A Convergent Synthesis of the Decacyclic Ciguatoxin Model Containing the F-M Ring Framework

DOI: 10.1021/jo990989b

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Journal of Organic Chemistry p. 9416 - 9429 (1999)

Update date:2022-09-26

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Authors:

Inoue, Masayuki

Sasaki, Makoto

Tachibana, Kazuo

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Article abstract of DOI:10.1021/jo990989b

A highly convergent synthesis of the decacyclic ciguatoxin model 2, which contains the F-M ring framework of the natural product, has been achieved through the assembly of pentacyclic oxonane 4 and JKLM ring fragment 5. The two key steps in the synthesis of the former compound are (i) a Lewis acid-mediated intramolecular reaction of a γ-alkoxyallylsilane with an acetal group to form an O-linked oxacycle and (ii) a SmI₂-mediated intramolecular Reformatsky reaction leading to construction of the annelated oxonane ring system. Preliminary biological investigations revealed that model compound 2 did not inhibit the binding of tritium-labeled dihydrobrevetoxin B to voltage-sensitive sodium channels at micromolar concentrations.

Full text of DOI:10.1021/jo990989b

9416

J . Org. Chem. 1999, 64, 9416-9429

A Con ver gen t Syn th esis of th e Deca cyclic Cigu a toxin Mod el

Con ta in in g th e F -M Rin g F r a m ew or k

Masayuki Inoue,^†,§Makoto Sasaki,*^,†,‡and Kazuo Tachibana*^,†,‡

Department of Chemistry, School of Science, The University of Tokyo, and CREST, J apan Science and

Technology Corporation (J ST), Hongo, Bunkyo-ku, Tokyo 113-0033, J apan

Received J une 21, 1999

A highly convergent synthesis of the decacyclic ciguatoxin model 2, which contains the F-M ring

framework of the natural product, has been achieved through the assembly of pentacyclic oxonane

4 and J KLM ring fragment 5. The two key steps in the synthesis of the former compound are (i) a

Lewis acid-mediated intramolecular reaction of a γ-alkoxyallylsilane with an acetal group to form

an O-linked oxacycle and (ii) a SmI₂-mediated intramolecular Reformatsky reaction leading to

construction of the annelated oxonane ring system. Preliminary biological investigations revealed

that model compound 2 did not inhibit the binding of tritium-labeled dihydrobrevetoxin B to voltage-

sensitive sodium channels at micromolar concentrations.

In tr od u ction

In addition, structure-activity relationship studies of

well-designed synthetic models may provide useful

topochemical information for the identification of the

common structural features necessary for the toxic

effect.

Ciguatoxin (CTX1B, 1) and its congeners, naturally

occurring polycyclic ethers originating from marine uni-

cellular algae, are the principle toxins for ciguatera fish

poisoning.^1,2These toxins reportedly bind to the same site

of voltage-sensitive sodium channels (VSSC) as brevetox-

ins, another class of structurally related marine toxins.³

The common structural feature of these polyether toxins

is that they possess conformationally flexible medium-

sized ether rings in the middle region of the molecules.

It is speculated that the conformational flexibility of these

marine toxins plays an important role in their high-

affinity binding to VSSC and leads to alteration of the

gating mechanism (or the inactivation mechanism) of the

channels.^2aHowever, the scarcity of ciguatoxins from

natural sources has prevented further investigations on

their interactions with VSSC. Thus, the total synthesis

of these toxins and the construction of more accessible

model compounds are necessary for additional studies.

In light of these demands, ciguatoxins have attracted

a great deal of attention from synthetic organic chemists,

and thus a wide variety of new synthetic methods and

strategies have been developed for their synthesis.^4,5At

first glance, construction of the hexahydrooxonine ring

F would appear to be one of the most formidable and

challenging problems for their synthesis. Recently, we

disclosed a convergent approach to the fused hexahy-

drooxonine ring system, featuring an intramolecular

reaction of a γ-alkoxyallylsilane with an acetal group to

form an O-linked oxacycle and a SmI₂-mediated intramo-

lecular Reformatsky reaction for constructing a fused

oxonane ring system.^4c,hTo understand the structural

requirements of ciguatoxins for their specific and high-

affinity binding to VSSC, we set out to synthesize

structurally simplified model compounds. Since the left-

hand portion, the A-E ring system, of ciguatoxin is

considered to form a rigid backbone, we anticipated that

this portion could be replaced with a trans-fused poly-

tetrahydropyran unit. In addition, synthetically prob-

lematic substituents on rings G and I seemed irrelevant

to the total shape of the molecule. In the course of our

studies to synthesize a biologically active model com-

pound as well as to execute the strategy for the total

synthesis, we designed a decacyclic ciguatoxin model 2,

containing the F-M ring framework of the natural

product, in which the conformationally rigid DE ring

* To whom correspondence should be addressed. E-mail: msasaki@

chem.s.u-tokyo.ac.jp (M.S.), ktachi@chem.s.u-tokyo.ac.jp (K.T.). Fax/

phone: +81-3-5841-8380.

^†The University of Tokyo.

^‡CREST, J apan Science and Technology Corp. (J ST).

^§Present address: Laboratory of Bioorganic Chemistry, Sloan-

Kettering Institute for Cancer Research, 1275 York Ave., New York,

NY 10021-6007.

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Published on Web 12/03/1999

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9417

F igu r e 1. Structure of ciguatoxin (CTX1B, 1) and decacyclic ciguatoxin model compound 2.

system of ciguatoxin was replaced with a 1,5-dioxadecalin

unit (Figure 1).

In this paper, we describe in detail the highly conver-

gent synthesis of the decacyclic ciguatoxin model 2 which

features the construction of the fused hexahydrooxonine

ring system based on our previously described strategy.^4c,d,h

compound, corresponding to the J KLM ring system, could

be easily derived from alcohol 7.^4jConstruction of the

oxonane ring in 4 would be feasible from the O-linked

oxacycle 6 by our previously developed SmI₂-mediated

Reformatsky reaction. O-Linked oxacycle 6 in turn could

be derived via route A or route B through intramolecular

reaction of γ-alkoxyallylsilane with acetal. Route A

involves the cyclization to yield oxepane, while route B

involves tetrahydropyran formation similar to the previ-

ous report.^4c,h

Resu lts a n d Discu ssion

Syn th etic P la n . The retrosynthetic analysis of deca-

cyclic compound 2 is shown in Scheme 1. The cis double

bond in the hexahydrooxonine ring of 2 was to be

introduced in the final stage of the synthesis, because it

causes severe broadening in the NMR.^1a-c,4c,hThe con-

struction of the tetrahydrooxocine ring in 2 was envi-

sioned to occur via silver salt-mediated hydroxydithioket-

al cyclization developed by Nicolaou and co-workers⁶from

3, which would be formed from aldehyde 4 and phospho-

nium salt 5 by a Wittig coupling reaction. The latter

To investigate the feasibility of route A, γ-alkoxyallyl-

silanes 12 and 14 were prepared by conventional meth-

ods, and each was subjected to Lewis acid-mediated

cyclization (Scheme 2). Unfortunately, treatment of 12

and 14 with TiCl₄-PPh₃did not give the desired products

13 and 15 at all. Only oxepanes with the cis stereochem-

istry were obtained in quite low yield (ca. 10%); thus,

alternate route B was adopted. Preliminary model ex-

periments revealed that a six-membered acetal ring fused

to an oxepane was so stable under acidic conditions that

its cyclization with a γ-alkoxyallylsilane in the presence

of Lewis acid would proceed via an S_N2 mechanism,

leading predominantly to the undesired anti product.⁷

Thus, seven-membered acetal 9 was defined as the

possible precursor for 6, and the former compound was

further traced back to aldehyde 10 and diol 11.

Syn th esis of th e O-Lin k ed Oxa cycle. The synthesis

of diol 11 began with the known alcohol 16 (Scheme 3),

which was obtained from methyl R-^D-glucopyranoside in

eight steps.⁸Routine protecting group manipulations

allowed for its conversion to allyl ether 17 in 68% overall

yield through the seven steps. Formation of the alkoxy-

substituted allylic anion of 17 using sec-BuLi, followed

by trapping with Bu₃SnCl, gave γ-alkoxyallylstannane

18 in 88% yield, which was oxidized with SO₃‚pyridine

and DMSO to provide aldehyde 19 (92%). Treatment of

(5) For synthetic work from other laboratories, see: (a) Alvarez, E.;

D´ıaz, M. T.; Pe´rez, R.; Mart´ın, J . D. Tetrahedron Lett. 1991, 32, 2241.

(b) Alvarez, E.; Zurita, D.; Mart´ın, J . D. Tetrahedron Lett. 1991, 32,

2245. (c) Za´rraga, M.; Mart´ın, J . D. Tetrahedron Lett. 1991, 32, 2249.

(d) Alvarez, E.; Rodr´ıguez, M. L.; Zurita, D.; Mart´ın, J . D. Tetrahedron

Lett. 1991, 32, 2253. (e) Suzuki, T.; Sato, O.; Hirama, M.; Yamamoto,

Y.; Murata, M.; Yasumoto, T.; Harada, N. Tetrahedron Lett. 1991, 32,

4505. (f) Sato, O.; Hirama, M. Synlett 1992, 705. (g) Alvarez, E.; Rico,

M.; Rodr´ıguez, R. M.; Zurita, D.; Mart´ın, J . D. Tetrahedron Lett. 1992,

33, 3385. (h) Ravelo, J . L.; Regueiro, A.; Mart´ın, J . D. Tetrahedron

Lett. 1992, 33, 3389. (i) Soler, M. A.; Palazo´n, J . M.; Mart´ın, V. S.

Tetrahedron Lett. 1993, 34, 5471. (j) Tanaka, S.; Isobe, M. Tetrahedron

1994, 50, 5633. (k) Oka, T.; Murai, A. Chem. Lett. 1994, 1611. (l)

Hosokawa, S.; Isobe, M. Synlett 1995, 1179. (m) Oguri, H.; Hishiyama,

S.; Oishi, T.; Hirama, M. Synlett 1995, 1252. (n) Oka, T.; Fujiwara,

K.; Murai, A. Tetrahedron 1996, 52, 12091. (o) Oishi, T.; Shoji, M.;

Maeda, K.; Kumahara, N.; Hirama, M. Synlett 1996, 1165. (p) Alvarez,

E.; Delgado, M.; D´ıaz, M. T.; Hanxing, L.; Pe´rez, R.; Mart´ın, J . D.

Tetrahedron Lett. 1996, 37, 2865. (q) Isobe, M.; Hosokawa, S.; Kira,

K. Chem. Lett. 1996, 473. (r) Alvarez, E.; D´ıaz, M. T.; Hanxing, L.;

Mart´ın, J . D. J . Am. Chem. Soc. 1995, 117, 1437. (s) Atsuta, H.;

Fujiwara, K.; Murai, A. Synlett 1997, 307. (t) Oishi, T.; Maeda, K.;

Hirama, M. Chem. Commun. 1997, 1289. (u) Oguri, H.; Hishiyama,

S.; Sato, O.; Oishi, T.; Hirama, M.; Murata, M.; Yasumoto, T.; Harada,

N. Tetrahedron 1997, 53, 3057. (v) Oishi, T.; Shoji, M.; Kumahara, N.;

Hirama, M. Chem. Lett. 1997, 845. (w) Oka, T.; Fujiwara, K.; Murai,

A. Tetrahedron Lett. 1997, 38, 8053. (x) Ami, E.; Kishimoto, H.; Ohrui,

H.; Meguro, H. Biosci. Biotechnol. Biochem. 1997, 61, 2019. (y) Oka,

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Chem. Commun. 1998, 1359. (bb) Isobe, M.; Nishizawa, R.; Hosokawa,

S.; Nishikawa, T. Chem. Commun. 1998, 2665. (cc) Hosokawa, S.; Isobe,

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Lett. 1999, 40, 1911 and references therein. (ee) Oguri, H.; Sasaki, S.;

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K.; Oishi, T.; Oguri, H.; Hirama, M. Chem. Commun. 1999, 1063.

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Veale, C. A. J . Am. Chem. Soc. 1989, 111, 5321.

(7) Reaction of γ-alkoxyallylsilane a with TiCl₄-PPh₃(CH₂Cl₂, -78

to 0 °C) yielded O-linked tricycle b with the undesired anti stereo-

chemistry in 42% yield together with the cis-isomer (20%).

(8) Zheng, W.; DeMattei, J . A.; Wu, J .-P.; Duan, J . J .-W.; Cook, L.

R.; Oinuma, H.; Kishi, Y. J . Am. Chem. Soc. 1996, 118, 7946.

9418 J . Org. Chem., Vol. 64, No. 26, 1999

Inoue et al.

Sch em e 2. Attem p ts To Con str u ct th e

Sch em e 1. Retr osysn th etic An a lysis of

Deca cyclic Cigu a toxin Mod el 2

Seven -Mem ber ed Rin g via

γ-Alk oxya llylsila n e-Aceta l Cycliza tion

Sch em e 3^a

Reagents and conditions: (a) t-BuCOCl, DMAP, Et₃N, CH₂Cl₂,

rt, quantitative; (b) H₂, Pd(OH)₂/C, EtOAc-MeOH; (c) Me₂C(OMe)₂,

CSA, CH₂Cl₂-DMF, 88% (two steps); (d) NaHMDS, allyl bromide,

THF-DMF (4:1), 0 °C to rt, 91%; (e) CSA, MeOH; (f) TBPSCl,

imidazole, DMF, 65 °C, 91% (two steps); (g) DIBALH, CH₂Cl₂, -78

°C, 93%; (h) sec-BuLi, Bu₃SnCl, THF, -78 °C, 88%; (i) SO₃‚Pyr,

Et₃N, DMSO, CH₂Cl₂, rt, 92%; (j) BF₃‚OEt₂, CH₂Cl₂, -90 °C; (k)

9-BBN-H, THF, rt, then H₂O₂, NaHCO₃, 94% (two steps); (l) CSA,

benzene, 80 °C, 73%.

amount of camphorsulfonic acid (CSA; 0.05 equiv) at 80

°C to produce acetal 21 in 73% yield as a 1:1 mixture of

diastereomers at the acetal. In this reaction a small

amount of the C-21 stereoisomer 22 was also obtained.

Epimerization at C-21 indicated that the ring opening

of 10 by â-elimination and subsequent ring closure by

hetero-Michael addition before acetalization occurred

under the reaction conditions.

19 with BF₃‚OEt₂provided 6/7-bicyclic alcohol 20 as a

single stereoisomer in high yield.⁹Hydroboration of the

olefin in 20 using 9-BBN-H, followed by oxidative

workup, afforded the desired diol 11 in 94% yield from

19.

Acetal formation between â-alkoxy aldehyde 10¹⁰and

diol 11 was carried out in the presence of a catalytic

Having successfully prepared acetal 21, the intramo-

lecular γ-alkoxyallylsilane-acetal cyclization was next

explored (Scheme 4). Metalation of 21 (a 1:1 mixture of

diastereomers) with sec-BuLi followed by treatment with

Me₃SiCl gave γ-alkoxyallyltrimethylsilane 9 as a mixture

of diastereomers in 79% yield, along with recovered pure

R-H isomer 21r (16%). Treatment of 9 with TiCl₄-PPh₃

provided O-linked oxacycle 23 with the desired stereo-

chemistry (23S,24R) as the major product albeit in

(9) (a) Yamada, J .-i.; Asano, T.; Kadota, I.; Yamamoto, Y. J . Org.

Chem. 1990, 55, 6066. (b) Yamamoto Y.; Yamada J .; Kadota I.

Tetrahedron Lett. 1991, 32, 7069. (c) Gevorgyan, V.; Kadota, I.;

Yamamoto, Y. Tetrahedron Lett. 1993, 34, 1313. (d) Kadota, I.;

Matsukawa, Y.; Yamamoto, Y. J . Chem. Soc., Chem. Commun. 1993,

1638. (e) Kadota, I.; Yamamoto, Y. Main Group Met. Chem. 1994, 17,

269.

(10) Aldehyde 10 was prepared from tri-O-acetyl-D-glucal in 13 steps

by a standard sequence of reactions, which is included in the Sup-

porting Information.

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9419

Ta ble 2. γ-Alk oxya llylm eta l-Aceta l Con d en sa tion

F igu r e 2. Stereochemical assignment of O-linked oxacycle 23

based on the proton-proton coupling constants. The stereo-

chemistry at C21 is derived from the chiral center of ^D-glucose.

step A^a

% yield

step B^b

% yield

entry

MR₃

Sch em e 4

SiMe₃

79 (16)

77 (26)

35 (30)

87 (12)

67 (20)

28 (24)

11 (11)

0 (25)

36 (16)

0 (0)

SiMe₂Ph

Si(i-Pr)₃

SiEt₃

5^c

SnBu₃

Numbers in parentheses represent the % yield of recovered

21r. Numbers in parentheses represent the % yield of cis-isomer

23. ^cTiCl₃(O-i-Pr) was used as a Lewis acid in step B.

gel and subjected to TiCl₄-PPh₃, yielding the desired 23

in only 29% yield together with three other stereoisomers,

24 (23R,24R), 26 (23R,24S), and 27 (23S,24S), in 28%,

27%, and 13% yields, respectively. Consequently, in the

case of the R-H isomer, the desired O-linked oxacycle 23

was obtained in only 9% overall yield from allyl ether

21r. On the other hand, the corresponding â-H isomer

9â, which was obtained in approximately 75% purity by

careful chromatographic separation of the diastereomeric

mixture, was subjected to Lewis acid-promoted cycliza-

tion to produce the desired 23 in 42% yield as the major

product together with a 30% yield of 24. The significant

difference in the diastereoselectivity observed for these

isomers, 9r and 9â, is not easily understood, but these

results indicate that these reactions do not proceed

through a complete S_N1 mechanism via the oxocarbenium

ion intermediate. Unusual steric congestion of the allyl-

silane moiety in 9r might have unfavorable effects on

the formation of the desired isomer 23.

Ta ble 1. Aceta l F or m a tion betw een Ald eh yd e 10 a n d

Diol 11

acid catalyst

(equiv)

time

entry

solvent temperature (h) yield R:â

To improve the yield of 23, selective formation of the

more favorable â-H isomer 21â was next examined (Table

1). Whereas conventional acetalization conditions led to

approximately 1:1 mixtures of the acetal isomers (entries

1-3), use of scandium trifluoromethanesulfonate¹¹as an

acid catalyst enhanced the formation of the â-H isomer

(R:â ) ca. 1:2, 90% combined yield, entry 4). Moreover,

under the reaction conditions in this case, acid-catalyzed

epimerization of 10 at the C-21 position due to the ring

opening-reclosure was not observed (vide supra).

Next, we investigated the influence of the trialkylmetal

groups on this cyclization reaction (Table 2). Allyl anion

derived from 21 (R:â ) 1:2) was treated with several

trialkylmetal chlorides (step A), and the resulting γ-alkoxy-

allylmetals were subjected to TiCl₄-PPh₃-promoted cy-

clization (step B). A change from trimethylsilane to

dimethylphenylsilane decreased the yield of the desired

allylsilane, presumably due to the lower nucleophilicity

of allyldimethylphenylsilane relative to allyltrimethyl-

silane (entry 2).¹²In the case of triisopropylsilane and

CSA (0.05)

CSA (1.0)

Me₃SiOTf (1.0) CH₂Cl₂

Sc(OTf)₃(0.1) benzene

benzene

CH₂Cl₂

80 °C

-78 °C

1:1

2:3

1:1

1:2

3^a

The bis(trimethylsilyl ether) of 11 was used.

modest and variable yields (28-43%), together with the

23R,24R diastereoisomer 24 (13-24%) and trace amounts

of two other stereoisomers. The newly generated stereo-

centers of the major product 23 were unambiguously

determined to be 23S,24R on the basis of proton-proton

coupling constants as illustrated in Figure 2.

To evaluate the difference in the stereoselectivity of

this cyclization between the two diastereomers at the

acetal position, each isomer was separately subjected to

the Lewis acid-mediated reaction (Scheme 5). Sequential

treatment of the pure R-H isomer 21r, obtained as the

recovered starting material in the allylsilylation reaction,

with sec-BuLi and Me₃SiCl produced a mixture of the

desired γ-alkoxyallylsilane 9r (32%), R-alkoxyallylsilane

25 (15%), and a significant amount of the starting

material 21r (25%). This result indicates that the allyl

ether portion of 21r was much more sterically hindered

than that of the corresponding â-H isomer. Allylsilane

9r was separated by column chromatography on silica

(11) (a) Fukuzawa, S.; Tsuchimoto, T.; Hotaka, T.; Hiyama, T.

Synlett 1995, 1077. (b) Ishihara, K.; Karumi, Y.; Kubota, M.: Yama-

moto, H. Synlett 1996, 839.

(12) Kadota, I.; Miura, K.; Yamamoto, Y. J . Chem. Soc., Chem.

Commun. 1991, 823 and references therein.

9420 J . Org. Chem., Vol. 64, No. 26, 1999

Inoue et al.

Sch em e 5

Sch em e 6^a

Reagents and conditions: (a) TBDMSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 95%; (b) OsO₄, NMO, t-BuOH-H₂O; (c) Pb(OAc)₄, benzene; (d)

MeMgBr, THF, -78 to 0 °C, 91% (three steps); (e) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, -78 °C to rt, 94%; (f) LDA, TMSCl, THF, -78 °C; (g)

NBS, THF, 0 °C; (h) CSA, MeOH, rt, 83% (three steps); (i) SO₃‚Pyr, Et₃N, DMSO, CH₂Cl₂, 0 °C; (j) SmI₂, THF, -78 °C, then Ac₂O, DMAP,

0 °C; (k) NaBH₄, CH₂Cl₂-MeOH, 0 °C; (l) PhOC(S)Cl, DMAP, CH₃CN, rt, 66% (five steps); (m) Bu₃SnH (20 equiv), Et₃B (0.2 equiv),

benzene, rt, 80%.

tributylstannane, the yields of step A were modest, and

none of the desired product was obtained in step B

(entries 3 and 5). These results indicate that both the

size and nucleophilicity of the trialkylmetal play a

significant role in steps A and B. Use of a triethylsilyl

group in step A resulted in the formation of allyltrieth-

ylsilane 28 (MR₃) SiEt₃) in 87% yield (entry 4).

Furthermore, in the subsequent step B, allyltriethylsi-

lane 28 (MR₃) SiEt₃) afforded the desired 23 as the

major product in better yield and reproducibility than

in the case of the original γ-allyltrimethylsilane.

Syn t h esis of t h e F GH R in g F r a gm en t . With the

desired O-linked oxacycle 23 in hand, our attention was

next focused on the construction of the oxonane ring,

which corresponds to ring F of ciguatoxin (Scheme 6).

Elaboration of 23 to aldehyde 6, the requisite cyclization

precursor, was carried out in a manner similar to that

of the previous report.^4c,d,hProtection of 23 as its TBDMS

ether 29 and oxidative cleavage of the double bond [(1)

OsO₄(cat.), NMO, acetone-H₂O; (2) Pb(OAc)₄, benzene]

gave an aldehyde, which reacted with methylmagnesium

bromide to afford alcohol 30 as a mixture of diastereo-

mers. Swern oxidation of 30 furnished methyl ketone 31

in 81% overall yield from 29. Enolization of 31 with LDA

and subsequent trapping of the enolate with trimethyl-

silyl chloride provided the silyl enol ether, which was

treated with NBS and then desilylated under acidic

conditions to provide alcohol 32 in 83% yield for the three

steps.

Oxidation of 32 with SO₃‚pyridine and DMSO led to

aldehyde 6, which was subjected to SmI₂-mediated in-

tramolecular Reformatsky reaction under the previously

reported optimal conditions.^4c,d,hThus, treatment of 6

with 5 equiv of SmI₂in THF at -78 °C gave, after in

situ acetylation using Ac₂O and DMAP, â-acetoxy ketone

33 in high yield as a single stereoisomer. When 33 was

purified by column chromatography on silica gel, partial

â-elimination of the acetoxyl group was observed, giving

the trans-R,â-unsaturated ketone; therefore, the crude

product was immediately reduced with sodium borohy-

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9421

Ta ble 3. Ra d ica l Red u ction of P h en ylth ioca r bon a te 35

% yield

entry

reagents and conditions

of 36

of 37

Bu₃SnH (5 equiv), AIBN (0.2 equiv), benzene, rt to 80 °C

Bu₃SnH (5 equiv), AIBN (0.2 equiv), toluene, 80 °C

Bu₃SnH (3 equiv), Et₃B (0.2 equiv), benzene, rt

Bu₃SnH (20 equiv), Et₃B (0.2 equiv), benzene, rt

Sch em e 7. Ra d ica l Red u ction of

P h en ylth ioca r bon a te 35

Sch em e 9^a

Sch em e 8^a

Reagents and conditions: (a) Bu₄NF, THF, rt; (b) TBPSCl,

imidazole, DMF, 0 °C, 82% (two steps); (c) (COCl)₂, DMSO, Et₃N,

CH₂Cl₂, -78 °C to rt, 94%; (d) EtSH, TiCl₄, CH₂Cl₂, -78 °C; (e)

Bu₄NF, THF, rt, 97% (two steps); (f) SO₃‚Pyr, Et₃N, DMSO,

CH₂Cl₂, 0 °C.

dride to afford 34 as a mixture of diastereomers. The

resulting alcohol 34 was then converted to phenyl thio-

carbonate 35 in 66% overall yield from 30.

Subsequent radical reduction of 35 proved to be

problematic (Table 3). When the reduction was performed

using Bu₃SnH (5 equiv) and AIBN (0.2 equiv) in benzene

or toluene at 80 °C, a mixture of the desired product 36

and its C29 isomer 37 was obtained, with the latter being

the predominant product (Table 3, entries 1 and 2).

Formation of the undesired isomer 37 was presumably

due to transannular hydrogen abstraction as shown in

Scheme 7. The yield of the desired 36 was improved by

carrying out the reaction at room temperature with

triethylborane¹³as a radical initiator (entry 3). An

optimal result was obtained using a large excess of

Bu₃SnH (20 equiv) in the presence of triethylborane (0.2

equiv) in benzene at room temperature (entry 4). It is

believed that the higher concentration of Bu₃SnH pre-

vented the competitive intramolecular radical abstraction

of the transannular hydrogen. By this method, an 80%

yield of acetate 36 was obtained.

Reagents and conditions: (a) BuLi, THF-HMPA, -78 °C to

rt, 63%; (b) Bu₄NF, THF, rt, 91%; (c) AgOTf, NaHCO₃, 4 Å

molecular sieves, silica gel, CH₃NO₂, rt, 76% (70% conversion);

(d) Ph₃SnH (10 equiv), AIBN(cat.), toluene, 110 °C, then m-CPBA,

CH₂Cl₂, 0 °C, 86%; (e) H₂, Pd(OH)₂/C, EtOAc-MeOH-AcOH, rt.

group as the tert-butyldiphenylsilyl (TBPS) ether pro-

vided monosilyl ether 38 (82% yield for the two steps),

which was then subjected to Swern oxidation to give

ketone 39 in 94% yield. Dithioketal formation from 39

proceeded smoothly in the presence of excess EtSH and

TiCl₄to afford, after desilylation with Bu₄NF, alcohol 40

in 97% yield for the two steps. Finally, oxidation of the

primary hydroxyl group in 40 with SO₃‚pyridine and

DMSO led to the desired aldehyde 4.

Phosphonium salt 5 was easily prepared from alcohol

7^4jby sequential treatment with I₂, PPh₃, and imidazole

followed by excess PPh₃in CH₃CN at 70 °C.

With the requisite aldehyde 4 and phosphonium salt

5 in hand, the stage was then set to couple these

fragments and further elaborate toward the target mol-

ecule 2 (Scheme 9). Generation of the ylide from phos-

phonium salt 5 using BuLi in the presence of HMPA in

Com p letion of th e Syn th esis of Deca cyclic Mod el

Com p ou n d 2. Elaboration of bis(silyl ether) 36 to

aldehyde 4 is summarized in Scheme 8. Desilylation of

36 using Bu₄NF and selective protection of the hydroxyl

(13) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. J pn. 1990,

63, 2578.

9422 J . Org. Chem., Vol. 64, No. 26, 1999

Inoue et al.

Sch em e 10^a

F igu r e 3. UP and DOWN conformers of decacyclic ciguatoxin

model compound 2.

smoothly afforded bromide 47. Unexpectedly, upon ex-

posure to KO-t-Bu in DMSO, only trace amounts of the

desired compound 2 were obtained presumably due to

decomposition of 47 under the basic reaction conditions.¹⁴

This result suggested that a protecting group for both

hydroxyl groups at C47 and C54 other than silyl ethers

was necessary for the final introduction of the double

bond on the oxonane ring. Thus, 44 was protected as its

bis(ethoxyethyl ether) 46 under the standard conditions

in a quantitative yield. After deacetylation of 46 with

DIBALH, the resultant alcohol was treated with meth-

anesulfonic anhydride in the presence of lithium bromide

and i-Pr₂NEt to give bromide 48 as a single stereoisomer.

As expected, exposure of 48 to KO-t-Bu in DMSO at room

temperature afforded the desired hexahydrooxonine 49

in 52% overall yield for the three steps.¹⁵Finally, removal

of the ethoxyethyl (EE) groups in 49 with PPTS furnished

the targeted compound 2 in a quantitative yield.

Reagents and conditions: (a) TBDMSOTf, 2,6-lutidine, CH₂Cl₂,

-78 °C, 84% from 43; (b) ethyl vinyl ether, PPTS, CH₂Cl₂, rt, 99%

from 43; (c) DIBALH, CH₂Cl₂, -78 °C; (d) Ms₂O, LiBr, i-Pr₂NEt,

CH₂Cl₂, 0 °C to rt; (e) KO-t-Bu, DMSO, rt, 52% from 46; (f) PPTS,

MeOH, rt, quantitative.

THF followed by addition of aldehyde 4 resulted in the

formation of (Z)-olefin 41 in 63% yield, which upon

treatment with Bu₄NF furnished hydroxy dithioketal 3

in 91% yield. Ring closure of 3 induced by silver trifluo-

romethanesulfonate gave rise to mixed thioketal 42 in

76% yield (based on 70% conversion), from which the

ethylthio group was reductively removed under radical

conditions using Ph₃SnH-AIBN, leading to decacyclic

polyether compound 43 in 86% yield.⁶Subsequent hy-

drogenation and hydrogenolysis of 43 to obtain diol 44

did not proceed at all, probably due to the contaminant

sulfur-containing materials including a trace amount of

starting 42, which might have deactivated the catalyst.

As expected, treatment of compound 43 with m-CPBA

for 1 h at 0 °C prior to hydrogenation led to smooth

conversion of 43 to 44. Hydrogenation of the double bond

and simultaneous hydrogenolysis of the benzyl group in

43 were achieved using Pearlman’s catalyst in EtOAc-

MeOH containing 1% AcOH to give 44 in excellent yield.

With the entire polycyclic ether framework in place,

all that remained for the completion of the synthesis of

2 was introduction of a cis double bond on the oxonane

ring. Since protection of the C47 hydroxyl group (e.g.,

pivaloyl, p-bromobenzoyl, and TBDMS) turned out to be

difficult due to its steric hindrance, the selective protec-

tion of the C54 hydroxyl group over the one at C47 before

introduction of the double bond was attempted (Scheme

10). Selective silylation using TBDMSOTf and 2,6-

lutidine at -78 °C gave monosilyl ether 45 in 84% yield

from 43. Deprotection of the acetyl group in 45 with

DIBALH, followed by treatment with methanesulfonic

anhydride in the presence of lithium bromide and Et₃N,

Con for m a tion a l Beh a vior of th e Mod el Com -

p ou n d s P ossessin g a Hexa h yd r ooxon in e Rin g. As

was the case with the previous reported 6/9/6-tricyclic

system,^4c,hthe H and ¹³C NMR signals on the hexahy-

drooxonine ring in 2 were severely broadened at room

temperature, which also closely mimics the ring F of

ciguatoxin.^1a-cThe dynamic NMR studies showed that 2

existed as an approximately 1:1 mixture of two conform-

ers. The structures of these two conformers were unam-

biguously assigned to be UP and DOWN (Figure 3) by

virtue of proton-proton coupling constants in pyridine-

d₅, an observation consistent with that of the tricyclic

model.^4c,hThe free energy of activation for this confor-

(14) Alkoxide c may suffer from Grob fragmentation to yield another

alkoxide d and dihydropyran e, which lead to further decomposition;

see: Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6,

(15) The corresponding olefin regioisomer could not be isolated in

this reaction.

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9423

mational change was estimated to be approximately 14.6

kcal/mol at the coalescence temperature (30 °C) in

pyridine-d₅from the chemical shift difference of olefin

signals between two conformers. It is worth noting that

the deduced conformation of the oxepane ring in 2 agrees

well with that of ring G in ciguatoxin, which indicates

that the entire shape of decacyclic model 2 would cor-

respond to that of the natural product except for its

molecular length.

Biologica l Stu d ies. The biological activity of decacy-

clic model compound 2 was evaluated. The binding

affinity of 2 to VSSC was examined using a competitive

inhibition assay with tritiated dihydrobrevetoxin B

([³H]PbTx-3).¹⁶The model compound 2 did not inhibit the

binding of [³H]PbTx-3 to rat brain synaptosomes or VSSC

reconstructed in liposome even at concentrations of up

to 100 µM, whereas ciguatoxin inhibits the binding of

PbTx-3 at the 100 pM level under similar conditions.

Assays at higher levels proved impractical owing to the

low solubility of 2 in aqueous media.

Next, to evaluate the action of 2 upon VSSC, [¹⁴C]guani-

dinium influx assay using neuroblastoma NB14 cells was

carried out.¹⁷[¹⁴C]Guanidinium has often been used as

a valid model for ²³Na⁺influx, replacing radioisotope

²³Na⁺, which is a γ-light emitter and very difficult to

handle in pharmacological experiments. Compound 2 did

not stimulate [¹⁴C]guanidinium ion influx through VSSC

at concentrations up to 30 µM.

Compared with ciguatoxin, the hydroxyl groups in 2

exist only in the right-hand portion of the molecule, which

make this molecule detergent-like in structure with an

amphiphilic dipole along the longitudinal direction. This

amphiphilic nature of 2 may result in its low solubility

in membranes due to micelle formation in aqueous media

and/or prevent 2 from binding to VSSC with appropriate

orientation when bound within membranes. Due to these

problems, it appears necessary to devise another assay

that efficiently evaluates the biological activity of 2.

Evaluation of noncompetitive binding, a procedure which

has not yet been highly studied, is a potential method

currently under investigation. Derivatization of 2 at the

left side to improve the solubility will also be investigated

in the future.

Exp er im en ta l Section ^4j

Alcoh ol 17. A solution of the known alcohol 16⁸(13.91 g,

29.2 mmol), DMAP (347 mg, 2.84 mmol), and Et₃N (14.0 mL,

100 mmol) in CH₂Cl₂(200 mL) was cooled to 0 °C and treated

with pivaloyl chloride (5.6 mL, 45.5 mmol). The mixture was

stirred for 2 h, and the reaction was quenched with saturated

aqueous NaHCO₃(80 mL). The resulting solution was diluted

with EtOAc (800 mL) and washed with 1 N aqueous HCl,

saturated aqueous NaHCO₃, and brine. Drying (Na₂SO₄),

filtration, concentration, and flash chromatography (silica gel,

EtOAc) gave pivalate ester (17.14 g, quantitative): ¹H NMR

(CDCl₃, 500 MHz) δ 7.22-7.35 (15H, m), 4.51-4.63 (6H, m),

4.05 (2H, m), 3.73 (1H, dd, J ) 10.7, 1.8 Hz), 3.64 (1H, dd, J

) 10.7, 4.6 Hz), 3.46 (1H, ddd, J ) 11.0, 9.5, 4.6 Hz), 3.35 (1H,

ddd, J ) 9.5, 4.6, 1.8 Hz), 3.20 (1H, ddd, J ) 9.2, 8.5, 2.4 Hz),

3.14 (1H, ddd, J ) 10.7, 9.2, 4.3 Hz), 2.69 (1H, ddd, J ) 11.3,

4.6, 4.3 Hz), 1.97 (1H, m), 1.84 (1H, m), 1.67 (1H, m), 1.44

(1H, m), 1.41 (1H, ddd, J ) 11.3, 11.0, 10.7 Hz), 1.16 (9H, s);

¹³C NMR (CDCl₃, 125 MHz) δ 178.6, 129.0, 128.9, 128.5, 128.4,

128.3, 127.9, 127.8, 127.7, 127.7, 127.5, 126.9, 126.8, 80.3, 79.8,

76.1, 73.4, 72.5, 71.1, 70.9, 69.3, 64,6, 35.2, 28.3, 27.2, 27.1,

24.9; HRMS (FAB) calcd for C₃₅H₄₄O₆Na [(M + Na)⁺] 583.3036,

found 583.3038.

To a solution of the above pivalate (17.13 g, 30.6 mmol) in

EtOAc-MeOH (1:1, 150 mL) was added 20% Pd(OH)₂/C (1.68

g), and the mixture was stirred under hydrogen overnight.

Additional 20% Pd(OH)₂/C (1.06 g) was added, and the stirring

was continued overnight. The catalyst was filtered off, and the

solvent was removed under vacuum to give triol, which was

used in the following reaction without further purification.

A solution of the triol and 2,2-dimethoxypropane (24 mL,

0.195 mol) in CH₂Cl₂-DMF (3:1, 200 mL) was treated with

camphorsulfonic acid (0.592 g, 2.55 mmol), and the solution

was stirred at room temperature for 1 h. The mixture was

poured into saturated aqueous NaHCO₃(300 mL), and the

aqueous layer was extracted with EtOAc (500 mL × 2). The

organic layer was washed with H₂O and brine, dried (Na₂SO₄),

filtered, and concentrated. The residue was subjected to flash

chromatography (silica gel, 0-60% EtOAc-hexane) to give

acetonide (8.47 g, 88% for the two steps): ¹H NMR (CDCl₃,

500 MHz) δ 4.05 (2H, m), 3.85 (1H, dd, J ) 10.7, 5.2 Hz), 3.64

(1H, dd, J ) 10.7, 10.7 Hz), 3.54 (1H, ddd, J ) 11.3, 9.2, 4.3

Hz), 3.42 (1H, ddd, J ) 11.0, 9.2, 4.6 Hz), 3.13 (1H, ddd, J )

10.7, 9.2, 5.2 Hz), 3.12 (1H, ddd, J ) 9.2, 6.7, 1.8 Hz), 2.28

(1H, ddd, J ) 11.3, 4.6, 4.3 Hz), 1.90 (1H, m), 1.82 (1H, m),

1.63-1.71 (2H, m), 1.48 (1H, ddd, 11.3, 11.3, 11.0 Hz), 1.46

(3H, s), 1.43 (1H, m), 1.38 (3H, s), 1.17 (9H, s); ¹³C NMR

(CDCl₃, 125 MHz) δ 178.8, 99.1, 81.9, 74.2, 69.8, 68.9, 64.3,

62.7, 38.9, 38.7, 29.2, 28.1, 27.2, 24.7, 19.1; HRMS (FAB) calcd

for C₁₇H₃₀O₆Na [(M + Na)⁺] 353.1940, found 353.1934.

A solution of the above acetonide (8.46 g, 25.6 mmol) in

THF-DMF (4:1, 400 mL) was treated with NaHMDS (1.0 M

solution in THF, 31 mL, 31 mmol) at 0 °C, and the mixture

was stirred for 30 min at 0 °C. To this solution was added

allyl bromide (3.6 mL, 42 mmol) at room temperature, and

the solution was stirred for 1 h. The reaction was quenched

with saturated aqueous NH₄Cl (100 mL), and the mixture was

diluted with EtOAc (1200 mL). The organic layer was washed

with H₂O and brine, dried (Na₂SO₄), and concentrated. Flash

chromatography (silica gel, 10-30% EtOAc-hexane) gave allyl

ether (8.59 g, 91%): ¹H NMR (CDCl₃, 500 MHz) δ 5.85 (1H,

dddd, J ) 17.1, 10.4, 5.8, 5.5 Hz), 5.24 (1H, dd, J ) 17.1, 0.9

Hz), 5.15 (1H, dd, J ) 10.4, 0.9 Hz), 4.07 (1H, dd, J ) 12.5,

5.5 Hz), 4.03 (2H, t, J ) 6.4 Hz), 3.90 (1H, dd, J ) 12.5, 5.8

Hz), 3.85 (1H, dd, J ) 10.7, 5.2 Hz), 3.62 (1H, dd, J ) 10.7,

10.7 Hz), 3.49 (1H, ddd, J ) 11.3, 9.5, 4.3 Hz), 3.21 (1H, ddd,

J ) 8.9, 8.9, 2.5 Hz), 3.14 (2H, m), 2.38 (1H, ddd, J ) 11.3,

4.3, 4.3 Hz), 1.92 (1H, m), 1.81 (1H, m), 1.66 (1H, m), 1.46

(3H, s), 1.41 (1H, ddd, J ) 11.3, 11.3, 11.3 Hz), 1.38 (3H, s),

1.36 (1H, m), 1.17 (9H, s); ¹³C NMR (CDCl₃, 125 MHz) δ 178.6,

134.6, 117.2, 99.1, 80.5, 76.3, 74.0, 69.9, 69.0, 64.4, 62.8, 38.7,

35.2, 29.2, 28.4, 27.2, 24.8, 19.1; HRMS (FAB) calcd for

Con clu sion

In conclusion, a convergent synthesis of the decacyclic

ciguatoxin model 2, containing the F-M ring framework

of the natural product, has been achieved. The described

synthesis demonstrates the power of our strategy for

constructing the fused hexahydrooxonine ring system

through (i) Lewis acid-mediated intramolecular conden-

sation of γ-alkoxyallylsilane with acetal to yield O-linked

oxacycles and (ii) SmI₂-mediated intramolecular Refor-

matsky-type reaction to construct the oxonane ring. The

importance of the molecular length and/or the hydrophi-

licity of the left-hand portion of ciguatoxins for biological

activity was also demonstrated. This work will provide

the basis for the total synthesis of ciguatoxins as well as

their simplified model compounds for further biological

evaluation.

(16) Rein, K. S.; Lynn, B.; Gawley, R. E.; Baden, D. G. J . Org. Chem.

1994, 59, 2107 and references therein.

(17) Tas, P. W. L.; Kress, H-.G.; Koschel, K. FEBS Lett. 1985, 182,

269.

₂₀H₃₄O₆Na [(M + Na)⁺] 393.2253, found 393.2228.

A solution of the above allyl ether (8.58 g, 23.2 mmol) in

9424 J . Org. Chem., Vol. 64, No. 26, 1999

Inoue et al.

MeOH (400 mL) was treated with camphorsulfonic acid (0.511

g, 2.20 mmol), the solution was stirred at room temperature

for 50 min, and then the reaction was quenched with Et₃N

(1.0 mL). The mixture was evaporated, and the residue was

diluted with EtOAc (1000 mL). The organic layer was washed

with saturated aqueous NaHCO₃and brine and dried (Na₂SO₄).

Filtration and concentration gave the crude diol, which was

used in the next reaction without further purification.

A mixed solution of the above diol and imidazole (9.47 g,

139 mmol) in DMF (60 mL) was treated with tert-butyldiphe-

nylsilyl chloride (TBPSCl) (18.5 mL, 71.3 mmol) at room

temperature. The mixture was heated for 17 h at 65 °C. The

resulting solution was poured into H₂O (500 mL), and the

aqueous layer was extracted with EtOAc (600 mL × 2). The

combined organic layers were washed with brine and dried

(Na₂SO₄). Filtration, concentration, and flash chromatography

(silica gel, 5-20% Et₂O-hexane) gave diTBPS ether (18.31 g,

91% for the two steps): ¹H NMR (CDCl₃, 500 MHz) δ 7.56-

7.68 (8H, m), 7.22-7.41 (12H, m), 5.69 (1H, dddd, J ) 17.3,

10.4, 5.7, 5.6 Hz), 5.06 (1H, dddd, J ) 17.3, 2.9, 1.4, 1.3 Hz),

5.03 (1H, dddd, J ) 10.4, 2.9, 1.4, 1.3 Hz), 4.04 (2H, dd, J )

6.4, 6.4 Hz), 3.99 (1H, dd, J ) 11.0, 1.8 Hz), 3.76 (1H, dddd, J

) 12.5, 5.8, 1.4, 1.3 Hz), 3.69 (1H, dd, J ) 11.0, 6.0 Hz), 3.58-

3.64 (2H, m), 3.31 (1H, ddd, J ) 9.0, 6.0, 1.8 Hz), 3.09 (1H,

ddd, J ) 9.2, 8.8, 1.6 Hz), 2.73 (1H, ddd, J ) 11.1, 9.2, 4.4

Hz), 2.05 (1H, ddd, J ) 11.8, 4.6, 4.4 Hz), 1.83-1.88 (2H, m),

1.66 (1H, m), 1.23-1.33 (2H, m), 1.16 (9H, s), 1.00 (9H, s), 0.95

(9H, s); ¹³C NMR (CDCl₃, 125 MHz) δ 178.6, 135.8, 135.8,

135.8, 135.7, 134.7, 134.3, 134.0, 133.8, 133.4, 129.7, 129.6,

129.6, 129.4, 129.4, 127.6, 127.5, 127.5, 117.0, 82.8, 79.7, 76.0,

69.7, 67.6, 64.5, 63.9, 39.0, 38.7, 31.6, 28.3, 27.2, 26.9, 26.8,

24.8, 22.6, 19.3, 19.2, 14.1; HRMS (FAB) calcd for C₄₉H₆₆O₆Si₂Na

[(M + Na)⁺] 829.4296, found 829.4324.

A solution of the above diTBPS ether (19.01 g, 23.6 mmol)

in CH₂Cl₂(150 mL) was cooled to -78 °C and treated with

DIBALH (1.0 M solution in toluene, 86 mL, 86 mmol). After

being stirred at -78 °C for 3 h, the reaction was quenched

with saturated aqueous sodium potassium tartrate (300 mL),

and the mixture was vigorously stirred at room temperature

until the layers were separated. The resulting solution was

diluted with EtOAc (800 mL) and washed with brine. The

combined organic layer was dried (Na₂SO₄), filtered, and

concentrated. Purification by flash chromatography (silica gel,

10-30% EtOAc-hexane) gave alcohol 17 (15.87 g, 93%): ¹H

NMR (CDCl₃, 500 MHz) δ 7.14-7.62 (20H, m), 5.70 (1H, dddd,

J ) 17.2, 10.4, 5.8, 5.7 Hz), 5.06 (1H, dd, J ) 17.2, 3.1 Hz),

5.05 (1H, dd, J ) 10.4, 3.1 Hz), 4.01 (1H, dd, J ) 11.0, 1.8

Hz), 3.76 (1H, dddd, J ) 12.5, 5.6, 1.2, 1.2 Hz), 3.57-3.67 (4H,

m), 3.51 (1H, ddd, J ) 11.0, 9.2, 4.6 Hz), 3.38 (1H, ddd, J )

9.2, 6.9, 1.8 Hz), 3.15 (1H, ddd J ) 11.1, 9.2, 2.0 Hz), 2.75

(1H, ddd, J ) 11.0, 9.2, 4.4 Hz), 2.05 (1H, ddd, J ) 11.6, 4.6,

4.4 Hz), 1.92 (1H, m), 1.63-1.74 (3H, m), 1.35 (1H, m), 1.30

(1H, ddd, J ) 11.6, 11.1, 11.0 Hz), 1.03 (9H, s), 0.90 (9H, s);

¹³C NMR (CDCl₃, 125 MHz) δ 135.8, 135.8, 135.7, 135.7, 134.7,

134.7, 133.8, 133.8, 129.7, 129.6, 129.5, 129.5, 128.3, 127.6,

127.5, 127.5, 117.1, 107.3, 82.8, 80.8, 75.8, 69.7, 67.8, 64.4, 62.8,

38.9, 29.2, 28.4; HRMS (FAB) calcd for C₄₄H₅₈O₅Si₂Na [(M +

Na)⁺] 745.3721, found 745.3702.

aqueous NaHCO₃, and brine, and dried (Na₂SO₄). Filtration,

concentration, and flash chromatography (silica gel, 10-20%

EtOAc-hexane containing 1% Et₃N) gave aldehyde 19 (14.63

g, 92%).

A solution of the aldehyde 19 (14.63 g, 14.51 mmol) in

CH₂Cl₂(200 mL) was cooled to -90 °C and treated with boron

trifluoride etherate (2.2 mL, 17.9 mmol). After being stirred

for 30 min at -90 °C, the reaction was quenched with

saturated aqueous NaHCO₃(100 mL) and allowed to warm to

room temperature. To this mixture was added saturated

aqueous KF (200 mL), and the resulting solution was vigor-

ously stirred overnight. The aqueous layer was extracted with

EtOAc (800 mL). The organic layer was washed with H ₂O and

brine, dried (Na₂SO₄), filtered, and concentrated. Flash chro-

matography (silica gel, 20-30% EtOAc-hexane) gave oxepane

20 (12.74 g), which was used in the following reaction without

further purification: ¹H NMR (C₆D₆, 500 MHz) δ 7.92-7.87

(4H, m), 7.72-7.68 (4H, m), 7.27-7.12 (12H, m), 5.71 (1H, ddd,

J ) 17.1, 10.7, 5.2 Hz), 5.15 (1H, ddd, J ) 17.1, 1.5, 1.5 Hz),

4.91 (1H, ddd, J ) 10.7, 1.5, 1.5 Hz), 4.22 (1H, dd, J ) 11.0,

1.8 Hz), 3.92 (1H, dd, J ) 11.0, 5.8 Hz), 3.84 (1H, ddd, J )

11.0, 9.2, 4.9 Hz), 3.51 (1H, m), 3.49 (1H, m), 3.36 (1H, m),

3.02 (1H, ddd, J ) 9.2, 9.2, 4.9 Hz), 2.94 (1H, ddd, J ) 11.3,

9.2, 4.0 Hz), 2.33 (1H, ddd, J ) 11.6, 4.6, 4.6 Hz), 1.88-1.49

(5H, m), 1.21 (9H, s), 1.09 (9H, s); ¹³C NMR (C₆D₆, 125 MHz)

δ 138.4, 136.4, 136.24 (x 2), 136.20, 134.6, 134.4, 134.3, 133.8,

130.02, 129.99, 129.8, 129.7, 128.5, 128.4, 128.3, 127.9, 114.6,

86.0, 83.3, 82.5, 79.6, 73.8, 68.3, 64.8, 41.6, 29.1, 27.2 (×2),

27.0, 19.7, 19.5.

Diol 11. A solution of oxepane 20 (12.74 g) in THF (120

mL) was cooled to 0 °C and treated with 9-BBN-H (110 mL,

0.5 M solution in THF, 55 mmol), and the mixture was stirred

for 2 h at room temperature. The solution was recooled to 0

°C, and the reaction was quenched with H₂O (10 mL). To the

mixture were added saturated aqueous NaHCO₃(80 mL) and

30% H₂O₂(80 mL) at 0 °C. The resulting solution was stirred

for 1 h at room temperature and diluted with EtOAc (700 mL).

The organic layer was washed with H₂O, saturated aqueous

Na₂SO₃, saturated aqueous NaHCO₃, and brine. Drying

(Na₂SO₄), filtration, concentration, and flash chromatography

(silica gel, 30-65% EtOAc-hexane) gave alcohol 11 (94% for

two steps): [R]²⁷_D) +12.0° (c 1.38, CHCl₃); IR (film) 3365 cm^-1

;

¹H NMR (CDCl₃, 500 MHz) δ 7.67-7.26 (20H, m, Si(C₆H₅)₂),

3.95 (1H, dd, J ) 11.3, 1.8 Hz, 38-H), 3.72 (1H, m, 30-H), 3.69-

3.60 (5H, m, 27-H₂, 38-H₂, 36-H), 3.35 (1H, ddd, J ) 8.2, 6.4,

4.3 Hz, 29-H), 3.30 (1H, ddd, J ) 9.2, 5.8, 1.8 Hz, 37-H), 2.99

(1H, ddd, J ) 9.2, 8.9, 3.4 Hz, 33-H), 2.90 (1H, ddd, J ) 11.6,

9.2, 4.0 Hz, 34-H), 1.96 (1H, ddd, J ) 11.6, 4.6, 4.6 Hz, 35-H),

1.84-1.65 (6H, m, 28-H₂, 31-H₂, 32-H₂), 1.45 (1H, ddd, J )

11.6, 11.6, 11.3 Hz, 35-H), 1.00 (9H, s, SiC₄H₉), 0.96 (9H, s,

SiC₄H₉); ¹³C NMR (CDCl₃, 125 MHz) δ 135.88, 135.84, 135.80,

135.7, 134.1, 133.92, 133.88, 133.4, 129.70, 129.67, 129.4,

129.3, 127.7, 127.5, 127.42, 127.37, 85.4, 82.8, 81.6, 80.8, 74.6,

67.6, 64.0, 60.8, 40.8, 37.3, 29.9, 26.9, 26.8, 26.4, 19.3, 19.2;

HRMS (FAB) calcd for C₄₄H₅₈O₆Si₂Na [(M + Na)⁺] 761.3670,

found 761.3667.

Aceta l 21. A solution of aldehyde 10 (3.00 g, 17.85 mmol)

and diol 11 (10.14 g, 13.73 mmol) in dry benzene (150 mL)

was treated with scandium trifluoromethanesulfonate (676 mg,

1.37 mmol) at room temperature. After being stirred at room

temperature for 3 h, the reaction mixture was diluted with

EtOAc (500 mL), washed with saturated aqueous NaHCO₃and

brine, dried (Na₂SO₄), and concentrated to afford an insepa-

rable mixture of acetal and the recovered aldehyde 10. This

crude residue was dissolved in MeOH-CH₂Cl₂(1:1, 150 mL),

and the solution was treated with sodium borohydride (700

mg, 18.5 mmol) and stirred at 0 °C for 10 min. The reaction

was quenched with saturated aqueous NH₄Cl (100 mL), and

the aqueous layer was extracted with CHCl₃(120 mL × 4).

The combined organic layers were dried (Na₂SO₄), filtered, and

concentrated. Flash chromatography (20% EtOAc-hexane)

gave acetal 21 (10.04 g, 82%) as an inseparable mixture of

diastereomers (R: â ) 1:2): IR (film) 3070, 2933, 2856, 1427,

Oxep a n e 20. A solution of alcohol 17 (12.85 g, 17.79 mmol)

in THF (200 mL) was cooled to -78 °C and treated with sec-

BuLi (52.0 mL, 1.03 M solution in cyclohexane, 53.6 mmol).

After 20 min at -78 °C, Bu₃SnCl (10.5 mL, 39.0 mmol) was

added to this mixture. After being stirred for 1 h at -78 °C,

the reaction was quenched with H₂O (50 mL), and the mixture

was diluted with EtOAc (600 mL). The organic layer was

washed with brine, dried (Na₂SO₄), filtered, and concentrated.

Flash chromatography (silica gel, 10-20% EtOAc-hexane

containing 1% Et₃N) gave allylstannane 18 (15.91 g, 88%).

A solution of allylstannane 18 (15.91 g, 15.75 mmol) and

Et₃N (11 mL, 78.9 mmol) in CH₂Cl₂-DMSO (220 mL, 10:1)

was cooled to 0 °C and treated with sulfur trioxide‚pyridine

complex (10.25 g, 64.40 mmol). The mixture was stirred at 0

°C for 30 min and then allowed to warm to room temperature,

and the stirring was continued for 1.5 h. The resulting solution

was diluted with EtOAc (600 mL), washed with H₂O, saturated

1081, 741, 704, 507 cm^-1

isomer) δ 7.67-7.26 (20H, m), 5.86 (1H, dddd, J ) 17.1, 10.4,

;

¹H NMR (CDCl₃, 500 MHz) (R-

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9425

5.5, 5.5 Hz), 5.23 (1H, dddd, J ) 17.1, 1.5, 1.5, 1.5 Hz), 5.13

(1H, dddd, J ) 10.4, 1.5, 1.5, 1.5 Hz), 4.88 (1H, dd, J ) 8.9,

2.5 Hz), 4.09 (1H, dddd, J ) 12.8, 5.5, 1.5, 1.5 Hz), 3.92 (1H,

dd, J ) 11.0, 1.8 Hz), 3.88 (1H, dddd, J ) 12.8, 5.5, 1.5, 1.5

Hz), 3.81 (2H, m, 17-H), 3.79 (1H, m), 3.69 (1H, dd, J ) 11.0,

5.5 Hz), 3.66 (1H, m), 3.44 (1H, dd, J ) 11.6, 11.6 Hz), 3.31

(1H, ddd, J ) 11.6, 11.6, 2.4 Hz), 3.29 (1H, m), 3.27 (1H, m),

3.22 (1H, ddd, J ) 9.8, 9.8, 1.8 Hz), 3.00 (1H, ddd, J ) 9.2,

9.2, 4.3 Hz), 2.97 (1H, ddd, J ) 10.4, 9.8, 4.3 Hz), 2.89 (1H,

ddd, J ) 11.6, 9.2, 3.7 Hz), 2.19 (1H, m), 2.12 (1H, ddd, J )

14.3, 8.9, 1.8 Hz), 2.02 (1H, ddd, J ) 11.6, 4.3, 4.3 Hz), 1.89-

1.44 (10H, m), 1.33 (1H, dddd, J ) 12.5, 12.5, 10.4, 4.9 Hz),

0.99 (9H, s), 0.95 (9H, s); ¹H NMR (CDCl₃, 500 MHz) (â-isomer)

δ 7.67-7.26 (20H, m), 5.86 (1H, m), 5.22 (1H, dddd, J ) 17.1,

1.8, 1.2, 1.2 Hz), 5.12 (1H, dddd, J ) 10.1, 1.8, 1.2, 1.2 Hz),

4.92 (1H, dd, J ) 8.6, 2.8 Hz), 4.06 (1H, m), 3.93 (1H, dd, J )

11.0, 1.5 Hz), 3.88 (1H, m), 3.82 (1H, m), 3.71-3.62 (4H, m),

3.54 (1H, ddd, J ) 12.5, 4.0, 4.0 Hz), 3.34-3.26 (3H, m), 3.20

(1H, m), 3.00 (1H, m), 2.98 (1H, m), 2.89 (1H, m), 2.19 (1H,

m), 2.13 (1H, m), 2.02 (1H, m), 1.88-1.47 (10H, m), 1.33 (1H,

m), 0.99 (9H, s), 0.96 (9H, s); ¹³C NMR (CDCl₃, 125 MHz) (R-

isomer) δ 135.94, 135.85, 135.81, 135.7, 135.0, 134.1, 134.0,

133.8, 133.3, 129.7, 129.6, 129.4, 129.3, 127.6, 127.5, 127.4,

127.36, 116.4, 99.1, 83.9, 82.9, 82.6, 80.9, 77.5, 77.1, 72.0, 69.7,

67.8, 67.5, 63.9, 63.7, 40.8, 36.3, 36.1, 29.7, 29.3, 27.8, 26.9,

26.8, 25.3, 19.3, 19.2; ¹³C NMR (CDCl₃, 125 MHz) (â-isomer)

δ 135.9, 135.82, 135.80, 135.7, 135.1, 134.2, 134.0, 133.8, 133.3,

129.7, 129.6, 129.4, 129.3, 127.6, 127.48, 127.39, 127.34, 116.7,

99.7, 83.2, 82.8, 82.2, 80.7, 80.3, 77.2, 69.9, 67.7, 67.5, 63.9,

58.3, 40.8, 36.4, 36.2, 29.8, 29.4, 27.81, 27.77, 26.9, 26.8, 25.4,

19.3, 19.2; HRMS (FAB) calcd for C₅₄H₇₂O₈Si₂Na [(M + Na)⁺]

927.4663, found 927.4650.

Allyltr ieth ylsila n e 28. A solution of acetal 21 (9.22 g, 10.38

mmol, R:â ) 1:2) in THF (150 mL) was cooled to -78 °C and

treated with sec-BuLi (1.03 M solution in cyclohexane, 12.0

mL, 14.1 mmol). After 20 min at -78 °C, triethylsilyl chloride

(2.0 mL, 11.9 mmol) was added to this mixture. After the

reaction mixture was stirred at -78 °C for 20 min, the reaction

was quenched with H₂O (30 mL), and the mixture was diluted

with EtOAc (500 mL). The organic layer was washed with

brine, dried (Na₂SO₄), and concentrated. Chromatography

(10-20% EtOAc-hexane) gave allyltriethylsilane 28 (9.03 g,

87%) as an inseparable mixture of diastereomers (R:â ) ca.

1:4) along with the recovered acetal 21r (1.16 g, 12%). Data

for the â-isomer of 28: ¹H NMR (500 MHz, CDCl₃) δ 7.67-

7.26 (20H, m), 5.85 (1H, d, J ) 6.1 Hz), 4.93 (1H, dd, J ) 8.6,

3.1 Hz), 4.29 (1H, ddd, J ) 8.6, 8.6, 6.1 Hz), 3.92 (1H, dd, J )

11.3, 1.8 Hz), 3.82 (1H, m), 3.67 (1H, dd, J ) 11.3, 5.5 Hz),

3.63 (3H, m), 3.52 (1H, ddd, J ) 12.8, 4.3, 4.3 Hz), 3.33-3.18

(5H, m), 2.99 (1H, ddd, J ) 8.2, 8.2, 4.3 Hz), 2.88 (1H, m),

2.12-1.23 (16H, m), 0.99 (9H, s), 0.95 (9H, s), 0.91 (9H, t, J )

7.9 Hz), 0.49 (6H, q, J ) 7.9 Hz).

m), 1.59 (1H, m), 1.53 (1H, m), 1.47 (1H, ddd, J ) 11.3, 11.3,

11.0 Hz), 1.40 (2H, m), 0.99 (9H, s), 0.95 (9H, s); ¹³C NMR

(125 MHz, CDCl₃) δ 135.93, 135.89, 135.83, 135.79, 135.67,

134.1, 133.9, 133.8, 133.4, 129.69, 129.67, 129.4, 129.3, 127.6,

127.5, 127.43, 127.38, 118.7, 83.9, 82.5, 82.0, 81.8, 81.0, 79.2,

77.3, 76.5, 76.4, 67.8, 67.5, 63.9, 61.1, 40.8, 37.3, 37.1, 29.2,

26.9, 26.8, 26.0, 25.40, 25.36, 19.3, 19.2; HRMS (FAB) calcd

for C₅₄H₇₂O₈Si₂Na [(M + Na)⁺] 927.4663, found 927.4665. Data

for 24: [R]²⁹) -5.1° (c 2.32, CHCl₃); IR (film) 3444 cm^-1; ¹H

NMR (500 MHz, CDCl₃) δ 7.68-7.27 (20H, m), 5.90 (1H, ddd,

J ) 17.4, 10.7, 6.7 Hz), 5.26 (1H, d, J ) 17.4 Hz), 5.15 (1H, d,

J ) 10.7 Hz), 3.94 (1H, dd, J ) 11.3, 1.8 Hz), 3.91 (1H, br d),

3.87 (1H, m), 3.65 (1H, dd, J ) 11.3, 5.8 Hz), 3.62 (3H, m,

27-H₂), 3.54 (1H, br), 3.46 (1H, ddd, J ) 9.5, 6.7, 3.1 Hz), 3.39

(1H, m), 3.37 (1H, m), 3.27 (1H, ddd, J ) 9.2, 5.8, 1.8 Hz),

3.23 (1H, ddd, J ) 11.9, 9.2, 4.3 Hz), 3.07 (1H, ddd, J ) 11.0,

9.2, 4.3 Hz), 2.93 (1H, ddd, J ) 9.8, 9.8, 4.3 Hz), 2.86 (1H,

ddd, J ) 11.3, 9.8, 4.3 Hz), 2.12 (1H, ddd, J ) 14.0, 7.0, 4.0

Hz), 2.02 (1H, m), 1.91 (1H, ddd, J ) 11.3, 4.3, 4.3 Hz), 1.83-

1.44 (10H, m), 1.41 (1H, ddd, J ) 11.3, 11.3, 11.3 Hz), 0.99

(9H, s), 0.95 (9H, s); ¹³C NMR (125 MHz, CDCl₃) δ 135.9 (×2),

135.82, 135.78, 135.71, 134.1, 133.9, 133.8, 133.4, 127.9 (×2),

129.4, 129.3, 127.7, 127.6, 127.40, 127.35, 116.9, 84.3, 82.7,

81.9, 81.5, 81.3, 80.1, 78.3, 74.1, 74.0, 68.2, 67.7, 64.0, 61.1,

40.7, 36.9, 33.0, 29.2, 26.9, 26.8, 26.3, 25.7, 24.2, 19.3, 19.2;

HRMS (FAB) calcd for C₅₄H₇₂O₈Si₂Na [(M + Na)⁺] 927.4663,

found 927.4671.

TBDMS Eth er 29. A solution of tetracyclic ether 23 (3.16

g, 3.56 mmol) in CH₂Cl₂(40 mL) was cooled to 0 °C and treated

sequentially with 2,6-lutidine (0.92 mL, 7.90 mmol) and

TBDMSOTf (0.90 mL, 3.92 mmol). After the reaction mixture

was stirred at 0 °C for 30 min, the reaction was quenched with

MeOH (0.5 mL). The mixture was diluted with EtOAc (200

mL) and Et₂O (40 mL), washed with 1 N aqueous HCl,

saturated aqueous NaHCO₃, and brine, dried (Na₂SO₄), and

concentrated. Flash chromatography (10-20% EtOAc-hex-

ane) gave TBDMS ether 29 (3.4578 g, 95%): [R]²⁸) +24.9°

(c 0.36, CHCl₃); IR (film) 2931, 2856, 1427, 1257, 1111, 1007,

837, 704 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.67-7.25 (20H,

m), 5.76 (1H, ddd, J ) 17.1, 10.4, 6.4 Hz), 5.24 (1H, d, J )

17.1 Hz), 5.04 (1H, d, J ) 10.4 Hz), 3.93 (1H, dd, J ) 11.3, 1.8

Hz), 3.88 (1H, m), 3.68 (1H, dd, J ) 11.3, 5.5 Hz), 3.59 (1H,

m), 3.58 (1H, m), 3.50 (2H, m), 3.40 (2H, m), 3.34 (1H, ddd, J

) 11.3, 11.3, 4.3 Hz), 3.26 (1H, ddd, J ) 8.9, 5.5, 1.8 Hz), 3.11

(1H, ddd, J ) 11.0, 8.9, 4.3 Hz), 3.00 (1H, ddd, J ) 11.0, 8.9,

4.3 Hz), 2.95-2.87 (3H, m), 2.32 (1H, ddd, J ) 11.6, 4.6, 4.3

Hz), 2.04 (1H, m), 1.96 (1H, ddd, J ) 11.6, 4.0, 4.0 Hz), 1.80-

1.37 (11H, m), 0.99 (9H, s), 0.95 (9H, s), 0.81 (9H, s), -0.07

(3H, s), -0.11 (3H, s); ¹³C NMR (125 MHz, CDCl₃) δ 135.94

(×2), 135.86, 135.78, 135.70, 134.2, 134.1, 133.8, 133.4, 129.7,

129.6, 129.4, 129.3, 127.6, 127.43 (×2), 127.37, 118.3, 82.5,

81.9, 81.6, 81.4, 79.9, 78.8, 77.3, 76.6, 76.5, 67.8, 67.6, 64.0,

59.5, 40.8, 38.2, 37.1, 29.3, 26.92, 26.85, 26.1, 25.9, 25.8, 25.4,

19.3, 19.2, 18.2, -5.4 (×2); HRMS (FAB) calcd for C₆₀H₈₆O₈Si₃Na

[(M + Na)⁺] 1041.5528, found 1041.5521.

Tetr a cyclic O-Lin k ed Oxa cycle 23. A solution of triph-

enylphosphine (7.09 g, 27.1 mmol) in CH₂Cl₂(100 mL) was

cooled to -78 °C and treated with TiCl₄(3.0 mL, 27.4 mmol),

and the resulting mixture was stirred at -78 °C for 10 min. A

solution of allyltriethylsilane 28 (9.03 g, 9.01 mmol) in CH₂Cl₂

(75 mL) was added dropwise over 10 min to this solution. The

resulting mixture was stirred at -78 °C for 30 min and at 0

°C for 30 min. The reaction was quenched with saturated

aqueous NaHCO₃(100 mL) and diluted with EtOAc-Et₂O (4:

1, 500 mL). The organic layer was washed with brine, dried

(Na₂SO₄), and concentrated. Flash chromatography (30-60%

EtOAc-hexane) gave tetracyclic ether 23 (2.09 g, 36%) and

Alcoh ol 30. A solution of TBDMS ether 29 (2.972 g, 2.916

mmol) and N-methylmorpholine N-oxide (50% in H₂O, 2.05 g,

8.75 mmol) in t-BuOMe-t-BuOH-H₂O (1:1:1, 66 mL) was

treated with OsO₄(75.0 mg, 0.295 mmol). The mixture was

stirred at room temperature overnight and diluted with EtOAc

(250 mL). The organic layer was washed with saturated

aqueous Na₂SO₃, H₂O, and brine, dried (Na₂SO₄), and concen-

trated to give crude diol.

A solution of the crude diol in benzene (40 mL) was treated

with Pb(OAc)₄(1.94 g, 4.38 mmol), and the resulting mixture

was stirred at room temperature for 30 min. The mixture was

diluted with EtOAc (250 mL), washed with H₂O, saturated

aqueous Na₂SO₃, saturated aqueous NaHCO₃, and brine, dried

(Na₂SO₄), and concentrated to give crude aldehyde.

A solution of the crude aldehyde in THF (40 mL) was cooled

to -78 °C and treated with methylmagnesium bromide (3.0

M solution in Et₂O, 3.0 mL, 9.0 mmol). The mixture was stirred

at -78 °C for 20 min and then at 0 °C for 30 min. The reaction

was quenched with saturated aqueous NH₄Cl (10 mL), and

the mixture was diluted with EtOAc (250 mL). The organic

its diastereoisomer 24 (1.33 g, 16%). Data for 23: [R]²⁹

)

+12.2° (c 0.81, CHCl₃); IR (film) 3475 cm^-1; ¹H NMR (500 MHz,

CDCl₃) δ 7.67-7.26 (20H, m), 5.74 (1H, ddd, J ) 17.4, 10.7,

7.0 Hz), 5.26 (1H, d, J ) 17.4 Hz), 5.10 (1H, d, J ) 10.7 Hz),

3.94 (1H, dd, J ) 11.3, 1.8 Hz), 3.88 (1H, m), 3.65 (1H, dd, J

) 11.3, 6.1 Hz), 3.60-3.56 (4H, m), 3.45 (1H, m), 3.42 (1H,

m), 3.34 (1H, ddd, J ) 11.6, 11.6, 4.6 Hz), 3.26 (1H, ddd, J )

9.2, 6.1, 1.8 Hz), 3.10 (1H, ddd, J ) 11.0, 9.2, 4.3 Hz), 3.00

(1H, ddd, J ) 11.3, 8.9, 4.6 Hz), 2.95-2.89 (3H, m), 2.30 (1H,

ddd, J ) 11.3, 4.3, 4.3 Hz), 2.04 (1H, m), 1.91 (1H, ddd, J )

11.6, 4.3, 4.3 Hz), 1.81 (1H, m), 1.74 (2H, m), 1.69-1.64 (3H,

9426 J . Org. Chem., Vol. 64, No. 26, 1999

Inoue et al.

layer was washed with brine, dried (Na₂SO₄), and concen-

trated. Flash chromatography (30% EtOAc-hexane) gave

alcohol 30 as a 5:1 mixture of diastereoisomers (2.778 g, 91%

hol 32 (101.0 mg, 83% for the three steps): [R]²⁹) +5.7° (c

0.97, CHCl₃); IR (film) 3473, 1732 cm^-1; H NMR (500 MHz,

CDCl₃) δ 7.66-7.25 (20H, m), 4.08 (1H, d, J ) 13.7 Hz), 4.05

(1H, d, J ) 13.7 Hz), 3.94 (1H, dd, J ) 11.0, 1.8 Hz), 3.93 (1H,

d, J ) 9.2 Hz), 3.88 (1H, br d, J ) 11.9 Hz), 3.59 (1H, dd, J )

11.0, 6.1 Hz), 3.56 (4H, m), 3.47 (1H, m), 3.37 (1H, ddd, J )

8.9, 4.6, 4.6 Hz), 3.34 (1H, ddd, J ) 11.6, 9.2, 6.4 Hz), 3.28

(1H, ddd, J ) 8.9, 6.1, 1.8 Hz), 3.04 (1H, ddd, J ) 11.0, 8.9,

4.3 Hz), 2.94 (1H, m), 2.93 (1H, m), 2.81 (1H, ddd, J ) 11.3,

9.2, 4.3 Hz), 2.38 (1H, ddd, J ) 11.9, 4.3, 4.3 Hz), 2.03 (1H,

m), 1.94 (1H, ddd, J ) 11.9, 4.3, 4.3 Hz), 1.83-1.53 (8H, m),

1.52 (1H, ddd, J ) 11.9, 11.6, 11.6 Hz), 1.41 (1H, m), 1.39 (1H,

ddd, J ) 11.9, 11.6, 11.3 Hz), 0.99 (9H, s), 0.95 (9H, s); ¹³C

NMR (125 MHz, CDCl₃) δ 197.8, 135.82 (×2), 135.78, 135.69,

134.1, 133.9, 133.8, 133.4, 129.7 (×2), 129.4, 129.3, 127.6,

127.5, 127.40, 127.38, 83.9, 83.1, 82.6, 81.4, 81.0, 79.9, 78.2,

75.6, 74.2, 67.8, 67.6, 64.1, 60.9, 40.7, 37.27, 37.24, 33.6, 29.0,

26.9, 26.8, 26.1, 26.0, 25.3, 19.3, 19.2; HRMS (FAB) calcd for

for the three steps): [R]²⁹) +6.37° (c 1.55, CHCl₃); IR (film)

3479 cm^-1; ¹H NMR (500 MHz, CDCl₃) (major isomer) δ 7.65-

7.25 (20H, m), 3.94 (1H, m), 3.93 (1H, br d, J ) 11.0 Hz), 3.88

(1H, m), 3.64 (1H, dd, J ) 11.0, 5.8 Hz), 3.60 (1H, ddd, J )

11.0, 9.2, 4.9 Hz), 3.54 (1H, m), 3.51-3.45 (3H, m), 3.40-3.20

(3H, m), 2.99-2.92 (3H, m), 2.87 (1H, ddd, J ) 11.3, 8.9, 4.0

Hz), 2.79 (1H, ddd, J ) 11.9, 9.2, 4.3 Hz), 2.35 (1H, ddd, J )

11.3, 4.3, 4.3 Hz), 2.03-1.36 (13H, m), 1.20 (1H, d, J ) 6.4

Hz), 0.99 (9H, s), 0.96 (9H, s), 0.81 (9H, s), -0.06 (3H, s), -0.10

(3H, s); ¹³C NMR (125 MHz, CDCl₃) (major isomer) δ 135.92,

135.87, 135.78, 135.69, 134.2, 134.0, 133.8, 133.5, 129.7, 129.6,

129.4, 129.3, 127.6, 127.5, 127.42, 127.38, 83.0, 82.7, 82.4, 81.9,

81.2, 80.7, 77.6, 76.7, 73.2, 67.8, 67.7, 64.7, 64.1, 59.6, 40.8,

38.4, 37.2, 29.2, 27.3, 26.93, 26.85, 26.4, 25.9, 25.4, 20.4, 19.3,

19.2, 18.2, -5.4, -5.5; HRMS (FAB) calcd for C₆₀H₈₈O₉Si₃Na

[(M + Na)⁺] 1059.5634, found 1059.5643.

₅₄H₇₁O₉BrSi₂Na [(M + Na)⁺] 1021.3718, found 1021.3698.

P h en ylth ioca r bon a te 35. A solution of R-bromoketo al-

Meth yl Keton e 31. A solution of oxalyl chloride (540 µL,

6.21 mmol) in CH₂Cl₂(20 mL) was cooled to -78 °C and

treated with DMSO (890 µL, 12.5 mmol). The resulting

solution was stirred at -78 °C for 10 min. To the solution was

added dropwise via cannula a solution of alcohol 30 (3.21 g,

3.09 mmol) in CH₂Cl₂(20 mL). After being stirred at -78 °C

for 30 min, the mixture was treated with Et₃N (3.5 mL, 25.1

mmol) and allowed to warm to room temperature. The solution

was stirred at room temperature for 30 min and diluted with

EtOAc-Et₂O (4:1, 250 mL). The organic layer was washed

with H₂O, saturated aqueous NaHCO₃, and brine, dried

(Na₂SO₄), and concentrated. Flash chromatography (20%

cohol 32 (417.2 mg, 0.4172 mmol) and Et₃N (300 µL, 2.15

mmol) in CH₂Cl₂-DMSO (3:1, 16 mL) was cooled to 0 °C and

treated with sulfur trioxide‚pyridine complex (270 mg, 1.70

mmol). After being stirred at 0 °C for 40 min, the mixture was

diluted with EtOAc (100 mL) and Et₂O (40 mL), washed with

H₂O and brine, dried (Na₂SO₄), and concentrated to give

aldehyde 6, which was used in the following reaction without

purification.

To a solution of SmI₂in THF (0.1 M, 21 mL, 2.10 mmol)

was added dropwise over 10 min a solution of the above

aldehyde 6 (0.4172 mmol) in THF (20 mL) at -78 °C, and the

resulting mixture was stirred at -78 °C for 45 min. Excess

SmI₂was quenched by exposure to dry oxygen until the deep

blue solution turned yellow. The mixture was directly treated

with acetic anhydride (400 µL, 4.24 mmol) and DMAP (102

mg, 0.835 mmol) and allowed to warmed to 0 °C. After being

stirred at 0 °C for 30 min, the solution was diluted with EtOAc

(200 mL), washed with 1 N aqueous HCl, saturated aqueous

Na₂SO₃, saturated aqueous NaHCO₃and brine, dried (Na₂SO₄),

and concentrated to give crude â-acetoxy ketone 33 (557 mg),

which was used in the following reaction without purification.

Analytically pure sample was purified by flash chromatogra-

phy (30-60% EtOAc-hexane) to afford 33 as a single diaste-

reomer: ¹H NMR (500 MHz, CDCl₃) δ 7.65-7.26 (20H, m),

5.46 (1H, br dd, J ) 10.4, 10.1 Hz), 4.08 (1H, d, J ) 9.5 Hz),

3.89 (1H, d, J ) 11.0 Hz), 3.87 (1H, br d, J ) 13.7 Hz), 3.59

(1H, dd, J ) 11.0, 5.5 Hz), 3.59 (1H, m), 3.41 (1H, ddd, J )

11.6, 9.5, 4.6 Hz), 3.33 (1H, m), 3.28-3.25 (2H, m), 3.10 (1H,

m), 3.06 (1H, dd, J ) 12.5, 2.8 Hz), 3.00 (2H, m), 2.90 (1H, m),

2.82 (1H, ddd, J ) 11.3, 9.2, 3.7 Hz), 2.60 (1H, dd, J ) 12.5,

10.4 Hz), 2.28 (1H, ddd, J ) 11.6, 4.0, 4.0 Hz), 2.04 (3H, s),

2.03-1.98 (3H, m), 1.78 (1H, ddd, J ) 15.0, 10.1, 7.6 Hz), 1.74-

1.59 (7H, m), 1.47 (2H, ddd, J ) 11.3, 11.3, 11.3 Hz), 0.98 (9H,

s), 0.94 (9H, s); ¹³C NMR (125 MHz, CDCl₃) δ 206.8, 170.4,

135.9 (×2), 135.8, 135.7, 134.1, 134.0, 133.8, 133.2, 129.7,

129.6, 129.4, 129.3, 127.7, 127.5, 127.4 (×2), 86.6, 83.0, 82.7,

82.2, 81.9, 80.5, 77.8, 77.4, 77.2, 76.0, 67.7, 66.9, 64.0, 51.9,

43.5, 40.8, 38.4, 28.9, 28.8, 26.9, 26.8, 26.5, 25.4, 21.3, 19.3,

19.2.

EtOAc-hexane) gave methyl ketone 31 (3.02 g, 94%): [R]²⁹

) +2.9° (c 0.98, CHCl₃); IR (film) 1730 cm^-1

;

¹H NMR (500

MHz, CDCl₃) δ 7.67-7.25 (20H, m), 3.93 (1H, dd, J ) 11.0,

1.5 Hz), 3.88 (1H, br d, J ) 11.6 Hz), 3.72 (1H, d, J ) 9.2 Hz),

3.62 (1H, dd, J ) 11.0, 5.8 Hz), 3.57 (1H, ddd, J ) 11.0, 9.2,

4.6 Hz), 3.50 (1H, m), 3.45 (2H, m), 3.41 (1H, m), 3.34 (1H,

ddd, J ) 11.6, 8.9, 6.4 Hz), 3.28 (2H, m), 3.01 (1H, ddd, J )

10.7, 8.9, 4.3 Hz), 2.93 (2H, m), 2.76 (1H, ddd, J ) 11.6, 9.2,

4.3 Hz), 2.39 (1H, ddd, J ) 11.6, 4.6, 4.6 Hz), 2.17 (3H, s),

2.02 (1H, m), 1.99 (1H, ddd, J ) 11.6, 4.6, 4.3 Hz), 1.81 (1H,

m), 1.75-1.62 (5H, m), 1.54-1.34 (5H, m), 0.99 (9H, s), 0.95

(9H, s), 0.80 (9H, s), -0.07 (3H, s), -0.12 (3H, s); ¹³C NMR

(125 MHz, CDCl₃) δ 205.3, 139.5, 135.84, 135.76, 135.69, 134.1,

133.93, 133.86, 133.4, 129.64, 129.57, 129.4, 129.3, 127.6,

127.44, 127.42, 127.38, 83.7, 82.8, 82.6, 81.5, 80.5, 80.0, 77.9,

75.9, 74.4, 67.8, 67.6, 64.1, 59.3, 40.7, 38.0, 37.4, 29.5, 29.0,

26.9, 26.8, 26.5, 26.2, 25.9, 25.4, 19.3, 19.2, 18.2, -5.4, -5.5;

HRMS (FAB) calcd for C₆₀H₈₆O₉Si₃Na [(M + Na)⁺] 1057.5477,

found 1057.5459.

r-Br om ok eto Alcoh ol 32. To a solution of LDA, prepared

from i-Pr₂NH (60 µL, 0.428 mmol) and BuLi (1.63 M solution

in hexane, 230 µL, 0.375 mmol), in THF (2 mL) was added

dropwise a solution of ketone 31 (125.3 mg, 0.1210 mmol) in

THF (4 mL) at -78 °C. The mixture was stirred at -78 °C for

20 min and treated with TMSCl (50 µL, 0.39 mmol). After 20

min at -78 °C, the reaction was quenched with H₂O, and the

solution was allowed to warm to room temperature. The

solution was diluted with EtOAc (60 mL), washed with brine,

dried (Na₂SO₄), and concentrated to give silyl enol ether, which

was used immediately in the next reaction.

A solution of the above crude â-acetoxy ketone 33 in

CH₂Cl₂-MeOH (1:1, 16 mL) was cooled to 0 °C and treated

with NaBH₄(32.0 mg, 0.846 mmol) portionwise. After 10 min

at 0 °C, the reaction was quenched with saturated aqueous

NH₄Cl (16 mL), and the solution was extracted with CHCl₃

(30 mL × 4). The combined organic layers were dried (Na₂SO₄)

and concentrated. Flash chromatography (2% MeOH-CHCl₃)

afforded alcohol 34 (389.8 mg), which was used in the next

reaction without further purification.

A solution of the silyl enol ether in THF (6 mL) was cooled

to 0 °C and treated with N-bromosuccinimide (65.0 mg, 0.365

mmol). After being stirred at 0 °C for 45 min, the mixture was

diluted with EtOAc (60 mL), washed with saturated aqueous

Na₂SO₃, H₂O, and brine, dried (Na₂SO₄), and concentrated to

give R-bromoketone, which was used in the following reaction

without purification.

A solution of the crude R-bromoketone in CH₂Cl₂-MeOH

(1:1, 6 mL) was cooled to 0 °C and treated with camphorsul-

fonic acid (6.0 mg, 0.026 mmol). After the resulting mixture

was stirred at 0 °C for 10 min and at room temperature for 45

min, the reaction was quenched with Et₃N, and the mixture

was concentrated. The residue was subjected to flash chroma-

tography (40-50% EtOAc-hexane) to give R-bromoketo alco-

A solution of the above alcohol 34 (376.3 mg, 0.3911 mmol)

and DMAP (478 mg, 3.912 mmol) in acetonitrile (10 mL) was

treated with phenyl chlorothiocarbonate (270 µL, 1.951 mmol)

at room temperature. After the mixture was stirred at room

temperature for 23 h, most of the solvent was removed by

evaporation, and the residue was diluted with EtOAc (100 mL).

The organic layer was washed with 1 N aqueous HCl,

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9427

saturated aqueous NaHCO₃, and brine, dried (Na₂SO₄), and

concentrated. Flash chromatography (10-20% EtOAc-hex-

ane) gave phenyl thiocarbonate 35 as a 1:1 mixture of

diastereomers (300 mg, 66% for the five steps): [R]²⁹_D) +23.5°

(c 0.59, CHCl₃); IR (film) 1732 cm^-1; ¹H NMR (500 MHz, CDCl₃,

a 1:1 mixture of diastereomers) δ 7.66-7.26 (23H, m), 7.09

(1H, d, J ) 7.3 Hz), 7.04 (1H, d, J ) 7.3 Hz), 5.75 (1/2H, m),

5.43 (1/2H, m), 5.19 (1H, m), 3.89 (2H, m), 3.63-3.49 (9/2H,

m), 3.37-3.26 (7/2H, m), 3.00-2.82 (4H, m), 2.66 (1/2H, ddd,

J ) 16.8, 5.2, 5.2 Hz), 2.44 (1/2H, ddd, J ) 12.2, 4.6, 4.6 Hz),

2.35 (1/2H, ddd, J ) 11.6, 4.3, 4.3 Hz), 2.25 (1/2H, ddd, J )

15.0, 7.3, 7.3 Hz), 2.14 (1/2H, ddd, J ) 15.0, 4.9, 4.9 Hz), 2.06-

1.55 (23/2H, m), 2.02 (3/2H, s), 2.00 (3/2H, s), 1.49 (1H, ddd, J

) 11.6, 11.6, 11.6 Hz), 1.37 (1H, m), 0.98 (9H, s), 0.96 (9/2H,

s), 0.95 (9/2H, s); ¹³C NMR (125 MHz, CDCl₃, a 1:1 mixture of

diastereomers) δ 194.4, 194.0, 170.5, 170.2, 153.4, 153.3, 136.0,

135.87, 135.85, 135.82, 135.79, 135.76, 135.69, 134.1, 134.0,

133.83, 133.79, 133.2, 133.1, 129.8, 129.7, 129.60, 129.57,

129.48, 129.45, 129.38, 129.33, 127.72, 85.2, 84.9, 84.8, 83.4,

83.0, 82.5, 82.3, 81.7, 81.3, 80.9, 80.7, 80.6, 80.4, 77.5, 77.2,

76.9, 76.2, 75.9, 75.6, 73.8, 69.3, 68.5. 67.8, 67.7, 67.6, 64.0,

63.9, 42.5, 41.6, 40.8, 39.13, 39.08, 36.9, 34.8, 29.9, 29.8, 29.2,

29.1, 26.91, 26.89, 26.84, 26.4, 25.3, 25.2, 21.4, 19.3, 19.2;

HRMS (FAB) calcd for C₆₃H₇₈O₁₁Si₂SNa [(M + Na)⁺] 1121.4701,

found 1121.4712.

A solution of the above iodide (236 mg, 0.2928 mmol) and

triphenylphosphine (768 mg, 2.93 mmol) in CH₃CN (3 mL) was

heated at 70-80 °C for 12 h. The mixture was cooled to room

temperature and concentrated. The residue was subjected to

flash chromatography (10% MeOH-EtOAc) to give phospho-

nium salt 5 (303 mg, 97%): [R]²⁹) -24.9° (c 0.55, CHCl₃);

IR (film) 2927, 2858, 1439, 1084, 1028, 939, 837, 739, 692 cm^-1

;

¹H NMR (CD₃CN, 500 MHz) δ 7.83-7.27 (25H, m), 4.68 (1H,

d, J ) 11.9 Hz), 4.58 (1H, d, J ) 11.9 Hz), 4.45 (1H, d, J )

11.9 Hz), 4.42 (1H, d, J ) 11.9 Hz), 4.24 (1H, m), 3.89 (1H,

dd, J ) 9.8, 1.5 Hz), 3.85-3.79 (2H, m), 3.60 (1H, dd, J ) 9.5,

0.9 Hz), 3.48 (1H, dd, J ) 3.4, 0.9 Hz), 3.45 (1H, m), 3.33 (1H,

dd, J ) 9.5, 9.5 Hz), 3.25-3.18 (2H, m), 3.00 (1H, br dd, J )

8.9, 8.9 Hz), 2.95 (1H, dd, J ) 9.5, 4.6 Hz), 2.28 (1H, m), 2.22

(1H, ddd, J ) 12.2, 4.9, 4.9 Hz), 2.08 (2H, m), 2.04 (1H, m),

1.52-1.42 (3H, m), 1.24 (1H, ddd, J ) 12.2, 11.3, 11.3 Hz),

1.17 (3H, d, J ) 7.3 Hz), 1.01 (3H, d, J ) 6.1 Hz), 0.94 (3H, d,

J ) 6.4 Hz), 0.70 (9H, s), -0.03 (3H, s), -0.18 (3H, s); ¹³C NMR

(CD₃CN, 125 MHz) δ 140.4, 139.7, 136.10, 136.09, 134.6, 134.5,

131.3, 131.2, 129.3, 129.2, 128.64, 128.56, 128.4, 128.3, 119.5,

118.8, 109.8, 88.1, 85.6, 81.5, 79.6, 79.0, 74.8, 73.0, 72.9, 72.2,

71.4, 70.9, 43.3, 42.4, 41.8, 41.0, 39.5, 26.0, 20.4, 19.2, 18.9,

18.3, 16.2, 13.9, -3.9, -4.8; HRMS (FAB) calcd for C₅₈H₇₄O₇SiP

[(M + I)⁺] 941.4941, found 941.4945.

TBP S Eth er 38. A solution of acetate 36 (384.8 mg, 0.4068

mmol) in THF (15 mL) was treated with Bu₄NF (1.0 M solution

in THF, 1.3 mL, 1.3 mmol), and the resulting mixture was

stirred at room temperature overnight. The solvent was

evaporated, and the residue was subjected to flash chroma-

tography (5% MeOH-CHCl₃) to give diol, which was used in

the following reaction without further purification.

Aceta te 36. A solution of phenyl thiocarbonate 35 (121.1

mg, 0.1119 mmol) and triethylborane (1.04 M solution in

hexane, 25 µL, 0.026 mmol) in benzene (5 mL) was treated

with Bu₃SnH (600 µL, 2.23 mmol) and stirred at room

temperature for 2 h. The mixture was concentrated, and the

residue was purified by flash chromatography (20-30% EtOAc-

hexane) to give acetate 36 (85.3 mg, 80%): [R]²⁸) +21.2° (c

A solution of the crude diol and imidazole (83.0 mg, 1.22

mmol) in DMF (6 mL) was cooled to 0 °C and treated with

TBPSCl (130 µL, 0.506 mmol). The resulting mixture was

stirred at 0 °C for 30 min and diluted with EtOAc (100 mL).

The organic layer was washed with H₂O (×2) and brine, dried

(Na₂SO₄), and concentrated. Flash chromatography (30-50%

EtOAc-hexane) gave TBPS ether 38 (236 mg, 82% for the two

0.61, CHCl₃); IR (film) 1732 cm^-1; ¹H NMR (500 MHz, CDCl₃)

δ 7.66-7.26 (20H, m), 5.03 (1H, m), 3.90 (1H, dd, J ) 11.3,

1.8 Hz), 3.87 (1H, m), 3.60 (1H, m), 3.59 (1H, dd, J ) 11.3, 5.8

Hz), 3.42 (1H, br dd, J ) 9.2, 5.2 Hz), 3.36 (1H, m), 3.32 (1H,

m), 3.27 (1H, ddd, J ) 9.2, 5.8, 1.8 Hz), 3.11-3.05 (2H, m),

2.95 (1H, m), 2.94-2.87 (3H, m), 2.24 (1H, ddd, J ) 11.6, 4.0,

4.0 Hz), 2.05 (1H, ddd, J ) 11.3, 3.7, 3.7 Hz), 1.99 (3H, s),

1.99 (1H, m), 1.85-1.64 (12H, m), 1.52 (1H, ddd, J ) 11.6,

11.3, 11.3 Hz), 1.47 (1H, ddd, J ) 11.3, 11.3, 11.3 Hz), 1.35

(1H, m), 0.98 (9H, s), 0.95 (9H, s); ¹³C NMR (125 MHz, CDCl₃)

δ 170.5, 135.9 (×2), 135.8, 135.7, 134.1, 134.0, 133.8, 133.2,

129.7, 129.6, 129.39, 129.36, 127.7, 127.5, 127.40, 127.36, 88.2,

83.0, 82.3, 81.3, 81.0, 80.9, 80.7, 77.7, 77.2, 71.7, 67.8 (×2),

64.0, 42.2, 40.9, 38.8, 32.5, 30.2, 29.3, 29.1, 27.0, 26.9, 26.8,

25.4, 21.4, 19.3, 19.2; HRMS (FAB) calcd for C₅₆H₇₄O₉Si₂Na

[(M + Na)⁺] 969.4760, found 969.4752.

steps): [R]²⁹) +4.1° (c 0.55, CHCl₃); IR (film) 3444, 1730

cm^-1; H NMR (CDCl₃, 500 MHz) δ 7.66-7.12 (10H, m), 5.05

(1H, m), 3.87 (1H, dd, J ) 10.4, 4.9 Hz), 3.86 (1H, m), 3.72

(1H, m), 3.71 (1H, dd, J ) 10.4, 7.3 Hz), 3.54 (1H, ddd, J )

8.9, 8.9, 3.1 Hz), 3.47 (1H, ddd, J ) 8.9, 4.3, 4.3 Hz), 3.31 (1H,

m), 3.24 (1H, ddd, J ) 8.9, 7.3, 4.9 Hz), 3.18 (1H, ddd, J )

11.9, 9.2, 4.0 Hz), 3.09 (2H, m), 2.97 (1H, ddd, J ) 9.2, 6.4, 6.4

Hz), 2.91 (1H, m), 2.89 (1H, m), 2.36 (1H, ddd, J ) 11.6, 4.3,

4.3 Hz), 2.21 (1H, ddd, J ) 11.9, 3.7, 3.7 Hz), 2.02 (3H, s),

1.99 (1H, m), 1.95-1.64 (12H, m), 1.51 (1H, ddd, J ) 11.9,

11.0, 11.0 Hz), 1.47 (1H, ddd, J ) 11.6, 11.6, 11.6 Hz), 1.34

(1H, m), 1.04 (9H); ¹³C NMR (CDCl₃, 125 MHz) δ 170.7, 135.6,

135.5, 132.53, 132.46, 129.93, 129.91, 127.8 (×2), 88.1, 82.5,

81.4, 81.3, 80.9, 80.8, 79.4, 77.7, 77.0, 71.8, 69.9, 67.7, 66.5,

42.5, 39.5, 38.8, 32.8, 30.0, 29.3, 29.1, 26.9, 26.8, 25.4, 21.4,

P h osp h on iu m Sa lt 5. A solution of alcohol 7 (213.1 mg,

0.3061 mmol) in benzene (7 mL) was treated sequentially with

triphenylphosphine (241 mg, 0.919 mmol), imidazole (63.0 mg,

0.925 mmol), and iodine (156 mg, 0.615 mmol), and the

resulting mixture was stirred at room temperature for 1 h.

The mixture was diluted with EtOAc (100 mL), washed with

saturated aqueous Na₂SO₃, H₂O, and brine, dried (Na₂SO₄),

and concentrated. Flash chromatography (10% EtOAc-hex-

19.1; HRMS (FAB) calcd for

731.3591, found 731.3599.

₄₀H₅₆O₉SiNa [(M + Na)⁺]

Keton e 39. A solution of oxalyl chloride (55 µL, 0.633 mmol)

in CH₂Cl₂(3 mL) was cooled to -78 °C and treated with DMSO

(95 µL, 1.34 mmol). The resulting solution was stirred at -78

°C for 10 min. To the solution was added dropwise via cannula

a solution of alcohol 38 (228.1 mg, 0.3217 mmol) in CH₂Cl₂(6

mL). After being stirred at -78 °C for 30 min, the mixture

was treated with Et₃N (360 µL, 2.56 mmol) and allowed to

warm to room temperature. The solution was stirred at room

temperature for 30 min and diluted with EtOAc (100 mL). The

organic layer was washed with H₂O and brine, dried (Na₂SO₄),

and concentrated. Flash chromatography (40% EtOAc-hex-

ane) gave the corresponding iodide (239 mg, 97%): [R]²⁸

)

-51.1° (c 0.20, CHCl₃); IR (film) 2927, 2858, 1456, 1252, 1088,

1028, 837, 775, 735, 696 cm^-1; H NMR (CDCl₃, 500 MHz) δ

7.36-7.20 (10H, m), 4.64 (1H, d, J ) 12.5 Hz), 4.60 (1H, d, J

) 12.5 Hz), 4.46 (1H, d, J ) 12.5 Hz), 4.44 (1H, d, J ) 12.5

Hz), 4.23 (1H, m), 3.94 (1H, dd, J ) 9.8, 1.8 Hz), 3.81 (1H, dd,

J ) 9.8, 5.2 Hz), 3.78 (1H, m), 3.58 (1H, d, J ) 9.5 Hz), 3.38

(1H, dd, J ) 9.5, 9.5 Hz), 3.36 (1H, d, J ) 3.1 Hz), 3.29 (2H,

m), 3.25 (1H, m), 2.99 (1H, ddd, J ) 9.2, 9.2, 2.4 Hz), 2.86

(1H, dd, J ) 9.2, 5.2 Hz), 2.27 (1H, m), 2.18 (1H, ddd, J )

12.2, 4.9, 4.9 Hz), 2.14-2.03 (3H, m), 1.73 (1H, m), 1.55 (1H,

m), 1.51 (1H, m), 1.37 (1H, ddd, J ) 12.2, 11.6, 11.6 Hz), 1.10

(3H, d, J ) 7.3 Hz), 1.03 (3H, d, J ) 6.1 Hz), 0.98 (3H, d, J )

6.4 Hz), 0.86 (9H, s), 0.04 (3H, s), 0.02 (3H, s); ¹³C NMR (CDCl₃,

125 MHz) δ 139.4, 138.2, 128.4, 128.1, 127.6, 127.5, 127.4,

127.2, 108.8, 87.0, 84.7, 81.1, 78.5, 77.4, 73.6, 72.2, 72.0, 71.4,

71.0, 69.8, 42.5, 41.5, 41.2, 40.4, 38.4, 36.0, 25.7, 20.0, 17.9,

16.0, 13.5, 2.9, -4.0, -4.7; HRMS (FAB) calcd for C₄₀H₅₉O₇SiNaI

[(M + Na)⁺] 829.2973, found 829.3000.

ane) gave ketone 39 (215.2 mg, 94%): [R]²⁹) +13.6° (c 0.55,

CHCl₃); IR (film) 1728 cm^-1

;

¹H NMR (CDCl₃, 500 MHz) δ

7.69-7.33 (10H, m), 5.06 (1H, m), 3.97 (1H, dd, J ) 11.3, 2.7

Hz), 3.90 (1H, dd, J ) 11.3, 4.9 Hz), 3.86 (1H, m), 3.63 (1H,

ddd, J ) 11.3, 9.5, 5.5 Hz), 3.56 (1H, ddd, J ) 8.9, 7.9, 4.9

Hz), 3.48 (1H, ddd, J ) 8.9, 4.0, 4.0 Hz), 3.36-3.29 (3H, m),

3.12 (2H, m), 2.94 (1H, m), 2.92 (1H, m), 2.89 (1H, dd, J )

16.8, 5.5 Hz), 2.33 (1H, dd, J ) 16.8, 11.3 Hz), 2.27 (1H, ddd,

J ) 11.9, 2.8, 2.8 Hz), 2.01 (1H, m), 2.00 (3H, s), 1.94-1.65

9428 J . Org. Chem., Vol. 64, No. 26, 1999

Inoue et al.

(12H, m), 1.56 (1H, m), 1.36 (1H, m), 1.01 (9H, s); ¹³C NMR

(CDCl₃, 125 MHz) δ 205.9, 170.6, 135.7 (×2), 133.43, 133.36,

129.62, 129.59, 127.57, 127.56, 88.2, 83.9, 81.4, 81.3, 81.2, 81.0,

80.0, 77.7, 77.0, 71.7, 67.8, 63.4, 46.7, 42.2, 38.9, 32.6, 29.7,

29.3, 29.1, 26.9, 26.7, 25.4, 21.4, 19.2; HRMS (FAB) calcd for

C₄₀H₅₄O₉SiNa [(M + Na)⁺] 729.3435, found 729.3448.

Dith iok eta l 40. A solution of ketone 39 (207 mg, 0.293

mmol) and EtSH (110 µL, 1.49 mmol) in CH₂Cl₂(8 mL) was

cooled to -78 °C and treated with TiCl₄(60 µL, 0.547 mmol).

After the mixture was stirred at -78 °C for 1.5 h, the reaction

was quenched with aqueous NaHCO₃(2 mL). The mixture was

diluted with EtOAc (100 mL), washed with brine, dried

(Na₂SO₄), and concentrated to give dithioketal, which was used

in the next reaction without purification. Analytically pure

sample was purified by chromatography (30% EtOAc-hex-

ane): ¹H NMR (CDCl₃, 500 MHz) δ 7.69-7.32 (10H, m), 5.07

(1H, m), 4.11 (1H, dd, J ) 11.3, 1.8 Hz), 3.88 (1H, m), 3.75

(1H, dd, J ) 11.3, 8.2 Hz), 3.67 (1H, ddd, J ) 11.0, 9.5, 4.0

Hz), 3.59 (1H, dd, J ) 8.2, 1.8 Hz), 3.51 (1H, ddd, J ) 8.9, 5.8,

5.8 Hz), 3.40 (1H, ddd, J ) 8.9, 4.6, 4.6 Hz), 3.32 (1H, ddd, J

) 11.3, 11.3, 4.3 Hz), 3.12 (2H, m), 2.98 (1H, m), 2.93 (1H, m),

2.91 (1H, m), 2.60-2.34 (4H, m), 2.32 (1H, dd, J ) 13.1, 4.0

Hz), 2.25 (1H, ddd, J ) 11.6, 3.7, 3.7 Hz), 2.00 (1H, m), 1.99

(3H, s), 1.95-1.64 (13H, m), 1.53 (1H, m), 1.35 (1H, m), 1.14

(3H, t, J ) 7.6 Hz), 1.09 (3H, t, J ) 7.6 Hz), 1.02 (9H, s); ¹³C

NMR (CDCl₃, 125 MHz) δ 170.4, 135.70, 135.68, 134.0, 133.8,

129.5, 129.4, 127.51, 127.48, 88.4, 86.5, 83.3, 81.4, 81.3, 81.2,

78.5, 77.7, 77.0, 71.9, 67.8, 64.1, 60.3, 42.8, 42.1, 38.8, 32.2,

30.4, 29.3, 29.0, 27.3, 26.8, 25.4, 23.4, 23.3, 21.4, 19.3, 14.24,

14.15.

) 12.8 Hz), 4.43 (1H, d, J ) 12.8 Hz), 4.23 (1H, d, J ) 8.9 Hz),

4.22 (1H, m), 3.93 (1H, dd, J ) 9.5, 1.5 Hz), 3.86 (1H, m), 3.80

(1H, dd, J ) 9.5, 4.9 Hz), 3.78 (1H, m), 3.76 (1H, m), 3.56 (1H,

d, J ) 9.5 Hz), 3.53 (1H, m), 3.41-3.28 (4H, m), 3.25 (1H, ddd,

J ) 11.3, 8.9, 4.6 Hz), 3.13-3.05 (3H, m), 2.94 (2H, m), 2.89

(1H, m), 2.82 (1H, dd, J ) 9.5, 5.2 Hz), 2.80 (1H, m), 2.68-

2.56 (4H, m), 2.37 (1H, dd, J ) 13.1, 4.0 Hz), 2.24 (1H, m),

2.19-1.47 (22H, m), 2.00 (3H, s), 1.34 (2H, m), 1.25 (3H, t, J

) 7.3 Hz), 1.12 (3H, t, J ) 7.3 Hz), 1.06 (3H, d, J ) 7.3 Hz),

1.02 (3H, d, J ) 6.1 Hz), 0.97 (3H, d, J ) 6.4 Hz), 0.87 (9H, s),

0.07 (3H, s), 0.05 (3H, s); ¹³C NMR (CDCl₃, 125 MHz) δ 170.4,

139.4, 138.2, 132.8, 128.4, 128.1, 127.6, 127.5, 127.4, 127.2,

126.4, 108.8, 88.4, 86.9, 84.7, 83.3, 81.7, 81.5, 81.4, 81.3, 81.2,

78.5, 78.2, 77.7, 77.4, 76.9, 73.8, 72.1, 72.0, 71.9, 71.4, 71.0,

70.4, 67.7, 63.3, 43.3, 42.5, 42.1, 41.5, 41.1, 40.3, 38.8, 38.4,

32.2, 31.0, 30.4, 29.3, 29.0, 27.6, 25.9, 25.4, 23.2, 23.0, 21.4,

20.0, 17.9, 16.0, 14.2, 14.1, 13.5, -4.0, -4.6; HRMS (FAB) calcd

for C₆₈H₁₀₂O₁₄SiS₂Na [(M + Na)⁺] 1257.6378, found 1257.6400.

Hyd r oxy Dith iok eta l 3. A solution of olefin 41 (206.2 mg,

0.1668 mmol) in THF (7 mL) was treated with Bu₄NF (1.0 M

solution in THF, 340 µL, 0.34 mmol) at room temperature, and

the mixture was stirred for 5 h. The solvent was evaporated,

and the residue was subjected to flash chromatography (30-

60% EtOAc-hexane) to give hydroxy dithioketal 3 (169.6 mg,

91%): [R]²⁸_D) -21.7° (c 0.83, CHCl₃); IR (film) 3444 cm^-1; ¹H

NMR (CDCl₃, 500 MHz) δ 7.35-7.26 (10H, m), 5.85 (1H, ddd,

J ) 11.3, 7.9, 7.9 Hz), 5.67 (1H, dd, J ) 11.3, 8.2 Hz), 5.06

(1H, m), 4.65 (1H, d, J ) 12.2 Hz), 4.60 (1H, d, J ) 12.2 Hz),

4.45 (1H, d, J ) 12.2 Hz), 4.43 (1H, d, J ) 12.2 Hz), 4.28 (1H,

d, J ) 8.2 Hz), 4.23 (1H, m), 3.93 (1H, dd, J ) 9.8, 1.5 Hz),

3.86 (1H, m), 3.83 (1H, m), 3.80 (1H, dd, J ) 9.8, 5.2 Hz), 3.78

(1H, m), 3.59 (1H, d, J ) 9.5 Hz), 3.53 (1H, m), 3.41-3.28 (5H,

m), 3.16 (1H, ddd, J ) 9.5, 7.0, 7.0 Hz), 3.10 (2H, m), 3.02

(1H, ddd, J ) 8.9, 5.5, 5.5 Hz), 2.93 (1H, m), 2.89 (1H, m),

2.88 (1H, dd, J ) 9.5, 4.6 Hz), 2.67-2.58 (4H, m), 2.57 (1H,

m), 2.42 (1H, m), 2.39 (1H, dd, J ) 13.1, 4.0 Hz), 2.29-1.47

(23H, m), 2.00 (3H, s), 1.32 (2H, m), 1.25 (3H, t, J ) 7.6 Hz),

1.14 (3H, t, J ) 7.6 Hz), 1.09 (3H, d, J ) 7.3 Hz), 1.01 (3H, d,

J ) 6.1 Hz), 0.97 (3H, d, J ) 6.4 Hz); ¹³C NMR (CDCl₃, 125

MHz) δ 170.4, 139.4, 138.2, 132.7, 128.4, 128.1, 127.6, 127.5,

127.4, 127.2, 126.4, 108.9, 88.3, 87.0, 84.7, 83.5, 81.56, 81.53,

81.26, 81.23, 80.5, 78.5, 78.1, 77.9, 77.7, 76.9, 74.1, 72.1, 72.0,

71.9, 71.4, 71.0, 69.6, 67.7, 62.7, 42.9, 42.5, 42.2, 41.6, 40.1,

40.0, 38.8, 38.4, 32.3, 31.9, 30.3, 29.3, 29.0, 27.5, 25.4, 23.6,

23.0, 21.4, 20.2, 15.8, 14.2, 14.0, 13.5; HRMS (FAB) calcd for

A solution of the above dithioketal in THF (8 mL) was

treated with Bu₄NF (1.0 M solution in THF, 0.6 mL, 0.6 mmol).

The reaction mixture was stirred at room temperature over-

night. The solvent was evaporated, and the residue was

subjected to flash chromatography (2% MeOH-CHCl₃) to give

dithioketal 40 (163.4 mg, 97% for the two steps): [R]²⁶

)

-13.0° (c 0.55, CHCl₃); IR (film) 3479 cm^-1; H NMR (CDCl₃,

500 MHz) δ 5.07 (1H, m), 3.93 (1H, dd, J ) 11.6, 2.7 Hz), 3.86

(1H, m), 3.74 (1H, ddd, J ) 11.0, 9.5, 4.0 Hz), 3.67 (1H, dd, J

) 11.3, 8.9 Hz), 3.60 (1H, dd, J ) 8.9, 2.7 Hz), 3.55 (1H, ddd,

J ) 9.2, 6.4, 6.4 Hz), 3.40 (1H, ddd, J ) 9.2, 4.9, 4.9 Hz), 3.31

(1H, ddd, J ) 11.6, 11.6, 4.6 Hz), 3.10 (3H, m), 2.93 (1H, m),

2.90 (1H, m), 2.68-2.51 (4H, m), 2.37 (1H, dd, J ) 13.1, 4.0

Hz), 2.24 (1H, ddd, J ) 11.6, 4.0, 4.0 Hz), 2.00 (3H, s), 1.98

(1H, m), 1.95-1.63 (13H, m), 1.52 (1H, m), 1.34 (1H, m), 1.24

(3H, t, J ) 7.3 Hz), 1.19 (3H, t, J ) 7.6 Hz); ¹³C NMR (CDCl₃,

125 MHz) δ 170.5, 83.3, 85.4, 83.4, 81.6, 81.3, 81.2, 78.2, 77.7,

76.9, 71.8, 67.7, 62.1, 59.9, 42.5, 42.2, 38.8, 32.3, 30.3, 29.3,

29.1, 27.5, 25.4, 23.7, 23.4, 21.4, 14.3, 14.1; HRMS (FAB) calcd

for C₂₈H₄₆O₈S₂Na [(M + Na)⁺] 597.2532, found 597.2538.

Ald eh yd e 4. A solution of dithioketal 40 (155.1 mg, 0.2698

mmol) and Et₃N (190 µL, 1.36 mmol) in CH₂Cl₂-DMSO (3:1,

6 mL) was cooled to 0 °C and treated with sulfur trioxide‚

pyridine complex (172 mg, 1.08 mmol). After being stirred at

0 °C for 30 min, the mixture was diluted with EtOAc (100 mL),

washed with H₂O (×2), and brine, dried (Na₂SO₄), and

concentrated to give crude aldehyde 3, which was used in the

following reaction without purification.

₆₂H₈₈O₁₄S₂Na [(M + Na)⁺] 1143.5513, found 1143.5532.

Mixed Th iok eta l 42. A heterogeneous mixture of hydroxyl

dithioketal 3 (175.2 mg, 0.1562 mmol), powdered 4 Å molecular

sieves (350 mg), silica gel (350 mg), NaHCO₃(131.2 mg, 1.561

mmol), and silver trifluoromethanesulfonate (160.6 mg, 0.6250

mmol) in dry nitromethane (1.6 mL) was stirred vigorously at

room temperature for 10 h. The mixture was diluted with

EtOAc (5 mL), filtered through Celite, and concentrated. Flash

chromatography (30-50% EtOAc-hexane) gave mixed thioket-

al 42 (88.5 mg, 53%) along with the recovered 3 (51.9 mg,

30%): [R]²⁹) +42.9° (c 0.11, CHCl₃); IR (film) 2931, 2866,

1732, 1456, 1248, 1078, 737, 698 cm^-1; H NMR (CDCl₃, 500

MHz) δ 7.36-7.26 (10H, m), 5.81 (1H, dddd, J ) 10.7, 6.7,

6.7, 1.2 Hz), 5.62 (1H, dd, J ) 10.7, 6.4 Hz), 5.05 (1H, m), 4.66

(1H, d, J ) 12.2 Hz), 4.56 (1H, d, J ) 12.2 Hz), 4.45 (1H, d, J

) 12.2 Hz), 4.43 (1H, d, J ) 12.2 Hz), 4.25 (1H, ddd, J ) 11.9,

9.2, 4.3 Hz), 4.22 (1H, m), 4.02 (1H, dd, J ) 6.4, 1.2 Hz), 3.92

(1H, dd, J ) 9.5, 1.8 Hz), 3.86 (1H, m), 3.80 (1H, m), 3.79 (1H,

dd, J ) 9.5, 4.9 Hz), 3.74 (1H, ddd, J ) 11.3, 9.2, 4.0 Hz), 3.56

(1H, m), 3.55 (1H, d, J ) 9.5 Hz), 3.41 (1H, ddd, J ) 8.9, 4.6,

4.6 Hz), 3.36-3.28 (4H, m), 3.10 (3H, m), 2.93 (1H, m), 2.89

(1H, m), 2.82 (1H, dd, J ) 9.2, 4.9 Hz), 2.57 (1H, m), 2.56 (1H,

m), 2.46 (1H, m), 2.37 (1H, dd, J ) 13.1, 3.7 Hz), 2.25 (2H, m,

22-H), 2.13 (1H, m), 2.08-1.46 (20H, m), 1.99 (3H, s), 1.34 (2H,

m), 1.25 (3H, t, J ) 7.6 Hz), 1.07 (3H, d, J ) 7.6 Hz), 0.99

(3H, d, J ) 5.8 Hz), 0.96 (3H, d, J ) 6.4 Hz); ¹³C NMR (CDCl₃,

125 MHz) δ 170.4, 139.3, 138.2, 131.0, 129.3, 128.4, 128.1,

127.59, 127.55, 127.51, 127.2, 108.9, 91.7, 88.5, 87.5, 84.5, 83.2,

83.20, 82.0, 81.7, 81.3, 81.2, 79.3, 78.5, 77.7, 77.6, 76.9, 74.3,

72.0, 71.9 (×2), 71.4, 71.0, 67.8, 67.3, 42.8, 42.4, 42.3, 41.5,

(Z)-Olefin 41. A solution of phosphonium salt 5 (294.7 mg,

0.2759 mmol) in THF (4 mL) was cooled to -78 °C and treated

with BuLi (1.63 M solution in hexane, 170 µL, 0.277 mmol).

The mixture was allowed to warm to 0 °C and stirred at 0 °C

for 30 min. After being cooled to -78 °C, the solution was

treated with HMPA (150 µL, 0.862 mmol), and a solution of

the above aldehyde 4 in THF (5 mL) was added dropwise via

cannula. The resulting solution was stirred at -78 °C for 20

min and then warmed to room temperature and stirred at that

temperature for 3.5 h. The mixture was concentrated, and the

residue was directly subjected to flash chromatography (20-

60% EtOAc-hexane) to give (Z)-olefin 41 (210.6 mg, 63% from

5): [R]²⁹_D) -42.0° (c 0.29, CHCl₃); IR (film) 2931, 2868, 1732,

1456, 1250, 1086, 837, 775, 737, 698 cm^-1; H NMR (CDCl₃,

500 MHz) δ 7.55-7.22 (10H, m), 5.85 (1H, ddd, J ) 11.0, 9.2,

4.9 Hz), 5.58 (1H, dd, J ) 11.0, 8.9 Hz), 5.08 (1H, m), 4.65

(1H, d, J ) 12.5 Hz), 4.58 (1H, d, J ) 12.5 Hz), 4.45 (1H, d, J

Synthesis of the Decacyclic Ciguatoxin Model

J . Org. Chem., Vol. 64, No. 26, 1999 9429

39.7, 39.3, 38.8, 38.4, 32.4, 30.8, 30.4, 29.3, 29.1, 27.4, 25.4,

21.4, 20.9, 19.9, 15.8, 14.7, 13.5; HRMS (FAB) calcd for

Hexa h yd r ooxon in e 49. A solution of bis(ethoxyethyl)

ether 46 (25.3 mg, 0.0277 mmol) in CH₂Cl₂(2 mL) was cooled

to -78 °C and treated with DIBALH (1.0 M solution in CH₂Cl₂,

100 µL, 0.1 mmol). After the mixture was stirred at -78 °C

for 30 min, the reaction was quenched with saturated aqueous

potassium sodium tartrate (2 mL), and the mixture was

vigorously stirred at room temperature until the layers were

separated. The aqueous layer was extracted with EtOAc (20

mL), and the combined organic layers were dried (Na₂SO₄) and

concentrated to give crude alcohol, which was used in the next

reaction without purification.

A solution of the above alcohol, LiBr (24.0 mg, 0.276 mmol),

and i-Pr₂NEt (75 µL, 0.431 mmol) in CH₂Cl₂(2 mL) was

treated with methanesulfonic anhydride (24.0 mg, 0.138

mmol). After being stirred at room temperature for 3 h, the

mixture was diluted with EtOAc (30 mL), washed with water

and brine, dried (Na₂SO₄), and concentrated to give crude

bromide 48.

A solution of the above bromide 48 in dry DMSO (1 mL)

was treated with KO-t-Bu (16.0 mg, 0.143 mmol). After the

mixture was stirred at room temperature for 75 min, the

reaction was quenched with H₂O, and the aqueous layer was

extracted with EtOAc (20 mL × 3). The combined organic

layers were dried (Na₂SO₄) and concentrated. Flash chroma-

tography (40% EtOAc-hexane) gave hexahydrooxonine 49

(13.1 mg, 52%): IR (film) 2933, 2870, 1456, 1375, 1336, 1281,

972, 949 cm^-1; HRMS (FAB) calcd for C₅₀H₈₀O₁₄Na [(M + Na)⁺]

927.5446, found 927.5455.

₆₀H₈₂O₁₄SNa [(M + Na)⁺] 1081.5323, found 1081.5320.

Tetr a h yd r ooxocin e 43. A solution of mixed thioketal 42

(60.6 mg, 0.056 mmol), AIBN (1 mg, 0.006 mmol), and Ph₃SnH

(197 mg, 0.561 mmol) in toluene (1.2 mL) was heated at 110

°C for 3 h. After being cooled to room temperature, the mixture

was concentrated, and the residue was purified by flash

chromatography (30-40% EtOAc-hexane) to give tetrahy-

drooxocine 43, which was dissolved in CH₂Cl₂(2 mL) and

treated with m-CPBA (80%, 15 mg, 0.070 mmol) at 0 °C. After

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

saturated aqueous Na₂SO₃. The mixture was extracted with

EtOAc (25 mL), washed with saturated aqueous NaHCO₃(×2),

dried (Na₂SO₄), and concentrated. Flash chromatography (30-

40% EtOAc-hexane) gave pure 43 (49 mg, 86%): [R]²⁹

)

+14.7° (c 0.17, CHCl₃); IR (film) 2935, 2869, 1730, 1454, 1373,

1250, 1082, 735, 698 cm^-1; ¹H NMR (500 MHz, C₆D₆) δ 7.43-

7.08 (10H, m), 5.92 (1H, dd, J ) 11.0, 5.2 Hz), 5.80 (1H, ddd,

J ) 11.3, 8.9, 1.8 Hz), 5.37 (1H, m), 4.65 (1H, d, J ) 11.9 Hz),

4.62 (1H, d, J ) 11.6 Hz), 4.17 (2H, s), 4.12 (1H, ddd, J )

11.0, 9.5, 5.2 Hz), 4.03 (1H, m), 4.00 (1H, d, J ) 9.5 Hz), 3.90

(1H, dd, J ) 9.5, 0.6 Hz), 3.88 (1H, m), 3.85 (1H, m), 3.76 (1H,

dd, J ) 9.5, 4.9 Hz), 3.70 (1H, br d, J ) 11.3 Hz), 3.69 (1H, dd,

J ) 9.8, 9.8 Hz), 3.53 (1H, d, J ) 3.1 Hz), 3.34 (1H, ddd, J )

12.2, 8.9, 4.0 Hz), 3.28 (1H, ddd, J ) 8.6, 4.0, 4.0 Hz), 3.21

(2H, m), 3.09-3.04 (2H, m), 2.99 (1H, dd, J ) 9.2, 4.9 Hz),

2.94-2.88 (2H, m), 2.84 (1H, ddd, J ) 11.3, 8.9, 4.6 Hz), 2.79-

2.72 (2H, m), 2.66 (1H, ddd, J ) 14.7, 11.0, 4.9 Hz), 2.45 (1H,

ddd, J ) 7.3, 4.9, 3.1 Hz), 2.37-2.34 (3H, m), 2.28-2.23 (2H,

m), 2.16-2.09 (2H, m), 2.00-1.62 (16H, m), 1.46 (1H, dq, J )

11.3, 6.7 Hz), 1.40 (1H, ddd, J ) 12.8, 4.3, 4.3 Hz), 1.30 (1H,

m), 1.21 (3H, d, J ) 6.1 Hz), 1.19 (1H, m), 1.10 (3H, d, J ) 7.3

Hz), 1.08 (3H, d, J ) 6.7 Hz); ¹³C NMR (125 MHz, C₆D₆) δ

170.1, 139.7, 138.9, 135.2, 128.6, 128.5, 128.3, 128.1, 127.69,

127.65, 126.3, 109.4, 88.8, 88.2, 85.3, 82.7, 82.6, 82.0, 81.9, 81.4,

81.2, 80.3, 79.0, 78.7, 78.4, 77.9, 77.5, 75.5, 75.0, 72.7, 72.6,

72.3, 71.6, 71.1, 67.6, 43.7, 43.1, 42.1, 40.4, 40.1, 39.5(x 2), 39.0,

33.6, 31.0, 30.5, 29.9, 29.8, 27.5, 25.8, 21.0, 20.0, 16.1, 13.8;

HRMS (FAB) calcd for C₅₈H₇₈O₁₄Na [(M + Na)⁺] 1021.5289,

found 1021.5271.

Deca cyclic Com p ou n d 2. A solution of hexahydrooxonine

49 (13.1 mg, 0.0144 mmol) in MeOH (2 mL) was treated with

PPTS (3.0 mg, 0.012 mmol), and the resulting mixture was

stirred at room temperature overnight. The reaction was

quenched with Et₃N, and the mixture was concentrated. The

residue was purified by flash chromatography (5% MeOH-

CHCl₃) to give decacyclic model compound 2 (11.0 mg, quan-

titative): [R]²⁹_D) -29.8° (c 0.17, CHCl₃); IR (film) 3446 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 5.74-5.61 (2H, br), 4.48 (1H,

m), 3.86 (1H, dd, J ) 10.1, 4.3 Hz), 3.85 (1H, m), 3.77 (1H, d,

J ) 10.1 Hz), 3.67 (1H, dd, J ) 3.7, 1.5 Hz), 3.66 (1H, m), 3.61

(1H, dd, J ) 9.8, 1.5 Hz), 3.55 (1H, br), 3.43 (1H, m), 3.31 (1H,

m), 3.22 (1H, dd, J ) 9.8, 9.8 Hz), 3.19-3.13 (3H, m), 3.07

(2H, m), 3.01 (1H, m), 2.94-2.89 (4H, m), 2.83 (1H, dd, J )

10.1, 5.2 Hz), 2.80-2.56 (2H, br), 2.34-1.35 (27H, m), 1.11

(1H, d, J ) 7.6 Hz), 1.02 (3H, d, J ) 6.4 Hz), 0.98 (3H, d, J )

6.7 Hz); HRMS (FAB) calcd for C₄₂H₆₄O₁₂Na [(M + Na)⁺]

783.4295, found 783.4285.

Bis(eth oxyeth yl eth er ) 46. A solution of tetrahydrooxocine

43 (26.5 mg, 0.0280 mmol) in EtOAc-MeOH (1:2, 2 mL) and

AcOH (25 µL) was treated with a catalytic amount of Pd(OH)₂/

C, and the mixture was stirred at room temperature under

hydrogen for 12 h. The catalyst was filtered, and the solvent

was removed to give diol 44, which was used in the following

reaction without purification: ¹H NMR (CDCl₃, 500 MHz) δ

5.03 (1H, m), 4.48 (1H, m), 3.86 (1H, m), 3.86 (1H, dd, J )

9.8, 4.3 Hz), 3.77 (1H, d, J ) 9.8 Hz), 3.67 (1H, dd, J ) 3.7,

1.5 Hz), 3.66 (1H, m), 3.61 (1H, dd, J ) 9.8, 1.5 Hz), 3.53 (1H,

m), 3.43 (1H, m), 3.30 (1H, m), 3.23 (1H, dd, J ) 9.8, 9.8 Hz),

3.18 (1H, m), 3.16 (1H, m), 3.13 (1H, m), 3.08 (2H, m), 3.00

(1H, ddd, J ) 10.4, 10.4, 3.1 Hz), 2.96-2.87 (4H, m), 2.83 (1H,

dd, J ) 9.5, 4.6 Hz), 2.31-1.32 (31H, m), 2.00 (3H, s), 1.11

(3H, d, J ) 7.6 Hz), 1.03 (3H, d, J ) 6.1 Hz), 0.98 (3H, d, J )

6.7 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 170.7, 109.3, 88.4, 86.3,

84.0, 83.8, 82.1, 81.5, 81.45, 81.42, 81.38, 81.03, 80.98, 78.4,

77.7, 77.1, 77.0, 75.7, 74.5, 72.0, 71.9, 71.7, 67.7, 45.7, 42.5,

42.0, 41.9, 40.5, 40.4, 38.8, 38.3, 36.9, 36.7, 32.7, 30.1, 29.3,

29.1, 27.2, 25.3, 21.4, 20.4, 19.7, 15.6, 13.4; MS (FAB) m/z 843

[(M + Na)⁺].

Ack n ow led gm en t. We thank Professor Emeritus T.

Yasumoto of Tohoku University and Professor M. Mu-

rata of Osaka University for valuable discussions and

advice throughout this work. We are grateful to Dr. K.

Konoki for biological studies of our model compound and

to Dr. M. Hentemann, Sloan-Kettering Institute for

Cancer Research, for critical reading of the manuscript.

This work was financially supported in part by a Grant-

in-Aid from the Ministry of Education, Science, Sports,

and Culture of J apan and a fellowship to M.I. from the

J apan Society for the Promotion of Science for Young

Scientists.

A solution of the above diol 44, ethyl vinyl ether (110 µL,

1.15 mmol), and PPTS (10.0 mg, 0.0398 mmol) in CH₂Cl₂(2

mL) was stirred at room temperature for 4 h and then directly

subjected to flash chromatography (50% EtOAc-hexane) to

give bis(ethoxyethyl) ether 46 (25.3 mg, 99%), which was used

in the following reaction without further purification: IR (film)

Su p p or tin g In for m a tion Ava ila ble: A synthetic scheme

for compound 10, experimental procedures for compounds 12

and 14, ¹H NMR spectra for compounds 2, 3, 5, 11, 17, 20, 21,

23, 24, 28-35, 38-44, 46, and 49, and ¹³C NMR spectra for

compounds 3, 5, 11, 21, 23, 24, 28, 29, 31-33, and 38-44.

This material is available free of charge via the Internet at

http://pubs.acs.org.

2935, 2870, 1732, 1456, 1375, 1338, 1250, 1082, 951 cm^-1

;

HRMS (FAB) calcd for C₅₂H₈₄O₁₆Na [(M + Na)⁺] 987.5657,

found 987.5670.

J O990989B

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