7.10- dihydroxy-8 , production

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. 

Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues. Blood-borne cholesterol is excluded from the CNS by the blood-brain barrier. Neurons express a form of cytochrome P-450, 46A, that oxidizes cholesterol to 24(S)-hydroxycholesterol [11] and may oxidize it further to 24,25 and 24,27-dihydroxy products [12]. In other tissues hydroxylation of the alkyl side chain of cholesterol at C22 or C27 is known to produce products that diffuse out of cells into the plasma circulation. Although the rate of cholesterol turnover in mature brain is relatively low, 24-hydroxylation may be a principal efflux path to the liver because it is not further oxidized in the CNS [10]. 

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... 

That the metabolism of melphalan occurs by the same reaction mechanism as that of mechlorethamine has been demonstrated in in vitro studies [65]. Under physiological conditions of temperature and pH, formation of the first and second aziridinium intermediates en route to the bis(hydroxyethyl) metabolite occurred with rate constants of ca. 0.017 and 0.041 min-1, respectively. After 60 min, ca. 2/3 of the drug had been converted to the monohydroxy and dihydroxy products in comparable amounts. In the presence of a phosphate buffer, competition between hydrolysis and phosphatolysis was seen, such that at completion of the reaction (4 h) the two major products were the dihydroxy and the hydroxy/phosphate metabolites, with the dihydroxy derivative produced in small amounts. Similar hydrolytic dehalogena-tion has also been observed for ifosfamide in acidic aqueous solution [69]. 

Three different ketoreductases were purified to homogeneity, and their biochemical properties were compared. Reductase I only catalyzes the reduction of ethyl diketoester 39 to its monohydroxy products 42 and 43 whereas reductase II catalyzes the formation of dihydroxy products from monohydroxy substrates. A third reductase (III) was identified which catalyzes the reduction of diketoester 39 to desired. vv -(3.R,5S)-dihydroxy ester 40a (Guo el al., 2006b). 

Treatment of pyridinyl cyclohexene 231 with perfluorinated oxaziridine 80 in TFA afforded dihydroxy product 232 in 72% yield <1998T7831>. The pyridine nitrogen is not oxidized under these conditions because TFA protonates the pyridine nitrogen atom. 

Hydrogenolysis of 5,6-a-epoxy-5a-cholestan-3 3-acetate (S3) over platinum oxide at room temperature and atmospheric pressure gave a very good yield of the 5a-hydroxy product, 54, which has the axial hydroxy group (Eqn. 20.38). Under the same conditions the 5,6-P-epoxy cholestane, 55, gave a number of different desoxy, monohydroxy and dihydroxy products. ... 

Prior to this publication the syntheses of racemic brazilin (ref. 115) and of racemic haematoxylin (ref. 116) were described by an alternative methodology. In the approach to brazilin the dihydroxybenzylidene derivative (J, Scheme 32) was methylated to form the trimethyl ether (I R = Me) and the analogous tribenzyl ether (I R = Bn) was synthesised from appropriate starting materials. (I R = Me was then epoxidised by treatment with hydrogen peroxide in alkaline solution. From treatment with sodium borohydride and then catalytic hydrogenation in acetic acid in the presence of Adams catalyst a mixture of dihydroxy products resulted. By mild cyclisation with perchloric acid, racemic brazilin trimethyl ether (T, R = Me) was derived. From the tribenzyl ether (I R = Bn) by a similar series of reactions, racemic brazilin tribenzyl ether (T R = Bn) was obtained and from hydrogenolysis, racemic brazilin was derived. The process is depicted in Scheme 36. 

A further experiment was done to look at oxidant concentration in the solid and in solution (Table 4). It was found that, even after thorough washing, the peracetic acid formed was very much concentrated in the solid. This would explain why zirconium phosphate inhibits the formation of free peracetic acid, as it suggests that peracid is formed but held in the interlayers. The selectivity to dihydroxy products may then be attributed to adsorption selectivity. This is our current understanding of the mechanism. 

Selectivity to dihydroxy products and the ratio of catecol to hydroquinone formed was also maintained. 

A comparison of the amorphous and crystalline forms of zirconium and tin phosphates was also made (Table 8). It is apparent that the crystalline forms show greater selectivity to the dihydroxy products. This is consistent with the oxidation largely taking place in the interlayers (which, of course, are not present to great extent in the amorphous form). 

With TS-1 as the catalyst, the oxidation products of phenol are hydro-quinone and catechol (para- and ort/to-hydroxyphenol), with minor yields of water and tar formed as by-products. Numerous early papers are concerned with this reaction (218), and patents (219) have been iiled. In the reaction catalyzed by TS-1, the conversion of phenol and the selectivity to dihydroxy products are significandy higher than achievable by either radical-initiated oxidation or acidic catalysts. The catechol/hydroquinone molar ratio is within the range of 0.5—1.3 and depends on the solvent. When the reaction occurs in aqueous acetone, the ratio is close to 1.3. It is believed that the product ratio is the result of restricted transition-state selectivity as well as mass transport shape selectivity associated with the different diffusivities of the ortho and para products. Hydroxylation at the para-position of phenol should be less hindered relative to that at the ortho-position, and hydroqui-none has a smaller kinetic diameter than catechol, facilitating diffusion. Tuel and Taarit (220) proposed that catechol is mainly produced at the external surface of TS-1 crystals. Thus, the different catechol/hydroquinone ratios obtained when methanol or acetone is used as a solvent could be explained by either rapid or very slow poisoning of external sites by organic deposits, respectively. Accordingly, the authors were able to show that tars were easily dissolved by acetone (i.e., external sites for catechol formation remained available in this solvent) while they were insoluble in methanol. 

A novel way of generating selectively 0-substituted CDs arises from the selectivity found on DIBALH-promoted debenzylation of perbenzylated derivatives. For example, the a-CD perether can be converted to the 6-monohydroxy compound or, in 82% yield, to the AD, 6,6 -dihydroxy product. Similar results were recorded for the p-CD and y -CD compounds. ... 

Ap-59 Okumura, T., Nozaki, Y., and Satoh, D., Chem. Pharm. Bull. (Tokyo) 1, 1143 (1964). 3i3,l4j3,21-Trihydroxy-5/3-pregnan-20-one gave IjS-hydroxylation with Absidla orchldis From 4,5-dehydrodlgltoxlgenone the 7/3-hydroxy and 7/3,12/3-dihydroxy products were characterized,... 

There are two possible ways that osmium tetraoxide can be used to dihydroxylate olefins. One reaction uses it in stoichiometric amounts and the other uses it in catalytic amounts in conjunction with another oxidant that recycles it in situ. In the former case, it is easy to track the origin of the oxygen atoms in the dihydroxy product as shown in the following. 

Cyclic p-diketones are selectively reduced to give p-hydroxyketones without the formation of dihydroxy products (Scheme 2.127) [918-921]. It is important, however, that the highly acidic protons on the a-carbon atom are fully replaced by substituents in order to avoid the (spontaneous) chemical condensation of the substrate with acetaldehyde, which is always present in yeast fermentations ... 

Reactivities of SLO-1 with various substrates other than linoleic acid have been reported. Bis-homo-y-linolenic acid (all-cw-8,l 1,14-eicosatrienoic acid) and arachidonic acid (all-cw-5,8,11,14-eicosatetraenoic acid) yield 15-hydroperoxy compound exclusively [257]. In the presence of a relatively high concentration of SLO-1, a double dioxygenation product, 8,15-dihydroperoxy-5,9,ll,13-eicosatetraenoic acid, is formed from arachidonic acid [eq. (18)] [225, 258]. The double dioxygenation of linoleic acid [246, 259] and a-linolenic acids has also been reported. In the latter case, the dioxygenation proceeds stepwise and the mono- and dihydroperoxy compounds are converted to 9(S),10- and 9(5), 16-dihydroxy products, respectively. 

Further studies revealed that this metabolite was derived from an epoxide intermediate that also contained three conjugated double bonds which they later termed LTA4 (Borgeat and Samuelsson, 1979b) thus, the dihydroxy product was termed LTB4 (Figure 1). LTB4 was later determined to be a potent activator of neutrophil functions in vitro (Ford-Hutchinson et al., 1980) and was implicated in neutrophil-mediated inflammation in in vivo models of its action (Samuelsson, 1983). 

Reactions in which a product remains in the him (as above) are complicated by the fact that the areas of reactant and product are not additive, that is, a nonideal mixed him is formed. Thus Gilby and Alexander [310], in some further studies of the oxidation of unsaturated acids on permanganate substrates, found that mixed hlms of unsaturated acid and dihydroxy acid (the immediate oxidation product) were indeed far from ideal. They were, however, able to ht their data for oleic and erucic acids fairly well by taking into account the separately determined departures from ideality in the mixed hlms. 

Figure Bl.16.11. Biradical and product fonnation following photolysis of 2,12-dihydroxy-2,12-dimethylcyclododecanone. Reprinted from [28].

Diazo coupling involves the N exocyclic atom of the diazonium salt, which acts as an electrophilic center. The diazonium salts of thiazoles couple with a-naphthol (605). 2-nitroresorcinol (606), pyrocatechol (607-609), 2.6-dihydroxy 4-methyl-5-cyanopyridine (610). and other heteroaromatic compounds (404. 611) (Scheme 188). The rates of coupling between 2-diazothicizolium salts and 2-naphthol-3.6-disulfonic acid were measured spectrophotometrically and found to be slower than that of 2-diazopyridinium salts but faster than that of benzene diazonium salts (561 i. The bis-diazonium salt of bis(2-amino-4-methylthiazole) couples with /3-naphthol to give 333 (Scheme 189) (612). The products obtained from the diazo coupling are usuallv highly colored (234. 338. 339. 613-616). 

Tartaric acid [526-83-0] (2,3-dihydroxybutanedioic acid, 2,3-dihydroxysuccinic acid), C H O, is a dihydroxy dicarboxyhc acid with two chiral centers. It exists as the dextro- and levorotatory acid the meso form (which is inactive owing to internal compensation), and the racemic mixture (which is commonly known as racemic acid). The commercial product in the United States is the natural, dextrorotatory form, (R-R, R )-tartaric acid (L(+)-tartaric acid) [87-69-4]. This enantiomer occurs in grapes as its acid potassium salt (cream of tartar). In the fermentation of wine (qv), this salt forms deposits in the vats free crystallized tartaric acid was first obtained from such fermentation residues by Scheele in 1769. 

Derivatives. Oxidation of pyrogaHol trimethyl ether with nitric acid, followed by reduction ia acetic anhydride and treatment of the product with aluminum chloride, affords 3,6-dihydroxy-2,4-dimethoxyacetophenone (228). 3,4,5-Trimethoxyphenol (antiarol) has been prepared by treatment of... 

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