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Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent

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University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2011 Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent Costyl Ngnouomeuchi Njiojob [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Heterocyclic Compounds Commons, Organic Chemicals Commons, and the Polycyclic Compounds Commons Recommended Citation Njiojob, Costyl Ngnouomeuchi, "Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent. " PhD diss., University of Tennessee, 2011. https://trace.tennessee.edu/utk_graddiss/1210 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Costyl Ngnouomeuchi Njiojob entitled "Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. David C. Baker, Major Professor We have read this dissertation and recommend its acceptance: Shawn Campagna, Ben Xue, Elizabeth Howell Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Costyl Ngnouomeuchi Njiojob December 2011 DEDICATION This dissertation is dedicated to my Parents Francois Ngnouomeuchi and Lydie T. Nguepnang Ngnouomeuchi who initiated my education process and gave me the zeal to always work hard in order to achieve success. I also give special thanks to my wife Tatiana K. Njiojob and my son Iann Davis N. Njiojob for their fabulous support during my years of graduate school. ii AKNOWLEDGEMENTS First, I would like to express my sincere gratitude to my research advisor Prof. David C. Baker for the opportunity he provided me with to do research in his group, and the encouragement and support throughout my years of graduate school. I also express my appreciation to Drs. Howell, Xue and Campagna, for accepting to serve in my dissertation committee and for their contribution to my research. I would also like to thank the past and present members of the Baker group: Dr. Medhanit Bahta, Dr. Julio Gutierrez and Dr. Riyam Kafri for teaching me various laboratory techniques; Dr. Samson Francis for his assistance with chemistry and computer related issues. Chad LeCroix for his assistance with NMR related problems. Steven Glass, Irene Abia, Yundi Gan, Bo Meng, Veronica Gantert, Andy Hahn, Andy Rowe, Andrew Moss, Robert Simion and Adnan Dervishi for their support and friendship throughout these years. I would also like to thank Dr. Carlos Steren for his assistance with 2D NMR techniques used for the elucidation of my final compounds and Dr. Joel Putnam for providing me with the chiral columns and knowledge required to analyze my final compounds. I will also use this opportunity to thank everybody in the Department of chemistry of the University of Tennessee-Knoxville who contributed to the accomplishment of this project. Finally, I am sincerely grateful to my Family: My parents Francois Ngnouomeuchi and Lydie Nguepnang T. Ngnouomeuchi for their incredible moral support and prayers throughout my years of graduate school. I am also thankful to my brothers and sisters Romeo N. Kepomi, Bernice N. Ngnouomeuchi, Yannick T. Ngnouomeuchi and Patricia N. Moffo for their encouragement and support. I am infinitely grateful to my wife Tatiana K. Njiojob for always iii being very supportive and patient throughout my years of graduate school and my son Iann Davis N. Njiojob for entertaining me during tough times. Above all, I give thanks to God who provided me with the necessary strength throughout these years. iv ABSTRACT Hydramycin is an antitumor antibiotic isolated from Streptomyces violaceus. It is a pyranoanthraquinone-type antitumor agent that has shown broad-spectrum activity against a variety of human-derived cancer cell lines. Among tumors evaluated at the National Cancer −10 Institute (lung, colon, melanoma, breast and prostate), GI50s were <10 M in the NCI's 60-cell- line panel. We embarked on the synthesis and evaluation of a simplified congener 2-(1-hydroxy- 1-(oxiran-2-yl)ethyl)-4H-naphtho[2,3-h]chromene-4,7,12-trione(17), which would facilitate synthesis while retaining the potent activity. Hydramycin has two chiral centers, and our goal is to design and synthesize all the possible enantiomers (four in total) for the congener of hydramycin 17 in order to ascertain which of the enantiomers is responsible for the observed antitumor activity. The use of enantiospecific techniques such as the Sharpless epoxidation was initially tried to introduce the chiral centers at a later stage during the multi-step synthesis and obtain the required pure enantiomers. Due to some limitations observed with this technique and many other asymmetric epoxidation techniques which utilize very substrate-specific ligands, we then modified the synthetic scheme to use another procedure, the Sharpless asymmetric dihydroxylation in order to obtain two of the pure enantiomers of this congener of hydramycin. The other two enantiomers are selectively obtained using the Sharpless asymmetric dihydroxylation procedure via cyclic sulfate intermediates, followed by a modified irreversible Payne rearrangement procedure. These routes then allowed us to obtain separately all four stereoisomers, each having more than 90% ee as determined on chiral columns with HPLC. The four stereoisomers have been fully characterized and will then be tested separately to ascertain which of the isomers is responsible for the observed antitumor activity. v TABLE OF CONTENTS I. INTRODUCTION………………………………………………………………...1 A. Anthraquinone…………………………………………………………………..1 B. Anthraquinone derivatives and their applications………………………………3 C. Pyranoanthraquinone and related biological activity………………………… 5 D. Hydramycin……………………………………………………………………..7 E. Mode of action of antitumor agents having hydramycin-like structures………..8 F. Hydramycin and antitumor activity……………………………………………..11 II. STATEMENT OF THE PROBLEM…………………………………………….16 A. Synthetic challenges…………………………………………………………….16 B. Research plan and general retrosynthetic strategy……………………………...18 C. Dissertation summary…………………………………………………………...20 III. DISCUSSION……………………………………………………………………...21 A. First attempt for the synthesis of asymmetric hydramycin congener 17………..21 B. Synthesis of a model compound to test the Sharpless asymmetric epoxidation reaction…………………………………………………………………………..27 C. Synthesis of second model compound to test the SAE reaction………………...28 D. Synthesis of asymmetric tertiary epoxy alcohols using the Cram-chelate rule….31 E. Second attempt to synthesize asymmetric hydramycin congener 17……………33 F. Attempts of enantioselective coupling reaction between the alkyne containing the tertiary allylic alcohol and the aldehyde intermediate……………………….36 vi G. Attempts to synthesize the asymmetric version of hydramycin congener 17 using the Sharpless asymmetric dihydroxylation technique…..............................39 1. First attempt for the synthesis of asymmetric hydrymacin congener 17A and 17A’ via the SAD route…………………………………………….……42 2. Final attempt for the synthesis of asymmetric hydramycin congeners 17A and 17A’ via the SAD reaction………………………………………………45 H. First attempt of the synthesis of two other hydramycin congeners 17B and 17B’……………………………………………………………………………...54 1. Mitsunobu trial on intermediate 16 or 18……………………………………54 2. Second attempt to synthesize the hydramycin congeners 17B and 17B’ by applying the Mitsunobu reaction to intermediate 20 and 21……………...55 I. Formation of a trans-diol using the modified irreversible Payne rearrangement reaction……………………………………………………………………….…..56 J. Analysis of final compounds and some asymmetric intermediates with 1D and 2D NMR spectroscopy, and chiral column HPLC…………………………….…65 IV. CONCLUSIONS AND FUTURE WORK…………………………………….…..77 V. EXPERIMENTALS………………………………………………………………...81 A. General methods………………………………………………………...........81 B. Preparation of tert-Butyldimethyl(pent-1-en-4-yn-3-yloxy)silane (34)...........82 C. Synthesis of 2-(4-((tert-Butyldimethylsilyl)oxy)-1-hydroxyhex-5-en-2-yn- 1-yl)-1-hydroxyanthracene-9,10-dione (35)……………………………….….85 D. Synthesis of 2-(prop-1-en-2-yl)-4H-naphtho[2,3-h]chromene-4,7,12-trione (40)……………………………………………………………………………86 vii E. Preparation of 2-(2-hydroxybut-3-en-2-yl)-4H-naphtho[2,3-h]chromene- 4,7,12-trione (55)…………………………………………………………….90 F. Preparation of 2-phenylbut-3-en-2-ol (63)…………………………………..92 G. Synthesis of (S)-1-((S)-oxiran-2-yl)-1-phenylethanol (61)…………………..93 H. Preparation of (E)-3-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-ol (4)……..97 I. Synthesis of tert-Butyl(dimethyl){[(2E)-3-methylpent-2-en-4-yn-1- yl]oxy}silane (6)……………………………………………………………..100 J. Preparation of 1-Hydroxy-9,10-dioxo-9,10-dihydroanthracene-2- carbaldehyde
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  • 215 F12-Notes-Ch 13

    215 F12-Notes-Ch 13

    Chem 215 F12-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: September 10, 2012 Chapter 13. Alcohols, Diols, and Ethers Overview: Chemistry and reactions of sp3 oxygen groups, particularly oxidation of an alcohol, ether formation, and reactions of oxirane (epoxide) groups. I. What are alcohols, phenols, and ethers? IUPAC names Common names Alcohols (R-OH) Primary alcohols CH3OH methanol methyl alcohol (1°-alcohols) CH3CH2OH ethanol ethyl alcohol pKa ~16-17 CH3CH2CH2OH 1-propanol n-propyl alcohol H3C C CH2OH 2-methyl-1-propanol isobutyl alcohol H3C H H3C C CH2OH 2,2-dimethyl-1-propanol neopentyl alcohol H3C CH3 H C Secondary alcohols 3 C OH 2-propanol isopropyl alcohol (2°-alcohols) H3C H pKa ~17-18 H C-CH 3 2 C OH 2-butanol sec-butyl alcohol H3C H Tertiary alcohols H3C C OH 2-methyl-2-propanol tert-butyl alcohol (3°-alcohols) H3C CH pKa ~19 3 Phenols (Ph-OH) pKa ~10-12 diethyl ether Ethers (R-O-R') CH3CH2-O-CH2CH3 Ph-O-CH=CH2 phenyl vinyl ether RO-: alkoxy CH3O methoxy CH3CH2O ethoxy ArO-: aryloxy PhO phenoxy II. Oxidation Oxidation – historical use of the term: (1) oxide (oxyd/oxyde) – the ‘acid’ form of an element; e.g., S + air → oxide of S (acid of sulfur) (2) oxidation or oxidize – to make such an acid, to make the oxide (3) oxygen – Lavoisier: substance in the air that makes acids; “the bringer of acids” = “oxygen” (4) oxidation or oxidize – to increase the % oxygen in a substance (reduction: to reduce the % oxygen) More modern definition: oxidation or oxidize – loss of electrons (coupled with reduction as gain of electrons) Note: The loss of electrons (oxidation) by one atom or compound must be matched by the gain of electrons (reduction) by another.