Divergent synthesis of the tetracyclic ethers of 6-X-7-6 ring systems

Tetrahedron 59 (2003) 5645–5659

Divergent synthesis of the tetracyclic ethers of 6-X-7-6

ring systems

*

Masayuki Inoue, Jin Wang, Guang-Xing Wang, Yoshihiro Ogasawara and Masahiro Hirama

*

Department of Chemistry, Graduate School of Science, Tohoku University, and SORST, Japan Science and Technology Corporation (JST),

Aramaki-aza, Aoba, Sendai 980-8578, Japan

Received 13 May 2003; revised 9 June 2003; accepted 9 June 2003

Abstract—Ladder-shaped polyether natural products show diverse biological activities with extreme potency. As the initial phase of detailed

SAR studies of bioactive polyethers, we set out to construct structurally simple mimics. This paper details the divergent synthesis of 6-X-7-6

tetracycles (X¼7, 8, or 9) starting from a simple 6-membered ether. Key reactions in the synthesis include (i) the direct formation of an O,S-

acetal by the coupling of an alcohol with an a-chlorosulﬁde, (ii) the construction of a 7-membered ring by radical cyclization, and (iii)

cyclization to the 7, 8 or 9-membered ring via a ring-closing metathesis reaction. The neutral reaction conditions of our strategy enable the

synthesis of a wide variety of substrates. The results of this study can be applied for the rapid construction of artiﬁcial polyether compounds

with diversiﬁed molecular shapes and sizes.

1. Introduction

The structural requirements for the sodium channel ligands,

as well as other biological activities, appear to be complex.

As a logical starting point for detailed SAR studies of

polyethers, we set out to construct structurally simple mimics

with various molecular sizes and shapes.¹³Using these

biological probes can hopefully deepen our understanding of

the essential topographical features for the potent activities of

these marine natural products. Herein, we present the efﬁcient

syntheses of 6-X-7-6 tetracycles 9–12, which can serve as

modules for various artiﬁcial polyethers, using a novel

assembly of structural fragments (Scheme 1).^14,15

The structures of many ladder-shaped polyethers from

marine sources have been recently determined using

extensive modern spectroscopic techniques (Fig. 1).¹The

most notable feature of these compounds lies in their

gigantic architectures that comprise trans/syn-fused ethers

of 5 to 9-membered rings. All these molecules possess the

extremely potent biological activities, i.e. neurotoxicity,

cytotoxicity, and antifungal activity. However, the biological

aspects of these molecules have not been fully investigated

due to the inadequate amounts of the isolated materials.

The receptor protein has been identiﬁed for only ciguatoxins

(CTX)^2,3and brevetoxins (BTX),^4,5which are selective

activators of voltage-sensitive sodium channels (VSSC) in

nerves, heart, and muscle.^6,7The speciﬁc binding site on the

channels is designated as site 5, although its precise location

within the VSSC has not been identiﬁed.⁸Very recently, we

have shown that gambieric acid-A (3)⁹and gambierol (4)^10,11

can inhibit the binding of BTX to site 5, and that the

inhibitory activities of natural polyethers 1–4 are pro-

portional to the size of the polycyclic regions of the

molecules; in other words, it is likely that, despite the

distinct difference in the backbone, 1–4 share a common

binding site.¹²

2. Synthesis plan of 6-X-7-6 tetracyclic ethers

To efﬁciently attain the diversiﬁed structures of reasonable

molecular sizes, our plan involved a uniﬁed strategy starting

from simple ether 5 (Scheme 1). Secondary alcohol 6 and

a-chlorosulﬁde 7,¹⁶both of which were derived from 5,

were to be coupled through the activation of 7 using a silver

salt. This type of O,S-acetal formation was developed by

Mukaiyama¹⁷and Hindsgaul¹⁸groups within the context of

their syntheses of oligosaccharides, and was successfully

applied to the synthesis of fused-polyether molecules in our

laboratory.¹⁴To construct the 7-X ring system (9–12, X¼7,

8, or 9), the resulting O,S-acetal 8 would be subjected to the

radical cyclization/ring-closing oleﬁn metathesis (RCM)^19,20

strategy, of which utility was demonstrated in our total

synthesis of CTX3C (1).³Structurally diverse decacycles

13, whose sizes are comparable to those of the natural

products, could be attained by applying the same coupling

Keywords: convergent synthesis; O,S-acetal; radical reactions; ring-closing

oleﬁn metathesis; polyether; ciguatoxin.

*

Corresponding authors. Tel.: þ81-22-217-6565; fax: þ81-22-217-6566;

e-mail: inoue@ykbsc.chem.tohoku.ac.jp;

hirama@ykbsc.chem.tohoku.ac.jp

doi:10.1016/S0040-4020(03)00913-X

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M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

Figure 1. Various ladder-shaped polyethers from marine sources.

method to tetracycles 9–12. Our synthetic methodology

would, therefore, allow for the efﬁcient preparation of a

number of fused-polyether mimics starting from the

common ether 5.

3. Synthesis of O-linked oxacycle

Compound 5 was prepared using the 6-endo-selective

epoxide-opening reaction, developed by Nicolaou, as a

key reaction (Scheme 2).^21,22Wittig reaction of 2-deoxy-D-

ribose, followed by acetalization, gave p-methoxybenzyl-

idene (MP) acetal 14 in 82% yield. After TBS-protection of

the secondary alcohol of 14, ester 15 was reduced to allylic

alcohol 16, which in turn was subjected to Sharpless

asymmetric epoxidation²³to afford epoxide 17 in 84%

overall yield (3 steps). Swern oxidation of alcohol 17 and

subsequent Wittig methylenation led to oleﬁn 18 in 74%

yield for 2 steps. Following the ﬂuoride-mediated removal

of the TBS group of 18, the resulting alcohol 19 was

exposed to acidic conditions using PPTS in CH₂Cl₂to

provide the desired 6-membered ether 5 (74% yield, 2

steps).

The right-hand piece 6 was prepared from 5 mainly through

protective group manipulations. Ozone oxidation of 5,

followed by reduction with NaBH₄, afforded diol 20, which

was subsequently protected with Bn groups to yield bis-Bn

ether 21 (79% yield, 2 steps). Removal of the MP acetal

group from 21, followed by TBS-protection/deprotection

sequence, provided primary alcohol 23 in 73% yield for 3

steps. Lastly, ethoxyethyl (EE) ether formation from 23 and

the subsequent TBS removal produced secondary alcohol 6

in 83% yield (2 steps).

Conversely, the left-hand piece 29 was afforded by the

modiﬁcation of the exo-oleﬁn of 5. TBS-protection (25,

98% yield) and subsequent hydroboration/oxidation (83%

yield) of 5 afforded alcohol 26, which was subjected to

SO₃·pyridine oxidation, then Wittig oleﬁnation to produce

oleﬁn 27 in 78% yield (2 steps). A second hydroboration

(27!28), followed by an oxidative work-up, led to primary

alcohol 28 in 77% yield. Finally, alcohol 28 was converted

to the requisite phenylsulﬁde 29 using (PhS)₂and n-Bu₃P

(92% yield).²⁴

The coupling between 6 and 29 was realized by the direct

method to form O,S-acetal 8. Initially, the chloride

Scheme 1. Synthesis plan of polyether mimics.

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

5647

Scheme 2. Reagents and conditions: (a) Ph₃PCHvCO₂Et, THF, reﬂux; (b) p-MeOPhCH(OMe)₂, CSA, CH₂Cl₂, 82% (2 steps); (c) TBSCl, imidazole, DMF;

(d) DIBAL, CH₂Cl₂, 2788C; (e) diethyl-D-tartrate, Ti(Oi-Pr)₄, MS4A, t-BuOOH, CH₂Cl₂, 2308C, 84% (3 steps); (f) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, 2788C;

(g) MePPh^þ₃Br², NaHMDS, THF, 08C, 74% (2 steps); (h) TBAF, THF; (i) PPTS, CH₂Cl₂, 08C, 74% (2 steps); (j) O₃, CH₂Cl₂/MeOH (5:1), 2788C, then

NaBH₄; (k) BnBr, NaH, THF/DMF (5:1), 79% (2 steps); (l) CSA, CH₂Cl₂/MeOH (1:1); (m) TBSCl, imidazole, DMF; (n) CSA, MeOH, 08C, 73% (3 steps);

(o) EVE, PPTS, CH₂Cl₂; (p) TBAF, THF, 83% (2 steps); (q) TBSCl, imidazole, DMF, 98%; (r) 9-BBN dimer, THF, then NaOH, H₂O₂, 83%; (s) SO₃·pyridine,

DMSO, Et₃N, CH₂Cl₂; (t) MePPh^þ₃Br², t-BuOK, THF, 08C, 78% (2 steps); (u) 9-BBN dimer, THF, then NaOH, H₂O₂, 77%; (v) (PhS)₂, n-Bu₃P, pyridine,

92%; (w) NCS, CCl₄; (x) 6 (1.2 equiv.), AgOTf, 2,6-di-t-butyl-4-methylpyridine (DTBMP), MS4A, CH₂Cl₂, 278 to 2308C, 86%; (y) TBAF, THF, room

temperature; (z) methyl propiolate, 4-methylmorpholine (NMM), CH₂Cl₂, 82% (2 steps); (aa) n-Bu₃SnH, AIBN, toluene, 80 8C, 97% (32/33¼3.2:1).

substituent was introduced to sulﬁde 29 by treatment with

N-chlorosuccinimide in CCl₄; the resulting a-chlorosulﬁde

7 was activated by silver triﬂate¹⁸in the presence of 6

(1.2 equiv.) and 2,6-di-t-butyl-4-methylpyridine to deliver

the desired O,S-acetal 8 in 86% yield as a 2:1 mixture of

epimers at the acetal carbon. The thiophenyl group of 8,

which could also be potentially activated by the silver salt,

was stable under the coupling conditions. Moreover, the

inertness of the acid-labile protective groups (EE, MP) of 8

demonstrated the neutral nature and high chemoselectivity

of this reaction.

7-membered ring 32 as a single diastereomer along with a

small amount of the non-cyclized product 33 (32/33¼3.2:1,

97% combined yield).^25,26Therefore, two stereocenters

were introduced with complete selectivity in this one

reaction. Moreover, the chirality of the acetal carbon was

inconsequential to the stereochemical outcome of the

radical cyclization, and thus stereoselective synthesis of

O,S-acetal 8 was not necessary. These features are

especially important for the facile and efﬁcient assembly

of complex natural and artiﬁcial products.

The stereoselectivity of the cyclization can be explained as

follows. Initially the stereochemical information of the

acetal carbon was lost upon formation of the radical

intermediate 31. The b-(E)-alkoxyacrylate favored the

extended s-trans over s-cis-conformation. Furthermore,

the steric interactions between the bulky alkoxy group and

the s-trans-alkoxyacrylate of the pseudo-equatorial 31eq

To prepare for the formation of 7-membered ring, TBS ether

8 was transformed to b-alkoxyacrylate 30 via a two-step

sequence: (i) TBAF in THF, and (ii) methyl propiolate and

4-methylmorpholine in CH₂Cl₂(82% yield, 2 steps).

Treatment of 30 (as a 2:1 mixture of diastereomers) with

n-Bu₃SnH in the presence of AIBN at 808C gave

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M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

resulted in the preference of the pseudo-axial 31ax, from

which the desired isomer 32 was the only possible outcome

among the four possible isomers.^3,14,25

Alcohol 36 was then successively subjected to SO₃·pyridine

oxidation and Wittig methylenation to generate diene 37

(74% yield, 2 steps). Although inert to RCM reaction using

45,²⁸diene 37 was cyclized using second-generation Grubbs

catalyst 46²⁹to give the 6-7-7-6 trans-fused polycyclic ether

system 9 in 31% yield. The indicated proton-proton

coupling constant in 9 (J¼9.0 Hz) veriﬁed the trans-

relationship established in the radical cyclization.

4. Synthesis of 6-X-7-6 ring system using RCM

The tetracycles 9–12 were synthesized from O-linked

oxacycle 32 via RCM as a key tactic (Scheme 3). Firstly,

6-7-7-6 ring system was synthesized. Stepwise reduction of

32 using DIBAL then NaBH₄afforded alcohol 34 in 70%

yield for 2 steps. Treatment of alcohol 34 with 2-nitrophenyl

selenocyanate and tributylphosphine produced the corre-

sponding 2-nitrophenyl selenide, which was converted to

oleﬁn 35 through elimination via hydroperoxide oxidation

(85% yield).²⁷Although the removal of the EE group of 35

under acidic conditions caused partial cleavage of the

MP-acetal, reformation was subsequently performed via

trans-acetalization to give alcohol 36 in 74% yield (2 steps).

Next, two oleﬁnic isomers (10 and 11) for 6-8-7-6 ring

systems were constructed. For the synthesis of isomer 10,

alcohol 36 was converted to nitrile 38 via tosylation

followed by displacement with NaCN (quantitative).

DIBAL reduction of the nitrile group of 38 and subsequent

Wittig oleﬁnation afforded the diene 39 in 50% yield along

with the recovery of the starting nitrile (20%). Diene 39 was

subjected to RCM in the presence of 45 to deliver the 6-8-7-

6 fused polycyclic ether 10 in 91% yield. Conversely, for the

synthesis of isomer 11, ester 32 was transformed to oleﬁn 40

Scheme 3. Reagents and conditions: (a) DIBAL, CH₂Cl₂, 2788C; (b) NaBH₄, MeOH, 70% (2 steps); (c) 2-nitrophenyl selenocyanate, n-Bu₃P, pyridine, THF,

then NaHCO₃, H₂O₂, 408C, 85%; (d) PPTS, MeOH, then p-MeOPhCH(OMe)₂, PPTS, CH₂Cl₂, 74%; (e) SO₃·pyridine, DMSO, Et₃N, CH₂Cl₂; (f) MePPh^þ₃Br²,

NaHMDS, THF, 08C, 74% (2 steps); (g) 46, CH₂Cl₂, 408C, 31%; (h) p-TsCl, pyridine, MS4A, 100%; (i) NaCN, DMSO, 508C, 100%; (j) DIBAL, CH₂Cl₂,

2788C; (k) MePPh₃^þBr², NaHMDS, THF, 08C, 50% (2 steps), recovered 38: 20%; (l) 45, CH₂Cl₂, 408C, 91%; (m) DIBAL, CH₂Cl₂, 2908C; (n) SO₃·pyridine,

DMSO, Et₃N, CH₂Cl₂; (o) MePPh^þ₃Br², NaHMDS, THF, 08C, 69% (3 steps); (p) PPTS, MeOH, then p-MeOPhCH(OMe)₂, PPTS, CH₂Cl₂, 89%;

(q) SO₃·pyridine, DMSO, Et₃N, CH₂Cl₂; (r) MePPh^þ₃Br², NaHMDS, THF, 08C, 66% (2 steps); (s) 45, CH₂Cl₂, 358C, 93%; (t) p-TsCl, pyridine, MS4A, 89%;

(u) NaCN, DMSO, 508C, 93%; (v) DIBAL, CH₂Cl₂, 2788C; (w) MePPh^þ₃Br², NaHMDS, THF, 08C, 75% (2 steps); (x) 45, CH₂Cl₂, 408C, 78%.

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

5649

via 3 steps (69% yield): (i) DIBAL reduction of 32, (ii)

SO₃·pyridine oxidation and (iii) Wittig methylenation.

Removal of the EE ether of 40 and subsequent reformation

of the MP-acetal afforded alcohol 41 (89% yield), which

was oxidized to the aldehyde, then converted to diene 42

through Wittig oleﬁnation (66% yield, 2 steps). Diene 42

was treated with 45 at 358C to undergo RCM, leading to the

8-membered ring 11 in 93% yield.

Mercury 200 (200 MHz), or a Varian INOVA 500

(500 MHz) spectrometer. Chemical shifts are reported in d

(ppm) using residual CHCl₃as an internal standard of d 7.26

and d 77.00 for ¹H and ¹³C NMR, respectively. Signal

patterns are indicated as s, singlet; d, doublet; t, triplet; q,

quartet; m, multiplet; br, broad peak. IR spectra were

recorded on a Perkin–Elmer Spectrum BX FT-IR spec-

trometer. MALDI-TOF mass spectra were measured on a

Applied Biosystems Voyager DE STR SI-3 instrument, and

ESI-TOFMS were on Applied Biosystems Mariner. Optical

rotations were recorded on a JASCO DIP-370 polarimeter.

Melting points were measured on a Yanaco MP-S3 micro

melting point apparatus.

Lastly, the 6-9-7-6 system of 12 was prepared as follows.

Nitrile 43 was obtained from alcohol 41 by tosylation

followed by cyanation (93% yield). DIBAL reduction of the

nitrile group of 43 to the aldehyde and subsequent Wittig

oleﬁnation gave diene 44 (75% yield, 2 steps), which was in

turn subjected to RCM using 45 as a catalyst to generate the

6-9-7-6 trans-fused polycyclic ether system 12 (78% yield).

Intriguingly, ¹H NMR signals of the 9-membered ring of 12

were severely broadened at room temperature due to slow

conformational change, while such a dynamic behavior was

not observed in the NMR spectra of the other ring systems

(9–11).³⁰

6.1.1. Alcohol 14. A solution of 2-deoxy-^D-ribose (100 g,

746 mmol) and (carbethoxymethylene)triphenyphosphor-

ane (549 g, 1.58 mol) in THF (750 mL) was heated to

reﬂux overnight. After concentration, the crude mixture was

dissolved in CH₂Cl₂(800 mL). To the solution were added

p-methoxybenzaldehyde dimethyl acetal (165 mL,

889 mmol) and CSA (34.6 g 149 mmol) at room tempera-

ture. After 1 day, the reaction mixture was quenched with

Et₃N (30 mL), concentrated, and subjected to column

chromatography (hexane/EtOAc¼10/1–3/1) to give

alcohol 14 as a colorless oil (196 g, 82%): [a]²_D⁷¼244.758

(c 1.63, CHCl₃); IR (ﬁlm) n 3464, 2978, 1716, 1655, 1081,

1034, 613 cm²¹; ¹H NMR (500 MHz, CDCl₃) d 7.40 (2H, d,

J¼9.0 Hz), 7.07 (1H, dt, J¼16.0, 7.0 Hz), 6.89 (2H, d,

J¼9.0 Hz), 5.96 (1H, dt, J¼16.0, 1.5 Hz), 5.44 (1H, s), 4.25

(1H, dd, J¼10.5, 4.5 Hz), 4.19 (2H, q, J¼7.0 Hz), 3.81 (3H,

s), 3.69 (1H, ddd, J¼10.5, 7.0, 3.5 Hz), 3.64 (1H, td,

J¼10.5, 4.5 Hz), 3.57 (1H, t, J¼10.5 Hz), 2.79 (1H, dddd,

J¼15.5, 7.0, 3.5, 1.5 Hz), 2.56 (1H, dtd, J¼15.5, 7.0,

1.5 Hz), 1.29 (3H, t, J¼7.0 Hz); ¹³C NMR (50 MHz,

CDCl₃) d 166.52, 159.97, 144.59, 129.97, 127.35, 123.82,

113.82, 113.56, 100.83, 80.32, 71.13, 65.18, 60.33, 55.24,

34.49, 14.18; MALDI-TOF-MS, calcd C₁₇H₂₂O₆Na

[MþNa]^þ345.131, found 345.128.

5. Conclusion

An efﬁcient and applicable coupling strategy was

developed, based on the direct construction of the O,S-

acetal from the alcohol and the a-chlorosulﬁde. The neutral

nature of the coupling strategy enabled the synthesis of a

wide variety of substrates with sensitive functionalities.

Application of this method to the divergent synthesis of 6-X-

7-6 tetracyclic systems (X¼7, 8, or 9) was demonstrated

starting with a 6-membered ether as the common inter-

mediate. We believe that the results from this study can

greatly contribute to rapid constructions of ladder-shaped

synthetic polyethers with the sizes of natural products.

Further studies toward the synthesis of artiﬁcial polyether

compounds with tailored biological activity are currently

underway in our laboratory.

6.1.2. Epoxide 17. To a solution of alcohol 14 (196 g,

399 mmol) and imidazole (41 g, 600 mmol) in DMF

(200 mL) was added TBSCl (63.1 g, 419 mmol). After

12 h, additional TBSCl (12.0 g, 79 mmol) was introduced.

The reaction mixture was quenched with MeOH (200 mL),

and concentrated. The residue was subjected to column

chromatography (hexane/EtOAc¼15/1–5/1) to give TBS

ether 15 as a colorless oil, which was used in the next

reaction without further puriﬁcation: IR (ﬁlm) n 2955, 1720,

1656, 1174, 837, 777 cm²¹; ¹H NMR (500 MHz, CDCl₃) d

7.39 (2H, d, J¼9.0 Hz), 7.06 (1H, dt, J¼15.5, 7.5 Hz), 6.88

(2H, d, J¼9.0 Hz), 5.93 (1H, dt, J¼15.5, 7.5 Hz), 5.44 (1H,

s), 4.19 (2H, q, J¼7.0 Hz), 4.17 (1H, dd, J¼10.5, 4.5 Hz),

3.80 (3H, s), 3.66 (1H, td, J¼8.0, 3.0 Hz), 3.58 (1H, td,

J¼10.5, 4.5 Hz), 3.55 (1H, t, J¼10.5 Hz), 2.74 (1H, dddd,

J¼15.5, 8.0, 3.0, 1.5 Hz), 2.45 (1H, dtd, J¼15.5, 8.0,

1.5 Hz), 1.29 (3H, t, J¼7.0 Hz), 0.90 (9H, s), 0.11 (3H, s),

0.09 (3H, s); ¹³C NMR (50 MHz, CDCl₃) d 166.31, 159.88,

144.73, 130.05, 127.27, 123.55, 113.48, 100.71, 80.83,

71.53, 66.17, 60.15, 55.18, 34.34, 25.60, 17.79, 14.20,

24.17, 24.85; MALDI-TOF-MS, calcd C₂₃H₃₆O₆SiNa

[MþNa]^þ459.217, found 459.199.

6. Experimental

6.1. General

All reactions sensitive to air or moisture were carried out

under argon or nitrogen atmosphere in dry, freshly distilled

solvents under anhydrous conditions, unless otherwise

noted. THF was distilled from sodium/benzophenone,

diethyl ether (Et₂O) from LiAlH₄, dichloromethane

(CH₂Cl₂), pyridine, triethylamine (Et₃N), and toluene

from calcium hydride, and DMF and DMSO from calcium

hydride under reduced pressure. All other reagents were

used as supplied unless otherwise stated.

Analytical thin-layer chromatography (TLC) was

performed using E. Merck Silica gel 60 F254 pre-coated

plates. Column chromatography was performed using 100–

210 mm Silica Gel 60N (Kanto Chemical Co., Inc.), and for

ﬂash chromatography 40–50 mm Silica Gel 60N (Kanto

Chemical Co., Inc.) was used.

¹H and ¹³C NMR spectra were recorded on a Varian

To a solution of the above TBS ether 15 in CH₂Cl₂

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M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

(533 mL) at 2788C was added DIBAL (878 mL, 878 mmol,

1.0 M in hexane) over 1 h. The reaction mixture was

quenched with MeOH (12 mL), and allowed to warm to

room temperature. After saturated aqueous potassium

sodium tartrate (300 mL) was added, the mixture was

diluted with EtOAc (300 mL), and stirred overnight. The

aqueous layer was extracted with EtOAc (£2). The

combined organic layer was dried over MgSO₄, concen-

trated, and subjected to column chromatography (hexane/

EtOAc¼10/1–4/1) to give allylic alcohol 16 as a colorless

oil, which was used in the next reaction without further

puriﬁcation: IR (ﬁlm) n 3413, 2955, 1614, 1518, 1463,

To a suspension of methyltriphenylphosphonium bromide

(52.2 g, 122 mmol) in THF (100 mL) at 08C was added

sodium bis(trimethylsilyl)amide (122 mL, 122 mmol, 1.0 M

in THF). To the resultant bright yellow ylide at 08C was

added the above aldehyde in THF (150 mL) over 10 min.

After 10 min, the reaction mixture was quenched with

acetone (10 mL), diluted with hexane/EtOAc (100 mL), and

washed with water (£2). The organic layer was dried over

MgSO₄and concentrated. The residue was subjected to

column chromatography (hexane/EtOAc¼8/1–2/1) to give

oleﬁn 18 as a colorless oil (30 g, 74% for 2 steps):

[a]¹_D⁸¼260.618 (c 2.12, CHCl₃); IR (ﬁlm) n 2956, 2929,

1463, 1389, 1172, 1111, 1036, 778 cm²^{1 1}H NMR

;

1390, 1252, 837 cm²¹

;

¹H NMR (500 MHz, CDCl₃) d

7.39 (2H, d, J¼9.0 Hz), 6.87 (2H, d, J¼9.0 Hz), 5.83

(1H, dt, J¼15.5, 6.5 Hz), 5.74 (1H, dt, J¼15.5, 5.5 Hz), 5.43

(1H, s), 4.15 (1H, dd, J¼9.5, 2.5 Hz), 4.09 (2H, d,

J¼5.5 Hz), 3.79 (3H, s), 3.60–3.55 (2H, m), 3.53 (1H, t,

J¼9.5 Hz), 2.61 (1H, dd, J¼13.5, 6.5 Hz), 2.30 (1H, dt,

J¼15.5, 6.5 Hz), 0.89 (9H, s), 0.10 (3H, s), 0.08 (3H, s); ¹³C

NMR (125 MHz, CDCl₃) d 159.83, 131.53, 130.31,

128.29, 127.29, 114.24, 113.48, 100.69, 81.78, 71.57,

66.04, 55.20, 34.25, 25.63, 17.82, 24.17, 24.81; MALDI-

TOF-MS, calcd C₂₁H₃₄O₅SiNa [MþNa]^þ417.207, found

417.205.

(500 MHz, CDCl₃) d 7.41 (2H, d, J¼9.0 Hz), 6.89 (2H, d,

J¼9.0 Hz), 5.59 (1H, ddd, J¼17.5, 10.0, 7.5 Hz), 5.47 (1H,

s), 5.47 (1H, dd, J¼17.5, 1.5 Hz), 5.27 (1H, dd, J¼10.0,

1.5 Hz), 4.18 (1H, dd, J¼10.5, 4.5 Hz), 3.80 (3H, s), 3.70

(1H, td, J¼9.5, 4.0 Hz), 3.68 (1H, td, J¼9.5, 4.5 Hz), 3.55

(1H, dd, J¼10.5, 9.5 Hz), 3.15 (1H, dd, J¼7.5, 4.0 Hz), 3.12

(1H, td, J¼5.5, 4.0 Hz), 2.00 (2H, m) 0.88 (9H, s), 0.10 (3H,

s), 0.09 (3H, s); ¹³C NMR (125 MHz, CDCl₃) d 159.92,

135.72, 130.22, 127.30, 119.31, 113.56, 100.69, 79.87,

71.75, 65.87, 58.21, 57.21, 55.26, 33.78, 25.66, 17.84,

24.27, 24.81; MALDI-TOF-MS, calcd C₂₂H₃₄O₅SiNa

[MþNa]^þ429.207, found 429.218.

To a suspension of diethyl-^D-tartrate (17 mL, 100 mmol),

titanium(IV) tetraisopropoxide (26 mL, 88 mmol) and

powdered molecular sieves 4A in CH₂Cl₂(300 mL) at

2308C was added the solution of the above alcohol 16 in

CH₂Cl₂(800 mL) dropwise over 30 min. After 30 min,

t-butylhydroperoxide (183 mL, 735 mmol, 4.0 M in

CH₂Cl₂) was added. The reaction mixture was stored at

2308C for 27 h. Then, the reaction mixture was ﬁltrated.

The ﬁltrate was diluted with EtOAc (600 mL), washed with

aqueous saturated Na₂S₂O₃, and dried over MgSO₄. The

residue was subjected to column chromatography (hexane/

EtOAc¼15/1–4/1) to give epoxide 17 as a pale yellow oil

(139.35 g, 84% for 3 steps): [a]¹_D⁸¼236.758 (c 1.68,

CHCl₃); IR (ﬁlm) n 2956, 1519, 1464, 1105, 1035,

6.1.4. Pyran 5. To a solution of oleﬁn 18 (30 g, 74 mmol) in

THF (74 mL) at room temperature was added TBAF

(81.4 mL, 81.4 mmol, 1.0 M in THF) dropwise. After

30 min, the reaction mixture was diluted with ether

(100 mL), washed with water (£2), dried over MgSO₄,

and concentrated. The residue was subjected to short

column chromatography to give the hydroxy epoxide 19,

which was used in the next reaction without further

puriﬁcation.

The above hydroxy epoxide 19 in CH₂Cl₂(740 mL) was

treated with PPTS (14.8 g, 59.2 mmol) at 08C. After 3 h,

Et₃N (11.4 mL, 65 mmol) was added and the solvent was

evaporated. The residue was subjected to column chroma-

tography (hexane/EtOAc¼5/1–2/1), and then recrystallized

from hexane/EtOAc to give pyran 5 as a colorless crystal

(15.8 g, 74% for 2 steps): mp 165–166.88C; [a]²_D⁹¼210.458

(c 0.91, CHCl₃); IR (ﬁlm) n 2931, 1433, 1359, 1301, 824,

779 cm²^{1 1}H NMR (500 MHz, CDCl₃) d 7.40 (2H, d,

;

J¼9.0 Hz), 6.88 (2H, d, J¼9.0 Hz), 5.46 (1H, s), 4.17 (1H,

dd, J¼10.5, 4.5 Hz), 3.91 (1H, ddd, J¼12.5, 5.5, 2.5 Hz),

3.80 (3H, s), 3.69–3.63 (2H, m), 3.62 (1H, ddd, J¼12.5, 7.0,

5.0 Hz), 3.54 (1H, t, J¼10.5 Hz), 3.22 (1H, td, J¼5.0,

2.5 Hz), 2.96 (1H, dt, J¼5.0, 2.5 Hz), 2.02 (1H, ddd,

J¼14.5, 5.0, 3.0 Hz), 1.96 (1H, ddd, J¼14.5, 7.0, 6.0 Hz),

1.79 (1H, t, J¼5.5 Hz), 0.88 (9H, s), 0.10 (3H, s), 0.09 (3H,

s); ¹³C NMR (125 MHz, CDCl₃) d 159.94, 130.18, 127.29,

113.58, 100.74, 79.85, 71.74, 65.81, 61.68, 57.78, 55.25,

52.87, 33.31, 25.64, 17.82, 24.26, 24.83; MALDI-TOF-

MS, calcd C₂₁H₃₄O₆SiNa [MþNa]^þ433.202, found

433.210.

1

747, 698 cm²¹; H NMR (500 MHz, CDCl₃) d 7.44–7.40

(2H, m), 6.93–6.87 (2H, m), 5.86 (1H, ddd, J¼16.5, 10.0,

7.0 Hz), 5.50 (1H, s), 5.45 (1H, dd, J¼16.5, 1.0 Hz), 5.38

(1H, dd, J¼10.0, 1.0 Hz), 4.32 (1H, dd, J¼10.5, 5.0 Hz),

3.80 (3H, s), 3.69 (1H, t, J¼10.5 Hz), 3.67 (1H, dd, J¼8.0,

7.0 Hz), 3.58 (1H, ddd, J¼12.0, 9.0, 4.5 Hz), 3.52 (1H, ddd,

J¼12.0, 8.0, 4.5 Hz), 3.41 (1H, ddd, J¼10.5, 9.0, 5.0 Hz),

2.52 (1H, dt, J¼12.0, 4.5 Hz), 1.74 (1H, q, J¼12.0 Hz); ¹³C

NMR (125 MHz, CDCl₃) d 160.16, 134.99, 127.48, 119.99,

113.72, 101.66, 83.89, 76.52, 73.01, 69.22, 68.91, 55.31,

37.07; ESI-MS, calcd C₁₆H₂₁O₅[MþH]^þ293.138, found

293.098.

6.1.3. Vinyl epoxide 18. To a solution of oxalyl chloride

(16.6 mL, 195 mmol) and DMSO (20.6 mL, 292 mmol) in

CH₂Cl₂(600 mL) at 2788C were added alcohol 17 (40 g,

97.4 mmol) in CH₂Cl₂(370 mL) and then Et₃N (67.8 mL,

487 mmol). After 1 h, the reaction mixture was washed with

saturated aqueous NH₄Cl, and then diluted with hexane/

EtOAc (1 L), and washed with saturated aqueous NaHCO₃

and brine. The organic layer was dried over MgSO₄and

concentrated to give the epoxy aldehyde, which was used in

the next reaction without puriﬁcation.

6.1.5. Bis-Bn ether 21. Ozone was bubbled through a

solution of pyran 5 (4.39 g, 15 mmol) in CH₂Cl₂/MeOH

(5:1, 456 mL) at 2788C until the color of solution turned

pale purple. Then, the reaction mixture was treated with

NaBH₄(2.84 g, 75 mmol), and the cooling bath was

removed. After being stirred at room temperature overnight,

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

5651

the reaction mixture was diluted with ether-EtOAc, washed

with saturated aqueous NH₄Cl and brine. The organic layer

was concentrated, and the residue was subjected to short

column chromatography to give diol 20, which was used in

the next reaction without further puriﬁcation.

TOF-MS, calcd for C₂₇H₄₀O₅SiNa [MþNa]^þ495.254,

found 495.243.

6.1.7. Alcohol 6. To a solution of compound 23 (116.5 mg,

0.246 mmol) and EVE (118 mL, 1.23 mmol) in CH₂Cl₂

(3 mL) was added PPTS (12.4 mg, 49.2 mmol). After 1 h,

the reaction mixture was diluted with EtOAc (20 mL), and

washed with saturated aqueous NH₄Cl and brine. The

organic layer was dried over MgSO₄, and concentrated to

give crude EE ether 24.

A solution of the above diol 20 in THF/DMF (5:1, 46 mL)

was treated with NaH (1.37 g 60% in oil, 34.3 mmol) and

BnBr (3.58 mL, 30.1 mmol) at 08C. After being stirred for

13 h at room temperature, the reaction mixture was diluted

with ether and washed with saturated aqueous NH₄Cl and

brine. The organic layer was dried over MgSO₄and

concentrated. The residue was subjected to column

chromatography (hexane/EtOAc¼15/1–5/1) to give bis-

Bn ether 21 as a colorless solid (5.63 g, 79% for 2 steps):

[a]¹_D⁷¼259.568 (c 0.82, CHCl₃); IR (ﬁlm) n 2869, 1615,

A solution of the above compound 24 in THF (2 mL) was

treated with TBAF (1 M solution in THF, 0.59 mL,

0.59 mmol). After being stirred for 3 h, the mixture was

diluted with EtOAc (20 mL), washed with saturated

aqueous NH₄Cl and brine, dried over MgSO₄, and

concentrated. The residue was subjected to ﬂash chroma-

tography (hexane/EtOAc¼1.8/1) to give alcohol 6 as a

colorless oil (88.2 mg, 83% for 2 steps): ¹H NMR

(500 MHz, CDCl₃) d 7.33–7.20 (10H, m), 4.77 (1/2H, q,

J¼6.6 Hz), 4.72 (1/2H, q, J¼6.6 Hz), 4.64–4.55 (3H, m),

4.42 (1H, d, J¼13.2 Hz), 3.92 (1/2H, dd, J¼10.5, 3.8 Hz),

3.62 (1/2H, dd, J¼10.5, 3.8 Hz), 3.79–3.71 (1H, m), 3.70–

3.60 (3H, m), 3.53–3.41 (3.5H, m), 3.36–3.27 (1.5H, m),

2.63–2.56 (1H, m), 1.48 (1H, dq, J¼11.8, 1.3 Hz), 1.32

(3H, d, J¼6.6 Hz), 1.22 (3H, m); ¹³C NMR (125 MHz,

CDCl₃) d 138.25, 138.00, 128.36, 128.3, 127.8, 127.79,

127.75, 127.69, 127.55, 127.53, 100.38, 100.06, 80.18,

19.99, 79.23, 78.47, 73.45, 73.43, 72.11, 71.95, 70.94,

70.93, 63.39, 69.28, 67.88, 66.76, 66.59, 61.79, 61.76,

37.54, 37.26, 19.69, 15.21, 15.16; MALDI-TOF-MS, calcd

for C₂₅H₃₄O₆Na [MþNa]^þ453.225, found 453.206.

1

1518, 1454, 1096, 1029, 830 cm²¹; H NMR (500 MHz,

CDCl₃) d 7.35–7.11 (12H, m), 6.82–6.78 (2H, m), 5.38

(1H, s), 4.53 (1H, d, J¼12.0 Hz), 4.49 (1H, d, J¼11.0 Hz),

4.46 (1H, d, J¼12.0 Hz), 4.33 (1H, d, J¼11.0 Hz), 4.24 (1H,

dd, J¼10.0, 5.0 Hz), 3.71 (3H, s), 3.67 (1H, dd, J¼10.5,

2.0 Hz), 3.63 (1H, t, J¼10.0 Hz), 3.60 (1H, dd, J¼10.5,

4.5 Hz), 3.54 (1H, dt, J¼10.5, 4.5 Hz), 3.45 (1H, td, J¼10.5,

2.0 Hz), 3.43 (1H, t, J¼10.0, 5.0 Hz), 3.30 (1H, dt, J¼10.5,

4.5 Hz), 2.53 (1H, dt, J¼10.5, 4.5 Hz), 1.59 (1H, q,

J¼10.5 Hz); ¹³C NMR (125 MHz, CDCl₃) d 160.10,

138.10, 137.84, 129.94, 128.55, 128.34, 127.86, 127.77,

127.76, 127.63, 127.43, 113.67, 101.51, 80.51, 76.22, 73.51,

73.22, 72.22, 71.08, 69.25, 69.09, 55.27, 34.89; MALDI-

TOF-MS, calcd C₂₉H₃₂O₆Na [MþNa]^þ499.209, found

499.210.

6.1.6. Alcohol 23. To a solution of MP-acetal 21 (4.20 g,

8.80 mmol) in MeOH/CH₂Cl₂(10 mL, 1:1) was added CSA

(0.410 g, 1.76 mmol). After 1.2 h, Et₃N (3 mL) was added,

and the solution was evaporated to give the crude diol,

which was used in the next reaction without puriﬁcation.

6.1.8. TBS ether 25. To a solution of alcohol 5 (4.38 g,

1.5 mmol) in DMF (15 mL) were added imidazole (3.06 g,

4.5 mmol) and TBSCl (4.52 g, 0.75 mol) at room tempera-

ture. The resultant mixture was stirred for 1.5 h. The

solution was diluted with EtOAc (100 mL), washed with

saturated aqueous NH₄Cl and brine, dried over MgSO₄, and

concentrated. The residue was subjected to ﬂash chroma-

tography (hexane/EtOAc¼8/1) to give the TBS ether 25 as a

colorless oil (5.973 g, 98%): [a]³_D²¼242.758 (c 0.68,

CHCl₃); IR (ﬁlm) n 2955, 2858, 1617, 1518, 1251, 1090,

1039, 837 cm²¹; ¹H NMR (500 MHz, CDCl₃) d 7.43 (2H, d,

J¼9.3 Hz), 6.9 (2H, d, J¼9.3 Hz), 5.92–5.83 (1H, m), 5.49

(1H, s), 5.36 (1H, d, J¼16.0 Hz), 5.26 (1H, d, J¼12.0 Hz),

4.34 (1H, dd, J¼10.0, 6.7 Hz), 3.81 (3H, s), 3.72–3.63 (2H,

m), 3.57–3.49 (2H, m), 3.42 (1H, dt, J¼10.0, 6.7 Hz), 2.42

(1H, m), 1.77 (1H, q, J¼10.0 Hz), 0.879 (9H, s), 0.071 (3H,

s), 0.051 (3H, s); ¹³C NMR (125 MHz, CHCl₃) d 160.09,

135.54, 129.92, 127.45, 117.78, 113.67, 101.58, 83.15,

76.39, 72.78, 70.44, 69.34, 55.26, 38.98, 25.68, 17.93,

24.29, 24.63; MALDI-TOF-MS, calcd for C₂₂H₃₆O₆SiNa

[MþNa]^þ429.207, found 429.203.

A solution of the above diol in DMF (10 mL) was treated

with imidazole (2.520 g, 36.9 mmol) and TBSCl (5.04 g,

33.4 mmol) at room temperature, and the resultant solution

was stirred for 3 h. The mixture was diluted with EtOAc

(100 mL), washed with saturated aqueous NH₄Cl and brine,

dried over MgSO₄, and concentrated to give the bis-TBS

ether 22, which was directly used in the next reaction.

To a solution of the bis-TBS ether 22 in MeOH (20 mL) was

added CSA (0.480 g, 1.76 mmol) at 08C. The solution was

stirred at 08C for 20 min, and Et₃N (2 mL) was added. The

mixture was concentrated, and the residue was subjected to

ﬂash chromatography (hexane/EtOAc¼5/1) to give alcohol

23 as a colorless oil (2.90 g, 73% for 3 steps): [a]³_D⁰¼24.378

(c 0.70, CHCl₃); IR (ﬁlm) n 3466, 2929, 2857, 1454, 1253,

1090, 837 cm²¹; ¹H NMR (500 MHz, CDCl₃) d 7.37–7.24

(10H, m), 4.63–4.54 (3H, m), 4.42 (1H, d, J¼11.1 Hz), 3.83

(1H, dd, J¼9.7, 2.8 Hz), 3.78 (1H, d, J¼9.7 Hz), 3.71–3.65

(1H, m), 3.62 (1H, dd, J¼11.1, 4.2 Hz), 3.60–3.52 (1H, m),

3.48 (1H, ddd, J¼14.6, 11.1, 4.2 Hz), 3.44–3.42 (1H, m),

3.25–3.20 (1H, m), 2.23–2.19 (1H, m), 2.2 (1H, brs), 1.5

(1H, q, J¼14.6 Hz), 0.89 (9H, s), 0.076 (6H, s); ¹³C NMR

(125 MHz, CDCl₃) d 138.36, 128.63, 128.08, 128.01, 82.30,

80.04, 73.76, 73.72, 73.69, 72.40, 71.52, 69.53, 66.69,

62.77, 39.38, 25.98, 25.96, 18.13, 23.95, 24.65; MALDI-

6.1.9. Alcohol 26. To a solution of oleﬁn 25 (0.407 g,

1 mmol) in THF (5 mL) was added 9-BBN dimer (0.537 g,

2.2 mmol). The solution was stirred for 38 h at room

temperature. Then, the reaction mixture was cooled to 08C,

and quenched with water (0.5 mL). After 10 min, 10%

NaOH solution (6 mL) and 30% H₂O₂(3 mL) were added.

The mixture was stirred for 30 h at room temperature, and

then diluted with EtOAc (80 mL). The organic layer was

5652

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

washed with brine, dried over MgSO₄, and concentrated.

The residue was subjected to ﬂash chromatography (hexane/

EtOAc¼15/1–6/1) to give alcohol 26 as a colorless oil

(0.351 g, 83%): [a]²_D⁸¼252.878 (c 0.40, CHCl₃); IR (ﬁlm) n

¹H NMR (500 MHz, CDCl₃) d 7.35 (2H, d, J¼9.6 Hz), 6.82

(2H, d, J¼9.6 Hz), 5.40 (s, 1H), 4.2 (1H, dd, J¼9.7, 4.1 Hz),

3.71–3.73 (2H, m), 3.72 (3H, s), 3.55 (1H, t, J¼9.7 Hz),

3.48–3.42 (2H, m), 3.36 (1H, dt, J¼9.6, 4.1 Hz), 3.34–3.26

(1H, m), 2.35–2.28 (1H, m), 2.06–1.99 (1H, m), 1.62 (1H,

q, J¼9.6 Hz), 1.60–1.53 (1H, m), 0.798 (9H, s), 0.006 (6H,

s); ¹³C NMR (125 MHz, CDCl₃) d 160.41, 130.07, 127.72,

113.97, 101.93, 83.39, 76.56, 73.42, 70.52, 69.44, 55.56,

39.01, 34.29, 25.95, 18.15, 23.85, 24.51. MALDI-TOF-

MS, calcd for C₂₂H₃₆O₆SiNa [MþNa]^þ447.217, found

447.208.

CHCl₃); IR (ﬁlm) n 3391, 2930, 2858, 1616, 1518, 1251,

1090, 1036, 836, 776 cm²¹; ¹H NMR (500 MHz, CDCl₃) d

7.42 (2H, d, J¼8.5 Hz), 6.89 (2H, d, J¼8.5 Hz), 5.48 (1H,

s), 4.27 (1H, dd, J¼11.1, 4.2 Hz), 3.81 (3H, s), 3.71–3.62

(3H, m), 3.54–3.45 (2H, m), 3.39–3.33 (1H, m), 3.23 (1H,

dt, J¼8.3, 2.7 Hz), 2.62–2.56 (1H, m), 2.02–1.95 (1H, m),

1.89–1.82 (1H, brs), 1.78–1.66 (3H, m), 1.44–1.39 (1H,

m), 0.89 (9H, s), 0.092 (6H, s); ¹³C NMR (125 MHz,

CDCl₃) d 160.28, 130.06, 127.63, 113.87, 101.80, 82.89,

76.69, 73.25, 70.36, 69.41, 63.11, 55.47, 39.07, 29.06,

28.36, 25.87, 18.07, 23.90, 24.60.

2955, 2858, 1615, 1518, 1251, 1089, 1036, 836, 776 cm²¹

;

6.1.12. Phenylsulﬁde 29. To a solution of alcohol 28

(216.6 mg,

0.326 mmol)

and

PhSSPh

(213 mg,

0.975 mmol) in pyridine (1 mL) was added n-Bu₃P

(250 mL, 0.326 mmol). The resultant yellow solution was

stirred until the starting material disappeared (ca. 24 h).

EtOAc (10 mL) was added, and the solution was washed

with NH₄Cl and brine, dried over MgSO₄, and concentrated.

The residue was subjected to ﬂash chromatography (hexane/

EtOAc¼20/1–15/1) to give phenylsulﬁde 29 as a pale

yellow oil (159.2 mg, 92%): [a]²_D⁴¼243.98 (c 0.516,

CHCl₃); IR (ﬁlm) n 2954, 1518, 1471, 1388, 1251, 1172,

6.1.10. Oleﬁn 27. To a solution of alcohol 26 (4.067 g,

9.58 mmol) in CH₂Cl₂(40 mL) were added DMSO

(4.08 mL, 57.5 mmol), Et₃N (13.35 mL, 95.78 mmol) and

SO₃·pyridine (3.81 g, 23.95 mmol) at room temperature.

The reaction solution was stirred for 3 h and then diluted

with EtOAc (100 mL). The mixture was washed with

saturated aqueous NaHCO₃, saturated aqueous NH₄Cl and

brine, dried over MgSO₄, and concentrated. The residue was

used in the next reaction without further puriﬁcation.

1

1090, 864, 836 cm²¹; H NMR (500 MHz, CDCl₃) d 7.41

(2H, d, J¼8.5 Hz), 7.33 (2H, d, J¼7.0 Hz), 7.28 (2H, t,

J¼7.0 Hz), 7.16 (1H, t, J¼7.0 Hz), 6.88 (2H, d, J¼8.5 Hz),

5.46 (1H, s), 4.25 (1H, dd, J¼10.0, 5.0 Hz), 3.79 (3H, s),

3.62 (1H, t, J¼10.0 Hz), 3.48 (1H, ddd, J¼11.5, 10.0,

4.5 Hz), 3.45 (1H, ddd, J¼11.5, 9.0, 4.5 Hz), 3.31 (1H, td,

J¼10.0, 5.0 Hz), 3.19 (1H, td, J¼9.0, 2.5 Hz), 2.94 (2H, td,

J¼7.5, 2.5 Hz), 2.36 (1H, dt, J¼11.5, 4.5 Hz), 2.00 (1H,

dddd, J¼13.5, 9.0, 6.5, 2.5 Hz), 1.71 (2H, m), 1.68 (1H, q,

J¼11.5 Hz), 1.43 (1H, dtd, J¼13.5, 9.0, 4.5 Hz), 0.89 (9H,

s), 0.07 (6H, s); ¹³C NMR (125 MHz, CDCl₃) d 160.10,

136.81, 129.97, 128.90, 128.81, 127.46, 125.68, 113.69,

101.61, 82.21, 76.62, 73.03, 70.40, 69.38, 55.23, 38.92,

33.59, 30.79, 25.72, 25.16, 17.91, 24.12, 24.78; MALDI-

TOF-MS, calcd C₂₉H₄₂O₅SSiNa [MþNa]^þ553.242, found

553.322.

To a suspension of methyltriphenylphosphonium bromide

(11.98 g, 33.52 mmol) in THF (40 mL) was added t-BuOK

(3.225 g, 28.73 mmol) at 08C. The resultant bright yellow

ylide was stirred at 08C for further 20 min, and the above

aldehyde in THF (20 mL) was added to this mixture. The

reaction mixture was stirred for 1.5 h at room temperature,

and then quenched with saturated aqueous NH₄Cl, and

diluted with EtOAc (100 mL). The organic layer was

washed with brine, dried over MgSO₄, and concentrated.

The residue was subjected to ﬂash chromatography

(hexane/EtOAc¼8/1) to give oleﬁn 27 as a colorless solid

(3.15 g, 78% for 2 steps): [a]²_D⁸¼249.128 (c 0.86, CHCl₃);

IR (ﬁlm) n 2955, 2858, 1616, 1518, 1251, 1090, 836,

776 cm²¹

;

¹H NMR (500 MHz, CDCl₃) d 7.43 (2H, d,

6.1.13. O,S-Acetal 8. To a solution of phenylsulﬁde 29

(320.3 mg, 0.603 mmol) in CCl₄(5 mL) was added NCS

(88.6 mg, 0.664 mmol) at room temperature. After being

stirred for 20 min, the reaction mixture was ﬁltrated and

concentrated to give the crude a-chlorosulﬁde 7, which was

used in the next reaction without puriﬁcation.

J¼11.1 Hz), 6.87 (2H, d, J¼11.1 Hz), 4.28 (1H, dd, J¼12.7,

4.2 Hz), 3.81 (3H, s), 3.68 (1H, dd, J¼13.9, 11.2 Hz), 3.55–

3.46 (2H, m), 3.37–3.32 (1H, m), 3.31–3.25 (1H, m), 2.62–

2.56 (1H, m), 2.42–2.36 (1H, m), 2.22–2.13 (1H, m), 1.50

(1H, q, J¼13.9 Hz); ¹³C NMR (125 MHz, CDCl₃) d 160.36,

135.14, 130.24, 127.74, 117.01, 113.96, 101.86, 82.41,

76.84, 73.32, 70.12, 69.67, 55.56, 39.15, 36.14, 25.99,

18.17, 23.73, 24.49; MALDI-TOF-MS, calcd for C₂₃H₃₆-

O₅SiNa [MþNa]^þ443.223, found 443.219.

To a solution of alcohol 6 (311.9 mg, 0.730 mmol) and

powdered molecular sieves 4A in CH₂Cl₂(5 mL) were

added AgOTf (190.0 mg, 0.724 mmol) and DTBMP

(253.0 mg, 1.21 mmol) at 2758C. After 10 min, the crude

a-chlorosulﬁde 7 in CH₂Cl₂(5 mL) was added slowly, and

the resultant mixture was stirred for 2 h below 2308C. The

reaction mixture was then passed through a short plug of

silica gel. The residue was subjected to ﬂash chromato-

graphy to give O,S-acetal 8 (hexane/EtOAc¼7/1) as a pale

yellow oil (498.0 mg, 86%, 2:1 diastereomeric mixture at

6.1.11. Alcohol 28. To a solution of oleﬁn 27 (3.15 g,

7.50 mmol) in THF (30 mL) was added 9-BBN dimer

(4.03 g, 16.5 mmol). The solution was stirred at room

temperature for 4 days. Then, the reaction mixture was

cooled to 08C, and quenched with water (5 mL). After

10 min, 10% NaOH solution (45 mL) and 30% H₂O₂

(22 mL) were added. The mixture was stirred for 30 h at

room temperature, and then diluted with EtOAc. The

organic layer was washed with brine, dried over MgSO₄,

and concentrated. The residue was subjected to ﬂash

chromatography (hexane/EtOAc¼8/1–3/1) to give alcohol

28 as a colorless oil (2.54 g, 77%): [a]³_D¹¼247.878 (c 0.82,

1

the acetal carbon): H NMR (500 MHz, CDCl₃) d 7.53–

7.48 (2H, m), 7.40 (1H, d, J¼9.1 Hz), 7.38–7.18 (13H, m),

6.88 (2H, d, J¼9.1 Hz), 5.43 (1H, s), 4.96–4.88 (1H, m),

4.82–4.70 (2H, m), 4.63–4.50 (3H, m), 4.43 (1H, dd,

J¼12.3, 4.2 Hz), 4.42–4.37 (2H, m), 4.33 (1H, dd, J¼11.2,

4.1 Hz), 4.27 (1H, dd, J¼12.3, 5.4 Hz), 4.21 (1H, dd,

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

5653

J¼12.3, 4.1 Hz), 3.94 (1/2H, d, J¼13.2 Hz), 3.86 (1/2H, d,

J¼13.2 Hz), 3.81 (3H, s), 3.50–3.36 (10H, m), 3.33–3.22

(1H, m), 3.17–3.08 (1H, m), 2.53–2.44 (1H, m), 2.38–2.30

(2H, m), 2.13–2.02 (1H, m), 1.89–1.80 (1H, m), 1.48–1.40

(1H, m), 1.34 (3H, d, J¼11.2 Hz), 1.20 (3H, m), 0.89 (9H,

s), 0.08 (6H, s); MALDI-TOF-MS, calcd for C₅₄H₇₄O₁₁-

SSiNa [MþNa]^þ981.461, found 981.397.

4.45 (1H, d, J¼11.5 Hz), 4.29 (1H, m), 3.94 (1H, dt, J¼9.5,

5.5 Hz), 3.81 (3H, s), 3.69 (3H, s), 3.79–3.62 (5H, m), 3.59

(1H, dt, J¼9.5, 5.0 Hz), 3.57–3.43 (3H, m), 3.45–3.21 (4H,

m), 3.22–3.14 (1H, m), 2.62–2.54 (1H, m), 2.55–2.44 (2H,

m), 2.33 (1H, ddd, J¼16.0, 8.5, 4.0 Hz), 1.95–1.80 (3H, m),

1.77 (1H, q, J¼11.0 Hz), 1.65 (1H, q, J¼11.0 Hz), 1.46 (1H,

q, J¼11.0 Hz), 1.33 (1.5H, d, J¼5.3 Hz), 1.31 (1.5H, d,

J¼5.3 Hz), 1.20 (3H, t, J¼7.0 Hz); MALDI-TOF-MS, calcd

for C₄₆H₆₀O₁₃Na [MþNa]^þ843.393, found 843.405.

6.1.14. b-Alkoxyacrylate 30. A solution of 8 (498.0 mg,

0.519 mmol) in THF (10 mL) was treated with TBAF

(0.79 mL, 0.79 mmol, 1 M in THF solution), and the

mixture was stirred at room temperature for 12 h. The

solvent was evaporated, and the residue was subjected to

ﬂash chromatography (hexane/EtOAc¼1/1) to give the

alcohol, which was used in the next reaction without

puriﬁcation.

6.1.16. Alcohol 34. A solution of oxepane 32 and by-

product 33 (465.7 mg, 3.2:1 mixture, 0.567 mmol) in

CH₂Cl₂(10 mL) was treated with DIBAL (1.1 mL,

1.13 mmol, 1.01 M in toluene) at 2788C for 30 min. The

reaction mixture was quenched with saturated aqueous

NH₄Cl, allowed to warm to room temperature, and diluted

with EtOAc. To this solution was added saturated aqueous

potassium sodium tartrate, and the resultant mixture was

stirred for 1 h. The organic layer was washed with brine,

dried over MgSO₄, and concentrated to give a mixture of the

aldehyde and the alcohol, which was subjected to the next

reaction without puriﬁcation.

To a solution of the above alcohol in CH₂Cl₂(5 mL) were

added methyl propiolate (0.71 mL, 7.91 mmol) and NMM

(0.54 mL, 5.44 mmol). After being stirred for 1.5 h, the

mixture was concentrated, and directly subjected to ﬂash

chromatography (hexane/EtOAc¼7/1–3/1) to give

b-alkoxyacrylate 30 as a colorless solid (395.4 mg, 82%

for 2 steps): IR (ﬁlm) n 2934, 1714, 1644, 1587, 1518, 1250,

To a solution of the crude mixture in MeOH (20 mL) was

added NaBH₄(53.6 mg, 1.42 mmol). After being stirred for

1 h, the reaction was quenched with saturated aqueous

NH₄Cl. The mixture was diluted with EtOAc, washed with

brine, dried over MgSO₄, and concentrated. The residue was

subjected to ﬂash chromatography (hexane/EtOAc¼2/1–

1/1) to give alcohol 34 (316.7 mg) as a colorless oil, which

1

1100, 831, 751 cm²¹; H NMR (500 MHz, CDCl₃) d 7.42

(2H, m), 7.41 (1H, d, J¼12.5 Hz), 7.32 (2H, d, J¼9.0 Hz),

7.28–7.11 (13H, m), 6.81 (2H, d, J¼9.0 Hz), 5.38 (1/4H, s),

5.37 (1/4H, s), 5.36 (1/2H, s), 5.27 (1H, d, J¼12.5 Hz), 4.72

(1/2H, m), 4.66 (1/2H, m), 4.56–4.42 (3.5H, m), 4.40 (1/4H,

d, J¼11.2 Hz), 4.39 (1/4H, d, J¼11.2 Hz), 4.31 (1/2H, d,

J¼11.3 Hz), 4.27 (1/4H, d, J¼11.3 Hz), 4.26 (1/4H, d,

J¼11.3 Hz), 4.17 (1/2H, dt, J¼15.0, 5.0 Hz), 4.11 (1/2H, dt,

J¼14.2, 4.8 Hz), 3.90–3.45 (6H, m), 3.68–3.55 (1H, m),

3.45–3.32 (1H, m), 3.44–3.12 (7H, m), 3.68 (3H, s), 3.62

(1H, s), 3.61 (1H, s), 3.60 (1H, s), 2.52–2.38 (2H, m), 1.90–

1.75 (2H, m), 1.75–1.56 (2H, m), 1.55–1.35 (2H, m), 1.23–

1.14 (3H, m), 1.11 (3H, m); ¹³C NMR (125 MHz, CDCl₃) d

170.80, 167.71, 167.58, 160.78, 160.62, 159.90, 138.13,

137.86, 137.64, 133.62, 133.42, 133.20, 133.12, 132.86,

129.44, 128.80, 128.68, 128.06, 128.00, 127.64, 127.55,

127.46, 127.30, 127.22, 113.43, 101.60, 101.31, 100.02,

99.72, 99.37, 98.13, 97.99, 90.11, 85.51, 85.31, 80.18,

80.01, 79.88, 79.77, 79.37, 79.20, 78.95, 75.72, 75.65,

75.47, 73.19, 73.06, 72.79, 72.69, 72.01, 71.88, 71.09,

70.77, 69.25, 69.03, 68.96, 68.87, 68.78, 68.56, 64.72,

64.29, 63.77, 63.41, 61.36, 60.73, 60.42, 60.11, 55.00,

50.95, 36.56, 34.65, 34.55, 33.56, 32.43, 32.36, 32.02,

31.94, 31.35, 29.71, 27.95, 27.79, 25.98, 22.43, 20.79,

19.93, 19.67, 15.12, 13.95; MALDI-TOF-MS, calcd for

C₅₂H₆₄O₁₃SNa [MþNa]^þ951.396, found 951.359.

1

was contaminated with the by-product arose from 33: H

NMR (500 MHz, CDCl₃) d 7.32 (2H, d, J¼8.5 Hz), 7.29–

7.11 (10H, m), 6.81 (2H, d, J¼8.6 Hz), 5.39 (1H, s), 4.53

(1H, d, J¼12.0 Hz), 4.49 (1H, d, J¼11.5 Hz), 4.46 (1H, d,

J¼12.0 Hz), 4.35 (1H, d, J¼11.3 Hz), 4.21 (1/2H, dd,

J¼10.3, 5.0 Hz), 4.18 (1/2H, dd, J¼10.3, 5.0 Hz), 3.80 (1H,

m), 3.71 (3H, s), 3.72–3.54 (6H, m), 3.54–3.35 (6H, m),

3.35–3.14 (6H, m), 3.14–3.06 (1H, m), 2.53–2.38 (2H, m),

2.36–2.17 (1H, m), 1.85–1.70 (3H, m), 1.71–1.56 (2H, m),

1.60 (1H, q, J¼11.3 Hz), 1.45–1.32 (1H, m), 1.24 (1.5H, d,

J¼7.0 Hz), 1.23 (1.5H, d, J¼7.0 Hz), 1.13 (1.5H, t,

J¼6.8 Hz), 1.11 (1.5H, t, J¼7.0 Hz); MALDI-TOF-MS,

calcd for C₄₅H₆₀O₁₂Na [MþNa]^þ815.398, found 815.360.

6.1.17. Oleﬁn 35. A solution of the above alcohol 34

(55.1 mg, 69.5 mmol) in THF (2 mL) containing 2-nitro-

phenyl selenocyanate (117.9 mg, 0.519 mmol) and pyridine

(56 mL, 0.692 mmol) was treated with tri-n-butylphosphine

(129 mL, 0.519 mmol) dropwise at room temperature. After

1 h, saturated aqueous NaHCO₃(109 mg, 1.30 mmol) was

added, and then H₂O₂(0.18 mL, 34.5% water solution) was

added dropwise at 08C. The ice bath was removed, and the

solution was stirred for additional 1 h at 408C. The reaction

mixture was quenched with saturated aqueous Na₂S₂O₃and

diluted with EtOAc. The organic layer was washed with

brine, dried over MgSO₄, and concentrated. The residue was

subjected to ﬂash chromatography (hexane/EtOAc¼6/1–5/

1) to give oleﬁn 35 as an orange oil (45.6 mg, 85%): IR

(ﬁlm) n 2933, 1615, 1518, 1496, 1303, 1250, 1171, 1029,

6.1.15. Oxepane 32. To a solution of alkoxyacrylate 30

(1.036 g, 1.115 mmol) and n-Bu₃SnH (0.6 mLþ0.9 mL,

5.576 mmol) in toluene (280 mL) was added AIBN

(154.0 mg, 0.938 mmol) in two portions. After being stirred

for 9 h at 808C, the reaction mixture was concentrated, and

subjected to ﬂash chromatography (hexane/EtOAc¼6/1–3/

1) to give an inseparable 3.2:1 mixture of the desired

oxepane 32 and the reduced byproduct 33 as a colorless

solid (883.4 mg, 97%): IR (ﬁlm) n 2935, 2870, 1738, 1617,

1518, 1030, 830, 786 cm²¹; ¹H NMR (500 MHz, CDCl₃) d

7.41 (2H, d, J¼9.0 Hz), 7.38–7.20 (10H, m), 6.90 (2H, d,

J¼8.5 Hz), 5.47 (3H, s), 4.77 (1H, m), 4.66–4.52 (3H, m),

829 cm²^{1 1}H NMR (500 MHz, CDCl₃) d 7.34 (2H, d,

;

J¼8.7 Hz), 7.26–7.15 (10H, m), 6.82 (2H, d, J¼8.7 Hz),

5.76 (1H, ddd, J¼17.0, 10.4, 5.5 Hz), 5.40 (1H, s), 5.25 (1H,

brd, J¼17.0 Hz), 5.06 (1H, brd, J¼10.4 Hz), 4.72 (1H, q,

5654

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

J¼5.3 Hz), 4.54 (1H, d, J¼12.2 Hz), 4.51 (1H, d,

J¼11.6 Hz), 4.47 (1H, d, J¼12.2 Hz), 4.36 (1H, d,

J¼11.3 Hz), 4.22 (1H, dd, J¼10.4, 4.8 Hz), 4.02 (1H, br),

3.72 (3H, s), 3.73–3.56 (7H, m), 3.46–3.35 (4H, m), 3.36–

3.30 (1H, m), 3.31–3.21 (3H, m), 3.15 (1H, td, J¼10.0,

4.5 Hz), 2.47 (1H, dt, J¼11.5, 4.4 Hz), 2.33 (1H, dt, J¼11.3,

4.2 Hz), 1.83–1.72 (3H, m), 1.72–1.65 (1H, m), 1.65 (1H,

q, J¼11.3 Hz), 1.39 (1H, q, J¼11.3 Hz), 1.23 (3H, d,

J¼5.3 Hz), 1.13 (3H, t, J¼7.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 160.03, 138.32, 138.05, 137.45, 129.93, 128.36,

128.27, 127.72, 127.69, 127.50, 127.43, 115.21, 113.63,

101.48, 99.72, 84.29, 82.00, 81.15, 80.25, 80.12, 78.26,

76.83, 73.41, 72.87, 72.18, 71.96, 71.25, 69.37, 69.30,

63.06, 61.48, 55.26, 36.79, 36.50, 26.15, 24.78, 19.92,

15.29; MALDI-TOF-MS, calcd for C₄₅H₅₈O₁₁Na [MþNa]^þ

797.387, found 797.395.

The above aldehyde was dissolved in THF (1.5 mL) and

added to a suspension of methyltriphenylphosphonium

bromide (289.8 mg, 0.811 mmol) and sodium bis(trimethyl-

silyl)amide (0.68 mL, 0.68 mmol, 1.0 M in THF solution) in

THF (1.5 mL) at 08C. After being stirred for 10 min, the

reaction mixture was quenched with saturated aqueous

NH₄Cl, diluted with EtOAc, washed with brine, dried over

MgSO₄, and concentrated. The residue was subjected to

ﬂash chromatography (hexane/EtOAc¼10/1–6/1) to give

diene 37 as a colorless solid (35.0 mg, 74% for 2 steps):

[a]²_D⁴¼235.328 (c 1.27, CHCl₃); IR (ﬁlm) d 3031, 1615,

1588, 1518, 1303, 1171, 1103, 829 cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.34 (2H, d, J¼8.6 Hz), 7.29–7.13

(10H, m), 6.81 (2H, d, J¼8.6 Hz), 5.85 (1H, ddd, J¼17.1,

10.5, 6.5 Hz), 5.69 (1H, ddd, J¼17.0, 10.5, 5.4 Hz), 5.40

(1H, s), 5.35 (1H, brd, J¼17.0 Hz), 5.21 (1H, brd,

J¼10.5 Hz), 5.20 (1H, dt, J¼17.0, 1.5 Hz), 5.03 (1H, dt,

J¼10.5, 1.4 Hz), 4.56 (1H, d, J¼12.2 Hz), 4.51 (1H, d,

J¼11.3 Hz), 4.48 (1H, d, J¼12.2 Hz), 4.35 (1H, d,

J¼11.3 Hz), 4.21 (1H, dd, J¼10.4, 4.7 Hz), 3.99 (1H, m),

3.72 (3H, s), 3.71–3.55 (4H, m), 3.54 (1H, br), 3.50–3.36

(3H, m), 3.35 (1H, ddd, J¼9.3, 4.0, 1.7 Hz), 3.26 (1H, td,

J¼9.5, 4.8 Hz), 3.14 (1H, dt, J¼10.0, 4.6 Hz), 3.08 (1H, m),

2.47 (1H, dt, J¼11.8, 4.5 Hz), 2.31 (1H, dt, J¼11.5, 4.3 Hz),

1.85–1.70 (3H, m), 1.67–1.55 (1H, m), 1.63 (1H, q,

J¼11.4 Hz), 1.44 (1H, q, J¼11.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 160.05, 138.28, 138.04, 137.21, 135.84, 129.95,

128.36, 128.30, 127.80, 127.72, 127.54, 127.45, 118.24,

115.08, 113.64, 101.49, 83.89, 81.85, 81.84, 81.52, 79.87,

77.61, 76.83, 76.31, 73.46, 72.82, 72.10, 71.28,

69.33, 69.06, 55.28, 36.91, 36.75, 26.14, 24.10; MALDI-

TOF-MS, calcd for C₄₂H₅₀O₉Na [MþNa]^þ721.335, found

721.271.

6.1.18. Alcohol 36. A solution of the EE ether 35 (253 mg,

0.328 mmol) in MeOH (23 mL) was treated with PPTS

(16.5 mg, 65.7 mmol) at room temperature, and the mixture

was stirred for 1 h. Then the solution was concentrated, and

the residue was used in the next reaction without

puriﬁcation.

To a solution of the above residue in CH₂Cl₂(10 mL) were

added p-methoxybenzaldehyde dimethyl acetal (73 mL,

0.393 mmol) and PPTS (15.6 mg, 62.1 mmol) at room

temperature. After being stirred for 40 min, the reaction

mixture was quenched with saturated aqueous NH₄Cl. The

mixture was diluted with EtOAc, washed with brine, dried

over MgSO₄, and concentrated. Silica gel was added to the

solution of the crude product in hexane, and the resultant

suspension was stirred overnight, and then subjected to ﬂash

chromatography (hexane/EtOAc¼2/1–1/1) to give alcohol

36 as a colorless solid (170 mg, 74%): [a]²_D⁸¼258.468 (c

1.45, CHCl₃); IR (ﬁlm) n 3482, 2934, 1615, 1518, 1363,

1249, 1171, 1082, 928, cm²¹; ¹H NMR (500 MHz, CDCl₃)

d 7.33 (2H, d, J¼8.5 Hz), 7.27–7.18 (8H, m), 7.16–7.12

(2H, m), 6.80 (2H, d, J¼8.6 Hz), 5.74 (1H, ddd, J¼17.0,

10.5, 5.5 Hz), 5.39 (1H, s), 5.23 (1H, dt, J¼17.0, 1.3 Hz),

5.06 (1H, dt, J¼10.4, 1.3 Hz), 4.51 (1H, d, J¼12.0 Hz), 4.49

(1H, d, J¼11.3 Hz), 4.44 (1H, d, J¼12.0 Hz), 4.32 (1H, d,

J¼11.3 Hz), 4.21 (1H, dd, J¼10.3, 4.7 Hz), 3.95 (1H, m),

3.80 (1H, dd, J¼11.6, 2.4 Hz), 3.70 (3H, s), 3.67 (1H, dd,

J¼10.5, 1.5 Hz), 3.64–3.53 (4H, m), 3.45–3.22 (6H, m),

3.19 (1H, m), 3.13 (1H, m), 2.47 (1H, dt, J¼12.1, 4.0 Hz),

2.33 (1H, dt, J¼11.5, 4.0 Hz), 1.83–1.71 (3H, m), 1.70–

1.61 (1H, m), 1.64 (1H, q, J¼11.3 Hz), 1.39 (1H, q,

J¼11.0 Hz); ¹³C NMR (125 MHz, CDCl₃) d 159.97,

137.92, 137.88, 137.27, 129.89, 128.33, 128.30, 127.77,

127.72, 127.65, 127.63, 127.39, 115.40, 113.57, 101.41,

84.46, 81.96, 81.24, 80.64, 79.69, 78.55, 73.37, 72.85,

72.08, 72.02, 71.18, 69.23, 69.14, 62.05, 55.20, 36.71,

36.23, 26.12, 25.04; MALDI-TOF-MS, calcd for

C₄₁H₅₀O₁₀Na [MþNa]^þ725.330, found 725.328.

6.1.20. 6-7-7-6 Ring system 9. To a solution of compound

37 (19.2 mg, 27.5 mmol) in CH₂Cl₂(13 mL) was added

second-generation Grubbs catalyst (46, 6.1 mg, 7.2 mmol)

at room temperature. After being stirred for 13 h at 408C, the

reaction mixture was quenched with Et₃N (0.20 mL) and

stirred for 2 h at room temperature. Concentration and ﬂash

chromatography (hexane/EtOAc¼6.5/1–4/1) gave the 6-7-

7-6 ring system 9 as a colorless solid (5.8 mg, 31%):

[a]²_D¹¼252.448 (c 0.33, CHCl₃); IR (ﬁlm) n 2929, 1614,

1517, 1369, 1249, 1173, 1038, 828 cm²¹

;

¹H NMR

(500 MHz, CDCl₃) d 7.34 (2H, d, J¼8.6 Hz); 7.30–7.16

(8H, m), 7.14 (2H, brd, J¼7.0 Hz), 6.82 (2H, d, J¼8.6 Hz),

5.74 (1H, dt, J¼12.3, 3.0 Hz), 5.58 (1H, dt, J¼12.3, 2.2 Hz),

5.40 (1H, s), 4.55 (1H, d, J¼12.3 Hz), 4.50 (1H, d,

J¼11.3 Hz), 4.49 (1H, d, J¼12.2 Hz), 4.32 (1H, d,

J¼11.3 Hz), 4.21 (1H, dd, J¼10.4, 4.7 Hz), 4.01 (1H, brd,

J¼9.0 Hz), 3.77 (1H, br), 3.73 (3H, s), 3.69 (1H, dd,

J¼10.0, 1.4 Hz), 3.58 (1H, dd, J¼10.4, 9.5 Hz), 3.57 (1H, d,

J¼9.8 Hz), 3.50–3.35 (3H, m), 3.32–3.20 (3H, m), 3.15

(1H, ddd, J¼10.5, 8.5, 4.3 Hz), 3.09 (1H, m), 2.43 (1H, dt,

J¼11.9, 4.4 Hz), 2.36 (1H, dt, J¼11.9, 4.3 Hz), 1.91–1.84

(2H, m), 1.87–1.75 (2H, m), 1.67 (1H, q, J¼11.4 Hz), 1.45

(1H, q, J¼11.5 Hz); ¹³C NMR (125 MHz, CDCl₃) d 160.10,

138.21, 137.99, 134.76, 130.63, 129.85, 128.38, 128.33,

127.85, 127.76, 127.72, 127.58, 127.46, 113.69, 101.60,

84.61, 83.81, 83.67, 82.45, 80.64, 79.80, 77.38, 73.59,

73.48, 72.03, 70.92, 69.28, 69.13, 55.30, 37.02, 36.76,

30.95, 27.60; MALDI-TOF-MS, calcd for C₄₀H₄₆O₉Na

[MþNa]^þ693.304, found 693.232.

6.1.19. Diene 37. To a solution of alcohol 36 (47.5 mg,

67.6 mmol) in CH₂Cl₂(2 mL), DMSO (1 mL) and Et₃N

(1 mL) was added SO₃·pyridine (53.8 mg, 0.338 mmol).

After 2 h, the reaction mixture was quenched with saturated

aqueous NaHCO₃, diluted with EtOAc, washed with brine,

dried over MgSO₄and concentrated to give the crude

aldehyde, which was directly used in the next reaction.

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

5655

6.1.21. Nitrile 38. To a solution of alcohol 36 (87.0 mg,

0.124 mmol) in pyridine (2 mL) were added powdered

molecular sieves 4A and p-toluenesulfonyl chloride

(377.7 mg, 1.98 mmol) in three portions. After being stirred

for 2 days, the reaction mixture was quenched with saturated

aqueous NaHCO₃, diluted with EtOAc, washed with brine,

dried over MgSO₄, and concentrated. The residue was

subjected to ﬂash chromatography (hexane/EtOAc¼4/1–2/

1) to give the tosylate as a colorless solid (106 mg, 100%):

[a]²_D⁵¼2160.388 (c 1.48, CHCl₃); IR (ﬁlm) n 2933, 1615,

(167 mL, 169 mmol, 1.01 M in toluene) at 2788C for

40 min. The reaction mixture was quenched with saturated

aqueous NH₄Cl, allowed to warm to room temperature, and

diluted with EtOAc. To the mixture was added saturated

aqueous potassium sodium tartrate, and the resultant

solution was stirred for 1 h. The mixture was diluted with

EtOAc, washed with brine, dried over MgSO₄, and

concentrated to give the crude aldehyde, which was directly

used in the next reaction.

1

1518, 1496, 1362, 1250, 1096, 976, 815 cm²¹; H NMR

The above aldehyde was dissolved in THF (2 mL) and

added to a suspension of methyltriphenylphosphonium

bromide (361.8 mg, 1.01 mmol) and sodium bis(trimethyl-

silyl)amide (0.84 mL, 1.0 M in THF solution) in THF

(2 mL) at 08C. After being stirred for 10 min, the reaction

mixture was allowed to warm to room temperature, and

stirred for another 20 min, and then quenched with saturated

aqueous NH₄Cl. The mixture was diluted with EtOAc,

washed with brine, dried over MgSO₄, and concentrated.

The residue was subjected to ﬂash chromatography

(hexane/EtOAc¼5/1–4/1) to give diene 39 as a colorless

solid (30.2 mg, 50%) along with 20% of recovered nitrile

38: [a]²_D⁶¼243.248 (c 1.355, CHCl₃); IR (ﬁlm) n 3069,

(500 MHz, CDCl₃) d 7.81 (2H, d, J¼9.0 Hz), 7.43 (2H, d,

J¼8.5 Hz), 7.37–7.22 (12H, m), 6.90 (2H, d, J¼8.5 Hz),

5.76 (1H, ddd, J¼17.0, 10.3, 5.7 Hz), 5.50 (1H, s), 5.31 (1H,

brd, J¼17.0 Hz), 5.13 (1H, d, J¼10.5 Hz), 4.58 (1H, d,

J¼12.3 Hz), 4.56 (1H, d, J¼11.3 Hz), 4.52 (1H, d,

J¼12.0 Hz), 4.43 (1H, d, J¼11.3 Hz), 4.33–4.23 (3H, m),

4.01 (1H, br), 3.81 (3H, s), 3.73–3.57 (4H, m), 3.54 (1H,

ddd, J¼11.8, 9.0, 4.2 Hz), 3.47–3.39 (2H, m), 3.40–3.32

(4H, m), 3.23 (1H, q, J¼7.8 Hz), 2.54 (1H, m), 2.47–2.39

(4H, m), 1.88–1.70 (4H, m), 1.73 (1H, q, J¼11.5 Hz), 1.43

(1H, q, J¼11.0 Hz); ¹³C NMR (125 MHz, CDCl₃) d 159.98,

144.72, 143.32, 139.22, 138.13, 137.80, 137.13, 132.86,

129.92, 129.73, 129.57, 12835, 128.30, 127.93, 127.77,

127.73, 127.70, 127.54, 127.42, 126.34, 115.74, 113.58,

101.42, 84.29, 81.89, 81.12, 80.37, 78.38, 77.92, 73.43,

72.90, 71.0, 71.61, 71.35, 69.24, 68.93, 68.90, 55.23, 36.72,

36.19, 26.09, 25.07, 21.57; MALDI-TOF-MS, calcd for

C₄₈H₅₆O₁₂SNa [MþNa]^þ879.339, found 879.324.

1

2936, 1638, 1518, 1497, 1303, 1030, 910, 829 cm²¹; H

NMR (500 MHz, CDCl₃) d 7.43 (2H, d, J¼8.7 Hz), 7.39–

7.23 (10H, m), 6.91 (2H, d, J¼8.7 Hz), 5.97 (1H, ddt,

J¼17.7, 10.2, 6.8 Hz), 5.83 (1H, ddd, J¼17.0, 10.5, 5.7 Hz),

5.49 (1H, s), 5.32 (1H, brd, J¼17.0 Hz), 5.19–5.08 (3H, m),

4.65 (1H, d, J¼12.2 Hz), 4.59 (2H, d, J¼12.0 Hz), 4.44 (1H,

d, J¼11.3 Hz), 4.31 (1H, dd, J¼10.3, 4.7 Hz), 4.08 (1H, br),

3.81 (3H, s), 3.77 (1H, dd, J¼11.0, 1.5 Hz), 3.72–3.65 (2H,

m), 3.63 (1H, br), 3.55–3.43 (3H, m), 3.41–3.32 (2H, m),

3.30–3.20 (2H, m), 3.15 (1H, ddd, J¼11.0, 9.3, 4.4 Hz),

2.62 (1H, br), 2.53 (1H, dt, J¼11.7, 4.3 Hz), 2.43 (1H, dt,

J¼11.5, 4.3 Hz), 2.29 (1H, dt, J¼14.3, 7.3 Hz), 1.95–1.79

(3H, m), 1.79–1.70 (1H, m), 1.74 (1H, q, J¼11.5 Hz), 1.46

(1H, q, J¼11.3 Hz); ¹³C NMR (125 MHz, CDCl₃) d 160.05,

138.46, 138.09, 137.37, 135.04, 129.94, 128.35, 128.27,

127.70, 127.65, 127.45, 116.74, 115.42, 113.64, 101.49,

84.54, 82.03, 81.29, 80.29, 80.12, 78.40, 76.85, 75.76,

73.34, 72.90, 72.40, 71.25, 69.31, 69.19, 55.28, 36.77,

36.64, 36.04, 26.17, 25.09; MALDI-TOF-MS, calcd for

C₄₃H₅₂O₉Na [MþNa]^þ735.350, found 735.272.

To a solution of the above tosylate (106 mg, 0.124 mmol) in

DMSO (3 mL) was added sodium cyanide (31.6 mg,

0.645 mmol) and then heated to 508C for 1 day. The

reaction mixture was quenched with saturated aqueous

NaHCO₃, diluted with EtOAc, washed with brine, dried

over MgSO₄, and concentrated. The residue was subjected

to ﬂash chromatography (hexane/EtOAc¼5/1–3/1) to give

nitrile 38 as a colorless solid (88.2 mg, 100%):

[a]²_D⁸¼238.878 (c 1.20, CHCl₃); IR (ﬁlm) n 2935, 2871,

1615, 1518, 1250, 928, 830, 736 cm²¹; ¹H NMR (500 MHz,

CDCl₃) d 7.43 (2H, d, J¼8.5 Hz), 7.40–7.23 (10H, m), 6.90

(2H, d, J¼8.6 Hz), 5.83 (1H, ddd, J¼16.7, 10.3, 6.0 Hz),

5.49 (1H, s), 5.35 (1H, d, J¼16.7 Hz), 5.21 (1H, d,

J¼10.2 Hz), 4.64 (1H, d, J¼12.3 Hz), 4.58 (1H, d,

J¼11.4 Hz), 4.58 (1H, d, J¼12.3 Hz), 4.46 (1H, d,

J¼11.4 Hz), 4.31 (1H, dd, J¼10.3, 4.7 Hz), 4.03 (1H, brt,

J¼5.0 Hz), 3.81 (3H, s), 3.78 (1H, d, J¼10.7 Hz), 3.73–

3.63 (3H, m), 3.57–3.44 (2H, m), 3.49–3.36 (3H, m), 3.40–

3.30 (1H, m), 3.35–3.27 (1H, m), 3.24 (1H, dt, J¼9.3,

5.2 Hz), 2.82 (1H, dd, J¼16.8, 3.6 Hz), 2.72 (1H, dd,

J¼16.6, 5.5 Hz), 2.56 (1H, dt, J¼11.7, 4.3 Hz), 2.44 (1H, dt,

J¼11.3, 4.3 Hz), 1.92–1.76 (4H, m), 1.75 (1H, q,

J¼11.5 Hz), 1.47 (1H, q, J¼11.4 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 160.00, 138.03, 137.72, 137.13,

129.84, 129.58, 128.38, 128.30, 127.83, 127.74, 127.72,

127.56, 127.40, 126.33, 117.19, 116.16, 113.59, 101.45,

84.78, 82.02, 81.59, 80.61, 79.22, 76.78, 75.64, 75.22,

73.44, 72.95, 71.72, 71.49, 69.20, 68.86, 55.23, 36.70,

36.22, 26.16, 25.79, 21.29; MALDI-TOF-MS, calcd for

C₄₂H₄₉NO₉Na [MþNa]^þ734.330, found 734.336.

6.1.23. 6-8-7-6 Ring system 10. To a solution of diene 39

(37.6 mg, 11.1 mmol) in CH₂Cl₂(19 mL) was added

(PCy₃)₂Cl₂RuvCHPh (45, 9.1 mg, 27.2 mmol) at 408C.

After being stirred for 13 h, the reaction mixture was

quenched with Et₃N (0.19 mL), and stirred for 3 h at room

temperature. Concentration and ﬂash chromatography

(hexane/EtOAc¼6/1–3/1) gave the 6-8-7-6 ring system 10

as a colorless solid (32.8 mg, 91%): [a]²_D⁵¼2131.228 (c

1.61, CHCl₃); IR (ﬁlm) d 2935, 1615, 1589, 1496, 1384,

1251, 1095, 990, 830 cm²¹; ¹H NMR (500 MHz, CDCl₃) d

7.34 (2H, d, J¼8.5 Hz); 7.28–7.16 (8H, m), 7.12 (2H, d,

J¼7.3 Hz), 6.81 (2H, d, J¼8.6 Hz), 5.70 (1H, dd, J¼11.0,

6.0 Hz), 5.63 (1H, dd, J¼11.8, 8.5 Hz), 5.39 (1H, s), 4.52

(1H, d, J¼12.3 Hz), 4.50 (1H, d, J¼11.2 Hz), 4.47 (1H, d,

J¼12.3 Hz), 4.28 (1H, d, J¼11.2 Hz), 4.21 (1H, dd, J¼11.4,

4.8 Hz), 4.07 (1H, brt, J¼7.5 Hz), 3.72 (3H, s), 3.65 (1H, d,

J¼10.6 Hz), 3.59 (1H, t, J¼10.1 Hz), 3.51 (1H, dd, J¼10.6,

5.0 Hz), 3.47–3.37 (2H, m), 3.34–3.21 (5H, m), 3.17 (1H,

ddd, J¼12.2, 9.3, 3.9 Hz), 3.10 (1H, dt, J¼9.8, 5.3 Hz), 2.64

6.1.22. Diene 39. A solution of nitrile 38 (60.1 mg,

84.4 mmol) in CH₂Cl₂(3 mL) was treated with DIBAL

5656

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

(1H, ddd, J¼14.3, 9.5, 4.9 Hz), 2.40 (1H, dt, J¼11.3,

4.3 Hz), 2.38–2.29 (2H, m), 2.00–1.89 (2H, m), 1.90–1.76

(2H, m), 1.66 (1H, q, J¼11.3 Hz), 1.44 (1H, q, J¼10.8 Hz);

¹³C NMR (125 MHz, CDCl₃) d 160.07, 138.32, 138.00,

135.53, 129.843, 128.35, 128.27, 127.78, 127.66, 127.64,

127.50, 127.44, 124.71, 113.65, 101.57, 84.06, 84.03, 83.04,

82.36, 82.04, 80.63, 76.87, 73.62, 73.34, 72.92, 70.83,

69.49, 69.27, 55.28, 37.01, 36.79, 31.32, 30.34, 27.47;

MALDI-TOF-MS, calcd for C₄₁H₄₈O₉Na [MþNa]^þ

707.320, found 707.315.

26.09, 25.27, 19.93, 19.87, 15.30; MALDI-TOF-MS, calcd

for C₄₆H₆₀O₁₁Na [MþNa]^þ811.403, found 811.405.

6.1.25. Alcohol 41. A solution of compound 40 (61.7 mg,

78.2 mmol) in MeOH (3 mL) was treated with PPTS

(4.6 mg, 18.3 mmol) at room temperature, and the resultant

mixture was stirred for 1 h. After concentration, the residue

was directly used in the next reaction.

To a solution of the above residue in CH₂Cl₂(3 mL) were

added p-methoxybenzaldehyde dimethyl acetal (29 mL,

0.156 mmol) and PPTS (3.8 mg, 15.12 mmol) at room

temperature. After being stirred for 1.5 h, the reaction

mixture was quenched with saturated aqueous NH₄Cl. The

organic layer was extracted with EtOAc, washed with brine,

dried over MgSO₄, and concentrated. The residue was

subjected to ﬂash chromatography (hexane/EtOAc¼3/1–

2/1) to give alcohol 41 as a colorless solid (49.7 mg, 89%):

[a]²_D⁷¼250.458 (c 1.02, CHCl₃); IR (ﬁlm) n 3470 (br), 2933,

6.1.24. Oleﬁn 40. A solution of the mixture of 32 and by-

product 33 (93.7 mg, 3.2:1 mixture, 0.114 mmol) in CH₂Cl₂

(3 mL) was treated with DIBAL (0.14 mL, 0.137 mmol,

1.01 M in toluene) at 2908C for 40 min. The reaction

mixture was quenched with saturated aqueous NH₄Cl,

diluted with EtOAc, and then saturated aqueous potassium

sodium tartrate was added. The solution was allowed to

warm to room temperature and stirred for 1 h. The organic

layer was extracted with EtOAc, washed with brine, dried

over MgSO₄, and concentrated. The residue was used in the

next reaction without puriﬁcation.

1

2870, 1615, 1304, 1250, 1172, 735, 699, 648 cm²¹; H

NMR (500 MHz, CDCl₃) d 7.34 (2H, d, J¼8.5 Hz), 7.29–

7.13 (10H, m), 6.82 (2H, d, J¼8.7 Hz), 5.74 (1H, ddt,

J¼16.8, 10.2, 6.8 Hz), 5.40 (1H, s), 5.02 (2H, m), 4.52 (1H,

d, J¼11.5 Hz), 4.50 (1H, d, J¼11.5 Hz), 4.45 (1H, d,

J¼12.0 Hz), 4.34 (1H, d, J¼11.3 Hz), 4.21 (1H, dd, J¼10.3,

4.8 Hz), 3.80 (1H, dd, J¼11.0, 2.3 Hz), 3.72 (3H, s), 3.68

(1H, d, J¼9.8 Hz), 3.64–3.55 (2H, m), 3.51–3.31 (7H, m),

3.29–3.16 (3H, m), 3.15–3.08 (1H, m), 2.46 (1H, m), 2.31

(1H, dt, J¼10.5, 4.2 Hz), 2.14 (2H, m), 1.84–1.69 (3H, m),

1.67–1.60 (1H, m), 1.60 (1H, q, J¼11.5 Hz), 1.38 (1H, q,

J¼10.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 160.02,

137.93, 137.90, 134.67, 129.94, 128.39, 128.39, 127.86,

127.73, 127.41, 117.41, 113.63, 101.45, 84.07, 81.84, 80.58,

80.54, 79.71, 79.16, 76.82, 73.46, 72.87, 72.05, 71.82,

71.21, 69.30, 69.20, 62.23, 55.27, 39.43, 36.58, 36.28,

26.14, 25.35; MALDI-TOF-MS, calcd for C₄₂H₅₂O₁₀Na

[MþNa]^þ739.345, found 739.288.

To a solution of the residue in CH₂Cl₂(2 mL), DMSO

(1 mL) and Et₃N (1 mL) was added SO₃·pyridine (93.6 mg,

0.588 mmol). After 2 h, the reaction mixture was quenched

with saturated aqueous NaHCO₃. The organic layer was

extracted with ether, washed with brine, dried over MgSO₄

and concentrated to give the aldehyde, which was used in

the next reaction without puriﬁcation.

To a suspension of methyltriphenylphosphonium bromide

(488.7 mg, 1.37 mmol) and sodium bis(trimethylsilyl)amide

(1.1 mL, 1.0 M in THF solution) in THF (1.5 mL) was

added the above aldehyde in THF (2 mL) at 08C. After being

stirred for 10 min, the reaction mixture was quenched with

saturated aqueous NH₄Cl. The organic layer was extracted

with EtOAc, washed with brine, dried over MgSO₄, and

concentrated. The residue was subjected to ﬂash chroma-

tography (hexane/EtOAc¼4/1) to give oleﬁn 40 as a

colorless solid (61.7 mg, 69% for 3 steps): IR (ﬁlm) n

3065, 3030, 2870, 1641, 1615, 1588, 1366, 1311, 1250,

6.1.26. Diene 42. To a solution of compound 41 (49.7 mg,

69.33 mmol) in CH₂Cl₂(2 mL), DMSO (1 mL) and Et₃N

(1 mL) was added SO₃·pyridine (111.1 mg, 0.698 mmol).

After 3 h, the reaction mixture was quenched with saturated

aqueous NaHCO₃. The mixture was diluted with EtOAc,

washed with brine, dried over MgSO₄and concentrated to

give the aldehyde, which was used in the next reaction

without puriﬁcation.

698 cm²^{1 1}H NMR (500 MHz, CDCl₃) d 7.34 (2H, d,

;

J¼8.5 Hz), 7.29–7.17 (10H, m), 6.81 (2H, d, J¼8.6 Hz),

5.74 (1H, m), 5.39 (1H, s), 5.01 (2H, m), 4.71 (1H, q,

J¼5.5 Hz), 4.54 (1H, d, J¼12.2 Hz), 4.49 (1H, d,

J¼11.5 Hz), 4.47 (1H, d, J¼12.5 Hz), 4.36 (1H, d,

J¼12.2 Hz), 4.21 (1H, dd, J¼10.3, 4.8 Hz), 3.83 (1/2H,

dd, J¼10.7, 1.2 Hz), 3.72 (3H, s), 3.71–3.53 (4H, m), 3.68–

3.57 (1H, m), 3.53–3.42 (3.5H, m), 3.45–3.35 (3H, m), 3.33

(1H, m), 3.30–3.15 (3H, m), 3.16–3.08 (1H, m), 2.44 (1H,

m), 2.29 (1H, dt, J¼10.6, 5.0 Hz), 2.19–2.07 (2H, m),

1.85–1.67 (3H, m), 1.67–1.61 (1H, m), 1.60 (1H, q,

J¼10.6 Hz), 1.36 (1H, q, J¼11.0 Hz), 1.25 (1.5H, d,

J¼5.3 Hz), 1.23 (1.5H, d, J¼5.3 Hz), 1.13 (1.5H, t,

J¼7.0 Hz), 1.12 (1.5H, t, J¼7.0 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 160.01, 138.30, 138.28, 138.05,

134.81, 134.67, 129.92, 128.35, 128.27, 127.73, 127.70,

127.51, 127.40, 117.33, 117.21, 113.62, 101.44, 99.89,

99.77, 83.96, 83.90, 81.89, 81.85, 80.44, 80.35, 80.27,

80.08, 80.06, 79.06, 79.01, 76.84, 76.81, 73.42, 73.40,

72.85, 72.10, 72.04, 71.69, 71.23, 69.33, 69.30, 64.88,

63.26, 61.44, 60.39, 55.26, 39.42, 36.59, 36.50, 26.13,

The above aldehyde was dissolved in THF (2.5 mL) and

added to a suspension of methyltriphenylphosphonium

bromide (297.1 mg, 0.832 mmol) and sodium bis(trimethyl-

silyl)amide (0.69 mL, 0.69 mmol, 1.0 M in THF solution) in

THF (2.2 mL) at 08C. After being stirred for 10 min at 08C,

the reaction mixture was quenched with saturated aqueous

NH₄Cl. The mixture was diluted with EtOAc, washed with

brine, dried over MgSO₄, and concentrated. The residue was

subjected to ﬂash chromatography (hexane/EtOAc¼8/1–

1/1) to give diene 42 as a colorless solid (32.8 mg, 66% for 2

steps): [a]²_D⁴¼241.078 (c 1.05, CHCl₃); IR (ﬁlm) n 2934,

1497, 1454, 1365, 1172, 927, 829 cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.28 (2H, d, J¼8.5 Hz), 7.24–7.06

(10H, m), 6.75 (2H, d, J¼8.5 Hz), 5.78 (1H, ddd, J¼17.2,

10.5, 6.5 Hz), 5.66 (1H, ddt, J¼16.8, 10.5, 7.0 Hz), 5.34

(1H, s), 5.28 (1H, d, J¼17.0 Hz), 5.15 (1H, d, J¼10.5 Hz),

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

5657

4.94 (1H, d, J¼16.8 Hz), 4.91 (1H, d, J¼10.5 Hz), 4.51 (1H,

d, J¼12.3 Hz), 4.44 (1H, d, J¼11.3 Hz), 4.42 (1H, d,

J¼12.3 Hz), 4.29 (1H, d, J¼11.3 Hz), 4.15 (1H, dd, J¼10.3,

5.0 Hz), 3.67 (3H, s), 3.65 (4H, m), 3.43–3.24 (5H, m),

3.24–3.14 (2H, m), 3.05 (1H, m), 2.97 (1H, m), 2.38 (1H,

dt, J¼11.8, 4.0 Hz), 2.23 (1H, dt, J¼11.5, 4.5 Hz), 2.05 (2H,

m), 1.77–1.62 (3H, m), 1.58–1.44 (1H, m), 1.54 (1H, q,

J¼11.3 Hz), 1.36 (1H, q, J¼11.3 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 160.02, 138.26, 138.02, 135.91, 134.91, 129.93,

128.36, 128.30, 127.82, 127.74, 127.54, 127.42, 118.24,

117.08, 113.63, 101.46, 83.98, 81.87, 81.77, 81.09, 79.85,

78.93, 76.87, 76.02, 73.45, 72.86, 72.03, 71.24, 69.32,

69.04, 55.27, 39.25, 37.07, 36.56, 26.11, 24.88; MALDI-

TOF-MS, calcd for C₄₃H₅₃O₉[MþH]^þ713.369, found

713.363.

m), 3.20 (1H, m), 2.52 (1H, dt, J¼11.7, 4.5 Hz), 2.45–2.39

(1H, m), 2.41 (3H, s), 2.22 (1H, dt, J¼14.0, 6.5 Hz), 2.13

(1H, dt, J¼14.0, 6.5 Hz), 1.86–1.76 (3H, m), 1.75–1.66

(1H, m), 1.68 (1H, q, J¼11.4 Hz), 1.39 (1H, q, J¼11.3 Hz);

¹³C NMR (125 MHz, CDCl₃) d 160.00, 144.72, 138.21,

137.83, 134.56, 132.92, 129.97, 129.75, 128.39, 128.33,

127.99, 127.82, 127.76, 127.58, 127.43, 117.57, 113.61,

101.42, 83.68, 81.64, 80.45, 80.23, 78.84, 77.93, 73.51,

72.88, 71.65, 71.34, 71.14, 69.28, 69.00, 68.90, 55.27,

39.48, 36.59, 36.16, 26.08, 25.20, 21.62; MALDI-TOF-MS,

calcd for C₄₉H₅₈O₁₂SNa [MþNa]^þ893.354, found

893.276.

To a solution of the above tosylate (98.3 mg, 0.113 mmol)

in DMSO (3 mL) was added sodium cyanide (33.3 mg,

0.679 mmol). After being stirred for 18 h at 508C, the

reaction mixture was quenched with saturated aqueous

NaHCO₃, diluted with EtOAc, washed with brine, dried

over MgSO₄, and concentrated. The residue was subjected

to ﬂash chromatography (hexane/EtOAc¼4/1–3/1) to give

a colorless solid (76.0 mg, 93%):

6.1.27. 6-8-7-6 Ring system 11. To a solution of diene 42

(32.8 mg, 46.0 mmol) in CH₂Cl₂(12 mL) was added

(PCy₃)₂Cl₂RuvCHPh (45, 10.9 mg, 12.2 mmol) in two

portions over 20 h at 358C. The reaction mixture was

quenched with Et₃N (0.16 mL), and concentrated. The

residue was subjected to ﬂash chromatography (hexane/

EtOAc¼8/1–7/1) to give the 6-8-7-6 ring system 11 as a

colorless solid (29.3 mg, 93%): [a]²_D⁴¼þ44.078 (c 1.03,

CHCl₃); IR (ﬁlm) n 2938, 1454, 1365, 1283, 1170, 1028,

nitrile 43 as

[a]²_D³¼243.648 (c 1.22, CHCl₃); IR (ﬁlm) n 2934, 1615,

1518, 1365, 1172, 1029, 927, 830 cm²^{1 1}H NMR

;

(500 MHz, CDCl₃) d 7.32 (2H, d, J¼8.5 Hz), 7.28–7.12

(10H, m), 6.80 (2H, d, J¼8.5 Hz), 5.73 (1H, ddt, J¼14.0,

10.2, 7.0 Hz), 5.38 (1H, s), 5.04 (1H, d, J¼14.0 Hz), 5.01

(1H, d, J¼10.2 Hz), 4.54 (1H, d, J¼12.2 Hz), 4.47 (1H, d,

J¼12.2 Hz), 4.46 (1H, d, J¼11.4 Hz), 4.34 (1H, d,

J¼11.4 Hz), 4.19 (1H, dd, J¼10.3, 4.7 Hz), 3.70 (3H, s),

3.67 (1H, d, J¼10.8 Hz), 3.61–3.53 (2H, m), 3.50 (1H, br),

3.46 (1H, td, J¼6.5, 3.2 Hz), 3.43–3.33 (2H, m), 3.34–3.28

(1H, m), 3.27–3.19 (2H, m), 3.21–3.13 (2H, m), 3.15–3.06

(1H, m), 2.69 (1H, dd, J¼16.7, 3.6 Hz), 2.60 (1H, dd,

J¼16.7, 5.5 Hz), 2.45 (1H, dt, J¼12.0, 4.0 Hz), 2.30 (1H, dt,

J¼11.5, 4.2 Hz), 2.19 (1H, dt, J¼14.0, 6.5 Hz), 2.07 (1H, dt,

J¼14.0, 7.0 Hz), 1.75–1.65 (3H, m), 1.66–1.58 (1H, m),

1.58 (1H, q, J¼11.5 Hz), 1.34 (1H, q, J¼11.0 Hz); ¹³C

NMR (125 MHz, CDCl₃) d 159.99, 138.06, 137.72, 134.26,

129.86, 128.38, 128.31, 127.83, 127.75, 127.73, 127.56,

127.38, 117.85, 117.12, 113.59, 101.42, 83.97, 81.60, 80.65,

80.58, 79.11, 75.54, 74.90, 73.46, 72.84, 71.67, 71.45,

69.22, 68.88, 55.23, 39.55, 36.55, 36.13, 26.09, 25.46,

21.35; MALDI-TOF-MS, calcd for C₄₃H₅₁NO₉Na

[MþNa]^þ748.346, found 748.357.

1

827, 813, 756 cm²¹; H NMR (500 MHz, CDCl₃) d 7.33

(2H, d, J¼8.6 Hz), 7.29–7.12 (10H, m), 6.81 (2H, d,

J¼8.6 Hz), 5.71 (1H, dd, J¼11.0, 4.8 Hz), 5.64 (1H, m),

5.39 (1H, s), 4.56 (1H, d, J¼12.3 Hz), 4.51 (1H, d,

J¼11.5 Hz), 4.48 (1H, d, J¼12.3 Hz), 4.32 (1H, d,

J¼11.2 Hz), 4.18 (1H, dd, J¼11.3, 4.9 Hz), 3.83 (1H, m),

3.72 (3H, s), 3.67 (1H, dd, J¼10.0, 1.2 Hz), 3.62–3.46 (3H,

m), 3.48–3.37 (3H, m), 3.26 (1H, m), 3.24–3.15 (3H, m),

3.13 (1H, m), 2.62 (1H, m), 2.45 (1H, dt, J¼12.0, 4.5 Hz),

2.32 (1H, dt, J¼11.3, 4.0 Hz), 2.32–2.24 (1H, m), 1.96 (1H,

m), 1.89 (1H, m), 1.83–1.71 (2H, m), 1.61 (1H, q,

J¼11.5 Hz), 1.42 (1H, q, J¼11.5 Hz); ¹³C NMR

(125 MHz, CDCl₃) d 160.05, 138.25, 138.05, 133.94,

129.87, 128.35, 128.29, 127.80, 127.68, 127.52, 127.44,

126.24, 113.65, 101.51, 84.22, 81.53, 80.37, 79.72, 79.69,

79.42, 78.29, 73.42, 73.12, 72.05, 70.92, 69.24, 69.03,

55.28, 37.74, 36.62, 32.46, 30.46, 29.33; MALDI-TOF-MS,

calcd for C₄₁H₄₈O₉Na [MþNa]^þ707.319, found 707.330.

6.1.28. Nitrile 43. To a solution of alcohol 41 (29.3 mg,

40.9 mmol) in pyridine (1.5 mL) were added powdered

molecular sieves 4A and p-toluenesulfonyl chloride

(76.4 mg, 0.401 mmol) in four portions. After being stirred

for 3 days, the reaction mixture was quenched with saturated

aqueous NaHCO₃, diluted with EtOAc, washed with brine,

dried over MgSO₄, and concentrated. The residue was

subjected to ﬂash chromatography (hexane/EtOAc¼4/1–3/

1) to give the tosylate as a colorless solid (31.9 mg, 89%):

[a]²_D⁴¼225.028 (c 1.02, CHCl₃); IR (ﬁlm) n 2933, 2870,

6.1.29. Diene 44. A solution of nitrile 43 (60.9 mg,

83.9 mmol) in CH₂Cl₂(3 mL) was treated with DIBAL

(166 mL, 167.8 mmol, 1.01 M in toluene) at 2788C, and the

resultant solution was stirred at 2788C for 1 h. The reaction

mixture was quenched with saturated aqueous NH₄Cl,

allowed to warm to room temperature, and then diluted with

EtOAc. To this mixture was added saturated aqueous

potassium sodium tartrate and the mixture was stirred for

1 h. The solution was extracted with EtOAc, washed with

brine, dried over MgSO₄, and concentrated. The crude

aldehyde was subjected to the next reaction without

puriﬁcation.

1

1615, 1250, 1176, 1095, 978, 931, 829 cm²¹; H NMR

(500 MHz, CDCl₃) d 7.81 (2H, d, J¼8.0 Hz), 7.43 (2H, d,

J¼9.0 Hz), 7.37–7.21 (12H, m), 6.90 (2H, d, J¼8.5 Hz),

5.80 (1H, ddt, J¼17.0, 10.2, 7.0 Hz), 5.50 (1H, s), 5.10 (2H,

m), 4.58 (1H, d, J¼12.0 Hz), 4.56 (1H, d, J¼12.0 Hz), 4.52

(1H, d, J¼12.2 Hz), 4.43 (1H, d, J¼11.3 Hz), 4.30 (1H, dd,

J¼10.3, 4.8 Hz), 3.81 (3H, s), 3.70 (1H, dd, J¼11.0,

1.3 Hz), 3.68 (1H, t, J¼10.3 Hz), 3.62 (1H, dd, J¼11.0,

4.6 Hz), 3.57–3.50 (3H, m), 3.41 (1H, m), 3.38–3.26 (7H,

The aldehyde was dissolved in THF (3 mL) and added to a

suspension of methyltriphenylphosphonium bromide

(299.7 mg, 0.839 mmol) and sodium bis(trimethylsilyl)-

amide (0.67 mL, 1.0 M in THF solution) in THF (3 mL) at

08C. After being stirred for 10 min at 08C, the reaction

5658

M. Inoue et al. / Tetrahedron 59 (2003) 5645–5659

mixture was allowed to warm to room temperature, and

stirred for another 20 min, and then quenched with saturated

aqueous NH₄Cl. The organic layer was extracted with

EtOAc, washed with brine, dried over MgSO₄, and

concentrated. The residue was subjected to ﬂash chroma-

tography (hexane/EtOAc¼9/1–7/1) to give diene 44 as a

colorless solid (45.6 mg, 75% for 2 steps): [a]²_D⁴¼238.548

(c 1.02, CHCl₃); IR (ﬁlm) n 2934, 1639, 1616, 1518, 1249,

1172, 1096, 915, 829 cm²¹; ¹H NMR (500 MHz, CDCl₃) d

7.34 (2H, d, J¼8.5 Hz), 7.29–7.14 (10H, m), 6.81 (2H, d,

J¼8.5 Hz), 5.88 (1H, ddt, J¼16.7, 10.1, 6.7 Hz), 5.73 (1H,

ddt, J¼16.7, 10.2, 6.7 Hz), 5.39 (1H, s), 5.07–4.97 (4H, m),

4.55 (1H, d, J¼12.3 Hz), 4.494 (1H, d, J¼12.3 Hz), 4.486

(1H, d, J¼11.3 Hz), 4.35 (1H, d, J¼11.3 Hz), 4.21 (1H, dd,

J¼10.4, 4.8 Hz), 3.71 (3H, s), 3.67 (1H, dd, J¼10.5,

1.6 Hz), 3.59 (1H, dd, J¼10.4, 5.3 Hz), 3.57 (1H, d,

J¼10.5 Hz), 3.50–3.44 (2H, m), 3.45–3.33 (2H, m),

3.31–3.21 (3H, m), 3.19–3.08 (2H, m), 3.00 (1H, ddd,

J¼10.8, 9.2, 4.5 Hz), 2.51 (1H, m), 2.42 (1H, dt, J¼11.5,

4.4 Hz), 2.30 (1H, dt, J¼11.5, 4.4 Hz), 2.22–2.08 (3H, m),

1.84–1.69 (3H, m), 1.67–1.57 (1H, m), 1.60 (1H, q,

J¼11.5 Hz), 1.34 (1H, q, J¼11.2 Hz); ¹³C NMR (125 MHz,

CDCl₃) d 160.02, 138.43, 138.07, 135.04, 134.70, 129.92,

128.34, 128.27, 127.71, 127.66, 127.45, 127.41, 117.35,

116.70, 113.62, 101.45, 84.12, 81.90, 80.43, 80.27, 80.05,

79.08, 76.84, 75.50, 73.33, 72.87, 72.32, 71.21, 69.30,

69.15, 55.26, 39.50, 36.65, 36.59, 36.12, 26.13, 25.43;

MALDI-TOF-MS, calcd for C₄₄H₅₄O₉Na [MþNa]^þ

749.366, found 749.310.

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(54.4 mg, 74.9 mmol) in CH₂Cl₂(30 mL) was added

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1518, 1495, 1172, 1092, 826, 747 cm²¹

;

¹H NMR

(500 MHz, CDCl₃, 2208C) d 7.44 (2H, d, J¼8.3 Hz),

7.40–7.29 (8H, m), 7.17 (2H, m), 6.92 (2H, d, J¼8.4 Hz),

5.82–5.65 (2H, m), 5.50 (1H, s), 4.65 (1H, d, J¼12.3 Hz),

4.60 (1H, d, J¼11.0 Hz), 4.57 (1H, d, J¼12.3 Hz), 4.34 (1H,

d, J¼11.0 Hz), 4.31 (1H, dd, J¼10.3, 4.6 Hz), 3.82 (3H, s),

3.78–3.65 (3H, m), 3.64–3.48 (3H, m), 3.45–3.36 (2H, m),

3.39–3.24 (3H, m), 3.20 (1H, m), 3.11 (1H, t, J¼9.4 Hz),

2.83–2.69 (2H, m), 2.55 (1H, m), 2.45 (1H, m), 2.38–2.24

(2H, m), 2.06–1.78 (4H, m), 1.72 (1H, q, J¼9.1 Hz), 1.59

(1H, q, J¼9.3 Hz); ¹³C NMR (125 MHz, CDCl₃, 2208C) d

159.79, 137.84, 137.66, 137.42, 129.41, 129.34, 128.68,

128.33, 128.05, 127.94, 127.87, 127.75, 127.67, 127.31,

113.51, 101.48, 101.40, 91.12, 85.14, 85.04, 82.99, 81.39,

80.22, 79.79, 78.35, 73.23, 73.11, 72.29, 71.09, 69.05,

68.52, 55.23, 38.51, 36.56, 36.23, 32.93, 31.63, 28.93,

27.40; MALDI-TOF-MS, calcd for C₄₂H₅₀O₉Na [MþNa]^þ

721.335, found 721.329.

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Acknowledgements

This work was supported in part by a grant from the Takeda

Science Foundation (M. I.).

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Refs. 2,3,4b,c,13b,25.

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