Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 3 81substituents are the most important factors governing the enantioselectionof the reduction. It is in fact possible that, due to the presence of the orthosubstituent, the prochiral benzophenone presents the two aromatic moietiesin different planes. The ketone can be almost coplanar with theunsubstituted aromatic ring to form a flat moiety while the aromatic ringbearing the ortho substituent is out of the plane (Fig 3.1).ROFig.3.1: Conformation of ortho substituted benzophenones.2-Bromo-(4'phenyl) benzophenone 25c, reduced under identicalexperimental conditions as used for 2-bromobenzophenone 25b gave (+)-2-bromo-4'phenyl-benzhydrol (+)-27c with an enantiomeric excess of higherthan 95% e.e. (scheme 3.10; table 3.4) and with 98% of chemical yield. It isinteresting to note that in this substrate two substituents are present on thetwo aromatic rings. The presence of a phenyl ring in the para position didnot lead to any loss of stereoselectivity in the chiral reduction probablybecause this did not change the overall geometry of the prochiral ketone.The enantiomeric excess was determinated by examining the carbinolicproton in the 1 H-NMR spectrum (200 MHz) in the presence of the chiralshift reagent tris [3-(heptafluoropropylhydroxy methylen)] camphoratoeuropium 3 [Eu(hfc) 3 ], and also confirmed by chiral HPLC ( Chiracel OD).The procedure was repeated for 4'-phenyl benzophenone 25a and ledto the racemic 4'-phenyl benzhydrole (±)-27a in 98% of chemical yield(scheme 3.10; table 3.4). 2-Fluoro-4'-phenyl benzophenone 25d wasreduced to (+) 2-fluoro 4'-phenyl benzhydrole (+)-27d with 80%enantiomeric excess and 98% of chemical yield (scheme 3.10; table 3.4).The loss of enantiomeric excess could be attributed to the reduced sterichindrance of the fluorine atom in comparison to the bromine. Theenantiomeric excess was determined by chiral HPLC (Chiracel OD), whileall attempts to examine the carbinolic proton in the 1 H-NMR spectrumrecorded in presence of the above chiral shift reagent failed.