New 1,3-amino alcohols derived from ketopinic acid and their application in catalytic enantioselective reduction of prochiral ketones

Article abstract of DOI:10.1016/S0957-4166(99)00043-9

New 1,3-amino alcohols, (1S,2S)- and (1S,2R)-1-hydroxylmethyl-2-amino- 7,7-dimethyl bicyclo[2,2,1]heptane (endo-4 and exo-4), were prepared from ketopinic acid via oximation and reduction. The enantioselective borane reduction of prochiral ketones catalyzed by the borane complex of exo-4 was examined.

Full text of DOI:10.1016/S0957-4166(99)00043-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 759–763
New 1,3-amino alcohols derived from ketopinic acid and their
application in catalytic enantioselective reduction of prochiral
ketones
Xingshu Li,a Chi-hung Yeung,a,∗ Albert S. C. Chan a,∗ and Teng-Kuei Yang b,∗
aUnion Laboratory of Asymmetric Synthesis and Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hong Kong, People’s Republic of China
bDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan
Received 8 January 1999; accepted 25 January 1999
Abstract
New 1,3-amino alcohols, (1S,2S)- and (1S,2R)-1-hydroxylmethyl-2-amino-7,7-dimethyl bicyclo[2,2,1]heptane
(endo-4 and exo-4), were prepared from ketopinic acid via oximation and reduction. The enantioselective borane
reduction of prochiral ketones catalyzed by the borane complex of exo-4 was examined. © 1999 Published by
Elsevier Science Ltd. All rights reserved.
1. Introduction
Chiral amino alcohols, usually prepared from natural homochiral amino acids, are important ligands in
asymmetric synthesis including the enantioselective catalytic borane reduction of prochiral ketones,1–5
enantioselective addition of dialkylzinc,6,7 asymmetric hydrogen transfer from alcohols to ketones8,9
and other asymmetric reactions.10,11 From an economic standpoint, it is desirable to develop new chiral
ligands from inexpensive materials and examine their application in asymmetric synthesis. Our study of
the synthesis of new amino alcohols involved the use of ketopinic acid which was easily derived from
camphor. In this paper, we wish to report the synthesis of new 1,3-amino alcohols, (1S,2S)- and (1S,2R)-
1-hydroxylmethyl-2-amino-7,7-dimethyl bicyclo[2,2,1]heptane endo-4 and exo-4 and their application
in the catalytic enantioselective reduction of alkyl aryl ketones.
2. Results and discussion
The synthetic route for compound 4 is summarized in Scheme 1. The reaction of ketopinic acid with
thionyl chloride and methanol produced the methyl ester of 1 in an almost quantitative yield. The ester of
∗
Corresponding author. E-mail: bcachan@polyu.edu.hk
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00043-9

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1 was oximated to give methyl ketopinate oxime 2 and the latter reacted with CH3I to give an intermediate
product 3 which was reduced with LiAlH4 to give amino alcohol 4 in an overall yield of about 50%.
Scheme 1.
An oxazaborolidine catalyst was prepared by treating exo-4 with a borane complex according to a
procedure published by Itsuno et al.1 and was used in situ for the homogenous catalytic reduction of
prochiral ketones.
The results of the catalytic reduction of acetophenone are listed in Table 1. It was quite clear from
Table 1 that the enantiomeric excess (e.e.) of the resulting alcohol was significantly influenced by the
Table 1
The enantioselective reduction of acetophenone with borane catalyzed by oxazaborolidinea,b,c

X. Li et al. / Tetrahedron: Asymmetry 10 (1999) 759–763
761
Table 2
The enantioselective catalytic reduction of prochiral ketones with boranea
reaction temperature. (Entry 3 and 7: the e.e. changed from 15% to 87% when the temperature was
increased from 0°C to 50°C.) These results are consistent with the results reported by Corey, et al.2,13,14
The molar ratio of the amino alcohol to the substrate is also an important factor influencing the
enantioselectivity of the reaction. The e.e. value increased with the increase of catalyst concentration
and the optimum molar ratio of exo-4 to the substrate was about 20%. Two different types of borane
complexes, BH3·THF and BH3·Me2S, have been tested and have been found to give similar results.
It should be noted that using ligands prepared from natural amino acids in the reduction of acetophe-
none gives (R)-sec-phenethyl alcohol, while the S-enantiomer is obtained by using exo-4 as a catalyst.
Since both enantiomers are often needed in asymmetric synthesis, the use of exo-4 complements the use
of the standard amino acid-derived amino alcohol as a chiral ligand in this class of reaction. A possible
transition state of the key reaction intermediate is shown below. The attack of the Re-face of the ketone
by the hydride leads to the S alcohol.
Other typical prochiral aromatic ketones were tested in the enantioselective borane reduction using
exo-4 as a chiral ligand (Table 2).
3. Experimental
Unless otherwise indicated, all reactions were carried out under an N2 atmosphere. Melting points were
measured using an electrothermal 9100 apparatus in capillaries and the data were uncorrected. Optical
rotations were measured on a Perkin–Elmer model 341 polarimeter at 20°C. NMR spectra were recorded
on a Bruker DPX-400 spectrometer. Mass analyses were performed on a Finnigan model mat 95 ST mass
spectrometer. HPLC analyses were performed using a Hewlett–Packard model HP 1050 LC interfaced
to an HP 1050 series computer workstation. GC analyses were performed using a Hewlett–Packard
HP 4890A apparatus. The ketopinic acid was prepared from camphorsulfonic chloride according to a
procedure in the literature12 and the other chemicals were purchased from Acros or Aldrich and were
used as received.

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3.1. Preparation of (1S)-7,7-dimethyl-2-oximino-bicyclo[2,2,1]heptane-1-carboxylic acid methyl ester
2
To a solution of 1.85 g ketopinic acid (10 mmol) in 20 ml methanol was added dropwise 1.2 g thionyl
chloride (10 mmol) at 0°C. The mixture was stirred at the same temperature for 1 h and then at room
temperature for 12 h. The methanol was removed under reduced pressure and benzene (2×30 ml) was
added to distill off the residual thionyl chloride. The crude product was dissolved in 2 ml pyridine and
10 ml absolute anhydrous ethanol and into the solution were added hydroxylamine hydrochloric acid
salt (1.4 g, 20 mmol) and sodium acetate (0.8 g, 10 mmol). The reaction mixture was heated at reflux
temperature for 3 h. After the solvents were removed in vacuo, 8 ml water and 20 ml diethyl ether were
added to the residue and the mixture was shaken vigorously to extract the product. The organic layer was
separated and the water layer was extracted with ether. The combined organic layers were washed with
brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was
purified by column chromatography (silica gel, hexane:ethyl acetate, 1:0.5, v/v) to afford a colorless solid
(1.94 g, 92% yield). 1H NMR (400 MHz, CDCl3): δ 0.98 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.28–1.33 (m,
1H), 1.73–1.80 (m, 1H), 1.91–1.95 (m, 2H), 2.03–2.07 (d, J=16.4, 1H), 2.34–2.41 (m, 1H), 2.67 (s, 1H),
3.75 (s, 3H, CH3).
3.2. (1S)-7,7-Dimethyl-2-(methoximido)-bicyclo[2,2,1]heptane-1-carboxylic acid methyl ester 3
To a suspension of 0.15 g sodium hydride (6.25 mmol) in 15 ml dry tetrahydrofuran was added a
solution of 1.17 g methyl ketopinate oxime 2 (5.5 mmol) in 5 ml dry THF at 0°C. The reaction mixture
was stirred at the same temperature for 1 h followed by the addition of 0.86 g CH3I (6 mmol). The
ice bath was removed and the stirring was continued for another 5 h. After removal of the THF under
reduced pressure, the residue was extracted with diethyl ether (3×15 ml). The combined organic layers
were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a light yellow
oil which was purified by column chromatography (hexane:ethyl acetate, 1:0.3, v/v, 1.08 g, 86% yield).
1H NMR (400 MHz, CDCl3): δ 1.03 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.28–1.29 (m, 1H), 1.71–1.78 (m,
1H), 1.90–1.93 (m, 2H), 2.05–2.09 (d, J=17.5, 1H), 2.36–2.37 (m, 1H), 2.63 (s, 1H), 3.76 (s, 3H, OCH3),
3.83 (s, 3H, OCH3).
3.3. (1S,2S)- and (1S,2R)-1-(Hydroxylmethyl)-2-amino-7,7-dimethyl bicyclo[2,2,1]heptane 4
A sample of 3 (0.3 g, 1.33 mmol) in 5 ml dry THF was added dropwise to a solution of 0.15 g
LiAlH4 and 25 ml dry THF at 0°C. The mixture was stirred at ambient temperature for 3 h and then at
reflux temperature for 12 h. Purification by column chromatography (methanol:ethyl acetate, 4:1) gave
the amino alcohols endo-4 (0.034 g, 15% yield) and exo-4 (0.11 g, 49% yield). The analytical data for
these products are as follows. (1) endo-4: m.p.=190–192°C; [α]D=39.8 (c 0.47, CH3OH); 1H NMR (400
MHz, CDCl3): 0.73–0.77 (dd, J=4.16, 4.10 Hz, 1H), 0.90 (s, 3H), 0.91 (s, 3H), 1.22–1.29 (m, 1H),
1.55–1.63 (m, 2H), 1.80–1.87 (m, 1H), 2.01–2.07 (m, 1H), 2.29–2.37 (m, 1H), 3.50–3.51 (t, J=1.80 Hz,
1H), 3.60–3.62 (d, J=10.14 Hz, 1H), 3.84–3.87 (d, J=10.19 Hz, 1H). 13C NMR (101 MHz, CDCl3):
19.07, 19.99, 23.49, 28.38, 41.47, 46.28, 47.83, 51.27, 56.31, 66.65; MS (ESI): 170 (M+1, 100), 153
1
(M−16, 4), 135 (M−35, 6). (2) exo-4: m.p.=199–201°C; [α]D −53.3 (c 0.57, CH3OH); H NMR (400
MHz, CDCl3): 0.92 (s, 3H, CH3), 1.05–1.07 (m, 2H), 1.18 (s, 3H, CH3), 1.40–1.42 (m, 1H), 1.58 (m,
1H), 1.69–1.72 (m, 2H), 1.83 (dd, J=8.84, 8.96 Hz, 1H), 3.05–3.08 (dd, J=5.00, 5.00 Hz, 1H), 3.81–3.87
(dd, J=11.60, 11.60 Hz, 2H); 13C NMR (101 MHz, CHCl3): 20.72, 21.74, 26.68, 32.57, 42.70, 46.13,
46.75, 51.49, 59.47, 64.02; MS (ESI): 170 (M+1, 100), 153 (M−16, 10), 135 (M−34, 8); exact mass
calcd for C10H20ON: 170.1545; found: 170.1547.

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3.4. A general procedure for the catalytic reduction of prochiral ketones
Under a nitrogen atmosphere, 16 mg of exo-4 in 2 ml of dry THF was added to 1 ml of 1 M BH3·THF
solution (1 mmol) at 0°C. The reaction mixture was stirred for 3 h at ambient temperature to form an
oxazaborolidine catalyst and then was warmed to 50°C. A solution of acetophenone (1 mmol) in 2 ml
dry THF was added dropwise over 50–60 min at the same temperature. After stirring for another hour the
reaction mixture was cooled to 0°C and was quenched with 1 ml of 2 M HCl solution. Ethyl acetate (5
ml) was added to extract the product and the organic layer was separated and concentrated in vacuo. Flash
chromatography of the material afforded the chiral alcohol. The e.e. value of the product was determined
by GC or HPLC analysis.
Acknowledgements
We thank the Hong Kong Polytechnic University and the Research Grants Council of Hong Kong
(project number ERB003) for financial support of this study.
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