Total Synthesis of (−)-Aplaminal

The total synthesis and assignment of absolute configuration of (−)-aplaminal (1), a cytotoxic metabolite from a sea hare possessing a triazobicyclo[3.2.1]octane skeleton, has been achieved. The synthesis entailed condensation of a monoprotected diamine (3) with dimethyl 2-oxomalonate (4) to generate the imidazolidine core (2). Introduction of the third nitrogen via Mitsunobu activation and azide displacement, followed by reduction and lactam formation (AlMe3), furnished (−)-aplaminal (1). Overall, the synthesis entailed 9 steps and proceeded in 19% overall yield.