Catalytic enantioselective hydrophosphonylation of ketimines using cinchona alkaloids

Article abstract of DOI:10.1021/ja908940e

(Chemical Equation Presented) Organocatalytic enantioselective hydrophosphonylation of ketimines using cinchona alkaloids and Na ₂CO₃ afforded products with high enantioselectivity. Both enantiomers of α-amino phosphonates can be pre

Full text of DOI:10.1021/ja908940e

Published on Web 12/03/2009
Catalytic Enantioselective Hydrophosphonylation of Ketimines Using
Cinchona Alkaloids
Shuichi Nakamura,* Masashi Hayashi, Yuichi Hiramatsu, Norio Shibata, Yasuhiro Funahashi, and
Takeshi Toru
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, Japan
Received October 28, 2009; E-mail: snakamur@nitech.ac.jp
Table 1. Enantioselective Addition of Phosphites to Ketimines
Optically active R-amino phosphonic acids and their derivatives
1a-i Using Various Cinchona Alkaloids and Bases
are useful building blocks for the preparation of pharmaceutical
targets1 such as the antibacterial agent alafosfalin,2 anti-HIV agents,3
inhibitors of enzymes,4 and peptidic materials having unique
structural properties. The enantioselective addition of phosphite to
imines (Pudovik reaction) is certainly one of the most versatile
routes for the preparation of optically active R-amino phosphonic
acids. Although high enantioselectivity and chemical yield have
been achieved in the hydrophosphonylation of imines derived from
aldehydes,5 enantioselective addition of phosphite to imines derived
entry
1
catalyst
R2
time (h)
2
yield (%)
ee (%)a
from ketones (ketimines) is still challenging because of their lower
reactivity and difficulty in enantiofacial discrimination.6 To improve
the bioactivity, stability, and utility of R-amino phosphonic acids,
the asymmetric synthesis of optically active quaternary R-amino
phosphonic acids is a significant objective. However, to date there
are no reports of the enantioselective hydrophosphonylation of
ketimines.7 Recently, we reported the first organocatalytic enan-
tiocomplementary hydrophosphonylation of N-sulfonylimines de-
rived from aldehydes catalyzed by commercially available pseu-
doenantiomeric cinchona alkaloids.8 We herein report the first
catalytic enantioselective hydrophosphonylation of ketimines using
cinchona alkaloids and a base.
1
2
3
4
5
6
7
8
1a quinine
1b quinine
1c quinine
1d quinine
1e quinine
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
36
36
24
12
36
60
20
20
36
14
27
60
60
60
60
60
60
60
68
19
19
72
68
63
2a
2b
2c
2d
2e
2f
2g
2h
2i
2e
2e
2e
2e
2e
2e
2e
2e
2e
-
-
9
52
89
78
9
81
94
73
-
89
86
88
63
68
99
99
72
-
-
15
21
31
59
40
43
33
59
-
86
90
-91
-58
61
97
-92
14
-
61
-
97
1f
quinine
1g quinine
1h quinine
9
1i
quinine
10b
11c
1e quinine
1e quinine
1e quinine
1e quinidine
1e cinconine
1e cinconidine
1e hydroquinine
1e hydroquinidine Ph
1e (DHQ)2PYR Ph
12c d
,
13c d
,
14c d
,
15c d
,
The enantioselective hydrophosphonylation reaction of various
ketimines with diphenyl phosphite (3.0 equiv) was carried out using
10 mol % catalyst loading of a variety of cinchona alkaloids along
with K2CO3 (1.0 equiv) (Table 1). Although the reactions of
N-acetyl- and N-diarylphosphonylketimines (1a-c) with diphenyl
phosphite using quinine did not afford good results, the reaction
of N-tosyl ketimine (1d) afforded the product 2d in good yield with
31% ee (entries 1-4). After the optimization of various substituents
on the nitrogen in the sulfonylimine, the 2,4,6-trimethylphenyl group
was found to be the best substitution to obtain high yield and high
enantioselectivity (entries 5-9). When the reaction was carried out
without a base such as K2CO3, the reaction did not proceed (entry
10). Switching the base from K2CO3 to Na2CO3 enhanced the
enantioselectivity (entry 5 vs 11). The enantioselectivity was
improved when the reaction was performed at -20 °C, although
the reactivity was lowered (entry 12). In optimization experiments
using various cinchona alkaloids in the reaction of 1e, a reaction
with hydroquinine and hydroquinidine was found to afford the two
enantiomers of 2e with high enantioselectivity (entries 12-18). The
reaction with a dialkyl phosphite, such as diethyl or dibenzyl
phosphite, did not afford good results (entries 19 and 20).9 The
reaction of 1e with diphenyl tert-butyldimethylsilylphosphite [TB-
SOP(OPh)2] instead of diphenyl phosphite did not afford any
product (entry 21). Importantly, lowering the catalyst loading to 2
and 0.5 mol % (entries 22 and 23), the latter of which represents
the lowest catalyst loading employed in the asymmetric hydro-
phosphonylation of imine, resulted in no significant loss of
16c d
,
17c d
,
18c d
,
19c
1e hydroquinidine Et
1e hydroquinidine Bn
20c
2j
-
2e
2e
2e
95
-
99
99
89
21c d e 1e hydroquinine
Ph
Ph
Ph
Ph
,
,
22c d f
1e hydroquinine
,
,
23c d g 1e hydroquinine
95
96
,
,
24c d h 1e hydroquinine
,
,
a Determined by HPLC analysis. b Without K2CO3. c Using Na2CO3
(1.5 equiv) instead of K2CO3. d The reaction was carried out at -20 °C.
e Using TBSOP(OPh)2 as a phosphite. f Using 2 mol % catalyst. g Using
0.5 mol % catalyst. h Under aerobic conditions.
enantioselectivity or yield. The reaction under aerobic conditions
also afforded 2e in high yield with good enantioselectivity (entry
24).
With these optimized conditions, the reactions of a series of
ketimines with diphenyl phosphite using hydroquinine or hydro-
quinidine were examined (Table 2). The reaction of ketimines
derived from substituted acetophenone using hydroquinine afforded
products 3-10 in high yield with high enantioselectivity (entries
1-9). Although the reaction of ketimine 1r derived from 4-phenyl-
2-butanone afforded product 11 with moderate enantioselectivity,
the reactions of ketimine 1s derived from the dialkyl ketone
1-cyclohexylethanone and ketimine 1t derived from ethyl phenyl
ketone also afforded the corresponding products 12 and 13 with a
good level of enantioselectivity (entries 10-12). The reaction of a
9
18240 J. AM. CHEM. SOC. 2009, 131, 18240–18241
10.1021/ja908940e  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Hydrophosphonylation of Ketimines 1e
and 1j-u Using Hydroquinine or Hydroquinidine
factor in the activation of phosphites. Therefore, the nitrogen in
cinchona alkaloids as a Brønsted base would activate the nucleo-
philicity of sodium phosphite by coordination with sodium ion. On
the other hand, protection of the hydroxyl group in hydroquinine
also did not give a good result (Table 1, entry 18). This result
implies that hydrogen bonding between the cinchona alkaloid
hydroxyl group and the ketimine plays a key role in exerting
enantioselectivity. Therefore, cinchona alkaloids act as dual-
activating organocatalysts. From the above considerations, Figure
1 shows a proposed transition state for the enantioselective
hydrophosphonylation using hydroquinine.
entry
1
R1
R2
cat.
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1e
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
Ph
p-tolyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
(S)-2e
(S)-3
(S)-4
(S)-5
(S)-6
(S)-7
(S)-8
(S)-9
(S)-10
(S)-11
(S)-12
(S)-13
(S)-14
(R)-2e
(R)-3
(R)-4
(R)-5
(R)-6
(R)-7
(R)-8
(R)-9
(R)-10
(R)-11
(R)-12
(R)-13
(R)-14
99
97
99
99
98
99
99
99
99
98
97
96
93
99
90
91
99
99
99
99
98
91
97
86
92
86
97
96
97
94
93
97
94
94
96
55
75
97
89
92
92
94
95
92
88
90
91
93
52
80
92
82
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
m-ClC6H4
m-BrC6H4
2-naphthyl
PhCH2CH2
cyclohexyl
Ph
9
10
11
12
13
14
15
16
17a
18a
19a
1t
1u
1e
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1-indanone
Ph
p-tolyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Figure 1. Proposed transition state for the hydrophosphonylation of 1e
using hydroquinine.
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
m-ClC6H4
m-BrC6H4
2-naphthyl
PhCH2CH2
cyclohexyl
Ph
In conclusion, we have provided the first catalytic enantioselec-
tive hydrophosphonylations of ketimines using commercially avail-
able cinchona alkaloids. This approach provides direct access to
both enantiomers of optically active quaternary R-amino phosphonic
acids with satisfactory yields and enantioselectivities.
20a b
,
21a b
,
22
23
24
25
26
Acknowledgment. This work was supported by the Tatematsu
Foundation.
1t
1u
1-indanone
a Using 10 mol % catalyst. b The reaction was carried out at -40 °C.
Supporting Information Available: Experimental procedures and
characterization data, including the X-ray crystal structure of (S)-5
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
cyclic ketimine 1u derived from 1-indanone afforded 14 in high
yield with good enantioselectivity (entry 13). Furthermore, the
reaction using hydroquinidine instead of hydroquinine afforded the
opposite enantiomers of products 3-14 with high enantioselectivity
(entries 14-26). Since most of the products were crystalline,
enantiomerically pure products were easily to obtain by single
recrystallization. For example, recrystallization of 92% ee (R)-3
from hexane/ethyl acetate afforded enantiomerically pure (R)-3
(entry 15). To the best of our knowledge, these results are the first
examples of catalytic enantioselective C-heteroatom bond forma-
tion involving ketimines.
References
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in trifluoroacetic acid (TFA)/anisole at room temperature to give
chiral R-amino phosphonate (S)-15 (Scheme 1).
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Scheme 1. Desulfonylation of (S)-2e
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M.; Kanai, M. Chem. ReV. 2008, 108, 2853. (b) Bella, M.; Gasperi, T.
Synthesis 2009, 1583, and references therein.
(7) For diastereoselective addition of lithiated phosphonates to chiral N-
sulfinylketimines, see: (a) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org.
Lett. 2001, 3, 1757. (b) Chen, Q.; Yuan, C. Synthesis 2007, 3779.
(8) Nakamura, S.; Nakashima, H.; Yamamura, A.; Shibata, N.; Toru, T. AdV.
Synth. Catal. 2008, 350, 1209. We also reported the enantioselective reaction
of N-sulfonylimines. See: (a) Nakamura, S.; Nakashima, H.; Sugimoto, H.;
Sano, H.; Hattori, M.; Shibata, N.; Toru, T. Chem.sEur. J. 2008, 14, 2145.
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2009, 1639.
The enantioselective hydrophosphonylation of 1e with diphenyl
phosphite gave products in good yield with good enantioselectivity,
although the reaction with TBSOP(OPh)2 did not afford product
2e (Table 1, entry 21). Furthermore, the reaction without a base
also did not afford a product (Table 1, entry 10). These results
show that the formation of the sodium salt of phosphite is a key
(9) The acidic proton in diethyl phosphite could not be removed by Na2CO3.
JA908940E
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