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.

Key words

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 
• 7 Uliss DB. Razdan RK. Dalzell HC. J. Am. Chem. Soc.  1974,  96:  7372 ; and cited references
• 9 Yamashita M. Shimizu T. Kawasaki I. Ohta S. Tetrahedron: Asymmetry  2004,  15:  2315 

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.

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.