Preparation of optically active deuterated primary alcohols: Enantioselective borodeuteride reduction of aldehydes catalyzed by cobalt complexes

Article abstract of DOI:10.1039/b303662f

The enantioselective borodeuteride reduction of aldehydes catalyzed by optically active β-ketoiminato cobalt complexes afforded the corresponding chiral deuterated primary alcohols with a high degree of deuteration and good enantiomeric excess.

Full text of DOI:10.1039/b303662f

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Preparation of optically active deuterated primary alcohols:
enantioselective borodeuteride reduction of aldehydes catalyzed by
cobalt complexes
Daichi Miyazaki, Kohei Nomura, Hiroshi Ichihara, Yuhki Ohtsuka, Taketo Ikeno and
Tohru Yamada*
L e t t e r
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan. E-mail: yamada@chem.keio.ac.jp;
Fax: +81 45 566 1716
Received (in Montpellier, France) 1st April 2003, Accepted 5th June 2003
First published as an Advance Article on the web 2nd July 2003
alcohols or amines in high yields with high enantiomeric
excesses.5 In this communication, we would like to report that
the cobalt-catalyzed reduction system with sodium borodeu-
teride was applied to aldehydes to provide a convenient and
preparative method for chiral deuterated primary alcohols
(Scheme 1).
The enantioselective borodeuteride reduction of aldehydes cata-
lyzed by optically active b-ketoiminato cobalt complexes afforded
the corresponding chiral deuterated primary alcohols with a high
degree of deuteration and good enantiomeric excess.
The enantioselective reduction of p-tolualdehyde was initi-
ally examined using sodium borodeuteride modified by tetra-
hydrofurfuryl alcohol (THFA) in the presence of 1 mol% of
a cobalt catalyst 1 (Scheme 2). The reaction was completed
in 4 h to afford the corresponding alcohol in high yield. Based
Isotopically-labeled compounds provide reliable chemical probes
for the investigation of the mechanisms in chemical and
biochemical processes1 in order to develop efficient catalysts
or specific medicines. As deuteride is one of the most available
isotopic atoms, the utilization of an optically active deuterated
primary alcohol2 is a conventional and established strategy for
the synthesis of the labeled compounds containing the deuter-
ide on a chiral center. It was reported that the chiral deuterated
primary alcohol can be prepared from the corresponding alde-
hyde by the following two procedures; e.g., the enantioselective
reduction of the deuterated aldehyde3 and the enantioselective
deuteride reduction of the aldehyde.3b,3d,4 Although the latter
required less synthetic steps, few methods have been reported
for the catalytic and enantioselective reduction3d,4 because of
the limited number of deuteride reducing agents. Sodium boro-
deuteride is an easily handled reducing agent and a commer-
cially available deuteride source, whereas there has been no
report on the catalytic enantioselective borodeuteride reduc-
tion of aldehydes. The highly enantioselective reductions of
ketones and ketimines with sodium borohydride were realized
in the presence of the optically active b-ketoiminato cobalt
complexes (Fig. 1) to afford the corresponding secondary
1
on the H NMR analysis of the corresponding MTPA ester,6
the enantiomeric excess of the benzyl-a-d alcohol was deter-
mined to be 10% ee along with a significant amount of benzyl
alcohol due to the reduction with hydride. It was reported that
the deuteride of sodium borodeuteride could be exchanged
with a proton from the alcohol.7 The reactive intermediate in
the borohydride reduction catalyzed by cobalt complexes has
been assumed to be cobalt-hydride species, which were
detected by FAB mass analysis.8 A solution of the cobalt
complex 1 with borodeuteride modified by THFA was then
analyzed by FAB mass spectroscopy, and it was actually
found that cobalt-deuteride existed along with cobalt-hydride
(Fig. 2(A)). These observations indicated that the hydrogen
of benzyl alcohol should be derived from the proton of
THFA, the modifier alcohol of borodeuteride. Accordingly,
it was expected that employing tetrahydrofurfuryl alcohol-d
(THFA-d) in place of THFA should generate pure cobalt-
deuteride to afford the reduced product with high isotopic
purity. As shown in Scheme 3, the THFA-d was prepared in
two steps; e.g., THFA was treated with chlorotrimethylsilane
and triethylamine to form the corresponding trimethylsilyl
ether with 85% yield after distillation (bp 82 ꢀC/30 mmHg),
and then subsequently hydrolyzed with deuterium oxide in
the presence of a catalytic amount of sulfuric acid-d2 to afford
THFA-d in 80% yield after distillation (bp 97 ꢀC/50 mmHg).
Its isotopic purity was determined by 1H NMR analysis to
be more than 99%. In the FAB mass spectrum of the cobalt
complex 1 treated with borodeuteride modified by THFA-d,
the peak of the cobalt-hydride in the FAB mass spectrum
disappeared and the corresponding cobalt-deuteride was
Fig. 1 Various optically active b-ketoiminato cobalt complexes.
Scheme 1 The enantioselective deuteride reduction of aldehydes.
1164
New J. Chem., 2003, 27, 1164–1166
DOI: 10.1039/b303662f
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Scheme 2 Enantioselective reduction of p-tolualdehyde with sodium
borodeuteride modified by tetrahydrofurfuryl alcohol.
Scheme 3 Preparation of tetrahydrofurfurylalcohol-d.
observed (Fig. 2(B)). By using the obtained THFA-d for boro-
deuteride modification, p-tolualdehyde was converted to p-
methylbenzyl-a-d alcohol with a greater than 95% deuteration
degree.
active deuterated primary alcohols with 73% and 72% ee,
respectively (entries 5 and 6).
The enantioselective reduction of deuterated aldehydes was
also attempted with sodium borohydride under similar condi-
tions. However, the optical yields of the chiral deuterated pri-
mary alcohols in the present system were not as high as those
for the borodeuteride reduction of aldehydes; for example,
2-naphthaldehyde-d and p-methoxybenzaldehyde-d were redu-
ced to 2-naphthalenemethyl-d alcohol and p-methoxybenzyl-
a-d alcohol with 21% and 60% ee, respectively, while 63%
and 73% ee were obtained for the enantioselective borodeu-
teride reduction of 2-naphthaldehyde and p-methoxybenz-
aldehyde (Scheme 4).9 These contrasting results might be
attributed to the isotope effect of the borodeuteride vs. boro-
hydride, that is the non-catalytic reduction by borodeuteride
itself could be suppressed10 and the enantioselectivity was
higher with the former procedure.
Various ketoiminato cobalt complexes were next examined
(Table 1). Each ligand of the cobalt complex was prepared
from the corresponding optically active 1,2-diarylethylenedi-
amine and 1,3-dicarbonyl compound. These complexes exhibited
excellent catalytic activity for the reduction of p-tolualdehyde
to afford the D-labeled alcohols in high yields, whereas their
enantiomeric excesses widely varied, being sensitive to the
structure of the cobalt complex catalysts (entries 1–7). Cata-
lysts 1 and 2 afforded a low ee of the deuterated alcohol
(entries 1 and 2), while the enantioselectivity was remarkably
improved when employing the 3 series catalysts derived from
the optically active 1,3-bis(2,4,6-trimethylphenyl)ethylenedi-
amine (entries 3–7). Among the series 3 catalysts, it was found
that catalyst 3e, having acetyl groups on both side chains, was
the most efficient catalyst for the reduction of p-tolualdehyde
with sodium borodeuteride (entry 7).
The catalytic and enantioselective borodeuteride reduction
was applied to the preparation of various chiral deuterated pri-
mary alcohols from the corresponding aldehydes (Table 2).
Various aryl aldehydes, such as benzaldehyde, 2-naphthalde-
hyde, and p-phenylbenzaldehyde were converted into the
corresponding chiral deuterated primary alcohols in high
yields with good enantioselectivities (entries 2–4). A high ee
was achieved in the reduction of p-methoxybenzaldehyde and
piperonal; they were converted to the corresponding optically
In summary, the enantioselective borodeuteride reduction
catalyzed by optically active b-ketoiminato cobalt complexes
was used for the preparation of chiral deuterated primary alco-
hols; high yields and high isotopic purities with good enantio-
meric excesses were achieved. Further applications to other
various aldehydes and aldimines are currently underway.
Experimental
Preparation of the premodified borodeuteride solution
To a suspension of NaBD4 (125.6 mg, 3 mmol) in CHCl3 (20
mL), tetrahydrofurfuryl alcohol (THFA; 1.16 mL, 12 mmol)
was added at 0 ꢀC under a dry nitrogen atmosphere. After
stirring for 30 min, the mixture was allowed to stand at room
Table 1 Various cobalt catalysts for the enantioselective borodeuter-
ide reductiona
Entry
Catalyst
% Yieldb
% eec
1
2
3
4
5
6
7
1
96
97
8
13
48
51
51
50
77
2
3a
3b
3c
3d
3e
98
100
97
97
100
a
Reaction conditions: to a solution of the cobalt catalyst and the
p-tolualdehyde was added a solution of the modified borodeuteride,
0.5 mmol of p-tolualdehyde, 0.005 mmol (1 mol %) of cobalt catalyst,
0.75 mmol of NaBD4 , 3 mmol of THFA-d in CHCl3 at 0 ꢀC, 3–4 h.
b
c
Isolated yield. Isotopic purity was > 95%. Determined by 1H
Fig. 2 FAB mass spectra of the cobalt complex treated with boro-
deuteride: (A) THFA modified and (B) THFA-d modified.
NMR analysis of the corresponding MTPA ester.
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Table
2
Enantioselective borodeuteride reduction of various
purified by silica gel column chromatography (hexane–
AcOEt) to give the corresponding optically active deuterated
primary alcohol.
aldehydesa
Determination of the enantiomeric excess of optically active
deuterated primary alcohols
N,N0-Dicyclohexylcarbodiimide (24.8 mg, 0.12 mmol) was
added to a solution of the optically active deuterated primary
alcohol (0.06 mmol) also containing (R)-(+)-a-methoxy-
a-(trifluoromethyl)phenylacetic acid (21.0 mg, 0.09 mmol),
N,N-dimethylaminopyridine (14.7 mg, 0.12 mmol) and
CH2Cl2 (3 mL); then the reaction mixture was stirred at room
temperature until the reaction reached completion. The mixture
was filtered off to remove the precipitate of N,N0-dicyclohexyl-
urea. The filtrate was evaporated and the residue was purified
by silica gel column chromatography (hexane–AcOEt) to give
the corresponding (R)-MTPA ester. The enantiomeric excess
Entry
1c
Aldehyde
% eeb
77
2c
3c
4c
5d
63
63
61
73
72
1
was determined by H NMR analysis of this ester.
Acknowledgements
We thank Prof. Minoru Ueda of Keio University for his help
with the FAB mass analysis.
6c
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8
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Enantioselective borodeuteride reduction of aldehydes
The absolute configuration of the chiral deuterated primary alco-
hol was determined by comparing the 1H NMR spectrum of the
corresponding MTPA ester with that in the literature.3d These
results indicated that the cobalt-deuteride or cobalt-hydride spe-
cies derived from the (R,R)-cobalt catalyst selectively attacked
the (Si)-face of the carbonyl in the aldehyde and is in accord with
the face selectivity of a carbonyl previously reported for the
Under a dry nitrogen atmosphere at reaction temperature
were placed the (S,S)-cobalt catalyst 1 (2.9 mg, 0.005 mmol),
the aldehyde (0.5 mmol) and CHCl3 (5 mL). The premodified
NaBD4 (5.2 mL, 0.75 mmol) was added to the reaction
mixture, which was stirred until the reaction was completed.
The reaction was quenched by a precooled aqueous THF
solution and pH 7 buffer solution, then the crude products
were extracted with AcOEt. The combined organic layers
were washed with brine and dried over anhydrous sodium
sulfate. After filtration and evaporation the residue was
borohydride reduction of ketones5d
.
10 2-Naphthaldehyde was treated with the modified borodeuteride
and borohydride simultaneously to afford 42% of 2-naphthalene-
methyl-d alcohol and 58% of 2-naphthalenemethyl alcohol,
respectively.
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