Synthetic studies on himbacine, a potent antagonist of the muscarinic M2 subtype receptor. Part 2: Synthesis and muscarinic M2 subtype antagonistic activity of the novel himbacine congeners modified at the C-3 position of lactone moiety

Bioorganic & Medicinal Chemistry 11 (2003) 1169–1186

Synthetic Studies on Himbacine, a Potent Antagonist of the

Muscarinic M₂Subtype Receptor. Part 2: Synthesis and

Muscarinic M₂Subtype Antagonistic Activity of the Novel

Himbacine Congeners Modiﬁed at the C-3 Position of

Lactone Moiety^y

Masanori Takadoi,^a,* Kentaro Yamaguchi^band Shiro Terashima^c

^aDiscovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1 Nogi, Nogi-machi, Tochigi 329-0114, Japan

^bChemical Analysis Center, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan

^cSagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan

Received 29 October 2002; accepted 12 December 2002

Abstract—With an aim to disclose the convergency and ﬂexibility of our previously explored synthetic route to natural himbacine 1,

and moreover, to clarify some novel aspects of the structure–activity relationships of 1, we prepared various structural types of

novel himbacine congeners, 3-demethylhimbacine (3-norhimbacine) 2 and 4-epi-3-demethylhimbacine (4-epi-3-norhimbacine) 4-epi-

2 and their enantiomers (ent-2 and ent-4-epi-2), 11-methylhimbacine 3, and 3-epihimbacine 4 in optically pure forms by employing

our methodology. All of the synthesized congeners correspond to the compounds modiﬁed at the C-3 position of g-lactone moiety

involved in 1. Among these congeners, 3-demethylhimbacine (3-norhimbacine) 2 was found to exhibit more potent muscarinic M₂

receptor binding aﬃnity than natural 1.

Introduction

Himbacine 1, a piperidine alkaloid isolated from the

bark of Galbulimima baccata in the magnolia family,

bears a characteristic structural feature in which the

perhydronaphtho[2,3-c]furan ring system consisting of

cis-fused g-lactone and trans-fused decaline moieties is

connected with trans-disubstituted piperidine via an (E)-

double bond (Fig. 1).⁸It was reported that 1 is a potent

antagonist of the muscarinic M₂receptor with 10 to

20-fold selectivity toward the M₁subtype.⁹Thus, it

appears that 1 is an excellent candidate for the reason-

able and attractive lead compound of a drug for the

treatment of Alzheimer’s disease.^6,10

It is well known that acetylcholine (ACh) is an impor-

tant transmitter that plays a key role in learning and

memory,²and that senile dementia associated with Alz-

heimer’s disease is directly correlated with the dimin-

ished levels of synaptic ACh in the cortical and

hippocampal areas of the brain.³Several treatments for

Alzheimer’s disease are currently under investigation

based on the cholinergic hypothesis of memory dys-

function.⁴It is anticipated that the synaptic ACh levels

can be modulated by the feedback mechanism of mus-

carinic M₂receptor, which acts as an autoreceptor.⁵

Thus, selective antagonism of M₂receptor has been

shown to enhance the ACh levels in vivo.⁶Accordingly,

the muscarinic M₂antagonists that are more selective

than other muscarinic receptor subtypes such as M₁,

M₃, and M₄receptors are expected to be novel drug

candidates for the treatment of Alzheimer’s disease.⁷

To disclose novel aspects of the structure–activity rela-

tionships of 1, and, moreover, to explore the promising

congeners of 1 which may show improved M₂aﬃnity

and subtype selectivity, we achieved a novel total

synthesis of 1 in 1999.¹¹The characteristic feature of our

explored synthetic route is a highly stereoselective

intermolecular Diels–Alder reaction of the tetra-

hydroisobenzofuran with the chiral furan-2(5H)-one

employed as a key step. Our explored synthetic route

was more convergent and ﬂexible for the synthesis of

novel congeners of 1 than routes reported previously.¹²

^yPart of this work has been the subject of a preliminary communi-

cation: see ref 1.

*Corresponding author. Tel.: +81-280-56-2201; fax: +81-280-57-1293;

e-mail: masanori.takadoi@mb2.kyorin -p harm.co.jp

doi:10.1016/S0968-0896(02)00665-X

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M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

Figure 1. Structures of natural himbacine 1, 3-demethylhimbacine 2, 4-epi-3-demethylhimbacine 4-epi-2, 11-methylhimbacine 3, and 3-epihimbacine 4.

Since then, we have synthesized various structural types

of novel congeners of 1 by employing our explored

synthetic route,^{11b, 13}and we have revealed interesting

aspects of the structure–activity relationships of these

congeners.

C₄-epimers. As we reported earlier,¹¹racemic bicyclic

lactone dl-7¹⁴was prepared in a 49% yield from tetra-

hydroisobenzofuran

5 and commercially available

furan-2(5H)-one 6 by employing a highly stereoselective

intermolecular Diels–Alder reaction. Hydrogenation of

the double bond in dl-7 was eﬀected using 10% Pd/C as

a catalyst, aﬀording dl-8 as a sole product in a 98%

yield. Thus, much like the previous case,¹¹the catalytic

reduction took place highly stereoselectively from the

less-hindered face. This was subjected to oxygen ring-

opening reaction followed by thermodynamic double

bond isomerization, providing dl-unsaturated alcohol

dl-10 by way of dl-9. The dl-unsaturated alcohol dl-10

was found to be a slightly unstable compound under

basic conditions. Catalytic hydrogenation of dl-10 over

PtO₂in ethanol smoothly gave dl-saturated alcohol dl-

11 as a sole product in a 66% combined yield from dl-8.

The lactone carbonyl group in dl-11 was protected by

sequential diisobutylaluminum hydride (DIBAL-H)

reduction and acetalization, aﬀording dl-acetal dl-12 in a

62% combined yield along with a small amount of dl-

furan derivative dl-13. Production of dl-13 might be

explained by acid-catalyzed dehydration of the hemiacetal

moiety followed by air oxidation. The C-4 hydroxyl group

of dl-12 was transformed to an exo-methylene group by a

two-step sequence involving tetrapropylammonium per-

ruthenate (VII) (TPAP)¹⁵oxidation of the secondary

hydroxyl group at the C-4 position and subsequent

methylenation of the resulting carbonyl group, produ-

cing the exo-methylene compound dl-15. Next, dl-15

was subjected to a sequential hydroboration-oxidation

sequence using borane–tetrahydrofuran complex at

ambient temperature, aﬀording the dl-4-carbinol dl-

16a,b as an inseparable mixture of 4b- and 4a-epimers

Prior to our studies, Kozikowski et al. reported the

structure–activity relationships of the himbacine con-

geners, demonstrating that the tricyclic lactone frame-

work and the N-methyl group in 1 are essential for the

muscarinic M₂subtype binding potency and selectivi-

ty.^9c,dTo our knowledge, little or no attention has been

paid to the signiﬁcance of the C-3 position of g-lactone

moiety of 1 for the muscarinic M₂receptor binding

activity in previous studies. Therefore, we focused our

attention on the eﬀect of the C-3 position of 1 (i.e.,

removal, carbon-chains extension, and stereo-inversion

of the C-3 methyl group) on the muscarinic M₂subtype

antagonistic activity. As a result of these studies, we

have succeeded in the ﬁrst total synthesis of 3-deme-

thylhimbacine (3-norhimbacine) 2 and 4-epi-3-deme-

thylhimbacine (4-epi-3-norhimbacine) 4-epi-2 and their

enantiomers (ent-2 and ent-4-epi-2),¹11-methylhimba-

cine 3, and 3-epihimbacine 4 (Fig. 1). Among these

novel congeners, 3-demethylhimbacine 2 bearing the

same absolute conﬁguration as that of natural 1 was

found to show more potent muscarinic M₂subtype

receptor binding aﬃnity than 1. We report here full

details of the synthesis of these novel congeners accom-

plished by featuring our previously explored synthetic

route, some unique stereochemical features encountered

in the congener’s syntheses, and their muscarinic recep-

tor binding aﬃnity.

1

in a ratio of 1:2 by H NMR analysis. In our previous

total synthesis of 1, the stereoselectivity of the hydro-

boration-oxidation sequence for introducing the C-4

hydroxymethyl group was 8:1(4 b:4a).¹¹This diﬀerent

stereoselectivity might be due to the steric eﬀect of the

C-3 methyl group involved in the g-lactone moiety.

Results and Discussion

Removal of the C-3 methyl group: synthesis of 3-deme-

thylhimbacine (3-norhimbacine) 2, 4-epi-3-demethylhim-

bacine (4-epi-3-norhimbacine) 4-epi-2, and their

enantiomers (ent-2 and ent-4-epi-2) (Schemes 1 and 2).

Due to the lack of a chiral center in furan-2(5H)-one

that can be used as the starting material for our synth-

esis of 3-demethylhimbacines (2, ent-2, 4-epi-2, and ent-

4-epi-2), we envisioned synthesizing these compounds

by optical resolution and epimer separation at the stage

of dl-4-carbinol dl-16 obtainable as a mixture of the

Without separation, dl-16a,b was directly converted to

the corresponding 4-bromobenzoate dl-17a,b in a 99%

yield by the reaction with 4-bromobenzoyl chloride in

the presence of triethylamine. Then, dl-17a,b, which was

a mixture of the dl-4b- and dl-4a-epimers, was subjected

to simultaneous optical resolution and epimer separa-

tion by means of HPLC using a CHIRALCEL OD

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1171

Scheme 1. Synthesis of 3-demethylhimbacine (I). (a) 2(5H)-Furanone 6, 5 M LiClO₄–Et₂O, 4,4⁰-thiobis(6-tert-butyl-m-cresol), rt, 48 h, 49%; (b) H₂,

10% Pd/C, EtOH, rt, 5 h, 98%; (c) LiN(TMS)₂, THF, À78 ꢁÀ40 ^ꢀC, 5 h, 99%; (d) DBU, toluene, 80 ^ꢀC, 4 h, 70%; (e) H₂, PtO₂, EtOH, rt, 2 h,

95%; (f) (i) DIBAL-H, Et₂O, À70 ^ꢀC, 1h, 85%, (ii) BF ₃–Et₂O, MeOH, À70 ^ꢀCꢁrt, 12 h, 62%; (g) TPAP, 4-methylmorpholine N-oxide, MS4A,

CH₂Cl₂, rt, 1h, 97%; (h) Ph ₃PCH₃I, NaN(TMS)₂, Et₂O, À78 ^ꢀCꢁrt, 6 h, 54%; (i) BH₃–THF, THF, 0 ^ꢀCꢁrt, 7 h, (ii) 10% H₂O₂, 10% NaOH, 0 ^ꢀC,

0.5 h, 82%; (j) 4-bromobenzoyl chloride, Et₃N, CH₂Cl₂, 0 ^ꢀCꢁrt, 18 h, 99%; (k) CHIRALCEL OD, 17a: 19%, ent-17a: 18%, 17b: 30%, ent-17b:

32%; (l) 10% NaOH, EtOH, rt, 0.5 h, 16a: 100%, ent-16a: 100%, 16b: 100%, ent-16b: 91 %.

Scheme 2. Synthesis of 3-demethylhimbacine (II). (a) (Cyanomethyl)trimethylphosphonium iodide, thiophenol, N,N-diisopropylethylamine, MeCN,

80 ^ꢀC, 2.5 h, 92%; (b) mCPBA, NaHCO₃, CH₂Cl₂, rt, 1.5 h, 82%; (c) (i) nBuLi, 20, 1,2-dimethoxyethane, À78 ꢁ0 ^ꢀC, 3 h, (ii) benzoyl chloride,

À78 ^ꢀCꢁrt, 1h, (iii) 3-(dimethylamino)propylamine, rt, 97% (a mixture of diastereomers); (d) 5% Na–Hg, Na ₂HPO₄, MeOH, rt, 1h, 63%; (e)

Jones reagent, acetone, rt, 1.5 h, 58%; (f) triﬂuoroacetic acid, CH₂Cl₂, rt, 0.5 h, 87%; (g) 37% HCHO aq, NaBH₃CN, CH₃CN, rt, 1h, 80%.

column, giving four stereoisomers 17a, ent-17a, 17b, and

ent-17b with high optical purity, as follows: 17a: 19%,

94% ee, t_R23.5 min; ent-17a: 18%, 99% ee, t_R22.7 min;

17b: 30%, 99% ee, t_R21.2 min; ent-17b: 32%, 98% ee,

t_R33.6 min. Optically pure samples of 17a, ent-17a, 17b,

and ent-17b were prepared by subsequent recrystalliza-

tions. To determine their absolute conﬁgurations, we

performed X-ray spectroscopic analysis of 17a and 17b,

which were considered to be diastereomeric with respect

to each other based on their ¹H NMR spectra, by

employing the heavy atom method. Based on the results

of X-ray analysis (Figs. 2 and 3), we deﬁnitely estab-

lished that (i) 17a and 17b bear the same absolute con-

ﬁgurations as that of natural 1 concerning the ring

junctions and the C-1methoxy group, (ii) 17a and 17b

were the 4b- and 4a-epimer, respectively, and (iii) ent-

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M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

Figure 3. Ortep drawing of (+)-4a-carbinyl 4-bromobenzoate 17b.

Figure 2. Ortep drawing of (+)-4b-carbinyl 4-bromobenzoate 17a.

Carbon-chain extension of the C-3 methyl group:

synthesis of 11-methylhimbacine 3 (Scheme 3)

17a and ent-17b were the enantiomers of 17a and 17b, as

shown in Scheme 1. Thus, in addition to 17a bearing the

same absolute conﬁguration as that of natural 1 at the

tricyclic moiety, we have its three stereoisomers ent-17a,

17b (the C₄epimer of 17a), and ent-17b. These stereo-

isomeric 4-bromobenzoates were successfully utilized

for synthesizing the novel himbacine congeners 3-deme-

thylhimbacines (3-norhimbacines) (2 and ent-2) and

their C₄epimers (4-epi-2 and ent-4-epi-2).

In order to disclose the relationship between the carbon

length at the C-3 position and the muscarinic M₂

antagonistic activity, we next examined the synthesis of

11-methylhimbacine

3

by

employing

tetra-

hydroisobenzofuran 5 and (S)-5-ethyl furan-2(5H)-one

25¹⁷as the starting materials. According to the reported

procedure, 25 was prepared from ethyl (E)-3-hexenoate

24 in ca. 75% ee optical purity. Following the same

synthetic scheme as previously developed for the pre-

paration of natural 1, we have readily obtained phenyl

sulﬁde 35 from 25 in 12 steps. At this stage, 35, which

was considered to be partially optically active, was sub-

jected to puriﬁcation by means of HPLC using a Chir-

alpak AD-H column, giving 35, 99% ee, and ent-35,

90% ee, in 81and 9% yields, respectively. Optically

pure phenyl sulﬁde 35 thus obtained was transformed to

sulfone 36, the key intermediate, in a quantitative yield.

The Julia–Lythgoe coupling reaction of 36 with 20 fol-

lowed by sequential oxidation, deprotection, and N-

methylation uneventfully aﬀorded the desired 3 in a

22% combined yield.

First, in order to achieve 3-demethylhimbacine (3-nor-

himbacine) 2, 17a was transformed to sulfone 19, the

key intermediate, by the three-step sequence involving

alkaline hydrolysis, benzenesulfenylation of 4b-carbinol

16a

using

(cyanomethyl)trimethylphosphonium

iodide,¹⁶and 3-chloroperoxybenzoic acid (mCPBA)

oxidation of phenyl sulﬁde 18. The Julia–Lythgoe cou-

pling reaction of 19 with the piperidine-2-carboxy-

aldehyde 20 was eﬀected at À78ꢁ0 ^ꢀC. Quenching the

coupling reaction with excess benzoyl chloride followed

by treatment of the resulting b-benzoxysulfone with 5%

Na–Hg in methanol in the presence of Na₂HPO₄gave

rise to (E)-4b-oleﬁn 21 in a 61% combined yield. In the

case of 4a-sulfone 4-epi-19, however, the coupling reac-

tion smoothly took place at À78 ^ꢀC in a similar manner

to that for the synthesis of natural 1. Diﬀerent reactivity

observed for 19 and 4-epi-19 might be explained by the

stability of the lithium anions derived from them.

Stereo-inversion of the C-3 methyl group: synthesis of

3-epihimbacine 4 (Scheme 4)

Finally, we explored the relationship between the ste-

reochemistry at the C-3 methyl group and the muscari-

nic M₂receptor binding activity. Our plan for

synthesizing 4 was the stereo-inversion of the C-3

methyl group of the known lactone 40,^11,12the inter-

mediate for the synthesis of natural 1, by successive ring

opening of g-lactone moiety and ring-closure to epi-

meric g-lactone with stereo-inversion. Thus, by follow-

ing the Lansbury’s and Blay’s procedure,¹⁸40 was

subjected to sequential hydrolysis of the g-lactone moi-

ety using potassium hydroxide in 95% methanol,

O-methanesulfonylation of the resulting hydroxy-

carboxylate, and lactone formation by the intramole-

Resulting (E)-4b-oleﬁn 21 was subjected to sequential

oxidative deprotection of the hemiacetal moiety, depro-

tection of the N-Boc group, and reductive N-methyla-

tion, furnishing 2 in a 40% combined yield. By the same

synthetic sequence, ent-17a, 17b, and ent-17b were also

successfully converted to ent-2, 4-epi-2, and ent-4-epi-2

in good yield by way of ent-19, 4-epi-19, and ent-4-epi-

19, respectively. To avoid confusion, the compounds

carrying the conﬁgurations corresponding to that of

natural 1 were only depicted in Scheme 2.

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1173

Scheme 3. Synthesis of 11-methylhimbacine. (a) See ref 17, 92% (two steps); (b) 5, 5M LiClO₄–Et₂O, 4,4⁰-thiobis(6-tert-butyl-m-cresol), rt, 72 h,

44%; (c) H₂, 10% Pd/C, EtOH, rt, 4 h, 74%; (d) LiN(TMS)₂, THF, À78 ꢁ À40 ^ꢀC, 5 h, 93%; (e) DBU, toluene, 80 ^ꢀC, 3 h, 72%; (f) H₂, PtO₂,

EtOH, rt, 4 h, 91%; (g) (i) DIBAL-H, Et₂O, À78 ^ꢀC, 1h, 87%, (ii) BF –Et₂O, MeOH, CH₂Cl₂, À78 ^ꢀCꢁrt, 16 h, 100%; (h) TPAP, 4-methylmor-

3

pholine N-oxide, MS4A, CH₂Cl₂, rt, 1.5 h, 70%; (i) Ph₃PCH₃I, NaN(TMS)₂, Et₂O, 0 ^ꢀCꢁrt, 14 h, 100%; (j) (i) BH₃–THF, THF, À78 ^ꢀCꢁrt, 10 h;

(ii) 30% H₂O₂, 10% NaOH, 0 ^ꢀC, 0.5 h, 34a: 70%, 34b: 8%; (k) (i) methanesulfonyl chloride, Et₃N, CH₂Cl₂, 0 ^ꢀC, 2 h, 79%; (ii) thiophenol, tBuOK,

DMSO, rt, 11 h, 71%, then HPLC separation, 35: 81%, ent-35: 9%; (l) mCPBA, NaHCO₃, CH₂Cl₂, rt, 1h, 100%; (m) (i) nBuLi, 20, 1,2-dime-

thoxyethane, À78ꢁ0 ^ꢀC, 3.5 h; (ii) benzoyl chloride, À78 ^ꢀCꢁrt, 0.5 h, (iii) 3-(dimethylamino)propylamine, rt, 0.5 h, 60% (a mixture of diaster-

eomers); (n) 5% Na–Hg, Na₂HPO₄, MeOH, rt, 1h, 66%; (o) Jones reagent, acetone, rt, 1h, 73%; (p) triﬂuoroacetic acid, CH ₂Cl₂, rt, 1h, 100%; (q)

37% HCHO aq, NaBH₃CN, CH₃CN, rt, 0.5 h, 81%.

cular S_N2 type ring closure of the carboxylate anion,

which aﬀorded 41 possessing the 3b-methyl group in a

28% yield along with 21% recovery of 40. These

sequential operations were performed in a one-pot pro-

cess. These epimers were separated by careful column

chromatography, and 41 was successfully transformed

to 4 in two steps in a 56% combined yield. Stereo-

chemistry at the C-3 position of the desired 4 was con-

ing the same absolute conﬁguration as natural 1 showed

superior M₂receptor binding aﬃnity and equal subtype

selectivity to those of 1, and that the other three stereo-

isomers ent-2, 4-epi-2, and ent-4-epi-2 showed only weak

M₂receptor binding aﬃnity compared to that of 1 and

2. Additionally, it appeared that, similar to the case for

1 and its C₄-epimer,^11bthe stereochemistry at the C-4

position plays an important role for exhibiting mus-

carinic M₂receptor binding aﬃnity. Moreover, 3 and 4

were found to show less potent muscarinic M₂subtype

1

ﬁrmed by NOESY analysis of its H NMR spectrum in

comparison with that for 1 (Fig. 4).

Table 1. In vitro binding activity of novel himbacine congeners

Muscarinic M₂receptor binding aﬃnity of novel

himbacine congeners

Entry

Compd

ÀlogK_i

M₂(brainstem)

M₁(cortex)

With completion of the synthesis of four 3-demethyl-

himbacine (3-norhimbacine) derivatives 2, ent-2, 4-epi-2,

and ent-4-epi-2, 11-methylhimbacine 3, and 3-epi-him-

bacine 4, they were subjected to receptor binding aﬃnity

assay against the muscarinic M₁and M₂subtype recep-

tors. The results were summarized in Table 1. Surpris-

ingly, we found that, despite lacking the 3a-methyl

group, 3-demethylhimbacine (3-norhimbacinbe) 2 bear-

1

2

3

4

5

6

7

1

7.17.9

7.4

6.0

6.2

6.3

2

ent-2

4-epi-2

ent-4-epi-2

3

8.1

6.1

6.4

6.7

7.4

6.4

6.8

4

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M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

Figure 4. NOESY correlation of 3-epihimbacine 4 and natural him-

bacine 1.

Scheme 4. Synthesis of 3-epihimbacine. (a) (i) KOH, 95% MeOH,

70 ^ꢀC, 2 h; (ii) methanesulfonyl chloride, Et₃N, THF, 0 ^ꢀCꢁrt, 1h;

(iii) NaOH, H₂O, 50 ^ꢀC, 1h, 36%; (b) triﬂuoroacetic acid, CH Cl₂, rt,

1h, 93%; (c) 37% HCHO aq, NaBH ₃CN, CH₃CN, rt, 0.5 h, 60%.

methylsilane (d=0) and/or residual solvents such as

chloroform (d=7.26) as an internal standard. Splitting

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

q, quartet; m, multiplet; br, broad peak. Measurements

of mass spectra were performed with a JMS-SX102A

mass spectrometer. Data for elemental analysis are

withinꢂ0.3% of the theoretical values and were deter-

mined by a Yanaco CHN-corder MT-5. Analytical and

preparative HPLC was carried out using a Hitachi

L-4200 UV–vis detector, a Hitachi L-6200 intelligent

pump, a Hitachi D-2500 chromato-integrator, and a GL

Sciences Model 557 LC column oven. Conditions for

separation were described for the respective experi-

mental parts. Unless otherwise noted, all the experi-

ments were carried out using anhydrous solvents under

an atmosphere of dry argon. Throughout this work,

Merck precoated TLC plates (Silica gel 60 F₂₅₄, 0.25

mm; Art. 5715) were used for thin layer chromato-

graphic (TLC) analysis, and all the spots were visualized

using ultraviolet (UV) light followed by coloring with

phosphomolybdic acid. Wako Gel C-200, Wako Gel C-

300, Silica gel 60 (0.040–0.063 mm, F₂₅₄; Art. 9385,

Merck Co., Ltd.), or Chromatorex¹NH-DM 1020

(100–200 mesh, Fuji Silysia Chemical, Ltd.) was used as

an adsorbent for the ﬂash column chromatography.

2

receptor binding aﬃnity than 1 and 2. Thus, it was

clearly indicated that the C-3 methyl group on the

g-lactone ring moiety is not important for muscarinic

M₂receptor binding aﬃnity and subtype selectivity, and

that carbon-chain extension and stereo-inversion of the

C-3 methyl group obviously decrease muscarinic M₂

receptor binding activity, probably due to their steric

eﬀects.

Conclusion

In conclusion, we have succeeded in synthesizing the

novel himbacine congeners 3-demethylhimbacine

(3-norhimbacine)

2 and 4-epi-3-demethylhimbacine

(4-epi-3-norhimbacine) 4-epi-2 and their enantiomers

(ent-2 and ent-4-epi-2), 11-methylhimbacine 3, and

3-epihimbacine 4 in optically pure forms. All of these

congeners were produced in order to study the eﬀect of

the C-3 methyl group of natural 1 on its activity. By

testing their muscarinic M₂subtype receptor binding

activity, we found that 3-demethylhimbacine (3-nor-

himbacine) 2 exhibits a more potent binding aﬃnity for

muscarinic M₂subtype receptor than does natural 1. To

the best of our knowledge, this is the ﬁrst case in which

muscarinic M₂subtype receptor binding activity more

potent than that of natural 1 has been exhibited by its

close congener.^9,10Further investigation of the phar-

macological evaluation of 2 is in progress.

(3aR*,4S*,9R*,9aR*)-4,9-Epoxy-3a,4,5,6,7,8,9,9a-octa-

hydronaphtho[2,3-c]furan-1(3H)-one (dl-7). To a solution

of lithium perchlorate (3.18 g) and 4,4⁰-thiobis (6-tert-

butyl-m-cresol) (0.96 g, 1.78 mmol) in diethyl ether (6

mL) were successively added 5 (6.54 g, 53.5 mmol) and 6

(3.00 g, 35.7 mmol), and the mixture was stirred at room

temperature for 48 h. The reaction mixture was diluted

with diethyl ether (100 mL) and poured into water (100

mL). The upper organic layer was separated, and the

aqueous layer was extracted with CH₂Cl₂(10 mLꢃ3).

The organic extracts were combined, dried over anhy-

drous magnesium sulfate (MgSO₄), ﬁltered, and then

concentrated in vacuo. Flash column chromatography

(hexane/ethyl acetate=4:1, 2:1, then 1:1) of the residue

gave dl-7 (3.62 g, 49%) as a colorless powder. This

crude material was immediately subjected to the next

reaction without further puriﬁcation by recrystalliza-

Experimental

All melting points were determined with a Yanaco MP-

500D micro melting point apparatus and are

uncorrected. Measurements of optical rotations were

carried out using a P-1020 automatic digital polari-

meter. Infrared (IR) spectra were recorded with a

JASCO FT/IR-5300 spectrometer. ¹H NMR spectra

were measured with a JEOL JNM-EX-400 (400 MHz)

spectrometer. ¹³C NMR spectra were taken with a

JEOL JNM-EX-400 (100 MHz) spectrometer. The che-

mical shifts are expressed in parts per million (d value)

downﬁeld from tetramethylsilane, using tetra-

ꢀ

1

tion. Mp 105–106 C. H NMR (400 MHz, CDCl₃): d

1.46–1.56 (m, 2H), 1.63–1.72 (m, 2H), 1.84–1.97 (m,

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1175

2H), 2.19–2.30 (m, 2H), 2.72 (td, J=8.3, 3.6 Hz, 1H),

2.81(d, J=7.8 Hz, 1H), 4.21 (dd, J=9.8, 3.9 Hz, 1H),

4.51(dd, J=9.8, 8.6 Hz, 1H), 4.71 (s, 1H), 5.04 (s, 1H).

IR (KBr): 2950, 1750, 1190 cm^À1. MS (EI) (m/z): 206

(M⁺), 122 (100). HRMS (EI) (m/z): calcd for C₁₂H₁₄O₃

(M⁺): 206.0943. Found, 206.0970.

with diluted aqueous citric acid solution (50 mL). The

lower aqueous layer was extracted with diethyl ether (10

mLꢃ3). The organic layers were combined, washed with

brine (20 mL), dried over anhydrous MgSO₄, ﬁltered,

and then concentrated in vacuo. Flash column chroma-

tography (hexane/ethyl acetate=1:2) of the residue gave

dl-10 (1.33 g, 70%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃): d 1.03 (qd, J=12.7, 3.5 Hz, 1H),

1.19–1.33 (m, 1H), 1.38–1.49 (m, 1H), 1.73 (d, J=3.9

Hz, 1H), 1.79–1.90 (m, 2H), 1.96–2.10 (m, 2H), 2.14–

2.22 (m, 1H), 2.31–2.38 (m, 1H), 3.02 (qd, J=8.3, 4.4

Hz, 1H), 3.21 (dq, J=8.3, 2.8 Hz, 1H), 3.83 (dt, J=7.3,

4.4 Hz, 1H), 4.24 (t, J=8.8 Hz, 1H), 4.45 (dd, J=9.3,

(3aR*,4R*,4aS*,8aR*,9S*,9aR*)-4,9-Epoxy-decahydro-

naphtho[2,3-c]furan-1(3H)-one (dl-8). A mixture of dl-7

(17.0 g, 82.4 mmol) and 10% Pd/C (1.70 g, 10% w/w) in

ethanol (300 mL) was stirred at room temperature for 5

h under H₂atmosphere (1atm). Insoluble materials

were ﬁltered and washed thoroughly with ethyl acetate

(100 mL). The ﬁltrates were combined and concentrated

in vacuo to give dl-8 (16.8 g, 98%) as a colorless pow-

der. Mp 90–91 ^ꢀC (hexane-ethyl acetate). ¹H NMR

(400 MHz, CDCl₃): d 1.04–1.21 (m, 2H), 1.30–1.57 (m,

4H), 1.68–1.78 (m, 2H), 2.01–2.17 (m, 2H), 3.00 (td,

J=8.3, 3.9 Hz, 1H), 3.05 (d, J=8.3 Hz, 1H), 4.10 (dd,

J=9.3, 4.0 Hz, 1H), 4.40 (d, J=4.9 Hz, 1H), 4.46 (t,

8.1Hz, H1), 5.34 (d,

J=3.0 Hz, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 25.7, 27.1, 31.8, 34.8, 39.0, 41.3,

41.5, 68.6, 72.0, 111.9, 141.5, 177.0. IR (neat): 3450,

2930, 1770, 1010 cm^À1. MS (EI) (m/z): 208 (M⁺), 164,

149, 135, 121, 107, 91 (100). HRMS (EI) (m/z): calcd for

C₁₂H₁₆O₃(M⁺): 208.1099. Found, 208.1095.

J=9.1Hz, H1 ), 4.75 (d,

J=4.9 Hz, 1H). ¹³C NMR

(3aR*,4R*,4aS*,8aR*,9aS*)-4-Hydroxy-decahydronaph-

tho[2,3-c]furan-1(3H)-one (dl-11). A mixture of dl-10

(5.12 g, 24.6 mmol) and PtO₂(0.50 g, 10% w/w) in eth-

anol (100 mL) was stirred at room temperature for 2 h

under H₂atmosphere (1atm). Insoluble materials were

ﬁltered and washed thoroughly with ethyl acetate (100

mL). The ﬁltrates were combined and concentrated in

vacuo to give dl-11 (4.93 g, 95%) as a colorless powder.

Mp 149–150 ^ꢀC (hexane–ethyl acetate). ¹H NMR

(400 MHz, CDCl₃): d 0.83–0.93 (m, 1H), 0.98–1.32 (m,

6H), 1.69–1.86 (m, 4H), 1.96 (d, J=3.9 Hz, 1H), 2.05–

2.12 (m, 1H), 2.62 (dt, J=12.7, 6.9 Hz, 1H), 3.01 (dq,

J=11.7, 7.2 Hz, 1H), 3.66 (ddd, J=10.3, 6.4, 3.7 Hz,

1H), 4.31 (dd, J=11.3, 9.3 Hz, 1H), 4.43 (dd, J=9.3,

8.3 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d 25.6, 25.6,

28.9, 30.6, 32.9, 38.2, 39.6, 40.8, 43.6, 68.1, 73.0, 178.9.

IR (KBr): 3440, 2920, 1750, 1190 cm^À1. MS (EI) (m/z):

210 (M⁺), 192, 182, 164, 85 (100). Anal. calcd for

C₁₂H₁₈O₃: C, 68.55; H, 8.63. Found: C, 68.52; H, 8.81.

(100 MHz, CDCl₃): d 19.4, 19.4, 19.5, 19.8, 37.8, 38.9,

39.6, 45.0, 72.4, 83.7, 86.2, 178.6. IR (KBr): 2940, 1760

cm^À1. MS (EI) (m/z): 208 (M⁺), 190, 179, 95 (100).

Anal. calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C,

68.97; H, 7.74.

(3aR*,4R*,4aS*,8aS*) - 4 - Hydroxy - 3a,4,4a,5,6,7,8,8a -

octahydronaphtho[2,3-c]furan-1(3H)-one (dl-9). To

a

solution of dl-8 (10.0 g, 48.0 mmol) in tetrahydrofuran

(500 mL), lithium bis(trimethylsilyl)amide (1.05 M solu-

tion in tetrahydrofuran, 228.7 mL, 0.24 mol) was added

dropwise at À70 ^ꢀC. The resulting mixture was stirred at

the same temperature for 5 h and then gradually

warmed to À40 ^ꢀC with stirring. After quenching the

reaction by adding diluted aqueous citric acid solution

(500 mL) at À40 ^ꢀC, the mixture was stirred at room

temperature for 5 min and concentrated in vacuo. The

residual aqueous mixture was extracted with diethyl

ether (150 mLꢃ3). The organic extracts were combined,

washed with brine (100 mL), dried over anhydrous

MgSO₄, ﬁltered, and then concentrated in vacuo. Flash

column chromatography (hexane/ethyl acetate=1:1) of

the residue gave dl-9 (9.87 g, 99%) as a yellow oil. This

material was directly used for the next reaction without

further puriﬁcation. ¹H NMR (400 MHz, CDCl₃): d

0.98–1.74 (m, 4H), 1.81–1.89 (m, 2H), 1.95–2.10 (m,

2H), 2.14–2.21 (m, 1H), 2.31–2.38 (m, 1H), 2.77–2.84

(m, 1H), 3.16–3.23 (m, 1H), 4.03 (dd, J=9.3, 3.4 Hz,

1H), 4.31 (dd, J=9.8, 8.3 Hz, 1H), 4.45 (dd, J=8.8, 8.1

Hz, 1H), 6.75 (t, J=2.8 Hz, 1H). MS (EI) (m/z): 208

(M⁺), 164, 149, 135, 121, 107, 91 (100). HRMS (EI) (m/

z): calcd for C₁₂H₁₆O₃(M⁺): 208.1099. Found,

208.1086.

(1S*,3aR*,4R*,4aS*,8aR*,9aS*) - Dodecahydro - 1 - meth-

oxynaphtho[2,3-c]furan-4-ol (dl-12) and (4R*,4aS*,8aR*)-

4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-c]furan-4-ol (dl-

13). To a solution of dl-11 (8.00 g, 38.0 mmol) in die-

thyl ether (500 mL), diisobutylaluminum hydride

(0.93 M solution in hexane, 122.7 mL, 0.11 mol) was

added dropwise at À70 ^ꢀC, and the mixture was stirred

at the same temperature for 1h. The reaction was

quenched by adding methanol and water (each 10 mL)

at À70 ^ꢀC, and the mixture was stirred at room tem-

perature for 1h. The precipitates formed were removed

by ﬁltration through a pad of Celite, and the collected

solid was washed with ethyl acetate/methanol (10:1)

(300 mL). The ﬁltrates were combined and concentrated

in vacuo. The residue was diluted with brine (300 mL),

and the aqueous mixture was extracted with a mixture

of dichloromethane and ethanol (10:1) (50 mLꢃ3). The

combined organic extracts were dried over anhydrous

MgSO₄, ﬁltered, and then concentrated in vacuo, to give

a crude anomeric mixture of the hemiacetals (6.88 g,

85%) as a colorless oil. This was directly subjected to

(3aR*,4R*,4aS*,9aS*)-4-Hydroxy-3a,4,4a,5,6,7,8,9a-oc-

tahydronaphtho[2,3-c]furan-1(3H)-one (dl-10). To

a

solution of dl-9 (1.89 g, 9.08 mmol) in toluene (5 mL)

was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

(6.79 mL, 45.4 mmol), and the mixture was heated at

80 ^ꢀC with stirring for 4 h. After cooling, the reaction

mixture was concentrated in vacuo and diluted with

diethyl ether (50 mL). The ethereal solution was washed

1

the next reaction without further puriﬁcation. H NMR

(400 MHz, CDCl₃): d 0.83–1.30 (m, 7H), 1.43–1.85 (m,

1176

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1

5H), 2.02–2.09 (m, 1H), 2.21 (dt, J=12.2, 6.2 Hz, 1H),

2.46 (d, J=2.9 Hz, 1H), 3.03–3.11 (m, 1H), 3.68 (ddd,

J=9.8, 5.9, 3.7 Hz, 1H), 3.98 (dd, J=10.3, 8.8 Hz, 1H),

4.16 (apparent t, J=8.8 Hz, 1H), 5.15 (d, J=3.0 Hz,

1H). MS (CI) (m/z): 195 (M⁺+H-H₂O) (100). HRMS

(CI) (m/z): calcd for C₁₂H₁₉O₂(M⁺+H-H₂O):

195.1385. Found, 195.1364.

a colorless powder. Mp 78-79 ^ꢀC (hexane). H NMR

(400 MHz, CDCl₃): d 1.08–1.33 (m, 5H), 1.39–1.49 (m,

1H), 1.68–1.86 (m, 4H), 1.95–2.04 (m, 2H), 2.56 (dt,

J=12.7, 6.6 Hz, 1H), 3.21–3.31 (m, 1H), 3.31 (s, 3H),

3.95 (t, J=9.1 Hz, 1H), 4.17 (dd, J=10.3, 8.8 Hz, 1H),

4.77 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): d 25.1, 25.4,

25.5, 32.5, 34.2, 40.9, 48.0, 50.0, 50.8, 54.4, 69.1, 109.4,

211.4. IR (KBr): 2940, 1700 cm^À1. MS (FAB) (m/z): 330

[(M⁺+diethanolamine)+H], 316, 298, 233 (100). Anal.

calcd for C₁₃H₂₀O₃: C, 69.61; H, 8.99. Found: C, 69.32;

H, 9.07.

To a solution of the crude hemiacetals (6.88 g, 32.4

mmol) in CH₂Cl₂(200 mL) and methanol (200 mL) was

added boron triﬂuoride diethyl etherate (5.98 mL, 48.6

mmol) at À70 ^ꢀC. The mixture was stirred at the same

temperature for 12 h and then gradually warmed to

room temperature with stirring. After the reaction was

quenched by adding triethylamine (6.78 mL, 48.6 mmol)

at 0 ^ꢀC, the resulting mixture was further stirred at room

temperature for 1h and then concentrated in vacuo.

The residue was diluted with diluted aqueous citric acid

solution (300 mL), and the aqueous mixture was

extracted with diethyl ether (100 mLꢃ3). The organic

extracts were combined, washed with brine (100 mL),

dried over anhydrous MgSO₄, ﬁltered, and then con-

centrated in vacuo. Flash column chromatography

(hexane/ethyl acetate=2:1) of the residue gave dl-12

(4.56 g, 62% from dl-11) as a colorless powder along

with dl-13 (236 mg, 4% from dl-11). dl-12: Mp 75-77 ^ꢀC

(1S*,3aS*,4aS*,8aR*,9aS*)-Dodecahydro-1-methoxy-4-

methylenenaphtho[2,3-c]furan (dl-15). To a suspension of

methyltriphenylphosphonium iodide (13.2 g, 32.5 mmol)

in diethyl ether (200 mL), sodium bis(trimethylsilyl)amide

(1M solution in toluene, 32.5 mL, 32.5 mmol) was

added dropwise under ice cooling, and the mixture was

stirred at room temperature for 0.5 h. The resulting

mixture was added dropwise to a solution of dl-14 (1.46

g, 6.51mmol) in diethyl ether (30 mL) at À78 ^ꢀC, and

the mixture was stirred at the same temperature for 6 h

and then gradually warmed to room temperature with

stirring. After quenching the reaction by adding cold

saturated aqueous ammonium chloride solution (30

mL), the mixture was ﬁltered through a pad of Celite,

and the collected solid was washed with diethyl ether

(200 mL). The ﬁltrates were combined and concentrated

in vacuo. The residue was diluted with water (50 mL),

and the aqueous mixture was extracted with diethyl

ether (30 mLꢃ3). The combined ethereal extracts were

washed with brine (30 mL), dried over anhydrous

MgSO₄, ﬁltered, and then concentrated in vacuo. Flash

column chromatography (hexane/ethyl acetate=10:1)

of the residue gave dl-15 (778 mg, 54%) as a yellow

powder. Mp 53-55 C. H NMR (400 MHz, CDCl₃): d

1.00–1.35 (m, 6H), 1.54–1.73 (m, 4H), 1.80–1.89 (m,

2H), 2.17–2.24 (m, 1H), 3.26–3.32 (m, 1H), 3.33 (s, 3H),

3.79 (dd, J=10.3, 8.1 Hz, 1H), 4.00 (dd, J=9.3, 8.3 Hz,

1H), 4.64 (s, 1H), 4.72 (t, J=2.0 Hz, 1H), 4.86 (t, J=1.8

Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d 26.1, 26.3,

28.8, 32.9, 34.4, 41.4, 42.0, 45.1, 46.5, 54.5, 70.6, 109.3,

109.9, 148.5. IR (KBr): 2930, 1440, 1380, 1190, 1030

cm^À1. MS (EI) (m/z): 222 (M⁺), 192 (100). HRMS (EI)

(m/z): calcd for C₁₄H₂₂O₂(M⁺): 222.1620. Found,

222.1605.

1

(hexane-ethyl acetate). H NMR (400 MHz, CDCl₃): d

0.81–1.05 (m, 4H), 1.11–1.30 (m, 3H), 1.45–1.51 (m,

1H), 1.63 (d, J=3.9 Hz, 1H), 1.63–1.84 (m, 3H), 2.02–

2.09 (m, 1H), 2.17 (dt, J=12.2, 6.2 Hz, 1H), 2.93–3.01

(m, 1H), 3.32 (s, 3H), 3.65 (ddd, J=10.3, 6.4, 4.2 Hz,

1H), 3.97 (dd, J=10.3, 8.3 Hz, 1H), 4.06 (t, J=9.1Hz,

1H), 4.63 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): d 25.9,

25.9, 29.0, 32.0, 33.3, 38.4, 41.4, 43.3, 44.2, 54.4, 67.8,

74.5, 109.5. IR (KBr): 3350, 2920, 1040 cm^À1. MS (EI)

(m/z): 193 (M⁺-H₂OMe), 176, 148, 101, 86 (100). Anal.

calcd for C₁₃H₂₂O₃: C, 68.99; H, 9.80. Found: 68.70; H,

9.66. dl-13: Mp 126–127 ^ꢀC (hexane). ¹H NMR

(400 MHz, CDCl₃): d 0.97–1.30 (m, 6H), 1.33–1.46 (m,

1H), 1.72–1.89 (m, 3H), 2.09 (ddd, J=16.1, 11.7, 1.8

Hz, 1H), 2.30–2.37 (m, 1H), 2.63 (dd, J=16.1, 4.9 Hz,

1H), 4.28 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.42 (s, 1H).

¹³C NMR (100 MHz, CDCl₃): d 25.8, 25.9, 27.4, 30.1,

34.1, 37.6, 48.0, 70.8, 120.9, 126.7, 136.8, 138.7. IR

(KBr): 3240, 2920, 1030 cm^À1. MS (EI) (m/z): 192 (M⁺)

(100). Anal. calcd for C₁₂H₁₆O₂: C, 74.97; H, 8.39.

Found: C, 74.89; H, 8.46.

ꢀ

1

(1S*,3aR*,4R*,4aS*,8aR*,9aS*)-Dodecahydro-1-meth-

oxynaphtho[2,3-c]furan-4-methanol and Its (4S*)-epimer

(dl-16a and dl-16b). To a solution of dl-15 (141 mg,

0.63 mmol) in tetrahydrofuran (5 mL), borane-tetra-

hydrofuran complex (1M solution in tetrahydrofuran,

952 mL, 0.95 mmol) was added dropwise at 0 ^ꢀC, and the

mixture was stirred at room temperature for 7 h. After

adding water (5 mL) to the reaction mixture at 0 ^ꢀC,

30% hydrogen peroxide (1.00 mL) and 10% sodium

hydroxide solution (1.00 mL) were added to the aqu-

eous mixture at the same temperature. After stirring for

0.5 h, the mixture was concentrated in vacuo. The resi-

due was diluted with water (10 mL), and the aqueous

mixture was extracted with diethyl ether (5 mLꢃ3). The

organic extracts were combined, washed with brine (5

mL), dried over anhydrous MgSO₄, ﬁltered, and then

(1S*,3aR*,4aS*,8aR*,9aS*)-Decahydro-1-methoxynaph-

tho[2,3-c]furan-4(1H)-one (dl-14). To a solution of dl-12

(691mg, 3.06 mmol), 4-methylmorpholine N-oxide (537

mg, 4.58 mmol), and molecular sieves (MS 4A, 1.50 g)

in CH₂Cl₂(6 mL) was added tetrapropylammonium

perruthenate (VII) (TPAP) (53.7 mg, 0.15 mmol) at

room temperature, and the mixture was stirred at the

same temperature for 1h. The reaction mixture was ﬁl-

tered through a pad of Celite, and the collected solid

was washed with diethyl ether (30 mL). The organic ﬁl-

trates were combined, washed with 10% sodium thio-

sulfate solution (20 mL) and brine (20 mL), dried over

anhydrous MgSO₄, ﬁltered, and then concentrated in

vacuo. Flush column chromatography (hexane/ethyl

acetate=2:1) of the residue gave dl-14 (667 mg, 97%) as

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1177

concentrated in vacuo. Flash column chromatography

(hexane/ethyl acetate=1:1) of the residue gave an inse-

parable mixture of dl-16a and its (4S*)-epimer dl-16b

(125 mg, 82%). MS (CI) (m/z): 241(M ⁺+H), 209

(100). This sample was directly subjected to the next

step without separation.

(2) A, b=93.81(2) ^ꢀ, V=994.2 (4) A³, Z=2, density

r

_calcd=1.414 g/cm³, m(Cu-K_a)=30.05 cm^À1, T=298 K,

size of crystal=0.40ꢁ0.37ꢁ0.34 mm^À1. The structure

was solved by direct methods and expanded using

Fourier techniques. Final R and Rw were 0.040 and

0.053, respectively, for 3207 reﬂections.

[(1S,3aR,4R,4aS,8aR,9aS) - Dodecahydro - 1 - methoxy-

naphtho[2,3-c]furan-4yl]methyl 4-bromobenzoate (17a),

its (4S)-epimer (17b), and their enantiomers (ent-17a and

ent-17b). To a solution of 4-bromobenzoic acid (226

mg, 1.12 mmol) in benzene (2 mL) was added thionyl

chloride (0.50 mL), and the solution was stirred at 80 ^ꢀC

for 1h. After concentration in vacuo, the residue was

diluted with CH₂Cl₂(2 mL), dl-16a, dl-16b (90.0 mg,

0.37 mmol) and triethylamine (261 mL, 1.87 mmol) were

added at 0 ^ꢀC. The mixture was stirred for 18 h with

gradual warming to room temperature. After dilution

with aqueous citric acid solution (10 mL), the reaction

mixture was extracted with ethyl acetate (3 mLꢃ3). The

organic extracts were combined, washed with brine (3

mL), dried over anhydrous MgSO₄, ﬁltrated, and then

concentrated in vacuo. Flush column chromatography

(hexane/ethyl acetate=4:1) of the residue gave a mix-

ture of 17a, ent-17a, 17b, and ent-17b (157 mg, 99%).

MS (FAB) (m/z): 577 [(M⁺+2,2⁰-dithiodiethanol)+H].

HRMS (FAB) (m/z): calcd for C₂₅H₃₈BrO₆S₂

[(M⁺+2,2⁰-dithiodiethanol)+H]: 577.1293. Found,

577.1246.

(c) ent-17a: [a]_D²²À41^ꢀ(c 0.63, CHCl₃). Mp 94–95 ^ꢀC

1

(pentane–ether). 99% ee by HPLC analysis. H NMR,

¹³C NMR, IR, and MS spectra of this sample were

identical to those described for 17a. HRMS (FAB) (m/

z): calcd for C₂₀H₂₄BrO₃(M⁺ÀHOMe): 391.0909.

Found, 391.0949. Anal. calcd for C₂₁H₂₇BrO₄: C, 59.58;

H, 6.43. Found: C, 59.47; H, 6.30.

(d) 17b: [a]²_D⁶+5.7^ꢀ(c 0.10, CHCl₃). Mp 107–108 ^ꢀC

(hexane). 99% ee by HPLC analysis. ¹H NMR

(400 MHz, CDCl₃): d 0.82–0.96 (m, 2H), 1.16–1.43 (m,

6H), 1.53–1.73 (m, 3H), 1.77–1.82 (m, 1H), 1.94–1.99

(m, 1H), 2.23 (dt, J=12.7, 6.4 Hz, 1H), 2.83 (dt,

J=10.1, 5.9 Hz, 1H), 3.31 (s, 3H), 3.83 (dd, J=11.3, 8.1

Hz, 1H), 4.07 (dd, J=9.3, 7.8 Hz, 1H), 4.26 (dd,

J=11.3, 8.3 Hz, 1H), 4.50 (dd, J=10.8, 4.2 Hz, 1H),

4.61(s, 1H), 7.59 (dt,

J=8.8, 2.3 Hz, 2H), 7.89 (dt,

J=8.8, 2.3 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): d

26.2, 27.1, 30.4, 32.8, 34.7, 34.8, 36.4, 37.7, 39.1, 41.1, 54.5,

66.4, 69.5, 110.2, 128.0, 129.2, 131.1, 131.1, 131.8, 131.8,

166.0. IR (KBr): 2940, 1710, 1590, 1270, 1110 cm^À1. MS

(FAB) (m/z): 528 [(M⁺+diethanolamine)+H]. HRMS

(FAB) (m/z): calcd for C₂₅H₃₉BrNO₆[(M⁺+diethano-

lamine)+H]: 528.1961. Found, 528.1935. Anal. calcd

for C₂₁H₂₇BrO₄: C, 59.58; H, 6.43. Found: C, 59.47; H,

6.32.

A mixture of 17a, ent-17a, 17b, and ent-17b (1.00 g) was

subjected to separation using HPLC [CHIRALCEL OD

(Daicel Chemical Industries, Ltd.), 2ꢃ25 cm; mobile

phase, hexane:2-propanol=95:5 (v/v)], aﬀording 17a

(186 mg, 19%), ent-17a (176 mg, 18%), 17b (299 mg,

30%), and ent-17b (317 mg, 32%), respectively. The

conditions for analytical HPLC were as follows:

CHIRALCEL OD (Daicel Chemical Industries, Ltd.),

1ꢃ25 cm; mobile phase, hexane:2-propanol=10:1 (v/v);

ﬂow rate, 1.0 mL/min; temperature, 40 ^ꢀC; monitoring,

254 nm. The retention times and ee values are as fol-

lows: 17b, 21.2 min, 99% ee; ent-17a, 22.7 min, 99% ee;

17a, 23.5 min, 94% ee; ent-17b, 33.6 min, 98% ee.

(e) X-ray structural analysis of 17b:¹⁹monoclinic space

group P2₁, a=11.14_ꢀ1 (2) A, b=8.876 (2) A, c=10.153

(2) A, b=93.53 (2) , V=1002.1 (3) A³, Z=2, density

r

_calcd=1.403 g/cm³, m(Cu-K_a)=29.81cm ^À1, T=298 K,

size of crystal=0.31ꢃ0.30ꢃ0.07 mm^À1. The structure

was solved by direct methods and expanded using

Fourier techniques. Final R and Rw were 0.041and

0.054, respectively, for 3938 reﬂections.

(f) ent-17b: [a]_D²⁶À5.5^ꢀ(c 0.10, CHCl₃). Mp 108–109 ^ꢀC

hexane). 99% ee by HPLC analysis. ¹H NMR, ¹³C

NMR, IR, and MS spectra of this sample were identical

to those described for 17b. HRMS (FAB) (m/z): calcd

(a) 17a: [a]²_D³+42^ꢀ(c 0.16, CHCl₃). Mp 93–94 ^ꢀC (pen-

tane-ether). 99% ee by HPLC analysis. ¹H NMR

(400 MHz, CDCl₃): d 0.69–1.34 (m, 6H), 1.52–1.81 (m,

6H), 1.85–1.98 (m, 2H), 2.17 (dt, J=11.7, 5.9 Hz, 1H),

2.82–2.89 (m, 1H), 3.32 (s, 3H), 3.94 (dd, J=10.8, 8.3

Hz, 1H), 4.00 (apparent t, J=8.3 Hz, 1H), 4.22 (dd,

J=11.7, 7.1 Hz, 1H), 4.36 (dd, J=11.7, 3.7 Hz, 1H), 4.59

(s, 1H), 7.59 (dt, J=8.8, 2.1Hz, 2H), 7.87 (dt, J=8.8, 2.1

Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): d 26.0, 26.4,

29.7, 30.1, 32.1, 34.0, 38.3, 38.4, 40.6, 44.7, 54.5, 66.3,

67.7, 109.1, 128.2, 129.0, 131.1, 131.1, 131.8, 131.8,

165.8. IR (KBr): 2920, 1720, 1590, 1270, 1100 cm^À1. MS

(FAB) (m/z): 391(M ⁺-HOMe), 362 (100). HRMS

(FAB) (m/z): calcd for C₂₀H₂₄BrO₃(M⁺-HOMe):

391.0909. Found, 391.0949. Anal. calcd for C₂₁H₂₇BrO₄:

C, 59.58; H, 6.43. Found: C, 59.68; H, 6.37.

for

C₂₅H₃₉BrNO₆

[(M⁺+diethanolamine)+H]:

528.1961. Found, 528.1920. Anal. calcd for

C₂₁H₂₇BrO₄: C, 59.58; H, 6.43. Found: 59.40; H, 6.26.

(1S,3aR,4R,4aS,8aR,9aS)-Dodecahydro-1-methoxynaph-

tho[2,3-c]furan-4-methanol and its enantiomer (16a and

ent-16a). (a) Preparation of 16a: To a solution of 17a

(186 mg, 0.44 mmol) in ethanol (3 mL), aq 10% sodium

hydroxide solution (2 mL) was added, and the mixture

was stirred at room temperature for 30 min. After con-

centration in vacuo, the mixture was diluted with water

(10 mL). The aqueous mixture was extracted with die-

thyl ether (5 mLꢃ3). The organic extracts were com-

bined, washed with brine (5 mL), dried over anhydrous

MgSO₄, ﬁltered, and then concentrated in vacuo. Flush

column chromatography (hexane/ethyl acetate=1:1) of

(b) X-ray structural analysis of 17a:¹⁹monoclinic space

group P2₁, a=12.243 (2) A, b=13.013 (3) A, c=6.254

1178

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

the residue gave 16a (196 mg, 100%) as a colorless oil.

[a]²_D⁴+105^ꢀ(c 0.98, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): d 0.82–1.09 (m, 5H), 1.16–1.29 (m, 2H), 1.37

(br, 1H), 1.48–1.52 (m, 1H), 1.59–1.88 (m, 5H), 2.12 (dt,

J=12.2, 6.2 Hz, 1H), 2.78–2.86 (m, 1H), 3.32 (s, 3H),

3.52 (dd, J=10.8, 7.3 Hz, 1H), 3.74 (dd, J=10.8, 3.4

Hz, 1H), 3.88 (dd, J=11.3, 8.3 Hz, 1H), 4.04 (apparent

t, J=8.6 Hz, 1H), 4.57 (s, 1H). ¹³C NMR (100 MHz,

CDCl₃): d 26.1, 26.5, 30.2, 32.2, 34.1, 37.9, 38.2, 40.6,

43.4, 44.8, 54.4, 66.8, 67.8, 109.1. IR (neat): 3450, 2920,

1450, 1100 cm^À1. MS (FAB) (m/z): 346 [(M⁺+dietha-

nolamine)+H]. HRMS (FAB) (m/z): calcd for

C₁₈H₃₆NO₅[(M⁺+diethanolamine)+H]: 346.2593.

Found, 346.2623.

mLꢃ3). The ethereal extracts were combined, washed

with brine (5 mL), dried over anhydrous MgSO₄, ﬁl-

tered, and then concentrated in vacuo. Flush column

chromatography (hexane/ethyl acetate=50:1, then 10:1)

of the residue gave 18 (149 mg, 92%) as a colorless oil.

[a]²_D⁴+171^ꢀ(c 0.53, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): d 0.77–1.05 (m, 5H), 1.17–1.29 (m, 2H), 1.46–

1.52 (m, 1H), 1.59–1.82 (m, 4H), 1.94–2.01 (m, 1H), 2.08

(dt, J=12.2, 6.2 Hz, 1H), 2.43 (dd, J=12.2, 11.1 Hz,

1H), 3.02–3.09 (m, 1H), 3.32 (s, 3H), 3.34 (dd, J=14.2,

3.9 Hz, 1H), 3.80 (dd, J=10.8, 8.1 Hz, 1H), 4.05

(apparent t, J=8.3 Hz, 1H), 4.58 (s, 1H), 7.14–7.19 (m,

1H), 7.25–7.52 (m, 4H). ¹³C NMR (100 MHz, CDCl₃): d

26.0, 26.5, 30.1, 32.3, 34.0, 36.0, 37.8, 40.5, 40.6, 41.3,

44.4, 54.5, 67.2, 109.5, 125.8, 128.9, 128.9, 128.9, 137.0.

IR (neat): 2920, 1580, 1480, 1440, 1100 cm^À1. MS (EI)

(m/z): 332 (M⁺), 300 (100). HRMS (EI) (m/z): calcd for

C₂₀H₂₈O₂S (M⁺): 332.1810. Found, 332.1824.

(b) Preparation of ent-16a: the compound ent-16a (99.6

mg, 100%) was prepared as a colorless oil from ent-17a

(176 mg, 0.42 mmol) in the same manner as described in

a). [a]²_D⁴À106 (c 1.08, CHCl₃). H NMR, ¹³C NMR,

ꢀ

1

IR, and MS spectra of this sample were identical to

those described for 16a. HRMS (FAB) (m/z): calcd for

C₁₈H₃₆NO₅[(M⁺+diethanolamine)+H]: 346.2593.

Found, 346.2571.

(b) Preparation of ent-18: the compound ent-18 (140

mg, 88%) was prepared as a brown oil from ent-16a

(114 mg, 0.48 mmol) in the same manner as described

for the preparation of 18. [a]²_D⁴À177^ꢀ(c 0.20, CHCl₃).

¹H NMR, ¹³C NMR, IR, and MS spectra of this sample

were identical to those described for 18. HRMS (EI) (m/

z): calcd for C₂₀H₂₈O₂S (M⁺): 332.1810. Found,

332.1824.

Preparation of (1S,3aR,4S,4aS,8aR,9aS)-dodecahydro-

1-methoxynaphtho[2,3-c]furan-4-methanol and its enan-

tiomer (16b and ent-16b). (a) Preparation of 16b: the

compound 16b (107 mg, 100%) was prepared as a color-

less powder from 17b (188 mg, 0.44 mmol) in a manner

similar to that described for the preparation of 16a. [a]_D²⁵

+30^ꢀ(c 0.35, CHCl₃). Mp 65–66 ^ꢀC. ¹H NMR

(400 MHz, CDCl₃): d 0.79–0.92 (m, 2H), 1.13–1.35 (m,

5H), 1.41–1.70 (m, 6H), 1.75–1.80 (m, 1H), 2.18 (dt,

J=12.2, 6.2 Hz, 1H), 2.87 (dt, J=10.1, 5.9 Hz, 1H), 3.32

(s, 3H), 3.59 (apparent t, J=9.6 Hz, 1H), 3.80 (dd,

J=10.8, 7.8 Hz, 1H), 3.85 (dd, J=10.3, 3.9 Hz, 1H), 4.03

(dd, J=9.3, 7.8 Hz, 1H), 4.59 (s, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 26.3, 27.2, 30.4, 32.8, 34.7, 34.8,

34.9, 36.8, 39.4, 39.5, 41.1, 54.4, 63.1, 69.6, 110.1. IR

(KBr): 3260, 2920, 1450, 1100, 1030 cm^À1. MS (CI) (m/z):

241(M ⁺+H), 223, 209 (100). HRMS (CI) (m/z): calcd

for C₁₄H₂₅O₃(M⁺+H): 241.1804. Found, 241.1803.

(1S,3aS,4S,4aS,8aR,9aS) - Dodecahydro - 1 - methoxy - 4 -

(phenylthio)methylnaphtho[2,3-c]furan and its enantiomer

(4-epi-18 and ent-4-epi-18). (a) Preparation of 4-epi-18:

The compound 4-epi-18 (112 mg, 79%) was prepared as

a colorless powder from 16b (102 mg, 0.42 mmol) in a

manner similar to that described for the preparation of

18. [a]²_D³À33^ꢀ(c 0.45, CHCl₃). Mp 104–105 ^ꢀC. ¹H

NMR (400 MHz, CDCl₃): d 0.79–0.96 (m, 2H), 1.13–

1.43 (m, 6H), 1.53–1.82 (m, 5H), 2.16 (dt, J=12.2, 6.2

Hz, 1H), 2.65 (dd, J=12.7, 10.8 Hz, 1H), 3.07 (dt,

J=10.1, 6.9 Hz, 1H), 3.30 (dd, J=12.7, 3.0 Hz, 1H),

3.32 (s, 3H), 3.74 (dd, J=10.8, 8.3 Hz, 1H), 3.99 (dd,

J=9.3, 8.1 Hz, 1H), 4.58 (s, 1H), 7.14–7.19 (m, 1H),

7.24–7.35 (m, 4H). ¹³C NMR (100 MHz, CDCl₃): d

26.3, 26.9, 30.3, 33.1, 33.7, 34.6, 34.7, 36.8, 38.3, 40.2,

40.5, 54.5, 69.4, 110.1, 125.9, 128.9, 128.9, 129.2, 129.2,

136.9. IR (KBr): 2930, 1580, 1090 cm^À1. MS (EI) (m/z):

332 (M⁺). HRMS (EI) (m/z): calcd for C₂₀H₂₈O₂S

(M⁺): 332.1810. Found, 332.1835.

(b) Preparation of ent-16b: the compound ent-16b (104

mg, 91%) was prepared as a colorless powder from ent-

17b (201mg, 0.47 mmol) similarly to the preparation of

16b. [a]²_D⁵À28^ꢀ(c 0.77, CHCl₃). Mp 65–66 ^ꢀC. ¹H

NMR, ¹³C NMR, IR, and MS spectra of this sample

were identical to those described for 16b. HRMS (CI)

(m/z): calcd for C₁₄H₂₅O₃(M⁺+H): 241.1804. Found,

241.1770.

(b) Preparation of ent-4-epi-18: the compound ent-4-epi-

18 (137 mg, 76%) was prepared as a colorless powder

from ent-16b (131 mg, 0.54 mmol) in a manner similar

to that described for the preparation of 18. [a]²_D²+34^ꢀ(c

0.10, CHCl₃). Mp 105–106 ^ꢀC. ¹H NMR, ¹³C NMR, IR,

and MS spectra of this sample were identical to those

described in (a). HRMS (EI) (m/z): calcd for C₂₀H₂₈O₂S

(M⁺): 332.1810. Found, 332.1827.

(1S,3aS,4R,4aS,8aR,9aS)-Dodecahydro-1-methoxy-4-

(phenylthio)methylnaphtho[2,3-c]furan and its enantiomer

(18 and ent-18). (a) Preparation of 18: to a solution of

16a (117 mg, 0.49 mmol) in acetonitrile (10 mL) were

added (cyanomethyl)trimethylphosphonium iodide (236

mg, 0.97 mmol), thiophenol (74.9 mL, 0.73 mmol), and

N,N-diisopropylethylamine (212 mL, 1.21 mmol), all at

room temperature, and the mixture was stirred at 80 ^ꢀC

for 2.5 h. The reaction mixture was concentrated in

vacuo, and the residue was diluted with water (10 mL).

The aqueous mixture was extracted with diethyl ether (5

(1S,3aS,4R,4aS,8aR,9aS)-Dodecahydro-1-methoxy-4-

(phenylsulfonyl)methylnaphtho[2,3-c]furan and its enan-

tiomer (19 and ent-19). (a) Preparation of 19: to a solu-

tion of 18 (149 mg, 0.45 mmol) in CH₂Cl₂(10 mL) were

added 3-chloroperoxybenzoic acid (65%, 358 mg, 1.35

mmol) and sodium bicarbonate (226 mg, 2.69 mmol) at

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1179

0 ^ꢀC, and the mixture was stirred at room temperature

for 1.5 h. After insoluble materials were ﬁltered oﬀ

through a pad of Celite, the collected solid was washed

with CH₂Cl₂(30 mL). The ﬁltrates were combined and

concentrated in vacuo. The residue was dissolved in

diethyl ether (20 mL). The ethereal solution was washed

with saturated aqueous sodium bicarbonate solution (5

mLꢃ2) and brine (5 mL). The organic layer was dried

over anhydrous MgSO₄, ﬁltered, and then concentrated

in vacuo. Flash column chromatography (hexane/ethyl

acetate=2:1) of the residue gave 19 (135 mg, 82%) as a

colorless powder. [a]²_D⁴+160^ꢀ(c 0.16, CHCl₃). Mp 159–

160 ^ꢀC (hexane–ethyl acetate). ¹H NMR (400 MHz,

CDCl₃): d 0.62–74 (m, 1H), 0.83–1.02 (m, 4H), 1.08–

1.27 (m, 2H), 1.45–1.52 (m, 1H), 1.57–1.77 (m, 5H),

2.05–2.14 (m, 1H), 2.69 (dd, J=14.7, 10.3 Hz, 1H),

3.11–3.20 (m, 1H), 3.29 (s, 3H), 3.30 (dd, J=14.2, 2.2

Hz, 1H), 3.71 (dd, J=10.8, 7.3 Hz, 1H), 4.05 (dd,

J=8.8, 7.6 Hz, 1H), 4.58 (s, 1H), 7.55–7.61 (m, 2H),

7.64–7.69 (m, 1H), 7.90–7.94 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 25.8, 26.4, 29.9, 31.9, 34.1, 36.5,

37.9, 40.5, 40.6, 44.0, 54.3, 57.5, 67.2, 109.6, 127.8,

127.8, 129.3, 129.3, 133.6, 140.0. IR (KBr): 2930, 1450,

1300, 1160 cm^À1. MS (FAB) (m/z): 470 [(M⁺+dietha-

nolamine)+H]. HRMS (FAB) (m/z): calcd for

C₂₄H₄₀NO₆S [(M⁺+diethanolamine)+H]: 470.2576.

Found, 470.2572. Anal. calcd for C₂₀H₂₈O₄S: C, 65.90;

H, 7.74. Found: C, 65.86; H, 7.73.

mg, 0.41mmol) in a manner similar to that described

for the preparation of 19. [a]²_D²À18^ꢀ(c 0.22, CHCl₃).

ꢀ

1

Mp 154–155 C (hexane–ethyl acetate). H NMR, ¹³C

NMR, IR, and MS spectra of this sample were identical

to those described for 4-epi-19. HRMS (FAB) (m/z):

calcd for C₂₄H₄₀NO₆S [(M⁺+diethanolamine)+H]:

470.2576. Found, 470.2578.

(2R,6S)-tert-Butyl 2-[2-(E)-[(1S,3aR,4R,4aS,8aR,9aS)-

dodecahydro-1-methoxynaphtho[2,3-c]furan-4-yl]ethenyl]-

6-methylpiperidine-1-carboxylate and its enantiomer (21

and ent-21). (a) Preparation of 21: To a solution of 19

(50.0 mg, 0.14 mmol) in 1,2-dimethoxyethane (2 mL),

n-butyllithium (1.5 M solution in hexane, 137 mL, 0.21

mmol) was added dropwise at À78 ^ꢀC, and the mixture

was stirred at the same temperature for 5 min. A solu-

tion of 20 (46.8 mg, 0.21mmol) in 1,2-dimethoxyethane

(1mL) was added dropwise to the mixture at À78 ^ꢀC,

and the resulting mixture was stirred at the same tem-

perature for 3 h and then gradually warmed to 0 ^ꢀC with

stirring. Benzoyl chloride (47.8 mL, 0.41mmol) was

added to the reaction mixture at À78 ^ꢀC, and the reac-

tion mixture was stirred at room temperature for 1h.

After quenching the reaction by adding 3-(dimethyl-

amino)propylamine (51.8 mL, 0.41mmol), the mixture

was diluted with aqueous citric acid solution (10 mL).

The aqueous mixture was extracted with diethyl ether (3

mLꢃ3). The ethereal extracts were combined, washed

with brine (3 mL), dried over anhydrous MgSO₄, ﬁl-

tered, and then concentrated in vacuo. Flash column

chromatography (hexane/ethyl acetate=10:1, 4:1, then

1:1) of the residue gave the b-benzoxysulfone (possibly a

mixture of the four diastereomers) (36.9 mg, 39%) as a

yellow oil with recovery of a portion of the starting 19

(30.0 mg, 60%). The structure of this adduct was deter-

mined by its MS spectrum. MS (FAB) (m/z): 801

[(M⁺+diethanolamine)+H]. HRMS (FAB) (m/z):

calcd for C₄₃H₆₅N₂O₁₀S [(M⁺+diethanolamine)+H]:

801.4360. Found, 801.4335.

(b) Preparation of ent-19: the compound ent-19 (152

mg, 99%) was prepared from ent-18 (140 mg, 0.42

mmol) in the same manner as described for the pre-

paration of 19. [a]_D²³À159^ꢀ(c 0.14, CHCl₃). Mp 160–

161 ^ꢀC (hexane–ethyl acetate). ¹H NMR, ¹³C NMR, IR,

and MS spectra of this sample were identical to those

described for 19. HRMS (FAB) (m/z): calcd for

C₂₄H₄₀NO₆S [(M⁺+diethanolamine)+H]: 470.2576.

Found, 470.2578. Anal. calcd for C₂₀H₂₈O₄S: C, 65.90;

H, 7.74. Found: C, 65.77; H, 7.85.

(1S,3aS,4S,4aS,8aR,9aS) - Dodecahydro - 1 - methoxy - 4 -

(phenylsulfonyl)methylnaphtho[2,3-c]furan and its enan-

tiomer (4-epi-19 and ent-4-epi-19). (a) Preparation of

4-epi-19: the compound 4-epi-19 (106 mg, 86%) was pre-

pared as a colorless powder from 4-epi-18 (112 mg, 0.34

mmol) in a manner similar to that described for the pre-

paration of 19. [a]_D²²+17^ꢀ(c 0.30, CHCl₃). Mp 153–

154 ^ꢀC (hexane–ethyl acetate). ¹H NMR (400 MHz,

CDCl₃): d 0.75–1.35 (m, 7H), 1.51–1.74 (m, 5H), 2.09 (dt,

J=12.7, 6.4 Hz, 1H), 2.14–2.19 (m, 1H), 2.82–2.91 (m,

1H), 2.95 (dd, J=14.2, 8.3 Hz, 1H), 3.26 (dd, J=14.7, 2.0

Hz, 1H), 3.28 (s, 3H), 3.74 (dd, J=10.3, 8.3 Hz, 1H), 4.00

(dd, J=9.3, 8.3 Hz, 1H), 4.55 (s, 1H), 7.55–7.61 (m, 2H),

7.64–7.69 (m, 1H), 7.89–7.94 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃): d 26.0, 26.3, 29.7, 32.1, 32.6, 34.0,

34.2, 39.1, 40.6, 40.6, 54.3, 56.9, 68.8, 109.5, 128.1, 128.1,

129.3, 129.3, 133.7, 139.7. IR (KBr): 2920, 1450, 1310,

1140 cm^À1. MS (FAB) (m/z): 470 [(M⁺+diethanolami-

ne)+H]. HRMS (FAB) (m/z): calcd for C₂₄H₄₀NO₆S

[(M⁺+diethanolamine)+H]: 470.2576. Found, 470.2567.

To a solution of the b-benzoxysulfone (36.9 mg) in

methanol (10 mL), 5% sodium amalgam (0.50 g) and

Na₂HPO₄(1.00 g) were added, and the mixture was

stirred at room temperature for 1h. Insoluble materials

were ﬁltered and thoroughly washed with ethyl acetate

(20 mL). The ﬁltrates were combined and concentrated

in vacuo. After adding water (10 mL), the aqueous

mixture was extracted with diethyl ether (3 mLꢃ3). The

ethereal extracts were combined, washed with brine (3

mL), dried over anhydrous MgSO₄, ﬁltered, and then

concentrated in vacuo. Flash column chromatography

(hexane/ethyl acetate=4:1) of the residue gave 21 (14.4

mg, 63%) as a colorless oil. In this case, formation of

the (Z)-oleﬁn was not observed by ¹H NMR analysis of

the crude reaction product. [a]²_D⁴+108^ꢀ(c 1.44, CHCl₃).

¹H NMR (400 MHz, CDCl₃): d 0.65–0.77 (m, 1H),

0.85–1.02 (m, 4H), 1.12–1.29 (m, 3H), 1.22 (d, J=6.4

Hz, 3H), 1.41–1.78 (m, 8H), 1.45 (s, 9H), 1.85–2.00 (m,

2H), 2.03–2.13 (m, 2H), 2.61–2.69 (m, 1H), 3.30 (s, 3H),

3.83 (dd, J=10.8, 8.3 Hz, 1H), 3.92 (apparent t, J=8.6

Hz, 1H), 3.95–4.02 (m, 1H), 4.35–4.40 (m, 1H), 4.57 (s,

1H), 5.10 (ddd, J=15.2, 9.3, 1.6 Hz, 1H), 5.48 (dd,

J=15.7, 5.2 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d

(b) Preparation of ent-4-epi-19: the compound ent-4-epi-

19 (123 mg, 82%) was prepared from ent-4-epi-18 (137

1180

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

13.4, 20.9, 25.3, 26.3, 26.4, 26.6, 28.5, 28.5, 28.5, 31.3,

32.1, 34.1, 40.2, 40.7, 41.2, 44.5, 45.8, 47.0, 52.2, 54.4,

67.9, 78.9, 109.5, 131.7, 133.3, 155.1. IR (neat): 2930,

1690, 1390, 1180, 1100 cm^À1. MS (FAB) (m/z): 434

(M⁺+H), 402, 376, 346 (100). HRMS (FAB) (m/z):

calcd for C₂₆H₄₄NO₄(M⁺+H): 434.3270. Found,

434.3278.

(FAB) (m/z): 539 [(M⁺+diethanolamine)+H]. HRMS

(FAB) (m/z): calcd for C₃₀H₅₅N₂O₆[(M⁺+diethanol-

amine)+H]: 539.4060. Found, 539.4108.

(b) Preparation of ent-4-epi-21: the b-benzoxysulfone

(37.0 mg, 39%) was prepared from ent-4-epi-19 (50.0

mg, 0.14 mmol) as a colorless oil with recovery of

starting ent-4-epi-19 (30.0 mg, 60%) in a manner similar

to that described for the preparation of the b-benzoxy-

sulfone from 19. HRMS (FAB) (m/z): calcd for

C₄₃H₆₅N₂O₁₀S [(M⁺+diethanolamine)+H]: 801.4360.

Found, 801.4376.

(b) Preparation of ent-21: the b-benzoxysulfone (51.9

mg, 34%) enantiomeric to that produced from 19 was

prepared from ent-19 (80.0 mg, 0.22 mmol) in the same

manner as described for the preparation of the b-ben-

zoxysulfone from 19 with recovery of starting ent-19

(51.0 mg, 64%). HRMS (FAB) (m/z): calcd for

C₄₃H₆₅N₂O₁₀S [(M⁺+diethanolamine)+H]: 801.4360.

Found, 801.4342.

The b-benzoxysulfone was subjected to elimination

reaction in the same manner as that described for the

preparation of 21 from the corresponding b-benzoxy-

sulfone, aﬀording ent-4-epi-21 (14.0 mg, 61%) as a col-

orless oil. [a]²_D³À51^ꢀ(c 1.20, CHCl₃). H NMR, ¹³C

1

The b-benzoxysulfone was subjected to elimination

reaction in a manner similar to that described for the

preparation of 21, aﬀording ent-21 (17.9 mg, 55%) as a

NMR, IR, and MS spectra of this sample were identical

to those described for 4-epi-21. HRMS (FAB) (m/z):

calcd for C₃₀H₅₅N₂O₆[(M⁺+diethanolamine)+H]:

539.4060. Found, 539.4108.

colorless oil. [a]²_D³À112^ꢀ(c 1.19, CHCl₃). ¹H NMR, ¹³

C

NMR, IR, and MS spectra of this sample were identical

to those described for 21. HRMS (FAB) (m/z): calcd for

C₂₆H₄₄NO₄(M⁺+H): 434.3270. Found, 434.3275.

(2R,6S)-tert-Butyl

2-[2-(E)-[(3aR,4R,4aS,8aR,9aS)-

decahydronaphtho[2,3-c]furan-1(3H)-on-4-yl]ethenyl]-6-

methylpiperidine-1-carboxylate and its enantiomer (22

and ent-22). (a) Preparation of 22: to a solution of 21

(14.4 mg, 33.2 mmol) in acetone (2 mL), Jones reagent

(0.20 mL) was added at room temperature, and the

mixture was stirred at the same temperature for 1.5 h.

After 2-propanol (1mL) was added, the reaction mix-

ture was concentrated in vacuo. The residue was diluted

with water (10 mL), and the aqueous mixture was

extracted with diethyl ether (3 mLꢃ3). The ethereal

extracts were combined, washed with brine (3 mL),

dried over anhydrous MgSO₄, ﬁltered, and then con-

centrated in vacuo. Flush column chromatography

(hexane/ethyl acetate=2:1) of the residue gave 22 (8.00

mg, 58%) as a colorless oil. [a]²_D⁴+83^ꢀ(c 0.48, CHCl₃).

¹H NMR (400 MHz, CDCl₃): d 0.68–0.80 (m, 1H),

0.93–1.29 (m, 6H), 1.23 (d, J=6.4 Hz, 3H), 1.38–2.13

(m, 12H), 1.45 (s, 9H), 2.55 (dt, J=12.7, 6.4 Hz, 1H),

2.66–2.75 (m, 1H), 3.98–4.05 (m, 1H), 4.19 (dd, J=11.7,

9.1Hz, 1H), 4.27 (apparent t, J=8.6 Hz, 1H), 4.36–4.41

(m, 1H), 5.11 (ddd, J=15.2, 9.8, 1.5 Hz, 1H), 5.56 (dd,

J=15.2, 5.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d

13.4, 20.9, 25.3, 26.2, 26.2, 26.4, 28.5, 28.5, 28.5, 30.7,

31.2, 33.6, 39.7, 39.8, 41.0, 44.8, 47.1, 52.1, 68.1, 79.1,

129.1, 134.9, 155.0, 179.3. IR (neat): 2920, 1780, 1680,

1390 cm^À1. MS (FAB) (m/z): 418 (M⁺+H), 318 (100).

HRMS (FAB) (m/z): calcd for C₂₅H₄₀NO₄(M⁺+H):

418.2957. Found, 418.2990.

(2R,6S)-tert-Butyl 2-[2-(E)-[(1S,3aR,4S,4aS,8aR,9aS)-

dodecahydro-1-methoxynaphtho[2,3-c]furan-4-yl]ethenyl]-

6-methylpiperidine-1-carboxylate and its enantiomer (4-

epi-21 and ent-4-epi-21). (a) Preparation of 4-epi-21: the

reaction of 4-epi-19 (50.0 mg, 0.14 mmol) and 20 (46.8

mg, 0.21mmol) in a manner similar to that described

for the preparation of 21 gave the corresponding b-

benzoxysulfone (possibly a mixture of the four diaster-

eomers) (40.0 mg, 42%) as a colorless oil with recovery

of a portion of the starting 4-epi-19 (29.0 mg, 58%),

after ﬂash column chromatography (hexane/ethyl ace-

tate=10:1, 4:1, then 1:1). Unlike the preparation of 21,

the addition reaction of the lithium anion derived from

4-epi-19 was ﬁnished at À78 ^ꢀC after 2.5 h without gra-

dual warming to 0 ^ꢀC. The structure of this adduct was

determined by its MS spectrum. MS (FAB) (m/z): 801

[(M⁺+diethanolamine)+H]. HRMS (FAB) (m/z):

calcd for C₄₃H₆₅N₂O₁₀S [(M⁺+diethanolamine)+H]:

801.4360. Found, 801.4318.

Treatments of the b-benzoxysulfone (40.0 mg) in the

same manner as described for the preparation of 21

from the corresponding b-benzoxysulfone gave 4-epi-21

(19.2 mg, 77%) as a colorless oil after ﬂash column

chromatography (hexane/ethyl acetate=4:1). In this

case, formation of the (Z)-oleﬁn was not observed by

¹H NMR analysis of the crude reaction product. [a]²_D³

+50^ꢀ(c 1.28, CHCl₃). H NMR (400 MHz, CDCl₃): d

1

0.79–0.93 (m, 2H), 1.06–1.36 (m, 6H), 1.24 (d, J=6.4

Hz, 3H), 1.46 (s, 9H), 1.42–1.82 (m, 8H), 1.88–2.00 (m,

2H), 2.15–2.22 (m, 2H), 2.47–2.56 (m, 1H), 3.34 (s, 3H),

3.79 (dd, J=10.8, 7.8 Hz, 1H), 3.98–4.05 (m, 2H), 4.39–

4.44 (m, 1H), 4.58 (s, 1H), 5.44 (dd, J=15.2, 3.9 Hz,

1H), 5.54 (ddd, J=15.7, 9.8, 1.6 Hz, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 13.6, 20.8, 25.3, 26.3, 26.3, 26.8,

28.5, 28.5, 28.5, 31.2, 33.0, 34.2, 34.5, 39.9, 41.1, 41.2,

41.3, 47.0, 52.0, 54.4, 69.6, 78.9, 110.2, 130.0, 132.9,

155.2. IR (neat): 2930, 1690, 1390, 1180, 1100 cm^À1. MS

(b) Preparation of ent-22: this compound ent-22 (5.10

mg, 62%) was prepared from ent-21 (8.50 mg, 19.6 mmol)

in the same manner as that described for the preparation

of 22. [a]²_D⁴À85^ꢀ(c 0.34, CHCl₃). H NMR, ¹³C NMR,

1

IR, and MS spectra of this sample were identical to those

described for 22. HRMS (FAB) (m/z): calcd for

C₂₅H₄₀NO₄(M⁺+H): 418.2957. Found, 418.2984.

(2R,6S)-tert-Butyl 2-[2-(E)-[(3aR,4S,4aS,8aR,9aS)-deca-

hydronaphtho[2,3 - c]furan - 1(3H) - on - 4 - yl]ethenyl] - 6 -

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1181

methylpiperidine-1-carboxylate and its enantiomer (4-

epi-22 and ent-4-epi-22). (a) Preparation of 4-epi-22:

The compound 4-epi-22 (12.0 mg, 60%) was prepared

as a colorless powder from 4-epi-21 (20.6 mg, 47.5

mmol) in a similar manner to that described for the

preparation of 22. [a]²_D⁴+14^ꢀ(c 0.59, CHCl₃). Mp 113–

(3aR,4S,4aS,8aR,9aS)-Decahydro-4-[2-(E)-[(2R,6S)-6-

methylpiperidin-2-yl]ethenyl]naphtho[2,3-c]furan-1(3H)-

one and its enantiomer (4-epi-23 and ent-4-epi-23). (a)

Preparation of 4-epi-23: The compound 4-epi-23 (6.20

mg, 93%) was prepared as a colorless powder from

4-epi-22 (8.80 mg, 21.1 mmol) in a manner similar to that

described for the preparation of 23. [a]²_D¹À28^ꢀ(c 0.41,

115 ^ꢀC. H NMR (400 MHz, CDCl₃): d 0.85–0.97 (m,

1

CHCl₃). Mp 103–105 ^ꢀC. H NMR (400 MHz, CDCl₃):

1

1H), 1.06–1.30 (m, 6H), 1.24 (d, J=6.9 Hz, 3H), 1.35–

1.79 (m, 8H), 1.46 (s, 9H), 1.82–2.02 (m, 3H), 2.17–2.22

(m, 1H), 2.56–2.66 (m, 2H), 4.00–4.07 (m, 1H), 4.21 (dd,

J=11.3, 8.8 Hz, 1H), 4.31 (apparent t, J=8.3 Hz, 1H),

4.40–4.44 (m, 1H), 5.45–5.54 (m, 2H). ¹³C NMR

(100MHz, CDCl₃): d 13.6, 20.8, 25.5, 26.1, 26.3, 26.6,

28.5, 28.5, 28.5, 30.9, 31.3, 33.7, 34.0, 37.3, 40.2, 40.9, 41.6,

47.1, 52.0, 69.0, 79.0, 128.5, 134.1, 155.1, 179.4. IR (KBr):

2930, 1770, 1690, 1400, 1370, 1180 cm^À1. MS (FAB) (m/

z): 418 (M⁺+H), 362 (100). HRMS (FAB) (m/z): calcd

for C₂₅H₄₀NO₄(M⁺+H): 418.2957. Found, 418.2953.

d 0.80–0.98 (m, 2H), 1.04–1.42 (m, 8H), 1.11 (d, J=6.4

Hz, 3H), 1.46–1.79 (m, 8H), 1.87–1.95 (m, 1H), 2.17

(dd, J=8.8, 2.7 Hz, 1H), 2.59–2.70 (m, 2H), 3.06–3.14

(m, 1H), 3.59 (dd, J=10.3, 5.2 Hz, 1H), 4.21 (dd,

J=11.3, 8.8 Hz, 1H), 4.32 (apparent t, J=8.3 Hz, 1H),

5.59 (dd, J=15.7, 8.8 Hz, 1H), 5.66 (dd, J=15.2, 5.9

Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d 19.6, 21.3,

26.2, 26.6, 30.9, 31.1, 31.4, 32.7, 33.7, 34.1, 37.2, 40.1,

41.2, 41.5, 46.3, 53.0, 69.0, 130.0, 134.2, 179.4. IR

(KBr): 2920, 1760, 1210, 1190 cm^À1. MS (FAB) (m/z):

318 (M⁺+H) (100). HRMS (FAB) (m/z): calcd for

C₂₀H₃₂NO₂(M⁺+H): 318.2433. Found, 318.2435.

(b) Preparation of ent-4-epi-22: The compound ent-4-

epi-22 (9.40 mg, 70%) was prepared from ent-4-epi-21

(14.0 mg, 32.3 mmol) in a manner similar to that descri-

bed for the preparation of 22. [a]²_D⁴À13^ꢀ(c 0.54,

(b) Preparation of ent-4-epi-23: the compound ent-4-epi-

23 (7.10 mg, 99%) was prepared from ent-4-epi-22 (9.40

mg, 22.5 mmol) in the same manner as that described for

the preparation of 23. [a]²_D²+30^ꢀ(c 0.33, CHCl₃). Mp

CHCl₃). Mp 112–114 ^ꢀC. H NMR, ¹³C NMR, IR, and

1

MS spectra of this sample were superimposable on

those described in (a). HRMS (FAB) (m/z): calcd for

C₂₅H₄₀NO₄(M⁺+H): 418.2957. Found, 418.2952.

ꢀ

1

105–107 C. H NMR, ¹³C NMR, IR, and MS spectra

of this sample were superimposable on those described

in (a). HRMS (FAB) (m/z): calcd for C₂₀H₃₂NO₂

(M⁺+H): 318.2433. Found, 318.2437.

(3aR,4R,4aS,8aR,9aS)-Decahydro-4-[2-(E)-[(2R,6S)-6-

methylpiperidin-2-yl]ethenyl]naphtho[2,3-c]furan-1(3H)-

one and its enantiomer (23 and ent-23). (a) Preparation

of 23: To a solution of 22 (8.00 mg, 19.2 mmol) in

CH₂Cl₂(1mL), triﬂuoroacetic acid (0.01 mL) was

added at room temperature, and the mixture was stirred

at the same temperature for 0.5 h. After the reaction

mixture was made alkaline by adding cold diluted aqu-

eous sodium hydroxide solution, the mixture was

extracted with diethyl ether (5 mLꢃ3). The ethereal

extracts were combined, washed with brine (5 mL),

dried over anhydrous MgSO₄, ﬁltered, and then con-

centrated in vacuo, giving 23 (5.30 mg, 87%) as a col-

orless oil. [a]²_D³+38^ꢀ(c 0.30, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): d 0.68–1.33 (m, 10H), 1.11 (d,

J=6.8 Hz, 3H), 1.43–1.88 (m, 9H), 2.06–2.14 (m, 1H),

2.56 (dt, J=12.7, 6.4 Hz, 1H), 2.66–2.75 (m, 1H), 3.06–

3.14 (m, 1H), 3.53–3.59 (m, 1H), 4.21 (dd, J=11.7, 8.8

Hz, 1H), 4.27 (apparent t, J=8.6 Hz, 1H), 5.20 (ddd,

J=15.7, 9.8, 1.3 Hz, 1H), 5.72 (dd, J=15.7, 6.2 Hz,

1H). ¹³C NMR (100 MHz, CDCl₃): d 19.6, 21.1, 26.2,

26.4, 30.7, 30.8, 31.2, 32.5, 33.6, 39.7, 39.8, 40.8, 41.0,

45.1, 46.4, 52.7, 68.1, 129.9, 135.7, 179.2. IR (neat):

2920, 1780, 1180, 1100 cm^À1. MS (FAB) (m/z): 318

(M⁺+H). HRMS (FAB) (m/z): calcd for C₂₀H₃₂NO₂

(M⁺+H): 318.2433. Found, 318.2453.

(3aR,4R,4aS,8aR,9aS)-Decahydro-4-[2-(E)-[(2R,6S)-1,6-

dimethylpiperidin - 2 - yl]ethenyl]naphtho[2,3 - c]furan -

1(3H)-one [3-demethylhimbacine (3-norhimbacine)] and

its enantiomer [ent-3-demethylhimbacine (ent-3-norhim-

bacine)] (2 and ent-2). (a) Preparation of 2: To a solu-

tion of 23 (5.30 mg, 16.7 mmol) in acetonitrile (1mL)

were added formaldehyde (37 wt.% solution in water,

0.10 mL) and sodium cyanoborohydride (2.31 mg, 36.7

mmol), and the mixture was stirred at room temperature

for 1h. The mixture was adjusted to pH 7.0 by adding

acetic acid, and it was further stirred at room tempera-

ture for 1h. After the addition of cold diluted aqueous

sodium hydroxide solution, the mixture was con-

centrated in vacuo, and the residue was extracted with

diethyl ether (3 mL ꢃ3). The ethereal extracts were

combined, washed with brine (3 mL), dried over anhy-

drous MgSO₄, ﬁltered, and then concentrated in vacuo.

Flash column chromatography (Chromatorex, hexane/

ethyl acetate=2:1) of the residue gave 2 (4.40 mg,

80%) as a colorless oil. [a]²_D⁴+69^ꢀ(c 0.44, CHCl₃). H

1

NMR (400 MHz, CDCl₃): d 0.70–1.30 (m, 9H), 1.00 (d,

J=6.4 Hz, 3H), 1.38–1.88 (m, 9H), 2.05–2.20 (m, 1H),

2.22 (s, 3H), 2.56 (dt, J=12.7, 6.4 Hz, 1H), 2.66–2.74

(m, 1H), 2.79–2.86 (m, 1H), 2.98–3.04 (m, 1H), 4.20

(dd, J=11.7, 8.8 Hz, 1H), 4.24 (apparent t, J=8.3 Hz,

1H), 5.20 (dd, J=15.2, 9.3 Hz, 1H), 5.65 (dd, J=15.7,

(b) Preparation of ent-23: the compound ent-23 (7.30

mg, 94%) was prepared as a colorless oil from ent-22

(10.2 mg, 24.4 mmol) in the same manner as that descri-

bed for the preparation of 23. [a]²_D³À38^ꢀ(c 0.28,

9.1Hz, H1 ).

¹³C NMR (100 MHz, CDCl₃): d 14.3,

19.0, 26.2, 26.4, 30.7, 31.3, 33.1, 33.3, 33.6, 39.7, 39.8,

40.9, 41.1, 41.1, 45.2, 53.4, 61.2, 68.1, 131.3, 134.5,

1

CHCl₃). H NMR, ¹³C NMR, IR, and MS spectra of

179.2. IR (neat): 2930, 1770, 1450, 1370, 1170 cm^À1

.

this sample were identical to those described in (a).

HRMS (FAB) (m/z): calcd for C₂₀H₃₂NO₂(M⁺+H):

318.2433. Found, 318.2435.

MS (FAB) (m/z): 332 (M⁺+H). HRMS (FAB) (m/z):

calcd for C₂₁H₃₄NO₂(M⁺+H): 332.2590. Found,

332.2609.

1182

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

(b) Preparation of ent-2: the compound ent-2 (4.50 mg,

59%) was prepared from ent-23 (7.30 mg, 23.0 mmol) in

a manner similar to that described for the preparation

25 (2.00 g, 67%) after ﬂash column chromatography

(hexane/ethyl acetate=2:1, then 1:1). This crude pro-

duct was immediately subjected to the next reaction

without further puriﬁcation. ¹H NMR (400 MHz,

CDCl₃): d 1.02 (t, J=7.3 Hz, 3H), 1.49–1.78 (m, 6H),

1.89–1.94 (m, 2H), 2.18–2.26 (m, 2H), 2.31 (dd,

J=7.8, 3.4 Hz, 1H), 2.82 (d, J=7.8 Hz, 1H), 4.29 (td,

J=6.4, 3.4 Hz, 1H), 4.69 (br, 1H), 5.03 (br, 1H). MS

(FAB) (m/z): 235 (M⁺+H). HRMS (FAB) (m/z):

calcd for C₁₄H₁₉O₃(M⁺+H): 235.1334. Found,

235.1326.

of 2. [a]²_D⁴À72^ꢀ(c 0.30, CHCl₃). H NMR, ¹³C NMR,

1

IR, and MS spectra of this sample were identical to

those described for 2. HRMS (FAB) (m/z): calcd for

C₂₁H₃₄NO₂(M⁺+H): 332.2590. Found, 332.2579.

(3aR,4S,4aS,8aR,9aS)-Decahydro-4-[2-(E)-[(2R,6S)-1,6-

dimethylpiperidin - 2 - yl]ethenyl]naphtho[2,3 - c]furan -

1(3H)-one [4-epi-3-demethylhimbacine (4-epi-3-norhim-

bacine)] and its enantiomer [ent-4-epi-3-demethylhimba-

cine (ent-4-epi-3-norhimbacine)] (4-epi-2 and ent-4-epi-

2). (a) Preparation of 4-epi-2: the compound 4-epi-2

(6.30 mg, 78%) was prepared as a colorless powder

from 4-epi-23 (7.70 mg, 24.3 mmol) in a manner similar

to that described for the preparation of 2. [a]²_D⁴À9.1^ꢀ(c

0.42, CHCl₃). Mp 86-88 ^ꢀC. ¹H NMR (400 MHz,

CDCl₃): d 0.81–0.97 (m, 1H), 1.01 (d, J=6.4 Hz, 3H),

1.06–1.32 (m, 8H), 1.37–1.79 (m, 8H), 1.87–1.95 (m,

1H), 2.21 (ddd, J=19.8, 7.8, 2.7 Hz, 1H), 2.22 (s, 3H),

2.60–2.70 (m, 2H), 2.76–2.85 (m, 1H), 3.03–3.09 (m,

1H), 4.22 (dd, J=11.3, 8.8 Hz, 1H), 4.34 (apparent t,

J=8.3 Hz, 1H), 5.55 (dd, J=15.9, 8.3 Hz, 1H), 5.62 (dd,

J=15.2, 8.3 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d

14.7, 19.1, 26.2, 26.6, 31.0, 31.4, 33.0, 33.4, 33.7, 34.1,

37.3, 40.2, 40.8, 40.9, 41.7, 53.3, 61.3, 69.0, 131.3, 132.7,

179.4. IR (KBr): 2930, 1760, 1450, 1370, 1210, 1180

cm^À1. MS (FAB) (m/z): 332 (M⁺+H) (100). HRMS

(FAB) (m/z): calcd for C₂₁H₃₄NO₂(M⁺+H): 332.2590.

Found, 332.2573.

(3S,3aR,4R,4aS,8aR,9S,9aR)-4,9-Epoxy-3-ethyl-decahy-

dronaphtho[2,3-c]furan-1(3H)-one (27). Hydrogenation

of 26 (2.56 g, 10.9 mmol) in a manner similar to that

described for the preparation of dl-8 from dl-7 gave 27

(1.90 g, 74%) as a colorless powder. [a]²_D²+29^ꢀ(c 0.26,

CHCl₃). Mp 92–94 ^ꢀC (hexane–ethyl acetate). H NMR

1

(400 MHz, CDCl₃): d 0.99 (t, J=7.3 Hz, 3H), 1.07–1.20

(m, 2H), 1.30–1.76 (m, 8H), 2.00–2.15 (m, 2H), 2.55 (dd,

J=8.8, 3.7 Hz, 1H), 3.08 (d, J=8.3 Hz, 1H), 4.20 (td,

J=6.4, 3.9 Hz, 1H), 4.38 (d, J=4.9 Hz, 1H), 4.75 (d,

J=4.9 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): d 9.13,

19.4, 19.5, 19.6, 19.9, 29.3, 38.9, 39.7, 43.8, 46.1, 83.6,

85.8, 86.1, 178.2. IR (KBr): 2940, 1740, 1220 cm^À1. MS

(EI) (m/z): 236 (M⁺). Anal. calcd for C₁₄H₂₀O₃: C,

71.16; H, 8.53. Found: C, 71.13; H, 8.52.

(3S,3aS,4R,4aS,8aS) - 3 - Ethyl - 4 - hydroxy - 3a,4,4a,

5,6,7,8,8a-octahydronaphtho[2,3-c]furan-1(3H)-one (28).

Reaction of 27 (1.90 g, 8.04 mmol) in the same manner

as described for the preparation of dl-9 from dl-8 gave

28 (1.77 g, 93%) as a pale yellow oil after ﬂash column

chromatography (hexane/ethyl acetate=1:1). This

crude product was directly used for the next reaction

without further puriﬁcation. ¹H NMR (400 MHz,

CDCl₃): d 0.96–2.08 (m, 10H), 1.10 (t, J=7.3 Hz, 3H),

2.15–2.36 (m, 2H), 2.63–2.70 (m, 1H), 2.74–2.80 (m,

1H), 4.01 (dd, J=9.3, 3.9 Hz, 1H), 4.40–4.47 (m, 1H),

6.69 (t, J=2.5 Hz, 1H). MS (EI) (m/z): 236 (M⁺), 218,

149 (100). HRMS (EI) (m/z): calcd for C₁₄H₂₀O₃(M⁺):

236.1412. Found, 236.1445.

(b) Preparation of ent-4-epi-2: the compound ent-4-epi-2

(4.70 mg, 63%) was prepared from ent-4-epi-23 (7.10

mg, 22.4 mmol) as a colorless powder in the same man-

ner as that described for the preparation of 2. [a]_D²⁴

+9.7^ꢀ(c 0.47, CHCl₃). Mp 85–87 ^ꢀC. H NMR, ¹³C

1

NMR, IR, and MS spectra of this sample were identical

to those described for 4-epi-2. HRMS (FAB) (m/z):

calcd for C₂₁H₃₄NO₂(M⁺+H): 332.2590. Found,

332.2569.

(S)-5-Ethylfuran-2(5H)-one (25). Compound 25 was

prepared as a volatile colorless oil from ethyl (E)-3-

hexenoate 24 following the reported procedure.¹⁷[a]_D²¹

+71^ꢀ(c 0.54, CHCl₃) [lit.,^17d[a]_D+95^ꢀ(c 3.61,

CHCl₃)]. Optical purity of this sample was calculated to

be ca. 75% ee based on its [a]_Dvalue. ¹H NMR

(400 MHz, CDCl₃): d 1.02 (t, J=7.3 Hz, 3H), 1.69–1.90

(m, 2H), 4.99–5.30 (m, 1H), 6.13 (dd, J=5.4, 2.0 Hz,

1H), 7.45 (dd, J=5.9, 1.5 Hz, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 9.03, 26.3, 84.4, 121.8, 156.0,

173.2. IR (neat): 2970, 1750, 1360, 1170 cm^À1. MS (EI)

(m/z): 112 (M⁺), 83 (100). HRMS (EI) (m/z): calcd for

C₆H₈O₂(M⁺): 112.0524. Found, 112.0514. These spec-

tra were identical to those reported.^17d

(3S,3aS,4R,4aS,9aS) - 3 - Ethyl - 4 - hydroxy - 3a,4,

4a,5,6,7,8,9a - octahydronaphtho[2,3 - c]furan - 1(3H) - one

(29). Treatment of 28 (1.77 g, 7.49 mmol) with 1,8-dia-

zabicyclo[5.4.0]undec-7-ene (DBU) (5.60 mL, 37.5

mmol) in a manner similar to that described for the

preparation of dl-10 from dl-9 gave 29 (1.27 g, 72%) as

a pale yellow oil after ﬂash column chromatography

(hexane/ethyl acetate=2:1). [a]²_D⁴+80^ꢀ(c 0.33, CHCl₃).

¹H NMR (400 MHz, CDCl₃): d 0.90–1.12 (m, 1H), 1.05

(t, J=7.3 Hz, 3H), 1.20–1.32 (m, 1H), 1.37–1.48 (m,

1H), 1.52–1.70 (m, 2H), 1.69 (d, J=4.4 Hz, 1H), 1.78–

2.09 (m, 4H), 2.14–2.22 (m, 1H), 2.30–2.37 (m, 1H), 2.61

(td, J=8.3, 4.9 Hz, 1H), 3.27 (dq, J=8.3, 2.4 Hz, 1H),

3.80 (dt, J=7.8, 4.4 Hz, 1H), 4.42 (td, J=8.3, 2.9 Hz,

1H), 5.33 (d, J=2.9 Hz, 1H). ¹³C NMR (100 MHz,

CDCl₃): d 10.2, 25.6, 27.1, 29.2, 31.8, 34.7, 41.3, 43.3,

43.9, 72.3, 82.7, 112.7, 141.3, 176.3. IR (neat): 3460,

2930, 1750, 1210 cm^À1. MS (EI) (m/z): 236 (M⁺), 218,

149 (100). HRMS (EI) (m/z): calcd for C₁₄H₂₀O₃(M⁺):

236.1412. Found, 236.1420.

(3S,3aR,4S,9R,9aR)-4,9-Epoxy-3-ethyl-3a,4,5,6,7,8,9,9a

- octahydronaphtho[2,3 - c]furan - 1(3H) - one (26). Diels–

Alder reaction of 5 (3.92 g, 32.1mmol) and 25 (3.00 g,

26.8 mmol) in a manner similar to that described for the

preparation of dl-7 from 5 and 6 gave 26 (0.91g, 15%)

as a yellow oil with recovery of a portion of the starting

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1183

(3S,3aS,4R,4aS,8aR,9aS)-Decahydro-4-hydroxy-3-ethyl-

naphtho[2,3-c]furan-1(3H)-one (30). Hydrogenation of

29 (400 mg, 1.69 mmol) over PtO₂(40.0 mg, 10% w/w)

in a manner similar to that described for the prepara-

tion of dl-11 from dl-10 gave 30 (382 mg, 95%) as a

colorless powder after ﬂash column chromatography

(hexane/ethyl acetate=1:1). [a]²_D³+32^ꢀ(c 0.33, CHCl₃).

Mp 183–184 ^ꢀC (hexane–ethyl acetate). ¹H NMR

(400 MHz, CDCl₃): d 0.81–1.33 (m, 7H), 1.06 (t, J=7.3

Hz, 3H), 1.54–1.88 (m, 6H), 2.05–2.13 (m, 1H), 2.16

(dqd, J=15.2, 7.8, 2.5 Hz, 1H), 2.58 (dt, J=9.8, 5.9 Hz,

1H), 2.61–2.69 (m, 1H), 3.64 (ddd, J=9.8, 5.9, 3.4 Hz,

1H), 4.55 (td, J=10.8, 2.5 Hz, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 10.4, 25.7, 25.7, 28.8, 29.3, 31.7,

32.9, 38.5, 41.7, 44.2, 45.4, 73.4, 82.4, 178.1. IR (KBr):

3480, 2920, 1740, 1250, 1210 cm^À1. MS (EI) (m/z): 238

(M⁺), 220 (100). Anal. calcd for C₁₄H₂₂O₃: C, 70.56; H,

9.30. Found: C, 70.32; H, 9.36.

HRMS (EI) (m/z): calcd for C₁₅H₂₄O₃(M⁺): 252.1725.

Found, 252.1732.

(1S,3S,3aS,4aS,8aR,9aS)-3-Ethyl-dodecahydro-1-meth-

oxy-4-methylenenaphtho[2,3-c]furan (33). Methylenation

of 32 (648 mg, 2.57 mmol) in a manner similar to that

described for the preparation of dl-15 from dl-14 gave

33 (645 mg, 100%) as a yellow oil after ﬂash column

chromatography (hexane/ethyl acetate=10:1). [a]_D²⁸

ꢀ

1

+43 (c 0.33, CHCl₃). H NMR (400 MHz, CDCl₃): d

1.01 (t, J=7.6 Hz, 3H), 1.04–1.33 (m, 7H), 1.38–1.49

(m, 1H), 1.59–1.73 (m, 4H), 1.80–1.90 (m, 2H), 2.24 (dt,

J=12.2, 6.2 Hz, 1H), 2.81 (dd, J=9.8, 6.4 Hz, 1H), 3.33

(s, 3H), 3.92 (td, J=8.8, 3.4 Hz, 1H), 4.59 (s, 1H), 4.71

(t, J=2.0 Hz, 1H), 4.81 (t, J=1.8 Hz, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 10.8, 26.1, 26.4, 28.8, 28.9, 33.3,

34.5, 41.6, 42.7, 47.7, 51.2, 54.1, 83.3, 108.9, 109.4,

149.1. IR (neat): 2920, 1640, 1450 cm^À1. MS (CI) (m/z):

251(M ⁺+H), 219 (100). HRMS (CI) (m/z): calcd for

C₁₆H₂₇O₂(M⁺+H): 251.2011. Found, 251.2029.

(1S,3S,3aS,4R,4aS,8aR,9aS) - 3 - Ethyl - dodecahydro - 1 -

methoxynaphtho[2,3-c]furan-4-ol (31). Reduction of 30

(1.00 g, 4.20 mmol) followed by O-methylation in the

same manner as described for the preparation of dl-12

from dl-11 gave 31 (924 mg, 87% from 30) as a colorless

powder after ﬂash column chromatography (hexane/

ethyl acetate=4:1) by way of a crude mixture of the

hemiacetals (873 mg, 87%). The anomeric mixture of the

(1S,3S,3aR,4R,4aS,8aR,9aS) - 3 - Ethyl - dodecahydro -1 -

methoxynaphtho[2,3-c]furan-4-methanol and its (4S)-epi-

mer (34a and 34b). Sequential hydroboration-oxidation

of 33 (200 mg, 0.80 mmol) in the same manner as descri-

bed for the preparation of dl-16 from dl-15 gave 34a (149

mg, 70%) as a pale yellow oil and 34b (15.5 mg, 7%) as a

colorless oil, respectively, after ﬂash column chromato-

graphy (hexane/ethyl acetate=5:1). 34a: [a]²_D⁵+38^ꢀ(c

0.40, CHCl₃). ¹H NMR (400 MHz, CDCl₃): d 0.84–1.08

(m, 6H), 1.06 (t, J=7.3 Hz, 3H), 1.09–1.28 (m, 2H),

1.37–1.89 (m, 8H), 2.16 (dt, J=11.7, 5.9 Hz, 1H), 2.44

(dt, J=9.8, 4.9 Hz, 1H), 3.33 (s, 3H), 3.58–3.64 (m, 1H),

3.73–3.78 (m, 1H), 4.03 (td, J=9.3, 2.4 Hz, 1H), 4.49 (s,

1H). ¹³C NMR (100 MHz, CDCl₃): d 11.4, 26.0, 26.5,

30.1, 31.2, 33.4, 34.1, 38.6, 40.7, 42.9, 43.9, 46.4, 54.0,

1

hemiacetals: H NMR (400 MHz, CDCl₃): d 0.81–1.08

(m, 4H), 1.04 (t, J=7.3 Hz, 3H), 1.13–1.30 (m, 3H),

1.43–1.84 (m, 6H), 1.89–1.99 (m, 1H), 2.05–2.11 (m, 1H),

2.24 (dt, J=12.2, 6.2 Hz, 1H), 2.33 (d, J=2.5 Hz, 1H),

2.61(dt, J=9.3, 5.9 Hz, 1H), 3.66 (ddd, J=10.3, 5.9, 4.3

Hz, 1H), 4.12 (td, J=9.3, 2.5 Hz, 1H), 5.07 (d, J=2.5 Hz,

1H). MS (EI) (m/z): 222 (M⁺ÀH₂O). HRMS (EI) (m/z):

calcd for C₁₄H₂₂O₂(M⁺ÀH₂O): 222.1620. Found,

222.1608. 31: [a]_D²⁶+47^ꢀ(c 0.27, CHCl₃). Mp 105–106 ^ꢀC

1

(hexane). H NMR (400 MHz, CDCl₃): d 0.80–1.07 (m,

62.8, 80.9, 108.0. IR (neat): 3450, 2920, 1450, 1300 cm^À1

.

4H), 1.05 (t, J=7.3 Hz, 3H), 1.12–1.31 (m, 3H), 1.54 (d,

J=4.4 Hz, 1H), 1.41–1.91 (m, 6H), 2.03–2.11 (m, 1H),

2.21(dt, J=12.2, 6.2 Hz, 1H), 2.52 (dt, J=8.8, 6.0 Hz,

1H), 3.32 (s, 3H), 3.63 (ddd, J=10.3, 5.9, 4.2 Hz, 1H),

4.09 (td, J=9.3, 2.5 Hz, 1H), 4.55 (s, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 11.2, 25.9, 26.0, 29.0, 32.2, 32.7,

33.3, 38.5, 43.9, 45.6, 46.4, 54.0, 74.6, 81.6, 108.4. IR

(KBr): 3420, 2920, 1450 cm^À1. MS (EI) (m/z): 222 (M⁺-

HOMe), 204, 176 (100). Anal. calcd for C₁₅H₂₆O₃: C,

70.83; H, 10.30. Found: C, 70.54; H, 10.38.

MS (EI) (m/z): 237 (M⁺ÀOMe), 207 (100). HRMS (EI)

(m/z): calcd for C₁₅H₂₅O₂(M⁺ÀOMe): 237.1855.

Found, 237.1853. 34b: [a]²_D⁷À4.6^ꢀ(c 1.03, CHCl₃). H

1

NMR (400 MHz, CDCl₃): d 0.81–0.96 (m, 2H), 1.04 (t,

J=7.6 Hz, 3H), 1.13–1.80 (m, 14H), 2.21 (dt, J=12.7,

6.4 Hz, 1H), 2.39 (dd, J=9.8, 6.4 Hz, 1H), 3.32 (s, 3H),

3.52–3.60 (m, 1H), 3.80–3.87 (m, 1H), 3.94 (ddd, J=9.8,

7.8, 3.4 Hz, 1H), 4.54 (s, 1H). ¹³C NMR (100 MHz,

CDCl₃): d 10.8, 26.3, 27.2, 29.4, 30.5, 33.3, 34.9, 34.9,

39.9, 40.2, 42.3, 42.4, 54.0, 63.1, 82.3, 109.1. IR (neat):

3430, 2920, 1450, 1100 cm^À1. MS (EI) (m/z): 239

(M⁺ÀC₂H₅) (100). HRMS (EI) (m/z): calcd for

C₁₄H₂₃O₃(M⁺ÀC₂H₅): 239.1647. Found, 239.1646.

(1S,3S,3aR,4aS,8aR,9aS)-3-Ethyl-decahydro-1-methoxy-

naphtho[2,3-c]furan-4(1H)-one (32). Oxidation of 31

(289 mg, 1.14 mmol) in a manner similar to that descri-

bed for the preparation of dl-14 from dl-12 gave 32

(254 mg, 89%) as a colorless powder after ﬂash column

chromatography (hexane/ethyl acetate=4:1). [a]_D²⁷

+102^ꢀ(c 1.10, CHCl₃). Mp 55-56 ^ꢀC. ¹H NMR

(400 MHz, CDCl₃): d 0.97 (t, J=7.6 Hz, 3H), 1.11–1.49

(m, 6H), 1.52–1.84 (m, 6H), 1.94–2.06 (m, 2H), 2.58

(dt, J=12.7, 6.4 Hz, 1H), 2.86 (dd, J=8.8, 6.9 Hz,

1H), 3.31 (s, 3H), 4.12 (td, J=7.8, 5.1Hz, 1H), 4.72 (s,

1H). ¹³C NMR (100 MHz, CDCl₃): d 10.4, 25.1, 25.5,

25.5, 30.5, 32.6, 34.2, 41.3, 49.4, 51.3, 54.1, 56.4, 83.6,

(1S,3S,3aS,4R,4aS,8aR,9aS) - 3 - Ethyl - dodecahydro - 1 -

methoxy-4-[(phenylthio)methyl]naphtho[2,3-c]furan (35).

To a solution of 34a (149 mg, 0.56 mmol) in CH₂Cl₂(5

mL) were added triethylamine (388 mL, 2.78 mmol) and

methanesulfonyl chloride (129 mL, 1.67 mmol) at 0 ^ꢀC.

The mixture was stirred at the same temperature for 4 h

and gradually warmed to room temperature. It was then

poured into water (5 mL) and extracted with diethyl ether

(5 mLꢃ3). The ethereal extracts were combined, washed

with brine (5 mL), dried over anhydrous MgSO₄, ﬁltered,

and then concentrated in vacuo. Flash column chroma-

tography (hexane/ethyl acetate=2:1) of the residue gave

108.9, 211.3. IR (KBr): 2920, 1690, 1450, 1110 cm^À1

MS (EI) (m/z): 252 (M⁺), 234, 221, 207, 192 (100).

.

1184

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

the crude O-mesylate of 34a (180 mg, 93%) as a color-

less oil. This material was immediately used for the next

reaction without further puriﬁcation. ¹H NMR

(400 MHz, CDCl₃): d 0.86–1.28 (m, 6H), 1.07 (d, J=7.3

Hz, 3H), 1.37–1.49 (m, 1H), 1.52–1.90 (m, 8H), 2.16–

2.22 (m, 1H), 2.45 (dt, J=10.3, 5.2 Hz, 1H), 3.01 (s,

3H), 3.32 (s, 3H), 3.99 (dt, J=8.8, 2 Hz, 1H), 4.15 (dd,

J=9.8, 7.8 Hz, 1H), 4.32 (dd, J=9.8, 3.4 Hz, 1H), 4.50

(s, 1H). MS (FAB) (m/z): 452 [(M⁺+diethanolami-

ne)+H]. HRMS (FAB) (m/z): calcd for C₂₁H₄₂NO₇S

18 gave 36 (209 mg, 100%) as a colorless powder after

ﬂash column chromatography (hexane/ethyl ace-

tate=2:1). [a]²_D⁴+85^ꢀ(c 0.14, CHCl₃). Mp 129–130 ^ꢀC

1

(hexane–ethyl acetate). H NMR (400 MHz, CDCl₃): d

0.53–0.63 (m, 1H), 0.85–1.00 (m, 4H), 1.06–1.23 (m,

2H), 1.08 (t, J=7.3 Hz, 3H), 1.48–1.84 (m, 7H), 2.01–

2.10 (m, 1H), 2.14–2.21 (m, 1H), 2.78 (dt, J=8.8, 5.4 Hz,

1H), 3.00 (dd, J=15.2, 9.1 Hz, 1H), 3.27 (dd, J=14.7,

1.8 Hz, 1H), 3.30 (s, 3H), 3.86 (td, J=9.3, 1.8 Hz, 1H),

4.47 (s, 1H), 7.55–7.61 (m, 2H), 7.64–7.69 (m, 1H), 7.89–

7.93 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): d 11.3, 25.8,

26.5, 29.9, 32.6, 33.1, 34.1, 36.9, 40.7, 41.0, 42.9, 45.8,

54.0, 55.6, 80.7, 108.3, 127.9, 127.9, 129.3, 129.3, 133.7,

139.8. IR (KBr): 2920, 1450, 1300, 1150 cm^À1. MS

(FAB) (m/z): 498 [(M⁺+diethanolamine)+H]. HRMS

(FAB) (m/z): calcd for C₂₆H₄₄NO₆S [(M⁺+diethanol-

amine)+H]: 498.2889. Found, 498.2893.

[(M⁺+diethanolamine)+H]:

452.2662.

452.2682.

Found,

To a solution of potassium t-butoxide (225 mg, 2.01

mmol) in methyl sulfoxide (5 mL), thiophenol (206 mL,

2.01mmol) was added at room temperature, and the

mixture was stirred at the same temperature for 10 min.

The resulting mixture was added to a solution of the

crude O-mesylate of 34a (465 mg, 1.34 mmol) in methyl

sulfoxide (5 mL), and the mixture was stirred at room

temperature for 14 h. The mixture was poured into cold

water (50 mL) and extracted with diethyl ether (10

mLꢃ3). The ethereal extracts were combined, washed

with brine (10 mL), dried over anhydrous MgSO₄, ﬁl-

tered, and then concentrated in vacuo. Flush column

chromatography (hexane/ethyl acetate=50:1, then 10:1)

of the residue gave 35 (346 mg, 71%) as a yellow oil. This

material was found to be ca. 75% ee based on the HPLC

analysis. The analytical conditions for HPLC were as

follows: CHIRALPAK AD-H (Daicel Chemical Indus-

tries, Ltd.), 0.46ꢃ25 cm; mobile phase, hexane:2-propa-

nol=95:5 (v/v); ﬂow rate, 0.3 mL/min; temperature,

40 ^ꢀC; monitoring, 254 nm. Accordingly, this sample

(317 mg) was subjected to separation using HPLC

[CHIRALPAK AD-H (Daicel Chemical Industries,

Ltd.), 2ꢃ25 cm; mobile phase, hexane/2-propanol=98:2

(v/v); ﬂow rate, 5.0 mL/min; temperature, 40 ^ꢀC; mon-

itoring, 254 nm], aﬀording major enantiomer 35 (279 mg,

81%) with the natural absolute conﬁguration as a color-

less powder and minor enantiomer ent-35 (31.9 mg, 9%)

with the unnatural absolute conﬁguration as a colorless

powder. The retention times and ee were as follows: 35:

15.0 min, 99% ee, and ent-35: 16.8 min, 90% ee. 35: [a]_D²²

+157^ꢀ(c 0.10, CHCl₃). Mp 65–66 ^ꢀC. ¹H NMR

(400 MHz, CDCl₃): d 0.77–1.11 (m, 5H), 1.08 (t, J=7.3

Hz, 3H), 1.16–1.30 (m, 2H), 1.43–1.83 (m, 7H), 1.97–2.04

(m, 1H), 3.33 (s, 3H), 3.97 (td, J=9.3, 2.3 Hz, 1H), 4.49

(s, 1H), 7.14–7.19 (m, 1H), 7.25–7.31 (m, 4H). ¹³C NMR

(100 MHz, CDCl₃): d 11.4, 26.0, 26.6, 30.2, 32.0, 33.5,

34.1, 35.3, 40.8, 41.2, 41.7, 42.4, 46.2, 54.0, 80.8, 108.2,

125.6, 128.6, 128.6, 128.9, 128.9, 137.4. IR (KBr): 2920,

1580, 1480, 1440, 1100 cm^À1. MS (FAB) (m/z): 360

(M⁺+H), 329 (100). HRMS (FAB) (m/z): calcd for

C₂₂H₃₂O₂S (M⁺+H): 360.2123. Found, 360.2170. ent-

35: [a]²_D⁴À139^ꢀ(c 0.14, CHCl₃). Mp 63–64 ^ꢀC. ¹H NMR,

¹³C NMR, IR, and MS spectra of this sample were iden-

tical to those described for 35. HRMS (FAB) (m/z): calcd

for C₂₂H₃₂O₂S (M⁺+H): 360.2123. Found, 360.2104.

(2R,6S) - tert - Butyl 2 - [2 - (E) - [(1S,3S,3aR,4R,4a-

S,8aR,9aS)-3-ethyl-dodecahydro-1-methoxynaphtho[2,3-

c]furan-4-yl]ethenyl]-6-methylpiperidine-1-carboxylate

(37). Reaction of 36 (110 mg, 0.28 mmol) and 20 (95.5

mg, 0.42 mmol) in a manner similar to that described for

the preparation of 21 from 19 gave the b-benzoxysulfone

(possibly a mixture of the four diastereomers) (52.9 mg,

26%) with recovery of a portion of the starting 36 (62.5

mg, 57%). Subsequent reduction of the b-benzoxy-

sulfone (52.9 mg) similarly to the preparation of 21 from

19 aﬀorded 37 (22.1mg, 66%) as a colorless oil after ﬂash

column chromatography (hexane/ethyl acetate=8:1). In

this case, formation of the (Z)-oleﬁn was not observed by

¹H NMR analysis of the crude reaction product. The

b-benzoxysulfone: MS (FAB) (m/z): 829 [(M⁺+dietha-

nolamine)+H]. HRMS (FAB) (m/z): calcd for

C₄₅H₆₉N₂O₁₀S [(M⁺+diethanolamine)+H]: 829.4673.

Found, 829.4689. 37: [a]²_D¹+42^ꢀ(c 0.10, CHCl₃). H

1

NMR (400 MHz, CDCl₃): d 0.62–0.76 (m, 1H), 0.84–1.02

(m, 6H), 1.00 (t, J=7.3 Hz, 3H), 1.14–1.78 (m, 11H),

1.23 (d, J=6.4 Hz, 3H), 1.44 (s, 9H), 1.86–2.08 (m, 3H),

2.12–2.19 (m, 1H), 2.20–2.28 (m, 1H), 3.31 (s, 3H), 3.94–

4.02 (m, 2H), 4.37–4.43 (m, 1H), 4.49 (s, 1H), 5.22 (ddd,

J=15.2, 9.8, 1 Hz, 1H), 5.47 (dd, J=15.2, 6.9 Hz, 1H).

¹³C NMR (100 MHz, CDCl₃): d 11.0, 13.4, 20.9, 25.8,

26.4, 26.5, 26.6, 28.5, 28.5, 28.5, 28.6, 31.3, 31.4, 33.1,

34.1, 40.4, 41.2, 46.2, 46.3, 46.5, 47.0, 54.0, 78.9, 80.9,

108.3, 132.9, 133.2, 155.1. IR (neat): 2920, 1690, 1460,

1390 cm^À1. MS (FAB) (m/z): 462 (M⁺+H), 374 (100).

HRMS (FAB) (m/z): calcd for C₂₈H₄₈NO₄(M⁺+H):

462.3583. Found, 462.3584.

(2R,6S)-tert-Butyl 2-[2-(E)-[(3S,3aR,4R,4aS,8aR,9aS)-3

-ethyl-decahydronaphtho[2,3-c]furan-1(3H)-on-4-yl]ethe-

nyl]-6-methylpiperidine-1-carboxylate (38). Oxidation of

37 (8.10 mg, 17.5 mmol) in the same manner as described

for the preparation of 22 from 21 gave 38 (5.70 mg,

73%) as a colorless oil after ﬂush column chromato-

graphy (hexane/ethyl acetate=5:1). [a]²_D⁴+49^ꢀ(c 0.57,

1

CHCl₃). H NMR (400 MHz, CDCl₃): d 0.63–0.75 (m,

1H), 0.80–1.07 (m, 4H), 1.00 (t, J=7.1 Hz, 3H), 1.13–

1.34 (m, 5H), 1.24 (d, J=6.4 Hz, 3H), 1.40–2.10 (m,

11H), 1.45 (s, 9H), 2.33 (dt, J=10.3, 6.4 Hz, 1H), 2.60

(dt, J=13.2, 6.7 Hz, 1H), 3.95–4.02 (m, 1H), 4.39–4.44

(m, 1H), 4.48 (ddd, J=10.3, 8.3, 2.0 Hz, 1H), 5.25 (dd,

(1S,3S,3aS,4R,4aS,8aR,9aS) - 3 - Ethyl - dodecahydro - 1 -

methoxy - 4 - [(phenylsulfonyl)methyl]naphtho[2,3 - c]furan

(36). Oxidation of 35 (192 mg, 0.53 mmol) in a manner

similar to that described for the preparation of 19 from

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

1185

J=15.2, 9.8 Hz, 1H), 5.53 (dd, J=15.2, 6.4 Hz, 1H).

¹³C NMR (100 MHz, CDCl₃): d 9.99, 13.4, 20.9, 25.6,

26.2, 26.4, 26.4, 28.5, 28.5, 28.5, 28.7, 31.3, 32.1, 33.7,

40.1, 41.5, 42.2, 45.4, 45.8, 47.1, 52.3, 79.1, 81.8, 131.6,

134.0, 155.1, 178.6. IR (neat): 2930, 1770, 1690, 1390,

1180 cm^À1. MS (FAB) (m/z): 446 (M⁺+H), 346 (100).

HRMS (FAB) (m/z): calcd for C₂₇H₄₄NO₄(M⁺+H):

446.3270. Found, 446.3262.

mmol) were added, and the mixture was stirred at room

temperature for 1h. Sodium hydroxide (21.6 mg, 0.54

mmol) and water (0.50 mL) were added, and the mix-

ture was warmed at 50 ^ꢀC for 1h. After acidiﬁcation

with diluted citric acid solution, the mixture was con-

centrated in vacuo. The residue was diluted with water

(10 mL) and extracted with diethyl ether (3 mL ꢃ3).

The ethereal extracts were combined, washed with brine

(3 mL), dried over anhydrous MgSO₄, ﬁltered, and then

concentrated in vacuo. Flush column chromatography

(hexane/ethyl acetate=2:1) of the residue gave 41 (13.2

mg, 28%) as a colorless oil with recovery of a portion of

the starting 40 (9.60 mg, 21%). [a]²_D³+88^ꢀ(c 0.12,

(3S,3aR,4R,4aS,8aR,9aS)-3-Ethyl-decahydro-4-[2-(E)-

[(2R,6S) - 6 - methylpiperidin - 2 - yl]ethenyl]naphtho[2,3 -

c]furan-1(3H)-one (39). Removal of the tert-butoxy-

carbonyl group of 38 (5.70 mg, 12.8 mmol) in a manner

similar to that described for the preparation of 23 from

22 gave 39 (4.40 mg, 100%) as a colorless oil. [a]²_D⁵+12^ꢀ

1

CHCl₃). H NMR (400 MHz, CDCl₃): d 0.62–0.73 (m,

1H), 0.83–1.30 (m, 6H), 1.24 (d, J=6.4 Hz, 3H), 1.43–

2.05 (m, 11H), 1.45 (s, 9H), 1.50 (d, J=6.9 Hz, 3H),

2.16–2.23 (m, 1H), 2.57 (dq, J=7.8, 6.5 Hz, 1H), 2.83

(dd, J=15.2, 8.3 Hz, 1H), 3.99–4.06 (m, 1H), 4.38–4.44

(m, 1H), 4.71 (dq, J=8.3, 6.9 Hz, 1H), 5.41 (ddd,

J=15.7, 9.3, 1.5 Hz, 1H), 5.59 (dd, J=15.7, 4.9 Hz,

1H). ¹³C NMR (100 MHz, CDCl₃): d 13.4, 20.9, 21.9,

25.3, 26.2, 26.3, 26.4, 28.5, 28.5, 28.5, 31.8, 33.0, 33.8,

39.8, 40.9, 41.8, 42.8, 45.3, 47.1, 52.1, 79.0, 79.2, 128.9,

135.4, 155.0, 179.1. IR (neat): 2930, 1770, 1690, 1390,

1180 cm^À1. MS (FAB) (m/z): 432 (M⁺+H), 375, 358,

332(100). HRMS (FAB) (m/z): calcd for C₂₆H₄₂NO₄

(M⁺+H): 432.3114. Found, 432.3121.

1

(c 0.44, CHCl₃). H NMR (400 MHz, CDCl₃): d 0.65–

0.76 (m, 1H), 0.77–1.07 (m, 4H), 1.00 (t, J=7.3 Hz, 3H),

1.11 (d, J=6.4 Hz, 3H), 1.17–1.33 (m, 5H), 1.39–1.79

(m, 8H), 1.85–1.97 (m, 2H), 2.04 (br, 1H), 2.05–2.13 (m,

1H), 2.34 (dt, J=10.8, 6.7 Hz, 1H), 2.61 (dt, J=13.2,

6.6 Hz, 1H), 3.08–3.15 (m, 1H), 3.52–3.59 (m, 1H), 4.49

(ddd, J=10.3, 7.8, 2.2 Hz, 1H), 5.27 (dd, J=15.2, 9.8

Hz, 1H), 5.70 (dd, J=15.7, 6.8 Hz, 1H). ¹³C NMR

(100 MHz, CDCl₃): d 9.78, 19.5, 21.2, 26.1, 26.4, 28.7,

30.8, 31.3, 32.1, 32.4, 33.6, 40.0, 41.4, 42.1, 45.4, 45.7,

46.4, 53.1, 81.6, 131.8, 134.6, 178.5. IR (neat): 2930,

1770, 1450, 1200, 1060 cm^À1. MS (FAB) (m/z): 346

(M⁺+H) (100). HRMS (FAB) (m/z): calcd for

C₂₂H₃₆NO₂(M⁺+H): 346.2746. Found, 346.2749.

(3R,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-[2-(E)-

[(2R,6S) - 6 - methylpiperidin - 2 - yl]ethenyl]naphtho[2,3 -

c]furan-1(3H)-one (42). Removal of the tert-butoxy-

carbonyl group of 41 (13.2 mg, 30.6 mmol) in the same

manner as described for the preparation of 23 from 22

(3S,3aR,4R,4aS,8aR,9aS)-3-Ethyl-decahydro-4-[2-(E)-

[(2R,6S)-1,6-dimethylpiperidin-2-yl]ethenyl]naphtho[2,3-

c]furan-1(3H)-one (11-methylhimbacine) (3). Reductive

N-methylation of 39 (4.40 mg, 12.7 mmol) in a manner

similar to that described for the preparation of 2 from

23 gave 3 (3.70 mg, 81%) as a colorless oil after ﬂash

column chromatography (Chromatorex, hexane/ethyl

acetate=2:1). [a]²_D⁴+35^ꢀ(c 0.37, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): d 0.68–1.07 (m, 5H), 1.00 (t, J=7.3

Hz, 3H), 1.01 (d, J=6.4 Hz, 3H), 1.13–1.33 (m, 5H),

1.38–1.80 (m, 8H), 1.85–1.96 (m, 2H), 2.05–2.14 (m,

1H), 2.22 (s, 3H), 2.35 (dt, J=10.8, 6.4 Hz, 1H), 2.62

(dt, J=13.2, 6.7 Hz, 1H), 2.81–2.89 (m, 1H), 2.99–3.06

(m, 1H), 4.49 (ddd, J=10.3, 7.8, 2.5 Hz, 1H), 5.27 (dd,

J=15.2, 10.1 Hz, 1H), 5.58 (dd, J=15.2, 9.3 Hz, 1H).

¹³C NMR (100 MHz, CDCl₃): d 9.69, 14.1, 19.0, 26.1,

26.5, 28.6, 31.5, 32.1, 32.6, 33.3, 33.6, 40.0, 41.2, 41.5,

42.2, 45.5, 45.9, 53.4, 61.4, 81.6, 133.3, 133.3, 178.5. IR

(neat): 2930, 1770, 1450, 1180, 1040 cm^À1. MS (FAB)

(m/z): 360 (M⁺+H) (100). HRMS (FAB) (m/z): calcd

for C₂₃H₃₈NO₂(M⁺+H): 360.2903. Found, 360.2899.

gave 42 (9.40 mg, 93%). [a]²_D³+46^ꢀ(c 0.63, CHCl₃). H

1

NMR (400 MHz, CDCl₃): d 0.63–0.75 (m, 1H), 0.82–

0.91 (m, 1H), 0.99–1.33 (m, 7H), 1.11 (d, J=6.4 Hz,

3H), 1.43–1.87 (m, 7H), 1.52 (d, J=6.9 Hz, 3H), 1.97

(ddd, J=13.7, 6.9, 1.9 Hz, 1H), 2.16–2.23 (m, 1H), 2.58

(dq, J=7.8, 6.6 Hz, 1H), 2.84 (dd, J=15.2, 7.8 Hz, 1H),

3.05–3.13 (m, 1H), 3.54–3.61 (m, 1H), 4.72 (dq, J=8.3,

6.9 Hz, 1H), 5.48 (ddd, J=15.7, 8.8, 1.1 Hz, 1H), 5.77

(ddd, J=15.7, 6.4, 0.8 Hz, 1H). ¹³C NMR (100 MHz,

CDCl₃): d 19.6, 21.3, 21.8, 26.2, 26.4, 30.9, 31.9, 32.6,

33.0, 33.8, 39.8, 40.9, 41.7, 42.7, 45.4, 46.4, 52.9, 79.2,

129.7, 136.3, 179.1. IR (neat): 2930, 1770, 1450, 1200

cm^À1. MS (FAB) (m/z): 332 (M⁺+H) (100). HRMS

(FAB) (m/z): calcd for C₂₁H₃₄NO₂(M⁺+H): 332.2590.

Found, 332.2617.

(3R,3aR,4R,4aS,8aR,9aS)-Decahydro-4-[2-(E)-[(2R,6S)-

1,6-dimethylpiperidin-2-yl]ethenyl]-3-methylnaphtho[2,3-

c]furan-1(3H)-one (3-epihimbacine) (4). Reductive N-

methylation of 42 (9.40 mg, 28.4 mmol) in a manner

similar to that described for the preparation of 2 gave 4

(5.90 mg, 60%) as a colorless oil. [a]²_D²+77^ꢀ(c 0.59,

(2R,6S)-tert-Butyl 2-[2-(E)-[(3R,3aR,4R,4aS,8aR,9aS)-

decahydro-3-methylnaphtho[2,3-c]furan-1(3H)-on-4-yl]-

ethenyl]-6-methylpiperidine-1-carboxylate (41). To

a

solution of 40^11,13(46.5 mg, 0.11 mmol) in 95% metha-

nol (1mL), powdered potassium hydroxide (7.26 mg,

0.13 mmol) was added at room temperature, and the

resulting mixture was heated at reﬂux for 2 h and con-

centrated in vacuo. The residual potassium salt was

suspended in tetrahydrofuran (1mL), and the suspen-

sion was cooled at 0 ^ꢀC. Triethylamine (150 mL, 1.08

mmol) and methanesulfonyl chloride (83.5 mL, 1.08

CHCl₃). H NMR (400 MHz, CDCl₃): d 0.65–0.78 (m,

1

1H), 1.00–1.33 (m, 6H), 1.00 (d, J=6.4 Hz, 3H), 1.38–

1.61 (m, 4H), 1.52 (d, J=6.8 Hz, 3H), 1.65–1.89 (m,

6H), 1.95–2.00 (m, 1H), 2.17–2.27 (m, 1H), 2.23 (s, 3H),

2.58 (dq, J=8.3, 6.7 Hz, 1H), 2.80–2.85 (m, 2H), 3.02–

3.07 (m, 1H), 4.69 (dq, J=8.3, 6.9 Hz, 1H), 5.49 (dd,

J=15.2, 9.3 Hz, 1H), 5.68 (dd, J=15.2, 8.8 Hz, 1H).

¹³C NMR (100 MHz, CDCl₃): d 14.4, 19.0, 21.9, 26.2,

1186

M. Takadoi et al. / Bioorg. Med. Chem. 11 (2003) 1169–1186

26.5, 32.0, 33.0, 33.1, 33.3, 33.8, 39.8, 40.9, 41.1, 41.8,

42.9, 45.6, 53.4, 61.3, 79.2, 131.4, 134.9, 179.1. IR

(neat): 2930, 1770, 1450, 1180, 1040 cm^À1. MS (FAB)

(m/z): 346 (M⁺+H) (100). HRMS (FAB) (m/z): calcd

for C₂₂H₃₆NO₂(M⁺+H): 346.2746. Found, 346.2738.

Hughes, G. K.; Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust.

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Binding assay

Receptor binding analyses for the muscarinic M₁and

M₂subtype receptors were performed using homo-

genates of the cerebral cortex and brainstem of a rat,

respectively. The radioligands used were [³H]-pir-

enzepine for the cerebral cortex and [³H]-quinuclidinyl

benzilate (QNB) for the brainstem. The homogenates

were incubated in a 50 mM Tris-buﬀer (pH 7.4) at 25 ^ꢀC

for 90 min, and then rapidly ﬁltrated on Whatman GF-

B ﬁlters. Radioactivity was counted using a liquid scin-

tillation counter. Non-speciﬁc binding was deﬁned in

the presence of 2 mM atropine. The test compounds

were dissolved in DMSO and diluted with buﬀer to the

ﬁnal concentrations. Competitive binding experiments

were performed in the presence of less than 0.1%

DMSO, which did not aﬀect the speciﬁc binding. The

equilibrium dissociation constants (K_i) were calculated

using the Cheng–Prusoﬀ equation, K_i=IC₅₀/(1+L/K_d),

where L and K_dwere the concentration and the dis-

sociation constants of the radioligands, respectively.

The K_dvalues were determined by Scatchard analysis.

Acknowledgements

We are grateful to Dr. H. Ohkubo and Dr. T. Ishizaki,

Kyorin Pharmaceutical Co. Ltd., for their numerous

valuable suggestions and encouragement. We would

also like to thank Dr. Y. Fukuda, Kyorin Pharmaceu-

tical Co. Ltd., for his discussions with us and for his

helpful suggestions. The in vitro binding activity assay

was performed by Dr. T. Kawai, Kyorin Pharmaceu-

tical Co. Ltd., to whom our thanks are also due.

14. The compound dl-7 was also synthesized by the Diels–

Alder reaction of 5 and maleic anhydride followed by reduc-

tion of one of the two carbonyl group with NaBH₄. See:

Tochtermann, W.; Bruhn, S.; Wolﬀ, C. Tetrahedron Lett.

1994, 35, 1165.

References and Notes

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19. The crystallographic data (excluding structure factors) for

compounds 17a and 17b have been deposited in the Cam-

bridge Crystallographic Data Centre under supplementary

publication numbers CCDC 183427 and 183426, respectively.

Copies of the data can be obtained, free of charge, on appli-

cation to CCDC, 12 Union Road, Cambridge CB21EZ, UK

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Article Doi

Synthetic studies on himbacine, a potent antagonist of the muscarinic M2 subtype receptor. Part 2: Synthesis and muscarinic M2 subtype antagonistic activity of the novel himbacine congeners modified at the C-3 position of lactone moiety

DOI: 10.1016/S0968-0896(02)00665-X

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