Enantioconvergent Nucleophilic Substitution Reaction of Racemic Alkyne-Dicobalt Complex (Nicholas Reaction) Catalyzed by Chiral Br?nsted Acid

Article abstract of DOI:10.1021/jacs.6b05948

Catalytic enantioselective syntheses enable a practical approach to enantioenriched molecules. While most of these syntheses have been accomplished by reaction at the prochiral sp²-hybridized carbon atom, little attention has been paid to enantioselective nucleophilic substitution at the sp³-hybridized carbon atom. In particular, substitution at the chiral sp³-hybridized carbon atom of racemic electrophiles has been rarely exploited. To establish an unprecedented enantioselective substitution reaction of racemic electrophiles, enantioconvergent Nicholas reaction of an alkyne-dicobalt complex derived from racemic propargylic alcohol was developed using a chiral phosphoric acid catalyst. In the present enantioconvergent process, both enantiomers of the racemic alcohol were transformed efficiently to a variety of thioethers with high enantioselectivity. The key to achieving success is dynamic kinetic asymmetric transformation (DYKAT) of enantiomeric cationic intermediates generated via dehydroxylation of the starting racemic alcohol under the influence of the chiral phosphoric acid catalyst. The present fascinating DYKAT involves the efficient racemization of these enantiomeric intermediates and effective resolution of these enantiomers through utilization of the chiral conjugate base of the phosphoric acid.

Full text of DOI:10.1021/jacs.6b05948

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Enantio-Convergent Nucleophilic Substitution Reaction of Racemic Alkyne-
Dicobalt Complex (Nicholas Reaction) Catalyzed by Chiral Brønsted Acid
Masahiro Terada, Yusuke Ota, Feng Li, Yasunori Toda, and Azusa Kondoh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b05948 • Publication Date (Web): 04 Aug 2016
Downloaded from http://pubs.acs.org on August 5, 2016
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Enantio-Convergent Nucleophilic Substitution Reaction of Racemic
Alkyne-Dicobalt Complex (Nicholas Reaction) Catalyzed by Chiral
Brønsted Acid
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
Masahiro Terada*,†,‡, Yusuke Ota†, Feng Li†, Yasunori Toda†, and Azusa Kondoh‡
†Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
‡Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku,
Sendai 980-8578, Japan
ABSTRACT: Catalytic enantioselective syntheses enable a practical approach to enantio-enriched molecules. While most
of these syntheses have been accomplished by reaction at the pro-chiral sp2-hybridized carbon atom, a little attention has
been paid to enantioselective nucleophilic substitution at the sp3-hybridized carbon atom. In particular, substitution at
the chiral sp3-hybridized carbon atom of racemic electrophiles has been rarely exploited. To establish an unprecedented
enantioselective substitution reaction of racemic electrophiles, enantio-convergent Nicholas reaction of an alkyne-
dicobalt complex derived from racemic propargylic alcohol was developed using chiral phosphoric acid catalyst. In the
present enantio-convergent process, both enantiomers of the racemic alcohol were transformed efficiently to a variety of
thioethers with high enantioselectivity. The key to achieving success is dynamic kinetic asymmetric transformation
(DYKAT) of enantiomeric cationic intermediates generated via dehydroxylation of the starting racemic alcohol under the
influence of the chiral phosphoric acid catalyst. The present fascinating DYKAT involves the efficient racemization of
these enantiomeric intermediates and effective resolution of these enantiomers through utilization of the chiral conjugate
base of the phosphoric acid.
chiral information of racemic electrophiles is transferred
to the corresponding substitution product through inver-
INTRODUCTION
sion at the stereogenic center via the SN2 pathway. There-
fore, in the conventional approach, kinetic resolution of
racemic electrophiles has been used to afford the substi-
tution product in an enantio-enriched form (Scheme 1a).2
In an alternative approach to the SN2 pathway (i.e., the SN1
protocol), the cationic intermediate generated as an elec-
trophile forms a contact ion pair with a leaving group that
makes enantio-control of the substitution product diffi-
cult. To circumvent this intrinsic feature of SN1 reactions,
several specific methods for enantioselective nucleophilic
substitution at the racemic stereogenic center have been
reported, such as SN1-type reactions by virtue of
During the past half century, significant progress has
been made toward the asymmetric synthesis of molecules
in an enantio-enriched form. Effort has been devoted to
the chemical synthesis of these molecules because of in-
creasing demand for enantio-enriched molecules in medi-
cine and material science. Among the methods for asym-
metric synthesis, enantioselective catalysis is one of the
representatives to produce these molecules in an efficient
and practical manner, most of which has been accom-
plished by reaction at the pro-chiral sp2-hybridized carbon
atom of double bonds, e.g., C=O, C=N, and C=C. Enanti-
oselective nucleophilic addition to pro-chiral electro-
philes such as aldehydes, ketones, imines, and electron
deficient double bonds is one of the most extensively in-
vestigated reactions, and substantial achievements have
been reported using chiral metal catalysts, enzymes, and
organocatalysts.1 In contrast, despite being one of the
most fundamental and powerful methods for the for-
mation of covalent bonds, enantioselective nucleophilic
substitution at the sp3-hybridized carbon atom has re-
ceived much less attention than the enantioselective nu-
cleophilic addition reactions. In particular, substitution
reaction at the chiral sp3-hybridized carbon atom of race-
mic electrophiles has rarely been exploited as a catalytic
enantioselective transformation, presumably because the
Scheme 1. Enantioselective Substitution Reaction of a
Racemic Electrophile
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
contriving the reaction system3 and allylic substitution4 as
Lewis acid. In some cases, the Nicholas reaction using
well as cross coupling reactions5,6 using transition metal
catalysts. The challenge of governing the stereochemical
outcome in enantioselective substitution reactions of ra-
cemic electrophiles provides a new frontier of enantiose-
lective catalysis for nucleophilic substitution (Scheme 1b),
in which enantio-convergence can be achieved from the
racemic electrophile to the enantio-enriched substitution
product without recovering unreacted enantiomer of the
electrophile.
enantio-enriched propargylic alcohols forms enantio-
enriched products in a stereo-retentive manner under
particular reaction conditions,9 while, in diastereo-facial
selective reactions of nucleophiles having an enantio-
enriched chiral auxiliary, racemization at the propargylic
position of the racemic alcohol is found to occur during
the course of the Nicholas reaction (Scheme 2b).10
1
2
3
4
5
6
7
8
We hence postulated that fluxional aspects of the enan-
tiomeric planar chiral intermediates A and A’ result in the
racemization at the propargylic position of these enanti-
omeric species under certain reaction conditions, alt-
hough a catalytic enantio-convergent Nicholas reaction
using racemic substrate 1 had never been reported.11,12 The
synthetic advantages of the Nicholas reaction include: i)
high regioselectivity at the propargylic position13 and ii)
wide scope of nucleophiles in inter- and/or intramolecu-
lar reactions. In this study, a thiol (Nu–H = RSH) was
used as the nucleophile to yield organosulfur compounds,
which are difficult to obtain by conventional asymmetric
catalysis using chiral metal complexes because the for-
mation of a relatively stable metal-sulfur bond, especially
for transition metal species, prevents efficient turnover of
the catalyst.14 Most of the useful and bioactive organosul-
fur compounds are enantio-enriched and widely present
in drugs and relevant molecules.15 Because of this, enanti-
oselective carbon-sulfur (C-S) bond formation is an espe-
cially important and challenging transformation.16 The
present report describes the first enantio-convergent
Nicholas reaction of thiol 2 with the dicobalt complex of
racemic propargylic alcohols 1 (Lv = OH) catalyzed by
chiral phosphoric acid 3 (Scheme 2c), which has recently
emerged as a versatile catalyst for a variety of enantiose-
lective transformations.17,18 In the present enantio-
convergent process, enantio-enriched thioethers 4 with a
broad range of substituent patterns were formed in a
highly enantioselective manner. The key to achieving en-
antio-convergence is the ability of the chiral conjugate
base of chiral phosphoric acid (R)-3 to function as a ste-
reo-differentiating agent of enantiomeric intermediates A
and A’ generated via dehydroxylation of the starting ra-
cemic alcohol 1 (Scheme 2b).19 The racemization between
these enantiomeric intermediates A and A’ coupled with
the efficient resolution of these enantiomers, namely dy-
namic kinetic asymmetric transformation (DYKAT),20 was
accomplished in the present enantio-convergent substitu-
tion reaction.
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
Introduction of an effective racemization process to the
reaction system is necessary to establish efficient enantio-
convergence of the nucleophilic substitution reaction,
because the initial chirality of the racemic electrophile
significantly affects the stereochemical outcome of the
substitution product. To overcome this intrinsic problem
associated with the use of the racemic electrophile, we
envisioned a metal-assisted protocol for realizing efficient
racemization of the electrophile and predicted that the
Nicholas reaction is beneficial for this purpose (Scheme
2a). The Nicholas reaction,7,8 in which a propargylic cati-
on stabilized by cobalt complex is involved as a reactive
intermediate, is generally promoted by a Brønsted or
Scheme 2. (a) Nicholas Reaction. (b) Racemization of
Cobalt-Stabilized Propargylic Cation. (c) Enantio-
Convergent Synthesis of Organosulfur Compounds by
Nicholas Reaction Catalyzed by Chiral Phosphoric Acid
Brønsted acid
HA
(or Lewis acid)
(a)
Lv
Nu
H
R1
Co2(CO)6
R1
Co2(CO)6
H
Nu-H
+
Nucleophilic
Substitution
R2
HA
R2
(Lv: Leaving group)
– HA
R1
R1
A
H
H
A
Co(CO)3
Nu
-H
Co(CO)3
H-Nu
H•Lv
– Lv-H
R2
R2
Co(CO)3
Co(CO)3
cobalt-stabilized propargylic cation
(b)
OH
Brønsted acid
HA
Brønsted acid
Co2(CO)4L2
R2
HA
R1
– H2O
– H2O
(±)-1 (Lv = OH)
R1
H
A
R2
A
racemization
Co(CO)2L
Co(CO)2L
R2
H
R1
Co(CO)2L
Co(CO)2L
planar chiral A
planar chiral A'
RESULTS AND DISCUSSION
R3
S
(c)
(R)-3
(5 mol%)
OH
At the outset of our study, a typical dicobalthexacar-
bonyl complex of racemic propargylic alcohol with a tri-
methylsilyl substituent at the alkynyl terminus was used
as the racemic electrophile of a substitution reaction with
benzenethiol (2a). However, initial attempts to promote
the substitution reaction with 2a using 10 mol% chiral
phosphoric acid (R)-3a in toluene did not result in for-
mation of the desired substitution product, even at 50 °C.
We, therefore, introduced the diphosphine ligand, dppm
[1,1-bis(diphenylphosphino)methane], instead of two-
Co2(CO)4L2
R3-SH
Co2(CO)4L2
R2
+
R1
R1
2
R2
(±)-1
enantio-enriched 4
G
O
O
G
=
P
OH
O
G
(R)-3
a: (R)-BINOL-derivatived b: (R)-H8-BINOL-derivatived
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
carbon monoxide ligands to enhance reactivity of the di-
8
9
(R)-3af c-hexane (0.1 M) 24 h
83
95
91
cobalt complex of propargylic alcohol 1.21 Thus, 1a com-
plexed with dppm was exposed to 2a in the presence of
(R)-3a (10 mol%) and molecular sieves (MS) 4A (used to
scavenge the water generated) in toluene at room tem-
perature for 24 h. As expected, the desired substitution
product 4a was obtained in an acceptable yield with fairly
good enantioselectivity (Table 1, entry 1). This promising
result prompted further investigation of the effect of sol-
vent because the Nicholas reaction involves a cationic
intermediate that should be responsible for the racemiza-
tion. The chemical yield and the enantioselectivity were
markedly dependent on the solvent used (entries 1-5).
Despite stabilization of the cationic intermediate by polar
solvents, such as acetonitrile and ethyl acetate, these po-
lar solvents considerably prevented the substitution reac-
tion (entries 2 and 3). More importantly, product 4a was
formed in nearly racemic mixtures. The use of methylene
chloride resulted in moderate conversion with low enan-
tioselectivity (entry 4), even though methylene chloride is
one of the most common solvents in chiral phosphoric
acid-catalyzed reactions.18 In contrast, the less polar sol-
vent cyclohexane significantly accelerated the reaction,
giving rise to the substitution product 4a in good yield
with high enantioselectivity (92% ee) within 2 h (entry
5).22 Further investigation of reaction conditions by
changing the concentration and catalyst loading was con-
ducted (entries 6-8). The enantioselectivity of 4a slightly
increased as the concentration decreased. Catalyst load-
ing could be reduced to 2.5 mol% without a significant
decrease in enantioselectivity, but required prolonged
reaction time and a slight decrease in yield (entry 8). The
H8-BINOL-derived chiral phosphoric acid (R)-3b also fa-
cilitated the reaction to afford 4a with the same enanti-
oselectivity (entry 9 vs. entry 7). Single-crystal X-ray dif-
fraction analysis revealed that the absolute stereochemis-
try of the major enantiomer of 4a was the (R)-
configuration.23 Thus, chiral phosphoric acid (R)-3 gave
(R)-4a.
1
2
3
4
5
6
7
8
(R)-3be c-hexane (0.1 M)
92
4 h
a Unless otherwise noted, all reactions were performed using
0.10 mmol of 1a, 0.15 mmol of 2a, and 0.010 mmol of catalyst
(R)-3 (10 mol%) in the indicated solvent (0.1 M) at room
temperature. b Isolated yield. c Enantiomeric excess was de-
termined by chiral stationary phase HPLC analysis. d Enanti-
omeric excess of 4a was determined after desilylation of 4a to
terminal alkyne derivative. e 5 mol%. f 2.5 mol%.
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
Optimized reaction conditions using chiral phosphoric
acid (R)-3a or (R)-3b were applied to a broad range of
racemic propargyl alcohol dicobalt complexes 1 and a va-
riety of thiols 2. In most cases, the thioether product 4
was obtained in high yield and enantioselectivity (Table
2). When a trimethylsilyl group was introduced to the
alkynyl terminus (entries 1-5), aromatic and aliphatic sub-
stituents were tolerated at the propargylic position, yield-
ing thioether 4 in good to excellent enantioselectivity.
The substituent effect of the alkynyl terminus was also
investigated, and the results showed that bulky tert-
butyldimethylsilyl, aliphatic, and aromatic substituents
could be used in the present reaction, affording 4 in high
yield with good enantioselectivity (entries 6-9), although
the substrate having R1 = methyl and R2 = phenyl substit-
uents exhibited a slight reduction in enantioselectivity
(entry 10). Further investigation of the thiol substituent
demonstrated that a variety of thiols 2 underwent reac-
tion to produce the corresponding products in excellent
yield, regardless of the steric bulkiness and acidity of the
thiols, including aliphatic thiol (entries 11-16), although a
slight reduction in enantioselectivity resulted from reac-
tion of aliphatic thiol (entries 15 and 16).
Table 2. Substrate Scopea
R3
(R)-3
OH
S
(5 mol%)
Co2(CO)4L2
R2
Co2(CO)4L2
R2
+
R3SH
R1
R1
cyclohexane
(0.1 M)
MS 4A, rt
2
(1.5 eq.)
4
(±)-1
(L2 = dppm)
Table 1. Optimization of Reaction Conditionsa
yield ee
entry (R)-3
4
R1
R2
R3
time
2 h
4 h >98 84d
(%)b (%)c,d
1
2
3a 4b Me
TMS
Ph
Ph
Ph
Ph
Ph
Ph
Ph
97
85
3b 4c n-Pent TMS
3be 4d i-Bu TMS
3be 4e i-Pr TMS
3
40 h 86
48 h 60
96d
time yield (%)b ee (%)c,d
4
97
entry CPA
solvent
5
3b 4f
Ph
TMS
TBS
2 h >98 84
1
(R)-3a
(R)-3a
(R)-3a
(R)-3a
toluene (0.1 M) 24 h
64
5
87
<5
<5
10
6
3b 4g Me
4 h 98
6 h 97
88
87
2
3
4
5
6
7
MeCN (0.1 M)
AcOEt (0.1 M)
CH2Cl2 (0.1 M)
24 h
24 h
24 h
7
3b 4h
3b 4i
3b 4j
Et
Et
Et
n-Bu
9
8
c-hex
Ph
Ph
Ph
Ph
3 h
24 h
24 h
4 h
98
92
94
97
98
89
9f
10f
11
12
90g
73g
92d
92d
44
91
95
94
(R)-3a c-hexane (0.1 M) 2 h
(R)-3a c-hexane (0.02 M) 12 h
(R)-3ae c-hexane (0.1 M) 4 h
92
93
92
3a 4k Me
3a 4l Et
3a 4m Et
Ph
TMS 4-BrC6H4
TMS 4-MeOC6H4
4 h
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
13
14
15
16
3be 4n
3be 4o
3ae 4p
3b 4q
Et
Et
Et
Ph
TMS 2-BrC6H4
TMS 2-MeOC6H4
98
94
97
87d
92d
84d
6 h
6 h
8 h
6 h
1
(±)-1k
(±)-1k
(±)-1k
(±)-1k
(R)-1kd
(S)-1ke
(S)-1ke
(S)-1ke
(S)-1ke
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
6.0
0.1
0.1
0 °C, 24 h
rt, 4 h
78
97
91
57 (R)
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
9
68 (R)
74 (R)
78 (R)
TMS
TMS
n-C8H17
n-C8H17
0.1
50 °C, 1 h
rt, 6 h
>98 84
0.02
0.1
95
a Reactions were conducted on 0.1 mmol scale. b Isolated yield.
rt, 1 h
>99 82 (R)
>99 34 (R)
c
Enantiomeric excess was determined by chiral stationary
0.1
rt, 6 h
phase HPLC. d Enantiomeric excess of 4 was determined after
0.1
0 °C, 48 h,
rt, 24 h
0 °C, 48 h
98
94
92
3 (R)
69 (R)
44 (S)
desilylation of 4 to 5 (R2 = H). 10 mol%. 0.02 M. g Enantio-
meric excess was determined after removal of cobalt complex
from 4 to derivatize propargyl thioether 6.
e
f
9
0.02
0.1
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
a Unless otherwise noted, all reactions were conducted using
0.05 mmol 1k, indicated amount of 2a, and 0.005 mmol cata-
lyst (R)-3a (10 mol%) in toluene. b Isolated yield. c Enantio-
meric excess was determined by chiral stationary phase
HPLC, after removal of cobalt complex from 4k to derivatize
propargyl thioether 6k. d 97% ee (R)-1k was used. e 96% ee
(S)-1k was used.
MECHANISTIC STUDIES
During the course of these studies, anomalous tempera-
ture and concentration effects were observed in the enan-
tio-convergent process, particularly when using 1k as the
substrate (R1 = methyl, R2 = phenyl) in toluene (Table 3).
For entries 1-3, a higher temperature resulted in better
enantioselectivity, even though product enantioselectivity
increased as reaction temperature decreased for a typical
catalytic enantioselective reaction. Furthermore, a lower
concentration resulted in better enantioselectivity (entry
4 vs. entry 2). In general, enantioselectivity is independ-
ent of concentration in a typical enantioselective reaction.
These findings prompted investigation of the mechanism
behind these intriguing phenomena. We thus conducted
the reaction using enantiomerically enriched alcohol 1k to
acquire mechanistic insights into the enantio-convergent
reaction. The Nicholas reaction partially involves reten-
tion of the chirality at the propargylic position under par-
ticular reaction conditions.9 If reaction of (R)-1k proceeds
in accordance with the retentive manner at the propar-
gylic position, (R)-4k should be formed. Considering this
stereochemical relation between reactant and product,
(R)-1k can be expected to be favorable in the present reac-
tion because of the formation of the (R)- product as the
major enantiomer under the influence of chiral phosphor-
ic acid (R)-3. In fact, (R)-1k was consumed much faster
than (±)-1k and underwent reaction with higher enanti-
oselectivity than that of (±)-1k (entry 5 vs. entry 2). In
contrast, reaction of (S)-1k proceeded sluggishly to yield
the inversion product (R)-4k with much lower enantiose-
lectivity than that of (±)- and (R)-1k (entry 6 vs. entries 2
and 5). In the reaction of (S)-1k, the racemization is ap-
parently indispensable to afford the inversion product
(R)-4k.24
To rationalize the anomalous temperature and concen-
tration effects observed (Table 3, entries 1-4), we pre-
formed additional reactions using (S)-1k under different
temperatures, concentrations, and equivalents of thiol 2a
(entries 7-9). These parameters significantly affect the
stereochemical outcome because of the involvement of
the racemization process. Reducing the reaction tempera-
ture markedly decreased the enantioselectivity (entry 7 vs.
entry 6). Reducing the concentration from 0.1 to 0.02 M
dramatically enhanced the enantioselectivity (entry 8 vs.
entry 6), while an increase in equivalents of thiol 2a led to
the formation of the opposite enantiomer (S)-4k as the
major isomer (entry 9). These results clearly indicate that
the stereochemical outcomes from the reactions of (S)-1k
are markedly influential in the anomalous temperature
and concentration effects observed in the reaction of (±)-
1k. A plausible mechanism of the present enantio-
convergent process is illustrated in Scheme 3. The relative
rate between racemization of the cationic intermediates
and the nucleophilic addition to these intermediates is
the key to achieving efficient enantio-convergence. At
lower concentrations, nucleophilic addition is suppressed
because of intermolecular processes; therefore, the race-
mization process (an intramolecular process) predomi-
nates over nucleophilic addition in which the chiral in-
formation of the unfavorable (S)-1k disappears efficiently.
In this regard, an increase in equivalents of thiol 2a accel-
erated the nucleophilic addition and hence most of the
chiral information of (S)-1k remained retentive to afford
(S)-4k as the major enantiomer. At higher temperatures,
the experimental results strongly suggest that the racemi-
zation process is markedly accelerated over nucleophilic
addition. To accomplish efficient enantio-convergence,
selective reaction of thiol 2a with one of the enantiomeric
cationic intermediates occurs under the influence of the
chiral conjugate base of (R)-3a to afford the correspond-
ing C-S bond formation product (R)-4k. The other enan-
tiomer is subjected to racemization, followed by thiol
addition through the same resolution pathway, and the
Table 3. Temperature and Concentration Effectsa
equiv. conc.
of 2a (M)
yield
(%)b
ee
entry
1k
conditions
(%)c
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Transformations by Organocatalysts” from MEXT, Japan. We
overall process enables the enantio-convergent Nicholas
1
2
3
4
greatly appreciate Takasago International Corporation for
supplying the enantio-enriched propargylic alcohols and
Daicel Corporation CPI Company for conducting chiral sta-
tionary phase HPLC analysis of 4h. We also thank JSPS for a
research fellowship for Young Scientists (Y.T. & F.L.).
reaction in a highly stereoselective manner.
Scheme 3. Plausible Mechanism of the Enantio-
Convergent Nicholas Reaction
5
6
7
REFERENCES
(1) (a) de Vries, J. G. Science of Synthesis, Stereoselective Synthe-
sis 1, Stereoselective Reactions of Carbon-Carbon Double Bonds;
Georg Thieme Verlag KG, 2010. (b) Molander, G. A. Science of
Synthesis, Stereoselective Synthesis 2, Stereoselective Reactions of
Carbonyl and Imino Groups; Georg Thieme Verlag KG, 2010. (c)
Evans, P. A. Science of Synthesis, Stereoselective Synthesis 3, Ste-
reoselective Pericyclic Reactions, Cross Coupling, and C-H and C-
X Activation; Georg Thieme Verlag KG, 2010.
8
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
(2) Čorić, I.; Kim, J. H.; Vlaar, T.; Patil, M.; Thiel, W; List, B. An-
gew. Chem., Int. Ed. 2013, 52, 3490.
(3) For selected examples in which pro-chiral intermediates can
form from racemic electrophiles, see: (a) Rueping, M.; Nachats-
heim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008,
47, 593. (b) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song, L.; Feng,
Z.; Gong, L.-Z. Org. Lett. 2009, 11, 4620. (c) Sun, F.-L.; Zeng, M.;
Gu, Q.; You, S.-L. Chem. Eur. J. 2009, 15, 8709. (d) Song, L.; Guo,
Q.-X.; Li, X.-C.; Tian, J.; Peng, Y.-G. Angew. Chem., Int. Ed. 2012,
51, 1899. (e) Wilcke, D.; Herdtweck, E.; Bach, T. Synlett 2011, 1235.
(f) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem.
Soc. 2011, 133, 3732. (g) Guo, W.; Wu, B.; Zhou, X.; Chen, P.;
Wang, X.; Zhou, Y.-G.; Liu, Y.; Li, C. Angew. Chem., Int. Ed. 2015,
54, 4522. (h) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Angew. Chem.,
Int. Ed. 2015, 54, 1910. (i) Chatupheeraphat, A.; Liao, H.-H.;
Mader, S.; Sako, M.; Sasai, H.; Atodiresei, I.; Rueping, M. Angew.
Chem., Int. Ed. 2016, 55, 4803, and references cited therein.
(4) For selected reviews on asymmetric allylic alkylations, see:
(a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (b)
Trost, B. M.; Crawley M. L. Chem. Rev. 2003, 103, 2921. (c) Lu, Z.;
Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258. (d) Butt, N. A.;
Zhang, W. Chem. Soc. Rev. 2015, 44, 7929.
(5) For selected examples, see: (a) Fischer, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 4594. (b) Liang, Y.; Fu, G. C. J. Am. Chem.
Soc. 2015, 137, 9523. (c) Mao, J.; Liu, F.; Wang, M.; Wu, L.; Zheng,
B.; Liu, S.; Zhong, J.; Bian, Q.; Walsh, P. J. J. Am. Chem. Soc. 2014,
136, 17662. (d) Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc.
2015, 137, 7128, and references cited therein.
(6) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.;
Peters, J. C.; Fu, G. C. Science 2016, 351, 681.
(7) Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 18,
4163.
(8) For reviews on Nicholas reaction, see: (a) Nicholas, K. M. Acc.
Chem. Res. 1987, 20, 207. (b) Müller, T. J. J. Eur. J. Org. Chem.
2001, 2021. (c) Teobald, B. J. Tetrahedron 2002, 58, 4133. (d) Díaz,
D. D.; Betancort, J. M.; Martín, V. S. Synlett 2007, 343.
(9) (a) Caffyn, A. J. M.; Nicholas, K. M. J. Am. Chem. Soc. 1993, 115,
6438. (b) Muehldorf, A. V.; Guzman-Perez, A.; Kluge, A. F. Tet-
rahedron Lett. 1994, 35, 8755. (c) Grée, D.; Madiot, V.; Grée, R.
Tetrahedron Lett. 1999, 40, 6399.
(10) (a) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem.
Soc. 1987, 109, 5749. (b) Jacobi, P. A.; Herradura, P. Tetrahedron
Lett. 1996, 37, 8297. (c) Jacobi, P. A.; Murphree, S.; Rupprecht, F.;
Zheng, W. J. Org. Chem. 1996, 61, 2413.
(11) For examples of asymmetric intermolecular Nicholas reac-
tions, see: (a) Montaña , A. M.; Cano, M. Tetrahedron 2002, 58,
933. (b) Ljungdahl, N.; Pera, N. P.; Andersson, K. H. O.; Kann, N.
Synlett 2008, 394. (c) Betancort, J. M.; Rodríguez, C. M.; Martín,
V. S. Tetrahedron Lett. 1998, 39, 9773. Also see: refs 9 and 10.
CONCLUSIONS
We have demonstrated the enantio-convergent Nicho-
las reaction of an alkyne-dicobalt complex derived from
racemic propargylic alcohols with thiol catalyzed by a
chiral phosphoric acid. The method provides a novel
strategy for enantioselective C-S bond formation through
an enantio-convergent process of the nucleophilic substi-
tution reaction using racemic alcohols, in which enantio-
enriched thioethers with a wide range of substituents can
be synthesized in a highly enantioselective manner. This
enantio-convergent process, namely DYKAT, is accom-
plished by efficient racemization of a pair of enantiomeric
cationic intermediates as well as by effective resolution of
these enantiomeric intermediates through the chiral con-
jugate base of the phosphoric acid. Further studies on the
application of enantio-convergent substitution reactions
of racemic substrates are in progress with the aim of de-
veloping even more efficient enantioselective transfor-
mations.
ASSOCIATED CONTENT
Supporting Information
The exploratory investigation, experimental procedures and
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: mterada@m.tohoku.ac.jp
Present Addresses
Y.T.: Department of Materials Chemistry, Faculty of Engi-
neering, Shinshu University, Wakasato, Nagano 380-8553,
Japan
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was partially supported by a Grant-in-Aid for Sci-
entific Research on Innovative Areas “Advanced Molecular
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
(12) For reviews on catalytic propargylic substitution, see: (a)
1
2
3
4
5
6
7
8
Miyake, Y.; Uemura, S.; Nishibayashi, Y. ChemCatChem 2009, 1,
342. (b) Detz, R. J.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2009, 6263. (c) Nishibayashi, Y. Synthesis 2012, 44,
489. (d) Zhang, D.-Y.; Hu, X.-P. Tetrahedron Lett. 2015, 56, 283.
(13) Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111, 1914.
(14) (a) Hegedus, L. L.; McCabe, R. W. Catalytic Poisoning; Mar-
cel Dekker, 1984. (b) Hutton, A, T, in Comprehensive Coordina-
tion Chemistry; Wilkinson, G., Gillard, R. D., McCleverty, J. A.,
Eds.; Pergamon, 1984; Vol. 5, p 1151.
9
(15) (a) Damani, L. A. Sulphur-Containing Drugs and Related
Organic Compounds; Wiley, 1989. (b) Ilardi, E. A.; Vitaku, E.;
Njardarson, J. T. J. Med. Chem. 2014, 57, 2832.
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
(16) For selected reviews on enantioselective carbon-sulfur bond
formations, see: (a) Clayden, J.; MacLellan, P. Beilstein J. Org.
Chem. 2011, 7, 582. (b) Chauhan, P.; Mahajan, S.; Enders, D.
Chem. Rev. 2014, 114, 8807. (c) Liu, W.; Zhao, X. Synthesis 2013,
45, 2051. (d) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205.
(17) For seminal studies, see: Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi,
D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(18) For selected reviews on chiral phosphoric acid catalysis, see:
(a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Syn-
thesis 2010, 1929. (c) Kampen, D.; Reisinger, C. M.; List, B. Top.
Curr. Chem. 2010, 291, 395. (d) Parmar, D.; Sugiono, E.; Raja, S.;
Rueping, M. Chem. Rev. 2014, 114, 9047.
(19) (a) Philipps, R. J.; Hamilton, G. L.; Toste, F. D. Nature Chem.
2012, 4, 603. (b) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013,
52, 518.
(20) For reviews on DYKAT, see: (a) Steinreiber, J.; Faber, K.;
Griengl, H. Chem. Eur. J. 2008, 14, 8060. (b) Trost, B. M.;
Fandrick, D. R. Aldrichimica Acta 2007, 40, 59. (c) Faber, K.
Chem. Eur. J. 2001, 7, 5004.
(21) (a) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120,
900. (b) Derdau, V.; Laschat, S.; Dix, I. Organometallics 1999, 18,
3859.
(22) The prolonged reaction (24 h at rt) of 1a with 2a using 10
mol % (R)-3a was conducted to confirm the racemization of
product 4a under the standard reaction conditions (Table 1,
entry 5: 2 h at rt). The % ee of product 4a (92% ee, 92% yield)
observed in the prolonged reaction was exactly same as that of
the standard conditions (92% ee, 91% yield). These results clearly
indicate that the product does not undergo racemization under
the standard reaction conditions.
(23) CCDC No. 1459022 [(R)-4a] contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Center
via
www.ccdc.cam.ac.uk/data_request/cif.
Absolute
configurations of other products were assigned by analogy. See
the Supporting Information for details.
(24) During the course of the reaction of (S)-1k with 2a, the
enantiomeric purity of (S)-1k was maintained in high level
(≥96% ee) and hence racemization of (S)-1k did not take place
primarily under the standard reaction conditions (Table 3, entry
6).
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
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
ACS Paragon Plus Environment