Janadolide is a cyclic depsipeptide natural product isolated from the marine cyanobacterium . Herein, we describe the total synthesis of janadolide, along with eight simplified analogues, via an efficient solid-phase strategy. Crucial to the synthesis of the natural product was the construction of a key polyketide fragment via an enantioselective (-)--chlorodiisopinocampheylborane-mediated reduction and a alkyl Suzuki reaction. Janadolide and the simplified analogues exhibited antitrypanosomal activity against pathogenic and parasites.