Rhodium-Catalyzed Enantioconvergent Isomerization of Homoallylic and Bishomoallylic Secondary Alcohols

Article abstract of DOI:10.1021/jacs.8b07007

We present herein an unprecedented enantioselective isomerization of homoallylic and bishomoallylic secondary alcohols, catalyzed by a commercially available rhodium-complex and a base. This catalytic redox-neutral process provides an effective access to chiral ketones in high efficiency and enantioselectivity, without the use of any stoichiometric reagent or generation of any waste. For the reaction of homoallylic alcohols, this system achieved not only a stereoconvergent access to chiral ketones bearing a β-stereocenter (up to 95%, 86% ee) but also a concomitant oxidative kinetic resolution of the alcohol substrates (S > 20). In the case of bishomoallylic alcohols, an intriguing ligand-induced divergent reactivity was observed. A terminal-to-internal alkene isomerization promoted by Rh/L7 followed by redox isomerization using Rh/BINAP system produced chiral ketones bearing a γ-stereocenter with high yield and enantioselectivity. Mechanistic studies provided strong support for the redox-isomerization pathway with chain walking of the key alkyl-Rh intermediate.

Full text of DOI:10.1021/jacs.8b07007

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Article
Rhodium-Catalyzed Enantioconvergent Isomerization
of Homoallylic and Bishomoallylic Secondary Alcohols
Rui-Zhi Huang, Kai Kiat Lau, Zhao-Feng Li, Tang-Lin Liu, and Yu Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07007 • Publication Date (Web): 15 Oct 2018
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Journal of the American Chemical Society
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Rhodium-Catalyzed Enantioconvergent Isomerization of
Homoallylic and Bishomoallylic Secondary Alcohols
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Rui-Zhi Huang,† Kai Kiat Lau,† Zhaofeng Li,‡ Tang-Lin Liu,*, †,‡ and Yu Zhao*,†
†Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543
‡ School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
Me
O
OH
R2
up to 95%
up to 95% ee
R1
R2
R1
catalytic [Rh], catalytic base
or
or
stereoconvergent isomerization;
no stoichiometric reagent or waste
Me
R2
OH
R2
R1
R1
up to 91%
up to 85% ee
O
()
Practical procedure to access chiral ketones with a or -stereocenter


Concomitant oxidative kinetic resolution of homoallylic alcohol substrates
ligand-controlled alkene or redox isomerization of bishomoallylic alcohols
ABSTRACT: We present herein an unprecedented enantioselective isomerization of homoallylic and bishomoallylic secondary
alcohols, catalyzed by a commercially available rhodium-complex and a base. This catalytic redox-neutral process provides an
effective access to chiral ketones in high efficiency and enantioselectivity, without the use of any stoichiometric reagent or generation
of any waste. For the reaction of homoallylic alcohols, this system achieved not only a stereoconvergent access to chiral ketones
bearing a β–stereocenter (up to 95%, 86% ee), but also a concomitant oxidative kinetic resolution of the alcohol substrates (S >20).
In the case of bishomoallylic alcohols, an intriguing ligand-induced divergent reactivity was observed. A terminal-to-internal alkene
isomerization promoted by Rh/L7 followed by redox isomerization using Rh/BINAP system produced chiral ketones bearing a γ-
stereocenter with high yield and enantioselectivity. Mechanistic studies provided strong support for the redox-isomerization pathway
with chain walking of the key alkyl-Rh intermediate.
Combining the power of the two strategies, the isomerization
INTRODUCTION
of remote alkenyl alcohols has also attracted much attention in
To achieve sustainable chemical synthesis, the atom, step and
recent years. However, only a few successful catalytic systems
redox economy of a new synthetic method represent key
were reported in the literature for such a challenging process.
parameters for the measure of its efficiency.1 Consequently,
While early success with ruthenium catalysis was disclosed by
cascade isomerization reactions are highly attractive due to
their redox-neutral, atom-economical nature, and their ability of
converting readily available materials to more complex target
molecules. The catalytic isomerization of allylic alcohols,
particularly, has proven to be a powerful tool to deliver
synthetically valuable carbonyl compounds with a highly
efficient procedure.2 Various transition metal catalysts have
been developed for this transformation.3 Highly
enantioselective isomerization of β-substituted primary allylic
alcohols has also been documented in the literature.4,5
In a related effort to readily access novel, complex structures,
the development of remote functionalization of alkenes has
witnessed great advancement in recent years.6,7 These processes
involve transition metal-catalyzed alkene functionalization
followed by a long-range isomerization through a chain-
walking pathway. With the achievement of stereocontrol, these
transformations provide unique advantage of establishing
stereogenic centers that are distant from the resultant
functionality.
the Grotjahn group,8 the Mazet group has introduced a couple
of Pd-catalyzed systems for a general and highly efficient long-
range isomerization of alkenyl alcohols of different substitution
patterns.9 Importantly, a few examples of enantioselective
isomerization of primary homoallylic alcohols with moderate to
good enantioselectivity was also documented in these work
(Scheme 1a). To the best of our knowledge, the isomerization
of remote alkenyl secondary alcohols with enantiocontrol
remains elusive in the literature.
Two key challenges need to be addressed in order to achieve
efficient and stereoselective isomerization of functionalized
secondary alcohols. Firstly, the reactivity of these compounds
are much lower than their primary alcohol counterpart, making
the achievement of both reactivity and selectivity extremely
difficult. Secondly, it is preferable to use the readily available
racemic substrates,10 thus a stereoconvergent transformation
needs to be realized instead of a simple kinetic resolution.11
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Scheme 1. Catalytic enantioselective isomerization of
Page 2 of 7
parameters was performed. The use of TBME as the solvent
was beneficial leading to a full conversion to 2a, however, at
the cost of reduced enantioselectivity (entry 9). Different
inorganic and organic bases were evaluated, from which the
usage of DABCO produced 2a in 72% yield and 84% ee (entry
10). The recovered 1a was also found to be highly
enantioenriched (98% ee). With a prolonged reaction time of 48
h, a high yield of 88% and high ee of 84% for 2a were finally
achieved with this stereoconvergent isomerization reaction
(entry 11).
1
2
3
4
5
6
7
8
alkenyl alcohols
primary
a) Mazet's enantioselective isomerization of
homoallylic alcohols
O
O
R
R
O
OH
Me
Me
5 mol% [Pd]/Binapine
or [Pd]/i-Pr-DUPHOS
up to 88% ee
or
or
NaBARF, cyclohexene
Ph
Ph
OH
O
Cy
Cy
36%, 62% ee
9
Table 1. Optimization of homoallylic alcohol isomerizationa
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2.5 mol % [Rh(COD)2]BF4
OH
OH
Me
O
This work
secondary
homoallylic/bishomoallylic alcohols
b)
: Stereoconvergent isomerization of
5 mol % ligand
+
Ph
Ph
Ph
Ph
Ph
Ph
30 mol % base
4Å MS, solvent, 50 oC, 24 h
1a
(S)-1a
(±)-
2a
L7
catalytic [Rh]/
OH
Me
O
OH
Ar
catalytic base
*
2a yield
2a ee
1a ee
+
R
Ar
entry
ligand
solvent
base
R
Ar
R
(%)b
(%)c
(%)c
50-90 °C
()
homoallylic alcohols
up to 48%, 98% ee
up to 95%, 86% ee
convergent isomerization
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L7
L7
L7
L7
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
TBME
TBME
TBME
TBME
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
DABCO
DABCO
DBU
60
45
49
18
14
81
30
95
93
72
88
50
38
32
10
30
30
70
86
20
70
84
84
90
44
54
22
62
56
--
kinetic resolution of
SM at 52-54% conv.
3
4
L7
[Rh]/
base
Me
[Rh]/(R)-BINAP
Me
R2
base
R2
R2
R1
R1
*
5
R1
*
50 °C
100 °C
OH
OH
()
O
6
()
homoallylic alcohols
up to 91%
up to 85% ee
bishomoallylic alcohols
7
50
--
80-95%
8
9
--
Our group has focused on the development of catalytic
enantioselective redox-neutral transformations for efficient
chemical synthesis. In particular, we are interested in
stereoconvergent transformations that convert readily available
racemic alcohols to valuable enantioenriched products.12 Very
recently, we introduced the first enantioselective isomerization
of secondary allylic alcohols to deliver chiral ketones bearing a
tertiary α-stereogenic center.13 Such a process is capable of
converting readily available, racemic alcohols to the
synthetically valuable chiral ketones in a stereoconvergent
fashion.
10
11d
12d
98
--
98
aReactions were carried out with 0.1 mmol of 1a, 2.5 mol % [Rh(COD)2]BF4, 5 mol
% chiral ligand, 30 mol % base and 50 mg 4 Å MS in 0.5 mL of solvent. bIsolated
yield. cDetermined by chiral HPLC analysis. d48 h reaction time.
O
O
F
PPh2
PPh2
F
O
O
PAr2
PAr2
O
O
PPh2
PPh2
PPh2
PPh2
F
F
Herein, we present the first catalytic enantioselective
isomerization of remote alkenyl secondary alcohols to deliver
chiral ketones bearing a β or γ-stereocenter in high yields and
enantioselectivity (Scheme 1b). This Rh-catalyzed process
O
O
L1
: (R)-BINAP
Ar = 3,5-tBu2-4-MeOC6H2
4:
L2
L3
: (R)-SDP
: (S)-DifluorPhos
L
(R)-DTBM-SegPhos
tBu
PPh2
utilizes commercially available catalysts and
a simple
PCy
2Cy2P
Ph2P
PCy2
P
PPh2
Me
Fe
Fe
Cy2P
tBu
procedure, and operates on both homoallylic and
bishomoallylic secondary alcohols. For the former case, an
intriguing pathway of oxidative kinetic resolution followed by
enantioselective alkene reduction is established. While for the
bishomoallylic alcohols, a significant ligand effect is identified,
resulting in an efficient alkene isomerization followed by
isomerization of the alkenyl alcohols.
Me
Me
Fe
Fe
Me
L7
L8
L5
L6
: (R)-JosiPhos
The excellent enantioselectivity obtained for the recovered
1a pointed to the possibility of a highly efficient oxidative
kinetic resolution. When DBU was used as the base, the
reaction could be easily controlled at ~50% conversion. Both
2a and recovered 1a were obtained in excellent ee of 90% and
98%, respectively (entry 12). Therefore, either kinetic
resolution or ennatioconvergent isomerization of homoallylic
alcohols could be achieved. Remarkably, the same catalytic
system promotes both alcohol oxidation and alkene reduction
steps with high level of enantiocontrol.
We first examined the scope of enantioselective
isomerization of homoallylic alcohols via the kinetic resolution
approach (Scheme 2). For the model substrate 1a, the S factor
was determined to be >50. A methyl substitution on either aryl
ring in the substrate structure could be well-tolerated; the
resolution/isomerization of 1b and 1c both worked out to be
excellent. For other substituted substrates, the observed lower
reactivity necessitated the use of DABCO and elevated
temperature of 70 °C to achieve 50-55% conv. The selectivity
RESULTS AND DISUSSION
Isomerization of homoallylic alcohols
We initiated our studies by using homoallylic alcohol 1a as
the model substrate and commercial Rh complex and Ag2CO3
as the catalysts (Table 1).13 Preliminary screening quickly
established that slightly elevated temperature of 50 °C was
necessary to achieve reasonable reactivity. Through systematic
screening of chiral ligands (as exemplified in entries 1-8), the
JosiPhos analog L7 proved to be optimal for enantioselectivity
of 2a, albeit with a low yield (entry 7). It is interesting to note
that the recovered 1a was also enantioenriched, indicating a
kinetic resolution of the racemic substrate.
To further improve the yield of 2a by using ligand L7,
screening of solvents, concentration and other reaction
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remained excellent in most cases. The electronic property of the
aryl substituent and in turn the oxidation of the benzylic
alcohol, however, showed a strong influence on the selectivity.
For more electron-rich substrate such as 1e, the
enantioselectivity dropped to S = 10. It is noteworthy that
functionalities such as halide or ester could be well-tolerated (
1f and 1g). For the case of 1h, the valuable acrylate-derived
alcohol could be recovered in a high 96% ee.
We then examined the scope of the enantio-convergent
isomerization to deliver ketone 2 (Scheme 3). The reaction
worked well for a range of aryl-substituted substrates to deliver
the ketones bearing a β-stereocenter in good to high level of
enantioselectivity and good isolated yield. Electronic variation
of the aryl group on the alcohol side was well-tolerated, ranging
from the very electron-donating dimethyl amino group (2i) to
electron-withdrawing ester (2g). Notably, the 1,4-dicarbonyl
product 2h was also accessed in good enantioselectivity, which
represents a challenge in the alternative enantioselective
conjugate addition to acyclic enones.14
1
2
3
4
5
6
7
8
Scheme 2. Rh-catalyzed kinetic resolution of homoallylic
alcohols via isomerizationa
9
2.5 mol % [Rh(COD)2]BF4
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Me
O
OH
R2
OH
R2
L7
5 mol %
A limitation of this catalytic system is the requirement of a
benzylic alcohol substrate to achieve good reactivity and
selectivity for the isomerization reaction. When a furan-
substituted homoallylic alcohol (R2 = furan) was tested, the
ketone product was obtained with a good 86% ee, albeit with
very low efficiency (<20% Conv.). When substrate bearing an
aliphatic alcohol was examined (e.g., R2 = Cy in 1), the reaction
only occurs at 100 ℃, with only ~30% ee for the product. The
identification of a more suitable catalytic system to expand the
scope of the products is currently under investigation.
+
R1
R2
R1
R1
30 mol % base
4Å MS, solvent
temp, time
1
()-
2
1
(S)-
DBU, TBME, 50 oC, 48 h
OH
Condition A:
OH
Ph
OH
Ph
Ph
Ph
Me
Me
1a
2a
1b
1c
: 47%, 98% ee
: 43%, 98% ee
: 46%, 96% ee
: 50%, 95% ee
2b
2c: 53%, 92% ee
53% Conv., S >50
: 50%, 90% ee
52% Conv., S >50
54% Conv., S >50
DABCO, toluene, 70 oC, 24 h
Condition B:
OH
OH
OH
Me
Ph
Ph
Ph
OMe
Br
1d
1e
2e
1f
2f
: 45%, 92% ee
: 48%, 66% ee
: 45%, 96% ee
2d
: 53%, 81% ee
: 47%, 78% ee
: 51%, 90% ee
54% Conv., S = 27
49% Conv., S = 10
53% Conv., S = 48
OH
OH
Ph
MeO
Ph
O
CO2Me
1h
:
45%, 96% ee
50%, 84% ee
1g
2g
: 48%, 98% ee
2hb:
: 52%, 82% ee
52% Conv., S >50
53% Conv., S = 48
aSee supporting information for details. The S factor was calculated using conversion
(C) determined by crude NMR and ee of SM 1: S = log[(1-C)(1-ee)]/log[(1-C)(1+ee)].
bThe reaction was carried out in TBME and 50 oC for 72 h.
Figure 1. Sequential selective oxidation and reduction
Scheme 3. Rh-catalyzed convergent isomerization of
homoallylic alcoholsa
It is interesting to note that this catalytic enantioselective
isomerization involves two sequential enantio-determining
steps. To clearly illustrate that, the enantioselectivity of 1a and
2a at different conversions was examined. As shown in Figure
1, the ee of the recovered substrate 1a gradually increased with
the conversion, which is characteristic of a kinetic resolution
process. On the other hand, the ee of 2a remained largely
constant throughout the reaction, even at high conversion. In
this isomerization reaction, the oxidative alcohol kinetic
resolution and enantioselective reduction of the alkene thus
operate independently, remarkably under the control of the
same chiral Rh-catalyst.
2.5 mol % [Rh(COD)2]BF4
Me
O
OH
R2
L7
5 mol %
R1
R2
R1
30 mol % DABCO
4Å MS, solvent, temp, 48 h
1
()-
2
TBME, 50 oC, 48 h
Condition C:
Me
O
Me
O
Me
Ph
O
Ph
Ph
Ph
Me
Me
2a
2b
2e
2g
2c
: 80%, 86% ee
: 88%, 84% ee
: 95%, 84% ee
toluene, 90 oC, 48 h
Me
Condition D:
Me
Me
O
Me
O
To understand the pathway involved in the isomerization
reaction, deuterium-labelling studies were carried out with
alcohols 1a-D-a and 1a-D-b (Scheme 4a). For the reaction of
1a-D-a, the deuterium was cleanly transferred to the terminal
position of the double bond, consistent with a redox-
isomerization mechanism. In the case of 1a-D-b, one of the
deuteriums on the α-carbon was transferred to the β-carbon in
the product structure. This observation provided a strong
O
Ph
Ph
Ph
NMe2
OMe
2d
: 85%, 78% ee
: 90%, 70% ee
2i
: 85%, 72% ee
Me
O
Me
O
Me
O
MeO
Ph
Ph
Ph
O
Br
CO2Me
support for
a “chain-walking” of the alkyl rhodium
2hb: 75%, 76% ee
2f
: 82%, 76% ee
: 81%, 84% ee
intermediate. Notably, both methylene protons in 2a-D-b were
deuterium-labeled, suggesting that either proton may be
transferred to the adjacent carbon in the chain-walking process.
aSee supporting information for details. bThe reaction was carried out in 70 oC.
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Scheme 4. Mechanistic studies of homoallylic alcohol
isomerization
a) Deuterium-labelling studies to elucidate H-transfer pathways of homoallylic alcohols
Page 4 of 7
with both the carbonyl and alkene moieties in the enone
intermediate. Hydrometallation of the alkene by rhodium-
hydride then proceeds regioselectively to yield Rh-complex C.
At this stage, direct protonolysis of this alkyl rhodium species
is likely to be extremely slow. Alternatively, intermediate C
undergoes β-hydride elimination with either methylene proton
to form Rh-bound enone D, likely as a mixture of alkene
geometrical isomers. Hydrometallation of the enone in a
formally conjugate reduction manner then yields E, which
easily tautomerizes to enolate F. Protonation of F by the
conjugate acid of the base catalyst then produces the
enantioenriched product 2a and completes the catalytic cycle.
It is noteworthy that based on the crossover experiment result
(Scheme 4b), the rhodium catalyst should keep coordination
with the intermediates through B to E. The chain-walking
process including β-hydride elimination (C to D) and
hydrometallation (D to E) likely proceed in a stereo-rententive
fashion, making the hydrometallation step (B to C) enantio-
determining.15
1
2
3
4
5
6
7
8
2.5 mol % [Rh(COD)2]BF4
(95%)
L7
D
5 mol %
(95%)
D
HO
O
30 mol % DABCO
4Å MS, TBME, 50 oC, 48 h
Ph
Ph
Ph
Ph
1a-D-a
2a-D-a
85%, 85% ee
OH
O
(83%)
D
Me
same as above
Ph
Ph
Ph
H/D D/H
(42%)
Ph
9
D
D
(83%)
(42%)
2a-D-b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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30
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32
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48
49
50
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60
1a-D-b
80%, 84% ee
b) Cross-over experiment
(95%)
(95%)
D
D
HO
O
Ph
Ph
Ph
Ph
2a-D-a
82%, 70% ee
1a-D-a
2.5 mol % [Rh(COD)2]BF4
L7
5 mol %
+
+
30 mol % DABCO
4Å MS, toluene, 90 oC, 48 h
Me
O
Isomerization of bishomoallylic alcohols
OH
Ph
Ph
With the successful enantioselective isomerization of
homoallylic alcohols in hand, we were attracted to the redox
isomerization of more challenging substrates such as
bishomoallylic alcohols. If such processes can be realized,
chiral ketones and in turn various functional molecules that bear
a remote stereocenter can be accessed in a highly efficient and
economical manner. Such compounds will be much more
difficult to access in an enantioselective manner using
alternative method.
OMe
OMe
2e
1e
(±)-
91%, 70% ee
<2% others
A crossover experiment using 1a-D-a and 1e was also carried
out (Scheme 4b), with 2a-D-a and 2e obtained as the only
products and no detection of any crossover product. Not only
did this suggest that the rhodium complex maintained
coordination with the substrate structure during the
isomerization reaction, it also provided important insight on the
enantio-determining step of this process.
Table 2. Optimization of bishomoallylic alcohol
isomerizationa
Scheme 5. Proposed reaction pathway for isomerization of
homoallylic alcohols
5 mol % [Rh(COD)2]BF4
Me
10 mol % ligand
Ph
OH
Ph
Ph
Ph
OH
HCH2
O
40 mol % Ag2CO3
4Å MS, toluene, 100 oC, 24 h
H
H
O
4a
Ph
B:
Ph
1a
Ph
Ph
3a
(±)-
H
H
H
H
entry
ligand
L1
yield (%)b
ee (%)c
62
2a
[Rh]
1
2
3
4
5
6
7
8
95
90
L2
62
B:
HB
L4
80
20
HB
[Rh]
Ph
[Rh]
O
O
L5
mess
86
--
HCH2
Ph
H
H
L9
32
Ph
Ph
H
H
H
L10
L11
L12
89
14
A
F
92
16
oxidative kinetic
resolution step
85
<5
aReactions were carried out with 0.1 mmol of 3a, 5 mol % [Rh(COD)2]BF4, 10 mol %
chiral ligands, 40 mol % Ag2CO3 and 50 mg 4 Å MS in 0.5 mL of solvent. bIsolated
yield. cDetermined by chiral HPLC analysis.
H
O
HCH2
Ph
H
[Rh]
O
Ph
H
[Rh]
Ph
Ph
E
O
H
H
tBu
O
O
P
P
B
O
O
H3C
H3C
PPh2
PPh2
PPh2 PPh2
Me
PPh2
PPh2
H
H
enantio-
determining
hydrometallation
Me
tBu
H
HCH2
O
O
[Rh]
O
H2CH
Ph
[Rh]
L9:
(S)-SegPhos
L10:
(R,R)-DIOP
L12:
(S,S)-BDPP
L11:
(R,R',S,S')-DuanPhos
Ph
Ph
Ph
H
H
H
Alkenyl alcohol 3a was chosen as the model substrate for the
D
C
initial investigation (Table 2). Preliminary optimization proved
that a higher catalyst loading as well as higher reaction
temperature were essential for the reactivity. Based on that,
further screening of chiral ligands was carried out at 100 ℃.
This reaction showed a drastically different ligand effect from
the previous studies (Table 2). Several chiral ligands were able
to produce the desired isomerization product 4a in good yield
(entries 1-3 and 5-8). The use of simple BINAP led to the
Based on the above observations, we propose the reaction
pathway for the isomerization of homoallylic alcohols as shown
in Scheme 5. Under basic condition, 1a interacts with Rh-
catalyst and gets deprotonated to form the corresponding
rhodium alkoxide intermediate A. The following β-hydride
elimination resolves racemic 1a through selective oxidation and
produces intermediate B, in which Rh-center likely coordinates
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Journal of the American Chemical Society
highest selectivity, which remained less than satisfactory (62%
62% ee for direct isomerization of 3a to 4a). In this step, partial
kinetic resolution of 5a was also observed, but the selectivity
was less than satisfactory. We then focused our effort on the
two-step isomerization of bishomoallylic alcohols to deliver
valuable chiral ketones bearing a γ–stereocenter.
1
2
3
4
5
6
7
8
ee, entry 1). Further extensive optimization of reaction
parameters, unfortunately, led to no improvement of the
enantioselectivity.
The scope of this isomerization was probed (see section IV
in SI for details). Under this set of conditions, a range of
bishomoallylic alcohols can be efficiently converted to the
corresponding ketones in high yield, albeit with only 60-75%
ee. The higher temperature required for these reactions led to a
significant decrease in the enantioselectivity. In order to further
optimize the system, we decided to study the reaction kinetics
in more details.
The alkene isomerization step catalyzed by Rh/L7 is
summarized in Scheme 7. Various substituents either on the
aryl group on 1,1-disubstituted alkene or on the benzylic
alcohol side were well-tolerated. The internal alkene products
were obtained in uniformly high yield of 85-95% as a single
olefin isomer. It is important to note that ligand L7 proved
essential in this non-stereoselective step, possibly due to its
steric bulkiness and substitution pattern.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Sequential isomerization of bishomoallylic
alcohol 3a
The subsequent isomerization of trisubstituted alkenes 5 to
deliver the valuable chiral ketones 4 is shown in Scheme 8. The
optimal set of conditions worked uniformly well for all the
substrates (5a-5m) to yield aryl ketones 4a-4m bearing a γ-
stereocenter with high yield and high enantioselectivity.
Recrystallization of 4j improved its enantioselectivity to 96%
ee, X-ray analysis of which confirmed the absolute
configuration of this class of products. Aliphatic alcohol
substrates instead of benzylic ones were also examined. The
alkene isomerization step worked smoothly; however, the redox
isomerization step proved to be much less efficient. Minimal
conversion to the desired ketone products was observed.
a)
Me
L7
2.5 mol% [Rh(COD)2]BF4, 5 mol%
Ph
OH
Ph
Ph
Ph
20 mol% Ag2CO3
4Å MS, toluene, 50 oC, 24 h
OH
5a
3a
(±)-
(±)-
>95% conv.
>20:1 E:Z
b)
Me
Me
5 mol% [Rh(COD)2]BF4, 10 mol% (R)-BINAP
Ph
OH
Ph
Ph
Ph
40 mol% Ag2CO3
4Å MS, toluene, 100 oC, 24 h
O
4a
5a
(±)-
>95% conv.
80% ee
Scheme 8. Scope for isomerization of internal homoallylic
alcohols
An intriguing observation was made when the previous
optimal ligand L7 was used (Scheme 6a). No desired 4a was
observed at all; instead, 3a was cleanly converted to the
corresponding racemic internal homoallylic alcohol 5a as a
single geometric isomer. This represents a complete switch in
mechanism: this Rh/L7 catalyst promotes a simple alkene
isomerization of 3a instead of the desired redox isomerization.
It is interesting to note that 5a is also a homoallylic alcohol
analogous to 1. Compared to the 1,1-disubstituted alkene in 1,
the trisubstituted alkene in 5a is likely much more sterically
congested so no effective isomerization of 5a can occur with
the Rh/L7 catalytic system.
Me
Me
5 mol% [Rh(COD)2]BF4
R2
R2
10 mol% (R)-BINAP
R1
R1
OH
O
40 mol% Ag2CO3
4Å MS, toluene, 100 oC, 24 h
5
4
(±)-
R
Me
Me
Me
Ph
Ph
Ph
Ph
O
O
O
R
4f
86%, 82% ee
(R = Me):
4b
83%, 85% ee
75%, 80% ee
88%, 82% ee
(R = Me):
(R = OMe):
(R = Cl):
(R = F):
4a: 90%, 80% ee
4g
4h
4i
76%, 76% ee
(R = OMe):
4c
4d
4e
85%, 74% ee
(R = Cl):
91%, 78% ee
(R = F):
80%, 82% ee
Ph
Scheme 7. Scope for alkene isomerization of bishomoallylic
alcohol 3
Me
Ph
O
2.5 mol % [Rh(COD)2]BF4
Me
4j: 90%, 84% ee
96% ee after recrystalization
L7
5 mol %
R2
R2
4j
R1
R1
20 mol % Ag2CO3
4Å MS, toluene, 50 oC, 24 h
OH
OH
5
3
(±)-
Me
(±)-
Me
>20:1 E:Z
Me
Me
Me
Ph
Ph
Ph
R
Me
Me
Me
O
O
O
Ph
Ph
Ph
4l: 69%, 82% ee
4m: 80%, 76% ee
Ph
4k: 89%, 84% ee
OH
OH
OH
5a: 90%
R
5f
91%
95%
95%
(R = Me):
(R = OMe):
(R = Cl):
5b
5c
5d
5e
90%
(R = Me):
(R = OMe):
92%
We were intrigued by the nature of this two-stage
isomerization reactions and carried out deuterium-labeling
studies for the two orthogonal steps. As shown in Scheme 9a,
in the alkene isomerization step catalyzed by Rh/L7, the
deuterium stayed at the benzylic position in 5a-D, suggesting
that the hydroxyl group is not directly involved in this alkene
isomerization step. In contrast, enantioselective isomerization
of homoallylic alcohol 5a-D by Rh/BINAP produced 4a-D
bearing the same pattern as 1a-D-a, suggesting a similar
isomerization pathway as that in Scheme 5.
5g
5h
5i
87%
(R = Cl):
85%
85%
(R = F):
(R = F):
5j
90%
(R = Ph):
Me
Me
Me
Me
Me
Ph
Ph
Ph
OH
5k: 85%
OH
5l: 95%
OH
5m: 80%
Considering this significant ligand effect in bishomoallylic
alcohol isomerization, we decided to examine the isomerization
of 5a to 4a using the effective ligands in Table 2 (Scheme 6b).
The use of Rh/BINAP resulted in an efficient isomerization of
5a to 4a, and with a much-improved ee of 80% (compared to
From entry 1, Table 2, Rh/BINAP can promote a direct
isomerization of 3a to 4a. We were curious whether that
proceeds through a direct isomerization or a two-stage alkene
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Journal of the American Chemical Society
isomerization followed by redox isomerization. In order to
probe that, the isomerization of 3a-D was carried out using
Rh/BINAP. As the result, 4a-D bearing deuterium labelling at
both positions was obtained (Scheme 9b). This strongly
suggests that both mechanisms are operative using the
Page 6 of 7
alcohols, a two-step sequential isomerization was developed to
yield enantioenriched ketones with distant chiral center in good
yield and high enantioselectivity. Mechanistic studies including
deuterium-labelling experiments provided strong support for
the alkene isomerization, redox isomerization as well as a
chain-walking mechanism for this versatile catalytic system.
Current efforts in our laboratory are focused on the
development of other enantioselective redox isomerization
processes to deliver valuable compounds in an economical
fashion.
1
2
3
4
5
6
7
8
Rh/BINAP system: either
a
direct isomerization of
bishomoallylic alcohol resulting in deuterium labelling at the
terminal position (80%), or a sequential alkene isomerization
followed by redox isomerization leading to 15% deuterium
labelling in the tertiary position. While the two-stage
isomerization provides 4a-D in 80% ee, the direct isomerization
represents the major and likely less enantioselective reaction
pathway. The combination of two pathways then resulted in a
lower enantioselectivity for the formation of 4a.
9
Scheme 10. Probe of alkene isomerization
a) Alkene isomerization for other substrates
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.5 mol % [Rh(COD)2]BF4
Me
L7
5 mol %
Ph
Ph
Scheme 9. Mechanism studies for bishomoallylic alcohol
isomerization
Ph
Ph
20 mol % Ag2CO3
4Å MS, toluene, 50 oC, 24 h
O
O
7
6
80%
a) Deuterium-labelling studies of two isomerizations
E/Z >10
Me
conditions in Scheme 7
Ph
Ph
Me
Ph
Ph
same as above
L7
)
(Rh/
HO
D
Me
HO
D
Me
(95%)
(95%)
Ph
Ph
5a-D
85%
3a-D
8
9
90%
E/Z >10
(95%)
Me
Me
Ph
D
conditions in Scheme 8
Ph
Ph
Ph
Me
HO
D
(95%)
O
same as above
Ph
Ph
4a-D
5a-D
87%, 80% ee
10
3
4
11
b) Deuterium-labelling study of direct isomerization of to
95%
D
(80%)
Ph
(15%)
O
D
conditions in Scheme 8
Ph
Ph
Ph
b) Proposed alkene isomerization via allylhydride intermediate
HO
3a-D
D
(95%)
4a-D
90%, 62% ee
H
R
R
Ph
Ph
[Rh]
H
H
H
Exploration of the alkene isomerization
To further probe the substrate requirement for the alkene
isomerization step, the corresponding alkenyl ketone 6 as well
as a simple 1,1-disubstituted alkene 8 were subjected to the
isomerization conditions (Scheme 10). Interestingly, high
efficiency could be obtained for both isomerization reactions.
These results suggest that this transformation requires no
hydride source or any polar functionality to proceed. An
exocyclic alkene 10 was also examined under the standard
conditions. Interestingly, a facile reaction took place to deliver
exclusively the endocyclic alkene 11, in which the alkene is not
in conjugation with the aryl substituent. This strongly suggests
that the isomerization is under kinetic control. Based on the
ample literature precedents on transition metal-catalyzed alkene
isomerization,16-17 we propose that this reaction likely proceeds
through an π-allylhydride mechanism as illustrated in Scheme
10b instead of metal-hydride insertion.
H
[Rh]
[Rh]
R
R
Ph
Ph
H
H
H
H
[Rh]
R
Ph
H
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
CONCLUSIONS
In conclusion, we have developed an unprecedented and
versatile rhodium-catalyzed enantioselective isomerization of
homoallylic and bishomoallylic secondary alcohols. This
catalytic redox-neutral process does not require any
stoichiometric reagent and generates no waste at all en route to
valuable chiral ketone products. For the homoallylic alcohols,
an oxidative kinetic resolution of the racemic substrates is
followed by enantioselective reduction to deliver ketones
bearing a β- stereocenter in a stereoconvergent fashion with
high level of enantiopurity. In the case of bishomoallylic
*zhaoyu@nus.edu.sg; *liuschop@swu.edu.cn
ORCID
Yu Zhao: 0000-0002-2944-1315
Tang-Lin Liu: 0000-0002-7318-4520
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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Journal of the American Chemical Society
Chem. Soc. 2009, 131, 10852−10853. (j) Masarwa, A.; Marek, I. Chem.
We are grateful for the financial support provided by the National
University of Singapore, the Ministry of Education (MOE) of
Singapore (R-143-000-613-112), A*STAR SERC (R-143-000-
648-305) and Chinese Fundamental Research Funds for the Central
Universities (XDJK2018C044).
Eur. J. 2010, 16, 9712−9721. (k) Kochi, T.; Hamasaki, T.; Aoyama, Y.;
Kawasaki, J.; Kakiuchi, F. J. Am. Chem. Soc. 2012, 134, 16544−16547. (l)
Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338,
1455−1458. (m) Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S.
J. Am. Chem. Soc. 2013, 135, 6830−6833. (n) Xu, L.; Hilton, M. J.; Zhang,
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