Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems

In light of the versatile synthetic potential of β-lactams on the one hand and the beneficial impact of fluorine on biological properties on the other hand, β-lactams bearing a trifluoromethyl group comprise interesting entities for the construction of novel targets with promising bioactivities. In this PhD thesis, the preparation and deployment of 4-trifluoromethyl-β-lactams as new building blocks toward a diverse set of functionalized CF3-amines and CF3-azaheterocycles was investigated. In particular, 3-benzyloxy-4-trifluoromethyl-β-lactams were conveniently synthesized as a first new class of building blocks. The aptitude of these systems with respect to ring-opening reactions was explored to enable an entry to functionalized aminopropane systems by either direct reductive β-lactam ring opening or initial carbonyl removal to azetidine intermediates, followed by ring opening. In addition, hydrogenolysis of the benzylether fragment in 3-benzyloxy-4-trifluoromethyl-β-lactams resulted in the formation of 3-hydroxy-4-trifluoromethyl-β-lactams as a second class of new building blocks. The latter alcohols enabled the construction of CF3-containing ring-rearranged products, including aziridines through a ring-contraction protocol via 3-chloro-β-lactam intermediates and dioxan-2-ones via initial O-allylation. Furthermore, alcohol oxidation gave rise to 3-oxo-4-trifluoromethyl-β-lactams as a third class of new building blocks. Attempts to form and trap the corresponding 2,3-dioxoazetidin-4-yl anions unexpectedly resulted in ring opening through C3-C4 bond fission, culminating in 2-[(2,2-difluorovinyl)amino]-2-oxoacetate products. This peculiar mechanism was investigated in depth, both experimentally and computationally. Finally, an addition/elimination sequence applied to 3-oxo-4-trifluoromethyl-β-lactams afforded 3-methylene-4-trifluoromethyl-β-lactams as a fourth class of new building blocks, which were shown to be eligible substrates for Michael additions, electrophilic additions and cycloadditions en route to a variety of stereodefined mono- and spirocyclic 4-CF3-β-lactams.

Grantor dc:publisher

Ghent University. Faculty of Bioscience Engineering

Year dc:date

2018

Author dc:creator

• Dao Thi, Hang

Contributors dc:contributor

• D'hooghe, Matthias
• Nguyen, Tuyen Van

• Chemistry

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://biblio.ugent.be/publication/8561326
https://biblio.ugent.be/publication/8561326/file/8561327

OAI identifier oai:identifier

oai:archive.ugent.be:8561326