Synthesis hydroxycarboxylic acid

Lactic acid [50-21-5] (2-hydroxypropanoic acid), CH CHOHCOOH, is the most widely occurring hydroxycarboxylic acid and thus is the principal topic of this article. It was first discovered ia 1780 by the Swedish chemist Scheele. Lactic acid is a naturally occurring organic acid that can be produced by fermentation or chemical synthesis. It is present ia many foods both naturally or as a product of in situ microbial fermentation, as ia sauerkraut, yogurt, buttermilk, sourdough breads, and many other fermented foods. Lactic acid is also a principal metaboHc iatermediate ia most living organisms, from anaerobic prokaryotes to humans. 

The second approach for the synthesis of 2-amino-3-hydroxycarboxylic acids starts with a chiral isothiocyanate which is added, via the tin enolate, to aldehydes. The initially formed adducts are immediately derivatized to the heterocycles, from which. yj 7-2-amino-3-hy-droxycarboxylic acids result after a three-step procedure. The diastereomeric ratios of the intermediate bis-heterocyclic products range from 93 7 to 99 1 (desired isomer/sum of all others)104. 

A way to anh-configurated a-amino-/ -hydroxycarboxylic acids is opened by the aldol addition of oxazolidine amides 7a and 7b. The method1061 is illustrated by a synthesis of (2R,3R)-p-hydroxyleucine (9) which is available from the major diastereomeric adduct 8 (d.r. 92 8) upon successive treatment with 1 N HC1 (30 min). 5 N HCl (100 C, 12 h), and propylene oxide (reflux in ethanol, 30 min). 

Oxazol-4-ones 132 have been prepared by Trost and co-workers via a microwave-assisted cyclocondensation of bromo imides in the presence of NaF [86]. These products where then employed for a Mo-catalyzed asymmetric synthesis of Q -hydroxycarboxylic acid derivatives 134 (Scheme 47). 

Dochnahl M, Fu GC (2009) Catalytic asymmetric cycloaddition of ketenes and nitroso compounds enantioselective synthesis of a-hydroxycarboxylic acid derivatives. Angew Chem Int Ed 48 2391-2393... 

Stereoselechve follow-up reactions of non-racemic cyanohydrins enable the synthesis of many other classes of important compounds with one or more stereogenic centers, such as 2-hydroxycarboxylic acids, 2-amino acids, etc. (Scheme 3). ... 

It is important that the synthesis should be carried out as quickly as possible, particularly the washing with alkali at 0°, since the latter tends to convert the product into cyctopentane-a-hydroxycarboxylic acid. 

The application of RCM to dihydropyran synthesis includes a route to 2,2-disubstituted derivatives from a-hydroxycarboxylic acids. In a one-pot reaction, the hydroxy esters undergo sequential O-allylation, a Wittig rearrangement and a second O-allylation to form allyl homoallyl ethers 8. A single RCM then yields the 3,6-dihydro-2//-pyran 9. The process is readily adapted not only to variably substituted dihydropyrans but also to 2-dihydrofuranyl and 2-tetrahydrooxepinyl derivatives and to spirocycles e.g. 10 through a double RCM (Scheme 4) <00JCS(P1)2916>. 

The need to achieve high yield in one-pot synthesis, coupled to the relative kinetic inertness of rhenium complex (e.g. compared to technetium) and the mild conditions required has led to the development of useful versatile rhenium(V) intermediates that can be quickly prepared in quantitative yield, and are metastable, i.e. kinetically labile enough to react rapidly with the final chelator, again in high yield. The most widely used ligands suitable for this purpose are polydentate hydroxycarboxylic acids such as glucoheptonate [116a], citrate (47), tartrate (48), and 2-hydroxyisobutyric acid (49) [159]. Examples are discussed elsewhere in this chapter. They are typically used in the presence of Sn(II) to reduce Re(VII) to Re(V), at moderately elevated temperature (50-100 °C) at pH 2-3 (acid pH promotes reduction of perrhenate, presumably by facilitat-... 

Block copolymers of (R,S)-(3-butyrolactone and eCL have been synthesized by combining the anionic ROP of the first monomer with the coordinative ROP of the second one (Scheme 15) [71]. The first step consisted of the synthesis of hydroxy-terminated atactic P(3BL by anionic polymerization initiated by the alkali-metal salt of a hydroxycarboxylic acid complexed with a crown ether. The hydroxyl end group of P(3BL could then be reacted with AlEt3 to form a macroinitiator for the eCL ROP. 

Terashima et al. 231) reported an asymmetric halolactonization reaction. This highly stereoselective reaction permits the synthesis of intermediates for the preparation of chiral a,a-disubstituted a-hydroxycarboxylic acids (227)231c), a-hydroxyketones (228) 231c), functionalized epoxides (229) 231d,e) and natural products 231h,j). Only amino acids have so far been used as a source of the chiral information in the asymmetric halolactonization reaction. Again, the best results have been obtained by using cyclic imino acid enantiomers, namely proline. 

This procedure was improved 123 for the synthesis of building units based on amino acids other than Gly, but with nonfunctionalized side chains (Table 6). To suppress the 3-elim-ination and racemization side reactions, triflates of a-hydroxycarboxylic acid esters 124 34 (L = OTf, Scheme 19) were used as substrates for the nucleophilic substitution. In order to prevent polyalkylation, the nucleophilic amine of to-BocNH- or co-tBu02C-alkylamines 33 were temporarily protected with the benzyl group. 115116 This protection also improved the yields and purity of Gly-based building units. In this case commercially available benzyl bromoacetate 34 (L=Br) was used as the substrate. In both cases the nucleophilic sub-... 

The presence of oe-hydroxycarboxylic acids together with a-aminoacids could lead to an estimate of the local concentration of ammonia when these molecules were synthesised. Such an estimation method implies the assumption that the syntheses of the two classes of molecules were simultaneous and started from the same organic substrate, i.e. aldehydes25 . From aldehydes, aminoacids can be obtained by the Strecker synthesis (aldehyde, HCN, NH3 in aqueous solution), while hydroxyacids can be synthesised from the cyanhydrin synthesis (aldehyde + HCN) followed by a hydrolysis. Nevertheless, it must be emphasised that all aminoacids detected in carbonaceous chondrites cannot be obtained by the Strecker synthesis. This remark limits the interest of the previous arguments concerning the concentration of NH3 during the accretion phase. 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

Tacke and his coworkers have recently reported the synthesis and structural characterization of a series of pentacoordinated anionic germanium complexes based on the Ge04C ligand framework340-344. The route to these compounds involves the reaction of (chloromethyl)trimethoxygermane with a secondary amine in the presence of triethy-lamine, followed by an exchange with two equivalents of bidentate ligands, such as aromatic 1,2-diols or a-hydroxycarboxylic acids, as shown for the synthesis of 114340 (equations 22 and 23). 

Interest in the synthesis of enantiopure 2-hydroxycarboxylic acids via asymmetric enzymatic transformations is still increasing and two pathways have risen into prominence recently. The first is based on enantioselective hydrocyanation of the appropriate aldehyde in the presence of an oxynitrilase (hydroxynitrile lyase, EC 4.1.2.10), which gives rise to the corresponding enantiomerically pure cyanohydrin, followed by chemical hydrolysis in the presence of strong acid (Figure 16.1, route a). This latter step generates copious quantities of salt and is not compatible with sensitive functional groups, which is a serious limitation. 

Alternatively, enantiopure 2-hydroxycarboxylic acids can be obtained via a dynamic kinetic resolution of the (chemically synthesized) cyanohydrin in the presence of an enantioselective nitrilase (EC 3.5.5.1) (see Figure 16.1, route b). Racemization of the cyanohydrin, via reversible dehydrocyanation, takes place readily at pH 7 or above. The methodology [1] is attractive on account of the mild reaction conditions and is industrially applied in the multiton-scale synthesis of (R)-mandehc acid [2]. 

I 76 Nitrilases m the Enantio%etective Synthesis of a-Hydroxycarboxylic Acids... 

Figure 16.3 Bienzymatic procedure for the synthesis of (S)-2-hydroxycarboxylic acids, using an (S)-specific hydroxynitrile lyase and a non-specific nitrilase in tandem.

The bienzymatic approach described above could also be advantageously applied to the synthesis of (R)-2-hydroxycarboxylic acids in cases where no satisfactorily enantioselective nitrilase is available (Figure 16.5). The best enantioselectivity in the hydrolysis of lb, for example, was 92% ee. The enantioselectivity of the hydroxynitrile lyase from ahnonds (PaHnL) in the synthesis of lb is also less then perfect [13], but we found that a combiCLEA of PaHnL and NIT-106 quantitatively converted 2b (O.IM starting concentration) into 3b with ee>99% R (reaction in 90 10 DlPE-buffer pH 5.5, as before) with very little (>3%) amide formation. 

In this paper, we report on the synthesis and structural characterization of a series of related zwitterionic (molecular) spirocyclic X Si-silicates (mononuclear A, Si-silicon(IV) complexes) containing two bidentate l,2-diolato(2-) ligands derived from a-hydroxycarboxylic acids, such as glycolic acid, 2 methyllactic acid, benzilic acid, and citric acid. In addition, some analogous zwitterionic X Ge-germanates (mononuclear X Ge-germanium(rV) complexes) are described. Furthermore, we report on the synthesis and structural characterization of related zwitterionic x Si,X Si -disilicates (binuclear X Si-... 

Seven a-hydroxycarboxylic acids (Cj to Cj) and 17 aliphatic dicarboxylic acids (Cj to Cg) have been found in Murchison (Peltzer et al, 1978 Lawless et al, 1974). Eight of the latter also were produced in a Miller-Urey synthesis (Zeitman et al, 1974). None have been looked for in the FTT synthesis thus far. 

---