Abstract
The title alkaloids, (−)-1, (−)-2, (−)-4 and (+)-5 respectively, have each been prepared from the enantiomerically enriched (74% ee) tetrahydroindolizine 14 which is itself obtained via an organocatalyzed and enantioselective intramolecular Michael addition reaction of the pyrrole 13 incorporating an N-tethered and β,β-disubstituted acrylaldehyde moiety.
Highlights
The alkaloid rhazinal [(−)-1],1 like its more well-known congener rhazinilam [(−)-2],2 is a potent spindle toxin by virtue of its capacity to disrupt the dynamic interconversion of tubulin and microtubules required for the normal mitotic division of cells.[3]
Magnus et al reported[7] a third synthesis, of racemic material, in 2001 whilst we have recently disclosed[8] the first total synthesis of (±)-rhazinal [(±)-1] as well as its Bnor-congener (±)-3
The synthetic route to the substrate required for studying the proposed enantioselective Michael addition reaction is shown in the early parts of Scheme 1
Summary
The alkaloid rhazinal [(−)-1],1 like its more well-known congener rhazinilam [(−)-2],2 is a potent spindle toxin by virtue of its capacity to disrupt the dynamic interconversion of tubulin and microtubules required for the normal mitotic division of cells.[3]. Subjection of this material to flash chromatography (silica, 1 : 4 v/v ethyl acetate–hexane elution) and concentration of the appropriate fractions (Rf 0.3) afforded the title compound 15 (679 mg, 84%) as a clear, colorless oil, [α]D –11 (c 0.9, CHCl3).
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