Selwyn C. Yorke

Naphtho[2,3-c]pyran-5,10-quinones. Syntheses of the racemates of quinone A, quinone A′, and deoxyquinone A dimethyl ethers of 7-methoxyeleutherin, and of isoeleutherin

Treatment of 3-(1-hydroxyethyl)-1,4,5,7-tetrarmethoxy-2-prop-2-enylnaphthalene (33) with potassium t-butoxide in dimethylformamide under nitrogen for a short time gave a high yield of trans-3,4-dihydro-5,7,9,10-tetramethoxy-1,3-dimethyl-1H-naphtho[2,3-c]pyran (41). This compound, with the same base and solvent, but in air, afforded a mixture comprising its cis-epimer (42), together with the two possible 4-hydroxy derivatives, namely (35) and (38). Silver(II) oxide oxidation of compounds (35), (38), (41), and (42) gave, respectively, the dimethyl ethers of quinone A, quinone A′, and deoxyquinone A, and also 7-methoxyeleutherin.

Synthesis and acetylation of naphthols as precursors to naturally derived naphthoquinones; crystal structure of the aphin-related 7-O-methyl quinone A

A route is described to 1,5,7-trialkoxy-4-naphthols. A method has been established to convert these compounds into the corresponding 3-acetyl-4-naphthols, in good yield, with a view to synthesizing naturally derived naphtho[2,3-c]pyran-5,10-quinones. Boron trichloride-induced monodemethylation of racemic Quinone A dimethyl ether was effected without perturbation of the pyran ring stereochemistry; this was confirmed by an X-ray crystallographic investigation.

Syntheses of the aphid pigment derivatives quinone A, quinone A′, and deoxyquinone A as racemates

3-Acetyl-5-methoxy-1,7-bisisopropoxy-4-naphthol (11) was converted in a number of high yielding transformations into the title quinones. Key steps were the stereospecific base-induced cyclisation in almost quantitative yield of 2-allyl-4,7-bisbenzyloxy-3-(1-hydroxyethyl)-1,5-dimethoxynaphthalene (18) into 7,10-bisbenzyloxy-3,4-dihydro-5,9-dimethoxy-trans-dimethyl-1H-naphtho[2,3-c]pyran (20) followed by the oxygenation of (20) to afford its two C-4 hydroxy epimers (23) and (26) in high combined yield, by potassium t-butoxide in dimethyl sulphoxide in the presence of oxygen. The efficient conversion of the major pseudoequatorial hydroxy compound (23) into the minor pseudoaxial hydroxy epimer (26)via the corresponding pseudoaxial chloro derivative was useful in providing increased quantities of precursors to quinone A′.

Naphthopyrans by ring-closure of substituted naphthalenes using potassium t-butoxide in dimethylformamide

Two 2-alkenyl-3-hydroxyalkyl-1,4-dimethoxynaphthalenes are cyclised with potassium t-butoxide in dimethylformamide to give 3-alkyl-3,4-dihydro-5,10-dimethoxynaphtho [2,3-c] pyrans under anaerobic conditions. One of these products is treated with the same solvent and base, but in air, to give the two possible 4-hydroxy derivatives.

Regioselective bromination, debromination and bromine migration in a 2-acetoxymethyl-4,5,7-trialkoxynaphthalene

Dibromination of 2-acetoxymethyl-4-isopropoxy-5,7-dimethoxynaphthalene 10 in buffered solution afforded the 3,8-dibromo derivative 13. Similar monobromination of compound 10 yielded the 8-bromo compound 15, whereas monobromination in the absence of the buffer yielded the isomeric 1-bromonaphthalene 16. Conversion of 15 into 16 was effected with trifluoroacetic acid. Selective monodebromination of the dibromo compound 13 gave rise to a third isomer, the 3-bromo compound 18.

An investigation into the unusual formation of an isocoumarin by acylation of 2,3,6-trimethoxytoluene with (E)-2-methylbut-2-enoic acid and trifluoroacetic anhydride

Prolonged reaction of 2,3,6-trimethoxytoluene with an excess of premixed (E)-2-methylbut-2-enoic acid and trifluoroacetic anhydride in air affords 5,6,8-trimethoxy-3,4,7-trimethylisocoumarin 11 in 66% yield as the sole product isolated, the structure of which was confirmed by X-ray crystallography. Shorter reaction times afford products which enable the identification of the reaction mechanism. This involves initial regioselective acylation, cyclisation of the derived α,β-unsaturated aryl ketone 5 to the cis/trans mixture of indanones 18 and 19 and O-acylation of these indanones to yield the indenyl ester 17. The indanones and compound 17 can all react with trifluoroacetic acid in the presence of atmospheric oxygen to afford the isocoumarin by a mechanism which requires the intermediacy of an α-keto indanyl hydroperoxide, which in turn undergoes an acid-catalysed Baeyer–Villiger-type rearrangement to incorporate oxygen, thereby giving the isocoumarin.

A short, convergent synthesis of aristolindiquinone

Aristolindiquinone, 2,5-dihydroxy-3,8-dimethyl-1,4-naphthoquinone 1, is synthesised by the regiochemical addition of 1-methoxy-1-trimethylsiloxypenta-1,3-diene 2 to 5-bromo-2-methoxy-3-methyl-1,4-benzoquinone 3. The regioisomer 2,8-dihydroxy-3,5-dimethyl-1,4-naphthoquinone 4 is prepared by reaction of the same diene 2 with 2-methoxy-3-methyl-1,4-benzoquinone 11. The former reaction readily provided sufficient quantities of aristolindiquinone 1 for biological evaluation for fertility regulation in rats, for which purpose it was found to be inactive.

The ansamycins: synthesis of the naphthoquinonoid nucleus of rifamycin W; crystal structure verification of a key naphthalenic intermediate

1,4-Benzoquinone has been converted into 8-acetyl-5,7-dihydroxy-6-methyl-3-propionylamino-1,4–naphthoquinone (29) in six steps in an overall yield of 20%. A key reaction involves the dimethylation of the intermediate 8-acetyl-3-acetylamino-1,4,5,7-tetramethoxynaphthalene (9); the structure has been confirmed by X-ray crystallography. Steric crowding prevents acetylation of 3-acetyl-1,4,5,7-tetramethoxy-6-methylnaphthalene (18) with premixed acetic acid and trifluoroacetic anhydride; 8-acetyl-1,4,5,7-tetramethoxy-6-methylnaphthalene (22) is converted by the same reagent into compound (18) by acetyl migration.

The acetylation of naphthoquinones: the synthesis of 3-acetyl-5-methoxy- and 3-acetyl-5,7-dimethoxy-1,4-naphthoquinones

The conversion of 5-methoxy- and 5,7-dimethoxy-1,4-naphthoquinones into their 3-acetyl derivatives is described. A key step is the Fries rearrangement of 1,5-dimethoxy-4-acetoxynaphthalenes to the corresponding 3-acetyl-4-naphthols with boron trifluoride–diethyl ether. Alternative Fries rearrangement of 1-acetoxy-4-hydroxy-5-methoxynaphthalenes gave the 3-acetylquinols, involving meta migration of the acetyl group. A convenient new synthesis of 2-acetyl-1,4-naphthoquinone is also reported.

Selective acylation of oxygenated naphthalenes

The synthesis of 1,4,5,7-teetraoxygenated naphthalenes is described, as well as their selective acylation at either C-3 or C-8 using either trifluoroacetic anhydride or acetic acid and trifluoroacetic anhydride; the potential of these reactions in the synthesis of naturally occurring naphthoquinones is referred to.