Scalable synthesis of saturated heterocyclic dimethyl phosphine oxides (derivatives of azetidine, pyrrolidine, piperidine, and morpholine) is disclosed. The key steps of the synthesis relied on the reactions of HP(O)Me 2 , i. e. the phospha-Mannich (the Kabachnik-Fields-type) condensation with cyclic imines or monoprotected diamines, palladium-catalyzed reactions of alkenyl halides or trifltates (generated from cyclic ketones), as well as base-mediated nucleophilic substitution, Michael addition, or oxirane ring opening. It was shown that introducing the P(O)Me 2 group into the saturated heterocyclic core had very strong impact on the compound's basicity: the corresponding α-, β-, and γ-isomeric derivatives were by ca. 4, 2, and 1.6 pK a units less basic, respectively, as compared to the parent saturated heterocycle. Meanwhile, the P(O)Me 2 -substituted compound was more basic than its SO 2 i-Pr and SO 2 NMe 2containing isosteres (by ca. 1.2 and 0.4 pK a units, respectively). It was also demonstrated that the P(O)Me 2 group typically increased the compound's hydrophilicity and aqueous solubility. In particular, the LogP values for the corresponding derivatives were by ca. 1.4-1.7 and 0.6 units lower than for the non-substituted counterpart and sulfonamide/sulfone isosteres, respectively. Finally, a potential of the synthesized building blocks to generate lead-like three-dimensional compound libraries was confirmed using the Nelson's LLAMA tool.

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