Kinetic Resolution of Allylic Alcohol with Chiral BINOL-Based Alkoxides: A Combination of Experimental and Theoretical Studies

Article abstract of DOI:10.1021/jacs.8b12796

The development and characterization of enantioselective catalytic kinetic resolution of allylic alcohols through asymmetric isomerization with chiral BINOL derivatives-based alkoxides as bifunctional Br?nsted base catalysts were described in the study. A number of chiral BINOL derivatives-based alkoxides were synthesized, and their structure-enantioselectivity correlation study in asymmetric isomerization identified a promising chiral Br?nsted base catalyst, which afforded various chiral secondary allylic alcohols (ee up to 99%, S factor up to >200). In the mechanistic study, alkoxide species were identified as active species and the phenol group of BINOL largely affected the high reactivity and enantioselectivity via hydrogen bonding between the chiral Br?nsted base catalyst and substrates. The strategy is the first successful synthesis strategy of various chiral secondary allylic alcohols through enantioselective transition-metal-free base-catalyzed isomerization. The applicability of the strategy had been demonstrated by the synthesis of the bioactive natural product (+)-veraguensin.

Full text of DOI:10.1021/jacs.8b12796

Subscriber access provided by University of South Dakota
Article
Kinetic Resolution of Allylic Alcohol with Chiral BINOL-based
Alkoxides: A Combination of Experimental and Theoretical Studies
Yidong Liu, Song Liu, Dongmei Li, Nan Zhang, Lei Peng, Jun Ao, Choong Eui Song, Yu Lan, and Hailong Yan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Dec 2018
Downloaded from http://pubs.acs.org on December 18, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Kinetic Resolution of Allylic Alcohol with Chiral BINOL-based
Alkoxides: A Combination of Experimental and Theoretical Studies
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
Yidong Liu,†,‡ Song Liu,#,‡ Dongmei Li,† Nan Zhang,† Lei Peng,† Jun Ao,† Choong Eui Song,§ Yu
Lan,*,# and Hailong Yan*,†
†Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences
and #School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
§Department of Chemistry, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi 440-746, Korea
ABSTRACT: The development and characterization of enantioselective catalytic kinetic resolution of allylic alcohols
through asymmetric isomerization with chiral BINOL derivatives-based alkoxides as bifunctional Brønsted base catalyst
were described in the study. A number of chiral BINOL derivatives-based alkoxides were synthesized and their structure-
enantioselectivity correlation study in asymmetric isomerization identified a promising chiral Brønsted base catalyst,
which afforded various chiral secondary allylic alcohols (ee up to 99%, s factor up to >200). In the mechanistic study,
alkoxide species were identified as active species and the phenol group of BINOL largely affected the high reactivity and
enantioselectivity via hydrogen bonding between the chiral Brønsted base catalyst and substrates. The strategy is the first
successful synthesis strategy of various chiral secondary allylic alcohols through enantioselective transition-metal-free
base catalyzed isomerization. The applicability of the strategy had been demonstrated by the synthesis of bioactive
natural product (+)-veraguensin.
Scheme 1. Design of a Brønsted Basic Bifunctional
Catalyst Containing Phenolate Anion as a Brønsted
Base Moiety
INTRODUCTION
Catalysis is one of the central themes in science.
Therefore, the design and application of new, efficient
types of catalysts are of fundamental importance.1
Recently, the development of a new type of chiral
Brønsted base catalyst has received considerable attention
since a range of important classes of organic reactions can
be promoted with a Brønsted base2. Brønsted bases can
accept a hydrogen (or proton) from an acidic source or
equivalent activated species. This proton transfer forms
the basis of the key activation component in the
formations of new chemical bonds. However, the intrinsic
nature of the ion pairing complex of Brønsted bases can
become a challenge in stereoinduction, especially when
the starting reagents are achiral. The catalyst with a
Brønsted base moiety and another site with hydrogen-
donating characteristics becomes a bifunctional Brønsted
base catalyst3 that can overcome the stereoinduction
problems. In such a way, the Brønsted base catalyst has
gained the ability to stabilize both nucleophile and
electrophile in the transition state. In the past two
decades, new bifunctional Brønsted base catalysts,
especially the catalysts containing nitrogen as a Brønsted
base moiety and hydrogen bonding moieties (XH group),
have been significantly improved due to mechanism
studies and insightful observations about Brønsted base
and hydrogen bond donor activation of substrates
(Scheme 1a).
a. Classical bifunctional catalysis
b. Our concept
chiral
chiral
scaffold
scaffold
phenolate
anion
X
H
X
H
hydrogen
bond donor
hydrogen
bond donor
NR2
O
M
tertiary
amine
Challenges:
stability ?
activity ?
H
H
X
X
substrate
substrate
selectivity ?
c. Previous work
d. This work
I
bulky
substituent
I
Ph
O
Ph
I
I
O
O
O
M
O
O
O
HO
M
O
O
O
O
A
H
I
H
I
I
I
M
A
= K, Cs / = F, CN, NR2
stable and storable
Chiral BINOL-based Alkoxides
Chiral Anion Generator
1,1’-Bi-2-naphthol (BINOL)4 is the common core
skeleton of the catalyst in asymmetric synthesis. Due to
the acidity of phenolic protons, BINOLs are often used as
Brønsted acid and/or hydrogen bond donor in
asymmetric catalysis. However, according to the
Brønsted–Lowry theory,5 the deprotonation of BINOLs
will occur at high pHs and give the phenolate anion (also
called phenoxide), which can act as the Brønsted base in
many reactions theoretically. In addition, the availability
of an additional phenol group of BINOL moiety offers the
stronger stereogenic-tuning to the activated and
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
stabilized transition state through the hydrogen bonding. alkoxide catalyst for the kinetic resolution of range of
racemic allylic alcohol via enantioselective isomerization8
(Scheme 3). Notably, the catalyst’s Brønsted base
component (phenolate anion) is identified as a basic unit
required for the catalytic activity, involving a base-
promoted proton abstraction as the activation step. The
chemistry to be detailed was enabled by a seemingly
trivial, yet ultimately crucial deviation from established
art in asymmetric catalysis.
1
2
3
4
5
6
7
8
However, due to the lack of the strategy to stabilize the
phenolate anion, a bifunctional binaphtholate catalyst
was seldom reported. Furthermore, all the reported
binaphtholate catalysts were in-situ generated with
strong alkali metal bases.6 Thus, it is necessary to develop
a stable and storable bifunctional binaphtholate catalyst
for both enriching the classes of catalysts and exploiting
new synthetic strategies (Scheme 1b).
9
Scheme 2. Preparation of Chiral BINOL Derivatives-
based Alkoxides
The catalytic isomerization of allylic alcohols
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
represents
a useful synthetic process to generate
aldehydes or ketones. In the development of the catalytic
enantioselective variant of this process, great
advancements had been achieved in the isomerization of
β-substituted primary allylic alcohols since the pioneering
reports by the Fu group,9 the Mazet group10 and others.11
As for the corresponding secondary allylic alcohols, only a
few kinetic resolution12 of racemic alcohols13 or
Ph
O
Ph
O
Ph
O
Ph
O
I
I
I
I
KOH
1.0 equiv
K
F
O
O
O
O
O
OH
HO
O
H
I
EA, 12 h
98% yield
I
I
I
1
MP 132-133 o
C
MP 163-164 o
C
stereospecific
isomerization
of
enantioenriched
substrates14 to β-substituted ketones had been reported.
Recently, Zhao15 made a landmark achievement in Rh-
catalyzed enantioselective isomerization of secondary
allylic alcohols. In particular, this work represents the
first enantioselective redox-neutral synthesis of ketones
with an α-tertiary stereocenter. In addition, enantiopure
allylic alcohols are versatile building blocks for
asymmetric synthesis and widely exist in complex natural
products.16 Their utility has been largely demonstrated in
Recently, we reported an easily accessible 1,1’-bi-2-
naphthol (BINOL)-based bis(hydroxy) polyethers bearing
phenols and polyether units for asymmetric cation-
binding catalysis.7 The ether oxygens act as a Lewis base
to coordinate metal ions such as K+, thus generating a
soluble chiral anion, which can be used as the base or
nucleophile in a confined chiral space. This new type of
cooperative cation-binding catalysis had been successfully
applied in various asymmetric reactions (Scheme 1c).
a
variety of organic transformations. Due to the
Inspired by these advancements, we envisioned
a
importance of allyl alcohol in organic synthesis, in our
preliminary study, we chose racemic (E)-4-hydroxy-1,4-
diphenylbut-2-en-1-one (±)-2a as the model substrate.
The deprotonation of allylic C-H easily occurred under
mild basic conditions and then the isomerization
proceeded logically.
complementary strategy, which represented a different
approach to expand the scope of this novel catalyst. In
principle, if we treated our catalyst with alkali metal salts
such as KOH, and K2CO3, a chiral BINOL derivatives-
based alkoxide would be generated. In the reaction, K+
might play a crucial role in stabilizing the phenolate
anion. A family of robust 1,1’-bi-2-naphthol (BINOL)-
based alkoxides were prepared. Especially, catalyst F with
the substituents at the C1 position of the chain was
prepared for the first time (Scheme 1d, 2). The prepared
chiral alkoxides had the high solubility in organic solvents
and were insensitive to water and air. The study aims to
evaluate this novel strategy and present a new chiral
RESULTS AND DISCUSSION
To verify the feasibility of the proposed process, a range of
potential catalysts, including chiral bifunctional catalysts
A-D17 and chiral BINOL derivatives-based alkoxides E-G,
were tested in the resolution of (±)-2a (Table 1). In order
to amplify potentially subtle differences among the
catalysts, the reactions were performed under a catalyst
load of 10 mol% at room temperature in o-xylene and
then quenched after 3 h. Under the above conditions,
chiral thiourea catalysts A-C showed the poor selectivity
(Table 1, entries 1-3). Surprisingly, quinine-derived
squaramide D provided a satisfactory s factor of 13 (31%
conversion), but the reaction proceeded sluggishly (Table
1, entry 4).
Scheme 3. Asymmetric Isomerization of Allylic
Alcohols Using Chiral BINOL Derivatives-based
Alkoxides
Ph
Ph
I
I
O
O
O
K+
O
O
O
H
I
I
H
Next, we screened the catalytic efficiency of a variety of
chiral BINOL derivatives-based alkoxide catalysts to shed
light on the relationship between the structures of
catalysts E-G and reaction outcomes. As shown in Table 1,
entry 5, when catalyst E1 having no substituent at the 3,3’-
position on the BINOL group was employed, a very low
level of conversion and enantioselectivity were observed.
However, the introduction of the substituents such as
CH3 (E2), CF3 (E3) and I (E4) on the 3,3’-positions of
OH
R2
kinetic resolution
via enantioselective
isomerization
O
R1
O
O
R2
OH
R2
R1
R1
O
O
R2
R1
OH
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
Table 1. Catalyst Screening and Optimization of Reaction Conditionsa
1
2
3
4
O
O
O
catalyst
Ph
Ph
OH
Ph
+
Ph
Ph
Ph
solvent, RT
OH
2a
O
2a
(S)-
3a
-
5
6
7
8
NHR
OMe
N
S
OMe
N
S
NH
H
R
N
H
N
N
N
bifunctional
amine catalyst
N
H
H
N
NH
N
H
NH
NHR
O
9
R = 3,5-(CF3)2C6H3
S
RHN
D
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
O
A
B
C
Ph
Ph
O
R
R
O
O
R
n
C1
C1
I
I
I
I
O
O
O
C2
C3
C2
C3
K
O
O
O
O
K
K
bifunctional
binaphtholate
catalyst
O
O
O
O
O
O
H
O
O
H
I
H
I
R
I
I
E1
E3
E5
E2
n = 1:
n = 2:
(R = H),
(R = CF3),
(R = I)
(R = CH3)
(R = I)
E4
G
F
entry
1e
catalyst
solvent
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
DCM
ee (%)b
68
-5
conv. (%)c
sd
7
2
2
13
1
30
35
32
-
50
7
30
2
76
-
A
B
C
D
E1
E2
E3
E4
E5
F
G
F
F
F
F
F
F
F
F
F
F
F
F
54
11
33
31
2e
3e
12
36
2
4e
5
13
6
7
8
9
10
11
12
13
14
15
98
95
90
-
98
57
98
23
97
-
57
54
52
<5
54
49
57
47
52
<5
<5
57
52
52
51
EA
Et2O
1,4-dioxane
THF
anisole
16
17
-
-
96
76
98
82
95
95
12
24
13
91
21
146
263
97
cyclopentyl methyl ether
di-n-butyl ether
MTBE
18
19
20
21f
22f,g
23f,h
di-n-butyl ether
di-n-butyl ether
di-n-butyl ether
50
49
11
aReaction conditions: (±)-2a (0.1 mmol), catalyst (0.01 mmol) in the solvent (1.0 mL) at RT for 3 h, unless otherwise specified.
bEnantiomeric excesses were determined by HPLC analysis. Conversion ratio was determined by H NMR spectroscopy. The
c
1
d
selectivity factors were calculated by the methods of Fiaud: s = ln[(1-Conv.)(1-ee)]/ln[(1-Conv.)(1+ee)]. All the reported s factors
e
f
g
h
were an average of 3 repeats. 12 h reaction time. 1.5 mL of di-n-butyl ether. 5 mol% catalyst loading. 1 mol% catalyst loading.
catalysts resulted in significantly higher catalytic activity
and enantioselectivity (entries 6, 7 and 8). The ether
chain length was also shown to play a crucial role in the
performance of the catalyst, which, as would be expected,
is responsible for the formation of a suitable chiral
coordination cage with potassium cation. The catalyst
bearing longer (n = 2) ether units showed almost no
activity (Table 1, entry 9). Finally, catalysts F and G with
the substituents at the C1 position of the chain were tested
(Table 1, entries 10 and 11). A comparison of catalysts E-G
illustrated that the presence of substituents at the C1
position of the chain affected the catalytic performance.
Gratifyingly, catalyst F with the phenyl rings at the C1
position of the chain showed the highest s factor (s factor
= 50 at 54% conversion) and was selected for further
optimization. Afterward, changing the solvent from o-
xylene to ether gave an improved enantioselectivity,
whereas 1,4-dioxane and THF resulted in the poor
conversion and the non-measurable degree of selectivity.
Finally, di-n-butyl ether was confirmed as the ideal
solvent for recovering (S)-2a with the excellent selectivity
and enantioselectivity (Table 1, entry 21). This high level
of selectivity could be maintained with lower catalyst
loading (Table 1, entries 22 and 23). Even with catalyst
loading of 1 mol%, excellent s-factor was obtained (s = 97
in Table 1, entry 23).
Next, the scope of the reaction was examined among a
range of racemic allylic alcohols under the optimized
conditions (Table 2). Generally, most of the recovered
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
Table 2. Substrate Scopea
1
O
O
O
2
3
4
F
5 mol%
R2
OH
R2
OH
R2
R1
R1
R1
+
di-n-butyl ether, RT
O
3
2
2'
(±)-
5
6
O
O
F
O
O
O
7
8
9
OH
OH
OH
OH
OH
2e
(S)-
2d
(S)-
2a
2b
2c
(S)-
(S)-
(S)-
96% ee, 51% conv.
44% yield, s = 90
95% ee, 49% conv.
45% yield, s = 306
95% ee, 49% conv.
48% yield, s = 263
94% ee, 50% conv.
46% yield, s = 108
96% ee, 50% conv.
47% yield, s = 194
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
O
O
O
O
O
OH
OH
OH
OH
F
Cl
F
2h
(S)-
2f
(S)-
2g
2i
(S)-
97% ee, 53% conv.
41% yield, s = 49
(S)-
93% ee, 50% conv.
48% yield, s = 118
98% ee, 51% conv.
46% yield, s = 153
99% ee, 52% conv.
43% yield, s = 120
Br
O
O
O
O
O
S
O
Cl
OH
OH
(S)-2m
OH
OH
OH
2j
2k
2l
(S)-
(S)-2n
99% ee, 52% conv.
42% yield, s = 124
(S)-
(S)-
93% ee, 51% conv.
47% yield, s = 63
99% ee, 55% conv.
42% yield, s = 51
96% ee, 51% conv.
42% yield, s = 124
94% ee, 50% conv.
48% yield, s = 160
O
O
O
O
O
OH
OH
OH
OH
OH
2s
(S)-
2p
2q
2r
(S)-
(S)-
(S)-
2o
(S)-
99% ee, 51% conv.
43% yield, s = 203
91% ee, 50% conv.
48% yield, s = 83
91% ee, 49% conv.
47% yield, s = 117
92% ee, 51% conv.
45% yield, s = 50
90% ee, 48% conv.
46% yield, s = 154
O
N
O
O
O
O
N
N
OH
OH
OH
OH
N
O
2wb
2t
2u
2v
(S)-
(S)-
(S)-
(S)-
91% ee, 48% conv.
50% yield, s = 181
92% ee, 49% conv.
48% yield, s = 122
98% ee, 51% conv.
45% yield, s = 162
93% ee, 49% conv.
43% yield, s = 227
O
O
O
O
S
Cl
Cl
OH
OH
OH
OH
2x
2y
2z
2aac
(S)-
(R)-
(R)-
(R)-
98% ee, 54% conv.
42% yield, s = 46
93% ee, 50% conv.
95% ee, 53% conv.
41% yield, s = 41
93% ee, 52% conv.
48% yield, s = 91
45% yield, s = 44
aUnless otherwise indicated, the reactions were carried out with (±)-2 (0.1 mmol), F (5 mol%) in di-n-butyl ether (1.5 mL) at
RT, please see Supporting Information for reaction time. Enantiomeric excesses were determined by HPLC analysis; conversion
ratio was determined by 1H NMR spectroscopy; isolated yield; the selectivity factors were calculated by the methods of Fiaud: s =
b
ln[(1-Conv.)(1-ee)]/ln[(1-Conv.)(1+ee)], all the reported s factors were an average of 3 repeats. Di-n-butyl ether/DCM (0.75
mL/0.75 mL) as solvent. cPerformed at 55 °C.
allylic alcohols were obtained with excellent ee values and
high s factors. The functional groups on the phenyl ring at
R1 and/or R2 position, such as methyl, isopropyl,
methoxyl, and halogen groups, were well tolerant to
current reaction systems, thus giving the corresponding
products (S)-2a-2k in excellent enantioselectivities and
good yields. The substrates bearing heterocyclic and alkyl
substituents at R1 position also led to the excellent
selectivity ((S)-2l-2w). Our protocol was also found to be
general with diverse R2 moieties. The substrates having
heteroaromatic as well as alkyl moiety at R2 afforded the
desired products, (S)-2x and (R)-2y-2aa, respectively, with
excellent enantioselectivity. The relative and absolute
configurations of (S)-2g were unambiguously established
by X-ray crystallographic analysis.18
Based on our experimental findings, a postulated
reaction pathway for this kinetic resolution is depicted in
Scheme 4. The chiral Brønsted base catalyst F might be
associated with substrates (R)-2a (R1 = R2 = Ph) to
generate intermediate G by hydrogen bonding. The
subsequent sp3 C-H bond cleavage of intermediate G
afforded bis-enol intermediate H. The isomerization of
bis-enol intermediate H gave the kinetic product 3a
together with the regeneration of the chiral Brønsted base
catalyst F, whereas the isomerization of (S)-2a (R1 = R2 =
Ph) occurred at a relatively low rate due to the higher
activation energy of the cleavage of the sp3 C-H bond
between the chiral Brønsted base catalyst F and (S)-2a,
thus leaving the unreactive (S)-2a.
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
Scheme 4. Proposed Reaction Pathway Scheme 5. Control Experiments
1
2
3
4
5
6
7
8
Ph
O
Ph
O
O
O
I
I
Ph
OH
Ph
Ph
1
10 mol%
O
K+
F
O
O
O
O
R2
OH
O
O
CDCl3, RT
H
I
R1
O
I
R2
(±)-2d
3d
R1
-2
no reaction
O
3
O
O
O
R2
OH
Isomerization
R1
Association
Ph
OH
F
10 mol%
2'
Ph
Ph
O
Ph
Ph
CDCl3, RT
I
I
I
3d
I
O
2d
2d
O
O
(R)-
O
O
K+
O
O
O
O
K+
>95% conversion
O
H
O
I
O
H
9
I
H
I
O
R2
OH
I
O
H
O
R2
R1
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
Ph
Ph
OH
R1
F
10 mol%
OH
Ph
Ph
G
H
I
CDCl3, RT
O
3d
<10% conversion
I
O
O
O
(S)-
O
O
K
O
H
I
H
I
O
R2
OH
To gain further insights into the mechanism of this
transformation, we measured the independent initial
rates on parallel reactions with substrates (±)-2d and (±)-
2d-D under the optimized reaction conditions (Scheme
6), which resulted in a strong primary intermolecular
0.2), strongly suggesting that the
deprotonation of allylic C-H was involved in the rate-
determining step.
R1
sp3 C-H cleavage
To confirm our proposed mechanism, a series of
control experiments were performed. Firstly, the
background reaction was tested. In the presence of
catalyst 1, the reaction did not proceed at all under the
optimized reaction conditions, demonstrating that F
played a crucial role in this reaction. Next, we performed
the reaction with optically pure 2d as the substrate. As
shown in Scheme 5, the reaction of (R)-2d (99% ee) gave
3d in the excellent yield under the optimized reaction
conditions (see Supporting Information, Figure S2).
However, the isomerization of (S)-2d (99% ee) proceeded
sluggishly (see Supporting Information, Figure S3). These
control experiments further confirmed that (R)-2d had a
faster reaction rate than (S)-2d.
KIE19 (5.1
±
Scheme 6. Kinetic Isotopic Effect
Intermolecular KIE = 5.1 ± 0.2
O
O
Ph
Ph
F
5 mol%
HO
H
di-n-butyl ether, 25 o
C
O
20 min
2d
3d
(±)-
Independent Reactions
O
O
Ph
F
5 mol%
Ph
di-n-butyl ether, 25 o
C
O
HO
2d D
D
20 min
3d
(±)-
-
(a)
(b)
Ph

G(M11)
G(M11)
Ph
O
Ph
Ph
O
I
I
kcal/mol
I
kcal/mol
O
I
O
O
O
O
O
O
O
K
K
O
O
H
H
H
I
H
I
I
I
O
O
OH
Ph
OH
Ph
Ph
Ph
TS1
TS2
O
O
11.4
Ph
OH
Ph
Ph
Ph
6.8
TS2
2a
(S)-
TS1
2a
(R)-
OH
0.0
0.0
TS1
TS2
-4.7
-5.3
F
F
O
O
-11.6
Ph
Ph
-12.3
CP5
CP2
Ph
2a
Ph
O
O
CP1
CP4
3a
3a
3a
2a
(R)-
-27.1
(S)-
-27.1
3a
CP3
Ph
O
-35.7
Ph
O
CP3
-35.7
Ph
O
Ph
Ph
Ph
Ph
O
Ph
I
I
I
I
I
I
O
O
O
CP4
O
CP1
I
I
O
O
O
O
O
O
K+
O
O
O
O
K+
O
O
K+
K+
O
I
O
H
O
O
H
H
O
H
I
H
I
O
I
I
H
I
O
I
I
Ph
Ph
Ph
F
F
Ph
H
OH
CP4
CP1
Ph
Ph
Ph
Ph
Ph
Ph
O
K+
Ph
Ph
O
I
I
I
I
I
I
O
O
O
I
I
O
O
O
O
O
O
O
K+
O
O
O
O
O
K+
K+
O
I
O
O
O
O
O
O
H
H
H
H
H
O
H
I
H
I
I
I
I
O
I
O
I
Ph
O
O
O
Ph
Ph
Ph
Ph
OH
Ph
Ph
Ph
CP5
CP3 O
CP3
CP2
Figure 1. (a) Free energy profile and structural information of the reaction pathway with (S)-2a as the substrate. (b) Calculated
free energy profiles of the reaction pathway with (R)-2a as the substrate. The values of bond lengths are given in angstroms.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
To elucidate the mechanism, density functional theory 0.648. The natural population analysis indicated that the
1
2
3
4
5
6
7
8
(DFT) method M11 was employed to study the mechanism
of the chiral BINOL-based alkoxides catalyzed kinetic
resolution of allylic alcohol.20 The calculated free energy
profile for the reaction pathway with (S)-2a as the
substrate is shown in Figure 1a. The coordination of (S)-2a
to the active catalyst F with hydrogen bond interaction
formed intermediate CP1 with 11.6 kcal/mol exothermic.
The subsequent intramolecular deprotonation, which
gave the bis-enol intermediate CP2, occurred via the
transition state TS1 with an overall barrier of 23.0
kcal/mol. The structural information of the transition
state TS1 showed that the bond lengths of the breaking C-
H bond and the forming O-H bond were 1.44 and 1.22 Å,
respectively. The isomerization of the bis-enol
intermediate CP2 gave the 1,4-diketone intermediate CP3.
The subsequent ligand exchange between CP3 and (S)-2a
generated the final product 3a and CP1 to complete the
catalytic cycle.
active site for F was the oxygen atom (O1) in naphthalen-
2-olate, which underwent the deprotonation of C-H bond
in (R)-2a.
Table 3. Distortion Energies and Interaction Energies
of the Transition States TS1 and TS2 Calculated by the
B3LYP/6-31G(d) Method
ΔE≠
ΔE≠
ΔE≠
ΔE≠
int
ΔE≠
3.2
dist(2a)
dist(F)
dist
9
TS1
TS2
41.3
32.9
11.6
11.1
52.9
44.0
-49.7
-46.1
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
-2.0
The distortion-interaction energy analysis21 was
employed to explain the reactivity trends of the kinetic
resolution. As shown in Table 3, the total activation
energy (ΔE‡) is devolved into the sum of distortion energy
(ΔE‡dist) and interaction energy (ΔE‡int) between distorted
reactants. According to B3LYP calculations of TS1, the
distortion energy was 52.9 kcal/mol and the interaction
energy was -49.7 kcal/mol. The distortion energy for TS2
was 44.0 kcal/mol, which was 8.9 kcal/mol lower than
that of TS1. The interaction energies of those two
transition states were close. Distortion-interaction energy
analysis indicated that the reactivity of the deprotonation
of (S)-2a and (R)-2a was controlled by the distortion
energy resulting from the difference in the distortion
energy between (S)-2a and (R)-2a.
The calculated free energy profile of the reaction
pathway with (R)-2a as the substrate is shown in Figure
1b. The overall activation barrier for the intramolecular
deprotonation transition state TS2 is 19.1 kcal/mol, which
is 3.9 kcal/mol lower than that of TS1. In transition state
TS2, the bond lengths of the breaking C-H bond and the
forming O-H bond are 1.46 and 1.22 Å, respectively. The
calculated results indicated that the chiral active catalyst
F reacted with (R)-2a to give the 1,4-diketone product 3a,
whereas (S)-2a would not be transformed into 1,4-
diketone product due to the high activation energy of the
transition state TS1.
Scheme 7. Asymmetric Synthesis of (+)-Veraguensina
OMe
OMe
O
O
OMe
OMe
F
5 mol%
OH
OH
2ab
di-n-butyl ether : DCM
(3 : 1), 48 h, RT
MeO
MeO
20.0 kcal/mol
OMe
OMe
(S)-
2ab
(±)-
1.463 g
99% ee, 44% recovered
a) imidazole,
TBS-Cl (52%)
b) Me2CuLi (77%)
OMe
OMe
O
O
c) KHMDS, HMPA
CH3I (96%)
OMe
OMe
OTBS
OTBS
MeO
MeO
4
5
OMe
OMe
K
0.648
d) TBAF
OH
e) BF3.Et2O
O1
-0.815
f) H2, Pd(OH)2/C
(43%, 3 steps)
O
O
MeO
MeO
OMe
OMe
MeO
MeO
OMe
OMe
(+)-veraguensin
6
17%, 6 steps
Ph
O
Ph
O
-20.0 kcal/mol
[]D25 = +34.5o (c 1.10, CHCl3)
I
lit. []D25 = +34.2o (c 1.10, CHCl3)
I
O
O
O
K+
aReagents and conditions: (a) imidazole, TBS-Cl, DMF, 40
O
H
oC, 1 h, 52%; (b) Me2CuLi, THF, -40 C, 1 h, 77%; (c)
o
I
I
F
o
KHMDS, HMPA, CH3I, THF, -78 C, 40 min, 96%; (d)
Figure 2. Electrostatic potential maps and the total natural
population analysis charges of certain atoms in catalyst F.
TBAF, THF, RT, 15 h; (e) BF3.Et2O, toluene, RT, 10 min; (f)
H2, Pd(OH)2/C, EtOAc, RT, 12 h, 43% for three steps.
To obtain more information for the active catalyst,
natural population analysis (NPA) towards catalyst F was
performed. The NPA charge value of certain atoms shown
in Figure 2 suggested that the negative charges of the
catalyst F were mainly located at the naphthalen-2-olate.
The charge of the oxygen atom (O1) in naphthalen-2-olate
was -0.815, whereas the charge of the potassium atom was
Optically active allylic alcohols are versatile building
blocks for the synthesis of natural products and
pharmaceuticals. For example, they are key intermediates
for the synthesis of natural products such as (+)-
veraguensin, (+)-verrucosin, (+)-calopiptin, and (-)-
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
virgatusin.22 To further illustrate the generality and
(1) For selected reviews, see: (a) Seayad, J.; List, B. Asymmetric
organocatalysis. Org. Biomol. Chem. 2005, 3, 719–724. (b)
Pellissier, H. Asymmetric organocatalysis. Tetrahedron 2007, 63,
9267–9331. (c) Dondoni, A.; Massi, A. Asymmetric
organocatalysis: from infancy to adolescence. Angew. Chem., Int.
Ed. 2008, 47, 4638–4660. (d) Marqués-López, E.; Herrera, R. P.;
Christmann, M. Asymmetric organocatalysis in total synthesis –
a trial by fire. Nat. Prod. Rep. 2010, 27, 1138–1167. (e) Giacalone,
F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Low-loading
asymmetric organocatalysis. Chem. Soc. Rev. 2012, 41, 2406–2447.
(f) Alemán, J.; Cabrera, S. Applications of asymmetric
organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42,
774–793. (g) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Catalytic
C − C bond-forming multi-component cascade or domino
reactions: pushing the boundaries of complexity in asymmetric
organocatalysis. Chem. Rev. 2014, 114, 2390–2431. (h) Atodiresei,
I.; Vila, C.; Rueping, M. Asymmetric organocatalysis in
continuous flow: opportunities for impacting industrial catalysis.
ACS Catal. 2015, 5, 1972–1985.
(2) For selected book and reviews, see: (a) Ting, A.; Schaus, S.
E. Brønsted Bases. In Comprehensive Enantioselective
Organocatalysis: Catalysts, Reactions, and Applications; Dalko, P.
I., Ed.; Wiley-VCH: Weinheim, 2013; Vol. 2, pp 343–363. (b)
O’Brien, P. Recent advances in asymmetric synthesis using chiral
lithium amide bases. J. Chem. Soc., Perkin Trans. 1 1998, 1439-
1457. (c) Shibasaki, M.; Yoshikawa, N. Lanthanide complexes in
multifunctional asymmetric catalysis. Chem. Rev. 2002, 102, 2187-
2209. (d) Collum, D. B.; McNeil, A. J.; Ramirez, A. Lithium
diisopropylamide: solution kinetics and implications for organic
synthesis. Angew. Chem., Int. Ed. 2007, 46, 3002–3017. (e)
Yamashita, Y.; Tsubogo, T.; Kobayashi, S. Chiral alkaline-earth
metal catalysts for asymmetric bond-forming reactions. Chem.
Sci. 2012, 3, 967–975. (f) Teng, B.; Lim, W. C.; Tan, C.-H. Recent
advances in enantioselective Brønsted base organocatalytic
reactions. Synlett 2017, 28, 1272–1277.
(3) For selected books and reviews, see: (a) Inokuma, T.;
Takemoto, Y. In Science of Synthesis, Asymmetric
Organocatalysis; List, B., Maruoka, K., Eds.; Thieme: Stuttgart,
2012; Vol. 2, pp 437–497. (b) Jang, H. B.; Oh, J. S.; Song, C. E. In
Science of Synthesis, Asymmetric Organocatalysis; List, B.,
Maruoka, K., Eds.; Thieme: Stuttgart, 2012; Vol. 2, pp 119–168. (c)
Singh, R. P.; Deng, L. In Science of Synthesis, Asymmetric
Organocatalysis; List, B., Maruoka, K., Eds.; Thieme: Stuttgart,
2012; Vol. 2, pp 41–117. (d) Marcelli, T.; van Maarseveen, J. H.;
Hiemstra, H. Cupreines and cupreidines: an emerging class of
bifunctional cinchona organocatalysts. Angew. Chem., Int. Ed.
2006, 45, 7496–7504. (e) Connon, S. J. Asymmetric catalysis with
bifunctional cinchona alkaloid-based urea and thiourea
organocatalysts. Chem. Commun. 2008, 2499–2510. (f) Palomo,
C.; Oiarbide, M.; López, R. Asymmetric organocatalysis by chiral
Brønsted bases: implications and applications. Chem. Soc. Rev.
2009, 38, 632–653. (g) Chauhan, P.; Chimni, S. S. Aromatic
hydroxyl group-a hydrogen bonding activator in bifunctional
asymmetric organocatalysis. RSC Adv. 2012, 2, 737–758. (h) Fang,
X.; Wang, C.-J. Recent advances in asymmetric organocatalysis
mediated by bifunctional amine–thioureas bearing multiple
hydrogen-bonding donors. Chem. Commun. 2015, 51, 1185–1197.
(4) For selected book and reviews, see: (a) Shibasaki, M.;
Matsunaga, S. In Privileged Chiral Ligands and Catalysts; Zhou,
Q.-L., Ed.; Wiley-VCH: Weinheim, 2011; Vol. 8, pp 295–332. (b)
Chen, Y.; Yekta, S.; Yudin, A. K. Modified BINOL ligands in
asymmetric catalysis. Chem. Rev. 2003, 103, 3155–3211. (c) Brunel,
J. M. BINOL: A versatile chiral reagent. Chem. Rev. 2005, 105,
857–897. (d) Shibasaki, M.; Matsunaga, S. Design and application
of linked-BINOL chiral ligands in bifunctional asymmetric
catalysis. Chem. Soc. Rev. 2006, 35, 269–279. (e) Parmar, D.;
1
2
3
4
5
6
7
8
synthetic utility of this methodology, we synthesized the
natural product (+)-veraguensin with this transformation
as a key step. (+)-Veraguensin was first isolated from the
Mexican tree Ocotea veragzlensis Mez. and exhibited the
significant neurite outgrowth promoting effect in
primary-cultured rat cortical neurons and NGF-
differentiated PC12 cells and protective effects against cell
death induced by several insults. Starting from (S)-2ab,
we synthesized (+)-veraguensin in 17% overall yield in six
steps, including the following key reactions. Firstly, after
anti-selective Michael addition to γ-oxyenone, syn-
selective α-methylation of the resulting ketone generated
the intermediate 5. Secondly, upon the treatment with
TBAF, the resulting ketol was immediately cyclized to
give hemiacetal 6 as a single isomer, which was
hydrogenated on Pd(OH)2 in EtOAc to give (+)-
veraguensin.
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
CONCLUSIONS
In conclusion, we developed an efficient chiral BINOL
derivatives-based alkoxide, which was used as the
Brønsted base catalyst for kinetic resolution of racemic
allylic alcohols through asymmetric isomerization. This
method represented a new approach for the preparation
of optically active allylic alcohols in excellent
1
enantioselectivities. An exhaustive H NMR mechanistic
study, deuterium incorporation experiments and DFT
calculation indicated that the deprotonation of allylic C-H
was probably involved in the rate-determining step. With
this transformation as a key step, we achieved the
asymmetric synthesis of bioactive natural product (+)-
veraguensin.
ASSOCIATED CONTENT
Supporting Information.
Experimental procedure and characterization data for all the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*yhl198151@cqu.edu.cn
*lanyu@cqu.edu.cn
Author Contributions
‡Y.L. and S.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This study was supported by the Fundamental Research
Funds for the Central Universities in China (Grant
CQDXWL-2014-Z003 and 2018CDXZ0002), the Scientific
Research Foundation of China (Grant 21772018, 21822303, and
21772020), and the Ministry of Science, ICT, and Future
Planning in Korea (Grant NRF-2014R1A2A1A01005794 and
NRF-2016-R1A4A1011451).
REFERENCES
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
Sugiono, E.; Raja, S.; Rueping, M. Complete field guide to
Adv. Synth. Catal. 2017, 359, 811–823. (h) Yu, L.; Wu, X.; Kim, M.
asymmetric BINOL-phosphate derived Brønsted acid and metal
catalysis: history and classification by mode of activation;
Brønsted acidity, hydrogen bonding, ion pairing, and metal
phosphates. Chem. Rev. 2014, 114, 9047–9153.
J.; Vaithiyanathan, V.; Liu, Y.; Tan, Y.; Qin, W.; Song, C. E.; Yan,
H. Asymmetric synthesis of 2-thiocyanato-2-(1-aminoalkyl)-
substituted 1-tetralones and 1-indanones with tetrasubstituted
carbon stereogenic centers via cooperative cation-binding
catalysis. Adv. Synth. Catal. 2017, 359, 1879–1891. (i) Park, S. Y.;
Hwang, I.-S.; Lee, H.-J.; Song, C. E. Biomimetic catalytic
transformation of toxic α-oxoaldehydes to high-value chiral α-
hydroxythioesters using artificial glyoxalase I. Nat. Commun.
2017, 8, 14877. (j) Tan, Y.; Luo, S.; Li, D.; Zhang, N.; Jia, S.; Liu, Y.;
Qin, W.; Song, C. E.; Yan, H. Enantioselective synthesis of anti−
syn-trihalides and anti−syn−anti-tetrahalides via asymmetric β-
elimination. J. Am. Chem. Soc. 2017, 139, 6431–6436. (k) Duan,
M.; Liu, Y.; Ao, J.; Xue, L.; Luo, S.; Tan, Y.; Qin, W.; Song, C. E.;
1
2
3
4
5
6
7
8
(5) (a) Brønsted, J. N. Some Remarks on the concept of acids
and bases. Rec. Trav. Chim. Pays Bas 1923, 42, 718−728 (German
title: Einige bemerkungen über den begriff der säuren und
basen). (b) Brønsted, J. N. The acid-basic function of molecules
and its dependency on the electric charge type. J. Phys. Chem.
1925, 30, 777−790. (c) Brønsted, J. N. Theory of the acidic-basic
function. Ber. Dtsch. Chem. Ges. B 1928, 61, 2049−2063 (German
title: Zur theorie der saure-basen-funktion). (d) Brønsted, J. N.
Acid and basic catalysis. Chem. Rev. 1928, 5, 231−338. (e) Lowry,
T. M. The uniqueness of hydrogen. J. Soc. Chem. Ind., London
1923, 42, 43−47. (f) Lowry, T. M. Co-ordination and acidity. J. Soc.
Chem. Ind., London 1923, 42, 1048−1052.
(6) (a) Schiffers, R.; Kagan, H. B. Asymmetric catalytic
reduction of ketones with hypervalent trialkoxysilanes. Synlett
1997, 1175–1178. (b) Holmes, I. P.; Kagan, H. B. The asymmetric
addition of trimethylsilylcyanide to aldehydes catalysed by
anionic chiral nucleophiles. part 1. Tetrahedron Lett. 2000, 41,
7453–7456. (c) Nakajima, M.; Orito, Y.; Ishizuka, T.; Hashimoto,
S. Enantioselective aldol reaction of trimethoxysilyl enol ether
catalyzed by lithium binaphtholate. Org. Lett. 2004, 6, 3763–
3765. (d) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. Chiral
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
Yan,
H.
Asymmetric
synthesis
of
trisubstituted
tetrahydrothiophenes via in situ generated chiral fluoride-
catalyzed cascade sulfa-Michael/Aldol reaction of 1,4-dithiane-
2,5-diol and α,β-unsaturated ketones. Org. Lett. 2017, 19, 2298–
2301. (l) Paladhi, S.; Liu, Y.; Kumar, B. S.; Jung, M.-J.; Park, S. Y.;
Yan, H.; Song, C. E. Fluoride anions in self-assembled chiral cage
for the enantioselective protonation of silyl enol ethers. Org.
Lett. 2017, 19, 3279–3282. (m) Paladhi, S.; Park, S. Y.; Yang, J. W.;
Song, C. E. Asymmetric synthesis of α‑fluoro-β-amino-oxindoles
with tetrasubstituted C − F stereogenic centers via cooperative
cation-binding catalysis. Org. Lett. 2017, 19, 5336–5339. (n)
Paladhi, S.; Hwang, I.-S.; Yoo, E. J.; Ryu, D. H.; Song, C. E. Kinetic
resolution
of
β-hydroxy
carbonyl
compounds
via
lithium binaphtholate aqua complex as
a highly effective
enantioselective dehydration using a cation-binding catalyst:
facile access to enantiopure chiral aldols. Org. Lett. 2018, 20,
2003–2006.
asymmetric catalyst for cyanohydrin synthesis. J. Am. Chem. Soc.
2005, 127, 10776–10777. (e) Hatano, M.; Horibe, T.; Ishihara, K.
Chiral lithium(I) binaphtholate salts for the enantioselective
direct Mannich-type reaction with a change of syn/anti and
absolute stereochemistry. J. Am. Chem. Soc. 2010, 132, 56–57. (f)
Kotani, S.; Kukita, K.; Tanaka, K.; Ichibakase, T.; Nakajima, M.
Lithium binaphtholate-catalyzed asymmetric addition of lithium
acetylides to carbonyl compounds. J. Org. Chem. 2014, 79, 4817–
4825. (g) Cai, H.; Nie, J.; Zheng, Y.; Ma, J.-A. Lithium
binaphtholate-catalyzed enantioselective enyne addition to
ketones: access to enynylated tertiary alcohols. J. Org. Chem.
2014, 79, 5484–5493. (h) Kotani, S.; Moritani, M.; Nakajima, M.
Chiral lithium binaphtholate for enantioselective Michael
addition of acyclic α-alkyl-β-keto esters to vinyl ketones. Asian J.
Org. Chem. 2015, 4, 616–618.
(7) (a) Yan, H.; Jang, H. B.; Lee, J.-W.; Kim, H. K.; Lee, S. W.;
Yang, J. W.; Song, C. E. A chiral-anion generator: application to
catalytic desilylative kinetic resolution of silyl-protected
secondary alcohols. Angew. Chem., Int. Ed. 2010, 49, 8915–8917.
(b) Yan, H.; Oh, J. S.; Lee, J.-W.; Song, C. E. Scalable
organocatalytic asymmetric Strecker reactions catalysed by a
chiral cyanide generator. Nat. Commun. 2012, 3, 1212. (c) Park, S.
Y.; Lee, J.-W.; Song, C. E. Parts-per-million level loading
organocatalysed enantioselective silylation of alcohols. Nat.
Commun. 2015, 6, 7512. (d) Li, L.; Liu, Y.; Peng, Y.; Yu, L.; Wu, X.;
Yan, H. Kinetic resolution of β-sulfonyl ketones through
enantioselective β-elimination using a cation-binding polyether
catalyst. Angew. Chem., Int. Ed. 2016, 55, 331–335. (e) Liu, Y.; Ao,
J.; Paladhi, S.; Song, C. E.; Yan, H. Organocatalytic asymmetric
synthesis of chiral dioxazinanes and dioxazepanes with in situ
generated nitrones via a tandem reaction pathway using a
cooperative cation binding catalyst. J. Am. Chem. Soc. 2016, 138,
16486–16492. (f) Vaithiyanathan, V.; Kim, M. J.; Liu, Y.; Yan, H.;
Song, C. E. Direct access to chiral β-fluoroamines with
quaternary stereogenic center through cooperative cation-
binding catalysis. Chem. - Eur. J. 2017, 23, 1268–1272. (g) Kim, M.
J.; Xue, L.; Liu, Y.; Paladhi, S.; Park, S. J.; Yan, H.; Song, C. E.
Cooperative cation-binding catalysis as an efficient approach for
enantioselective Friedel–Crafts reaction of indoles and pyrrole.
(8) For selected reviews and accounts, see: (a) van der Drift, R.
C.; Bouwman, E.; Drent, E. Homogeneously catalysed
isomerisation of allylic alcohols to carbonyl compounds. J.
Organomet. Chem. 2002, 650, 1−24. (b) Uma, R.; Crévisy, C.;
Grée, R. Transposition of allylic alcohols into carbonyl
compounds mediated by transition metal complexes. Chem. Rev.
2003, 103, 27−51. (c) Cadierno, V.; Crochet, P.; Gimeno, J.
Ruthenium-catalyzed isomerizations of allylic and propargylic
alcohols in aqueous and organic media: applications in synthesis.
Synlett 2008, 2008, 1105-1124. (d) Ahlsten, N.; Bartoszewicz, A.;
Martín-Matute, B. Allylic alcohols as synthetic enolate
equivalents: Isomerisation and tandem reactions catalysed by
transition metal complexes. Dalton Trans. 2012, 41, 1660−1670.
(e) Lorenzo-Luis, P.; Romerosa, A.; Serrano-Ruiz, M. Catalytic
isomerization of allylic alcohols in water. ACS Catal. 2012, 2,
1079−1086. (f) Cahard, D.; Gaillard, S.; Renaud, J.-L. Asymmetric
isomerization of allylic alcohols. Tetrahedron Lett. 2015, 56, 6159-
6169. (g) Li, H.; Mazet, C. Iridium-catalyzed selective
isomerization of primary allylic alcohols. Acc. Chem. Res. 2016,
49, 1232-1241.
(9) (a) Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M.-C.; Fu, G. C.
Enantioselective isomerization of allylic alcohols catalyzed by a
rhodium/phosphaferrocene complex. J. Am. Chem. Soc. 2000,
122, 9870-9871. (b) Tanaka, K.; Fu, G. C. A versatile new catalyst
for the enantioselective isomerization of allylic alcohols to
aldehydes: scope and mechanistic studies. J. Org. Chem. 2001,
66, 8177-8186.
(10) (a) Mantilli, L.; Gérard, D.; Torche, S.; Besnard, C.; Mazet,
C. Iridium-catalyzed asymmetric isomerization of primary allylic
alcohols. Angew. Chem., Int. Ed. 2009, 48, 5143–5147. (b) Mantilli,
L.; Mazet, C. Expanded scope for the iridium-catalyzed
asymmetric isomerization of primary allylic alcohols using
readily accessible second-generation catalysts. Chem. Commun.
2010, 46, 445–447.
(11) (a) Li, J.-Q.; Peters, B.; Andersson, P. G. Highly
enantioselective asymmetric isomerization of primary allylic
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
alcohols with an iridium–N,P complex. Chem. - Eur. J. 2011, 17,
direct rhenium-catalyzed [1,3]-transpositions of allylic alcohols
and their silyl ethers. Chem. Soc. Rev. 2014, 43, 4381–4394.
(17) Cinchona Alkaloids in Synthesis and Catalysis: Ligands,
Immobilization and Organocatalysis; Song, C. E., Ed.; Wiley-
VCH: Weinheim, 2009.
11143–11145. (b) Wu, R.; Beauchamps, M. G.; Laquidara, J. M.;
Sowa Jr., J. R. Ruthenium-catalyzed asymmetric transfer
hydrogenation of allylic alcohols by an enantioselective
isomerization/transfer hydrogenation mechanism. Angew.
Chem., Int. Ed. 2012, 51, 2106–2110. (c) Arai, N.; Sato, K.; Azuma,
K.; Ohkuma, T. Enantioselective isomerization of primary allylic
1
2
3
4
5
6
(18)
CCDC
1554627
contains
the
supplementary
crystallographic data for compound (S)-2g. (see Supporting
Information).
alcohols
into
chiral
aldehydes
with
the
tol-
7
8
9
binap/dbapen/ruthenium(II) catalyst. Angew. Chem., Int. Ed.
2013, 52, 7500–7504.
(19) Simmons, E. M.; Hartwig, J. F. On the interpretation of
deuterium kinetic isotope effects in C-H bond functionalizations
by transition-metal complexes. Angew. Chem., Int. Ed. 2012, 51,
3066–3072.
(12) For selected book and reviews on kinetic resolution, see:
(a) Kagan, H. B.; Fiaud, J. C. Kinetic Resolution. In Topics in
Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; John Wiley &
Sons: Canada, 1988; Vol. 18, pp 249–330. (b) Keith, J. M.; Larrow,
J. F.; Jacobsen, E. N. Practical considerations in kinetic resolution
reactions. Adv. Synth. Catal. 2001, 343, 5–26. (c) Vedejs, E.; Jure,
M. Efficiency in nonenzymatic kinetic resolution. Angew. Chem.,
Int. Ed. 2005, 44, 3974–4001.
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
(20) (a) Peverati, R.; Truhlar, D. G. Improving the accuracy of
hybrid meta-GGA density functionals by range separation. J.
Phys. Chem. Lett. 2011, 2, 2810–2817. (b) Qi, X.; Zhang, H.; Shao,
A.; Zhu, L.; Xu, T.; Gao, M.;Liu, C.; Lan, Y. Silver migration
facilitates isocyanide-alkyne [3 + 2] cycloaddition reactions:
combined experimental and theoretical study. ACS Catal. 2015,
5, 6640–6647. (c) Qi, X.; Liu, S.; Zhang, T.; Long, R.; Huang, J.;
Gong, J.; Yang, Z.; Lan, Y. Effective chirality transfer in [3+2]
reaction between allenyl-rhodium and enal: mechanistic study
based on DFT calculations. J. Org. Chem. 2016, 81, 8306–8311. (d)
Liu, S.; Qi, X.; Qu, L.-B.; Bai, R.; Lan, Y. C–H bond cleavage
occurring on a Rh(V) intermediate: a theoretical study of Rh-
catalyzed arene azidation. Catal. Sci. Technol. 2018, 8, 1645–1651.
(e) Long, R.; Huang, J.; Shao, W.; Liu, S.; Lan, Y.; Gong, J.; Yang,
Z. Asymmetric total synthesis of (-)-lingzhiol via a Rh-catalysed
[3+2] cycloaddition. Nat. Commun. 2014, 5, 5707.
(21) (a) Ess, D. H.; Houk, K. N. Distortion/interaction energy
control of 1,3-dipolar cycloaddition reactivity. J. Am. Chem. Soc.
2007, 129, 10646–10647. (b) Lan, Y.; Wheeler, S. E.; Houk, K. N.
Extraordinary difference in reactivity of ozone (OOO) and sulfur
dioxide (OSO): a theoretical study. J. Chem. Theory Comput.
2011, 7, 2104–2111. (c) Ess, D. H. Distortion, interaction, and
conceptual DFT perspectives of MO4-alkene (M = Os, Re, Tc,
Mn) cycloadditions. J. Org. Chem. 2009, 74, 1498–1508. (d) Liu,
S.; Lei, Y.; Qi, X.; Lan, Y. Reactivity for the Diels−Alder reaction
(13) For selected examples, see: (a) Kitamura, M.; Manabe, K.;
Noyori, R.; Takaya, H. Kinetic resolution of 4-hydroxy-2-
cyclopentenone
by
rhodium-catalyzed
asymmetric
isomerization. Tetrahedron Lett. 1987, 28, 4719–4720. (b) Hiroya,
K.; Kurihara, Y.; Ogasawara, K. Asymmetrization of meso 1,4-
enediol ethers by isomerization with a chiral binap-RhI catalyst.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2287–2289. (c) Ito, M.;
Kitahara, S.; Ikariya, T. Cp*Ru(PN) complex-catalyzed
isomerization of allylic alcohols and its application to the
asymmetric synthesis of Muscone. J. Am. Chem. Soc. 2005, 127,
6172–6173. (d) Ren, K.; Zhang, L.; Hu, B.; Zhao, M.; Tu, Y.; Xie, X.;
Zhang, T. Y.; Zhang, Z. Cationic-rhodium-catalyzed kinetic
resolution of allylic alcohols through a redox isomerization
reaction in a noncoordinating solvent. ChemCatChem 2013, 5,
1317–1320. (e) Ren, K.; Zhao, M.; Hu, B.; Lu, B.; Xie, X.;
Ratovelomanana-Vidal, V.; Zhang, Z. An enantioselective
approach to 4‑O‑protected-2-cyclopentene-l,4-diol derivatives
via a rhodium-catalyzed redox-isomerization reaction. J. Org.
Chem. 2015, 80, 12572–12579.
(14) For selected examples, see: (a) Bizet, V.; Pannecoucke, X.;
Renaud, J.-L.; Cahard, D. Ruthenium-catalyzed redox
of cumulenes: a distortion-interaction analysis along the
reaction pathway. J. Phys. Chem. A 2014, 118, 2638–2645.
(22) (a) Kitamura, M.; Hayashi, H.; Yano, M.; Tanaka, T.;
isomerization
of
trifluoromethylated
allylic
alcohols:
mechanistic evidence for an enantiospecific pathway. Angew.
Chem., Int. Ed. 2012, 51, 6467–6470. (b) Li, H.; Mazet, C. Catalyst-
directed diastereoselective isomerization of allylic alcohols for
the stereoselective construction of C(20) in steroid side chains:
scope and topological diversification. J. Am. Chem. Soc. 2015, 137,
10720–10727. (c) Martinez-Erro, S.; Sanz-Marco, A.; Gómez, A. B.;
Vázquez-Romero, A.; Ahlquist, M. S. G.; Martín-Matute, B. Base-
catalyzed stereospecific isomerization of electron-deficient
allylic alcohols and ethers through ion-pairing. J. Am. Chem. Soc.
2016, 138, 13408−13414.
(15) Liu, T.-L.; Ng, T. W.; Zhao, Y. Rhodium-catalyzed
enantioselective isomerization of secondary allylic alcohols. J.
Am. Chem. Soc. 2017, 139, 3643–3646.
(16) (a) Lumbroso, A.; Cooke, M. L.; Breit, B. Catalytic
asymmetric synthesis of allylic alcohols and derivatives and their
applications in organic synthesis. Angew. Chem., Int. Ed. 2013, 52,
1890–1932. (b) Volchkov, I.; Lee, D. Recent developments of
Maezaki, N.
A
stereocontrolled construction of rel-
(7S,8S,7’R,8’S)-7,7’-epoxylignan skeleton. Heterocycles 2007, 71,
2669–2680. (b) Kim, H.; Wooten, C. M.; Park, Y.; Hong, J.
Stereoselective synthesis of tetrahydrofuran lignans via BF3.OEt2-
promoted reductive deoxygenation/epimerization of cyclic
hemiketal: synthesis of (-)-odoratisol C, (-)-futokadsurin A, (-)-
veraguensin, (+)-fragransin A2, (+)-galbelgin, and (+)-talaumidin.
Org. Lett. 2007, 9, 3965–3968. (c) Matcha, K.; Ghosh, S. An
asymmetric route to total synthesis of the furano lignan (+)-
veraguensin. Tetrahedron Lett. 2010, 51, 6924–6927. (d) Harada,
K.; Kubo, M.; Horiuchi, H.; Ishii, A.; Esumi, T.; Hioki, H.;
Fukuyama, Y. Systematic asymmetric synthesis of all
diastereomers of (-)-talaumidin and their neurotrophic activity.
J. Org. Chem. 2015, 80, 7076–7088. (e) Chaimanee, S.;
Pohmakotr, M.; Kuhakarn, C.; Reutrakul, V.; Soorukram, D.
Asymmetric synthesis of ent-fragransin C1. Org. Biomol. Chem.
2017, 15, 3985–3994.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
Insert Table of Contents artwork here
1
2
3
4
5
Ph
O
Ph
O
I
I
O
O
O
K
O
H
I
H
stable bifunctional
binaphtholate catalyst
I
O
R2
OH
6
R1
7
8
9
sp3 C-H cleavage
O
O
R2
R2
OH
R1
R1
kinetic resolution via
enantioselective isomerization
O
O
28 examples, s up to >200
mild reaction condition
synthons for natural porducts



R2
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
R1
OH
10
ACS Paragon Plus Environment