Diphenylprolinol methyl ether: A highly enantioselective catalyst for Michael addition of aldehydes to simple enones

Article abstract of DOI:10.1021/ol0517729

(Chemical Equation Presented) Diphenylprolinol methyl ether catalyzes intermolecular Michael addition of simple aldehydes to relatively nonactivated enones with the highest enantioselectivities reported to date (95-99% ee) and significantly lower catalyst

Full text of DOI:10.1021/ol0517729

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4253-4256
Diphenylprolinol Methyl Ether: A Highly
Enantioselective Catalyst for Michael
Addition of Aldehydes to Simple Enones
Yonggui Chi and Samuel H. Gellman*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
gellman@chem.wisc.edu
Received July 26, 2005
ABSTRACT
Diphenylprolinol methyl ether catalyzes intermolecular Michael addition of simple aldehydes to relatively nonactivated enones with the highest
enantioselectivities reported to date (95 99% ee) and significantly lower catalyst loadings than have been typical in this arena.
−
The development of asymmetric Michael additions for C-C
bond formation is an important challenge in organic syn-
thesis. Metal-based catalysis has long been the dominant
approach,1 but recently organocatalytic methods have drawn
growing attention.2 Many successes have been realized by
applying organocatalysts to highly reactive Michael donors
or acceptors. For example, Michael additions of malonate
diesters3 or nitroalkanes4 to simple enones have been
reported. Alternatively, in pioneering work by Barbas et al.
and other groups, simple ketones or aldehydes have been
added to activated Michael acceptors such as nitroalkenes
or alkylidenemalonates.5 In contrast, Michael additions of
simple aldehydes to simple enones have received little
attention. Melchiorre and Jørgensen found modest enantio-
selectivities for such additions catalyzed by chiral pyrro-
lidines.6 List et al. subsequently reported highly enantiose-
lective intramolecular examples catalyzed by a MacMillan
imidazolidinone.7 Very recently, we described enantioselec-
tive catalysis (ee up to 92%) of intermolecular aldehyde/
enone reactions by chiral imidazolidinones in conjunction
with a catechol cocatalyst.8
(1) For reviews, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033-8061. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 2,
171-196. (c) Yamaguchi, M. In ComprehensiVe Asymmetric Catalysis
I-III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Berlin, Germany, 1999; Chapter 31.2.
(2) For recent reviews, see: (a) Miller, S. J. Acc. Chem. Res. 2004,
37,601-610. (b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-
724. (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175. (d) List, B. Acc. Chem. Res. 2004, 37, 548-557. (e) Notz, M.; Tanaka,
F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591. (f) Saito, S.;
Yamaoto, H. Acc. Chem. Res. 2004, 37, 570-579.
(3) (a) Halland, N.; Hansen, K. A.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 4955-4957. (b) Halland, N.; Aburel, P. S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661-665. (c) Hanessian, S.; Pham, V.
Org. Lett. 2000, 2, 2975-2978. (d) Kawara, A.; Taguchi, T. Tetrahedron
Lett. 1994, 35, 8805-8808.
(5) (a) Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737-
3740. (b) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org.
Lett. 2004, 6, 2527-2530. (c) Betancort, J. M.; Sakthivel, K.; Thayumana-
van, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441-4444. (d)
Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C.
F., III. Synthesis 2004, 1509-1521. (e) Wang, W.; Wang, J.; Li, H. Angew.
Chem., Int. Ed. 2005, 44, 1369-1371. (f) Ishii, T.; Fujioka, S.; Sekiguchi,
Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558-9559. (g) Andrey, O.;
Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559-2561. (h) Enders,
D.; Seki, A. Synlett 2002, 26-28.
(6) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151-
4157.
(7) Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004,
43, 3958-3960.
(4) (a) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002,
67, 8331-8338 (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257-
4259. (c)Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520-3530.
(8) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, ASAP
(DOI: 10.1021/ja0532584). In this study, an enamine intermediate was
observed. High catalyst loading (20 mol %) was required, and the ee values
were 82-92%.
10.1021/ol0517729 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/18/2005

Here we report that diphenylprolinol methyl ether (A),9 a
modest excursion beyond previously explored pyrrolidines,
can catalyze intermolecular Michael addition of simple
aldehydes to simple enones with the highest enantioselec-
tivities reported to date (95-99% ee) and significantly lower
catalyst loading (1-5 mol %) than has been typical in this
arena. We show that higher catalyst loading depresses
enantioselectivity, apparently because of product racemiza-
tion catalyzed by the pyrrolidine. With some substrates, the
use of a cocatalyst is necessary for optimal results.
reactivity of the nitrogen atom. Pyrrolidine F, which differs
from A in having methyl groups in place of phenyl groups
on the ring substituent, provides substantially lower yield
and enantioselectivity than does A.
The catalytic reaction appears to proceed via the enamine
formed by reaction of the pyrrolidine and the aldehyde.6 In
light of this hypothesis, it seemed surprising that B provided
lower conversion to product than did A, since one might
have predicted that the lesser degree of substitution on the
“side chain” of B would lead to more rapid enamine
formation and more rapid enamine reaction with enone for
B than for A.
We initially examined six substituted pyrrolidines (1 mol
% each) as potential catalysts for reaction between hydro-
cinnamaldehyde and methyl vinyl ketone (Table 1). Pyrro-
Table 2 shows the effect of catalyst loading on conversion
and product ee for Michael addition catalyzed by A. The
Table 1. Initial Studies of Michael Addition of
Hydrocinnamaldehyde to Methyl Vinyl Ketone
Table 2. Effect of Catalyst Loading
catalyst
(mol %)
time
(h)
conversion
(%)a
ee
(%)b
entry
temperature
1
2
3
4
5
20
5
2
1
5
7
24
24
24
24
rt
rt
rt
rt
94
99
90
60
90
65
86
>95
>95
>95
entry
catalyst
conversion (%)a
ee (%)b
1
2
3
4
5
6
A
B
C
D
E
F
60
28
<1
33
27
15
97
80
ndc
99
96
77
4 °C
a Measured by 1H NMR of crude reaction mixture. b Determined by a
1H NMR ee assay using chiral amines.
a Measured by 1H NMR of the crude reaction mixture. b Determined by
1H NMR ee assay using chiral amines; for details, see Supporting
reaction is nearly complete in 7 h when 20 mol % A is used,
but enantioselectivity is quite modest under these conditions.
Use of lower catalyst proportions leads to slower product
formation but higher enantioselectivity, as seen by comparing
results obtained with 5, 2, and 1 mol % A after 24 h. This
trend suggests that the pyrrolidine may play two roles under
the reaction conditions: catalysis of the Michael addition,
via enamine formation with the starting aldehyde, and
catalysis of product epimerization, via enamine formation
with the product aldehyde.12 Indeed, when pure Michael
adduct and pyrrolidine A were mixed, a steady erosion of
adduct enantiomeric excess was observed. We find that
products with the highest ee are obtained when the adduct
is separated from the catalyst as soon as the reaction nears
completion.
Table 3 shows results obtained under optimized conditions
(5 mol % A, 4 °C, 24-48 h) with six simple aldehydes and
two enones. Enantioselectivities are excellent (>95%), and
yields are good to excellent in all cases. Although some of
these reactions proceed well with only the pyrrolidine as a
catalyst, others require the use of the catechol G as a
cocatalyst.13 We recently discovered that catechols could
serve as cocatalysts for Michael additions that proceed by
a
Information. c Not determined.
lidine A performed best, providing excellent enantioselec-
tivity10 and good conversion. Quaternary substitution on the
substituent adjacent to the nitrogen seems to be important
for optimal reactivity and enantioselectivity, since B, lacking
the methoxy group, is inferior to A. Pyrrolidine B is typical
of the catalysts evaluated in the seminal study of Melchiorre
and Jørgensen,6 and the results we obtained with B are
consistent with their findings. The oxygen atom in A must
be etherified, as diphenylprolinol (C) was completely inac-
tive. We suspect that C forms a stable cyclic aminal upon
reaction with the aldehyde.11 Pyrrolidines D and E gave
excellent enantioselectivities but lower conversion than was
obtained with A; perhaps the electron-withdrawing ring
substituents (carboxyl or hydroxyl) diminish the nucleophilic
(9) Enders, D.; Kipphardt, H.; Gerdes, P.; Brena-Valle, L. J.; Bhushan,
V. Bull Soc. Chim. Belg, 1988, 97, 691-704.
(10) Enantiomeric excess in initial studies was determined by an NMR
assay; see: Chi, Y.; Peelen, T. J.; Gellman. S. H. Org. Lett. 2005, 7, 3469-
3472.
(11) C forms cyclic aminals with both aromatic and aliphatic aldehydes
under anhydrous acidic conditions. For examples, see: Zuo, G.; Zhang,
Q.; Xu, J. Heteroatom Chem. 2003, 14, 42-45. Okuyama, Y.; Nakano, H.;
Hongo, H. Tetrahedron: Asymmetry 2000, 11, 1193-1198.
(12) For an example of R-substituted aldehyde product racemization by
catalyst, see: List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657.
4254
Org. Lett., Vol. 7, No. 19, 2005

Jørgensen et al. that such silyl ethers catalyze the R-fluorina-
tion17 and R-sulfenylation18 of aldehydes with high enanti-
oselectivity. We compared A and the analogous trimethylsilyl
ether (H), both at 1 mol %, as catalysts for the Michael addi-
tion shown in Table 1. The TMS ether provided enantio-
selectivity comparable to that obtained with A, but H was a
less efficient catalyst, giving only 20% Michael adduct
conversion (vs 60% conversion with A).19
Table 3. Michael Addition of Aldehydes to Enones
reaction
additive G
(mol %)
time
(h)
yield
(%)a
ee
(%)
product
R1, R2
1
2
3
4
5
6
7
8
9
Me, Me
Et, Me
Pr, Me
i-Pr, Me
n-Hex, Me
Bn, Me
Me, Et
Et, Et
Pr, Et
i-Pr, Et
n-Hex, Et
Bn, Et
20
0
0
0
0
36
36
36
36
24
24
48
48
48
48
24
24
82
75
69
65
85
82
70
68
69
60b
87
87
97c
97c
>95d
98c
>95d
>95d
99c
We have conducted a preliminary assessment of pyrroli-
dine catalysis of aldehyde Michael additions to acceptors
bearing â-substituents, reactions that are important because
two adjacent stereogenic centers are created. Michael addition
of isovaleraldehyde to â-substituted alkylidenemalonates5c,d
proceeds with high diastereo- and enantioselectivity in the
presence of A. In contrast, A is only a poor catalyst for
Michael addition of aldehydes to cyclopentenone or acyclic
â-substituted enones. No Michael addition at all was detected
with cyclohexenone.
0
20
20
20
20
20
20
95c
>95d
99c
10
11
12
>95d
>95d
a Yield of isolated product after column chromatography on silica
gel. b Reaction at room temperature. c Determined by chiral stationary
phase GC of the corresponding carboxylic acids; the ee of the parent
1
aldehydes were also determined by a H NMR ee assay, giving ee higher
Our results show that pyrrolidine A is an outstanding
organocatalyst for Michael addition of simple aldehydes to
simple enones. Among the substrates we have examined,
however, small variations in structure can hinder the de-
sired reaction. In some cases such as replacement of methyl
vinyl ketone with ethyl vinyl ketone, which causes a small
increase in steric constraint, the reactivity deficit can be
remedied by introduction of an achiral catechol cocatalyst.
In other cases such as use of â-substituted enones, which
present a more demanding steric challenge, more sophisti-
cated catalyst design will be necessary to achieve useful
reactivity. Enzymes frequently employ bifunctional cataly-
sis to promote intrinsically difficult reactions, and we
therefore speculate that covalent linkage20 between the
optimized enamine moiety represented by A and the puta-
tive enone-activating moiety represented by catechol G will
allow efficient utilization of â-substituted enones. It is
noteworthy in this context that D and E, which bear potential
linkage sites, retain the excellent enantioselectivity mani-
fested by A, although the reactivity of D and E is somewhat
reduced relative to that of A. Use of chiral preorganized
segments to connect complementary catalytic groups could
provide both high catalytic activity and high stereochemical
induction.
than 95% in all cases. d Determined by a 1H NMR ee assay using chiral
amines.
nucleophilic activation of aldehydes (enamine formation);14
our current hypothesis is that the catechol electrophilically
activates the enone, via hydrogen bond donation to the
carbonyl oxygen.8,15
As our work was being completed, Hayashi et al. reported
that enantiomerically pure diphenylprolinol silyl ethers,
another modest excursion beyond previously explored pyr-
rolidine,5,6 could be used for enantio- and diastereoselective
addition of simple aldehydes to â-monosubstituted nitro-
alkenes.16 This paper followed closely upon reports from
(13) (a) Without catechol cocatalyst, these reactions gave only 1-35%
conversion after 48 h, except for reaction of hydrocinnamaldehyde and ethyl
vinyl ketone (63% conversion). (b) The use of catechol cocatalyst enhances
the reaction rates in all cases.
(14) For reviews of hydrogen bonding in catalysis, see: Schreiner, P.
R. Chem. Soc. ReV. 2003, 32, 289-296. Pilko, P. M. Angew. Chem., Int.
Ed. 2004, 43, 2062-2064. Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L.
Angew. Chem., Int. Ed. 2005, 44, 1758-1763. For recent examples, see:
Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424,
146. Vachal, P. Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012-
10014. Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 3418-3419
(17) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 794-797.
(18) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703-3706.
(19) Ref 16 reported a single Michael addition, hydrocinnamaldehyde
to methyl vinyl ketone, with 30 mol % H, giving 52% yield and 97% ee;
reaction time and temperature were not given.
(20) For relevant examples, see: (a) Krattiger, P.; Kovasy, R.; Revell,
J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101-1103. (b) Jarvo,
E. R.; Miller, S. J. Tetrahedron, 2002, 58, 2481-2495. (c) Vasbinder, M.
M.; Jarvo, E. R.; Miller, S. J. Angew. Chem., Int. Ed. 2001, 40, 2824-
2827. (d) Jarvo, E. R.; Copeland, G, T.; Papaioannou, N.; Bonitatebus, P.
J.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643.
(15) Other mechanisms of activation such as catechol catalysis of initial
enamine formation cannot be ruled out at this time.
(16) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int.
Ed. 2005, 44, 2-4.
Org. Lett., Vol. 7, No. 19, 2005
4255

Acknowledgment. This research was supported by NSF
Grant CHE-0140621. NMR spectrometers were purchased
with partial support from NIH and NSF. We thank Prof.
Shannon Stahl and his group for use of their gas chroma-
tography equipment and Prof. Timothy Peelen for helpful
discussions.
Supporting Information Available: Experimental de-
tails, chromatograms, and NMR spectra for ee determination.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0517729
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Org. Lett., Vol. 7, No. 19, 2005