Asymmetric syntheses of diarylheptanoid natural products (-)-centrolobine and (-)-de-O-methylcentrolobine via hetero-Diels-Alder reaction catalyzed by dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate]

Article abstract of DOI:10.1016/j.tet.2007.09.003

Catalytic asymmetric syntheses of (-)-centrolobine and (-)-de-O-methylcentrolobine have been achieved, incorporating?a hetero-Diels-Alder (HDA) reaction between 4-aryl-2-silyloxy-1,3-butadienes and phenylpropargyl aldehyde derivatives as a key step. The H

Full text of DOI:10.1016/j.tet.2007.09.003

Tetrahedron 63 (2007) 12037–12046
Asymmetric syntheses of diarylheptanoid natural products
(L)-centrolobine and (L)-de-O-methylcentrolobine via
hetero-Diels–Alder reaction catalyzed by dirhodium(II)
tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate]
Takuya Washio, Reika Yamaguchi, Takumi Abe, Hisanori Nambu,
*
Masahiro Anada and Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 17 August 2007; revised 3 September 2007; accepted 4 September 2007
Available online 7 September 2007
Abstract—Catalytic asymmetric syntheses of (ꢀ)-centrolobine and (ꢀ)-de-O-methylcentrolobine have been achieved, incorporating a
hetero-Diels–Alder (HDA) reaction between 4-aryl-2-silyloxy-1,3-butadienes and phenylpropargyl aldehyde derivatives as a key step. The
HDA reaction using dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh2(R-BPTPI)4, as a chiral Lewis acid
catalyst provides exclusively cis-2,6-disubstituted tetrahydropyran-4-ones in up to 93% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
approaches starting with optically active building blocks,
obtained by well-established asymmetric reactions or the
chiral pool method, have been devised to provide access to
the cis-2,6-disubstituted tetrahydropyran rings. These
include the Prins and related cyclizations,10a,g,h reductive
etherifications,8,10b one-pot cross metathesis–hydrogena-
tion–lactonization procedure,10c radical cyclization,10d
nucleophilic addition–stereoselective reduction protocol,10e
intramolecular oxy-Michael reaction,10f diastereoselective
ring rearrangement metathesis–isomerization sequence,10i
and FeCl3-mediated cyclization of 1,5-diol.10j
Diarylheptanoid natural products containing a tetrahydro-
pyran ring, such as centrolobine,1 de-O-methylcentrolo-
bine,1c,2 calyxins3 and diospongins,4 exhibit a wide range
of biological activities. Not surprisingly, therefore, these
compounds have aroused considerable interest within the
medicinal and synthetic chemistry communities.5–7
O
The hetero-Diels–Alder (HDA) reaction11 between dienes
and carbonyl compounds is one of the most straightforward
methods for constructing tetrahydropyran derivatives,
because of setting up to three new stereocenters in a single
step. Jacobsen and co-workers recently developed highly
enantio- and diastereoselective HDA reactions between
monooxygenated 1,3-dienes and simple aldehydes catalyzed
by tridentate Schiff base Cr(III) complexes.12 The Jacobsen
catalytic asymmetric HDA reaction has found numerous ap-
plications in total syntheses of tetrahydropyran-containing
natural products.13 However, the HDA reaction has not yet
been adapted to the diarylheptanoid tetrahydropyran
system.14 We recently reported that dirhodium(II) tetrakis-
[(S)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh2-
(S-BPTPI)4, is a highly efficient Lewis acid catalyst for
endo- and enantioselective HDA reactions of a diverse range
of aldehydes with Danishefsky-type dienes as well as with
monooxygenated dienes, in which up to 99% ee and turnover
numbers as high as 48,000 are achieved (Eq. 1).15,16 In order
RO
OH
_
R = Me: ( )-centrolobine (1)
R = H: ( )-de-O-methylcentrolobine (2)
_
(ꢀ)-Centrolobine (1) is an antibiotic isolated from the heart-
wood of Centrolobium robustum and from the stem of
Brosinum potabile in the Amazon rain forest.1 (ꢀ)-De-O-
methylcentrolobine (2), isolated from the same heartwood
of C. robustum, displays a good antileishmanial activity.1c,2
Solladie and co-workers accomplished the first asymmetric
total synthesis of (ꢀ)-centrolobine (1) in 2002, which also
established the absolute configuration of 1.8 Since then,
a number of groups have achieved the synthesis of 1 in
both racemic9 and optically active forms.10 A variety of
Keywords: Diarylheptanoids; Hetero-Diels–Alder reaction; (ꢀ)-Centrolo-
bine; (ꢀ)-De-O-methylcentrolobine; Chiral Rh(II) catalyst.
* Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981;
e-mail: hsmt@pharm.hokudai.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.003

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T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
to demonstrate the utility of this catalytic methodology, we
now address asymmetric syntheses of (ꢀ)-centrolobine (1)
and (ꢀ)-de-O-methylcentrolobine (2), focusing on the
Rh2(R-BPTPI)4-catalyzed HDA reaction between 4-aryl-
2-silyloxy-1,3-butadienes and phenylpropargyl aldehyde
derivatives.
enantiopure 2-chlorobenzaldehyde–Cr(CO)3 complex.17
However, to the best of our knowledge, no examples of an
HDA reaction between monooxygenated dienes bearing
phenyl groups at C4 and aldehydes have been reported.18
In this respect, Wessjohann and co-workers reported that
the BF3$OEt2-mediated reaction of 2-tert-butyldimethyl-
silyloxy-1,3-butadiene derivative, which has an aromatic
ring conjugated to the diene system, with crotonaldehyde
and cinnamaldehyde gave the classical Diels–Alder cyclo-
adducts as the sole products, rather than the expected HDA
products.19 Consequently, the development of the HDA
reaction between 4-aryl-2-silyloxy-1,3-butadienes and phe-
nylpropargyl aldehydes has become a challenging objective.
R1
O
R4
(R3 = OMe)
O
R2
R1
R3
>99% cis
up to 97% ee
TON up to 48,000
Et3SiO
R2
1. Rh2(S-BPTPI)4
CH2Cl2
H
R4
+
(1)
2. TFA
O
R1
2.2. Preparation of dienes and aldehydes
for the HDA reaction
O
R4
R
4 = aryl, alkyl
R1, R2 = H, Me
3 = OMe or Me
(R2 = H, R3 = Me)
O
alkenyl
R
At the outset of our studies, we expected that 4-(4-meth-
oxyphenyl)-2-triethylsilyloxy-1,3-butadiene (4a) and 4-
(4-benzyloxyphenyl)-2-triethylsilyloxy-1,3-butadiene (4b)
would serve as the diene components for the synthesis of 1
and 2, respectively. The dienes 4a and 4b were prepared
by the reaction of readily available a,b-unsaturated ketones
6a20 and 6b21 with Et3SiOTf in the presence of Et3N in
CH2Cl2 at 0 ꢁC (Scheme 2). 4-Phenyl-2-triethylsilyloxy-
1,3-butadiene (4c) as a model diene was also prepared
from benzalacetone (6c) under the same conditions.
alkynyl
Me
up to 99% ee
O
N
H
N
O
O
Rh Rh
Rh2(S-BPTPI)4
2. Results and discussion
2.1. Synthetic plan
O
OSiEt3
Et3SiOTf, Et3N
CH2Cl2, 0 °C
Our synthetic strategy for 1 and 2 based on the HDA reaction
is outlined retrosynthetically in Scheme 1. With the high
reactivity of phenylpropargyl aldehyde as a dienophile
previously identified,15 we envisioned that the Rh2-
(R-BPTPI)4-catalyzed HDA reaction between 4-aryl-2-tri-
ethylsilyloxy-1,3-butadienes 4 and phenylpropargyl aldehyde
derivatives 5 would provide cis-(2R,6S)-disubstituted tetra-
hydropyran-4-ones 3 as the key intermediates. The appropri-
ately protected intermediates 3 could be uneventfully
transformed into 1 and 2 via catalytic hydrogenation of the
triple bond and removal of the carbonyl group. For this
type of HDA reaction, Baldoli and co-workers reported
R
R
6a, R = OMe
6b, R = OBn
6c, R = H
4a, R = OMe (88%)
4b, R = OBn (85%)
4c, R = H (87%)
Scheme 2. Preparation of dienes 4a–4c.
Phenylpropargyl aldehydes 5a and 5b, bearing tert-butyl-
dimethylsilyloxy and methanesulfonyloxy groups at the
para-position on the benzene ring, were prepared by the
Sonogashira coupling22 of propargyl alcohol with iodo-
phenol derivatives 7a23 and 7b,24 and subsequent Dess–
Martin oxidation (Scheme 3).
a ZnCl2-promoted stereoselective HDA reaction of
4-(2-methoxyphenyl)-2-trimethylsilyloxy-1,3-butadiene with
O
6S
2R
O
O
RO
OH
PGO
3
R = Me: (–)-centrolobine (1)
OPG
R = H: (–)-de-O-methylcentrolobine (2)
HDA reaction
Rh2(R-BPTPI)4
O
N
OSiEt3
H
H
O
O
N
O
+
Rh Rh
OPG
PGO
Rh2(R-BPTPI)4
4
5
Scheme 1. Retrosynthetic analysis of (ꢀ)-centrolobine and (ꢀ)-de-O-methylcentrolobine.

T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
12039
H
16%
H 16%
O
I
O
a,b
6
H
R
O
MeO
2
R
7a, R = OTBS
7b, R = OMs
5a, R = OTBS (92%, two steps)
5b, R = OMs (90%, two steps)
3a
Scheme 3. Reagents and conditions: (a) propargyl alcohol, PdCl2(PPh3)2
(0.5 mol %), CuI (1 mol %), Et3N, 23 ꢁC; (b) Dess–Martin periodinane,
CH2Cl2, 0 ꢁC.
Figure 1. NOE experiments of 3a.
stereochemistry of 3c and 3d was established as (2R,6S)
by their transformation into 1 and 2, respectively (vide
infra).
2.3. Enantioselective HDA reaction
On the basis of our previous work,15 we initially evaluated
the HDA reaction between 4-(4-methoxyphenyl)-2-triethyl-
silyloxy-1,3-butadiene (4a) (1.5 equiv) and phenylpropargyl
aldehyde (5c) as a model system using 1 mol % of Rh2-
(R-BPTPI)4. The reaction in dichloromethane at room tem-
perature proceeded in 48 h, and, after treatment with TBAF,
gave the cis-2,6-disubstituted tetrahydropyran-4-one 3a as
the sole product in 83% yield with 91% ee (Table 1, entry
1). The cis-stereochemistry of 3a was established by the
1H NOE between C2-H and C6-H (Fig. 1). Encouraged by
this result, we next examined the reaction with p-tert-butyl-
dimethylsilyloxy-substituted phenylpropargyl aldehyde 5a.
However, the introduction of this substituent was found
to be detrimental as the reaction did not proceed under the
foregoing conditions. Even when 5 mol % of the catalyst
was used in refluxing dichloromethane, only 15% yield of
3b was isolated, though perfect cis-selectivity and 87% ee
were observed (entry 2). Thus, we were gratified to find
that the HDA reaction of 4a with aldehyde 5b bearing
a methanesulfonyloxy substituent as the electron-withdraw-
ing group proceeded smoothly to completion within 12 h,
and, after desilylation, gave exclusively the cis-2,6-disubsti-
tuted tetrahydropyran-4-one 3c for the synthesis of (ꢀ)-cen-
trolobine (1) in 87% yield with 93% ee (entry 3). The HDA
reaction of p-benzyloxy-substituted diene 4b with aldehyde
5b also worked well, providing tetrahydropyran-4-one
3d for the synthesis of (ꢀ)-de-O-methylcentrolobine (2)
in 84% yield with 90% ee (entry 4). The absolute
For comparison, the HDA reaction between 4-phenyl-2-tri-
ethylsilyloxy-1,3-butadiene (4c) and aldehyde 5b in the
presence of Rh2(R-BPTPI)4 was then attempted. However,
the reaction did not proceed at all (Eq. 2). These results
suggest that the combination of an increase in the HOMO
energy of silyloxydienes 4 and a decrease in the LUMO
energy of phenylpropargyl aldehydes 5 by means of the
para-substitutions on the benzene ring is crucial for the
success of this type of HDA reaction.
OSiEt3
H
Rh2(R-BPTPI)4
O
+
CH2Cl2, reflux
OMs
4c
5b
O
(2)
O
OMs
3e
As an alternative approach to cis-2,6-disubstituted tetrahy-
dropyran-4-ones, we finally investigated the HDA reaction
Table 1. Enantioselective hetero-Diels–Alder reactions catalyzed by Rh2(R-BPTPI)4
O
O
OSiEt3
H
N
1. Rh2(R-BPTPI)4
H
O
(1 mol %), CH2Cl2
O
O
N
+
O
2. TBAF, THF
23 °C, 0.5 h
Rh Rh
Rh2(R-BPTPI)4
R1
R2
R1
R2
4
5
3
Entry
4
R1
5
R2
H
OTBS
OMs
OMs
Temp, ꢁC
Time, h
Tetrahydropyran-4-one
Yield,a %
% ee
1
4a
4a
4a
4b
OMe
OMe
OMe
OBn
5c
5a
5b
5b
23
48
48
12
12
3a
83
15
87
84
91b,c
87b,c
93f
2d
3
Reflux
23
23
3b (R2¼OH)e
3c
3d
4
90f
a
Isolated yield.
b
c
d
e
f
Determined by HPLC (Daicel Chiralcel OD-H).
The absolute stereochemistry was not determined.
Rh2(R-BPTPI)4: 5 mol % was used.
Only phenol product was obtained due to the concomitant desilylation.
Determined by HPLC (Daicel Chiralpak AD-H).

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T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
between 4-methanesulfonyloxybenzaldehyde (8) and 6-(4-
benzyloxyphenyl)-2-triethylsilyloxy-1,3-hexadien-5-yne (9)25
(Eq. 3). However, no reaction occurred. This observation
again indicates that the sterically less-demanding and elec-
tron-deficient phenylpropargyl aldehydes are particularly
suitable dienophiles for the Rh2(R-BPTPI)4-catalyzed HDA
reaction with monooxygenated dienes.
in the presence of p-TsOH to produce tetrahydropyran 12 in
75% yield.27 Finally, removal of the methanesulfonyl group
with K2CO3 in MeOH completed the asymmetric synthesis
of (ꢀ)-centrolobine (1), mp 85.0–85.5 ꢁC (lit.,1c mp 84–
86 ꢁC), [a]D21 ꢀ93.7 (c 1.02, CHCl3) [lit.,1d [a]D ꢀ92.2 (c
1, CHCl3)], which also established the preferred absolute
stereochemistry of cycloadduct 3c as (2R,6S). The synthetic
material 1 exhibited identical spectroscopic data with those
1
reported for natural (ꢀ)-centrolobine (IR, H NMR, 13C
NMR, HRMS).1 Consequently, the stereochemical outcome
of the present HDA reaction can be rationalized on the basis
of the absolute stereochemical model we previously
proposed,15 which contains a hydrogen bond between the
formyl hydrogen atom and the carboxamidate oxygen
atom28 in rhodium catalyst–aldehyde complexes (Fig. 2).
The approach of dienes 4 in an endo mode to avoid intrusion
into the rhodium framework leads to the observed cyclo-
adducts 3 with a 2,6-cis-arrangement of substituents.
OSiEt3
H
Rh2(S-BPTPI)4
O
+
MsO
CH2Cl2, reflux
OBn
8
9
O
(3)
O
We then proceeded to the asymmetric synthesis of (ꢀ)-de-
O-methylcentrolobine (2) from tetrahydropyran-4-one 3d
(Scheme 4). Recrystallization of 3d with 90% ee from etha-
nol resulted in the production of an optically pure sample,
mp 135–136 ꢁC, [a]D20 ꢀ4.76 (c 3.20, CH3CN) in 73% yield.
Sequential catalytic hydrogenation of the triple bond and
hydrogenolysis of the benzyl ether in a single flask furnished
tetrahydoropyran-4-one 11 in 97% yield. The conversion of
11 to 2 was conducted in the same manner as that of 10 to 1.
The synthetic material 2 was spectroscopically (IR, 1H
NMR, 13C NMR, HRMS) identical with natural (ꢀ)-de-O-
methylcentrolobine,2a and also had an optical rotation,
[a]2D2 ꢀ96.1 (c 1.02, MeOH), in good agreement with the
literature value [lit.,2a [a]2D5 ꢀ95.1 (c 0.9, MeOH)]. Thus,
the preferred absolute stereochemistry of cycloadduct 3d
was established as (2R,6S).
MsO
OBn
3f
2.4. Syntheses of (L)-centrolobine and (L)-de-O-
methylcentrolobine
With the efficient construction of cis-2,6-disubstituted tetra-
hydropyran-4-ones 3c and 3d realized, the stage was now set
for the completion of asymmetric syntheses of (ꢀ)-centrolo-
bine (1) and (ꢀ)-de-O-methylcentrolobine (2). The syn-
thesis of 1 from tetrahydropyran-4-one 3c is illustrated in
Scheme 4. A single recrystallization of 3c with 93% ee
from ethanol produced optically pure material, mp 134–
135 ꢁC, [a]D22 ꢀ4.95 (c 1.02, CHCl3) in 76% yield. Catalytic
hydrogenation of the triple bond provided 10 in 96% yield.
Tosylhydrazone formation of ketone 10 with p-toluenesul-
fonyl hydrazine was followed by reduction with NaBH3CN
benzene fused
phthalimido group
O
O
a
O
Ar
O
RO
Et3SiO
OMs RO
OMs
(>99% ee after recrystallization)
3c, R = Me
3d, R = Bn
10, R = Me (96%)
11, R = H (97%)
H
O
O
N
O
N
R
Rh
b,c
d
O
RO
OMs
Ar
O
OSiEt3
12, R = Me (75%, two steps)
13, R = H (75%, two steps)
TBAF
R
O
O
[α]D21 _93.7° (c 1.02, CHCl3) for 1
lit.1d [α]D –92.2° (c 1, CHCl3)
Ar
O
3
[α]D22 _96.1° (c 1.02, MeOH) for 2
lit.2a [α]D25 _95.1° (c 0.9, MeOH)
RO
OH
1, R = Me (96%)
2, R = H (96%)
R
Ar = p-MsOC6H4
Scheme 4. Reagents and conditions: (a) H2, 10% Pd/C, EtOAc, 2 h (for 3c)
or 4 h (for 3d); (b) TsNHNH2, MeOH, reflux, 2 h; (c) NaBH3CN, TsOH,
DMF–sulfolane (1:1), 110 ꢁC, 1 h; (d) K2CO3, MeOH, reflux, 3 h.
R = MeO, BnO
Figure 2. Plausible stereochemical pathway.

T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
12041
3. Conclusion
4.2. Preparation of dienes
We have developed a highly enantio- and diastereoselective
HDA reaction between 4-aryl-2-silyloxy-1,3-butadienes and
phenylpropargyl aldehyde derivatives using Rh2(R-BPTPI)4
as a chiral Lewis acid catalyst, which provides a straight-
forward entry to cis-(2R,6S)-2-arylethynyl-6-aryl-tetra-
hydropyran-4-ones. This represents the first example of an
HDA reaction of 4-aryl-2-silyloxy-1,3-butadienes with alde-
hydes. Using this catalytic methodology, we have achieved
the asymmetric synthesis of (ꢀ)-centrolobine in seven steps
and 41% overall yield from 4-iodophenyl methanesulfonate
(7b), and the first asymmetric synthesis of (ꢀ)-de-O-methyl-
centrolobine in eight steps and 39% overall yield from 7b.
Further application of this methodology to catalytic asym-
metric synthesis of other diarylheptanoid natural products
is currently in progress.
4.2.1. trans-4-(4-Methoxyphenyl)-2-triethylsilyloxy-1,3-
butadiene (4a). To a solution of trans-4-(4-methoxy-
phenyl)-3-buten-2-one (6a)20 (1.5 g, 8.5 mmol) and Et3N
(2.4 mL, 17 mmol) in CH2Cl2 (20 mL) was added triethyl-
silyl trifluoromethanesulfonate (1.9 mL, 8.5 mmol) at 0 ꢁC.
After stirring at this temperature for 0.5 h, the reaction was
quenched with saturated NaHCO3 solution (10 mL), and
the whole was extracted with EtOAc (2ꢂ30 mL). The com-
bined organic layers were washed with brine (2ꢂ10 mL),
and dried over anhydrous Na2SO4. Filtration and evapora-
tion in vacuo followed by column chromatography (Wako-
gelÒ C-200, 100:1 hexane/EtOAc with 2% Et3N) provided
4a (2.17 g, 88%) as a colorless oil: TLC Rf¼0.40 (19:1
hexane/EtOAc); IR (film) 1634, 1606, 1588, 1510, 1252,
1026 cmꢀ1
;
1H NMR (270 MHz, CDCl3) d 0.77 (q,
J¼7.9 Hz, 6H, SiCH2CH3), 1.03 (t, J¼7.9 Hz, 9H,
SiCH2CH3), 3.81 (s, 3H, OCH3), 4.38 (s, 1H, C1–H), 4.39
(s, 1H, C1–H), 6.46 (d, J¼15.5 Hz, 1H, C3–H), 6.82 (d,
J¼15.5 Hz, 1H, C4–H), 6.83–6.89 (m, 2H, Ar), 7.33–7.38
(m, 2H, Ar); 13C NMR (100 MHz, CDCl3) d 5.0 (CH2),
6.8 (CH3), 55.2 (CH3), 95.3 (CH2), 113.9 (CH), 124.2
(CH), 127.9 (CH), 128.5 (CH), 129.5 (C), 155.2 (C), 159.1
(C); FAB-HRMS m/z calcd for C17H27O2Si (M+H)+
291.1775, found 291.1781. Anal. Calcd for C17H26O2Si:
C, 70.29; H, 9.02. Found: C, 70.04; H, 9.06.
4. Experimental
4.1. General
€
Melting points were determined on a Buchi 535 digital melt-
ing point apparatus and are uncorrected. IR spectra were
recorded on a JASCO FT/IR-5300 spectrometer and absor-
bance bands are reported in wavenumber (cmꢀ1). 1H NMR
spectra were recorded on JEOL JNM-EX 270 (270 MHz)
spectrometer and JEOL JNM-AL 400 (400 MHz) spectro-
meter. Chemical shifts are reported relative to internal
standard (tetramethylsilane: dH 0.00, CDCl3: dH 7.26 or ace-
tone-d6: dH 2.04). Data are presented as follows: chemical
shift (d, ppm), multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad), coupling constant and
integration. 13C NMR spectra were recorded on JEOL
JNM-AL 400 (100 MHz) spectrometer. The following inter-
nal references were used (CDCl3: d 77.0 or acetone-d6:
d 29.8). Optical rotations were measured on a JASCO
P-1030 digital polarimeter at the sodium D line (589 nm).
EIMS spectra were obtained on a JEOL JMS-FABmate spec-
trometer, operating with ionization energy of 70 eV. FABMS
spectra were obtained on a JEOL JMS-HX 110 spectrometer.
4.2.2. trans-4-(4-Benzyloxyphenyl)-2-triethylsilyloxy-
1,3-butadiene (4b). Following the procedure for the prepa-
ration of 4a, starting from trans-4-(4-benzyloxyphenyl)-
3-buten-2-one (6b)21 (1.3 g, 5.0 mmol), Et3N (1.4 mL,
10 mmol), and triethylsilyl trifluoromethanesulfonate
(1.1 mL, 5.0 mmol), 4b (1.56 g, 85%) was obtained as a col-
orless oil: TLC Rf¼0.33 (19:1 hexane/EtOAc); IR (film)
1632, 1605, 1588, 1508, 1241, 1020 cmꢀ1 1H NMR
;
(270 MHz, CDCl3) d 0.76 (q, J¼7.6 Hz, 6H, SiCH2CH3),
1.03 (t, J¼7.6 Hz, 9H, SiCH2CH3), 4.38 (s, 1H, C1–H),
4.39 (s, 1H, C1–H), 5.07 (s, 2H, PhCH2O), 6.46 (d,
J¼15.8 Hz, 1H, C3–H), 6.81 (d, J¼15.8 Hz, 1H, C4–H),
6.91–6.95 (m, 2H, Ar), 7.30–7.45 (m, 7H, Ar); 13C NMR
(100 MHz, CDCl3) d 5.0 (CH2), 6.8 (CH3), 69.9 (CH2),
95.4 (CH2), 114.8 (CH), 124.3 (CH), 127.3 (CH), 127.8
(CH), 127.9 (CH), 128.4 (CH), 129.7 (C), 136.7 (C), 155.2
(C), 158.3 (C); FAB-HRMS m/z calcd for C23H31O2Si
(M+H)+ 367.2093, found 367.2090. Anal. Calcd for
C23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.25; H, 8.27.
Column chromatography was carried out on Kanto silica gel
60 N (63–210 mesh) or WakogelÒ C-200 (75–150 mm). An-
alytical 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 chroma-
tography (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. Chir-
alcel OD-H and Chiralpak AD-H columns (0.46 cmꢂ25 cm)
from Daicel were used. Retention times (tR) and peak ratios
were determined with JASCO-Borwin analysis system.
4.2.3. trans-4-Phenyl-2-triethylsilyloxy-1,3-butadiene
(4c). Following the procedure for the preparation of 4a, start-
ing from trans-4-phenyl-3-buten-2-one (6c) (730 mg,
5.0 mmol), Et3N (1.4 mL, 10 mmol), and triethylsilyl tri-
fluoromethanesulfonate (1.1 mL, 5.0 mmol), 4c (1.08 g,
87%) was obtained as a colorless oil: TLC Rf¼0.35 (500:1
hexane/EtOAc); IR (film) 1588, 1328, 1023 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 0.77 (q, J¼7.7 Hz, 6H,
SiCH2CH3), 1.03 (t, J¼7.7 Hz, 9H, SiCH2CH3), 4.42 (s,
1H, C1–H), 4.44 (s, 1H, C1–H), 6.58 (d, J¼15.9 Hz, 1H,
C3–H), 6.87 (d, J¼15.9 Hz, 1H, C4–H), 7.20–7.26 (m, 1H,
Ar), 7.29–7.34 (m, 2H, Ar), 7.41–7.43 (m, 2H, Ar); 13C
NMR (100 MHz, CDCl3) d 4.9 (CH2), 6.7 (CH3), 96.3
(CH2), 126.4 (CH), 126.7 (CH), 127.6 (CH), 128.5 (CH),
129.1 (CH), 136.8 (C), 155.1 (C); EI-HRMS m/z calcd for
All non-aqueous reactions were carried out in flame-dried
glassware under argon atmosphere unless otherwise noted.
Reagents and solvents were purified by standard means.
Dehydrated CH2Cl2 was purchased from Kanto Chemical
Co., Inc. Rh2(R-BPTPI)4$3H2O was prepared from
D-ornithine according to the literature procedure of Rh2(S-
BPTPI)4$3H2O.15

12042
T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
C16H24O2Si (M)+ 260.1596, found 260.1597. Anal. Calcd
for C16H24OSi: C, 73.79; H, 9.29. Found: C, 73.59; H, 9.52.
6.15 (d, J¼15.4 Hz, 1H, C3–H), 6.46 (d, J¼15.4 Hz, 1H,
C4–H), 6.90–6.93 (m, 2H, Ar), 7.31–7.43 (m, 7H, Ar); 13C
NMR (100 MHz, CDCl3) d 4.9 (CH2), 6.7 (CH3), 69.9
(CH2), 87.4 (C), 92.7 (C), 97.1 (CH2), 109.0 (CH), 114.8
(CH), 115.8 (CH), 127.4 (CH), 128.0 (CH), 128.6 (CH),
132.9 (CH), 136.5 (C), 137.9 (CH), 154.4 (C), 158.7 (C);
EI-HRMS m/z calcd for C25H30O2Si (M)+ 390.2015, found
390.2006. Anal. Calcd for C25H30O2Si: C, 76.88; H, 7.74.
Found: C, 76.91; H, 7.91.
4.2.4. Preparation of trans-6-(4-benzyloxyphenyl)-2-tri-
ethylsilyloxy-1,3-hexadien-5-yne (9).
4.2.4.1. (4-Benzyloxyphenyl)propynal. To a solution of
3-(4-benzyloxyphenyl)-2-propyn-1-ol26 (2.0 g, 8.4 mmol)
and Et3N (5.8 mL, 42 mmol) in CH2Cl2 (15 mL)/DMSO
(15 mL) was added sulfur trioxide pyridine complex (3.3 g,
21 mmol) at 0 ꢁC. After stirring at this temperature for 1 h,
the mixture was diluted with EtOAc (20 mL), and poured
into saturated aqueous NH4Cl (20 mL). The whole was ex-
tracted with EtOAc (40 mL). The combined organic layers
were washed with water (15 mL) and brine (3ꢂ15 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo followed by column chromatography (silica gel, 19:1
hexane/EtOAc) provided the title compound (1.90 g, 96%)
as a pale yellow solid: mp 59.0–60.0 ꢁC; TLC Rf¼0.30 (9:1
hexane/EtOAc); IR (film) 2174, 1643, 1596, 1505,
4.3. Preparation of aldehydes
4.3.1. [4-(tert-Butyldimethylsilyloxy)phenyl]propynal
(5a). To a stirred mixture of (4-tert-butyldimethylsilyloxy)-
iodobenzene (7a)23 (2.0 g, 6.0 mmol), copper iodide (11 mg,
0.06 mmol, 1 mol %), PdCl2(PPh3)2 (21 mg, 0.03 mmol,
0.5 mol %), and propargyl alcohol (0.70 mL, 12 mmol)
was added Et3N (6 mL) at 0 ꢁC. After stirring at 23 ꢁC for
2 h, the reaction mixture was diluted with EtOAc (20 mL),
and filtered through a plug of Celite with EtOAc (10 mL).
Filtration and concentration in vacuo followed by column
chromatography (silica gel, 4:1 hexane/EtOAc) provided 3-
[4-(tert-butyldimethylsilyloxy)phenyl]prop-2-yn-1-ol (1.49 g,
95%) as a pale yellow oil: TLC Rf¼0.32 (3:1 hexane/
EtOAc); 1H NMR (400 MHz, CDCl3) d 0.20 (s, 6H,
Si(CH3)2), 0.97 (s, 9H, SiC(CH3)3), 1.66 (t, 1H, J¼6.2 Hz,
OH), 4.48 (d, 2H, J¼6.2 Hz, CH2OH), 6.76–6.79 (m, 2H,
Ar), 7.30–7.32 (m, 2H, Ar). To a solution of 3-[4-(tert-butyl-
dimethylsilyloxy)phenyl]prop-2-yn-1-ol (790 mg, 3.0 mmol)
in CH2Cl2 (10 mL) was added Dess–Martin periodinane
(1.3 g, 3.0 mmol) at 0 ꢁC. After stirring at this tempera-
ture for 3 h, the mixture was poured into an ice-cooled
solution of saturated aqueous NaHCO3 (5 mL) containing
Na2S2O3$H2O (0.5 g). The whole was extracted with EtOAc
(50 mL). The combined organic layers were washed with
water (2ꢂ5 mL) and brine (2ꢂ5 mL), and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo followed
by column chromatography (silica gel, 39:1 hexane/EtOAc)
provided 5a (760 mg, 97%) as a pale yellow oil: TLC
Rf¼0.37 (19:1 hexane/EtOAc); IR (film) 2244, 2184,
1254 cmꢀ1 1H NMR (400 MHz, CDCl3) d 5.11 (s, 2H,
;
PhCH2O), 6.97–7.00 (m, 2H, Ar), 7.34–7.43 (m, 5H, Ar),
7.55–7.58 (m, 2H, Ar), 9.39 (s, 1H, CHO); 13C NMR
(100 MHz, CDCl3) d 70.0 (CH2), 88.7 (C), 96.4 (C), 111.2
(C), 115.2 (CH), 127.4 (CH), 128.2 (CH), 128.6 (CH),
135.4 (CH), 135.9 (C), 161.1 (C), 176.7 (C]O); EI-HRMS
m/z calcd for C16H12O2 (M)+ 236.0837, found 236.0837.
Anal. Calcd for C16H12O2: C, 81.34; H, 5.12. Found: C,
81.23; H, 5.22.
4.2.4.2. trans-6-(4-Benzyloxyphenyl)-3-hexen-5-yn-2-
one. To a solution of (4-benzyloxyphenyl)propynal (1.0 g,
4.2 mmol) in acetone (5 mL) was added 10% aqueous
NaOH (5 mL). After stirring at this temperature for 24 h,
the reaction mixture was partitioned between EtOAc
(30 mL) and water (10 mL). The organic layer was washed
with water (5 mL) and brine (2ꢂ5 mL), and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo followed
by column chromatography (silica gel, 9:1 hexane/EtOAc)
provided the title compound (1.12 g, 96%) as a white solid:
mp 100–101 ꢁC; TLC Rf¼0.34 (4:1 hexane/EtOAc); IR
(film) 2190, 1659, 1592, 1505, 1251 cmꢀ1
;
1H NMR
1659 cmꢀ1; H NMR (270 MHz, CDCl3) d 0.23 (s, 6H,
1
(400 MHz, CDCl3) d 2.30 (s, 3H, COCH3), 5.09 (s, 2H,
PhCH2O), 6.53 (d, J¼15.9 Hz, 1H, C3–H), 6.84 (d, J¼
15.9 Hz, 1H, C4–H), 6.93–6.97 (m, 2H, Ar), 7.34–7.45 (m,
7H, Ar); 13C NMR (100 MHz, CDCl3) d 27.5 (CH3), 69.9
(CH2), 86.0 (C), 100.3 (C), 114.3 (C), 115.0 (CH), 124.1
(CH), 127.4 (CH), 128.1 (CH), 128.6 (CH), 133.6 (CH),
136.2 (C), 136.9 (CH), 159.6 (C), 197.1 (C]O); EI-
HRMS m/z calcd for C19H16O2 (M)+ 276.1150, found
276.1157. Anal. Calcd for C19H16O2: C, 82.58; H, 5.84.
Found: C, 82.76; H, 5.97.
Si(CH3)2), 0.98 (s, 9H, SiC(CH3)3), 6.84–6.86 (m, 2H, Ar),
7.50–7.52 (m, 2H, Ar), 9.39 (s, 1H, CHO); 13C NMR
(100 MHz, CDCl3) d ꢀ4.2 (CH3), 18.3 (C), 25.6 (CH3),
88.6 (C), 96.3 (C), 111.5 (C), 120.3 (CH), 135.1 (CH),
158.4 (C), 176.2 (C]O); EI-HRMS m/z calcd for
C15H20O2Si (M)+ 260.1232, found 260.1232. Anal. Calcd
for C15H20O2Si: C, 69.19; H, 7.74. Found: C, 68.96; H, 8.00.
4.3.2. (4-Methanesulfonyloxyphenyl)propynal (5b). Fol-
lowing the procedure of Sonogashira coupling of 7a, starting
from 4-iodophenyl methanesulfonate (7b)24 (7.5 g,
25 mmol), copper iodide (47 mg, 0.25 mmol, 1 mol %),
PdCl2(PPh3)2 (88 mg, 0.13 mmol, 0.5 mol %), propargyl al-
cohol (2.9 mL, 50 mmol), and Et3N (20 mL), 4-(3-hydroxy-
1-propynyl)phenyl methanesulfonate (5.31 g, 94%) was
obtained as a pale yellow solid: mp 56.0–56.5 ꢁC; TLC
Rf¼0.39 (1:2 hexane/EtOAc); 1H NMR (270 MHz, CDCl3)
d 1.71 (t, 1H, J¼6.3 Hz, OH), 3.16 (s, 3H, SO2CH3), 4.50
(d, 2H, J¼6.3 Hz, CH2OH), 7.22–7.27 (m, 2H, Ar), 7.46–
7.51 (m, 2H, Ar). Following the procedure of the
Dess–Martin oxidation of 3-[4-(tert-butyldimethylsilyloxy)-
phenyl]prop-2-yn-1-ol, starting from 4-(3-hydroxy-1-
4.2.4.3. trans-6-(4-Benzyloxyphenyl)-2-triethylsilyl-
oxy-1,3-hexadien-5-yne (9). Following the procedure for
the preparation of 4a, starting from trans-6-(4-benzyloxy-
phenyl)-3-hexen-5-yn-2-one (550 mg, 2.0 mmol), Et3N
(0.56 mL, 4.0 mmol), and triethylsilyl trifluoromethanesul-
fonate (0.45 mL, 2.0 mmol), 9 (703 mg, 90%) was obtained
as a colorless oil: TLC Rf¼0.32 (19:1 hexane/EtOAc); IR
(film) 2193, 1602, 1578, 1507, 1322, 1243, 1018 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d 0.74 (q, J¼8.2 Hz, 6H,
SiCH2CH3), 1.01 (t, J¼8.2 Hz, 9H, SiCH2CH3), 4.38 (s,
1H, C1–H), 4.40 (s, 1H, C1–H), 5.06 (s, 2H, PhCH2O),

T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
12043
propynyl)phenyl methanesulfonate (1.1 g, 5.0 mmol) and
Dess–Martin periodinane (2.1 g, 5.0 mmol), 5b (1.08 g,
96%) was obtained as a pale yellow solid: mp 84.5–
85.0 ꢁC; TLC Rf¼0.20 (2:1 hexane/EtOAc); IR (KBr)
2249, 2189, 1658, 1356, 1200, 1172, 1152 cmꢀ1; 1H NMR
(270 MHz, CDCl3) d 3.20 (s, 3H, OCH3), 7.32–7.37 (m,
2H, Ar), 7.64–7.70 (m, 2H, Ar), 9.43 (s, 1H, CHO); 13C
NMR (100 MHz, CDCl3) d 37.6 (CH3), 88.5 (C), 92.7 (C),
118.2 (C), 122.3 (CH), 134.7 (CH), 150.5 (C), 176.4
(C]O); EI-HRMS m/z calcd for C10H8O4S (M)+
224.0143, found 224.0144. Anal. Calcd for C10H8O4S: C,
53.56; H, 3.60; S, 14.30. Found: C, 53.45; H, 3.61; S, 14.25.
Recrystallization was performed by dissolving 3c (700 mg,
1.8 mmol, 93% ee) in 3 mL of hot EtOH. The pale yellow
needles formed at room temperature after standing overnight
were collected by suction, washed with 1 mL of ice cold
EtOH, and dried in vacuo to give optically pure 3c
(530 mg, 76%); mp 134–135 ꢁC; [a]D22 ꢀ4.95 (c 1.02,
CHCl3). The enantiopurity of 3c was determined to be
>99% ee by comparison of HPLC retention time with the
racemic sample.
4.4.2. (2R*,6S*)-2-Phenylethynyl-6-(4-methoxyphenyl)-
tetrahydropyran-4-one (3a) (Table 1, entry 1). According
to the typical procedure for HDA reaction, 3a was prepared
from diene 4a (130 mg, 0.45 mmol), phenylpropargyl alde-
hyde (5c) (39 mg, 0.30 mmol), and Rh2(R-BPTPI)4$3H2O
(4.3 mg, 0.003 mmol, 1 mol %) at 23 ꢁC for 48 h. The crude
product was purified by column chromatography (silica gel,
3:1 hexane/EtOAc) to provide 3a (76 mg, 83%) as a pale
yellow solid: mp 116–117 ꢁC; TLC Rf¼0.29 (3:1 hexane/
EtOAc); [a]2D3 ꢀ8.52 (c 1.02, CHCl3) for 91% ee; IR
4.4. HDA reaction
4.4.1. Typical procedure for the HDA reaction: (2R,6S)-
2-(4-methanesulfonyloxyphenylethynyl)-6-(4-methoxy-
phenyl)tetrahydropyran-4-one (3c) (Table 1, entry 3). To
a solution of (4-methanesulfonyloxyphenyl)propynal (5b)
(450 mg, 2.0 mmol) in CH2Cl2 (3 mL) was added Rh2(R-
BPTPI)4$3H2O (29 mg, 0.02 mmol, 1 mol %). Then the
color of the solution changed from pale yellow to brown.
After stirring for 5 min, a solution of trans-4-(4-methoxy-
phenyl)-2-triethylsilyloxy-1,3-butadiene (4a) (870 mg,
3.0 mmol) in CH2Cl2 (1 mL) was added at 23 ꢁC. After
stirring at this temperature for 12 h, the reaction mixture
turned into a deep green solution. The whole mixture was
concentrated in vacuo furnishing the deep green oil (1.3 g),
which was purified by column chromatography (WakogelÒ
C-200, 4:1 hexane/EtOAc with 2% Et3N) to give silyl enol
ether (1.0 g) as a colorless oil. Subsequently, to a solution
of the silyl enol ether in THF (4 mL) was added a solution
of TBAF in THF (1.0 M, 2.0 mL, 2.0 mmol) at 23 ꢁC. After
stirring at this temperature for 0.5 h, the mixture was poured
into a two-layer mixture of EtOAc (20 mL) and water
(10 mL), and the whole was extracted with EtOAc
(40 mL). The organic layer was washed with water
(15 mL) and brine (2ꢂ15 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (800 mg) as a pale yellow oil, which was
purified by column chromatography (silica gel, 3:2 hexane/
EtOAc) to give 3c (700 mg, 87%) as a pale yellow solid: mp
132–133 ꢁC; TLC Rf¼0.25 (3:2 hexane/EtOAc); [a]2D2
ꢀ4.59 (c 1.01, CHCl3) for 93% ee; IR (KBr) 2227, 1715,
(KBr) 2233, 1716 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d 2.62–2.92 (m, 4H, CH2COCH2), 3.81 (s, 3H, OCH3),
4.66 (dd, J¼2.6, 11.5 Hz, 1H, C6–H), 4.77 (dd, J¼3.0,
11.5 Hz, 1H, C2–H), 6.90–6.93 (m, 2H, Ar), 7.28–7.36 (m,
5H, Ar), 7.44–7.47 (m, 2H, Ar); 13C NMR (100 MHz,
CDCl3) d 47.8 (CH2), 49.1 (CH2), 55.3 (CH3), 67.7 (CH),
78.6 (CH), 86.0 (C), 86.4 (C), 114.0 (CH), 121.9 (C),
127.3 (CH), 128.2 (CH), 128.7 (CH), 131.8 (CH), 132.0
(C), 159.6 (C), 204.5 (C]O); EI-HRMS m/z calcd for
C20H18O3 (M)+ 306.1256, found 306.1258. Anal. Calcd for
C20H18O3: C, 78.41; H, 5.92. Found: C, 78.36; H, 5.99.
The enantiomeric excess of 3a was determined to be 91%
by HPLC with a Chiralcel OD-H column (9:1 hexane/
i-PrOH, 1.0 mL/min): tR¼17.4 min for major enantiomer;
tR¼25.7 min for minor enantiomer. In order to assign the ste-
reochemistry at C2 and C6, NOE studies were performed on
3a. Irradiation of C2–H showed NOE with C6–H (15.9%)
and C3–H (6.9%). Additionally, irradiation of C6–H ex-
hibited NOE with C2–H (15.8%), C5–H (7.0%), and the or-
tho proton of the 4-methoxyphenyl group (6.5%). These data
revealed cis-relationship between C2–H and C6–H. The
preferred absolute configuration of 3a was not determined.
4.4.3. (2R*,6S*)-2-(4-Hydroxyphenylethynyl)-6-(4-me-
thoxyphenyl)tetrahydropyran-4-one (3b) (Table 1, entry
2). According to the typical procedure for HDA reaction,
3b was prepared from diene 4a (130 mg, 0.45 mmol), (4-
tert-butyldimethylsilyloxyphenyl)propynal (5a) (78 mg,
0.30 mmol), and Rh2(R-BPTPI)4$3H2O (22 mg, 0.015 mmol,
5 mol %) at reflux for 48 h. The crude product was purified
by column chromatography (silica gel, 2:1 hexane/EtOAc)
to provide 3b (14.0 mg, 15%) as a pale yellow solid: mp
149–150 ꢁC; TLC Rf¼0.23 (1:1 hexane/EtOAc); [a]2D3
ꢀ4.07 (c 0.71, CHCl3) for 87% ee; IR (KBr) 3382 (br),
1362, 1174, 1148 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d 2.62–2.91 (m, 4H, CH2COCH2), 3.15 (s, 3H, SO2CH3),
3.81 (s, 3H, OCH3), 4.66 (dd, J¼2.8, 11.5 Hz, 1H, C6–H),
4.77 (dd, J¼3.2, 11.7 Hz, 1H, C2–H), 6.90–6.94 (m, 2H,
Ar), 7.22–7.27 (m, 2H, Ar), 7.32–7.36 (m, 2H, Ar), 7.48–
7.52 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3) d 37.4
(CH3), 47.4 (CH2), 48.9 (CH2), 55.2 (CH3), 67.3 (CH),
78.4 (CH), 84.7 (C), 87.2 (C), 113.9 (CH), 121.2 (C),
121.9 (CH), 127.2 (CH), 131.7 (C), 133.3 (CH), 148.9 (C),
159.4 (C), 204.1 (C]O); EI-HRMS m/z calcd for
C21H20O6S (M)+ 400.0980, found 400.0983. Anal. Calcd
for C21H20O6S: C, 62.99; H, 5.05; S, 8.01. Found: C,
62.86; H, 4.91; S, 7.99. The enantiomeric excess of 3c was
determined to be 93% by HPLC with a Chiralpak AD-H
column (1:1 hexane/i-PrOH, 1.0 mL/min): tR (major)¼
18.2 min for (2R,6S)-enantiomer; tR (minor)¼27.5 min for
(2S,6R)-enantiomer. The preferred absolute configuration
was established as (2R,6S) by transformation of 3c into 1
(vide infra).
2230, 1707 cmꢀ1 1H NMR (400 MHz, CDCl3) d 2.61–
;
2.92 (m, 4H, CH2COCH2), 3.81 (s, 3H, OCH3), 4.65 (dd,
J¼2.6, 11.5 Hz, 1H, C6–H), 4.76 (dd, J¼3.0, 11.7 Hz, 1H,
C2–H), 5.33 (br, 1H, OH), 6.74–6.78 (m, 2H, Ar), 6.89–
6.83 (m, 2H, Ar), 7.32–7.36 (m, 4H, Ar); 13C NMR
(100 MHz, CDCl3) d 47.9 (CH2), 49.1 (CH2), 55.3 (CH3),
67.8 (CH), 78.5 (CH), 84.5 (C), 86.5 (C), 113.8 (C), 114.0
(CH), 115.4 (CH), 127.4 (CH), 131.9 (C), 133.5 (CH),
156.4 (C), 159.5 (C), 205.3 (C]O); EI-HRMS m/z calcd

12044
T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
for C20H18O4 (M)+ 322.1205, found 322.1198. The enantio-
meric excess of 3b was determined to be 87% by HPLC with
a Chiralcel OD-H column (1:1 hexane/i-PrOH, 1.0 mL/
min): tR¼7.2 min for major enantiomer; tR¼10.4 min for
minor enantiomer. The preferred absolute configuration of
3b was not determined.
2.91 (m, 2H, CH2CH2CH), 3.13 (s, 3H, SO2CH3), 3.69–
3.76 (m, 1H, C6–H), 3.83 (s, 3H, OCH3), 4.58 (dd, J¼4.1,
10.0 Hz, 1H, C2–H), 6.91–6.95 (m, 2H, Ar), 7.18–7.33 (m,
6H, Ar); 13C NMR (100 MHz, CDCl3) d 30.9 (CH2), 37.2
(CH3), 37.7 (CH2), 47.6 (CH2), 49.3 (CH2), 55.3 (CH3),
75.9 (CH), 78.2 (CH), 113.9 (CH), 121.9 (CH), 126.9
(CH), 129.8 (CH), 132.7 (C), 140.7 (C), 147.3 (C), 159.2
(C), 206.5 (C]O); EI-HRMS m/z calcd for C21H24O6S
(M)+ 404.1293, found 404.1292. Anal. Calcd for
C21H24O6S: C, 62.36; H, 5.98; S, 7.93. Found: C, 62.07;
H, 5.87; S, 8.01.
4.4.4. (2R,6S)-2-(4-Methanesulfonyloxyphenylethynyl)-
6-(4-benzyloxyphenyl)tetrahydropyran-4-one (3d) (Ta-
ble 1, entry 4). According to the typical procedure for
HDA reaction, 3d was prepared from diene 4b (550 mg,
1.5 mmol), (4-methanesulfonyloxyphenyl)propynal (5b)
(220 mg, 1.0 mmol), and Rh2(R-BPTPI)4$3H2O (14 mg,
0.01 mmol, 1 mol %). The crude product was purified by
column chromatography (silica gel, 3:1 hexane/EtOAc) to
provide 3d (400 mg, 84%) as a pale yellow solid: mp 134–
135 ꢁC; TLC Rf¼0.35 (1:1 hexane/EtOAc); [a]2D3 ꢀ4.16 (c
3.13, CH3CN) for 90% ee; IR (KBr) 2232, 1720, 1352,
4.5.2. (2S,6R)-6-[2-(4-Methanesulfonyloxyphenyl)ethyl]-
2-(4-methoxyphenyl)tetrahydropyran (12). To a solution
of 10 (170 mg, 0.43 mmol) in MeOH (3 mL) was added
TsNHNH2 (80 mg, 0.43 mmol). The mixture was stirred at
reflux for 2 h. After cooling, the solvent was removed in
vacuo to give the crude product (260 mg) as a pale yellow
solid, which was used without further purification. To a solu-
tion of the crude tosylhydrazone (260 mg), TsOH$H2O
(25 mg, 0.13 mmol) in DMF (3 mL) and sulfolane (3 mL)
was added NaBH3CN (110 mg, 1.7 mmol) at 23 ꢁC. After
stirring at 110 ꢁC for 1 h, the mixture was cooled to room
temperature and poured into water (3 mL). The whole was
extracted with EtOAc (2ꢂ10 mL). The combined organic
layers were washed with water (2ꢂ5 mL) and brine
(2ꢂ5 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo followed by column chromato-
graphy (silica gel, 3:1 hexane/EtOAc) provided 12
(128 mg, 75%) as a white solid: mp 56.5–57.0 ꢁC; TLC Rf¼
0.25 (3:1 hexane/EtOAc); [a]2D1 ꢀ67.3 (c 1.00, CHCl3); IR
1172, 1152 cmꢀ1 1H NMR (400 MHz, CDCl3) d 2.60–
;
2.91 (m, 4H, CH2COCH2), 3.15 (s, 3H, SO2CH3), 4.66
(dd, J¼2.7, 11.3 Hz, 1H, C6–H), 4.77 (dd, J¼3.2, 11.8 Hz,
1H, C2–H), 5.08 (s, 2H, PhCH2O), 6.97–7.01 (m, 2H, Ar),
7.23–7.26 (m, 2H, Ar), 7.31–7.43 (m, 7H, Ar), 7.49–7.52
(m, 2H, Ar); 13C NMR (100 MHz, CDCl3) d 37.6 (CH3),
47.5 (CH2), 49.0 (CH2), 67.5 (CH), 69.9 (CH2), 78.5 (CH),
84.8 (C), 87.2 (C), 114.9 (CH), 121.3 (C), 122.0 (CH),
127.3 (CH), 127.4 (CH), 127.9 (CH), 128.5 (CH), 132.0
(C), 133.5 (CH), 136.6 (C), 149.0 (C), 158.7 (C), 204.3
(C]O); EI-HRMS m/z calcd for C27H24O6S (M)+
476.1294, found 476.1296. Anal. Calcd for C27H24O6S: C,
68.05; H, 5.08; S, 6.73. Found: C, 67.84; H, 5.07; S, 6.86.
The enantiomeric excess of 3d was determined to be 90%
by HPLC with a Chiralpak AD-H column (1:1 hexane/
i-PrOH, 1.0 mL/min): tR (major)¼28.6 min for (2R,6S)-
enantiomer; tR (minor)¼39.8 min for (2S,6R)-enantiomer.
The preferred absolute configuration was established as
(2R,6S) by transformation of 3d into 2 (vide infra).
1
(KBr) 1368, 1198, 1177, 1150 cmꢀ1; H NMR (400 MHz,
CDCl3) d 1.25–1.95 (m, 8H, C3–H, C4–H, C5–H, and
CH2CH2CH), 2.70–2.85 (m, 2H, CH2CH2CH), 3.12 (s,
3H, SO2CH3), 3.41–3.47 (m, 1H, C6–H), 3.81 (s, 3H,
OCH3), 4.30 (dd, J¼2.1, 11.1 Hz, 1H, C2–H), 6.86–6.90
(m, 2H, Ar), 7.15–7.19 (m, 2H, Ar), 7.21–7.24 (m, 2H,
Ar), 7.29–7.32 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d 24.0 (CH2), 31.1 (CH2), 31.3 (CH2), 33.3 (CH2), 37.2
(CH3), 37.9 (CH2), 55.3 (CH3), 76.9 (CH), 79.1 (CH),
113.5 (CH), 121.6 (CH), 126.9 (CH), 129.9 (CH), 135.6
(C), 141.9 (C), 147.1 (C), 158.6 (C); EI-HRMS m/z calcd
for C21H26O5S (M)+ 390.1501, found 390.1497. Anal. Calcd
for C21H26O5S: C, 64.59; H, 6.71; S, 8.21. Found: C, 64.34;
H, 6.53; S, 8.41.
Recrystallization was performed by dissolving 3d (400 mg,
0.84 mmol, 90% ee) in 2 mL of hot EtOH. The pale yellow
needles formed at room temperature after standing overnight
were collected by suction, washed with 1 mL of ice cold
EtOH, and dried in vacuo to give optically pure 3d
(290 mg, 73%); mp 135–136 ꢁC; [a]D20 ꢀ4.76 (c 3.20,
CH3CN). The enantiopurity of 3d was determined to be
>99% ee by comparison of HPLC retention time with the
racemic sample.
4.5.3. (L)-Centrolobine (1). To a solution of 12 (110 mg,
0.28 mmol) in MeOH (5 mL) was added K2CO3 (390 mg,
2.8 mmol). The mixture was stirred at reflux for 3 h. After
cooling, the reaction mixture was partitioned between
EtOAc (10 mL) and water (5 mL). The whole was extracted
with EtOAc (2ꢂ10 mL). The combined organic layers were
washed with water (2ꢂ5 mL) and brine (2ꢂ5 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo
followed by column chromatography (silica gel, 4:1 hexane/
EtOAc) provided 1 (82.0 mg, 96%) as a white solid: mp
85.0–85.5 ꢁC [lit.,1c mp 84–86 ꢁC]; TLC Rf¼0.25 (3:1
hexane/EtOAc); [a]D21 ꢀ93.7 (c 1.02, CHCl3) [lit.,1d [a]D
ꢀ92.2 (c 1, CHCl3)]; IR (KBr) 3385, 3013, 2936, 2857,
1613, 1514, 1454, 1366, 1304, 1246, 1177, 1078,
4.5. Synthesis of (L)-centrolobine
4.5.1. (2S,6S)-6-[2-(4-Methanesulfonyloxyphenyl)ethyl]-
2-(4-methoxyphenyl)tetrahydropyran-4-one (10). A solu-
tion of 3c (200 mg, 0.50 mmol, >99% ee) in EtOAc (10 mL)
was stirred with 10% Pd/C (20 mg) under 1 atm of H2 at
23 ꢁC for 2 h. The catalyst was removed by filtration, and
the filtrate was concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, 3:2 hexane/
EtOAc) to afford 10 (194 mg, 96%) as a white solid: mp
105–106 ꢁC; TLC Rf¼0.29 (1:1 hexane/EtOAc); [a]2D0
ꢀ72.6 (c 1.01, CHCl3); IR (KBr) 1717, 1368, 1198, 1177,
1
1
1150 cmꢀ1; H NMR (400 MHz, CDCl3) d 1.83–1.92 (m,
1036 cmꢀ1; H NMR (400 MHz, CDCl3) d 1.25–1.37 (m,
1H, CH2CHHCH), 2.02–2.11 (m, 1H, CH2CHHCH), 2.37–
2.47 (m, 2H, COCH2), 2.54–2.65 (m, 2H, COCH2), 2.74–
1H, C5–H), 1.45–1.55 (m, 1H, C3–H), 1.61–1.66 (m, 2H,
C4–H and C5–H), 1.67–1.76 (m, 1H, CH2CHHCH),

T. Washio et al. / Tetrahedron 63 (2007) 12037–12046
12045
1.80–1.95 (m, 3H, C3–H, C4–H, and CH2CHHCH), 2.61–
2.76 (m, 2H, CH2CH2CH), 3.41–3.46 (m, 1H, C6–H), 3.80
(s, 3H, OCH3), 4.29 (dd, J¼2.1, 9.0 Hz, 1H, C2–H), 4.66
(br, 1H, OH), 6.71–6.75 (m, 2H, Ar), 6.86–6.90 (m, 2H,
Ar), 7.03–7.07 (m, 2H, Ar), 7.29–7.33 (m, 2H, Ar); 13C
NMR (100 MHz, CDCl3) d 23.9 (CH2), 30.6 (CH2), 31.1
(CH2), 33.1 (CH2), 38.1 (CH2), 55.1 (CH3), 76.9 (CH),
78.9 (CH), 113.4 (CH), 114.8 (CH), 126.9 (CH), 129.3
(CH), 134.4 (C), 135.5 (C), 153.2 (C), 158.4 (C). EI-
HRMS m/z calcd for C20H24O3 (M)+ 312.1725, found
312.1733. The synthetic material 1 was identical in all
respects with the reported spectral data for the natural
substance (IR, 1H NMR, 13C NMR, HRMS), including
optical rotation.
(83.7 mg, 96%) was obtained as a white solid: mp 181–
182 ꢁC [lit.,2a mp 183 ꢁC]; TLC Rf¼0.21 (2:1 hexane/
EtOAc); [a]2D2 ꢀ96.1 (c 1.02, MeOH) [lit.,2a [a]2D5 ꢀ95.1 (c
0.9, MeOH)]; IR (KBr) 3362, 1614 cmꢀ1
;
1H NMR
(400 MHz, acetone-d6) d 1.20–1.90 (m, 8H, C3–H, C4–H,
C5–H, and CH2CH2CH), 2.55–2.70 (m, 2H, CH2CH2CH),
3.37–3.44 (m, 1H, C6–H), 4.25 (dd, J¼2.3, 11.3 Hz, 1H,
C2–H), 6.71–6.80 (m, 4H, Ar), 6.99–7.03 (m, 2H, Ar),
7.19–7.22 (m, 2H, Ar), 8.03 (br, 1H, OH), 8.17 (br, 1H,
OH); 13C NMR (100 MHz, acetone-d6) d 24.7 (CH2), 31.4
(CH2), 32.0 (CH2), 34.6 (CH2), 39.4 (CH2), 77.6 (CH),
79.8 (CH), 115.5 (CH), 115.8 (CH), 127.8 (CH), 130.1
(CH), 133.9 (C), 135.9 (C), 156.1 (C), 157.1 (C). EI-
HRMS m/z calcd for C19H22O3 (M)+ 298.1569, found
298.1576. The synthetic material 2 was identical in all
respects with the reported spectral data for the natural sub-
4.6. Synthesis of (L)-de-O-methylcentrolobine
1
stance (IR, H NMR, 13C NMR, HRMS), including optical
4.6.1. (2S,6S)-2-(4-Hydroxyphenyl)-6-[2-(4-methane-
sulfonyloxyphenyl)ethyl]tetrahydropyran-4-one (11).
Following the procedure for the preparation of 10, starting
from 3d (240 mg, 0.50 mmol, >99% ee) and 10% Pd/C
(25 mg), 11 (190 mg, 97%) was obtained as a white solid:
mp 45.0–46.0 ꢁC; TLC Rf¼0.20 (1:1 hexane/EtOAc); [a]2D3
ꢀ69.9 (c 1.09, CHCl3); IR (KBr) 3421 (br), 1713, 1364,
rotation.
Acknowledgements
This research was supported, in part, by a Grant-in-Aid for
Scientific Research on Priority Areas ‘Advanced Molecular
Transformations of Carbon Resources’ from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
T.W. is grateful to JSPS for a graduate fellowship. We thank
Ms. S. Oka, M. Kiuchi, A. Maeda, and H. Matsumoto of the
Center for Instrumental Analysis at Hokkaido University for
mass measurements and elemental analysis.
1173, 1147 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.83–
;
1.92 (m, 1H, CH2CHHCH), 2.01–2.10 (m, 1H,
CH2CHHCH), 2.37–2.47 (m, 2H, COCH2), 2.53–2.63 (m,
2H, COCH2), 2.74–2.91 (m, 2H, CH2CH2CH), 3.13 (s, 3H,
SO2CH3), 3.69–3.75 (m, 1H, C6–H), 4.56 (dd, J¼3.2,
10.4 Hz, 1H, C2–H), 5.06 (br, 1H, OH), 6.84–6.87 (m, 2H,
Ar), 7.18–7.28 (m, 6H, Ar); 13C NMR (100 MHz, CDCl3)
d 30.9 (CH2), 37.2 (CH3), 37.6 (CH2), 47.5 (CH2), 49.2
(CH2), 75.9 (CH), 78.2 (CH), 115.4 (CH), 121.8 (CH),
127.1 (CH), 129.8 (CH), 132.3 (C), 140.7 (C), 147.2 (C),
155.6 (C), 207.7 (C]O); EI-HRMS m/z calcd for
C20H22O6S (M)+ 390.1137, found 390.1131. Anal. Calcd
for C20H22O6S: C, 61.52; H, 5.68; S, 8.21. Found: C,
61.54; H, 5.70; S, 8.48.
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1151 cmꢀ1; H NMR (400 MHz, CDCl3) d 1.25–1.95 (m,
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Zhou, J.-Y.; Okamura, W. H. J. Med. Chem. 1991, 34, 2452–
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24. Lee, T.-S.; Kim, J.; Bae, J.-Y. Polymer 2004, 45, 5065–5076.
25. Diene 9 was prepared in three steps and 83% overall yield from
3-(4-benzyloxyphenyl)-2-propyn-1-ol.26 This procedure is in
Section 4.2.4.
26. Furst, M.; Ruck-Braun, K. Synlett 2002, 1991–1994.
27. Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am.
Chem. Soc. 1973, 95, 3662–3668.
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€
28. Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321–1329.