Phosphates prochiral

The antiviral agent virantmycin is an unusual chlorinated tetrahydroquinoline isolated from a strain of Streptomyces (Figure 6.10). Hydrolysis of a prochiral 2,2-disubstituted dimethyl malonate with PLE in DMSO-pH 8 phosphate buffer (1 4) was a key step in a stereodivergent synthesis of this natural product [57]. 

The asymmetric reduction of prochiral functional groups is an extremely useful transformation in organic synthesis. There is an important difference between isolated enzyme-catalyzed reduction reactions and whole cell-catalyzed transformations in terms of the recycling of the essential nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] cofactor. For isolated enzyme-catalyzed reductions, a cofactor recycling system must be introduced to allow the addition of only a catalytic amount (5% mol) of NAD(P)H. For whole cell-catalyzed reductions, cofactor recycling is automatically achieved by the cell, and the addition of a cofactor to the reaction system is normally not required. 

In this numbering system derivatives of the parent prochiral compound are given the prefix sn-. Thus, glycerol phosphate, used by cells to construct phospholipids, usually bears a phosphate group on the -CH2OH in the pro-R position of glycerol and is therefore su-3-glycerol phosphate. 

A phosphate diester of the form R0P020R is prochiral, since one of the non-alkylated oxygen (160) atoms must be replaced to produce chirality. A monoester... 

Pro-prochiral substrate giving pro-pro-prochiral product (i.e., monoester — phosphate). 

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... 

Enantioselective enzymatic ester hydrolyses of prochiral trimethylsilyl-substituted diesters of the malonate type have been applied for the synthesis of the related optically active monoesters68. As an example of this particular type of biotransformation, the enantioselective conversion of the diester 82 is illustrated in Scheme 17. Hydrolysis of compound 82 in phosphate buffer, catalyzed by porcine liver esterase (PLE E.C. 3.1.1.1) or horse liver acetonic powder (HLAP), gave the optically active monoester 83 (absolute configuration not reported) in 86% and 49% yield, respectively. The enantiomeric purities... 

The first enzymatic desymmetrizations of prochiral phosphine oxides was recently reported by Kielbasinski et al.88 Thus, the prochiral bis(methoxycarbonylmethyl)-phenylphosphine oxide 93 was subjected to the PLE-mediated hydrolysis in buffer affording the chiral monoacetate (RJ-94 in 72% ee and 92% chemical yield. In turn, the prochiral bis(hydroxymethyl)phenylphosphine oxide 95 was desymmetrized using either lipase-catalyzed acetylation of 95 with vinyl acetate as acyl donor in organic solvent or hydrolysis of 97 in phosphate buffer and solvent affording the chiral monoacetate 96 with up to 79% ee and 76% chemical yield. 

Stereochemical studies of phosphates are in some respects similar or analogous to studies of saturated carbon, insofar as both are tetrahedral centers and may be achiral, prochiral, or chiral depending upon the identities of the substituent groups. Important differences include a degree of variance in the mechanisms of substitution and their stereochemical consequences as well as many of the methods by which chiral centers are synthesized and analyzed for configuration. 

ATPases. A few pyrophosphotransferases catalyze substitution at Pg. P0 and Pg are prochiral centers and can be made chiral by stereospecific replacement of one or the other diastereotopic oxygen with sulfur or enrichment with lsO or nO. Py is an achiral center which can be made chiral either by replacement of one of the three equivalent oxygens with sulfur and stereospecific enrichment of another with 180 to give a chiral [180]phosphorothioate, or by stereospecific enrichment of one with nO and another with lsO to give a chiral [160, nO, lsO]phosphate. 

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. 

The CHF and CF2 groups are superior to CH2 as isosteres of oxygen and this has led to extensive interest in their chemistry. The a-difluorophosphonate analogues of the phosphates of L-serine (219), L-threonine (220), and L-allothreonine (221) have been prepared by highly enantioselective reactions of difluoromethylpho-sphonate carbanion with chiral esters. Lipase PS catalysed acetylation of prochiral 1,3-propandiol alkylphosphonates 222 is reported to be highly enantioselective and the resulting monoacetate enantiomers 223 have been used to synthesise a series of (o-phosphono-a-amino acids, 224 and 225.Other routes to 225, one of... 

Figure 5.60 Positional isotope exchange. The non-bridge oxygens of a phosphate are prochiral (enantiotopic if X and R are achiral, diastereotopic if they are not).The occurrence of positional exchange can be readily followed by NMR, with the P signals increasing in shielding in the order and the isotope shift increasing with bond order.

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