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Metal Carboxylate Salts As an Avenue to Protecting Group Free Peptide Couplings

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Metal Carboxylate Salts As an Avenue to Protecting Group Free Peptide Couplings Metal Carboxylate Salts as an Avenue to Protecting Group Free Peptide Couplings by Isaac Rakofsky A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto © Copyright by Isaac Rakofsky 2018 Metal Carboxylate Salts as an Avenue to Protecting Group Free Peptide Couplings Isaac Rakofsky Master of Science Department Of Chemistry University of Toronto 2018 Abstract Peptide coupling has had a long history, beginning its story in 1882 using the silver salt of glycine, continuing to solid phase peptide synthesis and the introduction of protecting groups. However protecting groups create a lot of needless waste. This thesis explores potential work in the area regarding the use of metal carboxylates as means to get around the need for these groups, as well as taking things further to do more than a single coupling couplings in one pot in solution phase chemistry. Despite variable success throughout, making a one-pot tripeptide in good yield and low epimerization was indeed achieved, with the help of these metal carboxylates and ONp esters. ii Acknowledgments I’d like to thank, first and foremost, Dr. Robert Batey for accepting me into his lab, and allowing me to the time to become a fully-fledged chemist under his guidance. Thank you to Anna Liza whose patience I tried many times, your administrative work was always appreciated. Thank you Darcy, Jack, Shawn and the whole NMR team over the years for helping me analyze my work and getting me the machines that I needed. Thank you to Dr. Sophie Rousseaux and all of the above, without who I would have never been able to get this thesis out before the deadline. All your kindness is appreciated. I’d like to thank Marvin Morales who handled all of my training and familiarized me with standard organic lab protocols. Next I’d like to thank PJ. Roest who helped coach and to get my chemistry up to speed as well as suggesting ideas for experiments over the course of the degree, to varying degrees of success. I’d also like to thank Anika Tarasewicz who also helped me massively with chemistry, and also sat through my stress rants, especially in these last few weeks of my degree. Maja Chojnacka, always eager to help me out as well, and great company when wanting to get sushi for lunch or being there when needing to unwind. Honourable mention to the rest of the Batey group for being a great bunch of people for more than just chemistry. Finally I’d like to thank my mom, dad and my brother Joseph who is my best friend, for helping me get to this point, and without them I probably would have never even gotten here. Joseph, I super miss you and I’m always looking forward to the next time we’re able to get together (living across the country makes it difficult). Success isn’t made by only one individual and it takes a village to raise a person. P.S. Shout out to Auntie Edie, Auntie Rachel and Uncle Sheldon P.P.S. Shout out to all my Montreal friends iii Table of Contents Acknowledgements.………………………………………………….…………….……………. iii List of Tables.………………………………………………………...………………………….. vi List of Figures.………………..…………………………………………………………………. xii List of Schemes.……….………..……………………………………………………………… xiii List of Appendices.….……………...…………………………………………………………….. x List of Abbreviations.………………………………………...………………………………….. xi Chapter 1 Introduction: History and Classic Methods of Amide Bond Formation………………1 1.1 Brief History of the Peptide Bond …………………………...……………………….1 1.2 Epimerization of Amino Acids….…………………………………………………….3 1.3 Common Method of C-terminus Activation ……...………………………………….5 1.3.1 Acid Chlorides ...……..……………………………………………………..6 1.3.2 Carbonyl diimidazole (CDI)……………………………………….………..7 1.3.3 Anhydrides…………………………………………………………………..8 1.3.4 Activated Esters……………………………………………………………..8 1.4 Direct Coupling using Ru …………………………………………………………...10 1.5 Overall Summary…………………………………………..………………………...11 1.6 References……...…………………………………………..………………………...11 Chapter 2 Calcium Carboxylate Salts and Their Use in Peptide Synthesis…………...……….. 14 2.1 The Utility of Carboxylate salts in Amide Bond Formation ....……………………...14 2.2 Results and Discussion….…………………………………………………………... 22 2.3 Conclusion………………………………… ……...………………………………... 28 2.4 References …………………………………….…...………………………………... 30 iv Chapter 3 Activated Esters and One-Pot Solution Phase Tripeptide Synthesis………………... 31 3.1 Protecting-Group Free Couplings of Amino Acids ....……………………….……... 31 3.2 Results and Discussion….…………………………………………………………... 34 3.3 Conclusion………………………………… ……...………………………………... 52 3.4 References …………………………………….…...………………………………... 54 Chapter 4 Copper-Lysine Complexes and Their Derivatizations………………………..…….. 55 4.1 The Utility of Carboxylate salts in Amide Bond Formation ....……………………...55 4.2 Results and Discussion….…………………………………………………………... 57 4.3 Conclusion………………………………… ……...………………………………... 62 4.4 References …………………………………….…...………………………………... 63 Chapter 5 Copper-Lysine Complexes and Their Derivatizations………………………..…….. 64 5.1 General Experimental…………………………………….. ....……………………... 64 5.2 Results and Discussion….…………………………………………………………... 65 5.3 References………………………………… ……...………………………………... 93 v List of Tables Table 2.1 Comparing modified Goodreid methods A and B for chosen model substrate .…….. 24 Table 2.2 Comparing the reactivity of the calcium and TBA salts of benzoic acid 2.16b and….25 Table 2.3 Comparing the reactivity of the calcium and TBA salts of Boc-Ala-OH 2.18a and ... 26 Table 2.4 Reaction of the calcium salt of Boc-Phe-OH 2.20a with select amines ….…………. 27 Table 3.1 Optimization of different carboxylate salts of leucine with different activating….…. 35 Table 3.2 Use of base and the free amino acid instead of amino acid salts …...…….…………. 37 Table 3.3 Altering conditions for tripeptide formation …..………………………….…………. 39 Table 3.4 Anthranilic acid as the middle “tripeptide” piece …..…………………….…………. 41 Table 3.5 Alternate methods for the formation of the lithium salt 3.14a and the effect on ……. 44 Table 3.6 Alternate methods for the formation of the metal salt 3.14b-e and the effect on ...…. 46 Table 3.7 Effect of using Leu salts instead of Phe salts on epimerization…………………….... 47 Table 3.8 Various reaction conditions for tripeptide Cbz-Phe-Phe-Ile-OMe 3.15 formation…...49 Table 3.9 Optimization of one pot-tripeptide conditions for formation of 3.15……..…………. 50 Table 3.10 Preliminary scope of tripeptides …...……………………………………………......51 Table 4.1 Decomplexation reactions ..………………………………………………………...... 58 Table 4.2 Improving formylation conditions for copper complex 4.9………………………...... 61 vi List of Figures Figure 1.1 Various Amino Acids and the pKa of their α-protons ..……………………………… 4 Figure 1.2 Assorted activating groups used for created the activated ester …...………………… 9 Figure 1.3 Mechanism of activation and coupling using [Ru] and ethoxyacetylene ….……….. 11 Figure 2.1 Select carboxylate salts reacted with amines by Batey and colleagues …………….. 15 Figure 2.2 H-NMR in CDCl3 of reaction shown in scheme 2.9 at 1.0 and 2.0 h …...………….. 22 Figure 3.1 Other potential activated acids for future testing …..………………………………..37 Figure 3.2 VT experiment displaying the methyl ester peak of non-coalescing peaks at 25 °C.. 42 Figure 4.1 Original proposed complex of copper-glycine …….……………………………….. 56 vii List of Schemes Scheme 1.1 Formation of protected dipeptide via silver(I) salt of glycine …..……………….…. 1 Scheme 1.2 Formation of Gly-Gly from diketopiperazine ...……....…………………………….. 1 Scheme 1.3 First example of the use of acid chlorides for peptide bond formation …………….. 2 Scheme 1.4 Method of generating peptide chains ……………………………………………….. 3 Scheme 1.5 Oxazolone formation causing epimerization of the -stereocentre in peptide…..….. 5 Scheme 1.6 Mechanism of Acid Chloride Formation from SOCl2 and (COCl)2……………..….. 6 Scheme 1.7 Epimerization of the -stereocentre via ketene formation………………………….. 7 Scheme 1.8 Mechanism of CDI activation and amine addition .......…………………………….. 7 Scheme 1.9 Formation of carbonic mixed anhydride 1.28 through ethyl chloroformate 1.27..…..8 Scheme 1.10 Mechanism of activation by HOBt & HOAt ………………………….…………. 10 Scheme 1.11 Reaction conditions for amide bond formation using ethoxyacetylene as a..……..10 Scheme 2.1 General method for the direct formation of amide bonds from metal carboxylates.. 15 Scheme 2.2 Formation of Cbz-Phg-Val-OBzl 2.8…...……………………………….………….16 Scheme 2.3 TiCl4 based method used by Liguori Group for amide bond formation ..…………. 16 Scheme 2.4 Proposed mechanism by Liguori group for TiCl4 activated amidation ...…………. 17 Scheme 2.5 General scheme for carboxylate salt formation and coupling by Kodomari group .. 18 Scheme 2.6 General procedure for the formation of the isobutyl anhydrides of the amino……..19 Scheme 2.7 Unintended reactivation of 2nd amino acid during 2nd step………..…….…………. 20 Scheme 2.8 The two methods used to generate calcium salts from the corresponding free……. 21 Scheme 2.9 Initial testing on coupling time required for reaction of the simple calcium salt….. 22 Scheme 2.10 General method for generating lithium salts published by Batey and coworkers... 23 Scheme 2.11 Using the Goodreid methods A and B on substrate 2.16a to verify yields for….... 23 viii Scheme 2.12 First attempts to utilize a one-pot approach for tripeptide synthesis using an……. 28 Scheme 3.1 Activation using p-NPCF and coupling of free acid in one pot ….…….…………..31 Scheme 3.2 Formation of benzotriazole esters and subsequent coupling to free amines ……….32 Scheme 3.3 One-pot activation and coupling of a free amino acid (AA2) using a mixed ethyl ...33 Scheme 3.4 In situ ONp ester activation of benzoic acid using EDC and subsequent coupling...38 Scheme 3.5 Coupling of two amino acids and one acid activation in a one-pot fashion ………. 39 Scheme 3.6 Two sequential in-situ ONp ester activations and couplings in one-pot ….………. 40 Scheme 3.7 Possible explanation of low yields from Table 3.4 …….……………….…………. 42 Scheme 4.1 Synthesis of Selective Monomethylated Lysine ….…………………….…………. 56 Scheme 4.2 Formation of selective ε-Cbz copper lysine complex …….…………….…………. 57 Scheme 4.3 Reduction of lysine ……………….…………………………………….…………. 59 Scheme 4.4 Attempts at obtaining the dimethylated ε-nitrogen product …...……….………….
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