Of a-hydroxy-P-amino acid

The syntheses of a-hydroxy P-amino acids has also been accomplished using a perhydropyrimidin-4-one template to direct the stereoselectivity of the hydroxylation,39 For example, the enolate of perhydropyrimidin-4-one 52 was diastereoselectively hydroxylated to obtain S3.40 Examination of several oxidizing agents and bases revealed LiHMDS and the... 

Ozonolysis/Oxidatlon Synthesis of a-Hydroxy-(3-Amino Acids (/ , )-2-Hydroxy-3-pentenenitrile was also shown to be an excellent chiral starting material for the s5mthesis of a-hydroxy-P-amino acids of high enantiomeric and diastereomeric purity [145] (Scheme 24). In this case the first step can be a DIBAL reduction (R = H) or a Grignard reaction (R = alkyl or aryl) and the ozonolysis is directly followed by oxidative workup (Jones reagent). Hydrolysis of the oxazolidinones provided the desired A -protected a-hydroxy-P-amino acids. 

A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-a-isocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to A,A-dibenzylphenylalanal 111 led predominantly to the awfi-adduct 112 (dr = 9 1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>. 

Similarly, the acid hydrolysis of p-lactam 7 has been described [55] to give the a-hydroxy p-amino acid 8, a suggested A -terminal component of angiotensinconverting enzyme inhibitor microginin 4, Scheme 2. The key precursor 7 was obtained through a Wittig olefination of the 4-formyl p-lactam 5, followed by simple elaboration of the resulting 6 (for a review on the use of 4 formyl p lactams in synthesis, see [56]). 

Kambourakis S, Rozzell JD. Ketoreductases in the synthesis of valuable chiral intermediates Application in the synthesis of a-hydroxy p-amino and p-hydroxy y-amino acids. Tetrahedron 2004 60 663-669. 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a, 3-unsaturated 2-acyl imidazoles. For example, C-phenyl 7V-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

Therefore we were interested in the development of a method for the asymmetric synthesis of cyclic and acyclic 5-hydroxy-P-amino acids 83-85 (Fig. 1.3.8). 

The synthesis of the protected 5-hydroxy P-amino acids 91 required a stereoselective amination of the vinyl sulfoximine 4 (Scheme 1.3.29). Carbamoylation of alcohols 4 with trichloroacetyl isocyanate afforded carbamates 86 in high yields. 

Work from this laboratory has demonstrated the synthetic potential of the ring opening at C2-C3 bond of a-hydroxy p-lactams to produce a-amino acid derivatives, Fig. 7. 

The hydroxynitrile lyase (HNL) class of enzymes, also referred to as oxynitrilases, consists of enzymes that catalyze the formation of chiral cyanohydrins by the stereospecific addition of hydrogen cyanide (HCN) to aldehydes and ketones (Scheme 19.36).275 279 These chiral cyanohydrins are versatile synthons, which can be further modified to prepare chiral a-hydroxy acids, a-hydroxy aldehydes and ketones, acyloins, vicinal diols, ethanolamines, and a- and P-amino acids, to name a few.280 Both (R)- and (.S )-selective HNLs have been isolated, usually from plant sources, where their natural substrates play a role in defense mechanisms of the plant through the release of HCN. In addition to there being HNLs with different stereo-preferences, two different classifications have been defined, based on whether the HNL contains a flavin adenine dinucleotide (FAD) co-factor. 

Although N -benzylated amino acids or peptides are known to be sterically hindered with respect to anninoacylation, acylation of A -(2-hydroxybenzyl) (Hbz) amino acid derivatives proceeds surprisingly well.P As shown in Scheme 1, the initial step in aminoacylation of A -Hbz-derivatized amino acid residues (Y = H) is esterification of the hydroxy group, which is followed by intramolecular, base-catalyzed O N acyl migration to produce the peptide bond.P l... 

Wahl, P., Anker, C., Traynelis, S.F., Egebjerg, J., Rasmussen, J.S., Krosgaard-Larsen, P., Madsen, U., 1998. Antagonist properties of a phosphono isoxazole amino acid at glutamate RI-4 (R,S)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid receptor sub-types. Mol. Pharmacol. 53, 590-596. 

Scheme 13.25) [70]. To demonstrate the utility of isoxazolidine adducts and 2-acyl imidazole moiety as a template, the conversions of the product to P hydroxy-P-amino acid derivatives were also reported. 2-Acyl imidazole moiety was converted into methyl ester in 97% yield through methylation with MeOTf, followed by treatment with MeOH/DBU (Scheme 13.25). 

Ring-opening of aziridinecarboxylic acids has been used in the conversion of threonine into /Areo-3-methylcysteine and in the synthesis of p-alkoxy-a-amino-acids. Improved methods have appeared for the synthesis of iV-(phosphono-acetyl)-amino-acids and for the preparation of y-esters of glutamic acid and (3-esters of aspartic acid. The protected P-hydroxy-a-amino-acids (278) are converted into a-fluoro-P-amino-acids (279) with DAST (Scheme 137). ... 

The a-methylene-p-hydroxy esters were obtained in the (R) configuration and the dioxanone in the (S) configuration, whereas the reaction with aromatic imines led to (S)-enriched N-protected-a-methylene-P-amino acid esters [44]. The mechanistic proposal for the reaction with imines, as shown in Figure 6.7, indicates more steric interaction in intermediate B than in intermediate A. As a result, intermediate A reacts to form the Morita-Baylis-Hillman product, whereas intermediate B prefers to redissociate into reactants. The difference in the rate of the elimination step of the two intermediates leads to the preference for the (S) configuration through equilibration between intermediates A and B. 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

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