Synthesis of optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one

Article abstract of DOI:10.1016/j.tetasy.2006.03.013

Bicyclo[2.2.2]octanone is an important building block for the synthesis of bioactive compounds and natural products. Herein, we present a new synthetic route for the formation of (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one derivatives via a catalytic as

Full text of DOI:10.1016/j.tetasy.2006.03.013

Tetrahedron: Asymmetry 17 (2006) 993–998
Synthesis of optically active
(1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one
Nikolay T. Tzvetkov,a Philip Schmoldt,a Beate Neumann,b Hans-Georg Stammlerb
and Jochen Mattaya,*
aOrganische Chemie I, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Postfach 100131, 33501 Bielefeld, Germany
bAbteilung fu¨r Ro¨ntgenstrukturanalyse AC III, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Universita¨tsstr. 25,
33615 Bielefeld, Germany
Received 22 February 2006; accepted 14 March 2006
Available online 12 April 2006
Abstract—Bicyclo[2.2.2]octanone is an important building block for the synthesis of bioactive compounds and natural products. Herein,
we present a new synthetic route for the formation of (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one derivatives via a catalytic asymmet-
ric Michael reaction in high stereoselectivity and yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
combines high product yield and an enantiomeric excess
of more than 90% on a multigram scale. The addition of
dimethyl malonate 2 to 1 employing the chiral catalyst 4
yielded 5 in 92% (Scheme 1).
Optically active derivatives with a bicyclo[2.2.2]octane
framework are important building blocks for the construc-
tion of molecules for mimicking bioactive compounds and
have been successfully employed in regio- and stereocon-
trolled transformations towards natural products.1–4 Our
initial intention was to synthesize compounds with a bicy-
clo[2.2.2]oct-5-en-2-one backbone based on substituted
cyclohex-2-en-1-ones as starting material for photochemi-
cal conversions via the oxa-di-p-methane rearrangement.5,6
Since our synthetic route involves the addition of malo-
nates to cyclohex-2-en-1-ones, which is achieved by a cata-
lytic asymmetric reaction on a scale of up to 100 g, we
implemented this asymmetric step in our synthesis, thus
providing an enantiomeric excess (>99% ee) of optically
active bicyclo[2.2.2]octanone derivatives.7–13
As previously reported, we also added powdered molecular
sieves (MS) 4 A to the reaction medium.14–16 In contrast to
˚
18
˚
˚
the MS beads 4 A, powdered MS 4 A greatly improved
the catalytic asymmetric Michael addition.14
The optical purity of 5 was higher than 99% and was deter-
mined via its ketalization with D-(ꢀ)-2,3-butanediol (>99%
1
ee, Fluka); only one diastereoisomer was detected by H
and 13C NMR spectroscopy (the chemical shifts of the
two diastereomers are different; see the Experimental)
and gas chromatography [a mixture of two diastereomers
gave two peaks, whereas the (R)-enantiomer 6 is only one
peak]. The absolute configuration of 5 was confirmed by
X-ray crystal structure analysis (Fig. 1).19
2. Results and discussion
The following decarboxylation reaction20 of 5 using LiIÆ
3H2O and acetalization of 7 produced 8 in an overall yield
of 69%. The reduction to alcohol 9 and reoxidation yielded
aldehyde 10 in acceptable 65% yield. This two-step proce-
dure is favoured over the direct reduction employing
reagents such as DIBAH, which yielded 10 in only 30%.
Treatment of 10 with phosphoric acid gave bicyclic com-
pound (ꢀ)-11 via an intramolecular aldol type cyclization
in 38% yield (Scheme 2).19
The asymmetric 1,4-addition of dimethyl malonate to
cyclohex-2-en-1-one is well documented in the litera-
ture.14–17 Among various additives for this addition reac-
tion, the use of a chiral binaphthol 3 based catalyst
*
Corresponding author. Tel.: +49 (0)521 1062072; fax: +49 (0)521
1066417; e-mail: mattay@uni-bielefeld.de
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.013

994
N. T. Tzvetkov et al. / Tetrahedron: Asymmetry 17 (2006) 993–998
O
O
O
O
O
*
O
O
O
O
O
O
a
b
+
R
R
*
O
O
O
O
O
1
5
6
2
chiral cat.
THF
OH
OH
O
O
O
+
LiAlH4
Al
Li
(-2HH)
O
(R)-1,1´-bi-2-naphthol
(R)-ALB Complex
[(R)-BINOL]
3
4
˚
Scheme 1. Reagents and conditions: (a) 0.1 M (R)-ALB in THF (1.0 mol %) (4), KO-t-Bu (0.9 equiv to ALB) in THF (0.25 M), MS 4 A, rt, 72 h, 92%
(>99% ee); (b) (2R,3R)-(ꢀ)-butanediol (>99% ee), p-TsOH, PhH, reflux 2 h, 96%.
cally pure bicyclo[2.2.2]octane systems,1,4,10,11,23–25 we con-
sider our strategy a useful supplement in this area.
3. Conclusion
In conclusion we have presented a new synthetic strategy
for the construction of optically active (1R,4S,6S)-6-
hydroxybicyclo[2.2.2]octan-2-one (ꢀ)-11. Thereby, the nec-
essary stereochemical information was introduced in the
first step of the reaction sequence by an asymmetric cata-
lytic 1,4-addition of dimethyl malonate to cyclohex-2-en-
1-one. This reaction can easily be carried out on a multi-
gram scale. The experimental and literature data (see the
Experimental for compounds 5 and 7–9) have proven the
high stereoselectivity (>99% ee) of the proposed synthetic
approach. By simply employing the optical antipode of
the catalyst, that is, (S)-binaphthol in the synthesis of the
catalyst, the corresponding (S)-enantiomer of 5 should be
easily accessible as well, emphasizing the flexibility of this
reaction sequence.
Figure 1. X-ray crystal structure analysis of 5.
The endo-epimer11,21 was the only product isolated,
deduced from the available IR- and NMR-spectroscopic
data (1D and 2D spectra including NOESY experiment21)
and the melting point11,21 of (ꢀ)-11. Fortunately, the rela-
tive endo-configuration of (ꢀ)-11 was confirmed by an
X-ray crystal structure analysis (Fig. 2).19
4. Experimental
Chiral catalyst (R)-aluminium-lithium-bis-(binaphthoxid)-
complex [(R)-ALB] was prepared according to the litera-
ture procedure.14 All solvents used were of analytically
pure quality or purified by distillation from potassium
and LiAlH4 under an argon atmosphere immediately be-
fore use in all reactions. Commercial (R)-1,10-bi-2-naph-
thol [(R)-BINOL, >99% ee, Fluka], dimethylmalonate
(Fluka) and cyclohex-2-en-1-one (Fluka), (2R,3R)-(ꢀ)-
butanediol (>99% ee, Fluka), LiAlH4 (Merck-Schuchardt),
potassium tert-butylate (Merck), p-toluene-sulfonacid
monohydrate (Aldrich), lithium iodate trihydrate (Fluka),
ethylene glycol (Fluka), oxalic acid dichloride (Aldrich)
were used as provided. NMR spectra were measured on a
Comparison with similarly formed bicyclo[2.2.2]-octe-
nones22 and the experimental data (see the Experimental)
led us to assume that (ꢀ)-11 has the (1R,4S,6S)-configura-
tion.10,11 Since none of the reactions presented in Scheme 2
causes isomerization at the stereogenic centre, the enantio-
meric purity of (ꢀ)-11 should be the same as that of com-
pound 5. In addition to recent reports by other groups
regarding synthesis and transformations of enantiomeri-

N. T. Tzvetkov et al. / Tetrahedron: Asymmetry 17 (2006) 993–998
995
O
O
O
O
O
O
O
O
a
b
R
R
R
*
*
*
O
O
O
5
7
8
O
O
O
O
O
4S
O
c
d
e
6S
OH
1R
R
R
*
*
O
OH
H
(-)-11
10
9
Scheme 2. Reagents and conditions: (a) LiIÆ3H2O, DMSO, 52%; (b) ethylene glycol, p-TsOH, PhH, reflux 2 h, 95%; (c) LiAlH4, Et2O, 86%; (d) (COCl)2,
DMSO, Et3N, CH2Cl2, 85%; (e) H3PO4, THF/water, reflux 2 h, 38%.
capillary column (25.0 m, 0.20 mm, 0.33 lm); software
Class 5000 V 2.0 and LabSolutions GCMSolution V 1.02
(Schimadzu); carrier gas helium (pressure 0.95 bar). GC
analysis was carried out using Shimadzu GC-17A/ver. 3
(FID detector and Class VP 4.2 software) equipped with
HP-5MS (Hewlett–Packard) capillary column (25.0 m,
0.20 mm, 0.33 lm). HPLC was performed on a silica gel
column (Macherey & Nagel Nucleosil 100-7, 250 · 21 mm
and 50 · 21; flow 10 mL minꢀ1) with use of a Merck-Hit-
achi pump (L-6250) and a Merck-Hitachi UV–vis-detector
(L-7420). Analytical thin-layer chromatography (TLC) was
carried out on silica gel thick plates (Alugramꢂ, 0.20 mm)
with fluorescent indicator SIL G/UV254 (Macherey &
Nagel). Column chromatography was carried out on silica
gel MN-60 (40–60 lm Macherey & Nagel).
4.1. Preparation of (R)-AlLibis(binaphthoxide) [(R)-ALB]
complex in THF solution 414,15
To a suspension of fresh LiAlH4 (powder, 189.8 mg,
5.0 mmol) in 20 mL of dry THF, (R)-BINOL (2.864 g,
Figure 2. X-ray crystal structure analysis of (ꢀ)-11.
10.0 mmol) in dry THF (20 mL, plus 5 mL · 2) was slowly
added via cannula and a septum at 0 ꢁC. After being stirred
Bruker DRX 500 (1H NMR: d = 500.13 MHz; 13C NMR:
at the same temperature under an argon atmosphere for
30 min and then at room temperature for an additional
70 min, the resulting white mixture was kept standing with-
out stirring overnight (22 h). The resulting solution was
used as 0.1 M (R)-ALB-complex in THF.
d = 125.77 MHz) instrument in CDCl3 with CHCl3 as ref-
1
erence (for H: d = 7.26 ppm; for 13C: d = 77.0 ppm) or
1
DMSO-d6 (for H: d = 2.49 ppm; for 13C: d = 39.7 ppm).
Infrared spectra (IR) were recorded on a Perkin–Elmer
841 Infrared Spectrophotometer or a Matson Genesis
Series ATT FT-IR spectrometer. Specific rotations were
measured on a Perkin–Elmer 341 polarimeter at the
sodium D line. Melting points were measured in an open
4.2. (R)-Dimethyl 2-(3-oxocyclohexyl)malonate 5 (100 g
scale reaction using 1.0 mol % of the (R)-ALB-KO-t-Bu
catalyst)14
capillary tube on a Buchi B-540 instrument and are
¨
uncorrected (to 100 0.3 ꢁC, to 250 0.5 ꢁC, to 400
0.8 ꢁC). Elemental analyses were carried out on a Perkin–
Elmer 240 instrument. High-resolution mass spectra
(HRMS) were recorded on a Micromass VG Autospec X
(Vacuum Generators, Manchester) with EI in positive ion
mode. GC/MS were recorded on a Shimadzu GC 17A/
MSQP 5050A equipped with a Hewlett–Packard 5MS
KO-t-Bu (483 mg) in 17 mL dry THF (0.253 M; 4.3 mmol),
66.0 g dimethyl malonate 2 (57.1 mL; 0.50 mol) and 48.1 g
cyclohex-2-en-1-one 1 (0.50 mol) were successively added
to a mixture of (R)-ALB-complex 4 (in dry THF, 0.05 M;
100 mL, 5.0 mmol) and 10 g freshly opened powdered
˚
molecular sieves 4 A (Fluka catalog No. 69836). After
being stirred for 72 h at room temperature, the reaction

996
N. T. Tzvetkov et al. / Tetrahedron: Asymmetry 17 (2006) 993–998
mixture was diluted with 100 mL ethyl acetate and filtered
over Celiteꢂ 545 to remove the molecular sieves. The fil-
trate was washed with 40 mL of 0.1 M hydrochloric acid
and extracted with 2 · 40 mL ethyl acetate. The combined
organic layers were washed with 2 · 10 mL saturated NaH-
CO3 solution, brine (2 · 50 mL), dried over Na2SO4 and
concentrated under reduced pressure. The crude product
was purified by repeated recrystallization (toluene/n-hex-
ane 1:1, 100 mL) to afford a combined yield of pure 5
(81.1 g). The remaining mother liquor was concentrated
and again purified by repeated recrystallization (toluene/
n-hexane 1:1, 40 mL) to give a combined yield of pure 5
(11.3 g) after filtration, which spontaneously recrystallized.
The remaining mother liquor was again concentrated yield-
ing a residue, which was then purified by alumina flash
chromatography (acetone/n-hexane 1:6) to give another
12.9 g of pure 5. The combined yield of 5 was 105.3 g
(0.46 mol; 92%; >99% ee). Most of the (R)-BINOL was
1.67–1.78 (m, 3H), 2.42 (ddd, J = 3.5/11.9/23.9 Hz, 1H),
3.24 (d, J = 8.5 Hz, 1H, 10-H), 3.55–3.62 (m, 2H, O–CH),
3.69 (s, 3H, O–CH3), 3.71 (s, 3H, O–CH3); 13C NMR
(CDCl3, 125 MHz): d = 16.78 (CH3), 17.03 (CH3), 22.32
(CH2), 29.02 (CH2), 35.67 (CH, C-3), 36.68 (CH2), 39.96
(CH2), 52.31 (2 · CH3, O–CH3), 57.01 (CH, C-10), 78.04
(2 · CH, O–CH), 107.60 (Cq, C-1), 168.84 (Cq, CO2CH3),
168.94 (Cq, CO2CH3).
Racemate: 13C NMR (CDCl3, 125 MHz): d = 16.78 (CH3),
16.96 (CH3), 17.03 (CH3), 17.08 (CH3), 22.32 (CH2), 22.64
(CH2), 29.01 (CH2), 29.07 (CH2), 35.27 (CH), 35.70 (CH),
35.76 (CH2), 36.68 (CH2), 39.96 (CH2), 40.89 (CH2), 52.28
(2CH3, O–CH3), 52.31 (2CH3, O–CH3), 57.01 (CH, C-10),
57.10 (CH, C-10), 77.84 (CH, O–CH), 78.04 (2CH, O–
CH), 78.24 (CH, O–CH), 107.60 (Cq), 107.66 (Cq),
168.80 (Cq), 168.83 (Cq, CO2CH3), 168.91 (Cq, CO2CH3),
~
168.94 (Cq, CO2CH3); IR (neat): m ¼ 2360, 2341, 1734,
recovered during chromatography as a fraction eluted after
1635, 1456, 1437, 1261, 1151, 1095, 1024, 796 cmꢀ1; MS
m/z (relative intensity): 300 (5), 257 (5), 241 (7), 197 (6),
170 (11), 169 (94), 165 (4), 153 (10), 141 (8), 128 (9), 127
(70), 125 (16), 124 (28), 115 (9), 114 (47), 97 (60), 96 (16),
81 (12), 79 (16), 69 (32), 67 (14), 59 (19), 55 (100), 53 (8),
43 (35), 42 (13), 41 (37), 39 (7); HRMS (EI): m/z calcd
for C15H24O6 300.1573, found 300.1571, deviation 0.24 ppm.
28
the main product 5; mp 56.5–57.5 ꢁC; ½aꢁD ¼ þ3:6 (c 2.28,
28
CHCl3) and ½aꢁD ¼ þ3:3 (c 1.00, CHCl3) {lit.15,17 for 5:
28
½aꢁD ¼ þ3:75 (c 2.28, CHCl3); mp 54.5–55.5 ꢁC; >99%
1
ee}; H NMR (CDCl3, 500 MHz): d = 1.47 (ddd, J = 3.6/
12.8/24.3 Hz, 1H), 1.66 (tddd, J = 4.4/12.5/12.5/12.5 Hz,
1H), 1.89–1.95 (m, 1H), 2.05 (ddd, J = 3.4/6.6/13.7 Hz,
1H), 2.20–2.27 (m, 2H), 2.35–2.40 (m, 1H), 2.42 (td,
J = 2.2/4.2 Hz, 1H), 2.51 (ddd, J = 3.8/8.1/19.9 Hz, 1H),
3.31 (d, J = 8.0 Hz, 1H, 10-H), 3.72 (s, 3H, O–CH3), 3.73
(s, 3H, O–CH3); 13C NMR (CDCl3, 125 MHz): d = 24.5
(CH2, C-5), 28.8 (CH2, C-4), 38.1 (CH, C-3), 40.9 (CH2,
C-6), 45.1 (CH2, C-2), 52.6 (2CH3, O–CH3), 56.6 (CH, C-
10), 168.1 (Cq, CO2CH3), 168.2 (Cq, CO2CH3), 209.5
4.4. (R)-Methyl 2-(3-oxocyclohexyl)acetate 7
(R)-Dimethyl 2-(3-oxocyclohexyl)-malonate
5
(80.0 g,
0.350 mol) and LiIÆ3H2O (60.0 g, 0.318 mol) in 500 mL
DMSO were heated for 25 min at 180 ꢁC in a 1000 mL
round bottomed flask equipped with a reflux condenser
(CO2 production). After cooling to room temperature,
the reaction mixture was diluted with 400 mL water and
portioned into two parts of 500 mL, each extracted with
3 · 150 mL diethyl ether. The combined organic phase
was washed with 2 · 100 mL brine, dried over Na2SO4
and concentrated under reduced pressure. The residue
was purified first by vacuum distillation (bp 86–89 ꢁC/
0.032 mbar), and secondly by Kugelrohr distillation
~
(Cq, C-1); IR (KBr): m ¼ 3472, 2960, 2873, 1737, 1435,
1258, 1157, 1105, 1062, 1017, 950, 929, 870, 795,
751 cmꢀ1; MS m/z (relative intensity): 228 (2), 197 (13),
168 (23), 165 (13), 157 (18), 153 (25), 141 (11), 137 (11),
136 (25), 133 (11), 132 (34), 101 (38), 100 (25), 99 (11), 98
(10), 97 (100), 96 (66), 95 (12), 81 (19), 79 (10), 74 (18),
69 (39), 68 (65), 67 (19), 59 (45), 55 (33), 53 (14), 42 (35),
41 (49).
(0.020 mbar/75 ꢁC for 1 h) yielding 31.9 g (52%) of a col-
28
4.3. (R)-2-(2,3-Dimethyl-1,4-dioxaspiro[4,5]dec-7-yl)-di-
methylmalonate 6
ourless oil; ½aꢁD ¼ þ8:9 (c 1.00, CHCl3) {lit.26 for (S)-iso-
25
mer: ½aꢁD ¼ ꢀ8:7 (c 0.96, CHCl3)}; 1H NMR (CDCl3,
500 MHz): d = 1.37 (dddd, J = 3.6/10.4/12.0/23.8 Hz,
1H), 1.60–1.70 (m, 1H), 1.87–1.93 (m, 1H), 1.97–2.04 (m,
1H), 2.05 (ddd, J = 1.3/11.3/14.0 Hz, 1H), 2.17–2.37 (m,
5H), 2.41 (tddt, J = 3.9/4.0/14.0/3.9 Hz, 1H), 3.64 (s, 3H,
O–CH3); 13C NMR (CDCl3, 125 MHz): d = 24.7 (CH2),
30.8 (CH2), 35.5 (CH, C-10), 40.7 (CH2), 41.0 (CH2), 47.4
(CH2), 51.6 (CH3, O–CH3), 172.1 (Cq, CO2CH3), 210.4
(Cq, C-1); IR (neat): ~m ¼ 3460, 2957, 2001, 1736, 1438,
1347, 1315, 1225, 1157, 1098, 1059, 1037, 998, 955, 911,
868, 851, 753, 704 cmꢀ1; MS m/z (relative intensity): 171
(5), 170 (17), 139 (10), 127, (10), 110 (19), 99 (33), 98
(10), 97 (100), 96 (20), 95 (32), 82 (20), 79 (8), 74 (26), 71
(8), 69 (20), 68 (19), 67 (18), 59 (35), 55 (71), 53 (13), 43
(23), 42 (30), 41 (71), 39 (28).
For determining the enantiomeric excess of the former
reaction (2R,3R)-(ꢀ)-butanediol (0.6 mL, 0.66 mmol,
>99% ee, Fluka), a catalytic amount of p-toluenesulfonic
˚
acid (p-TsOH) and 0.5 g molecular sieve 4 A were added
to a solution of 150 mg (0.60 mmol) of the adduct 5 in
5 mL benzene. After refluxing the solution for 2 h, 10 mL
of saturated NaHCO3 solution was added and the mixture
was extracted with 3 · 10 mL diethyl ether. The combined
organic phase was dried over MgSO4 and purified by
HPLC (EtOAc/cyclohexane 90:10) yielding 190 mg (96%)
of pure product as a yellowish oil after removal of the sol-
vent by Kugelrohr distillation (0.02 mbar/5 h). The same
28
procedure was used for the racemic mixture; ½aꢁD
¼
ꢀ12:9 (c 1.00, CHCl3); 1H NMR (CDCl3, 500 MHz):
d = 1.03 (dtd, J = 3.6/12.2/18.4 Hz, 1H), 1.19 (d, J =
5.7 Hz, 3H, CH3), 1.21 (d, J = 5.6 Hz, 3H, CH3), 1.32 (t,
J = 12.4 Hz, 1H), 1.43 (ddt, J = 4.9/12.5/13.4 Hz, 1H),
1.57 (ttd, J = 3.2/12.5/12.5 Hz, 1H), 1.62–1.66 (m, 1H),
4.5. (R)-Methyl 2-(1,4-dioxaspiro[4.5]dec-7-yl)acetate 8
To a solution of 28.0 g (0.165 mol) (R)-methyl 2-(3-
oxocyclohexyl)acetate 7, 26.0 g (0.419 mol) of dry ethylene

N. T. Tzvetkov et al. / Tetrahedron: Asymmetry 17 (2006) 993–998
997
˚
glycol and 10 g molecular sieves 4 A in a 100 mL of dry
4.7. (R)-2-(1,4-Dioxaspiro[4.5]dec-7-yl)acetaldehyde 10
benzene was added a catalytic amount of p-TsOH
(0.016 mol) and the mixture was stirred at reflux under
argon atmosphere for 2 h. After cooling to room tem-
perature, the reaction was carefully diluted with 100 mL
of water and extracted with 4 · 200 mL diethylether. The
combined organic layer was washed with 50 mL water,
50 mL saturated NaHCO3 solution, dried over Na2SO4
and was concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel
Dimethylsulfoxide (11.1 g, 142 mmol) in 32 mL dichloro-
methane was slowly added over a period of 15 min to a
solution of 9.00 g (70.9 mmol) oxalyl chloride in 154 mL
of dry dichloromethane under an argon atmosphere at
ꢀ78 ꢁC. Stirring was continued for 10 min at this tempera-
ture. Then, 12.0 g (64.4 mmol) of (R)-2-(1,4-dioxa-
spiro[4.5]dec-7-yl)-1-ethanol 9 in 50 mL dry dichloro-
methane was added over a period of 20 min and stirring
continued for an additional 15 min. The mixture was
quenched at ꢀ78 ꢁC with 32.6 g (322 mmol) triethylamine
in 10 mL dichloromethane and allowed to reach room
temperature. After adding 160 mL water, the phases were
separated and the aqueous phase was extracted with
2 · 100 mL dichloromethane. The combined organic phase
was washed with 100 mL brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (EtOAc/
(EtOAc/cyclohexane 20:80) yielding 33.6 g (95%) of
28
a colourless oil, Rf = 0.48; ½aꢁD ¼ þ3:1 (c 1.00, CHCl3)
25
{lit.27 for 7: ½aꢁD ¼ þ3:0 (c 0.14, CHCl3)}; 1H NMR
(CDCl3, 500 MHz): d = 0.83 (ddd, J = 3.4/12.8/24.4 Hz,
1H), 1.11 (t, J = 12.5 Hz, 1H), 1.26–1.33 (m, 1H), 1.37–
1.47 (m, 1H), 1.56–1.62 (m, 3H), 1.66 (ddd, J = 2.0/3.8/
12.8 Hz, 1H), 1.92–2.02 (m, 1H), 2.10–2.12 (m, 2H),
3.53 (s, 3H, O–CH3), 3.79–3.82 (m, 4H, O–CH2CH2–O);
13C NMR (CDCl3, 125 MHz): d = 22.6 (CH2), 31.20
(CH2), 32.4 (CH, C-10), 34.4 (CH2), 40.9 (CH2), 41.0
(CH2), 51.1 (CH3, O–CH3), 64.0 (CH2, O–CH2CH2–O),
64.1 (CH2, O–CH2CH2–O), 108.5 (Cq, C-1), 172.7 (Cq,
cyclohexane 80:20) yielding 10.1 g (85%) of a colourless
28
oil, Rf = 0.78; ½aꢁD ¼ þ1:5 (c 1.00, CHCl3); 1H
NMR (CDCl3, 500 MHz): d = 0.90–0.99 (m, 1H), 1.24
(t, J = 12.4 Hz, 1H), 1.40 (dd, J = 8.8/13.3 Hz, 1H), 1.50–
1.60 (m, 1H), 1.67–1.77 (m, 4H), 2.15–2.25 (m, 1H, 7-H),
2.30–2.33 (m, 2H, CH2–CHO), 3.90–3.94 (m, 4H,
O–CH2CH2–O), 9.72 (t, J = 2.2 Hz, 1H, CHO); 13C
NMR (CDCl3, 125 MHz): d = 22.9 (CH2), 30.4 (CH),
31.6 (CH2), 34.6 (CH2), 41.3 (CH2), 50.5 (CH2, CH2–
CHO), 64.2 (O–CH2), 64.3 (O–CH2), 108.7 (Cq), 202.2
~
CO2CH3); IR (neat): m ¼ 3518, 2946, 2677, 2006, 1738,
1435, 1354, 1335, 1283, 1171, 1095, 1046, 1014, 948, 930,
908, 845, 769, 684 cmꢀ1; MS m/z (relative intensity): 214
(4), 183 (8), 171 (19), 141 (42) 113 (16), 100 (11), 99
(100), 95 (8), 86 (37), 55 (26), 43 (10), 42 (15), 41 (25),
39 (6).
4.6. (R)-2-(1,4-Dioxaspiro[4.5]dec-7-yl)-1-ethanol 927
(CHO); IR (neat): m ¼ 3446, 2932, 1709, 1448, 1353,
~
1313, 1279, 1226, 1140, 1070, 1039, 948, 882, 845, 817,
766, 682 cmꢀ1; MS m/z (relative intensity): 184 (1), 141
(28), 113 (38), 99 (86), 96 (100), 87 (11), 69 (11), 55 (34),
43 (15), 42 (26), 41 (48), 39 (12); Elemental analysis calcd
(%) for C10H16O3 (184.232): C 65.19, H 8.75; found: C
64.93, H 8.32.
A solution of 26.0 g (0.121 mol) (R)-methyl 2-(1,4-dioxa-
spiro[4.5]dec-7-yl)acetate 8 in 35 mL dry diethyl ether
was added dropwise to
a
suspension of 5.53 g
(0.146 mol) LiAlH4 in 250 mL of dry diethylether under
an argon atmosphere. After complete addition, the mix-
ture was refluxed for 2 h. The reaction mixture was cooled
to room temperature and water was carefully added until
a white solid precipitated and hydrogen evolution was
completed (140 mL). The diethyl ether was decanted and
the white solid washed with 3 · 200 mL methyl-tert-butyl
ether (MTBE). The combined organic layers were washed
with 2 · 50 mL saturated NaHCO3 solution, dried over
Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica
gel (EtOAc/cyclohexane 50:50) yielding 19.5 g (86%) of a
4.8. (1R,4S,6S)-6-Hydroxybicyclo[2.2.2]octan-2-one (ꢀ)-11
A solution of 7.00 g (38.0 mmol) of (R)-2-(1,4-dioxa-
spiro[4.5]dec-7-yl)acetaldehyde 10 and 74 mL of a mixture
of 5 M phosphoric acid and THF (ratio 1:1) was heated at
reflux for 4 h. After reaching room temperature, the solu-
tion was concentrated under reduced pressure, diluted with
30 mL water and extracted with 3 · 100 mL diethylether.
The combined organic phase was washed with 100 mL of
saturated NaHCO3 solution, dried over Na2SO4 and con-
centrated under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc/cyclohex-
ane 60:40) yielding 2.01 g (38%, >99% ee) of a white solid,
Rf = 0.53. The crude crystalline material was recrystallized
28
1
colourless oil, Rf = 0.46; ½aꢁD ¼ þ3:3 (c 1.00, CHCl3); H
NMR (CDCl3, 500 MHz): d = 0.87 (ddd, J = 2.4/12.5/
25.1 Hz, 1H), 1.19 (t, J = 12.6 Hz, 1H), 1.35–1.53 (m,
5H), 1.67–1.75 (m, 4H), 1.75–1.77 (m, 1H, OH), 3.66
(dt, J = 1.4/6.9 Hz, 2H, 20-H), 3.88–3.93 (m, 4H, O–
CH2CH2–O); 13C NMR (CDCl3, 125 MHz): d = 23.1
(CH2), 31.8 (CH2), 32.2 (CH, C-3), 34.7 (CH2), 39.7
(CH2) 41.7 (CH2), 60.7 (CH2–OH), 64.1 (O–CH2), 64.3
from n-hexane/benzene 1:1 (12 mL) to give (ꢀ)-11 as white
21
crystals with mp = 197.4–199.8 ꢁC; ½aꢁD ¼ ꢀ5:2 (c 1.00,
22
CHCl3) {lit.10 for (ꢀ)-11: ½aꢁD ¼ ꢀ6:5 (c 1.00, CHCl3);
(O–CH2), 109.2 (Cq); IR (neat): m ¼ 3434, 2935, 1719,
mp 161–162 ꢁC; 95% ee}; NMR experiments: 1H, H/H-
~
1
1648, 1476, 1448, 1353, 1278, 1235, 1153, 1074, 947,
924, 897, 874, 845, 813, 763, 682 cmꢀ1; MS m/z (rela-
tive intensity): 186 (5), 144 (3), 143 (48), 141 (55), 113
(15), 100 (13), 99 (100), 86 (31), 55 (35), 43 (16), 42
(21), 41 (39), 39 (6); Elemental analysis calcd (%) for
C10H18O3 (186.248): C 64.49, H 9.74; found: C 64.29, H
10.26.
COSY, NOESY, 13C, DEPT, HMQC; H NMR (CDCl3,
500 MHz): d = 1.46–1.58 (m, 3H, 5-H and 2 · 8-H), 1.69
(ddd, J = 2.6/6.3/10.8 Hz, 1H, 7-H), 1.77 (dddd, J = 2.5/
4.1/7.5/14.3 Hz, 1H, 7-H), 2.11 (dddt, J = 2.6/4.0/8.0/
2.8 Hz, 1H, 5-H), 2.15 (dt, J = 9.7/2.7 Hz, 1H, 3-H), 2.20
(t, J = 2.9 Hz, 1H, OH), 2.23 (td, J = 6.0/3.0 Hz, 1H,
4-H), 2.30 (dt, J = 18.5/2.5 Hz, 1H, 3-H), 2.42 (dd,

998
N. T. Tzvetkov et al. / Tetrahedron: Asymmetry 17 (2006) 993–998
5. Zimmermann, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065–
3112.
6. Demuth, M.; Ritterskamp, P.; Weigt, E.; Schaffner, K. J. Am.
Chem. Soc. 1984, 106, 2064–2071.
7. Waldmann, H.; Weigerding, M.; Dreisbach, C.; Wandrey, C.
Helv. Chim. Acta 1994, 77, 2111–2116.
8. Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J.
W. Angew. Chem., Int. Ed. Engl. 1995, 34, 2386–2388.
9. Seebach, D.; Jaeschke, G.; Yang, Y. M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2395–2396.
10. Almqvist, F.; Frejd, T. Tetrahedron: Asymmetry 1995, 6, 957–
960.
11. Mori, K.; Nagano, E. Biocatalysis 1990, 3, 25–36.
12. Almqvist, F.; Eklund, L.; Frejd, T. Synth. Commun. 1993,
1499.
13. Kazlauskas, D. A. J. Am. Chem. Soc. 1989, 111, 4953–4959.
14. Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Org. Chem. 1998, 63, 7547–7551.
15. Xu, Y.; Ohori, K.; Ohshima, T.; Shibasaki, M. Tetrahedron
2002, 58, 2585–2588.
J = 3.8/6.4 Hz, 1H, 1-H), 4.21 (ddd, J = 2.5/3.9/9.0 Hz,
1H, 6-H); H NMR (DMSO-d6, 500 MHz): d = 1.36–1.50
1
(m, 3H, 5-H and 2 · 8-H), 1.56–1.66 (m, 2H, 2 · 7-H),
2.00 (ddd, J = 2.7/8.9/13.7 Hz, 1H, 5-H), 2.06 (dd,
J = 2.5/14.6 Hz, 1H, 3-H), 2.09 (td, J = 2.4/2.5 Hz, 1H,
3-H), 2.21 (dd, J = 3.4/6.6 Hz, 1H, 4-H), 3.30 (s, 1H,
OH), 3.99 (ddd, J = 2.8/3.3/9.2 Hz, 1H, 6-H), 4.93 (d,
J = 3.14 Hz, 1H, 1-H); 13C NMR (CDCl3, 125 MHz):
d = 19.9 (CH2, C-7), 23.6 (CH2, C-8), 27.6 (CH, C-4),
36.1 (CH2, C-5), 44.4 (CH2, C-3), 50.7 (CH, C-1), 69.1
~
(CH, C-6), 215.5 (Cq, C-2); IR (KBr): m ¼ 3561, 3427,
3286, 3214, 2952, 2861, 2844, 1718, 1450, 1400, 1326,
1294, 1220, 1091, 1043, 1008, 941, 883, 869, 839 cmꢀ1
;
MS m/z (relative intensity): 140 (6), 122 (14), 112 (8), 99
(4), 97 (14), 96 (8), 95 (11), 81 (20), 80 (100), 79 (31), 69
(12), 68 (11), 67 (14), 58 (11), 57 (17), 55 (41), 54 (16), 53
(12), 43 (20), 42 (15), 41 (38), 40 (8), 39 (25); Elemental
analysis calcd (%) for C8H12O2 (140.180): C 68.54, H
8.63; found: C 68.41, H 8.55.
16. Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 15837–15845.
17. Ohshima, T.; Xu, Y.; Takita, R.; Shibasaki, M. Tetrahedron
2004, 60, 9569–9588.
Supplementary data
˚
18. We found that the use of beads molecular sieves (MS) 4 A
yielded 5 in an enantiomer excess up to 18%.
19. CCDC-298971 5 and CCDC-298972 (ꢀ)-11 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supplementary data associated with 2D NMR experiments
are available from the authors on request.
Acknowledgements
20. Krapcho, A. P. Synthesis 1982, 805–822.
Financial support by the Volkswagen-Stiftung, Hannover
(Schwerpunkt Elektronentransfer), the Fonds der Chemis-
chen Industrie, Frankfurt and the University of Bielefeld’s
Innovationsfonds is gratefully acknowledged.
21. De Santis, B.; Iamiceli, A. L.; Bettolo, R. M.; Migneco, L.
M.; Scarpelli, R. Helv. Chim. Acta 1998, 81, 2375–2387.
22. Maleczka, R. E., Jr.; Paquette, L. A. J. Org. Chem. 1991, 56,
6538–6546.
23. Evans, D. A.; Golob, A. M.; Mandel, N. S.; Mandel, G. S. J.
Am. Chem. Soc. 1978, 100, 8170–8174.
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