Organophosphorus Compounds. Part 43. A Molecular Mechanics Study: the Structural Effect of Cyclic Esters of Phosphorus-based Acids in Hydrolytic Reaction

Hydrolytic reactions of some cyclic esters of alkylphosphates and phosphonates have been studied using molecular mechanics calculations A great deal of attention has been devoted to the hydrolytic behaviour of cyclic esters of phosphorus acids. Interest in this reaction has been largely associated with the understanding of the mechanism of enzymatic hydrolysis'-3 and the pseudorotation process4,' of these physiologically active phosphorus Unfortunately, there are few reports concerned with quantitative or semiquantitative studies of the hydrolytic reaction of cyclic organophosphorus esters. ' The electronegativity and HMO investigations provide a good explanation of the observed product ratio of the ring opening and retention in the hydrolysis of 2-methoxy-2-0x0-1,3,2-dioxaphospholane (1) and 2-methoxy-2-0x0-1,2-oxaphospholane (2), but these methods are unable to rationalize the effects of ring size and endocyclic substituent on the hydrolytic rate constant. The substituent effect on the alkaline hydrolysis of both cyclic and acyclic phosphonyl chlorides has been investigated successfully by us12-14 using Allinger's 1977 force field, MM2 1985 program. However, the effect of the ring size and endocyclic substituents has not been considered in that treatment. In this paper, molecular mechanics calculations (MM2 1985) are used to investigate the hydrolysis reaction of the following cyclic phosphorus compounds including (l), (2), 2-ethoxy-2-oxo-1,2-oxaphospholane (3), 2-ethoxy-2-0x0-1,2-oxaphosphorinane (4), 2-ethoxy-2-oxo-1,2-oxaphosphepane (5), diethyl ethylphosphonate (6), l-methoxy-l-oxo-2,2,3-trimethylphosphetane (7), and 1-methoxy-1-oxo-2,2,3,4,4-pentamethylphosphetane (8). The calculation results indicate that the ratio of the ring opening and retention products in the hydrolysis of (1) and (2), and the effect of the ring size and the endocyclic substituents are mainly controlled by the steric energy difference (AE or AAE) between the substrate and its pentaco-ordinated transition state. Calculations Allinger's 1977 force field and MM2 1985 program" were used and all calculations were carried out on a Vax-780 computer at Shanghai Institute of Organic Chemistry, Chinese Academy of Science. Since only van der Waals parameters are used in the program, the other parameters for the tetraco-ordinated and pentaco-ordinated phosphorus compounds were calibrated in our laboratory. ' For the calculations of pentaco-ordinated phosphorus compounds the MM2 force field was modified by us.12 In order to evaluate the difference in stability of trigonal bipyramid (TBP) and square pyramid (SP), 1,3-van der Waals (VDW) interactions between the atoms directly bonded to the pentaco-ordinated phosphorus atom were added into the MM2 force field. A similar method has been used to modify the MM1 force field by Holmes.'6 In the present treatment the VDW radius for 1,3-VDW interactions is different and larger than that for 1,4-or longer VDW interactions. This not only gives a reliable energy difference value between TBP and SPY but also the correct bond angles around the pentaco-ordinated phosphorus atom bonding with different atoms. If the initial conformation is assigned as trigonal bipyramidal or square pyramidal, after minimization the structure will basically remain TBP or SP because different natural bond length and bond angle parameters for TBP and SP are assigned in the program. However, the minimization structure may deviate slightly from the standard TBP or SP owing to steric interactions. In the present case only TBP or SP were considered since they are two well studied geometries in crystal structures. Also the leaving group in the alkaline hydrolysis reaction of phosphorus esters is usually considered to be located in the axial position of a trigonal bipyramid. Some parameters for particular groups are so far not available owing to a lack of experimental data. In such cases some approximation was made, for example, the calculation parameters for the bonds P-0-and P-OH2 were replaced by these for P-OH. The geometry of each compound and transition state was optimized by using the MM2 1985 program, and the most stable conformation was selected for comparison purposes. However, the general molecular mechanics calculations are only representative of the gas-phase conditions. In order to study the reactions in solution, the solvent effect should be taken into consideration, but this effect is very difficult to evaluate in a simple way. Fortunately, in the present investigation the reactions proceed through the TBP intermediates from the same substrate and in the same solvent and the difference is onl

Identification of RIP1 kinase as a specific cellular target of necrostatins

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis

Stereospecific Transformation of Protected P–H Group into P–O or P–N Group in One-Pot Reaction

A general and efficient procedure for converting 1,1-diethoxyalkylphosphinates into phosphonates or phosphonamides is described by the application of bromine with moderate to high yields and good purity in a one-pot reaction. <i>H</i>-Phosphinate reacts stereospecifically with bromine and subsequently couples with nucleophile to form the corresponding optically active R¹P­(O)­(OEt)­X with retention of configuration at the phosphorus center. For α-amino-<i>H</i>-phosphinates, the transformation could be realized without the protection of the amino group

Stereospecific Transformation of Protected P–H Group into P–O or P–N Group in One-Pot Reaction

A general and efficient procedure for converting 1,1-diethoxyalkylphosphinates into phosphonates or phosphonamides is described by the application of bromine with moderate to high yields and good purity in a one-pot reaction. <i>H</i>-Phosphinate reacts stereospecifically with bromine and subsequently couples with nucleophile to form the corresponding optically active R¹P­(O)­(OEt)­X with retention of configuration at the phosphorus center. For α-amino-<i>H</i>-phosphinates, the transformation could be realized without the protection of the amino group

Stereospecific Transformation of Protected P–H Group into P–O or P–N Group in One-Pot Reaction

A general and efficient procedure for converting 1,1-diethoxyalkylphosphinates into phosphonates or phosphonamides is described by the application of bromine with moderate to high yields and good purity in a one-pot reaction. <i>H</i>-Phosphinate reacts stereospecifically with bromine and subsequently couples with nucleophile to form the corresponding optically active R¹P­(O)­(OEt)­X with retention of configuration at the phosphorus center. For α-amino-<i>H</i>-phosphinates, the transformation could be realized without the protection of the amino group