Enantioselective total synthesis of δ-lactonic marine natural products, (+)-tanikolide and (-)-malyngolide, via RCM reaction

Article abstract of DOI:10.1016/S0040-4020(02)01160-2

Enantioselective total synthesis of δ-lactonic marine natural products, (+)-tanikolide and (-)-malyngolide isolated from Lyngbya majuscula, was achieved by using the Sharpless asymmetric epoxidation and a ring-closing metathesis, as key reactions.

Full text of DOI:10.1016/S0040-4020(02)01160-2

Tetrahedron 58 (2002) 8929–8936
Enantioselective total synthesis of d-lactonic marine natural
products, (1)-tanikolide and (2)-malyngolide, via RCM reaction
*
Hirotake Mizutani, Masayuki Watanabe and Toshio Honda
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
Received 20 August 2002; revised 9 September 2002; accepted 17 September 2002
Abstract—Enantioselective total synthesis of d-lactonic marine natural products, (þ)-tanikolide and (2)-malyngolide isolated from
Lyngbya majuscula, was achieved by using the Sharpless asymmetric epoxidation and a ring-closing metathesis, as key reactions. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
1
2
(
þ)-Tanikolide and (2)-malyngolide, both isolated from
the lipid extract of the marine cyanobacterium Lymgbia
majuscula, are naturally occurring d-lactonic bioactive
compounds, which contain a chiral quaternary carbon
center with a hydroxymethyl group as a common structural
feature. The structures of these compounds including the
absolute stereochemistries were determined by spectro-
scopic methods and also by the total synthesis. (þ)-
Tanikolide exhibited antifungal activity against Candida
albicans, and also showed an LD50 of 3.6 mg/ml against
3
,4
Scheme 1. Retrosynthetic analysis for (þ)-tanikolide and (2)-malyngolide.
1
brine shrimp and 9.0 mg/ml against the snail. It is also
known that (þ)-tanikolide has an opposite configuration at
the C-5 position to that of (2)-malyngolide showing
antimicrobial activity against Streptococcus pyogenes but
compounds, we are interested in the synthesis of both (þ)-
tanikolide 1 and (2)-malyngolide 2 by using a common
synthetic strategy.
1
no activity to C. albicans (Fig. 1).
Our retrosynthetic analysis for (þ)-tanikolide and (2)-
malyngolide is shown in Scheme 1, where introduction of a
chiral quaternary carbon center should readily be achieved
5
In 1990, we reported the enantioselective synthesis of (2)-
malyngolide, where the oxidative ring transformation of a
furylcarbinol derivative to the corresponding pyranone was
employed as the key reaction. As an extension of our work
on the synthesis of biologically active lactonic natural
6
by the Sharpless asymmetric epoxidation of allyl alcohol 6,
followed by regioselective epoxy-ring opening of chiral
epoxide 5 with a vinyl group. Moreover, we decided to
utilize a ring-closing metathesis (RCM) of diene 3, easily
derived from tert-alcohol 4, for the construction of a
d-lactone moiety, since this reaction seems to be one of the
most promising methods for the construction of both
7
carbacyclic and heterocyclic ring systems.
Thus, the starting materials were prepared as follows.
Figure 1. Structures (þ)-tanikolide and (2)-malyngolide.
2
. Results and discussion
Keywords: ring-closing metathesis; (þ)-tanikolide; (2)-malyngolide;
marine natural product; lactonic compound.
*
8
Treatment of tridecanal 7 with the Eschenmoser salt gave
a-methylene aldehyde 9, which, on reduction with sodium
Corresponding author. Tel.: þ81-3-5498-5791; fax: þ81-3-3787-0036;
e-mail: honda@hoshi.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01160-2

8930
H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
Scheme 3. Synthesis of (þ)-tanikolide. Reagents and conditions: (i) TsOH,
EtOH/H O (4:1), 808C (98%); (ii) H , 5% Pd–C, hexane, room temperature
85%); (iii) TBAF, THF, 08C (50% for 19, 43% for 18).
2
2
(
Scheme 2. Preparation of starting materials. Reagents and conditions:
i) methylene-N,N-dimethylammonium iodide, Et N, CH Cl , room
temperature (72% for 9, 81% for 10); (ii) NaBH , CeCl , MeOH, 08C to
room temperature (98% for 11, 90% for 12); (iii) L-(þ)-DIPT, Ti(O Pr)
TBHP, CaH , MS 3A, CH Cl , 2208C (82%); (iv) CuI, vinylmagnesium
bromide, THF, 2208C (69%); (v) TBSOTf, Pr
vi) EtMgBr, acryloyl chloride, THF, room temperature (74%).
(
3
2
2
found to be effective even with the use of 1 mol% of the
catalyst (B).
4
3
i
4
,
2
2
2
i
2
2 2
NEt, CH Cl , 08C (100%);
(
9
borohydride in the presence of cerium chloride in MeOH
furnished allyl alcohol 11 (Scheme 2).
The Sharpless asymmetric epoxidation of 11 with tert-butyl
hydroperoxide, titanium tetra-isopropoxide and L-(þ)-
diisopropyl tartrate gave epoxide 13 in 82% yield, whose
optical purity was determined as 96% ee based on the HPLC
analysis of its benzoate using the chiral stationary phase
Desilylation of d-lactone 17 with TBAF in THF gave the
desired primary alcohol 18 in 43% yield together with the
intramolecular 1,4-addition product 19 in 50% yield
(Scheme 3).
(
CHIRALCEL OB, Daicel Chemical Industries). Regio-
However, treatment of 17 with p-toluenesulfonic acid in
aqueous ethanol afforded 18 as the sole product in 98%
yield. Finally, catalytic hydrogenation of a,b-unsaturated
d-lactone 18 over 5% palladium on carbon under an
atmospheric pressure of hydrogen in hexane furnished
selective ring-opening of epoxide 13 was achieved by
treatment with vinylmagnesium bromide in the presence
of copper(I) iodide to provide the desired tert-alcohol
1
4. After protection of the primary hydroxy group of 14 as
a silyl ether, acylation of 15 was achieved by treatment
with ethylmagnesium bromide as the base and acryloyl
chloride to yield diene 16. Since we were able to establish
a convenient procedure for the preparation of a key
precursor in optically active form, our attention was
focused on searching for the best reaction conditions for
RCM.
(þ)-tanikolide 1, mp 44–468C; [a] ¼þ1.93 (c¼0.6,
D
4
b
CHCl ) {lit.,
3
mp 38–408C, [a] ¼þ2.3 (c¼0.7,
D
CHCl )}, whose spectroscopic data including specific
3
4
b
optical rotation value were identical with those reported.
Since we succeeded in the enantioselective synthesis of (þ)-
tanikolide in relatively short reaction sequences as above,
we decided to apply this strategy to the synthesis of (2)-
malyngolide 2. Recently, Marco et al. reported a similar
First, diene 16 was subjected to RCM by using 5 mol% of
1
0
4c
Grubbs’ reagent (A) as the catalyst in benzene at 708C for
5 h, where the desired a,b-unsaturated d-lactone 17 was
synthetic approach to (2)-malyngolide, in which they
1
observed that the RCM of the diene derived from tert-
alcohol with methacryloyl chloride afforded none of the
desired product, unfortunately. We, however, thought that
this type of cyclization would be a reasonable approach to
(2)-malyngolide based on the above results, and worth
attempting by using our own substrate. Thus, allyl alcohol
isolated in 86% yield (Table 1). When this reaction was
carried out in the presence of 5 mol% of Hoveyda-
recyclable ruthenium catalyst (B), which is known to be a
1
1
highly reactive catalyst for RCM, the yield was increased
to 96% as expected. It is noteworthy that this reaction was
12 was prepared from undecanal 8 by two steps, via 10, in
73% overall yield. As the configuration at the quaternary
chiral center of (2)-malyngolide was opposite to that of
tanikolide, D-(2)-diisopropyl tartrate was employed in the
Sharpless asymmetric epoxidation to produce chiral epoxide
Table 1. RCM for compound 16
1
2
20 with 95% ee (Scheme 4).
After ring-opening of epoxide 20 with vinylmagnesium
bromide, the resulting diol 21 was converted into mono-silyl
ether 22 as above, and then the remaining tert-hydroxy
group of 22 was acylated with methacryloyl chloride in the
presence of ethylmagnesium bromide as the base to give
ester 23 accompanied with the acyl rearranged product 24 in
a
Yield (%)
Catalyst
Mol%
Time (h)
Temperature (8C)
A
B
C
5
5
1
15
3
3
70
70
70
86
96
.99
48 and 43% yields, respectively. Attempted RCM of 23 with
5 mol% of Grubbs’ catalyst (A) for 15 h produced the
All reactions were carried out in benzene.
a
Isolated yield.

H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
8931
4.1.1. 2-Methylidenetridecanal (9). To a stirred solution of
tridecanal (5.0 g, 25.2 mmol) and triethylamine (10.5 ml,
75.6 mmol) in CH Cl was added Eschenmoser’s salt (9.3 g,
2 2
50.4 mmol) at ambient temperature, and the resulting
mixture was stirred for further 15 h. After addition of
saturated aqueous NaHCO3 solution, the mixture was
extracted with CH Cl , and the extract was dried over
2
2
Na SO . Evaporation of the solvent gave a residue, which
2
4
was purified by silica gel column chromatography (hexane/
AcOEt, 7:1) to afford compound 9 (3.8 g, 72%) as a
1
colorless oil. H NMR: d 0.88 (3H, t, J¼6.7 Hz, 13-CH ),
3
1
1
5
1
2
.20–1.35 (16H, br s, 5-, 6-, 7-, 8-, 9-, 10-, 11- and 12-CH ),
2
.35–1.51 (2H, m, 4-CH ), 2.23 (2H, t, J¼7.4 Hz, 3-CH ),
2
2
.98 (1H, d, J¼0.7 Hz, 14-CHH), 6.24 (1H, d, J¼0.7 Hz,
1
3
4-CHH), 9.54 (1H, s, CHO); C NMR: d 14.1, 22.7, 27.8,
9.2, 29.3, 29.4, 29.5, 29.6, 31.9, 133.8, 150.4, 194.8; IR
Scheme 4. Synthesis of (2)-malyngolide. Reagents and conditions:
(
(thin film): 1697, 1628, 1466, 940, 770, 725. Anal. calcd for
C H O: C, 79.94; H, 12.46. Found: C, 79.84; H, 12.20;
HRMS calcd for C H O (M ): 210.1984, found 210.2008.
14 26
i
i) D-(2)-DIPT, Ti(O Pr)
ii) Cul, vinylmagnesium bromide, THF, 2208C (77%); (iii) TBSOTf,
4 2 2 2
, TBHP, CaH , MS 3A, CH Cl , 2208C (83%);
1
4 26
(
þ
i
Pr
208C (48% for 23, 43% for 24); (v) catalyst B (5 mol%), benzene, 708C
88%); (vi) TsOH, EtOH/H2O (4:1), 808C (96%); (vii) H , 5% Pd–C,
2
NEt, CH
2
Cl
2
, 08C (95%); (iv) EtMgBr, methacryloyl chloride, THF,
2
(
2
4.1.2. 2-Methylidenetridecan-1-ol (11). To a solution of
CeCl ·7H O (5.0 g, 13.3 mmol) in MeOH (35.0 ml) were
hexane, room temperature (80% for 2, 12% for 27).
3
2
added successively NaBH4 (0.75 g, 20.0 mmol) and a
solution of aldehyde 9 (1.6 g, 6.67 mmol) in MeOH
(5.0 ml) at 08C. After being stirred for 2 h at room
temperature, the reaction was quenched by addition of
saturated aqueous NaHCO solution and the organic solvent
3
was evaporated to leave a residue. The residue was filtered
through the Celite pad, and the filtrate was extracted with
desired product 25 in 34% yield, fortunately. When 1 mol%
of the Hoveyda-recyclable ruthenium catalyst (B) was used
in the reaction, yield was increased to 68%. Finally, the best
yield (88%) was obtained by the use of 5 mol% of the
catalyst in benzene at 708C for 7 h. In order to accomplish
the total synthesis, deprotection of the silyl group of 25 with
p-toluenesulfonic acid in aqueous ethanol was carried out to
give the primary alcohol 26, which, on catalytic reduction
over 5% palladium on carbon under an atmosphere of
AcOEt. The organic layers were dried over Na SO , and
2 4
concentrated under reduced pressure to leave a residue,
which was purified by column chromatography on silica gel
(hexane/AcOEt, 7:1) to give allyl alcohol 11 (1.8 g, 96%) as
hydrogen, afforded (2)-malyngolide 2, [a] ¼213.8
D
4
d
1
(c¼0.7, CHCl ) {lit., [a] ¼213 (c¼2, CHCl )}, and
epi-malyngolide 27, in 80 and 12% yields, respectively.
a colorless oil. H NMR: d 0.88 (3H, t, J¼6.6 Hz, 13-CH
),
3
3
D
3
1.26–1.36 (18H, m, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- and
12-CH
), 1.44 (1H, t, J¼7.6 Hz, OH), 2.06 (2H, dd, J¼7.3,
7.9 Hz, 3-CH ), 4.87 (1H,
), 4.08 (2H, d, J¼6.1 Hz, 1-CH
dd, J¼1.2, 2.5 Hz, 14-CHH), 5.00 (1H, dd, J¼0.7, 1.5 Hz,
Again, the spectroscopic data of these compounds were
5
identical with those reported.
2
2
2
1
3
1
4-CHH); C NMR: d 14.1, 22.7, 27.8, 29.3, 29.4, 29.4,
29.5, 29.6, 31.9, 33.0, 65.9, 108.9, 149.3; IR (thin film):
310, 1660, 1465, 1027 890; HRMS calcd for C H O
3. Conclusion
3
1
4 28
þ
Thus, we have succeeded in the synthesis of (þ)-tanikolide
and (2)-malyngolide in relatively short steps by using a
common synthetic strategy, where RCM played an import-
ant role for the construction of heterocyclic ring systems.
Further applications of this methodology to the synthesis of
biologically active compounds including natural products
are in progress in this laboratory.
(M ): 212.2140, found 212.2148.
4.1.3. (2S)-2,3-Epoxy-2-undecanylpropan-1-ol (13). To a
stirred suspension of activated MS 3A (0.30 g) and CaH
(40 mg, 0.94 mmol) in CH Cl (2.5 ml) was added
(0.35 ml, 1.18 mmol) at room temperature. The
2
2
2
i
Ti(O Pr)
4
stirred mixture was cooled to 2208C, and treated with
L-(þ)-DIPT (0.33 g, 1.42 mmol) in CH Cl (2.0 ml). After
2
2
being stirred for 30 min at the same temperature, a solution
of allyl alcohol 11 (1.0 g, 4.72 mmol) in CH Cl (12.0 ml)
2 2
4. Experimental
was added dropwise to the solution, and the mixture was
stirred for further 1 h. TBHP (1.3 ml, 7.08 mmol) was then
added to this mixture over a period of 30 min. After being
4
.1. General experimental procedures
Melting points were measured with a Yanagimoto MP
apparatus and are uncorrected. IR spectra were obtained
using a JASCO FT/IR-200 spectrophotometer as thin films.
stirred for 48 h at 2208C, Me S (0.42 ml, 5.64 mmol) was
2
slowly added and the mixture was stirred for further 30 min
at the same temperature. To this mixture were added 10%
aqueous of tartaric acid (2.8 ml, 1.88 mmol), NaF (1.2 g,
29.2 mmol) and Et O (7.9 ml), and the resulting mixture
2
was vigorously stirred for 2 h at room temperature. The
precipitate was filtered off through a Celite pad. The filtrate
1
13
H NMR and C NMR spectra were obtained on JEOL
1
13
LAMBDA-270 ( H NMR: 270 MHz, C NMR: 76.8 MHz)
instrument for solutions in CDCl , and chemical shifts are
3
reported on the d-scale from internal TMS. MS spectra were
measured with a JEOL JMS-D 300 spectrometer. Elemental
analyses were performed on a Yanaco-MT5.
was washed successively with saturated aqueous NaHCO
solution and brine, and dried over Na SO . Evaporation of
3
2
4

8932
H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
the solvent gave a residue, which was purified by column
chromatography on silica gel (hexanes/AcOEt, 1:1) to give
epoxy alcohol 13 (0.88 g, 82%) as a colorless oil.
NMR: d 14.1, 22.7, 23.3, 29.3, 29.6, 30.2, 31.9, 36.3, 40.6,
67.9, 74.2, 118.8, 133.4; IR (thin film): 3390, 1640, 1470,
1060, 998, 912, 720. Anal. calcd for C H O : C, 74.94; H,
1
6 32 2
25
1
[
a] ¼212.6 (c¼1.05, CHCl ); H NMR: d 0.88 (3H, t,
12.58. Found: C, 75.15; H, 12.60; HRMS calcd for
þ
D
3
0
-, 7 -, 8 -, 9 - and 10 -CH ), 1.44–1.84 (2H, m, 1 -H ), 2.67
0
0
0
0
J¼6.7 Hz, 11 -CH ), 1.24–1.41 (18H, br s, 2 -, 3 -, 4 -, 5 -,
C H O (M 2H O): 239.2375, found 239.2389.
2
3
16 32
2
0
0
0
0
0
0
6
2
2
and 2.88 (each 1H, each d, J¼4.6 Hz, 3-CH ), 3.64 (1H, dd,
4.1.6. (4R)-4-(tert-Butyldimethylsilyloxymethyl)penta-
dec-1-en-4-ol (15). Diol 14 (810 mg, 3.16 mmol) and
2
J¼8.3, 12.2 Hz, 1-CHH), 3.78 (1H, dd, J¼3.6, 12.2 Hz,
1
3
i
1
2
1
7
-CHH); C NMR: d 14.0, 22.6, 24.6, 29.3, 29.4, 29.6,
9.7, 31.8, 31.9, 49.8, 60.0, 62.7; IR (thin film): 3440, 3050,
470, 1050, 895, 810, 720. Anal. calcd for C H O : C,
Pr NEt (1.30 ml, 7.59 mmol) were dissolved in CH Cl
2
2
2
(16.0 ml) under argon atmosphere. After being cooled to
08C, TBSOTf (0.90 ml, 3.80 mmol) was added dropwise to
the solution, and the mixture was stirred for further 30 min
at the same temperature. The reaction was quenched by
1
4 28 2
3.63; H, 12.36. Found: C, 73.42; H, 12.35; HRMS calcd for
þ
C H O (M ): 228.2089, found 228.2070. The ee of the
1
4 28 2
benzoate of 13 was determined to be 96% by HPLC analysis
on a Chiralcel OB (Daicel Chemical Industries) using
hexane– PrOH (99.5:0.5, v/v).
addition of saturated aqueous NH Cl solution and extracted
4
with CH Cl . The organic layers were washed with brine,
2
2
i
dried over Na SO , and removed volatiles under reduced
2 4
pressure. The residue was purified by column chromato-
graphy on silica gel (hexanes/AcOEt, 1:1) to afford alcohol
4.1.4. (2R)-1-Benzoyloxy-2,3-epoxy-2-undecanylpro-
pane. To a stirred solution of epoxy alcohol 13 (100 mg,
2
2
15 (1.17 g, 100%) as a colorless oil. [a] ¼þ5.81 (c¼1.07,
D
1
0
.44 mmol) in CH Cl (4.4 ml) was added Et N (0.18 ml,
3
CHCl ); H NMR: d 0.07 (6H, s, 2£SiMe), 0.86–0.93 (12H,
2
2
3
1
.32 mmol) at 08C under argon atmosphere, and benzoyl
m, 15-CH and tert-BuSi), 1.21–1.47 (20H, br s, 5-, 6-, 7-,
3
chloride (76.0 ml, 0.66 mmol) was added dropwise to the
mixture. After being stirred for 2 h at room temperature, the
reaction was quenched by addition of saturated aqueous
NH Cl solution, and extracted with CH Cl . The organic
8-, 9-, 10-, 11-, 12-, 13- and 14-CH ), 2.14–2.23 (2H, m,
2
3-CH ), 2.25 (1H, s, OH), 3.32 (1H, d, J¼9.6 Hz,
2
TBSOCHH), 3.38 (1H, d, J¼9.6 Hz, TBSOCHH), 4.96–
1
3
5.06 (2H, m, 1-CH ), 5.83 (1H, m, 2-CH); C NMR: d
2
4
2
2
layers were washed with brine, and dried over Na SO .
2
25.5, 14.1, 18.2, 22.7, 23.1, 25.8, 29.3, 29.6, 30.3, 32.0,
36.2, 40.9, 68.0, 73.7, 117.8, 134.1; IR (thin film): 3560,
3480, 1465, 1255, 1100, 1005, 910, 840, 775. Anal. calcd
for C H O Si: C, 71.28; H, 12.51. Found: C, 71.46; H,
4
Evaporation of the solvent gave a residue, which was
purified by column chromatography on silica gel (hexanes/
AcOEt, 1:1) to give benzoate of 13 (142 mg, 98%) as a
2
2 46 2
2
3
1
þ
colorless oil. [a] ¼22.44 (c¼1.00, CHCl ); H NMR: d
12.22; HRMS calcd for C H O (M 2TBSþH):
16 32 2
D
3
0
-, 4 -, 5 -, 6 -, 7 -, 8 -, 9 - and 10 -CH ), 1.44–1.84 (2H, m,
0
0
3
1
4
.88 (3H, t, J¼6.6 Hz, 11 -CH ), 1.19–1.52 (18H, br s, 2 -,
256.2402, found 256.2402.
3
0
0
0
0
0
0
0
0
0
2
-H ), 2.74 and 2.84 (each 1H, each d, J¼4.6 Hz, 3-CH ),
4.1.7. (4R)-4-Acryloyloxy-4-(tert-butyldimethylsilyloxy-
methyl)pentadec-1-ene (16). To a stirred solution of
alcohol 15 (1.28 g, 3.46 mmol) in THF (17.3 ml) was
added dropwise 1.0 M solution of ethylmagnesium bromide
in THF (3.81 ml, 3.81 mmol) at room temperature under
argon atmosphere. After being stirred for 20 min, acryloyl
chloride (0.56 ml, 6.92 mmol) was added slowly to the
solution, and the whole mixture was stirred for further 5 h at
room temperature. The reaction was quenched by addition
2
2
.26 and 5.52 (each 1H, each d, J¼12.0 Hz, 1-H ), 7.46 (2H,
2
m, m-PhH), 7.58 (1H, tt, J¼1.3, 7.4 Hz, p-PhH), 8.04–8.07
1
3
(
2H, m, o-PhH); C NMR: d 14.1, 22.7, 24.6, 29.3, 29.4,
2
1
1
9.5, 29.6, 31.9, 32.1, 50.7, 57.5, 66.2, 128.4, 129.7, 129.8,
33.1, 166.1; IR (thin film): 3000, 1726, 1466, 1452, 1270,
110, 710. Anal. calcd for C H O : C, 75.86; H, 9.70.
2
1 32 3
þ
Found: C, 75.97; H, 9.84; HRMS calcd for C H O (M ):
2
1 32 3
3
32.2351, found 332.2346.
of saturated aqueous NaHCO solution and the mixture was
3
4
.1.5. (4R)-4-Hydroxymethylpentadec-1-en-4-ol (14). To
extracted with AcOEt. The extract was washed with brine
and concentrated under reduced pressure to leave a residue,
which was purified by column chromatography on silica gel
(hexanes/AcOEt, 4:1) to give acrylate 16 (1.04 g, 74%) as a
a stirred suspension of CuI (280 mg, 1.50 mmol) in THF
20.0 ml) was added dropwise 1.0 M solution of vinyl-
magnesium bromide in THF (20.0 ml, 20.0 mmol) at 2208C
(
2
5
1
under argon atmosphere, and the mixture was stirred for
3
in THF (5.0 ml) was added to the mixture at same
temperature, and the resulting mixture was stirred for
further 48 h. After addition of saturated aqueous NH Cl
solution, the reaction mixture was filtered through the Celite
pad, and the filtrate was extracted with AcOEt. The extract
was washed with brine, dried over Na SO and concentrated
under the reduced pressure to leave a residue, which was
purified column chromatography on silica gel (hexanes/
AcOEt, 1:1) to give diol 14 (880 mg, 69%) as a colorless oil.
colorless oil. [a] ¼24.21 (c¼1.00, CHCl ); H NMR: d
D
3
0 min. A solution of epoxy alcohol 13 (1.14 g, 5.00 mmol)
0.02 (6H, s, 2£MeSi), 0.87 (12H, m, 15-CH and tert-BuSi),
3
1.20–1.34 (18H, br s, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- and 14-
CH ), 1.85 (2H, m, 5-CH ), 2.56 (1H, dd, J¼7.5, 14.0 Hz, 3-
2
2
CHH), 2.61 (1H, dd, J¼7.3, 14.0 Hz, 3-CHH), 3.70 and 3.80
4
(each 1H, each d, J¼10.1 Hz, CH OTBS), 5.06 (1H, br d,
2
J¼10.2 Hz, 1-CHH), 5.08 (1H, br d, J¼17.1 Hz, 1-CHH),
5.65–5.81 (2H, m, 2-CH and COCHCHH), 6.02 (1H, dd,
J¼10.4, 17.3 Hz, COCH), 6.29 (1H, dd, J¼1.7, 17.3 Hz,
2
4
1
3
COCHCHH); C NMR: d 25.5, 14.1, 18.1, 22.7, 22.8, 25.8,
29.3, 29.5, 29.6, 29.6, 29.8, 31.9, 32.9, 37.9, 63.4, 86.3, 118.3,
129.6, 129.8, 133.0, 165.1; IR (thin film): 1724, 1640, 1620,
1400, 1200, 1120, 980, 920, 840, 780. Anal. calcd for
C H O Si: C, 70.70; H, 11.39. Found: C, 70.58; H, 11.54.
2
4
1
[
a] ¼þ0.57 (c¼1.01, CHCl ); H NMR: d 0.88 (3H, t,
D
3
0
J¼6.6 Hz, 11 -CH ), 1.22–1.33 (18H, m, 6-, 7-, 8-, 9-, 10-,
3
1
1-, 12-, 13- and 14-CH ), 1.41–1.54 (2H, m, 5-CH ), 1.88
2 2
25 48 3
(
2H, br, 2xOH), 2.28 (2H, dt, J¼1.2, 7.6 Hz, 3-CH ), 3.47
2
(
2H, br d, J¼2.6 Hz, CH OH), 5.10–5.19 (2H, m, 1-CH ),
4.1.8. (5R)-5-(tert-Butyldimethylsilyloxy)methylhexadec-
2-en-5-olide (17). To a solution of acrylate 16 (50 mg,
2
2
1
3
5
.84 (1H, dddd, J¼7.4, 9.2, 11.9, 15.0 Hz, 2-CH);
C

H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
8933
0
(
.12 mmol) in benzene (24 ml) was added Ru catalyst (B)
0.74 mg, 1.20 mmol), and the mixture was stirred for 3.5 h
4.1.11. 2-Methylideneundecanal (10). To a stirred solution
of undecanal (1.0 g, 5.87 mmol) and triethylamine (2.5 ml,
17.6 mmol) in CH Cl was added Eschenmoser’s salt (1.6 g,
at 708C. After evaporation of the solvent under reduced
pressure, the residue was purified by column chromato-
graphy on silica gel (hexanes/AcOEt, 20:1) to give
compound 17 (46.6 mg, 100%) as a colorless oil.
2
2
8.81 mmol) at ambient temperature, and the resulting
mixture was stirred for further 14 h. After addition of
saturated aqueous NaHCO3 solution, the mixture was
extracted with CH Cl . The extract was dried over NaSO
4
2
3
1
[
(
a] ¼211.0 (c¼1.04, CHCl ); H NMR: d 0.02 and 0.04
D
3
2
2
each 3H, each s, 2£MeSi), 0.84–0.88 (12H, m, 16-CH
and concentrated under reduced pressure to leave a residue,
which was purified by silica gel column chromatography
(hexane/AcOEt, 7:1) to give the compound 10 (0.86 g, 81%)
3
and tert-BuSi), 1.18–1.48 (18H, br s, 7-, 8-, 9-, 10-, 11-, 12-,
3-, 14- and 15-CH ), 1.61–1.75 (2H, m, 6-CH ), 2.34
1
2
2
1
(
1H, ddd, J¼2.3, 3.8, 19.0 Hz, 4-CHH), 2.62 (1H, ddd,
as a colorless oil. H NMR: d 0.88 (3H, t, J¼6.6 Hz,
J¼1.9, 4.8, 19.0 Hz, 4-CHH), 3.53 and 3.67 (each 1H,
11-CH ), 1.21–1.35 (12H, br s, 5-, 6-, 7-, 8-, 9- and
3
each d, J¼10.1 Hz, TBSOCH ), 5.97 (1H, ddd, J¼2.0,
10-CH ), 1.36–1.52 (2H, m, 4-CH ), 2.44 (2H, t, J¼7.3 Hz,
2
2
2
2
3
2
8
1
.1, 9.9 Hz, 2-CH), 6.73 (1H, ddd, J¼4.0, 4.6, 9.9 Hz,
3-CH ), 5.99 (1H, s, 14-CHH), 6.24 (1H, d, J¼1.0 Hz,
2
1
3
13
-CH); C NMR: d 25.6, 25.6, 14.1, 18.1, 22.6, 23.0,
5.7, 28.9, 29.3, 29.4, 29.5, 29.6, 29.9, 31.9, 36.7, 65.8,
3.8, 120.5, 143.6, 163.5; IR (thin film): 1728, 1468,
464, 1383, 1254, 1114, 840, 810, 780. Anal. calcd for
14-CHH), 9.54 (1H, s, CHO); C NMR: d 14.1, 22.6, 27.7,
29.3, 29.4, 29.5, 31.9, 133.9, 150.4, 194.8; IR (thin film):
1697, 1628, 1466, 1380, 1330, 940. Anal. calcd for
C H O: C, 79.07; H, 12.27. Found: C, 79.06; H, 12.16;
1
2 22
þ
C H O Si: C, 69.64; H, 11.18. Found: C, 69.86; H,
1
HRMS calcd for C H O (M ): 182.1671, found 182.1661.
12 22
2
3
44
3
þ
1.27; HRMS calcd for C H O Si (M ): 396.3060,
23 44 3
found 396.3062.
4.1.12. 2-Methylideneundecan-1-ol (12). To a solution of
CeCl ·7H O (7.40 g, 19.8 mmol) in MeOH (45.0 ml) were
3
2
4.1.9. (5R)-5-Hydroxymethylhexadec-2-en-5-olide (18).
To a mixed solution of compound 17 (427 mg, 1.08 mmol)
added successively NaBH4 (0.56 g, 14.8 mmol) and a
solution of aldehyde 10 (1.80 g, 9.89 mmol) in MeOH
(5.0 ml) at 08C. After being stirred for 30 min at room
temperature, the reaction was quenched by addition of
in EtOH (14.4 ml) and H O (3.6 ml) was added TsOH·H O
2
2
(
20.5 mg, 0.11 mmol), and the mixture was stirred for 17 h
at 808C. After being cooled to room temperature, the
reaction was quenched by addition of brine, and the mixture
was extracted with Et O. The extract was dried over Na SO
4
and concentrated under reduced pressure to leave a residue,
which was purified by column chromatography on silica gel
saturated aqueous NaHCO solution and the organic solvent
3
was evaporated to leave a residue. The residue was filtered
through the Celite pad, and the filtrate was extracted with
AcOEt. The extract was dried over Na SO and concen-
2
2
2
4
trated under reduced pressure to leave a residue, which was
purified by column chromatography on silica gel (hexane/
AcOEt, 7:1) to give allyl alcohol 12 (1.62 g, 90%) as a
(
hexanes/AcOEt, 1:1) to give alcohol 18 (297 mg, 98%) as a
2
5
D
1
colorless oil. [a] ¼þ12.5 (c¼0.61, CHCl ); H NMR: d
3
1
0
9
.88 (3H, t, J¼6.7 Hz, 16-CH ), 1.22–1.35 (18H, br s, 7-, 8-,
colorless oil. H NMR: d 0.88 (3H, t, J¼6.6 Hz, 13-CH ),
3
3
-, 10-, 11-, 12-, 13-, 14- and 15-CH ), 1.63–1.84 (2H, m, 6-
2
1.23–1.35 (12H, m, 5-, 6-, 7-, 8-, 9- and 10-CH ), 1.37–
2
CH ), 1.91 (1H, dd, J¼5.9, 7.8 Hz, OH), 2.31 (1H, ddd,
1.52 (2H, m, 4-CH ), 2.06 (2H, dd, J¼7.3, 7.7 Hz, 3-CH ),
2
2
2
J¼1.6, 5.3, 19.0 Hz, 4-CHH), 2.78 (1H, ddd, J¼2.6, 3.3,
4.08 (2H, d, J¼4.5 Hz, 1-CH ), 4.87 (1H, dd, J¼1.2, 2.5 Hz,
2
0
0
13
1
3
9.0 Hz, 4-CHH), 3.56 (1H, dd, J¼7.8, 11.9 Hz, CHHOH),
1 -CHH), 5.01 (1H, d, J¼1.2 Hz, 1 -CHH); C NMR: d
14.1, 22.6, 27.7, 29.3, 29.4, 29.5, 29.5, 31.9, 33.0, 65.8,
108.9, 149.3; IR (thin film): 3324, 1650, 1466, 1458, 1028,
.75 (1H, dd, J¼5.9, 11.9 Hz, CHHOH), 6.02 (1H, ddd,
J¼1.7, 2.6, 9.9 Hz, 2-CH), 6.81 (1H, ddd, J¼3.4, 5.3,
1
3
þ
9
2
.9 Hz, 3-CH); C NMR: d 14.1, 22.7, 23.7, 28.1, 29.3,
9.4, 29.5, 29.6, 29.9, 31.9, 35.7, 66.4, 84.8, 120.4, 144.0;
896; HRMS calcd for C H O (M ): 184.1827, found
1
2 24
184.1813.
IR (thin film): 3430, 1740, 1466, 1380, 1250, 1060, 1030,
þ
9
found 281.2127.
60, 810; HRMS calcd for C H O (M 21): 281.2117,
1
4.1.13. (2R)-2,3-Epoxy-2-nonanylpropan-1-ol (20). To a
stirred suspension of activated MS 3A (0.30 g) and CaH2
7 29 3
(46 mg, 1.09 mmol) in CH Cl (2.7 ml) was added
Ti(O Pr) (0.4 ml, 1.36 mmol) at room temperature. The
2 2
i
4
.1.10. (1)-Tanikolide (1). A mixture of alcohol 18
4
(
(
297 mg, 1.05 mmol) and 5% palladium on carbon
59.4 mg) in hexane (30.0 ml) was stirred for 1 h at room
stirred mixture was cooled to 2208C, and treated with
D-(2)-DIPT (0.38 g, 1.63 mmol) in CH Cl (4.0 ml). After
being stirred for 30 min at the same temperature, a solution
2
2
temperature under an atmospheric pressure of hydrogen.
After filtration of the catalyst, the filtrate was concentrated
to leave a residue, which was purified by column
chromatography on silica gel (hexanes/AcOEt, 1:3) to
afford tanikolide 1 (254 mg, 85%) as a white solid. Mp 44–
of allyl alcohol 12 (1.0 g, 5.44 mmol) in CH Cl (13.6 ml)
2
2
was added dropwise to the solution, and the mixture was
stirred for further 1 h. TBHP (1.5 ml, 8.15 mmol) was added
to this mixture over a period of 30 min. After being stirred
2
5
1
4
68C [a] ¼þ1.93 (c¼0.59, CHCl ); H NMR: d 0.88 (3H,
for 48 h at 2208C, Me S (0.48 ml, 6.52 mmol) was slowly
2
D
3
t, J¼6.7 Hz, 16-CH ), 1.23–1.35 (18H, br, 7-, 8-, 9-, 10-,
added and the mixture was stirred for 30 min at the same
temperature. To this mixture were added 10% aqueous of
tartaric acid (3.3 ml, 2.17 mmol), NaF (1.4 g, 33.7 mmol)
3
1
and 6-CH ), 2.46–2.50 (2H, m, 2-CH ), 3.55 and 3.66 (each
1-, 12-, 13-, 14- and 15-CH ), 1.62–1.94 (6H, m, 3-, 4-CH
2 2
2
2
1
3
1
1
3
1
2
H, each dd, J¼6.8, 11.9 Hz, CH OH); C NMR: d 14.0,
and Et O (9.0 ml), and the resulting mixture was vigorously
2
2
6.6, 22.6, 23.3, 26.6, 29.2, 29.4, 29.5, 29.5, 29.7, 29.9,
1.8, 36.7, 67.3, 86.6; IR (thin film): 3420, 1734, 1714,
stirred for 2 h at room temperature. The precipitate was
filtered off through a Celite pad. The filtrate was washed
successively with saturated aqueous NaHCO solution and
þ
466, 1332, 1250, 1040; HRMS calcd for C H O (M ):
1
7
32
3
3
84.2351, found 284.2325.
brine, and dried over Na SO . Evaporation of the solvent
2
4

8934
H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
gave a residue, which was purified by column chromato-
graphy on silica gel (hexanes/AcOEt, 1:1) to give epoxy
29.5, 30.2, 31.9, 40.7, 67.9, 74.1, 118.9, 133.4; IR (thin
film): 3390, 1640, 1465, 1055, 915; HRMS calcd for
C H O (M 21): 227.2011, found 227.2028.
14 27 2
2
5
þ
alcohol 20 (0.9 g, 83%) as a colorless oil. [a] ¼þ13.6
D
1
(
9
8
c¼0.99, CHCl ); H NMR: d 0.88 (3H, t, J¼6.7 Hz,
3
0
0
0
-CH ), 1.68–1.83 (2H, m, 1 -H ), 2.67 and 2.89 (each 1H,
0
0
0
0
0
-CH ), 1.26–1.56 (14H, br s, 2 -, 3 -, 4 -, 5 -, 6 -, 7 - and
3
4.1.16. (4R)-4-(tert-Butyldimethylsilyloxymethyl)tridec-
i
0
1-en-4-ol (22). Diol 21 (450 mg, 1.97 mmol) and Pr NEt
2
2
2
each d, J¼4.6 Hz, 3-CH ), 3.64 (1H, dd, J¼8.2, 12.2 Hz,
(0.83 ml, 4.74 mmol) were dissolved in CH Cl (10.0 ml)
2
2
2
1
3
1-CHH), 3.78 (1H, dd, J¼3.5, 12.2 Hz, 1-CHH); C NMR:
d 14.1, 22.6, 24.6, 29.3, 29.5, 29.7, 31.8, 31.9, 49.8, 62.7; IR
under argon atmosphere. After being cooled to 08C,
TBSOTf (0.54 ml, 2.37 mmol) was added dropwise to the
solution, and the resulting mixture was stirred for 30 min at
the same temperature. The reaction was quenched by
(
thin film): 3428, 1465, 1050. Anal. calcd for C H O : C,
12 24 2
71.71; H, 12.16. Found: C, 71.95; H, 12.08; HRMS calcd for
C H O (M ): 200.1776, found 200.1756. The ee of the
þ
benzoate of 20 was determined to be 95% by HPLC analysis
addition of saturated aqueous NH Cl solution and extracted
4
1
2
24
2
with CH Cl . The extract was washed with brine, dried over
2
2
on a Chiralcel OB (Daicel Chemical Industries) using
i
hexane– PrOH (99.5:0.5, v/v).
Na SO , and concentrated under reduced pressure to leave a
2 4
residue, which was purified by column chromatography on
silica gel (hexanes/AcOEt, 3:1) to afford alcohol 22
2
3
4.1.14. (2S)-1-Benzoyloxy-2,3-epoxy-2-nonanylpropane.
To a stirred solution of epoxy alcohol 20 (77 mg,
(640 mg, 95%) as a colorless oil. [a] ¼26.68 (c¼1.00,
D
1
CHCl ); H NMR: d 0.05 (6H, s, 2£MeSi), 0.84–0.90 (12H,
3
0
.39 mmol) in CH Cl (3.9 ml) was added Et N (0.16 ml,
3
m, 13-CH and tert-BuSi), 1.12–1.39 (16H, m, 5-, 6-, 7-, 8-,
3
2
2
1
.16 mmol) at 08C under argon atmosphere, and then
9-, 10-, 11- and 12-CH ), 2.15–2.30 (2H, m, 3-CH ), 2.31
2
2
benzoyl chloride (67.0 ml, 0.58 mmol) was added dropwise
to the mixture. After being stirred for 30 min at room
temperature, the reaction was quenched by addition of
saturated aqueous of NH Cl, and extracted with CH Cl .
(1H, s, OH), 3.37 and 3.42 (each 1H, each d, J¼9.6 Hz,
0
1 -CH ), 5.01–5.12 (2H, m, 1-CH ), 5.73–5.12 (1H, m,
2
2
1
3
2-CH); C NMR: d 25.5, 14.1, 18.2, 22.7, 23.1, 25.8, 29.3,
29.6, 30.3, 31.9, 36.2, 40.9, 68.0, 73.7, 117.8, 134.1; IR (thin
film): 3572, 3472, 1640, 1465, 1255, 1095, 915, 840, 775.
Anal. calcd for C H O Si: C, 69.95; H, 12.55. Found: C,
4
2
2
The extract was washed with brine and dried over Na SO .
2
4
Evaporation of the solvent gave a residue, which was
purified by column chromatography on silica gel (hexanes/
AcOEt, 1:1) to give benzoate of 20 (106 mg, 91%) as a
2
0 42 2
þ
70.11; H, 12.35; HRMS calcd for C H O Si (M þ1):
2
0 42 2
343.3032, found 343.3060.
2
5
1
colorless oil. [a] ¼þ2.65 (c¼0.99, CHCl ); H NMR: d
D
3
0
-, 5 -, 6 -, 7 - and 8 -CH ), 1.56–1.69 (1H, m, 1 -HH), 1.81–
0
0
0
4
1
.86 (3H, t, J¼6.9 Hz, 9 -CH ), 1.25–1.44 (14H, br s, 2 -, 3 -,
4.1.17. (4S)-4-Acryloyloxy-4-(tert-butyldimethylsilyloxy-
methyl)tridec-1-ene (23) and (4S)-4-acryloyloxy- methyl-
4-(tert-butyldimethylsilyloxy)tridec-1-ene (24). To a stir-
red solution of alcohol 22 (272 mg, 0.80 mmol) in THF
(8.0 ml) was added dropwise 1.0 M solution of ethyl-
magnesium bromide in THF (1.59 ml, 1.59 mmol) at room
temperature under argon atmosphere. After being stirred for
30 min, methacryloyl chloride (0.23 ml, 2.39 mmol) was
added slowly to the solution, and the resulting mixture was
stirred for further 14 h at room temperature. The reaction
was quenched by addition of saturated aqueous NaHCO3
solution and the mixture was extracted with AcOEt. The
extract was washed with brine and concentrated under
reduced pressure to give a residue, which was purified by
column chromatography on silica gel (hexanes/AcOEt,
20:1). The first fraction gave methacrylate 23 (157 mg,
3
0
0
0
0
0
0
.92 (1H, m, 1 -HH), 2.74 and 2.83 (each 1H, each d,
2
0
J¼4.6 Hz, 3-CH ), 4.26 and 5.52 (each 1H, each d,
2
J¼12.0 Hz, 1-H ), 7.42–7.61 (3H, m, m- and p-PhH), 8.04
2
1
3
(
2H, m, o-PhH); C NMR: d 14.0, 22.6, 24.5, 29.2, 29.4, 29.6,
3
1.8, 32.0, 50.7, 57.5, 66.2, 128.4, 129.6, 129.7, 133.1, 166.1;
IR (thin film): 1724, 1452, 1315, 1270, 1180, 1120, 1070,
025, 710. Anal. calcd for C H O : C, 75.21; H, 9.29.
1
1
9 28 3
þ
Found: C, 74.96; H, 9.27; HRMS calcd for C H O (M ):
1
9 28 3
3
04.2038, found 304.2011.
4
.1.15. (4R)-4-Hydroxymethyltridec-1-en-4-ol (21). To a
stirred suspension of CuI (103 mg, 0.54 mmol) in THF
7.0 ml) was added dropwise 1.0 M solution of vinyl
magnesium bromide in THF (5.4 ml, 5.4 mmol) at 2208C
(
2
2
1
under argon atmosphere, and the mixture was stirred for
3
48%) as a colorless oil. [a] ¼þ3.25 (c¼0.99, CHCl ); H
D
3
0 min. A solution of epoxy alcohol 20 (360 mg, 1.8 mmol)
NMR: d 0.02 (6H, s, 2£MeSi), 0.84–0.89 (12H, m, 13-CH
3
in THF (3.0 ml) was added to the mixture at the same
temperature, and the resulting mixture was stirred for
further 48 h. After addition of saturated aqueous NH Cl
and tert-BuSi), 1.21–1.30 (14H, br s, 6-, 7-, 8-, 9-, 10-, 11-
and 12-CH ), 1.87–1.88 (5H, m, 5-CH and CCH ), 2.59
2
2
3
and 2.70 (each 1H, each dd, J¼7.4, 14.0 Hz, 3-CH ), 3.72
4
2
solution, the reaction mixture was filtered through the Celite
pad. The filtrate was extracted with AcOEt, and the extract
was washed with brine, dried over Na SO . Evaporation of
and 3.81 (each 1H, each d, J¼10.1 Hz, CH OTBS), 5.02–
2
5.13 (2H, m, 1-CH ), 5.46 (1H, m, CCHH), 5.65–5.82 (1H,
2
13
m, 2-CH), 5.99 (1H, dd, J¼0.9, 1.7 Hz, CCHH); C NMR:
d 25.6, 14.1, 18.1, 18.4, 22.7, 22.9, 25.7, 29.3, 29.5, 29.9,
31.9, 33.0, 37.9, 63.4, 86.0, 118.2, 124.5, 133.1, 137.5,
166.4; IR (thin firm): 1716, 1639, 1180, 1120, 840. Anal.
calcd for C H O Si: C, 70.01; H, 11.26. Found: C, 70.19;
2
4
the solvent gave a residue, which was purified column
chromatography on silica gel (hexanes/AcOEt, 1:1) to
afford diol 21 (317 mg, 77%) as a colorless oil.
2
4
1
[
a] ¼20.93 (c¼1.00, CHCl ); H NMR: d 0.88 (3H, t,
D
3
24 46 3
þ
J¼6.7 Hz, 13-CH ), 1.21–1.38 (12H, m, 7-, 8-, 9-, 10-, 11-
H, 11.29; HRMS calcd for C H O Si (M þ1): 411.3294,
3
24 47 3
and 12-CH ), 1.41–1.49 (1H, m, 6-CHH), 1.56–1.60 (1H,
2
found 411.3302. The second fraction gave isomer 24
(139 mg, 43%) as a colorless oil. H NMR: d 0.02 (6H, s,
1
m, 6-CHH), 1.89–1.90 (2H, m, 5-CH ), 2.28 (2H, d,
2
J¼7.6 Hz, 3-CH ), 3.48 (2H, d, J¼5.9 Hz, CH OH),
2£MeSi), 0.83–0.90 (12H, m, 13-CH and tert-BuSi),
2
2
3
5
.10–5.19 (2H, m, 1-CH ), 5.84 (1H, dddd, J¼7.6, 9.2,
1.22–1.35 (14H, br, 6-, 7-, 8-, 9-, 10-, 11- and 12-CH ),
2
2
1
3
1
1.9, 15.0 Hz, 2-CH); C NMR: d 14.1, 22.7, 23.3, 29.3,
1.69–1.97 (5H, m, 5-CH and COCCH ), 2.48–2.61 (2H,
2
3

H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
8935
1
3
m, 3-CH ), 3.63–3.80 (2H, m, CH OCO), 5.00–5.05 (2H,
2
m, 1-CH ), 5.57–5.72 (2H, m, 2-CH and COCCHH), 5.79
2
3.66 (1H, m, CHHOH); C NMR: d 14.1, 17.1, 22.6, 23.6,
25.2, 26.2, 29.2, 29.4, 29.5, 30.0, 31.8, 35.5, 36.6, 67.7,
86.9, 175.4; IR (thin film): 3422, 1728, 1710, 1460, 1378,
1328, 1252, 1218, 1102, 1068; HRMS calcd for C H O
6 30 3
2
(
1H, s, COCCHH); IR (thin film): 1730, 1678, 1640, 1466,
1
C H O Si (M ): 410.3216, found 410.3228.
376, 1252, 1116, 920, 840, 780; HRMS calcd for
þ
1
þ
(M ): 270.2195, found 270.2191. The second fraction gave
1
2
4 46 3
epi-malyngolide 27 (2.4 mg, 12%) as a colorless oil. H
NMR: d 0.88 (3H, t, J¼6.7 Hz, 14-CH ), 1.26–1.34 (16H,
4
.1.18. (5S)-2-Methyl-5-(tert-butyldimethylsilyloxy)-
3
methyl-tetradec-2-en-5-olide (25). To a solution of
methacrylate 23 (250 mg, 0.61 mmol) in benzene (122 ml)
was added Ru catalyst (B) (19 mg, 0.03 mmol), and the
mixture was stirred for 7 h at 708C. After evaporation of the
solvent under reduced pressure, the residue was purified by
column chromatography on silica gel (hexanes/AcOEt,
br, 6-, 7-, 8-, 9-, 10-, 11-, 12- and 13-CH ), 1.64–2.27 (7H,
2
m, 3-CH , 4-CH and 2-Me), 1.89–2.23 (1H, br, OH),
2
2.36–2.52 (1H, m, 2-CH), 3.61 (2H, S, CH OH); C NMR:
2
d 14.1, 17.2, 22.6, 23.1, 25.4, 27.1, 29.2, 29.5, 29.5, 29.9,
31.8, 35.2, 37.5, 61.0, 61.8, 67.7, 86.3, 175.3; IR (thin film):
3422, 1728, 1710, 1460, 1378, 1332, 1210, 1110, 1086;
2
1
3
þ
2
0:1) to give compound 25 (205 mg, 88%) as a colorless oil.
6
HRMS calcd for C H O (M ): 270.2195, found
1
6 30 3
2
D
1
[
(
a] ¼þ10.6 (c¼1.00, CHCl ); H NMR: d 0.02 and 0.04
270.2176.
3
each 3H, each s, 2£MeSi), 0.84–0.89 (12H, m, 14-CH and
3
tert-BuSi), 1.20–1.45 (14H, br s, 7-, 8-, 9-, 10-, 11-, 12- and
1
3
3-CH ), 1.62–1.69 (2H, m, 6-CH ), 1.89 (3H, dd, J¼1.9,
2
2
Acknowledgements
.6 Hz, 2-CH ), 2.26–2.39 (1H, m, 4-CHH), 2.49–2.62
3
(
TBSOCH ), 6.39–6.43 (1H, m, 3-CH); C NMR: d 25.6,
1H, m, 4-CHH), 3.51 and 3.64 (each 1H, each d, J¼9.9 Hz,
This work was supported by the Ministry of Education,
Culture, Sports, Science and Technology of Japan. We are
grateful to Professor A. H. Hoveyda, J. S. Kingsbury and
S. B. Garber (Boston College) for a most generous gift of
the ruthenium catalyst.
1
3
2
2
5.6, 14.1, 17.0, 18.1, 22.6, 23.0, 25.7, 29.2, 29.4, 29.9,
3
1
1.8, 36.6, 66.0, 83.7, 127.2, 137.5, 165.0; IR (thin film):
720, 1470, 1463, 1360, 1246, 1110, 840. Anal. calcd for
C H O Si: C, 69.20; H, 11.14. Found: C, 69.05; H, 11.06;
2
2 42 3
þ
HRMS calcd for C H O Si (M ): 382.2903, found
2
2 42 3
3
82.2900.
References
4
.1.19. (5S)-2-Methyl-5-hydroxymethyltetradec-2-en-5-
olide (26). To a mixed solution of compound 25 (170 mg,
.45 mmol) in EtOH (6.0 ml) and H O (1.5 ml) was added
TsOH·H O (8.5 mg, 0.04 mmol), and the mixture was
stirred for 15 h at 808C. After being cooled to room
temperature, the reaction was quenched by addition of brine
1. Singh, I. P.; Milligan, K. E.; Gerwick, W. H. J. Nat. Prod.
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0
2
2
2. Cardllina, J. H.; Moore, R. E.; Amold, E. V.; Clardy, J. J. Org.
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and the mixture was extracted with Et O. The extract was
2
dried over Na SO and concentrated to leave a residue,
2
4
which was purified by column chromatography on silica gel
hexanes/AcOEt, 1:1) to give alcohol 26 (115 mg, 96%) as a
(
4. For previous syntheses of (2)-malyngolide, see: (a) Wan, Z.;
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2
5
1
colorless oil. [a] ¼212.4 (c¼1.01, CHCl ); H NMR: d
D
3
0
9
1
4
1
.88 (3H, t, J¼6.7 Hz, 14-CH ), 1.20–1.35 (14H, br s, 7-, 8-,
3
-, 10-, 11-, 12- and 13-CH ), 1.60–1.78 (2H, m, 6-CH ),
2
2
.84–1.94 (4H, m, 2-CH and OH), 2.20–2.33 (1H, m,
3
-CHH), 2.66–2.79 (1H, m, 4-CHH), 3.54 (1H, d, J¼7.7,
2.0 Hz, CHHOH), 3.72 (1H, dd, J¼5.9, 12.0 Hz,
1
3
CHHOH), 6.47–6.50 (1H, m, 3-CH); C NMR: d 14.1,
1
6
1
found 268.2022.
6.9, 22.6, 23.8, 28.3, 29.2, 29.4, 29.4, 29.9, 31.8, 35.6,
6.4, 84.7, 127.3, 137.8; IR (thin film): 3424, 1714, 1366,
128, 1060; HRMS calcd for C H O (M ): 268.2038,
1
5. Honda, T.; Imai, M.; Keino, K.; Tsubuki, M. J. Chem. Soc.,
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þ
6 28 3
6. For reviews on Sharpless asymmetric epoxidation, see:
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Asymmetric Epoxidation with Titanium-Tartrate Catalysts.
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metric Synthesis, Morrison, J. D., Ed.; Academic: Tokyo,
1985; Vol. 5, pp 194–246.
4
.1.20. Malyngolide (2) and epi-malyngolide (27). A
mixture of alcohol 26 (20 mg, 0.07 mmol) and 5%
palladium on carbon (10 mg) in hexane (2.0 ml) was stirred
for 12 h at room temperature under an atmospheric pressure
of hydrogen. After filtration of the catalyst, the filtrate was
concentrated to leave a residue, which was purified by
column chromatography on silica gel (hexanes/AcOEt, 1:3).
The first fraction gave malyngolide 2 (16.1 mg, 80%) as a
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A. Angew. Chem. Int. Ed. Engl. 1971, 10, 5454. (b) Kinast, G.;
2
5
1
colorless oil. [a] ¼213.8 (c¼0.71, CHCl ); H NMR: d
D
3
0
.88 (3H, t, J¼6.7 Hz, 14-CH ), 1.21–1.34 (16H, br, 6-, 7-,
3
8
and 2-Me), 1.89–2.20 (3H, m, 3-CH and OH), 2.36–2.52
-, 9-, 10-, 11-, 12- and 13-CH ), 1.50–1.82 (5H, m, 4-CH
2
2
2
(
1H, m, 2-CH), 3.48 (1H, dd, J¼4.9, 12.1 Hz, CHHOH),

8
936
H. Mizutani et al. / Tetrahedron 58 (2002) 8929–8936
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1
283.
. (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Gemel,
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9
1
0. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H.
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12. The ee was determined by HPLC analysis of the benzoate of
20 using a chiral stationary phase (CHIRALCEL OB, Daicel
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