Hydroxyphenazine

Tautomerism questions arise with hydroxyphenazines and quinoxalines which contain hydroxyl groups in the aromatic ring. Does 5-hydroxyquinoxaline (62) show any tendency to exist as the tautomer (63) or 1-hydroxyphenazine (64) to exist as (65) Analogous tautomeric forms can also be written for 6-hydroxyquinoxaline and 2-hydroxyphenazine. 

Murakami E, U Deppenmeier, SW Ragsdale (2001) Characterization of the intramolecular electron transfer pathway from 2-hydroxyphenazine to the heterodisulfide reductase from Methanosarcina thermophila. J Biol Chem 276 2432-2439. 

The best-studied system producing antibiotics in the rhizosphere are fluorescent pseudomonads, producing up to seven different compounds, as summarized in Fig. 9 2-hydroxyphenazine-l-carboxylate, phenazine-l-carboxylate, 2-hydroxy-phenazine, pyrrolnitrin, pyocyanine, 2.4-diacetylphloroglucinol. and pyoluteorin (48). Nine genes have been identified in the synthesis of phenazine-1-carboxylic... 

Methanophenazine 239 functions as an electron carrier in the cytoplasmic membrane. The etherification of 2-hydroxyphenazine 237 with mesylate 238 was a key step in a total synthesis of 239 <00AC(E)2470>. 

The result of the retrosynthetic analysis of rac-lO is 2-hydroxyphenazine (9) and the terpenoid unit rac-23, which may be linked by ether formation [29]. The rac-23 component can be dissected into the alkyl halide rac-24 and the (E)-vinyl halide 25. A Pd(0)-catalyzed sp -sp coupling reaction is meant to ensure both the reaction of rac-24 and 25 and the ( )-geometry of the C-6, C-7 double bond. Following Negishi, 25 is accessible via carboalumination from alkyne 27, which might be traced back to (E,E)-farnesyl acetone (28). The idea was to produce 9 in accordance with one of the methods reported in the literature, and to obtain rac-24 in a few steps from symmetrical 3-methyl-pentane-1,5-diol (26) by selective functionalization of either of the two hydroxyl groups. 

The synthesis of 2-hydroxyphenazine (9) caused unexpected problems, though. The resultant yield of 9 was very low with both the condensation of 2-hydroxy-1,4-benzoquinone (33) [30], available from 1,2,4-trihydroxybenzene... 

To further elucidate the function of methanophenazine (10) as electron carrier its redox potential was determined [45]. As Scheme 2 reveals, the redox potential of lO/dihydro-10 must range somewhere between the values for F420H2/F420 ( 0 =-360 mV) [46] and H2/2H ( =-420 mV), and the redox potential of the heterodisulfide CoB-S-S-CoM (22). Whilst the values of F420H2/F420 and H2/2H" have long been known, the redox potential of 22 remained an unknown quantity. 2-Hydroxyphenazine (9) had proved to be a satisfactory model sub-... 

Table 2 Synthesis of phenazine ethers 10,44a-g by etherification of 2-hydroxyphenazine (9) with ROMs(-Br) and their redox potentials vs. SHE as determined by cyclic voltammetry in phosphate buffer at pH 7 using HMDE...

That the second option can also be successfully used has recently been revealed by our synthesis of 2-methoxyphenazine (117) [90]. The reduction of o-bromo-o -nitrodiphenylamine 132 accessible via intermolecular Pd-catalyzed JV-arylation provides the o-amino-o -bromodiphenylamine 133, which can then be cyclized to give 117 in a Pd-catalyzed intramolecular AT-arylation by employing Pd2(dba)3 as the Pd complex and 134 as the phosphine ligand. It should be noted that the outcome of both the intermolecular and the intramolecular AT-arylations heavily depends on the appropriate choice of the Pd complex as well as the phosphine. Ether cleavage leads to 2-hydroxyphenazine (9). 

Table 5 Characteristic thermochemical properties of QDO, 2-methylquinoxaline 1,4-dioxide, 2,3-dimethylquinoxaline 1,4-dioxide, and 2-hydroxyphenazine 5,10-dioxide, determined by Ribeiro da Silva et al.

Using ether-treated cells of P. aureofaciens, dicarbonyl-14C2 phenazme-l,6-dicarboxylic acid las (121)1 was found to be an efficient and specific precursor for phenazine-1-carboxylic acid (123), and also for 2-hydroxyphenazine-l-carboxylic acid (124). The rate of growth of the organism appeared to be important, because an incorporation was also recorded of the labelled (121) into (123), albeit at a lower level, with cultures that had been grown rapidly. The position of phenazine-1,6-dicarboxylic acid (121) as a universal intermediate in the biosynthesis of phenazines now seems secure. The previously reported failure of dimethyl phenazine-1,6-dicarboxylate (122) to act as a precursor of phenazines cf. Vol. 10, p. 28 Vol. 9, p. 29) has been confirmed with ether-treated cells of P. aureofaciens. Efficient hydrolysis of (125) to (123) did, however, occur.101... 

The photochemistry of ethyl esters of 2-oxo-carboxylic acids has the participation of both singlet and triplet excited states o. Triplet state lifetimes have been measured and the occurrence of Norrish type II splits in these molecules established. Other flash photolysis studies reported deal with the photoinduced tautomerism of 2-hydroxyphenazine °, 3-methylisoxazolo[5,4-b]pyridine °, and the photolysis of 4,4 -biphenylbiazide °. The tautomerism and phototautomerization of 4(3H)-pyridinethione has been examined theoretically by the infra red isolation technique . The effect of pressure on the photoinduced abstraction reaction of azanaphthalenes in mixed crystals of durene has also been studied. Photosolvolysis of arylmethanols also occurs in aqueous solutions of sulphuric acid . 

When phenolate anions are used as substrates, phenazine dioxides are produced. The same product—2-hydroxyphenazine dioxide (173 R1 = H, R2 = OH)—is formed, whether phenol, resorcinol, hydroquinone, or benzoquinone is used,9,390,392 illustrating the variability of the relationship between the oxidation levels of the substrates and products. Benzofuroxan, a trialkylphosphine, and a quinone produce blue-violet phos-phonium betaine derivatives (e.g., 173 R1 = PR3+, R2 = 0-).393 The ether 173 (R1 = H, R2 = O-alkyl) is produced from a hydroquinone monoether.390 1-Hydroxyphenazine dioxide (173 R1 = OH, R2 = H) can be prepared from benzofuroxan, cyclohexane- 1,2-dione, and a base, followed by oxidation of the mixture of mono- and di-iV-oxide formed.394 /J-Naphthol provides benzo[a] phenazine dioxide (174).9,390... 

It was of interest to see whether the betaine (171) would serve as a precursor for 2-hydroxyphenazine-l-carboxylic acid (177) and 2-hydroxyphenazine, which are produced by Ps. aureofaciens along with 1-carboxyphenazine (170). ° 2-Hydroxyphenazine-l-carboxylic acid could, it was thought, arise by opening of the epoxide ring of (172) in an alternative manner to the one which would give pyocyanin. In the event, however, only 1-carboxyphenazine served as a precursor for (177) and 2-hydroxyphenazine the respective levels of incorporation are in accord with the sequence (170)— (177)— 2-hydroxyphenazine. As 1-... 

Hydroxyphenazine-l-carboxylic acid (li) and 2-hy-droxyphenazine (lb) are believed to be derived sequentially from phenazine-1-carboxylic acid (Ih) via known biotransformation reactions, presumably via an arene oxide intermediate (Scheme 3). In Pseudomonas aureofaciens, an NADPH-dependent reductase is responsible for the hydroxylation to form li, whereas the subsequent decarboxylation to give lb occurs spontaneously and nonenzymatically. ... 

Phenazine-1-carboxylic acid, 2-hydroxyphenazine, and 2-hydroxyphenazine-l-carboxylic acid were extracted from Pseudamonas aureofaciens cultures and analyzed on a Cig column (A = 257 nm) using a 25-min 65/35/0.1 ->0/100/0.1 water/acetonitrile/TFA gradient [1001]. Elution of the components is complete in 15 min and the two carboxylic acids are not resolved using this gradient system. Therefore, it seems prudent to change to a shallower gradient or have an initial isocratic hold period prior to a gradient in order to force a separation. 

In 2013, along with the reports of biologically active compounds, derived by targeted syntheses, a multitude of natural products was found to display antibacterial, antifungal, and anticancer activities. Mehnaz and her colleagues isolated and characterized known compounds phenazine-1-carboxylic acid (159), 2-hydroxyphenazine-l-carboxylic acid (160), 2-hydroxyphenazine (161), and 2,8-dihydroxyphenazine (162) from the biocontrol strain Pseudomonas aurantiaca PB-St2 (Figure 7-9) (13JNP135). 

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