Total synthesis of bongkrekic acid via sequential suzuki-miyaura coupling reactions

Article abstract of DOI:10.1055/s-0029-1216928

An efficient total synthesis of (+)-bongkrekic acid, a potent apoptosis inhibitor, has been accomplished by employing a convergent strategy based on the Suzuki-Miyaura coupling of three fully functionalized segments. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216928

PAPER
2893
Total Synthesis of Bongkrekic Acid via Sequential Suzuki–Miyaura Coupling
Reactions
Total
S
ynthesis of Bon
a
gkrekic
A
c
k
id oto Kanematsu,a Mitsuru Shindo,b Masahiro Yoshida,a Kozo Shishido*a
a
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337287; E-mail: shishido@ph.tokushima-u.ac.jp
b
Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga 816-8580, Japan
Received 12 July 2009
middle (3) and the right (4). We planned to combine the
left and middle segments first by the Suzuki–Miyaura
coupling and then the C12–13 vinyl borate, derived from
the coupled segment (C1–C12), would be connected to
the right segment 4, again employing the same coupling
procedure. For the right segment, we envisioned two can-
didates, 4a and 4b. The choice of methoxymethyl (MOM)
and tert-butyl esters as protective groups at the C17 and
C22 carboxylic acid moieties was prompted by the neces-
sity to deprotect under acidic conditions at the final step.
The three segments 2, 3 and 4 would, in turn, be derived
from readily available 5-(tert-butyldimethylsilyl-
oxy)pent-2-yn-1-ol (5), 4-(benzyloxy)butan-1-ol (6) and
(R)-O-benzyl glycidyl ether (7), respectively.
Abstract: An efficient total synthesis of (+)-bongkrekic acid, a po-
tent apoptosis inhibitor, has been accomplished by employing a
convergent strategy based on the Suzuki–Miyaura coupling of three
fully functionalized segments.
Key words: apoptosis, conjugated diene, Suzuki–Miyaura cou-
pling, palladium, bongkrekic acid
Bongkrekic acid (BA; 1) is a toxic antibiotic produced by
the microorganism Burkholderia cocovenenans on par-
tially defatted coconut.1a It was discovered to be the factor
responsible for fatal food poisoning, and the high toxicity
has been attributed to its affinity for the ATP/ADP trans-
locator protein residing in the mitochondrial inner mem-
brane, which prevents oxidative phosphorylation
(IC50 = 2 × 10–8 M).2 In 1996, it was revealed that BA pre-
vents a number of phenomena linked to apoptosis: deple-
tion of nonoxidized glutathione, generation of reactive
oxygen species, translocation of NFkB, exposure of phos-
phatidylserine residues on the outer plasma membrane,
cytoplasmic vacuolization, chromatin condensation, and
oligonucleosomal DNA fragmentation.3 BA is also an ef-
ficient inhibitor of p53-dependent thymocyte apoptosis
induced by DNA damage.3 Since then, BA has become a
major biochemical tool for the investigation of apoptosis.
The structure of 1 was assigned as 3-carboxymethyl-17-
methoxy-6,18,21-trimethyldocosa-2,4,8,12,14,18,20-hep-
taenedioic acid by extensive NMR and MS studies.1b–d
The main structural features of the molecule are two
conjugated Z,E-dienoic acids, a Z,E-diene and two stereo-
genic centers at C6 and C17, which were determined to be
S and R, respectively, by a combination of NMR and CD
studies1d and by degradation studies.1e Owing to its char-
acteristic biological profile, the unique structural features
and limited availability by fermentation, BA (1) has been
a fascinating target of synthetic studies. The previous total
syntheses were reported by Corey4 in 1984 and our group5
in 2004. We now report an alternative total synthesis of
BA (1), featuring a three-segment coupling strategy em-
ploying the Suzuki–Miyaura protocol.6
22
CO2H
Suzuki–Miyaura
coupling
CO2H
3
1
OMe
17
14
4
6
13
CO2H
24
bongkrekic acid (1)
1
CO2MOM
I
HO
OTBS
OTBS
left segment (
5
2)
12
4
O
OBn
B
OH
HO
O
6
middle segment (
22
3)
CO2R
OMe
O
14
OBn
I
7
right segment (
4)
4a: R = tBu; 4b; R = MOM
Scheme 1
For the preparation of the left segment (2), the propargylic
alcohol 55 was initially subjected to the hydroalumination/
iodination reaction8 with Red-Al®, potassium tert-butox-
ide (t-BuOK)9 and iodine to provide the (Z)-iodide 8. The
stereochemistry was confirmed by a diagnostic NOE be-
tween the olefinic proton and the methylene protons. Se-
quential oxidation with manganese dioxide and sodium
Scheme 1 shows the retrosynthetic perspective based on
the dissection of 1 into three segments, the left (2), the
SYNTHESIS 2009, No. 17, pp 2893–2904
x
x.
x
x
.
2
0
0
9
Advanced online publication: 07.08.2009
DOI: 10.1055/s-0029-1216928; Art ID: C03009SS
© Georg Thieme Verlag Stuttgart · New York

2894
M. Kanematsu et al.
PAPER
nesium chloride in the presence of copper(I) iodide16 pro-
vided the homoallyl alcohol, which was reacted with
sodium hydride/iodo methane to produce (R)-21.17 After
ozonolysis, followed by reductive workup, the resulting
alcohol 22 was protected as the tert-butyldimethylsilyl
(TBS) ether 23. Debenzylation under Birch conditions,
followed by Swern oxidation and dibromoalkenylation,
furnished 26, which was converted into the ynolate 27 by
treatment with n-BuLi and methyl chloroformate.18 Con-
jugate addition19 of the methyl function using methyllith-
ium and copper(I) iodide, provided the (Z)-enoate 28,
whose stereochemistry was determined by the observed
NOE between the olefinic proton and the methyl group.
On exposure of the alcohol 29, prepared by reduction with
diisobutylaluminum hydride (DIBAL-H), to a mixture of
manganese dioxide and tert-butyl 2-(triphenylphosphora-
nylidene)propionate,20 the (Z,E)-diene 30 was produced in
excellent yield and with good stereoselectivity. Since the
desilylation of 30 with tetrabutylammonium fluoride re-
sulted in the isomerization of the conjugated dienoate
moiety, acidic conditions were required. As a result, treat-
ment of 30 with dilute hydrochloric acid in tetrahydrofu-
ran at room temperature provided the alcohol 31
quantitatively. DMP-mediated oxidation gave the alde-
hyde 32, which was reacted with the Wittig ylide prepared
in situ from triphenyl(iodomethyl)phosphonium iodide
and NaHMDS, to yield the vinyl iodide 4a with good (Z)-
selectivity (>20:1 by 1H NMR).21 At this stage, the stereo-
chemistry of the dienoate portion was established by the
observed NOEs shown in Scheme 4. Acidic hydrolysis of
the tert-butyl ester moiety in 4a under a variety of condi-
tions (e.g. aq HCl, HCl/Et2O, TFA, etc.), was unsuccess-
ful. When the reaction was conducted in formic acid
without solvent,22 the requisite carboxylic acid 33 was ob-
tained. It was then transformed into the MOM ester 4b,
which is another candidate for the right-hand segment, in
89% yield for the two steps (Scheme 4).
CH2OH
I
Red-Al®, tBuOK
then I2
H
5
Et2O, –50 °C to r.t.
79%
OTBS
H
H
NOE
8
R
1) MnO2, CH2Cl2, r.t.
MOMCl,
iPr2NEt
I
2
CH2Cl2, r.t.
92% (3 steps)
2) NaClO2, NaH2PO4
2-methylbut-2-ene
tBuOH, THF, H2O, r.t.
OTBS
9: R = CHO
10: R = CO2H
Scheme 2
chlorite (NaClO2)10 gave the carboxylic acid 10, which
was converted into the MOM ester 2 in good overall yield.
(Scheme 2)
The key to the preparation of the central segment 3 was
the construction of the C6-stereogenic center. According-
ly, we planned to use a diastereoselective alkylation em-
ploying the Evans’ oxazolidinone chiral auxiliary 14.11
The alcohol 612 was converted into the allyl alcohol 11 by
Swern oxidation, followed by vinylation. Johnson Claisen
rearrangement13 of 11 provided the ester 12,14 which was
condensed with the (S)-oxazolidinone 14 to give 15 in ex-
cellent overall yield. Treatment of 15 with sodium hexa-
methyldisilazide (NaHMDS) and methyl iodide afforded
the methylated product 16 in 86% yield and good diaste-
reoselectivity (>20:1 by 1H NMR). Reduction with lithi-
um aluminum hydride, followed by oxidation with Dess–
Martin periodinane (DMP) produced the aldehyde 18. The
elaboration of the aldehyde to the required vinyl borate
was achieved using the procedure developed by Takai.15
Thus, treatment of 18 with 19, catalytic chromium(II)
chloride, manganese, lithium iodide and trimethylsilyl
chloride (TMSCl), provided 20 in 70% yield from the al-
cohol 17. Debenzylation with the BCl3·SMe2 complex
gave the central segment alcohol 3 (Scheme 3).
With the three fully functionalized segments 2, 3 and 4 in
hand, we advanced to the coupling phase in order to com-
plete the total synthesis. Reaction of the iodide 2 with the
borate 3, in the presence of bis(triphenylphosphine)palla-
Preparation of the right-hand segments (4a,b) containing
another stereogenic center at C17, started from (R)-O-
benzyl glycidyl ether (7). Treatment of 7 with vinylmag-
1) MeC(OEt)3
propionic acid
140 °C, 88%
1) (COCl)2, DMSO
Et3N, CH2Cl2
–78 °C to r.t.
PivCl, Et3N
then LiCl, 14
O
O
OH
OBn
RO2C
OBn
OBn
6
N
O
2)
THF, –78 °C to r.t.
94% (2 steps)
2) LiHOH•H2O
THF, H2O, r.t.
MgCl
12: R = Et
13: R = H
Bn
11
15
THF, 0 °C to r.t.
84% (2 steps)
1) 19, CrCl2 (0.35 equiv)
Mn, LiI, TMSCl, THF
r.t., 70% (2 steps)
1) LiAlH4, THF, 0 °C
90%
O
NaHMDS, MeI
THF, –78 °C
O
OBn
N
R
OBn
O
2) DMP, NaHCO3
CH2Cl2, benzene
0 °C to r.t.
86% (dr > 20:1)
2) BCl3•SMe2
CH2Cl2, 0 °C to r.t.
98%
Bn
17: R = CH2OH
18: R = CHO
16
O
O
B
O
CHCl2
OR
B
NH
Bn
O
O
O
20: R = Bn
3: R = H
19
14
Scheme 3
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Bongkrekic Acid
2895
1) Li, liq. NH3, THF, –33 °C
90% (2 steps)
2) (COCl)2, DMSO, Et3N
CH2Cl2, –78 °C to r.t.
1)
MgCl
CuI, THF
–25 °C to 0 °C
1) O3 then NaBH4
CH2Cl2, MeOH
–78 °C to 0 °C, 95%
OMe
R
OMe
OMe
TBSO
OBn
OBn
7
RO
3) CBr4, Ph3P, iPr2NEt, CH2Cl2
2) TBSCl, imidazole
4-DMAP, CH2Cl2
0 °C
2) NaH, MeI
THF, 0 °C to r.t.
94% (2 steps)
24: R = CH2OH
25: R = CHO
26: R = CH=CBr2
22: R = H
23: R = TBS
0 °C~r.t., 88% (2 steps)
21
1) MnO2, Ph3P=C(Me)CO2tBu
CH2Cl2, benzene, 80 °C
99% (E/Z >99:1)
OMe
R
1) MeLi, CuI, THF
–78 °C, 87%
OMe
nBuLi, ClCO2Me
TBSO
H
TBSO
THF, –78 °C to 0 °C
88%
2) 3 M HCl (aq), THF
r.t., quant.
2) DIBAL-H, THF
–78 °C to 0 °C, 91%
CO2Me
NOE
27
3) DMP, NaHCO3
CH2Cl2, 0 °C to r.t., 98%
28: R = CO2Me
29: R = CH2OH
CO2tBu
1) [Ph3P+CH2I] I–, NaHMDS
HMPA, THF, –78 °C
69% (Z/E >20:1)
CO2R
21
MOMCl, iPr2NEt
OMe
OMe
CH2Cl2, 0 °C to r.t.
R
19
4b
I
H
89% (2 steps)
2) HCO2H, r.t.
30: R = CH2OTBS
31: R = CH2OH
32: R = CHO
NOE
4a: R = tBu
33: R = H
Scheme 4
dium(II) chloride and triethylamine in methanol at room oxidation to the carboxylic acids 39a,b using PDC or 1-
temperature, afforded 34 in 91% yield, which was oxi- methyl-azaadamantan-N-oxyl (1-Me-AZADO)23 resulted
dized to the corresponding aldehyde. Immediate conden- in a complex mixture of products, a stepwise oxidation
sation of the aldehyde with 19 under identical conditions was adopted for the conversion. Thus, 37a,b were oxi-
to those used for the preparation of 20, resulted in forma- dized with DMP to the aldehydes 38a,b, then re-oxidized
tion of the (E)-vinyl borate 35 as a single product. The with sodium chlorite to give 39a,b in 59% and 67% yield,
Suzuki–Miyaura coupling of 35 with the iodides 4a,b was respectively, for the two steps. It should be noted that the
examined, again under the same reaction conditions as be- crude carboxylic acids 39a,b contained a small amount of
fore, to give uneventfully the coupled products 36a,b in unidentified olefinic isomer(s), which could be separated
73% and 84% yield, respectively, without any isomeriza- by column chromatography. For a comparison of the fea-
tion of the olefinic moieties.
sibility of the final acidic hydrolysis to give BA (1), at-
tempted hydrolysis of 39a,b was examined. When 39a
was treated under acidic conditions [e.g. 6 M HCl (aq) in
Desilylation with the hydrogen fluoride–pyridine com-
plex provided the alcohols 37a,b. Since attempted direct
(Ph3P)2PdCl2, Et3N
MeOH, r.t., 91%
1) DMP, NaHCO3
CH2Cl2, 0 °C to r.t., 91%
CO2MOM
CO2MOM
O
R
I
B
OH
+
2) 19, CrCl2 (0.35 equiv)
Mn, LiI, TMSCl, THF
r.t., 71%
O
OTBS
3
OTBS
34: R = CH2OH
35: R = CHO
2
1) HF•pyridine, THF
pyridine, 0 °C to r.t.
for 37a: 84%
for 37b: quant.
2) DMP, CH2Cl2
benzene, 50 °C
CO2R
CO2MOM
4a,b, (Ph3P)2PdCl2
Et3N
CO2MOM
O
OMe
B
O
MeOH, r.t.
for 4a; 73%
for 4b; 84%
3) NaClO2, NaH2PO4
2-methylbut-2-ene
tBuOH, THF, H2O, r.t.
for 38a: 59% (2 steps)
for 38b: 67% (2 steps)
OTBS
OTBS
36
37a: R = tBu
37b: R = MOM
CO2R3
CO2R2
CO2R
OMe
4
CO2R
2
6 M HCl (aq)
OMe
R1
THF, r.t.
83%
38a: R1 = CH2OH; R2 = MOM; R3 = tBu
38b: R1 = CH2OH; R2 = R3 = MOM
39a: R1 = CHO; R2 = MOM; R3 = tBu
39b: R1 = CHO; R2 = R3 = MOM
40a: R1 = CO2H; R2 = MOM; R3 = tBu
40b: R1 = CO2H; R2 = R3 = MOM
41: R1 = CO2H; R2 = H; R3 = tBu
CO2R
CH2N2, Et2O
0 °C, quant.
R = H: bongkrekic acid (1)
42: R = Me
Scheme 5
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

2896
M. Kanematsu et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 135.87, 105.11, 67.23, 61.67,
48.18, 25.85, 18.24, –5.25.
THF, MeOH and CH2Cl2; TFA in CH2Cl2], it did not lead
to 1 but to the dicarboxylic acid 40 in moderate yields. On
the other hand, when the di-MOM ester 39b was treated HRMS (ESI): m/z [M+ + Na] calcd for C11H24O2NaSiI: 343.0590;
found: 343.0586.
with 6 M HCl (aq) in THF at room temperature for three
hours, the required hydrolysis proceeded smoothly to pro-
Methoxymethyl (Z)-5-tert-Butyldimethylsilyloxy-3-iodo-2-pen-
tenoate (2)
25
duce BA (1) {[a]D –51.9 (c 0.62, CHCl3); Lit.1b [a]589
+162.5}24 in 83% yield. The 1H NMR spectra of the syn-
thetic material was completely identical with that of au-
thentic BA. For further confirmation of specific rotation
and optical purity, 1 was converted into the corresponding
trimethyl ester 43 using diazomethane. Its optical rotation,
[a]D +87.2 (c 0.99, CHCl3), was in agreement with those
of the reported {[a]D +80 24; [a]D +80 (c 0.15, CHCl3)5;
[a]D +84 (c 0.24, CHCl3)}.25 Thus, it was confirmed that
the enantioselective total synthesis of BA (1) had been
completed (Scheme 5).
To a solution of 8 (2.18 g, 6.37 mmol) in CH2Cl2 (44 mL) at r.t., was
added MnO2 (8.3 g, 95.53 mmol). The reaction mixture was stirred
at r.t. for 7 h, then filtered through a pad of Celite and concentrated
to give the crude aldehyde 9 as a colorless oil. To a solution of 9 in
t-BuOH–THF–2-methylbut-2-ene (65 mL, 3:1:1) at r.t., was added
a solution of NaClO2 (2.88 g, 31.8 mmol) and NaH2PO4 (3.68 g, 1.7
w/w of aldehyde) in H2O (65 mL). The reaction mixture was stirred
at the same temperature for 5 h, then acidified with aq 3 M HCl
(21.23 mL, 63.69 mmol) and extracted with CH2Cl2 (3 × 50 mL).
The combined extracts were washed with brine (30 mL), dried over
MgSO4, filtered and concentrated. The residue was filtered through
silica gel column chromatography (hexane–EtOAc, 80:20) to give
carboxylic acid 10 as colorless needles (mp 49.8–50.9 °C). To a so-
lution of carboxylic acid 10 in CH2Cl2 (60 mL), was added DIPEA
(6.7 mL, 38.21 mmol) and MOMCl (2.4 mL, 31.84 mmol) at 0 °C.
The resulting mixture was stirred at r.t. for 45 min, then quenched
with H2O (20 mL) and extracted with CH2Cl2 (3 × 30 mL). The
combined extracts were washed with brine (20 mL), dried over
MgSO4, filtered and concentrated. The residue was purified by sili-
ca gel column chromatography (hexane–EtOAc, 95:5) to afford es-
ter 2.
In conclusion, we have accomplished an efficient, second-
generation total synthesis of bongkrekic acid (1) based on
the sequential Suzuki–Miyaura coupling of the three fully
functionalized segments 2, 3 and 4 in 14% overall yield
over 21 steps (longest linear sequence from 7). The
present strategy is convergent and flexible in order to ob-
tain a variety of derivatives and should be applicable to
the general synthesis of related compounds.
Yield: 2.35 g (92% for 3 steps); colorless oil.
All nonaqueous reactions were carried out under a positive atmo-
sphere of argon in dried glassware unless otherwise indicated. Ma-
terials were obtained from commercial suppliers and used without
further purification except when otherwise noted. Solvents were
IR (neat): 2952, 2857, 1736, 1471, 1385, 1099 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.46 (t, J = 1.0 Hz, 1 H), 5.33 (s,
2 H), 3.80 (t, J = 6.0 Hz, 2 H), 3.48 (s, 3 H), 2.93 (td, J = 6.1, 1.2
Hz, 2 H), 0.88 (s, 9 H), 0.06 (s, 6 H).
dried and distilled according to standard protocols. The 1H and 13
C
NMR spectra were recorded at 23 °C on a Jeol JNM-AL400 (1H,
400 MHz; 13C, 100 MHz) or Jeol GSX400 (1H, 400 MHz; 13C, 100
MHz) spectrometer. Chemical shifts are reported in ppm (from
TMS). When peak multiplicities are reported, the following abbre-
viations are used: s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet; br, broadened. IR spectra were recorded on a
Jasco FT/IR 410 spectrophotometer. Mass spectra were obtained on
a Waters Micromass LCT-premier. Optical rotations were deter-
mined on a Jasco P-1010. Melting points were measured on a
Yanaco MP-500D melting point apparatus and are uncorrected.
13C NMR (100 MHz, CDCl3): d = 163.53, 126.29, 118.35, 90.37,
60.98, 57.58, 50.99, 25.73, 18.09, –5.41.
HRMS (ESI): m/z [M+ + Na] calcd for C13H25O4NaSiI: 423.0465;
found: 423.0474.
(3RS)-6-Benzyloxyhex-1-en-3-ol (11)
To a solution of oxalyl chloride (2.3 mL, 26.63 mmol) in CH2Cl2 (25
mL) at –78 °C, was added DMSO (2.6 mL, 33.29 mmol). A solution
of alcohol 6 (2.0 g, 11.1 mmol) in CH2Cl2 (15 mL) was added to the
mixture dropwise and, after 30 min, Et3N (11.6 mL, 88.22 mmol)
was added. After stirring at –78 °C for 10 min, the reaction mixture
was allowed to come to r.t. and stirring was continued for 20 min.
The reaction mixture was diluted with H2O (20 mL) and concentrat-
ed in vacuo. The residue was extracted with Et2O (3 × 50 mL) and
the combined extracts were washed with brine (20 mL), dried over
MgSO4, filtered and concentrated to give the crude aldehyde as a
colorless oil, which was dissolved in THF (50 mL), then cooled to
0 °C. Vinylmagnesium chloride (1.44 M in THF, 11.6 mL, 16.64
mmol) was added dropwise via an addition funnel at 0 °C. The re-
action mixture was stirred at r.t. for 4 h, then quenched with sat. aq
NH4Cl (20 mL) at 0 °C, and extracted with EtOAc (3 × 50 mL). The
combined extracts were washed with brine (20 mL), dried over
MgSO4, filtered and concentrated. The residue was purified by sili-
ca gel column chromatography (hexane–EtOAc, 90:10) to afford al-
lyl alcohol 11.
(Z)-5-tert-Butyldimethylsilyloxy-3-iodo-2-penten-1-ol (8)
To a solution of Red-Al® (65% in toluene, 7.4 mL, 24.6 mmol) in
Et2O (50 mL) at 0 °C, was successively added t-BuOK (125.5 mg,
1.12 mmol) and a solution of 5 (2.40 g, 11.18 mmol) in Et2O (50
mL) dropwise. The reaction mixture was stirred for 2 h at r.t., then
cooled to 0 °C and anhydrous EtOAc (1.25 mL, 12.75 mmol) was
added. The reaction mixture was cooled to –50 °C, and I2 (4.26 g,
16.78 mmol) was added. After stirring for 6 h at r.t., the reaction
mixture was quenched with sat. aq Na2S2O3 (30 mL). The mixture
was stirred at r.t. for 1 h, then filtered through a pad of Celite and
extracted with EtOAc (3 × 75 mL). The combined extracts were
washed with brine (100 mL), dried over MgSO4, filtered and con-
centrated. The residue was purified by silica gel column chromatog-
raphy (hexane–EtOAc, 95:5) to afford allyl alcohol 8.
Yield: 3.02 g (79%); colorless oil.
Yield: 1.93 g (84% for 2 steps); colorless oil.
IR (neat): 3347, 2953, 2928, 1646, 1471, 1109 cm–1.
IR (neat): 3411, 3064, 2924, 2857, 1645, 1604, 1495, 1099, 992,
922, 737, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.92 (t, J = 6.0 Hz, 1 H), 4.19 (t,
J = 6.0 Hz, 2 H), 3.74 (t, J = 6.4 Hz, 2 H), 2.72 (t, J = 6.4 Hz, 2 H),
1.49 (t, J = 6.0 Hz, 1 H, OH, D2O exch.), 0.89 (s, 9 H), 0.06 (s, 6 H).
1H NMR (400 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 5.87 (ddd,
J = 17.2, 10.4, 6.0 Hz, 1 H), 5.23 (dt, J = 17.2, 1.4 Hz, 1 H), 5.10
(dt, J = 10.4, 1.4 Hz, 1 H), 4.52 (s, 2 H), 4.17–4.11 (m, 1 H), 3.52
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Bongkrekic Acid
2897
(t, J = 6.0 Hz, 2 H), 2.29 (d, J = 4.4 Hz, 1 H, OH, D2O exch.), 1.77–
1.59 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 172.48, 153.26, 138.49, 135.14,
130.97, 129.24, 128.75, 128.39, 128.15, 127.42, 127.28, 127.14,
72.64, 69.52, 65.98, 54.92, 37.70, 35.32, 29.26, 28.91, 27.01.
13C NMR (100 MHz, CDCl3): d = 141.01, 138.10, 128.28, 127.58,
127.51, 114.31, 72.85, 72.51, 70.19, 34.07, 25.64.
HRMS (ESI): m/z [M+ + Na] calcd for C25H29NO4Na: 430.1994;
found: 430.1993.
HRMS (ESI): m/z [M+ + Na] calcd for C13H18O2Na: 229.1204;
found: 229.1205.
(4S)-4-Benzyl-3-[(2S,4E)-8-benzyloxy-2-methyloct-4-enoyl]ox-
azolidin-2-one (16)
Ethyl (4E)-8-Benzyloxy-4-enoctanoate (12)
To a solution of amide 15 (3.59 g, 8.81 mmol) in THF (75 mL), was
added dropwise NaHMDS (1 M in THF, 10.3 mL, 10.57 mmol) at
–78 °C. The reaction mixture was stirred at –78 °C for 1 h, then a
solution of MeI (1.7 mL, 26.43 mmol) in THF (15 mL) was added
dropwise to the solution at –78 °C. The reaction mixture was stirred
for 1 h at –78 °C, then quenched with sat. aq NH4Cl (20 mL) and
concentrated in vacuo. The residue was extracted with EtOAc (3 ×
50 mL) and the combined extracts were washed with brine (20 mL),
dried over MgSO4, filtered and concentrated. The residue was puri-
fied by silica gel column chromatography (hexane–EtOAc, 85:15)
to afford amide 16.
To a solution of allyl alcohol 11 (7.94 g, 38.5 mmol) in triethyl
orthoacetate (160 mL), was added propionic acid (0.15 mL, 1.93
mmol). The reaction mixture was stirred at 140 °C for 3 h, then
quenched with brine–aq 1 M HCl (2:1; 50 mL) at 0 °C. After stir-
ring at r.t. for 30 min, the mixture was extracted with Et2O (3 × 50
mL). The combined extracts were washed with brine (20 mL), dried
over MgSO4, filtered and concentrated. The residue was purified by
silica gel column chromatography (hexane–EtOAc, 92.5:7.5) to af-
ford ester 12.
Yield: 9.47 g (88%); colorless oil.
IR (neat): 2938, 1732, 1455, 1104, 737, 698 cm–1.
Yield: 3.21 g (86%); colorless oil; [a]D27 +62.81 (c 1.50, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 5.50–5.37 (m,
2 H), 4.49 (s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.46 (t, J = 6.6 Hz,
2 H), 2.37–2.27 (m, 4 H), 2.07 (q, J = 6.9 Hz, 2 H), 1.66 (quint,
J = 7.15 Hz, 2 H), 1.25 (t, J = 7.0 Hz, 3 H).
IR (neat): 2931, 2853, 1781, 1698, 1103, 971, 739, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.20 (m, 10 H), 5.48 (dt,
J = 6.8, 15.0 Hz, 1 H), 5.38 (dt, J = 6.8, 15.0 Hz, 1 H), 4.67–4.61
(m, 1 H), 4.49 (s, 2 H), 4.15 (d, J = 5.2 Hz, 2 H), 3.76 (sext, J = 6.8
Hz, 1 H), 3.45 (t, J = 6.8 Hz, 2 H), 3.26 (dd, J = 3.0, 13.6 Hz, 1 H),
2.76 (dd, J = 9.4, 13.6 Hz, 1 H), 2.40 (ddd, J = 6.8, 6.8, 13.5 Hz,
1 H), 2.15–2.08 (m, 1 H), 2.07 (dt, J = 6.8, 6.8 Hz, 2 H), 1.66 (quint,
J = 6.8 Hz, 2 H), 1.20 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.11, 138.58, 130.83, 128.54,
128.26, 127.54, 127.41, 72.80, 69.60, 60.14, 34.28, 29.39, 28.98,
27.83, 14.19.
HRMS (ESI): m/z [M+ + Na] calcd for C17H24O3Na: 299.1623;
found: 299.1623.
13C NMR (100 MHz, CDCl3): d = 176.54, 152.99, 138.55, 135.25,
132.40, 129.37, 128.84, 128.27, 127.51, 127.41, 127.24, 127.19,
72.77, 69.61, 65.94, 55.23, 37.81, 37.80, 36.37, 29.40, 29.00, 16.82.
(4S)-4-Benzyl-3-[(4E)-8-benzyloxyoct-4-enoyl]oxazolidin-2-one
(15)
HRMS (ESI): m/z [M+ + Na] calcd for C26H31NO4Na: 444.2151;
found: 444.2155.
To a solution of ethyl ester 11 (9.41 g, 33.8 mmol) in MeOH–H2O
(190 mL, 3:1), was added LiOH·H2O (3.55 g of hydrate, 56% LiOH,
47.3 mmol of LiOH). The reaction mixture was stirred at r.t. for 4
h, then concentrated in vacuo. The residue was taken into Et2O (100
mL) and H2O (50 mL), then extracted with H2O (3 × 100 mL). The
combined aqueous extracts were acidified (pH <2) with aq 1 M HCl
(50 mL), then extracted with Et2O (3 × 100 mL). The organic layer
was washed with brine (50 mL), dried over MgSO4, filtered and
concentrated to give carboxylic acid 13 as a colorless oil. The crude
carboxylic acid was dissolved in THF (200 mL), then cooled to –
25 °C. Et3N (9.4 mL, 67.6 mmol) and pivaloyl chloride (5.4 mL,
43.94 mmol) were added to the solution and the mixture was stirred
at –25 °C for 1.5 h, then LiCl (4.30 g, 0.101 mol) and (4S)-4-benzyl-
2-oxazolidinone (14; 6.29 g, 35.49 mmol) were added to the solu-
tion. After being stirred for 12 h at r.t., the reaction was diluted with
EtOAc (100 mL) and H2O (100 mL). The mixture was filtered
through a pad of Celite and concentrated in vacuo. The residue was
extracted with EtOAc (3 × 100 mL) and the combined extracts were
washed with brine (50 mL), dried over Na2SO4, filtered and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 85:15) to afford amide 15.
(2S,4E)-8-Benzyloxy-2-methyloct-4-en-1-ol (17)
To a suspension of LiAlH4 (400 mg, 10.53 mmol) in THF (45 mL),
was added dropwise a solution of amide 16 (2.96 g, 7.02 mmol) in
THF (45 mL) at 0 °C. After being stirred at 0 °C for 6 h, the reaction
mixture was diluted with Et2O (90 mL), and quenched by slow ad-
dition of H2O (0.9 mL) at 0 °C. The mixture was stirred at r.t. for 1
h, then filtered through a pad of Celite and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane–EtOAc, 75:25) to afford alcohol 17.
Yield: 1.57 g (90%); colorless oil; [a]D29 –3.74 (c 1.26, MeOH).
IR (neat): 3394, 2923, 1103, 969, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 5.48–5.37 (m,
2 H), 3.47 (t, J = 6.6 Hz, 2 H), 3.52–3.40 (m, 2 H), 2.12–2.05 (m,
3 H), 1.91–1.84 (m, 1 H), 1.72–1.63 (m, 3 H), 1.23 (t, J = 6.6 Hz,
1 H), 0.89 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 38.55, 131.36, 128.29, 127.59,
127.45, 72.82, 69.68, 67.84, 36.45, 35.88, 29.51, 29.09, 16.36.
Yield: 12.91 g (94% for 2 steps); colorless oil; [a]D27 +42.56 (c 1.02,
CHCl3).
HRMS (ESI): m/z [M+ + Na] calcd for C16H24O2Na: 271.1674;
found: 271.1676.
IR (neat): 2920, 1774, 1701, 1103, 740, 700 cm–1.
(1E,3S,5E)-2-(9-Benzyloxy-3-methyl-1,5-nonadienyl)-4,4,5,5-
tetramethyl-1,3-dioxa-2-borolidine (20)
1H NMR (400 MHz, CDCl3): d = 7.33–7.20 (m, 10 H), 5.55–5.44
(m, 2 H), 4.70–4.64 (m, 1 H), 4.49 (s, 2 H), 4.21–4.14 (m, 2 H),
3.47 (t, J = 7.0 Hz, 2 H), 3.29 (dd, J = 3.0, 13.2 Hz, 1 H), 3.05 (dt,
J = 7.4, 17.1 Hz, 1 H), 2.96 (dt, J = 7.4, 17.1 Hz, 1 H), 2.75 (dd,
J = 9.6, 13.2 Hz, 1 H), 2.41–2.36 (m, 2 H), 2.12–2.07 (m, 2 H), 1.68
(quint, J = 7.0 Hz, 2 H).
To a solution of alcohol 17 (102.3 mg, 0.412 mmol) in CH2Cl2–ben-
zene (4 mL, 4:1), was added successively NaHCO3 (346 mg, 4.12
mmol) and Dess–Martin periodinane (227.1 mg, 0.535 mmol) at
0 °C. The reaction mixture was stirred for 1 h at r.t., then quenched
with a mixture of sat. aq NaHCO3 and sat aq Na2S2O3 (5:1; 10 mL)
and diluted with Et2O (10 mL). The mixture was stirred at r.t. for 0.5
h, then extracted with Et2O (3 × 10 mL). The combined extracts
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

2898
M. Kanematsu et al.
PAPER
were washed with brine (10 mL), dried over MgSO4, filtered and
concentrated to give aldehyde 18 as a colorless oil. To a suspension
of Mn (90.5 mg, 1.65 mmol), LiI (330.8 mg, 2.47 mmol), and anhy-
drous CrCl2 (17.7 mg, 0.14 mmol) in THF (5 mL) was added drop-
wise TMSCl (0.32 mL, 2.47 mmol). To the suspension was
successively added dropwise a solution of dichloromethyl boronic
ester 19 (173.7 mg, 0.842 mmol) in THF (4 mL) and a solution of
crude aldehyde 18 in THF (4.5 mL). The reaction flask was then
covered with foil to shade from light and stirred vigorously for 10 h
at r.t., then diluted with Et2O and quenched with a mixture of sat. aq
NaHCO3 and sat. aq Na2S2O3 (5:1; 20 mL). The mixture was filtered
through a pad of Celite and concentrated in vacuo. The residue was
extracted with EtOAc (3 × 20 mL) and the combined extracts were
washed with brine (10 mL), dried over MgSO4, filtered and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 95:5) to afford 20.
was extracted with Et2O (3 × 100 mL) and the combined extracts
were washed with brine (30 mL), dried over MgSO4, filtered and
concentrated to give a colorless oily residue which was taken up in
THF (330 mL). The solution was added dropwise to a suspension of
NaH [60% dispersion in mineral oil, 10.98 g, 0.275 mol; washed
with hexane (3 × 10 mL) and suspended in THF (330 mL)]. After
being stirred at r.t. for 1.5 h, the reaction mixture was cooled to
0 °C, then a solution of MeI (10.5 mL, 0.168 mol) in THF (165 mL)
was added dropwise via an addition funnel at 0 °C. After being
stirred at r.t. for 6 h, the reaction mixture was quenched with ice and
sat. aq NH4Cl (100 mL), then concentrated in vacuo. The residue
was extracted with Et2O (3 × 100 mL) and the combined extracts
were washed with brine (50 mL), dried over MgSO4, filtered and
concentrated. The residue was purified by silica gel column chro-
matography (hexane–EtOAc, 92.5:7.5) to afford methyl ether 21.
26
Yield: 29.5 g (94%); colorless oil; [a]D +2.78 (c 1.10, CHCl3)
{Lit.17 [a]D20 +2.86 (c 1.10, CHCl3)}.
Yield: 108 mg (70% for 2 steps); colorless oil; [a]D26 +10.92 (c 1.23,
CHCl3).
IR (neat): 2978, 2927, 2890, 2862, 1642, 1105, 996, 914, 737, 697
cm–1.
IR (neat): 2977, 2928, 2853, 1106, 969, 736, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34–7.27 (m, 5 H), 6.56 (dd,
J = 18.0, 6.8 Hz, 1 H), 5.44–5.32 (m, 3 H), 4.49 (s, 2 H), 3.46 (t,
J = 7.0 Hz, 2 H), 2.22 (quint, J = 6.8 Hz, 1 H), 2.13–2.05 (m, 3 H),
1.93 (dt, J = 13.5, 6.8 Hz, 1 H), 1.66 (quint, J = 7.0 Hz, 2 H), 1.27
(s, 12 H), 0.98 (d, J = 6.8 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.35–7.25 (m, 5 H), 5.80 (ddt,
J = 17.2, 10.2, 7.0 Hz, 1 H), 5.11–5.03 (m, 2 H), 4.55 (s, 2 H), 3.53–
3.48 (m, 2 H), 3.42 (s, 3 H), 3.46–3.41 (m, 1 H), 2.39–2.27 (m,
2 H).
13C NMR (100 MHz, CDCl3): d = 138.20, 134.35, 128.24, 127.53,
127.46, 117.05, 79.55, 73.26, 71.40, 57.35, 35.59.
13C NMR (100 MHz, CDCl3): d = 159.41, 138.67, 131.25, 128.65,
128.32, 127.62, 127.44, 82.98, 72.85, 69.73, 39.38, 39.09, 29.58,
29.10, 24.78, 24.75, 18.71.
HRMS (ESI): m/z [M+ + Na] calcd for C13H18O2Na: 229.1204;
found: 229.1205.
HRMS (ESI): m/z [M+ + Na] calcd for C23H35O3BNa: 393.2577:
found; 393.2577.
(3R)-4-Benzyloxy-3-methoxybutan-1-ol (22)
To a solution of 21 (2.77 g, 13.4 mmol) in CH2Cl2–MeOH (60 mL,
1:1) at –78 °C, was bubbled O3 until the starting material was con-
sumed (determined by TLC analysis). After removal of excess O3
by bubbling Ar gas for 15 min, the reaction was quenched by adding
NaBH4 (1.12 g, 29.5 mmol) at –78 °C. The mixture was allowed to
warm to 0 °C and stirred for 30 min. Sat. aq NH4Cl (20 mL) was
added and the mixture was diluted with EtOAc (60 mL) and concen-
trated in vacuo. The residue was extracted with EtOAc (3 × 100 mL)
and the combined extracts were washed with brine (30 mL), dried
over MgSO4, filtered and concentrated. The residue was purified by
silica gel column chromatography (hexane–EtOAc, 80:20) to afford
alcohol 22.
(4E,7S,8E)-7-Methyl-9-(4,4,5,5-tetramethyl-1,3-dioxa-2-boroli-
din-2-yl)-4,8-nonadien-1-ol (3)
To a solution of benzyl ether 20 (22.5 mg, 68.86 mmol) in CH2Cl2
(0.9 mL), was added dropwise BCl3·SMe2 (2.0 M in CH2Cl2, 0.04
mL, 75.74 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 1 h, then allowed to warm to r.t. The reaction mixture was fur-
ther stirred at r.t. for 8 h, then quenched with sat. aq NaHCO3 (1 mL)
at 0 °C and diluted with Et2O (10 mL). After being stirred at 0 °C
for 15 min, the mixture was extracted with Et2O (3 × 10 mL) and the
combined extracts were washed with sat. aq NaHCO3 (10 mL),
brine (10 mL), dried over Na2SO4, filtered and concentrated. The
residue was purified by silica gel chromatography (hexane–EtOAc,
70:30) to afford alcohol 3.
Yield: 2.69 g (95%); colorless oil; [a]D31 +27.80 (c 1.03, CHCl3).
IR (neat): 3419, 2931, 1496, 1383, 1090, 738, 699 cm–1.
Yield: 18.9 mg (98%); colorless oil; [a]D27 +13.01 (c 0.75, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.38–7.28 (m, 5 H), 4.56 (s, 2 H),
3.76 (dt, J = 11.2, 5.6 Hz, 2 H), 3.61–3.52 (m, 3 H), 2.49 (t, J = 5.4
Hz, 1 H, OH, D2O exch.), 1.83 (dt, J = 11.2, 5.6 Hz, 2 H).
IR (neat): 3444, 2977, 2930, 1636, 969 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.55 (dd, J = 18.0, 6.6 Hz, 1 H),
5.42–5.36 (m, 3 H), 3.64 (q, J = 6.6 Hz, 2 H), 2.25 (quint, J = 6.6
Hz, 1 H), 2.12–2.06 (m, 3 H), 2.01–1.94 (m, 1 H), 1.63 (quint,
J = 6.4 Hz, 2 H), 1.35 (t, J = 6.4 Hz, 1 H, OH, D2O exch.), 1.27 (s,
12 H), 0.99 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 137.86, 128.23, 127.51, 127.49,
78.88, 73.24, 71.56, 59.85, 57.45, 34.12.
HRMS (ESI): m/z [M+ + Na] calcd for C12H18O3Na: 233.1154;
found: 233.1154.
13C NMR (100 MHz, CDCl3): d = 159.30, 131.21, 128.90, 83.04,
62.34, 39.39, 39.13, 32.39, 28.83, 24.77, 24.74, 18.82.
(2R)-4-tert-Butyldimethylsilyloxy-2-methoxybutan-1-ol (24)
To a solution of 22 (300.1 mg, 1.43 mmol), imidazole (194.3 mg,
2.85 mmol) and DMAP (17.4 mg, 0.143 mmol) in CH2Cl2 (6 mL),
was added TBSCl (258.1 mg, 1.71 mmol) at 0 °C. The reaction mix-
ture was stirred for 0.5 h at r.t., then quenched with H2O (10 mL)
and extracted with CH2Cl2 (3 × 20 mL). The combined organic ex-
tracts were washed with brine and dried over MgSO4, filtered and
concentrated to give 23 as a colorless oil, which was used in the next
reaction without further purification. To a solution of 23 in THF/liq.
NH3 (13 mL, 3:10), was added Li (20 mg, 2.86 mmol) at –33 °C.
After being stirred at the same temperature for 20 min, NH4Cl (20
mg) was added to the reaction mixture and liq. NH3 was removed at
HRMS (ESI): m/z [M+ + Na] calcd for C16H29O3BNa: 303.2107;
found: 303.2107.
(2R)-1-Benzyloxy-2-methoxypent-4-ene (21)
To a suspension of CuI (2.91 g, 15.2 mmol) in THF (120 mL), was
added dropwise vinyl magnesium chloride (1.44 M in THF, 127
mL, 0.183 mol) and a solution of (R)-benzyl glycidyl ether 7 (25.1
g, 0.153 mol) in THF (80 mL) at –78 °C, successively. The reaction
mixture was stirred for 15 h at –25 °C, then at 0 °C for another 2 h.
The reaction was quenched with sat. aq NH4Cl (50 mL), then fil-
tered through a pad of Celite and concentrated in vacuo. The residue
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Bongkrekic Acid
2899
r.t. The residue was taken up in a mixture of Et2O (10 mL) and sat.
aq NH4Cl (10 mL), then extracted with Et2O (3 × 10 mL). The com-
bined extracts were washed with brine (10 mL), dried over MgSO4,
filtered and concentrated. The residue was purified by silica gel col-
umn chromatography (hexane–EtOAc, 90:10) to afford alcohol 24.
concentrated. The residue was purified by silica gel column chro-
matography (hexane–EtOAc, 95:5) to give ester 27.
Yield: 4.79 g (88%); colorless oil; [a]D28 +30.35 (c 1.46, CHCl3).
IR (neat): 2956, 2929, 2857, 2236, 1715, 1472, 1456, 1386, 1258,
1112 cm–1.
27
Yield: 300.8 mg (90% for 2 steps); colorless oil; [a]D +15.19 (c
1.05, MeOH).
1H NMR (400 MHz, CDCl3): d = 4.27 (dd, J = 7.6, 6.0 Hz, 1 H),
3.82–3.69 (m, 2 H), 3.79 (s, 3 H), 3.43 (s, 3 H), 2.02–1.87 (m, 2 H),
0.89 (s, 9 H), 0.05 (s, 6 H).
IR (neat): 3434, 2929, 2857, 1472, 1385, 1255, 1091 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.76–3.66 (m, 3 H), 3.54 (ddd,
J = 11.6, 5.8, 5.8 Hz, 1 H), 3.44 (quint, J = 8.5 Hz, 1 H), 3.40 (s,
3 H), 2.42 (t, J = 6.4 Hz, 1 H, OH, D2O exch.), 1.86–1.78 (m, 1 H),
1.75–1.66 (m, 1 H), 0.90 (s, 9 H), 0.07 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 153.57, 86.43, 77.26, 67.53,
58.33, 56.96, 52.57, 37.91, 25.78, 18.15, –5.55, –5.59.
HRMS (ESI): m/z [M+ + Na] calcd for C14H26O4SiNa: 309.1498;
found: 309.1504.
13C NMR (100 MHz, CDCl3): d = 78.98, 63.68, 59.26, 57.08, 33.87,
25.82, 18.16, –5.49, –5.52.
Methyl (2Z,4R)-6-tert-Butyldimethylsilyloxy-4-methoxy-3-
methyl-2-hexenoate (28)
HRMS (ESI): m/z [M+ + H] calcd for C11H27O3Si: 235.1729; found:
235.1732.
To suspension of CuI (1.36 g, 7.16 mmol) in THF (17 mL), was
added MeLi (0.98 M in THF, 14.6 mL, 14.33 mmol) at 0 °C. After
being stirred for 15 min at 0 °C, the reaction mixture was cooled to
–78 °C and a solution of 27 (1.71 g, 5.97 mmol) in THF (17 mL)
was added dropwise to the mixture. After being stirred for 3 h at
–78 °C, the resulting solution was quenched with sat. aq NH4Cl (10
mL) and extracted with EtOAc (3 × 30 mL). The combined extracts
were washed with brine (20 mL) and dried over MgSO4, filtered and
concentrated. The residue was purified by silica gel column chro-
matography (hexane–EtOAc, 95:5) to give ester 28.
(3R)-tert-Butyldimethylsilyloxy-5,5-dibromo-3-methoxypent-4-
ene (26)
To a solution of oxalyl chloride (4.8 mL, 51.92 mmol) in CH2Cl2
(60 mL), was added DMSO (5.0 mL, 33.29 mmol) in CH2Cl2 (15
mL) at –78 °C. A solution of alcohol 24 (5.07 g, 21.63 mmol) in
CH2Cl2 (50 mL) was added dropwise and, after 30 min, Et3N (22.6
mL, 0.162 mol) was added. After being stirred for 10 min at –78 °C,
the reaction mixture was allowed to warm to r.t. and stirring was
continued for 20 min. The reaction mixture was diluted with H2O
(20 mL) and concentrated in vacuo. The residue was extracted with
Et2O (3 × 30 mL) and the combined extracts were washed with
brine, dried over MgSO4, filtered and concentrated to give aldehyde
25 as a colorless oil. To a solution of CBr4 (14.35 g, 43.27 mmol) in
CH2Cl2 (50 mL) at 0 °C, Ph3P (22.7 g, 86.53 mmol) was added in
one portion. After being stirred at 0 °C for 40 min, DIPEA (17 mL,
97.35 mmol) and a solution of aldehyde 25 in CH2Cl2 (50 mL) were
added to the reaction mixture successively. The mixture was stirred
for 6.5 h at r.t., then diluted with hexane (100 mL), filtered through
a pad of Celite and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexane–EtOAc, 97.5:2.5) to
afford dibromide 26.
Yield: 1.57 g (87%); colorless oil; [a]D27 +32.53 (c 1.22, CHCl3).
IR (neat): 2953, 2929, 2857, 1723, 1651, 1472, 1464, 1385, 1255,
1219, 1150, 1106 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.81 (s, 1 H), 5.16 (dd, J = 4.4, 8.4
Hz, 1 H), 3.74–3.69 (m, 2 H), 3.69 (s, 3 H), 3.22 (s, 3 H), 1.84 (d,
J = 1.2 Hz, 3 H), 1.88–1.80 (m, 1 H), 1.73–1.66 (m, 1 H), 0.90 (s,
9 H), 0.06 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 166.00, 159.50, 118.50, 75.13,
59.82, 56.66, 50.92, 37.12, 25.87, 18.23, 18.20, –5.46.
HRMS (ESI): m/z [M+ + H] calcd for C15H31O4Si: 303.1992; found:
303.1995.
Yield: 7.40 g (88% for 2 steps); colorless oil; [a]D29 +1.69 (c 1.70,
MeOH).
(2Z,4R)-6-tert-Butyldimethylsilyloxy-4-methoxy-3-methylhex-
2-en-1-ol (29)
IR (neat): 2928, 2856, 1615, 1471, 1254, 1111 cm–1.
To a solution of ester 28 (2.26 g, 7.48 mmol) in THF (50 mL), was
added dropwise DIBAL-H (0.97 M in hexane, 23 mL, 22.45 mmol)
at –78 °C. The reaction mixture was allowed to warm to 0 °C then
stirred for 0.5 h at 0 °C. The reaction mixture was diluted with Et2O
(50 mL) and quenched by slow addition of H2O (2.3 mL) at 0 °C.
The mixture was stirred for 1 h at r.t., then filtered through a pad of
Celite and concentrated in vacuo. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 90:10) to afford allyl
alcohol 29.
1H NMR (400 MHz, CDCl3): d = 6.36 (d, J = 8.4 Hz, 1 H), 4.10
(ddd, J = 5.2, 8.3, 8.4 Hz, 1 H), 3.75–3.64 (m, 2 H), 3.32 (s, 3 H),
1.81–1.66 (m, 2 H), 0.90 (s, 9 H), 0.063 (s, 3 H), 0.058 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.58, 91.15, 78.10, 58.55,
56.83, 37.36, 25.90, 18.20, –5.36, –5.46.
HRMS (ESI): m/z [M+ + Na] calcd for C12H24O2SiBr2Na: 408.9810;
found: 408.9827.
Yield: 1.87 g (91%); colorless oil; [a]D24 –28.50 (c 1.08, CHCl3).
Methyl (4R)-6-tert-Butyldimethylsilyloxy-4-methoxy-2-hex-
ynoate (27)
IR (neat): 3402, 2953, 2930, 2885, 2857, 1472, 1385, 1255, 1106,
1088 cm–1.
To a solution of dibromide 26 (7.40 g, 19.06 mmol) in THF (100
mL), was added dropwise n-BuLi (2.49 M in hexane, 17 mL, 42.31
mmol) at –78 °C. After being stirred for 1 h at –78 °C, the resulting
solution was allowed to warm to r.t. and stirred for 1 h. The reaction
mixture was cooled to –78 °C and methyl chloroformate (3.24 mL,
41.93 mmol) in THF (50 mL) was added dropwise. After being
stirred for 0.5 h at –78 °C, the resulting solution was allowed to
warm to r.t. and stirred for 1 h. The reaction mixture was quenched
with sat. aq NH4Cl (10 mL) and concentrated in vacuo. The residue
was extracted with EtOAc (3 × 30 mL) and the combined extracts
were washed with brine (20 mL), dried over MgSO4, filtered and
1H NMR (400 MHz, C6D6): d = 5.62 (t, J = 6.8 Hz, 1 H), 4.36 (t,
J = 7.2 Hz, 1 H), 4.16–4.02 (m, 2 H), 3.65–3.60 (m, 1 H), 3.54–3.49
(m, 1 H), 3.04 (s, 3 H), 1.97–1.88 (m, 1 H), 1.63–1.54 (m, 1 H),
1.60 (s, 3 H), 1.54 (dd, J = 5.2, 7.2 Hz, 1 H), 0.96 (s, 9 H), 0.04 (s,
3 H), 0.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.20, 129.25, 74.99, 59.55,
57.52, 55.94, 36.26, 25.83, 18.24, 17.12, –5.29, –5.45.
HRMS (ESI): m/z [M+ + Na] calcd for C14H30O3SiNa: 297.1862;
found: 297.1865.
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

2900
M. Kanematsu et al.
PAPER
tert-Butyl (2E,4Z,6R)-8-tert-Butyldimethylsilyloxy-6-methoxy-
2,5-dimethylocta-2,4-dienoate (30)
1 H), 2.41 (ddd, J = 16.3, 4.0, 1.6 Hz, 1 H), 1.91 (s, 3 H), 1.84 (s,
3 H), 1.51 (s, 9 H).
To a solution of allyl alcohol 29 (1.25 g, 4.54 mmol) in benzene–
CH2Cl2 (25 mL, 3:1) was added MnO2 (5.93 g, 68.17 mmol) and
tert-butyl 2-triphenylphosphanylidene-propionate (5.5 g, 14.09
mmol) successively. The reaction mixture was stirred at 80 °C for
49 h, then filtered through a pad of Celite and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane–EtOAc, 97.5:2.5) to afford unsaturated ester 30.
13C NMR (100 MHz, CDCl3): d = 199.93, 167.65, 142.55, 130.20,
129.27, 125.11, 80.29, 73.35, 56.32, 47.44, 28.00, 18.49, 12.78.
HRMS (ESI): m/z [M+ + Na] calcd for C15H24O4Na: 291.1572;
found: 291.1574.
tert-Butyl (2E,4Z,6R,8Z)-9-Iodo-6-methoxy-2,5-dimethylnona-
2,4,8-trienoate (4a)
Yield: 1.72 g (99%); colorless oil; [a]D26 –38.03 (c 1.03, CHCl3).
To a suspension of triphenyl(iodomethyl)phosphonium iodide
(175.4 mg, 0.331 mmol) in THF (2.4 mL), was added NaHMDS
(1.03 M in THF, 0.32 mL, 0.331 mmol) at 0 °C. After being stirred
for 30 min at 0 °C, the reaction mixture was cooled to –78 °C and
HMPA (0.5 mL, 3.01 mmol) was added. The reaction mixture was
stirred at –78 °C for 30 min, then a solution of 32 (80.7 mg, 0.301
mmol) in THF (2 mL) was added dropwise to the mixture. After be-
ing stirred for 10 min at –78 °C, the resulting solution was quenched
with MeOH (0.44 mL) and extracted with Et2O (3 × 20 mL). The
combined extracts were washed with brine (10 mL), dried over
MgSO4, filtered and concentrated. The residue was purified by sili-
ca gel column chromatography (hexane–EtOAc, 95:5) to afford 4a.
IR (neat): 2954, 2929, 2858, 1703, 1634, 1600, 1471, 1463, 1389,
1271, 1254, 1173, 1107 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.46 (d, J = 12.4 Hz, 1 H), 6.32 (d,
J = 12.4 Hz, 1 H), 4.45 (dd, J = 8.6, 5.4 Hz, 1 H), 3.73–3.60 (m,
2 H), 3.20 (m, 3 H), 1.94–1.87 (m, 1 H), 1.90 (s, 3 H), 1.81 (s, 3 H),
1.69–1.61 (m, 1 H), 1.50 (s, 9 H), 0.90 (s, 9 H), 0.05 (s, 3 H), 0.04
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.86, 144.80, 131.09, 128.27,
124.87, 79.97, 75.27, 59.60, 56.22, 36.90, 28.11, 25.95, 18.68,
18.29, 12.31, –5.40, –5.42.
HRMS (ESI): m/z [M+ + Na] calcd for C21H40O4SiNa: 407.2594;
found: 407.2599.
Yield: 81.4 mg (69%); colorless oil; [a]D25 +115.99 (c 1.23, CHCl3).
IR (neat): 2976, 2924, 1700, 1634, 1608, 1385, 1273, 1256, 1171,
1099 cm–1.
tert-Butyl (2E,4Z,6R)-8-Hydroxy-6-methoxy-2,5-dimethylocta-
2,4-dienoate (31)
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 12.4 Hz, 1 H), 6.35
(d, J = 12.4 Hz, 1 H), 6.30 (d, J = 7.4 Hz, 1 H), 6.18 (q, J = 7.4 Hz,
1 H), 4.42 (t, J = 7.4 Hz, 1 H), 3.22 (s, 3 H), 2.54 (dt, J = 14.8, 7.4
Hz, 1 H), 2.34 (dt, J = 14.8, 7.4 Hz, 1 H), 1.90 (s, 3 H), 1.85 (s, 3 H),
1.51 (s, 9 H).
To a solution of 30 (2.57 g, 6.67 mmol) in THF (52 mL), was added
aq 3 M HCl (11.2 mL, 33.37 mmol). After being stirred at r.t. for 1
h, the reaction was quenched with sat. aq NaHCO3 (20 mL) and ex-
tracted with EtOAc (3 × 30 mL). The combined extracts were
washed with brine (20 mL), dried over MgSO4, filtered and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 75:25) to afford alcohol 31.
13C NMR (100 MHz, CDCl3): d = 167.87, 143.93, 137.05, 130.80,
128.62, 125.25, 84.40, 80.20, 77.00, 56.41, 39.00, 28.15, 18.56,
12.34.
Yield: 1.79 g (quant.); colorless oil; [a]D24 –35.32 (c 1.02, CHCl3).
HRMS (ESI): m/z [M+ + Na] calcd for C16H25O3INa: 415.0746;
found: 415.0746.
IR (neat): 3450, 2977, 2932, 1699, 1633, 1599, 1455, 1391, 1255,
1107 cm–1.
Methoxymethyl (2E,4Z,6R,8Z)-9-Iodo-6-methoxy-2,5-dimeth-
ylnona-2,4,8-trienoate (4b)
1H NMR (400 MHz, C6D6): d = 7.89 (d, J = 12.4 Hz, 1 H), 6.20 (d,
J = 12.4 Hz, 1 H), 4.51 (dd, J = 8.8, 4.8 Hz, 1 H), 3.58–3.45 (m,
2 H), 2.89 (m, 3 H), 1.95 (s, 3 H), 1.91–1.82 (m, 1 H), 1.64 (s, 3 H),
1.54 (br, 1 H, OH, D2O exch.), 1.43 (s, 9 H), 1.47–1.32 (m, 1 H).
tert-Butyl ester 4a (36.4 mg, 92.79 mmol) was stirred in aq formic
acid (98%, 0.8 mL) at r.t. for 30 min. The solvent was removed in
vacuo to give carboxylic acid 33 as a clear blue oil, which was taken
up in CH2Cl2 (0.8 mL). The solution was cooled to 0 °C and DIPEA
(0.1 mL, 0.557 mmol) and MOMCl (0.02 mL, 0.278 mmol) were
added at 0 °C. The reaction mixture was stirred for 15 min at r.t.,
then quenched with H2O (5 mL) and extracted with EtOAc (3 × 10
mL). The combined extracts were washed with brine (10 mL), dried
over MgSO4, filtered and concentrated. The residue was purified by
silica gel column chromatography (hexane–EtOAc, 94:6) to afford
MOM ester 4b.
13C NMR (100 MHz, CDCl3): d = 167.95, 144.64, 130.79, 128.45,
124.57, 80.26, 78.53, 61.00, 56.37, 36.17, 28.06, 18.61, 12.29.
HRMS (ESI): m/z [M+ + Na] calcd for C15H26O4Na: 293.1729;
found: 293.1727.
tert-Butyl (2E,4Z,6R)-6-Methoxy-2,5-dimethyl-8-oxoocta-2,4-
dienoate (32)
To a solution of alcohol 31 (147.8 mg, 0.547 mmol) in CH2Cl2 (4
mL), was added NaHCO3 (229.6 mg, 2.73 mmol) and Dess–Martin
periodinane (347.8 mg, 0.820 mmol) at 0 °C successively. The re-
action mixture was stirred for 1 h at r.t., then quenched with a mix-
ture of sat. aq NaHCO3 and sat. aq Na2S2O3 (5:1; 10 mL) and diluted
with Et2O (10 mL). The mixture was stirred at r.t. for 0.5 h, then ex-
tracted with Et2O (3 × 10 mL) and the combined extracts were
washed with brine (10 mL), dried over MgSO4, filtered and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 80:20) to afford aldehyde 32.
26
Yield: 31.3 mg (89% for 2 steps); colorless oil; [a]D +102.32 (c
1.10, CHCl3).
IR (neat): 3068, 2983, 2928, 1711, 1633, 1608, 1378, 1261, 1096,
1074 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 12.4 Hz, 1 H), 6.39 (d,
J = 12.4 Hz, 1 H), 6.32 (d, J = 7.2 Hz, 1 H), 6.19 (q, J = 7.2 Hz,
1 H), 5.35 (d, J = 6.0 Hz, 1 H), 5.33 (d, J = 6.0 Hz, 1 H), 4.43 (t,
J = 7.2 Hz, 1 H), 3.50 (s, 3 H), 3.23 (s, 3 H), 2.55 (dt, J = 14.6, 7.2
Hz, 1 H), 2.35 (dt, J = 14.6, 7.2 Hz, 1 H), 1.97 (s, 3 H), 1.88 (s, 3 H).
Yield: 143.2 mg (98%); colorless oil; [a]D26 –72.57 (c 1.44, CHCl3).
13C NMR (100 MHz, CDCl3): d = 167.91, 145.66, 136.93, 132.68,
126.43, 124.93, 90.58, 84.58, 77.19, 57.60, 56.47, 39.02, 18.79,
12.18.
IR (neat): 2976, 2932, 2722, 1730, 1698, 1634, 1601, 1455, 1391,
1276, 1257, 1169, 1112 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.76 (dd, J = 2.4, 1.6 Hz, 1 H),
7.48 (d, J = 12.0 Hz, 1 H), 6.35 (d, J = 12.0 Hz, 1 H), 4.88 (dd,
J = 9.6, 4.0 Hz, 1 H), 3.23 (s, 3 H), 2.79 (ddd, J = 16.3, 9.6, 2.4 Hz,
HRMS (ESI): m/z [M+ + Na] calcd for C14H21O4INa: 403.0382;
found: 403.0383.
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Bongkrekic Acid
2901
Methoxymethyl (2Z,4E,6S,8E)-3-[2-(tert-Butyldimethylsilyl-
oxy)ethyl]-12-hydroxy-6-methyl-dodeca-2,4,8-trienoate (34)
To a suspension of PdCl2(PPh3)2 (4.6 mg, 6.58 mmol) in MeOH (1
mL), was added at r.t. a solution of iodide 2 (58.0 mg, 0.145 mmol)
in MeOH (1.5 mL). After being stirred for 10 min, Et3N (0.11 mL,
0.79 mmol) and a solution of boronic ester 3 (36.9 mg, 0.132 mmol)
in MeOH (2.5 mL) were added successively. The reaction mixture
was stirred for 16 h at r.t., then filtered through a pad of Celite and
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane–EtOAc, 80:20) to afford alcohol 34.
was stirred vigorously for 19 h at r.t., then diluted with Et2O (20
mL) and quenched with a mixture of sat. aq NaHCO3 and sat. aq
Na2S2O3 (5:1; 20 mL). The mixture was filtered through a pad of
Celite and concentrated in vacuo. The residue was extracted with
EtOAc (3 × 30 mL) and the combined extracts were washed with
brine (20 mL), dried over MgSO4, filtered and concentrated. The
residue was purified by silica gel column chromatography (hexane–
EtOAc, 93:7) to afford 36.
Yield: 251.3 mg (68%); colorless oil; [a]D20 –4.47 (c 1.12, CHCl3).
IR (neat): 2955, 2928, 2856, 2344, 1722, 1635, 1599, 1470, 1463,
1383, 1252, 1134, 1095, 970 cm–1.
Yield: 51.3 mg (91%); yellow oil; [a]D20 –12.75 (c 1.14, CHCl3).
IR (neat): 3405, 2954, 2930, 2857, 1717, 1633, 1596, 1471, 1385,
1254, 1134, 1093, 1055, 968 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.48 (d, J = 16 Hz, 1 H), 6.62 (dt,
J = 18, 6.2 Hz, 1 H), 6.10 (dd, J = 16, 7.2 Hz, 1 H), 5.66 (s, 1 H),
5.43 (dt, J = 18, 1.4 Hz, 1 H), 5.46–5.33 (m, 2 H), 5.27 (s, 2 H), 3.73
(t, J = 6.8 Hz, 2 H), 3.47 (s, 3 H), 2.57 (t, J = 6.8 Hz, 2 H), 2.40–
2.33 (m, 1 H), 2.23–2.18 (m, 2 H), 2.14–2.07 (m, 3 H), 2.03–1.96
(m, 1 H), 1.26 (s, 12 H), 1.03 (d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.04
(s, 6 H).
1H NMR (400 MHz, CDCl3): d = 7.43 (d, J = 16.2 Hz, 1 H), 6.08
(dd, J = 16.2, 6.6 Hz, 1 H), 5.67 (s, 1 H), 5.46–5.39 (m, 2 H), 5.28
(d, J = 6.0 Hz, 1 H), 5.26 (d, J = 6.0 Hz, 1 H), 3.73 (t, J = 6.8 Hz,
2 H), 3.63 (br, 2 H), 3.47 (s, 3 H), 2.58 (t, J = 6.8 Hz, 2 H), 2.37
(quint, J = 6.6 Hz, 1 H), 2.11–2.05 (m, 4 H), 1.62 (quint, J = 6.8 Hz,
2 H), 1.46 (br, 1 H, OH, D2O exch.), 1.05 (d, J = 6.6 Hz, 3 H), 0.89
(s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 165.50, 153.73, 153.56, 144.35,
131.37, 128.22, 124.95, 115.97, 89.67, 82.92, 62.49, 57.34, 39.77,
37.80, 37.48, 35.75, 31.19, 25.86, 24.71, 19.38, 18.24, –5.34.
13C NMR (100 MHz, CDCl3): d = 165.56, 153.53, 144.16, 131.44,
128.44, 125.08, 115.90, 89.65, 62.48, 62.02, 57.32, 39.68, 37.72,
37.64, 32.13, 28.69, 25.81, 19.54, 18.21, –5.40.
HRMS (ESI): m/z [M+ + Na] calcd for C30H53O6BSiNa: 571.3602;
found: 571.3602.
HRMS (ESI): m/z [M+ + Na] calcd for C23H42O5SiNa: 449.2699;
found: 449.2700.
tert-Butyl 22-Methoxymethyl
(2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-20-(2-tert-Butyldimethyl-
silyloxyethyl)-6-methoxy-2,5,17-trimethyldocosa-
2,4,8,10,14,18,20-heptaenedioate (37a)
Methoxymethyl (2Z,4E,6S,8E)-3-(2-tert-Butyldimethylsilyloxy-
ethyl)-6-methyl-12-oxododeca-2,4,8-trienoate (35)
To a solution of alcohol 34 (74.4 mg, 0.174 mmol) in CH2Cl2 (2.5
mL), was added NaHCO3 (73.2 mg, 0.872 mmol) and Dess–Martin
periodinane (125.7 mg, 0.296 mmol) at 0 °C successively. The re-
action mixture was stirred for 1 h at r.t., then quenched with a mix-
ture of sat. aq NaHCO3 and sat. aq Na2S2O3 (5:1; 10 mL) and diluted
with Et2O (10 mL). The mixture was stirred at r.t. for 0.5 h, then ex-
tracted with Et2O (3 × 10 mL) and the combined extracts were
washed with brine (10 mL), dried over MgSO4, filtered and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 90:10) to afford aldehyde 35.
To a suspension of PdCl2(PPh3)2 (0.4 mg, 0.53 mmol) in MeOH (0.1
mL), was added a solution of iodide 4a (4.2 mg, 10.57 mmol) in
MeOH (0.15 mL) at r.t. After being stirred for 10 min, Et3N (0.025
mL, 0.53 mmol) and a solution of boronic ester 36 (5.8 mg, 10.57
mmol) in MeOH (0.25 mL) were added successively. The reaction
mixture was stirred for 3.5 h at r.t. then filtered through a pad of
Celite and concentrated in vacuo. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 95:5) to afford 37a.
Yield: 5.3 mg (73%); yellow oil; [a]D22 +68.86 (c 0.59, CHCl3).
IR (neat): 2955, 2929, 2856, 1702, 1634, 1598, 1456, 1387, 1255,
1173, 1133, 1095, 971 cm–1.
Yield: 67.5 mg (91%); colorless oil; [a]D25 –10.57 (c 1.09, CHCl3).
IR (neat): 2955, 2928, 2856, 2715, 1725, 1715, 1633, 1598, 1471,
1463, 1386, 1255, 1134, 1094, 969 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.49 (d, J = 16 Hz, 1 H), 7.44 (d,
J = 12 Hz, 1 H), 6.34 (d, J = 12 Hz, 1 H), 6.27 (dd, J = 14.8, 10.8
Hz, 1 H), 6.10 (dd, J = 16, 7.6 Hz, 1 H), 6.00 (t, J = 10.8 Hz, 1 H),
5.67 (dt, J = 14.8, 6.8 Hz, 1 H), 5.66 (s, 1 H), 5.46–5.33 (m, 2 H),
5.27 (s, 2 H), 5.21 (dt, J = 10.8, 7.2 Hz, 1 H), 4.33 (t, J = 7.2 Hz,
1 H), 3.73 (t, J = 6.8 Hz, 2 H), 3.47 (s, 3 H), 3.21 (s, 3 H), 2.62–2.55
(m, 1 H), 2.57 (t, J = 6.8 Hz, 2 H), 2.40–2.32 (m, 2 H), 2.18–1.98
(m, 6 H), 1.90 (s, 3 H), 1.83 (s, 3 H), 1.49 (s, 9 H), 1.03 (d, J = 6.8
Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
1H NMR (400 MHz, CDCl3): d = 9.75 (t, J = 1.8 Hz, 1 H), 7.48 (d,
J = 16 Hz, 1 H), 6.07 (dd, J = 16, 7.6 Hz, 1 H), 5.67 (s, 1 H), 5.47–
5.37 (m, 2 H), 5.27 (s, 2 H), 3.73 (t, J = 6.8 Hz, 2 H), 3.47 (s, 3 H),
2.57 (t, J = 6.8 Hz, 2 H), 2.49 (dt, J = 7.1, 1.8 Hz, 2 H), 2.40–2.31
(m, 3 H) 2.13–1.99 (m, 2 H), 1.03 (d, J = 6.4 Hz, 3 H), 0.89 (s, 9 H),
0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 202.13, 165.53, 153.49, 143.99,
129.78, 129.39, 125.22, 116.07, 89.73, 62.50, 57.38, 43.45, 39.61,
37.77, 37.48, 25.87, 25.13, 19.53, 18.27, –5.34.
13C NMR (100 MHz, CDCl3): d = 167.91, 165.51, 153.57, 144.56,
144.37, 134.85, 131.45, 131.12, 130.45, 128.25, 128.20, 125.57,
125.11, 124.95, 124.41, 115.96, 89.68, 80.06, 78.28, 62.50, 57.36,
56.33, 39.78, 37.80, 37.51, 32.90, 32.33, 32.02, 28.08, 25.85, 19.41,
18.50, 18.25, 12.29, –5.36.
HRMS (ESI): m/z [M+ + Na] calcd for C23H40O5SiNa: 447.2543;
found: 447.2541.
Methoxymethyl 3-[2-(tert-Butyldimethylsilyloxy)ethyl]-6-meth-
yl-13-(4,4,5,5-tetramethyl-1,3-dioxa-2-borolidin-2-yl)trideca-
2,4,8,12-tetraenoate (36)
HRMS (ESI): m/z [M+ + Na] calcd for C38H62O8SiNa: 709.4476;
found: 709.4476.
To a suspension of Mn (221.1 mg, 4.02 mmol), LiI (359.1 mg, 2.68
mmol), and anhydrous CrCl2 (28.9 mg, 0.235 mmol) in freshly dis-
tilled THF (12 mL), was added dropwise TMSCl (0.51 mL, 4.02
mmol). To the mixture was added dropwise a solution of 19 (282.9
mg, 1.34 mmol) in THF (7.2 mL) and a solution of aldehyde 35
(284.8 mg, 0.671) in THF (10.8 mL) successively. The reaction
flask was then covered with foil to shade the light and the reaction
Dimethoxymethyl (2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-20-(2-
tert-Butyldimethylsilyloxyethyl)-6-methoxy-2,5,17-trimethyl-
docosa-2,4,8,10,14,18,20-heptaenedioate (37b)
The same procedure used for the preparation of 37a was used to ob-
tain 37b.
Yield: 84%; yellow oil; [a]D23 +71.23 (c 1.14, CHCl3).
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

2902
M. Kanematsu et al.
PAPER
IR (neat): 2953, 2927, 2856, 1713, 1633, 1598, 1470, 1463, 1384,
1257, 1133, 1092, 984 cm–1.
5.27 (s, 2 H), 5.20 (dt, J = 10.8, 7.2 Hz, 1 H), 4.34 (t, J = 7.2 Hz,
1 H), 3.77 (q, J = 6.0 Hz, 2 H), 3.48 (s, 6 H), 3.22 (s, 3 H), 2.68–
2.54 (m, 3 H), 2.43–2.31 (m, 2 H), 2.17–2.00 (m, 6 H), 1.97 (s,
3 H), 1.81 (s, 3 H), 1.56–1.48 (br, 1 H, OH, D2O exch.), 1.04 (d,
J = 6.4 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.59 (d, J = 12 Hz, 1 H), 7.49 (d,
J = 16 Hz, 1 H), 6.39 (d, J = 12 Hz, 1 H), 6.27 (dd, J = 15, 11.2 Hz,
1 H), 6.10 (dd, J = 16, 7.2 Hz, 1 H), 6.00 (t, J = 11.2 Hz, 1 H), 5.67
(dt, J = 15, 6.8 Hz, 1 H), 5.66 (s, 1 H), 5.46–5.32 (m, 2 H), 5.34 (d,
J = 6.0 Hz, 1 H), 5.32 (d, J = 6.0 Hz, 1 H), 5.27 (s, 2 H), 5.20 (dt,
J = 11.2, 7.6 Hz, 1 H), 4.34 (t, J = 8.0 Hz, 1 H), 3.73 (t, J = 7.0 Hz,
2 H), 3.48 (s, 3 H), 3.47 (s, 3 H), 3.22 (s, 3 H), 2.63–2.56 (m, 1 H),
2.57 (t, J = 7.0 Hz, 2 H), 2.41–2.33 (m, 2 H), 2.18–2.00 (m, 6 H),
1.97 (s, 3 H), 1.85 (s, 3 H), 1.03 (d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H),
0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 167.93, 165.34, 153.16, 146.15,
144.80, 134.92, 132.91, 131.41, 130.53, 128.19, 125.99, 125.47,
124.84, 124.76, 124.10, 115.91, 90.42, 89.76, 78.35, 61.75, 57.41,
56.30, 39.72, 37.52, 37.47, 32.76, 32.19, 31.97, 19.36, 18.66, 12.08.
HRMS (ESI): m/z [M+ + Na] calcd for C32H48O8Na: 583.3247;
found: 583.3244.
13C NMR (100 MHz, CDCl3): d = 167.92, 165.49, 153.54, 146.17,
144.31, 134.97, 132.91, 131.39, 130.56, 128.28, 126.50, 125.50,
124.97, 124.87, 124.15, 115.96, 90.47, 89.66, 78.36, 62.49, 57.44,
57.32, 56.34, 39.75, 37.78, 37.49, 32.86, 32.29, 32.01, 25.83, 19.40,
18.70, 18.23, 12.12, –5.38.
tert-Butyl 22-Methoxymethyl
(2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-20-Carboxymethyl-6-
methoxy-2,5,17-trimethyldocosa-2,4,8,10,14,18,20-heptaene-
dioate (40a)
To a solution of alcohol 38a (34.4 mg, 60.06 mmol) in CH2Cl2–ben-
zene (1.1 mL, 4:1) was added Dess–Martin periodinane (50.9 mg,
0.12 mmol) at 0 °C. The reaction mixture was stirred for 5 min at
50 °C, then cooled to r.t. The reaction mixture was diluted with pen-
tane (2 mL), then filtered through a pad of Celite and washed with
a mixture of sat. aq NaHCO3 and sat. aq Na2S2O3 (1:1; 10 mL). The
aqueous layer was extracted with EtOAc (3 × 10 mL) and the com-
bined extracts were washed with brine (10 mL), dried over Na2SO4,
filtered and concentrated to give aldehyde 39a as a colorless oil. To
a solution of 39a in t-BuOH–THF–2-methylbut-2-ene (1.4 mL,
3:1:4), was added a solution of NaClO2 (47.6 mg, 0.42 mmol) and
NaH2PO4 (175 mg, 3.5 w/w of aldehyde) in H2O (1.05 mL) at r.t.
The reaction mixture was stirred for 1.5 h, then acidified with aq 3
M HCl (0.2 mL, 0.6 mmol) and extracted with CH2Cl2 (3 × 10 mL).
The combined extracts were washed with brine (5 mL), dried over
MgSO4, filtered and concentrated. The residue was purified by sili-
ca gel column chromatography (hexane–EtOAc, 35:65) to afford
40a.
HRMS (ESI): m/z [M+ + Na] calcd for C38H62O8SiNa: 697.4112;
found: 697.4112.
tert-Butyl 22-Methoxymethyl
(2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-20-(2-Hydroxyethyl)-6-
methoxy-2,5,17-trimethyldocosa-2,4,8,10,14,18,20-heptaene-
dioate (38a)
To a solution of 37a (59.3 mg, 86.3 mmol) in THF–pyridine (2 mL,
1:1) was added HF·pyridine (6.7 mL) at 0 °C. After being stirred for
7 h at r.t., the reaction mixture was quenched with sat. aq NaHCO3
(5 mL) at 0 °C then extracted with EtOAc (3 × 10 mL). The com-
bined extracts were washed with sat. aq NaHCO3 (5 mL), brine (5
mL), dried over MgSO4, filtered and concentrated. The residue was
purified by silica gel column chromatography (hexane–EtOAc,
80:20) to afford 38a.
Yield: 41.7 mg (84%); colorless oil; [a]D23 +71.49 (c 2.02, CHCl3).
Yield: 20.8 mg (59% for 2 steps); yellow oil; [a]D25 +58.44 (c 1.61,
CHCl3).
IR (neat): 3465, 2960, 2925, 2851, 1698, 1633, 1598, 1454, 1367,
1256, 1132, 1094, 1042, 982 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.51 (d, J = 16 Hz, 1 H), 7.44 (d,
J = 11.8 Hz, 1 H), 6.34 (d, J = 11.8 Hz, 1 H), 6.27 (dd, J = 15, 10.4
Hz, 1 H), 6.12 (dd, J = 16, 7.2 Hz, 1 H), 6.00 (t, J = 10.4 Hz, 1 H),
5.70 (s, 1 H), 5.67 (dt, J = 15 Hz, 6.4 Hz, 1 H), 5.46–5.33 (m, 2 H),
5.28 (s, 2 H), 5.21 (dt, J = 10.4, 8.0 Hz, 1 H), 4.34 (t, J = 7.2 Hz,
1 H), 3.78 (q, J = 6.2 Hz, 2 H), 3.48 (s, 3 H), 3.22 (s, 3 H), 2.69–
2.55 (m, 3 H), 2.42–2.32 (m, 2 H), 2.18–2.00 (m, 6 H), 1.90 (s,
3 H), 1.83 (s, 3 H), 1.50 (s, 9 H), 1.50–1.49 (br, 1 H, OH, D2O
exch.), 1.04 (d, J = 6.4 Hz, 3 H).
IR (neat): 3400–3110 (br), 2975, 2926, 2847, 1698, 1633, 1605,
1452, 1408, 1384, 1367, 1316, 1274, 1255, 1166, 1133, 1093, 986,
946 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.54 (d, J = 16 Hz, 1 H), 7.43 (d,
J = 12 Hz, 1 H), 6.34 (d, J = 12 Hz, 1 H), 6.28 (dd, J = 14.8, 10.8
Hz, 1 H), 6.13 (dd, J = 16, 7.2 Hz, 1 H), 5.99 (t, J = 10.8 Hz, 1 H),
5.76 (s, 1 H), 5.66 (dt, J = 14.8, 6.8 Hz, 1 H), 5.45–5.33 (m, 2 H),
5.28 (s, 2 H), 5.19 (dt, J = 10.8, 6.8 Hz, 1 H), 4.37 (t, J = 6.8 Hz,
1 H), 3.48 (s, 3 H), 3.39 (d, J = 16 Hz, 1 H), 3.34 (d, J = 16 Hz,
1 H), 3.23 (s, 3 H), 2.60 (dt, J = 14.4, 6.8 Hz, 1 H), 2.43–2.35 (m,
2 H), 2.17–2.05 (m, 6 H), 1.90 (s, 3 H), 1.83 (s, 3 H), 1.49 (s, 9 H),
1.04 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.00, 165.41, 153.18, 144.99,
144.59, 134.88, 131.55, 131.17, 130.47, 128.24, 125.62, 125.15,
124.80, 124.45, 116.04, 89.88, 80.15, 78.34, 61.88, 57.52, 56.37,
39.82, 37.60, 37.56, 32.85, 32.29, 32.05, 28.11, 19.45, 18.53, 12.32.
13C NMR (100 MHz, CDCl3): d = 174.39, 168.16, 165.15, 148.03,
145.57, 144.51, 134.97, 131.68, 131.27, 130.63, 128.31, 128.11,
125.65, 125.28, 124.65, 124.29, 118.24, 90.11, 80.31, 78.49, 57.60,
56.36, 40.04, 39.70, 37.57, 32.73, 32.14, 32.00, 28.14, 19.26, 18.34,
12.35.
HRMS (ESI): m/z [M+ + Na] calcd for C34H52O7Na: 595.3611;
found: 595.3611.
Dimethoxymethyl (2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-20-(2-
Hydroxyethyl)-6-methoxy-2,5,17-trimethyldocosa-
2,4,8,10,14,18,20-heptaenedioate (38b)
The same procedure used for the preparation of 38a was used to ob-
tain 38b.
HRMS (ESI): m/z [M+ + Na] calcd for C34H50O8Na: 609.3403;
found: 609.3403.
Dimethoxymethyl (2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-20-
Carboxymethyl-6-methoxy-2,5,17-trimethyldocosa-
2,4,8,10,14,18,20-heptaenedioate (40b)
The same procedure used for the preparation of 40a was used to ob-
tain 40b.
Yield: 100%; yellow oil; [a]D25 +62.60 (c 0.98, CHCl3).
IR (neat): 3440, 2956, 2924, 2850, 1716, 1634, 1597, 1450, 1381,
1260, 1134, 1092, 1039, 974 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.59 (d, J = 12 Hz, 1 H), 7.51 (d,
J = 16 Hz, 1 H), 6.38 (d, J = 12 Hz, 1 H), 6.27 (dd, J = 14.6, 11.2
Hz, 1 H), 6.11 (dd, J = 16, 7.6 Hz, 1 H), 5.99 (t, J = 10.8 Hz, 1 H),
5.70 (s, 1 H), 5.70–5.63 (m, 1 H), 5.42–5.31 (m, 2 H), 5.33 (s, 2 H),
26
Yield: 67% (over two steps); yellow oil; [a]D +57.35 (c 0.67,
CHCl3).
Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Bongkrekic Acid
2903
IR (neat): 3280–2400 (br), 2924, 2850, 1719, 1709, 1635, 1616,
1439, 1384, 1261, 1163, 1092, 984, 970 cm–1.
H), 2.21–2.01 (m, 5 H), 1.94–1.91 (m, 1 H), 1.94 (s, 3 H), 1.88 (s,
3 H), 1.07 (d, J = 6.0 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.58 (d, J = 12 Hz, 1 H), 7.54 (d,
J = 16 Hz, 1 H), 6.39 (d, J = 12 Hz, 1 H), 6.28 (dd, J = 15, 10.4 Hz,
1 H), 6.13 (dd, J = 16, 7.9 Hz, 1 H), 5.99 (t, J = 10.4 Hz, 1 H), 5.76
(s, 1 H), 5.67 (dt, J = 15, 6.8 Hz, 1 H), 5.48–5.32 (m, 4 H), 5.28 (s,
2 H), 5.18 (dt, J = 10.4, 8.0 Hz, 1 H), 4.37 (t, J = 7 Hz, 1 H), 3.48
(s, 3 H), 3.48 (s, 3 H), 3.40 (d, J = 15.6 Hz, 1 H), 3.34 (d, J = 15.6
Hz, 1 H), 3.23 (s, 3 H), 2.61 (dt, J = 14.4, 7.0 Hz, 1 H), 2.43–2.29
(m, 2 H), 2.17–2.00 (m, 6 H), 1.97 (s, 3 H), 1.85 (s, 3 H), 1.04 (d,
J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 176.82, 174.61, 170.67, 148.82,
148.40, 145.41, 135.80, 134.46, 131.45, 131.27, 128.04, 125.22,
125.11, 124.63, 124.23, 124.08, 118.24, 79.87, 56.67, 40.70, 39.94,
38.69, 33.06, 32.45, 32.10, 20.38, 18.51, 11.67.
HRMS (ESI): m/z [M+ + H] calcd for C28H37O7: 485.2539; found:
485.2534.
Methyl (2E,4Z,6R,8Z,10E,14E,17S,18E,20Z)-17-Methoxy-21-
methoxycarbonyl-3-methoxycarbonylmethyl-6,18-dimethyl-
docosa-2,4,8,12,14,18,20-heptaenoate (42)
To a solution of 1 (1.5 mg, 3.08 mmol) in Et2O (1 mL) at 0 °C, was
added dropwise a solution of CH2N2 in Et2O until the starting mate-
rial was consumed (determined by TLC analysis). After being
stirred for 30 min at 0 °C, the reaction mixture was quenched with
AcOH (0.5 mL) and concentrated, leaving a residue which was pu-
rified by chromatography on a silica gel column (hexane–EtOAc,
70:30) to afford trimethyl ester 42.
13C NMR (100 MHz, CDCl3): d = 174.92, 168.02, 165.06, 147.90,
146.09, 145.49, 135.03, 132.97, 131.55, 130.65, 128.06, 126.06,
125.48, 124.95, 124.57, 124.02, 118.17, 90.50, 90.01, 78.45, 57.51,
57.45, 56.30, 40.00, 39.59, 37.48, 32.73, 32.15, 31.95, 19.14, 18.66,
12.11.
HRMS (ESI): m/z [M+ + Na] calcd for C32H46O9Na: 597.3042;
found: 597.3040.
(Z)-3-[(1E,3S,5E,9E,11Z,14R,15Z,17E)-19-tert-Butoxy-14-
methoxy-3,15,18-trimethyl-19-oxononadeca-1,5,9,11,15,17-
hexaenyl]pent-2-enedioic Acid (41)
Yield: 1.7 mg (quant.); colorless oil; [a]D27 +87.15 (c 0.99, CHCl3).
IR (neat): 2951, 2925, 2850, 1742, 1713, 1635, 1615, 1435, 1381,
1325, 1260, 1195, 1110, 1059, 969 cm–1.
To a solution of 40a (17.3 mg, 29.48 mmol) in THF (1 mL) at r.t.,
was added aq 6 M HCl (0.5 mL). After being stirred for 3.5 h, the
reaction mixture was extracted with CHCl3 (3 × 10 mL) and the ex-
tracts were washed with brine (5 mL), dried over Na2SO4 and con-
centrated. The residual oil was purified by chromatography on a
silica gel column (CHCl3–MeOH, 95:5) to afford 41.
1H NMR (400 MHz, CDCl3): d = 7.51 (d, J = 15.6 Hz, 2 H), 6.37 (d,
J = 15.6 Hz, 1 H), 6.27 (dd, J = 15.6, 11.2 Hz, 1 H), 6.05 (dd,
J = 15.6, 7.6 Hz, 1 H), 6.00 (t, J = 11.2 Hz, 1 H), 5.70 (s, 1 H), 5.68
(dt, J = 15.6, 6.8 Hz, 1 H), 5.47–5.31 (m, 2 H), 5.22 (dt, J = 11.2,
6.8 Hz, 1 H), 4.35 (t, J = 6.8 Hz, 1 H), 3.76 (s, 3 H), 3.71 (s, 3 H),
3.68 (s, 3 H), 3.32 (s, 2 H), 3.22 (s, 3 H), 2.59 (dt, J = 14.8, 6.8 Hz,
1 H), 2.41–2.32 (m, 2 H), 2.18–1.98 (m, 6 H), 1.95 (s, 3 H), 1.84 (s,
3 H), 1.03 (d, J = 6.8 Hz, 3 H).
Yield: 10.6 mg (66%); yellow oil; [a]D24 +58.62 (c 0.50, CHCl3).
IR (neat): 3400–3150 (br), 2926, 1698, 1633, 1601, 1384, 1368,
1241, 1194, 1119, 1059, 984, 948 cm–1.
13C NMR (100 MHz, CDCl3): d = 170.73, 169.14, 166.35, 147.26,
145.57, 144.98, 135.05, 132.17, 131.56, 130.59, 128.24, 126.46,
125.63, 125.01, 124.67, 124.37, 118.33, 78.38, 56.41, 52.19, 51.85,
51.17, 40.40, 39.70, 37.55, 32.94, 32.38, 32.10, 19.29, 18.68, 12.33.
1H NMR (400 MHz, CDCl3): d = 7.49 (d, J = 16.4 Hz, 1 H), 7.43 (d,
J = 12 Hz, 1 H), 6.35 (d, J = 12 Hz, 1 H), 6.28 (dd, J = 14.8, 11.2
Hz, 1 H), 6.12 (dd, J = 16.4, 7.6 Hz, 1 H), 5.99 (t, J = 11.2 Hz, 1 H),
5.75 (s, 1 H), 5.66 (dt, J = 14.8, 7.2 Hz, 1 H), 5.44–5.30 (m, 2 H),
5.17 (dt, J = 11.2, 6.8 Hz, 1 H), 4.39 (t, J = 6.8 Hz, 1 H), 3.40 (d,
J = 16 Hz, 1 H), 3.35 (d, J = 16 Hz, 1 H), 3.23 (s, 3 H), 2.62 (dt,
J = 14, 6.8 Hz, 1 H), 2.41–2.35 (m, 2 H), 2.16–2.04 (m, 6 H), 1.90
(s, 3 H), 1.83 (s, 3 H), 1.50 (s, 9 H), 1.04 (d, J = 6.8 Hz, 3 H).
HRMS (ESI): m/z [M+ + H] calcd for C31H45O7: 529.3165; found:
529.3165.
Acknowledgment
13C NMR (100 MHz, CDCl3): d = 174.61, 170.01, 168.23, 148.88,
145.85, 144.40, 134.99, 131.71, 131.28, 130.65, 128.30, 128.04,
125.64, 125.37, 124.68, 124.13, 118.04, 80.40, 78.47, 56.29, 40.29,
39.63, 37.68, 32.76, 32.13, 31.91, 28.12, 19.39, 18.50, 12.36.
The authors are grateful to Daiso Co., Ltd. for kindly providing (R)-
benzyl glycidyl ether. We also thank Professor Yoshiharu Iwabu-
chi, Tohoku University, for providing 1-Me-AZADO. This work
was supported in part by a Grant-in-Aid program for Promotion of
Basic and Applied Researches for Innovations in Bio-oriented Indu-
stry.
HRMS (ESI): m/z [M+ + H] calcd for C32H45O7: 541.3165; found:
541.3167.
Bongkrekic Acid (1)
References
To a solution of 40b (1.0 mg, 1.74 mmol) in THF (0.3 mL), was add-
ed aq 6 M HCl (0.2 mL, 1.2 mmol). After being stirred at r.t. for 3
h, H2O was added and the mixture was extracted with CHCl3 (3 ×
10 mL). The combined extracts were washed with brine (5 mL),
dried over Na2SO4, filtered and concentrated. The residue was puri-
fied by silica gel column chromatography (CHCl3–MeOH, 95:5) to
afford bongkrekic acid 1.
(1) (a) van Veen, A. G.; Mertens, W. K. Recl. Trav. Chim. Pays-
Bas 1934, 53, 257. (b) Lijimbach, G. W. M.; Cox, H. C.;
Berends, W. Tetrahedron 1970, 26, 5993. (c) Lijimbach, G.
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Tetrahedron 1973, 29, 1541. (e) Zyblir, J.; Gaudemer, F.;
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Yield: 0.7 mg (83%); yellow oil; [a]D25 –51.90 (c 0.624, CHCl3).
IR (neat): 3500–2400 (br), 2924, 2853, 1694, 1682, 1633, 1601,
1417, 1384, 1272, 1095, 983, 946, 869, 756 cm–1.
(2) Stubb, M. Pharmacol. Ther. 1979, 7, 329.
(3) (a) Marchetti, P.; Castedo, M.; Susin, S. A.; Zamzami, N.;
Hirsch, T.; Macho, A.; Haeffner, A.; Hirsh, T.; Geuskens,
M.; Kroemer, G. J. Exp. Med. 1996, 184, 1155.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 12.4 Hz, 1 H), 7.44 (d,
J = 16 Hz, 1 H), 6.34 (d, J = 12.4 Hz, 1 H), 6.29 (dd, J = 13.4, 12.4
Hz, 1 H), 6.05 (t, J = 10.4 Hz, 1 H), 6.00 (dd, J = 16, 8.0 Hz, 1 H),
5.77–5.71 (m, 1 H), 5.73 (s, 1 H), 5.46–5.26 (m, 3 H), 4.34 (dd,
J = 8.8, 4.4 Hz, 1 H), 3.46 (d, J = 16 Hz, 1 H), 3.32 (d, J = 16 Hz,
1 H), 3.21 (s, 3 H), 2.47 (dt, J = 13.6, 8.8 Hz, 1 H), 2.40–2.24 (m, 2
(b) Marchetti, P.; Hirsh, T.; Zamzami, N.; Castedo, M.;
Decaudin, D.; Susin, S. A.; Masse, B.; Kroemer, G.
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Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York

2904
M. Kanematsu et al.
PAPER
(15) (a) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.;
Moriwake, T.; Utimoto, K. Synlett 1995, 963. (b) Takai, K.;
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(24) Since the optical rotation of the trimethyl ester derived from
our synthetic BA was identical to that of the trimethyl ester
derived from the natural BA, it was revealed that the optical
rotation reported by Berends1b was incorrect.
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Synthesis 2009, No. 17, 2893–2904 © Thieme Stuttgart · New York