Synthetic studies on gambieric acids, potent antifungal polycyclic ether natural products: Reassignment of the absolute configuration of the nonacyclic polyether core by NMR analysis of model compounds

Synthetic Studies on Gambieric Acids, Potent Antifungal Polycyclic

Ether Natural Products: Reassignment of the Absolute

Conﬁguration of the Nonacyclic Polyether Core by NMR Analysis of

Model Compounds

Haruhiko Fuwa,* Kazuya Ishigai, Tomomi Goto, Akihiro Suzuki, and Makoto Sasaki*

Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku UniVersity,

1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan

hfuwa@bios.tohoku.ac.jp; masasaki@bios.tohoku.ac.jp

ReceiVed February 14, 2009

A highly stereocontrolled, convergent synthesis of the A/B-ring fragment of gambieric acids (GAs) has

been developed on the basis of (i) a Suzuki-Miyaura coupling of the C1-C6 alkylborate and the C7-C17

vinyl iodide and (ii) a diastereoselective haloetheriﬁcation for the construction of the A-ring tetrahydrofuran

1

as key steps. Inspection of the H and ¹³C NMR chemical shifts of the synthesized A/B-ring model

compounds led to a stereochemical reassignment of the absolute conﬁguration of the polycyclic ether

core of GAs. This structure revision was further supported by a synthesis of the A/BC-ring model

1

compound of gambieric acid B and a comparison of its H and ¹³C NMR data with those of the natural

product.

Introduction

side chain containing the A-ring tetrahydrofuran. The gross

structure, including the relative stereochemistry of the polycyclic

ether domain, was established by Nagai, Yasumoto, and co-

workers based on extensive 2D-NMR analysis.³Subsequently,

the relative stereochemistry of the unassigned portions and the

absolute conﬁguration were determined by using the modiﬁed

Mosher’s method, conformational analysis based on ³J_H,Hvalues

and NOE correlations, and chiral ﬂuorimetric HPLC analysis.⁴

It has been reported that gambieric acids exhibit extraordinary

antifungal activity against Aspergillus niger, which is ap-

proximately 2000 times more potent than that of amphotericin

B, with minimal toxicity against mammals.⁵Additionally, a

possible role of GAA as an endogenous growth regulator of G.

toxicus has been reported on the basis of the observation that

GAA enhances the cell concentration of the dinoﬂagellate in a

Since the structure elucidation of brevetoxin B by Nakanishi

and co-workers more than two decades ago, the synthetically

challenging molecular architectures and the potent and diverse

biological activities of marine polycyclic ether natural products

have continued to stimulate the interests of chemists and

biologists.^1,2Gambieric acids A-D (GAA-GAD, Figure 1),

secondary metabolites of the ciguatera causative dinoﬂagellate

Gambierdiscus toxicus, represent formidable synthetic targets

due to the enormous molecular architecture comprised of the

B-J-ring nonacyclic polyether core arranged with a complex

(1) For reviews of marine polycyclic ether natural products, see: (a)

Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897–1909. (b) Scheuer, P. J.

Tetrahedron 1994, 50, 3–18. (c) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000,

293-314. (d) Yasumoto, T. Chem. Rec. 2001, 1, 228–242.

(2) For recent reviews of the synthesis of polycyclic ethers, see: (a)

Marmsa¨ter, F. P.; West, F. G. Chem.-Eur. J. 2002, 8, 4346–4353. (b) Evans,

P. A.; Delouvrie, B. Curr. Opin. Drug DiscoV. DeV. 2002, 5, 986–999. (c) Inoue,

M. Chem. ReV. 2005, 105, 4379–4405. (d) Nakata, T. Chem. ReV. 2005, 105,

4314–4347. (e) Fuwa, H.; Sasaki, M. Curr. Opin. Drug DiscoV. DeV. 2007, 10,

784–806. (f) Sasaki, M.; Fuwa, H. Nat. Prod. Rep. 2008, 25, 401–426. (g)

Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J. Angew. Chem., Int. Ed. 2008,

47, 7182–7225.

(3) (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.

(4) Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T.

Tetrahedron 2000, 56, 8995–9001.

(5) Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T. J. Antibiot.

1993, 46, 520–522.

4024 J. Org. Chem. 2009, 74, 4024–4040

10.1021/jo900332q CCC: $40.75 2009 American Chemical Society

Published on Web 05/07/2009

Synthetic Studies on Gambieric Acids

SCHEME 1. Initial Synthesis Plan for the A/B-Ring Model

Compound 1 of GAA

FIGURE 1. Proposed and revised structures of gambieric acids.

dose dependent manner with inhibition at higher concentrations.⁶

Inoue et al. reported that GAA competitively inhibits the binding

of the tritiated dihydrobrevetoxin B [³H]PbTx-3 to site 5 of the

voltage-sensitive sodium channels of excitable membranes,

although the afﬁnity is substantially weaker than that of

brevetoxins and ciguatoxins.⁷These intriguing biological activi-

ties coupled with their synthetically formidable molecular

architecture have engendered signiﬁcant interests of the synthetic

community.^8-12Herein, we describe our ﬁrst- and second-

generation approaches toward the stereocontrolled synthesis of

the A/B-ring fragment of GAs, along with the structure analyses

of the synthetic fragments based on NMR spectroscopy, which

culminated in a stereochemical reassignment of the absolute

conﬁguration of the nonacyclic polyether domain of GAs.¹³

SCHEME 2. Synthesis of Alkyne 3

Results and Discussion

Initial Approach toward the A/B-Ring Fragment of

GAA Based on an Acetylide/Aldehyde Coupling. We initially

envisioned the synthesis of the A/B-ring model compound 1 of

GAA as summarized in Scheme 1. In this plan, the A-ring

tetrahydrofuran of 1 was retrosynthetically dissected to hydroxy

alkene 2 on the basis of a diastereoselective bromoetheriﬁcation.

The hydroxy alkene 2 was, in turn, planned to be synthesized

by coupling of a lithium acetylide derived from alkyne 3 and

aldehyde 4.

with N-propionyl-(S)-benzyl-2-oxazolidinone (6) under the

Evans conditions,¹⁵giving alcohol 7 in 89% yield as a single

stereoisomer, as judged by 500 MHz H NMR (Scheme 2).

The synthesis of alkyne 3 commenced with a syn-aldol

1

reaction of aldehyde 5,¹⁴readily prepared from (R)-Roche ester,

Removal of the chiral auxiliary of 7 using sodium borohydride

in aqueous THF¹⁶led to diol 8 in 93% yield. After protection

of 8 as its p-methoxybenzylidene acetal, its regioselective

cleavage using DIBALH cleanly afforded alcohol 9 in 79% yield

for the two steps. Triﬂation followed by displacement with a

lithium acetylide derived from 1-(trimethylsilyl)acetylene and

n-BuLi, and subsequent removal of the trimethylsilyl group gave

alkyne 3 in 72% yield for the three steps.

(6) Sakamoto, B.; Nagai, H.; Hokama, Y. Phycologia 1996, 35, 350–353.

(7) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T. Toxicon

2003, 41, 469–474.

(8) (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.

(9) (a) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6, 1773–

1776. (b) Clark, J. S.; Kimber, M. C.; Robertson, J.; McErlean, C. S. P.; Wilson,

C. Angew. Chem., Int. Ed. 2005, 44, 6157–6162.

(10) Roberts, S. W.; Rainier, J. D. Org. Lett. 2007, 9, 2227–2230.

(11) Saito, T.; Nakata, T. Org. Lett. 2009, 11, 113–116.

(12) (a) Sato, K.; Sasaki, M. Org. Lett. 2005, 7, 2441–2444. (b) Sato, K.;

Sasaki, M. Angew. Chem., Int. Ed. 2007, 46, 2518–2522. (c) Sato, K.; Sasaki,

M. Tetrahedron 2007, 63, 5977–6003.

The synthesis of aldehyde 4 started with reduction of the

known lactone 10¹⁷using lithium aluminum hydride followed

(15) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,

2127–2129.

(16) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,

39, 7067–7070.

(13) For preliminary communications of this work, see: (a) Fuwa, H.; Suzuki,

A.; Sato, K.; Sasaki, M. Heterocycles 2007, 72, 139–144. (b) Fuwa, H.; Goto,

T.; Sasaki, M. Org. Lett. 2008, 10, 2211–2214.

(14) Araki, K.; Saito, K.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed.

2003, 43, 81–84.

(17) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc.

2002, 124, 14983–14992.

J. Org. Chem. Vol. 74, No. 11, 2009 4025

Fuwa et al.

TABLE 1. Acetylide/Aldehyde Coupling for the Assembly of 3 and 4^a

yields^c(%)

entry

base^b

n-BuLi

EtMgBr

n-BuLi/CeCl₃

3 (equiv)

conditions

13a

13b

recovered 4

1

2

3

4

5

6

1.1

2.0

3.0

1.1

2.0

THF, -78 to 0 °C

THF, -78 °C

THF/HMPA, -78 °C

THF, -60 °C to rt

THF, -78 °C

28

38

44

16

20

29

0

25

13

decomposed

no reaction

22

12

45

^aAll reactions were carried out by ﬁrst treating 3 with base for 30 min at the indicated conditions followed by addition of 4. ^b0.9 equiv of base

relative to 3 was used. ^cIsolated yields after puriﬁcation by ﬂash column chromatography on silica gel.

SCHEME 3. Synthesis of Aldehyde 4

prepared from alkyne 3 were ineffective for the present case

(entries 4-6). Application of the modiﬁed Mosher’s method¹⁸

to determine the C9¹⁹stereochemistry of the propargyl alcohol

13a revealed that the major diastereomer 13a possessed the

desired stereochemistry at C9. The undesired, minor diastere-

omer 13b could be converted to the desired 13a by Mitsunobu

inversion²⁰followed by reduction of the resultant benzoate (80%

yield for the two steps).

Half-reduction of the alkyne of 13a (H₂, Lindlar catalyst),

protection of the C9 hydroxy group as the TBS ether, and

cleavage of the p-methoxybenzyl (MPM) group afforded

hydroxy alkene 2 in 81% yield for three steps (Scheme 4). Upon

treatment of 2 with NBS in acetonitrile at room temperature,

diastereoselective cyclization of the A-ring²¹was smoothly

accomplished via a bromonium cation intermediate, giving rise

to bromide 14, which was immediately reduced under radical

conditions to deliver tricyclic compound 15 in 87% yield with

a diastereomer ratio of 4:1. The undesired C7 epimer was readily

separated by ﬂash column chromatography on silica gel. The

stereochemical outcome of the bromoetheriﬁcation can be

explained as illustrated in Figure 2. The major diastereomer 15

would be derived from the transition state A (TS-A) after radical

reduction, whereas TS-B would lead to the corresponding C7

epimer. TS-A would be energetically more stable than TS-B,

since TS-B suffers from an unfavorable steric repulsion between

the C51 methyl group and the C7-C9 moiety. Hydrogenolysis

of the benzyl ether and the benzylidene acetal of 15 followed

by reprotection of the 1,3-diol moiety gave alcohol 16 (84%

yield for the two steps). A two-stage oxidation of alcohol 16

and subsequent esteriﬁcation of the derived carboxylic acid

delivered methyl ester 17 in 72% yield for the three steps.

Finally, deprotection of the silyl groups (TASF, DMF, 84%

by selective protection of the primary alcohol of the derived

diol, giving pivalate 11 in 90% yield for the two steps (Scheme

3). Protection of the remaining secondary alcohol as the tert-

butyldimethylsilyl (TBS) ether followed by reductive cleavage

of the pivalate with DIBALH led to alcohol 12 in 98% yield

for the two steps. Oxidation of the alcohol 12 afforded aldehyde

4 in 89% yield.

With the requisite fragments in hand, we then focused our

attention on their assembly and the construction of the A-ring.

We examined the coupling of a lithium acetylide derived from

alkyne 3 and aldehyde 4 in detail (Table 1). By using 1.1 equiv

of alkyne 3 and n-BuLi in THF at -78 to 0 °C, a mixture of

diastereomers 13a and 13b was obtained in moderate yield (28%

and 16% yields, respectively, entry 1). These diastereomers were

separated by ﬂash chromatography on silica gel. Since it was

observed that the remainder of aldehyde 4 underwent decom-

position upon warming the reaction mixture to 0 °C, the

following experiments were performed at -78 °C. When the

molar amounts of alkyne 3 and n-BuLi were increased to 2

equiv, a slight improvement of the yields of 13a,b was observed

(entry 2). Finally, we found that the use of 3 equiv of alkyne 3

and n-BuLi was optimal for the present coupling reaction, giving

13a and 13b in 44% and 29% yields, respectively (entry 3).

The excess alkyne 3 employed in the reaction could be recovered

after ﬂash column chromatography on silica gel. Our further

attempts including the use of HMPA as a cosolvent or the use

of an alkynylcerium reagent or an alkynylmagnesium reagent

(18) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.

1991, 113, 4092–4096.

(19) The numbering of carbon atoms of all compounds in this paper

corresponds to that of the natural product.

(20) For a review, see: Mitsunobu, O. Synthesis 1981, 1-28.

(21) For selected related examples: (a) Fukuyama, T.; Wang, C.-L. J.; Kishi,

Y. J. Am. Chem. Soc. 1979, 101, 260–262. (b) Braddock, D. C.; Bhuva, R.;

Millan, D. S.; Pe´rez-Fuertes, Y.; Roberts, C. A.; Sheppard, R. N.; Solanki, S.;

Stokes, E. S. E.; White, A. J. P. Org. Lett. 2007, 9, 445–448.

4026 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

SCHEME 4. Synthesis of an A/B-Ring Model Compound 1

of GAA

FIGURE 2. Plausible explanation for the stereochemical outcome of

the bromoetheriﬁcation of 2.

1

TABLE 2. Deviation of H and ¹³C NMR Chemical Shifts between

Natural GAA and Synthetic Model Compound 1 (1:1 CD₃OD/

Pyridine-d₅)^a

position

2

¹H NMR [∆(δ_N-δ_S)]

¹³C NMR [∆(δ_N-δ_S)]

0.03

-0.01

-0.02

0.01

0.00

0.6

3

4

5

6

0.1

0.2

0.1

0.0

0.00

7

8

0.02

-0.06

0.09

-0.3

-1.3

9

0.00

1.3

10

0.20

0.04

-0.2

11

12

13

-0.26

1.2

-0.3

0.1

0.02

-0.04

-0.06

0.03

50

51

0.2

0.1

0.01

a

¹H and ¹³C NMR spectra of natural GAA and compound 1 were

recorded at 400 MHz (100 MHz) and 600 MHz (150 MHz),

respectively. Chemical shifts are reported in ppm relative to the internal

residual solvent (¹H NMR, CD₂HOD 3.31 ppm; ¹³C NMR, CD₃OD 49.8

ppm). δ_Nand δ_Sare chemical shifts of the natural product and synthetic

model compound 1, respectively.

the originally proposed structure of GAA should be reexamined.

However, structure analysis of the natural product was prohibited

due to the unavailability of the authentic sample as well as its

complex NMR spectroscopic data. Since Satake and co-workers

have assigned the relative stereochemistry of the A/B-ring

moiety and the absolute conﬁguration of the C9 hydroxy group

using natural GAB and its derivatives, we turned our attention

to the synthesis of an A/B-ring fragment of GAB for further

detailed investigation.

Improved Approach toward the A/B-Ring Fragment of

GAB Based on a Suzuki-Miyaura Coupling. Our initial

synthesis of the A/B-ring fragment 1 of GAA utilized the

coupling of a lithium acetylide derived from alkyne 3 and

aldehyde 4 as a key fragment assembly process (see Table 1).

However, it was necessary to employ a large excess of alkyne

3 to attain an acceptable level of conversion yield. Moreover,

the diastereoselectivity of the acetylide/aldehyde coupling was

moderate, giving an approximately 1.5:1 mixture of the desired

isomer and its epimer. It was necessary to separate these

diastereomers by careful ﬂash column chromatography on silica

gel and convert the undesired isomer to the desired one by the

Mitsunobu inversion/reduction sequence. These impractical

yield)²²and saponiﬁcation (LiOH, THF/MeOH/H₂O, 77% yield)

completed the synthesis of the A/B-ring fragment 1 of GAA.

1

Unexpectedly, the H and ¹³C NMR chemical shifts of the

synthetic fragment 1 did not match those of the corresponding

domain of natural GAA (Table 2). Clearly, the ¹H and ¹³C NMR

data of the C8-C11 moiety of synthetic 1 deviated signiﬁcantly

from those of the parent natural product, which suggested that

(22) (a) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J. A. J. Org. Chem. 1996,

61, 1082–1100. (b) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.;

Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436–6437.

J. Org. Chem. Vol. 74, No. 11, 2009 4027

Fuwa et al.

SCHEME 5. Synthesis Plan for an A/B-Ring Model

Compound 18a of GAB via Suzuki-Miyaura Coupling

tively, Sharpless asymmetric epoxidation of 23 using (+)-DET

as a chiral auxiliary led to hydroxy epoxide 30 in 83% yield as

a single stereoisomer, as judged by 500 MHz ¹H NMR.

Chlorination of 30 with PPh₃in CCl₄in the presence of NaHCO₃

gave chloro epoxide 31 in 85% yield. According to the Takano

protocol,²⁵exposure of 31 to excess LDA in THF at -40 °C

smoothly furnished propargylic alcohol 32 in 92% yield. After

iodination of 32 (NIS, AgNO₃, 93% yield), the resultant

iodoalkyne 33 was reduced with diimide generated in situ from

o-nitrobenzenesulfonyl hydrazide (NBSH) and Et₃N,²⁶giving

rise to vinyl iodide 22 in 96% yield. Thus, the C9 stereogenic

center was successfully established with complete stereocontrol

by means of Sharpless asymmetric epoxidation. The stereo-

chemistry of the C9 position was unambiguously conﬁrmed by

derivatization of alcohol 32 into the Mosher esters 35a,b as

shown in Scheme 7.

Assembly of the key intermediates and completion of the

synthesis are illustrated in Scheme 8. Iodide 21, prepared from

alcohol 9 by iodination under standard conditions, was treated

with t-BuLi in the presence of B-MeO-9-BBN²⁷to generate

alkylborate 20, which was in situ reacted with vinyl iodide 22

under the inﬂuence of a PdCl₂(dppf)/Ph₃As catalyst system and

Cs₂CO₃in aqueous THF/DMF at 50 °C, leading to the desired

cis-oleﬁn 36 in 75% yield. Protection of the hydroxy group of

36 as its TBS ether was followed by removal of the MPM group,

giving hydroxy alkene 19 in 80% yield for the two steps.

Diastereoselective bromoetheriﬁcation of 19 by its treatment

with NBS in acetonitrile at room temperature and the ensuing

reduction under radical conditions (n-Bu₃SnH, AIBN) delivered

tricyclic compound 37 in 69% yield for the two steps. In contrast

to the case of 2, the bromoetheriﬁcation of 19 proceeded with

complete stereocontrol, as judged by 500 MHz ¹H NMR of the

crude reaction mixture.²⁸The stereochemistries of the C4, C5,

and C7 positions were unambiguously established by NOESY

experiments on compounds 37 and 18a. Elaboration of 37 into

the A/B-ring fragment 18a of GAB was efﬁciently accomplished

through the previously described seven-step sequence. Not

aspects of the fragment assembly process were signiﬁcant

drawbacks for material throughput, which prompted us to devise

a more efﬁcient synthetic approach toward the A/B-ring

fragment of GAB.

We envisioned that hydroxy alkene 19, a key precursor for

the diastereoselective bromoetheriﬁcation, could be synthesized

from alkylborate 20 (prepared from iodide 21) and vinyl iodide

22 by Suzuki-Miyaura coupling²³(Scheme 5). The vinyl iodide

22 was easily traced back to allylic alcohol 23 with introduction

of the C9 stereogenic center by utilizing Sharpless asymmetric

epoxidation.

The synthesis of vinyl iodide 22 started with mesylation of

the known alcohol 24¹⁷followed by displacement with NaCN

to give nitrile 25 in 98% yield for the two steps (Scheme 6).

Exposure of 25 to MeLi (Et₂O, -78 to 0 °C) smoothly afforded

methyl ketone 26 in 85% yield after acidic workup. Desilylation

of 26 followed by hetero-Michael reaction of the derived alcohol

using methyl propiolate and N-methylmorpholine (NMM)

provided ꢀ-alkoxy acrylate 27. According to the Nakata

protocol,²⁴treatment of 27 with SmI₂in the presence of

methanol in THF at room temperature cleanly furnished lactone

28 in 74% yield as a single isomer, whose stereochemistry was

unambiguously conﬁrmed by NOE experiments as shown.

Reduction of the lactone of 28 with DIBALH followed by Wittig

homologation, and subsequent silylation of the resultant tertiary

alcohol led to enoate 29 in 89% yield for the three steps. After

reducing 29 with DIBALH to give allylic alcohol 23 quantita-

1

surprisingly, the H and ¹³C NMR spectroscopic data of the

synthetic model compound 18a did not match those of the

corresponding moiety of the natural GAB (Table 3). As in

1

the case of GAA, the H and ¹³C NMR chemical shifts of the

C7-C11 moiety clearly differed from those of the natural

product.²⁹

The spectroscopic discrepancies between the synthetic frag-

ments 1/18a and natural products led us to reexamine the

1

originally proposed structure of GAB. Since the H and ¹³C

NMR chemical shifts of the C2-C7 moiety of 1 and 18a were

in good agreement with those of the respective natural products,

(25) Takano, S.; Samizu, K.; Sugihara, T.; Ogasawara, K. J. Chem. Soc.,

Chem. Commun. 1989, 1344-1345.

(26) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.

(27) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885–7892.

(28) It is interesting that the difference of the C12 position between hydroxy

alkenes 2 and 19 affected the apparent diastereoselectivity of their respective

bromoetheriﬁcations. However, we notice that the net yield of tricyclic compound

15 was 70% from hydroxy alkene 2, which is comparable to that of tricyclic

compound 37 (69% yield from hydroxy alkene 19). Although the reason for

this result is not clear, we speculate that the undesired mode of cyclization (i.e.,

Figure 2, TS-B) of 19 would result in decomposition of the substrate. Similarly,

bromoetheriﬁcation/reduction of hydroxy alkene 48 proceeded with a seemingly

better diastereoselectivity (dr ) 3.5:1) than that of hydroxy alkene 63 (dr )

2:1), but the net yield of the desired tricyclic compound 49 (47%) was almost

the same as that of 65 (49%) (vide infra).

(23) For reviews of Suzuki-Miyaura coupling: (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.

(24) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron 2002, 58,

1853–1864.

(29) Similarly, the ¹H and ¹³C NMR chemical shifts of the C7-C11 moiety

of 18a in C₅D₅N differed from those of GAB in C₅D₅N. See the Supporting

Information for details.

4028 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

SCHEME 6. Synthesis of Vinyl Iodide 22

SCHEME 7. Synthesis of Mosher Esters 35a,b

of 21. On the other hand, vinyl iodide 42, the C9 epimer of 22,

was synthesized from allylic alcohol 23 simply by tuning the

chiral auxiliary used in the Sharpless asymmetric epoxidation,

yielding an approximately 7:3 mixture of diastereomers as

1

judged by 500 MHz H NMR. The undesired minor diastere-

omer could be removed by ﬂash column chromatography on

silica gel after the ensuing chlorination step. Coupling of the

requisite fragments was efﬁciently achieved under the optimized

Suzuki-Miyaura conditions [PdCl₂(dppf)/Ph₃As, Cs₂CO₃, aque-

ous THF/DMF, 50 °C], giving rise to cis-oleﬁns 43, 47, and 51

in high yields. Bromoetheriﬁcation of hydroxy alkenes 44 and

52 using NBS in acetonitrile at room temperature proceeded

smoothly to provide, after radical reduction (n-Bu₃SnH, AIBN),

tricyclic compounds 46 and 53 as a single stereoisomer,

respectively. On the other hand, under the identical conditions,

hydroxy alkene 48 gave tricyclic compound 49 in rather

moderate yield with low diastereoselectivity (dr ) 3.5:1). The

undesired C7 epimer could be separated by ﬂash column

chromatography on silica gel. The tricyclic compounds 46, 49,

and 53 thus prepared were elaborated to model compounds

18b-d in seven steps as described before. For each of the model

compounds, the stereochemistries of the C4, C5, and C7

stereogenic centers were established by NOESY experiments

as shown.

we focused our attention on the relative stereochemistry of the

C7-C11 moiety. Satake and co-workers assigned the relative

correlations between C7/C9 and C9/C11 mainly based on ³J_H,H

analysis and NOE data, while the C9 stereogenic center was

established by the modiﬁed Mosher’s method.⁴Since unam-

biguous assignment of the relative conﬁguration of the C7-C11

stereochemical triad was deemed necessary, we decided to

synthesize three possible diastereomers 18b-d as potential

candidates for the A/B-ring substructure of GAB (Figure 3).

The synthesis of model compounds 18b-d is outlined in

Scheme 9 (see the Supporting Information for details). The

convergence of our second-generation approach enabled us to

prepare and assemble the requisite fragments in an efﬁcient

manner. Thus, iodide ent-21 was readily prepared from (S)-

Roche ester 39 in the same way as described for the synthesis

1

Table 3 summarizes the deviations of the H and ¹³C NMR

chemical shifts of the synthetic model compounds 18a-d (δ_S)

1

from those of the natural GAB (δ_N). It is clear that the H and

¹³C NMR chemical shifts of the diastereomer 18c are in close

J. Org. Chem. Vol. 74, No. 11, 2009 4029

Fuwa et al.

1

TABLE 3. Deviation of H and ¹³C NMR Chemical Shifts between

Natural GAB and the Diastereomeric A/B-Ring Model Compounds

18a-d (in 1:1 CD₃OD/Pyridine-d₅)^a

SCHEME 8. Synthesis of an A/B-Ring Model Compound

18a of GAB

¹H NMR [∆(δ_N-δ_S)]

¹³C NMR [∆(δ_N-δ_S)]

position

2

18a

18b

18c

18d

18a

18b

18c

18d

0.06

0.00

0.02

0.04

0.06

0.01

0.05

0.10

0.02

0.01

0.08

0.09

0.02

0.00

0.06

0.6

0.7

3

4

5

6

0.0

0.3

0.1

0.2

0.0

0.3

0.4

0.1

0.3

0.1

0.3

0.2

0.0

0.2

0.5

-0.02 -0.01

0.02 -0.03

-0.02 -0.09

0.02 -0.11

7

8

0.06

0.16

0.02

0.11 -0.5 -2.3 -0.2 -2.4

0.0 0.6

0.00

0.19

-0.15 -0.09 -0.04 -0.29 -1.7 -1.0

0.12 -0.02 -0.04

0.08

0.09

0.10

9

10

0.18

0.04

1.4

0.5

0.4

0.8

0.1 -1.3

0.3

0.12 -0.11 -0.09

0.01 -0.11 -0.11

0.4

11

12

13

-0.39 -0.38 -0.06 -0.08

1.4

0.3

1.7

0.3

0.1

0.2

0.6

0.3

0.2

1.2

-0.05 -0.05 -0.06 -0.01

-0.10 -0.11 -0.05 -0.06

50

51

0.10

0.03

0.12

0.02

0.05

0.12

0.03

0.3

0.1

0.5

0.3

0.0

0.5

0.1

0.7

0.4

0.1

0.8

12Me -0.02 -0.03 -0.01 -0.01

a

¹H and ¹³C NMR spectra of natural GAB and model compounds

18a-d were recorded at 400 MHz (100 MHz) and 600 MHz (150

MHz), respectively. Chemical shifts are reported in ppm relative to the

internal residual solvent (¹H NMR, CD₂HOD 3.31 ppm; ¹³C NMR,

CD₃OD 49.8 ppm). δ_Nand δ_Sare chemical shifts of the natural product

and synthetic model compounds 18a-d, respectively.

agreement with those of the natural product, while the other

diastereomers showed different spectroscopic properties. Con-

formational analysis of 18c based on ³J_H,Hvalues (J_{7, 8b}) 10.2

Hz, J_{8a, 8b}) 13.2 Hz, J_{8a, 9}) 9.4 Hz, J_{9, 10a}) 8.4 Hz, J_{10a, 10b}

)

13.6 Hz, J_{10b, 11}) 9.0 Hz) and NOESY and HMBC spectra in

pyridine-d₅revealed that 18c reproduces not only the relative

stereochemistry but also the conformation of the C7-C11

moiety of the natural GAB (Figure 4). Since the absolute

conﬁguration of the C9 stereogenic center of 18c is opposite to

that of the natural product, as was determined unambiguously

by the modiﬁed Mosher’s method, 18c represents an enantiomer

of the A/B-ring substructure of GAB. Thus, the conﬁguration

of the polycyclic ether region of GAB should be corrected such

that it is opposite to the original assignment.

FIGURE 3. Structures of possible diastereomers 18a-d.

Second-Generation Synthesis and Structure Analysis of

the A/B-Ring Fragment of GAA. The successful stereochem-

ical reassignment of the originally proposed structure of GAB

encouraged us to reexamine the structure of GAA as well. In

view of biosynthesis, the structures of other natural congeners

of GAs should also be revised in a similar manner. Thus, we

embarked on the synthesis of model compound 54 based on

our second-generation strategy (Scheme 10). Reduction of

lactone 10 with DIBALH followed by Wittig homologation

using Ph₃PdCHCO₂Et, and subsequent silylation of the remain-

ing alcohol gave enoate 55 in 63% yield (three steps). The

enoate 55 was elaborated to vinyl iodide 61 in a manner similar

to that described for the synthesis of 22. Suzuki-Miyaura

coupling of 61 with alkylborate ent-20 generated in situ from

the corresponding iodide ent-21 under the optimized conditions

[PdCl₂(dppf)/Ph₃As, Cs₂CO₃, aqueous THF/DMF] furnished cis-

oleﬁn 62 (87% yield), which was converted to hydroxy alkene

63 by the standard protective group manipulations. Exposure

of 63 to NBS in acetonitrile at room temperature effected

diastereoselective bromoetheriﬁcation to afford, after reduction

of the derived bromide under radical conditions, an ap-

proximately 2:1 mixture of tricyclic compound 65 and its C7-

epimer, which was separated by ﬂash column chromatography

4030 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

SCHEME 9. Synthesis of the Three Diastereomeric Model Compounds 18b-d

on silica gel. Elaboration of 65 into the model compound 54

was achieved in seven steps as described previously. As

expected, the ¹H and ¹³C NMR spectroscopic data of the

synthetic model compound 54 matched those of the natural GAA

(Table 4). Thus, the absolute conﬁguration of the polycyclic

ether region of GAA should be corrected to be opposite to that

of the original assignment. Overall, we have successfully revised

the structures of all members of the GA family, as represented

in Figure 1.

Synthesis and Structure Analysis of an A/BC-Ring

Fragment of GAB. Having successfully revised the original

stereochemical assignment of the polycyclic ether region of GAs,

we embarked on the synthesis of the A/BC-ring fragment 67

of GAB in order to establish a reliable route readily applicable

to a total synthesis and the stereochemical conﬁrmation of the

revised structure by NMR analysis. Our synthesis plan for the

A/BC-ring fragment 67 is summarized in Scheme 11. It was

envisaged that the A-ring tetrahydrofuran of 67 would be

J. Org. Chem. Vol. 74, No. 11, 2009 4031

Fuwa et al.

SCHEME 10. Synthesis of the A/B-Ring Model Compound 54 of GAA

TABLE 4. Deviation of H and ¹³C NMR Chemical Shifts between

Natural GAA and the A/B-Ring Model Compound 54 (in 1:1

CD₃OD/Pyridine-d₅)^a

1

constructed by a diastereoselective bromoetheriﬁcation, although

this transformation has proven to be inefﬁcient for the synthesis

of model compounds with the desired stereochemistry (i.e., 18c

and 54). Hydroxy alkene 68 would be synthesized through a

Suzuki-Miyaura coupling of an alkylborate generated from

iodide ent-21 and vinyl iodide 69. Vinyl iodide 69 would be

prepared from tricyclic lactone 70, which would be accessible

from the known tetrahydropyran 71 corresponding to the C-ring.

The synthesis of vinyl iodide 69 commenced with silylation

of the known alcohol 71,³⁰giving TIPS ether 72 in 94% yield

(Scheme 12). Deprotection of the benzylidene acetal of 72 under

acidic conditions gave diol 73 in 90% yield, which was protected

(MOMCl, i-Pr₂NEt) to provide bis-MOM ether 74 in 96% yield.

Hydroboration of 74 using disiamylborane delivered alcohol 75

in a nearly quantitative yield, which was transformed to nitrile

76 via a mesylate in 94% yield (two steps). Treatment of 76

with MeMgBr in Et₂O gave methyl ketone 77 in 63% yield

along with recovered 76 (27%). After desilylation of 77 with

position

2

¹H NMR [∆(δ_N-δ_S)]

¹³C NMR [∆(δ_N-δ_S)]

0.01

0.04

0.6

3

4

5

6

-0.01

0.1

0.2

0.0

0.1

0.04

0.01

7

8

-0.01

0.00

-0.1

0.0

0.01

9

10

0.01

0.00

0.3

0.1

0.00

11

12

13

-0.07

-0.03

-0.04

-0.03

0.02

0.1

0.8

50

51

0.1

0.01

a

¹H and ¹³C NMR spectra of natural GAA and compound 54 were

recorded at 400 MHz (100 MHz) and 600 MHz (150 MHz),

respectively. Chemical shifts are reported in ppm relative to the internal

residual solvent (¹H NMR, CD₂HOD 3.31 ppm; ¹³C NMR, CD₃OD 49.8

ppm). δ_Nand δ_Sare chemical shifts of the natural product and synthetic

model compound 54, respectively.

TBAF (98% yield), the resultant alcohol was reacted with

methyl propiolate in the presence of NMM to afford ꢀ alkoxy

acrylate 78 in 98% yield. Exposure of 78 to SmI₂in the presence

of methanol in THF at room temperature cleanly furnished

tricyclic lactone 70 in 92% yield as a single stereoisomer. The

stereochemistry of 70 was established by NOE experiments as

shown. DIBALH reduction of 70 followed by Wittig reaction

using Ph₃PdCHCO₂Et, and subsequent silylation with trimeth-

ylsilylimidazole delivered TMS ether 79 in 75% yield (three

FIGURE 4. Selected NOESY and HMBC correlations of compound

18c (600 MHz, pyridine-d₅). Blue arrows denote NOESY correlations.

Red arrows denote HMBC correlations.

4032 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

4). A highly reactive reagent bis(sym-collidine)I⁺PF₆,³¹gener-

-

SCHEME 11. Synthesis Plan for the A/BC-Ring Fragment

67 of GAB

ated in situ from iodine and bis(sym-collidine)Ag⁺PF₆^-, smoothly

facilitated iodoetheriﬁcation to provide a 1:1 mixture of 86a,b

-

in 79% yield (entry 5). The use of bis(sym-collidine)Br⁺PF₆

was ineffective in the present case (entry 6).

The observed low diastereoselectivity of the haloetheriﬁcation

of 68 could be explained by considering two possible transition

states of the reaction (Figure 5). The transition state C (TS-C)

would give the desired diastereomer 86a, while TS-D would

lead to the undesired isomer 86b. TS-C suffers from a steric

repulsion between the C4 hydrogen and the C9 siloxy group

(PdTIPS), while TS-D involves an unfavorable interaction

between the C51 methyl group and the C7-C9 moiety. The

unsatisfactory results of the haloetheriﬁcation of 68 may be

attributable to these steric interactions present in possible

transition states. Based on these mechanistic considerations,

we thought that TS-C would become energetically more favored

than TS-D by removal of the bulky TIPS group of the C9

alcohol. Eventually, hydroxy alkene 87, prepared from 68 by

desilylation (TBAF, 100% yield), was treated with bis(sym-

collidine)I⁺PF₆in CH₂Cl₂at room temperature (Scheme 14).

-

As expected, we were pleased to ﬁnd that the diastereoselective

iodoetheriﬁcation proceeded cleanly to furnish iodide 88 in 83%

yield as a single stereoisomer (judged by 500 MHz ¹H NMR).

At this stage, the stereochemistries of the C4, C5, and C7

stereogenic centers were conﬁrmed by NOE experiments as

shown.

Completion of the synthesis of the A/BC-ring fragment 67

of GAB is depicted in Scheme 15. Protection of the hydroxy

group of 88 (Ac₂O, Et₃N, DMAP) gave acetate 89 in 100%

yield. Removal of the iodine atom of 89 was best achieved using

Ph₃SnH and AIBN in reﬂuxing THF, leading to tricyclic

compound 90 in 96% yield after hydrogenolysis of the benzyl

group. A two-stage oxidation (Dess-Martin periodinane; then

NaClO₂) and subsequent esteriﬁcation provided methyl ester 91

in 52% overall yield from 90 after puriﬁcation by ﬂash column

chromatography on silica gel. Finally, saponiﬁcation cleanly

furnished the A/BC-ring fragment 67 in 93% yield. The ¹H and

¹³C NMR chemical shifts of the synthesized 67 are in excellent

accordance with those of the natural GAB (Table 6). Thus, our

revised structure of GAB was conﬁrmed by the synthesis and

structure analysis of the tricyclic model compound 67.

steps), which was reduced with DIBALH to give allylic alcohol

80 almost quantitatively. Sharpless asymmetric epoxidation

using (-)-DET as a chiral auxiliary afforded hydroxy epoxide

81 in 94% yield as an approximately 9:1 mixture of diastere-

1

omers (judged by 500 MHz H NMR). Treatment of 81 with

Ph₃P in the presence of NaHCO₃in reﬂuxing CCl₄gave chloro

epoxide 82 (89% yield). Exposure of 82 to excess LDA

smoothly afforded propargylic alcohol 83 in 86% yield. Iodi-

nation (NIS, AgNO₃, 91% yield) followed by diimide reduction

of the resultant iodoalkyne 84 furnished vinyl iodide 69 in 91%

yield.

With the requisite fragment in hand, the fragment coupling

and the construction of the A-ring tetrahydrofuran were

investigated (Scheme 13). An alkylborate generated from

iodide ent-21 by treating with t-BuLi and B-MeO-9-BBN was

coupled with vinyl iodide 69 in the presence of a PdCl₂(dppf)/

Ph₃As catalyst system and Cs₂CO₃as a base in aqueous THF/

DMF at 50 °C, giving rise to cis-oleﬁn 85 in 88% yield.

After protection of 85 as the TIPS ether, the MPM group

was cleaved to give hydroxy alkene 68 in 77% yield for the

two steps.

Conclusion

We have developed two strategies for the synthesis of the

A/B-ring fragments of GAs. The ﬁrst-generation synthesis

employed an acetylide/aldehyde coupling as the fragment

assembly process. However, the low diastereoselectivity at

the C9 stereocenter and the necessity of employing large

excess amounts of the alkyne component were serious

drawbacks in terms of the material throughput, which made

this approach less attractive. In the second-generation ap-

proach, the C9 stereogenic center was introduced by Sharpless

asymmetric epoxidation and the fragment assembly was

efﬁciently achieved by Suzuki-Miyaura coupling. The

construction of the A-ring tetrahydrofuran was achieved by

diastereoselective bromoetheriﬁcation.

However, diastereoselective haloetheriﬁcation of 68 was

found to be quite challenging (Table 5). Treatment of 68 with

NBS in acetonitrile at room temperature gave an approximately

2.3:1 mixture of 86a, b in 43% combined yield (entry 1). The

rather low diastereoselectivity coupled with the unacceptable

yield led us to screen reaction conditions. An attempt to improve

the diastereoselectivity by performing the reaction at 0 °C proved

to be unfruitful (entry 2). Exposure of 68 to NIS in acetonitrile

at room temperature gave a 1:1 mixture of 86a,b in 46%

combined yield along with 33% of the starting material (entry

Surprisingly, the H and ¹³C NMR spectroscopic data of

the synthesized fragments of GAA and GAB (1 and 18a,

1

(30) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K.

Tetrahedron 1990, 46, 4517–4552.

J. Org. Chem. Vol. 74, No. 11, 2009 4033

Fuwa et al.

SCHEME 12. Synthesis of Vinyl Iodide 69

TABLE 5. Unfruitful Attempts at Haloetheriﬁcation of Hydroxy

Alkene 68

SCHEME 13. Synthesis of Hydroxy Alkene 68

entry

reagents and conditions

NBS, CH₃CN, rt

NBS, CH₃CN, 0 °C

NIS, CH₃CN, -40 to 0 °C

NIS, CH₃CN, rt

X yield (%) (86a/86b)^a

1

2

3

4

5

6

Br

I

43 (2.3:1)

24 (2.4:1)

26 (0.5:1)^b

46 (1.0:1)^c

79 (1.0:1)

13 (1.0:1)

respectively) did not match those of the corresponding moiety

of the respective natural products. In particular, substantial

deviation of the chemical shifts of the C8-C11 moiety was

observed. These spectroscopic discrepancies led us to

reexamine the originally proposed structure of GAB. Ac-

cording to Satake and co-workers, the relative stereochemical

I

I₂, bis(sym-collidine)AgPF₆, CH₂Cl₂, rt

Br₂, bis(sym-collidine)AgPF₆, CH₂Cl₂, rt Br

^aDiastereomer ratio was determined by ¹H NMR (500 MHz). ^b68

was recovered in 68% yield. ^c68 was recovered in 33% yield.

correlations

between

3

C7/C9 and C9/C11 were determined mainly based on J_H,H

analysis and NOE experiments, while the C9 stereogenic

center was established by the modiﬁed Mosher’s method.

Therefore, it was necessary to ascertain the relative conﬁg-

uration of the C7-C11 stereochemical triad in an unambigu-

ous manner. Eventually, we synthesized three possible

In addition, the applicability of our developed strategy for

the construction of the A/B-ring moiety in a more complex

situation was investigated through the synthesis of an A/BC-

ring fragment of GAB. Unfortunately, the haloetheriﬁcation

of hydroxy alkene 68 suffered from low diastereoselectivity.

After detailed mechanistic considerations on the possible

transition state models, we found that iodoetheriﬁcation of

the C9 unprotected hydroxy alkene 87 proceeded cleanly to

afford iodide 88 in excellent yield as a single stereoisomer.

diastereomers 18b-d and found that the H and ¹³C NMR

1

spectroscopic data of 18c were in excellent agreement with

those of the natural GAB. Thus, the absolute conﬁguration

of the polycyclic ether region of GAB should be revised such

that it is opposite to the original assignment. The structure

of GAA was similarly revised due to the fact that the ¹H and

¹³C NMR chemical shifts of the tricyclic model compound

54 matched those of the natural GAA.

1

The H and ¹³C NMR spectroscopic data of the A/BC-ring

fragment 67 were in excellent agreement with those of the

corresponding moiety of the natural GAB. Thus, our revised

4034 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

1

TABLE 6. Deviation of H and ¹³C NMR Chemical Shifts between

Natural GAB and the A/BC-Ring Model Compound 67 (in 1:1

CD₃OD/Pyridine-d₅)^a

position

2

¹H NMR [∆(δ_N-δ_S)]

¹³C NMR [∆(δ_N-δ_S)]

0.07

0.02

0.5

3

4

5

6

0.00

0.09

0.08

-0.01

0.03

0.1

0.3

0.1

0.2

7

8

0.03

-0.2

-0.4

-0.05

-0.03

0.05

-0.10

-0.05

0.02

FIGURE 5. Mechanistic considerations on haloetheriﬁcation of hy-

droxy alkene 68.

9

10

-0.3

SCHEME 14. Highly Diastereoselective Iodoetheriﬁcation of

87

11

12

13

0.7

0.1

0.3

0.01

-0.01

0.02

50

51

-0.1

0.0

0.04

12Me

-0.01

0.2

a

¹H and ¹³C NMR spectra of natural GAB and compound 67 were

recorded at 400 MHz (100 MHz) and 600 MHz (150 MHz),

respectively. Chemical shifts are reported in ppm relative to the internal

residual solvent (¹H NMR, CD₂HOD 3.31 ppm; ¹³C NMR, CD₃OD 49.8

ppm). δ_Nand δ_Sare chemical shifts of the natural product and synthetic

model compound 67, respectively.

revised structures of GAs will have to be done through total

synthesis. Further studies toward the total synthesis of GAs

are currently underway and will be reported in due course.

Experimental Section

SCHEME 15. Synthesis of the A/BC-Ring Model

Compound 67 of GAB

Triisopropylsilyl Ether 72. To a solution of alcohol 71 (6.87

g, 24.9 mmol) in CH₂Cl₂(170 mL) at 0 °C were added 2,6-lutidine

(5.8 mL, 49.8 mmol) and TIPSOTf (10 mL, 37.3 mmol). After

being stirred at 0 °C for 1.5 h, the reaction mixture was quenched

with saturated aqueous NaHCO₃. The mixture was diluted with

EtOAc, washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash column chromatography (silica gel, 2% EtOAc/hexanes) to

give triisopropylsilyl ether 72 (10.2 g, 94%) as a colorless oil: [R]¹⁹

D

-62.8 (c 1.00, CHCl₃); IR (ﬁlm) 2944, 2867, 1463, 1383, 1092,

1007, 924, 882, 819, 749, 681 cm^-1; ¹H NMR (500 MHz, CDCl₃)

δ 7.49-7.47 (m, 2H), 7.38-7.32 (m, 3H), 5.92 (ddd, J ) 17.0,

10.5, 6.0 Hz, 1H), 5.55 (s, 1H), 5.36 (m, 1H), 5.22 (m, 1H),

3.99-3.92 (m, 2H), 3.69-3.65 (m, 2H), 3.60 (dd, J ) 13.0, 4.0

Hz, 1H), 2.26 (ddd, J ) 12.0, 3.5, 3.5 Hz, 1H), 1.88 (ddd, J )

12.0, 12.0, 11.0 Hz, 1H), 1.53 (s, 3H), 1.03 (m, 21H); ¹³C NMR

(150 MHz, CDCl₃) δ 137.5, 136.4, 129.2, 128.4 (×2), 126.3 (×2),

117.6, 102.9, 78.8, 76.6, 76.2, 71.7, 68.9, 34.6, 18.2 (×3), 18.1

(×3), 14.8, 12.6 (×3); HRMS (FAB) calcd for C₂₅H₄₁O₄Si [(M +

H)⁺] 433.2769, found 433.2776.

Diol 73. To a solution of triisopropylsilyl ether 72 (10.2 g, 23.5

mmol) in CH₂Cl₂/MeOH (1:1, v/v, 160 mL) was added CSA (1.64

g, 23.5 mmol). After being stirred at room temperature for 4.5 h,

the reaction mixture was quenched with Et₃N and concentrated

under reduced pressure. The residue was puriﬁed by ﬂash column

chromatography (silica gel, 10-40% EtOAc/hexanes) to give diol

73 (7.23 g, 90%) as a colorless oil: [R]²¹_D-66.2 (c 1.00, CHCl₃);

IR (ﬁlm) 3427, 2944, 2868, 2359, 1463, 1120, 1057, 882, 824,

structures of GAs were further supported. The present study

underscores the important role of organic synthesis in the

structure elucidation of architecturally complex natural

products.³²However, an unambiguous conﬁrmation of our

1

680 cm^-1; H NMR (500 MHz, CDCl₃) δ 5.91 (ddd, J ) 17.0,

10.5, 6.0 Hz, 1H), 5.30 (m, 1H), 5.18 (m, 1H), 3.86 (m, 1H), 3.74

(31) (a) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793–5800. (b)

Gao, X.; Snider, B. B. J. Org. Chem. 2004, 69, 5517–5527.

(32) For a review, see: Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int.

Ed. 2005, 44, 1012–1044.

J. Org. Chem. Vol. 74, No. 11, 2009 4035

Fuwa et al.

(dd, J ) 9.0, 5.5 Hz, 1H), 3.64-3.74 (m, 3H), 2.24-2.20 (m, 2H),

2.15 (br, 1H), 1.69 (ddd, J ) 12.0, 11.5, 11.5 Hz, 1H), 1.18 (s,

3H), 1.03 (m, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 136.5, 117.1,

76.3, 75.8, 71.1, 68.5, 67.2, 38.1, 18.1 (×6), 13.0, 12.6 (×3); HRMS

(FAB) calcd for C₁₈H₃₇O₄Si [(M + H)⁺] 345.2456, found 345.2469.

Bis-methoxymethyl Ether 74. To a solution of diol 73 (7.23 g,

21.1 mmol) in CH₂Cl₂(150 mL) at 0 °C were added i-Pr₂NEt (73

mL, 423 mmol) and MOMCl (16 mL, 211 mmol). After being

stirred at 40 °C overnight, the solution was cooled to room

temperature. The reaction mixture was diluted with EtOAc, washed

with 1 M aqueous HCl, saturated aqueous NaHCO₃, and brine, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

Puriﬁcation of the residue by column chromatography (silica gel,

8% EtOAc/hexanes) gave bis-methoxymethyl ether 74 (8.59 g,

Methyl Ketone 77. To a solution of nitrile 76 (571.7 mg, 1.219

mmol) in diethyl ether (13.0 mL) at 0 °C was added MeMgBr (3.0

M solution in diethyl ether, 3.60 mL, 10.8 mmol) dropwise. After

being stirred at room temperature overnight, the reaction mixture

was quenched with saturated aqueous NH₄Cl at 0 °C. The mixture

was diluted with EtOAc, washed with H₂O and brine, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. Puriﬁca-

tion of the residue by ﬂash column chromatography (silica gel,

5-10% ether/benzene) gave methyl ketone 77 (358.9 mg, 63%)

as a colorless oil, along with recovered 76 (151.8 mg, 27%). Data

for 77: [R]¹⁹_D-55.6 (c 1.00, CHCl₃); IR (ﬁlm) 2945, 2868, 1719,

1

1464, 1149, 1101, 1040, 919, 882, 823, 680 cm^-1; H NMR (500

MHz, CDCl₃) δ 4.64-4.60 (m, 4H), 3.68 (dd, J ) 12.5, 5.0 Hz,

1H), 3.48-3.40 (m, 3H), 3.33 (s, 6H), 3.20 (td, J ) 1.5, 10.0 Hz,

1H), 2.50 (m, 1H), 2.42 (m, 1H), 2.30 (ddd, J ) 12.0, 4.5, 4,5 Hz,

1H), 2.21-2.15 (m, 1H), 2.11 (s, 3H), 1.66-1.51 (m, 2H), 1.09

(s, 3H), 1.04 (m, 21H); ¹³C NMR (125 MHz, CDCl₃) δ 209.0, 96.9,

96.1, 76.1, 74.3, 72.8, 72.0, 70.9, 55.4, 55.2, 40.1, 36.3, 29.9, 26.5,

18.2 (×3), 18.1 (×3), 13.5, 12.6 (×3); HRMS (FAB) calcd for

C₂₄H₄₉O₇Si [(M + H)⁺] 477.3242, found 477.3251.

ꢀ-Alkoxy Acrylate 78. To a solution of methyl ketone 77 (5.51

g, 11.7 mmol) in THF (80 mL) at 0 °C was added TBAF (1.0 M

solution in THF, 35.2 mL, 35.2 mmol). After being stirred at room

temperature for 30 min, the reaction mixture was diluted with

EtOAc, washed with saturated aqueous NH₄Cl and brine, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. Puriﬁca-

tion of the residue by ﬂash column chromatography (silica gel,

20-80% EtOAc/hexanes) gave crude alcohol, which was used in

the next reaction without further puriﬁcation.

96%) as a colorless oil: [R]²¹-49.5 (c 1.00, CHCl₃); IR (ﬁlm)

D

2945, 2868, 2359, 1463, 1102, 1037, 920, 882, 681 cm^-1; ¹H NMR

(600 MHz, CDCl₃) δ 5.93 (ddd, J ) 16.9, 10.8, 6.0, 1H), 5.24 (m,

1H), 5.14 (m, 1H), 4.68-4.62 (m, 4H), 3.77-3.71 (m, 2H),

3.55-3.46 (m, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 2.33 (ddd, J ) 12.0,

4.2, 4.2 Hz, 1H), 1.70 (ddd, J ) 12.0, 11.4, 11.4 Hz, 1H), 1.17 (s,

3H), 1.03 (m, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 136.7, 116.7,

96.9, 96.1, 76.3, 75.9, 72.7, 72.1, 70.9, 55.4, 55.3, 36.4, 18.1 (×6),

13.3, 12.6 (×3); HRMS (FAB) calcd for C₂₂H₄₅O₆Si [(M + H)⁺]

433.2980, found 433.2991.

Alcohol 75. To a solution of 2-methyl-2-butene in THF (80 mL)

at 0 °C was added borane dimethylsulﬁde complex (1.9 M solution

in THF, 16.0 mL, 30.4 mmol). After being stirred at 0 °C for 1 h,

a solution of bis-methoxymethyl ether 74 (8.59 g, 20.2 mmol) in

THF (30 mL + 2 × 5.0 mL rinse) was added. After being stirred

at 0 °C for 1 h, the reaction mixture was treated sequentially with

saturated aqueous NaHCO₃and 30% aqueous H₂O₂. The resultant

mixture was stirred at 0 °C for 10 min and then at room temperature

for 1 h. The mixture was diluted with EtOAc, washed with H₂O,

saturated aqueous Na₂SO₃, and brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. Puriﬁcation of the residue

by column chromatography (silica gel, 20% EtOAc/hexanes) gave

To a solution of the above crude alcohol in CH₂Cl₂(80 mL)

were added methyl propiolate (2.90 mL, 34.7 mmol) and NMM

(1.90 mL, 17.3 mmol), and the resultant solution was stirred at

room temperature overnight. Concentration under reduced pressure

followed by puriﬁcation by ﬂash column chromatography (silica

gel, 15-70% EtOAc/hexanes) gave ꢀ-alkoxy acrylate 78 (4.52 g,

98% for the two steps) as a colorless oil: [R]²¹-43.6 (c 1.00,

D

alcohol 75 (8.73 g, 98%) as a colorless oil: [R]²⁰-40.4 (c 1.00,

D

CHCl₃); IR (ﬁlm) 2950, 1713, 1642, 1439, 1359, 1288, 1202, 1146,

1110, 1041, 918 cm^-1;¹H NMR (600 MHz, CDCl₃) δ 7.43 (d, J )

6.6 Hz, 1H), 5.28 (d, J ) 12.6 Hz, 1H), 4.63-4.60 (m, 4H), 3.76

(dd, J ) 12.0, 4.8 Hz, 1H), 3.67 (s, 3H), 3.58 (m, 1H), 3.49-3.42

(m, 3H), 3.33 (s, 6H), 2.54 (m, 1H), 2.46-2.37 (m, 2H), 2.11 (s,

3H), 1.99 (m, 1H), 1.67 (m, 1H), 1.54 (m, 1H), 1.10 (s, 3H); ¹³C

NMR (150 MHz, CDCl₃) δ 208.4, 168.0, 161.1 (×2), 98.1, 96.8,

96.1, 80.1, 76.6, 72.2, 71.6, 70.8, 55.3, 51.2, 39.3, 31.9, 29.9, 25.9,

13.3; HRMS (FAB) calcd for C₁₉H₃₃O₉[(M + H)⁺] 405.2119,

found 405.2133.

CHCl₃); IR (ﬁlm) 2945, 2868, 2360, 1463, 1384, 1101, 1046, 919,

882, 680 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 4.63-4.59 (m, 4H),

3.80-3.73 (m, 2H), 3.62 (dd, J ) 4.5, 4.5 Hz, 1H), 3.55-3.53 (m,

2H), 3.46 (m, 2H), 3.33 (s, 6H), 3.20 (dd, J ) 7.5, 3.0 Hz, 1H),

2.31 (ddd, J ) 12.0, 4.0, 4.0 Hz, 1H), 2.05 (m, 1H), 1.70-1.64

(m, 2H), 1.21 (s, 3H), 1.04 (m, 21H); ¹³C NMR (125 MHz, CDCl₃)

δ 96.8, 96.0, 76.7, 76.2, 73.1, 72.6, 70.3, 62.0, 55.5, 55.3, 35.9,

33.6, 18.1 (×6), 13.3, 12,6 (×3); HRMS (FAB) calcd for

C₂₂H₄₇O₇Si [(M + H)⁺] 451.3086, found 451.3105.

Nitrile 76. To a solution of alcohol 75 (8.49 g, 19.2 mmol) in

CH₂Cl₂(125 mL) at 0 °C were added Et₃N (5.50 mL, 39.4 mmol)

and MsCl (2.29 mL, 29.6 mmol). After being stirred at 0 °C for

1 h, the reaction mixture was diluted with EtOAc, washed with

saturated aqueous NaHCO₃and brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. The crude mesylate was

used in the next reaction without puriﬁcation.

Lactone 70. To a solution of ꢀ-alkoxy acrylate 78 (4.52 g, 11.3

mmol) in THF (75 mL) were added MeOH (1.4 mL, 34 mmol)

and SmI₂(0.1 M solution in THF, 400 mL, 40 mmol). After being

stirred at room temperature for 1 h, the reaction mixture was

quenched with a 1:1 mixture of saturated aqueous NaHCO₃and

saturated aqueous Na₂S₂O₃. The resultant mixture was ﬁltered

through a plug of Celite, and the ﬁltrate was concentrated under

reduced pressure to remove the bulk of THF. The residue was

diluted with EtOAc, washed with saturated aqueous NaHCO₃,

saturated aqueous Na₂S₂O₃, and brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. Puriﬁcation of the residue

by ﬂash column chromatography (silica gel, 40-60% EtOAc/

To a solution of the above crude mesylate in DMSO (125 mL)

was added NaCN (4.73 g, 95.8 mmol). After being stirred at 60 °C

for 2 h, the reaction mixture was cooled to room temperature. The

mixture was diluted with diethyl ether, washed with H₂O and brine,

dried over Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. Puriﬁcation of the residue by column chromatography

(silica gel, 8-20% EtOAc/hexanes) gave nitrile 76 (8.11 g, 94%)

hexanes) gave lactone 70 (3.82 g, 92%) as a colorless oil: [R]²²

D

-37.9 (c 1.00, CHCl₃); IR (ﬁlm) 2946, 1784, 1453, 1384, 1253,

1211, 1145, 1110, 1038, 970, 941, 916 cm^-1; ¹H NMR (600 MHz,

CDCl₃) δ 4.64-4.62 (m, 4H), 4.19 (dd, J ) 10.8, 9.0 Hz, 1H),

3.71 (dd, J ) 12.0, 4.8 Hz, 1H), 3.48-3.42 (m, 3H), 3.33 (s, 6H),

3.18 (m, 1H), 2.71-2.63 (m, 2H), 2.34 (ddd, J ) 12.0, 4.8, 4.8

Hz, 1H), 2.08 (m, 1H), 2.00 (m, 1H), 1.96-1.90 (m, 2H), 1.67 (m,

1H), 1.38 (s, 3H), 1.14 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ

172.3, 96.8, 96.0, 87.0, 81.2, 77.4, 76.4, 72.9, 71.8, 71.3, 55.6, 55.3,

34.3, 33.2, 32.5, 30.1, 24.3, 13.2; HRMS (FAB) calcd for C₁₈H₃₁O₈

[(M + H)⁺] 375.2013, found 375.2018.

as a colorless oil: [R]²⁰-63.9 (c 1.00, CHCl₃); IR (ﬁlm) 2945,

D

2360, 1463, 1102, 1038, 919, 882, 680 cm^-1; ¹H NMR (500 MHz,

CDCl₃) δ 4.64-4.61 (m, 4H), 3.72 (dd, J ) 12.0, 5.0 Hz, 1H),

3.51-3.42 (m, 3H), 3.36 (m, 1H), 3.37 (s, 6H), 2.45-2.41 (m,

2H), 2.32 (ddd, J ) 11.5, 4.0, 4.0 Hz, 1H), 2.22 (m, 1H), 1.70-1.59

(m, 2H), 1.14 (s, 3H), 1.04 (m, 21H); ¹³C NMR (125 MHz, CDCl₃)

δ 119.7, 96.9, 96.1, 76.5, 73.0, 72.6, 71.9, 70.0, 55.4, 55.2, 36.2,

28.0, 18.2 (×3), 18.1 (×3), 13.6, 13.5, 12.6 (×3); HRMS (FAB)

calcd for C₂₃H₄₅O₆NSiNa [(M + Na)⁺] 482.2908, found 482.2923.

4036 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

Enoate 79. To a solution of lactone 70 (2.95 g, 7.89 mmol) in

CH₂Cl₂(80 mL) at -78 °C was added DIBALH (1.02 M solution

in hexane, 9.3 mL, 9.49 mmol). After being stirred at -78 °C for

30 min, the reaction mixture was quenched with MeOH and treated

with saturated aqueous potassium sodium tartrate. The mixture was

diluted with EtOAc and vigorously stirred at room temperature until

the layers became clear. The organic layer was separated and

washed with brine. The aqueous layers were combined and extracted

with EtOAc. The organic layers were combined, dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude lactol

was used in the next reaction without puriﬁcation.

1.21 (s, 3H), 1.11 (s, 3H), 0.91 (brs, 1H), 0.10 (s, 9H); ¹³C NMR

(125 MHz, C₆D₆) δ 132.0, 129.8, 97.1, 96.0, 88.8, 82.9, 78.3, 77.1,

76.5, 73.8, 72.4, 63.6, 55.2, 55.0, 39.4, 34.1, 33.8, 28.1, 24.8, 14.0,

2.6 (×3); HRMS (FAB) calcd for C₂₃H₄₄O₈SiNa [(M + Na)⁺]

499.2698, found 499.2708.

Hydroxy Epoxide 81. To a solution of allylic alcohol 80 (118.3

mg, 0.228 mmol) in CH₂Cl₂(3 mL) were added 4 Å molecular

sieves (59.0 mg) and (-)-diethyl tartrate (0.04 M solution in

CH₂Cl₂, 1.3 mL, 0.052 mmol). The mixture was cooled to -20

°C, and Ti(OⁱPr)₄(0.015 mL, 0.046 mmol) was added. The resultant

mixture was stirred at -20 °C for 30 min. To this mixture was

added t-BuOOH (3.7 M solution in isooctane, 0.12 mL, 0.44 mmol).

After being stirred at -20 °C overnight, the reaction mixture was

treated with wet Na₂SO₄, allowed to warm to room temperature,

and ﬁltered through a plug of Celite. The ﬁltrate was diluted with

EtOAc and washed with water and brine. The aqueous layers were

combined and extracted with EtOAc. The organic layers were

combined, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash column

chromatography (silica gel, 30-70% EtOAc/hexanes) to give

To a solution of the above crude lactol in toluene (80 mL) was

added Ph₃PdCHCO₂Et (3.30 g, 9.47 mmol). The resultant mixture

was stirred at 80 °C for 30 min. After cooling to room temperature,

the reaction mixture was concentrated under reduced pressure. The

residue was puriﬁed by ﬂash column chromatography (silica gel,

50% EtOAc/hexanes) to give alcohol (3.07 g, 89% for the two steps)

as a colorless oil: [R]¹⁹-32.1 (c 1.00, CHCl₃); IR (ﬁlm) 3480,

D

2937, 1719, 1654, 1458, 1371, 1320, 1267, 1148, 980, 918 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 6.97 (dt, J ) 15.5, 7.5 Hz, 1H),

5.88 (d, J ) 15.5 Hz, 1H), 4.64-4.59 (m, 4H), 4.17 (q, J ) 7.0

Hz, 2H), 3.69 (dd, J ) 11.5, 4.5 Hz, 1H), 3.48 (s, 2H), 3.37 (dd,

J ) 10.0, 2.0 Hz, 1H), 3.34 (s, 3H), 3.33 (s, 3H), 3.21 (m, 1H),

3.06 (m, 1H), 2.46 (dd, J ) 14.5, 8.0 Hz, 1H), 2.27-2.20 (m, 2H),

1.83 (m, 1H), 1.79-1.74 (m, 3H), 1.64-1.57 (m, 2H), 1.27 (t, J )

7.0 Hz, 3H), 1.15 (s, 3H), 1.13 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 166.5, 146.3, 123.3, 96.8, 95.8, 86.8, 82.3, 76.7, 75.5, 74.8, 73.3,

72.0, 60.2, 55.5, 55.3, 39.7, 33.6, 33.3, 27.4, 24.1, 14.2, 13.7; HRMS

(FAB) calcd for C₂₂H₃₉O₉[(M + H)⁺] 447.2589, found 447.2590.

To a solution of the above alcohol (1.85 g, 4.14 mmol) in CH₂Cl₂

(40 mL) at 0 °C was added trimethylsilylimidazole (0.91 mL, 6.21

mmol). After being stirred at room temperature overnight, the

reaction mixture was quenched with MeOH. The mixture was

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash column chromatography (silica gel, 20% EtOAc/hexanes) to

hydroxy epoxide 81 (105.9 mg, 94%) as a colorless oil: [R]²⁰

D

-19.3 (c 1.00, CHCl₃); IR (ﬁlm) 2948, 1452, 1378, 1252, 1149,

1

1104, 1040, 919, 840, 754 cm^-1; H NMR (500 MHz, C₆D₆) δ

4.66 (d, J ) 6.5 Hz, 1H), 4.62 (d, J ) 6.5 Hz, 1H), 4.55 (d, J )

6.5 Hz, 1H), 4.52 (d, J ) 6.5 Hz, 1H), 4.10 (dd, J ) 11.5, 5.0 Hz,

1H), 3.63 (dd, J ) 11.0, 5.0 Hz, 2H), 3.46 (dd, J ) 10.5, 2.5 Hz,

1H), 3.31 (m, 1H), 3.26-3.21 (m, 4H), 3.15 (s, 3H), 3.07 (dd, J )

11.5, 5.5 Hz, 1H), 2.94 (dd, J ) 11.5, 5.5 Hz, 1H), 2.87 (m, 1H),

2.73 (td, J ) 5.5, 1.5 Hz, 1H), 2.56 (ddd, J ) 11.5, 4.5, 4.5 Hz,

1H), 1.95-1.75 (m, 6H), 1.64-1.52 (m, 2H), 1.22 (s, 3H), 1.02

(s, 3H), 0.06 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 96.9, 95.8,

97.0, 82.2, 77.5, 76.7, 75.6, 73.5, 72.2, 57.9, 56.5, 55.6, 55.4, 44.7,

38.4, 33.6, 32.5, 27.4, 24.6, 13.8, 2.5 (×3); HRMS (FAB) calcd

for C₂₃H₄₄O₉SiNa [(M + Na)⁺] 515.2647, found 515.2650.

Chloro Epoxide 82. To a solution of hydroxy epoxide 81 (105.9

mg, 0.215 mmol) in CCl₄(4.0 mL) were added PPh₃(155.8 mg,

0.592 mmol) and NaHCO₃(13.3 mg, 0.158 mmol). After being

reﬂuxed for 1 day, the reaction mixture was concentrated under

reduced pressure. Puriﬁcation of residue by ﬂash column chroma-

tography (silica gel, 10-15% EtOAc/hexanes) gave chloro epoxide

82 (98.2 mg, 89%) as a colorless oil: [R]²¹_D-32.8 (c 1.00, CHCl₃);

IR (ﬁlm) 2949, 1456, 1377, 1252, 1149, 1104, 1077, 1046, 919,

840, 753 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 4.66-4.52 (m, 4H),

3.70 (dd, J ) 11.0, 4.5 Hz, 1H), 3.65 (dd, J ) 11.5, 5.0 Hz, 1H),

3.48-3.45 (m, 3H), 3.41 (dd, J ) 10.5, 2.0 Hz, 1H), 3.35 (s, 3H),

3.34 (s, 3H), 3.22 (td, J ) 9.5, 4.5 Hz, 1H), 3.14 (m, 1H), 3.30 (m,

2H), 2.32 (ddd, J ) 12.0, 4.5, 4.5 Hz, 1H), 1.92 (m, 1H), 1.84-1.60

(m, 6H), 1.13 (s, 3H), 1.10 (s, 3H), 0.06 (s, 9H); ¹³C NMR (125

MHz, CDCl₃) δ 96.9, 95.9, 87.0, 82.2, 77.5, 76.7, 75.6, 73.5, 72.2,

57.9, 56.5, 55.6, 55.4, 44.7, 38.4, 33.6, 32.5, 27.4, 24.6, 13.8, 2.5

(×3); HRMS (FAB) calcd for C₂₃H₄₃ClO₈SiNa [(M + Na)⁺]

533.2308, found 533.2321.

give enoate 79 (1.85 g, 84%) as a colorless oil: [R]²¹-23.5 (c

D

1.00, CHCl₃); IR (ﬁlm) 2930, 2857, 1721, 1656, 1462, 1368, 1259,

1

1174, 1101, 1053, 976, 836, 775, 698 cm^-1; H NMR (500 MHz,

CDCl₃) δ 6.96 (m, 1H), 5.84 (m, 1H), 4.65-4.58 (m, 4H), 4.16 (q,

J ) 7.5 Hz, 2H), 3.68 (dd, J ) 12.0, 5.0 Hz, 1H), 3.47 (s, 2H),

3.37-3.32 (m, 7H), 3.19 (td, J ) 9.0, 4.5 Hz, 1H), 3.03 (td, J )

12.0, 4.0 Hz, 1H), 2.41 (dd, J ) 14.5, 7.0 Hz, 1H), 2.21-2.15 (m,

2H), 1.92 (dd, J ) 13.5, 7.5 Hz, 1H), 1.80-1.55 (m, 4H), 1.26 (t,

J ) 7.5 Hz, 3H), 1.11 (s, 6H), 0.06 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 166.5, 147.0, 122.8, 96.8, 95.8, 87.7, 82.2, 77.7, 76.7,

75.6, 73.4, 72.1, 60.1, 55.5, 55.3, 38.7, 33.6, 33.4, 27.4, 24.4, 14.2,

13.7, 2.4 (×3); HRMS (FAB) calcd for C₂₅H₄₆O₉SiNa [(M + Na)⁺]

541.2803, found 541.2811.

Allylic Alcohol 80. To a solution of enoate 79 (2.54 g, 4.90

mmol) in CH₂Cl₂(45 mL) at -78 °C was added DIBALH (1.02

M solution in hexane, 12.0 mL, 12.2 mmol). After being stirred at

-78 °C for 30 min, the reaction mixture was quenched with MeOH,

and saturated aqueous potassium sodium tartrate was added. The

mixture was diluted with EtOAc and vigorously stirred at room

temperature until the layers became clear. The organic layer was

separated and washed with brine. The aqueous layers were

combined and extracted with EtOAc. The organic layers were

combined, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 50% EtOAc/hexanes) gave allylic

Propargylic Alcohol 83. To a freshly prepared solution of LDA

[prepared from diisopropylamine (0.140 mL, 0.977 mmol) and

n-BuLi (1.65 M solution in hexane, 0.540 mL, 0.891 mmol)] in

THF (0.5 mL) at -40 °C was added a solution of chloro epoxide

82 (98.2 mg, 0.192 mmol) in THF (1.0 mL + 2 × 0.4 mL rinse).

After being stirred at -40 °C for 30 min, the reaction mixture was

quenched with saturated aqueous NH₄Cl, diluted with EtOAc,

washed with H₂O and brine, dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography (silica gel, 30-40% EtOAc/hexanes) to

alcohol 80 (2.30 g, 99%) as a colorless oil: [R]²¹-26.6 (c 1.00,

D

CHCl₃); IR (ﬁlm) 3542, 2947, 2361, 1376, 1251, 1148, 1102, 1039,

919, 840, 754 cm^-1; H NMR (500 MHz, C₆D₆) δ 5.76-5.65 (m,

give propargylic alcohol 83 (78.0 mg, 86%) as a yellow oil: [R]²⁰

1

D

2H), 4.66 (d, J ) 6.0 Hz, 1H), 4.61 (d, J ) 6.5 Hz, 1H), 4.51 (d,

J ) 6.5 Hz, 1H), 4.49 (d, J ) 6.5 Hz, 1H), 3.95-3.90 (m, 3H),

3.62 (d, J ) 10.5 Hz, 1H), 3.59 (d, J ) 10.5 Hz, 1H), 3.35 (m,

1H), 3.30 (td, J ) 9.5, 4.0 Hz, 1H), 3.22 (s, 3H), 3.14 (s, 3H), 3.10

(m, 1H), 2.53 (ddd, J ) 12.0, 4.5, 4.5 Hz, 1H), 2.37 (m, 1H), 2.14

(m, 1H), 1.97-1.75 (m, 4H), 1.61 (dd, J ) 14.5, 11.0 Hz, 1H),

-41.4 (c 1.00, CHCl₃); IR (ﬁlm) 3455, 2947, 1377, 1252, 1218,

1

1148, 1104, 1039, 919, 840, 755, 680 cm^-1; H NMR (500 MHz,

CDCl₃) δ 4.70-4.63 (m, 4H), 4.56 (m, 1H), 3.74 (dd, J ) 12.0,

5.0 Hz, 1H), 3.60 (dd, J ) 9.0, 2.5 Hz, 1H), 3.51 (s, 2H), 3.38 (s,

3H), 3.37 (s, 3H), 3.33 (m, 2H), 2.93 (brs, 1H), 2.52 (d, J ) 2.0

Hz, 1H), 2.31 (ddd, J ) 11.5, 4.5, 4.5 Hz, 1H), 2.03-1.62 (m,

J. Org. Chem. Vol. 74, No. 11, 2009 4037

Fuwa et al.

7H), 1.17 (s, 3H), 1.16 (s, 3H), 0.12 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 96.9, 95.9, 87.1, 84.5, 81.9, 77.6, 76.7, 75.4, 73.4, 73.1,

72.1, 61.6, 55.6, 55.3, 38.4 (×2), 33.7, 27.4, 24.7, 13.7, 2.4 (×3);

HRMS (FAB) calcd for C₂₃H₄₂O₈SiNa [(M + Na)⁺] 497.2541,

found 497.2552.

3.34 (s, 3H), 3.31 (s, 3H), 3.22 (m, 1H), 3.16-3.08 (m, 2H), 2.29

(m, 1H), 2.22-2.09 (m, 2H), 1.94-1.84 (m, 3H), 1.80-1.71 (m,

3H), 1.68-1.49 (m, 5H), 1.13 (s, 3H), 1.12 (s, 3H), 1.02 (d, J )

7.0 Hz, 3H), 0.91 (d, J ) 7.0 Hz, 3H), 0.05 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃) δ 159.0, 138.4, 133.9, 131.3, 129.2, 128.9 (×2),

128.8, 128.4 (×2), 127.8 (×2), 127.6, 113.7 (×2), 96.9, 95.9, 88.3,

86.3, 81.6, 77.7, 76.6, 74.5, 73.5, 72.9, 72.1, 68.2, 67.1, 55.6, 55.3

(×2), 38.3, 37.6, 35.9, 34.4, 33.8, 32.1, 31.8, 27.4, 24.6, 15.8, 14.0,

13.7, 2.5 (×3); HRMS (FAB) calcd for C₄₆H₇₄O₁₁SiNa [(M + Na)⁺]

853.4893, found 853.4902.

Iodoalkyne 84. To a solution of propargylic alcohol 83 (149.6

mg, 0.290 mmol) in acetone (3.0 mL) at 0 °C were added NIS

(78.3 mg, 0.348 mmol) and AgNO₃(29.6 mg, 0.174 mmol). After

being stirred at 0 °C for 1 h, the reaction mixture was diluted with

EtOAc, washed with H₂O and brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. The residue was puriﬁed

by ﬂash column chromatography (silica gel, 25% EtOAc/hexanes)

Hydroxy Alkene 68. To a solution of cis-oleﬁn 85 (53.0 mg,

0.064 mmol) in CH₂Cl₂(1.0 mL) at 0 °C were added Et₃N (0.02

mL, 0.128 mmol) and TIPSOTf (0.025 mL, 0.096 mmol). After

being stirred at 0 °C for 4 h, the reaction mixture was quenched

with saturated aqueous NaHCO₃. The mixture was diluted with

EtOAc, washed with H₂O and brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. The residue was puriﬁed

by ﬂash column chromatography (silica gel, 10-30% EtOAc/

hexanes) to give triisopropylsilyl ether (50.6 mg, 80%) as a colorless

oil: [R]¹⁸_D-6.5 (c 1.00, CHCl₃); IR (ﬁlm) 2942, 2865, 1249, 1148,

to give iodoalkyne 84 (173.0 mg, 91%) as a colorless oil: [R]²⁰

D

-53.7 (c 0.51, CHCl₃); IR (ﬁlm) 3429, 2946, 2889, 2824, 1531,

1350, 1251, 1142, 1104, 1079, 1038, 919, 840 cm^-1; ¹H NMR (500

MHz, C₆D₆) δ 4.70-4.64 (m, 3H), 4.51 (s, 2H), 3.91 (dd, J )

11.5, 5.0 Hz, 1H), 3.60 (dd, J ) 19.0, 11.0 Hz, 2H), 3.53 (dd, J )

7.5, 2.0 Hz, 1H), 3.28-3.24 (m, 4H), 3.19 (m, 1H), 3.15 (s, 3H),

2.45 (ddd, J ) 11.5, 4.5, 4.5 Hz, 1H), 2.39 (brs, 1H), 2.06 (ddd, J

) 13.5, 7.0, 2.5 Hz, 1H), 1.97-1.77 (m, 3H), 1.75-1.69 (m, 2H),

1.50 (m, 1H), 1.21 (s, 3H), 0.99 (s, 3H), 0.06 (s, 9H); ¹³C NMR

(125 MHz, C₆D₆) δ 97.1, 96.5, 95.9, 87.0, 82.1, 78.0, 77.1, 75.6,

73.6, 72.5, 63.4, 55.3, 55.0, 39.2, 38.8, 34.2, 28.1, 24.6, 13.9, 2.5

(×3), 1.8; HRMS (FAB) calcd for C₂₃H₄₁IO₈SiNa [(M + Na)⁺]

623.1508, found 623.1516.

1

1084, 1038, 839 cm^-1; H NMR (500 MHz, CDCl₃) δ 7.34-7.25

(m, 7H), 6.88-6.85 (m, 2H), 5.53 (m, 1H), 5.31 (m, 1H), 4.71 (m,

1H), 4.65-4.57 (m, 4H), 4.51-4.44 (m, 4H), 3.77 (s, 3H), 3.62

(dd, J ) 11.5, 5.0 Hz, 1H), 3.54-3.45 (m, 5H), 3.33 (s, 3H), 3.31

(s, 3H), 3.20 (m, 1H), 3.13-3.08 (m, 2H), 2.34 (ddd, J ) 11.0,

3.5, 3.5 Hz, 1H), 2.12-2.01 (m, 2H), 1.91-1.59 (m, 10H), 1.49

(m, 1H), 1.13 (s, 3H), 1.08 (s, 3H), 1.06 (m, 21H), 0.96-0.93 (m,

6H), 0.04 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 159.0, 138.6,

135.9, 131.3, 129.0 (×2), 128.3 (×2), 127.6 (×2), 127.5, 126.6,

113.7 (×2), 96.8, 96.1, 86.2, 84.2, 81.5, 77.5, 76.7, 75.9, 74.3 (×2),

72.9, 72.3, 68.7, 66.6, 55.4, 55.3, 55.2, 39.2, 38.7, 36.2, 34.0, 33.9,

32.9, 32.5, 27.5, 24.7, 18.2 (×6), 15.3, 15.0, 13.7, 12.4 (×3), 2.5

(×3); HRMS (FAB) calcd for C₅₅H₉₄O₁₁Si₂Na [(M + Na)⁺]

1009.6227, found 1009.6240.

Vinyl Iodide 69. To a solution of iodoalkyne 84 (169.3 mg,

0.282 mmol) in THF/i-PrOH (1:1, v/v, 5.0 mL) at 0 °C were added

o-nitrobenzenesulfonyl hydrazide (286 mg, 1.32 mmol) and Et₃N

(0.180 mL, 1.32 mmol). After being stirred at room temperature

for 5 h, the reaction mixture was diluted with EtOAc, washed with

H₂O and brine, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash column

chromatography (silica gel, 10% acetone/hexanes) to give vinyl

iodide 69 (154.9 mg, 91%) as a colorless oil: [R]²⁰_D-13.5 (c 1.00,

CHCl₃); IR (ﬁlm) 3458, 2948, 1455, 1376, 1251, 1216, 1139, 1103,

1038, 919, 840, 753, 728, 680 cm^-1; ¹H NMR (500 MHz, CDCl₃)

δ 6.35 (m, 1H), 6.25 (m, 1H), 4.66-4.59 (m, 4H), 4.55 (m, 1H),

3.70 (dd, J ) 10.5, 5.5 Hz, 1H), 3.48 (s, 2H), 3.45 (dd, J ) 10.5,

2.5 Hz, 1H), 3.35 (s, 3H), 3.23 (s, 3H), 3.23-3.18 (m, 2H), 2.38

(ddd, J ) 11.5, 4.0, 4.0 Hz, 1H), 1.92 (m, 1H), 1.84 (ddd, J )

14.0, 5.0, 2.5 Hz, 1H), 1.80-1.70 (m, 2H), 1.68-1.59 (m, 3H),

1.14 (s, 3H), 1.13 (s, 3H), 0.08 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 143.3, 96.8, 95.6, 87.9, 82.6, 81.8, 77.6, 76.6, 75.2, 74.2,

73.3, 72.1, 55.5, 55.3, 38.3, 36.2, 33.7, 27.3, 24.5, 13.6, 2.5 (×3);

HRMS (FAB) calcd for C₂₃H₄₃IO₈SiNa [(M + Na)⁺] 625.1664,

found 625.1665.

To a solution of the above triisopropylsilyl ether (113.8 mg, 0.115

mmol) in CH₂Cl₂/pH 7 phosphate buffer (10:1, v/v, 3.3 mL) at 0

°C was added DDQ (28.5 mg, 0.127 mmol). After being stirred at

room temperature for 1 h, the reaction mixture was cooled to 0 °C

and treated with saturated aqueous NaHCO₃. The mixture was

diluted with EtOAc, washed with brine, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. Puriﬁcation of the residue

by ﬂash column chromatography (silica gel, 5-20% EtOAc/

hexanes) gave hydroxy alkene 68 (96.0 mg, 96%) as a colorless

oil: [R]¹⁸_D-11.3 (c 1.00, CHCl₃); IR (ﬁlm) 3522, 2940, 2866, 1464,

1

1251, 1102, 1038, 839, 734, 683, 504, 445 cm^-1; H NMR (500

MHz, CDCl₃) δ 7.34-7.25 (m, 5H), 5.39-5.31 (m, 2H), 4.98-4.58

(m, 5H), 4.51 (d, J ) 12.0 Hz, 1H), 4.47 (d, J ) 12.0 Hz, 1H),

3.67 (dd, J ) 11.5, 5.0 Hz, 1H), 3.55-3.44 (m, 4H), 3.35 (s, 3H),

3.33 (s, 3H), 3.22 (m, 1H), 3.15-3.13 (m, 2H), 3.10 (brs, 1H),

3.03 (m, 1H), 2.34-2.25 (m, 2H), 1.97 (m, 1H), 1.87 (m, 1H),

1.79-1.58 (m, 9H), 1.31 (m, 1H), 1.12 (s, 3H), 1.09 (s, 3H), 1.05

(m, 21H), 0.93 (d, J ) 6.5 Hz, 3H), 0.85 (d, J ) 7.0 Hz, 3H), 0.04

(s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 138.4, 134.8, 128.9, 128.4

(×2), 127.6 (×2), 127.5, 96.9, 95.4, 85.3, 81.6, 78.6, 77.5, 76.5,

75.6, 73.4, 72.9, 72.2, 68.4, 66.6, 55.5, 55.3, 39.9, 38.7, 35.5, 34.0,

33.4, 33.3, 32.9, 27.5, 24.5, 18.2 (×6), 15.7, 13.7, 12.4 (×3), 12.1,

2.5 (×3); HRMS (FAB) calcd for C₄₇H₈₆O₁₀Si₂Na [(M + Na)⁺]

889.5652, found 889.5662.

cis-Oleﬁn 85. To a solution of iodide ent-21 (111.7 mg, 0.232

mmol) in diethyl ether (2.3 mL) was added B-MeO-9-BBN (1.0 M

solution in hexane, 0.60 mL, 0.60 mmol). The resulting mixture

was cooled to -78 °C and treated with t-BuLi (1.58 M solution in

pentane, 0.51 mL, 0.81 mmol) at once. The mixture was stirred at

-78 °C for 5 min before THF (2.3 mL) was added. The resultant

mixture was allowed to warm to room temperature and stirred for

1 h. In a separate ﬂask, vinyl iodide 69 (104.2 mg, 0.173 mmol)

was dissolved in DMF (1.7 mL), to which PdCl₂(dppf)·CH₂Cl₂

(14 mg, 0.017 mmol), Ph₃As (21.2 mg, 0.069 mmol), and 3 M

aqueous Cs₂CO₃(0.17 mL, 0.51 mmol) were added sequentially.

The ethereal solution of alkylborate was then cannulated into the

DMF solution, and the resulting mixture was stirred at 50 °C

overnight. The reaction mixture was diluted with H₂O and extracted

three times with diethyl ether. The organic layers were combined,

washed with brine, dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. Flash column chromatography of the

residue (silica gel, 10-50% EtOAc/hexanes) gave cis-oleﬁn 85

Hydroxy Alkene 87. To a solution of hydroxy alkene 68 (50.6

mg, 0.058 mmol) in THF (1.0 mL) at 0 °C was added TBAF (1.0

M solution in THF, 0.15 mL, 0.15 mmol). After being stirred at

room temperature for 2.5 h, the reaction mixture was diluted with

EtOAc, washed with saturated aqueous NH₄Cl and brine, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. Puriﬁca-

tion of the residue by ﬂash column chromatography (silica gel,

70-90% EtOAc/hexanes) gave hydroxy alkene 87 (37.3 mg, 100%)

(127.2 mg, 88%) as a colorless oil: [R]¹⁸-7.4 (c 1.00, CHCl₃);

D

IR (ﬁlm) 2936, 1514, 1455, 1375, 1249, 1038, 840, 749, 698 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 7.34-7.23 (m, 7H), 6.85-6.83 (m,

2H), 5.53-5.43 (m, 2H), 4.66-4.57 (m, 5H), 4.51-4.44 (m, 4H),

3.77 (s, 3H), 3.67 (dd, J ) 11.5, 5.0 Hz, 1H), 3.53-3.40 (m, 5H),

as a colorless oil: [R]²⁰-14.3 (c 0.65, CH₃OH); IR (ﬁlm) 3445,

D

2934, 2878, 1456, 1375, 1217, 1147, 1099, 1076, 1037, 916, 740,

699 cm^-1; ¹H NMR (500 MHz, acetone-d₆) δ 7.35-7.33 (m, 4H),

4038 J. Org. Chem. Vol. 74, No. 11, 2009

Synthetic Studies on Gambieric Acids

7.27 (m, 1H), 5.50 (m, 1H), 5.41 (m, 1H), 4.70 (d, J ) 7.0 Hz,

1H), 4.64-4.57 (m, 4H), 4.52 (d, J ) 12.0 Hz, 1H), 4.48 (d, J )

12.0 Hz, 1H), 3.75 (dd, J ) 11.5, 5.0 Hz, 1H), 3.58-3.49 (m, 4H),

3.46 (d, J ) 10.5 Hz, 1H), 3.43 (d, J ) 10.5 Hz, 1H), 3.37-3.35

(m, 2H), 3.34 (s, 3H), 3.28 (s, 3H), 3.25-3.21 (m, 2H), 3.06 (m,

1H), 2.34 (ddd, J ) 12.0, 4.0, 4.0 Hz, 1H), 2.27 (m, 1H), 2.12 (m,

1H), 1.87-1.57 (m, 10H), 1.41 (m, 1H), 1.11 (s, 3H), 1.07 (s, 3H),

0.95 (d, J ) 6.0 Hz, 3H), 0.93 (d, J ) 6.0 Hz, 3H); ¹³C NMR (125

MHz, acetone-d₆) δ 140.0, 135.4, 130.3, 129.1 (×2), 128.4 (×2),

128.1, 97.4, 96.3, 86.6, 82.2, 77.8, 77.4, 76.7, 74.3, 74.1, 73.2, 72.8,

68.9, 66.3, 55.6, 55.2, 40.0, 39.7, 36.4, 34.5, 34.4, 33.7, 33.1, 28.4,

24.8, 15.0, 14.3, 14.0; HRMS (FAB) calcd for C₃₅H₅₈O₁₀Na [(M

+ Na)⁺] 661.3922, found 661.3928.

solution in THF, 1.0 mL, 0.60 mmol). To the resultant mixture

heated at 80 °C was added a solution of AIBN (4.9 mg, 0.030

mmol) in THF (1.0 mL) via cannula. After being reﬂuxed for

1.5 h, the reaction mixture was cooled to room temperature and

concentrated under reduced pressure. The residue was puriﬁed

by ﬂash column chromatography (silica gel, 15-90% EtOAc/

hexanes) to give crude material, which was used in the next

reaction without further puriﬁcation.

To a solution of the above crude material in MeOH (4.0 mL)

was added 20% Pd(OH)₂/C (26.8 mg). After the reaction mixture

was stirred at room temperature for 30 min under an atmosphere

of hydrogen, the catalyst was ﬁltered off, and the ﬁltrate was

concentrated under reduced pressure. The residue was puriﬁed

by ﬂash column chromatography (silica gel, 5% MeOH/CHCl₃)

to give tricyclic compound 90 (26.5 mg, 96% for the two steps)

as a colorless oil: [R]²⁸_D-25.6 (c 1.00, CHCl₃); IR (ﬁlm) 3477,

Iodide 88. To a solution of bis(sym-collidine)AgPF₆(13.7 mg,

0.028 mmol) in CH₂Cl₂(0.5 mL) was added I₂(5.7 mg, 0.022

mmol). After being stirred at room temperature for 5 min, a solution

of hydroxy alkene 87 (11.9 mg, 0.019 mmol) in CH₂Cl₂(0.8 mL

+ 2 × 0.4 mL rinse) was added. After being stirred at room

temperature for 30 min, the reaction mixture was ﬁltered through

a plug of Celite. The ﬁltrate was diluted with EtOAc and washed

with 10% aqueous Na₂S₂O₃and brine. The organic layer was dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

The residue was puriﬁed by ﬂash column chromatography (silica

gel, 60% diethyl ether/benzene) to give iodide 88 (11.6 mg, 83%)

1

3414, 2935, 1244, 1148, 1096, 1043, 834 cm^-1; H NMR (500

MHz, acetone-d₆) δ 5.18 (m, 1H), 4.66 (d, J ) 6.5 Hz, 1H),

4.61 (d, J ) 6.5 Hz, 1H), 4.60 (s, 2H), 4.09 (ddd, J ) 16.0, 9.0,

4.0 Hz, 1H), 3.75 (dd, J ) 11.5, 4.5 Hz, 1H), 3.65 (m, 2H),

3.60-3.55 (m, 2H), 3.47-3.42 (m, 4H), 3.32 (s, 3H), 3.29 (s,

3H), 3.22 (ddd, J ) 9.5, 9.5, 4.0 Hz, 1H), 3.09 (m, 1H), 2.35

(ddd, J ) 9.0, 4.0, 4.0 Hz, 1H), 2.27 (m, 1H), 1.99 (s, 3H),

1.96-1.82 (m, 3H), 1.80-1.74 (m, 3H), 1.73-1.55 (m, 7H),

1.19-1.12 (m, 1H), 1.11 (s, 3H), 1.04 (s, 3H), 1.02 (d, J ) 6.5

Hz, 3H), 0.89 (d, J ) 6.5 Hz, 3H); ¹³C NMR (125 MHz, acetone-

d₆) δ 170.4, 129.1, 97.4, 96.4, 86.0, 85.5, 82.8, 77.4, 76.9, 74.4,

74.1, 73.6, 72.8, 71.8, 55.6, 55.2, 42.0, 41.7, 40.2, 37.0, 36.6,

35.9, 34.5, 31.4, 28.4, 24.4, 21.4, 17.7, 14.2, 14.1; HRMS (FAB)

calcd for C₃₀H₅₅O₁₁[(M + H)⁺] 591.3739, found 591.3739.

Ester 91. To a solution of tricyclic compound 90 (16.7 mg,

0.027 mmol) in CH₂Cl₂(1.5 mL) at 0 °C was added Dess-Martin

periodinane (23 mg, 0.054 mmol). After being stirred at room

temperature, the reaction mixture was quenched with a 1:1

mixture of saturated aqueous NaHCO₃and saturated aqueous

Na₂SO₃. The resultant mixture was diluted with EtOAc, washed

with brine, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 70% EtOAc/hexanes) gave crude

aldehyde.

To a solution of the above aldehyde in THF/H₂O (5:1, v/v, 1.8

mL) were added 2-methyl-2-butene (0.016 mL, 0.153 mmol) and

NaH₂PO₄(2.8 mg, 0.023 mmol). The reaction mixture was cooled

to 0 °C and treated with NaClO₂(4.8 mg, 0.054 mmol). After being

stirred at room temperature for 1 h, the reaction mixture was diluted

with H₂O and acidiﬁed with 0.5 M aqueous HCl. The mixture was

extracted two times with EtOAc. The organic layers were combined,

dried over Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash column chromatography

(silica gel, 10% MeOH/CHCl₃) to give crude carboxylic acid, which

was used in the next reaction without puriﬁcation.

To a solution of the above carboxylic acid in MeOH/benzene

(1:1, v/v, 3.0 mL) was added TMSCHN₂(2.0 M solution in hexane,

0.023 mL, 0.046 mmol). After being stirred at room temperature

for 30 min, the resultant mixture was concentrated under reduced

pressure. Puriﬁcation of the residue by column chromatography

(silica gel, 70-100% EtOAc/hexanes) gave ester 91 (8.5 mg, 52%

for the three steps) as a colorless oil: [R]²⁸_D-16.7 (c 1.00, CHCl₃);

IR (ﬁlm) 3464, 2935, 2360, 1736, 1438, 1375, 1242, 1148, 1095,

1038, 917 cm^-1; ¹H NMR (500 MHz, acetone-d₆) δ 5.17 (m, 1H),

4.66 (d, J ) 7.0 Hz, 1H), 4.62-4.58 (m, 3H), 4.12 (m, 1H), 3.75

(dd, J ) 11.5, 4.5 Hz, 1H) 3.63 (s, 3H), 3.59 (s, 1H), 3.50 (dd, J

) 9.0, 4.0 Hz, 1H), 3.47-3.41 (m, 3H), 3.32 (s, 3H), 3.29 (s, 3H),

3.22 (ddd, J ) 9.5, 9.5, 4.0 Hz, 1H), 3.08 (ddd, J ) 13.0, 9.5, 4.0

Hz, 1H), 2.37-2.33 (m, 2H), 2.28 (m, 1H), 2.01-1.91 (m, 5H),

1.89-1.76 (m, 5H), 1.73-1.55 (m, 6H), 1.11 (s, 3H), 1.05 (d, J )

4.5 Hz, 3H), 1.05 (s, 3H), 0.90 (d, J ) 7.0 Hz, 3H); ¹³C NMR

(125 MHz, acetone-d₆) δ 173.2, 170.4, 129.1, 97.4, 96.4, 85.5, 84.9,

82.8, 77.4, 76.9, 74.4, 74.0, 72.8, 71.7, 55.6, 55.2, 51.6, 42.0, 41.6,

as a colorless oil: [R]¹⁹-7.2 (c 1.00, MeOH); IR (ﬁlm) 3434,

D

2935, 2876, 1595, 1453, 1236, 1075, 1043, 968, 838, 739, 699,

616 cm^-1; ¹H NMR (500 MHz, acetone-d₆) δ 7.35-7.34 (m, 4H),

7.28-7.25 (m, 1H), 4.66 (d, J ) 7.0 Hz, 1H), 4.62 (d, J ) 7.0 Hz,

1H), 4.61-4.58 (m, 2H), 4.52 (d, J ) 12.0 Hz, 1H), 4.48 (d, J )

12.0 Hz, 1H), 4.33 (dd, J ) 6.0, 3.0 Hz, 1H), 4.08 (d, J ) 4.0 Hz,

1H), 3.93 (ddd, J ) 9.0, 6.5, 2.5 Hz, 1H), 3.77 (dd, J ) 12.0, 4.0

Hz, 2H), 3.75-3.69 (m, 3H), 3.65-3.52 (m, 2H), 3.46 (d, J )

10.5 Hz, 1H), 3.43 (d, J ) 10.5 Hz, 1H), 3.31 (s, 3H), 3.29-3.28

(m, 5H), 2.41-2.36 (m, 2H), 2.29 (ddd, J ) 12.0, 8.0, 4.0 Hz,

1H), 1.96-1.61 (m, 10H), 1.23 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H),

1.01 (d, J ) 6.5 Hz, 3H), 0.93 (d, J ) 6.5 Hz, 3H); ¹³C NMR (125

MHz, acetone-d₆) δ 140.0, 129.0 (×2), 128.2 (×2), 128.1, 97.4,

96.4, 88.1, 88.0, 82.4, 77.4, 76.2, 75.9, 74.7, 74.6, 73.9, 73.2, 72.7,

68.4, 55.6, 55.2, 53.6, 42.2, 39.8, 38.1, 35.7, 34.5, 33.6, 31.9, 28.3,

24.6, 17.4, 14.7, 13.9; HRMS (FAB) calcd for C₃₅H₅₈IO₁₀[(M +

H)⁺] 765.3069, found 765.3080.

Acetate 89. To a solution of iodide 88 (41.0 mg, 0.054 mmol)

in THF (3.0 mL) at 0 °C were added Et₃N (0.04 mL, 0.273 mmol),

DMAP (0.70 mg, 0.005 mmol), and Ac₂O (0.02 mL, 0.219 mmol).

After being stirred at room temperature overnight, the reaction

mixture was cooled to 0 °C and quenched with MeOH. The mixture

was diluted with EtOAc, washed with 1 M aqueous HCl, saturated

aqueous NaHCO₃, and brine. The organic layer was dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The

residue was puriﬁed by ﬂash column chromatography (silica gel,

70% EtOAc/hexanes) to give acetate 89 (42.7 mg, 100%) as a

colorless oil: [R]¹⁹_D-10.0 (c 1.00, CH₃OH); IR (ﬁlm) 3462, 2932,

1734, 1373, 1237, 1097, 1038, 968, 698 cm^-1; ¹H NMR (500 MHz,

acetone-d₆) δ 7.35-7.32 (m, 4H), 7.28-7.25 (m, 1H), 4.81 (m,

1H), 4.65 (d, J ) 6.5 Hz, 1H), 4.63 (d, J ) 6.5 Hz, 1H), 4.60 (d,

J ) 6.5 Hz, 1H), 4.58 (d, J ) 6.5 Hz, 1H), 4.53-4.45 (m, 3H),

3.85 (ddd, J ) 10.0, 6.5, 4.0 Hz, 1H), 3.75-3.69 (m, 2H),

3.60-3.51 (m, 4H), 3.44 (dd, J ) 11.0, 7.0 Hz, 2H), 3.33 (s, 3H),

3.28 (s, 3H), 3.23 (m, 1H), 3.09 (m, 1H), 2.40 (m, 1H), 2.34-2.25

(m, 2H), 2.07 (s, 3H), 1.92-1.84 (m, 3H), 1.79-1.55 (m, 6H),

1.29-1.16 (m, 2H), 1.10 (s, 3H), 1.09 (s, 3H), 1.02 (d, J ) 6.5

Hz, 3H), 0.93 (d, J ) 6.5 Hz, 3H); ¹³C NMR (125 MHz, acetone-

d₆) δ 170.3, 140.1, 129.0 (×2), 128.2 (×2), 128.1, 97.4, 96.6, 87.7,

86.6, 82.7, 77.4, 76.7, 76.6, 75.7, 74.7, 74.3, 73.3, 72.7, 68.4, 55.6,

55.2, 48.7, 41.8, 40.3, 35.9, 35.7, 34.7, 33.6, 31.9, 28.4, 24.4, 21.3,

17.4, 14.6, 14.0; HRMS (FAB) calcd for C₃₇H₅₉IO₁₁Na [(M + Na)⁺]

829.2994, found 829.3004.

Tricyclic Compound 90. To a solution of acetate 89 (26.0

mg, 0.033 mmol) in THF (5.0 mL) was added Ph₃SnH (0.6 M

J. Org. Chem. Vol. 74, No. 11, 2009 4039

Fuwa et al.

40.2, 38.6, 36.6, 35.8, 34.5, 32.4, 28.4, 24.4, 21.4, 18.2, 14.1 (×2);

HRMS (FAB) calcd for C₃₁H₅₄O₁₂Na [(M + Na)⁺] 641.3508, found

641.3514.

87.6, 86.2, 84.2, 78.5, 78.1, 75.2, 73.9, 69.2, 56.6, 56.4, 46.0, 42.7,

41.4, 41.2, 40.3, 36.8, 35.7, 33.4, 29.4, 25.6, 19.6, 15.2, 15.1; HRMS

(FAB) calcd for C₂₈H₅₁O₁₁[(M + H)⁺] 563.3426, found 563.3439.

A/BC-Ring Model Compound 67. To a solution of ester 91

(6.0 mg, 0.010 mmol) in MeOH/THF/H₂O (1:1:1, v/v/v, 1.5 mL)

at 0 °C was added LiOH ·H₂O (2.2 mg, 0.049 mmol). After being

stirred at room temperature for 5.5 h, the reaction mixture was

cooled to 0 °C and acidiﬁed with 0.25 M aqueous HCl. The mixture

was extracted ﬁve times with EtOAc. The organic layers were

combined, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 20% MeOH/CHCl₃) gave the A/BC

Acknowledgment. We are grateful to Professor Masayuki

Satake (The University of Tokyo), Professor Yasukatsu Oshima

(Tohoku University), and Dr. Takeshi Yasumoto (Japan Food

Research Laboratories) for providing the ¹H and HSQC spectra

of gambieric acid B and for fruitful discussions. This work was

supported in part by a Grant-in-Aid for Scientiﬁc Research from

the Japan Society for the Promotion of Science (JSPS) and by

the Tohoku University G-COE program “International Center

of Research and Education for Molecular Complex Chemistry”

from the Ministry of Education, Culture, Sports, Science and

Technology (MEXT), Japan.

ring model compound 67 (5.1 mg, 93%) as colorless oil: [R]²⁷

D

-11.3 (c 0.45, MeOH); IR (ﬁlm) 3420, 2934, 1716, 1378, 1148,

1

1043, 918 cm^-1; H NMR (600 MHz, 1:1 C₅D₅N/CD₃OD) δ 4.62

(d, J ) 6.6 Hz, 1H), 4.60 (d, J ) 6.6 Hz, 1H), 4.57 (d, J ) 6.6 Hz,

1H), 4.55 (d, J ) 6.6 Hz, 1H), 4.43 (m, 1H), 4.17 (m, 1H), 3.84

(dd, J ) 11.4, 4.8 Hz, 1H), 3.58 (m, 1H), 3.49 (d, J ) 10.8 Hz,

1H), 3.45 (d, J ) 10.8 Hz, 1H), 3.40 (dd, J ) 9.6, 4.6 Hz, 1H),

3.28-3.19 (m, 8H), 2.40 (ddd, J ) 11.4, 4.2, 4.2 Hz, 1H), 2.34 (d,

J ) 15.0, 3.0 Hz, 1H), 2.13-2.09 (m, 2H), 2.03-1.92 (m, 4H),

1.80-1.59 (m, 7H), 1.50 (ddd, J ) 13.8, 9.6, 2.4 Hz, 1H), 1.19 (d,

J ) 6.6 Hz, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 0.81 (d, J ) 7.2 Hz,

3H), (three protons missing due to the H/D exchange); ¹³C NMR

(150 MHz, 1:1 C₅D₅N/CD₃OD) δ 176.8, 151.0, 130.1, 98.5, 97.5,

Supporting Information Available: Detailed synthetic

schemes for compounds 18b-d, experimental details for

compounds not described in Experimental Section, and copies

1

of H and ¹³C NMR spectra for all new compounds. This

material is available free of charge via the Internet at

http://pubs.acs.org.

JO900332Q

4040 J. Org. Chem. Vol. 74, No. 11, 2009

Article Doi

Synthetic studies on gambieric acids, potent antifungal polycyclic ether natural products: Reassignment of the absolute configuration of the nonacyclic polyether core by NMR analysis of model compounds

DOI: 10.1021/jo900332q

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