Chiral phosphoric acid catalyzed enantioselective transfer deuteration of ketimines by use of benzothiazoline as a deuterium donor: Synthesis of optically active deuterated amines

Article abstract of DOI:10.1021/ol3012869

By use of 2-deuterated benzothiazoline as a deuterium donor in combination with a chiral phosphoric acid, the transfer deuteration of ketimine and α-iminoester took place smoothly to give α-deuterated amines in high yields with excellent enantioselectivit

Full text of DOI:10.1021/ol3012869

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3312–3315
Chiral Phosphoric Acid Catalyzed
Enantioselective Transfer Deuteration of
Ketimines by Use of Benzothiazoline As a
Deuterium Donor: Synthesis of Optically
Active Deuterated Amines
Tsubasa Sakamoto, Keiji Mori, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro,
Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received May 9, 2012
ABSTRACT
By use of 2-deuterated benzothiazoline as a deuterium donor in combination with a chiral phosphoric acid, the transfer deuteration of ketimine and
R-iminoester took place smoothly to give R-deuterated amines in high yields with excellent enantioselectivities. The remarkable kinetic isotope
effect suggests that carbonÀdeuterium bond cleavage is the rate-determining step.
Deuterated compounds are an important class of mate-
rials that are used in various areas, including the analysis of
the metabolic pathways of bioactive compounds,1a,b the
determination of the mechanisms of both chemical and
enzymatic reactions,1c,d and NMR solvents.
Recently, ‘heavy drugs’ have emerged as novel drugs
that exhibit better stability and/or bioavailability than
their hydrogen analogs.2 For instance, the deuterium
substitution on the methylenedioxy moiety of deuterated
paroxetine,3 an antidepressant, altered the drug’s metabo-
lism and prolonged its activity in vivo. Telaprevir is gen-
erally acknowledged as an inhibitor of the hepatitis C
virus; however, the chiral center next to R-ketoamide
(S-configuration) in telaprevir tends to epimerize to furnish
an (R)-diastereoisomer that has ∼30-fold lower activity.
Through the deuteration of telaprevir, the epimerization of
telaprevir-d1 is retarded due to the presence of deuterium
(Figure 1).4 In both cases, the introduction of deuterium
improved the bioavailability.
The significance of deuteration has been growing at
a rapid pace. A number of practical methods for the
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ꢀ
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r
10.1021/ol3012869
Published on Web 06/22/2012
2012 American Chemical Society

the reactivity and enantioselectivity by changing the sub-
stituent at the 2-position of benzothiazoline (Figure 2).14
We hypothesized that the use ofdeuterated benzothiazoline,
which is readily accessible from D1-aldehyde, would enable ef-
ficient access to optically active deuterated amines (Scheme 1).
Figure 2. Benzothiazoline.
Figure 1. Deuterated pharmaceuticals.
deuteration, such as catalytic deuteration, conventional
deuteride reduction, and a HÀD exchange reaction, have
been reported.5 Although Yamada and co-workers re-
ported the enantioselective reduction of aldimine with
NaBD4,6 asymmetric deuteration is underexplored. We
focused on the deuteride reduction of imine6,7 as a versatile
reaction for the preparation of chiral R-deuterated amine.8
The enantioselective transfer hydrogenation of keti-
mines by the combined use of Hantzsch ester and chiral
phosphoric acid has emerged as a useful method for
the preparation of chiral amines.9 On the other hand, we
demonstrated that benzothiazoline10 functioned as a novel
hydrogen donor for the asymmetric transfer hydrogena-
tion of ketimines11 by means of chiral phosphoric acid.12,13
The advantages of benzothiazoline are twofold: (1)
benzothiazoline can be easily synthesized by mixing 2-
aminothiophenol and aldehyde; and (2) the ease of tuning
Scheme 1. Synthesis of Chiral Deuterated Amine
At the outset, we tried to perform the deuteride reduc-
tion of ketimine.11a On treatment of ketimine 2a with
2-deuterio-2-(2-naphthyl)benzothiazoline (3a) in the pre-
sence of a catalytic amount of chiral phosphoric acid 1 in
mesitylene at 50 °C, the transfer deuteration proceeded to
give corresponding R-deuterated amine 4a with excellent
enantioselectivity. Deuterium was incorporated at the
R-position of nitrogen (Scheme 2).
(6) For an example of enantioselective deuteration by use of NaBD4,
see: Miyazaki, D.; Nomura, K.; Yamashita, T.; Iwakura, I.; Ikeno, T.;
Yamada, T. Org. Lett. 2003, 5, 3555–3558.
(7) For the use of deuterated Hantzsch ester in the nonasymmetric
reaction, see: Fujii, M.; Aida, T.; Yoshihara, M.; Ohno, A. Bull. Chem.
Soc. Jpn. 1989, 62, 3845–3847.
(8) (a) Meyers, A. I.; Dickman, D. A. J. Am. Chem. Soc. 1987, 109,
1263–1265. (b) Lown, J. W.; Akhtar, M. H. J. Chem. Soc., Chem.
Commun. 1973, 511–513. (c) Battersby, A. R.; Staunton, J.; Summers,
M. C. J. Chem. Soc., Perkin Trans. 1 1976, 1052–1056.
Scheme 2. Transfer Deuteration of Ketimine by Use of
D-Benzothiazoline
(9) For reviews, see: (a) Zheng, C.; You, S.-L. Chem. Soc. Rev. 2012,
41, 2498–2518. (b) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett
2010, 852–865. (c) Rueping, M.; Dufour, J.; Schoepke, F. R. Green
Chem. 2011, 13, 1084–1105.
(10) Chikashita, H.; Miyazaki, M.; Itoh, K. J. Chem. Soc., Perkin
Trans. 1 1987, 699–706.
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Zhu, C.; Akiyama, T. Adv. Synth. Catal. 2010, 352, 1846–1850. (c)
Henseler, A.; Kato, M.; Mori, K.; Akiyama, T. Angew. Chem., Int. Ed.
2011, 50, 8180–8183. (d) Saito, K.; Akiyama, T. Chem. Commun. 2012,
48, 4573–4575. See also: (e) Zhu, C.; Falck, J. R. ChemCatChem 2011, 3,
1850–1851.
(12) For seminal work, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566–1568. (b) Uraguchi,
D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356–5357.
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Adv. Synth. Catal. 2006, 348, 999–1010. (b) Akiyama, T. Chem. Rev.
2007, 107, 5744–5758. (c) Terada, M. Synthesis 2010, 1929–1982. (d)
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(14) Zhu, C.; Akiyama, T. Synlett 2011, 1251–1254.
Org. Lett., Vol. 14, No. 13, 2012
3313

The kinetic isotope effect (kH/kD = 3.8) was observed in
the competitive reaction between H- and D-benzothiazo-
lines, which clearly implies that cleavage of the CÀH bond
is the rate-limiting step (Scheme 3).
Table 1. Optimization of Conditions for Asymmetric Deutera-
tion of Ketimine by Use of D-Benzothiazoline
Scheme 3. Competition Experiment between H- and D-Ben-
zothiazolines
yield of
4a/%a
ee of
4a/%b
yield of
5/%a
entry
time/h
1
32
28
42
26
45
98
97
97
98
21
15
22
0
2c
3d
4e
50
44
quant
a Isolated yield. b Determined by HPLC analysis on a chiral station-
ary phase using Daicel Chiralcel OD-H column. c MgSO4 was added.
d At 70 °C. e MS 5 A was added.
We propose the reaction mechanism shown in Figure 3.
Phosphoric acid activates ketimine as a Brønsted acid, and
phosphoryl oxygen forms a hydrogen bond with NÀH of
benzothiazoline. Then, the D-atom attacks ketimine as a
deuteride.
Table 2. Asymmetric Deuteration of Ketimines 2 by Use of
D-Benzothiazoline 3a
entry
Ar
time/h
yield/%a
ee/%b
1
2
3
4
5
6
7c
8
Ph
26
24
24
24
20
26
25
20
quant
90
98
98
98
97
98
97
95
97
2-naphthyl
p-tolyl
93
p-MeOC6H4
p-FC6H4
91
71
p-ClC6H4
p-NO2C6H4
m-NO2C6H4
97
Figure 3. Proposed reaction mechanism.
77
84
An acetal exchange between ketimine and D-benzothi-
azoline and a subsequent deuteride reduction proceeded to
give 5 as the byproduct. We investigated this deuteride
reduction in an effort to improve the yield of R-deuterated
amine 4a by suppressing the exchange reaction (Table 1).
Although the addition of a dehydrating reagent and the
increase in temperature were not effective in improving
the yields (entries 2 and 3), the addition of MS 5 A had a
beneficial effect, furnishing 4a quantitatively (entry 4).
With the optimized reaction conditions in hand, we
investigated the substrate scope of the reaction (Table 2).
We could obtain optically active R-deuterated amines in
high yields and with excellent enantioselectivities in all the
cases examined.
a Isolated yield. b Determined by HPLC analysis on a chiral station-
ary phase using Daicel Chiralcel OD-H column and Daicel Chiralpak
AD-H column. c MS 13 X was employed instead of MS 5 A.
Enantiomerically pure deuterated amine 4b could be
obtained by a single recrystallization from hexane. The
p-methoxyphenyl group of 4b was oxidatively cleaved by
trichloroisocyanuric acid (TCCA),15 and the adduct was
isolated as N-Boc amine 8 in good yield and in optically
pure form (Scheme 4).
The absolute configuration of deuterated R-aminoester
7a was determined to be (S) by X-ray crystallographic
analysis of 4-bromobenzoate 9 (Scheme 5).
As an application of the present methodology, deuter-
ated oxazolidinone 11 was prepared starting from 7a by
The deuteride reduction was successfully applied to
R-iminoesters (Table 3). 2-Deuterio-2-phenylbenzothiazo-
line proved to be the most effective hydrogen donor to give
corresponding R-amino R-aryl acetates with excellent
enantioselectivities.
(15) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.;
Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006,
47, 8109–8113.
3314
Org. Lett., Vol. 14, No. 13, 2012

Table 3. Asymmetric Deuteration of Iminoesters 6 by Use of
D-Benzothiazoline 3b
Scheme 5. Preparation of 4-Bromobenzoate 9
entry
Ar
time/h
yield/%a
ee/%b
1
Ph
4
94
97
97
96
94
99
97
93
92
90
2
2-naphthyl
p-tolyl
13
13
9
quant
91
Scheme 6. Transformation to Oxazolidinone Bearing Deuter-
ium Atom
3
4
p-MeOC6H4
o-FC6H4
96
5
4
96
6
m-FC6H4
p-FC6H4
5
77
7c
8d
9
15
3
81
p-NO2C6H4
2-thienyl
99
15
95
a Isolated yield. b Determined by HPLC analysis on a chiral station-
ary phase using Daicel Chiralcel OJ-H column and Daicel Chiralpak
AS-H, AD-H column. c Imine was generated in situ. d At 30 °C.
donor in combination with chiral phosphoric acid. The
large kinetic isotope effect (kH/kD = 3.8) indicates that
cleavage of the carbonÀdeuterium bond is the rate-
determining step.
Scheme 4. Deprotection of p-Methoxyphenyl Group on Nitro-
gen Atom
Acknowledgment. This work was partially supported by
a Grant-in Aid for Scientific Research on Innovative Areas
“Advanced Transformation by Organocatalysis” from the
Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan, and a Grant-in Aid for Scientific Research
from the Japan Society for the Promotion of Science.
Supporting Information Available. Experimental proce-
dures, characterization data, cif file of compound 9, and
copies of NMR and HPLC spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
LiAlH4 reduction followed by exposure to triphosgene
(Scheme 6).
In summary, we developed a novel method for the
transfer deuteration of ketimines with excellent enantio-
selectivities by use of benzothiazoline as the deuterium
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3315