Naphthoates

Triflates of phenols are carbonylated to form aromatic esters by using PhjP[328]. The reaction is 500 times faster if dppp is used[329]. This reaction is a good preparative method for benzoates from phenols and naphthoates (473) from naphthols. Carbonylation of the bis-triflate of axially chiral 1,1 -binaphthyl-2,2 -diol (474) using dppp was claimed to give the monocarboxy-late 475(330]. However, the optically pure dicarboxylate 476 is obtained under similar conditions[331]. The use of 4.4 equiv. of a hindered amine (ethyldiisopropylamine) is crucial for the dicarbonylation. The use of more or less than 4.4 equiv. of the amine gives the monoester 475. 

Methyl 3-hydroxy-2-naphthoate [883-99-8] M 202.2, m 73-74 , pK ,( -9.0. Crystd from MeOH (charcoal) containing a little water. 

Naphthalenedicarboxylic acid has been prepared by fusing dipotassium 2,6-naphthalenedisulfonate with potassium cyanide to give the corresponding dinitrile, which is hydrolyzed by oxidation of 2-methyl-6-acetylnaphthalene with dilute nitric acid at 200 by the thermal disproportionation of potassium a- or /3-naphthoate to dipotassium 2,6-naphthalenedicarboxylate and naphthalene and by the present method. The present method is much more convenient than earlier methods, if a suitable autoclave is available. 

Isobutyrate, 193 Monosuccinoate, 193 (E)-2-Methyl-2-butenoate (Tigloate), 193 o-(Methoxycarbonyl)benzoate, 193 p-P-Benzoate, 193 cx-Naphthoate, 193 Nitrate, 193... 

The rate of saponification of ethyl 2-thenoate, in contrast to ethyl 3-thenoate, was found to be considerably slower than predicted from the pKa of the acid, showing that the reactivities of thiophenes do not parallel those of benzene. The first explanation, that this was produced by a steric effect of the ring sulfur similar to the case in or /lo-substituted benzenes and in ethyl 1-naphthoate, could not be upheld when the same effect was found in ethyl 2-furoate. It was later ascribed to a stereospecific acid strengthening factor, involving the proper relation of the carboxylic hydrogen and the heteroatom, as the rate of saponification of 2-thienylacrylic acid was in agreement with that predicted from the acid constants. ... 

Hydroxy-3-naphthoic acid (1.BB grams) was dissolved in hot aqueous sodium hydroxide (0.5N 20 ml) and the resulting solution was slowly added to a solution of N-benzyl-N,N-dimethyl-N-2-phenoxyethylammonium chloride (2.9 grams) in water (5 ml). A gum separated at first but it solidified on scratching. After the addition was complete, the mixture was allowed to stand at room temperature for 2 hours and then filtered. The residue was washed with water and dried in vacuo to give N-benzyl-N,N-dimethyl-N-2-phenoxyethylammonium 2-hydroxy-3-naphthoate, MP 170°-171°C. 

Coleman et al. have performed a preliminary structure/activity study for a series of analogues of 77 [149]. They found that removal of the naphthoate moiety (88 Scheme 11.11) dramatically reduced the yield of DNA alkylation, while replacement of the NH2 group with O-benzyl (89 and 90) abolished DNA alkylation completely. Compound 91 alkylated DNA with reduced efficiency, so this effect is not simply due to a requirement for a hydrogen bond donor at this position. Perhaps the amide is required at this position to increase the ability of the C=0 to act as a hydrogen bond acceptor. Importantly, they found a strong correlation between the extent of in vitro DNA alkylation and cell culture cytotoxicity. 

These contrasting results for partial azinomycin structures are confusing, but may be due to subtle differences in experimental design. However, the results of Coleman et al. on azinomycin B itself provide considerable evidence that its binding to DNA does not involve intercalation, and that the naphthoate moiety is involved in more general hydrophobic interactions. 

Very recently, the Shipman group have made a further step towards a comprehensive structure/activity profile for noncovalent interactions between azinomycin B and DNA [152]. They synthesized simplified azinomycin analogues 69 and 96-98 (Scheme 11.13), retaining both the epoxide and aziridine alkylating functionalities, with systematically altered substitution on the naphthoate fragment, and analyzed their DNA crosslinking by gel electrophoresis. They found that cross-... 

The acetate labeling results clearly demonstrated a polyketide origin for the naphthoate fragment. This resulted in the hypothesis that the first enzyme-free intermediate in azinomycin biosynthesis would be naphthoate 102, with condensation to fonn a polyketone chain, reduction, cyclization, and dehydration/aromati-... 

Figure 11.15 Proposed pathway to the naphthoate fragment of azinomycin B.

Figure 11.16 Proposed NIH shift mechanism for hydroxyla-tion of the azinomycin naphthoate.

It is very likely that a similar Type I polyketide synthase constructs the naphthoate fragment of azinomycin B. This will be a very interesting enzyme to study, since it will need to perform an unprecedented three regioselective reduction reactions, as well as controlling the polyketide chain length and directing its cycliza-tion. 

Iwabuchi T, S Harayama (1998b) Biochemical and molecular characterization of l-hydroxy-2-naphthoate dioxygenase from Nocardioides sp. KP7. J. Biol. Chem. 273 8332-8336. 

Morawski B, RW Eaton, JT Rossiter, S Guoping, H Griengl, DW Ribbons (1997) 2-Naphthoate catabolic pathway in Burkholderia strain JT 1500. J Bacterial 179 115-121. 

Althongh the degradation of naphthalene-2-carboxylate by Burkholderia sp. strain JT 1500 involves the formation of 1-hydroxy naphthalene-2-carboxylate, this is not formed from the expected (l/ ,25)-di-l,2-dihydrodiol-2-naphthoate. Possibly, therefore, the reaction is carried out by a monooxygenase, or a dehydration step is involved. Subsequent reactions produced pyruvate and o-phthalate that was degraded via 4,5-dihydroxyphthalate (Morawski et al. 1997). Degradation of naphthalene carboxylates formed by oxidation of methyl groups has already been noted. 

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