Stereochemistry: an Introduction
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Prebiological Evolution and the Metabolic Origins of Life
Prebiological Evolution and the Andrew J. Pratt* Metabolic Origins of Life University of Canterbury Keywords Abiogenesis, origin of life, metabolism, hydrothermal, iron Abstract The chemoton model of cells posits three subsystems: metabolism, compartmentalization, and information. A specific model for the prebiological evolution of a reproducing system with rudimentary versions of these three interdependent subsystems is presented. This is based on the initial emergence and reproduction of autocatalytic networks in hydrothermal microcompartments containing iron sulfide. The driving force for life was catalysis of the dissipation of the intrinsic redox gradient of the planet. The codependence of life on iron and phosphate provides chemical constraints on the ordering of prebiological evolution. The initial protometabolism was based on positive feedback loops associated with in situ carbon fixation in which the initial protometabolites modified the catalytic capacity and mobility of metal-based catalysts, especially iron-sulfur centers. A number of selection mechanisms, including catalytic efficiency and specificity, hydrolytic stability, and selective solubilization, are proposed as key determinants for autocatalytic reproduction exploited in protometabolic evolution. This evolutionary process led from autocatalytic networks within preexisting compartments to discrete, reproducing, mobile vesicular protocells with the capacity to use soluble sugar phosphates and hence the opportunity to develop nucleic acids. Fidelity of information transfer in the reproduction of these increasingly complex autocatalytic networks is a key selection pressure in prebiological evolution that eventually leads to the selection of nucleic acids as a digital information subsystem and hence the emergence of fully functional chemotons capable of Darwinian evolution. 1 Introduction: Chemoton Subsystems and Evolutionary Pathways Living cells are autocatalytic entities that harness redox energy via the selective catalysis of biochemical transformations. -
Chapter 3 • Ratio: Cnh2n+2
Organic Chemistry, 5th Edition Alkane Formulas L. G. Wade, Jr. • All C-C single bonds • Saturated with hydrogens Chapter 3 • Ratio: CnH2n+2 Structure and Stereochemistry • Alkane homologs: CH3(CH2)nCH3 of Alkanes • Same ratio for branched alkanes H H H H H H CH H C C C C H H H H C CCH Jo Blackburn H H H H H H Richland College, Dallas, TX H => Butane, C4H10 Dallas County Community College District Chapter 3Isobutane, C H 2 © 2003, Prentice Hall 4 10 Common Names Pentanes H H H H H H H CH • Isobutane, “isomer of butane” H C C C C C H H H • Isopentane, isohexane, etc., methyl H H H H H H H C CCC H branch on next-to-last carbon in chain. H H H H • Neopentane, most highly branched n-pentane, C5H12 isopentane, C5H12 • Five possible isomers of hexane, CH3 18 isomers of octane and 75 for H3C C CH3 decane! CH3 => => neopentane, C5H12 Chapter 3 3 Chapter 3 4 Longest Chain IUPAC Names • The number of carbons in the longest • Find the longest continuous carbon chain determines the base name: chain. ethane, hexane. (Listed in Table 3.2, • Number the carbons, starting closest to page 81.) the first branch. • If there are two possible chains with the • Name the groups attached to the chain, same number of carbons, use the chain using the carbon number as the locator. with the most substituents. • Alphabetize substituents. H3C CH CH CH • Use di-, tri-, etc., for multiples of same 2 3 CH3 substituent. -
– 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. -
Stereochemistry of Alkanes and Cycloalkanes
STEREOCHEMISTRY OF ALKANES AND CYCLOALKANES CONFORMATIONAL ISOMERS 1 CONFORMATIONAL ISOMERS • Stereochemistry concerned with the 3-D aspects of molecules • Rotation is possible around C-C bonds in open- chain molecules • A conformation is one of the many possible arrangements of atoms caused by rotation about a single bond, and a specific conformation is called a conformer (conformational isomer). 2 SOME VOCABULARY • A staggered conformation is the conformation in which all groups on two adjacent carbons are as far from each other as possible. • An eclipsed conformation is the conformation in which all groups on two adjacent carbons are as close to each other as possible. • Dihedral angle is angle between the substituents on two adjacent carbons; changes with rotation around the C-C bond 3 MORE VOCABULARY • Angle strain is the strain caused by the deformation of a bond angle from its normal value. • Steric strain is the repulsive interaction caused by atoms attempting to occupy the same space. • Torsional strain is the repulsive interaction between two bonds as they rotate past each other. Torsional strain is responsible for the barrier to rotation around the C-C bond. The eclipsed from higher in energy than the staggered form. 4 CONFORMATION OF ETHANE • Conformation- Different arrangement of atoms resulting from bond rotation • Conformations can be represented in 2 ways: 5 TORSIONAL STRAIN • We do not observe perfectly free rotation • There is a barrier to rotation, and some conformers are more stable than others • Staggered- most stable: -
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. -
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. -
Module No. 20: Methods of Resolution Subject
Subject Chemistry Paper No and Title 1; Organic Chemistry-I (Nature of bonding and Stereochemistry) Module No and 21: Methods of Resolution Title Module Tag CHE_P1_M21 CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) Module No. 20: Methods of Resolution TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Methods of Resolution 3.1 Resolution by mechanical Separation of Crystals 3.2 Resolution by formation of Diastereoisomers 3.3 Resolution by Formation of molecular Complexes 3.4 Resolution by Chromatography 3.5 Resolution Through Equilibrium Asymmetric Transformation 3.6 Resolution Through Asymmetric Transformation 3.7 Resolution by Biochemical Transformation 3.8 Resolution Through inclusion Compounds 3.9 Methods Based on NMR Spectroscopy 3.9.1 Use of Diastereomers 3.9.2 Use of Shift Reagents 3.9.3 Use of Chiral Solvating Agents 4. Summary CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) Module No. 20: Methods of Resolution 1. Learning Outcomes After studying this module, you shall be able to Know that pure form of isomers can be obtained from a racemic mixture. Understand the process of resolution. Learn about the different methods of resolution. Analyse the efficacy of various methods of resolution. 2. Introduction In the previous modules we have discussed in detail various types of isomers, viz., enantiomers, diastereomers, erythro and threo isomers etc. When an enantiomer is converted into a racemic mixture or a racemic modification (usually through chemical reactions), this process is known as racemisation. Conversely, when a racemic modification is separated into its constituent enantiomers, the process is known as resolution. -
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. -
Organic Chemistry by Robert C
(2/94)(6,7,9/95)(8,9/97)(12/99)(1/00) Neuman Chapter 4 Chapter 4 Stereochemistry from Organic Chemistry by Robert C. Neuman, Jr. Professor of Chemistry, emeritus University of California, Riverside [email protected] <http://web.chem.ucsb.edu/~neuman/orgchembyneuman/> Chapter Outline of the Book ************************************************************************************** I. Foundations 1. Organic Molecules and Chemical Bonding 2. Alkanes and Cycloalkanes 3. Haloalkanes, Alcohols, Ethers, and Amines 4. Stereochemistry 5. Organic Spectrometry II. Reactions, Mechanisms, Multiple Bonds 6. Organic Reactions *(Not yet Posted) 7. Reactions of Haloalkanes, Alcohols, and Amines. Nucleophilic Substitution 8. Alkenes and Alkynes 9. Formation of Alkenes and Alkynes. Elimination Reactions 10. Alkenes and Alkynes. Addition Reactions 11. Free Radical Addition and Substitution Reactions III. Conjugation, Electronic Effects, Carbonyl Groups 12. Conjugated and Aromatic Molecules 13. Carbonyl Compounds. Ketones, Aldehydes, and Carboxylic Acids 14. Substituent Effects 15. Carbonyl Compounds. Esters, Amides, and Related Molecules IV. Carbonyl and Pericyclic Reactions and Mechanisms 16. Carbonyl Compounds. Addition and Substitution Reactions 17. Oxidation and Reduction Reactions 18. Reactions of Enolate Ions and Enols 19. Cyclization and Pericyclic Reactions *(Not yet Posted) V. Bioorganic Compounds 20. Carbohydrates 21. Lipids 22. Peptides, Proteins, and α−Amino Acids 23. Nucleic Acids ************************************************************************************** -
Stereochemistry of Bruice's Organic Chemistry Before Embarking on Comprehending This Summary
Enantioselective synthesis It helps if you review the concepts in Chapter 5: Stereochemistry of Bruice's Organic Chemistry before embarking on comprehending this summary Most of the molecules on earth are chiral, such as amino acids and carbohydrates. Enantioselective synthesis is an important means by which enantiopure chiral molecules may be obtained for study and medicine. The study of enantioselective synthesis has evolved from issues of diastereoselectivity, through auxiliary-based methods for the synthesis of enantiomerically pure compounds (diastereoselectivity followed by separation and auxiliary cleavage), to asymmetric catalysis. In the latter technology, enantiomers are the products, and highly selective reactions allow preparation - in a single step - of chiral substances in high enantiomeric excess (ee) for many reaction types. Enantioselective synthesis, also known as asymmetric synthesis, is organic synthesis that introduces one or more new and desired elements of chirality. This methodology is important in the field of pharmaceuticals because the different enantiomers or diastereomers of a molecule often have different biological activity. See examples from Chapter 5 of Bruice's Organic Chemistry. Methodologies of Asymmetric Synthesis Chiral pool synthesis Chiral pool synthesis is the easiest approach: A chiral starting material is manipulated through successive reactions using achiral reagents that retain its chirality to obtain the desired target molecule. This is especially attractive for target molecules having the similar chirality to a relatively inexpensive naturally occurring building-block such as a sugar or amino acid. However, the number of possible reactions the molecule can undergo is restricted, and lengthy synthetic routes may be required. Also, this approach requires a stoichiometric amount of the enantiopure starting material, which may be rather expensive if not occurring in nature, whereas chiral catalysis requires only a catalytic amount of chiral material. -
NMR and Stereochemistry Chem 4010/5326: Organic Spectroscopic Analysis
NMR and Stereochemistry Chem 4010/5326: Organic Spectroscopic Analysis © 2015 Andrew Harned General flow for solving structures C10H20O Molecular weight/formula (MS) Exact Mass: 156.1514 Molecular Weight: 156.2652 Functional groups (IR, NMR) Carbon connectivities (substructures) (NMR) Positions of functional groups within framework (gross structure) (2D NMR, coupling constants) How can this Stereochemical issues be solved??? Relative Stereochemistry (Diastereomers) Can be determined with many of the tools we have already discussed, along with some new ones Bifulco, G.; Dambruoso, P.; Gomex-Paloma, L.; Riccio, R. Chem. Rev. 2007, 107, 3744. NMR Spectroscopy Strategies for determining relative stereochemistry Chemical Shifts – Diastereotopic protons will have different chemical shifts, this will only tell you that diastereomers are present, cannot necessarily tell which is which by inspection only by comparison to known structures – Spatial orientation may place certain protons in shielding/deshielding portions of functional groups Coupling Constants – In acyclic systems, usually cannot tell which is which by inspection – Often must convert to rigid/cyclic structure Both require some knowledge of 3D structure –> Make model(s) NMR Spectroscopy Proximity of Protons Nuclear Overhauser Effect (nOe) – Through space interactions between nuclei, whether or not they are directly coupled – Magnitude decreases as inverse of sixth power of distance – Strongly irradiate one, get larger # in excited state – The others then shift to lower state to compensate -
Recent Advances in Biocatalyst Development in the Pharmaceutical Industry
Pharmaceutical Review Pharm. Bioprocess. (2013) 1(2), 179–196 Recent advances in biocatalyst development in the pharmaceutical industry Biocatalysts are increasingly employed as more efficient and environmentally safer Mingzi M Zhang†1, Xiaoyun alternatives to traditional chemical catalysts in the manufacturing of fine chemicals. Su†1, Ee Lui Ang1 & This is driven by advances in recombinant DNA technology, protein engineering and Huimin Zhao*1,2 bioinformatics, all of which are critical in the discovery, tailoring and optimization of 1Metabolic Engineering Research enzymes for industrial processes. In this article we review these key technological in- Laboratory, Institute of Chemical & Engineering Sciences, Agency for novations, as well as highlight the strategic application of these tools in the develop- Science, Technology & Research, ment of biocatalysts in the production of advanced pharmaceutical intermediates. Singapore 2Departments of Chemical & Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA The synthesis of pharmaceutical products covery and development for pharmaceutical *Author for correspondence: and therapeutic agents using biological sys- processes. For a comprehensive summary of Tel. : +1 217 333 2631 tems is becoming increasingly important for recent examples of biocatalyst application E-mail: zhao5@illinois. edu the healthcare industry. Integral to pharma- in the pharmaceutical industry, readers can †Authors contributed equally ceutical bioprocessing is the development refer