Total Syntheses of Kealiinines A–C

Abstract

Short total syntheses of the Leucetta-derived alkaloids, kealiinines A-C, have been accomplished using an intramolecular Friedel-Crafts-dehydration sequence of a bis benzylic diol. The precursor diol was obtained through a series of position specific Grignard reactions from 1-methyl-4,5-diiodoimidazole. C2-Azidation and hydrogenation of the azide then provided the reported structures of kealiinines A-C. While the 1H NMR data did not completely match for these materials, the HPLC data were consistent with the assigned structure of these materials.

Total syntheses and cytotoxicity of kealiiquinone, 2-deoxy-2-aminokealiiquinone and analogs

“…15 Our group has developed concise synthetic methods for the total syntheses o all of these natural products. 16, 17 The general strategy that we have adopted involves the elaboration of simple imidazoles and as such provides the opportunity to evaluate C2-deletion derivatives as well as to prepare other analogs.…”

Studies towards the Leucetta‐Derived Alkaloids Spirocalcaridine A and B – Possible Biosynthetic Implications

“…However, other pathways are feasible, including via ipso addition, followed by rearrangement via an intermediate related to 67 and then oxidation. [5a] Our own studies with this system points to another possibility in which spirocalcaridine (or closely related derivative) may undergo dehydration to 68 ; protonation of the carbonyl oxygen primes the system for rearrangement via a dienone-phenol rearrangement ( 69 → 70 , Scheme 7). Rearomatization to 71 and a second dehydration delivers the naphthimidazole derivatives, the kealiinines.…”

“…naamidine H ( 3 ), [3] whereas the isonaamine/isonaamidine group is functionalized at N1 and C4, e.g., isonaamidine E ( 4 ). [4] The fourth group of Leucetta alkaloids contains a naphthimidazole framework such as that found in the kealiinines, e.g., 5 [5] and kealiiquinones, e.g. 6 [6] and 7 .…”

“…Spiroleucettadine ( 11 ) and the related spironaamidine ( 12 ) can be envisioned to derive from the corresponding naamine derivative by oxidation of the imidazole 4,5-bond followed by an oxidative dearomatization. The final group of Leucetta -derived alkaloids that can be derived from naamine-type precursors are the kealiinines [5c] and kealiiquinones. [6–7] The former can be derived from an intramolecular Friedel-Crafts like process followed by oxidation, delivering the kealiinines.…”

“…Additional oxidation would then permit entry to the kealiiquinones. Our group has taken advantage of these putative relationships to accomplish total syntheses of calcaridine A, [8a, 8c] kealiinines A-C, [5a, 5b] kealiiquinone and 2-deoxy-2-aminokealiiquinone. [12] …”