title: Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control.
abstract: Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes.
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235-1822.|Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235-1822.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Batiste
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235-1822; jeffrey.n.johnston@vanderbilt.edu.|Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235-1822.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Johnston
mesh_terms: D003500:Cyclization / Q000502:physiology; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D047630:Depsipeptides; D047028:Macrocyclic Compounds
keywords: Mitsunobu; collective; macrocycle; oligomerization; total synthesis