Facile and stereoselective access to nonracemic tricyclic cyclobutanes by asymmetric intramolecular Michael-aldol reaction: Thermodynamic equilibrium and activation by iodonium ion

Article abstract of DOI:10.1021/jo010207q

Intramolecular Michael-aldol reactions of (-)-phenylmenthyl enoates tethered to cycloalkanone affords tricyclic cyclobutanes with high degrees of diastereochemical control. Kinetic and thermodynamic studies revealed that the Michael-aldol reaction is reversible under conditions in which trimethylsilyl iodide is used in the presence of hexamethyldisilazane at ambient temperature. Different levels of diastereoselectivity are observed when this cyclization process is carried out under kinetic vs thermodynamic conditions. Finally, an influence of added iodonium donors on the reaction rate has been noted.

Full text of DOI:10.1021/jo010207q

J . Org. Chem. 2001, 66, 4667-4672
4667
F a cile a n d Ster eoselective Access to Non r a cem ic Tr icyclic
Cyclobu ta n es by Asym m etr ic In tr a m olecu la r Mich a el-Ald ol
Rea ction : Th er m od yn a m ic Equ ilibr iu m a n d Activa tion by
Iod on iu m Ion
Kiyosei Takasu,* Megumi Ueno, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980-8578, J apan
mihara@mail.pharm.tohoku.ac.jp
Received February 26, 2001
Intramolecular Michael-aldol reactions of (-)-phenylmenthyl enoates tethered to cycloalkanone
affords tricyclic cyclobutanes with high degrees of diastereochemical control. Kinetic and thermo-
dynamic studies revealed that the Michael-aldol reaction is reversible under conditions in which
trimethylsilyl iodide is used in the presence of hexamethyldisilazane at ambient temperature.
Different levels of diastereoselectivity are observed when this cyclization process is carried out
under kinetic vs thermodynamic conditions. Finally, an influence of added iodonium donors on the
reaction rate has been noted.
Sch em e 1
In tr od u ction
Substances containing fused polycyclic cyclobutane
ring systems are found often in nature,1 and they serve
as key intermediates2 in routes to biologically and
medicinally important synthetic targets. Despite this,
stereocontrolled construction of the fused cyclobutanes
remains a difficult task in preparative organic chemistry.3
In recent studies, we have shown that intramolecular
Michael-aldol reactions can serve as powerful and
efficient methods to construct polycyclic cyclobutanes. In
addition, the ability to control relative stereochemistry
at four or five stereogenic centers in this process enhances
its synthetic power.4 Specifically, keto-R,â-unsaturated
esters undergo Lewis acid-base co-mediated sequential
Michael addition and aldol reaction to afford cyclobutane
derivatives. For example, treatment of keto-enoate 1 with
trimethylsilyl iodide-hexamethyldisilazane (TMSI-
* To whom correspondence should be addressed. (K.T.) Phone:
+81-22-217-6879;
fax:
+81-22-217-6877;
e-mail:
kay-t@
mail.pharm.tohoku.ac.jp. (M.I.) Phone: +81-22-217-6887; fax: +81-
22-217-6877.
(1) For representative examples, see: (a) Kepler, J . A.; Wall, M. E.;
Mason, J . E.; Basset, C.; McPhail, A. T.; Sim, G. A. J . Am. Chem. Soc.
1967, 89, 1260-1261. (b) Wilson, B. J .; Wilson, C. H.; Hayes, A. W.
Nature 1968, 220, 77-78. (c) de J esus, A. E.; Gorst-Allman, C. P.;
Steyn, P. S.; van Heerden, F. R.; Vleggaar, R.; Wessels, P. L.; Hull, W.
E. J . Chem. Soc., Perkin Trans. 1 1983, 1863-1868. (d) Schenk, H.;
Driessen, R. A. J .; de Gelder, R.; Goubits, K.; Nieboer, H.; Bru¨ggemann-
Rotgans, I. E. M.; Diepenhorst, P. Croat. Chem. Acta 1999, 72, 593-
606.
HMDS)5 produces the tricyclo[5.4.0.03,7]undecane 2, which
possesses the italicen skeleton.6 Also, reaction of keto-
enoate 3 using TBDMSOTf-NEt37 gives tricyclo[4.2.1.03,8]-
nonane 4, which contains the partial framework of
endiandric acids8 (Scheme 1).
The asymmetric version of this cyclization reaction
would be an extremely potent methodology to access
enantiomerically enriched, fused polycyclic cyclobutanes.
(2) For some examples, see: (a) Lange, G. L.; Lee, M. Synthesis 1986,
117-120. (b) Ue, M.; Tsukahara, H.; Kobiro, K.; Kakiuchi, K.; Tobe,
Y.; Odaira, Y. Tetrahedron Lett. 1987, 28, 3979-3980. (c) Haque, A.;
Ghatak, A.; Ghosh, S.; Ghoshal, N. J . Org. Chem. 1997, 62, 5211-
5214. (d) Winkler, J . D.; Doherty, E. M. J . Am. Chem. Soc. 1999, 121,
7425-7426. (e) Ihara, M.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K.
J . Org. Chem. 1994, 59, 8092-8100.
(5) Miller, R. D.; McKean, D. R. Synthesis 1979, 730-732.
(6) (a) Leimner, J .; Marschall, H.; Meier, N.; Weyerstahl, P. Chem.
Lett. 1984, 1769-1772. (b) Weyerstahl, P.; Marschall, H.; Wahlburg,
H.-C.; Christiansen, C.; Rustaiyan, A.; Mirdjalili, F. Flavour Fragrance
J . 1999, 14, 121-122.
(7) Emde, H.; Go¨tz, A.; Hofmann, K.; Simchen, G. Liebigs Ann.
Chem. 1981, 1643-1657.
(8) (a) Bandaranayake, W. M.; Banfield, J . E.; Black, D. S. C.; Fallon,
G. D.; Gatehouse, B. M. J . Chem. Soc., Chem. Commun. 1980, 162-
163. (b) Bandaranayake, W. M.; Banfield, J . E.; Black, D. S. C. J . Chem.
Soc., Chem. Commun. 1980, 902-903.
(3) Methods of Organic Chemistry; de Meijere, A., Ed.; Thieme:
Stuttgart, 1997; Vol. E17e.
(4) (a) Ihara, M.; Ohnishi, M.; Takano, M.; Makita, K.; Taniguchi,
N.; Fukumoto, K. J . Am. Chem. Soc. 1992, 114, 4408-4410. (b) Ihara,
M.; Taniguchi, T.; Makita, K.; Takano, M.; Ohnishi, M.; Taniguchi,
N.; Fukumoto, K.; Kabuto, C. J . Am. Chem. Soc. 1993, 115, 8107-
8115. (c) Ihara, M.; Taniguchi, T.; Yamada, M.; Tokunag, Y.; Fukumoto,
K. Tetrahedron Lett. 1995, 36, 8071-8074.
10.1021/jo010207q CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/24/2001

4668 J . Org. Chem., Vol. 66, No. 13, 2001
Takasu et al.
Sch em e 2a
yield, respectively (Table 1, entry 1), and the diastereo-
meric excess of 9a over 10a is 76% de. Reaction for an
11 h period gives significantly lower levels (33% de, entry
2) of diastereoselectivity. The de is also low for reactions
in ClCH2CH2Cl (18% de, entry 3). Reactions run at the
lower temperatures in CH2Cl2 are highly diastereoselec-
tive, and the yields of the silyl enol ether byproducts 11
are decreased (entries 4-6). For example, when the
reaction of 8a is carried out at -78 °C, 9a is obtained in
85% yield as the sole diastereomer. Reaction of 8a
promoted by using TMSOTf-HMDS, although showing
the same levels of diastereoselectivity, occurs at a re-
markably lower temperature (entries 7 and 8). The
cyclopentanone 8b also furnishes Michael-aldol adducts
9b and 10b under these conditions, and excellent dia-
stereoselectivities are achieved at -78 °C (entries 9 and
10).
a
Key: (a) LDA, HMPA, THF; (b) (CO2H)2‚H2O, THF-H2O; (c)
PhMenO2CCHdPPh3, MeCN.
To assign relative stereochemistry, 9a and 10a are
transformed into the corresponding tricyclic diols by the
reductive removal of the auxiliary, followed by desilyla-
tion. The diols 12 (Scheme 4) obtained from 9a and 10a
have known4b relative stereochemistry. Their specific
We recently described asymmetric Michael-aldol reac-
tions of 3 by using silyl triflate and C2 chiral amines.9
Asymmetric induction in theses processes is based on
initial enantioselective enol silylation. However, this
strategy cannot be applied to R-substituted ketones, such
as 1, since reaction of 1 with silyl triflate and amines
does not afford the desired Michael-aldol adduct, but
instead, it produces a kinetically stable silyl enol ether.4b,7
In the current investigation, we observed that Michael-
aldol reactions of R-substituted ketones can be promoted
by using TMSI-HMDS and related conditions. Impor-
tantly, by using 8-arylmenthol ester10 derivatives of
R-substituted ketones, asymmetric Michael-aldol reac-
tions can be achieved.11
rotations ([R]26 (c 1.0 CHCl3)) are -26.6 and +26.1,
D
respectively. The absolute configuration of 9a is deter-
mined by use of circular dichroism analysis of the derived
spirocyclohexanone acid 13, obtained by the treatment
of 9a with TBAF, followed by hydrolysis with NaOMe
(Scheme 5). The keto-acid 13 shows a weak positive
Cotton effect ([θ] ) +886, λext ) 308.6 nm). Application
of the octant rule13 suggests that the spiro carbon has
the (R)-configuration. On the basis of these findings, 9a
and 10a are assigned the (1S,2R,3R,7R)- and (1R,2S,-
3S,7S)-tricyclo[5.4.0.03,7]undecane stereochemistry, re-
spectively. The relative stereochemistries of 9b and 10b
are determined by using similar procedures, and the
absolute configurations of these substances is assumed
to be the same as those for 9a and 10a .
Michael-aldol reaction of 8c, which has a longer side
chain, by using TMSI-HMDS at room temperature gives
(1R,2R,3S,7S)-tricyclo[5.4.0.03,7]undecane 14 in 15% yield
along with the spiro compound 15 in 76% yield (4:1
pseudo-enantiomeric mixture) (Scheme 6). In this pro-
cess, 15 is produced by Michael addition of 8c, followed
by enol silylation of the keto-carbonyl group. This reac-
tion, although inefficiently producing 14, does not gener-
ate the pseudo-antipode. Also, reaction of 8c at -78 °C
only gives silyl enol ether 16. The relative and absolute
configuration of 14 is assumed to be the same as for 9a .
The absolute configuration of 15 is assigned by the
comparison of the circular dichroism spectrum of its
derived keto-acid with that of 13. Independent desilyla-
tion of 14 and 15, followed by hydrolysis, furnishes
different spiro keto-acids 17 and 18, respectively. Thus,
17 and 18 must have opposite relative configurations at
C(5) and C(6). Because of the flexibility of the longer
tether in 8c, the transition state for initial Michael
addition is not conformationally fixed; therefore, two
different products, 14 and 15, are formed.
Resu lts a n d Discu ssion
Asym m etr ic Mich a el-Ald ol Rea ction . The 8-phen-
ylmenthyl esters 8a -c are synthesized by use of minor
modifications of reported procedures4b (Scheme 2). For
example, R-alkylation of N-(cycloalkylidene)cyclohexyl-
amine (5) with 1-bromo-4,4-dimethoxyalkane (6) followed
by aqueous workup affords the R-substituted ketones 7.
Acetal cleavage followed by Wittig olefination12 trans-
forms 7 into the 8-phenylmenthyl enoates 8. The relative
configuration of the R-ketone position in 5 was not
determined. In any event, the chirality at this center is
lost during Michael-aldol reaction.
On the basis of the results of our previous studies,4
intramolecular Michael-aldol reaction of the R-substi-
tuted substrates (8) were performed by using TMSI-
HMDS conditions (Scheme 3). It is known that the
treatment of ketones with this mixed reagent system
predominantly gives thermodynamic silyl enol ethers.5
At ambient temperature, reaction of 8a with TMSI-
HMDS in CH2Cl2 affords tricyclo[5.3.0.03,7]undecanes, 9a
and 10a , as separable diastereomers. When the reaction
is quenched by the addition of water after 1 h, 9a , 10a ,
and silyl enol ether 11a are obtained in 44, 6, and 38%
Mech a n istic In sigh ts of In tr a m olecu la r Mich a el-
Ald ol Rea ction . The results presented above suggest
that an equilibrium is established between 9a , 10a , and
11a when 8a is treated with TMSI-HMDS at rt. This
proposal is supported by the observed variations seen in
(9) Takasu, K.; Misawa, K.; Yamada, M.; Furuta, Y.; Taniguchi, T.;
Ihara, M. Chem. Commun. 2000, 1739-1740.
(10) For reviews of 8-phenylmenthol as chiral auxiliary, see: (a)
Whitesell, J . K. Chem. Rev. 1992, 92, 953-964. (b) Regan, A. C. J .
Chem. Soc., Perkin Trans. 1 1999, 357-373.
(11) A part of this work was published as preliminary communica-
tion: Takasu, K.; Ueno, M.; Ihara, M. Tetrahedron Lett. 2000, 41,
2145-2148.
(12) Ihara, M.; Takino, Y.; Tomotake, M.; Fukumoto, K. J . Chem.
Soc., Perkin Trans. 1 1990, 2287-2292.
(13) Moffitt, W.; Woodward, R. B.; Moscowitz, A.; Klyne, W.;
Djerassi, C. J . Am. Chem. Soc. 1961, 83, 4013-4018.

Nonracemic Tricyclic Cyclobutanes
J . Org. Chem., Vol. 66, No. 13, 2001 4669
Ta ble 1. Asym m etr ic Mich a el-Ald ol Rea ction s of 8a a n d 8b
yield (%)
entry
substrate
reagent
solvent
CH2Cl2
temp (°C)
time (h)
9
10
11
de (%)f
1a
2a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8b
TMSI-HMDS
TMSI-HMDS
TMSI-HMDS
TMSI-HMDS
TMSI-HMDS
TMSI-HMDS
TMSOTf-HMDS
TMSOTf-HMDS
TMSI-HMDS
TMSI-HMDS
rt
rt
rt
0
-30
-78
rt
-30
rt
1
11
11
9
44
30
36
55
76
85
29
35
70e
73e
6
38
33
25
23
15
0
30
7
0
76
33
18
80
92
100
32
∼95
∼90
100
CH2Cl2
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
15
25
6
3a
4a
5a
9
3
0
6a
11
14
15
8
7b
8c
15
trace
∼5e
0
9d
10d
-78
20
0
a
b
d
TMSI (1.2)-HMDS (1.5 equiv). TMSOTf (1.2)-HMDS (1.5 equiv). c TMSOTf (3.0)-HMDS (3.0 equiv). TMSI (1.5)-HMDS (1.5
equiv). e The configuration was determined based on the reaction mechanism. f The diastereomeric excess (de) was determined based on
isolated yield. de ) (9 - 10)/(9 + 10).
Sch em e 3a
F igu r e 2. Diastereofacial selection of 8a .
ratio of 11a to the sum of 9a and 10a remains constant
throughout this period. In addition, exposure of 9a to
TMSI-HMDS at rt affords 10a , 11a , and unreacted 9a .
The stereochemical course of the Michael-aldol reac-
tions of 8a and 8b can be explained in the following
a
manner. Initially, the thermodynamically stable silyl enol
ether 11a and 11b is generated by reaction of 8a and
8b, respectively, with TMSI-HMDS. Mukaiyama-type
Michael addition and aldol reaction ensues to give 9 and/
or 10. A preference for the s-trans conformation of the
enoate moiety, caused by π-π attractive interactions,
appears to exist. This is indicated in the 1H NMR
spectrum of 8a by the downfield shifts of the vinyl
protons (∆δ ) -0.56 and -0.45 ppm for R- and â- protons,
respectively) and comparisons to related methyl ester
analogues.4b At low temperature, the diastereofacial
selection favoring 9 is controlled by π-stacking interaction
of the aromatic ring of the phenylmenthol moiety (Figure
2). Even at room temperature, the kinetic product 9 is
formed initially. However, at this temperature, reversible
Michael-aldol reaction promoted by TMSI-HMDS re-
sults in isomerization of the adducts via the silyl enol
ether.
R* ) (-)-8-phenylmethyl.
Sch em e 4a
a
Key: (a) DIBAL-H, CH2Cl2; (b)TBAF, TF.
Sch em e 5a
a
Key: (a) TBAF, THF; (b) NaOMe, H2O.
In contrast, a rather complex pathway is involved in
reaction of 8c. The products vs reaction time profile for
this process (Figure 3) shows that regioselective enolsi-
lylation occurs initially to form 16. At longer reaction
times, the amount of 15 increases at the expense of 16,
which decreases. Finally, at the end of the process, 16
has nearly disappeared, and 15 becomes the main
product. Simultaneously, 14 forms quickly in this mix-
ture, but it gradually disappears after ca. 10 h. The
behavior summarized above is consistent with the simul-
taneous operation of (1) a reversible Michael-aldol
reaction, which equilibrates 14 and 16 and (2) a non-
reversible Michael addition enol silylation sequence to
produce the stable 15. Actually, 15 is found to be
unreactive under the conditions used in this process.
F igu r e 1. Time course of the reaction of 8a to produce two
diastereomers with proportions of 9a (O) and 10a (0).
the product ratios as a function of reaction time (Figure
1, product ratios calculated by use of 1H NMR). After a 1
h reaction time, the amount of 9a is ca. 7× that of 10a ,
and as the reaction time increases, the 9a :10a ratio
increases, reaching a final ratio of ca. 11:9. The relative
Effect of Iod in e on th e Mich a el-Ald ol Rea ction .
In the course of these studies, we observed that the rate
of the Michael-aldol reaction is dependent on the purity

4670 J . Org. Chem., Vol. 66, No. 13, 2001
Takasu et al.
Sch em e 6a
a
Key: (a) TMSI, HMDS, CH2Cl2; (b) TBAF, THF; (c) NaOMe, H2O.
Con clu sion . In summary, we have developed an
effective asymmetric Michael-aldol methodology for the
construction of enantiomerically enriched, tricyclic cy-
clobutanes. In addition, the observations we have made
clearly show that the TMSI-HMDS promoted Michael-
aldol reaction is reversible at room temperature and, as
a result, that the stereoselectivity of the process is
dependent on the reaction temperature and time. Finally,
it is noteworthy that stereochemistry at the four stereo-
genic centers generated in these reactions is controlled
by 8-phenylmenthol chiral auxiliary.
F igu r e 3. Time course of the reaction of 8c to produce 14
(4), 15 (O), and 16 (0).
Exp er im en ta l Section
Ta ble 2. In flu en ce of Iod id e/Iod in e Ad d itive
entrya
color of TMSI
additive
yield (%) 9a
Gen er a l. All reactions were carried out under an inert
atmosphere. Anhyd THF, MeCN, and CH2Cl2 were purchased
from the Kanto Chemical Co., Inc. Dichloroethane, HMPA, and
HMDS were distilled from CaH2 under atmospheric or reduced
pressure. Unless otherwise described, pale red TMSI was used
for the Michael-aldol reaction. Unless otherwise described,
the materials were obtained from commercial suppliers and
used without further purification. Organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure
using an evaporator. The 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, and were reported
in ppm downfield from TMS (δ ) 0) for the 1H NMR and
relative to the central CDCl3 resonance (δ ) 77.00) for the 13C
NMR.
Gen er a l P r oced u r e for P r ep a r a tion of Aceta ls 7b,c. To
a solution of i-PrNH2 (1.4 equiv) in THF (0.65 M) at 0 °C was
added BuLi (1.53 M in hexane; 1.2 equiv). To this was added
a solution of N-(cyclopentylidene)cyclohexylamine (6b; 1.0
equiv) in THF (0.33 M) dropwise at -78 °C, and the solution
was stirred for 1 h at 0 °C. To the resulting mixture were added
HMPA (1.2 equiv) and then a solution of bromoacetal 5 (1.3
equiv) in THF (0.45 M) at 0 °C, and the resulting solution was
stirred for 1 h at the same temperature. After dilution with
Et2O, the mixture was washed with saturated NH4Cl and
brine. The organic layer was dried and concentrated. The
residue was purified by column chromatography on silica gel
with 25% AcOEt/hexane.
1
2
3
4
red-brown
colorless
colorless
colorless
85
24
15
46
nBu4NI (4 mol %)
NIS (4 mol %)
a
All reactions were carried out in the presence of 1.2 equiv of
TMSI and 1.5 equiv of HMDS in CH2Cl2 at -78 °C for 8-11 h.
of TMSI. For example, reaction of 8a with nonpurified
TMSI (red-brown color) resulted in high yielding genera-
tion of 9a (Table 2, entry 1). In contrast, when purified
TMSI (colorless) is used under otherwise identical reac-
tion conditions, 9a is produced in only low yield (entry
2). We believe that small amounts of iodide/iodine,
present in unpurified TMSI, enhances the rate of the
Micheal-aldol reaction. To test this proposal, the influ-
ence of iodide/iodine additives was investigated.15 Treat-
ment of 8a with purified TMSI and HMDS in the
presence of a catalytic amount of tetrabutylammonium
iodide led to the formation of 9a in a 15% yield (entry 3).
On the other hand, addition of a catalytic amount of
N-iodosuccinimide (NIS) markedly increased the produc-
tion of 9a (46% yield, entry 4). From these observations,
we conclude that the Michael-aldol reaction is activated
by iodonium cation (I+) donors rather than by iodide (I-).
Although the mechanistic reasons for this are not clear
at this time, we believe that interaction of the iodonium
cation donor with the electron-negative iodine atom of
TMSI might catalyze the initial enolsilylation step in the
overall process.
2-(4,4-Dim eth oxybu tyl)cyclop en ta n -1-on e (7b). 7b was
prepared from 1-bromo-4,4-dimethoxybutane (5a ; 1.61 g, 8.2
mmol) and 6b (1.06 g, 6.4 mmol) in 68% yield (0.88 g) as a
colorless oil. IR (neat) ν: 2946, 1735, 1452, 1125, 1060 cm-1
.
1H NMR (CDCl3): δ 4.37 (t, 1H, J ) 5.6 Hz), 3.32 (s, 6H), 2.37-
1.93 (m, 5H), 1.88-1.68 (m, 2H), 1.66-1.20 (m, 6H). 13C NMR
(CDCl3): δ 221.5, 104.4, 52.7, 52.6, 49.0, 38.0, 32.4, 29.4, 22.5,
20.6. LRMS (m/z): 199 (M+ - 1). HRMS (m/z): calcd for
(14) For a review of π-stacking effects in asymmetric synthesis,
see: J ones, G. B.; Chapman, B. J . Synthesis 1995, 475-497.
(15) When Michael-aldol reaction of 5a with a catalytic amount of
iodine (I2) was tested, rate enhancement was observed. Because of the
difficult handling of a small amount of I2, precise results could not be
obtained.
C
11H19O3, 199.1334; found, 199.1336.
2-(4,4-Dim eth oxyp en tyl)cyclop en ta n -1-on e (7c). 7c was
prepared from 1-bromo-5,5-dimethoxypentane (5b; 2.60 g, 12.3
mmol) and 6b (1.67 g, 10.1 mmol) in 58% yield (1.25 g) as a
colorless oil. IR (neat) ν: 2940, 1739, 1452, 1125, 1053 cm-1
.

Nonracemic Tricyclic Cyclobutanes
J . Org. Chem., Vol. 66, No. 13, 2001 4671
1H NMR (MHz, CDCl3): δ 4.35 (t, 1H, J ) 5.8 Hz), 3.31 (s,
6H), 2.36-1.94 (m, 5H), 1.89-1.69 (m, 2H), 1.66-1.43 (m, 3H),
1.42-1.19 (m, 5H). 13C NMR (CDCl3): δ 221.6, 104.4, 52.5,
48.9, 38.0, 32.2, 29.4, 27.2, 24.4, 20.6. LRMS (m/z): 213 (M+
- 1). HRMS (m/z): calcd for C12H21O3, 213.1491; found,
213.1448.
1.85 (m, 3H), 1.78-0.72 (m, 18H), 1.33 (s, 3H), 1.23 (s, 3H),
0.86 (d, 3H, J ) 6.6 Hz), 0.16 (s, 9H). 13C NMR (CDCl3): δ
171.9, 151.1, 128.0, 125.6, 125.3, 75.1, 74.2, 52.7, 52.6, 50.3,
41.9, 40.1, 39.4, 34.7, 34.5, 34.3, 31.7, 31.3, 30.3, 28.5, 27.0,
25.1, 25.0, 22.5, 21.7, 19.8, 1.68. LRMS (m/z): 496 (M+). HRMS
(m/z): calcd for C31H48O3S, 496.3370; found, 496.3369.
Gen er a l P r oced u r e for P r ep a r a tion of P h en ylm en th yl
En oa te 8a -c. A solution of 7 (1.0 equiv) and (CO2H)2‚2H2O
(5.0 equiv) in THF-H2O (1:1 v/v; 0.25 M) was stirred at rt for
4 h. The reaction mixture was diluted with Et2O, neutralized
with saturated NaHCO3 while being cooled, and then extracted
with Et2O. The organic layer was washed with brine, dried,
and concentrated to give the crude aldehyde, which was used
in the following reaction without further purification. A
solution of the above aldehyde and Ph3PdCHCO2PhMen12 in
MeCN was stirred at rt for 13 h. The mixture was concentrated
and purified by column chromatography on silica gel with 20%
AcOEt/hexane.
(1R,2S,3S,7S)-2-[(1R,2S,5R)-2-(1-Meth yl-1-ph en yleth yl)-
5-m e t h ylcycloh e xyloxyca r b on yl]-1-(t r im e t h ylsiloxy)-
tr icyclo[5.4.0.03,7]u n d eca n e (10a ). Colorless oil, [R]27D +32.0
(c 1.4, CHCl3). IR (neat) ν: 2950, 1715, 1245, 1215, 840, 760
1
cm-1. H NMR (CDCl3): δ 7.30-7.21 (m, 4H), 7.18-7.10 (m,
1H), 4.89 (ddd, 1H, J ) 10.8, 10.8, 4.4 Hz), 2.30 (dd, 1H, J )
7.3, 4.8 Hz), 2.17 (m, 1H), 1.99 (m, 1H), 1.93 (d, 1H, J ) 7.4
Hz), 1.86 (m, 1H), 1.76-0.76 (m, 19H), 1.31 (s, 3H), 1.21 (s,
3H), 0.87 (d, 3H, J ) 6.6 Hz), 0.10 (s, 9H). 13C NMR (CDCl3):
δ 172.6, 151.5, 128.1, 125.5, 125.1, 75.3, 74.1, 53.4, 52.6, 50.2,
42.2, 39.7, 38.0, 35.0, 34.4, 33.6, 32.0, 31.3, 30.6, 27.3, 36.7,
25.8, 25.1, 22.0, 21.7, 19.6, 2.02. LRMS (m/z): 496 (M+). HRMS
(m/z): calcd for C31H48O3Si, 496.3370; found, 496.3382.
1-(T r im e t h y ls ilo x y )-2-{[(1R ,2S ,5R )-2-(1-m e t h y l-1-
p h e n y le t h y l)-5-m e t h y lc y c lo h e x y lc a r b o n y l]-(4 E )-4-
p en t en yl}cycloh exen e (11a ).16 Colorless oil. 1H NMR
(CDCl3): δ 7.30-7.20 (m, 4H), 7.15-7.05 (m, 1H), 6.56 (dt,
1H, J ) 15.9, 6.9 Hz), 5.28 (dt, 1H, J ) 15.6, 1.5 Hz), 4.83
(ddd, 1H, J ) 10.8, 10.8, 4.5 Hz), 2.08-1.86 (m, 9H), 1.69-
0.78 (m, 3H), 1.30 (s, 3H), 1.21 (s, 3H), 0.86 (d, 3H, J ) 6.6
Hz), 0.17 (s, 9H).
2-{[(1R,2S,5R)-2-(1-Met h yl-1-p h en ylet h yl)-5-m et h yl-
cycloh exyloxyca r bon yl]-(4E)-4-p en ten yl}cycloh exa n on e
(8a ). 8a was prepared from 7a 4b (3.29 g, 15.3 mmol) in 52%
overall yield (3.36 g) in two steps as a colorless oil. [R]22D +1.4
(c 1.0, CHCl3). IR (neat) ν: 2925, 2850, 1710, 1650, 1265, 1130,
1
760, 700 cm-1. H NMR (CDCl3): δ 7.31-7.19 (m, 4H), 7.15-
7.05 (m, 1H), 6.51 (dt, 1H, J ) 15.5, 6.7 Hz), 5.27 (dt, 1H, J )
15.5, 0.9 Hz), 4.82 (ddd, 1H, J ) 10.7, 10.7, 4.3 Hz), 2.37 (tt,
1H, J ) 12.9, 3.3 Hz), 2.32-1.19 (m, 2H), 2.15-1.57 (m, 13H),
1.54-0.78 (m, 7H), 1.29 (s, 3H), 1.20 (s, 3H), 0.85 (d, 3H, J )
6.3 Hz). 13C NMR (CDCl3): δ 213.2, 165.9, 151.7, 148.3, 128.0,
125.5, 124.9, 121.8, 74.0, 50.5, 41.9, 41.6, 39.6, 34.5, 33.82,
33.78, 32.0, 31.1, 28.9, 27.9, 27.4, 16.5, 25.4, 25.3, 25.2, 24.8,
21.5. LRMS (m/z): 424 (M+). Anal. Calcd for C28H40O3: C,
79.20; H, 9.50. Found: C, 79.25; H, 9.25.
(1S,2R,3R,7S)-2-[(1R,2S,5R)-2-(1-Meth yl-1-ph en yleth yl)-
5-m e t h ylcycloh e xyloxyca r b on yl]-1-(t r im e t h ylsiloxy)-
tr icyclo[5.3.0.03,7]d eca n e (9b). Colorless oil, [R]25 -10.6 (c
D
0.9, CHCl3). IR (neat) ν: 2940, 1705, 1250, 880, 840, 760 cm-1
.
1H NMR (CDCl3): δ 7.32-7.22 (m, 4H), 7.19-7.10 (m, 1H),
4.86 (ddd, 1H, J ) 10.7, 10.7, 4.4 Hz), 2.39 (d, 1H, J ) 6.6
Hz), 2.27 (m, 1H), 2.02-1.80 (m, 4H), 1.76-0.71 (m, 16H), 1.30
(s, 3H), 1.23 (s, 3H), 0.86 (d, 3H, J ) 6.6 Hz), 0.14 (s, 9H). 13C
NMR (CDCl3): δ 171.7, 151.1, 128.1, 125.6, 125.3, 99.2, 82.6,
74.4, 57.9, 53.0, 50.3, 41.9, 40.1, 38.8, 37.4, 35.5, 34.5, 32.1,
31.3, 30.1, 28.4, 27.0, 25.5, 25.2, 24.1, 21.7, 1.5. LRMS (m/z):
482 (M+). Anal. Calcd for C30H46O3Si: C, 74.64; H, 9.60.
Found: C, 74.52; H, 9.48.
2-{[(1R,2S,5R)-2-(1-Meth yl-1-p h en yleth yl)-5-m eth ylcy-
cloh exyloxyca r b on yl]-(4E)-4-p en t en yl}cyclop en t a n on e
(8b). 8b was prepared from 7b (0.31 g, 1.5 mmol) in 41%
overall yield (0.26 g) in two steps as a colorless oil. IR (neat)
ν: 2940, 1730, 1700, 1260, 1165, 1150, 1120, 760 cm-1 1H
.
NMR (CDCl3): δ 7.28-7.21 (m, 4H), 7.13-7.07 (m, 1H), 6.50
(dt, 1H, J ) 15.7, 6.9 Hz), 5.27 (d, 1H, J ) 15.7 Hz), 4.83 (ddd,
1H, J ) 15.1, 10.7, 4.4 Hz), 2.37-1.38 (m, 18H), 1.32-0.79
Tr an sfor m ation in to Diol (-)-12 fr om 9a. (1S,2R,3R,7R)-
1-H y d r o x y -2-(h y d r o x y m e t h y l)t r ic y c lo [5.4.0.03,7]u n -
d eca n e ((-)-12). To a solution of 9a (45 mg, 0.090 mmol) in
CH2Cl2 (0.7 mL) was added 0.94 M DIBALH-hexane (0.22 mL,
0.31 mmol) at -78 °C and stirred for 3 h. The resulting mixture
was poured onto Et2O/H2O and then stirred for 1.5 h at rt.
After addition of MgSO4, the mixture was filtered through
Celite and evaporated to give the corresponding crude alcohol.
To a solution of the above alcohol in THF (0.7 mL) was added
1.0 M TBAF-THF (0.14 mL, 0.14 mmol), and it was stirred
for 30 min at rt. The resulting mixture was diluted with
AcOEt, washed with H2O and brine, dried over MgSO4, and
concentrated. The residue was purified by column chromatog-
raphy on silica gel with AcOEt to give (-)-12 (13 mg, 73% for
two steps) as colorless needles, mp 108-110 °C, whose spectral
data were identical with the reported racemate.4b [R]26D -26.6
(c 1.0, CHCl3).
(m, 3H), 1.30 (s, 3H), 1.21 (s, 3H), 0.86 (d, 3H, J ) 6.6 Hz). 13
C
NMR (CDCl3): δ 221.3, 165.9, 151.8, 148.0, 128.0, 125.5, 124.6,
121.9, 74.1, 50.4, 48.9, 41.6, 39.6, 38.0, 34.5, 31.9, 31.2, 29.4,
29.2, 27.5, 26.5, 25.8, 25.8, 25.1, 21.6, 20.6. LRMS (m/z): 410
(M+). Anal. Calcd for C27H38O3: C, 78.98; H, 9.33. Found: C,
78.94; H, 9.48.
2-{[(1R,2S,5R)-2-(1-Meth yl-1-p h en yleth yl)-5-m eth ylcy-
cloh exyloxyca r b on yl]-(5E)-5-h exen yl}cyclop en t a n on e
(8c). 8c was prepared from 7c (0.46 g, 2.1 mmol) in 53% overall
yield (0.48 g) in two steps as a colorless oil. IR (neat) ν: 2925,
1735, 1705, 1645, 1260, 760, 795 cm-1 1H NMR (CDCl3): δ
.
7.32-7.18 (m, 4H), 7.15-7.07 (m, 1H), 6.51 (dddd, 1H, J )
15.7, 6.9, 6.9, 1.9 Hz), 5.26 (d, 1H, J ) 15.7 Hz), 4.83 (ddd,
1H, J ) 10.4, 10.4, 4.4 Hz), 2.35-0.90 (m, 23H), 1.30 (s, 3H),
1.21 (s, 3H), 0.86 (d, 3H, J ) 6.6 Hz). 13C NMR (CDCl3): δ
221.5, 165.9, 151.7, 148.4, 127.9, 125.5, 124.9, 121.8, 74.0, 50.5,
48.9, 41.6, 39.6, 38.0, 34.5, 31.7, 31.2, 29.5, 29.3, 27.7, 27.4,
27.0, 26.5, 25.2, 21.6, 20.6. LRMS (m/z): 424 (M+). Anal. Calcd
for C28H40O3: C, 79.20; H, 9.50. Found: C, 79.16; H, 9.52.
Gen er a l P r oced u r e for Asym m etr ic Mich a el-Ald ol
Rea ction of 8a a n d 8b. To a solution of 8 and HMDS (1.5
equiv) in CH2Cl2 was added TMSI (1.2 or 1.5 equiv) at the
reaction temperature. After being stirred for several hours,
the mixture was diluted with Et2O and washed with saturated
NaHCO3 and brine. The organic layer was dried and concen-
trated. The residue was purified by column chromatography
on silica gel with 4% Et2O/hexane.
Tr a n sfor m a tion in to Diol (+)-12 fr om 10a . The trans-
formation into (+)-12 from 10a was carried out by the same
procedure as above. (+)-12 colorless needles, mp 109-111 °C,
whose spectral data were identical with the reported racemate.4b
[R]26 +26.1 (c 0.9, CHCl3).
D
[(1R,5R)-Sp ir o[4.5]d eca n -6-on e-1-yl]a cetic Acid (13). To
a solution of 9a (117 mg, 0.24 mmol) in THF (1.9 mL) was
added 1M TBAF-THF (0.35 mL, 0.35 mmol) and stirred for
12 h at rt. The mixture was diluted with AcOEt, washed with
H2O and brine, dried over MgSO4, and evaporated. The residue
was purified on silica gel with 8% Et2O/hexane to give the
corresponding spiro ketone as a colorless oil (38 mg, 32%). IR
(1S,2R,3R,7R)-2-[(1R,2S,5R)-2-(1-Meth yl-1-ph en yleth yl)-
5-m e t h ylcycloh e xyloxyca r b on yl]-1-(t r im e t h ylsiloxy)-
tr icyclo[5.4.0.03,7]u n d eca n e (9a ). Colorless oil, [R]27D -23.4
(c 1.1, CHCl3). IR (neat) ν: 2950, 1715, 1250, 1200, 840, 760
(neat) ν: 2940, 2850, 1715, 1695, 1175, 760 cm-1 1H NMR
.
(CDCl3): δ 7.34-7.21 (m, 4H), 7.20-7.18 (m, 1H), 4.79 (ddd,
1
cm-1. H NMR (CDCl3): δ 7.30-7.23 (m, 4H), 7.19-7.12 (m,
(16) Silyl enol ethers 11a and 16 were unstable against the
atmosphere. All analytical spectra except for 1H NMR could not be
obtained.
1H), 4.85 (ddd, 1H, J ) 10.8, 10.8, 4.4 Hz), 2.36 (d, 1H, J )
7.7 Hz), 2.26 (dd, 1H, J ) 8.0, 4.0 Hz), 2.22 (m, 1H), 2.00-

4672 J . Org. Chem., Vol. 66, No. 13, 2001
Takasu et al.
1H, J ) 10.8, 10.8, 4.5 Hz), 2.47-2.34 (m, 1H), 2.26-2.16 (m,
1H), 2.16-0.76 (m, 23H), 1.29 (s, 3H), 1.20 (s, 3H), 0.86 (d,
3H, J ) 6.6 Hz). 13C NMR (CDCl3): δ 213.9, 173.1, 151.5, 128.0,
125.4, 125.2, 74.1, 59.3, 50.2, 43.9, 41.8, 40.4, 39.6, 38.0, 35.5,
35.1, 34.4, 31.2, 29.9, 27.4, 26.52, 26.49, 25.4, 22.3, 21.7, 21.1.
HRMS (m/z): (M+) calcd for C28H40O3, 424.2975; found,
424.2962.
clop en ten e (16).16 Colorless oil, 1H NMR (CDCl3): δ 7.31-
7.20 (m, 4H), 7.15-7.05 (m, 1H), 6.53 (ddd, 1H, J ) 15.7, 6.9,
6.9 Hz), 5.27 (d, 1H, J ) 15.7 Hz), 4.84 (ddd, 1H, J ) 10.4,
10.4, 4.4 Hz), 2.30 (t, 1H, J ) 7.3 Hz), 2.18 (t, 1H, J ) 7.3 Hz),
2.14-0.77 (m, 20H), 1.30 (s, 3H), 1.21 (s, 3H), 0.85 (d, 3H, J )
6.6 Hz), 0.16 (s, 9H).
[(5R,6S)-Sp ir o[4.5]d eca n -1-on e-6-yl]a cetic Acid (17). 17
was prepared from 14 (7.4 mg, 15 µmol) in 39% overall yield
(6.5 mg) in two steps, according to the same procedure as
described in the preparation of 13. Colorless plates, mp 121-
A solution of the above ketone (38 mg, 0.089 mmol) and
NaOMe (48 mg, 0.89 mmol) in MeOH (2.0 mL) was refluxed
for 5 h. The mixture was quenched with H2O, evaporated, and
extracted with AcOEt. The aqueous layer was turned acidic
with 10% HCl and extracted with AcOEt. The combined
organic layer was washed with brine, dried over MgSO4, and
evaporated to give 13 as a colorless oil (12 mg, 64%). CD
(MeOH) λext, nm [θ]: 309 [+886]. UV (MeOH) λmax, nm (ꢀ): 284
124 °C, [R]24 +12.3 (c 0.94, CHCl3). IR (neat) ν: 3100 (br),
D
2950, 2885, 1735, 1710, 1450, 1405, 945, 700 cm-1. H NMR
1
(300 MHz, CDCl3): δ 2.64 (dd, 1H, J ) 16.3, 4.8 Hz), 2.35-
1.13 (m, 16H), 0.90 (m, 1H). HRMS (m/z): (M+) calcd for
C12H18O3, 210.1255; found, 210.1234.
[(5R,6R)-Sp ir o[4.5]d eca n -1-on e-6-yl]a cetic Acid (18). 18
was prepared from 15 (23 mg, 46 µmol) in 20% overall yield
(9.6 mg) in two steps, according to the similar procedure as
(34). IR (neat) ν: 3400 (br), 2925, 1695, 1440, 945 cm-1 1H
.
NMR (CDCl3): δ 2.65-2.52 (m, 1H), 2.52-2.38 (m, 1H), 2.36-
1.96 (m, 5H), 1.96-1.20 (m, 10H), 0.86 (br, 1H). 13C NMR
(CDCl3): δ 214.3, 179.4, 59.2, 44.2, 40.2, 38.0, 36.1, 34.8, 30.2,
26.4, 22.4, 21.3. HRMS (m/z): (M+) calcd for C12H18O3,
210.1255; found, 210.1260.
described in the preparation of 13. Colorless crystals, [R]24
D
+34.0 (c 0.67, CHCl3; ∼60% ee). IR (neat) ν: 3000 (br), 2920,
1
2850, 1725, 1700, 1440, 1180, 1160 cm-1. H NMR (300 MHz,
Asym m etr ic Mich a el-Ald ol Rea ction of 8c. To a solu-
tion of 8c (55 mg, 0.13 mmol) and HMDS (44 µL, 0.19 mmol)
in CH2Cl2 (0.9 mL) was added TMSI (28 µL, 0.20 mmol) at rt.
After being stirred for 20 h, the mixture was extracted with
Et2O and washed with saturated NaHCO3 and brine. The
organic layer was dried and concentrated. The residue was
purified by column chromatography on silica gel with 2% Et2O/
hexane to give 14 (9.3 mg, 15%) and 15 (48.8 mg, 76%).
(1R,2R,3S,7S)-2-[(1R,2S,5R)-2-(1-Meth yl-1-ph en yleth yl)-
5-m e t h ylcycloh e xyloxyca r b on yl]-3-(t r im e t h ylsiloxy)-
CDCl3): δ 2.56-1.15 (m, 17H), 1.05 (m, 1H). 13C NMR (75
MHz, CDCl3): δ 223.5, 178.1, 53.2, 38.4, 37.5, 37.0, 33.0, 28.6,
27.3, 25.4, 21.4, 18.7. HRMS (m/z): (M+) calcd for C12H18O3,
210.1255; found, 210.1271.
Tim e Cou r se of th e Rea ction of 8a u n d er TMSI-
HMDS. To a solution of 8a (105 mg, 0.247 mmol) in CH2Cl2
(1.7 mL) was added HMDS (85 µL, 0.0.371 mmol) and TMSI
(42 µL, 0.295 mmol) at rt. After the mixture was stirred for 1
h, a part of the mixture (about 0.3 mL) was taken out by a
syringe, diluted with Et2O, washed with a saturated solution
of NaHCO3 and brine, dried over MgSO4, and evaporated. After
the mixture was stirred for 5, 10, and 23 h, the same handling
as above was done. The ratio of 9a , 10a , and 11a was
determined by the integration from 1H NMR.
Mich a el-Ald ol Rea ction in th e P r esen ce of Iod id e/
Iod in e Ad d it ive. To a solution of 8a (0.10 mmol) and the
iodide/iodine additive (4.0 µmol) in CH2Cl2 (0.9 mL) was added
HMDS (0.15 mmol) and purified colorless TMSI (16 µL, 0.11
mmol) at -78 °C. After being stirred for 8 h, the mixture was
worked-up and purified according to the general procedure that
gave 8a .
tr icyclo[5.4.0.03,7]d eca n e (14). Colorless oil, [R]25 -10.2 (c
D
0.9, CHCl3). IR (neat) ν: 2920, 1710, 1245, 840, 755 cm-1. H
1
NMR (CDCl3): δ 7.32-7.21 (m, 4H), 7.20-7.10 (m, 1H), 4.85
(ddd, 1H, J ) 10.7, 10.7, 6.6 Hz), 2.61 (d, 1H, J ) 10.4 Hz),
2.37-2.24 (m, 1H), 2.00-0.68 (m, 22H), 1.33 (s, 3H), 1.23 (s,
3H), 0.85 (d, 3H, J ) 6.3 Hz), 0.14 (s, 9H). 13C NMR (CDCl3):
δ 172.6, 151.2, 128.1, 125.7, 125.4, 84.4, 74.3, 51.3, 50.5, 49.3,
42.2, 40.2, 38.3, 36.8, 34.5, 31.9, 31.4, 28.6, 27.1, 25.2, 24.6,
23.7, 21.8, 21.2, 20.9, 1.7. LRMS (m/z): 482 (M+). HRMS (m/
z): calcd for C31H48O3Si, 496.3370; found, 496.3411.
(5R*,6R*)-6-[(1R,2S,5R)-2-(1-Met h yl-1-p h en ylet h yl)-5-
m eth ylcycloh exyloxycar bon ylm eth yl]-1-(tr im eth ylsiloxy)-
sp ir o[4.5]d ec-1-en e (15) (4:1 Mixtu r e of (5R,6R)/(5S,6S)).
Colorless oil, [R]23 -11.4 (c 1.3, CHCl3). IR (neat) ν: 2920,
D
Ack n ow led gm en t. This work was partly supported
by a Grant-in-Aid for Encouragement of Young Scien-
tists (No. 12771347) and Scientific Research on Priority
Areas (Nos. 11119201 and 1147202) from the Ministry
of Education, Culture, Sports, Science and Technology,
J apan.
1720, 1640, 1245, 870, 840, 760 cm-1
.
1H NMR (CDCl3): δ
7.33-7.20 (m, 4H), 7.19-7.02 (m, 1H), 4.77 (ddd, 1H, J ) 10.7,
10.7, 4.4 Hz), 4.55 (t, 0.8H, J ) 2.3 Hz), 4.78 (t, 0.2H, J ) 2.3
Hz), 2.21-2.08 (m, 1H), 2.26-1.78 (m, 5H), 1.70-0.75 (m,
17H), 1.29 (s, 3H), 1.21 (s, 3H), 0.85 (d, 3H, J ) 6.6 Hz), 0.23
(s, 7.2H), 0.17 (s, 1.8H). 13C NMR (CDCl3): δ 211.1, 173.5,
158.0, 151.8, 128.1, 128.0, 125.4, 125.1, 122.4, 99.3, 74.1, 50.8,
50.4, 41.9, 39.7, 37.6, 36.2, 36.0, 34.5, 31.2, 28.4, 27.1, 26.6,
25.83, 25.79, 25.6, 22.6, 21.7, -0.14. LRMS (m/z): 496 (M+).
Anal. Calcd for C31H48O3Si: C, 74.95; H, 9.74. Found: C, 74.80;
H, 9.48.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
(300 MHz) for compounds 7b,c; 9a ; 10a ; 11a ; 13; 14; and 16-
18. This material is available free of charge via the Internet
at http://pubs.acs.org.
Tr im et h ylsiloxy-2-{[(1R,2S,5R)-2-(1-m et h yl-1-p h en yl-
eth yl)-5-m eth ylcycloh exyca r bon yl]-(5E)-5-h exen yl}-1-cy-
J O010207Q