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Communications
Asymmetric Catalysis
Highly Enantioselective Thiourea-Catalyzed
Nitro-Mannich Reactions**
Tehshik P. Yoon and Eric N. Jacobsen*
=
The addition of a nitroalkane across the C N bond of an
Figure 1. Urea and thiourea catalysts. Piv=pivaloyl.
imine [Eq. (1), PG = protecting group], known as the nitro-
hydrocyanation,[9] Mannich,[10] hydrophosphonylation,[11] and
acyl-Pictet–Spengler[12] reactions. Intrigued by the possibility
that these compounds might constitute an emerging class of
“privileged”[13] enantioselective catalysts, we investigated
their activity in the asymmetric nitro-Mannich reaction.
Herein, we report the discovery that the new thiourea catalyst
2b efficiently promotes the diastereoselective nitro-Mannich
reaction of nitroalkanes with N-Boc imines with high levels of
enantioselectivity.
Mannich (or aza-Henry) reaction, is a carbon–carbon bond-
forming process that can result in the generation of two
contiguous nitrogen-bearing stereogenic centers. This reac-
tion allows straightforward entry to a variety of nitrogen-
containing chiral building blocks such as vicinal diamines by
Our initial exploratory efforts directed toward thiourea-
catalyzed asymmetric nitro-Mannich reactions involved
screening of catalysts 1a and 1b, which had been developed
and optimized in the context of Strecker-type reactions.[9]
Surprisingly, while the first-generation Strecker urea catalyst
1a afforded promising activity in the model reaction of
nitroethane with benzaldehyde-derived N-Boc imine 3a
[Eq. (2)] (20% conversion, 2.1:1 syn:anti, 50% ee; Table 1,
[1,2]
reduction of the nitro group
and a-amino carbonyl
compounds by means of the Nef reaction.[3] As a result,
considerable effort has been directed toward the develop-
ment of catalytic asymmetric versions of the nitro-Mannich
reaction over the past several years. Shibasaki et al. have
described the enantioselective addition of nitroalkanes to N-
phosphinoyl imines using chiral ytterbium[4] and aluminum[5]
catalysts, while Jørgensen et al.
have reported asymmetric copper-
Table 1: Optimization of reaction conditions [Eq. (2), Ar=Ph].
catalyzed additions to a-iminoest-
ers.[6] Beyond these metal-cata-
lyzed variants, two reports of enan-
tioselective organocatalytic nitro-
Mannich reactions have appeared
recently. Takemoto et al. have
reported a bifunctional thiourea
catalyst that induces moderate
enantioselectivity in the addition
of nitromethane to a variety of
aromatic N-phosphinoyl imines,[7]
and Johnston et al. have developed
a chiral bisamidine triflate salt that effects the diastereose-
lective addition of nitroethane to a range of electron-deficient
N-Boc imines.[8]
Our laboratory has identified a family of chiral urea and
thiourea catalysts (e.g. 1a and 1b, Figure 1) that catalyze a
variety of enantioselective reactions with imines, including
Entry Cat. Solv.
Base (equiv) Mol. sieves T [8C] t [h] Conv. [%]
d.r.
(syn:anti)
ee [%]
(4 ꢀ)
1
2
3
4
5
6
7
1a
1b
2a
2a
2a
2a
2b
ether
ether
ether
Et3N (0.2)
Et3N (0.2)
Et3N (1)
À
À
À
À
+
+
+
23
23
0
0
0
4
4
20
0
34
>95
>95
36
2.1:1
–
50
–
18
24
24
24
18
7.5:1
8.4:1
10:1
11:1
15:1
92
91
92
91
92
toluene Et3N (1)
toluene Et3N (1)
toluene iPr2NEt (1)
toluene iPr2NEt (1)
0
0
>95
entry 1), the improved thiourea Strecker catalyst 1b[9b] failed
to accelerate this transformation (entry 2). Systematic varia-
tion of catalyst structure revealed that the simplified acet-
amide catalyst 2a provided excellent enantio- and diaster-
eoselectivity at 08C, although the poor solubility of the
catalyst in ether resulted in poor activity (entry 3, 34%
conversion, 7.5:1 syn:anti, 92% ee). On the other hand,
catalyst 2a displayed improved solubility in toluene, and the
reaction proceeded to completion within 24 h with similar
enantio- and diastereoselectivity (entry 4, > 95% conversion,
8.4:1 syn:anti, 91% ee). However, the reaction under these
conditions proved to be poorly reproducible and quite
sensitive to the purity of the starting imine; high ee values
were largely limited to the benzaldehyde-derived imine 3a.
After a screen of additives, it was discovered that the addition
of powdered 4-ꢀ molecular sieves improved the reproduci-
bility of the process and provided a more diastereoselective
[*] T. P. Yoon, Prof. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH through GM-43214, P50
GM069721, and a postdoctoral fellowship to T.P.Y.
Supporting information for this article is available on the WWW
466
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200461814
Angew. Chem. Int. Ed. 2005, 44, 466 –468