Facile synthesis of amino acid bicyclo[2.2.1]heptyl alcohol and its application for enantioselective additions of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0040-4039(00)00637-7

Enatioselective additions of diethylzinc to aldehydes were demonstrated, and good to moderate enantioselectivities (54 to 95% enantiomeric excess) were obtained. The ligand 4 was prepared from camphor and acetic acid in a facile process of four steps, and

Full text of DOI:10.1016/S0040-4039(00)00637-7

Tetrahedron Letters 41 (2000) 4587±4590
Facile synthesis of amino bicyclo[2.2.1]heptyl alcohol and its
application for enantioselective additions of diethylzinc to
aldehydes
Naoto Hanyu,a Takashi Mino,b Masami Sakamotoa and Tsutomu Fujitab,*
aGraduate School of Science and Technology, Chiba University, 1-33, Yayoicho, Inage-ku, Chiba 263-8522, Japan
bDepartment of Materials Technology, Faculty of Engineering, Chiba University, 1-33, Yayoicho, Inage-ku,
Chiba 263-8522, Japan
Received 17 February 2000; revised 12 April 2000; accepted 14 April 2000
Abstract
Enantioselective additions of diethylzinc to aldehydes were demonstrated, and good to moderate
enantioselectivities (54 to 95% enantiomeric excess) were obtained. The ligand 4 was prepared from camphor
and acetic acid in a facile process of four steps, and the chiral source was only inexpensive (+)-camphor.
# 2000 Elsevier Science Ltd. All rights reserved.
The catalytic enantioselective alkylation of aldehydes is a potentially useful method for preparing
chiral secondary alcohols.1 This structural feature is part of many natural products or precursors
as an important synthetic intermediate for various other functionalities. The addition of
dialkylzinc to aldehydes in the presence of chiral ligand is one of the most important methods in
this area, and many chiral ligands have been reported.2 In recent years, a wide variety of amino-
alcohols, b-3 or occasionally g-aminoalcohols,4 have been reported as chiral ligands. However,
d-aminoalcohols5 have rarely been reported and we could not ®nd ecient d-aminoalcohols for
an asymmetric addition reaction (highest 89% ee5b).
We have been investigating the lactonization of 3-hydroxy acid, which is prepared from a
carbonyl compound and carboxylic acid.6 When an optically active compound such as (+)-camphor
was used as the carbonyl compound in this reaction, chiral lactone was synthesized. Here, we
report easily available and ecient d-aminoalcohol 4 for the asymmetric addition of diethylzinc
to aldehydes.
The synthesis method for d-aminoalcohol 4 is described in Scheme 1. 3-Hydroxy acid 1 was
prepared stereoselectively from (+)-camphor and acetic acid by using lithium naphthalenide.6
Acetic acid dianion was selectively attacked from the endo-side of camphor, and no exo-adduct
* Corresponding author. Tel: +81 43 290 3386; fax: +81 43 290 3386; e-mail: fuji@galaxy.tc.chiba-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00637-7

4588
was observed. Compound 1 was easily converted to lactone 2 by using acidic materials. On the other
hand, Kim7 reported that the reaction of steric hindered 4,5-unsaturated acids with a catalytic
amount of iodine and led to uniodinated lactones. We employed this protocol with 1; namely, 1
was placed with 0.2 equivalents of iodine in acetonitrile at room temperature for 3 hours, and
lactone 2 was synthesized stereoselectively in good yield.8 The con®guration of 2 was determined by
the NMR technique; speci®cally, the NOEs were observed between proton a and methyl a proton
but not between proton b and methyl a proton. Accordingly, we deduced the 5S-con®guration
(Fig. 1).
Scheme 1. (a) Li-Nap., CH3COOH in THF; (b) I2 (0.2 equiv.) in MeCN; (c) Et2NH, AlCl3 in THF; (d) LAH in THF
Figure 1.
This mechanism is illustrated in Scheme 2, based on the report by Kim.7 Hydrogen iodide was
initially formed by the interaction of iodine with free carboxylic acid, and it reacted as Lewis acid.
After dehydration, intermediate cation I underwent a Wagner±Meerwein-type rearrangement9 to
intermediate II. Finally, the attack of the carbonyl oxygen on the cation formed lactone 2, and
iodine was reproduced. The reaction of 2 with diethylamine in the presence of aluminum chloride10
led to hydroxyamide 3 in 81% yield.11 Compound 3 could be easily reduced by lithium aluminum
hydride to d-aminoalcohol 4.12 It is noteworthy that: (1) the chiral source of 4 was inexpensive
(+)-camphor; (2) the reactions proceeded completely stereoselectively during the addition of acetic
acid and lactonization (®rst step and second step in Scheme 1); (3) racemization did not occur in
the amidation and reduction (third step and last step in Scheme 1).
The addition of diethylzinc to a series of aldehydes was carried out under the conditions shown
in Table 1, and the results are summarized in Table 1. Despite the reaction of 5g (entry 8), all

4589
Scheme 2.
reactions proceeded quantitatively. It is noteworthy that when 1 mol% of 4 was used as a ligand,
the reaction was quantitative and the enantiomeric excess was still high (97% yield, 91% ee, entry
2). Aromatic aldehydes were ethylated enantioselectively to produce corresponding (S)-alcohol 6
in relatively high enantiomeric excesses (entries 1±6), and the best result was obtained by the
reaction of 4-methylbenzaldehyde 4d to yield (S)-1-(40-methylphenyl)-1-propanol in 95%
enantiomeric excess. Although in the cases of cinnamaldehyde and 3-phenylpropionaldehyde the
yields were still high (98 and 80%, respectively), selectivity was moderate (entries 7 and 8).
Table 1
Enantioselective addition of diethylzinc to aldehydes using chiral ligand 4
In summary, d-aminoalcohol 4, which is ecient for asymmetric induction, was easily synthesized
in four steps from (+)-camphor. The addition of diethylzinc to aldehydes 5 in the presence of 4
resulted in good yields with high enantiomeric excesses.

4590
References
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Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. (c) Soai, K.; Niwa, S. Chem. Rev. 1992, 92,
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Martens, J. Tetrahedron: Asymmetry 1997, 8, 2007.
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Wandrey, C. Tetrahedron: Asymmetry 1997, 8, 1529. (c) Sola, L.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.;
Riera, A. Tetrahedron: Asymmetry 1997, 8, 1559. (d) Nugent, A. W. J. Chem. Soc., Chem. Commun. 1999, 1369.
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R. N. Tetrahedron Lett. 1988, 29, 5645. (c) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 1997,
8, 293. (d) Cho, B. T.; Kim, N. Tetrahedron Lett. 1994, 35, 4115.
5. (a) Genov, M. L.; Kostova, L.; Dimitrov, V. Tetrahedron: Asymmetry 1997, 8, 1607. (b) Genov, M. L.; Dimitrov,
V.; Ivanova, V. Tetrahedron: Asymmetry 1997, 8, 3703. (c) Knollmuller, M.; Ferencic, M.; Gartner, P.
Tetrahedron: Asymmetry 1999, 10, 3969.
6. Watanabe, S.; Suga, K.; Fujita, T.; Fujiyoshi, K. Israel J. Chem. 1970, 8, 731.
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8. Compound 2: 1H NMR (ꢀ, ppm): 1.03 (3H, s), 1.07 (3H, s), 1.17 (3H, s), 1.28 (1H, dd, J=10.2 and 1.5 Hz), 1.39±
1.48 (1H, m), 1.51±1.63 (2H, m), 1.66±1.76 (1H, m), 1.79±1.82 (1H, m), 1.87±1.92 (1H, m), 2.46 (1H, d, J=17.3
Hz), 2.59 (1H, d, J=17.3 Hz); 13C NMR (ꢀ, ppm): 17.81, 22.37, 23.84, 24.45, 24.73, 34.53, 39.69, 44.88, 48.48,
25
D
55.64, 95.21, 176.48; IR: 1765 cm^1; ‰ꢁŠ ^55.6 (c 1.00, C2H5OH); m.p. 125±127ꢀC; HRMS (FAB): m/z, calcd:
195.1385 [M+H]+; found: 195.1371.
9. (a) Wagner, R. J. Russ. Phys. Chem. Soc. 1899, 31, 690. (b) Meerwein, H. Ann. 1914, 405, 129.
10. Lesimple, P.; Bigg, D. C. H. Synthesis 1991, 306.
1
11. Compound 3: H NMR (ꢀ, ppm): 0.93 (3H, s), 1.01 (3H, s), 1.07 (3H, s), 1.12 (3H, t, J=7.1 Hz), 1.19 (3H, t,
J=7.1 Hz), 1.08±1.14 (1H, m), 1.34±1.43 (2H, m), 1.50±1.64 (2H, m), 1.66±1.71 (1H, m), 2.13±2.21 (1H, m), 2.45
(1H, d, J=14.8 Hz), 2.63 (1H, d, J=14.8 Hz), 3.24±3.47 (4H, m), 3.80 (1H, br-s); 13C NMR (ꢀ, ppm): 13.06, 14.42,
19.49, 23.75, 24.73, 25.47, 31.87, 33.96, 38.31, 40.46, 42.81, 45.16, 48.33, 54.36, 80.56, 172.97; IR: 3367, 2964, 1620
25
cm^1; ‰ꢁŠ ^19.1 (c 1.00, CH3CN); m.p. 122±123ꢀC; elemental analysis, calcd: C, 71.86; H, 10.93; N, 5.24; found:
D
C, 71.92; H, 11.08; N, 5.18.
1
12. Compound 4: H NMR (ꢀ, ppm): 0.88 (3H, s), 0.99 (3H, s), 1.03 (6H, t, J=7.2 Hz), 1.05 (3H, s), 1.01±1.08 (1H,
m), 1.12±1.18 (1H, m), 1.23±1.68 (5H, m), 1.87±1.96 (1H, m), 2.10±2.16 (1H, m), 2.24±2.35 (1H, m), 2.37 (1H, dq,
J=7.2 and 14.4 Hz), 2.51±2.61 (1H, m), 2.68 (2H, dq, J=7.2 and 14.4 Hz), 6.52 (1H, br-s); 13C NMR (ꢀ, ppm):
10.63, 19.59, 24.16, 25.58, 25.95, 29.88, 33.70, 37.29, 44.36, 45.74, 48.70, 50.59, 57.04, 78.62; IR: 3195, 3095, 2965
25
D
cm^1; ‰ꢁŠ ^11.4 (c 0.20, CH3CN); HRMS (FAB): m/z, calcd: 254.2484 [M+H]+; found: 254.2472.