1. Introduction

C₁₉-Diterpenoid alkaloids are a large family of highly complex polycyclic alkaloids, which are characterized by an intricate hexacyclic ring system, heavily substituted by a series of oxygen functions such as hydroxy, methoxy and acyloxy groups (Fig. 1) [1]. More than 600 family members have been isolated over the past 60 years. A survey of an extensive number of these alkaloids reveals anti-arrhythmic, anti-inflammatory, anti-epileptic, hypotensive, and bradycardic properties. This broad spectrum of biological activity can be attributed to the potent interactions of these alkaloids with voltage-dependent sodium, potassium, and calcium ion channels [2]. While the toxicity of the most of active compounds has so far limited their clinical application, less toxic derivatives are emerging that could prove to be promising drug candidates [3].

The structural intricacy and biological significance of C₁₉-diterpenoid alkaloids have attracted the great attention of many synthetic chemists over the last fifty decades. Early important and impressive contributions to the syntheses of the C₁₉-diterpenoid alkaloids including a synthesis of talatizamine 1, chasmanine 2, and 13-desoxydephonine 3 were made by Wiesner and coworkers in 1970's [4]. Recently, an elegant synthesis of neofinaconitine 4 was completed by the group of Gin using a highly convergent strategy [5]. Subsequently, Sarpong's group and Fukayama's group reported the total syntheses of liljestrandinine 6 and weisaconitine D 5 [6] and the first asymmetric total synthesis of (-)-cardiopetaline 7 [7] respectively, both of which employ a late-staged Wagner-Meerwein rearrangement from a C₂₀-DA skeleton as the key transformation. Despite numerous other synthetic efforts [8, 9], these compounds 1-7 remain the only seven natural C₁₉-diterpenoid alkaloid molecules completed by total syntheses to date. Some C₁₉-diterpenoid alkaloids with more complex oxygen functions and distinguished biological activities, e.g., aconitine 8 and methyllycaconitine, are still the highly attractive and challenging targets for total synthesis.

In view of our long-standing interest toward the chemistry of C₁₉-diterpenoid alkaloids with significant biological activities [9], we planned to initiate a new program to study the total synthesis of aconitine 8. To achieve this goal, we conceived that it was necessary to develop an efficient and scalable synthesis for the rapid construction of the unique tricyclic subunit of tricyclo [6.2.1.0] undecane core 12. Our whole synthetic plan based on this tricyclic skeleton is briefly outlined in Scheme 1, We envisioned that aconitine 8 can be firstly transformed to intermeidate 9 by means of a serials of functional groups interconversions. Then disconnections of C4-C5 and C3-C4 bond involving sequential 6-exo-trig radical cyclization [10] and Michael addition could greatly simplify the hexacyclic molecule into the less complicated tetracyclic structure 10, which might be further degraded into structure 11. With a successive alkylation and intramolecular aldol reaction strategy [11], 11 could be generated from 12 byinstallation of the five-membered ring F on ring B. Thus, development of a highly efficient synthetic route to access this tricyclic intermediate 12 is fairly crucial to realize our whole synthetic strategy.

Herein, we wish to report a short sequence to prepare this key tricyclic skeleton using an unprecedented oxidative dearomatization/dimerization/retro-DA/IMDA cascade reaction and WagnerMeerwein rearrangement as the key steps.

2. Results and discussion

As illustrated in Scheme 2, we began our synthetic study with the preparation of the phenol 21 tethering an oxygen substituted olefinic side chain. Thus, coupling 17 with the iodide derivative in presence of n-butyl lithium provided the 18. Removal of TBS protecting group followed by oxidation of primary alcohol with Dess-Martin periodinane afforded the aldehyde 19 in 90% yield. Barbier's allylation [12] of aldehyde 19 with allyl bromide in the presence of Zn/NH₄Cl followed by removal of the THP group under acidic condition furnished the allylic alcohol 20. Finally, selective protection of allylic alcohol with TBS provided the phenol 21, ready for the next crucial oxidative dearomatization/intramolecular Diels-Alder (IMDA) cascade reaction. Initial execution of phenol 21 to the oxidative condition by treatment with diacetoxyiodobenzene (PIDA) in a diluted methanonic solution at reflux gave the desired cycloadduct 23 as minor product while the intermolecular Diels-Alder cycloadduct dimer 22 as the major product [9b]. Gratifyingly, we next found this dimer 22 could be successfully converted to the cycloadduct 23 in excellent yield through a retroDA/IMDA process under a thermodynamic condition (heating at 180 ℃ in mesitylene) [13]. Thus, a cascade process involving oxidative dearomatization/dimerization/retro-DA/IMDA reaction could be actually applied to this transformation in one pot. Upon complete formation of dimer 22 by exposure of 21 to PIDA in methanol at low temperature, simply switch the solvent to mesitylene followed by heating at 180 ℃ directly led to the desired cycloadduct 22 in excellent yield and fairly good diastereoselectivity. The stereochemistry of 22 was assigned on the basis of the established endo cycloaddition mechanism [13a] as well as the observed NOE correlation between the methyl of TBS group and the olefin proton. It is worthwhile to mention that the high diastereoselectivity of this reaction make it possible to realize enantioselective synthesis of this important intermediate, as long as construction of the asymmetric chiral center of the secondary alcohol 20.

With the requisite tricycle functionality in place, the deformation of the [2.2.2]octane subunit of 23 to the [3.2.1] subunit by means of the Wagner-Meerwein rearrangment was addressed next. To realize this desired transformation, it is requisite to reduce the carbonyl group to hydroxy group then sulfonylation to achieve a suitable leaving group with desired α configuration, due to the concerted nature of this kind of rearrangement [9b]. Thus, after preliminary reductive conditions screening involving NaBH₄, LiAlH₄, Red-Al, LiEt₃BH, and Li/NH₃, we found the LiAlH₄ could give relatively the best result, leading to a separable mixture of stereoisomers 24a and 24b from which the desired α-OH isomer 24a could be isolated in 50% yield. While the isomeric ratio is quite low, the undesired isomer 24b (40% yield) could be separated and cleanly recycled to ketone 23 by Swern oxidation, to maximally avoid the loss of material. With the pure a-OH epimer in place, the Wagner-Meerwein rearrangement was focused next. To our delight, exposure of 24a to Tf₂O/pyridine in dichlomethane generated the crude triflate 25, which subsequently underwent a facile rearrangement upon purification by silica gel chromatography, affording the desired tricyclic compound 26 in 85% yield.

3. Conclusion

In summary, we have developed an efficient and concise synthetic approach for the first rapid construction of the unique BCD ring system 26 commonly found in the C₁₉-diterpenoid alkaloids in 21% yield for total nine steps. Keysteps include a highly efficient diastereoselective oxidative dearomatization/dimerization/retro-DA/IMDA cascade reaction and a quite convenient Wagner-Meerwein rearrangement. The double bond and oxygen substituents introduced in ring D of 26 provide the synthetic potential to realize the substitution pattern of aconitine-type diterpenoid alkaloid whereas the oxygen function (OTBS) on ring B woulddeliverampleopportunityfor installationof five-membered ring F and the following ring AE. Further studies toward the total synthesis of aconitine and other members of the C₁₉-diterpenoid alkaloids are currently underway in our laboratory.

4. Experimental

Unless otherwise indicated, all reactions were carried out under an atmosphere of argon or nitrogen. Unless otherwise noted, all chemicals and solvents were obtained from commercial vendors and used without further purification unless otherwise noted. Anhydrous THF were dried by distillation over sodium and benzophenone. DCM was dried by distillation over CaH₂. TLC inspections were carried on silica gel GF254 plates. Column chromatography was performed on silica gel (200–300 mesh, Qingdao Marine Chemical Factory, China). ¹H NMR and ¹³C NMR spectra were acquired on a Varian INOVA-400/54 spec-trometer and Agilent Technologies 600/54 Premium with TMS as internal standard, spectra recorded in CDCl₃ were referenced to residual CHCl₃ at 7.26 ppm for ¹H NMRor 77.0ppmfor ¹³C NMR. HRMS were obtained with a Waters Quattro Premier XE (Waters) mass spectrometer.

4.1. Preparation of compound 18

To a solution of 2-methoxyphenol THP ether 17 (2.00g, 9.61mmol) in 48mL THF at 0 ℃ was added n-butyl lithium (7.80mL, 1.6mol/L in hexane, 12.48mmol) dropwised. The resulting mixture was stirred at room temperature for 30min, and then the iodide derivative ICH₂CH₂OTBS (3.30g, 11.54mmol) was added at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 2h, and then the mixture was quenched with sat. aq NaHCO₃ (15mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (4 ×30mL). The combined organic phases were washed with brine (20mL), dried (Na₂SO₄), concentrated and purified by flash chromatography eluting with petroleum ether/ethyl acetate (15:1) to give compound 18 (light yellowoil, 2.88g, 82%). ¹H NMR (400MHz, CD₃OD): δ 7.00–6.96 (m, 1H), 6.91–6.85 (m, 1H), 6.81 (d, 1H, J=7.6Hz), 5.16 (m, 1H), 4.09 (m, 1H), 3.91–3.84 (m, 2H), 3.82 (s, 3H), 3.56–3.50 (m, 1H), 3.11–3.03 (m, 1H), 2.86–2.78 (m, 1H), 1.99–1.90 (m, 3H), 1.66–1.59 (m, 3H), 0.91 (s, 9H), 0.03 (d, 6H, J=4.8Hz); ¹³C NMR (151MHz, CD₃OD): δ 153.61, 146.22, 134.06, 124.81, 124.08, 111.92, 102.97, 64.77, 64.63, 56.23, 35.31, 31.98, 26.51, 26.41, 20.99, 19.16, -5.08, -5.09; HRMS (ESI⁺): m/z calcd. for C₂₀H₃₄O₄Si⁺ 367.2305 [M+H]⁺, found 367.2300.

4.2. Preparation of aldehyde 19

To a stirred solution of 18 (1.18g, 3.22 mmol) in THF (16 mL), TBAF (2.04g, 6.45 mmol) was added and stirred for 30min. After complete conversion as showed by TLC, the reactionwas quenched with sat. aq NaHCO₃ (5 mL) and extracted with EtOAc (3 ×20 mL). The combined organic phases was washed with brine, dried with Na₂SO₄ and concentrated invacuo. The crude materialwas purified by flash chromatography using PE: EtOAc (9:1 →3:1) to give alcohol 19s (yellow oil, 788mg, 97%).

A solution of alcohol 19s (560 mg, 2.22 mmol) in DCM (22 mL) was treated with NaHCO₃ (747 mg, 8.89 mmol) and DMP (1.89 g, 4.45 mmol) in turn at room temperature. The reaction mixture was stirred for 30 min and quenched with sat.aq Na₂S₂O₃ (10mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 ×20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), concentrated in vacuo and purified by flash chromatography on silica gel eluting with petroleum ether/ ethyl acetate (6:1) to give aldehyde 19 (colorless oil, 500mg, 90%). ¹H NMR (400MHz, CDCl₃): δ 9.69 (s, 1H), 7.06 (t, 1H, J=8.0Hz), 6.88 (d, 1H, J=8.4Hz), 6.77 (d, 1H, J=7.6Hz), 5.12 (d, 1H, J=4.0Hz), 3.95 (dd, 1H, J=10.8, 5.2Hz), 3.85 (s, 3H), 3.81–3.69 (m, 2H), 3.49 (dd, 1H, J=10.4, 5.2Hz), 2.00–1.79 (m, 3H), 1.66–1.51 (m, 3H); ¹³C NMR (151 MHz, CDCl₃): δ 200.63, 152.45, 144.90, 127.45, 124.40, 122.78, 111.65, 102.07, 64.17, 55.70, 45.39, 30.76, 25.03, 20.10; HRMS (ESI⁺): m/z calcd. for C₁₄H₁₈O₄⁺ 251.1283 [M+H]⁺, found 251.1281.

4.3. Preparation of phenol 20

A solution of 19 (200mg, 0.80mmol) in THF (2mL) and sat. aq NH₄Cl (8mL) was treated with zinc powder (210mg) and allyl bromide (0.28mL, 3.2mmol) in turn at room temperature. The reaction mixture was stirred for 30min at room temperature and quenched with sat.aq NaHCO₃ (10mL) at 0 ℃. The layers were separated and the aqueous layer was extracted with DCM (3 ×20mL). The combined organic layers were washed with brine, dried (Na₂SO₄), concentrated in vacuo and purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (6:1) to give alcohol 20s (yellow oil, 215mg, 92%).

To a stirred solution of 20s (230 mg, 0.79 mmol) in MeOH (7.9 mL), 3 mol/L HCl (0.8 mL, 2.37 mmol) was added at room temperature and stirred for 1h. The reaction was then quenched with sat. aq NaHCO₃ (3 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 ×15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (3:1) to give phenol 20 (yellow oil, 155mg, 95%). ¹H NMR (400MHz, CDCl₃): δ 6.83–6.71 (m, 3H), 5.93–5.82 (m, 1H), 5.18–5.12 (m, 2H), 4.03–3.95 (m, 1H), 3.88 (s, 3H), 2.91 (dd, 1H, J=14.0, 4.0Hz), 2.78 (dd, 1H, J=14.0, 7.6Hz), 2.39–2.30 (m, 1H), 2.28–2.19 (m, 1H). ¹³C NMR (151MHz, CDCl₃): δ 147.02, 144.02, 134.77, 124.67, 123.45, 119.56, 117.92, 109.40, 71.34, 55.89, 41.30, 37.61. HRMS (ESI⁺): m/z calcd. for C₁₂H₁₆O₃⁺ 209.1178 [M+H]⁺, found 209.1175.

4.4. Preparation of silyl ether 21

2, 6-Lutidine (0.17 mL, 1.44 mmol) and TBSOTf (0.16 mL, 0.72 mmol) was added dropwise to a solution of 20 (100 mg, 0.48 mmol) in DCM (4 mL) at 0 ℃ in turn. The reaction mixture was stirred for 1 h at this temperature, and then the mixture was diluted with sat. aq NH₄Cl (6 mL). The organic layers were separated and the aqueous layer was extracted with DCM (3 ×15 mL). The combined organic phases was washed with brine, dried (Na₂SO₄), concentrated in vacuo and purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (6:1) to give compound 21 (colorless oil, 124 mg, 80%). ¹H NMR (400 MHz, CDCl₃): δ 6.75 (d, 2H, J = 4.8 Hz), 6.72–6.67 (m, 1H), 6.57 (s, 1H), 5.85 (dt, 1H, J = 17.7, 7.2 Hz), 5.09–5.02 (m, 2H), 4.09– 4.02 (m, 1H), 3.87 (s, 3H), 2.86 (dd, 1H, J = 13.6, 4.8 Hz), 2.77 (dd, 1H, J = 13.6, 6.8 Hz), 2.22 (m, 2H), 0.87 (s, 9H), 0.01 (s, 3H), -0.10 (s, 3H); ¹³C NMR (151 MHz, CDCl₃): δ 147.05, 144.31, 135.01, 124.93, 124.18, 119.07, 117.08, 109.27, 72.23, 55.95, 41.36, 38.37, 25.87, 18.10, -4.82, -5.04; HRMS (ESI⁺): m/z calcd. for C₁₈H₃₀O₃Si⁺ 323.2042 [M+H]⁺, found 323.2045.

4.5. Preparation of cycloadduct 23

A solution of 21 (50 mg, 0.15 mmol) in MeOH (1.5 mL) was treated with PIDA (64 mg, 0.20 mmol) in one portion at 0 ℃. The resulting mixture was allowed to stir for 4 h at room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved with mesitylene (2 mL) and stirred 4 h at 180 ℃. The solvent was evaporated under reduced pressure by oil pump and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (30:1) to give ketone 23 (yellow solid, 49 mg, 90%). ¹H NMR (600 MHz, CDCl₃): δ 6.43 (t, 1 H, J = 7.4 Hz), 5.90 (d, 1 H, J = 7.8 Hz), 4.33 (m, 1 H), 3.33 (s, 3 H), 3.32 (s, 3 H) 3.06 (m, 1 H), 2.53 (dd, 1 H, J = 13.8, 8.4 Hz), 2.23–2.18 (m, 1 H), 2.16–2.11 (m, 1 H), 2.10–2.03 (m, 1 H), 1.61 (dd, 1 H, J = 13.8, 3.0 Hz), 1.23–1.18 (m, 1 H), 1.12 (ddd, 1 H, J = 12.0, 6.6, 1.8 Hz), 0.87 (s, 9 H), 0.03 (d, 6 H, J = 10.2 Hz); ¹³C NMR (151 MHz, CDCl₃): δ 200.86, 135.19, 133.95, 131.96, 130.89, 94.68, 73.06, 72.75, 59.30, 50.15, 49.87, 42.64, 39.84, 39.71, 38.65, 38.37, 37.08, 26.97, 25.85, 18.02, -4.87; HRMS (ESI⁺): m/z calcd. for C₁₉H₃₂O₄Si⁺ 353.2148 [M+H]⁺, found 353.2150.

4.6. Preparation of alcohol 24a and 24b

To a solution of compound 23 (80 mg, 0.23 mmol) in THF (2.4 mL) at 0 ℃ was added LiAlH₄ (0.25 ml, 1 mol/L in THF, 0.25 mmol) dropwise. After stirred for 3 h, the reaction was quenched by sat. aq NaOH (10 mL), filtered, and extracted with EtOAc (4 ×15 mL). The combined extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (20:1) to give the alcohol 24a (light yellow oil, 40 mg, 50%) and 24b (light yellow oil, 32 mg, 40%). For 24a: ¹H NMR (400 MHz, CDCl₃): δ 6.30–6.21 (m, 1 H), 6.00 (d, 1H, J = 8.0 Hz), 4.39– 4.32 (m, 1 H), 3.34 (d, 1H, J = 4.9 Hz), 3.28 (s, 3H), 3.20 (s, 3 H), 2.83– 2.79 (m, 1 H), 2.35–2.24 (m, 2H), 2.12 (m, 2 H), 1.68–1.59 (m, 1 H), 1.26–1.20 (m, 1 H), 1.02 (m, 1 H), 0.86 (s, 9H), 0.01 (d, 6 H, J = 4.8 Hz); ¹³C NMR (151 MHz, CDCl₃): δ 136.08, 130.51, 104.25, 79.86, 73.38, 51.86, 49.70, 49.43, 43.65, 43.18, 39.02, 38.44, 27.90, 25.81, 17.98, -4.85; HRMS (ESI⁺): m/z calcd. for C₁₉H₃₄O₄Si⁺ 355.2305 [M + H]⁺, found 355.2302.

4.7. Conversion of 24b to ketone 23

To a solution of oxalyl chloride (140 uL, 2 mol/L in DCM, 0.28 mmol) at -78 ℃ was added DMSO (0.5 mL, 2 mol/L in DCM, 1.00 mmol) dropwise, and the resulting mixture was stirred at -78 ℃ for 30 min, and then a solution of 24b (32 mg, 0.09 mmol) in DCM (1 mL) was added dropwise. After 1 h, Et₃N (0.2 mL, 1.35 mmol) was added dropwise, and stirred for 2 h, at which point it was warmed to -30 ℃. After 30 min, the reaction mixture was quenched with sat. aq NH₄Cl (7 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated to oil. Purification by flash chromatography (PE: EA = 30: 1) provided compound 23 (yellow solid, 30 mg, 94%).

4.8. Preparation of BCD tricyclic ring system 26

To a solution of alcohol 24a (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (41 mL, 0.51 mmol), Tf₂O (34 mL, 0.20 mmol) in turn at 0 ℃. The reaction mixture was stirred for 1 h, and quenched by saturated water (1 mL). The layers were seperated and the aqeous layer was extracted by DCM (4 × 5 mL). The combined organic solution was dried over anhydrous Na₂SO₄, then filtered and evaporated in vacuo. The residue was purified by flash silical gel column chromatography (Petroleum ether/ethyl acetate, 15:1) to get 26 (yellow oil, 31 mg, 85%). ¹H NMR (400 MHz, CDCl₃): δ 5.79–5.72 (m, 1 H), 5.51 (d, 1 H, J = 9.6 Hz), 4.15–4.10 (m, 1 H), 3.22 (s, 3 H), 3.19 (s, 3 H), 2.36 (t, 2 H, J = 6.4 Hz), 2.15 (d, 1 H, J = 6.0 Hz), 1.98 (m, 2 H), 1.72 (m, 1 H), 1.67 (s, 2 H), 1.61 (dd, 1 H, J = 13.6, 2.8 Hz), 0.84 (s, 9 H), 0.08 (s, 6 H); ¹³C NMR (151 MHz, CDCl₃): δ 135.32, 126.79, 111.45, 71.94, 67.91, 50.11, 47.68, 47.49, 43.61, 39.90, 35.07, 34.16, 30.35, 25.76, 25.73, 17.94, -4.98, -5.18; HRMS (ESI⁺): m/z calcd. for C₁₉H₃₄O₄Si⁺ 355.2305 [M + H]⁺, found 355.2300.

Acknowledgments

Financial support for this work was provided by the National Natural Science Foundation of China (No. 21472129 and No. 21272163).