The synthesis and anti-acetylcholinesterase activities of (+)-physostigmine and (+)-physovenine

Abstract

(+)‐Physostigmine and (+)‐physovenine have been synthesized. The anti‐acetylcholinesterase activities of these two bases, which have been investigated in vitro using erythrocyte acetylcholinesterase, have been found to be much lower than the corresponding activities of the alkaloids (‐)‐physostigmine and (‐)‐physovenine. Possible reasons for these activity differences are discussed.

Physovenines: Efficient Synthesis of (−)‐ and (+)‐Physovenine and Synthesis of Carbarnate Analogues of (−)‐Physovenine. Anticholinesterase Activity and Analgesic Properties of Optically Active Physovenines

“…Natural physovenine (2a) was shown to be as potent as natural (-)-physostigmine (la) in assays measuring inhibition of acetylocholinesterase (AChE) from human erythrocytes, whereas antipode 2b was practically inactive [2]. We now have repeated these experiments with 2, 2a, and 2b in assays 1.4+ 0.2 ' ) As described in [4].…”

“…Two of the alkaloids, (-)-physostigmine (la; see Scheme) and (-)-physovenine (2a), were reported to have potent anti-acetylcholinesterase (AChE) activity when assayed in vitro, measuring inhibition of AChE obtained from human erythrocytes [2], and l a is medically used to reduce intraocular tension in glaucoma, in the treatment of intestinal atony, and in the treatment of urinary retention [3]. Modification of the carbarnate group and of the Me-N(l) group in l a has afforded several potent analogs [4] [5].…”

“…Reaction of 6a with methyl isocyanate in dry Et,O in the presence of a trace of Na afforded natural (-)-physovenine (2a), identical in every respect with the alkaloid described [3] [7]. The unnatural antipode 2b was similarly prepared from (+)-eseroline (3b) and was identical with 2a except for opposite specific rotation [2]. Reaction of 6a with butyl isocyanate, octyl isocyanate, phenyl isocyanate, and cumyl isocyanate afforded carbamates 7aP10a, respectively.…”

“…Natural 2a was isolated from the basic extracts of Physostigma venenosum in 1911 [6] and its structure proposed on the basis of spectral data [7] and proven to be correct by a total synthesis of racemate 2 [8]. The (3aS)-configuration of 2a and the (3aR)-configuration of antipode 2b was elaborated by their enantiospecific synthesis from (-)-physiostigmine (la) [9] and (+)-physiostigmine (la), respectively [2]. …”

“…Having an easy access to optically active eserolines (3a, b) by total synthesis [13] [14], we decided, for the preparation of larger quantities of 2a, b, to follow the route chosen by Dale and Robinson [2], but to replace eserethole (ethyl ether of eseroline) by the corresponding methyl ether formed in situ. Thus, exhaustive methylation of (+)-eseroline (3a) with Me1 in dimethyl sulfoxide (DMSO) in the presence of powdered KOH, followed by quaternization of the methin bases with MeI, afforded 4a, which was not isolated but refluxed in situ with 7N NaOH to afford physovenol methyl ether (5a) in 70% overall yield (see Scheme).…”