Catalytic enantioselective ene reactions of imines: A simple approach for the formation of optically active α-amino acids

Article abstract of DOI:10.1039/a808019d

A highly enantioselective ene reaction of readily available tosyl α-imino esters with alkenes catalysed by only 0.1 mol% of chiral CuPF₆-BINAP complexes is presented.

Full text of DOI:10.1039/a808019d

Catalytic enantioselective ene reactions of imines: a simple approach for the
formation of optically active a-amino acids
Sulan Yao, Xiangming Fang and Karl Anker Jørgensen*
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark.
E-mail: kaj@kemi.aau.dk
Received (in Cambridge, UK) 15th October 1998, Accepted 21st October 1998
A highly enantioselective ene reaction of readily available
combination with copper( ) salts catalyse the ene reaction of a-
I
tosyl a-imino esters with alkenes catalysed by only 0.1 mol%
methylstyrene 1a with tosyl a-imino ester 2a giving adduct 3a
of chiral CuPF
6
–BINAP complexes is presented.
in good yield and up to 95% ee (Table 1, entries 1–6). The ee of
3
a is counterion-dependent and the highest ees are obtained
with PF and ClO as the anions; it is of practical importance
that CuPF can be used as this Lewis acid is safer, more stable
and easier to handle than CuClO . Changing the catalyst to (S)-
BINAP–CuClO leads to the opposite enantiomer with the same
The development of asymmetric catalytic reactions has in recent
years added a new and very important aspect to chemistry as it
allows one to use a small amount of chiral catalysts to form
6
4
6
4
1
directly optically active compounds.
4
The ene reaction of alkenes 1 with a-imino esters 2 can give
a-amino acids 3 which are among the most fundamental
compounds in nature (Scheme 1).
yield and ee. Choosing copper(II) as the Lewis acid in
combination with the BINAP ligands leads to a significant
reduction in the ee of 3a (entry 7). The combination of ligand 4b
with other Lewis acids gives only reasonable results in the case
H
N
HN
of silver(
R,R)-DIOP 4c and (R,R)-NORPHOS 4d leads only to very low
yield and ee of 3a when tested for the ene reaction in
combination with CuPF as the Lewis acid (entries 13, 14). The
results presented in Table 1 are all performed in THF; CH Cl
I
) (entries 8–12). The application of the chiral ligands
+
(
RO2C
2
CO R
1
2
3
6
Scheme 1
2
2
Within the last decade the asymmetric catalytic addition
reactions of carbonyl compounds have been developed to a
level where they can be performed with a high degree of
stereoselectivity.2 Compared with the highly efficient cata-
lytic enantioselective ene reaction of carbonyl compounds, the
related ene reaction of imines has only met with very limited
can also be used and similarly good results as those presented in
entries 1–6 are obtained. The latter solvent has the advantage
that the reaction course can easily be monitored by the colour
change; the coordination of 2a to the catalyst complex at the
reaction temperature gives a dark purple colour, and when the
reaction goes to completion the colour becomes a clear light
yellow. We have also tried various chiral bisoxazolines in
combination with different Lewis acids but only low to
moderate ees were obtained.
–4
5
success. The catalytic enantioselective ene reaction of imines
has, to the best of our knowledge, not yet been achieved
regardless of its potential broad application. One of the
problems with this reaction compared with the related reaction
of carbonyl compounds is that the imine probably competes
with the chiral ligand in coordinating to the Lewis acid and
therefore suppresses the chiral information from the ligand.
Recently the first catalytic enantioselective hetero-Diels–
The potential and scope of the ene reaction of various alkenes
1a–e with the tosyl a-imino ester 2a in the presence of (R)-Tol-
BINAP 4b–CuX as the catalyst are presented in Table 2.10
The results show that both aromatic (1a,b), cyclic (1c,d) and
simple aliphatic alkenes (1e) react with 2a in the presence of
6
7
8
Alder reaction, addition of enol silanes and alkylation of a-
9
imino esters 2 have been developed and a recent paper dealing
Table 1 The results for the reaction of a-methylstyrene 1a with the tosyl a-
imino ester 2a in the presence of the various chiral phosphine ligands 4a–d
and Lewis acids (10 mol%) at room temperature in THF
with the catalytic ene reaction of 2 with alkenes prompted us to
present our results at the present stage of investigations.
Here we present a highly enantioselective ene reaction of
Ts
Ts
alkenes with tosyl a-imino esters catalysed by chiral CuPF
6
–
N
HN
BINAP complexes. The strategy behind the catalytic enantiose-
+
Catalyst
10 mol%)
lective ene reaction of a-imino esters is the use of chiral
Ph
EtO2C
Ph
CO Et
2
(
phosphine ligands in combination with copper( ) salts. The
I
1a
2a
3a
chiral phosphine ligands (R)-BINAP 4a, (R)-Tol-BINAP 4b,
(R,R)-DIOP 4c and (R,R)-NORPHOS 4d have been found to be
Yield of
3a (%)
a
b
Entry
Ligand–metal salt
Ee (%)
H
1
2
3
4
5
6
7
8
9
4a–CuClO4
73
75
77
80
58
67
75
75
72
63
61
8
93
95
93
95
76
80
24
73
67
68
< 5
5
O
O
PPh2
PAr2
PAr2
Me
Me
PPh2
PPh2
4b–CuClO
4a–CuPF
4b–CuPF
4
6
H
6
H
H
4a–CuOTf
4b–CuOTf
4b–Cu(OTf)
4b–AgOTf
Ph2P
2
4
a Ar = Ph
b Ar = Tol
4c
4d
4
4b–AgClO
4b–AgSbF
4b–Pd(SbF
4b–RuArSbF
4c–CuPF
4d–CuPF
4
10
11
12
13
14
6
the most promising of the different ligands tested for the ene
reaction of a-methylstyrene 1a with tosyl a-imino ester 2a in
the presence of various Lewis acids. Some representative results
are presented in Table 1.
6 2
)
6
6
3
25
< 5
< 5
6
The results for the screening of the various ligands and Lewis
acids show that (R)-BINAP 4a and (R)-Tol-BINAP 4b in
a
Isolated yield. b Determined by chiral HPLC.
Chem Commun, 1998, 2547–2548
2547

Table 2 The results for the reaction of various alkenes 1a–e with the tosyl
6
a-imino ester 2a catalysed by (R)-Tol-BINAP 4b–CuX (X PF ,
cyclic and simple alkenes and the reaction provides a simple
method for the preparation of both optically active natural and
non-natural a-amino acids; the potential of the ene reaction
derives from the fact that it proceeds with only 0.1 mol% of the
=
a
4
ClO )
R2
R2
Ts
Ts
N
HN
CuPF –BINAP catalyst. Work is in progress to develop the
Catalyst
6
+
reaction further and to understand the mechanism.
Thanks are expressed to the Danish National Science
Foundation for financial support.
R1
a R1 = Ph, R2 = H
EtO C
2
R1
CO2Et
2
1
3a R1 = Ph, R2 = H
1
2a
1
2
b R = p-MeOC6H4, R = H
b R = p-MeOC6H4, R = H
c R = R2 = (CH2)3
1
Notes and references
c R = R2 = (CH2)3
1
d R = R2 = (CH2)4
1
1 Some recent books dealing with asymmetric catalysis: Advances in
Catalytic Processes: Asymmetric Chemical Transformations, ed. M.
Doyle, JAI, Greenwich, CT, 1995, vol. 1; Catalytic Asymmetric
Synthesis, ed. I. Ojima, VCH, Weinheim, 1993; M. Santelli and J.-M.
Pons, Lewis Acids and Selectivity in Organic Synthesis, CRC Press,
Boca Raton, 1995; Asymmetric Catalysis in Organic Synthesis, ed. R.
Noyori, Wiley Interscience, New York, 1993; L. F. Tietze and G.
Kettschau, Stereoselective Heterocyclic Synthesis I, ed. P. Metz,
Springer Verlag, Berlin, 1997, vol. 189, pp. 1–120; Transition Metals
for Fine Chemicals and Organic Synthesis, ed. M. Beller and C. Bolm,
Wiley Interscience, UK, 1998.
d R = R2 = (CH2)4
1
e R = Me, R2 = H
1
e R1 = Me, R2 = H
Yieldb
(%)
Eec
(%)
Load
(%)
Entry Catalyst
1
T/°C
t/h
1d
4b–CuClO
4b–CuClO
4
1a 10
1a 10
room temp. 18
room temp. 18
75
85
80
82
71
81
80
74
72
49
62
95
95
99
98
95
91
91
92
84
82
78
2
3
4
5
6
7
8
9
0
4
4b–CuPF
4b–CuPF
4b–CuPF
6
6
6
1a
1a
1a
1b
1b
1c
1d
1e
1e
1
220
38
22
24
15
36
18
60
17
60
0.5
0.1
1
0.1
0.5
1
0
0
0
2
For a general review of eneantioselective ene reactions, see K. Mikami
and M. Shimizu, Chem. Rev., 1992, 92, 1021.
4b–CuClO
4b–CuClO
4
4
0
220
0
3
See also e.g. K. Mikami, Pure Appl. Chem. 1996, 68, 639; K. Mauruoka,
Y. Hoshino, T. Shirasaka and H. Yamamoto, Tetrahedron Lett. 1988,
4b–CuPF
4b–CuPF
4b–CuPF
4b–CuPF
6
6
6
6
2
9, 3967; D. A. Evans, C. S. Burgey, N. A. Paras and S. W. Tregay,
1
1
a
2
1
0
0
e
J. Am. Chem. Soc., 1998, 120, 5824.
1
4
Examples of catalytic enantioselective hetero-Diels–Alder reactions of
aldehydes and ketones see e.g. K. Maruoka, T. Otoh, T. Shirasaka and
H. Yamamoto, J. Am. Chem. Soc. 1988, 110, 310; Q. Gao, K. Ishihara,
M. Mouri and H. Yamamoto, Tetrahedron, 1994, 50, 979; G. Keck,
X.-Y. Li and D. Krishamurthy, J. Org. Chem., 1995, 60, 5998; Q. Gai,
T. Maruyama, M. Mouri and H. Yamamoto, J. Org. Chem., 1992, 57,
1951; M. Bednarski and S. Danishefsky, J. Am. Chem. Soc., 1986, 108,
7060; M. Johannsen and K. A. Jørgensen, J. Org. Chem., 1995, 60,
5757; A. Graven, M. Johannsen and K. A. Jørgensen, Chem. Commun.,
2 2
All reactions were run in CH Cl on a 0.4 mmol scale unless otherwise
b
c
stated. Isolated yield. Determined by chiral HPLC using a Chiralcel OJ
or OD column. Solvent THF. e The reaction was performed on a 3 mmol
scale.
d
Ts
Ts
Ts
HN
N
N
+
+
4b–CuPF6
10%
CO2Et
3f 86% ee
CO2Et
5 65% ee
EtO2C
1
996, 3272; S. Yao, M. Johannsen, H. Audrian, R. G. Hazell and K. A.
1f
2a
Jørgensen, J. Am. Chem. Soc., 1998, 120, 8599; D. A. Evans and J. S.
Johnson, J. Am. Chem. Soc., 1998, 120, 4895; J. Thorhauge, M.
Johannsen and K. A. Jørgensen, Angew. Chem., Int. Ed., 1998, 37,
2404
Scheme 2
(
R)-Tol-BINAP 4b–CuX (X = PF
alkene 1a it appears that the reaction proceeds well using both
THF and CH Cl as these solvents, giving good yields and high
6 4
, ClO ) as the catalyst. For
5
Examples of ene reactions of related imines with alkenes are: O.
Achmatowicz and M. Pietraszkiewicz, J. Chem. Soc., Perkin Trans. 1,
2
2
1981, 2680; D. M. Tschan and S. M. Weinreb, Tetrahedron Lett., 1982,
23, 3015; K. Koch, J.-Y. Lin and F. W. Fowler, Tetrahedron Lett., 1983,
24, 1581; D. M. Tschan, E. Turos and S. M. Weinreb, J. Org. Chem.,
1984, 49, 5058; S. Hannesian and R.-Y. Yang, Tetrahedron Lett., 1996,
30, 5273.
ees of 3a at room temperature in the presence of 10 mol% of the
catalyst (entries 1, 2). Reducing the catalyst loading to 1, 0.5 and
even 0.1 mol% causes no significant reduction in the yield of 3a
and even higher enantioselectivities (up to 99%) are obtained
(entries 3–5). The p-methoxy substituted alkene 1b reacts in a
6 For catalytic enantioselective hetero-Diels–Alder reaction of imines: K.
Ishihara, M. Miyata, H. Hattori and Y. Yamamoto, J. Am. Chem. Soc.,
1994, 116, 10520; S. Kobayashi, S. Komiyama and H. Ishitani, Angew.
Chem., Int. Ed., 1998, 37, 797; S. Yao, M. Johannsen, R. G. Hazell and
K. A. Jørgensen, Angew. Chem., Int. Ed., 1998, in the press.
similar manner with 2a and an ee of up to 91% is obtained using
only 0.1 mol% catalyst loading (entry 7). Methylenecyclo-
pentane 1c reacts also in a highly enantioselective manner with
2
9
a with only 0.5 mol% of 4b–CuPF
2% ee is found (entry 8), while methylenecyclohexane 1d is
6
as the catalyst and up to
7
For catalytic enantioselective addition of enol silyl ethers to imines: E.
Hagiwara, A. Fujii and M. Sodeeoka, J. Am. Chem. Soc., 1998, 120,
less reactive and leads to a small reduction in ee compared with
c (entry 9). The reaction of isobutylene 1e with 2a in the
presence of (R)-Tol-BINAP 4b–CuPF as the catalyst (entries
0, 11) gives also the corresponding ene product 3e in
2
474; D. Ferraris, B. Young, T. Dudding and T. Lectka, J. Am. Chem.
1
Soc., 1998, 120, 4548; D. Ferraris, B. Young, C. Cox, W. J. Drury III,
T. Dudding and T. Lectka, J. Org. Chem., 1998, 63, 6090.
8 For catalytic enantioselective alkylation of imines: H. Nakamura, K.
Nakamura and Y. Yamamoto, J. Am. Chem. Soc., 1998, 120, 4242.
9 W. J. Drury III, D. Ferraris, C. Cox, B. Young and T. Lectka, J. Am.
Chem. Soc., 1998, in the press.
6
1
reasonable yields and with high ee; the latter reaction can be
performed in a gram scale with a catalytic loading of only 1
mol% without affecting the yield and ee. This reaction has been
used to assign the absolute stereochemistry of the ene product
1
0 Experimental procedure: A 0.008
prepared by the addition of CuPF ·4MeCN (15 mg, 0.04 mmol) and (R)-
Tol-BINAP (30 mg, 0.044 mmol) under N to a flame dried Schlenk
tube. The mixture was stirred for 1 h under vacuum, freshly distilled
CH Cl (5 ml) was added with a syringe under N and the light yellow
M solution of the catalyst was
6
3
e as this adduct is easily transformed to the N-tosylleucine
2
ethyl ester the stereochemistry of which is found to be S by
correlation with the same compound prepared from (S)-leucine.
The absolute stereochemistry of 3e indicates that the alkene
approaches the si-face of the tosyl a-imino ester 2a when
coordinated to the catalyst.
2
2
2
solution was stirred for 1–3 h until it had become absolute homoge-
neous. Catalytic reaction (1 mol% catalyst): To a flame dried Schlenk
tube was added freshly destilled CH
previously prepared catalyst solution (500 ml) under N
2
Cl
2
(1 ml) and an aliquot of the
and stirred for 5
2
,3-Dimethylbuta-1,3-diene 1f reacts with the tosyl a-imino
2
min; then the tosyl a-imino ester 2a (0.4 mmol) was added at room
temp. The dark purple solution was cooled to the desired reaction
temperature before the alkene (0.8 mmol) was added. Then the reaction
was kept at that temperature until the dark purple colour had changed
into a clear yellow solution (10–65 h). After evaporation of the solvent
the crude product was purified by flash chromatography (20% EtOAc–
pentane) to give the ene adduct.
ester 2a in the presence of (R)-Tol-BINAP 4b–CuPF (10
6
mol%) as the catalyst to give both the ene product 3f and the
hetero-Diels–Alder product 5, with a preference for the latter
(
3f:5 = 1:9) (Scheme 2). The ee of the ene adduct 3f was 86%
at room temperature, while 65% ee was found for 5.
We have presented a highly enantioselective ene reaction of
alkenes with tosyl a-imino esters catalysed by CuPF
6
–BINAP
complexes. The substrates for this ene reaction are aromatic,
Communication 8/08019D
2548
Chem Commun., 1998, 2547–2548
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