Development of a chiral bis(guanidino)iminophosphorane as an uncharged organosuperbase for the enantioselective amination of ketones

Article abstract of DOI:10.1021/ja408296h

Chiral bis(guanidino)iminophosphoranes were designed and synthesized as chiral uncharged organosuperbase catalysts that facilitate activation of less-acidic pro-nucleophiles. The newly developed bis(guanidino) iminophosphoranes, which possess the highest basicity among chiral organocatalysts reported to date, were proven to be a superb class of chiral organosuperbases by reaction of azodicarboxylates with 2-alkyltetralones and their analogues as the less acidic pro-nucleophiles.

Full text of DOI:10.1021/ja408296h

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Communication
Development of a Chiral Bis(guanidino)iminophosphorane as an Uncharged
Organosuperbase for the Enantioselective Amination of Ketones
Tadahiro Takeda, and Masahiro Terada
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Sep 2013
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Development of a Chiral Bis(guanidino)iminophosphorane as an Un-
charged Organosuperbase for the Enantioselective Amination of Ke-
tones
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Tadahiro Takeda,‡ Masahiro Terada*,†
†Department of Chemistry and Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku
University, Aoba-ku, Sendai 980-8578, Japan
‡Process Technology Research Laboratories, Daiichi Sankyo Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan
Supporting Information Placeholder
tral iminophosphorane core to enhance the basicity of the
ABSTRACT: Chiral bis(guanidino)iminophosphoranes were
iminophosphorane moiety, where the guanidine subunits
enable resonance extension to further stabilize the central
aminophosphonium cation generated through the deproto-
nation of a pro-nucleophile.5 It can be predicted that the
designed and synthesized as a chiral uncharged organo-
superbase catalyst that facilitates activation of less-acidic
pro-nucleophiles.
The
newly
developed
bis(guanidino)iminophosphorane which possesses the high-
est basicity among chiral organocatalysts reported to date
was proven to be a superb class of chiral organosuperbase by
the reaction of azodicarboxylates with 2-alkyl tetralones and
their analogues as the less acidic pro-nucleophiles.
newly
designed
pseudo
C2-symmetric
bis(guanidino)iminophosphoranes 1 allow to activate less
acidic pro-nucleophiles and open up a new avenue in enanti-
oselective catalysis using a chiral organosuperbase. Herein,
we
report
the
development
of
optically
pure
bis(guanidino)iminophosphoranes 1 as a superb class of chi-
ral organosuperbases for catalytic enantioselective transfor-
mation.
During the past decade, intensive interest has been devot-
ed to the development of chiral uncharged strong organo-
base catalysts.1 Among these reported organobase catalysts,
chiral guanidine and P1-phosphazene bases have emerged as
efficient enantioselective catalysts and tremendous progress
has been made in the development of a wide variety of enan-
tioselective reactions using these catalysts.2,3 However the
applications of these catalysts were limited to pro-
nucleophiles having a rather acidic proton, such as 1,3-
dicarbonyl compounds and nitroalkanes. They have been
seldom used for activation of less acidic pro-nucleophiles.
The development of much stronger chiral organobases is
highly demanded to overcome these intrinsic limitations. In
general, the basicity of the organobases increases with in-
creasing the resonance stability of their conjugate acids, the
protonated form of the organobases. For instance, introduc-
tion of phosphazene or guanidine subunit(s) to the imino-
phosphorane core stabilizes its conjugate acid, aminophos-
phonium cation, to afford a series of phosphazene organo-
superbases.4 However, the iminophosphoranes modified by
the additional phosphazene or guanidine subunits to develop
chiral organosuperbases have never been reported so far. We
Figure
1.
Structure
of
newly
designed
bis(guanidino)iminophosphorane catalyst in an optically
active form.
The characteristic feature of the newly designed
bis(guanidino)iminophosphorane catalysts 1 is underscored
by their helical chirality based on the 7,7-membered spirocy-
clic system. Since (1S,2S)-1,2-diphenyl-1,2-ethanediamine
((S,S)-DPEN) has been introduced to the catalyst molecule,
the central chirality of the DPEN combined with the helical
chirality of the spirocycle results in the formation of dia-
stereomeric catalysts. In fact, the two diastereomers of
bis(guanidino)iminophosphoranes 1a-d were formed with
moderate to high diastereoselectivity,6 when 1a-d were pre-
pared from commercially available (S,S)-DPEN in 4 steps and
then isolated as HCl or HBr salts. In this catalyst design, we
hence
designed
a
pseudo
C2-symmetric
bis(guanidino)iminophosphoranes 1 as a novel family of chi-
ral phosphazene organosuperbases (Figure 1). In this catalyst
design, two guanidine subunits were introduced to the cen-
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arranged the hydrogen bond donor and acceptor sites
ent assembly. In sharp contrast, in the crystalline state of
3
4
5
6
7
8
9
around the central phosphorous atom: the nitrogen atom of
the iminophosphorane moiety (N=P) functions as the hydro-
gen bond acceptor, while the N-H moiety attached to the
iminophosphorane core functions as the hydrogen bond do-
nor. Indeed, the side by side arrangement of the donor and
acceptor sites has been proven to be a fundamental approach
to designing efficient chiral organobase catalysts such as
chiral guanidines and P1-phosphasenes to achieve high enan-
tioselectivities.2
(P)-1a∙HCl obtained as the minor diastereomer, the C2-
symmetry was seriously impaired and the formation of two
hydrogen bonds to the chloride anion was also invalidated
(Figure 2b). Furthermore, conformation of the phenyl rings
of two DPENs was different in each DPEN unit: two phenyl
rings of one of two DPENs occupied the pseudo-equatorial
positions, while those of the other occupied pseudo-axial
positions presumably due to the relatively flexible 7-
membered ring spirocycle.
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At the outset of our studies, to gain a structural feature of
the newly designed chiral organosuperbases, a single-crystal
X-ray diffraction analysis of both diastereomeric HCl salts,
bis(guanidino)aminophosphonium 1a∙HCl (R = benzyl), was
conducted (Figure 2).7 As shown in Figure 2a, (M)-1a∙HCl,
Next, in order to validate the catalytic performance of
bis(guanidino)iminophosphoranes 1 as a chiral organosuper-
base, we selected an electrophilic amination of 2-
alkyltetralones 3 with azodicarboxylate 2 as an ideal probe on
the basis of the following considerations. In principle, the
activation of 2-alkyltetralones 3 as a nucleophile would be
difficult using conventional chiral organobase catalysts be-
cause of their low acidity and steric congestion at the reac-
tion site.8
The
results
are
shown
in
Table
1.
Bis(guanidino)iminophosphoranes 1 were generated in situ
from 1∙HX salts.9 Namely, the mixture of 1∙HX and tetralone
3 were treated with t-BuOK before the addition of azodicar-
boxylate 2. An initial attempt was performed using 10 mol%
of (M)-1a∙HCl with 10 mol% of t-BuOK at 0 °C. Fortunately,
the corresponding product 4a was obtained in fairly good
enantioselectivity (80% ee), albeit in low chemical yield (en-
try 1). The absolute configuration of product 4a was deter-
mined to be the (S)-form.10 On the basis of the X-ray crystal-
lographic analysis of 1a∙HCl (Figure 2), it could be predicted
that the helical chirality of 1 should be influential in the ste-
reochemical outcomes. As expected, (P)-1a∙HCl afforded 4a
in nearly racemic mixtures despite the excellent chemical
yield (entry 2). Further screening of the substituent intro-
duced at the cyclic guanidine units was continued using (M)-
1∙HX (entries 3-5). The introduction of sterically hindered
substituent such as benzhydryl and tert-butyl, giving (M)-
1b∙HCl and (M)-1c∙HCl, respectively, led to a slight increase
in the enantioselectivities (entries 3 and 4), albeit with a re-
duction of the chemical yield. (M)-1d∙HBr having the steri-
cally less hindered methyl substituent enhanced the enanti-
oselectivity, although the marked improvement was not de-
tected in the chemical yield (entry 5). In an effort to enhance
the chemical yield, we attempted to use an excess amount of
t-BuOK to (M)-1d∙HBr. It is noteworthy that the yield was
drastically improved without compromising the enantiose-
lectivity despite using excess t-BuOK (entry 6 and 7). How-
ever, a further increase in the amount of t-BuOK to 30 mol%
resulted in a slight decrease in ee (entry 8). As expected, the
reduction of the reaction temperature to -40 ºC enhanced the
enantioselectivity, but with a marked decrease in the yield
(entries 9 and 10). Interestingly, the yield was affected by the
counter cations of bases employed. NaN(SiMe3)2 was found
to be the superior base for this reaction (entry 11–13) and the
optimal reaction conditions were established as 10 mol% of
(M)-1d∙HBr and 20 mol% of NaN(SiMe3)2 in toluene at –
40 °C.11
Figure 2. ORTEP drawings of (a) (M)-1a∙HCl and (b) (P)-
1a∙HCl with probability ellipsoids drawn at the 50% level.
The solvent molecules and hydrogen atoms except N-H pro-
tons are omitted for clarity.
which was obtained as the major diastereomer, possesses
nearly the entire C2-symmetric structure. In addition, the
two N-H moieties attached at the central phosphorous atom
are arranged in approximately parallel to interact with the
chloride anion through two hydrogen bonds. It can be con-
sidered that these two N-H moieties would function as the
efficient hydrogen bond forming sites to direct the orienta-
tion of both a nucleophile and an electrophile in the transi-
Table 1. Electrophilic Amination of 2-Methyltetralone
with Azodicarboxylatea
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Table 2. Substrate Scopea
4
5
6
7
8
9
entry
1
1
base (mol%)
t-BuOK (10)
t-BuOK (10)
t-BuOK (10)
t-BuOK (10)
t-BuOK (10)
t-BuOK (15)
t-BuOK (20)
t-BuOK (30)
t-BuOK (15)
t-BuOK (20)
KN(SiMe3)2 (20)
T (°C) yield (%)b ee (%)c
(M)-1a
(P)-1a
(M)-1b
(M)-1c
(M)-1d
(M)-1d
(M)-1d
(M)-1d
(M)-1d
(M)-1d
(M)-1d
0
0
34
96
80
3
2
10
11
12
13
14
15
16
17
18
19
20
21
22
3
0
23
82
86
91
92
90
80
94
94
94
95
-
4
0
20
5
0
37
6
0
>99
98
7
0
8
0
97
9
–40
–40
–40
–40
–40
55
entry
1
3
3a
3b
3c
3c
3d
3e
3e
3f
4
4a
4b
4c
4c
4d
4e
4e
4f
T (°C)
–40
–40
–40
25
yield (%) b
>99 (97) d
ee (%) c
95 (97) d
96
10
11
12
13
66
53
(M)-1d NaN(SiMe3)2 (20)
(M)-1d LiN(SiMe3)2 (20)
>99
NR
2
98
3
18
90
23
24
a
Reactions were conducted with 1 equiv of 2 and 5 equiv of
3a in the presence of 10 mol% of 1∙HX and the indicated base
4
83
88
5
–40
–40
25
94
93
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b
in toluene (0.1 M) for 3 h under an argon atmosphere. Iso-
6
7
34
lated yield. c Determined by chiral stationary phase HPLC.
7
78
10
8
–40
–40
–40
–40
–40
–40
–40
–40
–40
–40
>99
>99
>99
77
93
With the Optimal reaction conditions in hand, the sub-
strate scope of this reaction was investigated (Table 2). The
positional effect of the methoxy substituent on the tetralone
aromatic ring was searched for thoroughly (entries 2–7).
Introduction of the substituent at either the 5- or 7-position
exhibited similarly to the unsubstituted tetralone in the
yields and enantioselectivities (entry 1 vs. entries 2 and 5).
Meanwhile, in the reaction of the 6- and 8-substituted tetra-
lones 3c and 3e, the higher temperature was required for
sufficient conversion (entries 3, 4, 6, and 7). More im-
portantly, the 8-substituted tetralone 3e showed much lower
enantioselectivity presumably due to the conformational
change in the ion pairs between protonated (M)-1d and eno-
late of 3e, where the methoxy group exists in close proximity
to the anionic oxygen atom of the enolate (entries 6 and 7).
The tetralones bearing electron withdrawing groups (3f and
3g) underwent the reaction with good yields and with a
slight decrease in enantioselectivities (entries 8 and 9). Next,
the structural effect on the cyclic ketones was examined.
Indanone (3h), benzosuberone (3i), chromanone (3j) and
thiochromanone (3k) derivatives are also useful substrates in
the present enantioselective amination, giving rise to the
corresponding products 4h-k in good to excellent yields
without marked reduction in the enantioselectivities (entry
10–13). A variety of alkyl substituents can be introduced to
the 2-position of the tetralone derivatives. Excellent enanti-
oselectivities were achieved in the reaction of tetralones 3l–n
(entry 14–16) in the exception of tetralone 3o having a coor-
dinatable substituent (Entry 17). It should be pointed out
that the reaction can be operated using 2.5 equiv of 3 without
compromising chemical yield and enantioselectivity (entry 1).
9
3g
3h
3i
4g
4h
4i
82
10
11
12
13
14
15
16
17
91
84
3j
4j
>99
>99
93
89
3k
3l
4k
4l
82
94
3m
3n
3o
4m
4n
4o
95
98
92
97
82
68
a Reactions were conducted with 1 equiv of 2 and 5 equiv of 3
in the presence of 10 mol% of (M)-1d∙HBr and 20 mol% of
NaN(SiMe3)2 (0.6 M toluene solution) in toluene (0.1 M) for 3
h under argon atmosphere. b Isolated yield. c Determined by
d
chiral stationary phase HPLC. In parenthesis, 2.5 eq. of 3a
was used.
In conclusion, we have developed novel chiral
bis(guanidino)iminophosphoranes as a superb class of the
uncharged chiral organosuperbase catalyst that facilitate the
reaction of less-acidic pro-nucleophiles, 2-alkyl tetralone
derivatives and their analogues, with azodicarboxylate. The
method provides efficient access to construct a quaternary
chiral center at the α-position of tetralone derivatives and
their analogues in a highly enantioselective manner. Further
studies are in progress to extend the range of applicable nu-
cleophiles and to discover catalytic enantioselective variants
of other processes.
ASSOCIATED CONTENT
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Fletschinger, M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.;
Supporting Information
Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von
Schnering, H. G.; Walz, L. Liebigs Ann. 1996, 1055. (d) Kaljurand, I.;
Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. J.
Org. Chem. 2005, 70, 1019. (e) Kolomeitsev, A. A.; Koppel, I. A.;
Rodima, T.; Barten, J.; Lork, E.; Röschenthaler, G.-V.; Kaljurand, I.;
Kütt, A.; Koppel, I.; Mäemets, V.; Leito, I. J. Am. Chem. Soc. 2005, 127,
17656.
Representative experimental procedures and spectral data for
bis(guanidino)iminophosphorane catalysts and the amina-
tion
products;
X-ray
crystallographic
data
for
bis(guanidino)iminophosphoranes and determination of the
configuration of product (CIF). This material is available free
of charge via the internet at http://pubs.acs.org.
(5) The pKa value of the achiral bis(guanidino)iminophosphorane
5
which had the similar backbone as newly designed
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AUTHOR INFORMATION
bis(guanidino)iminophosphorane catalysts 1 was reported to be 26.8
(in THF) (see reference 4e).
Corresponding Author
mterada@m.tohoku.ac.jp
ACKNOWLEDGMENT
(6) The diastereomeric ratio was roughly estimated ranging from
7:3 to 9:1 ((M)-form was major). The exact diastereomeric ratio
could not be determined because of the considerable amount of by-
products.
(7) The configurations of (M)-1d was also determined by a single-
crystal X-ray diffraction analysis of (M)-1d∙HBr. The configurations
of (M)-1b and (M)-1c were determined by the chemical shift of 31P
NMR spectra by analogy.
(8) For examples of the amination of activated tetralone deriva-
tives, see: (a) Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006,
137. (b) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128,
16044. (c) Liu, T.-Y.; Cui, H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-
Q.; Chen, Y.-C. Org. Lett. 2007, 9, 3671. (d) Jung, S. H.; Kim, D. Y.
Tetrahedron Lett. 2008, 49, 5527. (e) Kim, S. M.; Lee, J. H.; Kim, D. Y.
Synlett 2008, 2659. (f) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal,
V. H. Org. Lett. 2010, 12, 2028. (g) Zhao, Y.; Pan, Y.; Liu, H.; Yang, Y.;
Jiang, Z.; Tan, C.-H. Chem. Eur. J. 2011, 17, 3571. (h) Inokuma, T.;
Furukawa, T.; Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.; Matsuzaki,
K.; Takemoto, Y. Chem. Eur. J. 2011, 17, 10470.
(9) The neutralization of 1∙HX was conducted in accordance with
the Ooi’s procedure, see: Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am.
Chem. Soc. 2007, 129, 12392. The observation of free base form of
bis(guanidino)iminophosphorane (M)-1d was attempted by 31P NMR.
See supporting information for details.
This work was partially supported by a Grant-in-Aid for Sci-
entific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT, Japan and
a Grant-in-Aid for Scientific Research from the JSPS. We
gratefully acknowledge Dr. Eunsang Kwon (Analytical Center
for Giant Molecules, Tohoku University) and Mr. Shohei
Kawasaki (Daiichi Sankyo Co., Ltd.) for their kind support of
the X-ray crystallographic analysis.
REFERENCES
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bide, M.; López, R. Chem. Soc. Rev. 2009, 38, 632. (b) Superbases for
Organic Synthesis; Ishikawa, T., Ed.; John Wiley & Sons: Chippen-
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(2) For reviews on chiral guanidine and P1-phosphazene catalysis,
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134, 19370. (g) Wu, L.; Li, G.; Fu, Q.; Yu, L.; Tang, Z. Org. Biomol.
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(10) The absolute configuration of product 4a was determined by
the single-crystal X-ray diffraction analysis of the HBr salt of the
Boc-deprotected compound of 4a. See supporting information for
details.
(11) Applying (M,S)-6 (Ooi’s catalyst, see reference 2f and 9) in-
stead of (M)-1d∙HBr resulted in low yield (18% y, –57% ee) under the
same reaction conditions as table 1, entry 12.
(4) (a) Kondo, Y. In Superbases for Organic Synthesis; Ishikawa, T.,
Ed.; John Wiley & Sons: Chippenham, 2009; pp 145–185. (b) Schwe-
singer, R. Chimia 1985, 39, 269. (c) Schwesinger, R.; Schlemper, H.;
Hasenfratz, C.; Willaredt, J.; Dambacher, T.; Breuer, T.; Ottaway, C.;
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