Tổng hợp định hướng sử dụng giàn epoxyquinoid - Xiaoguang Lei

BOSTON UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES Dissertation TARGET AND DIVERSITY-ORIENTED SYNTHESIS USING EPOXYQUINOID SCAFFOLDS by XIAOGUANG LEI B., Peking University, 2001 Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2007 UMI Number: 3240630 Copyright 2006 by Lei, Xiaoguang All rights reserved. INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted.

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ProQuest Information and Learning Company 300 North Zeeb Road P. Box 1346 Ann Arbor, MI 48106-1346 © Copyright by XIAOGUANG LEI 2006 Approved by First Reader S< Second Reader This Dissertation is dedicated to my wife Jing Zhou, and to my parents #89 and 4E iv ACKNOWLEDGEMENTS First and foremost, I would like very much to thank my research advisor, Professor John A. for his great mentorship, faithful support and constant encouragement toward my Ph. John’s contagious enthusiasm for synthetic organic chemistry motivated me to embark on my scientific career in his research group, and his continuous pursuit for creative and independent thoughts as well as his diligent purposefulness for overcoming challenges in the scientific research has been inspiring me for my career as a synthetic chemist.

It has been a privilege to work under his instruction and it definitely has been one of the most precious memories in my life. I am very grateful to Professor James S. Panek for his helpful suggestions on my manuscripts, and his critical reading of this dissertation. I would also like to thank Professor Scott S.

Schaus, Professor John K. Snyder, and Professor Sean J. Elliot for valuable advice and suggestions. I would like to thank Professor Michael Y.

Sherman (School of Medicine, Boston University) and his group member Nava Zaarur for their collaborative efforts toward the biological evaluations of our chemical libraries. I would also like to thank Dr. Guillaume Cottarel (Cellicon Biotechnologies Inc.) for the helpful discussions and collaborations. I am very grateful to our friends Dr.

Emil Lobkovsky (Comell University) for x-ray crystal structure analysis, Professor Richard P. Johnson (University of New Hampshire) for assistance with Spartan calculations, and Professor Philip J. Proteau (Oregon State University) for providing authentic kinamycin D. I would like to sincerely thank my excellent colleagues and close friends Dr.

Chaomin Li, Dr. Ruichao Shen, and Shun Su for their insightful discussions, earnest help, tremendous support and sharing the most memorable time with me in Porco Laboratory. I wish them the best in their future careers. I would also like to thank all of the Porco group and CMLD members, Dr.

Aaron Beeler, Dr. Ping Lan, Dr. Adam Yeager, Dr. Nicolas Rabasso, Dr.

Sarathy Kesavan, Dr. Sivaraman Dandapani, Dr. Andreas Heutling, Dr. Eamon Comer, Dr.

Jean-Charles Marie, Dr. Xiang Wang, Dr. Dawn Troast, Yongbo Hu, Jianglong Zhu, Sujata Bardhan, Chong Han, Baudouin Gerard, Andrew Germain, Bill Phillips, Dani Solano, Andrew Kleinke, Ji Qi, Suwei Dong, Stephen Scully, Gerry Kagan, Huan Cong, Qiang Zhang, Dayle Acyuilano, Jiayi Yuan, Tony Ling, Terry Huang, Jamie Ryan, Nicholas Grigoriadis, Dan Bruggemeyer, Winnie Ong and Gina Min for making the Porco lab and CMLD wonderful places to conduct my Ph. I would like to thank Dr.

Jonathan Lee, Dr. Michael Creech and Chris Singleton for NMR and MS assistance, Alicia Downey, Katinka Csigi, Elaine Early, Mike Gooley, Charles Alongi, Paul Ferrari, Aruna Jain and Matthew Vigneau for their kind help. Finally, I want to express my sincere thanks and deepest love to my wife Jing. vi TARGET AND DIVERSITY-ORIENTED SYNTHESIS USING EPOXYQUINOID SCAFFOLDS (Order No.

) XIAOGUANG LEI Boston University Graduate School of Arts and Sciences, 2007 Major Professor: John A., Professor of Chemistry ABSTRACT The first enantioselective total synthesis of the ubiquitin-activating enzyme inhibitor (+)-panepophenanthrin has been achieved employing tartrate-mediated asymmetric nucleophilic epoxidation and stereoselective Diels-Alder dimerization of an epoxyquinol dienol monomer. Modification of the epoxyquinol monomer leading to panepophenanthrin by substitution of a tertiary hydroxyl for a methyl group led to mechanistic insight for the critical [4+2] dimerization. A complex, stereochemically well-defined chemical library with distinct skeletal frameworks has been achieved via elaboration of angular epoxyquinol scaffolds. The key strategy involved highly stereocontrolled [4+2] Diels-Alder cycloaddition of chiral, nonracemic epoxyquinol dienes to generate the scaffolds.

Further scaffold diversification involved hydrogenation, epimerization, dehydration, and condensation of the carbonyl functionality with alkoxyamine and carbazate building blocks. The overall process afforded 244 highly complex and functionalized compounds. Preliminary biological vii screening of the library revealed six compounds which showed significant inhibition of Hsp 72 induction. The first enantioselective total synthesis of the complex diazobenzofluorene natural product (-)-kinamycin C has been accomplished.

The synthesis relies on a hydroxyl-directed, asymmetric nucleophilic epoxidation process to establish the desired stereochemistry of the complex and highly functionalized D-ring subunit. Additional key reactions include Stille cross coupling, intramolecular Friedel-Crafts annulation, and late stage diazo formation. vill TABLE OF CONTENTS CHAPTER 1 Total Synthesis of (+)-Panepophenanthrin 1.1 Introduction to (+)-Panepophenanthrin 1.2 Retrosynthetic Plan for Panepophenanthrin 1.3 Total Synthesis of (+)-Panepophenanthrin A. Synthesis of the Chiral, Non-racemic Bromo- epoxyketone Scaffold B.

Completion of (+)-Panepophenanthrin Synthesis C. Mechanistic Studies for Diels-Alder Dimerization 1.4 Other Syntheses of Panepophenanthrin A. Baldwin’s Synthesis of Panepophenanthrin 15 B. Mehta’s Synthesis of Panepophenanthrin 16 1.6 Experimental Section 18 CHAPTER 2 Stereocontrolled Synthesis of a Complex Library via Elaboration of Angular Epoxyquinol Scaffolds 2.2 Methodology Development for Library Synthesis A.

Synthesis of Epoxyquinol Scaffolds 44 B. Further Elaboration of Angular Scaffolds 47 ix C. Further Scaffold Modification Using Oxime 52 Formation D.3 Synthesis of a Polymer-supported Anthracene as a Dienophile Scavenger A. Synthesis of the First-generation Resin 56 C.

Synthesis of the Second-generation Resin 57 D. Scope and Limitations 58 E. Application of the Second-generation Scavenger Resin 2.4 Parallel Synthesis of Angular Epoxyquinol Scaffolds 63 2.5 Streamlined Synthesis of Advanced Scaffolds 2. Analysis of Library Members 68 2.8 Preliminary Biological Evaluation 70 2.10 Experimental Section 75 CHAPTER 3 Total Synthesis of the Diazobenzofluorene Antibiotic (-)-Kinamycin C 3.

Previous Synthetic and Mechanistic Studies Towards 141 the Kinamycins 3.3 First Retrosynthetic Analysis for Kinamycin C 145 3.4 Asymmetric Synthesis of Kinamycin C 147 3.6 Experimental Section 163 BIBLIOGRAPHY 197 CURRICULUM VITAE 216 Xi LIST OF TABLES Table 2.1 Dienophile Sequestration Using Anthracene Resin P5 59 Table 2.2 Syntheses of Flavonoid Diels-Alder Cycloadducts 62 Xil LIST OF FIGURES Eigure 1.1 Ubiquitination Pathways Figure 1.2 Panepophenanthrin and Related Epoxyquinoid Natural Produts Figure 1.3 Retrosynthetic Analysis for Panepophenanthrin Figure 1.4 Mechanistic Proposal of Tartrate-Mediated Asymmetric Nucleophilic Epoxidation of Quinone Monoketal 6 Figure 1.5 Proposed Transition States for the Dimerization of Syn- monomer 20 Figure 1.6 Relative Energies for the Intermediates in the Two Paths 13 for Diels-Alder Dimerization Figure 1.7 B3LYP/6-31G*-optimized Transition-state for the Formation 13 of Panepophenanthrin Figure 1.8 Rationalization for the Unsuccessful Dimerization of syn- 15 monomer 20 Figure 2.1 Proton Alignment for Enolization 51 Figure 2.2 Prenylflavonoid Diels-Alder Natural Products 60 Figure 2.3 Angular Epoxyquinol Scaffolds 65 Figure 2.4 Representative Library Members 69 Figure 2.5 Representative Natural Products with 6-6-5 Ring Systems 69 Figure 2.6 Inhibition of induction of Hsp72 by angular compounds A1, 73 A3, A6, A7, A8 and A9 (3.0 uM concentration) xiii Figure 3.1 Kinamycins and Related Natural Products 137 Figure 3.2 Structure Elucidation for Kinamycins 139 Figure 3.3 Lomaiviticins A and B 138 Figure 3.4 Mechanistic Studies 145 Figure 3.5 Retrosynthetic Analysis for Kinamycin C 146 Figure 3.6 Mechanistic Proposal of Tartrate-Mediated Asymmetric 149 Nucleophilic Epoxidation of Quinone Monoketal 27 Figure 3.7 Revised Retrosynthetic Analysis for Kinamycin C 154 Figure 3.8 Proposed Mechanism for Intramolecular Friedel-Crafts 157 Annulation and Regioselective MOM Deprotection Figure 3.9 Summary for the Previously Reported Diazo Formations 159 Figure 3.10 Overview of the Asymmetric Total Synthesis of Kinamycin C 162 XIV LIST OF SCHEMES Scheme 1.1 Synthesis of Chiral, Non-racemic Bromo-epoxyketone Scaffolds Scheme 1.2 Synthesis of (+)-Panepophenanthrin Scheme 1.3 Proposed Reaction Pathways Scheme 1.4 Revised Synthesis for Panepophenanthrin Scheme 1.5 Possible Mechanisms For the Diels-Alder Dimerization 10 Scheme 1.6 Synthesis of New Diels-Alder Dimers 11 Scheme 1.7 Thermolysis of Hemiacetal-bridged (1) and Nonbridged (24) Scheme 1.8 Baldwin’s Synthesis of Panepophenanthrin 16 Scheme 1.9 Mehta’s Synthesis of Panepophenanthrin 17 Scheme 2.1 Target and Diversity-oriented Synthesis Using Epoxyketone 43 Scaffolds Scheme 2.2 Synthesis of Maleimide-derived Angular Epoxyquinol 45 Scaffolds Scheme 2.3 Synthesis of a Urazole-containing, Angular Epoxyquinol 46 Scaffold Scheme 2.4 Hydroxyl-directed Diels-Alder Cycloaddition 47 Scheme 2.5 Elaboration of an Angular Epoxyquinol Scaffold 49 Scheme 2.6 Hydrogenation of Cycloadduct 20 50 Scheme 2.7 Hydrogenation and Attempted Epimerization of the Urazole 31 XV Scaffold Scheme 2.8 Attempted Reductive N-N Bond Cleavage 52 Scheme 2.9 Scaffold Modification Using Oxime Formation 54 Scheme 2.10 Library Design 55 Scheme 2.11 Synthesis of a First-generation, Polymer-Supported 57 Anthracene P2 Scheme 2.12 Synthesis of a Second-generation Polymer-Supported 58 Anthracene P5 Scheme 2.13 Preparation of Model Flavonoid Dienes 61 Scheme 2.14 [4+2] Diels-Alder Cycloaddition and Relative - 61 Stereochemistry Assignment Scheme 2.15 Parallel Synthesis of Maleimide-derived, Angular Epoxyquinol 64 Scaffolds Scheme 2.16 Synthesis of Urazole-containing Scaffolds 64 Scheme 2.17 Synthesis of Advanced Scaffolds 66 Scheme 2.18 Library Synthesis 67 Scheme 3.1 Biosynthesis of the Kinamycins 140 Scheme 3.2 Hauser’s Synthesis of Prekinamycin 141 Scheme 3.3 Model System for the Synthesis of Kinamycin C 143 Scheme 3.4 Synthesis of the Basic Framwork of Kinamycin C 144 Scheme 3.5 Forward Synthesis Employing a Baylis-Hillman Reaction 147 Scheme 3.6 Asymmetric Nucleophilic Epoxidation 148 Xvi Scheme 3.7 Synthesis of Fragment A 150 Scheme 3.8 Reaction Screenings for Epoxide Opening 151 Scheme 3.9 Synthesis of Fragment B 152 Scheme 3.10 Attempted Stille Coupling 153 Scheme 3.11 Stille Coupling and Epoxide Opening 155 Scheme 3.12 Intramolecular Friedel-Crafts Annulation 156 Scheme 3.13 Attempted Condensation of Compound 47 160 Scheme 3.14 End Game for Kinamycin C 161 XVii LIST OF ABBREVIATIONS specific rotation Ac acetyl Ac,0 acetic anhydride BHT 2,6-di-tert-butyl-4-methylphenol Bn benzyl Boc t-butyl carbonate or t-butyl carbamate Bu butyl concentration calcd. catalytic Cl chemical ionization cm centimeter COSY correlation spectroscopy conc. conversion m-CPBA meta-chloroperoxybenzoic acid chemical shift dba trans, trans-dibenzylidene acetone DBU 1,8-diazabicyclo[5,4,0]undec-7-ene DCM dichloromethane XVIH DIBAL-H diisobutylaluminum hydride DIPT diisopropy! tartrate DMAP 4-(dimethylamino)pyridine DMF N,N-dimethyl formamide DMSO dimethyl] sulfoxide dr diastereomeric ratio EDS0 effective dose 50 ee enantiomeric excess EI electronic ionization eq equivalent Et ethyl EtOAc ethyl acetate h hour HIV human immunodeficiency virus HMBC heteronuclear multiple bond correlation HMDS hexamethyldisilazide HMQC heteronuclear multiple quantum coherence HOMO highest occupied molecular orbital HPLC high performance liquid chromatography HRMS high resolution mass spectroscopy Hz hertz IC50 inhibitory concentration 50% XIX 1mid. imidazole IR infrared KHMDS potassium bis(trimethylsilyl)amide LIHMDS lithium bis(trimethylsilyl)amide LRMS low resolution mass spectroscopy LUMO lowest occupied molecular orbital M molar Me methyl mg milligram MHz megahertz min minutes mmol millimole M.

melting point MS mass spectroscopy MS molecular seives uL micro liter NaHMDS sodium bis(trimethylsilyl)amide NF nucleus factor nM nanomolar NMR nuclear magnetic resonance NOE nuclear Overhauser effect Ph phenyl XX ppm parts per million PPTS pyridium p-toluenesulfonate room temperature Rt retention time SEAP secreted alkaline phosphatase TBAF tetra-n-butylammonium fluoride TBS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TBHP t-butyl hydroperoxide TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy TFA trifluroacetic acid THF tetrahydrofuran TLC thin layer chromatography Tr trityl (Ph3C) UV ultraviolet microwave XXI Chapter 1 Total Synthesis of (+)-Panepophenanthrin 1.1 Introduction to (+)-Panepophenanthrin The ubiquitin-proteasome pathway plays an important role in the regulation of several diverse cellular processes including cell division, signal transduction, apoptosis, receptor-mediated endocytosis, and gene transcription regulation.' The majority of proteins destined for degradation are associated by the attachment of multiple ubiquitin molecules which provide a recognition signal for the 26S proteasome.