STUDIES TOWARDS THE TOTAL SYNTHESIS OF RISTOCETIN A AND ORIENTICIN C AGLYCONES by DIANA V. CIUREA Submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Thesis Advisor: Professor Anthony J. Pearson Department of Chemistry CASE WESTERN RESERVE UNIVERSITY January, 2008 2 3 Dedicated to my family 4 Table of Contents List of Schemes……………………………………………………………………………7 List of Tables……………………………………………………………………………...9 List of Figures……………………………………………………………………………10 Acknowledgments………………………………………………………………………..11 List of Abbreviations…………………………………………………………………….12 Abstract…………………………………………………………………………………..18 Chapter 1. Glycopeptide Natural Products: Their Total Synthesis and Possible Applications of Arene-Ruthenium Chemistry 1.1 Introduction ……………………………………….……………………………..22 1.2 Biosynthesis and Chemical Synthesis of Glycopeptide Antibiotics ……..……...27 1.2.1 Classical Ullmann Diaryl Ether Coupling Reaction …………………….30 1.2.2 Triazene-Driven Diaryl Ether Synthesis – Variation on the Ullmann Ether Synthesis; Nicolaou’s Total Synthesis of Vancomycin …………………31 1.2.3 Palladium-Catalyzed Diaryl Ether Synthesis ………………..…………..33 1.2.4 TTN-Mediated Oxidative Phenolic Coupling……………………………34 1.2.5 Boronic Acid-Driven Diaryl Ether Synthesis……………………………37 1.2.6 Potassium Fluoride-Alumina Driven SNAr Reaction …………………...37 1.2.7 o-Nitro-Activated SNAr Reaction ……………………………………….38 1.2.8 Metal-Mediated SNAr Methodology …………………………………….41 5 1.3 Conclusions ……………………………………………………………………...52 1.4 References ……………………………………………………………………….53 Chapter 2. Synthetic Studies towards Ristocetin A via Ruthenium-Mediated SNAr Reaction 2.1 Introduction………………………………………………………………………65 2.2 Retrosynthetic Analysis………………………………………………………….65 2.3 Synthesis of the Required Amino Acid Derivatives……………………………..70 2.3.1 Synthesis of E Building Block 2.7……………………………………….70 2.3.2 Synthesis of F Building Block 2.9……………………………………….72 2.3.3 Synthesis of G Building Block 2.10 …………………………………... 81 2.4 Ruthenium-Mediated Intermolecular Nucleophilic Aromatic Substitution for FOG Synthesis…………………………………………………………………………84 2.5 Studies on Selective Removal of MEM in the Presence of Boc, Teoc and TBS Protective Groups……………………………………………………………….. 88 2.6 Conclusions…………………………..…………………………………………. 93 2.7 Experimental Section ..…………………………………………………………..94 2.8 References………………………………………………………………………122 Chapter 3. Synthesis of a Key Precursor for Orienticin C and Model Study on Ruthenium-Mediated Macrocyclization 3.1 Introduction……………………………………………………………………..126 3.2 Retrosynthetic Analysis………………………………………………………...127 6 3.3 Synthesis of the Required Amino Acids Derivatives and Related Building Blocks…………………………………………………………………………..130 3.3.1 Amino Acid Building Block E…………………………………………130 3.3.2 Synthesis of Dipeptide Acid 3.20 ……………….…..…………………131 3.3.3 Synthesis of Tripeptide 3.9 …………………………………………….133 3.3.4 Synthesis of Tripeptide-Ruthenium Acid 3.3 ………..………………...137 3.4 Model Study on Ruthenium-Mediated Macrocyclization………………………139 3.5 Conclusions …………………………………………………………………….143 3.6 Experimental Section…………………………………………………………...145 3.7 References………………………………………………………………………161 Appendix ………………………………………………………………………………163 Bibliography …………………………………………………………………………..184 7 List of Schemes Scheme 1.1 Total synthesis of vancomycin by Nicolaou et al .………………………32 Scheme 1.2 Total synthesis of orienticin C aglycone by Evans et al …………….…..36 Scheme 1.3 Synthesis of LY293111 by Sawyer et al ……………...………………....38 Scheme 1.4 Synthesis of vancomycin carboxylate binding poket model 1.29…...…...39 Scheme 1.5 Total synthesis of ristocetin A aglycone by Boger et al ……..………….41 Scheme 1.6 SNAr reaction in arene-metal complexes ………………………………..43 6 Scheme 1.7 SNAr reaction of the η -chlorobenzene tricarbonylchromium …………..43 Scheme 1.8 Manganese-mediated SNAr synthesis of diaryl ethers …………………..44 Scheme 1.9 Synthesis of the 14-membered CFG model system of ristocetin A aglycone …………………………………………………………………45 Scheme 1.10 Iron-mediated SNAr reaction for the synthesis of di- and triaryl ethers ...46 5 + - Scheme 1.11 Synthesis of [Ru(η -C5H5)(CH3CN)3] PF6 ……………………………48 Scheme 1.12 Synthesis of 14-membered EFG model system of teicoplanin …………49 Scheme 1.13 Synthesis of ABCD intermediate of ristocetin A and orienticin C aglycones ………………………………………………………………..50 Scheme 2.1 Synthesis of E building block 2.7……..……………..……….………….71 Scheme 2.2 Evans asymmetric synthesis of arylglycines by enolate azidation………73 Scheme 2.3 Synthesis of 3,5-dihydroxy-4-methylbenzoic acid (2.26) ………………75 Scheme 2.4 Synthesis of dibenzyloxy F amino alcohol 2.32 ……………………….. 76 Scheme 2.5 Synthesis of the F styrene 2.35 ………………………………………….80 Scheme 2.6 Synthesis of Teoc-protected F amino alcohol 2.9 ……………………….81 8 Scheme 2.7 Synthesis of G building block 2.42 .………………..……….…………...83 Scheme 2.8 Synthesis of G ring ruthenium complex 2.10 …………………………...83 Scheme 2.9 Synthesis of G ring ruthenium complex 2.44 …………………………...84 Scheme 2.10 MEM removal in the presence of Boc, Teoc, and TBS groups …………91 Scheme 2.11 Synthesis of the ruthenium-complex 2.50 ………………………………92 Scheme 3.1 Construction of the ABCD advanced intermediate 3.2 common to orienticin C and ristocetin A …………………………………………..128 Scheme 3.2 Synthesis of azide 3.17 ………………………………………………...130 Scheme 3.3 Synthesis of amino acid derivative 3.10 ……………………………….131 Scheme 3.4 Synthesis of dipeptide 3.20 …………………………………………….132 Scheme 3.5 Synthesis of asparagine derivative 3.27 ………………………………..134 Scheme 3.6 Synthesis of tripeptide 3.9………………………………………………136 Scheme 3.7 Synthesis of dipeptide 3.31 …………………………………………….137 Scheme 3.8 Synthesis of the 16-membered macrocycle 3.32 ……………………....141 9 List of Tables Table 2.1 Conditions for Sharpless AA reaction …………..………………...…….77 Table 2.2 AA reaction for the preparation of the F amino alcohol ………………...79 Table 2.3 SNAr reaction of F-phenol 2.9 with G-ruthenium halide 2.10 using 2,6-di- t-butyl phenoxide ……………………………………………..................86 Table 2.4 Optimization of SNAr for FOG synthesis ……………………………….87 Table 3.1 Tripeptide 3.28 synthesis ………………………………………………135 Table 3.2 Ruthenium-tripeptide acid 3.3 formation reaction ……………………..138 10 List of Figures Figure 1.1 Structures of vancomycin and teicoplanin ………..………….………….23 Figure 1.2 Mechanism of action of vancomycin ………………………………..…..25 Figure 1.3 The molecular basis of vancomycin resistance ……………………….....26 Figure 1.4 [Ψ[CH2NH]Tpg4] vancomycin aglycone ……………………………...26 Figure 1.5 Metal-arene complexes ………………………………………………….42 Figure 2.1 Structures of vancomycin and ristocetin A aglycones…………………...66 Figure 2.2 First retrosynthetic strategy for ristocetin A aglycone………………...…67 Figure 2.3 Second retrosynthetic strategy for the ristocetin A aglycone......………..68 Figure 2.4 Retrosynthetic analysis of EFG intermediate (2.6) of ristocetin A aglycone ……………………………………………………………………………69 Figure 3.1 Structures of vancomycin and orienticin C……………………………..126 Figure 3.2 Retrosynthetic analysis for orienticin C aglycone……………………...127 Figure 3.3 Retrosynthetic analysis for the ruthenium-tripeptide acid 3.3 …………129 Figure 3.4 Model system for testing the ruthenium-mediated cycloetherification ..140 1 Figure 3.5 400 MHz H NMR spectrum of 3.32 in CD3OD ………………………143 11 Acknowledgments I would like to express my gratitude to Professor Anthony Pearson who supported and encouraged me throughout my years spent at Case Western Reserve University and most importantly he stood by me when I encountered most difficult times. His broad knowledge of chemistry, enthusiasm and professionalism represents a standard for my future career. I would like to thank Professors Irene Lee, Lawrence Sayre, Malcolm Kenney, and Vernon Anderson for taking time to serve on my PhD committee. The financial support provided by the Department of Chemistry and National Institute of Health are greatly appreciated. I want to thank my labmates, past and present for the very friendly working environment they created and to the Romanian student community that shortened the distance between me and my country. Faculty, staff and students of the Department of Chemistry are gratefully acknowledged for working together to promote a friendly and productive work environment. I thank Professor Gheorghe Mateescu and his wife, Claudia for their kindness, love, hospitality and generosity. They have been my family here in Cleveland. I am grateful to my sister, Andreea and brother-in-law, Bogdan for their encouragement to come to US for my PhD studies and for their constant support which they provided throughout my graduate studies. My special thanks go to my parents for their constant help and support, no matter what barriers they had to overcome. 12 List of Abbreviations AA asymmetric aminohydroxylation Ac acetyl AD asymmetric dihydroxylation Ala alanine Alloc allyloxycarbonyl AQN anthraquinone Ar aryl atm atmosphere(s) binap [1,1’-binaphthalene]-2,2’-diylbis(diphenylphosphane) Bn benzyl BzCl benzyl chloride Boc tert-butyloxycarbonyl (Boc)2O di-tert-butyl dicarbonate BOP (1-benzotriazolyloxy) tris(dimethylamino)- phosphonium hexafluoride BOPCl N,N-bis-(2-oxo-3-oxazolidinyl)phosphinic chloride br. d broad doublet br. s broad singlet Bz benzyl Cbz benzyloxycarbonyl Cp cyclopentadienyl d doublet 13 dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCB 3,4-dichlorobenzyl DCC N,N’-dicyclohexylcarbodiimide Ddm 4,4’-dimethoxydiphenylmethyl DEAD diethyl azodicarboxylate DEPBT 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one DHQ hydroquinine DHQD hydroquinidine DIBAL diisobutylaluminum hydride DIPEA