Bicyclic diols and related derivatives as catalysts for the asymmetric diethylzinc addition to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2008.05.024

Chiral bicyclic diols based on bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane have been synthesized and their catalytic capacity in the asymmetric diethylzinc addition to benzaldehyde compared with those described for previously synthesized 2,6-bicyclo[2.

Full text of DOI:10.1016/j.tetasy.2008.05.024

Tetrahedron: Asymmetry 19 (2008) 1476–1483
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Tetrahedron: Asymmetry
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Bicyclic diols and related derivatives as catalysts for the asymmetric
diethylzinc addition to benzaldehyde
*
Cecilia Olsson, Annika Friberg, Torbjörn Frejd
Division of Organic Chemistry, Kemicentrum, Lund University, 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:
Chiral bicyclic diols based on bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane have been synthesized and
their catalytic capacity in the asymmetric diethylzinc addition to benzaldehyde compared with those
described for previously synthesized 2,6-bicyclo[2.2.2]octane-diols (BODOLs). The influence of the num-
ber of coordinating sites and the distance between them were studied.
Received 5 May 2008
Accepted 23 May 2008
Available online 28 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
which in its enantiomerically pure form in turn was described by
Weissfloch and Azerad.9 Thus, we used a modified combination
The asymmetric addition of diethylzinc to benzaldehyde has
been extensively studied,1–3 and is a convenient test reaction for
new metal coordinating ligands and catalysts. While a large num-
ber of amino alcohols have been found to be excellent catalysts for
the reaction,4 diols are often poor catalysts by themselves and are
frequently used as complexes with Ti(IV). A few cases of diol catal-
ysis in this reaction have been reported, including 2,6-bi-
cyclo[2.2.2]octane-diols (BODOLs), presented by our group.5–7
The yields and enantioselectivities were highly dependent on the
aryl side-group at the 2-position of the BODOLs. The best catalyst
was o-anisyl-bicyclo[2.2.2]octane-diol, giving (R)-1-phenylpropa-
nol of 92% ee. In an attempt to find more efficient and selective
diol-catalysts, we have synthesized novel bicyclic diols in the form
of 2,6-BODOLs, 2,5-BODOLs and 2,5-bicyclo[2.2.1]heptane-diols
(2,5-BHEDOLs ), which are presented in this report together with
their ability to act as enantioselective catalysts in the diethylzinc
addition to benzaldehyde.
of the published methods in order to synthesize (ꢀ)-5 (Schemes
1 and 2). A suitable starting material was the commercial mixture
of endo- and exo-5-norbornene-2-yl-acetate 1 (Scheme 1). Epoxi-
dation with magnesium monoperoxyphthalate (MMPP) in aqueous
ethanol, followed by recrystallization from ether afforded the pure
endo-epoxyacetate 2. Alkaline hydrolysis gave epoxyalcohol 3,
which was resolved by enzymatic transesterification using
Novozym 435 (immobilized lipase B from Candida antarctica) and
isopropenylacetate in toluene. In this process, the (+)-enantiomer
of 3 was enantioselectively acylated by the enzyme leaving alcohol
(ꢀ)-3 in high ee. Chiral GC analysisà was used to monitor the reac-
tion, which was disrupted when the ee of alcohol (ꢀ)-3 reached
>95% (at approximately 60% conversion). The addition of 4 Å MS
shortened the reaction time considerably. Ester (+)-2 with lower ee
(50–70% ee, depending on the degree of conversion) was hydrolyzed
and the resulting epoxy alcohol, (+)-3 (50–70% ee), was exposed to
another ester resolution procedure. Initially, the ee of (+)-2 was
>99%, but as the reaction proceeded, the ee of (+)-2 decreased. There-
fore, the reaction was disrupted when the ee of (+)-2 dropped below
95%, giving (+)-2 in high ee and reasonable yield. Lipase from
Candida rugosa has previously been used for the resolution9 but Nov-
ozym 435 is preferred since it is more durable and could be re-used
several times without any change in reactivity, if stored in toluene.
Reduction of epoxyalcohol (ꢀ)-3 with LiAlH4 gave diol (ꢀ)-4 as
the major product.9 Diol (ꢀ)-4 was selectively oxidized at the endo-
hydroxyl with nitric acid giving hydroxy ketone (ꢀ)-5.8 Diketone
(ꢀ)-6 was isolated as a by-product in 8% yield. The aryl side-groups
2. Results and discussion
2.1. Synthesis of bicyclo[2.2.1]heptane- and bicyclo[2.2.2]-
octane-diols
Hydroxy ketone (ꢀ)-5 seemed to be a suitable intermediate
derivative, which by some simple redox and addition reactions
would lead to the type of compounds that we required. Compound
( )-5 was previously reported by Toivonen starting from ( )-4,8
GC analysis was performed on a Supelco beta DEXTM 120 column. The alcohol was
à
* Corresponding author.
E-mail address: Torbjorn.Frejd@organic.lu.se (T. Frejd).
We suggest that the diols based upon the bicyclo[2.2.1]heptane framework
should be named BHEDOLs (bicyclo[2.2.1]heptane-diols).
best analyzed at 140 °C (isothermic) (tR (ꢀ)-3 23.0 min, (+)-3 24.0 min) and the ester
at 130 °C (isothermic) (tR (+)-2 25.3 min, (ꢀ)-2 25.8 min). The conversion was
calculated from the peak-areas without calibration.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.024

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
1477
i
ii
iii
O
O
O
O
+
OAc
OAc
OAc
OH
OH
1
2
3
(-)-3
(+)-2
Scheme 1. Reagents and conditions: (i) (1) MMPP, EtOH/H2O, rt, 4 h; (2) recrystallization from Et2O; (ii) 2 M NaOH, EtOH, rt, 30 min; (iii) Novozym 435, isopropenylacetate,
toluene, 4 Å MS.
HO
HO
O
Ph
O
vi
i
ii
+
Ph
OH
(-)-7
OH
O
OH
OH
O
(-)-3
(-)-4
(-)-5
iii
(-)-6
HO
O
v
iv
R
R
R
OH
OH
OH
OH
(-)-8: R=o-An
(-)-9: R= Ph
(-)-11: R= -An
o
(-)-14: R=o-An
(-)-15: R=Ph
(-)-12: R=Ph
(-)-10: R=1-Naphth (-)-13: R=1-Naphth
(-)-16: R=1-Naphth
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, 4 h, reflux; (ii) 33% HNO3, rt, 30 min; (iii) RMgX/RLi,, rt; (iv) TPAP, NMO, CH2Cl2, MS 4 Å, rt, 1.5 h; (v) NaBH4, MeOH, 0 °C,
15 min; (vi) PhMgCl, THF/Et2O, rt.
were then introduced by the reaction of hydroxy ketone (ꢀ)-5 with
the corresponding Grignard or organolithium reagent without pro-
tection of the alcohol. The C2-symmetric diol (ꢀ)-7 was synthe-
sized from diketone (ꢀ)-6 and phenylmagnesium chloride
according to a literature procedure.10 The product from the endo-
addition was not observed in any of the reactions and the conver-
sions were close to total in all reactions, which means that there
was no problem with enolate formation. For the introduction of
the phenyl and the 1-naphthyl-group, the corresponding Grignard
reagents gave the cleanest reactions except for the introduction of
the o-anisyl group, when the organolithium reagent was the better
choice. Oxidation of the remaining alcohol using TPAP/NMO fol-
lowed by selective reduction with NaBH4 in methanol afforded
diols (ꢀ)-14, (ꢀ)-15 and (ꢀ)-16.
Diols (+)-18 and (+)-19 were synthesized according to proce-
dures previously developed in our group.11 The 2,6-BODOLs (+)-
20 and (+)-21 were synthesized by the addition of the in situ
formed organolithium reagents (from the corresponding bromo-
aromatic compound and butyllithium) to hydroxy ketone (ꢀ)-17.
Mono methylated compounds (+)-22 and (+)-23 were obtained
i
ii
iii
R
R
O
R
OH
O
OH
(-)-17
OH OH
O
(+)-18: R= -An
(+)-22: R= -An
24: R= -An
o
o
o
(+)-23: R=Ph
(+)-19: R=Ph
(+)-20: R=o-C6H4OH
(+)-21: R=o-C6H4OCF3
Scheme 3. Reagents and conditions: (i) RMgX/RLi; (ii) MeI, KOH, THF, rt, overnight; (iii) spontaneous elimination upon storage.
O
R
R
R
i
ii
iii
R
OH
OH
OH
O
OH
(+)-25
OH
OH
(-)-29: R=o-An
(-)-30: R=Ph
(-)-26: R=o-An
(-)-27: R=Ph
(-)-28: R=1-Naphth
Scheme 4. Synthesis of 2,5-BODOLs.11

1478
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
from the corresponding diols by reaction with MeI and KOH in THF.
Compound (+)-22 slowly eliminated water upon standing at rt, giv-
ing unsaturated ether 24 (Scheme 3). However, it appeared more
stable in benzene solution in which no elimination was observed
after several weeks. To be sure of its purity, (+)-22 was purified
by chromatography and checked by 1H NMR before it was used
in the catalytic experiments.
phor, gave access to monoalcohol (ꢀ)-32 in >99% ee. It was
tested as a catalyst but it was inferior compared to its diol-ana-
logue (entry 16), which indicated that all three coordinating sites
indeed were necessary to reach high enantioselectivity.
Compound (+)-22 has three coordinating sites but only one of
them is a hydroxyl group, the other two being methoxy groups.
It gave the best yield in this study (97%), but the enantioselectivity
was much lower than for diol (+)-18, 26–44% ee and 90% ee,
respectively (entries 14 and 1). The corresponding compound with
the phenyl side chain, (+)-23, gave better enantioselectivity than
its corresponding diol but lower yield (entries 15 and 2). Unsatu-
rated ether 24, the product from spontaneous elimination of water
from (+)-22, was isolated and tested as a catalyst. As expected it
gave the racemic product in low yield (25%) (entry 17). It should
be noted that (+)-22 and (+)-23 were stable under the reaction con-
ditions and none of the corresponding unsaturated ethers were de-
tected after the reaction.
Both compounds (+)-20 and (+)-21 have three coordinating
groups. Compound (+)-20 gave a product of 72% ee in 69% yield
(entry 3). The isolated enantiomer had an (S)-configuration, which
indicated that the complex formed was different from the complex
formed by (+)-18, which gave the (R)-enantiomer. This was not
unexpected since the phenolic OH group is more acidic than the
aliphatic OH group and would react faster with the diethylzinc,
opening the possibility to form other complexes. Diol (+)-21 which
differs from (+)-18 only by the trifluoromethoxy group gave the
(R)-enantiomer in only 50% ee and 43% yield (Entry 4). The elec-
tron-withdrawing trifluoromethyl group would make the electrons
on the side chain oxygen less available for coordination to Zn com-
pared to the methyl group resulting in a weaker coordination,
which might be the reason that the lower yield and ee were
observed.
C2 symmetric ligands or catalysts can reduce the number of
competing diastereomeric transition state structures by a factor
of two and hence give better stereochemical control when com-
pared to closely related C1 symmetric derivatives. On the basis of
this, we included some C2-symmetric diols in the study. While
the C2-symmetric o-anisyl-BODOL (ꢀ)-29 was a poor catalyst com-
pared to its C1-symmetric analogue (ꢀ)-26, the opposite applied to
the C2-symmetric phenyl-BODOL (ꢀ)-30, which gave the same
yield as the C1-symmetric catalyst (ꢀ)-27, but gave 38% ee com-
pared to 18% ee (entries 11 and 12). Regarding the C2-symmetric
phenyl-BHEDOL, (ꢀ)-7, it was also an inefficient catalyst such as
its C1-symmetric analogue (ꢀ)-15 (entry 13).
Diols (ꢀ)-26-(ꢀ)-30 were synthesized according to procedures
previously developed by our group (Scheme 4).11
2.2. Catalysis
1,3-Diols lacking the rigidity of the bicyclic backbone were less
efficient catalysts according to our earlier studies.5 The bicyclic
framework of the 2,6-BODOLs places the coordinating groups at a
fixed distance from each other, which seemed to be important
for the formation of complexes with diethylzinc. With the 2,5-
BODOLs and 2,5-BHEDOLs, we have created catalysts with two
other distances between the hydroxyl groups. We undertook a
molecular mechanics computational energy minimization using
MACROMODEL v.6.512 to determine the O–O distances for the three cat-
alysts (ꢀ)-14, (+)-18 and (ꢀ)-26. For o-anisyl-2,6-BODOL (+)-18,
the distance between the two hydroxyl groups was 2.74 Å, while
for o-anisyl-2,5-BODOL (ꢀ)-26 the distance was 3.90 Å and for o-
anisyl-2,5-BHEDOL (ꢀ)-14 the distance was 3.65 Å.
The catalytic experiments were conducted in Et2O and hexane
(2:3) at 0 °C for 40 h using a catalyst loading of 5 mol %. The results
from the experiments are presented in Table 1. After the reaction,
the only compounds detected, besides the catalysts, were 1-phen-
ylpropanol, benzylalcohol and recovered benzaldehyde. The low
yield of 1-phenylpropanol corresponded to the high yield of the
recovered benzaldehyde. Thus, the given yields also gave a good
approximation of the degree of conversion. Comparing the results
from 2,6-BODOL (+)-18 and 2,5-BODOL (ꢀ)-26; the ee decreased
from 90% to 82% and the yield from 83% to 66% as the distance
between the hydroxyls increased (Table 1, entries 1 and 5). 2,5-
BHEDOL (ꢀ)-14, on the other hand, gave only 60% ee and 52%
yield even when the distance between the hydroxyl groups
was close to that of the 2,5-BODOL (Table 1, entry 8). The
bicyclo[2.2.1]heptane framework is more rigid than that of the
bicyclo[2.2.2]octanes, which may affect the possibility to form
the competent complexes.
The necessity of an extra coordinating group for 2,6-BODOLs, as
indicated from previous studies,5 was also valid for the 2,5-BODOLs
and 2,5-BHEDOLs. Thus the presence of the o-anisyl substituent
gave superior results within all three classes, compared to the
phenyl and 1-naphthyl substituents. Phenyl substituted 2,5-BOD-
OL (ꢀ)-27 gave only 18% ee and 31% yield (entry 6) while phenyl
substituted BHEDOL (ꢀ)-15 yielded 28% of almost racemic product
(2% ee, entry 9). However, 1-naphthtyl substituted BHEDOL (ꢀ)-16
gave a moderate ee of 38%, although the yield was only 28% (entry
10).
Thus, all three O-coordinating sites seemed necessary to
provide the required low-energy pathway. However, there is a
possibility that the complexes only involved one of the hydroxyls
and the oxygen of the side chain. To investigate this, we intended
to remove the secondary hydroxyl group from (+)-18 to obtain
monoalcohol 31 (Fig. 1). We tried diverse methods for deoxygen-
ation; conversion of the secondary alcohol to a better leaving
group13,14 with subsequent reduction,15,16 elimination using Bur-
gess’ reagent17 or conversion of the corresponding ketone to the
thioacetal18 or tosylhydrazone19 followed by reduction. Disap-
pointingly, the expected monoalcohol could not be detected in
any of these attempts. However, semi-preparative chiral HPLC
(OD-H column) separation of racemic 2-phenyl-bicyclo[2.2.1]hep-
tan-2-ol, 32, synthesized by the addition of AnMgBr to norcam-
The diethylzinc addition in the presence of the three o-anisyl-
substituted diols (ꢀ)-14, (+)-18 and (ꢀ)-26 and monoalcohol (+)-
22 was monitored over time (Fig. 2). We observed a much faster
reaction with the 2,6-substituted catalysts (+)-18 and (+)-22 than
with the 2,5-substituted catalysts (ꢀ)-14 and (ꢀ)-26. Monoalcohol
(+)-22 gave the fastest reaction with complete conversion of the
benzaldehyde after 22 h. However, as seen in Table 1, the enanti-
oselectivity was low. Diol (+)-18 was slower than monoalcohol
(+)-22, but high conversion was achieved after 40 h. Both 2,5-BHE-
DOL (ꢀ)-14 and 2,5-anisyl-BODOL (ꢀ)-26 were poor catalysts and
a substantial amount of benzaldehyde remained after 40 h.
Benzylalcohol is a common by-product in the diethylzinc addi-
tion, especially if the reaction is slow,1 which we also observed in
our experiments. Thus, while most reactions gave 5–8% of benzyl-
alcohol, the fast reaction using mono alcohol (+)-22 gave only 1%.
However, two catalysts, (+)-19 and (ꢀ)-29 gave more benzyl alco-
hol, 17% and 13%, respectively, even if they had similar reactivities
to many of the other catalysts. Thus, there seems to be no simple
correlation between the formation of benzyl alcohol and the rate
of reaction.
Since several of the tested catalysts were diols, it seemed possi-
ble that both ethyl groups of diethylzinc could be replaced by alco-

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
Table 1 (continued)
1479
Table 1
Application of bicyclic catalysts in the addition of diethylzinc to benzaldehyde
Entry
Catalyst
eea of 1-
phenylpropanol phenylpropanol
Yielda of 1-
Configureb of 1-
phenylpropanol
Entry Catalyst
eea of 1-
Yielda of 1-
Configureb of 1-
phenylpropanol phenylpropanol phenylpropanol
(%)
38
(%)
(%)
90
(%)
83
Ph
Ph
Ph
An
12
31
(R)
1
(R)
OH
OH
OH OH
(−)-30
(+)-18
Ph
Ph
13
14
6
19
97
(S)
(R)
2
3
4
5
6
rac
72
50
82
18
50
69
43
66
31
—
OH
OH
(−)-7
OH OH
(+)-19
An
Ph
26–44
(S)
(R)
(R)
(R)
OH
OH
O
(+)-22
OH OH
(+)-20
15
16
18
16
17
17
(R)
(S)
(S)
O
OH OH
(+)-21
OH
O
F3C
(+)-23
An
An
4
OH
OH
OH
(−)-32
(−)-26
Ph
17
rac
OH
An
OH
(−)-27
O
24c
a
1Naphth
Determined by GC analysis using a chiral Supelco betaDEX column. The yields
were calculated by the use of 1-decanol as internal standard.
b
7
8
12
60
2
50
52
28
28
29
(R)
(R)
(R)
(S)
(R)
Determined by the order of elution on the Supelco betaDEX column.
The specific rotation of 24 was not recorded.
c
OH
OH
(−)-28
An
OH
OH
An
An
(−)-14
OH
OH
31
32
Ph
Figure 1. Monoalcohols 31 and 32.
9
OH
OH
(−)-15
holates to form 2 equiv of ethane and a cyclic dialkoxy zinc
derivative. Prasad et al. showed that the cyclic zinc dialkoxide of
1,2-diphenylethane-1,2-diol, formed by heating a mixture of equi-
molar amount of diol and diethylzinc to 80 °C, was a more efficient
catalyst in the diethylzinc addition to benzaldehyde than the zinc
monoalkoxide of the same diol formed at room temperature.20
Apparently the exchange of the second ethyl group is rather slow.
To investigate if pre-heating of a mixture of our bicyclic diols and
diethylzinc would have any effect on the catalytic activity, we
heated a mixture of (+)-18 (5 mol %) and diethylzinc in hexane to
70 °C for 30 min before the mixture was cooled to 0 °C after which
10
11
38
44
1Naphth
OH
OH
(−)-16
An
An
OH
OH
(−)-29

1480
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
with the zinc alkoxide of the tertiary hydroxyl. The zinc alkoxide of
100
80
60
40
20
0
the tertiary hydroxyl has the possibility to form the complexes
shown in Figure 3, involving two tetra-coordinated Zn atoms,
which would be a likely coordination for zinc alkoxides.22 One of
the zinc atoms may act as a Lewis acid and coordinate to the oxy-
gen atom of the benzaldehyde. The other zinc atom serves to deli-
ver the ethyl group to one of the faces of the prochiral
benzaldehyde, which apparently orientates itself so as to expose
its re-face towards the ethyl-zinc bond. Several other reaction se-
quences and transition states may be possible. In order to gain dee-
per insights, separate investigations are required.
3. Conclusion
In conclusion, novel bicyclic diols have been synthesized and
applied as catalysts in the diethylzinc addition to benzaldehyde.
The results from this study confirm that a third coordinating site
at the aryl substituent is necessary to reach high enantioselectivity.
The coordination is sensitive to the distance between the coordi-
nating groups, since 2,5-BHEDOLs and 2,5-BODOLs were inferior
catalysts. A complex involving one diol, two molecules of diethyl-
zinc and one molecule of benzaldehyde is proposed, which would
explain the observations made in this investigation.
0
20
40
60
80
100
Time (h)
Figure 2. Diethylzinc addition monitored over time in the presence of (ꢀ)-14 (d),
(+)-18 (j), (ꢀ)-26 (ꢀ) and (+)-22 (N).
4. Experimental
diethyl ether and benzaldehyde were added. However, this had no
effect on the yield or the enantioselectivity. We therefore assume
that only one of the ethyl groups is exchanged under our ordinary
conditions.
4.1. General methods
All reactions were carried out in oven-dried glassware under a
nitrogen atmosphere. THF and diethyl ether were distilled from so-
dium and benzophenone, and benzaldehyde was distilled prior to
use. Anisol was filtered through a plug of neutral alumina before
use. 1-Naphthylmagnesiumbromide was synthesized according to
standard methods. Compounds (+)-18, (+)-19, (ꢀ)-26, (ꢀ)-27,
(ꢀ)-28, (ꢀ)-29 and (ꢀ)-3011 were synthesized according to previ-
ous procedures. All other compounds were purchased from Aldrich
Next, the amount of diethylzinc was varied to see if it had any
effect on the yield or the enantioselectivity. Equimolar amounts
of diethylzinc and benzaldehyde gave a slightly lower yield than
2 equiv of diethylzinc and the ee decreased somewhat, from 90%
to 86%. Two or 3 equiv of diethylzinc gave no difference in yield
or ee. On the other hand, when catalyst (+)-18 and diethylzinc
were used in equimolar amounts, no product was formed. This
means that a complex was formed between alkylzinc and (+)-18
by elimination of ethane but this complex could not alkylate the
benzaldehyde, despite the presence of an ethyl group bound to
Zn. Nevertheless, it did catalyze the alkylation if diethylzinc was
present in excess. The same observation was made for catalysis
by aminoalcohols.21
The reaction mechanism of the diethylzinc addition to alde-
hydes catalyzed by aminoalcohols has been extensively studied,
both experimentally and theoretically, and several types of transi-
tion states have been proposed.4 To the best of our knowledge, no
such studies have been performed on the reaction catalyzed by
diols. When diethylzinc reacts with an alcohol, ethane and the
ethyl-zinc alkoxide are likely to be formed. We speculate that the
reaction primarily took place at the least sterically hindered sec-
ondary hydroxyl, but the zinc alkoxide formed was in equilibrium
and used as delivered. TLC was carried out on silica gel (60 F254
,
Merck) and spots were visualized with UV light and then with a
solution of H3[P(Mo3O10)4] (25 g), Ce(SO4)2 (10 g) and H2SO4
(60 mL) in H2O (940 mL) or with a solution of p-methoxybenzalde-
hyde (10 mL), concd sulfuric acid (50 mL) and ethanol (95%,
940 mL). Flash chromatography was performed on Matrex (25–
70
l
m) silica gel. GC analyses were performed on a betaDEX col-
m film thickness). NMR
umn (Supelco, 30 m ꢁ 0.25 mm id, 25
l
spectra were recorded on a Bruker DRX 400 MHz spectrometer
using the residual solvent as internal standard if not otherwise
mentioned. Optical rotations were recorded on a Perkin–Elmer
241 polarimeter at 20 °C and are given in 10ꢀ1 deg cm2 gꢀ1. IR
spectra were recorded on a Shimadzu 8300 FTIR spectrometer.
Melting points were taken on a Sanyo Gallenkamp melting point
apparatus (MPD.350.BM3.5) and are uncorrected. Elemental analy-
ses were performed by H. Kolbe Mikroanalytisches Laboratorium,
Höhenweg 17, D-45470 Mülheim an der Ruhr.
4.2. General procedure: addition of Et2Zn to benzaldehyde
The catalyst (5 mol %) was dissolved in dry ether (2 mL) and
diethylzinc (1.0 M in hexane, 3 mL, 3.0 mmol) was added at 0 °C.
The mixture was stirred for 30 min and then freshly distilled
benzaldehyde (0.10 mL, 1.0 mmol) was added. The reaction was
stirred under N2 at 0 °C for 40 h, then satd aqueous NH4Cl was
added. Dichloromethane (10 mL) was used to extract the aqueous
phase on an IsoluteÒ Phase Separator column. Yields and ee were
determined by GC analysis on a Supelco betaDEX column (isother-
mal at 130 °C, flow rate 1 mL/min). 1-Decanol was used as internal
O
O
O
O
O
O
Zn
OH
H
H
Zn
Zn
H
Et
Zn
O
Et
Et
Et
Ph
H
Ph
Figure 3. Suggested transition state structures of catalyst (+)-18, diethylzinc and
benzaldehyde.

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
1481
standard. The retention times were benzaldehyde 4.6 min, benzyl-
alcohol 9.3 min, 1-decanol 13.7 min, (R)-1-phenylpropanol
14.1 min and (S)-1-phenylpropanol 14.8 min.
by solvent); HRMS (FAB+, direct inlet) [M]: calcd for C17H18O2:
254.1307 Found: 254.1304; (C17H18O2 requires C, 80.26; H, 7.13.
Found: C, 80.19; H, 7.18.)
4.3. Enzymatic resolution giving (+)-(1S,2R,4R,5R,6S)-2-acetoxy-
5,6-epoxynorbornane (+)-2 and (ꢀ)-(1R,2S,4S,5S,6R)-5,6-epoxy-
2-norbornol (ꢀ)-3
4.6. (ꢀ)-(1S,2S,4S,5S)-2,5-Diphenyl-bicyclo[2.2.1]heptane-2,5-
diol (ꢀ)-7
The title compound was synthesized following the same proce-
dure as for (ꢀ)-9, from (ꢀ)-6 (0.47 g, 3.8 mmol) and PhMgCl (2.0 M
in THF, 9.4 mL, 19 mmol). Recrystallization from toluene and col-
umn chromatography of the mother liquor (SiO2, pentane–diethyl
ether, 6:4) gave (ꢀ)-7 (0.63 g, 63%) of 97% ee as white crystals. The
1H NMR analysis was in accordance with literature.10
Novozym 435 (10.15 g), followed by isopropenylacetate
(17.5 mL, 158 mmol), was added to a solution of 3 (10.0 g,
80 mmol) in toluene (400 mL) at rt. MS 4 Å was added to the mix-
ture, then it was orbitally shaken at rt for 6 h. Novozym 435 was
filtered off and rinsed with toluene. The solvent was removed at re-
duced pressure to give a yellow oil, which was column chromato-
graphed (SiO2, heptane–EtOAc, 30:70) to give (+)-2 (7.82 g, 58%,
68% ee) and (ꢀ)-3 (3.85 g, 38%, 96% ee).
4.7. (ꢀ)-(1S,2S,4S,5R)-2-(2-Methoxy-phenyl)-bicyclo[2.2.1]-
heptane-2,5-diol (ꢀ)-8
Acetate (+)-2 (50–60% ee) was hydrolyzed by treatment with
2 M NaOH to give (+)-3 (9.17 g, 50–60% ee) and the above proce-
dure was repeated. The reaction was stopped after ꢂ4 h. Column
chromatography (SiO2, heptane–EtOAc, 30:70) gave (+)-2 (9.22 g,
74%) of 95% ee.
n-BuLi (2.5 M in hexane, 2.5 mL, 6.3 mmol) was added drop-
wise to a solution of anisol (0.70 mL, 6.5 mmol) in dry THF
(23 mL) at ꢀ70 °C. The resulting solution was allowed to warm
to 0 °C and stirred for at least 30 min. Then (ꢀ)-5 (0.30 g,
2.4 mmol) dissolved in THF (4 mL) was added. The resulting slurry
was stirred at rt for 2 h followed by the addition of sat. aqueous
NH4Cl (20 mL). The mixture was worked up as follows: extraction
with EtOAc (3 ꢁ 20 mL), washing of the collected organic phases
with satd aqueous NaHCO3 and brine followed by drying over
Na2SO4 and removal of the solvent at reduced pressure. The crude
product was column chromatographed (SiO2, CH2Cl2–i-PrOH, 95:5)
followed by recrystallization from toluene to give (ꢀ)-8 (0.36 g,
65%) in 94% ee as white crystals; TLC Rf 0.6 (CH2Cl2–i-PrOH,
4.4. (ꢀ)-(1S,2S,4S,5R)-2-Phenyl-bicyclo[2.2.1]heptane-2,5-diol
(ꢀ)-9
PhMgCl (2.0 M in THF, 4.5 mL, 9 mmol) was added to a solution
of (ꢀ)-5 (0.39 g, 3.1 mmol) in dry THF (10 mL) at 0 °C under an
argon atmosphere. A white precipitate was formed. The resulting
slurry was stirred at rt for 1 h then satd aqueous NH4Cl (10 mL)
was added. The organic phase was collected and the aqueous phase
was extracted with EtOAc (3ꢁ15 mL). The combined organic
phases were washed with brine followed by drying over Na2SO4
and removal of the solvent at reduced pressure. The residue was
recrystallized from heptane–EtOAc and the mother liquor was col-
umn chromatographed (SiO2, heptane–EtOAc, 40:60) to give (ꢀ)-9
(0.50 g, 82%) of 94% ee as white crystals; TLC Rf 0.4 (i-PrOH–CH2Cl2,
90:10); mp 127–129 °C; ½a D20
¼ ꢀ15 (c 1.1, CHCl3); IR (KBr)
ꢃ
3300 cmꢀ1 1H NMR (400 MHz, pyridine-d5) d 7.48–7.50 (1H, m),
;
7.28–7.32 (1H, m), 6.98–7.05 (2H, m), 6.05 (1H, d, J = 3.6 Hz),
5.01 (1H, s), 4.41–4.43 (1H, m), 3.73 (3H, s), 3.19–3.24 (1H, ddd,
J = 12.8, 6.9, 2.3 Hz), 2.95–2.96 (1H, m), 2.44–2.45 (1H, m), 2.29–
2.34 (1H, m), 2.11–2.14 (1H, dm, J = 9.9 Hz), 1.70–1.78 (2H, m),
1.55–1.57 (1H, dm, J = 9.9 Hz); 13C NMR (100 MHz, pyridine-d5) d
35.4, 35.7, 43.9, 45.8, 46.6, 55.7, 74.5, 79.0, 112.6, 121.0, 126.2,
128.7, 137.3, 158.6; HRMS (FAB+, direct inlet) [M]: calcd for
10:90); mp 158–163 °C;
½
a 2D0
ꢃ
¼ ꢀ20 (c 1.1, EtOH); IR (KBr)
3308 cmꢀ1 1H NMR (400 MHz, pyridine-d5) d 7.81–7.83 (2H, m),
;
7.40–7.44 (2H, m), 7.27–7.31 (1H, m), 6.56 (1H, s), 6.10 (1H, d,
J = 3.6 Hz), 4.48 (1H, m), 3.26–3.31 (1H, ddd, J = 12.7, 6.9, 2.3 Hz),
2.74 (1H, d, J = 3.7 Hz), 2.44–2.53 (2H, m), 2.08–2.12 (1H, dm,
J = 9.9 Hz), 1.66–1.80 (2H, m), 1.63 (1H, m); 13C NMR (100 MHz,
pyridine-d5) d 35.2, 36.3, 43.3, 46.9, 48.1, 74.5, 79.3, 127.0, 127.4,
128.7, 151.4; HRMS (ES+) [MꢀOH]: calcd for C13H15O: 187.1123.
Found: 187.1105. (C13H16O2 requires C, 76.44; H, 7.90. Found: C,
76.38; H, 8.02.)
C14H18O3: 234.1256. Found: 234.1253. (C14H18O3 requires C,
71.77; H, 7.74. Found: C, 71.72; H, 7.70.)
4.8. (+)-(1R,2R,4S,6S)-2-(2-Trifluoromethoxy-phenyl)-
bicyclo[2.2.2]octane-2,6-diol (+)-21
Trifluoromethoxybenzene (0.83 mL, 6.3 mmol) and TMEDA
(0.94 mL, 6.3 mmol) were dissolved in dry THF (13 mL) and
cooled to ꢀ78 °C. sec-BuLi (1.4 M in cyclohexane, 4.5 mL,
6.3 mmol) was added and the resulting yellow solution was stir-
red at ꢀ78 °C for 3.5 h. Then (ꢀ)-17 dissolved in THF (8 mL) was
added and the reaction was allowed to reach rt. After 1 h water
(20 mL) was added and the aqueous phase was extracted with
diethyl ether (3ꢁ30 mL). The combined organic phases were
washed with brine followed by drying over Na2SO4 and removal
of the solvent at reduced pressure. The residue was column chro-
matographed (SiO2, heptane–EtOAc, 70:30) to give (+)-21 (0.43 g,
68%) of >99% ee as yellow crystals. TLC Rf 0.51 (heptane–EtOAc,
4.5. (ꢀ)-(1S,2S,4S,5R)-2-(1-Naphthyl)-bicyclo[2.2.1]heptane-2,5-
diol (ꢀ)-10
The title compound was synthesized following the same proce-
dure as for (ꢀ)-9, from (ꢀ)-5 (0.3 g, 2.4 mmol) and 1 M 1-naph-
thylMgBr (7.1 mL, 7.1 mmol) in THF. Recrystallization from
EtOAc and column chromatography of the mother liquor (SiO2,
toluene–EtOAc, 1:1) gave (ꢀ)-10 (0.458 g, 75%) of 94% ee as white
crystals; TLC Rf 0.38 (CH2Cl2–i-PrOH, 9:1); ½a D20
¼ ꢀ91 (c 2.4,
ꢃ
EtOH); mp 187–188 °C; IR (KBr) 3362 cmꢀ1 1H NMR (400 MHz,
;
pyridine-d5) d 9.15 (1H, d, J = 8.6 Hz), 7.95–7.97 (1H, m), 7.84
(1H, d, J = 8.1 Hz), 7.68 (1H, d, J = 7.2 Hz), 7.49–7.60 (2H, m),
7.45 (1H, t, J = 7.7 Hz), 6.75 (1H, s), 6.15 (1H, d, J = 3.5 Hz), 4.54–
4.56 (1H, m), 3.36–3.42 (1H, m), 3.18 (1H, d, J = 4.1 Hz), 2.44–
2.46 (1H, m), 2.38 (1H, dm, J = 13.1 Hz), 2.25 (1H, dm,
J = 9.9 Hz), 2.10 (1H, dd, J = 13.1, 2.9 Hz), 1.86 (1H, dm,
J = 12.8 Hz), 1.72 (1H, d, J = 9.7 Hz); 13C NMR (100 MHz, pyri-
dine-d5) d 35.7, 36.0, 45.3, 46.6, 46.7, 74.6, 79.6, 122.5, 125.4,
125.6, 126.0, 128.4, 129.5, 129.7, 133.0, 146.1 (one peak hidden
1:1);
½
a 2D0
ꢃ
¼ þ60 (c 0.9, CHCl3); mp 73–75 °C; IR (NaCl)
3308 cmꢀ1 (very broad); 1H NMR (400 MHz, C6D6) d 0.85–1.00
(2H, m), 1.14–1.19 (2H, m), 1.54–1.59 (1H, m), 1.63–1.68 (1H,
m), 1.87 (1H, dt, J = 14.4, 2.0 Hz), 1.99–2.06 (1H, m), 2.22–2.26
(1H, m), 1.34 (1H, m), 3.21 (1H, s), 3.38 (1H, d, J = 9.2 Hz), 3.80–
3.86 (1H, m), 6.76–6.84 (2H, m), 7.02–7.04 (1H, m), 7.10–7.13
(1H, m); 13C NMR (100 MHz, C6D6) d 21.6, 23.6, 26.3, 37.8, 39.5,
44.3, 70.8, 76.6, 120.3, 122.9, 126.1, 127.9, 129.0, 138.6, 149.4;
HRMS (FAB+) [M+Na]: calcd for C15H17O3F3Na: 325.1027. Found:

1482
C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
325.1031; (C15H17O3F3 requires C, 59.60; H, 5.67. Found: C, 59.49;
H, 5.61.)
J = 10.6 Hz), 1.81 (1H, dAB, JAB = 10.6 Hz); 13C NMR (100 MHz, pyri-
dine-d5) d 37.8, 40.2, 44.6, 46.1, 52.2, 79.4, 122.3, 125.5, 126.1,
126.3, 129.0, 129.3, 129.7, 132.7, 144.8, 217.3 (one peak hidden
by solvent); HRMS (FAB+, direct inlet) [M]: calcd for C17H16O2:
252.1150. Found: 252.1156; (C17H16O2 requires C, 80.93; H, 6.39.
Found: C, 80.79; H, 6.43.)
4.9. (+)-(1R,2R,4S,6S)-2-(2-Hydroxy-phenyl)-bicyclo[2.2.2]-
octane-2,6-diol (+)-20
2-Bromophenol (0.73 mL, 6.3 mmol) was added to a solution
of n-BuLi (2.5 M in hexane, 5.0 mL, 12.6 mmol) in diethyl ether
(15 mL) at ꢀ78 °C. The colourless mixture was stirred at rt for
3.5 h, then cooled to ꢀ78 °C followed by the addition of (ꢀ)-17
(0.30 g, 2.1 mmol) dissolved in diethyl ether (20 mL). After 3 h,
satd aqueous NH4Cl was added to the yellow solution. The aque-
ous phase was saturated with NaCl and then extracted with
diethyl ether. The combined organic phases were washed with
brine followed by drying over Na2SO4 and removal of the solvent
at reduced pressure. The residue was column chromatographed
(SiO2, heptane–EtOAc 80:20) to give (+)-20 (0.17 g, 35%) of >99%
ee as a very viscous oil; TLC Rf 0.49 (heptane–EtOAc, 1:1);
4.12. (ꢀ)-(1S,4S,5S)-5-Hydroxy-5-(2-methoxy-phenyl)-
bicyclo[2.2.1]heptan-2-one (ꢀ)-11
The title compound was synthesized from (ꢀ)-8 (2.33 g,
10 mmol) following the same procedure as for (ꢀ)-12. The
resulting solid was column chromatographed (SiO2, heptane–
EtOAc, 70:30) to give (ꢀ)-11 (1.98 g, 85%) of 96% ee as a white
solid. Recrystallization from heptane–EtOAc gave 99% ee; TLC
Rf 0.42 (heptane–EtOAc, 1:1);
½
a 2D0
ꢃ
¼ ꢀ64 (c 1, CHCl3); mp
112.9–113.4 °C; IR (KBr) 3535, 3507, 1748 cmꢀ1
;
1H NMR
(400 MHz, pyridine-d5) d 7.42–7.44 (1H, m), 7.31–7.35 (1H, m),
6.99–7.06 (2H, m), 5.62 (1H, s), 3.70 (3H, s), 3.24 (1H, m),
3.17–3.22 (1H, dd, J = 17.5, 3.5 Hz), 2.60–2.61 (1H, m), 2.43–
2.48 (1H, m), 2.13–2.23 (2H, m), 1.69–1.76 (1H, m); 13C NMR
(100 MHz, pyridine-d5) d 37.5, 39.9, 44.1, 44.9, 52.3, 55.7, 78.4,
112.7, 121.1, 125.6, 129.2, 158.6, 217.3 (one peak hidden by sol-
½
a 2D0
ꢃ
¼ þ38 (c 0.56, CHCl3); IR (NaCl) 3308 (very broad) cmꢀ1
;
1H NMR (400 MHz, C6D6) d 0.60–0.69 (1H, m), 0.76–0.83 (1H,
m), 1.00–1.13 (2H, m), 1.25–1.31 (1H, m), 1.48–1.52 (1H, m),
1.59–1.67 (1H, m), 1.77 (1H, dt, J = 12.4, 2.8 Hz), 1.99–2.01 (1H,
m), 2.42 (1H, dt, J = 15.2, 2.8 Hz), 3.44–3.49 (1H, m), 6.15 (1H,
s), 6.76–6.80 (1H, m), 6.95–6.97 (1H, m), 7.10–7.14 (1H, m),
7.20–7.22 (1H, m), 10.29 (1H, s); 13C NMR (100 MHz, C6D6) d
20.4, 22.5, 26.1, 37.8, 39.7, 42.8, 71.7, 80.4, 119.0, 119.1, 127.4,
129.3, 129.8, 158.8; HRMS (FAB+) [M+Na]: calcd for C14H18O3Na:
257.1154. Found: 257.1154; (C14H18O3 requires C, 71.77; H, 7.74.
Found: C, 71.83; H, 7.80.)
vent); HRMS (ES+) [MꢀOH]: calcd for
C14H15O2: 215.1072.
Found: 215.1067; (C14H16O3 requires C, 72.39; H, 6.94. Found:
C, 72.42; H, 7.06.)
4.13. (ꢀ)-(1S,2S,4S,5S)-2-Phenyl-bicyclo[2.2.1]heptane-2,5-diol
(ꢀ)-15
4.10. (ꢀ)-(1S,4S,5S)-5-Hydroxy-5-phenyl-bicyclo[2.2.1]heptan-
2-one (ꢀ)-12
NaBH4 (0.056 g, 1.5 mmol) was added in portions at 0 °C to a
solution of (ꢀ)-12 (0.1 g, 0.5 mmol) in MeOH (10 mL). The resulting
solution was stirred at 0 °C for 15 min then water (5 mL) was
added. The aqueous phase was extracted with EtOAc, the combined
organic phases were washed with brine, dried (Na2SO4) and the
solvent was removed under reduced pressure. The residue was col-
umn chromatographed (SiO2, i-PrOH–CH2Cl2, 10:90) to give (ꢀ)-15
(0.090 g, 88%) of >99% ee as a white solid. TLC Rf 0.19 (heptane–
Compound (ꢀ)-9 (0.50 g, 2.4 mmol), NMO (0.56 g, 4.8 mmol),
MS 4 Å and TPAP (0.042 g, 0.12 mmol) were mixed in CH2Cl2
(50 mL). The resulting mixture was stirred at rt for 1.5 h, then
diluted with EtOAc and filtered through Celite/silica (rinsed with
EtOAc). The solvent was removed at reduced pressure and the
resulting oil was filtered through a pad of SiO2 (heptane–EtOAc,
1:1) to give (ꢀ)-12 (0.44 g, 91%) of 94% ee as a white solid.
Recrystallization from toluene gave >99% ee; TLC Rf 0.44 (hep-
EtOAc, 1:1); ½a 2D0
ꢃ
¼ ꢀ23 (c 0.6, EtOH); mp 71–72 °C; IR (KBr)
3457, 3377, 3296 cmꢀ1
;
1H NMR (400 MHz, pyridine-d5) d 7.83–
7.84 (2H, m), 7.41–7.45 (2H, m), 7.27–7.31 (1H, m), 4.58–4.63
(1H, m), 2.93 (1H, dd, J = 13.2, 3.0 Hz), 2.68 (1H, dt, J = 12.8,
3.3 Hz), 2.61–2.62 (1H, m), 2.47 (1H, m), 2.34 (1H, ddAB, J = 13.2,
4.9 Hz), 1.97–2.04 (1H, m), 1.69 (1H, dmAB, JAB = 10.7 Hz), 1.41
(1H, dmAB, JAB = 10.4 Hz); 13C NMR (100 MHz, pyridine-d5) d 33.4,
37.7, 37.7, 44.8, 49.7, 72.5, 80.4, 127.0, 127.4, 128.8 (one peak hid-
den by solvent); HRMS (ES+) [M+H]: calcd for C13H16O2: 204.1150.
Found: 204.1169; (C13H16O2 requires C, 76.44; H, 7.90. Found: C,
76.40; H, 7.81.)
tane–EtOAc, 1:1); ½a D20
ꢃ
¼ ꢀ56 (c 1.1, CHCl3); mp 101–103 °C; IR
(KBr) 3365, 1720 cmꢀ1
;
1H NMR (400 MHz, pyridine-d5)
d
7.75–7.78 (2H, m), 7.42–7.45 (2H, m), 7.30–7.34 (1H, m), 7.18
(1H, s), 3.23–3.29 (1H, dd, J = 17.5, 4.3 Hz), 2.95 (1H, m), 2.63–
2.70 (2H, m), 2.09–2.19 (2H, m), 1.82–1.85 (1H, m), 1.66–1.69
(1H, m); 13C NMR (100 MHz, pyridine-d5) d 38.4, 41.3, 44.1, 48.5,
53.2, 79.9, 128.0, 128.4, 129.9, 218.2 (one peak hidden by solvent);
HRMS (ES+) [M+H]: calcd for
C13H15O2: 203.1072. Found:
203.1069; (C13H14O2 requires C, 77.20; H, 6.98. Found: C, 77.33;
H, 6.91.)
4.14. (ꢀ)-(1S,2S,4S,5S)-2-(2-Methoxy-phenyl)-bicyclo[2.2.1]-
heptane-2,5-diol (ꢀ)-14
4.11. (ꢀ)-(1S,4S,5S)-5-Hydroxy-5-(1-naphthyl)-bicyclo[2.2.1]-
heptan-2-one (ꢀ)-13
The title compound was synthesized from (ꢀ)-11 (0.050 g,
0.22 mmol) following the same procedure as for (ꢀ)-15. The crude
product (ꢀ)-14 (0.051 g, 98%) of >99% ee (white solid) was pure
enough to be used without further purification; TLC Rf 0.13
The title compound was synthesized from (ꢀ)-10 (0.30 g,
1.2 mmol) following the same procedure as for (ꢀ)-12. The result-
ing solid was column chromatographed (SiO2, heptane–EtOAc, 1:1)
to give (ꢀ)-13 (0.27 g, 83%) of 94% ee as a white solid. Recrystalli-
zation from heptane–EtOAc gave >99% ee; TLC Rf 0.46 (heptane–
(heptane–EtOAc, 1:1);
½
a 2D0
ꢃ
¼ ꢀ28 (c 0.55, EtOH); mp 114–
117 °C; IR (KBr) 3545, 3465 cmꢀ1
;
1H NMR (400 MHz, pyridine-
d5) d 7.46–7.42 (1H, m), 7.32–7.28 (1H, m), 7.04–6.98 (1H, m),
5.98 (1H, br s), 4.62–4.58 (1H, m), 3.70 (3H, s), 3.01 (1H, dd,
J = 13.6, 2.9 Hz), 2.84 (1H, d, J = 4.7 Hz), 2.68 (1H, dt, J = 12.7,
3.6 Hz), 2.39 (1H, m), 2.21 (1H, dd, J = 13.6, 4.9 Hz), 2.05–1.97
EtOAc, 1:1); ½a 2D0
ꢃ
¼ ꢀ119 (c 1.15, t-BuOMe); mp 144–147 °C; IR
(KBr) 3447, 3071, 1728 cmꢀ1
;
1H NMR (400 MHz, pyridine-d5) d
9.03 (1H, d, J = 8.4 Hz), 7.96–7.99 (1H, m), 7.88 (1H, d, J = 8.1 Hz),
7.51–7.61 (3H, m), 7.46 (1H, t, J = 7.7 Hz), 7.36 (1H, s), 3.44 (1H,
d, J = 3.4 Hz), 3.37 (1H, dd, J = 17.6, 4.1 Hz), 2.63 (1H, br s), 2.51
(2H, m), 2.26 (1H, dd, J = 17.5, 4.7 Hz), 1.86–1.90 (1H, dm,
(1H, m), 1.62 (1H, dmAB
, JAB = 10.2 Hz), 1.46 (1H, dmAB,
JAB = 10.4 Hz); 13C NMR (100 MHz, pyridine-d5) d 32.5, 37.6, 37.9,
44.6, 47.2, 55.7, 72.8, 80.2, 121.0, 123.3, 126.2, 128.6, 137.8,

C. Olsson et al. / Tetrahedron: Asymmetry 19 (2008) 1476–1483
1483
158.5; HRMS (FAB+, direct inlet) [M]: calcd for C14H18O3: 234.1256.
Found: 234.1259; (C14H18O3 requires C, 71.77; H, 7.74. Found: C,
71.87; H, 7.68.)
4.17. (+)-(1R,2R,4S,6S)-6-Methoxy-2-phenyl-bicyclo[2.2.2]-
octan-2-ol (+)-23
The title compound was synthesized by following the same pro-
cedure as for (+)-22 starting from (+)-19 (0.45 g, 2.0 mmol). The
crude product was purified by column chromatography (SiO2, hep-
tane–EtOAc, 95:5) giving compound (+)-23 as white solid (0.38 g,
4.15. (ꢀ)-(1S,2S,4S,5S)-2-(1-Naphthyl)-bicyclo[2.2.1]heptane-
2,5-diol (ꢀ)-16
The title compound was synthesized following the same proce-
dure as for (ꢀ)-15 from (ꢀ)-13 (0.1 g, 0.4 mmol) to give (ꢀ)-16
(0.080 g, 79%) of >99% ee as a white solid; TLC Rf 0.24 (heptane–
80%, >99% ee); TLC Rf 0.72 (heptane–EtOAc, 1:1); ½a D20
¼ þ60 (c
ꢃ
1.1, CHCl3); mp ꢂ20 °C; IR (KBr) 3455 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 0.76–0.84 (1H, m), 0.99–1.02 (1H, m), 1.14–1.24 (1H,
m), 1.26–1.34 (1H, m), 1.58–1.64 (1H, m), 1.66–1.76 (2H, m),
1.89–1.91 (1H, m), 2.07 (1H, dt, J = 2.8, 14.8 Hz), 2.42 (1H, dt,
J = 2.8, 14.8 Hz), 2.96 (3H, s), 3.20–3.24 (1H, m), 5.62 (1H, s),
7.11–7.19 (1H, m), 7.27–7.31 (1H, m), 7.72–7.75 (1H, m); 13C
NMR (100 MHz, CDCl3) d 20.9, 23.5, 26.5, 35.1, 40.1, 43.7, 56.0,
75.5, 81.3, 127.1, 127.4, 128.3, 148.7; HRMS (FAB+, direct inlet)
EtOAc, 1:1); ½a 2D0
ꢃ
¼ ꢀ68 (c 1.1, EtOH); mp 155–157 °C; IR (KBr)
3320, 3251 cmꢀ1
;
1H NMR (400 MHz, pyridine-d5) d 9.26 (1H,
m), 7.97–7.95 (1H, m), 7.85 (1H, d, J = 8.1 Hz), 7.61 (1H, d,
J = 7.3 Hz), 7.58–7.43 (3H, m), 4.68–4.64 (1H, m), 3.39 (1H, dd,
J = 13.0, 2.8 Hz), 3.07 (1H, d, J = 4.5 Hz), 2.84 (1H, dt, J = 12.9,
3.4 Hz), 2.38 (1H, m), 2.29 (1H, ddAB, J = 12.9, 4.7 Hz), 2.15-2.08
(1H, m), 1.77 (1H, dmAB
,
JAB=10.1 Hz), 1.57 (1H, dmAB
,
[M+Na]: calcd for C15H20NaO2: 255.1361. Found: 255.1360.
(C15H20O2 requires C, 77.55; H, 8.68. Found: C, 77.45; H, 8.62.)
JAB = 10.1 Hz); 13C NMR (100 MHz, pyridine-d5) d 146.6, 132.9,
129.9, 129.6, 128.4, 126.0, 125.6, 125.5, 122.4, 80.8, 72.7, 48.2,
44.6, 39.6, 38.0, 32.8; HRMS (FAB+, direct inlet) [M]: calcd for
References
C17H18O2: 254.1307. Found: 254.1302; (The compound did not
pass elemental analysis due to remaining i-PrOH despite pro-
longed pumping under vacuum.)
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4.16. (+)-(1R,2R,4S,6S)-6-Methoxy-2-(2-methoxy-phenyl)-
bicyclo[2.2.2]octan-2-ol (+)-22
Powdered KOH (0.33 g, 6.6 mmol) was added to a solution of
(+)-18 (0.80 g, 3.2 mmol) and MeI (2.0 mL, 32 mmol) in THF
(15 mL). The mixture was stirred at rt over night. Then water
(15 mL) was added. The phases were separated and the aqueous
phase was extracted with Et2O. The combined organic phases were
washed with brine, dried over Na2SO4 and the solvent was re-
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umn chromatography (SiO2, heptane–EtOAc, 75:25) giving
compound (+)-22 as a white solid (0.74 g, 88%, >99% ee). TLC Rf
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0.43 (heptane–EtOAc, 1:1); ½a D20
¼ þ67 (c 1.5, CHCl3); mp 73–
ꢃ
77 °C; IR (KBr) 3540 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 1.04–1.14
(1H, m), 1.18–1.25 (1H, m), 1.31–1.42 (1H, m), 1.79–1.82 (1H,
m), 1.85–1.93 (1H, m), 2.01–2.07 (1H, m), 2.30–2.35 (1H, m),
2.38–2.42 (1H, m), 2.67–2.68 (1H, m), 3.13 (3H, s), 3.33 (3H, s),
3.36–3.43 (1H, m), 4.95 (1H, s), 6.62–6.64 (1H, m), 6.89–6.93
(1H, m), 7.06–7.13 (1H, m), 7.36–7.42 (1H, m); 13C NMR
(100 MHz, CDCl3) d 22.0, 24.4, 26.6, 34.3, 37.4, 41.3, 55.6, 56.0,
76.2, 81.2, 113.4, 120.8, 127.4, 128.3, 136.0, 159.6; HRMS (FAB+, di-
rect inlet) [M]: calcd for C16H22O3: 262.1569. Found: 262.1569. The
compound did not pass elemental analysis due to elimination of
water upon standing.
22. Wilkinson, G.; Stone, F. G. A.; Abel, E. W. Comprehensive Organometallic
Chemistry; Pergamon Press, 1982. p 837.