Cyclization into perhydronaphthalenones using samarium diiodide

Article abstract of DOI:10.1016/S0040-4020(03)00286-2

Samarium(II) diiodide has been employed to promote the intramolecular cyclization reactions of aldehydes or ketones onto α,β-unsaturated ketones. The cyclization reactions described herein provide a general approach to the syntheses of perhydronaphthalenones with a cis-relationship between the OH at C-5 and the proton or methyl group at C-4a with good diastereoselectivity under mild reaction conditions.

Full text of DOI:10.1016/S0040-4020(03)00286-2

Tetrahedron 59 (2003) 3385–3395
Cyclization into perhydronaphthalenones using
samarium diiodide
*
Masakazu Sono, Sachiko Onishi and Motoo Tori
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 5 January 2003; revised 21 February 2003; accepted 24 February 2003
Abstract—Samarium(II) diiodide has been employed to promote the intramolecular cyclization reactions of aldehydes or ketones onto a,b-
unsaturated ketones. The cyclization reactions described herein provide a general approach to the syntheses of perhydronaphthalenones with
a cis-relationship between the OH at C-5 and the proton or methyl group at C-4a with good diastereoselectivity under mild reaction
conditions. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
21.50 V (acrolein), and 21.42 V (methyl vinyl ketone),
respectively. Therefore, there is a possibility that the regio-
or stereo-selectivity will be changed according to reducing
potential of SmI2.
Samarium (lII) diiodide (SmI2) is a powerful, one-electron
reducing reagent, capable of reducing a wide range of
functional groups with a high stereo and/or regio
selectivity.1 One of the widely applied processes using
SmI2 involves the intramolecular ketyl olefin radical
coupling reaction to achieve carbon–carbon bond for-
mations between aldehydes or ketones and olefins. Most of
the reactions are classified as 4-exo,2 5-exo-,3 6-exo,4 or
7-exo-trig5 type cyclizations. Baldwin reported on the rules
for ring closure in the literature precedents.6 In Trigonal
system, 3 to 7-exo-trig are all favored processes. While 3 to
5-endo-trig are disfavored and 6 to 7-endo-trig are favored,
respectively. Our interest has focused on the 6-endo-trig-
type cyclization.
Moreover, some reactions of SmI2 are greatly accelerated
by addition of catalytic amount (1%) of NiI2.9 As a
consequence, the chemoselectivity of this reducing reagent
is also highly adjustable.10 Therefore, we are interested in
the trend in the diastereoselectivity of the reductive
cyclization reaction using SmI2 with various additives.
Recently, we reported the ability of SmI2 to promote the
cyclization of aldehyde–enone compounds having the
general structure 1 resulting in the formation of several
hydrindanones having the general structure 2 in moderate to
good yield.11 The addition of a proton source such as MeOH
and/or HMPA dramatically changes the product configur-
ation in some cases.
Noteworthy, the reducing potential of SmI2 can be tuned
with solvents, co-solvents, and additives, or by changes in
the reaction conditions. For example, the addition of HMPA
to the THF solution of SmI2 can change the reducing
potential of SmI2, referred to as Ag/AgNO3 electrode, from
21.33 to 22.05 V depending on the concentration of
HMPA.7 On the other hand, comparison of the half-wave
potential of a,b-unsaturated carbonyls with those of
corresponding saturated carbonyl compounds has been
extensively studied in electrochemistry.8 The first waves
of carbonyl groups, referred to as SCE, are 22.45 V
(cyclohexanone), 22.25 V (methyl ethyl ketone), 21.8 V
(propionaldehyde), 21.55 V (2-cyclohexen-1-one),
The studies described herein further detail the SmI2-
promoted 6-endo intramolecular reductive cyclization
reaction of enone- or ketone–enones 3 into perhydro-
naphthalenones 4, although a simple construction of the
perhydronaphtalene using SmI2 has been reported.12 For our
study, three continuous stereocenters were newly con-
structed during the reductive cyclization. The cis arrange-
ment for the hydroxyl group at C-5 and juncture proton or
methyl group at C-4a is predominant under the conditions
we used. The product configurations of the juncture
positions were changed by the addition of MeOH or
HMPA in some cases. The thermodynamic stability
between the cis and trans perhydronaphthalenones has
also been studied (Scheme 1).
Keywords: samarium diiodide; cyclization; perhydronaphthalenones.
*
Corresponding author. Tel.: þ81-88-622-9611x5631; fax: þ81-88-655-
3051; e-mail: tori@ph.bunri-u.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00286-2

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M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
GC–MS analysis (identified by the retention time and the
mass fragment pattern).
The results of the reductive cyclization of the aldehyde 10a
are shown in Table 1. The cis arrangement for the hydroxyl
group at C-5 and the juncture proton at C-4a is also seen in
11a14,19 and 12a,14,17–19 which were the major products
(entries 1, 2). When the reaction was performed at rt,
compound 14a13,17,19 was produced (entry 1). When MeOH
was added as a proton source, the ratio of 12a slightly
increased (entries 3–6). In the presence of HMPA, the yield
of the cyclized products decreased (entries 7, 8). An effect
due to the addition of NiI2 was not particularly observed
(entries 9, 10). Compounds 11a and 12a were subjected to
the isomerization conditions (K2CO3 in MeOH, reflux) and
the equilibration ratio was found to be 11a/12a¼0:100 by
GC. Under the equilibration conditions, compound 14a did
not afford the isomer 13a,19 which was not isolated from this
cyclization reaction.
Scheme 1.
2. Results and discussion
2.1. Synthesis of carbonyl compounds 10a, 10b, 10c,16
and 10d
The reaction of aldehyde 10b was next investigated and
these results are summarized in Table 2. Without any
additive, alcohol 11b13 was the main product (entries 1, 2).
The hydroxyl group at C-5 and the juncture proton at C-4a
were cis to each other as revealed by the NOESY spectrum.
When MeOH was added, the ratio of alcohol 12b13 was
raised regardless of the reaction temperature (entries 3–6).
The addition of HMPA or NiI2 produced a low yield (entries
7–10). Under the equilibration conditions (K2CO3 in
MeOH, reflux) compound 11b afforded a mixture of 11b
and 12b (ca. 21:79). Compound 12b isomerized into the
mixture of 11b and 12b (ca. 16:84). Ketone 14b13 became
equilibrated as a mixture of 13b15 and 14b (18:82) under the
same conditions.
The simple aldehyde 10a and aldehyde 10b having a
b-methyl group were prepared from cyclohexenone or
methylcyclohexenone with silyl protected bromobutanol via
the enone–alcohol 7a or 7b as summarized in Scheme 2.
The simple ketone 10c and ketone 10d having a b-methyl
group were prepared from cyclohexenone or methylcyclo-
hexenone with acetal 9 via the enone–ketone 7c or 7d,
respectively.
2.2. Cyclization with SmI2
The cyclization reactions were performed on a 0.1–
0.3 mmol scale of the starting material. The amount of
SmI2 employed was 3.0 equiv. for the simple enone–
aldehyde 10a. After the cyclization reaction, the cyclization
products were separated as a mixture of diastereoisomers by
silica gel column chromatography. Each diastereoisomer
was purified by HPLC, and the structure was determined by
mainly using 2D NMR experiments. The yields were
calculated from the mixture of the cyclization products
and the ratios of the diastereoisomers were determined by
The ketone–enone 10c was next studied (Table 3). Without
any additive at 08C, the diastereoisomers 11c,13 12c,14
13c,15 and 14c13 were all produced (entries 1, 2). In the
presence of MeOH, compound 12c was the main product
(entries 3–6). When HMPA was added, both compounds
11c and 12c, which had a cis relation about the hydroxyl
group at C-5 and methyl group at C-4a, were obtained in low
Scheme 2.

M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
Table 3. Reductive cyclization of 10c
3387
Table 1. Reductive cyclization of 10a
Entry
Additives
(equiv.)
Temperature
(8C)
Yield
(%) [ratioa]
(11c/12c/13c15/14c)
Entry
Additives
(equiv.)
Temperature
(8C)
Yield
(%) [ratioa]
(11a/12a/13a/14a)
1
2
3
4
5
6
7
8
–
–
rt
0
rt
0
rt
0
rt
0
87 [42:30:0:28]
100 [46:0:19:35]
82 [0:91:0:9]
85 [0:93:0:7]
81 [4:86:0:10]
96 [2:92:0:6]
10 [0:100:0:0]
33 [44:56:0:0]
85 [38:44:0:18]
54 [0:100:0:0]
1
2
3
4
5
6
7
8
9
10
–
–
rt
0
rt
0
rt
0
rt
0
100 [28:61:0:11]
100 [40:60:0:0]
97 [20:70:0:10]
96 [21:68:0:11]
91 [20:66:0:14]
99 [13:77:0:10]
50 [30:57:0:13]
43 [34:58:0:8]
95 [35:50:0:15]
97 [30:61:0:9]
MeOH (2)
MeOH (2)
MeOH (10)
MeOH (10)
HMPA (12)
HMPA (12)
NiI2 (2.0)
NiI2 (2.0)
MeOH (2)
MeOH (2)
MeOH (10)
MeOH (10)
HMPA (12)
HMPA (12)
NiI2 (2.0)
NiI2 (2.0)
9
10
rt
0
rt
0
a
a
Ratios were determined by GC analyses.
Ratios were determined by GC analyses.
yield (entries 7, 8). With NiI2 at rt, compounds 11c and 12c
were produced in moderate yields (entry 9). When NiI2 was
used at 08C, the yield was worse than the reaction at rt (entry
10). Compounds 11c and 12c were subjected to the
isomerization conditions (K2CO3 in MeOH, reflux) and
the equilibration ratio was found to be 11c/12c¼11:89.
Compound 14c afforded a mixture of isomers 13c15 and 14c
(5:95) under the same equilibrium conditions.
Table 4. Reductive cyclization of 10d
Table 2. Reductive cyclization of 10b
Entry
Additives
(equiv.)
Temperature
(8C)
Yield
(%) [ratioa]
(11d/12d/13d15/14d)
Entry
Additives
(equiv.)
Temperature
(8C)
Yield
(%) [ratioa]
(11b.12b/13b15/14b)
1
2
3
4
5
6
7
8
–
–
rt
0
rt
0
rt
0
rt
0
100 [69:19:3:9]
56 [52:25:0:23]
91 [30:51:11:8]
100 [26:63:5:6]
76 [26:56:15:3]
58 [24:61:9:6]
00b
1
2
3
4
5
6
7
8
9
10
–
–
rt
0
rt
0
rt
0
rt
0
54 [92:0:0:8]
67 [100:0:0:0]
97 [54:46:0:0]
81 [58:42:0:0]
92 [53:45:2:0]
88 [55:43:2:0]
64 [57:31:0:12]
75 [69:31:0:0]
51 [100:0:0:0]
30 [71:20:0:9]
MeOH (2)
MeOH (2)
MeOH (10)
MeOH (10)
HMPA (12)
HMPA (12)
NiI2 (2.0)
NiI2 (2.0)
MeOH (2)
MeOH (2)
MeOH (10)
MeOH (10)
HMPA (12)
HMPA (12)
NiI2 (2.0)
NiI2 (2.0)
00b
9
10
rt
0
71 [64:20:10:6]
86 [67:20:0:13]
rt
0
a
Ratios were determined by GC analyses.
Starting material was recovered.
a
b
Ratios were determined by GC analyses.

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M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
Scheme 3.
Finally, the enone 10d, which has a methyl group at the b
position, was subjected to a reaction with SmI2. As shown in
Table 4, compounds 11d13 and 12d14 were mainly observed
regardless of the reaction temperature and the addition of
MeOH (entries 1–6). Without any additive, the ratio of 11d
was greater than that of 12d (entries 1, 2). On the other hand,
the ratios of 12d were grater than that of 11d when MeOH
was added (entries 3–6). When HMPA was added, the
starting material 10d was recovered and no cyclized
products were obtained (entries 7, 8). This is presumably
because the ketone of the side chain and the substituted
b-position of the enone system are less reactive. With the
addition of NiI2, the ratios of products were almost the same
as that of the reaction with no additive (entries 9, 10). Under
the equilibration conditions (K2CO3 in MeOH, reflux),
compounds 11d and 12d were isomers of each other and the
ratio was 52:48. Compound 14d14 afforded the isomer 13d15
(13d/14d¼6:94).
radicals A, B, C, and D. When assessing the contribution of
various transition structures to the observed diastereo-
selectivities, we have postulated that conformations C and
D are unfavorable relative to conformations A and B (an
oxygen atom of the side chain locates outside of the
molecule), because the samarium-coordinated species are
sterically bulky. As conformation B has a steric hindrance of
proton at C-3 with R2, the conformation A must be
favorable. Thus the cyclization leads to the cis arrangement
for the hydroxyl group at C-5 and the juncture hydrogen at
C-4a as observed in compounds G and H.
When aldehyde 10a or 10b is reduced by SmI2, intermediate
A (R2¼H) is dominant. Therefore, the yields of 13a, 14a or
13b, 14b are very low. On the other hand, when ketone 10c
or 10d is reduced, the bulkiness of R2 leads the stabilization
of intermediate D (R2¼Me) more than in the time of 10a or
10b. As a result, the yields of cyclized products 13c, 14c or
13d, 14d are increased.
Without any additive, 12a, 11b, 11c and 11d were the major
products, respectively. The plausible mechanism is shown
below (Scheme 3).
Aldehyde 10a which does not have methyl group on the
cyclohexene ring, is reduced to afford intermediate E
(R2¼H) in Scheme 3. The intermediate E can be protonated
from both a and b side. On the other hand, the decaline
Samarium(II) reduces the aldehyde or ketone to afford
Scheme 4.

M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
3389
frame is bent due to the presence of the methyl group of
intermediate E derived from 10b. The protonation of E
occurs kinetically at the b face (convex face) to afford
ketone 11b.
(196.0 mg, 2.04 mol) in DMF (15 mL). The reaction
mixture was stirred for 30 min at rt and a DMF (25 mL)
solution of 8 (0.80 g, 3.01 mmol) and Et4NI (0.76 g,
2.96 mmol) were added. After 2.5 h the reaction was
quenched with sat. NH4Cl aq and Et2O was added. The
organic layer was separated and the aqueous layer was
extracted with several portions of Et2O. The combined
organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (10–20% Et2O in
hexane) to yield 6a (144.8 mg, 26%).
When MeOH was added as a proton source, the ratios of
12a, 12b, 12c, and 12d were increased, respectively. We
considered the mechanism as below. The reduction of
carbonyl groups by SmI2 proceeds under equilibrium
conditions, and the radical coupling and the protonation of
samarium enolates are competitive as illustrated in Scheme
4. If a proton source is present, after the enolate K is
protonated, the carbonyl groups of the side chain are
reduced to afford intermediates L, M, N, and O, which have
equatorial side chains. The side chain locates outside of the
molecule due to the same reason as mentioned above.
Conformer L has a steric hindrance between the R2 group
and the hydrogen at C-3. Therefore, conformer M is favored
to form the cyclized product Q giving 12a, 12b, 12c, and
12d.
Compound 6a. Oil; FTIR: 2931, 2858, 1676 cm21; 1H NMR
(300 MHz, CDCl3) d 0.02 (6H, s), 0.87 (9H, s), 1.42 (4H,
m), 1.95 (2H, quint, J¼6.3 Hz), 2.17 (2H, m), 2.33 (2H, m),
2.40 (2H, dd, J¼7.2, 6.3 Hz), 3.58 (2H, t, J¼6.3 Hz), 6.69
(1H, br t, J¼4.2 Hz); 13C NMR (75 MHz, CDCl3) d 25.3
(2CH3), 18.4 (C), 23.2 (CH2), 24.7 (CH2), 26.0 (3CH3), 26.1
(CH2), 29.2 (CH2), 32.6 (CH2), 38.6 (CH2), 63.1 (CH2),
139.7 (C), 145.0 (CH), 199.5 (C); MS (CI, CH4) m/z 283
(MþH)þ, 267, 225, 189, 151 (base), 133, 89, 75, 56; HRMS
(CI) found m/z 283.2097 (MþH)þ. C16H31O2Si requires
283.2093.
Addition of HMPA causes deterioration of yield. A rate of
reduction of a radical to the anion increased rapidly with
increasing HMPA concentration.1 This may cause decline
of the yield of cyclized products.
4.2.2. Synthesis of 7a. Enone 6a (160.0 mg, 0.57 mmol)
was treated with AcOH/H2O/THF (3:1:1, 5 mL) for 5 h at rt.
The reaction was quenched with 1 M NaOH aq and Et2O
was added. The organic layer was separated and the aqueous
layer was extracted with several portions of Et2O. The
combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (10–20% Et2O in
hexane) to yield 7a (70.8 mg, 74%).
NiI2 did not change the stereoselectivity of the intra-
molecular coupling reaction described herein.
3. Conclusion
Enone–aldehydes and -ketones were efficiently cyclized
with SmI2 in an intramolecular 6-endo-trig manner,
providing the corresponding perhydronaphthalenones.
Compound 7a. Oil; FTIR: 3371, 2936, 2866, 1706,
1668 cm21 1H NMR (300 MHz, CDCl3) d 1.38–1.59
;
(4H, m), 1.87 (1H, br s), 1.95 (2H, quint, J¼6.3 Hz), 2.18
(2H, br t, J¼7.3 Hz), 2.33 (2H, br dd, J¼10.4, 5.9 Hz), 2.40
(2H, dd, J¼7.3, 6.3 Hz), 3.62 (2H, t, J¼6.3 Hz), 6.71 (1H, t,
J¼4.1 Hz); 13C NMR (75 MHz, CDCl3) d 22.9 (CH2), 24.6
(CH2), 25.9 (CH2), 29.0 (CH2), 32.1 (CH2), 38.4 (CH2), 62.1
(CH2), 139.4 (C), 145.5 (CH), 199.8 (C); MS (EI) m/z 168
(Mþ), 150, 135, 122, 111, 107, 94, 79 (base), 67; HRMS
(EI) found m/z 168.1155 (Mþ). C10H16O2 requires
168.1151.
In general, the syntheses of perhydronaphthalenones with a
cis-relationship between the OH at C-5 and the substituent
at C-4a with good diastereoselectivity under mild reaction
conditions were achieved using SmI2.
4. Experimental
4.1. General
4.2.3. 6-Oxo-1-cyclohexene-1-butanal (10a). A solution of
7a (200.0 mg, 1.20 mmol) in CH2Cl2 (8 mL) was oxidized
with SO3–Py (477.0 mg, 3.0 mmol), DMSO (1.3 mL,
18.0 mmol), and Et3N (2.5 mL, 18.0 mmol) at for 2 h. The
organic materials were extracted with Et2O, washed with
brine and dried over MgSO4. The products were purified by
silica gel flash chromatography (SiO2 15 g, 20–40% AcOEt
in hexane) to afford 10a (105.9 mg, 57%).
Tetrahydrofuran (THF) was distilled from LiAlH4 under Ar
and then redistilled from sodium–benzophenone ketyl prior
to use. Samarium metal was purchased from Strem, Inc.,
and stored under Ar. Iodine was purchased from Aldrich.
HMPA was purchased from Aldrich and was distilled from
CaH2 and stored over 4 A molecular sieves under Ar.
t-BuOH was purchased from Aldrich and was distilled from
˚
magnesium and stored over 4 A molecular sieves under Ar.
˚
All the other commercially available reagents were used
without further purification. Standard benchtop techniques
were employed for handling air-sensitive reagents, and all
reactions were performed under Ar.
Compound 10a. Oil; FTIR: 2937, 2870, 2721, 1725,
1
1670 cm21; H NMR (300 MHz, CDCl3) d 1.71 (2H, br
quint, J¼7.5 Hz), 1.94 (2H, quint, J¼6.4 Hz), 2.18 (2H, br
tq, J¼7.8, 1.2 Hz), 2.29–2.42 (6H, m), 6.71 (1H, t,
J¼4.2 Hz), 9.72 (1H, t, J¼1.7 Hz); 13C NMR (75 MHz,
CDCl3) d 21.1 (CH2), 23.0 (CH2), 26.0 (CH2), 29.0 (CH2),
38.4 (CH2), 43.4 (CH2), 138.8 (C), 146.0 (CH), 199.3 (C),
202.5 (CH); MS (EI) m/z 166 (Mþ), 149, 138, 123 (base),
4.2. Experimental procedure for precursors 10a–d
4.2.1. Synthesis of 6a. To a DMF (5 mL) solution of
t-BuOK (539.0 mg, 4.8 mmol) was added cyclohexenone

3390
M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
110, 95, 79, 67, 55; HRMS (EI) found m/z 166.0965 (Mþ).
C10H14O2 requires 166.0994.
32.8 (CH2), 37.8 (CH2), 43.8 (CH2), 134.8 (C), 156.3 (C),
198.7 (C), 202.7 (C); MS (EI) m/z 180 (Mþ), 151, 137
(base), 124, 109, 96, 79, 69, 55; HRMS (EI) found m/z
180.1127 (Mþ). C11H16O2 requires 180.1150.
4.2.4. Synthesis of 6b. To a THF (200 mL) solution of
t-BuOK (21.60 g, 0.19 mol) was added 3-methylcyclo-
hexenone (8.76 g, 79.6 mol) in THF (300 mL) at rt. The
reaction mixture was stirred for 30 min at rt and a THF
(200 mL) solution of 8 (5.81 g, 21.8 mmol) was added.
After 7 h the reaction was quenched with sat NH4Cl aq and
Et2O was added. The organic layer was separated and the
aqueous layer was extracted with several portions of
Et2O. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to yield 6b
(17.70 g).
4.2.7. Synthesis of 7c. To a DMF (80 mL) solution of
t-BuOK (7.88 g, 70.4 mmol) was added cyclohexenone
(2.84 g, 29.6 mmol) in DMF (240 mL) at rt. The reaction
mixture was stirred for 50 min at rt and a DMF (240 mL)
solution of 9 (9.15 g, 44.0 mmol) was added. After 3 h the
reaction was quenched with sat NH4Cl aq and Et2O was
added. The organic layer was separated and the aqueous
layer was extracted with several portions of Et2O. The
combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (30–60% Et2O in
hexane) to yield 7c (1.09 g, 17%).
1
Compound 6b. FTIR: 2929, 2858, 1667, 1627 cm21; H
NMR (300 MHz, CDCl3) d 0.02 (6H, s), 0.87 (9H, s), 1.32
(2H,m), 1.50 (2H, m), 1.90 (2H, m), 1.91 (3H, s), 2.24–2.37
(6H, m), 3.58 (2H, t, J¼6.5 Hz); 13C NMR (75 MHz,
CDCl3) d 25.26 (CH3), 23.57 (CH3), 18.3 (C), 21.2 (CH3),
22.3 (CH2), 24.9 (CH2), 25.3 (CH2), 25.7 (CH3), 26.0
(2CH3), 32.8 (CH2), 32.9 (CH2), 37.8 (CH2), 63.1 (CH2),
135.7 (C), 155.3 (C), 198.8 (C); MS (CI, CH4) m/z 297
(MþHþ, base), 281, 239, 213, 165, 135, 89, 75, 61; HRMS
(CI) found m/z 297.2267 (MþH)þ. C17H33O2Si requires
297.2250.
Compound 7c. Oil; FTIR: 2930, 2855, 1670 cm21; 1H NMR
(300 MHz, CDCl3) d 1.30 (3H, s), 1.50 (2H, m), 1.63 (2H,
m), 1.97 (2H, q, J¼6.4 Hz), 2.19 (2H, tq, J¼7.5, 1.3 Hz),
2.34 (2H, ddt, J¼10.2, 6.0, 1.4 Hz), 2.42 (2H, dd, J¼6.9,
6.6 Hz), 3.92 (4H, m), 6.72 (1H, br t, J¼4.1 Hz); 13C NMR
(50 MHz, CDCl3) d 23.0 (CH2), 23.1 (CH2), 23.7 (CH3),
26.0 (CH2), 29.4 (CH2), 38.5 (CH2), 38.8 (CH2), 64.5
(2CH2), 110.0 (C), 139.5 (C), 145.2 (CH), 199.5 (C); MS
(EI) m/z 224 (Mþ), 209, 192, 121, 115, 87 (base), 79, 71, 55;
HRMS (EI) found m/z 224.1414 (Mþ). C13H20O3 requires
224.1412.
4.2.5. Synthesis of 7b. Enone 6b (17.70 g) in THF (50 mL)
was treated with TBAF (1.0 M in THF, 96 mL, 96 mmol)
for 12 h at rt. The reaction was quenched with water and
Et2O was added. The organic layer was separated and the
aqueous layer was extracted with several portions of
Et2O. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography on silica
gel (50–100% AcOEt in hexane) to yield 7b (2.32 g, 58%, 2
steps).
4.2.8. 2-(4-Oxopentyl)-2-cyclohexen-1-one (10c). Enone
7c (338.3 mg, 1.51 mmol) in THF (15 mL) was treated with
TsOH (67.7 mg, 0.36 mmol) and H2O (3 mL) for 48 h at rt.
The reaction was quenched with sat. NaHCO3 and Et2O was
added. The organic layer was separated and the aqueous
layer was extracted with several portions of Et2O. The
combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (5–45% Et2O in
hexane) to yield 10c (156.7 mg, 58%).
Compound 7b. FTIR: 3421, 2934, 2865, 1714, 1660 cm21
;
1H NMR (300 MHz, CDCl3) d 1.37 (2H, m), 1.56 (2H, m),
1.85–2.05 (3H, m), 1.93 (3H, s), 2.26–2.38 (6H, m), 3.64
(2H, t, J¼6.4 Hz); 13C NMR (75 MHz, CDCl3) d 21.2
(CH3), 22.2 (CH2), 24.6 (CH2), 25.1 (CH2), 32.3 (CH2), 32.8
(CH2), 37.8 (CH2), 62.5 (CH2), 135.5 (C), 155.7 (C), 199.2
(C); MS (EI) m/z 182 (Mþ), 164, 149 (base), 137, 125, 111,
93, 79, 67, 55; HRMS (EI) found m/z 182.1293 (Mþ).
C11H18O2 requires 182.1306.
Compound 10c. Oil; FTIR: 2937, 2869, 1713, 1672 cm21
;
1H NMR (300 MHz, CDCl3) d 1.68 (2H, br quint,
J¼7.8 Hz), 1.98 (2H, quint, J¼6.4 Hz), 2.14 (3H, s), 2.17
(2H, br td, J¼7.8, 1.4 Hz), 2.32–2.37 (2H, m), 2.39–2.56
(4H, m), 6.74 (1H, br t, J¼4.2 Hz); 13C NMR (75 MHz,
CDCl3) d 22.6 (CH2), 22.9 (CH2), 25.8 (CH2), 28.7 (CH2),
29.7 (CH3), 38.3 (CH2), 43.0 (CH2), 138.8 (C), 145.5 (CH),
199.2 (C), 208.7 (C); MS (EI) m/z 180 (Mþ), 165, 137, 123
(base), 110, 95, 81, 67, 55; HRMS (EI) found m/z 180.1150
(Mþ). C11H16O2 requires 180.1150.
4.2.6. 2-Methyl-6-Oxo-1-cyclohexene-1-butanal (10b). A
solution of 7b (50.0 mg, 0.27 mmol) in CH2Cl2 (2 mL) was
oxidized with SO3–Py (115.0 mg, 0.72 mmol), DMSO
(349.0 mg, 4.47 mmol), and Et3N (450.0 mg, 3.23 mmol)
at for 2 h. The organic materials were extracted with
Et2O, washed with brine and dried over MgSO4. The
products were purified by silica gel flash chromatography
(SiO2 15 g, 50–70% AcOEt in hexane) to afford 10b
(27.7 mg, 57%).
4.2.9. Synthesis of 7d. To a THF (80 mL) solution of
t-BuOK (852.8 mg, 7.6 mmol) was added 3-methylcyclo-
hexenone (495.0 mg, 4.5 mmol) in THF (3.0 mL) at rt. The
reaction mixture was stirred for 50 min at rt and a DMF
(240 mL) solution of 9 (1.00 g, 4.84 mmol) was added.
After 3 h the reaction was quenched with sat NH4Cl aq and
Et2O was added. The organic layer was separated and the
aqueous layer was extracted with several portions of
Et2O. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to yield 7d
(1.01 g, 94%).
Compound 10b. FTIR: 2937, 2869, 2721, 1722, 1660 cm21
;
1H NMR (300 MHz, CDCl3) d 1.64 (2H, m), 1.90 (2H, m),
1.95 (3H, s), 2.28–2.38 (6H, m), 2.42 (2H, td, J¼7.4,
1.7 Hz), 9.75 (1H, t, J¼1.7 Hz); 13C NMR (75 MHz,
CDCl3) d 21.3 (CH3), 21.4 (CH2), 22.2 (CH2), 24.5 (CH2),

M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
3391
Compound 7d. Oil; FTIR: 2980, 2940, 2880, 1660 cm21
;
after flash chromatography (SiO2, 0–60% AcOEt in
CHCl3).
1H NMR (200 MHz, CDCl3) d 1.29 (3H, s), 1.40 (2H, m),
1.61–1.68 (2H, m), 1.94 (3H, s), 1.85–1.98 (2H, m), 2.26–
2.40 (6H, m), 3.92 (4H, s); 13C NMR (200 MHz, CDCl3) d
21.2 (CH3), 22.3 (CH2), 23.6 (CH2), 23.7 (CH3), 25.2 (CH2),
32.8 (CH2), 37.9 (CH2), 39.0 (CH2), 64.6 (2CH2), 110.1 (C),
135.7 (C), 155.3 (C), 198.7 (C); MS (EI) m/z 238 (Mþ), 223,
193, 151, 135, 115, 87 (base), 79, 55; HRMS (EI) found m/z
238.1547 (Mþ). C14H22O3 requires 238.1569.
Entries 3 and 4. A solution of 10a (49.8 mg, 0.3 mmol) and
MeOH (19.0 mg, 0.6 mmol) in THF (1 mL) was treated
with SmI2 (0.1 M, 9 mL, 0.9 mmol) according to the general
procedure to afford a mixture of cyclized products (48.8 mg
and 48.4 mg respectively) after flash chromatography (SiO2,
0–60% AcOEt in CHCl3).
4.2.10. 3-Methyl-2-(4-oxopentyl)-2-cyclohexen-1-one
(10d). Enone 7d (1.01 g, 4.2 mmol) in THF (8 mL) was
treated with TsOH (40.0 mg, 0.21 mmol) and H2O (2 mL)
for 12 h at rt. The reaction was quenched with sat. NaHCO3
and Et2O was added. The organic layer was separated and
the aqueous layer was extracted with several portions of
Et2O. The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (10–45%
AcOEt in hexane) to yield 10d (513.6 mg, 63%).
Entries 5 and 6. A solution of 10a (49.8 mg, 0.3 mmol) and
MeOH (96.0 mg, 3 mmol) in THF (1 mL) was treated with
SmI2 (0.1 M, 9 mL, 0.9 mmol) according to the general
procedure to afford a mixture of cyclized products (45.9
and 49.8 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
Entries 7 and 8. A solution of 10a (49.8 mg, 0.3 mmol) in
THF (1 mL) was treated with SmI2 (0.1 M, 9 mL, 0.9 mmol)
and HMPA (645.0 mg, 3.6 mmol) according to the general
procedure to afford a mixture of cyclized products (25.2
and 21.6 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
Compound 10d. Oil; FTIR: 2930, 2870, 1710, 1660,
1630 cm21 1H NMR (200 MHz, CDCl3) d 1.51–1.66
;
(2H, m), 1.96 (3H, s), 1.88–1.99 (2H, s), 2.14 (3H, s), 2.24–
2.47 (8H, m); 13C NMR (200 MHz, CDCl3) d 21.2 (CH2),
22.2 (CH3), 23.1 (CH2), 24.4 (CH2), 29.8 (CH3), 32.8 (CH2),
37.8 (CH2), 43.4 (CH2), 135.1 (C), 156.1 (C), 198.7 (C),
209.1 (C); MS (EI) m/z 194 (Mþ), 151, 137 (base), 124, 108,
96, 79, 67, 55; HRMS (EI) found m/z 194.1308 (Mþ).
C12H18O2 requires 194.1307.
Entries 9 and 10. A solution of 10a (49.8 mg, 0.3 mmol) in
THF (1 mL) was treated with SmI2 (0.1 M, 9 mL, 0.9 mmol)
and NiI2 (10.0 mg, 0.03 mmol) according to the general
procedure to afford a mixture of cyclized products (47.8
and 48.9 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.3. Preparation of the SmI2 solution
Ketol 14a was purified on flash chromatography (SiO2,
20–60% AcOEt in CHCl3). Ketols 11a and 12a were
purified on HPLC (Nucleosil 380-05, 10f£250 mm, 40%
AcOEt in hexane) and recrystallization (CHCl3–AcOEt).
Samarium metal (496.3 mg, 3.3 mmol) was added under
flowing of Ar to an oven-dried, round-bottomed two-necked
flask containing a magnetic stirring bar and septum inlet.
Diiodomethane (803.5 mg, 3.0 mmol) was added to a
vigorously stirred suspension of samarium metal in THF
(30 mL). The mixture was vigorously stirred for 3 h at rt.
The resultant deep blue–green solution was directly used to
effect the following reactions.
4.5.1. (4aS,5S,8aS)-Rel-octahydro-5-hydroxy-1(2H)-
naphthalenone (11a). Retention time on GC: 8.60 min;
crystal: mp 100.8–102.58C; FTIR: 3394, 2938, 2871,
1
1704 cm21; H NMR (600 MHz, CDCl3) d 1.19 (1H, ddr,
J¼13.3, 11.1, 4.9 Hz), 1.31 (1H, dddd, J¼12.6, 11.5, 9.8,
4.7 Hz), 1.34 (1H, br s), 1.54–1.65 (2H, m), 1.70 (1H, ddt,
J¼13.9, 11.5, 4.3 Hz), 1.86–1.97 (3H, m), 2.07–2.13 (2H,
m), 2.23 (1H, br dq, J¼13.9, 4.2 Hz), 2.29 (1H, ddd,
J¼14.5, 11.5, 6.7, 1.3 Hz), 2.40 (1H, dtd, J¼14.5, 4.5,
1.5 Hz), 2.70 (1H, q, J¼4.9 Hz), 3.50 (1H, td, J¼9.8,
4.1 Hz); 13C NMR (150 MHz, CDCl3) d 21.0 (CH2), 22.3
(CH2), 24.7 (CH2), 25.2 (CH2), 34.8 (CH2), 41.3 (CH2), 46.6
(CH), 49.5 (CH), 68.7 (CH), 212.3 (C); MS (EI) m/z 168
(Mþ), 150, 111, 97 (base), 79, 67, 55; HRMS (EI) found m/z
168.1150 (Mþ). C10H16O2 requires 168.1151.
4.4. General procedure for the synthesis of
perhydronaphthalenes
A solution of SmI2 in THF was cooled to a fixed
temperature. A substrate and an additive in THF were
slowly added dropwise. The mixture was stirred at the
specific temperature for 30 min. The reaction was quenched
with a saturated aq. solution of Rochelle’s salt. The organic
materials were extracted with diethyl ether, washed with
brine and dried over MgSO4. The products were purified by
silica gel flash chromatography and HPLC. Gas chromato-
graphic analyses were carried out on a capillary column
[HP-20M 25 m£0.2 mm£0.2 mm, 50–1008C (208C/min)
followed by 100–2008C (58C/min)].
4.5.2. (4aS,5S,8aR)-Rel-octahydro-5-hydroxy-1(2H)-
naphthalenone (12a). Retention time on GC: 8.51 min;
crystal: mp 115.4–119.08C; FTIR: 3394, 2931, 2862,
1
1705 cm21; H NMR (600 MHz, C6D6) d 0.83 (1H, ddd,
J¼13.2, 11.5, 3.8 Hz), 0.86–0.97 (4H, m), 1.17–1.22 (1H,
m), 1.26 (1H, qt, J¼13.6, 4.1 Hz), 1.38 (1H, tdd, J¼11.8,
3.3, 1.1 Hz), 1.51 (1H, m), 1.59–1.64 (2H, m), 1.80 (1H, br
tdd, J¼13.6, 6.2, 1.1 Hz), 1.86 (1H, m), 2.08 (1H, m), 2.22
(1H, d quint, J¼13.6, 2.1 Hz), 2.87 (1H, br td, J¼10.0,
4.1 Hz); 13C NMR (150 MHz, CDCl3) d 23.0 (CH2), 25.1
(CH2), 26.1 (CH2), 28.3 (CH2), 35.5 (CH2), 41.5 (CH2), 51.7
4.5. SmI2 reduction of 10a (Table 1)
Entries 1 and 2. A solution of 10a (49.8 mg, 0.3 mmol) in
THF (1 mL) was treated with SmI2 (0.1 M, 9 mL, 0.9 mmol)
according to the general procedure to afford a mixture
of cyclized products (50.2 and 50.3 mg, respectively)

3392
M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
(CH), 53.0 (CH), 74.7 (CH), 209.3 (C); MS (EI) m/z 168
(Mþ), 150, 121, 111, 97 (base), 84, 79, 67, 55; HRMS (EI)
found m/z 168.1150 (Mþ). C10H16O2 requires 168.1151.
MeOH (35.0 mg, 1.1 mmol) in THF (0.5 mL) was treated
with SmI2 (0.1 M, 3.3 mL, 0.33 mmol) according to the
general procedure to afford a mixture of cyclized products
(18.6 and 17.7 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.5.3. (4aS,5R,8aR)-Rel-octahydro-5-hydroxy-1(2H)-
naphthalenone (14a). Retention time on GC: 8.78 min;
oil; FTIR: 3453, 2932, 2864, 1704 cm21
;
1H NMR
Entries 7 and 8. A solution of 10b (20.0 mg, 0.11 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 3.3 mL,
0.33 mmol) and HMPA (237.0 mg, 1.32 mmol) according
to the general procedure to afford a mixture of cyclized
products (13.0 and 15.1 mg, respectively) after flash
chromatography (SiO2, 0–60% AcOEt in CHCl3).
(600 MHz, CDCl3) d 1.20–1.28 (2H, m), 1.45 (1H, tdd,
J¼13.6, 5.0, 2.4 Hz), 1.53 (1H, tdd, J¼12.2, 3.0, 2.3 Hz),
1.57–1.71 (4H, m), 1.80 (1H, m), 1.85 (1H, qd, J¼12.2,
3.6 Hz), 1.94 (1H, m), 2.11 (1H, m), 2.32 (1H, tdd, J¼13.6,
6.2, 1.2 Hz), 2.37 (1H, m), 2.48 (1H, br td, J¼12.2, 3.3 Hz),
3.95 (1H, br q, J¼2.4 Hz); 13C NMR (150 MHz, CDCl3) d
18.8 (CH2), 24.9 (CH2), 26.2 (CH2), 28.6 (CH2), 33.1 (CH2),
41.7 (CH2), 48.0 (CH), 48.2 (CH), 69.6 (CH), 213.5 (C); MS
(EI) m/z 168 (Mþ), 150, 135, 122, 111, 97 (base), 84, 79, 67,
55; HRMS (EI) found m/z 168.1150 (Mþ). C10H16O2
requires 168.1151.
Entries 9 and 10. A solution of 10b (20.0 mg, 0.11 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 3.3 mL,
0.33 mmol) and NiI2 (3.0 mg, 0.01 mmol) according to the
general procedure to afford a mixture of cyclized products
(10.3 and 6.0 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.6. Isomerization of 11a
Ketol 11b was purified on flash chromatography (SiO2,
20–60% Et2O in hexane). Keto-ols 12b and 14b were
purified on HPLC (Nucleosil 50-5, 10f£250 mm, 30%
AcOEt in hexane).
K2CO3 (2.0 mg) was added to a MeOH (2 mL) solution of
11a (1.1 mg, 0.01 mmol) and the mixture was stirred
vigorously and refluxed for 12 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, 12a (1.0 mg) was prepared.
4.9.1. (4aS,5S,8aS)-Rel-octahydro-5-hydroxy-4a-methyl-
1(2H)-naphthalenone (11b). Retention time on GC:
;
8.88 min; oil; FTIR: 3448, 2940, 2871, 1699 cm21 1H
4.7. Isomerization of 12a
NMR (600 MHz, CDCl3) d 1.11 (3H, S), 1.40–1.48 (2H,
m), 1.53–1.62 (4H, m), 1.74 (1H, m), 1.86–1.95 (2H, m),
1.98 (1H, dq, J¼12.3, 4.12 Hz), 2.18 (1H, dtd, J¼13.8, 4.5,
1.6 Hz), 2.25 (1H, dddd, J¼14.4, 11.1, 7.1, 1.3 Hz), 2.30
(1H, br t, J¼4.1 Hz), 2.42 (1H, dtd, J¼14.7, 4.7, 1.6 Hz),
3.56 (1H, dd, J¼9.0, 4.3 Hz); 13C NMR (150 MHz, CDCl3)
d 20.8 (2CH2), 20.9 (2CH2), 30.3 (CH2), 33.3 (CH2), 40.7
(CH2), 42.9 (C), 55.5 (C), 70.4 (CH), 212.4 (C); MS (EI) m/z
182 (Mþ), 164, 149,125, 111 (base), 97, 79, 67, 55; HRMS
(EI) found m/z 182.1292 (Mþ). C11H18O2 requires
182.1307.
K2CO3 (2.0 mg) was added to a MeOH (2 mL) solution of
12a (4.0 mg, 0.02 mmol) and the mixture was stirred
vigorously and refluxed for 12 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, 12a (3.9 mg) was recovered.
4.8. Isomerization of 14a
K2CO3 (6.0 mg) was added to a MeOH (4 mL) solution of
14a (3.0 mg, 0.02 mmol) and the mixture was stirred
vigorously and refluxed for 13 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, 14a (3.0 mg) was recovered.
4.9.2. (4aS,5S,8aR)-Rel-octahydro-5-hydroxy-4a-
methyl-1(2H)-naphthalenone (12b). Retention time on
GC: 9.06 min; oil; FTIR: 3439, 2937, 2867, 2360,
1
1707 cm21; H NMR (600 MHz, CDCl3) d 0.78 (3H, s),
1.25–1.30 (1H, m), 1.35 (1H, tdd, J¼13.8, 12.0, 3.6 Hz),
1.46 (1H, tdd, J¼13.1, 12.0, 4.2 Hz), 1.54 (1H, td, J¼13.2,
4.4 Hz), 1.59 (2H, m), 1.73 (1H, m), 1.80 (1H, m), 1.88 (1H,
m), 2.03 (1H, m), 2,09 (1H, m), 2.16 (1H, dd, J¼11.4,
3.2 Hz), 2.32 (1H, td, J¼7.2, 1.2 Hz), 2.35 (1H, m), 3.49
(1H, dd, J¼11.1, 4.5 Hz); 13C NMR (150 MHz, CDCl3) d
11.1 (CH3), 19.8 (CH2), 22.5 (CH2), 22.7 (CH2), 30.0 (CH2),
36.3 (CH2), 41.1 (CH2), 44.7 (C), 56.7 (CH), 78.5 (CH),
212.0 (C); MS (EI) m/z 182 (Mþ), 167, 149,135, 111 (base),
98, 82, 67, 55; HRMS (EI) found m/z 182.1297 (Mþ).
C11H18O2 requires 182.1307.
4.9. SmI2 reduction of 10b (Table 2)
Entries 1 and 2. A solution of 10b (20.0 mg, 0.11 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 3.3 mL,
0.33 mmol) according to the general procedure to afford a
mixture of cyclized products (10.9 and 13.6 mg,
respectively) after flash chromatography (SiO2, 0–60%
AcOEt in CHCl3).
Entries 3 and 4. A solution of 10b (20.0 mg, 0.11 mmol) and
MeOH (7.0 mg, 0.22 mmol) in THF (0.5 mL) was treated
with SmI2 (0.1 M, 3.3 mL, 0.33 mmol) according to the
general procedure to afford a mixture of cyclized products
(19.6 and 16.3 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.9.3. (4aS,5R,8aR)-Rel-octahydro-5-hydroxy-4a-
methyl-1(2H)-naphthalenone (14b). Retention time on
GC: 9.13 min; oil; FTIR: 3450, 2927, 2867, 1701 cm21; 1H
NMR (600 MHz, CDCl3) d 0.81 (3H, s), 1.25 (1H, br s),
1.31 (1H, dt, J¼13.8, 3.0 Hz), 1.43 (1H, m), 1.55 (1H, m),
1.59 (2H, m), 1.63 (1H, m), 1.82 (1H, m), 1.89 (1H, m), 2.01
(1H, m), 2.22 (1H, td, J¼13.2, 4.6 Hz), 2.31 (2H, m), 2.69
Entries 5 and 6. A solution of 10b (20.0 mg, 0.11 mmol) and

M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
3393
(1H, dd, J¼12.3, 2.9 Hz), 3.52 (1H, br q, J¼3.0 Hz); 13C
NMR (150 MHz, CDCl3) d 17.2 (CH3), 18.8 (CH2), 20.0
(CH2), 22.2 (CH2), 28.6 (CH2), 33.9 (CH2), 41.2 (CH2), 43.5
(C), 50.8 (CH), 74.0 (CH), 213.9 (C); MS (EI) m/z 182
(Mþ), 164, 149,135, 125, 111 (base), 98, 82, 67, 55; HRMS
(EI) found m/z 182.1293 (Mþ). C11H18O2 requires
182.1307.
general procedure to afford a mixture of cyclized products
(20.7 and 24.2 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
Entries 7 and 8. A solution of 10c (25.0 mg, 0.14 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 4.2 mL,
0.42 mmol) and HMPA (300.0 mg, 1.68 mmol) according
to the general procedure to afford a mixture of cyclized
products (2.5 and 8.4 mg, respectively) after flash chroma-
tography (SiO2, 0–60% AcOEt in CHCl3).
4.9.4. (4aS,5R,8aS)-Rel-octahydro-5-hydroxy-4a-
methyl-1(2H)-naphthalenone (13b). The peak of 13b on
GC–MS was identified by isomerization of 14b. Retention
time on GC: 9.00 min; GC–MS (EI) m/z 182 (Mþ), 164,
149,138, 131, 125, 111 (base), 98, 95.
Entries 9 and 10. A solution of 10c (25.0 mg, 0.14 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 4.2 mL,
0.42 mmol) and NiI2 (5.0 mg, 0.02 mmol) according to the
general procedure to afford a mixture of cyclized products
(21.4 and 13.7 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.10. Isomerization of 11b
K2CO3 (6.0 mg) was added to a MeOH (3 mL) solution of
11b (10.0 mg, 0.05 mmol) and the mixture was stirred
vigorously and refluxed for 16 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (8.4 mg) of 11b and 12b
(21:79) was produced.
Compounds 11c, 12c, and 14c were purified on flash
chromatography (SiO2, 50–60% Et2O in hexane) and
HPLC (Nucleosil 50-5, 10B250 mm, 20% AcOEt in
CHCl3).
4.13.1. (4aS,5S,8aS)-Rel-octahydro-5-hydroxy-5-methyl-
1(2H)-naphthalenone (11c). Retention time 8.99 GC:
;
00 min; oil; FTIR: 3441, 2943, 2865, 1703 cm21 1H
4.11. Isomerization of 12b
K2CO3 (4.0 mg) was added to a MeOH (3 mL) solution of
12b (1.6 mg, 0.01 mmol) and the mixture was stirred
vigorously and refluxed for 37 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (1.6 mg) of 11b and 12b
(16:84) was produced.
NMR (600 MHz, CDCl3) d 1.22 (3H, s), 1.50–1.64 (7H,
m), 1.65–1.73 (3H, m), 1.81 (1H, br dt, J¼10.8, 5.1 Hz),
2.08 (1H, m), 2.23 (1H, m), 2.46 (1H, ddd, J¼14.7, 13.5,
6.5 Hz), 2.87 (1H, br dt, J¼13.2, 4.1 Hz); 13C NMR
(150 MHz, CDCl3) d 20.8 (CH2), 22.2 (CH2), 24.4 (CH2),
25.3 (CH2), 29.7 (CH3), 33.8 (CH2), 37.6 (CH2), 48.4 (C),
49.1 (C), 71.0 (C), 214.7 (C); MS (EI) m/z 182 (Mþ), 164,
149, 139, 124 (base), 111, 97, 84, 79, 67, 55; HRMS (EI)
found m/z 182.1296 (Mþ). C11H18O2 requires 182.1307.
4.12. Isomerization of 14b
K2CO3 (3.0 mg) was added to a MeOH (3 mL) solution of
14b (1.4 mg, 0.01 mmol) and the mixture was stirred
vigorously and refluxed for 37 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (0.9 mg) of 13b and 14b
(18:82) was produced.
4.13.2. (4aS,5S,8aR)-Rel-octahydro-5-hydroxy-5-
methyl-1(2H)-naphthalenone (12c). Retention time on
GC: 8.82 min; crystal: mp 93.0–100.58C; FTIR: 3440,
2935, 2864, 1705 cm21; 1H NMR (600 MHz, CDCl3) d 1.22
(3H, s), 1.25–1.35 (3H, m), 1.43–1.47 (2H, m), 1.57–1.66
(2H, m), 1.72–1.77 (2H, m), 1.87–1.94 (1H, m), 2.06–2.19
(3H, m), 2.28 (1H, tdd, J¼13.8, 6.6, 1.2 Hz), 2.40 (1H,
dquin, J¼13.8, 2.1 Hz); 13C NMR (150 MHz, CDCl3) d
20.6 (CH3), 22.1 (CH2), 24.8 (CH2), 25.1 (CH2), 26.0 (CH2),
41.8 (CH2), 42.1 (CH2), 52.0 (C), 53.9 (CH), 72.7 (C), 212.1
(C); MS (EI) m/z 182 (Mþ), 164, 149, 139, 131, 124 (base),
111, 97, 84, 79, 67, 55. Anal. found C, 72.65: H, 10.23: N,
0.02. requires C11H18O2 C, 72.49: H, 9.95.
4.13. SmI2 reduction of 10c (Table 3)
Entries 1 and 2. A solution of 10c (25.0 mg, 0.14 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 4.2 mL,
0.42 mmol) according to the general procedure to afford a
mixture of cyclized products (22.1 and 25.2 mg,
respectively) after flash chromatography (SiO2, 0–60%
AcOEt in CHCl3).
4.13.3. (4aS,5R,8aR)-Rel-octahydro-5-hydroxy-5-
methyl-1(2H)-naphthalenone (14c). Retention time on
GC: 8.75 min; oil; FTIR: 3385, 2932, 2858, 1685 cm21; 1H
NMR (600 MHz, C6D6) d 0.83 (3H, s), 0.87 (1H, td, J¼11.8,
3.5 Hz), 0.95 (1H, td, J¼13.5, 4.6 Hz), 1.19 (1H, tdd,
J¼13.2, 4.2, 3.3 Hz), 1.21–1.33 (4H, m), 1.35–1.39 (1H,
m), 1.42 (1H, tt, J¼13.3, 3.7 Hz), 1.46–1.49 (1H, m), 1.60
(1H, qt, J¼6.2, 3.1 Hz), 1.86 (1H, br td, J¼13.6, 6.2 Hz),
2.05 (1H, m), 2.11 (1H, tdd, J¼11.8, 3.4, 1.1 Hz), 2.24 (1H,
m); 13C NMR (150 MHz, C6D6) d 20.4 (CH2), 24.5 (CH2),
25.7 (CH2), 26.0 (CH2), 28.7 (CH3), 40.2 (CH2), 41.5 (CH2),
49.7 (CH2), 52.0 (CH), 70.2 (C), 210.8 (C); MS (EI) m/z 182
(Mþ), 164, 149, 139, 124 (base), 111, 97, 84, 79, 67, 55;
Entries 3 and 4. A solution of 10c (25.0 mg, 0.14 mmol) and
MeOH (9.0 mg, 0.28 mmol) in THF (0.5 mL) was treated
with SmI2 (0.1 M, 4.2 mL, 0.42 mmol) according to the
general procedure to afford a mixture of cyclized products
(20.7 and 21.5 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
Entries 5 and 6. A solution of 10c (25.0 mg, 0.14 mmol) and
MeOH (45.0 mg, 1.4 mmol) in THF (0.5 mL) was treated
with SmI2 (0.1 M, 4.2 mL, 0.42 mmol) according to the

3394
M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
HRMS (EI) found m/z 182.1292 (Mþ). C11H18O2 requires
182.1306.
THF (0.5 mL) was treated with SmI2 (0.1 M, 6 mL,
0.6 mmol) and HMPA (430.0 mg, 2.4 mmol) according to
the general procedure. Only the starting material was
recovered.
4.13.4. (4aS,5R,8aS)-Rel-octahydro-5-hydroxy-5-
methyl-1(2H)-naphthalenone (13c). The peak of 13c on
GC–MS was identified by isomerization of 14c. Retention
time on GC: 8.66 min; MS (EI) m/z 182 (Mþ), 164, 149,
139, 124, 111, 97 (base), 84, 79, 67, 55.
Entries 9 and 10. A solution of 10d (39.0 mg, 0.2 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 6 mL,
0.6 mmol) and NiI2 (6.0 mg, 0.02 mmol) according to the
general procedure to afford a mixture of cyclized products
(28.0 and 33.8 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.14. Isomerization of 11c
K2CO3 (2.0 mg) was added to a MeOH (3 mL) solution of
11c (2.9 mg, 0.02 mmol) and the mixture was stirred
vigorously and refluxed for 14 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (2.8 mg) of 11c and 12c
(11:89) was produced.
Compounds 11d, 12d, and 14d were purified on flash
chromatography (SiO2, 0–100% AcOEt in hexane) and
HPLC (Nucleosil 50-5, 10B250 mm, 20% AcOEt in
hexane).
4.17.1. (4aS,5S,8aS)-Rel-octahydro-5-hydroxy-4a,5-
dimethyl-1(2H)-naphthalenone (11d). Retention time on
GC: 9.56 min; oil; FTIR: 3480, 2940, 2870, 1700 cm21; 1H
NMR (600 MHz, CDCl3) d 0.96 (3H, s), 1.15 (3H, s),
1.35–1.39 (2H, m), 1.51 (1H, ddd, J¼11.4, 5.4, 1.3 Hz),
1.56–1.62 (2H, m), 1.68–1.76 (2H, m), 1.77–1.87 (2H, m),
1.93–1.97 (1H, m), 2.01 (1H, td, J¼18.6, 4.8 Hz),
2.12–2.18 (1H, m), 2.45 (1H, dd, J¼11.4, 4.2 Hz), 2.48–
2.55 (1H, m); 13C NMR (600 MHz, CDCl3) d 18.6 (CH3),
20.4 (CH2), 21.7 (CH2), 25.1 (CH3), 26.6 (CH2), 26.8 (CH2),
35.3 (CH2), 36.3 (CH2), 43.2 (C), 54.9 (CH), 72.9 (C), 215.6
(C); MS (EI) m/z 196 (Mþ), 181, 163, 137, 125, 111 (base),
97, 84; HRMS (EI) found m/z 196.1463 (Mþ). C12H20O2
requires 196.1463.
4.15. Isomerization of 12c
K2CO3 (11.0 mg) was added to a MeOH (11 mL) solution of
12c (15.0 mg, 0.08 mmol) and the mixture was stirred
vigorously and refluxed for 14 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (14.8 mg) of 11c and 12c
(11:89) was produced.
4.16. Isomerization of 14c
K2CO3 (4.0 mg) was added to a MeOH (5 mL) solution of
14c (3.2 mg, 0.02 mmol) and the mixture was stirred
vigorously and refluxed for 10 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (3.2 mg) of 13c and 14c (5:95)
was produced.
4.17.2. (4aS,5S,8aR)-Rel-octahydro-5-hydroxy-4a,5-
dimethyl-1(2H)-naphthalenone (12d). Retention time on
GC: 9.48 min; crystal; mp 122.0–124.28C; FTIR: 3470,
2940, 2870, 1700 cm21; 1H NMR (600 MHz, CDCl3) d 0.88
(3H, s), 1.26–1.32 (2H, m), 1.36 (3H, s), 1.39–1.42 (1H,
m), 1.45–1.49 (1H, m), 1.51 (1H, br s), 1.60–1.64 (1H, m),
1.70–1.76 (2H, m), 1.77–1.88 (3H, m), 1.97–2.02 (1H, m),
2.23–2.29 (1H, m) 2.30–2.37 (2H, m); 13C NMR
(600 MHz, CDCl3) d 14.3 (CH3), 20.3 (CH2), 21.8 (CH2),
22.1 (CH2), 22.7 (CH3), 31.1 (CH2), 37.0 (CH2), 41.2 (CH2),
46.0 (C), 54.8 (CH), 74.4 (C), 212.7 (C); MS (EI) m/z 196
(Mþ), 181, 138, 125, 111 (base), 97, 84; HRMS (EI) found
m/z 196.1458 (Mþ) C12H20O2 requires 196.1463.
4.17. SmI2 reduction of 10d (Table 4)
Entries 1 and 2. A solution of 10d (39.0 mg, 0.2 mmol) in
THF (0.5 mL) was treated with SmI2 (0.1 M, 6 mL,
0.6 mmol) according to the general procedure to afford a
mixture of cyclized products (39.3 and 22.0 mg,
respectively) after flash chromatography (SiO2, 0–60%
AcOEt in CHCl3).
4.17.3. (4aS,5R,8aR)-Rel-octahydro-5-hydroxy-4a,5-
dimethyl-1(2H)-naphthalenone (14d). Retention time on
GC: 9.42 min; crystal; mp 100.8–102.58C; FTIR: 3400,
2930, 2830, 1700 cm21; 1H NMR (600 MHz, CDCl3) d 0.82
(3H, s), 1.16 (3H, s), 1.30 (1H, br s), 1.36–1.42 (2H, m),
1.56–1.60 (2H, m), 1.62–1.67 (2H, m), 1.73–1.84 (2H, m),
1.99–2.04 (1H, m), 2.08 (1H, td, J¼13.2, 4.2 Hz), 2.29–
2.32 (2H, m), 2.77 (1H, dd, J¼12, 3 Hz); 13C NMR
(600 MHz, CDCl3) d 16.8 (CH3), 20.0 (CH2), 20.3 (CH2),
22.2 (CH2), 24.8 (CH3), 30.4 (CH2), 35.5 (CH2), 41.2 (CH2),
46.2 (C), 52.5 (CH), 74.0 (C), 214.3 (C); MS (EI) m/z 196
(Mþ), 181, 163, 138, 125, 111 (base), 97, 84; HRMS (EI)
found m/z 196.1473 (Mþ). C12H20O2 requires 196.1463.
Entries 3 and 4. A solution of 10d (39.0 mg, 0.2 mmol) and
MeOH (13.0 mg, 0.4 mmol) in THF (0.5 mL) was treated
with SmI2 (0.1 M, 6 mL, 0.6 mmol) according to the general
procedure to afford a mixture of cyclized products (35.9
and 39.4 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
Entries 5 and 6. A solution of 10d (39.0 mg, 0.2 mmol) and
MeOH (64.0 mg, 2 mmol) in THF (0.5 mL) was treated
with SmI2 (0.1 M, 6 mL, 0.6 mmol) according to the general
procedure to afford a mixture of cyclized products (29.9
and 22.9 mg, respectively) after flash chromatography
(SiO2, 0–60% AcOEt in CHCl3).
4.17.4. (4aS,5R,8aS)-Rel-octahydro-5-hydroxy-4a,5-
dimethyl-1(2H)-naphthalenone (13d). The peak of 13d
on GC–MS was identified by isomerization of 14d.
Entries 7 and 8. A solution of 10d (39.0 mg, 0.2 mmol) in

M. Sono et al. / Tetrahedron 59 (2003) 3385–3395
3395
Retention time on GC: 9.00 min; MS (EI) m/z 196 (Mþ),
181, 163, 138, 125, 111 (base), 97, 84, 71.
G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (c) Molander,
G. A. Acc. Chem. Res. 1998, 31, 603. (d) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321.
2. Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron
Lett. 1999, 40, 4913.
4.18. Isomerization of 11d
3. (a) Enholm, E. J.; Trivellas, A. Tetrahedron Lett. 1989, 30,
1063. (b) Kan, T.; Hosokawa, S.; Nara, S.; Oikawa, M.; Ito, S.;
Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59, 5532.
(c) Kan, T.; Nara, S.; Ito, S.; Matsuda, F.; Shirahama, H.
J. Org. Chem. 1994, 59, 5111. (d) Sakai, H.; Hagiwara, H.; Ito,
Y.; Hoshi, T.; Suzuki, T.; Ando, M. Tetrahedron Lett. 1999,
40, 2965.
K2CO3 (4.0 mg) was added to a MeOH (3 mL) solution of
11d (3.4 mg, 0.02 mmol) and the mixture was stirred
vigorously and refluxed for 41 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (3.3 mg) of 11d and 12d
(51:49) was produced.
4. Kito, M.; Sakai, T.; Yamada, K.; Matsuda, F.; Shirahama, H.
Synlett 1993, 158.
4.19. Isomerization of 12d
5. (a) Fukuzawa, S.; Iida, M.; Nakanishi, A.; Fujinami, T.; Sakai,
S. J. Chem. Soc., Chem. Commun. 1987, 920. (b) Fukuzawa,
S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc., Perkin
Trans. 1 1988, 1669.
K2CO3 (6.0 mg) was added to a MeOH (6 mL) solution of
12d (5.2 mg, 0.03 mmol) and the mixture was stirred
vigorously and refluxed for 41 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (5.1 mg) of 11d and 12d
(52:48) was produced.
6. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
7. (a) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett.
1987, 1485. (b) Shabangi, M.; Flowers, R. A., II. Tetrahedron
Lett. 1997, 38, 1137. (c) Shabangi, M.; Sealy, J. M.; Fuchs,
J. R.; Flowers, R. A., II. Tetrahedron Lett. 1998, 39, 4429.
8. Lund, H.; Baizer, M. M. Organic Electrochemistry; 3rd ed.,
Marcel Dekker: New York, 1991; p 453.
4.20. Isomerization of 14d
K2CO3 (7.0 mg) was added to a MeOH (7 mL) solution of
14d (6.5 mg, 0.03 mmol) and the mixture was stirred
vigorously and refluxed for 27 h. The organic materials
were extracted with diethyl ether, washed with brine and
dried over MgSO4. After filtration and evaporation of
solvent in vacuo, the mixture (6.4 mg) of 13d and 14d
(6:94) was produced.
9. Machrouhi, F.; Hamann, B.; Namy, J.-L.; Kagan, H. B. Synlett
1996, 633.
10. For general reviews see: (a) Soderquist, J. A. Aldrichim. Acta
1991, 24, 15. (b) Molander, G. A. Chem. Rev. 1992, 92, 29.
(c) Molander, G. A. Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1994; Vol. 46, p 211. (d) Molander, G. A.;
Harris, C. R. Chem. Rev. 1996, 96, 307.
11. Sono, M.; Nakashiba, Y.; Nakashima, K.; Tori, M. J. Org.
Chem. 2000, 65, 3099.
Acknowledgements
12. (a) Molander, G. A.; Etter, J. B. Tetrahedron Lett. 1984, 25,
3281. (b) Molander, G. A.; Etter, J. B. J. Org. Chem. 1986, 51,
1778.
We thank Dr M. Tanaka and Miss Y. Okamoto (Tokushima
Bunri University) for measurement of 600 MHz NMR and
mass spectra, respectively. X-Ray analysis was carried out
by Mr S. Takaoka (Tokushima Bunri University), to whom
many thanks are due. This work was supported in part by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, and Culture of Japan (No. 13672245).
13. The full structure was established by a combination of the 2D
NMR including the NOESY spectrum.
14. The structure was analyzed by X-ray crystallography.
15. Keto-alcohols 13b–d were not isolated. The ratios were
determined by using GC–MS peak area and fragment patterns.
16. Tokoroyama, T.; Tsukamoto, M.; Ito, H. Tetrahedron Lett.
1984, 25, 5067.
17. Hamon, D. P. G.; Richards, K. R. Aust. J. Chem. 1983, 36(11),
2243–2259.
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