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Total Synthesis of Cephalotaxus Alkaloids and Synthetic Studies Toward Bazzanin K

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Total Synthesis of Cephalotaxus Alkaloids and Synthetic Studies Toward Bazzanin K AN ABSTRACT OF THE DISSERTATION OF Xuan Ju for the degree of Doctor of Philosophy in Chemistry presented on May 22, 2019. Title: Total Synthesis of Cephalotaxus Alkaloids and Synthetic Studies toward Bazzanin K Abstract approved: ______________________________________________________ Christopher M. Beaudry Dearomatization reactions exist broadly in biosynthesis and chemical synthesis. The highly functionalized atoms of arenes can be masked by it aromaticity, and upon dearomatization, those reactive atoms can be readily applied to bond formation and further manipulation. The total synthesis of (–)-cephalotaxine and (–)- homoharringtonine is described via an oxidative furan opening-spontaneous transannular Mannich reaction. The first generation route involved the development of coupling reaction between 3-methoxyfuran-2-carboxylate and bromide to form diarylmethane. Due to the lack of electrophilicity in the ester functionality, the formation of a macrocycle was not observed. The second generation route utilized a Friedel-Crafts alkylation to avoid this problem, enabling the preparation of the macrocycle for the key transformation. Racemic cephalotaxinone was obtained by the oxidative furan opening-spontaneous transannular Mannnich reaction of the macrocycle. A Noyori asymmetric hydrogenation converted racemic cephalotaxinone to (–)-cephalotaxine in excellent yield and enantioselectivity (krel=278), (–)- cephalotaxine was advanced to (–)-homoharringtonine via a three-step sequence. The undesired enantiomer of cephalotaxinone could be recycled through an acid-mediated racemization. Molecular chirality plays a critical role in chemistry, biology, and medicine. Identification of chirality in molecules without sp3-hybridized stereogenic carbon atoms is not straightforward. Bazzanin K is a macrocyclic bis(bibenzyls) with diastereotopic protons at its two methylene position, indicating the possibility of conformational chirality. We describe a synthetic approach toward bazzanin K by a double Suzuki coupling. Sequential Suzuki couplings were tested and the desired terphenyl was isolated as two disastereomers. Ring closing metathesis of terphenyls furnished the phenanthrene moiety of Bazzanin K. The one-pot three-component Suzuki coupling reaction is under investigation. ©Copyright by Xuan Ju May 22, 2019 All Rights Reserved Total Synthesis of Cephalotaxus Alkaloids and Synthetic Studies toward Bazzanin K by Xuan Ju A DISSERTATION submitted to Oregon State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Presented May 22, 2019 Commencement June 2020 Doctor of Philosophy dissertation of Xuan Ju presented on May 22, 2019 APPROVED: Major Professor, representing Chemistry Head of the Department of Chemistry Dean of the Graduate School I understand that my dissertation will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my dissertation to any reader upon request. Xuan Ju, Author ACKNOWLEDGEMENTS I would like to express my thanks to my parents for their love and unconditional support through my graduate career at Oregon State University. I would like to thank my advisor, Professor Chris Beaudry, for his guidance over the last six years. He taught me the knowledge of conducting scientific researches and methods of solving problems critically. His mentorship has greatly contributed to my success in this program. I would also like to thank both past and present members of the Beaudry research group and members of the organic chemistry division for their support, especially Yi Lu and Xiaojie Zhang for their encouragement, support and friendship of throughout my degree program. CONTRIBUTION OF AUTHORS Patrick Salvo assisted with data collection for chapter 5. TABLE OF CONTENTS Page 1 Introduction and Background……………………………………………………….1 1.1 Introduction of Dearomatization Reaction……………………………………...1 1.2 Dearomatization in the Syntheses of Strychnine……………………………….2 1.3 Dearomatization Researches in the Beaudry group…………….………………4 2 Introduction of Cephalotaxine and Overview of the Previous Total Syntheses.........7 2.1 Isolation of Cephalotaxine and Homoharringtonine ……………………….......7 2.2 Chronic Myeloid Leukemia (CML)……………………………………….........7 2.3 Previous Total Syntheses of Cephalotaxine ………………………………........9 2.3.1 Sequential Construction - Construction of D/E ring, then C ring……........9 2.3.2 Sequential Construction - Construction of C/E ring, then D ring…..........11 2.3.3 Sequential Construction - Construction of C/D ring, then E ring……......12 2.3.4 Construction of Two Rings in One Step……….….….…………….........14 3 First Generation Route Toward (–)-Cephalotaxine and (–)-Homoharringtonine….18 3.1 Retrosynthetic Analysis of Cephalotaxine: First Generation Route…………..18 3.2 Preparation of Furan…………………………………………………………..18 3.3 Synthetic Efforts toward Macrocycle…………………………………………20 3.4 Supplemental Data……………………………………………………….........23 4 Total Synthesis of (–)-Cephalotaxine and (–)-Homoharringtonine: Second Generation Route…………………………………………………………………….41 4.1 Retrosynthetic Analysis of Cephalotaxine: Second Generation Route………..41 4.2 Preparation of the Macrocycle………………………………………………...41 TABLE OF CONTENTS (Continued) Page 4.3 Synthesis of Cephalotaxinone via Furan oxidation-Transannular Mannich Reaction ……………………………………………………………………………..44 4.4 Total Synthesis of (–)-Cephalotaxine and (–)-Homoharringtonine…………...47 4.5 Future Plan…………………………………………………………………….50 4.6 Supplemental Data ……………………………………………………………51 5 Introduction and Synthetic Studies toward Bazzanin K…………………………...95 5.1 Conformational Chirality……………………………………………………...95 5.2 Introduction of Macrocyclic Bisbibenzyls…………………………………….96 5.3 Introduction of Bazzanin K……………………………………………………97 5.4 Retrosynthetic Analysis……………………………………………………….98 5.5 Synthesis of Boronic Esters…………………………………………………...99 5.6 Sequential Suzuki Cross Couplings………………………………………….100 5.7 Double Suzuki Coupling……………………………………………………..103 5.8 Ring Closing Metathesis……………………………………………………..104 5.9 Supplemental Data…………………………………………………………...105 6 Summary and Furture Work……………………………………………………...139 LIST OF FIGURES Figure Page 2.1 Cephalotaxus Alkaloids …………………………………………………………..7 2.2 Philadelphia Chromosome and Imatinib (Gleevec)……………………………….8 2.3 Mechanism of Action of HHT ……………………………………………………8 2.4 C/D/E Ring System of Cephalotaxine……………………………………….……9 4.1 Binding Site of Narcilasine, Lycorine and Homoharringtonine…………………50 5.1 Recent Conformational Chirality Researches in Beaudry Group………………..95 5.2 Three Types of MBBs……………………………………………………………96 5.3 Structure of Asterelin A, Cavicularin and Bazzanin K…………………………..97 5.4 Structure of Bazzanin K and Cavicularin…………………….………………….97 5.5 Stereochemical Analysis of Terphenyl via NOESY Correlation Spectroscopy..103 LIST OF TABLES Table Page 4.1 Reaction Condition Screen for the Friedel–Crafts Alkylation…………………...43 4.2 Reaction Conditions Screened for Synthesizing Cephlotaxinone………………..45 4.3 Previous Total Syntheses of Cephalotaxine………………………………………49 5.1 Reaction Conditions Screen for First Suzuki Coupling………………………….101 5.2 Reaction Conditions Screen for Second Suzuki Coupling………………………102 LIST OF SCHEMES Scheme Page 1.1 Examples of Dearomatization………………….………………………………….1 1.2 Dearomatization in Woodward’s Total Synthesis of Strychnine………………….3 1.3 Dearomatization in Vanderwal’s Total Synthesis of Strychnine……….…………3 1.4 Dearomatization in the Total Synthesis of Cavicularin …………………………..4 1.5 Dearomatization in the Total synthesis of Arundamine…………………………..5 2.1 Semmelhack’s Total Synthesis of (±)-Cephalotaxine……………………………10 2.2 Mori’s Total Synthesis of (–)-Cephalotaxine……………………………………10 2.3 Chandrasekhar’s Total Synthesis of (±)-Cephalotaxine…………………………11 2.4 Gin’s Total Synthesis of (–)-Cephalotaxine……………………………………..11 2.5 Fuchs’ Total Synthesis of (±)-Cephalotaxine……………………………………12 2.6 Weinreb’s Total Synthesis of (±)-Cephalotaxine………………………………..13 2.7 Hanaoko’s Total Synthesis of (±)-Cephalotaxine………………………………..13 2.8 Li’s Formal Synthesis of (–)-Cephalotaxine……………………………………..14 2.9 Mariano’s Total Synthesis of (±)-Cephalotaxine………………………………...14 2.10 Li’s Total Synthesis of (±)-Cephalotaxine……………………………………...15 2.11 Ishibashi’s Total Synthesis of (–)-Cephalotaxine………………………………15 3.1 Retrosynthetic Analysis of Cephalotaxine……………………………………….18 3.2 Wasserman-based Furan Synthesis………………………………………………19 3.3 Alternative Way of Preparing the Furan…………………………………………20 3.4 Efforts toward Reduction of the Ester…………………………………………...20 3.5 Conversion of Ester to Other Functionalities……………………………………21 LIST OF SCHEMES (Continued) Scheme Page 3.6 Coupling Conditions for Preparing Diarylmethanes……………………………..21 3.7 Attempted Diarylmethane Synthesis……………………………………………..22 4.1 Retrosynthetic Analysis of Cephalotaxine: Second Generation Route…………..41 4.2 Preparation of the Furan and Benzyl Chloride ………………………………….42 4.3 Conditions for Removal of TBS Group………………………………………….43 4.4 Base-mediated Cyclization to Form the Macrocycle…………………………….44 4.5 Proposed Mechanism to Enamine 123 and Amine 124………………………….46 4.6 Racemic Synthesis of Cephalotaxinone………………………………………….46 4.7 Attempts to Synthesize (–)-Cephalotaxinone with Chiral Acids………………...47 4.8 Kinetic Resolution of Cephalotaxinone………………………………………….48 4.9 Racemization of (+)-Cephalotaxinone…………………………………………...48 5.1 Retrosynthetic Analysis of Bazzanin K………………………………………….98 5.2 Preparation of Boronic Ester 141………………………………………………...99 5.3 Preparation of Boronic Ester 142……………………………………………….100 5.4
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