2025 Volume 73 Issue 5 Pages 491-496
Veratridine is a neurotoxic compound classified into the cevanine group of the Veratrum alkaloids and is characterized by its highly functionalized hexacyclic structure. Here, we report the synthesis of the ABC-ring system of veratridine from a known cis-decalin. The cis-decalin was synthesized from 1,5-pentanediol by modification of a literature method. A site-selective acylation of the C3-hydroxy group with 3,4-dimethoxybenzoyl chloride, a chemo- and stereoselective (allyl)2Zn-mediated C9-allylation, and ring closing metathesis were employed as key transformations to construct the ABC-ring system of veratridine.
Veratridine (Fig. 1) is a neurotoxic compound derived from the seeds of the Veratrum plant.1,2) It binds to voltage-gated sodium ion channels to promote depolarization of the cell membrane, causing several secondary effects including Ca2+pump activity.3,4) Structurally, veratridine is characterized by its highly functionalized hexacyclic structure including a C-nor-D-homo steroid system and C3-veratroate, and is classified into the cevanine group of the Veratrum alkaloids.5,6) This class of steroidal alkaloids creates challenging targets for total synthesis, and several successful approaches to their complex architecture have been disclosed.7–12) Here, we report the synthesis of the tricyclic ABC-ring system of veratridine.
Our synthetic plan for ABC ring 1 is shown in Chart 1. We planned to synthesize ABC-ring 1 from AB-ring 2 by ring closing metathesis while retaining the olefin in the C-ring for future construction of the D-ring. AB-ring 2 could be synthesized from known cis-decalin 313–15) through installation of vinyl and allyl groups to the B-ring. cis-Decalin 3 can be easily prepared from 1,5-pentanediol (4) based on the literature methods.
The synthesis started with mono tetrahydropyranyl (THP) protection of 1,5-pentanediol (4), followed by Swern oxidation of the remaining hydroxy group of 5 to give 616) (Chart 2). From aldehyde 6 to diene 7, the literature method required a 4-step transformation, consisting of i) Wittig reaction with Ph3P = CHCO2Me, ii) diisobutylaluminium hydride (DIBAL-H) reduction, iii) MnO2-oxidation, and iv) Wittig reaction with Ph3P = CH2. We modified the sequence to a single step. Specifically, diene 7 was synthesized by the Horner–Wadsworth–Emmons reaction of 6 with diethyl allylphosphonate. Although the reaction in tetrahydrofuran (THF) provided a 1 : 1.4 mixture of 7 and its Z-isomer in poor yield (31%), addition of hexamethylphosphoric triamide (HMPA) as a co-solvent effectively improved both the yield and stereoselectivity (66% from 5, E : Z = 20 : 1). After acidic removal of the THP group of 7, the liberated hydroxy group was transformed to an aldehyde by Swern oxidation. Treatment of 9 with isopropenylmagnesium bromide was followed by Swern oxidation of the resulting 10 to provide enone 11. The Et2AlCl-mediated intramolecular Diels–Alder reaction of 11 selectively constructed the cis-decalin scaffold corresponding to the AB-ring system of veratridine, affording 3 (dr at C4 = 5.9 : 1).
Reagents and Conditions: (a) DHP, p-TsOH·H2O, THF, 80%; (b) (COCl)2, DMSO, CH2Cl2, −78°C; Et3N; (c) diethyl allylphosphonate, n-BuLi, HMPA, THF, 66% (2 Steps); (d) DOWEX 50W, MeOH; (e) (COCl)2, DMSO, CH2Cl2, −78°C; Et3N; (f) isopropenylmagnesium bromide, THF, 0°C, 66% (3 Steps); (g) (COCl)2, DMSO, CH2Cl2, −78°C; Et3N, 54%; (h) Et2AlCl, CH2Cl2, 0°C, 96% (dr at C4 = 5.9 : 1); (i) OsO4, NMO, acetone, H2O, 41%; (j) A (15 mol%), 3,4-dimethoxybenzoyl chloride, i-Pr2EtN, CH3CN, 57%; (k) TBSOTf, 2,6-lutidine, CH2Cl2, −78°C, 92%; (l) IBX, toluene, DMSO, 70°C; (m) I2, pyridine, CCl4, 50°C, 59% (2 steps); (n) vinylbronic acid pinacol ester, PdCl2(dppf) (5 mol%), K2CO3, DME, H2O, 50°C, 81%; (o) (allyl)2Zn, THF, 0°C, 87%; (p) Grubbs catalyst 2nd generation (10 mol%), toluene, 60°C, 92%
The dihydroxylation of the olefin of 3 with OsO4 proceeded from the convex face of the cis-decalin, affording 12 as the major product. 12 was purified by recrystallization, and the diol derived from the trans-decalin formed in the Diels–Alder reaction was easily removed. This recrystallization also enabled us to obtain a single crystal for unambiguously determining the cis-decalin system and C3,C4-β-diol in 12 by X-ray crystallographic analysis.17) The two hydroxy groups were then differentiated by acylation. Although the standard conditions using 3,4-(OMe)2BzCl, Et3N and 4-(dimethylamino)pyridine (DMAP)/3,4-(OMe)2BzOH, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), Et3N, and DMAP acylated the C4-hydroxy group, the C3-hydroxy group was selectively acylated with 3,4-(OMe)2BzCl by the action of catalyst A18) to afford 13. The remaining C4-hydroxy group was protected as the tert-butyldimethylsilyl (TBS) ether with tert-butyldimethylsilyl triflate (TBSOTf).
The B-ring of 14 was oxidized with 2-iodoxybenzoic acid (IBX) to enone 15, which was then iodinated. A vinyl group was attached to the C8-position by Suzuki–Miyaura coupling of 16 and vinylbronic acid pinacol ester to provide 17. We then attempted the stereoselective addition of an allyl group at the C9-ketone from the convex-face of the cis-decalin system to construct the requisite C9-stereocenter. However, the stereoselective addition of an allyl group was not an easy task because the adjacent C10-methyl group sterically shielded the C9-ketone, allowing a competitive concave attack of the allyl group to form the undesired C9-stereocenter. Furthermore, the C3-veratroate was labile to the nucleophile, liberating the hydroxy group. After several trials, we found that (allyl)2Zn19) delivered an allyl group to the C9-ketone from the convex face without touching the C3-veratroate, affording 2 in high yield. The C9-stereochemistry was determined by the nuclear Overhauser effect spectroscopy (NOESY) correlation between C10-CH3 and C11-CH2. The bulky and weakly nucleophilic dialkyl zinc reagent may have successfully discriminated the steric environment around the C9-ketone and the reactivity between the C9-ketone and C3-acyloxy groups. Finally, the ring-closing metathesis of 2 under the action of Grubbs 2nd catalyst successfully constructed the C-ring, giving rise to 1.
Site-selective acylation of the C3-hydroxy group by the action of catalyst A, (allyl)2Zn-mediated chemo- and stereoselective C9-allylation, and ring closing metathesis served as key transformations for the assembly of the ABC-ring system of veratridine from a known cis-decalin in 8 steps. Continuing studies toward veratridine from 1 are underway in our laboratory.
General methods: All reactions sensitive to air or moisture were carried out in dry solvents under an argon atmosphere unless otherwise noted. Analytical TLC was performed using Merck 60 F254 pre-coated silica gel plates (0.25 mm). Preparative TLC (PTLC) was performed using Merck 60 F254 pre-coated silica gel plates (0.50 mm). Column chromatography was performed using 40–100 μm Silica Gel 60N unless otherwise noted. IR spectra were recorded as a thin film on a NaCl disk using PerkinElmer, Inc. (Waltham, MA, U.S.A.) Spectrum 100 spectrometer. 1H- and 13C-NMR spectra were recorded on Bruker AVANCE II 400 or AVANCE NEO 500 spectrometer at room temperature. Chemical shifts were reported in ppm on the δ scale relative to CHCl3 (δ = 7.26 for 1H-NMR) and CDCl3 (δ = 77.0 for 13C-NMR) as internal references. Signal patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broaden peak. High-resolution mass spectra were measured on BRUKER DALTONICS micrOTOF (electrospray ionization-time-of-flight (ESI-TOF)).
Alcohol 53,4-Dihydro-2H-pyran (DHP, 10 mL, 110 mmol) was added to a solution of 1,5-pentanediol (4, 38 mL, 0.36 mol) and p-toluenesulfonic acid monohydrate (p-TsOH ∙ H2O, 1.15 g, 6.03 mmol) in THF (365 mL) at room temperature. The reaction mixture was stirred at room temperature for 14 h, and then concentrated. After adding H2O (80 mL), the resultant solution was extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel 370 g, hexane/EtOAc 1/2 to 1/3 to EtOAc) to afford crude 5, which was further purified by column chromatography using Biotage Selekt (Biotage® Sfär HC Duo 25 g, EtOAc in hexane 16% 1 column volume (CV), 16–100% 7 CV, 100% 5 CV) to afford 5 (16.5 g, 87.6 mmol, 80% yield) as a colorless oil. The characterization data was identical to those previously reported.16)
Diene 7Dimethyl sulfoxide (DMSO, 9.5 mL, 0.13 mol) in CH2Cl2 (30 mL) was added to a solution of oxalyl chloride (7.8 mL, 0.89 mol) in CH2Cl2 (445 mL) at −78°C. After stirring for 20 min, a solution of 5 (8.37 g, 44.5 mmol) in CH2Cl2 (30 mL) was added at −78°C. Et3N (62 mL, 0.45 mol) was added at −78°C, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and saturated aqueous NaHCO3 (150 mL) was added. The resultant mixture was extracted with Et2O (80 mL × 3), and the combined organic layers were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtrated, and concentrated to afford crude 6, which was used in the next reaction without further purification.
n-BuLi (2.0 M in hexane, 27 mL, 54 mmol) was added to a solution of diethyl allylphosphonate (9.2 mL, 53 mmol) in THF (166 mL) −78°C. After 10 min, HMPA (38 mL) was added. The mixture was stirred at −78°C for 3 h, and then a solution of the above crude 6 in THF (20 mL) was added. The reaction mixture was stirred at −78°C for 2 h, then was warmed to rt. After stirring for 18 h, saturated aqueous NH4Cl (50 mL) was added. The resultant mixture was extracted with a 4 : 1 mixture of hexane and EtOAc (100 mL × 3), and the combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtrated, and concentrated. The residue was purified by column chromatography using Biotage Selekt for three times (for the first: Biotage® Sfär HC Duo 25 g, EtOAc in hexane 0–15% 10 CV, 15% 2 CV, for the second: Biotage® Sfär HC Duo 10 g, EtOAc in hexane 0–5% 15 CV, 5% 17.8 CV, 5–9% 10.4 CV, 9–11% 0.5 CV, 11–20% 1.5 CV, 20% 0.3 CV, 20–40% 6.4 CV, 40–60% 2 CV, for the third: Biotage® Sfär HC Duo 25 g, EtOAc in hexane 0–5% 9.5 CV, 5–7% 2.6 CV, 7% 1.4 CV, 7–30% 0.8 CV, 30–50% 5.6 CV) to afford 7 (7.75 g with EtOAc, 79% purity, 29.2 mmol, 66% calculated yield for 2 steps) as a yellow oil. The characterization data was identical to those previously reported.16)
Triene 10DOWEX 50W (10.8 g) was added to a solution of diene 7 (11.2 g, 53.3 mmol) in MeOH (533 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 h, filtered, and concentrated to afford crude 8, which was used in the next reaction without further purification.
DMSO (11 mL, 0.15 mol) in CH2Cl2 (40 mL) was added to a solution of oxalyl chloride (9.3 mL, 0.11 mol) in CH2Cl2 (430 mL) at −78°C. After the mixture was stirred for 30 min, a solution of the above crude 8 in CH2Cl2 (40 mL) was added at −78°C. Et3N (44 mL, 0.32 mol) was added at −78°C, and then the reaction mixture was stirred at room temperature for 2 h. Then, saturated aqueous NaHCO3 (200 mL) was added. The resultant mixture was extracted with CH2Cl2 (100 mL ×3), and the combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtrated, and concentrated afford crude 9, which was used in the next reaction without further purification.
Isopropenylmagnesium bromide (approx. 0.5 M, 140 mL, 71 mmol) was added to a solution of the above crude 9 in THF (533 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min, and then saturated aqueous NH4Cl (150 mL) was added. The resultant mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with a saturated H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtrated, and concentrated. The residue was purified by column chromatography (silica gel 300 g, hexane/EtOAc 7/1 to EtOAc) to afford 10 (5.85 g, 35.2 mmol, 66% yield for 3 steps) as a yellow oil. The characterization data was identical to those previously reported.15)
Enone 11DMSO (9.8 mL, 0.14 mol) in CH2Cl2 (20 mL) was added to a solution of oxalyl chloride (8.1 mL, 92 mmol) in CH2Cl2 (420 mL) at −78°C. After the mixture was stirred for 30 min, a solution of 10 (7.66 g, 46.1 mmol) in CH2Cl2 (20 mL) was added. After 10 min, Et3N (39 mL, 0.28 mol) was added at −78°C. The reaction mixture was stirred at room temperature for 45 min, and then saturated aqueous NaHCO3 (200 mL) was added. The resultant mixture was extracted with CH2Cl2 (100 mL × 3), and the combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtrated, and concentrated. The residue was purified twice by column chromatography using Biotage Selekt (for the first: Biotage® Sfär HC Duo 25 g, EtOAc in hexane 2% 2 CV, 2–23% 10 CV, 23% 8.3 CV, for the second: Biotage® Sfär HC Duo 25 g, EtOAc in hexane 2% 2.4 CV, 2–23% 7 CV, 23% 3.6 CV) to afford 11 (4.07 g, 24.8 mmol, 54% yield) as a yellow oil. The characterization data was identical to those previously reported.15)
cis-Decalin 3Et2AlCl (1.0 M in n-hexane, 6.0 mL, 6.0 mmol) was added to a solution of 11 (1.99 g, 12.1 mmol) in CH2Cl2 (127 mL) at −78°C. The reaction mixture was stirred at −78°C for 3 h and at 0°C for 28 h. The reaction mixture was poured into saturated aqueous NaHCO3 (100 mL). The resultant mixture was extracted with CH2Cl2 (50 mL × 3), and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using Biotage Selekt (Biotage® Sfär HC Duo 25 g, EtOAc in hexane 2% 4 CV, 2–15% 10 CV, 15% 17 CV) to afford an inseparable mixture of 3 and its diastereomer (5.9 : 1, 1.90 g, 11.6 mmol, 96% yield) as a colorless oil. The characterization data was identical to those previously reported.15)
Diol 12OsO4 (4% in H2O, 6.1 mL 0.96 mmol) was added to a solution of decalin 3 (3.15 g, 19.2 mmol) and 4-methylmorpholine N-oxide (NMO, 6.09 g, 52.0 mmol) in a mixture of acetone and H2O (9 : 1, 96 mL) at room temperature. The reaction mixture was stirred at room temperature for 11 h, and then saturated aqueous Na2S2O3 (80 mL) was added. After 15 min, H2O (50 mL) was added. The resultant mixture was extracted with EtOAc (70 mL × 4), and the combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using Biotage Selekt (Biotage® Sfär HC Duo 25 g × 2, EtOAc in hexane 12–60% 15 CV, 60% 7 CV, 60–100% 8 CV, 100% 15 CV) to afford crude 12, which was recrystallized from Et2O to give 12 (1.55 g, 7.82 mmol, 41%) as colorless crystals.
M.p. 103.8–106.0°C. IR (ATR) ν 3361, 2955, 2933, 2916, 2895, 2877, 1698, 1456, 1445, 1259, 1064, 1050 cm−1. 1H-NMR (500 MHz, CDCl3) δ: 1.27 (3H, s) 1.33 (1H, td, J = 13.5, 4.6 Hz), 1.66 (1H, m), 1.73 (1H, m), 1.88–1.97 (3H, m), 1.98–2.06 (2H, m), 2.07 (3H, s), 2.13 (1H, dt, J = 11.1, 3.4 Hz), 2.24 (1H, m), 2.59 (1H, m), 3.46 (1H, dd, J = 11.1, 3.0 Hz), 3.98 (1H, m). 13C-NMR (125 MHz, CDCl3) δ: 20.0, 21.6, 27.1, 27.3, 27.4, 37.8, 45.5, 49.5, 69.6, 69.8, 215.1. HRMS (ESI) Calcd for C11H18O3Na 221.1148 [M + Na]+, Found 221.1149.
Compound 133,4-Dimethoxybenzoyl chloride (1.75 g, 8.72 mmol) was added to a solution of 12 (896 mg, 4.52 mmol), 2-aminoethyl diphenylborinate A (150 mg, 0.67 mmol) and i-Pr2EtN (2.4 mL, 14 mmol) in MeCN (23 mL) at room temperature. The resulting mixture was stirred at room temperature for 11 h, and then MeOH (0.55 mL, 14 mmol) was added. The reaction mixture was stirred for 0.5 h, and then a saturated aqueous NaHCO3 (10 mL) was added. The resultant mixture was extracted with EtOAc (15 mL × 3), and the combined organic extracts were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel 110 g, toluene/Et2O 2/3) to afford 13 (938 mg, 2.59 mmol, 57%) as a yellow amorphous solid and a 2 : 1 mixture of 13 and its regioisomer (165 mg, 45.5 mmol, 10%).
IR (ATR) ν 3498, 2939, 1699, 1600, 1514, 1449, 1417, 1346, 1289, 1267, 1221, 1175, 1132, 1106, 1020 cm−1. 1H-NMR (500 MHz, CDCl3) δ: 1.30–1.39 (1H, m), 1.34 (3H, s), 1.82 (1H, tdd, J = 13.4, 4.1, 2.5 Hz), 1.88–2.19 (7H, m), 2.23 (1H, dt, J = 11.4, 3.0 Hz), 2.23 (1H, dt, J = 11.4, 3.2 Hz), 2.29 (1H, m), 2.63 (1H, ddd, J = 15.3, 10.6, 10.1 Hz), 3.68 (1H, dd, J = 11.4, 2.8 Hz), 3.93 (3H, s, OMe), 3.95 (3H, s, OMe), 5.39 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 1.9 Hz), 7.67 (1H, dd, J = 8.5, 1.9 Hz). 13C-NMR (125 MHz, CDCl3) δ: 19.9, 21.5, 25.7, 27.2, 28.5, 37.9, 47.0, 49.5, 56.0, 56.1, 69.3, 74.0, 110.3, 112.2, 122.6, 123.5, 148.8, 153.3, 166.9, 214.7. HRMS (ESI) Calcd for C20H26O6Na 385.1622 [M + Na]+, Found 385.1621.
TBS Ether 14TBSOTf (1.7 mL, 7.4 mmol) was added to a solution of 13 (938 mg, 2.59 mmol) and 2,6-lutidine (0.90 mL, 7.8 mmol) in CH2Cl2 (26 mL) at −78°C. The reaction mixture was stirred at −78°C for 10 min, and then a saturated aqueous NaHCO3 (10 mL) was added. The resultant mixture was extracted with CH2Cl2 (15 mL ×3), and the combined organic extracts were washed with H2O (10 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using Biotage Selekt (Biotage® Sfär HC Duo 10 g, EtOAc in hexane 2–25% 10 CV, 25% 4.6 CV, 25–30% 3.5 CV, 30–41% 2.4 CV, 41–50% 4.6 CV, 100% 16 CV) to afford 14 (1.13 g, 2.37 mmol, 92%) as white amorphous solid.
IR (ATR) ν 2953, 2931, 2856, 2704, 1601, 1515, 1463, 1418, 1268, 1221, 1133, 1105, 1025 cm−1. 1H-NMR (500 MHz, CDCl3) δ: 0.03 (3H, s), 0.04 (3H, s), 0.79 (9H, s), 1.21–1.33 (1H, m), 1.34 (3H, s), 1.65–1.77 (1H, m), 1.81–2.00 (3H, m), 2.00–2.10 (3H, m), 2.26–2.33 (1H, m), 2.33–2.40 (1H, m), 2.59–2.68 (1H, m), 3.64 (1H, dd, J = 9.7, 2.7 Hz), 3.93 (3H, s), 3.94 (3H, s), 5.21–5.26 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 1.9 Hz), 7.68 (1H, dd, J = 8.5, 1.9 Hz). 13C-NMR (100 MHz, CDCl3) δ −4.9, −4.3, 17.9, 21.8, 25.3, 25.6, 25.8, 27.3, 28.3, 37.9, 47.6, 49.5, 55.95, 55.98, 69.5, 73.2, 110.2, 112.1, 123.38, 123.42, 148.6, 152.8, 165.8, 215.3. HRMS (ESI) Calcd for C26H40O6SiNa 499.2486 [M + Na]+, Found 499.2468.
Enone 16IBX (39% purity, 1.50 g, 2.1 mmol) was added to a solution of ketone 14 (337 mg, 707 μmol) in a mixture of toluene and DMSO (2 : 1, 8.7 mL) at room temperature. The reaction mixture was stirred at 70°C for 14 h, and then a saturated aqueous NaHCO3 (10 mL) was added. The resultant mixture was layers with Et2O (15 mL × 3), and the combined organic extracts were washed with H2O (10 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel 25 g, hexane/EtOAc 3/1) to afford crude 15, which was used without further purification.
Iodine (801 mg, 3.16 mmol) was added to a solution of the above crude 15 in a mixture of pyridine and CCl4 (1 : 1, 13 mL) at room temperature. The reaction mixture was stirred at 50°C for 14 h, and then H2O (10 mL) was added. The resultant mixture was extracted with Et2O (15 mL × 3), and the combined organic layers were washed with 1 M HCl (10 mL), H2O (10 mL), and brine (10 mL), dried over anhydrous Na2SO4, filtrated, and concentrated. The residue was purified by column chromatography (silica gel 55 g, toluene/Et2O 9/1 to 6/1) to afford 16 (251 mg, 418 μmol, 59% for 2 steps) as white amorphous solid and recovered 15 (96.1 mg, 202 μmol, 29%) as white amorphous solid.
IR (ATR) ν 2952, 2930, 2856, 1709, 1685, 1599, 1514, 1462, 1417, 1288, 1267, 1251, 1216, 1176, 1116, 1102, 1085, 1018 cm−1. 1H-NMR (400 MHz, CDCl3) δ: 0.00 (3H, s), 0.06 (3H, s) 0.78 (9H, s), 1.27 (3H, s), 1.36–1.46 (1H, m), 1.52–1.63 (1H, m), 1.87–1.95 (1H, m), 2.20–2.29 (1H, m), 2.40–2.48 (1H, m), 2.69–2.73 (2H, m), 3.58 (1H, dd, J = 10.9, 2.8 Hz), 3.92 (3H, s), 3.94 (3H, s), 5.26–5.30 (1H, m) 6.90 (1H, d, J = 8.4 Hz), 7.51–7.55 (2H, m), 7.65 (1H, dd, J = 8.4, 1.8 Hz). 13C-NMR (100 MHz, CDCl3) δ −5.0, −4.4, 17.8, 25.2, 25.6 (overlapped), 28.0, 28.9, 44.8, 47.6, 56.0 (overlapped), 69.4, 72.1, 102.4, 110.2, 112.2, 123.29, 123.32, 148.7, 152.9, 155.2, 165.6, 195.4. HRMS (ESI) Calcd for C26H37O6ISiNa 623.1296 [M + Na]+, Found 623.1289.
Compound 17[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (PdCl2(dppf), 55.8 mg, 76.3 μmol) was added to a solution of 16 (906 mg, 1.51 mmol), K2CO3 (1.32 g, 9.56 mmol), and vinylbronic acid pinacol ester (0.77 mL, 4.5 mmol) in a mixture of 1,2-dimethoxyethane (DME) and H2O (10 : 1, 30 mL) at room temperature. The reaction mixture was degassed by a freeze–pump–thaw method, and was stirred at 50°C for 3 h. Then H2O (10 mL) was added. The resultant mixture was extracted with CH2Cl2 (15 mL × 3), and the combined organic extracts were washed with H2O (10 mL) a brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel 55 g, hexane/EtOAc 10/1) to afford 17 (611 mg, 1.22 mmol, 81%) as a white amorphous solid.
IR (ATR) ν 2952, 2931, 2856, 1709, 1671, 1600, 1514, 1462, 1417, 1345, 1288, 1268, 1251, 1217, 1175, 1086, 1023 cm−1. 1H-NMR (400 MHz, CDCl3) δ –0.02 (3H, s), 0.03 (3H, s), 0.78 (9H, s), 1.24 (3H, s), 1.37 (1H, td, J = 13.6, 3.9 Hz), 1.55–1.67 (1H, m), 1.85–1.94 (1H, m), 2.16–2.23 (1H, m), 2.36–2.43 (1H, m), 2.62–2.80 (2H, m), 3.60 (1H, dd, J = 10.9, 2.9 Hz), 3.92 (3H, s), 3.93 (3H, s), 5.17 (1H, dd, J = 11.2, 0.96 Hz), 5.26–5.29 (1H, m), 5.62 (1H, dd, J = 17.6, 0.96 Hz), 6.56 (1H, dd, J = 17.6, 11.2 Hz), 6.79 (1H, m), 6.89 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 1.9 Hz), 7.65 (1H, dd, J = 8.4, 1.9 Hz). 13C-NMR (100 MHz, CDCl3) δ –5.1, –4.4, 17.8, 23.4, 25.2, 25.6, 25.7, 28.1, 44.5, 46.9, 56.0 (overlapped), 69.6, 72.5, 110.2, 112.2, 115.8, 123.3, 123.5, 131.5, 135.0, 140.7, 148.6, 152.8, 165.7, 201.2. HRMS (ESI) Calcd for C28H40O6SiNa 523.2486 [M + Na]+, Found 523.2484.
AB-Ring 2ZnCl2 (0.5 M in THF, 12 mL) was added to a solution of allylmagnesium chloride (2 M in THF, 6.0 mL) at 0°C. After 1,4-dioxane (4.0 mL) was added, the mixture was stirred at room temperature for 1 h. The supernatant of the solution as a (allyl)2Zn solution (11 mL) was added to a solution of 17 (297 mg, 593 μmol) in THF (12 mL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h, and then a saturated aqueous NH4Cl (10 mL) was added. The resultant mixture was extracted with EtOAc (15 mL × 3), and the combined organic extracts were washed with H2O (10 mL) a brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using Biotage Selekt (Biotage® Sfär HC Duo 25 g, Et2O in toluene 1–11% 14.5 CV, 11% 0.5 CV, 100% 5 CV) to afford 2 (281 mg, 518 μmol, 87%) as white amorphous solid.
IR (ATR) ν 3535, 2930, 2954, 2884, 2855, 1703, 1600, 1514, 1463, 1417, 1290, 1268, 1220, 1177, 1133, 1104, 1022 cm−1. 1H-NMR (400 MHz, CDCl3) δ −0.12 (3H, s), −0.02 (3H, s), 0.89 (9H, s), 1.21–1.31 (1H, m), 1.33 (3H, s), 1.53–1.69 (2H, m), 2.02 (1H, m), 2.12–2.26 (2H, m), 2.33–2.49 (3H, m), 2.62–2.80 (1H, m), 3.91 (3H, s), 3.93 (3H, s), 3.97 (1H, m), 4.98 (1H, dd, J = 10.9, 1.8 Hz), 5.06–5.16 (3H, m), 5.40 (1H, dd, J = 17.4, 1.8 Hz), 5.82 (1H, m), 5.89 (1H, m), 6.38 (1H, dd, J = 17.4, 10.9 Hz), 6.88 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 2.0 Hz), 7.70 (1H, dd, J = 8.5, 2.0 Hz). 13C-NMR (100 MHz, CDCl3) δ −5.3, −4.7, 14.1, 18.0, 22.6, 25.9, 28.5, 31.5, 39.5, 42.2, 42.6, 55.89, 55.94, 72.1, 72.8, 77.6, 110.0, 111.8, 113.9, 118.1, 122.5, 123.0, 123.7, 134.8, 136.3, 140.5, 148.4, 152.8, 166.2. HRMS (ESI) Calcd for C31H46O6SiNa 565.2956 [M + Na]+, Found 565.2958.
ABC-Ring 1Grubbs catalyst 2nd generation (3.0 mg, 3.5 μmol) was added to a solution of 2 (18.9 mg, 34.8 μmol) in toluene (0.87 mL) at room temperature. The reaction mixture was stirred at 60°C for 20 min, and then was concentrated. The residue was purified by PTLC (Et2O/toluene 1/6) to afford 1 (16.4 mg, 31.9 μmol, 92%) as a white amorphous solid.
IR (ATR) ν 3508, 2954, 2929, 2855, 1705, 1601, 1514, 1463, 1417, 1289, 1268, 1221, 1176, 1110, 1083, 1025, cm−1. 1H-NMR (400 MHz, CDCl3) δ: 0.05 (3H, s), 0.06 (3H, s), 0.79 (9H, s), 0.88 (3H, s), 1.64 (H, td, J = 14.0, 5.1 Hz), 1.71–1.79 (1H, m), 1.81–1.88 (1H, m), 2.15 (1H, dd, J = 10.8, 8.3 Hz), 2.29–2.45 (2H, m), 2.51 (1H, tdd, J = 14.1, 5.3, 2.5 Hz), 2.60 (1H, dd, J = 20.7, 3.2 Hz), 2.74 (1H, d, J = 17.8 Hz), 3.93 (3H, s), 3.94 (3H, s), 4.48 (1H, dd, J = 11.1, 3.1 Hz), 5.34–5.38 (1H, m), 5.55–5.59 (1H, m), 5.89–5.94 (1H, m), 6.12–6.16 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 1.9 Hz), 7.65 (1H, dd, J = 8.5, 1.9 Hz). 13C-NMR (100 MHz, CDCl3) δ −4.9, −4.2, 17.9, 23.9, 25.8, 27.9, 29.5, 30.3, 38.8, 42.2, 43.8, 55.89, 55.94, 71.4, 73.7, 81.9, 110.1, 112.0, 117.8, 123.3, 124.0, 130.0, 131.8, 146.9, 148.4, 152.5, 166.0. HRMS (ESI) Calcd for C29H42O6SiNa 537.2643 [M + Na]+, Found 537.2635.
This research was financially supported by the NOVARTIS Foundation (Japan) for the Promotion of Science, Grant-in-Aid for Scientific Research (B) (JSPS, 20H03366), Grant-in-Aid for Challenging Research (Pioneering) (JSPS, 22K18340) to D. U., Grant-in-Aid for Early-Career Scientists (JSPS, 20K15285), and Grant-in-Aid for Transformative Research Areas (A) Digitalization-driven Transformative Organic Synthesis (Digi-TOS) (MEXT, 22H05375, 24H01090/JP21A204) to K. F.
The authors declare no conflict of interest.
This article contains supplementary materials, “NMR spectra of all newly synthesized compounds.”
