Methylenedioxy derivatives, catechol

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

The methylenedioxy derivative can act in this way as the alternative substrate of the enzyme performing the microsomal hydroxylation, but the catechol formed may also contribute to the effect (Moore and Hewlett, 1958 Metcalf et al., 1966 Casida, 1970 Casida et al., 1966 Hennessy, 1965 1969 Hennessy and Whalen, 1966 Kuwatsuka, 1970). However, this does not explain the strength and duration of synergism produced by methylenedioxyphenyl compounds. Experimental results of Franklin (1974) indicate that during oxidative metabolism these compounds form an intermediate which strongly binds to cytochrome P-450 and thereby prevents further participation of the enzyme in oxidative metabolism. 

Methylenation of catechols. Bashah and Collins have converted various <3-dihydroxyphenols into the methylenedioxy derivative by addition of a solution of the phenol in aqueous NaOH to a mixture of dibromomethane, water, and this phase-transfer catalyst. Reported yields are 76-86%. Classical methods require anhydrous conditions and aprotic solvents. 

Various substituted and unsubstituted methylenedioxy derivatives of apomorphine and V-n-propylnorapomorphine have been studied by Baldessarini et and one of these, 10,11 -methylenedioxy-V-n-propylnorapomorphine, was found to be both a long-acting and an orally efficient prodrug (Fig. 33.28). The oral activity of the compound can be ascribed to the protection of the catechol system from the first-pass effects by the methylenedioxy group. The conversion to the free catechol is possible thanks to the hepatic microsomal enzymes (see Chapters 28 and 29 on drug metabolism). 

NPA and its potential pro-drug, / -10,11-methylenedioxy-A/-propylnorapomor-phine, have been measured in monkey plasma. Samples were prepared by SPE on ODS-modified columns and the residue divided so that the electroactive catechol could be separated (nitrile-modified silica HPLC column) and detected at a GCE (+0.7 V vs Ag/AgCl). The pro-drug was analysed on an octyl-modified HPLC column with detection at 280 nm. The LoDs were 0.5 and lOpgL for NPA and the methylenedioxy derivative, respectively. The corresponding /V-methyl homo-logues were used as internal standards. 

Catechols likewise undergo 0-alkylation under phase transfer conditions, yielding methylenedioxy derivatives on reaction with methylene bromide [8]. This reaction constitutes a useful route to this commonly occurring oxygen heterocycle as well as providing a facile protection method for 1,2-dihydroxyarenes. Dibromo-methane rather than the more reactive diiodomethane was used in this reaction because the latter is a source of iodide ion which poisons the phase transfer catalyst by selectively ion-pairing with the quaternary ammonium cation. Phenoxide ion can apparently compete successfully with bromide but not iodide in the formation of an extractable ion pair under these conditions. 

Catechols can be protected as diethers or diesters by methods that have been described to protect phenols. However, formation of cyclic acetals and ketals (e.g., methylenedioxy, acetonide, cyclohexylidenedioxy, diphenylmethylenedioxy derivatives) or cyclic esters (e.g., borates or carbonates) selectively protects the two adjacent hydroxyl groups in the presence of isolated phenol groups. 

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