Samarium(II)-promoted radical spirocyclization onto an aromatic ring

Article abstract of DOI:10.1021/jo034767w

Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of methyl 4-(4-oxoalkyl)benzoates with SmI₂ in the presence of i-PrOH and HMPA, yielding methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this chemistry, spiro[3.5] and -[5.5] systems, and sterically congested spiro[4.5] systems, were easily synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven to be extremely important: while an ester or amide functionality on the aromatic ring can promote the spirocyclization, a sulfonamide substituent causes ortho cyclization.

Full text of DOI:10.1021/jo034767w

Sa m a r iu m (II)-P r om oted Ra d ica l Sp ir ocycliza tion on to a n
Ar om a tic Rin g
Hiroaki Ohno, Mitsuaki Okumura, Shin-ichiro Maeda, Hiroki Iwasaki,
Ryutaro Wakayama, and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, J apan
t-tanaka@phs.osaka-u.ac.jp
Received J une 5, 2003
Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of
methyl 4-(4-oxoalkyl)benzoates with SmI2 in the presence of i-PrOH and HMPA, yielding methyl
1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this
chemistry, spiro[3.5] and -[5.5] systems, and sterically congested spiro[4.5] systems, were easily
synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven
to be extremely important: while an ester or amide functionality on the aromatic ring can promote
the spirocyclization, a sulfonamide substituent causes ortho cyclization.
In tr od u ction
A (Scheme 1) and the reversible nature of the radical
addition. The intermediate A, generated by the intramo-
lecular addition of the X radical 1 onto an aromatic ring,
can be easily converted into the Y radical 2 (aryl
migration) or a more stable rearranged product 3.8
Numerous examples of intramolecular aryl migration
from sulfur to carbon,9 oxygen to carbon,10 silicon to
carbon,11 and others12 are reported, although control of
the regioselectivity is sometimes difficult.13 To realize the
spirocyclization onto an aromatic ring, the spirohexadi-
enyl radical intermediate A should be effectively trapped
in an irreversible manner. Although some examples of
formation of the spirocycle 4 with a loss of aromaticity
by the capture of the intermediate A with an oxidant/
nucleophile (-e-/Z-)6 or a radical species (Z•)7 have been
Interest in spirocyclic systems derives from the unique
molecular structure and diverse biological activities of
this class of compounds. Among a number of synthetic
methods of spirocycles,1 those based on radical cyclization
are often quite effective: spirocycles can be efficiently
synthesized by an intramolecular radical attack onto a
cyclic olefin,2 intramolecular addition of tertiary cyclic
radicals to an alkene3 or alkyne,4 or cyclization of a
radical species possessing a preformed quaternary carbon
center.5 In contrast, synthesis of spirocycles by a radical
attack onto an aromatic ring is relatively limited,6,7
despite the availability of a wide range of aromatic
compounds. This is presumably because of both the
instability of spirocyclohexadienyl radical intermediate
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10.1021/jo034767w CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/30/2003
7722
J . Org. Chem. 2003, 68, 7722-7732

Samarium(II)-Promoted Radical Spirocyclization
SCHEME 1
SCHEME 2a
reported, reductive trapping of A (e-/Z+) is unknown. For
such a reductive conversion, we expected that SmI2/H+
might be an ideal system.
a
Reaction conditions: (a) SmI2 (3.5 equiv), THF; (b) SmI2 (5
equiv), HMPA (18 equiv), i-PrOH (2 equiv), THF, 0 °C.
Samarium(II)-mediated radical cyclization onto an
arene ring had been unprecedented until recently. In
1995, Schmalz and co-workers reported the successful
addition of ketyl radicals onto an arene-Cr(CO)3 complex
to form tricyclic products in good yields.14 Reissig and
co-workers reported samarium(II)-induced cyclization by
ketyl radical addition onto an appropriately substituted
arene ring to form 1,4-cyclohexadiene derivatives.15
Furthermore, related radical ortho cyclization onto a
formyl-substituted aryl ring was reported by Fang and
co-workers.16,17 However, samarium(II)-mediated spiro-
cyclization onto an arene ring is unprecedented, although
some spirocyclizations by the addition of the samarium
ketyl radical onto a cyclic or conjugate olefin are re-
ported.18
revealed that addition of HMPA20 to the reaction mixture
dramatically changes the cyclization mode: thus, treat-
ment of 5 with SmI2 in the presence of HMPA and i-PrOH
yielded a condensed ring, 7, bearing a cyclohexadienyl
moiety as a diastereomeric mixture.21 On the basis of
these results, we expected that the radical spirocycliza-
tion onto an aromatic ring could be possible starting from
benzoate 8 possessing an oxoalkyl group at the position
para to the ester group. Furthermore, the combination
of SmI2 and i-PrOH could also be an appropriate system
for the above-mentioned reductive capture of the spiro-
hexadienyl radical intermediate A (Scheme 1). In this
paper, we present a full account of our investigation into
the first radical spirocyclization onto an aromatic ring
mediated by SmI2.22
Recently, we found that a radical ipso substitution
reaction of the aromatic methoxy group is effectively
promoted by samarium(II) to afford cyclized products
such as 6 (Scheme 2).19 The detailed investigation
Resu lts a n d Discu ssion
Syn th esis of Requ isite Su bstr a tes. Various ben-
zoates bearing an alkyl ketone side chain were prepared
starting from formylbenzoates 10. Typically, as shown
in Scheme 3, Wittig olefination of methyl 4-formylben-
zoate (10a ) followed by catalytic hydrogenation of the
resulting alkene gave the acetal 11 in 61% yield, which
was treated with PPTS in a mixed solvent of water and
acetone to afford the corresponding aldehyde 12 in 99%
yield. Reaction of 12 with an alkylmagnesium halide gave
alcohols 13a -d , followed by oxidation with Dess-Martin
periodinane to afford the desired ketones 14a -d . Simi-
larly, as shown in Scheme 4, ketones 15-22 were
synthesized starting from aldehydes 10a -e (see the
Supporting Information).
(12) (a) Cadogan, J . I. G.; Hickson, C. L.; Hutchison, H. S.; McNab,
H. J . Chem. Soc., Chem. Commun. 1985, 643-644. (b) Black, M.;
Cadogan, J . I. G.; McNab, H. J . Chem. Soc., Chem. Commun. 1990,
395-396. (c) Lee, E.; Whang, H. S.; Chung, C. K. Tetrahedron Lett.
1995, 36, 913-914. (d) Amii, H.; Kondo, S.; Uneyama, K. Chem.
Commun. 1998, 1845-1846. (e) Wakabayashi, K.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Org. Lett. 2000, 2, 1899-1901. (f) Senboku,
H.; Hasegawa, H.; Orito, K.; Tokuda, M. Tetrahedron Lett. 2000, 41,
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6091.
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Commun. 1991, 877-879. (b) Leardini, R.; McNab, H.; Nanni, D.
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Motherwell, W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 137-
140. (d) da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 141-144. (e) Alcaide, B.; Rodr´ıguez-
Vicente, A. Tetrahedron Lett. 1998, 39, 6589-6592. (f) Wang, S.-F.;
Chuang, C.-P.; Lee, J .-H.; Liu, S.-T. Tetrahedron 1999, 55, 2273-2288.
(g) Ryokawa, A.; Togo, H. Tetrahedron 2001, 57, 5915-5921.
(14) (a) Schmalz, H.-G.; Siegel, S.; Bats, J . W. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2383-2385. (b) Schmalz, H.-G.; Kiehl, O.; Gotov,
B. Synlett 2002, 1253-1256. (c) Schwarz, O.; Brun, R.; Bats, J . W.;
Schmalz, H.-G. Tetrahedron Lett. 2002, 43, 1009-1013.
Heck olefination reaction of aryl halides 23 with
appropriate alkenes is a convenient method for our
substrate preparation (Scheme 5). Treatment of methyl
4-bromo-3-methylbenzoate (23a) with 4-penten-2-ol, n-Bu4-
NCl, LiCl, and LiOAc in the presence of Pd(OAc)2 in
(15) (a) Dinesh, C. U.; Reissig, H.-U. Angew. Chem., Int. Ed. 1999,
38, 789-791. (b) Nandanan, E.; Dinesh, C. U.; Reissig, H.-U. Tetra-
hedron 2000, 56, 4267-4277. (c) Berndt, M.; Reissig, H.-U. Synlett
2001, 1290-1292. (d) Gross, S.; Reissig, H.-U. Synlett 2002, 2027-
2030.
(19) Tanaka, T.; Wakayama, R.; Maeda, S.; Mikamiyama, H.;
Maezaki, N.; Ohno, H. Chem. Commun. 2000, 1287-1288.
(20) (a) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485-1486. (b) Miller, R. S.; Sealy, J . M.; Shabangi, M.; Kuhlman, M.
L.; Fuchs, J . R.; Flowers, R. A., II. J . Am. Chem. Soc. 2000, 122, 7718-
7722. (c) Knettle, B. W.; Flowers, R. A., II. Org. Lett. 2001, 3, 2321-
2324. (d) Prasad, E.; Flowers, R. A., II. J . Am. Chem. Soc. 2002, 124,
6895-6899.
(21) Ohno, H.; Wakayama, R.; Maeda, S.; Iwasaki, H.; Okumura,
M.; Iwata, C.; Mikamiyama, H.; Tanaka, T. J . Org. Chem. 2003, 68,
5909-5916.
(22) For a preliminary communication, see: Ohno, H.; Maeda, S.;
Okumura, M.; Wakayama, R.; Tanaka, T. Chem. Commun. 2002, 316-
317.
(16) (a) Shiue, J .-S.; Lin, M.-H.; Fang, J .-M. J . Org. Chem. 1997,
62, 4643-4649. (b) Kuo, C.-W.; Fang, J .-M. Synth. Commun. 2001,
31, 877-892.
(17) For
a related reaction, see: Yang, S. M.; Nandy, S. K.;
Selvakumar, A. R.; Fang, J .-M. Org. Lett. 2000, 2, 3719-3721.
(18) (a) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J .
Chem. Soc., Chem. Commun. 1986, 624-625. (b) Shibuya, K.; Nagaoka,
H.; Yamada, Y. J . Chem. Soc., Chem. Commun. 1991, 1545-1546. (c)
Merlic, C. A.; Walsh, J . C. J . Org. Chem. 2001, 66, 2265-2274. (d)
Sono, M.; Nakashiba, Y.; Nakashima, K.; Takaoka, S.; Tori, M.
Heterocycles 2001, 54, 101-104.
J . Org. Chem, Vol. 68, No. 20, 2003 7723

Ohno et al.
SCHEME 3a
SCHEME 5a
a
Reagents: (a) Ph3P+CH2CH2CH(-OCH2CH2O-)Br-, NaH,
THF; (b) Pd/C, H2, MeOH; (c) PPTS, H2O, acetone; (d) RMgX, THF;
(e) Dess-Martin periodinane, CH2Cl2.
SCHEME 4
a
Reagents: (a) 4-penten-2-ol, Pd(OAc)2, n-Bu4NCl, LiCl,
LiOAc‚2H2O, DMF; (b) 3-buten-2-ol, Pd(OAc)2, P(o-tol)3, Et3N; (c)
4-penten-2-ol, Pd(OAc)2, P(o-tol)3, Et3N; (d) Pd/C, H2, MeOH; (e)
Dess-Martin periodinane, CH2Cl2; (4) trans-2-vinylcyclohexanol,
Pd(OAc)2, P(o-tol)3, Et3N.
SCHEME 6a
DMF23 afforded methyl ketone 24 in a single step (51%
yield). Similarly, ketones 25, 26, 27, and 29 were
synthesized directly from the corresponding aryl bro-
mides 23b, 23c, 23d , and 23e, respectively, by the above
palladium-catalyzed reaction with 4-penten-2-ol or 3-buten-
2-ol. In contrast, since the reaction of methyl 3-bromo-
4-methylbenzoate (23d ) with 4-penten-2-ol under iden-
tical reaction conditions gave a complex mixture of
unidentified products, we prepared 28 by a three-step
sequence including the usual Heck olefination, catalytic
hydrogenation, and Dess-Martin oxidation. Benzoate 31
possessing a cyclohexanone moiety was synthesized
according to a similar three-step procedure including the
Heck reaction of methyl 4-iodobenzoate (23f) with trans-
2-vinylcyclohexanol.
a
Reagents: (a) MeC(-OCH2CH2O-)CH2CH2MgBr, THF; (b)
PPTS, H2O, acetone; (c) (TBS)Cl, imidazole, MeCN; (d) (TIPS)OTf,
imidazole, DMF.
SCHEME 7a
Methyl ketones 33a and 33b which bear a siloxy group
on the benzylic position were easily synthesized by the
reaction of 10a with a Grignard reagent followed by
cleavage of the ethylene acetal and silylation of the
a
Reagents: (a) 3% H2O2, 25% KOH; (b) LiOH‚H2O, MeOH,
H2O; (c) SOCl2, DMF, CH2Cl2, then 40% NHMe2.
secondary hydroxy group with (TBS)Cl or (TIPS)OTf
(Scheme 6). Finally, 4-substituted benzamide derivatives
35 and 37 were prepared by hydrolysis of the known
nitrile 3415c or hydrolysis of 14a followed by amidation
(23) (a) Larock, R. C.; Leung, W.-Y.; Sandra, S.-D. Tetrahedron Lett.
1989, 30, 6629-6632. (b) Taylor, E. C.; Wang, Y. Heterocycles 1998,
48, 1537-1554.
7724 J . Org. Chem., Vol. 68, No. 20, 2003

Samarium(II)-Promoted Radical Spirocyclization
TABLE 1. Op tim iza tion of th e Rea ction Con d ition s for th e Sp ir ocycliza tion of 14a a
amt of
HMPA
(equiv)
yield of 38a
+ 39a (%)
38a :39a
yield of
40a (%)
recovery of
14a (%)
entry
ROH
temp
rt
rt
rt
rt
rt
rt
rt
ratioc
1
2
3
4
5
6
7
8
9
i-PrOH
t-BuOH
H2O
18
18
18
18
18
0
10
18
18
84
68
9
12
10
0
18
93
84
2:1
2:1
2.5:1
2:1
2:1
0
0
0
17
18
0
0
0
0
0
0
33
19
72
17
21
0
BHTb
none
i-PrOH
i-PrOH
i-PrOH
i-PrOH
1:1.5
1:1.3
1.7:1
0 °C
-78 °C
0
a
b
All reactions were carried out in THF using 5 equiv of SmI2 and 2 equiv of a proton source. BHT ) 2,6-di-tert-butyl-4-methylphenol.
c Ratios were determined by 1H NMR.
SCHEME 8
of the resulting acid 36 with thionyl chloride and an
aqueous solution of dimethylamine, respectively (Scheme
7).
Sp ir ocycliza tion of th e pa r a -Su bstitu ted Ben -
zoa te Der iva tives. Having synthesized the requisite
substrates, we next investigated the SmI2-promoted
cyclization of the benzoates 14a . The results are sum-
marized in Table 1. As we expected, treatment of 14a
with a THF solution of SmI2 in the presence of HMPA
(18 equiv) and i-PrOH (2 equiv) gave spirocyclic com-
pounds 38a and 39a in 84% yield (38a :39a ) 2:1, entry
1). Similarly, t-BuOH is an effective proton source for the
spirocyclization (68% yield, entry 2). Although some other
proton sources such as water or 2,6-di-tert-butyl-4-
methylphenol (BHT)24 were employed (entries 3 and 4),
a considerable amount of the starting material was
recovered or an intractable mixture of 38a , 39a , and
dienylspirocycle 40a was obtained. When the reaction
was conducted in the absence of a proton source, only
10% of the spirocycles was obtained, and a considerable
amount of the starting material (72%) was recovered
(entry 5). Next, other conditions were investigated using
2 equiv of i-PrOH (entries 6-8). It was found that nearly
4 equiv of HMPA to SmI2 is necessary for the complete
conversion (compare entries 1, 6, and 7), which is in good
agreement with the observations by Flowers and Hou
that the addition of 4 equiv of HMPA to samarium iodide
solution leads to a complex with strong reducing ability.25
We found that lowering the reaction temperature to 0
°C increased the yield of 38a and 39a (93% yield, entry
8).
Cyclization of the ketyl radical intermediate 41 occurs
onto the more reactive carbon (position para to the ester
group) to give the unstable cyclohexadienyl radical
intermediate 42. Another molecule of SmI2 reduces 42
by single-electron transfer from the side of the oxygen
atom as depicted in 43, and cyclohexadienyl anion 4427
will be produced stereoselectively. Finally, protonation
of 44 followed by 1,4-reduction of the resulting enoate
28
45 by SmI2 gives a diastereomixture of 38a and 39a .
Considering the result that the spirocyclization reaction
in the absence of i-PrOH afforded the recovered starting
(26) An NOE experiment of epoxide 69 derived from 39a showed
reasonable correlations as shown below. Furthermore, treatment of a
mixture of 38a and 39a with DBU afforded the corresponding
isomerized product 70 as
a single isomer in 79% yield. For the
determination of relative configurations of other spirocycles, see the
Supporting Information.
Relative configurations of the synthesized spirocycles
were determined by NOE experiment and isomerization
of the double bonds.26 The configuration of the spirocyclic
quaternary center and the neighboring quaternary car-
bon was completely controlled. One explanation for the
observed stereochemical outcome is shown in Scheme 8.
(27) For related intermediates, see: (a) Lin, S.-C.; Yang, F.-D.;
Shiue, J .-S.; Yang, S.-M.; Fang, J .-M. J . Org. Chem. 1998, 63, 2909-
2917. (b) Yang, S.-M.; Fang, J . M. J . Org. Chem. 1999, 64, 394-399.
(28) Inanaga and co-workers reported that sterically crowded R,â-
unsaturated enoates undergo reduction of the double bond by SmI2-
HMPA; see: Inanaga, J .; Honda, Y.; Tabuchi, T.; Ohtsubo, K.;
Yamaguchi, M.; Hanamoto, T. Tetrahedron Lett. 1991, 32, 6557-6558.
For a related SmI2-mediated 1,4-reduction of unsaturated acids, see:
Concello´n, J . M.; Rodr´ıguez-Solla, H. Chem.sEur. J . 2002, 8, 4493-
4497.
(24) BHT is known as a selective protonating reagent for metal
enolates; see: (a) Hou, Z.; Yoshimura, T.; Wakatsuki, Y. J . Am. Chem.
Soc. 1994, 116, 11169-11170. (b) Fehr, C.; Galindo, J . Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1888-1889. (c) Nakamura, Y.; Takeuchi, S.;
Ohira, A.; Ohgo, Y. Tetrahedron Lett. 1996, 37, 2805-2508.
(25) (a) Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett. 1997,
38, 1137-1140. (b) Hou, Z.; Wakatsuki, Y. J . Chem. Soc., Chem.
Commun. 1994, 1205-1206. See also: (c) Hasegawa, E.; Curran, D.
P. Tetrahedron Lett. 1993, 34, 1717-1720.
J . Org. Chem, Vol. 68, No. 20, 2003 7725

Ohno et al.
TABLE 2. Sa m a r iu m (II)-Med ia ted Sp ir ocycliza tion of
products 38i, 39i, and other isomers, and 38j, 39j, and
other isomers, respectively (entries 8 and 9). It should
be clearly noted that the cyclization of these congested
siloxy derivatives 33a and 33b requires an increased
amount of i-PrOH: for example, cyclization of 33a in the
presence of 2 equiv of i-PrOH yielded only 49% of the
diastereomixture of the cyclized products along with the
recovered starting material (19%), while the cyclization
reaction using 24 equiv of i-PrOH smoothly proceeded
to give an 86% yield of the desired products without
recovering the starting material. These results also
support the reversible nature of the spirocyclization
reaction shown in Scheme 8.
th e pa r a -Su bstitu ted Ben zoa tesa
Relative configurations of the cyclized products were
determined by the base-mediated isomerization of the
diastereomixtures and NOE analysis of the epoxide
derivatives (see the Supporting Information). In all cases,
the hydroxy group of the cyclized products directs the
opposite side of the double bond of the cyclohexene
moiety, which can be rationalized by the proposed mech-
anism shown in Scheme 8.
Effect of th e Ar om a tic Su bstitu en ts. From the
above observations, para-substituted benzoates can be
effectively cyclized into the desired spirocycles in a
stereoselective manner by treatment with SmI2 in the
presence of HMPA and i-PrOH. Next, we investigated
other benzoates including ortho- and meta-substituted
ones. The results are summarized in Table 3. Reaction
of the ortho-substituted benzoate 15 gave an inseparable
mixture of the desired spiro compounds 46 (49% yield)
and 47 (7% yield).30 In this case, a small amount of a
condensed ring, 48, was obtained (8% yield) along with
other unidentified products. Stereoselective formation of
46 and 47 can be rationalized as depicted in Scheme 9:
formation of cyclohexadienyl anion 55, protonation, and
reduction of the double bond of the resulting 56 with
SmI2/HMPA28 would produce a mixture of 46 and 47 both
bearing a more stable R-CO2Me group. The minor product
48 would be produced by the rearrangement of the
cyclohexadienyl radical intermediate A (Scheme 1), fol-
lowed by single-electron transfer by SmI2. As we ex-
pected, cyclization of meta-substituted benzoate 16 af-
a
All reactions were carried out in THF at 0 °C under argon
using SmI2 (5 equiv) and i-PrOH. Ratios were determined by 1H
NMR.
b
material with a small amount of the desired spirocyclized
products (entry 5, Table 1), we anticipated that the
reaction from 14a to the cyclohexadienyl anion 44 would
be a reversible process and that the protonation of 44
shifts the equilibrium to the product. This assumption
is also supported by the reaction of 33a (Table 2) in the
presence of a larger amount of i-PrOH, which will be
discussed below.
Next, spirocyclization of various para-substituted ben-
zoates was investigated (Table 2). Similarly to the methyl
ketone 14a (entry 8, Table 1), ethyl and benzyl ketones
14b and 14c were cyclized into the corresponding spiro-
cycles 38b and 39b, and 38c and 39c, respectively, by
treatment with SmI2 in the presence of HMPA and
i-PrOH (entries 1 and 2). Sterically congested isopropyl
ketone 14d and less congested aldehyde 12b also under-
went spirocyclization under identical reaction conditions
(entries 3 and 4). While the three- and seven-membered
ring precursors 19 and 22 (Scheme 4) led to decomposi-
tion of the starting material, reaction of four- and six-
membered ring precursors 20 and 21 afforded the desired
spiro[3.5]nonenes 38f and 39f and spiro[5.5]undecenes
38g and 39g, respectively, although in low yields (24%
and 31%, entries 5 and 6). This spirocyclization is
extremely useful in that tricyclic spirocycles 38h and 39h
can be obtained stereoselectively29 in 58% yield by the
reaction of cyclohexanone derivative 31. Although the
stereoselectivities were not satisfactory, sterically highly
congested substrates 33a and 33b bearing a siloxy group
on the benzylic position smoothly cyclized into the desired
(29) Approach of the phenyl ring from the less hindered side (the
opposite side of the axial protons) affords cyclized products with the
observed stereochemistry.
(30) Although the separation of 46 and 47 was difficult at this stage,
reduction of this mixture with LiAlH4 afforded separable primary
alcohols 71 and 72. The relative configuration of 71 was determined
by NOE analysis. Furthermore, hydrogenation of the mixture of 46
and 47 in the presence of catalytic Pd/C gave the corresponding spiro-
[4.5]decane derivative 73 as a single isomer.
7726 J . Org. Chem., Vol. 68, No. 20, 2003

Samarium(II)-Promoted Radical Spirocyclization
TABLE 3. Cycliza tion of Va r iou s Su bstitu ted
Ben zoa tesa
SCHEME 10
derivatives 29 and 30 were used, the ethylated products
59 and 60 were mainly obtained (80% and 64% yield,
respectively). Although such ethylation is unprecedented
as far as we are aware, it would be possible by the action
of diiodoethane, which is used for preparation of the SmI2
solution. It is extremely interesting that the cyclization
of meta-substituted benzoates such as 16 (Table 3) and
27 and 28 (Scheme 10) to the condensed rings proceeds
only when the reacting aromatic carbon is unsubstituted,
while the para-substituted benzoates cyclized into spi-
rocycles by the radical attack onto the substituted
aromatic carbon (Tables 1 and 2).
Reaction of benzoates 24 and 25 (entries 3 and 4, Table
3) bearing a methyl group on the aromatic ring with SmI2
in the presence of HMPA and i-PrOH yielded spirocycles
51 and 52, and 53, respectively, in good yields. In
contrast, 3-methoxybenzoate derivative 17 (Scheme 4)
produced no spirocycle under identical reaction condi-
tions, while o-methoxybenzoate 26 yielded 54 as a 3:1
diastereomixture in a moderate yield (entry 5). This trend
is in good accordance with Reissig’s results: a related
samarium-mediated cyclization onto a methoxy-substi-
tuted aromatic ring regioselectively occurs at the position
meta to the methoxy group.31 For a reason that is unclear,
ortho-substituted benzoates 25 and 26 yield the cyclo-
hexadiene derivatives 53 and 54.
a
All reactions were carried out in THF at 0 °C under argon
using SmI2 (5 equiv) and i-PrOH. Ratios were determined by 1H
NMR.
b
SCHEME 9
forded no spirocyclic compound (entry 2), yielding an
unstable condensed cyclohexadiene, 49 (27% yield), and
an aromatized compound, 50 (27% yield). The unstable
diene 49 was gradually converted into the stable com-
pound 50 during purification. When the one-pot oxidation
was conducted with p-benzoquinone, the aromatized
product 50 was obtained in 69% yield as the sole product.
From these observations, the ketyl radicals can attack
the substituted benzene ring at the position para or ortho
to the ester group.
Next, activation of the arene ring by electron-with-
drawing groups other than the ester group was investi-
gated (Scheme 11). Exposure of the sulfonamide 18 to
the typical samarium-mediated cyclization conditions
gave a condensed ring, 62, in a stereoselective manner.
In contrast, the carboxamide 35 was easily cyclized into
the desired spirocycles 63 and 64 (2.6:1) in 55% yield.
Reaction of N,N-dimethylcarboxamide 37 afforded a
spirocycle, 65, with a cyclohexadiene moiety in 38% yield,
along with a condensed ring, 66 (24% yield). As one can
expect, the substrate without the ester group (5-phenyl-
pentan-2-one) gave no cyclized product. Considering these
results and Reissig’s observations using cyano-substitut-
ed substrates,31 an appropriate tuning of the electronic
density of the aromatic ring is extremely important for
The cyclization of benzoates such as 16 to condensed
rings has proven to be extremely sensitive to the sub-
stituents on the aromatic ring. As shown in Scheme 10,
4-methylbenzoate derivatives 27 and 28 cyclized onto the
carbon ortho to the ester group instead of the methylated
para carbon to afford the cyclized products 57 and 58,
respectively. However, when 2,4,6-trimethylbenzoate
J . Org. Chem, Vol. 68, No. 20, 2003 7727

Ohno et al.
SCHEME 11
SCHEME 13
(52-90% yield). Interestingly, when acetone was added
instead of the alkyl halide, the conjugated diene 40a was
obtained. When acetone-d6 was employed, incorporation
of deuterium was observed to give 40a -d (74% D). This
is presumably due to the reversible nature of this aldol-
type reaction of a highly stabilized cyclopentadienyl anion
with acetone. Furthermore, acetone would quench the
SmI2 to suppress the 1,4-reduction of the conjugated
diene 40a (Scheme 8).
We proposed that a diene such as 40a would be an
important intermediate for the present spirocyclization
(Scheme 8). Since the diene 40a was isolated in a pure
form, we subjected 40a to the samarium-mediated cy-
clization conditions. As we expected, treatment of the
diene 40a afforded the reduced products 38a and 39a
(1.3:1) in 63% yield, which is in good agreement with the
mechanism shown in Scheme 8.
SCHEME 12
the present samarium-promoted spirocyclization onto an
aromatic ring. Furthermore, the samarium ketyl radical
has proven to also be important for the spirocyclization:
exposure of the corresponding iodide 67 to the cyclization
conditions led to recovery of the starting material (Scheme
12). This result clearly demonstrates that the success of
the spirocyclization would be attributed to (1) the relative
persistence of ketyl radicals compared to alkyl radicals
under the reducing conditions, which provides more time
for the cyclization to occur, and (2) the perceived revers-
ibility of single-electron transfer to the carbonyls from
samarium(II), which minimizes side reactions by sup-
pressing the concentration of the ketyl radical.32
Con clu sion
In conclusion, we have developed samarium(II)-medi-
ated spirocyclization onto an aromatic ring. This reaction
can serve as a stereoselective synthetic route to spirocy-
clic compounds including spiro[3.5]nonenes, spiro[4.5]-
decenes, and spiro[5.5]undecenes starting from readily
available aromatic compounds. Introduction of an ap-
propriate electron-withdrawing group such as an ester
or amide group on the aromatic ring is necessary for the
successful spirocyclization. It is strongly suggested that
the spirocyclization would proceed through both the
formation of a cyclohexadienyl anion intermediate and
1,4-reduction of the cyclohexadiene intermediate.
Finally, to expand the synthetic utility of the spirocy-
clization and to understand the reaction mechanism, we
investigated capture of the cyclohexadienyl anion inter-
mediate by electrophiles (Scheme 13). When the ketone
14a was treated with SmI2 and HMPA in the absence of
any proton source followed by addition of allyl bromide,
benzyl bromide, or iodomethane, the expected cyclohexa-
dienes 68a -c were obtained in moderate to good yields
(31) Recently, Reissig and co-workers reported the related ketyl
radical cyclization onto the aromatic ring activated by a methoxy or
cyano group.15c In all cases, the position meta to the methoxy or cyano
group is more reactive than the other positions.
Exp er im en ta l Section
Compounds 23e,33 2-(2-bromoethyl)-2-methyl-1,3-dioxolane,34
and 3415c were synthesized according to the literature.
Gen er a l P r oced u r e for th e Wittig Rea ction F ollow ed
by P a lla d iu m -Ca ta lyzed Hyd r ogen a tion . Syn th esis of
Meth yl {4-[3-(2,5-Dioxola n yl)]p r op yl}ben zoa te (11). To a
solution of 2-[1,3-dioxolan-2-yl)ethyl]triphenyphosphonium bro-
mide [Ph3P+CH2CH2CH(-OCH2CH2O-)Br-; 19.6 g, 44.1 mmol]
in THF (100 mL) was added NaH (1.76 g, 44.1 mmol) at 0 °C.
(32) (a) Curran, D. P. Chemtracts: Org. Chem. 1994, 7, 351-354.
(b) Molander, G. A.; McKie, J . A. J . Org. Chem. 1994, 59, 3186-3192.
(33) Hart, H.; J anssen, J . F. J . Org. Chem. 1970, 35, 3637-3641.
(34) Petroski, R. J . Synth. Commun. 2002, 32, 449-455.
7728 J . Org. Chem., Vol. 68, No. 20, 2003

Samarium(II)-Promoted Radical Spirocyclization
After the mixture was stirred for 30 min at this temperature,
a solution of the aldehyde 10a (7.24 g, 44.1 mmol) in THF (20
mL) was added to the mixture, and stirring was continued for
1 h. Saturated NH4Cl was added to the mixture, and the whole
was extracted with EtOAc. The extract was washed with water
and brine and dried over MgSO4. The filtrate was concentrated
under reduced pressure to leave an oily residue, which was
purified by column chromatography over silica gel with n-hex-
ane-EtOAc (5:1) to give the corresponding alkene (9.86 g, 90%
yield). This alkene (9.86 g, 39.7 mmol) was then subjected to
catalytic hydrogenation in MeOH (90 mL) using Pd/C (423 mg)
under atmospheric pressure of hydrogen at room temperature
for 30 min. The mixture was filtered through Celite, and the
filtrate was concentrated under reduced pressure to an oil,
which was purified by column chromatography over silica gel
with n-hexane-EtOAc (5:1) to give the acetal 11 (6.76 g, 61%
yield in two steps) as a colorless oil: IR (KBr, cm-1) 1720 (Cd
O); 1H NMR (300 MHz, CDCl3) δ 1.63-1.80 (m, 4H, 2′-CH2
and 3′-CH2), 2.68 (t, J ) 7.5 Hz, 2H, 1′-CH2), 3.76-3.93 (m,
4H, OCH2CH2O), 3.86 (s, 3H, OMe), 4.83 (t, J ) 4.5 Hz, 1H,
1′′-H), 7.23 (d, J ) 8.1 Hz, 2H, Ar), 7.93 (d, J ) 8.1 Hz, 2H,
Ar); 13C NMR (75 MHz, CDCl3) δ 24.9, 32.9, 35.3, 51.5, 64.4
(2C), 103.8, 127.4, 128.0 (2C), 129.3 (2C), 147.3, 166.5; MS (EI)
m/z (rel intens) 250 (M+, 3), 73 (100); HRMS (EI) m/z calcd for
at room temperature, and the mixture was stirred for 30 min.
Saturated NaHCO3 and Na2S2O3 were added to the mixture,
and the whole was extracted with EtOAc. The extract was
washed with brine and dried over MgSO4. The filtrate was
concentrated under reduced pressure to leave a residue, which
was purified by column chromatography over silica gel with
n-hexane-EtOAc (2:1) to give the known ketone 14a 36 (1.35
g, 88% yield) as a colorless oil.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Di-
r ect Syn th esis of Keton es fr om Ar yl Br om id es 23. Syn -
th esis of Meth yl 3-Meth yl-4-(4-oxop en tyl)ben zoa te (24).
To a stirred solution of the aryl bromide 23a (729 mg, 3.18
mmol) in DMF (6.4 mL) were successively added 4-penten-2-
ol (0.491 mL, 4.77 mmol), Pd(OAc)2 (322 mg, 1.43 mmol), n-Bu4-
NCl (1.77 g, 6.36 mmol), LiCl (135 mg, 3.18 mmol), and LiOAc‚
2H2O (812 mg, 7.95 mmol), and the mixture was stirred at
100 °C for 55 h. After cooling, saturated NH4Cl was added to
the mixture, and the whole was extracted with Et2O. The
extract was dried over MgSO4. The filtrate was concentrated
under reduced pressure to leave a residue, which was purified
by column chromatography over silica gel with n-hexane-
EtOAc (5:1). Further purification by column chromatography
over silica gel with CHCl3-acetone (2:1) gave the ketone 24
(379 mg, 51% yield) as a colorless oil: IR (KBr, cm-1) 1716
(CdO); 1H NMR (300 MHz, CDCl3) δ 1.86 (tt, J ) 7.5, 7.5 Hz,
2H, 2′-CH2), 2.14 (s, 3H, CMe), 2.35 (s, 3H, CMe), 2.49 (t, J )
7.5 Hz, 2H, 3′-CH2), 2.65 (t, J ) 7.5 Hz, 2H, 1′-CH2), 3.89 (s,
3H, OMe), 7.18 (d, J ) 7.8 Hz, 1H, Ar), 7.79 (d, J ) 7.8 Hz,
1H, Ar), 7.82 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3) δ 19.2,
23.6, 30.0, 32.5, 42.9, 51.9, 127.2, 127.9, 128.9, 131.3, 136.2,
145.4, 167.2, 208.3; MS (EI) m/z (rel intens) 234 (M+, 19), 106
(100); HRMS (EI) m/z calcd for C14H18O3 234.1256, found
234.1251.
C
14H18O4 250.1205, found 250.1236.
Gen er a l P r oced u r e for th e Clea va ge of Eth ylen e
Acet a ls. Syn t h esis of Met h yl 4-(4-Oxob u t yl)b en zoa t e
(12). To a stirred solution of the acetal 11 (980 mg, 3.92 mmol)
in a mixed solvent of acetone (18 mL) and water (12 mL) was
added PPTS (98.4 mg, 0.392 mmol), and the mixture was
stirred under reflux for 12 h. Saturated NaHCO3 was added
to the mixture, and the whole was extracted with EtOAc. The
extract was washed with brine and dried over MgSO4. The
filtrate was concentrated under reduced pressure to leave a
residue, which was purified by column chromatography over
silica gel with n-hexane-EtOAc (2:1) to give the aldehyde 1235
(797 mg, 99% yield) as a colorless oil: IR (KBr, cm-1) 1720
(CdO); 1H NMR (300 MHz, CDCl3) δ 1.97 (tt, J ) 7.5, 7.2 Hz,
2H, 2′-CH2), 2.46 (t, J ) 7.2 Hz, 2H, 3′-CH2), 2.70 (t, J ) 7.5
Hz, 2H, 1′-CH2), 3.90 (s, 3H, OMe), 7.24 (d, J ) 7.5 Hz, 2H,
Ar), 7.96 (d, J ) 7.5 Hz, 2H, Ar), 9.76 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3) δ 23.1, 34.8, 42.9, 51.9, 128.0, 128.4 (2C),
129.7 (2C), 146.7, 166.9, 201.8; MS (EI) m/z (rel intens) 206
(M+, 13), 162 (100); HRMS (EI) m/z calcd for C12H14O3
206.0943, found 206.0942.
Gen er a l P r oced u r e for th e Gr ign a r d Rea ction . Syn -
th esis of Meth yl 4-(4-Hyd r oxyp en tyl)ben zoa te (13a ). To
a stirred solution of the aldehyde 12 (2.57 g, 12.5 mmol) in
THF (30 mL) was added MeMgBr (0.93 M in THF; 13.4 mL,
12.5 mmol) at -40 °C, and the mixture was stirred for 1 h.
Saturated NH4Cl was added to the mixture, and the whole
was extracted with EtOAc. The extract was washed with brine
and dried over MgSO4. The filtrate was concentrated under
reduced pressure to leave a residue, which was purified by
column chromatography over silica gel with n-hexane-EtOAc
(3:1) to give the alcohol 13a (1.55 g, 56% yield) as a colorless
oil: IR (KBr, cm-1) 3371 (OH), 1720 (CdO); 1H NMR (300
MHz, CDCl3) δ 1.19 (d, J ) 6.0 Hz, 3H, CMe), 1.44-1.86 (m,
5H, 2′-CH2, 3′-CH2 and OH), 2.69 (t, J ) 7.5 Hz, 2H, 1′-CH2),
3.77-3.88 (m, 1H, 4-H), 3.90 (s, 3H, OMe), 7.25 (d, J ) 8.1
Hz, 2H, Ar), 7.95 (d, J ) 8.1 Hz, 2H, Ar); 13C NMR (75 MHz,
CDCl3) δ 23.4, 27.1, 35.7, 38.6, 51.9, 67.6, 127.6, 128.3 (2C),
129.5 (2C), 147.9, 167.1; MS (EI) m/z (rel intens) 222 (M+, 8),
162 (100); HRMS (EI) m/z calcd for C13H18O3 222.1256, found
222.1261.
Gen er a l P r oced u r e for th e Syn th esis of Keton es Usin g
th e Usu a l Heck Rea ction . Syn th esis of Meth yl 4-Meth yl-
3-(4-oxop en tyl)ben zoa te (28) via Meth yl 3-(4-Hyd r oxy-
p en tyl)-4-m eth ylben zoa te. To a stirred solution of the aryl
bromide 23d (160 mg, 0.70 mmol) in Et3N (0.2 mL) were
successively added 4-penten-2-ol (0.18 mL, 1.75 mmol), Pd-
(OAc)2 (16 mg, 0.07 mmol), and P(o-tol)3 (43 mg, 0.14 mmol),
and the mixture was stirred at 75 °C for 21 h. After cooling,
water was added to the mixture, and the whole was concen-
trated under reduced pressure. The residue was extracted with
EtOAc, and the extract was washed with water and brine and
dried over MgSO4. The filtrate was concentrated under reduced
pressure to leave a residue, which was purified by column
chromatography over silica gel with n-hexane-EtOAc (3:1) to
give the corresponding styrene derivative. This styrene deriva-
tive was then subjected to catalytic hydrogenation in MeOH
(2 mL) using Pd/C (8 mg) under atmospheric pressure of
hydrogen at room temperature for 1 h. The mixture was
filtered through Celite, and the filtrate was concentrated under
reduced pressure to an oil, which was purified by column
chromatography over silica gel with n-hexane-EtOAc (3:1) to
give methyl 3-(4-hydroxypentyl)-4-methylbenzoate (114 mg,
70% yield in two steps): colorless oil; IR (KBr, cm-1) 3028
1
(OH), 1720 (CdO); H NMR (500 MHz, CDCl3) δ 1.20 (d, J )
6.3 Hz, 3H, CMe), 1.48-1.77 (m, 5H, 2′-CH2, 3′-CH2, and OH),
2.35 (s, 3H, CMe), 2.61-2.70 (m, 2H, 1′-CH2), 3.84 (tq, J )
6.3, 6.3 Hz, 1H, 4′-H), 3.89 (s, 3H, OMe), 7.19 (d, J ) 8.0 Hz,
1H, Ar), 7.76 (d, J ) 8.0 Hz, 1H, Ar), 7.81 (s, 1H, Ar); 13C NMR
(75 MHz, CDCl3) δ 19.5, 23.6, 26.2, 33.0, 39.0, 51.9, 67.9, 127.1,
127.8, 129.8, 130.2, 140.7, 141.6, 167.4; MS (EI) m/z (rel intens)
236 (M+, 9), 176 (100); HRMS (EI) m/z calcd for C14H20O3
236.1412, found 236.1393.
Gen er a l P r oced u r e for Dess-Ma r tin Oxid a tion . Syn -
th esis of Meth yl 4-(4-Oxop en tyl)ben zoa te (14a ). To a
stirred solution of the alcohol 13a (1.55 g, 6.98 mol) in CH2Cl2
(30 mL) was added Dess-Martin periodinane (2.96 g, 6.98 mol)
By a procedure identical with that described for the syn-
thesis of 14a from 13a , methyl 3-(4-hydroxypentyl)-4-meth-
ylbenzoate (114 mg, 0.48 mmol) was converted into the ke-
tone 28 (97 mg, 86% yield): colorless oil; IR (KBr, cm-1) 1718
(35) DeGraw, J . 1.; Tagawa, H.; Christie, P. H.; Lawson, J . A.;
Brown, E. G. J . Heterocycl. Chem. 1986, 23, 1-4.
(36) Kise, N.; Suzumoto, T.; Shono, T. J . Org. Chem. 1994, 59, 1407-
1413.
J . Org. Chem, Vol. 68, No. 20, 2003 7729

Ohno et al.
(CdO); 1H NMR (500 MHz, CDCl3) δ 1.87 (tt, J ) 8.0, 8.0 Hz,
2H, 2′-CH2), 2.14 (s, 3H, CMe), 2.36 (s, 3H, CMe), 2.50 (t, J )
8.0 Hz, 2H, CH2), 2.64 (t, J ) 8.0 Hz, 2H, CH2), 3.90 (s, 3H,
OMe), 7.20 (d, J ) 8.0 Hz, 1H, Ar), 7.77 (d, J ) 8.0 Hz, 1H,
Ar), 7.79 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3) δ 19.4, 23.7,
29.9, 32.3, 42.9, 51.8, 127.3, 127.8, 129.9, 130.3, 140.0, 141.7,
167.2, 208.8; MS (EI) m/z (rel intens) 234 (M+, 41), 177 (100);
HRMS (EI) m/z calcd for C14H18O3 234.1256, found 234.1273.
NH2), 7.24 (d, J ) 8.0 Hz, 2H, Ar), 7.75 (d, J ) 8.0 Hz, 2H,
Ar); 13C NMR (75 MHz, CDCl3) δ 24.8, 29.9, 34.8, 42.6, 127.5
(2C), 128.6 (2C), 131.1, 146.0, 169.5, 208.5; MS (EI) m/z (rel
intens) 205 (M+, 31), 131 (100); HRMS (EI) m/z calcd for C12H15
-
NO2 205.1103; found 205.1104.
4-(4-Oxop en tyl)ben zoic Acid (36). To a stirred solution
of the ester 14a (393 mg, 1.78 mmol) in a mixed solvent of
MeOH (63 mL) and water (21 mL) was added LiOH‚H2O (560
mg, 13.4 mmol) at 0 °C, and the mixture was stirred overnight
at room temperature. HCl (1 N) was added to the mixture,
and the mixture was concentrated under reduced pressure.
The residue was extracted with EtOAc, and the extract was
washed with water and brine and dried over MgSO4. The
filtrate was concentrated under reduced pressure to leave a
residue, which was purified by column chromatography over
silica gel with n-hexane-EtOAc (2:1) to give the acid 36 (334
Met h yl 4-[1-H yd r oxy-3-(2-m et h yl-1,3-d ioxola n -2-yl)-
p r op yl]ben zoa t e (32). To a vigorously stirring mixture of
magnesium (125 mg, 5.12 mmol) and THF (3 mL) was added
a solution of 2-(2-bromoethyl)-2-methyl-1,3-dioxolane34 (1.0 g,
5.13 mmol) in THF (3 mL), and the mixture was slightly
heated. After the exothermic reaction was completed, the
mixture was stirred for 10 min at room temperature. The
aldehyde 10a (421 mg, 2.56 mmol) was added to the mixture
at 0 °C, and the mixture was stirred for 2 h at 0 °C and a
further 1 h at room temperature. Saturated NH4Cl was added
to the mixture, and the whole was extracted with Et2O. The
extract was washed with water and brine and dried over
MgSO4. The filtrate was concentrated under reduced pressure
to leave a residue, which was purified by column chromatog-
raphy over silica gel with n-hexane-EtOAc (3:1) to give the
mg, 91% yield) as colorless crystals: mp 112 °C; IR (KBr, cm-1
)
3003 (CO2H), 1709 (CO2H); 1H NMR (500 MHz, CDCl3) δ 1.94
(tt, J ) 7.8, 7.0 Hz, 2H, 2′-CH2), 2.14 (s, 3H, CMe), 2.46 (t, J
) 7.0 Hz, 2H, CH2), 2.70 (t, J ) 7.8 Hz, 2H, CH2), 7.28 (d, J )
7.8 Hz, 2H, Ar), 8.04 (d, J ) 7.8 Hz, 2H, Ar); 13C NMR (75
MHz, CDCl3) δ 24.7, 30.0, 35.0, 42.6, 127.2 (2C), 128.6 (2C),
130.4, 148.1, 172.0, 208.6. Anal. Calcd for C12H14O3: C, 69.88;
H, 6.84. Found: C, 69.78; H, 6.81.
alcohol 32 (662 mg, 92% yield) as a colorless oil: IR (KBr, cm-1
)
3462 (OH), 1722 (CdO); 1H NMR (500 MHz, CDCl3) δ 1.29 (s,
3H, CMe), 1.66-1.86 (m, 4H, 2′-CH2 and 3′-CH2), 3.31 (br s,
1H, OH), 3.90 (s, 3H, OMe), 3.92-3.95 (m, 4H, OCH2CH2O),
4.73 (dd, J ) 5.5, 5.0 Hz, 1H, 1′-H), 7.40 (d, J ) 8.0 Hz, 2H,
Ar), 7.98 (d, J ) 8.0 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3) δ
23.7, 33.2, 34.9, 51.9, 64.47, 64.50, 73.5, 109.7, 125.6 (2C),
128.9, 129.6 (2C), 150.0, 167.0; MS (FAB) m/z (rel intens) 303
(MNa+, 74), 219 (100); HRMS (FAB) m/z calcd for C15H20NaO5
(MNa+) 303.1209, found 303.1203.
N,N-Dim et h yl-4-(4-oxop en t yl)b en za m id e (37). To a
stirred solution of the acid 36 (752 mg, 3.65 mmol) in a mixed
solvent of CH2Cl2 (1 mL) and DMF (0.1 mL) was added SOCl2
(0.40 mL, 5.50 mmol) at room temperature, and the mixture
was stirred for 2 h at this temperature. Aqueous 40% Me2NH
(1.19 g, 26.3 mmol) solution was added to the mixture over 30
min at 0 °C, and the mixture was stirred overnight at this
temperature. Saturated NH4Cl was added to the mixture, and
the whole was extracted with EtOAc. The extract was washed
with water and brine and dried over MgSO4. The filtrate was
concentrated under reduced pressure to leave a residue, which
was purified by column chromatography over silica gel with
EtOAc to give the amide 37 (493 mg, 61% yield) as a colorless
oil: IR (KBr, cm-1) 1713 (CdO), 1633 (CONMe2); 1H NMR (500
MHz, CDCl3) δ 1.90 (tt, J ) 7.5, 7.5 Hz, 2H, 2′-CH2), 2.12 (s,
3H, CMe), 2.44 (t, J ) 7.5 Hz, 2H, CH2), 2.64 (t, J ) 7.5 Hz,
2H, CH2), 2.99 (br s, 3H, NMe), 3.10 (br s, 3H, NMe), 7.20 (d,
J ) 8.0 Hz, 2H, Ar), 7.35 (d, J ) 8.0 Hz, 2H, Ar); 13C NMR (75
MHz, CDCl3) δ 24.9, 30.0, 34.8, 35.4, 39.7, 42.6, 127.3 (2C),
128.4 (2C), 134.0, 143.2, 171.7, 208.7; MS (EI) m/z (rel intens)
233 (M+, 75), 189 (100); HRMS (EI) m/z calcd for C14H19NO2
233.1416, found 233.1428.
Meth yl 4-[1-(ter t-Bu tyld im eth ylsilyloxy)-4-oxop en tyl]-
ben zoa te (33a ). To a stirred solution of the acetal 32 (726
mg, 2.59 mmol) in a mixed solvent of acetone (12 mL) and
water (8 mL) was added PPTS (65 mg, 0.26 mmol), and the
mixture was stirred under reflux overnight. Saturated NaH-
CO3 was added to the mixture, and the whole was extracted
with EtOAc. The extract was washed with brine and dried over
MgSO4. The filtrate was concentrated under reduced pressure
to leave a residue, which was purified by column chromatog-
raphy over silica gel with n-hexane-EtOAc (2:1) to give the
corresponding ketone (486 mg, 79% yield). This ketone (250
mg, 1.06 mmol) was treated with (TBS)Cl (191 mg, 1.27 mmol)
and imidazole (180 mg, 2.65 mmol) in MeCN (0.5 mL) at 40
°C for 2 h. Water was added to the mixture, and the whole
was extracted with EtOAc. The extract was washed with water
and brine and dried over MgSO4. The filtrate was concentrated
under reduced pressure to leave a residue, which was purified
by column chromatography over silica gel with n-hexane-
EtOAc (10:1) to give the silyl ether 33a (317 mg, 67% yield in
Gen er a l P r oced u r e for Sa m a r iu m -Med ia ted Sp ir ocy-
cliza tion (Wor k u p I). Syn th esis of Meth yl (1R*,5R*,8S*)-
1-Hydr oxy-1-m eth ylspir o[4.5]dec-6-en e-8-car boxylate (38a)
a n d Its (1R*,5R*,8R*)-Isom er (39a ). A mixture of samarium
(82.1 mg, 0.546 mmol) and 1,2-diiodoethane (118 mg, 0.420
mmol) in THF (4 mL) was stirred for 1.5 h. HMPA (0.263 mL,
1.51 mmol) was added to the mixture, and stirring was
continued for 10 min. After the mixture was cooled to 0 °C, a
solution of the ketone 14a (18.5 mg, 0.082 mmol) and i-PrOH
(0.013 mL, 0.168 mmol) in THF (2 mL) was added to the
mixture, and the mixture was stirred for 1 h. After the mixture
was exposed to air, silica gel was added to the mixture, and
the whole was concentrated under reduced pressure. The
residue was purified by column chromatography over silica gel
with n-hexane-EtOAc (4:1), and further purification by flash
chromatography over silica gel with CHCl3-acetone (40:1)
gave, in order of elution, 38a (7.5 mg, 40% yield) and 39a (10.0
mg, 53% yield).
1
two steps) as a colorless oil: IR (KBr, cm-1) 1724 (CdO); H
NMR (500 MHz, CDCl3) δ -0.17 (s, 3H, SiMe), 0.00 (s, 3H,
SiMe), 0.87 (s, 9H, CMe3), 1.82-1.99 (m, 2H, 2′-CH2), 2.09 (s,
3H, CMe), 2.36 (ddd, J ) 17.8, 8.5, 5.5 Hz, 1H, 3′-CHH), 2.51
(ddd, J ) 17.8, 8.3, 6.8 Hz, 1H, 3′-CHH), 3.89 (s, 3H, OMe),
4.78 (dd, J ) 6.5, 5.0 Hz, 1H, 1′-H), 7.35 (d, J ) 8.3 Hz, 2H,
Ar), 7.97 (d, J ) 8.3 Hz, 2H, Ar); 13C NMR (125 MHz, CDCl3)
δ -5.14, -4.83, 18.1, 25.7 (3C), 29.9, 34.0, 38.8, 51.9, 73.1,
125.7 (2C), 128.9, 129.5 (2C), 150.1, 166.9, 208.3. Anal. Calcd
for C19H30O4Si: C, 65.10; H, 8.63. Found: C, 65.23; H, 8.58.
4-(4-Oxop en tyl)ben za m id e (35). A mixture of the nitrile
3415c (1.26 g, 6.65 mmol), 3% H2O2 (34.2 g), and 25% KOH (1.9
g) was heated at 45 °C and stirred at room temperature for 3
h. The crystalline mass was collected by filtration and purified
by column chromatography over silica gel with EtOAc to give
the amide 35 (835 mg, 61% yield) as colorless crystals: mp
119 °C; IR (KBr, cm-1) 3390 (CONH2), 3197 (CONH2), 1709
(CdO), 1645 (CONH2); 1H NMR (500 MHz, CDCl3) δ 1.91 (tt,
J ) 7.8, 7.3 Hz, 2H, 2′-CH2), 2.12 (s, 3H, CMe), 2.44 (t, J )
7.3 Hz, 2H, CH2), 2.67 (t, J ) 7.8 Hz, 2H, CH2), 6.23 (br s, 2H,
Data for compound 38a (less polar isomer): colorless oil; IR
(KBr, cm-1) 3531 (OH), 1732 (CdO); 1H NMR (500 MHz,
CDCl3) δ 1.16 (s, 3H, CMe), 1.25 (br s, 1H, OH), 1.61-2.13
(m, 10H, 5 CH2), 3.04-3.08 (m, 1H, 8-H), 3.71 (s, 3H, OMe),
5.58 (dd, J ) 10.5, 2.5 Hz, 1H, 7-H), 5.72 (d, J ) 10.5 Hz, 1H,
6-H); 13C NMR (75 MHz, CDCl3) δ 19.2, 22.9, 23.9, 27.7, 38.0,
38.9, 41.9, 49.6, 51.9, 82.8, 123.4, 134.9, 174.9; MS (FAB) m/z
7730 J . Org. Chem., Vol. 68, No. 20, 2003

Samarium(II)-Promoted Radical Spirocyclization
231 (MLi+); HRMS (FAB) m/z calcd for C13H20LiO3 (MLi+)
231.1572, found 231.1573.
silica gel with n-hexane-EtOAc (2:1) to give, in order of
elution, 71 (30.8 mg, 71% yield) and 72 (4.4 mg, 10% yield).
Data for compound 48: colorless oil; IR (KBr, cm-1) 3413
Data for compound 39a (more polar isomer): colorless oil;
1
1
IR (KBr, cm-1) 3544 (OH), 1728 (CdO); H NMR (500 MHz,
(OH), 1716 (CdO); H NMR (500 MHz, CDCl3) δ 1.06 (s, 3H,
CMe), 1.36-1.88 (m, 6H, 10-CHH, 8-CH2, 9-CH2 and OH),
2.80-2.98 (m, 3H, 6-H and 3-CH2), 3.38 (d, J ) 13.5 Hz, 1H,
CDCl3) δ 1.18 (s, 3H, CMe), 1.46-2.13 (m, 11H, 5 CH2 and
OH), 3.04-3.07 (m, 1H, 8-H), 3.69 (s, 3H, OMe), 5.61 (d, J )
10.0 Hz, 1H, 6-H), 5.73 (dd, J ) 10.0, 4.0 Hz, 1H, 7-H); 13C
NMR (75 MHz, CDCl3) δ 19.2, 23.0, 23.6, 26.0, 38.1, 39.0, 40.2,
49.3, 51.8, 82.7, 123.1, 135.5, 174.5; MS (FAB) m/z 231 (MLi+);
HRMS (FAB) m/z calcd for C13H20LiO3 (MLi+) 231.1572, found
231.1573.
10-CHH), 3.74 (s, 3H, OMe), 5.82-5.90 (m, 2H, CHdCH); 13
C
NMR (75 MHz, CDCl3) δ 21.9, 23.8, 28.1, 30.9, 41.5, 51.0, 51.4,
75.6, 121.8, 122.8, 125.1, 145.6, 169.2; MS (FAB) m/z 223
(MH+); HRMS (FAB) m/z calcd for C13H19O3 (MH+) 223.1334,
found 223.1349.
Data for methyl 5-hydroxy-5-methyl-5,6,7,8-tetrahydronaph-
thalene-1-carboxylate: colorless oil; IR (KBr, cm-1) 3411 (OH),
1724 (CdO); 1H NMR (300 MHz, CDCl3) δ 1.55 (s, 3H, CMe),
1.72-2.03 (m, 5H, 2 CH2 and OH), 3.04-3.08 (m, 2H, 8-CH2),
3.87 (s, 3H, OMe), 7.26 (dd, J ) 7.8, 7.5 Hz, 1H, Ar), 7.71 (dd,
Gen er a l P r oced u r e for Sa m a r iu m -Med ia ted Sp ir ocy-
cliza tion (Wor k u p II). Meth yl (1R*,5S*,8R*)-1-Hyd r oxy-
1-(p h en ylm eth yl)sp ir o[4.5]d ec-6-en e-8-ca r boxyla te (38c)
a n d Its (1R*,5S*,8S*)-Isom er (39c). By a procedure identical
with that described for the synthesis of 38a and 39a from 14a ,
the ketone 14c (49 mg, 0.17 mmol) was treated with samarium
(165 mg, 1.10 mmol), diiodoethane (238 mg, 0.85 mmol),
i-PrOH (0.078 mL, 1.0 mmol), and HMPA (0.53 mL, 3.04
mmol) in THF (10.5 mL). After the mixture was exposed to
air, saturated NaHCO3 was added to the mixture, and the
whole was extracted with Et2O. The extract was washed with
water and brine and dried over MgSO4. The filtrate was
concentrated under reduced pressure to leave a residue, which
was purified by column chromatography over silica gel with
n-hexane-EtOAc (3:1) to give a mixture of the spirocycles 38c
and 39c (37 mg, 74% yield, 38c:39c ) 2:1). Further purification
by flash chromatography over silica gel with CHCl3-acetone
(80:1) gave, in order of elution, 38c (24.7 mg, 49% yield) and
39c (12.3 mg, 25% yield).
J ) 7.5, 1.5 Hz, 1H, Ar), 7.80 (dd, J ) 7.8, 0.6 Hz, 1H, Ar); 13
C
NMR (75 MHz, CDCl3) δ 20.2, 28.1, 31.1, 39.1, 52.0, 70.9,
125.9, 129.3, 130.0, 130.5, 137.4, 144.3, 168.5; MS (EI) m/z 220
(M+, 8), 205 (100); HRMS (EI) m/z calcd for C13H16O3 (M+)
220.1099, found 220.1120.
Data for compound 71 (less polar isomer): colorless oil; IR
1
(KBr, cm-1) 3255 (OH); H NMR (500 MHz, CDCl3) δ 1.22-
1.98 (m, 8H, 4 CH2), 1.41 (s, 3H, CMe), 2.07-2.21 (m, 2H,
9-CH2), 2.25-2.28 (m, 1H, 6-H), 2.74 (br, 1H, OH), 3.52
(br, 1H, OH), 3.60-3.68 (m, 2H, 1′-CH2), 5.57-5.65 (m, 2H,
CHdCH); 13C NMR (75 MHz, CDCl3) δ 17.6, 20.2, 23.5, 24.5,
32.4, 39.1, 43.0, 47.3, 64.3, 81.2, 127.7, 128.1; MS (FAB) m/z
219 (MNa+); HRMS (FAB) m/z calcd for C12H20NaO2 (MNa+)
219.1361, found 219.1337.
Data for compound 72 (more polar isomer): colorless oil;
Data for compound 38c (less polar isomer): colorless oil; IR
(KBr, cm-1) 3547 (OH), 1736 (CdO); 1H NMR (500 MHz,
CDCl3) δ 1.41-2.13 (m, 11H, 5 CH2 and OH), 2.67 (d, J ) 13.3
Hz, 1H, PhCHH), 2.75 (d, J ) 13.3 Hz, 1H, PhCHH), 3.07-
3.10 (m, 1H, 8-H), 3.72 (s, 3H, OMe), 5.72 (d, J ) 10.3 Hz, 1H,
CHdCH), 5.80 (d, J ) 10.3 Hz, 1H, CHdCH), 7.20-7.31 (m,
5H, Ph); 13C NMR (75 MHz, CDCl3) δ 19.2, 24.1, 28.2, 37.6,
38.9, 41.98, 42.02, 50.2, 51.9, 84.1, 123.7, 126.4, 128.3 (2C),
130.3 (2C), 134.8, 138.2, 174.9; MS (FAB) m/z (rel intens) 323
(MNa+, 100); HRMS (FAB) m/z calcd for C19H24NaO3 (MNa+)
323.1623, found 323.1595.
1
IR (KBr, cm-1) 3350 (OH); H NMR (500 MHz, CDCl3) δ 1.38
(s, 3H, CMe), 1.53-2.18 (m, 11H, 5 CH2 and 10-H), 2.46 (br,
1H, OH), 2.58 (br, 1H, OH), 3.60 (dd, J ) 11.0, 5.0 Hz, 1H,
1′-CHH), 3.99 (dd, J ) 11.0, 8.0 Hz, 1H, 1′-CHH), 5.70 (ddd, J
) 10.0, 3.0, 3.0 Hz, 1H, CdCH), 5.95 (ddd, J ) 10.0, 4.0, 2.0
Hz, 1H, CdCH); 13C NMR (75 MHz, CDCl3) δ 17.3, 21.6, 23.2,
23.8, 39.4, 40.3, 41.0, 50.5, 63.7, 80.9, 127.4, 131.3; MS (FAB)
m/z 219 (MNa+); HRMS (FAB) m/z calcd for C12H20NaO2
(MNa+) 219.1361, found 219.1353.
Met h yl (1R*,5S*,6R*)-1-H yd r oxy-1-m et h ylsp ir o[4.5]-
d eca n e-6-ca r boxyla te (73). A mixture of alkenes 46 and 47
(19.1 mg, 0.0852 mmol) was subjected to catalytic hydrogena-
tion in MeOH (2 mL) using Pd/C (9.1 mg) under atmospheric
pressure of hydrogen at room temperature. The mixture was
filtered through Celite, and the filtrate was concentrated under
reduced pressure to an oil, which was purified by column
chromatography over silica gel with n-hexane-EtOAc (5:1) to
give 73 (16.2 mg, 84% yield, single isomer) as a colorless oil:
Data for compound 39c (more polar isomer): colorless oil;
1
IR (KBr, cm-1) 3543 (OH), 1732 (CdO); H NMR (500 MHz,
CDCl3) δ 1.36-2.18 (m, 11H, 5 CH2 and OH), 2.67 (d, J ) 13.5
Hz, 1H, PhCHH), 2.77 (d, J ) 13.5 Hz, 1H, PhCHH), 3.07-
3.10 (m, 1H, 8-H), 3.70 (s, 3H, OMe), 5.75 (d, J ) 10.5 Hz, 1H,
6-H), 5.81 (dd, J ) 10.5, 4.3 Hz, 1H, 7-H), 7.21-7.30 (m, 5H,
Ph); 13C NMR (125 MHz, CDCl3) δ 19.2, 23.1, 26.0, 37.4, 38.7,
40.2, 42.5, 50.0, 51.8, 84.1, 123.3, 126.3, 128.2 (2C), 130.3 (2C),
135.4, 138.4, 174.4; MS (FAB) m/z (rel intens) 301 (MH+, 100);
HRMS (FAB) m/z calcd for C19H25O3 (MH+) 301.1804, found
301.1800.
Met h yl (6R*,7R*)-7-H yd r oxy-7-m et h ylb icyclo[4.4.0]-
d eca -1(2),4-d ien e-2-ca r boxyla te (48), Meth yl 5-Hyd r oxy-
5-m eth yl-5,6,7,8-tetr a h yd r on a p h th a len e-1-ca r boxyla te,
(1R*,5R*,6R*)-6-Hyd r oxym et h yl-1-m et h ylsp ir o[4.5]d ec-
7-en -1-ol (71), a n d (1R*,5R*,10S*)-10-Hyd r oxym eth yl-1-
m eth ylsp ir o[4.5]d ec-7-en -1-ol (72). By a procedure identical
with that described for the synthesis of 38a and 39a from 14a
(workup I), the ketone 15 (48.7 mg, 0.221 mmol) was converted
into an inseparable mixture of 46 and 47 (27.7 mg, 56% yield,
46:47 ) 7:1) and 48 (3.6 mg, 8% yield). Treatment of 48 (62.1
mg, 0.279 mmol) with p-benzoquinone (60.4 mg, 0.558 mmol)
in benzene afforded the corresponding aromatized product
methyl 5-hydroxy-5-methyl-5,6,7,8-tetrahydronaphthalene-1-
carboxylate. The inseparable mixture of 46 and 47 (49.4 mg,
0.220 mmol) was treated with LiAlH4 (1.0 M in Et2O; 0.220
mL, 0.220 mmol) in THF (1 mL). Saturated NH4Cl was added
to the mixture, and the whole was extracted with EtOAc. The
extract was washed with brine and dried over MgSO4. The
filtrate was concentrated under reduced pressure to leave a
residue, which was purified by column chromatography over
1
IR (KBr, cm-1) 3512 (OH), 1713 (CdO); H NMR (500 MHz,
CDCl3) δ 1.07-2.13 (m, 14H, 7 CH2), 1.12 (s, 3H, CMe), 2.49-
2.51 (m, 1H, 6-H), 3.71 (s, 3H, OMe), 4.42 (s, 1H, OH); 13C
NMR (75 MHz, CDCl3) δ 17.8, 21.8, 22.4, 25.1, 25.5, 27.7, 34.4,
38.9, 47.8, 47.9, 51.9, 80.4, 177.9; MS (FAB) m/z (rel intens)
227 (MH+, 43), 209 (100); HRMS (FAB) m/z calcd for C13H23O3
(MH+) 227.1647, found 227.1654.
Gen er a l P r oced u r e for th e On e-P ot Alk yla tion of th e
Cycloh exadien yl An ion In ter m ediates. Syn th esis of Meth -
yl 1-Hyd r oxy-1-m eth yl-8-(p r op -2-en yl)sp ir o[4.5]d eca -6,9-
d ien e-8-ca r boxyla te (68a ). By a procedure identical with
that described for the synthesis of 38a and 39a from 14a , a
solution of SmI2 in THF-HMPA was prepared from samarium
(267 mg, 1.77 mmol) and 1,2-diiodoethane (385 mg, 1.37 mmol).
The ketone 14a (60 mg, 0.273 mmol) and allyl bromide (0.118
mL, 1.37 mmol) were successively added to the solution of SmI2
at 0 °C. According to the general procedure (workup I), a
diastereomixture of the allylated spirocycle 68a (37 mg, 52%
yield, 1.2:1) was obtained.
Data for the less polar isomer: colorless oil; IR (KBr, cm-1
)
3535 (OH), 1728 (CdO); 1H NMR (500 MHz, CDCl3) δ 1.16 (s,
3H, CMe), 1.36 (s, 1H, OH), 1.57-2.01 (m, 6H, 3 CH2), 2.43-
2.47 (m, 2H, CH2CHdCH2), 3.69 (s, 3H, OMe), 5.02-5.07 (m,
J . Org. Chem, Vol. 68, No. 20, 2003 7731

Ohno et al.
2H, CHdCH2), 5.66 (dd, J ) 10.5, 2.5 Hz, 1H, CdCH), 5.70
(ddt, J ) 17.5, 10.3, 7.5 Hz, 1H, CHdCH2), 5.79 (dd, J ) 10.5,
2.5 Hz, 1H, CdCH), 5.89 (dd, J ) 10.5, 2.5 Hz, 1H, CdCH),
5.95 (dd, J ) 10.5, 2.5 Hz, 1H, CdCH); 13C NMR (75 MHz,
CDCl3) δ 19.7, 24.1, 37.9, 38.7, 45.1, 48.5, 51.3, 52.2, 83.4,
118.3, 126.2, 128.6, 130.1, 131.7, 133.3, 174.2; MS (FAB) m/z
(rel intens) 263 (MH+, 34), 245 (100); HRMS (FAB) m/z calcd
for C16H23O3 (MH+) 263.1647, found 263.1647.
purified by column chromatography over silica gel with n-hex-
ane-EtOAc (10:1) to give 67 (35 mg, 52% yield) as a colorless
oil: IR (KBr, cm-1) 1720 (CdO), 1281 (C-I); 1H NMR (500
MHz, CDCl3) δ 1.58-1.65 (m, 1H, 2′-CHH), 1.65-1.77 (m, 1H,
2′-CHH), 1.80-1.87 (m, 2H, 3-CH2), 1.89 (d, J ) 6.5 Hz, 3H,
CMe), 2.65 (ddd, J ) 14.0, 8.5, 6.5 Hz, 1H, PhCHH), 2.70 (ddd,
J ) 14.0, 7.0, 6.0 Hz, 1H, PhCHH), 3.89 (s, 3H, OMe), 4.13-
4.20 (m, 1H, 4′-H), 7.23 (d, J ) 8.0 Hz, 2H, Ar), 7.95 (d, J )
8.0 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3) δ 28.9, 29.7, 31.1,
34.9, 42.1, 52.0, 127.9, 128.4 (2C), 129.7 (2C), 147.3, 167.1; MS
(FAB) m/z (rel intens) 333 (MH+, 100); HRMS (FAB) m/z calcd
for C13H18IO2 (MH+) 333.0352, found 333.0356.
Data for the more polar isomer: colorless oil; IR (KBr, cm-1
)
3539 (OH), 1732 (CdO); 1H NMR (500 MHz, CDCl3) δ 1.12 (s,
3H, CMe), 1.56-1.98 (m, 7H, 3 CH2 and OH), 2.46 (d, J ) 7.0
Hz, 2H, CH2CHdCH2), 3.68 (s, 3H, OMe), 5.05 (d, J ) 16.0
Hz, 1H, CHdCHH), 5.06 (d, J ) 11.0 Hz, 1H, CHdCHH),
5.59-5.67 (m, 1H, CHdCH2), 5.65 (d, J ) 10.5 Hz, 1H,
CdCH), 5.70 (d, J ) 10.5 Hz, 1H, CdCH), 5.85 (d, J ) 10.5
Hz, 1H, CdCH), 5.88 (d, J ) 10.5 Hz, 1H, CdCH); 13C NMR
(75 MHz, CDCl3) δ 19.8, 24.0, 37.6, 38.5, 43.5, 48.6, 51.4, 52.2,
83.9, 118.1, 126.3, 128.4, 130.7, 132.0, 133.2, 174.3; MS (FAB)
m/z (rel intens) 263 (MH+, 54), 245 (100); HRMS (FAB) m/z
calcd for C16H23O3 (MH+) 263.1647, found 263.1649.
Gen er a l P r oced u r e for th e DBU-Med ia ted Alk en e Iso-
m er iza tion of Sp ir ocycles for th e Deter m in a tion of th e
Rela tive Con figu r a tion s. Syn th esis of Meth yl (1R*,5S*)-
1-Hydr oxy-1-m eth ylspir o[4.5]dec-7-en e-8-car boxylate (70).
To a stirred solution of the diastereomixture of 38a and 39a
(44.3 mg, 0.198 mmol; 38a :39a ) 1:1.2) in benzene (2 mL) was
added DBU (0.030 mL, 0.198 mmol), and the mixture was
stirred under reflux for 40 h. Concentration under reduced
pressure gave a residue, which was purified by column
chromatography over silica gel with n-hexane-EtOAc (2:1) to
give the isomerized product 70 (30.0 mg, 79% yield) as
a single isomer: colorless oil; IR (KBr, cm-1) 3510 (OH),
1713 (CdO); 1H NMR (500 MHz, CDCl3) δ 1.21 (s, 3H, CMe),
1.25 (br s, 1H, OH), 1.43-1.89 (m, 9H, 4 CH2 and CdCCHH),
2.10-2.20 (m, 2H, CdCCHH and CdCCHH), 2.49-2.54 (m,
1H, CdCCHH), 3.74 (s, 3H, OMe), 6.91-6.94 (m, 1H, CdCH);
13C NMR (75 MHz, CDCl3) δ 18.4, 22.3, 22.5, 25.2, 32.4, 33.2,
39.0, 45.9, 51.5, 82.0, 129.7, 138.7, 167.7; MS (EI) m/z (rel
intens) 224 (M+, 0.5), 192 (100); HRMS (FAB) m/z calcd for
Meth yl (1R*,5R*)-1-Hyd r oxy-1-m eth ylsp ir o[4.5]d eca -
6,8-d ien e-8-ca r boxyla te (40a ). By a procedure identical with
that described for the synthesis of 38a and 39a from 14a , a
solution of SmI2 in THF-HMPA was prepared from samarium
(82 mmol, 0.55 mmol) and 1,2-diiodoethane (141 mg, 0.50
mmol). The ketone 14a (50 mg, 0.23 mmol) and acetone (0.083
mL, 1.14 mmol) were successively added to the solution of SmI2
at 0 °C. According to the general procedure (workup II), the
diene 40a (15 mg, 30%) was obtained as a colorless oil: IR
(KBr, cm-1) 3523 (OH), 1720 (CdO); 1H NMR (500 MHz,
CDCl3) δ 1.24 (s, 3H, CMe), 1.62-1.96 (m, 7H, 3 CH2 and OH),
2.35 (dd, J ) 19.5, 5.0 Hz, 1H, 10-CHH), 2.74 (dd, J ) 19.5,
4.5 Hz, 1H, 10-CHH), 3.76 (s, 3H, OMe), 5.60 (d, J ) 9.8 Hz,
1H, CHdCH), 6.35 (d, J ) 9.8 Hz, 1H, CHdCH), 6.96 (dd, J
) 5.0, 4.5 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3) δ 18.8,
23.3, 29.5, 38.55, 38.60, 48.2, 51.6, 82.8, 120.6, 127.3, 133.2,
137.5, 166.1; MS (EI) m/z (rel intens) 222 (M+, 9), 91 (100);
HRMS (EI) calcd for C13H18O3 222.1256, found 222.1272.
Meth yl 4-(4-Iod op en tyl)ben zoa te (67). NaI (35 mg, 0.242
mmol) was added to a solution of the alcohol 13a (45 mg, 0.202
mmol) in CH3CN (0.3 mL) with stirring at room temperature.
(TMS)Cl (31 mg, 0.242 mmol) was added to the mixture, and
the mixture was stirred at 90 °C until the starting material
disappeared on TLC. Water was added to the mixture, and
the whole was extracted with Et2O. The extract was washed
with brine and dried over MgSO4. The filtrate was concen-
trated under reduced pressure to leave a residue, which was
C
13H20O3 (M+) 224.1412, found 224.1435.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Sports, and Culture of J apan.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and characterization for 13b-d , 14b-d , 15-22, 25-
27, 29-31, 33b, 38b,d -j, 39b,d -j, 50-54, 57-66, and 68b,c,
NOE and isomerization experiments for the determination of
relative configurations, and 1H NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034767W
7732 J . Org. Chem., Vol. 68, No. 20, 2003