Total synthesis of (+)-tanikolide, using regioselective elimination of a vicinal dibromoalkane

Article abstract of DOI:10.1246/bcsj.78.1549

Total synthesis of (+)-tanikolide, a bioactive δ-lactone of marine origin, was successfully accomplished by utilizing a bromoalkene derivative conveniently synthesized from the corresponding 1-acyloxy-2,3-dibromoalkane by the regioselective and mild HBr-elimination reaction, along with the Pd-mediated C-C coupling reaction and the Sharpless asymmetric epoxidation as key steps.

Full text of DOI:10.1246/bcsj.78.1549

ꢀ 2005 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 78, 1549–1554 (2005) 1549
Total Synthesis of (þ)-Tanikolide, Using Regioselective
Elimination of a Vicinal Dibromoalkane
ꢀ
Tadaaki Ohgiya, Kensuke Nakamura,1 and Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522
1Quantum Bioinformatics Group, Center for Promotion of Computational Science and Engineering,
Japan Atomic Energy Research Institute, 8-1 Umemidai, Soraku-gun, Kyoto 619-0215
Received February 28, 2005; E-mail: nisiyama@chem.keio.ac.jp
Total synthesis of (þ)-tanikolide, a bioactive ꢀ-lactone of marine origin, was successfully accomplished by utiliz-
ing a bromoalkene derivative conveniently synthesized from the corresponding 1-acyloxy-2,3-dibromoalkane by the re-
gioselective and mild HBr-elimination reaction, along with the Pd-mediated C–C coupling reaction and the Sharpless
asymmetric epoxidation as key steps.
We recently reported an efficient synthesis of 2-bromo-1-al-
kenes by the regioselective HBr-elimination reaction from the
corresponding 1-O-substituted-2,3-dibromoalkanes under mild
basic conditions using DBU or sodium acylates (NaOAc,
NaOPiv).1 The synthesis of biologically active natural prod-
ucts was demonstrated by employing our own synthetic proto-
col of 2-bromo-1-alkenes, as convenient substrates of transi-
tion metal-mediated coupling reactions (Fig. 1).1a,1b In the case
of the elimination reaction of 1-O-substituted-2,3-dibromoal-
kanes, the syn-(1R ,2R ) and anti-orientated (1R ,2S ) deriv-
atives will be expected to undergo the trans-elimination lead-
ing to the corresponding bromoalkenes (I, II), which would be
converted into tri-substituted olefinic structures (III, IV). We
have demonstrated an availability of the substituted bromoal-
kenes towards natural products synthesis. As part of such in-
vestigations, (þ)-tanikolide 1,2 a biologically active ꢀ-lactone
natural product, was synthesized by introducing of chiral cen-
ters into the alkenes (Fig. 2).1c
(þ)-Tanikolide 1, possessing a structure closely related to
that of (ꢁ)-malyngolide 2,3 was isolated from the marine Cy-
anobacterium, Lyngbia majuscula, collected in Tanikeli Island,
Madagascar. A peculiar feature of 1 is the chiral quaternary
carbon center with a hydroxymethyl group and a multicarbon
chain. Upon comparison with 2, obtained from the same source
collected in Hawaii, 1 has the opposite absolute stereochemis-
try, different lengths of the alkyl chain, and various biological-
ly activities as follows. Whereas 1 exhibited antifungal activity
against Candida albicans, toxicity against brine shrimp (LD50
of 3.6 mg/mL) and snail (LD50 of 9.0 mg/mL), 2 showed anti-
microbial activity against Streptococcus pyogenes and Myco-
ꢀ
ꢀ
ꢀ
ꢀ
O
O
O
O
OH
OH
(+)-1: Tanikolide
(-)-2: Malyngolide
Fig. 2. Structure of tanikolide and malyngolide.
Br
Alkyl
OAcyl or Aryl
2
3
1
Br
syn-orientated 1,2-dibromides (1R*,2R*)
anti-orientated 1,2-dibromides (1R*,2S*)
OAcyl or Aryl
Br
Alkyl
OAcyl or Aryl
Alkyl
Br
(I)
(II)
OAcyl or Aryl
Alkyl
Alkyl
Alkyl
OAcyl or Aryl
Alkyl
(III)
(IV)
Fig. 1. Regioselective trans-elimination reaction of 1-O-substituted-2,3-dibromoalkanes and their derivatization into appropriately
functionalized units.
Published on the web August 4, 2005; DOI 10.1246/bcsj.78.1549

1550 Bull. Chem. Soc. Jpn., 78, No. 8 (2005)
Total Synthesis of (þ)-Tanikolide Utilizing Bromoalkenes
bacterium smegmatis, and no activity against C. albicans.2,3
To contribute information about the structure-activity relation-
ship of these bioactive lactones, several synthetic studies of 1
have already been reported.4 The first total synthesis of (þ)-1
was achieved by the asymmetric hydrogen transfer reaction of
a tricyclic alcohol.4a The ring-closing metathesis (RCM) ap-
proach for the construction of the ꢀ-lactone moiety as a key
step was reported by two groups.4c,4d
We describe herein a synthesis of 1 by our bromoalkene ap-
proach, which involved the Pd-mediated coupling reaction5
and the Sharpless asymmetric epoxidation.6 How to direct
the elimination reaction leading to the corresponding alkenes
was also evaluated by theoretical calculations.
tron-withdrawing effect of which would improve the yield and
regioselectivity of the HBr-elimination reaction of the vicinal
dibromide 7.1 Ester 6, obtained in quantitative yield, was sub-
mitted to bromination with Pyr.-HBr3 to yield the racemic 7 in
95% yield. Regioselective trans-elimination of the vicinal di-
bromide carrying the p-nitrobenzoyloxy group at the adjacent
position with DBU1 provided the bromoalkene derivatives 8, 9,
and 10 in 94% yield (8:9:10 = 60:1:1). Their stereochemistry
was determined by the 1H NMR techniques involving the NOE
experiments.
To explain the preferential production of 8 from 7, we car-
ried out theoretical calculations. For the ab initio DFT calcula-
ꢀ
tions at B3LYP/6-31+G level, 7a and a hydroxyl anion were
used as a model system (Scheme 3, Fig. 3). The first transition
state (TS1) leads to the product 8a, and the second transition
state (TS2) leads to 10a. TS1 is calculated to be ca. 1.0
kcal/mol more stable than TS2. The gas phase calculation in-
dicates that the elimination reaction of a hydrogen atom at the
C-2 position and a bromine atom at the C-3 atom to produce 8a
is more feasible than the elimination at the opposite side to
produce 10a. This is probably due to a high acidity of the hy-
drogen at C-2 position by an electron-withdrawing effect of a
O-functional group at C-1 position, as compared with that at
C-3 position. The computational result is in good agreement
with the experimental regioselectivity between 8a and 10a.
The selectivity between 8a and 9a can be explained in the fol-
lowing manner. Three conformations of 7a are shown in Fig. 4.
The anti-conformation (7aa) is ready for the trans ꢁ-elimina-
tion to form product 8a. To form 9a, it has to undergo cis ꢁ-
elimination from 7ab or 7ac, which is less feasible compared
with trans ꢁ-elimination.
Results and Discussion
According to the retrosynthetic analysis (Scheme 1), the
targeted natural product 1 would be synthesized from 3 by
utilizing the Sharpless asymmetric dihydroxylation,7 or the
Sharpless asymmetric epoxidation6 to construct the tertiary
alcohol moiety, and the following assembly of the lactone
framework. The tri-substituted alkene 3 may be afforded by
the Pd-mediated coupling reaction5 from key intermediate 4,
which can be produced from allyl alcohol 5 by the regioselec-
tive HBr-elimination reaction.1
According to this plan, synthesis of 1 was started from pro-
tection of 5 with a p-nitrobenzoyl group (Scheme 2), the elec-
OBOM
O
O
C
10H21
COOEt
OH
1
3
The p-nitrobenzoyloxy group should be converted into other
O-functional groups to prevent formation of a ꢂ-allyl com-
plex8 under Pd-mediated coupling conditions. Thus, hydrolysis
of a mixture of bromoalkene derivatives 8, 9, and 10 under
basic conditions, followed by chromatographic separation,
afforded 11 in 94% yield, which was etherified to give the
BOM ether 4 in 98% yield (Scheme 4).
OBOM
Br
C10H21
OH
C10H21
5
4
Scheme 1. Retrosynthesis of tanikolide.
NO2
NO2
Br
C10H21
OH
a
b
C10H21
O
C
10H21
O
O
Br
O
5
6
7
NOE: 10.5%
NO2
c
NO2
NO2
Br
H
O
C
10H21
O
C
10H21
O
+
H
+
O
O
Br
O
C9H19
Br
8
9
10
Scheme 2. Reagents and conditions: a) 4-O2NC6H4COCl, Pyr., CH2Cl2, rt (100%). b) Pyr.-HBr3, AcOH, rt (95%). c) DBU, DMF,
ꢂ
50 C (94%; 8:9:10 = 60:1:1).
OH-
Br
Br
O
O
O
O
+
+
O
Br
O
Br
O
Br
O
7a
8a
9a
10a
Scheme 3. Model system of regioselective elimination reaction with hydroxyl anion.

T. Ohgiya et al.
Bull. Chem. Soc. Jpn., 78, No. 8 (2005) 1551
ꢀ
Fig. 3. Transition states of proton abstraction from dibromoalkane by hydroxyl anion optimized at B3LYP/6-31+G (distances are
in angstrom).
Table 1. Pd-Mediated Coupling Reactions of
BrZn(CH2)3COOEt
4 with
H
H
H
Me
Br
H
Me
CH2OAc
Br
H
BrZn
COOEt
OBOM
Br
OBOM
Pd catlyst
Br
CH2OAc
Br
Br
CH2OAc
H
Br
Me
C10H21
C10H21
COOEt
toluene-THF
90°C
4
3
7aa
7ab
7ac
Fig. 4. Three conformations of model compound 7a.
Pd catalyst
(equiv mol)
Pd(Ph3P)4
BrZn(CH2)3CO2Et
(equiv mol)
Entry
Yields/%
1
2
3
4
5
6
0.05
0.05
0.15
0.05
2
3
3
3
3
3
38
73
46
24
28
11
OH
Br
a
Pd(dppf)Cl2
A mixture of 8, 9, and 10
C10H21
Pd2(dba)2
Pd(Ph3P)2Cl2 0.05
Pd(Et3P)2Cl2 0.05
11
OBOM
OBOM
Br
b
c
C10H21
COOEt
C10H21
asymmetric epoxidation6 to give 13 in 99% yield with 94%
ee.9 The siloxy ether 14, obtained from 13 in quantitative
yield, was submitted to reductive-opening reaction of the ep-
oxy ring with LiEt3BH to give a 1:1 mixture of diol 15 and
the silyl-migrated isomer 16 in 94% yield, which without
separation was oxidized with PCC to give a 6:1 mixture of
the six-membered ring lactone 17 and the seven-membered
ring lactone 18 in 60% yield. Finally, exposure of the mixture
4
3
Scheme 4. Reagents and conditions: a) LiOH, dioxane,
ꢂC, followed by chromatographic separation (94%).
b) BOMCl, iPr2NEt, CH2Cl2, rt (98%). c) 5 mol %
Pd(dppf)Cl2, BrZn(CH2)3COOEt, THF–PhMe, 90 ꢂC
(73%).
0
22
The following Pd-mediated coupling reaction5 of the bro-
mo-alkene system was a crucial step. After inspection of sev-
eral reaction conditions, the desired Pd-mediated coupling re-
action5 with BrZn(CH2)3COOEt was achieved upon employ-
to TBAF provided (þ)-1 in 87% yield, ½ꢃꢃD þ1:9 (c 1.0,
25
CHCl3) {lit., ½ꢃꢃD þ2:3 (c 0.65, CHCl3)}.2 The synthetic
(þ)-1 was identical to the natural product under the full range
of spectroscopic data.2
ꢂ
ing 5 mol % of Pd(dppf)Cl2 in THF–PhMe at 90 C to give
In conclusion, upon employing our efficient and simple
bromoalkene synthesis by the regioselective HBr-elimination
reaction, the stereoselective total synthesis of (þ)-1 was con-
veniently achieved. Our strategy will be applicable to several
related natural and artificial compounds for investigation of
their structure–activity relationships.
the tri-substituted olefin 3 in 73% yield (Table 1). Upon utiliz-
ing other Pd-catalysts, such as Pd(Et3P)4 and Pd2(dba)3, a
considerable amount of byproducts was produced, contrary
to the decrease of yield of 3. Upon employing 15 mol % of
Pd(dppf)Cl2, 3 was obtained in lower yield than the case of
5 mol % of the catalyst, probably owing to promotion of the
degradation reaction.
Experimental
In the next stage, we selected the Sharpless asymmetric ep-
oxidation6 for construction of a chiral quaternary carbon center
(Scheme 5), while the Sharpless asymmetric dihydroxylation7
of 3 did not proceed at low temperature, and the enantioselec-
tivity of the oxidation product was less than 50% ee9 at ambi-
ent temperature. The BOM group of 3 cleaved under acidic
conditions to give the allyl alcohol 12 in 80% yield, to which
a chiral center was successfully introduced by the Sharpless
General. All reactions were carried out under an argon atmo-
sphere unless otherwise noted. Optical rotations were measured on
a JASCO DIP-360 digital polarimeter with a sodium (D line)
lamp. IR spectra were recorded on a JASCO FT/IR-410 spectro-
photometer. 1H NMR spectra and 13C NMR spectra were obtained
on JEOL JNM-GX400 spectrometers in CDCl3 using tetramethyl-
silane as an internal standard. High-resolution mass spectra were
obtained on a Hitachi M-80B GC-MS spectrometer operating at

1552 Bull. Chem. Soc. Jpn., 78, No. 8 (2005)
Total Synthesis of (þ)-Tanikolide Utilizing Bromoalkenes
OH
OH
OBOM
a
b
C
10H21
COOEt
C10H21
COOEt
C10H21
COOEt
O
3
12
13
OTBDPS
c
OH
OH
d
+
C
10H21
COOEt
OTBDPS
OH
C11H23
C11H23
O
OH
OTBDPS
14
15
16
e
f
O
+
O
O
O
C11H23
O
O
C11H23
OH
OTBDPS
OTBDPS
(+)-1
17
18
ꢂ
Scheme 5. Reagents and conditions: a) conc. HCl, EtOH, 50 C (80%). b) D-(ꢁ)-DET, TBHP, Ti(OiPr)4, MS4A, CH2Cl2, ꢁ30 ꢂC
ꢂ
ꢂ
(99%). c) TBDPSCl, Imd, DMF, rt (100%). d) LiEt3BH, THF, 60 C (94%; 15:16 = 1:1). e) PCC, MS4A, CH2Cl2, 0 C (60%;
17:18 = 6:1). f) TBAF, THF, rt (87%).
the ionization energy of 70 eV. Preparative and analytical TLC
were carried out on silica-gel plates (Kieselgel 60 PF254, E. Merck
AG., Germany) using UV light and/or 5% molybdophosphoric
acid in ethanol for detection. Kanto Chemical silica 60N (spheri-
cal, neutral, 63–210 mm) was used for column chromatography.
Synthesis of (E)-2-Tridecenyl 4-Nitrobenzoate (6). To a so-
lution of (E)-2-tridecen-1-ol (5) (1.00 g, 5.0 mmol) in CHCl3 (20
mL) were successively added Pyr. (3.58 g, 45 mmol) and 4-nitro-
benzoyl chloride (1.23 g, 6.6 mmol) at 0 ꢂC; the mixture was stir-
red at ambient temperature for 2.5 h. The mixture was diluted with
CHCl3, and washed with 1 mol/L aq HCl, H2O, and brine. The
organic layer was dried (Na2SO4), and concentrated in vacuo.
The residue was purified by silica-gel column chromatography
(hexane:EtOAc = 100:1) to yield 6 (1.75 g, quantitative yield)
as a colorless oil: IR (film) 2925, 2854, 1728, 1608, 1531, 1464
H, 5.76; N, 2.76%. Found: C, 47.52; H, 5.83; N, 2.66%.
Synthesis of a Mixture of 8, 9, and 10. To a solution of 7
(2.25 g, 4.4 mmol) ꢂin DMF (22.5 mL) was added DBU (713
ꢂ
mg, 4.7 mmol) at 0 C; the mixture was stirred at 60 C for 1.5
h. The mixture was diluted with Et2O and washed with H2O
and brine. The organic layer was dried (Na2SO4), and concentrat-
ed in vacuo. The residue was purified by silica-gel column chro-
matography (hexane:EtOAc = 100:1) to yield a 60:1:1 mixture
of 8, 9, and 10 (1.77 g, 94%) as a colorless oil. Selected spectro-
scopic data of (E)-2-bromo-2-tridecenyl 4-nitrobenzoate 8 in the
mixture: IR (film) 2925, 2854, 1731, 1645, 1608, 1531, 1466
1
cmꢁ1. H NMR ꢀ 0.88 (3H, t, J ¼ 6:8 Hz), 1.18–1.42 (14H, m),
1.44 (2H, m), 2.23 (2H, q, J ¼ 8:0 Hz), 5.10 (2H, s), 6.23 (2H,
t, J ¼ 8:0 Hz), 8.26 (2H, d, J ¼ 8:8 Hz), 8.31 (2H, d, J ¼ 8:8
Hz). 13C NMR ꢀ 14.1, 22.7, 29.0, 29.1, 29.3, 29.4, 29.57, 29.59,
30.0, 31.9, 64.7, 116.5, 123.5 (ꢄ2), 130.8 (ꢄ2), 135.1, 139.4,
150.6, 164.0. HRMS calcd for C20H28O4N (Mþ ꢁ Br) 346.2018,
found m=z 346.2002.
1
cmꢁ1. H NMR ꢀ 0.88 (3H, t, J ¼ 6:8 Hz), 1.18–1.35 (14H, m),
1.41 (2H, m), 2.09 (2H, q, J ¼ 6:8 Hz), 4.81 (2H, d, J ¼ 6:8
Hz), 5.68 (1H, td, J ¼ 6:8, 15.6 Hz), 5.89 (1H, td, J ¼ 6:8, 15.6
Hz), 8.22 (2H, d, J ¼ 8:8 Hz), 8.29 (2H, d, J ¼ 8:8 Hz). 13C NMR
ꢀ 14.1, 22.7, 28.9, 29.2, 29.4, 29.5, 29.7 (ꢄ2), 32.0, 32.3, 66.7,
123.0, 123.4 (ꢄ2), 130.6 (ꢄ2), 135.7, 137.8, 150.4, 164.4. Calcd
for C20H29O4N: C, 69.14; H, 8.41; N, 4.03%. Found: C, 69.19; H,
8.53; N, 3.88%.
Synthesis of (E)-2-Bromo-2-tridecen-1-ol (11). To a solution
of a 60:1:1 mixture of 8, 9, and 10 (589 mg, 1.4 mmol) in dioxane
(20 mL) was added H2O (5.4 mL) solution of LiOH–H2O (72 mg,
1.7 mmol) at ambient temperature; the mixture was stirred at the
same temperature for 30 min. The mixture was then diluted with
CHCl3 and washed with H2O and brine. The organic layer was
dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by silica-gel column chromatography (hexane:EtOAc = 50:1)
to yield 11 (361 mg, 94%) as a colorless oil: IR (film) 3336, 2924,
ꢀ
ꢀ
Synthesis of (2R ,3S )-2,3-Dibromotridecyl 4-Nitroben-
zoate (7). To a solution of 6 (129 mg, 0.37 mmol) in AcOH
(2 mL) was added Pyr.-HBr3 (131 mg, 0.41 mmol) at ambient
temperature; the mixture was stirred at the same temperature for
3 h. The mixture was diluted with CHCl3, and washed with 1
mol/L aq HCl, H2O, sat. aq NaHCO3, and brine. The organic lay-
er was dried (Na2SO4), and concentrated in vacuo. The residue
was purified by silica-gel column chromatography (hexane:
EtOAc = 100:1) to yield 7 (179 mg, 95%) as a colorless oil: IR
2854, 1643, 1466 cmꢁ1
.
1H NMR ꢀ 0.88 (3H, t, J ¼ 6:8 Hz),
1.18–1.36 (14H, m), 1.39 (2H, m), 1.91 (1H, t, J ¼ 6:3 Hz),
2.11 (2H, q, J ¼ 7:8 Hz), 4.30 (2H, d, J ¼ 6:3 Hz), 6.02 (1H, t,
J ¼ 7:8 Hz). 13C NMR ꢀ 14.2, 22.7, 29.1, 29.2, 29.35, 29.40,
29.57, 29.62, 29.7, 31.9, 62.6, 124.1, 135.4. Calcd for C13H25OBr:
C, 56.32; H, 9.09%. Found: C, 56.23; H, 8.93%.
(film) 2925, 2854, 1731, 1608, 1531, 1456 cmꢁ1 1H NMR ꢀ
.
0.88 (3H, t, J ¼ 6:8 Hz), 1.18–1.45 (14H, m), 1.49 (2H, m),
1.94–2.05 (2H, m), 2.17–2.27 (2H, m), 4.30 (1H, dt, J ¼ 3:2,
8.8 Hz), 4.54 (1H, m), 4.84 (1H, dd, J ¼ 6:4, 12.4 Hz), 4.95
(1H, dd, J ¼ 3:2, 12.4 Hz), 8.25 (2H, d, J ¼ 8:8 Hz), 8.33 (2H,
d, J ¼ 8:8 Hz). 13C NMR ꢀ 14.2, 22.7, 26.6, 28.9, 29.35, 29.42,
29.55, 29.60, 31.9, 36.9, 53.1, 54.9, 68.2, 123.6 (ꢄ2), 130.8
(ꢄ2), 134.8, 150.7, 163.9. Calcd for C20H29O4NBr2: C, 47.36;
Synthesis of (E)-1-(Benzyloxymethyl)oxy-2-bromo-2-tri-
decene (4). To a solution of 11 (950 mg, 3.4 mmol) in CH2Cl2
(25 mL) were successively addeꢂd iPr2NEt (4.45 g, 34 mmol) and
BOMCl (2.68 g, 17 mmol) at 0 C; the mixture was stirred at the
same temperature for 20 h. The mixture was diluted with CHCl3,
and then washed with 1 mol/L aq HCl, H2O, and brine. The
organic layer was dried (Na2SO4), and concentrated in vacuo.

T. Ohgiya et al.
Bull. Chem. Soc. Jpn., 78, No. 8 (2005) 1553
1
The residue was purified by silica-gel column chromatography
(hexane:EtOAc = 50:1) to yield 4 (1.34 g, 98%) as a colorless
3454, 2925, 2854, 1738, 1464 cmꢁ1. H NMR ꢀ 0.88 (3H, t, J ¼
6:4 Hz), 1.18–1.63 (21H, m), 1.68–1.81 (2H, m), 1.89 (2H, ddd,
J ¼ 5:2, 10.8, 14.0 Hz), 2.33 (2H, t, J ¼ 6:8 Hz), 2.86 (1H, t, J ¼
6:0 Hz), 3.68 (1H, d, J ¼ 11:6 Hz), 3.76 (1H, d, J ¼ 11:6 Hz),
4.13 (2H, q, J ¼ 7:2 Hz). 13C NMR ꢀ 14.2, 14.3, 20.2, 22.7,
26.7, 28.1, 29.4, 29.5, 29.56, 29.57, 29.6, 31.9, 33.1, 34.1, 60.4,
61.9, 62.8, 63.7, 173.3. Calcd for C19H36O4: C, 69.47; H,
11.07%. Found: C, 69.31; H, 10.91%.
Synthesis of Ethyl (5S,6S)-5,6-Epoxy-5-[(tert-butyldimethyl-
silyl)oxy]methylhexadecanoate (14). To a solution of 13 (48
mg, 0.15 mmol) in DMF (1 mL) were successively added Iꢂmd
(90 mg, 1.3 mmol) and TBDPSCl (106 mg, 0.39 mmol) at 0 C;
the mixture was stirred at ambient temperature for 13 h. The
mixture was diluted with Et2O, and washed with H2O and brine.
The organic layer was dried (Na2SO4), and concentrated in vacuo.
The residue was purified by silica-gel column chromatography
(hexane:EtOAc = 2:1) to yield 14 (83 mg, quantitative yield) as
oil: IR (film) 2924, 2854, 1643, 1496, 1456 cmꢁ1 1H NMR ꢀ
.
0.88 (3H, t, J ¼ 6:4 Hz), 1.18–1.36 (14H, m), 1.37 (2H, m),
2.01 (2H, q, J ¼ 7:8 Hz), 4.34 (2H, s), 4.66 (2H, s), 4.80 (2H,
s), 6.14 (1H, t, J ¼ 7:8 Hz), 7.27–7.37 (5H, m). 13C NMR ꢀ
14.2, 22.7, 29.1, 29.2, 29.38, 29.43, 29.60, 29.63, 29.8, 31.9,
66.4, 69.6, 93.1, 119.9, 127.7, 127.9 (ꢄ2), 128.4 (ꢄ2), 137.6,
137.9. Calcd for C21H33O2Br: C, 63.47; H, 8.37%. Found: C,
63.55; H, 8.36%.
Synthesis of Ethyl (Z)-5-[(Benzyloxymethyl)oxy]methyl-5-
hexadecenoate (3). To a solution of 4 (790 mg, 2.0 mmol) in
toluene (24 mL) were successively added Pd(dppf)Cl2 (80 mg,
0.098 mmol) and BrZn(CH2)3COOEt (0.5 mol/L solution in
THF, 12 mL, 6.0 mmol) at 0 ꢂC; the mixture was stirred at 90
ꢂC for 1 h. The mixture was diluted with CHCl3, and washed with
1 mol/L aq HCl, H2O, and then brine. The organic layer was dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica-gel column chromatography (hexane:EtOAc = 50:1) to
yield 3 (627 mg, 73%) as a colorless oil: IR (film) 2925, 2854,
22
a colorless oil: ½ꢃꢃD þ1:1 (c 1.0, CHCl3); IR (film) 2927,
2856, 1736, 1589, 1464 cmꢁ1
.
1H NMR ꢀ 0.88 (3H, t, J ¼ 6:8
Hz), 1.07 (9H, s), 1.16–1.48 (21H, m), 1.63–1.78 (3H, m), 1.83
(1H, m), 2.30 (2H, t, J ¼ 7:2 Hz), 2.77 (1H, t, J ¼ 6:0 Hz),
3.63 (1H, d, J ¼ 11:6 Hz), 3.72 (1H, d, J ¼ 11:6 Hz), 4.12 (2H,
q, J ¼ 7:2 Hz), 6.35–7.46 (6H, m), 7.66 (2H, t, J ¼ 8:0 Hz),
7.67 (2H, t, J ¼ 8:0 Hz). 13C NMR ꢀ 14.2, 14.3, 19.3, 20.3,
22.7, 26.8, 26.9 (ꢄ3), 28.1, 29.4, 29.52, 29.56, 29.60, 29.64,
32.0, 33.0, 34.5, 60.3, 62.6, 63.1, 63.4, 127.6 (ꢄ2), 129.7 (ꢄ2),
132.7 (ꢄ2), 133.2 (ꢄ2), 135.5 (ꢄ2), 135.6 (ꢄ2), 173.2. Calcd
for C35H54O4Si: C, 74.15; H, 9.60%. Found: C, 74.07; H, 9.47%.
Synthesis of (5R)-5-[(tert-Butyldimethylsilyl)oxy]methyl-5-
undecyl-ꢀ-hexadecylolactone (17) and (5R)-5-(tert-Butyldi-
methylsilyl)oxy-5-undecyl-"-hexylolactone (18). To a solution
of 14 (83 mg, 0.15 mmol) in dry THF (0.5 mL) was added
LiEt3BH (1.0 mol/L solution in THF, 1.5 mL, 1.5 mmol) at 0
ꢂC; the mixture was stirred at 60 ꢂC for 15 min. The mixture
was diluted with CHCl3, and then washed with H2O and brine.
The organic layer was dried (Na2SO4), and concentrated in vacuo.
The residue was purified by silica-gel column chromatography
(hexane:EtOAc = 3:2) to yield a 1:1 mixture of 15 and 16 (72.5
mg, 94%) as a colorless oil: IR (film) 3365, 2927, 2854, 1589,
1736, 1496, 1456 cmꢁ1
.
1H NMR ꢀ 0.88 (3H, t, J ¼ 6:4 Hz),
1.18–1.45 (19H, m), 1.77 (2H, quintet, J ¼ 7:2 Hz), 2.07 (2H,
q, J ¼ 7:2 Hz), 2.13 (2H, t, J ¼ 7:2 Hz), 2.29 (2H, t, J ¼ 7:2
Hz), 4.11 (2H, s), 4.12 (2H, q, J ¼ 7:6 Hz), 4.62 (2H, s), 4.74
(2H, s), 5.41 (1H, t, J ¼ 7:2 Hz), 7.27–7.37 (5H, m). 13C NMR
ꢀ 14.2, 14.3, 22.7, 23.4, 27.8, 29.35, 29.38, 29.6, 29.66, 29.67,
30.0, 31.9, 33.9, 34.7, 60.2, 64.4, 69.3, 93.7, 127.6, 127.7 (ꢄ2),
128.3 (ꢄ2), 131.0, 134.0, 137.9, 173.6. Calcd for C27H44O4: C,
74.96; H, 10.25%. Found: C, 74.88; H, 10.07%.
Synthesis of Ethyl (Z)-5-Hydroxymethyl-5-hexadecenoate
(12). To a solution of 3 (746 mg, 1.7 mmol) inꢂEtOH (25 mL)
were added conc. ꢂHCl (1.25 mL, 15 mmol) at 0 C; the mixture
was stirred at 50 C for 7 h. The mixture was then diluted with
CHCl3, and washed with H2O and brine. The organic layer was
dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by silica-gel column chromatography (hexane:EtOAc = 6:1)
to yield 12 (431 mg, 80%) as a colorless oil: IR (film) 3437, 2924,
2854, 1738, 1463 cmꢁ1
.
1H NMR ꢀ 0.88 (3H, t, J ¼ 6:8 Hz),
1.20–1.38 (19H, m), 1.78 (2H, quintet, J ¼ 7:6 Hz), 2.05 (2H,
q, J ¼ 7:6 Hz), 2.15 (2H, t, J ¼ 7:6 Hz), 2.30 (2H, t, J ¼ 7:6
Hz), 4.12 (2H, q, J ¼ 6:8 Hz), 4.14 (2H, s), 5.32 (1H, t, J ¼ 7:2
Hz). 13C NMR ꢀ 14.2, 14.3, 22.7, 23.5, 27.6, 29.34, 29.38, 29.6,
29.7 (ꢄ2), 30.1, 32.0, 33.8, 34.5, 60.2, 60.3, 129.7, 137.1,
173.8. Calcd for C19H36O3: C, 73.03; H, 11.61%. Found: C,
72.94; H, 11.55%.
1464 cmꢁ1. H NMR ꢀ 0.88 (3H, t, J ¼ 6:8 Hz), 0.90 (4.5H, s),
1
1.04 (4.5H, s), 1.16–1.64 (27H, m), 3.40 (1H, s), 3.48 (1H, s),
3.53 (1H, t, J ¼ 6:4 Hz), 3.62 (1H, t, J ¼ 6:4 Hz), 6.35–7.52
(6H, m), 7.63 (2H, d, J ¼ 6:4 Hz), 7.72 (2H, d, J ¼ 6:4 Hz). Calcd
for C33H54O5Si 0.2H2O: C, 74.72; H, 10.34%. Found: C, 74.61;
ꢅ
H, 10.17%.
Synthesis of Ethyl (5R,6S)-5,6-Epoxy-5-hydroxymethyl-
hexadecanoate (13).
To a solution of 1:1 mixture of 15 and 16 (72 mg, 0.14 mmol)
in dry CH2Cl2 (3 mL) were successively added MS4A powder
(100 mg) and PCC (155 mg, 0.72 mmol) at 0 ꢂC; the mixture
was stirred at the same temperature for 1 h. The mixture was fil-
tered and concentrated in vacuo. The residue was purified by prep-
arative TLC (hexane:acetone = 6:1) to yield a 6:1 mixture of 17
and 18 (43 mg, 60%) as a colorless oil: IR (film) 2927, 2854,
To a solution of D-(ꢁ)-DET (83 mg,
0.40 mmol) in dry CH2Cl2 (1 mL) were successively added
Ti(OiꢂPr)4 (116 mg, 0.41 mmol) and MS4A powder (100 mg) at
ꢁ30 C; the mixture was stirred at the same temperature for 20
min. To the reaction mixture were successively added 12 (90
mg, 0.29 mmol) in dry CH2Cl2 (3 mL) and TBHP (5.1 mol/L
in isooctane, 130 mL, 0.66 mmol) at ꢁ30 ꢂC; the mixture was
stirred at ꢁ30 ꢂC for 10 h. To the reaction mixture was added
1741, 1589, 1464 cmꢁ1
.
1H NMR ꢀ 0.88 (3H, t, J ¼ 6:8 Hz),
1.02 (1.26H, s), 1.06 (7.74H, s), 1.16–1.45 (18H, m), 1.60–1.90
(5.14H, m), 2.04 (0.86H, m), 2.45 (1.72H, t, J ¼ 6:8 Hz), 2.47
(0.28H, t, J ¼ 6:8 Hz), 3.56 (0.86H, d, J ¼ 10:4 Hz), 3.60
(0.86H, d, J ¼ 10:4 Hz), 3.82 (0.14H, d, J ¼ 12:8 Hz), 3.98
(0.14H, d, J ¼ 12:8 Hz), 6.35–7.47 (6H, m), 7.65 (3.44H, dd,
J ¼ 1:2, 8.0 Hz), 7.70–7.73 (0.56H, m). HRMS calcd for
ꢂ
10% H2O solution of L-(þ)-tartaric acid (3 mL) at ꢁ20 C; the
mixture was stirred at the same temperature for 30 min. After
the mixture was stirred at ambient temperature for 1 h, the mixture
was filtered, the filtrate was diluted with CHCl3, then washed with
H2O and brine. The organic layer was dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by silica-gel column
chromatography (hexane:EtOAc = 6:1) to yield 13 (94 mg, 99%,
C29H41O3Si (Mþ ꢁ Bu) 465.2825, found m=z 465.2832. This
t
mixture was submitted to the next reaction without further purifi-
cation.
22
94% ee9) as a colorless oil: ½ꢃꢃD ꢁ5:7 (c 1.0, CHCl3); IR (film)

1554 Bull. Chem. Soc. Jpn., 78, No. 8 (2005)
Total Synthesis of (þ)-Tanikolide Utilizing Bromoalkenes
Clardy, J. Org. Chem., 44, 4039 (1979).
Synthesis of (þ)-Tanikolide (1). To a solution of the 6:1 mix-
ture of 17 and 18 (43 mg, 0.082 mmol) in THF (1 mL) was added
TBAF (1 mol/L in THF, 150 mL, 0.15 mmol) at 0 ꢂC; the mixture
was stirred at ambient temperature for 1 h. The mixture was con-
centrated in vacuo. The residue was purified by silica-gel column
chromatography (hexane:EtOAc = 1:1) to yield 1 (20.4 mg, 87%)
4
a) R. M. Kanada, T. Taniguchi, and K. Ogasawara, Synlett,
2000, 1019. b) H. Tanaka, Y. Kozuki, and K. Ogasawara, Tetra-
hedron Lett., 43, 4175 (2002). c) H. Mizutani, M. Watanabe,
and T. Honda, Tetrahedron, 58, 8929 (2002). d) M. Carda, S.
Rodriguez, E. Castillo, A. Bellido, S. Diaz-Oltra, and J. A. Marco,
Tetrahedron, 59, 857 (2003). e) A. E. Koumbis, K. M. Dieti,
M. G. Vikentiou, and J. K. Gallos, Tetrahedron Lett., 44, 2513
(2003). f) J. M. Schomaker and B. Borhan, Org. Biomol. Chem.,
2, 621 (2004).
22
as a colorless oil: ½ꢃꢃD þ1:9 (c 1.0, CHCl3); IR (film) 3417,
1
2924, 2854, 1730, 1710, 1466 cmꢁ1. H NMR ꢀ 0.88 (3H, t, J ¼
6:4 Hz), 1.23–1.40 (18H, m), 1.55–1.78 (4H, m), 1.82–1.95 (2H,
m), 2.12 (1H, br), 2.42–2.55 (2H, m), 3.55 (1H, d, J ¼ 12:0
Hz), 3.66 (1H, d, J ¼ 12:0 Hz). 13C NMR ꢀ 14.2, 16.7, 22.7,
23.5, 26.6, 29.4, 29.5, 29.58, 29.63, 29.7, 29.8, 30.0, 31.9, 36.6,
5 E. Negishi, L. F. Valente, and M. Kobayashi, J. Am. Chem.
Soc., 102, 3298 (1980).
67.5, 86.5, 171.5. Calcd for C17H32O3 0.2H2O: C, 70.89; H,
ꢅ
6
a) M. G. Finn and K. B. Sharpless, ‘‘On the Mechanism
11.34%. Found: C, 70.73; H, 11.24%.
of Asymmetric Epoxidation with Titanium-Tartrate Catalysts.
Asymmetric Synthesis,’’ ed by J. D. Morrison, Academic, Tokyo
(1985), Vol. 5, pp. 247–308. b) T. Katsuki and K. B. Sharpless,
J. Am. Chem. Soc., 102, 5974 (1980).
This work was supported by a Grant-in-Aid for the 21st
Century COE program ‘‘KEIO Life Conjugate Chemistry’’,
as well as Scientific Research C from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
7
a) K. B. Sharpless, W. Amberg, M. Beller, H. Chen J.
Hartung, Y. Kawanami, D. Lubben, E. Manoury, Y. Ogino, T.
Shibata, and T. Ukita, J. Org. Chem., 56, 4585 (1991). b) K. B.
Sharpless, W. Amberg, Y. L. Bennai, G. A. Crispino, J. Hartung,
K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, and
X.-L. Zhang, J. Org. Chem., 57, 2768 (1992).
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J. H. Cardllina, II, R. E. Moore, E. V. Arnold, and J.
9
The optical purity was determined by the 400 MHz
1H NMR spectra of the corresponding MTPA esters.
3