Rhodium (I)-Catalyzed enantioselective activation of cyclobutanols: Formation of cyclohexane derivatives with quaternary stereogenic centers

Article abstract of DOI:10.1002/chem.200903225

The activation of carboncarbon o bonds is a complementary method to access uncommon and difficult-to-prepare organometallic species. Herein, we describe the activation of ierf-cyclobutanols through an enantioselective insertion of a chiral rhodium(I) complex into the C-C o bond of the cyclobutane, forming a quaternary stereogenic center and an alkyl-rhodium functionality that initiates ring-closure reactions. This technology provides access to a variety of substituted cyclohexane derivatives with quaternary stereogenic centers. The formation of different product families can be controlled by the employed set of reaction conditions and additives. In general, high yields and excellent enantioselectivities of up to 99% ee are obtained.

Full text of DOI:10.1002/chem.200903225

FULL PAPER
DOI: 10.1002/chem.200903225
Rhodium(I)-Catalyzed Enantioselective Activation of Cyclobutanols:
Formation of Cyclohexane Derivatives with Quaternary Stereogenic Centers
Tobias Seiser and Nicolai Cramer*[a]
Dedicated to Professor Alexandre Alexakis on the occasion of his 60th birthday
Abstract: The activation of carbon–
carbon s bonds is a complementary
method to access uncommon and diffi-
cult-to-prepare organometallic species.
Herein, we describe the activation of
tert-cyclobutanols through an enantio-
selective insertion of a chiral rhodiu-
stereogenic center and an alkyl-rhodi-
um functionality that initiates ring-clo-
sure reactions. This technology pro-
vides access to a variety of substituted
cyclohexane derivatives with quaterna-
ry stereogenic centers. The formation
of different product families can be
controlled by the employed set of reac-
tion conditions and additives. In gener-
al, high yields and excellent enantiose-
lectivities of up to 99% ee are ob-
tained.
Keywords: asymmetric catalysis
·
·
À
C C activation
· cyclobutane
À
m(I) complex into the C C s bond of
rhodium · ring expansion
the cyclobutane, forming a quaternary
Introduction
and aryl-rhodium species.[3] The site of the equilibrium is
largely determined by the electronic properties and the
steric bulk of the aromatic substituents. This report under-
scores the possibility to access organometallic species by b-
carbon eliminations. Substrate classes that are more biased
towards such fragmentation would provide an attractive
entry into unusual organometallics with novel reactivities.[4]
In this respect, small strained rings occupy a privileged posi-
The selective and catalytic functionalization of carbon–hy-
À
À
drogen (C H) and carbon–carbon (C C) bonds by transi-
tion-metal complexes has a significant and broad impact on
organic synthesis. The lack of pre-functionalization steps, re-
quired for traditional approaches, make such activation pro-
À
cesses economically and ecologically highly attractive. C H
À
activations are a vibrant and very active research area that
tion in C C activation reactions, because of the additional
recently underwent impressive progress.[1] In comparison,
driving force liberated by strain reduction in ring-opening
reactions.[5] The inherent strain and their convenient accessi-
bility make cyclobutane derivatives an attractive substrate
class. Furthermore, a selective insertion into one of the two
À
the development of efficient C C activation reactions large-
ly lags behind and a practical implementation of this con-
cept is still a major challenge for organometallic chemistry.[2]
À
À
This can be attributed to the fact that C C bonds are highly
enantiotopic C C bonds of a symmetrically substituted cy-
À
directed and even more inert than C H bonds. Furthermore,
clobutane ring would open opportunities for enantioselec-
tive activations, a largely unmet challenge in transition-
metal catalysis.[6] Pioneering studies from Uemuraꢀs group,
who reported an asymmetric palladium-catalyzed ring-open-
ing arylation of aryl-tert-cyclobutanols,[7] and reports from
Murakami and co-workers, who used a highly enantioselec-
tive rhodium-catalyzed transformation to construct benzocy-
clopentanones and dihydrocoumarines from cyclobuta-
nones,[8] underline the largely unexplored potential of this
concept. We envisioned capitalizing on the potential of an
enantioselective insertion in one of the two enantiotopic
bonds of cyclobutanol 1 to form intermediate 2 bearing an
alkyl-rhodium functionality next to a newly created quater-
nary stereogenic center (Scheme 1). As the chemical trans-
reductive elimination, the reverse pathway, is most often the
preferred reaction direction. Hartwig and Zhao recently
demonstrated that triarylcarbinols and rhodium complexes
are in an equilibrium with the corresponding diarylketones
[a] T. Seiser, Dr. N. Cramer
ETH Zurich, Laboratory of Organic Chemistry
HCI H 304, Wolfgang-Pauli-Strasse 10
8093 Zurich (Switzerland)
Fax : (+41)44-632-13-28
E-mail: Nicolai.cramer@org.chem.ethz.ch
Homepage: http://www.cramer.ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903225.
Chem. Eur. J. 2010, 16, 3383 – 3391
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3383

Table 1. Optimization of the reaction conditions.[a]
Entry L*
Base
Solvent
Yield
[%][b]
ee
[%][c]
1[d]
L1
Cs2CO3 dioxane, 5%
H2O
28
73 (S)
2[d]
3[d]
4[d]
5[d]
6
L1
L2
L5
L1
L1
L1
L1
L6
Cs2CO3 dioxane
Cs2CO3 dioxane
Cs2CO3 dioxane
99
90
97
73 (S)
73 (S)
92 (R)
Scheme 1. Proposed activation and cyclization model of allylic tert-cyclo-
butanols.
–
toluene
toluene
79 (5a) 76 (S)
71 (5a) 79 (S)
NEt3
formation does not take place directly at the hindered,
asymmetrically substituted carbon atom, this approach
should be well suited for demanding quaternary stereogenic
centers.[9]
7
K3PO4 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
79
99
83
99
<5
58
<5
99
92
95
92
99
79 (S)
80 (S)
77 (S)
84 (R)
–
8
9[d,e]
10[d,e] L7
11[d,e] L8
12[d,f] L9
We expected that intermediate 2 would be prone to a 1,4-
addition across the concomitantly formed activated olefin
moiety of 2 to yield cyclohexanone 3. Furthermore, the che-
lating environment created by the hydroxyl group and the p
unsaturation in the form of an alkyne, allene, or olefin of 1
would not only facilitate an association with the metal com-
plex, but also result in a structurally well-defined complex,
the rigidity of which would allow an efficient imprint of the
chirality of the ligand onto the substrate. We recently re-
ported that especially allenyl-substituted cyclobutanols are a
formidable starting point to access transient organometallic
species that are difficult to prepare otherwise.[10] Herein, we
report the full details and demonstrate further elaboration
of these reactive intermediates into a host of structurally di-
verse, highly substituted cyclohexane derivatives under dif-
ferent sets of reaction conditions.
43 (R)
–
13[d]
14
15
16
17
L10
L2
ent-L4
L3
83 (S)
85 (S)
96 (S)
95 (R)
91 (R)
L5
18
L5 (1 mol%
[Rh])
L5 (0.1 mol%
[Rh])
L5 (0.01 mol%
[Rh])
19
Cs2CO3 toluene
Cs2CO3 toluene
99
90 (R)
20[d]
>5
–
[a] Reaction conditions: 0.1 mmol 1a, 1.5 equiv base, 2.5 mol%
[{Rh(OH)(cod)}2], 6.0 mol% L*, 0.25m, 808C, 3–5 h. [b] Yield of isolated
product 4a. [c] Enantioselectivities were determined by HPLC with a
chiral stationary phase. [d] 1008C, 24 h. [e] 12 mol% L*. [f] With
AHCTUNGTRENNUNG
2.5 mol% [{RhACHTUNTGRNENUG(OAc)CAHTUNTGREN(NUNG C2H4)2}2].
Results and Discussion
In a first experiment, the model substrate trans-1-(3,3-dime-
thylallenyl)-3-methyl-3-phenylcyclobutanol (1a) was heated
to 808C in toluene in the presence of [{Rh(OH)
(2.5 mol%; cod=1,2-cyclooctadiene) and (R)-BINAP
(6 mol%; BINAP=2,2’-bis(diphenylphosphino)-1,1’-bi-
ACHTUNGTNER(NUNG cod)}2]
naphthyl (L1); Table 1).
Methylene cyclohexanone 5a was formed predominantly
under these conditions with a promising enantiomeric excess
of 76% (entry 5). However, during the course of the reac-
tion, 5a isomerized in a variable amount to enone 4a and
also decomposed to more polar products (vide infra). To
mitigate these side reactions, we screened auxiliary bases to
promote the isomerization to the more stable enone 4a.
Weak organic bases like triethylamine were not competent
(entry 6). Pleasingly, insoluble inorganic bases such as
cesium carbonate or potassium phosphate accelerated the
quire higher temperatures to go to completion and are ac-
companied with lower selectivities (entries 1–4). Dry, nonpo-
lar aromatic solvents (toluene or xylenes) turned out to be
optimal. Screening of further chiral ligands showed that
phosphoramidite (RRR)-L6 and (RSS)-L7 gave, in contrast
to Monophos (L8), product 4a in goods yields and in selec-
tivities comparable to BINAP (entries 9–11). (À)-Dolefine
(L9), a diene ligand, led to complete conversion and moder-
ate yield (entry 12), whereas Me-Duphos (L10) was essen-
tially inactive (entry 13). Biarylphosphines with a narrower
dihedral angle[11] than BINAP (80% ee, entry 8) increased
the enantioselectivity slightly. Thus, (R)-MeOBiphep (L2)
À
double-bond isomerization without interfering with the C C
bond-insertion event leading to a virtually quantitative yield
and 80% ee of the conjugated product (entries 7 and 8). The
solvent has a significant impact on the reaction time as well
as on the selectivity. Reactions in dioxane are slower and re-
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Chem. Eur. J. 2010, 16, 3383 – 3391

Enantioselective Activation of Cyclobutanols
FULL PAPER
provided enone 4a in 83% ee and (R)-Segphos (ent-L4) re-
sulted in 85% ee (entries 14 and 15). A significant improve-
ment was achieved with the sterically more demanding ho-
mologues (R)-DTBM-MeOBiphep (L3) and (S)-DTBM-
Segphos (L5; DTBM=3,5-di-tert-butyl-4-methoxyphenyl),
affording now 4a with an enan-
ucts 4, once again, in excellent yields and selectivities. It is
noteworthy, that in the 3-position mono-substituted cyclobu-
tanols rearranged smoothly to cyclohexenones 4 (entries 26–
29). Surprisingly, no trace of products arising from b-hydride
elimination was observed with these substrates, which sug-
tiomeric excess of 96% (L3)
[a]
À
Table 2. Scope of the rhodium(I)-catalyzed C C activation.
and 95% (L5) (entries 16 and
17). Noteworthy, the required
catalyst loading—starting with a
initial amount of 2.5 mol%
Entry
L*
1
R1/R2
4
Yield [%][b]
ee [%][c]
[{Rh(OH)ACHTUNGTRENNUNG(cod)}2]—could be re-
1
2
L3
L3
cis-1a
cis-1b
Ph/Me
Ph/Et
Et/Ph
p-ClC6H4/Me
Me/p-ClC6H4
p-MeC6H4/Me
Me/p-MeC6H4
2-Naph/Me
Me/2-Naph
Ph/Vinyl
4a
4b
4b
4c
4c
4d
4d
4e
4e
4 f
4 f
4g
4g
4h
4h
4i
97
99
99
88
99
87
99
85
97
85
74
80
91
81
80
65
89
99
78
96 (R)
97 (R)
96 (R)
95 (R)
96 (R)
94 (R)
95 (R)
94 (R)
94 (R)
90 (R)
90 (R)
94 (R)
97 (R)
96 (R)
99 (R)
91 (R)
97 (S)
94 (S)
90 (R)
duced to 0.1 mol% rhodium
without compromising the yield
of the reaction and only slightly
affecting the enantioselectivity
3
4
L5
L3
trans-1b
cis-1c
5
6
L5
L3
trans-1c
cis-1d
(90% ee
instead
95% ee,
7
8
L5
L3
trans-1d
cis-1e
entry 19).
With the aforementioned op-
timized conditions, we then ex-
plored the substrate scope and 11[d]
limitations of this process with
a host of different cyclobutanol
9
L5
L3
trans-1e
cis-1 f
10[d]
L5
L3
trans-1 f
cis-1g
Vinyl/Ph
iPr/Me
Me/iPr
tBu/Me
12
13
14
L5
L3
trans-1g
cis-1h
substrates 1. We first examined
15
L5
L5
L3
L5
trans-1h
1i
trans-1j
cis-1j
Me/tBu
16[d]
17[d]
18
Ph/2-pyridyl
Ph/CH2OBn
CH2OBn/Ph
p-ClC6H4/CO2Me
the opposite isomer cis-1a
yielding in full accordance with
the hypothesized mechanism
ent-4a in comparable yield and
selectivity (Table 2, entry 1).
Different aromatic substitutions
(entries 1–9) as well as alkyl
substituents (entries 12–15) are
well tolerated. Irrespective of
the substitution pattern, the re-
arranged products were gener-
ally obtained with high fidelity
in excellent yields and selectivi-
ties. The process also proved to
be tolerant to functional groups
that can potentially interfere
with transition-metal-catalyzed
processes: Terminal olefins (en-
tries 10 and 11) and pyridines
(entry 16 and 23) coordinate to
the rhodium complex and re-
quire higher temperature and
reaction times to go to comple-
tion. Aryl halides, benzyl
groups, and esters are perfectly
stable under these reaction con-
ditions (entries 4 and 5; 17 and
18; 19 and 24–25, respectively).
The dimethylallene can be ex-
changed for cyclic (entries 20
and 21) and for terminal allenes
(entries 22–25 and 27–29) to
4j
4j
4k
19
ent-L3
trans-1k
20[d]
21
L3
L5
cis-1l
91
93
93 (R)
92 (R)
trans-1l
22[d]
L5
1m
93
93 (R)
23[d]
24
L3
1n
57
70
89 (S)
91 (S)
ent-L3
cis-1o
25
26
L3
L5
trans-1o
52
94
87 (S)
85 (S)
1p
Ph/H
4p
27
28
29
ent-L3
ent-L3
ent-L5
cis-1q
trans-1q
cis-1r
85
94
88
88 (S)
97 (R)
93 (R)
[a] Reaction conditions: 0.1 mmol 1, 1.5 equiv Cs2CO3, 2.5 mol% [{Rh(OH)
ene (0.25m), 808C, 3 h. [b] Yield of isolated product 4. [c] Enantioselectivities were determined by HPLC with
yield the corresponding prod- a chiral stationary phase. [d] 1008C, 16 h.
ACHTUNGERTN(NUNG cod)}2], 6.0 mol% L3 or L5, tolu-
Chem. Eur. J. 2010, 16, 3383 – 3391
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3385

T. Seiser and N. Cramer
gests that either a mechanism involving rhodacyclic inter-
mediates[12] or a very fast addition to the allenone is opera-
tive. This somewhat unexpected tolerance allowed determi-
nation of the absolute configuration by a synthesis of the
celery ketone (4r),[13] and was additionally confirmed by the
optical rotation of the known compound 4q.[14]
The initial observation of the formation of the nonconju-
gated cyclohexanone isomer 5 prompted us to devise reac-
tion conditions for its selective formation. It was apparent
from the optimization studies that 5 is the initially predomi-
nantly formed product, and not being the thermodynamical-
ly stable isomer, it is converted under base or metal catalysis
over time to the more stable enone 4. Omitting the base
and performing the reaction for 4 h at 1008C forms cleanly
the nonconjugated isomer 5. However, even this compound
Figure 1. ORTEP representation of hydroperoxide 6 (probability ellip-
soids at 60%).
1
is the only observable product by H NMR spectroscopy of
nones 5 were obtained in moderate to good yields and ex-
cellent enantiomeric excesses matching those obtained for
enones 4 (Table 3). The somewhat fluctuating and reduced
yields relative to those obtained using the standard isomeriz-
ing conditions are a reflection of the lability of this com-
pound class.
the reaction mixture, and its isolation proved to be delicate.
Surprisingly, it turned out to be significantly more sensitive
towards oxidation than to base-catalyzed isomerization reac-
tions. Even under carefully controlled workup and purifica-
tion conditions, minimizing its exposure time to air and
silica gel, we only obtained hydroperoxide 6 in a virtually
quantitative yield (Scheme 2). The same, but significantly
Table 3. Synthesis of 3-isopropylidene cyclohexanones 5.[a]
Entry
L*
1
R1/R2
5
Yield [%][b] ee [%][c]
1
2
3
4
5
6
ent-L3 trans-1a Me/Ph
5a 92
5a 71
5b 84
5e 69
5j 42
95 (R)
96 (R)
97 (R)
94 (R)
92 (R)
90 (R)
L3
L3
cis-1a Ph/Me
cis-1b Ph/Et
ent-L3 trans-1e Me/2-Naph
ent-L5 cis-1j CH2OBn/Ph
ent-L3 trans-1k p-Cl-Ph/CO2Me 5k 49
[a] Reaction conditions: 0.1 mmol 1, 2.5 mol% [{Rh(OH)ACHTUNGTRENNUNG(cod)}2],
6.0 mol% L*, toluene (0.25m), 1008C, 4 h. [b] Yield of isolated product
5. [c] Enantioselectivities were determined after base-catalyzed isomeri-
zation to enones 4 by HPLC with a chiral stationary phase.
Scheme 2. Facile autoxidation of nonconjugated isomer 5a.
The inherent lability of products 5 prompted us to investi-
gate the possibility of sequential catalytic reactions that
would 1) avoid any isolation of this sensitive compound
class and 2) would take advantage of the additionally gener-
ated functionalities. For example, treatment of the reaction
mixture with dimethylphenylsilane promoted a rhodium-cat-
alyzed hydrosilylation[18] and directly formed silyl-protected
secondary alcohols 8 in high yields (Table 4). Although the
rhodium complex very efficiently promoted the reduction,
the observed diastereoselectivities of the hydrosilylation
event are only modest, slightly favoring the syn product. As
shown for cis-1a and trans-1a, the obtained products 8 are
enantiomers of each other, which indicates that the sub-
strate and not the chiral phosphine ligand governs the facial
selectivity of the reduction.
slower, process is observed when solutions of 5 are exposed
to air. The identity of the obtained hydroperoxide 6 was
confirmed by X-ray crystallographic analysis (Figure 1).[15]
We regard this surprisingly facile autoxidation[16] as being
responsible for the difficulties of our initial attempts to trace
the nonconjugated product 5. When the reaction mixture
was stirred after the completed rhodium-catalyzed rear-
rangement at ambient temperature under an atmosphere of
oxygen, and was subsequently treated with trimethylphos-
phite, alcohol 7 was produced in 80% yield. Despite these
obstacles, we succeeded in isolating the exocyclic olefinic
isomer 5a in 92% yield and 95% ee by adding Kishiꢀs radi-
cal inhibitor[17] during the workup and purification proce-
dure, which mostly suppressed the oxidative isomerization.
Applying these conditions and precautions to a range of
substrates, the corresponding 3-isopropylidene cyclohexa-
Furthermore, we investigated the possibility of a sequen-
tial conjugate reduction pathway of the obtained enones 4
to address the direct synthesis of ketones 3, one of our ini-
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Chem. Eur. J. 2010, 16, 3383 – 3391

Enantioselective Activation of Cyclobutanols
Table 4. Activation/cyclization/1,2-reduction cascade.[a]
FULL PAPER
Entry L*
1
R1/R2
cis-1a Ph/Me
L3 trans-1a Me/Ph
L3 cis-1b Ph/Et
8
Yield [%][b] ee [%][c] syn/anti[d]
Scheme 3. A RhI-catalyzed rearrangement/Baeyer–Villiger combination
leads to enol lactone 9.
1
2
3
4
5
L3
8a 80
8a 99
8b 80
96 (3R) 1.3:1
96 (3S) 1.2:1
97 (3R) 1.3:1
94 (3R) 1.2:1
85 (5S) 1.9:1
L5 trans-1e Me/2-Naph 8e 94
L5 cis-1p Ph/H 8p 85
observed, thus opening a door to access linear quaternary
stereogenic centers with this technique. Additionally, such
enol lactones are synthetically useful building blocks that
allow for further elaboration.[21]
[a] Reaction conditions: 0.1 mmol 1, 2.5 mol% [{Rh(OH)ACHTNUTRGNEUNG(cod)}2],
6.0 mol% L*, toluene (0.25m), 1008C, 4 h. [b] Yield of isolated product
8. [c] Enantioselectivities were determined on an aliquot before silane
addition by HPLC with a chiral stationary phase. [d] Diastereomeric
ratios were determined by proton NMR spectroscopy.
The putative mechanism of the rhodium-catalyzed rear-
rangement does not per se exclude olefin-substituted cyclo-
butanols as substrates and suggests that the initial b-carbon
elimination step should in principle proceed irrespective of
the 1-substituent on the cyclobutanol. However, the chelat-
ing environment offered by the allene facilitates the reaction
and to explore the limitations, we replaced it with a terminal
olefin. Exposure of vinyl cyclobutanol 10a to the standard
reaction conditions, led to the complete consumption of the
starting material within 3 h, which indicated that the b-
carbon cleavage of 10a occurred at a comparable rate to
that observed with the allene substrates 1 (Scheme 4). The
tial aims. Unfortunately, the utilized rhodium complex did
not prove to be a competent catalyst for 1,4-reductions.
However, the desired reaction proceeded smoothly upon ad-
dition of a mixture of copper tert-butoxide (1.2 mol%) and
poly(methylhydrosiloxane) (PMHS) as the bulk reduc-
tant.[19] The small excess of the DTBM-Segphos ligand pres-
ent in the reaction mixture is sufficient for a completely se-
lective and catalyst-controlled reduction (Table 5). This at-
Table 5. One-pot rearrangement/1,4-reduction sequence.[a]
Entry
1
R1/R2
3
Yield [%][b] ee [%][c] syn/anti[d]
1
2
3
4
cis-1a Ph/Me
trans-1a Me/Ph
cis-1e 2-Naph/Ph anti-3e 51
trans-1e Me/2-Naph syn-3e 55
anti-3a 74
syn-3a 65
95 (R,R) 1:>20
95 (S,R) >20:1
94 (R,R) 1:>20
94 (S,R) >20:1
Scheme 4. Product mixture formed from olefin cis-/trans-10a:
a) [{Rh(OH)
3 h.
ACHTUNGTERN(NGNU cod)}2] (2.5 mol%), rac-BINAP (6 mol%), toluene, 1108C,
[a] Reaction conditions: 0.1 mmol 1, 2.5 mol% [{Rh(OH)ACHTNUTRGNEUNG(cod)}2],
6.0 mol% ent-L5, 1.5 equiv Cs2CO3, toluene (0.25m), 808C, 3 h, then
1.2 mol% CuOtBu and 2.4 equiv PMHS, 58C, 48 h. [b] Yield of isolated
product 3. [c] Enantioselectivities were determined on an aliquot of 4
before silane addition by HPLC with a chiral stationary phase. [d] Diaste-
reomeric ratios were determined by proton NMR spectroscopy.
main product of the reaction mixture obtained from the re-
arrangement of 10a using rac-BINAP as the ligand is the ex-
pected cyclohexanone 11a, which is however only formed in
a moderate yield.
Three additional products (12–14) were identified that ac-
count for the remaining mass balance. The cyclization of
alkyl-rhodium species 15 occurs at a much lower rate than
that of the corresponding allene intermediate, which results
in a longer life span of 15 (Scheme 5). This species can now
participate in additional reaction pathways leading to the
observed product distribution. Apart from the expected con-
jugate addition forming enolate 16 and ultimately the de-
sired hexanone 11a, intermediate 15 adds in a 5-exo-trig,
counter-electronic fashion across the olefin to give 17. b-Hy-
dride elimination and re-addition then forms cyclopenta-
none 12 as a mixture of diastereomers. A third pathway in-
tractive feature allows the selective preparation of both dia-
stereomers of 3: Starting with isomer cis-1 leads exclusively
to anti-3 products (Table 5, entries 1 and 3). The correspond-
ing trans-1 is transformed in an analogous manner complete-
ly selectively to syn-3 (entries 2 and 4).
A complementary option for sequential catalysis is the
coupling of the rhodium-catalyzed rearrangement to a
second step operating under oxidative conditions. Exposure
of hexanone 4a after completion of the rearrangement to a
mixture of bis(trimethylsilyl) peroxide, SnCl4, and pyridine
promoted a Baeyer–Villiger reaction,[20] and gave e-enol lac-
tone 9 in good yields as the sole product (Scheme 3). Under
these conditions, a selective migration of the vinyl moiety
proceeded and no concurrent epoxidation of the olefin was
volves a 1,4-rhodium shift reaction[22] that presumably oper-
III
À
ates by means of a C H activation pathway involving Rh
intermediate 19 leading to aryl-rhodium species 20. Com-
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3387

T. Seiser and N. Cramer
apparent when the reaction is performed with cyclobutanol
10h, which has only one single substituent in the 3-position
(entry 10). In contrast to allene 1q, this substrate does not
cyclize anymore and yields instead enone 21, which arises
from a series of b-hydride eliminations and re-additions. A
substrate with a 1,2-disubstituted olefin (10i) is also reluc-
tant to cyclize and stalls at the ring-opened protonated prod-
uct 22 (entry 11).
Conclusion
In summary, we have demonstrated a highly enantioselective
rhodium-catalyzed carbon–carbon bond activation of sym-
metrically substituted cyclobutanols. The alkyl-rhodium spe-
cies generated thereby subsequently add intramolecularly
across a concomitantly formed allenone or enone to provide
cyclohexane derivatives in excellent yields and selectivities.
The reactivity as well as the selectivity of the activation is
largely independent of the substitution pattern, tolerates a
broad range of functional groups, and can be conducted
with catalyst loadings as low as 0.1 mol% rhodium. We fur-
ther showed its flexibility and synthetic potential by convert-
Scheme 5. Mechanistic manifold for the observed product distribution.
pound 20, in turn, adds either
in a 1,2-fashion to the carbonyl
group to yield indanol 13,[23] or
Table 6. Rhodium-catalyzed rearrangement of allylic tert-cyclobutanols.[a]
participates in a conjugate addi-
tion forming benzocyclohepta-
none 14.
We finally explored the reac-
tivity and selectivity pattern by
modulating the steric and elec-
tronic properties of several
vinyl-substituted cyclobutanols
(Table 6). The bulky ligand L3
improves the selectivity for the
cyclohexanones, and aryl-substi-
tuted substrates furnish 11 in
moderate yields and good to
excellent enantioselectivity (en-
tries 1 and 2). Spirocyclic sub-
strates react cleanly to cyclo-
hexanones 11 (entries 7–9),
whereas for substrate 10e that
has an electron-poor aromatic
Entry
10
R1/R2
R
11
Yield [%][b]
ee [%][c]
1[d]
2[d]
3[d]
4[d]
5
10a
10b
10c
10d
10d
Ph/Me
Me/2-Naph
tBu/Me
CH2OBn/Me
Me/CH2OBn
H
H
H
H
H
11a
11b
11c
11d
11d
63
63
71
99
93
88 (S)
98 (R)
95 (S)
96 (S)
95 (R)
98 (1R,3S)
8:1 d.r.
6[e]
10e
p-Cl-Ph/CO2Me
H
82
7
trans-10 f
75
94 (S)
8[d]
cis-10 f
74
93
88 (S)
92 (S)
À
substituent, the C H activation
pathway becomes dominant
and indanol 13e is exclusively
formed (entry 6). Cyclobutanols
lacking aromatic substituents
are almost exclusively convert-
ed to cyclohexanones 11 and
only a trace amount of cyclo-
pentanone is formed (entries 3–
5). The drastically slower cycli-
zation rate of the olefins rela-
9
10g
10
11
10h
10i
H/CH2OBn
H
99
99
–
–
CH2OBn/Me
Bu
[a] Reaction conditions: 0.1 mmol 10, 2.5 mol% [{Rh(OH)
12 h. [b] Yield of isolated products. [c] Enantioselectivities were determined by HPLC with a chiral stationary
ACHTUNGTERNUN(NG cod)}2], 6.0 mol% L3, toluene (0.25m), 1108C,
tive to the allenes also becomes phase. [d] 6.0 mol% ent-L3 was used. [e] 6.0 mol% of (S)-Difluorphos was used as ligand.
3388
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3383 – 3391

Enantioselective Activation of Cyclobutanols
FULL PAPER
air. Purification on silica gel (pentane/Et2O 1:1, Rf =0.13 pentane/Et2O
ing the same substrate under different sets of reaction condi-
tions and additives into structurally diverse sets of products.
These are often difficult to efficiently prepare by common
synthetic methods. Additionally, this study highlights the po-
tential of combining new catalytic activation modes with tra-
ditional reactivity patterns in coupled cascade processes to
maximize the increase in molecular complexity. Further ex-
ploitation of related cascade processes are ongoing and will
be reported in due course.
2:1) yielded hydroperoxide
6 (26.0 mg, 99%) as colorless crystals.
1H NMR (400 MHz, CDCl3): d=7.37–7.29 (m, 4H), 7.24–7.20 (m, 1H),
7.05 (s, 1H), 6.03 (s, 1H), 3.02–2.94 (m, 2H), 2.72–2.66 (m, 1H), 2.61–
2.56 (m, 1H), 1.43 (s, 3H), 1.36 (s, 3H), 1.31 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=199.6, 163.8, 146.8, 128.6, 126.6, 125.4, 125.3, 83.6,
49.5, 40.7, 39.1, 29.5, 23.3, 22.9 ppm; IR (ATR): n˜ =3286, 2966, 2873,
1812, 1723, 1650, 1601, 1498, 1445, 1412, 1379, 1359, 1302, 1287, 1235,
1201, 1152, 1117, 1072, 1031, 1002, 894, 852, 755, 699 cmÀ1; HRMS (EI):
m/z calcd for [C16H19O]+: 227.1430; found: 227.1432; [a]2D0 =À43 (c=0.88
in CHCl3).
Alcohol 7: Compound trans-1a (22.8 mg, 0.100 mmol), [{RhACHTNUGTRENUNG(cod)(OH)}2]
(1.14 mg, 2.50 mmol), and ent-L3 (6.90 mg, 6.00 mmol) were weighed into
an oven-dried vial equipped with a magnetic stirrer bar, sealed with a
rubber septum, and flushed with nitrogen. After the addition of dry tolu-
ene (0.4 mL), the reaction mixture was degassed by three freeze–pump–
thaw cycles, stirred for 10 min at 238C, and subsequently immersed into a
preheated oil bath (1008C) for 4 h. After TLC analysis showed the com-
plete conversion, the reaction mixture was cooled to 238C. The reaction
was stirred under an atmosphere of oxygen and subsequently triethyl
phosphite (35 mL, 0.200 mmol) was added and the mixture was stirred for
another 2 h at 238C. Direct purification of the reaction mixture on silica
gel (Et2O, Rf =0.45) yielded alcohol 7 (19.6 mg, 80%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d=7.35–7.28 (m, 4H), 7.24–7.18 (m, 1H),
6.20–6.05 (m, 1H), 2.93 (d, J=17.1 Hz, 2H), 2.66–2.54 (m, 2H), 1.39 (s,
3H), 1.36 (s, 3H), 1.33 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
199.9, 167.3, 146.5, 128.5, 126.5, 125.3, 122.3, 72.6, 49.6, 40.7, 39.5, 29.1,
28.2, 28.2 ppm; IR (ATR): n˜ =3393, 2973, 2931, 1877, 1658, 1498, 1446,
1359, 1311, 1289, 1230, 1177, 1072, 1031, 965, 907, 764, 700 cmÀ1; HRMS
Experimental Section
Representative procedure for the synthesis of enones 4: Compound
trans-1a (22.8 mg, 0.100 mmol), cesium carbonate (49.0 mg, 0.150 mmol),
[{RhACHTUNGTRENNUNG(cod)(OH)}2] (1.14 mg, 2.50 mmol), and L3 (6.90 mg, 6.00 mmol) were
weighed into an oven-dried vial equipped with a magnetic stirrer bar,
sealed with a rubber septum, and flushed with nitrogen. After the addi-
tion of dry toluene (0.4 mL), the reaction mixture was degassed by three
freeze–pump–thaw cycles, stirred for 10 min at 238C, and subsequently
immersed into a preheated oil bath (808C) for 3 h. After TLC analysis
showed the complete conversion, the reaction mixture was cooled to
238C and directly purified on silica gel (CH2Cl2, Rf =0.29) giving cyclo-
hexenone (S)-4a (21.7 mg, 95%, 96% ee) as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=7.25–7.11 (m, 5H), 5.82 (q, J=1.1 Hz, 1H), 2.83
(d, J=16.3 Hz, 1H), 2.72 (d, J=17.7 Hz, 1H), 2.50 (dd, J=0.8, 16.2 Hz,
1H), 2.48 (d, J=17.7 Hz, 1H), 2.33 (sept, J=5.0 Hz, 1H), 1.30 (s, 3H),
1.01 (d, J=5.0 Hz, 3H), 0.99 ppm (d, J=5.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=199.6, 168.8, 146.9, 128.5, 126.4, 125.2, 123.3, 49.8,
41.5, 40.5, 35.7, 28.9, 20.4, 20.3 ppm; IR (ATR): n˜ =2965, 1664, 1626,
1498, 1445, 1364, 1284, 1249, 1067, 1031, 905 cmÀ1; HRMS (EI): m/z calcd
for [C16H20O]+: 228.1509; found: 228.1508; [a]2D0 =À52.1 (c=0.88 in
CHCl3); HPLC separation (Chiralcel OD, 4.6ꢂ250 mm; 1% iPrOH/
(ESI): m/z calcd for [C16H20O2+H]+: 245.1536; found: 245.1535; [a]2D0
À68 (c=0.26 in CHCl3).
=
Representative procedure for the rearrangement/1,2-reduction sequence:
Compound trans-1a (22.8 mg, 0.100 mmol), [{Rh(cod)(OH)}2] (1.14 mg,
AHCTUNGTRENNUNG
2.50 mmol), and L3 (6.90 mg, 6.00 mmol) were weighed into an oven-dried
vial equipped with a magnetic stirrer bar, sealed with a rubber septum,
and flushed with nitrogen. After the addition of dry toluene (0.4 mL),
the reaction mixture was degassed by three freeze–pump–thaw cycles,
stirred for 10 min at 238C, and subsequently immersed into a preheated
oil bath (1008C) for 4 h. After TLC analysis showed the complete con-
version, the reaction mixture was cooled to 238C and dimethylphenylsi-
lane (46.7 mL, 0.300 mmol) was added to the reaction mixture. The reac-
tion mixture was stirred for 13 h at 308C and evaporated in vacuo. Purifi-
cation on silica gel (pentane to pentane/EtOAc 50:1, Rf =0.29) yielded
silyl ether (S)-8a (36.4 mg, 99%) as a colorless oil; d.r. (syn/anti)=1.2:1.
1H NMR (400 MHz, CDCl3; * denotes the signals of the minor isomer):
d=7.67–7.03 (m, 10H, 10H*), 3.80 (tt, J=11.0, 4.5 Hz, 1H), 3.53–3.40
(m, 1H*), 3.09 (dt, J=14.2, 1.9 Hz, 1H*), 2.94–2.81 (m, 1H), 2.77–2.60
(m, 1H, 1H*), 2.37 (ddt, J=13.1, 4.0, 2.1 Hz, 1H*), 2.07–1.90 (m, 2H),
1.84–1.72 (m, 1H, 3H*), 1.68 (t, J=3.4 Hz, 3H*), 1.66 (s, 3H), 1.63 (s,
3H), 1.57 (dd, J=13.1, 10.8 Hz, 1H), 1.52–1.49 (m, 1H*), 1.19 (s, 3H*),
1.08 (s, 3H), 0.42 (s, 6H), 0.36 (s, 3H*), 0.36 ppm (s, 3H*); 13C NMR
(100 MHz, CDCl3; signals of both diastereomers): d=152.0, 148.6, 139.5,
139.4, 134.7, 134.6, 130.7, 130.6, 129.3, 129.1, 128.9 (2C), 127.9, 127.7,
127.1, 126.8, 126.7, 126.3, 126.3, 125.3, 70.4, 69.4, 49.2, 48.4, 42.5, 41.7,
41.7, 41.4, 41.0, 40.6, 35.5, 25.7, 21.7, 21.6, 21.3, 21.3, À0.0, À0.1, À0.2,
À0.4 ppm; IR (ATR): n˜ =3059, 3021, 2960, 2927, 2902, 2862, 1497, 1444,
1428, 1374, 1252, 1117, 1080, 1058, 829, 786, 699 cmÀ1; HRMS (ESI): m/z
calcd for [C24H32OSi+NH4]+: 382.2561; found: 382.2564.
hexane, 1.0 mLminÀ1
17.00 min.
, 254 nm): tR (minor)=15.94 min, tR (major)=
Representative procedure for the synthesis of exocyclic double-bond iso-
mers 5: Compound trans-1a (22.8 mg, 0.100 mmol), [{Rh(cod)(OH)}2]
AHCTUNGTRENNUNG
(1.14 mg, 2.50 mmol), and ent-L3 (6.90 mg, 6.00 mmol) were weighed into
an oven-dried vial equipped with a magnetic stirrer bar, sealed with a
rubber septum, and flushed with nitrogen. After the addition of dry tolu-
ene (0.4 mL), the reaction mixture was degassed by three freeze–pump–
thaw cycles, stirred for 10 min at 238C, and subsequently immersed into a
preheated oil bath (1008C) for 4 h. After TLC analysis showed the com-
plete conversion, the reaction mixture was cooled to 238C and directly
purified on silica gel (degassed solvent, 0.2 mm in Kishi’s radical inhibitor,
pentane to pentane/EtOAc 14:1, Rf =0.30 pentane/EtOAc 15:1) giving
cyclohexanone (R)-5a (21.0 mg, 92%, 95% ee) as
a colorless oil.
1H NMR (400 MHz, CDCl3): d=7.38–7.29 (m, 4H), 7.24–7.18 (m, 1H),
3.27 (d, J=16.4 Hz, 1H), 2.97 (d, J=16.5 Hz, 1H), 2.88 (d, J=14.7 Hz,
1H), 2.74 (s, 2H), 2.54–2.48 (m, 1H), 1.66 (dd, J=7.9, 0.8 Hz, 6H),
1.26 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=209.5, 147.7, 128.4,
127.4, 126.2, 125.3, 123.2, 53.6, 46.0, 41.8, 40.7, 27.6, 20.7, 20.2 ppm; IR
(ATR): n˜ =3305, 3058, 2962, 2924, 2870, 1712, 1666, 1601, 1498, 1445,
1416, 1378, 1358, 1236, 1156, 1071, 1031, 908, 762, 700 cmÀ1; HRMS (EI):
m/z calcd for [C16H20O]+: 228.1509; found: 228.1510; [a]2D0 =À15 (c=0.45
in CHCl3); HPLC separations were carried out after DBU-promoted iso-
merization of 5a to 4a using the above conditions.
Representative procedure for the synthesis of ketones 3: Compound cis-
1a (22.8 mg, 0.100 mmol), cesium carbonate (49.0 mg, 0.150 mmol), [{Rh-
Hydroperoxide 6: Compound trans-1a (22.8 mg, 0.100 mmol), [{Rh-
AHCTUNGTRE(GNNNU cod)(OH)}2] (1.14 mg, 2.50 mmol), and ent-L5 (7.1 mg, 6.00 mmol) were
ACHTUNGTRENNUNG(cod)(OH)}2] (1.14 mg, 2.50 mmol), and ent-L3 (6.90 mg, 6.00 mmol) were
weighed into an oven-dried vial equipped with a magnetic stirrer bar,
sealed with a rubber septum, and flushed with nitrogen. After the addi-
tion of dry toluene (0.4 mL), the reaction mixture was degassed by three
freeze–pump–thaw cycles, stirred for 10 min at 238C, and subsequently
immersed into a preheated oil bath (808C) for 3 h. A solution of copper
tert-butoxide and PHMS in toluene (10 mm in Cu and 2.0m in PHMS,
0.12 mL, prepared according to ref. [19]) was added and the reaction was
weighed into an oven-dried vial equipped with a magnetic stirrer bar,
sealed with a rubber septum, and flushed with nitrogen. After the addi-
tion of dry toluene (0.4 mL), the reaction mixture was degassed by three
freeze–pump–thaw cycles, stirred for 10 min at 238C, and subsequently
immersed into a preheated oil bath (1008C) for 4 h. After TLC analysis
showed the complete conversion, the reaction mixture was cooled to
238C. Silica gel was added and the mixture was stirred for 2 min under
Chem. Eur. J. 2010, 16, 3383 – 3391
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3389

T. Seiser and N. Cramer
stirred for 48 h at 58C. The reaction was quenched with TBAF (1m in
THF, 0.26 mL, 0.260 mmol) and acetic acid (16 ml, 0.280 mmol) and the
mixture was stirred for 10 min. The mixture was poured into saturated
NH4Cl solution and extracted with EtOAc. The combined organic phases
were dried (MgSO4) and concentrated. Purification on silica gel (pen-
tane/EtOAc 15:1, Rf =0.28) yielded ketone (R,R)-3a (17.0 mg, 74%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d=7.40–7.26 (m, 4H), 7.23–
7.14 (m, 1H), 3.09–2.98 (m, 1H), 2.39–2.22 (m, 3H), 2.03–1.93 (m, 1H),
1.59 (dd, J=15.9, 10.0 Hz, 1H), 1.51–1.44 (m, 1H), 1.37 (s, 3H), 1.33–
1.27 (m, 1H), 0.83 ppm (dd, J=9.2, 6.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d=211.7, 146.3, 128.6, 126.0, 126.0, 52.3, 44.4, 42.3, 42.2, 39.4,
33.9, 32.3, 19.3, 19.1 ppm; IR (ATR): n˜ =2959, 2927, 2873, 1712, 1602,
Acknowledgements
We thank G. Cathomen for synthetic assistance and Dr. B. Schweizer for
the X-ray crystallographic analysis of compound 6. We are grateful to the
Swiss National Foundation (21-119750.01), Solvias AG for the MeOBi-
phep ligands, Takasago International Corporation for the Segphos li-
gands, and Umicore AG & Co. KG for the rhodium salts, as well as
Prof. Dr. E. M. Carreira for generous support. The Fonds der Chemi-
schen Industrie is acknowledged for a Liebig-Fellowship (N.C.) and a
Kekulꢄ-Fellowship (T.S.).
1499, 1460, 1445, 1388, 1369, 1304, 1265, 1244, 1227, 1031, 765, 701 cmÀ1
;
=
À
[1] For reviews on C H bond functionalization, see: a) F. Kakiuchi, S.
HRMS (EI): m/z calcd for [C16H22O]+: 230.1666; found: 230.1664; [a]2D0
À68 (c=0.29 in CHCl3); Rf =0.28 (pentane/EtOAc 15:1).
Murai, Acc. Chem. Res. 2002, 35, 826–834; b) M. Miura, M.
Nomura, Top. Curr. Chem. 2002, 219, 211–241; c) F. Kakiuchi, N.
Chatani, Adv. Synth. Catal. 2003, 345, 1077–1101; d) I. V. Seregin, V.
Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173–1193; e) F. Kakiuchi,
Top. Organomet. Chem. 2008, 24, 1–33; f) J. C. Lewis, R. G. Berg-
man, J. A. Ellman, Acc. Chem. Res. 2008, 41, 1013–1025.
Enol lactone 9: Compound cis-1a (22.8 mg, 0.100 mmol), cesium carbon-
ate (49.0 mg, 0.150 mmol), [{Rh(cod)(OH)}2] (1.14 mg, 2.50 mmol), and
AHCTUNGTRENNUNG
L3 (6.90 mg, 6.00 mmol) were weighed into an oven-dried vial equipped
with a magnetic stirrer bar, sealed with a rubber septum, and flushed
with nitrogen. After the addition of dry toluene (0.4 mL), the reaction
mixture was degassed by three freeze–pump–thaw cycles, stirred for
10 min at 238C, and subsequently immersed into a preheated oil bath
(808C) for 3 h. The reaction mixture was cooled to 238C, filtered over
silica gel, and then added as a solution in dichloromethane (0.20 mL) to
a 08C preformed suspension containing powdered 4 ꢃ molecular sieves
(35 mg), pyridine (4.0 ml, 0.05 mmol), tin(IV) chloride (1.0m in dichloro-
methane, 0.05 mL, 0.05 mmol), and bis(trimethysilyl) peroxide (0.087 mL,
0.400 mmol) in dichloromethane (0.8 mL). The ice bath was removed and
the reaction was stirred for 24 h at 238C. Sodium sulfite was added and
the suspension was stirred for 1 h at 238C. Purification on silica gel
(CH2Cl2, Rf =0.38) yielded enol lactone 9 (17.3 mg, 71%) as a colorless
oil. 1H NMR (400 MHz, CDCl3): d=7.42–7.30 (m, 4H), 7.26–7.20 (m,
1H), 6.42–6.35 (m, 1H), 3.26 (d, J=11.8 Hz, 1H), 2.65 (dd, J=11.8,
0.7 Hz, 1H), 2.56 (d, J=14.3 Hz, 1H), 2.43 (d, J=14.2 Hz, 1H), 2.12
(septd, J=6.8, 1.1 Hz, 1H), 1.49 (s, 3H), 0.94 (d, J=6.8 Hz, 3H),
0.85 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.4,
146.9, 136.0, 133.9, 128.6, 126.7, 125.1, 46.6, 43.6, 40.0, 32.1, 30.1, 21.2,
21.1 ppm; IR (ATR): n˜ =2965, 2874, 1755, 1657, 1498, 1464, 1445, 1321,
1186, 1175, 1146, 1093, 1043, 910, 819, 760, 700 cmÀ1; HRMS (EI): m/z
calcd for [C16H20O2]+: 244.1458; found: 244.1461; [a]2D0 =+14 (c=0.29 in
CHCl3).
À
[2] For reviews on C C bond functionalization, see: a) B. Rybtchinski,
D. Milstein, Angew. Chem. 1999, 111, 918–932; Angew. Chem. Int.
Ed. 1999, 38, 870–883; b) M. Murakami, Y. Ito, Top. Organomet.
Chem. 1999, 3, 97–129; c) C.-H. Jun, C. W. Moon, D.-Y. Lee, Chem.
Eur. J. 2002, 8, 2423–2428; d) M. E. van der Boom, D. Milstein,
Chem. Rev. 2003, 103, 1759–1792; e) C.-H. Jun, Chem. Soc. Rev.
2004, 33, 610–618; f) T. Satoh, M. Miura, Top. Organomet. Chem.
2005, 14, 1–20.
[3] P. Zhao, J. F. Hartwig, Organometallics 2008, 27, 4749–4757.
[4] For examples, see: a) T. Kondo, K. Kodoi, E. Nishinaga, T. Okada,
Y. Morisaki, Y. Watanabe, T.-A. Mitsudo, J. Am. Chem. Soc. 1998,
120, 5587–5588; b) Y. Terao, H. Wakui, T. Satoh, M. Miura, M.
Nomura, J. Am. Chem. Soc. 2001, 123, 10407–10408; c) H. Wakui, S.
Kawasaki, T. Satoh, M. Miura, M. Nomura, J. Am. Chem. Soc. 2004,
126, 8658–8659; d) D. Necas, M. Tursky, M. Kotora, J. Am. Chem.
Soc. 2004, 126, 10222–10223; e) A. Funayama, T. Satoh, M. Miura,
J. Am. Chem. Soc. 2005, 127, 15354–15355; f) S. Hayashi, K.
Hirano, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006, 128,
2210–2211; g) T. Nishimura, T. Katoh, T. Hayashi, Angew. Chem.
2007, 119, 5025–5027; Angew. Chem. Int. Ed. 2007, 46, 4937–4939;
h) T. Nishimura, T. Katoh, K. Takatsu, R. Shintani, T. Hayashi, J.
Am. Chem. Soc. 2007, 129, 14158–14159; i) R. Shintani, K. Takatsu,
T. Katoh, T. Nishimura, T. Hayashi, Angew. Chem. 2008, 120, 1469–
1471; Angew. Chem. Int. Ed. 2008, 47, 1447–1449.
Representative procedure for the synthesis of cyclohexanones 11: Com-
pound cis-10d (23.2 mg, 0.100 mmol), [{RhACTHNUTRGNEG(NU cod)(OH)}2] (1.14 mg,
2.50 mmol), and ent-L3 (6.90 mg, 6.00 mmol) were weighed into an oven-
dried vial equipped with a magnetic stirrer bar, sealed with a rubber
septum, and flushed with nitrogen. After the addition of dry toluene
(0.4 mL), the reaction mixture was degassed by three freeze–pump–thaw
cycles, stirred for 10 min at 238C, and subsequently immersed into a pre-
heated oil bath (1108C) for 12 h. After TLC analysis showed the com-
plete conversion, the reaction mixture was cooled to 238C and directly
purified on silica gel (pentane/EtOAc 15:1, Rf =0.19) yielding cyclohexa-
[5] For examples, see: nickel-catalyzed: a) M. Murakami, S. Ashida, T.
Matsuda, J. Am. Chem. Soc. 2006, 128, 2166–2167; iridium-cata-
lyzed: b) T. Nishimura, T. Yoshinaka, Y. Nishiguchi, Y. Maeda, S.
Uemura, Org. Lett. 2005, 7, 2425–2427; palladium-catalyzed: c) T.
Nishimura, K. Ohe, S. Uemura, J. Am. Chem. Soc. 1999, 121, 2645–
2646; d) T. Nishimura, S. Uemura, J. Am. Chem. Soc. 1999, 121,
11010–11011; e) R. C. Larock, C. K. Reddy, Org. Lett. 2000, 2,
3325–3327; rhodium-catalyzed: f) M. Hayashi, T. Ohmatsu, Y.-P.
Meng, K. Saigo, Angew. Chem. 1998, 110, 877–879; Angew. Chem.
Int. Ed. 1998, 37, 837–839; g) M. Murakami, T. Itahashi, Y. Ito, J.
Am. Chem. Soc. 2002, 124, 13976–13977; h) T. Matsuda, M. Makino,
M. Murakami, Angew. Chem. 2005, 117, 4684–4687; Angew. Chem.
Int. Ed. 2005, 44, 4608–4611; i) C. Aissa, A. Fꢅrstner, J. Am. Chem.
Soc. 2007, 129, 14836–14837; ruthenium-catalyzed: j) T. Kondo, A.
Nakamura, T. Okada, N. Suzuki, K. Wada, T. Mitsudo, J. Am. Chem.
Soc. 2000, 122, 6319–6320; Iron-catalyzed: k) A. Fꢅrstner, K.
Majima, R. Martin, H. Krause, E. Kattnig, R. Goddard, C. W. Leh-
mann, J. Am. Chem. Soc. 2008, 130, 1992–2004.
none (S)-11 (23.1 mg, 99%, 96% ee) as
a
colorless oil. 1H NMR
(300 MHz, CDCl3): d=7.38–7.24 (m, 5H), 4.51 (s, 2H), 3.23–3.15 (m,
2H), 2.43 (d, J=13.9 Hz, 1H), 2.31–2.24 (m, 2H), 2.11–2.05 (m, 1H),
1.98–1.82 (m, 3H), 1.56–1.43 (m, 1H), 0.95 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=211.9, 138.3, 128.2, 127.4, 127.2, 78.3, 73.2, 50.6,
41.0, 40.1, 33.2, 23.2, 22.0 ppm; IR (ATR): n˜ =2951, 2873, 1710, 1497,
1454, 1228, 1100, 1028, 737, 698 cmÀ1; HRMS (ESI): m/z calcd for
[C15H20O2+Na]+: 255.1356; found: 255.1354; [a]2D0 =À3 (c=1.00 in
CHCl3); HPLC separation (Chiralcel OJ, 4.6ꢂ250 mm; 5% iPrOH/
hexane, 1.0 mLminÀ1
,
254 nm): tR (minor)=12.93 min, tR (major)=
15.35 min), 96% ee.
[6] For a review, see: T. Seiser, N. Cramer, Org. Biomol. Chem. 2009, 7,
2835–2840.
[7] a) T. Nishimura, S. Matsumura, Y. Maeda, S. Uemura, Chem.
Commun. 2002, 50–51; b) S. Matsumura, Y. Maeda, T. Nishimura, S.
Uemura, J. Am. Chem. Soc. 2003, 125, 8862–8869.
[8] a) T. Matsuda, M. Shigeno, M. Makino, M. Murakami, Org. Lett.
2006, 8, 3379–3381; b) T. Matsuda, M. Shigeno, M. Murakami, J.
Am. Chem. Soc. 2007, 129, 12086–12087.
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Chem. Eur. J. 2010, 16, 3383 – 3391

Enantioselective Activation of Cyclobutanols
FULL PAPER
[9] a) J. D. Christopher, L. E. Overman, Proc. Natl. Acad. Sci. USA
2004, 101, 5363–5367; b) B. M. Trost, D. C. Jiang, Synthesis 2006,
369–396; c) Quaternary Stereocenters (Eds.: J. Christoffers, A.
Baro), Wiley-VCH, Weinheim, 2005.
[10] T. Seiser, N. Cramer, Angew. Chem. 2008, 120, 9435–9438; Angew.
Chem. Int. Ed. 2008, 47, 9294–9297.
[11] S. Jeulin, S. Duprat de Paule, V. Ratovelomanana-Vidal, J.-P. GenÞt,
N. Champion, P. Dellis, Proc. Nat. Acad. Sci. USA 2004, 101, 5799–
5804.
[12] P. A. Wender, N. M. Deschamps, R. Sun, Angew. Chem. 2006, 118,
4061–4064; Angew. Chem. Int. Ed. 2006, 45, 3957–3960.
[13] J. Zhou, V. Wakchaure, P. Kraft, B. List, Angew. Chem. 2008, 120,
7768–7771; Angew. Chem. Int. Ed. 2008, 47, 7656–7658.
[14] a) M. Carda, J. Van der Eycken, M. Vandervalle, Tetrahedron:
Asymmetry 1990, 1, 17–20; b) D. F. Taber, K. Kanai, Q. Jiang, G.
Bui, J. Am. Chem. Soc. 2000, 122, 6807–6808.
[16] a) A. Nickon, W. L. Mendelson, J. Org. Chem. 1965, 30, 2087–2089;
b) A. B. Smith III, J. Kingery-Wood, T. L. Leenay, E. G. Nolen, T.
Sunazuka, J. Am. Chem. Soc. 1992, 114, 1438–1449.
[17] Y. Kishi, M. Aratani, M. Tanino, T. Fukuyama, T. Goto, S. Inoue, S.
Sugiura, H. Kakoi, J. Chem. Soc., Chem. Commun. 1972, 64–65.
[18] H. Nishiyama, K. Itoh in Catalytic Asymmetric Synthesis, 2nd ed.
(Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, pp. 111–143.
[19] a) B. H. Lipshutz, B. A. Frieman, Angew. Chem. 2005, 117, 6503–
6506; Angew. Chem. Int. Ed. 2005, 44, 6345–6348; b) C. Deutsch, N.
Krause, B. H. Lipshutz, Chem. Rev. 2008, 108, 2916–2927.
[20] R. Gçttlich, K. Yamakoshi, H. Sasai, M. Shibasaki, Synlett 1997,
971–973.
[21] P. A. Aristoff, J. Org. Chem. 1985, 50, 1765–1766.
[22] Review: a) S. Ma, Z. Gu, Angew. Chem. 2005, 117, 7680–7685;
Angew. Chem. Int. Ed. 2005, 44, 7512–7517; Recent examples: b) T.
Miura, T. Sasaki, H. Nakazawa, M. Murakami, J. Am. Chem. Soc.
2005, 127, 1390–1391; c) T. Matsuda, M. Shigeno, M. Murakami, J.
Am. Chem. Soc. 2007, 129, 12086–12087; d) R. Shintani, K. Takatsu,
T. Katoh, T. Nishimura, T. Hayashi, Angew. Chem. 2008, 120, 1469–
1471; Angew. Chem. Int. Ed. 2008, 47, 1447–1449.
[15] Crystallographic data for 6: C16H20O3; Mr =260.33; orthorhombic;
space group P212121; a=8.2125(3), b=12.0678(5), c=14.2225(7) ꢃ;
V=1409.5(1) ꢃ3; Z=4; 1calcd =1.227 Mg mÀ3; T=173 K; reflections
collected: 2492; independent reflections: 2474 (Rint =0.040); RACTHNUGTRNEUNG(all)=
[23] T. Seiser, O. A. Roth, N. Cramer, Angew. Chem. 2009, 121, 6438–
6441; Angew. Chem. Int. Ed. 2009, 48, 6320–6323.
0.0608, wR(gt)=0.1373. CCDC-752893 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: November 25, 2009
Published online: February 9, 2010
Chem. Eur. J. 2010, 16, 3383 – 3391
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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