A N,N′-dioxide-copper(II) complex as an efficient catalyst for the enantioselective and diastereoselective mannich-type reaction of glycine schiff bases with aldimines

Article abstract of DOI:10.1002/chem.200900118

A study was conducted to demonstrate the efficient Mannich-type reaction of the glycine Schiff base 1 with aldimines using N'N-dioxide-copper(II) acetate complexes as catalysts. The efficient reaction helped in obtaining significant enantioselectivity and

Full text of DOI:10.1002/chem.200900118

DOI: 10.1002/chem.200900118
A N,N’-Dioxide–Copper(II) Complex as an Efficient Catalyst for the
Enantioselective and Diastereoselective Mannich-Type Reaction of Glycine
Schiff Bases with Aldimines
Deju Shang,[a] Yanling Liu,[a] Xin Zhou,[a] Xiaohua Liu,[a] and Xiaoming Feng*[a, b]
Optically active a,b-diamino acids are key structural com-
ponents in a variety of peptide antibiotics, antifungal dipep-
tides, and other biologically active compounds.[1] The Man-
nich-type reaction of glycine Schiff base 1 and related com-
pounds[2] with imines provides a direct and atom-economi-
cally favorable method for the construction of these com-
pounds (Scheme 1). Jørgensen and co-workers reported the
Hou et al. very recently realized the first highly anti-selec-
tive version of this reaction by using a chiral ferrocene-oxa-
zoline–copper(I) complex as the catalyst.[7] Despite these
impressive contributions, the development of new and effi-
cient asymmetric catalytic systems with both high diastereo-
and enantioselectivity is still challenging and in high
demand.[8]
With a tunable electronic and steric chiral environment,
N,N’-dioxides complexes have emerged as a new class of ef-
fective catalysts for various asymmetric reactions.[9–11]
Herein, we report our work on the efficient Mannich-type
reaction of the glycine Schiff base 1 with aldimines using
N,N’-dioxide–copper(II) acetate complexes as catalysts, for
which high yield, excellent enantioselectivity and anti diaste-
reoselectivity were obtained for a wide range of a,b-diamino
acid esters.[12]
Scheme 1. The Mannich-type reaction of glycine Schiff base 1 and ald-
ACHTUNGTRENNUNGimine 2.
In most of the previous reaction systems,[3–5,7,8] external
bases are usually required to realize high conversions. We
envisioned that the introduction of a counterion with stron-
ger Brønsted basicity to the copper salt might be an appeal-
ing choice. It can facilitate the deprotonation of the active
proton of the glycine Schiff base 1 to form a chiral copper
enolate in situ, and thus simplify the catalytic procedure.[13]
To our delight, preliminary experimental results confirmed
first example of this reaction using a phosphino-oxazoline–
copper(I) complex as the catalyst, for which excellent enan-
tioselectivity was obtained.[3] Subsequently, Maruokaꢀs
group disclosed their application of an N-spiro C2-symmetric
chiral quaternary ammonium catalyst in this transforma-
tion.[4] Shibasaki et al. developed a chiral two-center phase-
transfer catalyst to promote the reaction with extremely
high diastereoselectivity.[5] Kobayashiꢀs group found that a
chiral guanidine catalyst could catalyze the reaction with
good diastereo- and enantioselectivity.[6] All these efforts fo-
cused on the catalytic synthesis of syn-selective adducts.
this hypothesis. Cu
showed moderate to good catalytic activity for the reaction
(Table 1, entries 1–3). In particular, Cu(OAc)2·H2O and Cu-
(OAc)2 complexed with L1 promoted the reaction smoothly
ACHTNUGTRNENU(GN OAc)2·H2O, CuACHTUNTREGG(NNUN OAc)2, and CuACHTUNGTRENNUNG(acac)2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
to afford the desired anti adducts with 91:9 d.r. and
94% ee.[14] On the contrary, the reaction proceeded sluggish-
ly in the presence of other metal salts with weaker Brønsted
[a] D. Shang, Y. Liu, X. Zhou, Dr. X. Liu, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
Fax : (+86)28-8541-8249
basicity such as CuClO4, CuACHTNUGTREN(NUNG OTf)2, CuOTf, and CuCl
(Table 1, entries 4–7).
Further investigation of the ligand structure revealed that
the reactivity of this Mannich-type reaction was more sensi-
tive to the steric property rather than the electronic proper-
ty of the substituents on the phenyl ring. Increasing the
steric effect of the ligand dramatically decreased the reac-
tion efficiency (Table 1, entries 8, 9, and 13). No product
E-mail: xmfeng@scu.edu.cn
[b] Prof. Dr. X. Feng
State Key Laboratory of Oral Diseases
Sichuan University, Chengdu 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900118.
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Chem. Eur. J. 2009, 15, 3678 – 3681

COMMUNICATION
Table 1. Optimization of the Mannich-type reaction of glycine Schiff
(5 mol%), aldimine (0.1 mmol, 0.1m), and glycine Schiff
base 1 (1.5 equiv) in THF (1.0 mL) at 08C.
base 1 with aldimine 2a.[a]
Under the optimized conditions, the reaction generally
provided the corresponding a,b-diamino acid esters 3 in
good yields with high diastereo- and enantioselectivities
(Table 2). Aldimines with both electron-donating and elec-
Entry
L
Metal
Yield[%][b]
anti/syn[c]
ee[%][c]
Table 2. The Mannich-type reaction of glycine Schiff base 1 with ald-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L5
L5
L5
L5
Cu
Cu
Cu
N
70
74
51
trace
trace
trace
trace
76
91:9
91:9
54:46
37:63
67:33
65:35
45:55
93:7
91:9
–
93:7
92:8
85:15
90:10
93:7
93:7
93:7
93:7
94
94
0
12
81
73
49
95
92
–
94
94
52
95
94
94
94
95
AHCTUNGTRENNUNG
imine 2.[a]
.
CuClO4
Cu(OTf)2
(CuOTf)2·Tol
CuCl
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Entry
Imine
R
Yield[%][b]
anti/syn[c]
ee[%][c]
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
A
55
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Ph
95
85
>99(82)
99
94
>99
>99
99(97)
92
>99
>99(60)
99
99(91)
97
76
93:7
95:5
96:4
91:9
92:8
92:8
94
N
NR[h]
86
p-CH3C6H4
m-CH3C6H4
m-ClC6H4
m-CH3OC6H4
p-CH3OC6H4
p-CNC6H4
m-BrC6H4
m-NO2C6H4
p-NO2C6H4
p-CH3OC6H4
p-FC6H4
96
E
(96:4)
95(95)[d]
T
87
34
78
95
92
80
90
91
94
93
E
E
15[d,e]
16[d,e,f]
17[d,g]
18[d,e,i]
R
87:13
91:9(91:9)
90
R
T
91(92)[d]
T
9
85:15
86:14
95:5
92:8
93:7
94:6
85:15
93:7
86:14
91:9
90
A
10
11
12
13
14
15
16
17
18
19
90
(96:4)
96(96)[d]
[a] Unless otherwise noted, reactions were carried out with ligand
(10 mol%), metal (10 mol%), glycine Schiff base 1 (0.1 mmol), and
imine 2a (0.1 mmol) in THF (1.0 mL) at 08C for 26 h. [b] Yield of isolat-
ed product. [c] Determined by chiral HPLC analysis. [d] The ratio of 1/
2a was 1.5:1. [e] 5 mol% catalyst was used. [f] The reaction was carried
out under an air atmosphere. [g] 2.5 mol% catalyst was used. [h] No reac-
tion. [i] d-Proline-derived ligand L5 was employed to give 3a with oppo-
site configuration.
94
p-BrC6H4
E
92(92)[d,g]
m-PhOC6H4
o-CH3C6H4
p-PhC6H4
p-CF3C6H4
m-CF3C6H4
2-naphthyl
94
80[e]
94
90
95
92
99
90
91
93
2s
93:7
20
2t
>99
93:7
96
21
22
23
24
2u
2v
2w
2x
3,4-Cl2C6H3
2-thienyl
2-furyl
98
92
88
71
86:14
95:5
94:6
90
97
95
3-furyl
87:13
96[f]
[a] Unless otherwise noted, reactions were carried out with L5 (5 mol%),
Cu(OAc)2·H2O (5 mol%), 1 (0. 15 mmol), and 2 (0.1 mmol) in THF
AHCTUNGTRENNUNG
(1.0 mL) at 08C (see the Supporting Information for details). [b] Yield of
isolated product. [c] Determined by chiral HPLC analysis (see the Sup-
porting Information for details). [d] 2.5 mol% catalyst was used.
[e] 30 mol% catalyst was used. [f] 10 mol% catalyst was used. [g] The ab-
solute configuration was determined to be (2S, 3S) by comparing with lit-
erature data.[7]
was detected when the bulky ortho-substituted L4 was em-
ployed as the ligand (Table 1, entry 10). The electron-with-
drawing groups at the para position exhibited a positive
effect on both the yield and diastereoselectivity (Table 1, en-
tries 11 and 12 vs. 14). By increasing the amount of 1 to 1.5
equivalents and decreasing the catalyst loading to 5 mol%,
the yield was improved to 95% (Table 1, entry 15). More-
over, the stereoselectivity was maintained even in the pres-
ence of 2.5 mol% of catalyst, albeit with a little loss of the
yield (Table 1, entry 17). Similar results were obtained when
the reaction was carried out under an air atmosphere
(Table 1, entry 16). The employment of the d-proline-de-
rived ligand L5 gave access to the enantiomeric product ent-
3a with comparable results (Table 1, entry 18). Thus, the op-
tron-withdrawing groups at different positions were well tol-
erated in terms of the diastereo- and enantioselectivities; up
to 96:4 d.r. and 96% ee were obtained (Table 2, entries 1–
18). Condensed and fused ring aldimines 2s and 2t were
suitable substrates for the reaction, giving the corresponding
products 3s and 3t with 93% ee and 96% ee, respectively
(Table 2, entries 19 and 20). Disubstituted imine 2u reacted
smoothly with the glycine Schiff base 1 to provide the de-
sired a,b-diamino derivative 3u with 86:14 d.r. and 90% ee
(Table 2, entry 21). Notably, the current catalyst system was
rather efficient for the heteroaromatic substrates, which de-
livered the adducts in up to 97% ee and 95:5 d.r. (Table 2,
entries 22–24). When the catalyst loading was decreased to
timal
reaction
conditions
were
L5-CuACTHGUNTRENNU(G OAc)2·H2O
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www.chemeurj.org
3679

X. Feng et al.
2.5 mol%, good results can also be achieved, although a
slight decrease in efficiency was detected (Table 2, entries 3,
8, 11, and 13, values in parentheses). The absolute configu-
ration of adduct 3m was determined to be (2S, 3S) by com-
parison with literature data.[7]
Optically active dihydropyridones are important synthetic
intermediates used in the asymmetric synthesis of poly-
hydroxylated piperidine alkaloids.[15] This reaction offers a
convenient approach to the synthesis of such compounds.
Therefore, hydrolysis of the corresponding a,b-diamino acid
ester 3w[16] with 2n HCl, followed by protection with Boc2O
gave adduct 4 in 89% yield. Through an aza-Achmatowicz
reaction,[17] the Boc-protected derivative 4 could be easily
converted to dihydropyridone 5 in good yield at 08C
(Scheme 2).
This experimentally simple procedure provides various opti-
cally active anti-a,b-diamino acid esters in good yields with
up to 96:4 d.r. and 97% ee. The reaction features low cata-
lyst loading, no external additive, and good tolerance of an
air atmosphere. Moreover, excellent d.r. and ee values can
also be obtained in gram-scale. Further investigation of the
reaction mechanism of this catalytic system is in progress.
Experimental Section
General experimental procedure:
A mixture of ligand L5 (3.1 mg,
0.005 mmol), Cu(OAc)2·H2O (1.0 mg, 0.005 mmol), and imine 2a
AHCTUNGTRENNUNG
(25.9 mg, 0.1 mmol) were stirred in THF (0.85 mL) at 08C under an
argon atmosphere for 15 min. Glycine Schiff base 1 (0.15 mL, 1m in
THF) was added, and the reaction was stirred at 08C for 26 h. The crude
product was purified by flash chromatography directly (petroleum ether/
ethyl acetate, 6:1) to afford a white solid which was an inseparable mix-
ture of diastereomers (49 mg, 95% yield, 94% ee, d.r. 93:7).
Acknowledgements
We thank the National Natural Science Foundation of China (No.
20732003) and the Ministry of Education (No. 20070610019) for financial
support, as well as the Sichuan University Analytical & Testing Centre
for NMR and X-ray analyses, and the State Key Laboratory of Biothera-
py for HRMS analysis.
Keywords: asymmetric catalysis · diamino acid esters ·
diastereoselectivity · glycine Schiff base · Mannich reaction
Scheme 2. Elaboration of the adduct 3w for the Mannich-type reaction
of glycine Schiff base 1 and imine 2w.
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Schiff base 1.
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Mannich-Type Reaction of Glycine Schiff Bases with Aldimines
COMMUNICATION
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Received: January 16, 2009
Published online: February 19, 2009
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