Cyclic diester

Cyclic diesters are often even better substrates forlipases and esterases than acyclic derivatives. Small-ring monoacetates (28, n — 1-3) are obtained in higher yield and ee than the larger derivatives (for 28, n = 4 is only 50%) (43). Hydrolysis of tetrahydrofuran diester results in monoester (29) of ee > 99% (44). 

RNA can be hydrolyzed by alkali to 2 3 cyclic diesters of the mononucleotides, compounds that cannot be formed from alkah-treated DNA because of the absence of a 2 -hydroxyl group. The alkali lability of RNA is useful both diagnostically and analytically. 

Enzymatic synthesis of aliphatic polyesters was also achieved by the ringopening polymerization of cyclic diesters. Lactide was not enzymatically polymerized under mild reaction conditions however, poly(lacfic acid) with the molecular weight higher than 1 x 10" was formed using lipase BC as catalyst at higher temperatures (80-130°C). Protease (proteinase K) also induced the polymerization however, the catalytic activity was relatively low. 

Lipases CA, BC, and PF catalyzed the polymerization of ethylene dode-canoate and ethylene tridecanoate to give the corresponding polyesters. The enzyme origin affected the polymerization behaviors in using lipase BC catalyst, these bislactones polymerized faster than e-CL and DDL, whereas the reactivity of these cyclic diesters was in the middle of e-CL and DDL in using lipase CA. 

Figure 13.1.4 The synthesis of poly(lactic acid) (PLA) by a ring-opening polymerization of the cyclic diester of lactic acid (lactide).

Lactide (LA), the cyclic diester of lactic acid, has two stereogenic centers and hence exists as three stereoisomers L-lactide (S,S), D-lactide (R,R), and meso-lactide (R,S). In addition, rac-lactide, a commercially available racemic mixture of the (R,R) and (S,S) forms, is also frequently studied. PLA may exhibit several stereoregular architectures (in addition to the non-stereoregular atactic form), namely isotactic, syndiotactic, and heterotactic (Scheme 15). The purely isotactic form may be readily prepared from the ROP of L-LA (or D-LA), assuming that epimerization does not occur during ring opening. The physical properties, and hence medical uses, of the different stereoisomers of PLA and their copolymers vary widely and the reader is directed to several recent reviews for more information.736 740-743... 

Initially PDPs were synthesized by stepwise polycondensation of linear activated depsipeptide [93]. In 1985, Helder, Feijen and coworkers reported the synthesis of PDPs by ROP of a morpholine-2,5-dione derivative (cyclic dimer of ot-hydroxy- and a-amino acid cyclodepsipeptide, cDP) [94, 95]. The ROP method gives an alternative type of PDP by homopolymerization and also allows the copolymerization with other monomers (lactones and cyclic diesters) including LA, GA, and CL to give a wide variety of functional biodegradable materials. The synthesis of PDPs as functional biomaterials has been recently reviewed [17]. 

In this short section, cyclic compounds are discussed that are not strictly lactones since they contain an endocyclic structural motif of the type -O-CO-X- or -X-O-CO-. However, these compounds share with lactones the possibility to be hydrolyzed at the endocyclic -CO-O- bond. This is the case for cyclic diesters of carbonic acid (-O-CO-O-), cyclic esters of car-bamic acid (-0-C0-NH-), and cyclic anhydrides (-C0-0-C0-). One example of each class is presented here. 

A simple cyclic diester of carbonic acid is ethylene carbonate (7.96), a chemical with a toxicity profile resembling that of ethylene glycol (7.97). Metabolic studies have confirmed that ethylene carbonate is hydrolyzed very rapidly to ethylene glycol (whose oxidation is discussed in Chapt. 2 in [7]) and C02. Indeed, rats given an oral dose of ethylene carbonate did not excrete the unchanged xenobiotic in detectable amounts, and blood levels of the diester were ca. 100-fold smaller than those of ethylene glycol [178],... 

Figure 2.11 Pyrrolizidine alkaloid toxins including (a) the pyrrolizidine nucleus, (b) retronecine, a less toxic monoester, and (c) jacobine, a highly toxic cyclic diester.

This review aims at reporting on the synthesis of aliphatic polyesters by ROP of lactones. It is worth noting that lactones include cyclic mono- and diesters. Typical cyclic diesters are lactide and glycolide, whose polymerizations provide aliphatic polyesters widely used in the frame of biomedical applications. Nevertheless, this review will focus on the polymerization of cyclic monoesters. It will be shown that the ROP of lactones can take place by various mechanisms. The polymerization can be initiated by anions, organometallic species, cations, and nucleophiles. It can also be catalyzed by Bronsted acids, Lewis acids, enzymes, organic nucleophiles, and bases. The number of processes reported for the ROP of lactones is so huge that it is almost impossible to describe aU of them. In this review, we will focus on the more... 

A less direct strategy relies on the synthesis and ROP of substituted and/or imreactive functionalized lactones [100]. Two approaches can be implemented. In the first approach, the unreactive functional group is inserted directly inside the ring. It is worth recalling that cyclic diesters such as lactide and glycolide, for which... 

Despite the fact that glycolic acid has been successfully used as an acyl donor in esterification reactions with fatty alcohols, there are few reports dealing with the enzymatic ROP of glycolide [139], On the other hand, cyclic diesters based on ethylene glycol have been polymerized successfully by lipase catalysis and afford AA-BB-typepolyesters [140, 141],... 

Problem 16.26 (a) When heated, 2 mol of an a-hydroxyacid (n = 0) lose 2 mol of H 0 to give a cyclic diester (a lactide). Give the structural formulas for two diastereomers obtained from lactic acid, CH,CHOHCOOH, and select the diastereomer which is not resolvable. (6) Synthesize lactic acid from CH,CHO. ... 

In addition to the hydrolysis of monoesters of phosphoric acid, the hydrolysis of diesters of phosphoric acid is also susceptible to metal ion catalysis, in particular by multivalent cations such as barium, stannous, and cupric ions. The diesters which undergo metal ion-catalyzed hydrolyses include open-chain diesters and cyclic diesters containing both five- and six-membered rings (54). 

Considerable ingenuity was required in both the synthesis of these chiral compounds695 697 and the stereochemical analysis of the products formed from them by enzymes.698 700 In one experiment the phospho group was transferred from chiral phenyl phosphate to a diol acceptor using E. coli alkaline phosphatase as a catalyst (Eq. 12-36). In this reaction transfer of the phospho group occurred without inversion. The chirality of the product was determined as follows. It was cyclized by a nonenzymatic in-line displacement to give equimolar ratios of three isomeric cyclic diesters. These were methylated with diazomethane to a mixture of three pairs of diastereoisomers triesters. These dia-stereoisomers were separated and the chirality was determined by a sophisticated mass spectrometric analysis.692 A simpler analysis employs 31P NMR spectroscopy and is illustrated in Fig. 12-22. Since alkaline phosphatase is relatively nonspecific, most phosphate esters produced by the action of phosphotransferases can have their phospho groups transferred without inversion to 1,2-propanediol and the chirality can be determined by this method. 

The product l-phospho-(S)-propane-l/2-diol 1 (here shown as R at phosphorus) is converted by in-line ring closure to an equimolar mixture of three cyclic diesters. These are methylated to give six cyclic triesters. Of these, only 3 and 6 give sharp 31P resonance because the 170 in the others broadens the lines. 

The hydrolysis of RNA catalyzed by RNase A occurs in two distinct steps, with a 2, 3 -phosphate cyclic diester intermediate (see fig. 8.12). The intermediate can be identified relatively easily, because its breakdown is much slower than its formation. Ribonucleases do not hydrolyze DNA, which lacks the 2 -hydroxyl group needed for the formation of the cyclic intermediate. 

The dependence of kcat of RNase A on pH. The bell-shaped curve suggests that one histidine residue must be in the protonated state and another must be unprotonated. Similar pH dependences are found for the hydrolysis of either RNA or pyrimidine nucleoside-2, 3 -phosphate cyclic diesters. 

Ribonuclease A hydrolyzes RNA adjacent to pyrimidine bases. The reaction proceeds through a 2, 3 -phosphate cyclic diester intermediate. Formation and breakdown of the cyclic diester appear to be promoted by concerted general-base and general-acid catalysis by two histidine residues, and by electrostatic interactions with two lysines. These reactions proceed through pentavalent phosphoryl intermediates. The geometry of these intermediates resembles the geometry of vanadate compounds that act as inhibitors of the enzyme. 

Ruthenium tetroxide is a four-electron oxidant which directly transforms alkenic compounds into oxidative cleavage products, i.e. carbonyl compounds and carboxylic acids.288 The reaction can be visualized as proceeding according to a [4 + 2] cycloaddition of the cis-dioxo moiety with the alkene, resulting in the formation of a RuVI cyclic diester which decomposes to ruthenium(IV) dioxide and oxidative cleavage products (equation 114).288 This reaction can be made catalytic... 

The alkaloid croalbine (66) (mp 208-209°) was shown to be the cyclic diester of croalbinecine and trichodesmic acid (39). 

Yokoyama et al. also synthesized cyclic diesters (fulgenates) 7-9.[8 Because of their greater flexibility, their association constants with alkali metal cations were larger for the E and the Z forms than for the C forms. No cyclization was observed for combinations of 8E and Na+ and of 9E and K+ upon irradiation with UV light, because of changes in ground state conformations. 

An 0-18 isotopic shift on P-31 chemical shifts of epimeric 1, 3,2-dioxaphosphorinane esters (10) has been used to investigate the stereochemistry of hydroxide catalyzed hydrolysis in these aryl phosphorinane triesters. As shown in Scheme I the axial epimer of 2-(2,4-dinitrophenoxy)-2-oxo-trans-5,6-tetramethylene-l,3,2-dioxa-phosphorinane) 5a, was hydrolyzed in 0-18 enriched hydroxide. The cyclic diester, 8, was methylated with diazomethane in methanol. The P-31 NMR spectrum of the 0-18 labeled axial methyl phosporl-nane product, 2, showed three signals representing the unlabeled... 

Several review articles on biodegradable polymers and polyesters have appeared in the literature [12-22]. Extensive studies have been carried out by Al-bertsson and coworkers developing biodegradable polymers such as polyesters, polyanhydrides, polycarbonates, etc., and relating the structure and properties of aliphatic polyesters prepared by ROP and polycondensation techniques. In the present paper, the current status of aliphatic polyesters and copolyesters (block, random, and star-shaped), their synthesis and characterization, properties, degradation, and applications are described. Emphasis is placed primarily on aliphatic polyesters derived by condensation of diols with dicarboxylic acids (or their derivatives) or by the ROP of cyclic monoesters. Polyesters derived from cyclic diesters or microbial polyesters are beyond the scope of this review. 

The ROP of lactones, cyclic diesters (lactides and glycolides), and cyclic ket-ene acetals is an alternative method, which has been successfully employed to yield high molecular mass polymers under relatively mild conditions. This polyaddition reaction can be carried out with no or very limited side-reactions, and this makes it possible to control properties like molecular weight and molecular weight distribution (MWD). Both polycondensation and ROP have been reported in the literature for the synthesis of polyesters. 

Metabolism of the cyclic diesters retrorsine (166), monocrotaline (169), and crispatine (171) by a variety of mammalian liver microsome preparations and by Peptococcus heliotrinreducans has been reported. Mattocks and co-workers have studied the metabolism of retrorsine by liver microsome preparations from several sources 167-169) and have demonstrated the conversion of this alkaloid to the corresponding iV-oxide 167 and a pyrrolic metabolite formulated as 168. The formation of 168 via 167 and dehydration is mitigated against by the observation that retrorsine TV-oxide (167) does not give rise to a pyrrolic metabolite on incubation with rat liver microsomes 167), even though the enzyme system responsible for the production of 168 from retrorsine has many of the properties of the mixed-function oxygenases capable of N-oxidation 167,174). The metabolites of retrorsine... 

Extensive investigations have demonstrated that 0s04 reacts with alkenes in a 1,3-dipo-lar cycloaddition while forming the five-membered ring A of Figure 17.19 as an intermediate. A is a cyclic diester of an osmium(VI) acid. As such it will be hydrolyzed by the pre-... 

Fig. 17.24. Standard mechanism of the glycol cleavage with Pb(0Ac)4. The reaction proceeds preferentially via a cyclic diester of Pb(IV) acid, which decomposes in a one-step reaction to Pb(0Ac)2 and two equivalents of the carbonyl compound.

Kaplan, M.L. and Truesdale, E.A. (1976) [2.2]Paracyclophane by photoextrusion of carbon dioxide from a cyclic diester. Tetrahedron Letters, 17,... 

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