Enantioselective Addition of a 2-Alkoxycarbonyl-1,3-dithiane to Imines Catalyzed by a Bis(guanidino)iminophosphorane Organosuperbase

Article abstract of DOI:10.1002/anie.201508178

A chiral bis(guanidino)iminophosphorane catalyzes enantioselective addition reactions of a 1,3-dithiane derivative as a pronucleophile. The chiral uncharged organosuperbase facilitates the addition of benzyloxycarbonyl-1,3-dithiane to aromatic N-Boc-protected imines to provide optically active α-amino-1,3-dithiane derivatives, which are valuable versatile building blocks in organic synthesis.

Full text of DOI:10.1002/anie.201508178

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201508178
German Edition: DOI: 10.1002/ange.201508178
Organocatalysis
Enantioselective Addition of a 2-Alkoxycarbonyl-1,3-dithiane to
Imines Catalyzed by a Bis(guanidino)iminophosphorane
Organosuperbase
Azusa Kondoh, Masafumi Oishi, Tadahiro Takeda, and Masahiro Terada*
Abstract: A chiral bis(guanidino)iminophosphorane catalyzes
enantioselective addition reactions of a 1,3-dithiane derivative
as a pronucleophile. The chiral uncharged organosuperbase
facilitates the addition of benzyloxycarbonyl-1,3-dithiane to
aromatic N-Boc-protected imines to provide optically active a-
amino-1,3-dithiane derivatives, which are valuable versatile
building blocks in organic synthesis.
compounds, imines, and Michael acceptors, furnishes the
corresponding protected carbonyl compounds. In general,
a
stoichiometric amount of a strong base, such as
n-butyllithium, is required for generating the dithiane anion
prior to the reaction with electrophiles. The direct addition
reaction using a catalytic amount of a Brønsted base is rather
limited because of the low acidity at the 2-position, even if it is
a to an electron-withdrawing group, such as an alkoxycar-
[
7–9]
I
n recent years, much attention has been paid to the
bonyl group.
rare.
In particular, enantioselective variants are
[
10]
development of chiral uncharged strong organobase catalysts
and their application in a variety of enantioselective reac-
We envisioned that the enantioselective addition
reaction of 2-alkoxycarbonyl-1,3-dithianes 2 as less acidic
pronucleophiles with imines 3 by using our newly developed
catalyst 1 would afford optically active a-amino-1,3-dithiane
derivatives, which are known as valuable versatile building
blocks (Scheme 1). Currently, the synthesis of those com-
pounds relies on the asymmetric addition of 2-lithio-1,3-
dithianes to chiral N-sulfinyl- and N-phosphoryl imines where
a stoichiometric amount of a Brønsted base as well as a chiral
[
1]
tions. Many efficient catalysts, such as chiral guanidines and
P1 phosphazenes, have been developed to date, and they have
enabled many useful transformations that cannot be achieved
with conventional chiral tertiary amine catalysts, including
[
2,3]
cinchona alkaloids.
However, the application of these
catalysts is still limited to pronucleophiles bearing a rather
acidic proton, such as 1,3-dicarbonyl compounds and nitro-
alkanes, because of their inherent basicity. Thus, the develop-
ment of much stronger organobases, namely chiral organo-
superbases, is desirable to overcome these intrinsic limitations
and to pave the way to enantioselective transformations that
have never been achieved before. Recently, we have devel-
oped novel chiral bis(guanidino)iminophosphorane 1 as
a chiral uncharged organosuperbase catalyst that facilitates
[11,12]
auxiliary are required.
We herein report the realization of
the catalytic enantioselective addition reaction of 1,3-dithiane
derivatives to aromatic imines by using a chiral bis(guanidi-
no)iminophosphorane organosuperbase catalyst.
[4]
the activation of less acidic pronucleophiles. Its usability was
demonstrated in the enantioselective amination of 2-alkyl-
tetralone derivatives as less acidic pronucleophiles. To extend
the utility of the newly developed catalyst, particularly in
synthetically useful transformations, we focused our attention
on 2-alkoxycarbonyl-1,3-dithiane 2 as a less acidic pronucleo-
phile. The addition reaction of 1,3-dithianes is one of the most
[
5,6]
important umpolung reactions in organic synthesis.
The
Scheme 1. Enantioselective addition of 2-alkoxycarbonyl-1,3-dithianes
to imines catalyzed by (M)-1. PG=protecting group.
anion of 1,3-dithiane is regarded as an acyl anion equivalent,
and its reaction with various electrophiles, such as carbonyl
We began our investigation by evaluating the reaction of
2-benzyloxycarbonyl-1,3-dithiane (2a) as a pronucleophile
with N-Boc imine 3a. The catalyst was generated in situ by
treating (M)-1·HX, which possesses helical chirality because
of the spirocyclic structure and the central chirality of the
[
*] Dr. A. Kondoh, Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
M. Oishi, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University
(
(
1S,2S)-1,2-diphenyl-1,2-ethanediamine unit, with NaN-
SiMe ) prior to use. An initial attempt was made by reacting
3
2
1
1 mol% of (M)-1a·HBr with 10 mol% of NaN(SiMe ) in
3 2
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
toluene at À408C. As a result, the desired adduct 4a was
obtained in moderate yield, but with only 3% ee (Table 1,
entry 1). Replacing the solvent with an ethereal solvent, such
as THF or diethyl ether, improved the chemical yield, but the
enantioselectivity was still low (entries 2 and 3). The solvent
T. Takeda
Process Technology Research Laboratories, Daiichi Sankyo Co., Ltd
Edogawa-ku, Tokyo 134-8630 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508178.
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[
a]
[a]
Table 1: Initial screening.
Table 2: Imine scope.
[b]
[c]
Entry
1·HX
Inorganic
base
Solvent
Time
[h]
Yield
[%]
ee
[
b]
[%]
1
2
3
4
5
6
7
8
1a·HBr
1a·HBr
1a·HBr
1a·HBr
1b·HCl
1b·HCl
1b·HCl
1b·HCl
1b·HCl
1b·HCl
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
LiN(SiMe3)2
KN(SiMe3)2
tBuONa
toluene
THF
24
2
24
1
41
92
93
94
98
40
42
56
96
93
3
18
13
97
99
24
25
56
98
97
Et O
2
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
1
24
24
24
2
[
[
d]
e]
9
0
NaN(SiMe3)2
NaN(SiMe3)2
1
1
[
(
a] Reaction conditions: 2a (0.10 mmol), 3a (0.12 mmol), (M)-1·HX
0.011 mmol), inorganic base (0.010 mmol), solvent (0.50 mL), À408C.
[a] Reaction conditions: 2a (0.10 mmol), 3 (0.12 mmol), (M)-1b·HCl
(0.011 mmol), NaN(SiMe
[b] Conducted at À608C. [c] 1.0 mL of EtOAc.
[
b] Yields of isolated products. [c] The ee values were determined by
HPLC analysis on a chiral stationary phase. [d] 0.015 mmol of 1b·HCl
15 mol%) and 0.010 mmol of NaN(SiMe ) (10 mol%). [e] 0.010 mmol
3
)
2
(0.010 mmol), EtOAc (0.50 mL), À408C.
(
3
2
of 1b·HCl (10 mol%) and 0.020 mmol of NaN(SiMe ) (20 mol%).
3
2
Boc=tert-butoxycarbonyl.
effect became evident when ethyl acetate was employed
entry 4). The reaction reached completion within one hour,
(
and the product was obtained in high yield with excellent
enantioselectivity. Further improvement of both chemical
yield and the ee value was achieved by using (M)-1b·HCl as
the precatalyst (entry 5). The choice of the inorganic base for
the generation of the catalyst from precatalyst 1·HX was
found to be critical (entries 5–8). The use of LiN(SiMe ) ,
3
2
Scheme 2. Derivatization of (S)-4a. Reagents and conditions:
KN(SiMe ) , and tBuONa resulted in lower yields with lower
3
2
a) NaBH (10.0 equiv), THF/MeOH, 08C to RT, 14 h, 92%, 94% ee;
4
enantioselectivity. This is presumably due to the detrimental
effects of LiCl, KCl, and tBuOH, which are generated during
the catalyst activation in situ. Whereas in our previous report,
the use of excess inorganic base relative to precatalyst 1·HX
b) 47% HBr (aq.), MeOH, 408C, 2 h; c) TBSCl (1.5 equiv), imidazole
(
5.0 equiv), CH Cl , RT, 6 h, 91% (over 2 steps), 95% ee; d) TsCl
2 2
(
1.5 equiv), Et N (5.0 equiv), DMAP (50 mol%), CH Cl , RT, 6 h, 92%,
3
2
2
9
5% ee; e) NIS (8.0 equiv), acetone/H O, 08C, 10 min; f) NaBH4
2
[
4]
was essential to achieve high yields, the use of a slight excess
(6.0 equiv), THF, À788C, 1 h, 89% (over 2 steps), 91:9 d.r., 94/95%
ee. DMAP=dimethylaminopyridine, NIS=N-iodosuccinimide,
TBS=tert-butyldimethylsilyl, Ts =para-toluenesulfonyl.
of 1·HX relative to NaN(SiMe ) was optimal in the present
3
2
reaction (entries 5, 9, and 10). The absolute configuration of
product 4a was unambiguously determined to be S by single-
[
13]
crystal X-ray diffraction analysis.
With the optimized conditions in hand, the scope of
imines was investigated (Table 2). At first, ortho-, meta-, and
para-tolyl imines were tested, and the corresponding products
Finally, the derivatization of the product, including the
conversion of the 1,3-dithiane moiety into a ketone group,
was attempted (Scheme 2). The reduction of the benzyl ester
4
b–4d were obtained in high yields with high enantioselec-
moiety of (S)-4a into a hydroxy group with NaBH as the
4
tivities. Imines with an electron-donating group, such as
a methoxy group, or an electron-withdrawing group, such as
a chloro or a bromo group, at the para position of the benzene
ring underwent the reaction smoothly to provide products
reducing agent yielded (S)-5. After protecting the primary
hydroxy group with a TBS group, removal of the 1,3-dithiane
moiety was investigated. However, all attempts failed because
of the incompatibility of the N-Boc-protected amino moiety
with the conditions. Therefore, we decided to convert the
protecting group on the nitrogen atom into a tosyl group prior
to the 1,3-dithiane deprotection. Cleavage of the Boc group
under acidic conditions followed by chemoselective protec-
tion of the primary hydroxy group with TBSCl provided
primary amine (S)-6 in high yield. Tosylation of the amino
group proceeded smoothly to afford (S)-7. The conversion of
the 1,3-dithiane moiety of (S)-7 was achieved by treatment
4
e–4g in high yields with high enantioselectivities. The
reaction of 2-naphthyl imine proceeded without any prob-
lems, whereas the reaction of 1-naphthyl imine resulted in
moderate enantioselectivity. Heteroaromatic imines were
also applicable to this reaction. 2-Furyl and 2-thienyl imines
were compatible with the reaction conditions and afforded
the corresponding products 4j and 4k, respectively, in high
[14,15]
yields and with high enantioselectivity.
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Angewandte
Communications
with an excess amount of NIS in acetone/H O. Finally, the
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2
reduction of the resulting keto moiety with NaBH proceeded
4
[
in a diastereoselective manner to afford 3-amino-1,2-diol 9 in
[
16]
high yield. In the course of the derivatization, the optical
purity was not reduced.
1
537 – 1547; b) D. Uraguchi, S. Nakamura, H. Sasaki, Y. Kona-
In conclusion, we have developed a catalytic enantiose-
lective addition reaction of a 1,3-dithiane derivative as a less
acidic pronucleophile by using a chiral bis(guanidino)imino-
phosphorane organosuperbase catalyst. The addition of
benzyloxycarbonyl-1,3-dithiane to N-Boc-protected aromatic
imines proceeded in a highly enantioselective manner to
provide optically active a-amino-1,3-dithiane derivatives,
which are valuable versatile building blocks in organic
synthesis. Ongoing studies are focused on the development
of novel enantioselective transformations using chiral bis-
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Experimental Section
The reaction of 2a with 3a as a representative example: (M)-1b·HCl
2
(
8.1 mg, 0.011 mmol) was placed in a dried test tube and suspended in
EtOAc (1.0 mL), and the solvent was evaporated once. EtOAc
0.50 mL) was added again, and the resulting suspension was
2
(
Am. Chem. Soc. 2011, 133, 5695 – 5697.
degassed under reduced pressure. A solution of NaN(SiMe3)2 in
THF (1.9m, 5.3 mL, 0.010 mmol) was added to the suspension at room
temperature. After stirring for ca. 1 min, 1,3-dithiane 2a (25 mg,
[
[
4] a) T. Takeda, M. Terada, J. Am. Chem. Soc. 2013, 135, 15306 –
1
1
5309; b) T. Takeda, M. Terada, Aust. J. Chem. 2014, 67, 1124 –
128.
0
.10 mmol) was added, and the mixture was stirred for ca. 1 min. The
solution was then cooled to À408C, and N-Boc imine 3a (25 mg,
.12 mmol) was added. The resulting mixture was stirred at that
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aqueous NH Cl solution (ca. 0.50 mL). The aqueous phase was
4
extracted with EtOAc. The combined organic phase was dried over
Na SO and evaporated. The residue was purified by column
2
4
3
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(
[
[
[
[
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Acknowledgements
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65 – 377.
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas, “Advanced Molec-
ular Transformations by Organocatalysts”, from MEXT
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Keywords: asymmetric catalysis · 1,3-dithianes ·
organocatalysis · organosuperbases · phosphazenes
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15836–15839
Angew. Chem. 2015, 127, 16062–16065
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a (trifluoroethylthio)carbonyl
group. In this report, the reaction of 2-ethoxycarbonyl-1,3-
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reaction occurred because of the low acidity of the pronucleo-
1
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[14] Aliphatic imines were also examined. However, the reactions
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Received: September 1, 2015
Published online: October 20, 2015
5
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