Total Syntheses of a Family of Cadinane Sesquiterpenes

Total Syntheses of a Family of Cadinane Sesquiterpenes ... which was readily prepared on gram scale through an aldol-Henry reaction cascade and oxidat...
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Cite This: J. Org. Chem. 2018, 83, 5825−5828

Total Syntheses of a Family of Cadinane Sesquiterpenes Xin Bi,† Wenbo Xu,† Yanmin Yao,† Lili Zhou,† and Guangxin Liang*,†,‡ †

State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China

‡

S Supporting Information *

ABSTRACT: Concise total syntheses of (−)-(1R,6S,7S,10R)-hydroxycadinan-3-en-5-one (1), (+)-(1R,5S,6R,7S,10R)-cadinan3-ene-1,5-diol (2), and (+)-(1R,5S,6R,7S,10R)-cadinan-4(11)-ene-1,5-diol (3), three cadinane sesquiterpenes sharing identical trans-decalin carbon skeletons yet containing different oxidation states and substitution patterns, are reported. They were prepared from a common trans-decalin intermediate, which was readily prepared on gram scale through an aldol-Henry reaction cascade and oxidation sequence.

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from 4 through double bond isomerization and/or carbonyl group reduction operation. Such a trans-decalin system with a bridge-head tertiary hydroxyl group could be constructed based on an aldol-Henry reaction cascade and oxidation sequence developed in our group.4 Our synthesis commenced from tetrahydrocarvone 7, which conveniently offers two stereogenic centers in the targets (Scheme 2).5 Compound 7 was treated with LDA followed by 4-nitrobutanal to trigger an aldol-Henry reaction cascade to obtain a mixture of trans-decalin 8, which was used without purification to undergo subsequent oxidation using PCC to provide a single isomer 6 in 48% yield over two steps. The structure of 6 was confirmed by X-ray crystallographic analysis.6 Classical radical conditions (AIBN and n-Bu3SnH) were used to remove the nitro group to give ketone 5 in 82% yield.7 A variety of routine silylation conditions for protection of the tertiary hydroxyl group were unsuccessful. Finally, treatment of compound 5 with TMS-Imidazole and a catalytic amount of TBAF afforded its TMS ether 9 in 88% yield.8 After Eschenmoser’s methylenation reaction failed to install the desired exocyclic double bond in the substrate 9, we followed Colby’s two-step protocol to successfully obtain enone 4 in 70% yield.9 This short synthetic sequence allowed us to conveniently synthesize key intermediate 4 from readily available ketone 7 and 4-nitrobutanal in six steps in an overall yield of 24%.

erpenes exist as the largest class of natural products, and their diverse array of carbon scaffolds and oxidation states often lead to intriguing biological properties and make themselves highly attractive synthetic targets.1 The cadinane terpenoids are a class of sesquiterpenes featuring a decalin ring system bearing diverse oxidation patterns and rich stereochemical information. (−)-(1R,6S,7S,10R)-Hydroxycadinan-3en-5-one (1), (+)-(1R,5S,6R,7S,10R)-cadinan-3-ene-1,5-diol (2), and (+)-(1R,5S,6R,7S,10R)-cadinan-4(11)-ene-1,5-diol (3) are three unique cadinane sesquiterpenes which were isolated from brown alga Dictyopteris divaricata in the gulf of the Yellow Sea by Shi and co-workers (Figure 1).2 The structures of 1−3 were elucidated through extensive NMR studies, and the relative stereochemistry of both 1 and 3 were confirmed by Xray crystallographic analysis. The absolute configuration of 1 was determined from the CD spectrum. Apart from the commonly occurring trans-decalin system bearing multiple contiguous stereogenic centers, these sesquiterpenes feature an unusual bridgehead tertiary hydroxyl group, which could decrease the stability of the molecules through conceivable aromatization and poses an extra synthetic challenge. To date, no total syntheses of these appealing sesquiterpenes have been reported.3 Herein, we report concise asymmetric total syntheses of these cadinane sesquiterpenes. Our retrosynthetic analysis is depicted in Scheme 1. We envisioned that an advanced intermediate 4 with an external methylene group could serve as a common intermediate. All three natural products could be derived easily © 2018 American Chemical Society

Received: February 22, 2018 Published: April 26, 2018 5825

DOI: 10.1021/acs.joc.8b00505 J. Org. Chem. 2018, 83, 5825−5828

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The Journal of Organic Chemistry

Figure 1. (−)-(1R,6S,7S,10R)-hydroxycadinan-3-en-5-one (1), (+)-(1R,5S,6R,7S,10R)-cadinan-3-ene-1,5-diol (2), and (+)-(1R,5S,6R,7S,10R)cadinan-4(11)-ene-1,5-diol (3).

Scheme 1. Retrosynthetic Analysis of 1, 2, and 3

Scheme 2. Synthesis of Advanced Common Intermediate 4

Scheme 3. Synthesis of 1, 2, and 3

With a gram scale amount of the advanced common intermediate 4 readily in hand, we focused effort toward converting it to different natural products. Rhodium(III) chloride induced isomerization of the external methylene group10 and in situ desilylation to afford 1 smoothly,11 which upon LiAlH4 reduction formed 2. Finally, 3 was obtained in 81% overall yield via DIBAL reduction and desilylation using TBAF (Scheme 3). The optical rotation values of the synthetic samples of 1, 2, and 3 are of the same sign and almost identical to those reported for the three natural products, which confirm the proposed absolute configuration reported. In summary, we have achieved the first total syntheses of three structurally unique cadinane sesquiterpenes, (−)-(1R,6S,7S,10R)-hydroxycadinan-3-en-5-one (1), (+)-(1R,5S,6R,7S,10R)-cadinan-3-ene-1,5-diol (2), and (+)-(1R,5S,6R,7S,10R)-cadinan-4(11)-ene-1,5-diol (3). Key chemical transformations feature an aldol−Henry reaction cascade and oxidation sequence in the quick construction of the trans-decalin ring system, radical denitration reaction, and a transition metal catalyzed isomerization reaction of an external

double bond. The synthetic strategy allowed us to prepare the otherwise challenging synthetic targets asymmetrically in only seven to eight overall steps from tetrahydrocarvone 7. The high efficiency of the chemistry will be useful in other related natural product systems and will be reported in due course.

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EXPERIMENTAL SECTION

General Information. All sensitive reactions were performed under an atmosphere of argon. Commercially available reagents were used without further purification. THF and toluene were dried by distillation over Na/diphenyl ketone. Dichloromethane was dried by distillation over CaH2. TLC inspections were on silica gel GF254 plates. Column chromatography was performed on silica gel (200−300 mesh). Signal positions of 1H NMR and 13C NMR spectra were recorded in ppm with the abbreviations s, d, t, q, br, m, and app denoting singlet, doublet, triplet, quartet, broad, multiplet, and 5826

DOI: 10.1021/acs.joc.8b00505 J. Org. Chem. 2018, 83, 5825−5828

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The Journal of Organic Chemistry

C NMR (100 MHz, CDCl3) δ 210.2, 85.3, 61.3, 42.7, 42.5, 35.6, 35.1, 29.3, 26.6, 23.7, 22.6, 21.4, 16.2, 15.6, 2.7; IR (thin film) vmax 2953, 2873, 2834, 1717, 1636, 1456, 1252, 1144, 1091, 1030, 838, 745; HRMS (ESI) calcd for C17H33O2Si [M + H]+ 297.2244, found 297.2251; [α]19D 117 (c 0.16, MeOH); mp 54−56 °C. (4aR,5R,8S,8aS)-8-Isopropyl-5-methyl-2-methylene-4a((trimethylsilyl)oxy)octahydronaphthalen-1(2H)-one (4). To a 0 °C solution of LiHMDS (12.15 mL, 1.0 M in THF) was added a solution of 9 (1.76 g, 5.94 mmol) in THF (18 mL). The reaction mixture was allowed to warm to room temperature over 20 min, and then CF3CO2CH2CF3 (2.50 g, 12.75 mol) was added. After an additional 20 min of stirring at room temperature, a saturated aqueous solution of NH4Cl (20 mL) was added. The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil which was used in the next step without further purification. To a solution of the above yellow oil in toluene (35 mL) were added K2CO3 (2.54 g, 18.38 mmol), 18-crown-6 (0.41 g, 1.56 mmol), and paraformaldehyde (6.23 g, 207.55 mmol). The suspension was heated to 80 °C for 2 h and then heated to 90 °C for 4 h. The mixture was allowed to cool to room temperature, saturated aqueous NH4Cl (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure to give a solid. The crude product was purified by column chromatography (50:1, petroleum ether/ethyl acetate) to give 4 (1.29 g, 4.19 mmol, 70.5%) as a colorless oil. 4: Rf 0.90 (10:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 5.49 (d, J = 1.4 Hz, 1H), 4.94 (d, J = 1.6 Hz, 1H), 2.68−2.53 (m, 2H), 2.31 (d, J = 10.9 Hz, 1H), 2.18−2.07 (m, 2H), 1.96−1.87 (m, 1H), 1.77−1.72 (m, 1H), 1.63−1.58 (m, 1H), 1.35− 1.27 (m, 3H), 1.00−0.87 (m, 7H), 0.58 (d, J = 7.0 Hz, 3H), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.2, 146.8, 115.4, 81.9, 59.1, 43.0, 36.2, 34.8, 29.1, 28.5, 27.0, 22.8, 21.4, 15.8, 15.7, 2.6; IR (thin film) vmax 2959, 2933, 2897, 2873, 1706, 1444, 1251, 1135, 1085, 881, 678; HRMS (ESI) calcd for C18H33O2Si [M + H]+ 309.2244, found 309.2238; [α]19D −8 (c 0.20, MeOH). (−)-(1R,6S,7S,10R)-Hydroxycadinan-3-en-5-one (1). To a stirred solution of 4 (1.15 g, 3.73 mmol) in 95% ethanol (110 mL) was added RhCl3·xH2O (38% rhodium, 0.303 g, 1.12 mmol, 30 mol %). The reaction mixture was heated in a sealed tube to 115 °C for 35 min. After the solution was cooled to room temperature, it was filtered through a pad of Celite. Solvent was removed under reduced pressure to give a solid. The crude product was purified by column chromatography (20:1, petroleum ether/ethyl acetate) to give 1 (0.580 g, 2.45 mmol, 65.7%) as a white solid. 1: Rf 0.2 (8:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, acetone d6) δ 6.35−6.33 (m, 1H), 3.21 (s, 1H), 2.61−2.32 (m, 4H), 1.96−1.87 (m, 1H), 1.71−1.59 (m, 4H), 1.57−1.49 (m, 1H), 1.47− 1.40 (m, 1H), 1.37−1.32 (m, 1H), 1.13−1.03 (m, 1H), 0.90 (dd, J = 7.1, 8.5 Hz, 6H), 0.64 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone d6) δ 201.6, 137.2, 135.9, 76.9, 56.4, 42.6, 40.1, 37.2, 29.5, 27.9, 23.5, 21.9, 16.1, 15.8, 14.5; IR (thin film) vmax 3515, 2961, 2929, 2873, 1665, 1457, 1369, 1259, 1200, 1130, 1034, 998, 669; HRMS (ESI) calcd for C15H25O2 [M + H]+ 237.1855, found: 237.1855; [α]19D −48 (c 0.15, MeOH); mp 174−176 °C (lit. [α]20D −47 (c 0.18, MeOH); mp 179−180 °C).2 (+)-(1R,5S,6R,7S,10R)-Cadinan-3-ene-1,5-diol (2). A solution of 1 (0.050 g, 0.211 mmol) in THF (3 mL) was added dropwise to a suspension of LiAlH4 (40 mg, 1.1 mmol) in THF (7 mL) at 0 °C. After the reaction mixture was stirred for 30 min a small amount of water was carefully added to quench the reaction. The mixture was diluted with ethyl acetate (10 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 10 mL), and the combined organic layers were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give a yellow oil. The crude product was purified by column chromatography (8:1, petroleum ether/ethyl acetate) to give 2 (0.020 g, 0.0839 mmol, 40.0%) as a white solid. 13

apparent, respectively. All NMR chemical shifts were referenced to residual solvent peaks or to Si(CH3)4 as an internal standard; spectra recorded in CDCl3 were referenced to residual CHCl3 at 7.26 ppm for 1 H or 77.0 ppm for 13C. spectra recorded in acetone-d6 were referenced to residual acetone at 2.05 ppm for 1H or 206.2 and 29.9 ppm for 13C. All coupling constants, J, are quoted in Hz. IR spectra were reported in wave numbers (cm−1). (4S,4aR,5R,8S,8aS)-4a-Hydroxy-8-isopropyl-5-methyl-4nitrooctahydronaphthalen-1(2H)-one (6). To a solution of 7 (5.00 g, 32.4 mmol) in THF (50 mL) was added freshly prepared LDA solution (2.0 M in THF, 19.5 mL, 39.0 mmol) at −78 °C dropwise. The mixture was stirred at −78 °C for 30 min before a solution of 4nitrobutanal in THF (4.56 g, 38.9 mmol) was added. The reaction mixture was kept at −78 °C for 1 h and then warmed up to room temperature. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (50.0 mL) and then was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure to give a yellow oil that was used in the next step without further purification. To a solution of the above yellow oil in CH2Cl2 (160 mL) at 0 °C were added silica gel (10.0 g) and PCC (8.36 g, 39.00 mmol) in portions over a period of 5 min, the resulting mixture was stirred at 0 °C for 2 h. The solvent was removed under reduced pressure to give a brown solid. The crude product was purified by column chromatography (8:1 petroleum ether/ethyl acetate) to give 6 (4.22 g, 15.7 mmol, 48.4%) as a white solid. 6: Rf 0.40 (4:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 4.90 (d, J = 4.6 Hz, 1 H), 3.30 (dd, J = 11.6, 1.9 Hz, 1 H), 3.10 (td, J = 12.8, 7.6 Hz, 1 H), 2.54−2.38 (m, 2 H), 2.34−2.29 (m, 1 H), 2.11−2.01 (m, 1 H), 1.96−1.81 (m, 2 H), 1.64−1.60 (m, 2 H), 1.54−1.51 (m, 1 H), 1.26 (ddd, J = 26.2, 13.3, 3.1 Hz, 1 H), 1.01 (dd, J = 6.6, 1.0 Hz, 3 H), 0.90 (dd, J = 6.9, 1.5 Hz, 3 H), 0.66 (dd, J = 7.0, 1.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 210.1, 85.2, 80.9, 54.0, 38.1, 37.2, 36.0, 29.0, 27.9, 27.5, 22.0, 21.3, 15.7, 14.9; IR (thin film) vmax 3369, 2943, 2873, 2834, 1712, 1547, 1459, 1445, 1370, 1335, 1029, 970, 796; HRMS (ESI) calcd for C14H22NO4 [M − H]− 268.1554, found 268.1559; [α]19D −65 (c 0.21, MeOH); mp 110−112 °C. (4aR,5R,8S,8aS)-4a-Hydroxy-8-isopropyl-5-methyloctahydronaphthalen-1(2H)-one (5). n-Bu3SnH (5.92 g, 20.34 mmol) and AIBN (0.50 g, 3.05 mmol) were added to a solution of 6 (2.74 g, 10.17 mmol) in toluene (50 mL), and the mixture was heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature; the solvent was removed under reduced pressure to give a white solid. The crude product was purified by column chromatography (8:1, petroleum ether/ethyl acetate) to give 5 (1.86 g, 8.29 mmol, 81.5%) as a white solid. 5: Rf 0.50 (4:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 2.49−2.31 (m, 3H), 2.08−1.96 (m, 4H), 1.78 (tdd, J = 12.3, 7.7, 4.6 Hz, 1H), 1.67−1.62 (m, 1H), 1.57−1.45 (m, 3H), 1.31−1.20 (m, 2H), 1.05−0.98 (m, 1H), 0.91 (d, J = 6.8 Hz, 6H), 0.63 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 212.0, 79.8, 59.9, 43.1, 41.3, 36.1, 35.5, 29.2, 27.0, 23.8, 22.4, 21.3, 15.6, 15.2; IR (thin film) vmax 3502, 2958, 2934, 2871, 1711, 1613, 1462, 1370, 1309, 909, 634; HRMS (ESI) calcd for C14H28O2N [M + NH4]+ 242.2115, found 242.2114; [α]19D +62 (c 0.19, MeOH); mp 86−88 °C. (4aR,5R,8S,8aS)-8-Isopropyl-5-methyl-4a-((trimethylsilyl)oxy)octahydronaphthalen-1(2H)-one (9). 5 (1.65 g, 7.35 mmol) was dissolved in 6.0 mL of 1-(trimethylsilyl)-1H-imidazole at room temperature. Ten drops of TBAF solution (1.0 M, in THF) were added. The reaction mixture was stirred at room temperature for 2 h, before it was quenched with water (30 mL), and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure to give a yellow oil. The crude product was purified by column chromatography (50:1, petroleum ether/ethyl acetate) to give 9 (1.91 g, 6.44 mmol, 87.6%) as a colorless solid. 9: Rf 0.80 (10:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 2.40−2.26 (m, 3H), 2.09−1.86 (m, 5H), 1.61−1.29 (m, 5H), 1.00−0.88 (m, 7H), 0.59 (d, J = 7.0 Hz, 3H), 0.09 (s, 9H); 5827

DOI: 10.1021/acs.joc.8b00505 J. Org. Chem. 2018, 83, 5825−5828

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2: Rf 0.40 (8:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, acetone d6) δ 5.29 (d, J = 6.0 Hz, 1H), 3.77 (t, J = 8.3 Hz, 1H), 3.19 (d, J = 8.3 Hz, 1H), 2.61 (s, 1H), 2.51−2.45 (m, 1H), 2.19 (dd, J = 17.1, 6.2 Hz, 1H), 1.91 (dd, J = 17.1, 2.0 Hz, 1H), 1.70−1.61 (m, 5H), 1.51−1.44 (m, 1H), 1.43−1.34 (m, 2H), 1.31−1.25 (m, 1H), 1.1−0.99 (m, 1H), 0.91 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, acetone d6) δ 137.9, 120.4, 73.8, 73.4, 52.3, 44.6, 42.4, 38.0, 31.4, 27.7, 25.2, 22.6, 20.3, 16.5, 15.1; IR (thin film) vmax 3391, 2959, 2924, 2875, 2856, 1635, 1457, 1374, 1264, 1213, 1084, 1031, 996, 773; HRMS (ESI) Calcd for C15H26O2Na [M + Na]+ 261.1830, found: 261.1828; [α]19D +29 (c 0.14, MeOH); mp 164−166 °C (lit. [α]20D +29 (c 0.15, MeOH); described as colorless gum, no mp was reported).2 (+)-(1R,5S,6R,7S,10R)-Cadinan-4(11)-ene-1,5-diol (3). To a solution of 4 (0.050 g, 0.162 mmol) in toluene (3 mL) at 0 °C was added DIBAL-H (0.12 mL, 0.18 mmol) dropwise. After the reaction mixture was stirred for 30 min at 0 °C, a small amount of water was carefully added to quench the reaction. The mixture was diluted with ethyl acetate (10 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 10 mL), and the combined organic layers were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give a yellow oil that was used in the next step without further purification. To a solution of the above yellow oil in THF (5 mL) was added TBAF (0.18 mL, 0.18 mmol) at 20 °C. After 1 h, the solvent was evaporated and the resulting residue was purified by column chromatography (8:1, petroleum ether/ethyl acetate) to give 3 (0.03 g, 0.13 mmol, 81%) as a white solid. 3: Rf 0.80 (8:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, acetone d6) δ 4.77 (s, 1H), 4.70 (t, J = 2.1 Hz, 1H), 4.64 (d, J = 5.0 Hz, 1H), 4.32 (dd, J = 4.8, 1.9 Hz, 1H), 4.24 (s, 1H), 2.68 (td, J = 13.8, 5.0 Hz, 1H), 2.18−2.06 (m, 3H), 1.93 (ddd, J = 12.3, 8.1, 3.6 Hz, 1H), 1.68−1.62 (m, 1H), 1.59−1.48 (m, 1H), 1.42−1.36 (m, 1H), 1.29− 1.14 (m, 3H), 1.08−1.01 (m, 1H), 0.93 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, acetone d6) δ 152.3, 108.5, 74.0, 73.1, 50.8, 42.5, 39.2, 38.4, 31.2, 26.27, 26.26, 24.7, 21.9, 15.4, 14.9; IR (thin film) vmax 3387, 2957, 2931, 2873, 2859, 1699, 1497, 1457, 1396, 1253, 1213, 1084, 1023, 897; HRMS (ESI) calcd for C15H26O2Na [M + Na]+ 261.1830, found: 261.1826; [α]19D +54 (c 0.21, MeOH); mp 142−144 °C (lit. [α]20D +51 (c 0.17, MeOH); mp 139−140 °C).2

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REFERENCES

(1) (a) Breitmaier, E. Terpenes: Flavors, Fragrances, Pharmaca, Pheromones; Wiley-VCH: Weinheim, Germany, 2006. (b) For a review on efficient syntheses on terpenes, see: Jansen, D. J.; Shenvi, R. A. Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery. Future Med. Chem. 2014, 6, 1127−1148. (2) Song, F.; Fan, X.; Xu, X.; Zhao, J.; Yang, Y.; Shi, J. Cadinane Sesquiterpenes from the Brown Alga Dictyopteris Divaricate. J. Nat. Prod. 2004, 67, 1644−1649. (3) For selected syntheses of cadinane sesquiterpenes without a bridgehead hydroxyl group, see: (a) Ngo, K. S.; Brown, G. D. Synthesis of Amorphane and Cadinane Sesquiterpenes from Fabiana Imbricate. Tetrahedron 1999, 55, 15099−15108. (b) Fang, L.; Bi, F.; Zhang, C.; Zheng, G.; Li, Y. Total Synthesis of 4α, 5α, 10β-Trihydroxycadinane and Its C4-isomer: Structural Revision of a Natural Sesquiterpenoid. Synlett 2006, 2006, 2655−2657. (c) Foo, K.; Usui, I.; Götz, D. C.; Werner, E. W.; Holte, D.; Baran, P. S. Scalable, Enantioselective Synthesis of Germacrenes and Related Sesquiterpenes Inspired by Terpene Cyclase Phase Logic. Angew. Chem., Int. Ed. 2012, 51, 11491− 11495. (4) For development of the aldol-Henry cascade reaction and its application in the total synthesis of echinopines, see: (a) Xu, W.; Wu, S.; Zhou, L.; Liang, G. Total Syntheses of Echinopines. Org. Lett. 2013, 15, 1978−1981. For its application in the total syntheses africanane sesquiterpenes, see: (b) Zhou, L.; Yao, Y.; Xu, W.; Liang, G. Total Syntheses of (±)-Omphadiol and (±)-Pyxidatol C through a Cis-Fused 5,7-Carbocyclic Common Intermediate. J. Org. Chem. 2014, 79, 5345− 5350. (5) For a recent review on total syntheses using carvone, see: (a) Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products. Chem. Rev. 2017, 117, 11753−11795. For preparation of 7, see: (b) Fürstner, A.; Hannen, P. Platinum- and Gold-Catalyzed Rearrangement Reactions of Propargyl Acetates: Total Syntheses of (−)-α-Cubebene, (−)-Cubebol, Sesquicarene and Related Terpenes. Chem. - Eur. J. 2006, 12, 3006−3019. (6) See the Supporting Information for the crystal structure and crystallographic data (CIF). The crystallographic data have also been deposited with the Cambridge Crystallographic Data Centre (CCDC) as entry CCDC 1572018 and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif. (7) Kim, W. H.; Lee, J. H.; Danishefsky, S. J. Improved Dienophilicity of Nitrocycloalkenes: Prospects for the Development of a Trans-DielsAlder Paradigm. J. Am. Chem. Soc. 2009, 131, 12576−12578. (8) Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams, L. J. Allene Synthesis via C-C Fragmentation: Method and Mechanistic Insight. J. Am. Chem. Soc. 2009, 131, 12910−12911. (9) Riofski, M. V.; John, J. P.; Zheng, M. M.; Kirshner, J.; Colby, D. A. Exploiting the Facile Release of Trifluoroacetate for the αMethylenation of the Sterically Hindered Carbonyl Groups on (+)-Sclareolide and (−)-Eburnamonine. J. Org. Chem. 2011, 76, 3676−3683. (10) Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. Total Synthesis of Ingenol. J. Am. Chem. Soc. 2004, 126, 16300−16301. (11) To demonstrate the robustness of the chemistry, compound 1 has been scaled up in two separate pots affording 480 mg and 580 mg of product respectively. X-ray crystallographic analysis on compound 1 has been performed. Please see Supporting Information for its crystal structure and corresponding X-ray data. The crystallographic data have also been deposited with the Cambridge Crystallographic Data Centre (CCDC) as entry CCDC 1572019 and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00505. NMR spectra for new compounds and synthetic natural products (PDF) Crystallographic data for compound 6 (CIF) Crystallographic data for compound 1 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guangxin Liang: 0000-0003-3122-0332 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Key Research and Development Program of China (2017YFD0201404) and the National Natural Science Foundation of China (21372127, 21572104) for financial support. 5828

DOI: 10.1021/acs.joc.8b00505 J. Org. Chem. 2018, 83, 5825−5828