Synthetic approaches towards the skeleton of the crinine-type amaryllidaceae alkaloids from isoquinoline and total synthesis of (±)-elwesine

Abstract

The crinine-type alkaloids are characterized by the presence of the 5,10b-ethano-phenanthridine skeleton and represent an important subgroup within the large family of amaryllidaceae alkaloids. Based on the obvious structural relationship between crinine alkaloids and isoquinoline, a novel and concise synthetic approach towards these alkaloids from isoquinoline has been established. The viability of using a ring closure metathesis (RCM) reaction to create the C ring was investigated with a model system synthesized from 4-allylisoquinoline. A reductive alkylation sequence followed by the addition of allylmagnesium bromide to the resulting imine created a trans -3,4-diallyltetrahydroisoquinoline precursor to the crinane skeleton. RCM produced the desired phenanthridine derivative containing a two-carbon substituent for elaboration to the ethano bridge. Since the Grignard addition to the imine in the model study was not stereoselective, an alternate route was designed to close the D ring first. A Mitsunobu reaction on the 3-allyl-4,4-bis(2-hydroxyethyl)tetrahydroisoquinoline established the ethano bridge with complete control of the stereochemistry such that the remaining allyl and hydroxyethyl groups were trans . Subsequent conversion of the hydroxyethyl group to allyl followed by RCM gave the crinane skeleton with the required trans -fused C ring. This methodology has been extended to the total synthesis of the (¿)-crinane degradation product (¿)-?-2(3)-crinane and (¿)-elwesine.