A Short Enantioselective Total Synthesis of (-)-Linderol A

Abstract

An efficient short enantioselective total synthesis of (-)-linderol A was achieved via a five-step reaction with 30% overall yield, starting from 4-methoxyphloroacetophenone.

total synthesis - stereoselectivity - terpenylation - epoxides - hexahydrodibenzofuran

References and Notes

1 Mimaki Y. Kameyama A. Sashida Y. Miyata Y. Fujii A. Chem. Pharm. Bull.  1995,  43:  893 

2a Yamashita M. Ohta N. Kawasaki I. Ohta S. Org. Lett.  2001,  3:  1359 

2b Yamashita M. Ohta N. Shimizu T. Matsumoto K. Matsuura Y. Kawasaki I. Tanaka T. Maezaki N. Ohta S. J. Org. Chem.  2003,  68:  1216 

3a Yamashita M. Inaba T. Shimizu T. Kawasaki I. Ohta S. Synlett  2004,  1897 

3b Yamashita M. Inaba T. Nagahama M. Shimizu T. Kosaka S. Kawasaki I. Ohta S. Org. Biomol. Chem.  2005,  3:  2296 

3c Yamashita M. Shimizu T. Inaba T. Takada A. Takao I. Kawasaki I. Ohta S. Heterocycles  2005,  65:  1099 

4 Crombie L. Crombie WML. Firth DF. J. Chem. Soc., Perkin Trans. 1  1988,  1251 

5 4-Methoxyphloroacetophenone (4) was obtained from the commercially available phloroacetophenone and its synthesis has been previously described: Huang C. Da S. Li Y. Li Y. J. Nat. Prod.  1997,  60:  277 

6

Selected Physical Properties for 5[α]_D +14 (c 0.44, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 6.56 (s, 1 H, H_ar), 5.09 (s, 1 H, H2), 3.80 (m, 4 H, H3 and CH₃O), 2.40 (s, 3 H, CH₃), 2.31 (s, 3 H, CH₃), 2.12 (s, 3 H, CH₃), 2.03 (m, 2 H), 1.90 (m, 1 H), 1.78 (dt, 1 H, J = 2.3 Hz), 1.63 (s, 3 H, CH₃), 1.36 (m, 2 H), 0.86 (d, 3 H, J = 6.8 Hz, CH₃), 0.77 (d, 3 H, J = 6.8 Hz, CH₃) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 198.4 (C=O), 169.2 (C=O), 168.5 (C=O), 160.1 (Cq), 147.4 (Cq), 147.1 (Cq), 132.9 (Cq, C1), 124.9 (CH, C2), 124.3 (Cq), 102.6 (CH_ar), 55.9 (CH₃O), 42.5 (CH), 36.0 (CH, C3), 30.8 (CH₃), 30.6 (CH₂), 28.0 (CH, C4), 23.4 (CH₃), 22.3 (CH₂), 21.5 (CH₃), 21.1 (CH₃), 20.8 (CH₃), 15.9 (CH₃) ppm. LRMS (EI): m/z (%) = 402 (0.1) [M⁺], 359(52), 317(99), 290(22), 248(100), 233(30). HRMS (EI): m/z calcd for C₂₃H₃₀O₆: 402.2042; found: 402.2041.

7 Uliss DB. Razdan RK. Dalzell HC. J. Am. Chem. Soc.  1974,  96:  7372 ; and cited references

8

Experimental Procedure for 6The mixture of epoxides 2 and 2′ (52.8 mg, 0.126 mmol with a ratio of 2.6:1) was treated at r.t. with 2 mL of a 2% NaOH solution in MeOH-H₂O (1:1). The solution was stirred at r.t. for 1 h, then neutralized with 10% HCl. The mixture was extracted with CH₂Cl₂, the organic layer was washed with H₂O and dried over MgSO₄. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography (CH₂Cl₂-EtOAc, 90:10) to give 6 as a pale yellow solid (29 mg, 0.087 mmol, 69% or 87% from 2); mp 146-147 °C. IR (KBr): 3430, 2947, 2921, 1625, 1433, 1363, 1293, 1211, 1150, 1054, 831, 805 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 13.16 (s, 1 H, OH), 6.02 (s, 1 H, H2), 4.16 (dd, 1 H, J = 5.5, J = 1.0 Hz, H5a), 3.81 (s, 3 H, CH₃O), 3.11 (dd, 1 H, J = 11.1, 5.5 Hz, H9a), 2.60 (s, 3 H, CH₃), 1.80 (m, 3 H, H7 and CH _{i -Pr}), 1.61 (s, 1 H, OH), 1.50 (s, 3 H, CH₃), 1.40 (m, 2 H, H8), 1.10 (m, 1 H, H9), 0.90 (d, 3 H, J = 6.9 Hz, CH₃), 0.83 (d, 3 H, J = 6.9 Hz, CH₃) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 201.8 (C=O), 165.0 (C3), 162.0 (Cq_ar), 161.8 (Cq_ar), 113.1 (C9b), 102.9 (C4), 92.5 (C2), 92.3 (C5a), 69.3 (CH, C6), 55.4 (CH₃O), 46.5 (CH, C9), 39.6 (C9a), 35.2 (CH₂, C7), 31.1 (CH₃C=O), 28.2 (CH₃), 27.1 (CH _{i -Pr}), 21.7 (CH₃), 17.1 (C8), 15.3 (CH₃). LRMS (EI): m/z (%) = 334 (50) [M⁺], 318 (40), 249 (98), 233 (100), 207 (48), 195 (22). HRMS (EI): m/z calcd for C₁₉H₂₆O₅: 334.1780; found: 334.1788.

9 Yamashita M. Shimizu T. Kawasaki I. Ohta S. Tetrahedron: Asymmetry  2004,  15:  2315