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University of Missouri, St. Louis IRL @ UMSL Dissertations UMSL Graduate Works 8-2-2011 Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their hoP sphonate Analogs and New Chemistry of Vinyl Phosphonates Raj Kumar Malla University of Missouri-St. Louis, [email protected] Follow this and additional works at: https://irl.umsl.edu/dissertation Part of the Chemistry Commons Recommended Citation Malla, Raj Kumar, "Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their hospP honate Analogs and New Chemistry of Vinyl Phosphonates" (2011). Dissertations. 416. https://irl.umsl.edu/dissertation/416 This Dissertation is brought to you for free and open access by the UMSL Graduate Works at IRL @ UMSL. It has been accepted for inclusion in Dissertations by an authorized administrator of IRL @ UMSL. For more information, please contact [email protected]. Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their Phosphonate Analogs and New Chemistry of Vinyl Phosphonates by Raj Kumar Malla A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) University of Missouri-St. Louis August, 2011 Committee Prof. Christopher D. Spilling (Chair and Advisor) Prof. Alexei V. Demchenko Prof. Cynthia M. Dupureur Prof. Eike B. Bauer Abstract Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their Phosphonate Analogs and New Chemistry of Vinyl Phosphonates Raj Kumar Malla Doctor of Philosophy University of Missouri-St. Louis Prof. Christopher D. Spilling, Advisor This work is divided into 2 parts: a) total synthesis of (±)-cyclophostin, (±)-cyclipostin P and their monocyclic analogs b) development of a metathesis based methodology for transformation of vinyl phosphonates. Cyclophostin (1) and cyclipostins (2) are bioactive natural bicyclic organophosphates. Cyclophostin is a powerful inhibitor of acetyl cholinesterase (AChE), whereas members of the cyclipostins are potent inhibitors of hormone sensitive lipase (HSL). Cyclophostin (1) and cyclipostin (2) have the same structural core unit, but different phosphate ester substituents. While cyclophostin is a methyl ester, the members of the cyclipostins are phosphate esters of different alkyl groups of various length and structure at the phosphate center. ii First total synthesis of (±)-cyclophostin (1) and 14 monocyclic phosphonate analogs is reported. Similarly, synthesis of the natural product (±) cyclipostin P was achieved via a novel, high yielding one-pot transesterification of diastereomer of (±)-cyclophostin. This method acts as bridge from cyclophostin to any member of cyclipostins. The conversion can also be carried out with monocyclic phosphonate analogs. (±)-Cyclophostin and 14 monocyclic phosphonate analogs were tested against different members of the serine hydrolase family of enzymes at UMSL and at CNRS-Marseilles in France. The biological evaluation of these analogs was helpful in understanding the relationship between the structure and biochemistry of the molecules towards the inhibition of various enzymes. Vinyl phosphonates have the potential to be useful intermediates in organic synthesis. However, there are only a limited number of transformations reported for vinyl phosphonates. Although terminal vinyl phosphonates easily undergo cross metathesis reaction, internal vinyl phosphonate do not. A method for cross metathesis of allyl vinyl phosphonates based on relay process has been developed. iii Acknowledgement First and foremost, I have my sincere gratitude to Prof. Christopher D.Spilling for his continuous guidance and support throughout this work. This work is unimaginable with out his mentorship, support and advice. His modus operandi about “academic metallurgy” is simply awesome. It has been quite a privilege to work under his tutelage. I am also thankful to Prof. Alexei V. Demchenko, Prof. Cynthia Dupureur and Prof. Eike Bauer for being my committee and for their careful reading and critical comments on the manuscript. I am thankful to Prof. Rudolph Winter and Mr. Joe Kramer for their help with mass spectrometry. I am also grateful to Prof. Nigam P. Rath for the crystallographic study of some of my compounds and Dr. Rensheng Lu for NMR Spectroscopy. I would like to thank the department of chemistry, UMSL Graduate school, and the NIH for financial support for this study. I am thankful to Supratik Dutta and Elena Vasilieva from Dr. Dupureur’s lab at UMSL and Dr. Cavalier’s Lab at CNRS, Marseille, France for conducting some biochemical assays of compounds included in this work. I would like to thank my labmates Nuch, Saibal, Mahesh, Sue, Surendra, Ben and Mercy. All of you, I am really thankful for creating conducive environment in the lab. I also enjoyed the good company of my friends and people in the department thoughout this work. I would like to thank my advisor for Master’s degree thesis Prof. Mangala D. Manandhar, Tribhuvan University, Kathmandu, Nepal, for installing the scientific curiosity as well as iv showing me the ways towards this scientific horizon. Her guidance and encouragement were instrumental for choosing this career path. This work would not have been possible without the support from my family to whom, I would like to dedicate this dissertation. I am always grateful to my parents, Gokarna Malla and Madhu Malla, for their love and emotionally supporting my work. I am especially thankful to my wife Sabitri, for her continuous support and inspiration during this study, being excellent homemaker and for beautiful kids: Riti and Riwaz! v Table of Contents Abstract ............................................................................................................................... ii Chapter I.............................................................................................................................. 1 Introduction ......................................................................................................................... 1 1.1. Cyclophostin and the cyclipostins: Isolation and biological properties ................... 1 1.2. Specific aim of the study .......................................................................................... 6 1.3. Structural feature and retro synthetic analysis ......................................................... 6 1.4. Earlier synthesis of cyclophostin: route a 7 .............................................................. 8 1.5. Methods for synthesis of cyclic phosphates and phosphonates ............................. 10 1.6. Summary ................................................................................................................ 30 1.7. References .............................................................................................................. 32 Chapter II .......................................................................................................................... 36 Synthesis of (±)-Cyclophostin and (±)-Cyclipostin P ....................................................... 36 2.1. Structural features of cyclophostin ......................................................................... 36 2.1. Results and discussion ............................................................................................ 37 2.3. Transesterification of phosphate esters and synthesis of (±)-cyclipostin P from (±)- cyclophostin ............................................................................................................ 49 2.4. Biological testing of cyclophostin and cyclipostin P against serine hydrolases. ... 58 2.5. Summary ................................................................................................................ 59 2.6. General Experimental ............................................................................................. 60 vi 2.7. References .............................................................................................................. 69 Chapter III ......................................................................................................................... 72 Synthesis of Monocyclic Phosphonate Analogs of Cyclophostin and the Cyclipostins ... 72 3.1. Background ............................................................................................................ 72 3.2. Specific aim of the study ........................................................................................ 76 3.3. General strategy for the synthesis of 7-membered monocyclic phosphonate analogs ................................................................................................................................ 78 3.4. Result and Discussion ............................................................................................ 79 3.5. Synthesis of monocyclic phosphonate analogs of (±)-cyclipostin P ..................... 88 3.6. Investigation of Biological Activities of Phosphonate Analogs of the Cyclipostins and Cyclophostin .................................................................................................... 90 3.7. Summary ................................................................................................................ 95 3.8. General Experimental ............................................................................................. 96 3.9. References ............................................................................................................ 134 Chapter IV ......................................................................................................................
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