Enantiospecific Semisynthesis of Puupehedione-Type Marine Natural

Oct 30, 2017 - An enantiospecific semisynthesis of puupehedione was achieved from sclareolide in only 7 steps with an overall yield of 25%. The key dr...
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Enantiospecific Semisynthesis of Puupehedione-Type Marine Natural Products Hong-Shuang Wang,† Hui-Jing Li,*,† Xiang Nan,† Yuan-Yuan Luo,† and Yan-Chao Wu*,†,‡ †

School of Marine Science and Technology, Harbin Institute of Technology, Weihai 264209, China Beijing National Laboratory for Molecular Sciences, ICCAS, Beijing 100190, China

‡

S Supporting Information *

ABSTRACT: An enantiospecific semisynthesis of puupehedione was achieved from sclareolide in only 7 steps with an overall yield of 25%. The key drimanal trimethoxystyrene skeleton was constructed by the palladium-catalyzed cross-coupling reaction of an aryl iodine and a drimanal hydrazone. An in situ CAN-oxidation/intramolecular oxaStork−Danheiser transposition tandem reaction was used as a powerful tool to install concurrently the C and D rings of puupehedione in a one-pot fashion. Its applicability was also showcased by the semisynthesis of puupehenone and puupehenol.

P

natural puupehedione was not included in this investigation, which is possibly due to its inefficient synthesis. Barrero and Armstrong independently reported the acid-promoted cycloaddition of olefinic phenols followed by oxidative o-quinone formations to provide a mixture of puupehedione (1, C8-Meβ) and 8-epi-puupehedione (2, C 8-Me α) in 1:4 and 1:8, respectively (Figure 1a,b).8 As is mentioned by Barrero, the main cyclization adduct, under kinetic and thermodynamic conditions, arises from the hydroxyl attack on the less hindered α side.8a Indeed, the unnatural C8-epimers of this type of marine natural products are usually formed instead of the natural compounds. For example, Yamamoto reported that cycloaddition of an olefinic phenol in the presence of a Lewis acid-assisted chiral Brønsted acid followed by three conventional steps afforded 8-epi-puupehedione as the sole product (Figure 1c).9 To circumvent this inherent problem, AlvarezManzaneda developed an elegant palladium-promoted cycloisomerization of an olefinic phenol followed by hydrogenation to generate puupehenol, which underwent puupehenol oxidation to give the first enantiospecific puupehedione synthesis (Figure 1d).10 Afterward, we reported a new hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization tandem reaction of a hydroxy enone, which was followed by three conventional steps and a subsequent puupehenol oxidation to provide the enantiospecific puupehedione synthesis (Figure 1e).11 In connection with our consistent interest in the practical synthesis of functional molecules, herein we would like to report an accomplishment of the above goal by oxidative cycloisomerization of a drimanal

uupehedione (1, Figure 1), a marine natural product isolated from Verongid sponge in 1993,1 and its structure-

Figure 1. Synthesis of puupehedione (1).

related marine natural products2 have been selected as synthetic targets. It is noteworthy that this family of marine natural products has attracted increasing attention mainly due to their wide variety of biological activities including antitumor,3 antiviral,4 anti-HIV,5 antiangiogenesis,6 antituberculosis,7 etc. In one case, 12 puupehedione-type marine natural products and their derivatives had been selected in the course of a blind screening for new potential inhibitors of angiogenesis, in which the synthetic 8-epi-puupehedione (2, Figure 1) appeared as the most promising antiangiogenic compound.6 However, the © 2017 American Chemical Society

Received: September 24, 2017 Published: October 30, 2017 12914

DOI: 10.1021/acs.joc.7b02413 J. Org. Chem. 2017, 82, 12914−12919

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The Journal of Organic Chemistry

overall yield. Condensation of 9 with p-toluenesulfonyl hydrazide in MeOH at room temperature gave the desired drimanal hydrazone 6 in 98% yield within 12 h (Scheme 1). After the optimization of reaction conditions by varying the catalyst [Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd(TFA)2, Pd(OH)2, Pd(MeCN)2Cl2, Pd(TMEDA)Cl2], the base (K2CO3, KOH, Cs2CO3, Na2CO3) and the solvent (THF, DCE, dioxane, toluene), the cross-coupling reaction of aryl iodide 5 with drimanal hydrazone 6 was realized in the presence of Pd(PPh3)4 (10 mol %) and K2CO3 (4 equiv) in toluene at 110 °C for 8 h to afford drimanal trimethoxystyrenes 4 and 10 in 40% and 45% yields, respectively (85% overall yield, Scheme 1).14 Surprisingly, the chemoselective oxidation of 4, after the optimization of reaction conditions (Table 1), was accomplished by treatment with CAN at room temperature for half an hour to directly provide puupehedione (1) as the sole diastereoisomer in 47% yield (Scheme 1).

trimethoxystyrene (Figure 1f) from the readily available natural product sclareolide.12 On the basis of the above analysis, the D ring of puupehedione should be fully furnished as soon as the establishments of the labile C ring to avoid the generation of the unnatural C8-epimer. As shown in Figure 2, we envisaged

Figure 2. Retrosynthetic analysis of puupehedione (1).

Table 1. Optimization of the Reaction Conditions for the Oxidation of Drimanal Trimethoxystyrenes 4a

the concurrent installation of the C and D rings of puupehedione from drimanal benzoquinone 3 by using our previously developed hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization tandem reaction11 that could be deemed as an intramolecular oxa-Stork−Danheiser transposition.13 Drimanal benzoquinone 3 was thought to be prepared by the oxidation of drimanal trimethoxystyrene 4, which could in turn be synthesized by the cross-coupling reaction of aryl iodine 5 and drimanal hydrazone 6. Finally, drimanal hydrazone 6 could be synthesized from the readily available natural product sclareolide (7). We report herein the realization of this strategy by developing an enantiospecific and concise semisynthesis of puupehedione (1), as well as the facile syntheses of puupehenone (19) and puupehenol (20). With the above retrosynthetic analysis and related literature in mind, a new enantiospecific semisynthesis of puupehedione (1) has been accomplished as shown in Scheme 1. Using our Scheme 1. Synthesis of Puupehedione (1)

entry

oxidant

solvent (v/v)

temp (°C)

% yield (1/ 11)b

1 2 3 4 5 6 7c 8d 9 10

DDQ DDQ DDQ DDQ CAN CAN CAN AgO/HNO3 IBX NaIO4

acetone/H2O (10:1) DCM DCM DCM MeCN/H2O (1:1) MeCN/H2O (1:1) MeCN/H2O (1:1) 1,4-dioxane THF DCM/H2O (10:1)

0 −20 −40 −78 −5 0 rt rt rt to reflux rt to reflux

58 33 22 nr 32 38 47 94 nr nr

(2.3:1) (3.2:1) (4.8:1) (1:0) (1:0) (1:0) (12)

a

General conditions: 4 (1.0 equiv) and an oxidant agent (2.0 equiv) in solvent (concentration = 0.02 M) for 20 min. bDetermined by the 1H NMR spectrum. c−5 °C to rt. dAgO (2.0 equiv) and 6 N HNO3 (2.0 equiv) was used in 1,4-dioxane (concentration = 0.067 M) for 40 min. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. DCM = dichloromethane. IBX = 2-iodoxybenzoic acid. nr = no reaction.

The oxidation reaction of drimanal trimethoxystyrene 4 was next studied, and the representative results are shown in Table 1. We envisaged that oxidation of 4 under certain suitable conditions would generate drimanal benzoquinone 3 (Figure 2), which would in turn undergo an acid-promoted intramolecular oxa-Stork−Danheiser transposition to afford puupehedione (1).15 To probe the feasibility of this hypothesis (Figure 2), we first evaluated the reaction by using DDQ as the oxidizing agent (Table 1). Inspiringly, it was found that the two steps above were accomplished in one pot by treating 4 with DDQ in the mixture solvent of acetone/H2O (v/v, 10:1) at 0 °C for 20 min, which provided puupehedione (1) in 40.4% yield together with byproduct 12 in 17.6% yield (58% overall yield, 1/12 = 2.3:1, Table 1, entry 1). The ratios of 1 and 12 were increased when the reaction was performed in dichloromethane at lower reaction temperatures (Table 1, entries 1−3). However, the overall yields of 1 and 12 were decreased dramatically in these cases (Table 1, entries 1−3). When the

previous reported procedure,11 the treatment of commercially available and inexpensive sclareolide (7) with H2SO4 in HCO2H at room temperature for 3 h afforded 8-epi-sclareolide 8 in 98% yield. The stereospecific α-hydroxylation of the lactone of 8 followed by α-hydroxylation, lactone reduction, and subsequent oxidative cleavage of the resulting lactol with NaIO4 and K2CO3 afforded β-hydroxy aldehyde 9 in a 66% 12915

DOI: 10.1021/acs.joc.7b02413 J. Org. Chem. 2017, 82, 12914−12919

Note

The Journal of Organic Chemistry reaction was performed at −78 °C, no reaction took place and the starting material 4 was recovered (Table 1, entry 4). Further parameter optimization identified CAN as an effective oxidizing agent (Table 1, entries 5−7). Indeed, treatment of 4 with CAN in the mixture solvent of MeCN/H2O (v/v, 1:1) at −5 °C for 20 min afforded puupehedione (1), in 32% yield, as the sole product, and no byproduct 11 (Table 1, entry 5). The yield of 1 was increased up to 47% when the reaction temperature was increased from −5 °C to room temperature (Table 1, entries 5−7). No further increase was observed when the reaction was performed at higher temperatures. Several other oxidants have also been investigated (Table 1, entries 8− 10).16 Byproduct 12 was obtained as the sole product when the couple of AgO/HNO3 was used as the oxidizing agent (Table 1, entry 8). With the use of IBX or NaIO4 as the oxidizing agent, no products were detected even under reflux reaction conditions, and the starting materials were recovered (Table 1, entries 9 and 10). Happily, it was found that drimanal trimethoxystyrene 10 could also be used for the synthesis of puupehedione (1). Indeed, treatment of 10 with CAN in the mixture solvent of MeCN/H2O (v/v, 1:1) at room temperature for 20 min afforded puupehedione (1), in 44% yield, as the sole product, and no byproduct 11. When the mixture of 4 and 10 was used as the starting material, the reaction went equally well to afford the desired puupehedione (1) in 45% yield. The oxidation of 10 to 3 could be processed in a stepwise fashion through the oxidation intermediate of ortho-quinone methide-type intermediate 13,17 which was a common reactive intermediate in this type of compound and could be formed under mild conditions.18 The potential intramolecular hydrogen bond, between the 8-hydroxyl group and the 17-methoxyl group of drimanal trimethoxystyrene 10 (Scheme 2), might help to

puupehenone (19) and puupehenol (20), which is depicted in Scheme 3. Hydrogenolysis of the mixture of drimanal Scheme 3. Synthesis of Puupehenone (19) and Puupehenol (20)

trimethoxystyrenes 4 and 10 (Pd/C, H2, MeOH, 40 °C) provided drimanal trimethoxybezene 14 in 62% yield (Scheme 3). The treatment of 14 with DDQ in the mixture solvent of acetone/H2O (v/v, 10:1) at 0 °C for 30 min afforded byproduct 16 in 76% yield, as the sole product, and no desired drimanal p-benzoquinone 17 (Scheme 3).20 After much experimentation, the oxidation of 14 to the desired drimanal p-benzoquinone 17 was achieved by using CAN as the oxidizing agent. Treatment of 14 with CAN in the mixture solvent of MeCN/H2O (v/v, 1:1) at room temperature for 15 min afforded drimanal p-benzoquinone 17 and drimanal oquinone 18 in 84% and 9% yields, respectively (Scheme 3). The intramolecular oxa-Stork−Danheiser transposition of 17 to 18 was achieved in the presence of pTsOH at room temperature for 15 min. The resulting product 18 was used directly, without purification, in an enolization process in the presence of K2CO3 to give puupehenone21(19, 9 steps and 26% overall yield from sclareolide) in 92% yield from 17. However, reduction of 18 with NaBH4 in EtOH at room temperature for 10 min afforded puupehenol (20) in a 90% overall yield from 17.22 In conclusion, we described an enantiospecific and concise semisynthesis of puupehedione (1) from the readily available natural product sclareolide in only 7 long linear steps without using additional protecting groups. The key features of the present synthesis are the development of a palladium-catalyzed cross-coupling reaction of an aryl iodine and a drimanal hydrazone for the construction of the key drimanal trimethoxystyrene skeleton and the development of a powerful CAN-oxidation/intramolecular oxa-Stork-Danheiser transposition tandem reaction to concurrently install the C and D rings of puupehedione (1). The intramolecular oxa-Stork−Danheiser transposition tandem reaction was also used for the enantiospecific semisynthesis of puupehenone (19, 10 steps, 26% overall yield) and puupehenol (20, 10 steps, 26% overall yield). The synthetic route developed here is general and efficient and could also be applied to the synthesis of related

Scheme 2. Possible Mechanism for the Formation of Puupehedione (1) from Drimanal Trimethoxystyrenes 10

facilitate the desirable stereochemical correction between the C9−C15 double bond during the CAN oxidation of 10 as shown in Scheme 2 and thereby facilitated the conversion of 10 to puupehedione (1) in only one pot (Scheme 2). Thus, the enantiospecific semisynthesis of puupehedione (1) was achieved in 7 long linear steps with a 25% overall yield (Schemes 1). The spectroscopic and spectrometric data (1H NMR, 13C NMR, and HRMS) of the synthetic material are identical to those of natural puupehedione, and the undesired epimerization at the C8 position is avoided.19 The power of intramolecular oxa-Stork−Danheiser transposition is also showcased by the facile synthesis of 12916

DOI: 10.1021/acs.joc.7b02413 J. Org. Chem. 2017, 82, 12914−12919

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The Journal of Organic Chemistry

(Z)-Drimanal Trimethoxystyrene (4): IR (film) νmax 3675, 2925, 2359, 1508, 1457, 1387, 1217, 1203, 1075, 1042, 870 cm−1; 1H NMR (400 MHz, CD3OD) δ 6.70 (s, 1H), 6.59 (s, 1H), 6.53 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H), 1.77−1.72 (m, 1H), 1.68−1.65 (m, 1H), 1.64−1.57 (m, 3H), 1.77−1.72 (m, 1H), 1.45 (s, 3H), 1.39 (s, 3H), 1.25−1.24 (m, 2H), 1.22−1.17 (m, 1H), 1.12−1.07 (m, 1H), 1.02 (d, J = 13.2 Hz, 1H), 0.87 (s, 3H), 0.85 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 156.9, 152.0, 149.9, 143.8, 123.8, 121.2, 116.8, 99.3, 74.6, 57.6, 56.9, 56.7, 52.0, 43.3, 42.9, 40.8, 40.3, 35.1, 34.1, 32.2, 23.4, 22.2, 19.9, 19.5 ppm; HRMS (ESI) m/z calcd for C24H36O4Na [M + Na]+ 411.2506, found 411.2511. (E)-Drimanal Trimethoxystyrene (10): IR (film) νmax 3480, 2925, 2359, 1507, 1463, 1387, 1203, 1036, 874 cm−1; 1H NMR (400 MHz, CD3OD) δ 6.80 (s, 1H), 6.63 (s, 1H), 6.31 (s, 1H), 3.84 (s, 3H), 3.77 (s, 6H), 2.01−1.91 (m, 1H), 1.88−1.80 (m, 1H), 1.77−1.70 (m, 1H), 1.61−1.50 (m, 2H), 1.47−1.41 (m, 2H), 1.36 (s, 3H), 1.23−1.20 (m, 1H), 1.16 (d, J = 11.5 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H), 0.90 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 157.5, 151.6, 150.1, 144.6, 123.4, 120.8, 116.7, 100.2, 73.5, 57.5, 57.4, 56.8, 52.0, 43.1, 42.7, 42.7, 41.4, 35.0, 33.8, 32.7, 24.9, 22.3, 20.4, 19.7 ppm; HRMS (ESI) m/z calcd for C24H36O4Na [M + Na]+ 411.2506, found 411.2512. Puupehedione (1). To a solution of drimanal trimethoxystyrene 4/ 10 (0.19 g, 0.5 mmol) in acetonitrile (5 mL) was added dropwise a solution of CAN (0.55 g, 1 mmol) in water (5 mL) at −5 °C. The mixture so-obtained was moved to room temperature and stirred for 30 min before it was diluted with water (15 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under a vacuum. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/ petroleum ether (1:30 to 1:20) to give the puupehedione (1, 73 mg, 45%) as a red oil: IR (film) νmax 2922, 1653, 1646, 1603, 1559, 1393, 1229, 1065 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 6.12 (s, 1H), 5.95 (s, 1H), 2.09−2.06 (m, 1H), 2.03−2.00 (m, 1H), 1.88 (d, J = 9.0 Hz, 1H), 1.69 (d, J = 14.4 Hz, 1H), 1.60 (d, J = 14.2 Hz, 1H), 1.54 (s, 3H), 1.47−1.46 (m, 1H), 1.46−1.42 (m, 1H), 1.32−1.29 (m, 1H), 1.24 (s, 3H), 1.13 (d, J = 12.4 Hz, 1H), 0.96 (s, 3H), 0.89 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 180.9, 179.5, 169.4, 164.5, 138.3, 122.1, 115.3, 109.1, 81.8, 43.4, 41.6, 40.8, 38.6, 33.8, 32.7, 30.8, 29.5, 25.1, 21.1, 18.7, 16.7 ppm; HRMS (ESI) m/z calcd for C21H26O3Na [M + Na]+ 349.1774, found 349.1770. All spectral data match those of the natural puupehedione. Drimanal Trimethoxybezene (14). To a solution of drimanal trimethoxystyrene 4/10 (0.19 g, 0.5 mmol) in dry MeOH (15 mL) was added 10% Pd/C (50 mg), and the mixture was stirred for 4 h at 40 °C under a hydrogen atmosphere. The resulting mixture was then filtrated and concentrated. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/ petroleum ether (1:20 to 1:10) to give 14 (121 mg, 62%) as a white solid: IR (film) νmax 3543, 2921, 2841, 1520, 1454, 1204, 1183, 1111, 1034, 847, 815 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 6.46 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.89 (dd, J = 15.7, 7.6 Hz, 1H), 2.50 (dd, J = 15.7, 2.1, Hz 1H), 1.83 (d, J = 12.3 Hz, 2H), 1.74 (d, J = 12.3 Hz, 1H), 1.62−1.54 (m, 2H), 1.51−1.47 (m, 2H), 1.44−1.40 (m, 1H), 1.39−1.37 (m, 1H), 1.19−1.11 (m, 2H), 1.06 (s, 3H), 0.95−0.91 (m, 1H), 0.89 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 151.0, 147.4, 143.1, 124.4, 114.3, 97.9, 73.1, 59.0, 56.9, 56.4, 56.1, 56.0, 42.8, 42.0, 40.1, 39.0, 33.5, 33.4, 31.3, 22.7, 21.8, 18.4, 18.4, 15.2; HRMS (ESI) m/z calcd for C24H38O4Na [M + Na]+ 413.2662, found 413.2667. Drimanal p-Benzoquinone (17). To a solution of drimanal trimethoxybezene 14 (97 mg, 0.25 mmol) in acetonitrile (25 mL) was added dropwise a solution of CAN (0.34 g, 0.625 mmol) in water (25 mL) at −5 °C. The mixture so-obtained was removed to room temperature and stirred for 15 min before it was diluted with water (25 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under a vacuum. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/petroleum ether (1:20 to 1:10) to give 17 (82 mg,

natural products with more complex structures and interesting biological profiles.

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EXPERIMENTAL SECTION

General Experimental Methods. Common reagents and materials were purchased from commercial sources and were used without further purification. All experiments were carried out under an argon atmosphere in flame-dried glassware using standard inert techniques for introducing reagents and solvents unless otherwise noted. TLC plates were visualized by exposure to ultraviolet light (UV). IR spectra were recorded by using an Electrothermal Nicolet 380 spectrometer. High-resolution mass spectra (HRMS) were recorded by using an Electrothermal LTQ-Orbitrap mass spectrometer. Melting points were measured by using a Gongyi X-5 microscopy digital melting point apparatus and were uncorrected. 1H NMR and 13 C NMR spectra were obtained by using a Bruker Avance III 400 MHz NMR spectrometer. 8β-Hydroxy-11-drimanal aldehyde (9). The synthesis of 8βhydroxy-11-drimanal aldehyde 9 followed Wu’s procedures.14 Drimanal Hydrazone (6). To a solution of 8β-hydroxy-11-drimanal aldehyde 9 (0.48 g, 2 mmol) in MeOH (5 mL) was added 4methylbenzene-sulfonhydrazide (372 mg, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The volatile was removed under a vacuum to give drimanal hydrazone 6 (0.80 g, 98%) as a white solid without further purification: mp 101− 102 °C; IR (film) νmax 2945, 2359, 1164, 1075, 913, 812 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.69 (br s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 6.9 Hz, 1H), 7.28 (d, J = 7.4 Hz, 2H), 3.45 (s, 1H), 2.63 (br, s, 1H), 2.40 (s, 3H), 1.77 (t, J = 10.8 Hz, 2H), 1.54 (d, J = 12.7 Hz, 1H), 1.49 (s, 1H), 1.44 (d, J = 13.8 Hz, 1H), 1.36−1.34 (m, 2H), 1.22 (d, J = 13.0 Hz, 1H), 1.10 (d, J = 13.1 Hz, 1H), 1.03 (d, J = 14.4 Hz, 2H), 0.92 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H), 0.80 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 153.5, 144.0, 135.0, 129.6, 127.9, 72.1, 60.8, 55.0, 41.7, 41.7, 39.8, 38.43, 33.4, 33.1, 30.7, 21.6, 21.5, 18.2, 17.8, 15.9 ppm; HRMS (ESI) m/z calcd for C22H34N2O3SNa [M + Na]+ 429.2182, found 429.2188. 1-Iodo-2,4,5-trimethoxybenzene (5). To a solution of 1,2,4trimethoxybenzene (0.34 g, 2 mmol) in acetonitrile (5 mL) was added NIS (495 mg, 2.2 mmol) at room temperature, and the resulting mixture was stirred at that temperature for 5 h before it was diluted with EtOAc (20 mL). The mixture so-obtained was sequentially washed with saturated aqueous Na2CO3 (2 × 20 mL) and brine (2 × 20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under a vacuum. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/petroleum ether (1:25 to 1:15) to give 1-iodo-2,4,5-trimethoxybenzene (5, 0.53 g, 90%) as a yellow solid: mp 71−72 °C; IR (film) νmax 2934, 2838, 1497, 1434, 1203, 1023, 792 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 6.49 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.0, 150.2, 144.3, 122.0, 97.9, 73.0, 57.3, 56.7, 56.1 ppm; HRMS (ESI) m/z calcd for C9H11IO3Na [M + Na]+ 316.9645, found 316.9650. Drimanal Trimethoxystyrenes (4 and 10). To a solution of 1-iodo2,4,5-trimethoxybenzene (5, 0.49 g, 1.2 mmol) in toluene (10 mL) were added drimanal hydrazone 3 (0.29 g, 1 mmol), K2CO3 (0.62 g, 4.5 mmol), and Pd(PPh3)4 (58 mg, 0.05 mmol) at room temperature. The resulting mixture was heated to 110 °C and stirred at that temperature for 8 h before it was cooled to room temperature and diluted with EtOAc (30 mL). The mixture so-obtained was sequentially filtrated and washed with EtOAc (2 × 5 mL), and then the filtrate was washed with brine (2 × 30 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under a vacuum. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/ petroleum ether (1:20 to 1:10) to give drimanal (Z)-trimethoxystyrene 4 (155 mg, 40%) as a colorless oil and (E)-drimanal trimethoxystyrene 10 (175 mg, 45%) as a white solid. 12917

DOI: 10.1021/acs.joc.7b02413 J. Org. Chem. 2017, 82, 12914−12919

Note

The Journal of Organic Chemistry 84%) as a yellow solid: IR (film) νmax 3538, 2946, 1522, 1454, 1205, 1185, 1112, 1036, 849 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 5.93 (s, 1H), 3.81 (s, 3H), 2.78 (ddd, J = 18.7, 6.1, 1.3 Hz, 1H), 2.40−2.38 (m, 1H), 2.04 (d, J = 18.9 Hz, 1H), 1.76 (dd, J = 11.2, 3.4 Hz, 2H), 1.55−1.51 (m, 3H), 1.39−1.33 (m, 2H), 1.30 (dd, J = 6.0, 3.1 Hz, 1H), 1.15−1.07 (m, 1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.91−0.89 (m, 2H), 0.87 (s, 3H) 0.83 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 187.2, 182.3, 158.4, 153.0, 130.4, 107.8, 72.8, 57.3, 56.2, 56.1, 42.5, 41.8, 39.9, 39.0, 33.4, 33.3, 31.3, 30.8, 23.1, 21.7, 18.2, 15.2 ppm; HRMS (ESI) m/z calcd for C22H32O4Na [M + Na]+ 383.2193, found 383.2198. Drimanal o-Quinone (18). To a solution of drimanal pbenzoquinone 16 (54 mg, 0.15 mmol) in CH2Cl2 (3 mL) was added pTsOH (52 mg, 0.3 mmol) at room temperature, and the mixture was stirred for 15 min. The resulting mixture was washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and evaporated under a vacuum to give drimanal o-quinone 18 as a red oil: IR (film) νmax 2923, 2850, 2362, 1461, 1376, 1211, 1131, 1011, 814 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 5.81 (s, 1H), 2.99−2.97 (m, 1H), 2.80 (d, J = 20.4 Hz, 1H), 1.32 (s, 3H), 0.90 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H) ppm; HRMS (ESI) m/z calcd for C21H29O3 [M + H]+ 329.2111, found 329.2115. Cyclohexyl Trimethoxystyrene (16). To a solution of drimanal trimethoxybezene 14 (78 mg, 0.20 mmol) in acetonitrile/H2O (3 mL, 10:1) was added DDQ (91 mg, 0.40 mmol) at 0 °C. The mixture soobtained was stirred for 30 min before it was diluted with water (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under a vacuum. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/petroleum ether (1:20) to give 16 (59 mg, 76%) as a red oil: IR (film) νmax 2925, 2850, 1713, 1599, 1513, 1463, 1205, 1035, 908 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.52 (d, J = 16.5 Hz, 1H), 6.49 (s, 1H), 5.88 (d, J = 16.4 Hz, 1H), 3.88 (s, 3H), 3.88 (s, 3H), 3.80 (s, 3H), 2.40 (m, 3H), 2.15 (s, 1H), 1.96 (s, 3H), 1.15 (s, 3H), 1.02 (m, 1H), 0.93 (s, 3H), 0.91 (s, 3H), 0.88 (m, 2H), 0.83 (d, J = 5.8 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 209.3, 151.0, 148.9, 145.4, 143.5, 142.4, 119.7, 109.8, 98.2, 56.7, 56.7, 56.1, 53.4, 46.8, 42.1, 41.2, 40.6, 34.6, 33.6, 29.5, 21.9, 21.3, 18.7, 18.1 ppm; HRMS (ESI) m/z calcd for C24H36O4Na [M + Na]+ 411.2506, found 411.2503. Puupehenone (19). To a solution of drimanal p-benzoquinone 17 (54 mg, 0.15 mmol) in CH2Cl2 (3 mL) was added pTsOH (52 mg, 0.3 mmol) at room temperature, and the mixture was stirred for 15 min. The resulting mixture was washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and evaporated under a vacuum to give drimanal o-quinone 18 as a red oil. The drimanal o-quinone 18, without purification, was diluted with CH3CN (2 mL), followed by the addition of K2CO3 (10 mg, 0.075 mmol), and stirred for 1 h at room temperature. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under a vacuum. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/ petroleum ether (1:15 to 1:10) to give puupehenone (19, 45 mg, 92%) as a yellow oil: IR (film) νmax 3132, 2924, 1616, 1400, 1093 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.88 (s, br, 1H), 6.66 (d, J = 6.9 Hz, 1H), 6.20 (s, 1H), 5.86 (s, 1H), 2.17 (dd, J = 2.4, 11.4 Hz, 1H), 2.04 (d, J = 6.9 Hz, 1H), 1.68 (d, J = 6.9 Hz, 1H), 1.23 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 182.1, 162.8, 147.5, 140.4, 129.4, 106.1, 105.1, 78.9, 54.9, 53.9, 41.7, 40.8, 40.1, 39.3, 33.7, 33.3, 28.1, 21.9, 18.5, 18.1, 15.0 ppm; HRMS (ESI) m/z calcd for C21H29O3 [M + H]+ 329.2111, found 329.2106. All spectral data match those of the authentic puupehenone. Puupehenol (20). To a solution of drimanal p-benzoquinone 17 (54 mg, 0.15 mmol) in CH2Cl2 (3 mL) was added pTsOH (52 mg, 0.3 mmol) at room temperature, and the mixture was stirred for 15 min. The resulting mixture was washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and evaporated under a vacuum to give drimanal o-quinone 18 as a red oil. The drimanal o-quinone 18,

without purification, was diluted with EtOH (2 mL), followed by the addition of NaBH4 (11 mg, 0.3 mmol), and the mixture was stirred for 10 min at room temperature. The resulting mixture was cooled to 0 °C, quenched by the dropwise addition of aqueous 1 N HCl until gas evolution ceased, and concentrated under a vacuum. The crude product was dissolved in EtOAc (10 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (100−200 mesh) with EtOAc/petroleum ether (1:20 to 1:10) to give puupehenol (20, 44 mg, 90%) as a yellow oil: IR (film) νmax = 2924, 2852, 2359, 1661, 1456, 1376, 1223, 1160, 1133, 911, 734 cm−1; 1H NMR (400 MHz, CD3COCD3) δ 7.51 (s, OH), 7.08 (s, OH), 6.46 (s, 1H), 6.16 (s, 1H), 2.76 (dd, J = 17.5, 8.1 Hz, 1H), 2.59 (d, J = 17.6 Hz, 1H), 1.09 (s, 3H), 0.86 (s, 3H), 0.79 (s, 3H), 0.71 (s, 3H) ppm; 13C NMR (100 MHz, CD3COCD3) δ 148.7, 144.6, 139.4, 115.4, 113.8, 104.8, 75.5, 56.1, 50.5, 42.8, 41.5, 40.9, 39.2, 34.2, 33.9, 27.5, 22.9, 22.4, 19.3, 19.2, 14.9 ppm; HRMS (ESI) m/z calcd for C21H31O3 [M + H]+ 331.2268, found 331.2272. All spectral data match those of the authentic puupehenol.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02413. Copies of 1H and 13C NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yan-Chao Wu: 0000-0002-0111-7484 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project was supported by the National Science Foundation of China (21672046, 21272046, and 21372054) and HIT.NSRIF.201701.

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REFERENCES

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