Copper-Catalyzed Enantioselective Coupling between Allyl-boronates and Phosphates Using a Phenol-Carbene Chiral Ligand: Asymmetric Synthesis of Chiral Branched 1,5-Dienes

Article abstract of DOI:10.1055/s-0036-1591548

Details of the Cu-catalyzed enantioselective allyl-allyl coupling reaction between allylboronates and (Z)-allylic phosphates using a new chiral N -heterocyclic carbene (NHC) ligand containing a phenolic hydroxy group are presented. The copper catalysis delivers enantio-enriched chiral 1,5-dienes with a tertiary stereogenic center. Compatibility with various functional groups and the use of earth-abundant and relatively low-toxicity copper as a metal are attractive features of this protocol. The utility of the chiral phenol-NHC ligand for enantioselective copper catalysis with organoboron compounds is demonstrated and enantiodiscrimination models are discussed.

Full text of DOI:10.1055/s-0036-1591548

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
Y. Yasuda et al.
Paper
Synthesis
Copper-Catalyzed Enantioselective Coupling between Allyl-
boronates and Phosphates Using a Phenol–Carbene Chiral Ligand:
Asymmetric Synthesis of Chiral Branched 1,5-Dienes
Yuto Yasudaa
Hirohisa Ohmiya*b
Masaya Sawamura*a
R1
O
Ph
Ph
Cy
B
R2
Cu/L* (10 mol%)
O
R1
MeOK
N
N
+
THF
a Department of Chemistry, Faculty of Science, Hokkaido University,
Sapporo 060-0810, Japan
R2
Cy
H
OH
chiral 1,5-diene
L*
sawamura@sci.hokudai.ac.jp
OP(O)(OEt)2
b Division of Pharmaceutical Sciences, Graduate School of Medical
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-
1192, Japan
up to γ/α >99:1
up to 99% ee
phenol-NHC Ligand
ohmiya@p.kanazawa-u.ac.jp
Received: 19.12.2017
Accepted after revision: 12.02.2018
Published online: 20.03.2018
cently, Feringa’s group reported asymmetric cross-coupling
between allyl Grignard reagents and (E)-allyl bromides us-
ing a copper–chiral monodentate phosphoramidite catalyst,
but only moderate SN2’ regioselectivity was obtained.6 In
2014, Carreira and co-workers developed Ir-catalyzed re-
gio- and enantioselective allylic cross-coupling between
allylsilanes and secondary aromatic allylic alcohols.7 De-
spite these efforts, allyl–allyl coupling was limited to the
use of acyclic (E)-allylic electrophiles.
DOI: 10.1055/s-0036-1591548; Art ID: ss-2017-z0760-op
Abstract Details of the Cu-catalyzed enantioselective allyl–allyl cou-
pling reaction between allylboronates and (Z)-allylic phosphates using a
new chiral N-heterocyclic carbene (NHC) ligand containing a phenolic
hydroxy group are presented. The copper catalysis delivers enantio-
enriched chiral 1,5-dienes with a tertiary stereogenic center. Compati-
bility with various functional groups and the use of earth-abundant and
relatively low-toxicity copper as a metal are attractive features of this
protocol. The utility of the chiral phenol–NHC ligand for enantioselec-
tive copper catalysis with organoboron compounds is demonstrated
and enantiodiscrimination models are discussed.
COOH
O
O
MeO
MeO
Plakortide E
O
O
H
OH
O
Key words asymmetric catalysis, allylic substitution, synthetic meth-
ods copper catalysis, organoboron compounds
O
N
H
Chiral 1,5-dienes with a stereogenic center at the allylic/
homoallylic position are found in many important biologi-
cally active molecules, such as FK-506, plakortide E, and
chaetoglobosin A (Figure 1),1 and also serve as useful build-
ing blocks in organic synthesis due to the versatility of the
two alkene functionalities for further transformations.
While several methods have been developed to produce
chiral 1,5-dienes,2 enantioselective γ-substitution of allyl
alcohol derivatives with organometal reagents (allyl–allyl
coupling) using chiral transition-metal complexes as cata-
lysts is the most straightforward because it uses readily
available substrates.3
In 2010, Morken and co-workers reported the pioneer-
ing example of catalytic asymmetric allyl–allyl coupling;
Pd-catalyzed allyl–allyl coupling between substituted allyl-
boronates4 and (E)-allylic carbonates occurred with high
regio- and enantioselectivity.5 This protocol enabled access
to chiral 1,5-dienes containing contiguous stereogenic cen-
ters with high diastereo- and enantioselectivity. More re-
OH
O
O
HN
HN
O
OMe
OH
O
O
Chaetoglobosin A
FK-506
OH
O
Figure 1 Biologically active compounds
Recently, the Cu-catalyzed enantioselective allyl–allyl
coupling between allylboronates and allylic phosphates8–11
using a new chiral N-heterocyclic carbene (NHC) ligand
bearing a phenolic hydroxy group12,13 was reported. Reac-
tion occurred with exceptional γ-regioselectivity and high
enantioselectivity. Various functional groups were tolerat-
ed. The ability to use (Z)-aliphatic allylic substrates in the
copper catalysis was complementary to Morken’s Pd system
(in their reports, only primary (E)-allylic electrophiles were
used).5 The present report describes the details of further
studies of this Cu-catalyzed enantioselective allyl–allyl cou-
pling.8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
Y. Yasuda et al.
Paper
Synthesis
Enantioselective SN2′ allylic alkylation between non-al-
lylic alkylboranes (alkyl-9-BBN) and primary allylic sub-
strates using a catalytic amount of a chiral bisphos-
phine/copper(I) complex and a stoichiometric amount of
potassium alkoxide base has been reported.14 The results
prompted the initiation of a program to develop a Cu-cata-
lyzed enantioselective allylic substitution with allylboron
reagents. For screening of the reaction conditions, commer-
cially available allylboronic acid pinacol esters were used
instead of the allyl-9-BBN reagents (Table 1).15 During in-
vestigation of an effective achiral ligand that could selec-
tively produce the racemic, branched γ-substitution prod-
uct 3aa, a ring-saturated NHC/copper complex, prepared in
situ from 1,3-bis(2,4,6-trimethylphenyl)imidazolinium
chloride (SIMes·HCl), CuCl, and KOMe, produced coupling
product 3aa in high yield (93%) with exclusive γ-regioselec-
tivity (γ/α >99:1) from the reaction between 2-allyl-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1a) and γ-monosubsti-
tuted primary (Z)-allylic phosphate 2a in THF at –20 °C (en-
try 1). In contrast to the excellent performance of the ring-
saturated NHC ligand SIMes, the corresponding unsaturated
NHC ligand IMes, derived from 1,3-bis(2,4,6-trimethyl-
phenyl)imidazolium chloride (IMes·HCl), gave a mixture of
branched and linear products with a low γ/α regioselectivi-
ty (62:38) and moderate total product yield (entry 2).
Without a ligand, or with 1,10-phenanthroline (Phen) or
1,2-bis(diphenylphosphino)ethane (DPPE) as the ligand, no
reaction occurred (entries 3–5). The use of triphenylphos-
phine (Ph3P) as a monodentate phosphine ligand gave only
the linear α-substitution product (E)-4aa (entry 6).
Table 1 Ligand Effects in the Reaction between 1a and (Z)-2aa
Ph
(R)-3aa
H
CuCl (10 mol%)
ligand (10 mol%)
O
B
Ph
+
or
O
KOMe (1.2 equiv)
THF, 20 h
OP(O)(OEt)2
Ph
1a (1.6 equiv)
(Z)-2a
(E)-4aa
Entry
Ligand
Temp (°C)
Yield (%)b
γ/α (3aa/4aa)c
ee (%)d
1
2
SIMes·HCl
IMes·HCl
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–40
–20
–20
93
65
0
>99:1
62:38
–
–
–
3
none
–
4
Phen
0
–
–
5
DPPE
0
–
–
6
Ph3P
57
49
13
10
77
83
80
34
56
1:>99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
92:8
>99:1
–
7
(S,S)-L1·HCl
(S,S)-L2·HBF4
(S,S)-L3·HBF4
(S,S)-L4·HBF4
(S,S)-L5·HBF4
(S,S)-L5·HBF4
(S,S)-L6·HCl
(S,S)-L7·HBF4
2
8
50
54
85
92
99
67
82
9
10
11
12e
13
14
Ph
Ph
N
Ph
Ph
N
Ph
N
Ph
N
Cl
BF4
BF4
N
N
OH
R
(S,S)-L4•HBF4
(S,S)-L2•HBF4 (R = Me)
(S,S)-L3•HBF4 (R = OMe)
(S,S)-L1•HCl
Ph
Ph
Ph
Ph
Ph
Ph
N
BF4
BF4
Cl
Cy
Cy
N
N
N
N
N
Cy
Cy
OH
(S,S)-L5•HBF4
OH
OH
(S,S)-L6•HCl
(S,S)-L7•HBF4
a Data are taken from ref. 8. Reaction conditions: 1a (0.24 mmol), (Z)-2a (0.15 mmol), CuCl/ligand (10 mol%), KOMe (0.18 mmol), THF (0.6 mL), 20 h.
b Yield of isolated product.
c Determined by 1H NMR analysis of crude product.
d The ee was determined by HPLC.
e 1a (1.9 mmol) and (Z)-2a (1.2 mmol) were used. Reaction was conducted for 48 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
Y. Yasuda et al.
Paper
Synthesis
Based on these results, focus was placed on ring-satu-
rated chiral NHC ligands (Table 1, entries 7–14). The C2-
symmetric imidazolinium chloride (S,S)-L1·HCl,16 which
has two stereogenic carbon centers in the imidazolidine
ring with two N-mesityl groups, did not result in enanti-
oselectivity; the branched, nearly racemic coupling product
3aa was obtained with exclusive regioselectivity and mod-
erate yield (entry 7). When similar chiral NHC ligands bear-
ing a 2-methylphenyl (L2) or 2-methoxyphenyl (L3) group,
instead of one of the mesityl groups in L1, were used enan-
tioselectivity was moderate (50% and 54% ee), but yields
were low (entries 8 and 9). Next, the imidazolinium salt
L4·HBF4 bearing a 2-hydroxyphenyl group was used (entry
10). A previous report indicated that L4 exhibited high
ligand performance in enantioselective Cu-catalyzed allylic
substitution with terminal alkynes as pronucleophiles.12a
Fortunately, the Cu/L4 catalyst system produced better re-
sults; the coupling product was formed in greater yield
(77%) and with greater enantioselectivity (85% ee) com-
pared to the system using (S,S)-L2 or L3, without decreasing
regioselectivity. These results indicated that the phenolic
hydroxy group in L4 has a functional role. Changing the N-
mesityl group of L4·HBF4 to an N-2,4-dicyclohexyl-6-meth-
ylphenyl group to afford the new phenol–NHC chiral ligand
precursor L5·HBF4 resulted in greater enantioselectivity
(92% ee), a high yield (83%), and exceptional regioselectivity
(γ/α >99:1) (entry 11). Furthermore, higher enantioselec-
tivity was achieved (99% ee) by decreasing the reaction
temperature to –40 °C (entry 12). In contrast, the naph-
thol–NHC chiral ligands L6 and L712b were not effective (en-
tries 13 and 14).
Next, the effect of the copper salt (Table 2) was investi-
gated. When CuOAc was used as the catalyst, the regioselec-
tivity (γ/α 91:9) and enantioselectivity (76% ee) decreased
(entry 2). The use of Cu(OAc)2, instead of copper(I) salt, re-
sulted in a modest yield and low selectivities (entry 3).
Changing CuCl to CuOTf·toluene1/2 afforded similar selectiv-
ity, but a lower product yield (entry 4). Use of MesCu and
cationic Cu(MeCN)4PF6 was as effective as CuCl, and gave
comparable results (entries 5 and 6).
The effect of solvent is also shown in Table 2. Reaction in
toluene (entry 7) gave only the racemic product in moder-
ate yield (43%) and low regioselectivity (γ/α 64:36). Di-
chloromethane was ineffective in the reaction (26% yield,
γ/α 71:29, 51% ee) (entry 8). No reaction occurred in aceto-
nitrile or hexane (entries 9 and 10).
The effects of the leaving group and base are summa-
rized in Table 3. The use of an allyl bromide or chloride as
the allylic electrophile under the conditions described for
Table 1, entry 11, decreased both regio- and enantioselec-
tivity (entries 2 and 3).
The nature of the base had a significant impact on yield
and selectivities (Table 3). Use of NaOMe instead of KOMe
decreased regioselectivity (γ/α 89:11) and enantioselectivi-
ty (74% ee) (entry 4). No reaction occurred with LiOMe, due
to the greater solubility of LiCl or LiOP(O)(OEt)2, which may
form inactive copper species through ionic interactions
(entry 5). The structure of the alkoxide moiety of the base
also had a strong impact on yield, regioselectivity, and en-
antioselectivity. Thus, when KOMe was changed to a steri-
cally more demanding base, KOt-Bu, product yield was
moderate and both regioselectivity and enantioselectivity
decreased significantly (entry 6). This result suggests that
the trialkoxyboron ROBpin may participate in the reaction
Table 2 Effects of Copper Salt and Solventa
Entry Copper salt
Solvent
Yield (%)b γ/α
[(R)-3aa/(E)-4aa]c
ee (%)d
Table 3 Effects of Leaving Group and Basea
1e
2
3
4
5
6
7
8
9
CuCl
THF
THF
THF
83
85
68
48
85
73
43
26
0
>99:1
91:9
73:27
>99:1
>99:1
>99:1
64:36
71:29
–
92
76
52
90
89
88
0
Entry Leaving group
Base
Yield (%)b γ/α [(R)-
3aa/(E)-4aa]c
ee (%)d
CuOAc
Cu(OAc)2
1e
2
3
4
5
6
7
OP(O)(OEt)2 (2a)
Clf
KOMe
83
89
85
91
0
>99:1
92
64
20
74
–
KOMe
KOMe
NaOMe
LiOMe
KOt-Bu
K2CO3
94:6
82:18
89:11
–
CuOTf·toluene1/2 THF
Brg
MesCu
Cu(MeCN)4PF6
CuCl
THF
OP(O)(OEt)2 (2a)
OP(O)(OEt)2 (2a)
OP(O)(OEt)2 (2a)
OP(O)(OEt)2 (2a)
THF
toluene
DCM
67
0
63:37
–
50
–
CuCl
51
–
CuCl
MeCN
hexane
a Data are taken from ref. 8. Reaction conditions: 1a (0.24 mmol), (Z)-2
(0.15 mmol), CuCl/(S,S)-L5·HBF4 (10 mol%), base (0.18 mmol), THF (0.6
mL), –20 °C, 20 h.
10
CuCl
0
–
–
a Reaction conditions: 1a (0.24 mmol), (Z)-2a (0.15 mmol), Cu salt/(S,S)-
L5·HBF4 (10 mol%), KOMe (0.18 mmol), solvent (0.6 mL), –20 °C, 20 h.
b Yield of isolated product.
b Yield of isolated product.
c Determined by 1H NMR analysis of crude product.
d The ee was determined by HPLC.
c Determined by 1H NMR analysis of crude product.
d The ee was determined by HPLC.
e Table 1, entry 11.
e Table 1, entry 11.
f (Z)-(5-Chloro-3-penten-1-yl)benzene.
g (Z)-(5-Bromo-3-penten-1-yl)benzene.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
Y. Yasuda et al.
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Synthesis
because Lewis acids activate the phosphate leaving group
(see Scheme 7). The coupling reaction did not occur with
K2CO3 (entry 7).
ferent allylic positions, occurred with the allylic C–O bond
in the ether or carboxylic ester leaving group untouched
(entries 5–12 and 15).
Once the optimization of the reaction conditions was
implemented, the substrate scope was investigated.
(Z)-Allylic phosphates with various aliphatic substituents
were reacted with 1a using the Cu/L5 catalyst system (Table
4). When the 2-phenylethyl group of 2a was replaced with
a benzyl or octyl group, coupling proceeded with excellent
γ-selectivity and preservation of enantioselectivity (entries
1 and 3). A sterically more demanding γ-substituent, such
as a cyclohexyl group, was also tolerated and produced a
high level of enantioselectivity (80% ee) (entry 4).17 Nota-
bly, the enantioselective reaction with 2-butene-1,4-diol
derivatives, which have two potential leaving groups at dif-
The reaction has a broad functional group compatibility
(entries 2 and 5–12, 15–17). For example, allylic phos-
phates bearing a 1,3-benzodioxole (2c), THP ether (2f), ben-
zyl ether (2g), silyl ether (2h, 2q),17 pivalate (2i), carbamate
(2p), or p-toluenesulfonate (2r) group as a component of
the aliphatic γ-substituent reacted with 1a to produce the
corresponding 1,5-diene derivatives in good yields with
high enantioselectivities (85–97% ee) (entries 2, 5–8, 15–
17). A methoxy, trifluoromethyl, bromo, or dimethylamino
substituent was tolerated in the aromatic ring of a benzoate
group (entries 9–12). However, no reaction occurred with
the allylic phosphates bearing a nitro (2n) or cyano (2o)
group (entries 13 and 14).
Table 4 Scope of Allylic Phosphatesa
Entry
1
Phosphate OP = OP(O)(OEt)2
Product
Temp (°C)
–50
Yield (%)b,c
62
ee (%)d
86
H
3ab
OP
2b
2
–30
97
86
O
O
O
O
H
OP
2c
3ac
3
4
–40
–50
85
59
84
80
H
OP
3ad
2d
H
OP
3ae
2e
RO
RO
H
OP
3af–ai
2f–i
5
6
7
8
R = THP (2f)
R = Bn (2g)
R = TBS (2h)
R = Piv (2i)
3af
3ag
3ah
3ai
–30
–50
–50
–30
83
75
78
70
90
85
97
91
R
O
O
R
O
H
O
3aj–ao
2j–o
OP
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
Y. Yasuda et al.
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Synthesis
Table 4 (continued)
Entry
Phosphate OP = OP(O)(OEt)2
Product
Temp (°C)
Yield (%)b,c
ee (%)d
9
10
11
12
13
14
R = OMe (2j)
R = CF3 (2k)
R = Br (2l)
R = NMe2 (2m)
R = NO2 (2n)
R = CN (2o)
3aj
3ak
3al
3am
3an
3ao
–30
–30
–30
–30
–10
–10
85
61
65
87
0
92
90
90
91
–
0
–
15
–30
80
90
O
O
O
O
N
O
N
O
H
O
Ph
Ph
3ap
O
2p
OP
16
17
–40
–30
78
88
96
92
O
2
Si
O
Si
2 H
OP
2q
3aq
O
O
2
S
O
O
S O
OP
2 H
O
3ar
2r
a Data for entries 1–12 and 15–17 are taken from ref. 8. Reaction conditions: 1a (0.24 mmol), (Z)-2 (0.15 mmol), CuCl/(S,S)-L5·HBF4 (10 mol%), KOMe (0.18
mmol), THF (0.6 mL), 48 h.
b Yield of isolated product.
c Constitutional isomer ratio γ/α >20:1 (determined by 1H NMR analysis of crude product).
d The ee was determined by HPLC.
1a (1.6 equiv)
CuCl (10 mol%)
(S,S)-L5•HBF4 (10 mol%)
branched coupling product 3ah in 73% yield (0.98 g, 4.3
mmol) with 92% ee.
O
Si
Si
O
H
KOMe (1.2 equiv)
THF
–40 °C, 48 h
OP(O)(OEt)2
The Cu-catalyzed allyl–allyl coupling reaction between
1a and enantioenriched 2-butene-1,4-diol derivative (S)-2s
(99% ee) with (R,R)-L5·HBF4 (i.e., enantiomeric isomer of
(S,S)-L5·HBF4) gave the corresponding 1,5-diene 3as with
two adjacent stereogenic centers with an S,S-configuration
in modest yield (51%) and high diastereoselectivity (d.r.
90:10) (Scheme 2). Without a ligand, or with (S,S)-L5·HBF4,
the reaction gave no or only a trace of the coupling product.
Thus, the use of L5 is mandatory, and the (R,R)-L5/Cu sys-
tem and the (S)-2s substrate are a matched pair, while (S,S)-
L5/Cu complex and (S)-2s are mismatched. This result is in
(Z)-2h
5.9 mmol (2.0 g)
3ah, 92% ee
73% yield, γ/α >20:1
Scheme 1 Preparative scale reaction
The potential for scaling up the enantioselective allyl–
allyl coupling was examined on a preparative scale (Scheme
1). Reaction between allylboronate 1a (1.5 g, 9.4 mmol) and
allylic phosphate 2h (2.0 g, 5.9 mmol) afforded only the
CuCl (10 mol%)
ligand (10 mol%)
H
O
Si
O
Si
Bpin
+
KOMe (1.2 equiv)
THF
–40 °C, 48 h
OP(O)(OEt)2
(S)-2s
1a
(1.6 equiv)
H
(S,S)-3as
γ/α >20:1
99% ee
Ph
Ph
Cy
no ligand
; 0% yield
with (S,S)-L5•HBF4 ; trace
with (R,R)-L5•HBF4 ; 51% yield, d.r. 90:10
N
N
Cy
BF4
OH
(R,R)-L5•HBF4
Scheme 2 Construction of two adjacent stereogenic centers
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
Y. Yasuda et al.
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Synthesis
accord with a consideration of the Felkin–Anh model as de-
picted in Scheme 3, which predicts preferred approach of
the organocopper nucleophile to the Si face of the allylic
plane with a minimum A1,3 strain.
tively) (entries 1 and 2). Allylboronates 1d–f with a hexyl,
benzyl, or phenyl group at the β-position underwent reac-
tion to afford the coupling products with enantiomeric ex-
cesses greater than 80%, while the regioselectivities were
moderate (entries 3–5).18 Allylboronate 1g with a chloro
group at the β-position did not react (entry 6). In addition,
no reaction occurred with γ-substituted allylboronates such
as trans- or cis-crotylboronates.
CuL*
H
O
Si
O
Si
H
OP
The coupling reaction between 1a and cis-4-cyclopen-
tene-1,3-diol diphosphate 2u catalyzed by the Cu/L5 sys-
tem occurred with adequate enantioselectivity, giving the
trans-1,2-isomer 3au (Scheme 4, A).17,19 Reaction with cis-
2-cyclohexene-1,4-diol derivative 2v gave the trans-1,2-
isomer 3av with moderate enantiocontrol (66% ee)
(Scheme 4, B). These stereochemical results indicate that
the present Cu-catalyzed reaction proceeds through an
anti-SN2′-type reaction pathway. Morken’s Pd-catalyzed
protocol has not been applied to this type of cyclic allylic
electrophile involving a Z-alkene moiety.5
H
OP(O)(OEt)2
H
H
(S,S)-3as
(S)-2s
OTBS
Scheme 3 Felkin–Anh-type stereoselection model
Reactions of β-substituted allylboronate derivatives us-
ing the Cu/L5 catalyst system were investigated (Table 5).
Methallylboronate 1b and 2-ethyl-2-propen-1-ylboronate
1c reacted with (Z)-2a with excellent γ-selectivity (γ/α
>20:1) and high enantioselectivity (95% and 80% ee, respec-
Table 5 Scope of Allylboronates
Entry
1
Allylboronate
Phosphate OP = OP(O)(OEt)2
Product
Yield (%)b
77
γ/αc
>20:1
ee (%)d
95
2a
Ph
Ph
Bpin
H
1b
3ba
2
3
4
2a
2a
2a
50
87
59
>20:1
84:16
87:13
80
80
82
H
Bpin
1c
3ca
Ph
H
Bpin
1d
3da
Ph
H
Bpin
1e
3ea
5
6
89
78:22
83
OP
2t
H
H
Bpin
1f
3ft
2a
0
–
–
Cl
Ph
Cl
Bpin
1g
3ga
a Data for entries 1–5 are taken from ref. 8. Reaction conditions: 1 (0.24 mmol), (Z)-2 (0.15 mmol), CuCl/(S,S)-L5·HBF4 (10 mol%), KOMe (0.18 mmol), THF (0.6
mL), –50 °C (entry 1) or –30 °C (entries 2–6), 48 h.
b Yield of isolated product.
c Determined by 1H NMR analysis of crude product.
d The ee was determined by HPLC.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
Y. Yasuda et al.
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Synthesis
B).19 Interestingly, this reaction gave results similar to the
reaction with (E)-2a. The convergence observed in the
regioselectivity and stereochemistry suggests that (E)-2a
and 2a′ lead to a common equilibrium mixture of the allyl-
copper(III) species prior to reductive elimination (R.E.) to
form the product mixture (Scheme 6).20
OP(O)(OEt)2
(EtO)2(O)PO
H
H
(EtO)2(O)PO
2u
(A)
CuCl
–30 °C
(10 mol%)
(S,S)-L5•HBF4
(10 mol%)
(R,R)-3au
64% yield, 77% ee
γ/α >20:1, trans/cis >99:1
1a
(1.6 equiv) KOMe
(1.2 equiv)
Based on the assumption that the γ-selective reaction of
(Z)-2 also occurs via allylcopper(III) intermediates, a cata-
lytic cycle was proposed for the enantioselective allyl–allyl
coupling catalyzed by the Cu/L5 system, as shown in
Scheme 7.20 An alkoxycopper(I) complex A is formed from
reaction between CuCl, L5·HBF4, and KOMe. For this com-
plex, the chiral NHC ligand coordinates to copper as an an-
ionic C,O-bidentate ligand. Then, transmetalation between
A and an allylborate B21 affords the potassium phenoxo-
(allyl)cuprate C. Compound C forms a π-complex D with the
allylic phosphate 2, in which the copper is anti to the phos-
phate leaving group. The MeOBpin may activate the phos-
phate group as a Lewis acid.14d Subsequently, oxidative ad-
dition produces (π-en-σ-yl)copper(III) complex E1 with a
secondary sp3-carbon atom bound to copper. Facile reduc-
tive elimination of E1, which is faster than allylic 1,3-copper
migration to form E2, produces the branched γ-substitution
product 3 and regenerates the alkoxycopper(I) complex A
(see Figures 2 and 3 for enantiodiscrimination models).
Thus, the crucial dependence of regioselectivity on the
E/Z geometry of the allylic substrate 2 can be explained by
the greater instability of the allylcopper(III) intermediate
E2 compared to the corresponding copper(III) species E1
produced from the E-substrate, due to larger steric repul-
sion in the allyl moiety derived from the Z-substrate
(Scheme 6). Similar consideration may be applicable to the
corresponding transition states that determine the E/Z-iso-
meric product distribution.
(EtO)2(O)PO
OP(O)(OEt)2
THF, 48 h
H
2v
(EtO)2(O)PO
(B)
H
–20 °C
(R,R)-3av
52% yield, 66% ee
γ/α >20:1, trans/cis >99:1
Scheme 4 Use of cyclic allylic phosphates
Ph
OP(O)(OEt)2
Ph
(E)-2a
H
+
(E)-4aa (A)
CuCl
(10 mol%)
(S)-3aa, 71% ee
(S,S)-L5•HBF4
86% yield
branch/linear (γ/α) 18:82
(10 mol%)
1a
KOMe (1.2 equiv)
THF
(1.6 equiv)
OP(O)(OEt)2
–20 °C, 20 h
Ph
(S)-3aa, 74% ee
2a'
+
(B)
(E)-4aa
72% yield
branch/linear (α/γ) 12:88
Scheme 5 Reaction of (E)-2a and 2a'
In this study we also studied the reaction mechanism
and we herein propose a possible reaction pathway. The
alkene geometry of the allylic phosphates influences both
regio- and enantioselectivity. Thus, reaction between 1a
and (E)-2a under the conditions described in Table 1, entry
11 gave the linear α-substitution product (E)-4aa preferen-
tially, with minor formation of (S)-3aa (71% ee), the anti-
pode of the product derived from (Z)-2a (Scheme 5, A).19
This α-selectivity appeared to occur via allylic 1,3-migra-
tion of copper in the allylcopper(III) species. To gain insight
into the nature of the postulated allylcopper(III) species,
secondary allylic phosphate 2a′, a constitutional isomer of
(Z)-2a, was reacted under the same conditions (Scheme 5,
Reactions of the E- and Z-isomers of 2a gave the antipo-
des of 3aa (Table 1, entry 11 vs Scheme 5, A), and the prod-
uct from (Z)-2a was produced with greater enantioselectiv-
ity. This led to the proposal of the enantioselection models
shown in Figures 2 and 3. In the π-complex D (Scheme 7),
the chiral copper center adopts a tetrahedral coordination
geometry including the C,O-bidentate chelation. The K+ ion
bridges the phenoxide oxygen and MeOBpin, which inter-
(E)-2a
2a'
Ph
L
L
Cu
Cu
H
R.E.
R.E.
H
H
Ph
R
R
linear
product
branched
product
(E)
L
Cu
H
1,3-migration
flip
R
(E)
Scheme 6 Allylcopper(III) species
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

H
Y. Yasuda et al.
Paper
Synthesis
Ph
Ph
CuCl/L5•HBF4/2KOMe
Cy
– 2MeOH
– KBF4
– KCl
O
MeO
K+
N
N
B
–
R
H
O
Cy
O
Cu
B
A
branched product
MeO–Bpin
Cy
Ph
Ph
N
Ph
H
Ph
H
H
H
Cy
Cy
Ph
Ph
N
N
N
Cy
Cy
N
N
O
O
–
Ph
Cu
Cu
Ph
Cy
O
K+
Cu
H
Cy
H
H
H
N
Cy
C
N
R
R
disfavored
E2
E1
–
O
H
Cu
K+
R
H
MeO
pinB
O
R
D
OP(O)(OEt)2
+
R
(EtO)2POK
+
O
linear product
(not formed)
(EtO)2PO
MeO–Bpin
MeO–Bpin
Scheme 7 Postulated catalytic reaction pathway
acts with the phosphate leaving group as a Lewis acid.
These assumptions suggest four possible π-complexes (D1
and D2 for the major enantiomer; D3 and D4 for the minor
enantiomer) (Figure 2). Complex D1 is the most favorable,
because it results in the fewest steric repulsions between
catalyst and allylic phosphate. Complexes D2, D3, and D4
appear to be destabilized by steric repulsions between the
γ-substituent (R) and the non-hydroxylated N-aryl group or
one of the phenyl groups on the imidazolidine ring. These
conclusions are consistent with the experimental observa-
tions that the enantioselectivity is influenced by the steric
nature of the γ-substituent (R) (Table 4, entries 3 and 4) and
the non-hydroxylated N-aryl group in the phenolic NHC
ligands (Table 1, entries 10 and 11).
For the reaction of (E)-2 (Figure 3), the non-hydroxylat-
ed N-aryl group and/or the phenyl group on the imidazoli-
dine ring causes steric repulsion toward the γ-substituent
(R) for all postulated complexes D1′–D4′. These consider-
ations explain the more efficient enantioselection in the re-
action with allylic substrates having the Z-configuration.
Ph
H
R
H H
Ph
H
Ph
H
Ph
H
Cy
H
Cy
N
Ph
N
N
H
H
H
N
R
H
H
H
OMe
Cy
H
Cy
Cy
OMe
B
Ph
Cy
N
N
N
R
N
Cu
O
R
Cu
O
Cy
OMe
B
OMe
Cy
B
O
Cu
K
O
H
Cu
K
O
H
B
O
K
O
H
K
H
O
O
P
O
P
D1’
D3’
O
O
EtO
OEt
OEt
EtO
P
P
OEt
EtO
D1
EtO
D3
OEt
Ph
H
H H
Ph
NR
H
Ph
H
Ph
H
Ph
H
Ph
Cy
H
Cy
H
Cy
N
Ph
Cy
HN
N
H
RN
H
N
N
NH
H
H
Cy
Cy
Cy
Cy
Cu
Cu
O
O
Cu
Cu
O
O
EtO
OEt
OEt
O
O
O
H
H
O
O
O
R
R
EtO
OEt
K
K
K
K
OMe
MeO
P
P
MeO
OMe
P
P
EtO
O
B
B
OEt
B
EtO
O
B
D2
D4
D2’
D4’
major
enantiomer
minor
enantiomer
minor
enantiomer
major
enantiomer
Figure 2 Models for enantioselection with (Z)-2
Figure 3 Models for enantioselection with (E)-2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

I
Y. Yasuda et al.
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Synthesis
In conclusion, a versatile method has been developed for
Cu-catalyzed enantioselective allyl–allyl coupling between
allylboronates and acyclic and cyclic (Z)-allylic phosphates
to form various chiral 1,5-diene derivatives. Catalysis of a
copper(I) complex with a new phenol–NHC chiral ligand
enabled the reaction, demonstrating the utility of this class
of chiral ligands for enantioselective copper catalysis with
organoboron compounds.12 This Cu-catalyzed protocol pro-
vides efficient access to functionalized, enantioenriched
chiral 1,5-dienes with a stereogenic carbon center at the al-
lylic/homoallylic position. The broad functional group com-
patibility and the use of earth-abundant and relatively low-
toxicity copper as a metal are attractive features of this pro-
tocol. A functional role for the phenolic hydroxy group in
the chiral NHC ligand was suggested by the results.
n-BuLi in hexane (9.6 mL, 15.8 mmol) was dropped into a solution of
the TBS-protected alcohol (2.6 g, 14 mmol) in Et2O (29 mL) at –78 °C.
The reaction mixture was stirred for 30 min before formaldehyde
(877 mg, 29.2 mmol) was added to the mixture. The reaction vessel
was removed from the cooling bath. After 12 h of stirring at rt, the
reaction was quenched with H2O. The mixture was diluted with Et2O
and the organic layer was separated. The aqueous phase was extract-
ed with Et2O (2 × 15 mL) and the combined organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated under re-
duced pressure by rotary evaporation. Purification by flash chroma-
tography on silica gel (0–10% EtOAc/hexane) afforded the correspond-
ing propargyl alcohol (2.3 g, 10 mmol) in 73% yield.
A solution of the propargyl alcohol (1.1 g, 5 mmol) in hexane (4.3 mL)
and acetone (790 μL) was added to a mixture of Pd/CaCO3 (40.0 mg)
and quinoline (397 μL, 3.6 mmol), and then the reaction mixture was
filled with hydrogen gas. After confirmation of reaction completion
by 1H NMR spectroscopy, the Pd/CaCO3 was removed by filtration, and
the resulting solution was concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (0–10%
EtOAc/hexane) to give (S,Z)-4-[(tert-butyldimethylsilyl)oxy]-2-pent-
en-1-ol (874 mg, 4.0 mmol) in 80% yield.
NMR spectra were recorded on a JEOL ECX-400 instrument, operating
at 400 MHz for 1H NMR, 100.5 MHz for 13C NMR, and 128 MHz for 11
B
NMR acquisitions. Chemical shift values for 1H and 13C NMR data are
referenced to TMS and the residual solvent resonances, respectively.
Chemical shifts (δ) are reported in ppm. Mass spectra were obtained
with a Thermo Fisher Scientific Exactive, JEOL JMS-T100LP, or JEOL
JMS-700TZ mass spectrometer at the Instrumental Analysis Division,
Global Facility Center, Creative Research Institution, Hokkaido Uni-
versity. HPLC analyses were conducted on an HITACHI ELITE LaChrom
system with an HITACHI L-2455 diode array detector or an HITACHI
Chromaster system with an HITACHI 5430 diode array detector. Opti-
cal rotations were measured on a JASCO P-2200 polarimeter. TLC
analyses were performed on commercial glass plates bearing a 0.25-
mm layer of Merck silica gel 60 F254. Silica gel (Kanto Chemical Co., sil-
ica gel 60 N, spherical, neutral) was used for column chromatography.
IR spectra were measured with a Perkin-Elmer Spectrum One spec-
trometer. Melting points were measured on a Yanaco MP-500D appa-
ratus. Gel permeation chromatography (GPC) was performed with an
LC-908 system (Japan Analytical Industry Ltd., two in-line JAIGEL-2H
columns, CHCl3, 3.5 mL/min, UV and RI detectors).All reactions were
carried out under nitrogen or argon atmosphere. Materials were ob-
tained from commercial suppliers or prepared according to standard
procedures unless otherwise noted. CuCl and KOMe were purchased
from Aldrich Chemical Co., stored under nitrogen, and used as re-
ceived. THF was purchased from Kanto Chemical Co. and stored under
argon. 2-Allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a) was ob-
tained from commercial suppliers. Allylboronate 1g was prepared ac-
cording to the reported procedure.22 The synthesis of allylboronates
1b–f, allylic phosphates 2a–r, 2t–v, 2a′, and NHC ligands L1–7 has
been reported previously.8,12a (E)-4aa is known in the literature.3f
To a solution of (S,Z)-4-[(tert-butyldimethylsilyl)oxy]-2-penten-1-ol
(874 mg, 4.0 mmol) in pyridine (6.1 mL), (EtO)2P(O)Cl (697 μL, 4.8
mmol) and DMAP (24 mg, 0.2 mmol) were sequentially added at 0 °C.
After being stirred at rt for 3 h, the reaction mixture was diluted with
EtOAc (20 mL) and was treated with H2O (2 mL). The resulting mix-
ture was washed with saturated aq CuSO4 (3 × 10 mL) and brine, dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (10–45% EtOAc/hexane) to provide 2s (1.3 g, 3.8 mmol) in
94% yield. The ee value of (S)-2s (99% ee) was determined by chiral
HPLC analysis of the p-methoxybenzoate derivative of (S,Z)-4-[(tert-
butyldimethylsilyl)oxy]-2-penten-1-ol [CHIRALCEL® OD-3 column,
4.6 × 250 mm, Daicel Chemical Industries, hexane/2-propanol 99:1,
0.5 mL/min, 40 °C, 220 nm UV detector; tR = 13.7 (R-isomer), 17.7 min
(S-isomer) min].
Colorless oil; [α]D25 +150 (c 1.17, CHCl3); 99% ee.
IR (neat): 667, 775, 830, 975, 1026, 1254, 1369, 1393, 1473, 2858,
2930, 2957 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.06 (s, 3 H), 0.89 (s, 9 H),
1.20 (d, J = 6.4 Hz, 3 H), 1.34 (t, J = 7.2 Hz, 6 H), 4.11 (quintet, J = 7.2
Hz, 4 H), 4.55–4.69 (m, 3 H), 5.48 (dt, J = 11.2, 6.0 Hz, 1 H), 5.64 (dd, J =
11.2, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = –4.8, –4.6, 16.1 (d, J = 6.7 Hz), 18.1,
24.6, 25.7, 63.0 (d, J = 4.8 Hz), 63.7 (d, J = 5.7 Hz), 65.1, 122.3 (d, J = 6.6
Hz), 139.2.
HRMS–ESI: m/z [M + Na]+ calcd for C15H33O5NaPSi: 375.17271; found:
375.17227.
(S,Z)-4-[(tert-Butyldimethylsilyl)oxy]-2-penten-1-yl Diethyl Phos-
phate [(S)-2s]
Copper-Catalyzed Enantioselective Allyl–Allyl Coupling; Typical
Procedure
(S)-3-Butyn-2-ol (99% ee) (1.2 mL, 15 mmol) and imidazole (2.0 g, 30
mmol) were dissolved in DCM (30 mL) at 0 °C. Then, TBSCl (3.4 g, 22
mmol) was added to the mixture, and the solution was stirred at rt for
8 h. The reaction was quenched with H2O and the mixture was ex-
tracted with DCM (3 × 15 mL). The combined organic layer was dried
over MgSO4. Then, the drying agent was removed by filtration, and
the filtrate was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (0–5% EtOAc/hex-
ane) to give the TBS-protected alcohol derivative (2.6 g, 14 mmol) in
96% yield.
The reaction in Table 4, entry 1 is representative. CuCl (1.5 mg, 0.015
mmol), L5·HBF4 (9.8 mg, 0.015 mmol), and KOMe (12.6 mg, 0.18
mmol) were placed in a vial containing a magnetic stirring bar. The
vial was sealed with a Teflon®-coated silicon rubber septum, and then
the vial was evacuated and filled with argon. THF (0.6 mL) was added
to the vial, and then the mixture was stirred at rt for 30 min. Next, 2-
allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a; 45.3 μL, 0.24
mmol) was added. Finally, allylic phosphate 2b (42.6 mg, 0.15 mmol)
was added at –50 °C. After 48 h stirring at –50 °C, the reaction was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

J
Y. Yasuda et al.
Paper
Synthesis
quenched with saturated aq NH4Cl and the mixture was extracted
with Et2O (3 × 1 mL). The combined organic layer was dried over Mg-
SO4. Then, the drying agent was removed by filtration, and the result-
ing solution was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (hexane) to give
3ab (15.9 mg, 0.09 mmol) in 62% yield.
(R)-2-Vinyl-4-penten-1-yl 4-Bromobenzoate (3al)
Product 3al was purified by flash chromatography on silica gel (0–2%
EtOAc/hexane) (28.8 mg, 0.10 mmol, 65% isolated yield from 2l).
(R)-2-Vinyl-4-penten-1-yl 4-(Dimethylamino)benzoate (3am)
Product 3am was purified by flash chromatography on silica gel (0–
5% EtOAc/hexane) (34.0 mg, 0.13 mmol, 87% isolated yield from 2m).
Characterization Data for Allyl–Allyl Coupling Products
Full details for compounds 3aa–am, 3ap–ar, 3ba–ea, 3ft, 3au, and 3av
(R)-1-Benzyl 4-(2-Vinyl-4-penten-1-yl) Piperidine-1,4-dicarboxyl-
ate (3ap)
can be found in our previous report.8
Product 3ap was purified by flash chromatography on silica gel (5–
10% EtOAc/hexane) (43.0 mg, 0.12 mmol, 80% isolated yield from 2p).
(R)-(3-Vinyl-5-hexen-1-yl)benzene (3aa)
Product 3aa was purified by flash chromatography on silica gel (hex-
ane) [178.9 mg, 0.96 mmol, 80% isolated yield from (Z)-2a].
(R)-tert-Butyldimethyl[(4-vinyl-6-hepten-1-yl)oxy]silane (3aq)
Product 3aq was purified by flash chromatography on silica gel (0–1%
EtOAc/hexane) (29.8 mg, 0.12 mmol, 78% isolated yield from 2q).
(S)-(2-Vinyl-4-penten-1-yl)benzene (3ab)
Product 3ab was purified by flash chromatography on silica gel (hex-
ane) (15.9 mg, 0.09 mmol, 62% isolated yield from 2b).
(R)-4-Vinyl-6-hepten-1-yl 4-Methylbenzenesulfonate (3ar)
Product 3ar was purified by flash chromatography on silica gel (0–5%
EtOAc/hexane) (38.7 mg, 0.13 mmol, 88% isolated yield from 2r).
(S)-5-(2-Vinyl-4-penten-1-yl)benzo[d][1,3]dioxole (3ac)
Product 3ac was purified by flash chromatography on silica gel (5%
Et2O/hexane) (31.5 mg, 0.14 mmol, 97% isolated yield from 2c).
tert-Butyldimethyl{[(2S,3S)-3-vinyl-5-hexen-2-yl]oxy}silane (3as)
Product 3as was purified by flash chromatography on silica gel (0–2%
EtOAc/hexane) [22.2 mg, 0.09 mmol, 51% isolated yield from (S)-2s].
The absolute configuration of 3as was assigned by consideration of
the stereochemical pathway.
(R)-4-Vinyl-1-dodecene (3ad)
Product 3ad was purified by flash chromatography on silica gel (hex-
ane) (24.7 mg, 0.12 mmol, 85% isolated yield from 2d).
25
1
Colorless oil; [α]D +34 (c 0.37, CHCl3); d.r. 90:10 (determined by H
(R)-Hexa-1,5-dien-3-ylcyclohexane (3ae)
NMR analysis of the crude product).
Product 3ae was purified by flash chromatography on silica gel (pen-
tane) (14.6 mg, 0.09 mmol, 59% isolated yield from 2e).
IR (neat): 664, 772, 830, 910, 994, 1072, 1254, 1361, 1374, 1463,
1472, 1641, 2858, 2887, 2930, 2957, 3078 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.05 (s, 6 H), 0.89 (s, 9 H), 1.08 (d, J =
6.4 Hz, 3 H), 1.98–2.12 (m, 2 H), 2.34 (m, 1 H), 3.70 (quintet, J = 6.4 Hz,
1 H), 4.95–5.08 (m, 4 H), 5.59–5.88 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = –4.8, –4.3, 17.9, 20.8, 25.7, 34.5, 51.7,
70.5, 115.2, 115.8, 137.4, 139.1.
(R)-2-[(2-Vinyl-4-penten-1-yl)oxy]tetrahydro-2H-pyran (3af)
Product 3af was purified by flash chromatography on silica gel (0–2%
EtOAc/hexane) (24.3 mg, 0.12 mmol, 83% isolated yield from 2f); d.r.
1:1.
HRMS–APCI: m/z [M + H]+ calcd for C14H29OSi: 241.19822; found:
241.19826.
(R)-{[(2-Vinyl-4-penten-1-yl)oxy]methyl}benzene (3ag)
Product 3ag was purified by flash chromatography on silica gel (0–1%
EtOAc/hexane) (22.8 mg, 0.11 mmol, 75% isolated yield from 2g).
(R)-(5-Methyl-3-vinyl-5-hexen-1-yl)benzene (3ba)
Product 3ba was purified by flash chromatography on silica gel (hex-
ane) (23.1 mg, 0.12 mmol, 77% isolated yield from (Z)-2a).
(R)-tert-Butyldimethyl[(2-vinyl-4-penten-1-yl)oxy]silane (3ah)
Product 3ah was purified by flash chromatography on silica gel (0–1%
EtOAc/hexane) (26.6 mg, 0.12 mmol, 78% isolated yield from 2h).
(R)-(5-Methylene-3-vinylheptyl)benzene (3ca)
Product 3ca was purified by flash chromatography on silica gel (hex-
ane) (16.1 mg, 0.07 mmol, 50% isolated yield from (Z)-2a).
(R)-2-Vinyl-4-penten-1-yl Pivalate (3ai)
Product 3ai was purified by flash chromatography on silica gel (0–2%
EtOAc/hexane) (20.6 mg, 0.11 mmol, 70% isolated yield from 2i).
(R)-(5-Methylene-3-vinylundecyl)benzene (3da)
Product 3da was purified by flash chromatography on silica gel (hex-
ane) (35.3 mg, 0.13 mmol, 87% isolated yield from (Z)-2a).
(R)-2-Vinyl-4-penten-1-yl 4-Methoxybenzoate (3aj)
Product 3aj was purified by flash chromatography on silica gel (0–2%
EtOAc/hexane) (31.2 mg, 0.13 mmol, 85% isolated yield from 2j).
(R)-(2-Methylene-4-vinylhexane-1,6-diyl)dibenzene (3ea)
Product 3ea was purified by flash chromatography on silica gel (0–1%
Et2O/hexane) (24.7 mg, 0.08 mmol, 59% isolated yield from (Z)-2a).
(R)-2-Vinyl-4-penten-1-yl 4-(Trifluoromethyl)benzoate (3ak)
Product 3ak was purified by flash chromatography on silica gel (0–2%
EtOAc/hexane) (25.9 mg, 0.09 mmol, 61% isolated yield from 2k).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
Y. Yasuda et al.
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Synthesis
(R)-(4-Methyl-1,5-hexadien-2-yl)benzene (3ft)
(9) For the synthesis of chiral 1,5-diene derivatives through Cu-cat-
alyzed enantioselective coupling with diboron, allene, and
allylic phosphate, see: Meng, F.; McGrath, K. P.; Hoveyda, A. H.
Nature 2014, 513, 367.
Product 3ft was purified by flash chromatography on silica gel (hex-
ane) (23.0 mg, 0.13 mmol, 89% isolated yield from 2t). The isolated
branched product 3ft was contaminated with a trace amount of the
linear product.
(10) For reviews on Cu-catalyzed allylic substitutions, see:
(a) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez,
M. Chem. Rev. 2008, 108, 2796. (b) Harutyunyan, S. R.; den
Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev.
2008, 108, 2824. (c) Shintani, R. Synthesis 2016, 48, 1087.
(11) For Cu-catalyzed enantioselective allylic substitutions using
organoboron reagents and oxygen-functionalized NHC chiral
ligands, see: (a) Shintani, R.; Takatsu, K.; Takeda, M.; Hayashi, T.
Angew. Chem. Int. Ed. 2011, 50, 8656; Angew. Chem. 2011, 123,
8815. (b) Gao, F.; Carr, J. L.; Hoveyda, A. H. Angew. Chem. Int. Ed.
2012, 51, 6613; Angew. Chem. 2012, 124, 6717. (c) Jung, B.;
Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490. (d) Takeda, M.;
Takatsu, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2014, 79, 2354.
(e) Shi, Y.; Jung, B.; Torker, S.; Hoveyda, A. H. J. Am. Chem. Soc.
2015, 137, 8948. See also: (f) ref. 10c.
(1R,2R)-2-Allyl-3-cyclopenten-1-yl Diethyl Phosphate (3au)
Product 3au was purified by flash chromatography on silica gel (20–
50% EtOAc/hexane) (25.1 mg, 0.10 mmol, 64% isolated yield from 2u).
(1R,2R)-2-Allyl-3-cyclohexen-1-yl Diethyl Phosphate (3av)
Product 3av was purified by flash chromatography on silica gel (20–
50% EtOAc/hexane) (21.3 mg, 0.08 mmol, 52% isolated yield from 2v).
Funding Information
This work was supported by Grants-in-Aid for Scientific Research (B)
(12) For our previous work, see: (a) Harada, A.; Makida, Y.; Sato, T.;
Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2014, 136, 13932.
(b) Ohmiya, H.; Zhang, H.; Shibata, S.; Harada, A.; Sawamura, M.
Angew. Chem. Int. Ed. 2016, 55, 4777; Angew. Chem. 2016, 128,
4855. (c) Hojoh, K.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc.
2017, 139, 2184.
(13) For functionalized NHC ligands in asymmetric catalysis, see:
(a) Hameury, S.; Frémont, P.; Braunstein, P. Chem. Soc. Rev.
2017, 46, 632. (b) Pape, F.; Teichert, J. F. Eur. J. Org. Chem. 2017,
4206. (c) Peris, E. Chem. Rev. 2017, in press; DOI:
10.1021/acs.chemrev.6b00695.
(14) (a) Shido, Y.; Yoshida, M.; Tanabe, M.; Ohmiya, H.; Sawamura,
M. J. Am. Chem. Soc. 2012, 134, 18573. (b) Hojoh, K.; Shido, Y.;
Ohmiya, H.; Sawamura, M. Angew. Chem. Int. Ed. 2014, 53, 4954;
Angew. Chem. 2014, 126, 5054. See also: (c) Ohmiya, H.;
Yokobori, U.; Makida, Y.; Sawamura, M. J. Am. Chem. Soc. 2010,
132, 2895. (d) Nagao, K.; Yokobori, U.; Makida, Y.; Ohmiya, H.;
Sawamura, M. J. Am. Chem. Soc. 2012, 134, 8982.
(15) Use of the allyl-9-BBN reagent instead of 1a under the condi-
tions for Table 1, entry 12 resulted in a decrease in both enanti-
oselectivity (87% ee) and product yield (30%), but with the
exclusive regioselectivity (γ/α >99:1) unchanged.
(No. 15H03803), JSPS to H.O. and by CREST and ACT-C, JST to M.S.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591548.
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(17) The absolute configuration of 3ae and 3ah was determined by
comparison of the specific rotations with the values reported
previously; see ref. 5aThe absolute configuration of 3au was
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(18) The linear α-substitution product was the (E)-isomer.
(19) Data for Schemes 4 and 5 are taken from ref. 8.
(20) Nakamura and co-workers conducted DFT calculations on the
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ity is determined at the oxidative addition step as a conse-
quence of the asymmetric nature of MeCuCN–. Our proposed
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reaction proceeds through oxidative addition of a cuprate to
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Y. Yasuda et al.
Paper
Synthesis
elimination. However, the coordination number of copper in the
allylcopper(III) complex is different by virtue of bidentate coor-
dination of the anionic phenol–NHC chiral ligand (L). The
strongly electron-donating NHC coordination should render the
π-en coordination weaker, making the allylic 1,3-copper migra-
tion in the allylcopper(III) complex more feasible. See:
(a) Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc.
2008, 130, 12862. For the effect of a σ-donor ligand, see:
(b) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004,
126, 6287.
(21) Rapid formation of a tetravalent borate (B) was confirmed by
11B NMR spectroscopy; see ref. 8.
(22) Zhang, P.; Roundtree, I. A.; Morken, J. P. Org. Lett. 2012, 14, 1416.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L