Phthaloyl group

Epimerization at C(5) has not been observed under the conditions discussed for the preparation of C(6) epimers (see Section 5.11.3.8.4). It is possible to prepare 5 -epipenicillins, however, as shown in Scheme 28. Note particularly the successful removal of the phthaloyl group (step iii) in this sequence, a procedure which leads to /3-lactam cleavage when C(5) is the R, or natural, configuration. Silylation of (35) followed by DBN treatment afforded (36), which corresponds to epimerization at C(3), and (37), which corresponds to epimerization at C(3) and C(6). No product corresponding to only C(6) epimerization was observed (76JOC2561). 

The monothioacetal is also stable to 12 N hydrochloric acid in acetone (used to remove an TV-triphenylmethyl group) and to hydrazine hydrate in refluxing ethanol (used to cleave an A -phthaloyl group). It is cleaved by boron trifluoride etherate in acetic acid, silver nitrate in ethanol, and tiifluoroacetic acid. The monothioacetal is oxidized to a disulfide by thiocyanogen, (SCN)2- ... 

Figure 10.15. Examples of nucleophilic cleavage of phthaloyl groups [298,302],...

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

Gabriel synthesis, which is most often considered as a classical approach to primary amines, can be generalized as monoalkylation of a suitably protected ammonia derivative with subsequent removal of the phthaloyl group from nitrogen. Despite its wide applicability this procedure suffers, however, from several drawbacks ... 

The N -phthaloyl group (Phth), well known for the preparation of primary amines in the Gabriel synthesis,P was used more extensively as a temporary backbone amine protecting group in the early period of amino acid and peptide chemistry.t The resulting phthalimides ensure exhaustive substitution of the primary amine, i.e. removal of both acidic hydrogens, thus, moderating the nucleophilic character. 

Several methods have been developed for phthaloylation of primary amines. Originally, the phthaloyl group was introduced by treatment of anoino acids with phthalic anhydride at elevated temperatures of around The harsh reaction conditions of this... 

H-Phe-Gly-0H"H20 Typical Procedure for Cleavage of the Phthaloyl Group with Hydrazine Hy-drate ... 

After converting A -Phth-protected amines into the corresponding 2-(pyrrolidinocarbon-yl)benzamide derivative, Dieckmann reactions, ester hydrolysis, and transesterfication can be carried out. This strategy of pyrrolidine-based deactivation of phthaloyl-protected anoines followed by reclosure of the phthaloyl group has successfully been applied in the synthesis of (3-lactam antibiotics.P l... 

The crude product obtained in the preceding experiment is dissolved in ethanol (40 mL). after addition of hydrazine hydrate (1(X)%, 10 mL), the solution is stirred at 80°C for 1 h (removal of the phthaloyl group). Acetone (30 mL) is added, and the mixture is concentrated in vacuo. CodistiUation with acetone (30 mL) is repeated twice to remove hydrazine as the azine. The remainder is dried under high vacuum and dissolved in pyridine-acetic anhydride (2 1, 50 mL). After stirring for 18 h, concentration in vacuo, and codistillation with toluene (30 mL), the crude 33 is purified by flash chromatography on silica gel (70 g). Elution with acetone and then with dichloromethane-methanol 30 1 yields pure 33 overall yield 581 mg (72%) mp 137°C [a] -72.5 (c 0.25, CH Clj) R, 0.4 (CHCI3-CH3OH 10 1). 

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