Asymmetric bakers yeast reductions of bridgehead-substituted bicyclo[2.2.2]octane-2,6-dione derivatives followed by conversion into catalytically active BODOLs for the diethylzinc addition to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2010.06.003

4-Substituted bicyclo[2.2.2]octane-2,6-diones have been synthesized and tested as substrates in the enantioselective reduction with bakers yeast to give the corresponding hydroxy ketones. It was found that the derivative bearing a TIPSO group at the 4-pos

Full text of DOI:10.1016/j.tetasy.2010.06.003

Tetrahedron: Asymmetry 21 (2010) 1374–1381
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric baker’s yeast reductions of bridgehead-substituted
bicyclo[2.2.2]octane-2,6-dione derivatives followed by conversion into
catalytically active BODOLs for the diethylzinc addition to benzaldehyde
*
Sophie Manner, Cecilia Hansson, Johanna M. Larsson, Viveca T. Oltner, Torbjörn Frejd
Division of Organic Chemistry, Kemicentrum, PO Box 124, SE-221 00 Lund, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Substituted bicyclo[2.2.2]octane-2,6-diones have been synthesized and tested as substrates in the
enantioselective reduction with baker’s yeast to give the corresponding hydroxy ketones. It was found
that the derivative bearing a TIPSO group at the 4-position was not reduced at all while that with a
TBDMSO group gave 87% yield and 46% ee. Other 4-oxy functionalized derivatives were reduced with
varying yields (36–87%) and ees (10–82%). The best result was obtained for the 4-Oallyl derivative
(80% yield, 82% ee). The hydroxy ketones carrying the benzyloxy and allyloxy groups at the 4-position
were converted into the corresponding BODOLs, which were tested as catalysts in the diethylzinc addi-
tion to benzaldehyde. In this reaction the ees were 90% and 89%, respectively, which showed that BODOLs
substituted at the 4-position are essentially as good catalysts in this reaction as those bearing a hydrogen.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 March 2010
Revised 28 May 2010
Accepted 3 June 2010
Available online 3 July 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
Consequently, there should be a need for simple and small mole-
cules with unique structural features. Inspired by this and the con-
Bicyclo[2.2.2]octanes are often found as subunits in natural
products1–8 and they are frequently used as important building
blocks in total synthesis9–15 and as ligands in asymmetric cataly-
sis.16–25 New applications for bicyclo[2.2.2]octanes are presented
continuously. Recently, Baran et al. reported the synthesis of poly-
hydroxylated bicyclic systems, which exhibited enzyme-specific
tinuous need for novel chiral building blocks led us to examine 9 as
a substrate for asymmetric reduction with baker’s yeast. To the
best of our knowledge, 4-substituted bicyclo[2.2.2]octanes-2,6-
diones apart from 229 have not been investigated as substrates
for baker’s yeast reduction.
Herein we report the synthesis of 4-hydroxy- and 4-hydroxy-
methyl-substituted bicyclo[2.2.2]octane-2,6-dione derivatives
10–16 (Scheme 1) and their use as substrates in asymmetric reduc-
tion with baker’s yeast. Furthermore, two novel BODOLs (bicy-
clo[2.2.2]octane-2,6-diols) (+)-40 and (+)-41 were synthesized
from (ꢀ)-19 and (–)-22, respectively, and evaluated as catalysts
for the asymmetric diethylzinc addition to benzaldehyde.
inhibition against a
-glycosidase.26 Furthermore, innovative meth-
odology regarding the synthesis of the bicyclic systems, via a
one-pot domino-sequence, was recently published by Arseniyadis
et al., resulting in oxygenated bicyclo[2.2.2]octane derivatives.27,28
Moreover, they have served well as substrates in biotransforma-
tions resulting in optically active compounds, pioneered by Mori
et al. who in 1990 reported the highly enantioselective reduction
of bicyclo[2.2.2]octane-2,6-dione derivatives 1–4 using baker’s
yeast (Scheme 1).29,30 Several examples exist where optically ac-
tive hydroxy bicyclo[2.2.2]octanones serve as important chiral
building blocks in the synthesis of bioactive natural products.9,31–33
The development of bicyclo[2.2.2]octane derivatives, to be
used as ligands17,18,20,23,24,34–38 and scaffolds in natural product
mimetics,39,40 is an ongoing project in our laboratories. Recently,
we published two synthetic routes towards novel bridgehead hy-
droxy bicyclo[2.2.2]octane-2,6-dione 9 (Scheme 1).41 As reported
by Lipkus et al., the majority of the structures reported to the
CAS registry are based on a relatively small number of scaffolds.42
2. Results and discussion
2.1. Synthesis of substituted bridgehead hydroxy
bicyclo[2.2.2]octane-2,6-diones
The synthesis of 9 was recently reported.41 However, baker’s
yeast reduction of 9 showed a surprisingly low ee (46%). To inves-
tigate how the stereoselectivity of the reduction was influenced by
the substituent at the 4-position, bicyclo diketones 10–16 were
synthesized and tested as yeast substrates (Scheme 2). Starting
from 25,41 protection of the tertiary alcohol with various protect-
ing groups furnished 26–30. Hydroboration of the unsaturated ke-
tones, followed by oxidation with TPAP/NMO resulted in diketones
10–15 in 22–42% yields.
* Corresponding author. Tel.: +46 46 222 8125; fax: +46 46 222 8209.
E-mail address: Torbjorn.Frejd@organic.lu.se (T. Frejd).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.003

S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
1375
R2
O
R2
Asymmetric
reduction
R1
O
O
R1
OH
1 R1=R2=H
5 R1=R2=H (52%, 95% ee)
(−)−
1
2
1
2
2
3
4
6
(−)− R =H R =Me (58%, 98% ee)
R =H R =Me
Mori et al.29,30
7
(−)− R =Me R =H (59%, 99.5% ee)
1
2
1
2
R =Me R =H
1
2
1
2
8
R =(CH2)2OAc R =H
(+)− R =(CH2)2OAc R =H (71%, 98.8% ee)
9 R1=H R2=OTBS
17 R1=H R2=OTBS
(−)−
1
2
1
2
10
11
12
18
(+)− R =H R =OAc
R =H R =OAc
1
2
1
2
19
(−)− R =H R =OBn
R =H R =OBn
1
2
1
2
This report
20
R =H R =OpBrBn
(−)− R =H R =OpBrBn
13 R1=H R2=OSEM
21 R1=H R2=OSEM
(−)−
(−)−
14 R1=H R2=OAllyl
15
16
22 R1=H R2=OAllyl
1
2
1
2
23
24
R =H R =OTIPS
R =H R =OTIPS
1
2
1
2
R =H R =CH2OBn
R =H R =CH2OBn
Scheme 1. Asymmetric reduction of bicyclo[2.2.2]octane-2,6-diones with baker’s yeast.
followed by addition of
a,b-unsaturated ketone 34 furnished ter-
OH
O
OR
O
OR
O
tiary alcohol 35 in 62% yield.44 Finally, oxidative rearrangement
a
b
with PCC45 resulted in 36 in 61% yield.
For the following regioselective allylation of 36, the best results
were obtained using the method recently published by Shibata
et al.,46 employing organotantalum reagents generated from TaCl5
and allyltributyltin. In our case, initial allylation attempts in CH3CN
did result in 37, although in low yield. However, by adding stoichi-
ometric amounts of TMSCl and changing the solvent to THF, com-
plete conversion of 36 was observed, providing 37 in 60% yield.
Bicyclic hydroxy ketone 39 was then obtained according to our
previously developed methodology.41 Aldehyde 38 was generated
in situ via ozonolysis of olefin 37 followed by reductive quenching
with TEA. Subsequent stirring with SiO2 for 12 h generated hydro-
xy ketone 39. Finally, oxidation of crude 39 with TPAP/NMO re-
sulted in diketone 16 in 34% yield (from 37).
O
25
26 R=Ac
10 R=Ac
27 R=Bn
11 R=Bn
28 R=pBrBn
29 R=SEM
30 R=TIPS
12 R=pBrBn
13 R=SEM
15 R=TIPS
Scheme 2. Synthesis of bridgehead-substituted hydroxy bicyclo[2.2.2.]octan-2,6-
diones 10–15. Reagents and conditions: (a) 26: acetic acid anhydride, DMAP (cat.),
pyridine, rt, 12 h, 70% 27; (i) trimethylorthoformate, p-TsOH (cat.), MeOH, rt, 48 h;
(ii) BnBr, Bu4NI, NaH, THF, rt, 20 h, 93% 28; (i) trimethylorthoformate, p-TsOH (cat.),
MeOH, rt, 48 h; (ii) p-BrBnBr, Bu4NI, NaH, THF, rt, 20 h, 91% 29: SEMCl, DIPEA, DCM,
rt, 12 h, 70% 30: TIPSOTf, 2,6-lutidine, DCM, 0 °C, 2 h, 74%; (b) (i) 1 M BH3ꢁSMe2,
THF, 0 °C, 1 h; (ii) TPAP, NMO, 4 Å MS, rt, 4 h, 10 22%, 11 34%, 12 30%, 13 42%, 15
38%.
2.3. Asymmetric reduction with baker’s yeast
Allyloxy-substituted diketone 14 was synthesized starting from
hydroxy diketone 31 obtained by deprotection of silyl ether 941
(Scheme 3). Since direct allylation of 31 failed to produce the ex-
pected allyl ether 14, 31 was first converted into its bisacetal 32
whereafter the allylation was successfully performed using NaH
and allylbromide in DMF. Finally, the bisacetal was hydrolyzed
during aqueous acidic work-up, furnishing diketone 14 in 78%
yield.
Diketones 10–16 were then evaluated as substrates for baker’s
yeast-catalyzed asymmetric reduction (Scheme 5). The enantiose-
lectivity was strongly influenced by the size and shape of the
R-group. All diketones resulted in hydroxy ketones of lower ees
compared to the reduction of bicyclo[2.2.2]octane-2,6-dione 1
and 4-methyl bicyclo[2.2.2]octane-2,6-dione 2 (Scheme 1), which
according to literature gave 97% ee and 98% ee, respectively.29,47
For triisopropylsilyloxy (TIPSO)-substituted diketone 15, no con-
version was observed, probably due to the silyl group being too
bulky to fit into the catalytic site of the enzyme(s) and/or its low
water solubility. On the other hand, compound 9, carrying the
somewhat smaller tert-butyldimethylsilyloxy (TBSO-) substituent,
resulted in high yield and moderate ee (87%, 46% ee) as reported
previously.48
2.2. Synthesis of substituted bridgehead hydroxymethyl
bicyclo[2.2.2]octane-2,6-diones
A thorough literature survey showed that new methodology
had to be developed for the synthesis of substituted bridgehead
hydroxymethyl diketons such as 16, which resulted in the route
outlined in Scheme 4. BOMCl was stannylated, forming 33 accord-
ing to the method of Kaufman.43 Transmetallation of 33 with BuLi
The highest ee was obtained for allyloxy-substituted dike-
tone 14 (80%, 82% ee). Also, the trimethylsilylethoxymethoxy
OH
O
OTBS
O
OH
O
O
a
c
b
O
O
O
O
O
O
O
9
31
32
14
Scheme 3. Reagents and conditions: (a) (i) BF3ꢁOEt2 (1.1 equiv), MeCN, ꢀ5 °C, 1 h; (ii) 0.4 M NaHCO3 (aq), quantitative yield;41 (b) trimethyl orthoformate (8 equiv), p-TsOH
(0.2 equiv), MeOH, rt, 24 h, quantitative yield; (c) (i) NaH (3 ꢂ 4 equiv), DMF, 50 °C, 4 h; (ii) allyl bromide (20 equiv); (iii) 1 M HCl, 78%.

1376
S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
O
O
O
HO
OBn
34
BnO
SnBu3
OBn
a
b
c
OBn
33
35
36
37
d
O
OBn
OBn
f
e
O
O
O
O
OH
OBn
38
16
39
Scheme 4. Synthesis of 4-benzyloxymethylene-bicyclo[2.2.2]octane-2,6-dione 16. Reagents and conditions: (a) (i) 1.74 M BuLi, THF, ꢀ78 °C, 5 min; (ii) 34, ꢀ78 °C, 2 h; (b)
PCC, DCM, rt, 5 h, 54% from 34; (c) (i) allyltributyltin, TaCl5, THF, ꢀ40 °C, 1 h; (ii) 36, TMSCl, ꢀ40 °C, 48 h, 60%; (d) (i) O3, DCM, ꢀ78 °C, 10 min; (ii) TEA, ꢀ78 °C?rt, 1 h; (e)
SiO2, rt, 12 h; (f) TPAP, NMO, 4 Å MS, DCM, rt, 5 h, 34% from 37.
is controlled partly by the ability of the 4-substituents to partici-
pate in hydrogen bondings within the catalytic sites in the set of
reductases present in the yeast cells. For the substrates with oxy-
gen-linked substituents, a wide range of ees was achieved (0–
82%). The absence of a hydrogen bond accepting oxygen, attached
directly to the diketone skeleton as in 16 (R = CH2OBn) may be the
reason for the racemic mixture provided by this compound. In
addition, the low ee obtained for 10 (R = OAc, 10% ee) might be
the result of a hydrogen bond accepting oxygen at the wrong dis-
tance in the catalytic cavities. Consequently, the nature of the sub-
stituent at the 4-position is of crucial importance not only for
enantioselectivity but also for reactivity.
R
R
a
O
O
O
OH
9
( ) 17
R=OTBS
− − R=OTBS (87%, 46% ee)
10 R=OAc
11 R=OBn
(+)−18 R=OAc (73%, 10% ee)
( ) 19 R=OBn (86%, 69% ee)
− −
12
( ) 20
R=OpBrBn
− − R=OpBrBn (36%, 47% ee)
13 R=OSEM
14
( ) 21 R=OSEM (59%, 68% ee)
− −
( ) 22
R=OCH2CHCH2
15 R=OTIPS
16
− −
23 R=OTIPS (0%)
24
R=OCH2CHCH2 (80%, 82% ee)
R=CH2OBn
R=CH2OBn (66%, 0% ee)
Scheme 5. Asymmetric reduction with baker’s yeast of bridgehead-substituted
bicyclo[2.2.2]octanes 9–16. Reagents and conditions: (a) baker’s yeast, sucrose,
H2O, EtOH (5%v/v).
2.4. Synthesis and evaluation of catalytically active bridgehead
substituted BODOLs
Optically active bicyclo[2.2.2]octane-2,6-diols (BODOLs) have
been demonstrated to function as chiral ligands in the asym-
metric diethylzinc addition to aromatic aldehydes18,23,25 and
asymmetric titanium(IV)-catalyzed catecholborane reduction of
ketones.16,17,20–22 For the asymmetric diethylzinc addition, most
satisfactory results were obtained with BODOLs bearing an o-anisyl
substituent at the 2-position (89%, 92% ee). Thus, we decided to
transform optically active hydroxy ketones (ꢀ)-19 and (ꢀ)-22 into
2-o-anisyl BODOLs and investigate their catalytic capacity in the
asymmetric diethylzinc addition (Scheme 6).
(SEMO)-substituted diketone 13 and the benzyloxy-substituted
diketone 11 gave hydroxy ketones but with rather moderate ees
of 68% and 69%, respectively. Earlier attempts had shown that it
is possible to increase the ee of the obtained hydroxy ketones by
recrystallization.49 Thus, similar attempts to increase the ee were
made for (ꢀ)-19, resulting in an ee of over 99%. Unexpectedly,
introduction of a bromide substituent at the para-position of the
benzyl group 12 resulted in a much slower reaction and a modest
yield of 36%. In addition, the ee was somewhat lower (47%) than for
the benzyloxy-substituted substrate. Acetate-substituted diketone
10 gave the lowest ee (10%). When benzyloxymethyl (BnOCH2)-
substituted diketone 16 was used as a substrate, both prolonged
reaction times and increased amounts of yeast were necessary
for complete conversion. Disappointingly, Mosher ester analysis
showed a completely racemic mixture. Thus, insertion of a methy-
lene unit between the bicyclic skeleton and the benzyloxy moiety
still allowed for reduction but the stereoselectivity was lost.
When trying to interpret our results, we can only speculate
since no information exists regarding the active sites of the en-
zymes. Apparently, substituents at the 1-position, between the
two carbonyls, had little effect on the stereoselectivity, as higher
ees were obtained for the substituted diketones 3 and 4 (Scheme 1),
compared to the unsubstituted 1.29,30 However, as seen in
Scheme 5, substituents at the 4-position clearly affect both the
selectivity and reactivity. We envision that the stereoselectivity
OR
OR
a
O
OH
R=Bn
OMe OH OH
(—)-19
(+)-40
(+)-41
R=Bn
R=Allyl
( ) 22
— - R=Allyl
Scheme 6. Synthesis of BODOLs. Reagents and conditions: (a) o-AnLi, THF, rt, 1.5 h,
(+)-40 47%, (+)-41 48%.
Previous work showed that addition of organometallic reagents
to hydroxy ketone (ꢀ)-5 (Scheme 1) should be performed without
prior protection of the hydroxyl group in order to give reproducibly
high yields.21 Hence, (ꢀ)-19 and (ꢀ)-22 were treated with o-anis-

S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
1377
yllithium in THF, which resulted in (+)-40 and (+)-41 in 47% and
48% yield, respectively. Then, (+)-40 and (+)-41 were used as cata-
lysts for the asymmetric diethylzinc addition of benzaldehyde with
promising results. Both yields and enantioselectivity [(+)-40 90%,
90% ee, (+)-41 91%, 89% ee] were comparable to previous results
with BODOLs lacking the bridgehead substiutent,18 indicating that
substitution with an ether function at the 4-position does not af-
fect the efficiency and selectivity of the catalyst. The improvement
of the ee in comparison with the ee of the catalyst might be due to
the positive non-linear affect, which we have previously noticed.18
In addition, these results indicate potential for solid-phase anchor-
ing of the BODOLs with a linker attached at the 4-position.
The crude residue was purified by column chromatography (SiO2,
pentane/ether 8:2) to give 26 (0.89 g, 70%) as white crystals.
Rf = 0.28 (pentane/ether); (Calcd for C10H12O3: C, 66.65; H, 6.71.
Found: C, 66.49; H, 6.65); m
max/cmꢀ1 (KBr) 2974, 1734; mp 47.8–
48.7 °C; dH (400 MHz, benzene-d6) 6.40 (d, 1H, J = 8.7 Hz) 5.61
(dd, 1H, J = 6.5, 8.7 Hz) 2.83–2.79 (m, 1H) 2.76–2.71 (m, 1H) 2.21
(dAB, 1H, JAB = 17.3 Hz) 1.69–1.65 (m, 2H) 1.60 (s, 3H) 1.31–1.24
(m, 1H) 1.07–0.99 (m, 1H); dC(100 MHz, benzene-d6) 204.7,
169.2, 138.3, 124.7, 79.6, 47.8, 44.5, 29.4, 21.2, 20.5; HRMS
(FAB+): calcd for C10H13O3 (M+H): 181.0864. Found: 181.0882.
4.2. ( )-4-Benzyloxy-bicyclo[2.2.2]oct-5-en-2-one 27
Trimethyl orthoformate (0.76 mL, 7.0 mmol) and p-TsOH
(50 mg, 0.26 mmol) were added to a solution of 25 (0.30 g,
2.2 mmol) in methanol (7 mL) at rt. After 48 h, the majority of sol-
vent was removed under reduced pressure and the remaining dark
red liquid was filtered through a layer of Al2O3 and eluted with
heptane/EtOAc (1:1). Removal of the solvent under reduced pres-
sure gave acetal-protected 25 (0.36 g, 90%) as viscous oil which
was used directly in the next step. dH (400 MHz, benzene-d6)
6.17 (dAB, 1H, JAB = 8.5 Hz) 5.99 (ddAB, 1H, JAB = 8.5 Hz J = 6.6 Hz)
2.99 (s, 3H) 2.95 (s, 3H) 2.60–2.57 (m, 1H) 1.88–1.78 (m, 2H)
1.62 (d, 1H, J = 12.1 Hz) 1.57–1.51 (m, 1H) 1.38–1.30 (m, 1H)
1.19 (br s, 1H) 1.11–1.03 (m, 1H).
3. Conclusion
In conclusion, we have presented the synthesis of protected 4-
hydroxy methyl-bicyclo[2.2.2]octane-2,6-diones such as 16. Pro-
tected 4-hydroxy bicyclo[2.2.2]octane-2,6-diones 10–15 together
with 16 were then evaluated as substrates for asymmetric reduc-
tion with baker’s yeast. Highest enantioselectivity was obtained
in the reduction of the allyloxy-substituted diketone 14 resulting
in 80% yield of (ꢀ)-22 in 82% ee. In addition, BODOL ligands with
ethereal functions at the 4-position, such as (+)-40 and (+)-41,
showed promising results as catalysts in asymmetric diethylzinc
addition to benzaldehyde with 90% yield and 90% ee and 91% yield
and 89% ee, respectively.
Benzyl bromide (13.0 g, 76.0 mmol), tetrabutylammonium io-
dide (1.4 g, 3.8 mmol) and NaH (60% in mineral oil, 3.0 g, 76 mmol)
were added to a solution of crude acetal-protected 25 in dry THF
(100 mL) at rt. After 20 h, 1 M HCl was added until pH 2 followed
by extraction of the aqueous phase with EtOAc (3 ꢂ 40 mL). The
combined organic phases were washed with brine (80 mL) and
dried (MgSO4) before removal of the solvent under reduced pres-
sure. The crude residue was purified by column chromatography
(SiO2, heptane/EtOAc 9:1) to give 27 (8.0 g, 93%) as semi-crystalline
material. Rf = 0.13 (heptane/EtOAc 9:1); (Calcd for C15H16O2: C,
4. Experimental
Standard materials were obtained from commercial suppliers
and used without further purification unless otherwise stated.
THF and diethyl ether were distilled from sodium and benzophe-
none. DCM was dried over 4 Å MS. All moisture- and air-sensitive
reactions were carried out under an atmosphere of dry nitrogen
using oven-dried glassware. Chromatographic separations were
78.92; H, 7.06. Found: C, 79.10; H, 7.00); m
max/cmꢀ1 (NaCl) 1725;
performed on Matrex silica gel (25–70 lm). Thin-layer chromatog-
mp r t; dH (400 MHz, benzene-d6) 7.27 (d, 2H, J = 7.1 Hz) 7.22–
7.18 (m, 2H) 7.14–7.10 (m, 1H) 6.25 (d, 1H, J = 8.7 Hz) 5.68 (dd,
1H, J = 6.5, 8.6 Hz) 4.25 (s, 2H) 2.86–2.84 (m, 1H) 2.25 (ddAB, 1H,
JAB = 17.3 Hz, J = 3.5 Hz) 2.03 (dAB, 1H, JAB = 17.3 Hz) 1.53–1.46 (m,
1H) 1.42–1.30 (m, 2H) 1.11–1.03 (m, 1H); dC (100 MHz, benzene-
d6) 206.1, 139.5, 138.7, 128.5, 127.6, 127.4, 126.4, 78.7, 65.8,
48.3, 44.4, 29.5, 21.4; HRMS (FAB+) calcd for C15H17O2 (M+H):
229.1228. Found: 229.1226.
raphy was performed on precoated TLC glass plates with Silica Gel
60 F254 0.25 mm (Merck). Spots were visualized with UV light or by
staining with a solution of p-methoxybenzaldehyde (26 mL), gla-
cial acetic acid (11 mL), concentrated sulfuric acid (35 mL) and
95% ethanol (960 mL) or a solution of H3[P(Mo3O10)4] (25 g),
Ce(SO4)2 (10 g) and concentrated sulfuric acid (60 mL) in water
(940 mL) followed by heating. Optical rotations were measured
on a Perkin–Elmer 241 polarimeter at 20 °C and are given in
10ꢀ1 deg cm2 gꢀ1. NMR spectra were recorded on a Bruker DRX
400 MHz spectrometer at 400 MHz (1H) and at 100 MHz (13C)
using the residual solvent as internal standard. J values are given
in hertz. IR was recorded on a Shimadzu 8300 FTIR spectrometer.
Melting points were taken on a Sanyo Gallenkamp melting point
apparatus and are uncorrected. Elemental analyses were per-
formed by H. Kolbes Mikroanalytisches Laboratorium, Höhenweg
17, D-45470 Mülheim an der Ruhr. The enantiomeric excess of
the optical active alcohols was determined by conversion of the
alcohols into their Mosher ester derivatives50 followed by 1H
NMR analysis. 9, 25 and 3141 and 3343 were synthesized according
to literature procedures.
4.3. ( )-4-(4-Bromobenzyloxy)-bicyclo[2.2.2]oct-5-en-2-one 28
Starting from crude acetal-protected 25 (1.95 g, 10.6 mmol) and
4-bromo benzylbromide (5.30 g, 21.2 mmol), 28 was synthesized
according to the same procedure as 27, giving 28 (3.0 g, 91%) as
white crystals. Rf = 0.08 (heptane/EtOAc 9:1); (Calcd for
C
15H15O2Br: C, 58.65; H, 4.92; Br, 26.01. Found: C, 58.53; H, 5.03;
Br, 25.95);
m
max/cmꢀ1 (KBr) 1717; mp 72.6–73.1 °C; dH (400 MHz,
benzene-d6) 7.33–7.30 (m, 2H) 6.90–6.87 (m, 2H) 6.15 (d, 1H,
J = 8.7 Hz) 5.67 (dd, 1H, J = 8.7, 6.4 Hz) 4.01 (s, 2H) 2.86–2.83 (m,
1H) 2.18 (ddAB
, 1H, JAB = 17.3 Hz, J = 3.1 Hz) 1.96 (dAB, 1H,
JAB = 17.3 Hz) 1.48–1.41 (m, 1H) 1.36–1.28 (m, 2H) 1.10–1.01 (m,
1H); dC (100 MHz, benzene-d6) 206.2, 138.8, 132.0, 129.3, 126.9,
121.8, 79.1, 65.3, 48.7, 44.7, 29.9, 21.7; HRMS (FAB+) calcd for
4.1. ( )-4-Acetoxy-bicyclo[2.2.2]oct-5-en-2-one 26
C
15H16O2Br (M+H): 307.0334. Found: 307.0332.
Compound 25 (0.98 g, 7.1 mmol) was added to a mixture of ace-
tic anhydride (2.8 mL, 30 mmol) and DMAP (cat.) in pyridine
(8 mL) and stirred at rt over night. Satd NaHCO3 (aq) was then
added until pH 8 followed by extraction with EtOAc (4 ꢂ 10 mL).
The combined organic phases were washed with brine and dried
(Na2SO4) before removal of the solvent under reduced pressure.
4.4. ( )-4-(2-Trimethylsilanyl-ethoxymethoxy)-bicyclo
[2.2.2]oct-5-en-2-one 29
SEMCl (1.2 mL, 6.8 mmol) was slowly added to a stirred mixture
of 25 (0.27 g, 2.0 mmol) and Hünig’s base (1.9 mL, 11.0 mmol) in

1378
S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
DCM (7 mL) at rt. After 12 h, H2O was added and the aqueous phase
was saturated with NaCl (s) followed by extraction with EtOAc
(6 ꢂ 7 mL). The combined organic phases were washed with brine
and dried (Na2SO4) before removal of the solvent under reduced
pressure. The orange residue was purified by column chromatogra-
phy (SiO2, pentane/ether 9:1) to give 29 (368 mg, 70%) as a yellow
oil. Rf = 0.22 (pentane/ether 8:2); (Calcd for C14H24O3Si: C, 62.64; H,
4.6.2. 4-Benzyloxy-bicyclo[2.2.2]octan-2,6-dione 11
The title compound was synthesized by following the general
procedure for hydroboration followed by TPAP/NMO oxidation
from 27 (60.0 mg, 0.26 mmol). 11 (22 mg, 34%) was obtained as
white crystals. Rf = 0.18 (heptane/EtOAc 8:2); (Calcd for
C
15H16O3: C, 73.75; H, 6.60. Found: C, 73.59; H, 6.48); m
max/cmꢀ1
(KBr) 3030, 2949, 1742, 1717; mp 109.1–110.2 °C; dH (400 MHz,
benzene-d6) 7.22–7.12 (m, 5H) 3.91 (s, 2H) 3.02 (t, 1H, J = 2.8 Hz)
2.14 (dtAB, 2H, JAB = 18.0 Hz, J = 1.7 Hz) 2.04 (dAB, 2H, JAB = 17.5 Hz)
1.29–1.25 (m, 2H) 1.21–1.14 (m, 2H); dC (100 MHz, benzene-d6)
201.9, 138.9, 128.5, 128.2, 127.4, 74.2, 64.5, 63.2, 48.1, 28.5, 19.7;
HRMS (FAB+) calcd for C15H16O3Na (M+Na): 267.0997. Found:
267.0989.
9.01. Found: C, 62.49; H, 9.08); m
max/cmꢀ1 (KBr) 2953, 1734; dH
(400 MHz, benzene-d6) 6.44 (d, 1H, J = 8.7 Hz) 5.69 (dd, 1H,
J = 6.5, 8.6 Hz) 4.67 (s, 2H) 3.64 (t, 2H, J = 8.1 Hz) 2.86–2.84 (m,
1H) 2.38 (ddAB, 1H, J = 3.5 Hz, JAB = 17.5 Hz) 2.20 (dAB, 1H,
JAB = 17.5 Hz) 1.66–1.59 (m, 1H) 1.51–1.47 (m, 1H) 1.38–1.31 (m,
1H) 1.12–1.03 (m, 1H) 0.91 (t, 2H, J = 8.1 Hz) -0.02 (s, 9H); dC
(100 MHz, benzene-d6) 206.1, 139.5, 126.1, 90.5, 78.4, 65.3, 48.5,
45.7, 30.3, 21.3, 18.2, ꢀ1.4.
4.6.3. 4-(4-Bromobenzyloxy)-bicyclo[2.2.2]octan-2,6-dione 12
The title compound was synthesized by following the general
procedure for hydroboration followed by TPAP/NMO oxidation
from 28 (8.0 g, 26.0 mmol). 12 (2.6 g, 30%) was obtained as white
crystals. Rf = 0.11 (heptane/EtOAc 8:2); (Calcd for C15H15O3Br: C,
4.5. ( )-4-Triisopropylsilanyloxy-bicyclo[2.2.2]oct-5-en-2-one
30
55.75; H, 4.68. Found: C, 55.65, H, 4.54); m
max/cmꢀ1 (KBr) 1706,
At 0 °C, TIPSOTf (3.0 mL, 11.0 mmol) was added dropwise to a
solution of 2,6-lutidine (2.8 mL, 24.0 mmol) and 25 (1.0 g,
7.3 mmol) in DCM (7 mL). After stirring for 2 h at 0 °C, H2O
(10 mL) was added followed by extraction with DCM (4 ꢂ 10 mL).
The combined organic phases were dried (Na2SO4) before removal
of the solvent under reduced pressure. The crude residue was puri-
fied by column chromatography (SiO2, heptane/EtOAc 98:2) to give
30 (1.6 g, 74%) as a clear oil. Rf = 0.31 (heptane/EtOAc 98:2); (Calcd
for C17H30O2Si: C, 69.33; H, 10.27. Found: C, 69.39; H, 10.24);
1744; mp 139.9–140.4 °C; dH (400 MHz, benzene-d6) 7.33–7.30
(m, 2H) 6.80–6.77 (m, 2H) 3.69 (s, 1H) 3.03 (t, 1H, J = 2.8 Hz)
2.11–2.05 (m, 2H) 1.99–1.94 (m, 2H) 1.23–1.13 (m, 4H); dC
(100 MHz, benzene-d6) 202.1, 138.1, 132.1, 129.3, 122.0, 74.7,
64.0, 63.5, 48.4, 28.9, 20.0; HRMS (FAB+) calcd for C15H15O3BrNa
(M+Na): 345.0102. Found: 345.0077.
4.6.4. 4-(2-Trimethylsilanyl-ethoxymethoxy)-bicyclo
[2.2.2]octan-2,6-dione 13
m
max/cmꢀ1 (NaCl) 2944, 2866, 1731; dH (400 MHz, benzene-d6)
6.23 (d, 1H, J = 8.6 Hz) 5.66 (dd, 1H, J = 6.5, 8.5 Hz) 2.88–2.86 (m,
1H) 2.28 (ddAB 1H, J = 3.4 Hz, JAB = 17.4 Hz) 2.13 (dAB 1H,
The title compound was synthesized by following the general
procedure for hydroboration followed by TPAP/NMO oxidation
from 29 (0.14 g, 0.51 mmol). 13 (60 mg, 42%) was obtained as
white crystals. Rf = 0.28 (pentane/ether 6:4); (Calcd for C14H24O4Si:
,
,
JAB = 17.4 Hz) 1.56–1.50 (m, 1H) 1.45–1.32 (m, 2H) 1.13–0.88 (m,
22H); dC (100 MHz, benzene-d6) 206.4, 142.1, 125.4, 75.3, 48.8,
48.3, 33.9, 21.7, 18.4, 13.4; HRMS (FAB+) calcd for C17H31O2Si
(M+H): 295.2093. Found: 295.2093.
C, 59.12; H, 8.51. Found: C, 59.20; H, 8.46); m
max/cmꢀ1 (KBr) 2955,
1749, 1719; mp rt; dH (400 MHz, benzene-d6) 4.41 (s, 2H) 3.50 (t,
2H, J = 8.2 Hz) 3.05 (t, 1H, J = 2.9 Hz) 2.33 (dtAB, 2H, J = 1.7 Hz,
JAB = 18.3 Hz) 2.22 (dtAB, 2H, J = 1.5 Hz, JAB = 18.3 Hz) 1.44–1.40
(m, 2H) 1.22–1.17 (m, 2H) 0.85 (t, 2H, J = 8.2 Hz) -0.02 (s, 9H); dC
(100 MHz, benzene-d6) 202.0, 89.4, 74.1, 65.3, 63.4, 49.4, 29.3,
19.7, 18.1, ꢀ1.4.
4.6. General procedure for hydroboration followed by TPAP/
NMO oxidation
At 0 °C, BH3ꢁSMe2 (2 equiv) was added to a stirred solution of
the olefin (1 equiv) in diethyl ether. The resulting reaction mix-
ture was stirred at rt for 2 h whereafter the reaction was
quenched by careful addition of H2O. The aqueous phase was sat-
urated with NaCl (s) and extracted with EtOAc (four times). The
combined organic phases were dried (Na2SO4) before removal of
solvent under reduced pressure. The crude residue was dissolved
in DCM followed by addition of powdered MS 4 Å, NMO (7 equiv)
and TPAP (0.07 equiv) at rt. After 12 h, the reaction mixture was
filtered through a layer of SiO2 and eluted with EtOAc followed
by removal of solvent under reduced pressure. The crude residue
was purified by column chromatography (SiO2, heptane/EtOAc or
pentane/ether).
4.6.5. 4-Triisopropylsilanyloxy-bicyclo[2.2.2]octan-2,6-dione 15
The title compound was synthesized by following the general
procedure for hydroboration followed by TPAP/NMO oxidation
from 30 (74.0 mg, 0.25 mmol). 15 (30 mg, 38%) was obtained as
white crystals. Rf = 0.26 (pentane/ether 8:2); (Calcd for C17H30O3Si:
C, 65.76; H, 9.74. Found: C, 65.71; H, 9.65);
1747, 1713; mp 68.8–69.7 °C; dH (400 MHz, benzene-d6) 3.07 (t,
1H, J = 2.9 Hz) 2.28 (dAB 2H, JAB = 18.0 Hz) 2.14 (ddAB 2H,
m
max/cmꢀ1 (KBr) 2945,
,
,
J = 1.4 Hz, JAB = 16.9 Hz) 1.38–1.31 (m, 2H) 1.22–1.18 (m, 2H) 0.92
(d, 18H, J = 7.2 Hz) 0.83–0.72 (m, 3H); dC (100 MHz, benzene-d6)
202.2, 71.6, 63.1, 52.5, 32.8, 20.1, 18.3, 13.2; HRMS (FAB+) calcd
for C17H31O3Si (M+H): 311.2042. Found: 311.2045.
4.6.1. 4-Acetoxy-bicyclo[2.2.2]octan-2,6-dione 10
4.6.6. 4-(Allyloxy)-bicyclo[2.2.2]octane-2,6-dione 14
The title compound was synthesized by following the general
procedure for hydroboration followed by TPAP/NMO oxidation
from 26 (0.61 g, 3.4 mmol). 10 (0.15 g, 23%) was obtained as white
crystals. Rf = 0.31 (pentane/ether 1:1); (Calcd for C10H12O3: C,
Trimethyl orthoformate (1.75 mL, 16.0 mol) was added to a stir-
red mixture of 3141 (0.3 g, 2.0 mmol) and pTsOH (76 mg, 0.4 mmol)
in MeOH (14 mL) at rt. After 24 h, the majority of the solvent was
removed under reduced pressure and the crude residue was fil-
tered through a layer of Al2O3 and eluted with heptane/EtOAc
(1:1). Removal of the solvent under reduced pressure gave 32
(0.5 g, quant.), which was used directly in the next step. Crude
32 (0.5 g, 2.0 mmol) was dissolved in freshly distilled DMF
(40 mL) and NaH (60% disp. in oil, 0.33 g, 8.1 mmol) was added
at rt under a nitrogen atmosphere. The reaction mixture was
heated to 50 °C and another two portions of NaH (0.33 g, 8.1 mmol)
61.22; H, 6.16. Found: C, 61.31; H, 6.08); m
max/cmꢀ1 (KBr) 2978,
1717; mp 117.7–118.5 °C; dH (400 MHz, benzene-d6) 3.00 (t, 1H,
J = 2.9 Hz) 2.60 (dAB, 2H, JAB = 18.1 Hz) 2.55 (ddAB, 2H, J = 2.3 Hz,
JAB = 19.7 Hz) 1.67–1.63 (m, 2H) 1.49 (s, 3H) 1.19–1.13 (m, 2H);
dC (100 MHz, benzene-d6) 200.7, 169.2, 76.9, 62.9, 48.1, 28.3,
21.2, 19.1; HRMS (FAB+) calcd for C10H13O4 (M+H): 197.0814.
Found: 197.0809.

S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
1379
were added after 2 and 3 h, respectively. After 4 h of stirring at
50 °C, the temperature was decreased to 30 °C and allyl bromide
(3.5 mL, 41.0 mmol) was added. The mixture was stirred for an-
other 20 h, whereafter the mixture was cooled to rt and the reac-
tion was quenched by addition of 1 M HCl aqueous solution.
After an additional hour of stirring, the water phase was extracted
with EtOAc (3 ꢂ 30 mL) and the combined organic phases were
dried (MgSO4) before removal of the solvent under reduced pres-
sure. The crude residue was purified by column chromatography
(SiO2, heptane/EtOAc 95:5?9:1?1:1) to give 14 (0.31 g, 78%) as
138.4, 133.3, 128.3, 127.5, 127.4, 118.5, 75.1, 73.3, 48.8, 42.6,
40.9, 40.6, 30.9, 21.4; HRMS (FAB+) calcd for C17H23O2 (M+H):
259.1698. Found: 259.1685.
4.6.9. 4-Benzyloxymethyl-bicyclo[2.2.2]octane-2,6-dione 16
At ꢀ78 °C, a solution of 37 (0.30 g, 1.2 mmol) in DCM (60 mL)
was treated with O3 until the solution was persistently blue. Excess
of O3 was removed by purging the reaction mixture with N2
whereafter TEA (5.0 mL, 36.0 mmol) was added. The temperature
was allowed to reach rt before SiO2 (4 g) was added. After 12 h,
the mixture was filtered through a layer of SiO2 and eluted with
EtOAc before removal of the solvent under reduced pressure. Crude
39 was dissolved in DCM (6 mL) and treated with NMO (0.21 g,
1.8 mmol), 4 Å MS (2 g) and TPAP (38.0 mg, 0.11 mmol). After stir-
ring for 5 h at rt, the reaction mixture was diluted with EtOAc, fil-
tered through a pad of Celite/SiO2 and eluted with EtOAc. The
crude residue was purified by column chromatography (SiO2, pen-
tane/ether 7:3) to give 16 (101 mg, 34% from 37). Rf = 0.29 (pen-
tane/ether 1:1); (Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C,
white crystals. Rf = 0.47 (heptane/EtOAc, 1:1);
m
max/cmꢀ1 (KBr)
1744, 1710; mp 55–57 °C; dH (400 MHz, benzene-d6) 5.72–5.62
(m, 1H) 5.15–5.10 (m, 1H) 5.00–4.96 (m, 1H) 3.37–3.35 (m, 2H)
3.01–3.00 (m, 1H) 2.12–2.07 (m, 2H) 1.96–1.95 (m, 2H) 1.25–
1.20 (m, 2H) 1.17–1.11 (m, 2H); dC (100 MHz, benzene-d6) 202.3
(2C), 135.7, 116.0, 74.3, 63.7, 63.6, 48.5 (2C), 28.9, 20.0; HRMS
(FAB+) calcd for C11H14O3Na [M+Na]: 217.0841. Found: 217.0847.
4.6.7. ( )-3-Benzyloxymethyl-cyclohex-2-enone 36
A solution of BuLi (1.74 M in hexane, 1.12 mL, 1.95 mmol) was
added to a stirred solution of (benzyloxymethyl)tributylstannane
3343 (0.89 g, 2.2 mmol) in dry THF (7 mL) at ꢀ78 °C and the reaction
mixture was stirred for 5 min before 34 (0.14 mL, 1.44 mmol) was
added. After 2 h at ꢀ78 °C, satd NH4Cl (aq) was added and the reac-
tion was allowed to reach rt. 1 M HCl was added until pH 3 and the
aqueous phase was extracted with diethyl ether (5 ꢂ 20 mL). The
combined organic phases were washed with brine (50 mL) and
dried (Na2SO4) before removal of the solvent under reduced pres-
sure. The crude residue was used directly in the next step without
further purification. An analytical pure sample was obtained by col-
umn chromatography (SiO2, pentane/ether 9:1) to give 35 as clear
74.28; H, 6.94);
73.9–74.7 °C; dH (400 MHz, benzene-d6) 7.21–7.10 (m, 5H) 4.11
(s, 2H) 3.15 (t, 1H, J = 2.9 Hz) 2.63 (s, 2H) 1.94 (dAB 2H,
JAB = 18.6 Hz) 1.83 (dAB 2H, JAB = 18.6 Hz) 1.41–1.36 (m, 2H)
m
max/cmꢀ1 (NaCl) 2928, 2867, 1745, 1712; mp
,
,
1.07–1.02 (m, 2H); dC (100 MHz, benzene-d6) 204.5, 138.6, 128.6,
127.9, 127.6, 75.1, 73.2, 64.0, 46.1, 38.1, 26.3, 21.7; HRMS (FAB+)
calcd for C16H18O3Na (M+Na): 281.1154. Found: 281.1154.
4.7. General procedure for asymmetric reduction with baker’s
yeast
Regular baker’s yeast (260 g lꢀ1) was added to a solution of sac-
charose (230 g lꢀ1) and diketone (50 mmol lꢀ1) in water (5% v/v
EtOH). The resulting suspension was stirred at rt. When CO2 (g)
had stopped forming, additional yeast and saccharose were added
which was repeated until the starting material was consumed.
The suspension was then filtered through a layer of Celite, which
was rinsed several times with EtOAc. The aqueous phase was ex-
tracted with EtOAc (three times) before the combined organic
phases were dried (Na2SO4) followed by removal of the solvent un-
der reduced pressure. The crude residue was purified by column
chromatography.
oil. Rf = 0.50 (heptane/EtOAc 1:1); m
max/cmꢀ1 (NaCl) 3434, 3023,
2941; dH (400 MHz, CDCl3) 7.38–7.27 (m, 5H) 5.91–5.87 (m, 1H)
5.67 (dt, 1H, J = 2.1, 10.1 Hz) 4.61 (dAB, 1H, JAB = 12.1 Hz) 4.58
(dAB, 1H, JAB = 12.1 Hz) 3.41 (dAB, 1H, JAB = 9.0 Hz) 3.37 (dAB, 1H,
JAB = 9.0 Hz) 2.48 (s, 1H) 2.13–2.05 (m, 1H) 2.01–1.92 (m, 1H)
1.83–1.58 (m, 4H); dC (100 MHz, CDCl3) 138.1, 131.5, 129.3, 129.5,
128.4, 127.5, 127.3, 73.5, 69.5, 33.0, 25.4, 18.8.
PCC (0.95 g, 4.4 mmol, 3.8 equiv calcd on 80% yield in first step)
was added to a solution of crude 35 in dry DCM (8 mL) at rt. After
5 h, the reaction mixture was filtered through a layer of SiO2 and
eluted with EtOAc. The crude residue was purified by column chro-
matography (SiO2, pentane/ether 7:3) to give 36 (0.17 g, 54% from
4.7.1. (ꢀ)-(1R,4R,6S)-4-(tert-Butyldimethyl-silanyloxy)-6-endo-
hydroxy-bicyclo[2.2.2]octan-2-one (ꢀ)-17
34) as clear oil. Rf = 0.42 (heptane/EtOAc 1:1); m
max/cmꢀ1 (NaCl)
3032, 2945, 1671; dH (400 MHz, CDCl3) 7.29–7.17 (m, 5H) 6.08 (t,
1H, J = 1.5 Hz) 4.48 (s, 2H) 4.02 (d, 2H, J = 0.7 Hz) 2.34 (m, 2H)
2.21 (m, 2H) 1.94 (m, 2H); dC (100 MHz, CDCl3) 199.8, 161.5,
137.8, 128.7, 128.1, 127.9, 125.2, 73.0, 72.2, 38.0, 26.6, 22.7; HRMS
(FAB+) calcd for C14H16O2 (M): 216.1150. Found: 216.1156.
The title compound was synthesized following the general pro-
cedure for asymmetric reduction with baker’s yeast from 9 (0.12 g,
0.44 mmol). Consumption of the starting material took two days.
Purification by column chromatography (SiO2, pentane/ether 4:6)
gave (ꢀ)-17 (0.10 g, 87%, 46% ee) as white crystals. Rf = 0.15 (hep-
tane/EtOAc 7:3); ½a D20
ꢃ
¼ ꢀ8 (c 1.7, CHCl3); (Calcd for C14H26O3Si: C,
4.6.8. ( )-3-Allyl-3((benzyloxy)methyl)-cyclohexan-1-one 37
Allyltributyltin (2.5 mL, 8.1 mmol) was added to a stirred solu-
tion of TaCl5 (1.4 g, 3.9 mmol) in dry THF (5 mL) at ꢀ40 °C. After
3 h, 36 (0.21 g, 0.98 mmol) in dry THF (2 mL) was added followed
by TMSCl (0.40 mL, 3.2 mmol). The reaction was quenched after
48 h by addition of satd NH4Cl (aq) followed by slow warming of
the reaction mixture to rt. 1 M HCl was added until pH 3 followed
by extraction with EtOAc (5 ꢂ 10 mL). The combined organic
phases were washed with brine (2 ꢂ 20 mL) and dried (Na2SO4) be-
fore removal of the solvent under reduced pressure. The crude res-
idue was purified by column chromatography (SiO2, pentane/ether
92:8) to give 37 (0.15 g, 60%) as semi-crystalline material. Rf = 0.33
62.18; H, 9.69. Found: C, 62.26; H, 9.64); m
max/cmꢀ1 (KBr) 3456,
3377, 2961, 1719; mp 88.0–89.9 °C;; dH (400 MHz, pyridine-d5)
7.03 (s, 1H) 4.41–4.38 (m, 1H) 2.82 (dAB, 1H, JAB = 17.7 Hz) 2.71–
2.72 (m, 1H) 2.54 (ddAB, 1H, J = 3.2 Hz, JAB = 17.8 Hz) 2.42–2.34
(m, 1H) 2.07 (d, 1H, J = 13.1 Hz) 1.64 (s, 4H) 0.91 (s, 9H) 0.12 (s,
6H); dC (100 MHz, pyridine-d5) 211.8, 73.1, 68.0, 53.3, 51.3, 46.1,
33.3, 26.3, 19.3, 18.5, ꢀ1.5 (2C); HRMS (FAB+) calcd for C14H27O3Si
(M+H): 271.1729. Found: 271.1736.
4.7.2. (+)-(1R,4R,6S)-4-Acetoxy-6-endo-hydroxy-bicyclo[2.2.2]
octan-2-one (+)-18
The title compound was synthesized by following the general
procedure for asymmetric reduction with baker’s yeast from 10
(91.0 mg, 0.50 mmol). Consumption of the starting material took
two days. Purification by column chromatography (SiO2, pentane/
ether 3:7) gave (+)-18 (70 mg, 73%, 10% ee) as white crystals.
(heptane/EtOAc 8:2);
m
max/cmꢀ1 (NaCl) 3030, 2924, 1711; dH
(400 MHz, CDCl3) 7.38–7.28 (m, 5H) 6.16–6.15 (m, 1H) 4.56 (s,
2H) 4.11–4.10 (m, 2H) 2.42 (t, 2H, J = 6.7 Hz) 2.29 (t, 2H,
J = 5.9 Hz) 2.03 (p, 2H, J = 6.3 Hz); dC (100 MHz, CDCl3) 211.9,

1380
S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
Rf = 0.35 (pentane/ether 2:8); ½a D20
ꢃ
¼ þ2 (c 1.0, CH3Cl); (Calcd for
max/cmꢀ1
4.7.6. (ꢀ)-(1R,4R,6S)-4-(Allyloxy)-6-hydroxy-bicyclo[2.2.2]
C
10H14O4: C, 60.59; H, 7.12. Found: C, 60.67; H, 7.06);
m
octane-2-one (ꢀ)-22
(KBr) 3395, 2972, 1742, 1713; mp 87.6–88.5 °C; dH (400 MHz, pyr-
idine-d5) 7.19 (d, 1H, J = 2.4 Hz) 4.43–4.40 (m, 1H) 3.33 (ddAB, 1H,
J = 3.0 Hz, JAB = 17.8 Hz) 2.99 (ddAB, 1H, J = 3.2 Hz, JAB = 17.8 Hz)
2.76–2.67 (m, 2H) 2.54 (td, 1H, J = 2.4, 13.2 Hz) 2.12–1.98 (m,
2H) 1.96 (s, 3H) 1.73–1.61(m, 2H); dC (100 MHz, pyridine-d5)
210.4, 170.6, 79.3, 67.5, 51.1, 49.2, 41.6, 29.2, 22.5, 18.7; HRMS
(FAB+) calcd for C10H15O4 (M+H): 199.0970. Found: 199.0989.
The title compound was synthesized by following the general
procedure for asymmetric reduction with baker’s yeast from 14
(0.30 g, 1.54 mmol). Consumption of the starting material took
48 h. Purification by column chromatography (SiO2, heptane/EtOAc
55:45) gave (ꢀ)-22 (0.24 g, 80%, 82% ee) as white crystals. Rf = 0.10
(heptane/EtOAc 55:45); ½a D20
ꢃ
¼ ꢀ3:3 (c 1.0, CH2Cl2);
m
max/cmꢀ1
(KBr) 3384, 1710; mp 64.0–66.0 °C; dH (400 MHz, pyridine-d5)
6.05–5.95 (m, 1H) 5.39–5.33 (m, 1H) 5.15–5.11 (m, 1H) 4.42–
4.38 (m, 1H) 4.07–3.98 (m, 2H) 2.85 (ddAB, 1H, JAB = 17.8 Hz,
4.7.3. (ꢀ)-(1R,4R,6S)-4-Benzyloxy-6-endo-hydroxy-bicyclo
[2.2.2]octan-2-one (ꢀ)-19
J = 2.8 Hz) 2.73–2.71 (m, 1H) 2.59 (ddAB
, 1H, JAB = 17.8 Hz,
The title compound was synthesized by following the general
procedure for the asymmetric reduction with baker’s yeast from
11 (1.4 g, 5.6 mmol). Consumption of the starting material took
two days. Purification by column chromatography (SiO2, pentane/
ether 3:7) gave (ꢀ)-19 (1.2 g, 86%, 69% ee) as white crystals.
J = 3.2 Hz) 2.41–2.35 (m, 1H) 2.15–2.11 (m, 1H) 1.75–1.57 (m,
4H); dC (100 MHz, pyridine-d5) 211.6, 137.0, 115.9, 75.2, 67.7,
63.6, 51.3, 49.1, 41.8, 29.3, 19.0; HRMS (FAB+) calcd for C11H17O3
(M+H): 197.1178. Found: 197.1176.
Rf = 0.15 (pentane/ether 3:7); ½a D20
ꢃ
¼ ꢀ18 (c 1.0, CHCl3); (Calcd
4.7.7. Attempts towards 6-hydroxy-4-triisopropylsilanyloxy-
bicyclo[2.2.2]octan-2-one 23
for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.04; H, 7.28); mmax
/
cmꢀ1 (KBr) 3385, 2945, 2876, 1732; mp 105.8–106.8 °C; dH
(400 MHz, pyridine-d5) 7.48 (d, 2H, J = 7.2 Hz) 7.39 (t, 2H,
Attempt towards the title compound was performed following
the general procedure for asymmetrical reduction with baker’s
yeast from 15 (0.12 g, 0.40 mmol). The reaction mixture was stir-
red for seven days without conversion, only starting material was
recovered.
J = 7.5 Hz) 7.31 (t, 1H, J = 7.3 Hz) 7.08 (d, 1H, J = 3.0 Hz) 4.60 (dAB
,
1H, JAB = 11.5 Hz) 4.57 (dAB, 1H, JAB = 11.5 Hz) 4.46–4.41 (m, 1H)
2.94 (ddAB, 1H, J = 2.9 Hz, JAB = 17.7 Hz) 2.76–2.73 (m, 1H) 2.68
(ddAB, 1H, J = 3.3 Hz, JAB = 17.7 Hz) 2.49–2.42 (m, 1H) 2.21 (d, 1H,
J = 13.2 Hz) 1.80–1.64 (m, 4H); dC (100 MHz, pyridine-d5) 211.7,
140.6, 129.2, 128.4, 128.1, 75.6, 67.9, 64.8, 51.5, 49.2, 42.0, 29.5,
19.2; HRMS (FAB+) calcd for C15H19O3 (M+H): 247.1334. Found:
247.1335.
4.7.8. ( )-4-Benzyloxymethyl-6-hydroxy-bicyclo[2.2.2]octane-2-
one 24
The title compound was synthesized by following the general
procedure for asymmetric reduction with baker’s yeast from 16
(39.0 mg, 0.15 mmol). Consumption of the starting material took
five days. Purification by column chromatography (SiO2, pentane/
ether 35:65) gave 24 (26 mg, 66%, 0% ee) as white crystals.
Recrystallization from petroleum ether (40–60) (four times) re-
sulted in >99% ee. ½a D20
¼ ꢀ23 (c 1.0, CHCl3).
ꢃ
4.7.4. (ꢀ)-(1R,4R,6S)-4-(4-Bromobenzyloxy)-6-endo-hydroxy-
bicyclo[2.2.2]octan-2-one (ꢀ)-20
Rf = 0.30 (heptane/EtOAc 3:7); m
max/cmꢀ1 (NaCl) 3508, 2946, 2870,
1724; mp 68.2–70.2 °C; dH (400 MHz, pyridine-d5) 7.44–7.38 (m,
4H) 7.35–7.31 (m, 1H) 4.50 (s, 2H) 4.46–4.42 (m, 1H) 3.23 (s, 2H)
2.77–2.75 (m, 1H) 2.62 (ddAB, 1H, JAB = 18.2 Hz, J = 2.2 Hz) 2.33
(ddAB, 1H, JAB = 18.4 Hz, J = 3.2 Hz) 2.15–2.08 (m, 1H) 1.96–1.92
(m, 1H) 1.78–1.70 (m, 1H) 1.69–1.60 (m, 1H) 1.49–1.40 (m, 2H);
dC (100 MHz, pyridine-d5) 214.1, 139.8, 129.2, 128.2, 128.2, 77.5,
73.7, 68.8, 52.1, 47.2, 40.0, 38.2, 27.3, 20.8; HRMS (FAB+) calcd for
The title compound was synthesized by following the general
procedure for asymmetric reduction with baker’s yeast from 12
(0.18 g, 0.54 mmol). Consumption of the starting material took
11 days. Purification by column chromatography (SiO2, heptane/
EtOAc 1:1) gave (ꢀ)-20 (63 mg, 36%, 47% ee) as white crystals.
Rf = 0.09 (heptane/EtOAc 1:1); ½a D20
¼ ꢀ5 (CH2Cl2, c 1.0); (Calcd
ꢃ
for C15H17O3Br: C, 55.40; H, 5.27; Br, 24.57. Found: C, 55.34; H,
C16H20O3Na (M+Na): 283.1310. Found: 283.1312.
5.25; Br, 24.30); m
max/cmꢀ1 (KBr) 3381, 1720; mp 133.0–137.0 °C;
dH (400 MHz, pyridine-d5) 7.31–7.28 (m, 2H) 6.87–6.83 (m, 2H)
3.91 (dAB, 1H, JAB = 11.8 Hz) 3.87 (dAB, 1H, JAB = 11.8 Hz) 3.55–3.49
(m, 1H) 2.48 (d, 1H, J = 17.8 Hz) 2.18–2.16 (m, 1H) 2.14–2.12 (m,
1H) 1.80–1.73 (m, 1H) 1.65–1.59 (m, 1H) 1.28–1.19 (m, 3H) 1.04–
0.98 (m, 1H); dC (100 MHz, pyridine-d5) 211.4, 139.8, 132.0, 130.1,
121.6, 75.7, 67.7, 63.9, 51.3, 49.0, 41.9, 29.3, 19.0; HRMS (FAB+)
calcd for C15H17O3BrNa (M+Na): 347.0259. Found: 347.0252.
4.7.9. (+)-(1R,2R,4R,6S)-4-(Benzyloxy)-2-(2-methoxyphenyl)-
bicyclo[2.2.2]octane-2,6-diol (+)-40
o-Anisyllithium [prepared by addition of 2.5 M n-BuLi
(0.69 mL, 1.7 mmol) to anisol (0.28 mL, 2.6 mmol) in dry THF
(4.5 mL) at ꢀ72 °C] was added dropwise to a solution of (ꢀ)-19
(0.17 g, 0.69 mmol) in dry THF (5.5 mL) at rt. After 1.5 h, satd
NH4Cl (aq) was added. After 15 min, the phases were separated
and the aqueous phase was extracted with EtOAc (3 ꢂ 30 mL).
The combined organic phases were dried (Na2SO4) before re-
moval of the solvent under reduced pressure. The crude residue
was purified by column chromatography (SiO2, heptane/EtOAc
7:3) to give (+)-40 (0.11 g, 47%, 96% ee) as white crystals.
4.7.5. (ꢀ)-(1R,4R,6S)-6-endo-Hydroxy-4-(2-trimethylsilanyl-
ethoxymethoxy)-bicyclo[2.2.2]octan-2-one (ꢀ)-21
The title compound was synthesized by following the general
procedure for asymmetric reduction with baker’s yeast from 13
(0.15 g, 0.52 mmol). Consumption of the starting material took se-
ven days. Purification by column chromatography (SiO2, heptane/
EtOAc 6:4) gave (ꢀ)-21 (87 mg, 59%, 68% ee) as white crystals.
Rf = 0.09 (heptane/EtOAc 7:3); ½a D20
¼ þ3 (c 1.0, CH2Cl2); (Calcd
ꢃ
for C22H26O4: C, 74.55; H, 7.39. Found: C, 74.42; H, 7.38); mmax
/
cmꢀ1 (KBr) 3402; mp 119.0–121.0 °C; dH (400 MHz, benzene-d6)
7.36 (m, 2H) 7.23–7.19 (m, 2H) 7.13–7.09 (m, 2H) 7.02–6.98
(m, 1H) 6.76 (td, 1H, J = 7.6, 1.1 Hz) 6.42 (dd, 1H, J = 8.2,
1.1 Hz) 4.55 (d, 1H, J = 11.4 Hz) 4.39–4.31 (m, 3H) 4.17–4.09
(m, 1H) 3.00 (s, 3H) 2.54–2.43 (m, 3H) 2.24–2.19 (m, 2H) 1.39–
1.19 (m, 4H); dC (100 MHz, benzene-d6) 157.9, 140.9, 134.5,
128.8, 128.7, 128.0, 127.6, 126.6, 121.3, 112.3, 80.1, 74.8, 71.7,
64.2, 55.0, 47.7, 43.0, 40.1, 28.5, 21.1; HRMS (FAB+) calcd for
Rf = 0.24 (heptane/EtOAc 1:1); ½a D20
¼ ꢀ10 (c 1.5, CHCl3); (Calcd
ꢃ
for C14H26O3Si: C, 58.70; H, 9.15. Found: C, 58.64; H, 9.19); mmax
/
cmꢀ1 (KBr) 3410, 2953, 1715; mp 57.7–58.8 °C; dH (400 MHz, pyr-
idine-d5) 7.06 (d, 1H, J = 2.9 Hz) 4.95 (s, 2H) 4.45–4.41 (m, 1H) 3.75
(t, 2H, J = 8.2 Hz) 3.00 (dd, 1H, J = 17.9, 2.8 Hz) 2.77–2.72 (m, 2H)
2.55–2.49 (m, 1H) 2.27 (dt, 1H, J = 13.3, 2.2 Hz) 1.85–1.78 (m,
2H) 1.70–1.63 (m, 2H) 0.99 (t, 2H, J = 8.2 Hz) 0.03 (s, 9H); dC
(100 MHz, pyridine-d5) 211.7, 90.1, 75.6, 67.8, 65.5, 51.6, 50.6,
43.0, 30.3, 19.1, 18.7, ꢀ0.8.
C22H26O4Na (M+Na): 377.1729. Found: 377.1716.

S. Manner et al. / Tetrahedron: Asymmetry 21 (2010) 1374–1381
1381
4. Jayasuriya, H.; Herath, K. B.; Zhang, C.; Zink, D. L.; Basilio, A.; Genilloud, O.;
Diez, M. T.; Vicente, F.; Gonzalez, I.; Salazar, O.; Pelaez, F.; Cummings, R.; Ha, S.;
Wang, J.; Singh, S. B. Angew. Chem., Int. Ed. 2007, 46, 4684–4688.
5. Srikrishna, A.; Ravi, G. Tetrahedron 2008, 64, 2565–2571.
6. Tang, P.; Chen, Q.-H.; Wang, F.-P. Tetrahedron Lett. 2009, 50, 460–462.
7. Wang, H.; Yu, K. B.; Ding, L. S.; Luo, X. D.; Zhang, X. F. Acta Crystallogr., Sect. E:
Struct. Rep. Online 2009, 65, o1832.
8. Spangler, J. E.; Sorensen, E. J. Tetrahedron 2009, 65, 6739–6745.
9. Mori, K.; Matsushima, Y. Synthesis 1993, 406–410.
10. Paquette, L. A.; Poupart, M. A. J. Org. Chem. 1993, 58, 4245–4253.
11. Martin, S. F.; Assercq, J. M.; Austin, R. E.; Dantanarayana, A. P.; Fishpaugh, J. R.;
Gluchowski, C.; Guinn, D. E.; Hartmann, M.; Tanaka, T., et al Tetrahedron 1995,
51, 3455–3482.
12. Njardarson, J. T.; Wood, J. L. Org. Lett. 2001, 3, 2431–2434.
13. La Bella, A.; Leonelli, F.; De Salve, I.; Migneco, L. M.; Marini Bettolo, R. Helv.
Chim. Acta 2004, 87, 2120–2124.
14. La Bella, A.; Popolla, I.; Felici, M.; Leonelli, F.; Ceccacci, F.; Filocamo, L.;
Migneco, L. M.; Bettolo, R. M. ARKIVOC (Gainesville, FL, US) 2008, 80–90.
15. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440–467.
16. Almqvist, F.; Torstensson, L.; Gudmundsson, A.; Frejd, T. Angew. Chem., Int. Ed.
1997, 36, 376–377.
17. Sarvary, I.; Almqvist, F.; Frejd, T. Chem. Eur. J. 2001, 7, 2158–2166.
18. Sarvary, I.; Wan, Y.; Frejd, T. J. Chem. Soc., Perkin Trans. 1 2002, 645–651.
19. Sarvary, I. Lund University, 2002.
20. Sarvary, I.; Norrby, P.-O.; Frejd, T. Chem. Eur. J. 2004, 10, 182–189.
21. Friberg, A. Lund University, 2006.
4.7.10. (+)-(1R,2R,4R,6S)-4-(Allyloxy)-2-(2-methoxyphenyl)-
bicyclo[2.2.2]octane-2,6-diol (+)-41
The title compound was synthesized from (ꢀ)-22 (150 mg,
0.760 mmol) following the same procedure as for (+)-40 with a
reaction time of 3 h. The crude product was purified by column
chromatography (SiO2, heptane/EtOAc 6:4) to give (+)-41
(111 mg, 48%) of 82 % ee as an oil. Rf = 0.10 (heptane/EtOAc 6:4);
½
a 2D0
ꢃ
¼ þ9 (c 1.0, CH2Cl2);
m
max/cmꢀ1 (NaCl) 3469, 2919, 2853; dH
(400 MHz, benzene-d6) 7.08 (dd, 1H, J = 8.0, 2.0 Hz) 7.01–6.97 (m,
1H) 6.75 (dt, 1H, J = 7.6, 1.2 Hz) 6.41 (dd, 1H, J = 8.2, 1.1 Hz)
5.97–5.88 (m, 1H) 5.35–5.29 (m, 1H) 5.07–5.04 (m, 1H) 4.54 (d,
1H, J = 11.6 Hz) 4.36 (s, 1H) 4.14–4.06 (m, 1H) 3.86–3.76 (m, 2H)
3.00 (s, 3H) 2.50–2.36 (m, 3H) 2.21–2.12 (m, 2H) 1.35–1.16 (m,
4H); dC (100 MHz, benzene-d6) 157.9, 137.2, 134.5, 128.8, 126.6,
121.3, 115.2, 112.2, 80.1, 74.5, 71.7, 63.1, 55.0, 47.4, 43.0, 40.1,
28.4, 21.1; HRMS (FAB+) calcd for C18H24O4Na [M+Na]: 327.1575.
Found: 327.1579.
4.8. General procedure for catalytic enantioselective addition of
diethylzinc to benzaldehyde
22. Friberg, A.; Sarvary, I.; Wendt, O. F.; Frejd, T. Tetrahedron: Asymmetry 2008, 19,
1765–1777.
23. Olsson, C.; Friberg, A.; Frejd, T. Tetrahedron: Asymmetry 2008, 19, 1476–1483.
24. Olsson, C.; Helgesson, S.; Frejd, T. Tetrahedron: Asymmetry 2008, 19, 1484–
1493.
Freshly distilled benzaldehyde (102 ll, 1.00 mmol) was added
to a stirred solution of catalyst (0.5 mmol) in dry diethyl ether
(2.0 mL) at 0 °C. After 45 min, diethylzinc (1.0 M in hexane,
3.0 mL, 3.0 mmol) was added which resulted in a yellow solution.
After stirring for 40 h at 0 °C, satd NH4Cl (aq) (3.0 mL) was added.
When the gas formation had stopped and the solution had turned
colourless, the phases were separated and the aqueous phase was
extracted with DCM (4 ꢂ 1.25 mL). Yield and ee were determined
by chiral GC analysis using 1-decanol as internal standard. GC
(Supelco, betaDEX isothermal, 130 °C, 1 mL minꢀ1) benzaldehyde:
tR = 4.6 min; benzyl alcohol: tR = 9.3 min, 1-decanol: tR = 13.4 min,
(R)-1-phenylpropane-1-ol: tR = 13.8 min, (S)-1-phenylpropane-1-
ol: tR = 14.5 min. (+)-40 (90%, 90% ee); (+)-41 (91%, 89% ee).
25. Olsson, C. Lund University, 2008.
26. Baran, A.; Gunel, A.; Balci, M. J. Org. Chem. 2008, 73, 4370–4375.
27. Finet, L.; Dakir, M.; Castellote, I.; Arseniyadis, S. Eur. J. Org. Chem. 2007, 4116–
4123.
28. Finet, L.; Lena, J. I. C.; Kaoudi, T.; Birlirakis, N.; Arseniyadis, S. Chem. Eur. J. 2003,
9, 3813–3820.
29. Mori, K.; Nagano, E. Biocatalysis 1990, 3, 25–36.
30. Kitahara, T.; Miyake, M.; Kido, M.; Mori, K. Tetrahedron: Asymmetry 1990, 1,
775–782.
31. Mori, K.; Matsushima, Y. Synthesis 1995, 845–850.
32. Mori, K.; Matsushima, Y. Synthesis 1994, 417–421.
33. Nagano, E.; Mori, K. Biosci. Biotechnol. Biochem. 1992, 56, 1589–1591.
34. Almqvist, F.; Eklund, L.; Frejd, T. Synth. Commun. 1993, 23, 1499–1505.
35. Almqvist, F.; Frejd, T. Tetrahedron: Asymmetry 1995, 6, 957–960.
36. Almqvist, F.; Ekman, N.; Frejd, T. J. Org. Chem. 1996, 61, 3794–3798.
37. Widegren, M.; Dietz, M.; Friberg, A.; Frejd, T.; Hahn-Haegerdal, B.; Gorwa-
Grauslund, M. F.; Katz, M. Synthesis 2006, 3527–3530.
38. Friberg, A.; Johanson, T.; Franzen, J.; Gorwa-Grauslund, M. F.; Frejd, T. Org.
Biomol. Chem. 2006, 4, 2304–2312.
39. Almqvist, F.; Manner, S.; Thornqvist, V.; Berg, U.; Wallin, M.; Frejd, T. Org.
Biomol. Chem. 2004, 2, 3085–3090.
40. Thornqvist, V.; Manner, S.; Wendt, O. F.; Frejd, T. Tetrahedron 2006, 62, 11793–
11800.
41. Thornqvist, V.; Manner, S.; Wingstrand, M.; Frejd, T. J. Org. Chem. 2005, 70,
8609–8612.
42. Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F., III; Schenck, R. J.;
Trippe, A. J. J. Org. Chem. 2008, 73, 4443–4451.
Acknowledgments
We thank the Swedish Research Council, The Royal Physio-
graphic Society in Lund, The Research School in Medicinal Science
at Lund University and the Knut and Alice Wallenberg Foundation
for economic support. We also thank Karl-Erik Bergqvist for help
with NMR spectral data, Einar Nilsson for obtaining mass spectral
data, and Mikael Björklund for contributing to the experimental
work.
43. Kaufman, T. S. Synlett 1997, 1377–1378.
44. Johnson, C. R.; Medich, J. R. J. Org. Chem. 1988, 53, 4131–4133.
45. Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682–685.
46. Shibata, I.; Kano, T.; Kanazawa, N.; Fukuoka, S.; Baba, A. Angew. Chem., Int. Ed.
2002, 41, 1389–1392.
47. Almqvist, F. Lund University, 1996.
48. Thornqvist, V. Lund University, 2006.
References
1. Asaoka, M.; Ishibashi, K.; Yanagida, N.; Takei, H. Tetrahedron Lett. 1983, 24,
5127–5130.
2. Lal, A. R.; Cambie, R. C.; Rutledge, P. S.; Woodgate, P. D.; Rickard, C. E. F.; Clark,
G. R. Tetrahedron Lett. 1989, 30, 3205–3208.
49. Thornqvist, V.; Manner, S.; Frejd, T. Tetrahedron: Asymmetry 2006, 17, 410–415.
50. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
3. Kuo, Y.-H.; Chen, C.-H.; Huang, S.-L. Chem. Pharm. Bull. 1998, 46, 181–183.