Copper-catalyzed enantioselective allylic cross-coupling with alkylboranes

Article abstract of DOI:10.1016/j.tet.2015.05.048

Abstract We have presented full details of our work on alkylboranes, which we have introduced as new reagents for copper-catalyzed S_N2′-type enantioselective allylic substitutions. The copper catalysis delivered enantioenriched chiral products containing tertiary or quaternary carbon stereogenic centers branched with functionalized sp³-alkyl groups. The wide availability of alkylboranes via the established alkene hydroboration reaction is an attractive feature of these transformations. Various functional groups are tolerated in the substrates. A reaction pathway involving addition-elimination of a neutral alkylcopper(I) species with the allyl chloride substrate is proposed.

Full text of DOI:10.1016/j.tet.2015.05.048

Tetrahedron xxx (2015) 1e15
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed enantioselective allylic cross-coupling with
alkylboranes
,
Kentaro Hojoh a, Yoshinori Shido a, Kazunori Nagao a, Seiji Mori b, Hirohisa Ohmiya a
*
,
,
Masaya Sawamura a
*
a Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
b Faculty of Science, Ibaraki University, Mito 310-8512, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have presented full details of our work on alkylboranes, which we have introduced as new reagents
for copper-catalyzed SN20-type enantioselective allylic substitutions. The copper catalysis delivered
enantioenriched chiral products containing tertiary or quaternary carbon stereogenic centers branched
with functionalized sp3-alkyl groups. The wide availability of alkylboranes via the established alkene
hydroboration reaction is an attractive feature of these transformations. Various functional groups are
tolerated in the substrates. A reaction pathway involving additioneelimination of a neutral alkylcopper(I)
species with the allyl chloride substrate is proposed.
Received 4 April 2015
Received in revised form 13 May 2015
Accepted 14 May 2015
Available online xxx
Keywords:
Asymmetric catalysis
Copper catalyst
Allylic substitution
Alkylborane
Ó 2015 Elsevier Ltd. All rights reserved.
Quaternary carbon
1. Introduction
2. Results/discussion
Enantioselective allylic substitutions of organometallic reagents
under the influence of chiral transition metal catalysts are efficient
and versatile methods for asymmetric carbonecarbon bond for-
mation.1 In recent decades, reactions using organoboron com-
pounds as organometallic reagents for allylic substitutions have
achieved remarkable advances, given their broad substrate scopes
and functional group compatibilities.2e6 Unfortunately, however,
usable organoboron reagents have generally been limited to aryl-,
alkenyl-, allyl-, and allenylboron compounds, and the reactions of
alkylboron derivatives have been rare and underdeveloped until
very recently.7a In 2012, we reported the first catalytic enantiose-
lective allylic substitution reaction with alkylboron compounds
under catalysis of a chiral Cu(I) complex system. Later, the system
was extended to catalytic enantioselective construction of all-
carbon quaternary stereogenic centers.7b Herein, we present full
details of our studies on the use of alkylboranes for copper-
catalyzed SN20-type enantioselective allylic substitutions.8,9
2.1. Construction of tertiary carbon stereogenic centers using
-monosubstituted primary allylic substrates
g
2.1.1. Optimization. Previously, we reported that the allylealkyl
coupling between enantioenriched chiral secondary (Z)-allylic
phosphates and alkyl-9-BBN reagents proceeded with excellent g-
selectivity and stereospecificity under the influence of a catalytic
amount of a copper(I) salt and a stoichiometric potassium alkoxide
base (Scheme 1).8aec On the basis of this knowledge, we initiated
a program to develop an unprecedented catalytic enantioselective
allylic alkylation with alkylboranes. Initial screening of ligands was
conducted for the reaction of alkylborane 2a (0.25 mmol), which
was prepared from dimethoxyallylbenzene (1a), and
g-mono-
substituted primary allyl chloride (Z)-3a (0.2 mmol) in the presence
of CuCl (5 mol %) and MeOK in 1,4-dioxane at 35 ꢀC (Table 1).10 The
ring-unsaturated C2-symmetric N-heterocyclic carbene ligand
* Corresponding authors. Tel.: þ81 11 706 3434; fax: þ81 11 706 3749 (M.S.); tel.:
þ81 11 706 2719; fax: þ81 11 706 3749 (H.O.); e-mail addresses: ohmiya@sci.ho-
kudai.ac.jp (H. Ohmiya), sawamura@sci.hokudai.ac.jp (M. Sawamura).
Scheme 1. Copper-catalyzed cross-coupling between alkylboranes and secondary (Z)-
allylic phosphates.
http://dx.doi.org/10.1016/j.tet.2015.05.048
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
Table 1
Copper-catalyzed enantioselective allylic substitutions between alkylborane 2a and (Z)-3a under various conditionsa
Entry
Cu/L (mol %)
Cu salt
L
Solvent
Temp (ꢀC)
Yieldb,c (%)
eed (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
L1
L2
L3
L4
L5
L6
L7
L5
L5
L5
L5
L5
L5
L5
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
Toluene
DCM
Dioxane
Dioxane/DCM
Dioxane/DCM
Dioxane/DCM
35
35
35
35
35
35
35
35
35
35
10
10
10
5
3
0
5
0
d
37
47
61
d
7
40
41
d
74
77
77
80
25
48
0
99
11
7
Trace
23
81
83
55
9
10
11
12
13
14
5
10
10
10
10
CuOTf$(toluene)0.5
CuOTf$(toluene)0.5
a
The reaction was carried out with (Z)-3a (0.2 mmol), 2a (0.25 mmol), Cu salt, ligand (L), and MeOK (0.21 mmol, entries 1e10; 0.22 mmol, entries 11e14) in solvent (0.8 mL)
for 12 h (entries 1e10) or 48 h (entries 11e14). Alkylborane 2 was prepared in advance by hydroboration of 1 with the 9-BBN dimer at 60 ꢀC (1 h) and used without
purification.
b
The yield was determined by 1H NMR.
c
Constitutional isomer ratio g/a
>20:1 (determined by 1H NMR analysis of the crude product).
d
The enantiomeric excess was determined by HPLC analysis.
(L1)11 having 1-(1-naphthyl)ethyl groups at both nitrogen atoms
gave racemic 4aa (entry 1). The chiral phosphoramidite ligand (L2)
did not form an active catalyst (entry 2). Further screening of var-
ious chiral ligands revealed that introducing 3,5-di-tert-butyl-4-
methoxyphenyl (DTBM) substituents on the phosphorus atoms of
chiral bisphosphines was essential not only for enantiocontrol, but
also for catalytic activity with bisphosphine-based chiral copper
catalysts. (R)-DTBM-BINAP (L3) induced low catalytic activity and
enantioselectivity (entry 3). The use of DTBM-MeO-BIPHEP (L4)
gave better product yield and enantioselectivity (entry 4). The use
of (R)-DTBM-SEGPHOS12 (L5) led to an improvement in the product
substituted chiral bisphosphines, (R)-SEGPHOS (L6) or (R,R)-Qui-
nox P
(L7),13 resulted in complete inhibition of the reaction or loss
of enantiocontrol, respectively (entries 6 and 7). The introduction of
the DTBM substituents may have induced the deaggregation of
alkylcopper(I) species to form a catalytically active monomeric
copper complex.14
Next, the effect of solvent was examined in the reaction be-
tween 2a and (Z)-3a with the CuCleL5 catalyst system (Table 1,
entries 8e12). The use of THF or toluene as a solvent instead of
1,4-dioxane resulted in poor yields (11% and 7%) and lower
*
enantioselectivities (40% and 41% ees) (entries
8 and 9).
yield and enantioselectivity (entry 5), giving the branched
g
-sub-
Dichloromethane (DCM) as solvent inhibited the reaction almost
completely (entry 10). The enantioselection was improved to 74%
stitution product (S)-4aa ( >20:1). In contrast, non-DTBM-
g/a
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K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
3
ee by carrying out the reaction at 10 ꢀC with 10 mol % catalyst
loading in 1,4-dioxane, but with a serious reduction of the yield
(23%, entry 11). Finally, we found that the reaction proceeded
much more efficiently in a mixed solvent system, 1,4-dioxane/
DCM (1:3). The reaction with 10 mol % catalyst loading at 10 ꢀC
afforded (S)-4aa with 77% ee in 81% yield (entry 12). A slightly
higher yield (83%) was obtained by changing CuCl to
CuOTf$(toluene)0.5 with the enantioselectivity unchanged (entry
13). The enantioselection could be improved to 80% ee by re-
ducing the reaction temperature to 5 ꢀC at the expense of the
yield (55%) (entry 14).
2.1.4. Substrate scopes. Various terminal alkenes (1) and Z-allyl
chlorides (3) were subjected to 9-BBN-hydroboration and were
used for the enantioselective allylic substitution with the
CuOTf$(toluene)0.5/(R)-DTBM-SEGPHOS (L5) catalyst system
(Table 3).10 The reactions proceeded with excellent
g-selectivities
(g/a>20:1) and high enantioselectivities (76e90% ee). Terminal
alkenes having functional groups such as acetal, silyl ether, ester,
and phthalimide moieties at the terminal of the aliphatic chain
were compatible with the protocol (entries 1e8). Functional groups
such as chloro and silyl ether moieties in the allylic substrates were
also tolerated (entries 2, 7 and 8).
The tolerance of this reaction toward smaller or sterically more
2.1.2. Effects of leaving groups and bases. Effects of leaving groups
and bases were examined in the reaction of 2a and (Z)-3a under the
conditions for Table 1, entry 5 [CuCl/L5, 1,4-dioxane, 35 ꢀC]
(Table 2).10 Replacing the leaving group with a bromide or phos-
phate caused drastic reductions of the product yield and enantio-
selectivity (entries 1e3).
demanding
version of the
g
-substituents is demonstrated in the successful con-
g
-methyl or -cyclohexyl-substituted allyl chlorides
g
(3d, e), although reductions in yield and enantioselection were
observed (4dd, 70%, 81% ee; 4de, 53%, 76% ee, Table 3, entries 4 and
5). Unfortunately, the attempt to use the alkylborane (2g) derived
from styrene (1g) failed (entry 9).
Table 2
Effect of leaving groups and basesa
Entry
Leaving group
ROK
Yieldb,c (%)
eed (%)
1
2
3
4
5
6
7
Cl (Table 1, entry 5)
Br
OP(O) (OEt)2
Cl
Cl
Cl
Cl
MeOK
MeOK
MeOK
t-BuOK
PhOK
48
18
5
39
0
61
34
13
57
d
d
d
MeOLi
MeONa
Trace
0
a
The reaction was carried out with 3 (0.2 mmol), 2a (0.25 mmol), Cu salt (5 mol %), L5 (5 mol %), and base (0.21 mmol) in 1,4-dioxane (0.8 mL) for 12 h. Alkylborane 2 was
prepared in advance by hydroboration of 1 with the 9-BBN dimer at 60 ꢀC (1 h) and used without purification.
b
The yield was determined by 1H NMR.
c
Constitutional isomer ratio g/a
>20:1 (determined by 1H NMR analysis of the crude product).
d
The enantiomeric excess was determined by HPLC analysis.
Changing the alkoxide base from MeOK to the bulkier t-BuOK
2.1.5. Synthesis of chiral allylsilanes. The reaction between a
silylated allyl chloride (3g) and alkylboranes afforded enantioen-
riched
-stereogenic chiral allylsilanes (Table 4).10,16e18 For in-
stance, the reaction between alkylborane 2h, which was derived
from terminal alkene 1h, and 3g under the conditions optimized for
g-
decreased the yield (39%) and enantioselectivity (57% ee) (Table 2,
entry 4). No reaction occurred with the weaker base PhOK (entry 5).
The use of Li or Na methoxides also resulted in virtually no reaction
(entries 6 and 7).
a
The inefficiency of the Li or Na methoxides may reflect higher
solubilities of Li or Na salts, which may cause inhibitory effects in
the hydrophobic solution phase of the reaction mixture. This as-
sumption also explains the increase in the reaction efficiency when
DCM was used as a co-solvent with 1,4-dioxane (Table 1, entry 12).
the reaction of (Z)-3a proceeded with complete g-selectivity, and
afforded chiral allylsilane 4hg with 91% ee in 77% yield (entry 1).
The terminal alkenes (1c,e,f,i) bearing acetal, ester, phthalimide or
chloro moieties were also compatible with the protocol with
comparable enantioselectivities (entries 2e5).
2.1.3. Effect of alkene geometry. The reaction of allyl chloride 3a
with E-configuration under the optimized conditions (the condi-
tions for Table 1, entry 13) provided the product with the same
absolute configuration with 64% ee (Scheme 2, see Section 2.5 for
discussion on the effect of alkene geometries).10,15
2.2. Construction of quaternary carbon stereogenic centers
using g,g-disubstituted primary allylic substrates
2.2.1. Background on construction of quaternary carbon stereogenic
centers. Catalytic enantioselective construction of all-carbon
quaternary stereogenic centers in acyclic systems is one of the
biggest challenges in organic synthesis.19 One of the obstacles is
low reactivity due to the steric repulsion that occurs in the car-
bonecarbon bond formation step. It is also difficult to discrimi-
nate the enantiotopic faces due to steric congestion and the
diminished steric difference between the non-hydrogen
Scheme 2. Copper-catalyzed allylic substitutions of alkylborane and (E)-allyl chloride.
substituents.
To
this
end,
transition-metal-catalyzed
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K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
Table 3
Scope of enantioselective allylic substitution with alkylboranesa
Entry
1e
Alkene
Allyl chloride
Product
Yieldb,c (%)
93
eed (%)
88
2
3
71
71
83
88
(Z)-3a
4f
5
1d
1d
70
53
73
81
76
88
6
(Z)-3a
7
73
88
8
9
1f
(Z)-3c
(Z)-3a
72
0
90
d
d
a
The reaction was carried out with (Z)-3 (0.2 mmol), 2 (0.25 mmol), CuOTf$(toluene)0.5 (10 mol %), L5 (10 mol %), and MeOK (0.22 mmol) in 1,4-dioxane/DCM (1:3, 0.8 mL) at
10 ꢀC (entry 3) or 15 ꢀC (entries 1, 2, and 4e9) for 48 h (entries 2, 3, 7, and 9) or 72 h (entries 1, 4e6, and 8). Alkylborane 2 was prepared in advance by hydroboration of 1 with
the 9-BBN dimer at 60 ꢀC (1 h) and used without purification.
b
The yield of the isolated product.
c
Constitutional isomer ratio g/a
>20:1 (determined by 1H NMR analysis of the crude product).
d
e
f
The enantiomeric excess was determined by HPLC analysis.
Reaction on 1.0 mmol scale.
Compound 2 (0.34 mmol) and MeOK (0.3 mmol) were used.
enantioselective allylic substitutions with organometallic nucle-
ophiles such as organolithium, Grignard, diorganozinc or tri-
organoaluminum reagents have proven to be effective
strategies.1 Organoboron compounds have also been used for
enantioselective construction of all-carbon quaternary stereo-
genic centers through allylic substitution.4,5b However, the
methodology has not yet been generalized to allow the reaction
of sp3-alkylboron nucleophiles.
The aforementioned enantioselective copper-catalyzed reaction
was not applicable to the construction of quaternary stereogenic
centers (Section 2.1). However, only a slight modification to the
catalyst system enabled the construction of a quaternary stereo-
genic carbon center through copper-catalyzed enantioselective al-
2.2.2. Optimization. As shown in Table 5, we examined copper
complexes prepared from CuOTf$(toluene)0.5 (10 mol %) and vari-
ous DTBM-substituted chiral bisphosphine ligands for catalytic
activity,
g
-regioselectivity, and enantioselectivity in the reaction of
g,g-disubstituted allyl chloride (E)-5a with alkylborane 2a in the
presence of EtOK in 1,4-dioxane/DCM (1:3) at 25 ꢀC over 20 h (5a/
2a/EtOK 1:1.25:1.1) (Table 5, entries 1e4).20 Specifically, the catalyst
prepared from the DTBM-substituted TunePHOS-type chiral
bisphosphine (L8) did not promote the reaction at all (entry 1).21
(R)-DTBM-BINAP (L3) induced only low catalytic activity,
tivity, and enantioselectivity (entry 2). (R)-DTBM-SEGPHOS (L5),
which exhibited high performance in the reaction with -mono-
substituted primary allyl chlorides (Section 2.1), imparted moder-
ate -selectivity ( 6:1) and enantioselectivity (47% ee), but the
product yield was lower than that with L3 (entry 3). To our delight,
g-selec-
g
lylic substitution of alkylboranes and
chlorides.
g,
g-disubstituted allyl
g
g/a
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K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
5
Table 4
Synthesis of chiral allylsilanesa
Entry
1
Alkene
Product
Yieldb,c (%)
77
eed (%)
91
2
3
1c
1e
66
52
91
87
4
1f
85
88
90
91
5e
a
The reaction was carried out with (Z)-3g (0.2 mmol), 2 (0.25 mmol), CuOTf$(toluene)0.5 (10 mol %), L5 (10 mol %), and MeOK (0.22 mmol) in 1,4-dioxane/DCM (1:3, 0.8 mL)
at 15 ꢀC for 48 h (entries 1, 2, 4, and 5) or 72 h (entry 3). Alkylborane 2 was prepared in advance by hydroboration of 1 with the 9-BBN dimer at 60 ꢀC (1 h) and used without
purification.
b
The yield of the isolated product.
c
Linear isomer was not detected: g/a
>99:1 (1H NMR).
d
e
The enantiomeric excess was determined by HPLC analysis.
Reaction on 1.0 mmol scale.
Table 5
Copper-catalyzed enantioselective allylic substitutions between 2a and (E)-5a under various conditionsa
Entry
Ligand (L)
Solvent
Temp (ꢀC)
Yieldb (%)
g/
ac
eed (%)
1
2
3
4
L8
L3
L5
L4
L4
L4
Dioxane/DCM
Dioxane/DCM
Dioxane/DCM
Dioxane/DCM
THF/DCM
25
25
25
25
25
15
0
38
15
26
56
65
d
d
3.5:1
6:1
>20:1
>20:1
>20:1
21
47
83
81
81
5
6e
THF/DCM
a
The reaction was carried out with (E)-5a (0.2 mmol), 2a (0.25 mmol), CuOTf$(toluene)0.5 (10 mol %), ligand (L) (10 mol %), and EtOK (0.22 mmol) in solvent (0.8 mL) for 20 h.
Alkylborane 2 was prepared in advance through hydroboration of 1 with the 9-BBN dimer at 60 ꢀC (1 h) and used without purification.
b
Yield of the isolated product.
c
Determined by 1H NMR analysis of the crude product.
d
The enantiomeric excess was determined by HPLC analysis.
Reaction on 0.3 mmol scale. Compound 2a (0.52 mmol) and EtOK (0.45 mmol) were used.
e
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6
K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
the use of (R)-DTBM-MeO-BIPHEP (L4) led to a significant im-
provement in the regioselectivity and enantioselectivity (entry 4).
trisubstituted alkene moiety in the allylic substrate 5b was tol-
erated during the formation of diene 6ab (entry 8). The copper
catalyst system enabled the enantioselective coupling of allyl
chlorides having two alkyl substituents of almost equal steric
The alkylation occurred at the disubstituted
g-carbon atom of 5a (g/
a
>20:1), constructing the all-carbon quaternary stereogenic center
with 83% ee in favor of the formation of (S)-6aa (si-face attack),
albeit still with a low product yield.
demands at the
chloride 5c having ethyl and phenylethyl groups at the
reacted with high enantioselectivity (81% ee) (entry 9). Replacing
the ethyl group at the -position of 5c with a propyl group
slight reduction in the enantioselectivity
g
-position (entries 9 and 10). For example, allyl
g
-position
The product yield with the Cue(R)-DTBM-MeO-BIPHEP (L4)
system could be increased to 56% by changing the solvent to THF/
DCM (1:3) with the enantioselectivity almost unchanged (81% ee)
(Table 5, entry 5).20 The yield was further improved to 65% by
conducting the reaction at 15 ꢀC with an increased amount of the
2a/EtOK reagent (5a/2a/EtOK 1:1.7:1.5) (entry 6).
g
caused only
(entry 10).
a
2.3. Determination of absolute configurations of allylic cou-
pling products
2.2.3. Effect of bases. The effect of bases is summarized in Table 6.
The use of MeOK instead of EtOK under the conditions for Table 5,
entry 4 [CuOTf$(toluene)0.5, L4, dioxane/DCM, 25 ꢀC] decreased the
product yield (14% yield) with the regioselectivity and enantiose-
lectivity unchanged (entry 2). The use of t-BuOK resulted in no
reaction (entry 3).
Transformation of the coupling product 4bb to the p-nitro-
benzoate derivative 4bbb8c through ozonolysis and reduction
with NaBH4 followed by benzoylation confirmed the (R) absolute
configuration of 4bb (Scheme 4a). The absolute configuration of
allylsilane 4hg was determined to be R by the optical rotation of
(S)-undecan-3-ol (4hgc)22 by alkene reduction followed by Fle-
mingeTamao oxidation23 with retention of configuration
(Scheme 4b). The absolute configuration of the coupling product
6la with a quaternary stereogenic center was confirmed by op-
tical rotation of (S)-2-ethyl-2-methyl-4-phenyl-1-butanol (6laa)
obtained by ozonolysis followed by reduction with NaBH4
(Scheme 4c).24 Absolute configurations of the other coupling
products were assigned by consideration of the stereochemical
pathway.
Table 6
Effect of basesa
Entry
Base
Yieldb (%)
g/
ac
eed (%)
1 (Table 5, entry 4)
2
3
EtOK
MeOK
t-BuOK
26
14
0
20:1
20:1
d
83
83
d
a
The reaction was carried out with (E)-5a (0.2 mmol), 2a (0.25 mmol),
CuOTf$(toluene)0.5 (10 mol %), L4 (10 mol %), and EtOK (0.22 mmol) in solvent
(0.8 mL) for 20 h. Alkylborane 2 was prepared in advance through hydroboration of
1 with the 9-BBN dimer at 60 ꢀC (1 h) and used without purification.
b
Yield of the isolated product.
c
Determined by 1H NMR analysis of the crude product.
d
The enantiomeric excess was determined by HPLC analysis.
2.2.4. Effect of alkene geometry. The reaction of (Z)-5a under the
optimized conditions (the conditions for Table 5, entry 6) provided
(R)-6aa, the antipode of the product derived from (E)-5a, with 61%
ee in 85% yield (Scheme 3).20 This enantioselectivity is lower than
that for the reaction of (E)-5a (see Section 2.5 for discussion on
enantioselection models).
Scheme 4. Determination of absolute configuration.
Scheme 3. Copper-catalyzed allylic substitution of g,g-disubstituted (Z)-allyl chloride.
2.2.5. Substrate scopes. Various terminal alkenes having different
functional groups such as acetal, silyl ether, ester, chloro or benzyl
ether in the aliphatic chain were compatible with this protocol as
demonstrated by their reactions with (E)-5a (Table 7, entries
1e6).20 Ethylene also served as a suitable substrate (entry 7).20 This
2.4. Proposed reaction pathway for the copper-catalyzed al-
lylic alkylations
As proposed for the Cu-catalyzed allylealkyl coupling between
secondary allylic phosphates and alkylboranes,8aec an active orga-
nocopper species is likely in the form of a neutral organocopper(I)
species (C) rather than a monoorganoheterocuprate, since an alk-
oxide base is consumed for the formation of borate B, and the
copper center bearing the alkyl ligand and the bisphosphine ligand
reaction delivered an ethyl group to the fully substituted g-carbon
atom of 5a with enantioselectivity at a useful level.
The scope of
g,g-disubstituted allyl chlorides (5) successfully
employed is also shown in Table 7 (entries 8e10).20 An additional
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K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
7
Table 7
Scope of enantioselective allylic substitutions with alkylboranesa
Entry
1
Alkene
Allyl chloride
Product
Yieldb,c (%)
79
eed (%)
90
1c
(E)-5a
2
1d
1e
1i
(E)-5a
(E)-5a
(E)-5a
85
66
80
83
81
86
3
4e
5f
(E)-5a
70
86
6
7
8
(E)-5a
(E)-5a
68
63
54
81
71
73
1a
9e
1c
1c
75
67
81
71
10e
a
The reaction was carried out with (E)-5 (0.2 mmol), 2 (0.34 mmol), CuOTf$(toluene)0.5 (5 mol %), (R)-DTBM-MeO-BIPHEP (L4) (10 mol %), and EtOK (0.3 mmol) in THF/DCM
(1:3, 0.8 mL) at 15 ꢀC for 20 h. Alkylborane 2 was prepared in advance through hydroboration of 1 with the 9-BBN dimer at 60 ꢀC (1 h) and used without purification.
b
Yield of the isolated product.
c
Constitutional isomer ratio g/a
>20:1 (determined by 1H NMR analysis of the crude product).
d
e
f
The enantiomeric excess was determined by HPLC analysis.
Constitutional isomer ratio
Diastereomeric ratio (1:1).
g/a>10:1.
is coordinatively saturated upon alkene coordination. Therefore,
the addition of alkylcopper(I) species C would occur with anti
stereochemistry with respect to the leaving group, being followed
indicate that the alkoxyborane is not able to coordinate to the
chloride leaving group.25
The formation of the a-coupling product in the reaction of g,g-
by anti-
b
-elimination (Fig. 1).
disubstituted primary allylic substrates with (R)-DTBM-BINAP (L3)
or (R)-DTBM-SEGPHOS (L5) might be due to the formation of an
alkyl(ethoxo)cuprate species upon dissociation of one or two P
atoms of the chiral ligands (Table 5, entries 2 and 3). Such cuprate
species would undergo oxidative addition with 5 to form an iso-
Earlier, we proposed that the alkoxyborane, which is derived
from the transmetalation between CuXebisphosphine [A, X¼OMe,
OEt or Cl] and a trialkyl(alkoxo)borate B, might activate the chloride
leaving group through its Lewis-acidic character during the orga-
nocopper additioneelimination pathway [D/E/F-TS/G-TS/H/
I/4 or 6] (Fig. 1).7 However, our ongoing theoretical calculations
meric mixture of ([
bond either at the
sþ
p
]-allyl)copper(III) species with a CeCu
s
a
or g carbon atoms. Reductive elimination of
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8
K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
configuration suggests Ar1 has greater steric interaction with the R2
substituent (F-TS-4) than with the ClCH2 substituent (F-TS-3).
Enantioselection models for the reaction of -disubstituted
g,g
primary allylic phosphates are depicted in Fig. 3 based on the fact
that the reactions of E- and Z-isomers of 5a gave the antipodes of 6,
respectively, the former showing higher enantioselectivity (Table 5,
entry 6 vs Scheme 3). In the
p-complex E (see Fig. 1), the allyl
chloride substrate (5) bound to the tetrahedral copper center is in
proximity to the two P-substituents Ar1 and Ar3, which are axial
and equatorial substituents, respectively, of the bisphosphineeCu
chelate ring. The axial substituent Ar1 points toward the substrate
more than the equatorial Ar3. Rl and Rs indicate the larger and
smaller
major enantiomer of 6 in the reaction of (E)-5, has steric repulsion
only between Rs and Ar3, while the corresponding
-complex (E-2)
g-substituents of 5, respectively. E-1, which leads to the
p
leading to the minor enantiomer has larger steric repulsions be-
tween the ClCH2 group and Ar1 and between Ar3 and Rl. A similar
discussion should be applicable for the transition state (G-TS).
Fig. 1. Possible catalytic cycle.
these allylcopper(III) intermediates may form a mixture of the
and
-coupling products as minor products.26,27
a-
g
2.5. Proposed models for enantiodiscrimination
The enantioselection likely occurs at transition states of the
R1eCu addition across the CeC double bond. Enantioselection
models for the reaction of
g-monosubstituted primary allylic
phosphates (Z)-3 are given in Fig. 2 (F-TS-1 and F-TS-2). In this
model, the copper adopts tetrahedral coordination geometry, in
which the axis of the CeC double bond is coplanar with the CueR1
bond, Ar1 and Ar3 are equatorial, and Ar2 and Ar4 are axial. Im-
portantly, Ar1 points toward the allyl chloride substrate more sig-
nificantly than the other equatorial aryl group (Ar3). The axial aryl
groups (Ar2 and Ar4) are much more distal to the substrate.
According to these assumptions, F-TS-1 has less steric strain than F-
TS-2, because Ar1 is close to both the R2 and ClCH2 substituents in
F-TS-2, while F-TS-1 encounters the corresponding steric re-
pulsions only between Ar3 and the R2 substituent, which should be
relatively small due to the distal location of Ar3.
Fig. 3. Proposed models for enantiodiscrimination. Rl and Rs are the larger and smaller
g
scaffold of L4 is simplified with a polygonal line.
-substituents of 5, respectively. Ar1eAr4 are the P-substituents of L4. The biaryl
In the case of the reaction of (Z)-5, the p-complex (E-3) leading
In the case of the reaction with (E)-3, Ar1 causes steric repulsions
toward either the ClCH2 (F-TS-3) or R2 substituents (F-TS-4) (Fig. 2).
Consequently, the energy difference between F-TS-3 and F-TS-4 is
smaller than that between F-TS-1 and F-TS-2. These considerations
explain the more efficient enantioselection in the reaction with the
allylic substrate with Z-configuration (Table 1, entry 13 vs
Scheme 2). The observed stereoconvergency from the Z and E allylic
substrates affording the product with the identical absolute
to the major enantiomer, the antipode of the product from E-1, has
a steric repulsion between Ar3 and Rl, which should be larger than
the steric repulsion that occurs in E-1 (Rl vs Rs) (Fig. 3). On the other
hand, the steric repulsion between Ar3 and Rs in E-4 should be
smaller than that between Ar3 and Rl in E-2. These considerations
also match the observed trend that the enantioselectivity gradually
decreased with the increase of the size of the Rs substituent of (E)-5
(Table 7, entries 1, 9, and 10). This can be explained by the in-
creasing steric repulsion between Ar3 and Rs in E-1.
3. Conclusion
Here we have presented full details of our work on alkylboranes,
which we have introduced as new reagents for copper-catalyzed
SN20-type enantioselective allylic substitutions. The copper cataly-
sis delivered enantioenriched chiral products containing tertiary or
quaternary carbon stereogenic centers branched with functional-
ized sp3-alkyl groups. The wide availability of alkylboranes via the
established alkene hydroboration reaction is an attractive feature of
these transformations. Various functional groups are tolerated in
the substrates. The introduction of DTBM substituents on the
phosphorus atoms of chiral bisphosphines was important for pro-
Fig. 2. Models for enantiodiscrimination. Ar1eAr4 are the P-substituents of L5. The
biaryl scaffold of L5 is simplified with a polygonal line.
motion of the reaction. The catalytic activity,
g-selectivity, and
enantioselectivity of the reaction were very sensitive to the
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K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
9
dihedral angle of the axially chiral biaryl scaffolds in the Cu(I)e
bisphosphine complexes. A reaction pathway involving addi-
tioneelimination of a neutral alkylcopper(I) species with the allyl
chloride substrate is proposed.
(1.8 g, 9.6 mmol) and TMEDA (3.6 mL, 24 mmol) in THF (1.0 mL)
was added 2-phenylethylmagnesium bromide (0.7 M in THF,
13.7 mL, 9.6 mmol) at ꢁ40 ꢀC, and the resulting mixture was
stirred at ꢁ40 ꢀC for 30 min. To the mixture was added ethyl 2-
butynoate (0.9 g, 8 mmol) at ꢁ78 ꢀC, and the mixture was stirred
at ꢁ78 ꢀC for 2 h. Saturated NH4Cl aq was added and the mixture
was allowed to warm to rt. The resulting slurry was diluted with
EtOAc (50 mL) and washed with H2O and brine. The organic layer
was separated and dried over MgSO4. Then, the drying agent was
removed by filtration, and the resulting solution was evaporated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (0e10% EtOAc/hexane) provided
ethyl (E)-3-methyl-5-phenyl-2-pentenoate (1.7 g, 7.6 mmol) in
95% yield.
4. Experimental section
4.1. General
NMR spectra were recorded on a Varian Gemini 2000 spec-
trometer, operating at 300 MHz for 1H NMR and 75.4 MHz for 13
C
NMR, and a JEOL ECX-400, operating at 100.5 MHz for 13C NMR.
Chemical shift values for 1H and 13C are referenced to Me4Si and
the residual solvent resonances, respectively. Chemical shifts are
To
a stirred solution of ethyl (E)-3-methyl-5-phenyl-2-
reported in
d ppm. Mass spectra were obtained with Thermo
pentenoate (1.7 g, 7.6 mmol) in DCM was dropped DIBAL-H
(16.4 mL in 1.02 M hexane solution, 16.7 mmol) at ꢁ78 ꢀC and
the reaction was continued for 30 min at the same temperature.
Satd NH4Cl was added and the mixture was vigorously stirred for
10 min. Solid was filtered through Celite pad and the filtrate was
extracted with ether. The crude product was purified by flash
chromatography on silica gel (10e20% EtOAc/hexane) to give (E)-3-
methyl-5-phenyl-2-penten-1-ol (1.2 g, 6.6 mmol) in 87% yield.
To a solution of (E)-3-methyl-5-phenyl-2-penten-1-ol (1.2 g,
6.6 mmol) in DCM (13.2 mL), NCS (1.0 g, 7.3 mmol) and PPh3 (2.0 g,
7.9 mmol) were sequentially added at 0 ꢀC. After being stirred at rt
for 2 h, the solvent was removed under reduced pressure, and then
residue was filtered through a pad of Celite with EtOAc as an eluant.
The filtrate was evaporated under reduced pressure. The residue
was purified through flash chromatography on silica gel (hexane)
followed by Kugelrohr disitillation provided 5a (1.1 g, 5.6 mmol) in
80% yield.
Fisher Scientific Exactive, JEOL JMS-T100LP or JEOL JMS-700TZ at
the Instrumental Analysis Division, Equipment Management
Center, Creative Research Institution, Hokkaido University. Ele-
mental analysis was performed at the Instrumental Analysis
Division, Equipment Management Center, Creative Research In-
stitution, Hokkaido University. HPLC analyses were conducted on
a HITACHI ELITE LaChrom system with a HITACHI L-2455 diode
array detector. IR spectra were recorded on a PerkineElmer
Spectrum One. TLC analyses were performed on commercial
glass plates bearing 0.25-mm layer of Merck Silica gel 60F254
.
Silica gel (Kanto Chemical Co., Silica gel 60 N, spherical, neutral)
was used for column chromatography. Melting points were
measured on a Yanaco MP-500D apparatus. Gel permeation
chromatography (GPC) was performed by LC-908 (Japan Ana-
lytical Industry Ltd., two in-line JAIGEL-2H, CHCl3, 3.5 mL/min,
UV and RI detectors).
All reactions were carried out under nitrogen or argon atmo-
sphere. Materials were obtained from commercial suppliers or
prepared according to standard procedures unless otherwise noted.
4.2.4. Preparation of
g,g-Disubstituted (E)-Allyl chloride 5b. To
a solution of geraniol (1.5 g, 10 mmol) in DCM (20 mL), NCS (1.5 g,
11 mmol) and PPh3 (3.1 g, 12 mmol) were sequentially added at
0 ꢀC. After being stirred at rt for 2 h, the solvent was removed under
reduced pressure, and then residue was filtered through a pad of
Celite with hexane as an eluant. The filtrate was evaporated under
reduced pressure. The residue was purified by Kugelrohr dis-
itillation to provide 5b (1.4 g, 8 mmol) in 80% yield.
9-Borabicyclo[3,3,1]nonane dimer (9-BBN-H)2, CuOTf$(toluene)0.5
,
MeOK, EtOK, (R)-DTBM-MeO-BIPHEP (L4), and (R)-DTBM-BINAP
(L3) were purchased from Aldrich Chemical Co., stored under ni-
trogen, and used as it is. (R)-DTBM-SEGPHOS (L5) was purchased
from Strem Chemicals Inc., stored under nitrogen, and used as it is.
(R)-DTBM-TunePHOS (L8) was prepared according to the literature
procedure.21 Dichloromethane (DCM) was purchased from Kanto
ꢀ
Chemical Co., stored over 4 A molecular sieves under nitrogen. 1,4-
Dioxane was purchased from Kanto Chemical Co., distilled from
sodium/benzophenone and stored over 4 A molecular sieves under
4.3. Procedures for copper-catalyzed enantioselective allylic
substitution with alkylboranes
ꢀ
nitrogen. Alkenes 1ael are well known compounds. Allyl chrolides
3d, (E)-5a,b are found in the literature.28
4.3.1. Typical procedure for copper-catalyzed allylic substitutions
with
g-monosubstituted primary allyl chlorides (Table 3, entry 1). 2-
4.2. Preparation of allyl chlorides
(3-Buten-1-yl)-1,3-dioxane (1b) (196.6
mL, 1.3 mmol) and (9-BBN-
H)2 (151.2 mg, 0.625 mmol) were placed in a vial containing
a magnetic stirring bar. The vial was sealed with a TeflonÒ-coated
silicon rubber septum and the vial was evacuated and filled with
argon. 1,4-Dioxane (1.0 mL) was added to the vial, and then the
mixture was stirred at 60 ꢀC for 1 h to prepare an alkylborane. On
the other hand, CuOTf$(toluene)0.5 (26 mg, 0.1 mmol), (R)-DTBM-
SEGPHOS (L5) (118 mg, 0.1 mmol), and MeOK (77 mg, 1.1 mmol)
were placed in another vial. The vial was sealed with a TeflonÒ-
coated silicon rubber septum and the vial was evacuated and filled
with argon. After DCM (3.0 mL) was added to the vial, the mixture
was stirred at 25 ꢀC for 1 h. Next, the alkylborane solution was
transferred to the vial containing a Cu(I)eL5 complex. Then, allyl
chloride 3b (132.6 mg, 1.0 mmol) was added. After 72 h stirring at
15 ꢀC, diethyl ether was added to the mixture. The mixture was
filtered through a short plug of silica gel, which was then washed
with diethyl ether. After the solvent was removed under reduced
4.2.1. Preparation of (Z)-allyl chlorides 3aec, e, and f. Addition of
the lithium acetylides to formaldehyde gave the corresponding
propargylic alcohols. Next, Lindlar reduction followed by chlori-
nation (NCS, PPh3, DCM, rt) afforded the allylic chlorides 3aec, e,
and f.
4.2.2. Preparation of (Z)-1-dimethylphenysilyl-3-chloro-1-pentene
(3g). THP-protection of 2-propyn-1-ol followed by silylation gave
g
-silylated propargylic alcohol derivative. Next, DIBAL-H reduction
followed by deprotection (p-TsOH, MeOH) afforded -silylated al-
lylic alcohol. Finally, 3g was prepared by chlorination (NCS, PPh3,
DCM, rt) of the -silylated allylic alcohol.
g
g
4.2.3. Preparation of
g,g-disubstituted (E)-allyl chlorides 5a, c, and
d. The preparation of 5a is representative. To a solution of CuI
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10
K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
pressure, flash chromatography on silica gel (0e5% EtOAc/hexane)
provided 4bb (223.6 mg, 0.93 mmol) in 93% yield.
(m, 2H),1.75e1.85 (m, 2H), 2.13e2.20 (m, 2H), 3.55 (t, J¼6.6 Hz, 2H),
4.09 (d, J¼7.2 Hz, 2H), 5.58e5.72 (m, 2H). 13C NMR (75.4 MHz,
CDCl3)
d 26.2, 26.3, 31.9, 39.2, 44.7, 125.9, 134.7. HRMS-EI (m/z):
4.3.2. Typical procedure for synthesis of chiral allylsilanes (Table 4,
[M]þ calcd for C7H12Cl2, 166.03161; found, 166.03168.
entry 5). 6-Chloro-1-hexene (1i) (172 mL,1.3 mmol) and (9-BBN-H)2
(151.2 mg, 0.625 mmol) were placed in a vial containing a magnetic
stirring bar. The vial was sealed with a TeflonÒ-coated silicon
rubber septum and the vial was evacuated and filled with argon.
1,4-Dioxane (1.0 mL) was added to the vial, and then the mixture
was stirred at 60 ꢀC for 1 h to prepare an alkylborane. On the other
hand, CuOTf$(toluene)0.5 (26 mg, 0.1 mmol), (R)-DTBM-SEGPHOS
(L5) (118 mg, 0.1 mmol), and MeOK (77 mg, 1.1 mmol) were placed
in another vial. The vial was sealed with a TeflonÒ-coated silicon
rubber septum and the vial was evacuated and filled with argon.
After DCM (3.0 mL) was added to the vial, the mixture was stirred at
25 ꢀC for 1 h. Next, the alkylborane solution was transferred to the
vial containing a Cu(I)eL5 complex. Then, allyl chloride 3g (211 mg,
1.0 mmol) was added. After 48 h stirring at 15 ꢀC, diethyl ether was
added to the mixture. The mixture was filtered through a short plug
of silica gel, which was then washed with diethyl ether. After the
solvent was removed under reduced pressure, flash chromatogra-
phy on silica gel (hexane) provided 4ig (259.5 mg, 0.88 mmol) in
88% yield.
4.4.4. (Z)-(3-Chloro-1-propen-1-yl)cyclohexane (3e). Colorless oil.
IR (neat) 766, 890, 1249, 1448, 1651, 2850, 2924 cmꢁ1 1H NMR
.
(300 MHz, CDCl3) d 1.03e1.36 (m, 5H), 1.55e1.75 (m, 5H), 2.31e2.34
(m, 1H), 4.11 (d, J¼7.2 Hz, 2H), 5.43e5.57 (m, 2H). 13C NMR
(75.4 MHz, CDCl3)
d 25.6, 25.7, 32.9, 36.2, 39.8, 123.3, 141.4. HRMS-
EI (m/z): [M]þ calcd for C9H15Cl, 158.08623; found, 158.08626.
4.4.5. (Z)-tert-Butyl[(7-chloro-5-hepten-1-yl)oxy]dimethylsilane
(3f). Colorless oil. IR (neat) 773, 833, 1097, 1252, 1472, 2858,
2930 cmꢁ1.1H NMR (300 MHz, CDCl3)
d 0.05 (s, 3H), 0.06 (s, 3H), 0.89
(s, 9H), 1.41e1.56 (m, 4H), 2.11e2.18 (m, 2H), 3.62 (t, J¼6.0 Hz, 2H),
4.10 (d, J¼6.6 Hz, 2H), 5.62e5.66 (m, 2H).13C NMR (75.4 MHz, CDCl3)
d
ꢁ5.5, 18.2, 25.5, 25.9, 26.7, 32.2, 39.4, 62.8, 125.4, 135.4. HRMS-EI
(m/z): [MꢁCl]þ calcd for C13H27OSi, 227.1831; found, 227.1832.
4.4.6. (Z)-1-Dimethylphenysilyl-3-chloro-1-pentene (3g). Colorless
oil. IR (neat) 698, 782, 818, 1111, 1250, 1427, 1604, 2958 cmꢁ1 1H
.
NMR (300 MHz, CDCl3)
d
0.42 (s, 6H), 3.95 (d, J¼7.8 Hz, 2H), 5.92 (d,
J¼14.1 Hz, 1H), 6.51 (dt, J¼14.1, 7.8 Hz, 1H), 7.36e7.38 (m, 3H),
4.3.3. Typical procedure for construction of quaternary carbon ster-
7.53e7.56 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
d
ꢁ1.2, 43.8, 128.1,
eogenic centers using
5, entry 6). 3,4-Dimethoxy-1-allylbenzene (1a) (93.4
g
,
g
-disubstituted primary allyl chlorides (Table
L,
129.4, 132.7, 133.7, 138.3, 144.0. HRMS-EI (m/z): [MꢁCH3]þ calcd for
m
C10H12ClSi, 195.0397; found, 195.0399.
0.54 mmol) and (9-BBN-H)2 (64.2 mg, 0.26 mmol) were placed in
a vial containing a magnetic stirring bar. The vial was sealed with
a TeflonÒ-coated silicon rubber septum and the vial was evacuated
and filled with argon. THF (0.3 mL) was added to the vial, and then
the mixture was stirred at 60 ꢀC for 1 h to prepare an alkylborane.
Meanwhile, CuOTf$(toluene)0.5 (7.8 mg, 0.03 mmol), (R)-DTBM-
MeO-BIPHEP (L4) (35.5 mg, 0.03 mmol), and EtOK (39.9 mg,
0.45 mmol) were placed in another vial. This vial was sealed with
a TeflonÒ-coated silicon rubber septum and then evacuated and
filled with argon. After DCM (0.9 mL) was added to the vial, the
mixture was stirred at 25 ꢀC for 1 h. Next, the alkylborane solution
was transferred to the vial containing the Cu(I)eL4 complex. Next,
allyl chloride (E)-5a (58.5 mg, 0.3 mmol) was added. After 20 h
stirring at 15 ꢀC, diethyl ether was added to the mixture. The
mixture was filtered through a short plug of silica gel, which was
then washed with diethyl ether. After the solvent was removed
under reduced pressure, flash chromatography on silica gel (0e3%
EtOAc/hexane) provided 6aa (66.0 mg, 0.20 mmol) at 81% ee in 65%
yield.
4.4.7. (S)-1,2-Dimethoxy-4-(4-phenethyl-5-hexen-1-yl)benzene
(4aa). The product 4aa was purified by flash chromatography on
silica gel (0e10% EtOAc/hexane) followed by GPC (CHCl3) [59%
isolated yield from (Z)-3a]. Colorless oil. IR (neat) 699, 749, 1030,
1140, 1235, 1515, 1591, 2932 cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d
1.29e1.74 (m, 6H), 1.98e2.06 (m, 1H), 2.45e2.60 (m, 2H),
2.62e2.69 (m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.97e5.07 (m, 2H), 5.57
(dt, J¼17.1, 9.6 Hz, 1H), 6.69 (d, J¼6.6 Hz, 2H), 6.78 (d, J¼8.7 Hz, 1H),
7.15e7.19 (m, 3H), 7.25e7.30 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
d
29.1, 33.4, 34.5, 35.5, 36.7, 43.6, 55.7, 55.8, 111.1, 111.7, 115.0, 120.2,
125.7, 128.3, 128.5, 135.4, 142.9, 142.9, 147.1, 148.8. HRMS-EI (m/z):
25
[M]þ calcd for C22H28O2, 324.20893; found, 324.20883. [
a]
D
ꢁ0.75 (c 1.03, CHCl3) (77% ee). HPLC analysis [CHIRALCELÒ OD-3
column, 4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼97:3, 0.5 mL/min, 40 ꢀC, 254 nm UV detector, retention
time¼19.5 min for R isomer and 20.9 min for S isomer] revealed
that the enantiomeric excess of 4aa was 77%. The absolute config-
uration of 4aa was assigned by consideration of the stereochemical
pathway.
4.4. Characterization data
4.4.8. (R)-2-(5-Vinylnonyl)-1,3-dioxane (4bb). The product 4bb
was purified by flash chromatography on silica gel (0e5% EtOAc/
hexane) (93% isolated yield). Colorless oil. IR (neat) 908, 995, 1144,
4.4.1. (Z)-(5-Chloro-3-penten-1-yl)benzene (3a). Colorless oil. IR
(neat) 697, 742, 1250, 1453, 1496, 1652, 2931, 3027 cmꢁ1. 1H NMR
(300 MHz, CDCl3)
d
2.41e2.47 (m, 2H), 2.71 (t, J¼7.2 Hz, 2H),
1640, 2851, 2925 cmꢁ1 1H NMR (300 MHz, CDCl3)
. d 0.87 (t,
3.94e4.01 (m, 2H), 5.60e5.71 (m, 2H), 7.17e7.25 (m, 3H), 7.27e7.32
J¼7.2 Hz, 3H), 1.17e1.36 (m, 13H), 1.54e1.60 (m, 2H), 1.85e2.00 (m,
1H), 2.01e2.16 (m, 1H), 3.76 (td, J¼12.0, 2.1 Hz, 2H), 4.10 (dd,
J¼10.5, 4.8 Hz, 2H), 4.50 (t, J¼5.1 Hz, 1H), 4.89e4.96 (m, 2H), 5.51
(m, 2H). 13C NMR (75.4 MHz, CDCl3)
d 28.9, 35.3, 39.2, 126.0, 126.1,
128.5, 128.5, 134.1, 141.3. HRMS-EI (m/z): [M]þ calcd for C11H13Cl,
180.07058; found, 180.07060.
(ddd, J¼16.8, 10.5, 8.7 Hz, 1H). 13C NMR (75.4 MHz, CDCl3)
d 14.0,
22.7, 24.0, 25.7, 26.9, 29.3, 34.6, 34.8, 35.1, 43.9, 66.9, 102.5, 113.9,
4.4.2. (Z)-1-Chloro-2-heptene (3b). Colorless oil. IR (neat) 756,
143.7. HRMS-EI (m/z): [MꢁH]þ calcd for C15H27O2, 239.20110;
25
1250, 1458, 1652, 2930 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
0.91 (t,
found, 239.20061. [
a
]
þ0.33 (c 1.20, CHCl3). The ee value (88%
D
J¼7.2 Hz, 3H), 1.27e1.39 (m, 4H), 2.09e2.18 (m, 2H), 4.10 (d,
ee) was determined by chiral HPLC analysis of the p-nitrobenzoate
derivative obtained by the ozonolysis, reduction with NaBH4 fol-
lowed by benzoylation (p-nitrobenzoylchloride, DMAP, DCM, rt)
from 4bb [CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm, Daicel
Chemical Industries, hexane/2-propanol¼99:1, 0.5 mL/min, 40 ꢀC,
254 nm UV detector, retention time¼42.3 min for R isomer and
44.2 min for S isomer]. The literature data of the p-nitrobenzoate
J¼4.5 Hz, 2H), 5.58e5.69 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
d 13.8,
22.2, 26.7, 31.3, 39.5, 125.1, 135.6. HRMS-EI (m/z): [M]þ calcd for
C7H13Cl, 132.07058; found, 132.07047.
4.4.3. (Z)-1,7-Dichloro-2-heptene (3c). Colorless oil. IR (neat) 756,
1251, 1454, 1652, 2941 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 1.51e1.61
Please cite this article in press as: Hojoh, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.048

K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
11
derivative 4bbb confirmed the (R) absolute configuration of 4bb
silica gel (hexane) followed by GPC (CHCl3) (53% isolated yield).
Colorless oil. IR (neat) 679, 882, 909, 997, 1103, 1449, 1639, 2864,
(Scheme 4a).8c
2924 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 0.83e1.80 (m, 32H), 1.06 (s,
4.4.9. (S)-2-(10-Chloro-6-vinyldecyl)-1,3-dioxane (4cc). The prod-
uct 4cc was purified by flash chromatography on silica gel (0e5%
EtOAc/hexane) followed by GPC (CHCl3) (71% isolated yield). Col-
orless oil. IR (neat) 910, 995, 1144, 1640, 2851, 2925 cmꢁ1. 1H NMR
9H), 3.66 (t, J¼12.3 Hz, 2H), 4.89 (dd, J¼17.1, 2.1 Hz, 1H), 4.97 (dd,
J¼9.9, 2.1 Hz, 1H), 5.54 (dt, J¼17.1, 9.1 Hz, 1H). 13C NMR (75.4 MHz,
CDCl3)
d 11.9, 17.9, 25.8, 26.6, 26.6, 26.7, 27.3, 29.6, 31.1, 31.6, 32.9,
41.7, 50.0, 63.5, 114.8, 141.9. HRMS-EI (m/z): [MꢁC3H7]þ calcd for
(300 MHz, CDCl3)
d
1.21e1.47 (m, 13H), 1.56e1.69 (m, 2H), 1.71e1.80
C20H39OSi, 323.27702; found, 323.27741. [
a
]
D
25 ꢁ4.08 (c 1.12, CHCl3).
(m, 2H), 1.91e1.93 (m, 1H), 2.00e2.14 (m, 1H), 3.52 (t, J¼6.6 Hz, 2H),
3.76 (td, J¼12.3, 2.4 Hz, 2H), 4.08e4.12 (m, 2H), 4.50 (t, J¼5.2 Hz,1H),
4.93 (dd, J¼16.5, 2.1 Hz, 1H), 4.96 (dd, J¼10.2, 2.1 Hz, 1H), 5.49 (ddd,
The ee value (76% ee) was determined by chiral HPLC analysis of the
p-nitrobenzoate derivative obtained by the ozonolysis, reduction
with NaBH4 followed by benzoylation (p-nitrobenzoylchloride,
DMAP, DCM, rt) from 4de [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane, 0.25 mL/
min, 40 ꢀC, 254 nm UV detector, retention time¼61.0 min for R
isomer and 67.2 min for S isomer]. The absolute configuration of
J¼16.5, 10.2, 8.7 Hz, 1H). 13C NMR (75.4 MHz, CDCl3)
d 23.8, 24.4,
25.7, 26.9, 29.4, 32.6, 34.1, 34.8, 35.1, 43.9, 45.0, 66.9, 102.5, 114.4,
143.1. HRMS-EI (m/z): [MꢁH]þ calcd for C16H28ClO2, 287.17778;
found, 287.17776. [
a]
25 þ4.80 (c 1.10, CHCl3). The ee value (83% ee)
D
was determined by chiral HPLC analysis of the p-nitrobenzoate
derivative obtained by the ozonolysis, reduction with NaBH4 fol-
lowed by benzoylation (p-nitrobenzoylchloride, DMAP, DCM, rt)
from 4cc [CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm, Daicel
Chemical Industries, hexane/2-propanol¼97:3, 0.5 mL/min, 40 ꢀC,
254 nm UV detector, retention time¼35.4 min for R isomer and
39.1 min for S isomer]. The absolute configuration of 4cc was
assigned by consideration of the stereochemical pathway.
4de was a assigned by consideration of the stereochemical
pathway.
4.4.13. (S)-6-Phenethyl-7-octen-1-yl pivalate (4ea). The product
4ea was purified by flash chromatography on silica gel (0e5%
EtOAc/hexane) (73% isolated yield). Colorless oil. IR (neat) 698, 910,
1151, 1284, 1455, 1480, 1727, 2931 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
1.19 (s, 9H), 1.24e1.42 (m, 6H), 1.47e1.74 (m, 4H), 1.93e2.04 (m,
1H), 2.51 (ddd, J¼13.8, 10.2, 6.6 Hz, 1H), 2.65 (ddd, J¼13.8, 10.2,
4.4.10. (S)-Triisopropyl[(6-phenethyl-7-octen-1-yl)oxy]silane
(4da). The product 4da was purified by flash chromatography on
silica gel (0e5% EtOAc/hexane) (71% isolated yield). Colorless oil. IR
(neat) 679, 882, 1103, 1462, 2864, 2931 cmꢁ1. 1H NMR (300 MHz,
5.4 Hz, 1H), 4.03 (t, J¼6.6 Hz, 2H), 4.96e5.06 (m, 2H), 5.57 (ddd,
J¼17.1, 10.2, 8.7 Hz, 1H), 7.15e7.18, (m, 3H), 7.24e7.30 (m, 2H). 13
C
NMR (75.4 MHz, CDCl3) d 25.9, 26.7, 27.1, 28.4, 33.4, 34.8, 36.8, 38.6,
43.7, 64.4, 114.9, 125.7, 128.3, 128.5, 142.9, 143.0, 178.8. HRMS-EI (m/
25
CDCl3)
d
1.01e1.14 (m, 21H), 1.28e1.50 (m, 6H), 1.52e1.63 (m, 3H),
z): [M]þ calcd for C21H32O2, 316.24023; found, 316.24035. [
a]
D
1.65e1.75 (m, 1H), 1.93e2.05 (m, 1H), 2.51 (ddd, J¼13.8, 10.2, 6.6 Hz,
1H), 2.65 (ddd, J¼13.8, 10.2, 5.2 Hz, 1H), 3.65 (t, J¼6.6 Hz, 2H),
4.96e5.05 (m, 2H), 5.57 (ddd, J¼17.1, 10.4, 8.7 Hz, 1H), 7.15e7.18 (m,
ꢁ4.30 (c 1.25, CHCl3). The ee value (88% ee) was determined by
chiral HPLC analysis of the p-nitrobenzoate derivative obtained by
the ozonolysis, reduction with NaBH4 followed by benzoylation (p-
nitrobenzoylchloride, DMAP, DCM, rt) from 4ea [CHIRALCELÒ OD-3
column, 4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼95:5, 0.5 mL/min, 40 ꢀC, 254 nm UV detector, retention
time¼20.5 min for S isomer and 22.5 min for R isomer]. The ab-
solute configuration of 4ea was assigned by consideration of the
stereochemical pathway.
3H), 7.24e7.30 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
d 12.3,18.3, 26.2,
27.3, 33.3, 33.9, 35.4, 37.2, 44.1, 63.8, 115.1, 126.1, 128.8, 128.9, 143.3,
143.6. HRMS-EI (m/z): [MꢁC3H7]þ calcd for C22H37OSi, 345.26137;
found, 345.26098. [
a]
25 ꢁ3.07 (c 1.01, CHCl3). The ee value (88% ee)
D
was determined by chiral HPLC analysis of the alcohol derivative
obtained by hydroboration with 9-BBN-H from 4da [CHIRALCELÒ
OD-3 column, 4.6 mmꢂ250 mm, Daicel Chemical Industries, hex-
ane/2-propanol¼98:2, 0.5 mL/min, 40 ꢀC, 254 nm UV detector, re-
tention time¼27.2 min for R isomer and 31.4 min for S isomer]. The
absolute configuration of 4da was assigned by consideration of the
stereochemical pathway.
4.4.14. (S)-2-{10-[(tert-Butyldimethylsilyl)oxy]-6-vinyldecyl}isoindo-
line-1,3-dione (4ff). The product 4ff was purified by flash chro-
matography on silica gel (0e5% EtOAc/hexane) followed by GPC
(CHCl3) (73% isolated yield). Colorless oil. IR (neat) 718, 774, 834,
1096, 1254, 1395, 1712, 2857, 2929 cmꢁ1. 1H NMR (300 MHz, CDCl3)
4.4.11. (R)-Triisopropyl[(6-methyl-7-octen-1-yl)oxy]silane
(4dd). The product 4dd was purified by flash chromatography on
silica gel (hexane) (70% isolated yield). Colorless oil. IR (neat) 881,
909, 994, 1103, 1462, 2865, 2930 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 0.04 (s, 6H), 0.89 (s, 9H), 1.16e1.35 (m, 10H), 1.42e1.53 (m, 2H),
1.61e1.71 (m, 2H), 1.86e1.95 (m, 1H), 3.58 (t, J¼6.6 Hz, 2H), 3.67 (t,
J¼7.5 Hz, 2H), 4.91 (dd, J¼16.8, 2.1 Hz, 1H), 4.94 (dd, J¼10.5, 2.1 Hz,
1H), 5.48 (ddd, J¼16.8, 10.5, 8.7 Hz, 1H), 7.70e7.73 (m, 2H),
d
0.97 (d, J¼6.9 Hz, 3H), 1.01e1.10 (m, 21H), 1.10e1.40 (m, 6H),
7.83e7.86 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
d
ꢁ5.4, 18.2, 23.2,
1.44e1.61 (m. 2H), 2.10 (m, 1H), 3.66 (t, J¼12.3 Hz, 3H), 4.88e4.97
25.9, 26.6, 26.9, 28.5, 32.8, 34.7, 34.7, 38.0, 44.0, 63.2, 114.2, 123.2,
(m, 2H), 5.69 (ddd, J¼17.7 10.5, 7.8 Hz, 1H). 13C NMR (75.4 MHz,
132.3, 133.9, 143.3, 168.6. HRMS-ESI (m/z): [MþNa]þ calcd for
25
CDCl3)
d
11.9, 17.9, 20.1, 25.8, 27.0, 32.9, 36.6, 37.7, 63.4, 112.3, 145.1.
C26H41O3NNaSi, 466.27479; found, 466.27496. [
a
]
ꢁ0.41 (c 1.05,
D
HRMS-EI (m/z): [MꢁC3H7]þ calcd for C15H31OSi, 255.21442; found,
CHCl3). The ee value (88% ee) was determined by chiral HPLC
analysis of the p-nitrobenzoate derivative obtained by the ozonol-
ysis, reduction with NaBH4 followed by benzoylation (p-nitro-
benzoylchloride, DMAP, DCM, rt) from 4ff [CHIRALCELÒ AD-H
column, 4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼97:3, 0.5 mL/min, 40 ꢀC, 254 nm UV detector, retention
time¼32.2 min for R isomer and 35.1 min for S isomer]. The abso-
lute configuration of 4ff was assigned by consideration of the ste-
reochemical pathway.
26
255.21457. [
a
]
ꢁ4.88 (c 0.64, CHCl3). The ee value (81% ee) was
D
determined by chiral HPLC analysis of the p-nitrobenzoate
derivative obtained by the ozonolysis, reduction with NaBH4,
benzoylation (p-nitrobenzoylchloride, DMAP, DCM, rt) followed by
desilylation
from
4dd
[CHIRALCELÒ
OJ-3
column,
4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼95:5, 0.5 mL/min, 40 ꢀC, 254 nm UV detector, retention
time¼40.3 min for R isomer and 42.4 min for S isomer]. The ab-
solute configuration of 4dd was assigned by consideration of the
stereochemical pathway.
4.4.15. (S)-2-(10-Chloro-6-vinyldecyl)isoindoline-1,3-dione
(4fc). The product 4fc was purified by flash chromatography on
silica gel (0e5% EtOAc/hexane) (72% isolated yield). Colorless oil. IR
4.4.12. (R)-[(6-Cyclohexyl-7-octen-1-yl)oxy]triisopropylsilane
(4de). The product 4de was purified by flash chromatography on
(neat) 717, 911, 1394, 1708, 1773, 2932 cmꢁ1 1H NMR (300 MHz,
.
Please cite this article in press as: Hojoh, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.048

12
K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
CDCl3)
d
1.18e1.47 (m, 10H), 1.62e1.77 (m, 4H), 1.86e1.97 (m, 1H),
isolated yield). Colorless oil. IR (neat) 699, 996, 1144, 1246, 1625,
2850, 2953 cmꢁ1. 1H NMR (300 MHz, CDCl3)
0.25 (s, 3H), 0.26 (s,
3.52 (t, J¼6.6 Hz, 2H), 3.67 (t, J¼7.2 Hz, 2H), 4.93 (dd, J¼16.8, 1.8 Hz,
1H), 4.95 (dd, J¼10.2, 1.8 Hz, 1H) 5.48 (ddd, J¼16.8, 10.2, 9.0 Hz, 1H),
7.69e7.74 (m, 2H), 7.82e7.87 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
d
3H), 1.13e1.41 (m, 9H), 1.50e1.57 (m, 2H), 1.62e1.75 (m, 1H),
2.00e2.13 (m, 1H), 3.74 (dt, J¼12.0, 2.4 Hz, 2H), 4.06e4.11 (m, 2H),
4.47 (t, J¼5.1 Hz, 1H), 4.75e4.82 (m, 1H), 4.87 (dd, J¼10.2, 1.8 Hz,
1H), 5.56 (dt, J¼17.1, 10.2 Hz, 1H), 7.32e7.37 (m, 3H), 7.46e7.50 (m,
d
24.4, 26.6, 26.8, 28.4, 32.6, 34.1, 34.7, 37.9, 43.8, 45.0, 114.6, 123.2,
132.2, 133.9, 143.0, 168.6. HRMS-ESI (m/z): [MþNa]þ calcd for
25
C
20H26O2NClNa, 370.15443; found, 370.15468. [
a]
þ0.53 (c 1.07,
2H). 13C NMR (75.4 MHz, CDCl3)
d
ꢁ5.4, ꢁ4.6, 23.8, 25.7, 28.2, 29.0,
D
CHCl3). The ee value (90% ee) was determined by chiral HPLC
analysis of the p-nitrobenzoate derivative obtained by the ozonol-
ysis, reduction with NaBH4 followed by benzoylation (p-nitro-
benzoylchloride, DMAP, DCM, rt) from 4fc [CHIRALCELÒ AD-H
column, 4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼97:3, 0.5 mL/min, 40 ꢀC, 254 nm UV detector, retention
time¼166.9 min for R isomer and 179.2 min for S isomer]. The
absolute configuration of 4fc was assigned by consideration of the
stereochemical pathway.
29.1, 34.3, 35.1, 66.9, 102.4, 112.5, 127.7, 128.9, 134.1, 138.0, 139.9.
HRMS-ESI (m/z): [MþNa]þ calcd for C20H32O2NaSi, 355.20638;
26
found, 355.20672. [
a]
ꢁ5.64 (c 1.17, CHCl3). HPLC analysis
D
[CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm, Daicel Chemical
Industries, hexane/2-propanol¼99.9:0.1, 0.5 mL/min, 40 ꢀC, 254 nm
UV detector, retention time¼17.4 min for S isomer and 18.1 min for
R isomer] revealed that the enantiomeric excess of 4cg was 91%.
The absolute configuration of 4cg was assigned by consideration of
the stereochemical pathway.
4.4.16. (R)-Dimethylphenyl(1-undecen-3-yl)silane (4hg). The prod-
uct 4hg was purified by flash chromatography on silica gel (hexane)
(77% isolated yield). Colorless oil. IR (neat) 698, 811, 1113, 1248,
4.4.18. (R)-6-(Dimethylphenylsilyl)-7-octen-1-yl pivalate (4eg). The
product 4eg was purified by flash chromatography on silica gel
(0e5% EtOAc/hexane) (52% isolated yield). Colorless oil. IR (neat)
1428, 1626, 2924 cmꢁ1
.
1H NMR (300 MHz, CDCl3)
d
0.25 (s, 3H),
600, 812, 1152, 1284, 1626, 1727, 2932 cmꢁ1 1H NMR (300 MHz,
.
0.26 (s, 3H), 0.86 (t, J¼6.6 Hz, 3H), 1.13e1.37 (m, 14H), 1.62e1.76 (m,
1H), 4.77e4.83 (m, 1H), 4.88 (dd, J¼10.2, 2.1 Hz, 1H), 5.58 (dt, J¼17.1,
10.2 Hz, 1H), 7.32e7.36 (m, 3H), 7.48e7.51 (m, 2H). 13C NMR
CDCl3) d 0.25 (s, 3H), 0.26 (s, 3H), 1.18 (s, 9H), 1.10e1.50 (m, 6H),
1.52e1.60 (m, 2H), 1.69e1.76 (m, 1H), 4.00 (t, J¼6.6 Hz, 2H),
4.78e4.83 (m, 1H), 4.88 (dd, J¼10.2, 1.8 Hz, 1H), 5.57 (dt, J¼17.1,
10.2 Hz, 1H), 7.34e7.36 (m, 3H), 7.47e7.51 (m, 2H). 13C NMR
(75.4 MHz, CDCl3)
d
ꢁ5.8, ꢁ5.0,13.6, 22.2, 27.9, 28.7, 28.8, 28.9, 29.0,
31.4, 33.9, 112.0, 127.2, 128.5, 133.7, 137.7, 139.6. HRMS-EI (m/z):
(75.4 MHz, CDCl3)
d
ꢁ5.4, ꢁ4.6, 25.5, 27.1, 28.2, 28.4, 28.7, 34.2, 38.6,
[M]þ calcd for C19H32Si, 288.22733; found, 288.22732. [
a
]
27 ꢁ7.05 (c
64.4, 112.6, 127.7, 129.0, 134.1, 137.9, 139.8, 178.8. HRMS-ESI (m/z):
D
1.23, CHCl3). HPLC analysis [CHIRALCELÒ OJ-3 column, 4.6 mmꢂ250
[MþNa]þ calcd for C21H34O2NaSi, 369.22203; found, 369.22208.
25
mm/OJ-3
column,
4.6
mmꢂ250
mm/OJ-H
column,
[a
]
ꢁ8.09 (c 1.27, CHCl3). HPLC analysis [CHIRALCELÒ OD-3 col-
D
4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane, 0.25 mL/
min, 40 ꢀC, 254 nm UV detector, retention time¼55.0 min for S
isomer and 56.4 min for R isomer] revealed that the enantiomeric
excess of 4hg was 91%.
umn, 4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane,
0.25 mL/min, 40 ꢀC, 254 nm UV detector, retention time¼41.1 min
for S isomer and 43.0 min for R isomer] revealed that the enan-
tiomeric excess of 4eg was 87%. The absolute configuration of 4eg
was assigned by consideration of the stereochemical pathway.
Derivatization of 4hg (Scheme 4b). p-Toluenesulfonyl hydrazide
(186.2 mg,1.0 mmol) was placed in a screw-top test tube. Allylsilane
4hg (28.9 mg, 0.1 mmol), 1,4-dioxane (1 mL), and triethylamine
(0.14 mL,1.0 mmol) were sequentially added to the test tube at 25 ꢀC.
The resulting mixture was stirred at reflux for 24 h (monitored by
TLC). After the mixture was cooled to 25 ꢀC, water was added. The
aqueous layer was extracted with hexane (three times). The com-
bined organic layer was washed with water and brine, and then was
dried and concentrated. The crude product was used in the next step
without further purification. A vial containing the crude material of
4hga (29.1 mg, 0.1 mmol) was filled with argon. CH2Cl2 (1.0 mL) and
HBF4$OEt2 (0.23 mL, 0.28 mmol) were sequentially added at 25 ꢀC.
After 1.5 h stirring at 25 ꢀC, the mixture was quenched with water.
The aqueous layer was extracted with hexane (three times). The
combined organic layer was washed with water and brine, and then
was dried and concentrated. The crude product was used in the next
step without further purification. The fluorinated compound 4hgb
(23.2 mg, 0.1 mmol) was placed in a screw-top test tube. THF
(0.4 mL), MeOH (0.4 mL), KF (23.2 mg, 0.4 mmol), KHCO3 (100.2 mg,
1 mmol), 30% H2O2 aq (113.4 mg, 1 mmol) were sequentially added
at 25 ꢀC. After being stirred at 40 ꢀC for 24 h, the mixture was
quenched with Na2S2O3 aq. The aqueous layer was extracted with
ethyl acetate (three times). The combined organic layer was washed
with water and brine, and then was dried and concentrated. The
crude product was purified by flash column chromatography
4.4.19. (R)-2-[6-(Dimethylphenylsilyl)-7-octen-1-yl]isoindoline-1,3-
dione (4fg). The product 4fg was purified by flash chromatography
on silica gel (0e5% EtOAc/hexane) (85% isolated yield). Colorless oil.
IR (neat) 717, 1394, 1624, 1708, 1773, 2931 cmꢁ1. 1H NMR (300 MHz,
CDCl3)
d 0.24 (s, 3H), 0.25 (s, 3H), 1.16e1.43 (m, 6H), 1.54e1.74 (m,
3H), 3.63 (t, J¼7.2 Hz, 2H), 4.75e4.81 (m, 1H), 4.86 (dd, J¼10.2,
1.8 Hz, 1H), 5.55 (dt, J¼17.1, 10.2 Hz, 1H), 7.31e7.34 (m, 3H),
7.46e7.49 (m, 2H), 7.69e7.73 (m, 2H), 7.81e7.85 (m, 2H). 13C NMR
(75.4 MHz, CDCl3)
d
ꢁ5.4, ꢁ4.6, 26.5, 28.1, 28.4, 28.8, 34.2, 38.0,
112.6, 123.2, 127.7, 129.0, 132.3, 133.9, 134.1, 137.9, 139.8, 168.6.
HRMS-ESI (m/z): [MþNa]þ calcd for C24H29O2NNaSi, 414.18598;
27
found, 414.18631. [
a
]
þ4.99 (c 0.75, CHCl3). HPLC analysis
D
[CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm, Daicel Chemical
Industries, hexane/2-propanol¼99.5:0.5, 0.5 mL/min, 40 ꢀC,
254 nm UV detector, retention time¼31.6 min for S isomer and
33.4 min for R isomer] revealed that the enantiomeric excess of 4fg
was 90%. The absolute configuration of 4fg was assigned by con-
sideration of the stereochemical pathway.
4.4.20. (R)-(9-Chloro-1-nonen-3-yl)dimethylphenylsilane (4ig). The
product 4ig was purified by flash chromatography on silica gel
(hexane) (88% isolated yield). Colorless oil. IR (neat) 699, 894, 1122,
1248, 1427, 1625, 2855, 2928 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 0.25
(5e20% EtOAc/hexane) to yield (S)-undecan-3-ol (4hgc) as a color-
(s, 3H), 0.26 (s, 3H), 1.13e1.41 (m, 8H), 1.66e1.76 (m, 3H), 3.49 (t,
J¼6.9 Hz, 2H), 4.78e4.84 (m, 1H), 4.89 (dd, J¼9.9, 1.8 Hz, 1H), 5.58
(dt, J¼17.1, 9.9 Hz, 1H), 7.33e7.36 (m, 3H), 7.46e7.51 (m, 2H). 13C
25
less oil (10.2 mg, 0.06 mmol, 59% in 3 steps) [
a
]
þ4.38 (c 0.51,
D
CHCl3). {lit.22 (S) isomer, 84% ee, [
a]
20 þ5.2 (c 1, CHCl3)}.
D
NMR (75.4 MHz, CDCl3)
d
ꢁ5.4, ꢁ4.6, 26.6, 28.2, 28.4, 28.9, 32.5,
4.4.17. (R)-[8-(1,3-Dioxan-2-yl)-1-octen-3-yl]dimethylphenylsilane
(4cg). The product 4cg was purified by flash chromatography on
silica gel (0e5% EtOAc/hexane) followed by GPC (CHCl3) (66%
34.2, 45.1, 112.6, 127.7, 129.0, 134.1, 138.0, 139.9. HRMS-FI (m/z):
25
[M]þ calcd for C17H27ClSi, 294.15705; found, 294.15724. [
a]
D
ꢁ10.36 (c 1.30, CHCl3). HPLC analysis [CHIRALCELÒ OJ-3 column,
Please cite this article in press as: Hojoh, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.048

K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
13
4.6 mmꢂ250 mm/OJ-H column, 4.6 mmꢂ250 mm, Daicel Chemical
Industries, hexane, 0.25 mL/min, 40 ꢀC, 254 nm UV detector, re-
tention time¼36.9 min for S isomer and 38.1 min for R isomer]
revealed that the enantiomeric excess of 4ig was 91%. The absolute
configuration of 4ig was assigned by consideration of the stereo-
chemical pathway.
detector, retention time¼17.9 min for R isomer and 18.6 min for S
isomer]. The absolute configuration of 6da was assigned by con-
sideration of the stereochemical pathway.
4.4.24. (S)-6-Methyl-6-phenethyl-7-octen-1-yl pivalate (6ea). The
product 6ea was purified by flash chromatography on silica gel
(0e2% EtOAc/hexane) (66% isolated yield). Colorless oil. IR (neat)
698, 1284, 1151, 1727, 2862, 2935 cmꢁ1. 1H NMR (300 MHz, CDCl3)
4.4.21. (S)-1,2-Dimethoxy-4-(4-methyl-4-phenethyl-5-hexen-1-yl)
benzene (6aa). The product (S)-6aa was purified by flash chroma-
tography on silica gel (0e2% EtOAc/hexane) followed by GPC
(CHCl3) (65% isolated yield). Colorless oil. IR (neat) 698, 1030, 1236,
d
1.03 (s, 3H), 1.19 (s, 9H), 1.29e1.32 (m, 6H), 1.52e1.64 (m, 4H),
2.47e2.53 (m, 2H), 4.04 (t, J¼6.6 Hz, 2H), 4.95 (d, J¼17.4 Hz, 1H),
5.04 (d, J¼11.1 Hz, 1H), 5.75 (dd, J¼17.4, 11.1 Hz, 1H), 7.15e7.19 (m,
1260, 1515, 2935 cmꢁ1
.
1H NMR (300 MHz, CDCl3)
d
1.03 (s, 3H),
3H), 7.25e7.30 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
d 22.5, 23.7,
1.35e1.40 (m, 2H), 1.55e1.65 (m, 4H), 2.45e2.55 (m, 4H), 3.85 (s,
3H), 3.87 (s, 3H), 4.94 (d, J¼17.4 Hz, 1H), 5.04 (d, J¼10.8 Hz, 1H), 5.74
(dd, J¼17.4, 10.8 Hz, 1H), 6.70e6.72 (m, 2H), 6.79 (m, 1H), 7.13e7.18
26.8, 27.2, 28.6, 30.7, 38.7, 39.6, 40.9, 43.0, 64.4, 112.0, 125.6, 128.3
(2C), 143.3, 146.9, 178.7. HRMS-EI (m/z): [M]þ calcd for C22H34O2,
25
330.25588; found, 330.25630. [
a
]
þ7.36 (c 0.58, CHCl3). The ee
D
(m, 3H), 7.24e7.29 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
d
22.5,
value (81% ee) was determined by chiral HPLC analysis of the al-
dehyde derivative obtained by the ozonolysis followed by re-
duction with Me2S from 6ea [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm/
CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm, Daicel Chemical In-
dustries, hexane/2-propanol¼96:4, 0.7 mL/min, 40 ꢀC, 220 nm UV
detector, retention time¼29.7 min for R isomer and 30.6 min for S
isomer]. The absolute configuration of 6ea was assigned by con-
sideration of the stereochemical pathway.
26.2, 30.7, 36.2, 39.6, 40.5, 43.0, 55.8, 55.9, 111.1, 111.6, 112.0, 120.1,
125.5, 128.3 (2C), 135.3, 143.3, 146.9, 147.0, 148.7. HRMS-EI (m/z):
[M]þ calcd for C23H30O2, 338.22458; found, 338.22391. [
a]
23 þ5.81
D
(c 1.10, CHCl3). HPLC analysis [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼99.5:0.5, 0.5 mL/min, 40 ꢀC, 220 nm UV detector, re-
tention time¼106.7 min for R isomer and 112.5 min for S isomer]
revealed that the enantiomeric excess of 6aa was 81% ee. The ab-
solute configuration of 6aa was assigned by consideration of the
stereochemical pathway.
4.4.25. (S)-(9-Chloro-3-methyl-3-vinylnonyl)benzene
(6ia). The
product 6ia was purified by flash chromatography on silica gel
(hexane) followed by GPC (CHCl3) (80% isolated yield). Colorless oil.
IR (neat) 696, 909, 1453, 1495, 2858, 2930 cmꢁ1. 1H NMR (300 MHz,
4.4.22. (S)-2-(6-Methyl-6-phenethyl-7-octen-1-yl)-1,3-dioxane
(6ca). The product 6ca was purified by flash chromatography on
silica gel (0e2% EtOAc/hexane) (79% isolated yield). Colorless oil. IR
CDCl3)
d 1.03 (s, 3H), 1.26e1.48 (m, 6H), 1.52e1.61 (m, 4H),
(neat) 698, 909, 996, 1143, 2849, 2929 cmꢁ1
.
1H NMR (300 MHz,
1.72e1.79 (m, 2H), 2.47e2.53 (m, 2H), 3.53 (t, J¼6.6 Hz, 2H), 4.95
(dd, J¼17.4, 1.5 Hz, 1H), 5.04 (dd, J¼11.1, 1.5 Hz, 1H), 5.75 (dd, J¼17.4,
11.1 Hz, 1H), 7.15e7.20 (m, 3H), 7.25e7.30 (m, 2H). 13C NMR
CDCl3) d 1.01 (s, 3H), 1.26e1.43 (m, 8H), 1.54e1.64 (m, 5H), 2.08 (m,
1H), 2.46e2.52 (m, 2H), 3.76 (dt, J¼12.0, 2.4 Hz, 2H), 4.08e4.13 (m,
2H), 4.50 (t, J¼5.1 Hz, 1H), 4.93 (dd, J¼17.4, 1.5 Hz, 1H), 5.02 (dd,
J¼10.8, 1.5 Hz, 1H), 5.74 (dd, J¼17.4, 10.8 Hz, 1H), 7.15e7.19 (m, 3H),
(100.5 MHz, CDCl3)
d 22.5, 23.9, 26.9, 29.7, 30.7, 32.6, 39.6, 40.8,
43.0, 45.2, 111.9, 125.5, 128.3 (2C), 143.3, 147.0. HRMS-EI (m/z): [M]þ
7.25e7.30 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
d
22.6, 23.9, 24.0,
calcd for C18H27Cl, 278.1803; found, 278.18100. [
a]
26 þ6.49 (c 0.30,
D
25.8, 30.3, 30.7, 35.2, 39.6, 40.7, 43.0, 66.9, 102.4, 111.8, 125.5, 128.3
CHCl3). The ee value (86% ee) was determined by chiral HPLC
analysis of the aldehyde derivative obtained by the ozonolysis fol-
lowed by reduction with Me2S from 6ia [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm/
CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm, Daicel Chemical In-
dustries, hexane/2-propanol¼96:4, 0.7 mL/min, 40 ꢀC, 220 nm UV
detector, retention time¼39.6 min for R isomer and 41.3 min for S
isomer]. The absolute configuration of 6ia was assigned by con-
sideration of the stereochemical pathway.
(2C), 143.4, 147.1. HRMS-EI (m/z): [M]þ calcd for C21H32O2,
26
316.24023; found, 316.24002. [
a
]
þ2.06 (c 1.08, CHCl3). The ee
D
value (90% ee) was determined by chiral HPLC analysis of the al-
dehyde derivative obtained by the ozonolysis followed by re-
duction with Me2S from 6ca [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm/
CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm, Daicel Chemical In-
dustries, hexane/2-propanol¼96:4, 0.7 mL/min, 40 ꢀC, 220 nm UV
detector, retention time¼54.1 min for R isomer and 55.7 min for S
isomer]. The absolute configuration of 6ca was assigned by con-
sideration of the stereochemical pathway.
4.4.26. 2-[{(S)-7-Methyl-7-phenethyl-8-nonen-1-yl}oxy]tetrahydro-
2H-pyran (6ja). Diastereomeric ratio 1:1. The product 6ja was pu-
rified by flash chromatography on silica gel (0e2% EtOAc/hexane)
(70% isolated yield). Colorless oil. IR (neat) 1022, 1032, 1119, 2859,
4.4.23. (S)-Triisopropyl[(6-methyl-6-phenethyl-7-octen-1-yl)oxy]si-
lane (6da). The product 6da was purified by flash chromatography
on silica gel (0e1% EtOAc/hexane) (85% isolated yield). Colorless oil.
IR (neat) 679, 910, 1106, 1463, 2864, 2938 cmꢁ1. 1H NMR (300 MHz,
2931 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 1.02 (s, 3H), 1.23e1.36 (m,
6H), 1.54e1.87 (m, 12H), 2.47e2.53 (m, 2H), 3.38 (m, 1H), 3.51 (m,
1H), 3.73 (m, 1H), 3.87 (m, 1H), 4.58 (m, 1H), 4.94 (d, J¼17.4 Hz, 1H),
5.03 (d, J¼11.1 Hz, 1H), 5.75 (dd, J¼17.4, 11.1 Hz, 1H), 7.15e7.18 (m,
CDCl3)
d 1.05e1.12 (m, 24H), 1.21e1.32 (m, 6H), 1.50e1.64 (m, 4H),
2.47e2.53 (m, 2H), 3.66 (t, J¼6.6 Hz, 2H), 4.94 (dd, J¼17.4, 1.5 Hz,
1H), 5.04 (dd, J¼11.1, 1.5 Hz, 1H), 5.75 (dd, J¼17.4, 11.1 Hz, 1H),
7.15e7.17 (m, 3H), 7.24e7.29 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
3H), 7.25e7.30 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
d 19.7, 22.6,
24.0, 25.5, 26.3, 29.8, 30.3, 30.7, 30.8, 39.6, 40.9, 43.0, 62.4, 67.7,
98.8, 111.8, 125.5, 128.3 (2C), 143.4, 147.1. HRMS-EI (m/z): [M]þ calcd
28
d
12.0, 18.0, 22.6, 23.9, 26.6, 30.7, 33.0, 39.6, 40.9, 43.0, 63.4, 111.8,
for C23H36O2, 344.27153; found, 344.27045. [
a]
þ5.94 (c 0.87,
D
125.5, 128.3 (2C), 143.4, 147.1. HRMS-ESI (m/z): [MþH]þ calcd for
CHCl3). The ee value (86% ee) was determined by chiral HPLC
analysis of 7-(dimethoxymethyl)-7-methyl-9-phenyl-1-nonanol
obtained by the ozonolysis, reduction with Me2S followed by ace-
talization (MeOH, p-TsOH, rt) from 6ja [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm/
CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm, Daicel Chemical In-
dustries, hexane/2-propanol¼96:4, 0.7 mL/min, 40 ꢀC, 220 nm UV
detector, retention time¼39.6 min for R isomer and 41.2 min for S
27
C
26H47OSi, 403.33907; found, 403.33838. [
a
]
þ6.31 (c 0.92,
D
CHCl3). The ee value (83% ee) was determined by chiral HPLC
analysis of the aldehyde derivative obtained by the ozonolysis, re-
duction with Me2S from 6da [CHIRALCELÒ OD-3 column,
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm/
CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm, Daicel Chemical In-
dustries, hexane/2-propanol¼98:2, 0.3 mL/min, 40 ꢀC, 220 nm UV
Please cite this article in press as: Hojoh, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.048

14
K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
isomer]. The absolute configuration of 6ja was assigned by con-
sideration of the stereochemical pathway.
dimethoxyphenyl)propyl]-2-methyl-6-oxabicyclo[3.1.0]hexane ob-
tained by the ring closing metathesis (Grubbs second catalyst, DCM,
40 ꢀC) followed by epoxidation (m-CPBA, NaHCO3, DCM, 0 ꢀC) from
6ab [CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm, Daicel Chemical
Industries, hexane/2-propanol¼99:1, 0.5 mL/min, 40 ꢀC, 220 nm UV
detector, retention time¼46.0 min and 65.7 min for R isomer and
48.2 min and 85.3 min for S isomer]. The absolute configuration of
6ab was assigned by consideration of the stereochemical pathway.
4.4.27. (S)-[7-(Benzyloxy)-3-methyl-3-vinylheptyl]benzene
(6ka). The product 6ka was purified by flash chromatography on
silica gel (0e2% EtOAc/hexane) (68% isolated yield). Colorless oil. IR
(neat) 696, 733, 1102, 1454, 2862, 2936 cmꢁ1. 1H NMR (300 MHz,
CDCl3) d 1.03 (s, 3H),1.23e1.37 (m, 4H),1.52e1.64 (m, 4H), 2.47e2.52
(m, 2H), 3.46 (t, J¼6.6 Hz, 2H), 4.50 (s, 2H), 4.94 (d, J¼17.4 Hz, 1H),
5.04 (d, J¼10.8 Hz, 1H), 5.75 (dd, J¼17.4, 10.8 Hz, 1H), 7.14e7.18 (m,
4.4.30. (S)-2-(6-Ethyl-6-phenethyl-7-octen-1-yl)-1,3-dioxane
(6cc). The product 6cc was purified by flash chromatography on
silica gel (0e2% EtOAc/hexane) followed by GPC (CHCl3) (75% iso-
lated yield). Colorless oil. IR (neat) 698, 909, 998, 1143, 2851,
3H), 7.24e7.34 (m, 7H). 13C NMR (100.5 MHz, CDCl3)
d 20.7, 22.5,
30.5, 30.7, 39.6, 40.7, 42.9, 70.3, 72.9, 111.9, 125.5, 127.5, 127.7 (2C),
128.3 (2C), 138.6, 143.3, 147.0. HRMS-ESI (m/z): [MþNa]þ calcd for
22
C
23H30ONa, 345.21889; found, 345.21869. [
a
]
þ8.32 (c 0.43,
2929 cmꢁ1
.
1H NMR (300 MHz, CDCl3)
d
0.79 (t, J¼7.2 Hz, 3H),
D
CHCl3). HPLC analysis [CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm,
Daicel Chemical Industries, hexane/2-propanol¼95:5, 0.5 mL/min,
40 ꢀC, 220 nm UV detector, retention time¼49.1 min for R isomer
and 51.7 min for S isomer] revealed that the enantiomeric excess of
6ka was 81% ee. The absolute configuration of 6ka was assigned by
consideration of the stereochemical pathway.
1.20e1.45 (m, 10H), 1.53e1.63 (m, 5H), 2.08 (m, 1H), 2.41e2.47 (m,
2H), 3.76 (td, J¼12.0, 2.4 Hz, 2H), 4.08e4.13 (m, 2H), 4.51 (t, J¼5.1 Hz,
1H), 4.91 (dd, J¼17.4,1.5 Hz,1H), 5.08 (dd, J¼11.1,1.5 Hz,1H), 5.64 (dd,
J¼17.4, 11.1 Hz, 1H), 7.15e7.19 (m, 3H), 7.25e7.30 (m, 2H). 13C NMR
(100.5 MHz, CDCl3)
d 7.8, 23.3, 24.0, 25.9, 28.4, 30.1, 30.4, 35.3, 35.6,
38.3, 42.1, 66.9, 102.4, 112.7, 125.5, 128.3 (2C), 143.5, 146.6. HRMS-EI
26
(m/z): [M]þ calcd for C22H34O2, 330.25588; found, 330.25466. [
a]
D
4.4.28. (S)-(3-Ethyl-3-methyl-4-penten-1-yl)benzene
(6la). The
ꢁ5.63 (c 0.48, CHCl3). The ee value (81% ee) was determined by chiral
HPLC analysis of the aldehyde derivative obtained by the ozonolysis
followed by reduction with Me2S from 6cc [CHIRALCELÒ OD-3 col-
product 6la was purified by flash chromatography on silica gel
(hexane) followed by GPC (CHCl3) (63% isolated yield). Colorless oil.
IR (neat) 696, 752, 910, 1454, 2933, 2965 cmꢁ1. 1H NMR (300 MHz,
umn,
4.6
mmꢂ250
mm/CHIRALCELÒ
OD-H
column,
CDCl3)
d
0.82 (t, J¼7.5 Hz, 3H), 1.01 (s, 3H), 1.39 (q, J¼7.5 Hz, 2H),
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm,
Daicel Chemical Industries, hexane/2-propanol¼96:4, 0.7 mL/min,
40 ꢀC, 220 nm UV detector, retention time¼37.4 min for S isomer and
42.5 min for R isomer]. The absolute configuration of 6cc was
assigned by consideration of the stereochemical pathway.
1.51e1.61 (m, 2H), 2.47e2.53 (m, 2H), 4.95 (dd, J¼17.4, 1.5 Hz, 1H),
5.05 (dd, J¼10.8, 1.5 Hz, 1H), 5.74 (dd, J¼17.4, 10.8 Hz, 1H), 7.15e7.21
(m, 3H), 7.25e7.29 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
d 8.4, 22.0,
30.7, 33.1, 39.8, 42.6, 112.0, 125.5, 128.3 (2C), 143.4, 146.8. HRMS-EI
22
(m/z): [M]þ calcd for C14H20, 188.15650; found, 188.15651. [
a]
D
þ16.69 (c 0.63, CHCl3). The ee value (71% ee) was determined by
chiral HPLC analysis of 2-ethyl-2-methyl-4-phenyl-1-butanol ob-
tained by the ozonolysis followed by reduction with NaBH4 from
6la [CHIRALCELÒ OD-3 column, 4.6 mmꢂ250 mm/CHIRALCELÒ OD-
4.4.31. (S)-2-(6-Phenethyl-6-vinylnonyl)-1,3-dioxane
(6cd). The
product 6cd was purified by flash chromatography on silica gel
(0e2% EtOAc/hexane) followed by GPC (CHCl3) (67% isolated yield).
Colorless oil. IR (neat) 698, 908, 998, 1144, 2850, 2929 cmꢁ1 1H
.
H
column, 4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column,
NMR (300 MHz, CDCl3)
d
0.89 (t, J¼6.9 Hz, 3H), 1.19e1.47 (m, 12H),
4.6 mmꢂ250 mm, Daicel Chemical Industries, hexane/2-
propanol¼96:4, 0.7 mL/min, 40 ꢀC, 220 nm UV detector, retention
time¼39.6 min for R isomer and 44.5 min for S isomer].
1.53e1.62 (m, 5H), 2.04 (m, 1H), 2.41e2.47 (m, 2H), 3.76 (t,
J¼12.0 Hz, 2H), 4.08e4.13 (m, 2H), 4.51 (t, J¼5.1 Hz, 1H), 4.90 (d,
J¼17.4 Hz, 1H), 5.06 (d, J¼11.1 Hz, 1H), 5.65 (dd, J¼17.4, 11.1 Hz, 1H),
7.14e7.18 (m, 3H), 7.24e7.29 (m, 2H). 13C NMR (100.5 MHz, CDCl3)
Derivatization of 6la (Scheme 4c). Ozone was bubbled into
a solution of 6la (7.4 mg, 0.04 mmol) in MeOH/diethyl ether (1:10,
5.0 mL) at ꢁ78 ꢀC. After the starting material was completely dis-
appeared (monitored by TLC), NaBH4 (15.1 mg, 0.4 mmol) was
added and the mixture was allowed to warm to rt and it was further
stirred at the rt for 1 h. The mixture was quenched with water. The
aqueous layer was extracted with EtOAc (three times). The com-
bined organic layer was washed with water and brine, and then was
dried and concentrated. Purification by column chromatography
(silica gel, 5e15% EtOAc/hexane) yielded (S)-2-ethyl-2-methyl-4-
d
14.9, 16.6, 23.3, 24.0, 25.9, 30.1, 30.4, 35.3, 36.2, 38.7, 38.8, 42.1,
66.9, 102.4, 112.4, 125.5, 128.3 (2C), 143.4, 146.9. HRMS-EI (m/z):
[M]þ calcd for C23H36O2, 344.27153; found, 344.27039. [
a
]
22 ꢁ3.06
D
(c 0.23, CHCl3). The ee value (71% ee) was determined by chiral
HPLC analysis of the aldehyde derivative obtained by the ozonolysis
followed by reduction with Me2S from 6cd [CHIRALCELÒ OD-3
column, 4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column,
4.6 mmꢂ250 mm/CHIRALCELÒ OD-H column, 4.6 mmꢂ250 mm,
Daicel Chemical Industries, hexane/2-propanol¼96:4, 0.7 mL/min,
40 ꢀC, 220 nm UV detector, retention time¼29.9 min for S isomer
and 32.6 min for R isomer]. The absolute configuration of 6cd was
assigned by consideration of the stereochemical pathway.
phenyl-1-butanol (6laa) (3.8 mg, 0.02 mmol). {lit.24 (S) isomer,
20
96% ee, [
a]
ꢁ12.48 (c 0.125, CH2Cl2)}.
D
4.4.29. (S)-4-(4,8-Dimethyl-4-vinyl-7-nonen-1-yl)-1,2-
dimethoxybenzene (6ab). The product 6ab was purified by flash
chromatography on silica gel (0e2% EtOAc/hexane) followed by
GPC (CHCl3) (54% isolated yield). Colorless oil. IR (neat) 1031, 1235,
Acknowledgements
This work was supported by Grants-in-Aid for Young Scientists
(A) and Challenging Exploratory Research, Japan Society for the-
Promotion of Science to H.O. and by ACT-C, Japan Science and
Technology Agency to M.S. and S.M. and by CREST, Japan Science
and Technology Agency to M.S. K.N. thanks Japan Society for the
Promotion of Science for scholarship support.
1260, 1515, 2854, 2933 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d 0.95 (s,
3H),1.25e1.35 (m, 4H), 1.46e1.61 (m, 5H), 1.67 (s, 3H), 1.80e1.89 (m,
2H), 2.51 (t, J¼7.5 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.87 (dd, J¼17.4,
1.5 Hz, 1H), 4.97 (dd, J¼10.8, 1.5 Hz, 1H), 5.08 (m, 1H), 5.68 (dd,
J¼17.4, 10.8 Hz, 1H), 6.69e6.72 (m, 2H), 6.79 (m, 1H). 13C NMR
(100.5 MHz, CDCl3)
d 17.6, 22.5, 22.8, 25.7, 26.3, 36.3, 39.4, 40.4,
40.7, 55.8, 55.9, 111.1, 111.5, 111.7, 120.1, 125.0, 131.0, 135.4, 147.0,
References and notes
147.2, 148.7. HRMS-EI (m/z): [M]þ calcd for C21H32O2, 316.24023;
found, 316.24053. [
a
]
D
23 þ8.40 (c 0.50, CHCl3). The ee value (73% ee)
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Please cite this article in press as: Hojoh, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.048

K. Hojoh et al. / Tetrahedron xxx (2015) 1e15
15
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€
€
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crude materials after removal of the catalyst.
€
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Please cite this article in press as: Hojoh, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.048