An acyl-claisen approach to tetrasubstituted tetrahydrofuran lignans: Synthesis of fragransin A2, talaumidin, and lignan analogues

Synlett

Volumn , Issue 20, 2009, Pages 3315-3319

  Rye, Claire E ^a   Barker, David ^a  

^a UNIVERSITY OF AUCKLAND   (New Zealand)

Author keywords

Acyl Claisen reaction; Aza Claisen reaction; Lignans; Stereospecific synthesis; Tetrahydrofurans

Indexed keywords

FRAGRANSIN A2; LIGNAN DERIVATIVE; TALAUMIDIN; TETRAHYDROFURAN DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CLAISEN REARRANGEMENT; CYCLIZATION; REACTION ANALYSIS; STEREOSPECIFICITY; SYNTHESIS;

EID: 72149104763     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1218363     Document Type: Article

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36. (E)-Crotylamines were prepared from (E)-crotonaldehyde, by LAH reduction and PBr3 bromination to give (E)-crotyl bromide. Amine 5a was prepared by amination with morpholine at 0 C in CH2Cl2, whilst amine 5b was prepared using the sodium hydride derived sodium salt of pyrrolidine and TBAI in THF.
37. We found that the TES groups were cleaved during the dihydroxylation step to give extremely polar triols and the use of TBDMS groups was unsatisfactory as they did not spontaneously cleave during the cyclization step and, instead, gave unwanted products.
38. General Procedure for the Synthesis of Amides 4: To a stirred suspension of AlCl3 (0.1 mmol) in CH2Cl2 (5 mL) under an atmosphere of N2, a solution of (E)-4-(but-2- enyl)amine 5 (1 mmol) in CH2Cl2 (5 mL) was added dropwise, followed by diisopropylethylamine (1.5 mmol) dropwise. The resultant mixture was stirred at r.t. for 15 min, then a solution of acid chloride 6 (1.2 mmol) in CH2Cl2 (5 mL) was added dropwise and the reaction mixture was stirred at r.t. for 24 h. Aq NaOH (10 mL) was added, the layers were separated and the aqueous layer was further extracted with CH2Cl2 (3 ×15 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash chromatography to give the amides 4 in 2488% yields. General Procedure for the Synthesis of Ketones 7: To a solution of aryl bromide (1.2 mmol) in THF (20 mL) under an atmosphere of N2 at 78 C, was added, either n-BuLi (1.2 mmol for 8a) or t-BuLi (2.4 mmol for 8bd) and the resultant solution was stirred for 10 min. A solution of amide 4 (1 mmol) in THF (5 mL) was then added dropwise and the mixture was stirred at 78 C and slowly warmed to r.t. over 218 h. Sat. NH4Cl solution (20 mL) was added and the aqueous mixture was extracted with EtOAc (3 ×30 mL). The combined organic extracts were dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash chromatography to give the ketones 7 in 4396% yields. General Procedure for the Synthesis of Tetrahydrofurans 12: To a solution of alcohol 11 (1 mmol) and Et3N (1.6 mmol) in CH2Cl2 (25 mL) under an atmosphere of N2 was added MsCl (1.3 mmol) and the reaction mixture was stirred for 12 h. Sat NaHCO3 solution (10 mL) was added, the layers were separated and the aqueous layer was further extracted with CH2Cl2 (3 ×15 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified by flash chromatography to give the tetrahydrofurans 12 in 6381% yields.
39. Spectroscopic Data for Selected Products: ()-Dimethoxy-4-epi-larreatricin (12a): 1H NMR (400 MHz, CDCl3): d = 1.01 (m, 6 H, CHCH3), 1.78 (m, 2 H, CH), 3.78 (s, 6 H, OMe), 4.63 (d, J = 9.0 Hz, 2 H, OCH), 6.87 (d, J = 8.7 Hz, 4 H, 2-Ar), 7.31 (d, J = 8.4 Hz, 4 H, 3-Ar). 13C NMR (100 MHz, CDCl3): d = 13.7 (2 ×CH3), 51.0 (2 ×CH), 55.2 (OCH3), 88.0 (2 ×CH), 113.6 (2 ×CH), 127.4 (2 ×CH), 134.5 (q), 159.0(q). IR (film): 2954, 2833, 1609, 1584, 1507, 1454, 1299, 1239, 1169, 1025, 821, 726 cm1. MS (EI+): m/z (%) = 312 (8) [M+], 176 (100), 161 (60), 135 (12), 77 (6). Anal. Calcd for C20H24O3 [M+]: 312.17254. Found: 312.17286. The 1H NMR data was in agreement with the literature values.14 ()-2-(3,4-Dimethoxyphenyl)-3,4-dimethyl-5-(3-methoxy- 4-hydroxyphenyl)tetrahydrofuran (12b): 1H NMR (400 MHz, CDCl3): d = 1.12 (d, J = 6.4 Hz, 6 H, 3- and 4-CH3), 1.952.02 (m, 2 H, 3- and 4-H), 3.91 (s, 9 H, OMe), 4.75 (d, J = 10.0 Hz, 2 H, 2- and 5-H), 5.69 (br s, 1 H, OH), 6.816.92 (m, 6 H, Ar-H). 13C NMR (100 MHz, CDCl3): d = 14.3 (2 ×CH3), 47.8 (2 ×CH, C-3 and C-4), 56.0 (3 ×OCH3), 86.4 (2 ×CH, C-2 and C-5), 108.3 (2 ×CH), 114.1 (2 ×CH), 119 (2 ×CH), 129.1 (q), 140.1 (q), 146.1 (q), 146.8 (q). IR (film): 3426.6, 2967.1, 1766, 1607.1, 1519, 1459.9, 1380.0, 1275.8, 1237.2, 1176, 1033 cm1. MS (ESI): m/z (%) = 381 (11) [M + Na]+, 359 (8) [M + H]+, 259 (83), 237 (100), 191 (22). Anal. Calcd for C21H27O5: 359.1858 [M + H+]. Found: 359.1864. ()-Talaumidin (rac-2, 12c): 1H NMR (400 MHz, CDCl3): d = 1.03 (m, 6 H, 3- and 4-CH3), 1.78 (m, 2 H, 3- and 4-H), 3.91 (s, 3 H, OCH3), 4.61 (d, J = 5.2 Hz, 2 H, 2- and 5-H), 5.59 (br s, 1 H, OH), 5.94 (s, 2 H, OCH2O), 6.776.93 (m, 6 H, Ar-H). 13C NMR (100 MHz, CDCl3): d = 13.8 (CH3), 50.8 (CH), 51.1 (CH), 55.9 (OCH3), 88.2 (CH), 88.4 (CH), 100.9 (CH2), 106.5 (CH), 107.9 (CH), 108.5 (CH), 114.0 (CH), 119.4 (CH), 119.6 (CH), 134.1 (q), 136.5 (q), 145.1 (q), 146.5 (q). IR (film): 3468.5, 2959, 1770, 1609, 1515, 1488, 1447, 1365, 1273, 1243, 1036, 934 cm1. MS (ESI): m/z (%) = 343 (100) [M + H]+, 339 (8), 325 (17). Anal. Calcd for C20H23O5: 343.1545 [M + H+]. Found: 343.1551. The 1Hand 13C NMR data were in agreement with the literature values.2b ()-Fragransin A2 (rac-1, 12d): 1H NMR (300 MHz, CDCl3): d = 1.05 (d, J = 6.3 Hz, 6 H, 3- and 4-CH3), 1.76 (m, 2 H, 3- and 4-H), 3.91 (s, 6 H, OCH3), 4.61 (d, J = 9.3 Hz, 2 H, 2- and 5-H), 5.55 (s, 2 H, OH), 6.786.94 (m, 6 H, Ar-H). 13C NMR (75 MHz, CDCl3): d = 13.8 (2 ×CH3), 50.8 (CH), 51.1 (CH), 56.0 (OCH3), 88.2 (CH), 88.4 (CH), 106.6 (CH), 107.9 (CH), 108.6 (CH), 114.0 (CH), 119.4 (CH), 119.7 (CH), 134.1 (q), 136.9 (q), 145.1 (q), 146.9 (q). IR (film): 3451, 2958, 2926, 1772, 1607, 1515, 1460, 1247, 1036 cm1. MS (ESI): m/z (%) = 343 (100) [M + H]+, 321 (6), 301 (8), 292 (10), 259 (60). Anal. Calcd for C20H23O5: 343.1545 [M H+]. Found: 343.1536. The 1H- and 13C-NMR data were in agreement with the literature values.2b 2,5-Di(4-methoxyphenyl)-3-methyl-4- propyltetrahydrofuran (12e): 1H NMR (400 MHz, CDCl3): d = 0.83 (m, 3 H, CH2CH2CH3), 1.23 (m, 2 H, CH2CH2CH3), 1.34 (d, J = 6.8 Hz, 3 H, 3-CH3), 1.51 (m, 2 H, CH2CH2CH3), 2.09 (m, 1 H, 4-H), 2.45 (m, 1 H, 3-H), 3.82 (s, 6 H, OMe), 4.84 (d, J = 9.6 Hz, 2 H, 2- and 5-H), 6.90 (d, J = 8.4 Hz, 4 H, Ar-H), 7.26 (d, J = 8.8 Hz, 4 H, Ar-H). 13C NMR (100 MHz, CDCl3): d = 14.2 (CH3), 14.7 (CH3), 20.3 (CH2), 33.3 (CH2), 42.0 (CH), 51.7 (CH), 55.3 (OCH3), 85.2 (2 ×CH), 114.0 (2 ×CH), 128.3 (2 ×CH), 140.2 (q), 160.0(q). IR (film): 2958, 2339, 1773, 1613, 1516, 1462, 1299, 1251, 1171, 1034, 988, 833 cm1. MS (ESI): m/z (%) = 363 (3) [M + Na]+, 303 (4), 271 (100). Anal. Calcd for C22H28O3Na: 363.1931 [M + Na+]. Found: 363.1926. 2-(4-Methoxyphenyl)-3,4-dimethyl-5-phenyl tetrahydrofuran (12g): 1H NMR (400 MHz, CDCl3): d = 0.63 (d, J = 6.0 Hz, 3 H, 4-CH3), 1.04 (d, J = 6.0 Hz, 3 H, 3-CH3), 1.78 (m, 1 H, 3-H), 2.25 (m, 1 H, 4-H), 3.83 (s, 3 H, OCH3), 4.40 (d, J = 9.0 Hz, 1 H, 2-H), 5.17 (d, J = 9.0 Hz, 1 H, 5-H), 6.93 (d, J = 9.0 Hz, 2 H, Ar-H), 7.287.35 (m, 5 H, Ar-H), 7.43 (d, J = 9.0 Hz, 2 H, Ar-H). 13C NMR (100 MHz, CDCl3): d = 15.0 (CH3), 15.3 (CH3), 45.9 (CH), 48.5 (CH), 55.3 (OCH3), 83.0 (CH), 87.3 (CH), 113.8 (CH), 127.0 (CH), 127.8 (CH), 127.9 (CH), 132.9 (q), 141.0(q), 162.6 (q). IR (film): 2958, 2836, 1613, 1515, 1454, 1222, 1036, 825, 704 cm1. MS (ESI): m/z (%) = 283 (100) [M + H]+, 265 (42), 177 (19), 149 (16), 121 (36). Anal. Calcd for C19H23O2: 283.1693 [M + H+]. Found: 283.1680.