The Aminative Rearrangement of Dihydropyrans: A Novel Route to Substituted Proline Derivatives
File(s)
Murray-E-2007-PhD-Thesis
Author(s)
Murray, Elizabeth
Type
Thesis
Abstract
This thesis describes the investigation of the aminative rearrangement of 2-alkoxy
dihydropyrans, which presents a novel route to substituted proline derivatives.
Aziridination of the dihydropyran results in a ring-opening and subsequent ring
contraction to afford pyrrolidines with distinctive diastereoselectivity across the 2,3-
position. This selectivity is controlled by the manner of aziridination, and initially,
studies concentrated on the optimisation of the rearrangement in regard to the
conditions of aziridination.
Following the establishment of the optimal conditions, a range of substrates were
subjected to the aminative rearrangement reaction, followed by the in situ reduction of
the 5-ethoxy group, to furnish an array of 2,3-substituted 7V-tosyl-protected
pyrrolidines. This proved the tolerance of the procedure to various alkyl, aryl and
heteroatom substituents and allowed for the synthesis of either the 2,3-ds or 2,3-trans
isomers in reasonable to good diastereoselectivities, depending on the conditions of
aziridination.
Finally, the application of this methodology to the synthesis of enantiomerically
enriched substituted prolines was demonstrated though the initial application of an
asymmetric hetero-Diels-Alder reaction to form the dihydropyrans. Employing the
Wada chiral titanium TADDOL catalyst resulted in the enantioselective formation of
2-alkoxy-6-(phenylsulfonylmethyl)3,4-dihydro-2//-pyrans. Rearrangement of the
pyran and subsequent manipulation of the pyrrolidine allowed for the diastereo and
enantioselective synthesis of the proline derivative.
dihydropyrans, which presents a novel route to substituted proline derivatives.
Aziridination of the dihydropyran results in a ring-opening and subsequent ring
contraction to afford pyrrolidines with distinctive diastereoselectivity across the 2,3-
position. This selectivity is controlled by the manner of aziridination, and initially,
studies concentrated on the optimisation of the rearrangement in regard to the
conditions of aziridination.
Following the establishment of the optimal conditions, a range of substrates were
subjected to the aminative rearrangement reaction, followed by the in situ reduction of
the 5-ethoxy group, to furnish an array of 2,3-substituted 7V-tosyl-protected
pyrrolidines. This proved the tolerance of the procedure to various alkyl, aryl and
heteroatom substituents and allowed for the synthesis of either the 2,3-ds or 2,3-trans
isomers in reasonable to good diastereoselectivities, depending on the conditions of
aziridination.
Finally, the application of this methodology to the synthesis of enantiomerically
enriched substituted prolines was demonstrated though the initial application of an
asymmetric hetero-Diels-Alder reaction to form the dihydropyrans. Employing the
Wada chiral titanium TADDOL catalyst resulted in the enantioselective formation of
2-alkoxy-6-(phenylsulfonylmethyl)3,4-dihydro-2//-pyrans. Rearrangement of the
pyran and subsequent manipulation of the pyrrolidine allowed for the diastereo and
enantioselective synthesis of the proline derivative.
Version
Open Access
Date Issued
2007-05
Date Awarded
2007-05
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Armstrong, Alan
Schnider, Patrick
Sponsor
EPSRC
Roche
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)