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Enantiomers & Diastereomers
Chapter 5 Stereochemistry Chiral Molecules Ch. 5 - 1 1. Chirality & Stereochemistry An object is achiral (not chiral) if the object and its mirror image are identical Ch. 5 - 2 A chiral object is one that cannot be superposed on its mirror image Ch. 5 - 3 1A. The Biological Significance of Chirality Chiral molecules are molecules that cannot be superimposable with their mirror images O O ● One enantiomer NH causes birth defects, N O the other cures morning sickness O Thalidomide Ch. 5 - 4 HO NH HO OMe Tretoquinol OMe OMe ● One enantiomer is a bronchodilator, the other inhibits platelet aggregation Ch. 5 - 5 66% of all drugs in development are chiral, 51% are being studied as a single enantiomer Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs Ch. 5 - 6 2. Isomerisom: Constitutional Isomers & Stereoisomers 2A. Constitutional Isomers Isomers: different compounds that have the same molecular formula ● Constitutional isomers: isomers that have the same molecular formula but different connectivity – their atoms are connected in a different order Ch. 5 - 7 Examples Molecular Constitutional Formula Isomers C4H10 and Butane 2-Methylpropane Cl Cl C3H7Cl and 1-Chloropropane 2-Chloropropane Ch. 5 - 8 Examples Molecular Constitutional Formula Isomers CH O CH C H O OH and 3 3 2 6 Ethanol Methoxymethane O OCH and 3 C H O OH 4 8 2 O Butanoic acid Methyl propanoate Ch. 5 - 9 2B. Stereoisomers Stereoisomers are NOT constitutional isomers Stereoisomers have their atoms connected in the same sequence but they differ in the arrangement of their atoms in space. -
Unit 3 – Stereochemistry
Stereochemistry Stereochemistry refers to the 3-dimensional properties and reactions of molecules. It has its own language and terms that need to be learned in order to fully communicate and understand the concepts. New vocabulary and concepts Handedness Chirality Fischer Projections Depicting Asymmetric Carbons (R) and (S) Nomenclature Enantiomers Diastereomers Optical Activity Stereochemistry Isomers: Different compounds that have the same molecular formula (composition) but different connectivity. Two classes: - Structural (constitutional) isomers: same molecular formula but different bonding sequence - Stereoisomers: same molecular formula, same bonding sequence, but different arrangement in space. Handedness…..Chirality Handedness” right glove doesn’t fit the left hand. Superimposable: A term that describes the ability to precisely overlap one object over another. Only identical objects are superposable, everything else is non-superposable superimposable nonsuperimposable Chiral molecules & Chirality Center Chemical substances can be handed, and they are called chiral. Chiral Molecules: are molecules that are nonsuperimposable on their mirror image. A carbon atom that is bonded to four chiral carbon atom different groups is called chairal carbon atom or stereocenter (asymmetric carbon atom). It is sp3 carbon and labeled with a strict. Achiral: A molecule is achiral if it is superimposable on its mirror image H H Cl Cl Practices on Asymmetric Carbons Example: Identify all asymmetric carbons present in the following compounds. Br Br H OH H H CH2CH3 H C *C C C H Br CH3 * H H H H H H H H H3C Br CH3 * * OH * CH CHCOOH* 3 * * * Fischer Projections: ➢ It is a two-dimensional representation of a three-dimensional organic molecule by projection. -
付表 ⅠA 指定を受けた医薬の有効成分 Annex ⅠA Designated
付表ⅠA 指定を受けた医薬の有効成分 Annex ⅠA Designated Pharmaceutical Active Ingredients 号(Sub-heading) 品名 Description 2818.30 アルゲルドラート algeldrate 2833.22 アルスルフ alusulf 2842.10 アルマシラート almasilate 2842.10 シマルドラート simaldrate 2842.90 硫酸アルマドラ ート almadrate sulfate 2842.90 アルマガート almagate 2842.90 カルバルドラード carbaldrate 2842.90 ヒドロタルシト hydrotalcite 2842.90 マガルドラート magaldrate 2843.30 オーラノフィン auranofin 2843.30 金チオグリカニド aurothioglycanide 2843.30 金チオりんご酸ナトリウム sodium aurothiomalate 2843.30 金チオ硫酸ナトリウム sodium aurotiosulfate 2843.90 カルボプラチン carboplatin 2843.90 シスプラチン cisplatin 2843.90 デキソルマプラチン dexormaplatin 2843.90 エンロプラチン enloplatin 2843.90 イプロプラチン iproplatin 2843.90 ロバプラチン lobaplatin 2843.90 ミボプラチン miboplatin 2843.90 ネダプラチン nedaplatin 2843.90 オルマプラチン ormaplatin 2843.90 オキサリプラチン oxaliplatin 2843.90 セブリプラチン sebriplatin 2843.90 スピロプラチン spiroplatin 2843.90 ゼニプラチン zeniplatin 2844.40 アルツモマブ altumomab 2844.40 塩化セシウム(131Cs) cesium (131 Cs) chloride 2844.40 クロルメロドリン(197Hg) chlormerodrin (197 Hg) 2844.40 シアノコバラミン(57Co) cyanocobalamin (57 Co) 2844.40 シアノコバラミン(58Co) cyanocobalamin (58 Co) 2844.40 シアノコバラミン(60Co) cyanocobalamin (60 Co) 2844.40 エチオダイズド油(131I) ethiodized oil (131 I) 2844.40 くえん酸第二鉄(59Fe)注射液 ferric (59 Fe) citrate in 2844.40 フィブリノゲン(125I) fibrinogen (125 I) 2844.40 フルデオキシグルコー ス(18F) fludeoxyglucose ( 18 F) 2844.40 フルオロドパ(18F) fluorodopa (18 F) 2844.40 くえん酸ガリウム(67Ga) gallium (67 Ga) citrate 2844.40 金コロイド(198Au) gold (198 Au), colloidal 2844.40 イオベングアン(131I) iobenguane (131 I) 2844.40 よう化人血清アルブミン(125I) iodinated (125 I) human serum albumin 2844.40 よう化人血清アルブミン(131I) iodinated -
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. -
Kinetic Modeling of Chiral Amplification and Enantioselectivity Reversal in Asymmetric Reactions
J. Mex. Chem. Soc. 2007, 51(2), 117-121 Article © 2007, Sociedad Química de México ISSN 1870-249X Kinetic Modeling of Chiral Amplification and Enantioselectivity Reversal in Asymmetric Reactions Jesús Rivera Islas and Thomas Buhse* Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Colonia Chamilpa, 62209 Cuernavaca, Morelos, México. Tel/Fax: +52-7773297997, e-mail: [email protected]. Recibido el 30 de marzo de 2007; aceptado el 18 de mayo de 2007 Abstract: Nonlinear effects in asymmetric synthesis and the occa- Resumen: Los efectos no lineales en síntesis asimétrica y la inver- sionally observed reversal of the enantioselectivity of the employed sión de la enantioselectividad del catalizador empleado son evaluados catalyst are evaluated by a generalized kinetic approach. A non-auto- a través de un modelado cinético generalizado. Un sistema reactivo catalytic and an autocatalytic reaction system are considered as two autocatalítico y otro no autocatalítico son considerados como dos different prototype scenarios. It is predicted that during the course of escenarios prototipos diferentes. Se predice que durante el curso de la enantioselectivity reversal in the non-autocatalytic system a gradual inversión de la enantioselectividad en el sistema no autocatalítico transition between both optically active states under loss of chiral ocurre una transición gradual entre los dos estados óptimamente acti- amplification occurs while in the autocatalytic system a sharp transi- vos donde la amplificación quiral decae mientras en el sistema auto- tion under retention of chiral amplification is observed. catalítico ocurre una transición abrupta observándose la retención de Keywords: Asymmetric synthesis, chiral amplification, nonlinear la amplificación quiral. -
United States Patent (19) 11 Patent Number: 5,990,159 Meulemans Et Al
USOO5990159A United States Patent (19) 11 Patent Number: 5,990,159 Meulemans et al. (45) Date of Patent: Nov. 23, 1999 54 USE OF 5HT4 RECEPTOR ANTAGONISTS WO FOR OVERCOMING GASTRONTESTINAL 94.00113A 1/1994 WIPO. EFFECTS OF SEROTONIN REUPTAKE WO INHIBITORS 9408998A 4/1994 WIPO. WO 75 Inventors: Ann Louise Gabrielle Meulemans, 9427987A 12/1994 WIPO. Mol; Jean-Paul René Marie WO André Bosmans, Rijkevorsel, both of 9504737A 2/1995 WIPO. Belgium 73 Assignee: Janssen Pharmaceutica, N.V., Beerse, OTHER PUBLICATIONS Belgium Chemical Abstracts, vol. 122, No. 15, Apr. 10, 1995, 21 Appl. No.: 09/117,974 Abstract No. 178309, A. Lucchelli et al.: “The interaction of 22 PCT Filed: Feb. 7, 1997 antidepressant drugs with central and peripherical enteric 5-HT3 and 5-HT4 receptors”. 86 PCT No.: PCT/EP97/00586 S371 Date: Aug. 11, 1998 Primary Examiner Raymond Henley, III S 102(e) Date: Aug. 11, 1998 Attorney, Agent, or Firm-Ellen Ciambrone Coletti 87 PCT Pub. No.: WO97/29739 57 ABSTRACT PCT Pub. Date: Aug. 21, 1997 The present invention concerns the use of receptor antago 30 Foreign Application Priority Data nists of the 5HT4 receptor for avoiding, alleviating, Sup Feb. 15, 1996 EP European Pat. Off. .............. 962OO38O pressing or overcoming the gastrointestinal Side-effects of Serotonin reuptake inhibitors. The present invention also 51 Int. CI. A61K 31/34; A61K 31/135 concerns pharmaceutical formulations comprising 5HT4 52 U.S. Cl. ............................................. 514/469; 514/651 receptor antagonists for alleviating, Suppressing or overcom 58 Field of Search ...................................... 514/469, 651 ing the gastrointestinal Side-effects of Serotonin reuptake inhibitors, as well as pharmaceutical compositions compris 56) References Cited ing 5HT4 receptor antagonists and Serotonin reuptake FOREIGN PATENT DOCUMENTS inhibitors. -
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. -
Nonlinear Effects in Asymmetric Catalysis: a Personal Account Henri B
888 ACCOUNT Nonlinear Effects in Asymmetric Catalysis: A Personal Account Henri B. Kagan Laboratoire de Synthèse Asymétrique (ESA 8075), Institut de Chimie Moleculaire d’Orsay, Université Paris-Sud, 91405 Orsay, France Fax+33-1-69-15-46-80; E-mail: [email protected] Received 7 April 2001 Dedicated to Professor R. Noyori for his fundamental contributions to organic chemistry and asymmetric catalysis. of diastereomeric aggregate formation). Uskokovic et al. Abstract: The discovery of nonlinear effects (NLE) is recalled, and the main features of NLE are described. The origin of the nonlinear discovered that the nmr spectrum of dihydroquinine race- effects is discussed. The asymmetric amplification is especially mic or enantiopure are not identical, because of diastereo- 14 considered. The concept on nonlinear effects has been extended to meric solute-solute interactions. Horeau and Guetté pseudo-enantiomeric catalysts, to chiral reagents and to kinetic res- discussed in details in 1974 the diastereomeric interac- olution. The use of NLE as a mechanistic tool is underlined. tions in solution between enantiomers.15 In 1976 Wynberg Key words: asymmetric amplification, asymmetric catalysis, and Feringa demonstrated that some diastereoselective re- asymmetric depletion, asymmetric synthesis, chiral auxiliary, non- actions can give a different stereochemical outcome if the linear effects substrates are not enantiomerically pure.16 The authors called this effect “antipodal interaction effect”, it is relat- ed to non-bonded interactions. 1 Introduction In 1985 I was invited by Prof. Agami to give a seminar in Université Paris VI. After my lecture I discussed with This article does not intend to detail the area of nonlinear Prof. -
Catalytic Enantioselective Desymmetrization of Meso
Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents Jérémy Mérad, Mathieu Candy, Jean-Marc Pons, Cyril Bressy To cite this version: Jérémy Mérad, Mathieu Candy, Jean-Marc Pons, Cyril Bressy. Catalytic Enantioselective Desym- metrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents. SYNTHESIS, Georg Thieme Verlag, 2017, 49 (09), pp.1938-1954. 10.1055/s-0036- 1589493. hal-01687264 HAL Id: hal-01687264 https://hal.archives-ouvertes.fr/hal-01687264 Submitted on 18 Jan 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 1938–1954 1938 short review Syn thesis J. Merad et al. Short Review Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral ReaGents OH Jérémy Merad1 HO O Me Mathieu Candy O O Me O Jean-Marc Pons O ( )8 O ( )9 N H H H H Cyril Bressy* MeO Me HO OH -
In Vivo Electrophysiological Recordings of the Effects of Antidepressant Drugs
Experimental Brain Research (2019) 237:1593–1614 https://doi.org/10.1007/s00221-019-05556-5 REVIEW In vivo electrophysiological recordings of the efects of antidepressant drugs Paul J. Fitzgerald1 · Brendon O. Watson1 Received: 9 October 2018 / Accepted: 6 May 2019 / Published online: 11 May 2019 © The Author(s) 2019 Abstract Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic efects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local feld potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic efects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their efects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit fring patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common fnal efects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar efects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. -
Absolute Configuration Determination
Chirality in Pharmaceutical Compounds and Absolute Configuration Determination Crystallization: Screening, Application & Process Development X-ray Diffraction Unit Jordi Benet-Buchholz Barcelona, 11 April 2019 Institut Català d’Investigació Química Av. Països Catalans 16 1 43007 Tarragona (Spain) From chiral crystals to the absolute configuration of molecules: Is it an easy way? (–)-Galiellalactone *S OH R * *S O O *R Orthorhombic , P 2 2 2 Absolute configuration: 1 1 1 R1: 3,45 % 4S, 5aR, 7aR, 7bS Flack: 0.01(19) Hooft/Parsons: -0.06(04)/-0.04(05) • F. Nussbaum, R. Hanke, T. Fahrig, J. Benet-Buchholz; Eur. J. Org. Chem. 2004, 2783-2790. 2 Determination of Absolute Configuration of APIs Definitions in Chirality Precedents Methodologies Single Crystal X-ray Structure Determination: Background Candidate samples Sample and Crystal selection Validation and measurements Examples Final schedule 3 Chirality Definitions in Chirality: An object or a system is chiral if it is distinguishable from its mirror image; that is, it cannot be superposed onto it. The word chirality is derived from the Greek word meaning “hand” Paula Benet The most universally recognized example for chirality are the human hands. Live is chiral 4 Chirality Definitions in Chirality: - Each molecule which cannot be superposed with its mirror image is “chiral”. - Molecules with a mirror plane are called “achiral”. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom (four different substituents) Two mirror images of a chiral molecule are called enantiomers or optical isomers Foto cristall papallona 5 Conglomerate of crystals forming enantiomeric butterflies Chirality Definitions in Chirality: Pairs of enantiomers are often designated as “right- or left-handed”. -
Low Dose Pipamperone in Treating Mood and Anxiety Disorders
(19) & (11) EP 2 236 138 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 06.10.2010 Bulletin 2010/40 A61K 31/4545 (2006.01) A61K 45/06 (2006.01) A61P 25/22 (2006.01) A61P 25/24 (2006.01) (2006.01) (21) Application number: 09156752.9 A61K 31/343 (22) Date of filing: 30.03.2009 (84) Designated Contracting States: • van der Geest, Ronald AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 4835 AA, Breda (BE) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR (74) Representative: De Clercq, Ann G. Y. et al Designated Extension States: De Clercq & Partners cvba AL BA RS Edgard Gevaertdreef 10 a 9830 Sint-Martens-Latem (BE) (71) Applicant: PharmaNeuroBoost N.V. 3570 Alken (BE) Remarks: Claim .17-19,21-24ed to be abandoned due to non- (72) Inventors: payment of the claims fee (Rule 45(3) EPC). • Buntinx, Erik 3570, Alken (BE) (54) Low dose pipamperone in treating mood and anxiety disorders (57) The present invention relates to the use of combinations comprising pipamperone and an SSRI, SNDRI or SNRI and compositions comprising the same for the treatment of mood or anxiety disorders. EP 2 236 138 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 236 138 A1 Description Field of the invention 5 [0001] The invention relates to the field of neuropsychiatry. More specifically, the invention relates to the use of pipamperone in augmenting and in a faster onset of serotonin re- uptake inhibitors, such as SSRIs, SNDRIs and SNRIs, in treating mood and anxiety disorders.