Development of novel p-amidites and their application in the synthesis of the most densely phosphorylated compounds

Abstract: Phosphoanhydrides (P-anhydride) are omnipresent in biology. Among many, some key examples of P-anhydrides in biology are: ATP – the energy currency of all cells – and inorganic polyphosphate – essential for growth and survival in many organisms. Despite intensive research in the field of nucleoside polyphosphate chemistry, the development of a general and step economic process to access their modified analogs remains a formidable challenge. Also, to date, no single rational chemical synthesis has been established to provide access to tagged or natural monodisperse polyPs with different chain lengths.

This thesis discloses a general solution to the long-standing problem in the field of nucleotide and polyphosphate chemistry. A novel cyclic triphosphorylating reagent (c-PyPA) based on phosphoramidites (P-amidites) was developed. This reagent is obtained by the reaction of pyrophosphate with a reactive diisopropylaminodichlorophosphine. The derived c-PyPA couples to nucleosides and allows access to modified cyclotriphosphates that provides a general, high-yielding and step-economic synthesis of nucleoside triphosphates and their analogs without using protecting groups. Furthermore, a family of reagents was developed that provide access to non-hydrolysable phosphate conjugates based on the c-PyPA substructure. Not only do the reagents provide rapid access to modified cyclotriphosphates, but a range of nucleophiles such as imidazole, azide, fluoride were used in the linearization step to afford pure γ-labelled β,γ-modified nucleotides in an unprecedented good yields. In order to further demonstrate the utility of this approach, γ-imidaolides were prepared which culminated in the formation of capped hexaphosphate. This methodology was also applied to leverage phosphates as nucleophiles instead of alcohols to afford cyclic ultraphosphates. Subsequently, upon ring-opening by other modified phosphates these cyclic ultraphosphates enabled the synthesis of different and defined chain lengths of polyPs with P-N and P-O modifications. Overall, the developed novel methodology is the first concise synthesis to target densely charged modified or unmodified polyPs. Crucially, the derivative of c-PyPA reagents facilitates access to a large number of nucleotide analogs in a highly modular manner

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2020

Klassifikation und Themen

• Schlagwort: Polyphosphate

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2020
• Urheber: Singh, Jyoti
• Beteiligte Personen und Organisationen: Jessen, Henning Jacob ; Albert-Ludwigs-Universität Freiburg. Fakultät für Chemie und Pharmazie

Weitere Informationen

• DOI: 10.6094/UNIFR/154980
• URN: urn:nbn:de:bsz:25-freidok-1549802
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:49 MESZ