Assignment of Absolu te Configuration of Fischeri n by Com puted NMR Ch emical Shifts

Fische rin,a biologically active components of fu ngi, which causes tre mors and lethal peritonitis in mi ce, was ext racted from Neosartorya fischeri.۱ Fujimoto and co-wo rkersreported the partial configuration of fischerin.۱ They used NMR spectroscopic da ta to determ ine this pa rtial configuration for the fused bicyclic moiety of this compound.۱So, despite using powerful NMR techniques, Fujimoto an d co-workers were not able to assig n the relativ e configurations of the target molecule in the C۱۹, C۲۰, C۲۱ and C۲۲.۱On th e other hand , advanced methods in quantum chemistry facilitate the ra pid, accurat e, and reliabl e calculation of NMR chemical shifts. So, co mparing the calculated and experim ental chemical shifts w ll provide an efficient method in identifying and discrimin ating betwe en the proposed diastere oisomers.۲Considering the triangular fusion between C۲۰ and C۲۱ and assigned configuration of fused bicyclic moiety, four unassigned stereocenters allow for totally eight possi ble diastere omers for th e target com pound. They were used as probable structures of the target molecule in the quant um mechan ical treatments. The fir st step in this treatment was their conformational analys es in order to find candidate conf ormers at room tempera ture which contribute t o the experimental NMR spectra. In the next step, the postulated conformers, within a ۳ kCal window of the lo west energy, were subjected to exte nsive geome try optimiz ation followed by frequency calculations in order to confir m the nature of the optimized geom etries as minima and pr ovide their computed f ree energies. In the last step, among these exte nsively opti mized struct ures,those within a ۲. ۵ kCal wi ndow of the lowest en ergy were subjected to the chemical shieldin g calculations in dim ethylsulfoxide solvent. In order to get ac curate calculated chemical shieldings, Boltzman -weighted a veraging ba sed on relative free en ergiesof con formers at ۲۹۸.۱۵ K was used. The relative p opulations of conformers were computedas Pi Pj  expEi E j RT . Where Px and Ex are the relative population and computed free energy of the x conformer, respectively.In order to determ ine the correct configuration of the target molecule, the calculated chemical shifts were evaluated according to their largest and correct ed mean a bsolute deviation(CMA D: [ ۱nin ۱ calc exp ]) in each configuration. In order to confirm the conclusion of the CMAD analysis and get more confidence of which configuration is the correct one, the D P۴ probability analysis developed by Smith and Good man was also employed.۲Thus according to both the C MAD and DP۴ analyses, structure, shown below , was found to be correct for the target molecule.