N-phthaloyl amino acid

Auterhoff and Hansen (1970) showed that the CD spectra of N-phthaloyl-amino acids are sensitive to the polarity of the solvent and come to the conclusion that reliable coordination between the sign of the first Cotton effect and the absolute configuration is not possible. 

The incorporation of N-phthaloyl amino acids into the dirhodium(II) platform afforded excellent asymmetric cyclopropanation catalysts [81b, 97]. In contrast to other phthaloyl catalysts [97], the X-ray crystal structure of Rh2(S-PTTL)4 (2), reported by Fox et al. revealed that the four phthalimido groups are situated on one face of the catalyst in a chiral crown structure (Figure 9.10) [93]. The four Bu- groups are directed on the other face of the catalyst, and aU C- Bu bonds are parallel to the Rh-Rh bond. Compound 2 exhibits high diastereoselectivity and yields for cyclopropanation with a-alkyl-a-diazoesters (Table 9.2, entry 2). The enantiomeric excess (ee) increases with the a-alkyl diazoester substituent size, and the highest 99% ee and 95% yield were achieved in the reaction of styrene with ethyl-2-diazo-5-methylhexanoate [93]. 

Easton, C.J. and Hutton, C.A., Recent developments in the use of N-phthaloyl-amino acid derivatives in synthesis, Synlett, 457, 1998. 

As shown by Sato et al. N-phthaloyl derivatives of C-unprotected amino acids efficiently undergo decarboxylation upon irradiation [248,249]. In this case, the iV-phthaloyl a-amino acid of methionine 310 represents an exception, because the normal decarboxylation route is not followed. Two main products are obtained, the trans-hydroxy acid 313 and the tetracyclic lactone 314 [250, 251]... 

A much more elegant synthesis of polyimides by amine-imide exchange is based on the reaction of iV-ethoxycarbonyl phthalimides with amino acids to yield phthaloyl substituted amino acids [106]. Thus, reaction of N,N-bis(ethoxycarboxy)pyromellitimide with p, p-oxydianiline in NMP at room... 

Phthalimide protection is stable towards acids and bases, but can be cleaved with strong nucleophiles, such as hydrazines or sulfides, or by reduction with sodium boro-hydride [230]. More sensitive towards nucleophilic attack than unsubstituted phthalimide is tetrachlorophthalimide [33]. This group has been successfully used as N(a) protection of amino acids in the solid-phase synthesis of peptides (deprotection N2H4/DMF (15 85), 40 °C, 1 h coupling DIC/HOAt/amino acid (1 1 1), 3 equiv. of each, DMF, 25 °C, 4 h [294]). Typical conditions for the removal of phthaloyl protection on cross-linked polystyrene include treatment of the resin with hydrazine hydrate [295,296], with methyl hydrazine [297], or with primary aliphatic amines [298] in DMF, EtOH, or solvent mixtures for several hours at room temperature or above [296,299,300]. Illustrative examples are sketched in Figure 10.15. It has been claimed that the hydrazinolysis of polystyrene-bound phthalimides proceeds more readily in DCM or DCE than in DMF [301]. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

The phthalimlde group is typically introduced by reaction of a primary amine with phthalic anhydride in chloroform at 70 °C for 4 h (85-93% yield)1 or phthaloyl chloride in the presence of triethylamine [Scheme 8.10].20 2-Ch oro-carbonylbenzoic acid methyl ester in the presence of base [Scheme 8.11JT21-22 or N-ethoxycarbonylphthalimide23 have also been used with the latter reagent being especially useful for the -protection of a-amino acids [Scheme 8 12] m. 24... 

N-Phthaloyl derivatives of a-amino acids and alcohols can be obtained without racem-ization by reaction with 1 in THF (addition of triethylamine can be helpful). The HjNCOOCjH, also formed can be removed by evaporation under reduced pressure. Yields are generally 70-80%."... 

While the Al -phthaloyl (Phth)P 9 and Al -dithiasuccinoyl (Dts)t derivatives of amino acids are used as reversible protecting groups, the aliphatic N-maleoyl groupt is mainly exploited as a reactive handle for postsynthetic modifications of peptides with thiol-functionalized labels and probes, e.g. carbohydrates, lipids, and chromophores. These N -diacyl derivatives are highly stable to even strong acids, but are cleaved under basic conditions. 

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. 

Within A -Phth-protected amino acid derivatives the C—N bond is extremely susceptible to basic and nucleophilic conditions, thus, leading to unwanted base-catalyzed side reactions of the Phth derivatives in the course of synthetic steps. The applicability of the phthalimido chemistry has been extended by converting the phthalimido moiety into the corresponding 2-(pyrrolidinocarbonyl)benzamide derivative 81, thereby eliminating the base- and nucleophile-sensitivity of the parent phthaloyl derivative (Scheme... 

The major synthetic use of GABA is to prepare functionalized and/or substituted GABA derivatives. A simple example reacted N-phthaloyl-4-aminobutanoic acid (1.210) with ethanolic bromine and red phosphorus to give ethyl 2-bromo-4-phthal-imido butanoate, 1211. Clearly, the labile bromine moiety in 1.211 can be converted to a variety of other functionality via elimination or substitution reactions, making it an important synthetic intermediate. This is illustrated with 4-amino-... 

The same amino acid was prepared from N-phthaloyl alanine (6.229), which was converted to 6.230.136 Reduction of the ketone moiety led to 6.231, which is the phthalimide derivative of 6.226.134.135... 

The remarkable acylating properties of j3-thiolactones were recognized soon after the first thiolactone was synthesized. Knunyants and his coworkers prepared, in 1955, a pentapep-tide starting with a-acylamino-j3,j3-dimethyl-j5-thiolactone [16,17]. Optically active polypeptides containing cysteine were prepared by Fles et al by condensation of (7 )(-)-N-phthaloyl-, or (i )(+)-7V-tosyl-j8-thiolactone with esters of a-amino acids [3,10,18]. Preparation of polypeptides was performed at room temperature in dioxane as solvent. 

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