The total synthesis of the title compound has been accomplished. Among the key steps were (i) a conjugate addition-Robinson annulation-type sequence (see 4), (ii) intramolecular carbomercuration (see 3), (iii) a reduction-ketonization sequence (see 25), (iv) cycloetherification of an unactivated methylene group (see 28), and reductive amination (see 1). A highly preliminary SAR profile suggests that the functional cytotoxic pharmacophore of hispidospermidin involved a presentation of spermidine derivative 36 via linkage to a ball-like hydrophobic cage to its target.