Catalytic strategies for the synthesis of environmentally-responsive poly(aminoesters) : applications for the delivery of messenger RNA

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Polyesters are a remarkable class of polymeric materials that have been featured as biodegradable textiles, implantable biomedical devices, and drug delivery vehicles for therapeutic applications. However, the synthesis of polyesters with rich functional group diversity, narrow molecular weight distributions and targeted molecular weighs remains a significant challenge. The selective aerobic oxidation of 1,5-diols with [(neocuproine)Pd(OAc)]2(OTf)2 (neocuproine = 1,9-dimethylphenanthroline), A, yields cyclic lactones. A selection of functionalized 1,5-diols was investigated to explore the substrate scope and to determine compatible functional groups for the oxidative lactonization reaction using A. These studies led a general strategy for the synthesis of functionalized lactones, specifically N-substituted morpholin-2-ones. The organocatalytic ring-opening polymerization of N-acyl morpholin-2-ones occurs readily to generate functionalized poly(aminoesters) with N-acylated amines in the polyester backbone. The thermodynamics of the ring-opening polymerization depends sensitively on the hybridization of the nitrogen of the heterocyclic lactone. N-Acyl morpholin-2-ones polymerize readily to generate polymorpholinones, but the N-aryl or N-alkyl substituted morpholin-2-ones do not polymerize. Experimental and theoretical studies reveal that the thermodynamics of ring opening correlates to the degree of pyramidalization of the endocyclic N-atom. A wide range of novel polyesters was synthesized. Deprotection of the N-Boc protected polyaminoesters yields water-soluble, cationic materials. Three novel cationic water-soluble polyaminoesters (PAEs) were synthesized. These materials were shown to be stable in neutral D2O for over two days, however, upon exposure to alkaline or buffered conditions, two of the PAEs degraded rapidly and quantitatively to single small molecule products. An immolative mechanism is proposed to account for the exquisite selectivity of the observed in the controlled degradation. The rate of degradation is sensitive to pH, providing a new class of water-soluble materials which can be induced to degrade under specific environmental conditions.


Type of resource text
Form electronic; electronic resource; remote
Extent 1 online resource.
Publication date 2016
Issuance monographic
Language English


Associated with Blake, Timothy R
Associated with Stanford University, Department of Chemistry.
Primary advisor Waymouth, Robert M
Thesis advisor Waymouth, Robert M
Thesis advisor Kool, Eric T
Thesis advisor Xia, Yan
Advisor Kool, Eric T
Advisor Xia, Yan


Genre Theses

Bibliographic information

Statement of responsibility Timothy R. Blake.
Note Submitted to the Department of Chemistry.
Thesis Thesis (Ph.D.)--Stanford University, 2016.
Location electronic resource

Access conditions

© 2016 by Timothy Ray Blake
This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).

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