Phosphorus stereochemistry

With regard to the phosphorus stereochemistry, a new stereospecific synthesis of chiral 0,0-dialkyl thiophosphoric acids (6,7) has been developed which is based on the Horner-Wittig reaction of the optically active phosphonothionate carbanions containing the sulfoxide or dithioacetal moieties. The transformation of (R)-(+) 0-methyl 0-isopropyl methanephosphonothionate (10)(8) into (R)-(-) 0-isopropyl phosphorothioic acid (H) best Illustrates this method. 

These results and of course some of the Grignard results where retention mechanisms in phosphonates are preponderant show that caution must be taken when even a foundation stone of modern phosphorus stereochemistry is being considered. 

Such reactions are of importance in phosphorus stereochemistry since they provide excellent access to this class of compounds. Their course is strongly dependent on reaction conditions, and inversion, retention and racemization have been observed. 

Organo-Phosphorus Stereochemistry, Part 2, P(V) Compounds. Edit. W. E, McEwen, K. Darrell Berlin, Hutchinson and Ross, Inc., Stroudsburg, Pennsylvania,... 

II. The Pentavalent State in Phosphorus Stereochemistry A. General Considerations... 

The approach to phosphorus stereochemistry developed in this review rests on the experimental and the theoretical efforts of our collaborators, notably, S. Pfohl, E. A. Tsolis, J. F. Pilot, C. P. Smith and 0. P. Madan (F.R.) and P. Gillespie, P. Hoffmann, H. Klusacek and D. Marquarding (I.U.). One of us (F.R.) acknowledges the extended support of the Research whose outcome is presented here by the Cancer Institute of the National Institutes of Health, U.S.A., in the form of Grant CA-04769, and the National Science Foundation, U.S.A., in the form of Grant GP-6690. 

The barrier to inversion about phosphorus in phosphites is large enough for tricovalent phosphites chiral at phosphorus to be configurationally stable, but the conditions for the coupling of phosphoramidites epimerised them at P about 10 times faster than it coupled them, although the oxidation of phosphites to phosphates and thiophosphates proceeded with complete retention of phosphorus stereochemistry. ... 

The 180 isotope shift and the 170 quadrupolar effect in 31P NMR and their application in phosphorus stereochemistry have been reviewed recently by Cohn (106) and Tsai (105, 127). Figure 1 shows the 31P NMR spectrum of H3Pl704 (40 atom %170). The spectrum consists of a broad signal due to the 31P—170 species and a sharp signal due to the residual non-170-labeled species. Since the 170-enriched water always contains some 180 (180/170 = 0.67 in this case), the sharp signal contains both 160 and 180 species, as shown by the expanded... 

The substrate for the carboxylation is HCO3" rather than CO2 (4, 36). When the carboxylation is conducted with HC Os , the Pj produced contains a single atom of 0 (4, 37), apparently because the reaction occurs by way of a carboxy phosphate intermediate (Scheme IV). Carboxy phosphate is a known compound, but it is unstable, hydrolyzing in aqueous solution within a few seconds (58). Presumably at the active site of the enzyme, carboxy phosphate is protected from hydrolysis. Studies of phosphorus stereochemistry (39) and carbon, hydrogen, and oxygen isotope effects (40, 41) are consistent with this mechanism. Isotope effect studies indicate that the phosphate transfer step is rate determining (40). 

The intermediacy of the betaines used in the mechanistic discussions of the Wittig reaction has been questioned and Vedejs has proposed an alternative explanation. The Wittig reaction is subject to solvent effects that indicate a nonpolar transition state for stabilized ylids.There appears to be no direct evidence for the presence of betaines, and none have been isolated. Alternatively, Vedejs and Snoble detected oxaphosphetanes as the only observable intermediates in several Wittig reactions of nonstabilized ylids, using 3Ip NMR. In more recent work, Vedejs devised a test for the betaine mechanism based on changes in phosphorus stereochemistry in the proposed intermediates (betaine vs. oxaphosphetane). The results of this test suggested that "the conventional betaine mechanism l can play at most a minor role in the Wittig reaction".Vedejs points out that the "stereochemical test does not necessarily disprove mechanisms via intermediates with lifetimes that are short compared to the time scale of bond rotation. "494... 

In their review of phosphorus stereochemistry. Hall and Inch (1980b) have catalogued many nucleophilic substitution reactions at phosphorus whose product distribution and overall stereochemistry are dependent not only on solvent but also on other reaction conditions, in particular the presence of metal ions. They further conclude that mixed reaction pathways may be followed, with the possibility that initial attack of nucleophile may be directed apical to more than one specific ligand. This situation is easy to rationalize in five-membered rings with endocyclic N, O and S ligands, in which there is a fine balance between apical potentialities. 

As described above for diesters, it can be argued that, from a conceptual standpoint, the simplest phosphordiamidates are those where symmetry avoids the issues inherent to introduction of phosphorus stereochemistry. Recently, McGuigan and colleagues have claimed just such advantages for a diamidate strategy [119,... 

In the last section several oxazaphospholidine oxides, obtained by oxidation of the P(III) precursor with t-BuOOH, have already been described. There is also one report by Juge and co-workers in which they prepare oxazaphospholidine oxides and sulfides by in situ deboronation/oxidation of oxazaphospholidine boranes. This section illustrates some more derivatives, prepared directly from P(V) species and ephedrine. Chronologically, these types of compounds were studied earlier than the corresponding P(III) counterparts. Nowadays oxazaphospholidine boranes, not oxides, are the most important precursors used to prepare enantiopure phosphorus ligands. However, apart from historic interest, ephedrine-derived oxazaphospholidine oxides, sulfides and selenides occupy an important place in the study of phosphorus stereochemistry and conformational analysis. Only a few examples are described here. 

As shown in Scheme 5-13, Eq. (1), addition of racemic secondary phosphines to acrylonitrile gave tertiary phosphines with control of phosphorus stereochemistry. 

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