Reduction of keto derivatives

Olefin formation by reduction of keto derivatives via tosylhydrazones, 354 Olefin formation by reduction of thioketals, 356... 

The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

In a similar vein, the keto bridge in 5 can be replaced by oxygen with retention of activity. Reduction of acetophenone derivative 19 by means of sodium borohydride leads to the corresponding alcohol (20). Reaction with phosphorus tribromide with cyanide gives... 

Scheme 65 summarizes Mori s synthesis of 44 [97]. Reduction of keto ester A with baker s yeast gave hydroxy ester B of about 98% ee. Methylation of the dianion derived from B diastereoselectively gave C, which was converted to 44. This process enabled the preparation of about 10 g of (lS,5R)-44. 

Since aluminum alkoxides function effectively as catalysts for alcohol exchange in esters,38 89 reduction of keto esters by aluminum isopropoxide frequently yields the isopropyl ester of the hydroxy acid. Thus the reduction of the cyclopropane derivative XLIV gave the isopropyl ester of the reduced acid (XLV).40 Similarly the substituted methyl /3-keto ester (XLYI)41 gave upon reduction the isopropyl esters of the stereoisomeric reduced acids (XLVII). 

Methods for the capillary gas chromatographic separation of optical isomers of chiral compounds after formation of diastereoisomeric derivatives were developed. Analytical aspects of the GC-separation of diastereoisomeric esters and urethanes derived from chiral secondary alcohols, 2-, 3-, 4- and 5-hydroxy-acid esters, and the corresponding jf- and -lactones were investigated. The methods were used to follow the formation of optically active compounds during microbiological processes, such as reduction of keto-precursors and asymmetric hydrolysis of racemic acetates on a micro-scale. The enantiomeric composition of chiral aroma constituents in tropical fruits, such as passion fruit, mango and pineapple, was determined and possible pathways for their biosynthesis were formulated. 

Yamaguchi employed a strategy not unlike the Bartlett approach to brefeldin A, as depicted in Scheme 1.40. Keto diacid 189 was esterified and reduced with Ra(Ni) to afford a 92% yield of 245. Alcohol participation in a jyn-selective hydrolysis followed by reesterification with benzyl alcohol led to the formation of 246a and 246b in a 19 1 ratio. Protection of the alcohol as the acetate and hydrogenolysis of the benzyl ester followed by fractional recrystallization gave a 87% overall yield of 247. Acid 247 was converted to allylic alcohol 248 in 65% yield via Rosemund reduction of the derived acid chloride to the aldehyde and addition of vinylmagnesium bromide. 

Application of this method to the ring-A-protected A -keto-acetal (20), obtainable in 60% yield from 15a-hydroxycortexone, gave 14-anhydroscillare-none (21). Introduction of the 14jS-hydroxyl by reduction of the derived 14)5,15a-bromohydrin gave scillarenone, which was then reduced to scillarenin (22). 

Many stereo- and regioselective redox reactions have been carried out on a preparative scale by the catalysis of enzymes or microorganisms. The majority of these reactions involves the reduction of keto groups to chiral secondary alcohols or derivatives thereof Not only the reductions of CX-double bonds, but also selective dehydrogenations are of interest. A well-known example of a regioselective biocatalytic dehydrogenation is the formation of L-sorbose from D-sorbitol which is actually the key step in the synthesis of vitamin C. 

A number of reports have further advanced the utility of yeast reduction of 6-keto-esters as an enantioselective route to 8-hydroxy-esters. The use of methanol as carbon source rather than glucose can lead to higher enantioselectivities as can reductions of keto-amides, derived formally from NH,CH-C0,Et, rather than the... 

Keto derivatives are very rare compounds. Lindberg reported the formation of methyl 3-keto-D-glucopyranoside by chromic acid oxidation of the glucoside (4). 2-0-Methyl-L-a 2/Zo-3-hexulose has been prepared by reduction of a derivative of ascorbic acid 135b). 

A number of optically active, heteroatom-substituted carboxylic acid derivatives are excellent substrates for diastereoselective alkylation reactions. The ready availability of such chiral a-, (3-, and y-heteroatom-substituted carboxylic acid derivatives from the chiral pool and, more recently, through the implementation of catalytic, enantioselective methods (such as enantio-selective reduction of / keto esters Chapter 2, Section 2.7) makes this class of alkylations useful for the construction of stereochemically complex systems, particularly those containing quaternary stereogenic centers [54]. Key pioneering experiments in this area were disclosed independently by See-bach [55] and Prater [56]. 

Although ketones are typically reduced under conditions of ionic hydrogenation, Posner reported the chemoselective reduction of keto olefin 92 to afford (+)-estrone methyl ether (93) with excellent yield and selectivity (Equation 25) [70]. Another significant application of ionic hydrogenation was documented by Zav yalov with the cis-selective reduction of thiophene 94 en route to biotin derivative 95 (Equation 26) [71]. 

Lynestrenol is the des-3-oxo derivative of norethindrone (28). It has been prepared through a similar synthetic pathway as aHylestrenol (37) (52), ie, addition of potassium acetyUde, rather than aHyl magnesium bromide, affords lynestrenol (73). Lynestrenol is also available from norethindrone (28). Reduction of the 3-keto group is accompHshed by treating norethindrone (28) with sodium borohydride in the presence of trifluoro- or trichloroacetic acid... 

Methylation of avermectins B and B2 leads to the corresponding derivatives of the A series (49). A procedure involving the oxidation of the 5-methoxy group with mercuric acetate and NaBH reduction of the 5-keto-intermediate allows the conversion of the A to the B components (50). The 23-hydroxy group of the "2" components, after selective protection of the other secondary hydroxy groups, is converted to a thionocarbonate, which can be elirninated to give the 22,23-double bond of the "1" components alternatively it can be reduced with tributyltin hydride to the 22,23-dihydro derivatives (= ivermectins) (51). 

The reduction of the 16-keto function in kryptogenin (66) is a good example for the selectivity of sodium borodeuteride. The resulting 16a-di-16y -hydroxy analog (67) can then be cyclized to give a Iba-d -spirostane derivative (68). ... 

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