Yes / We describe a concise and straightforward approach to the total syntheses of (+)-Strictifolione and Cryptofolione in the longest linear sequences of four steps and six steps from 3-phenyl propanal and trans-cinnamaldehyde, respectively. The route utilized a titanium tetraisopropoxide/(R)-[1,1'-binaphthalene]-2,2'-diol catalyzed Mukaiyama aldol reaction, indium(0)-promoted Barbier reaction, and olefin cross-metathesis as the key reactions. / National Science Foundation of China [21062088, 21562020, and 21462004], the Science and Technology Plan Project of Jiangxi Province [No. 20151BBG70028, 20142BBE50006] and State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources [CMEMR2014-A04] for the funding support.

Poly(lactic acid), PLA, is a viable replacement to petroleum derived polymers due to its renewable feedstock, biodegradability and bioassimilability, yet improvements in its physical, thermal and mechanical properties are required before it can fully enter all commodity markets. This thesis investigates olefin cross-metathesis (CM) as a synthetic strategy to modify the properties of PLA. The use of novel lanthanide and actinide catalysts on the microstructure control of PLA are also explored. The Tebbe reagent was used in a new synthetic strategy to produce a novel olefin derivative of lactide (MML). Olefin CM of MML with hex-1-ene was successful but polymerisation pre- and post-CM was unsuccessful due to monomer instability. CM of another olefin derivative of lactide, 3-methylenated lactide (3-ML) was successful with aliphatic alkenes; hex-1-ene to dodec-1-ene. To overcome competing alcoholysis of the functionalised monomers, which prevented polymerisation, hydrogenation was used to remove the olefin entity followed by successful ring-opening polymerisation (ROP) to produce polymers of low glass-transition temperatures (Tg). Post-polymerisation CM on an olefin containing polymer P(β-heptenolactone) P(β-HL), with methyl acrylate and an epoxide, generated functionalised homopolymers with increased Tg’s. Co-polymerisation of lactide with β-HL generated novel gradient-copolymers. Olefin CM with 15 different cross-partners produced functionalised copolymers with different thermal properties. Based on this route a new methodology was created to introduce two unique functionalities into the polymer backbone by manipulation of the olefin reactivities. Finally, in a collaborative project, uranium and cerium catalysts, Me3SiOU(OArP)3 and Me3SiOCe(OArP)3 - designed out-with the group- were tested and compared as ROP catalysts for lactide. Both catalysts were active in living polymerisations of L-lactide and under immortal conditions the activity and rates of the catalysts were switched, accounted for by a change in the coordination sphere due to ligand displacement. ROP of rac-lactide using the uranium analogue produced heterotactic-biased PLA with a Pr = 0.79.

Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications. / Ph. D. / When it comes to drug administration, oral delivery is often preferred over other methods like intravenous injection since it is cheap, convenient, painless and easily conducted without requiring professional training or clinical environment. However, one of the most common issues for oral drugs to be absorbed by human body is that a large portion of drugs do not dissolve in water. An effective method to conquer this problem is to blend a properly designed polymer with the poorly dissolving drug, making the drug dissolve in water more effectively and thus be able to enter the bloodstream. Such polymers have to be safe, stable, non-toxic, and biodegradable. Cellulose is one of the most abundant polysaccharides on earth and it has inexhaustible source from wood, cotton and many other plants. Natural cellulose is a linear polymer and is highly crystalline and therefore does not tend to dissolve in water or any other simple organic solvents. Chemical modifications of cellulose to make derivatives (e.g. cellulose esters and ethers) will disrupt the crystallinity and make it more soluble and processible for many applications including coating, packaging, food and pharmaceuticals. The Edgar and Taylor groups have demonstrated that some cellulose derivatives with specific properties are very good polymer matrices to facilitate the delivery of poorly soluble drugs. These cellulose-based polymers can stabilize the active drugs, protect drug from the acidic stomach and make them more soluble in the digestive tract so they can be absorbed by human body. However, previous synthetic methods to prepare such cellulose derivatives are very timeand effort- consuming. Meanwhile, one polymer is usually not suitable for every drug since each drug will have different issues, for example different water solubility and/or stability in acidic stomach. Therefore, design and preparation of new polymers with enhanced performance is extremely desirable, which highly depends on development of new chemistry. This dissertation focuses on investigating novel chemistry to modify cellulose ethers and creating a broad range of polymer candidates for oral drug delivery. Unlike traditional methods, the new method is very mild and efficient with short reaction time, neutral pH, complete conversion and almost quantitative yield. It also allows incorporation with all kinds of functional groups to afford a variety of polymer structures. As a result, this method has enabled a library of polymers with diverse structures for drug delivery application and for structure-property relationship evaluations, which will further provide valuable information for designing nextgeneration polymers with optimized performance. The cellulose derivatives prepared in this way are also very promising for coating, food additive, and other biomedical applications.