Highly enantioselective rhodium(I)-catalyzed activation of enantiotopic cyclobutanone C-C bonds

Article abstract of DOI:10.1002/anie.201311009

The selective functionalization of carbon-carbon σ bonds is a synthetic strategy that offers uncommon retrosynthetic disconnections. Despite progress in C-C activation and its great importance, the development of asymmetric reactions lags behind. Rhodium(I)-catalyzed selective oxidative additions into enantiotopic C-C bonds in cyclobutanones are reported. Even operating at a reaction temperature of 130 °C, the process is characterized by outstanding enantioselectivity with the e.r. generally greater than 99.5:0.5. The intermediate rhodacycle is shown to react with a wide variety of tethered olefins to deliver complex bicyclic ketones in high yields.

Full text of DOI:10.1002/anie.201311009

Angewandte
Chemie
DOI: 10.1002/anie.201311009
ꢀ
C C Activation
Highly Enantioselective Rhodium(I)-Catalyzed Activation of
ꢀ
Enantiotopic Cyclobutanone C C Bonds **
Laetitia Souillart, Evelyne Parker, and Nicolai Cramer*
Abstract: The selective functionalization of carbon–carbon
s bonds is a synthetic strategy that offers uncommon retro-
ꢀ
synthetic disconnections. Despite progress in C C activation
and its great importance, the development of asymmetric
reactions lags behind. Rhodium(I)-catalyzed selective oxida-
ꢀ
tive additions into enantiotopic C C bonds in cyclobutanones
are reported. Even operating at a reaction temperature of
1308C, the process is characterized by outstanding enantiose-
lectivity with the e.r. generally greater than 99.5:0.5. The
intermediate rhodacycle is shown to react with a wide variety of
tethered olefins to deliver complex bicyclic ketones in high
yields.
ꢀ
T
he selective functionalization of carbon–carbon (C C)
s bonds by transition-metal catalysts is a prime challenge for
organometallic chemistry and represents a complementary
synthetic strategy that enables uncommon retrosynthetic
disconnections.[1] Important progress has been made over
ꢀ
Scheme 1. Asymmetric reactions involving a C C bond cleavage step.
ꢀ
the past decade in the field of C C activation. However,
ꢀ
despite their recognized importance, the development of
asymmetric reactions lags behind.[2,3] For instance, most
enantioselective variants have been reported for the b-
knowledge, processes in which the insertion into the C C
bond is the enantiodetermining step of the reaction are
elusive. Oxidative additions with chiral transition-metal
complexes able to selectively target one of two enantiotopic
ꢀ
ꢀ
carbon elimination mechanism that allows C C bond cleav-
ages adjacent to tertiary alcohols.[2c,3,4] For reactions involving
C C bonds are highly intriguing from a mechanistic point of
ꢀ
C C cleavage through oxidative addition at transition
view. Moreover, the maintenance of high levels of chiral
induction under the forcing reaction temperatures of such
activations is extremely challenging.
metals,[5] strained ketones have proven highly versatile.[3d–e,6–8]
ꢀ
Two asymmetric reactions of this type, in which the C C
ꢀ
cleavage step is not enantiodetermining, have recently been
reported. Murakami and co-workers showed asymmetric
nickel-catalyzed reactions of cyclobutanones (Scheme 1).[9]
In this case, the enantiodetermining step of the sequence
consists of an asymmetric initial oxidative cyclization, which is
then followed by a diastereoselective b-carbon elimination.
Dong and co-workers reported an asymmetric rhodium-
Herein, we report an enantiotopic C C bond activation
that proceeds with exceptionally high enantioselectivity
(Scheme 1). We selected cyclobutanone substrates 1, for
which Murakami, Itahashi, and Ito demonstrated the poten-
ꢀ
tial for C C bond activation by using the achiral and cationic
[Rh(nbd)dppp]PF6 complex.[11] Limited modifications to the
aryl part and monosubstituted cyclobutanones (R = H) led to
symmetric products with hydrogen atoms at both bridge-
ꢀ
catalyzed transformation involving the C C activation of
benzocyclobutanones.[10] After the achiral initial C C activa-
heads. In our study, the key enantiotopic C C activation of
ꢀ
ꢀ
tion, the enantiodetermining step occurred through facially
selective addition across the appended alkene moiety. To our
1 (R ¼ H) leads to the formation of a quaternary stereogenic
center (Scheme 2). The tethered olefin of the substrate
1 should not only provide an intramolecular acceptor but
should coordinate to RhI to give complex 2. Such coordina-
tion should favor a highly ordered transition state, thus
[*] L. Souillart, Dr. E. Parker, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA BCH 4305, 1015 Lausanne (Switzerland)
E-mail: Nicolai.cramer@epfl.ch
ꢀ
enabling good enantiodiscrimination for the C C cleavage
step to give 3. Subsequent migratory insertion forms acyl
rhodium species 4, which in turn undergoes reductive
elimination to give bicyclic ketone 5. Depending on the
degree of substitution at the double bond, further stereogenic
centers can then be created.
The initial evaluation of the reaction conditions was
conducted with model cyclobutanone 1a. Heating 1a in
dioxane at 1308C in the presence of Binap (L1) and [{Rh-
Homepage: http://isic.epfl.ch/lcsa
[**] This work is supported by the European Research Council under the
European Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 257891. We thank Dr. R. Scopelliti
for X-ray crystallographic analysis of 6.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311009.
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[a]
ꢀ
Table 1: Optimization of the enantioselective C C activation of 1a.
Entry [RhI]
L* Changes
[%] Yield[b]
e.r.[c]
Scheme 2. Mechanistic model for the rhodium(I)-catalyzed asymmetric
1
2
3
4
5
6
7
8
[{Rh(COD)Cl}2]
L1
L2
L3
L4
L5
L6
–
–
–
–
–
–
–
–
50
44
72
94
53
15
64
70
78
97
85
98.5:1.5
99:1
ꢀ
C C bond activation.
[{Rh(COD)Cl}2]
[{Rh(COD)Cl}2]
[{Rh(COD)Cl}2]
[{Rh(COD)Cl}2]
[{Rh(COD)Cl}2]
99.5:0.5
99.7:0.3
99.5:0.5
93.5:6.5
91:9
85:15
99:1
99.7:0.3
99.6:0.4
(COD)Cl}2] as the RhI source gave the desired product
bicyclic ketone 5a with an excellent enantiomeric ratio of
98.5:1.5 (Table 1, Entry 1; COD = 1,5-cyclooctadiene). How-
ever, moderate conversion restricted the yield to 50%.
Further evaluation of ligands of the Segphos family (L2–4)
further increased the enantioselectivity (Table 1, Entries 2–
4). Notably, the bulky congener DTBM-Segphos (L4)
resulted in the most active catalyst (Table 1, Entry 4).
Under these conditions, product 5a was obtained in 94%
yield with an exceptionally high enantiomeric ratio of 99.7:0.3
(Table 1, Entry 4).[12] The related DTBM-MeOBi-
[{Rh(COD)(OH)}2] L4
[Rh(COD)2]BF4
[{Rh(COD)Cl}2]
[{Rh(COD)Cl}2]
[{Rh(COD)Cl}2]
L4
9
10
11
L4 in toluene
L4 at 1108C
L4 2.5 mol%, 24 h
[a] Reaction conditions: 1a (0.05 mmol), [RhI] (2.50 mmol), L*
(3.00 mmol), 1.0m in dioxane at 1308C for 12 h; [b] Yield of isolated
product; [c] Determined by HPLC with a chiral stationary phase.
[a]
ꢀ
Table 2: Scope of the enantioselective C C activation of cyclobutanones 1.
phep L5 is less reactive and the reaction stalled at
slightly more than half conversion (Table 1, Entry 5).
Me-Duphos (L6) was not well suited for this trans-
formation (Table 1, Entry 6). Alternative RhI precur-
sors such [{Rh(COD)(OH)}2] or cationic [Rh-
(COD)2]BF4 were both detrimental to the yield and
enantioselectivity (Table 1, Entries 7 and 8), thus
indicating that the chloride counterion is important.
Replacing the dioxane by toluene also decreased the
reactivity (Table 1, Entry 9). On the other hand,
lowering the temperature to 1108C in dioxane
provided full conversion (Table 1, Entry 10). Finally,
the reaction works well with 2.5 mol% catalyst
loading and 24 h reaction time (Table 1, Entry 11).
The fact that the reaction had reached 63% con-
version after 12 h indicates that the catalyst maintains
activity over prolonged reaction times.
Entry Cyclobutanone 1
Ketone 5
[%] Yield[b]
e.r.[c]
1[d]
91
99.6:0.4
2[d]
78
95
96
89
99.8:0.2
99.6:0.4
99.6:0.4
99.6:0.4
With the reaction conditions established, we next
ꢀ
explored the generality of the C C activation process.
3
First, we evaluated different substituents of the
cyclobutanone moiety. Aliphatic and aromatic
groups, as well as esters, nitriles, and protected
ethers are well tolerated and provide products with
a variety of functionalized bridgeheads (Table 2,
entries 1–6). The yield and selectivity are consistently
excellent. Electronic modification of the aryl tether
has no influence on the reaction outcome (Table 2,
Entries 6–8).[13] Notably, the reaction is not limited to
terminal olefins. For instance, 1,1-disubstituted
alkenes deliver bicyclic ketones 5j and 5k with two
different quaternary stereogenic centers at the two
4[d]
5
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Table 2: (Continued)
bridgehead positions (Table 2, Entries 9 and 10). In
Entry Cyclobutanone 1
Ketone 5
[%] Yield[b] e.r.[c]
addition, 1,2-disubstituted alkenes react well and
fully maintain their stereochemical information. The
trans starting materials deliver ketones 5l–n (Table 2,
Entries 11–13). Importantly, no epimerization of the
stereogenic center at the a position of the carbonyl
group was detected under the reaction conditions and
the products were obtained with d.r. > 20:1 and
excellent enantioselectivity. Notably, the obtained
product is the thermodynamically less stable dia-
stereomer and can be isomerized by base to the more
stable one.[14] Attempts to obtain this isomer directly
6
92
81
88
99.7:0.3
7[d]
99.6:0.4
ꢀ
through C C activation failed. The corresponding
isomeric substrate 1o, which has a cis double bond,
does not give the rearranged product and only
degrades slowly under the reaction conditions
(Table 2, x 14). By contrast, a tri-substituted olefin
is well tolerated and reacts smoothly under the
described conditions to provide a rapid and conven-
ient entry to highly complex ketone 5p (Table 2,
Entry 15).
8[d]
>99.8:0.2
9[d]
95
89
90
99.6:0.4
99.4:0.6
The absolute configuration of the bicyclic ketone
1a was unambiguously established by X-ray crystal-
lographic analysis of the p-tosyl hydrazone derivative
6 (Scheme 3).[15]
10
97.7:2.3
d.r. >20:1
11[d]
99.8:0.2
d.r. >20:1
12
13
85
82
99.7:0.3
d.r. >20:1
Scheme 3. Synthesis of p-tosyl hydrazone derivative 6 and its ORTEP
representation.
14
15
0
–
The absolute configuration can be rationalized by
the speculative stereochemical pathway illustrated in
Scheme 4. Initially, substrate 1 coordinates to the
catalyst to give the square-planar RhI complex.
Subsequent oxidative addition would provide the
octahedral RhIII intermediates A or B. Intermediate
A is preferred over B because it avoids the very
unfavorable interaction between the olefin portion of
the substrate and a DTBM residue of ligand L4. This
arrangement also accounts for the broad tolerance of
substitution of the arene and cyclobutyl rings because
both are pointing away from the ligand bulk in
intermediates A and B.
73
98.3:1.7
[a] 1 (0.10 mmol), [{Rh(COD)Cl}2] (2.50 mmol), L4 (6.00 mmol), 1.0m in dioxane at
1308C for 12 h; [b] Yield of isolated product; [c] Determined by HPLC with a chiral
stationary phase. [d] [{Rh(COD)Cl}2] (5.00 mmol), L4 (12.0 mmol), 0.2m in dioxane
at 1308C for 24 h.
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Scheme 4. Speculative stereochemical pathway for the activation.
In summary, we report an asymmetric rhodium(I)-cata-
ꢀ
lyzed C C activation of cyclobutanones that gives efficient
access to the valuable bicycloheptanone scaffold with excep-
tionally high enantioselectivity. This demonstrates the feasi-
ꢀ
bility of selective oxidative additions of enantiotopic C C
bonds at high reaction temperatures. The method shown
allows rapid access to complex cyclic structure and serves as
ꢀ
a blueprint for the design of further asymmetric C C bond
activations.
Experimental Section
ꢀ
[4] For representative examples of asymmetric C C bond cleavages
Cyclobutanone 1a (18.6 mg, 0.100 mmol), [{Rh(COD)Cl}2] (1.14 mg,
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Published online: February 12, 2014
ꢀ
Keywords: asymmetric catalysis · C C activation ·
cyclobutanone · rearrangement · rhodium
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[13] Although not studied yet in detail, the reactivity is enhanced by
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ꢀ
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