Asymmetric Phosphorylations

Miller and co-workers have exploited the highly modular nature of peptide structures, along with mechanistic knowledge regarding peptide conformational control and the principles of nucleophilic catalysis to develop an assortment of synthetically unique, useful, and practical asymmetric transformations [22]. Representative examples are illustrated in Scheme 7. Particularly noteworthy is the asymmetric phosphorylation the resultant phosphate ester can be readily... 

Pizzarello S, Weber AL (2010) Stereoselective syntheses of pentose sugars under realistic prebiotic conditions. Orig Life Evol Biosph 40 3-10 Powner MW, Garland B, Sutherland JD (2009) Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Nature 459 239-242 Scumlimbrene BR, Miller SJ (2001) Discovery of a catalytic asymmetric phosphorylation through selection of a minimal kinase mimic a concise total synthesis of D-myo-inositol-phosphate. J Am Chem Soc 123 10125-10126... 

We were drawn to the catalytic, asymmetric phosphorylation of inositol for several reasons [20-22]. First, wyo-inositol possesses six hydroxyl groups, any one of which could potentially be phosphorylated by a chiral catalyst. Second, the diverse phosphorylation patterns of inositol phosphates correspond to equally diverse biological functions [23] excellent strategies for their synthesis existed. 

Sculimbrene BR, Miller SJ (2001) Discovery of a catalytic asymmetric phosphorylation through selection of a minimal kinase mimic a concise total synthesis of D-myo-inositol-l-phosphate. J Am Chem Soc 123 10125-10126... 

Sculimbrene BR, Morgan AJ, Miller SJ (2002) Enantiodivergence in small-molecule catalysis of asymmetric phosphorylation concise total syntheses of the enantiomeric H-myo-inositol-1-phosphate and D-myo-inositol-3-phosphate. J Am Chem Soc 124 11653-11656... 

Sculimbrene BR, Xu Y, Miller SJ (2004) Asymmetric syntheses of phosphatidylinositol-3-phosphates with saturated and unsaturated side chains through catalytic asymmetric phosphorylation. J Am Chem Soc 126 13182-13183... 

Jordan PA, Kayser-Bricker KJ, Miller SJ (2010) Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer enantioselective synthesis of D-myo-inositol-6-phosphate. Proc Natl Acad Sci USA 107 20620-20624... 

Sculimbrene BR (2004). Catalytic asymmetric phosphorylation. Ph.D. thesis. Boston College, Boston... 

Scheme 5.8 Catalytic cycle for peptide-catalyzed asymmetric phosphorylation.

By comparison with alcohol asymmetric acylation (i.e., esterification) as discussed above, alcohol asymmetric phosphorylation has not attracted so much attention from the synthetic community thus far. This is rather curious given the pivotal importance of phosphorylated alcohols in biological systems where three of the most important and weU-studied signal transduction pathways, the mitogen-activated protein kinase pathway (MAPK), adenylyl cyclase dependent pathway (cAMP), and inositol triphosphate/diacylglycerol pathway (IP3/DAG), all rely critically on chemo- and/or stereoselective alcohol phosphorylation/dephosphorylation by kinase/phosphatase enzymes, respectively [76]. 

The Miller group was the first to report catalytic asymmetric phosphorylation of alcohols, in 2001 [81]. They reported that D-myo-inositol-l-phosphate 82 could be prepared with high levels of enantiomeric purity by the ASD of 2,4,6-tribenzyl-myo-inositol (81) using diphenyl(chloro)phosphate and triethylamine in toluene at 0°C catalyzed by 2mol% of pentapeptide 79, which contains an N-terminal TT-methyl histidine residue as the nucleophile (Scheme 41.29). 

Sum V, Davies AJ, Kee TP (1992) New, chiral silylated organophosphorus(III) reagents syntheses and applications in the asymmetric phosphorylation of aldehydes. J Chem Soc, Chem Commun 1771-1773... 

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