Catechol transformation

Catechol conversion (Xi) was always less than 0.05, allowing the reaction to be carried out in the differential kinetic region. Before reaction, the catalyst was activated in N2 flow at 270°C for 30 min. The yields (Yi) of the monomethylated products were measured under steady-state conditions after 8-10 hours of the catalyst activity stabilisation. The rate of catechol transformation (-Ri) over different catalysts was used to compare catalytic activity. 

Figure 11.3 Example of Drug Guru input and output. The input structure is dopamine. The 10 output structures resulting from the 10 catechol transformations listed in Table 11.2 are shown...

Because mono and dibenzocrowns were among the first crowns to be synthesized, and because the syntheses of these molecules were relatively straightforward, quite a number of modifications in the basic skeleton have been reported. Some of these modifications have utilized substituted catechols as starting materials and others have involved transformations on the existing crown. 

Azaloxan (12) is an antidepressant agent. Its synthesis can be accomplished starting with the reaction of catechol (7) and 3,4-dibromobutyronitrile (obtained by addition of bromine to the olefin) to give l,4-benzodioxan-2-ylacetonitrile (8). A series of functional group transformations ensues [hydrolysis to the acid (9), reduction to the alcohol (10) and conversion to a tosylate (11)] culminating in an SN-2 displacement reaction on tosylate 11 with l-(4-piperidinyl)-2-imidazolidi-none to give azaloxan (12) [3]. 

An interesting combination of enzymatic with non-enzymatic transformation in a one-pot three-step multiple sequence was reported by Waldmann and coworkers [82]. Phenols 125 in the presence of oxygen and enzyme tyrosinase are hydroxylated to catechols 126 which are then oxidized in situ to ortho quinones 127. These intermediates subsequently undergo a Diels-Alder reaction with inverse electron demand by reaction with different dienophiles (Table 4.19) to give endo bicyclic 1,2-diketones 128 and 129 in good yields. 

But, after the induction period, the hydrolytic transformation into catecholate is very fast, within 5 to 10 minutes in all the cases. 

Polar functional groups such as alcohols or phenols 11 or trimethylsilanol 4 are transformed by monofunctional silylating reagents Me3SiX 12 into their hpophilic and often volatile trimethylsilyl ethers 13 whereas water is converted into persilyl-ated water (=Me3SiOSiMe3, hexamethyldisiloxane, HMDSO, 7, b.p. 100 °C). The persilylation of phenols and, in particular, catechol (or hydroquinone) systems (Scheme 2.1) protects them efficiently against air oxidation even at temperatures of up to 180 °C. (cf, e.g., the silylation-amination of purine nucleosides with dopamine hydrochloride in Section 4.2.4)... 

Catechol-O-methyltransferase (COMT EC 2.1.1.6) is located in many tissues and catalyzes the methylation of polyphenols. The methylation is a well-established pathway in the metabolism of flavonoids such as those that undergo 3, 4 -dihydrox-ylation of ring B excreted as 3 -0-methyl ether metabohtes in rat bile. " Recently, the apparent methylation of both cyanidin-3-glucoside and cyanidin-3-sambubioside (cyanidin is an anthocyanin with a 3, 4 -dihydroxylation of ring B) to peonidin-3-glucoside and peonidin-3-sambubioside was reported in humans. In rats, this transformation occurred mainly in the liver and was catalyzed by COMT."°... 

Dioxygenase. Although it is not involved in the transformation of PAHs, it may be noted for the sake of completeness that a catechol intradiol dioxygenase is involved in the fission of 1,2,4-trihydroxybenzene that is formed from a number of aromatic substrates (Rieble et al. 1994). 

FIGURE 9.29 Transformation of 2-halogenated benzoates to catechol by concomitant decarboxylation and dehalogenation. (From Neilson, A.H. and Allard, A.-S., The Handbook of Environmental Chemistry, Vol. 3R, Springer Verlag, 2002, pp. 1-74. With permission.)... 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

A departure from the catechol pattern of the natural neurotransmitters was achieved following application of the fact that arylsulfonamido hydrogens are nearly as acidic as phenolic OH groups. Nitration of p-benzyloxyacetophenone gave 18 which was reduced to 19 with Raney nickel and hydrazine, and in turn reacted with mesyl chloride to give sulfonamide 20. Methanesulfonate 20 was then transformed to soterenol (21), a clinically useful bronchodilator, in the... 

In only two further steps the aldehyde 2-158 was prepared, but this could not be transformed into the desired acetal 2-160 using catechol 2-159. 

In 1996, the first successful combination of an enzymatic with a nonenzymatic transformation within a domino process was reported by Waldmann and coworkers [6]. These authors described a reaction in which functionalized bicy-clo[2.2.2]octenediones were produced by a tyrosinase (from Agaricus bisporus) -catalyzed oxidation of para-substituted phenols, followed by a Diels-Alder reaction with an alkene or enol ether as dienophile. Hence, treatment of phenols such as 8-1 and an electron-rich alkene 8-4 in chloroform with tyrosinase in the presence of oxygen led to the bicyclic cycloadducts 8-5 and 8-6 in moderate to good yield (Scheme 8.1). It can be assumed that, in the first step, the phenol 8-1 is hydroxylated by tyrosinase, generating the catechol intermediate 8-2, which is then again oxidized enzy-... 

The metabolites identified [327] for each of these pathways are collected in Table 15 and once again, it should be emphasized that only the last two, catechol/anthranilate and coumarin pathways (named c and d, in Fig. 23) yield denitrogenated products. In summary, the four metabolic pathways identified for quinoline transformation, as shown in Fig. 23, are ... 

Tsutsui T, Hayashi N, Maizumi H, et al. 1997. Benzene-, catechol-, hydroquinone- and phenol-induced cell transformation, gene mutations, chromosome aberrations, aneuploidy, sister chromatid exchanges and unscheduled DNA synthesis in Syrian hamster embryo cells. Mutat Res 373 113-123. 

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