DOCSLIB.ORG

Chiral Olefins As Ligands for Asymmetric Catalysis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chiral Olefins As Ligands for Asymmetric Catalysis Chiral Olefins as Ligands for Asymmetric Catalysis M Hui-Wen Shih Group Meeting April 20, 2011 Johnson, J. B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840. Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482. A Brief History ! 1827: Zeise reports first metal-olefin complex H H K H H Cl Pt Cl Cl Zeise's salt ! 1962: Cope prepares the first chiral olefin H H Cl Cl H Pt racemic Pt H Cl NH Cl NH fractional Me Ph crystallization Me Ph Zeise, W. C. Poggendorffs Ann. Phys. 1827, 9, 632. Cope, A. C.; Howell, C. F.; Knowles, A. J. Am. Chem. Soc. 1962, 84, 3191. A Brief History ! 1981: Hosokawa and Murahashi develop catalytic asymmetric reaction with chiral allyl ligand Me Me OAc Pd Me 2 O OH Cu(OAc)2, O2, MeOH ! 2003: Field begins to accelerate with Hayashi's report of chiral diene ligands in rhodium catalysis 3.2 mol% Bn O O 2 Bn R R B(OH)2 R 1.5 mol% [RhCl(C2H4)2]2 R1 R2 R1 Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318. Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11509. Metal-Olefin Binding ! Dewar!Chatt!Duncanson model M M # donation $ back-donation Metal-olefin bond strength is determined by $ back-bonding Back-donation increases with metal principle quantum number ! Comparison of ligand binding energies, "Eint ! "Eint HAu L HAu* L* H H H H Me Me N C O HAu P HAu C HAu HAu HAu N Me HAu Me Me Me N H H H H 26.6 27.6 29.9 34.2 43.8 52.7 Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482. Metal-Olefin Binding ! Olefins have large preparation energies for binding ! "Eint "Eprep XnM L XnM L* L* double bond elongation "Eprep sp2 to sp3 rehybridization ! Factors that affect binding strength strain release > > > entropy O O O substituent electronics > CN > Ph > n-Bu CO2Me sterics > CO2Me Hartley, F. R. Chem. Rev. 1973, 73, 163. Tolman, C. A. J. Am. Chem. Soc. 1974, 96, 2780. Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482. Classes of Chiral Olefins M M !-allyl diene P N M M phosphane-olefin amine-olefin Classes of Chiral Olefins M M !-allyl diene P N M M phosphane-olefin amine-olefin Chiral Allyl Ligands ! 1981: First catalytic asymmetric reaction (Hosokawa and Murahashi, Osaka University) Me Me OAc Pd Me 2 O OH Cu(OAc)2, O2 or t-Bu-OOH MeOH 64% Y, 18% ee 43% Y, 17% ee MeO Me Cl MeOC O O O O 37% Y, 26% ee 63% Y, 21% ee 65% Y, 6% ee 71% Y, 1% ee 16% Y, 22% ee 28% Y, 18% ee 47% Y, 5% ee 38% Y, 0.1% ee Hosokawa, T.; Okuda, C.; Murahashi, S.-I. J. Org. Chem. 1985, 50, 1282. Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318. Chiral Allyl Ligands ! 1981: First catalytic asymmetric reaction (Hosokawa and Murahashi, Osaka University) Me Me OAc Pd Me 2 O OH Cu(OAc)2, O2 or t-Bu-OOH MeOH 64% Y, 18% ee 43% Y, 17% ee Me Me Me Pd Me H Me OAc Pd 2 HO Me OH LPdII LPd-OH Me O LPd-H Hosokawa, T.; Okuda, C.; Murahashi, S.-I. J. Org. Chem. 1985, 50, 1282. Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318. Chiral Allyl Ligands ! 1981: First catalytic asymmetric reaction (Hosokawa and Murahashi, Osaka University) Me Me OAc Pd Me 2 O OH Cu(OAc)2, O2 or t-Bu-OOH MeOH 64% Y, 18% ee 43% Y, 17% ee Me Me Me Me Me Me Pd Me H 1 Pd O 1 Me H HO Ph Modified catalyst Me sits in space under C-1 bridgehead Phenoxy coordination Phenyl blocks space under C-1 olefin is trans to ligand generates opposite enantiomer no enantioselectivity attack occurs from back face Hosokawa, T.; Okuda, C.; Murahashi, S.-I. J. Org. Chem. 1985, 50, 1282. Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318. Chiral Allyl Ligands ! Yamamoto: Pd-allyl complexes for enantioselective allylation Cl Pd 2 R1 X R1 N 5 mol% HN X SnBu3 Me R H THF or DMF, 0 oC R Bn Ph Pr Bn HN HN HN HN Ph Ph Ph c-hex 62% Y, 81% ee 74% Y, 0% ee 62% Y, 70% ee 64% Y, 40% ee Bn Bn Bn Bn HN CO2Me HN CO2Me HN CO2Me HN CO2Me Ph c-hex 2-Nap S 81% Y, 82% ee 63% Y, 60% ee 69% Y, 88% ee 77% Y, 69% ee Fernandes, R. A.; Yamamoto. Y. J. Org. Chem. 2004, 69, 3562. Nakamura, H.; Nakamura, K.; Yamamoto., Y. J. Am. Chem. Soc. 1998, 120, 4242. Chiral Allyl Ligands ! Yamamoto: Pd-allyl complexes for enantioselective allylation Cl Pd 2 SnBu R1 3 R1 N HN 5 mol% Me SiMe R H 3 o R H2O, THF, 0 C TBAF Bn Bn HN HN Ph c-hex N N H H 86% Y, 85% ee 84% Y, 50% ee 63% Y, 18% ee 77% Y, 7% ee Bn Bn Bn HN HN HN HN Ph c-hex Ph 4-pyr 86% Y, 91% ee 86% Y, 52% ee 83% Y, 84% ee 98% Y, 67% ee Fernandes, R. A.; Yamamoto. Y. J. Am. Chem. Soc. 2004, 69, 735. Fernandes, R. A.; Yamamoto., Y. J. Am. Chem. Soc. 2003, 125, 14133. Chiral Allyl Ligands ! Yamamoto: Pd-allyl complexes for enantioselective allylation Cl Pd 2 SnBu R1 3 R1 N HN 5 mol% Me SiMe R H 3 o R H2O, THF, 0 C TBAF Me Me Me Me Me Me Me Me favored disfavored no stereochemical Me Me Pd Me Me Pd Pd bias Pd R N R N N H H N Bn Bn trans-imine Bn cis-imine Bn H H R R Fernandes, R. A.; Yamamoto., Y. J. Am. Chem. Soc. 2003, 125, 14133. Classes of Chiral Olefins M M !-allyl diene P N M M phosphane-olefin amine-olefin Chiral Diene Ligands ! Classes of Chiral Diene Ligands F F F R R F R R R nbd bnd bdd bod R tfb Hayashi Hayashi Hayashi Hayashi Hayashi Me OMe Ph Me OMe Ph R1 Me Ph R Me cod cod Hayashi Carreira Carreira Grützmacher Ar Ar H O MsHN NHMs Me Me H Ar O tetrahydropentalenes Ar Xu, Lin, Laschat Du Du Trauner Rhodium-Catalyzed 1,4-Additions ! Hayashi's Seminal Publication Bn O 3.2 mol% O Bn PhB(OH)2 1.5 mol% [RhCl(C2H4)2]2 Ph o KOH, dioxanes/H2O, 30 C 94% Y, 96% ee O O O O 4-OMeC6H4 2-Np 4-CF3C6H4 n-C5H11 89% Y, 95% ee 96% Y, 96% ee 90% Y, 99% ee 73% Y, 88% ee O O O O Me i-PrO Ph Ph i-Pr Ph i-Pr Ph 88% Y, 88% ee 81% Y, 90% ee 81% Y, 97% ee 73% Y, 92% ee Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. Rhodium-Catalyzed 1,4-Additions ! Hiyashi's Seminal Publication Bn O 3.2 mol% O Bn PhB(OH)2 1.5 mol% [RhCl(C2H4)2]2 Ph o KOH, dioxanes/H2O, 30 C 94% Y, 96% ee ! Norbornadiene ligands are C2-symmetric Bn Ph Bn O Rh O O Ph Rh Bn Rh Ph Ph Bn Ph favored disfavored higher catalytic activity O O better reactivity compared to phosphine ligands Ph Ph Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. Rhodium-Catalyzed 1,4-Additions ! Catalytic cycle H O [Rh] [Rh] O H catalyst resting state 2 -1 Kdimer = 3.8 x 10 M OH [Rh] sol O PhB(OH)2 Ph rate insertion/hydrolysis [Rh(OH)(cod)] transmetallation 2 det. -1 -1 -1 -1 K1 = 16 M s catalyst step K1 = 6.7 M s O B(OH) H2O 3 Ph [Rh] sol Kina, A.; Yasuhara, Y.; Nishimura, T.; Iwamura, H.; Hayashi, T. Chem. Asian J. 2006, 1, 707. Rhodium-Catalyzed 1,4-Additions ! Comparison of reaction kinetics: diene vs. phosphine ligand H O OH transmetallation Ph insertion/ OH [Rh] [Rh] [Rh] [Rh] [Rh] O sol sol sol H hydrolysis catalyst resting state active catalyst 2 -1 -1 -1 -1 -1 [Rh(OH)(cod)]2 Kdimer = 3.8 x 10 M K1 = 6.7 M s K2 = 16 M s 2 -1 -1 -1 [Rh(OH)(binap)]2 Kdimer = 8 x 10 M K1 = 0.5 M s [Rh(OH)(cod)]2 equilibrium content of active catalyst is higher transmetallation occurs faster [Rh(OH)(cod)]2 is 20 times more reactive Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052. Kina, A.; Yasuhara, Y.; Nishimura, T.; Iwamura, H.; Hayashi, T. Chem. Asian J. 2006, 1, 707. Rhodium-Catalyzed 1,4-Additions: Catalyst Loading ! Catalyst loading can be decreased significantly 3.3 mol% Bn O Bn O (S,S)-Bn-bod) PhB(OH)2 1.5 mol% [RhCl(C2H4)2]2 Ph Benchmark PhB(OH)2 catalyst (mol% Rh) yield (%) ee (%) PhB(OH)2 1.0 quant 96 PhB(OH)2 0.1 quant 96 PhB(OH)2 0.05 79 96 PhB(OH) 0.01 0 -- impurity in boronic acid 2 deactivates catalyst (PhBO)3 0.01 quant 96 (PhBO)3 0.005 71 96 Chen, F.-X.; Kina, A.; Hayashi, T.
Load more

Recommended publications
  • Chiral Resolution Screening and Purification Kits Brochure
    Maybridge Chiral Resolution Screening and Purification Kits Offering rapid access to optically pure chiral compounds Maybridge Chiral Resolution Screening and Purification Kits Introduction Diastereomeric crystallization is a commonly used effective process to obtain optically pure chiral compounds from their racemic mixtures. However, choosing the optimal conditions for the process; e.g., combination of resolving agents and solvents, is time-consuming, tedious and labor-intensive. Maybridge Chiral Resolution Screening and Purification kits provide scientists with a quick and systematic approach to find the best separation conditions under which the target compound can be isolated with the highest yield and optical purity. Key features and benefits • Rapid Screening – the kits include 384 different combinations of resolving agents and solvents, increasing the chances of finding the optimal separation conditions • High Performance – development time reduced to one day • Efficient – as little as 0.4mmol of racemate required • Ready to Use – resolving agents and solvents are pre-dispensed in 96-well plates • Convenient – the screening kits provide positive results identifiable by a quick visual or optical inspection, and the purification and recovery kit allows easy recovery and purification of the enantiomers Types of Chiral Resolution Screening and Purification Kits Amount Plate Product name Description Selection guide racemate Product code type required Maybridge Chiral • 4 x 96 plates containing 32 different acidic Identifies optimal
    [Show full text]
  • Cross-Linked Protein Crystal Technology in Bioseparation and Biocatalytic Applications
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Aaltodoc Helsinki University of Technology, Department of Chemical Technology Technical Biochemistry Report 1/2004 Espoo 2004 TKK-BE-8 CROSS-LINKED PROTEIN CRYSTAL TECHNOLOGY IN BIOSEPARATION AND BIOCATALYTIC APPLICATIONS Antti Vuolanto Dissertation for the degree of Doctor in Science in Technology to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium KE 2 (Komppa Auditorium) at Helsinki University of Technology (Espoo, Finland) on the 20th of August, 2004, at 12 noon. Helsinki University of Technology Department of Chemical Technology Laboratory of Bioprocess Engineering Teknillinen korkeakoulu Kemian osasto Bioprosessitekniikan laboratorio Distribution: Helsinki University of Technology Laboratory of Bioprocess Engineering P.O. Box 6100 FIN-02015 HUT Tel. +358-9-4512541 Fax. +358-9-462373 E-mail: [email protected] ©Antti Vuolanto ISBN 951-22-7176-1 (printed) ISBN 951-22-7177-X (pdf) ISSN 0359-6621 Espoo 2004 Vuolanto, Antti. Cross-linked protein crystal technology in bioseparation and biocatalytic applications. Espoo 2004, Helsinki University of Technology. Abstract Chemical cross-linking of protein crystals form an insoluble and active protein matrix. Cross-linked protein crystals (CLPCs) have many excellent properties including high volumetric activity and stability. In this thesis CLPC technology was studied in bioseparation and biocatalytic applications. A novel immunoaffinity separation material, cross-linked antibody crystals (CLAC), was developed in this thesis for enantiospecific separation of a chiral drug, finrozole. Previously, the preparation of an antibody Fab fragment ENA5His capable of enantiospecific affinity separation of the chiral drug has been described.
    [Show full text]
  • Enzyme Supported Crystallization of Chiral Amino Acids
    ISBN 978-3-89336-715-3 40 Band /Volume Gesundheit /Health 40 Gesundheit Enzyme supported crystallization Health Kerstin Würges of chiral amino acids Mitglied der Helmholtz-Gemeinschaft Kerstin Würges Kerstin aminoacids Enzyme supported ofchiral crystallization Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 40 Forschungszentrum Jülich GmbH Institute of Bio- and Geosciences (IBG) Biotechnology (IBG-1) Enzyme supported crystallization of chiral amino acids Kerstin Würges Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 40 ISSN 1866-1785 ISBN 978-3-89336-715-3 Bibliographic information published by the Deutsche Nationalbibliothek. The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.d-nb.de. Publisher and Forschungszentrum Jülich GmbH Distributor: Zentralbibliothek 52425 Jülich Phone +49 (0) 24 61 61-53 68 · Fax +49 (0) 24 61 61-61 03 e-mail: [email protected] Internet: http://www.fz-juelich.de/zb Cover Design: Grafische Medien, Forschungszentrum Jülich GmbH Printer: Grafische Medien, Forschungszentrum Jülich GmbH Copyright: Forschungszentrum Jülich 2011 Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 40 D 61 (Diss. Düsseldorf, Univ., 2011) ISSN 1866-1785 ISBN 978-3-89336-715-3 The complete volume ist freely available on the Internet on the Jülicher Open Access Server (JUWEL) at http://www.fz-juelich.de/zb/juwel Neither this book nor any part of it may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
    [Show full text]
  • APPLICATIONS in ASYMMETRIC SYNTHESIS Carlos
    324 SYNTHESIS OF OCTAHYDROBENZO - 1, 2,3 - DIAZAPHOSPHOLIDINE - 2 - OXIDES AND THEIR DERIVATIVES: APPLICATIONS IN ASYMMETRIC SYNTHESIS DOI: http://dx.medra.org/ 10.17374/targets.2020.23.324 Carlos Cruz - Hernández a , José M. Landeros a , Eusebio Juaristi * a,b a Departamento de Química, Centro de Investigación y de E studios Avanzados, Avenida IPN 2508, 07360 Ciudad de México, Mexico b El Colegio Nacional, Luis González Obregón 23, Centro Histórico, 06020 Ciudad de México, Mexico (e - mail: [email protected]; [email protected]) Abstract. This chapter outlines recent efforts devoted to the synthesis of heterocycles that include the octahydrobenzo - 1,3,2 - diazaphospholidine - 2 - oxide fragment, as well as their application in asymmetri c synthesis. The first part of this review provides a brief discussion of the general structural characteristics of this phosphorus - containing heterocyclic scaffold. The second part describes the synthetic paths that were undertaken to synthesize the desir ed heterocycles , as well as some relevant considerations pertaining the spectroscopic characterization of the phosphorus - containing heterocycles of interest . The third part provides several illustrative examples where the novel chiral heterocycles were employed in ena ntioselective synthesis. The new phosphorus - containing heterocycles proved useful : i) as chiral auxiliaries in nucleophilic addition reactions, as well as as imine activators in electrophilic addition reactions; ii ) as c hiral ligands i n nucleophilic allylation and crotonylation of prochiral aldehydes , and iii) as c hiral organocatalysts in enantioselective aldol, Michael, and cascade reactions. Contents 1. Introduction 2. Synthesis of the octahydrobenzo - 1,3,2 - diazaphospho lidine - 2 - oxide s 2.1 . Conformational and configurational assignments 3 .
    [Show full text]
  • Enantiomeric Resolution and Absolute Configuration of a Chiral Δ-Lactam
    molecules Article Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds 1, 1, 1 1 Roberta Listro y, Giacomo Rossino y, Serena Della Volpe , Rita Stabile , Massimo Boiocchi 2 , Lorenzo Malavasi 3, Daniela Rossi 1,* and Simona Collina 1 1 Department of Drug Sciences, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] (R.L.); [email protected] (G.R.); [email protected] (S.D.V.); [email protected] (R.S.); [email protected] (S.C.) 2 Centro Grandi Strumenti, University of Pavia, via Bassi 21, 27100 Pavia, Italy; [email protected] 3 Department of Chemistry, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Academic Editor: Józef Drabowicz Received: 2 December 2020; Accepted: 18 December 2020; Published: 19 December 2020 Abstract: During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams.
    [Show full text]
  • Spherezymes: a Novel Structured Self-Immobilisation Enzyme
    BMC Biotechnology BioMed Central Research article Open Access Spherezymes: A novel structured self-immobilisation enzyme technology Dean Brady*1, Justin Jordaan1, Clinton Simpson1, Avashnee Chetty2, Cherise Arumugam2 and Francis S Moolman2 Address: 1CSIR Biosciences, Ardeer Road, Modderfontein, 1645 South Africa and 2CSIR Materials Science and Manufacturing, Meiring Naudé Road, Brummeria, Pretoria, 0001 South Africa Email: Dean Brady* - [email protected]; Justin Jordaan - [email protected]; Clinton Simpson - [email protected]; Avashnee Chetty - [email protected]; Cherise Arumugam - [email protected]; Francis S Moolman - [email protected] * Corresponding author Published: 31 January 2008 Received: 8 May 2007 Accepted: 31 January 2008 BMC Biotechnology 2008, 8:8 doi:10.1186/1472-6750-8-8 This article is available from: http://www.biomedcentral.com/1472-6750/8/8 © 2008 Brady et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Enzymes have found extensive and growing application in the field of chemical organic synthesis and resolution of chiral intermediates. In order to stabilise the enzymes and to facilitate their recovery and recycle, they are frequently immobilised. However, immobilisation onto solid supports greatly reduces the volumetric and specific activity of the biocatalysts. An alternative is to form self-immobilised enzyme particles. Results: Through addition of protein cross-linking agents to a water-in-oil emulsion of an aqueous enzyme solution, structured self-immobilised spherical enzyme particles of Pseudomonas fluorescens lipase were formed.
    [Show full text]
  • Distinction of Enantiomers by NMR
    REVIEWS Disinction of enantiomers by NMR spectroscopy using chiral orienting media Burkhard Luy Abstract | NMR spectroscopy is a very important analytical tool in modern organic and inorganic chemistry. Next to the identification of molecules and their structure determination, it is also used for the distinction of enantiomers and the measurement of enantiomeric purity. This article gives a brief review of the techniques being developed for enantiomeric differentiation by virtue of chiral alignment media and their induction of enantiomerically dependent anisotropic NMR parameters like residual dipolar couplings. An overview of existing chiral alignment media, a brief introduction into the basic theory and measurement of the various anisotropic parameters, and several example applications are given. 1. Introduction valuable compounds one doesn’t necessarily want to NMR spectroscopy is one of the most important irreversibly modify the substance. analytical tools in modern organic and inorganic Another possibility for the distinction of chemistry as it is the only tool that allows the enantiomers is the orientation of the molecule of determination of molecular structures at atomic interest in a so-called chiral alignment medium. resolution in solution. It is used to identify the In this case, the molecule is partially aligned constitution, conformation and configuration and anisotropic NMR parameters like residual of countless molecules every day. However, the quadrupolar couplings, residual dipolar couplings magnetic field used for the induction of the Zeeman and residual chemical shift anisotropy can be splitting is per se achiral so that enantiomers measured2–4. As the orientation in a chiral have identical properties and therefore identical alignment medium is different for the two NMR spectra.
    [Show full text]
  • Identifying a Diastereomeric Salt for a Challenging Chiral Resolution
    APPLICATION NOTE Identifying a diastereomeric salt for a challenging chiral resolution Advancing a therapeutic for MMV used Unchained Lab’s high-throughput malaria using the Big Kahuna techniques to deliver successful results in system approximately two weeks to a problem that Researchers at the Medicines for Malaria Ven- they had been trying to solve for more than one year using traditional methods. ture were pursuing a promising candidate for the treatment of malaria when they ran into a road- block. For over a year they attempted to develop a more direct method for isolating a key chiral The mission of MMV is to reduce the burden of intermediate. Until this challenge was overcome, malaria in disease-endemic countries by dis- the program was stalled and could not progress. covering, developing and facilitating the delivery Leveraging the power of Unchained Labs' Big Kahuna of new, effective and affordable anti-malarial system configured for preformulation, they over- drugs. They envision a world in which innovative came this roadblock by identifying and scaling-up medicines will cure and protect the vulnerable a viable chiral resolution method in just two and under-served populations at risk of malar- weeks. ia, and help to ultimately eradicate this terrible disease. In 1999, there were no compounds in the MMV portfolio. Ten years later, MMV had a The Medicines for Malaria robust portfolio consisting of 42 development Venture programs, including four anti-malarial com- Worldwide, 3.3 billion people are at risk for pounds in Phase 3 clinical trials and three com- malaria, which is prevalent in tropical and pounds in registration—all funded solely by MMV.
    [Show full text]
  • The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts
    S S symmetry Article The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts Dorottya Fruzsina Bánhegyi and Emese Pálovics * Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] * Correspondence: [email protected] Abstract: Knowing the eutectic composition of the binary melting point phase diagrams of the diastereomeric salts formed during the given resolution, the achievable F (F = eeDia*Y) value can be calculated. The same value can also be calculated and predicted by knowing the eutectic compositions of the binary melting point phase diagrams of enantiomeric mixtures of the racemic compound or the resolving agent. An explanation was sought as to why and how the crystalline precipitated diastereomeric salt—formed in the solution between a racemic compound and the corresponding resolving agent—may be formed. According to our idea, the self-disproportionation of enantiomers (SDE) has a decisive role when the enantiomers form two nonequal ratios of conformers in solution. The self-organized enantiomers form supramolecular associations having M and P helicity, and double helices are formed. Between these double spirals, with the formation of new double spirals, a dynamic equilibrium is achieved and the salt crystallizes. During this process between acids and bases, chelate structures may also be formed. Acids appear to have a crucial impact on these structures. It is assumed that the behavior of each chiral molecule is determined by its own code. This code validates the combined effect of constituent atoms, bonds, spatial structure, charge distribution, flexibility and complementarity. Citation: Bánhegyi, D.F.; Pálovics, E.
    [Show full text]
  • Chromatographic Studies of Protein-Based Chiral Separations
    separations Review Chromatographic Studies of Protein-Based Chiral Separations Cong Bi, Xiwei Zheng, Shiden Azaria, Sandya Beeram, Zhao Li and David S. Hage * Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA; [email protected] (C.B.); [email protected] (X.Z.); [email protected] (S.A.); [email protected] (S.B.); [email protected] (Z.L.) * Correspondence: [email protected]; Tel.: +1-402-472-2744; Fax: +1-402-472-9402 Academic Editor: W John Lough Received: 12 June 2016; Accepted: 12 August 2016; Published: 5 September 2016 Abstract: The development of separation methods for the analysis and resolution of chiral drugs and solutes has been an area of ongoing interest in pharmaceutical research. The use of proteins as chiral binding agents in high-performance liquid chromatography (HPLC) has been an approach that has received particular attention in such work. This report provides an overview of proteins that have been used as binding agents to create chiral stationary phases (CSPs) and in the use of chromatographic methods to study these materials and protein-based chiral separations. The supports and methods that have been employed to prepare protein-based CSPs will also be discussed and compared. Specific types of CSPs that are considered include those that employ serum transport proteins (e.g., human serum albumin, bovine serum albumin, and alpha1-acid glycoprotein), enzymes (e.g., penicillin G acylase, cellobiohydrolases, and α-chymotrypsin) or other types of proteins (e.g., ovomucoid, antibodies, and avidin or streptavidin). The properties and applications for each type of protein and CSP will also be discussed in terms of their use in chromatography and chiral separations.
    [Show full text]
  • A Review on Chiral Stationary Phases for Separation of Chiral Drugs
    International Journal of Pharmaceutical and Phytopharmacological Research (eIJPPR) | June 2020 | Volume 10 | Issue 3| Page 77-91 Celina Nazareth, A Review on Chiral Stationary Phases for Separation of Chiral Drugs A Review on Chiral Stationary Phases for Separation of Chiral Drugs Celina Nazareth*, Sanelly Pereira Department of Pharmaceutical Chemistry, PES’s Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Goa, India-403401. ABSTRACT The resolution of chiral drugs is important in pharmaceutical analysis. The enantiomers of a chiral drug having identical physical and chemical properties in an achiral environment can be distinguished in a chiral environment provided that there are suitable interactions with a chiral selector. The enantiomers of a chiral drug can act differently with one enantiomer exhibiting pharmacological activity and the other exhibiting undesirable toxic effects. It is therefore critical to separate and analyze racemic drugs. The United States Food and Drug Administration guidelines, therefore, make it mandatory to market only the active enantiomer of chiral drugs. The availability of innovative chiral stationary phases makes the identification of enantiomers faster and effective. This review describes the different chiral stationary phases based on Pirkle type, protein, cyclodextrin, polysaccharide, ligand exchange, macrocyclic antibiotics and chiral crown ethers used in chiral chromatography. The various mechanisms involved in the chiral recognition of enantiomers are summarized. Key Words: Chiral chromatography, chiral stationary phase, racemic drugs, enantiomer separation. eIJPPR 2020; 10(3):77-91 HOW TO CITE THIS ARTICLE: Celina Nazareth, Sanelly Pereira (2020). A Review on Chiral Stationary Phases for Separation of Chiral Drugs 10(3), pp.77-91. “ ”, International Journal of Pharmaceutical and Phytopharmacological Research, INTRODUCTION properties.
    [Show full text]
  • How to Obtain Enantiopure Drug Substance Through Crystallization?
    How to obtain enantiopure drug substance through crystallization? Chirality is defined as the geometric property of an object, like a molecule, of not being superimposable with its mirror image. The two mirror images of a chiral molecule are called enantiomers. Enantiomers have essentially identical physical and chemical properties. However, in chiral environments, such as the receptors and enzymes in the body, enantiomers may behave differently and therefore exhibit different pharmacokinetic properties and exert quantitatively or qualitatively different pharmacological or toxicological effects. Chemical synthesis of chiral molecules usually delivers a racemic mixture, i.e. a 50:50 mixture of two enantiomers. In the past, chiral drugs were usually developed as racemic mixtures since separation into the individual enantiomers was technically difficult to achieve. However, technological advances have opened up the possibility of producing single enantiomers on large scale. Since the development of racemic mixtures raises issues of acceptable manufacturing control and adequate pharmacologic and toxicologic assessment, it has become common practice to develop chiral drugs as single enantiomers rather than as racemic mixtures. The development of procedures to obtain single enantiomers therefore constitute an important component of contemporary development programs for chiral drug substances. Essentially, enantiopure drug substance may be obtained in three ways, namely through separation, asymmetric synthesis or chiral crystallization. Chiral crystallization is an attractive approach in early development, as it is cost-effective, broadly applicable and easily scaled up. Chiral resolution through crystallization may be achieved in several ways. One technique is conversion of the enantiomeric substance into a diastereomeric salt (diastereomeric resolution). Diastereomers are substances that contain more than one chiral center and are not mirror images of one another.
    [Show full text]