Organocatalytic asymmetric synthesis of protected α,β-diamino acids

Article abstract of DOI:10.1002/adsc.200900580

In the presence of the readily available quinine-derived catalyst 4d, highly diastereo- and enantioselective Mannich reactions of tosyl-protected imines and α-isothiocyanato imides proceeded to afford the protected α,β-diamino acids, useful building block

Full text of DOI:10.1002/adsc.200900580

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DOI: 10.1002/adsc.200900580
Organocatalytic Asymmetric Synthesis of Protected a,b-Diamino
Acids
Zugui Shi,a Peiyuan Yu,a Pei Juan Chua,a and Guofu Zhonga,*
a
Division of Chemistry & Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, 21 Nanyang Link, Singapore 637371, Singapore
Fax : (+65)-6791-1961; phone: (+65)-6316-8761; e-mail: guofu@ntu.edu.sg
Received: August 23, 2009; Published online: November 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900580.
Abstract: In the presence of the readily available
quinine-derived catalyst 4d, highly diastereo- and
enantioselective Mannich reactions of tosyl-protect-
ed imines and a-isothiocyanato imides proceeded to
afford the protected a,b-diamino acids, useful build-
ing blocks for natural products and biologically
active compounds, in good to excellent yields.
ties of the imines toward a-isothiocynato imide 1.[7]
When more reactive tosyl-protected phenylimine 2
was employed, to our delight, the reaction proceeded
smoothly to give the desired product in 92% yield,
though no enantioselectivity was achieved (Table 1,
entry 5). Encouraged by this promising result, three
new bifunctional catalysts 4k, 4l and 4m were de-
signed and synthesized for the reaction (Figure 1).
Unfortunately, they could not promote this transfor-
mation.[7] Another ten catalysts were then screened
Keywords: asymmetric catalysis; a,b-diamino acids;
Mannich reaction; organocatalysis; quinine deriva-
tives
Table 1. Catalyst screening.[a]
Amino acids, such as a-amino acids,[1] b-amino acids[2]
and b-hydroxy-a-amino acids,[3] are frequently found
in many biologically active peptides and natural prod-
ucts. They have attracted intensive investigation from
numerous research groups. However, a,b-diamino
acids,[4] which are also versatile intermediates in aca-
demic and industrial fields, as well as some other
types of amino acids, were less well studied, especially
with regard to their asymmetric syntheses. Although
some of the methodologies have realized asymmetric
versions by employing chiral ligand/metal complexes,
it still remains a big challenge to develop a more effi-
cient, economical and operationally simple strategy,
and at the same time avoiding toxic metals and ex-
pensive chiral ligands.[5] Herein, we report a catalytic
asymmetric synthetic protocol for the synthesis of the
protected a,b-diamino acids by the Mannich reactions
of tosyl-protected imines and a-isothiocyanato imides
with a cheap and readily available quinine derivative
as catalyst under the mild reaction conditions.[6]
Entry
4
t [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
5
5
24
4
5
73
92
81
99
92
91
78
50
95
88
95:5
95:5
91:9
95:5
–
95:5
87:13
95:5
67:33
89:11
43
85
40
>99
0
À48
À50
À40
À24
70
6
24
24
10
10
9
10[e]
4b
[a]
Reaction was performed at room temperature (238C) on
a 0.1 mmol scale in toluene (0.1M) using 1.2 equiv. of 2
and 10 mol% 4. Reaction conditions: see Experimental
Section.
Combined yield of both diastereoisomers.
Determined by H NMR on the crude mixture.
[b]
[c]
[d]
[e]
PMP- and Boc-protected phenylimines were first
examined for this transformation in the presence of
10 mol% catalyst 4e. However, no reactions occurred.
This was probably due to the reduced electrophilici-
1
Determined by chiral HPLC of the major isomer.
Reaction was performed at 0–48C.
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Zugui Shi et al.
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and we observed that Cinchona alkaloid derivatives
catalyzed the reaction giving low levels of asymmetric
induction (entries 1, 3 and 4–8), while simple BINOL-
derived phosphoric acid 4j could not induce any reac-
tion.[7] When the more acidic catalyst 4b (comparing
to 4a) was examined, the enantioselectivity was signif-
icantly increased to 85% ee (entry 2, 95:5 dr and 92%
yield).[8] Decreasing the reaction temperature to 0–
48C led to the diminished diastereo- and enantiose-
lectivity (entry 10, 70% ee and 89:11 dr). Protection
of the 9-hydroxy group on catalyst 4b with a benzoyl
group dramatically improved the catalytic efficiency,
thus achieving excellent stereoselective control
(entry 4, >99% ee and 95:5 dr).[9]
The effect of catalyst loading, solvent and reactant
concentration for this transformation was further in-
vestigated (Table 2). Catalyst 4d proved powerful
enough to afford product 3a in excellent yield (98%),
enantio- (98%) and good diastereoselectivity (90:10
dr), even with a low catalyst loading (1.0 mol% in
entry 5). Various non-polar solvents were well tolerat-
ed, with m-xylene giving the best result in the pres-
ence of 2.5 mol% catalyst 4d at room temperature
(entry 10, in 99% yield,>99% ee and 95:5 dr).
With the optimal reaction conditions in hand, the
scope of tosyl-protected imines was explored as
shown in Table 3. Aromatic, heteroaromatic and ali-
phatic Ts-protected imines were good substrates for
this reaction, affording the desired adducts in high
yields and stereoselectivities. Ts-protected 3 or 4-sub-
stituted and non-subsituted phenylimines were strong-
Figure 1. Structures of catalysts screened.
Table 2. Optimization of reaction conditions.
Entry
mol% (4d)
Solvent
M (1)
t [h]
Yield [%][a]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
10
7.5
5
toluene
toluene
toluene
toluene
toluene
toluene
benzene
CHCl3
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.05
3.5
4
4
5
13
5
10
24
8
5
2
99
91
97
94
98
94
74
60
96
99
99
99
95:5
93:7
95:5
95:5
90:10
95:5
95:5
92:8
95:5
96:4
95:5
96:4
>99
>99
>99
>99
98
>99
98
99
2.5
1.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
9
MTBE
96
10
11
12
m-xylene
m-xylene
m-xylene
>99
>99
>99
8
[a]
Combined yield of both diastereoisomers.
Determined by H NMR of the crude reaction mixtures.
Determined by chiral HPLC using chiral AD-H column or AS-H column of the major isomer.
[b]
[c]
1
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Adv. Synth. Catal. 2009, 351, 2797 – 2800

Organocatalytic Asymmetric Synthesis of Protected a,b-Diamino Acids
Table 3. Substrate scope.[a]
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Experimental Section
Typical Procedure for the Catalytic Synthesis of a,b-
Diamino Acids
To a stirred solution of catalyst 4d (2.5 mol%) and Ts-pro-
tected imines (0.12 mmol) in 1.0 mL of m-xylene, was added
a-isothiocyanato imide 1 (0.1 mmol). The reaction mixture
was kept stirring at room temperature (238C) for the time
given in Table 3. After the reaction was completed, solvent
was removed under reduced pressure, and then dried THF
was added and the mixture cooled to 0–48C. A THF solu-
tion of magnesium bromide ethanolate (2 mL, 3.0 equiv.),
preformed from methylmagnesium bromide (0.1 mL, 3M in
DCM) and ethanol (0.1 mL) in 2 mL of THF at 08C, was
slowly added. After 3 min, the reaction was quenched by sa-
turated aqueous NH4Cl. Then, the crude product was puri-
fied over silica gel chromatography with the eluent (hexane/
acetone from 8:1 to 2:1) to give the corresponding protected
a,b-diamino acid ethyl ester derivatives. The stereochemis-
try of the product was confirmed by the X-ray crystallo-
graphic analysis (CCDC 745237)[10] together with the NMR
spectroscopy.
Entry
R
t [h] Yield [%][b] dr[c]
ee [%][d]
1
2
3
4
5
6
Ph
5
90
99
97
92
98
99
96
80
91
99
90
97
90
96:4
97:3
96:4
97:3
97:3
93:7
>99
>99
>99
>99
>99
95
4-MeC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-ClC6H4
3-furyl
2-MeC6H4
2-FC6H4
2-thienyl
2-naphthyl
cinnamyl
n-butyl
4
3
5
4
2
7[e]
8[f]
9[e]
10
11[e]
12[e]
13[g]
6
89:11 98
91:9 91
67:33 97
93:7
95:5
72
10
6
99
97
5
30
48
80:20 98
83:17 86
[a]
Standard conditions, see Experimental Section.
Combined yield of both diastereoisomers.
Determined by H NMR of reaction mixtures.
Determined by chiral HPLC.
5 mol% 4d was used.
10 mol% 4d was used.
[b]
[c]
[d]
[e]
[f]
1
Acknowledgements
Research support from the Ministry of Education in Singa-
pore (ARC12/07, no. T206B3225) and Nanyang Technologi-
cal University (URC, RG53/07) is gratefully acknowledged.
[g]
10 mol% 4d and 20 mg 4 ꢁ MS were employed.
References
ly favoured on this catalytic platform, in ꢀ90%
yields, ꢀ95% ee and ꢀ93:7 dr (entries 1–6). For the
cases of 2-substituted Ts-protected imines, higher cat-
alyst loadings and longer reaction time were needed,
probably due to their steric hindrance and thus lower
diastereoselectivities were obtained. Their enantiose-
lectivities dropped a little bit, especially for 2-methyl
phenyl Ts-protected imine (entry 8, 91% ee). It is
worthwhile to note that, even with highly unstable ali-
phatic Ts-protected imine substrates, the Mannich re-
action could still proceed smoothly in excellent yield
with acceptable diastereoselectivity and good enantio-
selectivity in the presence of 10 mol% catalyst 4d and
20 mg of 4 ꢁ molecular sieves (entry 13, 90% yield,
86% ee and 83:17 dr).
In summary, we have developed a highly efficient
organocatalytic asymmetric protocol for preparation
of the enantiomerically pure protected a,b-diamino
acids, through the Mannich reaction between Ts-pro-
tected imines and a-isothiocyanato imide 1, catalyzed
by readily available and environmentally-friendly qui-
nine derived catalyst 4d under very mild conditions.
[1] a) C. Najera, J. M. Sansano, Chem. Rev. 2007, 107,
4584–4671; b) M. J. OꢂDonnell, Acc. Chem. Res. 2004,
37, 506–517.
[2] a) C. Cassani, L. Bernardi, F. Fini, A. Ricci, Angew.
Chem. Int. Ed. 2009, 48, 5694–5698; b) S. S. V. Rama-
sastry, H. Zhang, F. Tanaka, C. F. Barbas III, J. Am.
Chem. Soc. 2007, 129, 288–289; c) S. Saito, T. Tsubogo,
S. Kobayashi, Chem. Commun. 2007, 1236–1237;
d) J. W. Yang, M. Stadler, B. List, Angew. Chem. Int.
Ed. 2007, 46, 609–611; e) Y. Hayashi, W. Tsuboi, I.
Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew.
Chem. Int. Ed. 2003, 42, 3677–3680; f) B. Shen, J. N.
Johnston, Org. Lett. 2008, 10, 4397–4400; g) A. G.
Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124,
12964–12965.
[3] a) D. A. Evans, A. E. Weber , J. Am. Chem. Soc. 1986,
108, 6757–6761; b) M. C. Willis, G. A. Cutting, V. J.-D.
Piccio, M. J. Durbin, M. P. John, Angew. Chem. Int. Ed.
2005, 44, 1543–1545; c) L. Li, E. G. Klauber, D. Seidel,
J. Am. Chem. Soc. 2008, 130, 12248–12249.
[4] a) For a review of a,b-diamino acids, see: A. Viso,
R. F. de La Pradilla, A. Garca, A. Flores, Chem. Rev.
2005, 105, 3167–3196; b) for a review of vicinal di-
AHCTUNGTREGUNaNN mines, see: D. Lucet, T. L. Gall, C. Mioskowski,
Angew. Chem. Int. Ed. 1998, 37, 2580–2627.
[5] For selected examples involving asymmetric synthesis
of a,b-diamino acids, see: a) A. Singh, J. N. Johnston, J.
Am. Chem. Soc. 2008, 130, 5866–5867; b) J. Wang, T.
Adv. Synth. Catal. 2009, 351, 2797 – 2800
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2799

Zugui Shi et al.
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Shi, G. Deng, H. Jiang, H. Liu, J. Org. Chem. 2008, 73,
8563–8570; c) J. Hernaꢂndez-Toribio, R. G. Arrayꢃs,
J. C. Carretero, J. Am. Chem. Soc. 2008, 130, 16150–
16151; d) G. A. Cutting, N. E. Stainforth, M. P. John, G.
Kociok-Khn, M. C. Willis, J. Am. Chem. Soc. 2007, 129,
10632–10633; e) Z. Chen, H. Morimoto, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 2170–2171;
f) A. Singh, R. A. Yoder, B. Shen, J. N. Johnston, J.
Am. Chem. Soc. 2007, 129, 3466–3467; g) A. Okada, T.
Shibuguchi, T. Ohshima, H. Masu, K. Yamaguchi, M.
Shibasaki, Angew. Chem. Int. Ed. 2005, 44, 4564–4567;
h) T. Ooi, M. Kameda, J. Fujii, K. Maruoka, Org. Lett.
2004, 6, 2397–2399; i) L. Bernardi, A. S. Gothelf, R. G.
Hazell, K. A. Jørgensen, J. Org. Chem. 2003, 68, 2583–
2591.
with a-isothiocyanato imides was reported by Seidel
and co-workers, where the quinidine derivatives were
employed as catalysts, see: a) L. Li, M. Ganesh, D.
Seidel, J. Am. Chem. Soc. 2009, 131, ASAP; for our
work using this type of catalysts, see: b) B. Tan, Z. Shi,
P. J. Chua, G. Zhong, Org. Lett. 2008, 10, 3425–3428.
[7] For more details, please see the Supporting Informa-
tion.
[8] For the pioneering work, see: H. Li, Y. Wang, L. Tang,
L. Deng, J. Am. Chem. Soc. 2004, 126, 9906–9907.
[9] For the seminal work, see: H. Li, B. Wang, L. Deng, J.
Am. Chem. Soc. 2006, 128, 732–733.
[10] CCDC 745237 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[6] During the preparation of this manuscript, an excellent
work on the Mannich reactions of Bs-protected imines
2800
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