Common synthetic strategy for optically active cyclic terpenoids having a 1,1,5-trimethyl-trans-decalin nucleus: Syntheses of (+)-acuminolide, (-)-spongianolide A, and (+)-scalarenedial

TETRAHEDRON

Pergamon

Tetrahedron 57 .2001) 8425±8442

Common synthetic strategy for optically active cyclic terpenoids

having a 1,1,5-trimethyl-trans-decalin nucleus: syntheses of

ꢀ1)-acuminolide, ꢀ2)-spongianolide A, and ꢀ1)-scalarenedial

²

Noriyuki Furuichi, Toshiyuki Hata, Hartati Soetjipto, Mariko Kato and Shigeo Katsumura^p

School of Science, Kwansei Gakuin University, Uegahara 1-1-155, Nishinomiya 662-8501, Japan

Received 6 July 2001; accepted 6 August 2001

AbstractÐWe have developed a simple and practical method for providing enantiomerically pure bi-, tri-, and tetracyclic frameworks

having a 1,1,5-trimethyl-trans-decalin nucleus, and demonstrated their utility for terpenoid synthesis. Thus, we achieved the stereocontrolled

totalsyntheses of . 1)-acuminolide as a bicyclic, .2)-spongianolide A as a tricyclic, and .1)-scalarenedial as a tetracyclic terpenoid from the

corresponding optically pure cyclic b-ketoesters, which were obtained by repeating the same method of the ring construction, including the

ole®n cyclization with Lewis acid, followed by simple optical resolution using chiral auxiliaries for acetal formation, respectively. This is a

general and valuable strategy for the synthesis of enantiomerically pure cyclic terpenoids having the 1,1,5-trimethyl-trans-decalin nucleus.

1. Introduction

having a 1,1,5-trimethyl-trans-decalin nucleus .Fig. 1).

Some methods for synthesis of optically active terpenoids

having this nucleus have been developed including .1) the

derivation of the commercially available natural terpenoids,

.2)-sclareol⁶or .1)-sclareolide,⁷.2) biological resolution⁸

by an enzyme or microorganism, and .3) enantio- or dia-

stereoselective polyene cyclization.⁹Among them, bio-

mimetic cyclization of polyenes bearing a chiral epoxide

by treatment with Lewis acid or of dl-polyenes with a chiral

Lewis acid are very attractive and ef®cient methods. It

The carbon skeleton consisting of a 1,1,5-trimethyl-trans-

decalin nucleus is found in typical terpenoids such as

drimane sesquiterpene and labdane diterpene, and some of

them have been paid much attention because of their

attractive biological activities represented by warburganal¹

and forskolin.²In addition to these terpenes, acuminolide,³

spongianolide A,⁴and scalarenedial⁵can also be listed as

biologically interesting bi-, tri-, and tetracyclic terpenes

Figure 1. Naturalterpenoids having 1,1,5-trimethy-l trans-decalin nucleus.

Keywords: terpenes and terpenoiods; biologically active compounds; common synthetic strategy; 1,1,5-trimethyl-trans-decalin nucleus.

Corresponding author. Tel.: 181-0798-54-6381, fax: 181-0798-51-0914; e-mail: katumura@kwansei.ac.jp

Present address: Faculty of Science and Mathematics, Satya Wacana Christian University, Diponegoro 52-60, Salatiga 50711, Central Java, Indonesia.

p

²

PII: S0040-4020.01)00825-0

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N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

Figure 2. Synthetic strategy.

seems, however, that there is some limitation to application

of this biomimetic cyclization to the syntheses of a wide

variety of terpenoids having a 1,1,5-trimethyl-trans-decalin

nucleus, because suitable polyene structures for the smooth

cyclization are con®ned, and their synthesis is not

necessarily simple.

P388 cells, and the most potent activity was observed in

melanoma .Me12) .ED₅₀0.7 mg mL²¹) and prostate

.LNCaP) .ED₅₀0.8 mg mL²¹) cells.

.2)-Spongianolide A,⁴which was isolated along with

spongianolide B±F from a marine sponge, Spongia sp., is

a tricyclic sesterterpene, and was reported to inhibit

proliferation of the mammary tumor cell line MCF-7 .IC₅₀

0.5±1.4 mM) and protein kinase C .PKC) .IC₅₀20±30 mM).

Thus, some terpenoids possessing a g-hydroxybutenolide

moiety represented by manoalide, which strongly inhibits

phospholipase A₂.PLA₂),¹⁰and dysidiolide,¹¹which

shows antimitotic activity, as well as in acuminolide and

spongianolide A have been proposed to show quite

attractive biological activities.

Our common strategy to synthesize the enantiomerically

pure bi-, tri-, and tetracyclic skeleton bearing the 1,1,5-

trimethyl-trans-decalin nucleus, is to repeat a sequence of

the reactions for ring construction starting from cyclo-

geraniolvia ilnear b-ketoester formation and then ole®n

cyclization with Lewis acid to yield the corresponding

bicyclic b-ketoester. This method is easily applicable to

the ring construction from the bicyclic to the tricyclic, and

from the tricyclic to the tetracyclic b-ketoesters, with high

stereoselectivity. Furthermore, the cyclic b-ketoesters thus

obtained would be simply resolved by the same procedure

using the same chiralauxiilaries for an acetalformation. In

order to demonstrate the feasibility of this strategy, we

planned to synthesize some biologically interesting di-

and sesterterpenoids, and selected .1)-acuminolide, .2)-

spongianolide A, and .2)-scalarenedial as the target

molecules, which contain a bi-, tri-, and tetracyclic frame-

work and an unsaturated aldehyde function, respectively

.Fig. 2).

.2)-Scalarenedial,⁵which contains a 6/6/6/6 fused ring

system, was isolated from a marine sponge, a specimen of

C. mollor, and shows not only antitumor and anti-

in¯ammatory but also ®sh antifeedant property .LD₅₀

0.77 mg mL²¹in the Artemia salina shrimp bioassay).

.2)-Scalarenedial strongly inhibits the hydrolytic activity

of the hydrolytic enzyme, phospholipase A₂.PLA₂), as

well as manoalide.¹²In connection with our interest in

elucidating the inhibitory mechanism of PLA₂by some

aldehyde terpenoids represented by manoalide¹⁰or

scalaradial,¹²the stereocontrolled simple synthesis of the

enantiomerically pure tetracyclic scalarenedial is also a

very attractive subject. In scalaradial, it was reported that

the presence of a bulky group in the C-12 position, such as

an acetoxy group, might decrease the inhibitory activity

toward PLA₂.⁵

.1)-Acuminolide,³which is a highly oxidized diterpene

possessing a g-hydroxybutenolide function, was isolated

from the stem bark of a tree, Neouvaria acuminatissima,

and its two-dimensionalstructure was determined by

X-ray crystallography, but its absolute con®guration had

not been con®rmed. This terpene was reported to display

cytotoxic activity in human cancer cell lines and cultured

Herein, we report in detail the stereocontrolled total

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8427

Scheme 1.

syntheses of the optically active .1)-acuminolide,¹⁴.2)-

spongianolide A,¹⁵and .1)-scalarenedial,¹⁶and the deter-

mination of the absolute con®gurations of the former two. In

these syntheses, we demonstrate a simple, practical and ef®-

cient common strategy for the synthesis of optically active

cyclic terpenoids bearing the 1,1,5-trimethyl-trans-decalin

nucleus.

cedure, ef®cient transformation of the tricyclic b-ketoester

6 into tetracyclic b-ketoester 9 was successfully realized

through tricyclic allyl alcohol 7 and linear b-ketoester 8.

Initially, we anticipated a low cyclization yield because of

the relatively low solubility of 8 in CH₂Cl₂and the charac-

teristic 6/6/6/6 fused ring system of 9. Quite fortunately, no

serious problems were incurred in the tetracyclic ring

construction, and the tetracyclic 9 was easily obtained in

53% overall yield from 7.

2. Results and discussion

Thus, by using the same ole®n cyclization procedure, we

ef®ciently obtained bi-, tri-, and tetracyclic b-ketoesters 3,

6, and 9 as racemic forms.

2.1. Preparation of the bi-, tri-, and tetracyclic frame-

works by means of Lewis acid-mediated ole®n

cyclization

2.2. Optical resolution for preparation of the enantio-

merically pure cyclic b-ketoesters, and determination of

their absolute con®gurations

As a basic intermediate for the synthesis of cyclic terpenoids

bearing a 1,1,5-trimethyl-trans-decalin nucleus, we chose

racemic bicyclic b-ketoester 3,¹⁷which was simply

prepared from cyclogeraniol 1 by a sequence of bromina-

tion, condensation with the dianion of methylacetoacetate,

and then cyclization by a tin tetrachloride treatment

.Scheme 1). Use of tin tetrachloride in absolute dichloro-

methane substantially improved the yield of the cyclization.

The bicyclic b-ketoester 3 was transformed into bicyclic

allyl alcohol 4 by enolphosphonate formation with sodium

hydride and diethylchlorophosphate, introduction of a

methylgroup with itlhium dimethy-cluprate, and then

lithium aluminum hydride reduction of the ester group in

80% yield for three steps. Next, we applied the same

sequence as that from 1 into 3, to the allyl alcohol 4 and

obtained tricyclic b-ketoester 6 through linear b-ketoester 5

by bromination, b-ketoester formation, and then cycliza-

tion, in 52% yield. Furthermore, by using the same pro-

Resolution of the enantiomers of b-ketoesters 3, 6, and 9

thus synthesized was achieved by utilization of a chiral

auxiliary for acetal formation. We established two effective

resolution methods using the chiral 1,2-diol derivatives,

.2R,3R)-2,3-butanediol. A) and 1,4-di-O-benzyl-l-threitol

.B)¹⁸.Fig. 3).

Reaction of the bicyclic b-ketoester 3 with commercially

Figure 3. Optically active 1,2-diol derivatives as chiral auxiliaries.

8428

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

Scheme 2.

available .A), gave the corresponding acetalas a diastereo-

meric mixture. Unfortunately, these diastereomers were not

easily separated. A mixture of 10a and 10b, which were

obtained by reduction of the ester group, however, was

nicely separated by column chromatography on silica gel

.eluted with hexane containing from 2 to 10% ethyl acetate).

Thereafter, hydrolysis of the acetal by treatment with a

catalytic amount of p-TsOH in acetone and water at

room temperature gave the enantiomerically pure bicyclic

b-ketoalcohol .1)- and .2)-11 without dehydration, respec-

tively .Scheme 2). Fortunately, the same procedure as that

for 3 could be applied to the tricyclic b-ketoester 6

.Scheme 3). Thus, the enantiomerically pure tricyclic

b-ketoalcohol 13 was readily obtained via the correspond-

ing alcohol 12. The absolute con®gurations of 11 and 13

obtained were identicalwith those reported, namely . 2)-11

was .5S,9S,10S)¹⁹and .1)-13 was .5S,8R,9R,10S,14S),²⁰

respectively.

the enantiomerically pure tri-, and tetracyclic b-ketoesters

via the corresponding diols 15 and 16 .Scheme 4).

In order to determine the absolute con®guration of the

respective b-ketoesters, enantiomerically pure .2)-3 was

transformed into a sesquiterpene, albicanol, by a sequence

of Wittig ole®nation and then reduction of the ester group.

The spectraldata of albicanolthus synthesized were in good

agreement with those of .5S,9S,10S)-.1)-albicanol

24

20

.[a]_D110.4 .c 0.55, CHCl₃), literature¹⁹[a]_D113

.c 0.6, CHCl₃)). Thus, the absolute con®guration of .2)-3

was determined as .5S,9R,10S). The opticalrotation vaul es

of tri-, and tetracyclic b-ketoesters 6 and 9 thus resolved

were identicalwith those of the corresponding compounds,

which were derived from .2)-3, respectively. Accordingly,

the absolute con®gurations of .1)-6 and .2)-9 were

determined as .5S,8R,9R,10S,14S) and .5S,8R,9R,10S,13S,

14S,18R), respectively .Scheme 5).

Furthermore, we also tried another route to obtain the

enantiomerically pure cyclic b-ketoesters from the corre-

sponding racemic forms by using the chiralauxiilary . B)

.Scheme 4). Acetalformation of the bicycilc b-ketoester 3

with chiral1,2-diol. B), and then removalof the benzyl

group by hydrogenation produced diol 14. The diastereo-

meric mixture of 14 was also nicely separated by column

chromatography on silica gel .eluted with CHCl₃containing

from 1 to 6% CH₃OH). Then, acid treatment of each of them

gave the enantiomerically pure bicyclic b-ketoesters .1)-,

and .2)-3, respectively. By applying this resolution method

to the tri-, and tetracyclic b-ketoesters 6 and 9, we obtained

Thus, we succeeded in the preparation of enantiomerically

homogeneous cyclic b-ketoesters 3, 6, and 9, and b-keto-

alcohols 11 and 13 via ole®n cyclization and then simple

optical resolution. These compounds would be important as

chiralintermediates for the terpenoid synthesis.

2.3. Total synthesis of a bicyclic diterpene, ꢀ1)- and ꢀ2)-

acuminolide, and determination of its absolute

con®guration

The ®rst synthesis of acuminolide was reported in 1998

by Zoretic and co-workers starting from commercially

Scheme 3.

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8429

Scheme 4.

available .1)-sclareolide.⁷In that synthesis, the regio-

selectivity for the preparation of the desired intermediate

was not controlled, and also the stereoselectivity for the

construction of the C-12 asymmetric center was poor. In

addition, the opticalrotation vaule of the synthesized

acuminolide was not mentioned at all; therefore, the

absolute con®guration of the natural .1)-acuminolide had

not been determined yet.

For the totalsynthesis and determination of the absoulte

con®guration of a bicyclic diterpene, .1)-acuminolide, we

used the .2)-form of the bicyclic b-ketoalcohol 11 as the

starting material, whose absolute con®guration was already

determined as mentioned previously,¹⁹because most natural

terpenoids have S con®guration at the C-10 position. The

b-ketoalcohol .2)-11 was transformed into exomethylene

nitrile 18 by the known procedure;²¹thus, a sequence of

tosylation, cyanation, and then the Wittig reaction with

salt-free triphenylphosphonium methylide gave 18 in 94%

yield for three steps .Scheme 6). DIBAL reduction of 18

yielded the corresponding aldehyde, which was reacted with

3-lithiofuran prepared from 3-bromofuran and sec-BuLi in

Scheme 5. Determination of the absolute con®guration of b-ketoesters 3, 6,

and 9.

Scheme 6.

8430

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

Scheme 7.

situ at 2788C, to produce secondary alcohol 19 in 91% yield

for two steps as a mixture of diastereomers. Although the

diastereomers of 19 were narrowly distinguishable by TLC,

it could be used in the next oxidation without further

puri®cation. Although the oxidation of 19 with BaMnO₂,²²

MnO₂, PCC, PDC, and activated DMSO gave a poor

yield of the desired ketone 20, it was obtained in high

yield by the oxidation with Dess±Martin periodinane.²³

The exomethylene group of 20 was oxidized with osmium

tetraoxide to produce the corresponding diolas a singel

stereoisomer. The stereochemistry of the C-8 hydroxy

group was tentatively assigned as a, because the attack of

OsO₄from the b face would be prevented by the presence of

the axialmethylgroup at the C-10 position. Protection of the

primary hydroxy group of the diolwith a tert-butyl-

dimethylsilyl group afforded ketone 21. Then, the diastereo-

selective reduction of the carbonyl group of 21 was

examined .Scheme 7). Reduction with sodium borohydride

effected no stereoselectivity, and the obtained diols were

unstable in silica gel column chromatography. Reduction

of 21 with DIBAL followed by acid treatment gave 23 as

a major product in the ratio of 5:1 by ¹H NMR in 40% yield,

while L-Selectride^wreduction followed by acid treatment

produced cyclic ether 22 along with its C-12 stereoisomer

The synthesis of acuminolide was achieved by photo-

sensitized oxygenation of 22 in the presence of a catalytic

amount of tetraphenylporphine .TPP) and excess amount of

diisopropylethylamine in CH₂Cl₂at 2788C in 75% yield

.Scheme 7).^3,24The spectraldata and metling point of the

synthesized acuminolide were in good agreement with those

of the naturalproduct. ³However, to our surprise, the sign of

23

the opticalrotation vaule showed a minus .[ a]_D233.2

20

.c 1.25, CHCl₃)), which is contrary to that of the natural

acuminolide .[a]_D136.2 .c 1.34, CHCl₃)). Thus, the

synthesized acuminolide was the antipode of natural .1)-

acuminolide.

We synthesized .1)-acuminolide starting from .1)-11 by

the same procedure. The physicaland spectraldata, includ-

22

ing the opticalrotation vaule .[ a]_D134.6 .c 0.85,

CHCl₃)) of the synthesized acuminolide, were in good

agreement with those reported.³Furthermore, the melting

point of a mixture of synthesized .1)-acuminolide .mp

207.5±208.58C) and naturalacuminoilde .mp 207±208 8C)

showed no decrease. Thus, the absolute con®guration of the

.1)-acuminolide was determined as .5R,8S,9S,10R,12R),

which is ent-form against the usuaallbdane diterpene.

Thus, we achieved the stereoselective total synthesis of

natural. 1)-acuminolide and determination of the absolute

con®guration by the present synthesis.¹⁴

1

23 in the ratio of 15:1 by H NMR, in 80% yield. The

diastereomers of the alcohol resulting from the reduction

of 21 were not distinguishable from one another by TLC.

Tosylation of the crude alcohol with p-TsClin pyridine

followed by treatment of tetra-n-butylammonium ¯uoride

gave the same result as that of the acid treatment; hence,

we assumed that the reduction stereoselectively proceeded

to exclusively produce the .12R)-stereoisomer 24

.Scheme 8).

2.4. Total synthesis of a tricyclic sesterterpene, ꢀ2)-

spongianolide A, and determination of its absolute

con®guration

Synthesis of tricyclic sesterterpene, .2)-spongianolide A,

had not been reported and its absolute con®guration had

Scheme 8.

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8431

Scheme 9.

not been determined yet. In our synthetic study of this

tricyclic sesterterpene, ®rst, we started the synthesis from

the optically pure tricyclic b-ketoalcohol .1)-13 .Scheme

3). However, transformation from 13 into the corresponding

exomethylene compound by the Wittig reaction with tri-

phenylphosphonium methylide unfortunately proceeded

only in poor yield. Then, we adopted the enantiomerically

pure tricyclic b-ketoester .1)-6 as the starting material

.Scheme 9).

protection of the hydroxy group of 25 with a tert-butyl-

dimethylsilyl group, oxidation of the exomethylene moiety

with osmium tetraoxide stereoselectively produced the

corresponding diol 26 as a single isomer, the diol moiety

of which was protected by an acetonide formation with 2,2-

dimethoxypropane, and then tetra-n-butylammonium

¯uoride treatment followed by Swern oxidation of the

resulting hydroxy group produced aldehyde 28 in excellent

yield.

The Wittig reaction of the b-ketoester .1)-6 with the crude

solution of triphenylphosphonium methylide under the

coexisting metalsatl for 3 h caused severe epimerization

at the C-14 position .14a:14b1:4). However, the desired

exomethylene compound was obtained stereoselectively

.14a:14b1:11) within 30 min by using excess salt-free

Wittig ylide. The exomethylene compound thus obtained

was followed by reduction with lithium aluminum hydride

to yield alcohol 25. The C-14 stereoisomer was easily

separated by column chromatography on silica gel. After

Elongation of the ®ve-carbon unit containing the g-hy-

droxybutenolide moiety was ef®ciently achieved by our

own method utilizing the Wittig reagent, 2-trimethylsilyl-

4-furyltriphenylphosphonium methylide .W^p),²⁵followed

by photosensitized oxygenation.²⁶Thus, reaction of alde-

hyde 28 with furanmethylide .W^p), which was prepared

from the Wittig salt .W) by treatment with n-BuLi in dry

THF, nicely produced conjugated furan 29 in 86% yield as a

single geometrical isomer .Scheme 10). Photosensitized

oxygenation of silylfuran 29 chemoselectively proceeded

Scheme 10.

8432

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

Scheme 11.

and the corresponding g-hydroxybutenolide was regio-

speci®cally generated to produce 30 as a 1:1 mixture of

stereoisomers at the hydroxy group in the butenolide ring.

NMR of our synthesized 34, the chemicalshifts of 23 peaks

of the 24 signals were in good agreement with those

reported, and the signalat 127.5 ppm of our compound

was different from that reported at 141.6 ppm.²⁷Our synthe-

sized diol 34 was transformed into lactone 35 by using

MnO₂oxidation .Scheme 12). In this case, all of the

spectraldata of 35 thus obtained were in good agreement

with those reported. Consequently, the formal synthesis of

.1)-scalarenedial was thus achieved.¹⁶

Synthesis of spongianolide A was achieved by treatment of

30 with acid to yield 31, which was followed by acetylation

and then chemoselective hydrolysis of the acetyl group in

the butenolide moiety by treatment with aqueous sodium

hydrogen carbonate in methanol. The spectral and physical

data of the synthesized spongianolide A were in good

agreement with those reported [mp 224.5±225.58C,

[a]_D231.2 .c 0.58, CH₃OH), literature,⁴[a]_D231.9

24

.c 1.4, CH₃OH)]. Thus, we achieved the ®rst synthesis of

.2)-spongianolide A and also determined its absolute

con®guration as .5S,8R,9R,10S,13S,14S) by the present

synthesis.¹⁵

Scheme 12.

2.5. Formal synthesis of a tetracyclic sesterterpene, ꢀ1)-

scalarenedial

3. Conclusion

As a demonstration of our method for the construction of a

characteristic 6/6/6/6 fused ring system and in connection

with our interest in elucidating the inhibitory mechanism of

PLA₂by some unsaturated aldehyde terpenoids,¹³we under-

took a synthetic study of .1)-scalarenedial .Scheme 11).

The synthesis of .2)-scalarenedial was reported in 1997

by Corey's group via a biomimetic route involving the

enantiospeci®c tetracyclization reaction.²⁷

We have established a simple and practical method for

providing enantiomerically pure bi-, tri-, and tetracyclic

frameworks having a 1,1,5-trimethyl-trans-decalin nucleus,

and demonstrated their utility for terpenoid synthesis. Thus,

we achieved the stereocontrolled total or formal syntheses

of .1)-, and .2)-acuminolide as a bicyclic, .2)-spongiano-

lide A as a tricyclic, and .1)-scalarenedial as a tetracyclic

terpene from the corresponding optically pure bi-, tri-, and

tetracyclic b-ketoesters or b-ketoalcohols, which were

obtained by repeating the same method for the ring

construction and the simple optical resolution. A widely

applicable and ef®cient method for the synthesis of optically

active cyclic terpenoids having a 1,1,5-trimethyl-trans-

decalin nucleus was thus established.

The Wittig ole®nation of .1)-9 with excess triphenyl-

phosphonium methylide at room temperature for 10 min,

followed by reduction of the ester group successfully

produced alcohol 32. Use of one equivalent of the Wittig

reagent required longer reaction time, and caused severe

isomerization of the ester group. Epoxidation of the

exomethylene moiety in 32 with m-chloroperbenzoic acid

stereoselectively produced the corresponding epoxide 33 as

a single isomer. Among various trials to open the epoxide

ring in 33 into the corresponding allyl alcohol, camphor-

sulfonic acid treatment in THF±water at 808C successfully

yielded the desired diol 34 in 53% yield, the enantiomer of

which was transformed into .2)-scalarenedial by Corey's

group.²⁷The melting point and ¹H NMR of thus-synthesized

34 were in good agreement with those reported. In the ¹³C

4. Experimental

4.1. General

All commercially available reagents were used without

further puri®cation. All solvents were used after distillation.

Tetrahydrofuran .THF), diethylether, benzene and toul ene

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8433

were re¯uxed over and distilled from sodium. Dichloro-

methane was re¯uxed over and distilled from CaH₂.

Dimethylformamide .DMF) and dimethyl sulfoxide

.DMSO) were distilled from CaH₂under reduced pressure.

Methanol was re¯uxed over and distilled from magnesium.

Triethylamine, diisopropylamine and diisopropylethyl-

amine were re¯uxed over and distilled from KOH. Prepara-

tive separation was usually performed by column chromato-

graphy on silica gel .FUJI silysia Ltd., BW-200). IR spectra

were recorded on a JASCO FT/IR-8000 MCT-5E spectro-

1 h, and diethylchlorophosphonate .7.5 mL, 52 mmol) was

added dropwise at 08C. After the reaction mixture was stir-

red at room temperature for an additional10 min, water was

added at this temperature, and then the resulting mixture

was extracted with ethylacetate. The organic alyers were

combined, washed with water, brine, dried over MgSO₄,

®ltered and concentrated in vacuo, to give the corresponding

enolphosphonate, which was used without further puri®ca-

tion.

1

meter. H- and ¹³C NMR spectra were recorded at JEOL

To a suspension of copper iodide .15.5 g, 80 mmol) in

diethylether .100 mL) was added methylilthium .1.5 M

in diethylether, 107 mL, 160 mmo)l at 2508C. After the

mixture was stirred at 2408C for 10 min, a solution of the

crude enolphosphonate in diethylether .10 mL) was added

dropwise at 2508C. After the reaction mixture was stirred at

08C for 1 h, water was added, and the resulting mixture was

®ltered through a pad of Celite, and then the ®ltrate was

extracted with diethylether. The organic alyers were

combined, washed with a saturated aqueous NH₄Clsolution,

brine, dried over MgSO₄, ®ltered and concentrated in vacuo

to give the corresponding methylester, which was used with-

out further puri®cation.

a-400 spectrometer and chemicalshifts were represented

as d values relative to the internal standard TMS. Melting

points were uncorrected.

4.2. Common procedure to prepare bicyclic ꢀ3), tricyclic

ꢀ6) and tetracyclic b-ketoesters ꢀ9)

To a solution of allyl alcohol 1, 4 or 7 .32 mmol) and

pyridine .2.05 mL, 25 mmol) in diethyl ether .100 mL)

was added phosphorus tribromide .3.6 mL, 38 mmol) at

08C. After the reaction mixture was stirred at room tempera-

ture for 1 h, ice chips were added, and then the resulting

mixture was extracted with diethylether. The organic layers

were combined, washed with water, brine, dried over

MgSO₄, ®ltered and concentrated in vacuo to give the

corresponding bromide, which was used without further

puri®cation.

To a suspension of lithium aluminum hydride .3.1 g,

80 mmol) in diethyl ether .100 mL) was added dropwise a

solution of the crude methylester in diethyl ether .10 mL) at

08C. After the reaction mixture was stirred at room tempera-

ture for 12 h, water was added, and the precipitate was

®ltered through a pad of Celite, and then the ®ltrate was

concentrated in vacuo. Puri®cation by silica gel column

chromatography .from 3 to 10% ethylacetate in hexane)

gave the corresponding allyl alcohol 4 or 7 .80±89% for 3

steps).

To a suspension of sodium hydride .1.9 g, 48 mmol, 60% in

mineraloi)l in THF .100 mL) was added methylaceto-

acetate .4.4 mL, 41 mmol) at 08C. After the reaction

mixture was stirred at the same temperature for 10 min,

n-BuLi .1.5 M in hexane, 32 mL, 48 mmol) was added

dropwise. After the reaction mixture was stirred for an addi-

tional10 min, a soultion of the crude bromide in THF

.10 mL) was added at the same temperature. After the

resulting mixture was stirred at room temperature for 1 h,

ice chips were added, and then the resulting mixture was

extracted with diethylether. The organic alyers were

combined, washed with a saturated aqueous NH₄Clsolution,

brine, dried over mgSO₄, ®ltered and concentrated in vacuo

to give the corresponding linear b-ketoester 2, 5 or 8, which

was used without further puri®cation.

4.2.1. ꢀ4aS^p,8aS^p)-3,4,4a,5,6,7,8,8a-Octahydro-2,5,5,8a-

tetra-methyl-trans-naphthalene-1-methanol ꢀdl-4). Mp

1

90.0±91.08C; IR .KBr, cm²¹) 3368, 1458, 1435, 1375; H

NMR .400 MHz, CDCl₃) d 4.20 .d, 1H, J11.6 Hz), 4.04

.d, 1H, J11.6 Hz), 2.07 .m, 2H), 1.89 .m, 1H), 1.72 .s,

3H), 1.56 .m, 5H), 1.20 .m, 3H), 0.96 .s, 3H), 0.89 .s, 3H),

0.84 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 140.91,

132.43, 77.19, 58.27, 51.64, 41.62, 38.00, 36.75, 33.64,

33.22, 21.54, 20.64, 19.26, 18.90, 18.83; FAB¹HRMS

Found m/z 222.1983, Calcd for C₁₅H₂₆O M¹222.1984.

To a solution of crude linear b-ketoester 5 or 8 in dichloro-

methane .100 mL) was added tin tetrachloride .6.3 mL,

54 mmol) at 2108C. After being stirred at the same

temperature for 30 min, the reaction mixture was warmed

to room temperature, and stirred for an additional20 h. The

reaction mixture was poured into a 2N aqueous HClsoul -

tion, and then extracted with ethylacetate. The organic

layers were combined, washed with brine, dried over

mgSO₄, ®ltered and concentrated in vacuo. Puri®cation by

silica gel column chromatography .from 2 to 20% ethyl

acetate in hexane) followed by recrystallization from ethyl

acetate±hexane gave the corresponding cyclic b-ketoester

3, 6 or 9 .52±75% for 3 steps).

4.2.2. ꢀ1R^p,4aS^p,4bR^p,8aR^p,10aS^p)-3,4,4a,4b,5,6,7,8,8a,9,

10,10a-Dodecahydro-1-methoxycarbonyl-4b,8,8,10a-

tetra-methyl-trans-anti-trans-phenanthrene-2ꢀ1H)-one

ꢀdl-6). Mp 150.0±151.08C; IR .KBr, cm²¹) 1746, 1714; ¹H

NMR .400 MHz, CDCl₃) d 3.68 .s, 3H), 3.24 .s, 1H), 2.48

.ddd, 1H, J14.6, 5.6, 2.0 Hz), 2.31 .dddd, 1H, J14.6,

12.9, 7.6, 1.0 Hz), 2.00 .m, 1H), 1.70 .m, 5H), 1.40 .m,

5H), 1.17 .s, 3H), 0.94 .s, 3H), 0.90 .s, 3H), 0.88 .s, 3H),

0.83 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 205.60,

168.59, 69.98, 57.86, 56.61, 51.42, 42.57, 41.84, 40.81,

40.35, 40.10, 37.95, 33.38, 33.22, 21.91, 21.49, 18.42,

16.05, 15.43; Anal. found: C, 75.00; H, 10.09%. Calcd for

C₂₀H₃₂O₃: C, 74.96; H, 10.06%.

To a suspension of sodium hydride .1.75 g, 44 mmol, 60%

in mineral oil) in THF .120 mL) was added a solution of

cyclic b-ketoester 3 or 6 .40 mmol) in THF .10 mL) at 08C.

The reaction mixture was stirred at room temperature for

4.2.3. ꢀ4aS^p,4bR^p,8aR^p,10aS^p)-3,4,4a,4b,5,6,7,8,8a,9,10,

10a-Dodecahydro-4b,8,8,10a-tetramethyl-trans-anti-trans-

phenanthrene-1-methanol ꢀdl-7). Mp 127.0±129.08C; IR

8434

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

.KBr, cm²¹) 3380, 2926, 2361, 2344, 1460, 1387; ¹H NMR

.400 MHz, CDCl₃) d 4.18 .d, 1H, J11.5 Hz), 4.04 .d, 1H,

J11.5 Hz), 2.04 .m, 2H), 1.97 .m, 1H), 1.71 .m, 3H), 1.61

.m, 2H), 1.39 .m, 5H), 1.11 .m, 3H), 0.97 .s, 3H), 0.85 .s,

6H), 0.82 .s, 3H), 0.81 .s, 3H); ¹³C NMR .100 MHz, CDCl₃)

d 140.97, 132.28, 58.14, 56.42, 56.35, 42.11, 39.67, 38.28,

37.36, 34.01, 33.26, 21.73, 21.32, 19.16, 18.63, 18.59,

17.71, 16.37; FAB¹HRMS Found m/z 290.2598, Calcd

for C₂₀H₃₄O M¹290.2609.

4.3.1. ꢀ1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-Decahydro-5,5,8a-

tri-methyl-2-oxo-trans-naphthalene-1-methanol-2-

[ꢀꢀ1R,2R)-dimethyl)ethylene acetal] ꢀ10a) ꢀslower

24

moving diastereomer). Mp 122.5±123.08C; [a]_D

215.9 .c 1.00, CHCl₃); IR .KBr, cm²¹) 3517, 1146, 1115,

1084, 1020; H NMR .400 MHz, CDCl₃) d 3.91 .dd, 1H,

1

J10.8, 7.2 Hz), 3.80 .m, 1H), 3.63 .m, 1H), 3.55 .m, 1H),

3.00 .d, 1H, J8.4 Hz), 1.93 .m, 1H), 1.82 .m, 1H), 1.30 .d,

3H, J6.1 Hz), 1.23 .d, 3H, J6.1 Hz), 1.0±1.7 .m, 9H),

0.87 .s, 3H), 0.86 .s, 3H), 0.81 .s, 3H); ¹³C NMR .100 MHz,

CDCl₃) d 111.83, 77.88, 77.78, 59.67, 58.84, 54.97, 41.86,

39.49, 38.41, 37.67, 33.65, 33.24, 21.66, 20.07, 18.59,

18.37, 16.46, 15.68; Anal. found: C, 72.72; H, 10.90%.

Calcd for C₁₈H₃₁O₃: C, 72.91; H, 10.89%.

4.2.4. ꢀ1R^p,4aS^p,4bR^p,6aS^p,10aS^p,10bR^p,12aS^p)-3,4,4a,4b,

5,6,6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-1-

metho-xycarbonyl-4b,7,7,10a,12a-pentamethyl-trans]-

anti-trans-anti-trans-chrysene-2ꢀ1H)-one ꢀdl-9). Mp

207.0±208.08C; IR .KBr, cm²¹) 1746, 1719; ¹H NMR

.400 MHz, CDCl₃) d 3.68 .s, 3H), 3.21 .s, 1H), 2.47 .ddd,

1H, J14.6, 5.2, 1.7 Hz), 2.29 .m, 1H), 1.98 .m, 1H), 0.70±

1.85 .m, 18H), 1.16 .s, 3H), 0.90 .s, 3H), 0.86 .s, 3H), 0.83

.s, 3H), 0.81 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 205.57,

168.59, 70.02, 61.20, 58.32, 56.55, 51.41, 42.40, 42.05,

41.99, 40.87, 40.49, 39.90, 38.28, 37.50, 33.27, 21.85,

21.30, 18.59, 18.19, 17.26, 17.22, 16.31, 15.35; Anal.

found: C, 77.19; H, 10.43%. Calcd for C₂₅H₄₀O₃: C,

77.27; H, 10.37%.

4.3.2. ꢀ1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-Decahydro-5,5,

8a-tri-methyl-2-oxo-trans-naphthalene-1-methanol-2-

[ꢀꢀ1R,2R)-dimethyl) ethylene acetal] ꢀ10b) ꢀfaster moving

24

diastereomer). Mp 78.5±79.58C; [a]_D24.18 .c 1.03,

CHCl₃); IR .KBr, cm²¹) 3551, 1188, 1157, 1123, 1092,

1032; ¹H NMR .400 MHz, CDCl₃) d 3.82 .ddd, 1H,

J11.2, 8.4, 0.8 Hz), 3.73 .m, 2H), 3.61 .m, 1H), 3.25 .d,

1H, J10.0 Hz), 1.96 .m, 1H), 1.82 .m, 1H), 1.29 .d, 3H,

J2.0 Hz), 1.27 .d, 3H, J2.0 Hz), 1.0±1.7 .m, 9H), 0.88

.s, 3H), 0.84 .s, 3H), 0.82 .s, 3H); ¹³C NMR .100 MHz,

CDCl₃) d 111.83, 81.03, 76.36, 59.35, 58.87, 55.05,

41.82, 39.53, 38.94, 38.34, 33.71, 33.29, 21.78, 20.07,

19.31, 18.61, 18.59, 16.51, 15.54; Anal. found: C, 72.84;

H, 10.92%. Calcd for C₁₈H₃₂O₃: C, 72.93; H, 10.88%.

4.3. General procedure for the optical resolution using

the chiral auxiliary ꢀA)

To a solution of b-ketoester 3 or 6 .10 mmol) in benzene

.50 mL) was added .2R,3R)-.2)-2,3-butanediol. A) .1.0 g,

11 mmol) and a catalytic amount of p-toluenesulfonic acid.

After the reaction mixture was stirred under re¯ux condition

for 2 h, a saturated aqueous NaHCO₃solution was added,

and then the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with

brine, dried over MgSO₄, ®ltered and concentrated in

vacuo to give the corresponding acetal, which was used

without further puri®cation.

4.3.3. ꢀ1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-Decahydro-5,5,8a-

tri-methyl-2-oxo-trans-naphthalene-1-methanol

ꢀꢀ2)-

11).¹⁹Mp 68.0±69.08C; [a]_D238.3 .c 0.99, CHCl₃);

IR .KBr, cm²¹) 3262, 1709, 1146, 1046; ¹H NMR

.400 MHz, CDCl₃) d 3.96 .dd, 1H, J11.2, 9.5 Hz), 3.60

.brd, 1H, J10.7 Hz), 2.47 .ddd, 1H, J14.4, 5.1, 2.0 Hz),

2.32 .m, 2H,), 2.05 .m, 1H), 1.69 .m, 2H), 1.50 .m, 4H),

1.28 .m, 2H), 0.98 .s, 3H), 0.87 .s, 3H), 0.81 .s, 3H); ¹³C

NMR .100 MHz, CDCl₃) d 214.77, 65.33, 57.72, 53.45,

42.01, 41.66, 41.09, 39.02, 33.53, 23.23, 21.76, 18.73,

15.82.

24

To a suspension of lithium aluminum hydride .700 mg,

18.5 mmol) in diethyl ether .40 mL) was added dropwise

a solution of the crude acetal in diethyl ether .5 mL) at 08C.

After the reaction mixture was stirred at room temperature

for 12 h, water was added, and the precipitate was ®ltered

through a pad of Celite, and then the ®ltrate was concen-

trated in vacuo to give crude methylester .80±94% for 2

steps). Puri®cation by silica gel column chromatography

.from 2 to 10% ethylacetate in hexane) gave acetal 10a

and its diastereomer 10b, or 12a and its diastereomer 12b,

respectively.

4.3.4. ꢀ1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-Decahydro-5,5,8a-

ꢀꢀ1)-

tri-methyl-2-oxo-trans-naphthalene-1-methanol

24

11). Mp 67.5±68.58C; [a]_D138.5 .c 1.00, CHCl₃).

4.3.5. ꢀ1R,4aS,4bR,8aR,10aS)-1,2,3,4,4a,4b,5,6,7,8,8a,9,

10,10a-Tetradecahydro-4b,8,8,10a-tetramethyl-2-oxo-

trans-anti-trans-phenanthrene-1-methanol-2-[ꢀ1R,2R)-

dimethylethylene acetal] ꢀ12a) ꢀfaster moving diastereo-

23

mer). Mp 140.0±140.58C; [a]_D24.45 .c 1.00, CHCl₃);

IR .KBr, cm²¹) 3536, 2936, 2876, 2856, 1142, 1086, 1022;

¹H NMR .400 MHz, CDCl₃) d 3.81 .dd, 1H, J10.4,

8.4 Hz), 3.72 .m, 2H), 3.60 .ddd, 1H, J10.8, 10.8,

1.6 Hz), 3.25 .d, 1H, J10.4 Hz), 1.88 .m, 2H), 1.60 .m,

5H), 1.40 .m, 3H), 1.28 .d, 3H, J5.6 Hz), 1.27 .d, 3H,

J5.6 Hz), 1.26 .m, 1H), 1.14 .m, 1H), 0.85 .s, 3H), 0.85

.m, 4H), 0.83 .s, 3H), 0.82 .s, 3H), 0.80 .s, 3H); ¹³C NMR

.100 MHz, CDCl₃) d 111.70, 81.00, 76.38, 59.70, 59.25,

59.21, 56.40, 42.00, 41.15, 40.12, 38.83, 38.68, 37.55,

33.26, 21.33, 18.60, 18.32, 18.11, 16.84, 16.51, 16.45;

Anal. found: C, 75.90; H, 11.10%. Calcd for C₂₃H₄₀O₃: C,

75.78; H, 11.06%.

To a solution of the acetal .3.4 mmol) in acetone .30 mL)

was added a catalytic amount of p-toluenesulfonic acid and

water at room temperature. After the reaction mixture was

stirred for 12 h, a saturated aqueous NaHCO₃solution was

added, and then the resulting mixture was extracted with

ethylacetate. The organic alyers were combined, washed

with brine, dried over MgSO₄, ®ltered and concentrated in

vacuo. Puri®cation by silica gel column chromatography

.from 10 to 30% ethyl acetate in hexane) followed by

recrystallization from ethyl acetate±hexane gave the

corresponding optically active b-ketoalcohol 11 or 13

.89±100%).

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8435

4.3.6. ꢀ1S,4aR,4bS,8aS,10aR)-1,2,3,4,4a,4b,5,6,7,8,8a,9,

10,10a-Tetradecahydro-4b,8,8,10a-tetramethyl-2-oxo-

trans-anti-trans-phenanthrene-1-methanol-2-[ꢀ1R,2R)-

dimethylethylene acetal] ꢀ12b) ꢀslower moving diastereo-

NaHCO₃solution was added, and then the resulting mixture

was extracted with ethylacetate. The organic alyers were

combined, washed with brine, dried over MgSO₄, ®ltered

and concentrated in vacuo. Puri®cation by silica gel column

chromatography .from 10 to 30% ethylacetate in hexane)

followed by recrystallization from ethyl acetate±hexane

gave the corresponding optically active b-ketoester 3, 6,

or 9 .74±80%).

24

mer). Mp 207.5±208.08C; [a]_D29.20 .c 0.08, CHCl₃);

IR .KBr, cm²¹) 3512, 2968, 2940, 2852, 1142, 1076, 1020,

1000; ¹H NMR .400 MHz, CDCl₃) d 3.89 .ddd, 1H, J10.8,

7.6, 2.0 Hz), 3.78 .dq, 1H, J8.4, 6.0 Hz), 3.62 .ddd, 1H,

J9.6, 9.6, 1.6 Hz), 3.54 .dq, 1H, J8.4, 6.0 Hz), 3.00 .dd,

1H, J9.6, 1.6 Hz), 1.90 .m, 2H), 1.60 .m, 5H), 1.42 .m,

11H), 1.29 .d, 3H, J6.0 Hz), 1.22 .d, 3H, J6.0 Hz), 1.26

.m, 1H), 0.85 .s, 6H), 0.83 .m, 4H), 0.81 .s, 3H), 0.80 .s,

3H); ¹³C NMR .100 MHz, CDCl₃) d 111.70, 77.86, 77.77,

59.96, 59.58, 58.73, 56.44, 42.00, 41.09, 40.08, 38.74,

37.55, 37.50, 34.95, 33.27, 21.34, 18.87, 18.58, 18.34,

16.95, 16.44, 16.33; Anal. found: C, 75.87; H, 11.07%.

Calcd for C₂₃H₄₀O₃: C, 75.78; H, 11.06%.

4.4.1. ꢀ1R,4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-1-meth-

oxy-carbonyl-5,5,8a-trimethyl-trans-naphthalene-2ꢀ1H)-

one-2-[ꢀꢀ1S,2S)-diꢀhydroxymethyl))ethylene acetal] ꢀ14a)

ꢀslower moving diastereomer). Mp 123.0±124.08C;

[a]_D110.4 .c 1.18, CHCl₃); IR .KBr, cm²¹) 3476,

21

3447, 3285, 1716, 1207, 1155, 1126, 1034; ¹H NMR

.400 MHz, CDCl₃) d 4.09 .ddd, 1H, J8.8, 4.4, 3.6 Hz),

4.00 .ddd, 1H, J8.8, 4.9, 4.0 Hz), 3.81 .dd, 1H, J12.0,

3.6 Hz), 3.73 .dd, 1H, J11.6, 4.0 Hz), 3.66 .dd, 1H,

J12.0, 3.6 Hz), 3.64 .s, 3H), 3.62 .dd, 1H, J12.0,

4.0 Hz), 2.49 .s, 1H), 1.91 .dd, 1H, J9.0, 3.0 Hz), 1.52

.m, 6H), 1.21 .m, 3H), 1.18 .m, 3H), 0.91 .m, 1H), 0.89

.s, 3H), 0.86 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 171.82,

109.51, 79.15, 76.38, 63.09, 61.87, 61.63, 54.89, 51.09,

41.80, 39.91, 39.63, 39.19, 33.58, 33.19, 21.60, 19.64,

18.31, 14.88; Anal. found: C, 64.19; H, 9.11%. Calcd for

C₁₉H₃₂O₆: C, 64.02; H, 9.05%.

4.3.7. ꢀ1R,4aS,4bR,8aR,10aS)-1,2,3,4,4a,4b,5,6,7,8,8a,9,

10,10a-Tetradecahydro-4b,8,8,10a-tetramethyl-2-oxo-

trans-anti-trans-phenanthrene-1-methanol

ꢀꢀ1)-13).²⁰

24

Mp 136.0±137.08C; [a]_D125.9 .c 1.12, CHCl₃); IR

.KBr, cm²¹) 3404, 1716, 1378, 1030; H NMR .400 MHz,

1

CDCl₃) d 3.97 .ddd, 1H, J11.4, 9.6, 4.0 Hz), 3.58 .ddd,

1H, J11.2, 10.2, 3.6 Hz), 2.48 .dd, 1H, J10.4, 4.4 Hz),

2.44 .ddd, 1H, J14.0, 5.2, 2.0 Hz), 2.30 .m, 1H), 2.01 .m, 1H),

1.68 .m, 5H), 1.31 .m, 6H), 0.90 .m, 2H), 0.89 .s, 3H), 0.87 .s,

3H), 0.82 .s, 6H); ¹³C NMR .100 MHz, CDCl₃) d 214.68,

65.56, 58.19, 57.62, 56.28, 41.81, 41.73, 41.62, 40.50, 40.11,

37.94, 33.33, 33.19, 22.11, 21.46, 18.55, 18.45, 16.67, 16.18.

4.4.2. ꢀ1S,4aR,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-1-meth-

oxy-carbonyl-5,5,8a-trimethyl-trans-naphthalene-2ꢀ1H)-

one-2-[ꢀꢀ1S,2S)-diꢀhydroxymethyl)) ethylene acetal]

ꢀ14b) ꢀfaster moving diastereomer). Mp 127.0±127.58C;

24

[a]_D228.1 .c 1.18, CHCl₃); IR .KBr, cm²¹) 3500, 3440,

4.3.8. ꢀ1S,4aR,4bS,8aS,10aR)-1,2,3,4,4a,4b,5,6,7,8,8a,9,

10,10a-Tetradecahydro-4b,8,8,10a-tetramethyl-2-oxo-

trans-anti-trans-phenanthrene-1-methanol ꢀꢀ2)-13). Mp

3328, 3000, 1716, 1212, 1154, 1076, 1052; ¹H NMR

.400 MHz, CDCl₃) d 4.12 .ddd, 1H, J8.6, 2.4, 0.8 Hz),

4.07 .ddd, 1H, J12.4, 2.4, 0.8 Hz), 4.03 .ddd, 1H, J8.4,

3.6, 3.6 Hz), 3.88 .d, 1H, J10.4 Hz), 3.78 .ddd, 1H,

J10.4, 4.8, 3.6 Hz), 3.66 .s, 3H), 3.55 .m, 1H), 2.53 .s,

1H), 1.96 .dd, 1H, J8.0, 4.8 Hz), 1.90 .ddd, 1H, J12.8,

3.2, 3.2 Hz), 1.54 .m, 5H), 1.24 .m, 3H), 1.17 .s, 3H), 0.89

.s, 3H), 0.85 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 172.23,

109.14, 77.60, 75.50, 62.90, 61.60, 59.79, 54.47, 51.44,

41.80, 39.90, 39.31, 38.25, 33.50, 33.19, 21.45, 20.11,

18.36; Anal. found: C, 64.28; H, 9.08%. Calcd for

C₁₉H₃₂O₆: C, 64.02; H, 9.05%.

24

131.5±133.0a8C; [a]_D225.9 .c 1.30 CHCl₃).

4.4. General procedure for the optical resolution using

the chiral auxiliary ꢀB)

To a solution of b-ketoester 3, 6, or 9 .24 mmol) in benzene

.100 mL) was added 1,4-di-O-benzyl-l-threitol. B) .7.9 g,

26 mmol) and a catalytic amount of p-toluenesulfonic acid.

After the reaction mixture was stirred under re¯ux condition

for 2 h, a saturated aqueous NaHCO₃solution was added,

and then the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with

brine, dried over MgSO₄, ®ltered and concentrated in

vacuo to give the corresponding acetal, which was used

without further puri®cation.

4.4.3. ꢀ1R,4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-1-meth-

oxy-carbonyl-5,5,8a-trimethyl-trans-naphthalene-2ꢀ1H)-

22

one ꢀꢀ2)-3).¹⁷Mp 103.0±104.08C; [a]_D254.3 .c 0.82,

CHCl₃).

4.4.4. ꢀ1S,4aR,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-1-meth-

oxy-carbonyl-5,5,8a-trimethyl-trans-naphthalene-2ꢀ1H)-

To a solution of the crude acetal in ethyl acetate .100 mL)

was added Pd±C .4.8 g), and the mixture was stirred at

room temperature for 48 h under hydrogen atmosphere.

The reaction mixture was ®ltered and concentrated in

vacuo to give crude alcohol .90±100% for 2 steps). Puri®-

cation by silica gel column chromatography .from 1 to 6%

methanolin chol roform) gave acetal 14a and 14b, 15a and

15b, or 16a and 16b, respectively.

22

one ꢀꢀ1)-3). Mp 103.0±104.08C; [a]_D155.0 .c 1.05,

CHCl₃).

4.4.5. ꢀ1R,4aS,4bR,8aR,10aS)-3,4,4a,4b,5,6,7,8,8a,9,10,

10a-Dodecahydro-1-methoxycarbonyl-4b,8,8,10a-tetra-

methyl-trans-anti-trans-phenanthrene-2ꢀ1H)-one-2-

[ꢀꢀ1S,2S)-diꢀhydroxymethyl))ethylene acetal] ꢀ15a) ꢀfaster

24

moving diastereomer). Mp 223.0±225.08C; [a]_D

To a solution of the acetal .5.6 mmol) in methanol .50 mL)

was added a catalytic amount of a 2N aqueous H₂SO₄solu-

tion at room temperature. After the reaction mixture was

stirred for 48 h under re¯ux condition, a saturated aqueous

245.1 .c 1.16, CHCl₃); IR .KBr, cm²¹) 3483, 2940, 1730,

1200, 1148, 1132, 1046; ¹H NMR .400 MHz, CDCl₃) d 4.06

.m, 3H), 3.90 .d, 1H, J10.8 Hz), 3.77 .ddd, 1H, J12.4,

8436

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

4.8, 3.6 Hz), 3.65 .s, 3H), 3.55 .m, 1H), 2.53 .s, 1H), 1.97

.dd, 1H, J8.0, 4.8 Hz), 1.88 .ddd, 1H, J8.4, 3.6, 3.6 Hz),

1.51 .m, 10H), 1.18 .m, 1H), 1.17 .s, 3H), 0.85 .s, 6H), 0.84

.s, 3H), 0.81 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 172.21,

109.02, 77.60, 75.53, 63.11, 61.61, 59.80, 59.01, 56.68,

51.41, 41.99, 41.34, 40.01, 39.70, 38.02, 37.57, 33.27,

21.34, 18.97, 18.50, 18.08, 16.21, 15.98; Anal. found: C,

67.44; H, 9.49%. Calcd for C₂₄H₄₀O₆: C, 67.89; H, 9.50%.

J10.7 Hz), 3.78 .ddd, 1H, J12.0, 4.2, 3.9 Hz), 3.65 .s,

3H), 3.54 .m, 1H), 2.51 .s, 1H), 0.80±2.00 .m, 21H), 1.15 .s,

3H), 0.85 .s, 3H), 0.83 .s, 3H), 0.81 .s, 3H), 0.80 .s, 3H); ¹³C

NMR .100 MHz, CDCl₃) d 172.24, 109.11, 77.53, 77.21,

75.54, 63.12, 61.57, 61.20, 60.69, 59.77, 59.42, 56.57,

51.44, 42.10, 41.93, 41.45, 39.81, 39.54, 38.06, 37.53,

33.28, 21.31, 18.90, 18.64, 18.24, 17.45, 16.91, 16.16,

15.88; Anal. found: C, 70.44; H, 9.78%. Calcd for

C₂₉H₄₈O₆: C, 70.70; H, 9.82%.

4.4.6. ꢀ1S,4aR,4bS,8aS,10aR)-3,4,4a,4b,5,6,7,8,8a,9,10,

10a-Dodecahydro-1-methoxycarbonyl-4b,8,8,10a-tetra-

methyl-trans-anti-trans-phenanthrene-2ꢀ1H)-one-2-

[ꢀꢀ1S, 2S)-diꢀhydroxymethyl))ethylene acetal] ꢀ15b)

ꢀslower moving diastereomer). Mp 171.0±172.08C;

4.4.11. ꢀ1R,4aS,4bR,6aS,10aS,10bR,12aS)-3,4,4a,4b,5,6,

6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-1-methoxy-

carbonyl-4b,7,7,10a,12a-pentamethyl-trans-anti-trans-

anti-trans-chrysene-2ꢀ1H)-one ꢀꢀ2)-9). Mp 223.0±

225.08C; [a]_D219.3 .c 0.20, CHCl₃).

26

21

[a]_D120.6 .c 0.92, CHCl₃); IR .KBr, cm²¹) 3483,

1

2940, 1730, 1200, 1148, 1132, 1046; H NMR .400 MHz,

4.4.12. ꢀ1S,4aR,4bS,6aR,10aR,10bS,12aR)-3,4,4a,4b,5,6,

6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-1-methoxy-

carbonyl-4b,7,7,10a,12a-pentamethyl-trans-anti-trans-

anti-trans-chrysene-2ꢀ1H)-one ꢀꢀ1)-9). Mp 220.0±

221.08C; [a]_D120.2 .c 0.31, CHCl₃).

CDCl₃) d 4.10 .dt, 1H, J8.8, 4.0 Hz), 4.00 .dt, 1H, J8.8,

4.0 Hz), 3.81 .brm, 1H), 3.73 .brm, 1H), 3.64 .s, 3H), 3.58

.m, 2H), 2.50 .s, 1H), 2.18 .m, 1H), 1.88 .m, 1H), 1.49 .m,

10H), 1.20 .s, 3H), 1.14 .ddd, 1H, J13.6, 13.6, 4.0 Hz),

0.86 .s, 3H), 0.85 .s, 3H), 0.85 .m, 3H), 0.81 .s, 3H); ¹³C

NMR .100 MHz, CDCl₃) d 172.07, 109.70, 79.04, 77.64,

63.60, 62.12, 61.99, 59.79, 56.99, 51.37, 42.32, 41.67,

40.39, 39.93, 39.70, 37.91, 33.60, 21.67, 18.83, 18.34,

16.66, 16.41; Anal. found: C, 67.42; H, 9.44%. Calcd for

C₂₄H₄₀O₆: C, 67.89; H, 9.50%.

26

4.4.13. ꢀ1)-Albicanol¹⁹from bicyclic b-ketoester ꢀ2)-3.

To a suspension of methyltriphenylphosphonium bromide

.2.12 g, 5.94 mmol) in THF .8 mL) was added sodium

amide .231 mg, 5.94 mmol) at room temperature. After

being stirred for 40 min at 408C, the mixture was left to

stand at room temperature for 1 h. The resulting super-

natant, which contained the salt-free Wittig reagent, was

slowly added to a solution of bicyclic b-ketoester .2)-3

.300 mg, 1.19 mmol) in THF .4 mL) at 08C, and the result-

ing mixture was stirred at 308C for 3 h. After water was

added, the mixture was extracted with hexane. The organic

layers were combined, washed with brine, dried over

MgSO₄, ®ltered and concentrated in vacuo to give the corre-

sponding exomethylene compound, which was used without

further puri®cation.

4.4.7. ꢀ1R,4aS,4bR,8aR,10aS)-3,4,4a,4b,5,6,7,8,8a,9,10,

10a-Dodecahydro-1-methoxycarbonyl-4b,8,8,10a-tetra-

methyl-trans-anti-trans-phenanthrene-2ꢀ1H)-one ꢀꢀ1)-

24

6). Mp 170.0±172.08C; [a]_D129.1 .c 1.02, CHCl₃).

4.4.8. ꢀ1S,4aR,4bS,8aS,10aR)-3,4,4a,4b,5,6,7,8,8a,9,10,

10a-Dodecahydro-1-methoxycarbonyl-4b,8,8,10a-tetra-

methyl-trans-anti-trans-phenanthrene-2ꢀ1H)-one ꢀꢀ2)-

6). Mp 165.0±166.08C; [a]_D²³229.4 .c 0.86, CHCl₃).

4.4.9. ꢀ1R,4aS,4bR,6aS,10aS,10bR,12aS)-3,4,4a,4b,5,6,

6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-1-methoxy-

carbonyl-4b,7,7,10a,12a-pentamethyl-trans-anti-trans-

anti-trans-chrysene-2ꢀ1H)-one-2-[ꢀꢀ1S,2S)-diꢀhydroxy-

methyl))ethylene acetal] ꢀ16a) ꢀslower moving diastereo-

To a suspension of lithium aluminum hydride .90 mg,

2.38 mmol) in diethyl ether .3 mL) was added dropwise a

solution of the crude exomethylene compound obtained in

diethylether .2 mL) at 0 8C. After the reaction mixture was

stirred at room temperature for 12 h, water was added, and

the precipitate was ®ltered through a pad of Celite, and then

the ®ltrate was concentrated in vacuo. Puri®cation by silica

gelcoul mn chromatography .from 10 to 20% ethylacetate

in hexane) followed by recrystallization from ethyl acetate±

hexane gave .1)-albicanol .217 mg, 82% for 2 steps), as

26

mer). Mp 262.0±264.08C; [a]_D114.1 .c 0.17, CHCl₃);

IR .KBr, cm²¹) 3474, 3403, 2944, 1717; ¹H NMR

.400 MHz, CDCl₃) d 4.11 .dt, 1H, J8.8, 3.9 Hz), 4.00

.1H, J8.8, 3.9 Hz), 3.83 .brm, 1H), 3.75 .brm, 1H), 3.64

.s, 3H), 3.60 .m, 2H), 2.47 .s, 1H), 1.88 .m, 1H), 1.77 .m,

1H), 0.75±1.70 .m, 19H), 1.19 .s, 3H), 0.86 .s, 3H), 0.83 .s,

3H), 0.81 .s, 3H), 0.80 .s, 3H); ¹³C NMR .100 MHz, CDCl₃)

d 171.74, 109.43, 78.91, 77.20, 76.18, 63.29, 61.68, 61.57,

61.19, 59.88, 56.56, 51.06, 42.10, 41.98, 41.46, 39.80,

39.44, 37.88, 37.53, 33.28, 21.31, 18.63, 18.43, 18.24,

17.58, 16.86, 16.16, 16.00; Anal. found: C, 70.53; H,

10.09%. Calcd for C₂₉H₄₈O₆: C, 70.70; H, 9.82%.

24

colorless crystals: mp 69.0±71.08C; [a]_D110.4 .c 0.55,

CHCl₃); IR .KBr, cm²¹) 3384, 3080, 2868, 2856, 1644,

1464, 1390, 1026; H NMR .400 MHz, CDCl₃) d 4.94 .d,

1

1H, J1.6 Hz), 4.64 .d, 1H, J1.6 Hz), 3.84 .brdd, 1H,

J11.2, 3.2 Hz), 3.76 .dd, 1H, J10.8, 10.0 Hz), 2.43 .ddd,

1H, J12.8, 4.4, 2.4 Hz), 2.01 .m, 2H), 1.71 .m, 2H), 1.34 .m,

8H), 0.88 .s, 3H), 0.81 .s, 3H), 0.72 .s, 3H); ¹³C NMR

.100 MHz, CDCl₃) d 147.84, 106.25, 59.14, 58.71, 55.13,

41.94, 38.96, 37.84, 33.60, 33.44, 24.17, 21.71, 19.19, 15.26.

4.4.10. ꢀ1S,4aR,4bS,6aR,10aR,10bS,12aR)-3,4,4a,4b,5,6,

6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-1-methoxy-

carbonyl-4b,7,7,10a,12a-pentamethyl-trans-anti-trans-

anti-trans-chrysene-2ꢀ1H)-one-2-[ꢀꢀ1S,2S)-diꢀhydroxy-

methyl))ethylene acetal] ꢀ16b) ꢀfaster moving diastereo-

4.5. Total synthesis of ꢀ1)-, and ꢀ2)-acuminolide

26

mer). Mp 258.0±260.08C; [a]_D224.3 .c 0.15, CHCl₃);

4.5.1. 1-ꢀ3-Furyl)-2-[ꢀ1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-

decahydro-5,5,8a-trimethyl-2-methylene-1-trans-naphthyl]-

methylketone ꢀ20). To a solution of nitrile 18²¹.1.3 g,

IR .KBr, cm²¹) 3424, 2924, 2847, 1717; ¹H NMR

.400 MHz, CDCl₃) d 4.06 .m, 3H), 3.87 .d, 1H,

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8437

5.60 mmol) in toluene .40 mL) was added diisobutyl-

aluminum hydride .1.0 M in toluene, 11.2 mL,

11.2 mmol) at 08C. After the reaction mixture was stirred

at room temperature for 2 h, a 2N aqueous HClsolution was

added, and then the resulting mixture was extracted with

ethylacetate. The organic alyers were combined, washed

with brine, dried over MgSO₄, ®ltered and concentrated in

vacuo to give the corresponding aldehyde, which was used

without further puri®cation.

To a solution of the crude diol in DMF .25 mL) was added

tert-butyldimethylsilyl chloride .915 mg, 6.07 mmol) and

imidazole .486 mg, 7.14 mmol) at 08C. The reaction

mixture was stirred at room temperature for 1.5 h, a satu-

rated aqueous NaHCO₃solution was added, and then the

resulting mixture was extracted with diethyl ether. The

organic layers were combined, washed with brine, dried

over MgSO₄, ®ltered and concentrated in vacuo. Puri®ca-

tion by silica gel column chromatography .20% ethyl

acetate in hexane) gave silyl ether 21 .1.52 g, 90% for 2

23

To a solution of 3-bromofuran .1.23 g, 8.37 mmol) in

diethylether .15 mL) was added dropwise

steps): mp 124.5±126.08C; [a]_D24.50 .c 0.63, CHCl₃);

sec-BuLi

IR .KBr, cm²¹) 3530, 3125, 1672, 1512, 1462, 1254, 1088;

¹H NMR .400 MHz, CDCl₃) d 8.23 .s, 1H), 7.41 .brs, 1H),

6.81 .brs, 1H), 3.65 .d, 1H, J9.8 Hz), 3.41 .dd, 1H, J9.8,

1.5 Hz), 3.17 .s, 1H), 3.08 .dd, 1H, J16.1, 3.0 Hz), 2.40

.dd, 1H, J7.6, 3.0 Hz), 2.11 .dt, 1H, J12.7, 3.0 Hz), 1.1±

1.7 .m, 10H), 0.91 .s, 3H), 0.86 .s, 3H), 0.79 .s, 3H), 0.09 .s,

6H); ¹³C NMR .100 MHz, CDCl₃) d 195.94, 147.45,

143.66, 127.40, 109.08, 73.24, 64.20, 55.69, 54.06, 41.58,

39.53, 37.75, 36.92, 33.28, 33.15, 25.86, 21.45, 19.96,

18.33, 18.25, 15.72, 25.40; EI¹HRMS Found m/z

488.2984, Calcd for C₂₆H₄₄O₄Si M¹448.3009.

.1.0 M in cyclohexane, 7.30 mL, 7.30 mmol) over 10 min

at 2788C. After the reaction mixture was stirred for 30 min,

a solution of the crude aldehyde in diethyl ether .25 mL)

was added dropwise. After the reaction mixture was stirred

at 2788C for 30 min, a saturated aqueous NH₄Clsoultion

was added, and then the resulting mixture was extracted

with diethylether. The organic alyers were combined,

washed with brine, dried over MgSO₄, ®ltered and concen-

trated in vacuo to give coupling product 19 .1.51 g as a

mixture of diastereomer, 91% for 2 steps), which was

used without further puri®cation.

4.5.3. ꢀ2S,3aR,5aS,9aS,9bR)-2-ꢀ3-Furyl)-1,2,3a,4,5,5a,6,

7,8,9,9a,9b-dodecahydro-3a-hydroxymethyl-6,6,9a-tri-

methy-trans-naphtho[2,1-b]furan ꢀ22) and ꢀ2R,3aR,5aS,

9aS, 9bR)-2-ꢀ3-furyl)-1,2,3a,4,5,5a,6,7,8,9,9a,9b-dodeca-

hydro-3a-hydroxymethyl-6,6,9a-trimethy-trans-naphtho

[2,1-b]furan ꢀ23). To a solution of silyl ether 21 .300 mg,

0.67 mmol) in THF .6 mL) was added dropwise a solution

of L-Selectride^w.1.0 M in THF, 2.0 mL, 2.00 mmol) at

2788C. The reaction mixture was stirred for 30 min at

2788C, water was added, and then the resulting mixture

was extracted with ethylacetate. The organic alyers were

combined, washed with a saturated aqueous NH₄Clsolution

and brine, dried over MgSO₄, ®ltered and concentrated in

vacuo to give the corresponding alcohol, as a mixture of

diastereomers.

To a solution of the crude product 19 in dichloromethane

.25 mL) was added Dess±Martin periodinane .3.56 g,

8.39 mmol) at 08C. After the reaction mixture was stirred

at room temperature for 2 h, a saturated aqueous NaHCO₃

solution was added. After being stirred for an additional

15 min, the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with a

saturated aqueous NH₄Clsoultion and brine, dried over

MgSO₄, ®ltered and concentrated in vacuo. Puri®cation by

silica gel column chromatography .5% ethyl acetate in

hexane) gave ketone 20 .1.21 g, 80%): mp 99.0±100.08C;

[a]_D222.8 .c 0.96, CHCl₃); IR .NaCl, cm²¹) 3137,

24

1659, 1559, 1512, 1429, 1165; ¹H NMR .400 MHz,

CDCl₃) d 8.08 .dd, 1H, J1.5, 0.98 Hz), 7.43 .dd, 1H,

J2.0, 1.5 Hz), 6.78 .dd, 1H, J2.0, 0.98 Hz), 4.72 .d,

1H, J1.2 Hz), 4.37 .d, 1H, J1.2 Hz), 2.94 .dd, 1H,

J16.6, 9.8 Hz), 2.76 .dd, 1H, J16.6, 3.7 Hz), 2.65 .dd,

1H, J9.8, 2.9 Hz), 1.1±2.2 .m, 11H), 0.90 .s, 3H), 0.83 .s,

3H), 0.76 .s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 194.57,

149.25, 146.63, 144.06, 128.12, 108.79, 106.38, 55.03,

51.11, 41.99, 39.25, 38.95, 37.49, 36.39, 33.54, 33.50,

23.94, 21.75, 19.26, 14.75; EI¹HRMS Found m/z

300.2094, Calcd for C₂₀H₂₈O₂M¹300.2082.

To a dichloromethane .6 mL) solution of the crude

compound was added p-toluenesulfonyl chloride .126 mg,

0.67 mmol). After the reaction mixture was stirred for 2 h at

408C, a saturated aqueous NH₄Clsoul tion was added, and

then the resulting mixture was extracted with ethyl acetate.

The organic layers were combined, washed with brine, dried

over MgSO₄, ®ltered and concentrated in vacuo to give a

mixture of 22 and 23 .170 mg, 80% for 2 steps, the ratio was

1

15:1 by H NMR). Puri®cation by silica gel column chro-

4.5.2. 1-ꢀ3-Furyl)-2-[ꢀ1R,2R,4aS,8aS)-1,2,3,4,4a,5,6,7,8,

8a-decahydro-5,5,8a-trimethyl-2-hydroxy-2-tert-butyl-

dimethylsiloxymethyl-1-trans-naphthyl]methylketone

ꢀ21). To a solution of osmium tetraoxide .1.0 g, 3.93 mmol)

in pyridine .15 mL) was added dropwise a solution of

ketone 20 .1.07 g, 3.57 mmol) in pyridine .10 mL) at 08C.

After being stirred for 3 h at room temperature, the reaction

mixture was poured into an aqueous NaHSO₃.6.77 g,

56.43 mmol) solution .50 mL). After an additional 18 h,

the resulting mixture was extracted with ethyl acetate. The

organic layers were combined, washed with a saturated

aqueous CuSO₄solution and brine, dried over MgSO₄,

®ltered and concentrated in vacuo to give the corre-

sponding diol, which was used without further puri®ca-

tion.

matography .from 7 to 25% ethylacetate in hexane) gave

cyclic ether 22 .faster moving diastereomer) and 23 .slower

moving diastereomer).

23

Data for 22: Mp 100.0±101.08C; [a]_D110.6 .c 0.96,

CHCl₃₁); IR .KBr, cm²¹) 3555, 2998, 1503, 1462, 1053,

1028; H NMR .400 MHz, CDCl₃) d 7.402 .s, 1H), 7.398

.s, 1H), 6.43 .t, 1H, J1.4 Hz), 5.02 .m, 1H), 3.59 .d, 1H,

J10.7 Hz), 3.40 .dd, 1H, J10.7, 2.1 Hz), 2.1±2.4 .m,

3H), 1.0±2.0 .m, 12H), 0.98 .s, 3H), 0.96 .s, 3H), 0.95 .s,

3H); ¹³C NMR .100 MHz, CDCl₃) d 143.89, 139.17,

127.87, 108.90, 83.26, 72.99, 62.91, 61.16, 57.14, 42.31,

39.76, 36.45, 34.77, 33.47, 33.08, 30.16, 21.01, 20.35,

18.41, 15.41; FAB¹HRMS Found m/z 319.2239, Calcd

for [C₂₀H₃₀O₃1H]¹319.2273.

8438

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

22

Data for 23: [a]_D28.32 .c 1.16, CHCl₃); IR .NaCl,

cm²¹) 3349, 2129, 1508, 1458, 1157, 1026; ¹H NMR

.400 MHz, CDCl₃) d 7.39 .s, 1H), 7.37 .s, 1H), 6.34 .s,

1H), 5.10 .dd, 1H, J9.3, 2.2 Hz), 3.55 .s, 2H), 2.39 .dt,

1H, J11.6, 3.0 Hz), 2.17 .ddd, 1H, J13.5, 11.5, 9.3 Hz),

1.0±2.0 .m, 14H), 0.89 .s, 3H), 0.84 .s, 3H), 0.79 .s, 3H);

¹³C NMR .100 MHz, CDCl₃) d 143.61, 139.06, 128.83,

108.49, 83.89, 71.16, 61.20, 59.37, 57.37, 42.36, 39.68,

36.36, 34.44, 33.54, 33.12, 31.02, 21.02, 20.25, 18.41,

15.08; FAB¹HRMS Found m/z 319.2287, Calcd for

[C₂₀H₃₀O₃1H]¹319.2273.

To a suspension of lithium aluminum hydride .262 mg,

6.90 mmol) in diethyl ether .20 mL) was added dropwise

a solution of the crude exomethylene compound in diethyl

ether .5 mL) at 08C. After reaction mixture was stirred at

room temperature for 12 h, water was added, and the pre-

cipitate was ®ltered through a pad of Celite, and then the

®ltrate was concentrated in vacuo. Puri®cation by silica gel

column chromatography .from 10 to 20% ethyl acetate in

hexane) gave alcohol 25 .844 mg, 84% for 2 steps): mp

24

99.0±100.08C; [a]_D211.7 .c 1.05, CHCl₃); IR .KBr,

cm²¹) 3300, 1644, 1464, 1444; ¹H NMR .400 MHz,

CDCl₃) d 4.93 .d, 1H, J1.6 Hz), 4.64 .d, 1H, J1.6 Hz),

3.79 .m, 2H), 2.41 .ddd, 1H, J12.8, 4.4, 2.4 Hz), 2.00

.m, 2H), 1.66 .m, 5H), 1.36 .m, 6H), 0.86 .m, 2H),

0.86 .s, 3H), 0.81 .s, 3H), 0.80 .s, 3H), 0.72 .s, 3H); ¹³C

NMR .100 MHz, CDCl₃) d 147.79, 105.95, 59.83, 59.49,

58.68, 56.42, 41.97, 40.61, 40.04, 39.30, 37.80, 33.32,

33.23, 23.01, 21.43, 18.93, 18.56, 16.28, 16.25; EI¹

HRMS Found m/z 290.2592, Calcd for C₂₀H₃₄O M¹

290.2610.

4.5.4. ꢀ2)-Acuminolide. A solution of cyclic ether 22

.220 mg, 0.69 mmol), diisopropylethylamine .1.20 mL,

6.90 mmol), and a catalytic amount of 5,10,15,20-tetra-

phenyl-21H,23H-porphine in dichloromethane .5 mL) was

irradiated with halogen±tungsten lamp under oxygen

atmosphere for 1.5 h at 2788C. After the reaction mixture

was allowed to warm to room temperature, a saturated

aqueous oxalic acid solution was added, and then the result-

ing mixture was extracted with dichloromethane±methanol

.3:1). The organic layers were combined, dried over

MgSO₄, ®ltered and concentrated in vacuo. Puri®cation by

silica gel column chromatography .from 50 to 70% ethyl

acetate in hexane) followed by recrystallization from ethyl

acetate±hexane gave .2)-acuminolide .181 mg, 75%), as

4.6.2.

ꢀ1R,2S,4aR,4bS,8aS,10aR)-1,2,3,4,4a,4b,5,6,7,8,

8a,9,10,10a-Tetradecahydro-1-hydroxymethyl-4b,8,8,

10a-tetra-methyl-2,2⁰-di-O-isopropylidene-trans-anti-

trans-phenanthrene ꢀ27). To a solution of alcohol 25

.258 mg, 0.89 mmol) in DMF .8 mL) was added tert-butyl-

dimethylsilyl chloride .174 mg, 1.16 mmol), 4-.dimethyl-

amino)pyridine .22 mg, 0.18 mmol) and triethylamine

.0.19 mL, 1.33 mmol) at 08C. After the reaction mixture

was stirred at room temperature for 1.5 h, a saturated

aqueous NaHCO₃solution was added, and then the

resulting mixture was extracted with diethyl ether. The

organic layers were combined, washed with brine, dried

over MgSO₄, ®ltered and concentrated in vacuo to give

the corresponding silyl ether, which was used without

further puri®cation.

23

colorless crystals: mp 207.0±208.08C; [a]_D233.2 .c

1.25, CHCl₃); IR .KBr, cm²¹) 3503, 3355, 2946, 2897,

2872, 1752, 1653, 1468, 1142, 1053; H NMR .400 MHz,

1

CDCl₃1CD₃OD .9:1)) d 6.13 .s, 1H), 6.09 .s, 1H), 4.93

.brs, 1H), 3.67 .d, 1H, J11.1 Hz), 3.31 .d, 1H,

J11.1 Hz), 2.39 .brd, 1H, J8.8 Hz), 2.21 .m, 1H), 1.0±

2.0 .m, 14H), 0.90 .s, 3H), 0.83 .s, 3H), 0.80 .s, 3H); ¹³C

NMR .100 MHz, CDCl₃1CD₃OD .9: 1)) d 171.15, 170.14,

116.24, 98.09, 84.28, 74.13, 62.02, 60.92, 56.91, 41.94,

39.53, 36.14, 33.99, 33.03, 32.78, 28.86, 20.59, 20.09,

18.08, 15.23; Anal. found: C, 68.38; H, 8.59%. Calcd for

C₂₀H₃₀O₃: C, 68.55; H, 8.63%.

To a solution of osmium tetraoxide .248 mg, 0.98 mmol) in

pyridine .8 mL) was added dropwise a solution of crude

silyl ether in pyridine .3 mL) at 08C. After being stirred

for 4 h at room temperature, the reaction mixture was

poured into an aqueous NaHSO₃.1.64 g, 13.66 mmol)

solution .6 mL). The resulting mixture was stirred for an

additional18 h, and extracted with ethylacetate. The

organic layers were combined, washed with a saturated

aqueous CuSO₄solution and brine, dried over MgSO₄,

®ltered and concentrated in vacuo to give the corre-

sponding diol 26, which was used without further puri-

®cation.

23

4.5.5. ꢀ1)-Acuminolide.³Mp 207.5±208.58C; [a]_D

134.6 .c 0.85, CHCl₃); Anal. found: C, 68.18; H, 8.65%.

Calcd for C₂₀H₃₀O₃: C, 68.55; H, 8.63%. [lit.³mp 207±

20

2088C; [a]_D136.2 .c 1.34, CHCl₃)].

4.6. Total synthesis of ꢀ2)-spongianolide A

4.6.1. ꢀ1R,4aS,4bR,8aR,10aS)-1,2,3,4,4a,4b,5,6,7,8,8a,9,

10,10a-Tetradecahydro-4b,8,8,10a-tetramethyl-2-meth-

ylene-trans-anti-trans-phenanthrene-1-methanol ꢀ25). To

a suspension of methyltriphenylphosphonium bromide

.5.57 g, 15.60 mmol) in THF .40 mL) was added sodium

amide .609 mg, 15.60 mmol) at room temperature. After

being stirred for 40 min at 408C, the mixture was left to

stand at room temperature for 1 h. The resulting super-

natant, which contained the salt-free Wittig reagent, was

slowly added to a solution of tricyclic b-ketoester .1)-6

.1.10 g, 3.45 mmol) in THF .10 mL) at room temperature.

After the reaction mixture was stirred at 308C for 3 h, water

was added, and then the resulting mixture was extracted

with hexane. The organic layers were combined, washed

with brine, dried over MgSO₄, ®ltered and concentrated in

vacuo to give the corresponding exomethylene compound,

which was used without further puri®cation.

To a solution of the crude diol 26 in acetone .12 mL) was

added 2,2-dimethoxypropane .1.09 mL, 8.88 mmol) and a

catalytic amount of pyridinium p-toluenesulfonate at room

temperature. After the reaction mixture was stirred at the

same temperature, a saturated aqueous NaHCO₃solution

was added, and then the resulting mixture was extracted

with ethylacetate. The organic alyers were combined,

washed with brine, dried over MgSO₄, ®ltered and concen-

trated in vacuo to give the corresponding acetonide, which

was used without further puri®cation.

To a solution of the crude acetonide in THF .10 mL) was

added

tetra-n-butylammonium

¯uoride

.581 mg,

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8439

2.22 mmol) at room temperature. After the reaction mixture

was stirred for 3 h at 608C, water was added, and then the

resulting mixture was extracted with ethyl acetate. The

organic layers were combined, washed with brine, dried

over MgSO₄, ®ltered and concentrated in vacuo. Puri®ca-

tion by silica gel column chromatography .from 5 to 20%

ethylacetate in hexane) gave alcohol 27 .256 mg, 79% for 4

®ltered and concentrated in vacuo. Puri®cation by silica

gelcoulmn chromatography .from 5 to 20% ethylacetate

in hexane) gave silylfuran 29 .225 mg, 86%): mp 112.0±

)

113.08C; [a]_D216.4 .c 0.97, CHCl₃); IR .KBr, cm²¹

24

1

1685, 1636, 1252; H NMR .400 MHz, CDCl₃) d 7.53 .s,

1H), 6.70 .s, 1H), 6.31 .d, 1H, J15.2Hz), 5.84 .dd, 1H,

J15.2, 10.0 Hz), 3.90 .dd, 1H, J8.4, 2.0 Hz), 3.82 .d, 1H,

J8.4 Hz), 2.14 .d, 1H, J10.0 Hz), 2.09 .ddd, 1H, J12.4,

3.2, 3.2 Hz), 1.38 .s, 3H), 1.35 .m, 12H), 1.13 .s, 3H),

0.86 .m, 3H), 0.85 .s, 3H), 0.83 .s, 3H), 0.82 .s, 3H),

0.79 .s, 3H), 0.27 .s, 9H); ¹³C NMR .100 MHz, CDCl₃)

24

steps): mp 187.0±188.08C; [a]_D23.47 .c 1.01, CHCl₃);

1

IR .KBr, cm²¹) 3552, 3492, 3456, 1056, 1026; H NMR

.400 MHz, CDCl₃) d 3.82 .m, 4H), 3.14 .dd, 1H, J10.0,

1.6 Hz), 2.11 .ddd, 1H, J12.4, 3.2, 3.2 Hz), 1.87 .dd, 1H,

J5.2, 1.6 Hz), 1.65 .m, 5H), 1.44 .s, 3H), 1.39 .s, 3H), 1.27

.m, 7H), 0.95 .dd, 1H, J12.0, 2.4 Hz), 0.85 .s, 3H), 0.81

.m, 2H), 0.79 .s, 3H), 0.78 .s, 3H), 0.66 .s, 3H); ¹³C NMR

.100 MHz, CDCl₃) d 106.97, 86.12, 67.99, 59.57, 59.39,

56.22, 41.90, 40.60, 39.90, 38.87, 38.42, 37.44, 33.22,

28.56, 26.55, 21.31, 19.44, 18.54, 18.33, 17.03, 16.10;

Anal. found: C, 75.80; H, 11.04%. Calcd for C₂₃H₄₀O₃: C,

75.78; H, 11.06%.

d

161.21, 143.85, 124.86, 124.78, 124.45, 117.20,

107.10, 83.86, 68.39, 62.17, 59.72, 56.51, 42.03, 39.99,

39.74, 38.60, 37.54, 33.27, 33.25, 28.37, 26.49, 21.40,

19.44, 18.57, 18.14, 16.41, 16.31, 21.68; EI¹HRMS

Found m/z 498.3527, Calcd for C₃₁H₅₀O₂Si M¹

498.3529.

4.6.5. 2-Hydroxy-3-[2-ꢀꢀ1S,2S,4aR,4bS,8aS,10aR)-1,2,3,

4,4a,4b,5,6,7,8,8a,9,10,10a-Tetradecahydro-4b,8,8,10a-

tetramethyl-2,2⁰-di-O-isopropylidene-trans-anti-trans-

phenanthyl)-ꢀE)-ethynyl]-5-butenolide ꢀ30). A solution of

silylfuran 29 .117 mg, 0.24 mmol) and a catalytic amount of

5,10,15,20-tetraphenyl-21H,23H-porphine in dichloro-

methane .3 mL) was irradiated with halogen±tungsten

lamp under oxygen atmosphere for 1.5 h at 2788C. After

being allowed to warm to room temperature, the reaction

mixture was concentrated in vacuo to remove of the

solvents. Puri®cation by silica gel column chromatography

.50% ethylacetate in hexane) gave butenoilde 30 .74 mg,

74%), as a mixture of stereoisomers at the hydroxy group in

4.6.3.

ꢀ1S,2S,4aR,4bS,8aS,10aR)-1,2,3,4,4a,4b,5,6,7,8,

8a,9,10, 10a-Tetradecahydro-1-formyl-4b,8,8,10a-tetra-

methyl-2,2⁰-di-O-isopropylidene-trans-anti-trans-phen-

anthrene ꢀ28). To a solution of oxalyl chloride .0.14 mL,

1.576 mmol) in dichloromethane .5 mL) was added drop-

wise DMSO .0.13 mL, 1.89 mmol) at 2788C. After the

mixture was stirred for 10 min at the same temperature, a

solution of alcohol 27 .228 mg, 0.63 mmol) in dichloro-

methane .2 mL) was added. The resulting reaction mixture

was stirred for 40 min at 2788C, and triethylamine

.0.44 mL, 3.14 mmol) was added. After the mixture was

stirred for 10 min at room temperature, water was added,

and then the resulting mixture was extracted with diethyl

ether. The organic layers were combined, washed with

brine, dried over MgSO₄, ®ltered and concentrated in

vacuo. Puri®cation by silica gel column chromatography

.from 3 to 10% ethylacetate in hexane) gave adl ehyde 28

24

the butenolide ring: mp 203.0±205.08C; [a]_D218.5 .c

0.96, CHCl₃); IR .KBr, cm²¹) 3384, 3284, 1760, 1738,

1642, 1194, 1166, 1156; H NMR .400 MHz, CDCl₃) d

1

6.49 .dd, 1H, J15.6, 9.6 Hz), 6.41 .dd, 1H, J15.6,

1.2 Hz), 6.23 .brdd, 1H, J10.8, 7.6 Hz), 5.86 .s, 1H),

4.55 .brdd, 1H, J15.2, 8.0 Hz), 3.84 .m, 2H), 2.23 .dd,

1H, J10.0, 6.4 Hz), 2.11 .m, 1H), 1.50 .m, 9H), 1.38 .s,

3H), 1.14 .d, 3H, J15.6 Hz), 1.10 .m, 2H), 0.87 .s, 3H),

0.86 .m, 4H), 0.84 .s, 3H), 0.83 .d, 3H, J1.6 Hz), 0.80 .d,

1H, J0.8 Hz); ¹³C NMR .100 MHz, CDCl₃) d .171.18,

171.14), .141.31, 140.76), .125.69, 125.47), 115.79,

.107.34, 107.20), .97.50, 97.49), .83.75, 83.71), .68.37,

68.10), .62.87, 62.68), 59.46, 56.51, .42.23, 42.09), 41.94,

39.95, .39.63, 39.38), .38.97, 38.83), 37.58, .33.27, 33.23),

.28.29, 28.06), .26.45, 26.26), 21.36, 19.33, 18.50, 18.09,

16.41; Anal. found: C, 73.18; H, 9.41%. Calcd for

C₂₈H₄₂O₅: C, 73.33; H, 9.23%.

24

.190 mg, 84%): mp 195.0±196.08C; [a]_D213.3 .c 1.07,

CHCl₃); IR .KBr, cm²¹) 1712, 1052, 1032; ¹H NMR

.400 MHz, CDCl₃) d 9.98 .d, 1H, J4.0 Hz), 4.30 .dd,

1H, J8.8, 2.0 Hz), 3.93 .d, 1H, J8.8 Hz), 2.49 .d, 1H,

J4.0 Hz), 2.08 .ddd, 1H, J8.4, 3.2, 3.2 Hz), 1.63 .m,

6H), 1.40 .s, 3H), 1.28 .m, 6H), 1.22 .s, 3H), 1.03 .s, 3H),

0.85 .s, 3H), 0.82 .m, 3H), 0.80 .s, 3H); ¹³C NMR

.100 MHz, CDCl₃) d 205.29, 107.38, 82.78, 68.67, 67.70,

59.15, 56.43, 41.90, 40.65, 39.86, 39.69, 39.26, 37.57,

33.22, 28.25, 26.20, 21.34, 19.39, 18.44, 17.86, 17.11,

16.24; Anal. found: C, 76.18; H, 10.61%. Calcd for

C₂₃H₃₈O₃: C, 76.20; H, 10.56%.

4.6.6. 2-Hydroxy-3-[2-ꢀꢀ1S,2S,4aR,4bS,8aS,10aR)-1,2,3,

4,4a,4b, 5,6,7,8,8a,9,10,10a-Tetradecahydro-2-hydroxy-

2-hydro-xymethyl-4b,8,8,10a-tetramethyl-trans-anti-

trans-phenanthyl)-ꢀE)-ethynyl]-5-butenolide ꢀ31). To a

solution of butenolide 30 .63 mg, 0.14 mmol) in THF

.2 mL) was added a catalytic amount of a 2N aqueous

HClsoultion at room temperature. After being stirred for

48 h at 608C, the reaction mixture was ®ltered to remove

solvents, and then the diol 31 was obtained as a white solid

4.6.4. 4-[2-ꢀꢀ1S,2S,4aR,4bS,8aS,10aR)-1,2,3,4,4a,4b,5,6,7,

8,8a,9, 10,10a-Tetradecahydro-4b,8,8,10a-tetramethyl-

2,2⁰-di-O-isopropylidene-trans-anti-trans-phenanthyl)-

ꢀE)-ethynyl]-2-trimethylsilylfuran ꢀ29). To a solution of

2-trimethylsilyl-4-furyltriphenylphosphonium methylide

.W^p), which was prepared from the silylfuran±Wittig salt

.W) .320 mg, 0.65 mmol) and n-BuLi .1.5 M in hexane,

0.43 mL, 0.65 mmol) in THF .6 mL), was added dropwise

a solution of aldehyde 28 .194 mg, 0.54 mmol) in THF

.3 mL) at 08C. After the reaction mixture was stirred for

10 min at 08C, water was added, and then the resulting

mixture was extracted with diethylether. The organic layers

were combined, washed with brine, dried over MgSO₄,

24

.32 mg, 63%): mp 2388C .decompose); [a]_D12.28 .c

0.57, DMSO); IR .KBr, cm²¹) 3536, 3388, 3176, 2932,

2872, 2848, 1742, 1638, 1304, 1140, 1070; ¹H NMR

.400 MHz, DMSO-d₆) d 7.81 .s, 1H), 6.54 .brdd, 1H,

J14.8, 10.8 Hz), 6.27 .d, 1H, J15.6 Hz), 6.23 .s, 1H),

8440

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

6.01 .s, 1H), 4.32 .brs, 1H), 3.92 .brs, 1H), 3.49 .m, 1H),

2.50 .m, 1H), 2.09 .brs, 1H), 1.96 .d, 1H, J10.4 Hz),

1.38 .m, 11H), 0.90 .s, 3H), 0.86 .m, 4H), 0.82 .s, 3H),

0.79 .s, 3H), 0.78 .s, 3H); ¹³C NMR .100 MHz, DMSO-

d₆) d 171.17, 162.41, .142.35, 141.81), 124.03, 114.18,

97.83, 74.16, 66.39, 63.80, .63.10, 62.96), 59.86,

56.06, 42.34, 41.67, 38.45, 37.83, 37.16, 33.12, 32.95,

21.24, 18.41, 18.12, 17.68, 17.11, 16.10; FAB¹HRMS

Found m/z 441.2651, Calcd for [C₂₅H₃₈O₅1Na]¹

441.2619.

THF .5 mL) at room temperature. After the reaction mixture

was stirred at room temperature for 15 min, water was

added, and then the resulting mixture was extracted with

ethylacetate. The organic alyers were combined, washed

with a saturated aqueous NaHCO₃solution and brine, dried

over MgSO₄, ®ltered and concentrated in vacuo to give the

corresponding exomethylene compound, which was used

without further puri®cation.

To a suspension of lithium aluminum hydride .79 mg,

2.07 mmol) in THF .2 mL) was added dropwise a solution

of the crude exomethylene compound obtained in THF

.2 mL) at 08C. After the reaction mixture was stirred at

room temperature for 24 h, water and a 2N aqueous HCl

solution were added, and then the resulting mixture was

extracted with ethylacetate. The organic alyers were

combined, washed with brine, dried over MgSO₄, ®ltered

and concentrated in vacuo. Puri®cation by silica gel column

chromatography .from 1 to 10% ethylacetate in hexane)

4.6.7. ꢀ2)-Spongianolide A.⁴To a solution of diol 39

.49 mg, 0.12 mmol) in pyridine .2 mL) was added acetic

anhydride .0.03 mL, 0.35 mmol) at room temperature.

After the reaction mixture was stirred for 3 h at 508C, a

saturated aqueous CuSO₄solution was added, and then the

resulting mixture was extracted with ethyl acetate. The

organic layers were combined, washed with brine, dried

over MgSO₄, ®ltered and concentrated in vacuo to give

the corresponding diacetate, which was used without further

puri®cation.

gave alcohol 32 .130 mg, 70% for 2 steps): mp 170.0±

171.08C; [a]_D16.28 .c 0.11, CHCl₃); IR .KBr, cm²¹

)

22

3509, 2928, 2845, 1647; ¹H NMR .400 MHz, CDCl₃) d 4.92

.d, 1H, J1.5 Hz), 4.62 .d, 1H, J1.2 Hz), 3.82 .dd, 1H,

J11.0, 3.7 Hz), 3.77 .dd, 1H, J10.7, 9.5 Hz), 2.41

.ddd, 1H, J12.8, 4.3, 2.4 Hz), 1.90±2.04 .m, 2H), 1.20±

1.80 .m, 13H), 1.05±1.18 .m, 2H), 0.94 .m, 1H), 0.75±0.85

.m, 3H), 0.84 .s, 3H), 0.804 .s, 6H), 0.798 .s, 3H), 0.70

.s, 3H); ¹³C NMR .100 MHz, CDCl₃) d 147.86, 105.95,

61.02, 60.27, 59.50, 58.73, 56.48, 42.13, 41.99, 40.72,

39.84, 39.14, 38.10, 37.78, 37.48, 33.28, 22.96, 21.33,

18.65, 18.29, 17.77, 17.49, 16.21, 16.14; Anal. found:

C, 83.55; H, 12.05%. Calcd for C₂₅H₄₂O: C, 83.73; H,

11.80%.

To a solution of the crude diacetate obtained in methanol

.1 mL) was added a catalytic amount of a saturated aqueous

NaHCO₃solution at room temperature. After the reaction

mixture was stirred for 30 h at the same temperature, a

saturated aqueous NH₄Clsoul tion was added, and then the

resulting mixture was extracted with ethyl acetate. The

organic layers were combined, washed with brine, dried

over MgSO₄, ®ltered and concentrated in vacuo. Puri®ca-

tion by silica gel column chromatography .50% ethyl

acetate in hexane) followed by recrystallization from ethyl

acetate±hexane gave .2)-spongianolide A .28 mg, 52% for

2

steps), as colorless crystals: mp 224.5±225.58C;

[a]_D231.2 .c 0.60, CHCl₃); IR .KBr, cm²¹) 3428,

3408, 3300, 3268, 1740, 1726, 1642, 1196, 1142, 1040;

¹H NMR .400 MHz, acetone-d₆) d 6.71 and 6.70 .brdd,

1H, J16.0, 10.4 Hz), 6.46 .d, 1H, J15.6 Hz), 6.39 and

6.37 .s, 1H), 5.97 and 5.94 .s, 1H), 4.40 .d, 1H, J11.6 Hz),

4.05 .dd, 1H, J20.0, 11.6 Hz), 2.13 .d, 1H, J10.4 Hz),

2.06 .s, 3H), 1.54 .m, 9H), 1.10 .m, 3H), 1.05 .s, 3H), 0.88

.s, 3H), 0.87 .m, 4H), 0.86 .s, 3H), 0.83 .s, 3H); ¹³C NMR

.100 MHz, acetone-d₆) d 171.71, .171.43, 171.16), .162.72,

162.55), .141.41, 141.01), .126.22, 126.07), .116.18,

116.05), .98.64, 98.60), .73.68, 73.58), .68.12, 68.05),

.67.97, 67.85), 61.19, 57.40, 43.52, 42.82, 40.58, 39.01,

38.38, 38.29, 33.89, 33.67, 21.70, 20.86, 19.42, 19.24,

18.87, 17.76, 16.73; FAB¹HRMS Found m/z 443.2802,

Calcd for [C₂₅H₃₈O₅±OH]¹443.2619.

24

4.7.2. ꢀ1S,2S,4aR,4bS,6aR,10aR,10bS,12aR)-2-Epoxy-

methylene-1,2,3,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12,

12a-octa-decahydro-4b,7,7,10a,12a-pentamethyl-trans-

anti-trans-anti-trans-chrysene-1-methanol ꢀ33). To

a

solution of alcohol 32 .30 mg, 0.08 mmol) and a 0.5 M

aqueous NaHCO₃solution .0.35 mL, 0.17 mmol) in

dichloro-methane .2 mL) was added m-chloroperbenzoic

acid .17 mg, 0.10 mmol) at 08C. After the reaction mixture

was stirred at room temperature for 40 min, a saturated

aqueous NaHSO₃solution was added, and then the resulting

mixture was extracted with diethylether. The organic layers

were combined, washed with a saturated aqueous NaHCO₃

solution and brine, dried over MgSO₄, ®ltered and concen-

trated in vacuo. Puri®cation by silica gel column chromato-

graphy .from 6 to 10% ethylacetate in hexane) gave

21

epoxide 33 .27 mg, 85%): mp 235.0±237.08C; [a]_D

12.87 .c 0.73, CHCl₃); IR .KBr, cm²¹) 3509, 2932, 2845,

1701; ¹H NMR .400 MHz, CDCl₃) d 3.61 .ddd, 1H, J11.0,

11.0, 3.2 Hz), 3.40 .dd, 1H, J11.5, 10.3 Hz), 3.20 .dd, 1H,

J3.7, 2.2 Hz), 3.10 .d, 1H, J10.7 Hz), 2.71 .d, 1H,

J3.7 Hz), 1.20±2.00 .m, 18H), 1.14 .td, 1H, J13.2,

3.9 Hz), 1.04 .dd, 1H, J12.4, 2.9 Hz), 0.96 .td, 1H,

J13.2, 4.2 Hz), 0.85 .s, 3H), 0.832 .s, 3H), 0.827 .s,

3H), 0.81 .s, 3H), 0.80 .s, 3H); ¹³C NMR .100 MHz,

CDCl₃) d 61.86, 60.84, 59.69, 58.91, 56.42, 54.58, 51.76,

42.08, 41.96, 40.55, 39.80, 37.96, 37.46, 36.16, 33.27,

21.33, 20.41, 18.62, 18.28, 17.49, 17.26, 16.61, 16.19;

FAB¹HRMS Found m/z 375.3279, Calcd for

[C₂₅H₄₂O₂1H]¹375.3263.

4.7. Formal synthesis of ꢀ1)-scalarenedial

4.7.1. ꢀ1S,4aR,4bS,6aR,10aR,10bS,12aR)-1,2,3,4,4a,4b,5,

6,6a,7,8,9,10,10a,10b,11,12,12a-Octadecahydro-4b,7,7,

10a,12a-pentamethyl-2-methylene-trans-anti-trans-anti-

trans-chrysene-1-methanol ꢀ32). To a suspension of

methyltri-phenylphosphonium bromide .2.78 g, 7.78

mmol) in THF .12 mL) was added sodium amide

.304 mg, 7.78 mmol) at room temperature. After being

stirred for 40 min at 408C, the mixture was left to stand at

room temperature for 1 h. The supernatant, which contained

the salt-free Wittig reagent, was slowly added to a solution

of tetracyclic b-ketoester .1)-9 .200 mg, 0.52 mmol) in

N. Furuichi et al. / Tetrahedron 57 )2001) 8425±8442

8441

4.7.3. ꢀ1S,4aR,4bS,6aR,10aR,10bS,12aR)-1,4,4a,4b,5,6,

References

6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-1,2-di-

ꢀhydroxymethyl)-4b,7,7,10a,12a-pentamethyl-trans-anti-

trans-anti-trans-chrysene ꢀ34).²⁷To a solution of epoxide

33 .45 mg, 0.12 mmol) in THF .4 mL) and water .1 mL)

was added a catalytic amount of 10-camphorsulfonic acid

at room temperature. After the reaction mixture was stirred

under re¯ux condition for 3 h, a saturated aqueous NaHCO₃

solution was added, and then the resulting mixture was

extracted with ethylacetate. The organic alyers were

combined, washed with brine, dried over MgSO₄, ®ltered

and concentrated in vacuo. Puri®cation by silica gel column

chromatography .from 3 to 10% ethylacetate in hexane)

followed by recrystallization from ethyl acetate±hexane

gave diol 34 .24 mg, 53%), whose spectraldata were in

1. .a) Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron Lett. 1982,

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good corresponding with those reported²⁷: mp 214.0±

216.08C; [a]_D26.80 .c 0.20, CHCl₃); IR .KBr, cm²¹

)

21

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3360, 2920, 2845, 1721, 1672; ¹H NMR .400 MHz, CDCl₃)

d 5.78 .m, 1H), 4.35 .d, 1H, J12.0 Hz), 3.98 .d, 1H,

J12.0 Hz), 3.90 .dd, 1H, J10.8, 2.0 Hz), 3.69 .dd, 1H,

J10.8, 8.5 Hz), 0.75±2.20 .m, 20H), 0.89 .s, 3H), 0.87 .s,

3H), 0.84 .s, 3H), 0.83 .s, 3H), 0.72 .s, 3H); ¹³C NMR

.100 MHz, CDCl₃) d 136.64, 127.55, 67.45, 61.51, 60.79,

56.42, 54.95, 54.70, 42.13, 41.73, 41.06, 39.86, 37.58,

37.39, 35.57, 33.29, 22.50, 21.37, 18.61, 18.15, 17.63,

16.78, 16.42, 15.31.

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4.7.4. ꢀ1S,4aR,4bS,6aR,10aR,10bS,12aR)-1,4,4a,4b,5,6,

6a,7,8,9,10,10a,10b,11,12,12a-Hexadecahydro-4b,7,7,

10a,12a-pentamethyl-trans-anti-trans-anti-trans-chry-

seno [2,1-c] dihydro-2ꢀ3H)-furanone ꢀ35).²⁷To a solution

of diol 34 .8 mg, 0.02 mmol) in dichloromethane .3.0 mL)

was added manganese dioxide .240 mg) at room tempera-

ture. After being stirred for 15 min at the same temperature,

the reaction mixture was ®ltered through a pad of Celite, and

then the ®ltrate was concentrated in vacuo. Puri®cation by

silica gel column chromatography .from 2 to 8% ethyl ace-

tate in hexane) gave lactone 35 .6 mg, 75%), whose IR, ¹H-,

and ¹³C NMR were in good corresponding with those of

reported²⁷: IR .KBr, cm²¹) 2931, 1766; ¹H NMR

.400 MHz, CDCl₃) d 6.85 .m, 1H), 4.34 .t, 1H, J

9.3 Hz), 4.02 .t, 1H, J9.2 Hz), 2.75 .m, 1H), 2.35 .m,

1H), 2.10 .m, 1H), 0.75±2.20 .m, 15H), 0.90 .s, 3H), 0.84

.s, 6H), 0.80 .s, 3H), 0.75 .s, 3H); ¹³C NMR .100 MHz,

CDCl₃) d 170.23, 136.43, 126.93, 67.25, 61.34, 56.42,

54.84, 51.16, 42.07, 41.71, 40.84, 39.90, 37.62, 37.52,

34.29, 33.27, 24.10, 21.34, 18.57, 18.03, 17.16, 16.41,

14.01.

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Acknowledgements

We are gratefulto Professor A. Dougals Kinghorn of

Department of MedicinalChemistry and Pharmacognosy,

University of Illinois at Chicago for providing his natural

acuminolide. We thank Mr Yu Yamamoto and his co-work-

ers of the Institute for Life Science Research at Asahi

ChemicalIndustry Co., Ltd. for their high-resoul tion mass

spectra measurements and elemental analyses. This work

was partially supported by a Grant-in-Aid for Scienti®c

Research 09480415 from the Ministry of Education,

Science, Sports and Culture of Japan.

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Article Doi

Common synthetic strategy for optically active cyclic terpenoids having a 1,1,5-trimethyl-trans-decalin nucleus: Syntheses of (+)-acuminolide, (-)-spongianolide A, and (+)-scalarenedial

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