Total Syntheses of Aporphine Alkaloids via Benzyne Chemistry: An Approach to the Formation of Aporphine Cores

Abstract

Total syntheses of lysicamine, (±)-nuciferine, (±)-nornuciferine, (±)-zanthoxyphylline iodide, (±)-Omethylisothebaine, and (±)-trimethoxynoraporphine were accomplished by an approach that involves the formation of aporphine cores through reactions between an isoquinoline derivative and silylaryl triflates promoted by CsF. Unprecedented formations of aporphine cores proceeded in good yields presumably through [4 + 2] cycloaddition reactions followed by hydrogen migrations.

Facile total synthesis of lysicamine and the anticancer activities of the RuII, RhIII, MnII and ZnII complexes of lysicamine

“…Instead, crude materials were always used in the next step, and good yields were still obtained (82%–88%, 56% for ( V )). The overall synthesis required only six steps, whereas the latest report that used Fremy's salt as an effective oxidizing agent required nine steps to prepare the lysicamine end product [ 16 ]. Our route is clearly beneficial to the synthesis of a large number of lysicamine and related oxoaporphine alkaloids.…”

“…However, the source aporphines have limited commercial supply. The total synthesis of oxoaporphines has been reported both in the early years [ 6 – 9 ] and recently [ 14 – 16 ]. The reported syntheses have clear disadvantages, including numerous reaction steps, long reaction time, harsh reaction conditions, complicated work-up procedures, extensive use of organic solvents, etc .…”

Recent Advances for the C–C and C–N Bond Formation in the Synthesis­ of 1-Phenethyl-tetrahydroisoquinoline, Aporphine, Homoaporphine­, and β-Carboline Alkaloids

“…In order to prove the versatility of 14 in the synthesis of oxoaporphine alkaloids, non-phenolic 15 was oxidized with I 2 and NaOAc to give 16 in 90% yield, which was then oxidized in the presence of Fremy's salt (K 4 [ON(SO 3 ) 2 ] 2 ) to furnish lysicamine (17) in 64% (Scheme 1). 49…”

“…This approach was extended to the synthesis of (±)-nornuciferine (158), (±)-nuciferine (159), (±)-trimethoxynoraporphine (166), (±)-O-methylisothebaine (167), and (±)-zanthoxyphylline iodide (168). 49 The key intermediate 153 was prepared from 3,4-dimethoxyphenethylamine (68)…”

“…51 In the final step, 164 was N-deprotected in the presence of NaBH 4 to produce (±)-trimethoxynoraporphine (165) in quantitative yield (Scheme 24). 49 Additionally, the further N-alkylation and N,N-dialkylation of 165 in the presence of stoichiometric or excess methyl iodide resulted in the formation of (±)-O-methylisothebaine (166) (72%) and (±)-zanthoxyphylline iodide (167) (82%), respectively, after two steps from 164 (Scheme 25). 49 Scheme 25 Synthesis of (±)-O-methylisothebaine and (±)-zanthoxyphylline iodide…”