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

Thi Hang Dao (UGent)
(2018)
Author
Promoter
(UGent) and Tuyen Van Nguyen
Organization
Abstract
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.

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Citation

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Chicago
Dao, Thi Hang. 2018. “Synthesis of 4-(trifluoromethyl)azetidin-2-one Building Blocks and Their Transformation into Novel CF3-substituted Amines and Heterocyclic Systems”. Ghent, Belgium: Ghent University. Faculty of Bioscience Engineering.
APA
Dao, T. H. (2018). Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems. Ghent University. Faculty of Bioscience Engineering, Ghent, Belgium.
Vancouver
1.
Dao TH. Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems. [Ghent, Belgium]: Ghent University. Faculty of Bioscience Engineering; 2018.
MLA
Dao, Thi Hang. “Synthesis of 4-(trifluoromethyl)azetidin-2-one Building Blocks and Their Transformation into Novel CF3-substituted Amines and Heterocyclic Systems.” 2018 : n. pag. Print.
@phdthesis{8561326,
  abstract     = {In light of the versatile synthetic potential of \ensuremath{\beta}-lactams on the one hand and the beneficial impact of fluorine on biological properties on the other hand, \ensuremath{\beta}-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-\ensuremath{\beta}-lactams as new building blocks toward a diverse set of functionalized CF3-amines and CF3-azaheterocycles was investigated. In particular, 3-benzyloxy-4-trifluoromethyl-\ensuremath{\beta}-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 \ensuremath{\beta}-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-\ensuremath{\beta}-lactams resulted in the formation of 3-hydroxy-4-trifluoromethyl-\ensuremath{\beta}-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-\ensuremath{\beta}-lactam intermediates and dioxan-2-ones via initial O-allylation. Furthermore, alcohol oxidation gave rise to 3-oxo-4-trifluoromethyl-\ensuremath{\beta}-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-\ensuremath{\beta}-lactams afforded 3-methylene-4-trifluoromethyl-\ensuremath{\beta}-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-\ensuremath{\beta}-lactams.},
  author       = {Dao, Thi Hang},
  language     = {eng},
  pages        = {VIII, 201},
  publisher    = {Ghent University. Faculty of Bioscience Engineering},
  school       = {Ghent University},
  title        = {Synthesis of 4-(trifluoromethyl)azetidin-2-one building blocks and their transformation into novel CF3-substituted amines and heterocyclic systems},
  year         = {2018},
}