Modular Synthesis of Polyphenolic Benzofurans, and Application in the Total Synthesis of Malibatol A and Shoreaphenol

A modular strategy for the synthesis of hexacyclic dimeric resveratrol polyphenolic benzofurans is reported. The developed synthetic technology was applied to the total synthesis of malibatol A, shoreaphenol, and other biologically relevant poly-phenols.


Introduction
Polyphenolic secondary metabolites have attracted growing interest from the scientific community in recent years [1][2][3][4][5][6]. However, despite their fascinating molecular architectures and diverse biological properties, chemical syntheses of these natural products and/or designed analogues have been scarce [7,8]. With this in mind, and as a continuation of our chemical and biological investigations of polyphenolic natural products [9,10], we set out to develop a general strategy for the synthesis of dimeric, resveratrol-derived benzofurans represented by generic structure 1, as shown in Figure 1. We further demonstrated the developed technology in the total synthesis of malibatol A (2) and OPEN ACCESS shoreaphenol (3), two dimeric resveratrol polyphenolic benzofurans isolated from Hopea malibato and Shorea robusta, respectively [11][12][13].

Results and Discussion
Recognizing the hexacyclic structure represented by 1 containing four substituted phenyl rings, we envisaged a modular approach where each one of the phenyl rings can be installed independently and sequentially. Therefore, as outlined in Scheme 1, the proposed synthesis begin with stilbene aldehyde 4, a building block with two aromatic domains brought together through a Horner-Wadswoth-Emmons (HWE) olefination reaction [14] and a subsequent Vilsmeier formylation [15]. Introduction of a third aromatic domain through the addition of an organometallic aryl species 5 to aldehyde 4, followed by subsequent oxidation (IBX) should give ketone 6. The intermediate benzylic alcohol obtained prior to IBX oxidation has previously been demonstrated by Snyder and co-workers as a versatile intermediate to access a number of resveratrol derived natural products [7,8]. Carbonyl-directed selective demethylation of 6 should lead to phenol 7, setting the stage for the attachment of the final aromatic moiety through an alkylation with benzyl halide 8 or a Mitsunobu reaction [16] with benzyl alcohol 9. With benzyl ether 10 in hand, the formation of the benzofuran ring is anticipated through its initial benzylic deprotonation (LiTMP), followed by an intramolecular cyclization (11 to 12) and subsequent dehydration (12 to 13, p-TsOH•H 2 O), to deliver pentacyclic benzofuran 13 [17]. Finally, the olefinic functionality in stilbene 13 should serve as a versatile handle for either direct seven-membered ring formation, or further transformation (14, e.g. epoxidation) leading to functionalized hexacycles 1 upon ring closure.
With this general strategy in mind, its realization to generate a library of benzofuran polyphenols is illustrated in Tables 1. As shown in Table 1, aryl ketones 16 and benzyl ethers 17 were efficiently prepared in 8590% yield (over the two steps from 15) and 7195% yield (over the two steps from 16), respectively. Next, benzofuran formation from keto benzyl ethers 17 under the two-step procedure generally proceeded in good yields (7185% yield, Table 2), apart from the failure of p-bromo substrate to participate in the cyclization (entry 3, Table 2) and the less satisfactory dehydration for the acid sensitive furanyl substrate (entry 5, Table 2). Scheme 1. General, modular strategy for the construction of hexacyclic benzofuran 1  Finally, closure of the seven-membered ring was carried out under acidic conditions (p-TsOH•H 2 O) to give cyclized compound 20 in high yields (9095% yield, entries 1, 2, 57, Table 3). The incompatibility of the furanyl functionality under the acidic conditions was once again observed (entry 3, Table 3), and the electronically less favoured substrate 19d failed to participate in the FriedelCrafts type cyclization (entry 4, Table 3). In addition, we demonstrated a one-pot procedure to prepare hexacyclic benzofuran 20b directly from keto benzyl ether stilbene 17d (Scheme 2). This highly efficient, cascade process involving deprotonation-cyclization (LiTMP), dehydration and FriedelCrafts ring-closure (p-TsOH) illustrated the utility of the developed methodology in the synthesis of highly functionalized, polycyclic polyphenols, a useful structural class for both chemical and biological investigations. Next, the developed methodology was applied to the total synthesis of malibatol A (2) [18] and shoreaphenol (3), as shown in Scheme 3 [19]. In this instance, with pentacyclic benzofuran 19d in hand, construction of the oxygen-substituted, seven-membered ring in the malibatol A (2) and shoreaphenol (3) framework called for an intramolecular FriedelCrafts type epoxide-opening process. Thus, epoxidation of stilbene 19d under the bromohydrin protocol (NBS, NaOH), followed by treatment of the resulting epoxide (21) with BBr 3 resulted the concomitant cyclization and global demethylation as a one-pot process, presumably through the intermediacy of 22, giving racemic malibatol A (2) as a single diastereoisomer in 20% yield. Oxidation of malibatol A (2) in the presence of PDC then afforded shoreaphenol (3), despite the modest yield of 46%. Both malibatol A (2) and shoreaphenol (3) exhibited spectroscopic data ( 1 H-and 13 C-NMR) and mass spectrometry data matching those reported for the natural substances [11][12][13].

General
All reactions were carried out under a nitrogen or argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF) and methylene chloride (CH 2 Cl 2 ) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Methanol (MeOH), N,N'-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and benzene were purchased in anhydrous form and used without further purification. Acetone, water, ethyl acetate (EtOAc), diethyl ether (Et 2 O), methylene chloride (CH 2 Cl 2 ), and hexanes were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically ( 1 H-NMR) homogeneous materials, unless otherwise stated. Reactions were monitored by thin-layers chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of ammonium molybdate and anisaldehyde and heat as developing agents. E. Merck silica gel (60, particle size 0.0400.063 mm) was used for flash column chromatography. 1 H and 13 C-NMR spectra were recorded at 600 and 150 MHz, respectively, on a Bruker AV-600 instrument and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, pent = pentet, hex = hexet, br = broad. IR spectra were recorded on a Perkin-Elmer Spectrum One FTIR spectrometer with diamond ATR accessory. Melting points (m.p.) are uncorrected and were recorded on a Buchi B-540 melting point apparatus. Highresolution mass spectra (HRMS) were recorded on an Agilent ESI TOF (time of flight) mass spectrometer at 3500 V emitter voltage.

General procedure A (Preparation of diaryl ketones 16, Table 1)
To a solution of aldehyde 15 (2.0 mmol) in THF (20 mL) at 0 °C was added the appropriate Grignard reagent (0.5 M in THF, 3.0 mmol). The resulting mixture was stirred for 0.5 h before it was quenched with NH 4 Cl (5 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to afford the crude benzyl alcohol, which was used directly without further purification. To the solution of crude benzyl alcohol (obtained as above) in DMSO (5 mL) at 23 °C was added IBX (1.15 g, 4.1 mmol) in one portion. The resulting mixture was stirred for 2 h before it was quenched with Na 2 S 2 O 3 (5 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with Et 2 O (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. Flash column chromatography (silica gel) afforded diaryl ketone 16. Using this general procedure the following compounds were prepared: (2,4-Dimethoxyphenyl)(phenyl)methanone (16a). From 2,4-dimethoxybenzaldehyde and phenylmagnesium bromide. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded ketone 16a (412 mg, 85%) as a pale yellow foam. All physical properties of this compound were identical to those reported in literature [20].

General procedure B (Preparation of benzyl ethers 17,
To a solution of diaryl ketone 16 (1.0 mmol) in CH 2 Cl 2 (10 mL) at 0 °C was added BCl 3 (1.0 M in CH 2 Cl 2 , 1.5 mL, 1.5 mmol) dropwise. The resulting mixture was stirred for 1 h before it was quenched with NH 4 Cl (10 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to afford the crude phenol, which was used directly without further purification. To a solution of the crude phenol (obtained as above) in DMF (5 mL) at 0 °C was added NaH (80 mg, 60% wt/wt in mineral oil, 2.0 mmol). The resulting mixture was stirred for 0.5 h before benzyl bromide (or chloride) (1.4 mmol) was added. The reaction mixture was warmed to 23 °C and the progress was monitored by TLC analysis. Upon completion of the reaction (<4 h for most cases), the reaction mixture was quenched with NH 4 Cl (20 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with Et 2 O (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. Flash column chromatography (silica gel) afforded the desired benzyl ether 17. Using the described general procedure the following substances were prepared:

General procedure C (Preparation of benzofurans 19, Table 2)
To a solution of benzyl ether 17 (0.2 mmol) in THF (2 mL) at 0 °C was added LiTMP (0.5 M in THF, 2 mL, 1.0 mmol). The resulting mixture was stirred at 0 °C and the progress was monitored by TLC analysis. Upon completion of the reaction (~ 2 h for most cases), the reaction mixture was quenched with NH 4 Cl (5 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to afford crude tertiary alcohol 18, which was used directly without further purification. To a solution of the crude tertiary alcohol 18 (obtained as above) in CH 2 Cl 2 (3 mL) at 23 °C was added p-TsOH•H 2 O (38 mg, 0.2 mmol). The resulting mixture was stirred for 1 h before it was quenched with NaHCO 3 (3 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried (Na 2 SO 4 ) and concentrated in vacuo. Flash column chromatography (silica gel) afforded the desired benzofuran 19. Using this general procedure the following compounds were prepared: 3-diphenylbenzofuran (19a). From benzyl ether 17a. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded benzofuran 19a (50 mg, 83%) as a pale yellow oil. All physical properties of this compound were identical to those reported in literature [21].

Conclusions
In conclusion, a modular and efficient entry to the dimeric resveratrol derived polyphenolic benzofurans has been developed, and applied to the total synthesis of malibatol A (2) and shoreaphenol (3). In view of the largely untapped potential of the polyphenolic secondary metabolites, the synthetic methodology described herein should find wide application in the chemical and biological investigations of this fascinating class of compounds.