P-Hydroxy-a-amino acid esters

O Donnell imine 23 with various aldehydes, giving P-hydroxy-a-amino acid esters 44 with high enantiomeric excess,1401 as shown in Scheme 15. 

M. Horikawa, J. Bush-Petersen, E. J. Corey, Enantioselective Synthesis of P-Hydroxy-a-amino Acid Esters by Adol Coupling Using a Chiral Quaternary Ammonium Salt as Catalyst , Tetrahedron Lett. 1999, 40, 3843-3846. 

LLB, LiOH, and H2O promoted the direct aldol reaction of glycinate Schiff bases 12 with aldehydes 3, providing access to p-hydroxy-a-amino acid esters 13 (Scheme 4,bottom) [7],... 

OL, -Dehydroamino acids. N-Protected (Cbo and Boc) (3-hydroxy-a-amino acid esters (ethyl, benzyl) are converted into the corresponding a,p-dehydroamino acid derivatives by DAST and pyridine in CHiCl, at 0° (6.5-90% yield). The hydroxy group is probably converted into the —OSFiNlCiH,), derbative, which undergoes trans-e m -... 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

Shiori and co-workers used 5-substituted 4-oxazolecarboxylic acid esters 379 as p-hydroxy-a-amino acid synthons. They described a straightforward synthesis of 379 by acylation of an isocyanoacetic acid ester with an a-alkoxyacid 378 in the presence of diphenylphosphorylazide (DPPA) or diethylphosphoryl cyanide (DPPC) followed by base-catalyzed cyclization (Scheme 1.104). The reaction conditions do not epimerize optically active a-alkoxyacids. Dilute acid hydrolysis of 379 and reaction with (600)2 affords the protected aminotetronic acids 380. Stereoselective hydrogenation of 380 then yields the 1,4-lactones 381, key intermediates in the synthesis of amino sugars. A variety of a-alkoxyacids were studied, and some examples are shown in Table 1.30. 

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). ... 

P-Eliminations. 3-Elimination of the hydroxy group of TV-protected p-hydroxy-a-amino acids has been effected using DSC and Triethylamine. Reaction of Z-threonine with equimolar DSC/EtyN in acetonitrile gave exclusively the (Z)-isomer of Z-DBut-OMe (eq 4). Similarly, use of a 1 2 molar ratio of DSC gave the (Z)-isomer of Boc-DBut-OSuc, which on treatment with the methyl ester of alanine gave Z-DBut-Ala-OMe (eq 5). 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

Bis-p-nitrophenyl malonate (55M29) reacts with a-alkylamino-isobutyr-onitriles in xylene to give derivatives (16b) of tetramic acids with yields of 30-50% (86UP1 88UP1). The reaction of derivatized malonic acids with a-amino acid esters to 3-alkoxycarbonyl-l,5-dihydro-4-hydroxy-2-pyrrolones presents the same problems (see Section III). (See Fig. 8.)... 

Aziridine-2-carboxylic acid residues in peptides are isomerized with Nal and acetone to the corresponding dehydro-amino-acid component. p-Hydroxy-amino-acids are effectively dehydrated by NiV -carbonyldi-imidazole to give the corresponding dehydro-amino-acids. 2-Azidocarboxylic esters (286) are effectively converted into A-acetyldehydro-a-amino-acid esters (287) (Scheme 141) 4oa Esters of A-acyl-2-(diethoxyphosphoryl)glycine have been used in the synthesis of dehydro-amino-acid esters. ... 

Figure 11.85 Diastereoselective synthesis of an e.p. (2R,3S)-p-hydroxy-a-amino[l,2- C2]-carboxylic acid from (2S)-f C2]BABS via a (2R,3R)-oxirane[l,2- C2lcarboxylic acid ester...

The use of the aldol condensation to synthesize y-amino-p-hydroxy acids suffers from several drawbacks, such as possible racemization either of the initial carboxy group during its transformation to the a-amino aldehyde, or during any subsequent manipulations of the sensitive CHO moiety. An alternative route involves the direct activation of the carboxy group of the N-protected a-amino acids 30 followed by alkylation with enolates 17 to produce the corresponding p-oxo esters 31.[36 521 The P-oxo esters can be selectively reduced under various conditions to produce diastereomeric mixtures of the target compounds 18 but with retention of the chirality of the initial a-amino acid (Scheme 8). 

N-Methylated y-amino-p-hydroxy acids are accessible by the usual synthetic sequences, i.e. aldol condensation or y-amino-P-oxo ester reduction, starting from the corresponding N-methylated a-amino acids, but are obtained with low diastereoselectivity. 61-63 Alternatively, Brown allylboration of the ALBoc-ALMe amino aldehyde 16 (R1 = Bzl, X=Boc, Y = Me) gives the allyhc N-methylated intermediate 27 in 64% yield and 90% de (Scheme 12). 64 Oxidative cleavage of the alkenol is performed using the two-step ozonolysis and sodium chlorite oxidation sequence. 

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