BINOL-Al catalyzed kinetic resolution of citronellal analogues: synthesis of a variety of fragrances

Article abstract of DOI:10.1016/j.tetasy.2016.06.007

A chiral aluminum catalyst was used for the kinetic resolution of citronellal analogues. Racemic 3-alkylcitronellals gave optically active 5-alkylisopulegols with high enantioselectivity. Unreacted 3-alkylcitronellal analogues were obtained with low enant

Full text of DOI:10.1016/j.tetasy.2016.06.007

Tetrahedron: Asymmetry 27 (2016) 698–705
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
BINOL-Al catalyzed kinetic resolution of citronellal analogues:
synthesis of a variety of fragrances
a
a
b,
c,
c
Hisanori Itoh a, , Hironori Maeda , Shinya Yamada , Yoji Hori , Takashi Mino , Masami Sakamoto
⇑
⇑
⇑
a Taksasago International Corporation, 4-11, Nishi-Yawata 1-Chome, Hiratsuka City, Kanagawa 254-0073, Japan
b Department of Food and Cosmetic Science, Faculty of Bioindustry, Tokyo University of Agriculture, 196, Yasaka, Abashiri City, Hokkaido 099-2493, Japan
c Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A chiral aluminum catalyst was used for the kinetic resolution of citronellal analogues. Racemic 3-alkyl-
citronellals gave optically active 5-alkylisopulegols with high enantioselectivity. Unreacted 3-alkyl-
citronellal analogues were obtained with low enantioselectivity. The two main diastereoisomers of the
product were opposite to each other. The scents of 5-substituted isopulegols were evaluated. The chiral
recognition of the catalysts and their effects on the kinetic resolutions are also discussed.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 7 April 2016
Accepted 5 June 2016
Available online 23 June 2016
1. Introduction
reported on excellent enantioselective alcoholysis by the kinetic
resolution.8 Lu et al. researched the kinetic resolution of racemic
In the field study of organic synthesis, optically active products
are widely desired for the preparation of organic materials, aroma
chemicals and intermediates for medicine. A number of asymmet-
ric intermolecular or intramolecular ene reactions have been stud-
ied in order to provide practical synthetic methods for optically
active products. Ene and Prins reactions between carbonyl and ole-
fin groups have been reported.1 The intramolecular Prins reaction
is often a key reaction in the synthesis of natural products. Over-
man et al. reported a Briarellin F synthesis using a Prins reaction.1d
Kopecky and Rychnovsky reported the synthesis of
5-alkylcyclohexenones via Pd catalyzed 1,4-additions of aryl-
boronic acids.9 A silylation-based kinetic resolution of secondary
alcohols with a polystyrene-supported triphenylsilyl chloride was
reported by Wiskur et al.10a Wiskur et al. also presented the silyla-
tion-based kinetic resolution of
and linear free-energy relationship and rate studies on a silylation-
based kinetic resolution.10c Salvio et al. reported
kinetic
a
-hydroxy lactones and lactams,10b
a
resolution of phosphoric diester by cinchona alkaloid derivatives.11
These kinetic resolutions are mainly hydrolysis, reduction, oxi-
dation and ring-opening reactions, and other substituent changing
reactions.12 As an example of a ring-closing kinetic resolution,
Hoveyda and Schrock investigated the kinetic resolution of chiral
dienes by a chiral molybdenum catalyst.13
Leucascandrolide
A via a Mukaiyama aldol–Prins cyclization
cascade reaction.1e,f Recently, Zhenlei et al. presented total
synthesis of (ꢀ)-exiguolide with Prins cyclization as
a key
strategy.2 Lalli et al. researched a novel aza-Prins cyclization pro-
moted by a synergistic combination between a Lewis acid and a
Bronsted acid to afford piperidine.3
We previously reported on the kinetic resolution of racemic
citronellal with a variety of aluminum catalysts bearing chiral
ligands.14 The resolution was successfully preformed and afforded
optically active isopulegol and citronellal. Herein, we utilize a chi-
ral aluminum catalyst in the kinetic resolution of other substrates
(Scheme 1). The details of the resolution and the differences
between those of racemic citronellal are also investigated.
The kinetic resolution of racemic compounds is an important
method of asymmetric synthesis. An enormous number of kinetic
resolutions by enzymes or biocatalysts have been studied.4 Asym-
metric reactions utilizing kinetic resolutions by low temperature
have also been reported.5 Kinetic resolutions with organic and
organometallic catalyst have been studied in recent years.6 Kagan
et al. found a variety of kinetic resolutions and opened up a mod-
ern study of kinetic resolution.7 In recent articles, Aoyama et al.
R
R
R
CHO
CHO
chiral Al-catalyst
+
OH
⇑
Corresponding authors.
E-mail addresses: hisanori_itoh@takasago.com (H. Itoh), yh206286@bioindustry.
nodai.ac.jp (Y. Hori), tmino@faculty.chiba-u.jp (T. Mino).
Scheme 1. Kinetic resolution of citronellal analogues.
http://dx.doi.org/10.1016/j.tetasy.2016.06.007
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
699
Catalysts with substituted BINOL type ligands led to kinetic res-
olutions with lower performances than (R)-L1a-Al and (S)-L1a-Al.
The catalysts with 3,3-substituted BINOLs provided 2 with slower
reaction speeds. The reaction with (R)-L1b reached 37% conversion
in 5 h (entry 3). The ratio of anti-2/syn-2 was 69/31. The ee of anti-2
and syn-2 were significantly lower than the reactions with (R)-L1a,
31% and 26%, respectively. Compound (ꢀ)-1 was obtained with 8%
ee. The krel was 1.4 at 46% conversion. The catalyst ((R)-L1c)-Al sel-
dom afforded 2 in 19 h despite a loading of 10 mol % of the catalyst
(entry 4). The 6,60-substituted BINOL (R)-L1d also provided 2 with
low enantioselectivity at 39% conversion (entry 5).
2. Results and discussion
At first, a variety of ligands were utilized for the kinetic resolu-
tion and the results are shown in Table 1. The chiral ligands are
shown in Figure 1. The kinetic resolution of the racemic citronellal
analogue 3-vinylcitronellal ( )-115,16 with chiral aluminium cata-
lysts bearing (R)-BINOL (R)-L1a was successfully carried out (entry
1). The conversion was calculated as the total consumption of a
substrate. 3-Vinylcitronellal ( )-1 gave 5-vinylisopulegols 2 and
unreacted 1. The diastereoisomers of
(1a,2b,5b-2) and syn-2 (1 ,2b,5 -2). The diastereoselectivity of
2 were mainly anti-2
a
a
(R)-H8-BINOL (R)-L2a, with modified aromatic rings, was also
used for this resolution. Catalyst (R)-L1d provided 2 with low
enantioselectivity at 48% conversion (entry 6). The ratio of anti-2
was 71%. This was slightly higher than the reaction with L1a-Al.
The kinetic resolution of ( )-1 was also carried out using cata-
lysts bearing TADDOL type ligands. The results indicated that (R,
R)-1-naphthyl-TADDOL (R)-L3a-Al showed a chiral recognition
towards ( )-1 (entries 7 and 8). However, the resolution ability
was lower than that obtained with BINOL-Al. The catalyst with
one equivalent19 of (R)-L3a afforded (+)-2 with 34% ee of anti-2
and 35% ee of syn-2, and an opposite specific rotation of the reac-
tion with (R)-BINOL ((R)-L1a) (entry 7). The ratio of anti-2/syn-2
was 68%/32% at 27% conversion. The krel value was 1.1. Catalysts
with (S)-L3a ligands showed almost the same performance except
for the specific rotations as well as BINOL (entries 7 and 8). The cat-
alyst bearing (R,R)-9-phenanthryl-TADDOL (R)-L3b-Al20 loaded
10 mol % provided (+)-2. The ratio of anti-2 was 72% at 41% conver-
sion when (R)-L3a was used. The ee of anti-2 and syn-2 were 39%
and 44%. The diastereoselectivity of anti-2 and enantioselectivity
of (+)-2 were higher than when (R)-L3a was used.
anti-2 was 68% at 46% conversion, lower than that obtained with
citronellal.14 Other possible isomers were barely detected by GC.
The absolute configurations of
2 were determined with an
advanced Mosher method.17 The ee of anti-2 was 71%. The ee of
18
syn-2 reached 89%. By contrast, the ee of (ꢀ)-1 was 25%. The krel
of this resolution was 2.3 at 46% conversion.
Catalysts with (R)-L1a and (S)-L1a ligands showed almost the
same performance except with regards to the specific rotation
(entries 1 and 2). The reaction with (S)-L1a afforded (ꢀ)-2 and left
(+)-1. The ratio of anti-2/syn-2 was 68/32 at 50% conversion. The ee
of anti-2 was 69%, syn-2 was 85% and (+)-1 was 21%. The krel of this
resolution was 1.9 at 50% conversion.
R3
R2
R1
Ar Ar
O
O
OH
OH
OH
OH
OH
OH
Ar Ar
R3
R2
(R)-
(R)-
(R)-
R1
The results of the kinetic resolution of 3-vinylcitronellal ( )-1
with (S)-BINOL((S)-L1a)-Al are shown in Table 2. The ee of anti-2
gradually decreased as the reaction progressed. The ee of anti-2
was 68% at 8% conversion (entry 1, Table 2). The ee of anti-2 was
slightly then lower than 70% until 50% conversion (entries 2 and
3), and gradually decreased to 60%ee from 50% to 81% conversion
(entries 4 and 5). The ee value of syn-2 gradually increased over
(R)-L2a: R3 = H
: R1 = H, R2 = H
: R1 = Br, R2 = H
: R1 = SiPh3, R2 = H
(R)-L3a: Ar = 1-naphthyl
(R)-L3b: Ar = 9-phenanthryl
L1a
L1b
L1c
(R)-L1d: R1 = H, R2 = Br
Figure 1. Chiral ligands.
Table 1
Kinetic resolution of racemic 3-vinylcitronellal (( )-1) with aluminum complex with a variety of chiral ligands
(S)
(S)
(R)
(S)
CHO
CHO
(R)
Et3Al (5 mol%), chiral ligands (9 mol%)
toluene, 0-10 o
(R)
+
+
OH
OH
C
anti
syn
1
1
(-)-
(
)-
2
(+)-
Conv.a (%)
Ratio of anti/syn-2a
ee of anti/syn-2a,b (%)
ee of 1a (%)
krel
c
Entry
Ligand
Time (h)
1
2
(R)-L1a
(S)-L1a
(R)-L1b
(R)-L1c
(R)-L1d
(R)-L2a
(R)-L3a
(S)-L3a
(R)-L3b
0.5
0.5
5
19
7
2.5
4
1.5
1
46
50
37
3
39
48
27
49
41
68/32
68/32
69/31
—
67/33
71/29
66/34
68/32
72/28
71/89
ꢀ69/ꢀ85
ꢀ31/ꢀ26
—
25
ꢀ21
ꢀ8
< 1
ꢀ3
ꢀ7
2
2.3
1.9
1.4
—
1.1
1.2
1.1
1.2
1.2
3
4d
5
ꢀ28/ꢀ30
6d
7e,f
8f
9d,f
18/29
34/35
ꢀ31/ꢀ34
ꢀ6
39/44
ꢀ4
a
b
c
d
e
f
Determined by GC analysis.
Specific rotation was analyzed as a mixture of anti-2 and syn-2.
Calculated from the first-order rate law using the theoretical conversion value.18
10 mol % of Et3Al and 18 mol % of ligand were used.
4 mol % of Et3Al and 7.2 mol % of (R)-L3a were used.
Et3Al:ligand = 1:1.

700
H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
Table 2
Kinetic resolution of racemic 3-vinylcitronellal ( )-1 by (S)-BINOL ((S)-L1a)-Al catalyst
CHO
CHO
(
)
( )
S
R
Et3Al (5 mol%), (S)-BINOL ((S)-L1a) (9 mol%)
(S)
(S)
(R)
+
(R)
+
toluene, 0-10 o
C
OH
OH
anti-2
syn-2
(
)-1
(+)-1
(-)-2
Conv.a (%)
Ratio of anti-2/syn-2a
ee of anti-2a,b (%)
ee of syn-2a,b (%)
ee of 1a (%)
krel
c
Entry
Time (min)
1
2
3
4
5
0
15
30
60
90
8
34
50
69
81
68/32
69/31
68/32
68/32
66/34
68
69
69
62
60
70
86
85
88
91
2
12
21
29
30
1.3
1.8
1.9
1.7
1.4
a
b
c
Determined by GC analysis.
Specific rotation was analyzed as a mixture of anti-2 and syn-2.
Calculated from the first-order rate law using the theoretical conversion value.18
OH
OH
CHO
CHO
(S*)
(R*)
L1a
Et3Al (5 mol%), (R)-
(9 mol%)
(R*)
(I)
(R*)
+
(S* )
(S* )
+
toluene, 0-10 o
C
OH
OH
46% conv.
krel = 2.1a
anti
syn
(-)-4
(-)-3
( )-3
(anti / sy n = 65 / 35)b
77% ee
82% ee
21% ee
Bu
Bu
Bu
Bu
CHO
CHO
(
)
(S*)
(S*)
R*
Et3Al (5 mol%), (R)-L1a (9 mol%)
(R*)
(R*)
(II)
+
+
(S* )
OH
OH
toluene, 0-10 o
50% conv.
C
krel = 2.2a
anti
syn
(-)-6
(-)-5
( )-5
(anti / syn = 70 / 30)b,c
71% ee
27% ee
Ph
Ph
Ph
Ph
CHO
CHO
Et3Al (10 mol%), (R)-L1a (18 mol%)
(III)
+
+
toluene, 0-10 o
50% conv.
C
OH
OH
anti
syn
(
)-8
( )-7
( )-7
(anti / syn = 58 / 42)b
Scheme 2. Kinetic resolutions of a variety of racemic citronellal analogs with (R)-BINOL((R)-L1a)-Al. aCalculated from the first-order rate law using the theoretical conversion
value.18 bSpecific rotation was analyzed as a mixture of diastereoisomers. cWe could not find the analysis conditions for syn-6 chirality.
80% from 34% to 81% conversion (entries 2–5). The ee of syn-2
reached 91% ee at 81% conversion (entry 5). The results of ee of
the product anti-2 and syn-2 were higher than the product in the
kinetic resolution of citronellal.14 Additionally, the ee of 2 was still

H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
701
maintained over 60% after the conversion reached 50%. The
diastereoselectivity of anti-2 was maintained at approximately
68% over the resolution.
the major stereoisomer of anti-4 was opposite to that of the major
stereoisomer peak of anti-4 cyclized by (R)-BINOL ((R)-L1a)-Al in
the same way as the resolution of ( )-1. (ꢀ)-5-Ethylisopulegol
(ꢀ)-4 was obtained in this resolution. The diastereoselectivity of
anti-4 was 65%, which was slightly lower than that of anti-2 at
46% conversion ((I) vs entries 1 and 2, Table 1). The ee of anti-4
was 77%, syn-4 was 82% and (ꢀ)-3 was 21%. The krel was 2.2 at
46% conversion.
Next, in the kinetic resolution of racemic 3-butylcitronellal ( )-
5 with (R)-L1a-Al, optically active 5-butylisopulegol (ꢀ)-6 was
obtained with 70% diastereoselectivity of anti-6 (II). The
diastereoisomer of anti-6 was syn-6. Other isomers were
detected as less than 1% by GC as well as the resolution of 2 and
4. The product anti-6 was obtained with 71% ee and (ꢀ)-5 was
obtained with 27% ee at 50% conversion. The krel was 2.2 at 50%
conversion.
The kinetic resolution of 3-phenylcitronellal ( )-7 gave racemic
products ( )-8 at 61% conversion (III). 3-Phenylcitronellal ( )-7
provided ( )-8 with 58% diastereoselectivity of anti-8 and 42% of
syn-8. The bulky substituent decreases the diastereoselectivity of
anti-8 due to the bigger interactions between the catalysts. Thus
3-phenylcitronellal ( )-7, which has the biggest substitution of
the three analogues, provided 8 with not only the lowest diastere-
oselectivity but no enantioselectivity of 8 in the kinetic resolution.
Thus, it can be seen that the larger substituents at the 3-position of
citronellal lead to a lower yield of diastereoselective products and a
different tendency of the kinetic resolution.
By contrast, the unreacted citronellal analogue (+)-1 was
obtained with low enantioselectivity. The ee value of (+)-1 was
12% at 34% conversion (entry 2). The ee of (+)-1 increased during
the resolution. The ee of (+)-1 reached 29% at 50% conversion while
the ee of anti-2 was 69% and syn-2 was 69% (entry 3). At the start of
the reaction, the first-order krel value17 calculated with the ee of
(+)-1 was only 1.3 (entry 1). As the reaction proceeded, the krel
value was below 2 despite the ee values of the products anti-2
and syn-2 being over 60% and 80% respectively (entries 2–5).
The kinetic resolutions of racemic citronellal analogues, 3-
ethylcitronellal ( )-3,21,22 3-butylcitronellal ( )-521,23 and 3-
phenylcitronellal ( )-721,24 were successfully carried out. The
results are shown in Scheme 2. The substrates ( )-3 and ( )-5 were
highly-reactive compounds and gave the cyclization products by
GC injection. These kinetic resolution conversion values were cor-
rected by calculations.
The kinetic resolution of racemic 3-ethylcitronellal ( )-3 with
(R)-BINOL((R)-L1a)-Al gave optically active compounds (ꢀ)-3 and
(ꢀ)-4. The diastereoisomers of
4 were also mainly anti-4
(1a,2b,5b-4) and syn-4 (1a,2b,5a-4). Other possible isomers were
barely detected by GC as well as 2. The products of the two
diastereoisomers, anti-4 and syn-4, were provided as the opposite
stereoisomers by the confirmation from the chiral-GC chart of
the remaining (ꢀ)-3 cyclized by Al-MCM41 to 4.25 It showed that
Scheme 3. Chiral recognition of (R)-BINOL((R)-L1a)-Al catalyst.

702
H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
3,5-Dimethylheptenal was expected to form the 5-membered
When BINOL is substituted with bromine L1b or triphenylsilyl
groups L1c, the BINOL ring expand horizontally and become more
spatially similar, thus affording less chiral recognition (Fig. 2). (R)-
H8-BINOL L2a gives more bulky ring edges on its catalyst. The 3-
vinyl and methyl groups of 2 do not fit into the reaction site by
the bulky obstacle and afford far lower selectivity and enantiose-
lectivity of 2.13,28 1-NaphTADDOL(L3a)-Al also bears the same type
of aromatic rings, consisting of 1-naphthyl groups. These rings are
more flexible than those in BINOL-Al and thus afford 2 with lower
enantioselectivity. 9-PhenanthrylTADDOL (L3b)-Al has more bulky
aromatic rings than L3a-Al. The aromatic rings of L3b prevent ( )-1
from approaching to aluminum active site. Therefore L3b-Al
showed milder reactivity than L3a-Al.
3-Ethylcitronellal 3 and 3-butylcitronellal 5 followed the man-
ner of chiral recognition of these aluminium catalysts. However,
3-phenylcitronellal 7 has a more bulky substituent at its 3-carbon
group. The phenyl group is an obstacle the cyclization when the
carbonyl group of 3-phenylcitronellal approaches the gap between
the aromatic rings, the near point of the aluminium reaction site.
Hence the chiral recognition does not function and 7 gives racemic
8.
ring product. However, trace amounts of the cyclized alcohol were
detected in the reaction mixture using GC–MS. Methylcitronel-
lylketone26 and citronellic acid methyl ester gave no product.
The reaction follows an intramolecular ene reaction mechanism
catalysed by an aluminum complex as a Lewis acid.4,27 The car-
bonyl group of 3-alkylcitronellal is coordinated to an aluminum
active site, then a concerted reaction occurs to create the 6-mem-
bered ring, affording 5-alkylisopulegol.
Proposed intermediate states for the reaction are shown in
Scheme 3. 3-Vinylcitronellal ( )-1 was used as a typical substrate
for these resolutions. The chiral recognition in these catalysts is a
function of the BINOL type ligands L1 and L2 or TADDOL type
ligands L3. These complexes have a metal center between two par-
allel aromatic rings.14,28 During the transition state of the ring-
closing ene reaction, the aromatic rings are in close proximity to
3-vinylcitronellal. This narrow space results in the good diastereo-
and enantioselectivity seen in the reaction.
It is assumed that these aromatic rings are horizontally aligned
with respect to each other, so that the edge of the aromatic rings
can interact with the 3-vinyl group of ( )-1 when the carbonyl
group coordinates to the aluminium reaction site. 3-Vinylcitronel-
lal ( )-1 can be fitted between the two parallel aromatic rings of
(R)-L1a-Al when the carbon with the 3-vinyl group is located on
the opposite side of the aluminium reaction site. The bulky 3-vinyl
and 3-methyl substituents form the transition state into a cis-dec-
alin type conformation when the carbonyl group of ( )-1
approaches the aluminium reaction site. In addition, the propan-
2-ylidene group in 1 can fit into the outside edge of the narrow
space of the aromatic rings. Therefore these interactions between
the aromatic rings and 1 result in the formation of anti-2 and
syn-2 with high enantioselectivity (I and II). The narrow spacing
of the aromatic rings prohibits 1 from forming the other isomers
of 2.27
The scents of the isopulegol analogues were evaluated. Ana-
logues (ꢀ)-2, (ꢀ)-4, (ꢀ)-6 and ( )-8 have a floral green note. As
an additional characteristic, 5-ethylisopulegol (ꢀ)-4 has a fruity
note. (ꢀ)-5-Butyl isopulegol (ꢀ)-6 has a similar scent to (ꢀ)-2 with
a tobacco facet. Racemic 5-phenylisopulegol ( )-1 has a rose note
and some strong cinnamon aspect.
3. Conclusion
The chiral aluminum catalyst (R)-BINOL-Al performed kinetic
resolution of citronellal analogues. Racemic 3-alkylcitronellal gave
optically active 5-alkylisopulegol respectively with high enantios-
electivity. Unreacted citronellal analogues were obtained with
low enantioselectivity. The two main diastereoisomers of the
products were opposite stereoisomers to each other. The larger
substituents at the 3-position of citronellal afforded diastereose-
lective products in lower yields and a different tendency of the
kinetic resolution from that of citronellal. All of the isopulegol ana-
logues have a floral green note.
4. Experimental
4.1. General
Gas liquid chromatography (GC) was performed with a GC-
2010AF system (Shimadzu) or GC-353B (GL science) and D-2500
(Hitachi) using DB-WAX (30 m ꢁ 0.32 mm ꢁ 0.5
lm), IC-1
(30 m ꢁ 0.25 mm ꢁ 0.25 m), Chirasil-DEX-CB (25 m ꢁ 0.25 mm ꢁ
l
0.25
l
m), Beta DEXTM 225 (30 m ꢁ 0.25 mm ꢁ 0.25
lm), and Beta
lm) columns. Gas chromatog-
DEXTM 325 (30 m ꢁ 0.25 mm ꢁ 0.25
raphy–mass spectrometry (GC–MS) was performed with a GC-
QP2010 system (Shimadzu) using Rtx-1 (30 m ꢁ 0.25 mm ꢁ
0.25 l
m) columns. 1H NMR spectra were recorded on a Varian
500 Hz spectrometer. Chloroform was used as NMR solvent and
chemical shifts are reported as d values in parts per million relative
to trimethysilane (d = 0). Optical rotations were determined on a
JASCO P-1020 digital polarimeter (JASCO). Molecular orbital calcu-
lation was preceded by SCIGRESS V2 powered by Fujitsu. Graphical
drawings were performed with a Mathematica program. All other
reagents were purchased from Sigma–Aldrich, Wako Pure Chemi-
cal Industries, Ltd, Nacalai Tesque, Inc., Takasago International Cor-
poration, or Strem Chemicals Inc. They were used as-received. All
compounds used were of commercial grade.
Figure 2. Chiral recognition of (R)-BINOL((R)-L1a)-Al and (R)-3,30-diBr-BINOL((R)-
L1b)-Al catalysts.

H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
703
4.2. General procedure of citronellal analogues ( )-1, ( )-3, ( )-5
and ( )-7 kinetic resolution by a ring-closing ene reaction
catalyzed by (R)-BINOL-Al
(minor); 13C NMR (125 MHz, CDCl3): 19.9 (CH3), 27.8 (CH2), 31.3
(CH3), 37.1 (CH2), 38.8 (C), 40.6 (CH2), 50.2 (CH), 55.9 (CH3), 74.9
(CH), 84.8 (C), 112.2 (CH2), 113.5 (CH2), 121.5 (C), 123.8 (C),
126.1 (C), 127.5 (CH), 128.2 (CH), 128.7 (CH), 129.4 (CH), 129.7
(CH), 144.8 (CH), 146.1 (C) (major); 13C NMR (125 MHz, CDCl3):
22.2 (CH3), 27.1 (CH2), 31.3 (CH3), 35.8 (CH2), 37.8 (C), 41.1
(CH2), 50.5 (CH), 55.4 (CH3), 74.7 (CH), 85.0 (C), 112.5 (CH2),
113.5 (CH2), 121.5 (C), 123.8 (C), 127.5 (C), 127.5 (CH), 128.2
(CH), 128.7 (CH), 129.4 (CH), 129.7 (CH), 145.9 (C), 148.9 (CH)
(minor).
A mixture of (R)-BINOL (R)-L1a (57.2 mg, 0.200 mmol, 5 mol %,
1.8 equiv vs Al), triethylaluminium 1.0 mol/L toluene solution
(0.11 mL, 0.110 mmol, 5 mol %), and toluene (1.2 mL) as added to
a 50-mL Schlenk tube under an N2 atmosphere. After being stirred
at rt for over 1 h, the solution was cooled to less than 10 °C. The
citronellal analogue (2.22 mmol) was added dropwise slowly
under 10 °C and stirred for a given amount of time. Samples of
the solution were consecutively taken at given time periods and
analyzed by GC. The citronellal analogues in the reaction mixture
were collected by silica-gel column chromatography or preparative
TLC separation (heptane/AcOEt = 7/1) with 2,6-diphenylphenol
and reacted by Al-MCM-41 (cat. amount) in toluene at 80 °C in
order to analyze their enantioselectivity.23 The authentic samples
of racemic 2, 4, 6 and 8 were also prepared by cyclization catalyzed
by Al-MCM-41.
4.6. (R)-(5-Methyl-2-(prop-1-en-2-yl)-5-vinylcyclohexyl)3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate (1R,2S,5S/1R,2S,5R =
68/32) ((R)-MTPA ester of (+)-2)17
1H NMR (500 MHz, CDCl3): d 1.03 (3H, s), 1.23–1.51 (3H, m),
1.53 (3H, br), 1.55–1.72 (2H, m), 2.10–2.14 (1H, m), 2.19–2.24
(1H, m), 3.57 (3H, s), 4.58–4.84 (3H, m), 4.96 (1H, dd, J 17.5,
1.0 Hz), 5.16 (1H, dd, J 10.9, 0.8 Hz), 5.18–5.27 (1H, m), 7.35–7.60
(5H, m) (major); 1H NMR (500 MHz, CDCl3): d 1.14 (3H, s), 1.21–
1.71 (4H, m), 1.60 (3H, br), 1.87–1.93 (1H, m), 2.19–2.27 (2H, m),
3.52 (3H, s), 4.77–4.86 (3H, m), 4.91 (1H, dd, J 10.7, 1.0 Hz),
5.22–53.4 (2H, m), 7.35–7.60 (5H, m) (minor); 13C NMR
(125 MHz, CDCl3): 19.9 (CH3), 27.3 (CH2), 30.5 (CH3), 37.1 (CH2),
38.4 (C), 40.6 (CH2), 50.2 (CH), 55.9 (CH3), 74.9 (CH), 84.8 (C),
112.2 (CH2), 113.5 (CH2), 121.5 (C), 123.8 (C), 126.1 (C), 127.5
(CH), 128.2 (CH), 128.7 (CH), 129.4 (CH), 129.7 (CH), 144.8 (CH),
146.1 (C) (major); 13C NMR (125 MHz, CDCl3): 22.2 (CH3), 27.3
(CH2), 30.5 (CH3), 35.8 (CH2), 37.3 (C), 41.1 (CH2), 50.5 (CH), 55.4
(CH3), 74.7 (CH), 85.0 (C), 112.5 (CH2), 113.5 (CH2), 121.5 (C),
123.8 (C), 127.5 (C), 127.5 (CH), 128.2 (CH), 128.7 (CH), 129.4
(CH), 129.7 (CH), 145.9 (C), 148.9 (CH) (minor).
4.3. (R)-(ꢀ)-3-Vinyl-3,7-dimethyloct-6-enal ((R)-(ꢀ)-3-vinylcit-
ronellal) (ꢀ)-1 (Table 1, entry 1)
Obtained as a yellowish oil. Yield 152 mg from 400 mg of ( )-1
(38%). [
a]
20 = ꢀ14.1 (c 0.08, EtOH, 25% ee); 1H NMR (500 MHz,
D
CDCl3): d 1.16 (3H, s), 1.39–1.47 (2H, m), 1.58 (3H, s), 1.67 (3H,
s), 1.92 (2H, q, J 8.3 Hz), 2.34 (2H, qd, J 14.9, 2.8 Hz), 5.02 (1H, d,
J 17.6 Hz), 5.03–5.9 (1H, m), 5.11(1H, d, J 10.8 Hz), 5.85 (1H, dd, J
17.6, 10.9 Hz), 9.73 (1H, t, 2.8 Hz); 13C NMR (125 MHz, CDCl3):
17.6 (CH3), 22.6 (CH2), 23.4 (CH3), 25.6 (CH3), 39.0 (C), 41.4
(CH2), 53.1 (CH2), 113.2 (CH2), 124.0 (CH), 131.8 (C), 145.0 (CH),
203.3 (CHO); HRMS (FI): M+, found 180.1502. C12H20O requires
180.1514.
4.7. (S)-(+)-3-Vinyl-3,7-dimethyloct-6-enal ((S)-(+)-3-vinylcitro-
4.4. (+)-5-Vinyl-5-methyl-2-(prop-1-en-2-yl)cyclohexanol ((+)-
5-vinylisopulegol) (+)-2 (1R,2S,5S/1R,2S,5R = 68/32) (absolute
stereochemistry) (Table 1, entry 1)
nellal) (+)-1 (Table 1, entry 2)
Obtained as a yellow oil. Yield 48 mg at 81% conversion from
400 mg of ( )-1 (12%). [a]
20 = +11.6 (c 0.08, EtOH, 30% ee); 1H
D
Obtained as a colorless oil. Yield 189 mg from 400 mg of ( )-1
NMR (500 MHz, CDCl3): d 1.15 (3H, s), 1.39–1.45 (2H, m), 1.57
(3H, s), 1.67 (3H, s), 1.89–1.94 (2H, m), 2.29–2.40 (2H, m), 5.00
(1H, d, J 17.6 Hz), 5.03–5.9 (1H, m), 5.12(1H, d, J 10.8 Hz), 5.82
(1H, dd, J 17.5, 10.9 Hz), 9.72 (1H, t, 2.8 Hz); 13C NMR (125 MHz,
CDCl3): 17.5 (CH3), 22.5 (CH2), 23.4 (CH3), 25.6 (CH3), 38.9 (C),
41.3 (CH2), 53.0 (CH2), 113.1 (CH2), 124.0 (CH), 131.7 (C), 145.0
(47%). [a]
20 = +9.7 (c 0.11, EtOH, 71% ee (anti-2), 89%ee (syn-2));
D
1H NMR (500 MHz, CDCl3): d 1.01 (3H, s), 1.20–1.34 (3H, m),
1.42–1.65 (4H, m), 1.69 (3H, s), 1.70–1.80 (1H, m), 1.87–1.92
(1H, m), 2.10 (1H, ddd, J 12.9, 3.7, 2.6 Hz), 4.84–5.07 (3H, m),
5.75 (1H, dd, J 17.7, 11.0 Hz) (major); 1H NMR (500 MHz, CDCl3):
d 1.05 (3H, s), 1.20–1.65 (8H, m), 1.75 (3H, s), 1.82–1.92 (2H, m),
4.84–5.07 (3H, m), 5.82 (1H, dd, J 17.5, 1.8 Hz) (minor); 13C NMR
(125 MHz, CDCl3): 19.2 (CH3), 26.4 (CH), 31.5 (CH3), 36.9 (CH2),
38.9 (C), 44.8 (CH2), 54.7 (CH), 67.3 (CH), 112.4 (CH2), 112.9
(CH2), 145.9 (CH), 146.6 (C) (major); 13C NMR (125 MHz, CDCl3):
19.3 (CH3), 22.7 (CH3), 25.9 (CH2), 36.1 (CH2), 37.8 (C), 43.9
(CH2), 54.7 (CH), 67.4 (CH), 109.4 (CH2), 112.9 (CH2), 146.4 (C),
(CH), 203.2 (CHO); HRMS (FI): M+, found 180.1513. C12H20
requires 180.1514.
O
4.8. (ꢀ)-5-Vinyl-5-methyl-2-(prop-1-en-2-yl)cyclohexanol ((ꢀ)-
5-vinylisopulegol) (ꢀ)-2 (1S,2R,5R/1S,2R,5S = 66/34) (absolute
stereochemistry) (Table 1, entry 2)
149.9 (CH) (minor); HRMS (FI): M+, found 182.1676. C12H20
requires 182.1671 (mixture).
O
Obtained as a colorless oil. Yield 195 mg at 81% conversion from
400 mg of ( )-1 (49%). [
a
]
20 = ꢀ8.8 (c 0.03, EtOH, 60% ee (anti-2),
D
91%ee (syn-2)); 1H NMR (500 MHz, CDCl3): d 1.02 (3H, s), 1.20–
1.34 (3H, m), 1.42–1.65 (4H, m), 1.69 (3H, s), 1.70–1.80 (1H, m),
1.87–1.92 (1H, m), 2.10 (1H, ddd, J 12.9, 3.7, 2.6 Hz), 4.83–5.08
4.5. (S)-(5-Methyl-2-(prop-1-en-2-yl)-5-vinylcyclohexyl)3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate (1R,2S,5S/1R,2S,5R =
68/32) ((S)-MTPA ester of (+)-2)17
(3H, m), 5.75 (1H, dd,
J
17.7, 11.1 Hz) (major); 1H NMR
(500 MHz, CDCl3): d 1.05 (3H, s), 1.20–1.65 (8H, m), 1.75 (3H, s),
1.82–1.92 (2H, m), 4.83–5.08 (3H, m), 5.82 (1H, dd, J 17.5, 1.8 Hz)
(minor); 13C NMR (125 MHz, CDCl3): 19.2 (CH3), 26.4 (CH), 31.5
(CH3), 36.9 (CH2), 38.9 (C), 44.8 (CH2), 54.7 (CH), 67.3 (CH), 112.5
(CH2), 112.9 (CH2), 145.9 (CH), 146.6 (C) (major); 13C NMR
(125 MHz, CDCl3): 19.3 (CH3), 22.7 (CH3), 25.9 (CH2), 36.1 (CH2),
37.8 (C), 43.9 (CH2), 54.7 (CH), 67.4 (CH), 109.4 (CH2), 112.9
(CH2), 146.4 (C), 149.9 (CH) (minor); HRMS (FI): M+, found
182.1676. C12H20O requires 180.1514 (mixture).
1H NMR (500 MHz, CDCl3): d 1.00 (3H, s), 1.21–1.60 (4H, m),
1.66 (3H, t, J 0.9 Hz), 2.12–2.22 (3H, m), 3.52 (3H, d, J 1.1 Hz),
4.77–4.86 (3H, m), 4.92 (1H, dd, J 15.7, 1.0 Hz), 5.16 (1H, dd, J
10.9, 0.9 Hz), 5.18–5.27 (1H, m), 7.35–7.60 (5H, m) (major); 1H
NMR (500 MHz, CDCl3): d 1.16 (3H, s), 1.21–1.71 (4H, m), 1.73
(3H, t, J 0.9 Hz), 1.81–1.87 (1H, m), 2.15–2.28 (2H, m), 3.56 (3H,
d, J 1.3 Hz), 4.77–4.86 (3H, m), 4.90 (1H, dd, J 8.0, 1.0 Hz), 5.25
(1H, dd, J 17.8, 0.8 Hz), 5.27–5.34 (1H, m), 7.35–7.60 (5H, m)

704
H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
4.9. (ꢀ)-3-Ethyl-3,7-dimethyloct-6-enal ((ꢀ)-3-ethylcitronellal)
((ꢀ)-3) (Scheme 2, I)
4.13. 5-Methyl-5-phenyl-2-(prop-1-en-2-yl)cyclohexanol (3-
phenylisopulegol) 8 (1 ,2b,5b/1 ,2b,5 = 58/42) (Scheme 2, III)
a
a
a
Obtained as a yellowish oil. Yield 125 mg at 57% conversion
Obtained as a colorless oil. Yield 244 mg from 500 mg of ( )-7
(49%). 1H NMR (500 MHz, CDCl3): d 1.20 (3H, s), 1.35–1.50 (2H,
m), 1.52 (3H, s), 1.54–1.73 (4H, m), 1.90–2.07 (2H, m), 2.37 (1H,
dq, J 13.8, 3.0 Hz), 2.71 (1H, dt, J 13.4, 3.0 Hz), 3.85 (1H, ddd, J
10.5, 10.5, 4.5 Hz), 4.79 (2H, d, J 19.9 Hz), 7.10–7.45 (5H, m)
(major); 1H NMR (500 MHz, CDCl3): d 1.31 (3H, s), 1.35–1.73 (6H,
m), 1.77 (3H, s), 1.86–2.07 (3H, m), 2.29 (1H, dq, J 12.5, 1.9 Hz),
3.45 (1H, ddd, J 10.6, 10.6, 4.7 Hz) 4.92 (2H, d, J 18.7 Hz), 7.10–
7.45 (5H, m) (minor); 13C NMR (125 MHz, CDCl3): 19.1 (CH3),
26.4 (CH2), 35.3 (CH3), 36.9 (CH2), 40.0 (C), 44.9 (CH2), 54.8 (CH),
67.3 (CH), 112.7 (CH), 124.8 (CH), 125.7 (CH), 125.8 (CH), 128.2
(CH), 128.5 (CH), 146.3 (C), 151.2 (C) (major); 13C NMR
(125 MHz, CDCl3): 19.3 (CH3), 25.4 (CH3), 26.3 (CH2), 37.0 (CH2),
38.7 (C), 44.8 (CH2), 54.5 (CH), 67.8 (CH), 112.9 (CH), 124.8 (CH),
125.5 (CH), 125.8 (CH), 128.2 (CH), 128.5 (CH), 146.6 (C), 151.2
(C) (minor); HRMS (FI): M+, found 230.1644. C14H26O requires
230.1670 (mixture).
from 700 mg of ( )-3 (18%). [
a]
20 = ꢀ1.1 (c 0.01, CHCl3, 32% ee);
D
1H NMR (500 MHz, CDCl3): d 0.86 (3H, t, J 7.5 Hz), 1.03 (3H, s),
1.28–1.47 (4H, m), 1.60 (3H, s), 1.68 (3H, br), 1.90–1.98 (2H, m),
2.27 (2H, d, J 3.2 Hz), 5.00–5.15 (1H, m), 9.84 (1H, t, J 3.2 Hz); 13C
NMR (125 MHz, CDCl3): 8.0 (CH3), 17.6 (CH3), 22.3 (CH3), 24.8
(CH3), 25.6 (CH3), 32.3 (CH2), 36.2 (C), 39.6 (CH2), 52.4 (CH2),
124.3 (CH), 131.6 (C), 203.8 (CHO); HRMS (FI): M+, found
182.1653. C12H22O requires 182.1671.
4.10. (ꢀ)-5-Ethyl-5-methyl-2-(prop-1-en-2-yl)cyclohexanol ((ꢀ)-
3-ethylisopulegol)
(relative stereochemistry) (Scheme 2, I)
(ꢀ)-4
(1R⁄,2S⁄,5S⁄/1R⁄,2S⁄,5R⁄ = 65/35)
Obtained as a colorless oil. Yield 364 mg at 57% conversion from
700 mg of ( )-3 (52%). [
a]
20 = ꢀ7.17 (c 0.24, CHCl3, 73% ee (anti-4),
D
79% ee (syn-4)); 1H NMR (500 MHz, CDCl3): d 0.81–0.87 (3H, m),
0.90 (3H, s), 1.03–1.60 (7H, m), 1.77 (3H, br), 1.78–1.96 (3H, m),
3.66 (1H, ddd, J 10.5, 10.5, 4.5 Hz), 4.85–4.92 (2H, m) (major); 1H
NMR (500 MHz, CDCl3): d 0.82–0.85 (3H, m), 0.87 (3H, s), 1.02–
1.60 (7H, m), 1.73 (3H, br), 1.80–1.96 (3H, m), 3.60 (1H, ddd, J
10.7, 10.7, 4.5 Hz), 4.85–4.92 (2H, m) (minor); 13C NMR
(125 MHz, CDCl3): 7.6 (CH3), 19.3 (CH3), 22.1 (CH3), 26.1 (CH2),
34.7 (C), 36.4 (CH2), 38.2 (CH2), 44.6 (CH2), 55.1 (CH), 67.6 (CH),
112.7 (CH2), 146.7 (C) (major); 13C NMR (125 MHz, CDCl3): 7.9
(CH3), 19.3 (CH3), 22.1 (CH3), 25.8 (CH2), 34.7 (C), 36.6 (CH2),
38.2 (CH2), 44.6 (CH2), 54.8 (CH), 67.1 (CH), 112.7 (CH2), 146.7
(C) (minor); HRMS (FI): M+, found 182.1676. C12H22O requires
182.1671 (mixture).
Acknowledgments
We would like to thank Mr. Dean Walker for checking and cor-
recting some errors in English in this manuscript.
References
1. (a) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 51, 505–555; (b) Adams, D. R.;
Bhatnagar, S. P. Synthesis 1977, 661–672; (c) Snider, B. B. Comprehensive Organic
Synthesis, 1991. Vol. 2, p 527; (d) Corminboeuf, O.; Overman, L. E.; Pennington,
L. D. J. Am. Chem. Soc. 2003, 125, 6650–6652; (e) Kopecky, D. J.; Rychnovsky, S.
D. J. Am. Chem. Soc. 2001, 123, 8420–8421; (f) Jung, H. H.; Seiders, J. R.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2007, 46, 8464–8467.
2. Zhang, Z.; Xie, H.; Gao, L.; Song, Z. Org. Lett. 2015, 17, 4706–4709.
3. Durel, V.; Lalli, C.; Roisnel, T.; Weghe, P. J. Org. Chem. 2016, 81, 849–859.
4.11. (ꢀ)-3-nButyl-3,7-dimethyloct-6-enal ((ꢀ)-3-buthylcitron-
ellal) (ꢀ)-5 (Scheme 2, II)
4. Tokunaga et al. reported on
a variety of kinetic resolutions examples;
Tokunaga, M.; Kiyosu, J.; Obora, Y.; Tsuji, Y. J. Am. Chem. Soc. 2006, 128,
4481–4486.
Obtained as a yellowish oil. Yield 878 mg from 2.00 g of ( )-5
5. (a) Sakamoto, M.; Unosawa, A.; Kobaru, S.; Saito, A.; Mino, T.; Fujita, T. Angew.
Chem., Int. Ed. 2005, 44, 5523–5528; (b) Sakamoto, M.; Nosawa, U. A.; Kobaru,
S.; Fujita, K.; Mino, T.; Fujita, T. Chem. Commun. 2007, 3586–3588; (c)
Sakamoto, M.; Kato, M.; Aida, Y.; Fujita, K.; Mino, T.; Fujita, T. J. Am. Chem.
Soc. 2008, 130, 1132–1133; (d) Sakamoto, M.; Fujita, K.; Yagishita, F.; Unosawa,
A.; Mino, T.; Fujita, T. Chem. Commun. 2011, 4267–4629.
6. Klauck, M. I.; Patel, S. G.; Wiskur, S. L. J. Org. Chem. 2012, 77, 3570–3575.
7. Luukas, T. O.; Girard, C.; Fenwick, D. R.; Kagan, H. B. J. Am. Chem. Soc. 1999, 121,
9299–9306.
8. Aoyama, H.; Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obora, Y.; Tsuji, Y. J. Am.
Chem. Soc. 2005, 127, 10474–10475.
9. Gan, K.; Sadeer, A.; Ng, J. S.; Lu, Y.; Pullarkat, S. A. Org. Chem. Front. 2015, 2,
1059–1065.
(44%). [
a
]
D
20 = ꢀ10.9 (c 0.63, CHCl3, 27% ee); 1H NMR (500 MHz,
CDCl3): d 0.91 (3H, t, J 6.9 Hz), 1.04 (3H, s), 1.20–1.38 (8H, m),
1.60 (3H, s), 1.68 (3H, s), 1.90–1.98 (2H, m), 2.27 (2H, d, J 3.2 Hz),
5.05–5.11 (1H, m), 9.85 (1H, t, J 3.2 Hz); 13C NMR (125 MHz,
CDCl3): 14.2 (CH3), 17.6 (CH3), 22.3 (CH2), 23.6 (CH2), 25.3 (CH3),
25.7 (CH3), 25.8 (CH2), 36.1 (C), 39.7 (CH2), 40.1 (CH2), 52.9
(CH2), 124.3 (CH), 131.5 (C), 203.9 (CHO); HRMS (FI): M+, found
210.1969. C14H26O requires 210.1984.
4.12.
(ꢀ)-5-nButyl-5-methyl-2-(prop-1-en-2-yl)cyclohexanol
10. (a) Akhani, R. K.; Clark, R. W.; Yuan, L.; Wang, L.; Tang, C.; Wiskur, S. L.
ChemCatChem 2015, 7, 1527–1530; (b) Clark, R. W.; Deaton, T. M.; Zhang, Y.;
Moore, M. I.; Wiskur, S. L. Org. Lett. 2013, 15, 6132–6135; (c) Akhani, R. K.;
Moore, M. I.; Pribyl, J. G.; Wiskur, S. L. J. Org. Chem. 2014, 79, 2384–2396.
11. Salvio, R.; Moliterno, M.; Caramelli, D.; Pisciottani, L.; Antenucci, A.; D’Amico,
M.; Bella, M. Catal. Sci. Technol. 2016, 6, 2280–2288.
12. Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974–4001.
13. (a) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock, R. R. J. Am.
Chem. Soc. 1998, 120, 4041–4042; (b) La, D. S.; Alexander, J. B.; Cefalo, D. R.;
Graf, D. D.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 9720–
9721.
14. Itoh, H.; Maeda, H.; Yamada, S.; Hori, Y.; Mino, T.; Sakamoto, M. Org. Chem.
Front. 2014, 1, 1107–1115.
15. Saito, S.; Shimada, K.; Yamamoto, H. Synlett 1996, 720–721.
16. Chen, H.; Li, Y. Lett. Org. Chem. 2008, 5, 467–469.
17. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakasawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
18. The krel values of kinetic resolutions herein were calculated on the 1st order
formula in order to compare the results with the kinetic resolution of
citronellal; see Refs. 8,14.
((ꢀ)-3-buthylisopulegol) ((ꢀ)-6) (1R⁄,2S⁄,5S⁄/1R⁄,2S⁄,5R⁄ = 70/30)
(Scheme 2, II)
Obtained as a colorless oil. Yield 848 mg from 2.00 g of ( )-5
(42%). [
a
]
D
20 = ꢀ76.7 (c 0.60, CHCl3, 71% ee, (anti-6)); 1H NMR
(500 MHz, CDCl3): d 0.91–1.07 (6H, m), 1.10 (1H, t J 11.7 Hz),
1.14–1.41 (7H, m), 1.43–1.62 (3H, m), 1.74 (3H, s), 1.77–1.91
(3H, m), 3.65 (1H, ddd, J 10.7, 10.7, 4.4 Hz), 4.88 (2H, d, J 20.4 Hz)
(major); 1H NMR (500 MHz, CDCl3): d 0.88–0.91 (6H, m), 1.05
(1H, t, J 11.7 Hz), 1.14–1.41 (7H, m), 1.43–1.62 (3H, m), 1.75 (3H,
br), 1.77–1.91 (3H, m), 3.61 (1H, ddd, J 10.8, 10.5, 4.2 Hz), 4.88
(2H, d, J 20.4 Hz) (minor); 13C NMR (125 MHz, CDCl3): 14.1 (CH3),
19.3 (CH3), 22.7 (CH3), 23.6 (CH2), 25.4 (CH2), 26.1 (CH2), 34.7
(C), 36.9 (CH2), 45.1 (CH2), 45.9 (CH2), 55.1 (CH), 67.6 (CH), 112.7
(CH2), 146.7 (C) (major); 13C NMR (125 MHz, CDCl3): 14.1 (CH3),
19.3 (CH3), 23.5 (CH2), 25.4 (CH2), 25.8 (CH2), 29.4 (CH3), 34.7
(C), 37.1 (CH2), 44.9 (CH2), 45.9 (CH2), 54.8 (CH), 67.1 (CH), 112.7
(CH2), 146.7 (C) (minor); HRMS (FI): M+, found 210.1973.
19. The volume of TADDOL type ligands on an aluminium catalyst were optimized
as one equivalent of one aluminium atom.14
20. Cuenca, A.; Medio-Simón, M.; Aguilar, G. A.; Weibel, D.; Beck, A. K.; Seebach, D.
Helv. Chim. Acta 2000, 83, 3153–3162.
21. Meyer, S.; Wakabayashi, N.; Thing, E. G. Org. Prep. Proced. Int. 1979, 11, 97–99.
C14H26O requires 210.1984 (mixture).

H. Itoh et al. / Tetrahedron: Asymmetry 27 (2016) 698–705
705
22. Marshall, J. A.; Herold, M.; Eidam, H. S.; Eidam, P. Org. Lett. 2006, 24, 5505–
5508.
26. Mori, K.; Takahashi, Y. Liebigs Ann. Chem. 1991, 1057–1065.
27. (a) Mikami, K.; Sawa, E.; Terada, M. Tetrahedron: Asymmetry 1991, 2, 1403–
1412; (b) Mikami, K.; Terada, M.; Sawa, E.; Nakai, T. Tetrahedron Lett. 1991, 32,
6571–6574.
28. Itoh, H.; Maeda, H.; Yamada, S.; Hori, Y.; Mino, T.; Sakamoto, M. Org. Biomol.
Chem. 2015, 13, 5817–5825.
23. Cahiez, G.; Alami, M. Tetrahedron Lett. 1989, 30, 7365–7368.
24. Barboza, J. C. S.; Pétrier, C.; Luche, J. Tetrahedron Lett. 1985, 26, 829–830.
25. (a) Trasarti, A. F.; Marchi, A. J.; Apestegía, C. R. J. Catal. 2004, 224, 484–488; (b)
Nie, Y.; Chuah, G.; Jaenicke, S. Chem. Commun. 2006, 790–792; (c) Trasarti, A. F.;
ˆ
Marchi, A. J.; Apestegja, C. R. J. Catal. 2007, 247, 155–165.