Chiral ferrocenyl amino alcohols as catalysts for the enantioselective borane reduction of ketones

Article abstract of DOI:10.1016/S0957-4166(02)00338-5

The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalysts prepared in situ from chiral ferrocenyl amino alcohols. The corresponding chiral secondary amino alcohols were obtained with modest to high enantiomeric excesses (up to 90%) using (1S,2S)-2-amino-1-ferrocenyl-3,3-dimethyl-1-butanol 5c.

Full text of DOI:10.1016/S0957-4166(02)00338-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1241–1243
Chiral ferrocenyl amino alcohols as catalysts for the
enantioselective borane reduction of ketones
Thierry Brunin, Je´roˆme Cabou, Ste´phanie Bastin, Jacques Brocard and Lydie Pe´linski*
Laboratoire de Catalyse de Lille, Groupe de Synthe`se Organome´tallique, UMR CNRS 8010,
Ecole Nationale Supe´rieure de Chimie de Lille, BP 108, 59652 Villeneuve d’Ascq Cedex, France
Received 4 June 2002; accepted 27 June 2002
Abstract—The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine
catalysts prepared in situ from chiral ferrocenyl amino alcohols. The corresponding chiral secondary amino alcohols were
obtained with modest to high enantiomeric excesses (up to 90%) using (1S,2S)-2-amino-1-ferrocenyl-3,3-dimethyl-1-butanol 5c.
© 2002 Published by Elsevier Science Ltd.
1. Introduction
2. Results and discussion
Enantiomerically pure secondary alcohols are impor-
tant intermediates for various other functionalities such
as halides, amines, esters, and ethers. Hence, the asym-
metric synthesis of enantiomerically enriched secondary
alcohols has been extensively studied. Among the vari-
ety of asymmetric reactions leading to enantiomerically
pure alcohols, the enantioselective reduction of prochi-
ral ketones with borane in presence of a chiral ligand
has received considerable attention.1 Following on from
the original work of Itsuno2 and Corey,3 a great num-
ber of studies have been reported over the last decade
and many new compounds, derived from naturally
occurring and unnatural starting materials, have been
prepared in order to find more effective and economi-
cally attractive catalysts.4 However, to our knowledge,
the use of ferrocenyl amino alcohols in the reduction of
ketones has not been reported so far. Thus, it should be
of interest to investigate the catalytic ability of such
ligands. We have an ongoing interest in the synthesis
and application of chiral ferrocenyl amino alcohols in
enantioselective alkylation of aldehydes by diethylzinc5
and we thought to evaluate the effect resulting from the
introduction of a ferrocenyl moiety onto the catalysts.
In this communication, we report the synthesis of enan-
tiomerically pure ferrocenyl amino alcohols and their
application as ligands in the reduction of ketones by
borane.
The amino aldehydes 2a–c were obtained in two steps.
The amino functions of natural
1b and
L
-alaninol 1a, L-valinol
L
-tert-leucinol 1c were first protected with two
benzyl groups and the resulting N,N-dibenzylamino
alcohols were transformed into the amino aldehydes by
Swern oxidation. Compounds 2a–c were isolated in 97,
83, and 78% isolated overall yields, respectively
(Scheme 1).
Ferrocenyllithium, prepared by reaction of t-BuLi with
ferrocene in THF at −78°C, was added to the amino
aldehydes 2a–c providing a mixture of diastereomeric
compounds 3a/4a, 3b/4b and 3c/4c in 61, 51 and 50%
overall yield, respectively (Scheme 2). In agreement
with the literature,6 the ‘erythro’ isomer was the major
amino alcohol obtained: 3a/4a: 92/8, 3b/4b: 91/9. The
diastereomeric ratios were determined by HPLC analy-
sis of the crude isolated product and the diastereomers
were separated by silica gel column chromatography.
The coupling constant values J1,2 (Scheme 2) allowed to
* Corresponding author. Tel.: +33-3-20 43 48 93; fax: +33-3-20 43 65
85; e-mail: lydie.pelinski@ensc-lille.fr
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00338-5

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T. Brunin et al. / Tetrahedron: Asymmetry 13 (2002) 1241–1243
BH3 and the amino alcohols.9 The results are sum-
marised in Table 1.
In order to evaluate the catalytic behaviour of the
ligands, two levels of loading (10 and 100 mol%) were
utilised. In all cases, 1-phenylethanol with the (R)-enan-
tiomer predominating was obtained quantitatively. We
observed a decrease in the enantioselectivity with
decreasing reaction temperature, as has already been
reported in the literature10 (compare entries 3 and 4).
The results show that the enantioselectivity of the reac-
tion is very sensitive to the structure of the chiral
ligand. Increasing the bulkiness of the alkyl group on
the carbon bearing the amino function induces an
increase in the enantioselectivity when the amino alco-
hols were used at 10 mol% (entries 1, 4 and 6). How-
ever, this effect is less important when using
stoichiometric conditions (entries 2, 5 and 7). The pres-
ence of a tert-butyl group on the carbon bearing the
amino function for 5c gives the most satisfactory results
(entries 6 and 7). The enantioselectivities were 84%
using 10 mol% of 5c and 90% using 100 mol% of 5c.
Moreover, the difference between the enantiomeric
excesses obtained under the catalytic and stoichiometric
conditions for 5c is not important (De.e.=6%) in com-
parison with 5a (De.e.=59%) and 5b (De.e.=34%).
Scheme 2.
establish unambiguously the stereochemistry of the
diastereomers (3a: J1,2=6 Hz, 4a: J1,2=9.5 Hz, 3b:
J1,2=5 Hz, 4b: J1,2=8.5 Hz). The determination of the
ratio of diastereomers 3c/4c was not possible because of
the instability of the products and the absence of
separation by column chromatography and HPLC
analysis. Thus, the crude product was used in the next
step without purification and separation.
We observed a beneficial effect of the presence of the
ferrocenyl moiety in the amino alcohol: the replacement
of the phenyl group of norephedrine with a ferrocenyl
moiety for 5a provided higher enantioselectivity in the
respective reduction reaction (74.5% for norephedrine
and 81% for ferrocenyl ligand 5a).11
The primary amino alcohols were obtained by depro-
tection of the amino function. Thus, the two benzyl
groups of the ferrocenylamino alcohol 3a and 3b were
cleaved in the presence of a mixture of ammonium
formate and Pd–C in methanol providing 5a and 5b in
80 and 70% isolated yield, respectively (Scheme 3).7 The
same experimental procedure was applied to the mix-
ture 3c/4c leading to the diastereomer 5c in 52% yield.8
It has to be mentioned that attempts to deprotect the
minor diastereomers led to decomposition products.
Finally, we investigated the efficiency of ligand 5c in the
reduction of four representative aromatic ketones
Table 1. Enantioselective reduction of acetophenone with
BH3·THF using ferrocenyl amino alcohols 5a–ca
The primary ferrocenyl amino alcohols 5a–c were then
evaluated in the enantioselective reduction of acetophe-
none (Scheme 4). The reaction was carried out in THF
at 30°C with in situ generated oxazaborolidines using
Entry
Auxiliary (mol%)
E.e. (%)b
Conf.c
1
2
3
4
5
6
7
5a (10)
5a (100)
5b (10)d
5b (10)
5b (100)
5c (10)
20
81
45
54
88
84
90
R
R
R
R
R
R
R
5c (100)
a The chemical yields of isolated products were 95–100%.
b The e.e. values were determined by capilliary GC analysis with a
FC-cyclodex (0.24 mm×30 m) column.
c The absolute configuration of the product was determined by com-
parison of the sign of the specific rotation to the literature data.
d The reaction was carried out at 20°C.
Scheme 3.
Scheme 5.
Scheme 4.

T. Brunin et al. / Tetrahedron: Asymmetry 13 (2002) 1241–1243
1243
Table 2. Reduction of aromatic ketones with BH3·THF
using ferrocenyl amino alcohol 5c as catalyst (10 mol%)a
In Organic Reactions; Paquette, L. A., Ed.; John Wiley:
New York, 1998; Vol. 52, pp. 395–576.
2. Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem.
Soc., Chem. Commun. 1983, 469–470.
Entry
Ketone
E.e. (%)b
Conf.c
3. Corey, E.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1
2
3
4
1-Tetralone
Propiophenone
4-Chloroacetophenone
v-Bromoacetophenone
83
74
77
82
R
R
R
S
1987, 109, 5551–5553.
4. For recent examples, see: (a) Sato, S.; Watanabe, H.;
Asami, M. Tetrahedron: Asymmetry 2000, 11, 4329–4340;
(b) Fiaud, J.-C.; Maze´, F.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 3647–3655; (c) Pinho, P.; Guijarro,
D.; Andersson, P. G. Tetrahedron 1998, 54, 7897–7906;
(d) Zhou, H.-B.; Zhang, J.; Lu¨, S.-M.; Xie, R.-G.; Zhou,
Z.-Y.; Choi, M. C. K.; Chan, A. S. C.; Yang, T.-K.
Tetrahedron 2001, 57, 9325–9333.
5. (a) Bastin, S.; Agbossou-Niedercorn, F.; Brocard, J.;
Pe´linski, L. Tetrahedron: Asymmetry 2001, 12, 2399–2408;
(b) Bastin, S.; Brocard, J.; Pe´linski, L. Tetrahedron Lett.
2000, 41, 7303–7307.
a The chemical yields of isolated products were 100%. The reactions
were carried out at 30°C.
b The e.e. values were determined by capilliary GC analysis with a
FC-cyclodex (0.24 mm×30 m) column.
c The absolute configuration of the product was determined by com-
parison of the sign of the specific rotation with the literature data.
(Scheme 5) and these results are reported in Table 2.
Thus, the reduction of ketones using 10 mol% of 5c
gave excellent chemical yields and enantioselectivities
from 74 to 83%.
6. Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162.
7. Compound 5a: [h]D20=+74.0 (c 1.04, CHCl3); 1H NMR
(300 MHz, CDCl3): l 0.98 (d, J=6.5 Hz, 3H), 2.97 (qd,
J=4.8 and 6.5 Hz, 1H), 4.15–4.22 (m, 4H), 4.22 (s, 5H),
4.25 (d, J=4.8 Hz, 1H). Compound 5b: [h]2D0=+93.4 (c
0.54, CHCl3); 1H NMR (300 MHz, CDCl3): l 0.88 (d,
J=6.5 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H), 1.56–1.62 (m,
1H), 2.53 (dd, J=6.5 and 6.5 Hz, 1H), 4.18 (m, 2H), 4.21
(m, 1H), 4.24 (s, 5H), 5.27 (m, 1H), 4.33 (d, J=5.5 Hz,
1H).
3. Conclusion
A series of enantiomerically pure ferrocenyl amino
alcohols was prepared by stereoselective routes and
applied as catalytic ligands in the enantioselective
reduction of prochiral ketones, giving chiral alcohols
with modest to high enantioselectivities. Further inves-
tigations are in progress regarding the amelioration of
the design of ferrocenyl ligands of this type.
8. Compound 5c: [h]2D0=+173.7 (c 0.244, CHCl3); H NMR
1
(300 MHz, CDCl3): l 0.83 (s, 9H), 2.68 (d, J=4.5 Hz,
1H), 4.15–4.30 (m, 4H), 4.24 (s, 5H), 4.39 (d, J=4.5 Hz,
1H).
9. Typical procedure for the reduction of prochiral ketones:
Under nitrogen, BH3·THF (473 mL, 1 M) was added to a
solution of chiral ligand (0.236 mmol or 0.019 mmol) in
dry THF (10 mL) at 30°C. A solution of acetophenone
(473 mL, 0.189 mmol), in dry THF (5 mL), was added
dropwise over a period of 50 min at 30°C. After stirring
for 2 h at 30°C, MeOH (5 mL) and then HCl (5 mL, 3
M) were added to the reaction mixture. The alcohol
product was isolated by extraction with diethyl ether. The
organic layer was dried over Na2SO4. After concentration
by rotary evaporation, the product was analysed by
chiral GC.
Acknowledgements
The authors gratefully thank the ‘Ministe`re de la
Recherche et de la Technologie’ and the ‘Centre
National de la Recherche Scientifique’ for financial
support and Dr. Francine Agbossou-Niedercorn for
helpfull discussions.
10. (a) Brunel, J.-M.; Maffei, M.; Buono, G. Tetrahedron:
Asymmetry 1993, 4, 2255–2260; (b) Stone, B. J. Tetra-
hedron: Asymmetry 1994, 5, 465–472.
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