Chiral guanidinium salt catalyzed enantioselective phospha-Mannich reactions

Full text of DOI:10.1002/anie.200903971

Angewandte
Chemie
DOI: 10.1002/anie.200903971
Asymmetric Catalysis
Chiral Guanidinium Salt Catalyzed Enantioselective Phospha-Mannich
Reactions**
Xiao Fu, Wei-Tian Loh, Yan Zhang, Tao Chen, Ting Ma, Hongjun Liu, Jianmin Wang, and
Choon-Hong Tan*
The addition of phosphites [(RO)2P(O)H] to imines (Pudovik
À
reaction) is a widely utilized method for the formation of P C
bonds and the preparation of chiral a-amino phosphonic
acids.[1,2] Successful enantioselective approaches employed
catalysts such as metal complexes,[3] quinine,[4] thiourea,[5] and
chiral phosphoric acid.[6] a-Amino phosphonic acids and their
phosphonate esters are excellent inhibitors of proteases and
antibodies.[7] The biological activities of their phosphinic
acids[8] and phosphine oxides analogues have yet to be
thoroughly studied and may lead to important discoveries.
The lack of such studies may be a result of the absence of
reports on the use of other phosphorous nucleophiles such as
Table 1: Guanidine- and guanidinium-catalyzed phospha-Mannich reac-
tions.
secondary phosphine oxides [R2P(O)H] and H-phosphinates
[(RO)P(O)HR] for the addition to imines. The only previous
report on the preparation of P-chiral phosphinate esters
involved a resolution using phosphotriesterase.[9] Zhang and
Yuan reported the synthesis of optically pure a-amino-H-
phosphinic acids employing chiral ketimines.[10]
Electrophilic activation by small-molecule hydrogen-
bond donors has provided an important paradigm for the
design of enantioselective catalysts.[11] Salts of organic bases[12]
were shown to be successful in the activation of imines and
other anionic intermediates through hydrogen bonding. The
guanidinium salts[13] have also demonstrated this potential
and were used elegantly by Uyeda and Jacobsen to catalyze a
Claisen rearrangement.[14]
Guanidines and guanidiniums have been shown to be
powerful catalysts for enantioselective reactions.[15] Our goal
was to prepare simple, novel guanidine or guanidinium
catalysts. Guanidinium salt 1·2HBF4 was prepared from
diamine 2 and pyrrolidinium salt 3 in one step [Eq. (1)].
The free base guanidine 1 was obtained after basifying the
guanidinium salt 1·2HBF4 with a NaOH solution.
In preliminary studies, it was found that both the
guanidinium salt 1·2HBF4 and guanidine 1 can catalyze the
phospha-Mannich reaction between the secondary phosphine
oxide 4a and imines (Table 1, entries 1 and 5). Catalysts
Entry
Catalyst
T [8C]
t [h]
ee [%][a]
1
2
3
4
5
6
1 (base)
1·0.5HBF4
1·HBF4
1·1.5HBF4
1·2HBF4
1·HPF6
0
0
0
0
0
0
1.5
1.5
2.5
2.5
4
2.5
14
14
33
63
80
47
5
80
87
92
7
1·HBF4
À50
8[b]
1·HBArF
À50
[c]
4
[a] Determined by HPLC analysis on a chiral stationary phase. [b] 97%
yield. [c] HBArF4 =HB(3,5-(CF3)2C6H3)4. Ts=4-toluenesulfonyl.
1·xHBF4 (x = 0.5, 1, 1.5) were prepared by mixing different
ratios of the free base 1 and 1·2HBF4 (ratio = 1:3, 1:1, 3:1,
respectively). However, the highest ee value was obtained
with catalyst 1·HBF4, which carried a single proton (Table 1,
entry 3). Catalysts with different counterions, such as 1·HPF6
and 1·HBArF ,[16] were also tested for this reaction (Table 1,
4
entries 6 and 8). The optimum conditions were found using
1·HBArF at a reaction temperature of À508C (Table 1,
4
entry 8); the N-protected a-amino phosphine oxide 5a was
obtained in 92% ee.
[*] X. Fu, W.-T. Loh, Y. Zhang, Dr. T. Chen, T. Ma, H. Liu, J. Wang,
Prof. C.-H. Tan
Department of Chemistry, National University of Singapore (NUS)
3 Science Drive 3, Singapore (Singapore)
Fax: (+65)6779-1691
E-mail: chmtanch@nus.edu.sg
Homepage: http://staff.science.nus.edu.sg/~chmtanch
Under the optimum conditions, the phospha-Mannich
reaction was investigated with different imines (Table 2).
Both electron-donating (Table 2, entry 1) and electron-with-
drawing imines (Table 2, entry 2) provided adducts with high
ee values. The reaction time for complete conversion of the
bulky 2-naphthyl imine was 14 hours (Table 2, entry 3). A
heterocyclic imine (Table 2, entry 4) resulted in a product
with a high ee value. Imines derived from aliphatic aldehydes,
such as cyclohexanecarbaldehyde, gave adduct with 70% ee
[**] This work was supported by ARF grants (R-143-000-337-112 and R-
143-000-342-112) and a scholarship (to X.F.) from the National
University of Singapore.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903971.
Angew. Chem. Int. Ed. 2009, 48, 7387 –7390
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Table 2: Guanidinium-catalyzed (1·HBArF ) phospha-Mannich reaction
between phosphine oxides 4a–d and various imines.
Table 3: Guanidinium-catalyzed phospha-Mannich reaction of benzyl
benzylphosphinate 6a.
4
Entry[a]
Catalyst
T [8C]
t [h][b]
syn-7a
anti-7a
ee [%][c]
ee [%][c]
Entry
4
R
x
5
t
Yield ee
1
2
3
4
5
6
1·HBF4
1·HPF6
1·HCl
RT
RT
RT
RT
<1
<1
<1
<1
<1
48
60
20
24
20
20
10
3
30
42
65
72
82
23
20
5
[mol %]
[h] [%][a] [%][b]
1
2
3
4
4a 4-MeC6H4
4a 4-FC6H4
4a 2-naphthyl
4a 2-furyl
4a Cy
4a tBu
4a trans-PhCH CH
4b Ph
5
5
5
5
10
10
5
20
20
20
5b[c] 14 98
5c
92
90
92
87
70
91
90
56
1·HClO4
4
14 97
14 98
14 92
16 95
40 89
36 89
96 75
14 93
1·HBArF
RT
50
70
50
37
25
4
5d
5e
5 f
5g
5h
5i[f]
5j[f]
1·HBArF
1·HBArF
1·HBArF
1·HBArF
À20
À20
À20
À20
4
4
4
4
7[d]
8[e]
9[f]
5[d]
6
=
7
8[e]
9
[a] H-phosphinate/imine 1:1.2. [b] Determined by TLC analysis, 100%
conversion. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] Used CH2Cl2 as solvent; d.r. 1:1. [e] H-phosphinate/imine 2:1;
d.r. 3:1. [f] H-phosphinate/imine 3:1, CH2Cl2/toluene 1:1 as solvent;
d.r.=4:1. Bn=benzyl.
4c Ph
4d Ph
82
75;85
10
5k[g] 14 90
[a] Yield of isolated product. [b] Determined by HPLC analysis on a chiral
stationary phase. [c] The absolute configuration of 5b was assigned by
using X-ray crystallographic analysis (see the Supporting Information for
details). [d] Used tBuOMe as solvent. [e] Used CH2Cl2/Et2O (1:1) as
solvent. [f] Protecting group on the imine was 4-phenylbenzenesulfonyl.
[g] Protecting group on the imine was benzensulfonyl. Cy=cyclohexyl.
toluene 1:1) was used to make a balance between the reaction
rate and the ee value (Table 3, entry 9). The absolute and
relative stereochemistries were determined using X-ray
crystallographic analysis of syn-7g.
The phospha-Mannich reaction of benzyl benzylphosphi-
nate 6a can be additionally optimized by decreasing the
reaction temperature to À408C (Table 4, entry 1). Good
yields and high enantioselectivities of the major diastereoiso-
mer were observed. Several other aromatic N-benzenesul-
fonyl imines (Table 4, entries 2–4) and N-tosylated imines
(Table 4, entries 5–7) were investigated and they provided the
major diastereoisomers (d.r. from 4:1 to 7:1) 7a–7g with high
ee values. Different alkyl benzylphosphinates 6b–6e were
prepared to investigate the scope of the reaction (Table 5).
Adducts 7h,i were obtained with high ee values (Table 5,
entries 1–2). H-phosphinate 6d bearing an electron-donating
(Table 2, entry 5), whereas an imine derived from pivalalde-
hyde afforded the adduct with 91% ee (Table 2, entry 6). An
imine derived from trans-cinnamyl aldehyde provided adduct
5h with high a ee value (Table 2, entry 7). Diaryl phosphine
oxides 4b and 4c carrying phenyl and ortho-trifluoromethyl-
phenyl groups respectively, provided adducts with moderate
to good ee values (Table 2, entries 8 and 9). The racemic
phosphine oxide 4d added to phenyl imine to generate two
diastereisomers with a diastereomeric ratio (d.r.) of 1:1 and
high ee values (Table 2, entry 10).
We also found that the addition of H-phosphinates
[(RO)P(O)HR], such as benzyl benzylphosphinate 6a, to
imines can be catalyzed by 1·HBF4 (Table 3); however, the
reaction was slow and a low ee value was observed. Various
additives were used and inorganic bases such as K2CO3
increased the reaction rate without decreasing the ee value
(Table 3, entry 1). Guanidinium salts having different coun-
terions were investigated (Table 3, entries 2–5), and the
Table 4: Guanidinium-catalyzed phospha-Mannich reaction of benzyl
benzylphosphinate 6a and various imines.
catalyst 1.HBArF gave the most promising result when the
4
Entry[a] Ar
syn-7 t [h] Yield [%][b] d.r.[c] syn-7
ee [%][d]
reaction temperature was lowered to À208C (Table 3,
entry 6). After the reaction was complete, the catalyst was
recovered and NMR experiments revealed that the guanidi-
1
Ph
7a
7b
7c
7d
7e
7 f
39
35
108 90
100 85
39
40
65
83
90
6:1
6:1
4:1
4:1
6:1
7:1
3:1
94
2[e]
3[e]
4[e]
5[f]
6[f]
7
4-FC6H4
4-ClC6H4
4-MeC6H4
2-naphthyl
2-furyl
90
92
90
91
94
90
nium catalyst 1·HArF was unchanged; the catalyst was not
4
converted into guanidine 1 during the course of the reaction.
When CH2Cl2 was used as the solvent, a better ee value was
observed but the reaction rate was much slower (Table 3,
entry 7). The racemic 6a was used as the limiting reagent
(Table 3, entries 1–7) in these experiments, resulting in a
diastereomeric ratio (d.r.) of 1:1. When the amount of racemic
donor 6a was increased from 2:1 (Table 3, entry 8) to 3:1
(Table 3, entry 9), the ee value of the major diastereoisomer
(syn)[17] was increased to 82%. A solvent mixture (CH2Cl2/
93
71
92
=
trans-PhCH CH 7g
[a] H-phosphinate/imine 3:1. [b] Yield of isolated product of two iso-
mers. [c] Approximated by 1H NMR analysis and confirmed by HPLC
analysis on a chiral stationary phase. [d] Determined by HPLC analysis.
[e] Protecting group on the imine was benzenesulfonyl. [f] Used
15 mol% catalyst.
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(59.1 mg, 0.24 mmol, 3 equiv), K2CO3 (108.8 mg, 0.8 mmol, 10 equiv),
Table 5: Guanidinium-catalyzed phospha-Mannich reaction with alkyl
benzylphosphinates 6b–6e.
toluene (0.2 mL), and CH2Cl2 (0.2 mL) were added sequentially to a
5 mL RBF containing catalyst 1·HArF (11.0 mg, 0.008 mmol, 10
4
mol%). The reaction mixture was then cooled to À408C and stirred
for 0.5 h before the N-tosylated imine (19.7 mg, 0.08 mmol, 1 equiv)
was added. When the reaction was complete, the reaction mixture was
purified by flash chromatography (gradient elution with n-hexane/
ethyl acetate 10:1 to 1:1). Product 7a (33.5 mg, 83%) was obtained
with an ee value of 94% (syn-7a). The diastereoisomers were
separated with another flash chromatography (CH2Cl2/ethyl acetate
(10:1)).
Entry 6 (R)
syn-7
t
[h]
Yield d.r.[b] syn-7
[%][a]
ee [%][c]
1
6b (2-naphthyl-CH2)
7h
7i
7j
38
36
43
92
92
83
6.5:1 94
16:1 94
5:1 88
7:1 82
2
6c (4-CF3C6H4CH2)
6d (4-MeC6H4CH2)
=
3
4d
6e (trans-PhCH CHCH2) 7k
168 82
Received: July 20, 2009
Published online: September 8, 2009
[a] Yield of the two isolated isomers. [b] Determined by 1H NMR and
HPLC analyses. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] 20 mol% catalyst, À608C, the protecting group on the imine
was benzenesulfonyl.
Keywords: guanidinium · Mannich reactions · organocatalysis ·
.
phosphinates · synthetic methods
group and 6e bearing an alkenyl chain afforded modest
ee values (Table 5, entries 3–4). The best diastereoselectivity
(16:1) was obtained when highly electron-withdrawing H-
phosphinate 6c was used (Table 5, entry 3).
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was recovered in 85% yield. When the enantiomerically
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In summary, we have prepared a novel guanidinium
catalyst, obtained in a single step from a commercially
available diamine. With this catalyst, an asymmetric phos-
pha-Mannich reaction was developed using secondary phos-
phine oxides and H-phosphinates as the P nucleophile. By
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Experimental Section
Representative procedure for guanidinium salt 1·HArF catalyzed
4
enantioselective reaction between H-phosphinate 6a and phenyl N-
tosylated imine (Table 4, entry 1): Benzyl benzylphosphinate 6a
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7389

Communications
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