A review on catalytic asymmetric hydrogenation of C=O double bonds is presented in the first chapter. Noyori’s pioneering research on ruthenium complexes containing both phosphine and diamine ligands using [i superscript]PrOH and [t superscript]BuOK is described, this system gave impressive highly chemeo-selectivity for C=O bonds and extremely high enantioselectivity for a range of acetophenone derivatives. Numerous groups have been inspired by Noyori’s catalyst of the type RuCl₂(chiraldiphosphine)(chiraldiamine), these systems often give excellent results for acetophenone. However, these catalysts have limitations, they are found to be either inactive or unselective for hydrogenation of tetralones, dialkylketones, bulky ketones, some heterocyclic ketones and imines prove difficult using this system. In this project, we are searching for a new catalyst for asymmetric hydrogenation of ketones that solve the difficult challenges faced when using Noyori’s [Ru(diphosphine)(diamine)Cl₂] catalysts system. Departing from Noyori’s type catalyst in the second chapter is described our effort to synthesise new diamines derived from amino acids and the synthesis of [Ru(diamine)(diphosphine)Cl₂] complexes. These catalysts are tested in asymmetric hydrgenation of ketones. In the next two chapters the finding of a new tridentate P N NH₂ type ligand is reported and the novel ruthenium complex containing the tridentate ligand has been synthesised and characterised by X-ray crystallography and been found to be active in the hydrogenation of a range of C=O and C=N double bonds, including the enantioselective hydrogenation of normally unreactive bulky ketones with up to 93 % ee. The last chapter explains the transfer hydrogenation activity for this new catalyst, involving a novel method of transfer hydrogenation reaction under microwave irradiation.

The research described in this thesis focuses on the catalytic asymmetric hydrogenation of prochiral olefins using N, P – chelated iridium catalysts. This catalytic system is tolerant to a wide range of substrates and performs better than the well-known ruthenium- and rhodium-catalytic systems for substrates devoid of coordinating groups in proximity of the olefin. Low catalytic loadings (often <1 %) and the high atom efficiency of this reaction make it a synthetically useful method of chiral molecule synthesis. The primary aim of this thesis was to develop new catalysts that rapidly and efficiently hydrogenate a broad range of alkenes asymmetrically. Papers I and II describe the synthesis and evaluation of new, highly efficient, chiral N, P – ligated iridium complexes. These catalysts were obtained in relatively few steps, while leaving open possibilities to modify and fine-tune their structure. Their versatility is ideally suited to both industrial uses and to equip any catalyst box. Paper III deals with a common problem of defluorination of vinylic fluorides during the hydrogenation. The catalyst designed in that work performs well for several substrates giving very low defluorination rates making it a good starting point for further improvements to cover a broader scope of vinyl fluorides. The structures of the catalysts from papers I and III also offers an easy approach to attach the catalyst ligands to a solid support. Paper IV explores hydrogenation of vinyl boronates, which gives synthetically interesting borane compounds with high enantioselectivities. Taking into account the rich chemistry of organic boranes, these compounds are very important. Paper V deals with hydrogenation of diphenylvinylphosphine oxides and vinyl phosphonates, another important classes of substrates that give chiral phosphorous containing compounds of interest in many fields of chemistry: such as medicinal chemistry and organocatalysis. In papers VI and VII we explore the Birch reaction as a source of prochiral olefins. By combining asymmetric hydrogenation with it, we obtain a powerful method to create chiral compounds with excellent enantioselectivities that are next to impossible to make by other routes. The products of the asymmetric hydrogenation are further modified by other well-known transformation to create other induced stereogenic centres.

Process development of new complex reactions in the pharmaceutical and fine chemicals industries is challenging, and expensive. The field is beginning to see a bridging between fundamental first-principles investigations, and utilisation of data-driven statistical methods, such as machine learning. Nonetheless, process development and optimisation in these industries is mostly driven by trial-and-error, and experience. Approaches that move beyond these are limited to the well-developed optimisation of continuous variables, and often do not yield physical insights. This thesis describes several new methods developed to address research questions related to this challenge. First, we investigated whether utilising physical knowledge could aid statistics-guided self-optimisation of a C-H activation reaction, in which the optimisation variables were continuous. We then considered algorithmic treatment of the more challenging discrete variables, focussing on solvents. We parametrised a library of 459 solvents with physically meaningful molecular descriptors. Our case study was a homogeneous Rh-catalysed asymmetric hydrogenation to produce a chiral γ-lactam, with conversion and diastereoselectivity as objectives. We adapted a state-of-the-art multi-objective machine learning algorithm, based on Gaussian processes, to utilise the descriptors as inputs, and to create a surrogate model for each objective. The aim of the algorithm was to determine a set of Pareto solutions with a minimum experimental budget, whilst simultaneously addressing model uncertainty. We found that descriptors are a valuable tool for Design of Experiments, and can produce predictive and interpretable surrogate models. Subsequently, a physical investigation of this reaction led to the discovery of an efficient catalyst-ligand system, which we studied by operando NMR, and identified a parametrised kinetic model. Turning the focus then to ligands for asymmetric hydrogenation, we calculated versatile empirical descriptors based on the similarity of atomic environments, for 102 chiral ligands, to predict diastereoselectivity. Whilst the model fit was good, it failed to accurately predict the performance of an unseen ligand family, due to analogue bias. Physical knowledge has then guided the selection of symmetrised physico-chemical descriptors. This produced more accurate predictive models for diastereoselectivity, including for an unseen ligand family. The contribution of this thesis is a development of novel and effective workflows and methodologies for process development. These open the door for process chemists to save time and resources, freeing them up from routine work, to focus instead on creatively designing new chemistry for future real-world applications.

Transition-metal-catalyzed asymmetric hydrogenation is one of the most efficient, straightforward, and well-established methods for preparing enantiomerically enriched compounds. Over the past decades, significant progress has been made with iridium, rhodium and ruthenium complexes to asymmetric hydrogenate a selection of olefins, such as, α,β-unsaturated carboxylic acid derivatives, ketones, imines and phosphonates. Although these metals have been applied successfully in the hydrogenation of olefins, they differ in their substrate tolerance.  Ruthenium and rhodium based catalysts require a coordinating group in the vicinity of the C=C bond. However, iridium based catalysts do not require this coordinating group, hence, asymmetric hydrogenation with iridium catalysts has been widely used for both functionalized and unfunctionalized olefin substrates. This thesis focuses on expanding the substrate scope for asymmetric hydrogenation using chiral N,P-ligated iridium catalysts. Papers I and II investigate the asymmetric hydrogenation of prochiral N-heterocyclic compounds prepared by ring-closing metathesis using the iridium catalysts developed in our group.  These substrates are interesting as they bear resemblance to pharmaceutically active compounds and therefore have tremendous value in medicinal chemistry.  Excellent enantioselectivities, up to >99% ee and conversions were obtained. In papers III and IV we synthesized many unsaturated acyclic and cyclic sulfones with varying substitution patterns.  The sulfones were subjected to hydrogenation using our N,P-ligated iridium catalysts, producing the chiral sulfone products in high enantiomeric excess (up to 99% ee). This methodology was combined with the Ramberg-Bäcklund reaction, offering a novel route to chiral allylic and homoallylic compounds. In addition to obtaining these chiral compounds in good yields, no decrease in enantiomeric excess was observed after the Ramberg-Bäcklund reaction. This strategy has been applied in the preparation of the chiral building block for renin inhibitors.

In recent years two-phase catalysis has been established as a new field of catalyzed processes and has achieved industrial-scale importance in olefin hydroformylation. Two-phase reactions have a number of advantages, for example, ease of separation of catalyst and product, catalysts can be tailored to the particular problem, use of special properties and effects of water as a solvent, and low environmental impact. For higher olefins (* C6), the reaction suffers low activity due to low water solubility of higher olefins. Tricesium analog of TPPTS, m,m,m-trisulfonated triphenylphosphine, was synthesized and fully characterized. Two-phase olefin hydroformylation with Rh(acac)(CO)2 was investigated. The results indicated that both activity and selectivity (linear to branch aldehyde ratio) are similar to Rh/TPPTS system. The salt effect showed that increase the solution ionic strength will increase the selectivity and decrease the activity in the olefin hydroformylation with TPPTS. A new surface active phosphine, trisulfonated tris-m-(3henylpropyl)phenylphosphine, was synthesized and fully characterized. The results of biphasic olefin hydroformylation were consistent with aggregation of the ligand. The two phase 1-octene hydroformylation results showed that with only 3 methylene groups, there is no difference between the para and meta position of C3 group. A new chelating diphosphine, tetrasulfonated 2,2'-bis{di[p-(3 phenylpropyl)phenyl]phosphinomethyl}-1,1'-biphenyl,was prepared and fully characterized. Its application in two-phase hydroformylation of olefin showed enhanced activity and selectivity compared to the non-chelated phosphine analog. Finally, homogeneous asymmetric hydrogenation was carried out in the presence of a chiral surfactant in an attempt to affect asymmetric induction. The catalytic results showed that at a surfactant/Rh ratio of 25, the asymmetric hydrogenation of AACA-Me (a-Acetamidocinnamic Acid Methyl Ester) in methanol has no effect on asymmetric induction with the introduction of this chiral surfactant. / Master of Science

The work described in this thesis is focused on exploring the efficacy of iridium-catalysed asymmetric hydrogenation of precursors to chiral alcohols and chiral cyclohexanes. A range of allylic alcohols including γ,γ-dialkyl allylic alcohols and (Z)-allylic alcohols were prepared and evaluated in the asymmetric hydrogenation using iridium catalysts resulting in chiral alcohols in high yields and excellent enantioselectivity. This methodology was applied in the formal synthesis of Aliskiren, an efficient renin inhibitor drug, using the asymmetric hydrogenation of an allylic alcohol as a key-step. Another project concerned the dynamic kinetic resolution of racemic secondary allylic alcohols using Ir-N,P catalysts under hydrogenation conditions. A range of secondary allylic alcohols and protected alcohols were evaluated in the asymmetric hydrogenation via dynamic kinetic resolution using Ir-N,P catalysts. The corresponding chiral saturated alcohols were formed in good yield with excellent diastereoselectivites (up to 95/5) and enantioselectivities (&gt;99% ee). The last part of this thesis is directed towards the development of highly regio- and enantioselective asymmetric hydrogenation of 1,4-cyclohexadienes and its application in the preparation of useful chiral cyclohexenone intermediates. Non-functionalised, functionalised and heterocycle-containing cyclohexadienes were evaluated. Good yield of regioselectively mono-hydrogenated silyl protected enol ethers were obtained in most cases with excellent enantioselectivity. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 5: Manuscript.</p>

The thesis entitled Cholic Acid Bused New Chiral Auxiliaries: Development And Applications has been divided into three chapters. Chapter-I describes the synthesis of chiral auxiliaries (1.3) from cholic acid and Diets-Alder reactions on the corresponding a,B- unsaturated ester derivatives. Chapter-I1 deals with the asymmetric dihydroxylation of a,B unsaturated esters of steroidal alcohols (1-3). Chapter-HI describes asymmetric hydride reduction, hydrogenation and allylation of a-keto esters of cholic acid derivatives (1-3).

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-15T02:38:16Z (GMT). No. of bitstreams: 1 RodriguesJunior_ManoelTrindade_D.pdf: 6880388 bytes, checksum: 75844f02fc6611249ca702661e63582a (MD5) Previous issue date: 2009 / Resumo: O núcleo b-carbolina encontra-se amplamente distribuído entre os produtos naturais, incluindo alcalóides ioimbina (ioimbina e aloioimbina), corinanteidina (corinanteidina), rauwolfia (reserpina) e vinca (vincamina). Além disso, essas substâncias também têm demonstrado um amplo espectro de propriedades farmacológicas, incluindo atividade antitumoral, ansiolítica, hipnótica, anticonvulsivante, antiviral, antiparasitária e antimicrobiana. Sínteses totais eficientes da (+)-tripargina (59), em 6 etapas e 46% de rendimento global (-)-tripargina (59), em 6 etapas e 38% de rendimento global, (+)-deplancheina (60), em 11 etapas e 47% de rendimento global, (+)-debromoarborescidina A (61), em 5 etapas e 73% de rendimento global, (+)-harmicina (62), em 5 etapas e 56% de rendimento global (-)-harmicina (62), em 5 etapas e 52% de rendimento global, catin-6-ona (64), em 8 etapas e 45% de rendimento global e 20-metoxi-cantin-6-ona (65), em 8 etapas e 35% de rendimento global, foram realizadas com base na construção do sistema b-carbolínico via reação de Bischler-Napieralski e redução enantiosseletiva do intermediário diidro-b-carbolínico via reação de transferência de hidrogênio assimétrica usando o protocolo de Noyori. Estes compostos foram avaliados como agentes antiproliferativos contra um painel de células cancerígenas. Apenas cantin-6-ona (64) mostrou atividade contra a linhagem de célula 786-0 (célula de câncer renal). Estes compostos foram avaliados em bioensaios in vitro contra Leishmania brasiliensis, Leishmania amazonesis e Leishmania major e novamente apenas a cantin-6-ona (64) apresentou atividade contra Leishmania major (IC50=16,9 mM) e um índice de segurança altamente promissor (Si=94,7).Testes preliminares de toxidade in vivo mostraram que a harmicina (62) e a tripargina (59) são substâncias com potencial efeito sobre o sistema nervoso central. / Abstract: The b-carboline skeleton is widely distributed among natural products incluiding yohimbine (yohimbine and alloyohimbine), corynantheidine (corynantheidine), rauwolfia (reserpine) and vinca (vincamine) alkaloids. Furthermore, these coumpounds have also demonstrated a broad spectrum of pharmacological properties including ansiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic as well as antimicrobial activities. Concise and efficient total syntheses of (+)-trypargine (59), in 6 steps and 46% overall yield, (-)- trypargine (59), in 6 steps and 38% overall yield, (+)-deplancheine (60), in 11 steps and 47% overall yield, (+)-debromoarborescidine A (61), in 5 steps and 73% overall yield, (+)-harmicine (62), in 5 steps and 56% overall yield, (-)-harmicine (62), in 5 steps and 52% overall yield, canthin-6-one (64), in 8 steps and 45% overall yield and 10-methoxy-canthin-6-one (65), in 8 steps and 35% overall yield, were developed based on the construction of the b-carboline moiety via Bischler- Napieralski reaction and the enantioselective reduction of the dihydro-b-carboline intermediate via an asymmetric transfer hydrogenation reaction using Noyori's protocol. These compounds were evaluated as antiproliferative agents against a panel of cancer cell lines. Only canthin-6-one (64) has shown promising activity against cell line 786-0 (renal cell carcinoma). These compounds were evaluated in vitro bioassays against Leishmania major, Leishmania brasiliensis and Leishmania amazonesis and again canthin-6-one (64) displayed promising activity against Leishmania major (IC50=16,9 mM) and a highly promising safety index (Si=94,7). Preliminary tests of in vivo toxicity showed that harmicine (62) and trypargine (59) are substances with potential effect on the central nervous system. / Doutorado / Quimica Organica / Doutor em Ciências

Ce manuscrit présente une approche synthétique de la Mirabaline, macrocycle complexe d'origine marine. La synthèse du fragment nord a été achevée en utilisant des réactions clefs de Marshall et d'hydrogénation asymétrique associées ou non à un processus de dédoublement cinétique dynamique. La synthèse des fragments C et D a également été terminée. Des méthodes de contrôle de motifs aminoalcool 1,2 ont également été développées à l'aide de réactions d'hydrogénation asymétrique et de transfert d'hydrogène asymétrique via un dédoublement cinétique dynamique. / This manuscript presents a synthetic approach of Mirabalin, a complex macrocycle isolated from a marine sponge. The synthesis of the north fragment has been completed by using as key reactions a Marshall reaction and asymmetric hydrogenation combined or not with dynamic kinetic resolution process. The synthesis of fragments C and D has been completed as well. Methodologies for the control of 1,2-aminoalcohol moieties have also been developed using the asymmetric hydrogenation and asymmetric transfer hydrogenation via dynamic kinetic resolution.

Over the last two centuries, the discovery and application of catalysts has had a substantial impact on how and what chemicals are produced.Given their broad significance, our group has focused on developing new catalyst systems that are recoverable and reusable, in an attempt to reduce concomitant costs. Our efforts have centered on constructing a recyclable chiral heterogeneous catalyst capable of effecting asymmetric hydrogenations of olefins with high stereoselectivity. A class of phosphinoimidazoline ligands, developed by researchers at Boehringer-Ingelheim, known as BIPI ligands, have proven efficacious in the asymmetric reduction of alkenes. However, these chiral ligands are homogeneous and coordinated to precious metals, rendering them irrecoverable and expensive. To address these issues, our group has derivatized the BIPI ligand-metal complex and immobilized it to the surface of graphene oxide as well as polystyrene. Their efficacy and recyclability toward the asymmetric hydrogenation of a functionalized olefin have been evaluated. Another facet of our work has included developing a cost effective synthetic process to artemisinin, the gold standard drug in the treatment of malaria.As a natural product, artemisinin’s worldwide supply remains highly unpredictable, contributing to great price volatility.Combining the benefits of catalysis and the advantages of continuous flow chemistry, our research has sought to develop an economical approach to convert a biosynthetic precursor, artemisinic acid, to artemisinin in three chemical transformations. High-throughput experimentation allowed us to screen a prodigious number of catalysts and identify those effective in the asymmetric hydrogenation artemisinic acid to dihydroartemisinic acid, the first step in the transformation. This screening directed us to an inexpensive, heterogeneous ruthenium catalyst. The second step of the process includes the photooxygenation of dihydroartemisinic acid, which involves photochemically generated singlet oxygen. We have evaluated a commercially available heterogeneous photocatalyst packed in a transparent bed, surrounded by light emitting diodes in the continuous photooxygenation of dihydroartemisinic acid to dihydroartemisinic acid hydroperoxide. The third and final step, an acid induced hock cleavage, initiates an intricate cascading reaction that installs an endoperoxide bridge to deliver artemisinin. Our process afforded a 57% yield from dihydroartemisinic acid to artemisinin.