Bioorthogonal reactions, due to its excellent selectivity and time-efficiency, have emerged as a popular tool for protein and cell probing. Among all the bioorthogonal reactions, the inverse electron-demand Diels-Alder reaction (IEDDA) reaction has its advantage of bearing the fastest kinetics. Although the IEDDA reaction drew considerable attention in chemical biology in the last decade, challenges lie in finding the suitable dienophiles. Strained dienophiles, for example, trans-cyclooctene derivatives, can undergo ultrafast IEDDA reactions and therefore have been extensively developed. Unstrained alkenes and alkynes, however, have not been well investigated as IEDDA handles. In general, unstrained dienophiles are more straightforward to synthesise compared with strained dienophiles, therefore they are more accessible to researchers. In addition, the absence of a highly reactive bond makes unstrained dienophiles inert to biological nucleophiles, which allows effectively cellular labelling. In this dissertation, I described three different unstrained dienophiles for different biological purposes. Allyl handle is thiol-stable and non-toxic, which was utilised to label apoptotic cells in a pre-targeting manner. Enol ethers can react with tetrazines to decage protected amino acids and prodrugs. Potassium arylethynyltrifluoroborate, as a novel dienophile, was shown to react fast with pyridyl tetrazines controllably and this new IEDDA was applied to label proteins site-selectively and to fluorescently label two proteins orthogonally. In addition to IEDDA reactions, other bioorthogonal reactions were also developed using these versatile unstrained handles. Allyl-bearing amino acids and proteins can undergo an acetophenone-mediated hetero-[2+2] photocycloaddition with maleimide derivatives, expanding the toolbox of photo-triggered chemistry for protein modification. The potassium arylethynyltrifluoroborate handle was also found reactive in copper(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) and showcased the huge potential for protein labelling and multicolour cellular labelling.

Isatin-derived 1,2,4-triazines were employed as electron deficient azadienes in inverse electron demand Diels-Alder (IEDDA) chemistry with tethered alkynyl dienophiles, leading to biologically interesting heterocyclic lactam- and lactone-annulated α-carbolines in excellent yields under microwave promotion. The chemistry scope was probed using various alkynyl amines and alcohols, and the impact of the tether length between the triazines and the dienophiles was also investigated. This IEDDA methodology was subsequently applied to the synthesis of an α-carboline library, producing eighty-eight members starting with various isatin-derived triazines, indole-derivatives, and propargylamine derivatives. In a related project, a regioselective Lewis acid catalyzed amidation of dimethyl 5H-pyridazino[4,5-b]indole-1,4-dicarboxylate was established to selectively direct the amidation to occur at either the C1 or C4 ester positions. This chemistry was then applied to tether dienophiles to the pyridazinoindole ring via an amide linkage. Subsequent IEDDA cycloadditions of these pyridazinoindole/dienophile pairs afforded carbazoles in excellent yields under thermal conditions. The scope of this chemistry scope was also thoroughly probed, leading to a library of one hundred and eighty-eight members. The synthesis of a third heterocyclic scaffold using Diels-Alder chemistry was also accomplished. Asymmetric cycloadditions of anthrone with various maleimides were successfully achieved using different chiral organocatalysts. The identity of the optimal catalytic system depended upon the dienophile, with good enantioselectivities achieved (78-83% ee). This chemistry was successfully applied as the stereocontrol element in a Diels-Alder/Functional Group Transformation/retro-Diels-Alder sequence to prepare alkaloidal scaffolds in an optically enriched form.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第23923号 / 工博第5010号 / 新制||工||1782(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 浜地 格, 教授 森 泰生, 教授 秋吉 一成 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

The thesis work described herein explores two avenues of post-functionalization of conjugated polymers using ‘click’ chemistry. The first avenue utilizes the Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC) and the second an Inverse Electron-Demand Diels-Alder (IEDDA). In the first part of this thesis, various azide moieties were SPAAC ‘clicked’ onto a dibenzocyclooctyne-containing polymer, such as small molecules like para-phenyl-nitroazide, as well as larger azide-terminated chains like polystyrene and polyethylene glycol. Host-guest chemistry and self-healing organogels were also explored. The synthesis of each component, including the cyclooctyne diamine monomer, dialdehyde comonomer, resulting polymer, various azide moieties, as well as the SPAAC click reactions, are all described in detail along with extensive characterization. Similarly, the second part of this thesis involved the synthesis and characterization of several components, including the tetrazine monomer, fluorene comonomer, resulting polymer, and various TCO derivatives for the post-polymerization IEDDA ‘click’ reactions onto the backbone. Some of the click reactions described include small molecule TCO derivatives, polymeric PEG TCO, and a difunctional linker to generate a crosslinked foam. / Conjugated polymers attract significant attention due to their interesting optoelectronic and physical properties. Over the past few decades, tremendous effort has been devoted to expanding the structural diversity and applications of this class of macromolecules. The pursuit of structural variability of conjugated polymers has resulted in a broad range of research to understand their structure-property relationships via functionalization. This functionalization is crucial for tailoring performance in any given application. Thus, the ability to synthesize a library of homologous polymers would prove very useful. Efficiency is of utmost importance when creating a library of homologous conjugated polymers, as the faster a library can by synthesized, the sooner said polymers can be screened for any desirable properties. Such an approach requires a post-polymerization functionalization strategy, whereby a progenitor polymer undergoes efficient reactions at each repeat unit of the backbone. The work presented in this thesis involves synthesizing a reactive conjugated polymer scaffold, followed by efficiently post-polymerization functionalization via “click” chemistry. Two elegant click reactions are described in this work; the Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC) and Inverse Electron-Demand Diels-Alder (IEDDA). The SPAAC reaction allowed for rapid functionalization of triazole moieties on a dibenzocyclooctyne-containing polymer backbone, creating a small polymer library with a consistent degree of polymerization (DP). Grafting with polystyrene and polyethylene glycol azide-terminated polymers allowed the efficient syntheses of a series of graft-co-polymers with Mn values up to 800 kDa and varying solubilities. Secondly, The IEDDA reaction was applied to a poly(tetrazine-co-fluorene) conjugated polymer, which resulted in the rapid and quantitative functionalization of the polymer backbone with trans-cyclooctene derivatives. These reactive conjugated polymers were explored in a variety of applications, including supramolecular chemistry and gel formation. / Thesis / Doctor of Philosophy (PhD) / Conjugated polymers are a class of macromolecular materials that attract significant attention due to their interesting behaviors and properties. Under certain conditions, these polymers even display conductivities like that of metals. As such, they show promise in applications such as organic solar cells, chemical sensors, organic light-emitting diodes, and supercapacitors. Over the past few decades, tremendous effort has been devoted to expanding on the types of conjugated polymers as well as their structural diversity. This, of course, has resulted in polymers that exhibit vastly different behaviours depending on what they are made of. As certain applications (e.g.: solar cells) require polymers with very specific properties, being able to ‘tune’ a conjugated polymer to ‘match’ a required property would be extremely useful. This tuning of polymer properties can be successfully accomplished by attaching different structures onto the polymer chain by utilizing a reaction known as ‘post-polymerization functionalization’. In doing so, a starting reactive polymer can be transformed into an entirely different polymer with specific chemical properties and behaviors. The work presented in this thesis involves synthesizing two types of conjugated polymers and attaching various structures onto their backbones to yield different properties. The synthesis, characterization, and potential applications of said polymers are described herein.