Synthesis and structural revision of marine eicosanoid agardhilactone

Article abstract of DOI:10.1016/j.tetlet.2005.09.102

Synthesis of the marine eicosanoid agardhilactone has been achieved. The relative and absolute configuration of agardhilactone was successfully determined.

Full text of DOI:10.1016/j.tetlet.2005.09.102

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7945–7949
Synthesis and structural revision of marine eicosanoid
agardhilactone
Hiroaki Miyaoka,* Yoshinori Hara, Ikuo Shinohara,
Takao Kurokawa and Yasuji Yamada
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 8 August 2005; revised 14 September 2005; accepted 14 September 2005
Abstract—Synthesis of the marine eicosanoid agardhilactone has been achieved. The relative and absolute configuration of agardhi-
lactone was successfully determined.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Marine eicosanoids are of interest given their unique
structures, peculiar biosynthetic pathways, and biologi-
cal activities.1 Agardhilactone, first isolated from the
marine red algae Agardhiella subulata by Gerwick
et al., is a novel tricyclic eicosanoid containing d-lac-
tone, cyclopentane, and epoxide rings (Fig. 1).2 Initial
structural reports were based on the NMR analysis of
agardhilactone acetate, derived from agardhilactone.
However, the complete structure of agardhilactone was
not determined since agardhilactone is a particle constit-
uent. The relative configuration (C-6, C-8, C-9, and C-
10) of the cyclopentane ring system was determined to
be 6S*, 8R*, 9S*, and 10R*, based on coupling con-
stants and the NOESY analysis of agardhilactone ace-
tate. To date, the relative configuration at C-5 remains
unknown. The absolute configuration of the secondary
hydroxy group at C-18 was determined as being in the
S-configuration by converting agardhilactone to the
known methoxycarbonyl derivative. Although the pre-
cise biological function of agardhilactone has not been
reported, given its structural characteristics the eicosa-
noid might be an inhibitor of phospholipase A2.1
lariolide.4 To date, the total synthesis of agardhilactone
has not been reported. The synthesis of agardhilactone
was therefore conducted in the present study so as to
clarify its structure.
The authors began by synthesizing the model com-
pounds 1–4 of agardhilactone in an effort to determine
the relative configuration at C-5 and to confirm the rel-
ative configuration at C-6, C-8, C-9, and C-10 (Fig. 1).
The model compounds 1–4 correspond to four diaste-
reomers of 16,17-dihydro-18-dehydroxyagardhilactone.
The model compounds 1–4 were, respectively, synthe-
sized from 4-vinyldihydrofuran-2-one (5).5 The lactone
5 was treated with LDA and then 3-iodopropene to give
trans-lactone 6 as a single compound (Scheme 1). The
relative configuration of trans-lactone 6 was determined
by NOESY. trans-Configuration of two side chains was
O
O
O
O
H
6
H
H
Numerous attempts have been made to synthesize car-
bocyclic eicosanoids, prompted by their unique struc-
tural features and potential biological significance.1
The authors previously reported on the synthesis of
the carbocyclic eicosanoids, constanolactone3 and bacil-
5
5
8
8
10
O
O
9
OR
9
H
18
agardhilactone : R = H
1 : 5R*, 8R*, 9S*
2 : 5R*, 8S*, 9R*
3 : 5S*, 8R*, 9S*
4 : 5S*, 8S*, 9R*
agardhilactone acetate : R = Ac
(Gerwick's structures)
Keywords: Agardhilactone; Marine eicosanoid; Structural revision.
*
Figure 1. Proposed structure of agardhilactone and structure of model
Corresponding author. Tel.: +81 426 76 3080; fax: +81 426 76
compounds.
3073; e-mail: miyaokah@ps.toyaku.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.102

7946
H. Miyaoka et al. / Tetrahedron Letters 46 (2005) 7945–7949
TBDMSO
H
OH
OTBDMS
OTBDMS
b
O
O
H
H
H
7
H
H
5
a
b
a
6
10
O
H
O
7a
OH
OPiv
9
9
H
H
7a : 5α-OH
7b : 5β-OH
5
NOE
6
TBDMSO
H
TBDMSO
H
OTBDMS
OTBDMS
OTBDMS
H
H
H
+
H
O
8
9
c
8
5
10
9
11 OPiv
OPiv
7a
10
O
O
H
H
H
H
NOE
OTBDMS
NOE
H
H
10b
H
10a
8
TBDMSO
H
TBDMSO
H
OTBDMS
Scheme 1. Reagents and conditions: (a) LDA, 3-iodopropene, THF,
ꢀ78 ꢁC to rt, 74%; (b) (i) DIBALH, CH2Cl2, ꢀ78 ꢁC, 98%, (ii)
TBDMSOCH2CH2CH2CH2MgI, DME, 0 ꢁC, 73% (7a), 25% (7b); (c)
TsCl, DABCO, AcOEt, 0 ꢁC, 71%.
c
d
10a
I
O
O
H
H
11
12
indicated by the NOE correlation between H-6 and H-9
and between H-7 and H-10. Lactone 6 was reduced
to hemiacetal with DIBALH and the hemiacetal
was then treated with Grignard reagent (TBDMS-
OCH2CH2CH2CH2MgI)6 in DME to afford a mixture
of a-alcohol 7a and b-alcohol 7b (7a/7b = 3:1), which
were readily separated by silica gel chromatography.
The relative configuration of the hydroxy group at C-5
was determined by the NOESY of tetrahydrofuran 8
derived from a-alcohol 7a. a-Alcohol 7a was treated
with toluenesulfonyl chloride (TsCl) and 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) in AcOEt to give tetra-
hydrofuran 8. The NOE correlation between H-5 and
H-10 in tetrahydrofuran 8 indicated the relative config-
uration at C-5 and C-10 to be that as shown in Scheme
1. An a-configuration of the hydroxy group at C-5 was
found for 7a, while a b-configuration of the hydroxy
group at C-5 was found for 7b, a diastereomer of 7a.
O
O
H
H
e
O
1
O
O
H
f
10b
O
H
2
Scheme 2. Reagents and conditions: (a) (i) GrubbsÕ catalyst 1st
generation, CH2Cl2, rt, 99%, (ii) PivCl, pyridine, CH2ClCH2Cl, 0 ꢁC to
rt, 82%, (iii) TBDMSCl, imidazole, DMF, 45 ꢁC, 99%; (b) mCPBA,
Na2HPO4, CH2Cl2, 0 ꢁC to rt, 23% (10a), 77% (10b); (c) (i) DIBALH,
CH2Cl2, ꢀ78 ꢁC, 87%, (ii) Dess–Martin periodinane, NaHCO3,
CH2Cl2, rt, then Ph3P@CHCO2Me, reflux, 61%, (iii) DIBALH,
CH2Cl2, ꢀ78 ꢁC, 79%, (iv) Ts2O, pyridine, CH2Cl2, rt, then NaI,
acetone, rt, 72%; (d) hept-1-yne, CuI, NaI, K2CO3, DMF, rt, 63%; (e)
The ring-closing metathesis (RCM) reaction of a-alco-
hol 7a with 1st generation GrubbsÕ catalyst7 in CH2Cl2
afforded the cyclopentene derivative (Scheme 2). The
primary hydroxy group of the cyclopentene derivative
was protected as the pivalate, while the secondary
hydroxy group was protected as the TBDMS ether to
give cyclopentene 9. Epoxidation of cyclopentene 9 with
m-chloroperbenzoic acid (mCPBA) afforded a mixture
of a-epoxide 10a and b-epoxide 10b (10a/10b = 1:3).
The diastereomeric mixture was separated by silica gel
chromatography. The relative configuration of epoxides
10a and 10b was determined by NOESY. The epoxide of
10a was determined to be in the a-configuration from
the NOE correlation between H-9 and H-11, while the
epoxide of 10b was determined to be in the b-configura-
tion from the NOE correlation between H-9 and H-10.
a-Epoxide 10a was converted to allylic iodide 11 in
four steps consisting of (1) reductive removal of the
pivaloyl group with DIBALH, (2) oxidation of the
hydroxy group with Dess–Martin periodinane8 to give
the aldehyde followed by a Wittig reaction with
Ph3P@CHCO2Me, (3) reduction of the a,b-unsaturated
ester with DIBALH, and finally (4) tosylation of the
hydroxy group followed by treatment with NaI. The
coupling reaction of allylic iodide 11 with hept-1-yne
was achieved by treatment with CuI, NaI, and K2CO3
˚
(i) TBAF, DMF, 40 ꢁC, 73%, (ii) TPAP, NMO, MS 4 A,
CH2ClCH2Cl, rt, 60%, (iii) H2, 5% Pd on BaSO4, quinoline, MeOH,
rt, 79%; (f) (i) DIBALH, CH2Cl2, ꢀ78 ꢁC, 90%, (ii) Dess–Martin
periodinane, NaHCO3, CH2Cl2, rt, then Ph3P@CHCO2Me, reflux,
86%, (iii) DIBALH, CH2Cl2, ꢀ78 ꢁC, 77%, (iv) Ts2O, pyridine,
CH2Cl2, rt, then NaI, acetone, rt, 64%, (v) hept-1-yne, CuI, NaI,
K2CO3, DMF, rt, 79%, (vi) TBAF, DMF, 40 ꢁC, 69%, (vii) TPAP,
˚
NMO, MS 4 A, CH2ClCH2Cl, rt, 70%, (viii) H2, 5% Pd on BaSO4,
quinoline, MeOH, rt, 71%.
and gave enyne 12.9 The protective groups of the two
hydroxy groups were removed by treatment with tetra-
butylammonium fluoride (TBAF) to give the diol. The
diol was treated with tetrapropylammonium perruthe-
nate (TPAP) and 4-methylmorpholine N-oxide (NMO)
to give the d-lactone.10 Finally, alkyne hydrogenation
with 5% Pd on BaSO4 in the presence of quinoline affor-
ded model compound 1.11 Model compound 2 was syn-
thesized from b-epoxide 10b in a similar manner as
described above.

H. Miyaoka et al. / Tetrahedron Letters 46 (2005) 7945–7949
7947
Model compounds 3 and 4 were synthesized from
b-alcohol 7b (Scheme 3). The RCM reaction of b-alco-
hol 7b with 1st generation GrubbsÕ catalyst in CH2Cl2
afforded the cyclopentene derivative. The primary
hydroxy group of the cyclopentene derivative was pro-
tected as the pivalate to give cyclopentene 13. Protection
of the secondary hydroxy group in 13 as the TBDMS
ether gave cyclopentene 14. Epoxidation of cyclopentene
14 using mCPBA afforded predominantly b-epoxide 15b
(a-epoxide 15a/15b = 1:15). The mixture of the two dia-
stereomers was separated by silica gel chromatography.
The relative configuration of epoxides 15a and 15b was
determined by NOESY. The epoxide of 15a was deter-
mined to be in the a-configuration from the NOE corre-
lation between H-9 and H-11. The epoxide of 15b was
determined to be in the b-configuration from the NOE
correlation between H-9 and H-10. a-Epoxide 15a was
obtained stereoselectively by the epoxidation of b-alco-
hol 13 followed by protection of the secondary hydroxy
group. b-Alcohol 13 was treated with TBHP in the
presence of VO(acac)212 to give the a-epoxide as the sole
product. The hydroxy group in the a-epoxide was
protected as the TBDMS ether to afford a-epoxide
15a. a-Epoxide 15a and b-epoxide 15b were converted
to model compounds 3 and 4, respectively, according
to the aforementioned established method.
The NMR spectra of synthesized model compounds
1–413 were compared with those of agardhilactone
acetate.2 The NMR spectrum of 4 most closely resem-
bled that of agardhilactone acetate.2 Therefore, the
relative configuration of agardhilactone was estimated
to be 5S*, 6S*, 8S*, 9R*, and 10R*. On the basis of this
result, the authors examined the synthesis of natural
agardhilactone.
OR
OTBDMS
c
H
a
7b
The side-chain segment 19 (C14–C20) was synthesized
from (S)-3-hydroxypent-1-yne (16)14 (Scheme 4). The
hydroxy group in 16 was protected as the TBDPS ether
and subsequently treated with catecholborane15 and
then iodine16 to give E-iodoalkene 17. The coupling
reaction of E-iodoalkene 17 and (trimethylsilyl)acetyl-
ene was achieved by treatment with (Ph3P)4Pd, CuI,
and PrNH2 in benzene to give enyne 18.17 Removal of
the TMS and TBDPS groups in enyne 18 was carried
out by treatment with TBAF to give the alcohol. The
hydroxy group was acetylated to afford acetate 19.
OPiv
H
13 : R = H
14 : R = TBDMS
b
TBDMSO
H
TBDMSO
OTBDMS
OTBDMS
H
H
H
8
8
+
10
9
9
OPiv
OPiv
11
O
O
H
H
O
H
H
NOE
H
H
15b
15a
O
The coupling reaction of enyne 19 and allylic iodide 20,
which was a synthetic intermediate of model compound
4, was achieved by treatment with CuI, NaI, and K2CO3
and gave a mixture of dienynes 21 and 22 (Scheme 5).
Without purifying the mixture, the two TBDMS groups
in dienynes 21 and 22 were removed by treatment with
TBAF to give the corresponding diols. The diols were
treated with TPAP and NMO to give the d-lactones.
Partial hydrogenation of the alkynes with 5% Pd on
BaSO4 in the presence of quinoline afforded the diaste-
reomeric mixture of E,Z,E-trienes 23 and 24. Separation
of the diastereomeric mixture using a chiral HPLC col-
umn gave acetates 23 and 24.18 The spectral data of ace-
tate 23 were identical to those of agardhilactone
acetate.2 The absolute configuration of acetate 23 was
determined using a modified Mosher method19 for
H
e
d
13
15a
O
O
H
3
O
H
f
15b
O
H
4
Scheme 3. Reagents and conditions: (a) (i) GrubbsÕ catalyst 1st
generation, CH2Cl2, rt, 82%, (ii) PivCl, pyridine, CH2ClCH2Cl, 0 ꢁC to
rt, 86%; (b) TBDMSCl, imidazole, DMF, 45 ꢁC, 94%; (c) mCPBA,
Na2HPO4, CH2Cl2, 0 ꢁC to rt, 6% (15a), 91% (15b); (d) (i) TBHP,
VO(acac)2, CH2Cl2, rt, 83%, (ii) TBDMSOTf, 2,6-lutidine, CH2Cl2,
ꢀ78 ꢁC, 88%; (e) (i) DIBALH, CH2Cl2, ꢀ78 ꢁC, 84%, (ii) Dess–Martin
periodinane, NaHCO3, CH2Cl2, rt, then Ph3P@CHCO2Me, reflux,
83%, (iii) DIBALH, CH2Cl2, ꢀ78 ꢁC, 90%, (iv) Ts2O, pyridine,
CH2Cl2, rt, then NaI, acetone, rt, 73%, (v) hept-1-yne, CuI,
NaI, K2CO3, DMF, rt, 84%, (vi) TBAF, DMF, 40 ꢁC, 40%, (vii)
OH
OTBDPS
a
b
I
17
16
OTBDPS
OAc
20
c
˚
TPAP, NMO, MS 4 A, CH2ClCH2Cl, rt, 64%, (viii) H2, 5% Pd on
14
TMS
BaSO4, quinoline, MeOH, rt, 88%; (f) (i) DIBALH, CH2Cl2, ꢀ78 ꢁC,
96%, (ii) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt, then
Ph3P@CHCO2Me, reflux, 78%, (iii) DIBALH, CH2Cl2, ꢀ78 ꢁC,
94%, (iv) Ts2O, pyridine, CH2Cl2, rt, then NaI, acetone, rt, 62%, (v)
hept-1-yne, CuI, NaI, K2CO3, DMF, rt, 60%, (vi) TBAF, DMF, 40 ꢁC,
18
19
Scheme 4. Reagents and conditions: (a) (i) TBDPSCl, imidazole,
DMF, rt, 83%, (ii) catecholborane, 80 ꢁC, (iii) I2, NaOH aq, Et2O,
0 ꢁC, 75% (two steps); (b) (trimethylsilyl)acetylene, (Ph3P)4Pd, CuI,
PrNH2, benzene, rt, 63%; (c) (i) TBAF, THF, rt, 90%, (ii) AcCl,
DMAP, CH2Cl2, 0 ꢁC, 86%.
˚
69%, (vii) TPAP, NMO, MS 4 A, CH2ClCH2Cl, rt, 40%, (viii) H2, 5%
Pd on BaSO4, quinoline, MeOH, rt, 80%.

7948
H. Miyaoka et al. / Tetrahedron Letters 46 (2005) 7945–7949
was supported in part by a Grant-in-Aid for Scientific
OTBDMS
Research from The Ministry of Education, Culture,
Sports, Science and Technology (MEXT) and ÔHigh-
Tech Research CenterÕ Project for Private Universities:
matching fund subsidy from MEXT, 2002–2006.
TBDMSO
H
I
O
H
20
a
OTBDMS
OTBDMS
References and notes
TBDMSO
TBDMSO
H
OAc
H
OAc
1. (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2005,
22, 15–61, and previous reviews in the series; (b) Gerwick,
W. H. Biochim. Biophys. Acta 1994, 1211, 243–255; (c)
Gerwick, W. H. Chem. Rev. 1993, 93, 1807–1823.
2. Graber, M. A.; Gerwick, W. H. Tetrahedron Lett. 1996,
37, 4635–4638.
+
O
O
H
H
21
22
b
3. (a) Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron
2000, 56, 8083–8094; (b) Miyaoka, H.; Tamura, M.;
Yamada, Y. Tetrahedron Lett. 1998, 39, 621–624.
4. (a) Miyaoka, H.; Shigemoto, T.; Yamada, Y. Heterocycles
1998, 47, 415–428; (b) Miyaoka, H.; Shigemoto, T.;
Yamada, Y. Tetrahedron Lett. 1996, 37, 7407–7408.
5. Kondo, K.; Mori, F. Chem. Lett. 1974, 741–742.
6. (a) Deng, Y.; Salomon, R. G. J. Org. Chem. 1998, 63,
7789–7794; (b) Nystrom, J. E.; McCanna, T. D.; Helquist,
P.; Amouroux, R. Synthesis 1988, 56–58.
O
O
O
O
H
H
+
O
OR
O
OAc
H
H
24
23 : R = Ac
25 agardhilactone : R = H
c
7. Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 9606–9614.
8. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
Scheme 5. Reagents and conditions: (a) 19, CuI, NaI, K2CO3, DMF,
rt, 90% (21 and 22); (b) (i) TBAF, DMF, 60 ꢁC, 56%, (ii) TPAP, NMO,
˚
MS 4 A, CH2ClCH2Cl, rt, 67%, (iii) H2, 5% Pd on BaSO4, quinoline,
MeOH, rt, then separation by HPLC, 19% (23), 17% (24); (c) (i) NaOH
9. Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K.
Synthesis 1993, 65–66.
aq, THF, rt, (ii) DCC, DMAP, CH2Cl2, rt, 90% (two steps).
10. Guertin, K. R.; Kende, A. S. Tetrahedron Lett. 1993, 34,
5369–5372.
11. Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1956, 78,
2518–2524.
12. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136–6137.
OH
H
CO2Me
OH
a
23
O
13. Compound 1: A colorless oil; IR (neat) cmꢀ1: 2926, 1737;
1H NMR (400 MHz, CDCl3) d: 5.57 (1H, m), 5.43 (1H,
m), 5.33 (2H, m), 4.18 (1H, m), 3.52 (1H, d, J = 2.2 Hz),
3.37 (1H, d, J = 2.6 Hz), 3.18 (1H, d, J = 7.8 Hz), 2.74
(2H, t, J = 6.7 Hz), 2.55 (1H, dt, J = 17.3, 6.9 Hz), 2.41
(1H, dt, J = 17.3, 7.6 Hz), 2.06–1.78 (8H, m), 1.39–1.22
(7H, m), 0.89 (3H, t, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) d: 172.0, 131.2, 130.5, 128.7, 126.7, 83.6, 61.1,
57.7, 48.1, 43.3, 31.5, 30.4, 29.4, 29.3, 28.3, 27.1, 26.3, 22.5,
18.1, 14.0; ESIMS m/z: 341 (M++Na, 100); HRESIMS
m/z: 341.2088 (Calcd for C20H30O3Na: M++Na, 341.2093).
Compound 2: A colorless oil; IR (neat) cmꢀ1: 2925, 1738;
1H NMR (400 MHz, CDCl3) d: 5.58 (2H, m), 5.39 (2H,
m), 4.30 (1H, m), 3.45 (1H, d, J = 2.6 Hz), 3.37 (1H, m),
2.78 (2H, t, J = 6.3 Hz), 2.63 (1H, m), 2.57 (1H, m), 2.42
(1H, m), 2.14 (1H, m), 2.02 (2H, m), 1.91–1.66 (6H, m),
1.36–1.25 (6H, m), 0.88 (3H, t, J = 6.7 Hz); 13C NMR
(100 MHz, CDCl3) d: 171.7, 131.1, 131.0, 130.1, 126.8,
81.1, 61.3, 55.8, 44.0, 42.7, 31.5, 30.6, 30.5, 29.5, 29.3, 27.1,
26.2, 22.5, 18.8, 14.0; ESIMS m/z: 341 (M++Na, 78), 195
(100); HRESIMS m/z: 341.2110 (Calcd for C20H30O3Na:
M++Na, 341.2093).
H
26
OMTPA
H
b
c
CO2Me
O
H
27
Scheme 6. Reagents and conditions: (a) K2CO3, MeOH, rt, 60%; (b) (i)
(S)-MTPACl, DMAP, CH2ClCH2Cl, rt, (ii) H2, 10% Pd on C, MeOH,
rt, 25% (two steps); (c) (i) (R)-MTPACl, DMAP, CH2ClCH2Cl, rt, (ii)
H2, 10% Pd on C, MeOH, rt, 64% (two steps).
MTPA 27, which was derived from 23 via diol 26
(Scheme 6). Saponification of acetate 23 followed by
lactonization of the resulting dihydroxycarboxylic acid
yielded lactone 25.20 The spectral data of 25 were iden-
tical to those of agardhilactone.2 Therefore, the absolute
configuration of agardhilactone was determined to be
5S, 6S, 8S, 9R, 10R, and 18S.
Compound 3: A colorless oil; IR (neat) cmꢀ1: 2925, 1737;
1H NMR (400 MHz, CDCl3) d: 5.54 (1H, ddt, J = 15.3,
0.5, 6.2 Hz), 5.46 (1H, m), 5.33 (2H, m), 4.14 (1H, dt,
J = 3.0, 10.4 Hz), 3.56 (1H, br s), 3.32 (1H, d, J = 2.5 Hz),
2.76 (2H, t, J = 6.7 Hz), 2.66 (1H, d, J = 8.2 Hz), 2.55
(1H, ddd, J = 17.2, 7.0, 6.7 Hz), 2.42 (2H, m), 2.12–1.78
(7H, m), 1.41–1.25 (7H, m), 0.89 (3H, t, J = 6.7 Hz); 13C
NMR (100 MHz, CDCl3) d: 172.0, 131.4, 130.7, 128.4,
Acknowledgments
The authors are grateful to Professor William H. Ger-
wick, Oregon State University, for providing the
NMR spectra of agardhilactone acetate. This work

H. Miyaoka et al. / Tetrahedron Letters 46 (2005) 7945–7949
7949
126.4, 83.6, 61.1, 58.5, 48.6, 44.6, 31.5, 30.3, 29.4, 29.2,
28.4, 27.1, 26.5, 22.5, 18.1, 14.0; ESIMS m/z: 341
(M++Na, 100); HRESIMS m/z: 341.2068 (Calcd for
C20H30O3Na: M++Na, 341.2093).
9.2, 7.4 Hz), 2.12 (1H, dd, J = 13.5, 7.5 Hz), 2.06 (3H, s),
1.95–1.49 (7H, m), 0.90 (3H, t, J = 7.4 Hz); 13C NMR
(100 MHz, CDCl3) d: 171.8, 170.4, 131.6, 131.2, 130.3,
129.0, 128.4, 127.7, 78.5, 75.9, 60.1, 55.6, 44.7, 43.2, 30.9,
29.5, 27.5, 27.5, 27.2, 21.3, 18.8, 9.5; ESIMS m/z: 397
(M++Na, 88), 315 (100); HRESIMS m/z: 397.1966 (Calcd
for C22H30O5Na: M++Na, 397.1991).
Compound 4: A colorless oil; IR (neat) cmꢀ1: 2925, 1739;
1H NMR (400 MHz, CDCl3) d: 5.61 (1H, dt, J = 15.4,
6.2 Hz), 5.44 (3H, m), 4.23 (1H, dt, J = 11.7, 2.6 Hz), 3.45
(1H, br s), 3.39 (1H, m), 2.78 (2H, t, J = 6.5 Hz), 2.70 (1H,
t, J = 9.0 Hz), 2.60 (1H, m), 2.41 (1H, ddd, J = 17.7, 9.3,
7.4 Hz), 2.11 (1H, dd, J = 13.5, 7.5 Hz), 2.02 (2H, m),
1.95–1.70 (4H, m), 1.64–1.46 (2H, m), 1.36–1.25 (7H, m),
0.88 (3H, t, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) d:
171.8, 132.2, 131.1, 128.2, 126.8, 78.5, 60.2, 55.6, 44.7,
43.2, 31.5, 30.4, 29.5, 29.3, 27.5, 27.2, 27.1, 22.5, 18.8, 14.0;
ESIMS m/z: 341 (M++Na, 100); HRESIMS m/z: 341.2111
(Calcd for C20H30O3Na: M++Na, 341.2093).
24
Compound 24: ½aꢁD +165.2 (c 0.50, CHCl3); IR (neat)
cmꢀ1: 2925, 1733; 1H NMR (400 MHz, CDCl3) d:
6.49 (1H, dd, J = 15.3, 11.1 Hz), 6.01 (1H, t, J =
10.8 Hz), 5.64 (1H, dt, J = 15.4, 6.1 Hz), 5.60 (1H, dd,
J = 14.8, 7.4 Hz), 5.48 (2H, m), 5.21 (1H, q, J = 6.8 Hz),
4.24 (1H, dt, J = 11.7, 2.6 Hz), 3.46 (1H, br s), 3.40 (1H,
dd, J = 2.6, 1.4 Hz), 2.94 (2H, dd, J = 7.5, 6.2 Hz), 2.72
(1H, t, J = 9.1 Hz), 2.61 (1H, m), 2.42 (1H, ddd, J = 17.8,
9.3, 7.8 Hz), 2.12 (1H, dd, J = 13.6, 7.5 Hz), 2.06 (3H, s),
1.94–1.48 (7H, m), 0.90 (3H, t, J = 7.4 Hz); 13C NMR
(100 MHz, CDCl3) d: 171.8, 170.4, 131.6, 131.2, 130.3,
129.0, 128.4, 127.7, 78.5, 75.8, 60.1, 55.6, 44.7, 43.1, 30.8,
29.5, 27.5, 27.5, 27.1, 21.3, 18.8, 9.5; ESIMS m/z: 397
(M++Na, 100); HRESIMS m/z: 397.1980 (Calcd for
C22H30O5Na: M++Na, 397.1991).
14. Kunstler, T.; Schollmeyer, D.; Singer, H.; Steigerwald, M.
Tetrahedron: Asymmetry 1993, 4, 1645–1650.
15. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94,
4370–4371.
16. Brown, H. C.; Hamoka, T.; Ravindran, N. J. Am. Chem.
Soc. 1975, 97, 5786–5788.
17. (a) Nicolaou, K. C.; Ladduwahetty, T.; Taffer, I. M.;
Zipkin, R. E. Synthesis 1986, 344–347; (b) Sonogashira,
K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467–4470.
19. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H.
J. Am. Chem. Soc. 1991, 113, 4092–4096.
31
20. Agardhilactone (25): ½aꢁD ꢀ104.4 (c 0.09, CHCl3); IR
(neat) cmꢀ1: 3442, 2958, 1733; 1H NMR (400 MHz,
CDCl3) d: 6.49 (1H, m), 6.05 (1H, t, J = 11.0 Hz), 5.70
(1H, dd, J = 15.1, 6.8 Hz), 5.64 (1H, m), 5.42 (2H, m),
4.24 (1H, dt, J = 11.7, 2.8 Hz), 4.10 (1H, m), 3.46 (1H, br
s), 3.40 (1H, m), 2.94 (2H, dd, J = 7.4, 6.3 Hz), 2.72 (1H, t,
J = 8.9 Hz), 2.61 (1H, m), 2.42 (1H, ddd, J = 17.7, 9.2,
7.3 Hz), 2.12 (1H, dd, J = 13.5, 7.5 Hz), 1.94–1.70 (4H,
m), 1.65–1.49 (5H, m), 0.94 (3H, t, J = 7.4 Hz); 13C NMR
(100 MHz, CDCl3) d: 171.8, 136.4, 131.3, 129.3, 129.0,
128.7, 125.5, 78.5, 74.0, 60.2, 55.7, 44.6, 43.2, 30.9, 30.2,
29.5, 27.5, 27.2, 18.8, 9.7; ESIMS m/z: 355 (M++Na, 100);
HRESIMS m/z: 355.1877 (Calcd for C20H28O4Na:
M++Na, 355.1885).
18. A mixture of triene 23 and 24 was separated by HPLC
(CHIRALPAK AS-H, 0.46 cm·25 cm, hexane–isopropa-
nol = 82:18, flow rate: 2.0 mL/min) to give triene 23
(tR = 20.2 min) and triene 24 (tR = 28.2 min).
20
Compound 23: ½aꢁD ꢀ179.6 (c 0.52, CHCl3); IR (neat)
cmꢀ1: 2924, 1734; 1H NMR (400 MHz, CDCl3) d:
6.49 (1H, dd, J = 15.2, 11.0 Hz), 6.01 (1H, t, J =
11.0 Hz), 5.63 (1H, dt, J = 15.4, 6.2 Hz), 5.60 (1H, dd,
J = 15.5, 7.0 Hz), 5.48 (2H, m), 5.22 (1H, q, J = 6.8 Hz),
4.24 (1H, dt, J = 11.7, 2.6 Hz), 3.46 (1H, br s), 3.40 (1H,
dd, J = 2.6, 1.4 Hz), 2.94 (2H, dd, J = 6.9, 6.8 Hz), 2.71
(1H, t, J = 8.9 Hz), 2.61 (1H, m), 2.42 (1H, ddd, J = 17.7,