Amidoalkylation of hydrophosphoryl compounds

Dmitriev, M. E.; Rossinets, E. A.; Ragulin, V. V.

doi:10.1134/s1070363211060041

Cited by 18 publications

(14 citation statements)

References 13 publications

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“… 6 To prepare the P1-diversified set of phosphinic pseudodipeptides ( 6 – 12 ), the C → N strategy seemed more convenient (Scheme 1 ). This route usually involves a three-component amidoalkylation reaction between a carbamate, an aldehyde and an H -phosphinic acid, 50 such as 26 (which is obtained through a phospha-Michael addition of α-benzylacrylate to H 3 PO 2 , as described elsewhere 51 ). In our case, the synthetic challenge involved preparing aldehydes 13 – 19 , which are key substrates for the condensation.…”

Section: Results and Discussionmentioning

confidence: 99%

Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases

et al. 2014

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Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor–enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1′-extended structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1′ residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. Another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π–π stacking interaction between a pyridine ring and Tyr372.

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Section: Results and Discussionmentioning

confidence: 99%

Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases

et al. 2014

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“…As mentioned, the precise role of active carboxyl compounds (in the majority of cases, AcCl) as a driving force for the condensation remained incompletely clear. Recently, this aspect has been studied in detail by Dmitriev and Ragulin [ 64 , 65 , 66 ]. Although acetyl chloride was proven to give the highest yield (approximately 70% yield in the reaction of benzaldehyde, an alkyl carbamate and an alkyl acrylate or methacrylate-derived phosphorus component), other systems were almost equally efficient.…”

Section: Synthesis Of the Phosphinic αα'-Dipeptide Backbonementioning

confidence: 99%

“…Although acetyl chloride was proven to give the highest yield (approximately 70% yield in the reaction of benzaldehyde, an alkyl carbamate and an alkyl acrylate or methacrylate-derived phosphorus component), other systems were almost equally efficient. These systems included acetic anhydride alone or with the addition of trifluoroacetic or p -toluenesulfonic acid, which gave rise to 55-65% effectiveness of the condensation [ 64 , 65 ]. More importantly, careful inspection of the byproducts allowed the isolation of a biscarbamate 46 ( Scheme 13 ) and suggest its structure as the key intermediate of the process [ 65 ].…”

Section: Synthesis Of the Phosphinic αα'-Dipeptide Backbonementioning

confidence: 99%

Synthesis and Modifications of Phosphinic Dipeptide Analogues

Mucha

2012

Molecules

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Pseudopeptides containing the phosphinate moiety (-P(O)(OH)CH2-) have been studied extensively, mainly as transition state analogue inhibitors of metalloproteases. The key synthetic aspect of their chemistry is construction of phosphinic dipeptide derivatives bearing appropriate side-chain substituents. Typically, this synthesis involves a multistep preparation of two individual building blocks, which are combined in the final step. As this methodology does not allow simple variation of the side-chain structure, many efforts have been dedicated to the development of alternative approaches. Recent achievements in this field are summarized in this review. Improved methods for the formation of the phosphinic peptide backbone, including stereoselective and multicomponent reactions, are presented. Parallel modifications leading to the structurally diversified substituents are also described. Finally, selected examples of the biomedical applications of the title compounds are given.

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“…We suggested that transformation of biscarbamate IV into the iminium cation II might occur in the presence of a solid superacid via protonation of nitrogen or oxygen atom (C=O) of amide fragment of biscarbamate with Brønsted sites of the catalyst in an inert solvent followed by evolution of the carbamate [1][2][3][4]. The so…”

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confidence: 98%

“…We have earlier developed an efficient procedure to perform reaction of hydrophosphoryl compounds with aldehydes and alkyl carbamates in acetic anhydride upon cooling, and have proposed the mechanism of this multi-stage reaction [1][2][3][4]. According to the proposed mechanism, the formation of phosphorus-carbon bond is as a result of the Arbuzov reaction via nucleophilic attack of the trivalent phosphorus atom of acetyloxy derivative I at positively charged carbon atom of iminium cation II [1,2], the reactants being generated in situ under the reaction conditions from hydrophosphorylic compound III and N,N'-alkylidenebis(carbamate) IV, respectively [1,2]. Biscarbamates have been identified as stable (isolated from the reaction medium) intermediates formed from the reacting aldehydes and alkyl carbamates [1][2][3][4] (Scheme 1).…”

mentioning

confidence: 99%