The first enantioselective total synthesis of cyclomyltaylane-5α-ol and determination of its absolute stereochemistry

Article abstract of DOI:10.1039/b111594b

The tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5α-ol 1 has been synthesized starting from (S)-(+)-Hajos-Wiechert ketone analogue 10 via stereoselective Claisen rearrangement followed by SmI₂-promoted reductive cyclisation. Thus, the absolut

Full text of DOI:10.1039/b111594b

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The first enantioselective total synthesis of cyclomyltaylane-5ꢀ-ol
and determination of its absolute stereochemistry
Hisahiro Hagiwara,*a Hitoshi Sakai,a Takashi Uchiyama,a Yoshiaki Ito,b Noriyuki Morita,b
Takashi Hoshi,b Toshio Suzukib and Masayoshi Andob
1
a Graduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi,
Niigata 950-2181, Japan
b Faculty of Engineering, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received (in Cambridge, UK) 19th December 2001, Accepted 16th January 2002
First published as an Advance Article on the web 5th February 2002
The tetracyclic sesquiterpenoid (ϩ)-cyclomyltaylan-5α-ol 1 has been synthesized starting from
(S)-(ϩ)-Hajos–Wiechert ketone analogue 10 via stereoselective Claisen rearrangement followed by
SmI2-promoted reductive cyclisation. Thus, the absolute configuration has been established to be
2R,3R,4R,5S,6R,7R (cyclomyltaylane numbering) as depicted in structure 1.
Natural products having diverse structures and important
biological activities have been found from various natural
sources by the efforts of many research groups.1 Particularly,
liverworts contain structurally as well as physiologically inter-
esting organic molecules. Among them are cyclomyltaylane2
and myltaylane3 sesquiterpenoids which have unique tetra-
cyclic and tricyclic carbon frameworks respectively. Since the
isolation of cyclomyltaylenol2a (cyclomyltaylan-15-ol) 2 as the
first cyclomyltaylane natural product from the Japanese Mylia
taylorii (Hook.) S. Gray by Matsuo et al., cyclomyltaylan-3-ol2b
3 along with cyclomyltaylyl 10α-caffeate2b 4 from the Japanese
Bazzania japonica have been isolated by Asakawa et al. and
subsequently cyclomyltaylane2c 5 and (ϩ)-cyclomyltaylan-
5α-ol2d 1 from the Taiwanese Bazzania tridens and Reboulia
hemisphaerica by Wu et al. Their tricyclic congeners, (Ϫ)-
myltaylenol [myltayl-4(12)-en-15-ol]3a 6 and (Ϫ)-myltayl-4(12)-
en-5-ol3b 7, were also isolated by Matsuo et al. and Asakawa et
al. from the Mylia taylorii and the French Bazzania trilobata
respectively (Fig. 1).
tetracyclo[6.2.1.01,6.07,9]undecane ring with three contiguous
quaternary carbon centers and an absence of successful total
synthesis of cyclomyltaylane-type sesquiterpenoids, we set out
on a synthetic study of cyclomyltaylane-5α-ol 1 and delineate
herein the first enantioselective total synthesis of 1 thereby
establishing its absolute stereochemistry.4
Results and discussion
Our retrosynthetic design is illustrated briefly in Scheme 1. Final
Scheme 1
ring closure to the cyclopropane ring of 1 could be accom-
plished by an intramolecular substitution of ketone 8 which
could be derived by intramolecular reductive cyclisation of
formyl-enone 9 (R = O). The enone 9 in turn could be obtained
by stereoselective introduction of an allyl unit at the angular
position of the Hajos–Wiechert ketone analogue 10.
Though the absolute stereochemistry of the natural product
1 was unknown, we employed the optically active (S)-(ϩ)-
Hajos–Wiechert ketone analogue105 as a starting material
which was prepared by amino acid mediated asymmetric
intramolecular cyclisation of 2-methyl-2-(3-oxopentyl)cyclo-
pentane-1,3-dione 11 (Scheme 2). The reaction conditions
for cyclisation have already been developed by us in the
Fig. 1
Though biological activities of these sesquiterpenoids are
underdeveloped, cyclomyltaylyl 3-caffeate 4 inhibited release of
the superoxide anion from guinea-pig peritoneal macrophage
Ϫ
induced by O2 stimulant FMLP (formyl-methionyl-leucyl-
phenylalanine; 10Ϫ7 M) at ID50 7.5 µg mlϪ1 2b The relative stereo-
.
chemistries of every cyclomyltaylane natural product have been
determined by using modern NMR techniques, the absolute
configurations have not been established yet except for com-
pound 3 which was determined by the empirical CD octant rule.
Intrigued by its novel carbon framework containing tetramethyl-
DOI: 10.1039/b111594b
J. Chem. Soc., Perkin Trans. 1, 2002, 583–591
This journal is © The Royal Society of Chemistry 2002
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Scheme 2 Reagent, conditions and yields; i, -β-phenylalanine, D-CSA, MeCN, 30–70 ЊC, 5 days, 99% (45% after recrystallizations); ii, NaBH4,
MeOH, Ϫ25 ЊC, 100%, iii, TBDMSCl, imidazole, DMAP, DMF, r.t., 98%; iv, p-Br–C6H4COCl, DMAP, pyridine, r.t., 99%; v, MeI, t-BuOK,
t-BuOH, reflux, 65%; vi, LAH, Et2O, Ϫ78 ЊC, 98%; vii, n-BuLi, CS2, MeI, THF, 0 ЊC; viii, n-Bu3SnH, AlBN, toluene, reflux, 8 min, 92% in two steps;
ix, BH3ؒTHF, THF, r.t., 2.5 h, then NaOH, H2O2, r.t., overnight, 84%; x, PCC, 4 Å-MS, CH2Cl2, r.t., 9 h, 98% from 19, 89% from 20; xi, DBU,
t-BuOH, reflux, overnight, 90% from 21, 88% from 22; xii, KH, allyl bromide, THF, 0 ЊC 2 h, r.t. 2 h, 45–50 ЊC 5 h, toluene, reflux 12 h, 96%;
xiii, OsO4, NalO4, t-BuOH, H2O, r.t., 3 h, 81%.
preparation of optically active Wieland–Miescher ketone
analogue6 and successfully employed for the total syntheses of
several terpenoids.7 Thus treatment of 11 with -phenylalanine
and (ϩ)-camphorsulfonic acid by gradual warming to 80 ЊC
afforded (ϩ)-enedione 10 ([α]D ϩ297) as crystals in 45%
yield after recrystallisation. The enantiomeric excess of 10
was obtained by GLC analysis on a chiral stationary phase
(column: cyclodextrine-β-236M-19) to be more than 98% ee.
The absolute configuration of 10 was determined by applying
the exciton chirality method as follows. The carbonyl group at
C-1 in 10 was regio- and stereoselectively reduced with 0.26
equiv. of sodium borohydride in absolute EtOH at Ϫ20 ЊC to
give quantitatively β-alcohol 12 as a sole product which was
then treated with p-bromobenzoyl chloride in pyridine in the
presence of DMAP to afford p-bromobenzoate 14 in 99% yield
(Scheme 2).
formation of the cyclohexenone ring, the β-alcohol in 12 was
protected with TBDMSCl to afford TBDMS ether 13. Methyl-
ation with excess iodomethane (MeI) in the presence of t-BuOK
in t-BuOH at reflux temperature9 provided deconjugated
ketone 15 in 65% yield along with the recovered 13 (11%) and a
small amount of tetramethylindanone. Lithium aluminium
hydride (LAH) reduction of 15 afforded β-alcohol 16 as a sole
product in 98% yield. The stereochemistry of the resulting
hydroxy group of 16 was determined to be β-equatorial orient-
ation judging from coupling constants (9.2 and 7.4 Hz) of a
proton at C5.
The hydroxy group of the alcohol 16 was removed by
Barton’s radical protocol.10 Treatment of the alcohol 16 with
n-BuLi followed by successive addition of carbon disulfide and
MeI afforded xanthate 17. Then the xanthate 17 was sub-
jected to reaction with n-Bu3SnH in the presence of a catalytic
amount of AIBN in toluene at reflux for 8 min to give olefin 18
in 92% yield from 16. In order to arrange the cyclopentenone
moiety, hydroboration of the olefin 18 was carried out to pro-
vide regioselectively β-19 and α-alcohol 20 in 84% yield 1 : 1.9
ratio in favour of the latter indicating that the α-face of 18 was
less sterically crowded. Independent PCC oxidation of 19 and
20 in the presence of molecular sieves powder afforded ketone
21 and 22 in 98 and 89% yield respectively. A slower rate of
oxidation of 19 compared with 20 implies that the hydroxy
group of 19 is sterically more hindered. Treatment of the
ketones 21 and 22 with DBU in t-BuOH lead to the same
cyclopentenone 24 in 90% and 88% yield, respectively. In
benzene, the β-elimination required a longer reaction time and
resulted in a lower yield. Concomitant facile isomerisation
occurred from enone 23 to thermodynamically more stable 24
(Fig. 3), though the stereochemistry of 24 could not be assigned
by NMR techniques. Deducing from the cis-stereochemistries
of related compounds 28 and 29 determined by NOE (Fig. 4)
and calculated heat of formation of 23 (Ϫ41.5 kcal molϪ1) and
The CD spectrum of the benzoate 14 showed an exciton type
of positive first (∆ε ϩ 21.9 at 255 nm) and a negative second
(∆ε Ϫ37.4 at 203 nm) Cotton effect. This result clearly indicated
that the chirality between the two long axes of transition
moments of enone and benzoate chromophores was positive as
shown in Fig. 2.8
Thus, the absolute stereochemistry of the (ϩ)-enedione 10
was unambiguously established as (7aS). Prior to the trans-
Fig. 2
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Fig. 3
Fig. 4 Selected NOE of related compounds.
24 (Ϫ49.2 kcal molϪ1) by PM3 method, the enone 24 might have
cis-stereochemistry as depicted in the structure 24.
Introduction of the allyl unit was at first investigated by using
enone 29. D2O quenching of the enolate of 29 generated by
LDA at Ϫ78 ЊC incorporated deuterium in 93% yield at the
angular position. However, attempts of angular allylation of
the enolate of 29 generated by LDA with allyl bromide in the
presence of HMPA resulted in complete recovery of 29, prob-
ably due to steric hindrance imposed by bis-neopentyl position.
On the other hand, treatment of the enone 24 with potassium
hydride and allyl bromide furnished unstable O-allylated dienol
ether 25. After addition of toluene, the resulting solution was
heated at reflux and the desired allylenone 26 was furnished by
Claisen rearrangement as a single isomer in 96% yield in one
pot operation. Unfortunately, the stereochemistry of 26 could
not be determined by spectroscopic means. The stereoselective
introduction of the allyl group from the β-face of the enone 24
was finally proved by transformation of 26 into the natural
product 1. Present stereoselective introduction of the allyl unit
at angular position is explained by the fact that the Claisen
rearrangement proceeded from the less sterically congested
conformer 25B by assuming a chair like transition state (Fig. 5).
Scheme 3 Reagents conditions and yields; i, Sml2, t-BuOH, HMPA,
Ϫ78 ЊC, 62%; ii, TBDMSCl, DMAP, imidazole, DMF, r.t., overnight,
94%; iii, LiHMDS, MeI, THF, 0 ЊC, 83% (mixture of 33a and 33b);
iv, TBAF, THF, r.t., 90% (34a : 34b = 1 : 2.3); v, MsCl, Et3N, DCM, 94%
(from 34b), 76% (from 34a); vi, NaOEt, r.t., 93% (from 35b), 77% (from
35a); vii, LAH, 0 ЊC, 81%.
Fig. 5
Then, construction of the tricyclo[5.2.2.01,6]undecane frame-
work was investigated by intramolecular reductive cyclisation
of formyl enone 27 (Scheme 3). Recently, efficiency of reductive
cyclisation of alkyl or ketyl radical species generated by sam-
arium() iodide (SmI2) is well precedented.11 Enholm et al. and
other groups have reported SmI2-mediated intramolecular
reductive cyclisation of carbonyl groups with olefin or electron-
deficient olefins11,12 though these reactions proceeded only in
exo-trig mode. We anticipated that such methodology would be
applicable for our purpose, though a successful cyclisation
between the cyclic enone moiety and formyl group has not been
well precedented. To this end, the allyl group of olefin 26 was
oxidatively cleaved with a catalytic amount of OsO4 and excess
NaIO4 in t-BuOH–H2O to furnish formylenone 27 in 81% yield.
According to the literature procedure,13 SmI2 was prepared
as a 0.1 M solution in THF from excess metallic Sm and 1,2-
diiodoethane in THF at room temperature. Optimised reac-
tion conditions were investigated by using formyl-enone 37
alternatively prepared [Equation (1)].
(1)
after aqueous work up (Table 1, entry 1). With t- BuOH as a
proton source and excess HMPA in order to enhance reducing
ability of SmI2,14 the reaction of 37 with 1.8 equiv. of SmI2 at
room temperature for 0.5 h gave tricyclic hydroxyketone 40 and
41 in 5 and 18% yields respectively, along with the recovered
aldehyde 37 (11%) after aqueous work up (Table 1, entry 2).
From the TLC inspection of the aqueous layer, it was not poss-
ible to extract products 40 and 41 completely from the resulting
aqueous layer. Thus direct isolation was carried out by silica gel
column chromatography after quenching the reaction by add-
ition of silica gel in entries 3 to 5. When the enone-aldehyde 37
was treated with SmI2 and t-BuOH in the presence of excess
HMPA at Ϫ78 ЊC for 10 min, hydroxyketone 40 and 41 were
In an initial attempt, treatment of 37 with 3.0 equiv. of SmI2
gave the recovered aldehyde 37 (29%) and the enone 29 (18%)
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Table 1
Entry
Substrate
Reagents
Conditions
Product and yield (%)
1
2
37
37
Sml2 (3.0 equiv.)
r.t., 1.0 h
r.t., 0.5 h
37, 29
29, 18
41, 18
40, 5
37, 11
41, 1
40, 12
29, 44
41, 52
40, 24
Sml2 (1.8 equiv.)
t-BuOH (1.2 equiv.)
HMPA
Sml2 (3.0 equiv.)
t-BuOH (1.2 equiv.)
3a
4a
5a
37
37
27
r.t., 13 h
Sml2 (3.0 equiv.)
t-BuOH (1.2 equiv.)
HMPA
Sml2 (3.0 equiv.)
t-BuOH (1.2 equiv.)
HMPA
Ϫ78 ЊC, 10 min
Ϫ78 ЊC, 15 min
30, 43
31, 19
a The products were isolated without aqueous work up.
obtained in 24 and 52% yield (Table 1, entry 4). In a similar
manner, reaction of 27 provided the desired tricyclic product 30
and 31 in 43 and 19% yields respectively. The relative stereo-
chemistry of the major hydroxyketone 41 was confirmed by
NOE experiments as depicted in Fig. 6. In the minor hydroxy-
librated into more stable intermediate 39 and provided exo-
alcohol 30 or 41 preferentially. In the absence of HMPA, the
reaction became slow. An attempt at a higher reaction temper-
ature resulted in reductive elimination of the acetaldehyde unit
14a,16
to give enone 29 (path c),
During the course of our syn-
thetic study, Tori and his co-workers also reported similar 6-
endo-trig cyclisation of formylenone leading to hydrindanone.17
The final transformation to the natural product 1 to furnish
the tetracyclic framework by intramolecular cyclisation was
carried out as follows (Scheme 3). It was fortunate for our pur-
pose that the exo-hydroxyketone 30 predominated by the reduc-
tive cyclisation. The hydroxyketone 30 was protected in 94%
yield as the TBDMS ether 32 which was then methylated with
LiHMDS and MeI in THF at 0 ЊC to afford 33 as a diastereo-
meric mixture. Without separation, subsequent deprotection
of the TBDMS ether with TBAF provided alcohols 34a and
34b in a 1 : 2.3 ratio in 90% combined yield. These alcohols
were separately subjected to conventional mesylation to yield
mesylates 35a and 35b in 76 and 94% yield respectively. Intra-
molecular substitution of the mesylate 35a or 35b with
NaOEt18 provided cyclomyltaylan-5-one 36 in 77 or 93% yield
respectively. Finally, stereoselective reduction of the ketone 36
with LAH furnished (ϩ)-cyclomyltaylan-5α-ol 1 {[α]2D0 ϩ33
(c 0.3, CHCl3)} in 81% yield. Spectral data of the synthetic 1
were completely identical with those of natural product 1 {[α]D
ϩ36 (c 0.2, CHCl3)}2d thereby establishing the absolute stereo-
chemistry of the natural product 1 as depicted in structure 1.
In conclusion, we have achieved an enantioselective first total
synthesis of (ϩ)-cyclomyltaylan-5α-ol 1 starting from the
optically active (S)-(ϩ)-Hajos–Wiechert ketone analogue 10
via stereoselective Claisen rearrangement followed by SmI2-
mediated reductive coupling as key steps. The absolute con-
figuration of the natural product 1 was thus established to be
2R,3R,4R,5S,6R,7R (cyclomyltaylane numbering) as shown in
structure 1 in Fig. 1.
Fig. 6 Stereochemical assignments of pinacol products.
ketone 40, W-type long range coupling (1.2 Hz) between C2–H
(δ 4.71; dddd, J 9.6, 4.4, 4.4 and 1.2 Hz) and C4–Hexo (δ 2.20;
ddd, J 18.8, 4.4 and 1.2 Hz) established the orientation of the
hydroxy group to be endo (Fig. 6). In a similar manner, W-type
long range coupling was observed in the hydroxyketone 31. The
proton on a carbon with a hydroxy group in 30 appeared at a
higher field (δ 4.04) than the corresponding proton of 31
(δ 4.67). These results also confirmed stereochemistries of the
hydroxy groups of 30 and 31. When the reaction was run with-
out HMPA, reductive elimination of acetaldehyde predomin-
ated to give the enone 29 as a major product (Table 1, entry 3).
Plausible reaction pathway drawn from these results is
described in Scheme 4. Since the reduction potential of
cyclohexenone is lower (1.55 V vs. SCE) than propionaldehyde
(1.8 V vs. SCE),15 initially we anticipated that the reaction pro-
ceeded by chelation control through one-electron transfer to the
cyclopentenone moiety followed by intramolecular trapping of
the resulting radical by the formyl group in intermediate 42
(path b) to afford the endo-alcohol 31 or 40 as a major product.
However, exo-hydroxyketone 30 or 41 was isolated as a major
isomer with 3 equiv. of SmI2. Judging from these results, the
present reaction might proceed through the thermodynamically
controlled 6-endo-trig mode vinylogous pinacol coupling path-
way after two-electron transfer to 27 or 37 (path a). Steric
interference between the two Sm atoms coordinated to the
intermediary two alkoxy groups in the intermediate 38 equi-
Experimental
Mps were determined with a Yanaco MP hot-stage apparatus
and are uncorrected. IR spectra were recorded on a Shimadzu
FT/IR-4200 spectrophotometer in carbon tetrachloride unless
otherwise indicated. 1H-NMR spectra were obtained for
solutions in deuteriochloroform with Varian Gemini 200H
(200 MHz) and Unity 500plus (500 MHz) instruments with
tetramethylsilane as internal standard. J-Values are in Hz. 13C-
NMR spectra were obtained for solutions in deuteriochloro-
form with Varian Gemini 200H (50 MHz) and Unity 500plus
(125 MHz) instruments. Mass spectral data were obtained with
a Hitachi M-80B spectrometer. UV and CD spectra were
obtained by a JASCO J-720W instrument. Specific rotations
were measured with a Horiba SEPA-200 spectrophotometer for
586
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mixture was heated at 30 ЊC for 24 h, and the temperature was
raised in 10 ЊC intervals in every 24 h during 4 days. After the
mixture was stirred at 70 ЊC for 19.5 h, the solvent was evapor-
ated in vacuo and the residue was diluted with ethyl acetate. The
organic layer was washed with water and brine. The aqueous
layer was extracted with ethyl acetate six times. The combined
organic layer was washed with water and brine and dried over
anhydrous Na2SO4. Evaporation of the solvent in vacuo fol-
lowed by flash column chromatography (eluent ethyl acetate–
n-hexane = 1 : 2) of the residue afforded diketone 10 (17.6 g,
99% for 2 steps) as a brown viscous oil which crystallised in n-
hexane–diethyl ether at Ϫ78 ЊC. Recrystallization from diethyl
ether at Ϫ30 ЊC gave pale yellow needles (7.97 g, 45%) which
had mp 35.5–36.5 ЊC; [α]2D5 ϩ297 (c 1.03, benzene); νmax/cmϪ1
(CHCl3) 2955, 2932, 1748, 1659, 1449, 1354, 1117, 1082 and
1007; δH (200 MHz) 1.29 (s, 3H), 1.79 (s, 3H), 1.80 (dd, J 13.0,
7.0, 1H), 2.05 (dd, J 4.6, 2.8, 2H) and 2.35–3.10 (m, 6H).
An enantiomeric excess was obtained by GLC analysis on a
chiral stationary phase (Cyclodextrine-β-236M-19).
(1S,7aS)-(؉)-1-Hydroxy-4,7a-dimethyl-2,3,7,7a-tetrahydro-
1H-indene-5(6H)-one 12
To a stirred solution of the diketone 10 (1.03 g, 5.76 mmol)
in ethanol (20 ml) was added sodium borohydride (59 mg,
1.57 mmol) at Ϫ25 ЊC. After being stirred for 50 min at this
temperature, the reaction was quenched by the addition of
brine and the aqueous layer was extracted with ethyl acetate
three times. The combined organic layer was washed with brine
and dried over anhydrous Na2SO4. Evaporation of the solvent
followed by flash column chromatography (eluent ethyl acetate–
n-hexane = 1 : 1) of the residue provided alcohol 12 (1.11 g,
100%) as a pale yellow viscous oil which had [α]2D0 ϩ58.2
(c 1.03); νmax/cmϪ1 3424, 2969, 1659, 1449, 1354, 1210, 1159,
1100, 1074, 1046 and 787; δH (200 MHz) 1.09 (s, 3H), 1.62
(s, 3H), 1.70–1.89 (m, 2H), 2.15–2.18 (m, 2H), 2.37–2.45 (m,
2H), 2.54–2.61 (m, 2H) and 3.82 (dd, J 10.6, 7.3, 1H).
(1S,7aS)-(؉)-1-p-Bromobenzoyloxy-4,7a-dimethyl-2,3,7,7a-
tetrahydro-1H-indene-5(6H)-one 14
A mixture of the alcohol 12 (76 mg, 0.421 mmol), p-bromo-
benzoyl chloride (228 mg, 1.26 mmol) and DMAP (27 mg,
0.224 mmol) in anhydrous pyridine (4 ml) was stirred at room
temperature for 14.5 h under a nitrogen atmosphere. After add-
ition of water, the resulting solution was extracted with ethyl
acetate three times, and the combined organic layer was washed
with water three times and brine twice and dried over anhydrous
Na2SO4. Evaporation of the solvent in vacuo followed by
purification of the residue by MPLC (eluent ethyl acetate–
n-hexane = 1 : 3) provided benzoate 14 (151 mg, 99%) which
had UV (EtOH) λmax 246.5 nm (ε 15,072); CD (EtOH) λext
255 nm (∆ε ϩ21.9) and 203 (Ϫ37.4); νmax/cmϪ1 3042, 2944, 1721,
1657, 1591, 1485, 1271, 1119, 1017 and 851; δH (200 MHz) 1.30
(s, 3H), 1.71 (s, 3H), 1.85–2.15 (m, 3H), 2.35–2.81 (m, 5H), 5.04
(dd, J 10.2, 7.2, 1H), 7.60 (d, J 8.7, 2H) and 7.91 (d, J 8.7, 2H);
δC (50 MHz) 10.86 (q), 16.98 (q), 25.81 (t), 26.63 (t), 33.08 (t),
34.10 (t), 44.79 (s), 81.99 (d), 128.28 (s), 128.85 (s), 129.41 (s),
131.03 (d × 2), 131.77 (d × 2), 165.26 (s), 165.33 (s), 198.16 (s).
Scheme 4
solutions in chloroform unless otherwise indicated and are
given in 10Ϫ1 deg cm2 gϪ1. Medium-pressure liquid chromato-
graphies (MPLC) were carried out on a JASCO PRC-50
instrument with a silica gel packed column. Microanalyses were
carried out in the Instrumental Analysis Center for Chemistry,
Tohoku University.
(1S,7aS)-(؉)-4,7a-Dimethyl-1-(1,1,2,2-tetramethyl-1-
silapropoxy)-2,3,7,7a-tetrahydro-1H-indene-5(6H)-one 13
To a stirred solution of the alcohol 12 (2.88 g, 16.0 mmol)
in DMF (22 ml) was successively added imidazole (2.80 g,
41.1 mmol), DMAP (196.4 mg, 1.61 mmol) and TBDMSCl
(4.84 g, 32.1 mmol) at 0 ЊC under a nitrogen atmosphere. After
being stirred at room temperature overnight, the reaction was
quenched by addition of aq. ammonium chloride and the
aqueous layer was extracted with ethyl acetate three times. The
organic layer was washed with water and brine and dried over
(7aS)-(؉)-4,7a-Dimethyl-2,3,7,7a-tetrahydro-1H-indene-
1,5(6H)-dione 10
A solution of the triketone 11 (20.7 g, as a 100 mmol), -β-
phenylalanine (16.5 g, 100 mmol) and -camphorsulfonic acid
(11.6 g, 50 mmol) in acetonitrile (350 ml) was stirred at room
temperature under a nitrogen atmosphere overnight. Then the
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anhydrous Na2SO4. After evaporation of the solvent in vacuo,
the residue was purified by flash column chromatography
(eluent ethyl acetate–n-hexane = 1 : 30 then 1 : 10) and sub-
sequent MPLC (eluent ethyl acetate–n-hexane = 1 : 10) pro-
vided ether 13 (4.12 g, 98%) as a pale yellow viscous oil which
had [α]2D0 ϩ32.8 (c 1.02); νmax/cmϪ1 (neat) 2957, 1667, 1465, 1379,
1255, 1125, 1030 and 899; δH (200 MHz) 0.05 (s, 3H), 0.06 (s,
3H), 0.90 (s, 9H), 1.07 (s, 3H), 1.65 (s, 3H), 1.69–2.57 (m, 8H)
and 3.72 (dd, J 10.3, 7.3, 1H); δC (50 MHz) Ϫ4.9 (q), Ϫ4.5 (q),
10.6 (q), 15.3 (q), 17.9 (s), 25.7 (q × 3 and t), 29.9 (t), 33.3 (t),
43.2 (t), 45.3 (s), 81.0 (d), 128.6 (s), 167.7 (s) and 198.6 (s)
(Found: C, 69.08; H, 10.15%. Calc. for C17H30O2Si: C, 69.33;
H, 10.2%).
quenched by addition of aq. ammonium chloride. The aqueous
layer was extracted with ethyl acetate five times, and the com-
bined organic layer was washed with water and brine and dried
over anhydrous Na2SO4. Evaporation of the solvent in vacuo
followed by MPLC (eluent ethyl acetate–n-hexane = 1 : 20) of
the residue provided xanthate 17 (236 mg) as a reddish oil which
had νmax/cmϪ1 (CHCl3) 2996, 2857, 1462, 1258, 1123 and 1062;
δH (200 MHz) 0.03 (s, 6H), 0.89 (s, 9H), 1.09 (s, 6H), 1.21 (s,
3H), 1.71–2.44 (m, 3H), 2.16 (ddd, J 15.0, 9.1, 1.7, 1H), 2.30
(ddd, J 15.0, 7.4, 3.3, 1H), 2.55 (s, 3H), 3.83 (dd, J 9.1, 7.4, 1H),
5.32 (dd, J 11.0, 4.8, 1H) and 5.40 (dd, J 3.3, 1.7, 1H); δC Ϫ4.8
(q), Ϫ4.4 (q), 17.7 (q), 18.1 (s), 18.7 (q), 23.4 (t), 23.5 (q), 25.5
(q), 25.8 (q × 3), 36.6 (t), 38.1 (t), 39.4 (s), 46.9 (s), 83.6 (d), 89.6
(d), 119.5 (d), 154.5 (s) and 215.6 (s) (Found: C, 59.84; H,
8.98%. Calc. for C20H36O2S2Si: C, 70.07; H, 10.45%).
(1S,7aS)-(؉)-4,4,7a-Trimethyl-1-(1,1,2,2-tetramethyl-1-
silapropoxy)-1,2,4,6,7,7a-hexahydro-5H-inden-5-one 15
[(1S,7aS)-(؊)-4,4,7a-Trimethyl(2,4,5,6,7,7a-
hexahydroindenyloxy)]-1,1,2,2-tetramethyl-1-silapropane 18
To a stirred solution of the ether 13 (50 mg, 0.17 mmol) in
absolute tert-butanol (2-methylpropan-2-ol) (t-BuOH) (2 ml)
was added potassium tert-butoxide (t-BuOK) (95 mg, 0.85
mmol) at ambient temperature under a nitrogen atmosphere.
The resulting solution was heated at reflux temperature for
30 min and then iodomethane (MeI) (106 µl, 1.7 mmol) was
added. After being stirred for 1 h at the same temperature,
additional MeI (53 µl, 0.85 mmol) was added and stirring was
continued for 1 h. Removal of the solvent in vacuo followed by
purification of the residue by MPLC (eluent ethyl acetate–
n-hexane = 1 : 10) afforded the recovered ether 13 (5 mg, 11%)
and ketone 15 (34 mg, 65%) as a colorless oil which had [α]2D0
ϩ48.5 (c 1.10); νmax/cmϪ1 3072, 2959, 1715, 1462, 1240, 1125,
1042 and 905; δH (200 MHz) 0.05 (s, 6H), 0.90 (s, 9H), 1.15 (s,
3H), 1.20 (s, 3H), 1.27 (s, 3H), 1.60–1.92 (m, 2H), 2.20–2.50
(m, 2H), 2.52–2.69 (ddd, J 15.2, 10.3, 5.5, 1H), 3.91 (dd, J 8.8,
7.6, 1H) and 5.40 (dd, J 3.3, 2.0, 1H); δC Ϫ4.9 (q), Ϫ4.4 (q), 17.6
(q), 18.0 (s), 23.7 (q), 25.8 (q × 3), 28.0 (q), 33.9 (t), 35.0 (t), 37.9
(t), 46.8 (s), 48.3 (s), 81.5 (d), 119.7 (d), 154.2 (s) and 215.1 (s)
(Found: C, 70.14; H, 10.43%. Calc. for C18H32O2Si: C, 70.07;
H, 10.45%).
A solution of the xanthate 17 (234 mg, 0.514 mmol), tributyltin
hydride (315 µl, 1.33 mmol) and AIBN (11 mg, 0.06 mmol) in
toluene (4 ml) was heated at reflux for 8 min. After being cooled
to room temperature, the resulting solution was passed through
a silica gel column (eluent n-hexane involving a small amount
of triethylamine). Evaporation of the solvent followed by
MPLC (eluent n-hexane) of the residue provided olefin 18
(225.3 mg, 92%) as a colorless oil which had [α]2D0 Ϫ4.4 (c 0.318);
νmax/cmϪ1 (neat) 3075, 2959, 1462, 1363, 1256, 1121, 1038 and
885; δH (200 MHz) 0.03 (s, 6H), 0.89 (s, 9H), 1.02 (s, 3H), 1.06
(s, 3H), 1.07 (s, 3H), 1.10–1.89 (m, 6H), 2.06 (ddd, J 14.5, 9.4,
1.8, 1H), 2.22 (ddd, J 14.5, 7.6, 3.3, 1H) and 5.23 (dd, J 3.3, 1.7,
1H); δC Ϫ4.7 (q), Ϫ4.4 (q), 17.6 (q), 18.2 (s), 19.2 (t), 25.9
(q × 3), 28.7 (q), 30.5 (q), 34.0 (s), 37.1 (t), 39.9 (t), 40.8 (t), 47.1
(s), 84.1 (d), 116.1 (d) and 156.5 (s) (Found: C, 73.35; H,
11.56%. Calc. for C18H34OSi: C, 73.40; H, 11.63%).
(1S,6R,7R,9S)-(؉)-1,5,5-Trimethyl-9-(1,1,2,2-tetramethyl-1-
silapropoxy)bicyclo[4.3.0]nonan-7-ol 19 and (1S,6S,7S,9S)-(؉)-
1,5,5-trimethyl-9-(1,1,2,2-tetramethyl-1-silapropoxy)bicyclo-
[4.3.0]nonan-7-ol 20
(1S,5S,7aS)-(؊)-4,4,7a-Trimethyl-1-(1,1,2,2-tetramethyl-1-
silapropoxy)-1,2,4,6,7,7a-hexahydro-5H-inden-5-ol 16
To a stirred solution of the olefin 18 (1.22 g, 4.16 mmol) in THF
(20 ml) was added borane–tetrahydrofuran complex (12.5 ml,
12.5 mmol, 1.0 M solution in THF) at room temperature under
a nitrogen atmosphere. After being stirred for 2.5 h, the solution
was heated at reflux for 5.5 h and 3 M aq. sodium hydroxide
(28.0 ml, 84.0 mmol) and 30% H2O2 (9.4 ml, 83.1 mmol) were
added at room temperature. After being stirred overnight,
products were extracted with ethyl acetate twice and the com-
bined organic layer was washed with water and brine and dried
over anhydrous Na2SO4. Evaporation of the solvent in vacuo
followed by flash column chromatography (eluent ethyl acetate–
n-hexane = 1 : 10) of the residue afforded the alcohols (1.08 g,
84%, 19–20 = 1 : 1.9). Analytical samples were obtained by
MPLC (eluent ethyl acetate–n-hexane = 1 : 7) to give cis-fused
β-alcohol 19 as an oil and trans-fused α-alcohol 20 as white
needles in the order of elution.
To a stirred solution of the ketone 15 (1.84 g, 5.97 mmol) in
diethyl ether (35 ml) was added LAH (228 mg, 6.02 mmol) at
Ϫ78 ЊC under a nitrogen atmosphere. After being stirred for
30 min at Ϫ78 ЊC, the reaction was quenched by careful addi-
tion of aq. ammonium chloride. The resulting solution was
passed through a short silica gel column with the aid of ethyl
acetate. Evaporation of the solvent in vacuo gave alcohol 16
(1.83 g, 98%) as white needles which had mp 86.0–87.5 ЊC
(from n-hexane); [α]2D0 Ϫ4.2 (c 0.996); νmax/cmϪ1 3505, 3072,
2959, 1552, 1471, 1360, 1250, 1121, 1067 and 1040; δH (200
MHz) 0.03 (s, 6H), 0.89 (s, 9H), 1.04 (s, 6H), 1.14 (s, 3H),
1.35–1.90 (m, 5H), 2.12 (ddd, J 14.9, 9.2, 1.7, 1H), 2.30 (ddd,
J 14.9, 7.4, 3.3, 1H), 3.26 (dd, J 10.6, 4.4, 1H), 3.78 (dd, J 9.2,
7.4, 1H), 5.32 (dd, J 3.3, 1.7, 1H); δC Ϫ4.8 (q), Ϫ4.4 (q), 17.7
(q), 18.1 (s), 21.4 (q), 25.6 (q × 3), 25.9 (q), 27.9 (t), 37.3 (t),
38.2 (t), 39.5 (s), 47.0 (s), 78.0 (d), 83.8 (d), 118.5 (d) and 155.9
(s) (Found: C, 69.84; H, 11.04%. Calc. for C18H34O2Si: C,
69.62; H, 11.04%).
The β-alcohol 19 had [α]2D0 ϩ18.8 (c 0.128); νmax/cmϪ1 (CHCl3)
3430, 2932, 1474, 1462, 1389, 1362, 1258, 1080 and 993; δH
(200 MHz) 0.05 (s, 3H), 0.06 (s, 3H), 0.91 (s, 9H), 1.03 (s, 6H),
1.12 (s, 3H), 1.14–1.58 (m, 8H), 2.44 (ddd, J 15.3, 8.8, 4.5, 1H),
3.52 (d, J 4.5, 1H) and 4.12 (m, 1H); δC Ϫ4.9 (q), Ϫ4.4 (q), 18.1
(s), 18.4 (t), 23.8 (q), 25.9 (q × 3), 29.8 (q), 30.8 (q), 31.1 (s), 32.5
(t), 36.1 (t), 40.7 (s), 42.7 (t), 81.5 (d), 62.4 (d), 72.5 (d) and 83.1
(d) (Found: C, 69.10; H, 11.61%. Calc. for C18H36O2Si: C, 69.17;
H, 11.61%).
[(1S,5S,7aS)-4,4,7a-Trimethyl-1-(1,1,2,2-tetramethyl-1-
silapropoxy)-1,2,4,6,7,7a-hexahydro-5H-inden-5-
yl)oxy]methylthiomethane-1-thione 17
To a stirred solution of the alcohol 16 (156 mg, 0.514 mmol) in
THF (4.5 ml) was added n-BuLi (700 µl, 1.06 mmol, 1.52 M
solution in n-hexane) at 0 ЊC. After being stirred for 40 min,
carbon disulfide (240 µl, 4.00 mmol) was added. The resulting
solution was stirred for 1.5 h and then MeI (170 µl, 2.78 mmol)
was added. After being stirred for 1.5 h, the reaction was
The α-alcohol 20 had [α]2D0 ϩ51.1 (c 0.558); mp 92.0–92.5 ЊC
(from n-hexane); νmax/cmϪ1 (CHCl3) 3440, 2955, 1475, 1462,
1389, 1261, 1119, 1071 and 1028; δH (200 MHz) 0.002 (s, 6H),
0.80 (s, 3H), 0.86 (s, 9H), 0.97 (s, 3H), 1.01 (s, 3H), 1.72 (ddd,
588
J. Chem. Soc., Perkin Trans. 1, 2002, 583–591

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J 13.9, 8.7, 3.2, 1H), 1.94 (m, 1H), 3.71 (dd, J 8.7, 8.7, 1H) and
4.23 (ddd, J 9.6, 9.6, 3.2, 1H); δC (50 MHz) Ϫ4.8 (q), Ϫ4.5 (q),
13.8 (q), 19.4 (t), 21.6 (q), 25.8 (q), 33.9 (q), 38.0 (t), 42.0 (t),
42.4 (t), 60.4 (d), 70.7 (d) and 79.5 (d) (Found: C, 69.24;
H, 11.65%. Calc. for C18H36O2Si: C, 69.17; H, 11.61%).
DBU (160 µl, 1.07 mmol) at room temperature under a nitrogen
atmosphere. The resulting solution was heated at reflux tem-
perature overnight and then passed through a short silica gel
column. Evaporation of the solvent in vacuo followed by
MPLC purification (eluent ethyl acetate–n-hexane = 1 : 5) of the
residue afforded enone 24 (54 mg, 88%) as white crystals.
(1R,6R,9S)-(؉)-1,5,5-Trimethyl-9-(1,1,2,2-tetramethyl-1-
silapropoxy)bicyclo[4.3.0]nonan-7-one 21
(3aR,7aR)-(؊)-3a,7,7-Trimethyl-7a-prop-2-enyl-3a,4,5,6,7,7a-
hexahydro-1H-inden-1-one 26
To a stirred mixture of the alcohol 19 (94 mg, 0.30 mmol) and
4 Å molecular sieves (100 mg) in DCM (4 ml) was added PCC
(102 mg, 0.464 mmol) and the resulting slurry was stirred at
room temperature for 9 h. The mixture was diluted with ethyl
acetate and passed through a short silica gel column. The result-
ing organic layer was washed with water twice and brine and
dried over anhydrous Na2SO4. After evaporation of the solvent
in vacuo, the residue was chromatographed on a short silica gel
column to afford ketone 21 (92 mg, 98%) as white needles which
had [α]2D0 ϩ16.4 (c 0.554); mp 36.5–37.0 ЊC (from n-hexane);
νmax/cmϪ1 2955, 1740, 1475, 1462, 1256, 1149, 1105 and 1009; δH
(200 MHz) 0.02 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 0.88 (s, 3H),
0.93 (s, 3H), 1.03 (s, 3H), 1.04–1.79 (m, 6H), 1.80 (d, J 2.0, 1H),
2.18 (ddd, J 19.3, 7.7, 2.0, 1H), 2.55 (dd, J 19.3, 7.7, 1H)
and 4.31 (dd, J 7.7, 7.7, 1H); δC (50 MHz) Ϫ5.0 (q), Ϫ4.5 (q),
18.0 (t and s), 24.7 (q), 24.9 (q), 25.8 (q × 3), 32.0 (t), 32.3 (q),
32.4 (s), 39.5 (t), 43.8 (s), 45.8 (t), 64.8 (d), 71.3 (d) and 218.3 (s)
(Found: C, 69.65; H, 11.09%. Calc. for C18H34O2Si: C, 69.62;
H, 11.04%).
To a suspension of potassium hydride (133 mg, 9.95 mmol, 30%
in mineral oil, washed with n-hexane twice) in THF was added
a solution of the enone 24 (585 mg, 3.28 mmol) in THF (3 ml)
at 0 ЊC under a nitrogen atmosphere. After being stirred for
30 min, allyl bromide (1.75 ml, 20.1 mmol) was added to the
reaction mixture which was stirred at 0 ЊC for 2 h, room tem-
perature for 2 h and at 45–50 ЊC for 5 h. Then, toluene (40 ml)
was added to the resulting mixture and stirring was continued
at reflux temperature for 12 h. After evaporation of the solvent
in vacuo, the residue was purified by MPLC (eluent ethyl
acetate–n-hexane = 1 : 7) to afford enone 26 (689 mg, 96%) as a
colorless oil which had [α]2D0 Ϫ25.3 (c 0.198); νmax/cmϪ1 3081,
2944, 1712, 1638, 1601, 1462, 1392, 1163, 1117 and 993; δH
(500 MHz) 1.10 (s, 6H), 1.24 (s, 3H), 1.38–1.59 (m, 4H), 1.65–
1.92 (m, 2H), 2.60 (m, 2H), 4.90–5.05 (m, 2H), 5.77 (dddd,
J 17.0, 10.0, 7.1, 7.1, 1H), 5.97 (d, J 5.7, 1H) and 7.20 (d, J 5.7,
1H); δC (50 MHz) 17.31 (t), 25.32 (q), 27.74 (q), 28.95 (q), 35.35
(t), 35.87 (t), 36.38 (t), 36.64 (s), 49.14 (s), 58.58 (s), 116.61 (t),
131.19 (d), 136.85 (d), 170.59 (d) and 213.83 (s) (Found:
C, 82.25; H, 10.22%. Calc. for C15H22O: C, 82.52; H, 10.16%).
(1R,6S,9S)-(؉)-1,5,5-Trimethyl-9-(1,1,2,2-tetramethyl-1-
silapropoxy)bicyclo[4.3.0]nonan-7-one 22
To a stirred mixture of the alcohol 20 (117 mg, 0.374 mmol)
and 4 Å molecular sieves (125 mg) in DCM (4 ml) was added
PCC (126 mg, 0.561 mmol) and stirring was continued for 4 h at
room temperature. The mixture was diluted with ethyl acetate
and passed through a short silica gel column. The organic layer
was washed with water twice and brine and dried over
anhydrous Na2SO4. After evaporation of the solvent in vacuo,
the residue was chromatographed on a short silica gel column
to afford ketone 22 (104 mg, 89%) as white needles which had
2-[(3aR,7aR)-(؊)-3a,7,7-Trimethyl-1-oxo-3a,4,5,6,7,7a-
hexahydro-1H-inden-7a-yl]ethanal 27
To a stirred solution of the enone 26 (731 mg, 3.35 mmol) in
t-BuOH (100 ml) and water (50 ml) was successively added
osmium tetraoxide (14 mg, 0.0537 mmol) and sodium periodate
(3.58 g, 16.7 mmol) at room temperature. After being stirred for
3 h, the reaction mixture was poured into water. The resulting
mixture was extracted with ethyl acetate twice. The organic
layer was washed with aq. sodium hydrogencarbonate, water
and brine and dried over anhydrous Na2SO4. Evaporation of
the solvent in vacuo followed by MPLC purification (eluent
ethyl acetate–n-hexane = 1 : 5) of the residue afforded aldehyde
27 (599 mg, 81%) as a viscous oil which had [α]2D0 Ϫ10.7
(c 1.238); νmax/cmϪ1 2946, 2743, 1721, 1709, 1599, 1470, 1391,
1369, 1230, 1159, 1071 and 908; δH (200 MHz) 1.03 (s, 3H), 1.08
(s, 3H), 1.11 (s, 3H), 1.20–2.05 (m, 6H), 2.67 (dd, J 16.6, 3.3,
1H), 2.78 (dd, J 16.6, 2.0, 1H), 6.14 (d, J 5.8, 1H), 7.38 (d, J 5.8,
1H) and 9.73 (dd, J 3.3, 2.0, 1H).
[α]2D0 ϩ120.9 (c 0.412); mp 83.5–84.5 ЊC (from n-hexane); νmax
/
cmϪ1 2951, 1743, 1475, 1462, 1387, 1258, 1140 and 1030; δH
(200 MHz) 0.03 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 0.92 (s, 3H),
1.03 (s, 3H), 1.13 (s, 3H), 1.35–1.69 (m, 6H), 1.84 (ddd, J 12.4,
3.2, 3.2, 1H), 1.97 (dd, J 18.6, 8.2, 1H), 2.41 (ddd, J 18.6, 8.2,
1.0, 1H) and 3.83 (dd, J 8.2, 8.2, 1H); δC (50 MHz) Ϫ4.9 (q),
Ϫ4.5 (q), 13.6 (q), 18.1 (s), 19.2 (t), 21.5 (q), 25.8 (q × 8),
32.1 (q), 32.3 (s), 37.6 (t), 41.9 (t), 44.1 (t), 44.2 (s), 66.2 (d),
76.8 (d) and 211.8 (s) (Found: C, 69.82; H, 11.10%. Calc. for
C18H34O2Si: C, 69.62; H, 11.04%).
(1R,6R,7S,11S)-(؊)-11-Hydroxy-2,2,6-trimethyltricyclo-
[5.2.2.01,6]undecan-9-one 30 and (1R,6R,7S,11R)-(؊)-11-
hydroxy-2,2,6-trimethyltricyclo[5.2.2.01,6]undecan-9-one 31
(3aS,7aR)-(؊)-3a,7,7-Trimethyl-3a,4,5,6,7,7a-hexahydroinden-
1-one 24
From the ketone 21. To a stirred solution of the ketone 21
(91 mg, 0.293 mmol) in absolute t-BuOH (4 ml) was added
DBU (180 µl, 1.20 mmol) at room temperature under a nitrogen
atmosphere. The resulting solution was heated at reflux tem-
perature overnight and then passed through a short silica gel
column. Evaporation of the solvent in vacuo followed by col-
umn chromatography (eluent ethyl acetate–n-hexane = 1 : 5) of
the residue gave enone 24 (47 mg, 90%) as white crystals which
had [α]2D0 Ϫ85.2 (c 1.038); mp 30.5–32.0 ЊC (from n-hexane);
νmax/cmϪ1 3081, 2967, 1712, 1597, 1465, 1377, 1265, 1147 and
953; δH (200 MHz) 0.94 (s, 3H), 1.20 (s, 6H), 1.22–1.48 (m, 2H),
1.50–1.75 (m, 4H), 1.80 (s, 1H), 6.00 (d, J 5.7, 1H) and 7.38 (d,
J 5.7, 1H); δC (50 MHz) 17.4 (t), 24.7 (q), 29.0 (q), 31.6 (t), 32.8
(q), 35.9 (t), 61.8 (d), 131.6 (d) and 172.3 (d).
To a stirred solution of the aldehyde 27 (230 mg, 1.04 mmol),
absolute t-BuOH (121 µl, 1.25 mmol) and HMPA (4.0 ml) in
THF (40 ml) was added SmI2 (31.3 ml, 3.13 mmol, 0.1 M sol-
ution in THF) at Ϫ78 ЊC under a nitrogen atmosphere. After
being stirred for 15 min, the reaction was quenched by addition
of N,N Ј-dimethylaminoethanol (4 ml) and silica gel, and
stirring was continued for 1 h at room temperature. The reac-
tion mixture was passed through a short silica gel column.
Evaporation of the solvent in vacuo followed by MPLC (eluent
ethyl acetate–n-hexane = 3 : 2) purification of the residue
afforded tricyclic alcohol 31 (44 mg, 19%) as white needles and
isomeric tricyclic alcohol 30 (101 mg, 43%) as white needles in
the order of elution.
The alcohol 31 had mp 111–113 ЊC; [α]2D0 Ϫ32.2 (c 0.460);
νmax/cmϪ1 3630, 3465, 2947, 2870, 1744, 1468, 1227, 1080, 1029
and 995; δH (500 MHz) 0.90 (s, 3H), 1.14 (s, 3H), 1.20 (s, 3H),
From the ketone 22. To a stirred solution of the ketone 22
(106 mg, 0.340 mmol) in absolute t-BuOH (4.5 ml) was added
J. Chem. Soc., Perkin Trans. 1, 2002, 583–591
589

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1.05–1.20 (m, 2H), 1.29–1.39 (m, 2H), 1.46 (m, 1H), 1.57–1.71
(m, 3H), 2.04 (dd, J 4.5, 4.5, 1H), 2.20 (dddd, J 18.5, 4.9, 0.8,
0.8, 1H), 2.39 (dd, J 14.0, 10.0, 1H), 2.58 (d, J 18.5, 1H) and
4.67 (m, 1H); δC (50 MHz) 18.4, 21.4, 24.2, 26.2, 30.6, 32.8,
32.9, 34.9, 35.8, 48.6, 49.2, 64.1, 70.2 and 218.7 (Found:
C, 75.44; H, 10.10%. Calc. for C14H22O2: C, 75.63; H, 9.97%).
The alcohol 30 had mp 117–120 ЊC; [α]2D0 Ϫ28.3 (c 0.512);
νmax/cmϪ1 3627, 3011, 2870, 1744, 1433, 1073, 1040 and 970;
δH (500 MHz) 0.97 (s, 3H), 1.20 (s, 3H), 1.10–1.25 (m, 3H), 1.35
(s, 3H), 1.43 (br d, J 13.5, 1H), 1.48 (br d, J 13.5, 1H), 1.54
(d, J 18.5, 1H), 1.70 (m, 1H), 1.82 (dd, J 14.0, 7.2, 1H), 1.87 (dd,
J 14.0, 3.5, 1H), 2.01 (br d, J 5.1, 1H), 2.24 (br s, 1H), 2.35 (ddd,
J 18.5, 5.1, 0.9, 1H) and 4.01 (dd, J 7.2, 3.5, 1H); δC (50 MHz)
18.4, 21.9, 24.7, 26.4, 31.3, 32.4, 33.2, 35.8, 40.2, 48.1, 49.8,
64.1, 75.7 and 218.8 (Found: C, 75.49; H, 10.06%. Calc. for
C14H22O2: C, 75.63; H, 9.97%).
was washed with water and brine and dried over anhydrous
Na2SO4. Evaporation of the solvent in vacuo followed by puri-
fication of the residue on a short silica gel column and MPLC
(eluent ethyl acetate–n-hexane = 1 : 1) provided alcohol 33
(22 mg, 90%, 34a–34b = 1 : 2.3) as white crystals.
The exo-methyl alcohol 34 had mp 142–143 ЊC; [α]2D0 Ϫ37.2
(c 0.344); νmax/cmϪ1 3640, 2930, 2872, 1732, 1453 and 1016;
δH (200 MHz) 0.98 (s, 3H), 1.05–2.10 (m, 11H), 1.18 (3H, s),
1.25 (d, 3H, J 7.1), 1.35 (s, 3H) and 4.30 (dd, J 6.2, 4.3, 1H);
δC (50 MHz) 17.3, 18.8, 21.8, 24.9, 26.2, 32.2, 32.6, 33.1, 35.4,
45.3, 48.1, 56.3, 63.7, 77.1 and 221.3; m/z 236 (Mϩ, 22%), 163
(74), 123 (100), 95 (38), 69 (30) and 41 (51) (Found: Mϩ,
236.1705. Calc. For C15H24O2: Mϩ, 236.1776).
The endo-methyl alcohol 34b had mp 110–112 ЊC; [α]2D0 Ϫ3.4
(c 0.409); νmax/cmϪ1 3635, 2951, 2872, 1731, 1468, 1452 and
1006; δH (200 MHz) 0.97 (s, 3H), 1.01 (d, J 7.2, 3H), 1.05–2.05
(m, 10H), 1.22 (s, 3H), 1.40 (s, 3H), 2.59 (qd, J 7.2, 4.9, 1H)
and 4.30 (dd, J 7.7, 3.4, 1H); δC (50 MHz) 11.4, 18.5, 22.3,
24.7, 26.5, 30.3, 33.5, 33.9, 36.3, 41.9, 47.6, 54.5, 64.8, 69.3 and
221.9; m/z 236 (Mϩ, 23%), 193 (6), 163 (77), 123 (100), 95 (38)
and 41 (51) (Found: Mϩ, 236.1744. Calc. For C15H24O2: Mϩ,
236.1776).
(1R,6R,7S,11R)-2,2,6-Trimethyl-11-(1,1,2,2-tetramethyl-1-
silapropoxy)tricyclo[5.2.2.01,6]undecan-9-one 32
To a stirred solution of the alcohol 30 (26 mg, 0.116 mmol)
in DMF (2 ml) was successively added imidazole (16 mg,
0.239 mmol), a catalytic amount of DMAP and TBDMSCl
(54 mg, 0.359 mmol) at room temperature under a nitrogen
atmosphere. After being stirred overnight, the reaction was
quenched by addition of aq. ammonium chloride and the
aqueous layer was extracted with ethyl acetate four times. The
combined organic layer was washed with water and brine and
dried over anhydrous Na2SO4. Evaporation of the solvent in
vacuo followed by column chromatography (eluent ethyl
acetate–n-hexane = 1 : 10) of the residue provided TBDMS
ether 32 (37 mg, 94%) as a colorless oil which had [α]2D0 ϩ3.2
(c 1.046); νmax/cmϪ1 2960, 2861, 1734, 1460, 1260, 1159 and
1015; δH (200 MHz) 0.05 (s, 6H), 0.89 (s, 9H), 0.97 (s, 3H), 1.20
(s, 3H), 1.34 (s, 3H), 1.10–1.96 (m, 10H), 2.34 (dd, J 18.4, 5.3,
1H) and 3.87 (dd, J 6.4, 4.2, 1H); m/z 336 (Mϩ, 26%), 279
(100), 251 (11), 211 (14), 187 (13), 161 (23), 123 (12), 75 (52)
and 41 (15) (Found: Mϩ, 336.2533. Calc. for C20H36O2Si: Mϩ,
336.2484).
(1R,6R,7S,8S,11R)-2,2,6,11-Tetramethyl-10-oxotricyclo-
[5.2.2.01,6]-8-undecyl methane sulfonate 35
To a solution of the alcohol 34 (9 mg, 0.038 mol) in DCM
(1 ml) was added DMAP (0.5 mg, 0.004 mol), triethylamine
(13 µl, 0.094 mol) and methanesulfonyl chloride (6 µl,
0.075 mol) at 0 ЊC under a nitrogen atmosphere. After being
stirred at room temperature overnight, the reaction mixture was
directly chromatographed on a short silica gel column. After
evaporation of solvent, purification of the residue by MPLC
(eluent ethyl acetate–n-hexane = 1 : 1) provided mesylate 35
(9 mg, 76%) as a colourless oil which had δH (200 MHz) 0.99
(s, 3H), 1.20 (s, 3H), 1.30 (s, 3H), 1.30 (d, J 7.2, 3H), 1.05–1,85
(m, 7H), 2.05–2.20 (m, 2H), 2.29 (s, 1H), 3.05 (s, 3H) and 4.78
(dd, J 7.1, 3.3, 1H); δC (50 MHz) 11.3 (q), 18.3 (t), 21.9 (q), 24.6
(q), 26.4 (q), 29.8 (t), 31.9 (t), 33.5 (s), 36.0 (t), 38.5 (q), 41.7 (d),
47.7 (s), 53.0 (d), 60.3 (s) 78.5 (d) and 219.5 (s).
(1R,6R,7S,8RS,11R)-2,2,6,8-Tetramethyl-11-(1,1,2,2-tetra-
methyl-1-silapropoxy)tricyclo[5.2.2.01,6]undecan-9-one 33
(1R,6R,7S,8R,11R)-2,2,6,11-Tetramethyl-10-oxotricyclo-
[5.2.2.01,6]-8-undecyl methanesulfonate 35b
To a stirred solution of hexamethyldisilazane (118 µl, 0.562
mmol) in THF (1.5 ml) was added a solution of n-BuLi (317 µl,
0.499 mmol, 1.58 M solution in n-hexane) at 0 ЊC under a nitro-
gen atmosphere. After being stirred for 20 min, a solution of the
ketone 32 (42 mg, 0.125 mmol) in THF (2.0 ml) was added and
the resulting solution was stirred for 30 min at 0 ЊC. MeI (23 µl,
0.374 mmol) was added and stirring was continued for 35 min.
The reaction was quenched by addition of aq. ammonium
chloride and the aqueous layer was extracted with ethyl acetate
twice. The combined organic layer was washed with water and
brine and dried over anhydrous Na2SO4. Evaporation of the
solvent in vacuo followed by purification of the residue on short
silica gel column and MPLC (eluent ethyl acetate–n-hexane =
1 : 10) provided inseparable mixture of TBDMS ether 33
(36 mg, 83%) as a colorless oil which had δH (200 MHz) 0.05
(s, 6H), 0.90 (s, 9H), 0.98 (s, 1H), 1.18 (s, 0.3H), 1.22 (s, 0.7H),
1.34 (s, 0.3H), 1.38 (s, 0.7H), 1.00–1.95 (m, 12.3H), 2.55
(m, 0.7H), 3.91 (m, 0.3H) and 4.18 (dd, J 7.3, 3.0, 0.7H).
To a solution of the alcohol 34b (23 mg, 0.098 mmol) in DCM
(1 ml) was added DMAP (1.2 mg, 0.010 mol), triethylamine
(34 µl, 0.244 mol) and methanesulfonyl chloride (15 µl,
0.195 mol) at 0 ЊC under nitrogen atmosphere. After being
stirred at room temperature overnight, the reaction mixture was
directly chromatographed on a short silica gel column. After
evaporation of solvent, purification of the residue by MPLC
(eluent ethyl acetate–n-hexane = 1 : 1) provided mesylate 35
(29 mg, 94%) as a colorless oil which had δH (200 MHz) 0.98
(s, 3H), 1.10 (d, J 7.24, 3H), 1.23 (s, 3H), 1.15–1.80 (m, 6H),
1.92 (dd, J 14.9, 8.0, 1H), 2.21 (ddd, J 14.8, 3.2, 1.3, 1H), 2.38
(d, J 5.1, 1H), 2.78 (qd, J 7.3, 5.1, 1H), 3.03 (s, 3H) and 5.13
(dd, J 8.0, 3.2, 1H); δC (50 MHz) 17.1 (q), 18.7 (t), 21.6 (q), 24.8
(q), 26.0 (q), 30.6 (q), 32.0 (q), 33.0 (s), 35.1 (t), 38.5 (q), 44.6
(d), 48.2 (s), 54.3 (d), 63.1 (s), 83.4 (d) and 218.8 (s).
(1R,6R,7S,8R,11S)-2,2,6,9-Tetramethyltetracyclo-
[6.2.1.01,6.07,9]undecan-10-one ؍ (cyclomyltaylan-5-one 36
(1R,6R,7S,8RS,11R)-11-Hydroxy-2,2,6,8-tetramethyltricyclo-
[5.2.2.01,6]undecan-9-one 34
From the mesylate 35. To a stirred solution of sodium meth-
oxide prepared from NaH (4 mg, 0.086 mol, 60% in mineral oil)
in anhydrous ethanol (0.3 ml) was added a solution of the
mesylate 35 (9 mg, 0.029 mol) in ethanol (1 ml) at room tem-
perature under a nitrogen atmosphere. After being stirred for
2 h, the reaction was quenched by addition of aq. ammonium
chloride and the aqueous layer was extracted with ethyl acetate
twice. The combined organic layer was washed with water and
To a solution of the TBDMS ether 33 (36 mg, 0.104 mmol)
in THF (2 ml) was added TBAF (520 µl, 0.520 mmol, 1.0 M
solution in THF) at room temperature under a nitrogen atmos-
phere. After being stirred for 3 h, the reaction was quenched by
addition of aq. ammonium chloride and the aqueous layer was
extracted with ethyl acetate twice. The combined organic layer
590
J. Chem. Soc., Perkin Trans. 1, 2002, 583–591

View Article Online
brine and dried over anhydrous Na2SO4. Evaporation of the
solvent in vacuum followed by purification of the residue by
MPLC (eluent ethyl acetate–n-hexane = 1 : 30) provided ketone
36 (5 mg, 77%) as a colorless oil which had [α]2D0 ϩ22.5 (c 0.730);
νmax/cmϪ1 2944, 2894, 1734, 1458, 1377, 1225, 968 and 885;
δH (200 MHz) 0.83 (s, 3H), 1.07 (s, 3H), 1.08 (s, 3H), 1.10
(s, 3H), 1.10–1.20 (m, 2H), 1.40–1.65 (m, 4H) and 1.70–
1.95 (m, 4H); δC (125 MHz) 8.85, 18.78, 21.43, 25.31, 25.47,
26.78, 27.05, 28.44, 31.30, 33,43, 35.31, 39.17, 44.45, 55.75 and
215.98.
Thanks are also due to Soda Aromatics Co. for mass spectral
measurements.
References
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with water and brine and dried over anhydrous Na2SO4. Evap-
oration of the solvent in vacuo followed by purification of
the residue by MPLC (eluent ethyl acetate–n-hexane = 1 : 10)
provided ketone 36 (19 mg, 93%) as a colorless oil.
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(1R,6R,7S,8R,11S)-2,2,6,9-Tetramethyltetracyclo-
[6.2.1.01,6.07,9]undecan-10-ol ؍ (؉)-cyclomyltaylan-5ꢀ-ol 1
To a solution of the ketone 36 (12 mg, 0.056 mol) in ether (1 ml)
was added LAH (3 mg, 0.084 mol) at 0 ЊC under a nitrogen
atmosphere. After being stirred for 30 min, the reaction was
quenched by addition of aq. ammonium chloride and the
organic layer was dried over anhydrous Na2SO4. Evaporation
of the solvent in vacuum gave the residue which was purified by
MPLC (eluent ethyl acetate–n-hexane = 1 : 5) to afford (ϩ)-
cyclomyltaylan-5α-ol 1 (10 mg, 81%) which had [α]2D0 ϩ32.9 (c
0.307); δH (500 MHz) 0.89 (s, 3H), 0.89–0.90 (m, 1H), 0.93 (d,
5.5), 0.98 (s, 3H), 1.01 (s, 3H), 1.13 (s, 3H), 1.13–1.18 (m, 1H),
1.22 (dd, J 10.8, 1.0, 1H), 1.32–1.36 (m, 1H), 1.36 (dd, J 10.8,
1.0, 1H), 1.47 (m, 1H), 1.60 (ddddd, J 13.6, 13.6, 13,6, 4.2, 4.2,
1H), 1.88 (ddd, J 13.6, 13.6, 4.8, 1H), 1.99 (ddd, J 13.6, 13.6,
4.3, 1H) and 3.64 (br d, J 4.5, 1H); δC (125 MHz) 12.74 (q),
17.79 (d), 19.18 (t), 23.16 (q), 23.27 (s), 25.75 (q), 28.00 (t),
29.33 (q), 32.09 (s), 32.57 (t), 34.41 (d), 37.26 (t), 45.30 (s), 51.95
(s) and 86.02 (d).
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Acknowledgements
We thank Professor C.-L. Wu, Tamkang University, Taiwan for
spectral data of natural cyclomyltaylan-5α-ol 1 and Professor
E. Hasegawa, Department of Chemistry, Faculty of Science,
Niigata University for helpful discussions on Sm chemistry.
J. Chem. Soc., Perkin Trans. 1, 2002, 583–591
591