Catalytic phosphate protecting

The use of nucleophilic catalysis to accelerate condensation reactions has been extended further by the introduction of catalytic phosphate-protecting groups. Here further rate enhancements are achieved as a result of nucleophilic catalysis because of the neighboring group effect. 

Fig. 3. Monomer building block bearing the catalytic phosphate-protecting group, 2-(l-methylimidazol-2-yl)phenyl.

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

Schistosoma japonicum. The carbobenzoxy (CBz) protected template 160 was initially converted to the a, p-dehydrolactone 161 via the phosphate ester, before undergoing cycloaddition to ylide 162, generated in situ by acidic treatment of A(-benzyl-A(-(methoxymethyl)trimethylsilyl amine. The resultant cycloadduct (163) was isolated in 94% yield as a single diastereoisomer. Destructive template removal, by catalytic hydrogenation, released (5)-( )-cucurbitine, after ion-exchange chromatography, as the free amino acid in 90% yield (Scheme 3.46). 

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. 

In addition to the above reagents, which modify specific tyrosine residues in the protein, desensitization has been reported with pyridoxal phosphate, which forms a Schiff base derivative with lysyl residues (43). This reagent was first reported by Marcus and Hubert (43) to react with FDPase from swine kidney and to abolish AMP sensitivity with very little loss of catalytic activity. With liver FDPase most of the sensitivity to AMP is lost when 7-8 residues are incorporated, with concomitant loss of about 25% of the enzymic activity (43). The effects become irreversible when the Schiff base derivative is reduced with NaBH4 and Are-pyridoxyllysine has been isolated from the reduced complex. In the presence of AMP the sensitive lysine residues are protected, but the amount of PLP incorporated is increased (43). 

Harn, D.A., Cu, W., Oligino, L.D., Mitsuyama, M., Gebremichael, A. and Richter, D. (1992) A protective monoclonal antibody specifically recognizes and alters the catalytic activity of schistosome triose-phosphate isomerase. The Journal of Immunology 148, 562-567. 

Immobilized TEMPO has been used for the one-pot oxidation of alcohols to carboxylic acids as well.26 For this purpose TEMPO resin 1 was combined with two ion-exchange resins loaded with chlorite anions and hydrogen phosphate in the presence of catalytic amounts of potassium bromide and sodium hypochlorite in solution. The reaction required work-up for the removal of salts, but tolerated several protecting schemes and afforded pure products in good to excellent yields. The reaction is initiated by catalytic TEMPO oxidation of alcohols to aldehydes driven by dissolved hypochlorite followed by oxidation to the carboxylic acids effected by chlorite. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

The specific inhibition of D-fructose 1,6-diphosphatase by AMP decreases if the pH of the solution moves399 to above 9. Inhibition by AMP and catalytic activity can be lost by acetylation of the tyrosine residues with 1-acetylimidazole. The presence of substrate or allosteric effectors protects the tyrosine from acetylation.400 Pyridoxal phosphate can also desensitize the enzyme by forming a Schiff base with L-lysinyl residues401 this indicates some participation of L-lysinyl residues in allosteric regulation.401,402... 

Scheme 6 illustrates the use of these protecting groups in the phosphorylation of 2 -deoxynucleosides by Michelson and Todd. 5 -0-Trityl-thymidine (110) was phosphorylated with dibenzyl phosphorochloridate (44) to (111), which, after treatment with 80% acetic acid, afforded thymidine 3-(benzyl phosphate) (112). Catalytic hydrogenolysis of (112) gave thymidine 3 -phosphate. Acetylation of (110) yielded the 3 -acetate (114) which, on detritylation to (115), followed by phosphorylation, catalytic reduction, and deacetylation, gave thymidine 5 -phosphate (116), identical with the thymidylic acid obtained by enzymic hydrolysis of 2 -deoxyribonueleic acid. A rather similar sequence was applied to the preparation of the 2 -deoxycytidine analogs of (113) and (116). 

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