Synergistic chiral ion pair catalysts for asymmetric catalytic synthesis of quaternary α,β-diamino acids

Article abstract of DOI:10.1021/ol300510b

The combination of a chiral phosphate anion with a silver ion has been demonstrated as a powerful and synergistic ion pair catalyst for the aza-Mannich reaction. A series of valuable quaternary α,β-diamino acid derivatives was obtained in high yield, and with excellent diastereo- (up to 25:1 dr) and enantioselectivity (up to 99% ee). The adducts can be smoothly transformed into the corresponding protected chiral quaternary α,β-diamino acids by a one-pot hydrolysis reaction.

Full text of DOI:10.1021/ol300510b

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2010–2013
Synergistic Chiral Ion Pair Catalysts
for Asymmetric Catalytic Synthesis
of Quaternary r,β-Diamino Acids
Shi-Hui Shi, Fu-Ping Huang, Ping Zhu, Zhen-Wen Dong, and Xin-Ping Hui*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
huixp@lzu.edu.cn
Received February 28, 2012
ABSTRACT
The combination of a chiral phosphate anion with a silver ion has been demonstrated as a powerful and synergistic ion pair catalyst for the aza-
Mannich reaction. A series of valuablequaternaryR,β-diamino acid derivativeswas obtainedin high yield, and withexcellentdiastereo- (upto25:1dr)
and enantioselectivity (up to 99% ee). The adducts can be smoothly transformed into the corresponding protected chiral quaternary R,β-diamino
acids by a one-pot hydrolysis reaction.
Optically active R,β-diamino acids are very attractive
targets in organic synthesis because of their wide-ranging
biological significance and high versatility as synthetic
building blocks.1 In addition, chiral quaternary R,β-dia-
mino acids are incorporated into many biologically active
peptides, such as bleomycin, peplomycin, tuberactomycin
B, and the antifungalSch37137,2 toimpart conformational
stability and in some cases to impart antibiotic activity.3 In
recent years, interest in the synthesis of R,β-diamino acids
in an optically pure form has increased dramatically.4
Organic ion pair catalysis, particularly involving chiral
systems, has occupied a unique place in the recent
development of organic molecular catalysis,5À7 and its
useful features have attracted extensive attention from
industrial and academic communities. A chiral organic
ion pair catalytic approach to prepare quaternary R,β-
diamino acids was first developed by Ooi group in 2008.8
Since then, a handful of such protocols have been
€
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r
10.1021/ol300510b
Published on Web 04/03/2012
2012 American Chemical Society

described in the literature by several groups.8,9 Therefore,
it is of widespread interest to develop new chiral organic
ion pair catalytic approaches for the synthesis of chiral
quaternary R,β-diamino acids.
R-amino acids,11 very few reports have described the
efficient synthesis of chiral quaternary R,β-diamino acids
by the addition of oxazolones to N-tosyl aldimines, except
for a chiral tetraaminophosphonium carboxylate8 and a
cinchona alkaloid catalyst12 which offered excellent dia-
stereo- and enantioselectivitiy, respectively. As our group
works on the asymmetric synthesis of amino acids,13 we
decided to apply a synergistic ion pair catalyst in the
asymmetric addition of oxazolones to N-tosyl aldimines.
As anticipated, the aza-Mannich reaction worked well to
give the desired products in high yield, with excellent
diastereo- and enantioselectivity.
Scheme 1. Possible Pathways
In the first stage of the study, we investigated the
reaction of oxazolone 2a with N-benzoyl-1-methoxy-1-
phenylmethylamine (1a) in the presence of a catalytic
amount of the chiral phosphoric acid 3a in dichloro-
methane (Scheme 1). Unfortunately, in addition to our
desired reaction pathway of trapping the oxazole enolate
with the in situ generated imine (path A), possible side
reaction pathways included the dynamic kinetic resolution
of the oxazolone by chiral phosphoric acids (path B)14 and
the decomposition of compound 1a (path C). In the event,
the reaction gave a mixture of compounds 4 and 5, from
which the desired product 4 was isolated in 38% yield and
95% ee (Table 1, entry 1). To restrain two side reactions,
The direct Mannich reaction represents one of the
most straightforward approaches to access R,β-diamino
acids.1,2 Although oxazolones have been proven to be
excellent masked amino acid fragments10 and have pre-
viously been employed to synthesize chiral quaternary
Table 1. Optimization of Chemoselectivitya
ꢁ
(6) For reviews on organic ion pair catalysis, see: (a) Briere, J.-F.;
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J. Am. Chem. Soc. 2007, 129, 13404.
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J. Am. Chem. Soc. 2011, 133, 3339. (b) Zhang, Z.; Zheng, W.; Antilla,
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14088.
yield of
dr of
ee of
yield of
entry
additive
4 (%)b
4c
4 (%)d
5 (%)b
1
;
38
38
45
3:1
95
95
95
93
;
20
15
12
19
26
25
;
;
;
˚ꢀ
2
4 A MS (30 mg)
3:1
3:1
3:1
;
˚ꢀ
3
4 A MS (50 mg)
4
Na2SO4 (30 mg) 35
5
CaCl2 (22 mg)
trace
6
CuSO4
;
trace
28
;
;
7e
8f
9g
10:1
5:1
>99
80
ꢀ
ꢀ
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Chem. Soc. 2008, 130, 16150. (b) Singh, A.; Johnston, J. N. J. Am. Chem.
Soc. 2008, 130, 5866.
;
51
;
63 (6a) 8:1 (6a) 84 (6a)
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a Experimental conditions: a mixture of 1 (0.3 mmol), 2 (0.2 mmol),
and catalyst 3a (0.02 mol) in DCM (1 mL) was stirred at room
temperature for 12 h. b Isolated yield. c Determined by 1H NMR (400
MHz). d The enantiomeric excess was determined by chiral HPLC
analysis. e N-Benzoyl-1-benzotriazolyl-1-phenyl-methylamine (1b) was
used. f N-Benzylidenebenzamide (1c) was used. g N-Benzylidene-4-
methylbenzenesulfonamide (1d) was used.
€
36, 1432. (d) Trost, B. M.; Jakel, C.; Plietker, B. J. Am. Chem. Soc. 2003,
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2010, 132, 12222. (b) Alba, A.-N. R.; Companyo, X.; Valero, G.;
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A.; Cabrera, S.; Reyes, E.; Jørgensen, K. A. Chem.;Eur. J. 2008, 14,
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10958. (f) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard,
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2010, 43, 1317.
Org. Lett., Vol. 14, No. 8, 2012
2011

˚
paths B and C, removal of moisture (4 A molecular sieve
binol phosphate catalysts 3cÀg were also tested in the
aza-Mannich reaction between imine 1d and oxazolone
2a, and the results indicated that catalyst 3b gave the
best results (entries 4À8). When chiral sodium binol
phosphate 3h was used, a moderate yield and enantios-
electivity were afforded due to the weak Lewis acidity
of sodium compared to the silver cation (entry 9).
Further screening of solvents failed to improve the
yield as well as diastereo- and enantioselectivity
(entries 10À13). When the reaction temperature was
reduced to 0 °C, a 31% ee of product 6a was afforded
(entry 14).
and Na2SO4) and methanol (CaCl2 and CuSO4) was
employed as shown in Table 1. However, various additives
did not improve the chemoselectivity (entries 2À6). More-
over, N-benzoyl-1-methoxy-1-phenylmethylamine (1a)
was replaced with N-benzoyl-1-benzotriazolyl-1-phenyl-
methylamine (1b), N-benzylideneben-zamide (1c), and
N-benzylidenetoluene-sulfonamide (1d), respectively (entries
7À9). Fortunately, when substrate 1d was used, the adduct 6a
was smoothly obtained with a moderate yield as well as
diastereo- and enantioselectivity (entry 9).
Because chiral silver binol phosphate can efficiently
activate imines and imine precursors, imine precursors
1aÀ1b and imine 1d were used as substrates for the aza-
Mannich reaction in the presence of chiral organic ion pair
catalysts 3b (10 mol %) in dichloromethane at room
temperature, respectively. The results showed that the
imine precursors 1aÀ1b provided the adduct 4 with a low
yield and excellent enantioselectivity (Table 2, entries 1À2),
To demonstrate the generality of the ion pair catalyst 3b-
promoted asymmetric aza-Mannich reaction, a variety of
N-tosyl aldimines and oxazolones were explored (Table 3).
Table 3. Asymmetric Synthesis of Quaternary R,β-Diamino
Acid Derivativesa
Table 2. Representative Screening Results for the Reaction of
N-Tosyl Imine 1d and Oxazolone 2aa
time
(h)
yield
(%)c
ee
(%)d
entry
R1
R2
drb
1e
2e
3e
4
Ph
Me
36
36
36
48
48
48
48
48
48
48
48
48
48
48
48
15:1
25:1
11:1
16:1
18:1
17:1
19:1
16:1
20:1
19:1
18:1
20:1
7:1
94 (6a)
92 (6b)
95 (6c)
92 (6d)
84 (6e)
83 (6f)
93 (6g)
91 (6h)
88 (6i)
85 (6j)
90 (6k)
89 (6l)
88 (6m)
90 (6n)
58 (6o)
92
94
81
95
98
99
94
82
95
82
91
86
94
86
75
p-Me-Ph
p-Cl-Ph
Ph
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
5
p-Me-Ph
p-MeO-Ph
o-F-Ph
6
7
8
p-F-Ph
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
p-Br-Ph
2-C10H7
2-C4H3O
n-Pr
9
yield
(%)c
ee
(%)d
entry
catalyst
solvent
drb
10
11
12
13
14
15
1e
2f
3
3b
3b
3b
3c
3d
3e
3f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
Toluene
THF
4:1
42
36
94
91
94
92
94
95
80
93
90
91
88
83
94
98
92
87
81
78
73
66
89
88
78
69
53
31
9:1
15:1
16:1
14:1
9:1
21:1
10:1
4
5
a Experimental conditions unless otherwise stated: a mixture of 1 (0.2
mmol), 2 (0.3 mmol), and 3b (0.03 mmol) in dichloromethane (1 mL) was
stirred at room temperature. b Determined by 1H NMR (400 MHz).
c Isolated yield. d The enantiomeric excess was determined by chiral
HPLC analysis. e 10 mol % catalyst.
6
7
7:1
8
3g
3h
3b
3b
3b
3b
3b
4:1
9
12:1
13:1
11:1
5:1
10
11
12
13
14g
When the aza-Mannich reaction of aldimines 1eÀf and
oxazolone 2a were examined under the optimized condi-
tions, products 6b and 6c were obtained with 94% and
81% ee, respectively (entries 2 and 3). When the reaction of
aldimines 1d and oxazolone 2b was carried out under these
conditions, the product 6d was obtained in 70% yield due
to greater steric hindrance of the isopropyl group in
oxazolone 2b compared with the methyl group in 2a. Thus,
the aza-Mannich reactions of oxazolone 2b with aldimines
1dÀo were conducted in the presence of 15 mol % catalyst
3b for 48 h. As expected, our aza-Mannich reaction could
be extended to a range of N-tosyl aldimines, bearing
aromatic and heteroaryl groups (entries 1À14). Highyields
DCE
6:1
DCM
5:1
a Experimental conditions: a mixture of 1d (0.2 mmol), 2a (0.3
mmol), and catalyst 3 (0.02 mmol) in solvent (1 mL) was stirred at room
temperature for 36 h. b Determined by 1H NMR (400 MHz). c Isolated
yield. d The enantiomeric excess was determined by chiral HPLC analy-
sis. e Imine precursor 1a was used. f Imine precursor 1b was used. g The
reaction was carried out under 0 °C for 48 h.
whereas imine 1d gave the adduct 6a with 94% yield, 15:1 dr,
and 92% ee (entry 3). Furthermore, a series of chiral silver
(14) Lu, G.; Birman, V. B. Org. Lett. 2011, 13, 356.
2012
Org. Lett., Vol. 14, No. 8, 2012

and enantioselectivities were obtained. It should be noted
that N-tosyl aldimines with electron-donating aryl showed
excellent enantioselectivities (entries 5 and 6); aldimines
bearing electron-withdrawing groups at the para-position
of R1 aryl group gave slightly low enantioselectivities (entries
8, 11, and 12). With respect to ortho-position substituents and
the 2-naphthyl group, high enantioselectivities were also ob-
tained, probably due to steric effects (entries 7, 9, and 13).
Gratifyingly, alkyl-substituted N-tosyl aldimine (1o) smoothly
reacted with oxazolone 2b and product 6o was obtained with
58% yield and 75% ee (entry 15).
The structures of the products 6aÀowere characterized by
spectroscopic data and X-ray crystal structure analysis
(Figure 1).15 The absolute configuration of the product was
determined to be (R,S)-6e and (R,S)-6k by comparing the
optical rotation value with the literature.12 The absolute
configuration of the other products was assigned by analogy.
Scheme 2. Hydrolyzed to the Corresponding Protected Qua-
ternary R,β-Diamino Acids
the Ts-imine was activated by the coordination of the
counter silver ion with Ts-imine. At last, chiral phos-
phonium enolate attacked the active imine to form
product 6.
The synthetic versatility of the aza-Mannich adducts in
this reaction was illustrated by a further transformation.
Optically active quaternary R,β-diamino acid 7 was ob-
tained by using the protocol developed by Ooi et al.
(Scheme 2).8 The adduct 6e could react efficiently to afford
the corresponding Ts- and Bz- diprotected quarternary
R,β-diamino acid 7 with 93% yield.
In conclusion, we have developed a synergistic ion pair
catalyst that consists of a silver ion and a chiral phosphate
anion which can catalyze the aza-Mannich addition of
oxazolones to N-tosyl aldimines. Quaternary R,β-diamino
acid derivatives were obtained in high yield, with excellent
diastereo- and enantioselectivity. In addition, the metho-
dologyfor the synthesis of R,β-diamino acid derivatives is a
supplement to our previous work.
Figure 1. X-ray crystal structure of compound 6k.
Acknowledgment. We are grateful for financial support
of NSFC (No. 20702022, 21172099), Program “111”, and
International Cooperation Project (1011WCGA170).
In an illustration of the synergistic catalytic cycle,16 this
protocol probably involved the basic binol phosphate
anion abstracting the active proton of oxazolone to give the
corresponding chiral phosphonium enolate. Simultaneously,
Supporting Information Available. Experimental pro-
cedure, characterization data for the products, crystal-
lographic data of compound 6k (CIF). This material is
available free of charge via the Internet at http://pubs.acs.
org.
(15) CCDC 868973 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
daa_request/cif.
(16) Please see the Supporting Information for a figure of proposed
cooperative catalytic model.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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