A concise synthesis of the ab-ring fragment of (-)-gambierol

Article abstract of DOI:10.3987/COM-12-S(N)21

We describe herein a concise synthesis of the AB-ring fragment of gambierol, wherein silver(I) trifluoromethanesulfonate-catalyzed 6-endo cyclization of a hydroxy ynone was exploited for the formation of the A-ring.

Full text of DOI:10.3987/COM-12-S(N)21

HETEROCYCLES, Vol. 86, No. 1, 2012
127
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 127 - 132. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 24th May, 2012, Accepted, 15th June, 2012, Published online, 21st June, 2012
DOI: 10.3987/COM-12-S(N)21
A CONCISE SYNTHESIS OF THE AB-RING FRAGMENT OF
(!)-GAMBIEROL
Haruhiko Fuwa,* Kazuaki Hirota, and Makoto Sasaki*
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku,
Sendai
980-8577,
Japan.
Email:
hfuwa@bios.tohoku.ac.jp;
masasaki@bios.tohoku.ac.jp
Abstract – We describe herein a concise synthesis of the AB-ring fragment of
gambierol, wherein silver(I) trifluoromethanesulfonate-catalyzed 6-endo
cyclization of a hydroxy ynone was exploited for the formation of the A-ring.
This paper is dedicated to Professor Ei-ichi Negishi on the occasion of his 77th
birthday.
(!)-Gambierol (1, Figure 1) is a structurally complex marine polycyclic ether natural product that was
isolated from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus by Satake
and co-workers.1 The entire structure of 1 was elucidated by extensive 2D-NMR analysis and application
of a chiral anisotropic reagent. Satake et al. have reported that gambierol exhibits potent lethal toxicity
against mice with a minimal lethal dose value of 50 µg/kg (ip) and that the neurological symptoms caused
in mice resemble those shown by ciguatoxins, suggesting the possible role of 1 in ciguatera seafood
poisoning. Unfortunately, detailed biological studies on 1 had been precluded for almost a decade, due to
the extreme natural scarcity of 1. Motivated by the structural complexity as well as the biological aspects,
we have successfully completed the first total synthesis of 1 and enabled material supply for extensive
biological investigations.2,3 Consequently, we have identified that 1 inhibits voltage-gated potassium
channels (Kv channels) in mice taste cells in low nanomolar concentrations,4 while 1 acts as a weak
partial agonist of voltage-gated sodium channels in human neuroblastoma cells.5 Snyders and co-workers
have shown that 1 selectively inhibits the Kv1 and Kv3 subfamilies and that 1 binds to the previously
undescribed binding site present between the S5 and S6 segments of Kv3.1 channels.6 In addition, we
have recently found that the EFGH-ring domain of 1 plays a crucial role in inhibiting voltage-gated
potassium currents and that, in an in vitro model of Alzheimer’s disease, 1 and its truncated analogues are

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HETEROCYCLES, Vol. 86, No. 1, 2012
able to lower the amyloid ! (A!) and hyperphosphorylated tau levels with a possible implication of Kv
channel inhibition.7 Undoubtedly, 1 represents an intriguing molecular probe for the functional analysis of
Kv channels as well as for understanding downstream events of Kv channel inhibition.
HO
Me Me
O
H
H
H
H
HO
O
H
A
B
C
D
E
O
H
F
H
O
O
O
O
Me
H
H
H
H
G
O
Me
H
gambierol (1)
H
OH
Me
Figure 1. Structure of (!)-gambierol (1)
Toward an even more practical synthesis of 1, we describe herein a concise synthesis of the AB-ring
fragment of 1. We envisioned that the AB-ring fragment 2 would be readily accessible from
dihydropyrone 3, which in turn would be obtainable from the known tetrahydropyran 48 via standard
chemistry (Scheme 1).
BnO
O
Me Me
O
Me Me
O
Me Me
O
BnO
BnO
O
O
O
A
B
A
B
B
O
H
O
Ph
O
O
Ph
HO
O
Ph
H
H
H
H
H
2
3
4
Scheme 1. Synthesis plan toward the AB-ring fragment 2
Our initial synthetic approach toward 2 involved cyclodehydration of 1,3-diketone 5 (Scheme 2).9
Protection of 4 with triethylsilyl chloride (TESCl) and Et3N in the presence of a catalytic amount of
4-(dimethylamino)pyridine (DMAP) gave TES ether 6 in 95% yield. Ozonolysis of the double bond
delivered aldehyde 7 in 95% yield. Methylation with MeMgBr, followed by oxidation of the resultant
alcohol with 2-iodoxybenzoic acid (IBX), provided methyl ketone 8 in 75% yield (two steps). Enolization
of 8 with lithium hexamethyldisilazide (LHMDS) in the presence of ZnCl2 followed by addition of
4-benzyloxybutanal (9) (THF, !78 to !20 °C) afforded !-hydroxy ketone 10 as a 1.8:1 mixture of
diastereomers in 96% combined yield (stereochemistry not determined). Oxidation of 10 was most
efficiently performed with IBX in refluxing EtOAc10 to give 1,3-diketone 5 in 86% yield. Unexpectedly,
cyclodehydration of 5 was found to be rather problematic. Treatment of 5 with (+)-10-camphorsulfonic
acid (CSA) in methanol under reflux resulted in decomposition of the material, possibly due to the
instability of the diketone moiety. Accordingly, 5 was reacted with CSA initially at room temperature to
cleave the silyl ether and then at 60 °C to effect cyclodehydration. This modified procedure gave

HETEROCYCLES, Vol. 86, No. 1, 2012
129
dihydropyrone 11 with concomitant loss of the benzylidene acetal in 41% yield, along with a mixture of
several byproducts. Careful examination of the mixture revealed that the major byproduct was bicycle 12.
Running the reaction with pyridinium p-toluenesulfonate (PPTS) as an acid only provided a mixture of 12
and unidentified byproducts. The structure of 12 was assigned on the basis of extensive NMR studies on
12 and its acetate 13 as shown. Upon cleavage of the benzylidene acetal, the steric repulsion existing
between the 1,3-diaxial methyl groups of the tetrahydropyran would facilitate ring flipping, hemiacetal
formation, and dehydration to produce 12.
Scheme 2. Initial efforts toward the synthesis of the A-ring
The disappointing outcome of the cyclodehydration of 1,3-diketone 5 led us to investigate 6-endo
cyclization of hydroxy ynone 14 as the revised approach toward dihydropyrone 3 (Scheme 3). We have
previously shown that a variety of substituted dihydropyrones could be accessed based on silver(I)
trifluoromethanesulfonate (AgOTf)-catalyzed cyclization of the corresponding hydroxy ynones.11,12
Addition of a lithium acetylide generated from 5-benzyloxypentyne (15)13 to aldehyde 7 gave propargylic
alcohol 16 as a 1.6:1 mixture of diastereomers in 96% combined yield. Without separation, this material
was oxidized with IBX to deliver ynone 17 in 98% yield. Removal of the TES group was effected by
exposure to tetra-n-butylammonium fluoride (TBAF) buffered with acetic acid (93%). The resultant

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HETEROCYCLES, Vol. 86, No. 1, 2012
hydroxy ynone 14 was cyclized smoothly upon treatment with AgOTf in the presence of
2,6-di-tert-butylpyridine (DTBP),14 giving rise to dihydropyrone 3 in 88% yield.
Having established the reliable route to 3, our focus was shifted toward elaboration of the AB-ring
fragment 2 (Scheme 3). Hydrogenation of 3 proceeded in a stereoselective manner to give ketone 18 in
89% yield as a single stereoisomer. The newly generated stereogenic center was established through an
NOE experiment as shown. Stereoselective reduction of 18 to establish the C6 stereogenic center turned
out to be a challenging task. Even bulky reducing agents such as diisobutylaluminum hydride (DIBALH)
or L-selectride® provided the desired alcohol 19a with moderate diastereoselectivity (19a:19b =
1.4–1.8:1), while reduction with NaBH4 or LiAlH4 resulted in preferential formation of the undesired
alcohol 19b (19a:19b = ca. 1:6). However, we were fortunate to find that these diastereomeric alcohols
were readily separable by flash chromatography on silica gel, and the undesired 19b could be recycled by
oxidation with IBX (80%).15 Finally, benzylation of 19a afforded bis(benzyl) ether 2 in 85% yield,
successfully intercepting our previous synthesis of 1.
HO
BnO
BnO
Me Me
O
Me Me
O
OHC
O
O
15
n-BuLi
THF, –78 °C
IBX, DMSO, rt
98%
TESO
16
O
Ph
TESO
O
Ph
H
H
96% (d.r. 1.6:1)
7
AgOTf
DTBP
CH2Cl2, rt
O
O
BnO
Me Me
O
Me Me
O
BnO
H2, Pd/C, THF, rt
89% (d.r. >20:1)
O
O
A
B
88%
PGO
O
Ph
O
O
Ph
H
H
H
TBAF, AcOH
THF, rt
93%
17: PG = TES
14: PG = H
3
X
O
Y
H
Me Me
O
Me Me
O
DIBALH
THF, –78 °C
BnO
BnO
6
O
O
A
B
19a: 59%
19b: 33%
O
O
Ph
O
O
Ph
H
H
H
H
H
19a: X = OH, Y = H
19b: X = H, Y = OH
BnBr, KOt-Bu
n-Bu4NI, THF, rt
85%
IBX, DMSO, 40 °C
80%
NOE
18
2: X = OBn, Y = H
Scheme 3. Synthesis of the AB-ring fragment 2 via 6-endo cyclization of hydroxy ynone 14
In conclusion, we have devised a concise synthesis of the AB-ring fragment 2 of (!)-gambierol, by
exploiting AgOTf-catalyzed 6-endo cyclization of hydroxy ynone 14. The present synthesis allows an
efficient access to 2 from the B-ring tetrahydropyran 4 in nine steps, which compares favorably with our
previous synthesis (17 steps). Further studies on the chemistry and biology of (!)-gambierol and its
synthetic analogues are currently underway and will be reported shortly.

HETEROCYCLES, Vol. 86, No. 1, 2012
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ACKNOWLEDGEMENTS
This work was financially supported in part by Grants-in-Aid for Scientific Research on Innovative Areas
“Chemical Biology Using Bioactive Natural Products as Specific Ligands” (Nos. 23102016 and
24102517) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).
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