A Highly Stereoselective Total Synthesis of Hispidospermidin:  Derivation of a Pharmacophore Model

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