Total Synthesis and Biological Evaluation of Clavatadines C-E

04 April 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Described herein is 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 rapid fashion 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 by-products 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
total synthesis

Supplementary materials

Supporting Information Clavatadine C-E Total Synthesis
1D and 2D NMR Spectra, NCI-60 assay data


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