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Analogs of Cinchona Alkaloids Incorporating a 9,9′‐Spirobifluorene Moiety
Author(s) -
WinterWerner Barbara,
Diederich François,
Gramlich Volker
Publication year - 1996
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19960790509
Subject(s) - quinuclidine , chemistry , dihedral angle , enantiomer , moiety , cinchona , absolute configuration , conformational isomerism , quinoline , chiral resolution , ketone , stereochemistry , cinchona alkaloids , molecule , organic chemistry , enantioselective synthesis , hydrogen bond , catalysis
The Cinchona alkaloid analogs (+)‐ and (−)‐ 5 with a quinuclidine‐2‐methanol residue attached to C(2) of a 9,9′‐spirobifluorene moiety were prepared as a racemic mixture by reacting lithiated 2‐bromo‐9,9′‐spirobifluorene 7 with (2‐ethoxycarbonyl)quinuclidine (±)‐ 6 to give ketone (±)‐ 8 , followed by diastereoselective reduction with diisobutylaluminum hydride (DIBAL‐H). The absolute configuration at C(9) and C(8), i.e. , at the methanol bridge and the adjacent quinuclidine C‐atom, in the two enantiomers of 5 is identical to the configuration at the corresponding centers in (−)‐quinine ( 1 ) and (+)‐quinidine ( 2 ), respectively. For the optical resolution of (±)‐ 5 , a chiral stationary phase for HPLC was prepared by covalently bonding quinine via a thiol spacer to a silica‐gel surface. The enantiomer separation was accomplished at an α value of 1.61 with (±)‐ 5 being eluted last, in agreement with 1 H‐NMR studies in CDCl 3 which showed that (+)‐ 5 underwent a more stable host‐guest association with quinine than (−)‐ 5 . 1 H{ 1 H} Nuclear Overhauser effect (NOE) difference spectroscopical analysis of the host‐guest associations with quinine in CDCl 3 , combined with computer‐model examinations, allowed the assignment of the absolute configurations as (+)‐(8 R ,9 S )‐ 5 and (−)‐(8 S ,9 R )‐ 5 . A detailed conformational analysis displayed excellent agreement between the results of computational methods (Monte Carlo multiple minimum simulations, analyses of the total energy as a function of the flexible dihedral angles in the molecule) and 1 H{ 1 H}‐NOE difference spectroscopical data. It was found that (−)‐ 5 and (+)‐ 5 differ significantly in their conformational preference from their natural counterparts quinine ( 1 ) and quinidine ( 2 ). Whereas the natural alkaloids prefer the ‘open’ conformation, with the quinuclidine N‐atom pointing away from the quinoline ring, analog (±)‐ 5 adopts preferentially (by ca. 4 kcal mol −1 ) a ‘closed’ conformation, in which the quinuclidine N‐atom points into the cleft of the 9,9′‐spirobifluorene moiety. Since the basic quinuclidine N‐atom in the ‘closed’ conformation is sterically shielded from forming strong H‐bonds, the new Cinchona alkaloid analogs form less stable host‐guest associations via H‐bonding than quinine or quinidine.