Synthesis of optically-active benzylic amines; asymmetric reduction of ketoxime ethers with chiral oxazaborolidines

Article abstract of DOI:10.1016/S0957-4166(01)00358-5

The preparation of novel optically active benzylic amines by the enantioselective reduction of phenone oximes using chiral oxazaborolidine is described. The choice of the chiral 1,2-amino alcohol (S)-diphenylvalinol as chiral inducer and that of the benzy

Full text of DOI:10.1016/S0957-4166(01)00358-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2185–2189
Synthesis of optically-active benzylic amines; asymmetric
reduction of ketoxime ethers with chiral oxazaborolidines
Evelyne Fontaine,* Claudie Namane, Je´roˆme Meneyrol, Michel Geslin, Laurence Serva,
Eliane Roussey, Ste´phanie Tissandie´, Mohamed Maftouh and Pierre Roger
Recherche Exploratoire, Sanofi-Synthe´labo Recherche, 195 rte d’Espagne, 31036 Toulouse, France
Received 2 August 2001; accepted 9 August 2001
Abstract—The preparation of novel optically active benzylic amines by the enantioselective reduction of phenone oximes using
chiral oxazaborolidine is described. The choice of the chiral 1,2-amino alcohol (S)-diphenylvalinol as chiral inducer and that of
the benzyl group for the O-oxime substituent is explained. 23 primary amines are obtained, with high enantioselectivity
(e.e.=98%), good yield (74%) on preparative scale. A mechanistic explanation is proposed. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Herein, we describe, in the first part, the study of the
effect of the oxime ether O-substituent on the enan-
tioselectivity of the reduction using norephedrine as a
chiral inducer. In the second part, norephedrine is
replaced by the Itsuno ligand, (S)-diphenylvalinol. 24
examples are described. The third part deals with the
optimisation of the reaction and proposes a mechanistic
explanation of the high enantioselectivity.
Much attention has focussed on the asymmetric synthe-
sis of optically active amines because they play an
important role as starting materials for the synthesis of
many biologically active compounds1 and resolving
agents.
One of the easiest ways to obtain optically active
amines is by the asymmetric reduction of the CꢀN
double bond of ketoximes.2 The use of an oxazaboro-
lidine formed by condensation of a chiral 1,2-amino
alcohol with borane is one of the most successful
methods of enantioselective ketone reduction. Itsuno3
adapted this method to oxime reduction and the first
amino alcohols were those provided by the reduction of
the amino acids valine and proline. The next optimisa-
tion of the ligand design furnished a diphenyl derivative
of valine, which was highly effective in the enantioselec-
tive reduction of acetophenone methyl oxime.4 In 1988,
Sakito et al.5 described the efficiency of norephedrine as
a chiral ligand in the reduction of several oxime ethers.
Another aspect of the optimisation of the reduction of
ketoxime ethers is the nature of the oxime ether O-
substituents.4,5
2. Results
2.1. Effects of the oxime substituent
The oximes were classically prepared from the ketones
by addition of hydroxylamine.6 The mixture of (Z)-
and (E)-isomers obtained (in a ratio of 3:1) was easily
separated by simple chromatography purification and
then alkylated (NaH, RHal)4 to furnish O-alkylated
oximes 1a 1d. It is essential for the further reduction to
have pure isomer, as the two geometric isomers give the
opposite enantiomer.5 The results of the experimental
optimisation have been described,4,5 they imply the
ratio: 1 equiv. oxime:2.5 equiv. amino alcohol:5 equiv.
BH3. The reduction of oximes 1a–1d with the oxaz-
aborolidine of norephedrine gives a mixture of the
required amine 3 and hydroxylamines 2a–2d (readily
converted to amine 3 in the presence of lithium alu-
minium hydride).
* Corresponding author. E-mail: evelyne.fontaine@sanofi-synthelabo.
com
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00358-5

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E. Fontaine et al. / Tetrahedron: Asymmetry 12 (2001) 2185–2189
The results of the enantioselective reduction of oximes
1a–1d using the oxazaborolidine prepared from (−)-
norephedrine are summarised in Table 1.
increased markedly in the cases of oximes 1c and 1d,
from 90 to 98% and 91 to 99%, respectively. The benzyl
group is preferred to the ortho-nitrobenzyl group for
the next applications for practical aspects (availability
and chemical resistance to reducing agent).
Independent of the nature of the oxime substituent, the
reduction using (−)-norephedrine generally gives the
hydroxylamines 2 with an average yield of 42%. The
yield of the amine 3 is significantly increased in the case
of benzylic oximes 1c and 1d (20 and 30%) compared
with the alkyl homologue 1a and 1b (8 and 2%), and
the enantiomeric excess (e.e.) remains almost constant
(between 90 and 93%). Dougherty et al. described, in
their cyclic oxime case, the higher enantiomeric purity
of the ortho-nitrobenzyl analogue over the benzyl ana-
logue.7 In our case, the e.e. of the product from ortho-
nitrobenzyl substituted oxime 1d is nearly identical to
that formed from the benzyl analogue 1c.
These conditions were applied to three families of phe-
none benzyloximes on a larger scale.
In the three families; alkyl (propyl and butyl), cyclo-
alkylmethyl (cyclopropyl and cyclobutyl) and methoxy-
methyl the primary amines are obtained with high
optical purity, the Rb substituent could be either an
halogen (fluorine, chlorine or bromine), an alkyl
(methyl), a methoxy or a methylene dioxy group.
We can see from Table 3 that 24 different benzylic
amines were prepared by this method, Of these, 23 have
e.e. of >96%, (with a mean e.e. of 98%) and the average
yield is 74%. In the case of the fluorobutylbenzylamine
(entry m) the e.e. could not be measured. This reaction
sequence constitutes an excellent synthetic method for
the preparation of diverse chiral benzylic amines on
preparative scale (up to 20 g).
2.2. (S)-Diphenylvalinol results
According to Itsuno’s procedure,4 (S)-diphenylvalinol
was prepared from (S)-valine. By the addition of 6
equivalents of commercial phenylmagnesium bromide,
we obtained (S)-diphenylvalinol, in 87% yield. The
comparison of the two a-amino alcohols in the reduc-
tion of oximes 1c and 1d is shown in Table 2.
The (S)-diphenylvalinol ligand is easily recovered in the
last stage of the synthesis by precipitation of its hydro-
chloride salt. The recycling proposed by Itsuno et al.4
was tested with success in several cases and then
applied in all our syntheses.
The reduction using diphenylvalinol is more complete
than that using norephedrine, giving amine 3 (60%
yield) preferentially over hydroxylamines 2. The e.e. is
Table 1. Asymmetric reduction of oximes 1a 1d using (−)-norephedrine
Oxime
R
Time (h)
Yield (%) of hydroxylamines 2
Yield (%) of amine 3
E.e. (%)a of amine 3
1a
1b
1c
1d
Me
iso-Pr
Bn
70
70
16
16
45
48
43
33
8
2
20
30
90
93
91
90
o-NO2Bn
a E.e.s were determined by reversed-phase HPLC using crown-ether (Crownpak CR column) as chiral selector, the reference racemic amine was
obtained by reduction of oxime 1a with LiAlH4.
Table 2. Enantioselective reduction of oximes 1c and 1d using (−)-norephedrine or (S)-diphenylvalinol
1,2-Amino alcohol
(−)-Norephedrine
(S)-Diphenylvalinol
Oxime
Yield (%) of amine 3
E.e. (%)a of amine 3
1c
1d
1c
1d
20
30
60
60
91
90
99
98
a E.e. was determined by reversed-phase HPLC using crown-ether (Crownpak CR column) as chiral selector, the racemic amine was obtained by
reduction of oxime 1a with LiAlH4.

E. Fontaine et al. / Tetrahedron: Asymmetry 12 (2001) 2185–2189
Table 3. Asymmetric reduction of benzyloximes using (S)-diphenylvalinol
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E. Fontaine et al. / Tetrahedron: Asymmetry 12 (2001) 2185–2189
2.3. Further optimisation
4. Conclusion
In order to improve the experimental procedure of the
asymmetric reduction of O-benzyloxime with (S)-
diphenylvalinol complex, two parameters were
considered.
In conclusion, in the enantioselective reduction of phe-
none oximes, (S)-diphenylvalinol oxazaborolidine is dis-
tinctly more effective than (−)-norephedrine. 23 primary
benzylic amines were prepared by this method; the
average e.e. is excellent (98%), the mean yield 74%. The
(S)-diphenylvalinol is easily recovered in the last step of
the reaction. Most of the amines prepared are novel
compounds. The mechanistic explication proposed cor-
relates with the observed high e.e.s.
“ Solvent. In the case of the para-fluorinated cyclo-
propylmethyl oxime (entry q) the replacement of
tetrahydrofuran by diethyl ether improved the optical
purity of the amine formed (from an e.e. of 96.6 to
98.7%), the yield of the reaction remaining constant.
“ Molar ratio of oxime: reducing agent complex. Itsuno
et al.8 unsuccessfully investigated the catalytic use of
the chiral complex. In our case, the cyclopropyl-
methyl oxime (entry u) was treated with one equiva-
lent of diphenylvalinol complex instead of the 2.5
equivalents usually observed. The e.e. remained
excellent (98%) but the yield of the reaction decreased
(from 84 to 52%).
5. Experimental
All reactions were carried out under inert atmosphere.
5.1. Preparation of the ligand: (S)-2-amino-3-methyl-
1,1-diphenylbutan-1-ol
A solution of phenylmagnesium bromide (3.0 M, 600
mL, 1790 mmol) in diethyl ether was stirred at 0°C and
diluted with THF (300 mL), followed by portionwise
3. Discussion
addition of L-valine methyl ester hydrochloride (50 g,
3.1. Mechanistic consideration
298 mmol) while keeping the temperature below 10°C.
After stirring for 3 h at rt, the reaction mixture was
poured slowly into ice-cold ammonium chloride solu-
tion. Diethyl ether (500 mL) and ethyl acetate (500 mL)
were added to the mixture. After separation of the
phases, the aqueous phase was re-extracted with TBME
(tert-butyl methyl ether, 1 L). The combined organic
In 1987, Corey et al.9 reported 1H NMR, 11B NMR and
infrared spectroscopic evidence of the structure of vali-
nol chiral cycle 4. The oxazaborolidine 4 is unable to
reduce oximes.9 The addition of a second equivalent of
borane at the opposite site of the iso-propyl group gives
the effective chiral reducing agent 5. The complex 5% is
sterically unfavourable.
Our adaptation of the mechanism for the reduction of
ketone9 to amines agrees with the high enantioselectivity
observed. The nitrogen of the anti-geometric isomer is
complexed by the endocyclic borane allowing the chiral
hydrogen transfer via a six-membered cyclic transition
state 6.
phases were stirred at 0°C and acidified slowly with 35%
hydrochloric acid (about 40 mL) in water. The hydro-
chloride precipitate thus formed was filtered off and
rinsed with TBME. The mixture was then taken up in
dichloromethane (1 L) and water (1 L) and basified at
0°C with 35% sodium hydroxide (about 50 mL).
At this stage, the stereogenic centre is formed, benzylic
amines and (S)-diphenyl valinol are obtained after
work-up. This hypothetical mechanism illustrates a gen-
eral feature of the reaction.
After separation of the phases, the aqueous phase was
re-extracted with dichloromethane (1 L). The combined
organic phases were washed with water and then with
brine, dried over sodium sulphate and concentrated.

E. Fontaine et al. / Tetrahedron: Asymmetry 12 (2001) 2185–2189
2189
After crystallisation from iso-propyl ether, (S)-2-amino-
Acknowledgements
3-methyl-1,1-diphenylbutan-1-ol was obtained (61 g,
87%). [h]2D5=−127.8 (c=0.639, CHCl3). 1H NMR
(CDCl3, 200 MHz), l ppm, J Hz 7.00–7.60 (Ar, m,
10H); 5.24 (-OH, s, 1H); 3.66 (-CH-N, d, J=1.5, 1H);
1.53 (-CH-CH3, hept d, J=1.5 and 7, 1H); 1.16 (-NH2,
s, 2H); 0.81 (-CH3, 2d, J=7, 6H).
We are indebted to our analytical research department
for the analytical data: Claire Azalbert and Vale´rie
Midol-Monnet.
5.2. Synthesis of the enantiomeric amines: typical
procedure
References
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temperature was allowed to rise to room temperature
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