Toward the Total Synthesis of Norzoanthamine: The Development of a Transannular Michael Reaction Cascade PDF Download
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Author: Haoran Xue
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Norzoanthamine is a complex heptacyclic marine alkaloid isolated from colonial zoanthids. It potently inhibits loss of bone weight and strength in a postmenopausal osteoporosis mouse model, but its mode-of-action remains unknown. The scarcity of this natural product from its natural source and the need to access analogs for structure-activity relationship (SAR) study make it necessary to chemically synthesize this compound. However, the complex molecular skeleton, especially the highly functionalized and stereochemically complex ABC core structure of the natural product poses a significant challenge. As part of our efforts to develop a practical synthetic route to norzoanthamine, we systematically explored a transannular Michael reaction cascade in the context of the synthesis of angular 6-6-6 tricyclic ring system, a mimic of the ABC core structure of norzoanthamine. Using 1,7-bis-enones in the form of 14-membered macrocyclic lactone as model substrates, we demonstrated that both E,Z- and E,E-macrocycles underwent facile transannular reactions to give cis-syn-cis and trans-anti-trans ring systems, respectively. However, Z,E- and Z,Z- macrocycles did not cyclize under similar reactions. The similarities and differences between transannular Diels-Alder reactions and this transannular cyclization process were also disclosed. Building upon these preliminary studies, we developed a 12-linear step synthesis of the ABC carbocyclic core of norzoanthamine. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling based on selective alkylation of a bis-enolate, and a transannular Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core. Subsequent Claisen rearrangement enabled installation of a handle for introduction of the bottom piece to complete the total synthesis. Other efforts toward the total synthesis have also been discussed. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/149334
Author: Haoran Xue
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Norzoanthamine is a complex heptacyclic marine alkaloid isolated from colonial zoanthids. It potently inhibits loss of bone weight and strength in a postmenopausal osteoporosis mouse model, but its mode-of-action remains unknown. The scarcity of this natural product from its natural source and the need to access analogs for structure-activity relationship (SAR) study make it necessary to chemically synthesize this compound. However, the complex molecular skeleton, especially the highly functionalized and stereochemically complex ABC core structure of the natural product poses a significant challenge. As part of our efforts to develop a practical synthetic route to norzoanthamine, we systematically explored a transannular Michael reaction cascade in the context of the synthesis of angular 6-6-6 tricyclic ring system, a mimic of the ABC core structure of norzoanthamine. Using 1,7-bis-enones in the form of 14-membered macrocyclic lactone as model substrates, we demonstrated that both E,Z- and E,E-macrocycles underwent facile transannular reactions to give cis-syn-cis and trans-anti-trans ring systems, respectively. However, Z,E- and Z,Z- macrocycles did not cyclize under similar reactions. The similarities and differences between transannular Diels-Alder reactions and this transannular cyclization process were also disclosed. Building upon these preliminary studies, we developed a 12-linear step synthesis of the ABC carbocyclic core of norzoanthamine. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling based on selective alkylation of a bis-enolate, and a transannular Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core. Subsequent Claisen rearrangement enabled installation of a handle for introduction of the bottom piece to complete the total synthesis. Other efforts toward the total synthesis have also been discussed. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/149334
Author: Miguel A. Sierra
Publisher: Wiley-VCH
ISBN: 9783527654635
Category : Science
Languages : en
Pages : 288
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Book Description
Success comes in many forms and in synthesis it can be a failure that results in their ultimate successful solutions. This long-awaited sequel to "Dead Ends and Detours" retains the proven concept while featuring over 20 new case studies of failed strategies and their (successful) solutions in natural product total synthesis. Additionally, computational models are used to discuss the problem in much more detail and to provide readers with additional information not found in the primary literature. The topics range from classic synthetic reactions (e.g. Diels Alder reaction), metal-mediated coupling reactions, metathesis, and asymmetric catalysis to the importance of protecting and activating groups. This book will benefit not only graduate students in organic chemistry but also advanced researchers as they gain knowledge derived from the step-by-step analysis of mistakes made in the past and, thus be able to improve their own chemical reaction planning. With its coverage of the most commonly applied reaction types, the book perfectly complements its predecessor, which focuses on general aspects, such as reactivity and selectivity.
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Author: Stephen Michael Canham
Publisher:
ISBN: 9781267232779
Category :
Languages : en
Pages : 417
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Book Description
An important objective in organic synthesis is the rapid development of molecular complexity in a stereocontrolled manner. The Prins-pinacol cascade reaction developed in the Overman laboratories allows the concise stereocontrolled synthesis of a variety of complex heterocycles, and has been implemented in the synthesis of several natural products. While pinacol-terminated Prins cyclizations have successfully enabled the expedient generation of many complex carbocyclic and heterocyclic compounds, there are several limitations to their utility. The research reported in this dissertation provides additional insight into the scope and limitation of the Prins-pinacol reaction in the context of two natural product total syntheses. Chapter 1 describes the successful total synthesis of the Lycopodium alkaloid (+)-sieboldine A.A number of pinacol-terminated cyclizations, including a Prins-pinacol cascade, were examined to form the cis-hydrindanone core of sieboldine A. Of these, the mild Au(I) activation of an alkyne to promote a 1,6-enyne cyclization terminated by a semipinacol rearrangement proved to be the most synthetically useful. Formation of the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N, O-acetal of sieboldine A was a substantial challenge. In the end, activation of a thioglycoside precursor enabled a remarkably efficient cyclization, which ultimately led to the first enantioselective total synthesis of (+)-sieboldine A. Chapter 2 describes mechanistic investigations conducted to rationalize the unexplained stereochemical outcome of an intended Prins-pinacol cascade reaction for construction of the 8-oxabicyclo[3.2.1]octane ring system of (+)-aspergillin PZ. Deuterium labeling of the precursor substrate provided the first unambiguous evidence of a competitive 2-oxonia[3,3]sigmatropic/aldol mechanism to the desired Prins-pinacol reaction.
Author: Céline Joie
Publisher:
ISBN: 9783843916844
Category :
Languages : de
Pages : 155
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Author: Jie Jack Li
Publisher: Springer Science & Business Media
ISBN: 3642340652
Category : Science
Languages : en
Pages : 292
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Book Description
'Total Synthesis of Natural Products' is written and edited by some of today's leaders in organic chemistry. Eleven chapters cover a range of natural products, from steroids to alkaloids. Each chapter contains an introduction to the natural product in question, descriptions of its biological and pharmacological properties and outlines of total synthesis procedures already carried out. Particular emphasis is placed on novel methodologies developed by the respective authors and their research groups. This text is ideal for graduate and advanced undergraduate students, as well as organic chemists in academia and industry.
Author: W. Carruthers
Publisher: Elsevier
ISBN: 008091232X
Category : Science
Languages : en
Pages : 382
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Book Description
Demonstrates the wide scope of cycloaddition reactions, including the Diels-Alder reaction, the ene reaction, 1,3-dipolar cycloadditions and [2+2] cycloadditions in organic synthesis. The author, a leading exponent of the subject, illustrates the ways in which they can be employed in the synthesis of a wide range of carbocyclic and heterocyclic compounds, including a variety of natural products of various types. Special attention is given to intramolecular reactions, which often provide a rapid and efficient route to polycyclic compounds, and to the stereochemistry of the reactions, including recent and developing work on enantioselective synthesis.
Author: Douglass F. Taber
Publisher: Oxford University Press
ISBN: 0190646160
Category : Science
Languages : en
Pages : 289
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Book Description
A collection of Douglass Taber's columns originally published between 2013 - 2015 at www.organicchemistry.org
Author: Michael P. Doyle
Publisher: Academic Press
ISBN: 9780127863689
Category : Reduction (Chemistry)
Languages : en
Pages : 0
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Author: Robertus J. M. Klein Gebbink
Publisher: John Wiley & Sons
ISBN: 3527340610
Category : Technology & Engineering
Languages : en
Pages : 610
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Book Description
An expert overview of current research, applications, and economic and environmental advantages The study and development of new homogeneous catalysts based on first-row metals (Mn, Fe, Co, Ni, and Cu) has grown significantly due to the economic and environmental advantages that non-noble metals present. Base metals offer reduced cost, greater supply, and lower toxicity levels than noble metals?enabling greater opportunity for scientific investigation and increased development of practical applications. Non-Noble Metal Catalysis provides an authoritative survey of the field, from fundamental concepts and computational methods to industrial applications and reaction classes. Recognized experts in organometallic chemistry and homogeneous catalysis, the authors present a comprehensive overview of the conceptual and practical aspects of non-noble metal catalysts. Examination of topics including non-innocent ligands, proton-coupled electron transfer, and multi-nuclear complexes provide essential background information, while areas such as kinetic lability and lifetimes of intermediates reflect current research and shifting trends in the field. This timely book demonstrates the efficacy of base metal catalysts in the pharmaceutical, fine-chemical, and agrochemical industries, addressing both environmental and economic concerns. Providing essential conceptual and practical exploration, this valuable resource: -Illustrates how unravelling new reactivity patterns can lead to new catalysts and new applications -Highlights the multiple advantages of using non-noble metals in homogenous catalysis -Demonstrates how the availability of non-noble metal catalysis reduces costs and leads to immense savings for the chemical industry -Reveals how non-noble metal catalysis are more sustainable than noble metals such as palladium or platinum Non-Noble Metal Catalysis: Molecular Approaches and Reactions is an indispensable source of up-to-date information for catalytic chemists, organic chemists, industrial chemists, organometallic chemists, and those seeking to broaden their knowledge of catalytic chemistry.
Author: Debabrata Maiti
Publisher: John Wiley & Sons
ISBN: 3527346678
Category : Science
Languages : en
Pages : 450
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Book Description
A guide to contemporary advancements in the field of distal C-H functionalizations An important and dynamic topic within the modern field of organic synthesis, selective functionalization of C-H bonds can be used in a variety of applications across the pharmaceutical and agrochemical industries. Remote C-H Bond Functionalizations presents an inclusive account of the most recent developments and potential applications of performing variegated functionalizations selectively at the distal positions of organic compounds. Featuring contributions by an international team of experts, this authoritative volume provides deep insight into distal functionalizations, including detailed discussion of mechanisms, the engineering of templates, and the design of strategies. The text covers a diverse range of topics including C-H functionalization of palladium/norbornene catalysis, ruthenium-catalyzed remote functionalization, the non-directed distal C(sp2)-H, functionalization, transition metal catalyzed distal para-selective C-H functionalization, and much more. Reviewing contemporary advancements in the field while laying the foundation for future research, this important resource: Provides the most recent research and thorough coverage of the subject available in a single volume Offers practical information on C-H functionalizations in various industries Includes an up-to-date introduction to distal C-H functionalizations Remote C-H Bond Functionalizations is a must-read for every synthetic chemist, including chemists working with organometallics, organic chemists and researchers, and industrial chemists.
