Development of Polarized Nazarov Cyclizations Using Lewis Acid Catalysts and Application to the Total Synthesis of (+/-)-Merrilactone A. PDF Download
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Author: Wei He
Publisher:
ISBN: 9780549021780
Category :
Languages : en
Pages : 314
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The polarized Nazarov cyclization methodology was successfully extended to 2-silyloxyfuryl enone systems. The cyclization is efficient, stereospecific and produces a bicyclic system composed of a butenolide that is beta,gamma-fused to a cyclopentane ring. An interesting silicon transfer was observed in this cyclization. Three possible reaction pathways were proposed. However, mechanistic studies only render support to one of them.
Author: Wei He
Publisher:
ISBN: 9780549021780
Category :
Languages : en
Pages : 314
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Book Description
The polarized Nazarov cyclization methodology was successfully extended to 2-silyloxyfuryl enone systems. The cyclization is efficient, stereospecific and produces a bicyclic system composed of a butenolide that is beta,gamma-fused to a cyclopentane ring. An interesting silicon transfer was observed in this cyclization. Three possible reaction pathways were proposed. However, mechanistic studies only render support to one of them.
Author: Shuoliang Li
Publisher:
ISBN: 9781361428160
Category :
Languages : en
Pages :
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Book Description
This dissertation, "Application of the Nazarov Cyclization Reaction to the Synthesis of Guanacastepenes and Taiwaniaquinoids" by Shuoliang, Li, 李碩梁, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled APPLICATION OF THE NAZAROV CYCLIZATION REACTION TO THE SYNTHESIS OF GUANACASTEPENES AND TAIWANIAQUINOIDS Submitted by LI Shuoliang for the degree of Doctor of Philosophy at The University of Hong Kong in December 2006 The guanacastepenes are a novel family of natural products isolated and identified by Clardy in 2000-2001. Guanacastepene A is a potent antibiotic, demonstrating activity against methycillin and vancomycin-resistant strains of Staphylococcus aureus and Enterococcus faecalis. The guanacastepenes are characterized by a [5,7,6] tricyclic ring system with a highly oxidized hemisphere and a hydrophobic southern domain. Synthesis of the guanacastepene framework has been carried out by the application of carbene cyclization cycloaddition cascade (CCCC) reaction to construct the B, C-rings and a Nazarov cyclization to append the A-ring. A model study revealed that the hydroazulene core 1.38a bearing the correct stereochemistry at C11 and C12 of guanacastepene A could be synthesized with 98% yield via the Nazarov reaction of 1.37a using Lewis or Bronsted acids of moderate strength. In addition, a novel carbocationic rearrangement after the Nazarov cyclization of 1.37a which yields spirocyclic [4,5] decenones such as 1.43a with a 93:7 ratio in 96% yield via a secondary pathway, was found to be favored when strong Lewis or Bronsted acids were used instead. The CCCC reaction was used to construct the B, C-rings. Starting from L-glutamic acid, the key diazoketone 2.44c was synthesized in 29 steps. The CCCC reaction of 2.44c occurred under rhodium catalysis to give the desired 2.43c with 53% yield as the major product, which was readily isolated and purified by crystallization. α-Hydroxylation of the C-ring and silyl protection was found to result in an unexpected rearrangement and oxa-bridge opening to give 2.70. Subsequently, decarboxylation, olefination, ring opening and reduction of 2.43c, followed by the addition of the enone moiety generated 2.94. Treatment of 2.94 with boron trifluoride-etherate induced a Nazarov cyclization to furnish a single diastereomeric product 2.93 with 85% yield. Although the structure of this product has not been proven due to the inability to obtain its crystal structure, several characteristics suggest that it bears the tricyclic framework of the guanacastepenes: an NOE profile that shows the syn stereochemistry of the methyl and isopropyl groups on the A-ring, and the existence of dynamic conformers which related diastereomers bearing the wrong relative stereochemistry such as 2.23 do not have. The Nazarov reaction was also applied to the synthesis of members of another family of tricyclic diterpenoids, the taiwaniaquinoids, some of which show antitumor activity. Using commercially available β-cyclocitral, the total synthesis of taiwaniaquinol B was completed in five steps via an aromatic Nazarov reaction of 3.2 to give 3.1 in high yield. Besides the Nazarov reaction strategy, another route was used to generate 3.1 from 3.10 via enone 3.12 using sequential cationic cyclizations. Compound 3.12 was derivatized to 3.13, which completes formal total syntheses of taiwaniaquinol B, and taiwaniaquinone D, H. OTBDPSOO OEt O N 1.37a 1.43a 1.38a 2.44c CO Et O HO CO Et OTBDPS OTBS 2.43c 2.70
Author: Owen Scadeng
Publisher:
ISBN:
Category : Azides
Languages : en
Pages : 259
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Book Description
The five-membered carbocycle is a structural motif found in a plethora of natural products and bioactive compounds. The Nazarov reaction has emerged as an effective method to synthesize cyclopentenones and acts as a tool for adding structural complexity to molecular frameworks. This dissertation will discuss several projects involving the Nazarov cyclization and its use to build functionality to the cyclopentanoid framework. Chapter 1 provides a detailed recount of recent advances in Nazarov chemistry. Focus on methods to induce enantioselectivity, the use of alternative substrates as Nazarov reaction precursors, and the use of the Nazarov reaction in total synthesis is presented. Chapter 2 describes the formation of bridged bicyclic compounds via a [3+3]-cycloaddition between organoazides and the Nazarov intermediate. These cycloadducts were also found to thermally decompose to produce ring-enlarged dihydropyridones and 6-methylenepiperidinones. In Chapter 3, details the attempted development of a domino Nazarov cyclization/Baeyer-Villiger oxidation are provided. While the desired 3,4-dihydropyra-2-one was formed with the use of bis(trimethylsilyl)peroxide as the oxidant, optimization of the transformation failed to produce synthetically useful yields. Chapter 4 divulges the findings of Nazarov cyclizations of 2-hydroxyalkyl-1,4-diene-3-ones. Originally proposed as substrates that could undergo domino Nazarov cyclization/semipinacol rearrangements, these compounds were found to readily produce alkylidene cyclopentenones under Lewis acid conditions. These substrates provided insight into the effect that 2-hydroxyalkyl substituents have on the charge density of the oxyallyl cation intermediate of the Nazarov reaction and subsequent alkene formation.
Author: Vladimir Sofiyev
Publisher:
ISBN:
Category :
Languages : en
Pages : 266
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Book Description
Synthetic studies of the Thio-Nazarov Cyclization Biomimetic Total Syntheses of Shimalactones and Exiguamines Synthesis of Photoswitchable Dopamine Analogs Vladimir Sofiyev Doctor of Philosophy in Chemistry University of California, Berkeley Professor Dirk Trauner, Co-Chair Part 1 of this thesis describes progress towards thio-Nazarov electrocyclization utilizing substrates with a removable docking group, such as alkyl sulfides, for Lewis acid coordination. This work builds on the successful asymmetric catalysis of Nazarov electrocyclization using non-removable docking groups for coordination of Lewis acids. Parts 2 and 3 of this thesis describe the biomimetic syntheses of the natural products shimalactones and exiguamines respectively. While the synthesis of alkaloids exiguamines A and B is an improvement of our previous work, the synthesis of polyketides shimalactones A and B is their first synthesis and describes a novel intramolecular addition of a b-ketolactone across a diene. Both syntheses feature pericyclic reactions in their key step biomimetic cascade reactions. Part 4 of this thesis describes the synthesis of photoswitchable derivatives of dopamine, containing azobenzenes.
Author: Andrew Peter Marcus
Publisher:
ISBN:
Category :
Languages : en
Pages : 584
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Book Description
En route to a total synthesis of tetrapetalone A, we have discovered an unexpected steric facilitation of the Nazarov cyclization of aryl dienyl ketones. Chapter 1 describes the success of the Nazarov cyclization of substrates possessing substituents at both the alpha- and gamma-positions of the acyclic dienone. Substrates possessing only one substituent at either the alpha- or gamma-position proceed much more slowly, or not at all. Density functional theory calculations on the Lewis acid-bound substrates and their respective transition states were performed by Rebecca Davis in the research group of Prof. Dean Tantillo at the University of California, Davis. The computations correlate closely with the observed reactivity. The effect is observed across a series of aryl dienyl ketones with an electron-rich arene portion. Further evidence for this effect was shown by the difficulty of effecting the Nazarov cyclization of a cyclic aryl dienone at room temperature. Chapter 2 describes the application of the findings of the Nazarov study to the synthesis of the indanone portion of tetrapetalone A. Difficulties in differentiation of the C-12 and C-14 positions (tetrapetalone numbering) of the indanone led to the investigation of a meta-bromo-containing aryl dienone, which successfully underwent the Nazarov cyclization with 13:1 regioselectivity. Formation of the C-N bond was achieved by performing a lithium-halogen exchange on the aryl bromide and quenching with tosyl azide, the product of which was then reduced to the free amine using lithium aluminum hydride. Chapter 3 describes the elaboration of the aniline intermediate to a late-stage tetracycle en route to tetrapetalone A. Closure of the tetracycle was achieved by Friedel-Crafts acylation onto a pyrrole in a double oxidation cascade. This sequence is promoted by Dess-Martin periodinane as both the oxidant and the activating agent for the carbonyl moiety. Installation of the angular ethyl group at C-4 was achieved by Birch reduction of the resulting 2-ketopyrrole followed by quenching with iodomethane. The correct substitution pattern on the tetramic acid was achieved following oxidation to the alpha, beta-unsaturated lactam and subsequent copper-mediated conjugate addition of bis(pinacolato)diboron, followed by further oxidation.
Author: Robert Doran
Publisher: Springer
ISBN: 9783319205434
Category : Science
Languages : en
Pages : 0
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Book Description
This thesis addresses two fundamental areas in contemporary organic chemistry: synthesis of natural products and catalytic asymmetric synthesis. Firstly, a new methodology, developed by our research group, which allows the asymmetric synthesis of lactones, a structural unit ubiquitous in natural products, was utilised in the synthesis of a number of natural product analogues that showed significant biological activity. Secondly, the development of a catalytic asymmetric synthesis of a key structural motif present in a number of natural products and pharmaceuticals was accomplished. During the course of this work we discovered dual stereo control, which is significant because it allows the configuration of a new stereo centre to be controlled by a simple change of proton source.
Author: Baofu Zheng
Publisher: Open Dissertation Press
ISBN: 9781361418154
Category :
Languages : en
Pages :
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This dissertation, "Lewis Acid-catalyzed Asymmetric Atom and Group Transfer Radical Cyclization Reactions" by Baofu, Zheng, 鄭保富, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled LEWIS ACID-CATALYZED ASYMMETRIC ATOM AND GROUP TRANSFER RADICAL CYCLIZATION REACTIONS Submitted by Zheng Bao-Fu for the degree of Doctor of Philosophy at The University of Hong Kong in August 2005 Atom and group transfer radical cyclization reactions are powerful tools for the construction of cyclic compounds. The goal of this project is to develop asymmetric atom and group transfer radical cyclization reactions by the application of Lewis acids. (1) A new Lewis acid-catalyzed atom transfer radical cyclization reaction of unsaturated α-bromo oxazolidinone imides has been developed (Scheme 1). In the presence of a Lewis acid such as Mg(ClO ) and Yb(OTf), a series of trans cyclic 4 2 3 products were obtained in high yield (66-87%) from 0 C to room temperature. The loading of strong Lewis acids, such as Yb(OTf), can be reduced to 0.1-0.3 equivalent without significantly compromising the yield. Excellent diastereoselectivities could be achieved by using 1,2-stereocontrol or by chiral oxazolidinone auxiliary. For substrates 2.1d and 2.1e bearing a β-methyl substituent and a chiral auxiliary (S)-(-)-4-benzyl-5,5-dimethyl-2-oxazolidinone, respectively, the diastereomeric ratio of the products was greater than 50:1. (2) Lewis acid-catalyzed enantioselective group transfer radical cyclization reactions of unsaturated α-phenylseleno β-keto esters have been investigated. Unsaturated α-phenylseleno β-keto esters underwent radical cyclization in the presence of a chiral Lewis acid complex [Mg(ClO ) /(S)-t-Bu-Box] in toluene at -78 4 2 C when Et B/O is used as the radical initiator (Scheme 2). A variety of monocyclic 3 2 and bicyclic compounds, which constitute the core structures of many biologically interesting natural products, were obtained in good yields and moderate-to-excellent ee (up to 97%). This result represents the first examples of enantioselective group transfer radical cyclization reactions. (3) The Cu(I)-catalyzed bromine transfer radical cyclizations of a series of olefinic α-bromo 1,3-dicarbonyl compounds have been investigated. α-Monobromo β-keto esters and β-amide esters were found to be suitable substrates. The tandem bromine transfer radical cyclization-intramolecular S 2 reactions catalyzed by CuBr and ligand Me -TREN proceeded smoothly in dichloromethane at room temperature at 0.25 M substrate concentration (Scheme 3). The product formation was rationalized by a catalytic cycle with CuBr as the Br carrier followed by intramolecular S 2 reactions promoted by amine Me -TREN. This method constitutes an alternative approach to the construction of 3-aza-bicyclo[3.1.0]hexan-2-one and 3-aza- bicyclo[3.1.0]heptan-2-one derivatives (Figure 1), which are very important core structures of many biologically important compounds. (4) Bicyclo[3.1.0]hexan-2-one and bicyclo[4.1.0]heptan-2-ones (Figure 2) are versatile intermediates for the synthesis of many biologically active compounds and drugs. A novel and convenient method to prepare bicyclo[3.1.0]hexan-2-one-1- carboxylates has been developed. In the presence of NBS, Me -TREN, and CuBr, β- keto esters 5.1 bearing various olefin substituents were transformed to bicyclo[3.1.0]hexan-2-one-1-carboxylates 5.2 in moderate to good yields (Scheme 4). Scheme 1 Mg(C
Author: Åsa Sjöholm Timén
Publisher:
ISBN: 9789172835702
Category :
Languages : en
Pages : 61
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Author: Marie-Helene Larraufie
Publisher: Springer Science & Business Media
ISBN: 3319013246
Category : Science
Languages : en
Pages : 340
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Book Description
In this dissertation, Marie-Hélène Larraufie develops original radical and pallado-catalyzed methodologies to enable the synthesis of several classes of bioactive nitrogen-containing heterocycles. New radical cascades employing the N-acylcyanamide moiety offer straightforward routes to quinazolinones and guanidines, as well as new insights into the mechanism of homolytic aromatic substitutions. In parallel, Larraufie expands the scope of visible light photoredox catalysis to the ring opening of epoxides and aziridines, thus providing new sustainable alternatives for the generation of radicals. Furthermore, in a collaborative effort with the Catellani group, the author investigates dual palladium/norbornene catalysis. First, she develops a C-amination coupling variant of the Catellani reaction with unprotected amines which provides an expeditious route to phenanthridines. Then, she examines the influence of the chelating effect on Pd(IV) intermediates reactivity with the help of experimental studies and DFT calculations. The work in this thesis has resulted in numerous publications in high impact journals.The clarity and depth of the experimental section will be useful for students and researchers working in this field.
Author: William T. Spencer
Publisher:
ISBN:
Category :
Languages : en
Pages : 1058
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Book Description
"I. Oxidation-Initiated Nazarov Cyclization of Vinyl Alkoxyallenes. This chapter describes the development of an oxidation-triggered Nazarov cyclization of vinyl alkoxyallenes. First, we discuss how a successful use of this reaction in our laboratory's first generation synthesis of (ł)-Rocaglamide stimulated our interest in this transformation. An account of the biosynthetic pathways which proceed via rearrangement of an allene oxide to a cyclopentenone is given, followed by an analysis of earlier synthetic studies on the reaction. We then provide an overview of our efforts on the synthesis of substrates, the screening of conditions, and the eventual optimization of the oxidation-initiated Nazarov cyclization. Examination of substrate scope is rounded out by an analysis of experiments which give insight into the mechanism of the reaction. Finally, a mechanistic hypothesis based on these experiments and observed product diastereochemical outcomes is provided, offering an encouraging glimpse into the potential of the reaction to exhibit chirality memory. II. Efforts Toward an Improved Synthesis of Rocaglamide Amenable to Analog Synthesis. In this chapter, we describe studies conducted toward an improved synthesis of the insecticidal and antiproliferative cyclopenta[b]tetrahydrofuran natural product rocaglamide. First, an overview of the isolation and biosynthesis of the flavaglines, the class of natural products of which rocaglamide is a member, is provided. The insecticidal and anticancer activity of the flavaglines and of rocaglamide in particular are discussed, followed by an examination of the molecular mode of action of this class of natural products. Previous syntheses of rocaglamide are then covered. Efforts toward improving the synthesis of a key benzofuran aldehyde intermediate are presented, followed by discussion of the successful development of a versatile cyclopentenone scaffold formed through a tin-free oxidation-triggered Nazarov cyclization for the synthesis of rocaglamide derivatives. III. A Convenient Cycloaromatization Protocol for Synthesis of Polysubstituted Phenol Derivatives: Method Development and Mechanistic Studies In this chapter, a cycloaromatization method for the synthesis of polysubstituted phenols is described. We explain how this endeavor was sparked during our rocaglamide studies by a serendipitous discovery that benzyltrimethylammonium hydroxide catalyzes the cycloaromatization of a propargylic ether intermediate toward the synthesis of a rocaglamide analog. Then, after discussing existing methods for generating and cycloaromatizing allenyl diene systems, we give an overview on the synthesis of substrates, optimization of the reaction conditions, and screening of various substrates to test the scope of the reaction. Lastly, we analyze a series of mechanistic experiments that suggest the reaction proceeds through an electrocyclization followed by a combination of 1,3-proton transfer and sequential deprotonation-reprotonation"--Leaves vii-viii.
