Total synthesis of diastereomeric marine butenolides possessing a syn-aldol subunit at C10 and C11 and the related C11-ketone

Article abstract of DOI:10.1016/j.tet.2009.10.115

Two diastereomeric marine butenolides, (4S,10R,11R)- and (4S,10S,11S)-4,11-dihydroxy-10-methyldodec-2-en-1,4-olide, possessing a syn-aldol subunit at C10 and C11 have been efficiently synthesized by using a three-module coupling strategy. The enantiomeric syn-aldol modules prepared by the syn-selective aldol reaction of the norephedrine-derived chiral propionates were coupled with the chiral C3-C7 module via 1,3-dithiane bisalkylation. The butenolide ring was then installed via a high-yielding ring-closing metathesis (RCM) reaction. Oxidation of the diastereomeric C11-alcohols furnished the corresponding C11-ketones, which are produced by the same marine microorganism.

Full text of DOI:10.1016/j.tet.2009.10.115

Tetrahedron 66 (2010) 187–196
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of diastereomeric marine butenolides possessing a syn-aldol
subunit at C10 and C11 and the related C11-ketone
Yan Wang a b, Wei-Min Dai a
,
,b,
*
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
Center for Cancer Research and Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Two diastereomeric marine butenolides, (4S,10R,11R)- and (4S,10S,11S)-4,11-dihydroxy-10-methyldodec-
Received 13 September 2009
Received in revised form 28 October 2009
Accepted 31 October 2009
2
-en-1,4-olide, possessing a syn-aldol subunit at C10 and C11 have been efficiently synthesized by using
a three-module coupling strategy. The enantiomeric syn-aldol modules prepared by the syn-selective
aldol reaction of the norephedrine-derived chiral propionates were coupled with the chiral C3–C7
module via 1,3-dithiane bisalkylation. The butenolide ring was then installed via a high-yielding
ring-closing metathesis (RCM) reaction. Oxidation of the diastereomeric C11-alcohols furnished the
corresponding C11-ketones, which are produced by the same marine microorganism.
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 4 November 2009
Keywords:
Aldol
Butenolide
Dithiane
Ring-closing metathesis
Stereochemistry
1. Introduction
obtained the butenolides 1, 2 and 4 from two marine Streptomycete
strains B 3497 and B 5632. The former was collected from a North
2
In recent years, a group of butenolides (or furanones) possessing
a side chain of less than ten carbons at C4 has been isolated from
various marine microorganisms (Fig. 1). Laatsch and co-workers
Atlantic Ocean sediment and the latter was derived from muddy
sediment of a mangrove site near Auckland, New Zealand. Shin and
co-workers isolated the butenolides 2–4 along with other g-
1
butyrolactones produced by the strain M02750 of the genus
Streptomyces from shallow-water sediment collected from Ton-
OH
3
4
gyoung Bay, Korea. Gu and Zhu’s laboratory identified the bute-
nolides 1, 3 and 4 from the Streptoverticillium luteoverticillatum
strain 11,014 obtained from underwater sediment collected off the
coast of Taipingjiao, Qingdao, China. Butenolides 1, 3 and 4 were
reported to exhibit cytotoxicity against human leukemia K562 and
4
S
10
a: (4S,10R,11S)
b: (4S,10S,11R)
c: (4S,10R,11R)
d: (4S,10S,11S)
1
1 Me
H
H
O
Me
O
O
1
O
4
S
10
murine lymphoma P388 cell lines with IC50 values of 0.18ꢀ0.11 to
a: (4S,10R)
b: (4S,10S)
1
1 Me
4
8.73ꢀ1.44
mmol/mL.
O
Me
The structures of 1–4 have been established by NMR techniques
and the 4S configuration has been confirmed by the CD spectrum
2
that gives a positive
pdp transition at 208 nm. But the absolute
*
OH
4
S
configurations of the stereogenic centers on the side chains of 1, 2,
and 4 remain unknown. Laatsch and co-workers obtained bute-
nolide 1 as a 1:1 inseparable mixture of two diastereomers due to
the C10 and C11 stereogenic centers. For another diastereomeric
mixture of 1, the ratio and optical rotation data were not reported.
R
1
0
H
O
Me
O
2
3
: R = H; 4: R = Me
4
Figure 1. Structures of some marine butenolide alcohols and ketones.
The ketone 2 may also exist in diastereomeric forms because two
2
,3
different optical rotation values were reported. Moreover, the
stereochemical determination of 1, 2, and 4 is hampered by the fact
that there is no stereochemical communication among the bute-
nolide ring and the remote stereogenic center(s) on the side chain.
*
Corresponding author. Tel./fax: þ86 (571) 87953128.
E-mail addresses: chdai@ust.hk, chdai@zju.edu.cn (W.-M. Dai).
0
040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.115

188
Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
For example, the two C10–C11 anti-diastereomers 1a and 1b give
1. I , PPh
2 3
4
S
1
13
5
imidazole (85%)
identical H and C NMR spectra. This is also true for the two C10–
OH
TBSO
TBSO
I
O
H
5
C11 syn-diastereomers 1c and 1d and the two C10 epimers of 2
O
Me
2. 1% HCl, MeOH
3. TBSOTf
Me
(
vide infra). In order to correctly assign the absolute configurations
15
2,6-lutidine
5
for 1 (at C10 and C11) and 2 (at C10), optical rotation data of the
(
85% for 2 steps)
related diastereomers are needed.
5
Hedenstr o¨ m and co-workers reported an efficient synthesis of
Scheme 1. Synthesis of the iodide 5.
the two C10–C11 anti-diastereomers 1a and 1b from (R)-vinyl-
oxirane and the enantiomerically pure trans-3,4-disubstituted
tetrahydrothiophene via bisalkylation of 1,3-dithiane. This three-
Abiko and co-workers examined a series of norephedrine-de-
6
rived chiral propionates for the syn-selective aldol reaction of
12b
i-PrCHO.
The diastereofacial selectivity of the mesitylenesulfo-
module coupling sequence was followed by a ring-closing me-
tathesis (RCM) reaction7,8 to form the butenolide moiety. The two
namide-derived 13 is excellent (96:4) albeit its syn:anti ratio is
slightly lower (87:13). We performed the syn-selective aldol re-
action of acetaldehyde with (1S,2R)-13 in the presence of
C10–C11 syn-diastereomers 1c and 1d were prepared from 1a and
1
b, respectively, by the Mistunobu reaction with inversion of the
2 2
n-Bu BOTf and i-Pr NEt (Scheme 2). The syn-aldol 16 was obtained
configuration at C11 in only 5% yield. The optical rotation data of 1c
5
in 95% chemical yield and in a 90:10 mixture of syn- and anti-di-
and 1d were not reported.
1
astereomers as estimated by H NMR spectroscopy. The syn-di-
We have recently completed the total synthesis of 1a and 2a
by a similar three-module coupling approach based on 1,3-
dithiane bisalkylation of two different chiral iodides 5 and 7
R*
n-Bu BOTf, i-Pr NEt
2
2
Ph
O
O
OH
Fig. 2).9 Our approach to the butenolides is flexible and can be
78 °C, 2 h;
(
1S
Me
R*
2
R
O
then MeCHO
O
Me
amended for synthesis of other diastereomers. The iodide 5 used
in our previous work was of 82% ee according to the enantiose-
lectivity of the asymmetric dihydroxylation (see 8 and 9 in
Supplementary data).10 For obtaining accurate optical rotation
data of the diastereomers of 1 and 2, an alternative synthesis of 5
from the enantiomerically pure 10 is employed in the current
work. We report here on total synthesis of 1c and 1d and the C10
epimers 2a and 2b starting from the alcohols 12c and 12d, which
N
Me
78 °C, 1 h; 0 °C, 1 h
Me
MesSO2
Bn
(95%; dr = 90:10)
1
6
(1S,2R)-13
DHP, PPTS
(
99%)
CH Cl , 30 °C
2
2
1
. Dibal-H, THF
OTHP
O
OTHP
Me
Me
1
0R
11RMe
78 °C to rt, 1 h (95%)
R*
X
O
11
2. I , PPh , imidazole
are readily derived from the syn-selective aldol reaction of the
norephedrine-derived chiral propionates (1S,2R)-13 and (1R,2S)-
Me
2
3
THF, 0 °C to rt, 2.5 h
(92%)
1
2c: X = OH
8: X = I
17
1
3, respectively.12 Our current study enables assignment of the
1
absolute configurations for the marine-derived butenolide alco-
hols 1 and ketone 2.
Scheme 2. Synthesis of the chiral iodide 18.
CO Et
O
P
2
O
O
11: D-Mannitol
CO Et
EtO
2
Me
Me
10
EtO 14
1
,3-dithiane alkylation
RCM
OH
4
S
10
*
OTHP
4
S
1
1 Me
*
TBSO
TBSO
I
S
+
S
10
*
H
+
O
Me
H
I
* 11 Me
Me
7
O
1,3-dithiane alkylation
1
5
6
Ph
O
Ph
O
OTHP
OTHP
OTHP
OTHP
1
S
Me
Me
O
O
10R
11S Me
10S
10R
10S
2
N
R
HO
HO
11R Me
Me
HO
11RMe
Me
HO
11S Me
Me
Me
N
Me
MesSO2
Bn
1S,2R)-13
MesSO2
Bn
(1R,2S)-13
Me
(
(10R,11S)-12a
(10S,11R)-12b
(10R,11R)-12c
(10S,11S)-12d
Figure 2. A three-module coupling approach to the diastereomers of butenolide 1. The butenolide numbering system is used for the fragments.
2
. Results and discussion
astereomer 16 is not separable from its minor anti-diastereomer by
column chromatography over silica gel and the diastereomeric
We first synthesized the enantiomerically pure iodide 5 as given
in Scheme 1. The alcohol 15 was prepared from the -unsaturated
mixture of 16 was used in the synthesis of 12c (Scheme 2). Alcohol
ꢁ
a
,b
16 was protected as the THP ether at 30 C in CH
2
Cl
2
to give 17 in
ester 10, which was obtained by the olefination of triethyl phos-
phonoacetate (14 in Fig. 2) with the 1,2:5,6-diacetal derived from
99% yield. The chiral auxiliary in 17 was removed by Dibal-H re-
duction to furnish 12c (95%), which was then transformed into the
iodide 18 in 92% yield after treating with I –PPh –imidazole in THF.
2 3
The syn-aldol 19 was prepared in a similar manner from (1R,2S)-
13 in 91% chemical yield as an 87:13 mixture of syn- and anti-di-
astereomers (Scheme 3). We found that recrystallization could not
13
D
-mannitol (see Supplementary data for details). Treatment of 15
13c
with I
2
–PPh
3
–imidazole gave the corresponding iodide,
which
underwent acidic acetal hydrolysis and protection of the diol to
furnish the iodide 5 in 72% overall yield from 15.

Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
189
enrich the diastereomeric ratio of 19. Alternatively, we could obtain
a 92:8 diastereomeric mixture of 19 by fractional column chro-
matographic separation with H NMR spectroscopic analysis of the
yield. The THP ether in 30 was removed upon exposure to MeOH
ꢁ
and PPTS (40 C, 2 h) to furnish 1c in 88% yield. DMP oxidation of 1c
1
13
gave the ketone 2a in 91% yield. The C NMR data of 1c are con-
5
13
collected fractions and the sample was used for the synthesis of
sistent with those reported by Hedenstr o¨ m (Table 1). The C NMR
1
2d. Thus, protection of 19 as the THP ether 20 was followed by
Dibal-H reduction to afford the alcohol 12d in 94% overall yield
from 19. Treatment of 12d with I –PPh –imidazole gave the iodide
1 in 90% yield.
data of 2a are identical to our previously published data (not shown
9
in Table 1) and are well fit with those of naturally occurring ketone
2
2
3
2 reported by Laatsch (Table 1) and Shin (data not shown in Table
3
2
1), respectively.
The butenolide alcohol 1d and ketone 2b were synthesized in
a similar manner as illustrated in Scheme 5. All steps gave similar
yields as compared to those obtained for the diastereomers given in
Scheme 4, indicating the reliability of the synthetic chemistry. The
R*
Me
n-Bu BOTf, i-Pr NEt
2
7
2
Ph
O
O
OH
8 °C, 2 h;
1
R
R*
O
then MeCHO
Me 78 °C, 1 h; 0 °C, 1 h
O
Me
13
2
S
C NMR data of 1d are consistent with the reported data by
N
Me
19
5
13
MesSO2
Bn
1R,2S)-13
Hedenstr o¨ m (Table 1). We found that the C NMR data of 2a and
b are identical, concurring with the same observation for the C10–
(
91%; dr = 87:13; for a
sample, dr = 92:8,
see text)
2
(
C11 anti-diastereomers 1a and 1b, and the syn-diastereomers 1c
DHP, PPTS
5
(
100%)
and 1d, respectively. Table 2 lists all available optical rotation data
CH Cl , 30 °C
2
2
for the butenolide alcohols 1a–d and ketones 2a,b. According to the
1
. Dibal-H, THF
78 °C to rt, 1 h (94%)
OTHP
O
OTHP
Me
Me
optical rotation data reported by Laatsch and co-workers (Table 2,
1
0S
11S Me
2
R*
entry 1), it is highly possible that the two naturally occurring
X
O
2
. I , PPh , imidazole
butenolide alcohols should be (4S,10R,11S)-1a and (4S,10R,11R)-1c,
being different at the C11 configuration. If this is correct, we suggest
that the absolute configuration of the naturally occurring buteno-
2
3
Me
THF, 0 °C to rt, 2.5 h
(90%)
1
2d: X = OH
1: X = I
20
2
2
lide ketone 2 (Table 2, entry 6) isolated by Laatsch and co-workers
Scheme 3. Synthesis of the chiral iodide 21.
should be (4S,10R) by considering possible biosynthetic relevance
to the formation of the butenolide alcohols (4S,10R,11S)-1a and
We next carried out the 1,3-dithiane bisalkylation (Scheme 4).
Deprotonation of 1,3-dithiane 6 using n-BuLi gave the corre-
sponding carbanion which was alkylated with the iodide 18 to form
(4S,10R,11R)-1c. It is supported by the optical rotation data of our
synthetic (4S,10R)-2a as given in entry 9 of Table 2.
2
2 in 84% yield. Three equivalents of 6 were used but the stoichi-
ometry was not optimized. Compound 22 was deprotonated again
by n-BuLi in the presence of HMPA in THF followed by reacting with
3. Conclusion
5
to give 23 in 85% yield. Reduction of 23 by Raney-Ni under a hy-
In summary, we have synthesized two diastereomeric marine
butenolide alcohols (4S,10R,11R)-1c and (4S,10S,11S)-1d by using
the 1,3-dithiane-based three-module coupling approach previously
used for the synthesis of (4S,10R,11S)-1a. The enantiomerically
pure iodide module 5 is readily prepared from D-mannitol while the
14
drogen atmosphere afforded the product 24 in 93% yield. Selec-
tive removal of the primary TBS ether in 24 in a 1:1 mixed media of
acetic acid and TBAF (1 M in THF) gave the alcohol 25 in 83% yield.
Oxidation of 25 with Dess-Martin periodinane (DMP) gave the al-
dehyde 26 (87%), which underwent the Wittig olefination to form
the alkene 27 in 86% yield. Treatment of 27 with TBAF in THF re-
moved the TBS ether to give the allyl alcohol 28 in 95% yield. Ac-
ylation of 28 with acryloyl chloride and Et
9
Grubbs second generation catalyst for the RCM reaction. We could
9
chiral iodides 18 and 21 possessing the syn-aldol moiety are
obtained from the syn-selective aldol reactions of the norephe-
drine-derived chiral propionates 13. Our current work provides the
first set of optical rotation data for (4S,10R,11R)-1c and (4S,10S,11S)-
1d. In combination with the optical rotation data of (4S,10R,11S)-1a
3
N gave the acrylate 29 in
9
5% yield (Scheme 4). In our previous work, we used 10 mol %
5
and (4S,10S,11R)-1b reported by Hedenstr o¨ m and co-workers, we
reduce the catalyst loading to 5 mol % for the RCM reaction of 29
are able to assign the absolute configurations for the two naturally
occurring butenolide alcohols as (4S,10R,11S)-1a and (4S,10R,11R)-
ꢁ
(
CH
2
Cl
2
, 40 C, 4 h) and obtained the desired butenolide 30 in 90%
OTHP
Me
Me
OTHP
Me
Me
OTHP
Me
Me
6
, n-BuLi, THF
n-BuLi, HMPA
1. Raney-Ni, H2
EtOH, reflux
2
0 °C, 3 h;
H
S
THF 20 °C, 2 h;
I
TBSO
S
S
S
then 18, 40 °C
then 5, 78 °C, 2 h
OTBS
10 h (93%)
3
h (84%)
(85%)
2. AcOH-TBAF
(
1:1), rt, 8 h
1
8
22
23
(
83%)
1
. DMP, NaHCO3
OTHP
Me
Me
OTHP
Me
Me
OTHP
Me
Me
TBAF
CH Cl , rt (87%)
2
2
X
RO
+
THF, rt
2. Ph P MeBr
3
OH
OTBS
26: X = O
OTBS
(95%)
KHMDS, THF, 0 °C;
then, 26, 10 °C (86%)
28
24: R = TBS
25: R = H
27: X = CH2
CH =CHCOCl, Et N
2
3
(
95%)
CH Cl , rt, 4 h
2
2
OTHP
1. Grubbs 2nd cat (5 mol%)
0 °C, 4 h (90%)
OR
DMP
O
4
4S
10R
11R Me
NaHCO3
4S
10R
Me
Me
2
. PPTS, MeOH
H
CH Cl , rt
2
2
H
O
Me
O
Me
O
Me
4
0 °C, 2 h (88%)
(91%)
O
O
O
29
30: R = THP
4S,10R,11R)-1c: R = H
(4S,10R)-2a
(
Scheme 4. Total synthesis of butenolide alcohol (4S,10R,11R)-1c and butenolide ketone (4S,10R)-2a via 1,3-dithiane bisalkylation and RCM.

190
Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
Table 1
1
3C NMR data of the butenolide alcohols 1c and 1d and ketones 2a,b in CDCl
3
Atom
(4S,10R,11R)-1ca
125 MHz)
(4S,10R,11R)-1c
(100 MHz)
(4S,10S,11S)-1da
(125 MHz)
(4S,10S,11S)-1d
(100 MHz)
Natural 2b
(125 MHz)
(4S,10R)-2a
(100 MHz)
(4S,10S)-2b
(100 MHz)
(
1
2
3
4
5
6
7
8
9
1
1
1
1
CO
CH
CH
CH
CH
CH
CH
CH
CH
0 CH
1 CH/CO
2 CH
3 CH
173.15
121.57
156.23
83.38
33.16
24.97
29.60
27.12
32.42
39.67
71.31
20.26
14.11
173.14
121.54
156.23
83.39
33.15
24.95
29.60
27.10
32.41
39.67
71.30
20.25
14.11
173.17
121.58
156.26
83.39
33.17
24.97
29.61
27.13
32.42
39.69
71.33
20.27
14.15
173.13
121.53
156.22
83.37
33.14
24.94
29.59
27.10
32.41
39.68
71.29
20.23
14.12
173.0
121.4
156.2
83.2
32.9
24.7
29.2
26.8
32.5
47.0
212.6
27.9
16.1
173.09
121.59
156.17
83.29
33.06
24.79
29.30
26.96
32.62
47.11
212.80
28.03
16.29
173.07
121.58
156.14
83.28
33.07
24.82
29.31
26.96
32.62
47.10
212.75
28.00
16.29
2
2
2
2
2
3
3
a
Data taken from Ref. 5.
Data taken from Ref. 2.
b
OTHP
OTHP
Me
Me
OTHP
6
, n-BuLi, THF
n-BuLi, HMPA
1. Raney-Ni, H2
EtOH, reflux
2
0 °C, 3 h;
H
S
THF 20 °C, 2 h;
I
Me
TBSO
OTBS
Me
Me
S
S
S
then 21, 40 °C
then 5, 78 °C, 2 h
10 h (92%)
Me
3
h (84%)
(81%)
2. AcOH-TBAF
(
1:1), rt, 8 h
2
1
31
32
(
86%)
1
. DMP, NaHCO3
OTHP
Me
Me
OTHP
Me
Me
OTHP
TBAF
CH Cl , rt (97%)
2
2
X
RO
Me
+
THF, rt
100%)
2. Ph P MeBr
3
OH
OTBS
OTBS
Me
(
KHMDS, THF, 0 °C;
then, 35, 10 °C (83%)
3
7
35: X = O
3
33: R = TBS
34: R = H
6: X = CH
2
CH =CHCOCl, Et N
2
3
(
98%)
CH Cl , rt, 4 h
2
2
OTHP
1. Grubbs 2nd cat (5 mol%)
0 °C, 4 h (89%)
OR
DMP
O
4
4S
10S
11S Me
NaHCO
3
4S
10S
Me
Me
2
. PPTS, MeOH
H
CH Cl , rt
2
2
H
O
Me
O
Me
O
Me
(4S,10S)-2b
4
0 °C, 2 h (93%)
(98%)
O
O
O
38
39: R = THP
4S,10S,11S)-1d: R = H
(
Scheme 5. Total synthesis of butenolide alcohol (4S,10S,11S)-1d and butenolide ketone (4S,10S)-2b via 1,3-dithiane bisalkylation and RCM.
2
Table 2
1c. We also suggest (4S,10R)-2a as the butenolide ketone produced
by Streptomycete strain B 5632 on the basis of our optical rotation
data and by assuming its formation through the same biosynthetic
Optical rotation data for butenolide alcohols 1 and ketones 2
Entry
Sample
Optical Rotations
Optical Rotations
of Dai’s Samples
2
pathway as the butenolide alcohols 1.
2
2
1
2
3
4
5
6
7
8
9
Natural 1
[
a
]
D
þ84.5
a
b
b
(
1:1 mixture)
(c 0.119, MeOH)
2
0
20
(4S,10R,11S)-1a
(4S,10S,11R)-1b
(4S,10R,11R)-1c
(4S,10S,11S)-1d
Natural 2
[
(
[
(
a
]
D
þ70.9
[a
]
D
þ78.0
4. Experimental
d
c 0.115, MeOH)
(c 0.100, MeOH)
d
2
0
a
]
D
þ42.9
4.1. General methods
c 0.359, MeOH)
2
0
d
d
[
(
[
(
a
]
D
þ64.3
e
e
1H and 13C NMR spectra were recorded in CDCl
300 or 400 MHz for H and 75 or 100 MHz for C, respectively)
c 0.14, MeOH)
3
or acetone-d
6
2
0
a
]
D
þ33.6
1
13
(
c 0.14, MeOH)
2
2
with residual CHCl or acetone as the internal reference. IR
3
[
(
[
(
a
]
D
þ45
a
c 0.119, MeOH)
spectra were taken on an FTIR spectrophotometer. High-resolu-
tion mass spectra (HRMS) were measured by the CIþ method. All
reactions were carried out under a nitrogen atmosphere and
monitored by thin-layer chromatography on 0.25-mm E. Merck
silica gel plates (60 F-254) using UV light, or 7% ethanolic phos-
phomolybdic acid and heating as the visualizing methods. E.
Merck silica gel (60, particle size 0.040–0.063 mm) was used for
flash column chromatography. Yields refer to chromatographi-
2
5
Natural 2
a
]
D
þ18.4
c
c 0.18, MeOH)
2
0
(4S,10R)-2a
[
(
[
(
[
(
a
]
D
þ32.0
d
e
c 0.100, MeOH)
2
0
(4S,10R)-2a
a
]
D
þ49.4
c 0.175, MeOH)
2
0
10
(4S,10S)-2b
a
]
D
þ73.0
e,f
c 0.12, MeOH)
a
b
c
d
e
f
1
Data reported by Laatsch in Ref. 2.
Data taken from Ref. 5 for the synthetic samples described by Hedenstr o¨ m.
Data reported by Shin in Ref. 3.
Data for the samples containing 9% of (4R) diastereomers from Ref. 9.
Data from the current work.
See Note 15.
cally and spectroscopically ( H NMR) homogeneous materials. All
reagents were obtained commercially and used as-received.
ꢁ
Room temperature is around 23 C. For the THP-protected in-
1
termediates, a pair of diastereomers was recognized in the H and
13
C NMR spectra.

Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
191
þ
4
.2. (S)-5-Iodopentane-1,2-diol
d
C
6
)
d
108.1, 74.7, 68.7, 34.1, 29.9, 26.2, 24.8, 6.4; HRMS (CI ) calcd for
þ
þ
8
H
16IO
2
(MþH ) 271.0195, found 271.0193.
To a solution of (S)-4-(3-iodopropyl)-2,2-dimethyl-1,3-dioxola-
ne13c (1.540 g, 5.70 mmol) in MeOH (15 mL) was added 1% aqueous
HCl (1 mL, 0.29 mmol) at room temperature followed by stirring for
4.4.2. (2 S,3 R)-2-(1 -Iodo-2 -methyl-3 -butyloxy)tetrahydropyrane
(18). The chiral iodide 18 was prepared from the alcohol 12c
according to the general procedure A in 92% yield as a colorless oil;
0
0
0
0
0
2
h at the same temperature. The reaction was then cooled in an
ice-water bath and quenched by addition of saturated aqueous
NaHCO . The resultant reaction mixture was extracted with CH Cl
3ꢂ20 mL) and the combined organic layer was dried over anhy-
drous Na SO , filtered, and concentrated under reduced pressure.
R
f
¼0.65 (16.7% EtOAc in hexane); IR (film) 2939, 1452, 1378, 1133,
ꢃ1
1
3
2
2
1076, 1022 cm
;
H NMR (400 MHz, CDCl
3
)
d
4.67 (t, J¼3.6 Hz,
(
0.5H), 4.63 (dd, J¼5.2, 2.8 Hz, 0.5H), 3.94–3.83 (m, 1H), 3.82 (qd,
J¼6.4, 4.4 Hz, 0.5H), 3.75 (qd, J¼6.4, 4.4 Hz, 0.5H), 3.55–3.47 (m,
1H), 3.45 (dd, J¼9.2, 5.2 Hz, 0.5H), 3.32 (dd, J¼9.2, 5.8 Hz, 0.5H), 3.10
(dd, J¼9.6, 6.0 Hz, 0.5H), 3.06 (dd, J¼9.2, 7.4 Hz, 0.5H), 1.86–1.65 (m,
3H), 1.60–1.47 (m, 4H), 1.20 (d, J¼6.4 Hz, 1.5H), 1.08 (d, J¼6.0 Hz,
2
4
The residue was purified by column chromatography (silica gel,
eluting with 50% EtOAc in hexane) to give the diol (1.070 g, 82%) as
2
0
a white solid; [
hexane); IR (film) 3400, 2937, 2870, 1210,1080,1023 cm ; H NMR
400 MHz, CDCl
a
]
D
ꢃ3.30 (c 0.575, CHCl
3
); R
f
¼0.21 (50% EtOAc in
ꢃ1
1
13
1.5H), 1.06 (d, J¼6.8 Hz, 1.5H), 1.02 (d, J¼6.8 Hz, 1.5H); C NMR
(
3
)
d
3.77–3.71 (m, 1H), 3.68 (dd, J¼11.2, 3.2 Hz, 1H),
3
(100 MHz, CDCl ) d 100.2 and 95.6, 77.2 and 73.2, 63.0 and 62.6, 41.9
3
2
d
.46 (dd, J¼10.8, 7.6 Hz, 1H), 3.23 (t, J¼6.8 Hz, 2H), 2.09–1.85 (m,
and 41.4, 31.1, 25.5 and 25.4, 20.0 and 19.7, 18.6 and 15.9, 15.7 and
1
3
þ
þ
þ
H), 1.68 (br s 2H), 1.63–1.48 (m, 2H); C NMR (100 MHz, CDCl
3
)
15.7, 12.8 and 12.2; HRMS (CI ) calcd for C10
299.0508, found 299.0509.
H
20IO
2
(MþH )
þ
þ
þ
71.2, 66.7, 33.8, 29.5, 6.7; HRMS (CI ) calcd for C
12.9776, found 212.9769.
5
H
10IO (M –OH)
2
0 0 0 0 0
.4.3. (2 R,3 S)-2-(1 -Iodo-2 -methyl-3 -butyloxy)tetrahydropyrane
4
4
.3. (S)-4,5-Bis((tert-butyldimethylsilyl)oxy)-1-
(21). The chiral iodide 21 was prepared from the alcohol 12d
according to the general procedure A in 90% yield as a colorless oil.
Spectroscopic data of 21 are identical to those of 18.
9
iodopentane 5
To
a
solution of (S)-5-iodopentane-1,2-diol (956.0 mg,
ꢁ
4
.16 mmol) in dry CH
added 2,6-lutidine (1.5 mL, 12.50 mmol) and TBSOTf (2.4 mL,
2
Cl
2
(50 mL) cooled at ꢃ78 C was sequentially
4.5. General procedure B for syn-selective aldol
reactions of 13
ꢁ
1
0.40 mmol) under a nitrogen atmosphere. After stirring at ꢃ78 C
for 1 h, the reaction was quenched by addition of saturated aqueous
To a stirred solution of ester (1S,2R)-13 (1.900 g, 4.00 mmol) in
ꢁ
ꢁ
NaHCO
3
at 0 C. The resultant reaction mixture was extracted with
dry CH
2
Cl
2
(15 mL) cooled at ꢃ78 C was added i-Pr
2
EtN (2.1 mL,
ꢁ
EtOAc (3ꢂ50 mL) and the combined organic layer was washed with
brine, dried over anhydrous Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, eluting with 9.1% CH Cl in hexane) to
give the iodide 5 (1.900 g, 100%) as a colorless oil; [
.35, CHCl ); R Cl in hexane); IR (film) 2955, 2930,
858, 1472, 1257, 1120, 1084 cm
12.00 mmol) under a nitrogen atmosphere. After stirring at ꢃ78 C
2
4
2 2 2
for 5 min, n-Bu BOTf (1.0 M in CH Cl , 8.0 mL, 8.00 mmol) was
added dropwise over 20 min. The resultant solution was stirred at
ꢁ
2
2
ꢃ78 C for 2 h. Acetaldehyde (6.0 mmol, 0.34 mL) was added
2
0
ꢁ
a]
D
ꢃ11.04 (c
dropwise followed by stirring at ꢃ78 C for 1 h. The reaction was
ꢁ
1
2
d
3
f
¼0.50 (9.1% CH
2
2
allowed to warm to 0 C over 1 h and the reaction was quenched by
ꢃ1
1
;
H NMR (400 MHz, CDCl
3
)
addition of pH 7 buffer and MeOH (1/1, v/v, 20 mL). The reaction
mixture was diluted with MeOH to make a homogeneous solution.
3.72–3.64 (m, 1H), 3.53 (dd, J¼9.8, 5.2 Hz, 1H), 3.38 (dd, J¼10.0,
6
0
.8 Hz, 1H), 3.20 (t, J¼7.0 Hz, 2H), 2.00–1.44 (m, 4H), 0.89 (s, 9H),
After careful addition of 30% H
at room temperature for 14 h and then concentrated under reduced
pressure. The residue was partitioned between water and CH Cl
and the aqueous layer was extracted with CH Cl . The combined
organic layer was washed with brine, dried over anhydrous Na SO
2 2
O (10 mL), the mixture was stirred
13
.88 (s, 9H), 0.06 (s, 6H), 0.05 (s, 3H), 0.05 (s, 3H); C NMR
(
1
(
100 MHz, CDCl
3
)
d
72.1, 67.1, 35.2, 29.2, 26.0 (3ꢂ), 25.9 (3ꢂ), 18.3,
2
2
þ
þ
2
8.1, 7.5, ꢃ4.3, ꢃ4.7, ꢃ5.3, ꢃ5.4; HRMS (CI ) calcd for C17
H40IO
2
Si
2
2
þ
MþH ) 459.1612, found 459.1620.
2
4
,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, eluting with 16.7%
EtOAc in hexane) to afford the syn-aldol product 16 (2.000 g, 95%,
dr¼90:10).
4
.4. General procedure A for synthesis of alkyl iodides from
alcohols
To a solution of the chiral alcohol 15 (1.500 g, 9.36 mmol) in dry
ꢁ
0
0
0
0
THF (60 mL) cooled in an ice–water bath (0 C) was sequentially
4.5.1. (1S ,2R )-2 -(N-Benzyl-N-mesitylenesulfonyl)amino-1 -phenyl-
0
added PPh
3.40 mmol), and I
room temperature for 2.5 h. The reaction was quenched by addition
3
(6.130 g, 23.40 mmol), imidazole (1.600 g,
1 -propyl (2S,3R)-3-hydroxy-2-methylbutyrate (16). A white amor-
2
2
(5.330 g, 21.10 mmol) followed by stirring at
phous solid. A sample of 95:5 dr was obtained by fractional column
chromatographic separation and was used for the structural char-
of aqueous Na
50 mL) and CH
and extracted with CH
was dried over anhydrous Na
reduced pressure. The residue was purified by column chroma-
tography (silica gel, eluting with 6.25% EtOAc in hexane) to give
2
S
2
O
3
. The resultant mixture was diluted with water
(100 mL) and the aqueous layer was separated
acterization. R
f
¼0.10 (16.7% EtOAc in hexane); IR (film) 3542 (br s),
ꢃ1
1
(
2
Cl
2
2981, 2941, 1738, 1455, 1323, 1153 cm ; H NMR (300 MHz, CDCl )
3
2
Cl
2
(3ꢂ50 mL). The combined organic layer
SO , filtered, and concentrated under
d
7.74–7.54 (m, 10H), 7.40–7.33 (m, 2H), 6.28 (d, J¼4.2 Hz, 0.95H, the
2
4
major diastereomer), 6.24 (d, J¼4.2 Hz, 0.05H, the minor di-
astereomer), 5.02 (s, 2H), 4.50–4.29 (m, 2H), 2.91 (s, 6H), 2.66 (s,
3H), 2.57 (qd, J¼7.5, 3.3 Hz, 1H), 2.31 (br s, 1H), 1.55 (d, J¼7.5 Hz,
13c
13
(S)-4-(3-iodopropyl)-2,2-dimethyl-1,3-dioxolane (2.150 g, 85%).
3H),1.51 (d, J¼7.2 Hz, 3H),1.44 (d, J¼6.6 Hz, 3H); C NMR (100 MHz
CDCl
3
)
d
174.6, 142.6, 140.2 (2ꢂ), 138.5, 138.3, 133.3, 132.1 (2ꢂ),
4
.4.1. (S)-4-(3-Iodopropyl)-2,2-dimethyl-1,3-dioxolane13c. A color-
128.5 (2ꢂ),128.4 (2ꢂ),128.0,127.2 (2ꢂ),127.1,125.8 (2ꢂ), 78.4, 67.2,
20
13c
20
þ
less oil; [
R
a
]
D
þ6.67 (c 0.48, CHCl
3
); lit.
[a
]
D
þ7.09 (c 1.1, CHCl
3
);
56.8, 48.2, 44.9, 23.0 (2ꢂ), 20.9,19.4,12.6,10.2; HRMS (CI ) calcd for
þ
þ
f
¼0.53 (16.7% EtOAc in hexane); IR (film) 2984, 2935, 2870, 1378,
C
30
H38NO
5
S
(MþH ) 524.2471, found 524.2455.
ꢃ1
1
1
369, 1233, 1214, 1063, 857 cm ; H NMR (400 MHz, acetone-d
4.11 (quintet, J¼6.4 Hz, 1H), 4.03 (dd, J¼8.0, 6.0 Hz, 1H), 3.50 (dd,
J¼6.8, 6.8 Hz, 1H), 3.32 (t, J¼6.8 Hz, 2H), 2.02–1.80 (m, 2H), 1.64 (q,
6
)
0
0
0
0
d
4.5.2. (1R ,2S )-2 -(N-Benzyl-N-mesitylenesulfonyl)amino-1 -phenyl-
0
1 -propyl (2R,3S)-3-hydroxy-2-methylbutyrate (19). The syn-aldol 19
13
J¼7.2 Hz, 2H), 1.32 (s, 3H), 1.26 (s, 3H); C NMR (100 MHz, acetone-
was prepared from (1R,2S)-13 and acetaldehyde according to the

192
Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
general procedure B in 91% yield as a white amorphous solid and in
7:13 diastereomeric ratio. After careful fractional column chro-
matographic separation over silica gel the diastereomeric ratio of 19
was enriched to 92:8 and the materials were used for the followed
reactions. Spectroscopic data of 19 are identical to those of 16.
12c were combined for characterization and for use in the following
8
reactions. IR (film) 3416 (br), 2942, 1454, 1378, 1135, 1117,
ꢃ1
1
1022 cm ; H NMR (400 MHz, CDCl ) d 4.72–4.68 (m, 0.5H), 4.55–
3
4.50 (m, 0.5H), 4.04 (qd, J¼6.8, 3.2 Hz, 0.5H), 3.96–3.85 (m, 1.5H),
3.71–3.56 (m, 1H), 3.52–3.44 (m, 2H), 2.74 (br s, 1H), 1.99–1.90 (m,
1
H), 1.86–1.64 (m, 2H), 1.57–1.43 (m, 4H), 1.22 (d, J¼6.4 Hz, 1.5H),
4
.6. General procedure C for formation of THP ethers
1.10 (d, J¼6.4 Hz, 1.5H), 0.83 (d, J¼7.2 Hz, 1.5H), 0.80 (d, J¼7.2 Hz,
13
3
1.5H); C NMR (100 MHz, CDCl ) d 99.0 and 98.1, 77.0 and 72.6, 65.2
To a solution of the syn-aldol 16 (1.900 g, 3.60 mmol, dr¼90:10)
and 65.1, 64.4 and 62.8, 39.8 and 38.9, 31.3 and 31.0, 25.3 and 25.2,
þ
and PPTS (91.0 mg, 0.36 mmol) in dry CH
3
2
Cl
2
(30 mL) was added
20.9 and 19.8, 16.9 and 15.9, 12.2 and 10.4; HRMS (CI ) calcd for
þ
þ
,4-dihydro-2H-pyran (0.98 mL, 10.80 mmol) followed by stirring
C
10
H
21
O
3
(MþH ) 189.1491, found 189.1485.
ꢁ
at 30 C for overnight. The reaction mixture was diluted with Et
100 mL) and washed with brine. The organic layer was dried over
anhydrous Na SO , filtrated, and concentrated under reduced
pressure. The residue was purified by column chromatography
silica gel, eluting with 9.1% EtOAc in hexane) to give a 1:1 di-
astereomeric mixture of the THP ether 17 (2.180 g, 99%).
2
O
(
4.7.2. (2S,3S)-2-Methyl-3-((tetrahydropyran-2-yl)oxy)butan-1-ol
(12d). The chiral alcohol 12d was prepared from 20 according to
the general procedure D in 94% yield and in a 1:1 diastereomeric
ratio as a colorless oil. Spectroscopic data of 12d are identical to
those of 12c.
2
4
(
0
0
0
0
4
1
.6.1. (1S ,2R )-2 -(N-Benzyl-N-mesitylenesulfonyl)amino-1 -phenyl-
4.8. General procedure E for 1,3-dithiane monoalkylation
0
-propyl (2S,3R)-3-((tetrahydropyran-2-yl)oxy)-2-methylbutyrate
(
(
(
17). A white amorphous solid; R
film) 2946, 1738, 1454, 1325, 1241, 1153, 1032 cm
f
¼0.24 (9.1% EtOAc in hexane); IR
To a solution of 1,3-dithiane 6 (1.910 g, 15.94 mmol) in dry THF
ꢃ1
1
ꢁ
;
H NMR
(60 mL) cooled at ꢃ78 C was added n-BuLi (1.6 M in hexane,10 mL,
ꢁ
400 MHz, acetone-d
.90 (m, 4H), 5.87 (d, J¼4.4 Hz, 0.5H), 5.83 (d, J¼4.4 Hz, 0.5H), 4.89
), 4.86 (d, J¼16.4 Hz, 0.5H, PhCH ), 4.71–
, O–CH–O), 4.57 (t, J¼4.4 Hz, 0.5H, O–CH–O),
.14–3.50 (m, 2H), 3.84–3.66 (m, 1H), 3.43–3.33 (m, 1H), 2.64–2.45
6
)
d
7.45–7.40 (m, 2H), 7.30–7.19 (m, 6H), 7.05–
15.94 mmol). The resultant mixture was stirred at ꢃ78 C for
ꢁ
6
10 min and at ꢃ20 C for 3 h. The resultant dithiane anion solution
ꢁ
(
4
4
d, J¼17.2 Hz, 0.5H, PhCH
2
2
was then cooled in an CH
3
CN–dry ice bath at ꢃ40 C and a solution
.64 (m, 1.5H, PhCH
2
of the iodide 18 (1.580 g, 5.31 mmol) in dry THF (3 mL) was added
ꢁ
dropwise. The resultant mixture was stirred ꢃ40 C for another 3 h.
(
1
1
m, 1H), 2.48 (s, 6H), 2.30 (s, 1.5H), 2.30 (s, 1.5H), 1.71–1.30 (m, 6H),
.19 (d, J¼6.8 Hz, 1.5H), 1.18 (d, J¼6.8 Hz, 1.5H), 1.18 (d, J¼6.0 Hz,
.5H), 1.17 (d, J¼6.8 Hz, 1.5H), 1.14 (d, J¼6.8 Hz, 1.5H), 1.10 (d,
4
The reaction was quenched with saturated aqueous NH Cl (10 mL),
and the reaction mixture was extracted with ethyl acetate
(3ꢂ50 mL). The combined organic layer was dried over anhydrous
13
J¼6.0 Hz, 1.5H); C NMR (100 MHz, acetone-d
43.5 and 143.5, 140.8 (2ꢂ), 140.1 and 140.0, 139.6 and 139.6, 134.7
and 134.6, 133.0 (2ꢂ), 129.1 (2ꢂ), 129.0 and 129.0 (2ꢂ), 128.6 and
28.6, 128.6 and 128.4 (2ꢂ), 127.8, 126.9 (2ꢂ), 100.3 and 96.1, 78.8
and 78.7, 75.8 and 72.0, 63.0 and 62.7, 57.8, 49.0 and 48.9, 46.7 and
6
)
d
173.4 and 173.4,
2 4
Na SO , filtered, concentrated under reduced pressure, and the
1
residue was purified by column chromatography (silica gel, eluting
with 10% EtOAc in hexane) to give the monoalkylated product 22
(1.300 g, 84%).
1
0
0
0
0
00
4
2
C
6.2, 31.8 and 31.5, 26.2 and 26.2, 23.2 (2ꢂ), 20.8, 20.4 and 20.3,
4.8.1. (2 R,3 R)-2-[2 -Methyl-3 -((tetrahydropyran-2 -yl)oxy)-butyl]-
1,3-dithiane (22). A colorless oil; R
¼0.43 (10% EtOAc in hexane); IR
(film) 2937, 1456, 1378, 1132, 1116, 1076, 1022 cm
400 MHz, CDCl
þ
0.0 and 16.8, 14.1 and 13.9, 13.3 and 12.2; HRMS (CI ) calcd for
f
þ
þ
ꢃ1
1
35
H
46NO
6
S
(MþH ) 608.3046, found 608.3042.
;
H NMR
(
3
)
d
4.71 (t, J¼3.2 Hz, 0.5H), 4.64 (dd, J¼4.8, 2.4 Hz,
0
0
0
0
4
1
.6.2. (1R ,2S )-2 -(N-Benzyl-N-mesitylenesulfonyl)amino-1 -phenyl-
0.5H), 4.16 (dd, J¼8.8, 6.0 Hz, 0.5H), 4.09 (dd, J¼9.6, 5.2 Hz, 0.5H),
3.93–3.84 (m, 1H), 3.77–3.64 (m, 1H), 3.53–3.44 (m, 1H), 2.90–2.78
(m, 4H), 2.17–1.45 (m,11H),1.15 (d, J¼6.4 Hz,1.5H),1.05 (d, J¼6.4 Hz,
0
-propyl (2R,3S)-3-((tetrahydropyran-2-yl)oxy)-2-methylbutyrate
(20). The THP ether 20 was prepared from 19 according to the
13
general procedure C in 100% yield and in a 1:1 diastereomeric ratio
as a white amorphous solid. Spectroscopic data of 20 are identical
to those of 17.
1.5H), 0.93 (d, J¼6.8 Hz, 1.5H), 0.90 (d, J¼7.2 Hz, 1.5H); C NMR
(100 MHz, CDCl
3
) d 98.7 and 95.0, 76.7 and 73.1, 62.7 and 62.0, 45.6
and 45.6, 38.0 and 37.3, 35.2 and 33.8, 31.1, 30.5 and 30.4, 30.2 and
3
0.2, 26.2 and 26.1, 25.6 and 25.5, 19.9 and 19.3, 17.2 and 15.4, 15.2
þ
þ
þ
4
.7. General procedure D for Dibal-H reduction of esters
and 14.8; HRMS (CI ) calcd for C14
H O
27 2
S
2
(MþH ) 291.1447, found
291.1445.
To a solution of the THP ether 17 (1.900 g, 3.20 mmol) in dry THF
ꢁ
0
0
0
0
00
(
5
30 mL) cooled at ꢃ78 C was added Dibal-H (1.5 M in toluene,
4.8.2. (2 S,3 S)-2-[2 -Methyl-3 -((tetrahydropyran-2 -yl)oxy)butyl]-
1,3-dithiane (31). The monoalkylated dithiane 31 was prepared
from the chiral iodide 21 according to the general procedure E in
84% yield as a colorless oil. Spectroscopic data of 31 are identical to
those of 22.
.1 mL, 7.60 mmol). The resultant mixture was stirred at the same
temperature for 15 min and allowed to warm to room temperature
during 1 h. Then, the reaction was quenched by careful addition of
a 3:1 (v/v) solution of MeOH and pH 7 buffer (10 mL). A saturated
aqueous solution of sodium potassium tartrate (20 mL) was added
and the mixture was stirred at room temperature for about 1 h. The
4.9. General procedure F for 1,3-dithiane bisalkylation
mixture was diluted with water and CH
was extracted with CH Cl
(3ꢂ40 mL). The combined organic layer
was dried over anhydrous Na SO , filtrated, and concentrated un-
der reduced pressure. The residue was purified by column chro-
matography (silica gel, eluting with 16.7% EtOAc in hexane) to give
the alcohol 12c (565.0 mg, 95%).
2 2
Cl , and the aqueous layer
2
2
To a solution of the monoalkylated dithiane 22 (581.0 mg,
ꢁ
2
4
2.00 mmol) in dry THF (20 mL) cooled at ꢃ78 C was sequentially
added HMPA (0.47 mL, 2.73 mmol) and n-BuLi (1.6 M in hexane,
1.25 mL, 2.00 mmol) under a nitrogen atmosphere. The resultant
ꢁ
ꢁ
mixture was stirred at ꢃ78 C for 30 min and then at ꢃ20 C for 2 h.
ꢁ
The forming dithiane anion was cooled to ꢃ78 C again, and a solu-
4
(
0
.7.1. (2R,3R)-2-Methyl-3-((tetrahydropyran-2-yl)oxy)butan-1-ol
12c). A colorless oil of 1:1 diastereomeric mixture; R
¼0.33 and
.26 (16.7% EtOAc in hexane). The two separable diastereomers of
tion of the chiral iodide 5 (834.0 mg, 1.80 mmol) in dry THF (2 mL)
ꢁ
f
was added dropwise. The resultant mixture was stirred at ꢃ78 C for
2 h, and was allowed to warm to room temperature. The reaction

Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
193
was quenched with saturated aqueous NH
was extracted with ethyl acetate (3ꢂ20 mL). The combined organic
layer was washed with brine, dried over anhydrous Na SO , filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, eluting with 9.1% EtOAc in
hexane) to give the bisalkylated product 23 (683.0 mg, 85%).
4
Cl. The reaction mixture
(400 MHz, CDCl
3
)
d
4.70 (dd, J¼4.0, 3.2 Hz, 0.47H), 4.60 (dd, J¼4.8,
2.4 Hz, 0.53H), 3.97–3.85 (m, 1H), 3.66–3.44 (m, 4H), 3.40 (dd,
J¼9.6, 6.4 Hz,1H), 1.90–1.19 (m, 17H),1.16 (d, J¼6.4 Hz,1.6H), 1.05 (d,
J¼6.4 Hz, 1.4H), 0.90 (d, J¼6.8 Hz, 1.6H), 0.89 (s, 9H), 0.88 (s, 9H),
2
4
13
0.86 (d, J¼6.8 Hz, 1.4H), 0.05 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H);
C
NMR (100 MHz, CDCl
3
) d 99.5 and 95.4, 78.2 and 74.5, 73.2 and 73.2,
6
7.5 and 67.5, 62.9 and 62.3, 38.8 and 37.9, 34.4 and 34.4, 32.3 and
0
00
00
00
0
0
4
2
(
.9.1. (4S ,2 R,3 R)-2-[4 ,5 -Bis((tert-butyldimethylsilyl)oxy)pentyl]-
31.8, 31.3 and 31.2, 30.2 and 30.2, 27.4 and 27.3, 26.0 (3ꢂ), 25.9 (3ꢂ),
00
-[2 -methyl-3 -((tetrahydropyran-2%-yl)oxy)butyl]-1,3-dithiane
25.7 and 25.6, 25.2 and 25.1, 20.1 and 19.6, 18.4, 18.2, 18.2 and 15.6,
þ
23). A colorless oil. An analytic sample of 65:35 diastereomeric
mixture due to the chirality in THP was used for the following
characterization. R
15.4 and 15.2, ꢃ4.2, ꢃ4.7, ꢃ5.3, ꢃ5.4; HRMS (CI ) calcd for
þ
þ
C
28
H
60
O
4
Si
2
Na (MþNa ) 539.3928, found 539.3864.
f
¼0.68 (9.1% EtOAc in hexane); IR (film) 2952,
1
ꢃ1
0
0
0
0
0
0
2
d
930, 1471, 1456, 1255, 1114 cm
;
H NMR (400 MHz, CDCl
3
)
4.10.2. (2 S,8 S,9 S)-2-[1 ,2 -Bis((tert-butyldimethylsilyl)oxy)-8 -
methyl-9 -decyloxy]tetrahydropyran (33). The compound 33 was
prepared from 32 according to the general procedure G in 92% yield
as a colorless oil. An analytic sample of 54:46 diastereomeric
mixture due to the chirality in THP was used for the following
0
4.71–4.67 (m, 1H), 3.95–3.87 (m, 1H), 3.77–3.65 (m, 2H), 3.55–
.37 (m, 3H), 2.96–2.70 (m, 4H), 2.37 (dd, J¼14.8, 2.4 Hz, 0.35H),
.20 (dd, J¼14.8, 2.4 Hz, 0.65H),1.98–1.45 (m,16H),1.15 (d, J¼6.4 Hz,
3
2
1
.9H), 1.05 (d, J¼6.4 Hz, 1.1H), 1.03 (d, J¼6.8 Hz, 1.1H), 1.00 (d,
J¼6.4 Hz, 1.9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H),
characterization. R
1463, 1255, 1116 cm ; H NMR (400 MHz, CDCl
f
¼0.39 (4.8% EtOAc in hexane); IR (film) 2929,
1
3
ꢃ1
1
0
7
3
2
.05 (s, 3H), 0.04 (s, 3H); C NMR (100 MHz, CDCl
3
)
d
98.7 and 95.3,
3
)
d
4.70 (dd, J¼3.6,
7.9 and 75.1, 73.1, 67.2, 62.8 and 62.3, 54.5 and 54.4, 40.2 and 39.6,
3.2 Hz, 0.46H), 4.60 (dd, J¼5.2, 2.4 Hz, 0.54H), 3.94–3.85 (m, 1H),
3.67–3.44 (m, 4H), 3.40 (dd, J¼10.0, 6.4 Hz, 1H), 1.90–1.19 (m, 17H),
1.16 (d, J¼6.4 Hz, 1.4H), 1.05 (d, J¼6.0 Hz, 1.6H), 0.90 (d, J¼6.8 Hz,
9.6, 35.1 and 34.5, 34.5 and 33.4, 31.2 and 31.1, 26.2 (2ꢂ), 26.0 (3ꢂ),
5.9 (3ꢂ), 25.6 and 25.5, 25.3 and 25.3, 20.3 and 20.0, 20.1 and 19.6,
þ
1
8.4, 18.1, 17.3 and 15.3, 17.1, ꢃ4.3, ꢃ4.7, ꢃ5.3, ꢃ5.3; HRMS (CI )
1.4H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (d, J¼6.8 Hz, 1.6H), 0.05 (s, 6H),
þ
þ
13
calcd for C31
H
64
O
4
S
2
Si
2
Na (MþNa ) 643.3682, found 643.3668.
0.04 (s, 3H), 0.04 (s, 3H); C NMR (100 MHz, CDCl
3
)
d
99.5 and 95.4,
78.2 and 74.5, 73.2 and 73.2, 67.5 and 67.5, 62.9 and 62.3, 38.8 and
0
00
00
00
0
0
4
2
(
.9.2. (4S ,2 S,3 S)-2-[4 ,5 -Bis((tert-butyldimethylsilyl)oxy)pentyl]-
37.9, 34.4 and 34.4, 32.3 and 31.8, 31.3 and 31.2, 30.2 and 30.2, 27.4
and 27.3, 26.0 (3ꢂ), 25.9 (3ꢂ), 25.7 and 25.5, 25.2 and 25.1, 20.2 and
19.6, 18.4, 18.2, 18.2 and 15.6, 15.4 and 15.2, ꢃ4.2, ꢃ4.7, ꢃ5.3, ꢃ5.4;
00
-[2 -methyl-3 -((tetrahydropyran-2%-yl)oxy)butyl]-1,3-dithiane
32). The bisalkylated dithiane 32 was prepared from the mono-
alkylated dithiane 31 and the chiral iodide 5 according to the
general procedure F in 81% yield as a colorless oil. An analytic
sample of 59:41 diastereomeric mixture due to the chirality in THP
þ þ þ
60 4 2
HRMS (CI ) calcd for C28H O Si (M ) 516.4030, found 516.4008.
4.11. General procedure H for selective cleavage of primary
TBS ethers
was used for the following characterization. R
hexane); IR (film) 2953, 2930, 1472, 1463, 1256, 1114 cm ; H NMR
f
¼0.46 (9.1% EtOAc in
ꢃ1
1
(
(
2
1
1
0
d
400 MHz, CDCl
m, 2H), 3.54–3.35 (m, 3H), 2.95–2.68 (m, 4H), 2.37 (dd, J¼14.6,
.6 Hz, 0.59H), 2.20 (dd, J¼14.8, 2.0 Hz, 0.41H), 1.95–1.45 (m, 16H),
.14 (d, J¼6.4 Hz, 1.2H), 1.05 (d, J¼6.4 Hz, 1.8H), 1.02 (d, J¼6.8 Hz,
3
)
d
4.71–4.67 (m, 1H), 3.95–3.87 (m, 1H), 3.77–3.60
To a solution of the bis-TBS ether 24 (260.0 mg, 0.50 mmol) in
THF (12 mL) was added
a mixed solution of TBAF–AcOH
(50 mol %:50 mol %, 11.0 mL, 11.0 mmol) followed by stirring for 8 h
at room temperature. The reaction was quenched by addition of
.8H), 1.00 (d, J¼6.8 Hz, 1.2H), 0.88 (s, 9H), 0.88 (s, 9), 0.06 (s, 3H),
saturated aqueous NaHCO
with ethyl acetate (3ꢂ15 mL) and the combined organic layer was
washed with brine, dried over anhydrous Na SO , filtered, and
3
. The reaction mixture was extracted
13
3
.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR (100 MHz, CDCl )
98.6 and 95.3, 77.9 and 75.1, 73.2 and 73.1, 67.4 and 67.3, 62.7 and
2.3, 54.4 and 54.4, 40.7 and 39.9, 39.5 and 39.4, 35.1 and 34.6, 34.6
2
4
6
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, eluting with 16.7% EtOAc in
hexane) to give the primary alcohol 25 (168.0 mg, 83%).
and 33.4, 31.2 and 31.1, 26.2, 26.1, 26.0 (3ꢂ), 25.9 (3ꢂ), 25.6 and
2
1
C
5.5, 25.4 and 25.3, 20.4 and 20.2, 20.0 and 19.6, 18.4, 18.1, 17.3 and
þ
7.0, 15.2, ꢃ4.3, ꢃ4.6, ꢃ5.3, ꢃ5.4; HRMS (CI ) calcd for
þ
þ
31
65
H O
4
2
S Si
2
(MþH ) 621.3863, found 621.3830.
4.11.1. (2S,8R,9R)-2-((tert-Butyldimethylsilyl)oxy)-8-methyl-9-((tet-
0
rahydropyran-2 -yl)oxy)decan-1-ol (25). A colorless oil. An analytic
4
.10. General procedure G for reduction of 1,3-dithianes by
sample of 53:47 diastereomeric mixture due to the chirality in THP
Raney-Ni
was used for the following characterization. R
in hexane); IR (film) 3456 (br), 2931, 1463, 1378, 1255, 1113, 1077,
f
¼0.40 (16.7% EtOAc
ꢃ1
1
Raney-Ni was washed with excess absolute ethanol before use.
To a solution of 23 (730.0 mg, 1.18 mmol) in absolute ethanol
50 mL) was added Raney-Ni (3.0 g) followed by refluxing under
1023 cm
; H NMR (300 MHz, CDCl ) d
3
4.69 (dd, J¼3.6, 3.0 Hz,
0.47H), 4.59 (dd, J¼4.5, 3.0 Hz, 0.53H), 3.98–3.83 (m, 1H), 3.76–3.43
(m, 4H), 3.43 (dd, J¼11.1, 5.1 Hz, 1H), 1.91–1.19 (m, 18H), 1.15 (d,
J¼6.3 Hz, 1.6H), 1.04 (d, J¼6.6 Hz, 1.4H), 0.89 (s, 9H), 0.89 (d,
(
a hydrogen atmosphere (1.0 atm) for 10 h. After cooling to room
temperature the reaction mixture was filtrated off through a pad of
Celite and the solid materials were covered quickly by Celite to
avoid catching fire on exposure to air. After washing with additional
EtOH the combined filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography
13
J¼6.6 Hz, 1.4H), 0.85 (d, J¼6.6 Hz, 1.6H), 0.08 (s, 6H); C NMR
3
(75 MHz, CDCl ) d 99.4 and 95.4, 78.1 and 74.4, 72.9 and 72.9, 66.2,
62.9 and 62.3, 38.7 and 37.8, 33.9, 32.1 and 31.7, 31.3 and 31.1, 30.1,
27.3 and 27.2, 25.8 (3ꢂ), 25.6 and 25.5, 25.3, 20.1 and 19.6, 18.1, 18.1
þ
and 15.5, 15.4 and 15.3, ꢃ4.5, ꢃ4.6; HRMS (CI ) calcd for
þ
þ
(
silica gel, eluting with 4.8% EtOAc in hexane) to give the product 24
C
22
H
46
O
4
SiNa (MþNa ) 425.3063, found 425.3047.
(
565.0 mg, 93%).
4
.11.2. (2S,8S,9S)-2-((tert-Butyldimethylsilyl)oxy)-8-methyl-9-((tet-
0
0
0
0
0
0
0
4
.10.1. (2 S,8 R,9 R)-2-[1 ,2 -Bis((tert-butyldimethylsilyl)oxy)-8 -
rahydropyran-2 -yl)oxy)decan-1-ol (34). The primary alcohol 34
was prepared from the bis-TBS ether 33 according to the general
procedure H in 85% yield as a colorless oil. An analytic sample of
52:48 diastereomeric mixture due to the chirality in THP was used
0
methyl-9 -decyloxy]tetrahydropyran (24). A colorless oil. An ana-
lytic sample of 53:47 diastereomeric mixture due to the chirality in
THP was used for the following characterization. R
EtOAc in hexane); IR (film) 2930, 1463, 1255, 1115 cm ; H NMR
f
¼0.50 (4.8%
ꢃ1
1
for the following characterization. R
f
¼0.42 (16.7% EtOAc in hexane);

1
94
Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
ꢃ1
1
þ
þ
þ
IR (film) 3424 (br), 2930,1463,1378,1255,1113,1077,1023 cm ; H
NMR (400 MHz, CDCl
4.69 (dd, J¼3.6, 3.2 Hz, 0.48H), 4.60 (dd,
J¼5.2, 2.8 Hz, 0.52H), 3.97–3.84 (m, 1H), 3.75–3.69 (m, 1H), 3.68–
.40 (m, 4H), 1.94–1.20 (m, 18H), 1.16 (d, J¼6.4 Hz, 1.6H), 1.04 (d,
J¼6.4 Hz, 1.4H), 0.90 (J¼7.2 Hz, 1.4H), 0.90 (s, 9H), 0.86 (d, J¼6.4 Hz,
.6H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl
99.4 and 95.5, 78.2
and 74.5, 72.9 and 72.9, 66.3, 62.9 and 62.4, 38.8 and 37.8, 34.0 and
4.0, 32.2 and 31.7, 31.3 and 31.2, 30.1, 27.3 and 27.2, 25.8 (3ꢂ), 25.6
and 25.5, 25.4 and 25.4, 20.1 and 19.7, 18.1, 18.1 and 15.6, 15.4 and
HRMS (CI ) calcd for C13
H
21
O
3
(MþH ) 225.1491, found 225.1490.
13
3
)
d
The C NMR data of (4S,10R)-2a are listed in Table 1.
3
4.12.4. (4S,10S)-4-Hydroxy-10-methyl-11-oxododec-2-en-1,4-olide
(2b). The butenolide ketone 2b was prepared from the alcohol 1d
according to the general procedure I in 98% yield as a colorless oil;
1
3
) d
2
0
15
[a]
D
þ73.0 (c 0.12, MeOH);
(film) 2919, 1746, 1708, 1461, 1358, 1162, 1104 cm
(400 MHz, CDCl
R
f
¼0.44 (50% EtOAc in hexane); IR
ꢃ1
1
3
;
H NMR
3
)
d
7.44 (dd, J¼5.4,1.4 Hz,1H), 6.10 (dd, J¼5.6, 2.0 Hz,
þ
þ
þ
1
4
5.3, ꢃ4.4, ꢃ4.6; HRMS (CI ) calcd for C22
H
47
O
4
Si (MþH )
1H), 5.05–5.00 (m, 1H), 2.49 (sextet, J¼6.8 Hz, 1H), 2.12 (s, 3H), 1.81–
03.3244, found 403.3246.
1.72 (m, 1H), 1.70–1.59 (m, 2H), 1.50–1.21 (m, 7H), 1.08 (d, J¼7.2 Hz,
þ
þ
þ
3
H); HRMS (CI ) calcd for C13
H
21
O
3
(MþH ) 225.1491, found
13
4
.12. General procedure I for DMP oxidation of alcohols
225.1491. The C NMR data of (4S,10S)-2b are listed in Table 1.
4.13. General procedure J for Wittig olefination of aldehydes
Methyltriphenylphosphonium bromide was completely dried
To a solution of the primary alcohol 25 (60.0 mg, 0.15 mmol) in
CH
1
0
2
Cl
2
(10 mL) was sequentially added solid NaHCO
3
(126.0 mg,
Cl , 0.74 mL,
.22 mmol). After stirring for 2 h at room temperature, the reaction
. The resultant
.50 mmol) and Dess-Martin periodinane (0.3 M in CH
2
2
ꢁ
under high vacuum at 110 C before used. To a suspension of
was quenched by addition of aqueous Na
2
S
2
O
3
methyltriphenylphosphonium bromide (64.0 mg, 0.18 mmol) in
ꢁ
mixture was extracted with ethyl acetate (3ꢂ15 mL) and the com-
dry THF (3 mL) cooled at 0 C was added dropwise KHDMS (0.5 M
in toluene, 0.28 mL, 0.14 mmol), followed by stirred for 30 min at
the same temperature. The resultant yellow solution of the ylide
bined organic layer was washed with brine, dried over anhydrous
2 4
Na SO , filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluting
with 16.7% EtOAc in hexane) to give the aldehyde 26 (52.0 mg, 87%).
ꢁ
was cooled at ꢃ10 C followed by adding dropwise a solution of the
ꢃ2
aldehyde 26 (36.0 mg, 9.0ꢂ10 mmol) in dry THF (1 mL). After
stirred for 30 min, the reaction mixture was allowed to warm to
room temperature and then the reaction was quenched by addition
of water (1 mL). The mixture was extracted with ethyl acetate
(3ꢂ5 mL) and the combined organic layer was washed with brine,
4
.12.1. (2S,8R,9R)-2-((tert-Butyldimethylsilyl)oxy)-8-methyl-9-((tet-
0
rahydropyran-2 -yl)oxy)decanal (26). A colorless oil. An analytic
sample of 53:47 diastereomeric mixture due to the chirality in THP
was used for the following characterization. R
f
¼0.62 (16.7% EtOAc
2 4
dried over anhydrous Na SO , filtered, and concentrated under
ꢃ1
in hexane); IR (film) 2932, 1738, 1464, 1378, 1258, 1115, 1023 cm
;
reduced pressure. The residue was purified by column chroma-
tography (silica gel, eluting with 4.8% EtOAc in hexane) to give the
alkene 27 (31.0 mg, 86%).
1
H NMR (400 MHz, CDCl
3
)
d
9.57 (s, 1H), 4.68 (br t, J¼3.2 Hz, 0.47H),
4
3
.58 (br t, J¼4.0 Hz, 0.53H), 3.98–3.83 (m, 2H), 3.66–3.53 (m, 1H),
.50–3.43 (m, 1H), 1.88–1.17 (m, 17H), 1.14 (d, J¼5.6 Hz, 1.6H), 1.03
(
d, J¼5.6 Hz, 1.4H), 0.91 (s, 9H), 0.88 (d, J¼6.8 Hz, 1.4H), 0.84 (d,
4.13.1. (3S,9R,10R)-3-((tert-Butyldimethylsilyl)oxy)-9-methyl-10-
13
0
J¼6.8 Hz, 1.6H), 0.06 (s, 3H), 0.05 (s, 3H); C NMR (100 MHz, CDCl
3
)
((tetrahydropyran-2 -yl)oxy)undec-1-ene (27). A colorless oil. An
d
204.3, 99.4 and 95.4, 78.1 and 77.7, 77.6 and 74.4, 62.8 and 62.3,
analytic sample of 53:47 diastereomeric mixture due to the chirality
3
2
8.7 and 37.8, 32.6 and 32.6, 32.1 and 31.6, 31.3 and 31.1, 29.7 and
in THP was used for the following characterization. R
EtOAc in hexane); IR (film) 2932, 1464, 1378, 1254, 1116, 1078,
f
¼0.39 (4.8%
9.7, 27.2 and 27.1, 25.7 (3 ꢂ), 25.6 and 25.5, 24.6 and 24.6, 20.1 and
þ
ꢃ1
1
1
9.6, 18.2, 18.0 and 15.5, 15.3 and 15.2, ꢃ4.6, ꢃ5.0; HRMS (CI ) calcd
1024 cm
6.0 Hz, 1H), 5.12 (dt, J¼17.2, 1.6 Hz, 1H), 5.00 (br d, J¼10.4 Hz, 1H),
; H NMR (400 MHz, CDCl ) d
3
5.79 (ddd, J¼16.8, 10.4,
þ
þ
for C22
44
H O
4
SiNa (MþNa ) 423.2907, found 423.2927.
4
.70 (dd, J¼4.0, 3.2 Hz, 0.47H), 4.60 (dd, J¼5.2, 2.8 Hz, 0.53H), 4.06 (q,
4.12.2. (2S,8S,9S)-2-((tert-Butyldimethylsilyl)oxy)-8-methyl-9-((tet-
J¼6.0 Hz, 1H), 3.96–3.84 (m, 1H), 3.67–3.54 (m, 1H), 3.51–3.44 (m,
1H), 1.90–1.19 (m, 17H), 1.16 (d, J¼6.4 Hz, 1.6H), 1.04 (d, J¼6.4 Hz,
1.4H), 0.90 (d, J¼6.8 Hz, 1.4H), 0.89 (s, 9H), 0.85 (d, J¼6.8 Hz, 1.6H),
0
rahydropyran-2 -yl)oxy)decanal (35). The aldehyde 35 was prepared
from the primary alcohol 34 according to the general procedure I in
13
9
7%yieldasacolorlessoil.Ananalyticsampleof52:48diastereomeric
mixture due to the chirality in THP was used for the following char-
acterization. R
3
0.04 (s, 3H), 0.02 (s, 3H); C NMR (100 MHz, CDCl ) d 141.9 and 141.9,
113.4 and 113.3, 99.4 and 95.4, 78.1 and 74.4, 73.9 and 73.9, 62.9 and
62.3, 38.8 and 38.1, 38.1 and 37.8, 32.3 and 31.7, 31.3 and 31.2, 29.9
and 29.9, 27.3 and 27.3, 25.9 (3ꢂ), 25.6 and 25.6, 25.2 and 25.2, 20.1
f
¼0.56 (16.7% EtOAc in hexane); IR (film) 2931, 1737,
ꢃ1
1
1464,1377,1254,1115,1023 cm ; H NMR (400 MHz, CDCl
3
)
d
9.59(s,
þ
1
H), 4.69 (br t, J¼3.2 Hz, 0.48H), 4.60 (br t, J¼4.0 Hz, 0.52H), 3.97–3.84
and 19.6, 18.3, 18.1 and 15.6, 15.4 and 15.3, ꢃ4.4, ꢃ4.8; HRMS (CI )
þ
þ
(
m, 2H), 3.68–3.53 (m,1H), 3.52–3.44 (m,1H),1.90–1.18 (m,17H),1.16
calcd for C23
H
47
O
3
Si (MþH ) 399.3294, found 399.3278.
(
d, J¼6.0 Hz, 1.6H), 1.04 (d, J¼6.4 Hz, 1.4H), 0.92 (s, 9H), 0.89 (d,
13
J¼6.8 Hz, 1.4H), 0.85 (d, J¼6.8 Hz, 1.6H), 0.08 (s, 3H), 0.07 (s, 3H);
C
4.13.2. (3S,9S,10S)-3-((tert-Butyldimethylsilyl)oxy)-9-methyl-10-
0
NMR (100 MHz, CDCl
3
)
d
204.4, 99.5 and 95.5, 78.2 and 77.7, 77.7 and
((tetrahydropyran-2 -yl)oxy)undec-1-ene (36). The alkene 36 was
7
2
4.5, 62.9 and 62.4, 38.8 and 37.8, 32.6, 32.2 and 31.7, 31.3 and 31.2,
prepared from the aldehyde 35 according to the general procedure J
in 83% yield as a colorless oil. An analytic sample of 52:48 di-
astereomeric mixture due to the chirality in THP was used for the
9.8, 27.2 and 27.1, 25.8 (3ꢂ), 25.6 and 25.5, 24.7 and 24.6, 20.1 and
þ
1
C
9.7,18.2,18.1 and 15.6,15.4 and 15.3, ꢃ4.6, ꢃ4.9;HRMS(CI ) calcd for
þ
þ
22
H
44
O
4
Si (M ) 400.3009, found 400.2955.
following characterization. R
film) 2930, 1460, 1376, 1253, 1115, 1078, 1023 cm
(400 MHz, CDCl
f
¼0.52 (4.8% EtOAc in hexane); IR
ꢃ1
1
(
;
H NMR
4
.12.3. (4S,10R)-4-Hydroxy-10-methyl-11-oxododec-2-en-1,4-olide
3
) d
5.79 (ddd, J¼16.8, 10.8, 6.0 Hz, 1H), 5.12 (dt,
(2a). The butenolide ketone 2a was prepared from the alcohol 1c
J¼17.2, 1.6 Hz, 1H), 5.00 (dt, J¼10.8, 0.8 Hz, 1H), 4.70 (dd, J¼4.0,
3.2 Hz, 0.48H), 4.60 (dd, J¼4.8, 2.8 Hz, 0.52H), 4.06 (q, J¼6.0 Hz,1H),
3.96–3.84 (m, 1H), 3.67–3.54 (m, 1H), 3.51–3.44 (m, 1H), 1.90–1.19
(m, 17H), 1.16 (d, J¼6.8 Hz, 1.6H), 1.05 (d, J¼6.0 Hz, 1.4H), 0.90 (d,
J¼6.8 Hz, 1.4H), 0.89 (s, 9H), 0.85 (d, J¼6.8 Hz, 1.6H), 0.05 (s, 3H),
according to the general procedure I in 91% yield as a colorless oil;
2
0
[
2
a
]
D
þ49.4 (c 0.175, MeOH); R
933, 1748, 1710, 1462, 1358, 1164, 1106 cm ; H NMR (400 MHz,
CDCl
7.44 (dd, J¼5.8,1.4 Hz,1H), 6.10 (dd, J¼5.6, 2.0 Hz,1H), 5.05–
.00 (m, 1H), 2.49 (sextet, J¼6.8 Hz, 1H), 2.13 (s, 3H), 1.81–1.72 (m,
H), 1.70–1.59 (m, 2H), 1.50–1.21 (m, 7H), 1.08 (d, J¼6.8 Hz, 3H);
f
¼0.44 (50% EtOAc in hexane); IR (film)
ꢃ1
1
3
) d
13
5
1
3
0.03 (s, 3H); C NMR (100 MHz, CDCl ) d 141.9 and 141.9, 113.4 and
113.3, 99.5 and 95.4, 78.2 and 74.5, 73.9 and 73.9, 62.9 and 62.3,

Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
195
0
3
2
8.8 and 38.1, 38.1 and 37.8, 32.3 and 31.8, 31.3 and 31.2, 30.0 and
4.15.1. (3S,9R,10R)-9-Methyl-10-((tetrahydropyran-2 -yl)oxy)undec-
1-en-3-yl acrylate (29). A colorless oil. An analytic sample of 53:47
diastereomeric mixture due to the chirality in THP was used for the
9.9, 27.3 and 27.3, 25.9 (3ꢂ), 25.6 and 25.5, 25.3 and 25.2, 20.1 and
þ
19.6, 18.3, 18.1 and 15.6, 15.4 and 15.3, ꢃ4.4, ꢃ4.8; HRMS (CI ) calcd
þ
þ
for C23
H
47
O
3
Si (MþH ) 399.3294, found 399.3273.
following characterization. R
2
f
¼0.35 (9.1% EtOAc in hexane); IR (film)
ꢃ1
1
934, 1727, 1405, 1268, 1192, 1023 cm ; H NMR (400 MHz, CDCl
3
)
d
6.41 (dd, J¼17.2, 1.6 Hz,1H), 6.13 (dd, J¼17.2, 10.4 Hz, 1H), 5.87–5.76
4
.14. General procedure K for cleavage of secondary
(
m, 2H), 5.31 (q, J¼6.4 Hz,1H), 5.25 (d, J¼17.6 Hz,1H), 5.17 (dd, J¼10.4,
TBS ethers
0
0
1
0
.8 Hz, 1H), 4.69 (dd, J¼4.0, 3.2 Hz, 0.47H), 4.60 (dd, J¼5.2, 2.8 Hz,
.53H), 3.96–3.84 (m, 1H), 3.67–3.53 (m, 1H), 3.48 (dt, J¼11.6, 4.8 Hz,
H),1.87–1.18 (m,17H),1.16 (d, J¼6.4 Hz,1.6H),1.04 (d, J¼6.4 Hz,1.4H),
To a solution of the secondary TBS ether 27 (28.0 mg,
ꢃ2
7
.0ꢂ10 mmol) inTHF (5 mL) was added TBAF(1.0 M inTHF, 0.1 mL,
13
.90 (d, J¼6.8 Hz, 1.4H), 0.85 (d, J¼7.2 Hz, 1.6H); C NMR (100 MHz,
0
.10 mmol) followed by stirring for 6 h at room temperature. The
reaction was quenched by addition of water (3 mL). The reaction
mixture was extracted with ethyl acetate (3ꢂ5 mL) and the com-
bined organic layer was washed with brine, dried over anhydrous
CDCl
9.5 and 95.5, 78.1 and 75.0, 75.0 and 74.4, 62.9 and 62.4, 38.8 and
7.8, 34.2, 32.2and31.7, 31.3and31.2, 29.7and29.7, 27.2and27.2, 25.6
3
) d 165.5, 136.5 and 136.5, 130.6 and 130.5, 128.8, 116.6 and 116.6,
9
3
and 25.5, 25.1 and 25.0, 20.2 and 19.7, 18.1 and 15.6, 15.3 and 15.3;
HRMS (CI ) calcd for C20
2 4
Na SO , filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluting
þ
þ
þ
H
35
O
4
(MþH ) 339.2535, found 339.2531.
with 25% EtOAc in hexane) to give the allyl alcohol 28 (19.0 mg, 95%).
0
4
1
.15.2. (3S,9S,10S)-9-Methyl-10-((tetrahydropyran-2 -yl)oxy)undec-
-en-3-yl acrylate (38). The acrylate 38 was prepared from the al-
0
4
1
.14.1. (3S,9R,10R)-9-methyl-10-((tetrahydropyran-2 -yl)oxy)undec-
cohol 37 according to the general procedure L in 98% yield as a col-
orless oil. An analytic sample of 52:48 diastereomeric mixture due to
the chirality in THP was used for the following characterization.
-en-3-ol (28). A colorless oil. An analytic sample of 54:46 di-
astereomeric mixture due to the chirality in THP was used for the
following characterization. R
¼0.50 (25% EtOAc in hexane); IR (film)
422 (br), 2930, 1458, 1378, 1115, 1076, 1022 cm
400 MHz, CDCl
5.86 (ddd, J¼16.4, 10.0, 6.0 Hz, 1H), 5.21 (br d,
f
R
f
¼0.40 (9.1% EtOAc in hexane); IR (film) 2926,1726,1404,1267,1191,
ꢃ1
1
3
;
H NMR
ꢃ1
1
1
6
5
2
3
022 cm ; H NMR (400 MHz, CDCl
3
)
d
6.41 (dd, J¼17.2, 1.6 Hz, 1H),
(
3
) d
.13 (dd, J¼17.4,10.6 Hz,1H), 5.86–5.76 (m, 2H), 5.31 (q, J¼6.4 Hz,1H),
.25 (d, J¼17.6 Hz, 1H), 5.17 (dd, J¼10.8, 1.2 Hz, 1H), 4.69 (dd, J¼4.0,
.8 Hz, 0.48H), 4.59 (dd, J¼4.8, 2.8 Hz, 0.52H), 3.96–3.84 (m, 1H),
.68–3.53 (m,1H), 3.48 (dt, J¼11.2, 4.8 Hz,1H),1.87–1.18 (m,17H),1.16
J¼17.6 Hz, 1H), 5.09 (dd, J¼10.4, 1.6 Hz, 1H), 4.69 (dd, J¼4.4, 2.8 Hz,
0
3
.46H), 4.59 (dd, J¼4.8, 2.8 Hz, 0.54H), 4.09 (q, J¼6.4 Hz, 1H), 3.96–
.84 (m, 1H), 3.68–3.53 (m, 1H), 3.47 (dt, J¼11.6, 4.8 Hz, 1H), 1.87–
1
.18 (m,18H),1.15 (d, J¼6.4 Hz,1.6H),1.04 (d, J¼6.4 Hz,1.4H), 0.90 (d,
(
0
1
7
d, J¼6.8 Hz, 1.6H), 1.04 (d, J¼6.0 Hz, 1.4H), 0.90 (d, J¼6.4 Hz, 1.4H),
13
J¼6.8 Hz, 1.4H), 0.85 (d, J¼6.8 Hz, 1.6H); C NMR (100 MHz, CDCl
3
)
13
.85 (d, J¼6.8 Hz,1.6H); C NMR (100 MHz, CDCl
3
) d 165.5, 136.5 and
d
141.3 and 141.3, 114.5 and 114.5, 99.4 and 95.4, 78.1 and 74.5, 73.2,
2.8 and 62.3, 38.7 and 37.8, 37.0 and 37.0, 32.2 and 31.7, 31.3 and
36.5,130.6 and 103.6,128.8 and 128.8,116.6 and 116.6, 99.5 and 95.5,
8.1 and 75.0, 75.0 and 74.5, 62.9 and 62.4, 38.8 and 37.8, 34.2, 32.2
and 31.7, 31.3 and 31.2, 29.7 and 29.7, 27.2 and 27.2, 25.6 and 25.5, 25.1
and 25.0, 20.2 and 19.7,18.1 and 15.6,15.4 and 15.3; HRMS (CI ) calcd
6
3
1.2, 29.8, 27.3 and 27.2, 25.6 and 25.5, 25.3 and 25.3, 20.1 and 19.6,
þ
þ
þ
18.1 and 15.6,15.3 and 15.3; HRMS (CI ) calcd for C17
H O
33 3
(MþH )
þ
2
85.2430, found 285.2446.
þ
þ
for C20
H
35
O
4
(MþH ) 339.2535, found 339.2545.
0
4
.14.2. (3S,9S,10S)-9-Methyl-10-((tetrahydropyran-2 -yl)oxy)undec-
4
.16. General procedure M for RCM reactions
1-en-3-ol (37). The allyl alcohol 37 was prepared from the TBS
ether 36 according to the general procedure K in 100% yield as
a colorless oil. An analytic sample of 52:48 diastereomeric mixture
due to the chirality in THP was used for the following character-
ꢃ2
To a solution of the acrylate 29 (12.0 mg, 3.5ꢂ10 mmol) in dry
and degassed CH
2
Cl
2
(50 mL) was added a solution of Grubbs sec-
ꢃ3
ond generation catalyst (1.5 mg, 1.8ꢂ10 mmol) in dry and
ization. R
f
¼0.43 (25% EtOAc in hexane); IR (film) 3423 (br), 2926,
2 2
degassed CH Cl (2 mL). After being refluxed for 4 h under a nitro-
ꢃ1
1
1459, 1377, 1116, 1077, 1023 cm ; H NMR (400 MHz, CDCl ) d 5.87
3
gen atmosphere, the reaction mixture was concentrated under
reduced pressure and the residue was purified by column chro-
matography (silica gel, eluting with 25% EtOAc in hexane) to give
the butenolide 30 (9.9 mg, 90%).
(
ddd, J¼17.2, 10.4, 6.4 Hz,1H), 5.22 (dt, J¼16.8, 1.6 Hz,1H), 5.10 (ddd,
J¼10.0, 2.4, 1.2 Hz, 1H), 4.69 (dd, J¼4.4, 2.8 Hz, 0.48H), 4.60 (dd,
J¼4.4, 2.4 Hz, 0.52H), 4.09 (q, J¼6.8 Hz, 1H), 3.96–3.84 (m, 1H),
3
1
1
1
3
2
.68–3.53 (m, 1H), 3.48 (dt, J¼11.6, 4.8 Hz, 1H), 1.90–1.18 (m, 18H),
.16 (d, J¼6.4 Hz, 1.6H), 1.05 (d, J¼6.4 Hz, 1.4H), 0.90 (d, J¼6.8 Hz,
0
4
.16.1. (4S,10R,11R)-4-Hydroxy-10-methyl-11-((tetrahydropyran-2 -
yl)oxy)dodec-2-en-1,4-olide (30). A colorless oil. An analytic sample
of 52:48 diastereomeric mixture due to the chirality in THP was
13
.4H), 0.85 (d, J¼6.8 Hz, 1.6H); C NMR (100 MHz, CDCl
3
) d 141.3,
14.6 and 114.5, 99.4 and 95.5, 78.1 and 74.5, 73.3, 62.9 and 62.4,
8.7 and 37.8, 37.0, 32.2 and 31.7, 31.3 and 31.2, 29.7, 27.3 and 27.2,
5.6 and 25.5, 25.3, 20.1 and 19.7, 18.1 and 15.6, 15.4 and 15.3;
used for the following characterization. R
f
¼0.22 (25% EtOAc in
ꢃ1
1
hexane); IR (film) 2934, 1756, 1162, 1110, 1076, 1023 cm ; H NMR
þ
þ
þ
HRMS (CI ) calcd for C17
H
31
O
2
(M –OH) 267.2324, found 267.2306.
(
400 MHz, CDCl
3
) d 7.46–7.43 (m, 1H), 6.11–6.09 (m, 1H), 5.05–5.00
(
m, 1H), 4.68 (t, J¼3.6 Hz, 0.48H), 4.59 (dd, J¼4.8, 2.8 Hz, 0.52H),
4
.15. General procedure L for acylation of alcohols
3.98–3.84 (m, 1H), 3.69–3.54 (m, 1H), 3.48 (dt, J¼11.2, 4.8 Hz, 1H),
1
.87–1.19 (m, 17H), 1.16 (d, J¼6.8 Hz, 1.6H), 1.04 (d, J¼6.0 Hz, 1.4H),
ꢃ2
13
To a solution of the alcohol 28 (16.0 mg, 5.6ꢂ10 mmol) in dry
0.90 (d, J¼7.2 Hz, 1.4H), 0.85 (d, J¼6.4 Hz, 1.6H); C NMR (100 MHz,
ꢁ
CH
(
8
2
Cl
L,
2
(3 mL) cooled at 0 C was sequentially added triethylamine
3
CDCl ) d 173.1 and 173.1, 156.3 and 156.2, 121.5 and 121.5, 99.4 and
ꢃ2
16
m
11.2ꢂ10 mmol)
and
acryloyl
chloride
(7
mL,
95.6, 83.4 and 83.4, 78.1 and 74.5, 62.9 and 62.5, 38.7 and 37.8, 33.2,
32.0 and 31.6, 31.3 and 31.2, 29.6 and 29.6, 27.2 and 27.1, 25.6 and
ꢃ2
.4ꢂ10 mmol) followed by stirring for 4 h at room temperature.
Cl
(3ꢂ5 mL).
The combined organic layer was dried over anhydrous Na SO
þ
The reaction mixture was diluted with water (2 mL) and CH
2 mL) and the aqueous layer was extracted with CH Cl
2
2
25.5, 25.0, 20.1 and 19.7, 18.0 and 15.5, 15.4 and 15.3; HRMS (CI )
þ þ
30 4
calcd for C18H O (M ) 310.2144, found 310.2133.
(
2
2
2
4
,
0
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, eluting with 9.1%
EtOAc in hexane) to give the ester 29 (18.0 mg, 95%).
4.16.2. (4S,10S,11S)-4-Hydroxy-10-methyl-11-((tetrahydropyran-2 -
yl)oxy)dodec-2-en-1,4-olide (39). The butenolide 39 was prepared
from the acrylate 38 according to the general procedure M in 89%

196
Y. Wang, W.-M. Dai / Tetrahedron 66 (2010) 187–196
yield as a colorless oil. An analytic sample of 52:48 diastereomeric
mixture due to the chirality in THP was used for the following
Department of Chemistry, HKUST. The Laboratory of Asymmetric
Catalysis and Synthesis is established under the Cheung Kong
Scholars Program of The Ministry of Education of China. Some
preparatory work was carried out by Y. Wang at Zhejiang Univer-
sity, China.
characterization. R
f
¼0.26 (25% EtOAc in hexane); IR (film) 2921,
ꢃ1
1
1749, 1160, 1116, 1076, 1022 cm
;
H NMR (400 MHz, CDCl
3
)
d
7.46–7.44 (m, 1H), 6.12–6.09 (m, 1H), 5.05–5.00 (m, 1H), 4.68 (t,
J¼3.6 Hz, 0.48H), 4.60 (dd, J¼4.4, 2.8 Hz, 0.52H), 3.98–3.84 (m, 1H),
.69–3.54 (m, 1H), 3.48 (dt, J¼11.2, 4.8 Hz, 1H), 1.87–1.19 (m, 17H),
.16 (d, J¼6.4 Hz, 1.6H), 1.04 (d, J¼6.4 Hz, 1.4H), 0.90 (d, J¼6.8 Hz,
3
1
Supplementary data
13
1
.4H), 0.85 (d, J¼6.8 Hz, 1.6H); C NMR (100 MHz, CDCl
and 173.1, 156.2 and 156.2, 121.6 and 121.5, 99.4 and 95.7, 83.4 and
3.4, 78.1 and 74.5, 62.9 and 62.5, 38.7 and 37.8, 33.2, 32.1 and 31.6,
1.3 and 31.2, 29.6 and 29.6, 27.2 and 27.1, 25.6 and 25.6, 25.0, 20.1
3
) d 173.1
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.10.115.
8
3
þ
References and notes
and 19.8, 18.0 and 15.6, 15.4 and 15.3; HRMS (CI ) calcd for
C
þ
þ
18
H
31
O
4
(MþH ) 311.2222, found 311.2225.
1. For a recent review on marine natural products, see: Blunt, J. W.; Copp, B. R.;
Hu, W.-P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2009,
26, 170–244.
4
.17. General procedure N for cleavage of THP ethers
2
3
4
5
6
. Mukku, V. J. R. V.; Speitling, M.; Laatsch, H.; Helmke, E. J. Nat. Prod. 2000, 63,
1570–1572.
ꢃ2
A solution of the THP ether 30 (7.0 mg, 2.2ꢂ10 mmol) and PPTS
. Cho, K. W.; Lee, H.-S.; Rho, J.-R.; Kim, T. S.; Mo, S. J.; Shin, J. J. Nat. Prod. 2001, 64,
664–667.
. Li, D.-H.; Zhu, T.-J.; Liu, H.-B.; Fang, Y.-C.; Gu, Q.-Q.; Zhu, W.-M. Arch. Pharm. Res.
ꢃ3
ꢁ
(
0.6 mg, 2.2ꢂ10 mmol) in MeOH (3 mL) was stirred at 40 C (bath
temperature) for 2 h. The reaction mixture was then concentrated
under reduced pressure and the residue was purified by column
chromatography (silica gel, eluting with 50% EtOAc in hexane) to give
the butenolide alcohol (4S,10R,11R)-1c (4.5 mg, 88%).
2006, 29, 624–626.
. Karlsson, S.; Andersson, F.; Breistein, P.; Hedenstr o¨ m, E. Tetrahedron Lett. 2007,
48, 7878–7881.
. (a) Karlsson, S.; H o¨ gberg, H.-E. Org. Lett. 1999, 1, 1667–1669; (b) Karlsson, S.;
H o¨ gberg, H.-E. Synthesis 2000, 1863–1867.
7
. For reviews, see: (a) Grubbs, R. H.; Cahng, S. Tetrahedron 1998, 54, 4413–4459;
4
.17.1. (4S,10R,11R)-4,11-Dihydroxy-10-methyldodec-2-en-1,4-olide
(b) F u¨ rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (d) Schrock, R. R.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2003, 42, 4592–4633; (e) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199–2238; (f) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4490–4527; (g) Gradillas, A.; Perez-Castells, J. Angew.
Chem., Int. Ed. 2006, 45, 6086–6101; (h) Schrodi, Y.; Pederson, R. L. Aldrichimica
Acta 2007, 40, 45–52; (i) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243–
20
(1c). A colorless oil; [
a
]
D
þ64.3 (c 0.14, MeOH); R
f
¼0.31 (50% EtOAc
ꢃ1
in hexane); IR (film) 3449 (br), 2931, 1746, 1460, 1166, 1102 cm
;
1
H NMR (400 MHz, CDCl
3
)
d
7.44 (dd, J¼5.8, 1.4 Hz, 1H), 6.10 (dd,
´
J¼5.8, 1.8 Hz, 1H), 5.05–5.00 (m, 1H), 3.70 (qd, J¼6.8, 4.4 Hz, 1H),
1.82–1.72 (m, 1H), 1.72–1.60 (m, 1H), 1.55–1.23 (m, 9H), 1.14 (d,
251; (j) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
þ
J¼6.4 Hz, 3H), 1.13–1.07 (m, 1H), 0.87 (d, J¼6.4 Hz, 3H); HRMS (CI )
2003; Vols. 1–3.
þ
þ
13
calcd for C13
H
23
O
3
(MþH ) 227.1647, found 227.1664. The C NMR
8. (a) F u¨ rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463–2465; (b) F u¨ rstner, A.; Thiel,
O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65,
data of (4S,10R,11R)-1c are listed in Table 1.
2
7
204–2207; (c) Ghosh, A. K.; Leshchenko, S.; Noetzel, M. J. Org. Chem. 2004, 69,
822–7829.
4
.17.2. (4S,10S,11S)-4,11-Dihydroxy-10-methyldodec-2-en-1,4-olide
9. Dai, W.-M.; Shi, L.; Li, Y. Tetrahedron: Asymmetry 2008, 19, 1549–1556.
0. Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117,
0805–10816.
1. For recent reviews on modern aldol methods in total synthesis, see: (a)
Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506–7525; (b) Li, J.;
Menche, D. Synthesis 2009, 2293–2315.
1
(1d). The butenolide alcohol 1d was prepared from the THP ether
1
3
oil; [
9 according to the general procedure N in 93% yield as a colorless
1
2
0
a
]
D
þ33.6 (c 0.14, MeOH); R
f
¼0.31 (50% EtOAc in hexane); IR
ꢃ1
(
(
film) 3424 (br), 2925, 1756, 1454, 1165, 1098, 1057 cm ; H NMR
400 MHz, CDCl
12. (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586–2587; (b)
3
)
d
7.44 (dd, J¼5.6, 1.2 Hz, 1H), 6.10 (dd, J¼5.6,
Inoue, T.; Liu, J.-F.; Buske, D.; Abiko, A. J. Org. Chem. 2002, 67, 5250–5256.
13. (a) Kuszmann, J.; Tomori, E´ .; Meerwald, I. Carbohydr. Res. 1984, 128, 87–99; (b)
2
.0 Hz,1H), 5.05–5.00 (m, 1H), 3.70 (qd, J¼6.4, 4.4 Hz,1H),1.82–1.70
Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis 1986, 403–406;
(c) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989, 54, 5153–5161;
(
1
C
m, 1H), 1.70–1.61 (m, 1H), 1.51–1.22 (m, 9H), 1.14 (d, J¼6.4 Hz, 3H),
þ
.13–1.07 (m, 1H), 0.87 (d, J¼6.8 Hz, 3H); HRMS (CI ) calcd for
(d) Kang, E. J.; Cho, E. J.; Ji, M. K.; Lee, Y. E.; Shin, D. M.; Choi, S. Y.; Chung, Y. K.;
þ
þ
13
H
13 23
O
3
(MþH ) 227.1647, found 227.1649. The C NMR data of
Kim, J.-S.; Kim, H.-J.; Lee, S.-G.; Lah, M. S.; Lee, E. J. Org. Chem. 2005, 70,
6321–6329.
(
4S,10S,11S)-1d are listed in Table 1.
1
1
4. Panek, J. S.; Yang, M.; Solomon, J. Tetrahedron Lett. 1995, 36, 1003–1006.
5. The 1H NMR spectrum of (4S,10S)-2b is clean but its C NMR spectrum shows
two minor peaks at 29.7 and 24.8 ppm, that are likely the fatty grease con-
taminant introduced from the used solvent(s) (see the NMR spectrum on pages
of S144–S147 in Supplementary data for the detail). Unfortunately, the minor
impurity could not be removed after repeated separation. It is estimated that
pure sample of (4S,10S)-2b should have an optical rotation value slightly higher
than that given in Table 2.
13
Acknowledgements
This work is supported in part by a Competitive Earmarked
Research Grant (600808) from the Research Grants Council,
The Hong Kong Special Administrative Region, China and the