Studies on polynuclear furoquinones. Part 1: Synthesis of tri- and tetra-cyclic furoquinones simulating BCD/ABCD ring system of furoquinone diterpenoids

Summary Synthesis of phenanthro[1,2-b]furan-10,11-dione, the core nucleus present in Tanshinone-I is described in 8–10 steps starting from 2-bromo-3,4-dihydro-1-naphthaldehyde. The bromoaldehyde was converted to methyl 2-(2-bromo-1-naphthyl)acetate or 2-(2-bromo-1-naphthyl)acetonitrile following the protocol of functional group transformations. Subsequent Suzuki coupling of this ester/nitrile derivative with furan-2-boronic acid produced [2-(2-furyl)-1-naphthyl]acetic ester/nitrile which on hydrolysis furnished the corresponding acid derivative. Cyclization of the acid followed by oxidation of the phenol, with Fremy’s salt, produced the tetra-cyclic furoquinone, phenanthro[1,2-b]furan-10,11-dione. This method has also been extended for the synthesis of the tricyclic furoquinone, naphtho[1,2-b]furan-4,5-dione.


Results and Discussion
Our aim is to develop a general route for the synthesis of tricyclic/tetracyclic furoquinones with structural diversity. Our approach is shown in Scheme 1 and Scheme 2. In the synthesis of the tetra cyclic furoquinone 13, an easily available starting material 2-bromo-3,4-dihydro-1-naphthaldehyde 1 [34] was utilized as A, B ring precursor and commercially available furan 2-boronic acid as D-ring precursor. In the event of the synthesis, the C ring was constructed to reach the target molecule in 8-10 steps. The key steps in our synthesis deal with the formation of aryl-furyl C-C bond via Suzuki reaction [35] and the generation of the quinone functionality by oxidation of a phenolic intermediate ( Figure 2). Retrosynthesis of the molecule showed that the required phenolic compound can easily be achieved in 7-8 steps starting from 2-bromo-3,4-dihydro-1-naphthaldehyde (a substrate easily available by Vilsmeier-Haack reaction on 2-tetralone) and furan-2-boronic acid (a commercially available material) ( Figure 3). When 2-bromo-3,4-dihydro-1-naphthaldehyde (easily obtained in 68% yield by the reaction of 2-tetralone and PBr 3 /DMF in CHCl 3 at room temperature) was aromatized with DDQ in refluxing benzene, 2-bromo-1-naphthaldehyde (2) was produced in excellent yield. Reduction (NaBH 4 /EtOH) of the aldehyde 2 produced the alcohol 3 as a colorless solid, in 94% yield, which on reaction with PBr 3 /CCl 4 produced the bromide 4 as a light yellow solid. The bromide was then converted (KCN/DMF) to the nitrile derivative 5 which on hydrolysis (KOH/EtOH-H 2 O, reflux) followed by esterification with CH 2 N 2 furnished methyl 2-(2-bromo-1-naphthyl)acetate 7 in overall good yield. The bromo ester was then subjected to Suzuki reaction with furan-2-boronic acid.
Reaction of compound 7 with furan-2-boronic acid in the presence of Et 3 N and Pd(PPh 3 ) 4 (cat.) in DMF under argon atmo- sphere produced methyl [2-(2-furyl)-1-naphthyl]acetate 8 (77%) which when hydrolyzed furnished [2-(2-furyl)-1naphthyl]acetic acid (9) in 85% yield. The acid 9 was also synthesized via hydrolysis of the nitrile derivative 10 which in turn was obtained in 66% yield, by direct Suzuki reaction of 5 with furan-2-boronic acid. However in this case as the intermediate amide 11 produced was resistant to further hydrolysis, the reaction required prolonged reflux and also the yield was relatively poor. Even after reflux of the nitrile derivative 10 in KOH/ EtOH-H 2 O for 45 h 20% of the amide 11 was recovered along with 48% of the desired carboxylic acid. Change of solvent and conditions (e.g., replacement of ethanol with other high boiling alcohols or use of THF as co-solvent and higher temperature) produced no better result. The next step was the introduction of the phenol functionality. In this case our early attempt to prepare the phenol 12 by PPA cyclization of the acid 9 was unsuccessful. We however successfully prepared the phenol as a light yellow solid by cyclization of the acid 9 with trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) at room temperature in 71% yield. The phenol 12 was finally oxidized (with Fremy's salt) [36][37][38] (18), as a red solid, in 56% yield. The compounds have been characterized by usual spectroscopic analysis (NMR, IR and HRMS data) as well as by analogy with literature report [30].
In general we have developed a novel pathway for the synthesis of polynuclear furoquinones simulating BCD/ABCD ring of natural furoquinone (Tanshinone-I) and we believe the method has great potential towards the synthesis of various polynuclear furoquinone derivatives bearing electron donating/electron withdrawing functionality within its framework as bromoaldehyde derivatives bearing such groups can easily be obtained from corresponding ketones by Vilsmeier-Haack reaction. Very recently we have reported a general method for the synthesis of β-(2-furyl)-α,β-unsaturated aldehydes [39] via Suzuki reaction of β-bromo-α,β-unsaturated aldehydes. These substrates can be used for the synthesis of various non-natural tricyclic and "U-shaped" tetra cyclic furoquinone derivatives. The work is under progress and the results will be published in due course.

Phenanthro[1,2-b]furan-11-ol (12)
A mixture of compound 9 (100 mg, 0.39 mmol), 3 mL trifluoroacetic anhydride, 0.9 mL trifluoroacetic acid was stirred at room temperature overnight protecting from moisture. The mixture was then poured in ice cold saturated NaHCO 3 solution and stirred well and extracted thoroughly with CH 2 Cl 2 . The organic layer was washed with aq. NaHCO 3 solution and finally with H 2 O and dried (Na 2 SO 4 ). Removal of solvent afforded the crude product which was purified by column chromatography

Supporting Information
Supporting information features experimental procedures, analytical data and NMR spectra for some selected compounds.

License and Terms
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc) The definitive version of this article is the electronic one which can be found at: doi:10.3762/bjoc.5.47