AbstractSynthetic access to oligodepsipeptides (ODP), polymers with high potential in biomedicine, is given by the ring-opening polymerization (ROP) of morpholine-2,5-diones (MDs). Classically, the ROP of MDs is mostly conducted by coordination-insertion polymerization using metal-organics as a catalyst e.g. tin(II) di(2-ethyl hexanoate) (Sn(Oct)2). This ROP has been shown to be significantly more difficult to conduct than the corresponding ROP of dilactide, which was related to different electronic properties of the monomers and potential steric crowding. Here, we investigated the ROP of 3-(S)-sec-butylmorpholine-2,5-dione (BMD) by varying the catalyst’s hardness, comparing Sn(Oct)2 with the ethoxides of indium, magnesium, aluminum and iron(III), as well as with iron(II) acetate. The ROP of BMD with Sn(Oct)2 in bulk at 135 °C for 24 h gave ODP with a number-average molecular weight (Mn) = 4.5 kDa. Mg(OEt)2 gave the best results among the other investigated metal ethoxides with ODP of Mn = 4 kDa and a conversion ratio of 57 mol%. On the other hand, high polymerization temperature was needed (160 °C) in the case of In(OEt)3, which resulted in partial degradation, while Al(OEt)3 and Fe(OEt)3 did not result in polymerization. Very effective for the ROP of the studied MD proofed to be Fe(OAc)2, giving OBMD with a Mn = 5.8 kDa, a polydispersity of 1.1, a conversion ratio of 86 mol%, and no racemization. This catalyst likewise performed well in the polymerization of Ser- and Tyr-based MDs. Fe(II) is softer than Sn(II) and may support the ROP by promoting the alkoxide transfer step of the polymerization, while suppressing the formation of unreactive coordination complexes. In contrast, the metal alkoxides investigated were harder than Fe(II) or Sn(II), but had low steric demand. The results suggest that the hardness of the central atom is the key property in the polymerization, while steric considerations are of lower importance. In addition, a synthesis of MDs with protected side chains in improved yields was introduced. This was achieved by in situ formation of an alkyl iodide that is very effective in the ring closing reaction.