Catalytic asymmetric reactions for organic synthesis: The combined C-H activation/siloxy-cope rearrangement

Article abstract of DOI:10.1021/jo048429m

Tetrakis(N-[4-dodecylbenzenesulfonyl]-(L)-prolinate) dirhodium [Rh ₂(S-DOSP)₄]-catalyzed decomposition of vinyldiazoacetates in the presence of allyl silyl ethers results in the formation of the direct C-H insertion product and the p

Full text of DOI:10.1021/jo048429m

Catalytic Asymmetric Reactions for Organic Synthesis: The
Combined C-H Activation/Siloxy-Cope Rearrangement
Huw M. L. Davies* and Rohan E. J. Beckwith
Department of Chemistry, University at Buffalo, State University of New York,
Buffalo, New York 14260-3000
hdavies@acsu.buffalo.edu
Received September 7, 2004
Tetrakis(N-[4-dodecylbenzenesulfonyl]-(L)-prolinate) dirhodium [Rh2(S-DOSP)4]-catalyzed decom-
position of vinyldiazoacetates in the presence of allyl silyl ethers results in the formation of the
direct C-H insertion product and the product derived from a combined C-H activation/siloxy-
Cope rearrangement. Both products are formed with very high diastereoselectivity (>94% de) and
high enantioselectvity (78-93% ee). Under thermal or microwave conditions, the direct C-H
insertion product undergoes a siloxy-Cope rearrangement in a stereoselective manner.
SCHEME 1
Introduction
The ability to construct stereogenic centers with high
levels of stereocontrol at positions remote from any
activating functionality remains a major challenge in
synthetic organic chemistry, particularly in acyclic sys-
tems.1 A convenient approach is to establish a proximal
stereogenic center through 1,2-asymmetric induction
followed by chirality transfer through a sigmatropic
rearrangement.2,3 In this way the highly organized
transition state of the pericyclic process ensures that the
enantioinduction installed in the initial asymmetric step
is maintained. A very attractive example of this strategy
is the combination of the chiral auxiliary based asym-
metric syn-aldol reaction (between the enolate of the
unsaturated ester 1 and the unsaturated aldehyde 2) to
form the â-siloxyester 3 with the siloxy-Cope rearrange-
ment of 3 to form the silyl enol ether 4 (Scheme 1).4-7 In
this paper we describe an entirely different strategy for
achieving the equivalent of the tandem aldol reaction/
siloxy-Cope rearrangement. The key step is a rhodium
catalyzed enantioselective C-H activation between vinyl-
diazoacetate 6 and allyl silyl ether 5, which leads to the
formation of 4 either directly or via the â-siloxyester 3.
Our interest in this area arose from the development
of a practical intermolecular C-H activation method
based on rhodium-carbenoid induced C-H insertions.8-10
Diazoacetates 7 possessing an aryl donor group generate
highly chemoselective carbenoids capable of very effective
intermolecular C-H functionalization.11 When these
carbenoids are generated by the rhodium prolinate
catalyst Rh2(S-DOSP)4 (10) highly enantioselective reac-
tions are generally obtained.8-10 A most notable example
is the Rh2(S-DOSP)4-catalyzed reaction of 7 in the pres-
(1) For selected reviews on other methods for C-H activation, see:
(a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879. (b) Dyker,
G. Angew. Chem., Int. Ed. 1999, 28, 1698. (c) Arndsten, B. A.; Bergman,
R. G. Science 1995, 270, 1970. (d) Jia, C.; Kitamura, T.; Fujiwara, Y.
Acc. Chem. Res. 2001, 34, 633. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731. (f) Kakiuchi, F.; Chatani, N. Adv. Synth.
Catal. 2003, 345, 1077.
(2) For recent examples, see: (a) Nokami, J.; Ohga, M.; Nakamoto,
H.; Matsubara, T.; Hussain, I.; Kataoka, K. J. Am. Chem. Soc. 2001,
123, 9168. (b) Allin, S. M.; Baird, R. D.; Lins, R. J. Tetrahedron Lett.
2002, 43, 4195. (c) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9434.
(3) For a recent review of [3,3]-sigmatropic rearrangements, see:
Nubbemeyer, U. Synthesis 2003, 961 and references therein.
(4) For reviews on the siloxy-Cope rearrangement of chiral aldol
products, see: (a) Schneider, C.; Rehfeuter, M. Tetrahedron 1997, 53,
133. (b) Schneider, C. Synlett 2001, 1079.
(5) (a) Schneider, C.; Rehfeuter, M. Synlett 1996, 212. (b) Schneider,
C. Synlett 1997, 815. (c) Schneider, C. Eur. J. Org. Chem. 1998, 1661.
(d) Schneider, C.; Bo¨rner, C. Synlett 1998, 652. (e) Schneider, C.;
Rehfeuter, M. Tetrahedron Lett. 1998, 39, 9. (f) Schneider, C.; Reh-
feuter, M. Chem. Eur. J. 1999, 5, 2850. (g) Schneider, C.; Bo¨rner, C.;
Schuffenhauser, A. Eur. J. Org. Chem. 1999, 3353. (h) Schneider, C.;
Schuffenhauser, A. Eur. J. Org. Chem. 2000, 73. (i) Schneider, C.;
Reese, O. Angew. Chem., Int. Ed. 2000, 39, 2948. (j) Schneider, C.;
Reese, O. Synthesis 2000, 1689. (k) Schneider, C.; Reese, O. Chem.
Eur. J. 2002, 8, 2585.
(7) (a) Tomooka, K.; Nagasawa, A.; Wei, S.-Y.; Nakai, T. Tetrahedron
Lett. 1996, 37, 8895. (b) Tomooka, K.; Nagasawa, A.; Wei, S.-Y.; Nakai,
T. Tetrahedron Lett. 1996, 37, 8899.
(8) For a review on the catalytic enantioselective C-H activation
chemistry of diazo compounds, see: Davies, H. M. L.; Beckwith, R. E.
J. Chem. Rev. 2003, 103, 2861.
(9) For a recent review on the intermolecular C-H activation
chemistry of diazo compounds, see: Davies, H. M. L. J. Mol. Catal. A:
Chem. 2002, 189, 125.
(6) Black, W. C.; Giroux, A.; Greidanus; G. Tetrahedron Lett. 1996,
37, 4471.
10.1021/jo048429m CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/01/2004
J. Org. Chem. 2004, 69, 9241-9247
9241

Davies and Beckwith
TABLE 1. Solvent and Temperature Effects
temp,
°C
yield,b
%
de for
16a, %
ee for
16a, %
de for
17a, %
ee for
17a, %
entry
solventa
16a:17a
1
2
3
4
5
6
7
8
CH2Cl2
-40
23
-40
23
-20
23
-40
23
35
76
56
57
61
68
10
89
2.8:1.0
1.8:1.0
2.3:1.0
2.3:1.0
3.2:1.0
2.3:1.0
1.0:1.0
1.0:1.0
>98
>98
>98
>98
>98
>98
>98
>98
70
52
92
78
88
76
92
89
>98
>98
>98
>98
>98
>98
>98
>98
66
48
89
75
87
72
90
88
CH2Cl2
toluene
toluene
CF3toluene
CF3toluene
2,2-DMB
2,2-DMB
a 1,2-Dichloroethane failed to generate any of the desired products. b The combined yields of 16a and 17a are reported.
ence of silyl ethers 8, which generates the corresponding
syn-aldol type products 9 with up to 98% de and 96% ee
(eq 1).10d
is highly diastereo- and enantioselective, offering a facile
way of constructing 1,5-hexadienes 13. The reaction,
however, suffers from the competing formation of the
C-H activation product 14 and this is exacerbated by
the fact that in all the examples studied to date, the C-H
activation product is thermodynamically favored.12
The effective development of this combined C-H
activation/Cope rearrangement would require strategies
to circumvent the current problem of the competing
reactions. This led to the current study on the reaction
of vinyldiazoacetates with allyl silyl ethers because the
issue of competing reactions would be avoided (Scheme
1). Even though a mixture of the direct C-H activation
product 3 and C-H activation/Cope rearrangement
product 4 might be formed, the siloxy-Cope rearrange-
ment of 3 could be used to drive the reaction to the
desired product 4. This catalytic approach obviates the
need for a chiral auxiliary, which was used in the
conventional tandem aldol reaction/siloxy-Cope re-
arrangement,4-7 enhancing the practical appeal of the
chemistry. Herein we describe the realization of the
chemistry and outline the scope and limitations of such
an approach.
In addition, we have previously described a very
unusual C-H functionalization between the vinyldiazo-
acetate 11 and compounds containing allylic C-H bonds
(e.g. 12) through effectively a combined C-H activation/
Cope rearrangement protocol (eq 2).12 The transformation
Results and Discussion
The first stage of the study required the determination
of the general reactivity profile of the chemistry between
vinyldiazoacetates and allyl silyl ethers. The Rh2(S-
DOSP)4-catalyzed (1 mol %) decomposition of methyl
phenylvinyldiazoacetate 11 (2 equiv) in the presence of
TBS-protected crotyl alcohol 15a was used as the test
reaction (Table 1). We were delighted to find that the
desired operation could be effected as a single pot process
affording silyl enol ether 16a with >98% de and as a
single geometric isomer. The stereochemistry of the
product matched the major product 4 obtained in the
chiral auxiliary based stepwise approach4-7 and was in
agreement with the established model for a thermal Cope
rearrangement in which the silyl ether adopts a pseudo-
axial conformation in a chairlike transition state.13 In
addition to silyl enol ether product 16a, the direct C-H
insertion product 17a was also obtained with excellent
(10) For recent examples of enantioselective intermolecular C-H
activation of diazo compounds, see: (a) Davies, H. M. L.; Jin, Q. Org.
Lett. 2004, 6, 1769. (b) Davies, H. M. L.; Hopper, D. W.; Hansen, T.;
Liu, X.; Childers, S. R. Biorg. Med. Chem. Lett. 2004, 14, 1799. (c)
Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. J.
Am. Chem. Soc. 2003, 125, 6462. (d) Davies, H. M. L.; Beckwith, R. E.
J.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126. (e) Davies,
H. M. L.; Yang, J. Adv. Synth. Catal. 2003, 345, 1133. (f) Davies, H.
M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941. (g) Davies, H.
M. L.; Walji, A. M. Org. Lett. 2003, 5, 479.
(11) Davies, H. M. L.; Hodges, L. M.; Matasi, J. J.; Hansen, T.;
Stafford, D. S. Tetrahedron Lett. 1998, 39, 4417.
(12) (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. (c) Davies, H. M. L.;
Jin, Q. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5472. (d) Davies, H.
M. L.; Jin, Q. J. Am. Chem. Soc. 2004, 126, 10862.
(13) (a) Hill, R. K.; Gilman, N. W. J. Chem. Soc., Chem. Commun.
1967, 619. (b) Doering, W. von E.; Toscano, V. G.; Beasley, G. H.
Tetrahedron 1971, 27, 5299.
9242 J. Org. Chem., Vol. 69, No. 26, 2004

Catalytic Asymmetric Reactions for Organic Synthesis
TABLE 2. Effect of Catalyst
temp,
°C
yield,
%
ee for
16a, %
ee for
17a, %
entry
catalyst
solvent
16a:17a
1
2
3
Rh2(OOct)4
2,2-DMB
2,2-DMB
2,2-DMB
2,2-DMB
CH2Cl2
23
23
23
23
40
40
40
35
89
32
12
0
1.0:1.0
1.0:1.0
1.2:1.0
1.0:4.0
Rh2(S-DOSP)4
Rh2(S-biTISP)2
Rh2(S-PTTL)4
Rh2(R-BNP)4
Rh2(5S-MEPY)4
Rh2(S-IBAZ)4
89
3
88
3
4
59a
54a
5b
6
7
CH2Cl2
0
CH2Cl2
0
a Opposite enantiomer to that illustrated was obtained. b The reaction in toluene at 70 °C also failed to produce any desired products.
diastereoselectivity (>98% de). The stereochemistry of
17a was assigned as syn in accord with results reported
for similar systems.10d The formation of only 16a and 17a
demonstrates the regioselectivity of the vinylcarbenoid
chemistry as no product arose from reactions at the distal
methyl site in 15a.12d The ratio of 16a:17a obtained was
found to be influenced by solvent and temperature effects,
with lower temperatures and more polar solvents favor-
ing the formation of the combined C-H activation/siloxy-
Cope product 16a. Although not substantial, the greatest
effect was observed when conducting the reaction in
R,R,R-trifluorotoluene (PhCF3) at -20 °C, which favored
formation of 16a by 3.2:1.0 (Table 1, entry 5). When the
reaction was carried out in dichloromethane, a solvent
traditionally used in rhodium-carbenoid chemistry, sub-
stantially lower levels of asymmetric induction were
observed even at -40 °C (Table 1, entries 1 and 2). Less
polar solvents such as 2,2-dimethylbutane (2,2-DMB)
FIGURE 1. Structure of dirhodium catalysts.
tended to generate an equal mixture of 16a:17a irrespec-
activation to combined C-H activation/siloxy-Cope prod-
tive of temperature. As expected, lower temperatures
uct. Even so, the transition states for the two reactions
gave higher enantioinduction with levels up to 92% ee
for 16a (Table 1, entries 3 and 7). Overall, however, the
optimum conditions with regard to both yield and enan-
tioselectivity were obtained when the reaction was
conducted in a nonpolar solvent such as 2,2-DMB at
ambient temperatures. It is worthy to note that no
are likely to have considerable similarity because the
enantioselectivities for the two reactions are nearly the
same in all cases.
In an attempt to install greater control over the course
of the reaction such that only the C-H activation product
or solely the combined C-H activation/siloxy-Cope prod-
products were obtained as a result of additional C-H
uct could be obtained, a range of rhodium(II) catalysts
insertion following the formation of the initial C-H
were investigated (Table 2). Only the rhodium(II) car-
boxylate catalysts proved to be effective in generating a
carbenoid that was sufficiently reactive yet selective to
activation products, despite using an excess of the
vinyldiazoacetate 11.
On initial inspection, one might assume that silyl enol
undergo the desired C-H activation process (Table 2,
ether 16a was generated via a two-step process involving
entries 1-4). Pirrung’s phosphate catalyst, Rh2(R-BNP)4
C-H insertion to generate â-siloxy ester 17a followed by
(20),14 and Doyle’s Rh2(5S-MEPY)4 (21)15 and the more
a [3,3]-sigmatropic rearrangement. However, exposing
active Rh2(S-IBAZ)4 (22)16 all failed to generate any of
â-siloxy ester 17a to the standard reaction conditions
the products 16a and 17a (entries 5-7). The achiral
failed to generate any 16a and ester 17a was completely
catalyst Rh2(OOct)4 generates 16a:17a in a similar ratio
recovered (eq 3). It would appear that the siloxy-Cope
to Rh2(S-DOSP)4 but the yields were lower (entry 1). The
tetraprolinate catalyst Rh2(S-DOSP)4 is clearly the op-
timum catalyst with regard to yield and enantioinduction
(entry 2). The bridged tetraprolinate catalyst Rh2(S-
biTISP)2 (18)17 was not very effective in this chemistry,
generating 16a and 17a in low yield and very low
(14) Pirrung, M. C.; Zhang, J. Tetrahedron Lett. 1992, 33, 5987.
type product 16a was generated in a single step through
a competing pathway to the direct C-H activation
reaction, thereby generating effectively a mixture of C-H
(15) Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968.
(16) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
J. Org. Chem, Vol. 69, No. 26, 2004 9243

Davies and Beckwith
TABLE 3. Effect of Allyl Silyl Ether Structure
yield,
de for
16, %
ee for
16, %
de for
17, %
ee for
17, %
a
product
SiR3
R1
%
16:17
a
b
c
d
e
f
TBS
TBS
TBS
TMS
TMS
TMS
Me
85
69
94
82
85
98
1.0:1.0
2.5:1.0
1.4:1.0
1.3:1.0
4.2:1.0
1.4:1.0
>98
>98
>98
>98
>98
>98
89
>98
>98
>98
>98
>98
>98
88
91
91
90
91
91
(E)CH3CH2dCH-
92
C6H5
Me
(E)CH3CH2dCH-
C6H5
91
91b
93b
91b
a Combined yield of 16 and 17. b The corresponding aldehyde product was isolated and fully characterized.
SCHEME 2
enantioinduction (entry 3). Hashimoto’s C2-symmetric
phthalimido catalyst Rh2(S-PTTL)4 (19)18 displayed a
marked preference for the direct C-H activation pathway
to generate 16a:17a in a 1:4 ratio, but the overall yield
was very low (entry 4).
overall, although the level of enantioinduction is compa-
rable between a TMS and a more bulky TBS-protecting
group.
Predictions about the expected stereochemistry of the
C-H activation products 17 and the combined C-H
activation products 16 can be readily made by analogy
to some related reactions. The Rh2(S-DOSP)4-catalyzed
C-H activation of silyl ethers has been shown to give
very predictable stereoinduction favoring the formation
of the (S) configuration at the site of the original carbene
center.10d The C-H activation chemistry of allyl silyl
ethers with aryldiazoacetates has been shown to give
strong preference for the formation of the syn diastereo-
mer.10d The double bond geometries in 16 indicate that
the oxy-Cope rearrangement occurs through a chair
transition state and so 17c (2S,3R) would be expected to
rearrange to the 16c (4R,5S) isomer. This stereochemical
prediction for 16 is the same as was found in related
combined C-H activation/Cope rearrangement products
whose configuration was unambiguously assigned by
X-ray crystallography.19 To confirm that the predicted
stereochemical outcome is indeed occurring in this study,
the Rh2(R-DOSP)4 catalyzed reaction of p-bromostyryl-
diazoacetate 23 with 15c was conducted (Scheme 2). A
1.1:1.0 ratio of Cope-type product 24 to C-H activation
The nature of the allylic silyl ether substrate also
influenced the outcome of the reaction as demonstrated
in Table 3. Conducting the reaction in the presence of
silyl-protected (E,E)-hexadien-1-ol (15b or 15e) gave
much greater preference for the formation of 16 (Table
3, entries 2 and 5). Possibly the presence of an sp2 center
adjacent to the olefin of the silyl ether limits steric
crowding in the transition state enabling suitable align-
ment of the olefin orbitals thereby favoring the pathway
that generates the combined C-H activation/siloxy-Cope
type product. An aryl ring, however, adjacent to the olefin
has little influence on the product distribution, as
observed with silyl-protected cinnamyl alcohol (15c or
15f). In all cases the products were formed as single
double bond geometric isomers with excellent diastereo-
selectivity. The use of the less bulky TMS-protecting
group appears to give marginally better yields of products
(17) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287.
(18) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887.
9244 J. Org. Chem., Vol. 69, No. 26, 2004

Catalytic Asymmetric Reactions for Organic Synthesis
TABLE 4. Effect of Vinyldiazoacetate Structure
the silyl enol ether 30 and the direct C-H activation
product 31 with a slight preference for the siloxy-Cope
type product (eq 6). Once again 30 was formed essentially
yield,
%
de for ee for de for ee for
28:29 28, % 28, % 29, % 29, %
product
R
a
b
c
(E)PhCH2)CH- 73 1.6:1.0 >98
83
78
81
>98
>98
>98
83
76
80
Me
Et
66 1.0:1.6 >98
57 1.0:2.7 >98
product 25 was formed again with very high diastereo-
selectivity and good enantioselectivity (eq 4). The silyl
enol ether 24 was readily converted to the crystalline 2,4-
dinitrophenylhydrazone 26. The configuration of 26 was
unambiguously assigned as (4S,5R) by X-ray crystal-
lography (see Supporting Information).19 Thus, the Rh2
(S-DOSP)4 catalyzed reaction would form the (4R,5S)
configuration of 24 and 16c.
The combined C-H activation/siloxy-Cope rearrange-
ment is applicable to various 3-substituted vinyldiazo-
acetate systems. The generality of the process is illus-
trated by the Rh2(S-DOSP)4 reaction of vinyldiazoacetates
27a-c with TMS-protected cinnamyl alcohol substrate
(15f) (Table 4). A mixture of the combined C-H activa-
tion/siloxy-Cope rearrangement products, isolated as the
aldehydes 28a-c and the direct C-H activation products
29a-c, was obtained. The presence of an sp2 center
adjacent to the vinyl system as in 27a gives greater
preference for the Cope-type product 28 with sp3 centers
giving a preference for the direct C-H insertion product
29 (Table 4, cf. entry 1 with entries 2 and 3).
as a single diastereomer. Even though 31 was stable
under the reaction conditions, on heating at 210 °C in a
sealed tube following the general procedures of Schneider,4
31 rearranged to 30 in 51% yield with the same relative
and absolute configuration as the material formed from
the rhodium-catalyzed reaction.
Even though the thermal rearrangement of 31 to 30
was achievable, only a modest yield of 30 was obtained
under the harsh conditions. Consequently, the microwave-
assisted rearrangement20 of 31 was explored. When the
reaction was conducted with an ionic liquid additive (1-
ethyl-3-methyl-1H-imidazolium)21 in R,R,R-trifluorotolu-
ene (PhCF3), the aldehyde 32 was formed in 92% yield
without loss of stereochemistry (eq 7). In addition, when
the reaction was conducted in nonpolar solvents such as
hexane, in the presence of carboflon heating inserts22 to
aid heating, desilylation of the Cope product could be
predominantly avoided and the silyl enol ether 30 was
obtained.
A potential advantage of the combined C-H activation/
siloxy-Cope rearrangement over our previously published
C-H activation/Cope rearrangement12 is the opportunity
to drive the reaction to completion. This in theory enables
sole formation of the oxy-Cope type product to be achieved
simply by heating the mixture obtained from the Rh2(S-
DOSP)4-catalyzed reaction. Attempted thermal rear-
rangement of either C-H activation product 17a or
siloxy-Cope type product 16a derived from arylvinyldia-
zoacetates tended toward an equilibrium mixture of
products in a 1:1 ratio (eq 5). Even though it would
normally be expected for the siloxy-Cope rearrangement
to go to completion, in this case, the conjugated styryl
group in 17a makes the rearrangement thermodynami-
cally balanced.
The C-H functionalization/siloxy-Cope rearrangement
can be further enhanced by conducting the rhodium-
catalyzed and the microwave-induced reactions without
purification of intermediates. This is illustrated in the
reaction of 27b with the TMS protected alcohol 15d
(eq 8). Rh2(S-DOSP)4-catalyzed reaction of 27b in the
presence of 10 equiv of 15d in 2,2-DMB at ambient
temperature followed by removal of the solvent and
excess silyl ether prior to microwave-assisted heating
afforded aldehyde 32 in 53% yield over two steps in >98%
de and 81% ee.
The next question to be addressed was would the
relative stereochemistry be controlled by the allyl silyl
ether geometry. This issue was tested by reaction of TMS-
protected (Z)-crotyl ether 33 with vinyldiazoacetate 27b.
The Rh2(R-DOSP)4-catalyzed reaction followed by micro-
wave-assisted thermal rearrangement of the intermedi-
For the siloxy-Cope rearrangement to go to completion,
it was proposed that systems lacking extended conjuga-
tion would be required. To test this concept, the Rh2(S-
DOSP)4-catalyzed reaction of methyl 3-pentenediazoac-
etate 27b in the presence of TBS-protected crotyl alcohol
15a was examined. The reaction generated a mixture of
(20) For a review on microwave assisted organic synthesis see:
Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225.
(21) (a) Baxendale, I. R.; Lee, A.-L.; Ley, S. V. J. Chem. Soc., Perkin
Trans. 1 2002, 1850. (b) Leadbeater, N. E.; Torenius, H. M. J. Org.
Chem. 2002, 67, 3145.
(22) Carboflon heating inserts (part number SP-1125) were obtained
from CEM. For an example of the use of a similar heating additive in
organic synthesis, see: Barriault, L.; Denissova, I. Org. Lett. 2002, 4,
1371.
(19) The X-ray crystallographic data have been submitted to the
Cambridge Structure Database [Gerlits, O. O.; Coppens, P. Private
Communication (1078), 2004], Deposition no. CCDC 237997.
J. Org. Chem, Vol. 69, No. 26, 2004 9245

Davies and Beckwith
carbonic acid derivatives in a practical and catalytic
manner. Such systems have the potential to be useful
building blocks for organic synthesis owing to the estab-
lished stereocenters and the versatile enoate and alde-
hyde (or silyl enol ether) functionality. For instance,
conversion of the silyl enol ether 16d to the corresponding
aldehyde 38 and then treatment with benzylamine fol-
lowed by reduction of the resultant enamine gave the
piperidine system 39 as a 2:1 mixture, epimeric at C-2
(eq 11).4b The configuration of the major diastereomer of
39 was readily confirmed by proton NMR coupling values
and nOe experiments. Aldehyde 38 was also readily
converted to cyclopentanone 40 in 56% yield by means
of an intramolecular Stetter reaction (eq 12).24
ate gave the (4R,5R)-aldehyde 34 in 35% yield as a single
diastereomer with 76% ee (eq 9). The absolute stereo-
chemistry of the product ([R]23 -41.8 (c 0.44, CHCl3))
D
was confirmed by comparison with the literature com-
pound ([R]20D -51.0 (c 1, CHCl3)).5c As both enantiomers
of the catalyst are available, the combined C-H activa-
tion/siloxy-Cope rearrangement can be used to prepare
selectively any of the four stereoisomers of the product.
A drawback with this chemistry is the low yield of the
reaction of the cis-allyl ether 33 compared to its trans
counterpart 15d. To further define the reaction of vinyl-
diazoacetates with cis-allyl ethers, the reaction of 33 with
the phenylvinyldiazoacetate 11 was examined. The Rh2(R-
DOSP)4-catalyzed reaction gave a mixture of three prod-
ucts: the desired siloxy-Cope rearrangement product 35,
the direct C-H activation product 36, and the cyclopro-
pane 37 in a 1.6:1.0:2.3 ratio (eq 10). All three products
were formed with very high diastereoselectivity. This is
a useful example illustrating the boundaries in the
competition between cyclopropanation and C-H inser-
tion. The rhodium vinylcarbenoids act as sterically
demanding intermediates and effectively cyclopropanate
1-substituted, 1,1-disubstituted, and cis 1,2-disubstituted
alkenes.23 Thus with trans-allyl silyl ethers cyclopro-
panation does not occur but with cis-allyl silyl ethers
competition between cyclopropanation and C-H insertion
is much more balanced.
The stereochemistry of the combined C-H activation/
siloxy-Cope rearrangement can be rationalized by the
predictive model shown in Figure 2.14d The catalyst is
FIGURE 2. Predictive model for the stereochemistry of the
Rh2(S-DOSP)4-catalyzed combined C-H activation/siloxy-Cope
rearrangement.
considered to adopt a D2-symmetric arrangement and can
be simply viewed as a catalyst surface with a blocking
group in the front and a blocking group in the back.12d
In this model, the carbenoid initiates the insertion into
the C-H bond, but before the process is complete the two
vinyl groups enter into the Cope rearrangement. The
exact trajectory of approach of the allyl silyl ether is not
known, but the orientation shown in structure 41 predicts
the stereochemical outcome of the combined C-H activa-
tion/Cope rearrangement for both the two newly gener-
ated stereocenters and the two alkenes in 42. In this
model, the allyl silyl ether approaches from the front,
The combined C-H activation/siloxy-Cope rearrange-
ment offers a direct stereoselective route to the construc-
tion of a variety of γ,δ-substituted R,â-unsaturated
(24) (a) Stetter, H.; Kuhlmann, H. In Organic Reactions; Paquette,
L. A., Ed.; Wiley: New York, 1991; Vol. 40, p 407. (b) Ciganek, E.
Synthesis 1995, 1311. (c) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J.
Am. Chem. Soc. 2002, 124, 10298.
(23) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897.
9246 J. Org. Chem., Vol. 69, No. 26, 2004

Catalytic Asymmetric Reactions for Organic Synthesis
avoiding the blocking group in the back,12d and this leads
to the observed absolute stereochemistry of the reaction.
In summary, a novel reaction has been identified
involving a combined C-H activation/siloxy-Cope rear-
rangement. This offers a practical, catalytic approach for
the controlled generation of stereocenters at positions
remote from activating functionality. Furthermore, prod-
ucts lacking aryl functionality can be readily generated,
which contrasts with our extensive studies on the inter-
molecular C-H activation chemistry of aryldiazoace-
tates.9,10 The thermodynamically favored product in this
system is the siloxy-Cope type product, which distin-
guishes this work from our earlier studies on the com-
bined C-H activation/Cope rearrangement.12 The result-
ing γ,δ-substituted R,â-unsaturated carbonic acid de-
rivatives are well functionalized for use as chiral building
blocks in synthesis and future work will explore this
potential.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-0350536). We thank
Oksana O. Gerlits for the X-ray crystallographic analy-
sis and Professor Louis Barriault, University of Ottawa,
for interesting discussion regarding the use of heating
inserts in microwave-assisted organic reactions. We
thank the Royal Commission for the Great Exhibition
of 1851 for a fellowship to R.E.J.B.
Supporting Information Available: Full experimental
data for the compounds described in this paper. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO048429M
J. Org. Chem, Vol. 69, No. 26, 2004 9247