This thesis addresses two fundamental areas in contemporary organic chemistry: synthesis of natural products and catalytic asymmetric synthesis. Firstly, a new methodology, developed by our research group, which allows the asymmetric synthesis of lactones, a structural unit ubiquitous in natural products, was utilised in the synthesis of a number of natural product analogues that showed significant biological activity. Secondly, the development of a catalytic asymmetric synthesis of a key structural motif present in a number of natural products and pharmaceuticals was accomplished. During the course of this work we discovered dual stereo control, which is significant because it allows the configuration of a new stereo centre to be controlled by a simple change of proton source.

Catalytic Asymmetric Synthesis Seminal text presenting detailed accounts of the most important catalytic asymmetric reactions known today This book covers the preparation of enantiomerically pure or enriched chemical compounds by use of chiral catalyst molecules. While reviewing the most important catalytic methods for asymmetric organic synthesis, this book highlights the most important and recent developments in catalytic asymmetric synthesis. Edited by two well-qualified experts, sample topics covered in the work include: Metal catalysis, organocatalysis, photoredox catalysis, enzyme catalysis C–H bond functionalization reactions Carbon–carbon bond formation reactions, carbon–halogen bond formation reactions, hydrogenations, polymerizations, flow reactions Axially chiral compounds Retaining the best of its predecessors but now thoroughly up to date with the important and recent developments in catalytic asymmetric synthesis, the 4th edition of Catalytic Asymmetric Synthesis serves as an excellent desktop reference and text for researchers and students, from upper-level undergraduates all the way to experienced professionals in industry or academia.

From the reviews of the First Edition . . . "An excellent text . . . will no doubt provide the benchmark for comparative works for many years."-Journal of the American Chemical Society "A resounding success . . . the definitive current summaries on their respective subjects."-Synthesis Since this important work was first published in 1993, the field of catalytic asymmetric synthesis has grown explosively, spawning effective new methods for obtaining enantiomerically pure compounds on a large scale and stimulating new applications in diverse fields-from medicine to materials science. Catalytic Asymmetric Synthesis, Second Edition addresses these rapid changes through new or substantially revised contributions from highly recognized world leaders in the field. It presents detailed accounts of the most important catalytic asymmetric reactions known today, discusses recent advances, and retains from the previous edition essential and intriguing information on the initial development of certain processes. An excellent working resource for academic researchers and industrial chemists alike, the Second Edition features: * Contributions from Noyori, Sharpless, Kagan, Trost, Overman, Shibasaki, Doyle, Okamoto, Bolm, Carreira, and many other internationally renowned authorities * New chapters on asymmetric carbometallations, asymmetric amplification and autocatalysis, and asymmetric polymerization * Extended coverage of asymmetric carbene reactions, including asymmetric intramolecular carbene insertion to C-H bonds as well as asymmetric dihydroxylation and aminohydroxylation * Extended coverage of asymmetric carbon-carbon bond-forming reactions and applications * An appendix listing all chiral ligands in the book

This book covers advances in the methods of catalytic asymmetric synthesis and their applications. Coverage moves from new materials and technologies to homogeneous metal-free catalysts and homogeneous metal catalysts. The applications of several methodologies for the synthesis of biologically active molecules are discussed. Part I addresses recent advances in new materials and technologies such as supported catalysts, supports, self-supported catalysts, chiral ionic liquids, supercritical fluids, flow reactors and microwaves related to asymmetric catalysis. Part II covers advances and milestones in organocatalytic, enzymatic and metal-based mediated asymmetric synthesis, including applications for the synthesis of biologically active molecules. Written by leading international experts, this book consists of 16 chapters with 2000 References and illustrations of 560 schemes and figures.

This Issue contains one communication, six articles, and two reviews. The communication from Paola Vitale et al. represents a work where whole cells were used as biocatalysts for the reduction of optically active chloroalkyl arylketones followed by a chemical cyclization to give the desired heterocycles. Among the various whole cells screened (baker’s yeast, Kluyveromyces marxianus CBS 6556, Saccharomyces cerevisiae CBS 7336, Lactobacillus reuteri DSM 20016), baker’s yeast provided the best yields and the highest enantiomeric ratios (95:5) in the bioreduction of the above ketones. In this respect, valuable chiral non-racemic functionalized oxygen-containing heterocycles (e.g., (S)-styrene oxide, (S)-2-phenyloxetane, (S)-2-phenyltetrahydrofuran), amenable to be further elaborated on, can be smoothly and successfully generated from their prochiral precursors. Studies about pure biocatalysts with mechanistical studies, application in different reactions, and new immobilization methods for improving their stability were reported in five different articles. The article by Su-Yan Wang et al. describes the cloning, expression, purification, and characterization of an N-acetylglucosamine 2-epimerase from Pedobacter heparinus (PhGn2E). For this, several N-acylated glucosamine derivatives were chemically synthesized and used to test the substrate specificity of the enzyme. The mechanism of the enzyme was studied by hydrogen/deuterium NMR. The study at the anomeric hydroxyl group and C-2 position of the substrate in the reaction mixture confirmed the epimerization reaction via ring-opening/enolate formation. Site-directed mutagenesis was also used to confirm the proposed mechanism of this interesting enzyme. The article by Forest H. Andrews et al. studies two enzymes, benzoylformate decarboxylase (BFDC) and pyruvate decarboxylase (PDC), which catalyze the non-oxidative decarboxylation of 2-keto acids with different specificity. BFDC from Pseudomonas putida exhibited very limited activity with pyruvate, whereas the PDCs from S. cerevisiae or from Zymomonas mobilis showed virtually no activity with benzoylformate (phenylglyoxylate). After studies using saturation mutagenesis, the BFDC T377L/A460Y variant was obtained, with 10,000-fold increase in pyruvate/benzoylformate. The change was attributed to an improvement in the Km value for pyruvate and a decrease in the kcat value for benzoylformate. The characterization of the new catalyst was performed, providing context for the observed changes in the specificity. The article by Xin Wang et al. compares two types of biocatalysts to produce D-lysine L-lysine in a cascade process catalyzed by two enzymes: racemase from microorganisms that racemize L-lysine to give D,L-lysine and decarboxylase that can be in cells, permeabilized cells, and the isolated enzyme. The comparison between the different forms demonstrated that the isolated enzyme showed the higher decarboxylase activity. Under optimal conditions, 750.7 mmol/L D-lysine was finally obtained from 1710 mmol/L L-lysine after 1 h of racemization reaction and 0.5 h of decarboxylation reaction. D-lysine yield could reach 48.8% with enantiomeric excess (ee) of 99%. In the article by Rivero and Palomo, lipase from Candida rugosa (CRL) was highly stabilized at alkaline pH in the presence of PEG, which permitted its immobilization for the first time by multipoint covalent attachment on different aldehyde-activated matrices. Different covalent immobilized preparation of the enzyme was successfully obtained. The thermal and solvent stability was highly increased by this treatment, and the novel catalysts showed high regioselectivity in the deprotection of per-O-acetylated nucleosides. The article by Robson Carlos Alnoch et al. describes the protocol and use of a new generation of tailor-made bifunctional supports activated with alkyl groups that allow the immobilization of proteins through the most hydrophobic region of the protein surface and aldehyde groups that allows the covalent immobilization of the previously adsorbed proteins. These supports were especially used in the case of lipase immobilization. The immobilization of a new metagenomic lipase (LipC12) yielded a biocatalyst 3.5-fold more active and 5000-fold more stable than the soluble enzyme. The PEGylated immobilized lipase showed high regioselectivity, producing high yields of the C-3 monodeacetylated product at pH 5.0 and 4 °C. Hybrid catalysts composed of an enzyme and metallic complex are also treated in this Special Issue. The article by Christian Herrero et al. describes the development of the Mn(TpCPP)-Xln10A artificial metalloenzyme, obtained by non-covalent insertion of Mn(III)-meso-tetrakis(p-carboxyphenyl)porphyrin [Mn(TpCPP), 1-Mn] into xylanase 10A from Streptomyces lividans (Xln10A). The complex was found able to catalyze the selective photo-induced oxidation of organic substrates in the presence of [RuII(bpy)3]2+ as a photosensitizer and [CoIII(NH3)5Cl]2+ as a sacrificial electron acceptor, using water as oxygen atom source. The two published reviews describe different subjects with interest in the fields of biocatalysis and mix metallic-biocatalysis, respectively. The review by Anika Scholtissek et al. describes the state-of-the-art regarding ene-reductases from the old yellow enzyme family (OYEs) to catalyze the asymmetric hydrogenation of activated alkenes to produce chiral products with industrial interest. The dependence of OYEs on pyridine nucleotide coenzyme can be avoided by using nicotinamide coenzyme mimetics. In the review, three main classes of OYEs are described and characterized. The review by Yajie Wang and Huimin Zhao highlights some of the recent examples in the past three years that combine transition metal catalysis with enzymatic catalysis. With recent advances in protein engineering, catalyst synthesis, artificial metalloenzymes, and supramolecular assembly, there is great potential to develop more sophisticated tandem chemoenzymatic processes for the synthesis of structurally complex chemicals. In conclusion, these nine publications give an overview of the possibilities of different catalysts, both traditional biocatalysts and hybrids with metals or organometallic complexes to be used in different processes—particularly in synthetic reactions—under very mild reaction conditions.

The synthesis of enantiopure organic compounds is a key issue for several applications in pharmacology, food chemistry, agricultural chemistry, perfumery, materials science and other industrial sectors. Nowadays, asymmetric catalysis is undoubtedly the most important tool to achieve this goal. This technology, in fact, enables the production of large amounts of enantiomerically enriched compounds, employing relatively small quantities of chiral enantiopure catalysts, which is exactly what is accomplished by enzymes in nature. Since the pioneering works of Noyori, Knowles and Sharpless, which later earned them the Nobel Prize in Chemistry, asymmetric catalysis has experienced a rapid and relentless development in the last fifty years. The tremendous expansion of enantioselective transformations, the design of novel and more efficient organometallic and organic catalysts, the development of sophisticated bioreactors and cell factories, are just some of the elements responsible for such growth. However, new challenges of asymmetric catalysis are devoted to enhancing the process’s sustainability, by the introduction of recyclable and low-cost catalysts, and the use of renewable starting materials and energy source. This book provides an overview of some of these development directions and comprises a collection of review papers and a research article authored by renowned researchers actively involved in this field. The topics covered by the review papers are photoredox-catalyzed reactions of imines, asymmetric catalytic electrosynthesis, cooperative catalysis of chiral N-heterocyclic carbenes and Lewis acid, and asymmetric ring-opening reactions of epoxides catalyzed by metal–salen complexes. The research article presents a proline-catalyzed aldol reaction in water–methanol solvent mixture.

Corinna Reisinger has developed a new organocatalytic asymmetric epoxidation of cyclic and acyclic α,β-unsaturated ketones. In this thesis, Corinna documents her methodology, using primary amine salts as catalysts, and hydrogen peroxide as an inexpensive and environmentally benign oxidant. She describes the unprecedented and powerful catalytic asymmetric hydroperoxidation of α,β-enones, a process which produces optically active five-membered cyclic peroxyhemiketals in a single operation. She also proves the versatility and synthetic value of the cyclic peroxyhemiketals by converting them into highly enantioenriched acyclic and cyclic aldol products. Currently, these cyclic aldol products are inaccessible by any other synthetic means. Furthermore, cyclic peroxyhemiketals are precursors to optically active 1,2-dioxolanes which are of biological relevance. This work is a breakthrough in the field of asymmetric epoxidation chemistry and outlines the most efficient method in the literature for generating highly enantioselective cyclic epoxyketones known to date.

This Issue contains one communication, six articles, and two reviews. The communication from Paola Vitale and others represents a work where whole cells were used as biocatalysts for the reduction of optically active chloroalkyl arylketones followed by a chemical cyclization to give the desired heterocycles. Among the various whole cells screened (baker's yeast, Kluyveromyces marxianus CBS 6556, Saccharomyces cerevisiae CBS 7336, Lactobacillus reuteri DSM 20016), baker's yeast provided the best yields and the highest enantiomeric ratios (95:5) in the bioreduction of the above ketones. In this respect, valuable chiral non-racemic functionalized oxygen-containing heterocycles (e.g., (S)-styrene oxide, (S)-2-phenyloxetane, (S)-2-phenyltetrahydrofuran), amenable to be further elaborated on, can be smoothly and successfully generated from their prochiral precursors. Studies about pure biocatalysts with mechanistical studies, application in different reactions, and new immobilization methods for improving their stability were reported in five different articles. The article by Su-Yan Wang and others describes the cloning, expression, purification, and characterization of an N-acetylglucosamine 2-epimerase from Pedobacter heparinus (PhGn2E). For this, several N-acylated glucosamine derivatives were chemically synthesized and used to test the substrate specificity of the enzyme. The mechanism of the enzyme was studied by hydrogen/deuterium NMR. The study at the anomeric hydroxyl group and C-2 position of the substrate in the reaction mixture confirmed the epimerization reaction via ring-opening/enolate formation. Site-directed mutagenesis was also used to confirm the proposed mechanism of this interesting enzyme. The article by Forest H. Andrews and others studies two enzymes, benzoylformate decarboxylase (BFDC) and pyruvate decarboxylase (PDC), which catalyze the non-oxidative decarboxylation of 2-keto acids with different specificity. BFDC from Pseudomonas putida exhibited very limited activity with pyruvate, whereas the PDCs from S. cerevisiae or from Zymomonas mobilis showed virtually no activity with benzoylformate (phenylglyoxylate). After studies using saturation mutagenesis, the BFDC T377L/A460Y variant was obtained, with 10,000-fold increase in pyruvate/benzoylformate. The change was attributed to an improvement in the Km value for pyruvate and a decrease in the kcat value for benzoylformate. The characterization of the new catalyst was performed, providing context for the observed changes in the specificity. The article by Xin Wang and others compares two types of biocatalysts to produce D-lysine L-lysine in a cascade process catalyzed by two enzymes: racemase from microorganisms that racemize L-lysine to give D,L-lysine and decarboxylase that can be in cells, permeabilized cells, and the isolated enzyme. The comparison between the different forms demonstrated that the isolated enzyme showed the higher decarboxylase activity. Under optimal conditions, 750.7 mmol/L D-lysine was finally obtained from 1710 mmol/L L-lysine after 1 h of racemization reaction and 0.5 h of decarboxylation reaction. D-lysine yield could reach 48.8% with enantiomeric excess (ee) of 99%. In the article by Rivero and Palomo, lipase from Candida rugosa (CRL) was highly stabilized at alkaline pH in the presence of PEG, which permitted its immobilization for the first time by multipoint covalent attachment on different aldehyde-activated matrices. Different covalent immobilized preparation of the enzyme was successfully obtained. The thermal and solvent stability was highly increased by this treatment, and the novel catalysts showed high regioselectivity in the deprotection of per-O-acetylated nucleosides. The article by Robson Carlos Alnoch and others describes the protocol and use of a new generation of tailor-made bifunctional supports activated with alkyl groups that allow the immobilization of proteins through the most hydrophobic region of the protein surface and aldehyde groups that allows the covalent immobilization of the previously adsorbed proteins. These supports were especially used in the case of lipase immobilization. The immobilization of a new metagenomic lipase (LipC12) yielded a biocatalyst 3.5-fold more active and 5000-fold more stable than the soluble enzyme. The PEGylated immobilized lipase showed high regioselectivity, producing high yields of the C-3 monodeacetylated product at pH 5.0 and 4 °C. Hybrid catalysts composed of an enzyme and metallic complex are also treated in this Special Issue. The article by Christian Herrero and others describes the development of the Mn(TpCPP)-Xln10A artificial metalloenzyme, obtained by non-covalent insertion of Mn(III)-meso-tetrakis(p-carboxyphenyl)porphyrin [Mn(TpCPP), 1-Mn] into xylanase 10A from Streptomyces lividans (Xln10A). The complex was found able to catalyze the selective photo-induced oxidation of organic substrates in the presence of [RuII(bpy)3]2+ as a photosensitizer and [CoIII(NH3)5Cl]2+ as a sacrificial electron acceptor, using water as oxygen atom source. The two published reviews describe different subjects with interest in the fields of biocatalysis and mix metallic-biocatalysis, respectively. The review by Anika Scholtissek and others describes the state-of-the-art regarding ene-reductases from the old yellow enzyme family (OYEs) to catalyze the asymmetric hydrogenation of activated alkenes to produce chiral products with industrial interest. The dependence of OYEs on pyridine nucleotide coenzyme can be avoided by using nicotinamide coenzyme mimetics. In the review, three main classes of OYEs are described and characterized. The review by Yajie Wang and Huimin Zhao highlights some of the recent examples in the past three years that combine transition metal catalysis with enzymatic catalysis. With recent advances in protein engineering, catalyst synthesis, artificial metalloenzymes, and supramolecular assembly, there is great potential to develop more sophisticated tandem chemoenzymatic processes for the synthesis of structurally complex chemicals. In conclusion, these nine publications give an overview of the possibilities of different catalysts, both traditional biocatalysts and hybrids with metals or organometallic complexes to be used in different processes-particularly in synthetic reactions-under very mild reaction conditions.

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 #x1C;-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-#x1C;-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-#x1C;-vinyl-syn-aldols occurs under the sterodirecting effect of the #x1C;- 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.

Authored by two internationally recognized experts with an excellent track record, this much-needed reference summarizes latest research in the rapidly developing field of stereoselective synthesis of enantiomerically enriched amino acids, particularly of non-proteinogenic origin. It highlights several different catalytic and stoichiometric asymmetric methods for their synthesis and also provides information on origin, biological properties, different synthetic strategies and important applications in medicine and pharmacology. Essential reading for synthetic chemists working in the field of asymmetric synthesis, natural products and peptide synthesis, stereochemistry, medicinal chemistry, biochemistry, pharmacology, and biotechnology.