Construction of tricyclic enone, a common precursor for aphidicolane and stemodane B/C/D-ring system

Article abstract of DOI:10.1248/cpb.54.1138

Synthesis of a tricyclic enone (B/C/D ring system), a common key precursor for the aphidicolane- and stemodane-type diterpene, is described. The key reaction for the construction of the quaternary carbon center is allylation of epoxide at the more substit

Full text of DOI:10.1248/cpb.54.1138

1138
Chem. Pharm. Bull. 54(8) 1138—1143 (2006)
Vol. 54, No. 8
Construction of Tricyclic Enone, a Common Precursor for Aphidicolane
and Stemodane B/C/D-Ring System
Tetsuaki TANAKA,* Sachiko YAMAMOTO, Kei HIRAMATSU, Kazuo MURAKAMI, Hitoshi YOSHINO,
Debasis PATRA, Chuzo IWATA, and Hiroaki OHNO
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamadaoka, Suita, Osaka 565–0871, Japan.
Received March 9, 2006; accepted June 3, 2006; published online June 7, 2006
Synthesis of a tricyclic enone (B/C/D ring system), a common key precursor for the aphidicolane- and ste-
modane-type diterpene, is described. The key reaction for the construction of the quaternary carbon center is al-
lylation of epoxide at the more substituted carbon with an organotitanium reagent. Asymmetric reduction with
DIP-Cl followed by stereoselective cyclization of spirocyclic ketone and the functional group modification gave
the desired tricyclic enone in good yield.
Key words aphidicolane; stemodane; allylation; organotitanium reagent
The leaves of the rare littoral plant, Stemodia maritima L. longchamps and co-workers.57,58) These synthetic routes are
(fam. Scrophulariaceae), from Jamaica have long been used extremely important in that the complex tetracyclic skeleton
as a folk medicine for the treatment of venereal disease in the was constructed in an enantioenriched form; however, they
Caribbean Islands.1) Attracted by the reported medicinal are limited to the synthesis of a single aphidicolane or ste-
properties, Manchand and others isolated and characterized modane diterpene. Synthesis of other natural products or
structurally unique tetracyclic diterpenes, stemodin 1 and their analogs is not easily accessible by these routes because
stemodinone 2 (Fig. 1).2—7) Aphidicolin (3),8,9) which has a in many cases the A-ring having oxygen functionalities was
highly related tetracyclic ring system to stemodanes 1 and 2, constructed at the earlier stage of the synthetic routes. There-
was isolated from Cephalalosporium aphidicola by Hesp and fore, development of a systematic synthetic route leading to
co-workers and later found to occur in Nigrosporum sphaer- various kinds of aphidicolanes, stemodanes, and their
ica. The fusion of the five-membered C ring to B in ste- analogs in an enantiomerically pure form is desirable.
modanes 1 and 2 is cis in contrast to the trans fusion in
We then planned a novel flexible synthetic route which can
aphidicolin 3. Aphidicolin is known as a potent antitumor be applied to the synthesis of a variety of aphidicolanes and
(inhibits DNA replication and growth of several human and stemodanes, based on the asymmetric construction of the
neoplastic cells)10—12) and antiviral agent (promising activity B/C/D ring system followed by formation of the highly-func-
against Herpes simplex).13—15) Stemodanes, with a similar tionalized A-ring. A tricyclic enone 4 is considered as the
structure to aphidicolanes, is expected to have related phar- key intermediate, which would lead to either natural or non-
macological activities.
natural aphidicolanes and stemodanes by stereoselective hy-
Their important medicinal properties as well as the pres- drogenation of the double bond as shown in Chart 1. In this
ence of more than six stereocenters and four quaternary car- paper, we describe synthesis of the tricyclic enone 4 through
bons, especially the two adjacent quaternary carbons at C-9 allyltitanium-mediated regioselective ring-opening reaction
and C-10, make these natural products a worthy synthetic of epoxides at the more substituted carbon,59—61) developed
challenge.16) Although there are several reports on the syn- by our group (Chart 2).
thesis of stemodinone,17—20) other stemodanes,21—33) and
Synthetic Plan Our basic strategy is shown in Chart 3.
aphidicolanes34—53) in a racemic form, asymmetric synthesis The tricyclic enone 4 can be obtained from alcohol 6 by one-
of this class of compounds is relatively rare.54—58) The asym-
metric total synthesis of aphidicolin was first achieved by
Holton and co-workers in 1987.54) After that, formal synthe-
sis of (ꢀ)-aphidicolin was reported by Tanis55) and Fuku-
moto.56) Recently, total synthesis of aphidicolanes using
transannular Diels–Alder reaction was achieved by Des-
Fig. 1
Chart 1
∗ To whom correspondence should be addressed. e-mail: t-tanaka@phs.osaka-u.ac.jp
© 2006 Pharmaceutical Society of Japan

August 2006
1139
carbon elongation followed by cyclization. Access to the al- chloride in the presence of chlorotitanium triphenoxide to
cohol 6 was expected through intramolecular a-alkylation of give the alcohol 13 in 77% yield. Gas chromatography analy-
a ketone derived from the acetal 7, which would be prepared sis of their MTPA esters,67,68) 14a and 14b, revealed that the
by the regioselective allylation of the chiral epoxide 8.
alcohol 11 has the desired absolute configuration with 80%
First, we investigated asymmetric preparation of the epox- ee.
ide 11 by Sharpless asymmetric epoxidation62—64) (Chart 4).
Since the optical yield of the Sharpless epoxidation of 10
The allylic alcohol 10 was obtained from 1,4-cyclohexane- was unsatisfactory, the epoxide 11 was converted into 3,5-
dione 9 according to the literature.65,66) Epoxidation of the al- dinitrobenzoate 15 and recrystallized. Optical purity of the
cohol 10 with L-(ꢀ)-diethyl tartrate and titanium tetraiso- mother liquor was improved to 93% ee after repeated recrys-
propoxide gave the epoxide 11. The hydroxy group of 11 was tallization (Chart 5). However, this route to 11 is not an ideal
protected with a methoxymethyl group to afford the corre- process in terms of efficiency and atom economy.
sponding MOM ether 12, which was subjected to the allylti-
Next, preparation of the alcohol 13 through the asymmet-
tanium-mediated ring-opening reaction with allylmagnesium ric reduction was investigated (Chart 6). Racemic alcohol
(ꢁ)-13 was obtained in high yield by epoxidation of 10 with
t-BuOOH-VO(acac)2 and protection of the hydroxy group
with an MOM group, followed by the allylation with the tita-
nium reagent. Swern oxidation of (ꢁ)-13 gave the correspon-
ding ketone 16, which was subjected to the asymmetric re-
Chart 2
duction with (ꢂ)-DIP-Cl69—71) leading to borate 17 without
any side reactions of the terminal olefin. Oxidative work-up
of the resulting borate 17 afforded diol 18 with 96% ee,
which was determined by gas chromatography analysis of the
MTPA esters 14a and 14b. Thus, the key intermediate 18
was obtained in high enantiomeric excess by use of the
asymmetric reduction with DIP-Cl.
We next investigated the stereoselective construction of
the C/D-ring system by the intramolecular a-alkylation of
Chart 3. Synthetic Plan of Tricyclic Enone 4
keto-tosylate 19 (Chart 7). Keto-tosylate 19 was obtained by
tosylation of the primary hydroxy group of the diol 18 and
protection of the secondary alcohol. Regioselective a-alkyla-
tion of 19 (Rꢃprotecting group) under various reaction con-
ditions was unsuccessful. For example, treatment of 19 hav-
ing a TBDMS group with t-BuOK led to bicyclic products,
20 and 21 as a 3 : 1 mixture,72) which were produced by a-
alkylation at carbon a (route a) or carbon b (route b), respec-
tively.
Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, NaH, 0 °C to rt, then 9, ꢂ78 °C;
From these observations, stereoselective formation of the
D-ring by a-alkylation of the conformationally flexible ke-
tone 19 was proven to be difficult. However, the difficulty has
(b) ethylene glycol, p-TSA, reflux; (c) DIBAL-H, ꢂ78 °C, 45% from 9; (d) t-BuOOH,
(ꢀ)-diethyl tartrate, Ti(Oi-Pr)4, molecular sieves 4A, ꢂ20 °C, 82%; (e) MOMCl, (i-
Pr)2NEt, rt, 94%; (f) allylMgCl, ClTi(OPh)3, ꢂ50 °C to rt, 77%; (g) (ꢀ)- or (ꢂ)-MT-
PACl, Et3N, DMAP, rt.
Chart 4. Synthesis of Chiral Alcohol Derivative 13 via Sharpless Epoxida-
tion
been overcome by the use of a conformationally restricted
substrate as shown in Chart 8. Phenylselenenylation73,74) of
the diol 18 led to five-membered ring ether 22, which was
converted to tosylate 23. Treatment of 23 with NaH gave tri-
cyclic ketone 24 as the single isomer in 82% yield through
the stereoselective a-alkylation. Protection of the carbonyl
group followed by reductive deselenenylation75) then af-
forded the alcohol 6 in good yield.
Reagents and conditions: (a) 3,5-dinitrobenzoyl chloride, Et3N, DMAP, 0 °C to rt,
then recrystallization, 92%; (b) K2CO3, MeOH, 0 °C, 100%.
Finally, the B-ring was constructed by carbon chain elon-
Chart 5. Synthesis of Enantioenriched Epoxide by Recrystallization
Reagents and conditions: (a) VO(acac)2, t-BuOOH, reflux; (b) MOMCl, (i-Pr)2NEt, rt, 88% from 10; (c) allylMgCl, ClTi(OPh)3, ꢂ50 °C to rt, 77%; (d) oxalyl chloride, Et3N,
DMSO, ꢂ60 °C, 83%; (e) (ꢂ)-DIP-Cl, neat, rt; (f) 2 N NaOH, 30% H2O2, 0 °C, 75% from 16; (g) MOMCl, (i-Pr)2NEt, 0 °C, 32%; (h) (ꢀ)- or (ꢂ)-MTPACl, Et3N, DMAP, rt.
Chart 6. Synthesis of Chiral Alcohol Derivatives via Asymmetric Reduction

1140
Vol. 54, No. 8
(S)-2-(Hydroxymethyl)-1-oxaspiro[2.5]octan-6-one 6,6-Ethylene Ac-
etal (11) To a stirred solution of Ti(Oi-Pr)4 (9.6 ml, 32.6 mmol) and mo-
lecular sieves 4A in dry CH2Cl2 (10 ml) was added L-(ꢀ)-diethyl tartrate
(5.6 ml, 32.6 mmol) at ꢂ10 °C. After 10 min, tert-butylhydroperoxide (4.0 M
in toluene, 16.3 ml, 65.2 mmol) was added dropwise to the mixture under
gation and aldol cyclization as shown in Chart 9. Hydrobora-
tion of 6 and Swern oxidation of the resulting alcohol 26 led
to keto aldehyde 27. The chemoselective methylation of the
aldehyde 27 with methyltitanium triisopropoxide gave keto-
alcohol 28 in 94% yield. Swern oxidation of 28 followed by stirring. After 30 min, a solution of the allylic alcohol 10 (3.00 g, 16.3 mmol)
in dry CH2Cl2 (3 ml) was added dropwise to the mixture at ꢂ20 °C, and the
mixture was stirred for 4 h at ꢂ20 °C. To the mixture were successively
added water at 0 °C and 30% NaOH/saturated NaCl, and the mixture was
stirred vigorously at room temperature for 2 h. The organic phase was fil-
intramolecular aldol cyclization afforded the tricyclic enone
4 in good yield.
In conclusion, we have developed a reliable synthetic
method of the tricyclic enone 4 with high optical purity, a
common key intermediate for the asymmetric synthesis of
stemodane- and aphidicolane-type diterpenes. The quater-
nary carbon center was efficiently constructed by the allylti-
tanium-mediated regioselective ring-opening reaction of the
epoxide 12.
tered through Celite and dried over MgSO4. Concentration under reduced
pressure gave a residual oil, which was purified by column chromatography
over silica gel (n-hexane : EtOAcꢃ1 : 2) to afford the epoxide 11 (2.67 g,
82% yield) as a colorless oil: [a]D20 ꢂ14.7° (cꢃ1.20, CHCl3); IR (CHCl3)
1
cmꢂ1 3421 (OH); H-NMR (300 MHz, CDCl3) d: 1.54—1.95 (m, 8H), 3.05
(dd, Jꢃ6.7, 4.3 Hz, 1H, 2-H), 3.68—3.75 (dd, Jꢃ12.0, 7.0 Hz, 1H, OCHH),
3.83—3.90 (dd, Jꢃ12.0, 4.0 Hz, 1H, OCHH), 3.98 (t, Jꢃ2.7 Hz, 4H,
OC2H4O); 13C-NMR (75 MHz, CDCl3) d: 26.2, 32.0, 32.8 (2C), 61.0, 62.0,
63.6, 63.38, 64.40, 108.1; MS (EI) m/z: 200 (Mꢀ). Anal. Calcd for C10H16O4:
C, 59.98; H, 8.05. Found: C, 60.04; H, 7.94.
Experimental
General Methods Melting points are uncorrected. Nominal (LRMS)
and exact mass (HRMS) spectra were recorded on a JEOL JMS-01SG-2 or
(S)-2-(Methoxymethoxymethyl)-1-oxaspiro[2.5]octan-6-one 6,6-Ethyl-
ene Acetal (12) To a stirred solution of 11 (1.00 g, 5.00 mmol) in dry
CH2Cl2 (13 ml) were added (i-Pr)2NEt (1.80 ml, 1.00 mmol) and MOMCl
(0.75 ml, 10.0 mmol), and the mixture was stirred overnight at room temper-
ature. Saturated NaHCO3 was added to the mixture and the whole was ex-
tracted with CH2Cl2. The extract was washed with water and brine, and dried
over MgSO4. Concentration under reduced pressure gave a residual oil,
which was purified by column chromatography over silica gel (n-
hexane : EtOAcꢃ3 : 1) to afford the MOM ether 12 (1.17 g, 94% yield) as a
1
JMS-HX/HX 110A mass spectrometer. H-NMR spectra were recorded in
CDCl3. Chemical shifts are reported in parts per million downfield from in-
ternal Me4Si (sꢃsinglet, dꢃdoublet, ddꢃdouble doublet, dddꢃdoublet of
double doublet, tꢃtriplet, qꢃquartet, mꢃmultiplet). Optical rotations were
measured in CHCl3 with a JASCO DIP-360 digital polarimeter. For flash
chromatography, silica gel 60 H (silica gel for thin-layer chromatography,
Merck) or silica gel 60 (finer than 230 mesh, Merck) was employed.
1
colorless oil: [a]D25 ꢀ0.36° (cꢃ1.27, CHCl3); H-NMR (300 MHz, CDCl3)
d: 1.55—1.95 (m, 8H), 3.06 (dd, Jꢃ6.0, 5.1 Hz, 1H, 2-H), 3.38 (s, 3H,
OMe), 3.65 (dd, Jꢃ11.4, 6.0 Hz, 1H, OCHH), 3.73 (dd, Jꢃ11.4, 5.1 Hz, 1H,
OCHH), 3.97 (t, Jꢃ2.5 Hz, 4H, OC2H4O), 4.65 (d, Jꢃ6.6 Hz, 1H, OCHHO),
4.68 (d, Jꢃ6.6 Hz, 1H, OCHHO); 13C-NMR (75 MHz, CDCl3) d: 26.2, 32.0,
32.7, 32.8, 55.3, 61.1, 61.8, 64.37, 64.40, 66.0, 96.6, 108.2; MS (EI) m/z:
244 (Mꢀ). Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 58.91; H,
8.08.
4-[(R)-1-Hydroxy-2-(methoxymethoxy)ethyl]-4-(prop-2-enyl)cyclo-
hexan-1-one 1,1-Ethylene Acetal (13) from 12 To a stirred solution of
ClTi(OPh)3 (1.0 M in THF; 14.1 ml, 14.1 mmol) was added dropwise allyl-
magnesium chloride (2.0 M in THF; 9.4 ml, 18.9 mmol) at ꢂ78 °C. The mix-
ture was stirred for 1 h at ꢂ50 °C, and a solution of the epoxide 12 (1.15 g,
4.71 mmol) in THF (6 ml) was added to the mixture, and the mixture was
gradually warmed to 0 °C. Saturated KF was added to the mixture. The re-
sulting white precipitate was filtered off, and the filtrate was extracted with
Et2O. The extract was washed with 2 N NaOH, water, and brine, and dried
over MgSO4. Concentration under reduced pressure gave a residual oil,
which was purified by column chromatography over silica gel (n-
hexane : EtOAcꢃ5 : 1) to afford the alcohol 13 (1.04 g, 77% yield) as a col-
orless oil: [a]D24 ꢂ5.02° (cꢃ0.96, CHCl3); IR (CHCl3) cmꢂ1 3504 (OH),
1637 (CꢃC); 1H-NMR (300 MHz, CDCl3) d: 1.46—1.76 (m, 8H), 2.14 (dd,
Jꢃ13.9, 7.5 Hz, 1H, CHHCHꢃCH2), 2.34 (dd, Jꢃ13.9, 7.0 Hz, 1H,
CHHCHꢃCH2), 2.52 (br s, 1H, OH), 3.37 (s, 3H, OMe), 3.46—3.52 (m,
1H, 1ꢄ-H), 3.71—3.79 (m, 2H, 2ꢄ-CH2), 3.93 (s, 4H, OC2H4O), 4.66 (s, 2H,
OCH2O), 5.05—5.10 (m, 2H, CHꢃCH2), 5.81—5.94 (m, 1H, CHꢃCH2);
13C-NMR (75 MHz, CDCl3) d: 28.2, 28.6, 30.1, 30.3, 36.3, 38.1, 55.3, 64.1
(2C), 69.2, 74.0, 96.9, 108.7, 117.4, 134.9; MS (EI) m/z: 286 (Mꢀ). Anal.
Calcd for C15H26O5: C, 62.91; H, 9.15. Found: C, 63.06; H, 9.02.
Chart 7
Reagents and conditions: (a) PhSeCl, ꢂ78 °C; (b) 10% HCl, rt, 55% from 18; (c) p-
TsCl, Et3N, DMAP, 0 °C to rt, 85%; (d) NaH, 40 °C, 82%; (e) ethylene glycol, PPTS,
reflux; (f) Ca, liq. NH3, ꢂ33 °C, 95% from 24.
Chart 8. Formation of C-Ring via Spiro Tetrahydrofuran Derivative
Reagents and conditions: (a) BH3·SMe2, 0 °C to rt then 30% H2O2, 3 N NaOH, 0 °C to rt, 82%; (b) oxalyl chloride, Et3N, DMSO, ꢂ60 °C, 82%; (c) MeMgCl, ClTi(Oi-Pr)3,
ꢂ60 °C, 94%; (d) oxalyl chloride, Et3N, DMSO, ꢂ60 °C, 91%; (e) NaOH/MeOH, reflux, 91%.
Chart 9. Synthesis of Tricyclic Enone 4

August 2006
1141
4-{(1R)-1-[(2R)-2-Methoxy-2-(trifluoromethyl)phenylacetoxy]-2-
(methoxymethoxy)ethyl}-4-(prop-2-enyl)cyclohexan-1-one 1,1-Ethylene
Acetal (14a) To a stirred solution of 13 (8.0 mg, 0.030 mmol) in dry
CH2Cl2 (0.3 ml) were successively added Et3N (8.3 ml, 0.059 mmol), 4-di-
methylaminopyridine (DMAP; 3.3 mg, 0.030 mmol), and (ꢀ)-MTPACl
(7.9 ml, 0.045 mmol), and the mixture was stirred for 30 min at room temper-
ature. Saturated NaHCO3 was added to the mixture and the whole was ex-
tracted with CHCl3. The extract was washed with brine, and dried over
MgSO4. Concentration under reduced pressure gave a residual oil, which
was purified by column chromatography over silica gel (n-
hexane : EtOAcꢃ3 : 1) to afford the MTPA ester 14a (8.3 mg, 59% yield) as
a colorless oil: IR (CHCl3) cmꢂ1 1747 (CꢃO), 1639 (CꢃC); 1H-NMR
(500 MHz, CDCl3) d: 1.17—1.54 (m, 8H), 2.04—2.10 (m, 2H), 3.27 (s, 3H),
3.52 (s, 3H), 3.59—3.83 (m, 6H), 4.41 (d, Jꢃ6.5 Hz, 1H, CHHOMOM),
4.55 (d, Jꢃ6.5 Hz, 1H, CHHOMOM), 4.95 (m, 2H), 5.37 (d, Jꢃ7.5 Hz, 1H),
5.64—5.72 (m, 1H), 7.30—7.52 (m, 5H, Ph).
hexane : EtOAcꢃ2 : 1) to afford the ketone 16 (3.14 g, 83% yield) as a color-
1
less oil: IR (CHCl3) cmꢂ1 1718 (CꢃO), 1639 (CꢃC); H-NMR (270 MHz,
CDCl3) d: 1.42—1.65 (m, 6H), 1.96—2.09 (m, 2H), 2.24 (d, Jꢃ7.3 Hz, 2H),
3.31 (s, 3H), 3.86 (s, 4H), 4.33 (s, 2H), 4.61 (s, 2H), 4.90—5.10 (m, 2H),
5.59 (m, 1H); 13C-NMR (67.5 MHz, CDCl3) d: 29.8 (2C), 31.5 (2C), 42.4,
49.9, 55.6, 64.2 (2C), 68.4, 96.3, 108.1, 118.5, 132.6, 209.0; MS (EI) m/z:
284 (Mꢀ). Anal. Calcd for C15H24O5: C, 63.36; H, 8.51. Found: C, 63.26; H,
8.41.
(R)-4-(1,2-Dihydroxyethyl)-4-(prop-2-enyl)cyclohexan-1-one 1,1-Eth-
ylene Acetal (18) A mixture of (ꢂ)-DIP-Cl (293 mg, 0.915 mmol) and 16
(200 mg, 0.704 mmol) was stirred for 2 d. The mixture was concentrated
under reduced pressure to remove pinene. The residue was diluted with
EtOAc, and diethanolamine (192 mg, 1.83 mmol) was added to the mixture.
After stirring for 2 h, the mixture was filtered and concentrated in vacuo.
The residue was diluted with THF (5 ml), and 2 N NaOH (1 ml) and 30%
H2O2 (1 ml) were added dropwise to the mixture at 0 °C, and the mixture
was stirred for 2 h. After salting out, the whole was extracted with CHCl3,
and the extract was dried over MgSO4. Concentration under reduced pres-
sure gave a residue, which was purified by column chromatography over sil-
ica gel (n-hexane : EtOAcꢃ1 : 5) to afford the alcohol 18 (128 mg, 75%
yield) as a colorless oil: [a]D27 ꢂ5.59° (cꢃ1.27, CHCl3); IR (CHCl3) cmꢂ1
4-{(1R)-1-[(2S)-2-Methoxy-2-(trifluoromethyl)phenylacetoxy]-2-
(methoxymethoxy)ethyl}-4-(prop-2-enyl)cyclohexan-1-one 1,1-Ethylene
Acetal (14b) By a procedure identical with that described for the synthesis
of 14a from 13, the alcohol 13 (9.0 mg, 0.031 mmol) was converted into 14b
(9.6 mg, 61% yield) by the reaction with (ꢂ)-MTPACl: colorless oil; IR
1
(CHCl3) cmꢂ1 1747 (CꢃO), 1639 (CꢃC); H-NMR (500 MHz, CDCl3) d:
1
3439 (OH), 1637 (CꢃC); H-NMR (270 MHz, CDCl3) d: 1.35—1.70 (m,
1.47—1.58 (m, 8H), 2.05—2.20 (m, 2H), 3.20 (s, 3H), 3.52—3.75 (m, 5H),
3.85 (s, 4H), 4.37 (d, Jꢃ6.5 Hz, 1H, CHHOMOM), 4.40 (d, Jꢃ6.5 Hz, 1H,
CHHOMOM), 4.96—5.02 (m, 2H), 5.34 (d, Jꢃ7.5 Hz, 1H), 5.72—5.75 (m,
1H), 7.32—7.53 (m, 5H, Ph).
8H), 2.05 (dd, Jꢃ14.2, 7.4 Hz, 1H), 2.24 (dd, Jꢃ14.2, 7.2 Hz, 1H), 3.54 (m,
2H), 3.69 (m, 1H), 3.86 (s, 4H), 4.90—5.10 (m, 2H), 5.80 (m, 1H); 13C-
NMR (67.5 MHz, CDCl3) d: 28.4, 29.0, 30.4, 30.6, 36.6, 38.6, 62.9, 64.5
(2C), 76.9, 109.0, 118.0, 135.2; MS (EI) m/z: 242 (Mꢀ).
(S)-2-(3,5-Dinitrobenzoyloxy)methyl-1-oxaspiro[2.5]octan-6-one 6,6-
Ethylene Acetal (15) To a stirred solution of 11 (3.00 g, 15.0 mmol) in dry
CH2Cl2 (150 ml) were successively added Et3N (8.4 ml, 60.0 mmol), DMAP
(366 mg, 3.0 mmol), and 3,5-dinitrobenzoyl chloride (10.4 g, 45.0 mmol),
and the stirring was continued for 3 h at room temperature. Saturated
NaHCO3 was added to the mixture, and the whole was extracted with
CHCl3. The extract was washed with brine and dried over MgSO4. Concen-
tration under reduced pressure gave a residue, which was purified by column
chromatography over silica gel (n-hexane : EtOAcꢃ3 : 1) to afford the 3,5-
dinitrobenzoate 15 (5.44 g, 92% yield) as a colorless solid: mp 121—123 °C
(from n-hexane–EtOAc); [a]D24 ꢂ26.6° (cꢃ0.91, CHCl3); IR (CHCl3) cmꢂ1
1736 (CꢃO), 1630 (Ph), 1545 (NO2); 1H-NMR (270 MHz, CDCl3) d:
1.45—1.96 (m, 8H), 3.20 (dd, Jꢃ7.4, 4.0 Hz, 1H), 3.91 (s, 4H), 4.36 (dd,
Jꢃ12.1, 7.4 Hz, 1H), 4.71 (dd, Jꢃ12.1, 4.0 Hz, 1H), 9.11 (m, 2H), 9.17 (m,
1H); 13C-NMR (67.5 MHz, CDCl3) d: 26.3, 31.8, 32.7 (2C), 59.9, 61.7 (2C),
64.4 (2C), 65.4, 107.8, 122.6, 129.4, 129.5, 133.3, 148.6, 162.4; MS (EI)
m/z: 394 (Mꢀ). Anal. Calcd for C17H18N2O9: C, 51.78; H, 4.60; N, 7.10.
Found: C, 51.77; H, 4.61; N, 7.13.
(S)-2-(Hydroxymethyl)-1-oxaspiro[2.5]octan-6-one 6,6-Ethylene Ac-
etal (11) from 13 To a stirred solution of 15 (150 mg, 0.381 mmol) in
MeOH (4 ml) was added saturated aqueous K2CO3 (1 ml) at 0 °C, and the
mixture was stirred for 5 min at this temperature. Saturated NH4Cl was
added to the mixture, and the solvent was removed in vacuo. The residue
was diluted with EtOAc and washed with brine, and dried over MgSO4.
Concentration under reduced pressure gave a residual oil, which was purified
by column chromatography over silica gel (n-hexane : EtOAcꢃ1 : 2) to af-
ford the epoxy alcohol 11 (76.0 mg, 100% yield).
(ꢀ)-4-(1-Hydroxy-2-methoxymethoxy)ethyl-4-(prop-2-enyl)cyclo-
hexan-1-one 1,1-Ethylene Acetal [(ꢀ)-13] To a stirred solution of 10
(1.00 g, 5.43 mmol) in dry benzene (15 ml) were added VO(acac)2 (43.2 mg,
0.163 mmol) and tert-butylhydroperoxide (TBHP; 80% aqueous solution;
0.73 ml, 5.97 mmol), and the mixture was stirred under reflux for 5 min.
After cooling, the mixture was washed with saturated NaHCO3, water, and
brine, and dried over MgSO4. Concentration under reduced pressure gave a
residue, which was purified by column chromatography over silica gel (n-
hexane : EtOAcꢃ1 : 2) to afford the epoxy alcohol (ꢁ)-11 (1.02 g, 94%
yield). By a procedure identical with that described for the synthesis of 13
from 11, (ꢁ)-11 was converted into (ꢁ)-13.
4-[2-(Methoxymethoxy)-1-oxoethyl]-4-(prop-2-enyl)cyclohexan-1-one
1,1-Ethylene Acetal (16) To a stirred solution of oxalyl chloride (2.53 ml,
29.0 mmol) in dry CH2Cl2 (35 ml) was added DMSO (4.11 ml, 57.9 mmol) at
ꢂ60 °C, and the mixture was stirred for 15 min. To the mixture was added
dropwise (ꢁ)-13 (4.14 g, 14.6 mmol) in dry CH2Cl2 (43 ml), and the stirring
was continued for 1 h. To the mixture was added dropwise Et3N (12.1 ml,
86.8 mmol), and the mixture was stirred for 2 h. Water was added to the mix-
ture, and the whole was extracted with CH2Cl2. The extract was washed with
brine and dried over MgSO4. Concentration under reduced pressure gave a
residue, which was purified by column chromatography over silica gel (n-
(R)-4-(1-Hydroxy-2-methoxymethoxy)ethyl-4-(prop-2-enyl)cyclo-
hexan-1-one 1,1-Ethylene Acetal (13) from 18 To a stirred solution of 18
(10 mg, 0.041 mmol) in dry CH2Cl2 (0.4 ml) were added (i-Pr)2NEt (7.6 ml,
0.083 mmol) and MOMCl (3.1 ml, 0.041 mmol) at 0 °C, and the mixture was
stirred for 30 min at this temperature. Saturated NaHCO3 was added to the
mixture and the whole was extracted with CH2Cl2. The extract was washed
with water and brine, and dried over MgSO4. Concentration under reduced
pressure gave a residual oil, which was purified by column chromatography
over silica gel (n-hexane : EtOAcꢃ2 : 1) to afford the MOM ether 13
(3.8 mg, 32% yield).
(1R,3R)- and (1R,3S)-1-(Hydroxymethyl)-3-(phenylselenomethyl)-2-
oxaspiro[4.5]decan-8-one (22) To a stirred solution of 18 (150 mg,
0.620 mmol) in dry CH2Cl2 (4 ml) was added PhSeCl (178 mg, 0.930 mmol)
at ꢂ78 °C, and the mixture was stirred for 4 h. Saturated NaHCO3 was
added to the mixture, and the whole was extracted with CH2Cl2. The extract
was washed with water and brine, and dried over MgSO4. Concentration
under reduced pressure gave a residual oil, which was purified by short col-
umn chromatography over silica gel (n-hexane : EtOAcꢃ8 : 1) to afford the
corresponding THF derivative having an acetal moiety. To a stirred solution
of this compound in THF (5 ml) was added 10% HCl (3 ml), and the mixture
was stirred for 2 h at room temperature. The mixture was extracted with
EtOAc, and the extract was washed with saturated NaHCO3 and brine, and
dried over MgSO4. Concentration under reduced pressure gave a residue,
which was purified by column chromatography over silica gel (n-
hexane : EtOAcꢃ1 : 1) to afford 22 (120 mg, 55% yield) as a yellow oil: IR
(CHCl3) cmꢂ1 3429 (OH), 1713 (CꢃO); 1H-NMR (200 MHz, CDCl3) d:
1.70—2.00 (m, 6H), 2.33—2.41 (m, 4H), 3.00—3.28 (m, 2H), 3.60—3.95
(m, 3H), 4.27—4.46 (m, 1H), 7.25—7.57 (m, 5H, Ph).
(1R,3R)- and (1R,3S)-1-[(4-Methylphenylsulfonyloxy)methyl]-3-
(phenylselenomethyl)-2-oxaspiro[4.5]decan-8-one (23) To a stirred solu-
tion of 22 (15.0 g, 42.5 mmol) in dry CH2Cl2 (300 ml) were added Et3N
(11.8 ml, 85.0 mmol), DMAP (517 mg, 4.25 mmol), and p-TsCl (12.1 g,
63.8 mmol) at 0 °C, and the mixture was stirred for 6 h at room temperature.
Water was added to the mixture at 0 °C, and the whole was extracted with
CH2Cl2. The extract was washed with water and brine, and dried over
MgSO4. Concentration under reduced pressure gave a residue, which was
purified by column chromatography over silica gel (n-hexane : EtOAcꢃ3 : 1)
to afford the tosylate 23 (18.4 g, 85% yield) as a yellow oil: IR (CHCl3)
cmꢂ1 1720 (CꢃO); 1H-NMR (200 MHz, CDCl3) d: 1.61—1.87 (m, 6H),
2.13—2.50 (m, 4H), 2.45 (s, 3H), 2.93—3.16 (m, 2H), 3.80—4.05 (m, 3H),
4.24—4.31 (m, 1H), 7.23—7.86 (m, 9H, 2ꢅPh).
(1S,3R,5S,7R)- and (1S,3S,5S,7R)-3-(Phenylselenomethyl)-4-oxatricy-
clo[5.3.1.01.5]undecan-8-one (24) To a stirred solution of 23 (18.0 g,
35.5 mmol) in dry THF (400 ml) was added 60% NaH (1.7 g, 35.5 mmol),
and the mixture was stirred for 8 h at 40 °C. After cooling, the mixture was
poured into water, and the whole was extracted with CH2Cl2. The extract
was washed with water and brine, and dried over MgSO4. Concentration
under reduced pressure gave a residue, which was purified by column chro-

1142
Vol. 54, No. 8
was washed with brine, and dried over MgSO4. Concentration under reduced
pressure gave a residue, which was purified by column chromatography over
silica gel (n-hexane : EtOAcꢃ2 : 1) to afford (1R,5S)-5-[(R)- and (S)-3-hy-
droxybutyl]bicyclo[3.2.1]octane-2,6-dione 2,2-ethylene acetal (28) (a mix-
ture of diastereoisomers; 2.01 g, 94% yield).
matography over silica gel (n-hexane : EtOAcꢃ4 : 1) to afford the tricyclic
compound 24 (9.75 g, 82% yield) as a yellow oil: IR (CHCl3) cmꢂ1 1720
(CꢃO); 1H-NMR (200 MHz, CDCl3) d: 1.62—2.38 (m, 10H), 2.83 (m, 1H),
3.03—3.18 (m, 2H), 4.19—4.54 (m, 2H), 7.25—7.52 (m, 5H, Ph).
(1S,3R,5S,7R)- and (1S,3S,5S,7R)-3-(Phenylselenomethyl)-4-oxatricy-
clo[5.3.1.01.5]undecan-8-one 8,8-Ethylene Acetal (25) To a stirred solu-
tion of 24 (9.0 g, 26.9 mmol) in dry benzene (300 ml) were added ethylene
glycol (30.0 ml, 536 mmol) and pyridinium p-toluenesulfonate (PPTS;
2.00 g, 7.96 mmol), and the mixture was stirred under reflux with a Dean-
Stark trap for 6 h. After cooling, saturated NaHCO3 was added to the mix-
ture. The whole was extracted with Et2O, and the extract was washed with
brine and dried over MgSO4. Concentration under reduced pressure gave a
residue, which was purified by column chromatography over silica gel (n-
To a stirred solution of oxalyl chloride (1.24 ml, 1.41 mmol) in dry
CH2Cl2 (20 ml) was added DMSO (2.01 ml, 28.2 mmol) at ꢂ60 °C, and the
mixture was stirred for 15 min. A solution of 28 (1.80 g, 7.09 mmol) in dry
CH2Cl2 (25 ml) was added dropwise to the mixture, and the mixture was
stirred for 1 h. To the mixture was added dropwise Et3N (5.93 ml,
42.4 mmol), and the mixture was stirred for 2 h. Water was added to the mix-
ture, and the whole was extracted with CH2Cl2. The extract was washed with
brine and dried over MgSO4. Concentration under reduced pressure gave a
residue, which was purified by column chromatography over silica gel (n-
hexane : EtOAcꢃ3 : 1) to afford 29 (1.63 g, 91% yield) as a colorless oil:
[a]D24 ꢀ3.54° (cꢃ1.05, CHCl3); IR (CHCl3) cmꢂ1 1730 (CꢃO), 1710
(CꢃO); 1H-NMR (500 MHz, CDCl3) d: 1.42—1.81 (m, 7H), 2.00—2.03 (m,
1H), 2.12 (s, 3H), 2.16—2.46 (m, 5H), 3.84—4.04 (m, 4H); 13C-NMR
(67.5 MHz, CDCl3) d: 27.0, 29.6, 29.7, 32.2, 36.9, 38.7, 39.0, 42.4, 49.6,
64.4, 64.7, 109.5, 208.2, 220.0; MS (EI) m/z: 252 (Mꢀ), 181
(MꢀꢂCH3COCH2CH2). Anal. Calcd for C14H20O4: C, 66.65; H, 7.99.
Found: C, 66.79; H, 7.94.
1
hexane : EtOAcꢃ3 : 1) to afford 25 (9.99 g, 97% yield) as a yellow oil: H-
NMR (200 MHz, CDCl3) d: 1.18—1.35 (m, 2H), 1.40—2.32 (m, 9H),
2.93—3.20 (m, 2H), 3.79—3.99 (m, 4H), 4.10—4.20 (m, 1H), 4.36—4.49
(m, 1H), 7.22—7.53 (5H, Ph).
(1R,5R,7S)-6-Hydroxy-5-(prop-2-enyl)bicyclo[3.2.1]octan-2-one 2,2-
Ethylene Acetal (6) Ca (208 mg, 549 mmol) was added to liq. NH3
(70 ml), and the mixture was stirred for 10 min at ꢂ33 °C. To the mixture
was added a solution of 25 (208 mg, 549 mmol) in Et2O (7 ml), and the mix-
ture was stirred for 7 min. Aqueous NH4Cl was added to the mixture until a
blue color disappeared. NH3 was evaporated at room temperature, and water
was added to the residue. The whole was extracted with EtOAc, and the ex-
tract was washed with water and brine, and dried over MgSO4. Concentra-
tion under reduced pressure gave a residue, which was purified by column
(1R,8R)-Tricyclo[6.3.1.01,6]dodec-5-ene-4,9-dione 9,9-Ethylene Acetal
(4) To a stirred solution of 29 (128 mg, 0.508 mmol) in dry MeOH (5 ml)
was added NaOH (56.9 mg, 1.16 mmol), and the mixture was stirred under
reflux for 24 h. After cooling, water was added to the mixture, and the sol-
vent was removed in vacuo. The residue was diluted with EtOAc and washed
with brine, and dried over MgSO4. Concentration under reduced pressure
gave a residue, which was purified by column chromatography over silica
gel (n-hexane : EtOAcꢃ2 : 1) to afford the tricyclic enone 4 (108 mg, 91%
yield) as a colorless solid: mp 188—189 °C (from i-Pr2O); [a]D23 ꢀ95.7
chromatography over silica gel (n-hexane : EtOAcꢃ3 : 1) to afford
6
(120 mg, 98% yield) as a colorless oil: [a]D24 ꢀ26.8° (cꢃ1.21, CHCl3); IR
(CHCl3) cmꢂ1 3487 (OH), 1639 (CꢃC); 1H-NMR (500 MHz, CDCl3) d:
1.38—1.67 (m, 8H), 2.13—2.29 (m, 4H), 3.81—3.98 (m, 5H), 5.05—5.11
(m, 2H), 5.90 (m, 1H); 13C-NMR (67.5 MHz, CDCl3) d: 29.1, 31.6, 37.4,
39.1, 39.7, 42.9, 45.5, 64.0, 64.5, 75.9, 110.7, 116.9, 136.1; MS (EI) m/z:
224 (Mꢀ). Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.49; H,
8.94.
1
(cꢃ1.17, CHCl3); IR (CHCl3) cmꢂ1 1658 (CꢃO), 1620 (CꢃC); H-NMR
(500 MHz, CDCl3) d: 1.45—2.06 (m, 8H), 2.27—2.38 (m, 2H), 2.49—2.61
(m, 3H), 3.85—4.09 (m, 4H), 5.90 (s, 1H, CꢃCH); 13C-NMR (67.5 MHz,
CDCl3) d: 29.9, 31.7, 32.8, 33.5, 35.1, 42.3, 42.4, 43.5, 64.3, 64.7, 110.3,
122.6, 174.5, 199.3; MS (EI) m/z: 234 (Mꢀ). Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 71.62; H, 7.67.
(1R,5S,7S)-6-Hydroxy-5-(3-Hydroxypropyl)bicyclo[3.2.1]octan-2-one
2,2-Ethylene Acetal (26) To a stirred solution of 6 (3.00 g, 13.4 mmol) in
dry THF (60 ml) was added BH3·SMe2 (3.81 ml, 40.2 mmol) at 0 °C, and the
mixture was stirred for 1 h at room temperature. After the mixture was
cooled to 0 °C, 3 N NaOH (26.8 ml) and 30% H2O2 (8.21 ml) were added
dropwise and the mixture was stirred for 2 h. After salting out, the whole
was extracted with CHCl3 and the extract was dried over MgSO4. Concentra-
tion under reduced pressure gave a residue, which was purified by column
chromatography over silica gel (n-hexane : EtOAcꢃ1 : 2) to afford the diol
26 (2.72 g, 82% yield) as a colorless solid: mp 103—104 °C (from i-Pr2O);
[a]2D1 ꢀ28.5° (cꢃ0.82, CHCl3); IR (CHCl3) cmꢂ1 3400 (OH); 1H-NMR
(270 MHz, CDCl3) d: 1.29—1.57 (m, 12H), 2.04—2.16 (m, 1H), 2.18—2.24
(m, 1H), 2.69 (br, 1H), 3.50—3.63 (m, 2H), 3.74—3.92 (m, 4H); 13C-NMR
(67.5 MHz, CDCl3) d: 27.9, 29.4, 30.1, 31.4, 38.3, 39.6, 43.0, 45.9, 63.2,
64.3, 64.8, 75.5, 111.2; MS (EI) m/z: 242 (Mꢀ), 224 (MꢀꢂOH). Anal. Calcd
for C13H22O4: C, 64.44; H, 9.15. Found: C, 63.96; H, 9.11.
3-[(1S,5R)-7-oxobicyclo[3.2.1]octan-1-yl]propanal 4ꢁ,4ꢁ-Ethylene Ac-
etal (27) To a stirred solution of oxalyl chloride (3.75 ml, 43.0 mmol) in
dry CH2Cl2 (20 ml) was added DMSO (6.10 ml, 86.0 mmol) at ꢂ60 °C, and
the mixture was stirred for 15 min. To the mixture was added dropwise 26
(2.60 g, 10.7 mmol) in dry CH2Cl2 (25 ml), and the mixture was stirred for
1 h. Et3N (17.9 ml, 128 mmol) was added to the mixture, and the mixture
was stirred for 2 h. Water was added to the mixture and the whole was ex-
tracted with CH2Cl2. The extract was washed with brine and dried over
MgSO4. Concentration under reduced pressure gave a residue, which was
purified by column chromatography over silica gel (n-hexane : EtOAcꢃ2 : 1)
to afford the keto aldehyde 27 (2.09 g, 82% yield) as a colorless oil: [a]D21
ꢀ4.03° (cꢃ0.89, CHCl3); IR (CHCl3) cmꢂ1 1738 (CꢃO), 1724 (CꢃO); 1H-
NMR (500 MHz, CDCl3) d: 1.56—2.06 (m, 8H), 2.22—2.40 (m, 5H),
3.87—4.03 (m, 4H), 9.75 (s, 1H); 13C-NMR (67.5 MHz, CDCl3) d: 25.3,
29.6, 32.1, 36.9, 39.0, 39.1, 42.4, 49.6, 64.4, 64.8, 109.4, 201.7, 219.7; MS
(EI) m/z: 238 (Mꢀ).
Acknowledgements This work was supported by the Asahi Glass Foun-
dation and Grant-in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
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