Intramolecular cyclization-elimination

A few examples of ester prodrugs that are activated by intramolecular reactions have been mentioned in Sect. 8.3.1, 8.5.1, and 8.5.2. Here, we discuss the special case of some carboxylic acid esters of active alcohols or phenols that are released following an intramolecular cyclization-elimination reaction [168], The general reaction scheme of such reactions is shown in Fig. 8.8. 

Fig. 8.11. Simplified reaction mechanism of intramolecular cyclization-elimination of anthra-nilamide phenylcarbamates (8.135) [173]...

R = H) undergoes a variety of enzyme-catalyzed free-radical intramolecular cyclization reactions, followed by late-stage oxidations, eliminations, rearrangements, and O- and N-alkylations. Working from this generalization as an organizing principle, the majority of known AmaryUidaceae alkaloids can be divided into eight stmctural classes (47). 

A stmple and general synthesis of 2,2,4,5-tetrasubstituted furan-3(2//)-ones from 4-hydroxyalk-2-ynones and alkyl halides via tandem CO, addition-elimination protocol is described <96S 1431>. Palladiuni-mediated intramolecular cyclization of substituted pentynoic adds offers a new route to y-arylidenebutyrolactones <96TL1429>. The first total synthesis of (-)-goniofupyrone 39 was reported. Constmction of the dioxabicyclo[4.3.0]nonenone skeleton was achieved by tosylation of an allylic hydroxy group, followed by exposure to TBAF-HF <96TL5389>. 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2 1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a P-hydrogen elimination. 

Anions 207, derived from l-(diarylmethyl)benzotriazoles 206, can be oxidized with mild oxidants to relatively stable triaryl radicals 208. One of the possible reactions of radicals 208 is ring opening to give radicals 209. Elimination of nitrogen from 209 produces unstable species 210 that undergo intramolecular cyclization to phenan-thridines 211 (Scheme 25) <1996JHC607, 1998JOC1467>. When substituents X and Y are identical, products 211... 

In this approach, the SENA skeleton is assembled from nitroalkene (42) and nucleophile 56.With the exception of two examples (entries 1 and 2 in Table 3.2), the reaction does not stop at SENA 51, which either undergoes intramolecular cyclization through [3 + 2]-cycloaddition to give fused heterocycles (as a rule after elimination of trimethylsilanol) (198-200) or is involved in [3+ 2]-cycloaddition with specially added methyl vinyl ketone or methyl acrylate to form (after elimination of silanol) substituted isoxazolines in rather high yields (201). 

Scheme 4.10. Intramolecular cyclization or p-elimination of hydrozirconated allylic epoxides.

A detailed review of the ortho-effect in mass spectrometry was published by H. Schwarz [22]. He classified the processes related to the ortho-effect, gave examples of unusual elimination reactions, processes of intramolecular cyclization, exchange and reduction processes. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

Methyleneazetidones have been obtained [39, 40] under liquiddiquid and solidrliquid basic conditions (Table 5.19) from an intramolecular cyclization and elimination reaction of 3-bromo-2-(bromomethyl)propionamides (Scheme 5.9). Traditional methods for the preparation of such compounds are either not particularly adaptable for general use, or involve lengthy and vigorous reaction conditions. In... 

Prodrug activation occurs enzymatically, nonenzymatically, or, also, sequentially (an enzymatic step followed by a nonenzymatic rearrangement). As much as possible, it is desirable to reduce biological variability, hence the particular interest currently received by nonenzymatic reactions of hydrolysis or intramolecular catalysis [18][20], Reactions of cyclization-elimination appear quite promising and are being explored in a number of studies. 

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

A scheme depicting general base catalysis is shown in Fig. 7.2,b. Because the HO anion is more nucleophilic than any base-activated H20 molecule, intermolecular general base catalysis (Fig. 7.2,bl) is all but impossible in water, except for highly reactive esters (see below). In contrast, entropy may greatly facilitate intramolecular general base catalysis (Fig. 7.2,b2) under conditions of very low HO anion concentrations. Alkaline ester hydrolysis is a particular case of intermolecular nucleophilic attack (Fig. 7.2,cl). Intramolecular nucleophilic attacks (Fig. 7.2,c2) are reactions of cyclization-elimination to be discussed in Chapt. 8. 

Fig. 8.8. General reaction for the intramolecular activation of prodrugs by cyclization-elimination [168] [169]...

Thus, intramolecular activation (cyclization-elimination) in this series is modulated by steric factors. In addition, hydrolysis may be enzyme-catalyzed, depending on substrates and biological conditions. 

A similar type of intramolecular reaction was achieved with basic carbamates of4-hydroxyanisole (8.134, X = MeO, n = 2 or 3, Fig. 8.10) [171]. The drug itself is a clinically effective melanocytotoxic agent. Intramolecular nucleophilic attack again resulted in cyclization-elimination, the pro-moiety being recovered as an imidazolidinone (Fig. 8.10, n = 2). In the series examined, the compounds were stable at pH 4, and became more reactive at higher pH values. At pH 7.4 and 37°, chain length and substitution at the two N-atoms had a marked influence on the f1/2 values for hydrolysis (Table 8.10). First, it is clear that a shorter chain (Fig. 8.10, n = 2) favors intramolecular attack, but a decrease in tm values for hydrolysis for three compared... 

The prodrugs examined here undergo a common, two-step mechanism of activation (hence their designation as double prodrugs) first, hydrolysis of the carboxylate group occurs, followed by intramolecular nucleophilic substitution to liberate the active amine (for reviews see [168] [169] [237] [238]). Such reactions of cyclization-elimination are analogous to those discussed in Sect. 8.5.7. 

Fig. 8.22. 2-[(Acyloxy)methyl]benzamides (8.187) as double prodrugs of active amines. Activation is by cyclization-elimination in a two-step sequence, namely hydrolase-catalyzed hydrolysis of the carboxylate moiety followed by an intramolecular nucleophilic substitution with...

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

An alternative pathway (Scheme 8) could start from the two regioisomers 5 and 6, both isolated from Pseudopterogorgia elisabethae. Thus, after phosphorylation or protonation followed by elimination to dienylquinone 46, intramolecular cyclization would generate zwitterionic intermediate 47. Hydride... 

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