Phenacyl ester

A scion of the small reductive-elimination orthogonal set is the phenacyl group which, like the 2,2,2-trichloroethyl ester (section 6.5.1), is useful for deprotect-ing the C-terminus of a peptide under conditions that retain such stalwart N-protecting groups as Fmoc, Boc, and Cbz (see section 8.3). Phenacyl esters are more labile towards nucleophilic attack than standard esters but they are stable towards acidic conditions typically employed for deprotection in peptide synthesis such as HF or trifluoroacetic acid. 

Photodeprotection of phenacyl and substituted phenacyl esters promises to be an efficient and mild method for the deprotection of carboxylic acids in biological systems. -  

Methylthiomethyl esters have been prepared by reaction of triethylammonium salts of carboxylic acids with chlorodimethylsulfonium chloride or by reaction of the potassium salts of carboxylic acids with chloromethyl methyl sulfide in the presence of sodium iodide and 18-crown-6.  

---

Example. Dissolve 0 3 g. of />-chlorobenzoic ncid in a small quantity of warm ethanol (about 10 ml.), and ctlrefully add 5 o aqueous sodium hydroxide drop- wise until the solution is just pink to phenolphthalein. Evaporate to dryness on a water-bath. Dissolve the sodium -chlorobenzoate in a minimum of water, add a solution of 0-5 g. of phenacyl bromide in ethanol (about 5 ml.), and boil the mixture under reflux for i hour, and then cool. The phenacyl ester usually ciy stallises on cooling if it does not, add water dropnise with stirring to the chilled solution until separation of the ester just begins. Filter the ester, wash on the filter with water, drain and recrystallise from ethanol m.p. 90 . The /)-bromophenacyl ester is similarly prepared, and after recrystallisation from aqueous ethanol has m.p. 128 . (M.ps., pp. 543-545.)... 

Carboxylic Acids, Benzylthiouronium salts (p. 349), Phenacyl esters (p. 349), /(-Bromophenacyl esters (p. 349), N Benz lamides (p. 350), -Nitrobenzyl esters (p. 350). 

Acid B.P. M.P. 1 Anilide /hToIuI- dlde Amide phcnacyl Ester Nltro- benzyl Ester /)-Phenyl- phenacyl Ester S-Benzyl> Mo-thlu- ronlum Salt -Bromo- anlUde Hydrazlde ... 

Add B.P. H.P Anilide Amide phenacyl Ester benzyl Ester phenacyl Ester uronlum Salt ... 

Acid B.P. H.P. AnlUde p-Tolu4- dide 1 Amide p-Bromo- phenacyl ter p-Nitro- benzyl Ester p-Phenyl phenacyl Ester S-Benzyl- uo-thi- uronium Salt Other Derivatives... 

Under basic coupling conditions an aspartyl peptide that has a /3-phenacyl ester i converted to a succinimide. The use of PhSeH prevents the a,/3-rearrangement c the aspartyl residue during deprotection. 

A phenacyl ester is much more readily cleaved by nucleophiles than are othc esters such as the benzyl ester. Phenacyl esters are stable to acidic hydrolysis (e.g coned. HCh HBr/HOAc 50% CF3COOH/CH2Cl2 HF, 0°, 1 h ). 

Phenacyl esters can be prepared from the phenacyl bromide, a carboxylic acid, and potassium fluoride as base. These phenacyl esters can be cleaved by irradiation (313 nm, dioxane or EtOH, 20°, 6 h, 80-95 % yield, R = amino acids > 300 nm, 30°, 8 h, R = a gibberellic acid, 36-62% yield ). Another phenacyl derivative, RC02CH(C0C6H5)C6H3 3,5-(0CH3)2, cleaved by irradiation, has also been reported. ... 

Phenacyl esters can be prepared from the phenacyl bromide, a carboxylic acid. 

These workers used binary solvent systems over a range of mole fractions to determine, for each solute, the constants a and b of equation (8.2). For methyl and phenacyl esters, TLC was used, while overpressured layer chromatography (OPLC) was used for dansyl amino acids. Nurok and co-workers (11) also evaluated how the quality of a simulated separation varies with changing solvent strength by using the inverse distance function (IDF) or planar response function (PRF), as follows ... 

Substituted phenacyl anthranilates were prepared by reaction of sodium anthranilate with substituted phenacyl halides in DMF. The phenacyl esters were cyclized in polyphosphoric add or by heating to give the respective substituted 2-aryl-3-hydroxyquinoline-4(l. -ones in high yield <95CCC(60)1357>. 

The reaction of ethyl acetoacetate with simple hydroxy ketones has been compared with the corresponding reactions of the ketoses. The results obtained with l-hydroxy-2-propanone and 3-hydroxy-2-butanone, under the same experimental conditions as with D-fructose, establish a parallel between these reactions. However, as in the case of the aldoses, the yield is greater for these simpler hydroxy ketones than for the ketoses.9 The resultant esters, (XV and XVI), were obtained in the form of sirups, but the free acids, (XVII and XVIII), and their phenacyl esters are crystalline. The acids were shown to be identical with those of known structure described in the literature.9... 

H Kuroda, S Kubo, N Chino, T Kimura, S Sakakibara. Unexpected racemization of pro line and hydroxyproline phenacyl ester during coupling reactions with Boc-amino acids. Int J Pept Prot Res 40, 114, 1992. 

CC Yang, RB Merrifield. The P-phenacyl ester as a temporary protecting group to minimize cyclic amide formation during subsequent treatment of aspartyl peptides with HF. J Org Chem 41, 1032, 1976. 

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, easily prepared from carboxylic salts and phenacyl bromide nnder phase transfer catalysis, regenerate the original carboxylic acid by treatment with sodinm hydrogen telluride in DMF. ... 

---