Phosphates, chiral

Fig. 20 Diastereomeric purity and relative configuration of enantiopure chiral phosphate anions 15 to 18 isolated after initial precipitation...

Axially chiral phosphoric acid 3 was chosen as a potential catalyst due to its unique characteristics (Fig. 2). (1) The phosphorus atom and its optically active ligand form a seven-membered ring which prevents free rotation around the P-0 bond and therefore fixes the conformation of Brpnsted acid 3. This structural feature cannot be found in analogous carboxylic or sulfonic acids. (2) Phosphate 3 with the appropriate acid ity should activate potential substrates via protonation and hence increase their electrophilicity. Subsequent attack of a nucleophile and related processes could result in the formation of enantioenriched products via steren-chemical communication between the cationic protonated substrate and the chiral phosphate anion. (3) Since the phosphoryl oxygen atom of Brpnsted acid 3 provides an additional Lewis basic site, chiral BINOL phosphate 3 might act as bifunctional catalyst. 

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

Conversely, Charette and coworkers have shown that the chiral phosphate 23 could be used in catalytic amounts for the cyclopropanation of protected allylic alcohols (equation 97) . This was made possible by using DME as the additive to slow down the background cyclopropanation process, leading to racemic cyclopropane (Pathway A). Bis(iodomethyl)zinc was used as the stoichiometric reagent to regenerate the reactive iodomethylzinc phosphate (Pathway B). Excellent enantioselectivities were observed using this protocol however, the scope of the reaction is still quite limited. 

Evidence for an in-line SN2-like mechanism of most enzymatic phospho group transfer reactions comes largely from study of chiral phospho groups.663/692-695 A chiral phosphate can be introduced at either the a or (3 phosphorus of ATP by substitution of one of the oxygen atoms by sulfur. A chiral phospho group in the P position can be formed by substituting one oxygen by S and a second by lsO. 

R0P032 is pra-prochiral, since two oxygen atoms must be substituted to produce a chiral compound. Chiral phosphates have been synthesized de novo by using stereospecific chemical and enzymatic reactions with isotopic and/or atomic substitutions. For example, a chiral phosphorothioate may be synthesized from a prochiral phosphate by replacing an oxygen atom with a sulfur atom. Similarly, what would otherwise be a pro-prochiral phosphate has been synthesized as a chiral product by replacing one oxygen atom with sulfur and another... 

A new catalyst salt (20) that consists of an achiral ammonium ion and a chiral phosphate anion and which catalyses highly enantioselective transfer hydrogenations of ,/J-unsaturated aldehydes to the corresponding saturated derivatives has been developed. The underlying principle, namely asymmetric counteranion-directed catalysis, is claimed to be a new strategy for highly enantioselective synthesis.357... 

One other element which is conveniently available in three isotopic forms is oxygen. These isotopes have been used44 to synthesize 163,164) chiral phosphates of the type... 

The first chiral phosphates to be used for stereochemical analyses were chiral phosphorothioates, which were used to determine the stereochemical courses of ribonuclease, UDP-glucose pyrophosphorylase, adenylate kinase and several other kinases and synthetases. The chiral phosphorothioates either had sulfur in place of an oxygen at an otherwise prochiral center of a phosphodiester or phosphoanhydride or stereospecifically placed sulfur and 180 (or nO) in a terminal phosphoryl group. The syntheses and configurational analyses of the most important of these compounds are outlined in the following. 

Despite the broad utility of chiral phosphorothioates, certain enzymes, such as alkaline phosphatase and phosphoglycerate mutase, do not accept phosphorothioates as substrates. Stereochemical studies of these enzymes awaited the development of methods to synthesize and assign configurations to chiral phosphates. Chiral [l60, l70,180]phosphomonoesters and [l8OJphosphodiesters have been elegantly... 

Hydrogenation of Ketimines Chiral Phosphates Are Efficient Metal-Free Catalysts.213... 

A -oxides) In sulfones, the sulfur bonds with a tetrahedral array, but since two of the groups are always oxygen, no chirality normally results. However, the preparation of an optically active sulfone (2) in which one oxygen is and the other illustrates the point that slight differences in groups are all that is necessary. This has been taken even further with the preparation of the ester 3, both enantiomers of which have been prepared. Optically active chiral phosphates 4 have similarly been made. ... 

Finally, the bacterial PTE mentioned above has also been exhaustively studied with regard to its enantioselectivity. Initial studies used the known crystal structure of PTE to identify the substrate-binding pocket. This was then rationally evolved for enhancement and relaxation of the stereospecificity.97 Most recently, a combinatorial library has been screened for the resolution of chiral phosphate, phosphonate, and phosphinate esters.124 This work identified two variants with markedly different preferences for 5p- and Rp-enantiomers of 4-acetylphenyl methyl phenyl phosphate. One variant preferentially catalyzed hydrolysis of the 5p-enantiomer by a factor of 3.7 x 105, while the other preferentially catalyzed hydrolysis of the A p-enantiomer by a factor of 9.7 x 102 - an enantioselective discrimination of 3.6 x 108. 

Most chiral phosphates are prepared in the presence of organic amines or metal complexes with or without chiral features. By using chiral metal complexes as the SDAs, low-dimensional structures or interrupted open-framework structures tend to... 

In 2009, Xiao employed a half sandwich Cp lr(l 11) complex with different chiral monosulfonated OPEN ligands (Figure 7.2), earlier developed for imine reduction by the same group, in combination with a BINOL based chiral phosphate counteranion (TRIP anion), to reductively aminate 24 acetophenone derivatives (1.2 equiv) with p anisidine (limiting reagent) under the conditions of 1.0 mol% of the indicated Ir catalyst (Table 7.1), 5 bar (73 psi) H2, toluene, 35 °C, and 15 24h [14]. 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

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