Studies toward the total synthesis of gambieric acids: Stereocontrolled synthesis of a DEFG-ring model compound

Article abstract of DOI:10.1021/jo1008146

(Figure presented) A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki- Miyaura coupling. Conformational analysis of the model compound revealed that the nine-membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.

Full text of DOI:10.1021/jo1008146

pubs.acs.org/joc
Studies toward the Total Synthesis of Gambieric Acids: Stereocontrolled
Synthesis of a DEFG-Ring Model Compound
Haruhiko Fuwa,* Sayaka Noji, and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University,
2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
hfuwa@bios.tohoku.ac.jp; masasaki@bios.tohoku.ac.jp
Received April 26, 2010
A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly
potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki
;
Miyaura coupling. Conformational analysis of the model compound revealed that the nine-
membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.
Introduction
B) with minimal toxicity against mice or cultured mammalian
cells,4 although the biochemical mode of action remains to be
unraveled because of the lack of material supply from natural
sources. GAA is also known to displace tritium-labeled dihy-
drobrevetoxin-B ([3H]PbTx-3) bound to voltage-sensitive so-
dium ion channels (VSSCs) in micromolar concentrations.5
Nagai and co-workers reported that GAA acts as an endogen-
ous growth-regulating factor of G. toxicus.6 These intriguing
structural and biological aspects of GAs gained significant
interest from synthetic organic chemists.7
Gambieric acids (GAs), isolated from a strain of the
ciguatera causative dinoflagellate Gambierdiscus toxicus by
Yasumoto and co-workers, are structurally characterized by
the nonacyclic polyether core structure decorated with a
complex side chain containing a 2,5-trans-substituted tetra-
hydrofuran ring (Figure 1).1 The gross structure and partial
relative stereochemistry of gambieric acids was determined
by extensive 2D-NMR studies, and the complete stereo-
structure was subsequently proposed on the basis of degra-
dation experiments, application of the modified Mosher
analysis, and chiral HPLC analysis.2 Recently, chemical
synthesis and NMR analysis of the A/B- and A/BC-ring
model compounds of GAs in our group strongly suggested
that the absolute configuration of the nonacyclic polyether
core is opposite to that of the proposed structure, as shown
in Figure 1.3 Gambieric acid A (GAA), the representative
congener, displays extremely potent antifungal activity
(approximately 2,000 times more potent than amphotericin
Herein, we report in detail a stereocontrolled convergent
synthesis of the DEFG-ring skeleton 1 of GAs (Scheme 1).8
Our first-generation approach utilized Horner Wadsworth
;
;
Emmons (HWE) coupling as a key fragment assembly
(4) Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T.
J. Antibiot. 1993, 46, 520–522.
(5) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T.
Toxicon 2003, 41, 469–474.
(6) Sakamoto, B.; Nagai, H.; Yasumoto, T. Phycologia 1996, 35, 350–
353.
(7) (a) Kadota, I.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett. 2001, 42,
3645–3647. (b) Kadota, I.; Takamura, H.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 3649–3651. (c) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett.
2004, 6, 1773–1777. (d) Clark, J. S.; Kimber, M. C.; Robertson, J.; McErlean,
C. S. P.; Wilson, C. Angew. Chem., Int. Ed. 2005, 44, 6157–6162. (e) Sato, K.;
Sasaki, M. Org. Lett. 2005, 7, 2441–2444. (f) Roberts, S. W.; Rainier, J. D.
Org. Lett. 2007, 9, 2227–2230. (g) Sato, K.; Sasaki, M. Angew. Chem., Int. Ed.
2007, 46, 2518–2522. (h) Sato, K.; Sasaki, M. Tetrahedron 2007, 63, 5977–
6003. (i) Saito, T.; Nakata, T. Org. Lett. 2009, 11, 113–116.
(8) For a preliminary communication, see: Fuwa, H.; Noji, S.; Sasaki, M.
Chem. Lett. 2009, 38, 866–867.
(1) (a) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, T.;
Hirota, H. J. Am. Chem. Soc. 1992, 114, 1102–1103. (b) Nagai, H.; Murata,
M.; Torigoe, K.; Satake, M.; Yasumoto, T. J. Org. Chem. 1992, 57, 5448–
5453.
(2) Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T.
Tetrahedron 2000, 56, 8995–9001.
(3) (a) Fuwa, H.; Ishigai, K.; Goto, T.; Suzuki, A.; Sasaki, M. J. Org.
Chem. 2009, 74, 4024–4040. (b) Fuwa, H.; Goto, T.; Sasaki, M. Org. Lett.
2008, 10, 2211–2214. (c) Fuwa, H.; Suzuki, A.; Sato, K.; Sasaki, M.
Heterocycles 2007, 72, 139–144.
5072 J. Org. Chem. 2010, 75, 5072–5082
Published on Web 07/01/2010
DOI: 10.1021/jo1008146
r
2010 American Chemical Society

Fuwa et al.
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FIGURE 1. Structures of gambieric acids A D.
;
SCHEME 2. Synthesis of Aldehyde 6
SCHEME 1. First-Generation Synthesis Plan
to be a suitable means to construct the F-ring of 1, and diene
2 would be available from ester 4 via lactone 3 (Scheme 1).
The major challenge in the synthesis of 4 is the stereoselective
construction of the C25 stereogenic center. Indeed, the lack
of stereocontrol at C25 was a serious drawback in our
previous synthesis of the nonacyclic skeleton of GAs.7g,h
We envisaged that the desired ester 4 would be derived from
enoate 5 via stereoselective 1,4-reduction, and the latter
could be dissected to the D-ring aldehyde 6 and the G-ring
phosphonate 7 through a HWE reaction.
Synthesis of the D-Ring Fragment 6. The synthesis of the
D-ring fragment 6 is summarized in Scheme 2. The known
ester 811 was protected as its TMS ether 9. DIBALH reduc-
tion of 9 then gave aldehyde 6.
process, but this approach eventually proved to be un-
rewarding because of the difficulty in controlling the stereo-
chemistry of the C25 stereogenic center. The second-generation
Synthesis of the G-Ring Phosphonate 7. We started the
synthesis of the G-ring fragment 7 from the known alco-
hol 1012 (Scheme 3). A three-step sequence that involved
approach relied on Suzuki Miyaura coupling9 for the con-
Parihk Doering oxidation,13 Grignard reaction, and PCC
;
;
vergent union of the D- and G-ring fragments. The C25
stereogenic center was successfully defined by making use of
the intrinsic substrate bias of seven-membered cyclic ethers.
oxidation gave methyl ketone 11. Wittig methylenation of 11
with Ph3PdCH2 gave olefin 12. Stereoselective hydrobora-
tion of 12 using dicyclohexylborane in THF at room tem-
perature followed by alkaline peroxide workup afforded
alcohol 13 in 89% yield as a single stereoisomer.14 Oxidation
of 13 followed by Wittig methylenation delivered olefin 14.
The stereochemistry of the newly generated stereogenic
center was determined by NMR analysis of lactone A derived
Results and Discussion
First-Generation Synthesis Plan toward the DEFG-Ring
Skeleton. As already described in previous reports from this
laboratory, ring-closing metathesis (RCM)10 was considered
(9) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457–2483. (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4544–4568. (c) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633–9695. (d) Suzuki, A. Chem. Commun. 2005,
4759–4763.
(11) Morita, M.; Haketa, T.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10,
1679–1682.
(12) Nicolaou, K. C.; Hwang, C. K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am. Chem. Soc.
1990, 112, 3040–3054.
(10) For recent reviews, see: (a) Hoveyda, A. H.; Zhugralin, A. R. Nature
2007, 450, 243–251. (b) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int.
Ed. 2006, 45, 6086–6101. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (d) Deiters, A.; Martin, S. F.
Chem. Rev. 2004, 104, 2199–2238.
(13) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(14) For a related example, see: Toshima, K.; Jyojima, T.; Yamaguchi,
H.; Noguchi, Y.; Yoshida, T.; Murase, H.; Nakata, M.; Matsumura, S.
J. Org. Chem. 1997, 62, 3271–3284.
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SCHEME 3. Synthesis of Phosphonate 7
SCHEME 5. HWE Coupling of 6 and 7
HWE coupling of aldehyde 6 and phosphonate 7 under several
reaction conditions and found that the HWE coupling could
be efficiently achieved under Masamune Roush condi-
;
tions (i-Pr2NEt, LiCl, CH3CN, room temperature)16 to afford
enoate 5 in 75% yield as a 2:1 mixture of geometric isomers,
along withunreacted aldehyde 6in 24% yield (99% yield based
on recovered 6) (Scheme 5). The E/Z isomers were partially
(but not completely) separable by careful flash chromatogra-
phy on silica gel. The major isomer was tentatively assigned as
the E isomer, and this was confirmed at a later stage.
We next investigated stereoselective 1,4-reduction of eno-
ate 5 as summarized in Table 1. Enoate 5 was used as a 1:1
mixture of E/Z isomers. Treatment of 5 with magnesium
metal in MeOH gave a 1:3 mixture of 4 and 25-epi-4 in 73%
combined yield (entry 1). 1,4-Reduction of 5 by the action of
NiCl2/NaBH4 in wet MeOH17 accompanied concomitant
reduction of the terminal olefin, giving a 1:2 mixture of 16
and 25-epi-16 in 82% yield (entry 2). An attempt to reduce 5
with L-Selectride (EtOH, THF, -70 °C) did not yield any
1,4-reduction product (entry 3). Exposure of 5 to SmI2 in
THF/MeOH (4:1) at 0 °C gave a 1:5 mixture of 4 and 25-epi-4
in 91% yield (entry 4). We also found that the E/Z ratio of 5
did not affect the stereochemical outcome of its 1,4-reduc-
tion with SmI2/MeOH (entry 5). Reduction of 5 with SmI2/
MeOH in the presence of HMPA (THF, -78 °C) yielded a
1:2 mixture of 4 and 25-epi-4 in 97% yield (entry 6). Esters 4
and 25-epi-4 were separable by flash chromatography on
silica gel.
SCHEME 4. Derivatization of 14 to Lactone A
from olefin 14 (Scheme 4). The stereochemical outcome of
the hydroboration could be explained by considering the
conformation of olefin 12 (Figure 2). The TBS group within
14 was removed by treatment with TBAF, and the resultant
alcohol 15 was reacted with diazophosphonate 16 in the
presence of a catalytic amount of Rh2(OAc)4 in toluene at
100 °C to afford phosphonate 7 in good yield (80% yield
after one recycle).15
The stereochemistry of the major diastereomer 25-epi-4
was confirmed by its derivatization to lactone 25-epi-3 in
a three-step sequence involving deprotection of the TMS
group, saponification of the methyl ester, and ensuing lacto-
nization under Yamaguchi conditions18 (Scheme 6). The
observed NOE enhancement between 25-H and the C21
methyl group supported the undesired stereochemistry of
the C25 stereogenic center. Unfortunately, attempts to epi-
merize ester 25-epi-4 or lactone 25-epi-3 by base treatment
were not feasible.
FIGURE 2. Plausible rationale for the stereochemical outcome of
the hydroboration of olefin 12.
These disappointing results could be ascribed to the
intrinsic substrate bias of enoate 5; the si faces of (E)-5 and
Fragment Assembly and Investigations on the Stereoselective
Construction of the C25 Stereogenic Center. We examined
(15) (a) Paquet, F.; Sinay, P. Tetrahedron Lett. 1984, 25, 3071–3074.
(b) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985, 50, 5223–
5330. (c) Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron 1992, 48,
3991–4004. (d) Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.;
Kulagowski, J. J. Tetrahedron 1994, 50, 3195–3212.
(16) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
(17) Khurana, J. M.; Sharma, P. Bull. Chem. Soc. Jpn. 2004, 77, 549–552.
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
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TABLE 1. Screening of Reaction Conditions for 1,4-Reduction of 5
FIGURE 3. Plausible rationale for the stereochemical outcome of
the 1,4-reduction of enoate 5. The geometry of the double bond is
arbitrary.
obtained in only 20% yield from acid (Z)-19. We reasoned
the formation of lactone 17 from acid (Z)-19 occurred via
partial generation of a ketene from the intermediary acti-
vated mixed anhydride.19 From the reactivity difference
between acids (E)-19 and (Z)-19, we concluded that the
major isomer obtained in the HWE coupling of aldehyde 6
and phosphonate 7 was (E)-5. Unfortunately, our efforts to
reduce R,β-unsaturated lactone 17 in a chemo- and stereo-
selective manner gave only disappointing results. For exam-
ple, 1,4-reduction of R,β-unsaturated lactone 17 with SmI2
in THF/MeOH at 0 °C gave only a complex mixture of
unidentified products, whereas hydrogenation of 17 (H2
(0.8 MPa), THF/MeOH, room temperature) proceeded with
poor diastereoselectivity (dr 1.4:1) and accompanied satura-
tion of the terminal olefin.
entrya
reagents and conditions
products (yield,b drc)
1
2
3
Mg, MeOH, room temperature
NiCl2, NaBH4, MeOH, 0 °C
4 þ 25-epi-4 (73%, 1:3)
16 þ 25-epi-16 (82%, 1:2)
L-Selectride, EtOH, THF, -70 °C no reaction
4
SmI2, THF/MeOH (4:1), 0 °C
SmI2, THF/MeOH (4:1), 0 °C
4 þ 25-epi-4 (91%, 1:5)
5d
6
4 þ 25-epi-4 (90%, 1:5)
SmI2, HMPA, THF/MeOH (4:1), 4 þ 25-epi-4 (97%, 1:2)
-78 °C
aUnless otherwise stated, all reactions were carried out using 5
(E:Z = 1:1). bYields are based on a purified mixture of 4 and 25-epi-4
(or 16 and 25-epi-16). cDiastereomer ratios were determined on the basis
of 1H NMR analysis (500 MHz). dThe reaction was carried out using 5
(E:Z = 2:5).
The difficulties encountered during the investigations on
1,4-reduction of ester 5 and R,β-unsaturated lactone 17 led us
to revise the initial synthetic plan toward the DEFG-ring
skeleton 1.
Second-Generation Synthesis Plan toward the DEFG-Ring
Skeleton. At this stage, it occurred to us that the C25 stereo-
genic center could be defined by making use of the intrinsic
substrate bias of endocyclic enol ethers. More specifically, we
envisioned stereoselective hydroboration of seven-membered
endocyclic enol ether 20 as a suitable means to settle the
C25 stereogenic center, and the resultant alcohol 21 would
be easily elaborated to ester 4, the key intermediate in the
first-generation synthesis plan, via oxidative cleavage of the
seven-membered ether ring (Scheme 8). Endocyclic enol
ether 20 was planned to be synthesized from the D-ring
SCHEME 6. Derivatization of 25-epi-4 to 25-epi-3
olefin 22 and the (F)G-ring enol phosphate 23 via Suzuki
Miyaura coupling.20
;
Synthesis of the D-Ring Olefin 22. The D-ring olefin 22
was synthesized from silyl ether 9 (Scheme 9). A two-stage
reduction of 9 gave alcohol 24 in a nearly quantitative yield.
€
(19) For an example, see: Furstner, A.; Nevado, C.; Waser, M.; Tremblay,
M.; Chevrier, C.; Teply, F.; Aıssa, C.; Moulin, E.; Muller, O. J. Am. Chem. Soc.
(Z)-5 would be sterically encumbered by the G-ring tetra-
hydropyran (Figure 3).
ꢀ
€
¨
2007, 129, 9150–9161.
(20) For the synthesis of polycyclic ethers based on Suzuki Miyaura
;
We have also explored 1,4-reduction of R,β-unsaturated
lactone 17 to see whether the cyclic constraint of the seven-
membered lactone ring might be exploited to construct the
C25 stereogenic center in a stereoselective fashion (Scheme 7).
Deprotection of the TMS group within enoate 5 (E:Z = 3:1)
gave alcohols (E)-18 and (Z)-18, which were separable by
flash chromatography on silica gel. These alcohols were
individually hydrolyzed to give the respective carboxylic
acids (E)-19 and (Z)-19. Lactonization of acid (E)-19 under
Yamaguchi conditions afforded R,β-unsaturated lactone 17
in 98% yield. By contrast, the desired lactone 17 was
coupling, see: (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetra-
hedron Lett. 1998, 39, 9027–9031. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.;
Tachibana, K. Org. Lett. 1999, 1, 1075–1077. (c) Sasaki, M.; Ishikawa, M.;
Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889–1911. (d) Fuwa, H.;
Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124,
14983–14992. (e) Tsukano, C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc.
2005, 127, 4326–4335. (f) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden,
D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989–16999. (g) Nicolaou,
K. C.; Frederick, M. O.; Burtoloso, A. C. B.; Denton, R. M.; Rivas, F.; Cole,
K. P.; Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki, T. J. Am. Chem. Soc.
2008, 130, 7466–7476. (h) Nicolaou, K. C.; Aversa, R. J.; Jin, J.; Rivas, F.
J. Am. Chem. Soc. 2010, 132, 6855–6861. See also: (i) Sasaki, M.; Fuwa, H.
Nat. Prod. Rep. 2008, 25, 401–426. (j) Sasaki, M.; Fuwa, H. Synlett 2004,
1851–1874.
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SCHEME 7. Synthesis of R,β-Unsaturated Lactone 17 and Its
Attempted Reduction
SCHEME 8. Second-Generation Approach toward the DEFG-
Ring Skeleton 1
SCHEME 9. Synthesis of Olefin 22
to seven-membered lactone 30 in 90% yield, which was
treated with KHMDS in the presence of (PhO)2P(O)Cl22 to
furnish the (F)G-ring enol phosphate 23.
Fragment Assembly and Stereoselective Synthesis of Ester
4. The fragments 22 and 23 were assembled by means of
Suzuki Miyaura coupling (Scheme 11). Thus, hydroboration
;
of olefin 22 with 9-BBN-H in THF at room temperature
generated an alkylborane. This was, without isolation, treated
with aqueous Cs2CO3 and then with enol phosphate 23 and
Pd(PPh3)4 (10 mol %) in DMF at 50 °C, giving rise to
endocyclic enol ether 20 in 96% yield. Hydroboration of 20
Mesylation of 24 and treatment with PhSeSePh/NaBH4
yielded selenide 25 in 96% yield for the two steps. Finally,
oxidation of 25 with mCPBA and in situ treatment with Et3N
afforded olefin 22 in 85% yield (90% based on recovered 25).
Synthesis of the (F)G-Ring Enol Phosphate 23. The synthe-
sis of the (F)G-ring enol phosphate 23 commenced with
oxidation of alcohol 13 followed by Wittig reaction using
Ph3PdCHCO2Et to give enoate 26 in 87% yield for the
two steps (Scheme 10). Hydrogenation of 26 gave ester 27 in
100% yield. Reduction of 27 with LiAlH4 delivered alcohol
28 (100% yield), which was treated with acidic methanol to
remove the TBS group to afford diol 29 in 100% yield.
Oxidative lactonization of 29 with TEMPO/PhI(OAc)221 led
with BH3 SMe2 followed by alkaline oxidative workup gave a
3
2:1 mixture of diastereomeric alcohols 21 and 210 in 100% yield.
Although we found that epoxidation of 20 with dimethyldioxi-
rane (DMDO) and in situ reduction of the resultant epoxide23
proceeded in a stereoselective manner, the product yield was
moderate (30-54% yield), and several unidentified byproducts
€
(22) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Gartner, P.; Yang, Z.
J. Am. Chem. Soc. 1997, 119, 5467–5468.
(23) (a) Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.;
Honma, T.; Murai, A. J. Org. Chem. 1999, 64, 2616–2617. (b) Allwein, S. P.;
Cox, J. M.; Howard, B. E.; Johnson, H. W. B.; Rainier, J. D. Tetrahedron
2002, 58, 1997–2009. (c) Orendt, A. M.; Roberts, S. W.; Rainier, J. D. J. Org.
Chem. 2006, 71, 5565–5573.
(21) Ebine, M.; Suga, Y.; Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2010,
8, 39–42.
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SCHEME 10. Synthesis of Enol Phosphate 23
a later stage. The stereochemistry of the C25 stereogenic center
was established by an NOE experiment as shown.
Having defined the C25 stereogenic center, ketone 31 was
elaborated to the key intermediate ester 4 via oxidative
cleavage of the seven-membered ether ring. Enolization of
ketone 31 with LHMDS in the presence of TMSCl/Et3N
gave the corresponding enol silane, which was oxidized with
OsO4/NMO to deliver R-hydroxy ketone 32 as an incon-
sequential 1.2:1 mixture of diastereomers (86% yield for the
two steps). Treatment of 32 with Pb(OAc)4 in the presence of
NaHCO3 in MeOH/benzene resulted in a cleavage of the
seven-membered ether ring. The resultant aldehyde-ester 33
was immediately exposed to Ph3PdCH2 to afford ester 4 in
84% yield for the two steps. The stereochemical integrity
of the C25 stereogenic center was unaffected during these
synthetic manipulations, as judged by 1H NMR analysis of
ester 4. Thus, we were able to synthesize the key intermediate
ester 4 in a highly stereocontrolled manner.
Completion of the Synthesis of the DEFG-Ring Skeleton 1.
Elaboration of ester 4 into the targeted DEFG-ring skeleton
1 is summarized in Scheme 12. Desilylation of 4 with TBAF/
AcOH gave alcohol 34 in 100% yield. Saponification of the
methyl ester of 34 yielded hydroxy acid 35 in 88% yield.
At this stage, the minor C25 epimer was removed by flash
chromatography on silica gel. Lactonization of 35 under
Yamaguchi conditions afforded seven-membered lactone 3
in 90% yield. Reduction of 3 with DIBALH and in situ
acetylation according to the Rychnovsky protocol25 gave
R-acetoxy ether 36 in 97% yield as a 5.2:1 mixture of
diastereomers. The stereochemistry of the C26 stereogenic
center of the major isomer was tentatively assigned as R on
the basis of our previous experience.7e,g,h We then examined
stereoselective allylation of 36 with allyltrimethylsilane in the
presence of Lewis acid under various conditions. The best
were generated alongside. Therefore, we examined base-pro-
moted epimerization after oxidization of the diastereomeric
mixture of alcohols 21 and 210 with TPAP/NMO24 in 99%
yield. Gratifyingly, treatment of a 2:1 mixture of 31 and 25-epi-
31 with excess DBU in toluene at 100 °C resulted in significant
enrichment of the desired 31 (dr 14:1) with quantitative ma-
terial recovery. The minor diastereomer at C25 was removed at
SCHEME 11. Stereoselective Synthesis of Ester 4
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SCHEME 12. Completion of the Synthesis of the DEFG-Ring Skeleton 1
result was obtained when 36 was treated with BF3 OEt2 and
of the olefinic and the neighboring methylene protons signi-
ficantly broadened due to the slow conformational change of
the FG-ring moiety.28 More specifically, tetracyclic ether 37
exists as an interconvertable mixture of UP and DOWN
conformers, both of which had been successfully characterized
by recording NMR spectra at low temperature. Such confor-
mational behavior had also been reported for the F-ring of
ciguatoxins.29 Furthermore, recent studies by Hirama, Inoue,
and co-workers indicated that the conformational flexibility of
the F-ring of ciguatoxins is critically important for their potent
biological activities.30 Intrigued by the striking conformational
difference observed between 1 and 37, we analyzed the con-
3
excess allyltrimethylsilane in the presence of 4 A molecular
sieves in CH3CN/CH2Cl2 at -40 °C to room temperature.
This allylation was accompanied by cleavage of the benzy-
lidene acetal to give a diol. After acetylation of the resultant
diol, diene 2 was isolated in 56% yield for the two steps as a
single stereoisomer. The stereochemical outcome of the
allylation can be ascribed to the presence of the axially
disposed C21 methyl group, which would preclude axial
attack of allyltrimethylsilane and enforce the allylation to
proceed from the sterically less encumbered β-face of the
molecule. Finally, RCM of diene 2by its exposure to the Grubbs
second-generation catalyst (G-II)26 in CH2Cl2 at 40 °C furn-
ished the tetracyclic ether 1 in 100% yield, which represents the
DEFG-ring skeleton of GAs. The stereochemistry of 1 was
confirmed by an NOE experiment and 3JH,H analysis as shown.
Conformational Analysis of the Tetracyclic Ether 1. The 1H
NMR spectrum of the tetracyclic ether 1 recorded in CDCl3,
C6D6, or CD3OD/C5D5N (1:1) at 293 K showed a single set
of sharp signals, which is in accordance with that of natural
GAA measured in CD3OD/C5D5N (1:1) at 293 K.1b This
observation suggests that 1 exists as a single stable con-
former. However, this is in sharp contrast to our previous
finding on the 1H NMR spectrum (C5D5N, 298 K) of a struc-
turally related tetracyclic ether 37 representing the E0FGH-
ring skeleton of ciguatoxins (Figure 4),27 wherein the signals
3
formation of 1 on the basis of JH,H values and NOESY
correlations (Figure 5) and found that 1 adopts UP conforma-
tion exclusively. Molecular modeling studies31 suggested that
the DOWN conformer would suffer from severe transannular
interactions between the C30 methyl group and H-27 and
H-32, while such unfavorable nonbonding interactions would
not exist in the UP conformer (Figure 4).
Thus, the NMR spectroscopic analysis and molecular
modeling indicated that the F-ring of 1 exclusively adopts
the UP conformer, where the C30 methyl group acts as a
conformational locking device and does not undergo slow
conformational change as observed for ciguatoxins and the
E0FGH-ring model compound 37. This result suggests that
GAA would also exist solely as an UP conformer.
Conclusion
(24) For a review, see: Ley, S. V.; Normann, J.; Griffith, S. P. Synthesis
1994, 639–666.
(25) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317–
8320.
Although our initially designed strategy based on the
Horner Wadsworth Emmons coupling/1,4-reduction
;
;
(26) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(27) (a) Sasaki, M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett. 1999,
40, 1337–1340. (b) Sasaki, M.; Noguchi, T.; Tachibana, K. J. Org. Chem.
2002, 67, 3301–3310.
(28) For other examples, see: (a) Inoue, M.; Sasaki, M.; Tachibana, K.
Tetrahedron Lett. 1997, 38, 1611–1614. (b) Inoue, M.; Sasaki, M.; Tachibana,
K. Tetrahedron 1999, 55, 10949–10970. (c) Imai, H.; Uehara, H.; Inoue, M.;
Oguri, H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42, 6219–6222.
(d) Inoue, M.; Wang, G. X.; Wang, J.; Hirama, M. Org. Lett. 2002, 4, 1183–
1186. (e) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183–1186. (f) Takai, S.;
Sawada, N.; Isobe, M. J. Org. Chem. 2003, 68, 3225–3231.
(29) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.; Yasumoto,
T. J. Am. Chem. Soc. 1990, 112, 4380–4386.
(30) (a) Inoue, M.; Lee, N.; Miyazaki, K.; Usuki, T.; Matsuoka, S.;
Hirama, M. Angew. Chem., Int. Ed. 2008, 47, 8611–8614. (b) Ishihara, Y.;
Lee, N.; Oshiro, N.; Matsuoka, S.; Yamashita, S.; Inoue, M.; Hirama, M.
Chem. Commun. 2010, 46, 2968–2970.
(31) The UP and DOWN conformers of the DEFG-ring model com-
pound 1 were generated by conformational searches using MMFF force field
(CONFLEX ver. 6.7; CONFLEX Corporation: Tokyo, Japan) and geome-
trically optimized at the HF/6-31G*//PM3 level of theory (Spartan ’08;
Wavefunction, Inc.: Irvine, CA).
5078 J. Org. Chem. Vol. 75, No. 15, 2010

Fuwa et al.
JOCArticle
FIGURE 4. Conformational isomers of 1 and structure of 37.
(hydroboration/oxidation/epimerization) from endocyclic enol
ether 20 to ketone 31. The seven-membered ether ring was then
oxidatively cleaved to yield the key intermediate ester 4. The
E-ring was constructed via Yamaguchi lactonization and
stereoselective allylation as the key steps. Finally, the F-ring
was forged by RCM to complete the synthesis of the DEFG-
ring skeleton 1. Despite its structural similarity to our pre-
viously synthesized ciguatoxin E0FGH-ring model compound
37, the tetracyclic ether 1 was found to exist as a single stable
conformer in solution, where the C30 methyl group acts as a
conformational locking device. Further studies toward the
total synthesis of gambieric acids are currently underway in
our laboratory.
Experimental Section
Endocyclic Enol Ether 20. To a solution of lactone 30
(62.5 mg, 0.340 mmol) in THF (3 mL) were added HMPA
(0.18 mL, 1.0 mmol) and (PhO)2P(O)Cl (0.090 mL, 0.41 mmol),
and the solution was cooled to -78 °C. To this solution
was added KHMDS (0.5 M solution in toluene, 0.90 mL, 0.45
mmol), and the resultant solution was stirred at -78 °C for 1.5 h.
The reaction was quenched with 3% aqueous ammonia solu-
tion. The resultant mixture was diluted with diethyl ether and
allowed to warm to room temperature over a period of 20 min.
The resultant mixture was extracted with EtOAc, and the orga-
nic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
passed through a pad of silica gel (eluted with 20% EtOAc/
hexanes) to give enol phosphate 23, which was immediately used
in the next reaction.
To a solution of olefin 22 (76.4 mg, 0.220 mmol) in THF
(2 mL) was added a freshly prepared solution of 9-BBN-H dimer
(75 mg, 0.31 mmol) in THF (1 mL), and the resultant solution
was stirred at room temperature for 3 h. To this solution was
added 3 M aqueous Cs2CO3 solution (0.22 mL, 0.66 mmol), and
the resultant mixture was stirred at room temperature for
20 min. To this mixture were added a solution of the above
FIGURE 5. Conformational analysis of 1 (600 MHz 1H NMR,
C6D6).
sequence turned out to be unrewarding, we have eventually
succeeded in the synthesis of the DEFG-ring skeleton 1
of gambieric acids in a highly stereocontrolled manner. Suzu-
ki Miyaura coupling was utilized to assemble the D-ring
;
olefin 22 and the (F)G-ring enol phosphate 23, which afforded
endocyclic enol ether 20. The C25 stereogenic center was
successfully defined during the three-step transformation
J. Org. Chem. Vol. 75, No. 15, 2010 5079

Fuwa et al.
JOCArticle
crude enol phosphate 23 in DMF (1 mL þ 0.5 mL rinse) and
Pd(PPh3)4 (25.4 mg, 0.0220 mmol). The resultant mixture was
stirred at 50 °C for 17 h. After being cooled to room tempera-
ture, the reaction mixture was diluted with H2O and extracted
with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on
silica gel (3% to 5% EtOAc/hexanes) gave endocyclic enol ether
resultant solution was heated at 100 °C for 14.5 h. After being
cooled to room temperature, the reaction mixture was direc-
tly purified by flash chromatography on silica gel (10 to 15%
EtOAc/hexanes) to give diastereomerically enriched ketone 31
(0.61 g, 100%, dr 14:1 based on 500 MHz 1H NMR analysis) as a
colorless oil: [R]16D þ43.1 (c 0.88, CHCl3); IR (film) 2955, 1711,
1454, 1377, 1250, 1098, 1046, 867, 840, 753, 698 cm-1; 1H NMR
(500 MHz, C6D6) δ 7.67 (d, J = 7.5 Hz, 2H), 7.21 (dd, J = 7.5,
7.5 Hz, 2H), 7.12 (m, 1H), 5.34 (s, 1H), 4.19 (dd, J = 10.0, 5.0
Hz, 1H), 3.64 (dd, J = 11.5, 4.5 Hz, 1H), 3.55 (dd, J = 9.0, 4.0
Hz, 1H), 3.50 (dd, J = 10.0, 10.0 Hz, 1H), 3.33 (ddd, J = 12.5,
10.0, 4.5 Hz, 1H), 3.26 (ddd, J = 10.0, 10.0, 5.0 Hz, 1H), 3.21
(dd, J = 10.0, 2.0 Hz, 1H), 3.09 (dd, J = 9.5, 5.0 Hz, 1H), 3.00
(ddd, J = 11.5, 11.5, 2.5 Hz, 1H), 2.90 (ddd, J = 9.5, 9.5, 5.0 Hz,
1H), 2.85 (dd, J = 12.0, 2.0 Hz, 1H), 2.22 (dd, J = 11.0, 4.5 Hz,
20 (109.2 mg, 96%) as a colorless oil: [R]20 -41.2 (c 0.37,
D
C6H6); IR (film) 2939, 1455, 1250, 1097, 1016, 867, 839, 751, 417
cm-1; 1H NMR (500 MHz, C6D6) δ 7.67 (d, J = 7.5 Hz, 2H),
7.20 (dd, J = 7.5, 7.5 Hz, 2H), 7.12 (m, 1H), 5.35 (s, 1H), 4.70
(dd, J = 6.0, 6.0 Hz, 1H), 4.26 (dd, J = 10.0, 4.0 Hz, 1H),
3.75 3.65 (m, 2H), 3.53 (dd, J = 10.0, 10.0 Hz, 1H), 3.39 3.27
;
;
(m, 3H), 3.23 (dd, J = 9.0, 4.5 Hz, 1H), 3.02 (ddd, J = 12.0, 12.0,
2.0 Hz, 1H), 2.44 (ddd, J = 15.0, 10.0, 5.0 Hz, 1H), 2.32 (m, 1H),
2.27 2.18 (m, 2H), 2.18 2.08 (m, 2H), 2.05 (br d, J = 10.0 Hz,
1H), 2.20 2.13 (m, 2H), 2.13 2.00 (m, 2H), 1.92 (dd, J = 11.0,
;
11.0 Hz, 1H), 1.87 (m, 1H), 1.64 (m, 1H), 1.53 (m, 1H), 1.40
;
;
;
;
1H), 2.01 (d, J = 6.0 Hz, 1H), 1.95 (m, 1H), 1.63 (dddd, J =
15.0, 10.0, 10.0, 5.0 Hz,1H), 1.53 (dddd, J = 12.0, 12.0, 12.0, 4.0
Hz, 1H), 1.42 (ddddd, J = 13.0, 13.0, 13.0, 4.5, 4.5 Hz, 1H), 1.23
1.25 (m, 2H), 1.25 (s, 3H), 1.15 (m, 1H), 0.98 (d, J = 7.5 Hz, 3H),
0.13 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 216.4, 137.5, 129.1,
128.3 (2C), 126.2 (2C), 101.7, 87.6, 85.6, 83.7, 76.7, 75.3, 74.2,
73.8, 69.5, 67.6, 45.4, 44.1, 32.1, 31.1, 30.7, 25.6, 24.7, 22.4,
12.3, 2.5 (3C); HRMS (ESI) calcd for C29H45O7Si [(M þ H)þ]
533.2929, found 533.2938.
r-Hydroxy Ketone 32. To a solution of ketone 31 (453.5 mg,
0.8524 mmol, ca. 14:1 mixture of diastereomers at C25 stereo-
genic center) in THF (8 mL) were added TMSCl (2.20 mL,
17.3 mmol) and Et3N (2.30 mL, 16.5 mmol), and the resultant
solution was cooled to -78 °C. To this solution was added
freshly prepared LHMDS (1.0 M solution in THF, 4.30 mL,
4.30 mmol), and the resultant solution was stirred at -78 °C for
10 min and then allowed to warm to 0 °C over a period of 45 min.
The reaction was quenched with aqueous pH 7 phosphate
buffer. The resultant mixture was extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude
enol silane was immediately used in the next reaction.
(m, 1H), 1.21 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H), 0.13 (s, 9H); 13
C
NMR (125 MHz, C6D6) δ 159.5, 138.7, 128.9, 128.5, 128.3,
126.8 (2C), 104.5, 101.8, 85.4, 84.9, 76.9, 76.2, 74.9, 74.3, 69.6,
67.7, 46.0, 35.2, 33.3, 31.5, 29.1, 26.7, 26.4, 22.7, 14.4, 2.6 (3C);
HRMS (ESI) calcd for C29H45O6Si [(M þ H)þ] 517.2980, found
517.2987.
Alcohols 21 and 210. To a solution of endocyclic enol ether 20
(10.6 mg, 0.0205 mmol) in THF (1 mL) cooled to 0 °C was added
BH3 SMe2 (1.9 M solution in THF, 0.11 mL, 0.21 mmol), and
3
the resultant solution was stirred at room temperature for
70 min. To this solution cooled to 0 °C were added saturated
aqueous NaHCO3 solution (0.5 mL) and 30% aqueous H2O2
solution (0.3 mL), and the resultant mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with H2O
and extracted with EtOAc. The organic layer was washed with
saturated aqueous Na2S2O3 solution and then brine. The orga-
nic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash
chromatography on silica gel (20 to 25% EtOAc/hexanes) gave
an approximately 2:1 mixture of alcohol 21 and its diastereomer
To a solution of the above crude material in THF/H2O (4:1,
v/v, 8 mL) were added NMO (0.35 mL, 1.7 mmol) and OsO4
(0.039 M solution in t-BuOH, 2.1 mL, 0.082 mmol), and the
resultant mixture was stirred at room temperature for 14 h. The
reaction was quenched with saturated aqueous Na2SO3 solu-
tion. The resultant mixture was extracted with EtOAc, and the
organic layer was washed with H2O and then brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash chroma-
tography on silica gel (20 to 25% EtOAc/hexanes) gave
R-hydroxy ketone 32 (401.7 mg, 86% for two steps) as a 1.2:1
mixture of diastereomers. These diastereomers were separable
upon careful flash chromatography on silica gel. Data for major
210 (11.2 mg, 100%) as a colorless oil: [R]16 -10.1 (c 1.43,
D
CHCl3); IR (film) 3457, 2937, 1454, 1376, 1251, 1141, 1045, 867,
752, 678 cm-1 1H NMR (300 MHz, CDCl3, signals for the
;
major diastereomer) δ 7.46 (dd, J = 8.0, 1.5 Hz, 2H), 7.37 7.29
;
(m, 3H), 5.49 (s, 1H), 4.28 (dd, J = 10.5, 5.0 Hz, 1H), 3.89 (m,
1H), 3.65 (dd, J = 10.5, 10.5 Hz, 1H), 3.60 (m, 1H), 3.50 (ddd,
J = 13.0, 9.5, 4.5 Hz, 1H), 3.34 (ddd, J = 10.0, 10.0, 5.0 Hz, 1H),
3.10 3.08 (m, 4H), 3.03 (dd, J = 9.5, 5.5 Hz, 1H), 2.26 2.14
;
(m, 2H), 2.07 (m, 1H), 2.03 1.80 (m, 5H), 1.70 1.60 (m, 2H),
;
;
;
1.52 1.39 (m, 2H), 1.39 1.22 (m, 2H), 1.27 (s, 3H), 1.09 (d,
diastereomer: [R]26 þ48.9 (c 1.53, CHCl3); IR (film) 3480,
;
;
D
J = 7.0 Hz, 3H), 0.10 (s, 9H); 13C NMR (125 MHz, CDCl3,
signals for the major diastereomer) δ 129.1, 128.33, 128.31 (2C),
126.2 (2C), 101.8, 87.3, 86.0, 84.8, 79.1, 76.8, 76.5, 74.2, 73.9,
69.5, 68.2, 45.4, 38.2, 33.4, 32.4, 31.3, 26.2, 25.3, 22.4, 15.0,
2.6 (3C); HRMS (ESI) calcd for C29H46O7SiNa [(M þ Na)þ]
557.2911, found 557.2915.
2941, 2857, 1712, 1377, 1251, 1141, 1098, 1074, 997, 867, 840
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.46 (br d, J = 6.5 Hz,
2H), 7.37 7.29 (m, 3H), 5.48 (s, 1H), 4.75 (dd, J = 4.5, 4.5 Hz,
;
1H), 4.26 (dd, J = 10.0, 5.0 Hz, 1H), 3.91 (dd, J = 11.0, 3.5 Hz,
1H), 3.86 (dd, J = 10.0, 3.5 Hz, 1H), 3.67 (m, 1H), 3.64 (dd, J =
10.0, 10.0 Hz, 1H), 3.49 (ddd, J = 13.5, 9.0, 4.5 Hz, 1H), 3.43
(dd, J = 10.0, 5.0 Hz, 1H), 3.36 (ddd, J = 12.0, 12.0, 2.0 Hz,
Ketone 31. To a solution of an approximately 2:1 mixture of
alcohol 21 and its diastereomer 210 (633.6 mg, 1.19 mmol) in
CH2Cl2 (11 mL) were added 4 A molecular sieves (ca. 0.6 g),
NMO (697 mg, 5.95 mmol), and TPAP (42 mg, 0.12 mmol), and
the resultant mixture was stirred at room temperature for 1 h.
The reaction mixture was diluted with EtOAc and passed
through a pad of silica gel. The filtrate was concentrated under
reduced pressure to give an approximately 2:1 mixture of ketone
31 and its C25-epimer 25-epi-31 (620.9 mg, 99%).
1H), 3.31 (ddd, J = 9.0, 9.0, 4.5 Hz, 1H), 3.20 3.10 (m, 2H),
;
2.46 (ddd, J = 11.0, 3.5, 3.5 Hz, 1H), 2.23 (dd, J = 11.5, 4.5 Hz,
1H), 2.14 (dd, J = 12.0, 3.0, 1H), 2.02 (m, 1H), 1.91 1.78
;
(m, 2H), 1.68 (br d, J = 13.0 Hz, 1H), 1.65 1.44 (m, 3H), 1.35
;
(m, 1H), 1.25 (s, 3H), 0.78 (d, J = 7.5 Hz, 3H), 0.10 (s, 9H); 13
C
NMR (125 MHz, CDCl3) δ 215.6, 137.4, 129.1, 128.3 (2C), 126.1
(2C), 101.7, 86.4, 85.5, 81.7, 76.6, 75.52, 75.51, 74.2, 73.8,
69.4, 67.6, 45.3, 40.9, 31.1, 30.8, 25.4, 24.5, 22.3, 7.8, 2.5 (3C);
HRMS (ESI) calcd for C29H45O8Si [(M þ H)þ] 549.2878, found
To a solution of an approximately 2:1 mixture of ketone 31
and its C25-epimer 25-epi-31 (0.60 g, 1.1 mmol) in toluene
(11 mL) was added DBU (1.67 mL, 11.2 mmol), and the
25
549.2878. Data for minor diastereomer: [R]D -2.8 (c 1.07,
CHCl3); IR (film) 3500, 2927, 2854, 1716, 1377, 1251, 1097, 867,
5080 J. Org. Chem. Vol. 75, No. 15, 2010

Fuwa et al.
JOCArticle
840, 753, 423 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J =
6.5 Hz, 2H), 7.37 7.29 (m, 3H), 5.48 (s, 1H), 4.26 (dd, J = 10.0,
4.5 Hz, 1H), 4.03 (dd, J = 11.5, 6.5 Hz, 1H), 3.91 (dd, J = 12.0,
4.0 Hz, 1H), 3.84 (dd, J = 10.0, 4.0 Hz, 1H), 3.64 (dd, J = 10.5,
10.5 Hz, 1H), 3.59 (dd, J = 9.5, 5.0 Hz, 1H), 3.49 (ddd, J = 12.0,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography
on silica gel (20 to 40% EtOAc/hexanes) gave alcohol 34 (55 mg,
100%, ca. 12-13:1 mixture of diastereomers at C25 stereogenic
;
center) as a colorless foam: [R]25 þ28.5 (c 0.70, CHCl3); IR
D
9.0, 4.5 Hz, 1H), 3.40 3.27 (m, 2H), 3.27 3.18 (m, 2H), 3.18
(film) 3483, 2936, 2869, 1752, 1453, 1370, 1093, 1002, 699, 412
;
;
(br d, J = 10.0 Hz, 1H), 2.55 (ddd, J = 14.5, 7.0, 7.0 Hz, 1H),
2.23 (dd, J = 11.5, 4.5 Hz, 1H), 2.15 (br d, J = 12.0 Hz, 1H),
2.04 (m, 1H), 1.93 (m, 1H), 1.82 (dd, J = 12.0, 12.0 Hz, 1H),
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.46 (dd, J = 7.5, 1.0 Hz,
2H), 7.38 7.29 (m, 3H), 5.88 (m, 1H), 5.49 (s, 1H), 5.022 (d, J =
;
11.5 Hz, 1H), 5.017 (d, J = 16.0 Hz, 1H), 4.27 (dd, J = 11.0, 4.5
Hz, 1H), 4.05 (dd, J = 8.0, 4.5 Hz, 1H), 3.87 (dd, J = 11.0, 4.5
Hz, 1H), 3.70 (s, 3H), 3.64 (dd, J = 10.0, 10.0 Hz, 1H), 3.52 (ddd,
J = 13.0, 9.0, 4.0 Hz, 1H), 3.34 3.21 (m, 3H), 3.18 (br d, J =
;
9.0, 1H), 3.06 (dd, J = 9.0, 1.5 Hz, 1H), 2.82 (ddd, J = 14.0, 7.0,
1.77 1.65 (m, 2H), 1.56 (m, 1H), 1.38 1.28 (m, 2H), 1.26 (s,
;
;
3H), 0.84 (d, J = 7.5 Hz, 3H), 0.11 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 212.0, 137.4, 129.1, 128.3 (2C), 126.1 (2C), 101.7, 88.1,
85.5, 82.5, 79.1, 76.6, 75.6, 74.2, 73.8, 69.4, 67.8, 45.4, 37.6, 31.8,
30.9, 25.4, 25.0, 22.3, 9.7, 2.5 (3C); HRMS (ESI) calcd for
C29H44O8SiNa [(M þ Na)þ] 571.2698, found 571.2699.
7.0 Hz, 1H), 2.24 2.16 (m, 2H), 1.96 (m, 1H), 1.86 1.48 (m,
;
;
6H), 1.38 1.24 (m, 2H), 1.24 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H);
;
Ester 4. To a solution of R-hydroxy ketone 32 (14.9 mg,
0.0272 mmol) in benzene/MeOH (2:1, v/v, 0.9 mL) cooled to
0 °C was added Pb(OAc)4 (14.6 mg, 0.0330 mmol), and the
resultant mixture was stirred at room temperature for 35 min.
The reaction was quenched with saturated aqueous NaHCO3
solution, and the resultant mixture was filtered through a pad of
Celite. The filtrate was diluted with H2O and extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica
gel (20% EtOAc/hexanes) gave ester-aldehyde 33 (15.5 mg, ca.
99%), which was immediately used in the next reaction.
13C NMR (125 MHz, CDCl3) δ 173.0, 139.6, 137.3, 129.1, 128.3
(2C), 126.1 (2C), 115.0, 101.7, 85.1, 84.4, 76.6, 75.4, 74.2, 73.7,
71.1, 69.3, 67.7, 51.8, 45.1, 37.2, 30.6, 29.0, 25.0, 24.3, 21.7, 17.7;
HRMS (ESI) calcd for C28H40O8Na [(M þ Na)þ] 527.2615,
found 527.2604.
Carboxylic Acid 35. To a solution of alcohol 34 (258.4 mg,
0.5127 mmol, ca. 12-13:1 mixture of diastereomers at C25
stereogenic center) in THF/MeOH/H2O (1:1:1, v/v/v, 4.5 mL)
cooled to 0 °C was added LiOH H2O (33 mg, 0.79 mmol), and
3
the resultant mixture was stirred vigorously at room tempera-
ture for 4 h 15 min. The reaction mixture was cooled to 0 °C and
carefully acidified with 1 M aqueous HCl solution (pH ca. 4).
The resultant mixture was extracted repeatedly with CHCl3, and
the organic layer was dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (40% EtOAc/hexanes) gave
carboxylic acid 35 (222.2 mg, 88%) as a colorless oil. The minor
C25-epimer was removed at this stage. Data for 35: [R]25D þ13.0
(c 0.55, CHCl3); IR (film) 3436, 2935, 2869, 1725, 1455, 1370,
1093, 1006, 758, 680 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.46
To a suspension of Ph3PþCH3Br- (50 mg, 0.14 mmol) in THF
(1 mL) cooled to 0 °C was added NaHMDS (1.0 M solution in
THF, 0.10 mL, 0.10 mmol), and the resultant suspension was
stirred at 0 °C for 30 min. To this suspension was added a
solution of the above ester-aldehyde 33 (15.5 mg) in THF
(0.5 mL þ 0.2 mL rinse twice), and the resultant mixture was
stirred at 0 °C for 35 min. The reaction was quenched with
saturated aqueous NH4Cl solution. The resultant mixture was
diluted with EtOAc and washed with brine. The organic layer
was dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Purification of the residue by flash chromato-
graphy on silica gel (10 to 12% EtOAc/hexanes) gave ester 4
(dd, J = 7.5, 1.5 Hz, 2H), 7.38 7.30 (m, 3H), 5.89 (m, 1H), 5.50
;
(s, 1H), 5.07 5.00 (m, 2H), 4.27 (dd, J = 10.0, 5.0 Hz, 1H), 4.12
;
(dd, J = 6.0, 6.0 Hz, 1H), 3.89 (br d, J = 11.0 Hz, 1H), 3.67 (dd,
J = 10.0, 10.0 Hz, 1H), 3.53 (ddd, J = 13.0, 9.0, 4.5 Hz, 1H),
3.35 3.24 (m, 3H), 3.20 (d, J = 9.0 Hz, 1H), 3.09 (dd, J = 9.0,
1
(13.2 mg, 84% for the two steps) as a colorless oil. H NMR
;
2.0 Hz, 1H), 2.71 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.23 2.14 (m,
analysis of this material indicated that it was an approximately
12-13:1 mixture of diastereomers at C25 stereogenic center.
Data for 4: [R]17D þ19.2 (c 1.59, CHCl3); IR (film) 2952, 1752,
1375, 1251, 1142, 1098, 1002, 867, 840, 752, 698 cm-1; 1H NMR
;
2H), 2.04 (m, 1H), 1.84 1.72 (m, 3H), 1.67 (m, 1H), 1.56 (m,
;
1H), 1.46 1.33 (m, 2H), 1.25 (s, 3H), 1.24 (m, 1H), 1.10 (d, J =
;
7.0 Hz, 3H) (carboxylic acid proton is missing due to H/D
exchange); 13C NMR (125 MHz, CDCl3) δ 175.8, 139.7, 137.3,
129.1, 128.3 (2C), 126.2 (2C), 115.3, 101.7, 84.9, 84.0, 76.6, 75.4,
74.7, 74.3, 71.2, 69.3, 67.6, 45.0, 37.9, 30.4, 29.4, 25.0, 23.7, 21.6,
17.7; HRMS (ESI) calcd for C27H39O8 [(M þ H)þ] 491.2639,
found 491.2632.
(500 MHz, CDCl3) δ 7.46 (br d, J = 6.5 Hz, 2H), 7.38 7.30 (m,
;
3H), 5.88 (m, 1H), 5.48 (s, 1H), 5.03 (d, J = 12.0 Hz, 1H), 5.02
(dd, J = 16.0, 1.0 Hz, 1H), 4.27 (dd, J = 10.0, 4.5 Hz, 1H), 4.03
(dd, J = 8.5, 5.5 Hz, 1H), 3.88 (dd, J = 11.0, 4.5 Hz, 1H), 3.70 (s,
3H), 3.65 (dd, J = 10.0, 10.0 Hz, 1H), 3.49 (ddd, J = 12.5, 9.0,
4.0 Hz, 1H), 3.31 (ddd, J = 9.5, 9.5, 4.5 Hz, 1H), 3.28 3.21 (m,
Lactone 3. To a solution of carboxylic acid 35 (214.4 mg,
0.4378 mmol) in THF (8.8 mL) cooled to 0 °C were added Et3N
(0.130 mL, 0.933 mmol) and 2,4,6-Cl3C6H2COCl (0.200 mL,
1.28 mmol). The resultant mixture was stirred at room tempera-
ture for 40 min before being diluted with toluene (35 mL). The
mixed anhydride solution thus obtained was added dropwise to
a solution of DMAP (318 mg, 2.61 mmol) in toluene (44 mL)
heated at 100 °C over a period of 6 h. The reaction mixture was
cooled to room temperature, diluted with EtOAc, and washed
successively with 1 M aqueous HCl solution, saturated aqueous
NaHCO3 solution, and then brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography
on silica gel (10 to 30% EtOAc/hexanes) gave lactone 3 (185.9
mg, 90%) as amorphous solid: [R]24D þ40.9 (c 1.00, CHCl3); IR
(film) 2932, 2860, 1718, 1455, 1293, 1206, 1070, 1035, 752, 699,
;
2H), 3.16 (br d, J = 8.0 Hz, 1H), 3.03 (dd, J = 8.5, 1.5 Hz, 1H),
2.83 (ddd, J = 14.5, 7.0, 7.0 Hz, 1H), 2.22 (ddd, J = 11.0, 11.0,
4.5 Hz, 2H), 1.93 (m, 1H), 1.87 1.78 (m, 2H), 1.74 1.48 (m,
;
;
3H), 1.34 1.20 (m, 2H), 1.25 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H),
;
0.10 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.1, 139.6, 137.4,
129.1, 128.4 (2C), 126.2 (2C), 115.0, 109.7, 101.8, 85.5, 84.6,
76.7, 75.6, 74.3, 73.8, 69.4, 67.8, 51.7, 45.4, 37.2, 30.9, 29.2, 25.1,
24.3, 22.4, 17.8, 2.5 (3C); HRMS (ESI) calcd for C31H48O8SiNa
[(M þ Na)þ] 599.3011, found 599.3022.
Alcohol 34. A stock solution of TBAF/AcOH was prepared
from TBAF (1.0 M solution in THF, 5.00 mL, 5.00 mmol),
AcOH (0.300 mL, 5.25 mmol), and THF (4.7 mL). To a solu-
tion of ester 4 (59 mg, 0.10 mmol) in THF (1 mL) was added
the above stock solution of TBAF/AcOH (1.00 mL), and the
resultant solution was stirred at room temperature for 3 h. The
reaction mixture was diluted with EtOAc and washed succes-
sively with saturated aqueous NH4Cl solution, saturated aqu-
eous NaHCO3 solution, and then brine. The organic layer was
419 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.48 7.44 (m, 2H),
;
7.38 7.30 (m, 3H), 5.80 (ddd, J = 17.5, 10.5, 8.5 Hz, 1H), 5.51
;
(s, 1H), 5.08 (d, J = 17.5 Hz, 1H), 5.06 (d, J = 9.0 Hz, 1H), 4.42
J. Org. Chem. Vol. 75, No. 15, 2010 5081

Fuwa et al.
JOCArticle
(d, J = 4.5 Hz, 1H), 4.29 (dd, J = 10.5, 4.5 Hz, 1H), 3.88 (ddd,
J = 11.0, 2.0, 2.0 Hz, 1H), 3.68 (dd, J = 10.5, 10.5 Hz, 1H), 3.56
(ddd, J = 13.5, 9.5, 4.5 Hz, 1H), 3.48 3.33 (m, 3H), 3.25 (ddd,
J = 11.0, 11.0, 2.5 Hz, 1H), 3.03 (dd, J = 9.0, 2.0 Hz, 1H), 2.66
(ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.41 (dd, J = 12.0, 4.5 Hz, 1H),
2.17 (m, 1H), 2.08 (m, 1H), 1.99 (dd, J = 12.0, 12.0 Hz, 1H), 1.93
(m, 1H), 1.79 (br d, J = 11.5 Hz, 1H), 1.74 (s, 3H), 1.70 (m, 1H),
12.0, 12.0, 5.0 Hz, 1H), 1.26 (s, 3H), 1.23 (m, 1H), 1.08 (d, J = 7.0
Hz, 3H).
To a solution of the above diol (9.6 mg) in THF (1.2 mL)
cooled to 0 °C were added Et3N (0.048 mL, 0.35 mmol), DMAP
(2.8 mg, 0.023 mmol), and Ac2O (0.020 mL, 0.23 mmol), and the
resultant solution was stirred at room temperature for 1 h. The
reaction was quenched with MeOH at 0 °C. The resultant
mixture was diluted with EtOAc and washed successively with
1 M aqueous HCl solution, saturated aqueous NaHCO3 solu-
tion, and then brine. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (20%
EtOAc/hexanes) gave diene 2 (8.3 mg, 72%) as a colorless oil:
[R]25D þ30.1 (c 0.50, CHCl3); IR (film) 2935, 2852, 1744, 1456,
1373, 1240, 1039, 911 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.87
(ddd, J = 17.5, 10.5, 8.5 Hz, 1H), 5.77 (dddd, J = 17.0, 10.5, 6.5,
;
1.66 1.48 (m, 2H), 1.39 (dddd, J = 12.0, 12.0, 12.0, 5.0 Hz,
;
1H), 1.08 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
170.8, 138.8, 137.1, 129.1, 128.3 (2C), 126.1 (2C), 116.1, 101.8,
84.1, 82.7, 82.4, 78.4, 76.5, 76.2, 74.4, 69.1, 67.5, 44.3, 37.7, 30.1,
27.6, 25.1, 24.5, 20.3, 18.1; HRMS (ESI) calcd for C27H37O7
[(M þ H)þ] 473.2534, found 473.2544.
r-Acetoxy Ether 36. To a solution of lactone 3 (17.8 mg,
0.0377 mmol) in CH2Cl2 (1 mL) cooled to -78 °C was added
DIBALH (1.04 M solution in hexanes, 0.073 mL, 0.076 mmol),
and the resultant solution was stirred at -78 °C for 35 min. To
this solution were added pyridine (0.037 mL, 0.46 mmol), Ac2O
(0.043 mL, 0.46 mmol), and a solution of DMAP (60 mg, 0.49
mmol) in CH2Cl2 (0.5 mL). The resultant mixture was stirred at
-78 °C for 13 h and then allowed to warm to 0 °C over a period
of 1 h. The reaction was quenched with saturated aqueous
NH4Cl solution. The resultant mixture was diluted with EtOAc
and saturated aqueous potassium sodium tartrate solution and
stirred vigorously at room temperature until the layers became
clear. The organic layer was separated and washed successively
with 1 M aqueous HCl solution, saturated aqueous NaHCO3
solution, and then brine. The organic layer was dried over Na2-
SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (20%
EtOAc/hexanes) gave R-acetoxy ether 36 (18.9 mg, 97%) as an
6.5 Hz, 1H), 5.06 4.95 (m, 4H), 4.80 (ddd, J = 10.5, 10.5, 5.0
;
Hz, 1H), 4.16 4.06 (m, 2H), 3.86 (br d, J = 11.5 Hz, 1H), 3.76
;
(ddd, J = 6.0, 6.0, 2.0 Hz, 1H), 3.54 3.46 (m, 2H), 3.23 (ddd,
;
J = 11.5, 11.5, 2.5 Hz, 1H), 3.13 3.03 (m, 2H), 2.96 (br d, J =
;
9.0 Hz, 1H), 2.65 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.20 2.12 (m,
;
3H), 2.08 (m, 1H), 2.06 (s, 3H), 2.01 (s, 3H), 1.86 (ddd, J = 12.5,
12.5, 12.5 Hz, 1H), 1.76 (m, 1H), 1.64 1.47 (m, 5H), 1.34 (m,
;
1H), 1.33 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 171.0, 170.0, 139.8, 135.3, 116.9, 115.2, 85.2,
84.8, 80.7, 77.6, 77.2, 75.0, 74.5, 67.8, 67.1, 63.4, 44.3,
41.3, 37.8, 31.2, 26.8, 25.4, 23.5, 21.1, 20.9, 18.5, 15.4; HRMS
(ESI) calcd for C27H42O8Na [(M þ Na)þ] 517.2772, found
517.2760.
DEFG-Ring Skeleton 1. To a solution of diene 2 (1.8 mg,
0.0036 mmol) in degassed CH2Cl2 (1.3 mL) was added a solution
of the Grubbs second-generation catalyst (0.9 mg, 0.001 mmol)
in degassed CH2Cl2 (0.5 mL), and the resultant solution was
stirred at 40 °C for 19 h. After being cooled to room tempera-
ture, the reaction mixture was treated with Et3N and stirred at
room temperature for 1.5 h. The resultant mixture was concen-
trated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (15 to 20% EtOAc/hexanes)
gave DEFG-ring skeleton 1 (1.7 mg, 100%) as a yellow oil:
[R]26D þ59.2 (c 0.18, CHCl3); IR (film) 2931, 1745, 1541, 1241,
1096, 1044, 505, 457 cm-1; 1H NMR (600 MHz, CDCl3) δ 5.67
(ddd, J = 10.8, 10.8, 4.8 Hz, 1H), 5.42 (dd, J = 10.8, 10.8 Hz,
1H), 4.77 (ddd, J = 11.4, 11.4, 5.4 Hz, 1H), 4.12 (dd, J = 12.0, 1.8
Hz, 1H), 4.07 (dd, J = 12.0, 5.4 Hz, 1H), 3.89 (br d, J = 11.4 Hz,
1H), 3.80 (ddd, J = 8.4, 4.2, 4.2 Hz, 1H), 3.45 (m, 1H), 3.22 (ddd,
approximately 5.2:1 mixture of diastereomers: [R]25 þ31.0
D
(c 1.00, CHCl3); IR (film) 2935, 2867, 1750, 1455, 1368, 1233,
1092, 1013, 698 cm-1; 1H NMR (500 MHz, CDCl3, signals for
the major diastereomer) δ 7.45 (dd, J = 8.0, 2.0 Hz, 2H),
7.37 7.29 (m, 3H), 5.94 (ddd, J = 17.5, 10.5, 8.5 Hz, 1H),
;
5.94 (br s, 1H), 5.48 (s, 1H), 5.08 4.98 (m, 2H), 4.27 (dd, J =
;
10.5, 5.0 Hz, 1H), 3.88 (br d, J = 8.5 Hz, 1H), 3.79 (br s, 1H),
3.68 (dd, J = 10.5, 10.5 Hz, 1H), 3.58 (ddd, J = 11.5, 9.5, 4.5 Hz,
1H), 3.45 (br d, J = 5.0 Hz, 1H), 3.36 (ddd, J = 10.0, 10.0, 4.5
Hz, 1H), 3.25 (ddd, J = 10.5, 10.5, 4.5 Hz, 2H), 3.07 (br d, J =
9.0 Hz, 1H), 2.90 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.20 1.92 (m,
;
5H), 2.08 (s, 3H), 1.70 1.50 (m, 4H), 1.45 (m, 1H), 1.39 (s, 3H),
;
1.09 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3, signals
for the major diastereomer) δ 169.3, 140.2, 137.3, 129.0, 128.2
(2C), 126.1 (2C), 115.2, 109.7, 101.7, 91.6, 85.2, 83.6, 76.6, 76.0,
75.3, 74.3, 69.3, 67.8, 42.3, 37.2, 31.4, 29.0, 25.5, 24.2, 21.2,
21.0, 18.1; HRMS (ESI) calcd for C29H40O8Na [(M þ Na)þ]
539.2615, found 539.2629.
J = 11.4, 11.4, 3.6 Hz, 1H), 3.18 3.10 (m, 2H), 3.10 3.03 (m,
;
;
2H), 3.01 (dd, J = 9.6, 4.2 Hz, 1H), 2.78 (ddd, J = 12.3, 12.3, 4.2
Hz, 1H), 2.27 (dd, J = 12.0, 5.4 Hz, 1H), 2.12 (dddd, J = 16.2,
7.2, 7.2, 7.2 Hz, 1H), 2.08 (s, 3H), 2.03 (m, 1H), 2.01 (s, 3H), 1.93
Diene 2. To a solution of R-acetoxy ether 36 (8.2 mg, 0.016
mmol) in CH2Cl2/CH3CN (1:1, v/v, 1.0 mL) were added a
spatula tip of 4 A molecular sieves (ca. 5 mg) and allyltrimethyl-
silane (0.5 mL). The resultant mixture was cooled to -40 °C,
(m, 1H), 1.80 1.68 (m, 2H), 1.65 1.48 (m, 4H), 1.42 (dddd, J =
;
;
11.4, 11.4, 11.4, 5.4 Hz, 1H), 1.21 (s, 3H), 1.01 (d, J = 6.6Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 170.9, 169.9, 134.2, 126.4, 84.8,
84.00, 83.98, 82.0, 77.7, 75.4, 74.4, 68.7, 66.9, 63.3, 44.2, 32.3, 32.2,
32.1, 31.2, 26.2, 24.3, 21.0, 20.9, 15.9, 15.5; HRMS (ESI) calcd for
C25H39O8 [(M þ H)þ] 467.2639, found 467.2645.
treated with BF3 OEt2 (0.010 mL, 0.081 mmol), and allowed to
3
warm to room temperature over a period of 8.5 h. The reaction
was quenched with Et3N at -40 °C, and the resultant mixture
was filtered through a pad of Celite. The filtrate was concen-
trated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (40 to 70% EtOAc/hexanes)
gave a diol (5.1 mg, 78%): 1H NMR (500 MHz, CDCl3) δ 5.87
(ddd, J = 17.5, 9.5, 8.0 Hz, 1H), 5.78 (dddd, J = 17.0, 10.0, 7.0,
7.0 Hz, 1H), 5.09 4.94 (m, 4H), 3.90 3.80 (m, 2H), 3.79 3.67
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (A) (No. 21241050)
from Japan Society for the Promotion of Science (JSPS).
Supporting Information Available: Detailed experimental
procedures for compounds not included in the Experimental
Section and copies of 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
;
;
;
(m, 3H), 3.51 (dd, J = 2.5, 2.5, 1H), 3.23 (ddd, J = 11.0, 11.0, 2.5
Hz, 1H), 3.19 (m, 1H), 3.12 3.04 (m, 2H), 2.66 (ddd, J =
;
15.0, 7.5, 7.5 Hz, 1H), 2.22 2.13 (m, 2H), 2.12 2.00 (m, 3H),
; ;
1.88 1.68 (m, 4H), 1.62 1.46 (m, 3H), 1.31 (dddd, J = 12.0,
;
;
5082 J. Org. Chem. Vol. 75, No. 15, 2010