A homo-proline tetrazole as an improved organocatalyst for the asymmetric Michael addition of carbonyl compounds to nitro-olefins

Article abstract of DOI:10.1055/s-2005-862392

A new homo-proline tetrazole derivative 7 has been prepared and shown to have improved properties for achieving asymmetric Michael addition of carbonyl compounds to nitro-olefins.

Full text of DOI:10.1055/s-2005-862392

LETTER
611
A Homo-Proline Tetrazole as an Improved Organocatalyst for the Asymmetric
Michael Addition of Carbonyl Compounds to Nitro-Olefins
A
symmetric Mic
l
A
d
a
dition of
C
i
a
rbony
r
l
Compo
e
unds to Nitro-Ole
E
fins . T. Mitchell, Alexander J. A. Cobb, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 22 December 2004
organocatalyst 7 was undertaken (the rationale for which
is discussed later in this article) and its reactions as a
catalyst investigated (Scheme 1).
Abstract: A new homo-proline tetrazole derivative 7 has been pre-
pared and shown to have improved properties for achieving asym-
metric Michael addition of carbonyl compounds to nitro-olefins.
Initial investigations were extremely encouraging: treat-
ment of cyclohexanone and b-nitrostyrene with catalyst 7
provided a 43% yield and 80% ee (Table 1, entry 1). Op-
timisation studies were then carried out, and the effect of
solvent, concentration and reaction time were all investi-
gated (Table 1).9
Key words: asymmetric, nitro-Michael, organocatalysis, homo-
proline, tetrazole
The last few years have witnessed major advances in new
catalytic methods based on organic molecules.1 The reac-
tions can usually be performed under an aerobic atmo-
sphere with wet solvents and the catalysts are generally
inexpensive and air stable. Probably the most extensively
studied asymmetric organocatalytic system is based on
proline 1 (Figure 1),2 which accelerates a range of trans-
formations such as the aldol3 and Mannich reactions4,6 to-
gether with other a-functionalisations of ketones.5
Although these reactions are generally highly enantiose-
lective, they usually require polar solvents such as DMSO
due to the insoluble nature of proline itself in many
standard organic solvents.
Pleasingly, these investigations showed the new organo-
catalyst 7 gave improved enantioselectivities in this reac-
tion when compared to catalyst 2.
Scheme 1 Reagents and conditions: (a) Cbz-Cl, Et3N, CH2Cl2;
(b) Ts-Cl, pyridine, 20 °C, 77% overall; (c) NaCN, 50 °C, 93%; (d)
NaN3, NH4Cl, 150 °C, 73%; (e) 10% Pd/C, H2 (1 atm), HOAc–H2O
(9:1), 55%.
Figure 1
We and others have reported on the tetrazole analogue of
proline 2 as a more soluble and effective catalyst in a va-
riety of transformations.6,7 The tetrazole ring is commonly
used as a bioisostere for a carboxylic acid due to its similar
pKa.
The study showed again that the previous optimal solvent
system, IPA (propan-2-ol)–EtOH (1:1) is especially suc-
cessful. It can be seen that lowering the catalyst loading
deteriorates the yield (Table 1, entry 9) and increasing the
concentration leads to an increase in reaction rate (as indi-
cated by precipitation of product) but not to an increase in
conversion (Table 1, entries 3, 6, 7).
We have since reported on the use of this organocatalyst
in the far more challenging 1,4-addition of a ketone into a
nitro-Michael acceptor.7 Again, we showed that this
organocatalyst outperformed proline, particularly in the
context of enantioselectivity.
Perhaps most interesting is the observation that the reac-
tion works well using a relatively small amount of ketone.
In previous work in this area, reactions were generally
performed with between 10 and 20 equivalents of ketone.
Considerable effort has been devoted to this area and
many improvements to this reaction have been made.8,11
We realised that our previous enantioselectivities (32–
70% ee) using tetrazole 1, while better than proline, were
still only modest. Accordingly, the preparation of a new
Thus, these general conditions (Table 1, entry 5) were
applied to all subsequent examples. The very good perfor-
mance of tetrazole 7, particularly when compared to other
organocatalysts under these conditions for the same reac-
tion is clear (Table 2). Interestingly, homo-proline itself
gives no reaction under these conditions and even with
DMSO as a solvent, only 5% conversion was observed.
SYNLETT 2005, No. 4, pp 0611–0614
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862392; Art ID: D38604ST
© Georg Thieme Verlag Stuttgart · New York

612
C. E. T. Mitchell et al.
LETTER
Table 1 Initial Optimisation Study of Organocatalyst 7
reaction, in line with what has been proposed previously
for analogous systems.8e,10 Both propose an electrostatic
interaction between the nitro group and the nitrogen of the
pyrrolidine ring. One of these suggests that there may be
an extended hydrogen-bonded transition state 18;10 the
other proposes that there is a facial bias, induced by the
steric hindrance of the tetrazole and it is this which deter-
mines the selectivity as shown in 19 (Figure 2).8e
Entry Solvent
Concen- Time
Yield
(%)a,b
ee
tration
(M)
(d)
(%)c
We believed that, should model 18 apply, the transition
state would be less crowded for the homo-tetrazole 7 than
the tetrazole 2. Similarly, should the steric model 19 ap-
ply, then the homo-tetrazole side chain should be more
bulky, due to increased freedom of rotation. In both cases
this should lead to an improvement in the enantioselectiv-
ity, as was indeed observed.
1
2
DMSO
0.13
0.13
0.13
0.13
0.25
0.25
0.5
2
2
2
4
1
2
2
1
2
1
1
43
35
77
78
88
76
78
84
26
74
<20
80
85
90
89
91
88
89
90
92
90
N.d.
MeOH
3
IPA–EtOH, 1:1
IPA–EtOH, 1:1
IPA–EtOH, 1:1
IPA–EtOH, 1:1
IPA–EtOH, 1:1
IPA–EtOH, 1:1d
IPA–EtOH, 1:1e
IPA–EtOH, 1:1f
4
5
6
7
8
0.25
0.25
0.25
0.25
9
10
11
g
CH2Cl2
Figure 2
a Based on isolated product.
b All diastereomeric ratios (dr) determined by 1H NMR spectroscopy
and >19:1. Relative stereochemistry was confirmed by comparison
with literature data.
The enantioselectivities found in this reaction with our
new catalyst 7 are generally very good, and particularly
with cyclohexanone where they are consistently high.
This consistency suggests that the nature of the nitro-
Michael acceptor has less effect on the stereoselective
outcome of the reaction than the ketone. This observation
supports the second model 19 for the enantioselectivity,
since any electronic change of the nitrostyrene could lead
to a significant change in the interaction of model 18.
However, both mechanisms are still plausible, and further
work is underway to develop catalysts, which might sup-
port this conclusion.
c Determined by chiral HPLC (Daicel Chiralpak AD-H).
d 1 Equiv H2O added.
e Using 5 mol% catalyst.
f 20 Equiv ketone used.
g Based on conversion as seen by 1H NMR spectroscopy.
Having demonstrated the superiority of this organocata-
lyst over its predecessors 1 and 2, we set about testing a
range of ketones and a range of nitro-Michael acceptors
(Table 3).
The addition of acetic acid in an attempt to facilitate
enamine formation and hence increase yield does not give
consistent results. In the case of products 11 and 13, it
In order to discuss these results, it is first necessary to
examine the possible transition states. We postulate two
potential models for the stereochemical outcome of this
Table 2 Comparison of Organocatalysts under Optimised Conditions
Entry
Catalyst
Solvent
Yield (%)a
dr, syn:antib
>19:1
ee (%)c
51
1
2
3
4
1
IPA–EtOH, 1:1
IPA–EtOH, 1:1
DMSOd
52
80
<5
88
2
>19:1
62
Homo-proline
N.d.
N.d.
91
7
IPA–EtOH, 1:1
>19:1
a Based on isolated product.
b All dr determined by 1H NMR spectroscopy. Relative stereochemistry was confirmed by comparison with literature data.
c Determined by chiral HPLC (Daicel Chiralpak AD-H column).
d No reaction at all in IPA–EtOH, 1:1.
Synlett 2005, No. 4, 611–614 © Thieme Stuttgart · New York

LETTER
Asymmetric Michael Addition of Carbonyl Compounds to Nitro-Olefins
613
Table 3 Enantioselective 1,4-Nitro-Michael Addition Using Tetrazole Catalyst 7
Entry
Product
Conditionsa
Yield (%)b
dr, (syn:anti)c
ee (%)d
1
2
3
4
A
B
C
D
59
69
>19:1
>19:1
>19:1
N.d.
93
92
90
N.d.
71
<20e
11
e
5
6
A
B
74
68
–
–
93
92
e
12
13
7
8
A
B
51
66
>19:1
>19:1
90
91
9
10
A
B
61
34
>19:1
17:1
90
90
14
15
11
12
A
B
68
53
–
–
42
39
13
14
A
B
52
37
2.5:1
2:1
52 (1)
36 (2)
16
15
16
A
B
39
40
>19:1
>19:1
37
0
17
a Conditions: (A) as described; (B) 0.7 equiv HOAc added; (C) reaction performed at 30 °C; (D) 0.15 equiv p-TsOH added.
b Based on isolated yield.
c Determined by 1H NMR spectroscopy. Relative stereochemistry was confirmed by comparison with literature data.
d Determined by chiral HPLC.
e Anti product not observed by 1H NMR spectroscopy.
leads to increased yields with no significant change in a complete erosion of enantioselectivity (Table 3, entry
enantioselectivity. In other cases, it leads to a decrease in 16); possibly due to a significant increase in the uncataly-
yield (Table 3, entries 5, 6). This suggests that enamine sed reaction rate. However, the use of a very strong acid
formation may not be the rate determining step in all cas- suppressed the reaction completely (Table 3, entry 4).
es. In the case of the aldehyde, use of acetic acid leads to
Synlett 2005, No. 4, 611–614 © Thieme Stuttgart · New York

614
C. E. T. Mitchell et al.
LETTER
(5) Selected examples: (a) Wang, W.; Wang, J.; Li, H.
Finally, and perhaps most interestingly, the selectivity of
the reaction with the aldehyde to give 17, although consis-
tent with the other substrates in Table 3, is the reverse of
that normally found for this example in literature; selec-
tivity with aldehydes has been reported to be opposite to
that observed for ketones.8b,e,i,11,12 The reason for the
switch of enantioselectivity in literature is not completely
understood, but it has been proposed that there is a switch
from anti- to syn-enamine formation which would lead to
formation of the opposite enantiomer.11
Tetrahedron Lett. 2004, 45, 7243. (b) Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038.
(c) Wang, W.; Li, H.; Wang, J.; Liao, L. Tetrahedron Lett.
2004, 45, 8229. (d) Brochu, M. P.; Brown, S. P.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2004, 126, 4108.
(e) Kumaragurubaran, N.; Zhuang, W.; Bøgevig, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254.
(6) (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004,
558. (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.
(c) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5374. (d) Yamamoto, Y.;
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 5962. (e) Hartikka, A.; Arvidsson, P. I. Tetrahedron:
Asymmetry 2004, 15, 1831.
In conclusion, an improved catalyst 7 for the asymmetric
addition of a ketone to nitro-olefins has been developed,
giving enantiomeric excesses of up to 93% for a wide
range of ketones and nitro-olefins.
(7) (a) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S.
V. Chem. Commun. 2004, 1808. (b) Cobb, A. J. A.; Shaw,
D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biol.
Chem. 2005, 3, 84.
Acknowledgment
The authors wish to thank Avecia (to CETM), the EPSRC (Enginee-
ring and Physical Sciences Research Council (to AJAC and CETM)
and Novartis (through a Research Fellowship to SVL) for financial
support.
(8) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3,
2423. (b) Betancort, J. M.; Barbas, C. F. III Org. Lett. 2001,
3, 3737. (c) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Barbas, C. F. III Tetrahedron Lett. 2001, 42, 4441.
(d) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett.
2003, 5, 2559. (e) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F. III Synthesis
2004, 1509. (f) Andrey, O.; Vidonne, A.; Alexakis, A.
Tetrahedron Lett. 2003, 44, 7901. (g) Mase, N.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F. III Org. Lett.
2004, 6, 2527. (h) Fonseca, M. T. H.; List, B. Angew. Chem.
Int. Ed. 2004, 43, 3958. (i) Ishii, T.; Fujioka, S.; Sekiguchi,
Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558.
(j) Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli,
G. Adv. Synth. Catal. 2004, 346, 1147; and references
therein.
Catalyst synthesis details on request.
References
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(9) Typical Experimental Procedure.
To a suspension of catalyst (15 mol%) and nitro-olefin (0.5
mmol) in an i-PrOH–EtOH mix (1:1, 2 mL) was added
ketone (0.75 mmol, 1.5 equiv) and the resulting mixture
stirred at 20 °C for 24 h. After this time the reaction was
quenched with sat. NH4Cl (2 × 20 mL) and the aqueous
phase extracted with EtOAc (2 × 25 mL). The combined
organic layers were dried (MgSO4), filtered and evaporated
to give a residue which was further purified by flash column
chromatography using EtOAc and petroleum ether 40–60 as
eluent.
(10) Enders, D.; Seki, A. Synlett 2002, 26.
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(12) This was proven by comparison of chiral HPLC retention
times and also by an inversion of sign in the optical rotation
as compared to literature.
Synlett 2005, No. 4, 611–614 © Thieme Stuttgart · New York