Synthesis of a Quaternary <i>N</i>,<i>N′</i>‐Aminal‐Containing A–E Ring System of Palau′amine via an Enamide‐Type Overman Rearrangement Reaction

Imaoka, Takuya; Iwata, Makoto; Nagasawa, Kazuo

doi:10.1002/ejoc.201800086

Cited by 6 publications

(2 citation statements)

References 36 publications

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“…Moreover, its cyclic form is present in potent bioactive compounds and natural products, such as saxitoxin (blocker of voltage-gated sodium channels) and teixobactin (an antibiotic for resistant bacteria) (Scheme ). Because of these chemical and medicinal properties of cyclic guanidines, the development of a useful method for their synthesis has been of long-standing interest in organic synthesis. , There are various methods for synthesizing cyclic guanidines, such as intramolecular displacement, halocyclization, and others . Metal-catalyzed processes were developed, including alkene hydroamination (Ag), alkene carboamination (Pd), alkene diamination (Pd), alkyne hydroamination (Ag, Rh), alkyne carboamination (Pd), C–H amination (Rh), cyclization via (π-allyl) palladium intermediate, and carbenylative amination (Pd) .…”

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confidence: 99%

Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer and Radical-Polar Crossover

2021

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Cyclic guanidines are found in many biologically active compounds and natural products. Further, the formation of the atypical seven-membered ring of cyclic guanidine remains challenging because of a lack of efficient preparation strategies and low yield. Herein, a catalytic synthetic method for cyclic guanidines was developed via transition-metal hydrogen atom transfer and radical-polar crossover. This mild and functional-group-tolerant process enabled the cyclization of alkenyl guanidines bearing common protective groups, such as Cbz and Boc groups. This powerful method provided not only typical five- and six-membered rings but also the atypical seven-membered ring. The derivatization of the products afforded various heterocycles. We also investigated the selective cyclization of monoprotected or heteroprotected (TFA and Boc) alkenyl guanidines and their further derivatizations.

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Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer and Radical-Polar Crossover

2021

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“…This suggested to directly use the MOM-protected molecule (hereafter called MOMO) (Figure 1A) in order to test the ability of pH changes to remove MOM and, possibly, restore the cytotoxic activity of the native molecule climacostol. There are very few examples of MOM-derivative compounds for which their biological activities have been studied (Rowley et al, 1997; Mclennan et al, 2008; Bischoff et al, 2014; Imaoka et al, 2018). To date no small organic molecules containing MOM have been reported as cytotoxic prodrugs.…”

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The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

et al. 2019

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We synthesized and characterized MOMO as a new small molecule analog of the cytotoxic natural product climacostol efficiently activated in mild extracellular acidosis. The synthesis of MOMO had a key step in the Wittig olefination for the construction of the carbon-carbon double bond in the alkenyl moiety of climacostol. The possibility of obtaining the target ( Z )-alkenyl MOMO derivative in very good yield and without presence of the less active ( E )-diastereomer was favored from the methoxymethyl ether (MOM)-protecting group of hydroxyl functions in aromatic ring of climacostol aldehyde intermediate. Of interest, the easy removal of MOM-protecting group in a weakly acidic environment allowed us to obtain a great quantity of climacostol in biologically active (Z)-configuration. Results obtained in free-living ciliates that share the same micro-environment of the climacostol natural producer Climacostomum virens demonstrated that MOMO is well-tolerated in a physiological environment, while its cytotoxicity is rapidly and efficiently triggered at pH 6.3. In addition, the cytostatic vs. cytotoxic effects of acidified-MOMO can be modulated in a dose-dependent manner. In mouse melanoma cells, MOMO displayed a marked pH-sensitivity since its cytotoxic and apoptotic effects become evident only in mild extracellular acidosis. Data also suggested MOMO being preferentially activated in the unique extra-acidic microenvironment that characterizes tumoural cells. Finally, the use of the model organism Drosophila melanogaster fed with an acidic diet supported the efficient activity and oral delivery of MOMO molecule in vivo . MOMO affected oviposition of mating adults and larvae eclosion. Reduced survival of flies was due to lethality during the larval stages while emerging larvae retained their ability to develop into adults. Interestingly, the gut of eclosed larvae exhibited an extended damage (cell death by apoptosis) and the brain tissue was also affected (reduced mitosis), demonstrating that orally activated MOMO efficiently targets different tissues of the developing fly. These results provided a proof-of-concept study on the pH-dependence of MOMO effects. In this respect, MOM-protection emerges as a potential prodrug strategy which deserves to be further investigated for the generation of efficient pH-sensitive small organic molecules as pharmacologically active cytotoxic compounds.

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Non-peptidic natural products as ubiquitin-proteasome inhibitors

Sengupta

Mehta

2019

Tetrahedron

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Synthesis of a Quaternary N,N′‐Aminal‐Containing A–E Ring System of Palau′amine via an Enamide‐Type Overman Rearrangement Reaction

Cited by 6 publications

References 36 publications

Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer and Radical-Polar Crossover

Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer and Radical-Polar Crossover

The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

Non-peptidic natural products as ubiquitin-proteasome inhibitors

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