DOCSLIB.ORG

Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes molecules Review Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes Diego A. Alonso *, Alejandro Baeza *, Rafael Chinchilla *, Cecilia Gómez *, Gabriela Guillena *, Isidro M. Pastor * and Diego J. Ramón * Department of Organic Chemistry and Institute of Organic Synthesis (ISO), Faculty of Sciences, University of Alicante, PO Box 99, 03080 Alicante, Spain * Correspondence: [email protected] (D.A.A.); [email protected] (A.B.); [email protected] (R.C.); [email protected] (C.G.); [email protected] (G.G.); [email protected] (I.M.P); [email protected] (D.J.R.); Tel.: +34-96-590-3822 (R.C.) Academic Editor: Derek J. McPhee Received: 11 May 2017; Accepted: 26 May 2017; Published: 29 May 2017 Abstract: The asymmetric conjugate addition of carbon and heteroatom nucleophiles to nitroalkenes is a very interesting tool for the construction of highly functionalized synthetic building blocks. Thanks to the rapid development of asymmetric organocatalysis, significant progress has been made during the last years in achieving efficiently this process, concerning chiral organocatalysts, substrates and reaction conditions. This review surveys the advances in asymmetric organocatalytic conjugate addition reactions to α,β-unsaturated nitroalkenes developed between 2013 and early 2017. Keywords: nitroalkenes; Michael addition; organocatalysis; asymmetric synthesis 1. Introduction Asymmetric organocatalysis is still a relatively young field for the chemical research community. Thus, not too many years ago, the term ‘catalysis’ was normally associated to transition metal-mediated reactions or to enzyme-aided biocatalysis. However, small organic molecules can achieve remarkably stereoselective and efficient transformations. In addition, the employed organocatalysts are usually of low molecular weight, easy to synthesize, chemically robust, and affordable. Additionally, the organocatalytic reactions are often carried out under virtually ‘open-flask’ conditions. All these reasons have made asymmetric organocatalysis a nowadays fast-forwarding topic, which shows continuous and rapid developments [1–3]. Among all the array of asymmetric organocatalyzed reactions, the conjugate addition reaction of carbon nucleophiles to electron-deficient alkenes is one of the most important ways of creating C-C bonds [4–12]. Particularly, the asymmetric organocatalyzed conjugate addition of carbon nucleophiles to α,β-unsaturated nitroalkenes has attracted considerable attention, as the final enantioenriched γ-nitrocarbonyl compounds can be transformed into compounds of interest [13–17]. The present review covers asymmetric organocatalytic conjugate addition reactions to α,β-unsaturated nitroalkenes published from 2013 till the first quarter of 2017, concerning substrates, organocatalysts and reactions conditions. The review has been classified depending on the nucleophile employed in the conjugate addition. Thus, Michael reactions of carbon nucleophiles such as aldehydes, ketones, 1,3-dicarbonyl compounds, nitroalkanes and heterocycles will be presented, although these systems should be considered as ‘pro-nucleophiles’, the real nucleophiles being enamines, enolates or nitronates. Finally, recent developments in asymmetric organocatalytic enantioselective hetero-Michael reactions will also be considered. Molecules 2017, 22, 895; doi:10.3390/molecules22060895 www.mdpi.com/journal/molecules Molecules 2017, 22, 895 2 of 51 Molecules 2017, 22, 895 2 of 51 2. Carbon Nucleophiles 2. Carbon Nucleophiles Aldehydes and ketones have been the most frequently employed carbon nucleophiles (in fact, pro-nucleophiles)Aldehydes and in theketones asymmetric have been organocatalyzed the most freq Michaeluently employed addition reaction carbon tonucleophiles nitroalkenes. (in Chiral fact, primarypro-nucleophiles) and secondary in the aminesasymmetric have organocatalyzed been used as organocatalysts, Michael addition the presencereaction to of nitroalkenes. additives as co-catalysts,Chiral primary mainly and carboxylicsecondary acids,amines being have frequently been used necessary as organocatalysts, to achieve goodthe presence optical and of additives chemical yields.as co-catalysts, Concerning mainly the mechanismcarboxylic acids, of this being process, frequently although necessary there have to been achieve suggestions good optical that enols and arechemical the involved yields. nucleophilicConcerning species,the mechanism the nowadays of this acceptedprocess, catalyticalthough cycle there for have this been reaction suggestions involves enaminesthat enols asare nucleophiles the involved (Scheme nucleophilic1). Thus, species, the chiral the amine nowadays organocatalyst accepted Acatalyticwould reactcycle withfor this the carbonylreaction compoundinvolves enamines forming anas enaminenucleophilesB (for (Sch primaryeme amines,1). Thus, R 1the= H, chiral initially amine an imine organocatalyst in tautomeric A 1 equilibriumwould react with with the the carbonyl enamine) compound which would forming add an stereoselectively enamine B (for toprimary the nitroolefin, amines, R leading = H, initially to the nitronatean imine adductin tautomericC. This intermediateequilibrium iswith then the hydrolyzed enamine) driving which to would the final addγ-nitrocarbonyl stereoselectively compound to the andnitroolefin, the initial leading amine to organocatalyst. the nitronate Recentadduct mass C. This spectrometry intermediate studies is then support hydrolyzed this mechanism driving [18to ,19the]. Itfinal is interesting γ-nitrocarbonyl to remark compound that formation and the of initial cyclobutane amineD organocatalyst.and 1,2-oxazine RecentN-oxide massE derivatives spectrometry has beenstudies observed support in this this mechanism process, these [18,19]. compounds It is interesting being resting to remark states that of the formation organocatalyst of cyclobutane [20–24]. ItsD formationand 1,2-oxazine would N ‘remove’-oxide E thederivatives amine catalyst has been from observed the cycle, in this which process, would these explain compounds the mentioned being frequentresting states necessity of the oforganocatalyst adding acid [20–24] co-catalysts . Its fo forrmation achieving would good ‘remove’ results. the The amine presence catalyst of from an acid the notcycle, only which would would promote explain a faster the imine-enamine mentioned frequent equilibrium, necessity but also of wouldadding protonate acid co-catalysts the nitronate for Cachieving, blocking good the formationresults. The of presence the D and ofE anas acid byproducts. not only Thiswould could promote also be a achievedfaster imine-enamine internally if theequilibrium, amine catalyst but also bears would an acidic protonate functionality the nitronate [25]. InC, addition, blocking therethe formation are evidences of the that, D atand least E inas somebyproducts. cases, supportThis could the also re-formation be achieved of internally an enamine if the from amine intermediates catalyst bearsC/D an/ Eacidic, with functionality stereoselectivity [25]. nowIn addition, being controlled there are byevidences the diastereoselectivity that, at least in some of enamine cases, protonationsupport the [re-formation26]. Moreover, of thean presenceenamine offrom organic intermediates bases has C/ sometimesD/E, with stereoselectivity shown a positive now effect being as controlled co-catalyst, by as the they diastereoselectivity also can accelerate of theenamine reaction protonation after favoring [26]. Moreover, the creation the of presence the enamine of organic intermediate bases has [27 sometimes]. Furthermore, shown ifa suitablepositive H-formingeffect as co-catalyst, groups are as also they present also can in accelerate the chiral th aminee reaction catalyst after (bifunctional favoring the organocatalysts), creation of the enamine the nitro groupintermediate of thenitroalkene [27]. Furthermore, will be coordinated. if suitable H-form Therefore,ing thegroups enamine are also and thepresent electrophile in the chiral will be amine close enoughcatalyst to(bifunctional get a high enantioinduction. organocatalysts), the nitro group of the nitroalkene will be coordinated. Therefore, the enamine and the electrophile will be close enough to get a high enantioinduction. Scheme 1.1.Catalytic Catalytic cycle cycle of theof the conjugate conjugate addition addition of aldehydes of aldehydes and ketones and toketones nitroalkenes to nitroalkenes promoted bypromoted primary by or primary secondary or secondary chiral amines. chiral amines. In the case of pro-nucleophiles bearing much more acidic α-hydrogens than those on aldehydes In the case of pro-nucleophiles bearing much more acidic α-hydrogens than those on aldehydes and ketones (i.e., in the methylene group of 1,3-dicarbonyl compounds), chiral tertiary amines are and ketones (i.e., in the methylene group of 1,3-dicarbonyl compounds), chiral tertiary amines are usually employed as organocatalysts. Their basic character allows to deprotonate the pro- usually employed as organocatalysts. Their basic character allows to deprotonate the pro-nucleophile, nucleophile, leading to an enolate which coordinates with the protonated base. Similarly to aldehydes leading to an enolate which coordinates with the protonated base. Similarly to aldehydes and ketones, and ketones, if amine-containing bifunctional organocatalysts are employed, the nitro group of the if amine-containing bifunctional organocatalysts are employed, the nitro group of the nitroalkene can nitroalkene can be also
Load more

Recommended publications
  • Stoichiometric Reactions of Enamines Derived from Diphenylprolinol Silyl Ethers with Nitro Olefins and Lessons for the Correspon
    Helvetica Chimica Acta – Vol. 96 (2013) 799 Stoichiometric Reactions of Enamines Derived from Diphenylprolinol Silyl Ethers with Nitro Olefins and Lessons for the Corresponding Organocatalytic Conversions – a Survey1) by Dieter Seebach*, Xiaoyu Sun2a), Marc-Olivier Ebert, W. Bernd Schweizer, Nirupam Purkayastha2b), Albert K. Beck, Jçrg Duschmale´, and Helma Wennemers Laboratorium fr Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH-Zrich, Hçnggerberg HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zrich (phone: þ 41-44-632-2990; fax: þ 41-44-632-1144; e-mail: [email protected]) and Takasuke Mukaiyama2c), Meryem Benohoud2d), and Yujiro Hayashi* Tokyo University of Science, Department of Industrial Chemistry, Faculty of Engineering, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan and Department of Chemistry, Tohoku University, 6-3 Aramaki-Aza, Aoba-ku, Sendai, Miyagi 980-8578, Japan (phone: þ 81-22-795-3554; fax: þ 81-22-795-6566; e-mail: [email protected]) and Markus Reiher* Laboratorium fr Physikalische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH-Zrich, Hçnggerberg HCI F 235, Wolfgang-Pauli-Strasse 10, CH-8093 Zrich (phone: þ 41-44-633-4308; fax: þ 41-44-633-1595; e-mail: [email protected]) Dedicated to Jack D. Dunitz – friend and professor for the professors of LOC – on the occasion of his 90th birthday The stoichiometric reactions of enamines prepared from aldehydes and diphenyl-prolinol silyl ethers (intermediates of numerous organocatalytic processes) with nitro olefins have been investigated. As reported in the last century for simple achiral and chiral enamines, the products are cyclobutanes (4 with monosubstituted nitro-ethenes), dihydro-oxazine N-oxide derivatives (5 with disubstituted nitro- ethenes), and nitro enamines derived from g-nitro aldehydes (6, often formed after longer reaction times).
    [Show full text]
  • 6 Synthesis of N-Alkyl Amino Acids Luigi Aurelio and Andrew B
    j245 6 Synthesis of N-Alkyl Amino Acids Luigi Aurelio and Andrew B. Hughes 6.1 Introduction Among the numerous reactions of nonribosomal peptide synthesis, N-methylation of amino acids is one of the common motifs. Consequently, the chemical research community interested in peptide synthesis and peptide modification has generated a sizeable body of literature focused on the synthesis of N-methyl amino acids (NMA). That literature is summarized herein. Alkyl groups substituted on to nitrogen larger than methyl are exceedingly rare among natural products. However, medicinal chemistry programs and peptide drug development projects are not limited to N-methylation. While being a much smaller body of research, there is a range of methods for the N-alkylation of amino acids and those reports are also covered in this chapter. The literature on N-alkyl, primarily N-methyl amino acids comes about due to the useful properties that the N-methyl group confers on peptides. N-Methylation increases lipophilicity, which has the effect of increasing solubility in nonaqueous solvents and improving membrane permeability. On balance this makes peptides more bioavailable and makes them better therapeutic candidates. One potential disadvantage is the methyl group removes the possibility of hydro- gen bonding and so binding events may be discouraged. It is notable though that the N-methyl group does not fundamentally alter the identity of the amino acid. Some medicinal chemists have taken advantage of this fact to deliberately discourage binding of certain peptides that can still participate in the general or partial chemistry of a peptide. A series of recent papers relating to Alzheimers disease by Doig et al.
    [Show full text]
  • Diarylprolinol Derivatives in Organocatalysis from Another Point of View: Structural Aspects
    Diarylprolinol derivatives in organocatalysis from another point of view: structural aspects Eugenia Marqués-Lópeza* and Raquel P. Herrerab,c* a Technische Universität Dortmund, Organische Chemie. Otto-Hahn-Str. 6. 44227 Dortmund, Germany. b Laboratorio de Síntesis Asimétrica, Departamento de Química Orgánica. Instituto de Ciencia de Materiales de Aragón. Universidad de Zaragoza-CSIC. 50009 Zaragoza, Spain. c ARAID. Fundación Aragón I+D. Gobierno de Aragón, Zaragoza, Spain. e-mails: [email protected], [email protected] Fax: +34 976 762075 and +49 2317555363 1 Abstract The synthesis of complex active molecules has afforded the search for new methods and new processes in organic synthesis. In this context, organic metal free catalysis has appeared as a powerful tool being complementary to metal catalysis in the field of asymmetric synthesis. The success of this methodology has been increasing in the last decade and the research for new organocatalytic systems as well as new applications has attracted the interest of many research groups. Among all organocatalysts, diarylprolinol derivatives have emerged as powerful scaffolds for asymmetric catalysis, proof of that is the huge number of publications reported using this kind of structure as catalysts. However, only in a few cases, different aspects of the catalysts structures and additional additives have been largely studied and a plausible explanation has been given. In this sense, this review treats to illustrate these important and scarce examples and to give a very general vision relating to the application of diarylprolinol derivatives in organocatalytic transformations from another point of view: structural aspects. The influence of catalyst structure, electronic effects, and the use of additives will be the aim of discussion and comment in this work.
    [Show full text]
  • Organocatalysts for Enantioselective Synthesis of Fine Chemicals: Definitions, Trends and Developments Chiara Palumbo* and Matteo Guidotti
    SOR-CHEM Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments Chiara Palumbo* and Matteo Guidotti CNR-Institute of Molecular Sciences and Technologies, Via C. Golgi 19, Milan, Italy *Corresponding author’s e-mail address: [email protected] Published online: 17 December 2014 (version 1); 3 March 2015 (version 2); 23 July 2015 (version 3) Cite as: Palumbo C. and Guidotti M., ScienceOpen Research 2015 (DOI: 10.14293/S2199-1006.1.SOR-CHEM.AGZIIB.v3) Reviewing status: Please note that this article is under continuous review. For the current reviewing status and the latest referee’s comments please click here or scan the QR code at the end of this article. Primary discipline: Chemistry Keywords: Organocatalysts, Asymmetric synthesis, Fine chemicals, Covalent organocatalysis, Non-covalent organocatalysis Hydrogen-bonding, Organic synthesis ABSTRACT the right-handed enantiomer of a chemical or drug. For Organocatalysis, that is the use of small organic molecules to instance, some different fragrances are isomers of the same catalyze organic transformations, has been included among molecule: (S)-(−)-limonene (1) smells like turpentine, whereas the most successful concepts in asymmetric catalysis, and it (R)-(+)-limonene (2) smells like lemon (Figure 1a). One can has been used for the enantioselective construction of C–C, distinguish the two fragrances thanks to our nasal receptors, C–N, C–O, C–S, C–P and C–halide bonds. Since the seminal made of chiral molecules able to recognize the difference works in early 2000, the scientific community has been paying between the two enantiomers. an ever-growing attention to the use of organocatalysts for the Other examples are molecules used by insects as sexual synthesis, with high yields and remarkable stereoselectivities, attractors, pheromones, as well as most of commercialized of optically active fine chemicals of interest for the pharma- drugs.
    [Show full text]
  • Amino Acids. 7.1A a Novel Synthetic Route to L-Proline
    3494 J. Org. Chem. 1986,51, 3494-3498 Amino Acids. 7.1a A Novel Synthetic Route to L-Proline Karlheinz Drauz,*lb Axel Kleemann, Jiirgen Martens, and Paul Scherberich Forschung Chemie Organisch, Degussa AG, 0-6450 Hanau, West Germany Franz Effenberger* Institut fur Organische Chemie der Universitat Stuttgart, 0-7000 Stuttgart 80, West Germany Received April 1, 1986 Reaction of LBoxoproline esters L-2with phosgene at 0 OC gives ~-5,~dichloro-l-(chlorocarbonyl)prolineesters L-6,which readily lose hydrogen chloride to form ~-5-chloro-l-(chloroarbonyl)-4,5-dehydroprolineesters L-7. Catalytic hydrogenation (Pd/C, 180 bar) of L-7yields L-1-(chlorocarbony1)prolineesters L-15and thence, upon hydrolysis, L-proline (~17).A "one-pot reaction" for the whole sequence is described, starting from easily accessible L-5-oxoproline esters and yielding L-proline in 78% overall yield and 99.7% optical purity. Scheme I L-Proline is gaining increasing importance as the central component in pharmaceutical products and agricultural chemicals; several of its derivatives are valuable chiral auxiliary reagents. Some highly active ACE inhibitors, for H H hydrogenotion instance, are derived from L-proline, e.g., CaptopriP and its cyclic analogue2b and Merck's Enalapril.2c Bicyclic hydantoins derived from L-proline are employed as fun- L-J gicide~.~Chiral diamines that can be prepared from either L-proline or L-hydroxyproline in high optical purity have been employed as chiral auxiliary reagents in asymmetric syntheses4 (e.g., (S)-2-(anilinomethyl)pyrrolidine, (2S,2'S)-2-(hydroxymethyl)-l-[(l-methylpyrrolidin-2'-yl)- methyllpyrrolidine, (2S,4S)-2-(anilinomethyl)-l-ethyl-C pyrrolidinone8bor pyrrolidine." A technically interesting hydr~xypyrrolidine,~and (S)- 1-amino-2-(methoxy- variation is the preparation of D,L-proline from acrolein methyl)pyrrolidine)! with HCN and ammonia.8d The disadvantage of all these Until today, L-proline is obtained almost exclusively processes lies in the necessity for a resolution of the from protein hydrolysates by ion-exchange chromatogra- racemate.
    [Show full text]
  • Stereospecific Synthesis of Naphthoindolizidine and Tetrahydrobenzisoquinoline Derivatives Naresh Kumar University of Wollongong
    University of Wollongong Research Online University of Wollongong Thesis Collection University of Wollongong Thesis Collections 1983 Stereospecific synthesis of naphthoindolizidine and tetrahydrobenzisoquinoline derivatives Naresh Kumar University of Wollongong Recommended Citation Kumar, Naresh, Stereospecific synthesis of naphthoindolizidine and tetrahydrobenzisoquinoline derivatives, Doctor of Philosophy thesis, , University of Wollongong, 1983. http://ro.uow.edu.au/theses/2108 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] STEREOSPECIFIC SYNTHESIS OF NAPHTHOINDOLIZIDINE AND TETRAHYDROBENZISOQUINOLINE DERIVATIVES A THESIS submitted in fulfilment of the requirements for admittance to the degree of DOCTOR OF PHILOSOPHY of the UNIVERSITY OF WOLLONGONG by NARESH KUMAR The University of Wollongong P.O. Box 1144, Wollongong N.S.W. 2500 May 1983 TABLE OF CONTENTS SUMMARY INTRODUCTION A. Tylophora and Related Alkaloids B. The Stereochemistry of Phenanthroindolizidines C. Physiological Activity D. Previous Syntheses of Phenanthroindolizidine Alkaloids E. Previous Syntheses of Benzisoquinolines RESULTS AND DISCUSSION A. Aim and Proposed Synthetic Route B. Synthesis of Naphthalenylmethyl Chlorides C. N-Alkylation D. Cyclization Experiments Attempts of Intramolecular Alkylation Attempts of Intramolecular Acylation E. Reduction of Naphthoindolizidinones and Tetrahydrobenzisoquinolinones F. The N.M.R. Spectra of Amino-Acid Derivatives
    [Show full text]
  • Development and Application of New Chiral Β-Amino Alcohols in Synthesis and Catalysis
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 626 _____________________________ _____________________________ Development and Application of New Chiral β-Amino Alcohols in Synthesis and Catalysis Use of 2-Azanorboryl-3-Methanols as Common Intermediates in Synthesis and Catalysis BY PEDRO PINHO ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001 Dissertation for the Degree of Doctor of Philosophy in Organic Chemistry presented at Uppsala University in 2001 ABSTRACT Pinho, P. 2001. Development and Application of New Chiral β-Amino Alcohols in Synthesis and Catalysis. Use of 2-Azanorbornyl-3-Methanols as Common Intermediates in Synthesis and Catalysis. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 626. 43 pp. Uppsala. ISBN 91-554-5091-9. The development and application of unnatural amino alcohols, prepared via hetero-Diels-Alder reactions, in synthesis and catalysis is described. The studies are concerned with the [i] scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents, [ii] application of amino alcohols in the ruthenium transfer hydrogenation of ketones, [iii] use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones, and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i] The use of chiral exo-2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl- amines is described. At the same time the scope of the hetero-Diels-Alder reaction, used in their preparation, is extended by manipulations of the dienophiles. [ii] Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones.
    [Show full text]
  • Amino Alcohol Catalyzed Direct Asymmetric Aldol Reactions: Enantioselective Synthesis of Anti-A-Fluoro-B-Hydroxy Ketones
    Tetrahedron Letters Tetrahedron Letters 45 (2004) 5681–5684 Amino alcohol catalyzed direct asymmetric aldol reactions: enantioselective synthesis of anti-a-fluoro-b-hydroxy ketonesq Guofu Zhong,c,* Junhua Fana,b,c and Carlos F. Barbas, IIIa,b,c,* aThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA bThe Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA cThe Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Received 16 April 2004; revised 19 May 2004; accepted 19 May 2004 Abstract—Prolinol but not proline-(a recently established catalyst of simple intermolecular aldol reactions) was found to be an efficient catalyst for fluoroaldol reactions providing anti-a-fluoro-b-hydroxy ketones with good regio-, diasterio-, and enantio- selectivities. Ó 2004 Elsevier Ltd. All rights reserved. The replacement of hydroxy groups or hydrogen atoms aldehyde acceptor presents significant demands on the in drug molecules with fluorine has long been a strategy catalyst since the reaction can lead to the formation of for modifying their pharmacological activity.1 Due to three different regio- and diastereomeric products and fluorine’s strongly electron withdrawing nature, incor- their enantiomers (Scheme 1). Indeed, indirect regio- poration of fluorine into organic molecules alters their selective routes to the synthesis of racemic fluoroadols chemical and physiological
    [Show full text]
  • Asymmetric Synthesis of Functionalised Pyrrolidines and Their Application in Total Synthesis
    Asymmetric Synthesis of Functionalised Pyrrolidines and their Application in Total Synthesis Christopher James Maddocks Doctor of Philosophy University of York Department of Chemistry December 2020 Abstract The intramolecular aza-Michael reaction has been used effectively in the synthesis of nitrogen heterocycles, with several efforts made in recent years to do so asymmetrically. The selection of the Michael acceptor can play an important role in both the rate and enantioselectivity of the reaction. The research in this thesis demonstrates how the use of a chiral phosphoric acid can catalyse the intramolecular asymmetric aza-Michael reaction of a protected amine with an α,β- unsaturated thioester. The scope of the reaction was demonstrated in the synthesis of 2,2- and 3,3-spirocyclic pyrrolidines in high yields and enantioselectivity (Scheme 1). The synthesis of an unsubstituted pyrrolidine provided the core of two natural products (R)- bgugaine and (R)-irnidine and both succumbed to total synthesis. (R)-Bgugaine was synthesized in a 33% overall yield in 6 steps while (R)-irnidine was synthesized for the first time in an overall yield of 18% over 6 steps. Scheme 1. Asymmetric synthesis of spirocyclic pyrrolidines Scheme 2. Total synthesis of (R)-bgugaine and (R)-irnidine 1 Contents Abstract ...................................................................................................................................... 0 Contents ....................................................................................................................................
    [Show full text]