Azetidines and bisazetidines. Their synthesis and use as the key intermediates to enantiomerically pure diamines, amino alcohols, and polyamines

Ojima, Iwao; Zhao, Mangzhu; Yamato, Takehiko; Nakahashi, Kazuaki; Yamashita, Mitsuo; Abe, Rumiko

doi:10.1021/jo00018a012

Cited by 116 publications

(64 citation statements)

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“…Attempts to reduce the carbonyl group of 11-azaartemisinin 5 with reagents normally used both to convert amides to amines [17][18][19] and artemisinins into the 10-deoxo derivatives [20][21][22] were ineffective, in that starting material was returned or extensive degradation took place. Surprisingly, attempted removal of the carbonyl group in the methanesulfonyl derivative 7 using these same reagents also failed; the attachment of an electron-withdrawing group to the nitrogen atom was expected to attenuate the deactivating effect of the nitrogen atom on carbonyl reactivity characteristic of amides.…”

Section: Resultsmentioning

confidence: 99%

Preparation of N‐Sulfonyl‐ and N‐Carbonyl‐11‐Azaartemisinins with Greatly Enhanced Thermal Stabilities: in vitro Antimalarial Activities

et al. 2007

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As the clinically used artemisinins do not withstand the thermal stress testing required to evaluate shelf life for storage in tropical countries where malaria is prevalent, there is a need to develop thermally more robust artemisinin derivatives. Herein we describe the attachment of electron-withdrawing arene- and alkanesulfonyl and -carbonyl groups to the nitrogen atom of the readily accessible Ziffer 11-azaartemisinin to provide the corresponding N-sulfonyl- and -carbonylazaartemisinins. Two acylurea analogues were also prepared by treatment of the 11-azaartemisinin with arylisocyanates. Several of the N-sulfonylazaartemisinins have melting points above 200 degrees C and possess substantially greater thermal stabilities than the artemisinins in current clinical use, with the antimalarial activities of several of the arylsulfonyl derivatives being similar to that of artesunate against the drug-sensitive 3D7 clone of the NF54 isolate and the multidrug-resistant K1 strain of P. falciparum. The compounds possess relatively low cytotoxicities. The carbonyl derivatives are less crystalline than the N-sulfonyl derivatives, but are generally more active as antimalarials. The N-nitroarylcarbonyl and arylurea derivatives possess sub-ng ml(-1) activities. Although several of the azaartemisinins possess log P values below 3.5, the compounds have poor aqueous solubility (<1 mg L(-1) at pH 7). The greatly enhanced thermal stability of our artemisinins suggests that strategic incorporation of electron-withdrawing polar groups into both new artemisinin derivatives and totally synthetic trioxanes or trioxolanes may assist in the generation of practical new antimalarial drugs which will be stable to storage conditions in the field, while retaining favorable physicochemical properties.

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Section: Resultsmentioning

confidence: 99%

Preparation of N‐Sulfonyl‐ and N‐Carbonyl‐11‐Azaartemisinins with Greatly Enhanced Thermal Stabilities: in vitro Antimalarial Activities

et al. 2007

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“…It should be noted that the reductive cleavage of the two azetidine moieties of 94 were much faster than debenzylation in this case (Scheme 22). 9,82 …”

Section: Synthesis Of Amino Acids Dipeptides and Their Derivativementioning

confidence: 99%

Advances in the chemistry of ?-lactam and its medicinal applications

2012

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“…Alongside the known methods of azetidines synthesis from aminoalcohols and aminohalides [29,35,[189][190][191] the other reactions are also worth a thorough consideration: the regioselective cyclization of secondary homoallyl amines induced by selenium [192], the reduction of aminoketones and diketones followed by mesylation and aminolysis of alkanols [190], the cyclization of 3-(ammonio) propyl sulfates [193], the reduction of azetidinones [194].…”

Section: Preparation From Epoxy Compoundsmentioning

confidence: 99%