Synthesis of cis- and trans-5,8-Dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone.

Abstract

Sch 49210 (2) is a novel metabolite having antitumor and inhibitory phospholipase D activities and was isolated from a fungal culture broth by Chu et al. in 1994. 1) Compound 2 contains a unique structure, ketobisepoxydecalone with a spiroacetal linkage through a naphthalene moiety. CJ-12, 372 (4) isolated by Sakemi et al. 2) was shown to possess DNA gyrase inhibition activity and is a spiroacetal compound with 1,8-naphtalenediol (5) as compound 2. Recently, investigations of analogous compounds of 2 and 4 have been reported and the syntheses of a series of these naturally occurring spiroacetal-bridged compouds were published.3-11) The synthesis of bisepoxide 2 and naphthalene dimer 4 has not yet been published, however, we initially began to synthesize key compounds 1a and 3 for 2 and 4 (Chart 1). In this paper, we describe the first synthesis of cis -and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (1a, 1b) by two routes, and also the first synthesis of racemic triol 3. Results and Discussion2,3-Dihydro-5,8-dihydroxy-1,4-naphthoquinone (7) was synthesized from naphthazazine (6) as the starting material by applying the procedure 12) developed by Pearson et al. Reduction of 6 by 20 eq of stannous chloride under acidic conditions gave dihydro compound 7 in 90% yield (Chart 2). Diol 7 was used in the following procedure without purification because 7 is unstable to air-oxidation and returns to starting material 6 easily. Diol 7 was then reduced by treatment with large excess (24 eq) of NaBH 4 in the presence of a catalytic amount of CeCl 3 13-15) in tetrahydrofuran (THF) at room temperature to afford a mixture of 8a and 8b. Oxidation of a mixture of 8a and 8b using ceric ammonium nitrate (CAN) [16][17][18] as an oxidant in acetonitrile gave a mixture of 1a (cis) and 1b (trans).19) The mixture was separated by column chromatography to give crystals 1a and oil 1b in 34 and 50% yields, respectively (Chart 2). The stereostructures of 1a and 1b were decided as follows. The determination whether 1a and 1b are the cis or trans isomer by 1 H-NMR spectra presented great difficulty because each spectrum exhibits a complicated coupling pattern. Therefore, X-ray analysis of 1a was performed. The ORTEP view of 1a showed a cis diol structure and exhibited interesting stereochemical features as shown in Fig. 1. The cyclohexane ring adopts a half-chair conformation and two carbonyl groups in quinone are above so that they are apart from each cis hydroxyl group. From these results, it was proved that 1a and 1b are correspondent to a cis and trans diol, respectively.In the procedure shown in Chart 2, separation of 1a and 1b by column chromatography was difficult because their Rf values are very close in spite of the short process. We therefore developed another method for 1a and 1b as shown in Chart 3. Methylation of 6 by treatment with Ag 2 O and CH 3 I afforded 9 in 76% yield according to the procedure developed by Pearson and co-workers. 12) At first LiAlH 4 was used as a reducing agent, but 1,4-dihydroxy-5,8-dim...

Botrytone, a New Naphthalenone Pentaketide Produced by Botrytis fabae, the Causal Agent of Chocolate Spot Disease on Vicia faba

“…In particular, the metabolite 1 , having a molecular weight of 194 as deduced from its HR ESI MS spectrum, showed 1 H and 13 C NMR spectra (Table ) very similar to those of a racemic mixture of this triol prepared by selective reduction of 5-hydroxyjuglone in a research project aimed to prepare some bisepoxides, closely related dimers with antitumor activity, isolated from a culture broth of Nattrassia mangiferae . In particular, the 1 H NMR spectrum of 1 showed the presence of a para-disubstituted benzene ring for the presence of the two ortho-coupled protons (H-6 and H-7) appearing as two doublets ( J = 9.0 Hz) at δ 7.09 and 6.86, respectively .…”

“…12,13 In particular, the metabolite 1, having a molecular weight of 194 as deduced from its HR ESI MS spectrum, showed 1 H and 13 C NMR spectra (Table 1) very similar to those of a racemic mixture of this triol prepared by selective reduction of 5-hydroxyjuglone in a research project aimed to prepare some bisepoxides, closely related dimers with antitumor activity, isolated from a culture broth of Nattrassia mangiferae. 14 In particular, the 1 H NMR spectrum of 1 showed the presence of a paradisubstituted benzene ring for the presence of the two orthocoupled protons (H-6 and H-7) appearing as two doublets (J = 9.0 Hz) at δ 7.09 and 6.86, respectively. 15 The two substituents were two hydroxy groups as shown by the typical chemical shift values of the geminal carbons resonating in the 13 C NMR spectrum at δ 156.6 and 147.2 (C-8 and C-5) as well as those of the respective ortho-located carbons at δ 118.7 and 114.6 (C-7 and C-8a) and 126.9 and 126.2 (C-6 and C-4a), respectively.…”