Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Dec 27;113(52):14893-14897.
doi: 10.1073/pnas.1616462114. Epub 2016 Dec 14.

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Suzanne M Batiste  1   2 , Jeffrey N Johnston  3   2
Affiliations

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Suzanne M Batiste et al. Proc Natl Acad Sci U S A. .

Erratum in

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.

Keywords: Mitsunobu; collective; macrocycle; oligomerization; total synthesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
(A) Combined inter-/intramolecular esterification or amidation approaches to prepare macrocycles and functional group synthesis options for depsipeptide synthesis for both (B) linear and (C) macrocycle construction.
Fig. 2.
Fig. 2.
Representative macrocyclic oligomeric depsipeptide natural products and diagram summarizing cyclooligomeric depsipeptide diversity elements.
Scheme 1.
Scheme 1.
Total chemical synthesis of (natural) (−)-verticilide using MCO.
Fig. 3.
Fig. 3.
Effect of salts on the production of cyclooligomers using a Mitsunobu-based oligomerization/cyclization approach and didepsipeptide 5.
Scheme 2.
Scheme 2.
Synthesis of tetradepsipeptide 13 for Mitsunobu-based MCOs.
Fig. 4.
Fig. 4.
Mitsunobu-based MCO of d/l-macrocycle progenitor tetradepsipeptide 13: effect of salt additives on yield of 24-, 36-, and 60-membered ring formation.
Fig. 5.
Fig. 5.
Mitsunobu-based MCO of 15: effect of salt additives on yield of 6-, 18-, 24-, and 30-membered ring formation.
Scheme 3.
Scheme 3.
Synthesis of bassianolide (2).
See this image and copyright information in PMC

References

    1. Jones SB, Simmons B, Mastracchio A, MacMillan DWC. Collective synthesis of natural products by means of organocascade catalysis. Nature. 2011;475(7355):183–188. - PMC - PubMed
    1. Woodward RB, et al. Asymmetric total synthesis of erythromycin. 2. Synthesis of an erythronolide A lactone system. J Am Chem Soc. 1981;103(11):3213–3215.
    1. Paterson I, Laffan DDP, Rawson DJ. Studies in macrolide synthesis: A concise asymmetric synthesis of a macrolide intermediate for the erythronolides. Tetrahedron Lett. 1988;29(12):1461–1464.
    1. Evans DA, Dinsmore CJ, Evrard DA, DeVries KM. Oxidative coupling of arylglycine-containing peptides. A biomimetic approach to the synthesis of the macrocyclic actinoidinic-containing vancomycin subunit. J Am Chem Soc. 1993;115(14):6426–6427.
    1. Boger DL, Nomoto Y, Teegarden BR. Vancomycin and ristocetin models: Synthesis via the Ullmann macrocyclization reaction. J Org Chem. 1993;58(6):1425–1433.

Publication types

MeSH terms