Acids, hydroxy, synthesis

Two reports appeared simultaneously in 1988 describing the electrophilic animation with DTBAD of P-hydroxybutyrate and its l,3-dioxan-4-one protected form [22] and of various P-hydroxy esters [23]. The authors obtained similar results. P-Hydroxy esters 46 or 48 were deprotonated at the a-carbon with LDA (2 equiv.) in THF at low temperature and the resulting enolates reacted rapidly with DTBAD at -78 °C to give an easily separable mixture of syn and anti adducts 47 or 49 in which the anti diastereomer was the major compound. The adducts are very useful intermediates since compounds with anti stereochemistry are not easily accessible by other established methods for a-amino P-hydroxy acids synthesis (Schemes 24 and 25). 

Weber, A L, Prebiotic sugar synthesis hexose and hydroxy acid synthesis from glyceraldehyde catalyzed by iron(III)hydroxide oxide, J. Mol. Evol, 35, 1-6, 1992. 

Coumarin is usually prepared by heating salicylaldehyde with acetic anhydride and sodium acetate (i.e., the Perkin cinnamic acid synthesis, p. 23 6), whereby the 0" hydroxy-cinnamic acid (I) undergoes cyclisation to coumarin. Coumarins having substituents in the benzene ring can often be similarly prepared. 

Mandelic acid. This preparation is an example of the synthesis of an a-hydroxy acid by the cyanohydrin method. To avoid the use of the very volatile and extremely poisonous hquid hydrogen cyanide, the cyanohydrin (mandelonitrile) is prepared by treatment of the so um bisulphite addition compound of benzaldehj de (not isolated) with sodium cyanide ... 

Here is a more difficult example based also on a-hydroxy acids. Use the two phenyl groups as a clue for your first disconnetion in designing a synthesis for TM 135 ... 

Synthesis A mild base must be used to avoid the Cannizzaro reaction. The hydroxy acid A caimotbe isolated and cyclises spontaneously. (Fleming p.92). 

Synthesis (Just this one route ) The hydroxy acid in the final atep could not be isolated. 

Reactions and Uses. The common reactions that a-hydroxy acids undergo such as self- or bimolecular esterification to oligomers or cycHc esters, hydrogenation, oxidation, etc, have been discussed in connection with lactic and hydroxyacetic acid. A reaction that is of value for the synthesis of higher aldehydes is decarbonylation under boiling sulfuric acid with loss of water. Since one carbon atom is lost in the process, the series of reactions may be used for stepwise degradation of a carbon chain. 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

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). 

Butane, 2,3-0-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-catalyst in homogeneous asymmetric hydrogenation, 6, 781 Butane-1,4-dioic acid, 2,2-di(indolyl)-synthesis, 4, 226 Butanenitrile, 4-hydroxy-dihydropyran synthesis from, 3, 769 Butanoic acid, -y-aryl-y-amino-synthesis, 1, 433 1-Butanol... 

Hydropyridinyl radicals ESR, 2, 145 Hydroquinoline synthesis, 1, 441 Hydroquinones synthesis, 1, 417 of-Hydroxy acids dehydrogenation by flavins, 1, 253... 

Lumazine-6-carboxylic acid, 7-hydroxy-tautomerism, 3, 271 Lumazine-7-carboxylic acid synthesis, 3, 304 Lumazine-6,7-dicarboxylic acid decarboxylation, 3, 304 reactions, 3, 304 synthesis, 3, 320 Lumazine-6,7-dione catabolism, 3, 322... 

Pyridazine N-ethoxycarbonylimide photolysis, 3, 13 Pyridazine, 4-gJycosyloxy-rearrangement, 3, 15 Pyridazine, halo-applications, 3, 56 Pyridazine, hexahydro-, 3, 40 photoelectron spectra, 2, 20-21 Pyridazine, hydrazino-reductive cleavage, 3, 34 synthesis, 3, 35 Pyridazine, hydroxy-acidity, 3, 4 Pyridazine, 3-hydroxyl-oxide... 

Quinoline-4-carboxylic acid, 3-hydroxy-Pfitzinger synthesis, 2, 446 Quinoline-4-carboxylic acid, 2-methyl-synthesis, 2, 475... 

The use of carbohydrates as SM s has greatly expanded in recent years, and many cases have been summarized in a text by Hanessian.33 Several examples of such syntheses are indicated in Chart 15. Other commercially available chiral molecules such as a-amino acids or a-hydroxy acids have also been applied widely to the synthesis of chiral targets as illustrated by the last two cases in Chart 15. 

Lipoxygenation is the major pathway of dioxygenation of arachidonic acid in blood platelets and leads to the 12-5-hydroperoxy acid 12-HPETE and the corresponding 12-hydroxy acid 12-HETE. Several pathways for the synthesis of 12-HETE have been developed. However, despite the availability of this substance, its biological role remains undetermined. 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

The stereoselective synthesis ofruin -fi-amino-ct-hydroxy acid derivadves using nucleophilic epoxidadon of Tarydthio-Tnitroalkenes has been reported fEq. 4.411." ... 

A key transformation in Corey s prostaglandin synthesis is a Diels-Alder reaction between a 5-(alkoxymethyl)-l,3-cyclopenta-diene and a ketene equivalent such as 2-chloroacrylonitrile (16). As we have already witnessed in Scheme 3, it is possible to bring about a smooth [4+2] cycloaddition reaction between 5-substituted cyclopentadiene 15 and 2-chloroacrylonitrile (16) to give racemic 14 as a mixture of epimeric chloronitriles. Under these conditions, the diastereomeric chloronitriles are both produced in racemic form because one enantiotopic face of dienophile 16 will participate in a Diels-Alder reaction with the same facility as the other enantiotopic face. In subsequent work, Corey s group demonstrated that racemic hydroxy acid 11, derived in three steps from racemic 14 (see Scheme 3), could be resolved in a classical fashion with (+)-ephe-... 

Hie most representative member of this class of polyesters is the low-molar-mass (M 1000-3000) hydroxy-terminated aliphatic poly(2,2/-oxydiethylene adipate) obtained by esterification between adipic acid and diethylene glycol. This oligomer is used as a macromonomer in the synthesis of polyurethane elastomers and flexible foams by reaction with diisocyanates (see Chapter 5). Hydroxy-terminated poly(f -caprolactonc) and copolyesters of various diols or polyols and diacids, such as o-phthalic acid or hydroxy acids, broaden the range of properties and applications of polyester polyols. 

The carboxy-hydroxy reaction (direct esterification) is the most straightforward method of polyester synthesis. It was first reported in the 1930s by Carothers10 12 and is still a very widely used method for the synthesis of polyesters from diacids and diols (Scheme 2.12) or from hydroxy acids (Scheme 2.13). Direct... 

The reaction between acid anhydrides and diols is another convenient method of polyester synthesis. The reaction proceeds in two steps with the formation of an intermediate hydroxy acid (Scheme 2.15). 

Aromatic-aliphatic hydroxy acids, poly esterification of, 81 Aromatic-aliphatic polyesters, 32-35, 83 melting points of, 36 structure and properties of, 44-47 synthesis of, 69-71, 103-106 unsubstituted and methyl-substituted, 36-38... 

ASYMMETRIC SYNTHESIS OF (S)-a-SUBSTmJTED P-BROMO-a-HYDROXY ACIDS... 

Scheme 1. Asymmetric synthesis of (S)-a-substimted P-bromo-a-hydroxy acids...

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