Asymmetric Morita-Baylis-Hillman reactions catalyzed by chiral Bronsted acids

Article abstract of DOI:10.1021/ja037705w

Chiral BINOL-derived Bronsted acids catalyze the enantioselective asymmetric Morita-Baylis-Hillman (MBH) reaction of cyclohexenone with aldehydes. The asymmetric MBH reaction requires 2-20 mol % of the chiral Bronsted acid 2e or 2f and triethylphosphine a

Full text of DOI:10.1021/ja037705w

Published on Web 09/12/2003
Asymmetric Morita-Baylis-Hillman Reactions Catalyzed by Chiral Brønsted
Acids
Nolan T. McDougal and Scott E. Schaus*
Department of Chemistry, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
Received August 1, 2003; E-mail: seschaus@chem.bu.edu
The Morita-Baylis-Hillman reaction1 is the reaction of electron-
deficient alkenes with aldehydes, catalyzed by nucleophilic amines
or phosphines.2 The products of Morita-Baylis-Hillman (MBH)
reactions are highly functionalized allylic alcohols which, in
enantioenriched form, could be valuable chiral building blocks for
synthesis.3 However, the identification of an asymmetric MBH
reaction has been a challenge for organic chemistry. To date, efforts
toward this goal have focused on the addition of acrylates to
aldehydes. Notable developments include the use of chiral sultam
auxiliaries,4 quinidine-derived chiral nucleophilic amine catalysts,5
and chiral lanthanide Lewis acids for the tertiary amine-promoted
addition of acrylates to aldehydes.6 Herein, we report the first
example of a highly enantioselective asymmetric MBH reaction of
cyclohexenone with aldehydes using a chiral Brønsted acid as the
catalyst and triethylphosphine as the nucleophilic promoter.
Figure 1. Binaphthol-derived Brønsted acids.
Recent experiments demonstrated that the inclusion of mild
Brønsted acids such as phenol and BINOL in the tri-n-butylphos-
phine-promoted MBH reaction of cyclic enones with aldehydes
resulted in a significant increase in the overall rate of reaction.7
Although (R)-BINOL was found not to be optimal for the MBH
reaction, we postulated that the identification of a suitable chiral
Brønsted acid could be used in an asymmetric reaction. In this case,
the Brønsted acid may serve to promote the conjugate addition step
of the reaction, and then remain hydrogen-bonded to the resulting
enolate in the enantioselectivity-determining aldehyde addition step
(Scheme 1). Presumably, the chiral Brønsted-acid-stabilized enolate
formed after addition of the trialkylphosphine would act as the
nucleophile in the addition reaction.7
Table 1. Asymmetric Morita-Baylis-Hillman Reactions Catalyzed
by Binaphthol-Derived Brønsted Acidsa
c
entry
catalyst
% yieldb
%ee
1
2
3
4
5
6
7
8
9
5
74
73
73
69
9
70
84
43
15
1
32
48
79
86
31
88
86
3
2a
2b
2c
2d
2e
2f
3
Scheme 1. Proposed Catalytic Cycle for the
Brønsted-Acid-Catalyzed Morita-Baylis-Hillman Reaction
10
4
3
a Reactions were run with 1 mmol of 3-phenylpropanal, 1 mmol of
cyclohexenone, 0.5 mmol of PEt3, and 2 mol % catalyst in THF (1 M) at
0 °C for 36 h under Ar, followed by flash chromatography on silica gel.
b Isolated yield. c Determined by chiral HPLC analysis.
1 to the reaction mixture afforded the MBH product 5a in 74%
isolated yield and 32% ee (entry 2, Table 1).
Encouraged by these results, we evaluated other BINOL-derived
Brønsted acids in the reaction (Figure 1). During our investigation,
two structural features of the catalyst were found to be important
for achieving high enantioselectivity: saturation of the BINOL
derivative8 (entry 3, Table 1) and substitution at the 3,3′-positions
(entries 4-8). When (R)-3,3′-diphenyl-H8-BINOL 2c9 was used as
the catalyst in the MBH reaction, 5a was produced in 86% ee and
69% yield (entry 5). However, when mesityl-catalyst 2d10 was used,
the product was formed in low yield and correspondingly low
enantioselectivity (entry 6). We reasoned that the mesityl substituent
restricted rotation about the biaryl bond of the 3-substituent, a
structural prerequisite for catalysis. The highest levels of enantio-
selectivity were achieved using (R)-3,3′-(3,5-dimethylphenyl)-H8-
We first conducted experiments to assess the feasibility of using
chiral Brønsted acids to promote the asymmetric MBH reaction of
cyclohexenone with aldehydes (Figure 1, Table 1). The reaction
of cyclohexenone (1 equiv) with 3-phenylpropanal (1 equiv) using
PEt3 (0.5 equiv) in THF (1 M) yielded 5% of the desired product
at 0 °C after 48 h. However, the addition of 2 mol % (R)-BINOL
9
12094
J. AM. CHEM. SOC. 2003, 125, 12094-12095
10.1021/ja037705w CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Brønsted-Acid-Catalyzed Asymmetric
Morita-Baylis-Hillman Reactionsa
In summary, we have developed a highly enantioselective
asymmetric Morita-Baylis-Hillman reaction involving the addition
of cyclohexenone to aldehydes. The asymmetric reaction is
catalyzed by a chiral BINOL-derived Brønsted acid. The use of
small organic molecules as catalysts to promote asymmetric
reactions is a new frontier in reaction methodology development.11
Asymmetric Brønsted acid catalysis is a recent addition to this
emerging field.12 Further development of the asymmetric MBH
reaction and elucidation of the mechanism through which the
reaction proceeds will facilitate understanding of the chemical
principles which govern this new area of catalysis. Experiments
are ongoing and will be described in due course.
Acknowledgment. This research was supported by Boston
University and by an award from the Research Corporation. N.T.M.
was supported by a Presidential Fellowship from Boston University.
We gratefully acknowledge Profs. James Panek and John Porco
(BU) for helpful comments in the preparation of this manuscript.
Supporting Information Available: Experimental procedures,
characterization of all new compounds, and HPLC separations for
compounds 5a-5h (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972;
Chem. Abstr. 1972, 77, 34174q.
(2) For reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
ReV. 2003, 103, 811. (b) Langer, P. Angew. Chem., Int. Ed. 2000, 39,
3049. (c) The catalyzed R-hydroxyalkylation and R-animoalkylation of
activated olefins (the Morita-Baylis-Hillman reaction): Ciganek, E. In
Organic Reactions; Paquette, L. A., Ed.; Wiley: NewYork, 1997; Vol.
51, p 201. (d) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996,
52, 8001. (e) Drews, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
(3) (a) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124,
11616. (b) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeyama, S.
Tetrahedron Lett. 2001, 42, 7867. (c) Iwabuchi, Y.; Furukawa, M.; Esumi,
T.; Hatakeyama, S. Chem. Commun. 2001, 2030. (d) Trost, B. M.; Tsui,
H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534.
a Reactions were run with 1 mmol of aldehyde, 2 mmol of cyclohexenone,
2 mmol of PEt3, and 10 mol % catalyst in THF (1 M) at -10 °C for 48 h
under Ar, followed by flash chromatography on silica gel. b Isolated yield.
c Determined by chiral HPLC analysis. d 20 mol % catalyst.
(4) (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997,
119, 4317. (b) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729.
(5) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219. (b) Shi, M.; Jiang, J.-K. Tetrahedron:
Asymmetry 2002, 13, 1941.
(6) (a) Yang, K.-S.; Lee, W.-D.; Pan, J.-F.; Chen, K. J. Org. Chem. 2003,
68, 915. (b) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J.
Org. Chem. 1998, 63, 7183.
BINOL 2e as the catalyst (88% ee, entry 7), and employing 3,3′-
[3,5-bis(trifluoromethyl)phenyl]-catalyst 2f resulted in the greatest
levels of conversion (84% yield, entry 8).
It is interesting to note that removal of one Brønsted-acid
equivalent from the BINOL-derived catalyst, as is the case for
catalysts 3 and 4, resulted in diminished catalytic activity and no
enantioselectivity in the production of 5a (entries 9 and 10). Finally,
using trialkylphosphines such as PMe3 or P(n-Bu)3 in the reaction
afforded 5a in yields similar to that of PEt3, but lower enantio-
selectivities (50% and 64% ee, respectively).
Optimization of the reaction resulted in the identification of a
set of conditions that proved to work for a variety of aldehydes. In
general, the conditions that favored the production of 5 in high
yields and enantioselectivities were 2 equiv of PEt3 and cyclohex-
enone, and only 10-20 mol % of the chiral Brønsted acid 2e or 2f
at -10 °C in THF. Optimal results were obtained using catalyst 2f
in the MBH reaction of aliphatic aldehydes (Table 2, entries a, b),
while catalyst 2e afforded the best results with more hindered
aldehydes (entries d-f). The MBH reaction of conjugated aldehydes
such as benzaldehyde and cinnamaldehyde (entries g and h) resulted
in low yields and low enantioselectivities.
(7) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
(8) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.;
Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 2252.
(9) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc. 2002, 124,
10.
(10) Schrock, R. R.; Jamieson, J. Y.; Dolman, S. J.; Miller, S. A.; Bonitatebus,
P. J.; Hoveyda, A. H. Organometallics 2002, 21, 409.
(11) (a) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem.
Soc. 2003, 125, 6610. (b) Harmata, M.; Ghosh, S. K.; Hong, X.;
Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058.
(c) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192. (d) Juhl, K.; Jorgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 1498. (e) Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 661. (f) Paras, N. A.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 7894. (g) Paras, N. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2001, 123, 4370. (h) Jen, W. S.; Wiener, J. J. M.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. (i) Ahrendt, K.
A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243.
(12) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003,
424, 146. (b) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
10006. (c) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(d) Nakamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto, H. J. Am. Chem.
Soc. 2000, 122, 8120. (e) Nakamura, S.; Ishihara, K.; Yamamoto, H. J.
Am. Chem. Soc. 2000, 122, 8131.
JA037705W
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12095