20.10 Conjugate Additions
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Catalytic Direct Asymmetric Michael Reactions
ORGANIC LETTERS 2001 Catalytic Direct Asymmetric Michael Vol. 3, No. 23 Reactions: Taming Naked Aldehyde 3737-3740 Donors Juan M. Betancort and Carlos F. Barbas III* The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 [email protected] Received September 5, 2001 ABSTRACT Direct catalytic enantio- and diastereoselective Michael addition reactions of unmodified aldehydes to nitro olefins using (S)-2-(morpholinomethyl)- pyrrolidine as a catalyst are described. The reactions proceed in good yield (up to 96%) in a highly syn-selective manner (up to 98:2) with enantioselectivities approaching 80%. The resulting γ-formyl nitro compounds are readily converted to chiral, nonracemic 3,4-disubstituted pyrrolidines. The Michael reaction is generally regarded as one of the Typically, carbon nucleophiles that contain an active most efficient carbon-carbon bond forming reactions, and methylene center such as malonic acid esters, â-keto esters, studies concerning this reaction have played an important nitroalkanes, etc. have been studied in the Michael reaction. role in the development of modern synthetic organic Carbonyl compounds, and ketones in particular, have gener- chemistry.1 As the demand for optically active compounds ally only been used as donors following their preactivation has soared in recent years, much progress has been made in by conversion into a more reactive species such as enol or the development of asymmetric variants of this reaction, enamine equivalents.5,6 In these cases, additional synthetic providing for the preparation of Michael adducts with high enantiomeric purity.2 Though remarkable advances have been (3) (a) Chataigner, I.; Gennari, C.; Ongeri, S.; Piarulli, U.; Ceccarelli, S. -
Enantioselective Solvent-Free Robinson Annulation Reactions
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Publications of the IAS Fellows Proc. Indian Acad. Sci. (Chem. Sci.), Vol. 113, No. 3, June 2001, pp 197–213 Ó Indian Academy of Sciences Enantioselective solvent-free Robinson annulation reactions D RAJAGOPAL, R NARAYANAN and S SWAMINATHAN* Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India e-mail: [email protected] MS received 28 March 2001 Abstract. The enantioselective cyclization of the prochiral cyclic substrates 1 to 7 and 26, can be carried out in the neat using S-proline as catalyst. The substrates 18 to 22 and 27 could not be cyclized with S-proline but could be cyclized with a mixture of S-phenylalanine and d-camphorsulphonic acid. The enantioselective cyclization of prochiral acyclic triones 45 and 47 and also the racemic tricarbonyl compounds 54 to 57 could also be carried out in the neat using S-proline as catalyst. The optically active enediones obtained in the above cyclizations could also be obtained directly from 1,3-diones or 2-hydroxymethylene cycloalkanones in a one-pot reaction with methyl vinyl ketone (MVK) and S-proline in the absence of solvents. 13C NMR studies of the one-pot synthesis of S-11 and S-14 reveal that the annulations involve initial formation of an acid-base complex followed by a Michael reaction and then an enantioselective cyclization. Such enantioselective cyclizations probably occur on the surface of S-proline crystals. Keywords. Enantioselective annulation; cyclization; S-proline; S-phenylalanine; d-camphorsulphonic acid. -
Robinson Annulation
Robinson annulation The Robinson annulation is a chemical reaction used in organic Robinson annulation chemistry for ring formation. It was discovered by Robert Robinson Named after Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds.[1] The method uses a ketone and a methyl Reaction type Ring forming vinyl ketone to form an α,β-unsaturated ketone in a cyclohexane ring reaction by a Michael addition followed by an aldol condensation. This Identifiers procedure is one of the key methods to form fused ring systems. Organic robinson-annulation Chemistry Portal RSC ontology RXNO:0000380 ID Formation of cyclohexenone and derivatives are important in chemistry for their application to the synthesis of many natural products and other interesting organic compounds such as antibiotics and steroids.[2] Specifically, the synthesis of cortisone is completed through the use of the Robinson annulation.[3] The initial paper on the Robinson annulation was published by William Rapson and Robert Robinson while Rapson studied at Oxford with professor Robinson. Before their work, cyclohexenone syntheses were not derived from the α,β-unsaturated ketone component. Initial approaches coupled the methyl vinyl ketone with a naphthol to give a naphtholoxide, but this procedure was not sufficient to form the desired cyclohexenone. This was attributed to unsuitable conditions of the reaction.[1] Robinson and Rapson found in 1935 that the interaction between cyclohexanone and α,β-unsaturated ketone afforded the -
Recoverable Phospha-Michael Additions Catalyzed by a 4-N,N
molecules Article Recoverable Phospha-Michael Additions Catalyzed by a 4-N,N-Dimethylaminopyridinium Saccharinate Salt or a Fluorous Long-Chained Pyridine: Two Types of Reusable Base Catalysts Eskedar Tessema 1,†, Vijayanath Elakkat 1,† , Chiao-Fan Chiu 2,3,*, Jing-Hung Zheng 1, Ka Long Chan 1, Chia-Rui Shen 4,5, Peng Zhang 6,* and Norman Lu 1,7,* 1 Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 106, Taiwan; [email protected] (E.T.); [email protected] (V.E.); [email protected] (J.-H.Z.); [email protected] (K.L.C.) 2 Department of Pediatrics, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan 3 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan 4 Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; [email protected] 5 Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan 6 Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA 7 Development Center for Smart Textile, National Taipei University of Technology, Taipei 106, Taiwan Citation: Tessema, E.; Elakkat, V.; * Correspondence: [email protected] (C.-F.C.); [email protected] (P.Z.); Chiu, C.-F.; Zheng, J.-H.; Chan, K.L.; [email protected] (N.L.) Shen, C.-R.; Zhang, P.; Lu, N. † These authors contributed equally to this work. Recoverable Phospha-Michael Additions Catalyzed by a Abstract: Phospha-Michael addition, which is the addition reaction of a phosphorus-based nucle- 4-N,N-Dimethylaminopyridinium ophile to an acceptor-substituted unsaturated bond, certainly represents one of the most versatile and Saccharinate Salt or a Fluorous powerful tools for the formation of P-C bonds, since many different electrophiles and P nucleophiles Long-Chained Pyridine: Two Types can be combined with each other. -
Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione
Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione by Vanessa M. Marx Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Dalhousie University Halifax, Nova Scotia May 2011 © Copyright by Vanessa M. Marx, 2011 DALHOUSIE UNIVERSITY DEPARTMENT OF CHEMISTRY The undersigned hereby certify that they have read and recommend to the Faculty of Graduate Studies for acceptance a thesis entitled “Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione” by Vanessa M. Marx in partial fulfilment of the requirements for the degree of Doctor of Philosophy. Dated: May 19, 2011 Supervisor: _________________________________ Readers: _________________________________ _________________________________ _________________________________ Departmental Representative: _________________________________ ii DALHOUSIE UNIVERSITY DATE: May 19, 2011 AUTHOR: Vanessa M. Marx TITLE: Development of the Interrupted Nazarov Cyclization of Allenyl Vinyl Ketones, with Application to the Total Synthesis of the Cyclooctane Natural Product Roseadione DEPARTMENT OR SCHOOL: Department of Chemistry DEGREE: PhD CONVOCATION: October YEAR: 2011 Permission is herewith granted to Dalhousie University to circulate and to have copied for non-commercial purposes, at its discretion, the above title upon the request of individuals or institutions. I understand that my thesis will be electronically available to the public. The author reserves other publication rights, and neither the thesis nor extensive extracts from it may be printed or otherwise reproduced without the author’s written permission. The author attests that permission has been obtained for the use of any copyrighted material appearing in the thesis (other than the brief excerpts requiring only proper acknowledgement in scholarly writing), and that all such use is clearly acknowledged. -
Electron Deficient Heterocycle. Examples Abound
Pyridines Pyridines are the most commonly encountered π- electron deficient heterocycle. Examples abound. H O 4 N nifedipine 5 3 N NH2 (anti- angina) H CH3 6 2 MeO2C CO2Me N N 1 N NO2 nicotine niacin (nicitinamide) (in NADP) There are many classical syntheses of pyridines; only a few can be covered in the time available. 1. Hantzsch Synthesis Probably the conceptually simples pyridine synthesis would be a simple extension based on the Paal- Knorr pyrrole synthesis. In other words…. Paal-Knorr NH3 R5 R2 5 2 R N R OO H the shouldn't a 1,5-dicarbonyl do.... NH3 [O] 6 2 6 2 R R 6 2 R N R O O R N R H This is absolutely feasible. Furthermore, as you might expect, the 1,5-dicarbonyls are readily accessible by Michael reaction chemistry (1,4-, conjugate additions). The one- pot version of this, where the unsaturated carbonyl is prepared, the Michael reaction occurs, and the pyridine formation is accomplished, is quite common. It is called the Hantzsch synthesis. 4 O O 4 R O NH3 or O R O EtO2C CO2Et R4 NH4OAc EtO + + OEt EtO OEt ∆∆∆ H2O, O O O O OO ** R4 R4 FeCl3 EtO2C CO2Et EtO2C CO2Et ∆∆∆ H2O, N N H It’s rather forceful conditions, but the ester groups can be decarboxylated. The shown example is a symmetric case, but unsymmetrical ones can be done by doing the aldol condensation (here called a Knoevenagel) first, discretely, and then putting that compound (** ) into a separate reaction doing the subsequent steps. -
A Proline-Catalyzed Asymmetric Robinson Annulation Reaction
Tetrahedron Letters 41 (2000) 6951±6954 A proline-catalyzed asymmetric Robinson annulation reaction Tommy Bui and Carlos F. Barbas III* The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA Received 13 June 2000; revised 29 June 2000; accepted 30 June 2000 Abstract A single-step enantioselective synthesis of the Wieland±Miescher ketone (5) is presented. We show that l-proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson annulation reaction. Other chiral amines are identi®ed as catalysts of Michael and aldol addition reactions. # 2000 Elsevier Science Ltd. All rights reserved. Enantiopure Wieland±Miescher (W.M.) ketone (5) has proven to be a particularly useful synthon for the construction a variety of biologically active compounds including steroids, terpenoids, and more recently taxol.1 We recently disclosed an antibody aldolase-catalyzed Robinson annulation reaction of 2-methylcyclohexane-1,3-dione with methyl vinyl ketone in aqueous medium.2 This one-¯ask annulation provided the W.M. ketone in >95% ee. While the antibody eciently catalyzed the cyclodehydration step of this reaction with a rate enhancement exceeding 106, catalysis of the alkylation or Michael addition step was very modest, kcat/kun=125. An intriguing aspect of this study was that both antibody and the traditional catalysts for W.M. ketone preparation, l-proline, use an enamine-based reaction mechanism. Provided the success of antibody catalysis of both steps of the annulation reaction and the reported utility of rubidium salts of l-proline in asymmetric Michael addition reactions,3 we examined the potential of l-proline to catalyze the entire annulation reaction. -
Approach and Synthesis of Strychnos Alkaloids
N° d'ordre : 4155 THÈSE Présentée à L'UNIVERSITÉ BORDEAUX I ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES par Dawood Hosni DAWOOD POUR OBTENIR LE GRADE DE DOCTEUR SPÉCIALITÉ : CHIMIE ORGANIQUE ********************* TOWARDS THE SYNTHESIS OF MONOTERPENOIDS INDOLE ALKALOIDS OF THE ASPIDOSPERMATAN AND STRYCHNAN TYPE ********************* Soutenue le: 17 décembre 2010 Après avis de: MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur Devant la commission d'examen formée de : MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur POISSON Jean-François Chargé de recherche, CNRS Examinateur VINCENT Jean-Marc Directeur de recherche, CNRS Examinateur LANDAIS Yannick Professeur, Bordeaux 1 Directeur de thèse ROBERT Frédéric Chargé de recherche, CNRS Codirecteur de thèse - 2010 - Abbreviations ∆: reflux °C: celsius degrees Ac: acetyle ALB Aluminium Lithium bis(binaphthoxide) complex AIBN : azobis(isobutyronitrile) aq.: aqueous Ar : aromatic BINAP : 2,2'-bis(diphenylphosphino)-1,1'-binaphthyle BINAPO : 2-diphenylphosphino-2'-diphenylphosphinyl-1,1'-binaphthalene BINOL: 1,1’-bi-2-naphthol Boc: tert-butyloxycarbonyle BOX: Bisoxazoline Bz : benzoyle Bn: benzyle cat. : catalytic DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DCC: dicyclohexacarbodiimide dr.: diastereomeric ratio DIBAL-H: diisobutylaluminium hydride DIPEA: diisopropyléthylamine (Hünig Base) DMAP: dimethylaminopyridine DME: dimethoxyethane -
Carbonyl Condensation Reactions
24 Carbonyl Condensation Reactions 24.1 The aldol reaction 24.2 Crossed aldol reactions 24.3 Directed aldol reactions 24.4 Intramolecular aldol reactions 24.5 The Claisen reaction 24.6 The crossed Claisen and related reactions 24.7 The Dieckmann reaction 24.8 The Michael reaction 24.9 The Robinson annulation Ibuprofen is the generic name for the pain reliever known by the trade names of Motrin and Advil. Like aspirin, ibuprofen acts as an anti-infl ammatory agent by blocking the synthesis of prostaglandins from arachidonic acid. One step in a commercial synthesis of ibuprofen involves the reaction of a nucleophilic enolate with an electrophilic carbonyl group. In Chap- ter 24, we learn about the carbon–carbon bond-forming reactions of enolates with carbonyl electrophiles. 916 smi75625_ch24_916-948.indd 916 11/12/09 12:12:52 PM 24.1 The Aldol Reaction 917 In Chapter 24, we examine carbonyl condensations—that is, reactions between two car- bonyl compounds—a second type of reaction that occurs at the α carbon of a carbonyl group. Much of what is presented in Chapter 24 applies principles you have already learned. Many of the reactions may look more complicated than those in previous chapters, but they are fundamen- tally the same. Nucleophiles attack electrophilic carbonyl groups to form the products of nucleo- philic addition or substitution, depending on the structure of the carbonyl starting material. Every reaction in Chapter 24 forms a new carbon–carbon bond at the ` carbon to a carbonyl group, so these reactions are extremely useful in the synthesis of complex natural products. -
Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of Α,Β-Unsaturated Aldehydes
molecules Review Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes Zhonglei Wang 1,2 1 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; [email protected] 2 School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China Academic Editor: Ari Koskinen Received: 12 August 2019; Accepted: 19 September 2019; Published: 19 September 2019 Abstract: Chirality is one of the most important attributes for its presence in a vast majority of bioactive natural products and pharmaceuticals. Asymmetric organocatalysis methods have emerged as a powerful methodology for the construction of highly enantioenriched structural skeletons of the target molecules. Due to their extensive application of organocatalysis in the total synthesis of bioactive molecules and some of them have been used in the industrial synthesis of drugs have attracted increasing interests from chemists. Among the chiral organocatalysts, chiral secondary amines (MacMillan’s catalyst and Jorgensen’s catalyst) have been especially considered attractive strategies because of their impressive efficiency. Herein, we outline advances in the asymmetric total synthesis of natural products and relevant drugs by using the strategy of chiral secondary amine catalyzed reactions of α,β-unsaturated aldehydes in the last eighteen years. Keywords: bioactive natural products; pharmaceuticals; asymmetric total synthesis; chiral secondary amines; α,β-unsaturated aldehydes 1. Introduction In 2000, the MacMillan group [1] first described the fundamental concept of LUMO-lowering iminium-ion activation. In 2005, the Jørgensen group [2,3] reported diarylprolinol silyl ether catalysts, which have also been used in iminium-ion catalysis. -
A Novel Aza-Nazarov Cyclization of Quinazolinonyl Enones: a Facile Access to C- Ring Substituted Vasicinones and Luotonins
A Novel Aza-Nazarov Cyclization of Quinazolinonyl Enones: A Facile Access to C- Ring Substituted Vasicinones and Luotonins Sivappa Rasapalli,a* Vamshikrishna Reddy Sammeta,a Zachary F. Murphy,a Yanchang Huang,a Jeffrey A. Boertha, James A. Golena and Sergey N. Savinovb a Department of Chemistry and Biochemistry, University of Massachusetts, 287 Old Westport Rd, N. Dartmouth, MA-02747, USA. b Department of Biochemistry and Molecular Biology. UMass Amherst, Amherst, MA-01003, USA [email protected] Received Date (will be automatically inserted after manuscript is accepted) ABSTRACT: A facile four-step synthetic access to C-ring substituted luotonins and vasicinones has been realized via a novel super acid mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability and overall polarity of the reaction medium. Quinazolinone is one of the most privileged through inhibition of topoisomerase-I (topo-I), through pharmacophores in medicinal chemistry.1, 2 There are mechanism of action analogous to camptothecin (CPT) more than 20 drugs that are currently in market (3),8 which attracted the attention of medchem and containing thequinazolinone core.3 Additionally, synchem communities alike.9 This increased attention is pharmacologically important natural products harboring partly due to toxic side effects associated with CPT and the quinazolinone core are also abundant and are known its analogs, due to hydrolysis of the E-ring in basic pH to possess wide range of -
The Abnormal Michael Reaction: Scope, Limitations, and Mechanism
Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 1971 The Abnormal Michael Reaction: Scope, Limitations, and Mechanism. William George Haag III Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Recommended Citation Haag, William George III, "The Abnormal Michael Reaction: Scope, Limitations, and Mechanism." (1971). LSU Historical Dissertations and Theses. 2126. https://digitalcommons.lsu.edu/gradschool_disstheses/2126 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Historical Dissertations and Theses by an authorized administrator of LSU Digital Commons. For more information, please contact [email protected]. 72-17,764 HAAG, 3rd., William George, 1946- THE ABNORMAL MICHAEL REACTION: SCOPE, LIMITATIONS, AND MECHANISM. The Louisiana State University and Agricultural and Mechanical College, Ph.D., 1971 Chemistry, organic University Microfilms, A XEROX Company, Ann Arbor, Michigan © 1972 WILLIAM GEORGE HAAG, 3rd. ALL RIGHTS RESERVED THE ABNORMAL MICHAEL REACTION: SCOPE, LIMITATIONS, AND MECHANISM A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Biochemistry by William George Haag, 3rd B.S., Louisiana State University, 1968 December 19JI PLEASE NOTE: Some pages may have indistinct print. Filmed as received. University Microfilms, A Xerox Education Company ACKNOWLEDGMENT The author would like to acknowledge Professor G.E. Risinger for his suggestions, discussion, and encouragement. His ever-present influence made completion of this paper possible.