Nỗ lực tổng hợp Prostaglandin PGF2a - Luận án Tiến sĩ của Amy Marie Pollard

Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2016 Synthetic Efforts Towards the Synthesis of Prostaglandin PGF2a Amy Marie Pollard Louisiana State University and Agricultural and Mechanical College, amympollard@gmail.com Follow this and additional works at: https://digitalcommons.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Pollard, Amy Marie, "Synthetic Efforts Towards the Synthesis of Prostaglandin PGF2a" (2016). LSU Doctoral Dissertations.edu/gradschool_dissertations/2719 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please contactgradetd@lsu.

SYNTHETIC EFFORTS TOWARDS THE SYNTHESIS OF PROSTAGLANDIN PGF2 A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Amy Marie Pollard B., University of Tennessee, 2007 August 2016 i OTF, Cinco de Mayo 2013, you are the reason why I do what I do. -PAP ii ACKNOWLEDGMENTS I would like to thank Emmett Pollard for being supportive of my scientific explorations from playing with chemistry sets to helping me incorporate my company. Also thank you for helping me whenever I needed help with life. To Monica Kimbrough Baker, thank you for teaching me composure and to play for keeps.

I would like to thank my mother for being there for me. Sincere thanks go to Dr. Michael Miller for introducing me to wonderful world of biochemical research at the age of 14. Dean Jeffery Engler, thank you for allowing me to join your research group before I finished high school.

You both have been great mentors throughout my scientific career. To the Comprehensive Cancer Center at UAB, thank you for your support and for allowing me to be a part of your program. Michael Best, you were honestly the best. Thank you for convincing me that chemistry was as interesting as biochemistry and for being an overall excellent mentor and research professor.

I’d also like to thank my Sensei Paul and the UTK Martials Arts Club for teaching me to get back up after being thrown to the ground. I would like to sincerely thank my research advisor, Dr. Crowe, for letting me join his research group and for giving me a new perspective on organic chemistry; I will use it well. I would also like to thank Connie Davis for GCMS training and general advice.

Rafael Cueto, thank you for allowing me to use your lab and assistance with ozonolysis. Thanks also go to Dr. Dale Treleavan (1945-2013), Dr. Thomas Weldeghiorhis for the NMR training and analysis help.

I would like to thank Dean Guillermo Ferreya, and Dr. Carol Taylor for helping me through my graduate school experience. Lastly I would like to thank Dr. Roger Laine and Dr.

You both have helped me more times than I can count. Thank you for your counsel. You were there when things got crazy. I fear that a mere thank is not enough, but thank you.

iii TABLE OF CONTENTS ACKNOWLEDGMENTS. iii LIST OF TABLES. v LIST OF FIGURES. vi LIST OF IMAGES.

x LISTS OF SCHEMES. xi LIST OF ABBREVIATIONS. xvi CHAPTER 1: PROGRESS TOWARDS THE SYNTHESIS OF PROSTAGLANDIN PGF2a .1 Introduction to Prostaglandins .2 Methods of Prostaglandin Synthesis .3 Synthetic Design for Prostaglandin Synthesis .4 Discussion of Iodocyclization .5 Synthesis of 1-(benzyloxy)-4-vinylhex-5-en-3-ol and 1-((4-methoxybenzyl)oxy)-4- vinylhex-5-en-3-ol .6 Syntheses of 4-(iodomethyl)-6-methyl-1,3-dioxan-2-one model system for 4-(2- (benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one .7 Synthesis of 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one .8 Discussion of Stereochemical Assignments .9 Discussion of Gaussian Calculations .11 Experimental and Spectroscopic Data .125 iv LIST OF TABLES Table 1. Results from Hirama and Uei Iodocyclization Reactions.

Integration of tert-butyl pent-4-en-2-yl Carbonate Reaction Mixture. 26 Table 3 Reaction Conditions for Synthesis of tert-butyl pent-4-en-2-yl carbonate. Integration and Chemical Shifts of Major and Minor Iodocyclization Product from 4- (iodomethyl)-6-methyl-1,3-dioxan-2-one Crude, Spectra of Major and Minor Isomers Product. Reference Splitting Patterns and Chemical Shifts of Reaction Product (H1 500MHz)7.

Chemical shifts of 1-(benzyloxy)-4-vinylhex-5-en-3-yl tert-butyl carbonate Protons. Results and Conditions. Comparison of Previously Reported Iodocyclization Reaction Results. Chemical Shift (δ), Splitting, and Coupling Constant (J, Hz) values for H-NMR of 1.

Cosy Cross Peaks 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one. HSQCDEPT Cross Peaks 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan- 2-one. Summary of (4R,5R,6R)-4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3- dioxan-2-one Gaussian Calculation Results. Summary of (4R,5R,6R)-4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3- dioxan-2-one Gaussian Calculation Results.

55 v LISTOF FIGURES Figure 1. Chromatograph of Iodocyclization Product, Fragmented Product, and Extracted Ions 256, 230, and 103. GC of tert-butyl pent-4-en-2-yl carbonate Reaction Mixture. GC/MS Chromatograph and Spectra of tert-butyl pent-4-en-2-yl Carbonate Reaction Crude Using Duan, J.

4-(iodomethyl)-6-methyl-1,3-dioxan-2-one Crude, Spectra of Major and Minor Isomers Product from Mohapatra, D. 1H NMR of 1-(benzyloxy)-4-vinylhex-5-en-3-yl tert-butyl carbonate, 1. 1H NMR of BOC-ON Unsuccessful Reaction Crude with Chemical Shifts Similar to Chemical Shifts of Reaction Product. NMR of 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one.

Cosy of 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one. HSQCDEPT of 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one. Roesy of 4-(2-(benzyloxy)ethyl)-6-(iodomethyl)-5-vinyl-1,3-dioxan-2-one. 1H NMR Homonuclear Decoupling (500 MHz, Chloroform-d) δ 2.

1H-NMR Split Pattern for H-20a and H-20b. Smaller Carbonate Used in DFT B3LYP 6-31+ g(df, pd) calculations. Relative Conformational Energies (kcal/mol) of the Smaller Carbonate. 2-Phenyl-1,3-dioxane 1H-NMR (400MHz, CDCl3).

2-Phenyl-1,3-dioxane 13C-NMR (101Hz, CDCl3). 2-Phenyl-1,3-dioxane, GC/MS EI (filament voltage 70 eV). Penta-1,4-dien-3-ol, 1H-NMR (400MHz, CDCl3). Penta-1,4-dien-3-ol, 13C-NMR (101MHz, CDCl3).

1-(Benzyloxy)-4-vinylhex-5-en-3-ol, HSQC. 4-penten-2-ol, 1H-NMR (400 MHz, CDCl3). Pent-4-en-2-yl carbamate, 1H-NMR (400 MHz, CDCl3). 98 Figure 45 Pent-4-en-2-yl carbamate, 1H-NMR (400 MHz, benzene-d).

Pent-4-en-2-yl carbamate, 13 C-NMR (101 MHz, CDCl3). Pent-4-en-2-yl carbamate, 13 C-NMR (101 MHz, benzene-d). GC/MS of pent-4-en-2-yl carbamate, EI (filament voltage 70 eV). Tert-butyl pent-4-en-2-yl carbonate product from Kumar, D., 2011 procedure purified using AgNO3 10 wt% on silica, 1H-NMR (400 MHz, CDCl3).

Tert-butyl pent-4-en-2-yl carbonate reaction crude using Duan, J. Tert-butyl pent-4-en-2-yl carbonate product from Kumar, D., 2011 procedure purified using AgNO3 10 wt% on silica, 13C-NMR (101 MHz, CDCl3). GC/MS chromatograph and spectra of tert-butyl pent-4-en-2-yl carbonate product from Kumar, D., 2011 procedure purified using AgNO3 10 wt% on silica, EI (filament voltage 70 eV). GC/MS chromatograph and spectra of tert-butyl pent-4-en-2-yl carbonate reaction crude Duan, J.

GC/MS chromatograph and spectra of tert-butyl pent-4-en-2-yl carbonate reaction mixture, EI (filament voltage 70 eV). GC/MS chromatograph and spectra of tert-butyl pent-4-en-2-yl carbonate contaminant, EI (filament voltage 70 eV). GC/MS chromatograph and spectra of tert-butyl pent-4-en-2-yl carbonate contaminant, EI (filament voltage 70 eV). GC/MS of 4-(iodomethyl)-6-methyl-1,3-dioxan-2-one, EI (filament voltage 70 eV).

122 ix LIST OF IMAGES Image 1. Linoleic Acid C18:2, omega-6. Chiral Auxiliary (4R, 5R)-2-((1E, 3E)-penta-1, 3-dien-1-yl)-4, 5-diphenyl-1, 3-bis (phenylsulfonyl)-1, 3, 2-diazaborolidine. 18 x LISTS OF SCHEMES Scheme 1.

Enzymatic Cascade Producing Prostaglandins and Thromboxanes. Two Molecule Coupling Model. Three Molecule Coupling Model. Synthesis of Prostaglandin Core by Using a Diels-Alder Reaction and Radical Induced Skeletal Translocation.

Synthesis of Prostaglandin Core with Side Chain for Use in Two Component Method. One Pot Three Component Coupling Using a Chiral Catalyst to Synthesize a Prostaglandin. Retrosynthetic Design of Prostaglandin Synthesis. Route to Alkene 1.

13 Scheme 10 Iodocyclization of a 3-Acylamino Ester. Synthesis of Alcohols. Attempted Reduction Using Chary-Laxmi method. Synthesis of Aldehydes.

Synthesis of (E)-5-bromopenta-1,3-diene. Synthesis and Mechanism of 1-(benzyloxy)-4-vinylhex-5-en-3-ol and 1-((4- methoxybenzyl) oxy)-4-vinylhex-5-en-3-ol. Synthesis of Pent-4-en-2-yl Carbamate. Attempted Synthesis of 4-(iodomethyl)-6-methyl-1,3-dioxan-2-one Using Basic Work Up.

Synthesis of 4-(iodomethyl)-6-methyl-1,3-dioxan-2-one Using Acidic Workup. Reaction Product Fragmented and Products. Hecker and Heathcock Iodocyclization results. Synthesis of 4-(iodomethyl)-6-methyl-1,3-dioxan-2-one via Carbonate Cyclization.

Tert-butyl pent-4-en-2-yl carbonate and By-Products from pen-4-en-2-ol Reaction with Boc Anhydride. Synthesis of Carbonate 1.68 using Boc-ON and n-BuLi. Synthesis of 4-(iodomethyl)-6-methyl-1,3-dioxan-2-one from Carbonate. Synthesis of Carbonate 1.69 Using Steglich Esterification.

Attempted Synthesis of Carbonate 1.69 Using BOC-ON. Iodocyclization of 1-(benzyloxy)-4-vinylhex-5-en-3-yl tert-butyl carbonate. IBr Induced Cyclization by Duan and Smith. Formation of Minor Isomer, Sterically Unfavorable Pathway.

Formation of Major Isomer, Kinetically Favorable Pathway. 58 xii LIST OF ABBREVIATIONS AcCl Acetyl Chloride AChE Acetylcholinesterase AIBN Azobisisobutyronitrile COSY COrrelation SpectroscopY COX-1 Cyclooxygenase-1 COX-2 Cyclooxygenase-2 cPGES Prostaglandin E Synthase CSA Camphorsulfonic Acid DHA Docosahexaenoic acid DMAP N,N-Dimethylpyridin-4-amine DTGS Deuterated-TriGlycine Sulfate ESI Electrospray Ionization ETP Ethopabate FTIR Fourier Transform Infrared GRAS Generally Recognized as Safe GC/MS Gas Chromatography–Mass Spectrometry H Hour xiii HPLC High-performance Liquid Chromatography HSQCDEPT Heteronuclear Single Quantum Correlation Spectroscopy Distortionless Enhancement of Polarization Transfer LC Liquid Chromatography LHMDS Lithium bis(trimethylsilyl)amide NIS N-Iodosuccinimide NMR Nuclear Magnetic Resonance mPGES-1 Microsomal Prostaglandin E2 Synthase-1 mPGES-2 Microsomal Prostaglandin E2 Synthase-1 PCC Pyridinium Chlorochromate PGD2 Prostaglandin D2 PGE2 Prostaglandin E2 PGF2 Prostaglandin F2 PGG2 Prostaglandin G2 PGH2 Prostaglandin H2 PGI2 Prostaglandin I2 PGJ2 Prostaglandin J2 Py Pyridine xiv Rf Retardation Factor ROESY Rotating-Frame Overhauser SpectroscopY RT Room Temperature SERS Surface Enhanced Raman Scattering TNT Trinitrotoluene TOF Time of Flight p-TSA/TsOH p-Toluenesulfonic Acid TXA2 Thromboxane A2 TXB2 Thromboxane B2 xv ABSTRACT This dissertation describes strategies for synthesizing prostaglandin PGF2α. Our synthetic design creates the stereochemistry needed for the core and side chains of the target prostaglandin PGF2 and PGF2 synthase selective analogues while incorporating iodocyclization desymmetrization of acyclic dienes. A model system for 4-(iodomethyl)-6-methyl-1,3-dioxan-2- one was developed and synthesized for our target compound 4-(2-(benzyloxy)ethyl)-6- (iodomethyl)-5-vinyl-1,3-dioxan-2-one.

Both compounds were successfully synthesized providing useful stereocenters for completing the synthesis of prostaglandin PGF2 .Efforts toward total stereochemical control of PGF2α include the partial syntheses of bis- diethylanimedimethylsilane and of (4S,5S)-2-((1E,3E)-penta-1,3-dien-1-yl)-4,5-diphenyl-1,3- ditosyl-1,3,2-diazaborolidine.  xvi CHAPTER 1: PROGRESS TOWARDS THE SYNTHESIS OF PROSTAGLANDIN PGF2 1.1 Introduction to Prostaglandins Essential fatty acids omega-3, omega-6, including eicosapentaenoic and docosahexaenoic acid (DHA), precursors to prostanoids, are critical for circulation, production of hemoglobin, immune function, and anti-inflammatory response.1 A study reported in 2006 by R. Bayer suggests that omega-3 fatty acids are a possible treatment for inflammatory pain.2 Studies by Wall et al. concluded that increasing consumption of omega-3 fatty acids increases production of inflammation mediators and regulators.

3 Linoleic acid, a C18:2 omega-6 fatty acids (Image 1) is the precursor to arachidonic acid which is oxidized by cyclooxygenase 1 or 2 forming prostaglandin PGG2, an inflammatory stimulator. In the C18:2 type nomenclature, C18 represents the number of carbons in the chain; the 2 represents the number of alkenes in the chain. PGG2 is reduced by PGH2 synthase forming prostaglandin PGH2, which undergoes enzymatic reactions to produce five different prostaglandins: PGI2, PGF1α, PGF2α, PGE2, PGD2, and a thromboxane, TXA2. The primary prostaglandins undergo additional enzymatic reactions to form additional prostanoids, which are responsible for homeostasis, (Scheme 1).2 Methods of Prostaglandin Synthesis There are three major prostaglandin synthetic designs.

The first is synthesis of the core cyclopentane with appropriate side groups which can be used in subsequent reactions for attachment of α and ω chains. Linoleic Acid C18:2, omega-6 2 PGF2 Scheme 1. Enzymatic Cascade Producing Prostaglandins and Thromboxanes 3 The second is a two molecule coupling, where one molecule contains the cyclopentane core and an attached side chain. This molecule is coupled to a second chain, (Scheme 2).

The third method of prostaglandin synthesis is the three component coupling (Scheme 3).4 Following is an example of each approach. A derivative of Corey’s lactone was synthesized by Augustyns et al. 5 Lactone synthesis began with a Diels-Alder reaction of 1.13, followed by a radical induced skeletal translocation affording lactone product 1.15, which was isomerized to produce 1. Decarboxylmethylation with lithium chloride gave lactone 1.17 which was functionalized via bromohydrin formation followed by acetylation.

Radical debromination of the core structure was accompanied by the potential for side chain attachment 1. Two molecule coupling completed by Togashi et al. 6 commenced with the 1,1-dibromo alkene (1.20) coupling to an aldehyde chain affording alkyne 1. Swern oxidation transformed the hydroxyl group to a ketone giving product 1.

K-selectride was used to stereoselectively reduce the ketone carbonyl, producing alcohol 1. Reduction of the alkyne, followed by hydroxyl group acylation yielded 1.