Diketo esters

The p-chlorophenyl ether was used in this synthesis to minimize ring sulfonation during cydization of a diketo ester with concentrated H2SO4/ACOH. ... 

In a typical example, the keto ester (25) was irradiated to give the hydroxy lactone (26), which was dehydrated to 27. Ozonolysis of 27 gave the diketo ester... 

AnsueP This diketo-ester has five sites for enolisation ( in 30a). Attack of these enols on the other carbonyl groups could produce ring sizes from ihree to nine but only one stable non-bridged cyclic... 

The diketo-ester (1) has 1,4 1,5 and 1,6-dicarbonyl relationships. Both the 1,4 and 1,5 relationships can be disconnected at the branchpoint in the middle of the molecule, to give sensible intermediates such as (3) and (4), but difficult synthons (2) and (5). The 1,6 reconnection requires symmetrical Diels-Alder adduct (6). 

In a study aim to develop biocatalytic process for the synthesis of Kaneka alcohol, apotential intermediate for the synthesis of HMG-CoA reductase inhibitors, cell suspensions of Acine-tobacter sp. SC 13 874 was found to reduce diketo ethyl ester to give the desired syn-(AR,5S)-dihydroxy ester with an ee of 99% and a de of 63% (Figure 7.4). When the tert-butyl ester was used as the starting material, a mixture of mono- and di-hydroxy esters was obtained with the dihydroxy ester showing an ee of 87% and de of 51% for the desired, sy -(3/t,5,Sr)-dihydroxy ester [16]. Three different ketoreductases were purified from this strain. Reductase I only catalyzes the reduction of diketo ester to its monohydroxy products, whereas reductase II catalyzes the formation of dihydroxy products from monohydroxy substrates. A third reductase (III) catalyzes the reduction of diketo ester to, vv -(3/t,55)-dihydroxy ester. 

Wolberg, M., Hummel, W. and Muller, M. (2001) Biocatalytic reduction of beta,delta-diketo esters a highly stereoselective approach to all four stereoisomers of a chlorinated beta,delta-dihydroxy hexanoate. Chemistry -A European Journal, 7 (21), 4562-4571. 

In the consecutive hydrogenation of />,<5-diketo esters (Table 21.16), selection of the chiral ligand can determine the sense of diastereoselection, and the 3,5-syn dihydroxy product was formed predominantly upon use of a Ru-(S)-amino-phosphinephosphinite-((S)-AMPP) catalyst, although the enantioselectivity of the syn-product is poor (Table 21.16, entry 7) [103a]. Syn 3,5-diol formation... 

This reagent can also effect sequential diastereoselective reduction of a hydroxy diketo ester to afford an anti, anti-triol ester as the major product. The only other significant product is the anti, syn-triol (equation I). 

The Noyori reduction of various diketo esters in this series was very dependent upon the amount of add present in the reaction. Without the presence of a stoichiometric amount of add, the rate of reduction as well as the selectivity in the reduction dropped off. At higher pressures, the chemoselectivity of the reduction was poor resulting in die reduction of both alkene groups. Further, the carbonyl at C5 was never reduced under these reaction conditions but was absolutely necessary for the reduction of the C3 carbonyl. When C5 was in the alcohol oxidation state, no reduction was seen. A. Balog, unpublished results. 

Bases. VII. The Acylation of Ethyl Isobutyryl-isobutyrate and the Cyclization of a 3,5-Diketo-Ester by Means of Sodium Triphenylmethyl. J. Amer. chem. Soc. 61, 3567 (1939)-... 

Only a few publications dealing with this subject can be found in the literature. Hydrogenation of diketo esters A with chirally modified ruthenium catalysts resulted in mixtures of syn- and anti-dihydroxy esters C with varying enantiomeric excesses [5], A notable exception to this is represented by the recent work of Car-pentier et al., who succeeded in controlling the reduction of methyl 3,5-dioxohex-anoate at the initial step, namely the reduction of the P-keto group. The enantiomeric excess achieved was, nevertheless, limited to 78% at best [5a]. 

Highly enantioselective reduction of ethyl 6-benzyloxy-3,5-dioxohexanoate by ADH of Acinetohacter calcoaceticus has been reported (97 to >99% ee) [6]. Regi-oselectivity was not encountered, however, as was the case in the reduction of a variety of 3,5-dioxohexanoates A with baker s yeast [7]. The application of isolated enzymes in an anticipated regio- and enantioselective reduction of diketo esters A seemed most promising to us. 

An NADP(H)-dependent ADH of Lactobacillus brevis (LBADH) was identified as a suitable catalyst accepting a broad range of diketo esters A as substrate [8]. This stable enzyme is easily available in the form of a crude cell extract (recLBADH) from a recombinant E. coli strain [9]. The reaction with diketo esters la-lc was performed on a preparative scale, using substrate-coupled regeneration of NADPH (Scheme 2.2.7.2). 

The enzyme recLBADH is the first catalyst that has been found to allow the highly regio- and enantioselective synthesis of 5-hydroxy-P-keto esters by reduction of the respective diketo esters. This enzymatic reaction is of enormous preparative value. The substrates are readily available by acylation of P-keto ester bisenolates and the reaction only requires a simple batch technique which is easy to scale up. Reduction of the chlorinated compound la has been performed routinely on a 75 g scale in our laboratory (8 L fed batch), yielding (S)-2a in an isolated yield of 84% [10]. 

Scheme 2.2.7.3 Reduction of diketo ester la by baker s yeast whole-cell transformation.

A set of Saccharomyces cerevisiae reductases was screened in collaboration with J. D. Stewart s group (University of Florida). Itwas demonstrated that diketo ester la is accepted as substrate by at least three different NADP(H)-dependent reductases of this microorganism. Application of a cell-free system in preparative batches using enzyme-coupled coenzyme regeneration afforded (R)-2a with more than 99% enantiomeric excess [13]. 

In summary, it has been shown that the enzyme-catalyzed regio- and enantioselective reduction of 3,5-diketo esters can be performed advantageously on a preparative scale giving access to enantiopure (R)- and (S)-3,5-... 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

Substituted 1,3-diols are valuable intermediates in the synthesis of drugs and natural products [18]. Starting from the regio- and enantioselective enzymatic reduction of diketo esters described above, various methods to obtain enantio-merically pure 3,5-dihydroxy esters were developed. 

Scheme 2.2.7.6 Formation of dihydroxy ester syt)-(3R,5S)-5a via hydroxy keto ester (S)-2a through whole-cell biotransformation of diketo ester la.

Lactobacillus brevis whole-cell biotransformation When the reduction of diketo ester la was performed with whole cells of Lactobacillus brevis or L. kefir, formation of the 3,5-dihydroxy ester (3R,5S)-5a was observed [10, 22]. This was surprising since it is known that the prevailing alcohol dehydrogenase in I. brevis is the one described as LBADH [23] and since, moreover, this enzyme does not reduce P-keto 5-hydroxy ester 2a to the corresponding dihydroxy ester (Scheme 2.2.7.6). Under the conditions tested, further alcohol dehydrogenase activity is clearly present in I. brevis and I. kefir. Pfruender et al. optimized the production of L. kefir cells and used this biocatalyst for the one-pot synthesis of dihydroxy ester syn-(3R,5S)-5a using diketo ester la as starting material [24]. 

Scheme 2.2.7.11 Chiral building blocks evolved from diketo ester la via regio- and enantioselective enzymatic reduction.

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Theenol forms 19 (Scheme 8) of a,7-diketo esters add to DPD, giving low yields of 3//-pyrazoIes 21 via the hydroxypyrazolines. 20.8 Noncyclic products are also formed. 

An unexpected hydrolysis of an ethoxycarbonyl group was observed in the attempt to accomplish cyclodehydration (Section III,A) using diketo esters 613 (Eq. 45).451... 

If this type of condensation is carried out with hydrazinoisocytosines (182) and a,y-diketo esters, l//-pyrimido[4,5 -c ]-l, 2-diazepines (183) are formed as the major products. Only a small amount of pyrimido[4,5-c]pyridazines (184) can be isolated from these reactions (82JOC667). 

The reaction of phenols with the spiro /3-lactone (397), obtained from the reaction of diketene with ethyl diazoacetate, leads to coumarins (79JCS(Pl)525). Initial ring opening of the spiro compound to the diketo ester followed by regioselective intramolecular acylation would seem to be a possible mechanism (Scheme 129). 

Naturally, less scope is available with the ester component and the C-2 substituent in the chromone is commonly alkyl or ethoxycarbonyl, or is absent. The use of diethyl oxalate offers an added attraction the intermediate 1,3-diketo ester (436) readily undergoes transesterification, thereby allowing the synthesis of various chromone-2-carboxylic esters to be achieved from the one starting material (Scheme 148) (74JCS(P1)2570). 

Except for the well-documented conjugate additions of diethylaluminum cyanide,92 triethylaluminum-hydrogen cyanide and Lewis acid-tertiary alkyl isonitriles,93 examples of Lewis acid catalyzed conjugate additions of acyl anion equivalents are scant Notable examples are additions of copper aldimines (233),94, 94b prepared from (232), and silyl ketene acetals (234)940 to a,(3-enones which afford 1,4-ketoal-dehydes (235) and 2,5-diketo esters (236), respectively (Scheme 37). The acetal (234) is considered a glyoxylate ester anion equivalent. 

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