Asymmetric Total Syntheses of (−)-Antofine and (−)-Cryptopleurine Using (R)-(E)-4-(Tributylstannyl)but-3-en-2-ol

Abstract

The asymmetric total syntheses of the representative phenanthroindolizidine and phenanthroquinolizidine alkaloids, (-)-antofine and (-)-cryptopleurine, are described. An efficient synthetic pathway to the key intermediate 12, in enantiomerically pure form, was achieved by using a chiral building block (R)-9 and the Overman rearrangement with a total transfer of chirality. The problem of constructing the pyrrolidine and piperidine rings was successfully addressed, primarily by using a ring-closing metathesis reaction and a cross-metathesis reaction, respectively.

Total synthesis of phenanthroindolizidine alkaloids (±)-antofine, (±)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity

“…6,7 Due to low natural abundance of this compound type, various syntheses of 1a and other phenanthroindolizidine alkaloids, in both racemic and optically active forms, have been reported in an effort to further investigate the biochemical and pharmaceutical effects. [8][9][10][11][12][13][14] The most commonly reported synthetic methodology toward the highly condensed natural alkaloids (±)-1a and its geometric isomer (±)-deoxypergularinine (1b) involves formation of the biaryl bond of the phenanthrene ring system in the final step, after coupling of the aromatic residues with the appropriate heterocycle. The other common sequence to these alkaloids uses differentially substituted phenanthrenes as starting materials, which are coupled with the appropriate heterocycle through a halomethyl moiety.…”

Natural Products Containing Medium‐Sized Nitrogen Heterocycles Synthesized by Ring‐Closing Alkene Metathesis

“…Recently, Kim et al described two routes to enantiopure (−)-antofine [31,32]. Both routes began with the coupling of homoveratric acid (57) and p-anisaldehyde in order to form phenanthryl alcohol, the precursor of bromide 58 (Scheme 2.13).…”

Application of Olefin Cross-Metathesis to the Synthesis of Biologically Active Natural Products

“…Kim and co-workers recently described the syntheses of (-)-antofine and (-)-cryptopleurine [30]. The former exhibits activity against multi-drug resistant cancer cell-lines.…”

“…Desilylation was then effected to enable separation of 104 from the by-products probably resulting from the unproductive E-isomers of 102 and 103. (30). ROM/CM/RCM process in the synthesis of (+)-mycoepoxydiene.…”