The importance of conformational pre‐organization in successful macrocyclization reactions has been recognized ever since Eschenmoser’s synthesis of vitamin B12 and Woodward’s synthesis of erythromycin. Different approaches to productive preorganization are possible depending mainly on the degree of freedom in the choice of the structural elements. In diversity‐oriented synthesis, in which it is not imperative that the molecular framework has a fixed structure, matching building blocks can be used to assemble a macrocycle. In target‐oriented synthesis, more subtle structural elements have to be considered in order to pre‐organize the linear substrate into a folded conformer suitable for ring closure. In this microreview, some selected examples of macrocyclization reactions are presented to illustrate the different rational approaches. Special attention is paid to the role of intramolecular weak forces and protecting groups in the conformational pre‐organization that facilitates macrocyclization reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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[reaction: see text] Simply mixing amino alcohol A and thiol in toluene and TFA provided the corresponding amino sulfide B in excellent chemical yield and diastereoselectivity. A double SN2 process initiated by O-5 participation of the neighboring N-carbamate group was advanced to explain the overall retention of configuration at the chiral benzylic center.