Comments and Further Observations on the Structure of Eserine (Physostigmine)

Abstract

Petcher and Pauling have reported¹ the results of an X-ray investigation of the crystal structure of the alkaloid eserine (physostigmine) in which they established the absolute configuration of the alkaloid about the B/C ring junction and at the N_(l)-CH₃ and N₍₈₎-CH₃ groups to be as shown in I (R = CH₃, X = NCH₃). These authors erroneously state, however, that this absolute configuration had previously² been “confirmed by use of the nuclear Overhauser effect (NOE) in NMR spectroscopy”, whereas such studies had, in fact, only established the relative configuration of the B/C ring junction (which had previously³ been deduced from a study of the geometry of the molecule) and the relative configuration of the N₍₁₎-CH₃ and N₍₈₎-CH₃ groups. Further, Petcher and Pauling¹ disregard the earlier published chemical studies^{4, 5} which four years previously had independently and by different routes established the absolute configuration of the B/C ring unction in physostigmine to be as shown in I (R = CH₃, X = NCH₃), a fact that their X-ray studies only further confirmed. Longmore and Robinson⁵ further established, primarily from the results of comparative ORD investigations, that the absolute configuration about the B/C ring junction of the alkaloids N₍₈₎-norphysostigmine, physovenine and eseramine is as shown in I (R = H, X = NCH₃, R = CH₃, X = O, and R = CH₃, X = N.CO.NHCH₃, respectively). The results of earlier related studies^{6, 7} on geneserine, which before 1969 (ref. 8) was thought to have the structure of physostigmine N_(l)-oxide, showed it to have the absolute configuration as depicted in II, the indicated cis relationship of the N_(l)-methyl group and the C₍₂₎-proton being that which predominates at 20°C (ref. 6).