Spiroepoxide O-eq 2b was accordingly obtained as a colorless
liquid: de >98%; overall yield 7% (0.8 g). dH (300 MHz, CDCl3)
0.88 (3 H, d), 1.03–1.16 (2 H, m), 1.20–1.25 (2 H, m), 1.34–1.50
(1 H, m), 1.73–1.82 (4 H, m), 2.50 (2 H, s); dC (75 MHz, CDCl3)
21.5 (CH3), 31.4 (CH), 33.1 (2 × CH2), 33.8 (2 × CH2), 54.7 (CH2),
59.3 (C); m/z (EI) 126.1044 (M+, 4%, C8H14O requires 126.1045),
43 (14%), 54 (16), 55 (21), 81 (20), 84 (100), 97 (7), 111 (26).
as the appropriate solvent for stereoselective hydrogenation, since
the use of methanol and ethanol resulted in undesired byproducts.
For stereoselective hydrogenation, 5.0 g (40 mmol) 3,5-
dimethylcyclohex-2-enone was dissolved in 50 mL isopropanol
and 0.3 g Pd/C 5% was added. Hydrogenation was conducted at
2 atm for 1 hour at room temperature using a Parr apparatus.
The reaction mixture was filtered through Celite and the filtrate
diluted with 50 mL water. The ketone was extracted with pentane
(3 × 50 mL). The combined organic layers were washed with water
(3× 50 mL), dried over Na2SO4 and concentrated under reduced
pressure.
Ketone 3d was obtained as a yellow oil: de >99%; yield 93%
(4.7 g), containing trace amounts of solvent. dH (300 MHz, CDCl3)
0.94 (6 H, d), 1.75–1.89 (4 H, m), 2.24 (4H, d); dC (75 MHz, CDCl3)
22.1 (2 × CH3), 33.0 (2 × CH), 42.5 (CH2), 49.1 (2 × CH2), 211.0
(C). The reaction was repeated several times to obtain sufficient
amounts of starting ketone.
O-ax 6-tert-Butyl-1-oxaspiro[2.5]octane (1c)
Substrate 1c was prepared according to the procedure described
for compound 1b. The starting spiroepoxides 1c–2c were syn-
thesized by epoxidation of 4-tert-butylcyclohexanone (13.9 g,
90 mmol) using trimethylsulfonium iodide (31.0 g) and obtained
in 87% yield as a colorless liquid (13.5 g), in an epimeric mixture
of 1c (38%)–2c (62%).
From mixture 1c–2c (13.5 g, 80 mmol), the corresponding b-
bromohydrins were obtained in 89% yield as a yellow oil, as
a mixture of OH-ax 4c (42%)–OH-eq 5c (58%). Purification by
chromatography on silica gel with petroleum ether (bp 40–60 ◦C)–
diethyl ether (2 : 1) resulted in stereochemically pure OH-ax 4c as
a yellow oil: de = 97%; yield 13% (1.8 g). dH (300 MHz, CDCl3)
0.88 (9 H, s), 0.92–0.98 (1 H, m), 1.26–1.44 (4 H, m), 1.62–1.65
(2 H, m), 1.83–1.86 (2 H, m), 3.42 (2 H, s, broad); dC (75 MHz,
CDCl3) 22.4 (2 × CH2), 27.5 (3 × CH3), 32.3 (C), 35.8 (2 × CH2),
47.5 (CH2), 47.7 (CH), 69.2 (C).
Spiroepoxide O-ax 1c was eventually formed by ring closure of
OH-ax 4c and obtained as a colorless liquid: de = 97%; overall
yield 10% (1.1 g). dH (300 MHz, CDCl3) 0.87 (9 H, s), 0.94–1.08
(1 H, m), 1.09–1.41 (4 H, m), 1.75–1.89 (4 H, m), 2.61 (2 H, s); dC
(75 MHz, CDCl3) 25.2 (2 × CH2), 28.0 (3 × CH3), 32.9 (C), 33.8
(2 × CH2), 47.6 (CH), 54.2 (CH2), 58.7 (C); m/z (EI) 168.1516
(M+, 4%, C11H20O requires 168.1514), 41 (30%), 57 (86), 79 (24),
81 (26), 84 (100), 95 (13), 111 (40), 112 (23), 153 (56).
O-ax 5,7-Dimethyl-1-oxaspiro[2.5]octane (1d)
Substrate 1d was prepared according to the procedure de-
scribed for compound 1b. The starting spiroepoxides 1d–
2d were synthesized by epoxidation of the prepared cis-3,5-
dimethylcyclohexanone 3d (19.0 g, 151 mmol) using trimethyl-
sulfonium iodide (55.2 g). Spiroepoxides 1d–2d were obtained in
90% yield as a colorless liquid (19.0 g), as an epimeric mixture of
1d (67%)–2d (33%).
From mixture 1d–2d (19.0 g, 140 mmol), the corresponding
b-bromohydrins were obtained in 93% yield as a yellow oil, as
a mixture of OH-ax 4d (70%)–OH-eq 5d (30%). Purification by
chromatography on silica gel with petroleum ether (bp 40–60 ◦C)–
diethyl ether (2 : 1) resulted in stereochemically pure OH-ax 4d as
a yellow oil: de = 93%; yield 15% (2.9 g). dH (300 MHz, CDCl3)
0.44 (2 H, q), 0.84 (6 H, d), 1.57–1.83 (6 H, m), 1.87 (1 H, s, broad),
3.34 (2 H, s); dC (75 MHz, CDCl3) 22.1 (2 × CH3), 27.8 (2 × CH),
43.4 (CH2), 43.5 (2 × CH2), 47.3 (CH2), 70.9 (C).
O-eq 6-tert-Butyl-1-oxaspiro[2.5]octane (2c)
Spiroepoxide O-ax 1d was formed by ring closure of OH-ax 4d
and obtained as a colorless liquid: de = 93%; overall yield 10%
(0.6 g). dH (300 MHz, CDCl3) 0.54 (2 H, q), 0.85 (6 H, d), 1.14
(2 H, t, broad), 1.37 (2 H, t), 1.64–1.79 (2 H, m), 2.54 (2 H, s); dC
(75 MHz, CDCl3) 22.2 (2 × CH3), 30.1 (2 × CH), 41.0 (2 ×CH2),
43.0 (CH2), 53.5 (CH2), 58.6 (C); m/z (EI) 139.1123 (M+, 2%,
C9H15O requires 139.1127), 41 (10%), 55 (13), 67 (10), 68 (8),
69 (10), 95 (13), 98 (11), 125 (100), 139 (4).
Substrate 2c was accordingly prepared by ring closure from its cor-
responding b-bromohydrin OH-eq 5c. For this, stereochemically
pure OH-eq 5c has been isolated as a yellow oil: de >98%; yield
9% (1.2 g). dH (300 MHz, CDCl3) 0.86 (9 H, s), 0.93–1.10 (2 H, m),
1.20–1.30 (1 H, m), 1.54–1.61 (2 H, m), 1.73–1.76 (2 H, m), 2.00
(2 H, d), 2.27 (1 H, s, broad), 3.64 (2 H, s, broad); dC (75 MHz,
CDCl3) 24.3 (2 × CH2), 27.5 (3 × CH3), 32.1 (C), 36.6 (2 × CH2),
43.3 (CH2), 47.3 (CH), 70.4 (C).
Spiroepoxide 2c was obtained as a colorless liquid: de >98%;
overall yield 7% (0.5 g). dH (300 MHz, CDCl3) 0.87 (9 H, s), 1.02–
1.33 (5 H, m), 1.81–1.91 (4 H, m), 2.57 (2 H, s); dC (75 MHz, CDCl3)
26.6 (2 × CH2), 27.6 (3 × CH3), 32.3 (C), 33.9 (2 × CH2), 47.2
(CH), 55.0 (CH2), 60.0 (C); m/z (EI) 168.1516 (M+, 2%, C11H20O
requires 168.1514), 41 (36%), 57 (100), 79 (21), 81 (21), 84 (92),
95 (13), 111 (37), 112 (18), 153 (45).
O-eq 5,7-Dimethyl-1-oxaspiro[2.5]octane (2d)
Substrate 2d was accordingly prepared by ring closure from its
corresponding b-bromohydrin OH-eq 5d. For this, stereochemi-
cally pure OH-eq 5d has been isolated as a yellow oil: de = 90%;
yield 12% (2.3 g). dH (300 MHz, CDCl3) 0.48 (1 H, q), 0.86 (6 H,
d), 1.07 (1 H, t), 1.28–1.41 (2 H, m), 1.58–1.63 (2 H, m), 1.84 (2 H,
d, broad), 2.11 (1 H, s, broad), 3.55 (2 H, s); dC (75 MHz, CDCl3)
22.2 (2 × CH3), 29.7 (2 × CH), 43.3 (CH2), 44.3 (CH2), 44.6 (2 ×
CH2), 71.3 (C).
cis-3,5-Dimethylcyclohexanone (3d)
Ketone 3d was used as the starting compound for the synthesis of
substrates 1d and 2d. Ketone 3d was prepared by stereoselective
hydrogenation of 3,5-dimethylcyclohex-2-enone.26 From prelimi-
nary experiments, the sterically hindered isopropanol was selected
Spiroepoxide 2d was obtained as a colorless liquid: de = 90%;
overall yield 12% (0.4 g). dH (300 MHz, CDCl3) 0.58 (2 H, q), 0.88
(6 H, d), 1.14–1.19 (2 H, m), 1.38 (2 H, t), 1.50–1.64 (2 H, m), 2.51
(2 H, s); dC (75 MHz, CDCl3) 22.2 (2 × CH3), 31.8 (2 × CH), 41.9
3112 | Org. Biomol. Chem., 2007, 5, 3106–3114
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The Royal Society of Chemistry 2007
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