Thesis advisor: Jia Niu / Thesis advisor: Jim Morken / Polysaccharides make up one of the largest classes of nature’s macromolecules. However, they are severely understudied relative to other biomolecules such as proteins and DNA sequences. This is because discrete polysaccharides are difficult to isolate from nature or synthesize in laboratories in large enough quantities for thorough research. Polymerization is an efficient route to polysaccharides, yet has historically suffered from harsh conditions and lack of control. Herein, we investigate recent developments in the field of living polymerization as strategies towards synthesis of precision polysaccharides from 1,2- anhydrosugars. We specifically focus on cationic ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) ROP polymerization of 1,2-O-Bn-3,4,6-anhydromannose and 1,2-O-Bn-3,4,6-anhydroglucose. Our research screens various catalyst/initiating systems. Our findings demonstrate that cationic ROP and RAFT polymerization are unsuccessful in the living ROP of 1,2-anhydrosugars. / Thesis (MS) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Despite the degradability and biocompatibility of poly(α-hydroxy acids), their utility remains limited because their thermal and mechanical properties are inferior to those of commodity polyolefins, which can be attributed to the lack of side-chain functionality on the polyester backbone. Attempts to synthesize high-molecular-weight functionalized poly(α-hydroxy acids) from O-carboxyanhydrides have been hampered by scalability problems arising from the need for an external energy source such as light or electricity. Herein, an operationally simple, scalable method for synthesizing stereoregular, high-molecular-weight (>200 kDa) functionalized polyesters have been developed by means of controlled ring-opening polymerization of O-carboxyanhydrides mediated by a highly redox reactive manganese complex and a zinc-alkoxide. Mechanistic studies indicated that the ring-opening process proceeded via the Mn-mediated decarboxylation with alkoxy radical formation (Chapter 2). In addition to the polymerization, a two-step facile chemical recycling strategy for poly(α-hydroxy acids) was developed to achieve closed-loop life cycles (Chapter 3). Moreover, this synthetic strategy is not limited to preparing homopolymers and block copolymers but also to producing stereoblock and gradient copolymers (Chapter 4). In particular, the gradient copolymers exhibited better ductility and toughness than their corresponding homopolymers and block copolymers, highlighting the potential feasibility of functionalized polyesters as strong and resilient polymeric materials (Chapter 5). Next, an atom-economical, scalable method for block copolymerization of O-carboxyanhydrides and epoxides to prepare functionalized poly(ester-b-carbonates) with high molecular weights (>200 kDa) was identified, that uses a single Lewis acidic zinc complex at room temperature in the absence of pressurized CO2 (Chapter 6). Kinetic studies showed that the first stage of the process, ring-opening polymerization of the O-carboxyanhydrides, exhibited zero-order kinetics, suggesting that the polymerization rate was independent of monomer concentration, thus allowing for a sharp switch in mechanism without a tapering effect (Chapter 7). The obtained poly(ester-b-carbonates) showed better toughness than their corresponding homopolymers and outperformed some commodity polyolefins (Chapter 8). Exploring this new chemical space of poly(ester-b-carbonates) via stereosequence-controlled synthetic methods would be a critical step toward improving this promising class of functionalized sustainable polymers (Chapter 9). / Doctor of Philosophy / Poly(α-hydroxy acids) is an environmentally friendly alternative to petrochemical polyolefins due to their excellent degradability and biocompatibility. However, it is difficult to synthesize high-molecular-weight functionalized polyesters on a large scale due to the inefficient catalysts and the need for external energy, such as light and electricity. Herein, a highly reactive Mn/Zn catalytic system for controllable O-carboxyanhydrides (OCAs) polymerization has been designed. Compared with the previously reported catalytic system, this method can be used to produce low-cost, large-scale preparation of high molecular weight (>200 kDa) polyesters without the need for external energy sources (Chapter 2). In addition, our synthesized polyesters can be completely degraded under mild conditions, thereby achieving a circular economy in the polyester industry (Chapter 3). More importantly, our operationally simple synthetic method could afford polyesters with different compositions, such as homopolymers, block copolymers, stereoblock copolymers, and gradient copolymers (Chapter 4). In particular, the obtained gradient copolymer is tough and ductile that could compete with commercial polyolefins in terms of mechanical and thermal properties, such as low-density polyethylene (LDPE) (Chapter 5). Next, we developed a single Lewis acidic zinc complex to achieve the copolymerization of OCA and epoxide to synthesize poly(ester-b-carbonates), which enriches the class of degradable polymers (Chapter 6). Moreover, this copolymerization showed unique reaction kinetics that enabled the perfectly clean switching of the polymerization mechanism during chain propagation (Chapter 7). The obtained poly(ester-b-carbonates) showed better toughness than their corresponding homopolymers and outperformed some non-degradable plastics (Chapter 8). The exploration of novel degradable polymers by sequence-controlled polymerization to replace non-degradable polyolefin on the market will continue in the near future (Chapter 9).

A review of the chemistry of poly(lactic acid) was carried out with a focus on techniques and applications of PLA polymer and copolymers with reference to some of the work that has been accomplished over the last 20 years or so. A review of the characterisation techniques used to analyse PLA polymers and copolymers was also carried out giving reference to the equipment and methods used herein. An investigation into the potential of PLA as the hydrophilic portion of a polymeric surfactant was carried out. To develop PLA based surfactants, the ring opening polymerisation of lactide was carried out in a melt in the presence of a long chain alcohol (C₇ to C₂₀) or diol (C₄ & C₆) to produce AB or ABA type polymers that follow the traditional surfactant template. Stannous octanoate and 4-dimethylaminopyridine were typically used as catalysts due to their high activity and relative cheapness. PLA only shows good hydrophilicity with up to 12 lactic acid units in the chain. Above this the electrostatic interactions between polymer chains reduced water solubility. It was also noted that D,L-lactide produced more water soluble polymers (syndiotactic) than the enantiomerically pure L-lactide (isotactic polymer chains). An investigation of the hydrophobic properties of PLA was carried out to evaluate their usefulness for other biodegradable surfactant applications. To this end an investigation of sugars as the hydrophilic portion of the molecule was carried out. Due to problems with solubilising sugars, they were deemed unsuitable for use as initiatiors within the scope of this research. Choline chloride was then investigated as a potential hydrophilic initiator and indeed has produced some of the most water soluble of PLA polymers. Choline chloride presented several challenges as an initiator, its high melting point resulted in polar solvents such as t-butanol being employed. Alternatively, more success was achieved by preparation of a choline chloride eutectic mixture prior to the polymerisation. It was discovered that a choline chloride/urea eutectic mixture was capable of self initiation, thus required no further addition of catalyst, this result shows a potential step forward in PLA green chemistry. A final investigation into producing surface-active PLA in a one-pot process that required only a hydroxycarboxylate initiator was carried out. The production of PLA sodium or potassium salts was carried out in a melt polymerisation and the results show some promise. Initiators that have been employed include a range of a, b and g-hydroxycarboxylic acids. These work through tautomerisation to the alkoxide, which then initiates a living type polymerisation of lactide to produce surface-active polymers. As well as the synthesis of these polymers some analysis of the physical and aqueous properties of these materials was carried out. PLA sodium salts were shown to have reasonable surfactant ability (~45 mNm⁻¹) and low CMC values of around 5x10⁻⁹ mol cm⁻³. They were also shown to have some properties as emulsifiers, and in some cases showed non-Newtonian fluid behaviour such as shear-thinning (thixotropy) and shear-thickening (dilatant). The thermal characteristics of the polymers such as T[subscript]g and stability were assessed as well as their ability to retain water.

This thesis describes the synthesis and characterisation of novel mono and dinuclear homogenous [Zn(II)] and [In(III)] metal complexes. Their applications as catalysts for CO₂/epoxide or epoxide/anhydride ring opening copolymerisation and lactide ring opening polymerisation to generate polycarbonates and polyesters, respectively, are also reported. Chapter 3 reports the first indium phosphasalen catalysts for CO₂/cyclohexene oxide ring opening copolymerization. The catalysts are active at 1 bar pressure of CO₂ and are most effective without any co-catalyst. It is also possible to use the complexes to isolate and characterise the key intermediates in the catalytic cycle. Kinetic and spectroscopic analyses show that polymerisation proceeds via a rare cis-mononuclear coordination- insertion mechanism. Chapter 4 describes a series of mono and dinuclear zinc macrocycle catalysts with very high activities for the racemic lactide ring opening polymerisation. In most cases, the dinuclear zinc catalysts significantly out-perform the mono-zinc homologue. In addition, kinetic and spectroscopic investigations suggest a role for the ligand conformation in mediating rate. The catalysts perform very well under immortal conditions and operate at low catalyst loading, whilst conserving high activities. Chapter 5 presents four dinuclear zinc acetate salen catalysts for the ring opening copolymerisation of CO₂/cyclohexene oxide and phthalic anhydride/cyclohexene oxide. The catalysts show moderate activities for CO₂/epoxide copolymerisation but are highly active for epoxide/anhydride copolymerisation. Structure/activity relationship studies reveal that the more flexible and electron donating ligand displays the highest activity. Poly(ester-b-carbonate)s are also afforded using the most active catalyst in terpolymerisations of anhydride/epoxide/CO₂.

The thesis entitled “Studies on the Ring-opening Reactions of Vinylcyclopropanes, Vinylcyclobutanes, and other Small-ring Systems” is divided into four chapters. Chapter 1: Part A: Bromenium Catalyzed Tandem Ring-opening/Cyclization of Vinylcyclopropanes and Vinylcyclobutanes: A [3+2+1]/[4+2+1] Cascade for the Synthesis of Chiral Amidines. In this part of the Chapter, we discuss our serendipitous results in the reaction of vinylcyclopropanes (VCPs), like Δ2-carene under Sharpless aziridination conditions using chloramine-T and phenyltrimethylammonium tribromide (PTAB) as catalyst in acetonitrile. The reaction follows a [3+2+1] cascade pathway involving acetonitrile (Ritter-type reaction) to give chiral bicyclic amidines in very good yield. The reaction was found to be tolerant to hydroxyl- and keto-functionalities. . existence of a tight-carbocation intermediate. Our attempts to access bridged bicyclic amidines from vinylcyclobutanes like α-pinene resulted in the formation of bicyclo[4.3.1]pyrimidines successfully in moderate yields. Partial racemization of the product was observed and this observation was rationalized through competing cyclization pathways. Vinylcyclopropanes and Vinylcyclobutanes towards the Synthesis of Chiral Amidines. In this part of the chapter, we discuss our computational results obtained from modeling the reaction pathway in gas-phase and solvent dielectrics (acetonitrile). Initially, we modeled the ring-opening process, to visualize the geometrical features and the orbital interactions present in the tight-carbocation intermediate. We also modeled the competing cyclization pathways to justify the racemization observed in the case of α-pinene. Our calculations show that, the free energy of activation for the allylic substitution and the direct substitution pathways are nearly equal. Thus, the formation of both the enantiomers is feasible kinetically. the proposed cascade pathway. Chapter 2: Electrophile-Induced Indirect Activation of C-C Bond of Vinylcyclopropanes: A Masked Donor-Acceptor Strategy for the Synthesis of Z-Alkylidenetetrahydrofurans. In Chapter 2, we discuss the results of introducing VCPs as masked donor-acceptor systems under electrophilic conditions. Our aim was to activate the VCPs with in situ generated bromine electrophile to give a tight-carbocation as discussed in Chapter 1. Further, the tight-carbocation can be used to access novel heterocycles. formation of Z-alkylidienetetrahydrofurans with high stereoselectivity across the exocyclic double bond. An interesting reactivity of benzofuran derived VCPs was observed, where the ring-opening occurred concurrently adjacent to the heteroatom and at the benzylic position to give both cis- and trans-furofuran. methyl group on VCP as a chiral marker. Under our standard reaction conditions, cyclization resulted in the retention of configuration at the phenyl center. The retention of configuration results through a directed attack of hydroxyl group on the tight-carbocation. functionalized tetrahydrofurans Chapter 3: σ-Ferrier Rearrangement of Carbohydrate Derived Vinylcyclopropanes: A Facile Approach to Oxepane Analogs In the present chapter, we have presented the idea of a tight-carbocation through an electrophile-mediated activation of VCPs on carbohydrate derived VCPs through a σ-Ferrier rearrangement. We expected high stereoselectivity at the anomeric center assuming the existence of a tight carbocation intermediate. Reaction of glucose-derived VCPs resulted in the ring-expansion to oxepane analogues, but with poor diastereoselectivity. Similar selectivity was observed even in the case of galacto- derived VCPs. intermediate. The planar oxonium intermediate is a more stable intermediate but reacts with poor facial selectivity. With water as nucleophile, the reaction led to a diene aldehyde through a complete ring-opening of the oxepane formed, followed by the elimination of hydrogen bromide. the unsaturated oxepanes with facial diastereoselectivity. Chapter 4: One-Pot Synthesis of β-Amino/β-Hydroxyselenides and Sulfides from Aziridines and Epoxides. In this chapter, we present details of the reductive cleavage of aromatic disulfide and diselenide bonds mediated by Rongalite. The reagent reacts with disulfides to generate thiolate anion through a two-electron transfer mechanism. The thiolate anion was further utilized for nucleophile-mediated ring-opening of small-ring systems. The reaction of aziridines with aryl disulfides mediated by Rongalite, resulted in regioselective ring-opening to from β-aminosulfides. In the case of trisubstituted aziridines, the reaction led to a regioisomeric mixture of products. The reaction was found to be efficient for the ring-opening of epoxides as well. diselenides and Rongalite, successfully underwent cleavage of diselenide bond followed by ring-opening to give β-aminoselenides. The reaction was successful with epoxides as starting material to yield β-hydroxyselenides

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Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.

The biosynthesis of the steroid precursor molecule lanosterol is a remarkable process in which the enzyme-bound substrate 2,3-S-oxidosqualene forms four new carbocyclic rings by a cascade of cation-alkene addition reactions, followed by a series of 1,2-methyl and hydride shifts. The work presented in this thesis is a computational study of the reactions of compounds designed to model the oxidosqualene-lanosterol cyclisation in order to establish details of the mechanism of this amazing cyclisation. The initiation of oxidosqualene cyclisation has been modelled by the intermolecular reaction of protonated oxirane and methylpropene. The SN2-like ring opening of the protonated epoxide is strongly exothermic with a low barrier to reaction; the geometry of the gas phase reaction has been found to be significantly affected by hyperconjugative stabilisations and low energy steric interactions. The energy profile and geometry of this reaction can now be compared to analogous intramolecular reactions such as the formation of the lanosterol A-ring. The competing five- and six-membered cyclisations of a series of substituted A-ring model compounds was investigated. It has been found that the facile cleavage of the protonated epoxide causes the reaction to behave more as an electrophilic addition than as a nucleophilic ring-opening substitution. This behaviour accounts for the general preference of protonated epoxides to react at the more substituted carbon atom, while epoxides in neutral or basic media react at the least sterically hindered carbon. With consideration for Baldwin's rules for ring closure, it is seen that the series of model compounds generally favours six-membered ring formation endo at the epoxide. The formation of the lanosterol B-ring was studied using a bicyclic model system. Previous computational studies had predicted the B-ring to close with readily with an activation energy of less than 1 kcal mol-1, however the present study has found a significant barrier to cyclisation of ca. 5-7 kcal mol-1 in this gas-phase model at the HF/6-31G(d) level of theory. This barrier is thought to arise from the closure of the B-ring in a sterically hindered twist-boat conformation.

In this study a number of cage alkenes were synthesised and tested for activity towards ringopening metathesis polymerisation (ROMP) with the commercially available catalysts 55 (Grubbs-I) and 56 (Grubbs-II). The first group of monomers are derivatives of tetracyclo[6.3.0.04,1105,9]undec-2-en-6-one (1). The synthesis of these cage alkenes are summarised in Scheme 7.1. The cage alkene 126b was synthesised by a Diels-Alder reaction between 1 and hexachlorocyclopentadiene (9, Scheme 7.2). The geometry of 126b was determined from XRD data. Knowledge of the geometry of 126b also established the geometry of 127 since conformational changes during the conversion from 126b to 127 are unlikely. Synthesis of the cage alkene 125 by the cycloaddition of 9 to 118 failed. The cage alkene exo-11- hydroxy-4,5,6,7,16,16-hexachlorohexacyclo[7.6.1.03,8.02,13.010,14]hexa-dec-5-ene (124, Scheme 7.3) could therefore not be prepared. Synthesis of 125 by reduction of 126b with various reduction systems was not successful. Theoretical aspects of these reactions were investigated with molecular modelling. A possible explanation for the unreactive nature of 126b towards reduction is presented, but the lack of reactivity of 118 towards 9 eluded clear explanations. The synthesis of cage alkenes from 4-isopropylidenepentacyclo[5.4.0.02,6.03,10.05,9]-undecane-8,11- dione (23) did not meet with much success (Scheme 7.4). Numerous synthetic methods were investigated to affect the transformation from 134a/134b to 135 (Scheme 7.5). These attempts evolved into theoretical investigations to uncover the reasons for the observed reactivity. Possible explanations were established by considering the differences and similarities between the geometries and electronic structures of reactive and unreactive cage alcohols. ROMP of cage monomers based on 1 were mostly unsuccessful. Only the cage monomer 127 showed some reactivity. Endocyclic cage monomers with a tetracycloundecane (TCU) framework showed no reactivity. The results from NMR experiments verified the experimental results. Hexacyclo[8.4.0.02,9.03,13.04,7.04,12]tetradec-5-en-11,14-dione (3) exhibited notable ROMP reactivity. Examination of the orbitals of the cage alkenes used in this study suggested that the reactivity of 1 and 3 could possibly be enhanced by removal of the carbonyl groups. Decarbonylation of 1 and 3 yielded the cage hydrocarbons 159 and 175, respectively. ROMP tests revealed that 175 is an excellent monomer, but 159 was unreactive. The results obtained for the ROMP reactions in this study was rationalised by considering aspects such as ring strain, energy profiles, steric constraints, and frontier orbital theory. The concept of ring strain is less useful when describing the reactivity of cage alkenes towards ROMP and therefore the concepts of fractional ring strain and fractional ring strain energy (RSEf) were developed. A possible link between RSEf and the ROMP reactivity of cage alkenes was also established. The following criteria were put forth to predict the reactivity or explain the lack of reactivity of cage alkenes towards ROMP reactions with Grubbs-I and Grubbs-II. The criteria for ROMP of cage monomers: 1. Sufficient fractional ring strain energy (RSEf). 2. A reasonable energy profile when compared to a reference compound such as cyclopentene. 3. Ability to form a metallacyclobutane intermediate with reasonable distances between different parts of the cage fragment. 4. Sufficient ability of the polymer fragment to take on a conformation that exposes the catalytic site. 5. Sufficient size, shape, orientation and energy of HOMO and/or NHOMO at the alkene functionality of the cage monomer and of the LUMO at the catalytic site. / Thesis (Ph.D. (Chemistry))--North-West University, Potchefstroom Campus, 2012