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Regioselective Synthesis of Bicyclic Nucleosides and Unsymmetric Tetrasubstituted Pyrene Derivatives with a Strategy for Primary C-2 Alkylation




Dmytrejchuk, Ana

Type of Degree

PhD Dissertation


Chemistry and Biochemistry


CHAPTER 1 The incorporation of synthetic, tricyclic nucleic acid (TriNA) modifications into antisense oligonucleotides (ASOs) with therapeutic applications has been demonstrated to provide increased thermal stability relative to DNA and RNA, as well as leading nucleic acid modifications, such as locked nucleic acid (LNA). One of the major obstacles facing the development of complex nucleic acid modifications into viable ASO candidates is lengthy synthetic sequences. This work describes new synthetic strategies that involve the preparation of advanced nucleoside intermediates, which could obviate the use of inefficient glycosylation reactions (3 steps). Furthermore, using commercially available nucleosides as starting materials we envisioned a short synthetic approach to a bicyclo[n.2.1]undecane nucleoside intermediate, which takes advantage of regio- and chemoselective reactions. These intermediates could serve as molecular scaffolds from which multiple TriNA analogues can be prepared. CHAPTER 2 Pyrene is a well-known chromophore frequently used in organic fluorescent materials. Its unique properties such as long-lived excited (singlet) states and its ability to form excimers have been widely exploited in many scientific fields, making pyrene and its derivatives an important fluorophore in both fundamental and applied photochemical research. To tailor the specific electronic properties of pyrene and its applications in materials science, strategies to introduce substituents about the pyrene core have been developed. However, still a major limitation for the use of pyrene in general is the lack of synthetic protocols for non-symmetric, selective functionalization of the pyrene nucleus. This work describes the synthesis of 1,2,4,5-, 1,2,9,10-tetrasubstituted and 1,2,4,5,8-pentasubsutituted pyrenes, which has been achieved by initially functionalizing the K-region of pyrene. Bromination, acylation, and formylation reactions afford high to moderate levels of regioselectivity, which facilitate the controlled introduction of other functional groups about 4,5-dimethoxypyrene. Access to 4,5- dimethoxypyren-1-ol and 9,10-dimethoxypyren-1-ol enabled a rare, C-2 primary alkylation of pyrene.