Reduction of a-Amino Acids

This reaction is applicable to the reduction of a-amino acids to optically active a-amino aldehydes with high yields (Scheme 27) [53]. 

In a later report1, a total of 13 different auxiliaries were tested. These were based mainly on O-silylated or alkylated /1-amino alcohols, the precursors of which were available commercially or by reduction of a-amino acids. The /1-amino alcohols used were, for example, both enantiomers of 2-amino-3-methyl-l-butanol (valinol), (A)-2-amino-l-propanol (alaninol), (A)-... 

Enantiomerically pure aminoalcohols, which are readily available by reduction of a-amino acids, can be converted into alkoxycarbonylating reagents suitable for the solid-phase synthesis of oligocarbamates (Figure 16.26). Particularly convenient alkoxycarbonylating reagents are 4-nitrophenyl carbonates, which can be prepared from alcohols and 4-nitrophenyl chloroformate, and which react smoothly with aliphatic primary or secondary amines to yield the corresponding carbamates. 

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. 

Scheme 10 Reduction of a Amino Acid Thiazolidine Derivative1561...

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

The most convenient method of making a-aminoaldehydes is by reduction of a-amino acid esters using sodium amalgam [5, 6] by what has come to be known as the Akabori method. Alternatively, an a-halogenocarbonyl compound can be converted via the Gabriel synthesis into the aminocarbonyl... 

When employed in stoichiometric amounts, the oxazolidinone auxiliaries can be recovered and reused. Moreover, they are readily prepared by reduction of a-amino acids followed by conversion of the resulting 1,2-amino alcohols to the N-acyloxazo-lidinones. Both enantiomers of a given oxazolidinone are accessible. ... 

Akabori amino acid reactions. (1) Formation of aldehydes by oxidative decomposition of a-amino acids when heated with sugars. (2) Reduction of a-amino acids and esters by sodium amalgam and ethanolic hydrochloric acid to the corresponding a-amino aldehydes. (3) Formation of alkamines by... 

A classical synthesis of alkyl- and arylpyrazines involves dimerization of a-amino carbonyl compounds, which may be produced by many methods such as reduction of a-oximino ketones, aminolysis of a-halogeno ketones (Section 6.0T11.2), oxidation of a-amino alcohols and reduction of a-amino acids . The condensation of 1,2-diamines with a-dicarbonyl compounds is available for the synthesis of particularly quinoxaline derivatives (Section 6.03.11.1). The synthetic methods which rely on self-condensation, however, provide only symmetrically substituted pyra-... 

The utilization of a-amino acids and their derived e-amino 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-amino 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 g-amino alcohols can, In turn, be transformed Into oxazol1dinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions,5 enolates of N-acyl oxazolIdinones have been used in conjunction with asymmetric alkylations,5 halogenations,7 hydroxylations,8 acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

SCHEME 2. Formation of a-amino aldehydes via the reduction of a-amino acids or esters with sodium amalgam In the presence of ethanollc HCI. 

It should be noted that there are several other means by which the key a-aminocarbonyl intermediates of the Gutknecht synthesis may be prepared besides by the reduction of a-oximino ketones. The oxidation of a-aminoalcohols, reduction of a-amino acids and their derivatives, hydrolysis of a-acetamido ketones formed from a-amino acids and acetic anhydride by the Dakin-West reaction, and the reduction of a-azido, a-diazo, and a-nitro ketones all lead to dihydropyrazines by way of a-amino ketones. The Gastaldi synthesis provides an alternate use of a-oximino ketones, to afford dicyano pyrazines. ... 

Reduction of a-amino acids and esters by sodium amalgam and ethanolic hydrogen chloride to the corresponding a-amino aldehydes ... 

Chiral bis(oxazolines) such as 6, 8, or 9 are attractive ligands because they are easily synthesized from amino alcohols (Scheme 9). A wide variety of enantiomerically pure amino alcohols are commercially available while others are readily prepared by reduction of a-amino acids. Although oxazolines have... 

Ring fission occurs readily in many of these compounds. For example, azlactones, i.e. 4JT-oxazolin-5-ones containing an exocyclic C=C bond at the 4-position (508), are hydrolyzed to a-benzamido-a,/3-unsaturated acids (509), further hydrolysis of which gives a-keto acids (510). Reduction and subsequent hydrolysis in situ of azlactones is used in the synthesis of a-amino acids e.g. 508 -> 507). 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Ketoximes and oximes of 2-oxo-acids are hydrogenated to amines by [CoH(CN)5]3-. The latter reaction allows the preparation of a-amino-acids by reductive amination of 2-oxo-acids in aqueous ammonia. At 40-50 °C and 70 bar H2 the yields are ca. 90% [146]. 

There are very few reactions of real synthetic significance which proceed via condensation of two 1,3-electrophile-nucleophile species. Probably the most important of this latter type of reaction is the synthesis of pyrazines by self-condensation of an a-acylamino compound to the dihydropyrazine followed by aromatization (equation 132). The a-acylamino compounds, which dimerize spontaneously, are normally generated in situ, for example by treatment of a- hydroxy carbonyl compounds with ammonium acetate or by reduction of a-azido, -nitro or -oximino carbonyl compounds. Cyclodimerization of a-amino acids gives 2,5-dioxopiperazines (equation 133), many derivatives of which occur as natural products. Two further reactions which illustrate the 1,3-electrophile-nucleophile approach are outlined in equations (134) and (135), but su i processes are of little general utility. 

Asymmetric Hydrogenation. Asymmetric hydrogenation with good enantio-selectivity of unfunctionalized prochiral alkenes is difficult to achieve.144 145 Chiral rhodium complexes, which are excellent catalysts in the hydrogenation of activated multiple bonds (first, in the synthesis of a-amino acids by the reduction of ol-N-acylamino-a-acrylic acids), give products only with low optical yields.144 146-149 The best results ( 60% ee) were achieved in the reduction of a-ethylstyrene by a rhodium catalyst with a diphosphinite ligand.150 Metallocene complexes of titanium,151-155 zirconium,155-157 and lanthanides158 were used in recent studies to reduce the disubstituted C—C double bond with medium enantioselectivity. 

The optically active N-aminoindoline (265) has been applied to the asymmetric synthesis of a variety of a-amino acids (70JA2476, 2488). Starting from TV-benzoyl-1,2,3,4-tetrahy-droquinaldine (257), the chloro amide (258) was prepared by von Braun cleavage. Thermolysis converted (258) to the rrans-unsaturated amide (259) which was epoxidized. On base treatment the epoxide (260) underwent intramolecular nucleophilic displacement and amide hydrolysis to afford indoline (261) stereospecifically. Resolution of (261) was accomplished via the brucine salt of the N-o-carboxybenzoyl derivative (262). Alkaline hydrolysis, N-nitrosation and reduction yielded the levorotatory 1-aminoindoline (265). Reaction of... 

Na-Protected a-amino aldehydes 4 are mainly obtained from their corresponding a-amino acid derivatives. Generally the synthetic route proceeds via acid halides, esters, or active amides of a-amino acids that are then reduced. The reduction of N -protected acid halides and esters is often accompanied by some overreduction to the respective alcohols. However, reduction of active amides is apparently free from overreduction. The different procedures described in this review are listed in Table 3. 

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