Acknowledgements Firstly, I would like to thank Andy for all the help and guidance he has given me over the past few years; without his ideas and inspiration, this work would not have been possible. In particular, his input has made the project more interesting and varied, which has made my time in the lab an enjoyable one. Also, I would like to thank him for being a willing and efficient proof-reader, over the course of many presentations and reports during my time in York. I would like to thank Steve and Paul from Cytec Engineered Materials for their useful suggestions, support, funding, and for the GPC analysis of polymer samples. My thanks go to all the current and previous members of the AFP group. In particular, thanks to Matthew for his advice and expertise in the lab, and for trying to pass on his practical organic chemistry skills to a complete novice. I would like to thank Prof. Peter O’Brien for allowing the AFP group to make a home in his laboratory over the past few years, and for inviting me to his research meetings, which have proved invaluable to my progress as an organic chemist. Also, my thanks go to all the members of the PO’B group, both past and present, for providing enough banter to make the last two years fly by. My thanks also go the Taylor group, for letting me use their DMDO, and for giving me a desk space in their office. I would like to thank Dr. Karl Heaton for performing MALDI-MS analysis on the polymer samples. Also, thanks to Steve and Mike in stores for their assistance and banter over the years. My thanks go to all of the footballers in the department that I’ve had the pleasure of playing alongside and captaining, particularly to those who turned up and played in the pouring rain on many occasions. Finally, I would like to thank Stacey for her love and support over the past few years, but especially for brightening up the ends of the many long days I’ve spent writing-up.
Fraction of 83 (in a mixture of 10 and 83) Conversion to 85 / % PDi Tg / °C 0.25 21 1.31 166 0.33 25 1.34 176 0.50 24 1.43 180 0.67 15 1.34 184 0.75 15 1.40 190 Scheme 49: The co-polymerisation of styrene (10) and N-cyclohexylmaleimide (83) by ATRP, to produce co-polymers with a low PDi. As shown in Scheme 49, ATRP can be used for the co-polymerisation of styrene (10) and N-cyclohexylmaleimide (83) to produce the polymeric species (85) with a low PDi. Also in this work, it was shown that increasing the fraction of N-cyclohexylmaleimide (83) from 0.25 to 0.75 resulted in an increase in the Tg (166 - 190 °C) of the co-polymer (85); this is attributed to the higher proportion of the rigid 5-membered maleimide structure in the final polymer, which has a higher thermal stability than the more flexible styrene. Nitroxide mediated co-polymerisation of maleimides with styrene (10) can also be used to control the molecular weight distribution of maleimide polymers. For example, Lokaj and co-workers have shown that heating maleimide (86) and styrene (10) with TEMPO (15) can lead to a maleimide-styrene co-polymer (87) with a low PDi and good thermal stability (Scheme 50).99
Chapter 4: A New Synthetic Approach Towards Analogues of the Natural Product D-(+)-Showdomycin (61) Introduction Background The maleimide ring features prominently in a number of naturally occurring compounds, including farinomalein (35),72 pencolide (60),75 and D-(+)-showdomycin (61) (Figure 13).130 These molecules have shown promising antibiotic behaviour and commonly feature a maleimide that is at the 3-position. Both pencolide (60) and farinomalein (35) have been prepared in the laboratory, with the maleimide 3-substituent being installed through a maleic anhydride precursor; the synthesis of these molecules is discussed in Chapter 1. Figure 13: The structures of three maleimide-containing natural products; farinomalein (35), pencolide (60) and D-(+)-showdomycin (61). The most widely studied maleimide-containing natural product is the C-nucleoside antibiotic D-(+)-showdomycin (61), which was first isolated from Streptomyces showdoensis by Nishimura and co-workers in 1964.71 D-(+)-Showdomycin (61) contains a substituted furanose ring, with the primary alcohol and the maleimide group arranged in a cis configuration; the structure of 61, drawn as a Haworth projection, is shown in Figure 14. The biological activity of D-(+)-showdomycin (61) is believed to arise from the electron-deficient maleimide alkene, which can undergo conjugate addition reactions with nucleophiles, such as the thiol-containing cysteine residues that are found in proteins.131 Figure 14: The structure of D-(+)-showdomycin (61), drawn as a Haworth projection to emphasise the cis relationship between the 1° alcohol and the maleimide. Previous Syntheses of Showdomycin
H2O2. Our retro-synthetic analysis of EPM (74) is shown in Scheme 109. This approach involves first synthesising the N-allylmaleimide (97) pre-cursor from cheap, readily available, maleic anhydride (45) and N-allylamine (256), before subsequent epoxidation of the allyl group using a suitable oxidising agent. Scheme 109: The retro-synthetic analysis of EPM (74) from cheap, readily available starting materials maleic anhydride (45) and N-allylamine (256). Literature Methods for the Synthesis of N-Allylmaleimide (97) The traditional method for the synthesis of N-substituted maleimides is to first generate the maleamic acid derivative from maleic anhydride (45) and a suitable primary amine, before closing the 5-membered ring through heating. For example, this method was used by Jones and co-workers in 2011, whereby they prepared N-allylmaleimide (97) in 31% yield (Scheme 110); compound 97 was subsequently used as a substrate in their efforts to investigate stereoselective intermolecular Friedel-Crafts reactions.154 The low yield of (97) achieved using this procedure can be attributed to the sensitivity of the allyl group to the harsh acidic conditions required for the 5-exo-trig cyclisation. Scheme 110: The synthesis of N-allylmaleimide (97), as reported by Jones and In a 1992 paper,155 Braish and Fox reported another route towards the synthesis of maleimides, which involved the use of inexpensive reagents and mild reaction conditions to afford the maleimide products in good yields. This method also involves the reaction of maleic anhydride (45) with a suitable primary amine, to form the maleamic acid in quantitative yield (Scheme 111). A subsequent reaction using oxalyl chloride (257) and DMF (258) affords a chlorinated-succinimide intermediate, which was transformed into the maleimide product upon treatment with triethylamine (157). R Yield of Maleimide Product / % -CH2CH=CH2 (97) 68
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