Isomerization-Asymmetric Hydrogenation Sequence Converting Racemic β-Ylidenecycloalkanols into Stereocontrolled β-Substituted Cycloalkanols Using a Ru Catalytic System with Dual Roles

Article abstract of DOI:10.1002/adsc.201901269

Racemic β-ylidenecycloalkanols were transformed into the cis-β-substituted cycloalkanols with high enantio- and diastereoselectivities through an isomerization-asymmetric hydrogenation sequence with the (4,4′-bi-1,3-benzodioxole)-5,5′-diylbis[di(3,5-xylyl)phosphine (DM-Segphos)/2-dimethylamino-1-phenylethylamine (DMAPEN)-ruthenium(II) catalyst; such transformation hardly proceeded by single-step asymmetric hydrogenation. The reaction was usually carried out with a substrate-to-catalyst molar ratio of 500 under 4 to 10 atm of H₂ to afford the products in cis/trans ratio up to 99:1 and 98% ee. Mechanistic experiments suggested that this catalytic system reversibly formed two reactive species, types (I) and (II), through a ruthenacyclic amide intermediate. The amide complex and allylic alcohol reacted to afford the allylic alkoxide complex with partial or full removal of diamine (type (I)), and this type (I) complex catalyzed isomerization of the allylic alcohols into the racemic α-substituted ketones. The RuH₂ complex with chelation of diamine (type (II)) formed by reaction of the amide complex and hydrogen promoted asymmetric hydrogenation of racemic α-substituted ketone into the stereocontrolled β-substituted cycloalkanols through dynamic kinetic resolution. (Figure presented.).

Full text of DOI:10.1002/adsc.201901269

Title: Isomerization–Asymmetric Hydrogenation Sequence Converting
Racemic β-Ylidenecycloalkanols into Stereocontrolled β-
Substituted Cycloalkanols Using a Ru Catalytic System with Dual
Roles
Authors: Noriyoshi Arai, Yuki Okabe, and Takeshi Ohkuma
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10.1002/adsc.201901269
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201901269
Isomerization–Asymmetric Hydrogenation Sequence
Converting Racemic -Ylidenecycloalkanols into
Stereocontrolled -Substituted Cycloalkanols Using a Ru
Catalytic System with Dual Roles
Noriyoshi Arai,a Yuki Okabe,b and Takeshi Ohkumaa,*
a
Division of Applied Chemistry and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo,
Hokkaido 060-8628, Japan
Phone: (+81)-11-706-6599; Fax: (+81)-11-706-6598
E-mail: ohkuma@eng.hokudai.ac.jp
Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
reactions is difficult. We expected that a sequential
two-step transformation could be realized by using a
catalytic system that reversibly forms two active
species. In support of this idea, we recently reported
double asymmetric hydrogenation of ,-
disubstituted ,-unsaturated ketones into the -
substituted secondary alcohols in high enantio- and
diastereoselectivities using a Ru catalytic system with
dual roles.[2] Each of the two transformations, namely,
carbonyl hydrogenation of the enones into the allylic
alcohols and subsequent alkene hydrogenation into
the saturated alcohols, was promoted by the different
catalytic species reversibly forming with each other.
This successful result prompted us to investigate a
Ru catalytic system that promotes two sequential
reactions. The concept of this catalytic system is
shown in Scheme 1a. Both catalyst type (I) and type
(II) are reversibly formed via the ruthenacyclic amide
complex. The reaction of the amide complex with an
allylic alcohol provides the allylic alkoxide complex
(catalyst type (I)) through removal of the
dialkylamino group. Several Ru allylic alkoxides are
known to function as catalytic species in the
isomerization of allylic alcohols through a 1,3-
hydrogen shift.[3] On the other hand, when the amide
complex reacts with H2, the hydride complex
(catalyst type (II)) is obtained. We and other groups
have reported the hydrogenation of ketones catalyzed
by this type of Ru complexes.[4,5]
Abstract.
Racemic
-ylidenecycloalkanols
were
transformed into the cis--substituted cycloalkanols with
high enantio- and diastereoselectivities through an
isomerization–asymmetric hydrogenation sequence with
the
(4,4’-bi-1,3-benzodioxole)-5,5’-diylbis[di(3,5-
xylyl)phosphine
(DM-Segphos)/2-dimethylamino-1-
phenylethylamine (DMAPEN)–ruthenium(II) catalyst; such
transformation hardly proceeded by single-step asymmetric
hydrogenation. The reaction was usually carried out with a
substrate-to-catalyst molar ratio of 500 under 4 to 10 atm of
H2 to afford the products in cis/trans ratio up to 99:1 and
98% ee. Mechanistic experiments suggested that this
catalytic system reversibly formed two reactive species,
types (I) and (II), through
a ruthenacyclic amide
intermediate. The amide complex and allylic alcohol
reacted to afford the allylic alkoxide complex with partial
or full removal of diamine (type (I)), and this type (I)
complex catalyzed isomerization of the allylic alcohols into
the racemic -substituted ketones. The RuH2 complex with
chelation of diamine (type (II)) formed by reaction of the
amide complex and hydrogen promoted asymmetric
hydrogenation of racemic -substituted ketone into the
stereocontrolled -substituted cycloalkanols through
dynamic kinetic resolution.
Keywords: allylic alcohols; asymmetric catalysis; dynamic
kinetic resolution; hydrogenation; isomerization;
ruthenium; sequential reaction
Then we targeted to achieve a transformation of
racemic allylic alcohols (±)-1 into the chiral -
substituted alcohols 2 with high enantio- and
diastereoselectivities through an isomerization–
asymmetric hydrogenation sequence as shown in
Scheme 1b. The isomerization of (±)-1 into the
racemic -substituted ketones (±)-4 could be
promoted by the catalyst type (I), and then
Optically active metal complexes have made a
remarkable contribution to the progress of
asymmetric catalytic reactions.[1] Usually, these
complexes
are
appropriately
designed
as
(pre)catalysts for specifically targeted reactions. The
chemical features of the substrates are also significant
factors in such design. Therefore, development of a
catalyst that can efficiently promote multi-step
1
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10.1002/adsc.201901269
Advanced Synthesis & Catalysis
Scheme 2. Previous Works on the Formation of Optically
Active Saturated Alcohols through Asymmetric (Transfer)
Hydrogenation of Racemic Allylic Alcohols.
Scheme 1. Isomerization–Asymmetric Hydrogenation
Sequence from Racemic Secondary Allylic Alcohols to the
Optically Active Saturated Alcohols Using a Ru Catalyst
with Dual Roles.
We commenced screening the reaction conditions
for the isomerization–asymmetric hydrogenation
asymmetric hydrogenation of (±)-4 into the
optically active alcohols 2 could be catalyzed by the
species (II). The first reaction is regarded as a
functional group transformation (FGT) from a C=C
bond to a C=O bond without stereocontrol. The
sequence
using
racemic
(E)-2-
benzylidenecyclohexanol ((±)-1a) as
a
typical
substrate (Table 1). RuCl2[(S)-dm-segphos][(S)-
dmapen] ((SP,SN)-3a) was the first choice for a
catalyst precursor because it showed excellent
efficiency for the double asymmetric hydrogenation
of ,-disubstituted ,-unsaturated ketones into the
-substituted secondary alcohols in the presence of a
base.[2,11] When the reaction of (±)-1a was conducted
with (SP,SN)-3a at an S/C of 300 in a base (KOH)-
containing iPrOH under 20 atm of H2 in 24 h, the
desired (1R,2R)-2-benzylcyclohexanol ((1R,2R)-2a)
was quantitatively obtained in 82% ee with a
cis/trans ratio of 21:1 (Table 1, entry 1). It is
noteworthy that the complete conversion was
achieved using a less reactive trisubstituted alkenyl
compound.[10] Replacement of iPrOH with tBuOH as
a solvent and reduction of H2 pressure from 20 atm to
8 atm increased both the enantioselectivity and the
cis/trans ratio of 2a (entries 2 and 3). Interestingly,
use of the diastereomeric (S)-DM-Segphos/(R)-
DMAPEN–Ru(II) complex ((SP,RN)-3b) gave an even
better result (entry 4). The stereoselectivity was also
increased in a 4:1 tBuOH–Et3N mixed solvent (entry
5). The high catalytic activity of a (SP,RN)-3b–KOH
system completed the transformation in 2 h under 4
atm of H2 (entry 6). The reaction with an S/C of 500
in 4 h quantitatively afforded 2a in 97% ee with a
cis/trans ratio of 63:1 (entry 7). Complete conversion
of this transformation with an S/C of 1000 was
achieved by prolongation of the reaction time to 24 h
with maintenance of high stereoselectivity (entry 8).
The Segphos/DMAPEN–Ru(II) complex ((SP,RN)-3c)
with a less bulky diphosphine ligand was much less
active for this reaction (entry 9). Interestingly,
RuCl2[(S)-dm-segphos](dmf)n ((S)-3d) without a
diamine ligand feebly promoted even the
second step controls both
enantio- and
diastereoselection through the dynamic kinetic
resolution (DKR).[6,7] This two-step sequential
reaction could realize asymmetric hydrogenation of
racemic allylic alcohol into the saturated alcohol with
formal dynamic kinetic resolution (FDKR), which is
hardly achieved by the single-step transformation.
Usually asymmetric hydrogenation of racemic
secondary allylic alcohol is conducted through
(static) kinetic resolution (KR) to give the
enantiomerically enriched saturated alcohol and the
unreacted allylic alcohol (Scheme 2a).[8] The yield of
the desired optically pure product or the substrate is
at most 50% in principle. The enantiomeric purity of
the compounds depends on the conversion of the
reaction; therefore, the hydrogenation should be
stopped at the appropriate conversion, and then the
target compound should be separated from the
resulting mixture.
The sequential reactions of isomerization of
racemic secondary allylic alcohol followed by
asymmetric transfer hydrogenation of the resulting
ketone with chiral Ru catalysts have been reported
(Scheme 2b).[9] The racemic allylic alcohol was
converted to the saturated alcohol in up to 93% ee
with the use of EtOH or iPrOH as a reducing agent.
More than 2 mol% of catalyst (substrate-to-catalyst
molar ratio (S/C) of 50) was employed to advance the
reaction at a reasonable rate. The reaction was
applicable only to aryl vinyl carbinol, a mono-
substituted alkene, because the isomerization of the
multi-substituted alkenyl compounds was sluggish.[10]
2
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10.1002/adsc.201901269
Advanced Synthesis & Catalysis
Table 1. Isomerization–Asymmetric Hydrogenation
Sequence from (±)-1a[a]
Table 2. Isomerization–Asymmetric Hydrogenation
Sequence from (±)-1[a]
Entry 3[b] S/C[c] H2
[atm]
300 20
300 20
Solvent Time dr[d] ee[e]
Entry
1
S/C[b] H2
[atm] [h]
Time Yield
[%][c]
dr[d] ee[e]
[%]
[h]
[%]
1[f]
2
iPrOH
24
21:1 82
3a
3a
3a
3b
3b
3b
3b
3b
3c
3d
1
2
3
4
5
6
7
8
500
500
500
500
500
500
500
500
500
500
400
300
500
4
4
4
4
10
4
10
10
10
10
10
20
4
4
4
7
4
4
>99(96) 63:1 97
>99(95) 77:1 98
>99(97) 99:1 97
>99(97) 54:1 97
99(92) 55:1 95
>99(95) 57:1 96
98(82) 16:1 94
>99(96) 77:1 95
89(79) 17:1 95
99(96) 77:1 95
94(78) 14:1 76
99(92) 24:1 81
>99(94) 38:1 88
1a
1b
1c
1d
1e
1f
1g
1h
1i
tBuOH 24
tBuOH 24
tBuOH 24
25:1 90
32:1 92
82:1 95
90:1 96
53:1 97
63:1 97
47:1 96
3
4
5
6
300
300
300
300
500
8
8
8
4
4
A[g]
A[g]
A[g]
A[g]
A[g]
A[g]
24
2
4
24
2
2
9
4
7
8
1000 20
32
8
20
17
12
12
9[h]
300
300
4
4
nd
nd
nd
nd
9[f]
10
11
12
10[i]
1j
1k
1l
[a]
Unless otherwise stated, reactions were conducted at
30 °C with allylic alcohol 1a in solvent containing Ru
complex 3 and KOH. 2a was obtained in >99% yield in
13
1m
[b]
entries 1–8. nd: not determined.
3a: (SP,SN)-3a. 3b:
[a]
Unless otherwise stated, reactions were conducted at
(SP,RN)-3b. 3c: (SP,RN)-3c. 3d: (S)-3d. [c] Substrate/catalyst
(3) molar ratio. [d] cis-2a/trans-2a ratio determined by GC
analysis. [e] Data for cis-2a determined by HPLC analysis
30 °C with allylic alcohol 1 in a 4:1 mixture of tBuOH and
[b]
Et3N containing (SP,RN)-3b and KOH.
Substrate
(1)/catalyst (3b) molar ratio. [c] Yield of 2 determined by
1H NMR analysis. The yield of the isolated cis product is
[f]
[g]
on a chiral stationary phase. Reaction at 25 °C.
Reaction in a 4:1 mixture of tBuOH and Et3N. 2a (8%)
and 4a (17%) were obtained. 2a (2%) and 4a (7%) were
obtained.
A:
[h]
[d]
given in parenthesis. cis-2/trans-2 ratio determined by
[i]
1H NMR analysis. [e] Data for cis-2 determined by HPLC
[f]
analysis on a chiral stationary phase.
compounds were observed.
Undefined
isomerization of 1a under the reaction conditions
(entry 10).
was also suitable for this reaction (entry 9).
Notably, an alkylidene compound 1j was successfully
converted to the desired product 2j (entry 10). The
benzylidenecyclohexanol with a fused benzene ring
1k was a difficult substrate to convert with high
enantioselectivity, and thus the saturated alcohol 2k
was obtained in 76% ee, although the cis-selectivity
was still high (entry 11). The ring size of the substrate
affected the reaction rate and/or the enantioselectivity.
The reaction of the benzylidenecyclopenatanol
derivative 1l required 20 atm of H2 with an S/C of
300 to afford cis-2l in 81% ee (entry 12). The
cycloheptanol analogue 1m was smoothly converted
to cis-2m in 88% ee under 4 atm of H2 with an S/C of
500 (entry 13).
When the reaction of (±)-1a was carried out with
the (SP,RN)-3b–KOH catalyst (S/C = 300) under 1.5
atm of H2 for 0.5 h, the racemic -substituted ketone
(±)-4a was obtained as the major product in 88%
yield (Scheme 3, equation 1). The isomerization of
hindered tri-substituted alkene (±)-1a was sufficiently
A series of racemic (E)-2-benzylidenecyclohexanol
derivatives, 1a–1g, was applied to the transformation
catalyzed by the (SP,RN)-3b–KOH system with an S/C
of 500 under 4–10 atm of H2 (Table 2, entries 1–7).
The reaction of 2’-methyl- and 3’,5’-dimethylphenyl
derivatives, 1b and 1c, under 4 atm of H2
quantitatively afforded the saturated alcohols, 2b and
2c, in even higher enantiomeric purity (97%–98%)
with a higher cis/trans ratio (77:1–99:1) than
observed in the reaction of 1a (entries 1–3). The
benzylidene alcohols with electron-donating methoxy
and methylenedioxy moieties, 1d and 1e, were
converted with comparably high stereoselectivity
(entries
4
and 5). Substitution of electron-
withdrawing chloro and bromo groups (1f and 1g)
was allowed in this transformation (entries 6 and 7).
It took 32 h for complete conversion of 2’-
naphthylmethylidene compound 1h even under 10
atm of H2, but the stereoselective outcome was
excellent (entry 8). The furylmethylidene substrate 1i
3
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10.1002/adsc.201901269
Advanced Synthesis & Catalysis
Scheme 4. Plausible Mechanism of the Isomerization–
Hydrogenation Sequential Reaction of (±)-1a by a Ru
catalytic system with Dual Roles. P—P = (S)-DM-
SEGPHOS; X, Y = H or K; NH2—NMe2 = (R)-DMAPEN.
Scheme 3. Experiments for Mechanistic Consideration
(S/C = 300).
coordination of DMAPEN) and the DM-Segphos–
Ru(II) complex 3d without a diamine ligand were
much less reactive than 3b (entries 9 and 10). These
observations suggested that the DMAPEN ligand was
required to form the catalytic species even for the
isomerization of the allylic alcohol. However,
liberation of the NMe2 group of DMAPEN providing
a vacant coordination site was necessary to promote
the isomerization. Notably, no isomerization was
observed without pressure of H2, suggesting that the
isomerization catalyst has a RuH partial structure
(equation 6).
A plausible mechanism for the isomerization–
asymmetric hydrogenation sequence is shown in
Scheme 4. The Ru complex (SP,RN)-3b with a
potassium base is converted to the RuH amide
complex A in the presence of H2, and it acts as a
common species for catalytic cycles (I) and (II). The
amine proton can be reversibly replaced with a
potassium cation. Catalytic cycle (I) for isomerization
of the allylic alcohol: The amide complex A reacts
with the racemic allylic alcohol (±)-1a to give the
alkoxide complex B, which reversibly forms an
olefin-coordinated species C with partial or full
removal of diamine DMAPEN.[2,12,13] The
coordination stability of the diamine depends on the
steric hindrance around the NMe2 moiety.[14]
faster than the hydrogenation of ketone (±)-4a
under these conditions. The racemic ketone (±)-4a
was hydrogenated under the regular conditions (4 atm
H2) to quantitatively afford (1R,2R)-2a in almost the
same enantio- and diastereoselectivities through DKR
(equation 2). These results suggest that the
transformation of (±)-1a into (1R,2R)-2a consisted of
two-step sequential reactions of isomerization and
asymmetric hydrogenation as we expected. When the
reaction was carried out by using the deuterated
substrate at the C1 position (±)-1ad1 under the regular
conditions, the 55% deuterated product at the
benzylic position (1R,2R)-2ad1 was quantitatively
obtained with comparably high stereoselectivity
(equation 3). A separate investigation revealed that
the ketonic intermediate (±)-4ad1 was deuterated in
56% at the benzylic position (equation 4). These
results suggested that the H–D scrambling pathway
exists at the isomerization (1,3-H shift) step of 1a
into 4a.
The reaction using 3b with an addition of 40 equiv
of DMAPEN to Ru remarkably decreased the
reaction rate (equation 5). As shown in Table 1, both
the sterically less hindered Segphos/DMAPEN–
Ru(II) complex 3c (leading to the more stable
4
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10.1002/adsc.201901269
Advanced Synthesis & Catalysis
Figure 1. Structure of RuH2 species H derived from (SP,RN)-3b and diastereomeric TS-models in the hydrogenation of (±)-
4a through DKR (catalytic cycle (II)). Some aromatic groups and substituents in the TSs are omitted for clarity. X, Y = H
or K. Ar = 3,5-(CH3)2C6H3.
-Hydride elimination in species C gives a RuH2
complex D coordinated with an unsaturated ketone.
The 3-oxaallyl complex E is formed through hydride
migration from the Ru center to the -carbon of the
enone. H–D scrambling at the benzylic position as
observed by using a deuterated substrate 1ad1
(equations 3 and 4) occurs during this process,
because the two hydrides on Ru are respectively
derived from the -position of the alcohol 1a and
gaseous H2.[15] Removal of the saturated ketone (±)-
4a through keto–enol tautomerization, and reform of
the chelate structure of DMAPEN regenerates A.
Catalytic cycle (II) for hydrogenation of the saturated
ketone based on the previous mechanistic
investigations:[5,16] The amide complex A with H+ or
K+ reversibly forms the cationic species F, which is
below), and the carbonyl hydrogenation by the bulky
RuH2 species H shown in Scheme 4 occurs from the
equatorial direction.[18] The less reactive (S)-4a was
hydrogenated after conversion to the R isomer.
Therefore, cis-(1R,2R)-2a is selectively obtained
among four possible stereoisomers from (±)-4a
through DKR.
Figure 1 illustrates the molecular models of the
active RuH2 complex H derived from an (SP,RN)-3b–
KOH catalytic system and plausible diastereomeric
transition states (TSs) TSR4 and TSS4 in the
hydrogenation of (±)-4a with an equatorial
conformation based on the previous related
studies.[5,16,19] (R)-DMAPEN forms a -chelate
structure due to the preferential equatorial placement
of the phenyl substituent. The reaction proceeds
through the cyclic TS, TSR4 or TSS4 in which the
carbonyl hydride reduction with the RuH (blue
broken lines) is promoted by interaction with the
axially oriented proton or K+ on the diamine (green
broken line).[16f,g] The TSS4 suffers steric repulsion
between the equatorial-oriented benzyl group of (S)-
4a and the skewed chelate ring of the DMAPEN in
the catalyst. In contrast, TSR4 avoids such significant
repulsion because the benzyl moiety of (R)-4a enters
the channel formed by the Arax–P–Areq (Ar = 3,5-
(CH3)2C6H3) structure of DM-Segphos. Thus, (R)-4a
is preferably hydrogenated over the S isomer.
known to be detectable in alcoholic solvent.[16b,17]
F
and H2 reversibly afford G, and the following
deprotonation with a base gives active (S)-DM-
Segphos/(R)-DMAPEN–RuH2 complex H. The
racemic ketone (±)-4a is reduced by H through DKR,
affording the alcoholic product (1R,2R)-2a with
reformation of amide complex A. These species were
suggested to interact with the alkoxide produced by
the hydrogenation of acetophenone (an arimatic
ketone) in 2-propanol catalyzed by a related
diphosphine/diamine–Ru(II) complex.[16f,g]
Two
enantiomers
of
an
-substituted
cyclohexanone 4a are reversibly formed with each
other in the presence of an alkaline base (Supporting
Information, Scheme SI(1)).[6] The (SP,RN)-3b–KOH
catalyst kinetically selects (R)-4a with the stable chair
conformer possessing an equatorial benzyl group (see
In conclusion, we have reported herein the
transformation of racemic -ylidenecycloalkanols
into the saturated cis--substituted cycloalkanols with
high enantio- and diastereoselectivities through an
isomerization–asymmetric hydrogenation sequence
5
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10.1002/adsc.201901269
Advanced Synthesis & Catalysis
by using
a
catalytic system of the DM-
[1] See for example: a) Science of Synthesis:
Stereoselective Synthesis, Vols. 1 to 3 (Eds.; J. G. de
Vries, G. A. Molander, P. A. Evans), Thieme, Stuttgart,
2011; b) Comprehensive Chirality, Vols. 4 and 5 (Eds.:
E. M. Carreira, H. Yamamoto, M. Shibasaki, K.
Maruoka), Elsevier, Amsterdam, 2012.
Segphos/DMAPEN–Ru(II) complex with KOH,
which is hardly achieved by traditional single-step
asymmetric hydrogenation. In most cases the reaction
with an S/C of 500 under 4 to 10 atm of H2 smoothly
proceeded to yield the products in cis/trans ratio of
14:1 to 99:1 and 76% to 98% ee. The mechanistic
experiments suggested that this system reversibly
forms two catalytic species, C (type (I)) and H (type
(II)), via a common intermediate of ruthenacyclic
amide complex A shown in Scheme 4. Namely, the
amide complex A reacts with an allylic alcohol to
form the allylic alkoxide complex C through partial
or full removal of the diamine DMAPEN, which
promotes isomerization (1,3-H shift) of the allylic
alcohol into the racemic -substituted ketone
(catalytic cycle (I)). Reaction of A with H2 affords the
RuH2 complex H with chelation of DMAPEN, which
catalyzes asymmetric hydrogenation of racemic -
substituted ketone into the stereoregulated -
substituted cycloalkanol through DKR (catalytic
cycle (II)). The mode of stereoselection in the
hydrogenation of (±)-4a into (1R,2R)-2a is also
proposed.
[2] N. Arai, H. Satoh, R. Komatsu, T. Ohkuma, Chem.
Eur. J. 2017, 23, 8806–8809.
[3] Reviews for isomerization of allylic alcohols: a) R. C.
van der Drift, E. Bouwman, E. Drent, J. Organomet.
Chem. 2002, 650, 1–24; b) R. Uma, C. Crévisy, R.
Grée, Chem. Rev. 2003, 103, 27–51; c) G. C. Fu in
Modern Rhodium-Catalyzed Organic Reactions (Ed.: P.
A. Evans), Wiley-VCH, Weinheim, 2005, pp 79–91; d)
V. Cadierno, P. Crochet, J. Gimeno, Synlett 2008,
1105–1124; e) L. Mantilli, C. Mazet, Chem. Lett. 2011,
40, 341–344; f) N. Ahlsten, A. Bartoszewicz, B.
Martín-Matute, Dalton Trans. 2012, 41, 1660–1670; g)
P. Lorenzo-Luis, A. Romerosa, M. Serrano-Ruiz, ACS
Catal. 2012, 2, 1079–1086; h) D. Cahard, S. Gaillard,
J.-L. Renaud, Tetrahedron Lett. 2015, 56, 6159–6169.
[4] Selected reviews: a) T. Ohkuma, R. Noyori in The
Handbook of Homogeneous Hydrogenation, Vol. 3
(Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH,
Weinheim, 2007, pp. 1105–1163; b) N. Arai, T.
Ohkuma in Science of Synthesis: Stereoselective
Synthesis 2; Stereoselective Reactions of Carbonyl and
Imino Groups (Ed.: G. A. Molander), Thieme, Stuttgart,
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Experimental Section
Typical Procedure for the Isomerization–Asymmetric
Hydrogenation Sequence of 1a with (SP,RN)-3b
The ruthenium complex (SP,RN)-3b (1.3 mg, 1.2 μmol),
allylic alcohol 1a (117.4 mg, 0.624 mmol), and a Teflon-
coated stirring bar were placed in a 100 mL glass autoclave
that had been filled with argon. A mixture of 0.25 M KOH
in tBuOH (0.10 mL), tBuOH (2.4 mL), and Et3N (0.60
mL) that had been degassed by three freeze-thaw cycles
was transferred into the autoclave through a Teflon
cannula. The autoclave was then pressurized with H2 gas
(4 atm), and the solution was stirred vigorously at 30 °C
for 4 h. After careful release of the hydrogen, the
diastereomeric ratio of 2a was determined by GC analysis.
Column, SUPELCOWAX (0.25 mm × 30 m, DF = 0.25
μm); carrier, He (100 kPa); oven temp, 80 °C, held for 2
min, heated to 240 °C at a rate of 10 °C min–1, held for 7
min; tR of cis-2a, 19.87 min (98.5%); tR of trans-2a, 20.16
min (1.5%). After concentration of the solution,
purification by silica gel column chromatography
[5] Accounts: a) T. Ohkuma, N. Arai, Chem. Rec. 2016,
16, 2801–2819; b) T. Ohkuma, N. Kurono, N. Arai,
Bull. Chem. Soc. Jpn. 2019, 92, 475–504.
[6] For asymmetric hydrogenation of -alkyl and -aryl
cycloalkanones
with
diphosphine/diamine–Ru(II)
catalysts through DKR, see: a) T. Ohkuma, H. Ooka, M.
Yamakawa, T. Ikariya, R. Noyori, J. Org. Chem. 1996,
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Cheng, H.-F. Duan, B. M. Fan, L.-X. Wang, Q.-L.
Zhou, J. Org. Chem. 2005, 70, 2967–2973.
(hexane:ethyl acetate
=
9:1) gave (1R,2R)-2-
benzylcyclohexan-1-ol (2a) (114.2 mg, 0.600 mmol, 96%).
The enantiomeric excess of 2a was determined by HPLC
analysis. Column, CHIRALCEL OD-H (4.6 × 250 mm);
eluent, hexane:2-PrOH = 95:5; flow, 1.0 mLmin–1;
detector : UV 254 nm; column temp, 30 °C; tR of (1R,2R)-
2a, 6.26 min (98.5%); tR of (1S,2S)-2a, 8.19 min (1.5%),
97% ee. The procedures and chemical properties of
products in detail are described in the Supporting
Information.
[7] For stereoselective synthesis through DKR, see: R.
Noyori, M. Tokunaga, M. Kitamura, Bull. Chem. Soc.
Jpn. 1995, 68, 36–56.
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Acknowledgements
This work was supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (No. 19H02706).
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7
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Advanced Synthesis & Catalysis
COMMUNICATION
Isomerization–Asymmetric Hydrogenation
Sequence Converting Racemic -
Ylidenecycloalkanols into Stereocontrolled -
Substituted Cycloalkanols Using a Ru Catalytic
System with Dual Roles
Adv. Synth. Catal. Year, Volume, Page – Page
Noriyoshi Arai, Yuki Okabe, and Takeshi
Ohkuma*
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