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New Developments in the Asymmetric Stetter Reaction.

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Asymmetric Catalysis
New Developments in the Asymmetric
Stetter Reaction**
Mathias Christmann*
asymmetric catalysis · carbenes · organocatalysis ·
Stetter reaction · umpolung
Processes mediated by small nucleophilic catalysts are currently experiencing a renaissance. In addition to competing with well-established metal-catalyzed reactions, there is a tempting
opportunity to invert conventional reactivity patterns by exploiting the concept of polarity reversal (umpolung).[1]
Following this strategy, aldehydes can be
turned into acylanion equivalents[2]
through covalent activation with suitable nucleophiles (Scheme 1). Among
Schreckenberg extended this concept to
conjugate acceptors 7.[5] Since that time,
the 1,4-addition of aldehydes to a,bunsaturated carbonyl compounds has
become commonly known as the Stetter
reaction. If a prochiral acceptor is employed, chiral 1,4-dicarbonyl compounds such as 8 can be obtained, which
are important intermediates in the synthesis of biologically active molecules.
In an effort to impart stereoselectivity to both the benzoin condensation
densation,[6] many research groups have
been involved in the development of
chiral heteroazolium salt catalysts. The
cyclization of the salicylaldehyde-derived substrate 9 to the corresponding
chromanone 10 has become a benchmark for catalyst efficiency in intramolecular Stetter reactions (Scheme 2).
Scheme 2. Intramolecular Stetter reaction.
and the Stetter reaction, various chiral
catalysts have been developed over the
past four decades. Inspired by the pioneering work of Sheehan and Hunneman on the asymmetric benzoin con-
In 1996, Enders and co-workers
reported the first asymmetric Stetter
reaction. The key to their success was
the increased reactivity of the triazolium
salt 11 over that of previously used
thiazolium salts.[7] With the triazolium
unit embedded in the bicyclic framework of 12 (Bn = benzyl), Knight and
Leeper[8] obtained high enantioselectivities in the benzoin condensation, which
were further improved by Enders and
Kallfass with catalyst 13.[9] Recently,
Rovis and co-workers have made significant progress in the asymmetric
intramolecular Stetter reaction.[10]
DOI: 10.1002/anie.200500761
Angew. Chem. Int. Ed. 2005, 44, 2632 –2634
Scheme 1. Generation and reactions of acylanion equivalents.
several catalysts, thiazolium salts 1 serve
as precursors for nucleophilic carbenes
2, which in turn are able attack aldehydes 3 to form the so-called Breslow
intermediate 4.[3, 4] The 1,2-addition of
this species with an acceptor aldehyde 5
is referred to as the benzoin condensation. In the early 1970s, Stetter and
[*] Dr. M. Christmann
Institut fr Organische Chemie
RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax: (+ 49) 241-809-2127
[**] The author thanks the Fonds der Chemischen Industrie for a Liebig fellowship.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
With 20 mol % of the aminoindanolderived triazolium salt 14, the intramolecular Stetter reaction of 9 (R = Et)
proceeded smoothly to give the desired
product 10 in 94 % yield and 94 % ee.
With regard to the electronic nature of
the phenyl ring on the triazole nitrogen,
4-methoxy substitution proved to be
optimal. Catalyst 14 gave consistently
high yields and percent ee values with
substrates bearing a heteroatom in the g
position of the acceptor. In some cases,
for example, with the aliphatic substrate
17, the catalyst 16 was superior
(Scheme 3).
dominates over the
leading to benzoins
as the major products.
To circumvent this
Scheme 4. Generation of quaternary stereocenters.
problem, Scheidt and
co-workers[14] devised
catalyst during the course of a strategy that employs acylsilanes as
the reaction.
acylanion precursors.[15] As shown in
Following their elegant Scheme 5, the reaction between acylsiwork on small peptide cata- lane 24 and chalcone (25) as the conlysts, the Miller research jugate acceptor, catalyzed by thiazolium
Scheme 3. Intramolecular Stetter reaction of aliphatic
group also investigated the salt 26, proceeds smoothly to give 1,4substrates. KHMDS = potassium hexamethyldisilazide.
intramolecular asymmetric dicarbonyl product 27 in 77 % yield.
Stetter reaction.[13] For this
In their mechanistic model, a carpurpose, the terminal histi- bene catalyst 1 adds to the acylsilane 28
Rovis also took on the challenge of dine residue was replaced with thiazo- to give—after 1,2-silyl migration (Brook
generating quaternary stereocenters.[11] lylalanine (Taz) derivatives. An initial rearrangement)—the intermediate 29
Analogous to the experience with 14, screen with 9 (R = tBu) as the substrate (Scheme 6). The alcohol is believed to
the substitution pattern of the phenyl and 20 mol % of the catalyst 22 (Ts = p- induce a desilylation leading to the
ring was found to be the decisive factor toluenesulfonyl) afforded the corre- Breslow intermediate 4. The conjugate
in the catalyst design. Surprisingly, the sponding chromanone 10 in 40 % yield addition predominates in this case as a
pentafluorophenyl and 80 % ee. It was speculated that both result of the decreased electrophilicity
catalyst 15 was the most effective in this yield and selectivity might be improved of the acylsilane (in comparison with
case (up to 99 % ee), suggesting mecha- by the incorporation of Taz into small that of an aldehyde).
The 1,4-dicarbonyl products of Stetnistic differences from b-monosubstitut- peptides. With catalyst 23 (Boc = t-butoxycarbonyl), the product 10 could be ter reactions are ideal substrates for the
ed substrates (Scheme 4).
A critical reader might interject that obtained in promising 67 % yield and Paal–Knorr synthesis. Mller and coworkers[16] as well as Bharadwaj and
reactions with heteroazolium salts usu- 73 % ee.
In the intermolecular Stetter reac- Scheidt[17] have developed efficient oneally require as much catalyst as
20 mol %. Rovis notes that albeit with tion, self-condensation of the donor pot Stetter–Paal–Knorr protocols for
poorer selectivity, certain solvents can
allow much lower catalyst loadings. For
example, the reaction of 19 in the
presence of triazolium salt 15 at
1 mol % in isopropanol affords the desired product 20 in 78 % yield with
83 % ee. This holds promise for catalysts
with improved efficiency.
Scheme 5. Sila–Stetter reaction. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Bach and co-workers developed the
axially chiral N-arylthiazolium catalyst
21, which bears a menthol-derived backbone .[12] With this catalyst at 20 mol %
they were able to isolate the Stetter
product 10 (R = Me) in 75 % yield with
50 % ee. The low stereoselectivity was
ascribed to an atropisomerization of the
Scheme 6. Mechanistic proposal for the Sila–Stetter reaction.
Angew. Chem. Int. Ed. 2005, 44, 2632 –2634
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 7. Synthesis of roseophilin from Harrington and Tius. Bz = benzoyl.
the synthesis of highly substituted pyrroles.
Although the Stetter reaction can be
carried out these days with very good
yields and selectivities, only a few examples of its application toward the
synthesis of natural products have been
reported thus far.[18] Harrington and
Tius employed a diastereoselective intermolecular Stetter reaction and a ringclosing metathesis reaction as the key
steps in their elegant synthesis of roseophilin (33, Scheme 7).[19] The 1,4-dicarbonyl functionality in 32 serves as a
precursor for the central pyrrole unit of
the natural product.
The examples presented herein
show that from the development of
highly active catalysts and creative reaction design, asymmetric Stetter reactions have become a valuable addition
to the repertoire of efficient C C bondforming reactions. It can be expected
that these and other[20, 21] umpolung reactions will stimulate chemists to dare
new retrosynthetic disconnections in
their synthetic strategies.
[1] D. Seebach, Angew. Chem. 1979, 91,
259; Angew. Chem. Int. Ed. Engl. 1979,
18, 239.
[2] J. S. Johnson, Angew. Chem. 2004, 116,
1348; Angew. Chem. Int. Ed. 2004, 43,
[3] a) T. Ukai, R. Tanaka, T. Dokawa, J.
Pharm. Soc. Jpn. 1943, 63, 296; b) R.
Breslow, J. Am. Chem. Soc. 1958, 80,
[4] For a review, see: D. Enders, T. Balensiefer, Acc. Chem. Res. 2004, 37, 534.
[5] a) H. Stetter, M. Schreckenberg, Angew.
Chem. 1973, 85, 89; Angew. Chem. Int.
Ed. Engl. 1973, 12, 81; b) H. Stetter,
Angew. Chem. 1976, 88, 695; Angew.
Chem. Int. Ed. Engl. 1976, 15, 639.
[6] J. C. Sheehan, D. H. Hunneman, J. Am.
Chem. Soc. 1966, 88, 3666.
[7] D. Enders, K. Breuer, J. Runsink, J. H.
Teles, Helv. Chim. Acta 1996, 79, 1899.
[8] R. L. Knight, F. J. Leeper, J. Chem. Soc.
Perkin Trans. 1 1998, 1891.
[9] D. Enders, U. Kallfass, Angew. Chem.
2002, 114, 1822; Angew. Chem. Int. Ed.
2002, 41, 1743.
[10] M. S. Kerr, J. Read de Alaniz, T. Rovis,
J. Am. Chem. Soc. 2002, 124, 10 298.
[11] a) M. S. Kerr, T. Rovis, J. Am. Chem.
Soc. 2004, 126, 8876; b) T. Nakamura, O.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Hara, T. Tamura, K. Makino, Y. Hamada, Synlett 2005, 155.
J. Pesch, K. Harms, T. Bach, Eur. J. Org.
Chem. 2004, 2025.
S. M. Mennen, J. T. Blank, M. B. TranDub, J. E. Imbriglio, S. J. Miller, Chem.
Commun. 2005, 195.
A. E. Mattson, A. R. Bharadwaj, K. A.
Scheidt, J. Am. Chem. Soc. 2004, 126,
X. Linghu, J. S. Johnson, Angew. Chem.
2003, 115, 2638; Angew. Chem. Int. Ed.
2003, 42, 2534.
R. U. Braun, K. Zeitler, T. J. J. Mller,
Org. Lett. 2001, 3, 3297.
A. R. Bharadwaj, K. A. Scheidt, Org.
Lett. 2004, 6, 2465.
B. M. Trost, C. D. Shuey, F. DiNinno,
S. S. McElvain, J. Am. Chem. Soc. 1979,
101, 1284.
P. E. Harrington, M. A. Tius, J. Am.
Chem. Soc. 2001, 123, 8509.
For examples of conjugate umpolung,
see: a) C. Burstein, F. Glorius, Angew.
Chem. 2004, 116, 6331; Angew. Chem.
Int. Ed. 2004, 43, 6205; b) S. S. Sohn,
E. L. Rosen, J. W. Bode, J. Am. Chem.
Soc. 2004, 126, 14 370.
For the related addition of aldehydes to
acylimines, see: a) J. A. Murry, D. E.
Frantz, A. Soheili, R. Tillyer, E. J. J.
Grabowski, P. J. Reider, J. Am. Chem.
Soc. 2001, 123, 9696; b) D. E. Frantz, L.
Morency, A. Soheili, J. A. Murry, E. J. J.
Grabowski, R. D. Tillyer, Org. Lett.
2004, 6, 843.
Angew. Chem. Int. Ed. 2005, 44, 2632 –2634
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