Stereoselective synthesis of (-)-centrolobine

Article abstract of DOI:10.1016/j.tetasy.2013.12.019

The stereoselective synthesis of (-)-centrolobine has been accomplished starting from d-glyceraldehyde acetonide by a combination of chelation-controlled diastereoselective alkylation and ring-closing metathesis. A high degree of 1,3-asymmetric induction has been realized in an ether system.

Full text of DOI:10.1016/j.tetasy.2013.12.019

Tetrahedron: Asymmetry 25 (2014) 305–309
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (ꢀ)-centrolobine
⇑
Zunhua Yang, Hee-Doo Kim
College of Pharmacy, Sookmyung Women’s University, 53-12, Chungpa-dong, Yongsan-ku, Seoul 140-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 November 2013
Accepted 16 December 2013
The stereoselective synthesis of (ꢀ)-centrolobine has been accomplished starting from
D-glyceraldehyde
acetonide by
a combination of chelation-controlled diastereoselective alkylation and ring-closing
metathesis. A high degree of 1,3-asymmetric induction has been realized in an ether system.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
ters around an ether oxygen has become a key approach for the
general synthesis of numerous cyclic ethers with different sizes,
having alkyl substituents on both the carbons flanking the ether
linkage. Our interest in this molecule is due to our recent success
with chelation-controlled stereoselective alkylation.7 Herein we
report on an extension of this methodology to the asymmetric syn-
thesis of (ꢀ)-centrolobine.
A large number of cyclic ethers have been isolated from a wide
range of organisms with a broad range of biological activity.1 Some
compounds of this class contain a six-membered tetrahydropyran
ring usually with a syn-stereochemistry in the alkyl substituents on
both carbons flanking the ether linkage.2 For example, (ꢀ)-centrol-
obine (Fig. 1) has been the subject of significant synthetic effort
due to its tetrahydropyran ring structure and unique biological
activities. (ꢀ)-Centrolobine, isolated from the heartwood of Cen-
trolobium robustum and the stem of Brosimum potabile,3 exhibits
anti-inflammatory, and antibacterial as well as anti-leishmanial
activity.4 A handful of stereoselective syntheses of centrolobine
have been reported in the literature.5
Our synthetic strategy for (ꢀ)-centrolobine is outlined in
Scheme 1, which involved a chelation-controlled stereoselective
alkylation and RCM reaction as the key steps. It was anticipated
that the diastereoselective alkylation of chiral benzyloxyacetic acid
3 derived from chiral auxiliary 4, followed by the functional group
transformation of 2 would furnish acyclic diene 1 with the
requisite stereogenic center around the ether oxygen. Cyclization
of acyclic diene 1 via RCM using Grubbs catalyst, followed by
functional group elaboration would provide the target compound
(ꢀ)-centrolobine.
O
2. Results and discussion
H3CO
Figure 1. Structure of (ꢀ)-centrolobine.
OH
The synthesis of (ꢀ)-centrolobine started with the preparation
of chiral acetamide 5 as a substrate for the stereoselective alkyl-
ation reaction (Scheme 2). Chiral benzyl alcohol 4, readily prepared
from
D
-glyceraldehyde acetonide,8 was conjugated by a benzyl
However, based on the conformational preference of cis-over
trans-2,6-disubstituted tetrahydropyran, many of the previous
methods have relied on various cycloetherification reactions using
pre-installed chiral alcohol. However, the synthesis of centrolobine
using a cycloetherification method has the limitation of being only
applicable to six-membered cyclic ethers. Thus, the stereoselective
synthesis of cyclic ether derivatives with different ring sizes,
including six-membered tetrahydropyrans, requires a more gen-
eral method for the construction of the ring units. Considering
the availability of ring-closing metathesis (RCM) developed by
Grubbs et al.6 the stereoselective creation of two stereogenic cen-
ether linkage. Treatment of 4 with NaH, followed by O-alkylation
with 2-chloro-N,N-diethylacetamide in dimethoxyethane at
ꢀ10 °C afforded the chiral auxiliary-conjugated acetamide 5 in
80% yield. Generation of the corresponding enolate of 5 was carried
out with LHMDS in THF at ꢀ78 °C. The subsequent addition of 1-
(benzyloxy)-4-(2-iodoethyl)benzene produced an 11:1 ratio of
the syn-isomer 6a and anti-isomer 6b, isolated in 57% and 5%
yields, respectively. The absolute configuration of the newly cre-
ated stereogenic center on 6a could not be established at the pres-
ent stage, but it was tentatively assigned as (S) on the basis of our
proposed chelation model as shown in Figure 2.7a The preferential
formation of 6a over 6b could be rationalized by considering the
following chelation model of a highly organized enolate complex,
⇑
Corresponding author. Tel.: +82 2 710 9567; fax: +82 2 703 0736.
E-mail address: hdkim@sm.ac.kr (H.-D. Kim).
0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.019

306
Z. Yang, H.-D. Kim / Tetrahedron: Asymmetry 25 (2014) 305–309
O
O
X
O
O
FG
O
O
3
X
stereo selective
alkylation
FG
O
RCM
O
(-)-centrolobine
H3CO
OH
H3CO
H3CO
1
2
4
OR
H3CO
OR
Scheme 1. Retrosynthetic analysis for (ꢀ)-centrolobine.
O
O
O
O
O
O
O
CONEt2
CONEt2
O
ii
62%
i
ref. 6
O
OH
O
80%
80%
H3CO
H
O
H3CO
H3CO
5
6
4
D-glyceraldehyde
acetonide
OBn
dr=11:1
S
OH
O
CONEt2
OH
O
CONEt2
CONEt2
iv
86%
iii
98%
O
v
O
O
95%
H3CO
H3CO
H3CO
OBn
7
8
9
OBn
OBn
Scheme 2. Synthesis of dialkylated ether 9. Reagents and conditions: (i) NaH, DME, ꢀ10 °C, then ClCH2CONEt2; (ii) LHMDS, THF, ꢀ78 to 10 °C, then 4-benzyloxyphenethyl
iodide; (iii) PPTS, MeOH, reflux; (iv) TCDI, toluene, reflux; (v) P(OMe)3, reflux.
An alkoxy group at its a-position enables amide 9 to form sta-
NEt2
ble chelates upon treatment with organometallics, and does not
regenerate an electrophilic carbonyl group in situ for further reac-
tion, that is, amide 9 could act in the same way as a Weinreb
amide toward a Grignard reagent.9 Thus, when 9 was treated with
vinylmagnesium bromide at room temperature, the desired dienyl
ketone 10 was obtained in 70% yield. The stage was set for the
RCM. Exposure of diene 10 to the 2nd generation Grubbs’ cata-
lyst10 14 in dichloromethane at room temperature gave cyclohexe-
none 11 in 88% yield. Treatment of enone 11 with LiAlH4 in
refluxing THF produced alcohol 12 as a 2:1 inseparable mixture
of epimers in 87% isolated yield. The hydroxyl group could be
transformed into the corresponding thiocarbamate by treating
12 with TCDI in refluxing toluene. After conversion to the thiocar-
bamate, the two epimers became separable by silica gel chroma-
tography, and were isolated in 63% and 24% yields. However, the
separation of the two epimers was not important since the newly
created stereogenic centers were destined to be removed. The
major and minor epimers were combined for the next step. The
conversion routes to centrolobine with a variety of reagents and
conditions were explored and a one pot reaction from 13 to
centrolobine was discovered. By treatment with Raney–Nickel in
ethanol under a hydrogen atmosphere, 13 underwent deoxygen-
ation, debenzylation, and double bond reductions concomitantly
to generate (ꢀ)-centrolobine in 95% yield. The synthetic centrolo-
bine was identical in all aspects (1H NMR, 13C NMR and IR) to
those reported for natural (ꢀ)-centrolobine. The specific rotation
O
H
O
O
Li
+
O
OCH3
Figure 2. Plausible transition state for alkylation.
which resulted from tridentate chelation of the internal two oxy-
gens with a lithium ion.
In this model, the cyclic ring containing an enolate is puckered
to thus minimize the steric interaction with the nearby aromatic
ring. Thus, the electrophile approaches from the less hindered con-
vex side. Deprotection of the acetonide group on 6a was effected
with pyridinium p-toluenesulfonate in refluxing methanol, to give
diol 7 in 98% yield. The reaction of diol 7 with thiocarbonyldiimi-
dazole (TCDI) in refluxing toluene gave the cyclic thiocarbonate 8
in 86% yield. Upon exposure to trimethyl phosphite at reflux, cyclic
thiocarbonate 8 underwent reductive elimination to form the de-
sired vinyl compound 9 in 95% yield.
After installing the vinyl group, we next turned out attention to
the preparation of the requisite second vinyl group for the RCM
reaction. The subsequent cyclization and completion of the synthe-
sis of (ꢀ)-centrolobine is shown in Scheme 3.
of the synthetic sample {½a D27
ꢁ
¼ ꢀ89:3 (c 1, CHCl3)} was virtually
¼ ꢀ92:2
identical to the value reported by Alcantara et al. {½a D
ꢁ
(c 1, CHCl3)}.3d

Z. Yang, H.-D. Kim / Tetrahedron: Asymmetry 25 (2014) 305–309
307
MesN
NMes
14
Ph
O
O
O
NEt2
O
O
Cl
Cl
Ru
PCy3
i
O
H3CO
H3CO
ii 88%
70%
H3CO
11
10
9
OBn
OBn
OBn
N
OH
O
N
iii
v
iv
O
S
O
O
87%
87%
95%
H3CO
H3CO
H3CO
12
13
(-)-centrolobine
OH
OBn
OBn
Scheme 3. Synthesis of (ꢀ)-centrolobine starting from dialkylated ether 9. Reagents and conditions: (i) vinylmagnesium bromide, THF, rt; (ii) 14, CH2Cl2, rt; (iii) LiAlH4, THF,
reflux; (iv) TCDI, toluene, reflux; (v) H2, Ra-Ni, EtOH, rt.
crude residue was diluted with EtOAc (20 mL). The organic layer
was washed with water and brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography eluting with 33%
ethyl acetate in hexane to give the alkoxy amide 5 as an oil
3. Conclusion
In conclusion, we have shown that (ꢀ)-centrolobine can be pre-
pared efficiently from D-glyceraldehyde acetonide with 14% overall
yield in 11 steps involving chelation-controlled diastereoselective
alkylation and ring-closing metathesis. The stereoselective crea-
tion of two stereogenic centers around the ether oxygen has been
successfully achieved based on 1,3-asymmetric induction, which
has rarely been realized before in an ether system. Thus, the com-
bination of a chelation-controlled asymmetric induction and an
RCM might hold great potential as a solution for the general syn-
thesis of a variety of cyclic ethers with different sizes, having alkyl
substituents on both carbons flanking the ether linkage.
(2.0 g, 80%): ½a 2D8
ꢁ
¼ ꢀ67:5 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.26 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.42 (m, 2H), 4.12
(d, J = 13.6 Hz, 1H), 3.98 (d, J = 13.6 Hz, 1H), 3.80 (s, 3H), 3.66 (dd,
J = 6.0, 8.4 Hz, 1H), 3.57 (dd, J = 6.4, 8.4 Hz, 1H), 3.40–3.20 (m,
4H), 1.41 and 1.36 (s, 3H, each), 1.15–1.05 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 168.0, 159.8, 129.1, 129.0, 113.9, 109.9, 83.0,
78.9, 67.5, 66.0, 55.2, 41.0, 39.9, 26.6, 25.5, 14.1, 12.8; HRMS
(FAB) calcd for C19H30NO5 (M+H) 352.2124, observed 352.2131.
4.3. (S)-4-(4-(Benzyloxy)phenyl)-2-((R)-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)(4-methoxyphenyl)methoxy)-N,N-diethylbutan-
amide 6a
4. Experimental
4.1. General
To a solution of amide 5 (351 mg, 1.00 mmol) in anhydrous THF
(6 mL) was added dropwise an LHMDS solution (2.00 mL,
2.00 mmol, 1 M in THF) at ꢀ78 °C. After 0.5 h, a solution of
1-(benzyloxy)-4-(2-iodoethyl)benzene (1.18 g, 3.50 mmol) in THF
(8 mL) was added. The reaction mixture was then stirred at this
temperature for 4 h, quenched with brine (20 mL), and extracted
with EtOAc (2 ꢂ 50 mL). The organic layer was dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography eluting
with 30% ethyl acetate in hexane to give 2 diastereomers as a col-
orless oil. (S,R,R)-6a (320 mg, 57%): Rf = 0.50 (n-hexane–EtOAc =
Optical rotations were measured on a JASCO DIP 1000 digital
polarimeter. 1H NMR and 13C NMR spectra were obtained on a Var-
ian Inova 400 spectrometer and the chemical shifts are reported as
values in parts per million (d) relative to tetramethylsilane (TMS)
as the internal standard. The infrared spectra (IR) were recorded
on a JASCO FT/IR-430 spectrophotometer. Thin layer chromatogra-
phy (TLC) was carried out on 0.25 mm E. Merck precoated silica gel
glass plates (60F254). Column chromatography was performed
using the forced flow of the indicated solvent on Merck Kieselgel
60 (230–400 mesh). Unless otherwise noted, the materials were
obtained from commercially available sources and were used with-
out further purification. THF was freshly distilled from sodium
benzophenone ketyl under an argon atmosphere. DCM, DME, and
toluene were freshly distilled under a nitrogen atmosphere with
calcium hydride.
1:2); ½a 2D8
ꢁ
¼ ꢀ47:9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.42–7.28 (m, 5H), 7.23 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H),
6.86 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 4.37
(dd, J = 6.4, 12.8 Hz, 1H), 4.26 (d, J = 6.4 Hz, 1H), 3.97 (dd, J = 3.2,
9.2 Hz, 1H), 3.78 (s, 3H), 3.73 (d, J = 6.4 Hz, 2H), 3.46 (m, 1H),
3.30–2.90 (m, 3H), 2.79 (m, 1H), 2.46 (m, 1H), 2.09 (m, 1H), 1.77
(m, 1H), 1.36 and 1.34 (s, 3H, each), 1.06 (t, J = 6.8 Hz, 3H), 0.89
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 170.5, 159.7,
157.0, 137.1, 133.9, 129.7, 129.4, 128.5, 127.8, 127.4, 114.7,
113.8, 109.8, 80.5, 78.7, 75.0, 70.0, 65.9, 55.2, 40.7, 40.1, 35.0,
4.2. 2-((R)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(4-methoxy-
phenyl)methoxy)-N,N-diethylacetamide 5
To a solution of alcohol 4 (1.7 g, 7.1 mmol) in anhydrous dime-
thoxyethane (7 mL) was added NaH (60% in oil, 700 mg,
17.5 mmol) portionwise at room temperature. After 0.5 h, a solu-
tion of 2-chloro-N,N-diethylacetamide (1.3 mL, 9.2 mmol) in DME
(2 mL) was added to the reaction mixture at ꢀ10 °C. The mixture
was then stirred at this temperature for 2 h, quenched with meth-
anol and H2O (2 mL), then concentrated in vacuo. The resulting
31.2, 26.5, 25.7, 14.3, 12.9; IR (NaCl)
m 2933, 2360, 1649, 1611,
1511, 1455, 1243, 640; HRMS (FAB) calcd for C34H44NO6 (M+H)
562.3169, observed 562.3167. (R,R,R)-6b (29 mg, 5%): Rf = 0.45
(n-hexane–EtOAc = 1:2); ½a D28
ꢁ
¼ ꢀ24:4 (c 0.2, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.44–7.28 (m, 5H), 7.18 (d, J = 8.4 Hz, 2H),

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Z. Yang, H.-D. Kim / Tetrahedron: Asymmetry 25 (2014) 305–309
7.14 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz,
2H), 5.03 (s, 2H), 4.41 (dd, J = 7.6, 14.4 Hz, 1H), 4.24 (d, J = 8.0 Hz,
1H), 4.19 (dd, J = 4.0, 8.8 Hz, 1H), 3.75 (s, 3H), 3.60 (dd, J = 6.4,
8.4 Hz, 1H), 3.40 (dd, J = 7.6, 8.4 Hz, 1H), 3.20–2.70 (m, 6H), 2.09
(m, 1H), 1.80 (m, 1H), 1.38 and 1.35 (s, 3H, each), 0.95–0.80 (m,
6H); 13C NMR (100 MHz, CDCl3) d 170.9, 159.7, 157.0, 137.2,
134.1, 130.0, 129.6, 129.0, 128.5, 128.4, 127.8, 127.4, 114.7,
113.7, 110.0, 83.8, 79.3, 76.8, 70.0, 66.0, 55.2, 40.8, 40.1, 35.1,
fied by column chromatography eluting with 33% ethyl acetate in
hexane to give alkene 8 as a colorless oil (550 mg, 95%): Rf = 0.40
(n-hexane–EtOAc = 1:1); ½a D25
ꢁ
¼ ꢀ31:2 (c 0.3, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.40–7.20 (m, 7H), 6.92 (d, J = 8.4 Hz, 2H),
6.87 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.02 (m, 1H), 5.15
(m, 2H), 4.99 (s, 2H), 4.72 (d, J = 5.6 Hz, 1H), 3.95 (dd, J = 3.2,
9.2 Hz, 1H), 3.79 (s, 3H), 3.42 (m, 1H), 3.21 (m, 1H), 3.05 (m, 2H),
2.76 (m, 1H), 2.47 (m, 1H), 2.05 (m, 1H), 1.74 (m, 1H), 1.07 (t,
J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 171.0, 159.4, 157.0, 139.2, 137.2, 133.8, 132.4, 129.5, 129.0,
128.5, 127.9, 127.4, 115.7, 114.7, 113.9, 80.8, 74.1, 69.9, 55.2,
30.7, 26.7, 25.6, 14.2, 12.7; IR (NaCl)
1378, 1243, 632.
m 2918, 1648, 1511, 1456,
4.4. (S)-4-(4-(Benzyloxy)phenyl)-2-((1R,2R)-2,3-dihydroxy-1-(4-
methoxyphenyl)propoxy)-N,N-diethylbutanamide 7
40.7, 40.2, 35.3, 31.0, 14.3, 12.9; IR (NaCl) m 2917, 2359, 1653,
1508, 1457, 1243, 636; HRMS (FAB) calcd for C31H38NO4 (M+H)
488.2801, observed 488.2798.
To a solution of acetonide 6a (800 mg, 1.42 mmol) in MeOH
(20 mL) was added a catalytic amount of PPTS (30 mg). The reac-
tion mixture was then refluxed and stirred for 2 h, cooled down
to rt, evaporated to dryness, dissolved in CH2Cl2 (50 mL), washed
with water (10 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography eluting with 40% acetone in
hexane to give diol 7 as a colorless oil (726 mg, 98%): Rf = 0.40
4.7. (S)-6-(4-(Benzyloxy)phenyl)-4-((S)-1-(4-methoxyphenyl)-
allyloxy)hex-1-en-3-one 10
To a solution of amide 9 (470 mg, 0.96 mmol) in THF (10 mL)
was added vinyl magnesium bromide (1.44 mL, 1 M in THF,
1.44 mmol) dropwise at room temperature. The reaction mixture
was stirred for 1 h, then diluted with EtOAc (100 mL), washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography eluting with 12% EtOAc in hexane to give diene
10 as a colorless oil (300 mg, 70%): Rf = 0.75 (n-hexane–EtOAc =
(n-hexane–acetone = 3:2); ½a D25
ꢁ
¼ ꢀ110:4 (c 0.43, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.40–7.25 (m, 7H), 6.92 (d, J = 8.4 Hz, 2H),
6.71 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 5.16 (s, 1H), 4.97
(s, 2H), 4.00 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 8.4 Hz, 1H), 3.80 (m,
4H), 3.65–3.50 (m, 2H), 3.20 (m, 1H), 3.00 (m, 1H), 2.85–2.65 (m,
4H), 2.42 (m, 1H), 2.03 (m, 1H), 1.59 (m, 1H), 1.06 (t, J = 7.2 Hz,
3H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 172.6,
159.9, 157.0, 137.0, 133.3, 130.3, 129.5, 129.2, 128.5, 127.9,
127.4, 114.7, 114.1, 82.3, 74.9, 72.7, 69.9, 62.6, 55.3, 40.6, 40.5,
2:1); ½a 2D5
ꢁ
¼ ꢀ38:7 (c 0.37, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.40–7.20 (m, 7H), 6.94 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H),
6.82 (d, J = 8.4 Hz, 2H), 6.77 (m, 1H), 6.36 (d, J = 17.2 Hz, 1H),
5.98 (m, 1H), 5.75 (d, J = 10.4 Hz, 1H), 5.23 (d, J = 17.2 Hz, 1H),
5.15 (d, J = 10.4 Hz, 1H), 5.00 (s, 2H), 4.64 (d, J = 6.4 Hz, 1H), 3.87
(dd, J = 4.0, 8.4 Hz, 1H), 3.79 (s, 3H), 2.68 (m, 1H), 2.46 (m, 1H),
1.93 (m, 1H), 1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) d 201.7,
159.4, 157.0, 138.5, 137.1, 133.5, 131.9, 131.4, 130.9, 129.6,
129.3, 128.8, 128.7, 128.5, 127.9, 127.4, 116.2, 114.7, 113.9, 81.9,
35.6, 30.6, 14.3, 12.9; IR (NaCl)
m 3376, 2932, 1631, 1511, 1454,
1246; HRMS (FAB) calcd for C31H40NO6 (M+H) 522.2856, observed
522.2852.
4.5. (S)-4-(4-(Benzyloxy)phenyl)-N,N-diethyl-2-((R)-(4-methoxy-
phenyl)((R)2-thioxo-1,3-dioxolan-4-yl)methoxy)butanamide 8
80.8, 70.0, 55.3, 34.5, 30.6; IR (NaCl) m 2918, 2849, 2360, 1698,
1608, 1508, 1241, 636; HRMS (FAB) calcd for C29H30O4 (M+)
442.2144, observed 442.2143.
A mixture of diol 7 (720 mg, 1.38 mmol) and thiocarbonyldiim-
idazole (295 mg, 1.65 mmol) in toluene (15 mL) was heated at re-
flux for 1 h, then cooled down to rt, diluted with EtOAc (100 mL),
washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
by column chromatography eluting with 20% acetone in hexane to
give thiocarbonate 8 as a white foam (670 mg, 86%): Rf = 0.30 (n-
4.8. (2S,6S)-2-(4-(Benzyloxy)phenethyl)-6-(4-methoxyphenyl)-
2H-pyran-3(6H)-one 11
To a solution of diene 10 (300 mg, 0.68 mmol) in CH2Cl2
(150 mL, 4.5 ꢂ 10ꢀ3 M) was added 2nd generation Grubbs’ catalyst
14 (29 mg, 0.03 mmol) at room temperature. The reaction mixture
was stirred for 8 h, and then evaporated to dryness under reduced
pressure, which was purified by column chromatography eluting
with 10% EtOAc in hexane to give pyranone 11 as a colorless oil
hexane–acetone = 3:1); ½a D25
ꢁ
¼ ꢀ140:8 (c 0.4, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.40–7.25 (m, 7H), 7.00 (d, J = 8.4 Hz, 2H),
6.88 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 5.35 (dd, J = 5.2,
8.4 Hz, 1H), 4.99 (s, 2H), 4.94 (m, 1H), 4.61 (t, J = 8.4 Hz, 1H), 4.37
(d, J = 2.0 Hz, 1H), 3.95 (dd, J = 2.0, 8.4 Hz, 1H), 3.79 (s, 3H), 3.49
(m, 1H), 3.06 (m, 1H), 2.90–2.70 (m, 3H), 2.58 (m, 1H), 2.02 (m,
1H), 1.72 (m, 1H), 1.05 (t, J = 7.2 Hz, 3H), 0.71 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 192.4, 170.2, 160.3, 157.0, 137.1,
133.5, 129.5, 128.5, 127.8, 127.4, 127.0, 114.7, 114.2, 84.0, 77.5,
(220 mg, 88%): Rf = 0.30 (n-hexane–EtOAc = 6:1); ½a D25
¼ ꢀ183:9
ꢁ
(c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.45–7.25 (m, 7H),
7.11 (d, J = 8.8 Hz, 2H), 6.97 (dd, J = 1.6, 10.0 Hz, 1H), 6.93 (d,
J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.15 (dd, J = 2.4, 10.0 Hz,
1H), 5.26 (dd, J = 2.4, 4.0 Hz, 1H), 5.02 (s, 2H), 4.04 (m, 1H), 3.81
(s, 3H), 2.72 (m, 2H), 2.27 (m, 1H), 2.01 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 196.3, 159.8, 157.1, 150.9, 137.2, 133.9,
131.4, 129.6, 128.6, 127.9, 127.5, 126.8, 114.8, 114.2, 79.5, 76.5,
72.0, 71.1, 69.9, 55.3, 40.9, 40.4, 35.4, 30.5, 14.1, 13.0; IR (NaCl)
2929, 2383, 1611, 1511, 1455, 1290; HRMS (FAB) calcd for
32H38NO6S (M+H) 564.2420, observed 564.2415.
m
C
70.0, 55.4, 31.4, 30.0; IR (NaCl) m 2918, 1686, 1611, 1509, 1247,
632; HRMS (FAB) calcd for C27H26O4 (M+) 414.1831, observed
414.1835.
4.6. (S)-4-(4-(Benzyloxy)phenyl)-N,N-diethyl-2-((S)-1-(4-methoxy-
phenyl)allyloxy)butanamide 9
4.9. (2S,6S)-2-(4-(Benzyloxy)phenethyl)-6-(4-methoxyphenyl)-
3,6-dihydro-2H-pyran-3-ol 12
A mixture of thiocarbonate 7 (670 mg, 1.19 mmol) in trimethyl
phosphite (10 mL) was heated at reflux for 48 h, then cooled down
to rt, evaporated to dryness, dissolved in EtOAc (100 mL), washed
with water (50 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was puri-
To
a suspension of lithium aluminum hydride (15 mg,
0.39 mmol) in THF (2 mL) was added dropwise a solution of pyra-
none 11 (105 mg, 0.25 mmol) in THF (3 mL) at room temperature.

Z. Yang, H.-D. Kim / Tetrahedron: Asymmetry 25 (2014) 305–309
309
The reaction mixture was stirred and refluxed for 1 h, then cooled,
quenched with 1 drop of water and 20% NaOH, diluted with THF
(50 mL), dried over anhydrous K2CO3, filtered on Celite, and con-
centrated under reduced pressure. The crude product was purified
by column chromatography eluting with 25% EtOAc in hexane to
give allylic alcohol 12 as a colorless oil (92 mg, 87%): Rf = 0.20
(n-hexane–EtOAc = 3:1); 1H NMR (400 MHz, CDCl3) d 7.47–7.28
(m, 7H), 7.15 (d, J = 8.8 Hz, 2H), 6.94–6.88 (m, 4H), 6.20–5.80 (m,
2H), 5.10–5.00 (m, 3H), 4.05 (m, 1H), 3.80 (s, 3H), 3.59 (m, 1/3H),
3.35 (m, 2/3H), 2.91–2.65 (m, 2H), 2.17 (m, 1H), 1.85 (m, 1H);
HRMS (FAB) calcd for C27H28O4 (M+) 416.1988, observed 416.1984.
127.2, 115.1, 113.6, 79.2, 77.3, 55.3, 38.2, 33.2, 31.2, 30.7, 24.0;
IR (NaCl)
m 2934, 2856, 1613, 1514, 1454, 1246; HRMS (FAB) calcd
for C20H24O3 (M+) 312.1725, observed 312.1721.
Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2011-
0010857), and also supported by the Sookmyung Women’s Univer-
sity Research Grants 2011.
4.10. O-(2S,6S)-2-(4-(Benzyloxy)phenethyl)-6-(4-methoxyphenyl)-
3,6-dihydro-2H-pyran-3-yl 1H-imidazole-1-carbothioate 13
References
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The reaction mixture was refluxed for 4 h, cooled to rt, and evapo-
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(n-hexane–EtOAc = 2:1); ½a D25
ꢁ
¼ þ44:5 (c 0.2, CHCl3); 1H NMR
(400 MHz, CDCl3) d 8.04 (s, 1H), 7.45–7.28 (m, 8H), 7.10–6.80 (m,
7H), 5.91 (m, 2H), 5.02 (s, 2H), 4.55–4.30 (m, 3H), 3.77 (s, 3H),
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159.8, 157.0, 137.1, 135.4, 134.1, 133.1, 130.9, 130.8, 129.4,
128.6, 128.5, 127.9, 127.4, 126.2, 115.9, 114.7, 113.8, 78.8, 74.5,
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70.0, 55.2, 46.9, 36.8, 29.9; IR (NaCl)
1612, 1512, 1249, 629; HRMS (FAB) calcd for C31H31N2O4S (M+H)
527.2005, observed 527.2003. Minor (21 mg, 24%): Rf = 0.22
m 3032, 2925, 2837, 1696,
(n-hexane–EtOAc = 2:1); ½a D25
ꢁ
¼ ꢀ195:1 (c 1, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.99 (s, 1H), 7.45–7.24 (m, 8H), 7.15–6.80 (m,
7H), 6.15 (m, 1H), 5.88 (d, J = 10.0 Hz, 1H), 5.07 (s, 1H), 5.02 (s,
2H), 4.60–4.30 (m, 2H), 3.73 (s, 3H), 2.78 (m, 2H), 1.93 (m, 2H);
13C NMR (100 MHz, CDCl3) d 165.3, 159.0, 157.1, 137.1, 135.4,
134.0, 133.5, 130.9, 130.6, 129.4, 128.5, 127.9, 127.4, 127.0,
124.9, 115.9, 114.8, 113.4, 76.3, 75.1, 70.0, 55.2, 47.0, 36.8, 30.2;
IR (NaCl)
m 3032, 2929, 2836, 1689, 1613, 1512, 1467, 1247, 884.
4.11. 4-(2-((2R,6S)-6-(4-Methoxyphenyl)tetrahydro-2H-pyran-
2-yl)ethyl)phenol (centrolobine)
To a solution of thiocarbamate 10 (50 mg, 0.095 mmol) in EtOH
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at room temperature. The reaction mixture was stirred under a
hydrogen atmosphere for 10 h, diluted with CH2Cl2 (50 mL), dried
over anhydrous MgSO4, filtered on Celite, and concentrated under
reduced pressure. The crude product was purified by column chro-
matography eluting with 11% EtOAc in hexane to give (ꢀ)-centrol-
obine as a syrup (28 mg, 95%): Rf = 0.60 (n-hexane–EtOAc = 2:1);
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½
a 2D7
ꢁ
¼ ꢀ89:3 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.31 (d,
J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H),
6.68 (d, J = 8.4 Hz, 2H), 5.14 (s, 1H), 4.29 (dd, J = 2.0, 11.2 Hz, 1H),
3.78 (s, 3H), 3.44 (m, 1H), 2.67 (m, 2H), 1.95–1.20 (m, 8H);
13C NMR (100 MHz, CDCl3) d 158.7, 153.5, 135.7, 134.5, 129.5,
9. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
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