Synthetic studies of himbacine, a potent antagonist of the muscarinic M2 subtype receptor 1. Stereoselective total synthesis and antagonistic activity of enantiomeric pairs of himbacine and (2′S,6′R)-diepihimbacine, 4-epihimbacine, and novel himbacine congeners

Article abstract of DOI:10.1016/S0040-4020(02)01358-3

Total synthesis of an enantiomeric pair of himbacine 1 and ent-1 was achieved in a highly stereoselective manner by employing an intermolecular Diels-Alder reaction of tetrahydroisobenzofuran 8 with chiral furan-2(5H)-one (S)-9 and (R)-9, respectively, as a key step. An enantiomeric pair of (2′S,6′R)-diepihimbacine 24 and ent-24, 4-epihimbacine 4-epi-1, and novel himbacine congeners bearing the same tricyclic moiety as that of 1 were also successfully prepared by utilizing the key synthetic intermediates for 1, establishing the convergency and flexibility of the explored synthetic route. All of the synthesized compounds used were subjected to muscarinic M₂ subtype receptor binding affinity assay, disclosing novel aspects of the structure-activity relationships for 1.

Full text of DOI:10.1016/S0040-4020(02)01358-3

Tetrahedron 58 (2002) 9903–9923
Synthetic studies of himbacine, a potent antagonist of the
muscarinic M2 subtype receptor 1. Stereoselective total synthesis
and antagonistic activity of enantiomeric pairs of himbacine
and (20S,60R)-diepihimbacine, 4-epihimbacine, and novel
himbacine congeners
†
b
,
b
Masanori Takadoi,a Tadashi Katoh, Akihiro Ishiwata and Shiro Terashimab
,
*
aDiscovery Research Laboratories, Kyorin Pharmaceutical Company Ltd, 2399-1 Nogi, Nogi-machi, Tochigi 329-0114, Japan
bSagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Received 25 September 2002; accepted 21 October 2002
Abstract—Total synthesis of an enantiomeric pair of himbacine 1 and ent-1 was achieved in a highly stereoselective manner by employing
an intermolecular Diels–Alder reaction of tetrahydroisobenzofuran 8 with chiral furan-2(5H)-one (S)-9 and (R)-9, respectively, as a key step.
An enantiomeric pair of (20S,60R)-diepihimbacine 24 and ent-24, 4-epihimbacine 4-epi-1, and novel himbacine congeners bearing the same
tricyclic moiety as that of 1 were also successfully prepared by utilizing the key synthetic intermediates for 1, establishing the convergency
and flexibility of the explored synthetic route. All of the synthesized compounds used were subjected to muscarinic M2 subtype receptor
binding affinity assay, disclosing novel aspects of the structure–activity relationships for 1. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Himbacine 1, isolated from the bark of Galbulimima
baccata, is a potent antagonist of the muscarinic M2
subtype receptor.2 This alkaloid 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).
Figure 1. Structure of natural himbacine 1.
It is well known that senile dementia associated with
Alzheimer’s disease is directly correlated with diminished
muscarinic M2 receptors which regulate ACh release, the
latter which acts as an autoreceptor.9 Under these
levels of synaptic acetylcholine (ACh) in the cortical and
hippocampal areas of the brain,3 and current forms of
circumstances, the therapeutic agent requires the high M2/
therapy address this issue, relying on the cholinergic
hypothesis4 of memory dysfunction. Such therapies com-
M1 selectivity because of the post-synaptic localization of
the M1 receptor. Himbacine 1 was reported to be a potent
prise the following four approaches to enhance synaptic
antagonist of the muscarinic M2 subtype receptor with 10–
ACh levels, namely, use of an ACh esterase inhibitor,5 a
20-fold selectivity toward the M1 subtype. Therefore, much
choline acetyl transferase (ChAT) synthesis enhancer,6 a
attention has been focused on 1 by medicinal and synthetic
choline re-uptake enhancer,7 and a muscarinic receptor
agent.8 It has been reported that enhancement of synaptic
ACh levels can be achieved by antagonizing presynaptic
organic compound synthesis communities.10 Two total
syntheses of 1 have hitherto been achieved by Hart–
Kozikowski11 and Chackalamannil12 by employing intra-
molecular Diels–Alder reaction as their key steps.
Keywords: alkaloids; Diels–Alder reactions; natural products; asymmetric
synthesis.
In order to disclose novel aspects of the structure–activity
relationships of 1, and moreover, to explore the promising
congeners of 1 which may show more improved M2 subtype
selectivity, an efficient synthetic route to 1 was sought
*
Corresponding author. Tel.: þ81-280-56-2201; fax: þ81-280-57-1293;
e-mail: masanori.takadoi@mb2.kyorin-pharm.co.jp
Present address: RIKEN (The Institute of Physical and Chemical
Research), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
†
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01358-3

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M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
Scheme 1. Novel synthetic design of himbacine 1 featuring intermolecular Diels–Alder reaction.
which would be more convergent and flexible than those
that had been previously reported.11,12 We wish to report
here the novel total synthesis of an enantiomeric pair of
himbacine 1 and ent-1 accomplished by a method featuring
a highly stereoselective intermolecular Diels–Alder
reaction as a key step. This paper is also co0ncerned with
the synthesis of an enantiomeric pair of (20S,6 R)-diepihim-
bacine 24 and ent-24, 4-epihimbacine 4-epi-1, and novel
congeners of 1 prepared by employing the synthetic
intermediates of 1 along with their M2 antagonistic
activity.1 The latter studies were carried out in order to
gain a more thorough understanding of the convergency and
flexibility of the explored synthetic route and to disclose
novel aspects of the structure–activity relationships of these
molecules.
intermolecular Diels–Alder reactions are more convergent
and flexible than the corresponding intramolecular reac-
tions, especially in the synthesis of complex natural
products. Therefore, our approach was anticipated to be
not only more advantageous for the total synthesis of 1
itself, but also more useful for the exploration of novel
congeners of 1 by changing the starting tetrahydroiso-
benzofuran derivatives, the chiral furan-2(5H)-one deriva-
tives, and/or the chiral piperidine units. Actually, the
usefulness of the explored synthetic route was exemplified
by successful syntheses of enantiomeric ent-1 and some
novel congeners of 1. These studies were accomplished by
employing (R)-9 in place of (S)-9 and by constructing novel
structural features from the synthetic intermediates of 1.
2.2. Synthesis of natural himbacine 1
The starting materials, tetrahydroisobenzofuran 814 and
furan-2(5H)-one (S)-9,15 were synthesized in large quan-
tities according to the reported procedure with some
modifications. With 8 and (S)-9 in hand, the intermolecular
Diels–Alder reaction could then be examined (Scheme 2).
2. Results and discussion
2.1. Synthetic strategy
Our synthetic strategy as regards 1 is outlined in Scheme 1.
The key step of our synthesis was a highly stereoselective
intermolecular Diels–Alder reaction between tetrahydro-
isobenzofuran 8 and chiral furan-2(5H)-one (S)-9. Thus,
exo-selective construction of the cycloadduct 7 was
envisioned, based on a previously reported result of the
reaction of 8 with maleic anhydride.13 It was expected that
the four chiral centers of 7 could be introduced in a highly
stereoselective manner due to the (S)-chirality of the methyl
group at the C-5 position of (S)-9. All of the chiral centers of
tricyclic alcohol 4a bear the natural absolute configuration
of 1, and 4a was readily derived from 7 by sequential
hydrogenation to saturated tetracyclic compound 6 from a
convex face, ring opening of 6, followed by double bond
isomerization to unsaturated alcohol 5, and hydrogenation.
Introduction of an arylsulfonylmethyl group into 4 gave
tricyclic sulfone 2, which was connected to the bottom half
of 1, the piperidinaldehyde 3, according to Hart’s pro-
cedure11 featuring the Julia–Lythgoe olefination protocol,
followed by subsequent deprotection and N-methylation of
the piperidine moiety. It is generally accepted that
As shown in Table 1, heating of a mixture of 8 and (S)-9 in
the absence (entry 1) or the presence (entries 2–4) of Lewis
acid16,17 failed to afford 7. The same unsuccessful results
Scheme 2. Intermolecular Diels–Alder reaction of tetrahydroisobenzo-
furan 8 with (S)-furan-2(5H)-one (S)-9. (a) see Table 1; (b) H2, 10% Pd–C,
EtOH, rt, 12 h, 96%.

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9905
Table 1. Intermolecular Diels–Alder reaction of tetrahydroisobenzofuran 8
with furan-2(5H)-one (S)-9
included a cis–anti–cis ring system, and was confirmed by
single-crystal X-ray diffraction analysis, as shown in
Scheme 2.
Entrya
Catalyst
(equiv.)
Solvent
Conditions
Result
(yield of 7, %)b
Next, our synthetic efforts were focused on converting the
stereochemistries of 6 to those of 1, a cis–trans ring system
(Scheme 3). Toward this end, we first examined a ring-
opening reaction of the 7-oxabicyclo[2.2.1]heptane system
in 6. After conducting the experiments, it was found that this
reaction proceeded under basic conditions,23 giving rise to
hydroxyenone 10 in a 92% yield. Treatment of 10 with 1,8-
diazabicyclo[5.4.0]undec-7-ene efficiently underwent
double-bond isomerization to afford deconjugated alcohol
5 as the sole product in an 83% yield. This highly selective
formation of 5 may be explained by thermodynamic control.
In order to obtain saturated alcohol 4a bearing the desired
cis–trans ring system, catalytic hydrogenation of 5 was next
examined using the various catalytic systems shown in
Table 2.
1
2
3
4
5
6
7
8
9
10
None
None
1508C, 65 h Decomposition
rt–408C, 19 h Decomposition
SiO2–Et2AlCl
SiO2–TiCl4
Florisil
ZnCl2 (2.0)
(Ph3P)3RhCl (0.1) CF3CH2OH rt, 168 h
Toluene
Toluene
Toluene
CH2Cl2
rt, 9 h
rt, 48 h
rt, 48 h
Decomposition
No reaction
No reaction
16 (20)c
ZnI2 (0.5)
CH2Cl2
Et2O
Benzene
Et2O
rt, 120 h
rt, 48 h
rt, 24 h
rt, 168 h
59 (88)c
4 M LiNTf2
1 M LiBF4
5 M LiClO4
No reaction
Decomposition
58
a
Tetrahydroisobenzofuran 8 was allowed to react with furan-2(5H)-one
(S)-9 (1–1.5 equiv.).
The cycloadduct 7 was obtained as the sole product. No other reaction
products were detected by 1H NMR analysis of the crude reaction
mixture.
b
c
Corrected for the recovery of (S)-9.
Among the catalytic systems tested, hydrogenation of 5 in
the presence of PtO2 was found to produce the saturated
alcohol 4a as the sole product in a 96% yield (entry 4). On
the other hand, employing other catalytic systems for this
hydrogenation regularly gave a mixture of 4a and its isomer
4b (C-3a, 9a position, the himbacine numbering). The
structures of 4a and 4b were unambiguously determined by
single-crystal X-ray diffraction analyses. The ratio of 4a to
4b definitely depended on the metal species of the catalytic
systems. Formation of 4b may be explained by the double-
bond shift from C-8a, 9 to the C-3a, 9a position, followed by
hydrogenation from the sterically less hindered direction
opposite of the C-3 methyl group. However, the reason
remains unclear why such an abnormal hydrogenation took
place by catalytic systems not employing PtO2. Thus, the
stereoselective construction of the dodecahydro-
naphtho[2,3-c]furan ring system involved in 1 was readily
accomplished in four steps from exo-cycloadduct 7,
produced by the intermolecular Diels–Alder reaction.
were obtained by the reactions using LiNTf218 and LiBF4
(entries 8, 9). On the other hand, upon treatment with
Wilkinson’s catalyst20 (entry 6), ZnI2 (entry 7), or 5 M
LiClO4–Et2O21 (entry 10), the cycloaddition reaction took
place successfully, giving rise to cycloadduct 7. The
reaction under Livinghouse’s condition (entry 6) gave 7
with poor reproducibility. In the case of entry 7, the
isolation of 7 was found to be troublesome due to the
recovery of unreacted (S)-9. Among these conditions
examined, use of 5 M LiClO4–Et2O afforded the best
results, producing 7 as the sole product in a 58% yield. As
expected, it appeared that this Diels–Alder reaction
proceeded in a highly exo-selective manner, affording 7 as
the sole product. Exclusive formation of 7 was determined
19
1
by the H NMR analysis of the crude reaction product. To
the best of our knowledge, this is the first example of a
Diels–Alder reaction of furan and furan-2(5H)-one deriva-
tive.22 Since the structural determination of 7 by the spectral
data proved difficult, and because 7 was also found to be
fairly unstable, 7 was directly subjected to the next
hydrogenation. Thus, hydrogenation of 7 under convention-
al conditions occurred from the sterically less hindered
convex face to give the hydrogenated compound 6 as the
sole product in a 96% yield. The stereochemistry of 6
Prior to oxidation of the secondary hydroxy group at the C-4
position of 4a, the lactone moiety was protected in a form of
acetal by sequential reduction and acetalization, yielding
a-methyl acetal 11, the thermodynamically more stable
compound, in a 74% yield from 4a as almost the sole
product (Scheme 4). The hydroxy group at the C-4 position
of 11 was oxidized using the tetrapropylammonium
perruthenate(VII)-4-methylmorpholine N-oxide (TPAP-
NMO) system,24 producing ketone 12 in a 95% yield.
Methylenation of 12 by Wittig reaction provided exo-
methylene compound 13 in an 86% yield. Sequential
Table 2. Catalytic hydrogenation of deconjugated alcohol 5
Entrya
Catalystb
Ratio of 4a/4b (yield, %)c
1
2
3
4
Rh–Al2O3
10% Pd–C
Raney Ni
PtO2
1:1 (92)
5:1 (65)
10:1 (76)
1:0 (96)
a
Hydrogenation was carried out at rt in EtOH.
b
c
Scheme 3. Stereoselective construction of the tricyclic part 4a of 1.
(a) LiN(TMS)2, THF, 278 to 2408C, 4 h, 92%; (b) DBU, toluene, 1008C,
5 h, 83%; (c) see Table 2.
Amount of the catalyst corresponding to the 10% weight of 5 was used.
The ratio of 4a–4b was determined by the 1H NMR spectrum of the crude
reduction product.

9906
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
Scheme 5. Completion of the total synthesis of natural himbacine 1.
(a) nBuLi, 2788C, 1 h, 100% conversion (a mixture of the diastereomers);
(b) 5% Na–Hg, Na2HPO4, MeOH, rt, 2.5 h, 66%; (c) Jones reagent,
acetone, rt, 0.5 h, 100%; (d) trifluoroacetic acid, CH2Cl2, rt, 1.5 h, 100%;
(e) 37% HCHO aq., NaBH3CN, CH3CN, rt, 0.5 h, 91%.
Scheme 4. Synthesis of the sulfone 2, the key intermediate of 1. (a) (i)
DIBAL-H, Et2O, 2788C, 1 h, (ii) BF3·Et2O, MeOH, CH2Cl2, 260–rt, 12 h,
˚
74% (two steps); (b) TPAP, 4-methylmorpholine N-oxide, MS 4 A,
CH2Cl2, rt, 1.5 h, 95%; (c) Ph3PCH3I, NaN(TMS)2, Et2O, 08C to rt, 2 h,
86%; (d) (i) BH3·THF, THF, 2788C to rt, 3 h, (ii) 30% H2O2, 10% NaOH,
08C, 0.5 h, 14a:14b¼73:8%; (e) methanesulfonyl chloride, 4-(dimethyl-
amino)pyridine, Et3N, CH2Cl2, 08C to rt, 3 h, 100%; (f) thiophenol, tBuOK,
DMSO, rt, 3 h, 100%; (g) mCPBA, NaHCO3, CH2Cl2, rt, 2 h, 82%.
2.3. Synthesis of unnatural ent-himbacine ent-1
To clarify the relationship between the absolute configur-
ation of 1 and muscarinic M2 subtype antagonistic activity,
as well as to explore the convergency and flexibility of the
developed synthetic route to 1, we next planned to
synthesize the enantiomer of 1, unnatural ent-himbacine
ent-1, by using (R)-915 instead of (S)-9 as a starting material.
Synthesis of (R)-9 was accomplished starting with (R)-
methyl lactate. According to the synthetic scheme to 1
detailed above, we succeeded in obtaining ent-1 from (R)-9,
disclosing prominent aspects of the explored synthetic
route. Spectral data of ent-1 were superimposable on those
of 1. To avoid confusion, the compounds carrying natural
configurations are the only compounds depicted in Scheme
2–5.
hydroboration and oxidation gave rise to 4b-carbinol 14a in
a 73% yield along with the undesired C-4 epimer 14b in an
8% yield. When the hydroboration was carried out at 08C
instead of at 2788C, the ratio of 14a to 14b was reduced to
5:1. The structure of 14a bearing all of the desired chiral
centers in the tricyclic part of 1, was rigorously confirmed,
as shown by single-crystal X-ray diffraction analysis.
Stereoselective formation of 14a may reflect increased
steric hindrance of the b-face of 13.
With 14a in hand, transformation of 14a into the known
sulfone 211 was next examined. It was accomplished in an
82% combined yield by a three-step sequence involving O-
mesylation of the hydroxy group of 14a, replacement of the
O-mesyl group in 15 with a phenylsulfide group, and
oxidation of the resulting sulfide 16. Spectral and physical
data of 2 were identical to those that have previously been
reported.11
2.4. Synthesis of an enantiomeric pair of (20S,60R)-
diepihimbacine
In order to elucidate the structure–activity relationships
between the absolute configuration of the tricyclic moiety
on 1 and the piperidine moiety, 0 we next planned to
synthesize an enantiomeric pair of (2 S,60R)-diepihimbacine
24 and ent-24. It was expected that the synthesis of 24 could
be accomplished by the use of our explored synthetic route,
employing the sulfone 2 with a natural absolute configur-
ation and the chiral piperidinaldehyde ent-3 possessing an
unnatural absolute configuration.
The remaining task for the total synthesis was conversion of
2 to 1 according to the Hart–Kozikowski procedure11
(Scheme 5). Thus, the coupling reaction25,26 of 2 with
aldehyde 3, prepared according to the reported procedure,27
and a subsequent elimination reaction of the intermediary b-
hydroxy sulfone almost exclusively provided olefin 17
possessing (E)-stereochemistry in a 66% yield. Sequential
oxidation of the acetal moiety in 17 and deprotection of the
N-Boc group in 18 afforded the piperidine 19. Finally,
reductive N-methylation of 19 furnished natural himbacine
1 in a high yield over a three-step sequence. Physical and
spectral properties of the synthetic sample of 1 were found
to be identical to those previously reported.11b As described
above, our efforts culminated in the successful development
of a novel synthetic route to 1 in which the intermolecular
Diels–Alder reaction of 8 with (S)-9 is employed as the key
stereoselective reaction.
Thus, the Julia–Lythgoe coupling reaction of 2 and ent-3
was examined to produce 24 (Scheme 6). However, in
contrast to the cases for the synthesis of 1 and ent-1, the
starting material 2 was fully recovered when the reaction
was quenched by adding water. It seems likely that the retro-
aldol type of reaction might have occurred when the
materials were immersed in excess water, probably due to
the decreased stability of the in situ formed lithium aldolate
or an aldol-type product under protic conditions. After much

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
Table 3. In vitro binding activity of 1, ent-1, 24, ent-24, and 4-epi-1
9907
Entry
Compound
2log Ki
M1 (cortex)
M2 (brainstem)
1
2
3
4
5
6
1
7.1
7.2
5.9
6.5
6.5
6.1
7.9
7.9
6.3
6.7
6.7
5.7
1a
ent-1
24
ent-24
4-epi-1
a
Authentic sample of 1.28
against the muscarinic M1 and M2 subtype receptors were
performed. Results of these assays are shown in Table 3. In
contrast to 1, all of the tested compounds ent-1, 24, ent-24,
and 4-epi-1 were found to show very weak comparable
binding affinity against the muscarinic M1 and M2 subtype
receptors. These results clearly indicated that the stereo-
chemistry of both the tricyclic and the piperidine moieties of
1 play crucial roles in its strong muscarinic M2 antagonistic
activity.
Scheme 6. Synthesis of (20S,60R)-diepihimbacine 24. (a) nBuLi, DME,
278 to 2208C, 4 h; (b) (i) benzoyl chloride, 2208C to rt,1 h, (ii)
3-(dimethylamino)propylamine, rt, 1 h; (c) 5% Na–Hg, Na2HPO4, MeOH,
rt, 1 h, 33% (four steps) (recovery of 2: 51%); (d) Jones reagent, acetone, rt,
2 h, 68%; (e) trifluoroacetic acid, CH2Cl2, rt, 0.5 h, 91%; (f) 37% HCHO
aq., NaBH3CN, CH3CN, rt, 3 h, 73%.
2.7. Synthesis of some novel congeners of 1
With completion of the total synthesi0s of0enantiomeric pairs
of natural himbacine 1 and ent-1, (2 S,6 R)-diepihimbacine
24 and ent-24, and 4-epihimbacine 4-epi-1, we next
examined the synthesis of some novel congeners of 1.
These studies were performed in order to further examine
the convergency and flexibility of the explored synthetic
scheme, and moreover, to disclose novel aspects of the
structure–activity relationships. Studies of the synthesis and
muscarinic M2 subtype antagonistic activity of himbacine
congeners have thus far been reported by Kozikowski et al.10
and Chackalamannil et al.12c Our novel synthesis and
activity evaluation of 1, ent-1, 24, ent-24, and 4-epi-1
disclosed that the absolute configuration plays a pivotal role
in muscarinic M2 subtype antagonistic activity. Therefore, it
appeared that novel congeners of himbacine should be
synthesized in the natural configuration. Taking into
account these points, we designed some novel congeners
of 1, shown in Fig. 2. It was anticipated that the chiral
piperidine ring of 1 could be replaced with various
substituted heterocycles such as pyridine, imidazole,
morpholine, pyrrolidine, and piperidine derivative. More-
over, the (E)-olefin present in 1 was expected to be
substituted by its bioisosteres such as ether, ester,
carbamate, and amide bond species. Based on the above
considerations, the compounds, 26, 28, 30, 32, 35, 37, 39,
experimentation, it was finally found that quenching the
reaction of 2 and ent-3 by the addition of excess benzoyl
chloride successfully gave the desired benzoate 20 as a
diastereomeric mixture after removal of the excess benzoyl
chloride with 3-(dimethylamino)propylamine. Without
separation, the reaction mixture was directly subjected to
reductive elimination, giving rise to (E)-olefin 21 in a 33%
yield from 2, along with a 51% recovery of 2. In this case as
1
well, formation of the (Z)-olefin was not observed by H
NMR analysis of the crude reaction product. According to
the same synthetic procedure as that used for 1, 21 was
converted to the target compound 24 in a three-step
sequence involving oxidation of the hemiacetal moiety,
deprotection of the N-Boc group, and reductive N-methyl-
ation. The enantiomer of 24, ent-24, was also synthesized
employing ent-2 and 3 in the same manner as that described
for the synthesis of 24.
2.5. Synthesis of 4-epi-1
Next, in order to disclose the relationships between
muscarinic M2 subtype antagonistic activity and C-4
stereochemistry in the tricyclic moiety of 1, we examined
the synthesis of 4-epihimbacine 4-epi-1 by employing 4a-
carbinol 14b as a starting material. Thus, according to our
methodology featuring the Julia–Lythgoe coupling reaction
of the tricyclic sulfone and the chiral piperidinaldehyde that
was established by the synthesis of 24 as well, we have
readily succeeded in preparing 4-epi-1 from 14b in eight
steps.
2.6. Muscarinic M2 subtype binding activity of
enantiomeric pairs of natural himbacine 1 and ent-1 and
(20S,60R)-diepihimbacine, and 4-epihimbacine
With enantiomeric pairs of natural himbacine 1 and ent-1
and (20S,60R)-diepihimbacine 24 and ent-24, and 4-epihim-
bacine 4-epi-1 in hand, receptor binding affinity assays
Figure 2. Novel himbacine congeners designed as synthetic targets.

9908
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
8). Similarly, acylation of 11 with chloroacetyl chloride
followed by substitution with morpholine and Jones
oxidation furnished the morpholin-4-yl acetate derivative
35 by way of 2-chloroacetate 33 and acetal 34. The
N-(pyridin-2-yl) carbamate derivative 37 was prepared by
the reaction of 11 with 2-isocyanatopyridine in situ
generated from 2-picolinic acid and subsequent oxidation
with Jones reagent. In a similar fashion, 4b-carbinol 14a
was transformed to the homologous N-(pyridin-2-yl)
carbamate derivative 39 (Scheme 9). The (S)-1-Benzyl-
pyrrolidin-3-yl ether derivative 41 was synthesized using
commercially available (S)-1-benzylpyrrolidin-3-ol by way
of O-mesylate 15 derived from 14a. The 1-methylpiperidin-
3-yl ether derivative 44 was derived from 43 prepared by
etherification of 15 with readily obtainable (S)-1-(tert-
butoxycarbonyl)piperidin-3-ol29 followed by reduction of
the N-Boc group to an N-Me group with lithium aluminum
hydride. Furthermore, 4b-carbinamine 45 was prepared
from 14a by the Mitsunobu procedure30 and subsequent
removal of a phthalide moiety. This reaction was coupled
with 6-methyl-2-picolinic acid by use of EDCI as a coupling
reagent, affording the 2-methylpyridine-6-carboxamide 47
by way of acetal 46.
Scheme 7. Synthesis of himbacine congeners bearing the natural tricyclic
moiety (I). (a) nBuLi, 6-methylpyridine-2-carboxaldehyde, DME, 2788C,
1 h, 100%; (b) 5% Na–Hg, Na2HPO4, MeOH, rt, 2 h, 19%; (c) Jones
reagent, acetone, rt, 60% (for 26), 13% (for 28), 64% (for 30); (d) nBuLi,
1-methylimidazole-2-carboxaldehyde, DME, 2788C, 1 h, 62%; (e) 5%
Na–Hg, Na2HPO4, MeOH, rt, 4 h, 42% (for 27), 20% (for 29).
2.8. Muscarinic binding activity of some novel congeners
of himbacine 1
Using the thus obtained congeners of 1, receptor binding
affinity assays against the muscarinic M1 and M2 subtype
receptors were performed. Unfortunately, as shown in Table
4, all of the compounds tested exhibited poor M2 receptor
binding affinity and low selectivity compared to 1. In the
cases of (E)-olefin compounds (entry 2, 3), 2-methyl-
pyridine and 1-methylimidazole rings were found to be
unsuitable for binding muscarinic receptors, probably due to
the aromaticity and planar structures of these rings. The (Z)-
olefin 30 appeared to be unrewarding in a manner similar to
that of the (E)-olefin 28. The congeners bearing the
bioisosteres of the (E)-olefin structure, e.g., ether (entries
5, 9, 10), ester (entry 6), carbamate (entries 7, 8), and amide
(entry 11), also showed weak M1 and M2 receptor binding
affinity. These observations clearly suggest that the
conformations of these congeners might differ greatly
from that of 1.
41, 44, and 47 were designed as representative congeners
of 1, none of which had hitherto been prepared.
These congeners were readily prepared from the function-
alized intermediate for the synthesis of 1 such as 2, 11, and
14a.
Thus, conversions of 2 to the 2-methylpyridine derivative
26 and 1-methylimidazole derivatives, 28 and 30 were
readily obtained by employing a Julia–Lythgoe coupling
reaction followed by elimination, and then a Jones
oxidation, both in a similar manner to that described for
the total synthesis of 1 (Scheme 7). Alkylation of 11 with
commercially available 2-(chloromethyl)pyridine in the
presence of NaH, and subsequent Jones oxidation clearly
provided the 2-pyridylmethyl ether derivative 32 (Scheme
Scheme 8. Synthesis of himbacine congeners bearing the natural tricyclic moiety (II). (a) 2-(chloromethyl)pyridine hydrochloride, NaH, DMF, rt, 14 h, 43%;
(b) Jones reagent, acetone, rt, 37% (for 32), 55% (for 35), 13% (for 37); (c) chloroacetyl chloride, NaH, DMF, rt, 6 h, 83%; (d) morpholine, 1008C, 5 h, 84%;
(e) 2-picolinic acid, DPPA, Et3N, toluene, 1008C, 6 h, 64%.

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9909
Scheme 9. Synthesis of himbacine congeners bearing the natural tricyclic moiety (III). (a) 2-picolinic acid, DPPA, Et3N, toluene, 1008C, 7 h, 92%; (b) Jones
reagent, acetone, rt, 56% (for 39), 64% (for 41), 21% (for 44), 35% (for 47); (c) methanesulfonyl chloride, Et3N, CH2Cl2, 08C to rt, 2.5 h, 100%; (d) (S)-1-
benzylpyrrolidin-3-ol, NaH, DMF, 808C, 17 h, 8%; (e) (S)-1-(tert-butoxycarbonyl)piperidin-3-ol, NaH, DMF, 808C, 17 h, 38%; (f) lithium aluminum
hydride, THF, rt, 1 h, then 808C, 1 h, 100%; (g) phthalimide, diethyl azodicarboxylate, Ph3P, THF, 08C to rt, 7 h, 99%; (h) H2NNH2·H2O, EtOH, rt, 4 h, 52%;
(i) 6-methyl-2-picolinic acid, EDCI, CH2Cl2, rt, 5 h, 80%.
3. Conclusion
the intermediates for the total synthesis of 1, and these
congeners were then subjected to receptor binding affinity
assay. However, these latter congeners were unfortunately
also found to exhibit very weak muscarinic M2 subtype
receptor binding affinity and low selectivity. Although no
novel congener with a more prominent profile than 1 was
found, the successful synthesis of various structural types of
congeners clearly disclosed the convergency and flexibility
of the explored synthetic route to 1. Our goal to discover a
novel drug candidate targeting muscarinic M2 subtype
receptors for the treatment of Alzheimer’s disease still
remains to be achieved, and studies along this line are
ongoing in our laboratories.
In summary, we have succeeded in the highly stereo-
selective total synthesis of an enantiomeric pair of
himbacine 1, a potent antagonist of the muscarinic M2
subtype receptor, by employing an intermolecular Diels–
Alder reaction of 8 with (S)-9 as a key step. Our explored
synthetic route was successfully applied to the total
synthesis of unnatural himbacine ent-1, an enantiomeric
pair of (20S,60R)-diepihimbacine 24 and ent-24, and
4-epihimbacine 4-epi-1. Based on the observed muscarinic
receptor binding affinity assay of these compounds, it
appears that the absolute configuration of 1 plays a pivotal
role in its activity. Based on the results obtained, selected
novel congeners of 1 were further prepared by starting with
4. Experimental
4.1. General
Table 4. In vitro binding activity of some novel congeners of himbacine
Entry
Compound
2log Ki
M2 (brainstem)
All melting points were determined with a Yamato MP-500
melting point apparatus, a Yamaco MP-3 micro melting
point apparatus, or a Yanaco MP-500D micro melting point
apparatus, and are uncorrected. Measurements of optical
rotations were carried out using a Horiba SEPA-200
automatic digital polarimeter, a JASCO DIP-360 automatic
digital polarimeter, or 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 or an
Avance 500 (500 MHz) spectrometer. 13C NMR spectra
were taken with a JEOL JNM-EX-400 (100 MHz)
M1 (cortex)
1
2
3
4
5
6
7
8
1
7.1
5.2
5.2
,5.1
!5.1
!5.1
!5.1
!5.1
5.5
7.9
!6.1
!6.1
!6.1
!6.1
!6.1
!6.1
!6.1
!5.9
,5.4
!6.1
26
28
30
32
35
37
39
41
44
47
9
10
11
5.6
!5.1

9910
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
spectrometer or an Avance 500 (125 MHz) spectrometer.
The chemical shifts are expressed in parts per million (d
value) downfield from tetramethylsilane, using tetramethyl-
silane (d¼0) and/or residual solvents such as chloroform
(d¼7.26) 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 analyses are within ^0.3% of the
theoretical values, and were determined by a Yanaco
CHN-corder MT-5. Unless otherwise noted, all the
experiments were carried out using anhydrous solvents
under an atmosphere of dry argon. Throughout this
study, Merck precoated TLC plates (Silica gel 60
F254, 0.25 mm; Art. 5715) were used for thin layer
chromatographic (TLC) analysis, and all the spots were
visualized using 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 Chromatorexw NH-DM 1020
(100–200 mesh, Fuji Silysia Chemical, Ltd.) was used as
an adsorbent for the flash column chromatography.
anhydrous Na2SO4, filtered, then concentrated in vacuo, to
give 4,5-dihydroisobenzofuran (25.0 g, 84%) as a yellow
oil. H NMR (400 MHz, CDCl3): d 2.28–2.33 (m, 2H),
2.61–2.66 (m, 2H), 5.85 (dt, J¼9.8, 4.4 Hz, 1H), 6.42–6.47
(m, 1H), 7.10–7.13 (m, 1H), 7.24 (s, 1H). IR (neat): 3040,
2940, 1550, 1440, 1030, 790 cm21. MS (EI) m/z: 120 (Mþ),
91 (100). HRMS (EI) (m/z): calcd for C8H8O (Mþ):
120.0575. Found, 120.0581.
1
A mixture of 4,5-dihydroisobenzofuran (25.0 g, 0.21 mol)
and 10% Pd–C (3.00 g, 10% w/w) in ethanol (400 mL) was
stirred at 0–108C for 4 h under an atmosphere of H2 (1 atm).
Insoluble materials were filtered and thoroughly washed
with ethyl acetate (300 mL). The combined filtrates were
concentrated in vacuo to give 8 (12.0 g, 47%) as a pale
yellow oil. Bp 35–408C/3 mmHg. 1H NMR (400 MHz,
CDCl3): d 1.67–1.73 (m, 4H), 2.51–2.58 (m, 4H), 7.13 (s,
2H). IR (neat): 2930, 1670, 1440 cm21. MS (EI) m/z: 122
(Mþ) (100). HRMS (EI) (m/z): calcd for C8H10O (Mþ):
122.0732. Found, 122.0730. These spectral data were
identical to previously reported data.13,14
4.1.2. (R)- and (S)-5-Methylfuran-2(5H)-one [(R)- and
(S)-9]. According to the reported procedure,15 (R)-and (S)-
5-methylfuran-2(5H)-one [(R)- and (S)-9] were prepared
both as a volatile colorless oil from (R)-methyl lactate and
(S)-ethyl lactate, respectively. (R)-9: bp 110–
1158C/30 mmHg. [a]D25¼21008 (c 0.69, CHCl3) (lit.,15c
[a]D¼21008 (c 0.13, CHCl3)). 1H NMR (400 MHz,
CDCl3): d 1.46 (d, J¼6.8 Hz, 3H), 5.14 (qt, J¼6.8,
2.0 Hz, 1H), 6.11 (dd, J¼5.9, 2.0 Hz, 1H), 7.45 (dd,
J¼5.4, 1.5 Hz, 1H). IR (neat): 2990, 1760, 1170,
1110 cm21. MS (EI) m/z: 98 (Mþ), 83, 69, 55 (100).
HRMS (EI) (m/z): calcd for C5H6O2 (Mþ): 98.0368. Found,
98.0366. These spectra were identical to those reported
4.1.1. 3,4,5,6-Tetrahydrobenzo[c]furan (8). 4,5,6,7-Tetra-
hydroisobenzofuran-5-ol was prepared as a colorless oil
starting with furfuryl alcohol according to the reported
procedure.14a Bp 103–1058C/3 mmHg. 1H NMR
(400 MHz, CDCl3): d 1.56 (d, J¼4.9 Hz, 1H), 1.77–1.84
(m, 1H), 1.90–1.97 (m, 1H), 2.49–2.63 (m, 2H), 2.77 (dt,
J¼16.6, 6.0 Hz, 1H), 2.91 (dd, J¼15.7, 4.9 Hz, 1H), 4.10–
4.16 (m, 1H), 7.16–7.18 (m, 2H). IR (neat): 3360, 2930,
1640, 1440 cm21. MS (EI) m/z: 138 (Mþ), 120, 94 (100).
HRMS (EI) (m/z): calcd for C8H10O2 (Mþ): 138.0681.
Found, 138.0686.
To a solution of 4,5,6,7-tetrahydroisobenzofuran-5-ol
(34.1 g, 0.25 mol) and triethylamine (68.8 mL, 0.49 mol)
in CH2Cl2 (400 mL), methanesulfonyl chloride (28.7 mL,
0.37 mol) was added dropwise at 08C, and the resulting
mixture was stirred at the same temperature for 1.5 h, then
gradually warmed to rt. After concentration in vacuo, the
residue was poured into water (500 mL), and the aqueous
mixture was extracted with diethyl ether (100 mL£3). The
combined organic extracts were washed with brine
(100 mL), dried over anhydrous Na2SO4, filtered, then
concentrated in vacuo, to give 4,5,6,7-tetrahydroisobenzo-
furan-5-yl methanesulfonate (53.3 g, 100%) as an oil. This
material was immediately used for the next reaction without
previously.15c
(S)-9:
bp
105–1108C/30 mmHg.
[a]D21¼þ1168 (c 0.61, CHCl3) (lit.,15c [a]D¼þ1118 (c
1
1.23, CHCl3)). The H NMR, IR, and MS spectra of this
compound were superimposable on those described for
(R)-9.
4.1.3. (3S,3aR,4S,9R,9aR)-3a,4,5,6,7,8,9,9a-Octahydro-3-
methyl-4,9-epoxynaphtho[2,3-c]furan-1(3H)-one and its
enantiomer (7 and ent-7). (a) Preparation of 7. To a
solution of lithium perchlorate (1.06 g) in diethyl ether
(2 mL) was added 8 (558 mg, 3.4 mmol) and (S)-9 (224 mg,
2.3 mmol), and the mixture was stirred at rt for 168 h. The
reaction mixture was poured into water (20 mL), and the
resulting aqueous mixture was extracted with CH2Cl2
(10 mL£3). The combined organic extracts were dried
over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (CH2Cl2, then
CH2Cl2–ethyl acetate¼10:1) of the residue gave 7
(292 mg, 58%) as a colorless powder. This crude
material was immediately subjected to the next reaction
1
further purification. H NMR (400 MHz, CDCl3): d 1.99–
2.07 (m, 1H), 2.10–2.19 (m, 1H), 2.64–2.71 (m, 1H), 2.76–
2.85 (m, 1H), 2.90 (dd, J¼16.6, 6.4 Hz, 1H), 2.99–3.04 (m,
1H), 3.04 (s, 3H), 5.11–5.16 (m, 1H), 7.14–7.22 (m, 2H).
IR (neat): 3650, 2940, 1350, 1170 cm21. MS (EI) m/z: 216
(Mþ), 120 (100). HRMS (EI) (m/z): calcd for C8H12O2
(Mþ): 216.0456. Found, 216.0464.
1
without further purification. H NMR (400 MHz, CDCl3):
To the methanesulfonate (53.3 g, 0.25 mol), 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) (55.4 mL, 0.37 mol)
was added, and the mixture was heated at 808C for 2 h.
After cooling, the reaction was quenched by adding cold
water (500 mL), and the resulting aqueous solution was
extracted with hexane (100 mL£3). The combined organic
extracts were washed with brine (100 mL), dried over
d 1.45 (d, J¼6.4 Hz, 3H), 1.48–1.55 (m, 2H), 1.63–1.71
(m, 2H), 1.84–1.96 (m, 2H), 2.18–2.30 (m, 2H), 2.28
(dd, J¼7.6, 3.2 Hz, 1H), 2.87 (d, J¼7.8 Hz, 1H), 4.48
(qd, J¼6.4, 3.4 Hz, 1H), 4.72 (br, 1H), 5.03 (br, 1H). MS
(CI) m/z: 211 (MþþH), 197, 123 (100). HRMS (CI) (m/z):
calcd for C13H17O3 (MþþH): 221.1178. Found,
221.1176.

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9911
(b) Preparation of ent-7. The compound ent-7 (2.20 g, 72%)
was prepared from 8 (1.70 g, 14 mmol) and (R)-9 (1.37 g,
14 mmol) in the same manner as that described in (a). H
NMR spectrum of this sample was identical to that of 7
described in (a). HRMS (CI) (m/z): calcd for C13H17O3
(MþþH): 221.1178. Found, 221.1189.
This crude material was directly used for the next reaction
without further purification. 1H NMR (400 MHz, CDCl3): d
0.94–1.29 (m, 4H), 1.41 (d, J¼5.4 Hz, 1H), 1.52 (d,
J¼6.4 Hz, 3H), 1.56–1.77 (m, 3H), 1.94–2.04 (m, 2H),
2.58–2.64 (m, 1H), 2.74–2.81 (m, 1H), 4.01–4.04 (m, 1H),
4.61 (dq, J¼9.1, 5.9 Hz, 1H), 6.69 (t, J¼2.5 Hz, 1H). MS
(CI) m/z: 223 (MþþH). HRMS (CI) (m/z): calcd for
C13H19O3 (MþþH): 223.1334. Found, 223.1303.
1
4.1.4. (3S,3aR,4R,4aS,8aR,9S,9aR)-Decahydro-3-methyl-
4,9-epoxynaphtho[2,3-c]furan-1(3H)-one and its
enantiomer (6 and ent-6). (a) Preparation of 6. A mixture
of 7 (79.4 mg, 0.36 mmol) and 10% Pd–C (8.0 mg, 10%
w/w) in ethanol (5 mL) was stirred at rt for 12 h under an
atmosphere of H2 (1 atm). Insoluble materials were filtered
and thoroughly washed with ethyl acetate (20 mL). The
combined filtrates were concentrated in vacuo to give 6
(76.7 mg, 96%) as a colorless powder. [a]2D5¼þ448 (c 0.67,
CHCl3). Mp 150–1518C (colorless needles from hexane–
ethyl acetate). 1H NMR (400 MHz, CDCl3): d 1.02–1.18 (m,
2H), 1.32–1.56 (m, 4H), 1.40 (d, J¼6.4 Hz, 3H), 1.69–1.75
(m, 2H), 2.00–2.15 (m, 2H), 2.50 (dd, J¼8.3, 3.4 Hz, 1H),
3.12 (d, J¼7.8 Hz, 1H), 4.39 (qd, J¼6.4, 3.4 Hz, 1H), 4.40 (d,
J¼3.9 Hz, 1H), 4.75 (d, J¼4.9 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 19.5, 19.5, 19.6, 19.9, 22.5, 38.9, 39.7, 45.9, 46.3,
81.2, 83.7, 85.6, 178.0. IR (KBr): 1750 cm21. MS (EI) m/z:
222 (Mþ), 204, 193, 95 (100). HRMS (EI) (m/z): calcd for
C13H18O3 (Mþ): 222.1256. Found, 222.1239. Anal. calcd for
C13H18O3: C, 70.24; H, 8.16. Found: C, 69.97; H, 8.40.
(b) Preparation of ent-10. The compound ent-10 (1.35 g,
100%) was prepared from ent-6 (1.35 g, 6.1 mmol) in a
manner similar to the preparation of 10, described in a). 1H
NMR, and MS spectra of this sample were identical to those
described in a). HRMS (FAB) (m/z): calcd for C13H19O3
(MþþH): 223.1334. Found, 223.1315.
4.1.6. (3S,3aS,4R,4aS,9aS)-3a,4,4a,5,6,7,8,9a-Octahydro-
4-hydroxy-3-methylnaphtho[2,3-c]furan-1(3H)-one and
its enantiomer (5 and ent-5). (a) Preparation of 5. To a
solution of 10 (61.8 mg, 0.28 mmol) in toluene (2 mL), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (208 mL, 1.4 mmol)
was added, and the mixture was heated at 1008C for 5 h with
stirring. After cooling, the reaction was quenched by adding
diluted aqueous hydrochloric acid solution, and the mixture
was concentrated in vacuo. The residue was extracted with
CH2Cl2 (5 mL£3). The combined organic extracts were
dried over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (hexane–ethyl
acetate ¼1:1) of the residue gave 5 (51.2 mg, 83%) as a
colorless powder. [a]D20¼þ1488 (c 0.29, CHCl3). Mp 159–
1608C (colorless plates from hexane–ethyl acetate). 1H
NMR (500 MHz, CDCl3): d 1.00 (qd, J¼12.7, 3.5 Hz, 1H),
1.17–1.32 (m, 1H), 1.36–1.48 (m, 1H), 1.52 (d, J¼6.2 Hz,
3H), 1.69 (d, J¼4.2 Hz, 1H), 1.77–1.90 (m, 2H), 1.95–2.08
(m, 2H), 2.17–2.25 (m, 1H), 2.33 (dt, J¼14.2, 1.9 Hz, 1H),
2.56 (dt, J¼8.4, 4.7 Hz, 1H), 3.29 (dq, J¼8.6, 3.0 Hz, 1H),
3.82 (dt, J¼8.5, 4.4 Hz, 1H), 4.60 (dq, J¼8.6, 6.2 Hz, 1H),
5.31 (d, J¼2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): d
21.9, 25.6, 26.9, 31.8, 34.6, 41.0, 43.9, 46.8, 72.4, 77.5,
112.8, 141.1, 176.0. IR (KBr): 1730 cm21. MS (EI) m/z: 222
(Mþ), 204, 178, 168, 149 (100). Anal. calcd for C13H18O3:
C, 70.24; H, 8.16. Found: C, 70.29; H, 8.31.
(b) X-Ray structural analysis of 6.31: Orthorhombic space
˚
˚
group P212121, a¼8.066(1) A, b¼20.038(4) A, c¼
˚
7.196(1) A, a¼90.00(0)8, b¼90.00(0)8, g¼90.00(0)8,
V¼1163.1(4) A , Z¼4, density rcalcd¼1.27 g/cm3, Cu Ka
3
˚
˚
(l¼1.54178 A), T¼298 K, size of crystal¼0.10£0.10£0.02
mm21. The structure was solved by direct methods and
expanded using Fourier techniques. Final R and Rw were
0.0425 and 0.0487, respectively, for 1225 reflections.
(c) Preparation of ent-6. The compound ent-6 (1.36 g, 61%)
was prepared from ent-7 (2.20 g, 9.99 mmol) in a manner
similar to that described in (a). [a]2D5¼2438 (c 0.52, CHCl3).
Mp 148–1498C (colorless plates from hexane–ethyl
1
acetate). H NMR, 13C NMR, IR, and MS spectra of this
sample were identical with those described in (a). Anal.
calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.13; H,
8.04.
(b) Preparation of ent-5. The compound ent-5 (1.05 g, 78%)
was prepared from ent-10 (1.35 g, 6.1 mmol) in the same
manner as that described in (a). [a]2D3¼21488 (c 0.30,
CHCl3). Mp 156–1578C (colorless prisms from hexane–
4.1.5. (3S,3aS,4R,4aS,8aS)-3a,4,4a,5,6,7,8,8a-Octahydro-
4-hydroxy-3-methylnaphtho[2,3-c]furan-1(3H)-one and
its enantiomer (10 and ent-10). (a) Preparation of 10. To a
solution of 6 (110 mg, 0.50 mmol) in tetrahydrofuran
(20 mL), lithium bis(trimethylsilyl)amide (1 M solution in
tetrahydrofuran, 2.50 mL, 2.50 mmol) was added dropwise
at 2788C. The resulting mixture was stirred at the same
temperature for 4 h, and then gradually warmed to 2408C
with stirring. After quenching the reaction by adding
saturated aqueous ammonium chloride solution (2 mL) at
2408C, the mixture was stirred at rt for 5 min, then
concentrated in vacuo. Water (10 mL) was added to the
residue, and the mixture was extracted with diethyl ether
(5 mL£3). The combined organic extracts were dried over
anhydrous MgSO4, filtered, then concentrated in vacuo.
Flash column chromatography (hexane–ethyl acetate ¼2:1)
of the residue gave 10 (101 mg, 92%) as a colorless powder.
1
ethyl acetate). H NMR, 13C NMR, IR, and MS spectra of
this sample were identical to those described in (a). Anal.
calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.02; H,
8.26.
4.1.7. (3S,3aS,4R,4aS,8aR,9aS)-Decahydro-4-hydroxy-3-
methylnaphtho[2,3-c]furan-1(3H)-one and its enantio-
mer (4a and ent-4a). (a) Preparation of 4a. A suspension of
5 (375 mg, 1.7 mmol) and PtO2 (40 mg, 10% w/w) in
ethanol (5 mL) was stirred at rt for 16 h under an
atmosphere of H2 (1 atm). Insoluble materials were filtered
and thoroughly washed with ethyl acetate (20 mL). The
combined filtrates were concentrated in vacuo. Flash
column chromatography (CH2Cl2–ethyl acetate ¼4:1) of
the residue gave 4a (364 mg, 96%) as a colorless powder.
[a]2D5¼þ698 (c 0.41, CHCl3). Mp 185–1868C (colorless

9912
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
plates from hexane–ethyl acetate). 1H NMR (500 MHz,
CDCl3): d 0.81–0.92 (m, 1H), 0.98–1.30 (m, 6H), 1.54 (d,
J¼6.0 Hz, 3H), 1.69–1.77 (m, 2H), 1.74 (d, J¼4.0 Hz, 1H),
1.80–1.87 (m, 2H), 2.04–2.10 (m, 1H), 2.51 (dt, J¼10.1,
6.7 Hz, 1H), 2.67 (dt, J¼12.3, 6.6 Hz, 1H), 3.65 (ddd,
J¼10.2, 6.1, 4.0 Hz, 1H), 4.73 (dq, J¼11.9, 6.0 Hz, 1H). 13C
NMR (125 MHz, CDCl3): d 22.1, 25.7, 25.7, 28.9, 31.7,
33.0, 38.6, 41.9, 44.3, 48.2, 73.4, 77.4, 177.8. IR (KBr): 3460,
1740 cm21. MS (EI)m/z: 224 (Mþ), 206 (100). Anal. calcd for
C13H20O3: C, 69.61; H, 8.99. Found: C, 69.72; H, 8.93.
4a (1.88 g, 8.4 mmol) in diethyl ether (200 mL), diiso-
butylaluminum hydride (0.94 M solution in hexane,
26.7 mL, 25 mmol) was added dropwise at 2788C, and
the mixture was stirred at the same temperature for 1 h. The
reaction was quenched by adding methanol and water (each
10 mL) at 2788C, and the mixture was stirred at rt for 1 h.
The resulting precipitates were removed by filtration
through a pad of celite, and the collected residue was
washed with ethyl acetate (50 mL). The combined filtrates
were concentrated in vacuo. The residue was diluted with
brine, and the aqueous mixture was extracted with CH2Cl2
(5 mL£3). The combined organic extracts were dried over
anhydrous MgSO4, filtered, then concentrated in vacuo, to
give an anomeric mixture of the hemiacetal (1.89 g, 100%)
as a colorless oil. This material was directly subjected to the
next reaction without further purification. 1H NMR
(400 MHz, CDCl3): d 0.82–1.05 (m, 4H), 1.11–1.32 (m,
3H), 1.45 (d, J¼6.4 Hz, 3H), 1.47–1.84 (m, 5H), 2.05–2.11
(m, 1H), 2.26 (dt, J¼12.2, 6.2 Hz, 1H), 2.38 (d, J¼2.9 Hz,
1H), 2.56 (dt, J¼9.3, 5.9 Hz, 1H), 3.67 (ddd, J¼10.3, 5.9,
4.4 Hz, 1H), 4.32 (dq, J¼9.3, 6.1 Hz, 1H), 5.06 (d,
J¼2.5 Hz, 1H). IR (KBr): 3290, 2910, 1450 cm21. MS
(EI) m/z: 355 [[Mþ(TMS)2]þ2CH3]. HRMS (EI) (m/z):
calcd for C18H35O3Si2 [[Mþ(TMS)2]þ2CH3]: 355.2125.
Found, 355.2156.
(b) X-Ray structural analysis of 4a.31 Orthorhombic space
˚
˚
˚
3
group P2121, a¼8.859(2) A, b¼16.565(4) A, c¼8.175(2) A,
˚
a¼90.00(0)8, b¼90.00(0)8, g¼90.00(0)8, V¼1199.7(4) A ,
3
˚
Z¼4, density rcalcd¼1.24 g/cm , Cu Ka (l¼1.54178 A),
T¼298 K, size of crystal¼0.30£0.05£0.03 mm21. The
structure was solved by direct methods and expanded
using Fourier techniques. Final R and Rw were 0.0382 and
0.0402, respectively, for 1240 reflections.
(c) Preparation of ent-4a. The compound ent-4a (0.98 g,
93%) was prepared from ent-5 (1.04 g, 4.7 mmol) in a
similar manner to that described in (a). [a]2D2¼2698 (c 0.33,
CHCl3). Mp 185–1868C (colorless plates from hexane–
ethyl acetate). 1H NMR, 13C NMR, IR, and MS spectra of this
sample were identical to those described in (a). Anal. calcd for
C13H20O3: C, 69.61; H, 8.99. Found: C, 69.31; H, 9.09.
To a solution of the crude hemiacetal in CH2Cl2 (50 mL)
and methanol (50 mL) was added boron trifluoride diethyl
etherate (1.55 mL, 12.6 mmol) at 2608C, and the mixture
was stirred at the same temperature for 12 h, then gradually
warmed to rt with stirring. After the reaction was quenched
by adding triethylamine (1.75 mL, 13 mmol) at 08C, the
resulting mixture was further stirred at rt for 1 h, then
concentrated in vacuo. The residue was diluted with diluted
aqueous sodium bicarbonate solution, and the aqueous
mixture was extracted with CH2Cl2 (5 mL£3). The
combined organic extracts were dried over anhydrous
MgSO4, filtered, then concentrated in vacuo. Flash column
chromatography (hexane–ethyl acetate ¼2:1) of the residue
gave 11 (1.50 g, 74% from 4a) as a colorless powder.
[a]2D0¼þ908 (c 0.21, CHCl3). Mp 117–1188C (colorless
needles from hexane). 1H NMR (500 MHz, CDCl3): d
0.81–1.04 (m, 4H), 1.13–1.30 (m, 3H), 1.39 (d, J¼6.0 Hz,
3H), 1.45–1.53 (m, 2H), 1.60–1.74 (m, 2H), 1.77–1.84 (m,
1H), 2.04–2.11 (m, 1H), 2.20 (dt, J¼12.3, 6.0 Hz, 1H), 2.47
(dt, J¼9.1, 6.0 Hz, 1H), 3.32 (s, 3H), 3.64 (ddd, J¼9.6, 5.7,
3.5 Hz, 1H), 4.30 (dq, J¼9.1, 6.0 Hz, 1H), 4.53 (s, 1H). 13C
NMR (125 MHz, CDCl3): d 25.0, 26.0, 26.0, 29.1, 32.7,
33.4, 38.6, 44.1, 46.0, 48.6, 54.0, 74.6, 76.4, 108.5. IR
(KBr): 3410, 2980, 1450, 1440, 1360 cm21. MS (EI) m/z:
208 (Mþ2HOMe), 190, 162 (100). Anal. calcd for
C14H24O3: C, 69.96; H, 10.07. Found: C, 69.72; H, 9.82.
4.1.8. (3S,3aR,4R,4aS,8aR,9aR)-Decahydro-4-hydroxy-
3-methylnaphtho[2,3-c]furan-1(3H)-one (4b). (a) Prep-
aration of 4b. A mixture of 5 (199 mg, 0.89 mmol) and
Rh–Al2O3 (20 mg, 10% w/w) in ethanol (10 mL) was
stirred at rt for 2.5 h under an atmosphere of H2 (1 atm).
Insoluble materials were filtered and thoroughly washed
with ethyl acetate (20 mL). The combined filtrates were
concentrated in vacuo. Flash column chromatography
(hexane–ethyl acetate¼2:1) of the residue gave 4a
(100 mg, 50%) and 4b (85 mg, 42%), both as colorless
powders. 4b: [a]2D2¼2288 (c 0.18, CHCl3). Mp 2188C
1
(colorless needles from hexane–ethyl acetate). H NMR
(400 MHz, CDCl3): d 0.78–1.04 (m, 4H), 1.15–1.29 (m,
3H), 1.53 (d, J¼6.9 Hz, 3H), 1.68 (d, J¼5.4 Hz, 1H), 1.66–
1.83 (m, 3H), 2.03–2.11 (m, 2H), 2.28 (ddd, J¼9.8, 7.3,
4.4 Hz, 1H), 2.87 (td, J¼7.3, 1.5 Hz, 1H), 3.23 (dt, J¼9.3,
5.0 Hz, 1H), 4.55 (dq, J¼6.8, 4.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 16.4, 25.5, 25.7, 28.7, 29.8, 33.2,
35.7, 41.7, 47.1, 47.3, 71.0, 77.9, 177.8. IR (KBr): 3360,
2920, 1780, 1180 cm21. MS (EI) m/z: 224 (Mþ), 206 (100).
Anal. calcd for C13H20O3·0.1H2O: C, 69.06; H, 9.00. Found:
C, 69.27; H, 9.19.
(b) X-Ray structural analysis of 4b.31 Monoclinic space
˚
˚
˚
3
group P21, a¼11.32(1) A, b¼5.118(5) A, c¼11.09(1) A,
˚
a¼90.00(0)8, b¼110.63(7)8, g¼90.00(0)8, V¼601(1) A ,
(b) Preparation of ent-11. The compound ent-11 (0.89 g,
85%) was prepared from ent-4a (0.98 g, 4.4 mmol) in a
manner similar to the preparation of 11. Ent-hemiacetal:
3
˚
Z¼2, density rcalcd¼1.24 g/cm , Cu Ka (l¼1.54178 A),
T¼298 K, size of crystal¼0.30£0.20£0.12 mm21. The
structure was solved by direct methods and expanded
using Fourier techniques. Final R and Rw were 0.0600 and
0.0754, respectively, for 1219 reflections.
HRMS
(EI)
(m/z):
calcd
for
C18H35O3Si2
[[Mþ(TMS)2]þ2CH3]: 355.2125. Found, 355.2151. Ent-
11: [a]2D1¼2958 (c 0.34, CHCl3). Mp 118–1198C (colorless
needles from hexane). H NMR, 13C NMR, IR, and MS
1
4.1.9. (1S,3S,3aS,4R,4aS,8aR,9aS)-Dodecahydro-1-meth-
oxy-3-methylnaphtho[2,3-c]furan-4-ol and its enantio-
mer (11 and ent-11). (a) Preparation of 11. To a solution of
spectra of this sample were identical to those described in
(a). Anal. calcd for C14H24O3: C, 69.96; H, 10.07. Found: C,
69.73; H, 10.31.

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9913
4.1.10. (1S,3S,3aR,4aS,8aR,9aS)-Decahydro-1-methoxy-
3-methylnaphtho[2,3-c]furan-4(1H)-one and its enantio-
mer (12 and ent-12). (a) Preparation of 12. To a solution of
11 (1.05 g, 4.4 mmol), 4-methylmorpholine N-oxide (0.77 g,
(b) Preparation of ent-13: The compound ent-13 (684 mg,
88%) was prepared from ent-12 (786 mg, 3.3 mmol) in a
similar manner to that described in (a). [a]2D3¼2588 (c 0.29,
1
CHCl3). H NMR, 13C NMR, IR, and MS spectra of this
˚
6.56 mmol), and molecular sieves (MS 4 A, 2.50 g) in CH2Cl2
sample were identical to those described in (a). HRMS (CI)
(m/z): calcd for C15H25O2 (MþþH): 237.1855. Found,
237.1880.
(10 mL), tetrapropylammonium perruthenate (VII) (TPAP)
(76.8 mg, 0.22 mmol) was added at rt, and the mixture was
stirred at the same temperature for 1.5 h. The reaction mixture
was filtered through a pad of celite, and the collected residue
was washed with diethyl ether (100 mL). The combined
filtrates were washed with 10% aqueous sodium thiosulfate
solution (20 mL) and brine (20 mL), dried over anhydrous
MgSO4, filtered, then concentrated invacuo togive12(0.99 g,
95%) as a colorless powder. [a]2D0¼þ1658 (c 0.16, CHCl3).
4.1.12. (1S,3S,3aR,4R,4aS,8aR,9aS)-Dodecahydro-1-
methoxy-3-methylnaphtho[2,3-c]furan-4-methanol,
(1S,3S,3aR,4S,4aS,8aR,9aS)-dodecahydro-1-methoxy-3-
methylnaphtho[2,3-c]furan-4-methanol, and their enan-
tiomers (14a, 14b, ent-14a, and ent-14b). (a) Preparation
of 14a and 14b. To a solution of 13 (293 mg, 1.2 mmol) in
tetrahydrofuran (20 mL) was added borane–tetrahydro-
furan complex (1 M solution in tetrahydrofuran, 1.86 mL,
1.9 mmol) at 2788C. The mixture was stirred at the same
temperature for 3 h, and gradually warmed to rt. After
adding water (2 mL) to the reaction mixture at 08C, 30%
hydrogen peroxide (3.0 mL) and 10% aqueous sodium
hydroxide solution (3.0 mL) was added to the aqueous
mixture at the same temperature. After stirring for 0.5 h, the
mixture was concentrated in vacuo. The residue was diluted
with brine (20 mL), and the resulting mixture was extracted
with CH2Cl2 (10 mL£3). The combined organic extracts
were dried over anhydrous MgSO4, filtered, then concen-
trated in vacuo. Flash column chromatography (hexane–
ethyl acetate ¼4:1, then 1:1) of the residue gave 14a
(229 mg, 73%) and 14b (25.8 mg, 8%), respectively. 14a:
[a]2D5¼þ848 (c 0.43, CHCl3). Mp 92–938C (colorless
prisms from hexane). 1H NMR (500 MHz, CDCl3): d
0.84–1.13 (m, 6H), 1.18–1.29 (m, 2H), 1.39 (d, J¼6.0 Hz,
3H), 1.49–1.81 (m, 5H), 1.83–1.89 (m, 1H), 2.17 (dt,
J¼12.4, 6.0 Hz, 1H), 2.40 (dt, J¼9.1, 5.0 Hz, 1H), 3.33 (s,
3H), 3.58–3.65 (m, 1H), 3.74–3.79 (m, 1H), 4.23 (dq,
J¼9.3, 6.0 Hz, 1H), 4.48 (s, 1H). 13C NMR (125 MHz,
CDCl3): d 24.2, 26.1, 26.5, 30.2, 33.3, 34.1, 38.7, 40.7, 43.9,
45.2, 46.8, 53.9, 62.9, 75.5, 108.1. IR (KBr): 3450, 2930,
1
Mp 86–878C (colorless powder from hexane). H NMR
(500 MHz, CDCl3): d 1.10–1.50 (m, 6H), 1.33 (d, J¼6.1 Hz,
3H), 1.68–1.86 (m, 4H), 1.96–2.03 (m, 2H), 2.59 (dt, J¼12.7,
6.3 Hz, 1H), 2.80 (dd, J¼9.1, 6.9 Hz, 1H), 3.32 (s, 3H), 4.33
(dq, J¼9.2, 6.1 Hz, 1H), 4.71 (s, 1H). 13C NMR (125 MHz,
CDCl3): d 22.8, 25.1, 25.5, 25.6, 32.5, 34.3, 41.3, 49.5, 51.4,
54.1, 58.1, 78.4, 109.1, 210.8. IR (KBr): 2930, 1700,
1450 cm21. MS (FAB) m/z: 344 [(Mþþdiethanolamine)þH].
Anal. calcd for C14H22O3: C, 70.56; H, 9.30. Found: C, 70.26;
H, 9.29.
(b) Preparation of ent-12. The compound ent-12 (786 mg,
92%) was prepared from ent-11 (866 mg, 3.6 mmol) in the
same manner as that described in (a). [a]2D1¼21658 (c 0.41,
1
CHCl3). Mp 86–878C (colorless plates from hexane). H
NMR, 13C NMR, IR, and MS spectra of this sample were
identical to those described in (a). Anal. calcd for
C14H22O3·0.1H2O: C, 70.03; H, 9.32. Found: C, 70.24; H,
9.58.
4.1.11. (1S,3S,3aS,4aS,8aR,9aS)-Dodecahydro-1-meth-
oxy-3-methyl-4-methylenenaphtho[2,3-c]furan and its
enantiomer (13 and ent-13). (a) Preparation of 13. To a
suspension of methyltriphenylphosphonium iodide (9.96 g,
25 mmol) in diethyl ether (400 mL), sodium bis(trimethyl-
silyl)amide (0.60 M solution in toluene, 41.1 mL, 25 mmol)
was added under conditions of cooling with ice, and the
mixture was stirred at rt for 1 h. The resulting mixture was
added dropwise to a solution of 12 (1.17 g, 4.9 mmol) in
diethyl ether (30 mL) at 08C, and the mixture was stirred at
rt for 2 h. After quenching the reaction by adding cold
saturated aqueous ammonium chloride solution, the mixture
was concentrated in vacuo. The residue was diluted with
brine (100 mL), and the mixture was extracted with diethyl
ether (50 mL£3). The combined organic extracts were dried
over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (hexane–ethyl
acetate¼10:1) of the residue gave 13 (1.01 g, 86%) as a
yellow oil. [a]D20¼þ568 (c 0.53, CHCl3). 1H NMR
(500 MHz, CDCl3): d 0.99–1.33 (m, 6H), 1.26 (d,
J¼5.8 Hz, 3H), 1.59–1.73 (m, 4H), 1.80–1.91 (m, 2H),
2.25 (dt, J¼12.2, 6.2 Hz, 1H), 2.73 (dd, J¼9.4, 6.5 Hz, 1H),
3.33 (s, 3H), 4.20 (dq, J¼9.8, 6.0 Hz, 1H), 4.58 (s, 1H), 4.71
(s, 1H), 4.82 (s, 1H). 13C NMR (125 MHz, CDCl3): d 21.4,
26.1, 26.4, 28.9, 33.3, 34.5, 41.6, 42.8, 47.9, 53.4, 54.1,
78.2, 109.2, 109.3, 148.8. IR (neat): 2920, 1640, 1450,
1380 cm21. MS (CI) m/z: 237 (MþþH), 205 (100). HRMS
(CI) (m/z): calcd for C15H25O2 (MþþH): 237.1855. Found,
237.1832.
1450, 1400 cm21
.
MS (FAB) m/z: 360 [(Mþþ
diethanolamine)þH]. Anal. calcd for C15H26O3: C, 70.83;
H, 10.31. Found: C, 70.90; H, 10.49. 14b: A colorless oil.
[a]2D0¼þ118 (c 0.46, CHCl3). 1H NMR (500 MHz, CDCl3):
d 0.82–0.94 (m, 2H), 1.14–1.33 (m, 6H), 1.30 (d,
J¼6.0 Hz, 3H), 1.41–1.81 (m, 6H), 2.22 (dt, J¼13.1,
6.3 Hz, 1H), 2.31 (dd, J¼9.8, 6.3 Hz, 1H), 3.33 (s, 3H), 3.56
(dd, J¼10.6, 8.6 Hz, 1H), 3.84 (1H, dd, J¼10.6, 4.3 Hz,
1H), 4.15 (dq, J¼9.9, 6.0 Hz, 1H), 4.53 (s, 1H). 13C NMR
(125 MHz, CDCl3): d 21.8, 26.4, 27.2, 30.5, 33.2, 34.9,
35.0, 39.9, 40.0, 42.6, 44.8, 54.1, 63.1, 77.1, 109.3. IR
(KBr): 3420, 2920, 1450, 1375 cm21. MS (CI) m/z: 255
(MþþH), 237, 223 (100). HRMS (CI) (m/z): calcd for
C15H27O3 (MþþH): 255.1960. Found, 255.1942.
(b) X-Ray structural analysis of 14a.31 Monoclinic space
˚
˚
˚
3
group P21, a¼9.494(2) A, b¼8.489(2) A, c¼9.276(2) A,
˚
a¼90.00(0)8, b¼105.28(1)8, g¼90.00(0)8, V¼721.2(2) A ,
3
˚
Z¼2, density rcalcd¼1.17 g/cm , Cu Ka (l¼1.54178 A),
T¼298 K, size of crystal¼0.41£0.20£0.18 mm21. The
structure was solved by direct methods and expanded
using Fourier techniques. Final R and Rw were 0.0336 and
0.0437, respectively, for 1425 reflections.
(c) Preparation of ent-14a and ent-14b. These compounds,

9914
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
ent-14a (538 mg, 75%) and ent-14b (55.2 mg, 8%), were
prepared from ent-13 (664 mg, 2.8 mmol) in a manner
similar to the preparation of 14a and 14b, described in (a).
Ent-14a: [a]2D2¼2848 (c 0.53, CHCl3). Mp 93–948C
(colorless needles from hexane). Anal. calcd for
C15H26O3: C, 70.83; H, 10.31. Found: C, 70.59; H, 10.08.
Ent-14b: A yellow oil. [a]2D2¼2108 (c 0.42, CHCl3). HRMS
(CI) (m/z): calcd for C15H27O3 (MþþH): 255.1960. Found,
255.1985. 1H NMR, 13C NMR, IR, and MS spectra of these
samples were identical to those described in (a).
3-chloroperoxybenzoic acid (80%, 976 mg, 4.5 mmol) and
sodium bicarbonate (760 mg, 9.1 mmol) were added at 08C,
and the mixture was stirred at rt for 2 h. After the insoluble
materials were filtered off through a pad of celite, the
collected residue was washed with CH2Cl2 (20 mL).
The combined filtrates were concentrated in vacuo, and
the residue was dissolved in diethyl ether (50 mL). The
ethereal solution was washed with saturated aqueous
sodium bicarbonate solution (10 mL£3) and brine
(10 mL). The organic extracts were dried over anhydrous
MgSO4, filtered, then concentrated in vacuo. Flash column
chromatography (hexane–ethyl acetate¼2:1) of the residue
gave 2 (564 mg, 82%) as a colorless powder. [a]2D0¼þ1048
(c 0.35, CHCl3) (lit.11b [a]D20¼þ1008 (c 0.35, CHCl3)). Mp
127–1288C (colorless powder from hexane–ethyl acetate).
1H NMR (500 MHz, CDCl3): d 0.63 (qd, J¼12.2, 3.0 Hz,
1H), 0.85–1.03 (m, 4H), 1.09–1.24 (m, 2H), 1.45 (d,
J¼6.1 Hz, 3H), 1.48–1.77 (m, 5H), 2.06–2.13 (m, 1H),
2.19 (dt, J¼12.4, 6.0 Hz, 1H), 2.77 (dt, J¼8.8, 5.5 Hz, 1H),
2.99 (dd, J¼14.7, 9.5 Hz, 1H), 3.27 (dd, J¼14.7, 1.7 Hz,
1H), 3.30 (s, 3H), 4.09 (dq, J¼8.9, 6.1 Hz, 1H), 4.46 (s, 1H),
7.55–7.61 (m, 2H), 7.64–7.69 (m, 1H), 7.89–7.93 (m, 2H).
13C NMR (125 MHz, CDCl3): d 25.7, 25.8, 26.5, 29.9, 33.0,
34.1, 36.7, 40.8, 41.0, 45.0, 46.2, 53.9, 55.7, 75.3, 108.3,
127.9, 127.9, 129.3, 129.3, 133.7, 139.9. IR (KBr): 2920,
1450, 1380, 1310, 1140 cm21. MS (FAB) m/z: 484 [(Mþþ
diethanolamine)þH]. Anal. calcd for C21H30O4S: C, 66.63;
H, 7.99. Found: C, 66.33; H, 8.15.
4.1.13. (1S,3S,3aS,4R,4aS,8aR,9aS)-Dodecahydro-1-
methoxy-3-methyl-4-[(phenylsulfonyl)methyl]-
naphtho[2,3-c]furan and its enantiomer (2 and ent-2). (a)
Preparation of 2. To a solution of 14a (461 mg, 1.8 mmol)
in CH2Cl2 (20 mL) 4-(dimethylamino)pyridine (20.3 mg,
0.18 mmol), triethylamine (1.26 mL, 9.1 mmol), and
methanesulfonyl chloride (420 mL, 5.4 mmol) were added
at 08C. The mixture was stirred at the same temperature for
3 h, and gradually warmed to rt. The mixture was poured
into water (20 mL), and extracted with CH2Cl2 (3 mL£3).
The combined organic extracts were dried over anhydrous
MgSO4, filtered, then concentrated in vacuo. Flash column
chromatography (hexane–ethyl acetate¼2:1) of the residue
gave mesylate 15 (602 mg, 100%) as a viscous oil. This
material was immediately used for the next reaction without
1
further purification. H NMR (400 MHz, CDCl3): d 0.86–
1.28 (m, 8H), 1.37 (d, J¼ 5.9 Hz, 3H), 1.50–1.92 (m, 5H),
2.17–2.23 (m, 1H), 2.42 (dt, J¼10.3, 4.9 Hz, 1H), 3.01 (s,
3H), 3.33 (s, 3H), 4.10–4.15 (m, 2H), 4.20 (dq, J¼9.3,
6.1 Hz, 1H), 4.35 (dd, J¼9.8, 3.4 Hz, 1H), 4.49 (s, 1H). MS
(FAB) m/z: 438 [(Mþþdiethanolamine)þH]. HRMS (FAB)
(m/z): calcd for C20H40NO7S [(Mþþdiethanolamine)þH]:
438.2525. Found, 438.2548.
(b) Preparation of ent-2. The compound ent-2 (311 mg,
40% from ent-15) was prepared from ent-14a (532 mg,
2.1 mmol) by way of ent-15 (988 mg, 99%) and ent-16 in
the same manner similar as that described in (a).
Ent-15: HRMS (FAB) (m/z): calcd for C20H40NO7S
[(Mþþdiethanolamine)þH]: 438.2525. Found, 438.2519.
Ent-16: [a]2D5¼21408 (c 0.15, CHCl3), HRMS (EI) (m/z):
calcd for C21H30O2S (Mþ): 346.1967. Found, 346.1965.
Ent-2: [a]2D2¼21048 (c 0.35, CHCl3). Mp 129–1308C
(colorless powder from hexane–ethyl acetate). Anal.
calcd for C21H30O4S: C, 66.63; H, 7.99. Found: C,
66.35; H, 8.01. 1H NMR, 13C NMR, IR, and MS
spectra of these samples were identical to those described
in (a).
To a solution of potassium t-butoxide (305 mg, 2.7 mmol)
in methyl sulfoxide (10 mL), thiophenol (279 mL,
2.7 mmol) was added at rt, and the mixture was stirred at
the same temperature for 10 min. The resulting mixture was
added to a solution of crude 15 (602 mg, 1.8 mmol) in
methyl sulfoxide (10 mL), and the mixture was stirred at rt
for 3 h. The mixture was poured into diluted aqueous
sodium bicarbonate solution (20 mL), and extracted with
diethyl ether (10 mL£3). The combined organic extracts
were washed with brine (10 mL), dried over anhydrous
MgSO4, filtered, then concentrated in vacuo. Flash column
chromatography (hexane–ethyl acetate¼50:1, then 10:1) of
the residue gave phenylsulfide 16 (627 mg, 100%) as a
colorless powder. [a]2D5¼þ1428 (c 0.12, CHCl3) (lit.11b
4.1.14. (2R,6S)-tert-Butyl 2-formyl-6-methylpiperidine-
1-carboxylate and its enantiomer (3 and ent-3). These
compounds 3 and ent-3 were both prepared as unstable
colorless oils from commercially available dl-2-methyl-
piperidine by sequential optical resolution with (2R, 3R)-
(þ)-tartaric acid [for ent-3: (2S,3S)-(2)-tartaric acid],
protection with a tert-butoxycarbonyl group, and formyl-
ation according to the reported procedures.27 3:
[a]2D6¼þ1208 (c 1.03, CHCl3) (lit.11b [a]2D0¼þ1228 (c
1
[a]2D0¼þ138.58 (c 0.73, CHCl3)). Mp 42–438C. H NMR
(400 MHz, CDCl3): d 0.81–1.07 (m, 4H), 1.18–1.29 (m,
3H), 1.41 (d, J¼6.4 Hz, 3H), 1.49–1.83 (m, 5H), 1.97–2.05
(m, 1H), 2.12–2.18 (m, 1H), 2.55–2.62 (m, 1H), 2.67–2.72
(m, 1H), 3.31–3.35 (m, 1H), 3.33 (s, 3H), 4.18 (dq, J¼8.8,
6.2 Hz, 1H), 4.48 (s, 1H), 7.13–7.52 (m, 5H). 13C NMR
(100 MHz, CDCl3): d 25.1, 26.0, 26.6, 30.2, 33.3, 34.1,
35.2, 40.8, 41.4, 41.5, 44.5, 46.5, 54.0, 75.4, 108.3, 125.6,
128.6, 128.6, 128.9, 128.9, 137.3. IR (KBr): 2920, 1580,
1480, 1380 cm21. MS (EI) m/z: 346 (Mþ), 314 (100).
HRMS (EI) (m/z): calcd for C21H30O2S (Mþ): 346.1967.
Found, 346.1936.
1
0.96, CHCl3)). H NMR (400 MHz, CDCl3): d 1.12 (d,
J¼6.9 Hz, 3H), 1.46 (s, 9H), 1.36–1.77 (m, 6H), 3.63 (dt,
J¼11.3, 3.9 Hz, 1H), 4.27 (br, 1H), 9.30 (d, J¼3.4 Hz, 1H).
13C NMR (100 MHz, CDCl3): d 16.3, 16.5, 25.5, 28.3, 28.3,
29.4, 47.4, 59.3, 81.4, 196.4. One carbon was not observed.
IR (neat): 2940, 1730, 1690, 1360 cm21. MS (FAB) m/z:
228 (MþþH), 198, 172 (100). HRMS (FAB) (m/z): calcd for
C12H22NO3 (MþþH): 228.1600. Found, 228.1610. Ent-3:
[a]D22¼21288 (c 0.82, CHCl3). 1H NMR, 13C NMR, IR, and
MS spectra of this sample were identical to those of 3.
To a solution of 16 (627 mg, 1.8 mmol) in CH2Cl2 (50 mL),

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9915
HRMS (FAB) (m/z): calcd for C12H22NO3 (MþþH):
(m/z): calcd for C27H45NO4 (Mþ): 447.3349. Found,
447.3350.
228.1600. Found, 228.1602.
4.1.15. (2R,6S)-tert-Butyl 2-[2-(E)-[(1S,3S,3aR,4R,4a-
S,8aR,9aS)-Dodecahydro-1-methoxy-3-methyl-
naphtho[2,3-c]furan-4-yl]ethenyl]-6-methylpiperidine-
1-carboxylate and its enantiomer (17 and ent-17).
(a) Preparation of 17. To a solution of 2 (201 mg,
0.53 mmol) in 1,2-dimethoxyethane (10 mL) was added
dropwise n-butyllithium (1.54 M solution in hexane,
690 mL, 1.1 mmol) at 2788C, and the mixture was stirred
at the same temperature for 10 min. A solution of 3 (241 mg,
1.1 mmol) in 1,2-dimethoxyethane (2 mL) was added
dropwise to the mixture at 2788C, and the resulting solution
was stirred at the same temperature for 1 h. After quenching
the reaction by adding water (10 mL), the mixture was
diluted with brine (20 mL), and extracted with diethyl ether
(10 mL£3). The combined organic extracts were dried over
anhydrous MgSO4, filtered, then concentrated in vacuo.
Flash column chromatography (hexane–ethyl acetate¼9:1,
then 1:1) of the residue gave the b-hydroxy sulfone as a
diastereomeric mixture (145 mg, 45%) along with the
recovery of 2 (111 mg, 55%). The structure of this adduct
4.1.16. (2R,6S)-tert-Butyl 2-[2-(E)-[(3S,3aR,4R,4a-
S,8aR,9aS)-Dodecahydro-3-methyl-1-oxonaphtho[2,3-
c]furan-4-yl]ethenyl]-6-methylpiperidine-1-carboxylate
and its enantiomer (18 and ent-18). (a) Preparation of 18.
To a solution of 17 (155 mg, 0.35 mmol) in acetone (6 mL),
Jones reagent (0.90 mL, 3.1 mmol) was added at rt, and the
mixture was stirred at the same temperature for 0.5 h. After
adding water (10 mL), the mixture was concentrated in
vacuo. The residue was diluted with brine (10 mL), and the
aqueous mixture was extracted with diethyl ether (5 mL£3).
The combined organic extracts were dried over anhydrous
MgSO4, filtered, then concentrated in vacuo to give 18
(149 mg, 100%) as a colorless oil. [a]2D5¼þ688 (c 0.14,
CHCl3) (lit.11b [a]D20¼þ60.88 (c 0.55, CHCl3)). H NMR
1
(400 MHz, CDCl3): d 0.64–0.75 (m, 1H), 0.93–1.06 (m,
3H), 1.12–1.28 (m, 3H), 1.24 (d, J¼6.9 Hz, 3H), 1.42 (d,
J¼5.9 Hz, 3H), 1.44 (s, 9H), 1.50–2.12 (m, 12H), 2.24 (dt,
J¼10.3, 6.4 Hz, 1H), 2.61 (dt, J¼13.2, 6.6 Hz, 1H), 3.96–
4.03 (m, 1H), 4.40–4.46 (m, 1H), 4.64 (dq, J¼11.7, 5.6 Hz,
1H), 5.23 (ddd, J¼15.2, 10.3, 1.5 Hz, 1H), 5.53 (dd, J¼15.2,
5.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 13.4, 20.9,
22.2, 25.6, 26.1, 26.3, 26.4, 28.5, 28.5, 28.5, 31.2, 32.0,
33.7, 40.1, 41.6, 42.3, 45.7, 47.0, 48.8, 52.2, 77.0, 79.1,
131.3, 134.2, 155.0, 178.4. IR (neat): 2930, 1770,
1680 cm21. MS (FAB) m/z: 432 (MþþH), 375, 332 (100).
HRMS (FAB) (m/z): calcd for C26H42NO4 (MþþH):
432.3114. Found, 432.3126.
1
was determined by its characteristic H NMR (400 MHz,
CDCl3) signals. 1H NMR (400 MHz, CDCl3): d 1.46 (s, 9H,
N-Boc), 3.34 (s, 3H, OMe), 7.52–7.68 (m, 3H, Ph-H),
7.90–8.04 (m, 2H, Ph-H).
To a solution of the above adduct (334 mg, 0.55 mmol) in
methanol (14 mL) was added 5% sodium amalgam (5.96 g)
and Na2HPO4 (1.08 g), and the mixture was stirred at rt for
2.5 h. After quenching the reaction by adding water
(10 mL), the mixture was concentrated in vacuo. The
residue was diluted with brine (20 mL), and the aqueous
mixture was extracted with diethyl ether (10 mL£3). The
combined organic extracts were dried over anhydrous
MgSO4, filtered, then concentrated in vacuo. Flash column
chromatography (hexane–ethyl acetate¼5:1) of the residue
gave 17 (162 mg, 66%) as a colorless powder. In this case,
(b) Preparation of ent-18. The compound ent-18 (147 mg,
98%) was prepared from ent-17 (156 mg, 0.35 mmol) in the
same manner as that described in (a). [a]2D5¼2638 (c 0.50,
1
CHCl3). H NMR, 13C NMR, IR, and MS spectra of this
sample were identical with those described in a). HRMS
(FAB) (m/z): calcd for C26H42NO4 (MþþH): 432.3114.
Found, 432.3111.
1
formation of the (Z)-olefin was not observed by H NMR
analysis of the crude reaction product. [a]2D5¼þ938 (c 1.09,
CHCl3) (lit.11b [a]D20¼þ90.58 (c 0.38, CHCl3)). Mp 91–
4.1.17. (3S,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 and its enantiomer (19
and ent-19). (a) Preparation of 19. To a solution of 18
(149 mg, 0.35 mmol) in CH2Cl2 (2 mL), trifluoroacetic acid
(1.00 mL) was added at rt, and the mixture was stirred at the
same temperature for 1.5 h. After the reaction mixture was
made alkaline by adding cold diluted aqueous sodium
hydroxide solution, the mixture was concentrated in vacuo.
The residue was extracted with diethyl ether (5 mL£3). The
combined organic extracts were dried over anhydrous
MgSO4, filtered, then concentrated in vacuo to give 19
(115 mg, 100%) as a colorless oil. [a]2D1¼þ178 (c 0.27,
1
938C. H NMR (400 MHz, CDCl3): d 0.63–0.74 (m, 1H),
0.87–1.01 (m, 4H), 1.16–1.34 (m, 3H), 1.23 (d, J¼6.9 Hz,
3H), 1.29 (d, J¼5.9 Hz, 3H), 1.44 (s, 9H), 1.46–1.79 (m,
8H), 1.87–2.08 (m, 3H), 2.14–2.22 (m, 2H), 3.31 (s, 3H),
3.95–4.02 (m, 1H), 4.18 (dq, J¼8.3, 6.4 Hz, 1H), 4.41 (br,
1H), 4.48 (s, 1H), 5.21 (dd, J¼15.2, 10.3 Hz, 1H), 5.47 (dd,
J¼15.2, 6.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 13.4,
20.9, 24.8, 25.8, 26.4, 26.4, 26.6, 28.5, 28.5, 28.5, 31.4,
33.1, 34.1, 40.3, 41.3, 46.4, 46.6, 47.0, 48.7, 52.4, 53.9,
75.6, 78.9, 108.4, 133.0, 133.0, 155.1. IR (neat): 2930, 1690,
1390 cm21. MS (EI) m/z: 447 (Mþ), 415, 359, 315 (100).
HRMS (EI) (m/z): calcd for C27H45NO4 (Mþ): 447.3349.
Found, 447.3342.
1
CHCl3) (lit.11b [a]D20¼þ17.18 (c 0.56, CHCl3)). H NMR
(400 MHz, CDCl3): d 0.68–0.77 (m, 1H), 0.92–1.07 (m,
3H), 1.10 (d, J¼6.4 Hz, 3H), 1.08–1.36 (m, 4H), 1.41 (d,
J¼5.9 Hz, 3H), 1.40–1.77 (m, 10H), 1.81–1.89 (m, 1H),
2.05–2.13 (m, 1H), 2.24 (dt, J¼10.3, 6.4 Hz, 1H), 2.62 (dt,
J¼13.2, 6.7 Hz, 1H), 3.07–3.15 (m, 1H), 3.54 (q, J¼5.4 Hz,
1H), 4.64 (dq, J¼10.3, 6.2 Hz, 1H), 5.25 (ddd, J¼15.2, 9.8,
1.0 Hz, 1H), 5.70 (dd, J¼15.2, 6.9 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 19.7, 21.3, 22.3, 26.1, 26.4, 31.0,
31.3, 32.0, 32.6, 33.6, 40.0, 41.5, 42.3, 45.6, 46.4, 49.0,
53.1, 76.8, 131.5, 135.1, 178.3. IR (neat): 2930, 1770, 1450,
(b) Preparation of ent-17. The compound ent-17 (110 mg,
64%) was prepared from ent-2 (283 mg, 0.75 mmol)
and ent-3 (340 mg, 1.5 mmol) in a manner similar to
the preparation of 17, described in a). [a]2D3¼2888 (c
0.35, CHCl3). Mp 90–928C (colorless powder). 1H
NMR, 13C NMR, IR, and MS spectra of this sample
were identical to those described in (a). HRMS (EI)

9916
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
1200, 1060 cm21. MS (EI) (m/z): 331 (Mþ), 316 (100).
HRMS (EI) (m/z): calcd for C21H33NO2 (Mþ): 331.2511.
Found, 331.2496.
264 mL, 0.40 mmol) at 2788C, and the mixture was stirred
at the same temperature for 5 min. A solution of ent-3
(90.1 mg, 0.40 mmol) in 1,2-dimethoxyethane (1 mL) was
added dropwise to the mixture at 2788C, and the resulting
solution was stirred at the same temperature for 4 h.
Benzoyl chloride (92.0 mL, 0.79 mmol) was added to the
reaction mixture at 2208C, and the reaction mixture was
stirred at rt for 1 h. After quenching the reaction by adding
3-(dimethylamino)propylamine (99.7 mL, 0.79 mmol), the
mixture was diluted with diethyl ether (10 mL), and washed
with diluted aqueous citric acid solution (5 mL) and brine
(5 mL). The organic layer was dried over anhydrous
MgSO4, filtered, then concentrated in vacuo. Flash column
chromatography (hexane–ethyl acetate¼2:1) of the residue
gave a mixture of b-benzoyloxy sulfone 20 as a yellow oil
and 2 (159 mg), a starting material. The structure of 20,
possibly consisting of a mixture of four diastereomers, was
determined by its characteristic 1H NMR (400 MHz,
(b) Preparation of ent-19. The compound ent-19 (113 mg,
98%) was prepared from ent-18 (147 mg, 0.34 mmol) in a
manner similar to that described in a). [a]2D2¼2158 (c 0.44,
1
CHCl3). H NMR, 13C NMR, IR, and MS spectra of this
sample were identical to those described in (a). HRMS (EI)
(m/z): calcd for C21H33NO2 (Mþ): 331.2511. Found,
331.2518.
4.1.18. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-4-[2-(E)-
[(2R,6S)-1,6-dimethylpiperidin-2-yl]ethenyl]-3-methyl-
naphtho[2,3-c]furan-1(3H)-one [(1)-himbacine] and its
enantiomer (1 and ent-1). (a) Preparation of 1. To a
solution of 19 (115 mg, 0.35 mmol) in acetonitrile (6 mL),
formaldehyde (37 wt% solution in water, 0.30 mL) and
sodium cyanoborohydride (47.8 mg, 0.76 mmol) were
added, and the mixture was stirred at rt for 0.5 h. The
mixture was rendered pH 7.0 by adding acetic acid, and was
further stirred at rt for 1 h. After adding cold diluted aqueous
sodium hydroxide solution, the mixture was concentrated in
vacuo. The residue was extracted with diethyl ether
(10 mL£3), and the combined organic extracts were dried
over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (Chromatorex,
hexane–ethyl acetate¼5:1) of the residue gave 1 (109 mg,
91%) as a colorless powder. [a]2D4¼þ558 (c 0.21, CHCl3)
[authentic sample:28 [a]D24¼þ568 (c 0.21, CHCl3), (lit.:11b,12b
[a]2D0¼þ51.48 (c 1.01, CHCl3)). Mp 127–1288C (colorless
powder from hexane) (authentic sample:28 Mp 128–1298C
(recrystallized from hexane), lit.:11b,12b mp 129–1308C). 1H
NMR (400 MHz, CDCl3): d 0.70–0.75 (m, 1H), 0.93–1.06
(m, 3H), 1.00 (d, J¼6.4 Hz, 3H), 1.12–1.28 (m, 3H), 1.38–
1.47 (m, 2H), 1.40 (d, J¼6.4 Hz, 3H), 1.50–1.61 (m, 2H),
1.64–1.80 (m, 6H), 1.87 (ddd, J¼13.2, 5.9, 2.4 Hz, 1H),
2.07–2.14 (m, 1H), 2.22 (s, 3H), 2.22–2.27 (m, 1H), 2.63
(dt, J¼13.2, 6.7 Hz, 1H), 2.80–2.87 (m, 1H), 2.99–3.06 (m,
1H), 4.63 (dq, J¼11.0, 5.9 Hz, 1H), 5.26 (dd, J¼15.2,
9.8 Hz, 1H), 5.58 (dd, J¼15.0, 9.1 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 14.0, 19.0, 22.2, 26.1, 26.5, 31.5,
32.1, 32.6, 33.3, 33.6, 39.9, 41.2, 41.6, 42.3, 45.8, 49.2,
53.4, 61.4, 76.8, 133.4, 133.6, 178.3. IR (KBr): 2930, 2850,
1790, 1450 cm21. MS (EI) m/z: 345 (Mþ), 330 (100).
HRMS (EI) (m/z): calcd for C22H35NO2 (Mþ): 345.2668.
Found, 345.2696.
1
CDCl3) signals. H NMR (400 MHz, CDCl3): d 3.30 (s,
3H, OMe), 7.20–7.33 (m, 5H), 7.51–7.60 (m, 2H, Ph-H),
7.63–7.68 (m, 1H, Ph-H), 7.90–7.95 (m, 2H). MS (FAB)
m/z: 710 (MþþH), 578, 474, 358, 314, 154, 142 (100).
HRMS (FAB) (m/z): calcd for C40H56NO8S (MþþH):
710.3727. Found, 710.3776.
(b) Preparation of ent-20. A mixture of ent-20 and ent-2
(99.4 mg), a starting material, was prepared from ent-2
(60 mg, 0.16 mmol) as a yellow oil in a manner similar to
the preparation of 20, described in (a). 1H NMR, 13C NMR,
IR, and MS spectra of this sample were almost identical
with those described in (a). HRMS (FAB) (m/z): calcd for
C40H56NO8S (MþþH): 710.3727. Found, 710.3768.
4.1.20. (2S,6R)-tert-Butyl 2-[2-(E)-[(1S,3S,3aR,4R,4a-
S,8aR,9aS)-Dodecahydro-1-methoxy-3-methyl-
naphtho[2,3-c]furan-4-yl]ethenyl]-6-methylpiperidine-
1-carboxylate and its enantiomer (21 and ent-21).
(a) Preparation of 21. Treatment of the mixture of 20 and
2 (159 mg), using the same methods described for the
preparation of 17, gave 21 (38.9 mg, 68% from 2) as a
colorless oil, along with the recovery of 2 (51.3 mg, 51%)
after flash column chromatography (hexane–ethyl
acetate¼8:1, then 1:2). In this case, formation of the (Z)-
1
olefin was not observed by H NMR analysis of the crude
1
reaction product. [a]2D2¼þ168 (c 0.58, CHCl3). H NMR
(400 MHz, CDCl3): d 0.64–0.75 (m, 1H), 0.86–0.99 (m,
4H), 1.11–1.29 (m, 3H), 1.23 (d, J¼6.9 Hz, 3H), 1.28 (d,
J¼5.9 Hz, 3H), 1.44 (s, 9H), 1.41–1.80 (m, 8H), 1.86–1.97
(m, 2H), 2.03–2.09 (m, 1H), 2.14–2.23 (m, 2H), 3.31 (s,
3H), 3.90–3.96 (m, 1H), 4.17 (dq, J¼8.8, 6.1 Hz, 1H),
4.45–4.51 (m, 1H), 4.47 (s, 1H), 5.21 (ddd, J¼15.7, 9.8,
1.8 Hz, 1H), 5.49 (dd, J¼15.7, 4.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 13.7, 20.7, 24.7, 25.3, 26.4, 26.5,
26.7, 28.5, 28.5, 28.5, 31.4, 33.1, 34.1, 40.4, 41.3, 46.4,
46.6, 47.2, 48.6, 51.4, 54.0, 75.7, 79.0, 108.4, 132.4, 133.5,
155.2. IR (neat): 2930, 1690, 1390, 1180, 1100 cm21. MS
(EI) m/z: 447 (Mþ), 415, 359, 315 (100). HRMS (EI) (m/z):
calcd for C27H45NO4 (Mþ): 447.3349. Found, 447.3342.
(b) Preparation of ent-1. The compound ent-1 (101 mg,
86%) was prepared from ent-19 (113 mg, 0.34 mmol), in a
manner similar to the preparation of 1. [a]2D3¼2598 (c 0.29,
CHCl3). Mp 128–1308C (colorless powder from hexane).
1H NMR, 13C NMR, IR, and MS spectra of this sample were
superimposable on those described in (a). HRMS (EI) (m/z):
calcd for C22H35NO2 (Mþ): 345.2668. Found, 345.2674.
4.1.19. (2S,6R)-tert-Butyl 2-[2-Benzenesulfonyl-1-ben-
zoyl-2-[(1S,3S,3aR,4R,4aS,8aR,9aS)-dodecahydro-1-
methoxy-3-methylnaphtho[2,3-c]furan-4-yl]ethyl]-6-
methylpiperidine-1-carboxylate and its enantiomer (20
and ent-20). (a) Preparation of 20. To a solution of 2
(100 mg, 0.26 mmol) in 1,2-dimethoxyethane (2 mL) was
added dropwise n-butyllithium (1.5 M solution in hexane,
(b) Preparation of ent-21: The compound ent-21 (34.3 mg,
75% from ent-2) was prepared from the mixture of ent-20
and ent-2 (99.4 mg) similar to the preparation of 21,
described in (a). In this case, recovery of ent-2 was 21.3 mg

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9917
1
(36%). [a]2D2¼2178 (c 0.47, CHCl3). H NMR, 13C NMR,
4.1.23. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-4-[2-(E)-
[(2S,6R)-1,6-dimethylpiperidin-2-yl]ethenyl]-3-methyl-
naphtho[2,3-c]furan-1(3H)-one and its enantiomer (24
and ent-24). (a) Preparation of 24. Using the same methods
as those employed for the preparation of 1, 23 (10.2 mg,
30.8 mmol) was treated, giving 24 (7.80 mg, 73%) as a
colorless powder after flash column chromatography
(Chromatorex, hexane–ethyl acetate ¼2:1). [a]2D4¼þ6.68
(c 0.10, CHCl3). Mp 136–1388C (colorless powder from
IR, and MS spectra of this sample were identical to those
described in (a). HRMS (EI) (m/z): calcd for C27H45NO4
(Mþ): 447.3349. Found, 447.3309.
4.1.21. (2S,6R)-tert-Butyl 2-[2-(E)-[(3S,3aR,4R,4a-
S,8aR,9aS)-Dodecahydro-3-methyl-1-oxonaphtho[2,3-
c]furan-4-yl]ethenyl]-6-methylpiperidine-1-carboxylate
and its enantiomer (22 and ent-22). (a) Preparation of 22.
Treatment of 21 (33.1 mg, 73.9 mmol), using the same
methods as those described for the preparation of 18, gave
22 (21.7 mg, 68%) as a colorless oil after flush column
chromatography (hexane–ethyl acetate¼2:1). [a]2D4¼2168
(c 1.45, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.66–0.76
(m, 1H), 0.93–1.06 (m, 3H), 1.12–1.28 (m, 3H), 1.23 (d,
J¼6.8 Hz, 3H), 1.42 (d, J¼5.9 Hz, 3H), 1.44 (s, 9H), 1.46–
1.99 (m, 11H), 2.06–2.12 (m, 1H), 2.25 (dt, J¼10.3, 6.4 Hz,
1H), 2.61 (dt, J¼13.2, 6.6 Hz, 1H), 3.91–4.00 (m, 1H),
4.44–4.49 (m, 1H), 4.64 (dq, J¼9.8, 6.2 Hz, 1H), 5.24 (ddd,
J¼15.2, 9.8, 1.8 Hz, 1H), 5.57 (dd, J¼15.7, 5.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d 13.7, 20.6, 22.1, 25.3, 26.1,
26.4, 26.6, 28.5, 28.5, 28.5, 31.3, 32.0, 33.6, 40.1, 41.6,
42.4, 45.6, 47.3, 48.8, 51.4, 77.0, 79.1, 130.9, 134.7, 155.2,
178.4. IR (neat): 2930, 1780, 1680 cm21. MS (FAB) m/z:
432 (MþþH), 375, 332 (100). HRMS (FAB) (m/z): calcd for
C26H42NO4 (MþþH): 432.3114. Found, 432.3116.
1
hexane). H NMR (400 MHz, CDCl3): d 0.66–0.76 (m,
1H), 0.92–1.07 (m, 3H), 1.00 (d, J¼6.9 Hz, 3H), 1.11–1.30
(m, 3H), 1.38–1.59 (m, 4H), 1.43 (d, J¼6.4 Hz, 3H), 1.63–
1.80 (m, 6H), 1.84–1.89 (m, 1H), 2.11 (dt, J¼10.6, 5.9 Hz,
1H), 2.21–2.29 (m, 1H), 2.22 (s, 3H), 2.63 (dt, J¼13.2,
6.7 Hz, 1H), 2.83–2.88 (m, 1H), 3.02–3.07 (m, 1H), 4.65
(dq, J¼9.8, 6.1 Hz, 1H), 5.25 (dd, J¼15.2, 10.3 Hz, 1H),
5.59 (dd, J¼15.2, 8.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 14.0, 19.0, 22.2, 26.1, 26.4, 29.7, 31.2, 32.0,
33.2, 33.7, 40.0, 41.1, 41.4, 42.3, 45.8, 49.0, 53.4, 61.2,
76.7, 132.6, 133.7, 178.3. IR (KBr): 2930, 1780, 1440,
1200 cm21. MS (EI) m/z: 345 (Mþ), 330 (100). HRMS (EI)
(m/z): calcd for C22H35NO2 (Mþ): 345.2668. Found,
345.2675.
(b) Preparation of ent-24: The compound ent-24 (12.6 mg,
76%) was prepared from ent-23 (16.0 mg, 48.3 mmol) in a
manner similar to the preparation of 24. [a]2D1¼27.08 (c
0.40, CHCl3). Mp 135–137 8C (colorless powder from
(b) Preparation of ent-22: The compound ent-22 (10.5 mg,
73%) was prepared from ent-21 (15.0 mg, 33.5 mmol) in the
1
hexane). H NMR, 13C NMR, IR, and MS spectra of this
1
same manner as that described in a). H NMR, 13C NMR,
sample were superimposable on those described in (a).
HRMS (EI) (m/z): calcd for C22H35NO2 (Mþ): 345.2668.
Found, 345.2704.
IR, and MS spectra of this sample were identical with those
described in (a). [a]2D4¼þ148 (c 1.05, CHCl3). HRMS
(FAB) (m/z): calcd for C26H42NO4 (MþþH): 432.3114.
Found, 432.3118.
4.1.24. (1S,3S,3aR,4S,4aS,8aR,9aS)-Dodecahydro-1-
methoxy-4-(methanesulfonyloxy)methyl-3-methyl-
naphtho[2,3-c]furan (4-epi-15). The compound 4-epi-15
(76.9 mg, 82%) was prepared from 14b (71.8 mg,
0.28 mmol) as a yellow oil in the same manner as that
4.1.22. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[2-(E)-[(2S,6R)-6-methylpiperidin-2-yl]ethenyl]-
naphtho[2,3-c]furan-1(3H)-one and its enantiomer (23
and ent-23). (a) Preparation of 23. Using the same methods
as those employed for the preparation of 19, 22 (21.7 mg,
50.3 mmol) was treated, giving 23 (15.2 mg, 91%) as a
colorless oil. [a]D21¼þ158 (c 1.01, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.65–0.77 (m, 1H), 0.93–1.29 (m,
7H), 1.08 (d, J¼6.4 Hz, 3H), 1.41 (d, J¼5.9 Hz, 3H), 1.47–
1.80 (m, 10H), 1.84–1.91 (m, 1H), 2.10 (dt, J¼10.3, 5.9 Hz,
1H), 2.25 (dt, J¼10.3, 6.4 Hz, 1H), 2.62 (dt, J¼13.2, 6.6 Hz,
1H), 3.01–3.09 (m, 1H), 3.57 (q, J¼5.2 Hz, 1H), 4.65 (dq,
J¼9.8, 6.2 Hz, 1H), 5.24 (ddd, J¼15.7, 9.8, 1.5 Hz, 1H),
5.69 (dd, J¼15.7, 6.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 19.8, 21.5, 22.2, 26.1, 26.4, 30.6, 31.3, 32.0,
32.9, 33.6, 40.0, 41.5, 42.3, 45.6, 46.4, 49.0, 52.9, 76.8,
131.5, 135.1, 178.3. IR (neat): 2930, 1770, 1450,
1200 cm21. MS (FAB) m/z: 332 (MþþH) (100). HRMS
(FAB) (m/z): calcd for C21H34NO2 (MþþH): 332.2590.
Found, 332.2587.
1
described for the preparation of 15. H NMR (400 MHz,
CDCl3): d 0.83–0.95 (m, 2H), 1.13–1.40 (m, 5H), 1.30 (d,
J¼6.4 Hz, 3H), 1.51–1.62 (m, 2H), 1.63–1.72 (m, 2H),
1.77–1.81 (m, 1H), 1.82–1.88 (m, 1H), 2.18–2.28 (m, 2H),
3.02 (s, 3H), 3.32 (s, 3H), 4.13 (dq, J¼9.3, 5.9 Hz, 1H), 4.16
(dd, J¼9.8, 8.3 Hz, 1H), 4.41 (dd, J¼9.8, 4.4 Hz, 1H), 4.54
(s, 1H). MS (FAB) m/z: 438 [(Mþþdiethanolamine)þH].
HRMS (FAB) (m/z): calcd for C20H40NO7S [(Mþþ
diethanolamine)þH]: 438.2525. Found, 438.2506.
4.1.25. (1S,3S,3aS,4S,4aS,8aR,9aS)-Dodecahydro-1-
methoxy-3-methyl-4-(phenylsulfonyl)methylnaphtho-
[2,3-c]furan (4-epi-16). The compound 4-epi-16 (61.8 mg,
77%) was prepared from 4-epi-15 (76.9 mg, 0.23 mmol) as
a colorless powder in a manner similar to the preparation of
1
16. [a]2D5¼2188 (c 0.10, CHCl3). Mp 70–718C. H NMR
(400 MHz, CDCl3): d 0.82–0.94 (m, 2H), 1.12–1.43 (m,
5H), 1.22 (d, J¼5.9 Hz, 3H), 1.54–1.82 (m, 6H), 2.19 (dt,
J¼12.7, 6.4 Hz, 1H), 2.54 (dd, J¼9.8, 5.9 Hz, 1H), 2.60 (dd,
J¼12.7, 10.8 Hz, 1H), 3.30 (dd, J¼13.2, 2.9 Hz, 1H), 3.32
(s, 3H), 4.06 (dq, J¼9.3, 6.2 Hz, 1H), 4.52 (s, 1H), 7.14–
7.19 (m, 1H), 7.24–7.30 (m, 2H), 7.32–7.36 (m, 2H). 13C
NMR (100 MHz, CDCl3): d 21.8, 26.3, 26.9, 30.3, 33.4,
33.9, 34.7, 34.7, 36.9, 40.8, 41.9, 46.0, 54.1, 76.9, 109.3,
126.0, 128.8, 128.8, 129.7, 129.7, 136.6. IR (KBr): 2930,
(b) Preparation of ent-23. The compound ent-23 (6.70 mg,
83%) was prepared from ent-22 (10.5 mg, 24.3 mmol) in a
similar manner to that described in (a). 1H NMR, 13C NMR,
IR, and MS spectra of this sample were identical to those
described in (a). [a]2D1¼2148 (c 0.67, CHCl3). HRMS
(FAB) (m/z): calcd for C21H34NO2 (MþþH): 332.2590.
Found, 332.2601.

9918
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
1580, 1480, 1090, 1050 cm21. MS (FAB) m/z: 452 [(Mþþ
diethanolamine)þH]. HRMS (FAB) (m/z): calcd for
3H), 1.46 (s, 9H), 1.82–2.06 (m, 4H), 2.17–2.21 (m, 1H),
2.68 (dt, J¼13.2, 6.7 Hz, 1H), 3.99–4.07 (m, 1H), 4.40–
4.44 (m, 1H), 4.58 (dq, J¼10.8, 6.2 Hz, 1H), 5.45–5.54 (m,
2H). 13C NMR (100 MHz, CDCl3): d 13.6, 19.1, 20.8, 25.5,
26.1, 26.3, 26.5, 28.6, 28.6, 28.6, 31.0, 31.9, 33.8, 34.1,
39.0, 40.6, 40.7, 47.1, 49.8, 52.0, 77.2, 79.0, 128.6, 134.0,
155.1, 178.6. IR (neat): 2930, 1770, 1680, 1460 cm21. MS
(FAB) m/z: 432 (MþþH). HRMS (FAB) (m/z): calcd for
C26H42NO4 (MþþH): 432.3114. Found, 432.3109.
C25H42NO4S
Found, 452.2806.
[(Mþþdiethanolamine)þH]:
452.2835.
4.1.26. (1S,3S,3aS,4S,4aS,8aR,9aS)-Dodecahydro-1-
methoxy-3-methyl-4-(phenylsulfonyl)methylnaphtho-
[2,3-c]furan (4-epi-2). The compound 4-epi-2 (51.4 mg,
76%) was prepared as a colorless powder from 4-epi-16
(58.8 mg, 0.17 mmol) in a manner similar to the preparation
1
of 2. [a]2D6 ¼þ118 (c 0.39, CHCl3). Mp 159–1608C. H
4.1.29. (3S,3aR,4S,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[2-(E)-[(2R,6S)-6-methylpiperidine-2-yl]ethenyl]-
naphtho[2,3-c]furan-1(3H)-one (4-epi-19). The compound
4-epi-19 (3.60 mg, 100%) was prepared as a yellow oil from
4-epi-18 (4.70 mg, 10.9 mmol) in a manner similar to the
NMR (400 MHz, CDCl3): d 0.79–1.33 (m, 6H), 1.21 (d,
J¼6.4 Hz, 3H), 1.51–1.75 (m, 6H), 2.02–2.07 (m, 1H),
2.12 (dt, J¼12.4, 6.0 Hz, 1H), 2.77 (dt, J¼8.8, 5.5 Hz, 1H),
2.99 (dd, J¼14.7, 9.5 Hz, 1H), 3.27 (dd, J¼12.7, 6.4 Hz,
1H), 2.25–2.31 (m, 1H), 2.94 (dd, J¼14.7, 8.3 Hz, 1H),
3.28 (s, 3H), 3.28–3.32 (m, 1H), 4.07 (dq, J¼9.8, 6.1 Hz,
1H), 4.49 (s, 1H), 7.55–7.62 (m, 2H), 7.64–7.69 (m, 1H),
7.89–7.95 (m, 2H). 13C NMR (100 MHz, CDCl3): d 21.7,
26.0, 26.3, 29.7, 32.4, 32.9, 34.1, 34.2, 39.8, 42.0, 48.4,
54.0, 56.7, 76.5, 108.8, 128.2, 128.2, 129.3, 129.3, 133.7,
1
preparation of 19. [a]2D2¼2358 (c 0.36, CHCl3). H NMR
(400 MHz, CDCl3): d 0.81–0.98 (m, 2H), 1.06–1.38 (m,
7H), 1.13 (d, J¼6.9 Hz, 3H), 1.41 (d, J¼5.9 Hz, 3H), 1.48–
1.79 (m, 8H), 1.91 (ddd, J¼13.7, 6.9, 2.7 Hz, 1H), 2.03 (br,
1H), 2.05–2.11 (m, 1H), 2.14–2.20 (m, 1H), 2.70 (dt,
J¼13.2, 6.7 Hz, 1H), 3.08–3.16 (m, 1H), 3.56–3.62 (m,
1H), 4.58 (dq, J¼9.8, 6.4 Hz, 1H), 5.58 (dd, J¼15.2, 8.8 Hz,
1H), 5.64 (dd, J¼15.2, 5.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 19.1, 19.5, 21.1, 26.2, 26.6, 30.8, 31.1, 32.0, 32.5,
33.8, 34.1, 38.9, 40.5, 40.9, 46.4, 49.6, 52.9, 77.2, 130.4,
133.8, 178.6. IR (neat): 2920, 1770, 1450, 1200 cm21. MS
(FAB) m/z: 332 (MþþH). HRMS (FAB) (m/z): calcd for
C21H34NO2 (MþþH): 332.2590. Found, 332.2617.
139.5. IR (KBr): 2920, 1450, 1370, 1310, 1150, 1090 cm21
.
MS (FAB) m/z: 484 [(Mþþdiethanolamine)þH]. HRMS
(FAB)
(m/z):
calcd
for
C25H42NO6S
[(Mþþ
diethanolamine)þH]: 484.2733. Found, 484.2697.
4.1.27. (2R,6S)-tert-Butyl 2-[2-(E)-[(1S,3S,3aR,4S,4a-
S,8aR,9aS)-Dodecahydro-1-methoxy-3-methylnaphtho-
[2,3-c]furan-4-yl]ethenyl]-6-methylpiperidine-1-car-
boxylate (4-epi-17). The compound 4-epi-17 (2.60 mg,
33%) was prepared from 4-epi-2 (34.8 mg, 91.9 mmol) as a
colorless oil by way of b-benzoyloxy sulfone (12.6 mg,
19%) in the same manner as that described for the
preparation of 17. In this case, 4-epi-2 (27.5 mg, 79%)
was recovered by flash column chromatography at the stage
of b-benzoyloxy sulfone production. b-Benzoyloxy sul-
fone: HRMS (FAB) (m/z): calcd for C44H67N2O10S [(Mþþ
diethanolamine)þH]: 815.4516. Found, 815.4505. 4-epi-17:
[a]2D2¼þ348 (c 0.17, CHCl3). 1H NMR (400 MHz, CDCl3):
d 0.80–0.94 (m, 4H), 1.07–1.83 (m, 12H), 1.24 (d,
J¼6.9 Hz, 3H), 1.28 (d, J¼5.9 Hz, 3H), 1.46 (s, 9H),
1.88–2.01 (m, 3H), 2.06–2.14 (m, 1H), 2.24 (dt, J¼12.7,
6.4 Hz, 1H), 3.30 (s, 3H), 3.98–4.05 (m, 1H), 4.13 (dq,
J¼10.3, 6.1 Hz, 1H), 4.38–4.44 (m, 1H), 4.51 (s, 1H), 5.44
(dd, J¼15.7, 4.2 Hz, 1H), 5.54 (ddd, J¼15.7, 9.3, 1.5 Hz,
1H). 13C NMR (100 MHz, CDCl3): d 13.7, 20.8, 22.0, 25.2,
26.3, 26.8, 28.6, 28.6, 28.6, 31.2, 33.3, 34.4, 34.5, 40.5,
41.7, 42.6, 47.1, 49.1, 52.1, 54.0, 77.2, 78.9, 109.3, 130.1,
132.8, 155.2. One carbon was not observed. IR (neat): 2930,
1690, 1450, 1390, 1180 cm21. MS (FAB) m/z: 553 [(Mþþ
diethanolamine)þH]. HRMS (FAB) (m/z): calcd for
4.1.30. (3S,3aR,4S,4aS,8aR,9aS)-Decahydro-4-[2-(E)-
[(2R,6S)-1,6-dimethylpiperidine-2-yl]ethenyl]-3-methyl-
naphtho[2,3-c]furan-1(3H)-one (4-epi-1). The compound
4-epi-1 (2.40 mg, 64%) was prepared as a colorless oil from
4-epi-19 (3.60 mg, 10.9 mmol) in the same manner as that
described for the preparation of 1. [a]2D2¼27.78 (c 0.12,
CHCl3). 1H NMR (400 MHz, CDCl3): d 0.80–0.93 (m, 4H),
1.03 (d, J¼6.4 Hz, 3H), 1.11–1.32 (m, 4H), 1.33–1.72 (m,
10H), 1.42 (d, J¼5.9 Hz, 3H), 1.88–1.94 (m, 1H), 2.02–
2.11 (m, 1H), 2.17–2.27 (m, 1H), 2.23 (s, 3H), 2.70 (dt,
J¼13.2, 6.6 Hz, 1H), 2.81–2.90 (m, 1H), 3.03–3.10 (m,
1H), 4.58 (dq, J¼10.8, 5.9 Hz, 1H), 5.55 (dd, J¼14.7,
8.3 Hz, 1H), 5.62 (dd, J¼15.7, 8.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 14.1, 19.1, 22.7, 26.2, 26.6, 29.4,
30.0, 30.3, 31.0, 31.9, 33.8, 34.1, 39.0, 40.5, 40.7, 49.9,
55.9, 67.8, 77.2, 125.5, 125.5, 178.3. IR (neat): 2930, 1770,
1450, 1200 cm21. MS (FAB) m/z: 346 (MþþH). HRMS
(FAB) (m/z): calcd for C22H36NO2 (MþþH): 346.2746.
Found, 346.2720.
4.1.31. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[2-(E)-[6-methylpyridin-2-yl]ethenyl]naphtho[2,3-
C31H57N2O6
Found, 553.4251.
[(Mþþdiethanolamine)þH]:
553.4217.
c]furan-1(3H)-one (25). Treatment of
0.13 mmol) and 6-methylpyridine-2-carboxaldehyde
2 (50.0 mg,
(40.0 mg, 0.33 mmol), using the same methods as those
described for the preparation of 17, gave the corresponding
b-hydroxy sulfone (66.0 mg, 100%) as a yellow oil after
flash column chromatography (hexane–ethyl acetate¼1:1).
1H NMR (400 MHz, CDCl3): d 3.36, 3.37 (two s, 6H,
Me£2), 6.97 (m, 8H, aromatic protons). MS (CI) m/z: 500
(MþþH) (100). HRMS (CI) (m/z): calcd for C28H38NO5S
(MþþH): 500.2471. Found, 500.2452.
4.1.28. (2R,6S)-tert-Butyl 2-[2-(E)-[(3S,3aR,4S,4a-
S,8aR,9aS)-Dodecahydro-3-methyl-1-oxonaphtho[2,3-
c]furan-4-yl]ethenyl]-6-methylpiperidine-1-carboxylate
(4-epi-18). The compound 4-epi-18 (2.00 mg, 80%) was
prepared as a colorless oil from 4-epi-17 (2.60 mg,
5.81 mmol) in a manner similar to the preparation of 18.
[a]2D2¼24.58 (c 0.27, CHCl3). 1H NMR (400 MHz, CDCl3):
d 0.82–0.96 (m, 2H), 1.06–1.27 (m, 5H), 1.24 (d,
J¼6.9 Hz, 3H), 1.29–1.79 (m, 8H), 1.41 (d, J¼5.9 Hz,
The b-hydroxy sulfone (96.0 mg, 0.19 mmol) prepared in a

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9919
separate experiment was treated in a manner similar to that
described for the preparation of 17 to afford (E)-olefin 25
(12.3 mg, 19%) as a yellow oil. In this case, formation of the
6.20 (d, J¼11.7 Hz, 1H), 6.80 (d, J¼1.0 Hz, 1H), 7.06 (d,
.
J¼1.0 Hz, 1H). IR (neat): 2920, 1450, 1280, 1050 cm21
MS (EI) m/z: 330 (Mþ), 315, 298, 269 (100). HRMS (EI)
(m/z): calcd for C20H30N2O2 (Mþ): 330.2307. Found,
330.2322.
1
(Z)-olefin was not observed by TLC and H NMR analysis
of the crude reaction product. [a]2D4¼þ658 (c 0.42, CHCl3).
1H NMR (400 MHz, CDCl3): d 0.73–1.34 (m, 6H), 1.28 (d,
J¼6.4 Hz, 3H), 1.54–1.81 (m, 6H), 2.22–2.34 (m, 3H),
2.53 (s, 3H), 3.31 (s, 3H), 4.30 (dq, J¼9.3, 6.4 Hz, 1H), 4.52
(s, 1H), 6.35 (dd, J¼16.1, 9.3 Hz, 1H), 6.46 (d, J¼15.6 Hz,
1H), 6.96 (d, J¼7.3 Hz, 1H), 7.10 (d, J¼7.8 Hz, 1H), 7.49
Oxidation of 27 (31.2 mg, 94.4 mmol) and 29 (13.9 mg,
42.1 mmol) using a method similar to that used for the
preparation of 18, afforded 28 (4.00 mg, 13%) as a colorless
powder and 30 (8.50 mg, 64%) as a colorless oil,
respectively, after flash column chromatography (28: ethyl
acetate, 30: hexane–ethyl acetate¼1:4). 28: [a]2D7 2268 (c
0.40, CHCl3). Mp 171–1728C. 1H NMR (400 MHz,
CDCl3): d 0.71–0.81 (m, 1H), 1.00–1.28 (m, 5H), 1.45
(d, J¼5.9 Hz, 3H), 1.60–1.75 (m, 4H), 1.76–1.85 (m, 1H),
1.99 (ddd, J¼13.7, 6.4, 2.0 Hz, 1H), 2.26–2.35 (m, 2H),
2.66 (dt, J¼12.7, 6.4 Hz, 1H), 3.64 (s, 3H), 4.73 (dq, J¼9.8,
6.1 Hz, 1H), 6.28 (d, J¼15.7 Hz, 1H), 6.45 (dd, J¼15.5,
10.1 Hz, 1H), 6.83 (d, J¼1.5 Hz, 1H), 7.01 (d, J¼1.0 Hz,
1H). IR (KBr): 2920, 1770, 1450, 1200 cm21. MS (EI) m/z:
314 (Mþ) (100). HRMS (EI) (m/z): calcd for C19H26N2O2
(Mþ): 314.1994. Found, 314.1991. 30: [a]2D7¼þ1008 (c
(t, J¼7.6 Hz, 1H). IR (neat): 3420, 2920, 1590, 1450 cm21
.
MS (EI) m/z: 341 (Mþ), 326, 282, 266, 252, 120, 107 (100).
HRMS (EI) (m/z): calcd for C22H31NO2 (Mþ): 341.2355.
Found, 341.2402.
Oxidation of 25 (12.3 mg, 36.0 mmol) with Jones reagent
(0.50 mL), using a method similar to that used for the
preparation of 18, gave 26 (7.00 mg, 60%) as a colorless oil
after flash column chromatography (hexane–ethyl
acetate¼2:1). [a]D25¼2398 (c 0.70, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.73–1.32 (m, 6H), 1.42 (d,
J¼5.9 Hz, 3H), 1.54–1.86 (m, 5H), 1.91 (ddd, J¼13.2,
6.4, 2.1 Hz, 1H), 2.30–2.37 (m, 2H), 2.54 (s, 3H), 2.69 (dt,
J¼12.7, 6.4 Hz, 1H), 4.75 (dq, J¼7.8, 5.9 Hz, 1H), 6.41 (dd,
J¼15.7, 9.3 Hz, 1H), 6.49 (d, J¼15.7 Hz, 1H), 6.99 (d,
J¼7.3 Hz, 1H), 7.07 (d, J¼7.8 Hz, 1H), 7.51 (t, J¼7.6 Hz,
1H). IR (neat): 2930, 1770, 1450, 1200 cm21. MS (EI) m/z:
325 (Mþ), 281, 120 (100). HRMS (EI) (m/z): calcd for
C21H27NO2 (Mþ): 325.2042. Found, 325.2044.
1
0.17, CHCl3). H NMR (400 MHz, CDCl3): d 0.77–0.87
(m, 1H), 0.94–1.28 (m, 5H), 1.41 (d, J¼5.9 Hz, 3H), 1.60–
1.78 (m, 5H), 1.86–1.93 (m, 1H), 2.75–2.82 (m, 2H), 3.63
(s, 3H), 3.67 (td, J¼11.8, 4.9 Hz, 1H), 4.70 (dq, J¼10.3,
5.9 Hz, 1H), 5.57 (dd, J¼11.7, 10.3 Hz, 1H), 6.28 (d,
J¼11.7 Hz, 1H), 6.84 (d, J¼1.0 Hz, 1H), 7.07 (d, J¼1.0 Hz,
1H). IR (neat): 2920, 1770, 1200, 1060 cm21. MS (EI) m/z:
314 (Mþ) (100). HRMS (EI) (m/z): calcd for C19H26N2O2
(Mþ): 314.1994. Found, 314.1992.
4.1.32. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[2-(E)-(1-methylimidazol-2-yl)]ethenyl]naphtho[2,3-
c]furan-1(3H)-one (28) and its (Z)-isomer (30). Treatment
of 2 (100 mg, 0.26 mmol) and 1-methylimidazole-2-
carboxaldehyde (72.7 mg, 0.66 mmol), using the same
methods as those described for the preparation of 17, gave
the corresponding b-hydroxy sulfone (80.0 mg, 62%) as a
yellow oil after flash column chromatography (hexane–
4.1.33. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[(2-pyridylmethyl)oxy]naphtho[2,3-c]furan-1(3H)-one
(32). To a solution of 11 (29.0 mg, 0.12 mmol) in N,N-
dimethylformamide (3 mL), sodium hydride (60% dis-
persion in mineral oil, 12.1 mg, 0.30 mmol) was added at
rt, and the mixture was stirred at the same temperature for
30 min. 2-(Chloromethyl)pyridine hydrochloride (19.8 mg,
0.12 mmol) was added to the resulting solution at rt, and the
mixture was stirred at rt for 14 h. After quenching the
reaction by adding cold water (10 mL), the mixture was
extracted with diethyl ether (3 mL£3). The combined
organic extracts were washed with brine (3 mL), dried
over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (hexane–ethyl
acetate¼2:1) of the residue gave ether 31 (17.2 mg, 43%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): d 0.75–1.06
(m, 4H), 1.12–1.41 (m, 3H), 1.35 (d, J¼6.4 Hz, 3H), 1.59–
1.81 (m, 4H), 2.16–2.27 (m, 2H), 2.76 (dt, J¼9.3, 5.9 Hz,
1H), 3.33 (s, 3H), 3.41 (dd, J ¼10.8, 5.4 Hz, 1H), 4.35 (dq,
J¼9.3, 6.4 Hz, 1H), 4.50 (d, J¼13.2 Hz, 1H), 4.54 (s, 1H),
4.82 (d, J¼12.7 Hz, 1H), 7.18 (dd, J¼7.3, 5.7 Hz, 1H), 7.46
(d, J¼7.8 Hz, 1H), 7.69 (td, J¼7.8, 2.0 Hz, 1H), 8.54 (d,
J¼3.9 Hz, 1H). MS (FAB) m/z: 332 (MþþH), 300 (100).
HRMS (FAB) (m/z): calcd for C20H30NO3 (MþþH):
332.2226. Found, 332.2206.
1
ethyl acetate¼1:4). H NMR (400 MHz, CDCl3): d 3.78,
4.03 (two s, 6H, Me£2). MS (CI) m/z: 489 (MþþH), 457,
347 (100). HRMS (CI) (m/z): calcd for C26H37N2O5S
(MþþH): 489.2423. Found, 489.2404. This compound was
treated in a similar manner to that described for the
preparation of 17. This case differed from the preparation of
17 in that a mixture of (E)- and (Z)-olefin 27 and 29 was
produced. These compounds were separated by flash
column chromatography (hexane–ethyl acetate¼1:1, then
1:4) to give 27 (22.8 mg, 42%) as a colorless powder and 29
(10.7 mg, 20%) as a colorless oil. 27: [a]2D4¼þ488 (c 0.15,
1
CHCl3). Mp 176–1788C. H NMR (400 MHz, CDCl3): d
0.70–1.31 (m, 6H), 1.30 (d, J¼6.4 Hz, 3H), 1.47–1.83 (m,
6H), 2.18–2.31 (m, 3H), 3.31 (s, 3H), 3.61 (s, 3H), 4.29 (dq,
J¼8.3, 6.1 Hz, 1H), 4.51 (s, 1H), 6.23 (d, J¼15.7 Hz, 1H),
6.44 (dd, J¼15.7, 9.8 Hz, 1H), 6.80 (d, J¼1.0 Hz, 1H), 6.99
(d, J¼1.0 Hz, 1H). IR (KBr): 2920, 1440, 1280, 1100 cm21
.
MS (EI) m/z: 330 (Mþ), 315, 299, 270, 255, 109 (100).
HRMS (EI) (m/z): calcd for C20H30N2O2 (Mþ): 330.2307.
Found, 330.2340. 29: [a]2D4¼þ988 (c 0.71, CHCl3). 1H
NMR (400 MHz, CDCl3): d 0.81–1.30 (m, 6H), 1.29 (d,
J¼5.9 Hz, 3H), 1.51–1.74 (m, 6H), 2.32 (dt, J¼12.7,
6.2 Hz, 1H), 2.47 (dt, J¼9.3, 5.9 Hz, 1H), 3.29 (s, 3H), 3.59
(s, 3H), 3.67 (td, J¼10.8, 5.6 Hz, 1H), 4.24 (dq, J¼8.3,
6.1 Hz, 1H), 4.49 (s, 1H), 5.55 (dd, J¼11.7, 10.8 Hz, 1H),
Oxidation of 31 (17.2 mg, 52 mmol) in the same manner as
that described for the preparation of 18, gave 32 (6.00 mg,
1
37%) as a colorless oil. [a]2D0¼þ528 (c 0.60, CHCl3). H
NMR (400 MHz, CDCl3): d 0.74–1.46 (m, 7H), 1.48 (d,
J¼5.9 Hz, 3H), 1.61–1.87 (m, 4H), 2.16–2.24 (m, 1H),

9920
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
2.67 (dt, J¼12.2, 6.9 Hz, 1H), 2.73 (dt, J¼10.3, 6.8 Hz, 1H),
3.44 (dd, J¼10.3, 5.7 Hz, 1H), 4.54 (d, J¼12.7 Hz, 1H),
4.76 (dq, J¼9.8, 5.9 Hz, 1H), 4.79 (d, J¼12.7 Hz, 1H), 7.21
(dd, J¼7.8, 4.9 Hz, 1H), 7.45 (d, J¼7.8 Hz, 1H), 7.69–7.74
(m, 1H), 8.55 (d, J¼4.4 Hz, 1H). IR (neat): 2920, 1770,
1200, 1080 cm21. MS (EI) m/z: 315 (Mþ), 286, 272, 208,
108 (100). HRMS (EI) (m/z): calcd for C19H25NO3 (Mþ):
315.1834. Found, 315.1834.
one (37). A solution of 11 (100 mg, 0.42 mmol), 2-picolinic
acid (256 mg, 2.1 mmol), diphenylphosphoryl azide
(448 mL, 2.1 mmol), and triethylamine (580 mL,
4.2 mmol) in toluene (3 mL) was heated at 1008C for 6 h
with stirring, and then concentrated in vacuo. After
quenching the reaction by adding water (5 mL), the
resulting insoluble materials were filtered off, and the
filtrate was extracted with diethyl ether (3 mL£3). The
combined organic extracts were washed with brine (3 mL),
dried over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (hexane–ethyl
acetate¼2:1) of the residue gave carbamate 36 (95.5 mg,
64%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 0.91–
1.79 (m, 6H), 1.30 (d, J¼5.9 Hz, 3H), 1.85–1.92 (m, 1H),
2.32 (dt, J¼12.2, 6.2 Hz, 1H), 2.69 (dt, J¼8.3, 6.4 Hz, 1H),
3.30 (s, 3H), 4.34 (dq, J¼9.8, 6.4 Hz, 1H), 4.55 (s, 1H), 4.91
(dd, J¼11.3, 5.9 Hz, 1H), 6.99 (dd, J¼7.3, 4.7 Hz, 1H),
7.67–7.71 (m, 1H), 7.97 (d, J¼8.3 Hz, 1H), 8.23–8.25 (m,
1H). MS (FAB) m/z: 361 (MþþH), 327, 276 (100). HRMS
(FAB) (m/z): calcd for C20H29N2O4 (MþþH): 361.2127.
Found, 361.2126.
4.1.34. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[2-(4-morpholyl)acetoxy]naphtho[2,3-c]furan-1(3H)-one
(35). To a solution of 11 (100 mg, 0.42 mmol) in N,N-
dimethylformamide (3 mL), sodium hydride (60% dis-
persion in mineral oil, 99.9 mg, 2.5 mmol) was added at
rt, and the mixture was stirred at the same temperature for
30 min. Chloroacetyl chloride (99.4 mL, 1.25 mmol) was
added to the resulting solution at rt, and the mixture was
stirred at the same temperature for 6 h. After quenching the
reaction by adding cold water (5 mL), the mixture was
extracted with diethyl ether (3 mL£3). The combined
organic extracts were washed with brine (5 mL), dried
over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (hexane–ethyl
acetate¼10:1) of the residue gave chloroacetate 33
(110.0 mg, 83%) as a yellow oil. 1H NMR (400 MHz,
CDCl3): d 0.83–1.41 (m, 5H), 1.29 (d, J¼5.9 Hz, 3H),
1.51–1.54 (m, 1H), 1.66–1.82 (m, 4H), 2.31 (dt, J¼12.2,
6.2 Hz, 1H), 2.59 (dt, J¼8.8, 5.9 Hz, 1H), 3.30 (s, 3H), 4.05
(dd, J¼15.7, 12.2 Hz, 1H), 4.29–4.37 (m, 1H), 5.02 (dd,
J¼10.8, 6.2 Hz, 1H). MS (EI) m/z: 285 (Mþ2OMe), 162
(100). HRMS (EI) (m/z): calcd for C15H22ClO3
(Mþ2OMe): 285.1257. Found, 285.1257.
Treatments of 36 (95.5 mg, 0.26 mmol) in a manner similar
to the preparation of 18, gave 37 (11.9 mg, 13%) as a
colorless oil after flash column chromatography (hexane–
1
ethyl acetate¼2:1). [a]2D5¼þ368 (c 0.11, CHCl3). H NMR
(400 MHz, CDCl3): d 0.77–1.31 (m, 6H), 1.35–1.44 (m,
1H), 1.39 (d, J¼5.9 Hz, 3H), 1.64–1.98 (m, 5H), 2.71–2.81
(m, 2H), 4.73 (dq, J¼10.3, 6.1 Hz, 1H), 4.89 (dd, J¼11.2,
5.9 Hz, 1H), 6.98–7.06 (m, 1H), 7.70–7.76 (m, 1H), 8.00
(d, J¼8.3 Hz, 1H), 8.26–8.28 (m, 1H), 8.74 (br, 1H). IR
(neat): 2930, 1780, 1730, 1590, 1540, 1440, 1220 cm21. MS
(EI) m/z: 344 (Mþ), 326, 276, 206, 120 (100). HRMS (EI)
(m/z): calcd for C19H24N2O4 (Mþ): 344.1736. Found,
344.1745.
A solution of 33 (17.8 mg, 49 mmol) in morpholine
(43.0 mL, 0.49 mmol) was stirred at 1008C for 5 h. After
concentration in vacuo, flash column chromatography
(hexane–ethyl acetate¼2:1, then 1:2) of the residue gave
2-(4-morpholyl)acetate 34 (15.2 mg, 84%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d 0.81–1.34 (m, 6H), 1.28 (d,
J¼6.4 Hz, 3H), 1.50–1.55 (m, 1H), 1.63–1.78 (m, 5H),
2.29 (dt, J¼12.7, 5.9 Hz, 1H), 2.49–2.61 (m, 5H), 3.14 (d,
J¼16.6 Hz, 1H), 3.22 (d, J¼16.6 Hz, 1H), 3.30 (s, 3H), 3.75
(t, J¼4.7 Hz, 4H), 4.32 (dq, J¼9.3, 5.9 Hz, 1H), 4.53 (s,
1H), 5.00 (dd, J¼10.8, 5.9 Hz, 1H). MS (EI) m/z: 367 (Mþ),
352, 335, 100 (100). HRMS (EI) (m/z): calcd for
C20H33NO5 (Mþ): 367.2359. Found, 367.2338.
4.1.36. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[(2-pyridylcarbamoyl)oxymethyl]naphtho[2,3-c]furan-
1(3H)-one (39). Preparation of 38 (40.6 mg, 92%) as a
yellow oil from 14a (30.0 mg, 0.12 mmol) was carried out
in the same manner as that described for the preparation of
36. 1H NMR (400 MHz, CDCl3): d 0.84–1.33 (m, 7H), 1.32
(d, J¼5.9 Hz, 3H), 1.52–1.90 (m, 6H), 2.19 (dt, J¼12.2,
6.2 Hz, 1H), 2.43 (dt, J¼9.3, 4.7 Hz, 1H), 3.33 (s, 3H), 4.02
(dd, J¼11.3, 8.6 Hz, 1H), 4.21 (dq, J¼9.3, 6.2 Hz, 1H), 4.34
(dd, J¼10.8, 3.7 Hz, 1H), 4.49 (s, 1H), 6.98–7.01 (m, 1H),
7.35 (br, 1H), 7.66–7.71 (m, 1H), 7.95 (d, J¼8.3 Hz, 1H),
8.24–8.25 (m, 1H). MS (FAB) m/z: 375 (MþþH), 363, 343,
327, 154 (100). HRMS (FAB) (m/z): calcd for C21H31N2O4
(MþþH): 375.2284. Found, 375.2273.
Oxidation of 34 (15.2 mg, 41 mmol) in a manner similar to
that described for the preparation of 18, gave 35 (8.00 mg,
55%) as a colorless oil after flash column chromatography
(hexane–ethyl acetate¼1:1, then 1:2). [a]2D5¼þ418 (c 0.76,
CHCl3). 1H NMR (400 MHz, CDCl3): d 0.82–1.40 (m, 7H),
1.42 (d, J¼5.9 Hz, 3H), 1.57–1.81 (m, 4H), 1.89 (dd,
J¼10.8, 6.4 Hz, 1H), 2.53–2.62 (m, 5H), 2.72–2.78 (m,
1H), 3.16 (d, J¼16.6 Hz, 1H), 3.25 (d, J¼16.6 Hz, 1H), 3.76
(t, J¼4.7 Hz, 4H), 4.74 (dq, J¼12.2, 5.9 Hz, 1H), 4.97 (dd,
J¼11.3, 5.9 Hz, 1H). IR (neat): 2930, 1780, 1750,
1200 cm21. MS (EI) m/z: 351 (Mþ), 100 (100). HRMS
(EI) (m/z): calcd for C19H29NO5 (Mþ): 351.2046. Found,
351.2045.
Oxidation of 38 (40.6 mg, 0.11 mmol) in a manner similar
to the preparation of 18, gave 39 (21.8 mg, 56%) as a
colorless oil. [a]D24¼þ228 (c 0.10, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.84–1.31 (m, 7H), 1.44 (d,
J¼5.9 Hz, 3H), 1.63–1.94 (m, 6H), 2.42–2.47 (m, 1H),
2.64 (dt, J¼13.2, 6.7 Hz, 1H), 4.09–4.15 (m, 1H), 4.33 (dd,
J¼11.2, 3.9 Hz, 1H), 4.67 (dq, J¼9.8, 6.1 Hz, 1H), 7.00–
7.04 (m, 1H), 7.61 (br, 1H), 7.69–7.73 (m, 1H), 7.94 (d,
J¼8.3 Hz, 1H), 8.25–8.27 (m, 1H). IR (neat): 2930, 1770,
1730, 1540, 1310 cm21. MS (EI) m/z: 358 (Mþ), 210, 163,
135, 120 (100). HRMS (EI) (m/z): calcd for C20H26N2O4
(Mþ): 358.1893. Found, 358.1870.
4.1.35. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[(2-pyridylcarbamoyl)oxy]naphtho[2,3-c]furan-1(3H)-

M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
9921
4.1.37. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[(3S)-1-benzylpyrrolidin-2-yl]oxymethylnaphtho[2,3-
c]furan-1(3H)-one (41). To a solution of (S)-1-benzylpyr-
rolidin-3-ol (104 mg, 0.59 mmol) in N,N-dimethylforma-
mide (2 mL), sodium hydride (60% dispersion in mineral
oil, 39.1 mg, 0.98 mmol) was added at rt, and the mixture
was stirred at the same temperature for 20 min. O-Mesylate
15 (65.0 mg, 0.20 mmol) was added to the resulting solution
at rt, and the mixture was stirred at 808C for 17 h. After
quenching the reaction by adding cold water (10 mL), the
mixture was extracted with diethyl ether (3 mL£3). The
combined ethereal extracts were washed with brine (3 mL),
dried over anhydrous MgSO4, filtered, and then were
concentrated in vacuo. Flash column chromatography
(ethyl acetate) of the residue gave 40 (12.4 mg, 8%) as a
diethyl ether (3 mL£3). The combined organic extracts
were washed with brine (3 mL), dried over anhydrous
MgSO4, filtered, then concentrated in vacuo, to afford the
N-methyl derivative 43 (11.5 mg, 100%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d 0.80–1.35 (m, 10H), 1.31
(d, J¼5.9 Hz, 3H), 1.47–1.99 (m, 9H), 2.11–2.17 (m, 1H),
2.27 (s, 3H), 2.37 (dt, J¼10.3, 5.2 Hz, 1H), 2.62–2.68 (m,
1H), 2.89–2.95 (m, 1H), 3.26–3.34 (m, 1H), 3.32 (s, 3H),
3.39 (dd, J¼9.3, 7.8 Hz, 1H), 3.49 (dd, J¼8.8, 3.7 Hz, 1H),
4.20 (dq, J¼9.3, 6.1 Hz, 1H), 4.45 (s, 1H). MS (CI) m/z: 352
(MþþH) (100). HRMS (CI) (m/z): calcd for C21H38NO3
(MþþH): 352.2852. Found, 352.2891.
Oxidation of 43 (11.5 mg, 33.0 mmol) in a manner similar to
the preparation of 18, gave 44 (2.3 mg, 21%) as a yellow oil.
[a]2D4¼þ138 (c 0.23, CHCl3). 1H NMR (400 MHz, CDCl3):
d 0.83–1.35 (m, 10H), 1.45 (d, J¼5.9 Hz, 3H), 1.56–2.04
(m, 9H), 2.29 (s, 3H), 2.38–2.43 (m, 1H), 2.57 (dt, J¼12.7,
6.4 Hz, 1H), 2.63–2.71 (m, 1H), 2.87–2.96 (m, 1H), 3.30–
3.35 (m, 1H), 3.45 (apparent t, J¼8.6 Hz, 1H), 3.52 (dd,
J¼9.3, 3.2 Hz, 1H), 4.68 (dq, J¼10.3, 6.4 Hz, 1H). IR
(neat): 2930, 1770, 1450, 1200, 1070 cm21. MS (EI) m/z:
335 (Mþ), 320, 167, 149, 114, 99 (100). HRMS (EI) (m/z):
calcd for C20H33NO3 (Mþ): 335.2460. Found, 335.2492.
1
yellow oil. H NMR (400 MHz, CDCl3): d 0.77–1.09 (m,
5H), 1.17–1.30 (m, 2H), 1.29 (d, J¼6.4 Hz, 3H), 1.47–1.83
(m, 7H), 1.97–2.06 (m, 1H), 2.14 (dt, J¼11.7, 5.9 Hz, 1H),
2.36 (dt, J¼10.8, 5.4 Hz, 1H), 2.43 (dd, J¼9.8, 4.2 Hz, 1H),
2.52–2.62 (m, 2H), 2.86 (dd, J¼9.8, 6.4 Hz, 1H), 3.25–3.35
(m, 1H), 3.32 (s, 3H), 3.59 (d, J¼12.7 Hz, 1H), 3.64 (d,
J¼13.2 Hz, 1H), 3.88–3.93 (m, 1H), 4.19 (dq, J¼9.3,
5.9 Hz, 1H), 4.45 (s, 1H), 7.22–7.34 (m, 5H). MS (CI) m/z:
414 (MþþH). HRMS (CI) (m/z): calcd for C26H40NO3
(MþþH): 414.3008. Found, 414.2999.
4.1.39. (1S,3S,3aR,4R,4aS,8aR,9aS)-Dodecahydro-4-
aminomethyl-1-methoxy-3-methylnaphtho[2,3-c]furan
(45). To a solution of 14a (100 mg, 0.39 mmol), phthali-
mide (63.6 mg, 0.43 mmol), and triphenylphosphine
(113 mg, 0.43 mmol) in tetrahydrofuran (3 mL), diethyl
azodicarboxylate (92.9 mL, 0.59 mmol) was added at 08C,
and the mixture was stirred at rt for 7 h, then concentrated in
vacuo. Diluted aqueous citric acid solution (5 mL) was
added to the residue and extracted with diethyl ether
(3 mL£3). The combined organic extracts were washed
with brine (3 mL), dried over anhydrous MgSO4, filtered,
then concentrated in vacuo. Flash column chromatography
(hexane–ethyl acetate¼4:1) of the residue gave the
Oxidation of 40 (12.4 mg, 30 mmol) in a manner similar to
the preparation of 18, gave 41 (7.60 mg, 64%) as a colorless
oil after flash column chromatography (ethyl acetate–
1
methanol¼10:1). [a]2D4¼þ368 (c 0.76, CHCl3). H NMR
(400 MHz, CDCl3): d 0.79–1.29 (m, 8H), 1.42 (d,
J¼5.9 Hz, 3H), 1.62–1.88 (m, 6H), 2.01–2.10 (m, 1H),
2.40 (dt, J¼10.8, 5.4 Hz, 1H), 2.47 (dd, J¼10.3, 3.9 Hz,
1H), 2.53–2.65 (m, 3H), 2.79 (dd, J¼10.3, 6.4 Hz, 1H),
3.26–3.38 (m, 2H), 3.62 (q, J¼12.7 Hz, 2H), 3.88–3.93 (m,
1H), 4.66 (dq, J¼10.3, 5.9 Hz, 1H), 7.23–7.35 (m, 5H). IR
(neat): 2920, 1770, 1450, 1200 cm21. MS (EI) m/z: 397
(Mþ), 368, 320, 306, 159, 133, 120, 91 (100). HRMS (EI)
(m/z): calcd for C25H35NO3 (Mþ): 397.2617. Found,
397.2623.
1
phthalimide derivative (150 mg, 99%) as a yellow oil. H
NMR (400 MHz, CDCl3): d 0.80–1.26 (m, 6H), 1.40 (d,
J¼5.9 Hz, 3H), 1.51–1.73 (m, 5H), 1.83–1.90 (m, 1H),
2.21–2.26 (m, 1H), 2.34–2.43 (m, 2H), 3.31 (s, 3H), 3.49
(dd, J¼13.7, 5.9 Hz, 1H), 3.78 (dd, J¼13.7, 6.9 Hz, 1H),
4.23 (dq, J¼8.3, 5.9 Hz, 1H), 4.46 (s, 1H), 7.71 (dd, J¼5.4,
2.9 Hz, 2H), 7.83 (dd, J¼5.4, 3.0 Hz, 2H). MS (FAB) m/z:
489 [(Mþþdiethanolamine)þH]. HRMS (FAB) (m/z): calcd
for C27H41N2O6 [(Mþþdiethanolamine)þH]: 489.2965.
Found, 489.2939.
4.1.38. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
[(3S)-1-methylpiperidin-3-yloxymethylnaphtho[2,3-
c]furan-1(3H)-one (44). The compound 42 (25.1 mg,
38%), a colorless oil, was prepared from 15 (50.0 mg,
0.15 mmol) and (S)-1-(tert-butoxycarbonyl)piperidin-3-ol
(90.8 mg, 0.45 mmol) in the same manner as that described
1
for the preparation of 40. H NMR (400 MHz, CDCl3): d
0.79–1.28 (m, 10H), 1.31 (d, J¼5.9 Hz, 3H), 1.38–1.91 (m,
8H), 1.56 (s, 9H), 2.11–2.18 (m, 1H), 2.31–2.39 (m, 1H),
2.96–3.22 (m, 3H), 3.32 (s, 3H), 3.39–3.64 (m, 3H), 4.16–
4.25 (m, 1H), 4.46 (s, 1H). MS (FAB) m/z: 543 [(Mþþ
diethanolamine)þH]. HRMS (FAB) (m/z): calcd for
To a solution of the phthalimide derivative (150 mg,
0.39 mmol) in ethanol (5 mL) was added hydrazine hydrate
(0.20 mL), and the mixture was stirred at rt for 4 h, then
concentrated in vacuo. The residue was diluted with water
(10 mL) and extracted with diethyl ether (3 mL£3). The
combined organic extracts were washed with brine (3 mL),
dried over anhydrous MgSO4, filtered, then concentrated in
vacuo, to give 4b-carbinamine 45 (51.2 mg, 52%) as a
yellow oil. [a]D25¼þ858 (c 0.25, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.79–1.04 (m, 6H), 1.15–1.90 (m,
9H), 1.39 (d, J¼6.4 Hz, 3H), 2.11–2.20 (m, 1H), 2.39–2.48
(m, 2H), 2.97 (dd, J¼13.2, 3.9 Hz, 1H), 3.33 (s, 3H), 4.16
(dq, J¼9.3, 6.1 Hz, 1H), 4.48 (s, 1H). IR (neat): 3390, 2920,
1450 cm21. MS (FAB) m/z: 254 (MþþH), 222, 154 (100).
C29H55N2O7
Found, 543.3998.
[(Mþþdiethanolamine)þH]:
543.4009.
To a solution of 42 (14.3 mg, 33 mmol) in tetrahydrofuran
(5 mL), lithium aluminum hydride (3.7 mg, 98 mmol) was
added at rt, and the mixture was stirred at the same
temperature for 1 h, then heated at reflux for 1 h. After
quenching the reaction by adding water (5 mL), the
insoluble materials were filtered off. The filtrate was
concentrated in vacuo, and the residue was extracted with

9922
M. Takadoi et al. / Tetrahedron 58 (2002) 9903–9923
HRMS (FAB) (m/z): calcd for C15H28NO2 (MþþH):
constants, respectively, of the radioligands. The Kd values
were determined by Scatchard analysis.
254.2120. Found, 254.2104.
4.1.40. (3S,3aR,4R,4aS,8aR,9aS)-Decahydro-3-methyl-4-
(6-methylpyridine-2-carboxamido)methylnaphtho[2,3-
c]furan-1(3H)-one (47). A solution of 45 (46.2 mg,
Acknowledgements
0.18 mmol),
6-methyl-2-picolinic
acid
(75.0 mg,
We are grateful to Dr H. Ohkubo and Dr T. Ishizaki, Kyorin
Pharmaceutical Co. Ltd, for their numerous valuable
suggestions and for their encouragement. We would also
like to thank Dr Y. Fukuda, Kyorin Pharmaceutical 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 Pharmaceutical Co. Ltd, to whom our
thanks are also due. We also thank Mr Y. Ijuin, Sagami
Chemical Research Center, for the single-crystal X-ray
crystallographic analysis.
0.55 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride (EDCI) (105 mg, 0.55 mmol) in
CH2Cl2 (3 mL) was stirred at rt for 5 h, then concentrated
in vacuo. Diluted aqueous sodium hydroxide solution
(5 mL) was added to the residue, and the mixture was
extracted with diethyl ether (3 mL£3). The combined
organic extracts were washed with brine (3 mL), dried
over anhydrous MgSO4, filtered, then concentrated in
vacuo. Flash column chromatography (hexane–ethyl
acetate¼2:1) of the residue gave acetal 46 (54.1 mg, 80%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): d 0.91–1.10
(m, 5H), 1.17–1.30 (m, 3H), 1.40 (d, J¼5.9 Hz, 3H), 1.53–
1.73 (m, 2H), 1.76–1.87 (m, 2H), 1.98–2.05 (m, 1H), 2.19
(dt, J¼12.2, 6.2 Hz, 1H), 2.46 (dt, J¼9.8, 4.9 Hz, 1H), 2.58
(s, 3H), 3.09 (ddd, J¼13.7, 9.8, 5.7 Hz, 1H), 3.32 (s, 3H),
3.86 (ddd, J¼13.7, 5.9, 4.4 Hz, 1H), 4.24 (dq, J¼9.3,
6.1 Hz, 1H), 4.49 (s, 1H), 7.27 (d, J¼8.8 Hz, 1H), 7.72 (t,
J¼7.8 Hz, 1H), 7.97 (d, J¼7.8 Hz, 1H), 8.20 (br, 1H). MS
(EI) m/z: 372 (Mþ), 252, 220, 192, 176, 149. HRMS (EI)
(m/z): calcd for C22H32N2O3 (Mþ): 372.2413. Found,
372.2452.
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