Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry

Lücke, Daniel; Dalton, Toryn; Ley, Steven V.; Wilson, Zoe E.

doi:10.1002/chem.201504457

Cited by 41 publications

(31 citation statements)

References 48 publications

(49 reference statements)

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“…Finally, bassianolide was prepared in eight steps to establish the generality of approach while highlighting the advantage of a Mitsunobu reaction-based synthesis. Attempts to develop cyclooligomerization have historically suffered from direct cyclization (12)(13)(14)56), favoring medium ring sizes (e.g., 12-membered depsipeptide) and competitive epimerization (15, 60) during amide formation. The Mitsunobu substitution strategy used here provides the possibility for either the synthesis of collections of oligodepsipeptide macrocycle size congeners or the synthesis of a select ring size in high yield as well as the ability to frame-shift macrocycle size distribution by the judicious choice of monomer size (didepsipeptide vs. tetradepsipeptide).…”

Section: Resultsmentioning

confidence: 99%

“…The extension of this approach (Scheme 3) to a synthesis of bassianolide (55,56) (2) was also pursued as a means to estimate the level of generality that might be inherent to the approach and methods. Tetradepsipeptide 20 was prepared in a manner analogous to 13 and then, subjected to Mitsunobu conditions [DIAD (2 equiv), PPh 3 (3 equiv), benzene (5 mM)].…”

Section: Significancementioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

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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“…Compared with standard batch chemistry methods, continuous flow reactions have many significant advantages, such as better control and reproducibility, improved safety, cost efficiency, increased product quality and yield, etc. Through the efficient continuous flow multistep strategy, many natural and unnatural cyclic depsipeptides and peptidomimetics have been successfully synthesized, providing more possibilities for the discovery of new drugs …”

Section: Strategies To Develop Cyclic Peptides Into Therapeutic Agentsmentioning

confidence: 99%

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Jing

Jin

2019

Medicinal Research Reviews

119

130

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As a versatile therapeutic modality, peptides attract much attention because of their great binding affinity, low toxicity, and the capability of targeting traditionally “undruggable” protein surfaces. However, the deficiency of cell permeability and metabolic stability always limits the success of in vitro bioactive peptides as drug candidates. Peptide macrocyclization is one of the most established strategies to overcome these limitations. Over the past decades, more than 40 cyclic peptide drugs have been clinically approved, the vast majority of which are derived from natural products. The de novo discovered cyclic peptides on the basis of rational design and in vitro evolution, have also enabled the binding with targets for which nature provides no solutions. The current review summarizes different classes of cyclic peptides with diverse biological activities, and presents an overview of various approaches to develop cyclic peptide‐based drug candidates, drawing upon series of examples to illustrate each strategy.

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“…[34] The employed reactor was equipped with three inlets, A-C ( Figure 10). [34] The employed reactor was equipped with three inlets, A-C ( Figure 10).…”

Section: Solution-phase Continuous-flow Cyclic Depsipeptide Synthesimentioning

confidence: 99%

“…[34] The cycli-zation of precursor 49 was prepared by removing both the Boc and Bn groups in 48.C arboxylic acid 49 wasi ns itu-converted to the corresponding acid chloride 50 in ac ontinuousflow reactor.T he introduction of aD IEAs olution via inlet Ci nduced macrolactamization to afford the desired cyclic depsipeptide 51.Cyclization produced 0.41-0.56 mmol h À1 . [34] The cycli-zation of precursor 49 was prepared by removing both the Boc and Bn groups in 48.C arboxylic acid 49 wasi ns itu-converted to the corresponding acid chloride 50 in ac ontinuousflow reactor.T he introduction of aD IEAs olution via inlet Ci nduced macrolactamization to afford the desired cyclic depsipeptide 51.Cyclization produced 0.41-0.56 mmol h À1 .…”

Section: Solution-phase Continuous-flow Cyclic Depsipeptide Synthesimentioning

confidence: 99%

Peptide Synthesis Utilizing Micro‐flow Technology

Fuse

Otake

Nakamura

2018

Chemistry An Asian Journal

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Peptide drugs have garnered much attention in recent years. However, conventional peptides ynthesis requires an excessa mount of expensive reagents of low atom economy,a nd the large amount of waste produced by these reagents complicates the purification of desired peptides. Solid-phase approaches simplify the purification of these peptides, but these requiree xpensive solid-phase, excess amounts of reagents,s ubstrates, and solvents. This makes it important to develop high-yielding, cost-effective, andl ess wasteful synthetic approaches. Micro-flow technology (reac-tion space 1mm) has produced manya dvantages over conventional batch synthesis. Thea dvantages include precise control of short reactiont ime and temperature, high levels of light penetration efficiency,l oweredr isks of handling dangerous compounds, and ready scale-up withh igh reproducibility.M icro-flow peptides yntheses using these advantages have been reported in recent years. This review summarizes the solid-phase and solution-phases yntheses of a-a nd b-peptides and of cyclic peptidesu sing micro-flow technology.[a] Dr.

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Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry

Cited by 41 publications

References 48 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

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Peptide Synthesis Utilizing Micro‐flow Technology

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