SYNTHESIS OF HIGHLY ORDERED SEQUENCE DISTRIBUTIONS OF BROMINATED PLA AND ITS COMONOMERS BY PROTECTION/DEPROTECTION METHODS A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Xiang-Lin Yin May, 2014 SYNTHESIS OF HIGHLY ORDERED SEQUENCE DISTRIBUTIONS OF BROMINATED PLA AND ITS COMONOMERS BY PROTECTION/DEPROTECTION METHODS Xiang-Lin Yin Thesis Approved: Accepted: Advisor Dean of the College Dr. Coleen Pugh Dr. Stephen Z. D. Cheng Faculty Reader Dean of the Graduate School Dr. Abraham Joy Dr. George R. Newkome Department Chair Date Dr. Coleen Pugh ii ABSTRACT Previously, 2-bromo-3-hydroxypropionic acid (BrH)1 and glycolic acid (GA) were copolymerized with lactic acid (LA) by acid-catalyzed polyesterification to produce a functional group on the backbone of poly(lactic acid-co-glycolic acid). However, the molecular weight of the copolymer was less than the PLA homopolymer and when the amount of BrH or GA increased, the molecular weight of copolymer decreased. To compare the relative reactivity, BrH and GA were both end-capped with LA using protection/deprotection methods. Because BrH and GA were flanked by two lactic acid units, the reactivity of the trimer should be similar to that of pure LA. To avoid the hydroxy acid polymerizing by condensation polymerization when the dimers and trimers were synthesized, the alcohol group was protected by reaction with tert-butyldiphenylsilylchloride,2 and the carboxylic acid group was protected as a benzyl ester.3 After coupling the free hydroxy and free carboxylic acid groups of two units the protected one end was de-protected and then reacted with a monoprotected monomer to produce trimer. The trimers will be polymerized to obtain polymers with highly ordered sequence distribution by acid-catalyzed polyesterification. In addition, to determine whether acid-catalyzed reaction can destroy the well-defined sequence, a well-defined sequence polymerization was introduced.4 After this highly ordered sequence polymers were obtained by acid-catalyzed polyesterification, its degree of polymerization was obtained and compared iii with that of the random copolymer of the same composition. The degree of polymerization presents that the relative reactivity of GA and LA are similar. The reason why the molecular weight of highly ordered sequence polymer is less than that of the random one is that the segments of highly ordered sequence polymer are affinitive with each other to force the coil of it flow slowly through the column in GPC to obtain relatively low molecular weight. At the same time, two side deprotected brominated dimers (BrH-LA and LA-BrH) were also synthesized to obtain another brominated, sequence-controlled polymer and their properties will be characterized in the future. iv TABLE OF CONTENTS Page LIST OF TABLES ……….………………………………………………………...…..viii LIST OF SCHEMES……….…………………………………………...………………..ix LIST OF FIGURES …………………………………………………………………..…xii CHAPTER I. INTRODUCTION ……………………..……………………………………………….1 II. EXPERIMENTAL …………………...........................................................................23 2.1 Materials ……………………………………………………………...………..23 2.2 General Techniques ……………………..……..………………………………24 2.3 Synthesis of 2-bromo-3-hydropropionic acid ....………………,,..…………….24 2.4 Synthesis of methyl 2-bromo-3-hydroxypropionate …..…………………..…...25 2.5Synthesis of 2-bromo-3- ((tert-butyldiphenylsilyl)oxy)propionate ………….….26 2.6 Synthesis of 2-bromo-3- ((tert-butyldiphenylsilyl)oxy)propionic acid ………...27 2.7 Synthesis of benzyl (DL)-lactate (Bn-LA) …………………………..………...28 2.8 Synthesis of Bn-La-BrH-TBDPS(p-LB-p) ………………………..…………...29 2.9 Synthesis of methyl 2-((tert-butyldiphenylsilyl)oxy)propanoate ……….….….29 2.10 Synthesis of 2-((tert-butyldiphenylsilyl)oxy)propanoic acid (LA-Si) …...…...30 2.11 Synthesis of HOOC-La-BrH-TBDPS (HOOC-LB-p)………………………...31 v 2.12 Synthesis of Bn-La-BrH-OH(p-LB-OH)……………………………………...32 2.13 Synthesis of HOOC-La-BrH-OH (HOOC-LB-OH)…………………………..32 2.14 Synthesis of Bn-LBL-TBDPS (p-LBL-p)……………………………………..33 2.15 Synthesis of benzyl 2-bromo-3-hydropropanoate……………………………..34 2.16 Synthesis of Bn-BrH-La-TBDPS (p-BL-p)…………………………………...34 2.17 Synthesis of 2-bromo-3-((2-hydroxypropanoyl)oxy)propanoic acid……….…35 2.18 Synthesis of methyl 2-(tert-butyldimethylsilyloxy)propanoate……………….36 2.19 Synthesis of 2-(tert-butyldimethylsilyloxy)propanoic acid……………….…..37 2.20 Synthesis of Bn-LBL-TBDMS (p-LBL-p)……………………………………37 2.21 Synthesis of Bn-LBL-OH (p-LBL-OH)………………………………………38 2.22 Synthesis of benzyl glycolate (Bn-GA)……………………………………….39 2.23 Synthesis of Bn-GL-SiTBDP (p-GL-p)……………………………………….40 2.24 Synthesis of HOOC-GL-SiTBDP (HOOC-GL-p)…………………………….41 2.25 Synthesis of Bn-LGL-SiTBDP (p-LGL-p)……………………………………42 2.26 Synthesis of Bn-LGL-OH (p-LGL-OH)………………………………………42 2.27 Synthesis of HOOC-LGL-OH………………………………………………...43 2.28 Polymerization of poly (LGL) by acid-catalyzed……………………………..43 2.29 Polymerization of poly(lactic acid-co-2-bromo-3-hydroxypropionic acid) by acid-catalyzed (pTSA) (PLB6633)………………………………………………....44 2.30 Synthesis of the salt of 4-methylbenzenesulfonic acid and N,N- dimethylpyridin-4-amine (DPTS)………………………………………………….45 vi 2.31 Polymerization of poly (LGL) by DPTS……………………………………...45 III. RESULTS AND DISCUSSION ……………….…………………………………....47 3.0 Synthesis routes………………………………………………………………...47 3.1 Silyl Protection of the Hydroxy Acids ………………………..………………..49 3.2 Benzyl Protection of the Hydroxy Acids …………………………..…………..57 3.3 Synthesis of dimer ………………………………..…………………………….62 3.4 Synthesis of one side deprotected dimer………………………………………..67 3.5 Synthesis of two side deprotected dimer……………………………………….75 3.6 Synthesis of two side protected trimer…………………………………………82 3.7 Synthesis of one side deprotected trimer…………………………………….…90 3.8 Synthesis of two side deprotected trimer……………………………………….97 3.9 Synthesis of sequence controlled and random poly (glycolic acid-co-lactic acid)………………………………………………………………………………..100 IV.CONCLUSION……………………………………………………………………...107 REFERENCES ………………………………………………………………………...111 vii LIST OF TABLES Table Page 1.1 Naming conventions for segmers and polymers……………………………………..10 1.2 Degree of polymerization of PLGA, PLB and PLGB compared with PLA ………...15 viii LIST OF SCHEMES Scheme Page 1.1 Two conditions of biodegradation ……………………………………………………1 1.2 Synthesis of poly(lactic-alt-glycolic acid)…………………………………………….8 1.3 Synthesis of repeating sequence copolymers (RSCs)………………………………..11 1.4 Copolymerization of LA and BrH …………………………………………………...14 1.5 Trimer (LBL): lactic acid-2-bromo-3-hydroxypropinic acid-lactic acid and Trimer (LGL) : lactic acid-2-glycolic acid-lactic acid …………………………………………..15 1.6 Synthesis of bisprotected LGL trimer ……………………………………………….16 1.7 Synthetic strategy for Poly(LGL) copolymer ……………………………………….18 1.8 Synthesis of random polymer of PLG with amount ratio of lactic acid: glycolic acid=2:1 …………………………………………………………………………………18 1.9 Unsuccessful strategies of synthesizing diprotected LBL trimer……………..……..19 1.10 Synthesis of dimer (BrH-LA) after deprotecting two sides in one step reaction ….19 1.11 Synthesis of p-LBL-p trimer …………………..…………………………………...20 1.12 Synthesis of Poly(LBL) copolymer ………………………………………………..20 1.13 Protection group replacement. (TBDPS replaced by TBDMS) ……………………21 3.0.1 Synthesis trimer (LGL)…………………………………………………………….47 3.0.2 Synthesis of sequence-controlled poly(LGL) and random poly(lactic acid-co- glycolic acid)……………………………………………………………………………..48 ix 3.0.3 Synthesis of Bn-BrH-LA-TBDPS and HOOC-BrH-LA-OH……………………...48 3.0.4 Synthesis of Bn-LBL-OTBDPS and HOOC-LA-BrH-OH…………………..…….49 3.0.5 Synthesis of Bn-LBL-OH………………………………………………………….49 3.1.1 Synthesis of silyl protection of BrH ……………………………………………….49 3.1.2 Synthesis of silyl (TBDPS) protection of methyl lactic acid ……………………...53 3.1.3 Synthesis of 2-((tert-butyldimethylsilyl)oxy)propionic acid……………………....55 3.2.1 Synthesis of benzyl 2-hydroxypropionate ……………………………..………….57 3.2.2 Synthesis of benzyl 2-hydroxyacetate……………………………………………..58 3.2.3 Synthesis of benzyl 2-bromo-3-hydroxypropionate…………………………..…...60 3.3.1 Synthesis of the p-LA-BrH-p dimer ………………………………………………62 3.3.2 Synthesis of the p-BrH-LA-p dimer……………………………………………….63 3.3.3 Synthesis of p-GA-LA-p dimer……………………………………………………66 3.4.1 Hydrogenation of Bn-BrH-LA-TBDPS……………………………………………68 3.4.2 Synthesis of Bn-LA-BrH-OH (p-LB-OH)…………………………………………70 3.4.3 Synthesis of HOOC-GA-LA-TBDPS (HOOC-GL-p)……………………………..74 3.5.1 Synthesis of HOOC-LA-BrH-OH (HOOC-LB-OH)………………………………75 3.5.2 Synthesis of HOOC-BrH-LA-OH (HOOC-BL-OH)………………………………79 3.6.1 Synthesis of Bn-LA-BrH-LA-TBDPS (p-LBL-p)…………………………………82 3.6.2 Synthesis of Bn-LA-BrH-LA-TBDMS (p-LBL-p)………………………………...85 x 3.6.3 Synthesis of Bn-LA-GA-LA-TBDPS (p-LGL-p)………………………………….89 3.7.1 Synthesis of Bn-LA-BrH-LA-OH (p-LBL-OH)…………………………………...90 3.7.2 Synthesis of Bn-LA-GA-LA-OH (p-LGL-OH)……………………………………94 3.8.1 Synthesis of HOOC-LA-GA-LA-OH (LGL)………………………………………97 3.9.1 Synthesis of sequence controlled polymerization catalyst (DPTS)………………100 3.9.2 Synthesis of sequence controlled polymer Poly(LGL)……………….………..…101 3.9.3 Synthesis of poly(glycolic acid-co-lactic acid) by acid catalyst………………….101 xi LIST OF FIGURES Figure Page 1.1 The mechanism of Krebs cycle………………………………………………………..2 1.2 (A to C) Synthesis of sequence-defined artificial macromolecules with evolutionarily optimized biological mechanisms…………………………………………………………5 1.3 Going the long way: Attaching monomers one by one………………………………..6 1.4 Representative chemical approaches to sequence control…………………………….7