Current Organic Chemistry

ISSN: 1385-2728

Current Organic Chemistry
Volume 11, Number 18, December 2007

Contents

Special Issue on Organophosphorus Chemistry
Guest Editor: György Keglevich


Editorial Pp. 1592


Organophosphorus Supramolecular Chemistry. Part 2. Organophosphorus Receptors Pp. 1593-1609
Piotr Mlynarz, Ewa Rudzinska, Lukasz Berlicki and Pawel Kafarski
[Abstract]


6-Membered P-Heterocycles: Ring-Condensed 1,3,2 Diheterophosphorinane 2-Chalcogenides Pp. 1610-1625
Éva Frank and János Wölfling
[Abstract]


Comparison of the Ability of Pyridinium Aldoximes to Reactivate Human RBC Cholinesterases Inhibited by Ethyl- and Methyl-Paraoxon Pp. 1624-1634
Georg Petroianu and Huba Kalász
[Abstract]


ω-Phosphinyl-α-Amino Acids: Synthesis, and Development Towards Use as Therapeutic Agents Pp. 1635-1651
Nick J. Wardle, S. W. Annie Bligh and Harry R. Hudson
[Abstract]


Synthesis and Reactivity of Azidoalkylphosphonates -Phosphinates and Phosphine Oxides Pp. 1652-1668
Anna Gajda and Tadeusz Gajda
[Abstract]




Abstracts

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Editorial

Organophosphorus chemistry continues to be a highly important sector of organic chemistry, as shown by the numerous publications in this field. The 17th International Conference on Phosphorus Chemistry held in Xiamen (China) recently (http://icpc2007.xmu.edu.cn/) highlighted some of the most significant and exciting trends. The importance of this field is also acknowledged by the management of Current Organic Chemistry by encouraging me to put together the 3rd Organophosphorus Special Issue that, like the previous two special issues, summarizes recent results of some selected hot topics. The 10 articles are accommodated in two parts.

This series of publications starts with organophosphorus supramolecular chemistry, for which state-of-the-art progress in design and application is presented for host molecules bearing phosphate, phosphonate, phosphinate or phosphine oxide entities. The P-heterocyclic field is represented by a paper on the synthesis and conformation of 1,3,2-dioxa-, 1,3,2-oxaza-, and 1,3,2-diazaphosphorine 2-chalcogenides. This topic is also relevant from the point of view of potential biological activity, an aspect that is more directly involved in the next two articles. The first of these discusses the possible reactivation of RBC cholinesterases inhibited by paraoxon derivatives, while the other gives an overview on the synthesis of ω-phosphinyl-α -amino acids and their potential role as therapeutic agents.

Remaining with tetracoordinated P-compounds, the chemistry of azidoalkyl-phosphonates, -phosphinates and -phosphine oxides, as well as the phosphorylation of α-haloimines and that of thiophenes is discussed. In the next section, the use of Wittig- and aza-Wittig reactions in the synthesis of heterocycles and the synthesis and utilization of stabilized phosphorus ylides generated from triphenylphosphine and dialkyl acetylenedicarboxylate are summarized. Finally, antiaromaticity, a newly discovered phenomenon within the framework of organophosphorus chemistry, is explored.

The 3. Organophosphorus Special Issue has been divided into two parts published back to back. The five reviews included in this issue (Part I) is to be followed by five other articles in Volume 12 (Part II). The forthcoming papers are the following:


Phosphorylation of α-Haloimines: P–C vs. P–N Bond Formation
by Petro P. Onys’ko, Yuliya V. Rassukana and Anatoly D. Sinitsa

Phosphorylation of Thiophenes
by Sergei P. Ivonin, Andrey A. Tolmachev and Alexander M. Pinchyk

Ring Closure Reactions to Heterocyclic Systems with Implementation of Wittig- and aza-Wittig-Reactions
by György Hajós and Ildikó Nagy

Synthesis and Reactions of Stabilized Phosphorus Ylides
by Ali Ramazani, Ali Reza Kazemizadeh, Ebrahim Ahmadi, Nader Noshiranzadeh and Ali Souldozi

The Antiaromaticity of Four- and Five-Membered P-Heterocycles
by Zoltán Mucsi and Imre Csizmadia


György Keglevich
Department of Organic Chemistry and technology
Budapest University of Technology and Economics
H-1521 Budapest
Hungary


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Organophosphorus Supramolecular Chemistry. Part 2. Organophosphorus Receptors
Piotr Mlynarz, Ewa Rudzinska, Lukasz Berlicki and Pawel Kafarski

Despite their importance in biology and industry, organophosphorus compounds appear quite rarely as an object of supramolecular chemistry studies. Development of synthetic methods in organophosphorus chemistry enabled to design and synthesize compounds of complex structures and thus to develop organophosphorus supramolecular chemistry. In this review, a state-of art showing current progress in design and application of host molecules bearing phosphate, phosphonate, phosphinate or phosphine oxide entities is presented. These structural elements are involved in formation of specific nets of hydrogen bonds and/or electrostatic interactions with complexed molecules (guest molecules) via anionic phosphate or phosphonate residues. Such host molecules are usually designed mostly for a variety of analytical purposes, namely as components of sensors, as extractants, chiral discriminators, membrane carriers etc.


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6-Membered P-Heterocycles: Ring-Condensed 1,3,2 Diheterophosphorinane 2-Chalcogenides
Éva Frank and János Wölfling

Literature publications (up to the end of 2006) relating to the synthesis, biological significance and conformational behaviour of carbocycle- and heterocycle-condensed six-membered tetracoordinate P(V) 1,3,2-diheterophosphorinanes are reviewed. The replacement of carbon atoms of cyclohexane by P and O and/or N to form 1,3,2-dioxa-, 1,3,2-oxaza- or 1,3,2-diazaphosphorinanes introduces lone pair electrons instead of hydrogens and changes the bond angles and bond lengths, and can thereby lead to significantly different stereostructural preferences of the hetero ring as compared with those of cyclohexane. Although monocyclic 1,3,2-diheterophosphorinanes often exist in a chair conformation in both the solid and solution states, the existence of conformations other than a chair can predominate in some cases for steric and stereoelectronic reasons associated with the presence of bulky groups on the P-containing ring or in polycyclic rigid systems.

After a brief account on the most important pharmacological and stereochemical features, involving the configuration assignment and conformation determination of P-diheterophosphorinanes, the present review mainly focuses on the synthesis and stereostructural studies of carbo- and heterocycle-condensed derivatives, where the fused ring may exert considerable effects on the conformational behaviour of the P-hetero ring.


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Comparison of the Ability of Pyridinium Aldoximes to Reactivate Human RBC Cholinesterases Inhibited by Ethyl- and Methyl-Paraoxon
Georg Petroianu and Huba Kalász

Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). Pralidoxime (1) and obidoxime (2) are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is however disappointing.

The paper reviews the available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl-paraoxon (3) and methyl-paraoxon (4).

Reactivation ability is quantified in vitro via the IC₅₀ shift curve. The slope of the shift curve (tg α ) is used to quantify the magnitude of the protective effect (nM IC₅₀ increase per microM reactivator).

The ranking of reactivator potencies of the examined oximes determined with 4 as an inhibitor is essentially the same as the ranking obtained using 3 as an inhibitor. In the in vitro model used, the presence of ethyl vs. methyl substituents does not seem to significantly alter the in vitro ability of the examined oximes to reactivate the esterase.

In vitro derived results were subsequently validated in vivo in rats using 3 and 4 as cholinesterase inhibitors and various oximes as reactivator. Mortality data were compared and hazards ratios calculated using Cox proportional hazards model. Overall the ability of the in vitro testing (tg α determinations) to predict in vivo performance of the oximes is limited.

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ω-Phosphinyl-α-Amino Acids: Synthesis, and Development Towards Use as Therapeutic Agents
Nick J. Wardle, S. W. Annie Bligh and Harry R. Hudson

Literature publications (up to September 2006) concerning the synthesis of ω-phosphinyl-α-amino acids and their development towards use as therapeutic agents are reviewed. General and asymmetric methodologies for the preparation of straight-chain examples are described, including AP3-7 modulators of glutamate-responsive excitatory amino acid (EAA) receptors (i.e. ionotropic NMDA-, and metabotropic GrpIII mGlu-receptors), and the glutamate synthetase inhibitor phosphinothricin. Focusing primarily on the development of methods for introducing phosphonate and aminocarboxylate functions to the appropriate scaffold, approaches to conformationally constrained ω-phosphinyl-α-amino acids are also investigated, along with their relevance to the development of therapeutic regimens towards neurodegenerative disorders.


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Synthesis and Reactivity of Azidoalkylphosphonates, -Phosphinates and Phosphine Oxides
Anna Gajda and Tadeusz Gajda

This review will focus on the synthesis of α- and β azidoalkylphosphonic and phosphinic acids, -phosphine oxides and their derivatives as well as their reactions utilizing the azido group and/or phosphyl group. In the first part of this review synthetic routes to such azides will be reviewed. Generally, these compounds are achieved via nucleophilic substitution of hydroxy derivatives of phosphonates, -phosphinates, and -phosphine oxides by the Mitsunobu protocol or by the displacement of their sulfonates or halogen derivatives with azides. The ring-opening of phosphorus-containing oxiranes or cyclic vicinal sulfates with azides will also be discussed. Electrophilic azidation of the corresponding phosphorus-stabilized carbanions has also been described. In the second part of the review emphasis will be placed on the application of azido derivatives in organic synthesis. 1,3 Dipolar cycloaddition is an excellent tool in the construction of five-membered heterocycles. Therefore, the formation of 1,2,3-triazoles from alkynes, enamines and 2-oxoalkylidenetri-phenylphosphoranes will be discussed. Hence, the azido group is easily converted into amine, and phosphorus-containing azides can be considered to be azide-masked equivalents of amino derivatives or their N-protected derivatives. The application of such azides in the synthesis of phosphorus analogs of amino acids will be discussed. The synthesis of carbodiimides, imines, isothiocyanates and phosphonodipeptides has also been reviewed.