Hydroxy acids, preparation

The bis-deprotonation of arylacetic acids by Grignard reagents is known and the resulting bis(bromomagnesinm) salts (equation 49) have been nsed for preparing / -hydroxy acids (Ivanov reaction). 

Odling showed that calomel vapour amalgamates gold-leaf, and hence is dissociated. Erlenmeyer synthesised isobutyric acid, and prepared hydroxy-acids from cyanhydrins. ... 

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 ... 

A broad selection of Ti(III) compounds coordinated to a-hydroxy acids, dibotic acids, and 8-hydroxyquinoline has been prepared by the reaction... 

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). 

The 2-alkyl derivatives have been prepared to protect the stereogenic center of the a-hydroxy acid during alkylations. ... 

Of more direct interest is the preparation of 3-ethylquinuclidine by this method (Prelog, Sogtaric and Gustak (1940)). Ethyl tetrahydropyranyl ketone (X R = tetrahydropyranyl in X to XIV) was condensed wiA ethyl brpmoacetate (XI) to give the hydroxy-acid ester (XII) which was dehydrated by potassium acid sulphate at 90° to ethyl 3-(tetrahydro-pyranyl-4)-pentenate (XIII) and this hydrogenated to tie corresponding... 

B-Homosteroids have also been prepared by acid-catalyzed reaction of diazomethane with a,/5-unsaturated ketones. 3/ -Hydroxycholest-5-en-7-one acetate (57) reacts with diazomethane in the presence of concentrated fluoroboric acid, boron trifluoride etherate or aluminum chloride to give 3yS-hydroxy-B-homo-cholest-5-en-7a-one acetate (67). The 7a-keto group is reported to be chemically less reactive than an 11-keto group. 

A-Nor-B-homo steroids with different substitution patterns than those described above may be prepared by acid catalyzed cyclization of 3)3-hydroxy-5(10)-seco-cholest-tra/w-l(l0)-en-5-one acetate (134a) formed in 30-40% yield by mercuric oxide-iodine sensitized irradiation of cholestane-3j3,5a-diol... 

In addition to the above, Grignaid s leagent has been utilised m preparing olefines, etheis, ketonic esters, hydroxy-acids, quinols, amides, hydroxylammes, c., for details of wliicti books of reference must be consulted ... 

Oxazolidines are prepared to allow selective protection of the a- or co-COjU groups in aspartic and glutamic acids and a-hydroxy acids. 

Dioxanones have been prepared to protect a- or )3-hydroxy acids. 

Enzyme-catalyzed stereoselective hydrolysis allows the preparation of enantio-merically enriched lactones. For instance. Pseudomonas sp. lipase (PSL) was found to be a suitable catalyst for the resolution of 5-undecalactone and 5-dodecalactone (Figure 6.20). Relactonization of the hydroxy acid represents an efficient method for the preparation of both enantiomers of a lactone [67]. 

Another important class of pharmaceuticals which is prepared from chiral 2-hydroxy acids is the angiotensin-converting enzyme (ACE) inhibitors. (R)-3-phenylpropionaldehyde cyanohydrin is transformed into the corresponding 2-hydroxy ester which after activation by sulfonylafion reacts with dipetides to give, under inversion of configuration, ACE inhibitors known as prils (Scheme 6). ... 

In order to prepare multi-kilogram quantities of 1 our efforts were strictly focused on the development of an asymmetric route. Our retrosynthetic approach was centered on the preparation of cyclopentenone 27 which, we envisioned, could be elaborated to chiral hydroxy acid 26 through a series of asymmetric transformations (Scheme 7.4). Etherification of the hydroxy group of 26 with benzylic alcohol 25 followed by installation of (P)-nipecotate 23 at the acid position of 24, would furnish the drug candidate 1. This section will address the following ... 

The optically active glycols are a convenient starting material for the preparation of optically active carbinols, hydroxy-acids, etc. The biological method of asymmetric reduction is perhaps the only convenient method for the preparation of these glycols. The steps in the preparation of other optically active glycols arc identical with those of /-propylene glycol. In some cases it is found convenient to oxidize the chlorohydrin to the... 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

---