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DOI: 10.1055/s-0029-1217353
Thieme Chemistry Journal Awardees - Where Are They Now? Synthesis of (-)-Cubebol by Intramolecular Cyclopropanation of a Terminal Epoxide
Publication History
Publication Date:
12 June 2009 (online)
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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
- 1
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6a
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6b
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9a Formylation
using HCO2Et-NaH is known to lead to
cis-11 preferentially
(S:R = 7:93
at C-6), see:
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9b For kinetic formylation,
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References and Notes
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.
(1R,4R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo- [4.4.0.0¹,5]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.
15Characterisation data for (1S,4S,5S,6S,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.0¹,5]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.