Hydroxy ketones keto acids

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-... 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

Certain ketoximes can be converted to nitriles by the action of proton or Lewis acids. Among these are oximes of a-diketones (illustrated above), a-keto acids, a-dialkylamino ketones, a-hydroxy ketones, p-keto ethers, and similar compounds. These are fragmentation reactions, analogous to 17-25 and 17-26. For example, ot-dialkylamino ketoximes also give amines and aldehydes or ketones besides nitriles. 

Products detected or isolated from these oxidations include the corresponding a-hydroxy ketone and a-diketone and also adipic acid (from cyclohexanone) in up to 95 % yield. However, IrCI gives a-chloroketone in quantitative yield . Evidently when the rate of oxidation exceeds enolisation attack is on the keto form, probably via a complex, although this is definite only for Ce(IV) perchlorate, to give a radical, e.g. 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

Amides of keto acids were reduced to amides of hydroxy acids biochemically using Saccharomyces cerevisiae to give optically pure products [7059]. Refluxing with lithium aluminum hydride in ether for 6 hours reduced both the ketonic and the amidic carbonyl in A -methyl-5-phenyl-5-oxopentanamide and gave 82% yield of 5-methylamino-l-phenylpentanol [1134]. 

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. 

Diazo ketones are relatively easy to prepare (see 0-112). When treated with acid, they add a proton to give a-keto diazonium salts, which are hydrolyzed to the alcohols by the SnI or Sn2 mechanism.456 Relatively good yields of a-hydroxy ketones can be prepared in this... 

The reaction therefore constitutes a method for converting an organometallic compound R M to an aldehyde R CHO (see also 2-32), an oi-keto acid,809 a ketone R COR (see also 2-32), an a-hydroxy ketone, or a p-hydroxy ketone. In each case the C=N bond is hydrolyzed to a 0=0 bond (6-2). 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Thiamine pyrophosphate promotes the decarboxylation of a-keto acids and the cleavage of a-hydroxy ketones. 

CC 400 (1975) (a-hydroxy, halo and formyloxy ketones x-keto acid a- and jS-keto esters) 315 (1977) (x-PhSO, O, OAc ketones) 456 (1978) (trifluoromethyl ketones) 908 (1979) (bicyclic ketone) 599 (1983) (/ -keto carboxylates) 138 (1986) (2,2-dithioalkan-l-ones) 1368 (1987) 03-keto ester)... 

JOC 47 2820 (1982) (/1-diketones to hydroxy ketones) 50 127 (fi-keto carboxylate), 3411 (fi-diketones to hydroxy ketones) (1985) 51 1253 (2,2-dithioalkan-l-ones), 2795 (a-flooro ketones) (1986) 52192 (fi-keto esters), 256,1141,1359 (fi-keto esters), 2036 (/1-diketones to hydroxy ketones), 2086 (a-acetoxy ketone), 2244 (fi-keto ester), 3223 (cyclic /1-diketones to hydroxy ketones), 4363 (y- arid 5-keto acids) (1987) 53 860, 1969, 2589 (x-keto ester), 4405 (a-acyloxy ketone), 4962 (1988) 54 2238 (/S-diketone to fi-hydroxy ketone), 2274, 3221 (a-diketone to a-hydroxy ketone) (1989) 55 3917 (1990)... 

The reagent is effective for oxidative cleavage of a-glycols to aldehydes, of a-hydroxy ketones to an aldehyde and a carboxylic acid, and of a-diketones and a-keto iicids to acids.3... 

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... 

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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