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The use of N-sulfinyl imidates and halogenated N-sulfinyl imines as chiral building blocks in organic chemistry

Filip Colpaert (2011)
abstract
Despite the early understanding of the concept of chirality, a couple of decades ago, drugs containing stereogenic centers were developed and used mainly as racemates. However, since the emergence of new technologies that allow the preparation of pure enantiomers in significant quantities, the awareness and interest in the stereochemistry of drug action has increased and different stereoisomers are currently used for different therapeutic applications. Today, drug chirality and the stereoselective synthesis of organic compounds is of immense industrial interest and the recent trend in industry is to market the drugs in single-enantiomer dosage. During the first part of this research, it was shown that the use of 1-azaallylic anions derived from N-tert-butanesulfinyl imidates, as an unexplored class of nucleophiles, shows great potential in the asymmetric synthesis of a variety of new chiral biologically important compounds. In contrast to the unsuccessful alpha-alkylation of 1-azaallylic anions, derived from N-sulfinyl imines, with alkyl halides, it was demonstrated that the significantly more nucleophilic 1-azaallylic anions derived from N-tert-butanesulfinyl imidates were reactive enough to enable alpha-alkylation. The formed chiral alpha-substituted N-tert-butanesulfinyl imidates proved to be excellent building blocks for the synthesis of enantiopure amides, esters and N-sulfonyl imidates, which are known as potentially useful prodrugs. alpha-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane led to the first synthesis of chiral N-sulfinyl 3-alkyl- and 3-arylpiperidines. N-deprotection gave rise to a novel and general synthetic pathway for the synthesis of enantiomerically pure 3-substituted piperidines, a very important class of compounds, commonly found in natural products and drugs. In a next part, high anti-selective Mannich-type additions of an alpha-methyl substituted N-sulfinyl imidate across aromatic aldimines were performed, which led to the formation of N-sulfinyl beta-sulfonylamino imidates as promising chiral building blocks and new chiral beta-amino acid derivatives. Subsequently, N-tert-butanesulfinyl alpha-chloro acetimidate was evaluated as potential chiral building block in asymmetric synthesis. New chiral N-sulfinyl beta-amino-alpha-chloro imidates were formed by high anti-selective Mannich-type additions of N-sulfinyl alpha-chloro acetimidate across aromatic aldimines and N-(benzenesulfonyl)methyl carbamates. These beta-amino acid derivatives were used as building block for the synthesis of biologically important aziridine-2-carboxylic acid derivatives, the first synthesis of enantiopure trans-2-aryl-3-chloroazetidines and synthesis of biologically important oxazolidinones. Finally, the use of 1-azaallylic anions derived from cyclic N-tert-butanesulfinyl imidates were evaluated. In a second research part of this work, N-tert-butanesulfinyl alpha-chloroketimines were elaborated in addition reactions with Grignard reagents in the synthesis of chiral N-sulfinyl aziridines with a quaternary carbon at the 2-position. This filled up successfully an important gap in the synthesis of chiral N-sulfinyl aziridines starting from N-sulfinyl alpha-halo imines. Ring opening reactions of the N-sulfinyl 2,2-disubstituted aziridines with various nucleophiles led to the synthesis of new chiral derivatives of the biologically and synthetically important phenylethylamines. In a last objective of this PhD-research, a preliminary investigation was performed on the synthesis of N-sulfinyl beta-chloro imines, which after reductive cyclization should lead toward N-tert-butanesulfinyl azetidines, in an effort to fill up the important gap in the application of halo imines toward the synthesis of azaheterocycles.
Please use this url to cite or link to this publication:
author
promoter
UGent
organization
alternative title
Het gebruik van N-sulfinyl imidaten en gehalogeneerde N-sulfinyl iminen als chirale bouwstenen in de organische chemie
year
type
dissertation
publication status
published
subject
pages
VI, 220 + annexes pages
publisher
Ghent University. Faculty of Bioscience Engineering
place of publication
Ghent, Belgium
defense location
Gent : Faculteit Bio-ingenieurswetenschappen (A0.030)
defense date
2011-05-17 15:00
ISBN
9789059894334
language
English
UGent publication?
yes
classification
D1
additional info
dissertation in part contains copyrighted materials
copyright statement
I have transferred the copyright for this publication to the publisher
id
1205855
handle
http://hdl.handle.net/1854/LU-1205855
date created
2011-04-11 10:52:05
date last changed
2017-01-16 10:38:02
@phdthesis{1205855,
  abstract     = {Despite the early understanding of the concept of chirality, a couple of decades ago, drugs containing stereogenic centers were developed and used mainly as racemates. However, since the emergence of new technologies that allow the preparation of pure enantiomers in significant quantities, the awareness and interest in the stereochemistry of drug action has increased and different stereoisomers are currently used for different therapeutic applications. Today, drug chirality and the stereoselective synthesis of organic compounds is of immense industrial interest and the recent trend in industry is to market the drugs in single-enantiomer dosage.
During the first part of this research, it was shown that the use of 1-azaallylic anions derived from N-tert-butanesulfinyl imidates, as an unexplored class of nucleophiles, shows great potential in the asymmetric synthesis of a variety of new chiral biologically important compounds. In contrast to the unsuccessful alpha-alkylation of 1-azaallylic anions, derived from N-sulfinyl imines, with alkyl halides, it was demonstrated that the significantly more nucleophilic 1-azaallylic anions derived from N-tert-butanesulfinyl imidates were reactive enough to enable alpha-alkylation. The formed chiral alpha-substituted N-tert-butanesulfinyl imidates proved to be excellent building blocks for the synthesis of enantiopure amides, esters and N-sulfonyl imidates, which are known as potentially useful prodrugs. alpha-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane led to the first synthesis of chiral N-sulfinyl 3-alkyl- and 3-arylpiperidines. N-deprotection gave rise to a novel and general synthetic pathway for the synthesis of enantiomerically pure 3-substituted piperidines, a very important class of compounds, commonly found in natural products and drugs.
In a next part, high anti-selective Mannich-type additions of an alpha-methyl substituted N-sulfinyl imidate across aromatic aldimines were performed, which led to the formation of N-sulfinyl beta-sulfonylamino imidates as promising chiral building blocks and new chiral beta-amino acid derivatives.
Subsequently, N-tert-butanesulfinyl alpha-chloro acetimidate was evaluated as potential chiral building block in asymmetric synthesis. New chiral N-sulfinyl beta-amino-alpha-chloro imidates were formed by high anti-selective Mannich-type additions of N-sulfinyl alpha-chloro acetimidate across aromatic aldimines and N-(benzenesulfonyl)methyl carbamates. These beta-amino acid derivatives were used as building block for the synthesis of biologically important aziridine-2-carboxylic acid derivatives, the first synthesis of enantiopure trans-2-aryl-3-chloroazetidines and synthesis of biologically important oxazolidinones.
Finally, the use of 1-azaallylic anions derived from cyclic N-tert-butanesulfinyl imidates were evaluated.
In a second research part of this work, N-tert-butanesulfinyl alpha-chloroketimines were elaborated in addition reactions with Grignard reagents in the synthesis of chiral N-sulfinyl aziridines with a quaternary carbon at the 2-position. This filled up successfully an important gap in the synthesis of chiral N-sulfinyl aziridines starting from N-sulfinyl alpha-halo imines. Ring opening reactions of the N-sulfinyl 2,2-disubstituted aziridines with various nucleophiles led to the synthesis of new chiral derivatives of the biologically and synthetically important phenylethylamines.
In a last objective of this PhD-research, a preliminary investigation was performed on the synthesis of N-sulfinyl beta-chloro imines, which after reductive cyclization should lead toward N-tert-butanesulfinyl azetidines, in an effort to fill up the important gap in the application of halo imines toward the synthesis of azaheterocycles.},
  author       = {Colpaert, Filip},
  isbn         = {9789059894334},
  language     = {eng},
  pages        = {VI, 220 + annexes},
  publisher    = {Ghent University. Faculty of Bioscience Engineering},
  school       = {Ghent University},
  title        = {The use of N-sulfinyl imidates and halogenated N-sulfinyl imines as chiral building blocks in organic chemistry},
  year         = {2011},
}

Chicago
Colpaert, Filip. 2011. “The Use of N-sulfinyl Imidates and Halogenated N-sulfinyl Imines as Chiral Building Blocks in Organic Chemistry”. Ghent, Belgium: Ghent University. Faculty of Bioscience Engineering.
APA
Colpaert, F. (2011). The use of N-sulfinyl imidates and halogenated N-sulfinyl imines as chiral building blocks in organic chemistry. Ghent University. Faculty of Bioscience Engineering, Ghent, Belgium.
Vancouver
1.
Colpaert F. The use of N-sulfinyl imidates and halogenated N-sulfinyl imines as chiral building blocks in organic chemistry. [Ghent, Belgium]: Ghent University. Faculty of Bioscience Engineering; 2011.
MLA
Colpaert, Filip. “The Use of N-sulfinyl Imidates and Halogenated N-sulfinyl Imines as Chiral Building Blocks in Organic Chemistry.” 2011 : n. pag. Print.