Enantioselective 1,4-addition reactions of diphenyl phosphite to nitroalkenes catalyzed by an axially chiral guanidine

Article abstract of DOI:10.1021/ja0746619

A highly enantioselective 1,4-addition reaction of nitroalkenes with diphenyl phosphite was successfully accomplished using a newly developed axially chiral guainidine catalyst. A broad range of nitroalkenes, bearing not only aromatic but also aliphatic s

Full text of DOI:10.1021/ja0746619

Published on Web 10/26/2007
Enantioselective 1,4-Addition Reactions of Diphenyl Phosphite to
Nitroalkenes Catalyzed by an Axially Chiral Guanidine
Masahiro Terada,* Takashi Ikehara, and Hitoshi Ube
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received June 25, 2007; E-mail: mterada@mail.tains.tohoku.ac.jp
Table 1. Enantioselective 1,4-Addition Reaction of Nitroalkene
Optically active R- and â-amino phosphonic acids and their
(2a: R ) Ph) with Diphenyl Phosphite (3) Catalyzed by (R)-1a
phosphonate esters are an attractive class of compounds owing to
their potent biological activities as non-proteinogenic analogues of
R- and â-amino acids.1,2 Although several excellent methods for
enantioselective synthesis of R-amino phosphonate esters have been
established,3 using either metal-based catalysts or organocatalysts,4
asymmetric synthesis of â-amino phosphonate derivatives has been
largely unexplored, despite the intriguing therapeutic action of these
compounds.2 In this context, it is considered that asymmetric 1,4-
addition reaction of dialkyl phosphites to nitroalkenes5,6 provides
a practical route to the â-amino phosphonates, which can be
transformed from the corresponding 1,4-addition products,7 â-nitro
phosphonates, through simple reduction of the nitro group. The
development of catalytic enantioselective 1,4-addition reaction of
nitroalkenes with disubstituted phosphites is hence a substantial
step toward the synthesis of enantioenriched â-amino phospho-
nates.8 Recently, we successfully developed novel axially chiral
guanidines (1)9 as highly efficient Brønsted base catalysts for
promotion of enantioselective transformations10 via deprotonation
of 1,3-dicarbonyl compounds. Herein, we report the first highly
enantioselective 1,4-addition reaction of nitroalkenes (2) with
diphenyl phosphite (3) catalyzed by axially chiral guanidines (1)
(eq 1). The guanidine catalyst (1) successfully activated the
phosphorus nucleophile and enabled high enantioselectivity and
catalytic efficiency for a broad range of nitroalkenes bearing
aromatic or aliphatic substituents.
entry
1 (mol %)
solvent
temp
time
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
1a (5)
1b (5)
1c (5)
1d (5)
1e (5)
1d (5)
1d (5)
1d (5)
1d (5)
1e (5)
1e (1)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
i-Pr2O
CPMEc
t-BuOMe
t-BuOMe
t-BuOMe
0 °C
0 °C
0 °C
0 °C
0 °C
4 h
66
70
58
98
>98
91
92
81
>98
>98
94
6
16
43
83
79
87
86
86
92
92
92
20 min
20 min
10 min
10 min
30 min
2 h
4 h
1 h
10 min
2 h
-40 °C
-40 °C
-40 °C
-40 °C
-40 °C
-40 °C
10
11d
a Unless otherwise noted, all reactions were carried out using 0.0025
mmol of (R)-1 (5 mol %), 0.05 mmol of 2a, and 0.075 mmol of 3 (1.5
equiv) in 0.25 mL of indicated solvent in the presence of MS 4A (20 mg).
b Enantiomeric excess was determined by chiral HPLC analysis (see
Supporting Information for details). c Cyclopentyl methyl ether. d The
reaction was carried out using 0.002 mmol of (R)-1e (1 mol %), 0.2 mmol
of 2a, and 0.22 mmol of 3 (1.1 equiv) in 1.0 mL of tert-butyl methyl ether
in the presence of MS 4A (80 mg).
1-5). The enantioselectivity increased step by step with an increase
in the steric size of the alkyl moiety G (entries 1-3). The
introduction of 3,5-substituents to the phenyl ring of the Ar
substituents was the most effective in enhancing both the enanti-
oselectivity and catalytic efficiency (entries 4 and 5); the reaction
was completed within 10 min with a marked increase in enanti-
oselectivity relative to the catalyst (1c) having the unsubstituted
Ar group, regardless of the electronic properties of the Ar
substituents. As expected, lowering the temperature to -40 °C
resulted in an enhanced enantioselectivity (entry 6). Further
screening of ethereal solvents using (R)-1d revealed that tert-butyl
methyl ether was the best solvent among those examined (entries
6-9). Thus catalysis by (R)-1e was reinvestigated in tert-butyl
methyl ether. As a result, it was found that 2a was consumed
completely within 10 min even at -40 °C, while the enantiose-
lectivity was as high as that observed in catalysis by (R)-1d (entry
10 vs 9). The catalytic activity of (R)-1e is prominent; the catalyst
loading can be reduced from 5 to 1 mol % without any loss in
enantioselectivity (entry 10 vs 11).
With the optimized reaction conditions in hand, we then
investigated the scope of the enantioselective 1,4-addition reaction
using (R)-1e as a promising catalyst. As shown in Table 2, a broad
range of nitroalkenes (2) is applicable to the present transformation.
A series of nitroalkenes (2b-g) bearing aromatic substituents with
various electronic properties all proved to be excellent substrates
with respect to enantioselectivity and chemical yield (entries 1-6).
The reaction proceeded smoothly in the presence of 1 mol %
catalyst, giving the corresponding product (4b-g) in nearly
quantitative yield with high enantioselectivity. In contrast, het-
eroaromatic-substituted nitroalkenes (2h and i) gave the products
(4h and i) in modest yield (around 50%) under the optimized
During the course of our studies, enantioselective catalysis of
the 1,4-addition reactions of 2 with 3 were reported by Wang and
co-workers.11 In their report, moderate to high enantioselectivities
were attained through extensive screening of cinchona alkaloid
derivatives,12 which have been widely utilized as efficient orga-
nocatalysts. In our approach, we explored suitable substituents on
the axially chiral guanidine catalyst (1) by changing the alkyl moiety
G and the Ar group. An initial screening was performed in the
reaction of â-nitrostyrene (2a: R ) Ph) with diphenyl phosphite
(3) using 5 mol % of 1 in diethyl ether at 0 °C in the presence of
molecular sieves (MS) 4A.13 As shown in Table 1, it is noteworthy
that G and Ar substituents exhibited a strong impact not only on
the enantioselectivity but also on the catalytic efficiency (entries
9
14112
J. AM. CHEM. SOC. 2007, 129, 14112-14113
10.1021/ja0746619 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective 1,4-addition of Various Nitroalkenes (2)
with 3 Catalyzed by (R)-1e (1 mol %)a
and 1,4-addition products (4). This material is available free of charge
via the Internet at http://pubs.acs.org.
entry
2
4
time (h)
yield (%)b
ee (%)c
References
1
2
3
4
5
2b: 4-MeOC6H4-
2c: 4-BrC6H4-
2d: 2-MeOC6H4-
2e: 2-BrC6H4-
2f: 2-NO2C6H4-
2g: R-naphthyl
2h: 2-furyl
4b
4c
4d
4e
4f
4g
4h
4i
4.5
1
3
0.5
0.5
0.5
7
4.5
0.5
1
91
97
>98
98
96
>98
79
86
84
87
>98
91
91
88
94
97
94
89
91
80
85
87
(1) For reviews of the biological activity of R-amino phosphonic acids, see:
(a) Hiratake, J.; Oda, J. Biosci., Biotechnol., Biochem. 1997, 61, 211-
218. (b) Aminophosphonic and Aminophosphinic Acids; Kukhar, V. P.;
Hudson, H. R., Eds.; John Wiley & Sons: New York, 2000.
(2) For reviews of â-amino phosphonic acids, see: (a) Palacios, F.; Alonso,
C.; de los Santos, J. M. Chem. ReV. 2005, 105, 899-931. (b) Palacios,
F.; Alonso, C.; de los Santos, J. M. In EnantioselectiVe Synthesis of
â-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley: New
York, 2005; pp 277-317.
6
7d
8d
9e
10e
11
2i: thiophen-2-yl
2j: (CH3)2CHCH2-
2k: c-C6H11-
(3) For a review of enantioselective synthesis of R-amino phosphonate
derivatives, see: Ma, J.-A. Chem. Soc. ReV. 2006, 35, 630-636.
(4) For general reviews of organocatalysts, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138-5175. (b) Berkessel, A.; Gro¨ger,
H. Asymmetric Organocatalysis-From Biomimetic Concepts to Powerful
Methods for Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany,
2005. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 1520-1543.
4j
4k
4l
2l: CH3(CH2)4-
6
a Unless otherwise noted, all reactions were carried out using 0.002 mmol
of (R)-1e (1 mol %), 0.2 mmol of 2, and 0.22 mmol of 3 (1.1 equiv) in the
presence of MS 4A (80 mg) in 1.0 mL of tert-butyl methyl ether at -40
°C. b Isolated yield. c Enantiomeric excess was determined by chiral HPLC
analysis. Absolute configuration was determined to be S for 4i (see
Supporting Information for details). d The reaction was carried out using
0.01 mmol of (R)-1e (5 mol %) at -60 °C. e The reaction was carried out
using 0.01 mmol of (R)-1e (5 mol %).
(5) For a review of 1,4-addition reaction of phosphorus nucleophiles with
electron deficient alkenes, see: Enders, D.; Saint-Dizier, A.; Lannou, M.-
I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29-49.
(6) Asymmetric 1,4-addition reactions of nitroalkenes with dialkyl phosphites.
For chiral nitroalkenes, see: (a) Paulsen, H.; Greve, W. Chem. Ber. 1973,
103, 2114-2123. (b) Yamamoto, H.; Hanaya, T.; Kawamoto, H.; Inokawa,
S.; Yamashita, M.; Armour, M.-A.; Nakashima, T. T. J. Org. Chem. 1985,
50, 3516-3521. (c) Yamashita, M.; Sugiura, M.; Tamada, Y.; Oshikawa,
T.; Clardy, J. Chem. Lett. 1987, 1407-1408. For chiral dialkyl phosphites,
see: (d) Kolodiazhnyi, O. I.; Sheiko, S.; Grishkun, E. V. Heteroat. Chem.
2000, 11, 138-143. (e) Enders, D.; Tedeschi, L.; Bats, J. W. Angew.
Chem., Int. Ed. 2000, 39, 4605-4607. (f) Enders, D.; Tedeschi, L.; Fo¨rster,
D. Synthesis 2006, 1447-1460.
reaction conditions (1 mol % of (R)-1e, at -40 °C). This problem
could be circumvented by lowering the reaction temperature to
-60 °C and increasing the catalyst loading to 5 mol % (entries 7
and 8). Although aliphatic-substituted nitroalkenes (2j-l) exhibited
slightly lower enantioselectivities than those of their aromatic
counterparts (entries 9-11), their performance in the present
enantioselective reaction with diphenyl phosphite (3) is still good
taking into account their typically low reactivity in 1,4-addition
reactions; the corresponding products (4j-l) were obtained in high
chemical yield.
Finally, the reduction of the nitro group in 4a was examined
under modified nickel boride conditions (eq 2). The reduction was
readily accomplished in the presence of Boc2O to yield N-Boc
â-amino phosphonate (5) without compromising the integrity of
the stereogenic center.14
(7) For organocatalytic enantioselective hydrophosphination of electron
deficient alkenes, see: (a) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli,
M.; Mazzanti, A.; Sambri, L.; Melchiorre, P. Chem. Commun. 2007, 722-
724. (b) Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P.
Angew. Chem., Int. Ed. 2007, 46, 4504-4506. (c) Ibrahem, I.; Rios, R.;
Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Co´rdova, A. Angew.
Chem., Int. Ed. 2007, 46, 4507-4510. For 1,4-addition reaction of
nitoalkenes with dialkyl phosphites catalyzed by achiral guanidine
derivatives, see: (d) Jiang, Z.; Zhang, Y.; Ye, W.; Tan, C.-H. Tetrahedron
Lett. 2007, 48, 51-54.
(8) For enantioselective aminohydroxylation of R,â-unsaturated phosphonates,
see: (a) Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.;
Sisti, M. Tetrahedron: Asymmetry 1998, 9, 745-748. (b) Thomas, A.
A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379-8385. For enanti-
oselective Mannich reaction catalyzed by chiral copper complexes, see:
(c) Kjærsgaard, A.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 804-
808.
(9) (a) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454-
1455. (b) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128,
16044-16045.
(10) For a review of chiral guanidine catalysts, see: (a) Ishikawa, T.; Isobe,
T. Chem. Eur. J. 2002, 8, 552-557. For selected examples of enantiose-
lective catalysis by chiral guanidine derivatives, see: (b) Iyer, M. S.;
Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996,
118, 4910-4911. (c) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-
160. (d) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.;
Isobe, T. Chem. Commun. 2001, 245-246. (e) Kita, T.; Georgieva, A.;
Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem., Int. Ed. 2002,
41, 2832-2834. (f) Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.;
Thomas, D. A.; Caulkett, P. W. R. Tetrahedron Lett. 2003, 44, 8677-
8680. (g) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem.
2006, 2894-2897. (h) Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu,
X.; Xu, J.; Tan, C.-H. J. Am. Chem. Soc. 2006, 128, 13692-13693.
(11) Wang et al. reported that the 1,4-addition reaction of 2a with 3 catalyzed
by quinine (10 mol % catalyst, in xylenes at -55 °C for 6 days) afforded
the addition product (4a: R ) Ph) in 82% yield with 70% ee. See: Wang,
J.; Heikkinen, L. D.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Wang, W. AdV.
Synth. Catal. 2007, 349, 1052-1056.
In conclusion, we have demonstrated the highly enantioselective
1,4-addition reaction of nitroalkenes with diphenyl phosphite
catalyzed by a newly developed axially chiral guainidine. A broad
range of nitroalkenes, bearing not only aromatic but also aliphatic
substituents, is applicable to the present enantioselective reaction.
The method facilitates the highly enantioenriched synthesis of
â-amino phosphonate derivatives of biological and pharmaceutical
importance. Further studies utilizing the activation of phosphorus
nucleophiles by axially chiral guanidines are underway in our
laboratory.
(12) For a review of cinchona alkaloid derivatives as enantioselective orga-
nocatalysts, see: Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 7496-7504.
(13) MS 4A was employed as an acid scavenger to avoid deactivation of the
guanidine catalyst by acidic impurities which would be accidentally
generated via partial hydrolysis of diphenyl phosphite (3). The reaction
stopped in low conversion without MS 4A. For MS 4A as an acid
scavenger, see: (a) Weinstock, L. M.; Karady, S.; Roberts, F. E.;
Hoinowski, A. M.; Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.;
Sletzinger, M. Tetrahedron Lett. 1975, 46, 3979-3982. (b) Terada, M.;
Matsumoto, Y.; Nakamura, Y.; Mikami, K. Chem. Commun. 1997, 281-
282.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” (Grant No. 19020006) from
the Ministry of Education, Culture, Sports, Science and Technology,
Japan. We also acknowledge the JSPS Research Fellowship for
Young Scientists (H.U.) from the Japan Society for the Promotion
of Sciences.
(14) 5 was hydrolyzed to N-Boc protected phosphonic acid without considerable
loss of stereochemical integrity under hydrogenation conditions (see
Supporting Information for details); also see ref 11.
Supporting Information Available: Representative experimental
procedure, spectroscopic data for axially chiral guanidine catalysts (1),
JA0746619
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