Hydroxy-acids => ketones

Solid catalysts can be used, after being impregnated with chiral modifiers such as amines and a-hydroxy acids. Ketones having a second functionality either a or /3 to the carbonyl and able to coordinate to the metal center give best optical yields. This suggests that direct chelation of the substrate to the metal surface occurs. The reaction is used to produce a- and /3-hydroxy acids or esters and to reduce /3-diketones. Rather drastic conditions of P and T limit its scope to simple compounds. 

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... 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

Originally, a C-20 amine (prepared from a bisnorcholanic acid) was converted into its 7V-chloro derivative, dehydrohalogenated to the imine, converted into the A-acetylenanime, reacted with perbenzoic acid, then hydrolyzed to the 17a-hydroxy-20-ketone ... 

Hydroxy-20-cyanohydrins can be oxidized to 3-ketones in good yield with chromic acid, and the osmate ester of the unsaturated nitrile is also stable to this oxidant. " After hydrolysis of the osmate ester, the new 17-hydroxy-20-cyanohydrin which is presumably formed cannot be isolated, but loses hydrogen cyanide during the hydrolysis, and only the 17a-hydroxy-20-ketone is obtained. 

In a typical Knof procedure, 3jS-hydroxyandrost-5-en-17-one acetate is epoxidized with perbenzoic acid (or m-chloroperbenzoic acid ) to a mixture of 5a,6a- and 5)5,6)5-epoxides (75) in 99 % yield. Subsequent oxidation with aqueous chromium trioxide in methyl ethyl ketone affords the 5a-hydroxy-6-ketone (76) in 89% yield. Baeyer-Villiger oxidation of the hydroxy ketone (76) with perbenzoic acid (or w-chloroperbenzoic acid ) gives keto acid (77) in 96% yield as a complex with benzoic acid. The benzoic acid can be removed by sublimation or, more conveniently, by treating the complex with benzoyl chloride and pyridine to give the easily isolated )5-lactone (70) in 40% yield. As described in section III-A, pyrolysis of j5-lactone (70) affords A -B-norsteroid (71). Knof used this reaction sequence to prepare 3)5-hydroxy-B-norandrost-5-en-17-one acetate, B-noran-... 

Mandelic Acid.—The reaction furnishes a simple and general method for obtaining hydroxy-acids from aldehydes or ketones by the aid of the cyanhydrin. The formation of the cyanhydrin may be effected in the manner described or by the action of hydrochloric acid on a mixture of the aldehyde or ketone with potassium cyanide, or, as in the case of the sugais, by the use of liquid hydrocyanic acid and a little amme-nia. 

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 ... 

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 addition of HCN to aldehydes or ketones produces cyanohydrins (a-hydroxy nitriles). Cyanohydrins racemize under basic conditions through reversible loss of FiCN as illustrated in Figure 6.30. Enantiopure a-hydroxy acids can be obtained via the DKR of racemic cyanohydrins in the presence of an enantioselective nitriletransforming enzyme [86-88]. Many nitrile hydratases are metalloenzymes sensitive to cyanide and a nitrilase is usually used in this biotransformation. The DKR of mandelonitrile has been extended to an industrial process for the manufacture of (R)-mandelic acid [89]. 

Given these facts, what would be the structure of the hydroxy-acid formed by hydrolvsls of the Baeyer-Villiger product from bicyclic ketone (32) ... 

Reaction of ketones such as 1-menthone 398 with silylated glycolic acid 417 in the presence of catalytic amounts of TMSOTf 20 provides an lil-mixture of the l,3-dioxolan-4-ones 418 and 419 [35, 36]. Likewise, other aldehydes and ketones [37, 38] and pivaldehyde [39] react with substituted silylated glycohc adds 420 a, b and yS-hydroxy acids 420c to give, e.g., 421 a, b and 421c as mixtures [37-40]. Reaction of pivaldehyde with the persilylated hydroxy acid 420 d and TMSOTf 20 to... 

The reactivity of these oxidants towards organic substrates depends in a rough manner upon their redox potentials. Ag(II) and Co(III) attack unactivated and only slightly activated C-H bonds in cyclohexane, toluene and benzene and Ce(IV) perchlorate attacks saturated alcohols much faster than do Ce(lV) sulphate, V(V) or Mn(III). The last three are sluggish in action towards all but the active C-H and C-C bonds in polyfunctional compounds such as glycols and hydroxy-acids. They are, however, more reactive towards ketones than the two-equivalent reagents Cr(VI) and Mn(VIII) and in some cases oxidise them at a rate exceeding that of enolisation. 

A number of ketones, pharmaceutical compounds, alcohols and hydroxy acids have also been resolved on this phase [724,765-767]. A chiral polysiloxane phase with tartramide substituents has been used for the separation of enantiomers capable of hydrogen bonding interactions with the stationary phase, such as enantiomers containing carboxylic, hydroxyl and amine functional groups [768]. 

The conversion of 27 to chiral hydroxy acid 26 was envisioned to arise via a sequential reduction protocol where the ketone moiety of 27 would enantioselectively be reduced to give chiral allylic cyclopentenol 46 (Scheme 7.11). Subsequent 1,4-addition of hydride to the a,/J-unsaturated ester of 46, presumably assisted by... 

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