Biologically Active Macrocyclic Compounds – from Natural Products to Diversity‐Oriented Synthesis

Madsen, Claus B.; Clausen, Mads Hartvig

doi:10.1002/ejoc.201001715

Cited by 86 publications

(44 citation statements)

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“…To achieve all three of these goals without compromising synthetic efficiency or relevance to complex natural products, we were attracted to cyclodepsipeptides, in which biological activity is quite diverse (18)(19)(20)(21)(22)(23). Herein, we report rapid access to size-diverse collections of cyclooligodepsipeptides using a controlled oligomerization/macrocyclization sequence.…”

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confidence: 99%

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

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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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.Mitsunobu | total synthesis | collective | macrocycle | oligomerization I nterest in the preparation and use of small molecules exhibiting macrocyclic rings is growing at a tremendous pace, driving the development of new approaches, new chemical reactions, and the underlying chemistry and tools (catalysts) to support them. Historically, studies of macrocyclization reactions have been guided by natural products bearing unusually large carbocycles or mediumand large-ring lactones, amides, and ethers. Fragmentation reactions of polycyclic molecules have long played a role in access to medium-sized macrocycles, whereas macrocyclizations to lactones and amides are often accomplished from linear precursors at high dilution. Insofar as these efforts were typically driven by the goal to prepare a specific macrocycle, often in the form relevant to a natural product synthesis or an engineered constraint to a peptide, absent from the field is an approach that provides rapid access to collections (1) of natural product-like macrocycles, particularly from stereochemically complex, functionally rich, linear precursors (2-6).Pioneers in this area have recorded some success (Fig. 1). Esterification reactions of activated hydroxy acids have led predominantly to diolides, (7-10) and in a single case, oligolides (11). Amidation reactions of activated polypeptides were central to the preparations of macrocyclic peptides by Rothe and Kreiss (12,13) and Wipf and coworkers (14, 15), but they were low yielding and size nonselective. Burke and coworkers (16,17) have shown that the efficiency of an 18-membered oligol...

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confidence: 99%

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

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The thin-layer chromatography analyses were carried out using Merck DC Kieselgel 60 F254 plates. 1 H NMR spectra were recorded on a Varian Mercury 400 spectrometer (400 MHz) in CDCl3. 13 C NMR spectra were recorded on a Varian Mercury 400 spectrometer (100 MHz).…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3][4] Therefore, shortly after the publication of the pioneering work on the complexation of alkali metal ions by crown ethers, papers examining the synthesis and properties of modified crown ethers started to appear in the literature. In the 1970s, aromatic and/or heteroaromatic systems were introduced into the crown structure, owing to their limited lability.…”

Section: Introductionmentioning

confidence: 99%

“…In order to identify these compounds quantitatively, we adapted the HPLC method which we had previously used successfully for analysis of dynamic combinatorial libraries of macrocyclic imines. 23,24 Based on the library of macrocyclic amides ( Figure 2) we were able to measure the conversion of aromatic dimethyl esters (1)(2)(3) and compare the proportion between macrocyclic diamides 9-23 and tetraamides 24-38 as a molar ratio, after calibrating the UV detector (see Supplementary Materials). The best conversions were obtained for reactions involving diamine 7 (Table 1, entries 4, 9, and 14).…”

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The influence of salt additives on the macrocyclic product distributions in double-amidation reactions

Pikus¹,

Paśniczek²,

Jurczak³

2017

Arkivoc

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We present an improvement of our own method for synthesising macrocyclic compounds via doubleamidation reactions of aromatic dimethyl esters with five oxa-aliphatic α,ω-diamines of different lengths, leading to a large library of potential ion receptors. We studied the influence of various inorganic salts (NaCl, KCl, CsCl, NH4Cl, MgSO4, CaCl2, CuSO4) on the macrocyclization reaction. The results were analyzed in terms of substrate conversion and distribution of products, using high performance liquid chromatography (HPLC).

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“…Macrocycles are an underutilized class of molecules in drug discovery, 1,2,3 despite their unique ability to address difficult targets, 4 such as protein-protein interactions, a fact that can be attributed to the inherent difficulty in preparing large rings. 5 Macrocyclic peptides and peptidomimetics are a sub-class of macrocycles, the synthesis 6 and easy of cyclization 7,8 of which have been topics of excellent recent papers.…”

Section: Introductionmentioning

confidence: 99%

Observations on the Influence of Precursor Conformations on Macrocyclization Reactions

et al. 2016

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Macrocycles hold great promise in drug discovery as an underutilized class of lead compounds. The low abundance of these molecules can in part be explained by the inherent difficulties in the synthesis of macrocycles and the lack of general methods for their rapid assembly. We have undertaken a research program aimed at developing methods for facile synthesis of macrocycles from simple precursors. The synthesis of two new cyclization precursors is described and the results of their reaction with thionyl chloride are presented and discussed. Where one acyclic diol, smoothly underwent macrocyclization to afford a mixture of diastereomeric sulfites, subjection of the other precursor to identical reaction conditions resulted in the isolation of the linear dichloride. We hypothesize that there is a difference in the ability of the two molecules to adopt a conformation germane to macrocyclization, a proposition that is supported by conformational analyses using molecular mechanics.

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Biologically Active Macrocyclic Compounds – from Natural Products to Diversity‐Oriented Synthesis

Cited by 86 publications

References 58 publications

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

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

The influence of salt additives on the macrocyclic product distributions in double-amidation reactions

Observations on the Influence of Precursor Conformations on Macrocyclization Reactions

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