Cleavage of phenacyl esters

Cleavage of phenacyl esters (typical procedure)f To a solution of NaHTe (prepared by heating powdered tellurium (1.28 g, 10 mmol) and NaBH4 (0.75 g. 15 mmol) under Nj in DMF at 80-90°C for 30 min, and then cooling at room temperature) is added a solution of phenacyl benzoate (1.92 g, 8 mmol) in DMF (30 mL). An instantaneous reaction takes place and the mixture is stirred at room temperature for 20 min. The solvent is evaporated and the mixture poured into H2O (100 mL) and fdtered to remove the tellurium. The basic filtrate is washed with ether and then the aqueous solution is acidified with 6 N HCl and extracted with ether (3x50 mL). The ether extract is dried (MgS04) and evaporated to give benzoic acid (1.11 g (91%) m.p. 121-122°C). 

Methoxyphenacyl esters were first described by Sheehan and Umezawa in 1973.They studied the deprotection of a series of amino acids and found that the best yields were obtained when the photolysis was carried out in ethanol. The 4-methoxyphenacyl esters were formed by the reaction of the free acid with 4-methoxyphenacyl bromide in DMF containing triethylamine. Photolyses were carried out with a 450-W Hanovia mercury immersion lamp fitted with a Pyrex filter. The 4-methoxyphenacyl group was used in a synthesis of thymo-pentin analogues.The authors used zinc dust as the standard deprotection procedure for cleavage of phenacyl esters (see Section 2.2). 

Protection and deprotection. CuClj catalyzes tetrahydropyranylation of alcohols," as well as cleavage of phenacyl esters." In the latter process, oxygen is introduced into the refluxing medium (aqueous DMF). 

Most photocleavable linkers for carboxylic acids used today are based on the photoisomerization of 2-nitrobenzyl esters and on the light-induced cleavage of phen-acyl esters (Figure 3.10). Several possible mechanisms have been proposed for the photolytic cleavage of benzoin esters. One of the most recent is the dissociation of the excited phenacyl ester into a carboxylate and a phenacyl cation ( photosolvolysis , Figure 3.10 [136]). 

Phenacyl esters of benzoic acid, of amino acid derivatives, and of gib-berillin A3 undergo photolytic cleavage at >313 nm, giving, in each case, the free carboxylic acid and the corresponding acetophenone (see Scheme 29) 84,85 -pijg yjeijs Qf free carboxylic acids (33-96%) vary considerably,... 

Phenacyl esters of various N-a-Boc- N-a-Cbz- or tyN-dimethylamino-protected amino adds and dipeptides can be cleaved to the corresponding carboxylic acids on heating with bis(tributyltin)oxide in aprotic solvents [Scheme 6.72],23 There is no racemisation of the amino acid and peptide products. However there are some limitations to the method removal of tin residues from the product can diminish the yield and the Cbz group (but not a Boc) may undergo competitive cleavage. 

Protection of carboxyl groups. Phenacyl esters can be cleaved in 90% yield with Zn-HOAc/DMI. For peptides that are poorly soluble in DMF, cleavage can be effected with Zn-anthranilic acid-pyridine in a mixture of N-methylpyrrolidone and DM.SO (86-92% yield). 

An efficient non-addolytic and non-nucleophilic method for the selective cleavage of N -protected amino acid and short N -protected peptide methyl esters is the use of bis-(tributyltin) oxide (BBTO).P BBTO also cleaves phenacyl, benzyl, and several other primary alkyl esters. 

In a formal sense, alkyl ester type carboxy protecting groups, e.g. benzyl, allyl, 4-picolyl, and (9,10-dioxo-2-anthryl)methyl esters, can be viewed at as modified methyl esters. However, because of their specific properties and cleavage conditions these esters will be discussed separately. In this section a series of acetal, phthalimidomethyl, various phenacyl, acetonyl, 9-anthryhnethyl, and cyclopropyhnethyl esters will be presented. 

Boc-MTXl(l-41)-OH Typical Procedure for Cleavage of Peptide Phenacyl Esters via Reduction with Zn/AcOH " ... 

Scheme 16.9. Modification and photolytic cleavage of a phenacyl ester-based linker.

The haloacetophenone type of polymer reacted with N-protected amino acids and peptides — as already known from esterifications with the monomer reagent in conventional syntheses [74] — under milder conditions but in better loading yield compared to chloromethylated polystyrene, resulting in enhanced reactivity of the peptide phenacyl ester bond on polymer towards nucleophilic cleavage reagents [74—76]. (For further details on peptide cleavage, see Sect. 3.5.)... 

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