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

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.

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

References and Notes

<A NAME="RD40107ST-1">1</A> Thomson RH. Naturally Occurring Quinones   2nd ed.:  Academic Press; London: 1971. 

<A NAME="RD40107ST-2">2</A> Thomson RH. Naturally Occurring Quinones III: Recent Advances   3rd ed.:  Chapman and Hall; London: 1987. 

<A NAME="RD40107ST-3">3</A> Thomson RH. Naturally Occurring Quinones IV: Recent Advances   4th ed.:  Blackie; London: 1997. 

<A NAME="RD40107ST-4">4</A> Rudi A. Benayahu Y. Kashman Y. Org. Lett.  2004,  6:  4013 

<A NAME="RD40107ST-5">5</A> Venkateswarlu Y. Faulkner DJ. Steiner JLR. Corcoran E. Clardy J. J. Org. Chem.  1991,  56:  6271 

<A NAME="RD40107ST-6">6</A> Olson BS. Trauner D. Synlett  2005,  700 

<A NAME="RD40107ST-7">7</A> Rosa CP. Kienzler MA. Olson BS. Liang G. Trauner D. Tetrahedron  2007,  63:  6529 

<A NAME="RD40107ST-8">8</A> Stahl P. Waldmann H. Angew. Chem. Int. Ed.  1999,  38:  3710 

<A NAME="RD40107ST-9">9</A> Aoki S. Kong D. Matsui K. Rachmat R. Kobayashi M. Chem. Pharm. Bull.  2004,  52:  935 

<A NAME="RD40107ST-10">10</A> Takahashi Y. Kubota T. Fromont J. Kobayashi J. Tetrahedron  2007,  63:  8770 

<A NAME="RD40107ST-11">11</A> McMurry JE. Dushin RG. J. Am. Chem. Soc.  1989,  111:  8928 

<A NAME="RD40107ST-12">12</A> Umbreit MA. Sharpless KB. J. Am. Chem. Soc.  1977,  99:  5526 

<A NAME="RD40107ST-13">13</A> Fischer J. Reynolds AJ. Sharp LA. Sherburn MS. Org. Lett.  2004,  6:  1345 

<A NAME="RD40107ST-14">14</A> Godfrey JD. Mueller RH. Sedergran TC. Soundararajan N. Colandrea VJ. Tetrahedron Lett.  1994,  35:  6405 

<A NAME="RD40107ST-15">15</A> For related Claisen rearrangements, see ref. 16 and the following: Kahn PH. Cossy J. Tetrahedron Lett.  1999,  40:  8113 

<A NAME="RD40107ST-16">16</A> Yamaguchi S. Maekawa M. Murayama Y. Miyazawa M. Hirai Y. Tetrahedron Lett.  2004,  45:  6971 

<A NAME="RD40107ST-17">17</A> For a discussion of regioselectivity in rearrangements of aryl propargyl ethers, see: Yamaguchi S. Ishibashi M. Akasaka K. Yokoyama H. Miyazawa M. Hirai Y. Tetrahedron Lett.  2001,  42:  1091 

<A NAME="RD40107ST-18">18</A> For an earlier example of a microwave-assisted Claisen rearrangement of an aryl propargyl ether, see: Moghaddam FM. Sharifi A. Saidi MR. J. Chem. Res., Synop.  1996,  338 

<A NAME="RD40107ST-19">19</A> Ritter T. Stanek K. Larrosa I. Carreira EM. Org. Lett.  2004,  6:  1513 

<A NAME="RD40107ST-20">20</A>

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.

<A NAME="RD40107ST-21">21</A>

(±)-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.

<A NAME="RD40107ST-22">22</A>

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