Phosphorylation alcohols

Of the two major phosphohpid classes present in membranes, phosphoglycerides are the more common and consist of a glycerol backbone to which are attached two fatty acids in ester linkage and a phosphorylated alcohol (Figure 41-2). The fatty acid constiments are usually even-numbered carbon molecules, most commonly containing 16 or 18 carbons. They are unbranched and can be saturated or unsamrated. The simplest phosphoglyceride is phosphatidic acid, which is... 

Figure 41-2. A phosphoglyceride showing the fatty acids (R, and Rj), glycerol, and phosphorylated alcohol components. In phosphatidicacid, Rjis hydrogen.

The phosphorylation of alcohols by CEP-imidazole (41 X=N) with CEP-ring retention is already well-established. Following from the observation that CEP-pyrrole (41 X=CH) phosphorylates alcohols with CEP-ring opening, an explanation has been advanced based upon the differences in apicophilicities of the pyrrole and imidazole moieties in pentaco-ordinate intermediates (Scheme 10). A scale of relative reactivities based upon the reactions in the equations... 

Certain classes of lipids are susceptible to degradation under specific conditions. For example, all ester-linked fatty acids in triacylglycerols, phospholipids, and sterol esters are released by mild acid or alkaline treatment, and somewhat harsher hydrolysis conditions release amide-bound fatty acids from sphingolipids. Enzymes that specifically hydrolyze certain lipids are also useful in the determination of lipid structure. Phospholipases A, C, and D (Fig. 10-15) each split particular bonds in phospholipids and yield products with characteristic solubilities and chromatographic behaviors. Phospholipase C, for example, releases a water-soluble phosphoryl alcohol (such as phosphocholine from phosphatidylcholine) and a chloroform-soluble diacylglycerol, each of which can be characterized separately to determine the structure of the intact phospholipid. The combination of specific hydrolysis with characterization of the products by thin-layer, gas-liquid, or high-performance liquid chromatography often allows determination of a lipid structure. 

Single alkene diastereomers are accessible through a Wittig-Homer reaction only if it is performed in two steps (Figure 11.10). A 1 1 mixture of the phosphorylated lithium alkoxides syn- and anti-D is still formed but if the mixture is protonated at this point, the resulting phosphorylated alcohol diastereomers C can usually be separated without difficulty. The suitable diastereomer will be deprotonated with potassium-ferf-butoxide in the second step and then be converted into the stereouniform trans- or cis-alkene E via stereospecific oxaphosphetane formation and fragmentation. 

Phospholipid A lipid in which one of the hydroxyl groups of glycerol or sphingosine is esterified with a phosphorylated alcohol. 

Debenzylation of the benzyl esters of phosphoric acid has been employed in the synthesis of phosphorylated alcohols. Examples are shown in eqs. 13.2348 and 13.24.49 Tener and Khorana synthesized a-D-ribofuranose 1,5-diphosphate (36) by hydrogenolysis of the benzyl phenyl phosphate 35, first, in the presence of 5% Pd-C, and then in the presence of Adams platinum to remove, respectively, the benzyl and the phenyl groups (eq. 13.25).50... 

Phospholipids are amphipathic molecules, that is, they have parts of different polarity. The fatty acyl chains are nonpolar and hydrophobic whereas the phosphoryl alcohol head group is polar and can be solvated by H20. Phospholipids form bimolecular membranes in which the hydrophobic fatty acyl chains are located in the interior of the membrane (away from H20) and the head groups are on the surface (on either side of the membrane) and exposed to H20. Representing phospholipids as =0 (where = represents the fatty acyl chain and O the head group), we can represent such a phospholipid bilayer thus ... 

OUgo)phosphoric acid esters, e.g., phosphorylated alcohols, sugars... 

The platform on which phospholipids are built may be glycerol, a 3- carbon alcohol, or sphingosine, a more complex alcohol. Phospholipids derived from glycerol are called phosphoglycerides. A phosphoglyceride consists of a glycerol backbone to which two fatty acid chains (whose characteristics were described in Section 12.2.2) and a phosphorylated alcohol are attached. 

LTBA can also cleave selectively the P—C bond of acyl phosphonates 2.58, while preserving other functional groups [DSl] (Figure 2.28). Nevertheless, the reduction of similar compounds such as 2.59 by NaBH4 in EtOH buffered by boric acid does preserve the P—C bond and leads to diastereomeric a-phosphorylated alcohols [BS5, DSl] (Figure 2.28). After enolization by NaH, the P—C bond cleavage of acylphosphonates (Et0)2P(0)CH2C0R can be realized with LAH [HS7]. 

Phosphorylation. Alcohols are phosphorylated by phosphoric acid on heating with Re03(OH) and BU2NH in NMP. 

In a typical glycerophosphoUpid, the sn-1 and sn-2 positions are esterified (or sometimes ether-linked) with fatty acyl groups. The snS position is linked through an ester bond to a phosphate or a phosphorylated alcohol. If it is a phosphate, the molecule is known as a phos-phatidic add (or phosphatidate). 

Phosphorylation procedures using activated phosphate esters continue to be developed and esters of the type (3) may be conveniently prepared from monoalkyl phosphates and imidazole (or 2-hydroxypyridine) using bis-(2-pyridyl) disulphide and triphenylphosphine. -Nitrophenyl phosphate (4) and its symmetrical pyrophosphate (5) have been found to phosphorylate alcohols in the presence of pyridine and it is probable that... 

Similarly, the phosphorylated alcohols (440 R = H or CH2OAC) react with 1 -hydroxyuracil or 1 -hydroxythymidine in the pre,sence of Ph P/diethyl azodicarboxylate... 

To conclude this review we will breifly mention the conformation of (Lys)jj in lipid solutions. These lipids are associated with membranes and lipoproteins. We will illustrate the effect of two phosphoglycerides, which consist of a glycerol backbone, two fatty acid chains and a phosphorylated alcohol (Figure 10). These lipids are insoluble in water but... 

Phosphorylation. Alcohols may be phosphorylated in good yield by the reaction of phosphorous acid, mercury(II) chloride and A-methylimidazole (eq 1). An intermediate salt 1 is formed. This method has been used to prepare nucleoside 5 -phosphates in yields of 60-70%. Similarly, amines may be phosphorylated by reaction with phosphorus oxychloride andiV-methylimidazole (eq 2). ... 

Phosphorylation is a process involved in many cellular pathways such as activation or deactivation of enzymes. An extensive study of enantioselective phosphorylation reactions was reported by Miller and coworkers using several 7i-(Me)-histidine containing peptides. The proposed catalytic cycle involves the generation of an high energy phospho-imidazoUum ion and its reaction with the alcohol substrate in a site-specific manner. Following this mechanism, regio- and enantiopure phosphorylated alcohols can be prepared (Scheme 5.8). 

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]. 

Alternatively, the phosphorylated alcohol, Rf(CH2) 0P(0)Cl2, was treated with choline tosylate in pyridine. Subsequent hydrolysis gave the same perfluo-roalkylated phosphotidylcholine ... 

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