Premium
On the Origin of the Stereoselectivity in Organocatalysed Reactions with Trimethylsilyl‐Protected Diarylprolinol
Author(s) -
Dinér Peter,
Kjærsgaard Anne,
Lie Mette Alstrup,
Jørgensen Karl Anker
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200701244
Subject(s) - chemistry , enamine , substituent , pyrrolidine , double bond , transition state , medicinal chemistry , trimethylsilyl , enantiomer , alkene , stereochemistry , enantioselective synthesis , organic chemistry , catalysis
The origin of the enantioselectivity in the TMS‐protected (TMS=trimethylsilyl) prolinol‐catalysed α‐heteroatom functionalisation of aldehydes has been investigated by using density functional theory calculations. Eight different reaction paths have been considered which are based on four different conformers of the TMS‐protected prolinol–enamine intermediate. Optimisation of the enamine structures gave two intermediates with nearly the same energy. These intermediates both have an E configuration at the CC bond and the double bond is positioned anti or syn , relative to the 2‐substituent in the pyrrolidine ring. For the four intermediates, the chiral TMS‐protected‐diaryl substituent effectively shields one of the faces of the reacting CC bond in the enamine intermediate. A number of transition states have been calculated for the enantioselective fluorination by N ‐fluorobenzenesulfonimide (NFSI) and based on the transition‐state energies it has been found that the enantioselectivity depends on the orientation of the CC bond, being anti or syn , relative to the 2‐substituent on the pyrrolidine ring, rather than the approach of the electrophilic fluorine to the face of the reacting carbon atom in the enamine which is less shielded relative to the face with the highest shielding. The calculated enantiomeric excess of 96 % ee ( ee =enantiomeric excess) for the fluorination reaction corresponds well with the experimentally found enantiomeric excess—97 % ee . The transition state for the α‐amination reaction with the same type of intermediate has also been calculated by using diethyl azodicarboxylate as the amination reagent. The implication of the intermediate structures on the stereoselection of α‐functionalisation of aldehydes is discussed.