Asymmetric Syntheses of the Homalium Alkaloids (−)‑(<i>S</i>,<i>S</i>)‑Homaline and (−)‑(<i>R</i>,<i>R</i>)‑Hopromine

Abstract

The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methylbenzyl)­amide and lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methyl-<i>p</i>-methoxybenzyl)­amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (−)-(<i>S</i>,<i>S</i>)-homaline and (−)-(<i>R</i>,<i>R</i>)-hopromine. The asymmetric synthesis of (−)-(<i>S</i>,<i>S</i>)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (−)-(<i>R</i>,<i>R</i>)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4′<i>R</i>,4′′<i>S</i>)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (−)-(<i>R</i>,<i>R</i>)-hopromine