A- phenacyl esters

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 ). 

Perhaps more troublesome than the moderate yields is the necessity for reversed-phase high-performance liquid chromatography (HPLC) to purify the Fmoc protected amino acid glycosides. It has been reported,23 that the carboxylic acid moiety of an amino acid can be protected as a phenacyl ester and after glycosylation be removed with HOAc/Zn° (Scheme 5.7). Thus, a thioglycosyl donor, having a nonparticipating functionality at C(2), was reacted with the Fmoc protected phenacyl ester... 

Due to their increased reactivity toward nucleophiles, dipeptide a-phenacyl esters are prone to piperazine-2,5-dione (DKP) formation. Coupling of amino acid phenacyl esters with an activated carboxy component for dipeptide synthesis often results in substantial cyclization of the amino acid phenacyl esters via Schiff base formation (Scheme... 

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

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.)... 

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. 

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 ... 

A carboxylic acid (not the salt) can be the nucleophile if F is present. Mesylates are readily displaced, for example, by benzoic acid/CsF. Dihalides have been converted to diesters by this method. A COOH group can be conveniently protected by reaction of its ion with a phenacyl bromide (ArCOCH2Br). The resulting ester is easily cleaved when desired with zinc and acetic acid. Dialkyl carbonates can be prepared without phosgene (see 10-21) by phase-transfer catalyzed treatment of primary alkyl halides with dry KHCO3 and K2C03- ... 

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... 

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. 

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). 

The development of light-sensitive protective groups began in the early 1960s [129-131] and led to the identification of several functionalities that could be selectively cleaved under UV irradiation (for a review, see [132]). Some of these protective groups, such as 2-nitrobenzyl esters, carbonates, or carbamates [131,133-135], benzoin [136-139], and other phenacyl esters [140] were also found to be useful as photocleavable linkers. 

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]). 

Elution was performed using a concentration gradient of a methanol-acetonitrile-water ternary mixture. The initial proportions of the components at the beginning of the run were 40 40.5 18.5. The concentration of acetonitrile was then decreased linearly so that it reached 0% at 25 min while its concentration in the mobile phase was replaced with methanol at the same gradient rate. Elution was completed with a linear gradient of the methanol-water mixture so that the mobile phase usually contained 90% of methanol at 60-70 min and was 100% methanol at 90 min. The elution of phenacyl esters of 6 0-22 1 fatty acids was completed within 80 min at a flow rate of 1 ml/min (the detailed composition of the mobile phase is described in Table 1, elution mode E) (Fig. 4). 

An acetonitrile-water mobile phase could not resolve adjacent peaks of palmitoleic (16 1) and arachidonic (20 4) acids. Partial separation could be achieved with a decreased ratio of acetonitrile to water in the mobile phase, as reported by Borch (25), but this was inconvenient, owing to the substantial prolongation of the elution time (up to 4 h at a flow rate of 2 ml/min) and the specific column requirements (90 X 0.64-cm ID). These results demonstrate the importance of the carbon chain length and the number of double bonds with respect to the solubility of phenacyl derivatives in these two solvents. The retention time of phenacyl esters increases with increasing chain length and decreasing number of double bonds. 

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