Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity

Article abstract of DOI:10.1002/chem.200400355

Gambierol is a polycyclic ether toxin, which has been isolated from the marine dinoflagellate Gambierdiscus toxicus. A series of gambierol analogues have been prepared from an advanced intermediate of our total synthesis of gambierol and investigated for

Full text of DOI:10.1002/chem.200400355

FULL PAPER
Diverted Total Synthesis and Biological Evaluation of Gambierol Analogues:
Elucidation of Crucial Structural Elements for Potent Toxicity
Haruhiko Fuwa,[b, c] Noriko Kainuma,[b] Kazuo Tachibana,[b] Chihiro Tsukano,[a]
Masayuki Satake,[a] and Makoto Sasaki*[a]
Abstract: Gambierol is a polycyclic
ether toxin, which has been isolated
from the marine dinoflagellate Gam-
bierdiscus toxicus. A series of gambier-
ol analogues have been prepared from
an advanced intermediate of our total
synthesis of gambierol and investigated
for their toxicity against mice, thus pro-
viding the first systematic structure–ac-
tivity relationships (SAR) of this poly-
cyclic ether class of marine toxin. The
SAR studies described herein clearly
indicate that 1) the C28=C29 double
bond within the H ring and the unsatu-
rated side chain are the crucial struc-
tural elements required for exerting
potent biological activity and 2) the C1
and C6 hydroxy groups, the C30
methyl group, and the C37=C38 double
bond have little influence on the
degree of neurotoxicity against mice.
Keywords: ciguatoxins · gambierol ·
polycyclic ethers · structure–activity
relationships · total synthesis
Introduction
Gambierol (1) is another marine polycyclic ether toxin,
which was isolated along with ciguatoxin congeners from
culture cells of G. toxicus collected from the Rangiroa Pen-
insula in French Polynesia. Its gross structure including the
relative stereochemistry has been determined by extensive
NMR studies.[6] Subsequently, the absolute configuration
The fused polycyclic ether class of marine natural products
has attracted the attention of chemists and biologists owing
to their complex and large molecular architecture as well as
their potent and diverse biological activities.[1] Ciguatoxin
and its congeners, produced by the epiphytic dinoflagellate,
Gambierdiscus toxicus, are a representative family of marine
polycyclic ether toxins.[2,3] Ciguatoxins (CTXs) are the prin-
cipal toxins responsible for the ciguatera seafood poisoning
prevalent in the circumtropic area, from which more than
25000 patients suffer annually.[4] CTXs are known to exert
their potent neurotoxicity by binding to voltage-sensitive
sodium channels (VSSC) and altering their function.[5]
was established by derivatization and application of a modi-
fied Mosher analysis.[7] This intriguing toxic molecule con-
sists of a trans-fused octacyclic polyether core that contains
18 stereogenic centers and a partially conjugated triene side
chain, including a conjugated (Z,Z)-diene system, and thus
it provides a formidable synthetic challenge. Gambierol ex-
hibits potent neurotoxicity against mice with a minimal
lethal dose (MLD) of 50 mgkgꢀ1 by intraperitoneal (ip) in-
jection, and the neurological symptoms caused in mice re-
semble those shown by CTXs. This finding implies the possi-
bility that gambierol is also responsible for ciguatera sea-
food poisoning. Very recently, Inoue et al. reported that
gambierol inhibits the binding of dihydrobrevetoxin B
(PbTx-3) to VSSC, though its binding affinity is significantly
[a] C. Tsukano, Prof. Dr. M. Satake, Prof. Dr. M. Sasaki
Graduate School of Life Sciences, Tohoku University
Tsutumidori-Amamiya, Aoba-ku, Sendai 981–8555 (Japan)
Fax : (+81)227-178-897
E-mail: masasaki@bios.tohoku.ac.jp
[b] Dr. H. Fuwa, N. Kainuma, Prof. Dr. K. Tachibana
Graduate School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113–0033 (Japan)
[c] Dr. H. Fuwa
Present address:
Graduate School of Pharmaceutical Sciences
The University of Tokyo, Hongo
Bunkyo-ku, Tokyo 113–0033 (Japan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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4894 – 4909
lower than those of brevetoxins and ciguatoxins.[8] Over the
past decade, however, its extremely limited availability from
nature has precluded detailed biological studies on this neu-
rotoxin. Therefore, there have been strong demands for a
supply of useful quantities of this natural product to be pre-
pared by chemical total synthesis. Consequently, substantial
efforts have been devoted towards the synthesis of gambier-
ol[9] and, to date, two complete total syntheses have been re-
ported by us[10] and by Yamamoto and co-workers.[11] Now
that ample quantities of gambierol can be supplied by chem-
ical synthesis, we undertook studies aimed at gaining an un-
derstanding of the molecular basis of the biological mode of
action of this marine toxin. In this context, we have investi-
gated the structure–activity relationships (SAR) of gambier-
ol to establish the structural elements that are essential for
potent biological activity and the basis for the design and
synthesis of molecular probes useful for biological studies.
Herein, we describe in detail the total synthesis and biologi-
cal evaluation of a series of gambierol analogues, which cul-
minated in the elucidation of the crucial structural elements
required for potent neurotoxicity.[12]
Synthesis of the right-wing modified analogues: We first di-
rected our attention to the synthesis of the right-wing modi-
fied analogues of gambierol in order to evaluate the role of
the H-ring functionalities and the lipophilic triene side
chain. At the outset, we prepared analogues 3 and 4 to see
whether the octacyclic polyether core of 1 alone is a suffi-
cient minimal structure for exhibiting toxicity. Debenzyla-
tion of 2 by hydrogenolysis gave diol 3 in 94% yield
(Scheme 1). Subsequent removal of the acetyl groups under
Scheme 1. Reagents and conditions: a) H2, 20% Pd(OH)2/C, EtOAc, RT,
94%; b) K2CO3, MeOH, RT, 84%.
basic conditions afforded tetraol 4 in 84% yield. We also
synthesized analogue 5, which bears a heptyl side chain
(Scheme 2). Removal of the acetyl groups of 2 followed by
silylation with tert-butyldimethylsilyl trifluoromethanesulfo-
Results and Discussion
Only a few reports concerning the structure–activity rela-
tionships (SAR) of marine polycyclic ether toxins exist.[13]
Two plausible reasons for this are 1) the extremely limited
availability of these secondary metabolites from natural
sources and 2) the difficulties of altering the highly complex
and huge molecular structures by chemical means. In the
case of gambierol, we have solved the former problem by
our convergent total synthesis, which realized the prepara-
tion of ample quantities of this natural toxin. However,
owing to the presence of extremely sensitive functional
groups, including the labile triene side chain and the tertiary
allylic alcohol, the controlled chemical modification of gam-
bierol itself is seemingly quite difficult.[7] On the other hand,
information gained through the total synthesis suggested
that one would be able to overcome such a limitation by car-
rying out analogue synthesis, starting from an advanced in-
termediate that has a simple structure and sufficient func-
tional groups for further chemical manipulation.[14] During
the course of our total synthesis of gambierol, we establish-
ed a practical synthetic entry to the octacyclic polyether
core 2[9k,10] based on our modified Suzuki–Miyaura coupling
approach.[15,16] This advanced intermediate fulfilled the
above requirements and is available in a gram quantity.
Thus, we anticipated that the octacyclic polyether core 2
would be an ideal starting point for the diverted total syn-
thesis of gambierol analogues for SAR studies.
Scheme 2. Reagents and conditions: a) K2CO3, MeOH, RT; b) TBSOTf,
Et3N, DMF, 08C; c) CSA, MeOH/CH2Cl2 (1:1), 08C, 59% (three steps);
d) TPAP, NMO, 4 Š molecular sieves, CH2Cl2, RT; e) BrꢀPh3P+
(CH2)5CH3, NaHMDS, THF, 08C, 45% (two steps); f) HF·pyridine, THF,
RT, 72 %; g) H2, 20% Pd(OH)2/C, MeOH/EtOAc (1:1), RT, quantitative.
TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfonate; DMF=N,N-
dimethylformamide; CSA=dl-camphorsulfonic acid; TPAP=tetra-n-pro-
pylammonium perruthenate; NMO=N-methylmorpholine N-oxide;
NaHMDS=sodium bis(trimethylsilyl)amide.
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nate (TBSOTf) and triethylamine led to the bis-silyl ether 6.
Selective liberation of the C32[17] primary hydroxy group
under acidic conditions produced the alcohol in 59% yield
for the three steps. Oxidation of the alcohol using Leyꢁs con-
ditions [tetra-n-propylammonium perruthenate (TPAP), N-
methylmorpholine N-oxide (NMO)][18] and the ensuing
Wittig reaction with the ylide generated from n-hexyltriphe-
nylphosphonium bromide [BrꢀPh3P+(CH2)5CH3], afforded
(Z)-olefin 7 in 45% overall yield. Deprotection of the silyl
group with HF·pyridine followed by removal of the benzyl
groups with concomitant reduction of the double bond fur-
nished analogue 5 in 72% yield for the two steps.
Analogues 8--10, which possess the C30 axial methyl
group, were prepared as depicted in Scheme 3. The synthesis
of analogues 8 and 9 started from alcohol 11, which is avail-
able in 11 steps from 2.[10] Parikh–Doering oxidation of 11
and Wittig reaction of the derived aldehyde led to (Z)-
olefin 12 in 58% overall yield. Removal of the silyl protect-
ing groups by exposure to excess HF·pyridine furnished
34,35,37,38-tetrahydrogambierol (9) in 81% yield. Hydroge-
nation of 9 then afforded perhydrogambierol (8) in 59%
yield. The synthesis of analogue 10 also commenced with al-
cohol 11. Oxidation of 11 followed by Julia–Kociensky olefi-
nation[19] with a sulfone anion derived from 5-(pentane-1-
sulfonyl)-1-phenyl-1H-tetrazole (13) gave olefin 14 as an in-
separable mixture of geometric isomers with disappointingly
poor selectivity (E:Z=ca. 1:2, 70% overall yield). Several
attempts to improve the selectivity met with failure. Howev-
er, after deprotection of the silyl groups by treatment with
excess HF·pyridine, pure (32E)-34,35,37,38-tetrahydrogam-
bierol (10) was isolated by HPLC separation of the configu-
rational isomers.
18 were designed. Analogues 15 and 16 were synthesized
stereoselectively by palladium(0)-mediated cross-coupling[20]
of (Z)-vinyl bromide 19, accessible from 2 in 15 steps,[10]
with (Z)-vinylstannane 20 and the known (E)-vinylboronic
acid 21,[21] respectively (Scheme 4). The Stille coupling of
(Z)-vinyl bromide 19 with (Z)-vinyl stannane 20 under
Coreyꢁs modified conditions [[Pd(PPh3)4], CuCl, LiCl,
DMSO/THF (1:1), 608C][10,22] provided 37,38-dihydrogam-
bierol (15) in high yield. On the other hand, the Suzuki–
Miyaura coupling[13] of 19 with (E)-vinylboronic acid 21 with
a catalytic amount of [Pd(PPh3)4] and Na2CO3 in DME/H2O
(4:1) at 958C furnished (32E)-37,38-dihydrogambierol (16)
in excellent yield. The synthesis of analogue 17 is summar-
ized in Scheme 5. Oxidation of 11 and Takai iodo-olefina-
tion (CrCl2, CHI3)[23] of the derived aldehyde gave (E)-vinyl
iodide 22 together with its Z isomer in an acceptable selec-
tivity (E:Z>10:1 determined by 1H NMR spectroscopy,
71% combined yield). Global desilylation of 22 followed by
Stille coupling with (Z)-vinylstannane 23 under established
conditions[10] delivered (32E)-gambierol (17) along with a
small amount of its Z isomer, gambierol; these isomers were
separated by HPLC. Truncated analogue 18 was prepared
by the Stille coupling of 19 with tributyl(vinyl)tin
(Scheme 4).
To evaluate the H-ring functionalities, analogues 24–26,
each of which has the triene side chain in the natural form,
were designed and synthesized based on our total synthesis
of 1.[10] The synthesis of 28,29-dihydro-30-desmethylgambier-
ol (24) commenced with compound 6 (Scheme 6). Reductive
debenzylation of 6 by exposure to excess lithium di-tert-bu-
tylbiphenylide (LiDBB)[24] was followed by selective protec-
tion of the C1 hydroxy group to give tert-butyldiphenylsilyl
(TBDPS) ether 27 in 79% yield for the two steps. Further
silylation of the C6 hydroxy group and subsequent selective
cleavage of the C32 primary TBS ether under acidic condi-
To further investigate the effect of the multiunsaturated
side chain of parent 1, two isomeric diene analogues 15 and
16 and (32E)-analogue 17 as well as the truncated analogue
Scheme 3. Reagents and conditions: a) SO3·pyridine, Et3N, DMSO/CH2Cl2 (1:1), 08C; b) BrꢀPh3P+(CH2)5CH3, NaHMDS, THF, 08C, 58% (two steps);
c) HF·pyridine, THF, RT, 81%; d) H2, 10% Pd/C, EtOAc, RT, 59%; e) TPAP, NMO, 4 Š molecular sieves, CH2Cl2, RT; f) 5-(pentane-1-sulfonyl)-1-
phenyl-1H-tetrazole 13, KHMDS, THF, ꢀ788C!RT, 70% (two steps); g) HF·pyridine, THF, RT, 87%; h) HPLC separation of configurational isomers
(9: 58%; 10: 29%). DMSO=dimethylsulfoxide; HPLC=high-performance liquid chromatography.
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Gambierol Analogues
4894 – 4909
Scheme 4. Reagents and conditions: a) 20, [Pd(PPh3)4], CuCl, LiCl, DMSO/THF (1:1), 608C, 91%; b) 21, [Pd(PPh3)4], Na2CO3, DME/H2O (4:1), 958C,
91%; c) tributyl(vinyl)tin, [Pd(PPh3)4], CuCl, LiCl, DMSO/THF, 608C, 26% (45% based on recovered 19). DME=dimethoxyethane.
bierol (26), were prepared by using a similar chemistry to
that described for the synthesis of 24. 28,29-Dihydrogam-
bierol (25) was accessible from alcohol 11 (Scheme 7). After
reduction of the H-ring double bond of 11, the derived alco-
hol 30 was elaborated to analogue 25 by the sequence de-
scribed above. The synthesis of 30-desmethylgambierol (26)
commenced with enone 31,[10] which is derived from 2 in
five steps as previously reported (Scheme 8). Reduction of
the carbonyl group under Luche conditions[28] gave allylic al-
cohol 32 in 78% yield after separation of a small amount of
the undesired diastereomer by flash chromatography. Fur-
ther protecting-group manipulations led to alcohol 33, to
which the triene side chain was incorporated by modified
Stille coupling to afford analogue 26.
Synthesis of the left-wing modified analogues: With a series
of right-wing modified analogues in hand, we next turned
our attention to the modification of the C1 and C6 hydroxy
groups. 6-epi-Gambierol (34) and 6-deoxygambierol (35)
were targeted in order to evaluate the effect of the C6 hy-
droxy group on toxicity. Initially, the C6 axial-oriented hy-
droxy group of 36[10] was inverted through an oxidation–re-
duction sequence (Scheme 9). Alcohol 36 was oxidized with
Scheme 5. Reagents and conditions: a) TPAP, NMO, 4 Š molecular
sieves, CH2Cl2, RT; b) CrCl2, CHI3, THF, RT!408C, 71% (two steps);
TPAP in the presence of NMO and the resultant ketone was
reduced stereoselectively with NaBH4 (methanol/CH2Cl2,
ꢀ788C) to give alcohol 37 (d.r.=6.9:1) in good overall
yield. As shown in Figure 1, the stereochemistry at the C6
c) HF·pyridine, THF, RT, quantitative; d) 23, [Pd(PPh3)4], CuCl, LiCl,
DMSO/THF (1:1), RT, 84%.
1
tions led to alcohol 28 in 80% yield for the two steps. Oxi-
dation of 28 with SO3·pyridine and Corey–Fuchs olefina-
tion,[25] followed by stereoselective reduction of the derived
dibromoolefin under conditions [nBu3SnH, Pd(PPh3)4] re-
ported by Uenishi and co-workers[26] afforded (Z)-vinyl bro-
mide 29 in 47% overall yield. Global deprotection of the
silyl protective groups with HF·pyridine and the ensuing
Stille coupling with (Z)-vinylstannane 23[27] furnished ana-
logue 24 in 63% yield for the two steps. Two other ana-
logues, 28,29-dihydrogambierol (25) and 30-desmethylgam-
position of 37 was unambiguously confirmed by H NMR
analysis of the corresponding acetate (J5eq,6 =5.5 Hz, J5ax,6
=
10.8 Hz). Protection of 37 as the TBS ether gave tetra-silyl
ether 38, which was then elaborated to 6-epi-gambierol (34)
following the same protocol as described for the synthesis of
analogue 24. On the other hand, for the synthesis of 6-
deoxygambierol (35), alcohol 37 was treated with thiocarbo-
nyldiimidazole to give the imidazolylthiocarbonyl derivative
40. Reduction of 40 with nBu3SnH in the presence of 2,2’-
azobisisobutyronitrile (AIBN) produced deoxygenated
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Scheme 7. Reagents and conditions: a) H2, 10% Pd/C, EtOAc, room tem-
perature, 95%; b) SO3·pyridine, Et3N, DMSO/CH2Cl2 (3:2), 08C; c) CBr4,
PPh3, Et3N, CH2Cl2, 08C; d) nBu3SnH, [Pd(PPh3)4], benzene, RT, 74%
(three steps); e) HF·pyridine, THF, RT, quantitative; f) 23, [Pd(PPh3)4],
CuCl, LiCl, DMSO/THF (1:1), 608C, 64%.
Scheme 6. Reagents and conditions: a) LiDBB, THF, ꢀ78!ꢀ408C;
b) TBDPSCl, Et3N, DMAP, CH2Cl2, RT, 79% (two steps); c) TBSOTf,
Et3N, CH2Cl2, 08C!RT; d) CSA, MeOH/CH2Cl2 (1:1), 08C, 80% (two
steps); e) SO3·pyridine, Et3N, DMSO/CH2Cl2 (1:1), 08C; f) CBr4, PPh3,
Et3N, CH2Cl2, 08C; g) nBu3SnH, [Pd(PPh3)4], benzene, RT, 47% (three
steps); h) HF·pyridine, THF, RT, 92%; i) 23, [Pd(PPh3)4], CuCl, LiCl,
DMSO/THF (1:1), 608C, 68%. LiDBB=lithium di-tert-butylbiphenylide;
TBDPS=tert-butyldiphenylsilyl; DMAP=N,N-dimethylaminopyridine.
product 41, which was converted into the 6-deoxy analogue
35 via 42 in a way similar to that described above.
To investigate the role of the terminal C1 primary hy-
droxy group, we prepared 1-O-methylgambierol (43) and 1-
deoxygambierol (44) (Scheme 10). The synthesis of 1-O-
methylgambierol (43) commenced with (Z)-vinyl bromide
45. During the course of our total synthesis of gambierol, we
found that the three silyl protecting groups of 45 could be
differentially removed by controlling the reaction time of
the deprotection step. As expected, selective liberation of
the C1 hydroxy group was realized by brief exposure of 45
to HF·pyridine; this reaction gives rise to alcohol 46 in 86%
yield. Treatment of 46 with methyl trifluoromethanesulfo-
nate in the presence of 2,6-di-tert-butylpyridine afforded
Scheme 8. Reagents and conditions: a) NaBH4, CeCl3·7H2O, MeOH, 08C,
78%; b) TBSOTf, Et3N, CH2Cl2, 08C!RT; c) LiDBB, THF, ꢀ78!
ꢀ408C, 74% (two steps); d) TBDPSCl, Et3N, DMAP, CH2Cl2, RT, 85%;
e) TBSOTf, Et3N, CH2Cl2, 08C!RT; f) CSA, MeOH/CH2Cl2 (1:1), 08C,
81% (two steps); g) SO3·pyridine, Et3N, DMSO/CH2Cl2 (1:1), 08C;
h) CBr4, PPh3, Et3N, CH2Cl2, 08C, 47% (two steps); i) nBu3SnH,
[Pd(PPh3)4], benzene, RT; j) HF·pyridine, THF, RT; k) 23, [Pd(PPh3)4],
CuCl, LiCl, DMSO/THF (1:1), 608C, 34% (three steps).
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Gambierol Analogues
4894 – 4909
Scheme 10. Reagents and conditions: a) HF·pyridine, THF, RT, 86%;
b) MeOTf, 2,6-di-tert-butylpyridine, CH2Cl2, RT, 82%; c) MsCl, Et3N,
CH2Cl2, 08C; d) LiBHEt3, THF, 08C!RT, 96% (two steps); e) HF·pyri-
dine, THF, RT; f) 23, [Pd(PPh3)4], CuCl, LiCl, DMSO/THF (1:1), 608C,
86% (two steps) for 43, 82% (two steps) for 44. Ms=methanesulfonyl.
methyl ether 47 in high yield without affecting the sensitive
(Z)-vinyl bromide portion. Removal of the remaining silyl
protecting groups and the ensuing modified Stille coupling
with (Z)-vinylstannane 23 furnished 1-O-methyl analogue
43. 1-Deoxygambierol (44) was also prepared from alcohol
46 by reduction of the corresponding mesylate. Thus, treat-
ment of 46 with methanesulfonyl chloride in the presence of
triethylamine gave the corresponding mesylate, which was
reduced with LiBHEt3 to afford the deoxygenated product
48 in excellent yield. Elaboration of 48 into the desired ana-
logue 44 was readily accomplished as described for the syn-
thesis of 43.
Scheme 9. Reagents and conditions: a) TPAP, NMO, 4 Š molecular
sieves, CH2Cl2, RT, 97%; b) NaBH4, MeOH, ꢀ788C, 83%+12% of 36;
c) TBSOTf, Et3N, CH2Cl2, 08C!RT; d) (Im)2C=S, DMAP, toluene,
1108C, 94%; e) nBu3SnH, AIBN, toluene, 1108C; f) CSA, MeOH/
CH2Cl2 (1:1), 08C, 86% (two steps) for 39, 97% (two steps) for 42;
g) TPAP, NMO, 4 Š molecular sieves, CH2Cl2, RT; h) CBr4, PPh3, Et3N,
CH2Cl2, 08C; i) nBu3SnH, [Pd(PPh3)4], benzene, RT; j) HF·pyridine,
THF, RT; k) 23, [Pd(PPh3)4], CuCl, LiCl, DMSO/THF (1:1), 608C, 51%
(five steps) for 34, 46% (five steps) for 35. Im=imidazole; AIBN=2,2’-
azobisisobutyronitrile.
Biological evaluation: The toxicities (MLD values) of syn-
thetic gambierol (1) and its analogues against mice were
next determined by intraperitoneal (ip) injection. The re-
sults are summarized in Tables 1 and 2. All toxic analogues
except for compounds 43 and 44 caused death of the mice
within 15–30 min of ip injection at the minimum lethal dose
level indicated in Tables 1 and 2. In addition, at a lower
dose level for all the active analogues, mice showed typical
neurological symptoms, as observed in the case of gambier-
ol.[29] On the other hand, such changes were not observed
for the inactive compounds. For analogues 43 and 44, death
of the mice occurred 45–145 min after the ip injection.
Not surprisingly, simple analogues 3 and 4 were complete-
ly inactive, which clearly indicates that the octacyclic poly-
ether core structure itself does not exert toxicity. Analogues
5 and 8, both of which contain a heptyl chain in place of the
Figure 1. Confirmation of the stereochemistry at the C6 position by perti-
nent 1H NMR coupling constants: 3J5eq,6 =5.5 Hz, 3J5ax,6 =10.8 Hz. The
benzyl group was replaced with a methyl group for clarity.
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Table 1. Minimal lethal dose (MLD) values of gambierol (1) and right-wing modified analogues 3–5, 8–10, 15–18, and 24–26 against mice.
Structure
MLD
Relative
activity
Structure
MLD
Relative
activity
[mgkgꢀ1] (ip)
[mgkgꢀ1] (ip)
1
3
0.050–0.075
1
–
15
16
0.065
0.134
1
>8.20
1/2
(inactive)
4
5
8
>18.3
–
–
–
17
18
24
0.336
1.18
1/5
1/18
–
(inactive)
>7.63
(inactive)
>12.9
>11.9
(inactive)
7.95
(inactive)
9
1.66
1/25
–
25
26
1/120
1/5
10
>12.9
0.340
(inactive)
natural triene side chain, showed no detectable toxicity, un-
derlining the importance of the functionalities of the H ring
as well as the double bond(s) within the side chain.
analogue 17 retained lethality about fivefold less active than
that of the parent 1. By comparing the structures of 10 and
17, the conjugated diene system within the side chain again
turns out to be important for exhibiting potent toxicity. In
contrast, analogue 18, which bears a butadiene side chain,
was found to exhibit lower toxicity (MLD 1.18 mgkgꢀ1) than
compounds 15–17, which suggests that the length of the side
chain in gambierol is also important for toxicity.
During the evaluation of analogues 24–26, which possess
the natural triene side chain, we found that the C28=C29
double bond within the H ring has a considerable effect on
biological activity. To our surprise, 28,29-dihydro-30-desme-
thylgambierol (24) was completely inactive. 30-Desmethyl-
gambierol (26) displayed toxicity about fivefold less active
than 1 (MLD 0.34 mgkgꢀ1), whereas 28,29-dihydrogambierol
(25) was approximately 120-fold less active (MLD
7.95 mgkgꢀ1). These results strongly indicate that the C28=
C29 double bond is an indispensable structural element for
exerting potent toxicity, whilst the C30 methyl group is not
critical although it is possibly important. Reduction of the
C28=C29 double bond should cause significant changes in
The importance of the conjugated diene system within the
triene side chain was revealed by the evaluation of the toxic-
ity of the analogues that contain the H-ring functionalities.
34,35,37,38-Tetrahydrogambierol (9) exhibited only moder-
ate toxicity against mice (MLD 1.66 mgkgꢀ1, ca. 25-fold less
active than 1), and (32E)-34,35,37,38-tetrahydrogambierol
(10), in which the configuration of the C32=C33 double
bond is altered (Z!E), showed no detectable toxicity.
These results suggest that the conjugated diene system,
which strongly restricts the orientation of the side chain, is
an important and preferred structural feature for exhibiting
potent activity. On the other hand, 37,38-dihydrogambierol
(15) and (34E)-37,38-dihydrogambierol (16) were as potent
as the parent 1, which indicates that reduction of the C37=
C38 double bond and inversion of the configuration of the
C34=C35 double bond are irrelevant to toxicity. In addition
to these compounds, we evaluated the toxicity of (32E)-
gambierol (17) and the truncated analogue 18. Interestingly,
4900
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 4894 – 4909

Gambierol Analogues
4894 – 4909
Table 2. Minimal lethal dose (MLD) values of gambierol (1) and left-
wing modified analogues 34, 35, 43, and 44 against mice.
Methylgambierol (43) and 1-deoxygambierol (44) also re-
tained potent neurotoxicity (MLD 0.42 and 0.20 mgkgꢀ1, re-
spectively). However, these analogues required a longer
time to cause death in mice (45–145 min after ip injection)
than other active analogues, which suggests that these C1
modified analogues may have relatively low absorption and/
or distribution properties. In any case, it can be concluded
that the C1 and C6 hydroxy groups are not essential struc-
tural elements for exhibiting toxicity, though their presence
is preferred.
Structure
MLD [mgkgꢀ1
]
Relative activity
1
0.050–0.075
1
34
35
43
0.065
0.19
0.42
1
Conclusion
1/3
1/6
By virtue of our practical synthetic route to gambierol, di-
verted total synthesis of gambierol analogues and systematic
and detailed structure–activity relationship (SAR) studies of
this complex marine toxin have been realized for the first
time. The SAR study described herein has revealed that the
structural elements of gambierol indispensable for exhibiting
potent toxicity are the C28=C29 double bond, and the unsa-
turated side chain of specific length. In contrast to these im-
portant structural elements, the C1 and C6 hydroxy groups,
the C30 axial-oriented methyl group, and the C34=C35
double bond are not essential but are preferred functional
groups for exhibiting potent toxicity (Figure 3). The results
presented here will allow the rational design of photoaffinity
labeling and/or biotin-tagged probe molecules that will be
useful for detailed biological studies on gambierol. Further
studies along this line are currently underway and will be re-
ported elsewhere.
44
0.20
1/3
the conformation of the H ring and consequently the orien-
tation of the triene side chain. The drastic decrease in the
toxicity of analogue 25 could be ascribed to the conforma-
tional change of the right-wing of the molecule. This was
also supported by molecular mechanics calculations of com-
pounds 1, 25, and 26. A Monte Carlo conformational search
with the MM3* forcefield implemented in Macromodelꢂ ver-
sion 8.0 was carried out for each compound simulated in
water. Analogue 25, in which the C28=C29 double bond is
removed, adopts a conformation very different from that of
1, whereas the conformation of analogue 26, which lacks the
C30 methyl group, is similar to that of parent 1 (Figure 2).
Finally, the role of the C1 and C6 hydroxy groups was es-
tablished by analyzing analogues 34, 35, 43, and 44
(Table 2). Since both 6-epi-gambierol (34) and 6-deoxygam-
bierol (35) displayed activity comparable to that of parent 1,
it can be assumed that the C6 hydroxy group has essentially
no influence on the biological activity of gambierol. 1-O-
Figure 3. Summary of the structure-activity relationships of gambierol.
Experimental Section
General: All reactions sensitive to air and/or moisture were carried out
under an atmosphere of argon or nitrogen in oven-dried glassware with
anhydrous solvents. All anhydrous solvents were purchased from Kanto
Chemical Co. and used without further drying. Triethylamine was distil-
led from calcium hydride under an argon atmosphere. Tetrakis(triphenyl-
phosphine)palladium(0) was prepared according to the literature proto-
col[30] and stored under an atmosphere of argon below ꢀ208C. Lithium
chloride was dried by heating under a high vacuum prior to use. All
other reagents purchased were of the highest commercial quality and
used as received unless otherwise stated. Analytical thin-layer chroma-
tography was carried out by using E. Merck silica gel 60 F254 plates
(0.25 mm thickness). Flash chromatography was carried out with Fuji Si-
lysia silica gel BW300 (200–400 mesh). Optical rotations were recorded
on a JASCO DIP-350 digital polarimeter; specific optical rotations ([a]D)
Figure 2. Lowest energy conformers for gambierol (1), 28,29-dihydrogam-
bierol (25) and 30-desmethylgambierol (26). The A–E ring portion and
hydrogen atoms have been removed for clarity.
Chem. Eur. J. 2004, 10, 4894 – 4909
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4901

M. Sasaki et al.
FULL PAPER
are given in 10ꢀ1 degcm2 gꢀ1. Infrared spectra spectra were recorded on a
JASCO FT/IR-420 spectrometer. 1H and 13C NMR spectra were recorded
on a JEOL A500 or Bruker DRX-500 spectrometer. Chemical shifts are
reported in ppm downfield from tetramethylsilane with the solvent reso-
nance as the internal standard [1H NMR, CHCl3 (7.24), C6HD5 (7.15),
C5HD4N (8.50); 13C NMR, CDCl3 (77.0), C6H6 (128.0), C5D5N (135.5)],
and coupling constants (J) are reported in hertz (Hz). The following ab-
breviations are used to designate the multiplicities: s=singlet, d=dou-
blet, t=triplet, m=multiplet, br=broad. Low- and high-resolution mass
spectra were recorded on a JEOL SX-102A mass spectrometer under
fast atom bombardment (FAB) conditions using m-nitrobenzyl alcohol
(NBA) as the matrix. Experimental procedures and characterization data
for compounds 6, 7, 12, 13, 20, 27–30, 32, 33, 38–42, 47 and 48 are includ-
ed in the Supporting Information.
HRMS (FAB): m/z calcd for C56H80O11Na [M++Na]: 951.5598; found:
951.5646.
Pd(OH)2/C (cat.) was added to a solution of the above alcohol in ethyl
acetate/methanol (1:1, v/v, 2 mL). The resulting mixture was stirred at
room temperature under a hydrogen atmosphere for 2 days, and then fil-
tered through a plug of Celite. The filtrate was concentrated under re-
duced pressure to give analogue 5 (4.5 mg, quantitative) as an amorphous
solid: [a]2D9 =ꢀ4.6 (c=0.15 in CHCl3); IR (film): n˜max =3437, 2931, 2872,
1631, 1460, 1386, 1292, 1089, 1052, 755 cmꢀ1 1H NMR (500 MHz,
;
CD3OD): d=3.79 (dd, J=12.2, 3.7 Hz, 1H), 3.76–3.71 (m, 1H), 3.66–3.62
(m, 2H), 3.52–3.48 (m, 3H), 3.41–3.06 (m, 8H), 3.02 (dd, J=12.5, 3.4 Hz,
1H), 2.16 (ddd, J=11.6, 4.3, 4.3 Hz, 1H), 2.01–1.93 (m, 4H), 1.89–1.42
(m, 21H), 1.37–1.18 (m, 10H), 1.31 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H),
1.20 (s, 3H), 0.87 ppm (t, J=6.7 Hz, 3H); 13C NMR (125 MHz, CD3OD):
d=87.7, 86.1, 82.9, 81.3, 81.1, 80.3, 77.8, 77.2, 77.1, 76.2, 75.8, 75.5, 75.4,
75.1, 73.7, 73.4, 72.1, 62.9, 55.1, 49.6, 44.3, 38.7, 37.4, 36.2, 33.2, 33.1, 33.0,
30.5, 30.4, 29.9, 29.7, 29.6, 28.2, 27.8, 27.2, 25.3, 23.7, 21.9, 21.1, 18.8, 16.6,
14.4 ppm; HRMS (FAB): m/z calcd for C42H70O11Na [M++Na]: 773.4816;
found: 773.4803.
Analogue 3: Pd(OH)2/C (20%, cat.) was added to a solution of octacyclic
polyether 2 (14.8 mg, 0.0156 mmol) in ethyl acetate (2 mL). The resulting
mixture was stirred at room temperature under hydrogen atmosphere for
2 days and then filtered through a plug of Celite. The filtrate was concen-
trated under reduced pressure to give diol 3 (11.4 mg, 94%) as an amor-
phous solid: [a]2D9 =ꢀ5.2 (c=0.16 in CHCl3); IR (film): n˜max =3444, 2947,
34,35,37,38-Tetrahydrogambierol (9): HF·pyridine (0.2 mL) was added to
a solution of olefin 12 (8.5 mg, 0.0069 mmol) in THF (0.6 mL) cooled to
08C. The resulting mixture was stirred at room temperature for 3 days
and then poured into cold saturated aqueous NaHCO3. The aqueous
layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
CHCl3 3!5% methanol/CHCl3) to give 9 (4.3 mg, 81%) as an amor-
phous solid: [a]3D0 =+10.6 (c=0.12 in CHCl3); IR (film): n˜max =3439,
2875, 1739, 1650, 1458, 1382, 1239, 1089, 1049 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=4.98 (ddd, J=5.2, 3.1, 2.1 Hz, 1H), 4.11 (dd, J=11.6, 6.4 Hz,
1H), 3.99 (dd, J=11.6, 4.6 Hz, 1H), 3.80–3.72 (m, 3H), 3.69 (dd, J=2.8,
2.8 Hz, 1H), 3.65–3.57 (m, 2H), 3.47–3.39 (m, 2H), 3.34 (dd, J=11.0,
4.9 Hz, 1H), 3.20 (ddd, J=11.0, 9.8, 4.9 Hz, 1H), 3.17–3.05 (m, 3H), 3.01
(dd, J=12.8, 3.4 Hz, 1H), 2.58 (br, 1H), 2.23 (ddd, J=11.9, 4.6, 4.3 Hz,
1H), 2.10–1.33 (m, 29H), 1.32 (s, 3H), 1.30 (s, 6H), 1.22 ppm (s, 3H); 13C
NMR (125 MHz, CDCl3): d=170.7, 170.1, 84.8, 82.5, 81.3, 81.0, 80.0, 79.7,
79.1, 76.4, 75.9, 75.8, 75.2, 75.1, 73.9, 73.5, 73.0, 72.2, 72.0, 70.8, 65.0, 62.8,
53.9, 43.6, 37.4, 35.5, 32.4, 32.0, 29.2, 28.5, 27.2, 27.0, 24.8, 24.2, 21.3, 21.2,
20.8, 20.3, 18.2, 16.1 ppm; HRMS (FAB): m/z calcd for C40H62O14Na [M+
+Na]: 789.4037; found: 789.4033.
2928, 2871, 1620, 1459, 1381, 1077, 748 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=5.76 (dd, J=12.8, 2.8 Hz, 1H), 5.71 (ddd, J=11.0, 7.6, 7.3 Hz,
1H), 5.48 (dd, J=12.8, 1.8 Hz, 1H), 5.41 (dd, J=11.0, 9.5 Hz, 1H), 4.22–
4.20 (m, 2H), 3.79–3.76 (m, 2H), 3.70 (m, 1H), 3.64–3.59 (m, 2H),
3.45(m, 1H), 3.39–3.32 (m, 5H), 3.17–3.02 (m, 5H), 2.58 (m, 1H), 2.23
(ddd, J=11.9, 4.3, 4.3 Hz, 1H), 2.18–1.82 (m, 10H), 1.77–1.45 (m, 11H),
1.40–1.22(m, 5H), 1.32 (s, 3H), 1.30 (s, 6H), 1.28 (s, 3H), 1.22 (s, 3H),
0.87 ppm (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=137.9,
136.4, 130.8, 125.7, 84.8, 82.4, 82.2, 81.3, 79.9, 79.5, 79.1, 77.2, 76.3, 75.9,
75.8, 75.2, 75.1, 73.9, 72.2, 71.9, 71.8, 70.8, 62.8, 53.7, 43.6, 37.4, 35.5, 32.4,
32.1, 31.4, 29.2, 29.1, 28.6, 28.4, 27.0, 24.2, 22.5, 21.6, 21.3, 20.3, 18.2, 15.6,
14.0 ppm; HRMS (FAB): m/z calcd for C43H68O11Na [M++Na]: 783.4659;
found: 783.4670.
Analogue 4: K2CO3 (7.0 mg, 0.051 mmol) was added to a solution of di-
acetate 3 (5.3 mg, 0.0068 mmol) in methanol (1 mL). The resulting mix-
ture was stirred at room temperature overnight and concentrated under
reduced pressure. The residue was purified by flash chromatography
(silica gel, CHCl3 then 3!5!10% methanol/CHCl3) to give analogue 4
(3.9 mg, 84%) as an amorphous solid: [a]2D9 =ꢀ3.3 (c=0.11 in CHCl3);
IR (film): n˜max =3435, 2939, 2871, 1620, 1456, 1381, 1263, 1094, 754 cmꢀ1
;
1H NMR (500 MHz, CDCl3/CD3OD): d=3.93–3.85 (m, 3H), 3.85 (dd,
J=2.8, 2.8 Hz, 1H), 3.74–3.49 (m, 8H), 3.45–3.20 (m, 5H), 3.16 (dd, J=
12.2, 3.4 Hz, 1H), 2.32 (ddd, J=11.9, 4.3, 4.3 Hz, 1H), 2.22–2.05 (m, 5H),
2.01–1.53 (m, 18H), 1.44 (m, 3H), 1.43 (m, 3H), 1.41 (m, 3H), 1.34 ppm
(m, 3H); 13C NMR (125 MHz, CDCl3/CD3OD): d=87.8, 85.6, 83.0, 82.5,
80.8, 80.6, 79.8, 77.2, 76.8, 76.6, 75.8, 75.5, 74.9, 74.5, 73.04, 72.97, 71.5,
71.0, 64.7, 62.6, 54.5, 43.9, 38.0, 36.6, 32.6 (”2), 29.6, 29.3, 29.1, 27.7, 27.3,
24.8, 21.8, 20.9, 18.7, 16.5 ppm; HRMS (FAB): m/z calcd for C36H58O12Na
[M++Na]: 705.3826; found: 705.3815.
Perhydrogambierol (8): Pd/C (10%, cat.) was added to a solution of 9
(2.6 mg, 0.0034 mmol) in ethyl acetate (1 mL). The resulting mixture was
stirred at room temperature under a hydrogen atmosphere overnight and
then filtered through a plug of Celite. The filtrate was concentrated
under reduced pressure to give perhydrogambierol (8) (1.5 mg, 59%) as
an amorphous solid: [a]D30 =ꢀ15.2 (c=0.046 in CHCl3); IR (film): n˜max
=
3441, 2927, 2872, 1650, 1460, 1382, 1087, 1051 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=3.78–3.76 (m, 3H), 3.70 (m, 1H), 3.64–3.59 (m, 2H), 3.45
(ddd, J=13.7, 4.9, 4.9 Hz, 1H), 3.38–3.34 (m, 2H), 3.21–3.02 (m, 7H),
2.23 (ddd, J=11.6, 4.0, 4.0 Hz, 1H), 2.12–2.09 (m, 2H), 2.02–1.22 (m,
32H), 1.32 (s, 3H), 1.31 (s, 6H), 1.22 (s, 3H), 1.12 (s, 3H), 0.86 ppm (t,
J=6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=89.1, 84.9, 84.3, 82.4,
80.4, 79.9, 79.1, 76.4, 75.9, 75.8, 75.2, 75.1 (”2), 74.9, 73.9, 72.4, 72.2, 70.8,
62.8, 53.9, 43.6, 40.0, 37.3, 35.5, 32.4, 32.0, 31.8, 30.5, 29.6, 29.3, 29.2, 28.5,
27.7, 26.9 (”2), 24.5, 24.2, 22.7, 21.3, 20.3, 18.3, 16.2, 14.1 ppm; HRMS
(FAB): m/z calcd for C43H72O11Na [M++Na]: 787.4972; found: 787.5000.
Analogue 5: HF·pyridine (0.30 mL) was added to a solution of olefin 7
(8.7 mg, 0.0083 mmol) in THF (1 mL). The resulting mixture was stirred
at room temperature for 2 days and then poured into cold saturated
aqueous NaHCO3 and stirred at room temperature for 1 h. The aqueous
layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
30:40 ethyl acetate/hexanes) to give an alcohol (5.6 mg, 72%) as a color-
less oil: [a]2D9 =+22.9 (c=0.042 in benzene); IR (film): n˜max =3441, 2920,
1
1646, 1550, 1382, 1086 cmꢀ1; H NMR (500 MHz, C6D6): d=7.41–7.40 (m,
(32E)-34,35,37,38-Tetrahydrogambierol (10): N-Methylmorpholine N-
oxide (11.3 mg, 0.0962 mmol), tetra-n-propylammonium perruthenate
(cat.), and 4 Š molecular sieves were added to a solution of alcohol 11
(7.3 mg, 0.0063 mmol) in CH2Cl2 (1 mL). The resulting mixture was stir-
red at room temperature for 20 min and then filtered through a plug of
silica gel (eluted with ethyl acetate). The eluent was concentrated under
reduced pressure to give a crude aldehyde, which was immediately used
in the next reaction.
2H),7.31–7.28 (m, 2H), 7.23–7.07 (m, 6H), 5.49–5.40 (m, 2H), 4.98 (d,
J=12.2 Hz, 1H), 4.55 (d, J=12.2 Hz, 1H), 4.35 (dd, J=7.6, 4.3 Hz, 1H),
4.31 (s, 2H), 4.10 (dd, J=12.2, 4.0 Hz, H), 3.87 (ddd, J=14.6, 7.3, 4.3 Hz,
1H), 3.58–3.54 (m, 3H), 3.40–3.30 (m, 4H), 3.26 (dd, J=12.2, 3.4 Hz,
1H), 3.13 (ddd, J=11.3, 9.2, 4.9 Hz, 1H), 3.06–2.97 (m, 3H), 2.40 (ddd,
J=11.9, 4.3, 4.3 Hz, 1H), 2.34 (dd, J=11.6, 4.9 Hz, 1H), 2.22–1.93 (m,
10H), 1.87–1.44 (m, 14H), 1.34–1.04 (m, 7H), 1.32 (s, 3H), 1.25 (s, 3H),
1.20 (s, 3H), 1.13 (s, 3H), 0.87 ppm (t, J=6.7 Hz, 3H); 13C NMR
(125 MHz, C6D6): d=140.4, 139.5, 132.5, 130.4, 128.5, 128.3, 127.5, 85.1,
82.7, 81.9, 80.4, 80.3, 79.8, 79.5, 79.3, 77.8, 77.0, 76.1, 75.4, 74.9, 74.8, 74.7,
74.3, 74.1, 72.9, 72.7, 72.0, 70.5, 54.7, 44.7, 38.6, 37.0, 33.1, 33.0, 31.7, 29.5,
29.1, 28.5, 28.1, 27.9, 27.4, 26.4, 24.8, 22.9, 22.0, 21.6, 18.3, 16.3, 14.2 ppm;
KHMDS (0.5m in toluene, 0.065 mL, 0.065 mmol) was added to a solu-
tion of 5-(pentane-1-sulfonyl)-1-phenyl-1H-tetrazole (13) (20.6 mg,
0.07 mmol) in THF (0.5 mL) cooled to ꢀ788C . The resulting solution
was stirred at ꢀ788C for 40 min, and a solution of the above aldehyde in
THF (0.5 mL + 1.2 mL rinse) was added. The resultant mixture was stir-
4902
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 4894 – 4909

Gambierol Analogues
4894 – 4909
red at ꢀ788C for 1 h and then allowed to warm to room temperature.
This mixture was stirred at room temperature overnight and then
quenched with water. The solution was diluted with ethyl acetate, washed
with brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
8!10!20% ether/hexanes) to give olefin 14 as an inseparable 2:1 mix-
ture of isomers (5.4 mg, 70% for the two steps) as a colorless oil.
3.75 (dd, J=11.5, 4.4 Hz, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 3.51 (ddd, J=
10.6, 8.9, 5.0 Hz, 1H), 3.46–3.41 (m, 3H), 3.35 (m, 1H), 3.23–3.13 (m,
3H), 3.07–3.01 (m, 2H), 2.84 (d, J=1.8 Hz, 1H), 2.61 (s, 1H), 2.56 (t, J=
5.4 Hz, 1H), 2.11–2.06 (m, 3H), 1.96–1.69 (m, 8H), 1.65–1.37 (m, 13H),
1.30 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.202 (s, 3H), 1.198 (s, 3H),
0.89 ppm (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3CN): d=139.6,
136.9, 132.2, 130.0, 126.5, 125.5, 84.5, 82.4, 81.9, 80.9, 79.4, 79.2, 78.7, 76.0,
75.8, 75.7, 75.4, 74.8, 74.4, 73.5, 72.1, 71.7 (”2), 70.7, 61.5, 53.7, 43.1, 37.2,
35.6, 34.5, 31.9, 31.8, 28.7, 28.3, 26.9, 24.0, 22.1, 20.7, 20.3, 19.8, 17.6, 14.9,
13.0 ppm; HRMS (FAB): m/z calcd for C43H66O11Na [M++Na]: 781.4503;
found: 781.4520.
HF·pyridine (0.1 mL) was added to a solution of the above mixture of
isomers 14 (5.4 mg, 0.0044 mmol) in THF (0.3 mL) cooled to 08C. The re-
sulting mixture was stirred at room temperature for 4 days and then
poured into cold saturated aqueous NaHCO3. The aqueous layer was ex-
tracted several times with CHCl3. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was filtered through a plug of silica gel and eluted with 5%
methanol/CHCl3. Further purification by HPLC (Asahi-pack ODP-60,
50% CH3CN/H2O) gave 10 (0.98 mg, 29%) and (Z)-olefin analogue 9
(1.9 mg, 58%) as amorphous solids. 10: [a]3D0 =ꢀ17.7 (c=0.033 in
CHCl3); IR (film): n˜max =3437, 2927, 2872, 1623, 1463, 1383, 1086,
(E)-Vinyl iodide 22: N-Methylmorpholine N-oxide (10.2 mg,
0.0868 mmol), a catalytic amount of tetra-n-propylammonium perruthen-
ate, and 4 Š molecular sieves (ca. 10 mg) were added to a solution of al-
cohol 11 (10.5 mg, 0.0091 mmol) in CH2Cl2 (1 mL). The resulting mixture
was stirred at room temperature for 40 min and then filtered through a
plug of silica gel and eluted with ethyl acetate. The eluent was concen-
trated under reduced pressure to give a crude aldehyde, which was imme-
diately used in the next reaction.
1052 cmꢀ1 1H NMR (500 MHz, CDCl3): d=5.75 (m, 1H), 5.74 (dd, J=
;
12.9, 2.7 Hz, 1H), 5.47 (dd, J=15.6, 7.1 Hz, 1H), 5.47 (dd, J=12.9,
2.0 Hz, 1H), 4.20 (ddd, J=9.4, 2.7, 2.0 Hz, 1H), 3.85 (d, J=7.1 Hz, 1H),
3.79–3.76 (m, 2H), 3.70 (m, 1H), 3.66–3.58 (m, 2H), 3.45 (ddd, J=10.5,
4.9, 4.9 Hz, 1H), 3.36–3.31 (m, 2H), 3.17–3.03 (m, 4H), 3.02 (dd, J=12.9,
3.6 Hz, 1H), 2.24 (m, 1H), 2.13–1.83 (m, 9H), 1.76–1.47 (m, 10H), 1.38–
1.25 (m, 8H), 1.32 (s, 3H), 1.31 (s, 1H), 1.23 (s, 3H), 1.22 (s, 3H),
0.86 ppm (t, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=137.8,
136.3, 130.7, 126.1, 87.5, 84.7, 82.4, 81.2, 79.9, 79.4, 79.1, 76.3, 75.9, 75.8,
75.3, 75.2, 75.1, 73.9, 72.2, 71.9, 71.8, 70.8, 62.8, 53.7, 43.6, 37.3, 35.5, 32.5,
32.4, 32.0, 31.4, 29.2, 28.7, 28.5, 26.9, 24.2, 22.5, 21.7, 21.3, 20.3, 18.2, 15.6,
14.0 ppm; HRMS (FAB): m/z calcd for C43H68O11Na [M++Na]: 783.4659;
found: 783.4680.
A solution of the above aldehyde and iodoform (11.4 mg, 0.0290 mmol)
in THF (0.5 mL + 1 mL rinse) was added by cannula to a suspension of
CrCl2 (11.0 mg, 0.0895 mmol) in THF (0.5 mL). After stirring the mixture
at room temperature for 5 h, further CrCl2 (11.0 mg, 0.0895 mmol) and
iodoform (11.0 mg, 0.0279 mmol) were added. The resulting mixture was
stirred at room temperature for a further 4 h 40 min and then allowed to
warm to 408C. The reaction mixture was stirred at this temperature for
75 min and then poured into water and extracted several times with ethyl
acetate. The combined organic layers were washed with saturated aque-
ous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (silica gel, 5!10% ethyl acetate/hexanes) to give (E)-vinyl
iodide 22 (8.3 mg, 71%) as a colorless oil: 1H NMR (500 MHz, C6D6):
d=7.79–7.77 (m, 4H), 7.24–7.23 (m, 6H), 6.91 (dd, J=14.5, 4.0 Hz, 1H),
6.47 (dd, J=14.5, 1.7 Hz, 1H), 5.74 (dd, J=13.0, 2.5 Hz, 1H), 5.67 (dd,
J=13.0, 1.5 Hz, 1H), 4.22 (d, J=9.4 Hz, 1H), 4.01 (dd, J=12.2, 3.7 Hz,
1H), 3.89 (m, 1H), 3.86 (dd, J=4.0, 1.7 Hz, 1H), 3.72–3.65 (m, 3H),
3.38–3.34 (m, 2H), 3.28 (dd, J=11.9, 3.1 Hz, 1H), 3.18–3.08 (m, 3H),
3.03 (ddd, J=11.2, 8.2, 2.9 Hz, 1H), 2.98 (dd, J=12.7, 3.5 Hz, 1H), 2.44
(ddd, J=11.9, 4.3, 3.9 Hz, 1H), 2.32 (dd, J=11.6, 4.5 Hz, 1H), 2.14 (ddd,
J=7.9, 3.7, 3.7 Hz, 1H), 2.10–1.41 (m, 17H), 1.32 (s, 3H), 1.26 (s, 3H),
1.24 (s, 3H), 1.17 (s, 9H), 1.13 (s, 3H), 1.10 (s, 3H), 1.01 (s, 9H), 0.93 (s,
9H), 0.16 (s, 3H), 0.074 (s, 3H), 0.066 (s, 3H), 0.056 ppm (s, 3H); 13C
NMR (125 MHz, C6D6): d=143.9, 139.0, 136.0, 134.4, 130.7, 129.9, 128.5,
128.3, 88.3, 85.3, 82.9, 81.9, 80.2, 79.9, 79.7, 79.0, 77.1, 76.1, 76.0, 74.8,
74.1, 72.7, 72.4, 72.2, 72.1, 64.3, 54.4, 44.4, 39.2, 38.1, 32.4, 32.3, 29.2, 28.9,
27.9, 27.1, 26.2, 25.9, 24.7, 22.1, 21.9, 21.5, 19.5, 18.4, 18.3 (”2), 15.7, ꢀ1.9,
ꢀ2.2, ꢀ4.0, ꢀ4.9 ppm.
37,38-Dihydrogambierol (15): CuCl (39.6 mg, 0.400 mmol), LiCl (20.2 mg,
0.477 mmol), and [Pd(PPh3)4] (3.2 mg, 0.0028 mmol) were added to a sol-
ution of (Z)-vinyl bromide 19 (4.7 mg, 0.0061 mmol) and (Z)-vinylstan-
nane 20 (71.5 mg, 0.199 mmol) in degassed DMSO/THF (1:1, v/v, 2 mL).
The resulting mixture was stirred at 608C for 2.5 days and then quenched
with 5% NH4OH. The aqueous layer was extracted several times with
CHCl3. The combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography (silica gel, CHCl3 then 3!5% methanol/CHCl3) to
give 15 (4.2 mg, 91%) as an amorphous solid: [a]3D0 =ꢀ8.0 (c=0.11 in
methanol); IR (film): n˜max =3437, 2925, 2872, 1622, 1461, 1383, 1059 cmꢀ1
;
1H NMR (500 MHz, CD3CN): d=6.46 (dd, J=11.6, 11.4 Hz, 1H), 6.32
(ddd, J=11.6, 10.7, 1.1 Hz, 1H), 5.70 (dd, J=12.9, 2.7 Hz, 1H), 5.56 (m,
1H), 5.42 (m, 1H), 5.39 (dd, J=12.9, 1.9 Hz, 1H), 4.31 (d, J=8.9 Hz,
1H), 4.21 (ddd, J=9.4, 2.7, 1.9 Hz, 1H), 3.75 (dd, J=11.5, 4.4 Hz, 1H),
3.68 (m, 1H), 3.59 (m, 1H), 3.55–3.38 (m, 4H), 3.34 (m, 1H), 3.23–3.13
(m, 3H), 3.07–3.00 (m, 2H), 2.83 (d, J=1.9 Hz, 1H), 2.61 (s, 1H), 2.53 (t,
J=5.4 Hz, 1H), 2.19–2.08 (m, 3H), 1.97–1.69 (m, 8H), 1.65–1.38 (m,
13H), 1.30 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H),
0.90 ppm (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3CN): d=140.6,
135.0, 131.1, 128.5, 127.9, 125.3, 85.6, 83.1, 82.9, 82.0, 80.4, 80.2, 79.8, 77.1,
76.8, 76.7, 76.5, 75.9, 75.5, 74.6, 73.1, 72.7 (”2), 71.7, 62.5, 54.8, 44.1, 38.2,
36.6, 32.9 (”2), 30.0, 29.7, 29.3, 27.9, 25.0, 23.5, 21.7, 21.4, 20.8, 18.7, 15.9,
14.0 ppm; HRMS (FAB): m/z calcd for C43H66O11Na [M++Na]: 781.4503;
found: 781.4529.
(32E)-Gambierol (17): HF·pyridine (0.1 mL) was added to a solution of
(E)-vinyl iodide 22 (8.3 mg, 0.0065 mmol) in THF (0.3 mL) cooled to
08C. The resulting mixture was stirred at room temperature for 4 days
and then poured into cold saturated aqueous NaHCO3. The aqueous
layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
CHCl3 then 3!5% methanol/CHCl3) to give a triol (5.7 mg, quantita-
tive) as an amorphous solid: [a]3D0 =ꢀ190.8 (c=0.015 in CHCl3); IR
(film): n˜max =3434, 2947, 2874, 1609, 1458, 1382, 1085, 1049, 681 cmꢀ1 1H
;
(34E)-37,38-Dihydrogambierol (16): Na2CO3 (2.2 mg, 0.0133 mmol), (E)-
vinylboronic acid 21 (12.8 mg, 0.112 mmol), and [Pd(PPh3)4] (5.2 mg,
0.0045 mmol) were added to a solution of (Z)-vinyl bromide 19 (5.0 mg,
0.0065 mmol) in DME/water (4:1, v/v, 1 mL). After being stirred at 958C
for 4.5 h, the reaction mixture was diluted with CHCl3 and washed with
brine. The aqueous layer was separated and extracted with CHCl3. The
combined organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (silica gel, CHCl3 then 2% methanol/CHCl3) to give analogue
16 (4.5 mg, 91%) as an amorphous solid: [a]3D0 =+17.0 (c=0.155 in meth-
anol); IR (film): n˜max =3436, 2951, 2874, 1635, 1460, 1381, 1123,
NMR (500 MHz, CDCl3): d=6.66 (dd, J=14.5, 4.9 Hz, 1H), 6.41 (dd, J=
14.5, 1.5 Hz, 1H), 5.67 (dd, J=12.9, 2.6 Hz, 1H), 5.47 (dd, J=12.9,
1.7 Hz, 1H), 4.16 (d, J=9.4 Hz, 1H), 3.99 (dd, J=4.9, 1.5 Hz, 1H), 3.84–
3.75 (m, 2H), 3.70 (m, 1H), 3.64–3.58 (m, 2H), 3.45 (ddd, J=10.5, 8.8,
5.1 Hz, 1H), 3.35–3.28 (m, 2H), 3.17–3.03 (m, 4H), 3.01 (dd, J=12.8,
3.6 Hz, 1H), 2.59 (s, 1H), 2.23 (ddd, J=11.7, 4.4, 4.0 Hz, 1H), 2.11–1.97
(m, 6H), 1.94–1.81 (m, 2H), 1.76–1.41 (m, 16H), 1.32 (s, 3H), 1.30 (s,
6H), 1.22 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=142.5, 137.9,
131.1, 128.6, 87.9, 84.7, 82.4, 81.4, 79.8, 79.2, 79.1, 76.3, 75.82, 75.77, 75.6,
75.2, 75.1, 73.9, 72.2, 72.0, 71.5, 70.7, 62.8, 53.6, 43.5, 37.3, 35.5, 32.4, 31.8,
29.2, 28.5, 26.9, 24.1, 21.5, 21.3, 20.3, 18.2, 15.6 ppm; HRMS (FAB): m/z
calcd for C38H57IO11Na [M++Na]: 839.2843; found: 839.2808.
1073 cmꢀ1 1H NMR (500 MHz, CD3CN): d=6.39 (ddd, J=15.1, 11.1,
;
1.1 Hz, 1H), 6.11 (dd, J=11.1, 11.1 Hz, 1H), 5.74 (m, 1H), 5.70 (dd, J=
12.9, 2.7 Hz, 1H), 5.39 (dd, J=12.9, 1.9 Hz, 1H), 5.28 (dd, J=11.1,
8.4 Hz, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.21 (ddd, J=9.5, 2.7, 1.9 Hz, 1H),
CuCl (34.7 mg, 0.351 mmol), LiCl (20.2 mg, 0.470 mmol), and [Pd(PPh3)4]
(3.4 mg, 0.0029 mmol) were added to
a
solution of the above triol
Chem. Eur. J. 2004, 10, 4894 – 4909
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4903

M. Sasaki et al.
FULL PAPER
(4.7 mg, 0.0058 mmol) and (Z)-vinylstannane 23 (20.2 mg, 0.0564 mmol)
in degassed DMSO/THF (1:1, v/v, 0.5 mL). The resulting mixture was
stirred at room temperature overnight and then quenched with 5%
NH4OH. The aqueous layer was extracted several times with CHCl3. The
combined organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (silica gel, CHCl3 then 5% methanol/CHCl3) to give 17 (3.7 mg,
84%) as an amorphous solid: [a]3D0 =ꢀ62.5 (c=0.10 in methanol); IR
red at 608C for 2 days and then quenched with 5% NH4OH. The aque-
ous layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
CHCl3 then 3% methanol/CHCl3) to give 24 (2.9 mg, 68%) as an amor-
phous solid: [a]3D0 =+8.0 (c=0.12 in CH3OH); IR (film): n˜max =3436,
1
2925, 2870, 1627, 1381, 1192, 1054 cmꢀ1; H NMR (500 MHz, CDCl3): d=
6.33–6.22 (m, 2H), 5.70 (dddd, J=17.1, 10.1, 6.4, 6.4 Hz, 1H), 5.49 (dd,
J=17.1, 7.9 Hz, 1H), 5.32 (dd, J=9.8, 8.5 Hz, 1H), 4.95 (dd, J=17.1,
1.8 Hz, 1H), 4.90 (dd, J=10.1, 1.5 Hz, 1H), 4.25 (dd, J=8.5, 5.2 Hz, 1H),
3.72–3.67 (m, 3H), 3.60 (m, 1H), 3.54–3.51 (m, 2H), 3.38–3.28 (m, 3H),
3.25 (dd, J=11.0, 4.9 Hz, 1H), 3.08–2.91 (m, 5H), 2.85–2.83 (m, 2H),
2.14 (dd, J=11.9, 4.3 Hz, 1H), 2.03–1.14 (m, 23H), 1.23 (s, 3H), 1.214 (s,
3H), 1.209 (s, 3H), 1.13 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
135.9, 131.7, 130.4, 125.8, 124.1, 115.4, 84.7, 82.4, 81.6, 80.4, 79.9, 79.1,
76.3, 75.9, 75.8, 75.2, 75.1, 75.0, 73.9, 73.5, 72.2, 72.0, 70.8, 70.5, 62.8, 53.9,
43.6, 37.3, 35.5, 32.4, 32.3, 31.7, 29.2, 28.52, 28.46, 27.1, 26.9, 24.2, 21.3,
20.3, 18.2, 16.1 ppm; HRMS (FAB): m/z calcd for C42H64O11Na [M+
+Na]: 767.4346; found: 767.4344.
(film): n˜max =3435, 2930, 2871, 1630, 1445, 1382, 1058 cmꢀ1 1H NMR
;
(500 MHz, CD3CN): d=6.59 (dd, J=15.3, 11.2 Hz, 1H), 6.08 (dd, J=
11.2, 10.8 Hz, 1H), 5.84 (dddd, J=17.2, 10.2, 6.3, 6.3 Hz, 1H), 5.79 (dd,
J=15.3, 5.2 Hz, 1H), 5.69 (dd, J=12.9, 2.7 Hz, 1H), 5.44 (ddd, J=10.8,
7.7, 7.7 Hz, 1H), 5.38 (dd, J=12.9, 1.8 Hz, 1H), 5.05 (dd, J=17.2, 1.8 Hz,
1H), 4.98 (dd, J=10.2, 1.8 Hz, 1H), 4.21 (ddd, J=9.4, 2.7, 1.8 Hz, 1H),
3.97 (d, J=5.2 Hz, 1H), 3.75 (dd, J=11.4, 4.5 Hz, 1H), 3.67 (m, 1H),
3.59–3.34 (m, 6H), 3.23–3.13 (m, 3H), 3.06–3.01 (m, 2H), 2.95–2.91 (m,
3H), 2.84 (m, 1H), 2.56 (m, 1H), 2.12 (m, 1H), 1.98–1.71 (m, 8H), 1.67–
1.41 (m, 11H), 1.30 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H),
1.12 ppm (s, 3H); 13C NMR (125 MHz, CD3CN): d=140.7, 137.7, 132.2,
131.0, 130.0, 129.6, 127.9, 115.4, 87.2, 85.5, 82.9, 82.0, 80.4, 80.2, 79.7, 77.0,
76.8, 76.7, 76.2, 75.8, 75.4, 74.5, 73.1, 72.7 (”2), 71.7, 62.5, 54.7, 44.1, 38.2,
36.6, 32.8 (”2), 32.5, 29.7, 29.3, 27.9, 25.0, 21.7, 21.5, 20.8, 18.6, 15.9 ppm;
HRMS (FAB): m/z calcd for C43H64O11Na [M++Na]: 779.4346; found:
779.4326.
28,29-Dihydrogambierol (25): Triethylamine (0.060 mL, 0.430 mmol) and
the SO3·pyridine complex (40.5 mg, 0.254 mmol) were added to a solution
of alcohol 30 (20.1 mg, 0.0172 mmol) in CH2Cl2/DMSO (3:2, v/v,
1.25 mL) cooled to 08C. The resulting mixture was stirred at 08C for
40 min and then diluted with diethyl ether. The solution was washed with
1m aqueous HCl, saturated aqueous NaHCO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to give a
crude aldehyde, which was used in the next reaction without purification.
Analogue 18: CuCl (8.6 mg, 0.087 mmol), LiCl (4.5 mg, 0.11 mmol), and
[Pd(PPh3)4] (0.8 mg, 0.0007 mmol) were added to a solution of (Z)-vinyl
bromide 19 (1.1 mg, 0.0014 mmol) and tributyl(vinyl)tin (0.015 mL,
0.050 mmol) in degassed DMSO/THF (1:1, v/v, 1 mL). The resulting mix-
ture was stirred at 608C for 2 days. The mixture was then cooled to room
temperature, diluted with CH2Cl2, and treated with 3% NH4OH. The re-
sulting mixture was stirred at room temperature for 10 min. The aqueous
layer was extracted with CHCl3, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (silica gel, CHCl3!2% methanol/CHCl3) and then HPLC
(Asahi-pack ODP-50, 45% CH3CN/H2O) to give diene 18 (0.27 mg,
26%) and 19 (0.45 mg). 18: [a]2D4 =+96.3 (c=0.02 in CHCl3); 1H NMR
(600 MHz, C5D5N): d=7.14 (m, 1H), 6.48 (s, 1H), 6.34 (dd, J=11.4,
11.4 Hz, 1H), 6.27 (d, J=12.6 Hz, 1H), 6.05–5.94 (m, 2H), 5.85 (d, J=
12.6 Hz, 1H), 5.27 (d, J=16.8 Hz, 1H), 5.18 (d, J=9.6 Hz, 1H), 5.13
(brs, 1H), 4.83 (d, J=7.2 Hz, 1H), 4.58 (brd, J=9.0 Hz, 1H), 4.22 (brd,
J=10.8 Hz, 1H), 4.16 (m, 1H), 3.96 (brs, 1H), 3.92–3.86 (m, 2H), 3.73
(m, 1H), 3.64 (m, 1H), 3.59 (m, 1H), 3.46 (brd, J=11.4 Hz, 1H), 3.34–
3.22 (m, 4H), 2.46 (m, 1H), 2.25 (m, 1H), 2.18–2.02 (m, 6H), 2.02–1.66
(m, 11H), 1.63 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H), 1.33 ppm
(s, 3 H); 13C NMR (125 MHz, C5D5N): d=141.5, 134.3, 132.4, 130.6,
130.1, 118.6, 85.1, 84.0, 82.7, 81.8, 80.0, 79.9, 79.3, 76.8, 76.5, 76.3, 75.8,
75.2, 74.9, 74.1, 72.7, 72.6, 72.3, 71.2, 62.1, 54.5, 44.0, 38.0, 37.1, 32.9, 32.7,
29.9, 39.0, 27.9, 24.7, 21.8, 21.5, 21.0, 18.3, 15.8 ppm; HRMS (FAB): m/z
calcd for C40H60O11Na [M++Na]: 739.4033; found: 739.4036.
PPh3 (93.5 mg, 0.356 mmol) was added to a solution of CBr4 (57.8 mg,
0.174 mmol) in CH2Cl2 (1 mL) cooled to 08C. The resulting mixture was
stirred at 08C for 30 min. Triethylamine (0.100 mL, 0.716 mmol) followed
by a solution of the above aldehyde in CH2Cl2 ( 1 mL+0.75 mL rinse)
were added to this solution. The resulting mixture was stirred at 08C for
30 min and then quenched with saturated aqueous NaHCO3. The solution
was washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was filtered through a plug of silica gel (eluted with 10% ether/benzene)
and the eluent was concentrated to give a dibromoolefin, which was used
in the next reaction without further purification.
nBu3SnH
(0.023 mL,
0.0855 mmol)
and
[Pd(PPh3)4]
(4.2 mg,
0.0036 mmol) were added to a solution of the above dibromoolefin in
benzene (1 mL). After the resulting mixture was stirred at room temper-
ature for 1 h, further nBu3SnH (0.014 mL, 0.0520 mmol) and [Pd(PPh3)4]
(cat.) were added. This reaction mixture was stirred at room temperature
for an additional 15 min and then concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, 15!30%
ether/hexanes) to give a (Z)-vinyl bromide (16.4 mg, 74% for the three
steps) as a colorless oil: [a]D30 =+8.5 (c=0.48, benzene); IR (film): n˜max
=
2948, 2860, 1622, 1466, 1381, 1252, 1088, 834, 779, 703, 611 cmꢀ1 1H
;
NMR (500 MHz, C6D6): d=7.79–7.77 (m, 4H), 7.23–7.22 (m, 6H), 5.92–
5.88 (m, 2H), 4.56 (d, J=7.9 Hz, 1H), 3.98 (dd, J=12.2, 3.9 Hz, 1H),
3.88 (m, 1H), 3.71–3.64 (m, 4H), 3.48 (ddd, J=9.8, 9.5, 4.3 Hz, 1H),
3.38–3.34 (m, 4H), 3.26 (m, 1H), 3.13–3.02 (m, 4H), 2.41 (ddd, J=7.6,
3.7, 3.7 Hz, 1H), 2.31–2.26 (m, 2H), 2.13–1.92 (m, 7H), 1.85–1.35 (m,
14H), 1.31 (s, 3H), 1.25 (s, 3H), 1.19 (s, 3H), 1.17 (s, 9H), 1.12 (s, 3H),
1.08 (s, 3H), 1.00 (s, 9H), 0.98 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.07 (s,
3H), 0.06 ppm (s, 3H); 13C NMR (125 MHz, C6D6): d=136.0, 134.4,
133.3, 129.9, 128.3, 110.5, 86.3, 85.2, 82.9, 82.4, 80.8, 80.3, 79.7, 78.5, 77.1,
76.11, 76.07, 74.8 (”2), 74.1, 74.0, 72.7, 72.4 (”2), 64.3, 54.7, 44.4, 39.2,
38.6, 38.1, 32.9, 32.4, 30.4, 30.2, 29.2, 29.0, 28.3, 27.9, 27.1, 26.5, 26.2 (”2),
24.7, 22.1, 21.5, 19.5, 18.4, 16.4, ꢀ1.7, ꢀ2.0, ꢀ4.0, ꢀ4.9 ppm; HRMS
(FAB): m/z calcd for C66H10579BrO11Si3Na [M++Na]: 1259.6046; found:
1259.6079; calcd for C66H10581BrO11Si3Na [M++Na]: 1261.6046; found:
1261.6039.
28,29-Dihydro-30-desmethylgambierol (24): HF·pyridine (0.2 mL) was
added to a solution of (Z)-vinyl bromide 29 (7.2 mg, 0.0058 mmol) in
THF (0.6 mL) cooled to 08C. The resulting mixture was stirred at room
temperature for 4.5 days and then poured into cold saturated aqueous
NaHCO3. The aqueous layer was extracted several times with CHCl3.
The combined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash chro-
matography (silica gel, CHCl3 then 3!5% methanol/CHCl3) to give a
triol (4.3 mg, 92%) as an amorphous solid: 1H NMR (500 MHz, CDCl3):
d=6.33 (dd, J=7.5, 1.5 Hz, 1H), 6.15 (dd, J=7.5, 7.5 Hz, 1H), 4.37 (ddd,
J=7.5, 4.5, 1.5 Hz, 1H), 3.94 (m, 1H), 3.79–3.76 (m, 2H), 3.70 (m, 1H),
3.65–3.58 (m, 2H), 3.48–3.40 (m, 3H), 3.34 (dd, J=11.0, 4.5 Hz, 1H),
3.17–3.02 (m, 5H), 2.59 (m, 1H), 2.23 (ddd, J=12.0, 4.5, 4.0 Hz, 1H),
2.12–2.07 (m, 2H), 2.02–1.42 (m, 20H), 1.32 (s, 3H), 1.31 (s, 3H), 1.30 (s,
3H), 1.22 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=134.9, 110.2,
84.7, 83.6, 82.4, 80.1, 79.9, 79.8, 79.1, 76.3, 75.84, 75.79, 75.2, 75.1, 74.4,
73.9, 73.5, 72.2, 71.9, 70.8, 62.8, 53.9, 43.6, 37.3, 35.5, 32.4, 32.1, 29.2, 28.5,
28.0, 26.9, 26.6, 24.2, 22.3, 20.3, 18.2, 16.1 ppm.
HF·pyridine (0.25 mL) was added to a solution of this (Z)-vinyl bromide
(13.2 mg, 0.0106 mmol) in THF (0.75 mL) cooled to 08C. The resulting
mixture was stirred at room temperature for 7 days and then poured into
cold saturated aqueous NaHCO3. The aqueous layer was extracted sever-
al times with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, CHCl3 then 1!3%
methanol/CHCl3) to give a triol (8.2 mg, quantitative) as an amorphous
CuCl (33.9 mg, 0.342 mmol), LiCl (22.1 mg, 0.521 mmol), and [Pd(PPh3)4]
(3.3 mg, 0.0029 mmol) were added to
a solution of the above triol
(4.3 mg, 0.0056 mmol) and (Z)-vinylstannane 23 (54.2 mg, 0.151 mmol) in
degassed DMSO/THF (1:1, v/v, 1.5 mL). The resulting mixture was stir-
4904
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4894 – 4909

Gambierol Analogues
4894 – 4909
solid: [a]2D9 =+112.6 (c=0.11 in CHCl3); IR (film): n˜max =3440, 2946,
HF·pyridine (0.1 mL) was added to a solution of the above material in
THF (0.3 mL) cooled to 08C. The resulting mixture was stirred at room
temperature for 3 days and then poured into cold saturated aqueous
NaHCO3. The aqueous layer was extracted several times with CHCl3.
The combined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was filtered through a
plug of silica gel (eluted with 5% methanol/CHCl3) and the eluent was
concentrated to give the product, which was used in the next step without
further purification.
2876, 1627, 1459, 1384, 1282, 1085, 1048, 912, 737 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=6.39 (d, J=7.3 Hz, 1H), 6.14 (dd, J=8.2, 7.3 Hz,
1H), 4.36 (d, J=8.2 Hz, 1H), 3.78–3.75 (m, 2H), 3.69 (m, 1H), 3.64–3.59
(m, 2H), 3.47–3.39 (m, 3H), 3.34 (dd, J=10.4, 4.6 Hz, 1H), 3.17–3.03 (m,
5H), 2.98 (m, 1H), 2.23 (ddd, J=11.9, 4.0, 4.0 Hz, 1H), 2.12–2.09 (m,
2H), 2.02–1.43 (m, 21H), 1.32 (s, 3H), 1.30 (s, 6H), 1.22 (s, 3H),
1.17 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=132.7, 110.7, 85.4,
84.9, 82.44, 82.36, 80.1, 79.9, 79.1, 76.4, 75.9, 75.8, 75.7, 75.2, 75.1, 74.2,
73.9, 72.2 (”2), 70.8, 62.8, 53.9, 43.6, 37.8, 37.4, 35.5, 32.4, 32.2, 29.2, 28.5,
27.8, 27.0, 26.0, 24.2, 21.3, 20.3, 18.3, 16.2 ppm; HRMS (FAB): m/z calcd
for C38H5779BrO11Na [M++Na]: 791.3043; found: 791.3018; calcd for
C38H5781BrO11Na [M++Na]: 793.2970; found: 793.2999.
CuCl (23.3 mg, 0.235 mmol), LiCl (13.0 mg, 0.307 mmol), and [Pd(PPh3)4]
(2.2 mg, 0.0019 mmol) were added to a solution of the above material
and (Z)-vinylstannane 23 (35.8 mg, 0.100 mmol) in degassed DMSO/THF
(1:1, v/v, 1 mL). The resulting mixture was stirred at 608C for 2 days and
then quenched with 5% NH4OH. The aqueous layer was extracted sever-
al times with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, CHCl3 then 1!3!5%
methanol/CHCl3) to give 26 (1.5 mg, 34% for the three steps) as an
amorphous solid: [a]3D1 =ꢀ48.2 (c=0.017 in methanol); 1H NMR
(500 MHz, CD3CN): d=6.47 (dd, J=11.9, 10.6 Hz, 1H), 6.34 (ddd, J=
11.9, 10.7, <1 Hz, 1H), 5.87 (dddd, J=17.1, 10.1, 6.4, 6.4 Hz, 1H), 5.66
(ddd, J=12.8, 2.4, 2.4 Hz, 1H), 5.59–5.52 (m, 2H), 5.41 (dd, J=10.6,
9.5 Hz, 1H), 5.05 (dd, J=17.1, 1.5 Hz, 1H), 4.98 (dd, J=10.1, 1.5 Hz,
1H), 4.16–4.12 (m, 2H), 4.05 (m, 1H), 3.75 (dd, J=11.6, 4.6 Hz, 1H),
3.68 (m, 1H), 3.59 (m, 1H), 3.51 (ddd, J=10.1, 8.5, 4.9 Hz, 1H), 3.47–
3.44 (m, 2H), 3.41–3.33 (m, 2H), 3.21 (dd, J=11.6, 4.3 Hz, 1H), 3.20–
3.13 (m, 2H), 3.07–3.01 (m, 2H), 2.96–2.94 (m, 2H), 2.89 (d, J=5.5 Hz,
1H), 2.83 (s, 1H), 2.52 (t, J=5.5 Hz, 1H), 2.09 (m, 1H), 1.97–1.70 (m,
8H), 1.65–1.40 (m, 11H), 1.30 (s, 6H), 1.26 (s, 3H), 1.19 ppm (s, 3H); 13C
NMR (125 MHz, CD3CN): d=137.5, 135.5, 133.4, 131.8, 131.1, 127.7,
125.7, 115.6, 85.5, 82.9, 81.0, 80.8, 80.5 (”2), 80.1, 79.8, 77.1, 76.8, 75.9,
75.5, 74.6, 73.8, 73.6, 73.1, 72.6, 71.8, 62.5, 54.7, 44.1, 38.2, 36.6, 32.9, 32.8,
32.3, 29.7, 29.3, 27.9, 25.0, 21.7, 20.8, 18.6, 15.9 ppm; HRMS (FAB): m/z
calcd for C42H62O11Na [M++Na]: 765.4190; found: 765.4179.
CuCl (25.0 mg, 0.253 mmol), LiCl (13.0 mg, 0.307 mmol), and [Pd(PPh3)4]
(2.8 mg, 0.0024 mmol) were added to
a solution of the above triol
(3.2 mg, 0.0041 mmol) and (Z)-vinylstannane 23 (37.9 mg, 0.106 mmol) in
degassed DMSO/THF (1:1, v/v, 1 mL). The resulting mixture was stirred
at 608C for 2 days and then quenched with 5% NH4OH. The aqueous
layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
CHCl3 then 1!3!5% methanol/CHCl3) to give 25 (2.0 mg, 64%) as an
amorphous solid: [a]3D0 =+12.8 (c=0.11 in CHCl3); IR (film): n˜max =3437,
2930, 2871, 1622, 1384, 1051 cmꢀ1 1H NMR (500 MHz, CD3CN): d=
;
6.46–6.36 (m, 2H), 5.84 (dddd, J=17.1, 10.4, 6.4, 6.4 Hz, 1H), 5.55 (m,
1H), 5.37 (dd, J=10.4, 10.4 Hz, 1H), 5.05 (dd, J=17.1, 1.5 Hz, 1H), 4.98
(dd, J=10.4, 1.5 Hz, 1H), 4.39 (d, J=8.9 Hz, 1H), 3.75 (dd, J=11.9,
4.3 Hz, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 3.55–3.33 (m, 6H), 3.21 (dd, J=
11.0, 4.0 Hz, 1H), 3.18–3.13 (m, 2H), 3.04 (m, 1H), 3.00 (dd, J=12.8,
3.4 Hz, 1H), 2.96–2.93 (m, 2H), 2.83 (m, 1H), 2.53 (m, 2H), 2.10 (m,
1H), 1.97–1.40 (m, 23H), 1.30 (s, 6H), 1.26 (s, 3H), 1.18 (s, 3H),
1.03 ppm (s, 3H); 13C NMR (125 MHz, CD3CN): d=137.6, 131.2, 130.6,
126.0, 125.6, 115.5, 85.6, 84.6, 82.9, 81.7, 80.9, 80.5, 79.8, 77.1, 76.8, 76.7,
75.9, 75.8, 75.5, 75.1, 74.6, 73.2, 72.8, 71.8, 62.5, 55.0, 44.1, 38.32, 38.26,
36.6, 33.3, 32.9, 32.3, 29.7, 29.3, 28.7, 27.9, 26.3, 25.0, 21.7, 20.8, 18.7,
16.5 ppm; HRMS (FAB): m/z calcd for C43H66O11Na [M++Na]: 781.4503;
found: 781.4478.
6b-Alcohol 37: N-Methylmorpholine N-oxide (20.9 mg, 0.178 mmol), a
catalytic amount of tetra-n-propylammonium perruthenate, and 4 Š mo-
lecular sieves were added to
a solution of alcohol 36 (15.8 mg,
0.0136 mmol) in CH2Cl2 (2 mL). The resulting mixture was stirred at
room temperature for 4 h and then directly subjected to flash chromatog-
raphy (silica gel, 30% ethyl acetate/hexanes) to give a ketone (15.3 mg,
97%) as a colorless oil: [a]2D8 =+4.5 (c=0.20 in benzene); IR (film):
30-Desmethylgambierol (26): Triethylamine (0.023 mL, 0.236 mmol) and
the SO3·pyridine complex (29.1 mg, 0.183 mmol) were added to a solution
of alcohol 33 (13.5 mg, 0.0118 mmol) in CH2Cl2/DMSO (1:1, v/v, 1 mL)
cooled to 08C. The resulting mixture was stirred at 08C for 30 min before
dilution with diethyl ether. The solution was washed with 1m aqueous
HCl, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a crude aldehyde,
which was used in the next reaction without further purification.
n˜max =2951, 2862, 1738, 1645, 1465, 1384, 1256, 1092, 834, 777, 704 cmꢀ1
;
1H NMR (500 MHz, C6D6): d=7.77–7.76 (m, 4H), 7.25–7.23 (m, 6H),
5.79 (dd, J=13.2, 2.3 Hz, 1H), 5.72 (d, J=13.2 Hz, 1H), 4.34 (d, J=
9.2 Hz, 1H), 4.16 (ddd, J=9.7, 5.2, 4.6 Hz, 1H), 3.76–3.73 (m, 2H), 3.62–
3.59 (m, 2H), 3.47–3.39 (m, 2H), 3.36–3.31 (m, 2H), 3.12 (dd, J=11.5,
4.0 Hz, 1H), 3.09–3.02 (m, 5H), 2.43–2.39 (m, 3H), 2.20 (dd, J=15.5,
11.5 Hz, 1H), 2.09–1.68 (m, 11H), 1.64–1.44 (m, 5H), 1.31 (s, 3H), 1.28
(s, 3H), 1.22 (s, 3H), 1.17 (s, 9H), 1.15 (s, 3H), 1.12 (s, 3H), 1.01 (s, 9H),
0.96 (s, 9H), 0.16 (s, 3H), 0.14 (s, 6H), 0.12 ppm (s, 3H); 13C NMR
(125 MHz, C6D6): d=201.9, 139.4, 136.0, 134.2, 130.5, 130.0, 128.5, 89.7,
85.1, 82.3, 81.9, 80.8, 80.2, 79.9, 79.8, 79.7, 78.7, 78.4, 76.9, 76.1, 75.0, 72.7,
72.6, 72.2, 63.9, 63.8, 54.5, 44.4, 44.0, 38.1, 32.60, 32.56, 28.9, 28.6, 27.4,
27.1, 26.1, 26.0, 24.7, 22.2, 21.6, 20.6, 19.4, 18.6, 18.31, 18.29, 15.7, ꢀ1.9,
ꢀ2.1, ꢀ4.9, ꢀ5.1 ppm; HRMS (FAB): m/z calcd for C65H102O12Si3Na [M+
+Na]: 1181.6577; found: 1811.6609.
PPh3 (61.5 mg, 0.234 mmol) was added to a solution of CBr4 (42.9 mg,
0.129 mmol) in CH2Cl2 (1 mL) cooled to 08C. The resulting mixture was
stirred at 08C for 30 min. Triethylamine (0.066 mL, 0.473 mmol) followed
by a solution of the above crude aldehyde in CH2Cl2 (0.5 mL+0.5 mL
rinse) were added to this solution. The resultant mixture was stirred at
08C for 90 min and then quenched with saturated aqueous NaHCO3. The
solution was diluted with ethyl acetate, washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was filtered through a plug of silica gel
(eluted with 10!15% ether/benzene) and the eluent was concentrated
to give a dibromoolefin (7.3 mg, 47% for the two steps) along with alco-
hol 33 (6.8 mg, 50%). The dibromoolefin was used immediately in the
next step without further purification.
NaBH4 (13.5 mg, 0.357 mmol) was added to a solution of the above
ketone (84.5 mg, 0.0730 mmol) in methanol (5 mL) cooled to 08C. The
resulting mixture was stirred at 08C for 25 min and then quenched with
saturated aqueous NH4Cl. The solution was diluted with ethyl acetate,
washed with water and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (silica gel, 20!30% ethyl acetate/hexanes) to give 6b-alcohol
37 (70.1 mg, 83%) as a colorless oil along with recovered 36 (9.9 mg,
12%). 37: [a]2D8 =ꢀ8.9 (c=0.21 in benzene); IR (film): n˜max =3399, 2950,
nBu3SnH (0.0065 mL, 0.0242 mmol) and
a
catalytic amount of
[Pd(PPh3)4] were added to a solution of the above dibromoolefin (7.3 mg,
0.0056 mmol) in benzene (1 mL). After stirring the resulting mixture at
room temperature for 90 min, additional nBu3SnH (0.0065 mL,
0.0242 mmol) and [Pd(PPh3)4] (cat.) were added. After 30 min, further
nBu3SnH (0.0065 mL, 0.0242 mmol) and [Pd(PPh3)4] (cat.) were added.
The reaction mixture was stirred at room temperature for an additional
30 min and then concentrated under reduced pressure. The residue was
filtered through a plug of silica gel (eluted with 25% ether/hexanes) and
the eluent was concentrated to give (Z)-vinyl bromide, which was conta-
minated with over-reduced product.
2862, 1647, 1467, 1384, 1255, 1088, 834, 773, 704 cmꢀ1
;
1H NMR
(500 MHz, C6D6): d=7.78–7.76 (m, 4H), 7.23–7.22 (m, 6H), 5.80 (dd, J=
13.2, 2.9 Hz, 1H), 5.73 (d, J=13.2 Hz, 1H), 4.35 (m, 1H), 4.16 (ddd, J=
8.0, 6.3, 5.2 Hz, 1H), 3.78–3.75 (m, 2H), 3.65–3.62 (m, 2H), 3.51–3.44 (m,
3H), 3.36 (dd, J=10.9, 5.2 Hz, 1H), 3.32 (m, 1H), 3.16–3.04 (m, 5H),
2.76 (dd, J=11.5, 3.4 Hz, 1H), 2.45 (ddd, J=12.0, 4.6, 4.0 Hz, 1H), 2.41
Chem. Eur. J. 2004, 10, 4894 – 4909
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4905

M. Sasaki et al.
FULL PAPER
(ddd, J=12.6, 4.6, 4.6 Hz, 1H), 2.33 (dd, J=11.5, 4.0 Hz, 1H), 2.11–1.86
(m, 8H), 1.76–1.38 (m, 10H), 1.32 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H), 1.17
(s, 9H), 1.16 (s, 3H), 1.14 (s, 3H), 1.01 (s, 9H), 0.97 (s, 9H), 0.17 (s, 3H),
0.15 (s, 6H), 0.12 ppm (s, 3H); 13C NMR (125 MHz, C6D6): d=139.4,
136.0, 134.4, 130.5, 129.9, 128.5, 89.7, 85.1, 83.1, 82.3, 80.3, 80.0, 79.8, 79.7,
78.7, 77.8, 77.5, 77.0, 76.9, 76.1, 74.6, 72.8, 72.6, 72.2, 64.1, 63.9, 54.5, 44.6,
38.1, 37.5, 32.6, 32.3, 29.1, 29.0, 27.6, 27.1, 26.1, 26.0, 24.7, 22.5, 21.7, 19.4,
18.6, 18.31, 18.28, 16.3, 15.7, ꢀ1.9, ꢀ2.1, ꢀ4.9, ꢀ5.1 ppm; HRMS (FAB):
m/z calcd for C65H104O12Si3Na [M++Na]: 1183.6733; found: 1183.6730.
5.2 Hz, 1H), 3.16–3.10 (m, 3H), 3.06–3.01 (m, 2H), 2.98 (dd, J=12.0,
4.0 Hz, 1H), 2.22 (ddd, J=11.5, 4.6, 4.0 Hz, 1H), 2.15–2.06 (m, 2H),
2.02–1.84 (m, 6H), 1.73–1.45 (m, 11H), 1.31 (s, 3H), 1.30 (s, 3H), 1.29 (s,
3H), 1.25 (s, 3H), 1.22 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
138.2, 131.6, 131.1, 112.7, 84.8, 83.9, 82.4, 81.6, 80.1, 79.9, 79.5, 79.4, 79.1,
77.8, 76.54, 76.49, 76.1, 75.8, 74.4, 72.2, 72.0, 71.8, 62.8, 53.7, 43.7, 37.4,
37.0, 32.4, 31.8, 29.7, 29.2, 28.6, 26.9, 24.2, 21.3, 18.2, 15.9, 15.6 ppm;
HRMS (FAB): m/z calcd for C38H5779BrO11Na [M++Na]: 791.2982;
found: 791.3021; calcd for C38H5781BrO11Na [M++Na]: 793.2970; found:
793.3018.
6-epi-Gambierol
(34):
N-Methylmorpholine
N-oxide
(14.7 mg,
0.125 mmol), a catalytic amount of tetra-n-propylammonium perruthen-
ate, and 4 Š molecular sieves were added to a solution of alcohol 39
(7.7 mg, 0.0066 mmol) in CH2Cl2 (1 mL). The resulting mixture was stir-
red at room temperature for 25 min and then filtered through a plug of
silica gel (eluted with ethyl acetate). The eluent was concentrated under
reduced pressure to give crude aldehyde, which was immediately used in
the next reaction.
CuCl (28.3 mg, 0.286 mmol), LiCl (17.2 mg, 0.406 mmol), and [Pd(PPh3)4]
(2.0 mg, 0.0017 mmol) were added to
a solution of the above triol
(2.9 mg) and (Z)-vinylstannane 23 (40.7 mg, 0.1136 mmol) in degassed
DMSO/THF (1.1 mL). The resulting mixture was stirred at 608C for
2.5 days and then quenched with 5% NH4OH. The aqueous layer was ex-
tracted several times with CHCl3. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, CHCl3 then
2!5% methanol/CHCl3) to give 34 (2.2 mg, 80% for the two steps) as
PPh3 (34.4 mg, 0.131 mmol) was added to a solution of CBr4 (21.2 mg,
0.0639 mmol) in CH2Cl2 (0.75 mL) cooled to 08C was added. The result-
ing mixture was stirred at 08C for 30 min. Triethylamine (0.0400 mL,
0.287 mmol) followed by a solution of the above aldehyde in CH2Cl2
(0.75 mL+0.5 mL rinse) were added to this solution. The resultant mix-
ture was stirred at 08C for 40 min and then quenched with saturated
aqueous NaHCO3. The solution was diluted with ethyl acetate, washed
with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was filtered
through a plug of silica gel (eluted with 10% diethyl ether/benzene) and
the eluent was concentrated to give dibromoolefin (7.7 mg,
0.0057 mmol), which was immediately used in the next reaction.
an amorphous solid: [a]D28 =+4.3 (c=0.047, CHCl3); IR (film): n˜max
=
3425, 2941, 2867, 1645, 1532, 1466, 1389, 1267, 1053, 752 cmꢀ1 1H NMR
;
(500 MHz, CD3CN): d=6.45 (dd, J=11.6, 11.1 Hz, 1H), 6.38 (dd, J=
11.6, 11.4 Hz, 1H), 5.82 (dddd, J=17.2, 10.1, 6.3, 6.3 Hz, 1H), 5.71 (dd,
J=12.9, 2.7 Hz, 1H), 5.54 (m, 1H), 5.46 (m, 1H), 5.38 (dd, J=12.9,
1.9 Hz, 1H), 5.05 (ddd, J=17.2, 3.5, 1.7 Hz, 1H), 4.98 (ddd, J=10.1, 3.5,
1.5 Hz, 1H), 4.31 (d, J=8.9 Hz, 1H), 4.21 (ddd, J=9.4, 2.7, 1.9 Hz, 1H),
3.53–3.39 (m, 6H), 3.34 (dd, J=11.1, 4.7 Hz, 1H), 3.19–3.13 (m, 3H),
3.06–2.93 (m, 5H), 2.82 (m, 1H), 2.62 (s, 1H), 2.56 (t, J=5.4 Hz, 1H),
2.10 (m, 1H), 1.97 (dd, J=11.0, 4.8 Hz, 1H), 1.94–1.89 (m, 3H), 1.85–
1.77 (m, 4H), 1.65–1.33 (m, 11H), 1.30 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H),
1.20 (s, 3H), 1.17 ppm (s, 3H); 13C NMR (125 MHz, CD3CN): d=140.3,
138.7, 131.5, 131.1, 129.3, 127.5, 126.0, 115.6, 85.5, 83.1, 83.0, 81.9, 80.4,
80.3, 80.2, 79.7, 78.2, 78.0, 77.1, 76.9, 76.7, 76.4, 74.8, 73.1, 72.7 (”2), 62.4,
54.7, 44.6, 38.8, 38.2, 32.9, 32.2, 29.6 (”2), 29.3, 27.8, 25.0, 21.7, 21.3, 18.6,
16.2, 15.9 ppm; HRMS (FAB): m/z calcd for C43H64O11Na [M++Na]:
779.4346; found: 779.4371.
nBu3SnH (0.0046 mL, 0.0171 mmol) and
a
catalytic amount of
[Pd(PPh3)4] were added to a solution of the above dibromoolefin (7.7 mg,
0.0057 mmol) in benzene (1 mL). After stirring the mixture at room tem-
perature for 2 h, further nBu3SnH (0.0046 mL, 0.0171 mmol) and
[Pd(PPh3)4] (cat.) were added. The reaction mixture was stirred at room
temperature for an additional 30 min and then concentrated under re-
duced pressure. The residue was purified by flash chromatography (silica
gel, 10!15!20% ether/hexanes) to give a (Z)-vinyl bromide (5.2 mg,
64% for the three steps) as a colorless oil: [a]2D8 =ꢀ8.4 (c=0.119 in ben-
zene); IR (film): n˜max =2931, 2858, 1621, 1465, 1381, 1254, 1081, 840, 773,
6-Deoxygambierol (35): N-Methylmorpholine N-oxide (14.0 mg,
0.119 mmol), a catalytic amount of tetra-n-propylammonium perruthen-
ate, and 4 Š molecular sieves were added to a solution of alcohol 42
(9.9 mg, 0.0096 mmol) in CH2Cl2 (1.5 mL). The resulting mixture was stir-
red at room temperature for 25 min and then filtered through a plug of
silica gel (eluted with ethyl acetate). The eluent was concentrated under
reduced pressure to give a crude aldehyde, which was immediately used
in the next reaction.
706, 607 cmꢀ1 1H NMR (500 MHz, C6D6): d=7.79–7.77 (m, 4H), 7.24–
;
7.22 (m, 6H), 6.12 (dd, J=7.4, 7.4 Hz, 1H), 6.02 (d, J=7.4 Hz, 1H), 5.90
(dd, J=12.6, 2.3 Hz, 1H), 5.76 (dd, J=12.6, 1.7 Hz, 1H), 4.53 (d, J=
7.4 Hz, 1H), 4.35 (ddd, J=9.2, 2.3, 1.7 Hz, 1H), 3.68–3.66 (m, 2H), 3.61
(ddd, J=10.9, 9.2, 5.2 Hz, 1H), 3.55 (dd, J=10.3, 5.2 Hz, 1H), 3.45 (ddd,
J=10.3, 9.2, 5.2 Hz, 1H), 3.37 (dd, J=10.9, 5.2 Hz, 1H), 3.24 (m, 1H),
3.12–3.09 (m, 4H), 3.05 (dd, J=13.2, 3.4 Hz, 1H), 2.76 (dd, J=11.5,
3.4 Hz, 1H), 2.45 (dd, J=11.7, 4.6 Hz, 1H), 2.37 (ddd, J=8.0, 8.0, 4.6 Hz,
1H), 2.28 (dd, J=10.9, 4.0 Hz, 1H), 2.08–1.94 (m, 7H), 1.80–1.74 (m,
3H), 1.68–1.51 (m, 6H), 1.45 (m, 1H), 1.39 (s, 3H), 1.29 (s, 3H), 1.24 (s,
3H), 1.17 (s, 9H), 1.14 (s, 6H), 1.06 (s, 9H), 0.94 (s, 9H), 0.25 (s, 3H),
0.17 (s, 3H), 0.11 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (125 MHz, C6D6):
d=139.3, 136.0, 134.4, 132.8, 131.1, 129.9, 128.5, 113.0, 85.1, 84.2, 83.1,
82.5, 80.23, 80.19, 80.0, 79.7, 78.6, 77.63, 77.61, 77.4, 77.0, 76.1, 74.3, 72.9,
72.6, 72.3, 64.2, 54.5, 44.5, 39.8, 38.1, 32.40, 32.37, 29.1, 29.0, 27.7, 27.1,
26.2, 26.0, 24.7, 22.2, 21.7, 19.4, 18.6, 18.31, 18.27, 16.3, 15.7, ꢀ1.8, ꢀ2.1,
ꢀ3.7, ꢀ4.8 ppm; HRMS (FAB): m/z calcd for C66H10379BrO11Si3Na [M+
+Na]: 1257.5889; found: 1257.5891; calcd for C66H10381BrO11Si3Na [M+
+Na]: 1259.5890; found: 1259.5837.
PPh3 (58.1 mg, 0.222 mmol) was added to a solution of CBr4 (34.5 mg,
0.104 mmol) in CH2Cl2 (0.75 mL) cooled to 08C. The resulting mixture
was stirred at 08C for 25 min. Triethylamine (0.0550 mL, 0.394 mmol) fol-
lowed by a solution of the above aldehyde in CH2Cl2 (0.75 mL + 1.0 mL
rinse) were added to this solution. The reaction mixture was stirred at
08C for 30 min and then quenched with saturated aqueous NaHCO3. The
solution was diluted with ethyl acetate, washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was filtered through a plug of silica gel
(eluted with 10% ether/benzene) and the eluent was concentrated to
give a dibromoolefin (9.1 mg, 0.0077 mmol), which was immediately used
in the next reaction.
nBu3SnH (0.0101 mL, 0.0385 mmol) and
a
catalytic amount of
[Pd(PPh3)4] were added to a solution of the above dibromoolefin (9.1 mg,
0.0077 mmol) in benzene (1.2 mL). The resulting mixture was stirred at
room temperature for 75 min and then concentrated under reduced pres-
sure. The residue was purified by flash chromatography (silica gel, 30!
35!40% ether/hexanes) to give a (Z)-vinyl bromide (7.3 mg, 66% for
the three steps) as a colorless oil: [a]2D8 =+5.3 (c=0.087 in benzene); IR
HF·pyridine (0.2 mL) was added to a solution of the above (Z)-vinyl bro-
mide (4.5 mg, 0.0037 mmol) in THF (0.6 mL) cooled to 08C. The result-
ing mixture was stirred at room temperature for 3 days and then poured
into cold saturated aqueous NaHCO3. The aqueous layer was extracted
several times with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, 3!5% methanol/
CHCl3) to give a triol (2.9 mg, quantitative) as an amorphous solid:
[a]2D8 =+23.4 (c=0.10, CHCl3); IR (film): n˜max =3416, 2929, 2867, 1621,
(film): n˜max =2944, 1631, 1459, 1382, 1255, 1079, 1029, 840, 705 cmꢀ1 1H
;
NMR (500 MHz, C6D6): d=7.79–7.77 (m, 4H), 7.24–7.22 (m, 6H), 6.12
(dd, J=7.7, 7.2 Hz, 1H), 6.02 (dd, J=7.2, 0.9 Hz, 1H), 5.89 (dd, J=13.0,
2.7 Hz, 1H), 5.75 (dd, J=13.0, 1.9 Hz, 1H), 4.52 (d, J=7.7 Hz, 1H), 4.34
(ddd, J=9.5, 2.7, 1.9 Hz, 1H), 3.72–3.65 (m, 2H), 3.59 (ddd, J=10.9, 9.6,
4.8 Hz, 1H), 3.43 (ddd, J=10.6, 8.7, 4.9 Hz, 1H), 3.35 (dd, J=11.3,
5.5 Hz, 1H), 3.26–3.18 (m, 2H), 3.17–3.01 (m, 5H), 2.45 (dd, J=12.2,
4.2 Hz, 1H), 2.36–2.33 (m, 2H), 2.07–1.87 (m, 6H), 1.80–1.23 (m, 13H),
1380, 1266, 1082, 735 cmꢀ1 1H NMR (500 MHz, CDCl3): d=6.47 (d, J=
;
7.4 Hz, 1H), 6.22 (dd, J=8.0, 7.4 Hz, 1H), 5.75 (dd, J=13.2, 2.9 Hz, 1H),
5.50 (dd, J=13.2, 1.7 Hz, 1H), 4.36 (d, J=8.0 Hz, 1H), 4.20 (m, 1H),
3.64–3.61 (m, 3H), 3.52 (m, 1H), 3.47–3.40 (m, 2H), 3.34 (dd, J=10.9,
4906
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4894 – 4909

Gambierol Analogues
4894 – 4909
1.39 (s, 3H), 1.31 (s, 3H), 1.27 (s, 3H), 1.18 (s, 9H), 1.13 (s, 3H), 1.12 (s,
3H), 0.94 (s, 9H), 0.11 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (125 MHz,
C6D6): d=139.3, 136.0, 134.4, 132.8, 131.1, 129.9, 128.5, 113.0, 85.1, 84.2,
83.5, 82.7, 82.5, 80.2, 79.9, 79.7, 78.9, 78.6, 77.1, 76.1, 74.5, 73.7, 72.8, 72.5,
72.3, 64.2, 54.5, 44.7, 38.9, 38.2, 32.5, 32.4, 30.4, 29.2, 29.0, 28.4, 27.1, 26.0,
24.7, 22.2, 22.0, 20.8, 19.4, 18.3, 18.2, 15.7, ꢀ1.8, ꢀ2.1 ppm; HRMS
(FAB): m/z calcd for C60H8979BrO10Si2Na [M++Na]: 1127.5075; found:
1127.5110; calcd for C60H8981BrO10Si2Na [M++Na]: 1129.5073; found:
1129.5061.
3.58 (ddd, J=10.9, 9.7, 5.2 Hz, 1H), 3.42–3.32 (m, 4H), 3.23 (dd, J=12.0,
2.9 Hz, 1H), 3.14–3.05 (m, 3H), 3.02 (dd, J=13.2, 3.4 Hz, 1H), 2.42 (ddd,
J=12.0, 4.6, 4.0 Hz, 1H), 2.35–2.28 (m, 2H), 2.14 (m, 1H), 2.10–1.94 (m,
6H), 1.77–1.36 (m, 11H), 1.39 (s, 3H), 1.30 (s, 3H), 1.24 (s, 3H), 1.12 (s,
3H), 1.10 (s, 3H), 1.00 (s, 9H), 0.94 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H),
0.07 (s, 3H), 0.06 ppm (s, 3H); 13C NMR (125 MHz, C6D6): d=139.3,
132.8, 131.1, 112.9, 85.1,84.2, 82.8, 82.5, 80.3, 79.9, 79.7, 78.6, 77.7, 76.1,
75.9, 74.9, 74.5, 74.1, 72.6, 72.5 (”2), 72.3, 62.7, 54.5, 44.3, 39.1, 38.1, 32.8,
32.4, 29.7, 29.0, 27.8, 26.1, 26.0, 24.7, 22.2, 22.0, 21.4, 18.4, 18.31, 18.27,
15.7, ꢀ1.8, ꢀ2.1, ꢀ4.0, ꢀ4.9 ppm; HRMS (FAB): m/z calcd for
C50H8579BrO11Si2Na [M++Na]: 1019.4712; found: 1019.4726; calcd for
C50H8581BrO11Si2Na [M++Na]: 1021.4705; found: 1021.4711.
HF·pyridine (0.2 mL) was added to a solution of the above (Z)-vinyl bro-
mide (7.3 mg, 0.0064 mmol) in THF (0.6 mL) cooled to 08C. The result-
ing mixture was stirred at room temperature for 4 days and then poured
into cold saturated aqueous NaHCO3. The aqueous layer was extracted
several times with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, CHCl3 then 2!4!6%
methanol/CHCl3) to give a triol (4.5 mg, 94%) as an amorphous solid:
[a]2D7 =+7.2 (c=0.067 in CHCl3); IR (film): n˜max =3437, 2937, 2875, 1645,
1-O-Methylgambierol (43): HF·pyridine (0.2 mL) was added to a solution
of methyl ether 47 (6.9 mg, 0.0068 mmol) in THF (0.6 mL) cooled to
08C. The resulting mixture was stirred at room temperature for 5 days
and then poured into cold saturated aqueous NaHCO3. The aqueous
layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
50!70!80% ethyl acetate/hexanes) to give a diol (5.2 mg, 98%) as an
1464, 1386, 1268, 1074, 776, 677 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
6.47 (d, J=6.9 Hz, 1H), 6.22 (dd, J=8.6, 6.9 Hz, 1H), 5.75 (dd, J=13.2,
2.9 Hz, 1H), 5.50 (dd, J=13.2, 1.7 Hz, 1H), 4.36 (d, J=8.6 Hz, 1H), 4.20
(ddd, J=9.2, 2.9 1.7 Hz, 1H), 3.64–3.59 (m, 2H), 3.48–3.40 (m, 3H), 3.34
(dd, J=11.5, 5.2 Hz, 1H), 3.19–3.10 (m, 4H), 3.07–3.03 (m, 2H), 2.22
(ddd, J=11.5, 4.6, 4.0 Hz, 1H), 2.15–2.07 (m, 2H), 2.02–1.89 (m, 4H),
1.84–1.34 (m, 15H), 1.314 (s, 3H), 1.309 (s, 3H), 1.30 (s, 3H), 1.29 (s,
3H), 1.22 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=138.2, 131.6,
131.1, 112.7, 84.8, 83.8, 82.7, 82.2, 81.6, 79.8, 79.5, 79.3, 79.0, 76.6, 76.1,
75.8, 74.3, 73.5, 72.2, 72.0, 71.8, 62.9, 53.7, 43.8, 38.2, 37.4, 32.7, 31.8, 30.2,
29.4, 28.6, 27.6, 24.2, 21.5, 21.3, 20.4, 18.2, 15.6 ppm; HRMS (FAB): m/z
calcd for C38H5779BrO10Na [M++Na]: 775.3033; found: 775.2999; calcd
for C38H5781BrO10Na [M++Na]: 777.3021; found: 777.3036.
amorphous solid: [a]D27 =+21.6 (c=0.080 in CHCl3); IR (film): n˜max
=
3426, 2942, 2876, 1630, 1381, 1219, 1047, 773 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=6.47 (d, J=7.4 Hz, 1H), 6.22 (dd, J=8.6, 7.4 Hz, 1H), 5.75
(dd, J=13.2, 2.9 Hz, 1H), 5.50 (dd, J=13.2, 1.7 Hz, 1H), 4.36 (d, J=
8.6 Hz, 1H), 4.20 (m, 1H), 3.76–3.72 (m, 2H), 3.69 (m, 1H), 3.48–3.40
(m, 2H), 3.38–3.34 (m, 3H), 3.32 (s, 3H), 3.29–3.10 (m, 3H), 3.08–3.03
(m, 2H), 2.23 (ddd, J=12.0, 4.6, 4.0 Hz, 1H), 2.12–2.08 (m, 2H), 2.02–
1.97 (m, 3H), 1.92–1.46 (m, 14H), 1.32 (s, 3H), 1.314 (s, 3H), 1.306 (s,
3H), 1.30 (s, 3H), 1.22 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
138.2, 131.7, 131.1, 112.6, 84.8, 83.9, 82.5, 81.6, 79.9, 79.4, 79.1, 76.4, 76.1,
76.0, 75.8, 75.2, 74.6, 73.8, 72.6, 72.2, 72.0, 71.8, 70.8, 58.6, 53.7, 43.6, 37.3,
35.4, 32.2, 31.8, 28.5, 27.1, 25.8, 24.2, 21.33, 21.31, 20.3, 18.2, 15.6 ppm;
HRMS (FAB): m/z calcd for C39H5979BrO11Na [M++Na]: 805.3138;
found: 805.3157; calcd for C39H5981BrO11Na [M++Na]: 807.3127; found:
807.3096.
CuCl (34.9 mg, 0.353 mmol), LiCl (23.0 mg, 0.543 mmol), and [Pd(PPh3)4]
(4.2 mg, 0.0036 mmol) were added to
a solution of the above triol
(4.4 mg, 0.0059 mmol) and (Z)-vinylstannane 23 (52.5 mg, 0.147 mmol) in
degassed DMSO/THF (1:1, v/v, 1.5 mL). The resulting mixture was stir-
red at 608C for 2 days and then quenched with 5% NH4OH. The aque-
ous layer was extracted with CHCl3. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, CHCl3 then
1!2!3% methanol/CHCl3) to give 35 (3.3 mg, 76%) as an amorphous
solid: [a]2D8 =+33.7 (c=0.115 in benzene); IR (film): n˜max =3433, 2941,
CuCl (30.8 mg, 0.311 mmol), LiCl (15.2 mg, 0.359 mmol), and [Pd(PPh3)4]
(2.7 mg, 0.0023 mmol) were added to
a solution of the above diol
(3.4 mg, 0.0043 mmol) and (Z)-vinylstannane 23 (62.3 mg, 0.174 mmol) in
degassed DMSO/THF (1:1, v/v, 1.7 mL). After stirring the mixture at
608C for 2 days, the reaction was quenched with 5% NH4OH. The aque-
ous layer was extracted several times with CHCl3. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel,
50!60% ethyl acetate/hexanes) to give 43 (2.9 mg, 88%) as an amor-
phous solid: [a]2D8 =+45.0 (c=0.110 in benzene); IR (film): n˜max =3427,
2874, 1631, 1452, 1380, 1268, 1073, 755 cmꢀ1 1H NMR (500 MHz,
;
CD3CN): d=6.45 (dd, J=11.6, 10.9 Hz, 1H), 6.38 (dd, J=11.6, 11.3 Hz,
1H), 5.83 (dddd, J=17.1, 10.1, 6.3, 6.3 Hz, 1H), 5.70 (dd, J=12.9, 2.7 Hz,
1H), 5.56 (m, 1H), 5.46 (dd, J=10.9, 8.3 Hz, 1H), 5.38 (dd, J=12.9,
1.9 Hz, 1H), 5.05 (ddd, J=17.1, 3.5, 1.7 Hz, 1H), 4.98 (ddd, J=10.1, 3.5,
1.5 Hz, 1H), 4.31 (d, J=8.3 Hz, 1H), 4.21 (ddd, J=9.4, 2.7, 1.9 Hz, 1H),
3.51 (ddd, J=10.6, 8.8, 4.9 Hz, 1H), 3.47–3.39 (m, 4H), 3.34 (dd, J=11.3,
4.9 Hz, 1H), 3.21 (dd, J=11.3, 4.1 Hz, 1H), 3.18–3.12 (m, 3H), 3.05–3.00
(m, 2H), 2.96–2.93 (m, 2H), 2.67 (s, 1H), 2.55 (t, J=5.3 Hz, 1H), 2.08
(m, 1H), 1.96–1.83 (m, 4H), 1.78–1.40 (m, 17H), 1.30 (s, 3H), 1.27 (s,
3H), 1.24 (s, 3H), 1.21 (s, 3H), 1.20 ppm (s, 3H); 13C NMR (125 MHz,
CD3CN): d=140.6, 137.5, 131.5, 131.1, 129.3, 127.5, 126.0, 115.6, 85.6,
83.3, 83.1, 82.9, 82.0, 80.5, 80.2, 79.9, 79.7, 77.1, 76.8, 76.5, 75.0, 74.3, 73.1,
72.7 (”2), 62.5, 54.8, 44.7, 39.2, 39.3, 33.1, 32.9, 32.3, 30.8, 29.8, 29.4, 28.6,
25.0, 21.9, 21.4, 20.8, 18.7, 15.9 ppm; HRMS (FAB): m/z calcd for
C43H64O10Na [M++Na]: 763.4397; found: 763.4404.
2943, 2873, 1631, 1385, 1268, 1072, 755 cmꢀ1 1H NMR (500 MHz,
;
CD3CN): d=6.46 (dd, J=11.5, 10.9 Hz, 1H), 6.38 (dd, J=11.5, 11.5 Hz,
1H), 5.83 (dddd, J=17.2, 10.3, 6.3, 6.3 Hz, 1H), 5.70 (dd, J=12.6, 2.3 Hz,
1H), 5.55 (m, 1H), 5.46 (m, 1H), 5.39 (dd, J=12.6, 1.7 Hz, 1H), 5.05 (dd,
J=17.2, 3.5 Hz, 1H), 4.98 (dd, J=10.3, 3.5 Hz, 1H), 4.31 (d, J=8.0 Hz,
1H), 4.21 (m, 1H), 3.74 (dd, J=12.0, 4.6 Hz, 1H), 3.67 (m, 1H), 3.59 (m,
1H), 3.51 (ddd, J=10.3, 9.2, 5.2 Hz, 1H), 3.42 (ddd, J=10.9, 9.7, 5.2 Hz,
1H), 3.36–3.30 (m, 3H), 3.29 (s, 3H), 3.23–3.13 (m, 3H), 3.07–3.00 (m,
2H), 2.96–2.93 (m, 2H), 2.82 (d, J=1.8 Hz, 1H), 2.65 (s, 1H), 2.09 (m,
1H), 1.97–1.90 (m, 3H), 1.86–1.69 (m, 4H), 1.64–1.38 (m, 12H), 1.30 (s,
3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H), 1.20 ppm (s, 3H); 13C NMR
(125 MHz, CD3CN): d=140.6, 137.5, 131.5, 131.1, 129.3, 127.5, 126.0,
115.6, 85.6, 83.1, 82.9, 81.9, 80.4, 80.2, 79.7, 77.0, 76.8, 76.7, 76.5, 75.9,
75.3, 74.5, 73.1 (”2), 72.7 (”2), 71.2, 58.5, 54.7, 44.1, 38.2, 36.6, 33.0, 32.9,
32.2, 29.3, 27.9, 26.4, 25.0, 21.7, 21.3, 20.8, 18.7, 15.9 ppm; HRMS (FAB):
m/z calcd for C44H66O11Na [M++Na]: 793.4503; found: 793.4524.
Alcohol 46: HF·pyridine (0.15 mL) was added to a solution of tris-silyl
ether 45 (11.1 mg, 0.0090 mmol) in THF (0.9 mL) cooled to 08C. The re-
sulting mixture was stirred at 08C for 15 min and then warmed to room
temperature. The reaction mixture was stirred for 3.5 h and then poured
into cold saturated aqueous NaHCO3. The aqueous layer was extracted
several times with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, 20!40% ethyl acetate/
hexanes) to give primary alcohol 46 (7.7 mg, 86%) as a colorless oil:
[a]2D8 =+14.2 (c=0.093 in benzene); IR (film): n˜max =3436, 2929, 2857,
1-Deoxygambierol (44): HF·pyridine (0.3 mL) was added to a solution of
compound 48 (10.6 mg, 0.0108 mmol) in THF (0.9 mL) cooled to 08C.
The resulting mixture was stirred at room temperature for 5 days and
then poured into cold saturated aqueous NaHCO3. The aqueous layer
was extracted with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, 40!60% ethyl acetate/
1623, 1465, 1382, 1255, 1078, 878, 777 cmꢀ1 1H NMR (500 MHz, C6D6):
;
d=6.11 (dd, J=7.4, 6.9 Hz, 1H), 6.01 (d, J=6.9 Hz, 1H), 5.89 (dd, J=
13.2, 2.9 Hz, 1H), 5.76 (dd, J=13.2, 1.7 Hz, 1H), 4.52 (d, J=7.4 Hz, 1H),
4.34 (m, 1H), 3.99 (dd, J=12.6, 4.0 Hz, 1H), 3.85 (m, 1H), 3.65 (m, 1H),
hexanes) to give a diol (7.4 mg, 91%) as an amorphous solid: [a]D28
+35.5 (c=0.110 in CHCl3); H NMR (500 MHz, CDCl6): d=6.47 (d, J=
7.4 Hz, 1H), 6.22 (dd, J=8.0, 7.4 Hz, 1H), 5.75 (dd, J=12.6, 2.9 Hz, 1H),
=
1
Chem. Eur. J. 2004, 10, 4894 – 4909
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4907

M. Sasaki et al.
FULL PAPER
5.50 (dd, J=12.6, 1.7 Hz, 1H), 4.35 (d, J=8.0 Hz, 1H), 4.20 (m, 1H),
3.76–3.69 (m, 3H), 3.48–3.40 (m, 2H), 3.34 (dd, J=9.8, 4.6 Hz, 1H),
3.18–3.10 (m, 3H), 3.08–3.03 (m, 2H), 2.23 (ddd, J=11.5, 4.6, 4.6 Hz,
1H), 2.12–2.08 (m, 2H), 2.02–1.81 (m, 5H), 1.77–1.35 (m, 12H), 1.32 (s,
3H), 1.31 (s, 3H), 1.30 (s, 6H), 1.22 (s, 3H), 0.88 ppm (t, J=6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=138.2, 131.6, 131.1, 112.6, 84.8, 83.9,
82.5, 81.6, 79.8, 79.4, 79.1, 76.3, 76.1, 76.0, 75.8, 75.2, 74.7, 73.8, 72.2, 72.0,
71.8, 70.9, 53.7, 43.6, 37.9, 37.3, 35.4, 31.8, 28.5, 27.1, 24.2, 21.32, 21.30,
20.3, 18.8, 18.2, 15.6, 14.0 ppm; HRMS (FAB): m/z calcd for
C38H5779BrO10Si2Na [M++Na]: 775.3033; found: 775.3008; calcd for
C38H5781BrO10Si2Na [M++Na]: 777.3021; found: 777.2978.
[5] a) J.-N. Bidard, H. P. M. Vijverberg, C. Freiln, E. Chungue, A.-M.
Legrand, R. Bagnis, M. Lazdunski, J. Biol. Chem. 1984, 259, 8353;
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[8] M. Inoue, M. Hirama, M. Satake, K. Sugiyama, T. Yasumoto, Toxi-
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[9] a) I. Kadota, C.-H. Park, M. Ohtaka, N. Oguro, Y. Yamamoto, Tetra-
hedron Lett. 1998, 39, 6365; b) I. Kadota, C. Kadowaki, N. Yoshida,
Y. Yamamoto, Tetrahedron Lett. 1998, 39, 6369; c) I. Kadota, A.
Ohno, Y. Matsukawa, Y. Yamamoto, Tetrahedron Lett. 1998, 39,
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Tetrahedron Lett. 2000, 41, 8371; f) I. Kadota, A. Ohno, K. Matsuda,
Y. Yamamoto, J. Am. Chem. Soc. 2001, 123, 6702; g) H. Fuwa, M.
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i) Y. Sakamoto, G. Matsuo, H. Matsukura, T. Nakata, Org. Lett.
2001, 3, 2749; j) J. M. Cox, J. D. Rainier, Org. Lett. 2001, 3, 2919;
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Kadota, C.-H. Park, K. Sato, Y. Yamamoto, Tetrahedron Lett. 2001,
42, 6195; m) I. Kadota, C. Kadowaki, H. Takamura, Y. Yamamoto,
Tetrahedron Lett. 2001, 42, 6199; n) I. Kadota, C. Kadowaki, C.-H.
Park, H. Takamura, K. Sato, P. W. H. Chan, S. Thorand, Y. Yamamo-
to, Tetrahedron 2002, 58, 1799; o) I. Kadota, A. Ohno, K. Matsuda,
Y. Yamamoto, J. Am. Chem. Soc. 2002, 124, 3562; p) I. Kadota, H.
Takamura, K. Sato, Y. Yamamoto, J. Org. Chem. 2002, 67, 3494;
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2981; b) H. Fuwa, N. Kainuma, K. Tachibana, M. Sasaki, J. Am.
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CuCl (42.9 mg, 0.433 mmol), LiCl (26.5 mg, 0.625 mmol), and [Pd(PPh3)4]
(6.2 mg, 0.0054 mmol) were added to
a solution of the above diol
(5.2 mg, 0.0069 mmol) and (Z)-vinylstannane 23 (105.1 mg, 0.2935 mmol)
in degassed DMSO/THF (1:1, v/v, 3 mL). The resulting mixture was stir-
red at 608C for 2 days and then poured into cold saturated aqueous
NaHCO3. The aqueous layer was extracted several times with CHCl3.
The combined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash chro-
matography (silica gel, 30!35!40% ethyl acetate/hexanes) to give 44
(4.6 mg, 90%) as an amorphous solid: [a]2D8 =+19.2 (c=0.15 in benzene);
IR (film): n˜max =3340, 2950, 2874, 1730, 1631, 1458, 1384, 1266, 1078, 806,
752, 679 cmꢀ1 1H NMR (500 MHz, CD3CN): d=6.46 (dd, J=11.5,
;
11.5 Hz, 1H), 6.38 (dd, J=11.5, 10.9 Hz, 1H), 5.83 (dddd, J=17.2, 10.3,
6.3, 6.3 Hz, 1H), 5.70 (dd, J=13.2, 2.9 Hz, 1H), 5.56 (m, 1H), 5.46 (dd,
J=10.9, 8.0 Hz, 1H), 5.39 (dd, J=13.2, 1.7 Hz, 1H), 5.05 (dd, J=17.2,
3.5 Hz, 1H), 4.98 (dd, J=10.7, 3.5 Hz, 1H), 4.31 (d, J=8.0 Hz, 1H), 4.21
(m, 1H), 3.74 (dd, J=11.5, 4.6 Hz, 1H), 3.67 (m, 1H), 3.59 (m, 1H), 3.51
(ddd, J=10.3, 9.2, 5.2 Hz, 1H), 3.42 (ddd, J=10.9, 9.7, 5.2 Hz, 1H), 3.34
(dd, J=10.9, 4.6 Hz, 1H), 3.23–3.13 (m, 3H), 3.07–3.00 (m, 2H), 2.96–
2.93 (m, 2H), 2.82 (m, 1H), 2.65 (s, 1H), 2.10 (m, 1H), 1.97–1.90 (m,
6H), 1.86–1.77 (m, 3H), 1.70–1.26 (m, 10H), 1.30 (s, 3H), 1.29 (s, 3H),
1.25 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H), 0.87 ppm (t, J=6.9 Hz, 3H); 13C
NMR (125 MHz, CD3CN): d=140.8, 137.7, 131.7, 131.2, 129.5, 127.6,
126.2, 115.7, 85.7, 83.3, 83.1, 82.1, 80.6, 80.4, 79.9, 77.2, 76.9 (”2), 76.6,
76.0, 75.4, 74.7, 73.3, 72.8 (”2), 71.9, 54.9, 44.3, 38.7, 38.4, 36.7, 33.0, 32.4,
29.5, 28.1, 25.1, 21.9, 21.5, 21.0, 19.6, 18.1, 16.1, 14.5 ppm; HRMS (FAB):
m/z calcd for C43H64O10Na [M++Na]: 763.4397; found: 763.4423.
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Mouse toxicity assay: All the synthetic analogues were purified by HPLC
(Asahipak ODP-506D, f 4.6”150 mm, CH3CN/H2O as eluent, l 210 nm).
Each sample was dissolved in 1% Tween 60 (0.5–0.8 mL) by sonication
and intraperitoneally injected into a ddY strain male mouse (12–17 g
body weight).
[12] A portion of this work has previously been communicated: H.
Fuwa, N. Kainuma, M. Satake, M. Sasaki, Bioorg. Med. Chem. Lett.
2003, 13, 2519.
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Acknowledgements
Financial support was provided by CREST, the Japan Science and Tech-
nology Agency (JST) and Suntory Institute for Bioorganic Research
(SUNBOR).
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4908
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Chem. Eur. J. 2004, 10, 4894 – 4909

Gambierol Analogues
4894 – 4909
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Received: April 10, 2004
Published online: August 17, 2004
Chem. Eur. J. 2004, 10, 4894 – 4909
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4909