Hydroxy-acids from keto aldehydes

Generally the conditions required to carry out the Horner-Wittig reaction are not compatible with sensitive functional groups such as hydroxy-, nitro-, and keto-aldehydes these residues must normally be protected. However, the use of a heterogeneous base such as K CO in either aqueous or organic media allows the condensation of these sensitive substrates with activated phosphorates to take place directly. The synthesis of Royal Jelly acid from 8-... 

More recently, the same group achieved a simple, highly stereocontrolled total synthesis of (+)-hirsutic acid (Scheme LXXIX) ". This chirally directed effort developed subsequent to reaction of dl-728 with (+)-di-3-pinanylborane, alkaline hydrogen peroxide oxidation, chromatography, PCC oxidation, and hydrogenolysis. The dextrorotatory hydroxy ketone 729 was nicely crafted into keto aldehyde 730 from which 720 was readily obtained. Once again, the Wacker oxidation played an instrumental role in annulation of the third five-membered ring. The remainder of the asymmetric synthesis was completed as before. 

Various biotransformations concerning the decarboxylation of a-keto acids and the formation of ot-hydroxy ketones with different aldehydes as cosubstrates have been performed with either whole cell-systems, mainly fermenting yeast [116,143-151], or isolated enzymes from wheat germ [27,33,120,152], yeast... 

The product is the lactone derived from the hydroxy acid that would result from a normal Cannizzaro reaction. Chiral additives have been used, but with bis(oxazo-lidine) derivatives the reaction proceeded with poor enantioselectivity. ° a-Keto aldehydes give internal Cannizzaro reactions ... 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

When an ester enolate reacts with an aldehyde or a ketone, the product is a hydroxy-ester. This disconnection is shown for both partners. If the reaction is turned around, the reaction of an enolate derived from an aldehyde or a ketone and then with an ester gives a keto-aldehyde or a diketone. Both disconnections are shown. The enolate alkylation reaction involves disconnection of an alkyl halide fragment from an aldehyde, ketone, or ester. In addition, the malonic acid and acetoacetic acid syntheses have unique disconnections. 

Hydroxy acids.—Optically active a-hydroxy-acids are obtained from a-keto-aldehydes by the combined effect of glutathione and the immobilized enzymes glyoxalase I and The reaction appears to provide a practical method for preparing 1—10 g quantities, with enantiomeric excesses in the range 75—99%. The 5-absolute configuration of (+)-2-hydroxy-2,3-dimethylbutanoic acid has been established by chemical correlation with the silyl ketone (14). Work... 

Further work on the preparation of cryt/iro-2-alkyl-3-hydroxy-esters (140) by various condensations between propionic acid derivatives and aldehydes has been reported " the use of zirconium enolates seems to be particularly efficacious. Rules for predicting the stereochemical outcome of condensations between lithium enolates of esters and ketones and a-alkoxy-aldehydes have also been delineated. Pure erythro-isomer (140) can also be obtained in some cases by reduction of the corresponding jS-keto-ester with zinc borohydride. In related work it has been found that sodium borohydride in isopropanol reduces t-butyl a-alkoxy-j8-keto-esters to the corresponding -hydroxy compounds with erythro-threo ratios of between 2 1 and 20 1 in favour of the eryt/iro-isomer. In an extension of his previous work, Frdter has reported that dianions derived from cyclohexanol (141) can be alkylated with 95% stereoselectivity, to give (142). When the starting alcohol (141) is optically pure, a sequence of alkylation and oxidation leads to 2-ethoxycarbonylcyclohexanones with 76% enantiomeric enrichments. 

There are many reports describing the preparation of various butyrolac-tones from AAs. When r-butyl 2-dibenzylaminoacetate in the form of its Li-enolate was treated with (5)-0-benzyllactic aldehyde, a mixture of four diastereoisomeric hydroxy-AAs was obtained. After separation and further treatment, three lactones were obtained (Scheme 17) (87T2317). Similar compounds were obtained from a-acylamino-y-keto acids after cycliza-tion (75CC905). 

Nearly all the water-soluble vitamins are heterocyclic compounds. Among the first to be isolated was thiamine (vitamin Bi) (62), deficiency of which causes degenerative changes in the nervous system, including the multiple peripheral neuritis characteristic of beriberi. Thiamine deficiency can arise from decomposition of the vitamin by bacteria in the gut. In mammalian metabolism the hydroxy group of thiamine is esterified to give cocarboxylase (thiamine pyrophosphate) which catalyzes the decarboxylation of a-keto acids to aldehydes, acyloins or acids, and their transformation into acyl phosphates. 

Apart from the large number of different a-keto acids which may be decarboxylated by PDC, only a few of the resulting aldehydes may be transferred to a second aldehyde molecule to form an a-hydroxy ketone [151]. Besides acetaldehyde, which is the best acylanion equivalent, propionaldehyde and butyraldehyde have been condensed to benzaldehyde by baker s yeast after decarboxylation of the corresponding a-keto acids [116,149]. 

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