Asymmetric total synthesis of (+)-equilenin utilizing two types of cascade ring expansion reactions of small ring systems

Article abstract of DOI:10.1039/b003578p

Enantioselective synthesis of (+)-equilenin 1 utilizing two types of cascade ring expansion reactions of small ring systems is described.The first key step is an asymmetric epoxidation-ring expansion reaction of cyclopropylidene derivatives to afford chiral cyclobutanones. We found that both the fructose-derived chiral ketone and the chiral (salen)Mn(III) complex were effective catalysts for the asymmetric induction. The second key step is the palladium-promoted cascade ring expansion-intramolecular insertion reaction of the isopropenylcyclobutanol. Solvents were an important factor for the diastereoselective formation of hydrindanes. By utilizing these methodologies, the asymmetric total synthesis of (+)-equilenin 1 has been accomplished. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b003578p

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Asymmetric total synthesis of (؉)-equilenin utilizing two types
of cascade ring expansion reactions of small ring systems
Masahiro Yoshida, Mohamed Abdel-Hamid Ismail, Hideo Nemoto† and Masataka Ihara*
1
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578, Japan
Received (in Cambridge, UK) 4th May 2000, Accepted 14th June 2000
Published on the Web 24th July 2000
Enantioselective synthesis of (ϩ)-equilenin 1 utilizing two types of cascade ring expansion reactions of small ring
systems is described. The first key step is an asymmetric epoxidation–ring expansion reaction of cyclopropylidene
derivatives to afford chiral cyclobutanones. We found that both the fructose-derived chiral ketone and the chiral
(salen)Mn() complex were effective catalysts for the asymmetric induction. The second key step is the palladium-
promoted cascade ring expansion–intramolecular insertion reaction of the isopropenylcyclobutanol. Solvents
were an important factor for the diastereoselective formation of hydrindanes. By utilizing these methodologies,
the asymmetric total synthesis of (ϩ)-equilenin 1 has been accomplished.
Introduction
Steroids are one of the most widely distributed groups of
natural products and display a variety of physiological activ-
ities.1 Since the first total synthesis of equilenin was achieved
by Bachmann et al. in 1939,2 numerous synthetic strategies for
steroids have been developed over the second half of the twen-
tieth century.3 Several elegant approaches have been developed
which could construct the steroidal framework in a single step,
such as cationic cyclisation,4 transition metal promoted reac-
tion,5 radical cyclisation,6 and the double Michael reaction.7
These ‘cascade’ reactions are effective methods to synthesise
steroids. However, the number of total syntheses of steroids is
rather limited compared to the volume of literature dealing
with the partial synthesis of steroids and selective functionaliz-
ations of the steroidal tetracycles.8
Here we describe a novel strategy for the enantioselective
synthesis of the steroid (ϩ)-equilenin 1, using two types of
cascade ring expansion reactions of small ring systems.9 The
first ring expansion reaction is the asymmetric epoxidation–ring
expansion reaction, which involves the asymmetric epoxidation
of an aryl-substituted cyclopropylidene derivative to form
the chiral oxaspiropentane, followed by its enantiospecific
rearrangement to the chiral cyclobutanone (Scheme 1).10 For
Scheme 2 Pd()-promoted cascade ring expansion–insertion reaction.
propenyl group to a palladium() complex, followed by ring
expansion of the cyclobutanol ring, insertion of the olefin, and
elimination of palladium to construct the desired steroidal
framework in a single step.
Results and discussion
Synthetic plan
Scheme 3 shows our retrosynthetic analysis of (ϩ)-equilenin
1. The naphthalene-fused trans-hydrindane‡ 2, which is the
important intermediate for the synthesis of (ϩ)-equilenin,
could be constructed by the palladium-promoted cascade ring
expansion and insertion process of the isopropenylcyclo-
butanol derivative 3. It was anticipated that the desired fused
hydrindane 2 could be stereoselectively obtained by the proper
choice of reagents and reaction conditions. The chiral cyclo-
butanone 4, a precursor of 3, could be prepared via asymmetric
epoxidation–ring expansion reaction from the cyclopropylidene
derivative 5, which would be derived from the 1-hydroxy-2-
naphthaldehyde 6.
Scheme 1 Cascade asymmetric epoxidation–ring expansion reaction.
methods of asymmetric induction, we have utilised Shi’s
fructose-derived chiral ketone with Oxone11 or Jacobsen’s
chiral (salen)Mn() complex with NaClO,12 which are excellent
reagents for asymmetric epoxidation reactions. The second ring
expansion reaction is the palladium-promoted ring expansion–
insertion reaction of isopropenylcyclobutanols, the method-
ology of which has been previously reported by us (Scheme
2).13,14 This reaction was initiated by coordination of the iso-
Synthesis of chiral cyclobutanone
Our investigations began with the enantioselective synthesis
† Present address: Faculty of Pharmaceutical Sciences, Toyama
Medical and Pharmaceutical University, Suginami 2630, Toyama
930-0194, Japan.
‡ IUPAC name for hydrindane is hexahydroindane.
DOI: 10.1039/b003578p
J. Chem. Soc., Perkin Trans. 1, 2000, 2629–2635
This journal is © The Royal Society of Chemistry 2000
2629

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Table 1 Asymmetric epoxidation–ring expansion reaction using chiral ketone 9a
ent-4
10
Oxone
(equiv.)
Recovered
5 (%)
Entry
9 (equiv.)
Solvent
pH
Yield (%)
Ee (%)b
Yield (%)
Ee (%)b
1
2
3
4
1.0
1.0
1.0
0.2
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
CH3CN
DME
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
10.5
10.5
10.5
10.5
10.5
9.0
24
61
37
43
40
—
—
33
—
—
—
30
61
—
50
—
—
—
60
63
—
19
33
43
22
—
—
60
57
40
34
53
—
—
72
5
6c
7
10.5
a The reaction was carried out using substrate 5, chiral ketone 9, Oxone, and K2CO3 in solvent–0.05 M Na2B4O7ؒ10H2O of aqueous Na2(EDTA)
(4 × 10Ϫ4 M) solution (1:1 v/v) at 0 ЊC for 1 h. b Enantiomeric excess was determined by HPLC chiral column (Chiralcel OA). c Instead of K2CO3,
NaOH was used to maintain the reaction pH at 9.0.
Scheme 4 Reagents and conditions: a, Tf2O, DMAP, pyridine, 0 ЊC,
61%; b, tri-n-butyl(vinyl)stannane, Pd(PPh3)4, LiCl, THF, reflux, 98%;
c, cyclopropylidenetriphenylphosphorane, NaH, THF, 62 ЊC, 70%.
were observed by using 2 equiv. of 9 (entry 5). Furthermore,
when the reaction was carried out at pH 9.0, the substrate was
completely consumed to give ent-4 with 63% ee in 61% yield
(entry 6). Interestingly, the lactone 10 was exclusively obtained
with 72% ee in 60% yield by using 2 equiv. of Oxone at pH 10.5
(entry 7). This is a novel method to synthesise the chiral
γ-butyrolactones from cyclopropylidene derivatives in a one-
Scheme 3 Retrosynthesis of (ϩ)-equilenin.
pot process.17
of the cyclobutanone 4 by the asymmetric epoxidation–ring
expansion reaction of cyclopropylidene derivative 5. The sub-
strate 5 was synthesised as follows (Scheme 4). The triflate 7,
prepared from 1-hydroxy-2-naphthaldehyde 615 (61% yield),
was subjected to the Stille reaction16 with tri-n-butyl(vinyl)-
stannane to give the vinylnaphthaldehyde 8 (98% yield). Sub-
sequently, the Wittig cyclopropylidenation of 8 provided the
cyclopropylidene derivative 5 in 70% yield.
Next, the asymmetric epoxidation reaction was attempted
using the chiral (salen)Mn() complex (Scheme 5). When a
With the substrate 5 in hand, asymmetric epoxidation using
the fructose-derived ketone 9 and Oxone11 was first examined.
The results are summarized in Table 1. When the reaction was
carried out using 1 equiv. of 9 and Oxone in CH3CN–H2O
(adjusted to pH 10.5), the expected reaction proceeded to give
the chiral cyclobutanone ent-4 in 33% yield with 50% ee (entry
1). The lactone 10, which would be the product of further
oxidation, was also obtained as a byproduct along with the
recovered substrate 5. When the reactions were performed in
DME and dioxane, only the lactone 10 was obtained with low
ee in poor yield (entries 2 and 3). An attempt to use a catalytic
amount of chiral ketone 9 (0.2 equiv.) failed (entry 4). However,
considerable improvements in the yield and enantiomeric excess
Scheme 5 Asymmetric epoxidation–ring expansion reaction using
chiral (salen)Mn complex 12.
mixture of 5, 5 mol% of (R,R)-(salen)Mn() complex 12 and
4-phenylpyridine N-oxide (4-PPNO) in CH2Cl2 was treated
with NaClO as the oxidant at 0 ЊC, the reaction successfully
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J. Chem. Soc., Perkin Trans. 1, 2000, 2629–2635

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desired enantiomer 4. Therefore, we decided to utilize this
method for the synthesis of (ϩ)-equilenin 1.
Diastereoselective construction of a naphthalene-fused
hydrindane
Next, our attention was focused on the diastereoselective con-
struction of the naphthalene-fused trans-hydrindane. We have
already developed the palladium-promoted ring expansion–
insertion reaction, which can synthesize benzene- and
naphthalene-fused hydrindanes in a one-pot process.13 How-
ever, several issues need to be addressed before utilizing
this reaction in the synthesis of (ϩ)-equilenin; (1) the
naphthalene–hydrindanes were not stereoselectively obtained
from isopropenylcyclobutanol; (2) the olefin-isomerized prod-
ucts were obtained as the major products. To overcome these
hurdles, we closely scrutinized the reaction conditions in
order to construct the naphthalene-fused trans-hydrindane
diastereoselectively from 1813 (Table 2). These studies
revealed that the olefin isomerization could be effectively
suppressed by using Pd(OAc)2 (entry 2) instead of
13
PdCl2(MeCN)2 (entry 1). Furthermore, we were delighted to
find that the diastereoselectivity could be controlled by the
proper choice of the solvent. Thus, in non-polar solvents
such as toluene, the fused cis-product 2113 was predomin-
antly produced (entry 3). In contrast, both the fused
trans- and cis-products 1913 and 21 were formed in polar
solvents such as DMF, THF, DMPU, NMP (entries 2, 4, 5
and 6). In particular, the trans-product 19 was selectively
provided by using a mixture of HMPA and THF (entries 7
and 8).
Fig. 1
proceeded to provide the desired chiral cyclobutanone 4 with
a fair enantiomeric excess in a moderate yield (78% ee, 55%
yield). Furthermore, when the reaction was carried out utilizing
the demethoxylated substrate 11, the corresponding cyclo-
butanone 13 was obtained with a high enantiomeric excess
(93% ee, 67% yield).
The absolute configuration of 4 was determined by the
improved Mosher’s method developed by Kusumi et al.18 Thus,
reduction of 4 with NaBH4 led to the cyclobutanol 14 and its
diastereomer 15 in 61 and 35% yields (Scheme 6). The stereo-
Scheme 7 shows the proposed mechanisms for the diastereo-
Scheme 7 Proposed mechanisms for diastereoselectivities observed.
selectivity observed in the above process. It is presumed that the
selectivity of the products depends on the conformation of the
isopropenyl group during the cascade reaction. Thus, the ring
expansion reaction would proceed via the intermediate TS A in
a non-polar solvent such as toluene to give the cis-product 21,
in which the palladium would be associated with both the olefin
and the hydroxy group. In contrast, in the case of polar solvents
such as HMPA, the reaction would take place via TS B to afford
the trans-product 19, in which the palladium would be associ-
ated with only the olefin because the solvent coordinates to
palladium as a ligand.
Scheme 6 Reagents and conditions: a, NaBH4, MeOH, rt, 61% of 14
and 35% of 15; b, (R)-MTPA, DCC, DMAP, CH2Cl2, rt, quant.;
c, (S)-MTPA, DCC, DMAP, CH2Cl2, rt, quant.
chemistries of 14 and 15 were determined by 1H-NOESY.
When the major isomer 14 was treated with (R)- and (S)-MTPA
[α-methoxy-α-(trifluoromethyl)phenylacetic acid], the corre-
sponding MTPA esters 16 and 17 were formed in quantitative
yield. On the basis of the ∆δ values (∆δ = δ(S)-ester Ϫ δ(R)-ester), the
absolute configuration of 4 was determined as S (Fig. 1).
It has been made clear that the method using chiral (salen)-
Mn() catalyst 12 is more suitable for the production of the
Asymmetric total synthesis of (؉)-equilenin
With an efficient method for the chiral synthesis of the
naphthalene-fused hydrindane in hand, we investigated the
asymmetric total synthesis of (ϩ)-equilenin 1. Thus,
the chiral cyclobutanone 4, which was obtained with 78%
ee in 55% yield from 5, was stereoselectively converted to
J. Chem. Soc., Perkin Trans. 1, 2000, 2629–2635
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Table 2 Cascade ring expansion and insertion reactions of 18a
Product
Entry
Reagent
Solvent
Time/h
19:20:21:22b
trans:cisc
Yield (%)
1d
2
3
4
5
6
7
8
PdCl2(CH3CN)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMF
DMF
Toluene
THF
DMPU
NMP
HMPA–THF = 9:1
HMPA–THF = 4:1
10
10
10
10
10
10
10
10
4:48:15:33
47:5:43:5
3:0:88:9
34:18:41:7
46:18:36:0
52:8:36:4
58:15:25:2
61:14:24:1
52:48
52:48
3:97
52:48
64:36
60:40
73:27
75:25
56
61
61
36
81
52
47
61
a The reaction was carried out under argon at room temperature by using an equimolar amount of reagent. b The isomer ratios were determined by
1H NMR integration of angular methyl signals (δ 0.55 for 19, δ 0.67 for 20, δ 1.19 for 21 and δ 1.15 for 22). c trans:cis is equal to 19 ϩ 20:21 ϩ 22.
d This result has been previously reported by us (see ref. 13).
the isopropenylcyclobutanol 3 by Grignard reaction with
isopropenylmagnesium bromide in the presence of cerium tri-
chloride19 (82% yield) (Scheme 8). The stereochemistry of 3 was
determined by an NOE experiment. Next, the palladium-
promoted cascade ring expansion–insertion reaction was
examined. When 3 was treated with Pd(OAc)2 in HMPA–THF
(1:4), a 73:27 mixture of the trans- and cis-fused products 2
and 23 was obtained in 60% yield. To complete the synthesis of
equilenin, the mixture of 2 and 23 was exposed to osmium
tetraoxide and sodium periodate to furnish the diketone 24 in
59% yield, after separation of the diastereomer. Finally, the
selective reduction of the benzylic ketone of 24 was performed
20
by hydrogenolysis on Pt/C in the presence of PdCl2 to afford
equilenin methyl ether 25 (82% yield), which could be purified
as in an optically pure form by recrystallization. Since 25 had
been converted to 1 by treatment with boron tribromide,21 our
asymmetric synthesis of (ϩ)-equilenin 1 was complete.
Conclusion
In summary, we have established a novel method for the
enantioselective synthesis of steroidal frameworks utilizing two
types of cascade ring expansion reactions of small ring systems,
which has been successfully applied to the total synthesis of
(ϩ)-equilenin 1. (ϩ)-Equilenin 1 was synthesized from the
readily available naphthaldehyde 6 in 9 steps. The key features
of the synthetic strategy include (1) the chiral (salen)Mn()
complex or fructose-derived chiral ketone catalysed cascade
asymmetric epoxidation–ring expansion reaction of cyclo-
propylidene derivatives affording chiral cyclobutanones, and (2)
the stereoselective formation of naphthalene-fused hydrindanes
via a cascade ring expansion–olefin insertion reaction using
palladium catalysts.
Scheme 8 Reagents and conditions: a, isopropenylmagnesium bromide,
CeCl3, THF, Ϫ78 ЊC, 82%; b, Pd(OAc)2, HMPA–THF (1:4), rt, 60%,
2:23 = 73:27 and 7% of endo-olefin isomer; c, OsO4, NaIO4, acetone–
H2O, 59% from 2; d, H2, Pt/C, PdCl2, EtOH, rt, 82%.
graphy was performed on silica gel 60N (Merck, 100–210
mesh, 60 Å), and flash column chromatography was per-
formed on silica gel 60 (Merck, 40–100 mesh, 60 Å) using
the indicated solvent. A Shimazdu LC-10AD instrument was
employed for HPLC, equipped with a Shimadzu SPD-10A
as a UV detector at 254 nm. CHIRALCEL OA (0.46 × 25
cm, Daicel Chemical) was used as an HPLC chiral column.
All melting points were determined on a Yanaco micro melt-
ing point apparatus and are uncorrected. Optical rotations
were measured with a Horiba SEPA-300 high sensitive
Experimental
All non-aqueous reactions were carried out under a positive
atmosphere of argon or nitrogen in dried glassware unless
otherwise indicated. Materials were obtained from commercial
suppliers and used without further purification except when
otherwise noted. Solvents were dried and distilled according
to standard procedures. The phrase ‘residue upon work-up’
refers to the residue obtained when the organic layer was
separated and dried over anhydrous MgSO4 and the solvent
was evaporated under reduced pressure. Column chromato-
polarimeter and are given in units of 10Ϫ1 deg cm2 gϪ1
.
IR spectra were measured on a JASCO IR Report-100
spectrometer. NMR spectra were recorded on a Hitachi R-300,
Varian Gemini 2000, or JEOL JNM-GX 500 spectrometer
with tetramethylsilane or chloroform as an internal standard.
Mass spectra were recorded on a JEOL JMS-DX-303 or JMS-
AX-500 spectrometer.
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6-Methoxy-1-trifluoromethylsulfonyloxynaphthalene-2-carb-
aldehyde 7
buffer (2 mL) [0.05 M Na2B4O7ؒ10H2O in 4 × 10Ϫ4 M aqueous
Na2(EDTA), adjusting with 1.0 M aqueous KH2PO4 for pH
9.0], tetrabutylammonium hydrogen sulfate (4.4 mg, 0.013
mmol) and the ketone 9 (61.5 mg, 0.252 mmol). After the reac-
tion mixture had been cooled to 0 ЊC, a solution of Oxone (78.0
mg, 0.126 mmol) in aqueous Na2(EDTA) (4 × 10Ϫ4 M, 1.5 mL)
was added dropwise over a period of 1.5 h, while the reaction
pH was maintained at pH 9.0 by addition of 0.5 M aqueous
NaOH. After the stirring had been continued for 1 h at the
same temperature, the reaction mixture was diluted with water
and extracted with AcOEt. The combined extracts were washed
with saturated aqueous NaCl. The residue upon work-up was
chromatographed on silica gel with hexane–AcOEt (95:5 v/v)
as eluant to give the cyclobutanone ent-4 (19.4 mg, 61% yield,
63% ee) as a colourless oil, [α]D25 Ϫ28.5 (c 0.1 in CHCl3);
νmax(neat)/cmϪ1 1780; δH(300 MHz, CDCl3) 2.21–2.22 (1H, m,
COCH2CHH), 2.24–2.55 (1H, m, COCH2CHH), 3.07–3.13
(1H, m, COCHH), 3.18–3.27 (1H, m, COCHH), 3.91 (3H, s,
OMe), 4.95–5.05 (1H, m, COCH), 5.44 (1H, dd, J = 18.0
and 2.2 Hz, CHCHH), 5.76 (1H, dd, J = 12.0 and 2.2 Hz,
CHCHH), 7.08 (1H, dd, J = 18.0 and 12.0 Hz, CHCH2), 7.11–
7.15 (2H, m, 2 × ArH), 7.35 (1H, d, J = 8.8 Hz, ArH), 7.65 (1H,
d, J = 8.8 Hz, ArH) and 7.96 (1H, d, J = 8.8 Hz, ArH); δC(75
MHz, CDCl3) 19.6, 44.9, 55.3, 63.3, 106.1, 118.8, 122.2, 125.3,
126.8, 127.3, 127.4, 129.4, 133.9, 134.1, 135.6, 157.6 and 209.5;
m/z (EI) 252.1150 (Mϩ, C17H16O2 requires 252.1149). Enantio-
meric excess was determined by HPLC analysis (CHIRALCEL
OA column, 10% propan-2-ol–hexane, 0.5 mL minϪ1, λ = 254
nm, 23 ЊC, retention times 21.1 min (R) and 26.2 min (S)).
To a stirred solution of the naphthaldehyde 615 (5.0 g, 24.7
mmol) and a catalytic amount of DMAP in pyridine (200 mL)
was added dropwise Tf2O (4.6 mL, 24.7 mmol) at 0 ЊC; stirring
was continued for 1 h at the same temperature. The resulting
solution was diluted with water and extracted with AcOEt. The
combined extracts were washed sequentially with 10% HCl,
saturated aqueous NaHCO3, and saturated aqueous NaCl. The
residue upon work-up was chromatographed on silica gel with
hexane–AcOEt (9:1 v/v) as eluant to give the triflate 7 (5.03 g,
61%) as colourless needles, mp 79 ЊC (Et2O) (Found: C, 46.70;
H, 2.73. C13H9O5F3S requires C, 46.71; H, 2.71%); νmax(CHCl3)/
cmϪ1 1685; δH(300 MHz, CDCl3) 3.98 (3H, s, OMe), 7.21 (1H,
d, J = 2.5 Hz, ArH), 7.34 (1H, dd, J = 9.4 and 2.5 Hz, ArH),
7.81 (1H, d, J = 8.8 Hz, ArH), 7.97 (1H, d, J = 8.8 Hz, ArH),
8.12 (1H, d, J = 9.4 Hz, ArH) and 10.40 (1H, s, CHO); δC(75
MHz, CDCl3) 55.4, 106.1, 116.6, 120.8, 121.2, 121.6, 123.8,
124.2, 127.6, 140.0, 147.3, 161.0 and 186.4; m/z 334 (Mϩ).
6-Methoxy-1-vinylnaphthalene-2-carbaldehyde 8
To a slurry of LiCl (5.50 g, 38.6 mmol) and Pd(PPh3)4 (884 mg,
0.765 mmol) in THF (200 mL) was added a solution of the
triflate 7 (6.4 g, 19.2 mmol) and vinyltri-n-butyltin (7.31 mL,
24.9 mmol). The mixture was refluxed for 12 h with stirring,
cooled to rt, and diluted with AcOEt. The resulting solution
was washed sequentially with water, 10% NH4OH, water,
and saturated aqueous NaCl. The residue upon work-up was
chromatographed on silica gel with hexane–AcOEt (9:1 v/v) as
eluant to give the vinylnaphthaldehyde 8 (4.01 g, 98%) as
colourless needles, mp 89 ЊC (Et2O) (Found: C, 79.21; H, 5.70.
C14H12O2 requires C, 79.23; H, 5.70%); νmax(neat)/cmϪ1 1620
and 1685; δH(300 MHz, CDCl3) 3.91 (3H, s, OMe), 5.48 (1H, dd,
J = 17.4 and 1.8 Hz, CHCHH), 5.99 (1H, dd, J = 11.1 and 1.8
Hz, CHCHH), 7.17 (1H, d, J = 2.4 Hz, ArH), 7.23 (1H, dd,
J = 9.0 and 2.4 Hz, ArH), 7.35 (1H, dd, J = 17.4 and 11.1 Hz,
CHCHH), 7.73 (1H, d, J = 9.0 Hz, ArH), 7.98 (1H, d, J = 9.0
Hz, ArH), 8.12 (1H, d, J = 9.0 Hz, ArH) and 10.41 (1H, s,
CHO); δC(75 MHz, CDCl3) 55.4, 106.6, 119.4, 123.8, 125.6,
126.6, 126.9, 127.9, 129.7, 130.8, 137.8, 143.4, 160.1 and 192.5;
m/z 212 (Mϩ).
(R)-4-(6-Methoxy-1-vinyl-2-naphthyl)butan-4-olide 10
To a stirred solution of the cyclopropylidene derivative 5 (22.1
mg, 0.0936 mmol) in acetonitrile (3 mL) were added the buffer
(2 mL) [0.05 M Na2B4O7ؒ10H2O in 4 × 10Ϫ4 M aqueous
Na2(EDTA), adjusting with 1.0 M aqueous KH2PO4 for pH
10.5], tetrabutylammonium hydrogen sulfate (3.4 mg, 0.010
mmol) and the ketone 9 (45.6 mg, 0.187 mmol). After the reac-
tion mixture had been cooled to 0 ЊC, a solution of Oxone
(115.8 mg, 0.187 mmol) in aqueous Na2(EDTA) (4 × 10Ϫ4 M,
1.5 mL) was added dropwise over a period of 1.5 h while the
reaction pH was maintained at pH 10.5 by addition of K2CO3.
After stirring had been continued for 1 h at the same temper-
ature, the reaction mixture was diluted with water and extracted
with AcOEt. The combined extracts were washed with satur-
ated aqueous NaCl. The residue upon work-up was chromato-
graphed on silica gel with hexane–AcOEt (80:20 v/v) as eluant
to give the butyrolactone 10 (15.0 mg, 60% yield, 72% ee) as a
colourless oil, [α]D25 ϩ43.1 (c 1.0 in CHCl3); νmax(neat)/cmϪ1 1770;
δH(300 MHz, CDCl3) 2.13–2.28 (1H, m, 3-H), 2.54–2.67 (1H,
m, 3-H), 2.68–2.74 (2H, m, 2 × 2-H), 3.92 (3H, s, OMe), 5.40
(1H, dd, J = 17.4 and 1.8 Hz, CHCHH), 5.81 (1H, dd, J = 11.4
and 1.8 Hz, CHCHH), 5.93 (1H, dd, J = 9.3 and 6.3 Hz, 4-H),
7.07 (1H, dd, J = 17.4 and 11.4 Hz, CHCH2), 7.11–7.19 (2H, m,
2 × ArH), 7.48 (1H, d, J = 8.8 Hz, ArH), 7.73 (1H, d, J = 8.8
Hz, ArH) and 7.97 (1H, d, J = 8.8 Hz, ArH); δC(75 MHz,
CDCl3) 29.5, 31.2, 55.4, 79.6, 106.3, 119.2, 122.8, 123.0, 126.9,
127.3, 127.5, 131.6, 133.2, 134.7, 134.8, 158.2 and 177.4; m/z
(EI) 268.1095 (Mϩ, C17H16O3 requires 268.1100). Enantiomeric
excess was determined by HPLC analysis (CHIRALCEL OA
column, ethanol, 0.5 mL minϪ1, λ = 254 nm, 23 ЊC, retention
times 12.7 min (R) and 15.8 min (S)).
2-(Cyclopropylidenemethyl)-6-methoxy-1-vinylnaphthalene 5
To a stirred suspension of NaH (691 mg, 60% suspension in oil,
17.3 mmol) in THF (140 mL) was added cyclopropyltriphenyl-
phosphonium bromide (6.93 g, 17.3 mmol) at rt. After the
mixture had been stirred for 10 h at 62 ЊC, a solution of the
vinylnaphthaldehyde 8 (1.83 g, 8.64 mmol) in THF (20 mL) was
added dropwise, and stirring was continued for 1 h at the same
temperature. The reaction mixture was diluted with water and
extracted with AcOEt. The combined extracts were washed
with saturated aqueous NaCl. The residue upon work-up was
chromatographed on silica gel with hexane–AcOEt (99:1 v/v)
as eluant to give the cyclopropylidene derivative 5 (1.40 g, 70%)
as a colourless oil, νmax(neat)/cmϪ1 1620; δH(300 MHz, CDCl3)
1.16–1.21 (2H, m, 2 × cyclopropyl H), 1.46–1.55 (2H, m,
2 × cyclopropyl H), 3.92 (3H, s, OMe), 5.44 (1H, dd, J = 18.0
and 2.2 Hz, CHCHH), 5.82 (1H, dd, J = 11.0 and 2.2 Hz,
CHCHH), 7.07–7.23 (4H, m, 2 × ArH, CCHC and CHCH2),
7.61 (1H, d, J = 8.8 Hz, ArH) and 8.00–8.04 (2H, m, 2 × ArH);
δC(75 MHz, CDCl3) 0.5, 4.1, 54.9, 106.3, 116.9, 118.2, 122.0,
123.9, 124.7, 126.1, 127.2, 128.3, 130.7, 133.6, 133.7, 133.8 and
157.3; m/z (EI) 236.1201 (Mϩ, C17H16O requires 236.1200).
General procedure for the asymmetric epoxidation–ring
expansion reaction using the chiral (salen)Mn complex
To a stirred solution of the cyclopropylidene derivative 5 (700
mg, 2.96 mmol), the (R,R)-(salen)Mn complex 12 (31.8 mg,
0.148 mmol) and 4-phenylpyridine N-oxide (203 mg, 1.18
mmol) in CH2Cl2 (20 mL) was added dropwise a 0.55 M solu-
tion of NaClO in a phosphate buffer (3.94 mL, 3.55 mmol,
Asymmetric epoxidation–ring expansion reaction using fructose-
derived ketone (entry 6, Table 1)
To a stirred solution of the cyclopropylidene derivative 5
(30 mg, 0.126 mmol) in acetonitrile (3 mL) were added the
J. Chem. Soc., Perkin Trans. 1, 2000, 2629–2635
2633

View Article Online
adjusted to pH 11.3) at 0 ЊC. After stirring had been continued
for 0.5 h at the same temperature, the reaction mixture was
diluted with water and extracted with AcOEt. The combined
extracts were washed with saturated aqueous NaCl. The residue
upon work-up was chromatographed on silica gel with hexane–
AcOEt (95:5) as eluant to give the cyclobutanone 4 (412 mg,
55%, 78% ee) as a colourless oil, [α]D25 ϩ37.5 (c 0.2 in CHCl3).
Other spectral data were consistent with those of the ent-4.
CHCHH), 6.96 (1H, dd, J = 18.0 and 11.2 Hz, CHCH2), 7.12
(1H, s, ArH), 7.13 (1H, d, J = 10.2 Hz, ArH), 7.30–7.38 (3H, m,
3 × PhH), 7.43–7.47 (2H, m, 2 × PhH), 7.52 (1H, d, J = 9.0 Hz,
ArH), 7.71 (1H, d, J = 9.0 Hz, ArH) and 7.98 (1H, d, J = 10.2
Hz, ArH); m/z (EI) 470.1685 (Mϩ, C17H18O2 requires 470.1704).
(S)-MTPA ester 17
By following the same procedure described for 16, (S)-MTPA
ester 17 was prepared from (S)-MTPA in quantitative yield,
colourless oil, νmax(neat)/cmϪ1 1740; δH(300 MHz, CDCl3) 1.76
(1H, dddd, J = 21.0, 9.9, 8.1 and 2.1 Hz, 3-H), 2.12 (1H, dddd,
J = 20.1, 9.9, 8.1 and 1.5 Hz, 4-H), 2.30 (1H, dddd, J = 21.0, 8.1,
1.8 and 1.5 Hz, 3-H), 2.52 (1H, dddd, J = 20.1, 8.1, 2.1 and 1.8
Hz, 4-H), 3.54 (3H, s, MTPA OMe), 3.92 (3H, s, OMe), 4.05
(1H, q, J = 8.1 Hz, 2-H), 5.23 (1H, dd, J = 18.0 and 2.1 Hz,
CHCHH), 5.51 (1H, q, J = 8.1 Hz, 1-H), 5.63 (1H, dd, J = 11.2
and 2.1 Hz, CHCHH), 6.87 (1H, dd, J = 18.0 and 11.2 Hz,
CHCH2), 7.11 (1H, s, ArH), 7.12 (1H, d, J = 10.2 Hz, ArH),
7.28–7.37 (3H, m, 3 × PhH), 7.44–7.47 (2H, m, 2 × PhH),
7.49 (1H, d, J = 8.7 Hz, ArH), 7.69 (1H, d, J = 8.7 Hz, ArH)
and 7.95 (1H, d, J = 10.2 Hz, ArH); m/z (EI) 470.1700 (Mϩ,
C17H18O2 requires 470.1704).
(S)-2-(1-Vinyl-2-naphthyl)cyclobutanone 13
Yield 67%, 93% ee; [α]D25 ϩ79.7 (c 3.5 in CHCl3). Enantiomeric
excess was determined by HPLC analysis (CHIRALCEL OA
column, 10% propan-2-ol–hexane, 0.5 mL minϪ1, λ = 254 nm,
23 ЊC, retention times 13.9 min (R) and 16.2 min (S)). Other
spectral data were consistent with those of the racemic cyclo-
butanone.13
(1R,2S)- and (1S,2S)-2-(6-Methoxy-1-vinyl-2-naphthyl)cyclo-
butanols 14 and 15
To a stirred solution of the cyclobutanone 4 (21.3 mg, 0.0805
mmol) in MeOH (5 mL) was added NaBH4 (22.4 mg, 0.0864
mmol) at 0 ЊC. After stirring had been continued for 1 h at the
same temperature, the reaction mixture was diluted with water
and extracted with AcOEt. The combined extracts were washed
with saturated aqueous NaCl. The residue upon work-up was
chromatographed on silica gel with hexane–AcOEt (94:6 v/v)
as eluant to give the cyclobutanol 14 (12.8 mg, 61%) as a colour-
less oil, νmax(neat)/cmϪ1 3400; δH(300 MHz, CDCl3) 1.57–1.65
(1H, m, 3-H), 1.83–1.91 (1H, m, 4-H), 2.03 (1H, br s, OH),
2.08–2.15 (1H, m, 3-H), 2.28–2.36 (1H, m, 4-H), 3.69–3.77 (1H,
m, 2-H), 3.92 (3H, s, OMe), 4.33 (1H, q, J = 8.0 Hz, 1-H), 5.41
(1H, dd, J = 18.0 and 2.0 Hz, CHCHH), 5.76 (1H, dd, J = 11.0
and 2.0 Hz, CHCHH), 7.06–7.13 (3H, m, 2 × ArH and
CHCH2), 7.47 (1H, d, J = 8.5 Hz, ArH), 7.67 (1H, d, J = 8.5
Hz, ArH) and 8.01 (1H, d, J = 9.0 Hz, ArH); δC(75 MHz,
CDCl3) 20.1, 29.6, 49.2, 55.4, 73.1, 106.1, 118.6, 121.7, 124.8,
126.4, 127.1, 127.5, 133.5, 134.4, 134.7, 134.8 and 157.2; m/z
(EI) 254.1317 (Mϩ, C17H18O2 requires 254.1307). Further
elution gave the diastereomer 15 (8.5 mg, 35%) as a colourless
oil, νmax(neat)/cmϪ1 3300; δH(300 MHz, CDCl3) 1.34 (1H, br s,
OH), 1.97–2.05 (1H, m, 4-H), 2.16–2.25 (1H, m, 3-H), 2.41–
2.48 (1H, m, 4-H), 2.49–2.56 (1H, m, 3-H), 3.93 (3H, s, OMe),
4.12 (1H, q, J = 7.0 Hz, 2-H), 4.58 (1H, br s, 1-H), 5.41 (1H, dd,
J = 18.0 and 2.0 Hz, CHCHH), 5.74 (1H, dd, J = 11.0 and 2.0
Hz, CHCHH), 7.01 (1H, dd, J = 18.0 and 11.0 Hz, CHCH2),
7.11–7.17 (2H, m, 2 × ArH), 7.57 (1H, d, J = 8.5 Hz, ArH), 7.73
(1H, d, J = 8.5 Hz, ArH) and 8.05 (1H, m, ArH); δC(75 MHz,
CDCl3) 21.2, 30.2, 44.5, 55.4, 70.8, 106.0, 118.8, 121.6, 125.9,
126.4, 127.3, 127.4, 130.6, 133.9, 134.4, 136.2 and 157.4; m/z
(EI) 254.1316 (Mϩ, C17H18O2 requires 254.1307).
(؉)-(1S,2S)-1-Isopropenyl-2-(6-methoxy-1-vinyl-2-naphthyl)-
cyclobutanol 3
To a stirred suspension of CeCl3 (1.83 g, 7.42 mmol) in THF
(30 mL) was added a 1.0 M solution of isopropenylmagnesium
bromide in THF (6.36 mmol) at Ϫ78 ЊC. After stirring had been
continued for 1 h, a solution of the cyclobutanone 4 (536 mg,
2.12 mmol) in THF (5 mL) was added dropwise to this reaction
mixture at the same temperature and the temperature was then
raised to rt during 2 h. The reaction mixture was treated with
saturated aqueous NH4Cl and extracted with Et2O. The com-
bined extracts were washed with saturated aqueous NaCl. The
residue upon work-up was chromatographed on silica gel with
hexane–AcOEt (95:5 v/v) as eluant to give the isopropenyl-
cyclobutanol 3 (512 mg, 82%) as a colourless oil (Found:
C, 81.35; H, 7.70. C20H22O2 requires C, 81.60; H, 7.53%);
[α]2D5 ϩ62.7 (c 3.5, CHCl3); νmax(neat)/cmϪ1 3400; δH(300 MHz,
CDCl3) 1.88 (3H, s, CMe), 2.01–2.09 (1H, m, 3-H), 2.13–2.20
(1H, m, 4-H), 2.42–2.58 (2H, m, 3-H and 4-H), 3.91 (3H, s
OMe), 4.29 (1H, t, J = 7.5 Hz, 2-H), 4.81 (1H, s, CCHH), 4.98
(1H, s, CCHH), 5.32 (1H, dd, J = 18.0 and 2.2 Hz, CHCHH),
5.74 (1H, dd, J = 11.0 and 2.2 Hz, CHCHH), 6.97 (1H, dd,
J = 18.0 and 11.0 Hz, CHCH2), 7.10–7.16 (2H, m, 2 × ArH),
7.64 (2H, m, 2 × ArH) and 8.03 (1H, d, J = 8.8 Hz, ArH); δC(75
MHz, CDCl3) 18.7, 21.6, 31.3, 44.5, 55.0, 81.2, 105.7, 109.7,
118.4, 121.7, 125.9, 126.9, 127.2, 127.5, 130.9, 133.6, 134.5,
136.5, 148.6 and 157.3; m/z 294 (Mϩ).
(؊)-11-Oxoequilenin methyl ether 24
(R)-MTPA ester 16
To a stirred solution of the isopropenylcyclobutanol 3 (80.2 mg,
0.273 mmol) in HMPA–THF (1:4) (5 mL) was added Pd(OAc)2
(73.6 mg, 0.328 mmol) at rt; stirring was continued for 5 h at
the same temperature. The resulting solution was diluted with
water and extracted with AcOEt. The combined extracts were
washed with saturated aqueous NaCl. The residue upon work-
up was chromatographed on silica gel with hexane–AcOEt
(98:2 v/v) as eluant to give the naphthalene–hydrindanes 2 and
23 (2:23 = 73:27, 47.6 mg, 60%) and the endo-olefin isomer
(5.6 mg, 7%) as a colourless oil, 2 ϩ 23: νmax(neat)/cmϪ1 1740;
δH(300 MHz, CDCl3) 0.55 (2.19H, s, 13-Me), 1.20 (0.81H, s, 13-
Me), 1.82–1.94 (0.27H, m, 15-H), 2.11–2.26 (1.73H, m), 2.30–
2.52 (3H, m), 2.63–2.72 (1H, m), 2.91–3.01 (0.73H, m, 14-H),
3.29 (0.27H, t, J = 9.2 Hz, 14-H), 3.92 (3H, s, OMe), 5.43–5.54
(0.73H, m, CCHH), 5.46 (0.54H, s, CCH2), 5.51–5.52 (0.73H,
m, CCHH), 7.11–7.19 (2H, m, 2 × ArH), 7.29 (1H, d, J = 8.4
Hz, ArH), 7.63 (0.27H, d, J = 8.4 Hz, ArH), 7.70 (0.73H, d,
To a stirred solution of the cyclobutanol 14 (8.1 mg, 0.0324
mmol) in CH2Cl2 (2 mL) were added (R)-MTPA (11.4 mg,
0.0481 mmol) and a catalytic amount of DMAP at rt. After
stirring had been continued for 12 h at the same temperature,
the reaction mixture was diluted with NH4Cl and extracted
with AcOEt. The combined extracts were washed with satur-
ated aqueous NaCl. The residue upon work-up was chromato-
graphed on silica gel with hexane–AcOEt (97:3 v/v) as eluant
to give the (R)-MTPA ester 15 (16.3 mg, quant.) as a colourless
oil, νmax(neat)/cmϪ1 1740; δH(300 MHz, CDCl3) 1.75 (1H, dddd,
J = 20.7, 9.9, 8.1 and 2.4 Hz, 3-H), 2.02 (1H, dddd, J = 20.1, 9.9,
8.1 and 1.2 Hz, 4-H), 2.29 (1H, dddd, J = 20.7, 8.1, 1.8 and 1.2
Hz, 3-H), 2.51 (1H, dddd, J = 20.1, 8.1, 2.4 and 1.8 Hz, 4-H),
3.48 (3H, s, MTPA OMe), 3.92 (3H, s, OMe), 4.09 (1H, q,
J = 8.1 Hz, 2-H), 5.31 (1H, dd, J = 18.0 and 2.1 Hz, CHCHH),
5.50 (1H, q, J = 8.1 Hz, 1-H), 5.68 (1H, dd, J = 11.2 and 2.1 Hz,
2634
J. Chem. Soc., Perkin Trans. 1, 2000, 2629–2635

View Article Online
2 W. E. Bachmann, W. Cole and A. L. Wilds, J. Am. Chem. Soc., 1939,
61, 974.
J = 8.4 Hz, ArH), 8.31 (0.73H, d, J = 8.4 Hz, ArH) and 8.39
(0.27H, d, J = 8.4 Hz, ArH); m/z (EI) 292.1455 (Mϩ, C20H20O2
requires 292.1462).
3 For reviews, see (a) R. Pappo, Annu. Rep. Med. Chem., 1967, 307;
(b) A. A. Akhrem and Y. A. Titov, Total Steroid Synthesis,
Plenum Press, New York, 1970; (c) Steroids, Vol. 8, ed. W. F.
Johns, M. T. P. International Review of Science, Organic
Chemistry, Butterworths, London, 1973; (d) The Total Synthesis
of Natural Products Vol. 2, ed. J. W. ApSimon, Wiley-Interscience,
New York, 1973; (e) W. S. Johnson, Angew. Chem., Int. Ed. Engl.,
1976, 15, 9; ( f ) T. Kametani and H. Nemoto, Heterocycles, 1978,
10, 349; (g) T. Kametani and H. Nemoto, Tetrahedron, 1981, 37,
3; (h) M. B. Groen and F. Zeelen, Recl. Trav. Chim. Pays-Bas,
1986, 105, 465; (i) M. B. Groen and F. Zeelen, Nat. Prod. Rep.,
1994, 11, 607; (j) H. Nemoto and K. Fukumoto, Tetrahedron,
1998, 54, 5425.
4 (a) W. S. Johnson, V. R. Fletcher, B. Chenera, W. R. Bartlett,
F. S. Tham and R. K. Kullnig, J. Am. Chem. Soc., 1993, 115,
497; (b) E. J. Corey, S. C. Virgil, H. Cheng, C. H. Baker, S. P. T.
Matsuda, V. Singh and S. Sarshar, J. Am. Chem. Soc., 1995, 117,
11819.
5 (a) R. L. Funk and K. P. C. Vollhardt, J. Am. Chem. Soc., 1980, 102,
5253; (b) Y. Zhang, G. Wu, G. Agnel and E. Negishi, J. Am. Chem.
Soc., 1990, 112, 8590; (c) V. Gauthier, B. Cazes and J. Gore,
Tetrahedron Lett., 1991, 32, 915; (d) J. Bao, V. Dragisich,
S. Wenglowsky and W. D. Wulff, J. Am. Chem. Soc., 1991, 113, 9873;
(e) R. Grigg, R. Rasul and V. Savic, Tetrahedron Lett., 1997, 38,
1825; ( f ) L. F. Tietze, T. Nöbel and M. Spescha, J. Am. Chem. Soc.,
1998, 120, 8971.
To a stirred solution of the mixture of 2 and 23 (2:23 =
73:27, 23.0 mg, 0.079 mmol) in acetone–H2O (1:1) (5 mL) was
added to 2% w/v solution of OsO4 in water (0.10 mL, 0.008
mmol) at rt. After stirring had been continued for 15 min,
NaIO4 (42.1 mg, 0.197 mmol) was added during 30 min, and
stirring was continued for 2 h at the same temperature. The
reaction mixture was quenched with saturated aqueous
Na2S2O3, and extracted with AcOEt. The combined extracts
were washed with saturated aqueous NaCl. The residue upon
work-up was chromatographed on silica gel with hexane–
AcOEt (9:1 v/v) as eluant to give the diketone 24 (13.7 mg, 59%
from 2) as colourless needles, mp 184 ЊC (decomp.) (MeOH);
[α]D25 Ϫ31.7 (c 0.1 dioxane); νmax(neat)/cmϪ1 1660 and 1740;
δH(300 MHz, CDCl3) 0.83 (3H, s, 13-Me), 2.08–2.22 (1H, m,
15-H), 2.35–2.52 (1H, m, 15-H), 2.58–2.77 (2H, m, 2 × 16-H),
2.70 (1H, d, J = 18.9 Hz, 12-H), 2.94 (1H, d, J = 18.9 Hz, 12-H),
3.34 (1H, dd, J = 12.5 and 6.3 Hz, 14-H), 3.94 (3H, s, OMe),
7.15 (1H, d, J = 2.8 Hz, ArH), 7.29–7.38 (2H, m, 2 × ArH), 7.98
(1H, d, J = 8.7 Hz, ArH) and 9.22 (1H, d, J = 8.7 Hz, ArH);
δC(75 MHz, CDCl3) 15.0, 21.9, 35.8, 46.0, 48.8, 48.9, 55.3,
106.6, 121.8, 123.7, 126.7, 127.0, 128.0, 134.1, 140.9, 157.6,
199.0 and 217.8; m/z (EI) 294.1246 (Mϩ, C19H18O3 requires
294.1256).
6 (a) Y. W. Andemichael, Y. Huang and K. K. Wang, J. Org. Chem.,
1993, 58, 1651; (b) T. Takahashi, S. Tomida, Y. Sakamoto and
H. Yamada, J. Org. Chem., 1997, 62, 1912.
7 M. Ihara, T. Takahashi, N. Shimizu, Y. Ishida, I. Sudow and
K. Fukumoto, J. Chem. Soc., Perkin Trans. 1, 1989, 529.
8 J. R. Hanson, Steroids, 1996, 13, 373.
9 Part of the present work has been published as a preliminary
communication: H. Nemoto, M. Yoshida, K. Fukumoto and
M. Ihara, Tetrahedron Lett., 1999, 40, 907.
10 Syntheses of the chiral cyclobutanones by other methods: H.
Nemoto and K. Fukumoto, Synlett, 1997, 863, and references cited
therein.
11 Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang and Y. Shi, J. Am. Chem.
Soc., 1997, 119, 11224.
12 (a) W. Zhang and E. N. Jacobsen, J. Org. Chem., 1991, 56, 2296;
(b) E. N. Jacobsen, W. Zhang, A. R. Muci, J. R. Ecker and L. Deng,
J. Am. Chem. Soc., 1991, 113, 7063.
13 H. Nemoto, J. Miyata, M. Yoshida, N. Raku and K. Fukumoto,
J. Org. Chem., 1997, 62, 7850.
14 For our recent work on the palladium-catalysed ring expansion
reactions of cyclobutanols: (a) H. Nemoto, M. Nagamochi
and K. Fukumoto, J. Chem. Soc., Perkin Trans. 1, 1993, 2329;
(b) H. Nemoto, M. Nagamochi, H. Ishibashi and K. Fukumoto,
J. Org. Chem., 1994, 59, 74; (c) H. Nemoto, M. Shiraki and
K. Fukumoto, Synlett, 1994, 599; (d) H. Nemoto, J. Miyata
and K. Fukumoto, Tetrahedron, 1996, 52, 10363; (e) H. Nemoto,
M. Yoshida and K. Fukumoto, J. Org. Chem., 1997, 62, 6450;
( f ) H. Nemoto, J. Miyata and M. Ihara, Tetrahedron Lett., 1999, 40,
1933; (g) H. Nemoto, E. Takahashi and M. Ihara, Org. Lett., 1999,
1, 517.
(؉)-Equilenin methyl ether 25
To a stirred solution of the diketone 24 (7.5 mg, 0.0255 mmol)
in EtOH (2 mL) was added a catalytic amount of Pt/C and
PdCl2 under an atmospheric pressure of hydrogen at rt, and
stirring was continued for 30 min. The reaction mixture was
filtered through Celite. The residue upon work-up was chrom-
atographed on silica gel with hexane–AcOEt (97:3 v/v) as eluant
to give equilenin methyl ether (25) (5.9 mg, 82%). The product
was recrystallized from MeOH to give the optically pure 25
as colourless needles, mp 198 ЊC (decomp.) [lit.,21 mp 197 ЊC
(decomp.)]; [α]D25 ϩ78.9 (c 0.4 dioxane) [lit.,21 [α]2D5 ϩ82.8 (c 1.0
dioxane)]; νmax(neat)/cmϪ1 1730; δH(300 MHz, CDCl3) 0.81
(3H, s, 13-Me), 1.83–2.09 (2H, m, 2 × 15-H), 2.17–2.26 (1H, m,
16-H), 2.40 (1H, dt, J = 8.6 and 19.3 Hz, 12-H), 2.50–2.61 (1H,
m, 16-H), 2.70 (1H, dd, J = 18.9 and 8.6 Hz, 12-H), 3.15–3.22
(1H, m, 11-H), 3.26–3.35 (2H, m, 11-H and 14-H), 3.94 (3H, s,
13-Me), 7.14 (1H, d, J = 2.7 Hz, ArH), 7.19 (1H, dd, J = 9.5
and 2.7 Hz, ArH), 7.28 (1H, d, J = 8.5 Hz, ArH), 7.64 (1H, d,
J = 8.5 Hz, ArH) and 7.88 (1H, d, J = 9.5 Hz, ArH); m/z 280
(Mϩ). The 1H NMR spectrum of 25 was in complete agreement
with that of an authentic sample.21
15 C. Bilger, P. Demerseman and R. Royer, Eur. J. Med. Chem., 1987,
22, 363.
16 W. J. Scott and J. K. Stille, J. Am. Chem. Soc., 1986, 108, 3033.
17 M. Yoshida, M. A.-H. Ismail, H. Nemoto and M. Ihara,
Heterocycles, 1999, 50, 673.
18 I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem.
Soc., 1991, 113, 4092.
19 T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima and Y.
Kamiya, J. Am. Chem. Soc., 1989, 111, 4392.
Acknowledgements
We thank Professor Ogasawara, Pharmaceutical Institute,
Tohoku University, Sendai, for providing the 1H NMR
spectrum of 25. M. Y. acknowledges support by a Research
Fellowship from the Japan Society for the Promotion of
Science (JSPS) for Young Scientists.
20 A. J. Birch and G. S. R. Subba Rao, Tetrahedron Lett., 1967, 23,
2763.
21 S. Takano, K. Inomata and K. Ogasawara, J. Chem. Soc., Chem.
Commun., 1990, 1544.
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J. Chem. Soc., Perkin Trans. 1, 2000, 2629–2635
2635