Diastereoisomeric assignment in a pacifenol derivative using vibrational circular dichroism

The configuration of a chiral center in semisynthetic (−)‐(2 R ,5 R ,5a R ,8ζ,9a S )‐ 2,8‐dibromo‐2,5,9,9a‐tetrahydro‐5‐hydroxy‐5,8,10,10‐tetramethyl‐6 H ‐2,5a‐methano‐1‐benzoxepin‐7(8 H )‐one ( 3 or 4 ), prepared in two steps from (−)‐(2 R ,5 R ,5a R ,7 S ,8 S ,9a S )‐2, 7‐dibromo‐8‐chloro‐2,5,7,8,9,9a‐hexahydro‐5,8,10,10‐tetramethyl‐6 H ‐2,5a‐methano‐1‐benzoxepin‐5‐ol, known as pacifenol 1 , has been determined using vibrational circular dichroism (VCD) measurements. The vibrational spectra (IR and VCD) of diastereoisomers 3 and 4 were calculated using density functional theory (DFT) at the B3LYP/DGDZVP level of theory for the two conformers that in each case account for the total energetic distribution found in the first 10 kcal/mol range. The DFT conformational optimization of the 8 R diastereoisomer 3 indicates the cyclohexanone exists almost exclusively in a boat conformation with a β‐equatorial bromine atom and an α‐axial methyl group at the chiral center alpha to the carbonyl group, while for the 8 S diastereoisomer 4 a 5:1 conformational distribution in favor of a chair conformation with an α‐axial bromine atom and a β‐equatorial methyl group is calculated, suggesting due to well‐known chair versus boat relative stabilities that the plausible diastereoisomer would be the 8 S molecule. A comparison of the IR spectrum of the reaction product with the calculated spectra of 3 and 4 provided no means for the diastereoisomeric assignment, while from comparison of the VCD spectra it became immediately evident that the rearranged molecule possesses the 8 R absolute configuration as shown in 3 , in concordance with a single crystal X‐ray diffraction study that could be refined to an R ‐factor of 2.9%. Chirality 21:E208–E214, 2009. © 2009 Wiley‐Liss, Inc.