Catalytic Regio- and Enantioselective Proton Migration from Skipped Enynes to Allenes

Article abstract of DOI:10.1016/j.chempr.2018.11.022

Chiral allenes are highly valuable as versatile synthetic intermediates and core skeletons of various functional organic molecules. Despite marked recent advances, the straightforward catalytic enantioselective synthesis of hydrocarbon allenes from readil

Full text of DOI:10.1016/j.chempr.2018.11.022

Article
Catalytic Regio- and Enantioselective Proton
Migration from Skipped Enynes to Allenes
Xiao-Feng Wei, Takayuki
Wakaki, Taisuke Itoh, ..., Miho
Hatanaka, Yohei Shimizu,
Motomu Kanai
hatanaka@ms.naist.jp (M.H.)
shimizu-y@sci.hokudai.ac.jp (Y.S.)
kanai@mol.f.u-tokyo.ac.jp (M.K.)
HIGHLIGHTS
A catalytic conversion of achiral
skipped enynes to chiral allenes is
developed
Soft-soft interactions between the
catalyst and the substrates play a
key role
The chiral ligand of the catalyst
controls both regio- and
enantioselectivity
DFT calculations rationalize the
ligand effects in reactivity and
selectivity
A catalytic enantioselective proton migration of skipped enynes to allenes is
developed. A newly identified chiral ferrocenyl phosphine ligand plays critical
roles in controlling both regio- and enantioselectivity. The method offers a new
concept to convert readily available and abundant feedstock hydrocarbons into
high-value-added molecules by reconstituting C–H bond connectivity without
relying on polar functional groups.
Wei et al., Chem 5, 1–15
March 14, 2019 ª 2018 Elsevier Inc.
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Article
Catalytic Regio- and Enantioselective
Proton Migration from Skipped
Enynes to Allenes
Xiao-Feng Wei,1 Takayuki Wakaki,1 Taisuke Itoh,1 Hong-Liang Li,1 Takayoshi Yoshimura,2
1,6,
1,7,
Aya Miyazaki,3 Kounosuke Oisaki,1 Miho Hatanaka,2,3,4,5, Yohei Shimizu,
and Motomu Kanai
*
*
*
SUMMARY
The Bigger Picture
Catalytic conversions of readily
available feedstock hydrocarbons
to value-added fine chemicals will
vastly expand the scope of
Chiral allenes are highly valuable as versatile synthetic intermediates and core
skeletons of various functional organic molecules. Despite marked recent ad-
vances, the straightforward catalytic enantioselective synthesis of hydrocarbon
allenes from readily available starting materials without relying on polar func-
tional groups is still very challenging. Here, we report a copper(I)-catalyzed
enantioselective proton migration from skipped enynes to allenes as an efficient
approach in chiral allene synthesis. With catalyst loading as low as 0.5 mol %, the
reaction proceeds smoothly under mild conditions without the need for addi-
tional stoichiometric reagents or generation of waste. Novel chiral ligand L6
plays a critical role in furnishing high catalyst activity, promoting regioselective
protonation to produce allenes instead of conjugated enynes, and inducing
axial chirality of allenes. The multiple roles of the chiral ligand are rationalized
by density functional theory calculations.
organic molecules. Because of the
lack of polar functional groups in
hydrocarbons, however,
conversions of hydrocarbons
require activation of unactivated
chemical bonds. Moreover, the
control of various types of
selectivity, including regio- and
enantioselectivity, is extremely
challenging. Here, we disclose a
catalytic enantioselective proton
migration of readily available
achiral skipped enynes to chiral
allenes. The product allenes are
versatile chiral building blocks for
value-added fine chemicals, such
as drugs and advanced functional
materials. Moreover, density
functional theory calculations
shed light on the origin of regio-
and enantioselectivity control.
The experimental and theoretical
approaches to the one-step,
catalyst-controlled reconstitution
of the C–H bond connectivity in
hydrocarbons will be a foundation
for a large-scale production of
value-added fine chemicals.
INTRODUCTION
Chiral allenes are a unique structural motif in biologically active compounds, phar-
maceuticals, and advanced materials.1,2 Due to their diverse reactivity and axial
chirality, allenes are also useful chiral building blocks in organic synthesis.3–14 Histor-
ically, the synthesis of enantiomerically enriched allenes15–25 mainly relied on
chirality-transfer processes from enantiomerically enriched propargylic amine or
alcohol derivatives, such as the Crabbe´ -type reaction,26–40 stereospecific rearrange-
ments,41–43 and SN20 reactions.44–52 Catalytic enantioselective synthesis of axially
chiral allenes from prochiral or racemic starting materials is a current topic of inter-
est.21–25 Representative methods in this category include (1) addition reactions to
conjugated enynes or diynes,53–63 (2) allylic substitution reactions or [3 + 2] cycload-
ditions through alkylidene p-allylpalladium intermediates,64–75 (3) palladium-cata-
lyzed allylic b-hydride elimination of internal enol triflates,76 (4) nickel-catalyzed
propargyl Claisen rearrangement,77 (5) deprotonative C(sp2)–H functionalization
of racemic allenes,78–81 (6) alkynylogous Mukaiyama aldol reaction,82 (7) copper-
catalyzed cross-coupling reactions between terminal alkynes and diazo com-
pounds,83–85 (8) enzymatic desymmetrization,86 (9) kinetic resolution,87–89 (10)
copper-catalyzed SN20 reaction of propargyl dichlorides,90,91 and (11) proton migra-
tion reactions from propargyl compounds to allenes.92–95 Despite the existence of
various methods for catalytic asymmetric synthesis of allenes, methods that produce
hydrocarbon allenes without relying on polar functional groups are extremely
limited.
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We are interested in the proton migration approach96–111 because of its apparent
simplicity while having fundamental complexity in furnishing regioselectivity for
the protonation step (Scheme 1A). Previous examples of the catalytic asymmetric
proton migration approach affording chiral allenes in high enantioselectivity
predominantly relied on installing an electron-withdrawing group (EWG) to
the substrates to facilitate deprotonation and regioselective protonation
(Scheme 1B).93–95 Arai and Shioiri’s report provided the sole example using a hydro-
carbon 1,3-diarylalkyne substrate without EWG; however, the enantioselectivity was
only 35% enantiomeric excess (ee), and the scope of the reaction was not described
(Scheme 1C).92 Here we disclose that regio- and enantioselective proton migration
under a more complex setting from skipped enynes 1 to allenes 2 is possible without
relying on EWGs, by identifying a copper(I) catalyst containing a properly tuned chi-
ral ligand L6 (Scheme 1D, equation 3).
We previously reported that a copper(I) alkoxide/Ph-BPE (L1) complex exhibits high
Brønsted basicity toward skipped enynes 1, allowing for catalytic enantioselective
addition of enynes to ketones via a proton-transfer mechanism (Scheme 1D,
equation 1).112 Chemoselective acidification of a propargylic C3–H bond in skipped
enynes 1 in the presence of ketones through a soft-soft interaction between alkyne
p-electrons and a copper(I) ion of the catalyst is critical for direct and chemoselective
generation of nucleophilic organocopper species from hydrocarbon substrates con-
taining an intrinsically less acidic proton than ketones. The fact that the regio- and
enantioselective C–C bond formation occurred at the terminal C5 position, produc-
ing homoallylic tertiary alcohol 4, is another key feature of the previous study. There
are three potential nucleophilic sites at C1, C3, and C5 for the three isomeric inter-
mediate organocopper species 5, 6, and 7 existing in equilibrium. Here, we address
the following questions: (1) is the regioselectivity at the C5 position general for other
electrophiles, and (2) is the regioselectivity switchable depending on the ligand?
RESULTS AND DISCUSSION
Optimization of Proton Migration from Skipped Enynes to Allenes
We began our development of the catalytic enantioselective synthesis of allenes
through proton migration using 1-phenyl-4-penten-1-yne (1a) as a model substrate,
1Graduate School of Pharmaceutical Sciences,
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
H2O as a proton source, and a 10 mol % catalyst loading (Table 1). A catalyst gener-
ated from mesitylcopper (MesCu) and (S,S)-Ph-BPE (L1), an optimized catalyst for
enantioselective addition to ketones,112 afforded conjugated enyne 3a as the sole
product through C5 protonation (Table 1, entry 1; Scheme 1D, equation 2).
Although most commercially available chiral ligands afforded mixtures of re-
gioisomers, 2a (or its enantiomer) and 3a, with low regio- and enantioselectivity
(Table S1), the modified Josiphos ligand L2 containing a methoxy substituent at
the ortho position of the aryl group (Ar0) exhibited exceptionally high regio- and
enantioselectivity (Table 1, entry 2, 92% yield, 2a:3a = 9.8:1, 2a = 82% ee). In
contrast, p-OMe-substituted ligand L3 exhibited comparably high reactivity to L2,
albeit with much lower regio- and enantioselectivity (Table 1, entry 3, 92% yield,
2a:3a = 1.4:1, 2a = 6% ee). To further evaluate the effects of the o-OMe substituent
on Ar0, we examined ligand L4 containing o-Me substituents. In this case, however,
the reaction was dramatically retarded (Table 1, entry 4). We synthesized L5 contain-
ing o-OiPr groups, intending to increase the steric bulkiness while maintaining the
electronic properties of L2. Although the catalyst activity of L5 was higher than
that of L4, the product yield and regio- and enantioselectivity were much lower
than that of L2 (Table 1, entry 5, 23% yield, 2a:3a = 1.9:1, 2a = 34% ee). In contrast,
substituents on the other diarylphosphine moiety (Ar) did not significantly influence
2Institute for Research Initiatives, Nara Institute of
Science and Technology, 8916-5 Takayama-cho,
Ikoma, Nara 630-0192, Japan
3Graduate School of Materials Science, Nara
Institute of Science and Technology, 8916-5
Takayama-cho, Ikoma, Nara 630-0192, Japan
4Data Science Center, Nara Institute of Science
and Technology, 8916-5 Takayama-cho, Ikoma,
Nara 630-0192, Japan
5PRESTO, Japan Science and Technology
Agency, Honcho, Kawaguchi, Saitama 332-0012,
Japan
6Present address: Department of Chemistry,
Faculty of Science, Hokkaido University, Sapporo,
Hokkaido 060-0810, Japan
7Lead Contact
*Correspondence: hatanaka@ms.naist.jp (M.H.),
shimizu-y@sci.hokudai.ac.jp (Y.S.),
kanai@mol.f.u-tokyo.ac.jp (M.K.)
https://doi.org/10.1016/j.chempr.2018.11.022
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Scheme 1. Catalytic Enantioselective Synthesis of Allenes from Alkynes via Proton Migration
(A) General scheme of enantioselective proton migration for allene synthesis.
(B) EWG-assisted catalytic enantioselective proton migration to allenes.93–95
(C) Catalytic enantioselective proton migration to allenes without relying on EWG (only one substrate).92
(D) Ligand-enabled catalytic enantioselective proton migration to allenes from the present study.
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Table 1. Optimization of the Reaction Conditions
MesCu (10 mol %)
ligand (10 mol %)
proton source (2 equiv)
5
3
*
Ph
1
+
THF (0.5 M)
rt, 4 hr
Ph
Ph
H
1a
(R)-2a
3a
ee (%)a
Entry
1
Proton Source
Ligand
L1
Yield (%)
qaunt.
92
2a:3a
1:>20
9.8:1
1.4:1
–
H2O
–
2
H2O
L2
82b
6b
3
H2O
L3
92
4
H2O
L4
trace
23
–
5
H2O
L5
1.9:1
8.8:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
34b
80
6
H2O
L6
85
7c,d
8c,d
9c,d
10c,d
11c,d,e
12c,d,f
13c,d,e
14c,e,h
H2O
L2
31
78b
68b
76b
84b
80b
82b
84
MeOH
L2
45
EtOH
L2
33
methoxyethanol
methoxyethanol
–
L2
58
L2
94
L2
7
methoxyethanol
methoxyethanol
L6
94 (92)g
80
L6
84
PAr'2
L2: Ar' = o-MeO-C6H4
L3: Ar' = p-MeO-C6H4
L4: Ar' = o-Me-C6H4
L5: Ar' = o-iPrO-C6H4
Ar2P
Ph
Fe
Ph
P
Ar = p-MeO-3,5-di-Me-C6H2
P
L2-L5
Ph
Ph
(S,S)-Ph-BPE (L1)
Ar'2P
PPh2
Fe
L6: Ar' = o-MeO-C6H4
General reaction conditions: 1a (0.1 mmol), H2O (0.2 mmol), MesCu (0.01 mmol), and ligand (0.01 mmol)
were reacted in THF (200 mL) at room temperature for 4 hr. Yields were determined by 1H NMR analysis of
the crude mixture using 1,3,5-trimethylbenzene as an internal standard. See also Table S1.
aEnantiomeric excess (ee) was determined by chiral high-performance liquid chromatography.
b(S)-2a was obtained as the major enantiomer.
cConcentration of 1a in the reaction mixture was 1 M.
d1 mol % catalyst loading.
e0.2 equiv of methoxyethanol was used.
fNo proton source was added.
gIsolated yield is shown in parentheses.
h0.5 mol % catalyst loading.
the catalytic properties (Table 1, entry 6); ligand L6 containing a diphenylphosphine
moiety (Ar = Ph) produced results comparable with those of L2 (85% yield, 2a:3a =
8.8:1, 2a = 80% ee). These results indicate the critical importance of the o-OMe
substituent on the Ar0 groups of L2 and L6 for exhibiting high catalyst activity and
regio- and enantioselectivity.
4
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Next, we attempted to improve the catalyst turnover. When the catalyst loading was
lowered to 1 mol % with L2, the yield of 2a decreased to 31% with increased regio-
selectivity (Table 1, entry 7, 2a:3a = >20:1). Screening a proton source (Table 1, en-
tries 7–12) revealed that methoxyethanol was a good candidate; 2a was obtained in
58% yield with a slightly improved 84% ee (entry 10). The yield of 2a was increased to
94% by decreasing the amount of methoxyethanol to 0.2 equiv (entry 11). This bene-
ficial effect of reducing the amount of the proton source on product yield was not
observed when H2O was used instead of methoxyethanol (data not shown). In the
absence of any additional proton source based on the consideration that substrate
1a itself would act as a proton source, the reactivity significantly decreased (entry
12). Because synthesizing L2 containing Ar = p-MeO-3,5-di-Me-C6H2 groups is
not an easy task, we evaluated the performance of more easily accessible ligand
L6 under the thus-optimized conditions. L6 exhibited reactivity and selectivity
comparable with L2, affording 2a in 94% yield, >20:1 regioselectivity, and 84% ee
(Table 1, entry 13). Comparable results were obtained using 0.5 mol % catalyst
loading (Table 1, entry 14).
Substrate Scope of Proton Migration from Skipped Enynes to Allenes
We then examined the substrate scope of the reaction under the optimized condi-
tions using 1–10 mol % catalyst, depending on the reactivity of the substrates
(Scheme 2 and Table S2). For substrates containing a terminal vinyl group
(R2 = H), enantioselectivity was almost consistent (84%–85% ee) when R1 was a
phenyl, a tolyl, or a thiophenyl group (2a–2d). The enantioselectivity gradually
increased according to the size of the R2 group: 84% ee (R2 = H: 2a), 90% ee
(R2 = Me: 2e), and 91% ee (R2 = Et: 2h), when R1 = Ph. An aliphatic substituent
at the R1 group was also competent, despite slightly decreased enantioselectivity
(2g: 80% ee). Dienyne 1g is, however, an especially challenging substrate because
of elongated conjugation. The intermediate organocopper species contains four
possible protonation sites (Scheme 1D, R1 = cyclohexenyl). Nevertheless, it is note-
worthy that allene 2g was obtained as the exclusive product. Fixing the R2 group as
an ethyl group, excellent enantioselectivity was produced with various aromatic
groups at R1 (2h–2n: 90%–94% ee). A wide range of substituents were tolerated
at the R2 group, including sterically more hindered heptyl (2o), isopropyl (2p), iso-
butyl (2q), and benzyl (2r) groups, an aryl group (2s), and functionalized trimethyl-
silylmethyl (2t) and benzyloxymethyl (2u) groups, affording the products with
excellent enantioselectivity (R86% ee). In all cases, the enantioselective proton-
ation proceeded with excellent regioselectivity (12:1 / 20:1 regioisomeric ratio
[rr]), affording allene products.
The reaction was scalable, providing the basis for a practical and straightforward
synthesis of enantiomerically enriched allenes starting from commercially available
materials (Scheme 3). Thus, after skipped enyne 1a was prepared through a cop-
per-catalyzed substitution reaction,113 enantioselective proton migration was con-
ducted in gram-scale with 0.5 mol % catalyst loading. The reaction proceeded
smoothly to give product 2a in 71% yield with perfect regioselectivity and 86% ee.
Mechanistic Investigations
Deuteration Experiments
To gain insight into the reaction mechanism, we conducted deuteration experiments
by using 5 equiv D2O as a deuterium source (Scheme 4). When a Cu/L1 catalyst was
used, the product was conjugated enyne 3a with deuteration at the C3 and C5 po-
sitions (equation 1). Allene 2a through deuteration at the C1 position was not
observed at all in this case. In sharp contrast, deuterium was incorporated only at
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MesCu (1 10 mol %)
L6 (1 10 mol %)
methoxyethanol (20 mol %)
*
R1
R2
R1
R2
THF (0.5 1 M)
20oC rt, 4 40 hr
H
2
1
Ph
S
Ph
H
H
H
H
H
2a
92% yield
2b
90% yield
2c
91% yield
2d
80% yield
2e
85% yield
84% ee, >20 : 1 rr
(1 mol %), rt, 4 hr
85% ee, 12 : 1 rr
(1 mol %), rt, 4 hr
84% ee, > 20 : 1 rr
(2.5 mol %), rt, 16 hr
84% ee, >20 : 1 rr
(5 mol %), rt, 4 hr
90% ee, > 20 : 1 rr
(10 mol %), rt, 7 hr
OMe
F
Ph
H
H
H
H
H
2f
2g
2h
2i
2j
93% yield
61% yield
76% yield
39% yield
63% yield
88% ee, > 20 : 1 rr
(5 mol %), rt, 4 hr
80% ee, > 20 : 1 rr
(5 mol %), rt, 4 hr
91% ee, > 20 : 1 rr
90% ee, > 20 : 1 rr
(5 mol %), 20°C, 40 hr
90% ee, > 20 : 1 rr
(5 mol %), 0°C, 18 hr
(5 mol %), 0oC, 14 hr
Ph
tBu
OMe
H
S
H
H
H
H
2k
2l
2m
2n
2o
91% yield
75% yield
65% yield
49% yield
59% yield
90% ee, > 20 : 1 rr
(5 mol %), 0°C, 18 hr
94% ee, > 20 : 1 rr
(5 mol %), 0°C, 18 hr
91% ee, > 20 : 1 rr
(5 mol %), 0°C, 14 hr
93% ee, > 20 : 1 rr
(5 mol %), 0°C, 18 hr
91% ee, > 20 : 1 rr
(5 mol %), 0°C, 18 hr
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
Ph
2r
99% yield
TMS
OBn
2u
2s
2t
2p
2q
86% yield
95% yield
72% yield
89% yield
86% ee, > 20 : 1 rr
(5 mol %)
46% yield
90% ee, > 20 : 1 rr
(5 mol %), 10°C, 40 hr
90% ee, > 20 : 1 rr
(10 mol %)
90% ee, > 20 : 1 rr
(2.5 mol %)
rt, 7 hr
90% ee, > 20 : 1 rr
(5 mol %)
92% ee, > 20 : 1 rr
(5 mol %), 0°C, 18 hr
20°C, 40 hr
10°C, 14 hr
10°C, 18 hr
Scheme 2. Substrate Scope of Cu(I)/L6-Catalyzed Enantioselective Proton Migration from Skipped Enynes to Allenes
General reaction conditions: 1 (0.1 mmol), methoxyethanol (0.02 mmol), MesCu (0.001–0.01 mmol), and L6 (0.001–0.01 mmol) were reacted in THF
(100–200 mL) at the indicated temperature and time. See also Table S2.
the C1 and C3 positions with a Cu/L6 catalyst, with C1 as the major deuteration site
(equation 2). These results provide two important mechanistic insights. First, repro-
tonation of the intermediate organocopper species at the C3 position competed in
both proton migration pathways: from 1a to 3a with Cu/L1 and from 1a to 2a with
Cu/L6. Second, the ratio of 2a and 3a was kinetically determined depending on
the catalyst; 2a or 3a was not detected as an intermediate for the generation of 3a
or 2a in the Cu/L1- or Cu/L6-catalyzed pathway, respectively. The fact that deute-
rium was not incorporated at the C5 position in 2a also ruled out the possibility
that 2a was generated through 3a.
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CuI (10 mol %), Na2SO3 (50 mol %)
H
K2CO3 (1 equiv), DBU (18 mol %)
Br
+
Ph
Ph
DMF, rt, 4 hr
1a
91% yield
3-g scale
(1.5 equiv)
(1 equiv)
MesCu (0.5 mol %), L6 (0.5 mol %)
methoxyethanol (20 mol %)
*
Ph
71% yield
86% ee, >20:1 rr
THF, rt, 24 hr
H
1-g scale
2a
Scheme 3. Practical Synthesis of Enantioenriched Allenes
DFT Calculations
To understand the basis for the ligand-dependent switch of the two reaction path-
ways (see Table 1, entries 1 and 6), we performed density functional theory (DFT)
calculations. We first identified allenylcopper 5a (R1 = Ph, R2 = R3 = H; Scheme 1D)
as the most stable isomer among the three organocopper intermediates, 5a, 6a,
and 7a, in the presence of a phosphine ligand, L1 or L6 (Scheme 1D and Figure S1).
Propargylcopper 6a was the least stable of the three isomers, both in the absence
and presence of a phosphine ligand, due to deconjugation of the two p orbitals of
the C–C double and triple bonds in the organo propargyl ligand derived from 1a.
Formation of 6a was also kinetically less favored because of the low reactivity of
sp3-C3 and the high activation barrier of isomerization from 5a to 6a (Figure S2).
The stability did not differ significantly between allenylcopper 5a and allylcopper
7a, however, in the absence of a phosphine ligand (Figure S1). The orbital
coefficiencies at the C1, C3, and C5 positions in the highest occupied
molecular orbital (HOMO) of the anion derived from 1a were almost identical (Fig-
ure S3). Thus, the relative stability of 5a to 7a in the presence of a phosphine ligand
must be due not to electronic factors, but rather to the difference in the extent of
steric repulsion between the two ligands on the copper atom, i.e., a phosphine
ligand and an organo ligand derived from 1a. The allenyl organo ligand in 5a
bends away from a phosphine ligand on the copper atom, whereas the allyl
organo ligand in 7a is planar. The difference in the shape of the organo ligands
should lead to more severe steric repulsion between the phosphine ligand and
the allyl organo ligand in 7a than the allenyl organo ligand in 5a. This notion is
consistent with the results of the DFT calculations for the ligand-dependent energy
difference between allenylcopper 5a and allylcopper 7a (Figure S1); the energy
difference between 5a and 7a was greater for the sterically more hindered
phosphine ligand L6 (DG = 4.0 kcal molꢀ1) than for L1 (DG = 1.6 kcal molꢀ1).
Focusing on the HOMO of 1a, the orbital population on the alkyne moiety (at
C1 and C2 positions) was the largest, which indicated that the formation of 5a
from 1a could be the most favored pathway (Figure S4). Even if 7a was formed,
the proton transfer to 2a and 3a could be inhibited due to the steric hindrance
of the phosphine ligand and the low reactivity of sp3-C5, respectively.
Therefore, 7a could rearrange to 5a, whose activation barriers were only 12.6
and 16.7 kcal molꢀ1 for L1 and L6 systems, respectively (Figure S2). In addition,
the existence of an equilibrium between organocopper intermediates (5a, 6a, or
7a) and 1a, which was confirmed by the deuteration experiments (Scheme 4, equa-
tion 2), also support the notion that the proton transfer would proceed through the
most stable allenylcopper 5a.
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36% D
H/D
MesCu (10 mol %)
5
3
3a
L1 (10 mol %)
1
89% yield
> 20 : 1 rr
H/D
(1)
(2)
Ph
Ph
Ph
16% D
1a
THF (0.5 M)
rt, 2 hr
+
19% D
H/D
H
D2O
(5 equiv)
2a
53% yield
> 20 : 1 rr
H
MesCu (10 mol %)
0% D
H/D
83% D
L6 (10 mol %)
Scheme 4. Deuteration Experiments
The most stable organocopper intermediate was consistently 5a, irrespective of
phosphine ligand L1 or L6; therefore, the ligand-dependent regioselectivity in the
proton migration step could be determined by the transition states (TSs) for proton-
ation of allenylcopper 5a. Thus, we compared the TSs for protonation pathways at
the C1 (TS-C1) and C5 (TS-C5) positions of 5a, where a H2O molecule coordinating
to the copper atom functions as an active proton source (Figure 1A). As a control
without a ligand on the copper atom, TS-C5 (9) for protonation at the C5 position
of 5a, affording conjugated enyne 3a, was 22.1 kcal molꢀ1 more stable than TS-C1
(8) for protonation at the C1 position affording allene 2a (Figure 1B). The energy dif-
ference between the two TSs is most likely due to the greater structural distortion of
the four-membered ring in TS-C1 (8, magenta) than of the eight-membered ring in
TS-C5 (9, blue). For the Cu/L1 system, TS-C5 (11) was still more stable than TS-C1
(10) (Figure 1C). For the Cu/L6 system, however, TS-C5 (13) was 3.4 kcal molꢀ1
less stable than TS-C1 (12), supporting our experimental results that the favorable
protonation pathway switched to the C1 position when the Cu/L6 catalyst was
used (Figure 1D).
The switch of favored TS structures depending on the ligands was due to distinct
sensitivity of the four- and eight-membered ring TSs of TS-C1 and TS-C5, respec-
tively, to the steric hindrance of the ligands—bulky ligand L6 destabilized the
sterically more congested eight-membered TS-C5 to a greater extent than the
less congested four-membered TS-C1. More quantitatively, we parameterized
the ligand-caused distortion energy (LCDE) by subtracting the energy value of 8
or 9 in the absence of a ligand (Figure 1B) from the energy value of the four- or
eight-membered ring moiety in 10/12 or 11/13 (Figures 1C and 1D) by maintaining
the ring conformation but eliminating the ligand. The LCDEs of the eight-membered
rings in 11 and 13 were 19.7 and 31.7 kcal molꢀ1, respectively. The difference re-
flected the greater steric hindrance of L6 than L1. In contrast, the LCDE of the
four-membered ring of TS-C1 was not significantly affected by the ligands:
8.6 kcal molꢀ1 for 10 and 9.6 kcal molꢀ1 for 12. Therefore, according to the increase
in the steric hindrance of the ligands, TS-C5 was destabilized to a greater extent than
TS-C1, resulting in inhibition of the formation of 3a when sterically demanding ligand
L6 was used.
The DFT calculations also rationalized the absolute configuration of major product
(R)-2a using L6 (Figures 2 and S6). Ligand L6 hindered three areas around the copper
atom by the aryl substituents on the phosphorus atoms (Figure 2A, shown in green).
For TS 12 affording (R)-2a (the experimentally obtained major enantiomer), the
8
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Figure 1. Comparison of TSs for Two Protonation Pathways
(A) Chemical formulae of TSs for C1 protonation (TS-C1) and C5 protonation (TS-C5).
(B) Ligandless system.
(C) Cu/L1 system.
(D) Cu/L6 system.
The Gibbs free activation energies DGǂ and their differences DDG are in kcal molꢀ1. Four- and eight-membered rings are shown in magenta and blue,
respectively. The Gibbs free energy profiles are shown in Figure S5.
phenyl and vinyl substituents of the allenyl organo ligand were positioned at the ste-
rically less-hindered areas (Figure 2B). On the other hand, the vinyl substituents,
especially the substituent at the C4 position (R2), protruded to the sterically hindered
area in TS 14 affording (S)-2a (Figure 2C). As a result, 12 (R2 = H) was 4.6 kcal molꢀ1
more stable than 14 (R2 = H), leading to the formation of (R)-2a as the major product
enantiomer. The observation that the enantioselectivity was higher according to ste-
ric hindrance of the R2 group (see the results of 2a, 2e, and 2h in Scheme 2) is consis-
tent with these models. The characteristic three hindered areas were also observed
in the copper complexes of L2 and L5 (Figure S7). Despite the similar steric profile
between the copper complexes of L6 and L2 (enantiomeric), less-hindered areas
were narrower for L5 than L6 and L2. This difference in the steric profile around
the copper atom can be a reason for the lower enantioselectivity by L5 (Table 1).
The copper complexes of L3 and other ligands shown in Table S1 exhibited only
two or fewer numbers of hindered areas (Figure S7). Thus, the orientation of allenyl
organo ligand can be flexible, resulting in the small energy difference between two
diastereomeric TSs producing enantiomer products (corresponding to 12 and 14),
i.e., lower ee than the copper complexes of L2 and L6.
Finally, we assessed the origins of the dramatic difference in catalyst activity be-
tween Cu/L2 and Cu/L4 despite the minimum structural difference between
the two phosphine ligands (Ar0 = o-MeOC6H4 for L2 and o-MeC6H4 for L4, see
Table 1, entries 2 and 4). Figure 3 shows the two conformers (open and closed forms)
of the CuOH/L2 and CuOH/L4 complexes. For the reactive CuOH/L2 complex, open
form 15 with a large space around the copper atom was more stable than closed
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Figure 2. Rationalization of the Absolute Configuration of the Product
˚
(A) Topographic steric map of L6. The area shown in green represents more hindered area. The position of Cu is set to DZ = 0.0 A.
(B) TS 12 affording the observed major enantiomer of product (R)-2a.
(C) Diastereomeric TS 14 affording (S)-2a.
The Gibbs free activation energies DGǂ are in kcal molꢀ1
.
form 16 with an o-OMe substituent inducing steric hindrance, thus creating a narrow
space around the copper atom. In the stable open form 15, the o-OMe group in the
Ar0 substituent faced opposite the copper atom to form a C–H,,,OMe hydrogen
bond (Figure 3A). Unlike the CuOH/L2 complex, however, closed form 18 was
more stable than open form 17 for the non-reactive CuOH/L4 complex; 17 was de-
stabilized by the steric repulsion (Figure 3B). In closed forms 16 and 18, there is not
enough space for substrate 1 to access the catalytically active copper center. There-
fore, catalyst activity will be low for these conformers. The stable conformer of the
marginally reactive CuOH/L5 complex containing o-OiPr substituents was the
open form (Table 1, entry 5); however, the probability of the closed form of
CuOH/L5 was greater than that of the closed form of CuOH/L2 (Figure S8). The de-
pendency of the catalyst activity on the ligand structure observed in Table 1 was in
accordance with the probability of the open form. Overall, the ligand needs to be
bulky to inhibit the undesired C5 protonation pathway through the eight-membered
ring TS (TS-C5 in Figure 1), although a ligand that was too bulky could cause low
catalyst activity by obstructing the access of substrate 1 to the copper catalytic cen-
ter (Figure 3).
Conclusion
We developed a copper-catalyzed enantioselective proton migration from skipped
enynes to chiral allenes (Scheme 2). The reaction proceeded under mild conditions
independent of the EWGs in the substrates. Thus, readily available, non-chiral hy-
drocarbon skipped enynes were facilely and practically converted to isomeric chiral
hydrocarbon allenes of high synthetic values114,115 through a catalyst-controlled
regio- and enantioselective proton-transfer process (see Scheme 3 for an example).
Sterically demanding chiral Josiphos-type ligand L2 and L6 bearing a di(ortho-me-
thoxyphenyl)phosphine moiety (Ar02P) was critically important for furnishing the
three essential factors to the reaction with high levels (Table 1): (1) catalyst activity,
(2) regioselectivity, and (3) enantioselectivity. DFT calculations theoretically revealed
10
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Figure 3. Gibbs Free Energy Differences of Optimized Structures
Open and closed conformations of CuOH/L2 (A) and CuOH/L4 (B). See also Figure S8 for other ligands.
the origins of the ligand effects on these three factors. For high catalyst activity, a
non-conventional intramolecular hydrogen bond between the o-OMe substituent
on the phosphorus atom and the benzylic methine proton of the ferrocenyl group
afforded enough space for the substrates to access the catalytically active copper
center (Figure 3). For regioselective protonation of the intermediate allenylcopper
species, sterically demanding L6 selectively destabilized the undesired pathway
for protonation at the C5 position producing conjugated enyne 3, which proceeded
through a sterically congested eight-membered ring TS, relative to the desired
pathway for protonation at C1 proceeding through a more compact four-membered
ring TS and affording chiral allene 2 (Figure 1). The relative stability of diastereomeric
transition state models 12 and 14 dictated the enantioselectivity (Figure 2). There-
fore, our answers to the two questions raised in the Introduction are as follows.
Question (1): is the regioselectivity at the C5 position general for other electro-
philes? Answer: yes. Addition reactions to ketones and protons both proceed at
the C5 position when the same ligand L1 is used. Question (2): is the regioselectivity
switchable depending on the ligand? Answer: yes. The regioselective protonation
proceeds at either the C5 or C1 position when ligand L1 or L2/L6 is used, respec-
tively. The method developed in this study offers a cutting-edge concept to synthe-
size value-added chiral hydrocarbon allenes from readily available non-chiral
skipped enynes by reconstituting C–H bond connectivity in a single molecule
through catalytic regio- and enantioselective proton migration without relying on
polar functional groups.
EXPERIMENTAL PROCEDURES
A Gram-Scale Procedure for Catalytic Enantioselective Proton Migration
In an argon-filled glovebox, an oven-dried glassware reaction vessel (50 mL) was
charged with a magnetic stirring bar, L6 (25.6 mg, 40 mmol, 0.5 mol %), mesitylcop-
per (7.2 mg, 40 mmol, 0.5 mol %), methoxyethanol (126 mL, 1.6 mmol, 20 mol %), and
THF (8 mL). The resulting pale-yellow solution was stirred at room temperature un-
der argon atmosphere for 10 min. Skipped enyne 1a (1.14 g, 8 mmol, 1 equiv) was
added dropwise to the vessel. After stirring at room temperature for 24 hr, the
mixture was passed through a short pad of silica-gel column chromatography using
1
hexane as an eluent. After evaporation of the solvent, the rr was determined by H
NMR analysis of the crude mixture. Product 2a was obtained in a pure form as color-
less oil in 71% yield (806 mg) after silica-gel flash chromatography (eluent: hexane).
Computational Details
All potential energy surfaces were described with DFT and the B3LYP-D3 func-
tional,116–118 including the solvation effect with the polarized continuum model
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(PCM)119 and a dielectric constant of 7.4257 (tetrahydrofuran). The basis sets were
SDD for Cu and Fe,120 6-311G(d,p) for P and atoms in the substrates, and
6-31G(d) for atoms in the ligands.121,122 The approximate local minima and TSs
were explored with the artificial force-induced reaction (AFIR) method,123 then all
the obtained structures were fully reoptimized for the electronic energy. The TSs
were confirmed by the intrinsic reaction coordinate (IRC) calculations.124 The Gibbs
free energies were evaluated with the Gibbs free energy correction terms at 298.15 K
and 1 atm. The geometry optimization, IRC, and AFIR calculations were performed
using the GRRM (Global Reaction Route Mapping) program125 with energies and en-
ergy derivatives computed by the Gaussian09 program.126 The topographic steric
map127 was drawn by our originally implemented program.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, eight
figures, and two tables and can be found with this article online at https://doi.org/
10.1016/j.chempr.2018.11.022.
ACKNOWLEDGMENTS
This work was supported by Japan Society for the Promotion of Science KAKENHI
grant numbers JP17H06442 (M.K.) (Hybrid Catalysis), JP17H06445 (M.H.) (Hybrid
Catalysis), and JP15K07851 (Y.S.); by the Japan Science and Technology Agency
through the PRESTO program (JPMJPR15NE) (M.H.); and by a research grant from
the Kobayashi International Scholarship Foundation (M.K.). We also acknowledge
the computer resources provided by the Academic Center for Computing and Me-
dia Studies at Kyoto University and by the Research Center of Computer Science at
the Institute for Molecular Science.
AUTHOR CONTRIBUTIONS
X.-F.W., Y.S., and M.K. designed the research. X.-F.W., T.W., T.I., and H.-L.L. synthe-
sized the catalysts and the substrates. X.-F.W. and T.W. performed the catalytic re-
actions; M.H., T.Y., and A.M. performed the DFT calculations. X.-F.W., T.W., K.O.,
M.H., Y.S., and M.K. analyzed the data. X.-F.W., M.H., Y.S., and M.K. co-wrote the
paper. All the authors discussed the results and commented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: June 11, 2018
Revised: October 31, 2018
Accepted: November 29, 2018
Published: January 10, 2019
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