Concise Synthesis of (+)-β- and γ-Apopicropodophyllins, and Dehydrodesoxypodophyllotoxin

Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-β- and γ-apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin. The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were easily accessed from a nickel-catalyzed reductive cascade approach developed in our group.


Introduction
Lignans are a class of secondary metabolites in various plants, and most of them have demonstrated interesting biological properties [1,2], thus attracting the attention of the synthetic chemists [3,4]. Some of 2,7 -cyclolignans such as 7,8,8 ,7 -tetrahydronaphthalene (THN), 7 ,8 -dihydronaphthalene (DHN) and 7 -arylnaphthalene types are exemplified in Scheme 1a. Hong and co-workers used organocatalytic domino Michael-Michael-aldol reactions to construct THN skeleton of galbulin and realized its first enantioselective synthesis [5]. Barker and co-workers completed the first asymmetric synthesis of (−)-cyclogalgravin based on a key construction of C2-C7 bond from in situ generated quinoid intermediate [6]. Notably, the other two structurally distinct class of lignans could also be obtained from a common precursor in their syntheses. Ramana et al. proposed a dehydrative cyclization of an aldehyde intermediate to build the DHN unit of sacidumlignan B, whose subsequent aromatization led to the synthesis of sacidumlignan A [7]. We were also involved in this fascinating field and achieved the synthesis of these three molecules through Ueno-Stork radical cyclization and Friedel-Crafts reaction [8,9]. However, almost all of the above syntheses applied stepwise strategies (i.e., a sequence of C2-C7 , C8-C8 , then C1-C7 bonds formation in our previous routes) for construction of the central core [10].

Results and Discussion
Recently, we completed a new synthesis of podophyllotoxin [11,12], an aryltetralin lignan used as building block for the chemotherapeutic drugs etoposide and teniposide. The key reaction is a Ni-catalyzed reductive tandem coupling [13][14][15][16][17][18][19] of dibromide A that led to the simultaneous construction of C8-C8 and C1-C7 bonds in THN framework of B (Scheme 1b). We envision that this Starting from the commercially available 6-bromopiperonal and 3,4,5-trimethoxyphenyl bromide, the chiral β-bromo acetal 1 was straightforwardly prepared as in gram-scale according to a known route [11]. Under a fully intramolecular reductive nickel-catalysis ligated by ethyl crotonate (Scheme 2), diastereodivergent (+)-deoxypicropodophyllin (2) and (+)-isodeoxypodophyllotoxin (3) were obtained in 50% overall yield after a conversion of acetal moiety to the corresponding lactone. With aryltetralin lactones 2 and 3 in hand, the designed regiocontrolled oxidation in central aliphatic ring could be executed (vide infra). First of all, the increase of an unsaturation degree at either C8-C8′ or C7′-C8′ location was pursued in order to get (+)-β-apopicropodophyllin (5) and (+)-γ-apopicropodophyllin (6) quickly. As shown in Scheme 3, the introduction of a phenylselenyl group at C8′ position of (+)-deoxypicropodophyllin (2) was done by an initial enolization and subsequent quench with phenylselenyl bromide (PhSeBr) at −78 °C. The generated products as two diastereoisomers (4a and 4b) were separated by column chromatography on silica gel in 95% overall yield. The α-phenylselenide 4a is supposed to adopt a pseudo-boat conformation, where the hydrogen atom at C8 is arranged cis to the -SePh. The requisite syn-elimination of phenylselenoxide in situ generated Starting from the commercially available 6-bromopiperonal and 3,4,5-trimethoxyphenyl bromide, the chiral β-bromo acetal 1 was straightforwardly prepared as in gram-scale according to a known route [11]. Under a fully intramolecular reductive nickel-catalysis ligated by ethyl crotonate (Scheme 2), diastereodivergent (+)-deoxypicropodophyllin (2) and (+)-isodeoxypodophyllotoxin (3) were obtained in 50% overall yield after a conversion of acetal moiety to the corresponding lactone. With aryltetralin lactones 2 and 3 in hand, the designed regiocontrolled oxidation in central aliphatic ring could be executed (vide infra). Starting from the commercially available 6-bromopiperonal and 3,4,5-trimethoxyphenyl bromide, the chiral β-bromo acetal 1 was straightforwardly prepared as in gram-scale according to a known route [11]. Under a fully intramolecular reductive nickel-catalysis ligated by ethyl crotonate (Scheme 2), diastereodivergent (+)-deoxypicropodophyllin (2) and (+)-isodeoxypodophyllotoxin (3) were obtained in 50% overall yield after a conversion of acetal moiety to the corresponding lactone. With aryltetralin lactones 2 and 3 in hand, the designed regiocontrolled oxidation in central aliphatic ring could be executed (vide infra). First of all, the increase of an unsaturation degree at either C8-C8′ or C7′-C8′ location was pursued in order to get (+)-β-apopicropodophyllin (5) and (+)-γ-apopicropodophyllin (6) quickly. As shown in Scheme 3, the introduction of a phenylselenyl group at C8′ position of (+)-deoxypicropodophyllin (2) was done by an initial enolization and subsequent quench with phenylselenyl bromide (PhSeBr) at −78 °C. The generated products as two diastereoisomers (4a and 4b) were separated by column chromatography on silica gel in 95% overall yield. The α-phenylselenide 4a is supposed to adopt a pseudo-boat conformation, where the hydrogen atom at C8 is arranged cis to the -SePh. The requisite syn-elimination of phenylselenoxide in situ generated First of all, the increase of an unsaturation degree at either C8-C8 or C7 -C8 location was pursued in order to get (+)-β-apopicropodophyllin (5) and (+)-γ-apopicropodophyllin (6) quickly. As shown in Scheme 3, the introduction of a phenylselenyl group at C8 position of (+)-deoxypicropodophyllin (2) was done by an initial enolization and subsequent quench with phenylselenyl bromide (PhSeBr) at −78 • C. The generated products as two diastereoisomers (4a and 4b) were separated by column chromatography on silica gel in 95% overall yield. The α-phenylselenide 4a is supposed to adopt a pseudo-boat conformation, where the hydrogen atom at C8 is arranged cis to the -SePh. The requisite syn-elimination of phenylselenoxide in situ generated from oxidation of 4a [20], eventually provided (+)-β-apopicropodophyllin (5) with in vivo insecticidal activity against the fifth-instar larvae of Brontispa longissima [21]. Its 1 H NMR spectral data (Table S2) and optical rotation were in agreement with the reported data by Toste and Meyers [22,23]. The structure was later unambiguously confirmed by its single-crystal analysis ( Figure 1) [24]. In contrast, the hydrogen atom at C7 is oriented at cis-position of C8 -PhSe in the favored half-chair conformer of β-phenylselenide 4b. Thus, a double bond within C7 -C8 was formed upon the subjection of 4b to m-CPBA, therefore affording to (+)-γ-apopicropodophyllin (6) in 88% yield. As shown in Table S3, 1 H NMR spectra of the synthetic 6 was accord with the literature [25]. from oxidation of 4a [20], eventually provided (+)-β-apopicropodophyllin (5) with in vivo insecticidal activity against the fifth-instar larvae of Brontispa longissima [21]. Its 1 H NMR spectral data (Table S2) and optical rotation were in agreement with the reported data by Toste and Meyers [22,23]. The structure was later unambiguously confirmed by its single-crystal analysis (Figure 1) [24]. In contrast, the hydrogen atom at C7′ is oriented at cis-position of C8′-PhSe in the favored half-chair conformer of β-phenylselenide 4b. Thus, a double bond within C7′-C8′ was formed upon the subjection of 4b to m-CPBA, therefore affording to (+)-γ-apopicropodophyllin (6) in 88% yield. As shown in Table S3, 1 H NMR spectra of the synthetic 6 was accord with the literature [25].  Next, the potential aromatization within tetralin lactone was investigated. As shown in Scheme 4, one-step conversion of (+)-isodeoxypodophyllotoxin (3) to dehydrodesoxypodophyllotoxin (7) was realized in 56% yield promoted by a mixture of N-bromosuccinimide (NBS) and dibenzoyl peroxide (BPO) in refluxing CCl4. The plausible mechanism of this tandem reaction would be radical bromination [26] catalyzed by BPO occurs firstly, and a fast elimination of the resulting labile benzylbromide followed by further oxidation, providing the central benzene ring in 7. 1 H NMR spectra data (Table S4) of synthetic dehydrodesoxypodophyllotoxin was consistent with previous report [27]. from oxidation of 4a [20], eventually provided (+)-β-apopicropodophyllin (5) with in vivo insecticidal activity against the fifth-instar larvae of Brontispa longissima [21]. Its 1 H NMR spectral data (Table S2) and optical rotation were in agreement with the reported data by Toste and Meyers [22,23]. The structure was later unambiguously confirmed by its single-crystal analysis (Figure 1) [24]. In contrast, the hydrogen atom at C7′ is oriented at cis-position of C8′-PhSe in the favored half-chair conformer of β-phenylselenide 4b. Thus, a double bond within C7′-C8′ was formed upon the subjection of 4b to m-CPBA, therefore affording to (+)-γ-apopicropodophyllin (6) in 88% yield. As shown in Table S3, 1 H NMR spectra of the synthetic 6 was accord with the literature [25].  Next, the potential aromatization within tetralin lactone was investigated. As shown in Scheme 4, one-step conversion of (+)-isodeoxypodophyllotoxin (3) to dehydrodesoxypodophyllotoxin (7) was realized in 56% yield promoted by a mixture of N-bromosuccinimide (NBS) and dibenzoyl peroxide (BPO) in refluxing CCl4. The plausible mechanism of this tandem reaction would be radical bromination [26] catalyzed by BPO occurs firstly, and a fast elimination of the resulting labile benzylbromide followed by further oxidation, providing the central benzene ring in 7. 1 H NMR spectra data (Table S4) of synthetic dehydrodesoxypodophyllotoxin was consistent with previous report [27]. Next, the potential aromatization within tetralin lactone was investigated. As shown in Scheme 4, one-step conversion of (+)-isodeoxypodophyllotoxin (3) to dehydrodesoxypodophyllotoxin (7) was realized in 56% yield promoted by a mixture of N-bromosuccinimide (NBS) and dibenzoyl peroxide (BPO) in refluxing CCl 4 . The plausible mechanism of this tandem reaction would be radical bromination [26] catalyzed by BPO occurs firstly, and a fast elimination of the resulting labile benzylbromide followed by further oxidation, providing the central benzene ring in 7. 1 H NMR spectra data (Table S4) of synthetic dehydrodesoxypodophyllotoxin was consistent with previous report [27]. Scheme 4. One-step conversion of tetralin to arylnaphthalene skeleton.

General Procedure
For product purification by flash column chromatography, SiliaFlash P60 (particle size: 40-63 μm, pore size 60A) and petroleum ether (bp. 60-90 °C) were used. All solvents were purified and dried by standard techniques and distilled prior to use. All of experiments were conducted under an argon or nitrogen atmosphere in oven-dried or flame-dried glassware with magnetic stirring, unless otherwise specified. Organic extracts were dried over Na2SO4 or MgSO4, unless otherwise noted. 1 H and 13 C-NMR spectra were taken on a Bruker AM-400, AM-600 and Varian mercury 300 MHz spectrometer with TMS as an internal standard and CDCl3 as solvent unless otherwise noted. HRMS were determined on a Bruker Daltonics APEXII 47e FT-ICR spectrometer with ESI positive ion mode. The X-ray diffraction studies were carried out on a Bruker SMART Apex CCD area detector diffractometer equipped with graphite-monochromated Cu-Kα radiation source. Melting points were measured on Kofler hot stage and are uncorrected. (4a and 4b) A solution of 2 [11] (100 mg, 0.25 mmol) in THF (8 mL) under argon was cooled to −78 °C, followed by the addition of freshly prepared LDA (0.5 mmol, 2.0 equiv). The stirred solution was maintained at this temperature for 20 min, and a solution of PhSeBr (118 mg, 0.5 mmol, 2.0 equiv) in THF (3 mL) was then added. The resulting mixture was stirred for 20 min at −78 °C, and then quenched by water (1 mL). The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (2 × 8 mL) and brine (8 mL) respectively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 4:1 → petroleum ether/EtOAc =2:1) on silica gel to afford 4a (90 mg, 65% yield) as a white solid and 4b (42 mg, 30% yield) as a white solid.

General Procedure
For product purification by flash column chromatography, SiliaFlash P60 (particle size: 40-63 µm, pore size 60A) and petroleum ether (bp. 60-90 • C) were used. All solvents were purified and dried by standard techniques and distilled prior to use. All of experiments were conducted under an argon or nitrogen atmosphere in oven-dried or flame-dried glassware with magnetic stirring, unless otherwise specified. Organic extracts were dried over Na 2 SO 4 or MgSO 4 , unless otherwise noted. 1 H and 13 C-NMR spectra were taken on a Bruker AM-400, AM-600 and Varian mercury 300 MHz spectrometer with TMS as an internal standard and CDCl 3 as solvent unless otherwise noted. HRMS were determined on a Bruker Daltonics APEXII 47e FT-ICR spectrometer with ESI positive ion mode. The X-ray diffraction studies were carried out on a Bruker SMART Apex CCD area detector diffractometer equipped with graphite-monochromated Cu-Kα radiation source. Melting points were measured on Kofler hot stage and are uncorrected. (4a and 4b) A solution of 2 [11] (100 mg, 0.25 mmol) in THF (8 mL) under argon was cooled to −78 • C, followed by the addition of freshly prepared LDA (0.5 mmol, 2.0 equiv). The stirred solution was maintained at this temperature for 20 min, and a solution of PhSeBr (118 mg, 0.5 mmol, 2.0 equiv) in THF (3 mL) was then added. The resulting mixture was stirred for 20 min at −78 • C, and then quenched by water (1 mL). The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (2 × 8 mL) and brine (8 mL) respectively, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 4:1 → petroleum ether/EtOAc =2:1) on silica gel to afford 4a (90 mg, 65% yield) as a white solid and 4b (42 mg, 30% yield) as a white solid. Characterization data for 4a: R f = 0.42 (petroleum ether/EtOAc = 1:1); 1

Conflicts of Interest:
The authors declare no conflict of interest.