Preparation of Highly Alkoxy‐Substituted Naphthaldehyde Derivatives – A Regioselective Approach to Building Blocks for the Synthesis of Rubromycins

Abstract

An efficient synthesis of highly substituted naphthaldehyde derivatives 8 was required for the planned synthesis of compounds of the rubromycin family. Three different routes towards this goal were attempted. Route I started with 1,5-dihydroxynaphthalene (10), and the pentaalkoxy-substituted naphthaldehyde 17 was obtained in a straightforward sequence in moderate overall yield. Route II employed an aryne cycloaddition to generate the functionalized naphthalene skeleton. This sequence smoothly provided the bromonaphthalene derivative 19, which served as a very suitable precursor of aldehyde 24, boronic acid 25, and finally the unsymmetrically substituted hexaalkoxynaphthalene derivative 18. Unfortunately, though, the regioselective formylation of 18 to provide the desired aldehyde 8a was not possible, this key compound being obtained only in low yield. Whereas an attempted Claisen rearrangement of O-allylated derivative 30 furnished the wrong regioisomer 33, the ortho-Fries re-

Total Syntheses of Cytotoxic, Naturally Occurring Kalasinamide, Geovanine, and Marcanine A

“…[19] Similar methods have been applied to aromatic compounds, but to our knowledge this is the first report on its application to heteroaromatic compounds. Acidic cleavage of the oxygen bridge mediated by paratoluenesulfonic acid [20] provided free phenol 16.…”

2-Methylsulfanylbenzo[f]isoquinoline

“…Electrocyclic ring closure then occurs onto the more reactive and favored naphthyl 1-position [14][15][16] as opposed to the alternative, less reactive, dis-favored 3-position. Loss of hydrogen and aromatization then gives the benzo[f]isoquinoline 4.…”

Rubromycins: Structurally Intriguing, Biologically Valuable, Synthetically Challenging Antitumour Antibiotics

“…Starting from 20 we required 12 steps to obtain the crucial precursor compound 77 in 9 % overall yield (16 steps with respect to commercially available starting material). [23] For the synthesis of 6-iodoisocoumarin-3-carboxylate derivative 82 we converted vanillin (78) into ester 79 within five steps. Lactone formation was achieved by olefination of 79 with phosphonate 80 and intramolecular condensation of silyl enol ether 81.…”