Thieme Chemistry Journal Awardees - Where Are They Now? Synthesis of (-)-Cubebol by Intramolecular Cyclopropanation of a Terminal Epoxide

Abstract

A synthesis of (-)-cubebol from l-menthone is described. The key step involves efficient (90%) and completely stereocontrolled intramolecular cyclopropanation of an unsaturated α-lithiated terminal epoxide.

Key words

cubebol - intramolecular cyclopropanation - lithium 2,2,6,6-tetramethylpiperidide - epoxide - total synthesis

References and Notes

• 1 Tanaka A. Tanaka R. Uda H. Yoshikoshi A. J. Chem. Soc., Perkin Trans. 1  1972,  1721 
• 2 Velazco MI, Wuensche L, and Deladoey P. inventors; US Patent,  6214788.  ; Chem. Abstr. 2000, 133, 265959
• 3a Torri S. Okamoto T. Bull. Chem. Soc. Jpn.  1976,  49:  771 
• 3b See also: Piers E. Britton RW. de Wall W. Can. J. Chem.  1971,  49:  12 
• 4 Fürstner A. Hannen P. Chem. Eur. J.  2006,  12:  3006 
• 5 Fehr C. Galindo J. Angew. Chem. Int. Ed.  2006,  45:  2901 
• 6a Hodgson DM. Chung YK. Paris J.-M. J. Am. Chem. Soc.  2004,  126:  8664 
• 6b Hodgson DM. Chung YK. Nuzzo I. Freixas G. Kulikiewicz KK. Cleator E. Paris J.-M. J. Am. Chem. Soc.  2007,  129:  4456 
• 7 For a recent example in natural product synthesis, see: Tashiro T. Mori K. Tetrahedron: Asymmetry  2008,  19:  1215 
• 8a Nwaukwa SO. Keehn PM. Tetrahedron Lett.  1982,  23:  35 
• 8b Malkov AV. Baxendale IR. Bella M. Langer V. Fawcett J. Russell DR. Mansfield DJ. Valko M. Kocovsky P. Organometallics  2001,  20:  673 
• 9a Formylation using HCO₂Et-NaH is known to lead to cis-11 preferentially (S:R = 7:93 at C-6), see: Kashima C. Miwa Y. Shibata S. Nakazono H. J. Heterocycl. Chem.  2002,  39:  1235 
• 9b For kinetic formylation, see: Zayia GH. Org. Lett.  1999,  1:  989 
• 10a Dreiding AS. Hartman JA. J. Am. Chem. Soc.  1953,  75:  939 
• 10b Searles S. Mortensen HE. J. Org. Chem.  1962,  27:  1979 
• 10c Vig OP. Bhatia MS. Verma AK. Matta KL. J. Indian Chem. Soc.  1970,  47:  277 
• 12 Gu Y. Snider BB. Org. Lett.  2003,  5:  4385 
• 13 Hodgson DM. Chung YK. Paris J.-M. Synthesis  2005,  2264 

11

Characterisation Data for (3R,6S)-6-Isopropyl-3-methyl-
2-methylenecyclohexanol (12): [α]_D ^²5 -100.9 (c = 1.42, CHCl₃). IR: 3480 (br), 3067 (w), 2958 (s), 2933 (s), 2870 (m), 1644 (w), 1475 (w), 1450 (w), 1029 (m), 948 (m), 905 (s) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.02 (d, J = 1.0 Hz, 1 H, =CH₂), 4.73 (d, J = 1.5 Hz, 1 H, CH₂), 3.83 (br s, 1 H, CHOH), 2.20-2.29 (m, 1 H, CHMe₂), 1.94-2.03 (m, 1 H, CHMe), 1.79-1.84 (m, 1 H, H-4a), 1.62-1.71 (m, 1 H,
H-5a), 1.56 (d, J = 5.5, 1 H, OH), 1.17-1.29 (m, 2 H, H-5b, H-6), 1.09 (d, J = 6.5 Hz, 3 H, CHMe), 0.95-1.02 (m, 1 H, H-4b), 0.93 (d, J = 7.0 Hz, 3 H, Me of CHMe₂), 0.87 (d, J = 7.0 Hz, 3 H, Me of CHMe₂). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.9 (=C), 100.6 (=CH₂), 74.3 (COH), 51.9 (C-6), 36.7 (CHMe), 35.9 (C-4), 26.5 (CHMe₂), 23.0 (C-5), 20.9 (Me of CHMe₂), 18.1 (CHMe), 15.8 (Me of CHMe₂). MS (CI⁺): m/z (%) = 152 (11), 151 (100), 150 (4). HRMS (CI): m/z
[M - OH]⁺ calcd for C₁₁H₁₉: 151.1487; found: 151.1488.

14

(1R,4R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo- [4.4.0.0^¹,5]decan-4-ol (15): n-BuLi (1.6 M in hexanes, 3.75 mL, 6.0 mmol) was added to a stirred solution of 2,2,6,6-tetramethylpiperidine (1.0 mL, 6.0 mmol) in t-BuOMe (30 mL) at -78 ˚C. The resulting pale yellow solution of LTMP was stirred at r.t. for 15 min and then cooled to 0 ˚C in an ice-bath. To a stirred solution of epoxide 6 (593 mg, 2.85 mmol) in t-BuOMe (14 mL) at 0 ˚C was added the above LTMP solution dropwise via a cannula over 3 h. The reaction mixture was stirred at r.t. for 17 h, then MeOH (3 mL) was added, the mixture was evaporated under reduced pressure and the residue dry-loaded onto a small amount of SiO₂ and purified by column chromatography (SiO₂, gradient elution, 20-35% Et₂O-PE) to give a white solid, cyclopropyl alcohol 15 (534 mg, 90%); R _f 0.4 (40% Et₂O-PE); mp 74-76 ˚C; [α]_D ^²5 -10.7 (c = 0.33, CHCl₃). IR: 3608 (w), 3447 (br), 3018 (m), 2958 (m), 2928 (m), 2870 (m), 1385 (w), 1371 (w), 1216 (s) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.22 (br s, 1 H, CHOH), 2.00-2.07 (m, 1 H, H-2a,), 1.79-1.88 (m, 1 H, H-10), 1.60-1.65 (m, 1 H, H-9a), 1.50-1.59 (m, 2 H, CHMe₂, H-3a), 1.38-1.45 (m, 3 H, H-2b, H-3b, H-8a), 1.20 (d, J = 4.5 Hz, 1 H, OH), 1.02-1.09 (m, 1 H, H-7), 1.00 (d, J = 6.5 Hz, 3 H, CHMe), 0.91-0.93 (m, 1 H, H-5), 0.91 (d, J = 7.0 Hz, 3 H, Me of CHMe₂), 0.87 (d, J = 7.0 Hz, 3 H, Me of CHMe₂), 0.82-0.85 (m, 1 H, H-8b), 0.52-0.60 (m, 1 H, H-9b), 0.38 (t, J = 3.0 Hz, 1 H, H-6). ^¹³C NMR (100 MHz, CDCl₃): δ = 75.1 (C-4), 44.1 (C-7), 35.5 (C-5), 34.5 (C-1), 33.5 (C-10), 31.6 (C-3), 31.4 (C-9), 29.9 (CHMe₂), 28.6 (C-2), 26.5 (C-8), 24.5 (C-6), 20.0 (CHMe), 19.6 (Me of CHMe₂), 19.1 (Me of CHMe₂). MS (CI⁺): m/z (%) = 208 (10) [M]⁺, 191 (100) [M - OH]⁺. HRMS (CI): m/z [M - OH]⁺ calcd for C₁₄H₂₃: 191.1800; found: 191.1811.

15

Characterisation data for (1S,4S,5S,6S,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.0^¹,5]decan-4-ol (17): [α]_D ^²5 +28.0
(c = 1.0, CHCl₃). IR: 3310 (br), 2954 (s), 2971 (s), 1470 (m), 1443 (w), 1383 (w), 1327 (w), 1057 (w), 974 (s) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.21 (d, J = 5.0 Hz, 1 H, CHOH), 1.95-2.03 (m, 1 H, H-2a), 1.88-1.94 (m, 1 H, H-10), 1.69-1.72 (m, 1 H, H-3a), 1.46-1.62 (m, 3 H, H-7, H-8a, H-9a), 1.32-1.43 (m, 3 H, CHMe₂, H-2b, H-3b), 1.08 (d, J = 7.0 Hz, 3 H, CHMe), 1.01 (d, J = 3.5 Hz, 1 H, H-5), 0.92 (d, J = 6.5 Hz, 3 H, Me of CHMe₂), 0.89 (d, J = 6.5 Hz, 3 H, Me of CHMe₂), 0.86-0.88 (m, 1 H, H-9b), 0.71-0.84 (m, 1 H, H-8b), 0.68 (t, J = 4.2, 1 H, H-6). ^¹³C NMR (100 MHz, CDCl₃): δ = 75.6 (C-4), 40.3 (C-7), 33.2 (C-10), 33.0 (C-3), 32.9 (C-5), 32.4 (C-1), 31.5 (C-2), 31.2 (CHMe₂), 28.6 (C-9), 23.55 (C-6), 23.5 (C-8), 20.8 (Me of CHMe₂), 20.7 (Me of CHMe₂), 20.5 (CHMe). MS (CI⁺): m/z (%) = 193 (1), 192 (13), 191 (100) [M - OH]⁺, 190 (26), 189 (37). HRMS (CI): m/z [M - OH]⁺ calcd for C₁₄H₂₃: 191.1800; found: 191.1806.