Hydroxyl-functionalized lactones

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. 

Trost and coworkers [131] synthesized oxaheterocycles by a Pd-catalyzed addition of terminal alkynes onto hydroxyalkynoates, followed by an intramolecular addition of the hydroxyl functionality on the triple bond. Simple lactonization may take place as a side reaction. 

The position of the functional groups along the eremophilane core was confirmed by an HMBC experiment. In particular, the correlations C-lO/OH-1, H-6, H-9 C-8/H-9, H-6, H-13 C-2/OH-1, H-4 and C-12/H-13 were consistent with the disposition of the ketone, hydroxyl and lactone functionalities. 

The mechanism of the enzymatic polymerization is shown in Fig. 25 and can be decomposed into three main steps. First, a complex is formed between the enzyme and the lactone. The second step is based on the nucleophihc activation of the lactone by the hydroxyl function belonging to a serine residue of the active... 

A key point should be to identify the rate-limiting step of the polymerization. Several studies indicate that the formation of the activated open monomer is the rate-limiting step. The kinetics of polymerization obey the usual Michaelis-Menten equation. Nevertheless, all experimental data cannot be accounted for by this theory. Other studies suggest that the nature of the rate-limiting step depends upon the structure of the lactone. Indeed, the reaction of nucleophilic hydroxyl-functionalized compounds with activated opened monomers can become the rate-limiting step, especially if stericaUy hindered nucleophilic species are involved. 

The reaction is generally applicable to a variety of substrate types, as illustrated in Table I.10 Compatible functionality includes hydroxyl, ester, lactone, acid, ketone, and electron-poor olefins such as those conjugated to a-ketones. Some selectivity between isolated double bonds is also found. The reaction generally gives nearly quantitative yields with simple olefins... 

For C-extension in the (5/ )-hydroxyhexanal case it was found (58), that the pyranoid lactol form 41 is so stable that reaction with Wittig ylides cannot be effected under standard conditions. Thus, the acylic form had to be elaborated, which was effected by thioketalization, acetylation (41 - 43) and desulfurization, the resulting 5-O-blocked hexanal 44 then smoothly affording the olefin 45. Liberation of the hydroxyl function and ensuing lactonization... 

The reaction of cyclohexenamides with nucleophiles such as water, alcohols, or thiols, produced carboxylic acid, esters, or thioesters. Reaction with acetylenic dipolarophiles in acidic conditions produced highly functionalized pyrroles via a complex mechanism, implying as intermediates 1,3-dipoles and bycyclic cycloaddition products. Reaction of cyclohexenamides containing protected hydroxylic functions with AcCl/MeOH produced < -lactones, while cyclohexenamides, bearing in Ri an o-aminophenyl group, easily cyclized to 1, 4-benzodiazepine-2, 5-diones. 

It was to be expected that the lactone group in XL would be split with LiAIBU to form a primary and a tertiary hydroxyl function. Instead, however, the reduction products XLII, XLIII, and XLIV, the structure and configuration of which were confirmed by the synthesis, were obtained. In the case of the polyamines XLII, all the C and N atoms of... 

The oxidation of the primary hydroxyl function at C1 of a sugar alcohol to a carboxyl function leads to the corresponding aldonic acid. Further oxidation of the remaining terminal hydroxyl function of an aldonic acid to a carboxyl function leads to an aldaric acid. Both, aldonic and aldaric acids easily form lactones through intramolecular condensation reactions. As an exam-... 

The melt condensation of acid and hydroxyl functional group normally requires exact stoichiometry, elevated temperature, and a long reaction cycle. Such a route would not be possible to utilize to produce block polymers from lactones and other vinyl monomers. However, a rather facile route leading to polyester formation can be realized by the ring-opening polymerization of lactones as seen from the scheme ... 

Functionalized y-lactones are important synthetic intermediates for a number of biologically active natural products [102]. An interesting strategy based upon the AD reaction of unsatuxated esters or carbamates, combined with the spontaneous kinetic cycHzation to form five-membered ring lactones, has recently been established (Scheme 27). Thus, asymmetric dihydroxylation of p,y- and y,8-un-saturated esters 73 and 74 results in the hydroxyl-substituted lactones 75 or the side-chain functionaUzed system 76 respectively, in high optical purity. This strategy was appHed to the synthesis of numerous natural products. 

The pheromone 151 possesses an anti-relationship between the two hydroxyl functions built in its structure (Scheme 43). The estabUshment of such an antistereochemistry requires the AD of a (Z)-olefin, a process which usually proceeds with moderate enantiocontrol. To overcome this difficulty, Lohray [120] performed the asymmetric dihydroxylation of the isomeric ( )-alkene 149 and inverted selectively one of the chiral center via an intramolecular lactonization reaction on the derived cyclic sulfate 150. 

The acid treated ID-MA copolymer, with lactone, acid and hydroxyl absorptions in the IR, was heated for 2 hr. at 200°C. The IR spectrum of the recovered polymer showed considerable sharpening of the 1760 cm- band and elemental analysis supportive of head-to-head poly (y-crotonolactone), VII, production. However, absorptions in the same spectrum suggested the polymer retained a small amount of carboxylic acid and hydroxyl functionality. 

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