The new method for introduction of an allyl group into the angular position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one and its application to chiral Wieland-Miescher type compound synthesis

Article abstract of DOI:10.1248/cpb.53.207

The stereoselective introduction of an allyl group into the angular position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one was accomplished using Birch reduction and an enolate trapping reaction. It was determined that the allyl group was

Full text of DOI:10.1248/cpb.53.207

February 2005
Chem. Pharm. Bull. 53(2) 207—213 (2005)
207
The New Method for Introduction of an Allyl Group into the Angular
Position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one
and Its Application to Chiral Wieland–Miescher Type Compound Synthesis
a,b
Kou HIROYA,*,a Taisuke TAKAHASHI,a,b Katsunori SHIMOMAE,a and Takao SAKAMOTO
a Graduate School of Pharmaceutical Sciences, Tohoku University; Aoba-ku, Sendai 980–8578, Japan: and b Tohoku
University 21st Century COE Program “Comprehensive Research and Education Center for Planning of Drug
Development and Clinical Evaluation”; Sendai, Japan.
Received September 28, 2004; accepted November 10, 2004; published online November 11, 2004
The stereoselective introduction of an allyl group into the angular position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-
hexahydro-1-benzopyran-5-one was accomplished using Birch reduction and an enolate trapping reaction. It was
determined that the allyl group was introduced via an unexpected conformation-flipped from the initially formed
one. Two diastereomeric Wieland–Miescher type compounds, having the allyl group at the angular position,
were synthesized as optically pure forms.
Key words betulin; triterpene; Birch reduction; enolate trapping
catalyst (Fig. 3).3—6) The optically pure 6a can be obtained by
a single recrystallization, and can be utilized for subsequent
syntheses of many natural products.7—11) However, the
cyclization reaction of compounds with side chains other
than a methyl group (e.g., allyl group 7b) was observed to
have serious depreciation of the optical yield.12) In addition,
proline did not work as a catalyst for this reaction, meaning a
stoichiometric amount of proline is required to complete the
reaction. If expensive synthetic proline has to be used, this
presents a serious economic obstacle. Therefore, before start-
ing the synthesis of the betulin analogues, it was decided to
develop an efficient method for synthesizing optically pure
bicyclo[4.4.0]decaline derivatives.
Triterpenoid compounds are of interest because they occur
widely in nature and have unique biological activities.
Recently, Naganuma and his colleagues found that three nat-
ural triterpenes, betulin (1), uvaol (2), and soyasapogenol B
(3), have reducing effects against the toxicity of cadmium
chloride in HepG2 cells (Fig. 1).1) They also reported that
betulin induced certain proteins, though not metallothionein,
which is the representative protein in reducing heavy metal
toxicity.1)
To clarify the reduction mechanism of cadmium toxicity,
we investigated the relationship between expression of activi-
ties and structures, with particular focus on the functional
groups of betulin, using its analogues. The results showed
that both the polar functional group, found at either the C3 or
C28 positions, and the isopropenyl group play important
roles in reducing cadmium toxicity and the cytotoxicity of
betulin (1).2) However, it is difficult to carry out further
investigation into the bioactivities of betulin because the only
functional groups of this compound are hydroxyl and
isopropenyl, both of which are crucial for its activity. There-
fore, we decided to synthesize analogues of betulin, which
could not be otherwise derived from natural products. Our
synthetic strategy is summarized in Fig. 2, which shows the
pentacyclic ring system being divided into two fragments:
the AB fragment 4 and the DE fragment 5. Since our focus
was on the angular substituents between the D and E rings,
the starting material for 5 needed to be the optically pure
bicyclo[4.4.0]decaline derivative 6b, and the starting material
for 4 the Wieland–Miescher ketone 6a.
Results and Discussion
The essential features of the synthesis reaction are illus-
trated in Figs. 4 and 5. When the optically active diketone 8
was treated under acidic conditions, a mixture of the two
diastereomers 9a and 9b resulted. However, by using an acid-
catalyzed dehydration reaction, the mixture of 9a and 9b was
converted to the single enantiomer 10. Using a dissolving-
metal reduction reaction with 10, it was expected that 11a
The optically active Wieland–Miescher type bicyclic
ketone 6a was effectively synthesized from the prochiral
tricarbonyl compound 7a, using chiral proline as a chiral
Fig. 2. Retrosynthetic Analysis of Betulin (1)
Fig. 3
Fig. 1
∗ To whom correspondence should be addressed. e-mail: hiroya@mail.tains.tohoku.ac.jp
© 2005 Pharmaceutical Society of Japan

208
Vol. 53, No. 2
Chart 1
Fig. 4. Synthetic Strategy for Both 13a and 13b
Fig. 6
which was synthesized from the known diol 2113) using the
usual acetalization process (3,3-dimethoxypentane, PPTS,
CH2Cl2, rt, 11 h, 95%), was reduced to the alcohol 23
(LiAlH4, THF, 0 °C, 15 min, 99%).14—19) The resulting
hydroxyl group was converted to bromine under standard
conditions (CBr4, PPh3, Et3N, CH2Cl2, rt, 2 h, 86%), produc-
ing 24. Unfortunately, efforts using the alkylation reactions20)
to produce 26 failed, with the isolable compounds consisting
either of a mixture of the alcohol 23 and the methyl ether 27,
or the enol ether 28. Thus, our focus shifted from synthesiz-
ing 26 from the alkylation reaction of 1,3-cyclohexanedione
(25) to the construction of the substituted 1,3-cyclohexa-
none-ring system from d-keto-ester derivative 29 (Fig. 6).
Ethyl acetoacetate (30) was regioselectively alkylated with
the bromide 24 by the dianion method (NaH, BuLi, THF-
HMPA, 0 °C, then 24, rt, 1 h, 86%),21) producing a good yield
of 31. This was then alkylated again with ethyl 3-bromo-
propanoate (32) at the C2 position of 31 to provide 33 (NaH,
THF, 31, rt, 2 h, 89%). To remove the ethoxylcarbonyl group,
33 was subjected to alkaline hydrolysis conditions (KOH,
tBuOH–H2O, reflux, 5 h), acidified with 3 N HCl, followed by
both decarboxylation and deacetalization reactions by reflux-
ing the mixture. Finally, the mixture was concentrated under
reduced pressure to remove the volatile materials and
refluxed in methanolic HCl (AcCl, MeOH) to produce a 74%
yield of 5-substituted 6,8-dioxabicyclo[3.2.1]octane deriva-
tive 36 as the sole product (Chart 2). The conversion from 33
to 36 can be handled in one flask and can be applied to gram-
scale synthesis.
Fig. 5. Synthetic Strategy for Both (8aS)-16 and (8aR)-19
would be the predominant intermediate product, since the
bulky substituent on C2 occupies the equatorial position,
whereas it occupies the axial position in intermediate product
11b. Alkylation of the enolate 11a at the angular position
C4a again gave two conformers, 12a and 12b. For both eno-
late 12a and 12b, allyl bromide comes from the axial direc-
tion (from the b face for 12a and the a face for 12b), accord-
ing to the stereoelectronic effects. This might be expected to
provide (2S,4aS,8aS)-13a and (2S,4aR,8aS)-13b, respectively.
Although the selective reaction favors efficient synthesis,
diastereomeric 13a and 13b are separable, and it is expected
that both could be used as the target molecule. Using the
reaction sequence described from 10 to 13a and 13b, the
chirality at C2 of 10 was transferred to the C4a positions of
13a and 13b. This can be considered to be the same as the
desymmetrization of the prochiral carbonyl group of the
diketone 8 (Fig. 4).
Optically active (8aS)-16 can be synthesized from 13b via
the enol ether 14, followed by hydrolysis and an intramolecu-
lar aldol reaction (Method A). Alternately, (8aR)-19 can be
synthesized via 17 by hydrolysis of the enol ether, oxidation
of the secondary alcohol, and an intramolecular aldol reac-
tion (Method B). Similarly, (8aR)-19 and (8aS)-16 can be
synthesized from 13a, using Methods A and B, respectively
(Fig. 5).
Having established a synthetic route for 36, which is the
synthetic equivalent of 26, the cyclization reaction of 36 was
investigated (Table 1). Lewis acids (entries 1 and 2), a weak
Brønsted acid (entry 3), and a carboxylate (entry 4) did not
promote any reaction and 36 was completely recovered.
However, reaction of 36 with TfOH in CH2Cl2 or trifluoro-
toluene produced the desired bicyclic compound 10, with
yields of 71% or 28%, respectively (entries 5 and 6). The
solvent effect of this reaction was remarkable, with the reac-
Based on the concept described above, a chiral side chain
unit, 24, synthesized from commercially-available (S)-malic
acid (20), was introduced to 1,3-cyclohexanedione (25). The
results are summarized in Chart 1. The ester group of 22,

February 2005
209
Chart 2
Table 1. Cyclization Reaction of 36 to 10
Chart 3
Entry
Acid (1 eq)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
BF3·OEt2
TiCl4
CSA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
72
72
72
72
24
24
3
No reaction
No reaction
No reaction
No reaction
71
TFA
TfOH
TfOH
TfOH
PhCF3
ClCH2CH2Cl
28
79
Chart 4
38b is not yet clear. There does not appear to be a large
energy difference between the two conformers, but the C–O
bond is parallel to the p orbital of the enolate in the
conformer 38a. Therefore, one possible reason for 38a’s
predominance might be the stabilizing effect of the C–O anti-
bonding orbital by ligation of the enolate p orbital (Chart 3).
A detailed investigation of this stereochemical outcome is
now in progress in our laboratory.
Our next step was conversion of 39 to the target mole-
cules, (8aS)-16 and (8aR)-19, which are essentially enan-
tiomers. Synthesis of the former was examined first (Chart
4). The TBS group was eliminated using standard conditions
(HF pyridine, THF, rt, 30 min, 100%) and the resulting
hydroxyl group was converted to iodide, producing 42 with
good yield (I2, PPh3, imidazole, CH2Cl2, rt, 17 h, 88%). E2
elimination of the iodide was carried out with DBU in DMF
at 100 °C, and the resulting unstable enol ether, 43, was
hydrolyzed under acidic conditions, without isolation, to
provide the acetal 44 (3 N HCl, rt, 3 h, 45% from 42). Acety-
lation of 44 (Ac2O, Et3N, DMAP, CH2Cl2, rt, 6 d, 79%) re-
sulted in 45, and was then subjected to an intramolecular
aldol reaction using pyrrolidine enamine (pyrrolidine, ben-
zene, rt, 24 h, then reflux, 3.5 h, 79%), to provide the desired
46, which is equivalent to (8aS)-16 (RꢁAc).
tion time shortened and the yield slightly improved by using
ClCH2CH2Cl (entry 7).
To introduce the angular substituents, the hydroxyl group
was protected by a TBS group (TBSCl, imidazole, DMF, rt,
12 h, 100%), followed by reductive alkylation of the a, b-un-
saturated ketone moiety of 37. The TBS ether 37 was reacted
under Birch reduction conditions (Li, liq. NH3, THF ꢀ78 °C,
1 h), followed by the direct addition of allyl bromide to the
mixture to produce the desired ketone 39, with a 36% yield,
together with an unidentified polyallylated compound.22) The
1
stereochemistry of 39 was determined by H-NMR, with the
observed n.O.e. shown in the inset of Chart 3. The coupling
pattern of the proton in the C8a position showed typical
equatorial orientation (a broad singlet) and n.O.e. was
observed between the protons in the C2 and C8a positions.
Therefore, as expected, protonation at the b position of the
carbonyl group (C8a) occurred from the a face to afford an S
configuration at C8a. Furthermore, the b proton (equatorial)
in the C4 position displayed an unexpectedly low field shift
1
in H-NMR, the result of the anisotropy effect of the car-
bonyl group. Using the molecular model, this low field shift
in 40 does not seem possible. It is difficult to accept that allyl
bromide approached from the a face (equatorial orientation)
in 38b, due to the stereoelectronic effect for a successive
alkylation reaction. We speculate that the alkylation occurred
after a flipping of conformation from 38b to 38a, and then
proceeded from the a face. Why 38a was predominant over
The other isomer, 55, was synthesized according to Charts
5 and 6. The carbonyl group of 39 was reduced by LiBH4 in
MeOH–Et2O at ꢀ30 °C to produce a separable mixture of di-
astereomeric alcohols 48 and 49. The hydroxyl group of the

210
Vol. 53, No. 2
what long, each reaction can be carried out on a large scale
and without any loss of the optical purity. Optimization of
the synthetic route and the synthesis of betulin and its ana-
logues are currently in progress in our laboratory.
Experimental
General Procedures All melting points were determined with Yazawa
Micro Melting Point BY-2 and are uncorrected. 1H-NMR spectra (400 or
600 MHz) and 13C-NMR spectra (100 or 150 MHz) were recorded on JEOL
JMN AL-400 or JEOL ECP-600 spectrometers, respectively. Chemical shifts
(d) are given from TMS (0 ppm) as internal standard for 1H-NMR and
13CDCl3 (77.0 ppm) for 13C-NMR. Mass spectra and high resolution mass
spectra were measured on JEOL JMS-DX303 and MS-AX500 instruments,
respectively. IR spectra were recorded on a Shimadzu FTIR-8400. The spe-
cific rotations were measured on a JASCO P-1010 polarimeter.
Chart 5
Methyl (4S)-2,2-Diethyl-1,3-dioxolane-4-acetate (22) 3,3-Dimethoxypen
-
tane (2.2 g, 19.8 mmol) and PPTS (120 mg, 0.46 mmol) were added to a
solution of methyl (3S)-3,4-dihydroxybutylate (21)15) (2.0 g, 15.2 mmol) in
CH2Cl2 (40 ml) at room temperature and stirred for 11 h. The solvent and
excess reagent were evaporated and the residue was purified by silica gel
column chromatography (AcOEt) to afford 22 (2.9 g, 95%) as a colorless oil.
[a]1D7ꢂ18.7° (cꢁ1.25, CHCl3). IR (neat) cmꢀ1: 1740, 1439, 1202, 1171,
1
1078. H-NMR (400 MHz, CDCl3) d: 0.90 (6H, t, Jꢁ7.5 Hz), 1.62 (2H, q,
Jꢁ7.5 Hz), 1.64 (2H, q, Jꢁ7.5 Hz), 2.52 (1H, dd, Jꢁ15.7, 6.6 Hz), 2.75 (1H,
dd, Jꢁ15.7, 6.6 Hz), 3.60 (1H, t, Jꢁ7.7 Hz), 3.70 (3H, s), 4.18 (1H, dd,
Jꢁ8.3, 6.6 Hz), 4.46 (1H, quint, Jꢁ6.6 Hz). 13C-NMR (100 MHz, CDCl3) d:
7.9, 8.2, 29.6, 29.8, 38.6, 51.8, 69.8, 72.2, 113.0, 170.9. MS m/z: 173
(MꢂꢀCH2CH3, 60), 99 (100). HR-MS m/z: 173.0776 (Calcd for C8H13O4:
173.0814).
Chart 6
(4S)-4-(2-Hydroxyethyl)-2,2-diethyl-1,3-dioxolane (23)14—19) A solu-
tion of 22 (5.0 g, 24.7 mmol) in THF (30 ml) was added to a suspension of
LiAlH4 (1.4 g, 37.1 mmol) in THF (150 ml) at 0 °C and the mixture was
stirred for 15 min at the same temperature. Et2O was added to the mixture
and 28% aqueous ammonia solution was added to the mixture. The resulting
inorganic precipitate was filtered through a Celite pad and the filtrate was
concentrated in vacuo. The residue was chromatographed on silica gel
(AcOEt) to provide 23 (4.3 g, 99%) as a colorless oil. [a]1D7 ꢂ2.2° (cꢁ1.27,
CHCl3) [lit. for S-enantiomer16): [a]D ꢂ1.5 (cꢁ1.0, CH2Cl2), for R enan-
tiomer19): [a]D25 ꢀ2.6° (cꢁ0.935, CHCl3)]. IR (neat) cmꢀ1: 3414, 1464,
1173, 1082, 1057, 918. 1H-NMR (400 MHz, CDCl3) d: 0.90 (3H, t,
Jꢁ7.3 Hz), 0.91 (3H, t, Jꢁ7.3 Hz), 1.63 (2H, q, Jꢁ7.3 Hz), 1.65 (2H, q,
Jꢁ7.3 Hz), 1.80—1.85 (2H, m), 2.38 (1H, br), 3.54 (1H, t, Jꢁ7.9 Hz), 3.80
(2H, br), 4.10 (1H, dd, Jꢁ7.9, 6.4 Hz), 4.24 (1H, m). 13C-NMR (100 MHz,
CDCl3) d: 8.0, 8.3, 29.6, 29.9, 35.5, 60.6, 70.1, 75.4, 112.9. MS m/z: 145
(MꢂꢀCH2CH3, 79), 71 (100). HR-MS m/z: 145.0845 (Calcd for C7H13O3:
145.0865).
Chart 7
major isomer 48 was expected to have an a configuration,
obtained by being reduced from the axial direction. This was
confirmed by the observation of n.O.e. between the C3 and
C5 protons (Chart 5).
The hydroxyl group of 48 was acetylated (Ac2O, Et3N,
DMAP, rt, 12 h, 97%) and the TBS group was eliminated by
TBAF in THF at rt, to produce 51 in a quantitative yield.
(4S)-4-(2-Bromoethyl)-2,2-diethyl-1,3-dioxolane (24) CBr4 (23.8 g,
71.7 mmol), Et3N (9.7 g, 95.6 mmol), and 23 (8.3 g, 47.8 mmol) were succes-
sively added to a solution of PPh3 (41.4 g, 0.16 mol) in CH2Cl2 (200 ml) at
Conversion from 51 to the acetal 53 was carried out under 0 °C and the mixture was stirred for 2 h at room temperature. Et2O was
added to the mixture and filtered through a Celite pad. The filtrate was con-
essentially the same conditions applied to 41, giving a 58%
overall yield [(1) I2, PPh3, imidazole, CH2Cl2, rt, 1 h; (2)
centrated in vacuo and the residue was purified by silica gel chromatography
[AcOEt–hexane (1 : 5)] to give 24 (9.8 g, 86%) as a colorless oil. [a]1D6
DBU, DMF, 100 °C, 10 h; (3) 3 N HCl, rt, 5 min]. Finally, 53
was oxidized (PCC, NaOAc, Celite, MS 4A, CH2Cl2, rt, 9 h,
66%) and the second ring cyclized (pyrrolidine, benzene,
reflux, 1.5 h, 82%), to complete the synthesis of 55, which is
equivalent to (8aR)-19 (RꢁAc) (Chart 6).
The absolute configurations of the final products 46 and 55
were confirmed by synthesizing 5623,24) from each of these
products and comparing the specific rotations of the resul-
tants to that of the known compound (R)-5612) (Chart 7). The
optical purities of both (R)-56 and (S)-56 were determined by
chiral HPLC to be more than 99% ee.
ꢀ24.3° (cꢁ1.25, CHCl3). IR (neat) cmꢀ1: 2972, 2939, 2882, 1464, 1173,
1078, 1059, 920. 1H-NMR (400 MHz, CDCl3) d: 0.89 (6H, t, Jꢁ7.3 Hz),
1.62 (2H, q, Jꢁ7.3 Hz), 1.64 (2H, q, Jꢁ7.3 Hz), 2.04 (1H, dtd, Jꢁ14.4, 7.5,
4.4 Hz), 2.15 (1H, ddt, Jꢁ14.4, 7.5, 4.4 Hz), 3.48—3.56 (3H, m), 4.11 (1H,
dd, Jꢁ7.9, 6.2 Hz), 4.24 (1H, m). 13C-NMR (100 MHz, CDCl3) d: 8.0, 8.3,
29.5, 29.6, 29.9, 37.0, 69.5, 74.2, 112.9. MS m/z: 209, 207 (MꢂꢀCH2CH3,
99, 100), 135, 133 (30, 31), 57 (98). HR-MS m/z: 208.9985 (Calcd for
C7H12O281Br: 209.0001), 207.0007 (Calcd for C7H12O279Br: 207.0021).
[(4S)-2,2-Diethyl-1,3-dioxolan-4-yl]-3-oxo-hexanoic Acid Ethyl Ester
(31) Ethyl acetoacetate (30) (10 g, 76.9 mmol) was added to a suspension
of NaH (oil free, 3.8 g, 94.2 mmol) in THF (200 ml) and HMPA (20 ml) at
0 °C. After being stirred for 10 min at the same temperature, BuLi (1.32 M
solution in hexane, 64.1 ml, 84.6 mmol) was added and the stirring was con-
tinued for another 10 min. 24 (9.1 g, 38.5 mmol) was added to the mixture
and stirred for 1 h at room temperature. The mixture was neutralized with
3 N HCl and the aqueous solution was extracted with Et2O. The combined
organic solution was washed with aqueous saturated NaCl solution, dried
over anhydrous MgSO4, and concentrated. The residue was purified by silica
gel column chromatography [AcOEt–hexane (1 : 6)] to afford 31 (9.5 g,
Conclusion
A new stereoselective method for the introduction of an
allyl group at the angular position of chiral 10 using Birch
reduction and an alkylation reaction was established.
Although the synthetic routes for both 46 and 55 are some- 86%) as a colorless oil. [a]1D8 ꢂ13.1° (cꢁ1.27, CHCl3). IR (neat) cmꢀ1
:

February 2005
211
1
1744, 1717, 1080, 1031, 920. H-NMR (400 MHz, CDCl3) d: 0.89 (3H, t,
Jꢁ7.3 Hz), 0.89 (3H, t, Jꢁ7.4 Hz), 1.28 (3H, t, Jꢁ7.2 Hz), 1.54—1.72 (8H,
m), 2.61 (2H, t, Jꢁ7.0 Hz), 3.43 (2H, s), 3.46 (1H, t, Jꢁ9.9 Hz), 4.04 (2H,
m), 4.19 (2H, q, Jꢁ7.2 Hz). MS m/z: 286 (Mꢂ, 2), 257 (100). HR-MS m/z:
286.1772 (Calcd for C15H26O5: 286.1780).
added to liquid NH3 (distilled over sodium metal, 5 ml) at ꢀ78 °C. After
being stirred for 10 min, a solution of 37 (740 mg, 2.5 mmol) in anhydrous
THF (4 ml) was added and the mixture was stirred for 50 min at the same
temperature. Allyl bromide (1.5 g, 12.5 mmol) was added to the mixture and
stirred at ꢀ78 °C for 1 h and at ꢀ33 °C for 50 min. The reaction was
t
Ethyl 7-[(4S)-(2,2-Diethyl-1,3-dioxolan-4-yl)]-3-ethoxycarbonyl-4-oxo-
heptanoate (33) Compound 31 (7.3 g, 25.5 mmol) was added to a suspen-
sion of NaH (oil free, 1.5 g, 38.3 mmol) in THF (200 ml) at 0 °C. After being
stirred for 30 min at the same temperature, ethyl-3-bromopropionate (32)
(5.5 g, 30.6 mmol) was added and the stirring was continued for 2 h at room
temperature. The mixture was extracted with Et2O and the combined organic
solution was washed with saturated aqueous NaCl solution. The organic
solution was dried over anhydrous MgSO4 and concentrated to afford the oil,
which was purified by silica gel column chromatography [AcOEt–hexane
(1 : 5)] to provide 33 (8.8 g, 89%, an inseparable diastereomeric mixture) as
a colorless oil. IR (neat) cmꢀ1: 1735, 1716, 1375, 1182, 1080, 1024, 920.
1H-NMR (400 MHz, CDCl3) d: 0.89 (3H, t, Jꢁ7.3 Hz), 0.89 (3H, t,
Jꢁ7.3 Hz), 1.26 (3H, t, Jꢁ7.3 Hz), 1.27 (3H, t, Jꢁ7.3 Hz), 1.52—1.70 (4H,
m), 1.60 (2H, q, Jꢁ7.5 Hz), 1.62 (2H, q, Jꢁ7.5 Hz), 2.15 (2H, t, Jꢁ7.2 Hz),
2.34 (2H, td, Jꢁ7.2, 2.0 Hz), 2.52—2.69 (2H, m), 3.46 (1H, m), 3.56 (1H, t,
Jꢁ7.2 Hz), 4.02—4.07 (2H, m), 4.13 (2H, q, Jꢁ7.1 Hz), 4.19 (2H, q,
Jꢁ7.1 Hz). MS m/z: 357 (MꢂꢀCH2CH3, 6), 311 (100). HR-MS m/z:
357.1923 (Calcd for C18H29O7: 357.1913).
quenched with BuOH and stirred at room temperature to evaporate liquid
NH3. The mixture was extracted with Et2O and the combined organic solu-
tion was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and concentrated. The residue was purified by silica gel column
chromatography [AcOEt–hexane (1 : 50)] to give 39 (300 mg, 36%) as a col-
orless oil. [a]1D7 ꢀ55.9° (cꢁ1.13, CHCl3). IR (neat) cmꢀ1: 1709, 1458, 1256,
1128, 1094, 1065, 837, 777. 1H-NMR (600 MHz, CDCl3) d: 0.03 (6H, s),
0.72 (9H, s), 1.09 (1H, td, Jꢁ13.4, 4.5 Hz), 1.26—1.33 (1H, m), 1.50 (1H,
m), 1.81—1.88 (2H, m), 2.09—2.16 (3H, m), 2.30 (1H, br d, Jꢁ15.1 Hz),
2.41 (1H, dt, Jꢁ13.4, 3.3 Hz), 2.44—2.51 (2H, m), 3.36—3.40 (1H, m),
3.44 (1H, dd, Jꢁ10.5, 5.5 Hz), 3.58 (1H, dd, Jꢁ10.5, 5.5 Hz), 3.71 (1H,
br s), 5.01—5.07 (2H, m), 5.58 (1H, ddt, Jꢁ17.7, 9.9, 7.2 Hz). 13C-NMR
(150 MHz, CDCl3) d: ꢀ5.3, ꢀ5.1, 18.4, 21.0, 25.2, 25.9, 26.4, 28.8, 38.3,
41.5, 51.8, 66.8, 78.7, 81.7, 118.3, 131.9, 212.9. MS m/z: 338 (Mꢂ, 0.3), 281
(59), 197 (69), 105 (60), 75 (100). HR-MS m/z: 338.2231 (Calcd for
C19H34O3Si: 338.2277).
(2S,4aS,8aS)-4a-Allyl-2-(hydroxymethyl)-octahydro-1-benzopyran-5-
one (41) HF-pyridine solution (0.5 ml) was added to a solution of 39
(160 mg, 0.48 mmol) in THF (5 ml) at 0 °C and the mixture was stirred for
30 min at room temperature. The mixture was extracted with Et2O and the
combined organic solution was washed with saturated aqueous NaCl solu-
tion, dried over anhydrous MgSO4, and the solvent was evaporated. The
residue was chromatographed on silica gel [AcOEt–hexane (1 : 1)] to afford
41 (110 mg, 100%) as a colorless oil. [a]1D5 ꢀ63.9° (cꢁ1.24, CHCl3). IR
(neat) cmꢀ1: 3435, 1705, 1447, 1130, 1072, 1042, 995, 918. 1H-NMR
(600 MHz, CDCl3) d: 1.12 (1H, ddd, Jꢁ13.4, 10.0, 7.8 Hz), 1.25 (1H, br s),
1.35—1.40 (2H, m), 1.84—1.89 (2H, m), 2.09—2.17 (3H, m), 2.29—2.33
(1H, m), 2.42 (1H, dt, Jꢁ13.4, 3.4 Hz), 2.49 (2H, dd, Jꢁ13.9, 7.0 Hz),
3.42—3.48 (2H, m), 3.48—3.55 (1H, m), 3.76 (1H, br s), 5.04—5.08 (2H,
m), 5.57 (1H, ddt, Jꢁ16.6, 10.2, 7.1 Hz). 13C-NMR (150 MHz, CDCl3) d:
21.0, 24.4, 26.3, 28.5, 38.3, 41.4, 51.8, 66.1, 78.4, 81.8, 118.5, 131.6, 212.6.
MS m/z: 224 (Mꢂ, 9), 193 (100). HR-MS m/z: 224.1392 (Calcd for
C13H20O3: 224.1412).
(2S,4aS,8aS)-4a-Allyl-2-(iodomethyl)-octahydro-1-benzopyran-5-one
(42) PPh3 (326 mg, 1.2 mmol), imidazole (90 mg, 1.3 mmol), and I2
(314 mg, 1.2 mmol) were successively added to a solution of 41 (93 mg,
0.41 mmol) in anhydrous CH2Cl2 (4 ml) at room temperature and stirred for
17 h. The solvent was evaporated and Et2O was added to the residue. The
organic solution was washed with washed with saturated aqueous Na2S2O3
solution and the aqueous solution was extracted with Et2O. The combined
organic solution was washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and the solvent was evaporated. The residue was
purified by silica gel chromatography [AcOEt–hexane (1 : 2)] to afford 42
(121 mg, 88%) as a colorless oil. [a]1D5ꢀ16.3° (cꢁ1.36, CHCl3). IR (neat)
cmꢀ1: 1705, 1445, 1124, 1067, 920. 1H-NMR (400 MHz, CDCl3) d: 1.13
(1H, td, Jꢁ13.3, 4.4 Hz), 1.39 (1H, dtd, Jꢁ16.0, 12.3, 4.1 Hz), 1.69 (1H,
ddt, Jꢁ16.0, 4.4, 2.4 Hz), 1.84—1.92 (2H, m), 2.10—2.20 (3H, m), 2.28—
2.35 (1H, m), 2.41 (1H, dt, Jꢁ12.7, 3.4 Hz), 2.44—2.54 (2H, m), 3.10 (1H,
dd, Jꢁ10.2, 6.2 Hz), 3.13 (1H, dd, Jꢁ10.2, 5.1 Hz), 3.32 (1H, dddd, Jꢁ12.0,
6.2, 5.1, 2.4 Hz), 3.76 (1H, s), 5.00—5.17 (2H, m), 5.57 (1H, ddt, Jꢁ16.3,
9.5, 7.3 Hz). 13C-NMR (100 MHz, CDCl3) d: 9.7, 21.1, 26.4, 28.5, 28.8,
38.3, 41.2, 51.3, 77.0, 82.0, 118.5, 131.5, 212.2. MS m/z: 334 (Mꢂ, 37), 292
(100), 193 (46), 165 (43). HR-MS m/z: 334.0410 (Calcd for C13H19IO2:
334.0430).
4-[(1S,5S)-6,8-Dioxabicyclo[3.2.1]oct-5-yl]-butyric Acid Methyl Ester
(36) KOH (1.1 g, 19.4 mmol) was added to a solution of 33 (3.4 g,
8.8 mmol) in BuOH (50 ml) and H2O (12 ml) and refluxed for 5 h. After
t
being cooled to room temperature, the mixture was acidified by 3 N HCl and
was refluxed for 5 h. The solvent was evaporated at the reduced pressure and
the residue was dissolved into MeOH. AcCl (6.9 g, 88.2 mmol) was added to
the solution at 0 °C and stirred at room temperature for 12 h. The mixture
was neutralized with saturated aqueous NaHCO3 solution and the aqueous
phase was extracted with AcOEt. The organic solution was washed with
saturated aqueous NaCl solution, dried over anhydrous MgSO4, and the
solvent was evaporated. The residue was purified by silica gel column chro-
matography [AcOEt–hexane (1 : 5)] to provide 36 (1.4 g, 74% from 33) as a
colorless oil. [a]1D8 ꢀ42.1° (cꢁ1.02, CHCl3). IR (neat) cmꢀ1: 1736, 1437,
1259, 1175, 1109, 1016, 907. 1H-NMR (400 MHz, CDCl3) d: 1.48 (1H, m),
1.61—1.85 (9H, m), 2.35 (2H, t, Jꢁ7.2 Hz), 3.66 (3H, s), 3.81 (1H, t,
Jꢁ6.2 Hz), 3.91 (1H, d, Jꢁ6.2 Hz), 4.51 (1H, br). 13C-NMR (100 MHz,
CDCl3) d: 16.9, 18.7, 28.4, 34.08, 34.13, 36.7, 51.5, 69.0, 74.8, 108.4,
173.9. MS m/z: 214 (Mꢂ, 2), 129 (100). HR-MS m/z: 214.1189 (Calcd for
C11H18O4: 214.1205).
(2S)-2-Hydroxymethyl-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one (10)
(Table 1, Entry 7) A mixture of 36 (1.0 g, 4.7 mmol) and TfOH (0.70 g,
4.7 mmol) in ClCH2CH2Cl (60 ml) was refluxed for 3 h. The reaction mix-
ture was concentrated in vacuo and the residue was purified by silica gel
chromatography [CHCl3–MeOH (20 : 1)] to afford 10 (0.67 g, 79%) as color-
less solid. The analytical sample was recrystallized from AcOEt to provide
colorless needles (mp 88—89 °C). [a]1D7 ꢂ211.0° (cꢁ1.21, MeOH). IR
(neat) cmꢀ1: 3422, 1589, 1404, 1254, 1186, 1036, 638. 1H-NMR (400 MHz,
CD3OD) d: 1.50—1.62 (1H, m), 1.85—1.94 (3H, m), 1.92—2.07 (1H, m),
2.26—2.29 (3H, m), 2.36—2.39 (2H, m), 3.59 (1H, dd, Jꢁ12.1, 5.7 Hz),
3.64 (1H, dd, Jꢁ12.1, 4.3 Hz), 3.92—3.97 (1H, m). 13C-NMR (100 MHz,
CD3OD) d: 18.4, 22.0, 23.9, 29.6, 37.4, 64.8, 79.6, 112.1, 174.5, 200.8. MS
m/z: 182 (Mꢂ, 56). HR-MS m/z: 182.0936 (Calcd for C10H14O3: 182.0943).
(2S)-2-(tert-Butyldimethylsilanyloxymethyl)-2,3,4,6,7,8-hexahydro-1-
benzopyran-5-one (37) Imidazole (190 mg, 2.9 mmol) and TBSCl
(320 mg, 2.2 mmol) were added successively to a solution of 10 (260 mg,
1.4 mmol) in anhydrous DMF (20 ml) at 0 °C and the mixture was allowed to
stir at room temperature for 12 h. The mixture was extracted with Et2O and
the combined organic solution was washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and the solvent was evaporated. The
residue was purified by silica gel column chromatography [AcOEt–hexane
(1 : 3)] to afford 37 (420 mg, 100%) as a colorless oil. [a]1D6 ꢂ125.5°
(cꢁ1.24, CHCl3). IR (neat) cmꢀ1: 1626, 1396, 1250, 1182, 837. 1H-NMR
(400 MHz, CDCl3) d: 0.08 (6H, s), 0.90 (9H, s), 1.62 (1H, m), 1.89—1.97
(3H, m), 2.08—2.17 (1H, m), 2.34—2.43 (5H, m), 3.71 (2H, dd, Jꢁ10.9,
5.1 Hz), 3.78 (2H, dd, Jꢁ10.9, 5.1 Hz), 3.98 (1H, m). 13C-NMR (100 MHz,
CDCl3) d: ꢀ5.22, ꢀ5.18, 17.2, 20.9, 23.1, 25.7, 25.9, 28.7, 36.7, 65.0, 77.7,
111.4, 171.1, 198.0. MS m/z: 296 (Mꢂ, 0.2), 281 (40), 239 (100). HR-MS
m/z: 296.1790 (Calcd for C16H28O3Si: 296.1808).
(4aS,8aS)-4a-Allyl-2-hydroxy-2-methyl-octahydro-1-benzopyran-5-
one (44) DBU (580 mg, 3.8 mmol) was added to a solution of 42 (430 mg,
1.3 mmol) in anhydrous DMF (7.0 ml) at room temperature and stirred at
100 °C for 9.5 h. The reaction mixture was acidified (ca. pH 4) using 3 N
HCl solution and stirred at room temperature for 3 h. The mixture was ex-
tracted with Et2O and the combined organic solution was washed with satu-
rated aqueous NaCl solution, dried over anhydrous MgSO4, and concen-
trated. The residue was chromatographed on silica gel [AcOEt–hexane
(1 : 2)] to afford 44 (130 mg, 45% from 42) as a colorless oil. [a]1D7 ꢀ123.9°
1
(cꢁ1.02, CHCl3). IR (neat) cmꢀ1: 3412, 1701, 1119, 1067, 1009, 920. H-
NMR (400 MHz, CDCl3) d: 1.57 (3H, s), 1.57—1.63 (2H, m), 1.68—1.73
(1H, m), 1.85 (2H, br), 2.08—2.22 (4H, m), 2.27—2.32 (1H, m), 2.49 (2H,
m), 4.28 (1H, br), 5.00—5.10 (2H, m), 5.59 (1H, ddt, Jꢁ16.8, 9.5, 7.2 Hz).
13C-NMR (100 MHz, CDCl3) d: 21.4, 24.5, 26.2, 29.8, 31.7, 38.6, 41.5,
(2S,4aS,8aS)-4a-Allyl-2-(tert-butyldimethylsilanyloxymethyl)-octahy-
dro-1-benzopyran-5-one (39) Lithium metal (38 mg, 5.5 mmol) was

212
Vol. 53, No. 2
50.9, 74.2, 95.7, 118.3, 131.6, 212.7. MS m/z: 224 (Mꢂ, 12), 206 (54), 123
(51), 43 (100). HR-MS m/z: 224.1405 (Calcd for C13H20O3: 224.1412).
CDCl3) d: 0.05 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 1.43—1.67 (9H, m),
1.78—1.79 (1H, m), 2.04 (3H, s), 2.18 (1H, dd, Jꢁ14.3, 8.1 Hz), 2.27 (1H,
dd, Jꢁ14.3, 7.1 Hz), 3.32—3.36 (1H, m), 3.44 (1H, br s), 3.50 (1H, dd,
Jꢁ10.5, 5.4 Hz), 3.66 (1H, dd, Jꢁ10.5, 6.1 Hz), 5.05 (1H, d, Jꢁ16.1 Hz),
5.06 (1H, d, Jꢁ10.5 Hz), 5.38 (1H, dd, Jꢁ11.4, 4.5 Hz), 5.82 (1H, ddt,
Jꢁ16.1, 10.5, 7.7 Hz). 13C-NMR (100 MHz, CDCl3) d: ꢀ5.2, ꢀ5.0, 18.4,
19.3, 21.3, 24.2, 26.0, 26.3, 26.5, 28.3, 36.5, 38.8, 66.8, 71.6, 78.7, 78.8,
117.6, 134.0, 170.5. FAB-MS m/z: 383 (Mꢂꢂ1), 325, 265, 173.
(2S,3S)-3-Acetoxy-2-allyl-2-(3-oxobutyl)cyclohexanone
(45) Et3N
(13 mg, 0.13 mmol), Ac2O (6.5 mg, 0.064 mmol), and a catalytic amount of
DMAP were added to a solution of 44 (9.5 mg, 0.042 mmol) in anhydrous
CH2Cl2 (1 ml) at room temperature and stirred for 6 d. The solvent and
excess reagents were evaporated at reduced pressure and the residue was
extracted with Et2O. The organic solution was washed with saturated aque-
ous NaCl solution, dried over anhydrous MgSO4, and concentrated. The
residue was purified by silica gel column chromatography [AcOEt–hexane
(1 : 2)] to afford 45 (8.9 mg, 79%) as a colorless oil. [a]1D7 ꢂ5.4° (cꢁ1.40,
CHCl3). IR (neat) cmꢀ1: 1738, 1713, 1373, 1236, 1169, 1030, 920. 1H-NMR
(400 MHz, CDCl3) d: 1.61 (1H, br), 1.68—1.74 (1H, m), 1.83—1.97 (3H,
m), 2.05 (3H, s), 2.05—2.13 (1H, m), 2.13 (3H, s), 2.19—2.30 (2H, m), 2.33
(1H, dd, Jꢁ11.0, 5.5 Hz), 2.37—2.42 (2H, m), 2.49 (1H, dd, Jꢁ14.2,
6.6 Hz), 4.98—5.08 (3H, m), 5.60 (1H, dddd, Jꢁ16.9, 9.1, 7.9, 6.8 Hz). 13C-
NMR (100 MHz, CDCl3) d: 20.2, 21.1, 23.8, 25.4, 30.1, 36.2, 37.2, 38.0,
55.1, 75.4, 118.6, 132.6, 169.7, 207.5, 210.8. MS m/z: 266 (Mꢂ, 1), 206
(32), 136 (37), 43 (100). HR-MS m/z: 266.1508 (Calcd for C15H22O4:
266.1518).
(1S,8aS)-1-Acetoxy-8a-allyl-1,2,3,4,8,8a-hexahydro-6(7H)-naph-
thalenone (46) Pyrrolidine (39 mg, 0.55 mmol) was added to a solution of
45 (150 mg, 0.55 mmol) in benzene (5 ml) at room temperature and stirred
for 24 h at the same temperature, followed by being refluxed for 3.5 h. The
mixture was extracted with AcOEt and the combined organic solution was
washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4,
and concentrated. The residue was chromatographed on silica gel
[AcOEt–hexane (1 : 2)] to afford 46 (110 mg, 79%) as a colorless solid. The
analytical sample was recrystallized from hexane to provide colorless nee-
dles (mp 75—76 °C). [a]D22 ꢀ37.8° (cꢁ1.22, CHCl3). IR (neat) cmꢀ1: 1732,
1672, 1373, 1238, 1161, 1018, 962, 920. 1H-NMR (400 MHz, CDCl3) d:
1.73—1.89 (4H, m), 1.93—2.10 (2H, m), 2.05 (3H, s), 2.31—2.41 (2H, m),
2.44—2.54 (4H, m), 5.00 (1H, br s), 5.18 (1H, d, Jꢁ17.2 Hz), 5.19 (1H, d,
Jꢁ10.0 Hz), 5.79 (1H, ddt, Jꢁ17.2, 10.0, 7.2 Hz), 5.89 (1H, s). 13C-NMR
(100 MHz, CDCl3) d: 20.4, 21.3, 25.5, 26.9, 31.7, 34.0, 38.4, 42.6, 74.8,
119.5, 126.9, 131.9, 165.7, 170.0, 198.5. MS m/z: 248 (Mꢂ, 5), 206 (100),
188 (70), 165 (89), 147 (76), 123 (52), 43 (60). HR-MS m/z: 248.1387
(Calcd for C15H20O3: 248.1412).
(2S,4aS,5S,8aS)-5-Acetoxy-4a-allyl-2-hydroxy-octahydro-1-benzopy-
ran-5-one (51) TBAF (1.0 M solution in THF, 1.5 ml, 1.50 mmol) was
added to a solution of 50 (478 mg, 1.25 mmol) in THF (5 ml) at 0 °C and
stirred for 4 h at room temperature. The mixture was extracted with AcOEt
and the combined organic solution was washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and concentrated. The residue was
chromatographed on silica gel [AcOEt–hexane (1 : 2)] to afford 51 (337 mg,
100%) as a colorless oil. [a]1D5 ꢂ22.9° (cꢁ1.16, CHCl3). IR (neat) cmꢀ1
:
1
3435, 1732, 1448, 1375, 1244, 1088, 1028, 914, 880. H-NMR (400 MHz,
CDCl3) d: 1.23—1.29 (1H, m), 1.33 (1H, br d, Jꢁ16.8 Hz), 1.43—1.79 (8H,
m), 2.04 (3H, s), 2.14 (1H, br), 2.19 (1H, dd, Jꢁ14.4, 7.0 Hz), 2.28 (1H, dd,
Jꢁ14.4, 8.1 Hz), 3.40—3.44 (1H, m), 3.48 (1H, s), 3.55 (2H, br s), 5.06 (1H,
d, Jꢁ16.9 Hz), 5.07 (1H, d, Jꢁ10.3 Hz), 5.36 (1H, dd, Jꢁ11.1, 4.3 Hz), 5.82
(1H, ddt, Jꢁ16.9, 10.3, 8.1 Hz). 13C-NMR (100 MHz, CDCl3) d: 19.2, 21.2,
23.3, 26.3, 26.5, 28.1, 36.5, 38.8, 66.2, 71.3, 78.3, 78.8, 117.8, 133.7, 170.4.
FAB-MS m/z: 269 (Mꢂꢂ1), 209.
(2S,4aS,5S,8aS)-5-Acetoxy-4a-allyl-2-(iodomethyl)-octahydro-1-ben-
zopyran-5-one (52) PPh3 (560 mg, 2.2 mmol), imidazole (160 mg, 2.3
mmol), and I2 (540 mg, 2.2 mmol) were successively added to a solution of
51 (190 mg, 0.71 mmol) in anhydrous CH2Cl2 (5 ml) at room temperature
and stirred for 1 h. The solvent was evaporated and the residue was extracted
with AcOEt. The organic solution was washed with washed with saturated
aqueous Na2S2O3 solution and the aqueous phase was extracted with AcOEt.
The combined organic solution was washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and the solvent was evaporated. The
residue was purified by silica gel chromatography [AcOEt–hexane (1 : 5)] to
afford the iodide 52 (260 mg, 96%) as a colorless oil; [a]1D7 ꢂ35.3° (cꢁ1.25,
1
CHCl3). IR (neat) cmꢀ1: 1734, 1373, 1242, 1032, 999, 914, 669. H-NMR
(400 MHz, CDCl3) d: 1.40—1.69 (9H, m), 1.75—1.83 (1H, m), 2.04 (3H,
s), 2.19 (1H, dd, Jꢁ14.4, 6.8 Hz), 2.28 (1H, dd, Jꢁ14.4, 7.8 Hz), 3.20 (2H,
d, Jꢁ5.4 Hz), 3.23—3.30 (1H, m), 3.49 (1H, br s), 5.055 (1H, d,
Jꢁ16.7 Hz), 5.065 (1H, d, Jꢁ10.1 Hz), 5.39 (1H, dd, Jꢁ11.4, 4.8 Hz), 5.80
(1H, dddt, Jꢁ16.7, 10.1, 7.8 Hz). 13C-NMR (100 MHz, CDCl3) d: 10.0,
19.3, 21.3, 26.3, 26.5, 27.4, 28.3, 36.2, 38.5, 71.4, 77.0, 79.3, 117.8, 133.7,
170.4. MS m/z: 378 (Mꢂ, 0.2), 336 (11), 276 (100), 237 (24), 149 (55), 148
(43). HR-MS m/z: 378.0682 (Calcd for C15H23IO3: 378.0692).
(2S,4aS,5S,8aS)-4a-Allyl-2-(tert-butyldimethylsilanyloxymethyl)-5-hy-
droxy-octahydro-1-benzopyran-5-one (48) and (2S,4aS,5R,8aS)-4a-Allyl-
2-(tert-butyldimethylsilanyloxymethyl)-5-hydroxy-octahydro-1-benzopy-
ran-5-one (49) MeOH (35 mg, 1.1 mmol) and LiBH4 (2.4 mg, 0.092
mmol) were successively added to
a solution of 40 (31 mg, 0.092
mmol) in Et2O (5 ml) at ꢀ30 °C and stirred for 15 min at the same tempera-
ture. The mixture was extracted with Et2O and the combined organic solu-
tion was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was evaporated. The residue was chromatographed
on silica gel [AcOEt–hexane (1 : 19)] to afford 49 (2 mg, 6%) as a colorless
(4aS,5S,8aS)-5-Acetoxy-4a-allyl-2-hydroxy-2-methyl-octahydro-1-ben-
zopyran-5-one (53) DBU (25 mg, 0.16 mmol) was added to a solution of
52 (20 mg, 0.054 mmol) in anhydrous DMF (0.5 ml) at room temperature
and stirred at 100 °C for 10 h. The reaction mixture was acidified (ca. pH 3)
using 3 N HCl solution and stirred at room temperature for 5 min. The mix-
ture was extracted with Et2O and the organic solution was washed with satu-
rated aqueous NaHCO3 solution. The aqueous solution was extracted with
AcOEt and the combined organic solution was washed with saturated aque-
ous NaCl solution, dried over anhydrous MgSO4, and concentrated. The
residue was chromatographed on silica gel [AcOEt–hexane (1 : 2)] to afford
the acetal 53 (8.7 mg, 60% from 53) as a colorless oil. [a]D22 ꢀ23.4°
(cꢁ1.06, CHCl3). IR (neat) cmꢀ1: 3433, 1734, 1719, 1375, 1244, 1217,
1
oil. H-NMR (400 MHz, CDCl3) d: 0.06 (6H, s), 0.89 (9H, s), 1.34—1.68
(5H, m), 1.68—1.93 (5H, m), 2.02—2.21 (2H, m), 3.20 (1H, br), 3.32 (1H,
br d, Jꢁ1.7 Hz), 3.39—3.49 (1H, m), 3.52—3.68 (3H, m), 4.92—5.08 (2H,
m), 5.62—5.79 (1H, m). From the later fraction, 48 (26 mg, 84%) was
obtained as a colorless oil. [a]1D6 ꢀ4.4° (cꢁ1.32, CHCl3). IR (neat) cmꢀ1
:
3412, 1450, 1254, 1084, 837, 717. 1H-NMR (600 MHz, CDCl3) d: 0.05 (3H,
s), 0.06 (3H, s), 0.89 (9H, s), 1.25 (1H, br s), 1.43 (1H, td, Jꢁ13.2, 5.4 Hz),
1.52—1.66 (6H, m), 1.71 (1H, tt, Jꢁ8.0, 2.8 Hz), 1.75—1.80 (1H, m), 2.05
(1H, dt, Jꢁ13.2, 3.1 Hz), 2.11 (1H, dd, Jꢁ14.0, 7.4 Hz), 2.25 (1H, dd,
Jꢁ14.0, 7.4 Hz), 3.33—3.38 (1H, m), 3.40 (1H, br s), 3.51 (1H, dd, Jꢁ10.5,
5.4 Hz), 3.65 (1H, dd, Jꢁ10.5, 5.6 Hz), 4.12 (1H, dd, Jꢁ11.2, 4.4 Hz),
5.05—5.11 (2H, m), 5.91 (1H, ddt, Jꢁ17.3, 9.6, 7.4 Hz). 13C-NMR
(150 MHz, CDCl3) d: ꢀ5.3, ꢀ5.2, 18.4, 19.8, 23.9, 25.9, 26.5, 28.1, 30.2,
36.2, 39.8, 66.8, 69.0, 78.5, 79.3, 117.5, 135.0. FAB-MS m/z: 341 (Mꢂꢂ1).
(2S,4aS,5S,8aS)-5-Acetoxy-4a-allyl-2-(tert-butyldimethylsilanyl-
oxymethyl)-octahydro-1-benzopyran-5-one (50) Et3N (140 mg, 1.4 mmol),
Ac2O (280 mg, 2.8 mmol), and a catalytic amount of DMAP were succes-
sively added to a solution of 48 (310 mg, 0.92 mmol) in anhydrous CH2Cl2
(6 ml) at room temperature and stirred for 12 h. The solvent and excess
reagents were evaporated at reduced pressure and the residue was extracted
with Et2O. The combined organic solution was washed with saturated aque-
ous NaCl solution, dried over MgSO4, and concentrated. The residue was
purified by silica gel column chromatography [AcOEt–hexane (1 : 5)] to
afford 50 (340 mg, 97%) as a colorless oil. [a]1D5 ꢂ9.3° (cꢁ1.27, CHCl3). IR
1
1028, 914. H-NMR (400 MHz, CDCl3) d: 1.26—1.49 (3H, m), 1.42 (3H,
s), 1.58—1.87 (7H, m), 2.04 (3H, s), 2.15—2.35 (2H, m), 4.02 (2H, br s),
5.00—5.10 (2H, m), 5.34 (1H, dd, Jꢁ11.4, 4.3 Hz), 5.87 (1H, m). 13C-NMR
(100 MHz, CDCl3) d: 19.2, 21.2, 24.2, 25.9, 26.5, 30.3, 30.5, 36.5, 37.8,
70.7, 70.9, 95.4, 117.5, 133.9, 170.5. MS m/z: 251 (MꢂꢀOH, 13), 250
(MꢂꢀH2O, 10), 166 (45), 132 (49), 107 (49), 43 (100). HR-MS m/z:
250.1549 (Calcd for C15H22O3: 250.1569).
(2R,3S)-3-Acetoxy-2-allyl-2-(3-oxobutyl)-cyclohexanone (54) Celite,
powdered molecular sieves 4 Å, and a solution of 53 (78 mg, 0.29 mmol) in
anhydrous CH2Cl2 (1.5 ml) were added to a suspension of PCC (190 mg,
0.87 mmol) and NaOAc (24 mg, 0.29 mmol) in anhydrous CH2Cl2 (1.5 ml) at
room temperature. After being stirred for 9 h, Florisil was added and stirred
for several minutes. The mixture was filtered through a Celite pad and the
filtrate was concentrated at reduced pressure. The residue was purified by
silica gel column chromatography [AcOEt–hexane (1 : 2)] to afford 54
(51 mg, 66%) as a colorless oil. [a]2D4 ꢀ17.5° (cꢁ1.11, CHCl3). IR (neat)
1
cmꢀ1: 1738, 1711, 1373, 1232. H-NMR (600 MHz, CDCl3) d: 1.79—1.88
1
(neat) cmꢀ1: 1736, 1364, 1242, 1086, 1028, 837, 777. H-NMR (400 MHz,

February 2005
213
(2H, m), 1.91—1.97 (3H, m), 2.05 (3H, s), 2.12 (3H, s), 2.06—2.22 (2H, (31.9 mg) in anhydrous CH2Cl2 (1.5 ml) and stirred for 18 h at room temper-
m), 2.28—2.37 (2H, m), 2.43—2.52 (3H, m), 5.02—5.12 (3H, m), 5.60 (1H, ature. Florisil and Et2O was added to the mixture and filtered through a
ddt, Jꢁ11.6, 6.6, 4.9 Hz); 13C-NMR (150 MHz, CDCl3) d: 20.5, 21.0, 25.0, Celite pad. The filtrate was concentrated and the residue was purified by
25.3, 30.1, 33.7, 37.5, 38.1, 54.5, 75.7, 118.9, 132.4, 169.8, 207.3, 211.9. silica gel column chromatography [AcOEt–hexane (1 : 2)] to afford (R)-56
MS m/z: 266 (Mꢂ, 1), 206 (32), 163 (34), 148 (46), 136 (52), 43 (100). HR-
MS m/z: 266.1503 (Calcd for C15H22O4: 266.1518).
(1S,8aR)-1-Acetoxy-8a-allyl-1,2,3,4,8,8a-hexahydro-6(7H)-naph-
thalenone (55) Pyrrolidine (2.5 mg, 0.036 mmol) was added to a solution
of 54 (9.5 mg, 0.036 mmol) in benzene (0.5 ml) at room temperature and
(17.9 mg, 51% from 56) as colorless oil; [a]2D1 ꢂ72.8° (cꢁ0.28, CHCl3)
[lit.12) [a]D25ꢂ90° (cꢁ1.1, CHCl3)]. The other spectral data were identified
with those of (S)-56.
HPLC Conditions for (S)-56 and (R)-56 HPLC column: DICEL CHI-
RALCEL OD-H. Solvent: iPrOH–hexane (2.5 : 97.5). Flow rate: 0.5 ml/min.
stirred for 12 h at the same temperature, followed by being refluxed for Retention time: (S)-57; 44.5 min, (R)-57; 43.1 min.
40 min. The mixture was extracted with AcOEt and the combined organic
solution was dried over anhydrous MgSO4, and concentrated. The residue
was chromatographed on silica gel [AcOEt–hexane (1 : 2)] to afford 55
(7.3 mg, 82%) as a colorless oil. [a]1D6 ꢂ46.4° (cꢁ1.03, CHCl3). IR (neat)
References
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1
cmꢀ1: 1732, 1674, 1373, 1238, 1036, 916. H-NMR (400 MHz, CDCl3) d:
1.49 (1H, qt, Jꢁ13.2, 4.5 Hz), 1.76—1.84 (2H, m), 1.91—1.99 (2H, m),
2.10 (3H, s), 2.10—2.17 (1H, m), 2.20—2.24 (1H, m), 2.32—2.39 (2H, m),
2.42—2.51 (2H, m), 2.65 (1H, dd, Jꢁ14.5, 6.8 Hz), 4.80 (1H, dd, Jꢁ11.5,
4.6 Hz), 5.07 (1H, d, Jꢁ10.1 Hz), 5.14 (1H, dd, Jꢁ17.0, 1.3 Hz), 5.78 (1H,
m), 5.91 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 21.2, 23.8, 26.8, 30.8,
32.2, 34.0, 36.9, 43.7, 78.4, 118.2, 127.1, 133.9, 164.5, 170.1, 198.9. MS
m/z: 248 (Mꢂ, 0.1), 220 (10), 188 (19), 165 (23), 139 (25), 105 (100), 77
(25). HR-MS m/z: 248.1389 (Calcd for C15H20O3: 248.1412).
(S)-8a-Allyl-3,4,8,8a-tetarahydro-1,6(2H,7H)-naphthalenedione [(S)-
56] DBU (34.2 mg, 0.225 mmol) was added to a solution of 46 (46.5 mg,
0.187 mmol) in methanol (1.0 ml) at room temperature and the mixture was
stirred for 3.5 h at the same temperature. The mixture was concentrated at
the reduced pressure. 3% HCl and H2O were added to the residue and
extracted with Et2O. The combined organic solution was successively
washed with saturated aqueous NaHCO3 and NaCl solution, dried over an-
hydrous MgSO4. The solvent was evaporated to provide the crude alcohol
(36.6 mg), which was used to the next reaction without further purification.
PDC (0.211 g, 0.561 mmol) was added to a solution of the crude alcohol
(36.6 mg) in anhydrous CH2Cl2 (1.5 ml) and stirred for 18 h at room temper-
ature. Florisil and Et2O was added to the mixture and filtered through a
Celite pad. The filtrate was concentrated and the residue was purified by
silica gel column chromatography [AcOEt–hexane (1 : 2)] to afford (S)-56
(29.6 mg, 77% from 46) as colorless oil. [a]2D2 ꢀ80.4° (cꢁ0.55, CHCl3)
12) Hanselmann R., Benn M., Synth. Commun., 26, 945—961 (1996).
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Moriwake T., Chem. Lett., 1984, 1389—1392 (1984).
14) Masamune S., Ma P., Okumoto H., Ellingboe J. W., Ito Y., J. Org.
Chem., 49, 2834—2837 (1984).
[lit.12) for R-enantiomer: [a]2D5 ꢂ90° (cꢁ1.1, CHCl3)]. IR (neat) cmꢀ1: 1710, 15) Shishido K., Sukegawa Y., Fukumoto K., Kametani T., Heterocycles,
1670. 1H-NMR (600 MHz, CDCl3) d: 1.72 (1H, qt, Jꢁ13.4, 4.3 Hz), 2.03—
2.11 (1H, m), 2.14—2.20 (1H, m), 2.23 (1H, dt, Jꢁ14.8, 4.5 Hz), 2.42 (1H,
d, Jꢁ4.5 Hz), 2.42—2.44 (1H, m), 2.49—2.51 (1H, m), 2.52—2.54 (1H, m),
24, 641—645 (1986).
16) Börjesson L., Csöregh I., Welch C. J., J. Org. Chem., 60, 2989—2999
(1995).
2.56 (1H, dd, Jꢁ14.6, 7.7 Hz), 2.64—2.70 (2H, m), 2.79 (1H, td, Jꢁ13.5, 17) Arth H.-L., Sinerius G., Fessner W.-D., Liebigs Ann., 1995, 2037—
5.4 Hz), 5.12—5.16 (2H, m), 5.56—5.64 (1H, m), 5.90 (1H, d, Jꢁ 1.4 Hz).
13C-NMR (150 MHz, CDCl3) d: 23.2, 26.0, 31.8, 33.2, 38.2, 39.6, 54.5,
119.2, 126.3, 131.5, 164.8, 197.9, 209.1. MS m/z: 204 (Mꢂ, 33.1), 43 (100).
2042 (1995).
18) Smith III A. B., Chen S. S.-Y., Nelson F. C., Reichert J. M., Salvatore
B. A., J. Am. Chem. Soc., 119, 10935—10946 (1997).
HR-MS m/z: 204.1158 (Calcd for C13H16O2: 204.1150). Anal. Calcd for 19) Sneddon H. F., Gaunt M. J., Ley S. V., Org. Lett., 5, 1147—1150
C13H16O2: C, 76.44; H, 7.90. Found: C, 76.28; H, 7.99. (2003).
(R)-8a-Allyl-3,4,8,8a-tetarahydro-1,6(2H,7H)-naphthalenedione [(R)- 20) Rajamannar T., Palani N., Balasubramanian K. K., Synth. Commun.,
56] DBU (31.3 mg, 0.205 mmol) was added to a solution of 55 (42.5 mg, 23, 3095—3108 (1993).
0.171 mmol) in methanol (1.0 ml) at room temperature and the mixture was 21) Ishida T., Wada K., J. Chem. Soc., Perkin Trans. 1, 1979, 323—327
stirred for 6 h at the same temperature. The mixture was concentrated at the (1979).
reduced pressure. 3% HCl and H2O were added to the residue and extracted 22) Jiang X., Covey D. F., J. Org. Chem., 67, 4893—4900 (2002).
with Et2O. The combined organic solution was successively washed with 23) Reusch W., Grimm K., Karoglan J. E., Martin J., Subrahamanian K. P.,
saturated aqueous NaHCO3 and NaCl solution, dried over anhydrous
MgSO4. The solvent was evaporated to provide the crude alcohol (31.9 mg),
which was used to the next reaction without further purification.
Toong, Y.-C., Venkataramani P. S., Yordy J. D., Zoutendam P., J. Am.
Chem. Soc., 99, 1953—1958 (1977).
24) Ziegler F. E., Wallace O. B., J. Org. Chem., 60, 3626—3636 (1995).
PDC (0.258 g, 0.685 mmol) was added to a solution of the crude alcohol