WO2021260392A1

WO2021260392A1 - Polymer

Info

Publication number: WO2021260392A1
Application number: PCT/GB2021/051623
Authority: WO
Inventors: Rongjun Chen; Li Yu; Yuying Tang; Xinyu Lu
Original assignee: Imperial College Innovations Ltd
Current assignee: Ip2ipo Innovations Ltd
Priority date: 2020-06-25
Filing date: 2021-06-25
Publication date: 2021-12-30
Anticipated expiration: 2022-12-25
Also published as: GB202009720D0; GB202010493D0

Abstract

There is provided a method of producing a polymer, the method comprising contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer. The monomers are cyclic and the polymerisation reaction is either a ring opening polymerisation (ROP) reaction or a ring opening copolymerisation (ROCOP) reaction. The invention also extends to the polymers per se and uses thereof.

Description

Polymer The present disclosure is concerned with polymers. In particular, the disclosure is concerned with a method of producing polymers, as well as the polymers per se. Highly organized biomacromolecules play a crucial role in nature. For example, DNA stores huge genetic information for the development, functioning, growth and reproduction of all known living organisms and many viruses, via perfectly defining the sequential arrangements of four different nitrogen-containing nucleobase monomer units^{1, 2} (adenine [A], thymine [T], cytosine [C] and guanine [G]), and the refined sequence regulations of diverse peptides direct the folding of chains into precise tertiary three-dimensional structures, endowing proteins with various highly specific activities³. However, in many research fields the commonly used artificial macromolecules are mainly copolymers with simple chain microstructures, such as statistical copolymers⁴, in which the primary structure (monomer sequence) is generally poorly controlled, leading to indisciplinable and unpredictable structural, physicochemical and biological properties. Hence, developing highly ordered sequence- controlled artificial polymers containing the structural and functional complexity towards molecular precision as revealed in nature would be a significant breakthrough with many potential applications in a variety of fundamental and applied explorations including healthcare, pharmaceutical, biotechnology, nanoscience and nanotechnology^{5, 6}. Over the past several decades, tremendous efforts have been devoted to manipulating the architecture of artificial polymer materials. Solid-phase iterative peptide synthesis is arguably the first most successful example, opening up a new era of artificial sequence-control polymers^7-9. Nevertheless, the coupling, filtration and washing process is typically time-consuming^{10, 11} and the insoluble solid supports are often expensive¹². Moreover, the solid-phase coupling reaction rates are restricted by monomer diffusion into the solid support, ultimately resulting in poor yields¹³. Overall, the solid-phase iterative synthesis is difficult to scale up, limiting the potential for numerous real-world applications^{12, 14}. To overcome these limitations, a number of liquid-phase iterative synthesis approaches have been proposed and exploited in the last decade to enable synthesis of sequence- controlled polymers with a wider range of chemical functionalities on a larger scale (gram rather than milligram)^{15, 16}. The premiere liquid-phase iterative synthesis method based on the use of soluble supporters was reported by Lutz and co-workers¹⁷. It was only an optimization of the solid-phase methodology for synthesis of artificial sequence-controlled oligomers via cycloaddition and amidification reactions. Subsequently, high-order acrylic multiblock copolymers were synthesized by Whittaker and co-workers via iterative one-pot Cu(0)-mediated radical polymerizations (SET- LRP)^18-21 and Haddleton^{22, 23} and Junkers^24-26 introduced sequence-controlled acrylic multiblock copolymers by photoinduced iterative copper polymerization. Additionally, an iterative reversible addition−fragmentation chain transfer (RAFT) polymerization approach was employed by Perrier and co-workers^27-30, yielding impressive sequence- controlled multiblock copolymers. Recently, an iterative exponential growth approach has been developed by Johnson, Jamison and their co-workers^{14, 31} to synthesize sequence-controlled macromolecules with a molecular weight above 3 kDa. Critically, however, in the majority of these liquid-phase iterative strategies, chain-transfer agents and the halide (used in transition-metal-mediated approaches) are normally attached to the backbone chains even after purification, which may be undesirable in certain future applications¹². A further limitation to applying the polymers synthesised via these approaches is owing to their rarely biocompatible or biodegradable backbones³². Consequently, increasing interest has been emerging in sequence-controlled polyesters because of their inherent superior biocompatibility and biodegradability. Williams et al.³³ reported the use of a liquid-phase kinetic control approach for block copolyester synthesis. Due to different relative reactivities of monomers as determined from homopolymerization³⁴, a dizinc catalyst was able to switch between distinct polymerization cycles and show a high monomer selectivity among mixtures of several different monomers, such as lactones, epoxides and anhydrides. The monomers with significantly faster rates of insertion into the zinc intermediate were consumed first to form the first block and monomers with lower insertion rates were then polymerized to constitute subsequent blocks. It opened up a new way of chemoselective polymerization for synthesis of block copolyesters with predictable compositions and sequences. Nevertheless, owing to the kinetic nature of monomers, this kind of block copolyesters are typically amenable only to some fixed sequence. This approach cannot offer a precise control over the chain length of each block, which makes it difficult to fine tune polymer properties. Therefore, it is timely and highly challenging to develop a simple and readily scalable technology for synthesis of sequence-controlled artificial polyesters with a high level of structural and site-selective functional complexities and tunable physicochemical and biological properties. The present invention arose from the inventors’ work in attempting to overcome the problems associated with the prior art. In accordance with a first aspect of the invention, there is provided a method of producing a polymer, the method comprising contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer, wherein the plurality of monomers are a plurality of molecules of formula (I):

, wherein X¹ is CO, CR¹R², SO or SO₂; X² is O, NR³ or S; X³ is CR⁴R⁵ or CO; each X⁴ is independently CR⁶R⁷, NR⁸, CO, O, S, SO or SO₂; n is 0 or an integer which is at least 1; R¹ and R² are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; R³ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, COOR⁹ or CONR⁹R¹⁰; R⁴ and R⁵ are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; R⁶ and R⁷ are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N3; or one or more pairs of substituents, together with the atoms to which they are attached, independently form an optionally substituted 3 to 20 membered ring, wherein each pair of substituents consists of two of R¹ to R⁷; R⁸ and R⁹ are each a protecting group; and R¹⁰ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Advantageously, the method allows a novel quantitative one-pot iterative living ring- opening polymerization (QOIL-ROP) approach for the scalable production of well- defined sequence-controlled functional polymers with desirable biocompatibility via successive sequential addition of monomers without intermediate purification. The method can be used to produce polymers with relatively narrow molecular weight distributions (MWDs) and extraordinary agreement between the theoretical and experimental molecular weights. Various properties, including the physicochemical properties and biodegradation behaviours of resultant polymers can be tuned by precisely controlling monomer types, monomer sequences and chain length. The biological activity of the polymers could also be tuned. This strategy offers new perspectives for integration of structural versatility and further functional diversity into both water-soluble and water-insoluble sequence-controlled artificial polymers. The term “alkyl” as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. The alkyl may be a primary, secondary, or tertiary hydrocarbon. C_1-30 alkyls include for example methyl, ethyl, n-propyl (1-propyl), isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. The or each alkyl may be an optionally substituted C_1-30 alkyl, an optionally substituted C_1-20 alkyl, an optionally substituted C_1-12 alkyl, an optionally substituted C_1-6 alkyl or an optionally substituted C_1-3 alkyl. An alkyl group can be unsubstituted or substituted. A substituted alkyl may be substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N3, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted alkyl may be a halogenated alkyl, i.e. an alkyl substituted with one or more halogens. A halogenated alkyl may be substituted with one or more further substituents. The term “alkenyl” refers to olefinically unsaturated hydrocarbon groups which can be unbranched or branched. Accordingly, an alkenyl may contain one or more double bonds between adjacent carbon atoms. C2-C30 alkenyl includes for example vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl. The or each alkenyl may be an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-12 alkenyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-3 alkenyl. An alkenyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N₃, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted alkenyl may be a halogenated alkenyl, i.e. an alkenyl substituted with one or more halogens. A halogenated alkenyl may be substituted with one or more further substituents. The term “alkynyl” refers to acetylenically unsaturated hydrocarbon groups which can be unbranched or branched. Accordingly, an alkynyl may contain one or more triple bonds between adjacent carbon atoms. An alkynyl group may further contain one or more double bonds between adjacent carbon atoms. The C₂-C₃₀ alkynyl includes for example propargyl, propynyl, butynyl, pentynyl and hexynyl. The or each alkynyl may be an optionally substituted C_2-30 alkynyl, an optionally substituted C_2-20 alkynyl, an optionally substituted C_2-12 alkynyl, an optionally substituted C_2-6 alkynyl or an optionally substituted C_2-3 alkynyl. An alkynyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N3, an optionally substituted C_2-30 alkenyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted alkynyl may be a halogenated alkynyl, i.e. an alkynyl substituted with one or more halogens. A halogenated alkynyl may be substituted with one or more further substituents. “Aryl” refers to an aromatic 6 to 20 membered hydrocarbon group. Examples of a C₆- C₂₀ aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl and indanyl. The or each aryl may be an optionally substituted C_6-12 aryl. An aryl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N3, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted aryl may be a halogenated aryl, i.e. an aryl substituted with one or more halogens. A halogenated aryl may be substituted with one or more further substituents. The term “bicycle” or “bicyclic” as used herein can refer to a molecule that features two fused rings, which are a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl, a heteroaryl, or a heterocycle. In one embodiment, the rings are fused across a bond between two atoms. The bicyclic moiety formed therefrom shares a bond between the rings. In another embodiment, the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of the rings to form a bridgehead. Similarly, a “bridge” is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound. In another embodiment, the bicyclic molecule is a “spiro” or “spirocyclic” moiety. The spirocyclic group may be a cycloalkyl, a cycloalkenyl, a cycloalkynyl, a heteroaryl, or a heterocycle which is bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety. In one embodiment, the spirocyclic group is a cycloalkyl, a cycloalkenyl or a cycloalkynyl and is bound to another cycloalkyl, cycloalkenyl or cycloalkynyl. In another embodiment, the spirocyclic group is a cycloalkyl, a cycloalkenyl or a cycloalkynyl and is bound to a heterocycle. In a further embodiment, the spirocyclic group is a heterocycle and is bound to another heterocycle. In still another embodiment, the spirocyclic group is a heterocycle and is bound to a cycloalkyl, a cycloalkenyl or a cycloalkynyl. “Cycloalkyl” refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 20 membered ring system. The or each cycloalkyl may be an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-12 cycloalkyl or an optionally substituted C3-6 cycloalkyl. Representative examples of a cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. A cycloalkyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N3, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted cycloalkyl may be a halogenated cycloalkyl, i.e. a cycloalkyl substituted with one or more halogens. A halogenated cycloalkyl may be substituted with one or more further substituents. “Cycloalkenyl” refers to a non-aromatic, olefinically unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 20 membered ring system. Accordingly, a cycloalkenyl may contain one or more double bonds between adjacent carbon atoms in the ring. The or each cycloalkenyl may be an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-12 cycloalkenyl or an optionally substituted C_3-6 cycloalkenyl. A cycloalkenyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N₃, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted cycloalkenyl may be a halogenated cycloalkenyl, i.e. a cycloalkenyl substituted with one or more halogens. A halogenated cycloalkenyl may be substituted with one or more further substituents. “Cycloalkynyl” refers to a non-aromatic, acetylenically unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 20 membered ring system. Accordingly, a cycloalkynyl may contain one or more triple bonds between adjacent carbon atoms in a ring. A cycloalkenyl may also contain one or more double bonds between adjacent carbon atoms in a ring. The or each cycloalkynyl may be an optionally substituted C_3-20 cycloalkynyl, an optionally substituted C_3-12 cycloalkynyl or an optionally substituted C_3- ₆ cycloalkynyl. A cycloalkynyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N3, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted cycloalkynyl may be a halogenated cycloalkynyl, i.e. a cycloalkynyl substituted with one or more halogens. A halogenated cycloalkynyl may be substituted with one or more further substituents. “Heteroaryl” refers to a monocyclic or bicyclic aromatic 5 to 20 membered ring system in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorous. The heteroaryl may be an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 5 to 10 membered heteroaryl. Examples of 5 to 20 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include for example those where a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring. A heteroaryl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N₃, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted heteroaryl may be a halogenated heteroaryl, i.e. a heteroaryl substituted with one or more halogens. A halogenated heteroaryl may be substituted with one or more further substituents. “Heterocycle” or “heterocyclyl” refers to 3 to 20 membered monocyclic, bicyclic, polycyclic or bridged molecules in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorous. A heterocycle may be saturated or partially saturated. A heterocyclic group may be an optionally substituted 3 to 20 membered heterocycle or an optionally substituted 3 to 12 membered heterocycle. Exemplary 3 to 20 membered heterocycle groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6- tetrahydropyridine-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane, and oxazine. A heterocycle group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹, CONR¹¹R¹², CN, N₃, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R¹¹ is a protecting group and R¹² is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group. Accordingly, the optionally substituted heterocycle may be a halogenated heterocycle, i.e. a heterocycle substituted with one or more halogens. A halogenated heterocycle may be substituted with one or more further substituents. A “protecting group” may be understood to be a substituent configured to prevent the adjacent group from reacting in a polymerisation reaction. Suitable protecting groups are known in the art. For instance, the or each protecting group may be selected from the group consisting of an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, COOR¹³, fluorenylmethoxycarbonyl (Fmoc), tosyl (Ts), benzyl, Si(R¹³)₃, 4,4’-dimethoxytrityl (DMTr) and tetrahydropyranyl (THP), where R¹³ is an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl or an optionally substituted C6-12 aryl. The C_1-30 alkyl may be a methyl, an ethyl, an isopropyl or a tert-butyl. The C6-12 aryl may be phenyl. Accordingly, the or each protecting group may be tert-butyl, BOC, Fmoc, Ts, benzyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS/TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), DMTr or THP. In embodiments where one or more pairs of substituents, together with the atoms to which they are attached independently form an optionally substituted 3 to 20 membered ring, the ring may be an optionally substituted C_3-20 cycloalkyl ring, an optionally substituted C_3-20 cycloalkenyl ring, an optionally substituted C_3-20 cycloalkynyl ring, an optionally substituted C_6-20 aryl ring, an optionally substituted 5 to 20 membered heteroaryl ring or an optionally substituted 3 to 20 membered heterocycle ring. The pair of substituents may be attached to the same atom. Alternatively, the pair of substituents may be attached to adjacent atoms. The initiator may have a molecular weight between 10 and 20,000 Da, between 20 and 10,000 Da, between 40 and 10,000 Da, between 60 and 5,000 Da, between 80 and 3,000 Da or between 100 and 2,000 Da. The initiator may be a microinitiator. An initiator may be considered to be a microinitiator if it has a molecular weight of less than 2,000 Da, less than 1,500 Da or less than 1,000 Da, more preferably less than 750 Da or less than 500 Da, and most preferably less than 250 Da, less than 200 Da or less than 150 Da. Alternatively, the initiator may be a macroinitiator. An initiator may be considered to be a macroinitiator if it has a molecular weight of at least 2,000 Da. A macroinitiator may have a molecular weight of between 2,000 and 20,000 Da, between 2,500 and 10,000 Da or between 3,000 and 5,000 Da. The initiator may be an alcohol or an amine. The alcohol may be a primary alcohol. The amine may be ammonia, a primary amine, a secondary amine or a tertiary amine. In some embodiments, the initiator is benzyl alcohol. Alternatively, the alcohol may be polyethylene glycol (PEG). PEG may be a microinitiator or a macroinitiator. PEG may have a molecular weight between 50 and 10,000 Da, between 100 and 10,000 Da, between 200 and 5,000 Da, between 300 and 3,000 Da or between 400 and 2,000 Da. Where the initiator is a polymer, the molecular weight may be the number average molecular weight (M_n). It may be appreciated that the ratio of the initiator to the plurality of monomers may vary depending upon the desired degree of polymerisation (DPn). The molar ratio of the initiator to the plurality of monomers may be between 1:1 and 1:1000, between 1:1 and 1:500, between 1:1 and 1:250, between 1:1 and 1:100, between 1:1 and 1:50 or between 1:1 and 1:40. In some embodiments, the molar ratio of the initiator to the plurality of monomers is between 1:1 and 1:20, between 1:1 and 1:10 or between 1:2 and 1:6. In alternative embodiments, the molar ratio of the initiator to the plurality of monomers is between 1:2.5 and 1:30, between 1:5 and 1:20 or between 1:7.5 and 1:15. In further alternative embodiments, the molar ratio of the initiator to the plurality of monomers is between 1:5 and 1:40, between 1:10 and 1:30 or between 1:15 and 1:25. The method may comprise contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur and, to thereby obtain a modified polymer, wherein the further plurality of monomers are a plurality of molecules of formula (I). The further plurality of monomers may be the same as the first plurality of monomers. Alternatively, the further plurality of monomers may be different to the first plurality of monomers. The method may comprise contacting the modified polymer with a yet further plurality of monomers, to cause a further polymerisation reaction to occur and, to obtain a further modified polymer, wherein the further plurality of monomers are a plurality of molecules of formula (I). The further plurality of monomers may be the same as one or more of the plurality of monomers used in the preceding steps. Alternatively, the further plurality of monomers may be different to the plurality of monomers used in the preceding steps. It may be appreciated that the ratio of the polymer or the modified polymer to the further plurality of monomers may vary depending upon the desired DP_n. The molar ratio of the polymer or the modified polymer to the plurality of monomers may be between 1:1 and 1:1000, between 1:1 and 1:500, between 1:1 and 1:250, between 1:1 and 1:100, between 1:1 and 1:50 or between 1:1 and 1:40. In some embodiments, the molar ratio of the polymer or the modified polymer to the plurality of monomers is between 1:1 and 1:20, between 1:1 and 1:10 or between 1:2 and 1:6. In alternative embodiments, the molar ratio of the polymer or the modified polymer to the plurality of monomers is between 1:2.5 and 1:30, between 1:5 and 1:20 or between 1:7.5 and 1:15. In further alternative embodiments, the molar ratio of the polymer or the modified polymer to the plurality of monomers is between 1:5 and 1:40, between 1:10 and 1:30 or between 1:15 and 1:25. Accordingly, the method may comprise: (a) contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer; and (b) contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur, and to thereby obtain a modified polymer, wherein each of the plurality of monomers are a plurality of molecules of formula (I) and may be the same or different to the plurality of monomers used in the other step. The method may not comprise any further polymerisation reactions. Alternatively, the method comprises: (a) contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer; (b) contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur, and to thereby obtain a modified polymer; and (c) contacting the modified polymer with a further plurality of monomers, to cause a further polymerisation reaction to occur, and to thereby obtain a further modified polymer, wherein each of the plurality of monomers are a plurality of molecules of formula (I) and may be the same or different to the plurality of monomers used in the other steps. Step (c) may be repeated. For instance, step (c) could be repeated at least 1 time, at least 2 times, at least 3 times, at least 4 times or at least 5 times. For instance, step (c) could be repeated between 1 and 100 times, between 1 and 50 times, between 1 and 25 times, between 1 and 10 times, between 1 and 5 times or between 1 and 2 times. The plurality of monomers used in any polymerisation reaction may all have the same chemical formula. Accordingly, the polymerisation reaction may be a ring opening polymerisation (ROP) reaction. Alternatively, or additionally, the plurality of monomers used in any polymerisation reaction may comprise a first molecule of formula (I) and a second molecule of formula (I), wherein the first and second molecules are different. The plurality of monomers used in any of the polymerisation reactions may comprise a plurality of first molecules of formula (I) and a plurality of second molecules of formula (I). Accordingly, the polymerisation reaction may be called a ring opening copolymerisation (ROCOP) reaction. The plurality of monomers and the initiator or polymer may be contacted in the presence of the catalyst. The catalyst may be an organocatalyst or an organometallic catalyst. The catalyst may be tin(II) 2-ethylhexanoate (Sn(Oct)2), t-Bu-P4 or a salt thereof. The molar ratio of the catalyst to the initiator or polymer may be between 1:100 and 100:1, between 1:75 and 75:1, between 1:50 and 50:1, between 1:25 and 25:1, between 1:10 and 10:1, between 1:5 and 5:1 or between 1:2 and 2:1. In some embodiments, the molar ratio of the catalyst to the initiator or polymer is about 1:1. The plurality of monomers and the initiator or polymer may be contacted at a temperature between 0 and 500 °C, between 5 and 400 °C or between 10 and 300 °C, more preferably between 15 and 200 °C, between 20 and 160 °C or between 25 and 140 °C, and most preferably between 30 and 120 °C or between 35 and 115 °C. In some embodiments, the plurality of monomers and the initiator or polymer are contacted at a temperature between 50 and 200 °C, between 60 and 180 °C, between 70 and 160 °C or between 80 and 140 °C, and most preferably between 90 and 130 °C, between 100 and 120 °C or between 105 and 115 °C. In alternative embodiments, the plurality of monomers and the initiator or polymer are contacted at a temperature between 10 and 100 °C, between 15 and 80 °C or between 20 and 60 °C, and most preferably between 30 and 50 °C or between 35 and 45 °C. The plurality of monomers and the initiator or polymer may be contacted under an inert atmosphere. For instance, the plurality of monomers and the initiator or polymer may be contacted under a nitrogen or argon atmosphere. In embodiments where at least one of the monomers comprises a protecting group, the method may comprise removing the protecting groups. The method may comprise removing the protecting groups after a desired number of polymerisation reactions have been conducted. Suitable methods for removing protecting groups are known in the art. The method may comprise purifying the polymer. The method may comprise purifying the polymer after a desired number of polymerisation reactions have been conducted. The method may comprise purifying the polymer after the protecting groups have been removed. Alternatively, the method may comprise purifying the polymer before the protecting groups have been removed. Suitable purification techniques are known in the art. For instance, purifying the polymer may comprise dissolving the polymer in a first solvent and precipitating it into a second solvent. It may be appreciated that the choice of the first and second solvents may depend upon the polymer to be purified. For instance, the first solvent may comprise dichloromethane (DCM). The second solvent may comprise hexane or methanol. Alternatively, the first solvent may comprise dimethyl sulphoxide (DMSO). The second solvent may comprise diethyl ether. The second solvent may be cold. Accordingly, the second solvent may be at a temperature of less than 20 °C, less than 15 °C, less than 10 °C, less than 5 °C or less than 0°C. The second solvent may be at a temperature between -150 and 20 °C, between -100 and 10 °C, between -80 and 5 °C or between -50 and 0 °C. Alternatively, or additionally, purifying the polymer may comprise using a flash column method. The method may not comprise a purification step between subsequent polymerisation reactions. The inventors have found that purification is not required between subsequent polymerisation reactions. This enables the polymer to be produced more quickly and in a higher yield. In some embodiments, the plurality of monomers comprise a compound of formula (I) which is an ester or anhydride. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ia):

The plurality of monomers may comprise an ester-ether or an anhydride-ether cyclic monomer. Accordingly, at least one X⁴ may be O or S. The plurality of monomers may comprise an ester-amide, anhydride-amide, ester-sulphoamide or anhydride- sulphoamide cyclic monomer. Accordingly, an adjacent pair of X⁴ groups may be CO and NR⁸ or SO₂ and NR⁸. Alternatively, each of X⁴ may be CR⁶R⁷ or NR⁸. Preferably X³ is CR⁴R⁵. Accordingly, the compound of formula (I) is preferably an ester. In some embodiments, R⁴ and R⁵ may independently be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Preferably, R⁴ and R⁵ are independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R⁴ and R⁵ are H, a halogen or methyl. In some embodiments, R⁴ and R⁵ are both H.In some embodiments, the plurality of monomers comprise a compound of formula (I) which is an ether. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ib):

R¹ and R² may independently be H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl or an optionally substituted C_2-30 alkynyl. Preferably, R¹ and R² are independently H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl or an optionally substituted C_2-20 alkynyl. R¹ and R² may independently be H, a halogen, an optionally substituted C_1-12 alkyl, an optionally substituted C_2-12 alkenyl or an optionally substituted C_2-12 alkynyl. R¹ and R² may independently be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Preferably, R¹ and R¹ are independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R¹ and R² are H, a halogen or methyl. In some embodiments, R¹ and R² may be H. Preferably X³ is CR⁴R⁵. R⁴ and R⁵ may independently be H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl or an optionally substituted C_2-30 alkynyl. R⁴ and R⁵ may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl or an optionally substituted C_2-20 alkynyl. In some embodiments, the plurality of monomers comprise a compound of formula (I) which is an amide. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ic):

R³ may be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Preferably, R³ is independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R³ is H, a halogen or methyl. In some embodiments, R³ is H. Preferably X³ is CR⁴R⁵. In some embodiments, R⁴ and R⁵ may independently be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Preferably, R⁴ and R⁵ are independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R⁴ and R⁵ are H, a halogen or methyl. In some embodiments, the plurality of monomers comprise a compound of formula (I) which is a sulphoamide. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Id):

R³ may be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Preferably, R³ is independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R³ is H, a halogen or methyl. In some embodiments, R³ is H. Preferably X³ is CR⁴R⁵. In some embodiments, R⁴ and R⁵ may independently be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Preferably, R⁴ and R⁵ are independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R⁴ and R⁵ are H, a halogen or methyl. n may be 0 or an integer between 1 and 20, or more preferably between 1 and 10. Accordingly, n may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In one embodiment, n is an integer between 2 and 8, between 3 and 6 and most preferably n is 4. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ie):

, wherein X¹ to X⁴ are as defined above; and X⁵ to X⁷ are each independently CR⁶R⁷, NR⁸, CO, O, S, SO or SO₂. In some embodiments, X¹ is CO and X² is O. In some embodiments, X¹ is CR¹R² and X² is O. In some embodiments, X¹ is CO and X² is NR³. In some embodiments, X¹ may be SO₂ and X² may be NR³. In one preferred embodiment, X¹ is CO and X² is O. In an alternative preferred embodiment, X¹ is CR¹R² and X² is O. Preferably, R⁴ and R⁵ are H, a halogen or methyl. In some embodiments, X³ is CH₂. Each of X⁴ to X⁷ may independently be CR⁶R⁷ or NR⁸. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰, NR⁹R¹⁰, CN or N3. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰ or NR⁹R¹⁰. Each of X⁴ to X⁷ may independently be CHR⁷ or NR⁸. Each of X⁴ to X⁷ may independently be CH2, CHNR⁹R¹⁰, CHOR¹⁰, CHN3 or NR⁸. R¹⁰ may be H, an optionally substituted C1-15 alkyl or a protecting group. R¹⁰ may be H, an optionally substituted C_1-6 alkyl or a protecting group. R¹⁰ may be H, a C_1-3 alkyl or a protecting group. In some embodiments, R¹⁰ is H, methyl or tert-butyldimethylsilyl. In some embodiments, X⁴ is CR⁶R⁷. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰, NR⁹R¹⁰, CN or N3. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰ or NR⁹R¹⁰. X⁴ may be CH₂. In some embodiments, X⁵ is CR⁶R⁷. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰, NR⁹R¹⁰, CN or N₃. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰ or NR⁹R¹⁰. X⁵ may be CH2, CHNR⁹R¹⁰ or CHOR¹⁰. R¹⁰ may be H, an optionally substituted C1-15 alkyl or a protecting group. R¹⁰ may be H, an optionally substituted C_1-6 alkyl or a protecting group. R¹⁰ may be H, a C_1- ₃ alkyl or a protecting group. In some embodiments, R¹⁰ is H, methyl or tert- butyldimethylsilyl. In alternative embodiments, X⁵ is NR⁸. In some embodiments, X⁶ is CR⁶R⁷. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰, NR⁹R¹⁰, CN or N₃. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰ or NR⁹R¹⁰. X⁶ may be CH2. In some embodiments, X⁷ is CR⁶R⁷. R⁶ and R⁷ may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, OR¹⁰, NR⁹R¹⁰, CN or N₃. R⁶ and R⁷ may independently be H, OR¹⁰, NR⁹R¹⁰, CN or N₃. R⁶ and R⁷ may independently be H or N₃. X⁷ may be CHR⁷. X⁷ may be CH₂ or CHN₃. The or each protecting group may be tert-butoxycarbonyl (Boc) protecting group. In some embodiments, the plurality of monomers may comprise a compound or a plurality of compounds of one or more of formula (If) to (Ik):

The compound of formula (Ig) may be a compound of formula (Igi):

The compound of formula (Ih) may be a compound of formula (Ihi) or (Ihii) and is preferably a compound of formula (Ihiii) or a compound of formula (Ihiv):

The compound of formula (Ij) may be a compound of formula (Iji):

The compound of formula (Ik) may be a compound of formula (Iki):

In an alternative embodiment, n is 0 or an integer between 1 and 5, between 3 and 6 or n is 0 or an integer between 1 and 3, and most preferably n is 0. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Il):

( ) In some embodiments, X¹ is CO and X² is O. In some embodiments, X¹ is CR¹R² and X² is O. In some embodiments, X¹ is CO and X² is NR³. In some embodiments, X¹ may be SO₂ and X² may be NR³. In a preferred embodiment, X¹ is CR¹R² and X² is O. Preferably, X³ is CR⁴R⁵. Accordingly, the compound may be a compound of formula (Ili):

R¹ and R² may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl or an optionally substituted C_2-20 alkynyl. Preferably, R¹ and R² are independently H, a halogen, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. More preferably, R¹ and R² are H, a halogen or methyl. In some embodiments, R¹ and R² may be H. Accordingly, the compound may be a compound of formula (Ilii):

R⁴ and R⁵ may independently be H, a halogen, an optionally substituted C_1-20 alkyl, an optionally substituted C_2-20 alkenyl or an optionally substituted C_2-20 alkynyl. R⁴ may be an optionally substituted C_1-12 alkyl, an optionally substituted C_2-12 alkenyl or an optionally substituted C_2-12 alkynyl. In some embodiments, R⁴ is a C_1-12 alkyl, a C_2-12 alkenyl or a C_2-12 alkynyl. In other embodiments, R⁴ is an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. R⁴ may be an optionally substituted C_1-3 alkyl, an optionally substituted C_2-3 alkenyl or an optionally substituted C_2-3 alkynyl. The alkyl, alkenyl or alkynyl may be substituted with NR¹¹R¹², OR¹², SR¹², SSR¹², COOR¹¹ or CONR¹¹R¹². In some embodiments, the alkyl, alkenyl or alkynyl is substituted with OR¹², SR¹², COOR¹¹ or CONR¹¹R¹². R¹² may be H, an optionally substituted C_1-12 alkyl, an optionally substituted C_2-12 alkenyl or an optionally substituted C_2-12 alkynyl. Preferably, R¹² is H, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. In some embodiments, R¹² is H. Alternatively, R¹² may be an optionally substituted C_1-3 alkyl, an optionally substituted C_2-3 alkenyl or an optionally substituted C_2-3 alkynyl. Accordingly, R¹² may be –CH₂CH₂COOR¹¹. The or each protecting group may be tert- butoxycarbonyl (Boc) protecting group or tert-butyl. R⁵ may be H, a halogen, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. In some embodiments, R⁵ is H, a halogen, an optionally substituted C_1-3 alkyl, an optionally substituted C_2-3 alkenyl or an optionally substituted C_2-3 alkynyl. In some embodiments, R⁵ is H, a halogen or methyl. The compound of formula (Il) may be a compound of any one of formula (Iliii) to (Ilxii):

Subsequent to contacting the initiator or polymer with a plurality of monomers, the method may comprise removing one or more protecting groups. In embodiments where the method comprises contacting the polymer with a plurality of monomers multiple times, the method may comprise removing the protecting groups after the final time the polymer has been contacted with a plurality of monomers. Accordingly, the method may comprise removing the protecting groups after the desired number of polymerisation reactions have been conducted. Prior to contacting the plurality of monomers and the initiator or polymer, the method may comprise producing the plurality of monomers. Producing a plurality of monomers may comprise contacting a compound of formula (II) with an oxidant, wherein the compound of formula (II) is:

, wherein X¹, X³ and X⁴ are as defined above and n is an integer of at least 1. The inventors note that prior art methods of producing a compounds of formula (I) require the use of silica gel column chromatography to obtain these final pure compounds. However, this is not required using the above method. This means the method can be conducted more quickly and is easier to scale. Accordingly, the compound of formula (II) may be a compound of formula (IIa):

, wherein X⁵ to X⁷ are also as defined above. Accordingly, the compound of formula (IIa) may be a compound of formula (IIb) to (IIe):

The compound of formula (IIc) may be a compound of formula (IIci):

The compound of formula (IId) may be a compound of formula (IIdi) or (IIdii), and is preferably a compound of formula (IIdiii), or a compound of formula (IIdiv).

The compound of formula (IIe) may be a compound of formula (IIei):

The oxidant may be a peroxy compound, a metal oxide, a metalloid oxide or a monooxygenase. For instance, the oxidant may be meta-chloroperoxybenzoic acid (mCPBA), cobalt (II,III) oxide (Co₃O4₎, iron (III) oxide (Fe₂O₃), antimony (III) oxide (Sb₂O₃), manganese dioxide (MnO₂), chromium (III) oxide (Cr₂O₃), cobalt (II) oxide (CoO), tin (IV) oxide (SnO₂) or cyclopentadecanone monooxygenase. The molar ratio of the oxidising agent to the compound of formula (II) may be between 100:1 and 1:100, between 50:1 and 1:50 or between 25:1 and 1:25, more preferably is between 15:1 and 1:10, between 10:1 and 1:5 or between 7:1 and 1:2, and most preferably is between 5:1 and 1:1 or between 4:1 and 2:1. In some embodiments, the molar ratio of the oxidising agent to the compound of formula (II) is about 3:1. The oxidising agent and the compound of formula (II) may be contacted at a temperature between 10 and 250 °C, more preferably between 20 and 150 °C or between 30 and 100°C, and most preferably between 40 and 90 °C, between 50 and 80°C or between 60 and 70 °C. The method may comprise recrystallizing the compound of formula (I). The inventors have found that a recrystallization step is sufficient to obtain the compounds in the required purity. In accordance with a second aspect, there is provided a polymer of formula (III):

, wherein X¹ is CO, CR¹R², SO or SO₂; X² is O, NR³ or S; X³ is CR⁴R⁵ or CO; each X⁴ is independently CR⁶R⁷, NR⁸, CO, O, S, SO or SO₂; n is 0 or an integer of at least 1; R¹ and R² are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; R³ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, COOR⁹ or CONR⁹R¹⁰; R⁴ and R⁵ are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; R⁶ and R⁷ are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N3; or one or more pairs of substituents, together with the atoms to which they are attached, independently form an optionally substituted 3 to 20 membered ring, wherein each pair of substituents consists of two of R¹ to R⁷; R⁸ and R⁹ are each independently H, a protecting group, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N3; and R¹⁰ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group; X⁸ is O, S or NR¹⁴; R¹⁴ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or R¹⁵(OCH₂CH₂)p-; R¹⁵ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or

; m defines a number of mers within the polymer, and is an integer of at least 2; p is an integer of at least 1; and the polymer is not polycaprolactone (PCL). X¹ to X⁴, R¹ to R⁷, R¹⁰ and n may be as defined in relation to the first aspect. The terms “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heteroaryl”, “heterocycle”, “heterocyclyl” and “protecting group” may be as defined in relation to the first aspect expect R¹¹ may be H, a protecting group, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N3. It may be understood that the definitions of R⁸, R⁹ and R¹¹ may differ between the first and second aspects. These groups are defined as being a protecting group in the monomer of the first aspect. However, the or each protecting group can be removed after polymerisation. Accordingly, the polymer of the second aspect does not have to contain the protecting groups, and may comprise alternative groups in these positions. R⁸ and R⁹ may be H or a protecting group. The protecting group may be Boc. R¹¹ may be H or a protecting group. The protecting group may be Boc. m may be an integer of at least 2, at least 5, at least 10, at least 20, at least 30, at least 40 or at least 50. m may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 20 and 100, between 30 and 75 or between 40 and 60. The polymer may have a molecular weight of at least 250 Da, at least 500 Da, at least 1,000 Da, at least 2,000 Da, at least 3,000 Da, at least 4,000 Da, at least 5,000 Da, at least 6,000 Da, at least 7,000 Da, at least 8,000 Da, at least 9,000 Da or at least 10,000 Da. The polymer may have a molecular weight between 250 and 10,000,000 Da, between 500 and 1,000,000 Da, between 1,000 and 500,000 Da, between 2,000 and 100,ooo Da, between 3,000 and 50,000 Da, between 4,000 and 25,000 Da, between 5,000 and 20,000 Da, between 6,000 and 15,000 Da, between 7,000 and 14,000 Da, between 8,000 and 13,000 Da or between 9,000 and 12,000 Da or between 10,000 and 11,000 Da. The molecular weight may be the number average molecular weight (Mn). The molecular weight may be calculated by nuclear magnetic resonance (NMR) analysis using an initiator as the reference. In some embodiments, R¹⁴ is an optionally substituted C1-20 alkyl, an optionally substituted C_2-20 alkenyl, an optionally substituted C_2-20 alkynyl, an optionally substituted C_6-12 aryl, an optionally substituted C_3-12 cycloalkyl, an optionally substituted C_3-12 cycloalkenyl, an optionally substituted C_3-12 cycloalkynyl, an optionally substituted 5 to 12 membered heteroaryl or an optionally substituted 3 to 12 membered heterocycle. Preferably, R¹⁴ is an optionally substituted C_1-12 alkyl, an optionally substituted C_2-12 alkenyl or an optionally substituted C_2-12 alkynyl. More preferably, R¹⁴ is an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. Even more preferably, R¹⁴ is an optionally substituted C_1-3 alkyl, an optionally substituted C_2-3 alkenyl or an optionally substituted C_2-3 alkynyl, and most preferably is an optionally substituted methyl. The alkyl, alkenyl or alkynyl may be substituted with a C_6-20 aryl, a C_3-20 cycloalkyl, a C_3-20 cycloalkenyl, a C_3-20 cycloalkynyl, a 5 to 20 membered heteroaryl or a 3 to 20 membered heterocycle. Preferably, the alkyl, alkenyl or alkynyl is substituted with a C_6-12 aryl, a C_3-12 cycloalkyl, a C_3-12 cycloalkenyl, a C_3-12 cycloalkynyl, a 5 to 12 membered heteroaryl or a 3 to 12 membered heterocycle. Most preferably, the alkyl, alkenyl or alkynyl is substituted with a phenyl. In some embodiments, R¹⁴ is

In alternative embodiments, R¹⁴ is R¹⁵(OCH₂CH₂)_p-. p may be an integer of between 2 and 500, between 5 and 300, between 10 and 200, between 20 and 150 or between 30 and 125. p may be an integer between 2 and 100, between 4 and 50, between 6 and 40, between 8 and 30 or between 9 and 20. p may be an integer between 2 and 200, between 5 and 100, between 10 and 75, between 20 and 60 or between 30 and 50. Alternatively, p may be an integer between 50 and 200, between 75 and 150, or between 100 and 125. In some embodiments, R¹⁵ is H, an optionally substituted C_1-15 alkyl, an optionally substituted C2-15 alkenyl or an optionally substituted C2-15 alkynyl. R¹⁵ may be H, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. R¹⁵ may be H, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. R¹⁵ may be H or methyl. In other embodiments, R¹⁵ is X¹ to X⁴, n and m may be as defined above.

In some embodiments, X⁸ is O. The polymer may be a homopolymer or a copolymer. The copolymer may be a block copolymer, a statistical copolymer, a random copolymer or a combination thereof. It may be appreciated that a mer is a repeating unit within a polymer. It may be appreciated that in embodiments where the polymer is a homopolymer, X¹ to X⁴ and n will be the same for all of the mers in the polymer. Alternatively, in embodiments where the polymer is a copolymer, the polymer will comprise at least two mers, wherein at least one of X¹ to X⁴ and/or n is different between the at least two mers. The polymer may comprise one or more mers of formula (IVa):

Alternatively, or additionally, the polymer may comprise one or more mers of formula (IVb):

Alternatively, or additionally, the polymer may comprise one or more mers of formula (IVc):

Alternatively, or additionally, the polymer may comprise one or more mers of formula (IVd):

n may be as defined in relation to the first aspect. Accordingly, in embodiments where n is 4, the polymer may comprise one or more mers of formula (IVe):

, wherein X⁵ to X⁷ are independently CR⁶R⁷, NR⁸, CO, O, S, SO or SO₂. The polymer may comprise one or more mers of formula (IVf), (IVg), (IVh), (IVj) and/or (IVk):

It may be appreciated that the mer of formula (IVf) may be referred to as PCL. As explained above, the polymer is not polycaprolactone. However, as also explained above, one or more of the mers of the polymer may be of formula (IVf). In this embodiment, the polymer may be a copolymer. Accordingly, it may comprise further mers which are not of formula (IVf). One or more mers of formula (IVg) may be mers of formula (IVgi) or (IVgii):

It may be appreciated that a mer of formula (IVgi) may be referred to as P^tBOOC. One or more mers of formula (IVh) may be mers of one of formula (IVhi) to (IVhvi):

It may be appreciated that a mer of formula (IVhiii) may be referred to as P^tBOC and a mer of formula (IVhv) may be identified as P^tBMOOC. One or more mers of formula (IVj) may be mers of one of formula (IVji) and (IVjii):

It may be appreciated that a mer of formula (IVji) may be referred to as P^tBOO. One mer of formula (IVk) may be mer of formula (IVki):

It may be appreciated that the mer of formula (IVki) can alternatively be referred to as PN₃CL. The polymer may be a compound of formula (IIIa): R¹⁴-X⁸-A_m1-b-(-B_m2-stat-C_m6-)-b-A_m3-b-(-B_m4-stat-C_m7-)-b-A_m5-H (IIIa) , wherein A is a mer of formula (IVg); B is a mer of formula (IVf); C is a mer of formula (IVh); and each of m1 to m7 is 0 or an integer of at least 1, at least one of m1, m3, m5, m6 and m7 is an integer of at least 1, and the sum of m1 to m7 is an integer of at least 2. It may be appreciated that b, when provided between adjacent sections of a polymeric formula, indicates that the adjacent sections are arranged sequentially. Accordingly, the polymer, or the relevant portion thereof, may be viewed as a block copolymer. It may be appreciated that stat, when provided between adjacent sections of a polymeric formula, indicates that the adjacent sections are provided together in a statistical arrangement. Accordingly, the polymer, or the relevant portion thereof, may be viewed as a statistical copolymer. It may be appreciated that the sum of m1 to m7 is m, and may be as defined above. In some embodiments, m6 and/or m7 may be an integer of at least 1. m1 to m5 may each be 0 or an integer of at least 1, at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16 or at least 18. m1 to m5 may each be 0 or an integer between 1 and 100, between 1 and 50, between 2 and 25, between 3 and 15, between 3 and 10 or between 4 and 6. m6 and m7 may each be 0 or an integer of at least 1 or at least 2. m6 and m7 may each be 0 or an integer between 1 and 100, between 1 and 50, between 1 and 25, between 1 and 10, between 1 and 5 or between 2 and 3. In one embodiment, m1, m3 and m5 are all 6, m2 and m4 are both 4 and m6 and m7 are both 2. In an alternative embodiment, m2 to m7 are 0. Accordingly, the polymer may be a polymer of formula (IIIai): R¹⁴-X⁸-Am1-H (IIIai) , wherein m1 is an integer of at least 2. In this embodiment, m1 is equal to m, and may be as defined above. Accordingly, m1 may be an integer of at least 2, at least 5, at least 10, at least 20, at least 30, at least 40 or at least 50. m1 may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 20 and 100, between 30 and 75 or between 40 and 60. In some embodiments, m1 may be an integer between 20 and 50. In some embodiments, m1 may be 24, 30 or 50. In an alternative embodiment, m6 and m7 may be 0. Accordingly, the polymer may be a compound of formula (IIIaii): R¹⁴-X⁸-Am1-b-Bm2-b-Am3-b-Bm4-b-Am5-H (IIIaii) m1 to m5 may each be 0 or an integer of at least 1, at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16 or at least 18, wherein at least one of m1, m3 and m5, is an integer of at least 1. m1 to m5 may each be 0 or an integer between 1 and 100, between 4 and 50, between 6 and 25, between 8 and 20 or between 10 and 18, wherein at least one of m1, m3 and m5, is an integer of at least 1. In one embodiment, m1 to m5 are each 6. In another embodiment, m1, m2 and m4 are 6, m3 is 12 and m5 is 0. In another embodiment, m1 is 18, m2 is 12 and m3 to m5 are 0. In yet another embodiment, m1, m3 and m5 may be 4 and m2 and m4 may be 6. In embodiments where n is 0, the polymer may comprise one or more mers of formula (IVl):

The one or more mers of formula (IVl) may be mers of formula (IVli):

The one or more mers of formula (IVl) may be mers of one or more of formulae (IVlii) to (IVlxi):

R¹² may be H, an optionally substituted C_1-12 alkyl, an optionally substituted C_2-12 alkenyl or an optionally substituted C_2-12 alkynyl. Preferably, R¹² is H, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. In some embodiments, R¹² is H. In alternative embodiments, R¹² is an optionally substituted C_1-3 alkyl, an optionally substituted C_2-3 alkenyl or an optionally substituted C_2-3 alkynyl. Accordingly, R¹² may be –CH₂CH₂COOR¹¹. R¹¹ may be a protecting group, H, a C_1-12 alkyl, a C_2-12 alkenyl or a C_2-12 alkynyl. Preferably, R¹¹ is a protecting group, H, a C_1-6 alkyl, a C_2-6 alkenyl or a C_2-6 alkynyl. Most preferably, R¹¹ is a protecting group or H. The protecting group may be tert- butoxycarbonyl (Boc) protecting group or tert-butyl. It may be appreciated that the mer of formula (IVlii) can alternatively be referred to as PBO. The polymer may be a compound of formula (IIIb): R¹⁴-X⁸-Dm8-b-Em9-H (IIIb) ,wherein D is a mer of formula (IVlxi); E is a mer of formula (IVliv); and each m8 and m9 are each an integer of at least 1. m may be an integer of at least 2, at least 5, at least 10, at least 20, at least 30, at least 40 or at least 50. m may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 20 and 100, between 30 and 75 or between 40 and 60. Alternatively, the polymer may be a compound of formula (IIIc):

(IIIc) Accordingly, in some embodiments, the polymer may be a polymer of formula (IIIbi): R¹⁵-(-OCH₂CH₂-)p-X⁸-Fm-H (IIIci) , where F is a mer of formula (IVf), formula (IVgi), formula (IVhiii), formula (IVhv), formula (IVji), formula (IVki) or formula (IVlii). In some embodiments, R¹⁵ is H, an optionally substituted C_1-15 alkyl, an optionally substituted C_2-15 alkenyl or an optionally substituted C_2-15 alkynyl. R¹⁵ may be H, an optionally substituted C_1-6 alkyl, an optionally substituted C_2-6 alkenyl or an optionally substituted C_2-6 alkynyl. R¹⁵ may be H, a C_1-3 alkyl, a C_2-3 alkenyl or a C_2-3 alkynyl. R¹⁵ may be H or methyl. m may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 15 and 400 or between 20 and 300. In other embodiments, R¹⁵ is

. X¹ to X⁴, n and m may be as defined above. In some embodiments, R¹⁵ may be a mer of formula (IVlii). Each m may be an integer between 2 and 50, between 2 and 30, between 2 and 20, between 3 and 10 or between 4 and 6. The polymer may be a polymer of any one of formula (101) to (147):

In accordance with a third aspect, there is provided a use of the polymer of the second aspect as an antimicrobial agent, to store information or in nanoscience or nanotechnology, wherein the use as an antimicrobial agent excludes use in a therapeutic application.

The charge, multifunctionality, hydrophobicity-hydrophilicity balance, sequence and/or molecular weight of the polymer of the second aspect can be manipulated to provide a polymer with antimicrobial properties. Accordingly, the polymer could be used in an antimicrobial application.

Alternatively, or additionally, the polymers of the second aspect maybe used to store information. For instance, information can be written, read and erased at the molecular level by controlling synthetic polymer chains. Different building blocks with specific molecular weights and functionality can be defined as o-bit and 1-bit and detected by NMR, size exclusion chromatography (SEC) and/or other techniques. Another possibility is that if the synthetic polymer chains consist of different types of building blocks, much more information could be stored, like DNA. The digital information encoded can then be deciphered. Furthermore, the novel polyesters are readily biodegradable. Thus, the information encrypted in the polyester chains can be erased by specific enzymes in water and/ or directly by water.

The polymer of the second aspect can also be used in the field of nanoscience and nanotechnology since the controllable sequences, degradability, multifunctionalities and stimuli-responsiveness can precisely control folding and self-assembly behaviour of polymer molecules, leading to formation of various self-assembled soft matter systems.

In accordance with a fourth aspect, there is provided a fibre comprising the polymer of the second aspect. A fibre made from the sequence-controlled multifunctional polymers of the second aspect could be useful for not only drug delivery and tissue engineering, but also other applications including membrane separation and purification.

In accordance with a fifth aspect, there is provided a medicament or a vaccine comprising the polymer of the second aspect.

The polymer could be used to provide targeted delivery of a small-molecule drug and/or a macromolecular drug including a peptide, a protein and/or a nucleic acid. Accordingly, the polymer could be used in a drug delivery or gene therapy application. In particular, this can be achieved by precisely controlling the chain length, the functionality, the distribution of positive and/or negative charges and/or the distribution of hydrophobic and/or hydrophilic segments of the polymer.

The polymers can also be used as vaccine adjuvants for example by mixing vaccines with the polymers. They can also be used for applications in vaccine delivery formulations.

In accordance with a sixth aspect, there is provided the polymer of the second aspect for use in therapy. In accordance with a seventh aspect, there is provided the polymer of the second aspect for use in drug delivery, gene therapy, tissue engineering, medical imaging and/or sensing and/or in treating a microbial infection. It is noted that PCL and PEG are widely used in drug delivery and tissue engineering. When it comes to tissue engineering, PCL and PEG suffer from some shortcomings such as slow degradation rate and low cell adhesion. These could be addressed by designing specific polymers with specific monomer types, monomer sequences and multifunctionality. Since the method of the first aspect allows the production of the polymer of the second aspect with controllable sequences, functionalities and degradability, a suitable polymer can be produced which overcomes the limitations of PCL and PEG.

The microbial infection may be a bacterial infection or a viral infection.

In maybe appreciated that, imaging and/or sensing moieties can be built into the polymers. The resulting polymers, and also particles or vesicles developed from them, can be useful for medical imaging and/or sensing. All features described herein (including any accompanying claims, abstract and drawings), and/ or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/ or steps are mutually exclusive. For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, in which: -

Figures la-ig show the structure of pentablock polyesters, with protected functional groups, synthesized via a quantitative one-pot iterative living ring-opening polymerization (QOIL-ROP) without intermediate purification. In particular, Figures la and lb show the structure of the pentablock polyesters using tert-butyl 7-oxo-1,4- oxazepane-4-carboxylate (tBOOC) (A) as the model monomer with the same DP_n = 6 per block, identified as A6A6A6A6A6 (a), and variable DP_n = 4 or 6, identified as A₄A₆A₄A₆A₄ (b), respectively. Figures lc-ie show the structure of the pentablock copolyesters composed of tBOOC (A) and e-caprolactone (CL) (B), altering the monomer sequences with the same DP_n = 6 per block, identified as A₆B₆A₆B₆A₆, A₆B₆A₆A₆B₆, and A₆A₆A₆B₆B₆, respectively. Figure if shows the structure of the pentablock copolyester with variableDP_n = 4 or 6, identified as A₄B₆A₄B₆A₄. Figure lg shows the structure of the pentablock copolyesters composed of tBOOC (A), CL (B) and tert-butyl (7-oxooxepan-4-yl)carbamate (tBOC) (C), with the sameDP_n= 6 per block (Ac, or B₄C₂), identified as A₆B₄C₂A₆B₄C₂A₆;

Figures 2a-2g show the structure of the pentablock polyesters of Figures ta-ig after deprotection;

Figure 3 shows a schematic representation of synthesis of sequence-controlled pentablock functional polyesters. All pentablock polyesters were prepared in toluene at 110 °C with benzyl alcohol as an initiator and with Sn(0ct)₂ as a catalyst via QOIL-ROP by consecutive sequential addition of monomers without intermediate purification. During the cycles, chain extensions were confirmed by NMR and SEC. The sequence- controlled pentablock polyesters were obtained after 5 successive chain extensions. Finally, the Boc protecting group was cleaved to generate water-soluble sequence- controlled pentablock functional polyesters;

Figures 4a-4g show synthesis and characterization of the sequence-controlled polyesters with protected functional groups shown in Figures la and lg, i.e. A6A6A6A6A6 and A₆B₄C₂A₆B₄C₂A₆, respectively. Figure 4a shows ¹H NMR traces (400MHz) for synthesis of A6A6A6A6A6 in deuterated chloroform (CDCl₃). Values to the left of each spectrum indicate a monomer conversion >98% for all chain extensions; values to the right indicate the number of sequential monomer additions. Figure 4b shows molecular weight distributions for successive block extensions of A6A6A6A6A6 determined by SEC. The y-axis ‘w (log M)’ label represents the differential logarithmic molecular weight. Figure 4c shows evolution of theoretical (black line) and experimental molecular weights M_n (squares) and M_w (triangles) determined by SEC and dispersities M_w/M_n (circles) versus the number of cycles for synthesis of A₆A₆A₆A₆A_{6. n,th} = [Monomer]o x p x M_Monomer/[Initiator]₀ + M_intiator, p was the monomer conversion. Figure 4d shows ¹H NMR spectra for consecutive block formations of A₆B₄C₂A₆B₄C₂A₆ in CDCl₃. Figure 4e shows molecular weight distributions of synthesis of A₆B₄C₂A₆B₄C₂A₆ determined by SEC. Figure 4f shows evolution of theoretical (black line) and experimental molecular weights M_n (squares) and _w (triangles) determined by SEC and dispersities (circles) versus the number of cycles for preparation of A₆B₄C₂A₆B₄C₂A₆;

Figures 5a-5d show scale-up synthesis of the sequence-controlled pentablock copolyester with protected functional groups shown in Figure id, i.e. A₆B₆A₆A₆6₆.

Figure 5a shows ¹H NMR spectra for consecutive block formations of A₆B₆A₆A₆B₆, in CDCI₃. Figure 5b shows molecular weight distributions of synthesis of A₆B₆A₆A₆B₆, determined by SEC. Figure 5c shows evolution of theoretical (black line) and experimental molecular weights _n (squares) and _w (triangles) determined by SEC and dispersities (circles) versus the number of cycles for preparation of A₆B₆A₆A₆B₆ Figure 5d shows the total amount of obtained product (after precipitation purification);

Figures 6a and 6b show the kinetics of ROP of the A block. Figure 6a shows plots of conversion and in ([ ]₀/[ ]) as a function of time. Figure 6b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the Sn(0ct)₂-catalyzed ROP of A block in toluene at 110 °C. [Monomer]₀ = 0.75 M, and [Monomer]₀: [Initiator]: [Catalyst] = 20:1:1;

Figures 7a and 7b show the kinetics of ROP of the B block. Figure 7a shows plots of conversion and in ([ ]₀/[ ]) as a function of time. Figure 7b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the Sn(0ct)₂-catalyzed ROP of B block in toluene at 110 °C. [Monomer]₀ = 0.75 M, and [Monomer]₀: [Initiator]: [Catalyst] = 45:1:1;

Figures 8a and 8b show the kinetics of ROP of the BC block. Figure 8a shows plots of conversion and in ([ ]₀/[ ]) as a function of time. Figure 8b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the Sn(0ct)₂-catalyzed ROP of BC block in toluene at 110 °C. [Monomer]₀ = 0.75 M, [M] _O:[M]_CO =2:1, and [Monomer]₀: [Initiator]: [Catalyst] = 24:1:1;

Figures 9a-9d show physicochemical and biodegradation properties of sequence- controlled pentablock polyesters. Figure 9a shows the differential scanning calorimetry (DSC) traces of the seven synthesized sequence-controlled polyesters with protected functional groups, along with their corresponding T_g values listed. Figure 9b shows enzymatic biodegradation of water-soluble sequence-controlled, functional, deprotected polyesters as a function of time at 37 °C in deuterium oxide (D₂0). Figures 9c and 9d show hydrolysis of water-soluble sequence-controlled, functional, deprotected polyesters as a function of time at 37 °C at pH 5 (c) and 7.4 (d) in D₂0. The degradation degrees were determined by ¹H NMR;

Figure 10 shows the synthetic route for obtaining monomers tert-butyl 7-oxo-i,4- oxazepane-4-carboxylate (tBOOC, A), tert-butyl (7-oxooxepan-4-yl)carbamate (tBOC, C), tert-butyl N-methyl-N-(7-oxooxepan-4-yl) carbamate (tBMOOC) and 5-(tert- Butyldimethylsiloxy)Oxepane-2-One (tBOO); Figure 11 shows the thermogravimetric analysis (TGA) traces of the seven synthesized sequence-controlled pentablock polyesters with protected functional groups along with their corresponding T_d values listed;

Figure 12 shows the ¹H NMR spectra of (a) e-decalactone (DL) monomer and (b) the reaction mixture by bulk polymerization in CDCl₃. The monomer conversion was 94-7%;

Figure 13 shows the ¹H NMR spectra of (a) tert-butyl 7-oxooxepane-4-carboxylate (tBOCO) monomer and (b) the reaction mixture in CDCl₃. The monomer conversion was 90%; Figure 14 shows ¹H NMR traces for synthesis of the pentablock A₁₀A₁₀A₁₀A₁₀A₁₀ homopolyester in CDCl₃. The monomer conversion in each cycle was >98%. Values to the left of each spectrum indicate a monomer conversion >98% for all chain extensions; values to the right indicate the number of sequential monomer additions. The molecular weight of pentablock A₁₀A₁₀A₁₀A₁₀A₁₀ homopolyester was 10,858 Da calculated by ¹H NMR;

Figure 15 shows the ¹H NMR spectra of (a) CL monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCl₃, using PEG (M_n = 2,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 99.2%;

Figure 16 shows the SEC trace of the reaction mixture corresponding to Figure 15; Figure 17 shows the ¹H NMR spectra of (a) CL monomer and PEG (M_n = 5,000 Da) mixture and (b) reaction mixture in CDCl₃, using PEG (M_n = 5,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 99.6%;

Figure 18 shows the SEC trace of the reaction mixture corresponding to Figure 17; Figure 19 shows the lH NMR spectra of (a) tBOOC monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 2,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 98.5%;

Figure 20 shows the SEC trace of the reaction mixture corresponding to Figure 19; Figure 21 shows the lH NMR spectra of (a) tBOOC monomer and PEG (M_n = 5,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 5,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 98.5%

Figure 22 shows the SEC trace of the reaction mixture corresponding to Figure 21; Figure 23 shows the lH NMR spectra of (a) tBOC monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 2,000 Da) as a macroinitiator and toluene as a solvent; Figure 24 shows the SEC trace of the reaction mixture corresponding to Figure 23; Figure 25 shows the lH NMR spectra of (a) tBOC monomer and PEG (M_n = 5,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 5,000 Da) as a macroinitiator and toluene as a solvent;

Figure 26 shows the SEC trace of the reaction mixture corresponding to Figure 25; Figure 27 shows the lH NMR spectra of (a) tBMOOC monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 2,000 Da) as a macroinitiator and toluene as a solvent;

Figure 28 shows the SEC trace of the reaction mixture corresponding to Figure 27; Figure 29 shows the lH NMR spectra of (a) tBMOOC monomer and PEG (M_n = 5,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 5,000 Da) as a macroinitiator and toluene as a solvent;

Figure 30 shows the SEC trace of the reaction mixture corresponding to Figure 29; Figure 31 shows the lH NMR spectra of (a) 2-Azido- -caprolactone (N₃CL) monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 2,000 Da) as a macroinitiator and toluene as a solvent;

Figure 32 shows the SEC trace of the reaction mixture corresponding to Figure 31; Figure 33 shows the lH NMR spectra of (a) N₃CL monomer and PEG (M_n = 5,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 5,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 97.4%; Figure 34 shows the SEC trace of the reaction mixture corresponding to Figure 33;

Figure 35 shows the lH NMR spectra of (a) tBOO monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 2,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 98%;

Figure 36 shows the SEC trace of the reaction mixture corresponding to Figure 35; Figure 37 shows the lH NMR spectra of (a) tBOO monomer and PEG (M_n = 5,000 Da) mixture and (b) reaction mixture in CDCI3, using PEG (M_n = 5,000 Da) as a macroinitiator and toluene as a solvent. The monomer conversion was 98.9%;

Figure 38 shows the SEC trace of the reaction mixture corresponding to Figure 37; Figures 39a-39i show the structures of quasi pentablock polyethers synthesized via the QOIL-ROP method without intermediate purification;

Figures 40a and 40b shows the structures of the polyethers shown in Figures 39h and 391 after deprotection;

Figure 41 shows a schematic representation of synthesis of sequence-controlled pentablock functional polyethers. All pentablock polyethers were prepared in toluene at 40 °C with benzyl alcohol as an initiator and t-Bu-P₄ as a catalyst via QOIL-ROP by consecutive sequential addition of monomers without intermediate purification. During the cycles, chain extensions were confirmed by NMR and SEC. The pentablock polyethers were obtained after 5 successive chain extensions. Where applicable, the pentablock polyethers with protected functional groups were then deprotected; Figures 42a and 42b show the kinetics of ROP of the D block; Figure 42a shows plots of conversion and in ([ ]₀/[ ]) as a function of time; Figure 42b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of D block in toluene at 40 °C. [Monomer]₀ = 5.7 M, and [Monomer]₀: [Initiator]: [Catalyst] = 100:1:1;

Figures 43a and 43b show the kinetics of ROP of the E block; Figure 43a shows plots of conversion and in ([ ]₀/[ ]) as a function of time; Figure 43b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of E block in toluene at 40 °C. [Monomer]₀ =

3.2 M, and [Monomer]₀: [Initiator]: [Catalyst] = 100:1:1;

Figures 44a and 44b show the kinetics of ROP of the F block; Figure 44a shows plots of conversion and in ([ ]₀/[ ]) as a function of time; Figure 44b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of F block in toluene at 40 °C. [Monomer]₀ =

2.3 M, and [Monomer]₀: [Initiator]: [Catalyst] = 100:1:1;

Figures 45a and 45b show the kinetics of ROP of the G block. Figure 45a shows plots of conversion and in ([ ]₀/[ ]) as a function of time. Figure 45b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of G block in toluene at 40 °C. [Monomer]₀ =

3.1 M, and [Monomer]₀: [Initiator]: [Catalyst] = 100:1:1;

Figures 46a and 46b show the kinetics of ROP of the H block; Figure 46a shows plots of conversion and in ([ ]₀/[ ]) as a function of time; Figure 46b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of H block in toluene at 40 °C. [Monomer]₀ =

4.4 M, and [Monomer]₀: [Initiator]: [Catalyst] = 100:1:1;

Figures 47a and 47b show the kinetics of ROP of the I block; Figure 47a shows plots of conversion and in ([ ]₀/[ ]) as a function of time; Figure 47b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of I block in toluene at 40 °C. [Monomer]₀ =

4.2 M, and [Monomer]₀: [Initiator]: [Catalyst] = 100:1:1;

Figure 48a shows ¹H NMR traces (400MHz) for synthesis of D₂₀D₂₀D₂₀D₂₀D₂₀ using the BO monomer 1,2-epoxybutane (D) in deuterated chloroform (CDCl₃), with benzyl alcohol as an initiator. Values to the left of each spectrum indicate a monomer conversion >99% for all chain extensions; values to the right indicate the number of sequential monomer additions; Figure 48b shows molecular weight distributions for successive block extensions of D₆D₆D₆D₆D₆ determined by SEC. The y-axis ‘w (log M)’ label represents the differential logarithmic molecular weight; Figure 48c shows evolution of theoretical (black line) and experimental molecular weights _n (squares) and M_w (triangles) determined by SEC and dispersities _w/ _n (circles) versus the number of cycles for synthesis of D₆D₆D₆D₆D₆. M_{n,t h} = [Monomer]₀ x p x M_Monomer/[Initiator]₀ + M_initiator, P was the monomer conversion;

Figure 49 shows ¹H NMR spectra of (a) BO monomer and PEG (M_n = 2,000 Da) mixture and (b) reaction mixture in CDCl _3, using PEG (M_n =2,000 Da) as a macroinitiator and toluene as a solvent for synthesis of PEG₄₅-b-PBO₁₀. The monomer conversion was 99%; and

Figure 50 shows hemolysis of red blood cells (RBCs) after 1 h of incubation with the sequence-controlled co-polyether L_10OF_5O, synthesized using benzyl alcohol as an initiator, as a function of pH and polymer concentration.

Example 1 - Synthesis of sequence-controlled multiblock polyesters In this study, a number of members of the lactone monomer family were used, in order to form functional sequence-controlled multiblock polyesters. The inventors assign coding letters A, B and C to tert-butyl 7-oxo-i,4-oxazepane-4-carboxylate, e- caprolactone and tert-butyl (7-oxooxepan-4-yl) carbamate monomers, respectively. Monomers A and C were generated by Baeyer-Villiger oxidation reactions of the commercially available corresponding cyclohexanone derivatives in the presence of m- CPBA with only one-step preparation and easy purification by recrystallization, as shown in Fig. 10. Monomer B was obtained from a commercial supplier.

The quasi pentablock A6A6A6A6A6 polyester (Fig. la) with protected functional groups in backbones and a number-average degree of polymerization(DP_n) of 6 for each block was first designed and synthesized using tert-butyl 7-oxo-i,4-oxazepane-4-carboxylate (monomer A) as the building block to demonstrate this new approach.

Each chain extension process was performed via sequential ROP under a nitrogen atmosphere catalyzed by Sn(0ct)₂ in toluene. Polymerization temperature in each cycle was maintained at 110 °C and the molar ratio of Sn(0ct)₂ to initiating benzyl alcohol ([CAT]/[initiator]) was kept at no larger than 1:1 to minimize possible transesterification side reactions. Sn(0ct)₂ is a commonly used effective and versatile catalyst approved by the U.S. FDA⁴², which is easy to handle and soluble in common organic solvents and lactones. Compared with most organocatalysts (TBD, DBU or others), Sn(0ct)₂ is bulkier and can greatly reduce possible transesterification side reactions. The first building block with a number-averaged molecular weight ( _n) of 1,259 Da ( Đ = M_w/ _n = 1.29, where D stands for dispersity) was then formed. After ¹H

NMR spectroscopy confirmed a very near quantitative monomer conversion (>99%) and the complete consumption of the monomer in this first step (Fig. 4a), the second aliquot of dehydrated and degassed monomer in toluene was subsequently fed into the reactor via a gas-tight syringe under the aforementioned conditions without purification of the first block. As the subsequently fed monomer can react again with the living propagating polymer block chain, the new chain extension was attained through repeated additions of monomers. ¹H NMR analysis confirmed a very near quantitative monomer conversion (>98%) (Fig. 4a). Size exclusion chromatography (SEC) analysis verified successful chain extensions with the molecular weight distribution (MWD) clearly shifting to a higher molecular weight, an observable decrease in dispersity ( Đ = 1.18) and a remarkable agreement between the theoretical and experimental molecular weights (Fig. 4b). This consecutive polymerization- sampling-extension process was conducted successfully five times to yield the final quasi pentablock polyester with a GPC M_n of 5,423 Da. This method enabled an unprecedented realization of both the relatively narrow MWDs and the great agreement between theoretical and experimental molecular weights (Table 1) during successive monomer addition cycles.

Table 1: Characterization data for the synthesis of the quasi pentablock A₆A₆A₆A₆A₆ polyester including monomer conversions, molecular weights and dispersities

These data verified the living intermediate polymeric chain with an active end group possessing a further polymerization ability. Moreover, the further reduction in dispersities upon chain extension (Table 1) also exhibited that the sequential polyester block formation proceeded in a well-controlled polymerization manner. Throughout all the sequential monomer addition processes, SEC analysis revealed unimodal distributions with obvious shifts to higher molecular weights (Fig. 4b), while ¹H NMR confirmed quantitative monomer conversions (>98%) following each monomer addition (Fig. 4a and Table 1). These results demonstrated that the new QOIL-ROP technique could successfully synthesize highly ordered sequence-controlled functional block polyesters.

The quasi pentablock A₄A₆A₄A₆A₄ polyester (Fig. lb) with variable DP_n (4 or 6 for each block) was synthesized to demonstrate a precise control of the molecular weight (or chain length) of each block, which can enable a remarkable manipulation of polymer chemical structure, self-assembly and micro- and macroscopic properties. As shown in Table 2, the A₄A₆A₄A₆A₄ polyester exhibited an M_n of 4,171 Da and a relatively narrow MWD ( Đ = 1.20). The experimental molecular weights of intermediate and final polyesters were in good agreement with the corresponding theoretical values. The quantitative monomer conversion (>98%) and precise DP_n control during block formation in each cycle were confirmed by ¹H NMR and SEC. These results manifested the feasibility of accurate regulation of the desired DP_n for each block in well-defined, sequence-controlled multiblock polyesters through the new QOIL-ROP approach.

Table 2: Characterization data for the synthesis of the quasi pentablock A₄A₆A₄A₆A₄ polvester including monomer conversions, molecular weights and dispersities

The sequence-controlled pentablock copolyesters with three different patterns, A₆B₆A₆B₆A₆, A₆B₆A₆A₆B₆, and A₆A₆A₆B₆B₆, (Fig. 1c-1e) were then synthesized under the optimized conditions, in order to demonstrate that diverse levels of polyester structural complexity can be readily achieved. The hydrophobic e-caprolactone (Monomer B) segments were introduced to the relatively hydrophilic A block, conferring the tunable range of physicochemical properties of final amphiphilic functional sequence- controlled pentablock copolyesters with high-order architecture, thereby unlocking their potential for widespread applications of the third to seventh aspects described above.

Remarkably, in each block formation cycle of both A₆B₆A₆B₆A₆ (M_n = 4,051 Da) and A₆A₆A₆B₆B₆ (M_n = 4,176 Da) copolyesters, nearly full monomer conversions (>98%) were confirmed by ¹H NMR, revealing the quantitative synthesis of well-defined sequence-controlled pentablock copolyesters. In both cases, SEC analysis indicated successful chain extensions with distinct shifts to higher molecular weights with relatively narrow MWDs ( Đ = 1.27 and 1.25 for A₆B₆A₆B₆A₆ and A₆A₆A₆B₆B₆, respectively) and the good agreement between theoretical and experimental molecular weights (Tables 3 and 4), validating the high level of polymerization control for such complex structures.

Table 2: Characterization data for the synthesis of the A6B6A6B6A6 including monomer conversions, molecular weights and dispersities

Table 4: Characterization data for the synthesis of the A6A6A6B6B6 including monomer conversions, molecular weights and dispersities

The sequence-controlled pentablock A₆B₆A₆B₆6₆ copolyester (Fig. id and 3) was chosen to demonstrate scale-up synthesis on a multigram scale (-56 g) (Fig. 5d). This is advantageous over the reported solid-phase peptide synthesis⁷, or liquid-phase molecular-sieving polyether synthesis³⁷ and even iterative exponential growth approaches^, which are typically limited to production at milligram level. It is noteworthy that even in this large-scale process, quantitative monomer conversions (>98%) and relatively narrow MWDs ( Đ = 1.26-1.36) were still well retained and experimental molecular weights (M_n) were in good agreement with theoretical values throughout the consecutive monomer addition cycles (Fig. 5a-5C and Table 5). The excellent control of quantitative polymerization of sequence-controlled multiblock copolyesters at large scale exhibits the robustness and commercialization potential of this new QOIL-ROP approach.

Table 5: Characterization data for the synthesis of the A6B6A6A6A6 including monomer conversions, molecular weights and dispersities

Additionally, the inventors decided to synthesize another sequence-controlled pentablock Az,B₆A,,B₆A,, copolyester (Fig. if) to further demonstrate the notable precise regulation of the molecular weight (or chain length) of each block of the copolyester through this technique. As shown in Table 6, the final copolyester had an M_n of 3,273 Da and a relatively narrow MWD (f) ~ 1.33). The quantitative conversions (>98%) and the good agreement between theoretical and experimental molecular weights were confirmed by ¹H NMR and SEC throughout each chain extension cycle with the desired variable DP_n.

Table 6: Characterization data for the synthesis of the A4B6A4A6B4 including monomer conversions, molecular weights and dispersities

All these results showed the capacity of the new QOIL-ROP technique for synthesis of well-defined sequence-controlled multiblock polymers.

Furthermore, different monomers can be introduced into a same chain extension cycle to jointly contribute to the formation of some specific block of sequence-controlled polymers via ring-opening copolymerization (ROCOP). To demonstrate this, a sequence-controlled copolyester, A₆B₄C₂A₆B₄C₂A₆ (Fig. lg), in which the building block B₄C₂ consists of monomers B and C together, was synthesized through a switchable process between ROP and ROCOP.

Indeed, monomers B and C in the same building block were found to collectively contribute to the chain propagation cycle efficiently, resulting in a desired sequence- controlled pentablock copolyester with an M_n of 4,324 Da and a relatively low Đ of 1.30. The accurate DP_n control in each block formation was evidenced by the relatively narrow MWDs (D ~ 1.30) and the good correlation between theoretical and experimental molecular weights in all cycles (Fig. 4d-4f and Table 7).

Table 7: Characterization data for the synthesis of the A6 B4 C2 A6B4,C2A6including monomer conversions, molecular weights and dispersities

Therefore, the new approach allowed a switchable process between the two distinct polymerization cycles: ROP and ROCOP. Meanwhile, after all the sequence-controlled polyesters were purified only at the final cycle, their experimental molecular weights determined by ¹H NMR and SEC analyses were well consistent with the corresponding theoretical values (Table 8). This further suggests that the sequence-controlled, multifunctional, multiblock polymers synthesized using this new robust approach are only required for purification at the final cycle of chain extension. Table 8: Summary of characteristics of the sequence-controlled pentablock polyesters synthesized through OOIL-ROP after the final purification step

Kinetics experiments were performed to confirm the living ROP of A, B and BC blocks, respectively, catalyzed by Sn(0ct)₂ at 110 °C in toluene. A first-order kinetics relationship between the polymerization time and monomer conversion was found (Figs. 6a, 7a and 8a). It showed that the Sn(0ct)₂-catalyzed ROP of A, B or BC blocks in toluene all followed a living polymerization mechanisms⁸, meaning that polymer chains can grow at a relatively constant rate so that the number of kinetic-chain carriers can be essentially constant throughout the polymerization.³⁹ _’ ⁴⁰ This ensures the precise DP_n (chain length) control in each chain extension cycle. Notably, the chain propagation rate constants ( k_p ) of A, B and BC blocks were calculated to be 9.0 x to^-3 min^-1, 9.1 x 10- ³ min^-1 and 9.2 x to^-3 min^-1, respectively, as determined from the plots of monomer conversion versus reaction time. Thanks to the similar chain propagation rates, the extent of the undesirable transesterification reactions can be furthest minimized even if monomers were configured in any optional desired sequence⁴¹ _’ ⁴². In addition, the molecular weights of A, B and BC blocks, respectively, increased linearly with the monomer conversion (Figs. 6b, 7b and 8b), indicating that the monomers were converted to the resulting polyesters proportionally, which further confirmed the controlled polymerization nature⁴³’ ⁴⁴.

Full monomer conversion is usually not recommended throughout polymerization due to the accumulation of different side reactions, such as the chain transfer and termination in reversible addition-fragmentation chain transfer (RAFT) and atom- transfer radical polymerization (ATRP)¹⁸, and transesterification in ROP of lactones³³. The extent of transesterification side reactions must be understood since it could scramble the sequence-controlled polyester structure. However, this is not a problem for synthesis of polyesters through the new QOIL-ROP approach since transesterification could be avoided. The NMR spectra of all the crude sequence- controlled pentablock copolyesters only showed major carbonyl peaks of each block and their junctions. As comparison, new carbonyl signals evolved from transesterification in corresponding pentablock copolyesters treated with the well-known transesterification catalyst i,5,7-triazabicyclo[4.4.o]dec-5-ene (TBD, at 50 °C for 72 h) and statistical copolyesters with a similar chain length, This suggests that there was no detectable transesterification in the sequence-controlled multiblock polyesters synthesized through the new QOIL-ROP method. In addition, SEC data showed narrow MWDs throughout all the polymerization processes, further confirming the absence of transesterification.

DSC and TGA analyses were carried out to evaluate how the physical thermal properties (glass transition temperatures T_g and decomposition temperatures T_d) of these resulting sequence-controlled polyesters can be tuned by precisely controlling monomer sequences and chain lengths. These sequence-controlled polyesters were sticky oils at room temperature and showed clear glass transitions (T_g) (Fig. 9a), whereas no detectable melting temperatures (T_m) were observed in the range -90 to 70 °C, verifying the amorphous nature of both homo- and copolyesters. The T_g increased with increasing the polyester molecular weights, while above T_d these polyesters underwent thermal decomposition to form various volatiles, resulting in the rapid weight loss (Fig. 11). The sequence-controlled copolyesters showed that T_g and T_d values were dependent on the monomer type, monomer sequence and polyester molecular weight, tunable over the range of -45.4 to -35.4 °C and 212 to 2.2.7 °C, respectively. These sequence-controlled polyesters with longer chains and more orderly packed structures displayed higher T_g probably due to their more rigid chains⁵¹.

The deprotection of sequence-controlled pentablock polyesters can be achieved through the simple and widely used reaction with trifluoroacetic acid (TFA) (molar ratio of TFA:Boc group in excess of 35:1) under a nitrogen atmosphere and at room temperature. The peaks at 1.46 ppm attributed to the Boc protons were not observed in the ¹H NMR spectra, showing that all protecting Boc groups were removed and the water-soluble sequence-controlled, multifunctional pentablock polyesters were obtained. Meanwhile, no evident degradation was detected by ¹H NMR, indicating that the polyesters were relatively stable due to the reduced nucleophilicity of the amine groups upon protonation45. Furthermore, SEC measurements showed the decreased molecular weights after deprotection (Table 9), further confirming the successful deprotection. However, considering that the hydrodynamic volume of the water-soluble sequence-controlled multifunctional pentablock polyesters was considerably different from that of polystyrene standards²⁷, the experimental molecular weights were lower than the theoretical values.

Table 9: Summary of characteristics of the deprotected pentablock polyesters

Moreover, in addition to the only end group post-modification of many conventional polymers including the U.S. Food and Drug Administration (FDA)-approved PCL⁵² and PEG⁵³, we can expect that the water-soluble sequence-controlled pentablock polyesters allow for site-selective post-functionalization at a later stage through the introduction of reactive groups in backbones and side chains⁴⁷

An enzymatic biodegradation study at 37 °C was performed to investigate how the monomer type, monomer sequence and chain length determined biodegradation behaviors of the water-soluble, sequence-controlled, multifunctional pentablock polyesters. As shown in Fig. 9b, the sequence-controlled polyesters with a higher level of hydrophilicity were enzymatically degraded faster by lipase. It needs to be pointed out that the monitoring of enzymatic biodegradation of those polyesters was stopped on day 9 due to the inactivation of lipase⁴⁸ _’ ⁴ ₉. in addition, these water-soluble, sequence- controlled, multifunctional polyesters with longer chains and more orderly packed structures displayed lower enzymatic biodegradation rates, probably due to their more rigid chains⁵⁴ _’ ⁵⁵. Furthermore, a hydrolysis study at pH 7.4 and 5 at 37 °C was performed to explore how hydrolytic properties of the water-soluble, sequence-controlled, multifunctional pentablock polyesters could be tuned by regulating the monomer type, monomer sequence and chain length (Fig. 9c and 9d). It was found that these sequence-controlled polyesters were hydrolyzed faster at pH 7.4 than at pH 5, which is consistent with the pH-dependent hydrolytic degradation profiles of other amino-functionalized polyesters⁴⁵ _’ ⁵⁰. The more rapid hydrolytic degradation at pH 7.4 was caused by the attack of the deprotonated amine groups at the backbone ester units. As comparison, the protonated amine groups at lower pH exhibited the reduced nucleophilicity, leading to the slower hydrolytic degradation. Additionally, these sequence-controlled polyesters with a higher level of hydrophilicity were hydrolyzed faster. By precisely regulating the water-soluble, sequence-controlled, multifunctional polyesters to have longer chains and more orderly packed structures, their chain would become more rigid, thus resulting in lower hydrolytic degradation rates⁵⁴ _’ ⁵⁵.

Conclusion A new QOIL-ROP strategy has been established for the scale-up synthesis of well- defined, sequence-controlled, multifunctional multiblock polyesters with each block reaching nearly full monomer conversion and relatively narrow MWDs throughout all sequential chain extension cycles, without any intermediate purification steps which are however essential for the other reported iterative polymerization methods. Also remarkably, the final global deprotection of protecting groups can result in novel water- soluble, biocompatible, multiblock polyesters with controlled sequences and multifunctionality which allow for site-selective post-functionalization. Moreover, the physicochemical properties and biodegradation behaviors of those water-soluble polyesters can be fine-tuned by precisely controlling monomer types, sequences and chain lengths. Importantly, the demonstrated ease of quantitative synthesis on a large scale further highlights the robustness and commercialization potential of the new strategy. Such a tractable approach (the scalability of the process and quantitative monomer conversions) can pave a new pathway for the synthesis of new families of biocompatible and biodegradable polymers with precisely controllable monomer sequences and chain lengths. The novel, sequence-controlled, multifunctional polymers will be promising in the wide range of applications of the third to seventh aspects described above.

Example 2 - Maximizing conversion To enable multiple cycles to be carried out without purification being conducted between cycles, it is important to maintain a high monomer conversion. Accordingly, the inventors investigated properties of the monomer and initiator which could affect the percentage conversion.

First, the inventors attempted to conduct the polymerization reaction using a lactone substituted with a butyl group in the 2 position (Fig. 12). It will be appreciated that the 2 position is identified as “X³” in the chemical formulae defined above. The monomer conversion rate was 94.7%, lower than for the monomers used in Example 1 which were unsubstituted in the 2 position. The reduction in the conversion rate would appear to be caused by steric hindrance. Accordingly, this suggests that only monomers which are unsubstituted or have small substituents in the 2 position may be used in the polyester reaction.

Next, the inventors attempted to conduct the polymerization reaction using a lactone substituted with a protected ester group in the 4 position (Fig. 13). The monomer conversion was 90%. Again, this is significantly less than the conversion rates reported in Example 1. The inventors believe that this may have been caused due to the ester bond in the side chain being attacked by the catalyst, resulting in the formation of byproducts during polyester synthesis. Example 3 - Polymers with higher molecular weights

The inventors then used the same method of producing a polymer to produce a polyester with a higher molecular weight. As shown in Fig. 14, the inventors were able to use their method to successfully synthesize a polyester with a molecular weight of 10,858 Da (measured by ¹H NMR).

Accordingly, the method developed by the inventors can be used to synthesize high molecular weight polymers.

Example 4 - Synthesis of polyesters using macroinitiators The inventors then decided to test whether their method could be applied to the synthesis of polyesters using macroinitiators. The inventors were able to obtain the polyesters using mono-functional PEG (M_n = 2,000 or 5,000 Da) as an initiator (Figs. 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35 and 37). A summary of the monomer conversion rates is provided in Table 10. The inventors have shown that their QOIL-ROP strategy can also be used to synthesize polyesters using macroinitiators. Mono-functional PEG with molecular weights of 2,000 and 5,000 Da can be used as initiators with quantitative monomer conversions.

Table 10: Characterization data for the synthesis of the polyesters using PEG with molecular weights of 2.000 and 5.000 Da as initiators

Example 5 - Synthesis of sequence-controlled multiblock polvethers

The inventors then decided to test whether their method could be applied to the synthesis of polyethers. The inventors were able to obtain the quasi pentablock polyethers shown in Figs. 39 to 41. A summary of the monomer conversion rates is provided in Table 11. Table 11: Summary of epoxy monomers used to synthesize quasi pentablock polvethers. monomer conversions rates, polvether molecular weights and dispersities

^a The M_n and Đ of polyethers were determined by SEC.

In this study, a number of members of the epoxy monomer family were used, in order to form functional sequence-controlled multiblock polyethers. The inventors assigned coding letters D - L to monomers listed in Table 11. Those monomers were obtained from a commercial supplier.

The quasi pentablock D₂₀D₂₀D₂₀D₂₀D₂₀ polyether (Fig. 39a) and a number-average degree of polymerization ( DP_n ) of 20 for each block was first designed and synthesized using 1,2-epoxybutane (monomer D) as the building block to demonstrate this new approach.

Each chain extension process was performed via sequential ROP under a nitrogen atmosphere catalyzed by f-Bu-P₄ in toluene. Polymerization temperature in each cycle was maintained at 40 °C and the molar ratio of t-Bu-P₄ to initiating benzyl alcohol

([CAT]/[initiator]) was kept at no larger than 1:1. t-Bu-P₄ is a commonly used effective and versatile catalyst approved by the U.S. FDA⁴², which is easy to handle and soluble in common organic solvents. The first building block with a number-averaged molecular weight ( _n) of 1571 Da ( Đ = _w/ _n = 1.09, where Đ stands for dispersity) was then formed. After ¹H NMR spectroscopy confirmed a very near quantitative monomer conversion (>99%) and the complete consumption of the monomer in this first step (Fig. 48a), the second aliquot of dehydrated and degassed monomer in toluene was subsequently fed into the reactor via a gas-tight syringe under the aforementioned conditions without purification of the first block. As the subsequently fed monomer can react again with the living propagating polymer block chain, the new chain extension was attained through repeated additions of monomers. ¹H NMR analysis confirmed a very near quantitative monomer conversion (>99%) (Fig. 48a). Size exclusion chromatography (SEC) analysis verified successful chain extensions with the molecular weight distribution (MWD) clearly shifting to a higher molecular weight, an observable decrease in dispersity (Đ = 1.11) and a remarkable agreement between the theoretical and experimental molecular weights (Figs. 48b and 48c). This consecutive polymerization-sampling-extension process was conducted successfully five times to yield the final quasi pentablock polyester with a GPC _n of 5,578 Da. This method enabled an unprecedented realization of both the relatively narrow MWDs and the great agreemeet between theoretical and experimental molecular weights (Table 12) during successive monomer addition cycles.

These data verified the living intermediate polymeric chain with an active end group possessing a further polymerization ability. Moreover, the further reduction in dispersities upon chain extension (Table 12) also exhibited that the sequential polyether block formation proceeded in a well-controlled polymerization manner. Throughout all the sequential monomer addition processes, SEC analysis revealed unimodal distributions with obvious shifts to higher molecular weights (Figs. 48b and 48c), while ¹H NMR confirmed quantitative monomer conversions (>99%) following each monomer addition (Fig. 48a and Table 12). These results demonstrated that the new QOIL-ROP technique could successfully synthesize highly ordered sequence-controlled functional block polyethers.

Kinetics experiments were performed to confirm the living ROP of D, E, F, G, H and I monomers, respectively, catalyzed by t-Bu-P₄ at 40 °C in toluene. A first-order kinetics relationship between the polymerization time and monomer conversion was found (Figs. 42a, 43a, 44a, 45a, 46a and 47a). It showed that the t-Bu-P₄ -catalyzed ROP of D, E, F, G, H and I monomers in toluene all followed a living polymerization mechanism³⁸, meaning that polymer chains can grow at a relatively constant rate so that the number of kinetic-chain carriers can be essentially constant throughout the polymerization.³⁹⁴⁰ This ensures the precise DP_n (chain length) control in each chain extension cycle. In addition, the molecular weights of D, E, F, G, H and I homopolyethers, respectively, increased linearly with the monomer conversion (Figs. 42b, 43b, 44b, 45b, 46b and 47b), indicating that the monomers were converted to the resulting polyethers proportionally, which further confirmed the controlled polymerization nature⁴³ _’ ⁴⁴. Conclusion

The inventors have shown that their QOIL-ROP strategy can also be used to synthesize well-defined, sequence-controlled, multifunctional multiblock polyethers. As with the polyesters, each block of the polyethers reached nearly full monomer conversion. Additionally, narrow MWDs were observed.

Example 6 - Synthesis of polvethers through a mono-directional or bi-directional chain extension using PEG as an initiator

The inventors then decided to test whether their method could be applied to the synthesis of polyethers using PEG as an initiator. The inventors were able to obtain the polyethers using PEG with different molecular weights as microinitiators or macroinitiators, following the same mono-directional chain extension method described in Example 1 except the replacement of the microinitiator benzyl alcohol with mono-functional PEG. According to the ¹H NMR spectrum shown in Fig. 49 (M_n,_PEG=2000), the BO monomer (D) conversion rate was calculated to be 99.0%. A summary of the quantitative monomer conversion rates (>98%) through mono- directional chain extensions using PEG with different molecular weights (500 - 2,000 Da) is provided in Table 13.

The inventors then extended the application of their method to the synthesis of polyethers through a bi-directional chain extension using bi-functional PEG as an initiator. As shown in Table 13, when the molecular weight of PEG ranged from 400 to 2,000, the BO monomer conversion was quantitative, changing from 98.7% to 98.5%. When M_n,_PEG ≥ 4, 000, the BO monomer conversion was lower below the quantitative rate required for the QOIL-ROP method.

Table 13: Characterization data for the synthesis of the polvethers using PEG with different molecular weights as initiators

Conclusion

The inventors have shown that their QOIL-ROP strategy can also be used to synthesize polyethers through the mono-directional or bi-directional chain extension using PEG microinitiators or macroinitiators. PEG with molecular weights of 2,000, 1,000, 750, 600, 500 and 400 Da can be used as initiators with quantitative monomer conversion rates (>98%).

Example 7 - pH-Dependent cell membrane activity of the co-polvether at different concentrations

The inventors then demonstrated that the polymers could be designed to be cell membrane active. The co-polyether L₁₀₀F_5O, labelled as polymer 128, was synthesized using benzyl alcohol as an initiator according to the same method as described in Example 5.

This polymer consists of one block containing the side chain with the ionizable carboxylic acid groups, which enable the polymer to display pH-responsiveness, and the other block containing relatively long hydrophobic aliphatic chains, which enhance the polymer-cell membrane interaction. As shown in Fig. 50, at the concentration of 0.5 mg mL/¹, the polymer displayed pH-responsive cell membrane activity. At higher pH ranging from 5.5 and 7.4, the polymer was non-membrane-lytic. Upon protonation of its carboxylic acid groups at pH 5.0 which is the characteristic pH of late endososomes, the polymer lysed approximately 60% RBCs, suggesting the potential application of the polymer for efficient intracellular delivery of therapeutic agents through release of endocytosed materials from endo/lysosomes into the cytoplasm. When the concentration was sufficiently high at 1.0 mg mL/¹, the polymer caused high hemolysis at the pH range tested (74-4.5) . The efficient membrane destabilization at neutral or near-neutral pH is favorable for in vitro and ex vivo cell engineering, controlled by intracellular delivery of biological molecules through membrane permeabilizing, for cell-based therapies.

The pH-dependent cell membrane activity of the polymers can be manipulated by the type and sequence of monomers, degree of polymerization, charge (e.g., positive vs. negative, and charge density), hydrophobicity-hydrophilicity balance. The new QOIL- ROP method can be used to readily synthesize a library of novel, sequence-controlled, multifunctional polymers including polyesters and polyethers for intracellular delivery of agents of pharmaceutical agents.

Methods Typical protocol for synthesis of sequence-controlled pentablock polyesters. A three-neck flask charged with a rubber septum, a magnetic stir bar, monomer A (3 g, 13.95 mmol), benzyl alcohol (0.25 g, 2.33 mmol) and 10 ml anhydrous toluene was immersed into an oil bath at 140 °C. Toluene was removed by azeotropic distillation under a nitrogen atmosphere to remove traces of water. The solution was further degassed by nitrogen sparging for 30 min and the reaction temperature was set at 110 °C. Sn(0ct)₂ (0.94 g, 2.33 mmol) was then added by a micro pipette under a positive nitrogen pressure. The polymerization flask was then resealed, and the polymerization was conducted at 110 °C under nitrogen protection with vigorous stirring. Samples of the reaction mixture were carefully removed for NMR and SEC analyses. The sample for NMR was simply diluted with CDCl₃, while that for SEC analysis was diluted with tetrahydrofuran (THF). After the monomer was totally consumed, the further degassed and dehydrated monomer solution was carefully injected via gas tight syringe and again the solution was allowed to polymerize at no °C with vigorous stirring under a nitrogen atmosphere. For the iterative chain extension, the above polymerization-sampling-extension procedure was repeated as required. The amount of monomer to be added to the reactor in each cycle was calculated according to the desired DP_n of each building block and the amount of initiator removed from the system was taken into account to calculate the amounts of reagents for the next addition cycle. In each cycle, samples were taken to monitor the polymerization. After five cycles, the final crude product was dissolved in 3 mL of DCM and precipitated dropwise into 60 mL of cold hexane to obtain pure sequence-controlled pentablock polyesters.

Global deprotection of polyesters. The sequence-controlled pentablock polyester (200 mg) was azeotropically distilled by toluene in vacuum, dissolved in 2 mL of anhydrous DCM and then 2 ml TFA was added to a round-bottomed flask under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 h under nitrogen and subsequently all the solvents were evaporated. Then the polyester was redissolved in DMSO and precipitated in cold diethyl ether three times to yield the final water-soluble, multifunctional, sequence-controlled pentablock polyester.

A protocol for synthesis of sequence-controlled pentablock polyethers. A three-neck flask charged with a rubber septum, a magnetic stir bar, monomer (20 eq), benzyl alcohol (1 eq) and 10 mL of anhydrous toluene was immersed into an oil bath at 140 °C. Toluene was removed by azeotropic distillation under a nitrogen atmosphere to remove traces of water from the flask. The solution was further degassed using nitrogen sparging for 30 min. t-Bu-P4 (1 eq) was then added by a gas tight syringe under a positive nitrogen pressure. The polymerization was conducted at 40 °C under nitrogen protection with vigorous stirring. A sample of the reaction mixture was carefully removed for NMR and SEC analysis. The polymer solution samples for NMR were simply diluted with CDCl₃, while the sample for SEC analysis was diluted with THF. After the monomer was totally consumed in each iterative chain extension, the further degassed and dehydrated monomer solution was carefully injected via gas tight syringe and again the solution was allowed to polymerize at 40 °C with vigorous stirring under a nitrogen atmosphere. The above polymerization-sampling-extension procedure was repeated as required. In each cycle, a sample was taken. The amount of initiator removed from the system was taken into account for the calculations of the next cycle. This procedure was applied to epoxy monomers F, K and L.

Alternative protocol for synthesis of sequence-controlled pentablock polyethers. The monomers were distilled over calcium hydride once prior to use. A three-neck flask charged with a rubber septum, a magnetic stir bar, monomer (25 mL) and 0.6 mg of anhydrous calcium hydride was immersed into an oil bath at the temperature which was 30 degrees higher than the monomer boiling point under a nitrogen atmosphere to remove traces of water from the flask. The distilled monomer (20 eq), benzyl alcohol (1 eq) and anhydrous toluene was added to a round flask. The solution was further degassed using nitrogen sparging for 30 min. t-Bu-P4 (1 eq) was then added by a gas tight syringe under a positive nitrogen pressure. The polymerization was conducted at 40 °C under a nitrogen protection with vigorous stirring. A sample of the reaction mixture was carefully removed for NMR and SEC analysis. The polymer solution samples for NMR were simply diluted with CDCl₃, while the sample for SEC analysis was diluted with THF. After the monomer was totally consumed in each iterative chain extension, the further degassed and dehydrated monomer solution was carefully injected via gas tight syringe and again the solution was allowed to polymerize at 40 °C with vigorous stirring under a nitrogen atmosphere. The above polymerization-sampling-extension procedure was repeated as required. In each cycle, a sample was taken. The amount of initiator removed from the system was taken into account for the calculations of the next cycle. This procedure was applied to epoxy monomers D, E, G, H, I and J For both of the above methods, after several cycles, a solution of the crude product was placed in a round-bottomed flask and concentrated. The final crude polymer was purified via the flash column method to yield a sequence-controlled multiblock polyether. Polymer K and L were deprotected with the TFA/DCM solvent mixture. NMR. ¹H NMR and ¹³C{1H} NMR spectra were recorded on a Bruker AVANCE III-400 MHz spectrometer with working frequencies of 400 (¹H) and 101 (¹³C) MHz at room temperature using CDCl₃ or D₂0 as solvent. The chemical shifts were given in ppm and referenced to proton resonances of residual non-deuterated solvents: CDCl₃, δ _H = 7.26 ppm, δc = 77.16 ppm; D₂0, δ _H = 4.79 ppm. The crude polymer mixture samples taken from the polymerization reactions for NMR were simply diluted with CDCl₃. SEC. The molecular weights, molecular weight distributions and dispersities were characterized by an Agilent 1260 Infinity II instrument containing a refractive index detector with gel permeation chromatography (GPC)-grade THF as the eluent, at a flow rate of 1.0 mL-min^-1 at 40 °C. One PLgel 5 pm Guard and two PLgel 5 pm Mixed D columns were used in series. Near-monodispersed, linear polystyrene standards were used to calibrate the instrument. The crude polymer mixture samples taken from the polymerization reactions were diluted with GPC-grade THF and filtered through a polytetrafluoroethylene (PTFE) membrane with a 0.2 pm pore size before injection (too pL) and used for SEC characterization unless stated otherwise. Another SEC, Shimadzu Prominence GPC System was used to characterize the molecular weights and dispersities of the deprotected sequence-controlled polyesters with three mixed-bed SEC columns in series (two TSKgel SuperHZM-M and one TSKgel SuperHZiooo) calibrated by polystyrene standards and with GPC-grade DMF containing 0.1 wt.% LiBr as a mobile phase at a flow rate of 1.0 mL-min^-1 at 60 °C. All deprotected polymer samples (10 mg) were dissolved in GPC grade DMF containing 0.1 wt.% LiBr (1 mL) and filtered through a PTFE membrane with a 0.2 pm pore size before injection (too pL). The differential refractive index (dRI) of each sample was monitored via a Shimadzu's RID-10A detector. DSC. The thermal property and glass transition temperature (T_g) of the sequence- controlled multiblock polyesters were measured using a DSC Q2000 instrument (TA Instruments, UK), where each sample was run with a Tzero aluminium pan sealed with a hermetic lid and a sealed empty crucible was used as a reference. The DSC instrument was calibrated using indium. Samples were heated from room temperature to 70 °C, at a rate of 10 °C.min^-1 under a helium flow and were kept at 70 °C for 2 min to erase the thermal history. Subsequently, the samples were cooled to -90 °C, at a rate of 10 °C-mim 1 and kept at -90 °C for a further 2 min, followed by a heating procedure from -90 to 70 °C, at a rate of 10 °C-min^-1. Each sample was run for three heating-cooling cycles. The T_g was determined as the midpoint of the transition recorded from the third heating cycle.

TGA. Thermogravimetric analysis of polymer samples was performed on a TA Instruments Discovery TGA. After the platinum pans were tared, the samples were run at a heating rate of 10 ^°C-min ^-1 under a N₂ atmosphere from 50 to 700 °C.

Hemolysis assay. Hemolysis assay was employed to examine the membrane- destabilizing activity of the synthesized polymers. The specific polymer stock solution was added into o.1 M phosphate buffer (pH 5.0-7.4) or 0.1 M citric buffer (pH 4.0-5. o) to achieve the polymer buffer solution at the desired polymeric concentrations and pH. Sheep RBCs were washed three times with 300 mosm PH7.4 phosphate-buffered saline and the polymer buffer solution was used to resuspend the RBC pellet. The final cell concentration was controlled to be within the range of 1 - 2 x to⁸ RBCs mL^-1, ensuring the absorbance of hemoglobin solution was proportional to the number of lysed RBCs. Negative control (RBCs suspended in buffer only) and positive control (RBCs lysed with deionized water) were prepared with the same cell concentration. The samples were incubated at 37 °C in a shaking water bath (too rpm) for 1 h, and then centrifuged at 3500 rpm for 3 min. The absorbance of the supernant from each sample was measured at 540 nm using a UV-Vis spectrophotometer (Thermo Scientific, UK) and the percentages of hemolysis were calculated. References

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Claims

Claims l. A method of producing a polymer, the method comprising contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer, wherein the plurality of monomers are a plurality of molecules of formula (I):

, wherein X¹ is CO, CRC¹R², SO or SO₂;

X² is O, NR³ or S;

X3 is CR⁴R⁵ or CO; each X4 is independently CR⁶R⁷, NR⁸, CO, O, S, SO or S0₂; n is o or an integer which is at least 1; R¹ and R² are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃;

R³ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, COOR⁹ or CONR⁹R¹⁰;

R⁴ and R⁵ are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃;

R⁶ and R⁷ are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; or one or more pairs of substituents, together with the atoms to which they are attached, independently form an optionally substituted 3 to 20 membered ring, wherein each pair of substituents consists of two of R¹ to R⁷;

R⁸ and R⁹ are each a protecting group; and

R¹⁰ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group.

2. The method according to claim 1, wherein the initiator has a molecular weight of less than 2,000 Da, less than 1,500 Da or less than 1,000 Da.

3. The method according to claim 1 or claim 2, wherein the initiator is an alcohol or an amine, and preferably is benzyl alcohol.

4. The method according to any preceding claim, wherein the method comprises contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur and, to thereby obtain a modified polymer, wherein the further plurality of monomers are a plurality of molecules of formula (I).

5. The method according to claim 4, wherein the method comprises contacting the modified polymer with a yet further plurality of monomers, to cause a further polymerisation reaction to occur and, to obtain a further modified polymer, wherein the further plurality of monomers are a plurality of molecules of formula (I).

6. The method according to claim 4 or claim 5, wherein the method does not comprise a purification step between subsequent polymerisation reactions.

7. The method according to any preceding claim, wherein the plurality of monomers used in a polymerisation reaction all have the same chemical formula.

8. The method according to any preceding claim, wherein the plurality of monomers used in a polymerisation reaction comprise a first molecule of formula (I) and a second molecule of formula (I), wherein the first and second molecules are different.

9. The method according to any preceding claim, wherein the plurality of monomers and the initiator or polymer are contacted in the presence of the catalyst, preferably wherein the catalyst is an organocatalyst or an organometallic catalyst.

10. The method according to any preceding claim, wherein the plurality of monomers comprise a compound or a plurality of compounds of formula (la), formula (lb), formula (Ic) and/or (Id):

da)

li. The method according to any preceding claim, wherein n is o or an integer between l and 20.

12. The method according to any preceding claim, wherein the plurality of monomers comprise a compound or a plurality of compounds of one or more of formula (If) to (Ik) or (Ilii):

13. The method according to any preceding claim, wherein prior to contacting the plurality of monomers and the initiator, the method comprises producing the plurality of monomers, and producing a plurality of monomers comprises contacting a compound of formula (II) with an oxidant, wherein the compound of formula (II) is:

, wherein X¹, X³ and X⁴ are as defined in any preceding claim and n is an integer of at least l.

14. A polymer of formula (III):

, wherein X¹ is CO, CR¹R², SO or S0₂;

X² is O, NR³ or S; X³ is CR⁴R⁵ or CO; each X⁴ is independently CR⁶R⁷, NR⁸, CO, O, S, SO or S0₂; n is o or an integer of at least 1;

R¹ and R² are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃;

R⁴ and Rs are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; R⁶ and R? are each independently H, a halogen, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; or one or more pairs of substituents, together with the atoms to which they are attached, independently form an optionally substituted 3 to 20 membered ring, wherein each pair of substituents consists of two of R¹ to R⁷;

R⁸ and R⁹ are each independently H, a protecting group, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle, SR¹⁰, SSR¹⁰, OR¹⁰, NR⁹R¹⁰, COOR⁹, CONR⁹R¹⁰, CN or N₃; and R¹⁰ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or a protecting group;

X⁸ is O, S orNR¹⁴

R¹⁴ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle or R¹⁵(OCH₂CH₂) _p-;

R¹⁵ is H, an optionally substituted C_1-30 alkyl, an optionally substituted C_2-30 alkenyl, an optionally substituted C_2-30 alkynyl, an optionally substituted C_6-20 aryl, an optionally substituted C_3-20 cycloalkyl, an optionally substituted C_3-20 cycloalkenyl, an optionally substituted C_3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 membered heterocycle

m defines a number of mers within the polymer, and is an integer of at least 2; p is an integer of at least 1; and the polymer is not polycaprolactone (PCL).

15. The polymer of claim 14, wherein the polymer comprises one or more mers of formula (IVa), (IVb), (IVc) and/or (IVd):

16. The polymer of claim 14 or claim 15, wherein the polymer comprises one or more mers of formula (IVf), (IVg), (IVh), (IVj), (IVk) and/or (IVli):

17. The polymer of any one of claims 14 to 16, wherein the polymer is any one of formula (101) to (147):

18. A use of the polymer of any one of claims 14 to 17 as an antimicrobial agent, to store information or in nanoscience or nanotechnology, wherein the use as an antimicrobial agent excludes use in a therapeutic application.

19. A fibre comprising the polymer of one of claims 14 to 17.

20. A medicament or a vaccine comprising the polymer of any one of claims 14 to

17· 21. The polymer of any one of claims 14 to 17 for use in therapy.

22. The polymer of any one of claims 14 to 17 for use in drug delivery, gene therapy, tissue engineering, medical imaging and/ or sensing and/ or in treating a microbial infection.