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

Chapter 3 84leading to a distortion of the active conformation. Since the reduction ofketones proved to be unsuccessful, this class of enantiopure alcohols wasobtained by a different procedure described in the next paragraphs.The enantiomeric excess of the above compounds was determinatedby 1 H-NMR with the corresponding esters formed with (S)-(-)-1-camphanicchloride. The method of analysis will be described in detail in the nextparagraph. Analysis by chiral HPLC (Chiracel OD) of the free alcohols ledto identical results. It is interesting to note that all first attempts to determinethe enantiomeric excess were, as in the case of the chiral benzhydoles, doneby NMR and using shift reagents. Unfortunately none of the many triedreagents was able to resolve completely the signals in the spectrum. For thisreason it was necessary to synthesize the corresponding camphanic ester.3.4.3.1. Determination of the enantiomeric excess in (+)-27iby 1 H-NMR.The enantiomeric excess of (+)-27i was determined by 1 H-NMRafter esterification of (+)-27i with (S)-(-)-1-camphanic chloride. Theprinciple is based on the known property of diasteroisomers to producedifferent NMR spectra, next to different physical properties. Calculationof the relative diasteroisomeric ratios in the 1 H-NMR was done with thecrude product mixture in order to avoid a possible loss of a singlediasteroisomer or partial racemization during sample processing.The crude 1 H-NMR spectrum of the reaction products of (±)-27iand (S)-(-)-1-Camphanic chloride showed only one perfectly resolvedsignal, allowing integration: the β proton in the furane ring of thebenzo[b]furane moiety.The 1 H-NMR of the free alcohol (±)-27i showed the β-proton ofthe furan ring at 6.46 ppm and the carbinol proton at 6.28 ppm, the latterbeing frequently a doublet because of the coupling between this protonand the alcoholic proton at 2,76 ppm (Fig. 3.2). Generally, if water waspresent in the sample, due to the low exchange rate between water and thealcoholic proton, this resulting signal was broad and the carbinolic protonappeared as a singlet (the coupling constant is very small and it is notdetectable); the same effect was found at high concentrations of the NMRsample. In the absence of these two effects the doublet signals appeared