Chiral phosphate synthesis

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... 

The recent development in the stereochemical study of these reactions has already been covered by several reviews (16,17,101-108). The aim of this survey is to provide a general view of the synthesis and configurational analysis of chiral phosphates, and of the significance of stereochemical results in enzyme mechanisms. 

Description of the synthesis of phosphodiesters (prochiral phosphorus center) is beyond the scope of this chapter. Only the chemical synthesis of chiral phos-phomonoesters (4-6) and chiral inorganic phosphates (7) are discussed. The chiral phosphates or chiral phosphorothioates obtained from enzyme reactions are not described in this section. 

Simultaneously and independently, Cullis and Lowe developed a second general methodology for the synthesis of, 0, 0-labeled chiral phosphate monoesters (76, 77). This synthesis relies upon the synthesis of a cyclic hydrobenzoin triester of the alcohol or phosphoric acid followed by hydrogenolysis to liberate the isotopically labeled monoester product (Fig. 2). Hydrobenzoin, chiral by virtue of stereospecific labeling with 0 and 0, is the source of the two specified oxygen isotopes, and O is derived from H2 0 via P OCL. The reader is referred to the articles by Cullis and Lowe for details of the synthesis. 

Lowe, Cullis, and co-workers have described general methods for the synthesis of oxygen chiral phosphorothioate monoesters (see Figs. 3 and 4). The synthesis by Cullis is strictly analogous to the synthesis of chiral phosphate monoesters by Knowles except that (- )-ephedrine is thiophosphorylated with PSCI3... 

Phosphorus Compounds. - The synthesis of the chiral phosphate (494) has been described. The silyl ether ds-Me3SiOCMe=CMeOSiMe3 reacts with Me0P(0)p3 to yield the dioxaphospholen (495). Treatment of the tetramer (496) with boron trifluoride affords the di-co-ordinated phosphorus compound (497). The imines (499) are obtained when the 1,2,3-diaza-phospholine (498) is heated with aryl azides. The oxazaphospholine (500) decomposes to trimethyl phosphate and the nitrile ylide (CF3)2C-N=CPh. ... 

The ability to synthesise oligonucleotides containing modified phosphodiester linkages continues to be of great interest in the therapeutic area. In particular it is desirable to confer through these modifications enhanced cell permeability properties and nuclease resistance. Several previous candidates that confer these properties have modified the pho,sphodiester linkage in such a way that creates a chiral centre at phosphorus. The resultant complex mixture of diastereoisomers all meet the above requirements to different extents, Over the past year efforts have therefore concentrated on the synthesis of achiral alternative linkages or stereospecific syntheses of chiral phosphate modifications. A number of literature summaries in this area have appeared recently. 

Stereoisomerism and Connectivity 300 Total Synthesis of an Antibiotic with a Staggering Number of Stereocenters 303 The Descriptors for the Amino Acids Can Lead to Confusion 307 Chiral Shift Reagents 308 C2 Ligands in Asymmetric Synthesis 313 Enzymatic Reactions, Molecular Imprints, and Enantiotopic Discrimination 320 Biological Knots—DNA and Proteins 325 Polypropylene Structure and the Mass of the Universe 331 Controlling Polymer Tacticity—The Metallocenes 332 CD Used to Distinguish a-Helices from [3-Sheets 335 Creating Chiral Phosphates for Use as Mechanistic Probes 335... 

Inch and his co-workers continue to use carbohydrate derivatives in the synthesis of chiral esters of phosphorus acids and for studies of the displacement reactions of these esters. For example, the tetrahydro-l,3,2-oxazaphosphorine-2-ones (74) and (76) were synthesized and cleaved to give the chiral phosphonate (75) and the chiral phosphate (77), as illustrated in Schemes 35 and 36. 2-Thiones related to (74) and (76) were also prepared and used to obtain such chiral thiophosphates as (78) from (79). Attack on the acyclic S -methyl phos-... 

Chiral anion phase-transfer catalysis has been extended to the asymmetric synthesis of allylic fluorides (Scheme 7.10) [20]. The key with this chemistry was judicious selection of the electrophilic fluorine source. Selectfluor displays poor solubility in nonpolar solvents such as cyclohexane however, combining this F source with a chiral phosphate salt generated afforded a soluble ion pair that promoted the chemistry. A wide range of... 

The first account of the synthesis of an oxygen chiral phosphate monoester was reported in 1978 by Knowles and co-workers (Abbott et ai, 1978, 1979). This ester, a diastereomer of l-phospho-(5)-1,2-propanediol, was selected as the synthetic target because the general method of configurational analysis that Knowles devised for monoesters was based on the ability to assign the configuration of the diastereomers at phosphorus of this particular phosphate monoester. The chemical steps in this synthesis are shown in Fig. 1. Briefly, [ OJPOCls, prepared in hi yield from and... 

Methods have been developed for the synthesis of essentially any oxygen chiral phosphate ester of biological importance, and the P-NMR methods described and illustrated in this chapter provide a convenient method for determining their configurations and elucidating the stereochemical consequences of enzyme-catalyzed phosphoryl and nucleotidyl transfer reactions. 

Much effort has been placed in the synthesis of compounds possessing a chiral center at the phosphoms atom, particularly three- and four-coordinate compounds such as tertiary phosphines, phosphine oxides, phosphonates, phosphinates, and phosphate esters (11). Some enantiomers are known to exhibit a variety of biological activities and are therefore of interest Oas agricultural chemicals, pharmaceuticals (qv), etc. Homochiral bisphosphines are commonly used in catalytic asymmetric syntheses providing good enantioselectivities (see also Nucleic acids). Excellent reviews of low coordinate (coordination numbers 1 and 2) phosphoms compounds are available (12). 

Inspired by the separation ability of cyclic selectors such as cyclodextrins and crown ethers, Malouk s group studied the synthesis of chiral cyclophanes and their intercalation by cation exchange into a lamellar solid acid, a-zirconium phosphate aiming at the preparation of separation media based on solid inorganic-organic conjugates for simple single-plate batch enantioseparations [77-80]. 

Most of the phosphorus compounds described in the previous sections are chiral and racemic. Attempting their resolution - that is a physical separation of the enantiomers - was obviously attractive and this was realized as early as 1965 by Hellwinkel, who obtained both optical antipodes of 2 [18]. A patent on the synthesis and possible applications of enantiopure phosphate 2 was even filed at the time [103]. 

Mikami and Yoshida extended the scope of this method considerably by using propargyl phosphates and chiral proton sources [94], The propargylic phosphates thereby have been found to be advantageous owing to their high reactivity towards palladium and the extremely low nudeophilicity of the phosphate group [95]. In some cases, it was even possible to obtain allenes from primary substrates, e.g. ester 194 (Scheme 2.60) [96]. A notable application of this transformation is the synthesis of the allenic isocarbacydin derivative 197 from its precursor 196 [97]. 

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