Total Synthesis and Biological Evaluation of Clavatadines C–E

Abstract

We described herein the application of a convergent and protecting-group avoidant approach that led to the first total synthesis of the marine natural products clavatadine D ( 4 ) and E ( 5 ), and the second total synthesis of clavatadine C ( 3 ). In each case, a key amide-coupling afforded an immediate precursor of each natural product in a rapid manner from structurally similar western and eastern portions that derived from an ester of l -tyrosine and butane-1,4-diamine, respectively. A deprotection step free of detectable byproducts cleanly provided the remaining known members of the clavatadine family of natural products. Each total synthesis required five steps (longest linear sequence) with overall yields of 30–37%, 26–39%, and 28–50% for clavatadine C ( 3 ), D ( 4 ), and E ( 5 ), respectively. A screen of their potential anticancer activity against the NCI-60 cell line panel revealed cytotoxicity levels up to 38% across a broad spectrum of tumor types. Although clavatadine C ( 3 ) was relatively benign, clavatadine D ( 4 ) exhibited 20–38% growth inhibition against a wide array of cancer cell types including leukemia, non-small-cell lung, colon, ovarian, and breast. Clavatadine E ( 5 ) was active against two types of human brain tumors.

Marine natural products

“…439 The structure of echinosulfonic acid D has been synthesised, one year aer it was revised independently by three groups as reported in last year's review. 1,440 Aaptamine-type alkaloids suberitines A-D were synthesised for the rst time, 441 as were pyrrole-containing metabolites denigrin D and E. 442 Somewhat surprising given its age, the rst (racemic) synthesis of archetypical bromotyrosine compound psammaplysin A, which was rst reported in 1982, was accomplished in 2022, 443 as was the synthesis of related spiroisoxazolines clavatadine D and E. 444 The rst total syntheses of merosesquiterpenoid dysiherbol C and D, 445 dactyloquinone A, 446 and amino-sesquiterpenoids boneratamide A-C, 447 and two halichonic acids were reported. 448 Both the relative and absolute congurations of lamellodysidine A were conrmed following its synthesis.…”

Impact of Pitch Modification on Anode Properties: Effect of Additive Type

“…In the presence of heat, any C�O bond can chemically react with a hydrogen atom present on the surface to form −OH. 19 Moreover, a hydrogen bond is a much stronger intermolecular bond than an electrostatic bond; 19 thus, this hydrogen bonding explains the better penetration into nonmodified LQI, possibly forming more hydrogen bonds with the coke than for a nonmodified HQI.…”