Copper(II)-catalyzed highly enantioselective addition of enamides to imines: The use of einamides as nucleophiles in asymmetric catalysis

Article abstract of DOI:10.1002/anie.200353237

High-yielding efficient routes to optically active amino acid and 1,3-diamine derivatives have been achieved by the catalytic enantioselective addition of enamides to imines using a chiral copper catalyst (see scheme). This reaction demonstrates the utili

Full text of DOI:10.1002/anie.200353237

Angewandte
Chemie
Enantioselective Synthesis
dichloromethane at 08C for 15 min to afford b-aminoimine
4aa. The yield (83%) and enantioselectivity (85%) were
determined after conversion of 4aa to b-amino ketone 5aa by
treatment with acid (HBr in EtOH/H2O).[5] Enamides 2b, 2c,
and 2d were also investigated in the reaction. The highest
ee value (93%) was obtained with 2d. Interestingly, enamines
2e and 2 f reacted with 1a under the same reaction conditions
to afford 5aa in high yields, but no asymmetric induction was
observed.
Copper(ii)-Catalyzed Highly Enantioselective
Addition of Enamides to Imines: The Use of
Enamides as Nucleophiles in Asymmetric
Catalysis**
Ryosuke Matsubara, Yoshitaka Nakamura, and
Shu¯ Kobayashi*
The results obtained employing other imines and enam-
ides are summarized in Table 1. Several imines, including an
Enamides are potentially useful and atom-economical nucle-
ophiles that contain amide or carbamate moieties after
nucleophilic additions. While enamides can be easily pre-
pared,[1] handled, and stored at room temperature, their use in
organic synthesis is limited.[2] To the best of our knowledge,
there have been no reports of using enamides as nucleophiles
in asymmetric catalysis. We describe here the first example of
the enantioselective addition of enamides to imines using a
chiral copper catalyst.
Initially, we examined the reaction of enamide 2a with
imine 1a[3,4] in the presence of a chiral copper catalyst
(10 mol%) prepared from Cu(OTf)2 and chiral diamine 3a
(Scheme 1).[4b,c] The addition reaction proceeded smoothly in
Table 1: Enantioselective addition of enamides to imines.
Entry
Imine
Enamide
Yield [%][a]
ee [%][b]
1
1a
1a
1b
1c
1d
1a
1b
1a
1a
1a
1b
1c
1c
2d
2d
2d
2d
2d
2g
2g
2h
2i
2j
2j
2k
2k
94(91)[c]
92
72
89
78
97
76
89
93
83
76
84
81
93(93)[c]
93
94
91
87
90
92
90
91
88
91
83
84
2[d]
3
4
5[e]
6
7
8
9
10
11
12
13[d]
[a] Yield of isolated product. [b] Determination by high-performance
liquid chromatographic analysis. Details are given in the Supporting
Information. [c] Cu(OTf)2 (10 mol%) and 3a (10 mol%). [d] Diamine 3b
was employed instead of 3a. [e] Diamine 3c was employed instead of 3a.
N-carbamate-protected imine,[6] were treated with 2d in the
presence of the chiral copper catalyst (10 mol%) to afford the
corresponding adducts in high yields with high enantiomeric
excesses. It was also observed that the reaction proceeded
efficiently when 5 mol% of the catalyst was employed.
Enamides with aromatic substituents were as successful as
substrates as those with alkyl substituents. The use of chiral
diamine 3b instead of 3a was also effective. All the reactions
proceeded smoothly at 08C over 15 minutes, and high yields
and high levels of enantioselectivity were attained with a wide
range of substrates. We also conducted the reaction of (E)-
and (Z)-2-methyl-substituted enamides (E)-2l and (Z)-2l[7]
with imine 1a in the presence of the chiral copper catalyst
(10 mol%) in dichloromethane at 08C for 30 min (Scheme 2).
Enamide (E)-2l was treated with 1a to give the adduct in a
high yield with good syn selectivity (syn adduct: 94% ee).
However, the reaction of (Z)-2l with 1a also gave the
syn adduct as the major product, but the yield and diastereo-
and enantioselectivities were lower. It is noted that syn-
Scheme 1. The copper-catalyzed enantiomeric addition of an enamide
2 with an imine 1 to yield a b-aminoimine 4, which on treatment with
acid produces a b-amino ketone 5. Boc=tert-butoxycarbonyl, Bn=ben-
zyl, OTf=trifluoromethanesulfonate.
[*] R. Matsubara, Y. Nakamura, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo, Hongo
Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)356-840-634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by CREST and SORST, the Japan
Science Technology Agency (JST), and a Grant-in-Aid for Scientific
Research from the Japan Society of the Promotion of Sciences
(JSPS). R.M. thanks the JSPS fellowship for Japanese Junior
Scientists.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353237
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Communications
Scheme 2. The reaction of (E)- and (Z)-2-methyl-substituted enamides
(E)-2l and (Z)-2l with imine 1a in the presence of a chiral copper
catalyst.
adducts were obtained preferentially in both reactions in
which the (E)- and (Z)-enamides were used.
A characteristic of addition reactions of enamides with
imines is the formation of a b-aminoimine 4 as an end
product. Although b-aminoimines are readily converted into
b-amino ketones 5 after treatment with acid, the treatment of
1a with 2d, LiAlH(OtBu)3, and LiI[8] in the same pot afforded
a 1,3-diamine product 6 in an 87% yield with good
diastereoselectivity (Scheme 2, syn:anti = 14:86; no epimeri-
zation was observed during the transformation). Diamine 6
Figure 1. X-ray structure of 8.
added to this green solution and the mixture stirred at 08C for
15 min to afford the adduct 5aa in a yield of 90% and 82% ee.
In summary, we have developed highly enantioselective
reactions of enamides with imines using a chiral copper
catalyst. This is the first example of the use of enamides as
nucleophiles in asymmetric catalysis. The use of enamides has
advantages over that of other nucleophilic enolate equiva-
lents, such as silicon and tin enolates, enamines, etc., from an
atom-economical point of view. From a synthetic standpoint,
functional groups bearing nitrogen atoms have been success-
fully introduced by using enamides as nucleophiles, and
efficient ways to optically active amino acid and 1,3-diamine
derivatives have been developed. Further investigations into
applying this reaction to preparing biologically interesting
compounds, studying the reaction mechanism, and elucidat-
ing the structure of the chiral copper catalyst are in progress.
was further transformed into lactam
7 in high yield
(Scheme 3). Thus, these enantioselective reactions provide
new routes to optically active 1,3-diamine derivatives, which
are versatile chiral building blocks for the synthesis of natural
products, drugs, ligands, etc.[9]
Scheme 3. a) 1. Cu(OTf)2 (10 mol%), 3a (11 mol%), CH2Cl2, 08C,
2. LiAlH(OtBu)3/LiI, Et2O, À458C (87% yield, syn:anti=14:86).
b) Pd/C (10 mol%), H2, AcOEt, AcOH (71% yield).
Received: November 3, 2003
Revised: December 27, 2003 [Z53237]
A plausible mechanism of this reaction may include an
aza-ene-type pathway via an acyclic transition state.[10]
Preliminary kinetic studies using FT-IR spectroscopic analysis
suggest direct formation of b-aminoimine 4 from imine 1.[11]
In addition, N-methyl-substituted enamide 2m did not react
with 1a under the standard reaction conditions. The stereo-
selectivities observed for the reactions of (E)-2l and (Z)-2l
with 1a support the proposed acyclic transition states being
formed during the reaction pathway. The catalyst was
prepared by treating Cu(OTf)2 with chiral diamine 3a in
CH2Cl2 to give a green color, and then adding water to form
the dimeric copper species 8 (blue color). The X-ray structure
of 8 is shown in Figure 1.[12,13] The coordination mode of 8 and
that of the Cu(ClO4)2·diamine complex[4c] may help ration-
alize the reaction stereoselectivity. In addition, while 8 was
found to be a less-effective catalyst for the addition of
enamide 2d to imine 1a,[14] a blue-colored solution of 8 in
CH2Cl2 turned green when 8 was treated with two equivalents
of trifluoromethanesulfonic acid. Compounds 1a and 2d were
Keywords: amino acids · asymmetric catalysis · copper ·
.
1,3-diamines · enamides
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Chemie
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[11] Experimental details are given in the Supporting Information.
[12] 8: [{Cu(OH)(OTf)(3a)}2]. Elemental analysis (%) calcd for
C74H66Cu2F6N4O8S2: C 61.53, H 4.61, N 3.88; found: C 61.37, H
4.70, N 3.80. Further details are given in the Supporting
Information. CCDC-224229 (8) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from www.ccdc.cam.ac.uk/conts/retrieving.html,
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or
deposit@ccdc.cam.ac.uk.
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[14] Enamide 2d was treated with 1a in dichloromethane at 08C for
15 min in the presence of 8 (10 mol%) to afford 5aa in a yield of
78% and 8% ee.
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