anti-Selective aldol reactions of chiral alcohol substituted γ-benzyloxyl vinylogous urethanes and the synthesis of 3-benzyloxyl-4-hydroxylalkan-2-ones

Article abstract of DOI:10.1016/j.tetasy.2017.10.003

The anti-selective aldol reaction of chiral alcohol-substituted γ-benzyloxy vinylogous urethanes is described. The use of (1S,2R,4R)-1-(hydroxydiphenylmethyl)-7,7-dimethylbicyclo[2,2,1]-heptan-2-ol as a chiral auxiliary in the aldol reaction of a vinylogous urethane enolate was found to provide anti-products in good yields with moderate to excellent enantioselectivities. The major anti-vinylogous urethane lactones were transformed into 3-benzyloxyl-4-hydroxylalkan-2-ones in good yields.

Full text of DOI:10.1016/j.tetasy.2017.10.003

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
anti-Selective aldol reactions of chiral alcohol substituted
c-benzyloxyl vinylogous urethanes and the synthesis of
3-benzyloxyl-4-hydroxylalkan-2-ones
a,
b
b
⇑
Yu-Jang Li
, Chuan-Chung Chung , Pin-Zu Chen
a Department of Applied Chemistry, National Chiayi University, 300 University Road, Chiayi City 60004, Taiwan
b Department of Applied Chemistry, Chaoyang University of Technology, 168 Gifeng E. Road, Wufeng, Taichung County 41349, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
The anti-selective aldol reaction of chiral alcohol-substituted
c-benzyloxy vinylogous urethanes is
Received 6 July 2017
Revised 22 September 2017
Accepted 1 October 2017
Available online xxxx
described. The use of (1S,2R,4R)-1-(hydroxydiphenylmethyl)-7,7-dimethylbicyclo[2,2,1]-heptan-2-ol as
a chiral auxiliary in the aldol reaction of a vinylogous urethane enolate was found to provide anti-prod-
ucts in good yields with moderate to excellent enantioselectivities. The major anti-vinylogous urethane
lactones were transformed into 3-benzyloxyl-4-hydroxylalkan-2-ones in good yields.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
2 was obtained by the acylation of 2-benzyloxyacetyl chloride 1
with Meldrum’s acid in 85% yield.4 Chiral alcohols 3a-f were then
The syn-selective aldol reaction of chiral vinylogous urethane
enolate anions with various aldehydes have been successfully
developed to generate syn-chiral vinylogous urethane lactones
with high enantioselectivities. These syn-vinylogous urethane lac-
tones were then used as important intermediates for the synthesis
of natural products, such as virginiamycin M2, zaragizic acid A, (+)-
KDO, okadaic acid, (+)-asperlin and their derivatives.1,2 In compar-
ison to the many studies on the syn-selective aldol reaction of chi-
ral vinylogous urethane enolate anions, anti-selective aldol
reactions of chiral vinylogous urethane enolate anions have been
less studied. In previous studies we have shown that chiral alco-
reacted respectively with 2 in toluene at reflux to provide chiral
ketoesters 4a-f in 57–76% yields.5 Condensation of 4a-f with pyrro-
lidine furnished chiral
c-benzyloxy vinylogous urethanes 5a-f in
96–99% yields (Schemes 1 and 2).6
Chiral alcohol-substituted vinylogous urethanes 5a-f were sub-
jected to aldol reaction studies. A typical procedure for the aldol
reaction of chiral alcohol-substituted vinylogous urethanes was
conducted using 2.5 (Entries 1–5) or 3.5 (Entry 6) equivalents of
LDA as a base. Kinetic deprotonation of 5a-f at ꢀ78 °C for 30 min
was followed by warming to room temperature for 20 min. After
re-cooling to ꢀ78 °C and stirring for 30 min, 2.5 equiv.of isobu-
tyraldehyde (1 mol/L in THF, 2.5 mL) were added to the reaction
mixture. Warming to room temperature over two hours followed
by quenching with aqueous ammonium chloride (1 mol/L) pro-
hol-substituted vinylogous urethanes, with c-methyl substitution,
can react with various aldehydes to give anti-selective aldol prod-
ucts in good yields and with moderate to good enantioselectivities.
This was applied to the synthesis of pre-lactone B.3 Herein, we
report investigations on the chiral anti-selective aldol reactions
and their product transformations, involving the use of chiral alco-
O
hol-substituted vinylogous urethanes with
substitution.
c-benzyloxyl
O
O
O
O
O
BnO
R*OH 3a-f
O
O
O
O
toluene
BnO
BnO
2. Results and discussion
Cl
57-76 %
1
2
OR*
We began with the synthesis of various chiral alcohol substi-
tuted vinylogous urethanes. 2-(2-Benzyloxyacetyl)-Meldrum acid
O
pyrrolidine
O
O
PhH
96-99 %
N
OR*
OBn
4a-f
5a-f
⇑
Corresponding author.
E-mail address: yjli@mail.ncyu.edu.tw (Y.-J. Li).
Scheme 1. Synthesis of vinylogous urethane lactone 5.
https://doi.org/10.1016/j.tetasy.2017.10.003
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
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Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
due to it being less efficient in solvating the enolate aggregation
OH
(Entries 3–5) (Table 2).
OH
OH
When vinylogous urethane 5f was reacted with various aldehy-
des, the reaction provided compounds 7a-i in reasonable 60–81%
yields. The reactions of straight chain aliphatic aldehydes showed
excellent diastereoselectivities (93–97%) and moderate to good
enantioselectivities (86–94%) (Entries 1–4). Reactions of 2-(benzy-
loxy)acetaldehyde and (E)-but-2-enal showed good diastereoselec-
tivities (91%), but moderate enantioselectivities (77–85%) (Entries
5, 6). Although reactions of simple benzaldehydes showed moder-
ate 74% diastereoselectivity and 86% enantioselectivity (Entry 7),
reactions of bulkier aryl aldehydes showed significantly lower
diastereoselectivity (57–64%) and enantioselectivity (63–68%)
(Entries 8, 9). In addition to the bulkiness of the aldehyde used
in entry 9, the oxygen atoms on the aryl substituents may disrupt
the regular vinylogous urethane enolate aggregation, therefore
lower both diastereoselectivity and enantioselectivity (Table 3).
The X-ray crystallographic structure of anti-6 was analyzed to con-
firm the structural assignments as shown in Fig. 1.7
OH
OH
3c
3a
3b
R*OH=
OH
OH
Ph
O
O
N
iPr
N
Et
Ph
iPr
Et
3d
3e
3f
Scheme 2. Chiral alcohol 3a–f.
vided vinylogous urethane lactones anti-6 and syn-6 in moderate
to good yields. The diastereoselectivity (anti-6 vs. syn-6) and enan-
tioselectivity of anti-6 obtained from the individual reaction were
determined respectively by regular and chiral HPLC analysis (Chi-
ralcelÒ OD). Studies showed that the reaction of 5f with isobu-
tyraldehyde provided the best diastereoselectivity (92%) and
enantioselectivity (98%) (Table 1).
When the aldol reaction of vinylogous urethane 5f was per-
formed in a different solvent system, it showed that the reaction
gave comparable results (with slightly lower ee) when ether was
used as the solvent (Entry 2). Solvent systems involving toluene
provided less satisfactory yields and stereoselectivities, mainly
Acid hydrolysis of vinylogous urethane lactone anti-6 under 4 M
HCl condition did not provide the expected enamine hydrolyzed b-
keto lactone 8 as in the previous
Instead, a decarboxylated product 11 was obtained in 90% yield.
Presumably, the further decarboxylation process from b-ketol d-
lactone 8 to ketone 11 may be assisted by the existence of the
c
-methyl substituted case.3
Table 1
Results of the anti-aldol reaction studies of 5a–f
O
O
OR*
O
O
O
LDA, iPrCHO
+
N
N
N
THF
OBn
OBn
OBn
5a-f
anti-6
syn-6
Entry
Vinylogous urethane
% Yielda
% de
% eeb
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
78
83
80
73
70
81
47
47
36
56
18
92
8
31
41
53
14
98
a
Combined isolated yields of anti- and syn-products.
The ee values and de values were determined by HPLC analysis on a Chiralcel OJ column [detected at 290 nm; eluent, n-hexane/ethanol, 94/6 (v/v)].
b
Table 2
Results of the anti-aldol reaction studies of 5f under different solvent systems
O
O
O
H
O
N
O
O
LDA,
solvent, -78oC
+
O
OH
N
N
OBn
OBn
OBn
syn-6
5f
anti-6
Entry
Solvent
% Yielda
% de
% eeb
1
2
3
4
5
THF
Et2O
81
77
68
66
43
92
90
77
77
27
98
85
85
86
64
Toluene/THF (1:1)
Tolene/Ether (1:1)
Toluene
a
Combined isolated yields of anti- and syn-products.
The ee values were determined by HPLC analysis on a Chiralcel OD column; flow rate 0.5 mL/min [detected at 290 nm; eluent, hexane/iPrOH = 3/1].
b
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Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 3
Aldol reaction of 5f with various aldehydes
O
O
O
O
N
R
H
O
O
LDA,
O
THF, -78oC
OH
N
R
N
R
OBn
OBn
OBn
syn-7a-i
+
anti-7a-i
5f
Entry
R
Product
% Yielda
% de
% eeb
1
2
3
4
5
6
7
8
9
Me
Et
Pr
Bu
7a
7b
7c
7d
7e
7f
7g
7h
7i
60
69
75
77
70
75
81
81
72
93
94
95
97
91
91
74
64
57
86
94
94
93
85
77
86
68
63
CH2OBn
CH@CHMe(E)
Ph
1-napth
2,3,4-(OMe)3-6-(CH2OMe)-Ph
a
Combined isolated yields of anti- and syn-products.
The ee values of anti-products were determined by HPLC analysis on a Chiralcel OD or AD-H or AD column; flow rate 0.5 mL/min [detected at 290 nm; eluent,
b
hexane/iPrOH = 3/1].
Table 4
Hydrolysis anti-7a-h
O
O
OH
O
4N HCl
R
N
R
OBn
12a-h
OBn
anti-7a-h
Entry
R
Products
% Yielda
1
2
3
4
5
6
7
8
Me
Et
Pr
Bu
12a
12b
12c
12d
12e
12f
90
88
91
88
83
83
85
88
CH2OBn
CH@CHMe(E)
Ph
12g
12h
1-napth
a
Isolated yield.
Figure 1. ORTEP view of the X-ray crystallographic structure of anti-6 (thermal
ellipsoids are shown at 30% probability).
For the purpose of confirming the absolute configuration of
anti-7a-i, hydrogenolysis of 11 under a hydrogen atmosphere using
palladium on carbon afforded dihydroxy compound 13 in 78%
hydrogen bonding between the carbonyl and OBn of the interme-
diate 9 (Scheme 3).
Since 1,2-diols are essential moieties in a variety of biologically
active natural products, compounds such as 11 providing differen-
tiated dihydroxyl groups would be highly desirable.8,9 Therefore,
anti-7a-h compounds were subsequently subjected to the hydrol-
ysis to provide 3-benzyloxyl-4-hydroxyalkan-2-one compounds
12a-h in good yields (83–91%) (Table 4).
yield. Compound 13 has the same rotation [a]
26 = +64.7 (c 0.1,
D
CHCl3), as an authentic compound; [lit.
[a]D = +73.0 (c 1.0,
CHCl3)],8e which indicates that the absolute stereochemistry of
the anti-6 product generated from the aldol reaction is (5R,6S)
(Scheme 4).
OH+
O
H2O
O
HO
OH
O
O
O
HCl
N
O
OBn
anti-6
OBn
OBn
H+
8
9
O
CH3 OH
OBn
O
OH
-CO2
O
HO
10
11
OBn
Scheme 3. Plausible mechanism for the hydrolysis of 6-anti.
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Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
coupling constant was reported in hertz (Hz). Optical rotation
was measured at ambient temperature on Jasco P-1010
a
CH3 OH
CH3 OH
(3S)
(4S)
O
Pd/C, H2
polarimeter using a NaD (586 nm) lamp quartz cell with a path
length of 0.1 dm; abs values were corrected for the rotation of cell
with solvent. Mass spectra were recorded on a VG-7035 mass spec-
trometer at an ionizing voltage of either 70 or 20 eV; alternatively,
samples were analyzed by the Instrument Center of The National
Science Counsel at National Chung Hsing University.
(5R)
O
O
(6S)
N
OBn
OH
OBn
anti-6
11
13
Scheme 4. Hydrogenolysis of 11.
4.2. Synthesis of ketoesters 4a-f
To account for the absolute configuration of anti-6, resulting
from the reaction of 5f with an aldehyde, a plausible mechanism
is shown in Scheme 5. The 6-membered ring enolate moiety in
the transition state A is anti to the gem-dimethyl group of the chiral
auxiliary, which will encounter less steric hindrance than in tran-
sition state A0, whereas the 6-membered ring enolate moiety is
syn to the gem-dimethyl group of the chiral auxiliary. Therefore,
the reaction was expected to occur preferentially from the more
stable transition state A in a Si-Re fashion to generate aldolate B,
which would then cyclize to give vinylogous urethane lactone
anti-6 (5R,6S) as the major enantiomer.
4.2.1. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 4-(benzyloxy)-
3-oxobutanoate 4a
To (ꢀ)-menthol 3a (1.25 g, 8 mmol) in a 100 mL round-bottom
flask was added 5-(2-benzyloxy-acetyl)-2,2-dimethyl-1,3-dioxane-
4,6-dione 2 (2.34 g, 8 mmol) and xylene (40 mL) as solvent. The
mixtures were heated to reflux for 6 h, then concentrated in vacuo
to remove solvent. The crude material was purified by flash chro-
matography (n-hexane/EtOAc = 4:1) to give 2.13 g of ketoesters
4a in 77% yield. Colorless oil. Rf = 0.80 (n-hexane/EtOAc = 4:1);
[
a
]
26 = ꢀ53.1 (c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.41–
D
7.29 (m, 5H), 4.80–4.62 (m, 1H), 4.60 (s, 2H), 4.14 (s, 2H), 3.53 (s,
2H), 2.03–0.80 (m, 9H), 0.89 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 7.1 Hz,
3H), 0.74 (d, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 201.4,
166.4, 136.8, 128.3(2C), 127.9, 127.6(2C), 75.3, 74.6, 73.2, 46.7,
46.1, 40.5, 34.0, 31.2, 25.9, 23.1, 21.8, 20.6, 16.0; HRMS-EI calcd
for C21H30O4, 346.2144 found 347.2214.
3. Conclusion
In conclusion, aldol reactions of a series of alcohol-substituted
vinylogous urethanes with c-benzyloxyl substitution were studied.
The resulting aldol products from the reaction of vinylogous
urethane 5 provide moderate to good diastereoselectivities and
enantioselectivities. Compounds anti-7a-h were hydrolyzed with
4 M HCl to provide 3-benzyloxyl-4-hydroxyalkan-2-one com-
pounds with differentiated 1,2-dihydroxy moieties in good yields.
Finally, a plausible mechanism was proposed to account for the
generation of the major enantiomer. Further studies on synthetic
applications as well as mechanistic studies of the reaction are cur-
rently in progress in our laboratory.
4.2.2. (1R,2R,3R,5S)-2,6,6-Trimethylbicyclo[3.1.1]heptan-3-yl 4-
(benzyloxy)-3-oxobutanoate 4b
This was synthesized according to the general procedure, on an
8 mmol scale in 76% yield. Colorless oil. Rf = 0.70 (n-hexane/EtOAc
= 4:1); [
a
]
26 = ꢀ32.7 (c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d
D
7.39–7.30 (m, 5H), 5.13–5.01 (m, 1H), 4.60 (s, 2H), 4.15 (s, 2H),
3.54 (s, 2H), 2.64–1.61 (m, 7H), 1.21 (s, 3H), 1.08 (d, J = 7.5 Hz,
3H), 0.94 (s, 3H); 13C NMR (50 MHz, CDCl3) d 201.1, 166.4, 136.6,
128.0(2C), 127.5, 127.3(2C), 74.7, 74.3, 72.8, 46.9, 45.8, 43.1, 40.6,
37.7, 35.1, 32.9, 26.9, 23.2, 20.0; HRMS-EI calcd for C21H28O4,
344.1988 found 344.1902.
4. Experimental
4.1. General
NMR spectra were taken with a Varian Mercury-200 nuclear
magnetic resonance spectrometer (200 MHz for 1H NMR, 50 MHz
for 13C NMR) in CDCl3. Chemical shifts were reported in parts per
million (ppm) relative to internal standard CDCl3 (7.24 ppm), and
4.2.3. (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 4-
(benzyloxy)-3-oxobutanoate 4c
This was synthesized according to the general procedure, on an
8 mmol scale in 79% yield. Colorless oil. Rf = 0.70 (n-hexane/EtOAc
O
O
O
O
Ph
Ph
+Li
Ph
Ph
O-
O
H
H
Re
H
O-
OLi
H
(S)
LiO
d- O
5
Li+
d+
OBn
OBn
6
N
(R)
N
N
Si
OBn
H
H
A
B
anti-6 (5R,6S)
O
O
O
O
Ph
Ph
O
Ph
O-
Li+
Ph
H
O-
OLi
(R)
H
5
+Li
6
N
(S)
N
N
d+
d-
Re
OBn
OBn
OBn
H
H
H
A'
B'
anti-6 (5S,6R)
O
H
LiO
Si
Scheme 5. Plausible mechanism for the generation of anti-6 (5R,6S) from the reaction of enolate of 5f with aldehydes.
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Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
= 4:1); [
a
]
26 = ꢀ20.8 (c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d
23.6, 22.0, 20.7, 16.5; HRMS-EI calcd for C25H37NO3, 399.2773
found 399.2781.
D
7.41–7.29 (m, 5H), 4.98–4.88 (m, 1H), 4.60 (s, 2H), 4.15 (s, 2H),
3.56 (s, 2H), 2.42–0.83 (m, 7H), 0.89 (s, 3H), 0.86 (s, 3H), 0.82 (s,
3H); 13C NMR (50 MHz, CDCl3) d 201.6, 167.2, 136.8, 128.5(2C),
128.0, 127.8(2C), 81.1, 74.8, 73.4, 48.7, 47.7, 46.2, 44.7, 36.4,
27.8, 26.9, 19.6, 18.7, 13.3; HRMS-EI calcd for C21H28O4, 344.1988
found 344.1994.
4.3.2. (1R,2R,3R,5S)-2,6,6-Trimethylbicyclo[3.1.1] heptan-3-yl
(E)-4-(benzyloxy)-3-(pyrrolidin-1-yl)but-2-enoate 5b
This was synthesized according to the general procedure on a 5
mmol scale in 98% yield. Pale-yellow oil. [
a
]
26 = ꢀ26.9 (c 0.2, CH2-
D
Cl2); 1H NMR (200 MHz, CDCl3) d 7.39–7.23 (m, 5H), 5.10–5.00 (m,
1H), 4.99 (d, J = 11.4 Hz, 1H, ABq), 4.93 (d, J = 11.4 Hz, 1H, ABq),
4.62 (s, 2H), 4.56 (s, 1H), 3.62–3.02 (br, 4H), 2.68–1.50 (m, 7H),
2.00–1.79 (m, 4H), 1.21 (s, 3H), 1.10 (d, J = 7.5 Hz, 3H), 0.98 (s,
3H); 13C NMR (50 MHz, CDCl3) d 168.5, 156.3, 138.2, 128.1(2C),
127.8(2C), 127.4, 86.6, 72.4, 71.6, 67.8, 64.4, 47.7, 47.5, 43.7,
41.3, 38.2, 36.3, 33.5, 27.4, 25.5, 24.9, 23.6, 20.5; HRMS-EI calcd
for C25H35NO3, 397.2617 found 397.2617.
4.2.4. (1S,2R,4R)-1-(Diethylcarbamoyl)-7,7-dimethylbicyc[2.2.1]
heptan-2-yl 4-(benzyloxy)-3-oxobutanoate 4d
This was synthesized according to the general procedure, on an
8 mmol scale in 65% yield. Colorless oil. Rf = 0.36 (n-hexane/EtOAc
= 4:1); [
a
]
26 = ꢀ22.6 (c 0.3, CH2Cl2); 1H NMR (200 MHz, CDCl3) d
D
7.25 (m, 5H), 5.10 (dd, J = 6.0, 5.1 Hz, 1H), 4.48 (s, 2H), 4.01 (s,
2H), 3.54–3.43 (br, 2H), 3.40 (s, 2H), 3.14–2.96 (br, 2H), 2.03–
1.14 (m, 7H), 1.25 (s, 3H), 1.07 (s, 3H), 1.05–0.91 (m, 6H); 13C
NMR (50 MHz, CDCl3) d 201.0, 169.7, 165.9, 136.6, 128.2(2C),
127.7, 127.5(2C), 79.3, 74.5, 73.1, 58.5, 50.9, 45.4, 44.4, 40.0, 40.1,
39.3, 29.8, 26.6, 21.4, 21.3, 13.8, 12.3; HRMS-EI calcd for
4.3.3. (1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl (E)-4-
(benzyloxy)-3-(pyrrolidin-1-yl)but-2-enoate 5c
This was synthesized according to the general procedure on a 5
C25H35NO5, 429.2515 found 429.2506.
mmol scale in 99% yield. Pale-yellow oil. [
a
]
26 = ꢀ25.1 (c 0.2, CH2-
D
Cl2); 1H NMR (200 MHz, CDCl3) d 7.40–7.22 (m, 5H), 5.00 (d, J =
11.4 Hz, 1H, ABq), 4.91(d, J = 11.4 Hz, 1H, ABq), 4.92–4.84 (m,
1H), 4.62 (s, 2H), 4.59 (s, 1H), 3.61–3.05 (br, 4H), 2.43–0.90 (m,
7H), 1.92–1.83 (m, 4H), 0.92 (s, 3H), 0.87(s, 3H), 0.85(s, 3H); 13C
NMR (50 MHz, CDCl3)d 168.8, 156.0, 138.0, 127.9(3C), 127.6(2C),
127.3, 86.3, 77.2, 72.2, 64.2, 48.4, 47.6, 47.4, 44.7, 36.8, 27.8,
27.0, 24.8(2C), 19.5, 18.6, 13.4; HRMS-EI calcd for C25H35NO3,
397.2617 found 397.2610.
4.2.5. (1S,2R,4R)-1-(Diisopropylcarbamoyl)-7,7-dimethylbicyc
[2.2.1]heptan-2-yl 4-(benzyloxy)-3-oxobutanoate 4e
This was synthesized according to the general procedure, on an
8 mmol scale in 57% yield. Colorless oil. Rf = 0.55 (n-hexane/EtOAc
= 4:1); [
a
]
26 = ꢀ27.7 (c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) d
D
7.39–7.20 (m, 5H), 5.05 (dd, J = 7.3, 3.7 Hz, 1H), 4.53 (s, 2H), 4.15
(hep, J = 6.8 Hz, 1H), 4.07 (s, 2H), 3.48 (s, 2H), 3.23 (hep, J = 6.8
Hz, 1H), 2.31–1.20 (m, 7H), 1.36 (d, J = 4.9 Hz, 6H), 1.28 (s, 3H),
1.24 (s, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H); 13C
NMR (50 MHz, CDCl3) d 201.3, 169.4, 166.2, 136.7, 128.4(2C),
127.9, 127.7(2C), 80.3, 74.7, 73.3, 59.2, 51.4, 47.1, 46.2, 45.5,
44.6, 39.9, 29.7, 26.7, 21.8, 21.5, 21.0, 20.5, 20.4, 20.4; HRMS-EI
calcd for C27H39NO5, 457.2828 found 457.2836.
4.3.4. (1S,2R,4R)-1-(Diethylcarbamoyl)-7,7-dimethylbicyc[2.2.1]
heptan-2-yl(E)-4-(benzyloxy)-3-(pyrrolidin-1-yl)but-2-enoate
5d
This was synthesized according to the general procedure on a 5
mmol scale in 97% yield. Pale-yellow oil. [
a]
D
26 = ꢀ54.3 (c 0.1, CH2-
Cl2); 1H NMR (200 MHz, CDCl3) d 7.41–7.22 (m, 5H), 5.12 (dd, J =
7.1, 4.0 Hz, 1H), 4.96 (d, J = 11.4 Hz, 1H, ABq), 4.79 (d, J = 11.4 Hz,
1H, ABq), 4.59 (s, 2H), 4.45 (s, 1H), 3.70–3.41 (m, 4H), 3.37–2.89
(br, 4H), 2.09–0.99 (m, 7H), 2.00–1.79 (br, 4H), 1.37 (s, 3H),1.36–
0.99 (m, 6H), 1.16 (s, 3H); 13C NMR (50 MHz, CDCl3) d 170.9,
167.7, 156.7, 138.2, 128.1(2C), 127.8(2C), 127.5, 85.9, 76.4, 72.4,
64.4, 58.8, 50.9, 47.8(2C), 44.9, 40.2, 39.8(2C), 30.3, 26.9, 24.9
4.2.6. (1S,2R,4R)-1-(Hydroxydiphenylmethyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-yl 4-(benzyloxy)-3-oxobutanoate 4f
This was synthesized according to the general procedure, on an
8 mmol scale in 62% yield. Colorless oil. Rf = 0.57 (n-hexane/EtOAc
= 4:1); [a]
26 = +72.1 (c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d
D
7.78–7.59 (m, 4H), 7.41–7.29 (m, 5H), 7.31–7.12 (m, 6H), 5.22
(dd, J = 7.8, 3.9 Hz, 1H), 4.55 (s, 2H), 3.96 (s, 2H), 3.15 (s, 2H),
2.39–1.12 (m, 7H), 1.45 (s, 3H), 0.64 (s, 3H); 13C NMR (50 MHz,
CDCl3) d 200.9, 164.1, 149.1, 143.2, 136.6, 128.4(2C), 128.3(2C),
127.9, 127.8(2C), 127.7(2C), 126.6(2C), 126.4, 126.0, 125.8(2C),
82.4, 80.9, 74.5, 73.2, 58.9, 51.2, 47.5, 44.9, 38.1, 31.1, 26.8, 24.3,
22.4; HRMS-EI calcd for C33H36O5, 512.2563 found 512.2569.
(2C), 21.8, 21.7, 13.9, 12.6; HRMS-EI calcd for
482.3145 found 482.3145.
C29H42N2O4,
4.3.5. (1S,2R,4R)-1-(Diisopropylcarbamoyl)-7,7-dimethylbicyc
[2.2.1]heptan-2-yl (E)-4-(benzyloxy)-3-(pyrrolidin-1-yl)but-2-
enoate 5e
This was synthesized according to the general procedure on a 5
4.3. Synthesis of 5a-f
mmol scale in 96% yield. Pale-yellow oil. [
a
]
26 = ꢀ30.4 (c 0.2, CH2-
D
Cl2); 1H NMR (200 MHz, CDCl3) d 7.40–7.25 (m, 5H), 5.09 (d, J =
11.5 Hz, 1H, ABq), 5.02 (dd, J = 7.5, 3.7 Hz, 1H), 4.72 (d, J = 11.5
Hz, 1H, ABq), 4.58 (s, 2H), 4.50 (s, 1H), 4.27 (hep, J = 6.6 Hz, 1H),
3.62–2.96 (br, 4H), 3.24 (hep, J = 6.6 Hz, 1H), 2.29–1.12 (m, 7H),
1.99–1.78 (m, 4H), 1.40 (d, J = 6.8 Hz, 6H), 1.36 (s, 3H), 1.17 (s,
3H), 1.20–1.01 (m, 6H); 13C NMR (50 MHz, CDCl3) d 170.5, 167.9,
156.8, 138.3, 128.2(2C), 127.9(2C), 127.6, 86.0, 77.7, 72.4, 64.5,
59.5, 51.2, 47.9, 47.1, 46.1, 45.0, 40.5, 30.0, 27.0, 22.1, 21.8, 21.1,
20.8, 20.5, 20.4; HRMS-EI calcd for C31H46N2O4, 510.3458 found
510.3466.
4.3.1. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl (E)-4-(benzy-
loxy)-3-(pyrrolidin-1-yl)but-2-enoate 5a
To 4a (1.73 g, 5 mmol) in a 50 mL round-bottom flask was
added benzene (20 mL) as the solvent, followed by the addition
of pyrrolidine (0.5 ml, 6.0 mmol) and tert-butyl alcohol (0.5 mL,
5.23 mmol). The mixtures were heated to reflux under Dean–Stark
apparatus to remove water. After 10 h, the reaction mixtures were
concentrated in vacuo to remove the solvent to give 1.96 g of 5a in
98% yield. The material was used directly in the next reaction with-
out further purification. Pale-yellow oil. [
a]
D
26 = ꢀ45.4 (c 0.1, CH2-
Cl2); 1H NMR (200 MHz, CDCl3) d 7.42–7.18 (m, 5H), 4.94 (s, 2H),
4.74–4.58 (m, 1H), 4.60 (s, 2H), 4.51 (s, 1H), 3.75–2.91 (br, 4H),
2.09–0.80 (m, 9H), 1.95–1.79 (m, 4H), 0.88 (d, J = 6.0 Hz, 3H),
0.87 (d, J = 6.0 Hz, 3H), 0.77 (d, J = 6.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3) d 168.1, 156.4, 138.3, 128.2(2C), 127.9(2C), 127.5, 86.4,
72.4, 71.6, 64.5, 47.8(2C), 47.3, 41.5, 34.4, 31.4, 26.2, 25.1(2C),
4.3.6. (1S,2R,4R)-1-(Hydroxydiphenylmethyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-yl (E)-4-(benzyloxy)-3-(pyrrolidin-1-yl)but-2-
enoate 5f
This was synthesized according to the general procedure on a 5
mmol scale in 96% yield. Pale-yellow oil. [
a
]
26 = ꢀ49.9 (c 0.1, CH2-
D
Cl2); 1H NMR (200 MHz, CDCl3) d 7.80–7.63 (m. 4H), 7.38–6.90 (m,
Please cite this article in press as: Li, Y.-J.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.003

6
Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
11H), 5.11 (dd, J = 7.5, 4.2 Hz, 1H), 4.87 (d, J = 11.9 Hz, 1H, ABq),
4.57 (d, J = 11.4 Hz, 1H, ABq), 4.57 (s, 1H), 4.40 (d, J = 11.5 Hz, 1H,
ABq), 4.32 (d, J = 11.5 Hz, 1H, ABq), 4.23 (s, 1H), 3.63–3.31 (br,
2H), 3.30–2.99 (br, 2H), 2.41–1.03 (m, 7H), 1.99–1.78 (br, 4H),
1.54 (s, 3H), 0.56 (s, 3H); 13C NMR (50 MHz, CDCl3)d 165.7, 157.0,
149.0, 143.8, 138.2, 128.2, 128.1, 128.0, 127.8, 127.4, 127.3,
126.6, 126.2, 125.9, 84.9, 81.2, 79.3, 71.9, 63.9, 58.8, 50.9, 47.7,
for C17H21NO3, 287.1521 found 287.1512. syn-7a: 2% yield, pale-
yellow oil. Rf = 0.27 (n-hexane/acetone = 2:1); 1H NMR (200 MHz,
CDCl3) d 7.40–7.21 (m, 5H), 4.84 (s, 1H), 4.68 (d, J = 11.2 Hz, 1H,
ABq), 4.47 (d, J = 11.2 Hz, 1H, ABq), 4.57–4.45 (m, 1H), 4.18 (d, J
= 3.0 Hz, 1H), 3.72–3.05 (br, 4H), 2.02–1.78 (br, 4H), 1.56 (d, J =
6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 168.1, 154.2, 137.7,
128.4(2C), 127.8, 127.6(2C), 86.4, 75.2, 70.5, 68.4, 47.7, 47.3, 25.4,
38.8, 30.7, 27.0, 24.5, 22.6; HRMS-EI calcd for
565.3192 found 565.3191.
C
37H45NO4,
24.5, 16.1; HRMS-EI calcd for
287.1519.
C17H21NO3, 287.1521 found
4.4. General procedure for the reaction of 5a-f with
isobutyraldehyde
4.5.2. 5-Benzyloxy-6-ethyl-4-pyrrolidin-1-yl-5,6-dihydro-pyran-
2-one anti-7b and syn-7b
This was synthesized according to the general procedure on a 1
mmol scale in 69% yield, 94% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 14.4 min (major), tR = 15.7
min (minor)]. anti-7b: 66% yield, pale-yellow oil. 94% ee, [HPLC
Chiralcel OD, hexane/iPrOH = 3/1; flow rate 0.5 mL/min; tR = 20.6
min (major), tR = 24.0 min (minor)]. Rf = 0.25 (n-hexane/acetone =
4.4.1. 5-Benzyloxy-6-isopropyl-4-pyrrolidin-1-yl-5,6-dihydro-
pyran-2-one anti-6 and syn-6
To a THF solution (4 mL) of 5f (565 mg, 1 mmol) was added a
THF solution of LDA (1 mol/L, 2.5 mL) at ꢀ78 °C. (2.5 eqiv. LDA
for 5a-e, 3.5 equiv. LDA for 5f). The temperature of the reaction
mixture was allowed to rise to 20 °C during a period of 40 min.
After re-cooled to ꢀ78 °C and stirred for 30 min, a solution of
isobutyraldehyde (1N in THF, 4 mL) was added to the reaction mix-
ture. This mixture was then allowed to warm to room temperature
slowly over a period of 2 h. The reaction was quenched by the addi-
tion of aqueous ammonium chloride (1N, 5 mL), extracted with
ethyl acetate (5 mL ꢁ 2) then dried over anhydrous sodium sulfate,
followed by concentration to afford the crude material. The crude
was purified by flash chromatography (n-hexane:acetone, 1:1) to
give anti-6 and syn-6 in 81% yield. 92% de, [HPLC Hypersil Silica,
hexane/iPrOH = 3/1; flow rate 0.5 mL/min; tR = 13.0 min (major),
tR = 14.1 min (minor)]. anti-6: 78% yield, colorless solid, mp 118–
119 °C; 98% ee, [HPLC Chiralcel OD, hexane/iPrOH = 3/1; flow rate
0.5 mL/min; tR = 18.6 min (major), tR = 22.5 min (minor)]. Rf =
2:1); [a]
26 = ꢀ22.5 (c 0.1, CH2Cl2), 94% ee; 1H NMR (200 MHz,
D
CDCl3) d 7.39–7.18 (m, 5H), 4.66 (d, J = 11.3 Hz, 1H, ABq), 4.56 (d,
J = 11.3 Hz, 1H, ABq), 4.63 (s, 1H), 4.57–4.50 (m, 1H), 4.05(s, 1H),
3.53–3.00 (br, 4H), 2.02–1.78 (br, 4H), 1.64–1.38 (m, 2H), 1.03 (t,
J = 7.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 165.8, 152.9, 137.0,
128.4(2C), 127.9(3C), 85.1, 78.6, 71.3, 69.4, 47.5, 46.9, 25.9, 25.2,
24.5, 10.5; HRMS-EI calcd for
C18H23NO3, 301.1678 found
301.1688. syn-7b: 3% yield, pale-yellow oil. Rf = 0.29 (n-hexane/
acetone = 2:1); 1H NMR (200 MHz, CDCl3) d 7.40–7.21 (m, 5H),
4.82 (s, 1H), 4.64 (d, J = 11.4 Hz, 1H, ABq), 4.45 (d, J = 11.4 Hz, 1H,
ABq), 4.26 (d, J = 3.1 Hz, 1H), 4.27–4.15 (m, 1H), 3.73–3.00 (m,
4H), 2.16–1.69 (m, 6H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (50 MHz,
CDCl3) d 167.9, 154.0, 137.8, 128.3(2C), 127.7, 127.5(2C), 86.7,
80.5, 69.2, 68.3, 47.6, 47.2, 25.3, 24.5, 23.6, 10.0; HRMS-EI calcd
for C18H23NO3, 301.1678 found 301.1681.
0.36 (n-hexane/acetone = 2:1); [
a]
26 = ꢀ25.6 (c 0.2, CH2Cl2), 98%
D
ee; 1H NMR (200 MHz, CDCl3) d 7.39–7.20 (m, 5H), 4.64 (s, 1H),
4.62 (d, J = 11.4 Hz, 1H, ABq), 4.52 (d, J = 11.4 Hz, 1H, ABq), 4.22
(d, J = 9.2 Hz, 1H), 4.19 (s, 1H), 3.49–2.98 (br, 4H), 2.00–1.81 (m,
1H), 1.98–1.77 (br, 4H), 1.02 (d, J = 6.6 Hz, 3H), 0.91(d, J = 6.6 Hz,
3H); 13C NMR (50 MHz, CDCl3) d 165.9, 152.9, 136.9, 128.3(2C),
127.9(3C), 85.2, 82.3, 69.5, 69.2, 47.4, 46.8, 30.4, 25.1, 24.4, 19.5,
19.2; HRMS-EI calcd for C19H25NO3, 315.1834 found 315.1826.
syn-6: 3% yield, pale-yellow oil. Rf = 0.39 (n-hexane/acetone, 2:1);
1H NMR (200 MHz, CDCl3) d 7.39–7.20 (m, 5H), 4.84 (s, 1H), 4.66
(d, J = 11.4 Hz, 1H, ABq), 4.44 (d, J = 11.4 Hz, 1H, ABq), 4.39 (d, J =
3.0 Hz, 1H), 3.82 (dd, J = 10.0, 3.0 Hz, 1H), 3.81–3.01 (m, 4H),
2.40–2.13 (m, 1H), 2.03–1.70 (br, 4H), 1.20 (d, J = 6.5 Hz, 3H),
1.07 (d, J = 6.5 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 167.9, 153.9,
137.8, 128.0(2C), 127.4, 127.2(2C), 86.4, 84.2, 67.9, 67.7, 47.4,
46.9, 28.5, 25.1, 24.3, 19.3, 18.5; HRMS-EI calcd for C19H25NO3,
315.1834 found 315.1830.
4.5.3. 5-Benzyloxy-6-propyl-4-pyrrolidin-1-yl-5,6-dihydro-pyran-
2-one anti-7c and syn-7c
This was synthesized according to the general procedure on a 1
mmol scale in 75% yield, 95% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; 0.5 mL/min; tR = 12.8 min (major), tR = 15.3 min
(minor)]. anti-7c: 73% yield, 94% ee, [HPLC Chiralcel OD, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 19.0 min (major), tR = 22.3
min (minor)]. Pale yellow solid, mp 124–125 °C; Rf = 0.33 (n-hex-
ane/acetone = 2:1); [
a]
26 = ꢀ22.7 (c 0.1, CH2Cl2), 94% ee; 1H NMR
D
(200 MHz, CDCl3) d 7.40–7.25 (m, 5H), 4.70 (s, 1H), 4.69–4.60 (m,
1H), 4.66 (d, J = 11.3 Hz, 1H, ABq), 4.57 (d, J = 11.3 Hz, 1H, ABq),
4.05 (s, 1H), 3.59–3.08 (br, 4H), 2.02–1.80 (br, 4H), 1.89–1.36 (m,
4H), 0.94 (t, J = 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 165.8,
153.0, 137.0, 128.4(2C), 127.9(3C), 85.1, 76.9, 71.1, 69.4, 47.5,
46.9, 34.7, 29.5, 25.2, 24.4, 19.1, 13.6; IR (CH2Cl2) 2926, 1671,
1593, 1451, 1220 cmꢀ1; HRMS-EI calcd for C19H25NO3, 315.1834
found 315.1837. syn-7c: 2% yield, pale-yellow oil. Rf = 0.36 (n-hex-
ane/acetone = 2:1); 1H NMR (200 MHz, CDCl3) d 7.38–7.20 (m, 5H),
4.81 (s, 1H), 4.65 (d, J = 11.3 Hz, 1H, ABq), 4.45 (d, J = 11.3 Hz, 1H,
ABq), 4.30–4.21 (m, 1H), 4.22 (d, J = 3.0 Hz, 1H), 3.68–3.01 (br,
4H), 2.02–1.70 (br, 4H), 1.90–1.39 (m, 4H), 0.97 (t, J = 7.3 Hz,
3H); 13C NMR (50 MHz, CDCl3) d 167.9, 154.1, 137.8, 128.3(2C),
127.6, 127.4(2C), 86.7, 78.7, 69.6, 68.3, 47.6, 47.2, 32.3, 25.3,
24.5, 18.6, 13.8; HRMS-EI calcd for C19H25NO3, 315.1834 found
315.1834.
4.5. Reactions of 5f with aldehydes
4.5.1. 5-Benzyloxy-6-methyl-4-pyrrolidin-1-yl-5,6-dihydro-pyran-
2-one anti-7a and syn-7a
This was synthesized according to the general procedure on a 1
mmol scale in 60% yield, 93% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 20.5 min (major), tR = 22.0
min (minor)]. anti-7a: 58% yield, pale-yellow oil. 86% ee, [HPLC
Chiralcel OD, hexane/iPrOH = 3/1; flow rate 0.5 mL/min; tR = 24.0
min (major), tR = 27.6 min (minor)]. Rf = 0.23 (n-hexane/acetone =
2:1); [
a
]
26 = ꢀ7.2 (c 0.2, CH2Cl2), 86% ee; 1H NMR (200 MHz, CDCl3)
4.5.4. 5-Benzyloxy-6-butyl-4-pyrrolidin-1-yl-5,6-dihydro-pyran-
2-one anti-7d and syn-7d
This was synthesized according to the general procedure on a 1
mmol scale in 77% yield, 97% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 11.1 min (major), tR = 12.8
min (minor)]. anti-7d: 76% yield, Pale yellow solid, mp 128–129
D
d 7.40–7.23 (m, 5H), 4.90–4.79 (m, 1H), 4.69 (s,1H), 4.67 (d, J =
11.1 Hz, 1H, ABq), 4.57 (d, J = 11.1 Hz, 1H, ABq), 4.00 (s,1H), 3.60–
3.03 (br, 4H), 2.02–1.80 (br, 4H), 1.37 (d, J = 6.8 Hz, 3H); 13C NMR
(50 MHz, CDCl3)d 165.9, 152.8, 137.0, 128.4(2C), 128.0, 127.9(2C),
84.9, 73.2, 72.7, 69.5, 47.6, 47.0, 25.3, 24.5, 18.7; HRMS-EI calcd
Please cite this article in press as: Li, Y.-J.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.003

Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
°C; 93% ee, [HPLC Chiralcel OD, hexane/iPrOH = 3/1; flow rate 0.5
mL/min; tR = 18.4 min (major), tR = 20.9 min (minor)]. Rf = 0.35
NMR (50 MHz, CDCl3) d 167.5, 254.2, 137.8, 131.1, 128.4(2C),
127.8, 127.6(2C), 124.9, 86.5, 79.5, 70.8, 68.9, 47.7, 47.3, 25.4,
(n-hexane/acetone = 2:1); [
a]
26 = ꢀ32.0 (c 0.3, CH2Cl2), 93% ee; 1H
24.5, 17.9; HRMS-EI calcd for
313.1681.
C19H23NO3, 313.1678 found
D
NMR (200 MHz, CDCl3) d 7.39–7.22 (m, 5H), 4.68 (s, 1H), 4.65–
4.59 (m, 1H), 4.66 (d, J = 11.1 Hz, 1H, ABq), 4.59 (d, J = 11.1 Hz,
1H, ABq), 3.54–3.03 (br, 4H), 2.01–1.78 (br, 4H), 1.61–1.22 (m,
6H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 165.8,
152.9, 137.1, 128.4 (2C), 127.9 (3C), 85.2, 77.2, 71.7, 69.4, 47.5,
47.0, 32.5, 27.9, 25.2, 24.5, 22.3, 13.8; HRMS-EI calcd for
4.5.7. 5-Benzyloxy-6-phenyl-4-pyrrolidin-1-yl-5,6-dihydro-pyran-
2-one anti-7g and syn-7g
This was synthesized according to the general procedure on a 1
mmol scale in 81% yield, 74% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 ml/min; tR = 12.1 min (major), tR = 21.9
min (minor)]. anti-7g: 71% yield, white solid, mp 147–148 °C;
86% ee, [HPLC Chiralcel OD, hexane/iPrOH = 3/1; flow rate 0.5 mL/
min; tR = 34.7 min (major), tR = 48.7 min (minor)]. Rf = 0.33 (n-hex-
C20H27NO3, 329.1991 found 329.1984. syn-7d: 1% yield, pale-yel-
low oil. Rf = 0.36 (n-hexane/acetone = 2:1); 1H NMR (200 MHz,
CDCl3) d 7.41–7.20 (m, 5H), 4.84 (s, 1H), 4.67 (d, J = 11.5 Hz, 1H,
ABq), 4.47 (d, J = 11.5 Hz, 1H, ABq), 4.37–4.20 (m, 2H), 3.76–3.03
(br, 4H), 2.07–1.73 (br, 4H), 1.66–1.09 (m, 6H), 0.94 (t, J = 6.6 Hz,
3H); 13C NMR (50 MHz, CDCl3) d 167.9, 154.1, 137.9, 128.3 (2C),
127.7, 127.5 (2C), 86.7, 79.0, 69.6, 68.3, 47.6, 47.2, 30.0, 27.5,
25.3, 24.5, 22.5, 13.9; HRMS-EI calcd for C20H27NO3, 329.1991
found 329.1987.
ane/acetone = 2:1); [
a
]
26 = ꢀ26.8 (c 0.2, CH2Cl2), 86% ee; 1H NMR
D
(200 MHz, CDCl3) d 7.40–7.15 (m, 10H), 5.73 (s,1H), 4.74 (d, J =
11.4 Hz, 1H, ABq), 4.68 (d, J = 11.4 Hz, 1H, ABq), 4.67 (s, 1H), 4.41
(s, 1H), 3.43–2.89 (br, 4H), 1.83–1.65 (br, 4H); 13C NMR (50 MHz,
CDCl3) d 165.8, 152.4, 136.6, 128.2(2C), 128.1(2C), 127.8(2C),
127.5(2C), 125.4(2C), 85.2, 77.9, 73.5, 70.1, 47.2; IR (CH2Cl2)
4.5.5. 5-Benzyloxy-6-benzyloxymethyl-4-pyrrolidin-1-yl-5,6-
dihydro-pyran-2-one anti-7e and syn-7e
2926, 1684, 1595, 1453, 1221 cmꢀ1
;
HRMS-EI calcd for
C22H23NO3, 349.1678 found 349.1674. syn-7g: 10% yield, white
This was synthesized according to the general procedure on a 1
mmol scale in 70% yield, 91% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 12.9 min (major), tR = 17.1
min (minor)]. anti-7e: 67% yield, pale yellow solid, decomposed
253 °C; 85% ee, [HPLC Chiralcel AD-H, hexane/iPrOH = 3/1; flow
rate 0.5 mL/min; tR = 19.8 min (minor), tR = 21.7 min (major)]. Rf
solid, mp 155–156 °C; Rf = 0.30 (n-hexane/acetone = 2:1); 1H
NMR (200 MHz, CDCl3) d 7.63–6.91 (m, 10H), 5.44 (d, J = 2.3 Hz,
1H), 4.79 (s, 1H), 4.41 (d, J = 2.3 Hz, 1H), 4.31 (d, J = 11.1 Hz, 1H,
ABq), 4.02 (d, J = 11.1 Hz, 1H, ABq), 3.51–3.00 (br, 4H), 2.02–1.69
(br, 4H); 13C NMR (50 MHz, CDCl3) d 167.3, 155.1, 137.2, 135.9,
128.3(2C), 128.0(3C), 127.6, 127.5(2C), 126.3(2C), 85.3, 79.7, 72.2,
= 0.28 (n-hexane/acetone = 2:1); [
a]
26 = ꢀ24.5 (c 0.2, CH2Cl2), 85%
70.9, 47.7, 47.2, 25.2, 24.4; HRMS-EI calcd for
349.1678 found 349.1677.
C22H23NO3,
D
ee; 1H NMR (200 MHz, CDCl3) d 7.43–7.20 (m, 10H), 4.86 (dd, J =
9.1, 5.0 Hz, 1H), 4.64 (s, 2H), 4.65 (d, J = 12.0 Hz, 1H, ABq), 4.50
(d, J = 12.0 Hz, 1H, ABq), 4.51 (s, 1H), 4.41 (s, 1H), 3.74 (dd, J =
9.6, 5.0 Hz, 1H), 3.56 (dd, J = 9.4, 9.4 Hz, 1H), 3.48–3.05 (br, 4H),
2.02–1.72 (br, 4H); 13C NMR (50 MHz, CDCl3) d 165.5, 152.7,
137.5, 136.9, 128.4(4C), 128.2(2C), 128.1, 127.9, 127.7(2C), 84.6,
75.2, 73.3, 69.6, 68.8, 68.5, 47.6, 46.9, 25.3, 24.5; HRMS-EI calcd
for C24H27NO4, 393.1940 found 393.1934. syn-7e: 3% yield, pale-
yellow oil. Rf = 0.29 (n-hexane/acetone = 2:1); 1H NMR (200 MHz,
CDCl3) d 7.42–7.20 (m, 10H), 4.79 (s, 1H), 4.62 (s, 2H), 4.65 (d, J
= 11.5 Hz, 1H, ABq), 4.53 (d, J = 11.5 Hz, 1H, ABq), 4.57–4.43 (m,
2H), 4.00–3.81 (m, 2H), 3.62–3.03 (br, 4H), 2.01–1.77 (br, 4H);
13C NMR (50 MHz, CDCl3) d 167.0, 154.4, 137.8, 137.6, 128.4(2C),
128.3(2C), 127.9(3C), 127.7, 127.5(2C), 86.3, 77.3, 73.7, 69.5, 68.2,
4.5.8. 5-Benzyloxy-6-naphthalen-1-yl-4-pyrrolidin-1-yl-5,6-
dihydro-pyran-2-one anti-7h and syn-7h
This was synthesized according to the general procedure on a 1
mmol scale in 81% yield, 64% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 10.9 min (minor), tR = 16.9
min (major)]. anti-7h: 66% yield, white solid, mp 135–136 °C;
68% ee, [HPLC Chiralcel AD, hexane/iPrOH = 3/1; flow rate 0.5 mL/
min; tR = 40.4 min (major), tR = 49.1 min (minor)]. Rf = 0.25 (n-hex-
ane/acetone = 2:1); [a]
26 = +30.0 (c 0.2, CH2Cl2), 68% ee; 1H NMR
D
(200 MHz, CDCl3) d 8.02–7.27 (m, 12H), 6.54 (s, 1H), 4.85 (s, 1H),
4.88 (d, J = 11.1 Hz, 1H, ABq), 4.75 (d, J = 11.1 Hz, 1H, ABq), 4.75
(d, J = 1.2 Hz, 1H), 3.61–3.00 (br, 4H), 2.01–1.70 (br, 4H); 13C
NMR (50 MHz, CDCl3) d 166.6, 152.3, 137.3, 133.7, 132.5, 129.9,
129.3, 128.8, 128.5(2C), 128.1, 127.9 (2C), 126.8, 125.8, 125.3,
124.3, 122.2, 86.0, 78.1, 72.3, 69.1, 47.7, 47.3, 25.3, 24.4; HRMS-
EI calcd for C26H25NO3, 399.1834 found 399.1833. syn-7h: 15%
yield, pale-yellow oil. Rf = 0.22 (n-hexane/acetone = 2:1); 1H NMR
(200 MHz, CDCl3) d 8.16–6.80 (m, 12H), 6.19 (d, J = 1.4 Hz, 1H),
4.84 (s, 1H), 4.56 (d, J = 1.4 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H, ABq),
3.68 (d, J = 11.0 Hz, 1H, ABq), 3.45–3.06 (br, 4H), 2.02–1.70 (br,
4H); 13C NMR (50 MHz, CDCl3) d 167.5, 155.5, 136.8, 133.3,
130.9, 129.4, 129.2, 128.6, 127.9(3C), 127.6(4C), 126.4, 125.7,
125.4(2C), 121.5, 84.9, 76.8, 71.6, 71.1, 47.8, 47.2, 25.1, 24.3;
HRMS-EI calcd for C26H25NO3, 399.1834 found 399.1837.
67.5, 47.7, 47.5, 25.3, 24.7; HRMS-EI calcd for
393.1940 found 393.1936.
C24H27NO4,
4.5.6. 5-Benzyloxy-6-propenyl-4-pyrrolidin-1-yl-5,6-dihydro-
pyran-2-one anti-7f and syn-7f
This was synthesized according to the general procedure on a 1
mmol scale in 75% yield, 91% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 13.0 min (major), tR = 18.8
min (minor)]. anti-7f: 72% yield, white solid, mp 109–110 °C; 77%
ee, [HPLC Chiralcel OD, hexane/iPrOH = 3/1; flow rate 0.5 mL/
min; tR = 23.0 min (major), tR = 27.4 min (minor)]. Rf = 0.31 (n-hex-
ane/acetone = 2:1); [
a]
26 = ꢀ49.5 (c 0.1, CH2Cl2), 77% ee; 1H NMR
D
(200 MHz, CDCl3) d 7.39–7.20 (m, 5H), 5.90–5.39 (m, 2H), 5.06
(d, J = 6.7 Hz, 1H), 4.66 (s, 1H), 4.69 (d, J = 11.4 Hz, 1H, ABq), 4.58
(d, J = 11.4 Hz, 1H, ABq), 4.05 (s, 1H), 3.49–2.99 (br, 4H), 1.99–
1.75 (br, 4H), 1.65 (d, J = 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) d
165.9, 152.8, 136.9, 130.6, 128.3(2C), 127.9(3C), 126.5, 85.3, 77.4,
72.3, 69.9, 47.4, 46.9, 25.1, 24.4, 17.6; IR (CH2Cl2) 2926, 1666,
1590, 1447, 1219 cmꢀ1; HRMS-EI calcd for C19H23NO3, 313.1678
found 313.1674. syn-7f: 3% yield, pale-yellow oil. Rf = 0.33 (n-hex-
ane/acetone = 2:1); 1H NMR (200 MHz, CDCl3) d 7.41–7.18(m, 5H),
6.12–5.71 (m, 2H), 4.82 (s, 1H), 4.81–4.69 (m, 1H), 4.67 (d, J = 11.2
Hz, 1H, ABq), 4.53 (d, J = 11.2 Hz, 1H, ABq), 4.27 (d, J = 3.1 Hz, 1H),
3.65–3.06 (br, 4H), 2.03–1.75 (br, 4H), 1.79 (d, J = 6.2 Hz, 3H); 13C
4.5.9. 5-Benzyloxy-4-pyrrolidin-1-yl-6-(2,3,4-trimethoxy-6-
methoxymethyl-phenyl)-5, 6-dihydro-pyran-2-one 7
This was synthesized according to the general procedure on a 1
mmol scale in 72% yield, 57% de. [HPLC Hypersil Silica, hexane/i-
PrOH = 3/1; flow rate 0.5 mL/min; tR = 23.2 min (major), tR = 25.4
min (minor)] anti-7i: 57% yield, pale-yellow solid, mp 157–158
°C; 63% ee, [HPLC Chiralcel AD-H, hexane/iPrOH = 3/1; flow rate
0.5 mL/min; tR = 15.1 min (major), tR = 20.0 min (minor)]. Rf =
0.21 (n-hexane/acetone = 2:1); [
a
]
26 = ꢀ35.6 (c 0.3, CH2Cl2), 63%
D
ee; 1H NMR (200 MHz, CDCl3) d 7.39–7.08 (m, 5H), 6.79 (s, 1H),
5.73 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H), 4.59
Please cite this article in press as: Li, Y.-J.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.003

8
Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(d, J = 11.4 Hz, 1H, ABq), 4.49 (d, J = 11.4 Hz, 1H, ABq), 4.36 (d, J =
10.5 Hz, 1H, ABq), 4.12 (d, J = 10.5 Hz, 1H, ABq), 3.88 (s, 3H), 3.86
(s, 3H), 3.84 (s, 3H), 3.38 (s, 3H), 3.41–3.18 (br, 4H), 2.05–1.79
(br, 4H); 13C NMR (50 MHz, CDCl3) d 166.9, 158.2, 153.8, 153.1,
141.9, 136.9, 133.5, 128.3(2C), 127.9, 127.8(2C), 121.9, 108.5,
83.6, 74.9, 74.0, 72.3, 71.9, 61.4, 60.7, 58.4, 55.9, 48.9(2C), 29.6
(2C); HRMS-EI calcd for C27H33NO7, 483. 2257 found 483.2254.
syn-7i: 15% yield, pale-yellow solid, mp 169–170 °C; Rf = 0.22 (n-
hexane/acetone = 2:1); 1H NMR (200 MHz, CDCl3) d 7.23–6.98(m,
6H), 5.67 (d, J = 2.3 Hz, 1H), 4.88 (d, J = 13.8 Hz, 1H, ABq), 4.70 (d,
J = 13.8 Hz, 1H, ABq), 4.65 (s, 1H), 4.20 (d, J = 2.3 Hz, 1H), 4.14 (d,
J = 10.7 Hz, 1H, ABq), 3.96 (d, J = 10.7 Hz, 1H, ABq), 3.86 (s, 3H),
3.83 (s, 3H), 3.82 (s, 3H), 3.29 (s, 3H), 3.23–3.08 (br, 4H), 1.99–
1.70(br, 4H); 13C NMR (50 MHz, CDCl3) d 166.8, 156.0, 152.8,
150.0, 139.9, 146.6, 135.2, 127.9(2C), 127.7(2C), 127.6, 117.9,
106.4, 84.3, 75.8, 73.9, 72.6, 71.5, 60.7, 60.4, 57.9, 55.5, 47.6,
47.2, 25.0, 24.1; HRMS-EI calcd for C27H33NO7, 483. 2257 found
483.2254.
4.6.5. (3S,4S)-3-Benzyloxy-4-hydroxy-octan-2-one 12d
Pale-yellow oil. Rf = 0.35 (n-hexane/acetone = 2:1);
26
[
a
]
=
D
ꢀ145.3 (c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.42–7.27(m,
5H), 4.65 (d, J = 11.5 Hz, 1H, ABq), 4.49 (d, J = 11.5 Hz, 1H, ABq),
3.92–3.79(m, 1H), 3.73(d, J = 4.9 Hz, 1H), 2.23(s, 3H), 1.58–1.19
(m, 6H), 0.89(t, J = 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 210.4,
137.0, 128.6(2C), 128.2, 127.9(2C), 87.8, 73.1, 72.1, 32.1, 27.7,
27.5, 22.5, 13; HRMS-EI calcd for C15H22O3, 250.1569 found
250.1566.
4.6.6. (3S,4S)-3,5-Bis-benzyloxy-4-hydroxy-pentan-2-one 12e
26
Pale-yellow oil. Rf = 0.45 (n-hexane/acetone = 2:1);
[
a
]
=
D
ꢀ30.5 (c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.42–7.20 (m,
10H), 4.61 (d, J = 11.5 Hz, 1H, ABq), 4.58–4.42 (m, 2H), 4.45 (d, J
= 11.5 Hz, 1H, ABq), 4.11–4.00 (m, 1H), 3.87 (d, J = 6.4 Hz, 1H),
3.65–3.48 (m, 2H), 2.22 (s, 3H); 13C NMR (50 MHz, CDCl3) d
209.7, 137.6, 136.9, 128.5 (2C), 128.4 (2C), 128.1, 128.0 (2C),
127.8 (3C), 84.4, 73.4, 73.1, 70.9, 69.9, 27.2; HRMS-EI calcd for
C19H22O4, 314.1518 found 314.1521.
4.6. Synthesis of 11 and 12a-h
4.6.7. (3S,4S)-3-Benzyloxy-4-hydroxy-hept-5-en-2-one 12f
4.6.1. (3S,4S)-3-Benzyloxy-4-hydroxy-5-methyl-hexan-2-one 11
To anti-6 (60 mg, 0.19 mmol) in 10 mL round bottom flask with
THF (2 mL) was added 4 M HCl aqueous solution (0.95 mL, 3.8
mmol) and let to stir for 36 h. The reaction mixture was added 1
N NH4Cl aqueous solution (5 mL) then extracted with CH2Cl2 (15
mL ꢁ 2), combined organic layers were dried over anhydrous
sodium sulfate, followed by concentration to afford the crude
material. The crude was purified by flash chromatography (n-hex-
ane:acetone, 3:1) to give 40 mg of 11 in 90% yield. Pale-yellow oil.
Pale-yellow oil. Rf = 0.51 (n-hexane/acetone = 2:1); [
a]
26 = ꢀ9.3
D
(c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.42–7.26 (m, 5H),
5.83–5.40 (m, 2H), 4.68 (d, J = 11.6 Hz, 1H, ABq), 4.53 (d, J = 11.6
Hz, 1H, ABq), 4.39–4.30 (m, 1H), 3.85 (d, J = 4.9 Hz, 1H), 2.19 (s,
3H), 1.70 (d, J = 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 209.7,
137.0, 129.9, 128.6(2C), 128.3, 128.2, 128.0(2C), 87.5, 73.4, 73.2,
27.5, 17.8; HRMS-EI calcd for C14H18O3, 234.1256 found 234.1258.
Rf = 0.58 (n-hexane/acetone = 2:1); [
a]
D
26 = ꢀ39.9 (c 0.2, CH2Cl2); 1H
4.6.8. (3S,4S)-3-Benzyloxy-4-hydroxy-4-phenyl-butan-2-one 12g
26
NMR (200 MHz, CDCl3) d 7.42–7.28 (m, 5H), 4.61 (d, J = 11.4 Hz, 1H,
ABq), 4.46 (d, J = 11.4 Hz, 1H, ABq), 3.77 (d, J = 6.1 Hz, 1H), 3.62 (dd,
J = 6.0, 5.9 Hz, 1H), 2.26 (s, 3H), 1.93–1.78 (m, 1H), 0.96 (d, J = 6.8
Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 211.1,
136.9, 128.5(2C), 128.1, 127.9(2C), 85.7, 76.5, 72.7, 29.5, 27.1, 19.3,
16.7; HRMS-EI calcd for C14H20O3, 236.1412 found 236.1410.
Pale-yellow oil. Rf = 0.51 (n-hexane/acetone = 2:1);
[
a
]
=
D
ꢀ22.1 (c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.21–7.05 (m,
10H), 4.90 (d, J = 6.5 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H, ABq), 4.29
(d, J = 11.5 Hz, 1H, ABq), 3.94 (d, J = 6.5 Hz, 1H), 3.42–3.29 (br,
1H), 2.09 (s, 3H); 13C NMR (50 MHz, CDCl3) d 210.1, 139.8, 136.7,
128.3(2C), 128.1(2C), 127.9, 127.8, 127.7(2C), 126.7(2C), 87.5,
74.1, 73.1, 27.2; HRMS-EI calcd for C17H18O3, 270.1256 found
270.1255.
4.6.2. (3S,4S)-3-Benzyloxy-4-hydroxy-pentan-2-one 12a
26
Pale-yellow oil. Rf = 0.43 (n-hexane/acetone = 2:1);
[
a]
=
D
ꢀ16.9 (c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.42–7.30 (m,
5H), 4.67 (d, J = 11.5 Hz, 1H, ABq), 4.51 (d, J = 11.5 Hz, 1H, ABq),
4.17–4.01 (m, 1H), 3.72 (d, J = 4.9 Hz, 1H), 2.23 (s, 3H), 1.19 (d, J
= 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 210.4, 136.9, 128.6(2C),
128.2, 127.9 (2C), 88.3, 73.3, 68.2, 27.4, 18.4; HRMS-EI calcd for
4.6.9. (3S,4S)-3-Benzyloxy-4-hydroxy-4-naphthalen-1-yl-butan-
2-one 12h
Pale-yellow oil. Rf = 0.45 (n-hexane/acetone = 2:1); [
a]
26 = ꢀ9.0
D
(c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.99–7.00 (m, 12H),
5.73 (d, J = 5.8 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H, ABq), 4.22 (d, J =
5.8 Hz, 1H), 4.17 (d, J = 11.5 Hz, 1H, ABq), 2.09 (s, 3H); 13C NMR
(50 MHz, CDCl3) d 209.4, 136.6, 135.0, 133.6, 130.6, 128.9, 128.7,
128.4 (2C), 128.2 (2C), 128.1, 126.2, 125.6, 125.3, 124.4, 123.0,
86.6, 73.2, 71.5, 28.1; HRMS-EI calcd for C21H20O3, 320.1412 found
320.1409.
C12H16O3, 208.1099 found 208.1095.
4.6.3. (3S,4S)-3-Benzyloxy-4-hydroxy-hexan-2-one 12b
26
Pale-yellow oil. Rf = 0.48 (n-hexane/acetone = 2:1);
[
a]
=
D
ꢀ26.8 (c 0.1, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.41–7.26 (m,
5H), 4.65(d, J = 11.4 Hz, 1H, ABq), 4.49 (d, J = 11.4 Hz, 1H, ABq),
3.82–3.71 (m, 2H), 2.24 (s, 3H), 1.60–1.41 (m, 2H), 0.96 (t, J = 7.3
Hz, 3H); 13C NMR (50 MHz, CDCl3) d 210.6, 136.9, 128.6(2C),
128.2, 127.9(2C), 87.5, 73.5, 73.1, 27.4, 25.5, 9.9; HRMS-EI calcd
for C13H18O3, 222.1256 found 222.1258.
4.7. Synthesis of 13
To Pd/C (100 mg) with MeOH (3 mL) in a 10 mL round bot-
tom flask was added compound 11 (100 mg, 0.42 mmol) in 1
mL MeOH. The reaction misture was hydrogenated under hydro-
gen atmosphere (1 atm) for 3 h, the reaction was filtered, fol-
lowed by concentration to afford the crude material. The crude
was purified by flash chromatography (n-hexane:acetone, 3:1)
to give 57 mg of 13 in 93% yield. Pale-yellow oil. Rf = 0.36 (n-
4.6.4. (3S,4S)-3-Benzyloxy-4-hydroxy-heptan-2-one 12c
26
Pale-yellow oil. Rf = 0.56 (n-hexane/acetone = 2:1);
[
a]
=
D
ꢀ56.4 (c 0.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) d 7.42–7.30 (m,
5H), 4.64 (d, J = 11.5 Hz, 1H, ABq), 4.48 (d, J = 11.5 Hz, 1H, ABq),
3.99–3.82 (br, 1H), 3.73 (d, J = 4.9 Hz, 1H), 2.23 (s, 3H), 1.50–1.21
(m, 4H), 0.91 (t, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3) d
210.5, 136.9, 128.6(2C), 128.2, 127.9(2C), 87.8, 73.1, 71.8, 34.5,
27.5, 18.8, 13.9; HRMS-EI calcd for C14H20O3, 236.1412 found
236.1409.
hexane/acetone = 2:1);
[a]
26 = +64.7 (c 0.1, CHCl3); 1H NMR
D
(200 MHz, CDCl3) d 4.18 (d, J = 5.5 Hz, 1H), 3.49 (t, J = 5.6 Hz,
1H), 2.29 (s, 3H), 2.02–1.85 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H),
0.94 (d, J = 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 210.1, 78.6,
77.9, 29.9, 27.7, 19.5, 16.9.
Please cite this article in press as: Li, Y.-J.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.003

Y.-J. Li et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
3. Li, Y.-J.; Hung, H.-Y.; Liu, Y.-W.; Lin, P.-J.; Huang, H.-J. Tetrahedron 2011, 67, 927–
935.
Acknowledgments
4. (a) Zawacki, F. J.; Crimmins, M. T. Tetrahedron Lett. 1996, 37, 6499–6502; (b)
Lloyd, J.; Finlay, H. J.; Atwal, K.; Kover, A.; Prol, J.; Yan, L.; Bhandaru, R.; Vaccaro,
W.; Huynh, T.; Huang, C. S.; Conder, M.; Jenkins-West, T.; Sun, H.; Li, D.;
Levesque, P. Bioorg. Med. Chem. Lett. 2009, 19, 5469–5473.
We would like to thank the Ministry of Science and Technology
of Taiwan (NSC-89-2113-M-324-003 & MOST-105-2113-M-415-
005) for generous financial support. Partial support of the Mass
spectrometer facility provided by National Chung-Hsing University
is also acknowledged.
5. Chiral alcohols 3a-c were purchased commercially from AldrichÒ, synthesis of
3d, 3e see: Oppolzer, W.; Radinov, R.; Rumen, N. Tetrahedron Lett. 1988, 29,
5645–5648; Syntheses of 3f see: Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J.; Yang, K.-S.;
Lain, J.-C.; Lin, C.-H.; Chen, K. J. Org. Chem. 1999, 64, 6993–6998.
6. E configuration of 5a–f were assigned by analogous to the X-ray structures of
the related compounds in Ref. 3.
A. Supplementary data
7. CCDC 1490189 contain the supplementary crystallographic data for anti-6.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
Supplementary data (1H and 13C NMR spectra for compounds
4a-f, 5a-f, anti-6, anti-7a-i, and 12a-h are provided) associated
with this article can be found, in the online version, at
https://doi.org/10.1016/j.tetasy.2017.10.003.
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Please cite this article in press as: Li, Y.-J.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.003