A model study for the total synthesis of (±)-scopadulin: Stereoselective construction of the A/B ring system with desired functionalities

Article abstract of DOI:10.1016/S0040-4020(00)00995-9

A model study toward the total synthesis of (±)-scopadulin is described. Stereocontrolled synthesis of the A/B ring system with desired functionalities was achieved by stereoselective cyanation of a bicyclic enone with Et₂AlCN, diastereoselective construction of a quaternary carbon at C-4 with LDA-BOMCl, and conversion of the cyano group into a methyl group.

Full text of DOI:10.1016/S0040-4020(00)00995-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 127±134
A model study for the total synthesis of (^)-scopadulin:
stereoselective construction of the A/B ring system with
desired functionalities
S. M. Abdur Rahman, Hiroaki Ohno, Hitoshi Yoshino, Norifumi Satoh, Mahoto Tsukaguchi,
*
Kazuo Murakami, Chuzo Iwata, Naoyoshi Maezaki and Tetsuaki Tanaka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 22 September 2000; accepted 23 October 2000
AbstractÐA model study toward the total synthesis of (^)-scopadulin is described. Stereocontrolled synthesis of the A/B ring system with
desired functionalities was achieved by stereoselective cyanation of a bicyclic enone with Et2AlCN, diastereoselective construction of a
quaternary carbon at C-4 with LDA-BOMCl, and conversion of the cyano group into a methyl group. q 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
we turned our attention to the synthesis of a model
compound 4, which bears the same functionalities and
stereochemical con®guration as those of scopadulin (3).
Herein we wish to report the synthetic studies of model
compound 4 in full detail.8
The plant Scoparia dulcis has long been used as a traditional
medicine in Paraguay, India and Taiwan for hypertension
and stomach disorders.1 Several scopadulane diterpenes
such as scopadulcic acid A (1), scopadulcic acid B (2)
were isolated from this plant by T. Hayashi and
co-workers.2 The continued investigation of Hayashi's
group on this plant resulted in isolation and characterization
of a novel tetracyclic diterpenoid, scopadulin (3), in 1990.3
This is the ®rst example of an aphidicolane type diterpenoid
from a higher plant. The structure of scopadulin was deter-
mined by spectroscopic studies, and ®nally con®rmed by a
single crystal X-ray crystallography of its acetone solvate3
(Fig. 1).
2. Results and discussion
2.1. Stereoselective construction of A/B-ring system with
a quaternary carbon center at C-4
We had already established a synthetic pathway of the inter-
mediate 6 (Eq (1)),7b which could be as a key intermediate
for the synthesis of scopadulin. Therefore, cyclohex-2-en-1-
one 7 was taken as the starting material for our model study.
We initially planned to synthesize the model compound 4
via a bicyclic enone 11 bearing a methyl substituent at C-4
The challenging structural complexity of scopadulin due to
the presence of three quaternary carbons and eight stereo-
centers coupled with its notable antiviral and cytotoxic
activities3 makes it a worthy synthetic target. Although
synthetic pathways of scopadulcic acid A (1)4 and
scopadulcic acid B (2)4b,5 have been established in recent
years, no synthetic approach towards scopadulin (3) is
reported to date.6 After a successful synthesis of aphidi-
colin,7 we were inspired to synthesize this novel diter-
penoid. However, progress of our synthetic study was
hampered due to several failed attempts to construct the
A/B ring system with desired functionalities. Accordingly,
²
(Scheme 1).
ꢀ1†
The enone 11 was synthesized in a straightforward manner
as depicted in Scheme 1. Barbier alkylation of 7 provided
Keywords: diastereoselection; copper and compounds; conjugate addition;
deamination.
* Corresponding author. Tel.: 16-6879-8210; fax: 16-6879-8214; e-mail:
t-tanaka@phs.osaka-u.ac.jp
²
For convenience of description, the numbering of carbons of the
compounds 4, 11, 15, 16, 20±22, 24±26, 28, and 30 (Fig. 1, Schemes
1±6) was that used for scopadulin (3).
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00995-9

128
S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
Scheme 2. Reagent and condition: (vinyl)2Cu(CN)Li2, 2788C!08C.
time had no effect. Moreover, the small amount of the viny-
lated product formed was an inseparable mixture of two
isomers. Other reagents such as (vinyl)2Cu(CN)Li2´2LiCl,
(vinyl)2Cu(CN)(ZnCl)2´4LiCl,11 or (vinyl)MgBr±CuBr´
DMS4b were also ineffective. We reasoned that the presence
of both methyl groups at C-4 and C-10 prevented the reagent
from reacting with the substrate, presumably due to steric
hindrance.
Figure 1.
the allyl alcohol 8, which was oxidized to give the enone 9,
both in good yields. Conjugate addition of Me2CuLi to 9
afforded the ketone 10 in nearly quantitative yield. The
desired enone 11 was obtained in excellent yield by treat-
ment of 10 with 10% HCl and subsequent intramolecular
aldol condensation of the crude diketone.
We assumed that the remaining quaternary carbon at C-4
with the desired stereochemistry could be constructed by an
attack of a vinyl cuprate such as (vinyl)2Cu(CN)Li2 from
Due to very low yield and formation of an intractable
mixture of the vinylated ketones, we next planned a
different route. We synthesized a similar enone 15
lacking a methyl substituent at C-4 in the same way
(Scheme 3). Barbier reaction of 7, subsequent oxidation,
9
the less hindered side of 11 (Scheme 1). As shown in
Scheme 2, we simply investigated the conjugate addition
of a vinyl cuprate to some enones. Treatment of isophorone
13 with (vinyl)2Cu(CN)Li2 yielded a vinylated product 14 in
60% yield. The enone 15 (vide infra) bearing the same
skeleton as 11 also gave 16 (68% yield); however, formation
of the undesired 4,10-cis isomer predominated (cis/
transˆ5:1).10 In the case of 11, the vinylation proceeded
hardly (,10% yield) under similar reaction conditions.
Increased loading of vinyl cuprate or prolonged reaction
Scheme 3. Reaction conditions: (a) Li, 2-(-3-chloropropyl)-1,3-dioxolane,
THF, ultrasound, rt (67%); (b) PCC, Al2O3, CH2Cl2, rt (97%); (c) Me2CuLi,
Et2O, 220!08C; (d) HCl, MeOH, 658C; (e) TSA, PhH, Dean±Stark
device, 1108C (78%, two steps); (f) Et2AlCN, TMSCl, PhH, 08C; (g)
NaBH4, MeOH±THF (2:1), rt (100%); (h) TMSCl, pyridine, DMAP,
CH2Cl2, 08C (89%); (i) LDA, BOMCl, THF, 278!08C; (j) TBAF, THF,
458C.
Scheme 1. Reaction conditions: (a) Li, 2-(3-chloropropyl)-2-methyl-1,3-
dioxolane, THF, ultrasound, rt; (b) PCC, Al2O3, CH2Cl2, rt; (c) Me2CuLi,
Et2O, 220!08C; (d) HCl, MeOH, 658C; (e) TSA, PhH, Dean±Stark,
1108C.

S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
129
Scheme 4. Reaction conditions: (a) LiAlH4, THF, 2788C!re¯ux; (b)
H2N±NH2´H2O, diethylene glycol, 1958C, then KOH, 2108C.
Scheme 6. Reaction conditions: (a) RuCl2(PPh3) (0.8 equiv.), PhH, rt; (b)
K2CO3, H2N±NH2´H2O, diethylene glycol, 170!2108C; (c) BzOTf, 2,6-
lutidine, CH2Cl2 08C; (d) H2, Pd/C, MeOH, rt; (e) Jones reagent, acetone, rt.
and 1,4-addition of methyl group to the enone 17 afforded
the ketone 18. Acid treatment of 18 furnished the enone 15
in good yield.
With this enone 15 in hand, we explored a different route via
a conjugate addition of a cyano group and stereoselective
a-alkylation.12 Thus, treatment of the enone 15 with
Et2AlCN in benzene provided the desired nitrile 19 along
with some of the A/B-cis product.13 However, when the
reaction was conducted in the presence of TMSCl in
benzene, 19 was obtained as a single isomer. Reduction of
the ketone 19 and TMS protection of the resulting alcohol
proceeded to give the silyl ether 20 with the requisite stereo-
chemistry, in excellent yields. The stereochemistry of 20
was con®rmed by NOE analyses. Irradiation of the signals
of the 4-H led to NOE enhancement of the signals of 5-H
and 6-H. In contrast, no NOE was observed between
10-methyl and 4-H, 5-H, or 6-H. After several attempts to
generate a quaternary carbon at C-4, a convenient strategy
reported by Overman was followed (Scheme 3).4c Stereo-
selective alkylation was performed by treating the nitrile 20
with LDA and freshly distilled benzyloxymethyl chloride.14
Deprotection of the TMS group afforded the alcohol 22. The
stereochemistry was con®rmed in this stage by NOE analy-
sis. Strong NOE enhancement of 5-H and 10-H was
observed when 6-H was irradiated (see the structure 22 in
Scheme 3).
cyano group into a methyl group. We speculated that the
partial reduction of the nitrile 22 by LiAlH4 would produce
the aminal 23, which would give the desired 4,10-dimethyl-
ated alcohol 24 by Wolff±Kishner reduction (Scheme 4).5b
However, the desired conversion did not proceed. Rather,
we found that the diol 25 was unexpectedly formed in low
yield upon exposure of the crude mixture obtained by
LiAlH4 reduction of 22 to the Wolff±Kishner conditions.
Further experiments revealed that the product obtained by
LiAlH4-reduction was a primary amine instead of the
aminal 23, and that the amine was then converted into the
primary alcohol 25 under the basic condition. Since Over-
man in his total synthesis of scopadulcic acid B described an
ef®cient formation of an aminal using a similar nitrile whose
cyano group is located at C-10 instead of C-4,5b we could
not explain the cause of this unsuccessful result. Although
we investigated other conversion methods of the cyano
group into a methyl15 or formyl group16 (limonene±Pd/
C,15 LiAlH4,16a,b FeCl3±Isopropyl chloride,16c DIBAL-H,
etc.), all our attempts were unsuccessful.
Next, we turned our attention to the formation of the alcohol
25 from the amine 26 (Scheme 5). After considerable
experimentation, we found that the diol 25 could be
obtained in 65% yield from the amine 26 by treating with
KOH in diethylene glycol at 2108C.8 At the same time, we
also investigated other routes for ef®cient conversion of the
nitrile 21 to the diol 25. Thus, hydrolysis of the cyano group
of 21 into a carboxyl group, esteri®cation, and subsequent
LiAlH4 reduction of the resulting ester provided the diol 25
in good yields. It should be noted that we observed variable
yields (50±83%) in the conversion of 21 into 27.
2.2. Conversion of the hindered cyano group into a
methyl group and subsequent functional group
modi®cations
Our next plan was the conversion of the axial hindered
After the synthesis of the diol 25, we completed the synthe-
sis of the model compound 4 via the 4,10-dimethyl deriva-
tive 24 (Scheme 6).17 The primary hydroxy group of 25 was
selectively oxidized by RuCl2(PPh3)318 to yield the aldehyde
28 (63% yield) together with the recovered starting material
(33%). The aldehyde was then reduced to a methyl group by
Huang±Minlon reduction19 to give 24 in 79% yield. The
conventional benzoylation of the secondary alcohol of 24
using BzCl±pyridine was sluggish (20% yield; re¯ux, 28 h).
Although benzoylation using freshly prepared BzOTf20 and
pyridine was also unsatisfactory (27%), an improved yield
was obtained using BzOTf and 2,6-lutidine (47%). The
Scheme 5. Reaction conditions: (a) LiAlH4, THF, 278!758C; (b) KOH,
diethylene glycol, 2108C; (c) KOH, K2CO3, 1408C; (d) TMSCHN2, Et2O,
08C; (e) LiAlH4, THF, 08C.

130
S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
benzyl group of 29 was removed, and Jones oxidation of the
resulting primary alcohol of 30 afforded the compound 4
with all the desired functionalities.
(2.5 mL) at 08C. The reaction mixture was stirred at rt for
1 h. The mixture was ®ltered through a plug of celite eluting
with hexane/EtOAc (1:1). The ®ltrate was concentrated.
Puri®cation of the concentrate by column chromatography
(1:1 hexane/EtOAc) gave 9 (213 mg, 71%) as a colorless
1
oil. IR (KBr) cm21: 1668, 1624, 1119. H NMR (CDCl3,
3. Conclusion
500 MHz) d: 1.31 (s, 3H), 1.60±1.66 (m, 4H), 1.96±2.02
(m, 2H), 2.31 (t, Jˆ7.0 Hz, 2H), 2.29 (t, Jˆ6.0 Hz, 2H),
2.36 (t, J ˆ7.0 Hz, 2H), 3.90±3.98 (m, 4H), 5.89 (s, 1H).
13C NMR (CDCl3, 125 MHz) d: 21.3, 22.7, 23.8, 29.6, 37.3,
38.0, 38.6, 64.7 (2C), 109.7, 125.8, 166.1, 199.8. MS (EI) m/
z (%): 224 (M1, 5.9), 209 (7.3), 87 (100). HRMS (EI) Calcd
for C13H20O3: 224.1412. Found: 224.1415.
Toward the total synthesis of scopadulin, we have estab-
lished an ef®cient route for stereoselective construction of
the A/B ring system model with the desired functionalities.
Stereoselective cyanation of a bicyclic enone followed by
a-alkylation of the resulting nitrile afforded the nitrile
bearing a quaternary carbon center at C-4 with the desired
stereochemistry. Conversion of the cyano into a methyl
group, and appropriate modi®cation of functional groups
yielded the model compound of scopadulin with all the
desired functionalities. Application of this ef®cient route
to the total synthesis of (^)-scopadulin is now being investi-
gated in this laboratory.
4.1.3. 3-Methyl-3-[3-(1-methyl-2,5-dioxolanyl)propyl]-
cyclohexan-1-one (10). To a stirred suspension of CuI
(1.41 g, 7.40 mmol) in Et2O (13 mL) was added dropwise
MeLi (1.14 M in Et2O; 12.9 mL, 14.8 mmol) at 2208C and
the mixture was stirred for 15 min. A solution of 9 (832 mg,
3.71 mmol) in Et2O (3 mL) was then added dropwise at
2108C and the reaction mixture was warmed to 08C.
After stirring for 1.5 h at 08C, the reaction mixture was
neutralized by aqueous NH4Cl. The whole was extracted
with EtOAc (5 times). Finally, the combined organic phases
were washed with water and brine, dried (MgSO4) and
concentrated. Puri®cation of the concentrate by column
chromatography (3:1 hexane/EtOAc) afforded 10 (858 mg,
4. Experimental
4.1. General methods
Melting points are uncorrected. Nominal (LRMS) and exact
mass (HRMS) spectra were recorded on a JEOL JMS-01SG-
1
96%) as a colorless oil. IR (KBr) cm21: 1709, 1115. H
1
2 or JMS-HX/HX 110A mass spectrometer. H and 13C
NMR (CDCl3, 500 MHz) d: 0.89 (s, 3H), 1.15±1.40 (m,
4H), 1.28 (s, 3H), 1.49±1.63 (m, 4H), 1.80±1.86 (m, 2H),
2.08 (d, Jˆ13.5 Hz, 1H), 2.16 (d, Jˆ13.5 Hz, 1H), 2.23±
2.27 (m, 2H), 3.87±3.94 (m, 4H). 13C NMR (CDCl3,
125 MHz) d: 17.9, 22.1, 23.8, 24.9, 35.8, 38.6, 39.8, 41.0,
42.0, 53.8, 64.6 (2C), 109.9, 212.1. MS (FAB) m/z (%): 241
(MH1, 51), 87 (100). HRMS (FAB) Calcd for C14H25O3
(MH1): 241.1804. Found: 241.1818.
NMR spectra were recorded in CDCl3. Chemical shifts are
reported in parts per million down®eld from internal Me4Si
(sˆsinglet, dˆdoublet, ddˆdouble doublet, dddˆdoublet of
double doublet, tˆtriplet, dtˆdouble triplet, mˆmultiplet).
For column chromatography, silica gel 60 (0.063±0.200 mm,
Merck) was employed. For ¯ash chromatography, silica gel
60 (0.040±0.063 mm, Merck) was employed. THF, CH2Cl2,
and benzene were freshly distilled prior to use.
4.1.4. 6,10-Dimethylbicyclo[4.4.0]dec-1(10)-en-2-one
(11). 10% HCl (5.4 mL) was added to a solution of 10
(838 mg, 3.49 mmol) in MeOH (10 mL), and the resulting
mixture was heated at 658C for 2 h. The reaction was neutra-
lized by saturated NaHCO3, and MeOH was evaporated.
The aqueous layer was then extracted with EtOAc, and
the extract was washed with water and brine, dried
(MgSO4), ®ltered and concentrated. The residue was ®ltered
through a short column of silica gel and the ®ltrate was
concentrated. The concentrate was dissolved in benzene
(110 mL), p-toluenesulfonic acid monohydrate (100 mg,
0.526 mmol) was added, and the resulting mixture was
re¯uxed (Dean±Stark device) at 1108C for 8 h. The reaction
mixture was washed with saturated NaHCO3 and water,
dried (MgSO4), ®ltered and concentrated. Puri®cation of
the concentrate by column chromatography (1:1 hexane/
EtOAc) yielded 11 (553 mg, 89% in two steps) as a yellow
oil. IR (KBr) cm21: 1684, 1624. 1H NMR (CDCl3,
500 MHz) d: 0.99 (s, 3H), 1.24±1.50 (m, 2H), 1.58±1.71
(m, 4H), 1.75 (s, 3H), 1.84±1.91 (m, 1H), 1.92±2.02 (m,
1H), 2.02±2.07 (m, 2H), 2.31 (ddd, Jˆ15.0, 13.0, 7.5 Hz,
1H), 2.49 (ddd, Jˆ15.0, 5.0, 2.0 Hz, 1H). 13C NMR (CDCl3,
125 MHz) d: 18.3, 20.8, 25.3, 26.7, 31.8, 33.2, 38.3,
40.2, 43.3, 122.5, 130.0, 206.4. MS (EI) m/z (%): 178
(M1, 100). HRMS (EI) Calcd for C12H18O: 178.1358.
Found: 178.1377.
4.1.1. 1-[3-(1-Methyl-2,5-dioxolanyl)propyl]cyclohex-2-
en-1-ol (8). Li dispersion (30%; 188 mg, 2.44 mmol),
washed with dry hexane, was suspended in THF (6 mL)
under argon. 7 (97%, 0.20 mL, 2.00 mmol) and 2-(3-chlor-
opropyl)-2-methyl-1,3-dioxolane (0.50 mL, 3.20 mmol)
were added. The mixture was sonicated for 30 min on an
ultrasonic bath. The mixture was cooled to 08C, Li was
quenched by water, and the resulting mixture was neutra-
lized by aqueous NH4Cl. The whole was extracted with
EtOAc, and the extract was washed with water and brine,
dried (MgSO4), and concentrated. The concentrate was puri-
®ed by column chromatography (1:1 hexane/EtOAc) to give
324 mg (72%) of 8 as a colorless oil. IR (KBr) cm21: 3466,
1
1647, 1142. H NMR (CDCl3, 500 MHz) d: 1.32 (s, 3H),
1.45±1.72 (m, 11H), 1.92±1.95 (m, 1H), 2.02±2.05 (m,
1H), 3.91±3.97 (m, 4H), 5.63 (d, Jˆ10.5 Hz, 1H), 5.80
(ddd, Jˆ10.5, 4.0, 3.0 Hz, 1H). 13C NMR (CDCl3,
125 MHz) d: 18.2, 19.0, 23.7, 25.2, 34.4, 39.6, 42.3, 64.6
(2C), 69.7, 110.1, 129.9, 132.6. MS (EI) m/z (%): 226 (M1,
0.2), 87 (100). HRMS (EI) Calcd for C13H22O3: 226.1569.
Found: 226.1577.
4.1.2. 3-[3-(1-Methyl-2,5-dioxolanyl)propyl]cyclohex-2-
en-1-one (9). To a stirred suspension of PCC (564 mg,
2.62 mmol) and Al2O3 (523 mg) in CH2Cl2 (6 mL) was
added a solution of 8 (302 mg, 1.34 mmol) in CH2Cl2

S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
131
4.1.5. 3-[3-(2,5-Dioxolanyl)propyl]cyclohex-2-en-1-one
(17). By a procedure similar to that described for the
preparation of 8 from 7, 7 (97%, 1.35 mL, 13.5 mmol)
was converted into 1-[3-(2,5-dioxolanyl)propyl]cyclohex-2-
resulting mixture was re¯uxed (Dean±Stark device) at
1108C for 1.5 h. The mixture was then washed with satu-
rated NaHCO3 and water, dried (MgSO4), ®ltered and
concentrated. Puri®cation of the concentrate by column
chromatography (2:1 hexane/EtOAc) yielded 15 (181 mg,
81% combined yield; 78% in two steps) as an oil. IR (KBr)
en-1-ol (1.92 g, 67%) as a colorless oil. IR (KBr) cm21
:
1
3462, 1706, 1142. H NMR (CDCl3, 500 MHz) d: 1.45±
1.71 (m, 11H), 1.88±1.92 (m, 1H), 1.99±2.10 (m, 1H),
3.79±3.86 (m, 2H), 3.91±3.98 (m, 2H), 4.84 (t, Jˆ5.0 Hz,
1H), 5.60 (d, Jˆ10.0 Hz, 1H), 5.77 (ddd, Jˆ10.0, 5.0,
3.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz) d: 18.2, 19.0,
25.2, 34.3, 35.4, 42.1, 64.8 (2C), 69.6, 104.5, 130.0,
132.6. Anal. Calcd for C12H20O3: C, 67.89; H, 9.50.
Found: C, 67.90; H, 9.39. According to the procedure
for the synthesis of 9 from 8, 1-[3-(2,5-dioxolanyl)-
1
cm21: 1682, 1620. H NMR (CDCl3, 500 MHz) d: 1.02 (s,
3H), 1.40 (td, Jˆ12.5, 4.5 Hz, 1H), 1.51±1.61 (m, 2H),
1.64±1.70 (m, 3H), 1.83±1.88 (m, 1H), 1.93±2.02 (m,
1H), 2.08±2.20 (m, 2H), 2.26 (ddd, Jˆ16.5, 12.5, 7.5 Hz,
1H), 2.50±2.55 (m, 1H), 6.36 (dd, Jˆ4.5, 3.0 Hz, 1H). 13C
NMR (CDCl3, 125 MHz) d: 17.8, 19.3, 25.5, 25.9, 35.6,
37.8, 38.9, 40.4, 133.2, 144.6, 202.9. MS (EI) m/z (%):
164 (M1, 100). HRMS (EI) Calcd for C11H16O: 164.1201.
Found: 164.1211.
propyl]cyclohex-2-en-1-ol
(1.0 g,
4.71 mmol)
was
converted into 17 (963 mg, 97%) as a colorless oil. IR
(KBr) cm21: 1668, 1624, 1140. 1H NMR (CDCl3,
500 MHz) d: 1.58±1.68 (m, 4H), 1.93±1.98 (m, 2H),
2.22±2.27 (m, 4H), 2.32 (t, Jˆ6.5 Hz, 2H), 3.79±3.85
(m, 2H), 3.89±3.96 (m, 2H), 4.84 (t, Jˆ4.5 Hz, 1H),
5.85 (s, 1H). 13C NMR (CDCl3, 125 MHz) d: 21.2,
22.7, 29.6, 33.2, 37.3, 37.7, 64.9 (2C), 104.1, 125.9,
165.8, 199.8. MS (EI) m/z (%): 210 (M1, 4.1), 99 (29.7),
73 (100). HRMS (EI) Calcd for C12H18O3: 210.1256. Found:
210.1266.
4.1.8. (1Sp,2Sp,6Rp)-6-Methyl-10-oxobicyclo[4.4.0]-
decane-2-carbonitrile (19). A solution of 15 (315 mg,
1.92 mmol) in benzene (5 mL) was added dropwise to a
solution of Et2AlCN (1.0 M in toluene, 5.7 mL) under stir-
ring at 08C. After being stirred at 08C for 2 h, a viscous
solution of Et3N (2.60 mL, 18.7 mmol) and TMSCl
(1.20 mL, 9.53 mmol) in benzene (1.5 mL) was added
using a canula. The resulting mixture was warmed to rt,
and Et2O (80 mL) and saturated aqueous NaHCO3
(35 mL) were added carefully. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with saturated
aqueous NaHCO3, dried (K2CO3), ®ltered and concentrated
to give the crude silyl enol ether. The concentrate was then
dissolved in 10:1 THF±H2O (17 mL) and 1N HCl (0.17 mL)
was added and the mixture was stirred at rt for 15 min. The
resulting mixture was diluted with ether (40 mL), and
K2CO3 (533 mg) was added. The mixture was stirred for
10 min, dried (Na2SO4), ®ltered, and concentrated. Puri®ca-
tion of the residue by ¯ash chromatography (3:1 hexane/
EtOAc) gave 330 mg (90%) of 19 as a colorless solid.
Recrystallization (hexane/Et2O) provided an analytically
pure coarse powder: mp 95±968C. IR (KBr) cm21: 2235,
1712. 1H NMR (CDCl3, 500 MHz) d: 1.10 (s, 3H), 1.31 (td,
Jˆ14.0, 4.5 Hz, 1H), 1.50 (tt, Jˆ14.0, 4.5 Hz, 1H), 1.56±
1.64 (m, 4H), 1.80±1.90 (m, 1H), 1.92±2.01 (m, 2H), 2.10
(d, Jˆ14.6 Hz, 1H), 2.23±2.30 (m, 2H), 2.45 (dt, Jˆ14.6,
3.3 Hz, 1H), 2.97 (br s, 1H). 13C NMR (CDCl3, 125 MHz)
d: 18.1, 18.7, 21.4, 23.4, 29.4, 39.4, 39.8, 40.5, 41.9, 57.3,
121.6, 208.0. MS (EI) m/z (%): 191 (M1, 32), 111 (100).
HRMS (EI) Calcd for C12H17NO: 191.1310. Found:
191.1334.
4.1.6. 3-[3-(2,5-Dioxolanyl)propyl]-3-methylcyclohexan-
1-one (18). By a procedure similar to that described for
the preparation of 10 from 9, 17 (460 mg, 2.19 mmol) was
converted into 18 (475 mg, 96%) as a colorless oil. IR (KBr)
1
cm21: 1709, 1142. H NMR (CDCl3, 500 MHz) d: 0.89 (s,
3H), 1.21±1.29 (m, 2H), 1.30±1.40 (m, 2H), 1.48±1.53 (m,
1H), 1.57±1.64 (m, 3H), 1.78±1.87 (m, 2H), 2.07 (d,
Jˆ13.4 Hz, 1H), 2.16 (d, Jˆ13.4 Hz, 1H), 2.19±2.28 (m,
2H), 3.78±3.85 (m, 2H), 3.89±3.96 (m, 2H), 4.81 (t,
Jˆ4.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) d: 17.9,
22.1, 24.9, 34.4, 35.7, 38.6, 41.0, 41.6, 53.7, 64.8 (2C),
104.4, 212.1. MS (FAB) m/z (%): 227 (MH1, 100).
HRMS (FAB) Calcd for C13H23O3 (MH1): 227.1647.
Found: 227.1657.
4.1.7. 6-Methylbicyclo[4.4.0]dec-1(10)-en-2-one (15).
Aqueous HCl (10%; 2.7 mL) was added to a solution of
18 (392 mg, 1.73 mmol) in MeOH (5 mL), and the resulting
mixture was heated at 658C for 4 h. The reaction was neutra-
lized by saturated NaHCO3, and MeOH was evaporated.
The aqueous layer was then extracted with EtOAc, and
the extract was washed with water and brine, dried
(MgSO4), ®ltered and concentrated. The residue was puri-
®ed by column chromatography (3:7!3:2 EtOAc/hexane)
to give 230 mg (73%) of 10-hydroxy-6-methylbicyclo-
[4.4.0]decan-2-one along with 54 mg (19%) of 15 as an
oil. 10-Hydroxy-6-methylbicyclo[4.4.0]decan-2-one: IR
4.1.9. (1Sp,2Sp,6Rp,10Rp)-10-hydroxy-6-methyl-
bicyclo[4.4.0]decane-2-carbonitrile. To a solution of 19
(135 mg, 0.706 mmol) in MeOH±THF (2:1, 5 mL) was
added NaBH4 (35 mg, 0.925 mmol) at 08C. The mixture
was warmed to rt and stirred for 1 h. Aqueous NH4Cl
(excess) was added. The whole was concentrated, and the
concentrate was extracted with EtOAc. The extract was
washed with water and brine, dried (MgSO4) and concen-
trated. The concentrate was puri®ed through a short silica
gel column (1:1 hexane/EtOAc) to provide 136 mg (100%)
1
(KBr) cm21: 3412, 1705. H NMR (CDCl3, 500 MHz) d:
0.94 (s, 3H), 1.12±1.24 (m, 3H), 1.51 (dt, Jˆ14.0, 3.0 Hz,
1H), 1.60±1.68 (m, 2H), 1.78±2.10 (m, 6H), 2.25±2.29 (m,
1H), 2.54 (td, Jˆ14.0, 7.0 Hz, 1H), 4.01 (td, Jˆ11.0, 4.0 Hz,
1H). 13C NMR (CDCl3, 125 MHz) d: 19.9, 22.0, 28.0, 30.2,
35.2, 37.3, 38.7, 39.2, 67.6, 69.8, 214.1. MS (EI) m/z (%):
182 (M1, 1.5), 111 (100). HRMS (EI) Calcd for C11H18O2:
182.1307. Found: 182.1326. To a solution of the above
alcohol (250 mg, 1.37 mmol) in benzene (25 mL) was
added p-TsOH´H2O (38 mg, 0.2 mmol) under stirring. The
of the title compound as a colorless oil. IR (KBr) cm21
:
3508, 2235. 1H NMR (CDCl3, 500 MHz) d: 1.03±1.10
(m, 2H), 1.30±1.61 (m, 7H), 1.41 (s, 3H), 1.82 (d,
Jˆ3.5 Hz, 1H), 1.84±1.98 (m, 3H), 2.06±2.11 (m, 1H),

132
S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
2.75 (m, 1H), 3.98 (m, 1H). 13C NMR (CDCl3, 125 MHz) d:
16.6, 18.8, 20.1, 29.0, 31.4, 34.6, 34.9, 43.0, 43.3, 48.6,
71.6, 123.6. MS (EI) m/z (%): 193 (M1, 11.2), 95 (100).
HRMS (EI) Calcd for C12H19NO (M1): 193.1467. Found:
193.1471.
0.14 mmol) was added to a solution of 21 (25 mg,
0.065 mmol) in THF (0.6 mL) and the solution was heated
at 458C for 8 h. The reaction mixture was cooled to rt, Et2O
(2 mL) and brine (1.5 mL) was added and the mixture was
stirred for 15 min. The organic phase was separated and the
aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine, dried (MgSO4),
®ltered and concentrated. The residue was puri®ed on silica
gel column (5:1 hexane/EtOAc) to afford 18.5 mg (91%) of
22 as a colorless solid. Recrystallization from hexane
provided pure 22. Mp 90±918C. IR (KBr) cm21: 3506,
4.1.10. (1Sp,2Sp,6Rp,10Rp)-6-Methyl-10-(trimethyl-
siloxy)bicyclo-[4.4.0]decane-2-carbonitrile (20). To a
solution of (1Sp,2Sp,6Rp,10Rp)-10-hydroxy-6-methyl-
bicyclo[4.4.0]decane-2-carbonitrile (53 mg, 0.274 mmol)
in CH2Cl2 (1.5 mL) was added DMAP (8.35 mg,
0.068 mmol) and pyridine (0.46 mL) at 08C. TMSCl
(0.127 mL, 1.00 mmol) was then added and stirred at 08C
for 1.5 h. Saturated NaHCO3 (5 mL) was added, and the
reaction mixture was extracted with CH2Cl2, dried
(MgSO4) and concentrated. The concentrate was puri®ed
by column chromatography (3:1 hexane/Et2O) to give 20
(64.5 mg, 89%) as a white solid. Recrystallization from hex-
ane±Et2O provided analytically pure 20 as colorless
1
2231. H NMR (CDCl3, 500 MHz) d: 1.03±1.12 (m, 2H),
1.29 (d, Jˆ2.5 Hz, 1H), 1.31±1.42 (m, 5H), 1.44 (s, 3H),
1.52±1.63 (m, 2H), 1.84±1.90 (m, 2H), 1.93±2.02 (m, 2H),
3.47 (d, Jˆ8.8 Hz, 1H), 3.59 (d, Jˆ8.8 Hz, 1H), 4.17 (m,
1H), 4.54 (d, Jˆ11.5 Hz, 1H), 4.57 (d, Jˆ11.5 Hz, 1H),
7.27±7.36 (m, 5H). 13C NMR (CDCl3, 125 MHz) d: 16.5,
19.1, 20.4, 34.5, 34.6, 35.8, 38.7, 42.8, 44.1, 51.4, 66.5,
73.8, 74.4, 123.7, 127.8 (2C), 128.0, 128.5 (2C), 137.2.
MS (EI) m/z (%): 313 (M1, 5.4), 265 (9.3), 91 (100).
HRMS (EI) Calcd for C20H27NO2: 313.2042. Found:
313.2043.
1
needles. Mp 74±758C. IR (KBr) cm21: 2357. H NMR
(CDCl3, 500 MHz) d: 0.14 (s, 9H), 1.00±1.06 (m, 2H),
1.19 (dd, Jˆ4.0, 2.5 Hz, 1H), 1.33±1.41 (m, 4H), 1.37 (s,
3H), 1.52±1.64 (m, 2H), 1.74±1.77 (m, 1H), 1.85±1.92 (m,
2H), 2.06±2.09 (m, 1H), 2.58±2.62 (m, 1H), 3.87 (m, 1H).
13C NMR (CDCl3, 125 MHz) d: 0.01 (3C), 16.7, 18.9, 20.1,
29.5, 32.0, 34.7, 34.9, 43.0, 43.7, 49.1, 71.4, 123.1. MS
(FAB) m/z (%): 266 (MH1, 100), 250 (55). HRMS (FAB)
Calcd for C15H28NOSi (MH1): 266.1940. Found: 266.1942.
Anal. Calcd for C15H27NOSi: C, 67.87; H, 10.25; N, 5.28.
Found: C, 68.03; H, 10.11; N, 5.29.
4.1.13. (1Rp,2Rp,6Rp,10Rp)-10-(Aminomethyl)-10-(benzyl-
oxymethyl)-6-methylbicyclo[4.4.0]decan-2-ol (26). To a
solution of 22 (20 mg, 0.064 mmol) in THF (2.3 mL) was
added LiAlH4 (1.0 M in ether; 1.2 mL, 1.2 mmol) at 2788C,
and the resulting mixture was warmed to rt and then re¯uxed
for 4 h. The solution was cooled to 08C, quenched by
successive addition of H2O (47 ml), 2N NaOH (47 mL)
and H2O (146 mL). The resulting heterogeneous mixture
was stirred at rt for 2 h, ®ltered, and the solid was
washed with EtOAc. The combined ®ltrates were
concentrated. Crystallization from hexane yielded 26
(16.8 mg, 83%) as white granules. Mp 92±948C. IR
(KBr) cm21: 3369, 3292, 1587. 1H NMR (CDCl3,
500 MHz) d: 1.06±1.59 (m, 11H), 1.35 (s, 3H), 1.70±
1.74 (m, 1H), 1.89±1.98 (m, 2H), 2.79 (d, Jˆ12.8 Hz,
1H), 3.14 (d, Jˆ9.0 Hz, 1H), 3.22 (d, Jˆ12.8 Hz, 1H),
3.57 (d, Jˆ9.0 Hz, 1H), 4.05 (m, 1H), 4.46 (d, Jˆ12.0 Hz,
1H), 4.52 (d, Jˆ12.0 Hz, 1H), 7.28±7.37 (m, 5H). 13C
NMR (CDCl3, 125 MHz) d: 17.1, 18.2, 22.6, 34.6,
34.9, 38.0, 42.5, 43.4, 44.5, 47.0, 52.9, 64.6, 73.3,
76.7, 127.4 (2C), 127.6, 128.4 (2C), 138.6. MS (EI)
m/z (%): 317 (M1, 6.8), 91 (100). HRMS (EI) Calcd
for C20H31NO2: 317.2355. Found: 317.2353.
4.1.11. (1Rp,2Rp,6Rp,10Rp)-2-(Benzyloxymethyl)-6-
methyl-10-(trimethylsiloxy)bicyclo[4.4.0]decane-2-
carbonitrile (21). To a stirred solution of diisopropylamine
(0.105 mL, 0.749 mmol) in THF (0.85 mL), n-BuLi (1.6 M
in hexane; 0.46 mL, 0.736 mmol) was added dropwise at
2788C, and the mixture was warmed to 08C for 30 min.
Then a solution of 20 (85 mg, 0.32 mmol) in THF
(0.85 mL) was added dropwise and the resulting solution
was stirred for 20 min. The yellow solution obtained was
cooled to 2788C and freshly distilled benzyloxymethyl
chloride (0.085 mL, 0.61 mmol) was added rapidly. The
reaction mixture was warmed to 08C. After stirring at 08C
for 1.5 h, the reaction mixture was quenched with saturated
aqueous NaHCO3 (excess). The whole was then extracted
with EtOAc, and the extract was washed with brine, dried
(MgSO4), ®ltered and concentrated. Puri®cation of the
concentrate by ¯ash chromatography (60:1 hexane/EtOAc)
yielded 112 mg (91%) of 21 as a colorless oil. IR (KBr)
4.1.14. (1Rp,2Rp,6Rp,10Rp)-10-(Benzyloxymethyl)-10-
(hydroxymethyl)-6-methylbicyclo[4.4.0]decan-2-ol (25).
A mixture of 26 (10 mg, 0.0315 mmol), KOH (100 mg,
1.75 mmol, excess) and diethylene glycol (0.6 mL) were
placed in a round-bottom ¯ask equipped with a re¯uxing
condenser and the mixture was heated at 2108C for 3 h. The
black solution was then cooled to rt, Et2O (2 mL) and H2O
(1.5 mL) were added. The organic phase was separated and
the aqueous layer was extracted with EtOAc. The combined
organic layers were then washed with brine, dried (MgSO4),
®ltered and concentrated. Puri®cation of the residue by
column chromatography (5:1 hexane/EtOAc) gave 6.5 mg
(65%) of 25. Recrystallization from hexane/Et2O provided
1
cm21: 2231. H NMR (CDCl3, 500 MHz) d: 0.07 (s, 9H),
1.07 (t, Jˆ12.8 Hz, 2H), 1.40 (s, 3H), 1.32±1.42 (m, 4H),
1.58 (m, 1H), 1.72±2.02 (m, 6H) 3.42 (d, Jˆ9.0 Hz, 1H),
3.57 (d, Jˆ9.0 Hz, 1H), 4.00 (m, 1H), 4.46 (d, Jˆ12.3 Hz,
1H), 4.60 (d, Jˆ12.3 Hz, 1H), 7.30±7.38 (m, 5H). 13C NMR
(CDCl3, 125 MHz) d: 0.34, 16.5, 19.1, 20.5, 34.6, 34.7,
36.1, 38.2, 43.1, 44.2, 49.2, 66.4, 72.7, 73.5, 123.3, 127.9
(2C), 128.0, 128.5 (2C), 137.5. MS (FAB) m/z (%): 386
(MH1, 37), 91 (100). HRMS (FAB) Calcd for
C23H35NO2Si (MH1): 386.2515. Found: 386.2502.
4.1.12. (1Rp,2Rp,6Rp,10Rp)-2-(Benzyloxymethyl)-10-
hydroxy-6-methylbicyclo[4.4.0]decane-2-carbonitrile
(22). A solution of n-Bu4NF (1.0 M in THF; 0.14 mL,
an analytically pure white solid: mp 1398C. IR (KBr) cm21
:
3236 (br). H NMR (CDCl3, 500 MHz) d: 1.33 (s, 3H),
1.06±1.59 (m, 11H), 1.84±1.87 (m, 1H), 1.90±1.99 (m,
1

S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
133
1H), 3.39 (d, Jˆ9.0 Hz, 1H), 3.47 (d, Jˆ12.5 Hz, 1H), 3.48
(d, Jˆ9.0 Hz, 1H), 4.14 (br s, 2H), 4.20 (s, 1H), 4.21 (d,
Jˆ12.5 Hz, 1H), 4.47 (d, Jˆ12.0 Hz, 1H), 4.52 (d,
Jˆ12.0 Hz, 1H), 7.27±7.37 (m, 5H). 13C NMR (CDCl3,
125 MHz) d: 16.9, 18.4, 22.3, 34.6, 35.4, 35.6, 42.7, 44.5,
46.2, 52.2, 66.2, 66.3, 73.5, 78.2, 127.5 (2C), 127.6, 128.4
(2C), 138.3. MS (FAB) m/z (%): 319 (MH1, 25), 91 (100).
HRMS (FAB) Calcd for C20H31O3 (MH1): 319.2273.
Found: 319.2269.
2H), 2.38 (d, Jˆ14.5 Hz, 1H), 3.32 (s, 1H), 3.43 (d,
Jˆ8.5 Hz, 1H), 3.59 (d, Jˆ8.5 Hz, 1H), 4.26 (m, 1H),
4.42 (d, Jˆ12.0 Hz, 1H), 4.48 (d, Jˆ12.0 Hz, 1H), 7.26±
7.36 (m, 5H), 10.10 (s, 1H). 13C NMR (CDCl3, 125 MHz) d:
16.5, 18.7, 22.4, 32.9, 34.5, 35.1, 43.5, 44.1, 52.7, 53.7,
66.4, 73.7, 75.6, 127.5 (2C), 127.8, 128.4 (2C), 137.7,
211.4. MS (FAB) m/z (%): 339 (MNa1, 48), 91 (100).
HRMS (FAB) Calcd for C20H28NaO3 (MNa1): 339.1936.
Found: 339.1958.
4.1.15. Methyl (1Rp,2Sp,6Rp,10Rp)-2-(benzyloxymethyl)-
10-hydroxy-6-methylbicyclo[4.4.0]decane-2-carboxylate
(27). To a solution of 21 (27 mg, 0.070 mmol) in MeOH
(2.3 mL) were added KOH (176 mg, excess) and K2CO3
(75 mg), and the mixture was concentrated by a stream of
N2. The residue was then heated at 1408C for 24 h. After
cooling, the resulting residue was dissolved in water (6 mL),
and Et2O (6 mL) was added. The mixture was cooled to 08C
and acidi®ed to pH 2 by 1N HCl. The organic layer was
separated and the aqueous layer was extracted with EtOAc
(10 mL£5). The combined organic layers were washed with
brine, dried (MgSO4) and concentrated to give the crude
acid. The crude acid was then dissolved in dry Et2O
(4 mL), and TMSCHN2 (2.0 M in hexane, 90 mL,
0.18 mmol) was added at 08C. After 30 min the mixture
was concentrated. The residue was puri®ed by column chro-
matography (5:1 hexane/EtOAc) to give 27 (20.2 mg, 83%)
4.1.18. (1Rp,2Rp,6Rp,10Rp)-10-(Benzyloxymethyl)-6,10-
dimethylbicyclo[4.4.0]decan-2-ol (24). A mixture of 28
(6 mg, 0.0189 mmol), K2CO3 (10 mg, 0.072 mmol), hydra-
zine monohydrate (0.2 mL) in diethylene glycol (0.8 mL)
was re¯uxed at 1708C. After 2 h at 1708C, the reaction ¯ask
was opened and heated to 1908C to distill out excess hydra-
zine and water and again the reaction mixture was re¯uxed
at 2108C for 2.5 h. The reaction mixture was cooled to rt,
H2O (1 mL) and Et2O (1.5 mL) were added, and the mixture
was neutralized by 1N HCl at 08C. The organic layer was
separated and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine, dried
(MgSO4), ®ltered, and concentrated. Puri®cation of the
concentrate by column chromatography (5:1 hexane/
EtOAc) provided 4.5 mg (79%) of 24 as a colorless oil. IR
1
(KBr) cm21: 3548, 1602. H NMR (CDCl3, 500 MHz) d:
1.06±1.87 (m, 14H), 1.14 (s, 3H), 1.27 (s, 3H), 3.00 (d,
Jˆ9.0 Hz, 1H), 3.36 (d, Jˆ9.0 Hz, 1H), 4.20 (br, s, 1H),
4.45 (d, Jˆ12.5 Hz, 1H), 4.51 (d, Jˆ12.5 Hz, 1H), 7.28±
7.36 (m, 5H). 13C NMR (CDCl3, 125 MHz) d: 16.9, 18.4,
20.0, 22.5, 34.4, 36.2, 38.1, 38.7, 44.2, 45.8, 49.9, 68.0,
73.2, 79.8, 127.4 (2C), 128.2, 128.3 (2C), 138.8. MS
(FAB) m/z (%): 325 (MNa1, 19), 91 (100). HRMS (FAB)
Calcd for C20H30NaO2 (MNa1): 325.2143. Found:
325.2140.
1
as a colorless oil. IR (KBr) cm21: 3448, 1730. H NMR
(CDCl3, 500 MHz) d: 1.02 (s, 3H), 1.09±1.52 (m, 8H),
1.63 (s, 1H), 1.78±1.88 (m, 1H), 1.90±1.99 (m, 2H), 2.44±
2.48 (m, 1H), 3.41 (d, Jˆ8.5 Hz, 1H), 3.75 (d, Jˆ8.5 Hz,
1H), 3.77 (s, 3H), 4.25 (m, 1H), 4.44 (d, Jˆ12.5 Hz, 1H),
4.51 (d, Jˆ12.5 Hz, 1H), 5.43 (d, Jˆ2.5 Hz, 1H), 7.27±7.37
(m, 5H). 13C NMR (CDCl3, 125 MHz) d: 16.4, 19.4, 20.9,
34.3, 34.7, 35.2, 44.4, 44.8, 50.7, 52.6, 52.8, 65.2, 73.8,
77.7, 127.3, 127.6 (2C), 128.3, 138.0 (2C), 179.5. MS (EI)
m/z (%): 346 (M1, 0.1), 91 (100). HRMS (EI) Calcd for
C21H30O4: 346.2144. Found: 346.2126.
4.1.19. (1Rp,2Rp,6Rp,10Rp)-10-(Hydroxymethyl)-6,10-
dimethylbicyclo[4.4.0]decan-2-yl benzoate (30). To a
solution of 24 (8 mg, 0.026 mmol) in CH2Cl2 (0.5 mL)
was added dropwise 2,6-lutidine (65 mL, 0.56 mmol) at
08C. BzOTf (44 mL, 0.27 mmol) was then added dropwise
and the resulting mixture was maintained at 08C for 2 h.
Et2O (3 mL) and NaHCO3 (0.3 mL) were added. The
organic layer was separated and the aqueous layer was
extracted with Et2O. The combined organic layers were
washed with brine, dried (MgSO4), ®ltered, and concen-
trated. Puri®cation of the concentrate by column chromato-
graphy (4:1 hexane/Et2O) gave 5.0 mg (47%) of 29 as a
colorless oil. Compound 29: IR (KBr) cm21: 1724, 1603.
1H NMR (CDCl3, 500 MHz) d: 0.90 (s, 3H), 1.19±1.56 (m,
8H), 1.45 (s, 3H), 1.73±1.83 (m, 4H), 1.99 (d, Jˆ14.0 Hz,
1H), 2.93 (d, Jˆ9.0 Hz, 1H), 3.41 (d, Jˆ9.0 Hz, 1H), 4.46
(d, Jˆ12.3 Hz, 1H), 4.57 (d, Jˆ12.3 Hz, 1H), 5.58 (m, 1H),
7.28±7.37 (m, 5H), 7.46 (t, Jˆ7.5 Hz, 2H), 7.56 (t,
Jˆ7.5 Hz, 1H), 8.06±8.08 (m, 2H). 13C NMR (CDCl3,
125 MHz) d: 17.5, 18.4, 19.5, 22.6, 32.6, 34.6, 37.8, 38.5,
44.0, 45.2, 48.1, 71.0, 73.2, 78.8, 127.3 (2C), 127.4, 128.3
(2C), 128.4 (2C), 129.6 (2C), 131.1, 132.7, 138.9, 166.3.
The compound 29 (8 mg, 0.0197 mmol) was subjected to
catalytic hydrogenolysis over Pd/C (8 mg) in MeOH at
atmospheric pressure overnight at rt. The reaction mixture
was ®ltered, and the ®ltrate was concentrated. The concen-
trate was puri®ed by column chromatography (2:1 hexane/
4.1.16. Preparation of the diol (25) from (27). To a solu-
tion of 27 (38 mg, 0.1098 mmol) in THF (1.6 mL) was
added a solution of LiAlH4 (1.0 M in Et2O; 0.4 mL,
0.4 mmol) at 08C. The resulting mixture was stirred at 08C
for 2 h. The mixture was quenched by a sequential addition
of H2O (20 mL), 2N NaOH (20 mL), and H2O (83 mL) and
the resulting heterogeneous mixture was then stirred at rt for
1 h. The mixture was ®ltered and the solid was washed with
EtOAc. The combined organic layers were concentrated and
the concentrate was puri®ed by column chromatography
(1:1 hexane/EtOAc) to provide 25 (32 mg, 92%) as a
white solid.
4.1.17. (1Rp,2Sp,6Rp,10Rp)-2-(Benzyloxymethyl)-10-
hydroxy-6-methylbicyclo[4.4.0]decane-2-carbaldehyde
(28). RuCl2-(PPh3)3 (30 mg, 0.031 mmol) was added to a
solution of 25 (12 mg, 0.0377 mmol) in benzene (0.9 mL),
and the resulting mixture was stirred at rt for 24 h. The black
solution obtained was concentrated and the residue was
chromatographed on silica gel (3:1 hexane/EtOAc) to afford
28 (7.5 mg, 63%) as a thick oil, together with 3.9 mg (33%)
of recovered 25. Compound 28: IR (KBr) cm21: 3477, 1708.
1H NMR (CDCl3, 500 MHz) d: 1.03 (s, 3H), 1.10±1.15 (m,
2H), 1.32±1.48 (m, 6H), 1.59±1.70 (m, 2H), 1.87±1.94 (m,

134
S. M. A. Rahman et al. / Tetrahedron 57 (2001) 127±134
T.; Kamei, K.; Murata, T.; Yoshino, H.; Imanishi, T.;
Kim, S.-W.; Iwata, C. Chem. Pharm. Bull. 1995, 43, 193.
(b) Tanaka, T.; Okuda, O.; Murakami, K.; Yoshino, H.;
Mikamiyama, H.; Kanda, A.; Kim, S.-W.; Iwata, C. Chem.
Pharm. Bull. 1995, 43, 1407.
EtOAc) to give 30 (5.6 mg, 90%) as a colorless oil. IR (KBr)
1
cm21: 3456, 1713, 1601. H NMR (CDCl3, 500 MHz) d:
0.90 (s, 3H), 1.15±1.62 (m, 10H), 1.46 (s, 3H), 1.65 (d,
Jˆ2.4 Hz, 1H), 1.74±1.87 (m, 2H), 2.00 (d, Jˆ14.5 Hz,
1H), 3.16 (dd, Jˆ10.5, 4.0 Hz, 1H), 3.60 (dd, Jˆ10.5,
4.0 Hz, 1H), 5.64 (m, 1H), 7.44±7.48 (m, 2H), 7.55±7.59
(m, 1H), 8.06±8.08 (m, 2H). 13C NMR (CDCl3, 125 MHz)
d: 17.5, 18.3, 19.1, 22.5, 32.7, 34.6, 37.9, 38.1, 44.1, 45.2,
48.1, 70.7, 71.3, 128.5 (2C), 129.6 (2C), 131.0, 132.8,
166.3. MS (FAB) m/z (%): 317 (MH1, 20), 136 (100).
HRMS (FAB) Calcd for C20H29O3 (MH1): 317.2117.
Found: 317.2105.
8. We have recently communicated the discovery of a novel
conversion method of primary aliphatic amines into primary
alcohols and its application to the synthesis of the model
compound 4, see: Rahman, S. M. A.; Ohno, H.; Maezaki,
N.; Iwata, C.; Tanaka, T. Org. Lett. 2000, 2, 2893.
9. This cuprate can be used for construction of quaternary
carbons bearing a vinyl group. For examples, see: (a)
Hashimoto, S.; Sonegawa, M.; Sakata, S.; Ikegami, S. J.
Chem. Soc., Chem. Commun. 1987, 24. (b) Boring, D. L.;
Sindelar, R. D. J. Org. Chem. 1988, 53, 3617.
4.1.20. (1Rp,2Rp,6Rp,10Rp)-10-Benzoyloxy-6,10-di-
methylbicyclo-[4.4.0]decane-2-carboxylic acid (4). A
solution of 30 (4 mg, 0.0126 mmol) in acetone (0.5 mL)
was treated with Jones reagent dropwise until TLC indicated
that no starting material was present. The reaction mixture
was diluted with CH2Cl2, and the whole was washed with
water and brine sequentially, dried (MgSO4), ®ltered and
concentrated. Puri®cation of the concentrate by column
chromatography (3:1 hexane/EtOAc) gave 3.5 mg (84%)
of 4 as a white solid. Recrystallization (hexane) afforded a
pure colorless solid: mp 182±1838C. IR (KBr) cm21: 2931
10. Ziegler reported that copper-mediated vinylation of a similar
cyclic enone occurred from the same face of the 6-methyl
group: see Ref. 4b.
11. (a) Ibuka, T.; Nakai, K.; Habashita, H.; Bessho, K.; Fujii, N.
Tetrahedron 1993, 49, 9479. (b) Habashita, H.; Kawasaki, T.;
Takemoto, Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63,
2392.
12. Construction of the quaternary carbon center with the desired
stereochemistry has proven to be extremely dif®cult. Treat-
ment of the b-methylated enone 31 with Et2AlCN in benzene
gave 32 with undesired stereochemistry. Therefore, we
planned to introduce a cyano and benzyloxymethyl group at
C-4 by a slight modi®cation of the reported procedure by
Overman: see Ref. 4c.
1
(br), 1716. H NMR (CDCl3, 500 MHz) d: 1.28 (m, 4H),
1.34 (s, 3H), 1.48 (s, 3H), 1.56±1.88 (m, 8H), 2.05 (m, 1H),
2.09 (d, Jˆ2.0 Hz, 1H), 5.37 (m, 1H), 7.46 (m, 2H), 7.56 (m,
1H), 8.05 (m, 2H). 13C NMR (CDCl3, 125 MHz) d: 17.5,
18.1, 22.3, 29.7, 32.3, 34.5, 39.8, 43.6, 45.3, 47.1, 49.6,
73.1, 128.2 (2C), 128.5 (2C), 130.9, 132.8, 166.1, 182.0.
MS (FAB) m/z (%): 353 (MNa1, 100). HRMS (FAB)
Calcd for C20H26NaO4 (MNa1): 353.1729. Found:
353.1727.
References
1. Hostettmann, K. Phytochemistry of Plants Used in Traditional
Medicine; Oxford University Press: New York, 1995.
2. (a) Hayashi, T.; Kishi, M.; Kawasaki, M.; Arisawa, M.;
Shimizu, M.; Suzuki, S.; Yoshizaki, M.; Morita, N.; Tezuka,
Y.; Kikuchi, T.; Berganza, L. H.; Ferro, E.; Basualdo, I.
Tetrahedron Lett. 1987, 28, 3693. (b) Hayashi, T.; Kishi,
M.; Kawasaki, M.; Arisawa, M.; Morita, N. J. Nat. Prod.
1988, 51, 360.
13. The undesired A/B-cis product was successively isomerized
into 19 by treating with NaOMe.
14. Commercially available benzyloxymethyl chloride was an
effective alkylating reagent similar to benzyloxymethyl
bromide (not commercially available). These reagents should
be freshly distilled prior to use.
3. Hayashi, T.; Kawasaki, M.; Miwa, Y.; Taga, T.; Morita, N.
Chem. Pharm. Bull. 1990, 38, 945.
15. (a) Kindler, K.; Luhrs, K. Liebigs Ann. Chem. 1965, 685, 36.
(b) Kindler, K.; Luhrs, K. Ber. 1966, 99, 227.
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17. Attempted conversion of the primary hydroxy group of 25 into
a methyl group via radical-mediated reductions of thiocar-
bamate was unsuccessful.
18. Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1981, 22, 1605.
6. Recent examples of the synthesis of other aphidicolanes, see:
Â
(a) Belanger, G.; Deslongchamps, P. Org. Lett. 2000, 2, 285.
19. (a) Huang-Minlon, J. Am. Chem. Soc. 1946, 68, 2487.
(b) Huang-Minlon, J. Am. Chem. Soc. 1949, 71, 3301.
20. Brown, L.; Koreeda, M. J. Org. Chem. 1984, 49, 3875.
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7. (a) Tanaka, T.; Murakami, K.; Okuda, O.; Inoue, T.; Kuroda,