Unmasked acyl group

I 5.4 Reactions of Acylzirconocene Chlorides as Unmasked Acyl Group Donors... 

Reactions of Acylzirconocene Chlorides as "Unmasked Acyl Group Donors 5.4.4.5 Cu-catalyzed cross-coupling reactions... 

Recent chemical accomplishments based on acylzirconocene chloride complexes indicate the potential utility of this reagent, not only as a nucleophilic donor of an unmasked acyl group but also as a characteristic dichotomous reagent in carbon—carbon bond-forming reactions. Although there have been many reports on the reactions of acylmetal complexes, the ready availability, stability, and notable reactivity of acylzirconocene complexes — especially acylzirconocene chloride complexes — merits their recognition as useful reagents. Further research on the reactivity of acylzirconocene species is anticipated to lead to the discovery of new synthetic applications. 

To replace the aforementioned acyl-main group and acyl-transition metal complexes, the natural course of events was to search for a stable and easy-to-handle acyl-metal complex that reacts as an unmasked acyl anion donor. Thus, the salient features of acylzirconocene chlorides as unmasked acyl anion donors remained to be explored. In the following, mostly carbon—carbon bond-forming reactions with carbon electrophiles using acylzirconocene chlorides as acyl group donors are described. 

Selective dearoylation of peraroylated -D-ribofuranosyl nucleosides has been carried out. When sodium methoxide in THF was used, the 2 -and 3 -hydroxy groups were unmasked, giving the 5 -0-acyl nucleoside. N-Acyl groups on the heterocyclic bases were unaffected. The reaction was successfully carried out with benzoyl, toluoyl and... 

The choice of the acyl substituent X for Diels-Alder reactions of l-N-acylamino-l,3-butadicnes depends on the particular synthetic problem. The acyl substituent has a moderate effect on the cycloaddition reactivity of these dienes, and also determines what amine unmasking procedures are required. As a result of their stability and the variety of amine deprotection procedures available, " the diene carbamates are the components of choice in most cases. A particularly attractive aspect of the diene synthesis detailed here is the ability to tailor the amino-protecting group... 

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. 

The use of masked acyl anion equivalents in a synthetic protocol requires additional steps to unmask the carbonyl unit. Sometimes the deprotection procedures are incompatible with sensitive compounds thus, a direct nucleophilic acylation protocol is desirable. While C-nucleophilic carbonyl groups do not... 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

The synthesis of 3-benzylcyclobutanone (3) is an illustration of an overall intramolecular alkylation of an acyl anion equivalent (Section 5.9). The a,a>-dihalide is 2-benzyl-l,3-dibromopropane, and the acyl anion equivalent is methyl methylthiomethyl sulphoxide2 the product is 1-methylsulphinyl-l-methylthio-3-benzylcyclobutane which is obtained as a mixture of cis/trans isomers [(9) and (10)] (Expt 7.3). Aqueous acid hydrolysis in ethereal solution unmasks the carbonyl group. The possible mechanism of the reaction is via a Stevens-type rearrangement of the intermediate sulphur ylide, which may proceed in a pericylic, radical or ion pair fashion. 

Carreira s opening retrosynthetic move on zaragozic acid C disengaged its C(6) O-acyl side chain, and blocked its three carboxyls as acid-labile /-butyl esters (Scheme 7.1). The C(7)-hydroxyl was then protected as an acid-labile /-butyl carbonate group to provide compound 1 as a subtarget. Carreira felt that protection of this hydroxyl was necessary because previous work on 0(6)-deacylated zaragozic acid had shown that the C(7)-OH was more susceptible to O-acylation, possibly for electronic reasons. The same study also revealed that the C(4) tertiary OH could be left unmasked during such a forward acylation. 

A more narrowly defined group within this second set of compounds is the set of mechanism-activated inhibitors. These are compounds which do not have a second pre-existing reactive functionality. Rather, they use the normal catalytic machinery of the enzyme to generate, or unmask, a reactive species in the acyl-enzyme intermediate (E I). This new species then alkylates a second, suitably placed, active-site residue and permanently inactivates (binds to) the enzyme (even if deacylation of Ser-195 subsequently occurs). Efficient mechanism-activated inhibitors are those which have a high ratio of alkylation (Atj) to release k of the active enzyme. Because the second reactive functionality is only generated in the active site,... 

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