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Synlett 2020; 31(03): 290-294
DOI: 10.1055/s-0039-1691559
DOI: 10.1055/s-0039-1691559
letter
Synthetic Studies on Bilobalide
This work was financially supported by the Japan Society for the Promotion of Science (JSPS KAKENHI Grant number JP17H01523) and by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from the Japan Agency for Medical Research and Development (AMED) under Grant Number JP19am0101099.Further Information
Publication History
Received: 24 November 2019
Accepted after revision: 12 December 2019
Publication Date:
10 January 2020 (online)
Abstract
We disclose our synthetic studies on bilobalide, which features a Diels–Alder reaction of a cyclic anhydride to form two contiguous quaternary carbon centers, desymmetrization of a symmetric diol, and construction of a cyclic acetal under acidic conditions with inversion of configuration at an allylic position.
Key words
desymmetrization - Diels–Alder reaction - Mukaiyama hydration - quaternary carbon - tertiary alcoholSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1691559.
- Supporting Information
-
References and Notes
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- 13 3a,7a-Bis((benzyloxy)methyl)-3-(tert-butyl)-3a,4,7,7a-tetrahydro-1H-inden-1-ol (18a and 18b): To a solution of enone 16 (23 mg, 0.061 mmol) in THF (1.0 mL) was added tert-butyllithium (1.53 M solution in hexane, 0.048 mL, 0.073 mmol) at –78 °C, and the mixture was stirred for 15 min. The reaction was then quenched with water, and the resulting mixture was extracted three times with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residual oil containing 17 was used for the next step without further purification. To a stirred solution of the above crude material in toluene (1.0 mL) was added 2,3,4,5-tetrafluorophenylboronic acid (2 mg, 0.01 mmol) at room temperature. The mixture was heated at 50 °C with stirring for 2 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (EtOAc–hexane = 1:3) to give a 2:1 mixture of 18a and 18b (18 mg, 0.042 mmol, 68%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.35–7.23 (m, 10 H), 5.75 (d, J = 2.8 Hz, (1/3)1 H), 5.73 (m, (2/3)1 H), 5.68–5.60 (m, (1/3)2 H+(2/3)1 H), 5.57 (d, J = 1.6 Hz, (2/3)1 H), 4.98 (d, J = 1.6 Hz, (2/3)1 H), 4.52–4.28 (m, (1/3)4 H+(2/3)4 H), 4.03 (d, J = 11.2 Hz, (1/3)1 H), 3.81–3.75 (m, (1/3)1 H+(2/3)1 H), 3.53–3.47 (m, (1/3)2 H+(2/3)1 H), 3.38–3.25 (m, (1/3)2H + (2/3)2H), 2.48–2.14 (m, (1/3)2 H+(2/3)4 H), 2.03 (d, J = 18.0 Hz, (1/3)1 H), 1.76 (d, J = 18.8 Hz, (1/3)1 H), 1.10 (s, (1/3)9 H), 1.09 (s, (2/3)9 H). 13C NMR (100 MHz, CDCl3): δ = 157.4, 156.7 (C), 139.0, 138.5 (C), 138.4, 136.8 (C), 128.5 (CH), 128.4 (CH), 128.2 (CH), 128.2 (CH), 128.2 (CH), 128.0 (CH), 127.6 (CH), 127.4 (CH), 127.4 (CH), 127.3 (CH), 126.3, 125.7 (CH), 124.7, 123.5 (CH), 81.0, 80.3 (CH), 74.1 (CH2), 73.5 (CH2), 73.5 (CH2), 73.3 (CH2), 73.0 (CH2), 72.8 (CH2), 72.7 (CH2), 72.6 (CH2), 54.6, 53.9 (C), 52.3, 48.4 (C), 34.5, 34.3 (C), 34.1 (CH2), 30.8, 30.8 (CH3), 29.4 (CH2), 28.3 (CH2), 25.7 (CH2). HRMS (ESI+): m/z calcd for C29H36NaO3: 455.2562; found: 455.2549
- 14 3a,4-Bis((benzyloxy)methyl)-5-(tert-butyl)-4-(2,2-dimethoxyethyl)-2-methoxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan (21a and 21b): To a stirred solution of allyl alcohol 18a and 18b (mixture of diastereomers, 4 mg, 0.01 mmol) in dichloromethane (1.0 mL) was added a solution of ozone in dichloromethane at −78 °C. The reaction was quenched with triphenylphosphine (6 mg, 0.02 mmol) and removal of the solvent under reduced pressure gave a crude material containing 19 and 20, which was used in the next step without further purification. To a solution of the crude material in MeOH (1.0 mL) was added concentrated sulfuric acid (0.004 mL, 0.08 mmol) at room temperature. After stirring for 30 min, the reaction was then quenched with solid NaHCO3 and the mixture was concentrated in vacuo. To the residue was added water, and the mixture was extracted three times with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc–hexane, 1:6) to give a 3:2 mixture of 21a and 21b (3 mg, 0.006 mmol, 57%) as a colorless oil. Compound 21a (major isomer): 1H NMR (400 MHz, CDCl3): δ = 7.35–7.20 (m, 10 H), 5.56 (d, J = 1.6 Hz, 1 H), 4.98 (d, J = 7.6 Hz, 1 H), 4.94 (d, J = 5.6 Hz, 1 H), 4.59 (d, J = 1.6 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.34 (d, J = 12.0 Hz, 1 H), 4.29 (d, J = 12.0 Hz, 1 H), 4.16 (d, J = 12.0 Hz, 1 H), 3.73 (d, J = 9.6 Hz, 1 H), 3.65 (d, J = 10.4 Hz, 1 H), 3.64 (d, J = 9.6 Hz, 1 H), 3.48 (d, J = 10.4 Hz, 1 H), 3.29 (s, 3 H), 3.19 (s, 3 H), 3.14 (s, 3 H), 2.34 (d, J = 12.8 Hz, 1 H), 2.18 (dd, J = 14.8, 7.6 Hz, 1 H), 2.02 (dd, J = 12.8, 5.6 Hz, 1 H), 1.80 (d, J = 14.8 Hz, 1 H), 1.15 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 153.5 (C), 138.7 (C), 138.3 (C), 128.4 (CH), 128.2 (CH), 128.1 (CH), 127.6 (CH), 127.5 (CH), 127.2 (CH), 126.6 (CH), 105.5 (CH), 103.4 (CH), 90.1 (CH), 73.4 (CH2), 72.0 (CH2), 71.9 (CH2), 71.6 (CH2), 59.3 (C), 58.6 (C), 54.7 (CH3), 53.6 (CH3), 52.4 (CH3), 39.0 (CH2), 37.6 (CH2), 34.6 (C), 31.3 (CH3). HRMS (ESI+): m/z calcd for C32H44NaO6: 547.3036; found: 547.3021. Compound 21b (minor isomer): 1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (m, 10 H), 5.68 (d, J = 2.0 Hz, 1 H), 5.06 (dd, J = 5.6, 5.2 Hz, 1 H), 4.74 (d, J = 7.6 Hz, 1 H), 4.60 (d, J = 2.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 4.36 (d, J = 12.8 Hz, 1 H), 4.33 (d, J = 12.8 Hz, 1 H), 4.22 (d, J = 12.0 Hz, 1 H), 3.62 (d, J = 10.0 Hz, 1 H), 3.57 (d, J = 9.6 Hz, 1 H), 3.45 (d, J = 10.0 Hz, 1 H), 3.34 (s, 3 H), 3.31 (d, J = 9.6 Hz, 1 H), 3.20 (s, 3 H), 3.12 (s, 3 H), 2.39 (dd, J = 13.2, 5.6 Hz, 1 H), 2.16 (dd, J = 14.8, 7.6 Hz, 1 H), 2.00 (dd, J = 13.2, 5.2 Hz, 1 H), 1.95 (d, J = 14.8 Hz, 1 H), 1.15 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 152.1 (C), 138.7 (C), 138.2 (C), 128.7 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 127.7 (CH), 127.5 (CH), 127.2 (CH), 106.5 (CH), 103.1 (CH), 89.9 (CH), 73.4 (CH2), 72.7 (CH2), 72.2 (CH2), 72.2 (CH2), 59.8 (C), 58.5 (C), 55.2 (CH3), 53.4 (CH3), 52.2 (CH3), 39.2 (CH2), 39.0 (CH2), 34.5 (C), 31.3 (CH3). HRMS (ESI+): m/z calcd for C32H44NaO6: 547.3036; found: 547.3038
- 15 Oxidative rearrangement of 17 with PCC, followed by reduction of the resulting enone 26 with DIBAL-H, afforded one of the isomers of alcohol 18b (Scheme 4), ozonolysis of which furnished 20. Acetal formation from 20 under the same conditions afforded 21a and 21b in 60% yield. For details, see ref. 16.
- 16 3a,7a-Bis((benzyloxy)methyl)-3-(tert-butyl)-3a,4,7,7a-tetrahydro-1H-inden-1-ol (18b): Enone 16 (30 mg, 0.081 mmol) was converted into 17 according to the procedure described in ref 13. The crude material 17 was dissolved in dichloromethane (5.0 mL), and Celite (64 mg) and pyridinium chlorochromate (33 mg, 0.16 mmol) were added to the resulting solution at room temperature. After stirring for 30 minutes, the solution was filtered through a pad of silica gel and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EtOAc–hexane, 1:3) to give enone 26 (30 mg, 0.069 mmol, 86%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.30–7.21 (m, 10 H), 6.07 (s, 1 H), 5.80–5.75 (m, 1 H), 5.73–5.65 (m, 1 H), 4.34 (d, J = 12.0 Hz, 1 H), 4.29 (d, J = 12.0 Hz, 1 H), 4.28 (s, 2 H), 3.93 (d, J = 9.2 Hz, 1 H), 3.75 (d, J = 9.2 Hz, 1 H), 3.73 (d, J = 9.6 Hz 1 H), 3.59 (d, J = 9.6 Hz, 1 H), 2.47–2.36 (m, 2 H), 2.25–2.20 (m, 2 H), 1.22 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 210.0 (C), 189.5 (C), 138.3 (C), 138.0 (C), 131.2 (CH), 128.2 (CH), 127.6 (CH), 127.4 (CH), 125.4 (C), 73.3 (CH2), 73.1 (CH2), 72.6 (CH2), 72.3 (CH2), 57.2 (C), 56.8 (C), 36.8 (C), 31.1 (CH3), 30.6 (CH2), 30.4 (CH2). Three CH peaks of phenyl groups were not observed, perhaps due to overlapping. To a solution of enone 26 (30 mg, 0.069 mmol) in dichloromethane (1.2 mL) was added diisobutylaluminium hydride (1.0 M solution in hexane, 0.14 mL, 0.14 mmol) at –78 °C, and the mixture was stirred for 15 min. The reaction was then quenched with saturated aqueous potassium sodium tartrate. The mixture was extracted three times with dichloromethane. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc–hexane, 1:3) to give 18b (29 mg, 0.067 mmol, 97%) as a single diastereomer and as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.23 (m, 10 H), 5.76 (d, J = 2.4 Hz, 1 H), 5.67–5.57 (m, 2 H), 4.52 (d, J = 12.4 Hz, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 4.33 (d, J = 12.4 Hz, 1 H), 4.30 (d, J = 11.6 Hz, 1 H), 4.03 (d, J = 11.6 Hz, 1 H), 3.79 (dd, J = 11.6, 2.4 Hz, 1 H), 3.52 (d, J = 9.2 Hz, 1 H), 3.48 (d, J = 9.2 Hz, 1 H), 3.31 (d, J = 10.4 Hz, 1 H), 3.26 (d, J = 10.4 Hz, 1 H), 2.44 (d, J = 18.0 Hz, 1 H), 2.38 (d, J = 18.8 Hz, 1 H), 2.03 (d, J = 18.0 Hz, 1 H), 1.76 (d, J = 18.8 Hz, 1 H), 1.10 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 157.4 (C), 139.0 (C), 136.8 (C), 138.0 (C), 128.4 (CH), 128.2 (CH), 128.2 (CH), 128.0 (CH), 127.5 (CH), 127.2 (CH), 126.3 (CH), 123.5 (CH), 80.3 (CH), 73.3 (CH2), 73.0 (CH2), 72.8 (CH2), 72.6 (CH2), 54.0 (C), 48.4 (C), 34.5 (C), 34.1 (CH2), 30.8 (CH3), 29.4 (CH2); one CH peak of a phenyl group was not observed, perhaps due to overlapping. HRMS (ESI+): m/z calcd for C29H36NaO3: 455.2562; found: 455.2560.
- 17 NMR data for one of the epimers are available in the literature of the Corey’s synthesis.
- 18 (5-(tert-Butyl)-4-(2,2-dimethoxyethyl)-2-methoxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3a,4-diyl)dimethanol (22b): A mixture of 21b (3 mg, 0.005 mmol) and 10% Pd/C (56 mg, 0.053 mmol) in THF (0.5 mL) was stirred for 6 h at room temperature under H2 (1 atm), before the mixture was filtered though a pad of Celite. The filtrate was concentrated to afford a crude material, which was purified by preparative TLC (EtOAc) to give 22b (1 mg, 0.003 mmol, 65%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 5.82 (d, J = 2.0 Hz, 1 H), 5.09 (dd, J = 6.0, 4.4 Hz, 1 H), 4.88 (d, J = 2.0 Hz, 1 H), 4.69 (dd, J = 6.8, 3.6 Hz, 1 H), 3.99 (dd, J = 12.0, 6.8 Hz, 1 H), 3.76 (dd, J = 11.6, 4.4 Hz, 1 H), 3.68 (dd, J = 11.6, 7.2 Hz, 1 H), 3.46 (dd, J = 12.0, 6.0 Hz, 1 H), 3.34 (s, 9 H), 3.30 (m, 1 H), 2.91 (m, 1 H), 2.23–2.17 (m, 3 H), 1.97 (dd, J = 14.0, 4.4 Hz, 1 H), 1.19 (s, 9 H), 13C NMR (100 MHz, CDCl3): δ = 130.5 (CH), 105.9 (CH), 102.4 (CH), 86.9 (CH), 65.6 (CH2), 65.1 (CH2), 61.9 (C), 60.1 (C), 55.3 (CH3), 53.1 (CH3), 52.6 (CH3), 40.4 (CH2), 38.2 (CH2), 34.6 (C), 31.4 (CH3). HRMS (ESI+): m/z calcd for C18H32NaO6: 367.2097; found: 367.2101.
- 19 The isomers 21a and 21b showed different reactivity in the Mukaiyama hydration. The reaction of the major isomer 21a proceeded sluggishly under the same conditions to produce the corresponding tertiary alcohol in 16% yield even after 5 h.
- 20a Isayama S, Mukaiyama T. Chem. Lett. 1989; 18: 1071
- 20b Obradors C, Martinez RM, Shenvi RA. J. Am. Chem. Soc. 2016; 138: 4962
- 21 3a,4-Bis((benzyloxy)methyl)-5-(tert-butyl)-4-(2,2-dimethoxyethyl)-2-methoxyhexahydro-2H-cyclopenta[b]furan-5-ol (23): A solution of 21b (6 mg, 0.01 mmol), Mn(dpm)3 (7 mg, 0.01 mmol) and triphenylphosphine (4 mg, 0.02 mmol) in cyclohexane (0.5 mL) was prepared in a test tube, which was charged with O2. To this mixture was added monoisopropoxy(phenyl)silane (6 μL, 0.03 mmol), and the resulting mixture was stirred at room temperature for 20 min before it was concentrated in vacuo. The residue was purified by preparative TLC (EtOAc–hexane, 1:3) to give 23 (4 mg, 0.008 mmol, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.18 (m, 10 H), 5.13 (dd, J = 6.4, 2.8 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.44 (dd, J = 8.8, 1.6 Hz, 1 H), 4.41 (d, J = 9.2 Hz, 1 H), 4.35 (d, J = 12.0 Hz), 4.28 (d, J = 11.6, 1 H), 4.26 (s, 1 H), 4.06 (d, J = 11.6 Hz, 1 H), 3.58 (d, J = 10.8, 1 H), 3.43 (d, J = 10.8 Hz, 1 H), 3.40 (s, 3 H), 3.37 (s, 2 H), 3.22 (s, 3 H), 3.11 (s, 3 H), 2.80 (dd, J = 15.2, 9.2 Hz, 1 H), 2.65 (dd, J = 15.6, 1.6 Hz, 1 H), 2.60 (dd, J = 13.6, 2.8 Hz, 1 H), 2.47 (dd, J = 13.6, 6.4 Hz, 1 H), 1.84 (dd, J = 15.6, 8.8 Hz, 1 H), 1.60 (d, J = 15.2 Hz, 1 H), 1.01 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 138.4 (C), 137.8 (C), 128.3 (CH), 128.3 (CH), 127.8 (CH), 127.6 (CH), 127.5 (CH), 127.5 (CH), 107.9 (CH), 103.7 (CH), 88.9 (C), 88.2 (CH), 74.5 (CH2), 73.4 (CH2), 72.3 (CH2), 71.9 (CH2), 59.5 (C), 58.4 (C), 55.1 (CH3), 53.1 (CH3), 51.9 (CH3), 43.6 (CH2), 40.8 (CH2), 39.8 (C), 35.7 (CH2), 28.3 (CH3). HRMS (ESI+): m/z calcd for C32H46NaO7: 565.3141; found: 565.3158.
- 22 3a-(tert-Butyl)-2,6,8-trimethoxyoctahydro-1H-cyclopenta[1,2-b:4,3-b′:2,3-c′′]trifuran (25): To a stirred solution of dimethyl sulfoxide (19 μL, 0.27 mmol) in dichloromethane (0.5 mL) was added dropwise oxalyl chloride (16 μL, 0.18 mmol) at –78 °C. After stirring for 10 min at –78 °C, to the mixture was added dropwise a solution of triol 24 (1 mg, 0.003 mmol) in dichloromethane (0.5 mL), and the resulting mixture was stirred for another 40 min at –78 °C. To the mixture was added triethylamine (62 μL, 0.45 mmol) before it was allowed to warm to room temperature. After stirring for another 20 min at room temperature, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc–hexane = 1:3) to give 25 (1 mg, 0.003 mmol, 97%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 5.12 (dd, J = 6.4, 6.0 Hz, 1 H), 5.06 (dd, J = 6.4, 4.8 Hz, 1 H), 4.65 (s, 1 H), 4.53 (d, J = 10.0 Hz, 1 H), 4.16 (dd, J = 7.2, 5.6 Hz, 1 H), 3.64 (d, J =10.0 Hz, 1 H), 3.43 (s, 3 H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.62 (dd, J = 15.2, 6.4 Hz, 1 H), 2.39 (dd J = 14.4, 6.0 Hz, 1 H), 2.35 (dd, J = 14.8, 7.2, 1 H), 2.16 (dd, J = 14.8, 5.6 Hz, 1 H), 1.94 (dd, J = 15.2, 4.8 Hz, 1 H), 1.85 (dd, J = 14.4, 6.4 Hz, 1 H), 1.08 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 108.8 (CH), 107.3 (CH), 103.6 (CH), 100.8 (C), 87.4 (CH), 70.3 (CH2), 68.8 (C), 63.2 (C), 56.2 (CH3), 56.1 (CH3), 54.7 (CH3), 43.1 (CH2), 41.3 (CH2), 37.8 (C), 35.8 (CH2), 27.2 (CH3; detected as a cross peak in the HMQC spectrum). HRMS (ESI+): m/z calcd for C18H30NaO6: 365.1940; found: 365.1940.