An Acyl-Claisen Approach to Tetrasubstituted Tetrahydrofuran Lignans: Synthesis of Fragransin A₂, Talaumidin, and Lignan Analogues

Abstract

A simple and stereocontrolled synthesis of racemic 2,3,4,5-tetrasubstituted tetrahydrofurans was achieved from acyl-Claisen derived syn-disubstituted amides.

Key words

tetrahydrofurans - acyl-Claisen reaction - aza-Claisen reaction - lignans - stereospecific synthesis

References and Notes

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11

(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.

13

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.

15

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 24-88% 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 8b-d) 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 2-18 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 43-96% 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 1-2 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 63-81% yields.

16

Spectroscopic Data for Selected Products:
(±)-Dimethoxy-4-epi-larreatricin (12a): ^¹H NMR (400 MHz, CDCl₃): δ = 1.01 (m, 6 H, CHCH ₃), 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): δ = 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 cm^-¹. 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): δ = 1.12 (d, J = 6.4 Hz, 6 H, 3- and 4-CH₃), 1.95-2.02 (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), 6.81-6.92 (m, 6 H, Ar-H). ^¹³C NMR (100 MHz, CDCl₃): δ = 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 cm^-¹. 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):
δ = 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), 6.77-6.93 (m, 6 H, Ar-H). ^¹³C NMR (100 MHz, CDCl₃): δ = 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 cm^-¹. MS (ESI): m/z (%) = 343 (100) [M + H]⁺, 339 (8), 325 (17). Anal. Calcd for C₂₀H₂₃O₅: 343.1545 [M + H⁺]. Found: 343.1551. The ^¹H- and ^¹³C NMR data were in agreement with the literature values.^²b(±)-Fragransin A₂ (rac -1, 12d): ^¹H NMR (300 MHz, CDCl₃): δ = 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), 6.78-6.94 (m, 6 H, Ar-H). ^¹³C NMR (75 MHz, CDCl₃): δ = 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
cm^-¹. 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-propyltetrahydro-furan (12e): ^¹H NMR (400 MHz, CDCl₃): δ = 0.83 (m, 3 H, CH₂CH₂CH ₃), 1.23 (m, 2 H, CH₂CH ₂CH₃), 1.34 (d, J = 6.8 Hz, 3 H, 3-CH₃), 1.51 (m, 2 H, CH ₂CH₂CH₃), 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):
δ = 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 cm^-¹. 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 tetrahydro-furan (12g): ^¹H NMR (400 MHz, CDCl₃): δ = 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), 7.28-7.35 (m, 5 H, Ar-H), 7.43 (d, J = 9.0 Hz, 2 H, Ar-H). ^¹³C NMR (100 MHz, CDCl₃): δ = 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 cm^-¹. 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.