Cyclization-elimination

OH elimination from ortho substituted aldoximes 179 (X = CH2, NH, O) may be at least partially the result of a hydrogen migration/cyclization/elimination process, whereby the heterocycles 182 are formed72 (46). A metastable peak shape analysis, the investigation of 2H-labelled derivatives and the study of positional isomers indicate that in addition to 182 the protonated isocyanide 183 is formed via a mechanism which is not fully understood. However, it is known that the generation of 183 occurs without any detectable interaction with the XH ortho substituent. 

As shown in Scheme 14, a sulfuric acid-catalyzed dehydration-cyclization-elimination domino sequence starting from protonation of the secondary hydroxy group of the indolo[2,3- ]quinolizidine 112 led to the isolation of the pentacyclic compound 113 in good yield <1999EJ03429>. 

The unsubstituted quinazolidine system 5 was constructed from mesylate 173. The key feature in this synthesis is based on a cyclohydrocarbonylation of the protected 4-amino-l,6-heptadiene 169 catalyzed by Rh(acac)(CO)2-BIPHEPHOS. Formation of the hemiamidal-aldehyde 171 took place by hydroformylation of the two olefin moieties and cyclization. Elimination of water gave 172, which, after treatment with NaBFE, subsequent mesylation to 173, and catalytic hydrogenation, afforded 5 (Scheme 29) <1998TL4599>. 

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

This section presents selected examples of the use of zeolites and related porous materials for transformations of carbohydrates, that fall beyond the scope of the previous paragraphs. They include the use of zeolites in click chemistry and in a variety of reactions, including the synthesis of anhydro sugars, cyclization, elimination, and addition reactions to the carbonyl group. 

In the case of the fluorine-substituted allene 85 with Ag(I) catalyst, only the product of a cyclization/elimination process, the furan 86, was produced (Scheme 15.20)... 

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. 

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. 8.8. 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 stability of a large series of /V-(2-carbamoylphcnyl)carbamalcs was explored in buffer and in diluted human plasma. As shown in Table 8.11, the rate of nonenzymatic cyclization-elimination was very sensitive to the nature of the carboxamido substituent (R in 8.135, Fig. 8.11). Alkyl substituents... 

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

Fig. 8.12. Activation of hemiester prodrugs of phenols by acid-catalyzed hydrolysis (Reaction a), base-catalyzed hydrolysis (Reaction b), and cyclization-elimination (Reaction c). Enzymatic hydrolysis not shown (adapted from [174]). 

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. 

The first case presented is that of 2-[(acyloxy)methyl]benzamides of the general structure 8.187 (Fig. 8.22) [239]. Two model compounds were examined (NRR = MeNH or morpholino, R" = Me) they reacted, as expected, to give the secondary amine and phthalide in quantitative yields. At pH 9.3 and 60°, chemical hydrolysis was 2-10 times faster than the subsequent cyclization-elimination. At pH 7.4 and 37°, the chemical hydrolysis was slow (f1/2 ca. 400 h), while hydrolysis in human plasma was fast (tm 3.2 and 1.4 h, respectively). 

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...

Fig. 8.24. Schematic representation of cyclic, double prodrugs of peptides and their mechanism of activation by enzymatic ester cleavage, followed by cyclization-elimination [168][169][238]...

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

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... 

Fig. 11.18. Cyclization-elimination reactions in the in vitro and in vivo metabolism of nephrotoxic 2-haloethylamines (11.133). Aziridine (11.134) formation is probably a reaction of tox-ification, whereas oxazolidin-2-one (11.136) is clearly a reaction of detoxification [155][156].

In the improved synthesis of Ifetroban described above, environmental concerns due to special handling of copper bromide waste and hazards associated with hexa-methylene tetramine (HMT) on manufacturing scale led to further perfection of the synthesis. Mechanistic considerations suggested that an oxidized form of aminoamide B (Scheme 4) would eliminate the necessity for a late-stage copper-mediated oxidation. This was indeed accomplished. The cyclization-elimination sequence was initiated by a Lewis acid and completed by base-mediated elimination to afford the Ifetroban penultimate. In addition to eliminating the need for copper bromide and HMT, this modification helped to reduce the cost of the product by an additional 15%. 

S. Castro and M. W. Peczuh, Sequential cyclization-elimination route to carbohydrate-based oxepines, J. Org. Chem., 70 (2005) 3312-3315. 

A cyclizing elimination of water is described in Sect. 13.2 heating of 220 gives quantitatively 221 in the solid state (Scheme 28). 

Electrochemically generated NO3 has been reported to add to medium-ring alkynes and alkynones to furnish bicyclic ketones and epoxy ketones, respectively.50 The postulated mechanism involves the addition of N03 to the alkyne followed by transannular cyclization/elimination of NO3. 

Recently, a cyclization-elimination route to carbohydrate-based oxepines is proposed (Scheme 11). After silyl protection and hydroboration/oxidation, starting hept-l-enitols 31 give the protected heptan-l-itols 32. Swern oxidation of the latter followed by sequential acetal formation/cyclization provide methyl 2-deoxyseptanosides 33 that undergo elimination reactions to give the carbohydrate-based oxepines 34 <2005JOC3312>. 

Scheme 41 Benzothiazole synthesis via copper-catalyzed cyclization-elimination...

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