Effect of the Michael Acceptor in the Asymmetric Intramolecular Stetter Reaction

Article abstract of DOI:10.1055/s-2003-41458

The effect of different Michael acceptors was evaluated in the catalytic asymmetric intramolecular Stetter reaction. Utilizing a readily prepared chiral triazolium salt as a nucleophilic carbene precursor, the reactivity and selectivity of substrates containing different electron-deficient double bonds was shown to vary significantly under identical reaction conditions.

Full text of DOI:10.1055/s-2003-41458

1934
CLUSTER
Effect of the Michael Acceptor in the Asymmetric Intramolecular Stetter
Reaction
E
ffect of the Michae
l
A
a
cceptor in
r
the Asym
k
metric Intramolec
S
ula
r
Stetter Re
.
action Kerr, Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
Fax +1(970)4911801; E-mail: rovis@lamar.colostate.edu
Received 20 June 2003
In the course of our investigations into the aliphatic series
Abstract: The effect of different Michael acceptors was evaluated
in the catalytic asymmetric intramolecular Stetter reaction. Utiliz-
ing a readily prepared chiral triazolium salt as a nucleophilic car-
bene precursor, the reactivity and selectivity of substrates
for the formation of cycloalkanones, we became intrigued
by a large difference in reactivity among homologous sub-
strates. For example, aliphatic aldehyde 3 cyclized to form
containing different electron-deficient double bonds was shown to cyclopentanone 5 in high yield and excellent enantio-
vary significantly under identical reaction conditions.
selectivity (Equation 1) while aldehyde 6, differing by a
single methylene unit, was unreactive under identical con-
ditions (Equation 2). This result spawned further investi-
gations into the reactive species involved in this
transformation.
Keywords: nucleophilic carbenes, catalytic asymmetric Stetter,
Michael acceptors, umpolung chemistry
The Stetter reaction takes advantage of umpolung1 of the
aldehyde reactivity in which an acyl anion equivalent at-
tacks an electron-deficient olefin.2 It was first established
by Stetter in 1976 that a catalytic amount of thiazolium
salt in the presence of a weak base could mediate the ad-
dition of aldehydes into activated double bonds.3,4 An in-
tramolecular variant of the reaction was reported by
Ciganek almost 20 years later describing its use in the
formation of chromanones.5 This same process was first
rendered asymmetric by Enders6,7 utilizing a chiral triazo-
lium salt in the presence of base to catalyze the formation
of the 1,4-ketoesters in good yield and moderate selec-
tivity.
20%
Cl
N
O
O
N
N
Ph
CO2Et
CO2Et
Bn
4
5
20% KHMDS, PhMe
24 h
3
81% yield,
95%ee
Equation 1
20%
Cl
N
O
CO2Et
N
N
Ph
We began to investigate the asymmetric Stetter reaction in
connection with our interest in the development of a fam-
ily of chiral nucleophilic carbenes for organic synthesis.
Of particular appeal to us were carbenes of type 17i and 2,
which take advantage of a fused-ring structure to lock
chiral information into a defined space (Figure 1). Under
optimized conditions, we had demonstrated that a variety
of aldehydes react with pendant a,b-unsaturated esters to
form 5- and 6-membered rings in good yield (63–95%)
and high enantioselectivity (82–96%).8
Bn
4
No Reaction
20% KHMDS, PhMe
24 h
6
Equation 2
While the initial report by Stetter has shown that the reac-
tion may be performed with a,b-unsaturated nitriles, ke-
tones, and esters,2 matching of catalyst and Michael
acceptor seems to be important. For example, a significant
amount of data has been collected that suggests thiazoli-
nylidene carbenes are most effective for the addition of al-
dehydes to a,b-unsaturated ketones, while cyanide anion
is a more effective catalyst for a,b-unsaturated esters and
nitriles.2 With this in mind, we set out to investigate
whether triazolinylidene carbenes9 would be susceptible
to these same limitations or could provide a more general
solution to this problem. We reasoned that the most elec-
tron-deficient systems would be the most reactive, as
attack of the acyl anion equivalent would be more facile.
However, concerns existed with regard to the enantio-
selectivity of these cyclizations, as well as reaction condi-
tion compatibility.
X
X
O
N
N
R''
N
N
N
N
R
R
R'
R'
1
2
Figure 1
SYNLETT 2003, No. 12, pp 1934–1936
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41458; Art ID: Y00803ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Effect of the Michael Acceptor in the Asymmetric Intramolecular Stetter Reaction
Table 1 Effect of Michael Acceptor
1935
We initiated our studies by examining the effect of the
Michael acceptor olefin geometry. We were intrigued to
find that while parent substrate 7 cyclized with high enan-
tioselectivity and in moderate yield (Equation 3), no reac-
tion was observed in the case of Z-alkene 10 under
stoichiometric reaction conditions (Equation 4). This
prompted us to focus subsequent investigations on acti-
vated E-alkenes.
O
20%
N BF4
N
N
O
O
EWG
O
EWG
8
O
20% KHMDS, PhMe
Entry EWG
Reaction
time (h)
Yield (%)
ee (%)
O
20%
BF4
N
1
2
3
24
24
1
0
–
O
N
N
O
O
CO2Et
O
CO2Et
(95% Recovered
starting material)
NH2
11
8
58
95
92
O
20% KHMDS, PhMe
24 h
O
7
9
58% yield
95%ee
OEt
7
90
O
Equation 3
Et
N
12
O
100%
BF4
N
4
5
24
24
78
0
75
–
N
N
O
13
CO2Et
No reaction
90% recovered
starting material
8
O
100% KHMDS, PhMe
24 h
10
O
H
14
Equation 4
6
24
0
–
NO2
15
In attempts to implement a uniform series of substrates
containing electron deficient E-alkenes, substrates 11–15
were prepared from salicylaldehyde. These were in turn
subjected to standard asymmetric Stetter conditions
(Table 1).
(Entries 5 and 6). In contrast to the amide in entry 1, the
starting material was entirely consumed.
With this insight in hand, we turned our attention to the al-
iphatic series. Ketone 16 was prepared and subjected to
standard reaction conditions (Equation 5). Unfortunately,
the corresponding cyclohexanone was not formed under
these conditions, a fact which we ascribe to the greater
conformational freedom of the aliphatic linker compared
to the fused aromatic linker of substrate 12. We rational-
ized that increasing the electrophilicity of the Michael ac-
ceptor in this system may prove effective. To that end, we
prepared alkylidene malonate 17. In the event of exposure
to our Stetter conditions, cyclohexanone 18 was obtained
in 97% isolated yield and 82% ee (Equation 6). Notewor-
thy in this example is that the greater reactivity of the
alkylidene malonate is not accompanied by a significant
decrease in selectivity. This result reinforces the observa-
tion that more electrophilic p-systems are ideal in secur-
ing the highest reactivity in these substrates. Also of
interest is that the proton that resides a to the esters is rel-
atively acidic (pKa ca. 13), yet does not protonate the car-
bene and terminate the reaction. This also suggests that
the failure of the primary amide 11 to undergo cyclization
is due to a decreased electrophilicity of the Michael ac-
ceptor. This encouraging result indicates that more func-
tionalized substrates relevant to complex molecule total
synthesis may be well tolerated in this reaction.
Unfortunately, a,b-unsaturated amide 11 provided no
product with near quantitative recovery of starting materi-
al, entry 1. We suspect that the olefin is not sufficiently ac-
tivated for electrophilic attack in this particular catalyst-
aldehyde complex. Alternately, the protons on the amide
nitrogen may be acidic enough to protonate the catalyst
and effectively end the catalytic cycle, as it is well estab-
lished that nucleophilic carbenes are strong bases.10
Parent substrate a,b-unsaturated ester 7 reacts under these
conditions to produce the corresponding ketoester in 58%
yield and 95% ee (Entry 2). With the analogous a,b-unsat-
urated ketone 12, we observe a significant increase in
yield compared with the ester substrate 7 (Entry 3). Of
further note is that the reaction only takes 1 hour for full
consumption of this substrate. This large increase in reac-
tivity is accompanied by a slight decrease in enantioselec-
tivity to 92% ee. a,b-Unsaturated nitrile 13 provides the
cyclized adduct in 78% yield albeit with diminished enan-
tioselectivity (75% ee, Entry 4). This result may point to
the requirement of a carbonyl functionality for optimum
enantioselectivity.
In the reaction of both a,b-unsaturated aldehyde 14 and
nitro compound 15, no product formation was detected
Synlett 2003, No. 12, 1934–1936 © Thieme Stuttgart · New York

1936
M. S. Kerr, T. Rovis
CLUSTER
In conclusion, we have demonstrated that the asymmetric
intramolecular Stetter reaction is sensitive to the nature of
the Michael acceptor. A variety of functional groups, in-
cluding ester, ketone, nitrile, and malonate are effective in
activating the olefins to attack by the chiral acyl anion
equivalent. Both reactivity and selectivity are affected by
the electrophilicity of the olefin. Studies aimed at under-
standing the mechanism and widening the scope of this re-
action are ongoing.
Acknowledgment
The authors thank Colorado State University for startup funds, the
V. P. of Research for a Faculty Research Grant, Merck Research
Laboratories and Glaxo-SmithKline for partial support of this re-
search.
References
(1) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(2) Stetter, H.; Kuhlmann, H. Organic Reactions, Vol. 40;
Paquette, L. A., Ed.; Wiley: New York, 1991, 407.
(3) Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2891.
(4) Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 3427.
(5) Ciganek, E. Synthesis 1995, 1311.
O
20%
Bn
Cl
N
O
N
N
Ph
4
No Reaction
(6) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim.
Acta 1996, 79, 1899.
20% KHMDS, PhMe
24 h
(7) The mechanistically related asymmetric benzoin reaction
has received far more attention, see: (a) Sheehan, J. C.;
Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666.
(b) Sheehan, J. C.; Hara, T. J. Org. Chem. 1974, 39, 1196.
(c) Martí, J.; Castells, J.; López-Calahorra, F. Tetrahedron
Lett. 1993, 34, 521. (d) Yamashita, K.; Sasaki, S.-i.; Osaki,
T.; Nango, M.; Tsuda, K. Tetrahedron Lett. 1995, 36, 4817.
(e) Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta
1996, 79, 1217. (f) Knight, R. L.; Leeper, F. J. Tetrahedron
Lett. 1997, 38, 3611. (g) Gerhard, A. U.; Leeper, F. J.
Tetrahedron Lett. 1997, 38, 3615. (h) Dvorak, C. A.;Rawal,
V. H. Tetrahedron Lett. 1998, 39, 2925. (i) Knight, R. L.;
Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891.
(j) Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41,
1743.
16
Equation 5
O
CO2Et
CO2Et
O
CO2Et
CO2Et
20%
Cl
N
N
N
Ph
Bn
4
17
18
20% KHMDS, PhMe
36 h
97%
82% ee
Equation 6
(8) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298.
(9) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.;
Melder, J.-P.; Ebel, K.; Brode, S. Angew Chem., Int. Ed.
Engl. 1995, 34, 1021.
(10) (a) Alder, R. W.; Allen, P. R.; Williams, S. J. Chem.
Commun. 1995, 1267. (b) Kim, Y.-J.; Streitwieser, A. J. Am.
Chem. Soc. 2002, 124, 5757.
Synlett 2003, No. 12, 1934–1936 © Thieme Stuttgart · New York