TOTAL SYNTHESIS OF THE CRINANE-TYPE AMARYLLIDACEAE ALKALOIDS (+)-MARITIDINE AND (+)-OXOMARITIDINE

• Main Author: Ding, Lixin
• Other Authors: David E Minter
• Format: Others
• Language: en
• Published: Texas Christian University 2010
• Subjects: College of Science and Engineering
• Online Access: http://etd.tcu.edu/etdfiles/available/etd-04262010-120745/

The crinane-type alkaloids are characterized by the presence of the 5,10b-ethanophenanthridine skeleton and represent an important subgroup within the large family of Amaryllidaceae alkaloids, many of which exhibit interesting biological activities. Although they have been the subjects of extensive synthetic investigations over the years, the crinane-type alkaloids have never been synthesized from isoquinoline or substituted isoquinolines, despite the obvious structural relationship between the crinane skeleton and isoquinoline nucleus. In this dissertation, total synthesis of crinane-type alkaloids (+)-maritidine and (+)-oxomaritidine from 6,7-dimethoxyisoquinoline are described. By employing the boron-activated enamine alkylation chemistry developed by the Minter group, isoquinoline and substituted isoquinolines were transformed to 4,4-disubstituted 1,4-dihydroisoquinolines, which then underwent an asymmetric allylation with allylzinc bromide in the presence of a lithiated bis(oxazoline) ligand. Since the resulting homoallylic secondary amine is the key intermediate in the asymmetric total synthesis of crinane alkaloids from isoquinoline, the methodology of this transformation had been investigated and developed. These 1,4-dihydroisoquinolines with a variety of substituents at the C-4 position all underwent the reactions smoothly and enantioselectively. Subsequent conversions including the construction of the crinane skeleton, stereoselective epoxidation and regioselective isomerization of the epoxide to form the allylic alcohol finally gave the pure single enantiomers of (+)-maritidine and (+)-oxomaritidine.