Catalytic asymmetric C-H activation of silyl enol ethers as an equivalent of an asymmetric Michael reaction [7]

Full text of DOI:10.1021/ja0035607

2070
J. Am. Chem. Soc. 2001, 123, 2070-2071
prone to cyclopropanation. Indeed, the cyclopropanation of vinyl
ethers with ethyl diazoacetate has been extensively applied in
organic synthesis.14 However, the rhodium-carbenes derived from
vinyldiazoacetates and aryldiazoacetates are much more chemo-
selective, both electronically15 and sterically,16 than the traditional
rhodium-carbenes derived from ethyl diazoacetate. No examples
are known of intermolecular cyclopropanation of trans-alkenes
or more highly substituted alkenes by these carbenes. Conse-
quently, even though the double bond in vinyl ethers is electron
rich, we anticipated that effective C-H insertion would occur.
As the C-H insertion is considered to involve a transition state
with build-up of positive charge on carbon,12 good regiocontrol
between the two allylic positions was expected. Furthermore, by
modifying the size of the functionality around the C-H insertion
site good diastereocontrol should also be feasible.
Catalytic Asymmetric C-H Activation of Silyl Enol
Ethers as an Equivalent of an Asymmetric Michael
Reaction
Huw M. L. Davies* and Pingda Ren
Department of Chemistry
State UniVersity of New York at Buffalo
Buffalo, New York 14260-3000
ReceiVed October 2, 2000
The development of chemoselective methods for C-H activa-
tion would broaden the range of strategies that could be used for
the synthesis of complex molecules.1,2 A very attractive method
for catalytic asymmetric C-H activation is the C-H insertion
chemistry of metal-carbenes.3 The enantioselective intramolecular
version of the metal-carbene C-H insertion is well established.4
Recently, we demonstrated that the enantioselective intermolecular
version of this reaction is also very effective with rhodium-
carbenes containing both electron-withdrawing and electron-
donating groups.5 [Rh2(S-DOSP)4] is an exceptional chiral catalyst
for this transformation.6 Since then, highly enantioselective C-H
activation of alkanes,7 alkenes,8 polyenes,9 tetrahydrofuran,7
N-BOC protected cyclic amines,10 and allyl silyl ethers11 have
been reported.12 In this paper we describe the application of the
asymmetric C-H activation to the synthesis of products that
would be more typically derived from an asymmetric Michael
reaction.13 The key step is the Rh2(S-DOSP)4-catalyzed decom-
position of methyl aryldiazoacetates in the presence of silyl enol
ethers (eq 1).
The initial evaluation of this reaction was carried out with TIPS
enol ether 1. Rh2(S-DOSP)4-catalyzed decomposition of methyl
p-bromophenyldiazoacetate (2a) at 23 °C in the presence of 4
equiv of 1 in 2,2-dimethylbutane as solvent resulted in the
formation of the desired C-H insertion products 3a and 4a in a
2:1 ratio with a combined yield of 80% (eq 2). The diastereomers
were readily separated by chromatography, and the major
diastereomer 3a was formed in 90% ee while the minor diaste-
reomer 4a was formed in 78% ee. On lowering the reaction
temperature to -30 °C, the enantioselectivity for 3a and 4a was
improved to 95% ee and 85% ee, respectively, but the yield was
decreased (44% yield). By using 1, however, as the limiting agent
(2 equiv of 2a) an excellent yield (86%) of 3a and 4a was
obtained. Methyl phenyldiazoacetate (2b) undergoes similar C-H
insertions to 2a.
To confirm that the structure of the carbene was the critical
factor that caused the C-H insertion to be the dominant reaction
pathway, the reaction catalyzed by Rh2(S-DOSP)4 was repeated
with ethyl diazoacetate instead of 2a. This resulted in the
formation of a 76:24 mixture of cyclopropane diastereomers 5
and the C-H insertion product 6. Rh2(S-DOSP)4 enhances the
C-H insertion because the same reaction catalyzed by Rh2(OOct)4
gave a 96:4 ratio of 5 to 6. From these results it is clear that the
carbene structure is critical for effective C-H insertions with silyl
enol ethers, but Rh2(S-DOSP)4 also enhances the C-H insertion
pathway.
The C-H activation of vinyl ethers is an intriguing proposition,
because the double bond is very electron rich, which makes it
(1) For recent reviews, see: (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV.
1997, 97, 2879. (b) Dyker, G. Angew. Chem., Int. Ed. Engl. 1999, 28, 1698.
(c) Arndsten, B. A.; Bergman, R. G. Science 1995, 270, 1970.
(2) For a recent example of application of a C-H activation reaction to
total synthesis, see: Johnson. J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122,
6321.
(3) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York,
1998; pp 112-162.
(4) Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron:
Asymmetry 1998, 9, 3145
(5) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(6) (a) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. (b) Davies, H. M.
L. Aldrichim. Acta 1997, 30, 105.
(7) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000,
122, 3063.
(8) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725.
(9) (a) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1,
233. (b) Davies, H. M. L.; Stafford, D. G.; Hansen, T.; Churchill, M. R.;
Keil, K. M. Tetrahedron Lett. 2000, 41, 2035.
(10) (a) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. A. J. Am.
Chem. Soc. 1999, 121, 6509. (b) Axten, J. M.; Ivy, R.; Krim, L.; Winkler, J.
D. J. Am. Chem. Soc. 1999, 121, 6511.
(11) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1,
383.
(12) For a general review, see: Davies, H. M. L.; Antoulinakis, E. G. J.
Organomet. Chem. 2001, 617, 47.
(14) (a) Ebibger, A.; Heinz, T.; Umbricht, G.; Pfaltz, A. Tetrahedron 1998,
54, 10469. (b) Schumacher, R.; Dammast, F.; Reissig, H.-U. Chem. Eur. J.
1997, 3, 614. (c) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73. (d) Reissig,
H.-U. The Chemistry of the Cyclopropyl Group; Rappoort, Z., Ed.; Wiley:
New York, 1987; Part 1, p 375.
(13) For a general review on the asymmetric Michael addition, see:
Yamaguchi, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, pp 1121-
1139.
(15) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(16) (a) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Fall, M. J. J.
Am. Chem. Soc. 1996, 118, 6897. (b) Davies, H. M. L.; Hu, B. Heterocycles
1993, 35, 385.
10.1021/ja0035607 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 2071
standard conditions, with the silyl enol ether 13a as the limiting
agent at -30 °C, the C-H insertion product 14a was formed in
In our previous studies on the C-H activation, we have found
that highly diastereoselective reactions are possible at methylene
sites as long as the methylene substituents are of different
size.10a,11,12 Consequently, the reaction of the vinyl ether 7 was
explored. This resulted in the formation of the diastereomeric
C-H insertion products 8 and 9 in an 81% overall yield and an
improved ratio of 81:19. A trace (2-3%) of the primary C-H
insertion product was also observed. The enantioselectivity for
the formation of both 8 and 9 was high (89% ee and 88% ee,
respectively). Considering that the vinyl ether 7 has three allylic
positions, the selective formation of one diastereomeric pair of
the possible C-H insertion products underscores the chemo-
selectivity that is possible in these C-H insertions.
66% isolated yield and 71% ee. Under these conditions, the
conversion of 13a is essentially quantitative but 25-30% of the
cyclopropanation product is also formed.17 This is the first
example of an aryldiazoacetate undergoing intermolecular cy-
clopropanation of a trisubstituted alkene. A similar reaction with
the TBDPS enol ether 13b generated 14b in 84% ee and >90%
de.
Demonstration that the C-H insertion products could be
converted to the equivalent products of a Michael addition was
readily achieved (eq 7). Desilylation of 11 generated the ketone
16 in 98% yield, which could be recrystallized to enantiomeric
purity (>99% ee). The absolute stereochemistry of 16 was
determined by X-ray crystallography to be RR,2S.18
In summary, the efficient C-H insertion of vinyl ethers by
aryldiazoacetates demonstrates the broad range of C-H activation
chemistry that is possible with this system. The carbenoid structure
and catalysts are crucial for the success of this chemistry. The
reaction with the acyclic enol silyl ethers 13 is especially
promising because excellent diastereocontrol is possible with this
system. Studies are underway to determine the full scope of this
reaction for the synthesis of compounds that would be typically
made by an asymmetric Michael reaction.
The C-H insertions can also be carried out with the more
elaborate silyl enol ether 10. The Rh2(S-DOSP)4-catalyzed reaction
of 2a with 10 resulted in the formation of the major diastereomer
11 in 90% ee and the minor diastereomer 12 in 73% ee with a
combined yield of 68%. This transformation is an excellent
example of the potential of this chemistry because the corre-
sponding Michael reaction would not be possible as the required
enone would be the keto tautomer of 1-naphthol.
Acknowledgment. Financial support of this work by the National
Science Foundation (CHE 9726124) and the National Institutes of Health
(GM57425) is gratefully acknowledged. We thank Mr. Yuegang Zhang
for the X-ray structure determination.
Supporting Information Available: Full experimental data for
compounds 3a, 4a, 3b, 4b, 8, 9, 11, 12, 14, 15, and 16, and X-ray
crystallographic data for 16 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA0035607
(17) The cyclopropane product 15 was formed in >90% de and 92% ee.
The highly stereoselective cyclopropanation is typical of Rh2(S-DOSP)4-
catalyzed aryldiazoacetate cyclopropanations (see ref 6).
(18) The absolute stereochemistry for the major diastereomers of the other
C-H insertion products is tentatively assigned by assuming a similar mode
of asymmetric induction for all the substrates. The stereochemistry of the minor
C-H insertion product was determined by epimerization of the major product.
Treatment of 3a (89%ee, RR,1S) with DBU at 80 °C overnight resulted in
equilibration to RS,1S diastereomer 4a (85%ee), which, according to the
retention time on HPLC, is the enantiomer of the minor diastereomer 4a from
the C-H insertion. Hence, the minor C-H insertion product 4a is assigned
to be the (RR,1R) configuration.
Extension of the chemistry to the acyclic TIPS enol ether 13a
resulted in a major change in the chemistry. With this substrate,
the diastereoselectivity of the C-H insertion was very high
(>90% de), presumably because the methylene substituents
(CdC(OSiR3)Ph and Me) are very different in size. Under the