Phosphorus Stereochemistry Research Articles

Analogies between silicon and phosphorus stereochemistry—I: Influence of the leaving group on the stereochemistry of nucleophilic displacement at phosphorus

Stereochemistry of cyclic halogenophosphates has been studied by adding aryloxides, in THF. All extra parameters being equal, the fluoro substituent which is of the more electronegative (and the more apicophilic) is displaced with the more predominant retention F>Cl≈Br. Such behaviour cannot be explained with the usual concepts of phosphorus stereochemistry and, in particular, the generally accepted view of apical attack giving the more stable P V intermediate. By contrast, strong analogies with the stereochemistry observed at silicon are clearly evidenced. Like for silicon compounds, front-side attack could explain predominant retention, particularly in P-F bond cleavage. Trigonal bipyramidal intermediates with the entering group in equatorial position and the leaving group in apical position, or square-pyramidal geometries may be envisaged.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part 7. Stereochemistry of alkoxide-induced ring-opening of 1,3,2-dioxaphosphorinan-2-ones, and of migration of alkyl alkyl phosphoryl groups between the 4- and 6-positions of glucose

Cyclic glucose 4,6-(ethyl phosphates) undergo ring-opening in dilute sodium methoxide to afford glucose 4-(ethyl methyl phosphates) as the kinetically favoured products. Ring-opening occurs with preponderant inversion of configuration. On storage in sodium methoxide glucose 4-(ethyl methyl phosphates) afford glucose 6-(ethyl methyl phosphates) with retention of configuration at phosphorus. The stereochemical results for the ring-opening and migration reactions are fully consistent with the intermediacy of trigonal bipyramidal intermediates, which break down by apical departure of the leaving group before pseudorotation or after simple pseudorotational sequences. The configurations at phosphorus of the glucose 4(R)- and 4(S)-, and 6(R)- and 6(S)-(ethyl methyl phosphates) are established by independent synthetic sequences.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part V. Preparation and some reactions of tetrahydro-1,3,2-oxazaphosphorine-2-ones and -2-thiones

The configurations at phosphorus in pairs of tetrahydro-1,3,2-oxazaphosphorines, epimeric at phosphorus and prepared by treatment of methyl 6-deoxy-2,3-di-O-methyl-6-methylamino-α-D-glucopyranoside (1) with phosphonic dihalides, have been established by spectroscopic methods. Treatment of the glucopyranoside derivative (1) with phosphoric or phosphorothioic trichloride afforded 2-chlorotetrahydro-1,3,2-oxazaphosphorine derivatives which on treatment with sodium alkoxides (aryloxides) under mild conditions were converted, with inversion of configuration at phosphorus, into the corresponding 2-alkoxy-(aryloxy-) derivatives. All displacement reactions of the exocyclic substituent at phosphorus occurred with inversion of configuration. With sodium alkoxides under more vigorous conditions the tetrahydro-1,3,2-oxazaphosphorines underwent endocyclic P–N fission as well as P–O fission, both reactions occurring with inversion of configuration. Acid-catalysed endocyclic fission reactions also occurred with inversion of configuration at phosphorus. Methyl 2,3-di-O-methyl-α-D-glucopyranoside cyclic (R)-4(O),6(N)-NP-dimethylphosphonamidothioate was degraded to (R)-ethyl methylphosphonothioic acid by successive treatment with sodium ethoxide and dilute hydrochloric acid.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part IV. Ring-opening reactions of 1,3,2-dioxaphosphorinan-2-ones and related compounds with grignard reagents and with sodium methoxide

The 1,3,2-dioxaphosphorinan-2-one ring in methyl 2,3-di-O-methyl-α-D-glucopyranoside (R)- and (S)-4,6-alkyl-(or aryl-)phosphonates is opened by Grignard reagents by attack at phosphorus with inversion of configuration and with preponderant cleavage of the bond between phosphorus and O-6 of the glucopyranoside unit. By contrast, in the corresponding 1,3,2-dioxaphosphorinan-2-thiones the stereochemistry at phosphorus and the nature of the P-substituent determines whether the P–O(4) or the P–O(6) bond is cleaved preponderantly and whether the cleavage occurs with inversion or retention of configuration. Ring opening of the foregoing dioxaphosphorinans with sodium methoxide results first in the preponderant formation of glucopyranoside 4-[methyl alkyl-(or aryl-)phosphonates (phosphonothioates)]. Migration of the P-substituent from O-4 to O-6 then occurs. The stereochemistry of the ring-opening and migration reactions is discussed. The stereochemistry of the ring-opening reaction, with Grignard reagents, of the 1,3,2-oxathiaphosphorinan ring in methyl 2,3-O-methyl-6-thio-α-D-glucopyranoside (S)- and (R)-4,6-methylphosphonothioates and the corresponding ethyl phosphorothioates is also described. The 2-methyl-1,3,2-oxathiaphosphorinan-2-ones with sodium methoxide in methanol undergo P–O bond fission with inversion of configuration, in contrast to the corresponding 2-ethoxy-derivatives which undergo P–S cleavage with probable retention of configuration at phosphorus. On storage in methanol containing sodium methoxide methyl 2,3-di-O-methyl-6-thio-α-D-glucopyranoside 6-(methyl methylphosphonothioate) is converted with preponderant inversion of configuration into the corresponding 4-(methyl methylphosphonates).

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part I. Stereochemistry of 1,3,2-dioxaphosphorinan-2-ones and synthesis of optically active phosphine oxides

Pairs of 1,3,2-dioxaphosphorinan-2-ones, epimeric at phosphorus, have been prepared by treatment of methyl 2,3-di-O-methyl-α-D-glucopyranoside and -galactopyranoside with phosphonic or phosphoric dihalides. The configuration at phosphorus in these derivatives has been assigned on the basis of n.m.r. and i.r. data and of comparison of the rates of formation and relative stabilities of the epimers. For the formation of the 1,3,2-dioxaphosphorinan-2-ones it is suggested that the kinetic preference for the thermodynamically less stable isomers depends on steric interactions in twist-ring transition intermediates, and that the subsequent equilibration depends on the relative stabilities of the chair conformers. The conversions of methyl 2,3-di-O-methyl-α-D-glucopyranoside (R)- and (S)-4,6-methyl phosphonate into (S)- and (R)-ethylmethylphenylphosphine oxide, respectively, by sequential addition of phenylmagnesium bromide and ethylmagnesium bromide provide examples of the utility of carbohydrate 1,3,2-dioxaphosphorinan-2-ones for the stereospecific synthesis of optically active phosphine oxides.

Use of carbohydrate derivatives for studies of phosphorus stereochemistry. Part III. Stereochemical course of nucleophilic displacements of 2-substituents in 1,3,2-dioxaphosphorinan-2-ones and related compounds

The stereochemistry of displacement of 2-substituents from 1,3,2-dioxaphosphorinan-2-ones, 1,3,2-oxathiaphosphorinan-2-ones, and 1,3,2-dioxaphosphorinan-2-thiones has been shown to depend on the nature of both the entering and the leaving group. Inversion of configuration has been observed for reactions involving good leaving groups and weak nucleophiles whereas with less good leaving groups and stronger nucleophiles the displacement reactions proceed with retention of configuration.

Studies on Organic Fluorine Compounds. XI. Reaction of Arylfluorophosphoranes with Alcohols

Reaction of phenyltetrafluorophosphorane (III) with 1-pentanol (IV) or 2-pentanol (V) resulted in the formation of olefins and fluoroalkanes considered to have been formed via the olefins. This is in contrast with the fact that the reaction of difluorotriphenylphosphorane (I) and diphenyltrifluorophosphorane (II) with IV and/or V preferentially gives fluoroalkanes thought to have been formed by direct fluorination of the alcohols. The experimental results were investigated by the stereochemistry of phosphorus.

Crystal and molecular structure of cyclophosphamide hydrate

The X-ray structure of cyclophosphamide (1) shows that the chair-form ring possesses an equatorial dialkyl amino-group and an axial phosphoryl oxygen in contrast to the opposite phosphorus stereochemistry reported for structures of similar systems wherein a variety of other groups replace the dialkyl amino-ring substituent.