Mono esters, from diesters

Kumler, W. D., Eiler, J. J. The Acid Strength of Mono and Diesters of Phosphoric Acid. The n-Alkyl Esters from Methyl to Butyl, the Esters of Biological Importance, and the Natural Guanine Phosphoric Acids. J. Am. Chem. Soc. 1943, 65, 2355-2361. 

Another group of meso diesters are the acyclic compounds 30 and 31. Pig liver esterase is good at forming the mono-ester 33 and this compound can be transformed by selective reduction into either 32 or 34. These lactones are enantiomers so that either series may be entered from the same meso starting material.12 In addition the precarious chirality of 33 is more secure in the lactones. 

Many developments have come from Corey s laboratories in the lactacystin area since the synthesis described above.24 One strategy we have not mentioned before is the use of an enzyme, pig liver esterase (chapter 29) in the selective hydrolysis of one of two enantiotopic ester groups in the malonate 161. An MeS group is used to block enolisation and prevent racemisation of the product 162. The mono ester 162 is initially formed in 67% ee improved by one crystallisation of the quinine salt to 95% ee. The pyrrolidine ring 164 is made in an unusual way by first forming the amide 163 and then cyclising the diester by carbonyl condensation. The new chiral centre in 164 is not controlled but disappears in the next step. 

The presence of the mono-salt function makes the mono-esters much more soluble in solvents such as Polysol, DMSO-dg and D20 than the corresponding diesters. The rather wide divergence in chemical shift noted for the compounds examined in Polysol solution most probably arises from the varying amounts of H20 which are often present in such solutions. Based upon the information supplied in the table above, it can be inferred that the chemical shifts of the sulfuric acid ester/salts appear at highest field in relatively dry Polysol solution shifting to lower field as the amount of H20 increases and finally reach maximum deshielding when the solvent is 100% H20 (D20). 

We have seen the formation of sulfonate esters from sulfinic acids. Sulfuric acid (A) can form esters as well—either the monoesters (B) or the diester (C), which is known as a dialkyl sulfate. Esters of phosphoric acid (D) play a prominent role in biology. The phosphate linkages in nucleotides (see Chapter 28, Section 28.5) are important. Using D as a template, draw the mono- and diesters of phosphoric acid using cyclopentanol as the alcohol component. Take each of the phosphate esters you have drawn and draw the product you will obtain when they are treated with a base such as sodium hydride (NaH). 

Long chain alkyl esters of ferulic acid are common constituents in the family. From the seeds of Hyoscyamus niger even a diester, 1,24-tetracosanediol diferulate could be isolated (Ma et al. 2002). Solanum tuberosum started to accumulate long chain alkyl (mono)esters three to seven days after wound treatment. The alcohol components ranged from hexadecyl (Cj Hjj) to octacosyl (C gHj,) all even numbers plus two esters of odd chain length alkanols [nonadecyl (Cj Hj ), heneicosyl (C jH j)]. The major metabolites were represented by hexadecyl and octadecyl ferulates. The authors suppose that the formation of all these ferulates is temporally and spatially correlated with suberin formation since they were restricted to the wound periderm (Bernards and Lewis 1992). For a coherent account of suberin chemistry interested readers are directed to a review on the macromolecular aromatic domain in suberized tissues (Bernards and Lewis 1998). 

These alkylation procedures can benefit greatly from the use of microwave activation, which can reduce reaction times by a factor of 60. Moreover, the often tedious separation of high boiling solvents (DMF, DMSO, HMPA) can be omitted, if reactions are conducted under solvent-free conditions in the presence of ferf-BuOK as a base and a phase transfer catalyst such as Aliquat 336. Chemical yields are comparable to those obtained using classical procedures and only traces of dialkylated byproducts have been detected. Moreover, microwave treatment of the diester product with LLF or LiCl (Krapcho procedure) under solvent-free conditions provides the corresponding mono-ester by selective decarbalkoxylation . 

Keto esters are obtained by the carbonylation of alkadienes via insertion of the aikene into an acylpalladium intermediate. The five-membered ring keto ester 22 is formed from l,5-hexadiene[24]. Carbonylation of 1,5-COD in alcohols affords the mono- and diesters 23 and 24[25], On the other hand, bicy-clo[3.3.1]-2-nonen-9-one (25) is formed in 40% yield in THF[26], 1,5-Diphenyl-3-oxopentane (26) and 1,5-diphenylpent-l-en-3-one (27) are obtained by the carbonylation of styrene. A cationic Pd-diphosphine complex is used as the catalyst[27]. 

When a mixture of phosphoric acid and phosphoric acid esters is titrated with a sodium hydroxide solution two potential jumps can be observed. The first jump results from the acid group of the diester, the first neutralization step of the monoester, and the first neutralization step of free phosphoric acid. The second potential jump is caused by the second neutralization steps of the monoester and of the free phosphoric acid. The third step of neutralization of the free phosphoric acid cannot be covered by this method. Titration of acid esters can only be used for the determination of mono- and diesters of phosphoric acid when the amount of free phosphoric acid is separately ascertained. 

Especial points which emerge from these studies include (a) the almost complete absence of reactivity of the hydroxy-groups of simple carbohydrates in water, which is attributed to their powerful solvation by water preventing a close approach of any other solute and (b) the ability of ester groups to interact with proton-acceptors. The refractive index tests, examination of m.p. or b.p., and infrared spectra of certain mono- and poly-esters appear to be interpreted most simply by assuming the formation of weak CH bonds by ester groups under the activating influence of the adjacent (5—0 double bond. These bonds can account for certain properties of l 2-diesters and for the adsorption of proton-acceptor solutes by cellulose acetates. 

Pyrrolizidine alkaloids have a wide distribution, but are characteristic of certain genera of the Boraginaceae (e.g. Heliotropium, Cynoglossum, and Symphytum), the Compositae/Asteraceae (e.g. Senecio) and the Leguminosae/Fabaceae (e.g. Crotalaria). The pyrrolizidine bases rarely occur in the free form, but are generally found as esters with rare mono- or di-basic acids, the necic acids. Thus, senecionine (Figure 6.18) from Senecio species is a diester of retronecine with senecic acid. Inspection of the ten-carbon skeleton... 

The purity of lanolin and standard tests have been described in the European Pharmacopoeia (EP), in The United States Pharmacopoeia (USP), and according to other national standards.13,14 Lanolin is a semisolid with a melting point of approximately 40 6°C and has a molecular weight in the range of 790 to 880 Da. Lanolin is a complex and variable mixture of mainly esters, diesters, hydroxy esters (87.0-93.5%, w/w),7 8 15 lanolin alcohols (6.0-12.5%, w/w), lanolin acids (<0.5%, w/w), and lanolin hydrocarbons (<1.0%, w/w). The latter are also called paraffins and petrolatum by the EP and USP, respectively.13,14 16-18 Approximately 40% of the esters are a-hydroxy esters. Due to the extremely complex nature of lanolin, the true number of different esters present is unknown. Barnett calculated the theoretical number of monoester combinations from random combinations of 69 aliphatic lanolin alcohols, 6 sterols, and 138 saturated lanolin acids to total 10,350.8 This is most probably an underestimate of the total number of esters, as dibasic acids and dihydric alcohols also occur naturally in lanolin.19 Further combinations of cyclic mono- and di-esters may be formed by dehydration and from inter- and intra-esterification due to heating during the manufacturing process.7 8... 

A simple one-pot procedure for the synthesis of Fmoc-protected aspartic and glutanoic acid tert-butyl esters is shown in Scheme tert-Butylation of unprotected Asp and Glu can be effected in dioxane with excess isobutene using 4-toluenesulfonic add as catalyst. Subsequent Fmoc derivatization results in a mixture of the mono-tert-butyl esters (co/a 65/35 for Glu and 50/40 for Asp) with an overall yield of 55-60% contaminated with small amounts of d -tert-butyl esters. This procedure has the advantage that the Fmoc group is introduced without prior isolation or purification of the aspartic and glutamic tert-butyl esters. Whilst the diesters are readily removed by extraction with organic solvents, the Fmoc-Asp/Glu(OtBu)-OH derivatives are isolated by crystallization from dichloromethane/petroleum ether. 

The diester (or methylacrylate) cyclization reactions give the cyclic mono-, di-, or tetraamides. These materials must be reduced to provide the polyaza-crown compounds. The reduction process is usually carried out using diborane-THF or lithium aluminum hydride. The best results were obtained with a large excess of borane, however, a stable boron complex with the macrocycle often results. It is difficult to separate the macrocycle from the complex. Reduction of [12]N3 diamide with borane-THF always gave the stable complex. This problem was avoided by first forming N-tosyl[12]N,-diamide using the ester cyclization method followed by reduction with borane-THF and detosylation with HBr/phenol (Helps et al., 1989b). 

In principle, the interaction of a phosphorus(III) ester with an co-haloalkylamine should lead to an (co-aminoalkyl)phosphonic diester or a phosphinic acid analogue (Scheme 11). Such examples in the classical Michaelis-Arbuzov mould have been widely reported, but success in their outcome depends on the relative nucleophilicities of nitrogen and phos-phorus(III) centres towards the displacement of halogen. The interaction of triethyl phosphite and a halogen-substituted tertiary amine, such as 2-chloroethyldiethylamine, does not lead to a phosphonic diester, and in this particular case the product is a piperazinium diquaternary salt. However, successful Michaelis-Arbuzov reactions have been carried out between the bis(bromomethyl)phthalazines 130 (to both the mono- and di-phosphonic acid stages) and the series of [co-(2-cyano-4-pyridine)alkyl]phosphonic diesters 132 (n = 1-4) have been prepared from the 4-pyridinealkyl bromides 131 as precursors to the phosphonoalkylpiperidinecarboxylic acids 133 . ... 

Apart from their enormous importance in biochemistry, phosphate esters have many technological applications. Industrial production began in the 1920s and had become significant by the middle of the twentieth century. Some of the more important products of today are listed in Table 12.29. They are not always pure compounds - commercial tricresyl phosphate, for example, may contain a mixture of meta- and para-substituted groups. Commercial phosphate esters are frequently very toxic. Commercial applications often utilise mono- and diester mixtures, usually obtained by the method in (5.292). 

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