Direct catalytic asymmetric mannich-type reaction of β-keto phosphonate using a dinuclear Ni2-Schiff base complex

Article abstract of DOI:10.1021/ol800965t

(Chemical Equation Presented) Direct catalytic asymmetric Mannich-type reactions of β-keto phosphonates are described. A homodinuclear Ni ₂-Schiff base complex promoted the reaction at 0°C, giving β-amino phosphonates in up to 90% yield, 20:1 dr, and 99% ee. Control experiments suggested that two Ni metals are important for achieving high yield and stereoselectivity.

Full text of DOI:10.1021/ol800965t

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3239-3242
Direct Catalytic Asymmetric
Mannich-Type Reaction of ꢀ-Keto
Phosphonate Using a Dinuclear
Ni2-Schiff Base Complex
Zhihua Chen, Kenichiro Yakura, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo 7-3-1,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Received April 26, 2008
ABSTRACT
Direct catalytic asymmetric Mannich-type reactions of ꢀ-keto phosphonates are described. A homodinuclear Ni2-Schiff base complex promoted
the reaction at 0 °C, giving ꢀ-amino phosphonates in up to 90% yield, 20:1 dr, and 99% ee. Control experiments suggested that two Ni metals
are important for achieving high yield and stereoselectivity.
The phosphonic acid functional group is regarded as a
bioisostere of a carboxylic acid group. Aminophosphonic
acid derivatives are useful structural motifs as haptens in
catalytic antibody generation and as targets for enzyme
inhibitors.1 Several catalytic asymmetric methods for the
synthesis of optically active R-amino phosphonic acid
derivatives have been reported,2 but catalytic asymmetric
methods for ꢀ-amino phosphonic acid derivatives are lim-
ited.3,4 Although catalytic asymmetric direct Mannich(-type)
reactions for synthesizing ꢀ-amino acid derivatives have been
intensively investigated over the past decade,5,6 there are very
few corresponding direct Mannich-type approaches for the
synthesis of ꢀ-amino phosphonic acid derivatives, possibly
due to the higher pKa of the R-proton in phosphonic acid
derivative donors than in carboxylic acid derivative donors.7
Jørgensen et al. reported the first catalytic enantio- and
diastereoselective direct Mannich-type reaction of ꢀ-keto
(1) ReView: Aminophosphonic and Aminophosphinic Acids, Chemistry
and Biological ActiVity; Kukhar, V. P., Hudson, H. R., Eds.; John Wiley &
Sons: New York, 2000.
(3) Catalytic asymmetric Mannich-type approach: (a) Kjærsgaard, A.;
Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 804. (b) Catalytic asymmetric
aminohydroxylation approaches: Cravotto, G.; Giovenzana, G. B.; Pagliarin,
R.; Palmisano, G.; Sisti, M. Tetrahedron: Asymmetry 1998, 9, 745. (c)
(2) Review: Gro¨ger, H.; Hammer, B. Chem.-Eur. J. 2000, 6, 943. (a)
For selected examples of catalytic asymmetric approaches, see also:
Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247. (b)
Kitamura, M.; Tokunaga, M.; Pham, T.; Lubell, W. D.; Noyori, R.
Tetrahedron Lett. 1995, 36, 5769. (c) Sasai, H.; Arai, S.; Tahara, Y.;
Shibasaki, M. J. Org. Chem. 1995, 60, 6656. (d) Kobayashi, S.; Kiyohara,
H.; Nakamura, Y.; Matsubara, R. J. Am. Chem. Soc. 2004, 126, 6558. (e)
Pawar, V. D.; Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. J. Am.
Chem. Soc. 2006, 128, 6308. (f) Joly, G. D.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 4102. (g) Saito, B.; Egami, H.; Katsuki, T. J. Am. Chem.
Soc. 2007, 129, 1978. For selected chiral auxiliary-based approaches, see:
(h) Tager, K. M.; Taylor, C. M.; Smith, A. B., III J. Am. Chem. Soc. 1994,
116, 9377. (i) Davies, F. A.; Prasad, K. R. J. Org. Chem. 2003, 68, 7249,
and references therein.
Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379
(4) General review on the synthesis of ꢀ-amino phosphonates: Palacios,
F.; Alonso, C.; de los Santos, J. M. Chem. ReV. 2005, 105, 899
.
.
(5) A general review on catalytic asymmetric Mannich(-type) reactions:
(a) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541. For recent
reviews on direct catalytic asymmetric Mannich(-type) reactions affording
ꢀ-amino carbonyl compounds, see: (b) Marques, M. M. B. Angew. Chem.,
Int. Ed. 2006, 45, 348. (c) Shibasaki, M.; Matsunaga, S. J. Organomet.
Chem. 2006, 691, 2089. (d) Ting, A.; Schaus, S. E. Eur. J. Org. Chem.
2007, 5797. (e) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg,
P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008, 37, 29
.
10.1021/ol800965t CCC: $40.75
Published on Web 07/09/2008
2008 American Chemical Society

phosphonates, giving ꢀ-amino phosphonates in up to 84-43%
ee.3a The imine in their studies was, however, limited to an
N-Ts-imino ester. Thus, the development of a new comple-
mentary method applicable to imines with various substit-
uents is highly desirable to broaden the availability of diverse
optically active ꢀ-amino phosphonates. Herein, we report the
utility of a homodinuclear Ni2-Schiff base 1a complex
(Figure 1) to address this issue. The bimetallic Ni complex
Table 1. Optimization of Reaction Conditions
metal
sources
Schiff
solvent
(× M)
yield
% ee
a
a
entry M1 M2 base
additive (%) drb (anti)
1
2
3
4
5
6
7
8
9
Cu Sm
Cu Sm
Ni Sm
Cu Cu
Ni Ni
Ni Ni
Ni Ni
Ni Ni
Ni Ni
1a THF (0.2)
1b THF (0.2)
1b THF (0.2)
1b THF (0.2)
1b THF (0.2)
1b EtOAc (0.2) none
1b CH2Cl2 (0.2) none
1b toluene (0.2) none
none
none
none
none
none
91 20:1
95 20:1
1
2
95 18:1 1c
95 20:1 28c
92 10:1 80
43 10:1 77
22 10:1 70
65 33:1 98
1b toluene (0.2) 13X MS 75
5:1 93
10 Ni Ni
1b toluene (0.8) none 83 15:1 96
a Cu(OAc)2, Sm(O-iPr)3, and Ni(OAc)2 were used as metal sources.
b
Determined by H NMR analysis. c ent-4aa was obtained in major.
1
and ꢀ-keto phosphonate 3a in high yield (95-91%) and
diastereoselectivity (20:1) at 0 °C, but with poor enantiose-
lectivity (entry 1, 1% ee, and entry 2, 0% ee). A homodi-
nuclear Ni2-Schiff base 1b complex,10b which was recently
developed for the Mannich-type reaction of nitroacetates and
related active methylene compounds, gave promising results.
When the reaction was performed in THF (0.2 M) at 0 °C,
product 4aa was obtained in 92% yield, 10:1 diastereose-
lectivity, and 80% ee after 48 h (entry 5). In contrast, other
dinuclear Schiff base 1b complexes gave poor enantiose-
lectivity (entries 2-4). Changing the solvent to toluene
improved the diastereo- and enantioselectivity to 33:1 and
98% ee, respectively, but the reactivity decreased (entry 8,
65% yield). The addition of 13X MS improved the yield to
75%, but the diastereo- and enantioselectivity decreased
Figure 1. Structures of dinucleating Schiff bases 1a and 1b, N-Boc
imines 2, and ꢀ-keto phosphonates 3 and a proposed structure of a
homodinuclear Ni2-Schiff base 1b complex.
promoted the Mannich-type reaction of various aryl and
heteroaryl N-Boc imines 2 with ꢀ-keto phosphonates 3 at 0
°C, giving products in 90-43% yield, 20:1-2:1 dr, and
99-47% ee.
Initially, we screened various Lewis acid/Brønsted base
bifunctional chiral metal catalysts8 developed for direct
Mannich-type reactions of other donors in our group9 and
found bimetallic Schiff base 1 complexes10,11 to be promising
candidates. Optimization studies are summarized in Table
1. In entries 1 and 2, Cu-Sm-Schiff base 1a10a or 1b
complexes promoted the Mannich-type reaction of imine 2a
(9) La catalyst: (a) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 9588. Zn catalysts: (b)
Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M.
J. Am. Chem. Soc. 2004, 126, 8777, and references therein. (c) Yoshida,
T.; Morimoto, H.; Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2005, 44, 3470. In catalyst: (d) Harada, S.; Handa, S.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365. Ba
catalyst: (e) Yamaguchi, A.; Aoyama, N.; Matsunaga, S.; Shibasaki, M.
Org. Lett. 2007, 9, 3387. Y catalyst: (f) Sugita, M.; Yamaguchi, A.;
Yamagiwa, N.; Handa, S.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2005,
7, 5339.
(6) For selected examples of direct catalytic asymmetric Mannich-type
reactions using 1,3-dicarbonyl and related active methylene compounds as
donors: (a) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem.-Eur. J. 2003, 9, 2359. (b) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356. (c) Hamashima, Y.; Sasamoto, N.; Hotta, D.;
Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem, Int. Ed. 2005, 44,
1525. (d) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc.
2005, 127, 11256. (e) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc.
2006, 128, 6048. (f) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun.
2006, 1191. (g) Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto, Y.
Synthesis 2007, 2571. (h) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 5630. (i) Singh, A.; Johnston, J. N. J. Am. Chem.
Soc. 2008, 130, 5866, and references therein. See also ref 10b. For other
examples, see reviews in ref 5.
(10) (a) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 4900. (b) Chen, Z.; Morimoto, H.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (c) Handa, S.; Nagawa,
K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008,
47, 3230.
(11) For selected examples of related bifunctional bimetallic Schiff base
complexes in asymmetric catalysis, see: (a) DiMauro, E. F.; Kozlowski,
M. C. Org. Lett. 2001, 3, 1641. (b) Annamalai, V.; DiMauro, E. F.; Carroll,
P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973, and references
therein. (c) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 9928. (d) Li, W.; Thakur, S. S.; Chen, S.-W.; Shin, C.-K.;
Kawthekar, R. B.; Kim, G.-J. Tetrahedron Lett. 2006, 47, 3453 references
therein. For related early studies with dinuclear Ni2-Schiff base complexes
as epoxidation catalysts, see also: (e) Oda, T.; Irie, R.; Katsuki, T.; Okawa,
H. Synlett 1992, 641.
(7) For example, pKa of diethyl malonate is 16.4 (in DMSO), while
that of triethyl phosphonoacetate is 18.6 (in DMSO).
(8) Recent reviews on bifunctional Lewis acid/Brønsted base asymmetric
metal catalysis: (a) Matsunaga, S.; Shibasaki, M. Bull. Chem. Soc. Jpn.
2008, 81, 60. (b) Shibasaki, M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35,
269.
3240
Org. Lett., Vol. 10, No. 15, 2008

(entry 9, dr ) 5:1, 93% ee).12 Under concentrated reaction
conditions (toluene, 0.8 M) in the absence of 13X MS,
complete conversion was observed. Product 4aa was obtained
in 83% yield, and good diastereo- and enantioselectivity were
maintained (entry 10, dr ) 15:1, 96% ee).
When using other ꢀ-keto phosphonates 3b and 3c, only
modest reactivity and enantioselectivity were observed
(entries 13-14). With isomerizable alkyl N-Boc imines, yield
was poor (<20%), possibly due to competitive isomerization
to enecarbamates. Further studies to broaden the generality
of the ꢀ-keto phosphonate donors are ongoing. The relative
and absolute configuration of product 4ha was unequivocally
determined by single-crystal X-ray analysis (Figure 2).
The optimized reaction conditions were applied to various
aryl and heteroaryl N-Boc imines 2 (Table 2). The reaction
Table 2. Substrate Scope and Limitation in Mannich-Type
Reaction of N-Boc Imines with ꢀ-Keto Phosphonatesa
yieldb
Ar 3
additive product (%) drc v(anti)
% ee
entry
1
imine
Figure 2. ORTEP plot of ꢀ-amino phosphonate 4ha.
Ph
2a 3a none
2a 3a none
2a 3a none
2b 3a none
2c 3a none
2d 3a none
4aa
4aa
4aa
4ba
4ca
4da
83 15:1 96
85 17:1 98
2d Ph
3e
4
5
6
7
8
9
Ph
78
9:1 93
Control experiments (Scheme 1) demonstrated that neither
a mononuclear Ni-Schiff base 1b complex nor Ni-salen
5a-5c complexes were effective for the present reaction,
resulting in poor reactivity and enantioselectivity (65-21%
3-thienyl
3-furyl
2-furyl
90 17:1 98
82 13:1 99
75
6:1 98
4-Me-C6H4 2e 3a 13X MS 4ea
4-MeO-C6H4 2f 3a 13X MS 4fa
63 10:1 95
86
64
7:1 87
6:1 85
4-F-C6H4
2g 3a 13X MS 4ga
2h 3a 13X MS 4ha
10 4-Cl-C6H4
43 11:1 84
73 2:1 92
71 20:1 84
11 3-MeO-C6H4 2i 3a none
12 2-naphthyl 2j 3a none
4ia
4ja
4ab
4ac
Scheme 1. Negative Control Experiments Using Mononuclear
Ni-Schiff Base 1b and Ni-Salen 5a-5c Complexes
13f Ph
14 Ph
2a 3b none
2a 3c none
51
47
6:1 47
8:1 55
a Reactions were run using imines 2 (0.4 mmol scale) and 1.1 equiv of
3a in toluene (0.8 M) at 0 °C for 48 h unless otherwise noted. b Isolated
yield after purification by column chromatography. c Determined by 1H
NMR analysis. d Reaction was run in 2.0 mmol scale. e Reaction was run
using 5 mol % of Ni2-1b catalyst for 72 h. f Reaction was run at 25 °C.
of N-Boc imine 2a proceeded smoothly both in 0.4 and 2.0
mmol scale (entries 1 and 2). With 5 mol % catalyst loading,
product was obtained in 78% yield and 93% ee after 72 h
(entry 3). The reaction proceeded smoothly with heteroaryl
imines 2b-2d, giving the products in 90-75% yield, 17:
1-6:1 dr, and 99-98% ee (entries 4-6).13 With aryl imines
2e-2j with substituents, the reactivity was much lower than
with imine 2a (entries 7-12). Thus, in entries 7-10, the
reactions were performed in the presence of 13X MS to
improve the yield of the products at the expense of
stereoselectivity, giving products in 86-43% yield, 11:1-6:1
dr, and 95-84% ee. Although the present Ni2-Schiff base
1b complex afforded good reactivity and enantioselectivity
with various aryl and heteroaryl imines (entries 1-12), there
still remained limitations on ꢀ-keto phosphonate donors.
yield, 53-1% ee). We assume that cooperative functions of
the two Ni metal centers in the Ni2-1b complex are
important for achieving good enantioselectivity as well as
reactivity. We speculate that the Ni-aryloxide moiety in the
Ni2-1b complex may function as a Brønsted base to generate
a Ni-enolate from ꢀ-keto phosphonate 3,14 which would
react with N-Boc imines 2 that are nicely fixed by the other
Lewis acidic Ni metal center. The postulated transition state
(12) Molecular sieves type 13X (13X MS) purchased from Fluka were
utilized after flame-drying activation under reduced pressure (ca. 1.0 kPa).
Other molecular sieves such as 4 Å molecular sieves and 5 Å molecular
sieves gave less satisfactory results.
(14) For recent other examples of bifunctional chiral mono-Ni(II) catalyst
for activation of 1,3-dicarbonyl and related compounds to form Ni-enolates
as key intermediates, see: (a) Evans, D. A.; Seidel, D. J. Am. Chem. Soc.
2005, 127, 9958. (b) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc.
2007, 129, 11583. (c) Suzuki, T.; Hamashima, Y.; Sodeoka, M. Angew.
Chem., Int. Ed. 2007, 46, 5435.
(13) In contrast to furyl and thienyl imines, the use of pyridyl imines
was unsuccessful, giving products in only poor enantioselectivity.
Org. Lett., Vol. 10, No. 15, 2008
3241

model to afford anti-4 as a major adduct is shown in Figure
3. Mechanistic studies to elucidate the precise reaction
mechanism are ongoing.
heteroaryl N-Boc imines 2 promoted by a homodinuclear
Ni2-Schiff base 1b complex. The reaction proceeded at 0
°C, and ꢀ-amino phosphonates were obtained in 90-43%
yield, 20:1-2:1 dr, and 99-47% ee. Further studies to
broaden the substrate scope, especially ꢀ-keto phosphonate
donors 3, by tuning the dinuclear Ni2-Schiff base 1 complex
are ongoing.
Acknowledgment. We thank Mr. H. Morimoto and Mr.
T. Nitabaru at the University of Tokyo for X-ray crystal-
lography work. This research was supported by a Grant-in-
Aid for Specially Promoted Research, a Grant-in-Aid for
Scientific Research (A), and a Grant-in-Aid for Encourage-
ments for Young Scientists (A) (for SM) from JSPS and
MEXT, and Mitsubishi Chemical Cooperation Fund (for
SM).
Figure 3. Hypothetical transition state model of direct Mannich-
Supporting Information Available: Detailed experimen-
tal procedures, spectral data for new compounds, and X-ray
crystallography data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
type reaction with ꢀ-keto phosphonate using the Ni2-1b catalyst.
In summary, we developed direct catalytic asymmetric
Mannich-type reactions of ꢀ-keto phosphonates with aryl and
OL800965T
3242
Org. Lett., Vol. 10, No. 15, 2008