Studies toward the total synthesis of gambieric acids: Convergent synthesis of the GHIJ-ring fragment having a side chain

Article abstract of DOI:10.1016/j.tetlet.2010.11.127

A stereocontrolled synthesis of the GHIJ-ring fragment having a side chain of gambieric acids, which are potent antifungal polycyclic ether natural products, has been achieved. The synthesis features convergent assembly of the tetracyclic polyether skelet

Full text of DOI:10.1016/j.tetlet.2010.11.127

Tetrahedron Letters 52 (2011) 548–551
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies toward the total synthesis of gambieric acids: convergent synthesis
of the GHIJ-ring fragment having a side chain
⇑
Koichi Tsubone, Keisuke Hashizume, Haruhiko Fuwa, Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereocontrolled synthesis of the GHIJ-ring fragment having a side chain of gambieric acids, which are
potent antifungal polycyclic ether natural products, has been achieved. The synthesis features convergent
assembly of the tetracyclic polyether skeleton by using aldol coupling and stereoselective construction of
the J-ring side chain by a cerium chloride-promoted Julia–Kocienski reaction.
Received 1 November 2010
Revised 23 November 2010
Accepted 24 November 2010
Available online 27 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Gambieric acids
Polycyclic ethers
Aldol coupling
Julia–Kocienski reaction
Gambieric acids A–D (1–4, Fig. 1) are marine polycyclic ether
natural products isolated from the ciguatera causative dinoflagel-
late Gambierdiscus toxicus by Nagai, Yasumoto, and co-workers.1
These polycyclic ethers exhibit extremely potent antifungal activ-
ity against Aspergillus niger 2000 times greater than that of ampho-
tericin B, whereas they show only moderate toxicity against mice
or cultured mammalian cells.2 It has also been reported that gam-
bieric acid A enhances the cell concentration of G. toxicus in a dose-
dependent manner with inhibition at higher concentrations, sug-
gesting the possible role of gambieric acid A as an endogenous
growth regulator of G. toxicus.3 Moreover, Inoue et al. have recently
reported that gambieric acid A inhibits the binding of tritiated
brevetoxin-B derivative ([3H]PbTx-3) to voltage-sensitive sodium
channels, although its binding affinity is significantly lower than
those of brevetoxins and ciguatoxins.4 Their extraordinary com-
plex molecular architecture coupled with highly potent antifungal
activity has prompted considerable interest from the synthetic
community.5–9 As part of our continuing studies toward the total
synthesis of gambieric acids, we have recently reassigned the abso-
lute configuration of the polycyclic ether domain of gambieric
acids.5e,f We describe herein a convergent synthesis of the GHIJ-
ring system having a side chain.
the development of an efficient method for synthesis of the side
chain is indispensable for the total synthesis. We envisioned that
introduction of the side chain to the J-ring would be achieved by
Julia–Kocienski olefination10 of ketone 6 and 1-phenyl-1H-tetra-
zol-5-yl sulfone 7. Although we have previously described a syn-
thesis of the GHIJ-ring fragment in its antipodal form based on
acetylide–aldehyde coupling,5b,c the present synthesis relied on
an alternative convergent strategy. It was planned that the tetracy-
clic polyether 6 would be synthesized through aldol coupling of the
G- and J-rings (8 and 9, respectively), a cyclodehydration to form
the H-ring, and reductive etherification to build the I-ring.
The synthesis of the G-ring is shown in Scheme 2. The known
alcohol 1011 was protected as the TES ether 11. Subsequent ozon-
olysis of the double bond afforded aldehyde 8 in 96% yield for the
two-steps.
The synthesis of the J-ring 9 started with the known epoxy alco-
hol 12.12 Regioselective epoxide ring-opening with Ti(OBn)4
13
afforded diol 13 in 79% yield (Scheme 3). Selective sulfonylation
of the primary alcohol followed by treatment with K2CO3 gave
epoxide 14 (91%, two-steps), which was then treated with dimeth-
ylsulfonium methylide (Me3SI, n-BuLi)14 to afford allylic alcohol 15
in 94% yield. Protection as the PMB ether using PMBOC(@NH)CCl3
in the presence of La(OTf)315 was followed by hydroboration of the
double bond with disiamylborane to afford alcohol 16 in 81% yield
for the two-steps. Benzyl protection and removal of the TBDPS
group provided primary alcohol 17 (77%, two-steps), which was
subjected to Swern oxidation and a one-pot Wittig reaction to
afford (E)-enoate 18 in 95% yield. DIBALH reduction followed by
Sharpless asymmetric epoxidation16 of the resultant allylic alcohol
gave epoxy alcohol 19 (81%, two-steps), which was oxidized with
Our synthesis plan toward the GHIJ-ring fragment 5 is outlined
in Scheme 1. Stereocontrolled construction of a trisubstituted al-
kene in the J-ring side chain poses a significant synthetic challenge.
The only synthesis of the J-ring side chain has been reported by Ka-
dota et al.,6b but their synthesis suffered from low yield. Therefore,
⇑
Corresponding author. Tel.: +81 22 217 6212; fax: +81 22 217 6213.
E-mail address: masasaki@bios.tohoku.ac.jp (M. Sasaki).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.127

K. Tsubone et al. / Tetrahedron Letters 52 (2011) 548–551
549
Me
H
H
OTES
H
H
Me Me
O
R1
HO
HO
H
H
Me
H
F
O
C
H
O
Me
H
OH
H
O
G
O
I
B
D
O
E
O
t-Bu Si
t-Bu
Me Me
G
O
H
O
J
H
H
O
H
OTBS
O
H
H
H
Me
O
O
H
O
H
H
Me
H
I
A
O
H
H
gambieric acid A (1): R1 = R2 = H
gambieric acid B (2): R1 = Me, R2 = H
gambieric acid C (3): R1 = H, R2
gambieric acid D (4): R1 = Me, R2
J
H
5
Me
O
Me
HO2C
Me
H
Me
OR2
=
CO2H
=
O
Me
Figure 1. Structures of gambieric acids A–D (1–4) and the GHIJ-ring fragment 5.
b,c
a
OBn
OH
OBn
OBn
OTES
O
H
Me
H
H
TBDPSO
OH
O
G
O
I
TBDPSO
HO
TBDPSO
O
t-Bu Si
t-Bu
Me Me
H
O
J
O
OTBS
12
13
14
O
O
H
H
H
Me
H
d
5
Me
O
O
N
OBn
OBn
g,h
e,f
S
OTBS
N
N
N
HO
O
TBDPSO
TBDPSO
HO
7
OBn
O
OH
OTES
Ph
H
H
Me
H
H
PMB
PMB
17
16
15
O
O
O
t-Bu Si
t-Bu
Me
i
O
O
O
O
H
H
Me
H
OBn
OBn
j,k
6
O
HO
EtO2C
O
OBn
O
OBn
PMB
l,m
Me
Me
H
Me
PMB
18
PMB
O
CHO
O
O
OBn
O
+
J
19
G
Ph
O
OTES
Me
O
OBn
H
Me
H
HO
OBn
OBn
n
8
9
O
O
OBn
O
OBn
o,p
Scheme 1. Synthesis plan for the GHIJ-ring fragment 5.
Me
H
Me
PMB
20
NOE
21
PMB
PMBO
HO
OBn
O
O
OBn
H
H
Me
H
H
Me
CHO
q-s
O
O
G
J
O
O
b
O
OBn
Me
O
OBn
Me
22
H
Me
H
Ph
O
OR
Ph
O
OTES
9
8
10: R = H
11: R = TES
a
Scheme 3. Reagents and conditions: (a) Ti(Oi-Pr)4, BnOH, toluene, 85 °C, 79%; (b)
MesSO2Cl, pyridine, rt; (c) K2CO3, MeOH, rt, 91% (two-steps); (d) Me3SI, n-BuLi, THF,
ꢁ30 °C to rt, 94%; (e) PMBOC(@NH)CCl3, La(OTf)3, toluene, rt; (f) (Sia)2BH, THF, 0 °C
to rt; then 3 M aq NaOH, H2O2, 0 °C to rt, 81% (two-steps); (g) KOt-Bu, BnBr, THF, rt;
(h) 10% aq KOH, THF/MeOH, 70 °C, 77% (two-steps); (i) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢁ78 °C to rt; then Ph3P@C(Me)CO2Et, rt, 95%; (j) DIBALH, CH2Cl2, ꢁ78 °C, 99%; (k)
(+)-DET, Ti(Oi-Pr)4, TBHP, 4 Å molecular sieves, CH2Cl2, ꢁ40 °C, 82%; (l) TEMPO, aq
NaClO, KBr, aq NaHCO3, CH2Cl2, 0 °C; (m) Ph3PCH3Br, NaHMDS, THF, 0 °C, 93% (two-
steps); (n) DDQ, CH2Cl2/H2O, rt, 72%; (o) KOt-Bu, PMBCl, TBAI, DMF, rt, 98%; (p)
(Sia)2BH, THF, 0 °C to rt; then 3 M aq NaOH, H2O2, rt, 100%; (q) SO3ꢀpyridine, DMSO,
Et3N, CH2Cl2, rt; (r) MeMgBr, Et2O, ꢁ78 °C; (s) TPAP, NMO, 4 Å molecular sieves,
CH2Cl2, rt, 83% (three-steps).
Scheme 2. Reagents and conditions: (a) TESCl, imidazole, CH2Cl2, rt, 100%; (b) O3,
CH2Cl2, ꢁ78 °C; then PPh3, ꢁ78 °C to rt, 96%.
TEMPO/NaClO17 and subsequently subjected to a Wittig reaction to
afford vinyl epoxide 20 in 93% yield for the two-steps. Upon treat-
ment with DDQ, cleavage of the PMB group with concomitant 6-
endo cyclization18 took place to give tetrahydropyran 21 in 72%
yield.19 The stereochemistry of 21 was confirmed by an NOE as
shown. Protection of the secondary alcohol as the PMB ether and
hydroboration of the terminal olefin afforded primary alcohol 22
(98%, two-steps), which was then converted into methyl ketone 9
in a three-step sequence involving oxidation to the aldehyde, a
reaction with MeMgBr, and TPAP/NMO oxidation20 (83% for the
three-steps).
With the two desired fragments in hand, their aldol coupling
was then undertaken. Treatment of dibutylboron enolate derived
from the methyl ketone 9 (n-Bu2BOTf, i-Pr2NEt, Et2O)21 with alde-
hyde 8 (1.5 equiv) afforded the desired aldol adduct 23 as an incon-
sequential 5:1 mixture of diastereomers in 74% combined yield
(Scheme 4). Oxidation of the secondary alcohol with Dess–Martin
periodinane22 afforded diketone 24 in 91% yield. Treatment of 24
with PPTS in methanol at 80 °C effected deprotection of the TES
and benzylidene acetal protective groups with concomitant cyc-
lodehydration23 to form the H-ring, leading to dihydropyrone 25
in 95% yield. Construction of the I-ring was carried out without
incident following the previously described route.5b,c,24 The diol
within 25 was protected as its di-tert-butylsilylene to afford 26
in 93% yield. Luche reduction (97%),25 hydroboration of the derived
enol ether with BH3ꢀTHF (80%), followed by protection as the bis-
TES ether, afforded 27 in 94% yield. Removal of the PMB group with
DDQ followed by oxidation of the resultant alcohol provided
ketone 28 in 85% yield for the two-steps. After cleavage of the
TES ethers with TsOH (93%), treatment of the resultant ketodiol
with Et3SiH and TMSOTf in propionitrile at ꢁ78 °C led to the de-
sired GHIJ-ring skeleton 29 as a single diastereomer in 87% yield.26

550
K. Tsubone et al. / Tetrahedron Letters 52 (2011) 548–551
PMB
R
PMB
O
PMB
O
O
H
Me
H
Me
O
O
OBn
O
OBn
O
OBn
c
a
O
RO
RO
O
Me
O
OBn
O
Ph
O
O
O
OBn
O
O
OBn
H
H
Me
CHO
Me
H
H
Me
H
H
Me
25: R = H
H
O
TES
9
d
23: R = H, OH
24: R = O
b
26: R,R = Si(t-Bu)2
Ph
O
OTES
8
e-g
NOEs
TES
O
OR
OR
Me
TES
O O
R PMB
H
Me
H
H
Me
H
H
H
O
H
h,i
j,k
O
OBn
O
O O
OBn
O
OBn
36
O
O
t-Bu Si
t-Bu
O
37
38
t-Bu Si
t-Bu
t-Bu Si
t-Bu
O
O
O
OBn
O
O
O
OBn
O
O
O
OBn
H
H
H
Me
H
H
H
Me
H
H
H
Me
H
28
27: R = TES
29: R = H
30: R = Ac (J36,37 = J37,38 = 10.0 Hz)
l-n
O
OTES
OTES
OTES
H
H
Me
H
H
Me
H
H
Me
H
H
H
H
o-q
r-t
O
OH
O
O
O
O
O
t-Bu Si
t-Bu
O
t-Bu Si
t-Bu
O
Me
t-Bu Si
t-Bu
O
O
O
OPiv
O
O
O
OH
O
O
O
O
H
H
Me
H
H
H
H
Me
H
H
H
H
Me
H
31
32
6
Scheme 4. Reagents and conditions: (a) 9, Bu2BOTf, i-Pr2NEt, Et2O, 0 °C; then 8, ꢁ78 °C, 74%; (b) Dess–Martin periodinane, CH2Cl2/t-BuOH, rt, 91%; (c) PPTS, MeOH, 80 °C,
95%; (d) t-Bu2Si(OTf)2, 2,6-lutidine, DMF, rt, 93%; (e) NaBH4, CeCl3ꢀ7H2O, MeOH/CH2Cl2, 0 °C, 97%; (f) BH3ꢀTHF, THF, 0 °C; then 3 M aq NaOH, H2O2, 0 °C to rt, 80%; (g) TESOTf,
2,6-lutidine, CH2Cl2, rt, 94%; (h) DDQ, CH2Cl2/H2O, 0 °C; (i) TPAP, NMO, 4 Å molecular sieves, CH2Cl2, 0 °C to rt, 85% (two-steps); (j) TsOH, CH2Cl2/MeOH, rt, 93%; (k) Et3SiH,
TMSOTf, EtCN, ꢁ78 °C, 87%; (l) TESOTf, 2,6-lutidine, CH2Cl2, rt, 97%; (m) H2, Pd(OH)2/C, EtOAc, rt, 97%; (n) PivCl, pyridine, 0 °C, 85%; (o) Dess–Martin periodinane, CH2Cl2, rt,
80%; (p) Ph3PCH3Br, NaHMDS, THF, 0 °C, 83%; (q) DIBALH, CH2Cl2, ꢁ78 °C, 96%; (r) Dess–Martin periodinane, CH2Cl2, rt; (s) MeMgBr, THF, ꢁ78 °C; (t) Dess–Martin
periodinane, CH2Cl2, rt, 51% (three-steps).
The stereochemistry of 29 was unambiguously established based
on the NMR analysis of the corresponding acetate 30 (Ac2O, pyri-
dine, 95%) as shown.
shown in Scheme 5. After extensive experimentation on model
compounds, we finally found that the Julia–Kocienski reaction of
methyl ketone 6 with sulfone 7 was best accomplished under mod-
ified conditions using cerium chloride.28,29 Thus, the lithiation of
sulfone 7 with LDA (THF, ꢁ78 °C), followed by addition to ketone
6 in the presence of cerium chloride (ꢁ78 to 0 °C), gave rise to
the desired trisubstituted (E)-olefin 530 in 58% yield, along with
the corresponding (Z)-isomer 34 (18%). The stereochemistry of 5
was established by NOEs, as shown. To the best of our knowledge,
there is no previous example of Julia–Kocienski olefination using
organocerium derivatives.
In summary, we have synthesized the gambieric acids GHIJ-ring
fragment having a side chain through a convergent strategy. Key
reactions of the synthesis include: (i) aldol reaction to couple the
G- and J-rings; (ii) acid-catalyzed cyclodehydration to form the
H-ring; and (iii) a cerium chloride-promoted modified Julia–
Kocienski reaction for stereoselective introduction of the J-ring
side chain. Further studies toward the total synthesis of gambieric
acids are currently underway and will be reported in due course.
Having constructed the tetracyclic ether skeleton, we next
turned our attention to introduction of the side chain to the J-ring.
Thus, the alcohol 29 was elaborated to the requisite precursor,
methyl ketone 6 (Scheme 4). Protection of 29 as the TES ether,
removal of the benzyl ethers by hydrogenolysis, followed by selec-
tive protection of the primary alcohol as the pivaloate ester led to
alcohol 31 in 80% overall yield. Dess–Martin oxidation and Wittig
methylenation, followed by reductive removal of the pivaloyl
group with DIBALH, afforded primary alcohol 32 in 64% yield for
the three-steps. Alcohol 32 was then transformed to methyl ketone
6 by a three-step sequence (51% overall yield), setting the stage for
appending the side chain by Julia–Kocienski olefination.
The required sulfone 7 was prepared from the known alcohol
3327 by the reaction with 1-phenyl-1H-tetrazole-5-thiol under
Mitsunobu conditions, followed by oxidation with mCPBA as
OTES
H
H
Me
H
H
Acknowledgments
O
O
Me
O
t-Bu Si
t-Bu
Me
HO
OTBS
This work was supported by a Grant-in-Aid for Scientific
Research (A) (No. 21241050) from the Japan Society for the Promotion
of Science (JSPS). A research fellowship for K.T. from JSPS is thank-
fully acknowledged.
O
O
O
O
33
H
H
Me
H
6
Me
O
O
a,b
S
OTBS
c
N
N
N
7
N
Ph
OTES
References and notes
H
Me
H
H
O
O
I
Me
OTBS
+
O
Me Me
G
H
O
J
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Me
t-Bu
H
H
H
Me
H
H
H
H
5 (58%)
34 (18%)
NOEs
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TBS
O
TBS
O
Me
7, LDA
additive
+
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Me Me
Me
OTBS
THF
–78 to 0 °C
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O
O
OTBS
H
H
A
CeCl3
none
80% (E/Z = 1.6:1)
38% (E/Z = 1:1)
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O
Me
I Ph3P
OBn
(MeO)2P
OBn
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Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 127–160.
22. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277; (c) Meyer, S. D.; Schreiber, S. L. J. Org. Chem.
1994, 59, 7549.
23. For an example, see: Kawamura, K.; Hinou, H.; Matsuo, G.; Nakata, T.
Tetrahedron Lett. 2003, 44, 5259.
24. Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 2739.
25. (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226; (b) Gemal, A. L.; Luche, J. L. J.
Am. Chem. Soc. 1981, 103, 5454.
B
C
30. Physical data for 5: ½a D24
ꢁ23.1 (c 0.28, CHCl3); IR (neat) 3441, 2954, 1645, 1471,
ꢂ
1083, 835 cmꢁ1 1H NMR (600 MHz, C6D6) d 5.09 (d, J = 8.2 Hz, 1H), 4.82 (s, 1H),
;
4.77 (s, 1H), 4.26 (dd, J = 10.0, 4.8 Hz, 1H), 4.14 (dd, J = 8.6, 3.4 Hz, 1H), 3.90 (dd,
J = 10.0, 10.0 Hz, 1H), 3.79 (ddd, J = 11.0, 9.6, 4.4 Hz, 1H), 3.73 (ddd, J = 10.0, 9.6,
4.8 Hz, 1H), 3.56 (d, J = 9.3 Hz, 1H), 3.51 (dd, J = 9.6, 5.9 Hz, 1H), 3.39 (dd, J = 9.6,
7.2 Hz, 1H), 3.21 (ddd, J = 11.6, 9.6, 4.4 Hz, 1H), 3.14 (dd, J = 12.7, 4.5 Hz, 1H),
3.09 (dd, J = 9.6, 9.3 Hz, 1H), 2.82 (dd, J = 12.4, 3.8 Hz, 1H), 2.68 (m, 1H), 2.58
(dd, J = 13.1, 4.5 Hz, 1H), 2.45 (dd, J = 13.4, 3.4 Hz, 1H), 2.37 (dd, J = 13.1,
12.7 Hz, 1H), 2.32 (dd, J = 13.4, 8.6 Hz, 1H), 2.25 (ddd, J = 11.7, 4.4, 3.8 Hz, 1H),
2.18 (dd, J = 11.4, 4.4 Hz, 1 H), 1.85 (ddd, J = 12.4, 11.7, 11.0 Hz, 1H), 1.69–1.65
(m, 4H), 1.27 (s, 3H), 1.21 (s, 3H), 1.14 (s, 9H), 1.13 (t, J = 7.9 Hz, 9H), 1.08 (s,
9H), 1.05 (d, J = 6.9 Hz, 3H), 0.99 (s, 9H), 0.78 (q, J = 7.9 Hz, 6H), 0.07 (s, 3 H),
0.07 (s, 3H); 13C NMR (150 MHz, C6D6) d 146.0, 132.8, 130.1, 110.0, 83.8, 82.3,
78.5, 78.4, 77.9, 77.2, 74.4, 72.9, 70.3, 69.4, 68.4, 68.2, 43.9, 42.5, 35.9, 35.5,
33.8, 27.7 (3C), 27.3 (3C), 26.1 (3C), 22.8, 20.1, 18.5, 17.7, 16.9, 15.9, 10.5, 7.2
(3C), 5.5 (3C), ꢁ5.1, ꢁ5.2; HRMS (ESI) calcd for C45H84O8Si3Na [(M+Na)+]
859.5366, found 859.5388.
26. Direct treatment of 28 with Et3SiH and TMSOTf in propionitrile at ꢁ78 °C
afforded 29 as a single diastereomer in a somewhat lower yield (72%).
27. Jones, T. K.; Reamer, R. A.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998; For the
synthesis of ent-7, see: Brandl, T.; Hoffmann, R. W. Eur. J. Org. Chem. 2004, 4373.
28. Pioneering works on organocerium reagents in organic synthesis, see: (a)
Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.;