Cyclic diesters

Perhaps the most important signaling molecule in human biochemistry is the phosphate diester cyclic adenosine monophosphate, commonly known as cAMP. cAMP is part of many signahng pathways, a sequence of steps in which some physiological signal—say the arrival of a hormone molecule at a cell surface— is translated into a physiological outcome. Here is its stracture ... 

Cyclic Diesters. Cyclic diesters were subjected to the lipase-catalyzed ringopening polymerization. Lactide, cyclic dimer of lactic acid, was polymerized by lipase PC in bulk at high temperature (80-130°C) to produce poly(lactic acid) with Mw up to 2.7 x 10 (189,190). Protease (proteinase K) also induced the polymerization of lactide however, the catalytic activity was relatively low. 

Claisen condensation 2 Esters — j8-ketoester 1,7-diester cyclic /3-ketoester (intramolecular Dieckmann condensation) (23-1)... 

Some of these compounds are used as potential intermediates for the preparation of 4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5d]pyridazines (78). The diesters (77) are hydrolyzed under appropriate conditions to free acids (79), whose monopotassium salts (80) yield the cyclic anhydrides (81) under the influence of thionylchloride. Pyrolysis of 79, Rj = a-thienyl, results in its decarboxylation to 82. 

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). 

Catechols can be protected as diethers or diesters by methods that have been described to protect phenols. However, formation of cyclic acetals and ketals (e.g., methylenedioxy, acetonide, cyclohexylidenedioxy, diphenylmethylenedioxy derivatives) or cyclic esters (e.g., borates or carbonates) selectively protects the two adjacent hydroxyl groups in the presence of isolated phenol groups. 

The bis(silyloxy)cyclobutenes are also subject to a variety of special reactions. Probably the most interesting is the observation that they readily undergo a ring-opening reaction leading to a butadiene derivative. This reaction has already been used to prepare large-ring diketones from cyclic 1,2-diesters. 

A two-carbon ring expansion of cyclic ketones was achieved by the addition of acetylenic esters and diesters to the enamine derivatives of the ketones, and reported almost simultaneously from several laboratories (337-343). The intermediate bicyclic adduct could be isolated in some cases. 

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

Mechanism of the Dieckmann cyclization of a 1,7-diester to yield a cyclic /3-keto ester product. 

Polyesters have been obtained in organic medium by polyesterification of hydroxy acids,328,329 hydroxy esters,330 stoichiometric mixtures of diols and diacids,331-333 diols and diesters,334-339 and diols and cyclic anhydrides.340 Lipases have also been reported to catalyze ester-ester interchanges in solution or in die bulk at moderate temperature.341 Since lipases obviously catalyze the reverse reaction (i.e., hydrolysis or alcoholysis of polyester), lipase-catalyzed polyesterifications can be regarded as equilibrium polycondensations taking place in mild conditions (Scheme 2.35). 

As far as dialkyl sulfosuccinates are concerned, there are minor variation possibilities known from the market products. Most of the substances available are dialkyl sulfosuccinates. The variation is limited to the fatty chain. Either linear, branched, or cyclic aliphatic groups are used. No ethoxylated sulfosuccinate diesters could be recognized. 

Basic Properties of Sulfosuccinate Diesters It is very difficult to establish general structure-function relationships for the sulfosuccinate diesters, although they are very similar in structure and functionalities. Looking at the variety known for these compounds, only different hydrocarbon chains—branched, linear, or cyclic—are in use. In the following chapter, basic properties of these compounds depending on the substituents used are described. 

The benzyl phosphonate triesters 100 reacted with isocyanates under similar conditions to give the corresponding cyclic urea phosphonate diesters 101 (2). 

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. 

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).

An estimate of the rate enhancement associated with the intramolecular phosphorylation can be made by using isopropyl p-nitrophenyl methyl-phosphonate as a model for the covalent intermediate formed in the initial step of the reaction of cycloheptaamylose with bis (p-nitrophenyl) me thy 1-phosphonate. The first-order rate constant for the alkaline hydrolysis of isopropyl p-nitrophenyl methylphosphonate at pH 9.86 can be obtained from the data of van Hooidonk and Groos (1970) kun = 1.4 X 10-5 sec-1. This value may be compared with the maximal rate constant for the reaction of cycloheptaamylose with bis(p-nitrophenyl) methylphosphonate— k2 = 1.59 X 10-1 sec-1 at pH 9.86—which must be a minimal value for the rate of the intramolecular phosphorylation. This comparison implies a kinetic acceleration of at least 104 which is similar to rate enhancements associated with the formation of cyclic phosphates from nucleoside phosphate diesters. 

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]. 

The most convincing evidence in favor of a uniform 3,5-diester linkage between nucleotides has been obtained by the action of various enzymes on synthetic diesters of known constitution.218 217 Ribonuclease and spleen extracts were found to act only on nucleoside 3-(benzyl hydrogen phosphates), but not on other isomers, to give nucleoside cyclic phosphates which are broken down further to give nucleoside 3-phosphates. It is concluded, by analogy, that polynucleotides, which are substrates for these enzymes, also possess ester groupings at the 3-positions, rather than at the... 

A novel synthesis of D-glucose 6-phosphate (in 55% yield) has been reported it involves alcoholysis of the cyclic phosphate of catechol with 1,2-O-isopropylidene-a-D-glucofuranose, followed by acid hydrolysis of the so-formed phosphoric diester.192 The reagent... 

Reaction of the sodium salt of a cyclic phosphite diester with a bis-benzylic halide... 

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