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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)
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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author
promoter
UGent and Tuyen Van Nguyen
organization
alternative title
Synthese van 4-(trifluormethyl)azetidin-2-onen en hun omzetting tot nieuwe CF3-gesubstitueerde aminen en heterocyclische systemen
year
type
dissertation
publication status
published
subject
pages
VIII, 201 pages
publisher
Ghent University. Faculty of Bioscience Engineering
place of publication
Ghent, Belgium
defense location
Gent : Campus Coupure (lokaal A0.030)
defense date
2018-05-24 10:00
language
English
UGent publication?
yes
classification
D1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8561326
handle
http://hdl.handle.net/1854/LU-8561326
date created
2018-05-08 10:29:24
date last changed
2018-05-09 07:09:41
@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},
}

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.