Lactones nucleophilic attack

The existence of n-complex intermediates can be inferred from experiments in which they are trapped by nucleophiles under special circumstances. For example, treatment of the acid 1 with bromine gives the cyclohexadienyl lactone 2. This product results from capture of the n-complex by intramolecular nucleophilic attack by the carboxylate group ... 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Nucleophilic attack of alcohols (e.g., ethanol) on a-lactones gives different regiochemistry depending on the snbstitnent R. In cases where R is alkyl or phenyl, ethanol reacts with a-lactones to prodnce a-ethoxyacids 3, presnmably via zwit-terionic form When R is the strongly electron-withdrawing trifluoromethyl... 

After the nucleophilic attack by the hydroxyl function of the active serine on the carbonyl group of the lactone, the formation of the acyl-enzyme unmasks a reactive hydroxybenzyl derivative and then the corresponding QM. The cyclic structure of the inhibitor prevents the QM from rapidly diffusing out of the active center. Substitution of a second nucleophile leads to an irreversible inhibition. The second nucleophile was shown to be a histidine residue in a-chymotrypsin28 and in urokinase.39 Thus, the action of a functionalized dihydrocoumarin results in the cross-linking of two of the most important residues of the protease catalytic triad. 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation /ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>. 

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

Treatment of carboxyaldehydes 252 with hydrazine hydrate in ethanolic KOH under refluxing conditions provides an easy entry to the novel imidazo[2,l-4][l,3]thiazole fused diazepinones 253 via lactone ring opening by intramolecular nucleophilic attack of the amino group of the intermediate hydrazone which could not be isolated (Equation 31) <2006TL2811>. 

Fig. 10.16. Comparison of the metabolism of A4-valproic acid (10.54), a metabolite of valproic acid, with that of ethyl A4-valproate (10.57), a synthetic analogue. Both compounds undergo cytochrome P450 catalyzed oxygenation to form the corresponding epoxides (10.55 and 10.58, respectively). The former reacts intramolecularly to form the lactone 10.56 and is not detectably a substrate for epoxide hydrolase. Epoxide 10.58, in contrast, is a substrate for epoxide hydrolase, forming the diol 10.59, which, in turn, carries out an intramolecular nucleophilic attack to form lactone 10.56 [136],...

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Mass spectroscopic analysis of the gas phase revealed that 53 is formed with the concomitant generation of H2. Based on the proposed catalytic cycle for silyUbrmylation (Scheme 6.12), the formation of 53 and 54 can be explained by the intervention of 55 (n=2), which plays a pivotal role in the differentiation between intramolecular nucleophilic attack of the hydroxy group and reductive elimination of 54. Thus, the addition of base is believed to accelerate the conversion of 55 to the rhodate anion 56. This notation is supported by the fact that the introduction of a strong base such as DBU is advantageous for the selective formation of a lactone framework. 

Cationic ROP of lactones in the presence of an alcohol proceeds by an activated monomer mechanism similar to that for cyclic ethers (Sec. 7-2b-3-b) [Endo et al., 2002 Lou et al., 2002]. Propagation proceeds by nucleophilic attack of the hydroxyl end group of a propagating chain on protonated (activated) monomer ... 

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