Enantioselective total synthesis and correction of the absolute configuration of megislactone

Article abstract of DOI:10.1016/j.tet.2008.02.054

The title compound, one of the constituents from Iryanthera megistophylla, has been synthesized in enantiopure forms. The stereogenic centers at C-2 and C-3 were constructed by using a chiral auxiliary induced asymmetric aldolization and the C-4 was derived from the corresponding optically active lactates. The carbon-carbon double bond in the side chain was derived from a pure cis vinyl iodide using a Suzuki coupling with an alkyl borane formed in situ from the corresponding terminal alkene. A previously unknown (partial) cis to trans transformation of an isolated C-C double bond in a long alkyl chain was observed during the deprotection of TBS group with CAN. Somewhat unexpectedly, the otherwise undetectable co-presence of the trans isomer of the remote double bond in a long alkyl chain was clearly revealed in ¹H and ¹³C NMR in the presence of a lactone ring. The present work unambiguously shows that the absolute configuration of the natural compound is the antipode of the one originally reported. Some errors in the previous ¹H and ¹³C NMR signal assignments are also corrected.

Full text of DOI:10.1016/j.tet.2008.02.054

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4408e4415
www.elsevier.com/locate/tet
Enantioselective total synthesis and correction of the absolute
configuration of megislactone
*
Guo-Bao Ren, Yikang Wu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 17 December 2007; received in revised form 25 January 2008; accepted 17 February 2008
Available online 21 February 2008
Abstract
The title compound, one of the constituents from Iryanthera megistophylla, has been synthesized in enantiopure forms. The stereogenic cen-
ters at C-2 and C-3 were constructed by using a chiral auxiliary induced asymmetric aldolization and the C-4 was derived from the correspond-
ing optically active lactates. The carbonecarbon double bond in the side chain was derived from a pure cis vinyl iodide using a Suzuki coupling
with an alkyl borane formed in situ from the corresponding terminal alkene. A previously unknown (partial) cis to trans transformation of an
isolated CeC double bond in a long alkyl chain was observed during the deprotection of TBS group with CAN. Somewhat unexpectedly, the
otherwise undetectable co-presence of the trans isomer of the remote double bond in a long alkyl chain was clearly revealed in 1H and 13C NMR
in the presence of a lactone ring. The present work unambiguously shows that the absolute configuration of the natural compound is the antipode
1
of the one originally reported. Some errors in the previous H and 13C NMR signal assignments are also corrected.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Aldols; Lactones; Condensation; Cyclization; Heterocycles
O
1. Introduction
O
1
1'
17'
18'
2
O
O
19'
5
15
15
26'
3
Megislactone (1) was isolated from the bark of Iryanthera
megistophylla in 2002 by Hudson and Towers.1 The original
structure of this compound was proposed to be 1a, with the
relative configuration determined by NMR spectroscopy and
the absolute configuration established by comparison of the
optical rotation of a derivative (alleged to be 2a) with that
of a known/similar compound (3).
Aldol motif-containing compounds are one of the types of
compounds that are particularly interesting to our group.2 As
an extension of our synthesis of blastmycinone and antimycin
A3b, we started the synthesis of megislactone. Herein we wish
to report the details.
5
4
OH
OH
1b
5
25'
1a
(2S,3S,4S)
(2R,3R,4R)
Corrected structure
Originally proposed structure
O
O
O
O
10
15
22
5
(R)
[ ]D
29.8
(R)
2a
3
2. Results and discussions
Our synthetic plan is outlined in Scheme 1. In a previous2d
work, we observed that removal of a similar TES protecting
group on the hydroxyl group g to the carbonyl group bonded
to a chiral auxiliary led to immediate formation of a five-mem-
bered lactone. Although the relative configurations of the three
stereogenic center-array in aldol 4a are less favorable (unable
* Corresponding author.
E-mail address: yikangwu@mail.sioc.ac.cn (Y. Wu).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.054

G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
4409
O
I
S
OH
O
CHO
2
4
O
3
O
N
15
I
THF
87%
Ph3P
13
OTBS
+
5
OH
H
15
Bn
(2R,3R,4R)
1a
(2R,3R,4R)
11'
12
6
4a
cis/trans = 11:1
S
O
O
O
(R)
I
O
N
+
InCl3
H
MeO
7a
DIBAL-H
BEt3/I2
83%
OTBS
6a
15
OH
(R)-Methyl lactate
TBSO
Bn
(cis only)
5a
6
14
11
I
CO2H
15
Scheme 2.
S
+
O
8a
NH
Bn
available 14 as the starting material, the anticipated 11 was
isolated in 83% yield, with the content of the trans isomer
1
well below the detection limits of 300 MHz H NMR.
+
12
6
9
10
11
Scheme 1.
Another fragment (10) needed for the Suzuki coupling was
synthesized as shown in Scheme 3. Alkylation of the known
propargyl ether 159 with commercially available dibromide
16 led to 17 in 92% yield. Exposure of 17 to H2 (50 atm)/
PdeC for 3 days led to saturation of the triple bonds and con-
current removal of the benzyl protecting groups. One of the
two hydroxyl groups in the known diol 1810 was then pro-
tected as TBS (tert-butyldimethylsilyl) ether, leaving the other
ready for transformation into the corresponding iodide. After
the subsequent elimination mediated by t-BuOK in THF, the
terminal alkene 10 was obtained in 75% yield from 19.
to form all-trans substituted lactone ring) than those in blast-
mycinone, we still thought that this concurrent deprotec-
tionelactonization deserved a try here.
The stereogenic centers at C-2/C-3 were planned to form by
an asymmetric aldolization between 5a and 6a under the con-
ditions3 developed by Crimmins. The aldehyde 6a could be
obtained from lactate 7a, a common commercially available
reagent. And the chiral auxiliary 8a can be readily prepared
from (R)-phenylalanine using a practical procedure4 recently
developed by our group. Thus, the major challenge of the syn-
thetic work appears to be associated with the long chain car-
boxylic acid 9.
OBn OBn
HO HO
n-BuLi
H2/Pd-C
THF
87%
OBn
Br Br
THF
+
An important and unavoidable task in the synthesis of 9
is to secure the geometry of the carbonecarbon double bond.
Because this double bond is located in a long alkyl chain and
remote from any other functionality, separation of the double
bond isomers would be extremely difficult. Even spectroscopic
detection of the presence of the double bond isomers may be
unfeasible. Therefore, from the beginning Suzuki coupling5 of
a cis vinyl iodide was opted for constructing this isolated dou-
ble bond because of its high level of stereoselectivity. Hence, it
follows that the geometry of the double bond in the end prod-
uct is determined by that of the vinyl iodide precursor (11).
One of the reliable ways to prepare pure cis-116 is to reduce
the corresponding terminal iodoalkyne with diimide.6 How-
ever, because both the precursor and the reagent (KO2CN]
NCO2K) are potentially hazardous compounds, in the first try
we chose to use the perhaps less selective but much more fea-
sible protocol7 reported by Stork and Zhao. Starting from the
known aldehyde 12 and Wittig reagent 13 (prepared in situ
from Ph3PþCIHIꢀ by treatment with NaHMDS) the expected
vinyl iodide was formed smoothly in 87% yield as a 11:1 mix-
HMPA
92%
10
18
15
12
16
17
10
TBSCl
DMAP
67%
imdazole
CH2Cl2
t-BuOK
TBSO
TBSO
HO
TBSO
THF
I2/PPh3
imidazole
toluene
I
75%
(2 steps)
10
12
12 20
19
12
1) 9-BBN/THF
2) 11/PdCl2(PPh3)2
89%
CO2H
15
PDC
DMF
87%
TBAF
OTBS
OH
THF
15
15
95%
21
22
9
6
6
6
Scheme 3.
The Suzuki coupling is usually performed with PdCl2(dppf)
or Pd(PPh3)4 as the catalyst. However, in the present work the
coupling product was also obtained in good yields using
PdCl2(PPh3)2,11 which is readily accessible and more stable
than Pd(PPh3)4.
The isolated 21 was then treated with n-Bu4NF (TBAF) to
remove the TBS protecting group, affording alcohol 22. Fi-
nally, the hydroxyl group was oxidized into the corresponding
carboxylic acid with pyridinium dichromate12 (PDC) in DMF,
affording the desired acid 9 in 87% yield.
1
ture of the cis and trans isomers as shown by H NMR. Al-
though the desired cis isomer predominated, removal of the
minor isomer by chromatography turned out to be unfeasible
(Scheme 2).
Failed to obtain the pure cis iodide by the Wittig olefina-
tion, our attention was next paid to the InCl3/DIBAL-
H/Et3B/I2 protocol developed by Oshima8 and co-workers.
Following the procedure of the literature with commercially

4410
G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
Acylation of chiral auxiliary 8a with acid 9 was performed
configuration (i.e., 6b and 8b) to replace 6a and 8a (Scheme
5). The enantiopure end product (1b) thus obtained indeed
shows a compatible optical rotation ([a]2D8 ꢀ18.3 (c 1.65,
CHCl3)) with that ([a]D20 ꢀ13 (c 1.0, CHCl3)) of the natural
under the conditions13 of Andrade. The aldolization between
5a and 6a mediated by TiCl4 gave the enantiopure syn aldol
4a in 71% yield (Scheme 4). Further treatment of 4a with
4 N HCl to remove the TBS protecting group resulted in spon-
taneous lactonization, affording the target compound 1a.
1
megislactone. And the H and 13C NMR data are also consis-
tent with those reported for the natural megislactone.
S
CO2H
15
O
S
CO2H
O
DCC
S
DCC
S
DMAP
DMAP
O
N
O
N
+
O
NH
Bn
+
1'
O
NH
Bn
17
85%
17
15
82%
Bn
6
Bn
6
5b
5a
6
8a
9
6
9
8b
6b/TiCl4
( )-Spartiene 6a/TiCl4
( )-Spartiene
67%
71%
O
1
S
OH
4
O
S
O
OH
4
O
17'
18'
HCl
THF
88%
HCl
THF
2
2
2
2
O
19'
5
3
O
N
15
26'
3
O
N
O
3
15
3
OTBS
15
4
89%
OTBS
15
OH
(2S,3S,4S)
4
5
5
25'
Bn
(2R,3R,4R)
4a
OH
(2R,3R,4R)
[ ]D 17.9 (c 0.8, CHCl3)
Bn
(2S,3S,4S)
1a
1b
18.3 (c 1.65, CHCl3)
6
6
[ ]D
4b
Scheme 5.
Scheme 4.
1
All the spectroscopic data of our synthetic 1a are consis-
tent14 with those reported1 in the literature, except that the op-
tical rotation (þ17.9) has an opposite sign. It seems what we
obtained is the antipode of the natural product. As the absolute
configurations of all stereogenic centers in this work are se-
cured by the methodologies adopted, we next looked into
the original assignment for the natural compound again to
seek possible explanation for the opposite rotation. It was
then noticed that the absolute configuration of the isolated nat-
ural compound was entirely based on comparison of the sign
of the optical rotation of their 2a (obtained by treatment of
the natural megislactone with Al2O3 without specifying the
yield) with that of 3 reported in the literature. However, with-
Comparison of the H and 13C NMR data of 1b with those
reported for the natural one is given in Tables 1 and 2. It ap-
pears that the two sets of data agree very well with each other.
However, a few minor errors in the original assignments are
also detected during careful analysis of the spectroscopic
data: C5 and C260 are now switched, because in the HMQC
spectrum the carbon connected to the methyl protons (doublet)
at d 1.40 is that at d 13.8, not at d 14.1. The HMQC spectrum
also unmistakably reveals that the four protons in the region of
d 1.74e1.41 are connected to C-10 and C-20 in this way: on go-
ing from 1.74 to 1.41, the first two protons are linked to C-10
and the next two are attached to C-20.
To gain further evidence for the absolute configuration, for-
mal dehydration of synthetic 1a and 1b was also performed by
converting the OH into corresponding mesylate followed by
treatment with Bu4NF. Without involving any carbocation in-
termediate, an indirect elimination of water is expected to be
much less likely to cause any carbon framework rearrange-
ment compared with direct1 dehydration of water over
Al2O3. The elimination product from 1a and 1b gave an opti-
cal rotation of ꢀ16.6 and þ16.2, respectively (Scheme 6),
1
out H/13C NMR and IR data, the correct molecular weight
(i.e., MS result) alone cannot guarantee the genuine identity
of the sampledit is not impossible that their ‘2a’ was some
other compound generated on Al2O3 during the intended dehy-
dration, with the same molecular weight but a different struc-
ture from 2a.
The antipode of 1a was then synthesized using the same
route but with an auxiliary and an aldehyde of the opposite
Table 1
Comparison of 1H NMR data of the synthetic and natural megislactone (1b)
Synthetic 1b (this work)
Natural 1b
Previous assignment
Present assignment
5.34 (t, J¼4.7 Hz, 2H)
4.62 (dq, J¼4.8, 6.4 Hz, 1H)
4.19 (ddd, J¼4.6, 4.3, 3.9 Hz, 1H)
2.53 (m, 1H)
5.33 (dt, J¼9.4, 4.6 Hz, 2H)
4.61 (dq, J¼4.6, 6.5 Hz, 1H)
4.19 (dd, J¼3.9, 4.6 Hz, 1H)
2.52 (m, 1H)
H-170 and H-180
H-170 and H-180
H-4
H-4
H-3
H-2
H-3
H-2
2.50e2.36 (br s, 1H)
2.02e1.93 (m, 4H)
1.74e1.68 (m, 1H)
(not given)
2.00 (m, 4H)
OH
H-160 and H-190
H-160 and H-190
1.70 (m, 1H)
1.51 (m, 2H)
1.45 (m, 1H)
H-10a
H-10a
1.59e1.52 (m, 1H)
1.50e1.41 (m, 2H)
1.40 (d, J¼6.7 Hz, 3H)
1.39e1.20 (s, 38H)
H-20
H-10b
H-5
H-10b
H-20
H-5
1.39 (d, J¼6.5 Hz, 3H)
1.38e1.20 (m, 38H)
0.86 (t, J¼6.5 Hz, 3H)
H-30 to H-150, H-200 to H-250
H-260
H-30 to H-150, H-200 to H-250
H-260
0.87 (t, J¼7.1 Hz, 3H)

G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
4411
Table 2
Comparison of 13C NMR data of the synthetic and natural megislactone (1b)
O
O
1) MsCl/Et3N
2) TBAF
90% (2 steps)
O
O
15
15
1a
Synthetic 1b
(this work)
Natural 1b
Previous assignment
Present assignment
5
2a
5
(R)
[ ]D
OH
(2R,3R,4R)
17.9 (c 0.8, CHCl3)
178.0
129.8
129.8
78.4
177.6
129.9
129.9
78.2
C-1
C-1
16.6 (c 0.85, CHCl3)
[ ]D
C-170
C-180
C-4
C-170
C-180
C-4
O
O
2
O
73.9
49.3
74.1
49.2
C-3
C-2
C-3
C-2
1) MsCl/Et3N
15
O
3
1b
15
4
5
2) TBAF
94% (2 steps)
2b
OH
(2S,3S,4S)
a
5
C-240
(S)
31.9
29.8e29.1
31.9e29.3
C-30 to C-50 and
C-200 to C-240
C-20
C-30 to C-50 and
C-200 to C-230
[ ]D
16.2 (c 1.55, CHCl3)
[ ]D
18.3 (c 1.65, CHCl3)
29.0
28.4
Scheme 6.
28.4
27.22
27.15
22.6
14.1
13.8
178.0
a
C-10
C-10
C-20
C-160 and C-190
C-250
C-260
C-5
27.2
27.2
C-190
triplet was observed. In 13C NMR, an extra line appeared at
130.34. Because in such a molecular setup, any changes in
the relative configurations of the stereogenic centers in the lac-
tone ring inevitably lead to unmistakable changes in 1H NMR,
the only possible explanation for the additional signals in
NMR must be co-presence of a trans double bond isomer.
As no trans isomer could be detected with the 1a prepared us-
ing HCl instead of CAN, the isomerization must be caused by
CAN.
C-160
(Not given)
14.1
13.9
C-5
C-260
C-1
177.6
C-1
This carbon is assigned as C-240 rather than C-200 on the basis of the fol-
lowing arguments: (a) Compound 10 does not show this carbon in 13C NMR,
which contains the C-200, but 11 does. (b) 13C NMR simulation using Chem-
Draw 9.0 suggests that the third carbon from the terminal methyl group has
a chemical shift of 31.8, whereas that for C-200 would be 29.9.
with all spectroscopic data fully consistent with their struc-
tures. Thus, the absolute configuration of the natural megislac-
tone must be as shown by structure 1b, the antipode of the
originally proposed 1a.
It is interesting to note that the final deprotectionelactoni-
zation could also be achieved by using CAN (ceric ammonium
nitrate)/MeOH, a set of conditions known for cleaving silyl
protecting groups. However, the product obtained under such
conditions shows slight difference at the eCH]CHe region
in 1H NMR and 13C NMR (Fig. 1). In 1H NMR, an additional
set of lines partially overlapped with the original broadened
3. Conclusions
Both (þ)- and (ꢀ)-megislactone have been synthesized
through a highly stereoselective route. The spectroscopic
data of the synthetic sample clearly show that absolute config-
uration of the natural compound must be the antipode of the
originally proposed. Some minor corrections are also made
to the original spectroscopic assignments. An interesting
partial isomerization of the cis carbonecarbon double bond
mediated by CAN was observed during the desilylatione
cyclization step.15 The otherwise undetectable co-presence
Figure 1. Comparison of the 1H and 13C NMR spectra. (A) and (B): partial 1H NMR of the 1b formed using CAN and HCl, respectively. (C) and (D): partial 13
NMR of the 1b formed using CAN and HCl, respectively. The extra signal at d 5.35 in (A) and d 130.3 in (C) stem from the trans CeC double bond isomer. Other
C
parts of the 1H and 13C NMR spectra of the two samples are identical to each other.

4412
G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
of the trans isomer revealed by the remote lactone ring in the
end product is also noteworthy.
at ambient temperature under H2 (50 atm) for 3 d. The solids
were filtered off. The filtrate was concentrated on a rotary
evaporator. The residue was chromatographed on silica gel
(3:1 PEeTHF) to yield the known diol 1810 (1.320 g,
4.61 mmol, 87%) as a white powder: mp 95e96 ꢁC (lit.16
97 ꢁC). 1H NMR (300 MHz, CDCl3) d 3.64 (t, J¼6.6 Hz,
4H), 1.54 (m, 4H), 1.26 (s, 26H).
4. Experimental
4.1. General
Unless otherwise stated, the 1H NMR and 13C NMR spectra
were recorded in deuterochloroform at ambient temperature
using a Varian Mercury 300 or a Bruker Avance 300 instru-
ment (operating at 300 MHz for proton). The FTIR spectra
were scanned with a Nicolet Avatar 360 FTIR spectrometer.
EIMS and EIHRMS were recorded with an HP 5989A and
a Finnigan MAT 8430 mass spectrometer, respectively. The
ESIMS and ESIHRMS were recorded with a PE Mariner
API-TOF and an APEX III (7.0 Tesla) FTMS mass spectro-
meter, respectively. The melting points were uncorrected. Op-
tical rotations were recorded on a Jasco P-1030 polarimeter.
Dry THF was distilled from Na/Ph2CO under N2. Dry
HMPA, DMF, and DMSO were stirred with CaH2 at ambient
temperature under N2 for 4 d before being distilled under re-
4.4. Monosilyl protection of diol 18 (19)
TBSCl (787 mg, 5.16 mmol) was added in portions to a so-
lution of diol 18 (1.343 g, 4.69 mmol), imidazole (351 mg,
5.16 mmol) and DMAP (57 mg, 0.47 mmol) in dry CH2Cl2
(470 mL). The mixture was then stirred at ambient tempera-
ture for 24 h before being washed with aq saturated NaHCO3,
water and brine, and dried over Na2SO4. The solvent was re-
moved by rotary evaporation. The residue was purified by flash
chromatography on silica gel (4:1 PEeTHF) to furnish the
mono TBS ether 19 (1.266 g, 3.17 mmol, 67%) as a colorless
1
oil: H NMR (300 MHz, CDCl3) d 3.68 (t, J¼7.2 Hz, 2H),
3.65 (t, J¼6.6 Hz, 2H), 1.62e1.46 (m, 4H), 1.31 (s, 28H),
0.95 (s, 9H), 0.10 (s, 6H); 13C NMR (75 MHz, CHCl3)
d 63.4, 63.0, 32.9, 32.8, 29.7e29.4 (all the remaining/
unresolved alkyl carbons), 26.0, 25.8, 25.7, 18.4, ꢀ5.3;
FTIR (film) 3449, 2926, 2854, 1466, 1400, 1255, 1102, 836,
775 cmꢀ1. ESIMS m/z 401.5 ([M+H]+). ESIHRMS calcd for
C24H53O2Si ([M+H]+): 401.3809; found: 401.3525.
˚
duced pressure and kept under N2 over activated 4 A molecu-
lar sieves. Dry CH2Cl2 was distilled over CaH2 and kept over
˚
activated 4 A molecular sieves. All other solvents and reagents
were commercially available and used as-received without any
further purification. PE (chromatography eluent) stands for pe-
troleum ether (bp 60e90 ꢁC). DCC stands for N,N0-dicyclo-
hexyldiimide. DMAP stands for 4-dimethylamino-pyridine.
DMF stands for N,N0-dimethylformamide.
4.5. Transformation of alcohol 19 into iodide 20
4.2. Alkylation of alkyne 15 with dibromide 16 (17)
I2 (64 mg, 0.253 mmol) was added to a solution of 19
(78 mg, 0.195 mmol), imidazole (20 mg, 0.293 mmol) and
PPh3 (78 mg, 0.293 mmol) in dry toluene (2 mL) stirred at am-
bient temperature. After 20 min, another portion of imidazole
(7 mg, 0.097 mmol) was introduced, followed by PPh3 (26 mg,
0.097 mmol), and I2 (21 mg, 0.097 mmol). When the reaction
was complete as shown by TLC, aq saturated aqueous
Na2S2O3 (5 mL) was added, followed by EtOAc. The phases
were separated. The organic layer was washed in turn with
water and brine before being dried over NaSO4. Removal of
the solvent and column chromatography (50:1 PEeEt2O)
gave iodide 20 (95 mg, 0.186 mmol, 95%) as a colorless oil:
1H NMR (300 MHz, CDCl3) d 3.61 (t, J¼6.8 Hz, 2H), 3.20
(t, J¼7.0 Hz, 2H), 1.81 (q, J¼7.1 Hz, 2H), 1.51 (m, 2H),
1.27 (s, 28H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR
(75 MHz, CHCl3) d 63.3, 33.6, 32.9, 30.5, 29.7e29.4 (all
the remaining/unresolved alkyl carbons), 28.5, 26.0, 25.8,
18.4, 7.3, ꢀ5.3. FTIR (film) 2926, 2854, 1436, 1254, 1101,
836, 775, 761 cmꢀ1; EIMS m/z (%) 453 ([MꢀC4H9]+, 12),
325 (7), 215 (10), 125 (27), 111 (58), 97 (99), 75 (100);
EIHRMS calcd for C20H42OSiI ([MꢀC4H9]+) 453.2050; found
453.2064.
n-BuLi (2.5 M in hexanes, 16.7 mL, 41.7 mmol) was added
dropwise to a solution of the propargyl ether 15 (6.100 g,
41.7 mmol) in dry THF (40 mL) stirred at 0 ꢁC under N2.
The stirring was continued at 0 ꢁC for 10 min before dry
HMPA (10 mL) was introduced, followed by a solution of
dibromodecane 16 (3.281 g, 10.0 mmol) in dry THF (10 mL).
The stirring was continued at ambient temperature for 48 h.
The reaction was quenched with water. The mixture was ex-
tracted with Et2O. The organic phase was washed with water
and brine, and dried over Na2SO4. Removal of the solvent
and chromatography on silica gel (40:1 PEeEt2O) gave the
bisbenzyl ether 17 (4.219 g, 0.20 mmol, 92%) as a yellow
oil: 1H NMR (300 MHz, CDCl3) d 7.38e7.26 (m, 10H),
4.59 (s, 4H), 4.16 (t, J¼2.3 Hz, 4H), 2.26e2.20 (m, 4H),
1.56e1.41 (m, 4H), 1.38e1.26 (m, 16H); 13C NMR
(75 MHz, CHCl3) d 137.6, 128.3, 128.0, 127.7, 87.3, 75.7,
71.3, 57.7, 29.6, 29.5, 29.1, 28.8, 28.6, 18.7; FTIR (film)
3087, 3030, 2927, 2854, 1496, 1454, 1072, 736 cmꢀ1. EIMS
m/z (%) 367 ([MꢀBn]+, <0.7), 91 (100). Anal. Calcd for
C32H42O2: C, 83.79; H, 9.23. Found C, 84.06; H, 9.41.
4.3. Conversion of bisbenzyl ether 17 into diol 18
4.6. Synthesis of alkene 10 from iodide 20
A mixture of 17 (2.440 g, 5.32 mmol) and 10% PdeC
(244 mg) in THF (20 mL) in a stainless steel bomb was stirred
t-BuOK (1.564 g, 14.0 mmol) was added in one portion to
a solution of 20 (1.362 g, 2.67 mmol) in dry THF (20 mL) and

G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
4413
stirred at ambient temperature. When TLC showed completion
of the reaction, H2O (5 mL) was added, followed by EtOAc
(100 mL). The phases were separated. The organic layer was
washed with water and brine before being dried over NaSO4.
Rotary evaporation and column chromatography (PE) afforded
the terminal alkene 10 (803 mg, 2.10 mmol, 79%) as a color-
(s, 42H), 0.89 (s, 9H), 0.88 (t, J¼7.1 Hz, 3H), 0.06 (s, 6H);
13C NMR (75 MHz, CHCl3) d 129.9 (2C’s), 63.3, 32.9, 31.9,
29.8e29.3 (all the remaining/unresolved alkyl carbons), 27.2
(2C’s), 26.0, 25.8, 22.7, 18.4, 14.1, ꢀ5.3; FTIR (film) 3004
(w), 1464, 1255, 1102, 836, 761 cmꢀ1; EIMS m/z (%) 465
([MꢀC4H3]þ, 12.6), 325 (56), 297 (8), 105 (100), 75 (87);
EIHRMS calcd for C30H61OSi ([MꢀC4H9]þ): 465.4492;
found: 465.4499.
1
less oil: H NMR (300 MHz, CDCl3) d 5.82 (ddt, J¼17.1,
10.2, 6.6 Hz, 1H), 5.02e4.90 (m, 2H), 3.60 (t, J¼6.6 Hz,
2H), 2.05 (dt, J¼6.6 Hz, 2H), 1.58e1.42 (m, 2H), 1.26 (s,
26H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CHCl3)
d 139.3, 114.1, 63.3, 33.8, 32.9, 29.7e29.2 (all the remaining/
unresolved alkyl carbons), 28.94, 26.0, 25.8, 18.4, ꢀ5.3; FTIR
(film) 2927, 2855, 1464, 1255, 1102, 836, 775 cmꢀ1; EIMS
m/z (%) 367 ([MꢀCH3]þ, 0.74), 325 (32), 297 (7), 75 (100),
55 (14); EIHRMS calcd for C23H47OSi ([MꢀCH3]þ):
367.3396; found: 367.3404.
4.9. Removal of the TBS group in 21 (22)
A solution of the alkene 21 (378 mg, 0.72 mmol) and
TBAF (1.0 M solution in THF, 1.44 mL) in dry THF (5 mL)
was stirred at ambient temperature for 2 h. H2O (5 mL) was
then added to the reaction mixture, followed by Et2O. The
phases were separated. The organic layer was washed with
water, brine, and dried over anhydrous Na2SO4. Removal of
the solvent and flash chromatography (4:1 PEeEtOAc) gave
the alcohol 22 (280 mg, 0.69 mmol, 95%) as a white solid:
mp 46e48 ꢁC. 1H NMR (300 MHz, CDCl3) d 5.34 (t, J¼
4.5 Hz, 2H), 3.64 (t, J¼6.5 Hz, 2H), 2.00 (m, 4H), 1.59e1.53
(m, 2H), 1.26 (s, 42H), 0.88 (t, J¼6.6 Hz, 3H); 13C NMR
(75 MHz, CHCl3) d 129.9 (2C’s), 63.1, 32.8, 31.9, 29.8e
29.3 (all the remaining/unresolved alkyl carbons), 27.2 (2C’s),
4.7. Transformation of alkyne 14 into cis vinyl iodide 11
DIBAL-H (1.0 M solution in cyclohexane, 6.5 mL) was
added to a solution of anhydrous InCl3 (1.499 g, 6.75 mmol)
in dry THF (20 mL) and stirred at ꢀ78 ꢁC under N2. The
stirring was continued at that temperature for 0.5 h. Alkyne
14 (651 mg, 4.72 mmol) was then added, followed by Et3B
(1.0 M solution in THF, 1.0 mL). After stirring at ꢀ78 ꢁC
for another 3 h, iodine (7.62 g, 30.0 mmol) was introduced.
The stirring was continued at ꢀ78 ꢁC for 30 min. The mixture
was poured into aq saturated NaHCO3. The excess I2 was
decomposed by addition of aq saturated NaS2O3. The mixture
was filtered through Celite. The filtrate was extracted with
Et2O. The phases were separated. The organic layer was
washed with water and brine, and dried over Na2SO4. Rotary
evaporation and chromatography on silica gel (n-hexane)
yielded the known vinyl iodide 116 (1.045 g, 3.93 mmol, 83%)
25.7, 22.7, 14.1; FTIR (KBr) 3327, 2920, 2851, 719 cmꢀ1
;
EIMS: m/z (%) 390 ([MꢀH2O]þ, 2.19), 110 (20), 96 (67),
92 (74), 69 (69), 55 (100), 41 (64); EIHRMS calcd for
C28H54 ([MꢀH2O]þ): 390.4226; found: 390.4228.
4.10. PDC oxidation of 22 (9)
A mixture of 22 (95 mg, 0.233 mmol) and PDC (524 mg,
1.39 mmol) in dry DMF (5 mL) was stirred at ambient temper-
ature until TLC showed completion of the reaction. Water
(10 mL) was then added to the mixture, followed by Et2O.
The phases were separated. The organic layer was washed
with water, brine, and dried over anhydrous Na2SO4. Rotary
evaporation and column chromatography on silica gel (6:1 to
3:1 PEeEtOAc) afforded the acid 9 (85 mg, 0.201 mmol,
1
as a colorless oil: H NMR (300 MHz, CDCl3) d 6.18e6.15
(m, 2H), 2.16e2.10 (m, 2H), 1.43e1.27 (m, 12H), 0.89 (t, J¼
6.6 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 141.4, 82.1, 34.7,
31.8, 29.4, 29.2, 29.1, 27.9, 22.7, 14.1.
1
4.8. Suzuki coupling between 10 and 11 (21)
86%) as a white solid: mp 46e47 ꢁC. H NMR (300 MHz,
CDCl3) d 5.34 (t, J¼4.5 Hz, 2H), 2.34 (t, J¼7.4 Hz, 2H),
2.02e1.98 (m, 4H), 1.63 (m, 2H), 1.25 (s, 40H), 0.88 (t,
J¼6.8 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 180.3, 129.9
(2C’s), 34.1, 31.9, 29.8e29.1 (all the remaining/unresolved al-
kyl carbons), 27.2 (2C’s), 24.7, 22.7, 14.1; FTIR (KBr) 3449,
2918, 2850, 1696, 1472, 942, 718 cmꢀ1; ESIMS m/z 421.3
([MꢀH]ꢀ). ESIHRMS calcd for C28H54NaO2 ([MþNa]þ):
445.4016; found: 445.4014.
A solution of 9-BBN (0.5 M solution in THF, 1.0 mL,
0.5 mmol) and the terminal olefin 10 (76 mg, 0.2 mmol) in
dry THF (2 mL) was stirred at ambient temperature for 3 h be-
fore aq NaOH (1 N, 0.6 mL) was added. The stirring was con-
tinued at ambient temperature for an additional 30 min. The
reaction mixture was then transferred via a syringe to a mixture
of vinyl iodide 11 (48 mg, 0.18 mmol) and Pd(PPh3)2Cl2
(28 mg, 0.04 mmol) in THFeH2O (3:1 v/v, 2 mL). The result-
ing mixture was stirred at ambient temperature for 1 h. The
solids were filtered off through Celite. The filtrate was washed
in turn with 1 N aq NaOH, H2O, and brine, before being dried
over anhydrous Na2SO4. Rotary evaporation and flash chroma-
tography on silica gel (n-hexane) gave the cis alkene 21
(84 mg, 0.16 mmol, 89%) as a colorless oil: 1H NMR
(300 MHz, CDCl3) d 5.34 (t, J¼4.5 Hz, 2H), 3.60 (t, J¼
6.7 Hz, 2H), 2.04e1.98 (m, 4H), 1.53e1.43 (m, 2H), 1.26
4.11. Acylation of chiral auxiliary 8a with acid 9 (5a)
DCC (132 mg, 0.642 mmol, 1.5 equiv) was added in one
portion to a suspension of the acid 9 (181 mg, 0.428 mmol),
DMAP (10 mg, 0.086 mmol, 0.2 equiv), and the chiral auxil-
iary 8a (91 mg, 0.471 mmol, 1.1 equiv) in dry CH2Cl2
(1 mL) and stirred at 0 ꢁC. The mixture was stirred at the
same temperature for 10 min and then at ambient temperature

4414
G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
until TLC showed full consumption of the starting 9. The mix-
ture was filtered through Celite. The filtrate was concentrated
and chromatographed on silica gel (5:1 PEeCH2Cl2) to yield
5a (217 mg, 0.363 mmol, 85%) as a colorless oil: [a]2D7 ꢀ52.8
(c 0.85, CHCl3). 1H NMR (300 MHz, CDCl3) d 7.34e7.21 (m,
5H), 5.35 (t, J¼4.8 Hz, 2H), 4.97e4.89 (m, 1H), 4.35e4.25
(m, 2H), 3.44e3.18 (m, 3H), 2.76 (dd, J¼13.4, 10.0 Hz,
1H), 2.02e1.95 (m, 4H), 1.78e1.67 (m, 2H), 1.26 (s, 40H),
0.89 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 185.4,
174.2, 135.3, 129.9 (2C’s), 129.4, 129.0, 127.4, 70.2, 59.9,
37.6, 37.5, 31.9, 29.7e29.0 (all the remaining/unresolved al-
kyl carbons), 27.2 (2C’s), 24.4, 22.7, 14.1; FTIR (KBr)
3064, 2924, 2853, 1702, 1465, 1366, 1324, 1192, 967,
743, 701 cmꢀ1; ESIMS: m/z 620.2 ([MþNa]þ). ESIHRMS
calcd for C38H63NO2SNa ([MþNa]þ): 620.4472; found:
620.4479.
The combined organic phases were washed in turn with water
and brine before being dried over anhydrous Na2SO4. Rotary
evaporation and column chromatography on silica gel (6:1
PEeEtOAc) gave 1a (21 mg, 44.0 mmol, 88%) as a white
1
powder: mp 52e53 ꢁC. [a]D27 17.9 (c 0.8, CHCl3). H NMR
(300 MHz, CDCl3) d 5.35 (t, J¼4.8 Hz, 2H), 4.62 (dq,
J¼4.9, 6.6 Hz, 1H), 4.19 (m, 1H), 2.53 (m, 1H), 2.01 (m,
5H), 1.79e1.70 (m, 1H), 1.63e1.58 (m, 1H), 1.55e1.42
(m, 2H), 1.40 (d, J¼6.2 Hz, 3H), 1.25 (s, 38H), 0.88 (t,
J¼7.0 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 177.7, 129.9
(2C’s), 78.2, 74.1, 49.2, 31.9, 29.8e29.3 (all the remaining/un-
resolved alkyl carbons), 28.4, 27.3, 27.2 (2C’s), 22.7, 14.1,
13.9; FTIR (KBr) 3435, 2926, 2850, 1759, 1472, 1194,
1050, 963, 719 cmꢀ1; ESIMS m/z 479.4 ([MþH]þ), 501.4
([MþNa]þ). ESIHRMS calcd for C31H58O3Na ([MþNa]þ):
501.4278; found: 501.4287.
4.12. Aldol condensation between 5a and 6a (4a)
4.14. Conversion of 1a into 2a
Freshly distilled TiCl4 (42 mL, 0.381 mmol) was added via
a syringe to a solution of 5a (217 mg, 0.363 mmol) in dry
CH2Cl2 (3 mL) and stirred at ambient temperature under an ar-
gon atmosphere. The resulting yellow solution was stirred for
5 min before neat (ꢀ)-sparteine (0.21 ml, 0.908 mmol) was
added dropwise (giving a purple solution). After stirring at
ambient temperature for 20 min, the reaction flask was placed
into a ꢀ78 ꢁC cooling bath. With stirring, a solution of alde-
hyde 6a (340 mg, 1.81 mmol) in dry CH2Cl2 (1 mL) was intro-
duced via syringe. The resultant mixture was stirred at ꢀ78 ꢁC
for 2 h and at 0 ꢁC for another 2 h. The reaction was quenched
with aq NH4Cl. The mixture was filtered through Celite. The
filtrate was washed in turn with water and brine. The organic
phase was dried over anhydrous Na2SO4. Rotary evaporation
and column chromatography on silica gel (8:1 PEeEA)
yielded the aldol 4a (204 mg, 0.26 mmol, 71%) as a colorless
oil: [a]2D7 ꢀ23.9 (c 1.95, CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.34e7.25 (m, 5H), 5.35 (t, J¼4.6 Hz, 2H), 4.95 (m, 1H),
4.86 (m, 1H), 4.33e4.19 (m, 2H), 3.87e3.73 (m, 2H), 3.31
(dd, J¼13.4, 3.1 Hz, 1H), 2.76 (dd, J¼13.2, 10.6 Hz, 1H),
2.46 (d, J¼6.0 Hz, 1H), 2.08e1.96 (m, 4H), 1.79e1.64 (m,
1H), 1.49e1.41 (m, 1H), 1.38e1.21 (s, 43H), 0.89 (s, 9H),
0.88 (t, J¼7.4 Hz, 3H), 0.07 (d, J¼7.4 Hz, 6H); 13C NMR
(75 MHz, CHCl3) d 184.7, 175.1, 135.3, 129.9 (2C’s), 129.4,
129.0, 127.4, 74.9, 70.0, 69.9, 60.4, 45.3, 37.6, 31.9, 29.9e
29.3 (all the remaining/unresolved alkyl carbons), 27.2
(2C’s), 26.6, 26.4, 25.8, 22.7, 20.6, 17.9, 14.1, ꢀ3.9, ꢀ4.9;
FTIR (film) 3544, 3064, 2925, 2854, 1694, 1497, 1372, 1321,
964, 837, 778, 744 cmꢀ1; ESIMS m/z 786.7 ([MþH]þ).
ESIHRMS calcd for C47H84NO4SSi ([MþH]þ): 786.5885;
found: 786.5889.
Et3N (44 mL, 0.314 mmol) and MsCl (27 mL, 0.314 mmol)
were added dropwise to a solution of 1a (15 mg, 0.031 mmol)
in dry CH2Cl2 (1.5 mL) and stirred in an ice-water bath. The
cooling bath was removed. The mixture was stirred at ambient
temperature for 5 h. H2O (5 mL) and Et2O (20 mL) were
added to the reaction mixture. The phases were separated.
The aqueous phase was back-extracted with Et2O
(3$10 mL). The combined organic phases were washed with
brine and dried over anhydrous Na2SO4. The solvent was re-
moved by rotary evaporation. The residue was dissolved in
dry acetone (2 mL) and treated with TBAF (1.0 M solution
in THF, 102 mL, 3.0 equiv) at ambient temperature until
TLC showed completion of the reaction. H2O (5 mL) and
Et2O (10 mL) were added. The phases were separated. The
aqueous phase was back-extracted with Et2O (3$10 mL). After
removal of the solvent, the residue was chromatographed on
silica gel (15:1 PEeEt2O) to give 19 as a white powder
(13 mg, 90% from 1a): mp 25e26 ꢁC. [a]D27 ꢀ16.6 (c 0.85,
1
CHCl3). H NMR (300 MHz, CDCl3) d 6.99 (s, 1H), 5.34
(m, 2H), 5.00 (m, 1H), 2.27 (t, J¼7.0 Hz, 2H), 2.01 (m, 4H),
1.54e1.42 (m, 2H), 1.40 (d, J¼6.6 Hz, 3H), 1.26 (s, 38H),
0.88 (t, J¼6.5 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 173.0,
148.8, 134.3, 129.9 (2C’s), 77.4, 31.9, 29.8e29.2 (all the re-
maining/unresolved alkyl carbons), 27.4, 27.2 (2C’s), 25.2,
22.7, 19.2, 14.1; FTIR (KBr) 2925, 2853, 1762, 1465, 1317,
1075, 951, 856, 721 cmꢀ1; ESIMS m/z 461.3 ([MþH]þ),
483.3 ([MþNa]þ). ESIHRMS calcd for C31H57O2 ([MþH]þ):
461.4353; found: 461.4369.
4.15. Acylation of 8b with acid 9 (5b)
The procedure was the same as that for synthesis of 5a
given above. Yield: 82%. Data for 5b: [a]2D7 þ51.9 (c 1.45,
4.13. Synthesis of 1a
1
CHCl3). H NMR (300 MHz, CDCl3) d 7.37e7.21 (m, 5H),
A solution of 4 (39 mg, 49.7 mmol) and HCl (4 N, 0.10 mL,
0.40 mmol, 8.0 equiv) in THF (2 mL) was stirred at ambient
temperature for 12 h. After neutralization with aq saturated
NaHCO3, the mixture was extracted with Et2O (three times).
5.35 (t, J¼4.8 Hz, 2H), 4.96e4.90 (m, 1H), 4.33e4.25 (m,
2H), 3.38e3.18 (m, 3H), 2.76 (dd, J¼13.3, 10.1 Hz, 1H),
2.02e1.91 (m, 4H), 1.75e1.68 (m, 2H), 1.26 (s, 40H), 0.89
(t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 185.3,

G.-B. Ren, Y. Wu / Tetrahedron 64 (2008) 4408e4415
4415
174.1, 135.3, 129.83, 129.81, 129.4, 128.9, 127.3, 70.2, 59.9,
37.6, 37.5, 31.9, 29.7e29.0 (all the remaining/unresolved
alkyl carbons), 27.2 (2C’s), 24.4, 22.6, 14.1; FTIR (KBr)
2924, 2853, 1700, 1465, 1456, 1400, 1367, 1324, 1192, 967,
3H); 13C NMR (75 MHz, CHCl3) d 173.9, 148.8, 134.3, 129.8
(2C’s), 77.4, 31.9, 29.7e29.2 (all the remaining/unresolved al-
kyl carbons), 27.3, 27.2 (2C’s), 25.1, 22.6, 19.2, 14.1; FTIR
(KBr) 2925, 2853, 1760, 1318, 1027 cmꢀ1; ESIMS m/z
461.4 ([MþH]þ), 483.4 ([MþNa]þ). ESIHRMS calcd for
C31H56O2Na ([MþNa]þ): 483.4173; found: 483.4174.
743, 722, 701 cmꢀ1
;
ESIMS m/z 620.2 ([MþNa]þ).
ESIHRMS calcd for C38H63NO2SNa ([MþNa]þ): 620.4472;
found: 620.4470.
Acknowledgements
4.16. Aldol condensation between 5b and 6b (4b)
This work was supported by the National Natural Science
Foundation of China (20372075, 20321202, 20672129,
20621062, 20772143) and the Chinese Academy of Sciences
(‘Knowledge Innovation’, KJCX2.YW.H08).
The procedure was the same as that for synthesis of 4a given
above. Yield: 67%. Data for 4b: [a]2D7 þ23.8 (c 1.85, CHCl3).
1H NMR (300 MHz, CDCl3) d 7.34e7.23 (m, 5H), 5.35 (t,
J¼4.6 Hz, 2H), 4.95 (m, 1H), 4.86 (m, 1H), 4.33e4.16 (m,
2H), 3.87e3.75 (m, 2H), 3.31 (dd, J¼13.0, 3.0 Hz, 1H), 2.76
(dd, J¼13.1, 10.0 Hz, 1H), 2.45 (d, J¼6.0 Hz, 1H), 2.05e
1.99 (m, 4H), 1.78e1.64 (m, 1H), 1.49e1.41 (m, 1H), 1.26
(s, 43H), 0.89 (s, 9H), 0.88 (t, J¼7.4 Hz, 3H), 0.07 (d,
J¼7.4 Hz, 6H); 13C NMR (75 MHz, CHCl3) d 184.7, 175.1,
135.3, 129.9 (2C’s), 129.4, 129.0, 127.4, 74.9, 70.0, 69.9,
60.4, 45.3, 37.6, 31.9, 29.9e29.3 (all the remaining/unresolved
alkyl carbons), 27.2 (2C’s), 26.6, 26.4, 25.8, 22.7, 20.6, 17.9,
14.1, ꢀ3.9, ꢀ4.9; FTIR (film) 3544, 3064, 2925, 2854, 1694,
1497, 1372, 1321, 964, 837, 778, 744 cmꢀ1; ESIMS m/z
808.5 ([MþNa]þ). ESIHRMS calcd for C47H83NO4SSiNa
([MþNa]þ): 808.5704; found: 808.5709.
References and notes
1. Ming, D. S.; Lopez, A.; Hillhouse, B. J.; French, C. J.; Hudson, J. B.;
Towers, G. H. N. J. Nat. Prod. 2002, 65, 1412e1416.
2. See, e.g.: (a) Wu, Y.-K.; Shen, X.; Tang, C.-J.; Chen, Z.-L.; Hu, Q.; Shi,
W. J. Org. Chem. 2002, 67, 3802e3810; (b) Wu, Y.-K.; Shen, X.; Yang,
Y.-Q.; Hu, Q.; Huang, J.-H. J. Org. Chem. 2004, 69, 3857e3865; (c) Wu,
Y.-K.; Sun, Y.-P. Chem. Commun. 2005, 1906e1908; (d) Yang, Y.-Q.; Wu,
Y.-K. Chin. J. Chem. 2005, 23, 1519e1522; (e) Sun, Y.-P.; Wu, Y.-K. Syn-
lett 2005, 1477e1479 (and erratum Synlett 2006, 1132); (f) Wu, Y.-K.;
Sun, Y.-P. J. Org. Chem. 2006, 71, 5748e5751; (g) Wu, Y.-K.; Sun,
Y.-P. Org. Lett. 2006, 8, 2831e2834; (h) Wu, Y.-K.; Yang, Y.-Q. J. Org.
Chem. 2006, 71, 4296e4301; (i) Shen, X.; Yang, Y.-Q.; Hu, Q.; Huang,
J.-H.; Gao, J.; Wu, Y.-K. Chin. J. Chem. 2007, 25, 802e807.
3. (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883e7884; (b) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc.
1998, 120, 9084e9085.
4.17. Synthesis of 1b
4. Wu, Y.-K.; Yang, Y.-Q.; Hu, Q. J. Org. Chem. 2004, 69, 3990e3992.
5. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A.
J. Am. Chem. Soc. 1989, 111, 314e321.
The procedure was the same as that for synthesis of 1a from
4a given above. Yield: 89%. Data for 1b: mp 53e54 ꢁC (lit.1
53e54 ꢁC). [a]D28 ꢀ18.3 (c 1.65, CHCl3) (lit.1 [a]2D0 ꢀ13 (c 1.0,
6. (a) Coleman, B. E.; Cwynar, V.; Hart, D. J.; Havas, F.; Mohan, J. M.;
Patterson, S.; Ridenour, S.; Schmidt, M.; Smith, E.; Wells, A. J. Synlett
2004, 1339e1342; (b) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975,
40, 1083e1090.
1
CHCl3)). H NMR (300 MHz, CDCl3) d 5.35 (t, J¼4.7 Hz,
2H), 4.62 (dq, J¼4.8, 6.4 Hz, 1H), 4.19 (ddd, J¼3.9, 4.3,
4.6 Hz, 1H), 2.53 (m, 1H), 2.50e2.36 (br, 1H), 2.02e1.93 (m,
4H), 1.74e1.68 (m, 1H), 1.59e1.52 (m, 1H), 1.50e1.41 (m,
2H), 1.40 (d, J¼6.7 Hz, 3H), 1.39e1.20 (s, 38H), 0.87 (t,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CHCl3) d 178.0, 129.8
(2C’s), 78.4, 73.9, 49.3, 31.9, 29.7e29.1 (all the remaining/
unresolved alkyl carbons), 28.4, 27.22, 27.15 (2C’s), 22.6,
14.1, 13.8; FTIR (KBr) 3445, 2918, 2850, 1759, 1472, 1207,
1051, 986, 718 cmꢀ1; ESIMS: m/z 501.4 ([MþNa]þ).
ESIHRMS calcd for C31H58O3Na ([MþNa]þ): 501.4278;
found: 501.4277.
7. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173e2174.
8. Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2003, 68, 6627e6631.
9. Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito, S.
J. Org. Chem. 2003, 68, 3702e3705.
10. Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690e4691.
11. (a) King, A. O.; Negishi, E.-i.; Villani, F. J., Jr.; Silveira, A., Jr. J. Org.
Chem. 1978, 43, 358e360; (b) Tsuji, J. Organic Synthesis with Palladium
Compounds; Springer: New York, NY, 1980; p 3.
12. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399e402.
13. Andrade, C. K. Z.; Rocha, R. O.; Vercillo, O. E.; Silva, W. A.; Matos,
R. A. F. Synlett 2003, 2351e2352.
14. However, the vicinal coupling (9.4 Hz) between the two cis olefinic pro-
tons at d 5.33 (dt, J¼9.6, 4.6 Hz, 2H) reported in the Ref. 1 is absent in
our spectrum (cf. Fig. 1). To our knowledge if two vicinal or geminal
protons have an identical chemical shift in 1H NMR, no line-splitting
corresponding to the coupling between them can be observed.
15. The intermediates prepared using the cisetrans mixture of 9 showed
identical 1H and 13C NMR and [a]D data to those prepared from pure
cis-9.
4.18. Conversion of 1b into 2b
The procedure was the same as that for synthesis of 2a from
1a given above. Yield: 94% from 1b. Data for 2b: mp 26e
27 ꢁC. [a]2D7 þ16.2 (c 1.55, CHCl3). 1H NMR (300 MHz,
CDCl3) d 6.99 (d, J¼1.1 Hz, 1H), 5.34 (t, J¼4.8 Hz, 2H), 5.00
(m, 1H), 2.26 (t, J¼7.5 Hz, 2H), 2.01 (m, 4H), 1.57e1.41 (m,
2H), 1.40 (d, J¼6.7 Hz, 3H), 1.26 (s, 38H), 0.88 (t, J¼7.2 Hz,
16. Pattision, F. L. M.; Howell, W. C.; Mcnamara, A. J.; Schneider, J. C.;
Walker, J. F. J. Org. Chem. 1956, 21, 739e747.