Chapter 23 Reaction Summary
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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. -
The Claisen Condensation
Lecture 19 The Claisen Condensation •• •• • • O • O • – • CH3COCH2CH3 • CH2 COCH2CH3 March 29, 2016 Chemistry 328N Exam Tomorrow Evening!! Review tonight 5PM -6PM Welch 1.316 Chemistry 328N Some “loose ends” before we go on Spectrosopy of acid derivatives A selective reduction for your tool box Chemistry 328N Reduction of Acid Derivatives Acids (page 679-681) Esters (page 738-739) Please work through the example on 738 Amides (page 739-742) Nitriles (page 742) Selective reductions with NaBH4 Chemistry 328N DIBAlH Diisobutylaluminum hydride (DIBAlH) at -78°C selectively reduces esters to aldehydes •at -78°C, the tetrahedral intermediate does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated Stable at low temperature Chemistry 328N Infrared Spectroscopy C=O stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester, or amide. C=O stretching frequency n O O O O O CH3CCl CH3COCCH3 CH3COCH3 CH3CNH2 1822 cm-1 1748 1736 cm-1 1694 cm-1 and 1815 cm-1 Chemistry 328N Infrared Spectroscopy Anhydrides have two peaks due to C=O stretching. One from symmetrical stretching of the C=O and the other from an antisymmetrical stretch. C=O stretching frequency n O O CH3COCCH3 1748 and 1815 cm-1 Chemistry 328N Infrared Spectroscopy Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching that is “all alone” in the 2210-2260 cm-1 region. Chemistry 328N Hydrolysis and Decarboxylation Chemistry 328N t-Butyl esters Chemistry 328N t-Butyl esters Chemistry 328N t-Butyl ester hydrolysis Note which bond is broken in this hydrolysis !! Chemistry 328N Recall our discussion of the acidity of protons a to carbonyls The anion is stabilized by resonance The better the stabilization, the more acidic the a proton Acidity of a protons on“normal” aldehydes and ketones is about that of alcohols and less than water…pKa ~ 18-20 Some are far more acidic, i.e. -
The Claisen Condensation Is a Carbon–Carbon Bond Forming Reaction That Occurs Between Two Esters Or One Ester and Another Carb
Claisen Ester Condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. Requirements ❖ At least one of the reagents must be enolizable (have an α-proton and be able to undergo deprotonation to form the enolate anion). ❖ There are a number of different combinations of enolizable and nonenolizable carbonyl compounds that form a few different types of Claisen. ❖ The base used must not interfere with the reaction by undergoing nucleophilic substitution or addition with a carbonyl carbon. ❖ For this reason, the conjugate sodium alkoxide base of the alcohol formed (e.g. sodium ethoxide if ethanol is formed) is often used, since the alkoxide is regenerated. ❖ In mixed Claisen condensations, a non-nucleophilic base such as lithium diisopropylamide, or LDA, may be used, since only one compound is enolizable. ❖ LDA is not commonly used in the classic Claisen or Dieckmann condensations due to enolization of the electrophilic ester. ❖ The alkoxy portion of the ester must be a relatively good leaving group. ❖ Methyl and ethyl esters, which yields methoxide and ethoxide, respectively, are commonly used. Types Mechanism ❖ In the first step of the mechanism, an α-proton is removed by a strong base, resulting in the formation of an enolate anion, which is made relatively stable by the delocalization of electrons. ❖ Next, the carbonyl carbon of the (other) ester is nucleophilically attacked by the enolate anion. ❖ The alkoxy group is then eliminated (resulting in (re)generation of the alkoxide), and the alkoxide removes the newly formed doubly α-proton to form a new, highly resonance-stabilized enolate anion. -
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 -
CHEM 330 Topics Discussed on Sept. 18 Principle: a Claisen Condensation Promoted by Nah/Cat. Etoh Takes Place So That All Steps
CHEM 330 Topics Discussed on Sept. 18 Principle: a Claisen condensation promoted by NaH/cat. EtOH takes place so that all steps but the final deprotonation of EtOH by NaH are reversible. Consequently, the system will tend to attain a thermodynamic energy minimum, and the product that forms will be the thermodynamically most favorable one. A reaction occurring under such conditions is said to proceed under thermodynamic control Principle: mixing one equivalent of pure ethyl acetoacetate with excess pure ethanol in the presence of a catalytic amount of EtONa will induce a reverse Claisen condensation ("retro-Claisen"), resulting in conversion of the starting acetoacetate into two molecules of ethyl acetate (the thermodynamically more favorable state of the system): – CH3-CO-CH2-COOEt + EtOH —[ cat. EtO ]—> 2 CH3-COOEt (overall ΔG < 0) Principle of microscopic reversibility: in each step of any given transformation, the forward and the reverse reactions occur along the same mechanistic pathway; i.e., by identical mechanisms operating in reverse Example: a reverse Claisen condensation occurs as follows: O O O O Na + Na + H–OEt OEt OEt OEt pKa ≈ 12 H pKa ≈ 17 + H–OEt + H–OEt 5 Keq ≈ 10 although the above equilibrium is shifted to the right, there will always be some residual free EtO and ethyl acetoacetate in the medium. Under the usual approximations (CHEM 203): –5 –3 [CH3COCH2COOEt] = [EtO ] ≈ 10 ≈ 3•10 – These residual concentrations of EtO( ) and CH3COCH2COOEt are sufficient to induce a slow, but inexorable, reverse reaction. O O O O O O + Na OEt OEt OEt OEt OEt OEt + H–OEt + H–OEt Na + H–OEt O O OEt OEt OEt Na H notice that the reversible reaction depends on proton exchanges among the various species: NaH removes all such protons and suppresses the retro-Claisen process lecture of Sept 18 p. -
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.