Total Synthesis of Kanamienamide and Clarification of Biological Activity

Abstract

The total synthesis of kanamienamide, an enamide with an enol ether and an 11-membered macrolactone of marine origin, was achieved. The synthesis features the construction of an enamide adjacent to an enol ether by Buchwald amidation and an 11-membered ring by Mitsunobu lactonization. In addition, on the basis of the biological assay of synthetic 1, we clarified that kanamienamide (1) was not an apoptosis-like cell death inducer, as reported in the isolation paper, and revealed its real biological activity as a necrosis-like cell death inducer.

Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications

“…For example, the total synthesis of janadolide ( 72 ), isolated from an Okeania sp. Compound 72 showed potent antitrypanosomal activity with an IC 50 value of 47 nM, without cytotoxicity against human cells [ 210 ]. The steps of the total synthesis of 72 were due to the macrolactamization of the proline moiety and fatty acid moiety manifested by the amide bond, as seen in Scheme 2 [ 227 ].…”

Formal Synthesis of Kanamienamide

“…26 The spectroscopic data and optical rotation of this key intermediate were identical to the reported values. 2,3 In conclusion, we have developed a convergent approach to the synthesis of the macrocycle-containing (Z)vinyl iodide 2, which constitutes a formal synthesis of kanamienamide. This strategy provided access to the elevenmembered macrocycle by an efficient macrolactamization.…”

“…2 The unique structural features and the appealing biological activity of kanamienamide have stimulated considerable interest among the synthesis community, as reflected by two total syntheses reported by the groups of He 2 and Suenaga. 3 Apart from a late-stage copper-catalyzed enamide formation between an enol ether amide and a macrocycle-bearing vinyl iodide intermediate, the pivotal aspect of the assembly of this natural product is the construction of the macrocyclic core. The elegant work of He and co-workers featured a ring-closing metathesis reaction [Scheme 1(A)], whereas Suenaga's strategy employed a Mitsunobu lactonization [Scheme 1(B)].…”

Total Synthesis of Carolacton and Demethylcarolactons with Potent Antiviral Activity

“…Next, 9 underwent Krische allylation with 7 smoothly, furnishing the homoallylic alcohol 13 as a single diastereoisomer. Tosylation of 13 followed by reductive deoxygenation 22 gave 15 in 91% yield over two steps. Finally, 15 was converted to aldehyde 6 through sequential deprotection and oxidation (Scheme 2B).…”