The asymmetric Baylis-Hillman reaction

Full text of DOI:10.1021/ja970079g

J. Am. Chem. Soc. 1997, 119, 4317-4318
The Asymmetric Baylis-Hillman Reaction
4317
Linda Joy Brzezinski, Sara Rafel, and James W. Leahy*
Figure 1.
Table 1
Department of Chemistry, UniVersity of California
Berkeley, California 94720-1460
ReceiVed January 9, 1997
The controlled construction of carbon-carbon bonds is of
fundamental importance in organic chemistry. Unfortunately,
there are relatively few methods for performing this task with
absolute stereocontrol. We wish to report here an asymmetric
variation of the Baylis-Hillman reaction as a novel method to
realize this objective.
The tertiary amine catalyzed addition of an acrylate to an
aldehyde is widely referred to as the Baylis-Hillman reaction
1
(
Figure 1). This reaction activates an acrylate group to form
a carbon-carbon bond via nucleophilic attack of an aldehyde,
thereby creating a new stereocenter. Selective formation of this
stereocenter would provide a route to optically enriched
R-methylene-â-hydroxy esters, useful building blocks in organic
1
synthesis. These compounds have previously been converted
Scheme 1
to a variety of other products with high stereospecificity,
including aziridines, epoxides, triols, and anti aldol adducts.
2
3
4
5
Numerous attempts have been made to introduce stereoselec-
tivity into the Baylis-Hillman reaction using optically pure
amine catalysts,6 aldehydes,7 and acrylates.8 However, no
reliable, highly enantioselective process has emerged to date.
We have found a system that routinely provides Baylis-Hillman
products in greater than 99% enantiomeric excess in moderate
to excellent yields with a variety of achiral aldehydes. Chiral
auxiliaries have been proven to be a highly effective method
of introducing stereochemistry into a molecule in a recoverable
fashion.9 Particularly useful in this regard has been the
that were essentially optically pure.12 The reaction works best
10
when the aldehyde substrates are unbranched at the R-position,
as evidenced by the results with isobutyraldehyde (2d) and
benzaldehyde (2h). Furthermore, the auxiliary was fortuitously
cleaved under the reaction conditions by incorporation of a
second equivalent of the aldehyde, thereby rendering 1 as a
camphor-derived Oppolzer’s sultam. It is readily available
as either antipode and typically leads to excellent transfer of
1
1
chirality.
In practice, Oppolzer’s sultam was found to be an ideal
auxiliary in the Baylis-Hillman reaction (Table 1). The reaction
proceeded smoothly with a variety of aldehydes to yield products
1
3
renewable source of chirality in this case.
The 1,3-dioxan-4-ones produced in this manner were easily
converted into R-methylene-â-hydroxy esters (Scheme 1). As
mentioned above, this is a versatile template for further
manipulation. For example, products such as 3 were directly
converted into the corresponding anti aldol adducts (4) via
(
1) For recent reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001. (b) Drewes, S. E.; Roos, G. H. P. Tetrahedron
988, 44, 4653.
2) Atkinson, R. S.; Fawcett, J.; Russel, D. R.; Williams, P. J. J. Chem.
1
(
Soc., Chem. Commun. 1994, 2031. For an excellent review on directed
reactions, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993,
5,14
directed reduction of the olefin.
Given the difficulty typically
9
3, 1307.
5
(
3) Bailey, M.; Mark o´ , I. E.; Ollis, W. D. Tetrahedron Lett. 1991, 32,
associated with direct generation of this stereochemical array,1
2
687.
(
4) Mark o´ , I. E.; Giles, P. R.; Janousek, Z.; Hindley, N. J.; Declercq,
(12) A representative procedure for this transformation is as follows: A
solution of acrylate 111 (500 mg, 1.85 mmol) in CH2Cl2 (2 mL) was cooled
to 0 °C, and propionaldehyde (2.0 mL, 27 mmol) was added followed by
DABCO (20.7 mg, 0.19 mmol). The solution was stirred at 0 °C for 12 h
and then concentrated under reduced pressure without heat. The residue
was purified by flash column chromatography to provide 2b (310.3 mg,
98%) as a clear oil.
(13) While all auxiliaries can theoretically be reused/regenerated, they
are often carried through several synthetic steps, thereby reducing the overall
efficiency of this asymmetric induction. In this case, however, the auxiliary
is automatically removed under the reaction conditions, regenerating the
sultam for subsequent use without additional work. Typically, 90% of the
theoretical amount of the sultam can be recovered from the reaction by
further elution of the flash column.
(14) Generation of the anti aldol adducts via a directed reduction served
the additional purpose of allowing us to confirm the stereochemical outcome
of the Baylis-Hillman reactions by comparison with known scalemic
products. These compounds (such as 4) have been previously reported in
enantiomerically pure fashion (Meyers, A. I.; Yamamoto, Y. J. Am. Chem.
Soc. 1981, 103, 4278).
(15) For useful reviews of the aldol reaction, see: (a) Heathcock, C. H.
In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984;
Vol. 3, pp 112-212. (b) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top.
Stereochem. 1982, 13, 1. (c) Heathcock, C. H. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
2, pp 133-238.
J.-P.; Tinant, B.; Feneau-Dupont, J.; Svendsen, J. S. Recl. TraV. Chim. Pays-
Bas 1995, 114, 239.
(
(
5) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190.
6) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6,
1
2
2
241.
(
7) Drewes, S. E.; Khan, A. A.: Rowland, K. Synth. Commun. 1993,
3, 183.
(
8) (a) Drewes, S. E.; Emslie, N. D.; Khan, A. A. Synth. Commun. 1993,
3, 1215. (b) Basavaiah, D.; Gowriswari, V. V. L.; Sarma, P. K. S.; Rao,
P. D. Tetrahedron Lett. 1990, 31, 1621. (c) Gilbert, A.; Heritage, T. W.;
Isaacs, N. S. Tetrahedron: Asymmetry 1991, 2, 969. (d) Khan, A. A.;
Emslie, N. D.; Drewes, S. E.; Field, J. S.; Ramesar, N. Chem. Ber. 1993,
1
26, 1477. (e) Drewes, S. E.; Emslie, N. D.; Karodia, N.; Khan, A. A.
Chem. Ber. 1990, 123, 1447. (f) Jensen, K. N.; Roos, G. H. P. S. Afr. J.
Chem. 1992, 45, 112.
(
9) See: Ager D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96,
8
35 and references cited within.
(
10) Several reviews have appeared, including the following: (a)
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241. (b) Kim, B. H.; Curran,
D. P. Tetrahedron 1993, 49, 293. (c) Oppolzer, W. Tetrahedron 1987, 43,
1
969. (d) Oppolzer, W. Pure Appl. Chem. 1988, 60, 39.
(
11) (a) Weismiller, M. C.; Towson, J. C.; Davis, F. A. Org. Synth. 1990,
6
9, 154. (b) Towson, J. C.; Weismiller, M. C.; Lal, G. S.; Sheppard, A. C.;
Davis, F. A. Org. Synth. 1990, 69, 158. (c) Ho, G. J.; Mathre, D. J. J. Org.
Chem. 1995, 60, 2271.
S0002-7863(97)00079-6 CCC: $14.00 © 1997 American Chemical Society

4318 J. Am. Chem. Soc., Vol. 119, No. 18, 1997
Communications to the Editor
Figure 2.
Scheme 2
favored in reactions where a Lewis acid is present to chelate
1
0a
the carbonyl group and the sulfonyl group.
Conversely, in 9
the carbonyl is preferentially oriented anti to the sulfonyl group
in nonchelated reactions in order to minimize dipole interactions
10b
between these groups.
This anti configuration should there-
fore be favored in the Baylis-Hillman reaction. In all reactions
with acrylate 1, addition to the re face of the acrylate is
10
favored, presumably due in this case to steric interactions with
the axial oxygen of the sulfonyl group, which effectively
1
0
prevents addition to the bottom (si) face.
Reaction of the aldehyde at the re face of the enolate is
represented by 10, with the proton favorably approaching over
the bulky quaternary ammonium group. Such a reaction would
generate 11, a product similar to that obtained via a syn aldol
this serves as a practical alternative, affording the adducts in
optically pure fashion in short order. These reductions also
helped to confirm the absolute stereochemical outcome of the
initial Baylis-Hillman reactions.
A demonstration of the utility of this reaction is manifested
1
5
addition.
elimination of the tertiary amine.
The R-stereocenter is subsequently lost upon
16
In summary, we have demonstrated that Oppolzer’s sultam
can be used in the Baylis-Hillman reaction to obtain products
of very high enantiomeric purity. These cyclic products can
easily be opened to give optically pure R-methylene-â-hydroxy
esters, which are useful building blocks in organic synthesis
and precursors to anti aldol adducts. The absolute stereochem-
istry of these compounds has been assigned through conversion
to known products and by the total synthesis of tulipalin B.
Coupled with the pronounced acceleration of this reaction at
in the total synthesis of tulipalin B (6, Scheme 2), the contact
dermatitic agent in tulip bulbs.17 The product could be obtained
in essentially two steps from 2f.18
Two factors are instrumental in controlling the absolute
stereochemistry of the products: the demonstrated preference
10
of acrylate 1 for addition to its C(R) re face and the
requirement of an open transition state. The addition of catalyst
2
0
to 1 results in formation of the Z enolate,19 which could lie in
low temperature, this should prove to be a generally useful
and practical synthetic transformation, and work is underway
to further expand the utility of these products.
either of the two rotamers 8 or 9 (Figure 2). Rotamer 8, with
the carbonyl syn to the sulfonyl group, has been shown to be
(
16) The absolute stereochemistry of products such as 2 had never been
Acknowledgment. We gratefully acknowledge the National Science
Foundation (NSF CHE-9502507) and the National Heart Foundation
M1987) for their generous financial support of this work. We also
wish to thank the Research Corporation (1995 Cottrell Scholar Award
to J.W.L.), Eli Lilly and Company (predoctoral fellowship to L.J.B.),
and the Generalitat de Catalunya (Gaspar de Portol a` postdoctoral
fellowship to S.R.) for their assistance. This paper is dedicated to the
memory of Professor William G. Dauben.
rigorously proven (see Khan, A. A.; Emslie, N. D.; Drewes, S. E.; Field, J.
S.; Ramesar, N. Chem. Ber. 1993, 126, 1477). Conversion of these products
into known anti aldol adducts such as 4 unequivocally established the
absolute sense of asymmetric induction in the initial Baylis-Hillman
(
14
reactions. As an additional test, the anti aldol adducts were also subjected
to Mosher’s ester analysis, and the data were in complete agreement with
the structures assigned (see: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092).
(
17) Slob, A. Phytochemistry 1972, 12, 811.
(
18) The synthetic material prepared in this fashion was virtually identical
Supporting Information Available: Experimental procedures and
characterization data for compounds 2-7 (7 pages). See any current
masthead page for ordering and Internet access instructions.
with natural tulipalin B. The (S) stereochemistry of tulipalin B has previously
been confirmed by synthesis from malic acid (see: Papageorgiou, C.;
Benezra, C. J. Org. Chem. 1985, 50, 1145 and references cited within).
(
19) While either enolate geometry could be generated via the Michael
addition of the catalyst to the acrylate in a reversible fashion, Drewes has
JA970079G
proposed the Z-enolate as an explanation of the rate enhancement observed
1
b
with 3-quinuclidinol.
(20) Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521.