Absolute Configuration of Isomeric Mono-Acetyl Tropane Alkaloids Using Chromatography-Assisted Chemical Correlation

Abstract

Objective: To establish the absolute configurations of isomeric 6β-acetyl-3α-tropanol (3) and 3α-acetyl-6β-tropanol (4), constituents of several species of Datura and other genera, using a combination of a simple hemi-synthetic pathway starting from racemic 6β-hydroxytropinone (1) to produce 3α,6β-tropanediol (2), and the use of chiral liquid chromatography coupled with mass and laser optical rotation detectors (LC-MS and LC-OR). Methods: In the case of 3, mono acetylation of the more reactive OH group at C-6 in 2 was achieved under controlled reaction conditions, while more vigorous conditions produced exclusively 3α,6β-diacetyltropane (5). On the other hand, isomer 4 was obtained by partial hydrolysis of the acetyl group at C-6 in 5. Samples of the three compounds were then subjected to chiral LC-MS and LC-OR, which showed chromatograms composed of two peaks of opposite optical rotation. Next, ten consecutive LC injections followed by fraction collection of the column elution, produced a set of micro-scale samples of opposite enantiomeric composition for each mono ester, which were then derivatized by further acetylation to convert the partially enantioenriched samples into their corresponding diacetates. The resulting samples were then evaluated using LC-MS, which allowed the correlation between the enantiomers of 3 and 4 with those of 5. Results: Considering that the absolute configuration of (−)-5 has been assigned previously as (1 S, 3 S, 5 R, 6 S), these chromatographic comparisons established the absolute configurations of monoacetates 3 and 4 as (−)-(1 S, 3 S, 5 R, 6 S)-3 and (+)-(1 R, 3 R, 5 S, 6 R)-3, and (−)-(1 S, 3 S, 5 R, 6 S)-4 and (+)-(1 R, 3 R, 5 S, 6 R)-4, respectively. Conclusion: A methodology based on chiral liquid chromatography allowed the establishment of the absolute configuration of isomeric monoacetates of tropandiol 3 and 4, directly from the racemic mixtures, and without resorting to the isolation of enantiomerically pure samples.