Hydroxyacids, Formation

Figure 8.10 Reaction pathways of amino acid and hydroxyacid formation from carbonyl compounds, hydrogen cyanide, and ammonia...

Other asymmetric syntheses, based on aldol condensation of chiral a-sulfinyl carbanions with carbonyl compounds, are the formation of / -hydroxyketones from /J-sulfinylhydrazones 166211-214, of /3, /l -dihydroxyketones from 3-(p-tolylsulfinyl-methyl)-A2-methylisoxalinones 167215, of /1-hydroxyacids from 2-(p-tolylsulfinylmethyl)oxazolines 168216 and of /J-hydroxyesters from ethyl-p-tolylsulfinyl-W-methoxyacetamide 169217. 

The next step is not immediately obvious. The generation of an ethyl ester from a lactone can be accommodated by transesterification (we might alternatively consider esterification of the free hydroxyacid). The incorporation of chlorine where we effectively had the alcohol part of the lactone leads us to nucleophilic substitution. That it can be SnI is a consequence of the tertiary site. Cyclopropane ring formation from an Sn2 reaction in which an enolate anion displaces a halide should be deducible from the structural relationships and basic conditions. 

Problem 16.25 jS-Hydroxyacids (n = 1) readily undergo dehydration but do not yield a lactone. Give the strueture of the product and account for its formation. 

Each synthetase module contains three active site domains The A domain catalyzes activation of the amino acid (or hydroxyacid) by formation of an aminoacyl- or hydroxyacyl-adenylate, just as occurs with aminoacyl-tRNA synthetases. However, in three-dimensional structure the A domains do not resemble either of the classes of aminoacyl-tRNA synthetases but are similar to luciferyl adenylate (Eq. 23-46) and acyl-CoA synthetases.11 The T-domain or peptidyl carrier protein domain resembles the acyl carrier domains of fatty acid and polyketide synthetases in containing bound phos-phopantetheine (Fig. 14-1). Its -SH group, like the CCA-terminal ribosyl -OH group of a tRNA, displaces AMP, transferring the activated amino acid or hydroxy acid to the thiol sulfur of phosphopan-tetheine. The C-domain catalyzes condensation (peptidyl transfer). The first or initiation module lacks a C-domain, and the final termination module contains an extra termination domain. The process parallels that outlined in Fig. 21-11.1... 

Esterification of carboxylic acids with alcohols, including bulky secondary ones, by equimolar di-2-thienyl carbonate (2-DTC) in the presence of a catalytic amount of 4-(dimethylamino)pyridine in toluene solvent at room temperature followed by addition of a catalytic amount of hafnium(IV) trifluoromethanesulfonate, Hf(OTf)4, afforded the corresponding esters in good to high yields. In step 1 (Scheme 1), interaction of the acid and 2-DTC (1) produces the thienyl ester (2) with evolution of CO2 and formation of 2(5H)-thiophenone (3). In step 2, the added Hf(OTf)4 forms with (2) an activated complex (4), alcoholysis of which yields the ester (5) and a further molecule of 2(5H)-thiophenone.1 The procedure was also effective for converting [Pg.48]

Thermodynamic factors can be divided into enthalpic and entropic components. The difference between five- and six-membered rings is shown in the formation of lactones 16 and 18 from hydroxyacids 15 and 17. Enthalpy favours the six-membered ring as the transition state is more stable but entropy favours the five-membered ring as there is a higher chance that 15 will be in a favourable conformation for cyclisation. 

An effective new method for the synthesis of macrocyclic lactones has been developed by Corey and Nicolau (75). In this method both the hydroxyl and the carboxyl groups have been activated by formation of a 2-pyridin-ethiol ester. Vertaline was obtained in 67% yield when this procedure was applied to the corresponding hydroxyacid (76). 

It can be prepared by treatment of 3-amino-2//-azirines (e.g. 3-(dimethyl-amino)-2,2-dimethyl-2//-azirine) with an amino acid or peptide and, finally, with a (u-hydroxyacid. The formation of the oxazolone, VI/121, is observed when VI/120 is treated with acid. The ring enlargement step, the conversion of VI/121 to VI/122, is observed under the same conditions. The transformation of (-)-(R,R)2- 2-[2-(2-hydroxy-2-phenylacetamido)-2-methylpropionato]-2-phenylacetamido -N,N,2-trimethylpropionamide (VI/123) to (-)-(R,R)-3,3,9,9-tetramethyl-6,12-diphenyl-l,7-dioxa-4,10-diazacyclododecane-2,5,8,ll-tetrone (VI/126) in dry toluene/hydrochloric acid at 100° was observed in a 88 % yield. Compounds VI/124 and VI/125 are discussed to be intermediates. In an analogous reaction sequence cyclopeptides can be synthesized [93]. 

Table III presents separation data for R-(+)-MTPA derivatives of some 4-hydroxyacid esters obtained from chiral -lactones. The esterified alcoholic substituent strongly influenced the separation. Since the oc-values for the separation of R-(+)-MTPA derivatives of methyl-esters were very low, the lactones were converted to 4-hydroxyacid ethylesters by interesterification with so-diumethylate. Although base line separation was not attained (using a 30 m column), the method could be applied to control the formation of optically pure -lactones and 4-hydroxyacid esters during microbiological processes (13). ...

It seems that the biogenesis of 3-acetoxyacidesters in pineapple is an enantio-selective process, comparable to the formation of esters of secondary alcohols in passion fruits. As the enzymic hydrolysis of ethyl 3-acetoxyhexanoate by Candida utilis leads to the (S)-configurated hydroxycompound (see Figure 4), only (S)-3-hydroxyacid esters are esterified to the corresponding 3-aceto-xycompounds in pineapple. 

Figure 9. Possible pathway to explain the formation of (S)-3-hydroxyacid esters, (S)-3-acetoxyacid esters, and (S)-5-acetoxyacid asters in pineapple.

Formation of cyclic macromolecules is observed in polycondensation, where macromolecules contain reactive groups both at the ends and within the chain, e.g., for polycondensation of hydroxyacids ... 

Another example of the activation of a hydroxy acid was described by Rastetter and Phillion [60] First the 0-protected hydroxyacid 68 reacts with a thiol group containing crown ether 67. Then the resulting thioester 69 reacts with potassium mrt-butoxide to give the alkoxide. At the same time a complexation of the potassium ion by the [18]crown-6 part of the molecule occurs. Thus, the alkoxide ion comes close to the carbonyl group of the molecule, so that nucleophilic attack leading to ring formation is facilitated (cooperation of dilution principle, template effect, and ion pair interaction). 

To form the amide derivatives, the acid and amine are condensed in the presence of such agents as N,N -carbonyldiimidazole (18) or a carbodiimide and 1-hydroxybenzotriazole (17). The amides can also be formed via the add chlorides (200,201). Bjorkman (199) described a novel approach to the formation of diastereomeric amides The NSAID indoprofen was coupled by means of ethyl chloroformate to L-leucinamide in a reaction that is complete in 3 min. The derivatives were separated by RP LC, and the procedure was used to study the disposition of the drug in surgical patients (199). Others have adopted this derivatization scheme (209). The chloroformate activation method has also been used with (R)-[42] for resolution of several acids (210). It was found that when hydroxyacids were derivatized, not only did the reaction produce the desired amide moiety at the carboxyl group, but the hydroxyl group was converted to the carbonate derivative of the chloroformate (210). 

One exception to this generalization is the formation of the cis hydroxyacid by the hydrogenation of 4-carboxycyclohexanone (24) over Raney nickel in base (Eqn. 18.20).57 The production of this stereoisomer is probably the result of transannular participation by the carboxy group. 

Figure VIII shows the enantiomeric composition of various hydroxy- and acetoxyacid esters and of if -hexa-and -octalactone isolated from pineapple. Methyl 3-hydroxyhexanoate and methyl 3-acetoxyhexanoate are mainly of the (S)-configuration corresponding to intermediates of B-oxidation. The optical purity of the 5-acetoxy esters is lower than of the 3-acetoxy derivatives. The lactones were mainly of the (R)-configuration. Figure IX presents a possible pathway to explain the formation of these compounds. Methyl (S)-(+)-3-hydroxyhexanoate and methyl (S)-3-acetoxyhexanoate may be derived from (S)-3-hydroxyhexanoyl-CoA by transacylation with methanol and acetyl-CoA, respectively. The biosynthesis of 5-hydroxyacids is still unknown, but they may be formed by elongation of 3-hydroxyacids with malonyl-ACP. This hypothesis could explain their varying enantiomeric composition relative to the 3-hydroxyacids. However, hydration of unsaturated acids and/or the reduction of 5-oxoacids may be involved.

Finally, there must be significant interaction between the solvent and solute to favor solubilization. This is related to the relative polarities of the solvent and solute (partition coefficients, dielectric constants and solubility parameters). Solubilization is improved by the formation of hydrogen bonds (e.g. hydroxyacids) or the electrostatic effects that occur with small, highly charged ions (e.g. sodium). 

Fig. 2 The loss of munber average molecular weight, weight loss and formation of lactic acid and glycohc acid as a percentage of the theoretical amount during hydrolysis of polyfiactide-co-glycolide) (50/50). The degradation starts by molecular weight decrease, which is followed by weight loss and formation of monomeric hydroxyacids...

During aging of PHVB in sterile water at pH 7 and 60 °C, 2-butenoic acid (crotonic acid), 2-pentenoic acid, 3-hydroxybutyric acid, 3-hydroxyvaleric acid, 3-hydroxybutyrate dimer, 3-hydroxybutyrate-3-hydroxyvalerate dimer and 3-hydroxyvalerate dimer were formed [99]. The weight loss was, however, only 2% after 200 days at 60 °C. Monomers, oligomers and derivatives, produced by dehydration at the OH-terminus were identified after alkaline hydrolysis of PHB [110]. In accordance CZE showed that the accelerated hydrolysis of PHB leads to the formation of hydroxyacid oligomers and a series of peaks formed by a side reaction leading to a C=C bond at the noncarboxylic acid end [111]. Kinetics of the abiotic hydrolysis of PHB in acid and alkaline media were monitored by following the forma-... 

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