Amino acid derivatives, asymmetric synthesis

Recent developments regarding the utility of chiral amino acids in asymmetric synthesis of natural products were reported. Examples of such syntheses are the preparation of carbohydrates from (S)-glutamic acid 257), (S)-alanine 258), or (S)-threonine 259), and syntheses of alkaloids 260), terpenes 26I), peptide 262) derivatives, and toxines 263>. 

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

By using a mixture of ethyl acetate and D2O as solvent for hydrogenation, up to 75% deuterium is incorporated in the reduced product.13 This result indicates that the role of water here is not only as a solvent. Research on asymmetric hydrogenation in an aqueous medium is still actively being pursued. The method has been applied extensively in the synthesis of various amino acid derivatives.14... 

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the first example of a metal-catalyzed enan-tioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2-59). 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

D.M. Shendage, R. Froehlich, K. Bergander, G. Haufe, Asymmetric synthesis of y-fluorinated a-amino acid derivatives, Eur. J. Org. Chem. (2005) 719-727. 

Most commonly, a-phenylethylamine is used as chiral amine in the asymmetric Strecker synthesis. Amino acid derivatives have also been used quite successfully as chiral amines. Especially (S)-tert.-butylglycine tert.-butyl ester was proven to be a powerful chiral inductor iM>). The optical yields were as high as 96.5%. The best results were obtained in nonpolar solvents such as n-hexane 140>. 

The asymmetric Strecker synthesis was also applied in the preparation of other chiral products. In these reactions japanese chemists 141> always used amino acid derivatives as the chiral amine component which is responsible for the induction of asymmetry. 

The bacteriostatic gliotoxin was prepared206 by a total synthesis involving an asymmetric Michael-addition. A chiral amino acid derivative served as chiral auxiliary in the key step. 

Scheme 1.3.12 Asymmetric synthesis of the a-amino acid derivatives 26 and -27.

To conclude the asymmetric synthesis of the new bicyclic amino acids the protected amino acid 81 was treated with CF3SO3H in CH2CI2, affording the amino acid derivative 82 in high yield [51]. 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192], The (+)- or (-)-lO-(N, Af-dicyclohexylsulfamoyl)isobomeol was used as chiral auxiliary in the intramolecular cyclization of /V-(/>methoxybenzyI)-/V-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the (1-lactam ring (Scheme 85). 

It is also important to note that the potential synthetic utility of the asymmetric alkylation protocol discussed in this section has been fruitfully demonstrated by its application to the stereoselective synthesis of various biologically adive natural products possessing unique a-amino acid derivatives as their structural components [27,28]. 

Cinchona alkaloids, of course, have occupied the central position in the design of chiral PTCs. By employing a simple chemical transformation of the tertiary amine ofthe natural cinchona alkaloids to the corresponding quaternary ammonium salts, using active halides (e.g., aryl-methyl halides), a basic series of PTCs can be readily prepared. Cinchona alkaloid-derived PTCs have proved their real value in many types of catalytic asymmetric synthesis, including a-alkylation of modified a-amino acids for the synthesis of higher-ordered a-amino acids [2], a-alkylation of... 

Besides the asymmetric alkylation of 1 for the synthesis of higher a-amino acid derivatives, the Park-Jew group applied their dimeric cinchona-PTCs to the... 

The vast synthetic utility of the asymmetric phase-transfer alkylation of glycine Schiff base 2 has been realized by its successful application to the synthesis of various useful amino acid derivatives and natural products. 

Scheme 8.1 Asymmetric synthesis of amino acid derivatives.

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Very recently the Shibasaki group extended the range of application of their asymmetric two-center catalysts 31 to the synthesis of amino acid derivative intermediates for aeruginosin 298-A and analogs thereof [39]. Aeruginosin has a tetrapeptide-like structure and contains non-standard a-amino acids. The synthesis of the key intermediate (S)-20r, bearing a bulky substituent, is shown in Scheme 3.17 [39]. In the presence of the catalyst R,R) 31 the desired amino acid derivative (S)-20r was obtained in 80% yield and with 88% ee [39]. The catalyst 31, which is very stable under basic conditions, could be recovered in 80-90% yield and re-used efficiently [39]. 

Synthesis of Unnatural Amino Acid Derivatives by Asymmetric Alkylation... 

Lygo has extended his asymmetric alkylation methodology to the synthesis of bis-a-amino acids (Scheme 4) [11], Bis-amino acids, such as meso-diaminopirnelic acid, dityrosine and isodityrosine, are found in nature and are thought to act as cross-linking agents which stabilise structural proteins in plants and bacteria. For example, asymmetric alkylation of the Schiff base 3 with the dibromide 13, catalysed by the quaternary ammonium salt le, gave the bis-amino acid derivative 14 in >95% ee. 

Asymmetric Catalytic Aminoalkylations New Powerful Methods for the Enantioselective Synthesis of Amino Acid Derivatives, Mannich Bases, and Homoallylic Amines... 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate a-amino nitriles to provide a-amino acids (Scheme 1), was first reported in 1850 [1], This method has been applied on an industrial scale toward the synthesis of racemic a-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of a-amino acids [2]. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of a-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance. 

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