3-Hydroxy-2-amino esters

Stereoselective syn-aldol reaction syn-3-hydroxy-2-amino esters Reaction of the lithium enolate of ethyl N, N-dimethylglycine (1) with aldehydes in the presence of B(C2Hs)3 (1 equiv.) results in. ry -3-hydroxy-2-amino acid esters in >95% de (equation 1). The high diastereoseiectivity is explained by the exclusive or predominant... 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

The Sharpless regioreversed asymmetric aminohydroxylation protocol was used as a key step in the total synthesis of ustiloxin D by M.M. Joullie and co-workers.The ( )-ethyl cinnamate derivative was subjected to in situ generated sodium salt of the N-Cbz chloroamine in the presence of catalytic amounts of the anthraquinone-based chiral ligand to afford the desired A/-Cbz protected (2S,3R)-(3-hydroxy amino ester in good yield and with good diastereoselectivity. 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

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-... 

Corey s auxiliary reagent 10 is also applied in order to obtain a f/-2-bromo-3-hydroxy-carboxylic esters in enantiomeric purities of 91-98%. The a-bromo esters thus obtained are useful intermediates for the preparation of a-unsubstituted /Miydroxy esters as well as for 2-amino-3-hydroxy- and 3-amino-2-hydroxycarboxylates64a b. 

Amino- und Hydroxy-carbonsaure-ester werden mit iiberschiissigem Natrium-bis-[2-methoxy-athoxyj-dihydrido-aluminat in siedendem Benzol innerhalb einiger Minuten re-duziert7. 

Yu, H., and Langer, R., Pseudopoly(amino acids) A study of the synthesis and characterization of poly(acyl-hydroxy-proline esters). Macromolecules. 22, 3250-3255, 1989. 

Succinic anhydride also may react with protein phenolate side chains of tyrosine residues and the —OH group of aliphatic hydroxy amino acids (Figure 1.82). The phenolate ester derivatives are unstable above pH 5.0, whereas the serine and threonine esters are more stable but may be cleaved by treatment with hydroxylamine at basic pH (Gounaris and Perlman, 1967). 

Cyanohydrins are starting materials of widespread interest for preparing important compounds such as a-hydroxy acids/esters, a-amino acids, / -amino alcohols, a-hydroxy aldehydes, vicinal diols, and a-hydroxy ketones. Cyanohydrin compounds can be synthesized using various chiral catalysts such as cyclic... 

The most widely applied principle is haptenylation of amino groups via A-hydroxy succinimide esters (NHS-ES). For convenient protein-labeling procedures,... 

Similarly, treatment of a-tosylamino-substituted allene 83 provided the expected a-amino ester 232 in good yield [74], The analogous reaction could also be performed with methoxyallene-aziridine adduct 46, which furnished enantiomerically pure /3-amino acid 233 [46], Although the ozonolysis approach seems to constitute a versatile and flexible method for the construction of a-amino and a-hydroxy esters, only a few examples have been reported so far. 

After protection, the a-hydroxy esters can be reduced by DIBAL-H into O-protected a-hydroxyaldehydes that are very useful synthetic intermediates (e.g., leukotrienes,7-9 ionophore antibiotics,10 insect pheremones,11 etc.). The secondary hydroxyl group of the a-hydroxy esters may also be substituted with inversion of configuration after activation as triflates of nosylates (p-nitrobenzenesulfonates) to give a-alkyl esters12 ora-amino esters.13... 

B. Methyl 2-(benzylamino)methyl-3-hydroxybutanoate. A dried, 2-L, onenecked, round-bottomed flask, equipped with a magnetic stirring bar, is charged with 68.7 g (0.53 mol) of methyl 3-hydroxy-2-methylenebutanoate and 800 mL of anhydrous methanol. After the addition of 57.7 mL (0.53 mol) of benzylamine (Note 1), the mixture is stirred at room temperature for 48 hr (Note 3). The methanol is removed under reduced pressure to leave 125.6 g (100%) of the amino ester as a clear oil, essentially pure by 1H NMR analysis (Note 4). 

Reduction of Hydroxy Esters, Amino Esters, Keto Esters, Oximino Esters and Ester Acids... 

Table 28 Reduction of hydroxy esters, amino esters, keto esters, oximino esters and add-esters...

A stereochemical behavior similar to that of the 1-bromo-l-lithio aUcene 164 with regard to chiral aldehydes is shown by the hthiated methoxyallene 183. When added to iV,iV-dibenzylated a-aminoaldehydes 188, it reacts with non-chelate control so that awh -carbinols 189 are obtained predominantly. Diastereomeric ratios of 189 190 range from 80 20 to 95 5. As outlined above, the hydroxyalkylated allenes 189/190 can be converted into furanones 191/192 upon treatment with potassium f-butoxide and subsequent acid hydrolysis" . When, on the other hand, the adducts of 183 to the aldehydes 193 are submitted to an ozonolysis, A-protected a-hydroxy-/3-amino esters 194/195 result (Scheme 25)"" . 

The scope was then extrapolated to the two-step three-component aza-Baylis-Hillman setup to obtain (3-amino-a-methylene structures. A two-step approach was chosen to avoid the competition between the aldehyde and the imine for the reaction with the enolate, that would lead to mixtures of Baylis-Hillman and aza-Baylis-Hillman adducts, that is (3-hydroxy and (3-amino esters [87]. 

The title phosphonate and related substances undergo thermal decomposition to B-acyl ketenes at temperatures in excess of 50°C. Thus thermolysis in the presence of alcohols, amines, a-hydroxy esters, and a-amino esters affords the corresponding g-keto esters and amides the latter two classes can be cyclized upon subsequent base treatment to unsaturated tetronic and tetramic acids and the related phosphonate reagents. ... 

By ozonolysis and subsequent in situ acylation in the presence of base, the enantiopure 1,2-oxazine 177 (R = Bn) was converted to the highly functionalized a-amino-/ -hydroxy ester 181 along with a minor product 5-hydroxylated oxazine 182 <2005EJ0998>. Similarly, D-erythrose-derived syn- and 7 // -compounds 183 afforded the expected diastereomeric syn- and /f-oxazine esters 184 and 5-hydroxylated oxazine 185 <2005EJ0998>. The arbinose-derived anti-configured 1,2-oxazine 186 was subjected to an ozonolysis/elimination sequence which provided the desired functionalized a-amino ester 187 in 75% yield. 

Strongly acidic conditions gives the amino alcohol. However, the reaction can be stopped at an intermediate stage if it is carried out under mild conditions. For example, the initially formed amino ester can be isolated or trapped in certain cases although it is more commonly rearranged to the hydroxy amide, typically under mildly basic conditions (Schemes 8.88 and 8.89). The configuration of the oxazoline at the 4 and 5-positions is normally retained under the hydrolysis... 

For other chiral reagents and application of this method to other classes of compounds, such as a-amino esters, a-hydroxy esters, amino alcohols, chiral a-deuterated benzylamine, phosphorus compounds, and the use of nuclei other than hydrogen (l3C, 19F), see reference 186 and Section D.4.1. 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

The carbonyl ylide generated from metal carbene can also add to C=0 or C=N bonds. The [2 + 3]-cycloaddition of carbonyl ylide with G=0 bond has been used by Hodgson and co-workers in their study toward the synthesis of zaragozic acid as shown in Scheme n 27a,27d Recently, a three-component reaction approach to syn-a-hydroxy-f3-amino ester based on the trapping of the carbonyl ylide by imine has been reported.The reaction of carbonyl ylide with aldehyde or ketone generally gives l,3-dioxolanes. Hu and co-workers have reported a remarkable chemoselective Rh2(OAc)4-catalyzed reaction of phenyl diazoacetate with a mixture of electron-rich and electron-deficient aryl aldehydes. The Rh(ii) carbene intermediate reacts selectively with electron-rich aldehyde 95 to give a carbonyl ylide, which was chemospecifically trapped by the electron-deficient aldehyde 96 to afford 1,3-dioxolane in a one-pot reaction (Equation (12)). 

Because 3-substituted 1,2-amino alcohols and even P-alkyl-y-hydroxy-5-amino esters are potentially precursors to pharmacologically interesting materials, further investigations have been carried out to extend the methodology in this direction. Thus, the reduction of the ketone moiety of 56 by applying L-selectride or lithium tri-t-butoxyaluminum hydride opened access to the cis-amino lactones 58 (45-54% yield de = 90-94%) and the trans-amino lactones 58 (67-76% yield de > 98%), respectively (Scheme 1.1.16). Monodebenzylation with cerium ammoni-... 

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