Bifunctional pyridyl alcohols with the bicyclo[3.3.0]octane scaffold in the asymmetric addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tet.2004.07.015

Some new pyridyl alcohols with the cis-bicyclo[3.3.0]octane scaffold were synthesized and used as chiral ligands for the enantioselective addition of diethylzinc to aldehydes. Ligands 4 were found to be far superior to the C ₂-symmetric ligands

Full text of DOI:10.1016/j.tet.2004.07.015

Tetrahedron 60 (2004) 8861–8868
Bifunctional pyridyl alcohols with the bicyclo[3.3.0]octane scaffold
in the asymmetric addition of diethylzinc to aldehydes
*
Yu-Wu Zhong, Chang-Sheng Jiang, Ming-Hua Xu and Guo-Qiang Lin
*
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 28 June 2004; revised 8 July 2004; accepted 8 July 2004
Available online 18 August 2004
Abstract—Some new pyridyl alcohols with the cis-bicyclo[3.3.0]octane scaffold were synthesized and used as chiral ligands for the
enantioselective addition of diethylzinc to aldehydes. Ligands 4 were found to be far superior to the C2-symmetric ligands 2 in terms of
enantioselectivities. Quantitative yields and enantiomeric excesses of up to 92% were obtained when the ligand 4 was used. The carbonyl
function in 4 proved to be beneficial for the high enantioselectivities in the addition of diethylzinc to aldehydes. Conversion of the carbonyl
group into oxime or oxime ether group led to a sort of more active ligands, which catalyzed the same reaction with rate acceleration.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
nucleophile,6 as shown in transition state A in Figure 1. It
occurred to us that if there is a secondary basic site
(represented as Nu in B in Figure 1) in the same ligand well
positioned to coordinate with zinc atom Zn(2), the
dissociation of Zn(2)–O(2) bond in A might occur.
Accordingly, the transition state would shift from A to B,
which included a chair-like six-membered ring structure.7
Over the past decade, much attention has been paid to the
design and synthesis of novel chiral ligands for the
asymmetric processes.1 Among them, the development of
bifunctional ligand systems for the asymmetric construction
of C–C bonds is of great interest.2,3 The secondary basic
sites in chiral ligands provided an additional interaction
between the ligand and the reagent, which usually resulted
in an improved reactivity and stereoselectivity.4
In our laboratory, we are interested in the application of
some structurally interesting molecules for asymmetric
synthesis.8 Synthesis of new chiral ligands bearing the cis-
bicyclo[3.3.0]octane scaffold and their applications in
asymmetric reactions are one of our recent projects.8c,d
The appealing semi-caged structure of the cis-
bicyclo[3.3.0]octane framework is anticipated to provide a
peculiar chiral environment in asymmetric processes.
Amino alcohols catalyzed addition of diethylzinc to
aldehydes was so extensively explored that it has become
as one of the model reactions in the asymmetric catalysis.5 It
is generally accepted that this reaction proceeds via a dual
activation of the aldehyde electrophile and the diethylzinc
In our previous work,8c we reported the synthesis of the C2-
symmetric bis-pyridyl alcohol 2 (Scheme 1) and mono-
pyridyl alcohol 4 from the chiral diketone 19 which was
easily obtained from 1,5-cyclooctadiene, and their appli-
cation as novel chiral ligands in the enantioselective
addition of diethylzinc to aldehydes. To our surprise, C2-
symmetric ligand 2 was found to only induce very low
enantioselectivity (7% ee) in the diethylzinc addition to
benzaldehyde, while ligand 4, with a carbonyl group in the
bicyclo[3.3.0]octane scafflod, was found much more
efficient in catalyzing the same reaction and provided the
product with 92% ee in quantitative yield. Similar good ees
(89–92%) were observed in the reaction with other
aldehydes. To explain these results, we envisioned that the
carbonyl group in ligand 4 might be involved in the
Figure 1.
Keywords: Bicyclo[3.3.0]octane; Bifunctional ligand; Pyridyl alcohol;
Diethylzinc; Secondary basic site.
* Corresponding authors. Tel.: C86-21-64163300x3206; fax: C86-21-
64166263;
e-mail
addresses:
xumh@mail.sioc.ac.cn;
lingq@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.015

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Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
coordination with zinc atom and stabilize the reaction
transition state, as depicted in Figure 1.
In this paper, we wish to report our detailed studies. We
found that the unmasked carbonyl group in ligand 4 acted as
a secondary basic group in this reaction, and was important
for maintaining the high stereoselectivities. The modifi-
cation of 4 by converting the carbonyl function into oxime
or oxime ether group led to a kind of more efficient ligands,
which catalyzed the addition of diethylzinc to aldehydes
with an obvious acceleration effect.
2. Results and discussion
To address whether the carbonyl group in ligand 4 had
contribution to the high enantioselectivity observed in the
diethylzinc addition to aldehydes, we first consider to
convert the carbonyl group into other functions to see if it
would result in an apparent impact on the stereoselectivity
when applied to the reaction. Reduction of the carbonyl
group into methylene moiety was certainly the first choice.
Scheme 1. The synthesis of compounds 2 and 4.
Unfortunately, direct reduction, including Wolff-Kishner–
Huang reduction10 and reduction of tosylhydrazone by
sodium cyanoborohydride,11 was proved to be unsuccessful.
Thus, a different approach was then taken. As shown in
Scheme 2, by converting the ent-4 (the enantiomer of 4) into
its dithioketal counterpart 5, followed by the reaction with
Raney-nickel in 2-propanol,12 we successfully obtained the
designed compound 6. In addition, compound 7 and 813
were also synthesized via Wittig reaction of ent-4 with
CH3PPh3I, followed by the hydrogenation reaction.
With compounds 5, 6, 7 and 8 in hand, we investigated their
efficiency as chiral ligand respectively in the diethylzinc
addition to aldehydes under the same conditions8c as ligand
Scheme 2. The synthesis of compounds 5, 6, 7, and 8. (a) HSCH2CH2SH,
BF3OEt2, CH2Cl2, Quant. (b) Raney-nickel, EtOH, reflux, Quant. (c)
CH3PPh3I, t-BuOK, 82%. (d) Pd/C, MeOH, H2 (1 atm), 85%.
Table 1. Comparison of the stereoselectivity of the product induced by ligand 4 and 5–8a
Entry
Ligand
Aldehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
p-Tolualdehyde
1-Naphthaldehyde
trans-Cinnamaldehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
Benzaldehyde
p-Chlorobenzaldehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
p-Tolualdehyde
1-Naphthaldehyde
trans-Cinnamaldehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
p-Tolualdehyde
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4
4
4
4
4
4
5
5
5
6
6
7
7
7
7
7
7
8
8
8
8
8
8
O98
84
92
91
91
91
89
51
78
76
77
79
77
77
79
77
78
76
33
77
78
75
79
74
33
O98
O98
O98
O98
90
90
85
O98
95
88
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
93
O98
O98
O98
98
O98
O98
O98
98
1-Naphthaldehyde
trans-Cinnamaldehyde
O98
90
a
The absolute configuration of products catalyzed by 4 is R, while it is S when catalyzed by 5–8.
Isolated yield after the column chromatography.
Determined by chiral HPLC analysis.
b
c

Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
8863
To gain some insight into this interesting phenomena, X-ray
analysis of 2 and 4 were performed (Figs. 3 and 5).14 X-ray
analysis of 2 (Fig. 3) revealed that there was a hydrogen
bonding between hydroxyl O(2)H and oxygen atom O(1),
˚
and the distance between two oxygen atoms was 2.74 A.
The two nitrogen atoms in the quinoline ring were hidden in
the back side of the bicyclo[3.3.0]octane framework, and
neither of them had a hydrogen bonding with the hydroxy
moiety. It was reasonable to assume when 2 was used to
catalyze the addition of diethylzinc to aldehyde, the real
catalyst could be depicted in Figure 4, wherein zinc atom
Figure 2. Proposed transition state.
Figure 3. X-ray analysis of ligand 2.
Zn(2) did not coordinate with the nitrogen atom. It was
obvious that the surroundings of zinc atoms Zn(1) and Zn(2)
was free from steric hindrance, which resulted in the low
stereo-induction.
On the other hand, the X-ray analysis of 4 (Fig. 5) showed a
Figure 4. Proposed catalyst when 2 was used as the ligand. X, Y may be the
ethyl, aldehyde group, or as part of the oligmer form.
4 was used. The experimental results were summarized in
Table 1. As we can see, when the ligand 5, 6, 7 or 8 was
used, the obtained ee value of the corresponding product
was 10% or more lower than that obtained by using ligand 4.
For benzaldehyde (entries 7, 10, 12, 18), substituted
benzaldehydes (entries 8, 9, 11, 13, 14, 15, 19, 20, 21)
and 1-naphthaldehyde (entries 16, 22), the ee value of the
product decreased from 90% level (entries 1–5) to 77% or
so. For trans-cinnamaldehyde (entries 17, 23) a similar
decrease from 51% (entry 6) to 33% was observed. These
results indicate that the presence of the carbonyl group in
ligand 4 is indeed important for maintaining the high ee in
this reaction.
Considering the differences between ligand 4 and 6–8, it
might be reasonable to postulate that the carbonyl group in
ligand 4 was employed as a secondary basic site, in other
words, the reaction might proceed via a transition state as
shown in Figure 2 (XZO), where the carbonyl group
coordinated with zinc atom Zn(2) to act as a secondary basic
group. In the case of ligand 5, although the sulfur atom
could be a secondary basic site, it was still not as effective as
ligand 4, which suggested that the planar conformation of
the carbonyl group of ligand 4 was also an important factor
for inducing the high enantioselectivity.
Figure 5. X-ray analysis of ligand 4.

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Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
Scheme 3. The synthesis of ligands 9–12.
hydrogen bonding between the hydroxyl O(2)H and the
nitrogen atom in the pyridine ring. When 4 was used to
catalyze the addition of diethylzinc to aldehyde, the real
catalyst was possible as described in Figure 2. Zinc atom
Zn(1) combined with hydroxyl oxygen atom, and coordi-
nated with the nitrogen atom in the pyridine ring. Zinc atom
Zn(2) coordinated with hydroxyl oxygen atom. The
carbonyl oxygen was also possibly involved in the
stabilizing the six-membered chair-like transition state.
Taking advantage of the steric hindrance of bicyclo[3.3.0]-
octane backbone and methyl group in the pyridine ring, the
reaction using ligand 4 gave higher enantioselectivities.
group with Lawesson’ reagent or P2S5.15,16 Efforts to
convert the carbonyl group into imine analogous also failed,
presumably due to the presence of the hydroxy and pyridine
moiety within the molecule.
We then turned our attention to the oxime and oxime ether
group which were reluctantly used in chiral ligands or
auxiliaries due to the usual formation of a mixture of
geometric isomers.17 However, two advantages of oxime
and oxime ether are appealing: (1) they are more electron-
donating than imine; (2) the high stability toward hydrolytic
conditions would allow them for separation via flash column
chromatography easily. Keeping these in mind, we prepared
the oxime ligand 9 from ligand ent-4. Methylation of 9
afford the O-methyl oxime ether ligand 10 (Scheme 3). The
E/Z isomers of oxime 9 were inseparable by column
chromatography. However, the corresponding oxime ether
E-10 and Z-10 could be separated by flash column
chromatography.18
To further prove our hypothesis, we envisioned that if X in
the proposed transition state (Fig. 2) is replaced by sulfur
atom or nitrogen atom, which will have a more electron-
donating potential and thus the ethyl group bound to Zn(2)
atom would be more nucleophilic. As a result, an
accelerated reaction rate could be observed in the same
reaction. Disappointingly, we were unsuccessful in con-
verting the carbonyl group of ligand ent-4 into thiocarbonyl
Interestingly, when oxime ligand 9 was used to catalyze the
Table 2. Comparison of the reaction rational catalyzed by ligands 4, 9–12a
Entry
RCHO
Ligand
Catalyst loading
(mol%)
Temperature
(8C)
Reaction time
(h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
p-Chlorobenzl-
dehyde
4
9
9
Z-10
E-10
11
11
12
12
11
10
5
10
3
4
3
5
2
6
3.5
0 to rt
0
K20
0
0
0
K20
0
K20
0
24
10
24
10
10
10
44
10
30
11
O98
O98
O98
O98
O98
O98
O98
O98
O98
94
92
81
84
83
85
88
90
86
88
87
11
12
p-Anisaldehyde
trans-Cinnamal-
dehyde
Cyclohexane-
carboxyalde-
hyde
11
11
4
4
0
0
12
8
O98
88
88
51
13
11
4.5
0
11
O98
69d
a
The absolute configuration of all products is S except in entry 1 which is R.
Isolated yield after the column chromatography.
The ee was determined by chiral HPLC analysis unless otherwise noted.
b
c
d
The ee was determined by comparison of the specific optical rotation with the literature, see Ref. 19.

Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
8865
addition of diethylzinc to benzaldehyde, a distinctive
acceleration phenomenon was observed. The reaction was
completed in only 10 h at 0 8C with 5 mol% of loading
(entry 2, Table 2). In comparison, the reaction needed 24 h
at rt for completion when 10 mol% of ligand 4 was used
(entry 1, Table 2). Considering a relatively lower ee of 81%
was observed, the reaction temperature was reduced to
K20 8C (entry 3), which resulted in a prolonged reaction
time (24 h) and a slight enhancement of ee to 84%. Similar
acceleration effect was also observed when oxime ether
Z-10 or E-10 was used as the ligands (entries 4 and 5). It was
worth noting that the addition reaction catalyzed by Z-10 or
E-10 afforded the product with the same sense and almost
the same ee value, which indicated the geometry (Z or E) of
the oxime ether played a minor role in the stereoinduction of
this reaction.
catalyze the enantioselective addition of diethylzinc to
aldehydes. C2-symmetric ligand 2 was found less effective
than unsymmetric ligand 4. Over 90% ees were found when
4 was used to catalyze the reactions. The carbonyl group in
pyridyl alcohol 4 was evidenced to be important in
achieving the high enantioselectivity. Conversion of this
carbonyl group into oxime or oxime ether motif led to a kind
of more efficient ligand, which catalyzed the same reaction
with a higher reaction rate. The work to expand the use of
these ligands in other asymmetric reactions is in progress.
4. Experimental
4.1. General
Melting points are uncorrected. Optical rotations were
1
Comparison of entry 2 and entries 4, 5 revealed that the
oxime ether ligand was more efficient than the correspond-
ing oxime ligand in terms of the enantioselectivity. There-
fore, we turned to prepare other oxime ethers with the hope
to find more efficient ligands. As shown in Scheme 3, TBS
(t-butyldimethylsilyl) oxime ether ligand 11 and TBDPS
(t-butyldiphenylsilyl) oxime ether ligand 12 were syn-
thesized from oxime 9 in quantitative yields. When 3 mol%
of 11 was employed as the ligand (entry 6), the reaction was
completed within 10 h to furnish the product with a slight
increase of ee (88%) than ligand 10. A decrease in
temperature from 0 to K20 8C resulted in a further increase
of ee to 90%, in sacrifice of the reaction time (44 h) (entry
7). Attempts to employ compound 12 with a bulkier silyl
ether group as the ligand to further increase the ee proved to
be unsuccessful (entries 8 and 9). Extension of the substrate
to substituted benzaldehydes (entries 10 and 11) and
aliphatic aldehydes (entries 12 and 13) using TBS–oxime
11 as ligand also showed an acceleration effect, though the
ee of the product decreased slightly in comparison with that
induced by ligand 4.
measured on a Perkin–Elmer 241MC polarimeter. H and
13C NMR spectra were taken in CDCl3 on 300 and 75 MHz
FT-spectrometers, respectively, using SiMe4 as the internal
reference. IR spectra were recorded on a Bio-Rad FTS-185
IR spectrometer. Mass spectra were recorded by the EI
method, and HRMS were measured on a Finnigan MAT-
8430 mass spectrometer. Elemental analyses were per-
formed on Heraeus Rapid-CHNO. Enantiomeric excess (ee)
determination was carried out using HPLC with Chiralcel
OD, AS, AD, OJ columns. The silica gel used for flash
chromatography was 300–400 mesh. All solvents were
dried by standard methods. Unless otherwise noted,
commercially available reagents were used without further
purification.
4.1.1. (1S,5S,6S)-6-Hydroxy-6-(6-methylpyridin-2-yl-
methyl)-bicyclo[3.3.0]octan-2-one, ethylene thioketal, 5.
Pyridyl alcohol ent-4 (490 mg, 2 mmol) was dissolved in
anhydrous dichloromethane (50 mL) in a 100 mL flame-
dried three-necked flask under an argon atmosphere,
followed by the addition of Boron trifluoride diethyl
etherate (1.33 mL, 10 mmol) and 1,2-ethanedithiol
(0.32 mL, 4 mmol). This solution was stirred at rt overnight
and quenched by the saturated aqueous NaHCO3. The
organic layer was separated, and the water layer was
extracted with dichloromethane. The combined organic
layers were washed with brine and dried over with
anhydrous Na2SO4. Purification by flash column chroma-
tography afforded 630 mg of 5 as a white solid in
quantitative yield. Mp 72 8C; [a]2D0 C5.38 (c 1.50,
CHCl3); 1H NMR (300 MHz, CDCl3): d 1.40–1.99 (m,
7H), 2.16 (m, 1H), 2.32 (m, 1H), 2.49 (s, 3H), 2.76 (m, 1H),
2.87 (s, 2H), 3.23 (m, 4H), 6.00–6.60 (br, 1H), 6.89 (d, JZ
7.8 Hz, 1H), 7.00 (d, JZ8.1 Hz, 1H), 7.50 (td, JZ7.8,
1.2 Hz, 1H); FT-IR (KBr, cmK1): 3367, 3062, 2922, 1594,
1576, 1459, 1416; EIMS (m/z, %): 321 (MC, 12.85), 303
(MCKH2O, 1.93), 262 (15.30), 260 (30.29), 228 (30.13),
162 (12.89), 149 (33.32), 134 (13.55), 107 (100.00), 106
(26.84); 13C NMR (75 MHz, CDCl3): d 24.26, 25.40, 30.08,
38.32, 38.75, 39.94, 42.99, 46.35, 51.26, 56.91, 75.82,
81.90, 120.88, 121.03, 137.11, 157.05, 158.86; HRMS for
C17H23NOS2 (MC), calcd: 321.1221, found 321.1211.
This acceleration effect is in accordance with our
hypothesis. When the carbonyl group in 4 (or ent-4) was
converted into oxime or oxime ether group that had a more
electron-donating potential, the ethyl group bound to Zn(2)
atom should be more nucleophilic. As a result, an
accelerated reaction occurred. Considering the relative
position of the carbonyl group and the hydroxyl group in
ligand 4 (see X-ray analysis in Figure 5), the lone pair
electrons of the carbonyl oxygen atom are almost bisected
by the O(1)–O(2) line. So unlikely they could be directed to
one zinc atom at the same time. The experimental fact that
both E- and Z-oxime ether (entries 4 and 5, Table 2) gives
the same enantioselectivities with the same sense also
implies that the lone pair electrons would not be involved in
the transition state. Most likely it is the p electrons of the
carbonyl group that interact with the zinc atom Zn(2) in
the supposed transition state B in Figure 1. Clarification of
the real mechanism calls for further investigation.
3. Conclusion
4.1.2. (1S,2S,5S)-2-(6-Methylpyridin-2-ylmethyl)-bi-
In summary, some new pyridyl alcohols with the cis-
bicyclo[3.3.0]octane scaffold were synthesized and used to
cyclo-[3.3.0]octan-2-ol, 6. Thioketal
1.1 mmol) was dissolved in ethanol (20 mL), followed by
5
(360 mg,

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Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
the addition of 1 g of Raney nickel. The resulting mixture
was then refluxed for 2 h. The cooled solution was filtered
through celite and washed with ethanol. Purification by flash
column chromatography provided 260 mg of pyridyl
alcohol 6 as an oil in quantitative yield. [a]2D0 C4.48 (c
1.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.34 (m, 5H),
1.63 (m, 5H), 2.13 (m, 1H), 2.45 (m, 1H), 2.52 (s, 3H), 2.90
(m, 2H), 6.16 (br, 1H), 6.92 (d, JZ7.6 Hz, 1H), 7.02 (d, JZ
7.7 Hz, 1H), 7.49 (m, 1H); FT-IR (film, cmK1): 3348, 3068,
2948, 1579, 1459, 798; EIMS (m/z, %): 231 (MC, 1.82), 162
(21.33), 149 (34.49), 134 (10.72), 108 (10.59), 107 (100.00),
106 (12.04), 79(6.97), 41(7.16); 13C NMR (75 MHz,
CDCl3): d 24.27, 27.31, 27.57, 30.15, 34.43, 39.82, 43.22,
46.46, 52.46, 81.67, 120.85, 120.92, 136.97, 157.04, 159.36;
HRMS for C15H21NO (MC), calcd: 231.1623, found
231.1641.
Figure 6. The establishment of the relative configuration of ligand 8 by
NOESY analysis.
The relative configuration of 8 was confirmed by its NOESY
analysis, see Figure 6.
4.1.5. (1S,5S,6S)-6-Hydroxy-6-(6-methylpyridin-2-yl
methyl)-bicyclo-[3.3.0]octan-2-one oxime, 9. To a sol-
ution of 37 mg of hydroxylamine hrdrochloride in 5 mL of
ethanol was added ent-4 (65 mg, 0.26 mmol) and sodium
acetate (43 mg, 0.53 mmol). The resulting mixture was
stirred at rt for 30 min. After evaporation of the solvent, the
residue was partitioned between CH2Cl2 (10 mL) and brine
(10 mL). The water layer was extracted with CH2Cl2. The
combined organic layer was dried over Na2SO4 and then
evaporated in vacuo. The residue was purification by flash
column chromatography to give 9 (61 mg, yield 88%) as a
white solid. [a]D20 C136.78 (c 0.60, CHCl3); 1H NMR
(CDCl3, 300 MHz) d: 1.56–2.05 (m, 6H), 2.06–2.37 (m,
2H), 2.52 (s, 3H), 2.63 (m, 1H), 2.87 (m, 1H), 3.03 (m,
1.5H), 3.40 (m, 0.5H), 6.21 (br, 1H), 6.93 (d, JZ7.5 Hz,
1H), 7.02 (d, JZ8.1 Hz, 1H), 7.52 (t, JZ7.8 Hz, 1H), 8.41
(br, 1H); FT-IR (KBr, cmK1): 3393, 3188, 3075, 2957,
1674, 1597, 1579, 1459, 950; EIMS (m/z, %): 260 (MC,
1.67), 243 (MCKOH, 19.24), 225 (8.88), 163 (7.04), 162
(17.64), 134 (12.90), 108 (10.95), 107 (100.00), 106 (12.45).
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76.
Found: C, 69.05; H, 7.72; N, 10.62.
4.1.3. (1S,2S,5S)-6-Methylene-2-(6-methylpyridin-2-yl
methyl)-bicyclo-[3.3.0]octan-2-ol, 7. To a 100 mL three-
necked round-bottomed flask was added PPh3CH3I
(606 mg, 1.5 mmol) and THF (20 mL) under argon
atmosphere at 0 8C. While the mixture was stirred,
t-BuOK (168 mg, 1.5 mmol) was added. The resulting
yellow solution was stirred for 30 min, followed by the slow
addition of a solution of 245 mg of pyridyl alcohol ent-4
(1 mmol) in 10 mL of THF. Stirring was continued for 10 h
at 0 8C. Then, 10 mL water was added to quench the
reaction. Usual workup followed by flash column chroma-
tography afforded 7 (200 mg, yield 82%) as a colorless oil.
[a]2D0 C80.08 (c 1.25, CHCl3); 1H NMR (CDCl3, 300 MHz)
d: 1.53 (m, 2H), 1.73 (m, 3H), 1.95 (m, 1H), 2.23 (m, 2H),
2.45 (m, 1H), 2.51 (s, 3H), 2.92 (m, 3H), 4.74 (m, 1H), 4.83
(m, 1H), 6.20 (br, 1H), 6.92 (d, JZ7.6 Hz, 1H), 7.02 (d, JZ
7.7 Hz, 1H), 7.52 (t, JZ7.6 Hz, 1H); FT-IR (film, cmK1):
3335, 3068, 2951, 1654, 1579, 1459, 877; EIMS (m/z, %):
243 (MC, 8.09), 107 (100.00), 149 (16.99), 162 (16.91), 134
(14.74), 108 (12.09), 79 (10.79), 77 (8.79); 13C NMR
(CDCl3, 75 MHz) d: 24.20, 25.97, 30.51, 34.86, 39.36,
46.05, 47.62, 52.95, 82.04, 103.67, 121.03, 121.05, 137.14,
157.09, 159.17, 159.26; HRMS for C16H19N (MCKH2O),
calcd.: for 225.1529, found 225.1518.
4.1.6. 4.6. (1S,5S,6S)-6-Hydroxy-6-(6-methylpyridin-2-yl
methyl)-bicyclo[3.3.0]octan-2-one O-methyl oxime, 10.
Potassium tert-butoxide (166 mg, 1.48 mmol) was added
into a solution of oxime 9 (350 mg, 1.34 mmol) in 15 mL of
DMSO. The mixture was stirred at rt for 30 min, followed
by the addition of the iodomethane (0.094 mL, 1.48 mmol).
After 1 h, the mixture was diluted with ethyl acetate
(300 mL) and washed with brine. The residue after
concentration was subjected to flash chromatography to
afford Z-10 (40 mg), E-10 (50 mg) and a mixture of Z-10
and E-10 (100 mg) with a total yield of 60%. The ratio of
Z-10/E-10 was confirmed to be 1:2 by 1H NMR analysis of
the crude product.
4.1.4. (1S,2S,5S,6R)-6-Methyl-2-(6-methylpyridin-2-yl
methyl)-bicyclo-[3.3.0]octan-2-ol, 8. To a solution of 7
(410 mg, 1.68 mmol) in methanol (20 mL) was added
57 mg of 10% Pd/C. The mixture was hydrogenated for
48 h under 1 atm of H2, and then filtered through a pad of
celite. The filtrate was concentrated and purified by flash
column chromatography to give 8 (348 mg, yield 85%) as a
colorless oil. [a]D20 C21.88 (c 1.50, CHCl3); 1H NMR
(CDCl3, 300 MHz) d: 0.88 (d, JZ6.3 Hz, 3H), 1.13 (m, 2H),
1.39 (m, 4H), 1.56 (m, 2H), 1.75 (m, 1H), 2.14 (t, JZ7.5 Hz,
1H), 2.34 (m, 1H), 2.45 (s, 3H), 2.85 (s, 2H), 5.84 (br, 1H),
6.8 (d, JZ7.8 Hz, 1H), 6.94 (d, JZ7.8 Hz, 1H), 7.45 (t, JZ
7.8 Hz, 1H); FT-IR (film, cmK1): 3352, 3065, 1595, 1579,
1459, 1097, 795; EI-MS (m/z, %): 245 (MC, 1.19), 227
(MCKH2O, 3.74), 162 (18.99), 149 (36.55), 134 (9.67),
108 (10.73), 107 (100.00), 106 (13.13), 79 (5.89), 41 (5.87);
13C NMR (CDCl3, 75 MHz) d: 14.02, 23.09, 23.31, 25.15,
32.82, 36.54, 39.78, 46.24, 47.27, 51.68, 80.97, 119.85,
119.89, 135.97, 156.12, 158.53; HRMS for C16H23NO
(MC), calcd.: 245.1780, found: 245.1794.
Minor isomer (Z, less polar). [a]2D0 C217.68 (c 0.75,
CHCl3); 1H NMR (CDCl3, 300 MHz) d: 1.49–1.81 (m, 5H),
2.08 (m, 1H), 2.27 (m, 2H), 2.50 (s, 3H), 2.61 (m, 1H), 2.81–
2.98 (AB, dAZ2.84, dBZ2.96, JABZ14.4 Hz, 2H), 3.30 (m,
1H), 3.80 (s, 3H), 6.24 (br, 1H), 6.90 (d, JZ7.6 Hz, 1H),
7.02 (d, JZ7.8 Hz, 1H), 7.52 (t, JZ7.8 Hz, 1H); FT-IR
(film, cmK1): 3324, 2945, 1595, 1577, 1459, 1056; EIMS
(m/z, %) 275 (MCCH, 100.00), 276 (13.75), 257 (4.67),
244 (3.23), 243 (17.61), 226 (3.74), 225 (10.30), 107
(15.18); 13C NMR (CDCl3, 75 MHz) d: 24.15, 24.28, 27.68,
31.23, 39.56, 43.72, 45.77, 52.19, 61.22, 82.07, 120.96,
121.12, 137.18, 157.25, 159.07, 170.47.

Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
8867
Major isomer (E, more polar). [a]2D0 C124.38 (c 1.15,
CHCl3); 1H NMR (CDCl3, 300 MHz) d: 1.59–1.71 (m, 3H),
1.87 (m, 2H), 2.05 (m, 1H), 2.35 (m, 1H), 2.40–2.70 (m,
2H), 2.50 (s, 3H), 2.81–3.02 (AB, dAZ2.83, dBZ2.99,
JABZ14.4 Hz, 2H), 3.10 (m, 1H), 3.83 (s, 3H), 6.92 (d, JZ
7.8 Hz, 1H), 7.02 (d, JZ7.8 Hz, 1H), 7.52 (t, JZ7.8 Hz,
1H); FT-IR (film, K1): 3325, 2953, 1596, 1579, 1460, 1053,
756; EIMS (m/z, %) 275 (MCCH, 7.27), 243 (27.01), 225
(23.85), 162 (21.51), 134 (17.88), 108 (13.61), 107 (100.00),
79 (9.12), 65 (8.12); 13C NMR (CDCl3, 75 MHz) d: 23.78,
24.27, 28.37, 29.09, 39.70, 45.65, 46.16, 61.27, 82.17,
120.99, 121.12, 137.16, 157.27, 159.10, 171.05; HRMS for
C16H22N2O2 (MC), calcd: 274.1681, found: 274.1719.
Purification by flash column chromatography afforded the
addition product. The enantiomeric excess of the obtained
product was determined by chiral HPLC analysis.
Acknowledgements
We are grateful to the financial assistance by the NSFC
(20172063 and 203900506), the Major State Basic Develop-
ment Program (6200077506) and Chinese Academy of
Sciences. We are also grateful to the suggestion given by the
referees during the review of this article.
4.1.7. (1S,5S,6S)-6-Hydroxy-6-(6-methylpyridin-2-yl
methyl)-bicyclo-[3.3.0]octan-2-one
O-(tert-butyl-
References and notes
dimethylsilyl) oxime, 11. To a solution of oxime 9
(130 mg, 0.5 mmol) and imidazole (140 mg, 2 mmol) in
CH2Cl2 (10 mL) was added tert-butyldimethylsilyl chloride
(151 mg, 1 mmol). The stirring was continued for 4 h at rt.
The resulting mixture was diluted with CH2Cl2 and washed
with brine. Purification by flash column chromatography
provided 190 mg of 11 as a colorless oil in quantitative
1. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
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2. For selective reviews, see: (a) Shibasaki, M.; Sasai, H.; Arai,
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1
yield. [a]2D0 C97.08 (c 0.80, CHCl3); H NMR (CDCl3,
300 MHz) d: 0.08 (s, 6H), 0.85 (s, 4.5H), 0.86 (s, 4.5H),
1.20–1.90 (m, 5H), 1.95–2.20 (m, 1H), 2.26–2.32 (m, 1H),
2.44 (s, 3H), 2.50 (m, 1H), 2.84 (dd, JZ14.7 Hz, 3.6 Hz,
1H), 2.95 (dd, JZ14.3, 5.7 Hz, 1H), 3.05 (m, 0.5H), 3.33
(m, 0.5H), 6.25 (br, 1H), 6.85 (m, 1H), 6.96 (d, JZ8.1 Hz,
1H), 7.45 (t, JZ7.8 Hz, 1H); FT-IR (film, cmK1): 3335,
2956, 1596, 1579, 1461, 1249, 915, 837, 781; EIMS (m/z,
%): 374 (MC, 3.01), 318 (18.35), 317 (MCKC4H9, 73.64),
225 (35.67), 162 (13.53), 108 (16.21), 107 (100.00), 106
(18.35), 75 (40.24); HRMS. for C21H34N2O2Si (MC), calcd:
374.2390, found 374.2359.
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4.1.8. (1S,5S,6S)-6-Hydroxy-6-(6-methylpyridin-2-yl
methyl)-bicyclo[3.3.0]octan-2-one O-(tert-butyldiphenyl-
silyl) oxime, 12. Prepared from oxime 9 and tert-
butyldiphenylsilyl chloride in a similar way as described
in Section 4.1.7. [a]D20 C84.88 (c 0.55, CHCl3); H NMR
1
(CDCl3, 300 MHz) d: 1.08 (s, 9H), 1.50–2.00 (m, 6H), 2.34
(m, 2H), 2.53 (s, 3H), 2.63–3.09 (m, 3.5H), 3.54 (m, 0.5H),
6.00–6.50 (br, 1H), 6.92 (m, 1H), 7.03 (d, JZ7.2 Hz, 1H),
7.36 (m, 6H), 7.50 (m, 1H), 7.72 (m, 4H); FT-IR (film,
cmK1): 3323, 3072, 2959, 1595, 1579, 1460, 1429, 1114,
914, 740, 701, 506; EIMS (m/z, %): 498 (MC, 0.57), 442
(21.89), 441 (MCKC4H9, 62.21), 225 (80.36), 199 (70.68),
198 (19.12), 197 (22.14), 107 (100.00), 106 (23.60); HRMS
for C31H38N2O2Si (MC), calcd: 498.2703, found 498.2710.
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4.2. General procedure for the asymmetric addition of
diethyl zinc to arylaldehydes
To a solution of ligand (0.05 mmol) in toluene (2.3 mL) at
0 8C was added 15% wt solution of diethylzinc in hexane
(2.3 mL, 2.0 mmol). The resulting mixture was stirred for
30 min at 0 8C, followed by the addition of the freshly
distilled benzaldehyde (1.0 mmol). The reaction mixture
was stirred at 0 8C to completion, and then quenched with
saturated aqueous NH4Cl. The water layer was extracted
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8868
Y.-W. Zhong et al / Tetrahedron 60 (2004) 8861–8868
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18. O-methylation of oxime (1S,5S,6S)-9 afforded a mixture of E
and Z isomers of (1S,5S,6S)-10 in a ratio of 2:1 as determined
by 1H NMR analysis. Attempts to assign their configuration by
NOESY analysis proved unsuccessful. 13C NMR correlation
method adopted by many authors20 was also abortive in our
case. So we tentatively assumed that the major isomer of 10
had the E form oxime ether with the methoxy group anti to the
bridged carbon, and the minor isomer had the Z form oxime
ether.
12. Paquette, L. A.; Encyclopedia of Reagents for Organic
Synthesis, Vol. 6; Wiley: New York, 1995 p 4401.
13. Shown in Scheme 2 is the major isomer of 8 whose relative
configuration has been evidenced by the NOESY analysis, see
Section 4.
14. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 242959 and 242960, respectively.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK fax: 144-(0)1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk
19. [a]2D0 C3.938 (c 3.50, CHCl3). Literature: [a]2D0ZC5.68 (c
1.09, CHCl3) for R enantiomer with 96% ee. Paquette, L. A.;
Zhou, R. J. Org. Chem. 1999, 64, 7929.
15. (a) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O.
Org. Synth. 1984, 62, 158. (b) Scheibye, S.; Shabana, R.;
Lawesson, S.-O. Tetrahedron 1982, 38, 993. (c) Deng, S.-L.;
Chen, R.-Y. Synthesis 2002, 2527. (d) Cherkasov, R. A.;
Kutyrev, G. A.; Pudovik, A. N. Tetrahedron 1985, 41, 2567.
16. Paquette, L. A.; Encyclopedia of Reagents for Organic
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20. (a) Hawkes, G. E.; Herwig, K.; Roberts, J. D. J. Org. Chem.
1974, 39, 1028. (b) Farser, R. R.; Dhawan, K. L. J. Chem. Soc.
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Coward, J. K. J. Org. Chem. 1989, 54, 3436.