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Total synthesis of atorvastatin via a late-stage, regioselective 1,3-dipolar münchnone cycloaddition
Tetrahedron Letters 56 (2015) 3208–3211
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of atorvastatin via a late-stage, regioselective 1,3-dipolar münchnone cycloaddition Justin M. Lopchuk, Gordon W. Gribble ⇑ Department of Chemistry, Dartmouth College, Hanover, NH 03755-3564, USA
a r t i c l e
i n f o
Article history: Received 25 November 2014 Revised 15 December 2014 Accepted 17 December 2014 Available online 26 December 2014
a b s t r a c t Atorvastatin was prepared in seven steps from commercially available 4-fluorophenylacetic acid. The key 1,3-dipolar cycloaddition was conducted regioselectively using a complex münchnone which was prepared in five steps on decagram scale. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Münchnone 1,3-Dipolar cycloaddition Atorvastatin Pyrrole Mesoionic
First described by Huisgen in 1964,1 münchnones (1,3-oxazolium-5-olates) are five-membered mesoionic heterocycles which undergo facile 1,3-dipolar cycloadditions with various types of unsaturated compounds to yield a diverse array of heterocyclic scaffolds.2 In particular, when alkynes or electron-deficient alkenes are engaged as the dipolarophile, highly substituted pyrroles are furnished as the products. Due in part to the ubiquity and sustained interest in nitrogen-containing heterocycles, münchnones have seen a renaissance in the literature.3 Recent reports have described new syntheses of pyrrole4 and isoindole5 systems, palladium-,6 gold-,7 and silver-catalyzed8 münchnone reactions, and the use of the recently discovered phospha-munchnones.9
As one of the top selling pharmaceuticals in history, atorvastatin (1) has been the subject of many synthetic studies to improve its preparation, particularly the pyrrole core and pendant chiral diol (Fig. 1) (see Scheme 1 for our retrosynthesis).10
Figure 1. Atorvastatin and previously explored model systems.
⇑ Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946. E-mail address: [email protected] (G.W. Gribble). http://dx.doi.org/10.1016/j.tetlet.2014.12.104 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Scheme 1. Retrosynthetic plan to atorvastatin.
J. M. Lopchuk, G.W. Gribble / Tetrahedron Letters 56 (2015) 3208–3211 Table 1 Model study15–19
Entry
Münchnone
Dipolarophile
Product ratio (15:16)
Yield (%)
1 2 3 4 5 6
11 12 11 12 11 12
13 13 7 7 14 14
4:96 97:3 17:83 98:2 8:92 52:48
83 79 78 91 81 90
DIPC = N,N0 -diisopropylcarbodiimide.
Table 2 Solvent study13
Entry
Solvent
1 2 3 4 5 6
THF DMF MeCN Toluene Nitrobenzene DMSO
Reaction with Münchnone 11
Reaction with Münchnone 12
Ratio (18:19)
Yield (%)
Ratio (18:19)
Yield (%)
92:8 83:17 92:8 93:7 78:22 79:21
94 72 69 79 68 73
14:86 9:91 9:91 11:89 12:88 1:>99
81 64 76 67 58 51
The pyrrole core of atorvastatin has been successfully prepared by a variety of methods, including the Paal–Knorr cyclization, the reductive cyclization of azides, and 1,3-dipolar cycloadditions. A number of attempts to utilize münchnones in the construction of the pyrrole have been reported; however, the cycloadditions were generally plagued by poor regioselectivity or low yields (Fig. 1, 2–5).11
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Following up on our recent interest in the regioselectivity of münchnone cycloadditions,12 we sought to apply these concepts to effect a late-stage 1,3-dipolar cycloaddition with complex münchnone 8. Since we have routinely prepared our münchnone precursors on decagram scale,13 we envisioned conducting the 1,3-dipolar cycloaddition as the penultimate step followed by a known deprotection to furnish atorvastatin (see Scheme 1).14 We began with a model system using münchnones 11 and 12 with dipolarophiles 7, 13, and 14 (Table 1). The cycloadditions of the dipolarophiles (Table 1, entries 1, 3, and 5) with münchnone 11 (2-phenyl-4-methyl substituted) gave pyrroles 15a and 15b in good yield and high regioselectivity. This is in good agreement with a similar system reported by Pandey, but delivers the opposite regiochemistry compared to atorvastatin.11c However, when isomeric münchnone 12 (2-methyl-4-phenyl substituted) was used with alkynes 7 and 13, good yields and excellent regiochemistry were obtained which matched the desired functionalization pattern for atorvastatin. Interestingly, when nitro-substituted alkene 14 was employed as the dipolarophile, the cycloaddition was unselective. Although 1,3-dipolar cycloadditions are not always influenced by the choice of solvent,20 we conducted a solvent screen to see if any of the regioselectivities might be improved. Interestingly, the use of more dipolar solvents (e.g., DMF, DMSO) noticeably improved the regioselectivity of münchnone 12 while degrading the regioselectivity of münchnone 11 (Table 2). With these results in hand, we turned our attention to the preparation of atorvastatin (Scheme 2). Esterification and bromination of commercially available 4-fluorophenylacetic acid delivered abromo ester 9 in 95% yield over two steps.21 Condensation with chiral amine 1022 followed by acylation with isobutyryl chloride gave amide 21 in 76% yield over two steps.23,24 Selective hydrolysis of the methyl ester furnished münchnone precursor 22 in 93% yield (decagram scale, only one column purification) to set up the key cycloaddition.25 As suggested by our model study, the reaction of alkyne 7 with münchnone 8 (cyclized 22 with DIPC in situ) afforded known protected atorvastatin 6 as a single observable isomer in 91% yield.26 Deprotection with HCl and NaOH gave atorvastatin in 89% yield which matched the literature data (Scheme 2).27 In conclusion, we have prepared atorvastatin via a late-stage, regioselective 1,3-dipolar cycloaddition using complex münchnone 8 in seven steps from commercially available 4-fluorophenylacetic acid (20). Münchnone precursor 22 was prepared on decagram scale in five steps with only one chromatographic
Scheme 2. Synthesis of atorvastatin.
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J. M. Lopchuk, G.W. Gribble / Tetrahedron Letters 56 (2015) 3208–3211
purification. Despite being known for more than 50 years, münchnones and other mesoionics continue to find new uses in synthesis; other application of münchnones to natural and non-natural targets are underway in our laboratory and will be reported in due course. Acknowledgments J.M.L. acknowledges support from the Department of Education GAANN fellowship. G.W.G. acknowledges support from the Donors of the Petroleum Research Fund, administered by the American Chemical Society, and by Wyeth. References and notes 1. Huisgen, R.; Gotthardt, H.; Bayer, H. O. Angew. Chem., Int. Ed. Engl. 1964, 3, 136. 2. (a) Potts, K. T. Mesoionic Ring Systems In 1,3-Dipolar Cyclo-addition Chemistry; Padwa, A., Ed.; Wiley: NY, 1984; vol. 2, p 1; (b) Gribble, G. W. Mesoionic Ring Systems In The Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: Hoboken, NJ, 2002; vol. 59, p 681; (c) Gribble, G. W. Mesoionic Oxazoles In The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy; Taylor, E. C., Wipf, P., Eds.; John Wiley & Sons: Hoboken, NJ, 2003; vol. 60, p 473. Part A. 3. Reissig, H.-U.; Zimmer, R. Angew. Chem., Int. Ed. 2014, 53, 9708. 4. (a) Lopchuk, J. M.; Gribble, G. W. Heterocycles 2011, 82, 1617; (b) Lopchuk, J. M.; Gribble, G. W. Tetrahedron Lett. 2011, 52, 4106. 5. (a) Lopchuk, J. M.; Gribble, G. W. Tetrahedron Lett. 2014, 55, 2809; (b) Fang, Y.; Larock, R. C.; Shi, F. Asian J. Org. Chem. 2014, 3, 55. 6. (a) Lu, Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430; (b) Worrall, K.; Xu, B.; Bontemps, S.; Arndtsen, B. A. J. Org. Chem. 2011, 76, 170; (c) Quesnel, J. S.; Arndtsen, B. A. Pure Appl. Chem. 2013, 85, 377. 7. Melhado, A. D.; Amarante, G. W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 3517. 8. (a) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776; (b) For a related silicon-catalyzed method, see: Peddibhotla, S.; Tepe, J. J. Synthesis 2003, 1433. 9. St-Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366. 10. (a) Harrington, P. J. Lipitor (Atorvastatin Calcium), Chapter 9. In Pharmaceutical Process Chemistry for Synthesis: Rethinking the Routes to Scale-Up; Wiley & Sons: New York, 2011; pp 294–359; (b) For a recent approach to the chiral diol, see: Kawato, Y.; Chaudhary, S.; Kumagai, N.; Shibasaki, M. Chem. Eur. J. 2013, 19, 3802. 11. (a) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. J. Med. Chem. 1991, 34, 357; (b) Park, W. K. C.; Kennedy, R. M.; Larsen, S. D.; Miller, S.; Roth, B. D.; Song, Y.; Steinbaugh, B. A.; Sun, K.; Tait, B. D.; Kowala, M. C.; Trivedi, B. K.; Auerbach, B.; Askew, V.; Dillon, L.; Hanselman, J. C.; Lin, Z.; Lu, G. H.; Robertson, A.; Sekerke, C. Bioorg. Med. Chem. Lett. 2008, 18, 1151; (c) Pandey, P. S.; Rao, T. S. Bioorg. Med. Chem. Lett. 2004, 14, 129. 12. (a) Lopchuk, J. M.; Hughes, R. P.; Gribble, G. W. Org. Lett. 2013, 15, 5218; (b) For a related study, see: Morin, M. S. T.; St-Cyr, D. J.; Arndtsen, B. A.; Krenske, E. H.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 17349. 13. For the detailed preparation of münchnones 11 and 12, including their reaction with b-nitrostyrene and related systems, see Ref. 12a. 14. For a review of methods of deprotection leading to atorvastatin, see Ref. 10a. For the method used in this work, see Ref. 27b. 15. General experimental procedure for the preparation of pyrroles 15a/b and 16a/ b. See Ref. 12a for detailed preparation of the münchnone precursors and cycloadditions: a round bottom flask was charged with münchnone precursor (3 equiv), dipolarophile (1 equiv), and dry THF. The reaction was placed under nitrogen and DIPC (3 equiv) added at room temperature. The mixture was heated to reflux for 24 h or until complete consumption of the dipolarophile was observed by TLC. The reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was directly purified by flash chromatography to afford the desired pyrrole. 16. Methyl 1-benzyl-2-methyl-4,5-diphenyl-1H-pyrrole-3-carboxylate (15a): 1H NMR (500 MHz, CDCl3) d 7.35–7.26 (m, 3H), 7.22–7.15 (m, 8H), 7.09–7.07 (m, 2H), 6.96 (dt, 2H, J = 7.3, 2.4 Hz), 5.08 (s, 2H), 3.65 (s, 3H), 2.52 (s, 3H); 13C NMR (125 MHz, CDCl3) d 166.2, 137.4, 135.8, 135.6, 131.9, 131.4, 131.0, 130.5, 128.6, 127.9, 127.4, 127.1, 126.9, 125.5, 125.5, 123.8, 111.3, 50.6, 48.0, 10.8; HRMS (ESI+) calcd for C26H24NO2 (MH+) 382.1807, found 382.1805. 17. Methyl 1-benzyl-5-methyl-2,4-diphenyl-1H-pyrrole-3-carboxylate (15b): 1H NMR (500 MHz, CDCl3) d 7.41–7.25 (m, 13H), 6.93–6.91 (m, 2H), 4.99 (s, 2H), 3.42 (s, 3H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3) d 165.7, 138.3, 137.8, 136.0, 132.3, 131.3, 130.7, 130.5, 128.8, 128.3, 128.0, 127.6, 127.3, 126.2, 125.7, 123.4, 112.2, 50.4, 47.7, 11.8; HRMS (ESI+) calcd for C26H24NO2 (MH+) 382.1807, found 382.1794. The structure was confirmed by X-ray crystallography.28 18. 1-Benzyl-2-methyl-N,4,5-triphenyl-1H-pyrrole-3-carboxamide (16a): 1H NMR (500 MHz, CDCl3) d 7.36–7.08 (m, 19H), 7.00–6.95 (m, 2H), 5.08 (s, 2H), 2.61 (s, 3H); 13C NMR (125 MHz, CDCl3) d 164.4, 138.8, 138.7, 135.7, 135.1, 131.9,
19.
20.
21. 22. 23.
24.
25.
26.
131.6, 131.6, 131.3, 129.1, 129.0, 128.9, 128.4, 128.0, 127.6, 127.5, 125.9, 123.6, 121.2, 120.3, 115.1, 48.1, 12.2; HRMS (ESI+) calcd for C31H27N2O (MH+) 443.2123, found 443.2119. 1-Benzyl-5-methyl-N,2,4-triphenyl-1H-pyrrole-3-carboxamide (16b): 1H NMR (500 MHz, CDCl3) d 7.47–7.44 (m, 4H), 7.41–7.37 (m, 6H), 7.33–7.23 (m, 5H), 7.13–6.97 (m, 6H), 5.01 (s, 2H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) d 163.0, 138.6, 137.9, 135.4, 136.3, 132.1, 131.4, 131.2, 130.9, 128.9, 128.8, 128.7, 128.6, 128.5, 127.5, 127.3, 125.8, 123.2, 120.1, 119.3, 116.4, 48.0, 10.8; HRMS (ESI+) calcd for C31H27N2O (MH+) 443.2123, found 443.2123. Kanemasa, S. Effect of External Reagents In The Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley: Hoboken, NJ, 2002; Vol. 59, p 755. Sweeney, J. B.; Tavassoli, A.; Carter, N. B.; Hayes, J. F. Tetrahedron 2002, 58, 10113. Chiral amine 10 was purchased from Accela ChemBio, Inc. and used as received without further purification. Methyl 2-((2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2 dimethyl-1,3-dioxan-4yl)ethyl)amino)-2-(4-fluorophenyl)acetate as a mixture of two diastereomers (23): A solution of 9 (7.58 g, 30.7 mmol) in MeCN (100 mL) was added to a round bottom flask charged with amine 10 (9.7 g, 35.5 mmol) and MeCN (50 mL). Triethylamine (6.77 mL, 48.5 mmol) was added to the reaction dropwise and the mixture stirred at room temperature overnight. After the reaction was concentrated in vacuo, the residual oil was dissolved in ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 37 as a thick, pale orange oil (14 g with residual ethyl acetate, quant.). 1H NMR (300 MHz, CDCl3) d 7.34 (t, 2H, J = 7.1 Hz), 7.05–6.99 (m, 2H), 4.34 (s, 1H, first diastereomer), 4.32 (s, 1H, second diastereomer), 4.28–4.18 (m, 1H), 4.02–3.88 (m, 1H), 3.69 (s, 3H), 2.69– 2.51 (m, 2H), 2.42 (dd, 1H, J = 15.1, 7.1 Hz), 2.27 (dd, 1H, J = 15.2, 6.1 Hz), 1.72– 1.61 (m, 3H), 1.43 (s, 9H), 1.36 (s, 3H), 1.34 (s, 3H), 1.20–1.09 (m, 1H); HRMS (ESI+) calcd for C23H35NO6F (MH+) 440.2448, found 440.2441. Methyl 2-(N-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan4-yl)ethyl)isobutyramido)-2-(4-fluorophenyl)acetate as a mixture of two diastereomers (21): A solution of 23 (13.5 g, 30.7 mmol) in CH2Cl2 (100 mL) was cooled in an ice bath and treated with an ice cold solution of isobutyryl chloride (3.65 mL, 34.9 mmol) in CH2Cl2 (50 mL). After stirring for 10 min, the mixture was treated with triethylamine (8.9 mL, 63.6 mmol) in CH2Cl2 (20 mL) dropwise. The reaction was stirred at 0 °C for 1 h then warmed to room temperature and stirred a further 6 h. The solution was diluted with CH2Cl2 (200 mL) and poured into 1 M HCl (150 mL). The layers were quickly separated. The organic layer was washed with satd sodium bicarbonate, water, and brine. The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude 21 as a thick, orange oil. The product was purified by flash chromatography (silica gel, 10–50% ethyl acetate in hexanes) to afford 21 as a pale yellow oil (11.9 g, 76%, over two steps). 1H NMR (300 MHz, CDCl3) d 7.29–7.24 (m, 2H), 7.04 (td, 2H, J = 10.7, 2.0 Hz), 5.80 (s, 1H, first diastereomer), 5.79 (s, 1H, second diastereomer), 4.19–4.08 (m, 1H), 3.73 (s, 3H), 3.67–3.57 (m, 1H), 3.53–3.42 (m, 1H, first diastereomer), 3.39–3.30 (m, 1H), 3.26–2.14 (m, 1H, second diastereomer), 2.92–2.82 (m, 1H), 2.42–2.33 (m, 1H), 2.27–2.18 (m, 1H), 1.71–1.48 (m, 3H), 1.43 (s, 9H), 1.35 (s, 3H), 1.30 (d, 3H, J = 3.4 Hz), 1.16 (d, 6H, J = 6.9 Hz), 1.08–0.92 (m, 1H); 13C NMR (75 MHz, CDCl3) d (for one diastereomer only) 178.5, 171.1, 170.4, 162.9 (J = 247 Hz), 131.6 (J = 6.0 Hz), 131.0, 115.9 (J = 22 Hz), 98.9, 66.3, 66.1, 61.6, 52.6, 42.7, 42.5, 37.3, 36.8, 36.4, 30.7, 30.2, 28.3, 19.9, 19.8, 19.8; HRMS (ESI+) calcd for C28H41NO7F (MH+) 510.2867, found 510.2874. 2-(N-(2-((4R,6R)-6-(2-(tert-Butoxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4yl)ethyl)isobutyramido)-2-(4-fluorophenyl)acetic acid as a mixture of two diastereomers (22): A round bottom flask was charged with 21 (11.9 g, 23.3 mmol) and methanol (200 mL) and stirred at room temperature. A solution of 1 M LiOH (65 mL) was added and the reaction stirred for 4 h when TLC indicated complete consumption of starting material. The mixture was concentrated to remove the methanol and water was added (50 mL). 1 M HCl was added until the pH was <7 and copious amounts of precipitate formed. The mixture was quickly extracted with ethyl acetate (3 150 mL). The combined organic layers were washed with brine and dried over sodium sulfate, filtered, and concentrated in vacuo to afford 22 as a white foam (10.8 g, 93%). 1H NMR (300 MHz, CDCl3) d 7.34–7.30 (m, 2H), 7.07–7.03 (m, 2H), 5.55 (s, 1H, first diastereomer), 5.48 (s, 1H, second diastereomer), 4.21–4.13 (m, 1H), 3.76–3.68 (m, 1H), 3.59–3.48 (m, 1H), 3.38–3.32 (m, 1H, first diastereomer), 3.28–3.22 (m, 1H, second diastereomer), 2.92–2.85 (m, 1H), 2.41–2.36 (m, 1H), 2.28–2.22 (m, 1H), 1.69–1.62 (m, 1H, first diastereomer), 1.58–1.52 (m, 1H, second diastereomer), 1.43 (s, 9H), 1.37 (d, 3H, J = 4.4 Hz), 1.31 (s, 3H), 1.14 (d, 6H, J = 6.6 Hz), 1.08–1.00 (m, 1H); 13C NMR (75 MHz, CDCl3) d (for one diastereomer only) 179.5, 172.9, 170.4, 162.9 (J = 248 Hz), 131.2 (J = 7.8 Hz), 130.6, 116.2 (J = 22 Hz), 99.0, 66.3, 66.2, 63.4, 43.9, 42.7, 36.9, 36.4, 36.3, 30.9, 30.2, 28.3, 19.9, 19.7, 19.6; HRMS (ESI+) calcd for C26H39NO7F (MH+) 496.2711, found 496.2705. Protected atorvastatin, Tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,329 dioxan-4-yl)acetate (6): A round bottom flask was charged with münchnone precursor 22 (496 mg, 1.00 mmol), acetylene 7 (111 mg, 0.500 mmol), and dry THF (20 mL). The reaction was placed under nitrogen and DIPC (156 lL, 1 mmol) added at room temperature. The mixture was heated to reflux for 24 h. The reaction was cooled to room temperature and concentrated in vacuo.
J. M. Lopchuk, G.W. Gribble / Tetrahedron Letters 56 (2015) 3208–3211 The residue was directly purified by flash chromatography to afford 6 as a clear, colorless oil which solidified upon standing (298 mg, 91%). 1H NMR (300 MHz, CDCl3) d 7.18–7.14 (m, 9H), 7.07 (d, 2H, J = 8.0 Hz), 6.99–6.94 (m, 3H), 6.88 (s, 1H), 4.18–4.04 (m, 2H), 3.86–3.80 (m, 1H), 3.70–3.68 (m, 1H), 3.60–3.54 (m, 1H), 2.37 (dd, 1H, J = 15.3, 7.1 Hz), 2.23 (dd, 1H, J = 15.3, 6.1 Hz), 1.69–1.66 (m, 2H), 1.53 (d, 6H, J = 7.1 Hz), 1.43 (s, 9H), 1.36 (s, 3H), 1.29 (s, 3H), 1.09–1.01 (m, 1H); 13C NMR (75 MHz, CDCl3) d 170.4, 165.1, 163.5, 161.5, 141.7, 138.6, 134.9, 133.5, 133.4, 130.7, 129.0, 128.9, 128.6, 128.5, 128.5, 126.8, 123.7, 122.0, 119.8, 115.7, 115.6, 115.5, 98.9, 80.9, 66.6, 66.1, 42.7, 41.1, 38.3,
3211
36.2, 30.1, 28.3, 26.3, 22.0, 21.8, 19.9; HRMS (ESI+) calcd for C40H48N2O5F (MH+) 655.3547, found 655.3546. 27. (a) Chen, B.-C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Hangeland, J. J.; Ahmed, S. Z.; Jemal, M. J. Labelled Compd. Radiopharm. 2000, 43, 261; (b) Kawato, Y.; Iwata, M.; Yazaki, R.; Kumagi, N.; Shibasaki, M. Tetrahedron 2011, 67, 6539. 28. Lopchuk, J. M.; Gribble, G. W.; Jasinski, J. P. Acta. Crystallogr. 2014, E70, o338. 29. Gao, J.; Guo, Y. H.; Wang, Y. P.; Wang, X. J.; Xiang, W. S. Chin. Chem. Lett. 2011, 22, 1159.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of atorvastatin via a late-stage, regioselective 1,3-dipolar münchnone cycloaddition Justin M. Lopchuk, Gordon W. Gribble ⇑ Department of Chemistry, Dartmouth College, Hanover, NH 03755-3564, USA
a r t i c l e
i n f o
Article history: Received 25 November 2014 Revised 15 December 2014 Accepted 17 December 2014 Available online 26 December 2014
a b s t r a c t Atorvastatin was prepared in seven steps from commercially available 4-fluorophenylacetic acid. The key 1,3-dipolar cycloaddition was conducted regioselectively using a complex münchnone which was prepared in five steps on decagram scale. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Münchnone 1,3-Dipolar cycloaddition Atorvastatin Pyrrole Mesoionic
First described by Huisgen in 1964,1 münchnones (1,3-oxazolium-5-olates) are five-membered mesoionic heterocycles which undergo facile 1,3-dipolar cycloadditions with various types of unsaturated compounds to yield a diverse array of heterocyclic scaffolds.2 In particular, when alkynes or electron-deficient alkenes are engaged as the dipolarophile, highly substituted pyrroles are furnished as the products. Due in part to the ubiquity and sustained interest in nitrogen-containing heterocycles, münchnones have seen a renaissance in the literature.3 Recent reports have described new syntheses of pyrrole4 and isoindole5 systems, palladium-,6 gold-,7 and silver-catalyzed8 münchnone reactions, and the use of the recently discovered phospha-munchnones.9
As one of the top selling pharmaceuticals in history, atorvastatin (1) has been the subject of many synthetic studies to improve its preparation, particularly the pyrrole core and pendant chiral diol (Fig. 1) (see Scheme 1 for our retrosynthesis).10
Figure 1. Atorvastatin and previously explored model systems.
⇑ Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946. E-mail address: [email protected] (G.W. Gribble). http://dx.doi.org/10.1016/j.tetlet.2014.12.104 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Scheme 1. Retrosynthetic plan to atorvastatin.
J. M. Lopchuk, G.W. Gribble / Tetrahedron Letters 56 (2015) 3208–3211 Table 1 Model study15–19
Entry
Münchnone
Dipolarophile
Product ratio (15:16)
Yield (%)
1 2 3 4 5 6
11 12 11 12 11 12
13 13 7 7 14 14
4:96 97:3 17:83 98:2 8:92 52:48
83 79 78 91 81 90
DIPC = N,N0 -diisopropylcarbodiimide.
Table 2 Solvent study13
Entry
Solvent
1 2 3 4 5 6
THF DMF MeCN Toluene Nitrobenzene DMSO
Reaction with Münchnone 11
Reaction with Münchnone 12
Ratio (18:19)
Yield (%)
Ratio (18:19)
Yield (%)
92:8 83:17 92:8 93:7 78:22 79:21
94 72 69 79 68 73
14:86 9:91 9:91 11:89 12:88 1:>99
81 64 76 67 58 51
The pyrrole core of atorvastatin has been successfully prepared by a variety of methods, including the Paal–Knorr cyclization, the reductive cyclization of azides, and 1,3-dipolar cycloadditions. A number of attempts to utilize münchnones in the construction of the pyrrole have been reported; however, the cycloadditions were generally plagued by poor regioselectivity or low yields (Fig. 1, 2–5).11
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Following up on our recent interest in the regioselectivity of münchnone cycloadditions,12 we sought to apply these concepts to effect a late-stage 1,3-dipolar cycloaddition with complex münchnone 8. Since we have routinely prepared our münchnone precursors on decagram scale,13 we envisioned conducting the 1,3-dipolar cycloaddition as the penultimate step followed by a known deprotection to furnish atorvastatin (see Scheme 1).14 We began with a model system using münchnones 11 and 12 with dipolarophiles 7, 13, and 14 (Table 1). The cycloadditions of the dipolarophiles (Table 1, entries 1, 3, and 5) with münchnone 11 (2-phenyl-4-methyl substituted) gave pyrroles 15a and 15b in good yield and high regioselectivity. This is in good agreement with a similar system reported by Pandey, but delivers the opposite regiochemistry compared to atorvastatin.11c However, when isomeric münchnone 12 (2-methyl-4-phenyl substituted) was used with alkynes 7 and 13, good yields and excellent regiochemistry were obtained which matched the desired functionalization pattern for atorvastatin. Interestingly, when nitro-substituted alkene 14 was employed as the dipolarophile, the cycloaddition was unselective. Although 1,3-dipolar cycloadditions are not always influenced by the choice of solvent,20 we conducted a solvent screen to see if any of the regioselectivities might be improved. Interestingly, the use of more dipolar solvents (e.g., DMF, DMSO) noticeably improved the regioselectivity of münchnone 12 while degrading the regioselectivity of münchnone 11 (Table 2). With these results in hand, we turned our attention to the preparation of atorvastatin (Scheme 2). Esterification and bromination of commercially available 4-fluorophenylacetic acid delivered abromo ester 9 in 95% yield over two steps.21 Condensation with chiral amine 1022 followed by acylation with isobutyryl chloride gave amide 21 in 76% yield over two steps.23,24 Selective hydrolysis of the methyl ester furnished münchnone precursor 22 in 93% yield (decagram scale, only one column purification) to set up the key cycloaddition.25 As suggested by our model study, the reaction of alkyne 7 with münchnone 8 (cyclized 22 with DIPC in situ) afforded known protected atorvastatin 6 as a single observable isomer in 91% yield.26 Deprotection with HCl and NaOH gave atorvastatin in 89% yield which matched the literature data (Scheme 2).27 In conclusion, we have prepared atorvastatin via a late-stage, regioselective 1,3-dipolar cycloaddition using complex münchnone 8 in seven steps from commercially available 4-fluorophenylacetic acid (20). Münchnone precursor 22 was prepared on decagram scale in five steps with only one chromatographic
Scheme 2. Synthesis of atorvastatin.
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purification. Despite being known for more than 50 years, münchnones and other mesoionics continue to find new uses in synthesis; other application of münchnones to natural and non-natural targets are underway in our laboratory and will be reported in due course. Acknowledgments J.M.L. acknowledges support from the Department of Education GAANN fellowship. G.W.G. acknowledges support from the Donors of the Petroleum Research Fund, administered by the American Chemical Society, and by Wyeth. References and notes 1. Huisgen, R.; Gotthardt, H.; Bayer, H. O. Angew. Chem., Int. Ed. Engl. 1964, 3, 136. 2. (a) Potts, K. T. Mesoionic Ring Systems In 1,3-Dipolar Cyclo-addition Chemistry; Padwa, A., Ed.; Wiley: NY, 1984; vol. 2, p 1; (b) Gribble, G. W. Mesoionic Ring Systems In The Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: Hoboken, NJ, 2002; vol. 59, p 681; (c) Gribble, G. W. Mesoionic Oxazoles In The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy; Taylor, E. C., Wipf, P., Eds.; John Wiley & Sons: Hoboken, NJ, 2003; vol. 60, p 473. Part A. 3. Reissig, H.-U.; Zimmer, R. Angew. Chem., Int. Ed. 2014, 53, 9708. 4. (a) Lopchuk, J. M.; Gribble, G. W. Heterocycles 2011, 82, 1617; (b) Lopchuk, J. M.; Gribble, G. W. Tetrahedron Lett. 2011, 52, 4106. 5. (a) Lopchuk, J. M.; Gribble, G. W. Tetrahedron Lett. 2014, 55, 2809; (b) Fang, Y.; Larock, R. C.; Shi, F. Asian J. Org. Chem. 2014, 3, 55. 6. (a) Lu, Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430; (b) Worrall, K.; Xu, B.; Bontemps, S.; Arndtsen, B. A. J. Org. Chem. 2011, 76, 170; (c) Quesnel, J. S.; Arndtsen, B. A. Pure Appl. Chem. 2013, 85, 377. 7. Melhado, A. D.; Amarante, G. W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 3517. 8. (a) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776; (b) For a related silicon-catalyzed method, see: Peddibhotla, S.; Tepe, J. J. Synthesis 2003, 1433. 9. St-Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366. 10. (a) Harrington, P. J. Lipitor (Atorvastatin Calcium), Chapter 9. In Pharmaceutical Process Chemistry for Synthesis: Rethinking the Routes to Scale-Up; Wiley & Sons: New York, 2011; pp 294–359; (b) For a recent approach to the chiral diol, see: Kawato, Y.; Chaudhary, S.; Kumagai, N.; Shibasaki, M. Chem. Eur. J. 2013, 19, 3802. 11. (a) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. J. Med. Chem. 1991, 34, 357; (b) Park, W. K. C.; Kennedy, R. M.; Larsen, S. D.; Miller, S.; Roth, B. D.; Song, Y.; Steinbaugh, B. A.; Sun, K.; Tait, B. D.; Kowala, M. C.; Trivedi, B. K.; Auerbach, B.; Askew, V.; Dillon, L.; Hanselman, J. C.; Lin, Z.; Lu, G. H.; Robertson, A.; Sekerke, C. Bioorg. Med. Chem. Lett. 2008, 18, 1151; (c) Pandey, P. S.; Rao, T. S. Bioorg. Med. Chem. Lett. 2004, 14, 129. 12. (a) Lopchuk, J. M.; Hughes, R. P.; Gribble, G. W. Org. Lett. 2013, 15, 5218; (b) For a related study, see: Morin, M. S. T.; St-Cyr, D. J.; Arndtsen, B. A.; Krenske, E. H.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 17349. 13. For the detailed preparation of münchnones 11 and 12, including their reaction with b-nitrostyrene and related systems, see Ref. 12a. 14. For a review of methods of deprotection leading to atorvastatin, see Ref. 10a. For the method used in this work, see Ref. 27b. 15. General experimental procedure for the preparation of pyrroles 15a/b and 16a/ b. See Ref. 12a for detailed preparation of the münchnone precursors and cycloadditions: a round bottom flask was charged with münchnone precursor (3 equiv), dipolarophile (1 equiv), and dry THF. The reaction was placed under nitrogen and DIPC (3 equiv) added at room temperature. The mixture was heated to reflux for 24 h or until complete consumption of the dipolarophile was observed by TLC. The reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was directly purified by flash chromatography to afford the desired pyrrole. 16. Methyl 1-benzyl-2-methyl-4,5-diphenyl-1H-pyrrole-3-carboxylate (15a): 1H NMR (500 MHz, CDCl3) d 7.35–7.26 (m, 3H), 7.22–7.15 (m, 8H), 7.09–7.07 (m, 2H), 6.96 (dt, 2H, J = 7.3, 2.4 Hz), 5.08 (s, 2H), 3.65 (s, 3H), 2.52 (s, 3H); 13C NMR (125 MHz, CDCl3) d 166.2, 137.4, 135.8, 135.6, 131.9, 131.4, 131.0, 130.5, 128.6, 127.9, 127.4, 127.1, 126.9, 125.5, 125.5, 123.8, 111.3, 50.6, 48.0, 10.8; HRMS (ESI+) calcd for C26H24NO2 (MH+) 382.1807, found 382.1805. 17. Methyl 1-benzyl-5-methyl-2,4-diphenyl-1H-pyrrole-3-carboxylate (15b): 1H NMR (500 MHz, CDCl3) d 7.41–7.25 (m, 13H), 6.93–6.91 (m, 2H), 4.99 (s, 2H), 3.42 (s, 3H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3) d 165.7, 138.3, 137.8, 136.0, 132.3, 131.3, 130.7, 130.5, 128.8, 128.3, 128.0, 127.6, 127.3, 126.2, 125.7, 123.4, 112.2, 50.4, 47.7, 11.8; HRMS (ESI+) calcd for C26H24NO2 (MH+) 382.1807, found 382.1794. The structure was confirmed by X-ray crystallography.28 18. 1-Benzyl-2-methyl-N,4,5-triphenyl-1H-pyrrole-3-carboxamide (16a): 1H NMR (500 MHz, CDCl3) d 7.36–7.08 (m, 19H), 7.00–6.95 (m, 2H), 5.08 (s, 2H), 2.61 (s, 3H); 13C NMR (125 MHz, CDCl3) d 164.4, 138.8, 138.7, 135.7, 135.1, 131.9,
19.
20.
21. 22. 23.
24.
25.
26.
131.6, 131.6, 131.3, 129.1, 129.0, 128.9, 128.4, 128.0, 127.6, 127.5, 125.9, 123.6, 121.2, 120.3, 115.1, 48.1, 12.2; HRMS (ESI+) calcd for C31H27N2O (MH+) 443.2123, found 443.2119. 1-Benzyl-5-methyl-N,2,4-triphenyl-1H-pyrrole-3-carboxamide (16b): 1H NMR (500 MHz, CDCl3) d 7.47–7.44 (m, 4H), 7.41–7.37 (m, 6H), 7.33–7.23 (m, 5H), 7.13–6.97 (m, 6H), 5.01 (s, 2H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) d 163.0, 138.6, 137.9, 135.4, 136.3, 132.1, 131.4, 131.2, 130.9, 128.9, 128.8, 128.7, 128.6, 128.5, 127.5, 127.3, 125.8, 123.2, 120.1, 119.3, 116.4, 48.0, 10.8; HRMS (ESI+) calcd for C31H27N2O (MH+) 443.2123, found 443.2123. Kanemasa, S. Effect of External Reagents In The Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley: Hoboken, NJ, 2002; Vol. 59, p 755. Sweeney, J. B.; Tavassoli, A.; Carter, N. B.; Hayes, J. F. Tetrahedron 2002, 58, 10113. Chiral amine 10 was purchased from Accela ChemBio, Inc. and used as received without further purification. Methyl 2-((2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2 dimethyl-1,3-dioxan-4yl)ethyl)amino)-2-(4-fluorophenyl)acetate as a mixture of two diastereomers (23): A solution of 9 (7.58 g, 30.7 mmol) in MeCN (100 mL) was added to a round bottom flask charged with amine 10 (9.7 g, 35.5 mmol) and MeCN (50 mL). Triethylamine (6.77 mL, 48.5 mmol) was added to the reaction dropwise and the mixture stirred at room temperature overnight. After the reaction was concentrated in vacuo, the residual oil was dissolved in ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 37 as a thick, pale orange oil (14 g with residual ethyl acetate, quant.). 1H NMR (300 MHz, CDCl3) d 7.34 (t, 2H, J = 7.1 Hz), 7.05–6.99 (m, 2H), 4.34 (s, 1H, first diastereomer), 4.32 (s, 1H, second diastereomer), 4.28–4.18 (m, 1H), 4.02–3.88 (m, 1H), 3.69 (s, 3H), 2.69– 2.51 (m, 2H), 2.42 (dd, 1H, J = 15.1, 7.1 Hz), 2.27 (dd, 1H, J = 15.2, 6.1 Hz), 1.72– 1.61 (m, 3H), 1.43 (s, 9H), 1.36 (s, 3H), 1.34 (s, 3H), 1.20–1.09 (m, 1H); HRMS (ESI+) calcd for C23H35NO6F (MH+) 440.2448, found 440.2441. Methyl 2-(N-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan4-yl)ethyl)isobutyramido)-2-(4-fluorophenyl)acetate as a mixture of two diastereomers (21): A solution of 23 (13.5 g, 30.7 mmol) in CH2Cl2 (100 mL) was cooled in an ice bath and treated with an ice cold solution of isobutyryl chloride (3.65 mL, 34.9 mmol) in CH2Cl2 (50 mL). After stirring for 10 min, the mixture was treated with triethylamine (8.9 mL, 63.6 mmol) in CH2Cl2 (20 mL) dropwise. The reaction was stirred at 0 °C for 1 h then warmed to room temperature and stirred a further 6 h. The solution was diluted with CH2Cl2 (200 mL) and poured into 1 M HCl (150 mL). The layers were quickly separated. The organic layer was washed with satd sodium bicarbonate, water, and brine. The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude 21 as a thick, orange oil. The product was purified by flash chromatography (silica gel, 10–50% ethyl acetate in hexanes) to afford 21 as a pale yellow oil (11.9 g, 76%, over two steps). 1H NMR (300 MHz, CDCl3) d 7.29–7.24 (m, 2H), 7.04 (td, 2H, J = 10.7, 2.0 Hz), 5.80 (s, 1H, first diastereomer), 5.79 (s, 1H, second diastereomer), 4.19–4.08 (m, 1H), 3.73 (s, 3H), 3.67–3.57 (m, 1H), 3.53–3.42 (m, 1H, first diastereomer), 3.39–3.30 (m, 1H), 3.26–2.14 (m, 1H, second diastereomer), 2.92–2.82 (m, 1H), 2.42–2.33 (m, 1H), 2.27–2.18 (m, 1H), 1.71–1.48 (m, 3H), 1.43 (s, 9H), 1.35 (s, 3H), 1.30 (d, 3H, J = 3.4 Hz), 1.16 (d, 6H, J = 6.9 Hz), 1.08–0.92 (m, 1H); 13C NMR (75 MHz, CDCl3) d (for one diastereomer only) 178.5, 171.1, 170.4, 162.9 (J = 247 Hz), 131.6 (J = 6.0 Hz), 131.0, 115.9 (J = 22 Hz), 98.9, 66.3, 66.1, 61.6, 52.6, 42.7, 42.5, 37.3, 36.8, 36.4, 30.7, 30.2, 28.3, 19.9, 19.8, 19.8; HRMS (ESI+) calcd for C28H41NO7F (MH+) 510.2867, found 510.2874. 2-(N-(2-((4R,6R)-6-(2-(tert-Butoxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4yl)ethyl)isobutyramido)-2-(4-fluorophenyl)acetic acid as a mixture of two diastereomers (22): A round bottom flask was charged with 21 (11.9 g, 23.3 mmol) and methanol (200 mL) and stirred at room temperature. A solution of 1 M LiOH (65 mL) was added and the reaction stirred for 4 h when TLC indicated complete consumption of starting material. The mixture was concentrated to remove the methanol and water was added (50 mL). 1 M HCl was added until the pH was <7 and copious amounts of precipitate formed. The mixture was quickly extracted with ethyl acetate (3 150 mL). The combined organic layers were washed with brine and dried over sodium sulfate, filtered, and concentrated in vacuo to afford 22 as a white foam (10.8 g, 93%). 1H NMR (300 MHz, CDCl3) d 7.34–7.30 (m, 2H), 7.07–7.03 (m, 2H), 5.55 (s, 1H, first diastereomer), 5.48 (s, 1H, second diastereomer), 4.21–4.13 (m, 1H), 3.76–3.68 (m, 1H), 3.59–3.48 (m, 1H), 3.38–3.32 (m, 1H, first diastereomer), 3.28–3.22 (m, 1H, second diastereomer), 2.92–2.85 (m, 1H), 2.41–2.36 (m, 1H), 2.28–2.22 (m, 1H), 1.69–1.62 (m, 1H, first diastereomer), 1.58–1.52 (m, 1H, second diastereomer), 1.43 (s, 9H), 1.37 (d, 3H, J = 4.4 Hz), 1.31 (s, 3H), 1.14 (d, 6H, J = 6.6 Hz), 1.08–1.00 (m, 1H); 13C NMR (75 MHz, CDCl3) d (for one diastereomer only) 179.5, 172.9, 170.4, 162.9 (J = 248 Hz), 131.2 (J = 7.8 Hz), 130.6, 116.2 (J = 22 Hz), 99.0, 66.3, 66.2, 63.4, 43.9, 42.7, 36.9, 36.4, 36.3, 30.9, 30.2, 28.3, 19.9, 19.7, 19.6; HRMS (ESI+) calcd for C26H39NO7F (MH+) 496.2711, found 496.2705. Protected atorvastatin, Tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,329 dioxan-4-yl)acetate (6): A round bottom flask was charged with münchnone precursor 22 (496 mg, 1.00 mmol), acetylene 7 (111 mg, 0.500 mmol), and dry THF (20 mL). The reaction was placed under nitrogen and DIPC (156 lL, 1 mmol) added at room temperature. The mixture was heated to reflux for 24 h. The reaction was cooled to room temperature and concentrated in vacuo.
J. M. Lopchuk, G.W. Gribble / Tetrahedron Letters 56 (2015) 3208–3211 The residue was directly purified by flash chromatography to afford 6 as a clear, colorless oil which solidified upon standing (298 mg, 91%). 1H NMR (300 MHz, CDCl3) d 7.18–7.14 (m, 9H), 7.07 (d, 2H, J = 8.0 Hz), 6.99–6.94 (m, 3H), 6.88 (s, 1H), 4.18–4.04 (m, 2H), 3.86–3.80 (m, 1H), 3.70–3.68 (m, 1H), 3.60–3.54 (m, 1H), 2.37 (dd, 1H, J = 15.3, 7.1 Hz), 2.23 (dd, 1H, J = 15.3, 6.1 Hz), 1.69–1.66 (m, 2H), 1.53 (d, 6H, J = 7.1 Hz), 1.43 (s, 9H), 1.36 (s, 3H), 1.29 (s, 3H), 1.09–1.01 (m, 1H); 13C NMR (75 MHz, CDCl3) d 170.4, 165.1, 163.5, 161.5, 141.7, 138.6, 134.9, 133.5, 133.4, 130.7, 129.0, 128.9, 128.6, 128.5, 128.5, 126.8, 123.7, 122.0, 119.8, 115.7, 115.6, 115.5, 98.9, 80.9, 66.6, 66.1, 42.7, 41.1, 38.3,
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36.2, 30.1, 28.3, 26.3, 22.0, 21.8, 19.9; HRMS (ESI+) calcd for C40H48N2O5F (MH+) 655.3547, found 655.3546. 27. (a) Chen, B.-C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Hangeland, J. J.; Ahmed, S. Z.; Jemal, M. J. Labelled Compd. Radiopharm. 2000, 43, 261; (b) Kawato, Y.; Iwata, M.; Yazaki, R.; Kumagi, N.; Shibasaki, M. Tetrahedron 2011, 67, 6539. 28. Lopchuk, J. M.; Gribble, G. W.; Jasinski, J. P. Acta. Crystallogr. 2014, E70, o338. 29. Gao, J.; Guo, Y. H.; Wang, Y. P.; Wang, X. J.; Xiang, W. S. Chin. Chem. Lett. 2011, 22, 1159.