Enantio- and diastereoselective hetero-Diels-Alder reactions between 4-methyl-substituted Rawal's diene and aldehydes catalyzed by chiral dirhodium(II) carboxamidates: Catalytic asymmetric synthesis of (-)-cis-aerangis lactone

Article abstract of DOI:10.1016/j.tetasy.2013.10.016

The first catalytic asymmetric hetero-Diels-Alder (HDA) reaction between 3-tert-butyldimethylsilyloxy- 1-dimethylamino-1,3-pentadiene (4-methyl-substituted Rawal's diene) and aldehydes is described. With 3 mol % of dirhodium(II) tetrakis[N-benzene-fused-p

Full text of DOI:10.1016/j.tetasy.2013.10.016

Tetrahedron: Asymmetry 25 (2014) 63–73
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantio- and diastereoselective hetero-Diels–Alder reactions
between 4-methyl-substituted Rawal’s diene and aldehydes
catalyzed by chiral dirhodium(II) carboxamidates: catalytic
asymmetric synthesis of (ꢀ)-cis-aerangis lactone
⇑
⇑
Yudai Watanabe, Naoyuki Shimada, Masahiro Anada , Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first catalytic asymmetric hetero-Diels–Alder (HDA) reaction between 3-tert-butyldimethylsilyloxy-
1-dimethylamino-1,3-pentadiene (4-methyl-substituted Rawal’s diene) and aldehydes is described. With
3 mol % of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh2((S)-BPTPI)4, the
cycloaddition reaction proceeded exclusively in an endo fashion and gave, after a novel sequential treat-
ment with dimethyl acetylenedicarboxylate and acetyl chloride, the corresponding 2,3-cis-disubstituted
dihydropyranones with up to 98% ee and perfect diastereoselectivity. The utility of this catalytic protocol
was demonstrated by an asymmetric synthesis of the (ꢀ)-cis-aerangis lactone.
Received 11 September 2013
Accepted 17 October 2013
Available online 13 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
reported that Rh2((S)-BPTPI)4 2, a dirhodium(II) carboxamidate
complex that incorporates (S)-3-(benzene-fused-phthalimido)-2-
Catalytic asymmetric hetero-Diels–Alder (HDA) reactions
between electron-rich dienes and aldehydes represent one of the
most powerful and straightforward methods for the construction
of optically active, six-membered oxygen-containing heterocy-
cles.1 Since the pioneering work of Danishefsky et al. with a chiral
Eu(III) complex in 1983,2 a number of powerful catalytic systems
based on chiral Lewis acids such as Al,3 V(IV),4 B,5 Ti(IV),6 Cu(II),7
Cr(III),8 Co(III),9 Rh(III),10 Zn(II),11 Zr(IV),12 lanthanides,13 Mg(II),14
and In(III)15 complexes of well-designed ligands as well as asym-
metric organocatalysis16,17 have been developed to achieve high
levels of enantioselectivity for HDA reactions of aldehydes with
various types of dienes, such as 1-methoxy-3-(trimethylsilyloxy)-
1,3-butadiene (Danishefsky’s diene),2–5,6b–d,7a,c,8a,c–i,9–14,15a,c,17b
1-dimethylamino-3-silyloxy-1,3-butadiene (Rawal’s diene),16 and
piperidinonate as chiral bridging ligands, is a highly efficient Lewis
acid catalyst for endo-selective and enantioselective HDA reactions
of aldehydes with Danishefsky-type dienes as well as monooxy-
genated dienes, in which up to 99% ee and turnover numbers as
high as 48,000 were achieved.21,22 However, the HDA reactions
with silyloxydienes 3 and 6 bearing a terminal methyl substituent
have limitations in that only highly reactive aldehydes such as p-
nitrobenzaldehyde 4a and
a,b-acetylenic aldehyde 4b have met
with any real success, and no reaction occurred with other alde-
hydes under the same conditions (Eq. (1)–(3)). More recently, we
reported the first example of a chiral Lewis acid-catalyzed HDA
reaction between Rawal’s diene 8a and aldehydes (Eq. 4),23 in
which the Rh2((S)-BPTPI)4-catalyzed cycloaddition proceeded
through the same concerted [4+2] mechanism in an endo manner
as that with Danishefsky-type dienes to give, after treatment with
acetyl chloride, dihydropyranone derivatives 9 with up to 99% ee.
In this protocol, the applicable aldehydes include not only aro-
1,3-dimethoxy-1-trimethylsilyloxy-1,3-butadiene
(Brassard’s
diene).6f,7b,c,15b
Chiral dirhodium(II) carboxamidates have been widely recog-
nized as a new class of effective Lewis acid catalysts since Doyle
et al. disclosed the robustness and unique reactivity of dirho-
dium(II) tetrakis[methyl 1-(3-phenylpropanoyl)-2-oxoimidazoli-
dine-4(S)-carboxylate], Rh2((4S)-MPPIM)4 1, (Fig. 1) in
enantioselective HDA reactions of Danishefsky’s diene with
electron-poor aromatic aldehydes.18–20 In this area, we recently
matic, a,b-acetylenic, and a,b-olefinic aldehydes, but also sterically
hindered aliphatic aldehydes that were less effective dienophiles
when a Danishefsky-type diene was used. It is well documented
that Rawal’s diene displays significantly higher reactivity than that
of Danishefsky’s diene in the Diels–Alder reaction.24 Thus, we ex-
pected that the use of Rawal-type dienes bearing a terminal substi-
tuent could solve the problem encountered with Danishefsky-type
diene derivatives 3. As part of our interest in further extending the
diene scope and utility of Rh2((S)-BPTPI)4, we herein report on a
catalytic asymmetric HDA reaction between the hitherto unknown
⇑
Corresponding authors. Tel.: +81 11 706 3236; fax: +81 11 706 981.
E-mail addresses: anada@pharm.hokudai.ac.jp (M. Anada), hsmt@pharm.hokudai.
ac.jp (S. Hashimoto).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.016

64
Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
O
the addition of tert-butylchlorodimethylsilane afforded 4-methyl-
O
N
substituted Rawal’s diene 8b {(1E,3Z)/(1E,3E) = 74:26} as an insep-
arable mixture in 81% yield (Scheme 1). The stereochemistry of
(1E,3Z)-8b was established by the 1H NOE between C4–CH3 and
Si(CH3)2. Since attempts to improve the stereoselectivity were
unsuccessful, diene 8b {(1E,3Z)/(1E,3E) = 74:26}, as such, was used
for the HDA reaction.
Ph
N
H
N
H
O
O
N
O
CO2Me
Rh
Rh
Rh
Rh
Rh2((S)-BPTPI)42
Rh2((4S)-MPPIM)41
2.2. Enantioselective HDA reaction
Figure 1. Chiral Rh(II) carboxamidates.
On the basis of our previous work, we initially explored the HDA
reaction between diene 8b {(1E,3Z)/(1E,3E) = 74:26} (1.5 equiv)
3-tert-butyldimethylsilyloxy-1-dimethylamino-1,3-pentadiene
and hydrocinnamaldehyde 4c using 3 mol % of Rh2((S)-BPTPI)4
2
(4-methyl-substituted Rawal’s diene) and aldehydes.12,25–27
(Scheme 2). The reaction was performed in dichloromethane at
OSiEt3
O
O
Ar
R
Me
1. Rh2((S)-BPTPI)4
(1 mol %)
2
H
H
R
Me
+
CH2Cl2, 23 °C
O
Me
Rh2((S)-BPTPI)4
endo
O
Et3SiO
R
MeO
2. TFA
ð1Þ
ð2Þ
3a
: R = H
NO2
[(1E,3Z)/(1E,3E) = 69:31]
3b: R = Me
4a
NO2
MeO
>99% cis
5a (R = H): 97% (96% ee)
5b
(R = Me): 92% (97% ee)
O
OSiEt3
1. Rh2((S)-BPTPI)4
(1 mol %)
2
Me
Me
CH2Cl2, –20 °C
+
OHC
Ph
2. TFA
Me
Me
O
4b
6
Ph
7
>99% cis
81% (97% ee)
OSiEt3
1. Rh2((S)-BPTPI)4
(1 mol %)
CH2Cl2, 23 °C
2
R
Me
Ph
+
OHC
no reaction
ð3Þ
ð4Þ
MeO
3a
2. TFA
4c
: R = H
[(1E,3Z)/(1E,3E) = 74:26]
3b: R = Me
OTBS
2
1. Rh2((S)-BPTPI)4
(1 mol %)
O
CH2Cl2
OHC
R
+
2. AcCl, –78 °C
Me2N
4
O
R
8a
9
R = aryl, heteroaryl
alkynyl, styryl, alkyl
up to 99% ee
ꢀ20 °C for 6 h and was followed by treatment at ꢀ78 °C with
acetyl chloride according to Rawal’s protocol.29 In this reaction,
2,3-cis-disubstituted 2,3-dihydro-4H-pyran-4-one 5c was obtained
in 37% yield with no signs of the formation of a trans-isomer, and
the entirely unexpected trisubstituted dihydropyran 11 was also
isolated as a 1:1 mixture of diastereomers in 40% yield. The
cis-stereochemistry of 5c was established by the 1H NMR coupling
constant between C2-H and C3-H (4.1 Hz). The enantioselectivity
2. Results and discussion
2.1. Preparation of 4-methyl-substituted Rawal’s diene 8b
Rawal-type dienes bearing terminal substituents were previ-
ously unknown. The requisite Rawal-type diene was prepared
according to the procedure of Rawal et al.24 Treatment of readily
available
a
,b-unsaturated ketone 1028 with NaHMDS followed by

Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
65
Me
Si
O
O
OTBS
Me
1% NOE
Me
1. NaHMDS, THF
40°C, 0.5 h
Me
Me
2. TBSCl
81%
1%
NOE
4
1
Me2N
Me2N
10
Me2N
(1E,3Z)-8b
(1E,3Z)/(1E,3E) = 74:26
8b
Scheme 1. Preparation of 4-methyl-substituted Rawal’s diene 8b.
OTBS
O
Me2N
OTBS
3
1. Rh2((S)-BPTPI)4 2 (3 mol %)
Me
3
Me
Me
CH2Cl2, –20°C, 6 h
Ph
+
+
2
2
OHC
6
1'
2. AcCl, –78°C
Me2N
O
Ph
O
O
H
Ph
H
4c
(1E,3Z)/(1E,3E) = 74:26
8b (1.5 equiv)
Me
H
10%
5c
37% (94% ee)
NOE
8.3% NOE
11
2
(1:1 mixture of diastereomers)
40%
–AcNMe2
–TBSCl
path a
–TBSCl
8b
path c
path b
Ph
OTBS
Me
OTBS
OTBS
Me
H
Me
Rh2((S)-BPTPI)4
endo
Me
Cl–
+
O
AcCl
Et3SiO
Me2N
+
O
Me2N
O
Ph
Me2N
O
Ph
–AcNMe2
Ph
Cl–
12a
13
Ac
14
OTBS
OTBS
Me
Me
CH2Cl2, 0 °C
10 min
+
MeO2C
CO2Me
84%
Me2N
CO2Me
(1E,3Z)/(1E,3E) = 74:26
CO2Me
8b
15
OTBS
Me
O
O
OTBS
1. Rh2((S)-BPTPI)4 2 (3 mol %)
CH2Cl2, –20 °C, 6 h
Me
Me
Ph
+
OHC
+
2. DMAD (1 equiv), 0 °C
3. AcCl, –78 °C
Me2N
4c
Ph
CO2Me
(1E,3Z)/(1E,3E) = 74:26
CO2Me
15
26% (based on
8b
5c
97% (94% ee)
(1.5 equiv)
8b
)
Scheme 2. Enantioselective HDA reaction between 4-methyl-substituted Rawal’s diene 8b and hydrocinnamaldehyde 4c catalyzed by Rh2((S)-BPTPI)4 2.
of this reaction was determined to be 94% ee by HPLC analysis with
a Daicel Chiralcel OD-H column. The exclusive formation of cis-2,3-
dihydropyranone 5c indicates that only the (1E,3Z)-isomer of 8b
participated in the HDA reaction through a concerted [4+2]
mechanism in an endo mode, whereas the (1E,3E)-isomer of 8b
was not consumed under the same conditions as might be ex-
pected from Danishefsky’s studies.30,31 The 2,3-cis/2,6-trans-ste-
reochemistries of 11 were determined by the 1H NMR coupling
constant between C2-H and C3-H (3.8 Hz) and the 1H NOE between
C2-H and C10-H, respectively. There was very little doubt that by-
product 11 originated from the cycloadduct 12a and the remaining
diene 8b during the work-up with acetyl chloride. The formation of
11 by way of a Mukaiyama–Michael addition of 8b to dihydropyr-
anone 5c could be ruled out simply because no detectable Mukaiy-
ama–Michael reaction between 5c and 8b was observed under the
work-up conditions (acetyl chloride in the presence or absence of
2, CH2Cl2, ꢀ78 °C). As proposed by Huang and Rawal, 5c would
be formed by N-acetylation of cycloadduct 12a and subsequent
b-elimination triggered by the attack by the chloride ion on the
silyl group (path a).29 However, the foregoing results suggested an-
other possibility, that an oxocarbenium ion 14 associated with
chloride ion formed by removal of N,N-dimethylacetamide might
also be an intermediate. While 14 would lead to the formation of
5c (path b), the nucleophilic addition of the remaining diene 8b
to 14 from the less hindered face could explain the formation of
11 (path c). An attempt to use excess amounts of aldehyde 4c
(1.5 equiv relative to diene 8b) did not improve the product yield,
because only the (1E,3Z)-isomer of 8b was consumed in the HDA
reaction30 while the (1E,3E)-isomer of 8b that is sterically hindered
to arrange in an s-cis conformation might contribute to nucleo-
philic addition to 14. At this point, we envisaged that after comple-
tion of the cycloaddition, when the reaction solution was treated
with highly reactive dienophiles prior to the acetyl chloride
work-up, the remaining 8b would be consumed to suppress the

66
Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
Table 1
Enantioselective HDA reaction between 4-methyl-substituted Rawal’s diene 8b and aldehydes catalyzed by Rh2((S)-BPTPI)4 2a
OTBS
Me
O
1. Rh ((S)-BPTPI)
2
2
2
4
H
(3 mol %), CH Cl
2
Me
R
+
O
R
2. DMAD, 0 °C
3. AcCl, –78 °C
Me N
O
5
2
4
(1E,3Z)/(1E,3E) = 74:26
8b (1.5 equiv)
Entry
Aldehyde R
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4c
4d
4e
4f
4g
4h
4i
4a
4j
4k
4b
4l
C6H5CH2CH2
nC5H11
BnOCH2CH2
(E)-C6H5CH@CH
C6H5
4-CH3C6H4
4-ClC6H4
4-NO2C6H4
2-Furyl
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ40
ꢀ60
ꢀ40
ꢀ40
ꢀ78
ꢀ78
23
6
6
6
24
8
24
24
0.1
2
5c
5d
5e
5f
5g
5h
5i
5a
5j
5k
5l
97
95
92
74
98
91
89
93
83
81
82
85
63
61
94
92
90
83
94
85
90
98
96
91
97
91
40
29
9
10
11
12
13
14
BnOCH2
4
C6H5C„C
nC5H11C„C
cC6H11
0.2
0.2
48
48
5m
5n
5o
4m
4n
4-CH3OC6H4
0
a
b
c
All reactions were performed on a 0.3 mmol scale (0.5 M) with 1.5 equiv of 8b.
Yields of isolated product 5.
Determined by HPLC.
formation of 11. In a separate experiment, we confirmed that the
cycloaddition of 8b {(1E,3Z)/(1E,3E) = 74:26} with 2 equiv of
dimethyl acetylenedicarboxylate (DMAD) proceeded smoothly at
0 °C to completion within 10 min to give 84% isolated yield of
dimethyl phthalate 15.32 Eventually, we found that the yield of
cis-2,3-dihydropyranone 5c could be greatly improved to 97%
without compromising the enantioselectivity (94% ee) by using
new work-up conditions via a sequential treatment with DMAD
and acetyl chloride.
the corresponding HDA products in similarly high yields and
enantioselectivities (91–98% ee) when the reactions were con-
ducted at low temperatures (ꢀ40 to ꢀ78 °C) to prevent back-
ground reactions (entries 8–12). However, sterically hindered
cyclohexanecarbaldehyde 4m and electron-rich p-anisaldehyde
4n proved to be unsuitable substrates in terms of both product
OTBS
With the optimized work-up conditions in hand, we then inves-
tigated the scope of the reaction with respect to the aldehyde com-
ponent (Table 1). In all cases, cis-2,3-dihydropyranones 5 were
obtained as the sole products with no evidence of the formation
of the trans-isomers, thus confirming the exclusive preference for
a concerted HDA mechanism in an endo mode. Good to high yields
and good to excellent enantioselectivities were consistently
obtained at ꢀ20 °C with straight-chain aliphatic aldehydes 4c–e,
trans-cinnamaldehyde 4f, benzaldehyde 4g, and p-tolualdehyde
4h (83–94% ee, entries 1–6). The absolute configuration of
5d was assigned as (2R,3S) by the transformation of ent-5d to
(ꢀ)-cis-aerangis lactone (vide infra). The absolute configuration
of 5g was determined to be (2S,3S) by its conversion to the
known (2S,3S)-methyl 3-hydroxy-2-methyl-3-phenylpropanoate
Me
H
a
+
O
Me2N
4d
(1E,3Z)/(1E,3E) = 74:26
8b
OH
O
O
Me
Me
c,d
b
O
18
5d
ent-
92% ee
Me
Me
e
16 {[a
]
D = ꢀ18.4 (c 0.59, CHCl3), lit.,33
½
a 2D0
ꢁ
¼ ꢀ19:3 (c 1.74, CHCl3)}
O
O
(Scheme 3). The use of highly reactive aldehydes such as
O
O
electron-poor aromatic aldehydes 4i and 4a, furfural 4j, benzyloxy-
(–)-cis-aerangis lactone 17
19
acetaldehyde 4k, and
a,b-acetylenic aldehydes 4b and 4l, afforded
[α]D22 = –67.2 (c 1.06, CHCl3)
O
Lit.35c [α]D14 = –63.5 (c 1.28, CHCl3)
N
O
Me
H
N
Me
Ph
O
a–c
MeO
Ph
O
O
OH
Rh
Rh
O
5g (94% ee)
16
[α]D22 = –18.4 (c 0.59, CHCl3)for 94% ee
2
Rh2((R)-BPTPI)4 ent-
20
Lit.33
[
]
D
= –19.3 (c 1.74, CHCl3) for (2S,3S)-
α
16
Scheme 4. Reagents and conditions: (a) (i) Rh2((R)-BPTPI)4 ent-2 (3 mol %), CH2Cl2,
ꢀ20 °C, 6 h; (ii) DMAD, 0 °C; (iii) AcCl, ꢀ78 °C, 95% (92% ee); (b) NaBH4, CeCl3ꢂ7H2O,
EtOH, ꢀ10 °C, 91%; (c) ( )-camphorsulfonic acid, H2O/THF, 65 °C; (d) TPAP, NMO,
4 Å-MS, CH2Cl2, 23 °C, 77% (two steps); (e) H2, Pd/C, EtOAc, 23 °C, 97%.
Scheme 3. Reagents and conditions: (a) O3, CH2Cl2–MeOH (1:1), ꢀ78 °C then Me2S;
(b) LiOH, H2O2, H2O; (c) trimethylsilyldiazomethane, MeOH, toluene, 61% (three
steps).

Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
67
2.4. Stereochemical outcome
Si
OTBS
The stereochemical outcome of the present HDA reaction can be
rationalized on the basis of the absolute stereochemical model we
have previously proposed,21a,22,23 which contains a hydrogen
bond39 between the formyl hydrogen atom and the carboxamidate
oxygen atom in the rhodium catalyst–aldehyde complex (Fig. 2).
The approach of the (1E,3Z)-isomer of diene 8b from the less hin-
dered Si-face of the aldehyde in an endo mode to avoid intrusion
into the rhodium framework leads to the observed cycloadduct 5.
This model can also explain the total lack of reactivity of the
(1E,3E)-isomer of 8b since the methyl substituent at C4 in the ste-
rically disfavored s-cis conformation would suffer from severe ste-
ric interactions with the face of the rhodium(II) catalyst.
R
benzene fused phthalimido group
Me
OTBS
Me
H
O
NMe2
O
N
O
N
Rh
Me2N
O
R
12
AcCl
O
Me
O
R
2,3-cis-5
3. Conclusion
O
We have developed a catalytic asymmetric HDA reaction be-
tween 4-methyl-substituted Rawal’s diene 8b and aldehydes.
With 3 mol % of Rh2((S)-BPTPI)4, the cycloaddition reaction pro-
ceeded exclusively in an endo mode and gave, after a novel
sequential treatment with DMAD and acetyl chloride, the corre-
sponding 2,3-cis-disubstituted 2,3-dihydro-4H-pyran-4-ones with
up to 98% ee and perfect diastereoselectivity. Of particular note is
that even the best known catalytic system3a with 4-methyl-
substituted Danishefsky’s diene does not afford such a perfect
cis-selectivity. This represents the first example of the use of a
4-methyl-substituted Rawal’s diene in a [4+2]-cycloaddition reac-
tion, whether asymmetric or nonasymmetric. Using this catalytic
protocol, we achieved an asymmetric synthesis of (+)-cis-aerangis
lactone 17 in five steps in 65% overall yield from hexanal 4d.
Further application of this method to the catalytic asymmetric
synthesis of biologically active natural products is currently in
progress.
Me
O
R
5
2,3-trans-
Si
OTBS
Me
R
AcCl
H
O
NMe2
OTBS
O
O
Me
R
Rh
N
N
Me2N
O
12
3-epi-
Figure 2. Plausible stereochemical course.
4. Experimental
4.1. General
yield and enantioselectivity (entries 13 and 14), although perfect
cis-selectivity was observed in each case.
2.3. Catalytic asymmetric synthesis of (ꢀ)-cis-aerangis lactone
Melting points were determined on a Yamato melting point
apparatus model MP-21 and are uncorrected. IR spectra were re-
corded on a JASCO FT/IR-5300 spectrometer and absorbance bands
are reported in wavenumber (cmꢀ1). 1H NMR spectra were re-
corded on JEOL JNM-ECX 400P (400 MHz) spectrometer or JEOL
JNM-ECA 500 (500 MHz) spectrometer. Chemical shifts are re-
ported relative to internal standard (tetramethylsilane; dH 0.00,
CDCl3; dH 7.26 or C6D6; dH 7.16). Data are presented as follows:
chemical shift (d, ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad), coupling con-
stant, and integration. 13C NMR spectra were recorded on JEOL
JNM-ECX 400P (100 MHz) spectrometer. The following internal
references were used (CDCl3; d 77.0 or C6D6; d 128.0). Optical rota-
tions were measured on a JASCO P-1030 digital polarimeter at the
sodium D line (589 nm). EI-MS spectra were obtained on a JEOL
JMS-FABmate spectrometer, operating with ionization energy of
70 eV. Analytical thin layer chromatography (TLC) was carried
out on Merck Kieselgel 60 F254 plates with visualization by UV
light, anisaldehyde stain solution, or phosphomolybdic acid stain
solution. Analytical high performance liquid chromatography
(HPLC) was performed on a JASCO PU-1580 intelligent HPLC pump
with JASCO UV-1575 intelligent UV/VIS detector. Detection was
performed at 254 nm. Chiralcel OD-H and Chiralpak AD-H columns
(0.46 cm ꢃ 25 cm) from Daicel were used. Retention times (tR) and
peak ratios were determined with JASCO-ChromNAV analysis
system.
In order to illustrate the utility of the present catalytic protocol,
we conducted an asymmetric synthesis of (ꢀ)-cis-aerangis lactone
17, an odoriferous component of the Aerangis species (Scheme 4).34
A number of asymmetric syntheses of cis-aerangis lactone recently
have been reported,35 including the baker’s yeast-mediated asym-
metric reduction of a 3-methyl-4-keto acid,35a Evans’ aldol reac-
tion,35b,c Sharpless asymmetric epoxidation and TBSOTf-mediated
intramolecular hydride transfer of a chiral epoxy alcohol,35d asym-
metric chlorination of citronellal using MacMillan’s organocatalyst
and 1,2-epoxide formation,35e and continuous flow hydrogenation/
biocatalytic oxygenation.35f
The HDA reaction between Rawal-type diene 8b and hexanal 4b
in the presence of 3 mol % of Rh2((R)-BPTPI)4 ent-2 proceeded
uneventfully at ꢀ20 °C to give, after sequential treatment with
DMAD and acetyl chloride, cis-2,3-dihydropyranone ent-5d in
95% yield with 92% ee. Luche reduction36 of ent-5d followed by a
Ferrier rearrangement37 and TPAP oxidation38 gave
a,b-unsatu-
rated d-lactone 19 in 63% yield. Catalytic hydrogenation of the
double bond of 19 furnished (ꢀ)-cis-aerangis lactone 17 in 97%
yield. The synthetic material 17 was spectroscopically (1H and
13C NMR, IR and HRMS) identical to natural (ꢀ)-cis-aerangis
lactone, and also had a specific rotation of ½a D22
¼ ꢀ67:2 (c 1.06,
ꢁ
CHCl3), which is in good agreement with the literature value
{lit.,35c
½
a 1D4
ꢁ
¼ ꢀ63:5 (c 1.28, CHCl3)}.

68
Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
All nonaqueous reactions were carried out in flame-dried glass-
1H, C3–H), 2.68 (ddd, J = 7.2, 9.5, 14.3 Hz, 1H, CH2CHHPh), 2.81
(ddd, J = 5.4, 9.5, 14.3 Hz, 1H, CH2CHHPh), 4.35 (dt, J = 4.1, 9.5 Hz,
1H, C2–H), 5.34 (d, J = 5.9 Hz, 1H, C5–H), 7.18–7.23 (m, 3H, ArH),
7.28–7.32 (m, 2H, ArH), 7.35 (d, J = 5.9 Hz, 1H, C6–H); 13C NMR
(100 MHz, CDCl3) d 9.8 (CH3), 31.4 (CH2), 31.9 (CH2), 43.7 (CH),
81.0 (CH), 105.6 (CH), 126.2 (CH), 128.4 (CH), 128.5 (CH), 140.7
(C), 162.5 (CH), 197.2 (C); EI-HRMS m/z calcd for C14H16O2 (M+)
216.11503, found 216.11484. The enantiomeric excess of 5c was
determined to be 94% by HPLC with a Chiralcel OD-H column
(9:1 hexane/i-PrOH, 1.0 mL/min): tR = 10.5 min for major enantio-
mer; tR = 18.8 min for minor enantiomer. The preferred absolute
configuration of 5c was not determined.
ware under an argon atmosphere unless otherwise noted. Reagents
and solvents were purified by standard means. Dehydrated CH2Cl2
and THF were purchased from Kanto Chemical Co., Inc. Chiral
dirhodium(II) carboxamidates 2 and ent-2 were prepared accord-
ing to the literature procedure.21a
4.2. Preparation of 4-methyl-substituted Rawal’s diene
4.2.1. 3-tert-Butyldimethylsilyloxy-1-dimethylamino-1,3-penta-
diene 8b
To a solution of NaHMDS in THF (1.0 M, 3.6 mL, 3.6 mmol) was
added a solution of (E)-1-N,N-dimethlyamino-2-penten-3-one 1028
(380 mg, 3.0 mmol) in THF (5 mL) at 40 °C. After stirring for 0.5 h, a
solution of tert-butylchlorodimethylsilane (540 mg, 3.6 mmol) in
THF (5 mL) was added to the reaction mixture, and stirred for
1.5 h. Ether (50 mL) was then added to the mixture, and the result-
ing suspension was filtered through a pad of dry Celite. The filter
cake was washed with ether (100 mL), and the filtrate was concen-
trated in vacuo. The resulting dark orange oil was subjected to
bulb-to-bulb distillation (75–78 °C, 0.3 mmHg) to yield 8b
(590 mg, 81%, 1E,3Z/1E,3E = 74:26) as a light-yellow oil; IR (film)
Data for 4-(tert-butyldimethylsilyloxy)-6-[(E)-40-dimethyl-
amino-10-methyl-20-oxo-30-butenyl]-3-methyl⁄-2-(2-phenylethyl)-
3,6-dihydro-2H-pyran {1:⁄1 mixture of (10R⁄,2R ,3S⁄,6R⁄)-diastereo-
mer and (10S⁄,2R⁄,3S⁄,6R )-diastereomer} 11. TLC Rf = 0.39 (1:1
hexane/EtOAc); IR (film) 2952, 1651, 1626, 1571, 1286,
1201 cmꢀ1; d 0.09 (s, 1.5H, SiCH3), 0.10 (s, 1.5H, SiCH3), 0.16
(s, 1.5H, SiCH3), 0.17 (s, 1.5H, SiCH3), 0.89 (s, 4.5H, SiCCH3), 0.93
(s, 4.5H, SiCCH3), 0.98 (d, J = 7.2 Hz, 1.5H, C3–CH3), 0.99 (d,
J = 6.8 Hz, 1.5H, C3–CH3), 1.04 (d J = 6.8 Hz, 1.5H, C6–CCH3), 1.27
(d J = 6.8 Hz, 1.5H, C6–CCH3), 1.59 (m 1H, CHHCH2Ph), 1.66 (m,
0.5H, CHHCH2Ph), 1.80–1.97 (m, 2H, CHHCH2Ph and C3–H), 2.54
(ddd, J = 4.1, 7.3 13.1 Hz, 0.5H, CH2CHHPh), 2.61 (ddd, J = 3.6, 7.3,
15.8 Hz, 0.5H, CH2CHHPh), 2.73–3.07 (m, 8H, CH2CHHPh, C6–CH
and N(CH3)2), 3.72 (dt, J = 3.6, 9.4 Hz, 0.5H, C2–H), 3.82 (dt,
J = 3.6, 9.1 Hz, 0.5H, C2–H), 4.28 (dd, J = 3.2, 9.4 Hz, 0.5H, C6–H),
4.50 (dd, J = 3.2, 9.1 Hz, 0.5H, C6–H), 4.76 (d, J = 3.2 Hz, 0.5H, C5–
H), 4.85 (d, J = 3.2 Hz, 0.5H, C5–H), 5.01 (d, J = 12.7 Hz, 0.5H,
NC@C–H), 5.07 (d, J = 12.7 Hz, 0.5H, NC@C–H), 7.18–7.28 (m, 3H,
ArH), 7.24–7.31 (m, 2H, ArH), 7.53 (d, J = 12.7 Hz, 0.5H, NC-H),
7.59 (d, J = 12.7 Hz, 0.5H, NC-H); 13C NMR (100 MHz, CDCl3) d
ꢀ4.7 (CH3), ꢀ4.8 (CH3), ꢀ4.3 (CH3), ꢀ4.4 (CH3), 11.31 (CH3),
11.34 (CH3), 14.6 (CH3), 15.6 (CH3), 18.02 (C), 18.04 (C), 25.59
(CH3), 25.64 (CH3), 32.8 (CH2), 32.9 (CH2), 33.8 (CH2), 33.9 (CH2),
37.8 (CH), 38.0 (CH), 44.7 (CH3), 44.8 (CH3), 49.8 (CH3), 50.0
(CH3), 71.1 (CH), 71.7 (CH), 74.5 (CH), 75.3 (CH), 77.17 (C), 77.22
(C), 94.9 (CH), 96.0 (CH), 101.6 (CH), 102.9 (CH), 125.6 (CH),
125.8 (CH), 128.2 (CH), 128.37 (CH), 128.40 (CH), 128.42 (CH),
142.3 (C), 142.7 (C), 152.5 (C), 152.6 (C), 153.2 (CH), 154.0 (CH),
199.49 (C), 199.53 (C) EI-HRMS m/z calcd for C27H43NO3Si (M+)
457.30122, found 457.30274. In order to assign the stereochemis-
try at C2 and C6, NOE studies were performed on 11. Irradiation of
C2–H showed an NOE with C10–H (8.8%). Additionally, irradiation
of C10–H exhibited an NOE with the C2–H (10.0%). These data
revealed trans-relationship between C2–H and C6–CH.
2929, 2885, 2797, 1650, 1472, 1352, 1254 cmꢀ1
;
1H NMR
(500 MHz, C6D6) d 0.26 (s, 6H, Si(CH3)2, Z), 0.28 (s, 6H, Si(CH3)2,
E), 1.12 (s, 9H, SiC(CH3)3, E), 1.14 (s, 9H, SiC(CCH3)2, Z), 1.81 (d,
J = 7.2, 3H, C5–H3, E), 1.83 (d, J = 7.2 Hz, C5–H3, Z), 2.31 (s, 9H,
N(CH3)2, Z), 2.35 (s, 9H, N(CH3)2, E), 4.69 (q, J = 7.2 Hz, 1H, C4–H,
E), 4.70 (q, J = 7.2 Hz, 1H, C4–H, Z), 4.95 (d, J = 13.1 Hz, 1H, C2-H,
Z), 5.15 (d, J = 13.1 Hz, 1H, C2–H, E), 6.51 (d, J = 13.1 Hz, 1H,
C2–H, Z), 6.83 (d, J = 13.1 Hz, 1H, C2–H, E); 13C NMR (100 MHz,
C6D6) d ꢀ3.5 (CH3, E), ꢀ2.7 (CH3, Z), 12.4 (C, E), 12.6 (C, Z), 19.2
(CH3, Z), 19.4 (CH3, E), 26.9 (CH2, E), 26.9 (CH2, Z), 40.9 (CH3, E),
40.9 (CH3, Z), 93.6 (CH, E), 93.6 (CH, Z), 96.8 (CH, Z), 99.6 (CH, E),
99.6 (CH, Z), 100.0 (CH, E), 140.1 (CH, E), 141.2 (CH, Z), 150.6 (C,
E), 150.9 (C, Z); EI-HRMS m/z calcd for
C
13H13NO2Si (M+)
241.1862, found 241.1870. In order to assign the stereochemistry
of the major isomer, NOE studies were performed on 8b. Irradia-
tion of C4–CH3 showed an NOE with Si(CH3)2 (1.0%). Additionally,
irradiation of Si(CH3)2 exhibited NOE with the C4–CH3 (1.0%).
These data revealed the cis-relationship between C4–CH3 and the
tert-butyldimethylsilyloxy group.
4.3. Enantioselective HDA reaction between 4-methyl-substituted
Rawal’s diene and aldehydes using acetyl chloride work-up
4.3.1. (2R⁄,3S⁄)-3-Methyl-2-(2-phenylethyl)-2,3-dihydro-4H-pyran-
4-one 5c
A solution of diene 8b (109 mg, 0.45 mmol, Z/E = 74:26) in
CH2Cl2 (0.3 mL) was added to a solution of hydrocinnamaldehyde
4c (40.2 mg, 0.30 mmol) and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg,
0.009 mmol, 3 mol %) in CH2Cl2 (0.3 mL) at ꢀ20 °C. After stirring
at this temperature for 6 h, the whole mixture was cooled to
ꢀ78 °C and treated dropwise with a 1 M solution of AcCl in CH2Cl2
(0.60 mL, 0.60 mmol). After stirring for 30 min, the reaction was
quenched with saturated NaHCO3 (3 mL) and extracted with EtOAc
(2 ꢃ 10 mL). The combined organic layers were washed with water
(3 mL) and brine (2 ꢃ 3 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product,
which was purified by column chromatography (silica gel, 6:1 to
1:1 hexane/EtOAc) to provide 5c (24.1 mg, 37%) as a colorless oil
and 11 (56.2 mg, 40%) as a colorless oil.
4.4. Diels–Alder reaction between 4-methyl-substituted Rawal’s
diene and DMAD: dimethyl 4-tert-butyldimethylsilyloxy-3-
methylbenzene-1,2-dicarboxylate 15
To a solution of diene 8b (54.4 mg, 0.20 mmol) in CH2Cl2
(0.4 mL) was added a solution of dimethyl acetylenedicarboxylate
(56.8 mg, 0.40 mmol) in CH2Cl2 (0.4 mL) at 0 °C. After stirring for
10 min, the reaction mixture was concentrated in vacuo. The crude
product was purified by column chromatography (silica gel, 9:1
hexane/EtOAc) to provide 15 (56.9 mg, 84%) as a yellow oil; TLC
Rf = 0.41 (4:1 hexane/EtOAc); IR (film) 2953, 1740, 1724, 1588,
1278, 1257, 1193 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.24 (s, 6H,
;
Si(CH3)2), 1.00 (s, 9H, SiCCH3), 2.15 (s, 3H, C3–CH3), 3.85 (s, 3H,
CO2CH3), 3.94 (s, 3H, CO2CH3), 6.80 (d, J = 8.6 Hz, 1H, C5–H), 7.77
(d, J = 8.6 Hz, 1H, C6–H); 13C NMR (100 MHz, CDCl3) d ꢀ4.2 (CH3),
13.2 (CH3), 18.2 (C), 25.6 (CH3), 52.2 (CH3), 52.5 (CH3), 118.2
(CH), 119.6 (C), 126.5 (C), 129.3 (CH), 137.7 (CH), 158.1 (C), 165.9
(C), 169.8 (C); EI-HRMS m/z calcd for C17H26O5Si (M+) 338.1550,
found 338.1548.
Data for 5c. TLC Rf = 0.35 (4:1 hexane/EtOAc); ½a D19
¼ þ96:4 (c
ꢁ
1.04, CHCl3) for 94% ee; IR (film) 2949, 1676, 1596, 1454, 1404,
1265 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.09 (d, J = 7.3 Hz, 3H,
;
C3–CH3), 1.82 (ddt, J = 3.6, 7.2, 9.5, 14.0 Hz, 1H, CHHCH2Ph), 2.18
(ddt, J = 5.4, 9.5, 14.0, 1H, CHHCH2Ph), 2.36 (dq, J = 4.1, 7.3 Hz,

Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
69
4.5. General procedure for the enantioselective HDA reaction
between 4-methyl-substituted Rawal’s diene and aldehydes
for the major enantiomer. The preferred absolute configuration of
5e was not determined.
4.5.1. (2R⁄,3S⁄)-3-Methyl-2-(2-phenylethyl)-2,3-dihydro-4H-
pyran-4-one 5c
4.5.4. (2S⁄,3S⁄)-3-Methyl-2-[(E)-2-phenylethenyl]-2,3-dihydro-4H-
pyran-4-one 5f40
A solution of diene 8b (109 mg, 0.45 mmol, Z/E = 74:26) in
CH2Cl2 (0.3 mL) was added to a solution of hydrocinnamaldehyde
4c (40.2 mg, 0.30 mmol) and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg,
0.009 mmol, 3 mol %) in CH2Cl2 (0.3 mL) at ꢀ20 °C. After stirring
at this temperature for 6 h, a solution of dimethyl acetylenedicar-
boxylate (DMAD) (42.6 mg, 0.3 mmol) in CH2Cl2 (0.6 mL) was
added and the mixture was stirred at 0 °C for 10 min. The whole
mixture was cooled to ꢀ78 °C and treated dropwise with a 1 M
solution of AcCl in CH2Cl2 (0.60 mL, 0.60 mmol). After stirring for
ca. 30 min, the reaction was quenched with saturated NaHCO3
(3 mL) and extracted with EtOAc (2 ꢃ 10 mL). The combined
organic layers were washed with water (3 mL) and brine
(2 ꢃ 3 mL), and dried over anhydrous Na2SO4. Filtration and evap-
oration in vacuo furnished the crude product, which was purified
by column chromatography (silica gel 5 g, 9:1 hexane/EtOAc) to
provide 5c (42.1 mg, 97%) as a colorless oil and 15 (39.6 mg, 26%
based on 8b) as a colorless oil.
According to the general procedure, 5f was prepared from diene
8b (109 mg, 0.45 mmol, Z/E = 74:26), trans-cinnamaldehyde 5f
(39.6 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2 (12.9 mg,
0.009 mmol, 3 mol %) at ꢀ20 °C. The crude product was purified
by column chromatography (silica gel, 9:1 hexane/EtOAc) to pro-
vide 5f (47.4 mg, 74%) as a yellow oil; TLC Rf = 0.57 (2:1 hexane/
EtOAc);
½
a 2D2
ꢁ
¼ þ170:1 (c 1.05, CHCl3) for 83% ee; 1H NMR
(400 MHz, CDCl3) d 1.14 (d, J = 7.2 Hz, 3H, C3–CH3), 2.62 (ddd,
J = 3.6, 7.2, 14.5 Hz, 1H, C3–H), 5.07 (ddd, J = 0.9, 3.6, 6.3 Hz, 1H,
C2–H), 5.42 (dd, J = 0.9, 5.9 Hz, 1H, C5–H), 6.27 (dd, J = 6.3,
15.8 Hz, 1H, CH@CHPh), 6.75 (d, J = 15.8 Hz, 1H, CH@CHPh),
7.26–7.43 (m, 6H, Ar and C6–H). The enantiomeric excess of 5f
was determined to be 83% by HPLC with a Chiralcel OD-H column
(9:1 hexane/i-PrOH, 1.0 mL/min): tR = 11.1 min for the major enan-
tiomer; tR = 16.1 min for the minor enantiomer. The preferred
absolute configuration of 5f was not determined.
4.5.5. (2S,3S)-3-Methyl-2-phenyl-2,3-dihydro-4H-pyran-4-one
5g3a
According to the general procedure, 5g was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), benzaldehyde 4g
4.5.2. (2R,3S)-3-Methyl-2-pentyl-2,3-dihydro-4H-pyran-4-one
5d
According to the general procedure, 5d was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), hexanal 4d (30.0 mg,
0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg, 0.009 mmol,
3 mol %) at ꢀ20 °C. The crude product was purified by column
chromatography (silica gel, 9:1 hexane/EtOAc) to provide 5d
(52.1 mg, 95%) as a colorless oil; TLC Rf = 0.40 (4:1 hexane/EtOAc);
(31.8 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2 (12.9 mg,
0.009 mmol, 3 mol %) at ꢀ20 °C. The crude product was purified
by column chromatography (silica gel, 9:1 hexane/EtOAc) to pro-
vide 5g (55.2 mg, 98%) as a coloress oil; TLC Rf 0.34 (4:1 hexane/
EtOAc); ½a 2D1
ꢁ
¼ ꢀ4:2 (c 1.12, CHCl3) for 94% ee; ½a D21
¼ ꢀ17:3 (c
ꢁ
½
a 2D2
ꢁ
¼ þ139:6 (c 1.22, CHCl3) for 92% ee; IR (film) 2935, 1681,
1.04, C6H6); 1H NMR (400 MHz, CDCl3) d 0.93 (d, J = 7.3 Hz 3H,
C3–CH3), 2.59 (dddd, J = 1.4, 3.2, 7.3, 16.9 Hz, 1H, C3–H), 5.47 (dd,
J = 1.4, 5.9 Hz, 1H, C5–H), 5.53 (d, J = 3.2 Hz, 1H, C2-H), 7.32ꢀ7.35
(m, 3H, ArH), 7.39ꢀ7.43 (m, 2H, ArH), 7.51 (d, J = 5.9 Hz, 1H, C6–
H). The enantiomeric excess of 5g was determined to be 94% by
HPLC with a Chiralcel OD-H column (9:1 hexane/i-PrOH, 1.0 mL/
min): tR (major) = 8.9 min for the (2S,3S)-enantiomer; tR (min-
or) = 10.2 min for the (2R,3R)-enantiomer.
1597 cmꢀ1; 1H NMR (400 MHz, CDCl3) d 0.91 (t, J = 7.2 Hz, 3H, CH2-
CH3), 1.07 (d, J = 7.2 Hz, 3H, C3–CH3), 1.33–1.58 (m, 7H, CHHCH2-
CH2CH2CH3), 1.83 (m, 1H, C2–CHH), 2.36 (ddd, J = 3.6, 7.6,
15.3 Hz, 1H, C3–H), 4.34 (m, 1H, C2–H), 5.33 (d, J = 5.8 Hz, 1H,
C5–H), 7.32 (d, J = 5.8 Hz, 1H, C6–H); 13C NMR (100 MHz, CDCl3)
d 9.5 (CH3), 13.7 (CH3), 22.4 (CH2), 24.8 (CH2), 30.0 (CH2), 31.4
(CH2), 43.6 (CH), 82.1 (CH), 105.4 (CH), 162.7 (CH), 197.6 (C@O);
EI-HRMS calcd for C11H18O2 (M)+ 182.13068, found 182.13038.
The enantiomeric excess of 5d was determined to be 92% by HPLC
with a Chiralcel OD-H column (19:1 hexane/i-PrOH, 1.0 mL/min):
tR(major) = 5.6 min for the (2R,3S)-enantiomer; tR(minor) = 6.1 min
for the (2S,3R)-enantiomer.
4.5.6. (2S⁄,3S⁄)-3-Methyl-2-(4-methylphenyl)-2,3-dihydro-4H-
pyran-4-one 5h
According to the general procedure, 5h was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), p-tolualdehyde 4h
(36.0 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2 (12.9 mg,
4.5.3. (2R⁄,3S⁄)-2-(2-Benzyloxyethyl)-3-methyl-2,3-dihydro-4H-
pyran-4-one 5e
0.009 mmol, 3 mol %) at ꢀ20 °C. The crude product was purified
by column chromatography (silica gel, 9:1 hexane/EtOAc) to pro-
vide 5h (55.2 mg, 91%) as a white solid; mp 71.0–72.5 °C; TLC
According to the general procedure, 5e was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), 3-benzyloxypropional-
dehyde 4e (49.3 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O 2
(12.9 mg, 0.009 mmol, 3 mol %) at ꢀ20 °C. The crude product was
purified by column chromatography (silica gel, 9:1 hexane/EtOAc)
to provide 5e (67.9 mg, 92%) as a colorless oil; TLC Rf = 0.43 (2:1
Rf = 0.38 (4:1 hexane/EtOAc); ½a D23
¼ þ12:0 (c 1.17, CHCl3) for
ꢁ
85% ee; IR (film) 1674, 1598, 1267 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.94 (d, J = 7.7 Hz, 3H, C3–CH3), 2.37 (s, 3H, Ar–CH3), 2.57 (dq,
J = 1.4, 7.7 Hz, 1H, C3–H), 5.46 (dd, J = 1.4, 5.8 Hz, 1H, C2–H), 5.50
(d, J = 3.6 Hz, 1H, C5–H), 7.22–7.26 (m, 4H, Ar), 7.49–7.51 (d,
J = 3.6 Hz, 1H, C6–H); 13C NMR (100 MHz, CDCl3) d 9.9 (CH3), 21.1
(CH3), 46.0 (CH), 83.1 (CH), 105.7 (CH), 125.4 (C), 129.2 (CH),
133.3 (C), 137.8 (C), 162.6 (CH), 197.5 (C@O); EI-HRMS m/z calcd
for C13H14O2 (M)+ 202.09938, found 202.09943. The enantiomeric
excess of 5h was determined to be 97% by HPLC with a Chiralcel
OD-H column (19:1 hexane/i-PrOH, 1.0 mL/min): tR = 8.8 min for
the major enantiomer; tR = 10.6 min for the minor enantiomer.
The preferred absolute configuration of 5h was not determined.
hexane/EtOAc); ½a D22
ꢁ
¼ þ79:0 (c 1.03, CHCl3) for 90% ee; IR (film)
1674, 1595, 1269, 1217 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 1.09
(d, J = 7.4 Hz, 3H, C3–CH3), 1.86 (m, 1H, C2–CHH), 2.10 (m, 1H,
C2–CHH), 2.38 (dddd, J = 1.1, 3.4, 7.4, 14.9 Hz, 1H, C3–H), 3.62
(m, 2H, C2–CH2CH2), 4.51 (s, 2H, PhCH2O), 4.61 (dt, J = 3.4,
9.2 Hz, 1H, C2–H), 5.34 (d, J = 6.3 Hz, 1H, C5–H), 7.27–7.37 (m,
6H, Ar and C6–H); 13C NMR (100 MHz, CDCl3) d 9.6 (CH3), 30.5
(CH2), 43.6 (CH), 65.6 (CH2), 73.0 (CH2), 78.9 (CH), 105.5 (CH),
127.5 (CH), 127.6 (CH), 128.3 (CH), 137.9 (C), 162.4 (CH), 197.1
(C@O); EI-HRMS calcd for
C
14H15O3 (M)+ 231.10212, found
4.5.7. (2S⁄,3S⁄)-2-(4-Chlorophenyl)-3-methyl-2,3-dihydro-4H-
pyran-4-one 5i
According to the general procedure, 5i was prepared from diene
8b (109 mg, 0.45 mmol, Z/E = 74:26), p-chlorobenzaldehyde 4i
231010182. The enantiomeric excess of 5e was determined to be
92% by HPLC with a Chiralcel OD-H column (9:1 hexane/i-PrOH,
1.0 mL/min): tR = 10.1 min for the minor enantiomer; tR = 11.2 min

70
Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
(42.2 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2
(12.9 mg,
1H, PhCHHO), 4.63 (d, J = 12.2 Hz, 1H, PhCHHO), 5.36 (dd, J = 0.9,
5.8 Hz, 1H, C5–H), 7.30–7.39 (m, 6H, Ar and C6–H); The enantio-
meric excess of 5k was determined to be 91% by HPLC with a Chi-
ralcel OD-H column (19:1 hexane/i-PrOH, 1.0 mL/min):
tR = 16.8 min for the major enantiomer; tR = 18.5 min for the minor
enantiomer. The preferred absolute configuration of 5k was not
determined.
0.009 mmol, 3 mol %) at ꢀ40 °C. The crude product was purified
by column chromatography (silica gel, 9:1 hexane/EtOAc) to pro-
vide 5i (59.5 mg, 89%) as a yellow solid; mp 69.0–70.0 °C; TLC
Rf = 0.33 (4:1 hexane/EtOAc); ½a D23
¼ þ5:57 (c 1.02, CHCl3) for
ꢁ
90% ee; IR (film) 1681, 1599, 1267 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.92 (d, J = 7.2 Hz, 3H, C3–CH3), 2.56 (dq, J = 1.4, 7.2 Hz, 1H, C3–
H), 5.48 (dd, J = 1.4, 5.8 Hz, 1H, C2–H), 5.50 (d, J = 3.6 Hz, 1H, C5–
H), 7.28–7.41 (m, 3H, Ar and C6–H), 7.49–7.51 (m, 2H, Ar); 13C
NMR (100 MHz, CDCl3) d 9.8 (CH3), 45.8 (CH), 82.3 (CH), 105.9
(CH), 126.8 (C), 128.8 (CH), 133.9 (C), 134.8 (C), 162.3 (CH), 196.9
(C@O); EI-HRMS m/z calcd for C12H11ClO2 (M)+ 222.04476, found
222.94485. The enantiomeric excess of 5i was determined to be
90% by HPLC with a Chiralcel OD-H column (9:1 hexane/i-PrOH,
1.0 mL/min): tR = 7.9 min for the major enantiomer; tR = 11.5 min
for the minor enantiomer. The preferred absolute configuration
of 5i was not determined.
4.5.11. (2S⁄,3S⁄)-3-Methyl-2-(2-phenylethynyl)-2,3-dihydro-4H-
pyran-4-one 5l
According to the general procedure, 5l was prepared from diene
8b (109 mg, 0.45 mmol, Z/E = 74:26), phenylpropargylaldehyde 4b
(39.0 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2 (12.9 mg,
0.009 mmol, 3 mol %) at ꢀ78 °C. The crude product was purified
by column chromatography (silica gel, 9:1 hexane/EtOAc) to pro-
vide 5l (52.2 mg, 82%) as a colorless oil; TLC Rf = 0.23 (4:1 hex-
ane/EtOAc); ½a 2D1
ꢁ
¼ þ447 (c 1.03, CHCl3) for 97% ee; IR (KBr)
2224, 1684, 1597, 1240, 1011 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d
4.5.8. (2R⁄,3S⁄)-3-Methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-
pyran-4-one 5a21a
1.31 (d, J = 7.1 Hz, 3H, C3–CH3), 2.81 (dq, J = 4.7, 7.1 Hz, 1H, C3–
H), 5.40 (d, J = 4.7 Hz, 1H, C2–H), 5.46 (d, J = 6.0 Hz, 1H, C5–H),
7.29–7.36 (m, 4H, Ar and C6–H), 7.44–7.48 (m, 2H, Ar); 13C NMR
(100 MHz, CDCl3) d 10.5 (CH3), 44.2 (CH), 73.5 (CH), 82.0 (C),
88.7 (C), 106.6 (CH), 121.3 (C), 128.3 (CH), 129.1 (CH), 131.9
(CH), 160.8 (CH), 194.1 (C@O); EI-HRMS m/z calcd for C14H11O2
(MꢀH)+ 211.0759, found 211.0764. The enantiomeric excess of 5l
was determined to be 97% by HPLC with a Chiralcel OD-H column
(9:1 hexane/i-PrOH, 0.5 mL/min): tR = 16.3 min for the major enan-
tiomer; tR = 19.0 min for the minor enantiomer. The preferred
absolute configuration of 5l was not determined.
According to the general procedure, 5a was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), p-nitrobenzaldehyde
4a (45.0 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg,
0.009 mmol, 3 mol %) at ꢀ60 °C. The crude product was purified
by column chromatography (silica gel, 4:1 hexane/EtOAc) to pro-
vide 5a (64.9 mg, 93%) as a yellow solid; mp 146.0–147.0 °C; TLC
Rf = 0.44 (2:1 hexane/EtOAc); ½a D20
¼ ꢀ14:1 (c 1.02, CHCl3) for
ꢁ
98% ee [lit.,20a
[
a]
D = ꢀ13.5 (c 0.90, CHCl3) for 96% ee]; 1H NMR
(400 MHz, CDCl3) d 0.92 (d, J = 7.4 Hz, 3H, C3–CH3), 2.65 (dq,
J = 2.8, 7.4 Hz, 1H, C3–H), 5.53 (d, J = 6.0 Hz, 1H, C5–H), 5.62 (d,
J = 2.8 Hz, 1H, C2–H), 7.52–7.57 (m, 3H, Ar and C6–H), 8.30 (m,
2H, Ar); The enantiomeric excess of 5a was determined to be 98%
by HPLC with a Chiralcel OD-H column (3:1 hexane/i-PrOH,
1.0 mL/min): tR = 10.4 min for major enantiomer; tR = 15.6 min
for the minor enantiomer. The preferred absolute configuration
of 5a was not determined.
4.5.12. (2S⁄,3S⁄)-3-Methyl-2-(1-heptynyl)-2,3-dihydro-4H-
pyran-4-one 5m
According to the general procedure, 5m was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), 2-octynal 4l (37.3 mg,
0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg, 0.009 mmol,
3 mol %) at ꢀ78 °C. The crude product was purified by column
chromatography (silica gel, 19:1 hexane/EtOAc) to provide 5m
(52.6 mg, 85%) as a colorless oil; TLC Rf = 0.50 (4:1 hexane/EtOAc);
4.5.9. (2S⁄,3S⁄)-2-Furyl-3-methyl-2,3-dihydro-4H-pyran-4-one 5j40
According to the general procedure, 5j was prepared from diene
8b (109 mg, 0.45 mmol, Z/E = 74:26), 2-furfural 4j (28.8 mg,
0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg, 0.009 mmol,
3 mol %) at ꢀ40 °C. The crude product was purified by column
chromatography (silica gel, 9:1 hexane/EtOAc) to provide 5j
(44.3 mg, 83%) as a coloress oil; TLC Rf = 0.57 (2:1 hexane/EtOAc);
½
a 2D4
ꢁ
¼ þ256 (c 1.13, CHCl3) for 91% ee; IR (KBr) 2224, 1681, 1599,
1264 cmꢀ1; 1H NMR (400 MHz, CDCl3) d 0.90 (t, J = 7.2 Hz, 3H, CH2-
CH3), 1.21–1.55 (m, 9H, C3–CH3 and CH2CH2CH2CH3), 2.23 (dt,
J = 2.3, 7.3 Hz, 2H, C„CCH2), 2.68 (dq, J = 4.5, 7.2 Hz, 1 H, C3–H),
5.16 (dt, J = 1.8, 4.5 Hz, 1H, C2–H), 5.41 (d, J = 5.9 Hz, 1H, C5–H),
7.25 (d, J = 5.9 Hz, 1H, C6–H); 13C NMR (100 MHz, CDCl3) d 10.3
(CH3), 13.9 (CH3), 18.5 (CH2), 22.0 (CH2), 27.9 (CH2), 30.9 (CH2),
44.2 (CH), 73.3 (CH), 73.4 (C), 90.1 (C), 106.4 (CH), 160.9 (CH)
194.7 (C@O); EI-HRMS m/z calcd for C13H17O2 (M)+ 205.12285,
found 205.12306. The enantiomeric excess of 5m was determined
to be 91% by HPLC with a Chiralcel OD-H column (50:1 hexane/i-
PrOH, 1.0 mL/min): tR = 6.0 min for the minor enantiomer;
tR = 7.6 min for the major enantiomer. The preferred absolute con-
figuration of 5m was not determined.
½
a 2D1
ꢁ
¼ þ403 (c 1.02, CHCl3) for 96% ee; 1H NMR (400 MHz, CDCl3)
d 1.10 (d, J = 7.2 Hz, 3H, C3–CH3), 2.93 (dq, J = 5.0, 7.2 Hz, 1H,
C3–H), 5.45 (d, J = 5.0 Hz, 1H, C2–H), 5.46 (d, J = 4.5 Hz, 1H,
C5–H), 6.37–6.39 (m, 2H, Ar), 7.30 (d, J = 4.5 Hz, 1H, C6–H), 7.42
(m, 1H, Ar); The enantiomeric excess of 5j was determined to be
96% by HPLC with a Chiralcel OD-H column (19:1 hexane/i-PrOH,
1.0 mL/min): tR = 11.9 min for the minor enantiomer; tR = 12.7 min
for the major enantiomer. The preferred absolute configuration of
5j was not determined.
4.5.13. (2R⁄,3S⁄)-2-Cyclohexyl-3-methyl-2,3-dihydro-4H-pyran-
4-one 5n3a
According to the general procedure, 5n was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), cyclohexanecarbalde-
4.5.10. (2R⁄,3S⁄)-2-(2-Benzyloxymethyl)-3-methyl-2,3-dihydro-
4H-pyran-4-one 5k41
According to the general procedure, 5k was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), benzyloxyacetaldehyde
4k (45.1 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O 2 (12.9 mg,
0.009 mmol, 3 mol %) at ꢀ40 °C. The crude product was purified
by column chromatography (silica gel, 9:1 hexane/EtOAc) to pro-
vide 5k (56.3 mg, 81%) as a colorless oil; TLC Rf = 0.47 (2:1 hex-
hyde 4m (33.6 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2
(12.9 mg, 0.009 mmol, 3 mol %) at 23 °C. The crude product was
purified by column chromatography (silica gel, 9:1 hexane/EtOAc)
to provide 5n (36.7 mg, 63%) as a colorless oil; TLC Rf = 0.39 (4:1
hexane/EtOAc); ½a D22
ꢁ
¼ þ69:4 (c 1.36, CHCl3) for 40% ee; 1H NMR
ane/EtOAc); ½a 2D2
ꢁ
¼ þ91:9 (c 1.23, CHCl3) for 91% ee; 1H NMR
(400 MHz, CDCl3) d
0.88–1.29 (m, 8H, C3–CH3 and cC6H11),
c
(400 MHz, CDCl3) d 1.06 (d, J = 7.2 Hz, 3H, C3–CH3), 1.86 (ddq,
J = 0.9, 3.6, 7.2 Hz, 1H, C3–H), 3.60 (dd, J = 4.5, 10.3 Hz, 1H, C2–
CHH), 3.81 (dd, J = 7.2, 10.3 Hz, 1H, C2–CHH), 4.56 (d, J = 12.2 Hz,
1.62–1.77 (m, 5H, C6H11), 2.15 (m, 1H, C2–CH), 2.41 (ddq, J = 1.4,
3.2, 7.7 Hz, 1H, C3–H), 3.94 (dd, J = 3.2, 10.4 Hz, 1H, C2–H), 5.32
(dd, J = 1.4, 5.9 Hz, 1H, C5–H), 7.35 (d, J = 5.9 Hz, 1H, C6–H);

Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
71
The enantiomeric excess of 5n was determined to be 40% by HPLC
with a Chiralcel OD-H column (9:1 hexane/i-PrOH, 0.5 mL/min):
tR = 10.2 min for the major enantiomer; tR = 11.6 min for the minor
enantiomer. The preferred absolute configuration of 5n was not
determined.
CH2Cl2 (0.3 mL) at ꢀ20 °C. After stirring at this temperature for
6 h, a solution of DMAD (426 mg, 3.0 mmol) in CH2Cl2 (6.0 mL)
was added and the mixture was stirred at 0 °C for 10 min. The mix-
ture was cooled to ꢀ78 °C and treated dropwise with a 1 M solu-
tion of AcCl in CH2Cl2 (6.0 mL, 6.0 mmol). After stirring for
30 min, the reaction was quenched with saturated aqueous
NaHCO3 (8 mL), and the whole mixture was extracted with EtOAc
(2 ꢃ 30 mL). The combined organic layers were washed with water
(8 mL) and brine (2 ꢃ 8 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product,
which was purified by column chromatography (silica gel, 9:1 hex-
ane/EtOAc) to provide ent-5d (514 mg, 94%) as a colorless oil;
4.5.14. (2S⁄,3S⁄)-2-(4-Methoxyphenyl)-3-methyl-2,3-dihydro-4H-
pyran-4-one 5o
According to the general procedure, 5o was prepared from
diene 8b (109 mg, 0.45 mmol, Z/E = 74:26), p-anisaldehyde 4n
(40.8 mg, 0.30 mmol), and Rh2((S)-BPTPI)4ꢂ3H2O
2 (12.9 mg,
0.009 mmol, 3 mol %) at 0 °C. The crude product was purified by
column chromatography (silica gel, 6:1 hexane/EtOAc) to provide
½
a 2D2
ꢁ
¼ ꢀ140:1 (c 1.03, CHCl3) for 92% ee; The enantiomeric excess
5o (39.8 mg, 61%) as
a
white solid; mp 63.0–65.0 °C; TLC
of ent-5d was determined to be 92% by HPLC with a Chiralcel OD-H
column (19:1 hexane/i-PrOH, 1.0 mL/min): tR = 5.6 min for (2R,3S)-
enantiomer; tR = 6.1 min for (2S,3R)-enantiomer.
Rf = 0.27 (4:1 hexane/EtOAc); ½a D21
¼ þ10:7 (c 1.13, CHCl3) for
ꢁ
29% ee; IR (KBr) 1666, 1599, 1252 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.95 (d, J = 7.2 Hz, 3H, C3–CH3), 2.56 (ddq, J = 1.4, 3.2, 7.2 Hz, 1H,
C3–H), 3.83 (s, 3H, ArO–CH3), 5.46 (dd, J = 1.4, 5.9 Hz, 1H, C5–H),
5.49 (d, J = 3.2 Hz, 1H, C2–H), 6.93–6.95 (m, 2H, Ar), 7.26–7.28
(m, 2H, Ar), 7.50 (d, J = 5.9 Hz, 1H, C6–H); 13C NMR (100 MHz,
CDCl3) d 9.9 (CH3), 46.1 (CH), 55.3 (CH3), 82.9 (CH), 105.7 (CH),
114.1 (CH), 126.8 (CH), 128.8 (CH), 160.1 (C), 162.6 (CH), 197.6
(C@O); EI-HRMS m/z calcd for C13H14O3 (M)+ 218.09429, found
218.09408. The enantiomeric excess of 5o was determined to be
29% by HPLC with a Chiralcel OD-H column (9:1 hexane/i-PrOH,
1.0 mL/min): tR = 10.7 min for the major enantiomer; tR = 12.8 min
for the minor enantiomer. The preferred absolute configuration of
5o was not determined.
4.7.2. (2S,3S,4S)-3-Methyl-2-pentyl-3,4-dihydro-2H-pyran-4-ol 18
To a solution of ent-5d (514 mg, 2.8 mmol) and CeCl3ꢂ7H2O
(2.68 g, 7.2 mmol) in EtOH (30 mL) was added NaBH4 (227 mg,
6.0 mmol) at ꢀ10 °C. After stirring at this temperature for 4 h,
the reaction was poured into water (20 mL), and the whole mixture
was extracted with EtOAc (2 ꢃ 60 mL). The combined organic lay-
ers were washed with brine (20 mL) and dried over anhydrous Na2-
SO4. Filtration and evaporation in vacuo followed by column
chromatography (silica gel, 7:1 hexane/EtOAc) provided 18
(438 mg, 91%) as a colorless oil. TLC Rf = 0.60 (2:1 hexane/EtOAc);
½
a 2D2
ꢁ
¼ ꢀ6:3 (c 1.03, CHCl3) for 92% ee; IR (film) 3366, 2934,
1644, 1228 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 0.88ꢀ0.93 (m, 6H,
4.6. Determination of the absolute configuration of 5g
CH2CH3 and C3–CH3), 1.31–1.58 (m, 7H, CHHCH2CH2CH2CH3),
1.71 (m, 1H, C2–CHH), 2.00 (dtt, J = 1.8, 7.2, 13.6 Hz, 1H, C3–H),
3.90 (ddd, J = 1.8, 4.1, 8.6 Hz, 1H, C2–H), 4.53 (d, J = 7.2 Hz, 1H,
C4–H), 4.59 (dt, J = 1.8, 6.3 Hz, 1H, C5–H), 6.31 (dd, J = 1.8, 6.3 Hz,
1H, C6–H); 13C NMR (100 MHz, CDCl3) d 5.3 (CH3), 14.0 (CH3),
22.5 (CH2), 25.5 (CH2), 31.5 (CH2), 31.7 (CH2), 35.3 (CH), 66.4
(CH), 78.3 (CH), 103.3 (CH), 144.7 (CH); EI-HRMS calcd for
4.6.1. (2S,3S)-Methyl 2-hydroxy-2-methyl-3-phenylpropionate 1633
Ozone was bubbled through
a solution of 5g (20.0 mg,
0.11 mmol) in CH2Cl2 (2 mL) and MeOH (2 mL) at ꢀ78 °C for
10 min. After ozonolysis, the reaction was purged with O2 for
5 min, and Me2S (31 mg, 0.5 mmol) was added. The mixture was al-
lowed to warm to 23 °C for 4 h. Next, LiOH (21.0 mg 0.5 mmol) and
30% solution of H2O2 in water (0.10 mL, 1.0 mmol) were added to the
reaction mixture, and the mixture was stirred overnight. The mix-
ture was acidified with 1 M hydrochloric acid (3 mL), and extracted
with EtOAc (2 ꢃ 10 mL). The organic layer was washed with water
(3 mL) and brine (3 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product (17.2 mg) as
a white solid, which was used without further purification.
C
11H19O2 (MꢀH)+ 183.13850, found 183.13848.
4.7.3. (2S,3S)-3-Methyl-2-pentyl-2,3-dihydro-2H-pyran-6-one 19
To a solution of 18 (236 mg, 1.3 mmol) in THF/H2O (9:1,
130 mL) was added ( )-camphorsulfonic acid (149 mg, 0.64 mmol)
at 23 °C and the mixture was stirred at 65 °C for 2 h. The reaction
was quenched with saturated aqueous NaHCO3 (5 mL) and the
whole mixture was extracted with EtOAc (60 mL). The organic lay-
ers were washed with water (20 mL) and brine (2 ꢃ 20 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product, which was used without further
purification.
To a solution of the crude acid in toluene (0.9 mL) and MeOH
(0.1 mL) was added trimethylsilyldiazomethane (2 M in Et2O,
0.07 mL, 0.14 mmol) at 23 °C. After stirring at this temperature
for 1 h, the reaction mixture was concentrated in vacuo and the
residue was purified by column chromatography (silica gel, 4:1
hexane/EtOAc) to afford 16 (11.8 mg, 61%) as a colorless oil; TLC
N-Methylmorpholine-N-oxide (247 mg, 2.2 mmol) was added
to a mixture of crude hemiacetal (194 mg, 1.1 mmol) and MS 4 Å
(550 mg) in CH2Cl2 (10 mL) at 23 °C. After stirring for 10 min, tet-
rapropylammonium perruthenate (17.6 mg, 0.05 mmol) was
added and the mixture was stirred for an additional 3 h. The reac-
tion mixture was passed through a short plug of silica gel and the
filtrate was concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel, 9:1 hexane/EtOAc) to afford 19
(150 mg, 77%) as a colorless oil; TLC Rf = 0.33 (4:1 hexane/EtOAc);
Rf = 0.48 (1:1 hexane/EtOAc); ½a D22
¼ ꢀ18:4 (c 0.59, CHCl3) for
ꢁ
94% ee {lit.,33
½
a 2D0
ꢁ
¼ ꢀ19:3 (c 1.74, CHCl3) for the (2S,3S)-enantio-
mer}; 1H NMR (400 MHz, CDCl3) d 1.12 (d, J = 7.4 Hz, 3H, C2–CH3),
2.79 (dq, J = 4.0, 7.4 Hz, 1H, C2–H), 2.94 (br, 1H, OH), 3.67 (s, 3H,
OCH3), 5.10 (d, J = 4.0 Hz, 1H, C3–H), 7.25–7.33 (m, 5H, Ar). This
product 16 exhibited spectroscopic data identical to (2S,3S)-16.33
Thus, the preferred absolute stereochemistry of 5g was determined
to be (2S,3S).
½
a 2D2
ꢁ
¼ ꢀ180 (c 1.04, CHCl3) for 92% ee; IR (film) 2934, 1718,
1250 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.90 (t, J = 7.2 Hz, 3H,
;
4.7. Asymmetric synthesis of (ꢀ)-cis-aerangis lactone 17
CH2CH3), 1.03 (d, J = 6.8 Hz, 3H, C3–CH3), 1.25–1.58 (m, 7H,
CHHCH2CH2CH2CH3), 1.81 (m, 1H, C2–CHH), 2.36 (m, 1H, C3–H),
4.40 (m, 1H, C2–H), 5.96 (dd, J = 0.9, 9.5 Hz, 1H, C5–H), 7.33 (dd,
J = 5.9, 9.5 Hz, 1H, C4–H); 13C NMR (100 MHz, CDCl3) d 11.0
(CH3), 13.8 (CH3), 22.3 (CH2), 24.7 (CH2), 31.2 (CH2), 31.4 (CH2),
31.8 (CH), 80.0 (CH), 119.6 (CH), 151.7 (CH), 164.7 (C@O); EI-HRMS
calcd for C11H18O2 (M)+ 182.13068, found 182.13039.
4.7.1. (2S,3R)-3-Methyl-2-pentyl-2,3-dihydro-4H-pyran-4-one
ent-5d
A solution of diene 8b (1.09 g, 0.45 mmol, Z/E = 74:26) in CH2Cl2
(3.0 mL) was added to a solution of hexanal 4d (300 mg, 3.0 mmol)
and Rh2((R)-BPTPI)4ꢂ3H2O ent-2 (129 mg, 0.09 mmol, 3 mol %) in

72
Y. Watanabe et al. / Tetrahedron: Asymmetry 25 (2014) 63–73
11. Du, H.; Long, J.; Hu, J.; Li, X.; Ding, K. Org. Lett. 2002, 4, 4349–4352.
4.7.4. (ꢀ)-cis-Aerangis lactone 1735
12. Kobayashi et al. reported on the asymmetric 2,3-trans-selective HDA reaction
between 4-methyl- or 2,4-dimethyl-substituted Danishefsky-type dienes and
aldehydes Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc.
2003, 125, 3793–3798.
A solution of 19 (138 mg, 0.76 mmol) in EtOAc (5 mL) was stir-
red with 10% Pd/C (28 mg) under 1 atm of H2 at 23 °C for 1 h. The
catalyst was removed by filtration, and the filtrate was concen-
trated in vacuo. The residue was purified by column chromatogra-
phy (silica gel, 7:1 hexane/EtOAc) to afford 17 (134 mg, 97%) as a
13. Furuno, H.; Hayano, T.; Kambara, T.; Sugimoto, Y.; Hanamoto, T.; Tanaka, Y.;
Jin, Y. Z.; Kagawa, T.; Inanaga, J. Tetrahedron 2003, 59, 10509–10523.
14. Du, H.; Zhang, X.; Wang, Z.; Bao, H.; You, T.; Ding, K. Eur. J. Org. Chem. 2008,
2248–2254.
15. (a) Yu, Z.; Liu, X.; Dong, Z.; Xie, M.; Feng, X. Angew. Chem., Int. Ed. 2008, 47,
1308–1311; (b) Lin, L.; Kuang, Y.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 3868–
3871; (c) Zhao, B.; Loh, T.-P. Org. Lett. 2013, 15, 2914–2917.
colorless oil; TLC Rf = 0.45 (4:1 hexane/EtOAc); ½a D22
¼ ꢀ67:2 (c
ꢁ
1.06, CHCl3) for 92% ee {lit.,35c
½
a 1D4
ꢁ
¼ ꢀ63:5 (c 1.28, CHCl3) for
the (2S,3S)-enantiomer}; IR (film) 2936, 1735, 1240 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 0.90 (t, J = 6.8 Hz, 3H, CH2CH3), 0.96 (d,
J = 6.8 Hz, 3H, C3–CH3), 1.31–1.51 (m, 7H, CHHCH2CH2CH2CH3),
1.66–1.71 (m, 2H, C2–CHH and C4–H), 1.99–2.06 (m, 2H, C3–H
and C4–H), 2.53 (dd, J = 6.8, 7.7 Hz, 2H, C5–H), 4.29 (m, 1H, C2–
H); 13C NMR (100 MHz, CDCl3) d 12.4 (CH3), 13.9 (CH3), 22.4
(CH2), 25.1 (CH2), 26.0 (CH2), 26.6 (CH2), 29.2 (CH), 31.5 (CH2),
31.8 (CH2), 82.9 (CH), 171.9 (C@O); EI-HRMS calcd for C11H20O2
(M)+ 184.14594, found 184.14633.
16. For examples of enantioselective HDA reactions between Rawal’s diene and
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Acknowledgments
This research was supported, in part, by a Grant-in-Aid for Sci-
entific Research from the Japan Society for the Promotion of Sci-
ence (JSPS) and also by a Grant-in-Aid for Scientific Research on
Innovative Areas ‘Organic Synthesis Based on Reaction Integration’
(No. 2105) from the Ministry of Education, Culture, Sports, Science
and Technology, Japan. Y.W. is grateful to JSPS for a graduate fel-
lowship. We thank Ms. S. Oka and M. Kiuchi of Center for Instru-
mental Analysis at Hokkaido University for technical assistance
in the MS.
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