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Synlett 2008(4): 575-577  
DOI: 10.1055/s-2008-1032090
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (±)-Smenochromene D (Likonide B) Using a Regioselective Claisen Rearrangement

Marjorie Bruder, Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: c.j.moody@nottingham.ac.uk;
Further Information

Publication History

Received 3 December 2007
Publication Date:
12 February 2008 (online)

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Abstract

A synthesis of the unusual ansa farnesyl hydroquinone smenochromene D (likonide B) is described, in which the key steps are a regioselective microwave-mediated Claisen rearrangement of an aryl propargyl ether to deliver the chromene ring, and macrocyclisation via an intramolecular Mitsunobu reaction.

Key words

natural products - ansa-macrocycles - rearrangements - chromenes - Mitsunobu reaction

    References and Notes

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6-Hydroxy-2-[(3 E ,7 E )-9- tert -butyldimethylsilyloxy-4,8-dimethylnona-3,7-dienyl]-7-methoxy-2-methyl-2 H -chromene (7b): A solution of the propargyl aryl ether (98 mg, 0.21 mmol) in N,N-diethylaniline (3.5 mL) in a sealed tube was heated at 140 °C for 40 min at 300 W in a CEM Discover™ microwave reactor. The reaction mixture was evaporated and the resulting oil was purified by flash chromatography on silica gel, eluting with light PE-Et2O (8:2), to give the title compound (85 mg, 87%) as a orange-yellow oil. IR (CHCl3): 3630, 3553, 2929, 2856, 1628, 1583, 1501, 1458, 1360, 1290, 1124 cm-1. 1H NMR (400 MHz, CDCl3): δ = 6.56 (s, 1 H, H-5), 6.41 (s, 1 H, H-8), 6.27 (d, J = 9.8 Hz, 1 H, H-4), 5.47 (d, J = 9.8 Hz, 1 H, H-3), 5.38 (m, 1 H, CH=CMe), 5.19 (s, 1 H, OH), 5.13-5.16 (m, 1 H, CH=CMe), 4.02 (s, 2 H, OCH2), 3.86 (s, 3 H, OMe), 2.10-2.14 [m, 4 H, OC(Me)CHHCH2, =CHCH2CH2], 2.00-2.03 (m, 2 H, =CHCH2CH2), 1.66-1.75 [m, 2 H, OC(Me)CHHCH2], 1.61 (s, 6 H, 2 × CMe=CH), 1.39 (s, 3 H, Me), 0.93 (s, 9 H, CMe3), 0.08 (s, 6 H, SiMe2). 13C NMR (100 MHz, CDCl3): δ = 146.7 (C), 146.6 (C), 139.2 (C), 135.0 (C), 134.3 (C), 127.6 (CH), 124.3 (CH), 122.4 (CH), 121.5 (CH), 113.9 (CH), 111.7 (C), 100.0 (CH), 78.1 (C), 68.6 (CH2), 55.9 (Me), 40.9 (CH2), 39.3 (CH2), 26.0 (CH2), 25.9 (Me), 25.8 (Me), 22.6 (CH2), 18.4 (C), 15.9 (Me), 13.4 (Me), -5.3 (Me). HRMS (EI): m/z [M + Na]+ calcd for C28H44O4Si: 495.2901; found: 495.2918.

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(±)-Smenochromene D [(±)-Likonide B](2): Into a stirring 8 mM solution of 6-hydroxy-2-[(3E,7E)-9-hydroxy-4,8-dimethylnona-3,7-dienyl]-7-methoxy-2-methyl-2H-chromene (8; 50 mg, 0.14 mmol) and dipiperidinyl azodicarboxylate (105 mg, 0.42 mmol) in anhyd toluene (17.4 mL) was bubbled argon for 10 min, while cooling the solution to 0 °C. A first batch (40 µL) of tributylphosphine (140 µL, 0.55 mmol) was added dropwise and the reaction mixture was stirred for 20 min at 0 °C followed by the addition of a second batch of tributylphosphine (100 µL). The reaction mixture was then allowed to reach r.t. and was stirred for 24 h. A second batch of dipiperidinyl azodicarboxylate was added at 0 °C, tributylphosphine was added over 1 h and the whole was stirred for 8 h at r.t. H2O was added to the mixture and the aqueous phase was extracted into EtOAc (2 ×). The organic layer was reduced in vacuo, the crude product was taken up in light PE and filtered. The resulting solution was dried over MgSO4, filtered and evaporated in vacuo. The crude oil was purified by flash chromatography on silica gel, eluting with hexane-EtOAc (9:1), to give the title compound (13 mg, 27%). IR (CHCl3): 3630, 2930, 1618, 1503, 1450, 1365, 1289, 1124 cm-1. 1H NMR (400 MHz, DMSO): δ = 6.61 (s, 1 H, H-16), 6.38 (d, J = 9.9 Hz, 1 H, H-1), 6.34 (s, 1 H, H-19), 5.41 (d, J = 9.8 Hz, 1 H, H-2), 4.85-4.87 (m, 1 H, H-6), 4.74-4.78 (m, 1 H, H-10), 4.38 (d, J = 11.4 Hz, 1 H, H-12), 4.07 (d, J = 11.4 Hz, 1 H, H-12′), 3.66 (s, 3 H, H-22), 1.96-2.12 (m, 4 H, H-9, H-5, H-8), 1.83-1.92 (m, 1 H, H-5′), 1.64-1.68 (m, 1 H, H-4), 1.53-1.62 (m, 5 H, H-8, H-15, H-4′), 1.41 (s, 3 H, H-13), 1.32 (s, 3 H, H-14). 13C NMR (100 MHz, DMSO): δ = 153.0 (C), 149.8 (C), 138.9 (C), 131.2 (CH), 131.0 (C), 129.6 (C), 126.3 (CH), 125.6 (CH), 123.2 (CH), 118.9 (CH), 112.9 (C), 99.9 (CH), 78.9 (CH), 78.6 (C), 55.3 (OMe), 40.7 (CH2), 38.5 (CH2), 29.7 (Me), 24.0 (CH2), 22.5 (CH2), 14.2 (Me), 13.9 (Me). HRMS (ES): m/z [M + Na]+ calcd for C22H28O3: 363.1931; found: 363.1919. The cyclic dimer 9 (13 mg, 13%) was also isolated.

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A similarly modest yield in the macrocyclisation step was also observed in the previous synthesis of smenochromene D (ref. 6).