A Novel and Efficient Total Synthesis of Cephalotaxine

Abstract

[reaction: see text] Total synthesis of cephalotaxine (CET), the parent member of a class of structurally unique antileukemia Cephalotaxus alkaloids, was accomplished on the basis of a conceptually novel strategy featuring transannular reductive skeletal rearrangements as the key transformations for the construction of the pentacyclic ring skeleton of CET. The synthetic potential of the designated Clemmensen-Clemo-Prelog-Leonard reductive rearrangement was demonstrated for the first time in a facile synthesis of the benzazepine subunit of CET. A novel endocyclic enamine (cyclopentenone) annulation was discovered and rationalized as an unusual azo-Nazarov-type cyclization.

Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates

“…[53] Exposure of enamine 149 to acetic acid and FeSO 4 in air ensues an acid-catalyzed autoxidation process forming conjugated system 150 . Acid-catalyzed tautomerization allows the formation of 151 , in resonance with pentadienyl cation 152 .…”

Some New Nazarov Chemistry

“…[65] ( 48) An interesting and unusual approach to cephalotaxine alkaloids that makes use of a Nazarov reaction is due to Li and co-workers. [66,67] Warming the keto enamine 144 in the presence of Fe II and air in acetic acid leads to the enone 147 in 57 % yield [Equation (49)]. This process can be understood as taking place through a series of steps starting with oxidation to 145.…”

Acetic Acid Accelerated Visible‐Light Photoredox Catalyzed N‐Demethylation of N,N‐Dimethylaminophenyl Derivatives

“…In the presence of oxygen, electron transfer from a-amino radical C to O 2 yields peroxyl radical D. [20] Acetic acid could protonate the resulting peroxyl radical D to generate hydroperoxide radical cation E. [21] Radical cation E might also facilitate single electron transfer from A to afford hydroperoxide F and cation radical B, followed by deprotonation of B with the acetate anion to provide C. [22] At the last step, hydroperoxide F undergoes tautomerization-dehydration to yield instable Nhydroxymethyl derivative G* (carbinolamine) and Nformyl derivative H. Both derivatives are ultimately formed by the well-precedential process of disproportionation. [23] While, due to the inherent instability of N-hydroxymethyl derivative G*, it decomposed spontaneously in the solution to furnish the demethylated product and formaldehyde.…”