Protected primary amino acids

This type of catalyst is created by simply introducing protection to the functional group at the side chain of amino acids (8-11). In particular, a L-threonine core has been shown to be extremely powerful in asymmetric induction. Hydrophobic protective groups were often introduced, and it is beheved that hydrophobic effects might play important roles for reactions performed in aqueous medium. 

Quite recently, chiral diamines have been recognized as effective catalysts in asymmetric catalysis [16]. Utilizing primary amino acid structural scaffolds, several novel diamine catalysts have been developed, which can be classified as primarysecondary diamines (12-14) and primary-tertiary diamines (15-18). Notably, such diamines are often used in combination with Bronsted acid additives for effective activation of substrates. 

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A series of lithium salts of protected primary amino acids (105, n = 0-2) catalyse asymmetric Michael addition of malonates to 2-cyclohexen-l-one. The -amino salt (n = 1) gave higher ee than either the y- or the a-. A mechanistic study using DPT has been carried out to identify how the -amino salt better coordinates the imine intermediate and maximizes ee. 

This group was developed for the protection of amino acids. It is formed from 4-ethoxy-l,l,l-trifluoro-3-buten-2-one in aqueous sodium hydroxide (70-94% yield). Primary amino acids form the Z-enamines, whereas secondary amines such as proline form the -enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane at rt. ... 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

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]. 

Protection of pyrroles and indoles. These heterocycles undergo t-butoxycar-bonylation in 80-95% yield on reaction with 1 and a catalytic amount of DMAP in acetonitrile. The Boc group is cleaved almost instantaneously by TFA at 25°.1 The same conditions are useful for protection of the indole group of tryptophan.2 Primary amino acid esters can be converted into bis(Boc) derivatives, and amino groups of peptides also undergo t-butoxycarbonylation.3... 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

The primary amine of an amino acid as its tosylate salt can be protected by coordination with a crown ether. The protection scheme was sufficient to allow the HOBt/DDC coupling of amino acids. The crown is removed by treatment with diisopropylethylamine or KCl solution. 

This group was developed for the protection of primary amides of amino acids. It is introduced by amide bond formation with the benzhydrylamine. It is cleaved with 1 MSiCl4/anisole/TFA/0° or 1 MTMSOTf/thioanisole/TFA, 0°. Cleavage occurs by initial sulfoxide reduction followed by acidolysis. ... 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

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