lab, which gives a highly enantioenriched epoxide that can be further functionalized to give both enantiomers of mefloquine.</p> / Dissertation

A new class of oxazolidinone chiral auxiliary has been synthesized from various α-amino acids, incorporating a perfluoroalkyl functional chain as a soluble support. This feature allows the chiral auxiliaries to be employed under standard solution-phase reaction conditions, and rapidly purified from crude mixtures using fluorous solid phase extraction (FSPE). Our investigation of these new materials has been divided into two main sections. To obtain the chiral auxiliaries in multi-gram quantities a synthetic protocol was designed, where efficiency and reproducibility were the primary objectives. Meeting these goals required an extensive study of the reactivity of perfluoroalkyl nucleophiles. This study identified a versatile and scalable protocol for the perfluoroalkylation of the required amino acid starting materials. These results have allowed us to design a general, five-step synthetic pathway to create the fluorous chiral auxiliaries quickly and effectively. The new auxiliaries were then applied in several model reactions, specifically chosen to examine the reactivity and behavior of these compounds. In particular, the auxiliaries were tested for their stereoselectivity, recyclability, and ease of purification, in a series of Aldol reactions, 1,3 dipolar cycloadditions, and radical conjugate additions. This set of model reactions, combined with the facile and efficient synthesis clearly demonstrates that these new chiral auxiliaries are useful alternatives to the non-fluorous oxazolidinone chiral auxiliaries currently employed in stoichiometric asymmetric syntheses. / February 2006

I. Completion of a Total Synthesis of Peloruside A: The completion of a 22 step synthesis of the marine natural product peloruside A is presented. The second generation strategy cuts 10 steps from longest linear sequence of the Evans group’s first generation synthesis of peloruside A by changing the order of fragment coupling operations and maintaining \(C_1\) and \(C_9\) at their final oxidation states over the course of most of the synthesis. Key steps include two highly diastereoselective aldol fragment couplings, a tin tetrachloride mediated hydrosilylation and a macrolactonization on a seco acid containing no cyclic templating elements. II. Studies toward the Total Synthesis of Spiro-Prorocentrimine: The development of an intermolecular Diels–Alder approach toward the marine natural product spiro–prorocentrimine is described. This work began with the adaptation of the Evans group’s previous intramolecular Diels–Alder approach. It was found that protonated imines bearing non-coordinating counterions were of sufficient reactivity to allow cycloaddition to occur even on dienes that were unreactive under the previous best conditions. In the course of these studies, isomerization of a macrocyclic diene during the course of a Diels–Alder reaction complicated the stereochemical outcome of the reaction. Reaction conditions to suppress the isomerization and obtain Diels–Alder adducts bearing the correct configuration at both \(C_9\) and \(C_{33}\) were developed based on a qualitative consideration of the pKas of species present in the reaction. The of several macrocyclic dienes was examined to help explain the course of the Diels–Alder reaction. Other key steps include an iron catalyzed olefin formation, the highly diastereoselective hydrogenation of a trisubstituted olefin in the presence of an enol ether, protecting group studies to suppress the contraction of a 15 membered lactone to a 6 membered lactone and studies of a protecting group strategy to allow installation of a sulfate. Lessons learned from this work and previous efforts are combined in a proposal for a bioinspired synthesis of spiro-prorocentrimine with a longest linear sequence of less than 30 steps. / Chemistry and Chemical Biology

By simply hydrogenating enones in the presence of aldehydes at ambient temperature and pressure, aldol adducts are generated under neutral conditions in the absence of any stoichiometric byproducts. Using cationic rhodium complexes modified by tri(2-furyl)phosphine, highly syn-diastereoselective reductive aldol additions of vinyl ketones are achieved. Finally, using novel monodentate TADDOL-like phosphonite ligands, the first highly diastereo- and enantioselective reductive aldol couplings of vinyl ketones were devised. These studies, along with other works from our laboratory, demonstrate that organometallics arising transiently in the course of catalytic hydrogenation offer byproduct-free alternatives to preformed organometallic reagents employed in classical carbonyl addition processes. Existing methods for enantioselective carbonyl allylation, crotylation and tert-prenylation require stoichiometric generation of pre-metallated nucleophiles, and often employ stoichiometric chiral modifiers. Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium C,O-benzoate catalyst, enantioselective carbonyl allylations, crotylations and tert-prenylations are achieved in the absence of stoichiometric metallic reagents or stoichiometric chiral modifiers. Moreover, under transfer hydrogenation conditions, primary alcohols function dually as hydrogen donors and aldehyde precursors, enabling enantioselective carbonyl addition directly from the alcohol oxidation level. / text

<p>In the first part of this dissertation, the first asymmetric anti selective aldol addition of a ketone-derived donor that is independent of the structure of the ketone is described. This transformation is facilitated by the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Under certain conditions, this transformation not only exhibits near perfect anti selectivity and enantioselectivity but also does so via thermodynamic control. Simple manipulation of the reaction conditions allows for the <italic>O</italic>-benzylation of the prepared aldol products and the subsequent removal of the ACC auxiliary to give the &beta;-benzyloxy ketone. Both symmetric and asymmetric ketones can be utilized, and aldol products that would otherwise be difficult if not impossible to prepare via conventional methods are able to be prepared.</p><p>The second part of this dissertation describes the asymmetric total synthesis of (+)- and (-)-mefloquine hydrochloride, a potent antimalarial compound. The synthesis is based on an ACC-mediated asymmetric Darzens reaction between an &alpha;-chloro ketone and a quinoline-based aldehyde. This novel methodology gives a highly enantioenriched epoxide that can be further functionalized to prepare both enantiomers of the antimalarial drug.</p> / Dissertation

A new class of oxazolidinone chiral auxiliary has been synthesized from various α-amino acids, incorporating a perfluoroalkyl functional chain as a soluble support. This feature allows the chiral auxiliaries to be employed under standard solution-phase reaction conditions, and rapidly purified from crude mixtures using fluorous solid phase extraction (FSPE). Our investigation of these new materials has been divided into two main sections. To obtain the chiral auxiliaries in multi-gram quantities a synthetic protocol was designed, where efficiency and reproducibility were the primary objectives. Meeting these goals required an extensive study of the reactivity of perfluoroalkyl nucleophiles. This study identified a versatile and scalable protocol for the perfluoroalkylation of the required amino acid starting materials. These results have allowed us to design a general, five-step synthetic pathway to create the fluorous chiral auxiliaries quickly and effectively. The new auxiliaries were then applied in several model reactions, specifically chosen to examine the reactivity and behavior of these compounds. In particular, the auxiliaries were tested for their stereoselectivity, recyclability, and ease of purification, in a series of Aldol reactions, 1,3 dipolar cycloadditions, and radical conjugate additions. This set of model reactions, combined with the facile and efficient synthesis clearly demonstrates that these new chiral auxiliaries are useful alternatives to the non-fluorous oxazolidinone chiral auxiliaries currently employed in stoichiometric asymmetric syntheses.