Asymmetric Organocatalysis
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Thiourea Derivatives of Tröger's Base
General Papers ARKIVOC 2009 (xiv) 124-134 Thiourea derivatives of Tröger’s base: synthesis, enantioseparation and evaluation in organocatalysis of Michael addition to nitroolefins Delphine Didiera and Sergey Sergeyeva,b* a Université Libre de Bruxelles (ULB), Laboratoire de Chimie des Polymères, CP 206/01, Boulevard du Triomphe, 1050 Brussels, Belgium b University of Antwerp, Department of Chemistry, Groenenborgerlaan 171, 2020 Antwerp, Belgium E-mail: [email protected] Abstract The catalytic activity of racemic thiourea derivatives of Tröger’s base (±)-2–4 in Michael additions of malonate derivatives to trans-β-nitrostyrene was studied. Due to the low basicity of Tröger’s base, the outcome of the addition reactions was strongly dependent on the pKa of the nucleophile. Thiourea catalysts (±)-2, 3 were resolved on the chiral stationary phase Whelk O1. Unfortunately, enantiopure catalysts 2 and 3 showed no stereoselectivity in the Michael addition. Keywords: Tröger’s base, thiourea, Michael addition, catalysis, WhelkO1 Introduction In the recent years, asymmetric organocatalysis has emerged as a competitive, environment- friendlier alternative to catalysis with transition metal complexes. While simple molecules such as derivatives of proline have been receiving a great deal of attention due to their availability, considerable effort has been directed towards searching for novel chiral scaffolds for asymmetric organocatalysis.1 Tröger’s base 1 is a chiral diamine bearing two stereogenic bridge-head nitrogen atoms (Figure 1). The two aromatic rings fused to the central bicyclic framework are almost perpendicular to each other, creating a rigid, V-shaped C2-symmetrical molecular scaffold with a distance of ca. 1nm between the two extremities.2 Due to its chirality and relatively rigid geometry, one would intuitively expect a considerable interest for analogues of Tröger’s base in the field of asymmetric synthesis and catalysis. -
– with Novozymes Enzymes for Biocatalysis
Biocatalysis Pregabalin case study Smarter chemical synthesis – with Novozymes enzymes for biocatalysis The new biocatalytic route results in process improvements, reduced organic solvent usage and substantial reduction of waste streams in Pregabalin production. Introduction Biocatalysis is the application of enzymes to replace chemical Using Lipolase®, a commercially available lipase, rac-2- catalysts in synthetic processes. In recent past, the use of carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester biocatalysis has gained momentum in the chemical and (1) can be resolved to form (S)-2-carboxyethyl-3-cyano-5- pharmaceutical industries. Today, it’s an important tool for methylhexanoic acid (2). Compared to the first-generation medicinal, process and polymer chemists to develop efficient process, this new route substantially improves process and highly attractive organic synthetic processes on an efficiency by setting the stereocenter early in the synthesis and industrial scale. enabling the facile racemization and reuse of (R)-1. The biocatalytic process for Pregabalin has been developed It outperforms the first-generation manufacturing process also by Pfizer to boost efficiency in Pregabalin production using by delivering higher yields of Pregabalin and by resulting in Novozymes Lipolase®. substantial reductions of waste streams, corresponding to a 5-fold decrease in the E-Factor from 86 to 17. Development of the biocatalytic process for Pregabalin involves four stages: • Screening to identify a suitable enzyme • Performing optimization of the enzymatic reaction to optimize throughput and reduce enzyme loading • Exploring a chemical pathway to preserve the enantiopurity of the material already obtained and lead to Pregabalin, and • Developing a procedure for the racemization of (R)-1 Process improvements thanks to the biocatalytic route Pregabalin chemical synthesis H Knovenagel CN condensation cyanation KOH 0 Et02C CO2Et Et02C CO2Et Et02C CO2Et CNDE (1) CN NH2 1. -
A Reminder… Chirality: a Type of Stereoisomerism
A Reminder… Same molecular formula, isomers but not identical. constitutional isomers stereoisomers Different in the way their Same connectivity, but different atoms are connected. spatial arrangement. and trans-2-butene cis-2-butene are stereoisomers. Chirality: A Type of Stereoisomerism Any object that cannot be superimposed on its mirror image is chiral. Any object that can be superimposed on its mirror image is achiral. Chirality: A Type of Stereoisomerism Molecules can also be chiral or achiral. How do we know which? Example #1: Is this molecule chiral? 1. If a molecule can be superimposed on its mirror image, it is achiral. achiral. Mirror Plane of Symmetry = Achiral Example #1: Is this molecule chiral? 2. If you can find a mirror plane of symmetry in the molecule, in any achiral. conformation, it is achiral. Can subject unstable conformations to this test. ≡ achiral. Finding Chirality in Molecules Example #2: Is this molecule chiral? 1. If a molecule cannot be superimposed on its mirror image, it is chiral. chiral. The mirror image of a chiral molecule is called its enantiomer. Finding Chirality in Molecules Example #2: Is this molecule chiral? 2. If you cannot find a mirror plane of symmetry in the molecule, in any conformation, it is chiral. chiral. (Or maybe you haven’t looked hard enough.) Pharmacology of Enantiomers (+)-esomeprazole (-)-esomeprazole proton pump inhibitor inactive Prilosec: Mixture of both enantiomers. Patent to AstraZeneca expired 2002. Nexium: (+) enantiomer only. Process patent coverage to 2007. More examples at http://z.umn.edu/2301drugs. (+)-ibuprofen (-)-ibuprofen (+)-carvone (-)-carvone analgesic inactive (but is converted to spearmint oil caraway oil + enantiomer by an enzyme) Each enantiomer is recognized Advil (Wyeth) is a mixture of both enantiomers. -
Part I Principles of Enzyme Catalysis
j1 Part I Principles of Enzyme Catalysis Enzyme Catalysis in Organic Synthesis, Third Edition. Edited by Karlheinz Drauz, Harald Groger,€ and Oliver May. Ó 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. j3 1 Introduction – Principles and Historical Landmarks of Enzyme Catalysis in Organic Synthesis Harald Gr€oger and Yasuhisa Asano 1.1 General Remarks Enzyme catalysis in organic synthesis – behind this term stands a technology that today is widely recognized as a first choice opportunity in the preparation of a wide range of chemical compounds. Notably, this is true not only for academic syntheses but also for industrial-scale applications [1]. For numerous molecules the synthetic routes based on enzyme catalysis have turned out to be competitive (and often superior!) compared with classic chemicalaswellaschemocatalyticsynthetic approaches. Thus, enzymatic catalysis is increasingly recognized by organic chemists in both academia and industry as an attractive synthetic tool besides the traditional organic disciplines such as classic synthesis, metal catalysis, and organocatalysis [2]. By means of enzymes a broad range of transformations relevant in organic chemistry can be catalyzed, including, for example, redox reactions, carbon–carbon bond forming reactions, and hydrolytic reactions. Nonetheless, for a long time enzyme catalysis was not realized as a first choice option in organic synthesis. Organic chemists did not use enzymes as catalysts for their envisioned syntheses because of observed (or assumed) disadvantages such as narrow substrate range, limited stability of enzymes under organic reaction conditions, low efficiency when using wild-type strains, and diluted substrate and product solutions, thus leading to non-satisfactory volumetric productivities. -
Page 1 of 108 RSC Advances
RSC Advances This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 108 RSC Advances Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis Majid M. Heravi,* Vahideh Zadsirjan, Behnaz Farajpour Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran Email: [email protected] Abstract Various chiral oxazolidinones (Evans' oxazolidinones) have been employed as effective chiral auxiliaries in the asymmetric alkylation of different enolates. This strategy has been found promising and successful when used as key step (steps) in the total synthesis of several biologically active natural products. In this report, we try to underscore the applications of Manuscript oxazolidinones as chiral auxiliary in asymmetric alkylation, and particularly in crucial chiral inducing steps in the total synthesis of natural products, showing biological activities. -
Chapter 4: Stereochemistry Introduction to Stereochemistry
Chapter 4: Stereochemistry Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane Me Me Me C Me H Bu Bu Me Me 2-methylhexane H H mirror Me rotate Bu Me H 2-methylhexame is superimposable with its mirror image Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane H C Et Et Me Pr Pr 3-methylhexane Me Me H H mirror Et rotate H Me Pr 2-methylhexame is superimposable with its mirror image Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane .Compounds that are not superimposable with their mirror image are called chiral (in Greek, chiral means "handed") 3-methylhexane is a chiral molecule. .Compounds that are superimposable with their mirror image are called achiral. 2-methylhexane is an achiral molecule. .An atom (usually carbon) with 4 different substituents is called a stereogenic center or stereocenter. Enantiomers Et Et Pr Pr Me CH3 Me H H 3-methylhexane mirror enantiomers Et Et Pr Pr Me Me Me H H Me H H Two compounds that are non-superimposable mirror images (the two "hands") are called enantiomers. Introduction To Stereochemistry Structural (constitutional) Isomers - Compounds of the same molecular formula with different connectivity (structure, constitution) 2-methylpentane 3-methylpentane Conformational Isomers - Compounds of the same structure that differ in rotation around one or more single bonds Me Me H H H Me H H H H Me H Configurational Isomers or Stereoisomers - Compounds of the same structure that differ in one or more aspects of stereochemistry (how groups are oriented in space - enantiomers or diastereomers) We need a a way to describe the stereochemistry! Me H H Me 3-methylhexane 3-methylhexane The CIP System Revisited 1. -
Organocatalytic Cyclopropanation of (E)-Dec-2-Enal: Synthesis, Spectral Analysis and Mechanistic Understanding
Organocatalytic Cyclopropanation of (E)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding. Marta Meazza, Agnieszka Kowalczuk, Sarah Watkins, Simon Holland, Thomas A. 5 Logothetis, Ramon Rios Faculty of Natural & Environmental Sciences, Department of Chemistry, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, United Kingdom In memoriam Klaus Burger ABSTRACT 10 An undergraduate experiment combining synthesis, NMR analysis and mechanistic understanding is reported. The students perform an organocatalyzed cyclopropanation reaction of (E)-dec-2-enal and are then required to determine the diastereoselectivity and assign the relative configuration of each product using NMR spectroscopy. 15 ABSTRACT GRAPHIC Journal of Chemical Education 8/20/18 Page 1 of 21 KEYWORDS Upper Division Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Asymmetric Synthesis, 20 NMR Spectroscopy, Diastereomers. BACKGROUND In recent years, catalysis has had a huge impact on the nature of organic synthesis. With the increasing emphasis on green chemistry and sustainable processes, the development of new, highly enantioselective methodologies for the 25 synthesis of new, 3D scaffolds has become of paramount importance for organic chemists. A clear example is the 2001 Nobel Prize awarded to K. B. Sharpless, R. Noyori and W. S. Knowles for their contributions to this field. A further step towards the development of greener methodologies was made in 2000 with the “renaissance” of organocatalysis by the pioneering works of B. List1 and D.W.C. 30 MacMillan.2 List et al.1 developed the first intermolecular enantioselective aldol reaction catalyzed by proline through enamine activation, while MacMillan and coworkers2 developed the first organocatalyzed enantioselective Diels-Alder reaction through iminium activation. -
1,2-Asymmetric Induction in Carbonyl Compounds - a Computational Study
1,2-Asymmetric Induction in Carbonyl Compounds - A Computational Study by Jeffrey Retallick B.Sc., University of New Brunswick, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science In the Graduate Academic Unit of Chemistry Supervisor(s): Ghislain Deslongchamps, Ph.D., Chemistry Examining Board: Rodney Cooper, M.Sc., Computer Science, Chair External Examiner: Ben Newling, Ph.D., Physics This thesis is accepted by the Dean of Graduate Studies THE UNIVERSITY OF NEW BRUNSWICK October, 2019 © Jeffrey Retallick, 2020 Abstract In asymmetric synthesis, it is important to reliably predict the major stereoisomeric prod- uct of a reaction. One such reaction is the nucleophilic addition to a carbonyl compound featuring an adjacent chiral carbon. Several reaction models exist in literature to predict the facial selectivity of these reactions. These models provide simple visual drawings to quickly predict the major product of such a reaction without requiring exhaustive quantum mechanical calculations. These models are used on a daily basis, and some models per- form better than others, making it valuable to investigate which ones are the most effective. For the first time in this thesis, high-level computations have been performed on all of the literature models to verify their efficacy. The results of this thesis offers a definitive answer that the Felkin-Anh and Wintner models are the most effective, and that bent bond theory offers an interesting insight on the mechanics of these reactions. ii Dedication Kyle, Nan, and Taryn. iii Acknowledgements Thanks to my family for their support. Ghislain, thank you for putting up with me over the past while. -
Chapter 8. Chiral Catalysts José M
Chapter 8. Chiral Catalysts José M. Fraile, José I. García, José A. Mayoral 1. The Origin of Enantioselectivity in Catalytic Processes: the Nanoscale of Enantioselective Catalysis. Enantiomerically pure compounds are extremely important in fields such as medicine and pharmacy, nutrition, or materials with optical properties. Among the different methods to obtain enantiomerically pure compounds, asymmetric catalysis1 is probably the most interesting and challenging, in fact one single molecule of chiral catalyst can transfer its chiral information to thousands or even millions of new chiral molecules. Enantioselective reactions are the result of the competition between different possible diastereomeric reaction pathways, through diastereomeric transition states, when the prochiral substrate complexed to the chiral catalyst reacts with the corresponding reagent. The efficiency of the chirality transfer, measured as enantiomeric excess [% ee = (R−S)/(R+S) × 100], depends on electronic and steric factors in a very subtle form. A simple calculation shows that differences in energy of only 2 kcal/mol between these transition states are enough to obtain more than 90% ee, and small changes in any of the participants in the catalytic process can modify significantly this difference in energy. Those modifications may occur in the near environment of the catalytic centre, at less than 1 nm scale, but also at longer distances in the catalyst, substrate, reagent, solvent, or support in the case of immobilized catalysts. This is the reason because asymmetric -
Amino Acid Catalyzed Direct Asymmetric Mannich Type Reactions Employing Unmodified Donors: Structure Based Catalyst Screening for Anti/Syn Selectivity
Asian Journal of Chemistry Vol. 20, No. 7 (2008), 5203-5208 Amino Acid Catalyzed Direct Asymmetric Mannich Type Reactions Employing Unmodified Donors: Structure Based Catalyst Screening for Anti/syn Selectivity SUBHENDU DAS and RAJESH K. SINGH* Department of Chemistry, North Orissa University, Takatpur, Baripada-757 003, India E-mail: [email protected] Amino acid catalyzed direct Mannich-type additions to N-Tos protected α-imino ethyl glyoxylate employing unmodi- fied carbonyl donors is described. The reaction was performed in DMSO using a catalytic amount (30 mol %) of L-proline and its derivatives providing a facile route to functionalized β-keto substituted α-amino acid derivatives with excellent diastereo- and enantioselectivities. Unmodified 3-pentanone and cyclohexanone were used as donors for the one pot gener- ation of two quaternary stereocenter. Organocatalysis using L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate were typically syn-diastereoselective. Anti-diastereoselectivity was achieved using (S)-2-methoxymethyl-pyrrolidine and L-proline benzyl ester. Stereochemical outcomes are explained on the basis of previously proposed transition state and the reasons governing syn- and anti-selectivity are described. Poor selectivity of (S)-2-methoxy-methylpyrrolidine compared to L-proline benzyl ester in contrast to earlier reports are expla- ined in terms of a fast cis-trans event and possible sterics. Key Words: Amino acids, Mannich reaction, Anti/syn Selectivity. INTRODUCTION Stereoselective transformation employing asymmetric organocatalysis is a rapidly growing field1-3. Reactions utilizing proline as chiral enantio- selective organocatalyst in catalytic amount has been the focus of great interest recently4,5. Organocatalytic reactions of proline and its derivatives has been well demonstrated for its versatility and potential to create both functional and structural diversity6. -
Kem-4.450 Asymmetric Synthesis
KemKem--4.4504.450 AsymmetricAsymmetric SynthesisSynthesis Prof. Ari Koskinen Laboratory of Organic Chemistry © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 ChiralityChirality andand DifferingDiffering PropertiesProperties OO Carvone spearmint odor caraway NH NH 2 H 2 H Aspartame HO2C NCO2Me HO2C NCO2Me (Nutrasweet) O O sweet bitter O O Thalidomide N N O O OON OON H H sedative, hypnotic teratogenic © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PharmaceuticalsPharmaceuticals Growing need for enantiopure compounds Enantiomers/diastereomers may have adverse effects Diastereomers usually easier to separate Enantiomers: FDA required © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PharmaceuticalsPharmaceuticals Penicillamine: NH2 NH2 CO2H CO2H SH SH antidote for Pb, Au, Hg can cause optic atrophy => blindness Timolol: O OH O OH H H N O N N O N N N N N S S adrenergic blocker ineffective © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SalesSales ofof EnantiomericEnantiomeric DrugsDrugs andand IntermediatesIntermediates Chem. Eng. News 2001, 79 (40), 79-97. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 AsymmetricAsymmetric InductionInduction -- DefinitionsDefinitions Chirality - handedness Asymmetry - lacking all symmetry (except E) B Dissymmetry - lacking some element of symmery H NB!!! Molecules can be chiral but not asymmetric! -
Catalytic Asymmetric Synthesis
Catalytic Asymmetric Synthesis Dr Alan Armstrong Rm 313 (RCS1), ext. 45876; [email protected] 7 lectures Recommended texts: “Catalytic Asymmetric Synthesis, 2nd edition”, ed. I Ojima, Wiley-VCH, 2000 (or 1st ed., 1993, which contains most of the lecture material) “Asymmetric Synthesis”, G Procter, Oxford, 1996 Aims of course: To give students an understanding of the basic principles of asymmetric catalysis, and to demonstrate these in the context of state-of-the-art catalytic asymmetric processes for C-C bond formation and redox processes. Course objectives: At the end of this course you should be able to: • Recognise the types of functional groups which can be prepared by catalytic asymmetric methods discussed in the course; • Use this knowledge in planning the synthesis of enantiomerically enriched compounds from given prochiral starting materials; • Outline the scope and limitations of any methods you propose, with respect to parameters such as turnover, substrate and functional group tolerance, availability of catalysts and/or ligands etc Course content (by lecture, approximately): 1. Introduction and general principles of asymmetric catalysis. Oxidation of functionalised olefins: asymmetric epoxidation of allylic alcohols and enones 2. Oxidation of unfunctionalised olefins: epoxidation, dihydroxylation and aminohydroxylation. 3. Reduction of olefins: asymmetric hydrogenation. 4. Reduction of ketones and imines 5. Asymmetric C-C bond formation: nucleophilic attack on carbonyls, imines and enones 6. Asymmetric transition metal catalysis in C-C bond forming reactions (cross-couplings, Heck reactions, allylic substitution, carbenoid reactions) 7. Chiral Lewis acid catalysis (aldol reactions, cycloadditions, Mannich reactions, allylations) 1 Catalytic Asymmetric Synthesis - Lecture 1 Background and general principles • Why asymmetric synthesis? The need to prepare pharmaceuticals and other fine chemicals as single enantiomers drives the field of asymmetric synthesis.