Stereospecific Synthesis of (+)- and (-)-Cyclooctenone Derivatives Using a Ring Expansion Reaction with Me3SiSnBu3 and CsF

Article abstract of DOI:10.1021/ja983168h

Novel synthesis of an eight-membered compound by the ring expansion reaction of a two-carbon unit was developed using the stannyl anion generated from Me₃SiSnBu₃ and CsF in DMF. cis- and trans-cyclooctenone derivatives were synthesized from cyclohexanone derivatives having vinyl iodide in a tether by treatment with Me₃SiSnBu₃ and CsF in DMF in a stereospecific manner. The trans-cyclooctenone derivative was isomerized to the cis-isomer in the presence of Me₃SiSnBu₃ and CsF. It is known that the trans-eight-membered ring is an asymmetric compound. Using this procedure, (+)- and (-)-trans-cyclooctenone derivatives could be synthesized from the corresponding optically active cyclohexanone derivatives.

Full text of DOI:10.1021/ja983168h

J. Am. Chem. Soc. 1999, 121, 1217-1225
1217
Stereospecific Synthesis of (+)- and (-)-Cyclooctenone Derivatives
Using a Ring Expansion Reaction with Me3SiSnBu3 and CsF
Alice Emi Imai, Yoshihiro Sato, Mayumi Nishida, and Miwako Mori*
Contribution from the Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
ReceiVed September 3, 1998
Abstract: Novel synthesis of an eight-membered compound by the ring expansion reaction of a two-carbon
unit was developed using the stannyl anion generated from Me3SiSnBu3 and CsF in DMF. cis- and trans-
cyclooctenone derivatives were synthesized from cyclohexanone derivatives having vinyl iodide in a tether by
treatment with Me3SiSnBu3 and CsF in DMF in a stereospecific manner. The trans-cyclooctenone derivative
was isomerized to the cis-isomer in the presence of Me3SiSnBu3 and CsF. It is known that the trans-eight-
membered ring is an asymmetric compound. Using this procedure, (+)- and (-)-trans-cyclooctenone derivatives
could be synthesized from the corresponding optically active cyclohexanone derivatives.
Among medium-sized cyclic compounds, the eight-membered
ones are the most difficult to construct due to the high degree
of ring strain and transannular interactions presented by these
molecules. They occur widely in nature, particularly in higher
plants and marine organisms, and many cyclooctanoid natural
products have been found to exhibit interesting biological
activities. Precapnelladiene,1b dactylol,1c and poitediol1d (Figure
Figure 1.
1) are examples of sesquiterpenes isolated from marine sources
NX or CsF produced a stannyl anion7 via hypervalent silicate,
which is a useful tool in synthetic organic chemistry (eq 1).6
that contain this ring size in their skeletons, and they have been
the target of several synthetic works.1
Some examples of ring expansion from six- to eight-
membered rings are described in the literature, most of which
apply to the Claisen2 or oxy-Cope rearrangement.3 We planned
the construction of an eight-membered ring by a ring expansion
4,5
Ring Expansion to Cyclooctadiones from Cyclohexadiones
Using Me3SiSnBu3 and F-. Reaction of cyclohexadione
derivative Ia with the stannyl anion should produce vinyl anion,6
which reacts with the carbonyl group intramolecularly to
produce the four-membered product IIa (Scheme 1). Then the
ring opening of IIa would give the two-carbons-enlarged ring
IIIa.8
reaction using the stannyl anion generated from Me3SiSnBu3
(1) and CsF.6 Reaction of Me3SiSnBu3 in the presence of R4-
(1) (a) Petasis, N.; Patane, M. A. Tetrahedron 1992, 48, 5757 and
references therein. (b) Ayanogulo, E.; Gebreyesus, T.; Beechan, C.; Djerassi,
C, Tetrahedron 1979, 35, 1035. (c) Schitz, F.; Hollenbeak, K. H.; Vanderah,
D. J. Tetrahedron 1978, 34, 2719. (d) Fenical, W.; Shulte, G. R.; Finer, J.;
Clardy, J. J. Org. Chem. 1978, 43, 3628.
(2) (a) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A. J. Am. Chem.
Soc. 1984, 106, 6868. (b) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A.
J. Am. Chem. Soc. 1985, 107, 7352.
(3) Paquette, L. A.; Liang, S.; Galatsis, P. Synth. Lett. 1990, 663.
(4) (a) Tamborski, C.; Soloski, E. J. J. Org. Chem. 1963, 28, 237. (b)
Schumann, H.; Ronecker, S. Z. Naturforsch. B 1967, B22, 452. (c) Chenard,
B. L.; Van Zyl, C. M. J. Org. Chem. 1986, 51, 3561.
(5) (a) Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet. Chem. 1981,
215, 49. (b) Kosugi, M.; Ohya, T.; Migita, T. Bull. Chem. Soc. Jpn. 1983,
56, 3539. (c) Mitchell, T. N.; Killing, H.; Dicke, R.; Wickenkamp, R. J.
Chem. Soc., Chem. Commun. 1985, 354. (d) Mitchell, T. N.; Wickenkamp,
R.; Amamria, A.; Dicke, R.; Schneider, U. J. Org. Chem. 1987, 52, 4868.
(e) Murakami, M.; Morita, Y.; Ito, Y. J. Chem. Soc., Chem. Commun. 1990,
428. (f) Murakami, M.; Amii, H.; Takizawa, N.; Ito, Y. Organometallics
1993, 12, 4223. (g) Hada, M.; Tanaka, Y.; Ito, M.; Murakami, M.; Amii,
H.; Ito, Y.; Nakatsuji, H. J. Am. Chem. Soc. 1994, 116, 8754. (h) Casson,
S.; Kocienski, P.; Reid, G.; Smith, N.; Street, J. M.; Webster, M. Synthesis
1994, 1301. (i) Murakami, M.; Yoshida, T.; Kawanami, S.; Ito, Y. J. Am.
Chem. Soc. 1995, 117, 6408. (j) Ito, Y.; Bando, T.; Matsuura, T.; Ishikawa,
M. J. Chem. Soc., Chem. Commun. 1986, 980. (k) Tsuji, Y.; Obora, Y. J.
Am. Chem. Soc. 1991, 113, 9368. (l) Lipshutz, B. H.; Reuter, D. C.;
Ellsworth, E. L. J. Org. Chem. 1989, 54, 4975. (m) Chenard, B. L.; Laganis,
E. D.; Davidson, F.; RajanBabu, T. V. J. Org. Chem. 1985, 50, 3666. (n)
Obora, Y.; Tsuji, Y.; Asayama, M.; Kawamura, T. Organometallics 1993,
12, 4697.
(6) (a) Mori, M.; Kaneta, N.; Isono, N.; Shibasaki, M. Tetrahedron Lett.
1991, 32, 6139. (b) Mori, M.; Kaneta, N.; Isono, N.; Shibasaki, M. J.
Organomet. Chem. 1993, 455, 255; (c) 1994, 464, 35. (d) Mori, M.; Isono,
N.; Kaneta, N.; Shibasaki, M. J. Org. Chem. 1993, 58, 2972. (e) Mori, M.;
Hashimoto, A.; Shibasaki, M. J. Org. Chem. 1993, 58, 6503. (f) Honda,
T.; Mori, M. Chem. Lett. 1994, 1013. (g) Sato, H.; Isono, N.; Okamura,
K.; Date, T.; Mori, M. Tetrahedron Lett. 1994, 35, 2035. (h) Kinoshita,
A.; Mori, M. Chem. Lett. 1994, 1475. (i) Isono, N.; Mori, M. J. Org. Chem.
1995, 60, 115. (j) Isono, N.; Mori, M. Tetrahedron Lett. 1995, 36, 9345.
(k) Isono, N.; Mori, M. Main Group Met. Chem. 1996, 19, 277. (l) Sato,
H.; Isono, N.; Miyoshi, I.; Mori, M. Tetrahedron 1996, 52, 8143. (m) Isono,
N.; Mori, M. J. Org. Chem. 1996, 61, 7867.
(7) Stannyl anion prepared from organotin halides: (a) Kuivila, H. G.;
Considine, J. L.; Kennedy, J. D. J. Am. Chem. Soc. 1972, 94, 7206. (b)
Kitching, W.; Olszowy, H.; Waugh, J.; Doddrel, D. J. Org. Chem. 1978,
43, 898. (c) Blake, D.; Coates, G. E.; Tate, J. M. J. Chem. Soc. 1961, 618.
(d) Tamborsky, C.; Ford, F. E.; Lehn, W. L.; Moore, G. J.; Soloski, E. J.
J. Org. Chem. 1962, 27, 619. (e) Tamborsky, C.; Ford, F. E.; Soloski, E.
J. J. Org. Chem. 1963, 28, 181. Stannyl anion prepared from hexa-
organoditins: (f) Still, W. C. J. Am. Chem. Soc. 1977, 99, 4836. (g) J. Am.
Chem. Soc. 1978, 100, 1481. (h) Quintard, J. P.; Hauvette-Frey, S.; Pereyre,
M. Bull. Soc. Chim. Belg. 1978, 87, 505. Stannyl anion prepared from
organotin hydrides: (i) Corriu, R. J. P.; Guerin, C. J. Organomet. Chem.
1980, 197, C19.
10.1021/ja983168h CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/29/1999

1218 J. Am. Chem. Soc., Vol. 121, No. 6, 1999
Imai et al.
Table 1. Reaction of 2 with Me3SiSnBu3 and CsF
Scheme 1. Our Plan for the Ring Expansion Reaction Using
Me3SiSnBu3
yield (%)
run
substrate
R1
R2
7
8
9
1
2
3
4
6a
6b
6c
6d
Me
H
Me
H
H
H
24
39
38
58
17
3
25
33
16
34
CH2OAc
CH2OAc
Scheme 2. Synthesis of the Starting Materiala
Scheme 4
Scheme 5. Synthesis of Vinyl Iodide
a Conditions: (i) Ac2O, Py, CH2Cl2, 45%. (ii) MaI, TMSCl, CH3CN,
35%. (iii) MsCl, Et3N, quant. (iv) Cs2CO3, NaI, DMF.
Scheme 3
Ring Expansion to Cycloalkanones Using Me3SiSnBu3 and
CsF. Our plan was slightly modified to increase the yield of
the expanded product because the reaction of Ia with Me3-
SiSnBu3 and CsF is reversible and the yield of the dehaloge-
nation product increases, as shown in Scheme 4. If the leaving
group is placed at the 3-position of cyclohexanone Ib, having
a vinyl group at the side chain, Ib would give cycloalkanone
IIIb via IIb by treatment with Me3SiSnBu3 and CsF.
At first, we examined whether cyclopentanone derivative 12
could be expanded to cycloheptenone derivative 13 or 15. For
the synthesis of cyclopentanone derivatives, cyclopentadione
10 was reduced with DIBAL-H at -78 °C to give cis-11 and
trans-11 in 61% and 10% yields, respectively (Scheme 5). In
this report, cis and trans refer to the relative positions of the
mesylate and the side chain containing the vinyl iodide. The
stereochemistry of cis-11 was determined by an NOE experi-
ment. Mesylation of each isomer proceeded smoothly to provide
cis-12 and trans-12 in 76% and 79% yields, respectively.
When the five-membered substrate cis-12 was treated with
4 equiv of Me3SiSnBu3 and 4 equiv of CsF9 in DMF at room
temperature, the Michael adduct 13 was obtained in 25% yield
along with dehalogenation product trans-14, which underwent
further substitution of the mesyl group by the stannyl anion in
To examine the ring expansion reaction according to our plan,
the starting cyclohexadione derivatives 6 were prepared as
shown in Scheme 2. The vinyl iodide 3b as the side chain was
prepared from 2-butyne-1,4-diol (2a). The stereochemistry of
3b was determined by an NOE experiment. Condensation of 4
or 5 with 3b or 3c proceeded smoothly to give 6a-d, having a
vinyl iodide in a tether.
When a DMF solution of cyclohexadione 6a, 2 equiv of Me3-
SiSnBu3, and 2 equiv of CsF was stirred at room temperature
for 1.5 h, the expanded cyclooctadione 7a was obtained in 24%
yield along with the corresponding Michael adduct 8a in 17%
yield (Scheme 3). As a byproduct, dehalogenation product 9a
was formed in 25% yield. Similar results were obtained in the
ring expansion of cyclohexanediones 6b-d, as shown in Table
1. Compounds 6c and 6d, having a longer side chain, gave good
results (runs 3 and 4).
These results indicate that the ring expansion reaction of a
two-carbon unit was realized from cyclohexadione 6, having
vinyl iodide as a side chain, using Me3SiSnBu3 and CsF and
that an eight-membered product was formed.
(8) (a) Grob, C. A.; Baumann, W. HelV. Chim. Acta 1955, 38, 594. (b)
Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. (c) Schreiber, S. J.
Am. Chem. Soc. 1980, 102, 6163. (d) Mahajan, J. R.; de Araujo, H. C.
Synthesis 1981, 49.
(9) Because of the low molecular weight of the seven-membered R,â-
unsaturated ketone 15 formed, an excess amount of Me3SiSnBu3 and CsF
was used in order to convert it to the corresponding Michael addition product
13.

Stereospecific Synthesis of (+)- and (-)-Cyclooctenones
J. Am. Chem. Soc., Vol. 121, No. 6, 1999 1219
Scheme 9
Figure 2.
Scheme 10
Scheme 6. Reaction of Cyclopentenes with Me3SiSnBu3 and
CsF
Scheme 7
Scheme 8. Synthesis of the Starting Vinyl Iodide
Scheme 10). When the solvent was changed from DMF to THF,
cis-18a was obtained in 70% yield (run 2). Since it was clear
that cis-19a was obtained from cis-18a and the stannyl anion,
cis-17a was treated with 1.5 equiv of Me3SiSnBu3 and CsF in
DMF at room temperature to give cis-18a as a main product
(run 3). On the other hand, when the trans-isomer 17a was
treated in a similar manner, cis-19a was obtained in 36% yield
as a main product, and trans-isomer 18a was obtained in 1%
yield (run 4). A slight excess of Me3SiSnBu3 and CsF gave
trans-18a in 33% yield from trans-17a (run 5). It is interesting
that the trans-eight-membered ring, which is the smallest trans-
cycloalkene isolable at room temperature,12 was obtained under
these reaction conditions. The stereochemistry of each isomer,
cis-18a and trans-18a, was determined by NOE experiments.
24% yield (Scheme 6). On the other hand, the reaction of trans-
12 did not give any expanded cycloheptenone, and only a
substitution product, cis-14, was isolated in 51% yield. However,
the result of an NOE experiment and the spectral data of cis-14
revealed that these two products (trans- and cis-14) were
epimers. This indicates that substitution of the mesyloxy group
by the stannyl group occurred with inversion of configuration.
This is in good agreement with the results obtained by San
Filippo and Silberman10a and Ashby and DePriest,10b who
verified that the substitution of optically active tosylate by
trimethylstannylsodium or -lithium occurred with complete
inversion of configuration by an SN2 pattern, as shown in
Scheme 7.
Next, we tried to synthesize an eight-membered compound
by a ring expansion reaction. The starting cyclohexanones cis-
and trans-17 were prepared by reduction of cyclohexadione
derivative 6 with NaBH4 followed by mesylation (Scheme 8).
The stereochemistry was determined by the NOE experiments
on cis- and trans-17a (Figure 2), and we designated cis and
trans as the relative positions of the mesylate and the side chain
containing the vinyl iodide. In the case of the reduction of 6b
with NaBH4, only a small amount of trans-16b was obtained
(Table 2, run 2). Thus, cis-16b was converted into trans-16b
using Mitsunobu’s reaction (Scheme 9).11
1
The H NMR spectra of cis-18a at room temperature showed
broad peaks, but those of trans-18a appeared as sharp signals.
The result of a lower-temperature experiment (-50 °C) con-
ducted on cis-18 indicates that these peaks are clearly sharp
(1H NMR spectra are contained in Supporting Information).
The reactions of various cyclohexanone derivatives 17 with
Me3SiSnBu3 and CsF were examined. When cis-17b was treated
with Me3SiSnBu3 (3 equiv) and CsF (3 equiv) in DMF in a
similar manner, cis-18b and cis-19b were obtained in 9% and
49% yields, respectively. In a similar treatment of trans-17b
with Me3SiSnBu3 and CsF, trans-18b was obtained as a main
product (run 7). Both cis-17c and trans-17c were reacted with
Me3SiSnBu3 (2 equiv) and CsF (2 equiv) in DMF to give cis-
18c and trans-18c in yields of 73% and 41%, respectively (runs
8 and 9). In all the reactions of trans-17 with Me3SiSnBu3 and
CsF, no trans-19 was obtained, and cis-19 and trans-18 were
isolated. Although it is not clear at this stage why cis-19a was
obtained from trans-17a (run 4), the reaction is thought to
proceed in a stereospecific manner (runs 3 and 5). When the
leaving group and the cleaving carbon-carbon bond in the
intermediary four-membered compound V generated from cis-
When a DMF solution of cis-17a was stirred in the presence
of Me3SiSnBu3 (3 equiv) and CsF (3 equiv) at room temperature
for 2 h, cis-19a was obtained in 86% yield (Table 3, run 1;
(10) (a) San Filippo, J., Jr.; Silberman, J. J. Am. Chem. Soc. 1982, 104,
2831. (b) Ashby, E. C.; DePriest, R. J. Am. Chem. Soc. 1982, 104, 6144.
(11) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380. (b) Mitsunobu, O. Synthesis 1981, 1.
(12) (a) Ziegler, K.; Wilms, H. Justus Liebigs Ann. Chem. 1950, 567, 1.
(b) Cope, A. C.; Pike, R. I.; Spencer, C. F. J. Am. Chem. Soc. 1953, 75,
3212.

1220 J. Am. Chem. Soc., Vol. 121, No. 6, 1999
Imai et al.
Table 2. Reduction of 6 with NaBH4 Followed by Mesylation
cis-16
trans-16
run
substrate
R1
R2
yield (%)
cis-17 yield (%)
R1
R2
yield (%)
trans-17 yield (%)
1
2
3
6a
6b
6c
Me
H
Me
H
H
30
70
36
90
95
90
Me
H
Me
H
H
67
8
61
87
quant
96
CH2OAc
CH2OAc
Table 3. Reaction of cis- and trans-17 with Me3SiSnBu3 and CsFa
yield (%)b
cis-19
amount of 1
(equiv)
run
substrate
R1
R2
solvent
cis-18
trans-18
1
2
3
4
5
6
7
8
9
cis-17a
cis-17a
cis-17a
trans-17a
trans-17a
cis-17b
trans-17b
cis-17c
Me
Me
Me
Me
Me
H
H
Me
Me
H
H
H
H
H
H
H
3
3
1.5
3
1.5
3
3
2
2
DMF
THFc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
0
70
42
0
0
9
0
73
0
86
0
4
36
0
49
4
0
0
0
1
33
0
32
0
41
CH2OAc
CH2OAc
0
0
trans-17c
a Reaction was carried out at room temperature in DMF. b Isolated yield. c Reaction was carried out at 0 °C.
Scheme 11
Scheme 12
Synthesis of the Optically Active trans-Cyclooctenone
Derivative. It is known that the trans-cyclooctene derivative is
an asymmetric compound,14 and it has attracted interest on
account of its strained structure and conformation. There have
been few reports on its synthesis,15 and reports are even more
scarce with respect to chiral forms.16 Thus, we planned to
prepare (+)- and (-)-trans-18 from (+)- and (-)-trans-17, using
this stannyl anion-promoted stereospecific ring expansion reac-
tion (Scheme 13). For the synthesis of chiral trans-18, we chose
(()-trans-17c as the starting material, and the resolution of (()-
trans-16c was examined.
17a are placed in antiperiplanar positions, the ring opening
reaction is thought to proceed as shown in Scheme 11. On the
other hand, trans-17a would proceed via V′, which satisfies the
antiperiplanar positions required for synchronous fragmentation.8
This mechanism can equally account for nonformation of a ring-
expanded product from trans-12. The bicyclic intermediate VI
formed from cyclopentanone derivative cis-12 gave a ring
expansion product, although the yield was low. However, trans-
isomer 12 did not give the ring expansion product. The C-OMs
bond of intermediate VI′ is not placed at an antiperiplanar
position in relation to the ring junction bond that will be cleaved
if the bicyclic intermediate VI′ is formed. cis-Eight-membered
cyclic compounds occur widely in nature, and cis-18c is thought
to be a key intermediate for the synthesis of precapnelladine,
dactylol, or poitediol.
Various attempts were made to get the optically pure (+)-
or (-)-trans-16, and we were able to separate trans-20 and
(13) Isomerization preferably occurs with trans-18 rather than trans-19;
because trans-19a was never obtained as a product from the reaction
mixture, it was rationalized that, in the presence of an excess amount of
stannyl anions, trans-18a first isomerizes to cis-18a, which then undergoes
a conjugated addition, leading to cis-19a.
(14) (a) Cope, A. C.; Ganelin, C. R.; Johnson, H. W., Jr.; Van Auken,
T. V.; Winkler, J. S. J. Am. Chem. Soc. 1963, 85, 3276. (b) Cope, A. C.;
Mehta, A. S. J. Am. Chem. Soc. 1964, 86, 5626. (c) Cope, A. C.; Pawson,
B. A. J. Am. Chem. Soc. 1965, 87, 3649. (d) Bach, R. D.; Mazur, U.;
Hamama, I.; Lauderback, S. K. Tetrahedron 1963, 28, 1955. (e) Manor, P.
C.; Shoemaker, D. P.; Parkes, P. S. J. Am. Chem. Soc. 1970, 92, 5260.
(15) (a) Coke, J. L.; Cooke, M. P., Jr.; Mourning, M. C. Tetrahedron
Lett. 1968, 18, 2247. (b) Reese, C. B.; Shaw, A. J. Am. Chem. Soc. 1970,
92, 2566. (c) Whitham, G. H.; Wright, M. J. Chem. Soc. (c) 1971, 886. (d)
Prior, M. J.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 1 1986, 683. (e)
Vedejs, E.; Snoble, K. A. J.; Fuchs, P. L. J. Org. Chem. 1973, 38, 3561.
Synthesis by photoisomerization of cis-cyclooctene: (f) Swenton, J. S. J.
Org. Chem. 1969, 34, 3217. (g) Deyrup, J. A.; Betkouski, M. J. Org. Chem.
1972, 37, 3561. (h) Inoue, Y.; Takamuku, S.; Sakurai, H. Synthesis 1977,
111.
To investigate why cis-19 was obtained from trans-17 in the
presence of an excess amount of Me3SiSnBu3 and CsF, trans-
isomer 18a was treated with 3 equiv of Me3SiSnBu3 and CsF
(Scheme 12). As a result, trans-19a and cis-19a were obtained
in 17% and 51% yields, respectively. The former product, trans-
19a, was further treated in a similar manner to give cis-19a in
high yield. These results show that isomerization of trans to
cis occurs, although it is not clear whether the isomerization is
caused by the stannyl anion or radical.13
(16) (a) Corey, E. J.; Shulman, J. I. Tetrahedron Lett. 1968, 33, 3655.
(b) Aratani, T.; Nakanishi, Y.; Nozaki, H. Tetrahedron 1970, 26, 4339. (c)
Newton, P. F.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 1 1979, 3072.

Stereospecific Synthesis of (+)- and (-)-Cyclooctenones
J. Am. Chem. Soc., Vol. 121, No. 6, 1999 1221
Scheme 13. Synthesis of Optically Active
trans-Cyclooctenone
Scheme 16
Scheme 17a
Scheme 14
Scheme 15a
a Conditions: (i) AcOH-THF-H2O, (3:1:1), rt, 5 h. (ii) Ac2O,
DMAP, py, CH2Cl2, rt, 1 h. (iii) (TMSOCH2)2, TMSOTf, CH2Cl2, rt.
(iv) K2CO3, MeOH, rt, 2.5 h. (v) MsCl, Et3N. (vi) FeCl3‚H2O, CH2Cl2,
rt.
be followed by a hydride shift to give ent-17c, as shown in
Scheme 16.
Thus, we changed the synthetic route of trans-17c to avoid
racemization. Namely, the carbonyl group should be protected
until the hydroxy group is converted into the mesyloxy group.
After the separation of the diastereomeric mixture of trans-20
and -20′, we attempted ketalization of trans-20, but it proceeded
in a low yield. However, replacement of the TBDMS group by
an acetyl group gave a good result. That is, desilylation of trans-
20 afforded the primary alcohol trans-22, which was acetylated
to give trans-23 in 98% yield (Scheme 17). The ketalization of
2317 followed by hydrolysis gave (-)-trans-25, which was
monoacetylated to give (-)-trans-26. Then secondary alcohol
was mesylated to give the protecting starting material (-)-trans-
27. The best condition for deketalization was the reaction with
FeCl3‚6H2O in CH2Cl2 at room temperature,18 which resulted
a Conditions: (i) K2CO3, MeOH. (ii) TBAF. (iii) Ac2O/Py. (iv) MsCl,
Et3N. (v) Me3SiSnBu3, CsF.
trans-20′, obtained from (()-trans-16e and (R)-O-acetylman-
delic acid, respectively, by chromatography on silica gel, whose
diastereomeric excesses are 100% (Scheme 14). Each isomer
was converted into trans-17c and trans-17c′, respectively, which
were treated with Me3SiSnBu3 and CsF (Scheme 15). Unfor-
tunately, the [R]D values of (+)-trans-18c and (-)-trans-18c
were low and not the same. Back on the synthetic route, an
examination by HPLC revealed that trans-17c and -17c′ were
almost racemized (37% and 7% ee, respectively), despite the
separation of the diastereomeric pair trans-20 and trans-20′ in
100% de. During the conversion of trans-16 or -16′ to trans-17
or -17′, oxetane VII would be partially formed, and this would
(17) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.

1222 J. Am. Chem. Soc., Vol. 121, No. 6, 1999
Imai et al.
Scheme 18a
a Conditions: (i) (+)-MTPA, DCC, DMAP, CH2Cl2, rt, 3 days, 67%.
(ii) (-)-MTPA, DCC, DMAP, CH2Cl2, rt, 3 days, 48%.
Scheme 19a
Figure 3.
a Conditions: (i) K2CO3, MeOH. (ii) TBAF. (iii) Ac2O/Py. (iv)
Me3SiSnBu3, CsF.
in 97% yield of (+)-trans-17c after 3 h. In a similar manner,
trans-20′ was converted into (-)-trans-17c in high yield. An
HPLC analysis of the final substrate (+)- and (-)-trans 17c
(89% and 87% ee, respectively) indicated that the protection
of the carbonyl group as the ketal before the mesylation step
substantially, but not completely, prevented racemization. The
mechanism for this process is unclear.
The absolute configuration of (-)-trans-26, and consequently
of (+)-trans-17c, was determined as S by the improved
Mosher’s method developed by Kusumi et al.19 utilizing the
MTPA esters of (-)-trans-26 (Scheme 18; Figure 3).
Treatment of (+)-trans-17c and (-)-trans-17c with Me3-
SiSnBu3 and CsF in DMF at room temperature for 3 h gave
(-)-trans-18c and (+)-trans-18c in yields of 30% and 31%,
respectively (Scheme 19). The [R]D values for them are -285.8°
(c 1.17, CHCl3) and +292.7° (c 0.98, CHCl3), respectively).
Their CD spectra, shown in Figure 4, strongly suggest that they
are enantiomeric isomers. Thus, we succeeded in the syntheses
of (+)- and (-)-trans-cyclooctenone derivatives 17c in optically
active forms using a ring expansion reaction with Me3SiSnBu3
and CsF.
In conclusion, a novel synthesis of an eight-membered
compound from cyclohexanone derivatives having vinyl iodide
in a tether was developed by the ring expansion reaction of a
two-carbon unit using the stannyl anion generated from Me3-
SiSnBu3 and CsF. The reaction proceeded in a stereospecific
manner, and cis- and trans-cyclooctenone derivatives were
obtained. It is interesting that the trans-eight-membered ring,
which is the smallest trans-cycloalkene isolable at room
temperature, was obtained under these reaction conditions, and
Figure 4.
that trans-cyclooctene was isomerized to cis-cyclooctene in the
presence of Me3SiSnBu3 and CsF in DMF. It is known that the
trans-cyclooctene derivative is an asymmteric compound. There
have been few reports on its synthesis as a chiral form. We
succeeded in the synthesis of (+)- and (-)-trans-cyclooctenone
derivatives from the corresponding optically active (-)-and (+)-
trans-cyclohexanone derivatives.
Experimental Section
General. All manipulations were performed under an argon atmo-
sphere unless otherwise mentioned. All solvents and reagents were
purified when necessary using standard procedures. Column chroma-
tography was performed on silica gel 60 (70-230 mesh, 60 Å), and
flash chromatography was performed on silica gel 60 (230-400 mesh,
60 Å) using the indicated solvent. Melting points are uncorrected. Flash
column chromatography was performed on silica gel 60 (Merck, 230-
400 mesh) using the identical solvent.
General Procedure for Ring Expansion Reaction. To a solution
of cyclohexanone derivative (1 equiv) and CsF (3 equiv) was added
Me3SiSnBu3 (3 equiv) in DMF at 0 °C, and the solution was stirred at
room temperature for several hours. The reaction was monitored by
TLC. To this solution was added aqueous NH4Cl solution, and the
aqueous layer was extracted with ethyl ether. The organic layer was
washed with brine, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel to give the eight-
membered product.
(18) Sen, S.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrat, J. J. Org.
Chem. 1997, 62, 6684.
(19) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.

Stereospecific Synthesis of (+)- and (-)-Cyclooctenones
J. Am. Chem. Soc., Vol. 121, No. 6, 1999 1223
Ring Expansion to Cyclooctadione. 1,1,6-Trimethyl-4-meth-
ylidene-3,7-cyclooctanedione (7a), 1,1,6-Trimethyl-4-(tributyl-
stannyl)methyl-3,7-cyclooctanedione (8a), and 2,5,5-Trimethyl-2-
(2-propenyl)-1,3-cyclohexanedione (9a). Following the general pro-
cedure for the ring expansion, 165 mg (0.52 mmol) of the diketone
6a, upon reaction with 0.36 mL (1.03 mmol) of Me3SiSnBu3 and 156.5
mg (1.03 mmol) of CsF in 3.5 mL of DMF, afforded, after 2 h of
reaction at room temperature, 39.5 mg (17%) of the Michael adduct
8a, 25 mg (25%) of the dehalogenated product 9a, and 24 mg (24%)
of the R,â-unsaturated cyclooctanedione 7a. These products were
purified by silica gel column chromatography (hexane/EtOAc 20:1, 10:
2 H), 2.05 (s, 3 H), 2.43-2.53 (m, 2 H), 2.55-2.63 (m, 3 H), 2.69-
2.75 (m, 1 H), 2.94 (dd, J ) 4.2, 14.5 Hz, 1 H), 4.87 (d, J ) 5.3 Hz,
2 H), 5.83 (t, J ) 5.3 Hz, 1 H); 13C NMR (CDCl3) δ 15.32, 21.32,
25.13, 37.96, 39.90, 41.20, 49.32, 63.96, 138.32, 139.56, 171.27, 205.07,
214.98; MS m/z 238 (M+), 107,178, 43; EI-HRMS m/z calcd for
C13H18O4 238.1205, found 238.1230. 9d: 34% yield; IR (neat) 2940,
1
2360, 2342, 1736, 1712, 1696 cm-1; H NMR (CDCl3) δ 1.22 (s, 3
H), 1.86-1.97 (m, 2 H), 2.01 (s, 3 H), 2.51 (d, J ) 7.0 Hz, 2 H),
2.58-2.65 (m, 4 H), 4.44 (d, J ) 5.7 Hz, 2 H), 5.51 (ddd, J ) 7.0,
7.0, 15.5 Hz, 1 H), 5.57 (ddd, J ) 5.7, 5.7, 15.5 Hz, 1 H); 13C NMR
(CDCl3) δ 17.36, 20.49, 20.85, 38.25, 39.01, 64.36, 64.84, 128.60,
129.09, 170.62, 209.70; MS m/z 238 (M+), 178, 127, 43; EI-HRMS
m/z calcd for C11H15O2 (M+ - OAc) 179.1072, found 179.1101.
4-Methyl-2-(tributylstannyl)methyl-4-cyclohepten-1-one (13) and
(2S*,3R*)-2-Methyl-2-(2-propenyl)-3-(tributylstannyl)methylcyclo-
pentanone (trans-14). Following the general procedure for the ring
expansion, 84 mg (0.23 mmol) of the cis-substrate 13, upon reaction
with 0.33 mL (0.94 mmol) of Me3SiSnBu3 and 142 mg (0.94 mmol)
of CsF in 1.7 mL of DMF, afforded, after 2 h of reaction at room
temperature, 25 mg (25%) of the Michael adduct 13 and 24 mg (24%)
of the product trans-14. These compounds were purified by preparative
thin-layer chromatography (hexane/EtOAc 20:1). 13: IR (neat) 2956,
1; 8:1 as gradient elution). 7a: IR (neat) 2960, 2928, 2870, 1698 cm-1
;
1H NMR (CDCl3) δ 0.98 (s, 3 H), 1.09 (s, 3 H), 1.13 (s, 3 H), 2.25 (d,
J ) 12.3 Hz, 1 H), 2.37 (d, J ) 11.7 Hz, 1 H), 2.45 (dd, J ) 9.4, 14.3
Hz, 1 H), 2.48 (d, J ) 12.3 Hz, 1 H), 2.54 (d, J ) 11.7 Hz, 1 H),
2.62-2.65 (m, 1 H), 2.86 (dd, J ) 4.3, 14.3 Hz, 1 H), 5.37 (br s, 1 H),
6.12 (d, J ) 1.7 Hz, 1 H); 13C NMR (CDCl3) δ 15.63, 29.32, 29.81,
34.92, 36.79, 50.48, 50.72, 50.87, 126.35, 145.19, 200.68, 212.40; MS
m/z 194 (M+), 179, 166, 110, 95, 83, 67; EI-HRMS m/z calcd for
C12H18O2 194.1307, found 194.1307. 8a: IR (neat) 2956, 2924, 2870,
1702 cm-1; H NMR (CDCl3) δ 0.76 (dd, J ) 9.4, 12.9 Hz, 1 H),
1
0.82-0.90 (m, 15 H), 0.97 (dd, J ) 6.0, 12.9 Hz, 1 H), 1.07 (d, J )
6.9 Hz, 3 H), 1.12 (s, 3 H), 1.14 (s, 3 H), 1.27-1.32 (m, 6 H), 1.43-
1.48 (m, 6 H), 2.02 (ddd, J ) 3.3, 6.8, 15.1 Hz, 1 H), 2.13 (d, J )
11.7 Hz, 1 H), 2.22 (d, J ) 11.7 Hz, 1 H), 2.30 (ddd, J ) 3.6, 10.1,
15.1 Hz, 1 H), 2.53 (d, J ) 11.7 Hz, 1 H), 2.56-2.61 (m, 2 H), 2.62
(d, J ) 11.7 Hz, 1 H);13C NMR (CDCl3) δ 9.52, 12.22, 13.62, 14.79,
27.33, 28.24, 29.01, 31.66, 35.80, 36.42, 46.48, 48.25, 49.33, 50.04,
211.73, 212.63; 119Sn NMR (CDCl3) δ -7.7; MS m/z 486 (M+), 429,
251, 177; EI-HRMS m/z calcd for C24H46O2Sn 486.2520, found
1
2924, 1732 cm-1; H NMR (CDCl3) δ 0.68-0.83 (m, 7 H), 0.87-
0.92 (m, 9 H), 1.00-1.05 (m, 1 H), 1.28-1.32 (m, 6 H), 1.43-1.50
(m, 6 H), 1.73 (s, 3 H), 2.15-2.17 (m, 3 H), 2.43-2.48 (m, 2 H),
2.67-2.68 (m, 1 H), 3.01-3.13 (m, 1 H), 5.53-5.54 (m, 1 H). 13C
NMR (CDCl3) δ 9.74, 12.04, 13.73, 23.77, 26.31, 27.46, 29.24, 41.08,
41.93, 48.03, 123.37, 136.86, 215.52; 119Sn NMR (CDCl3) δ -12.449;
MS m/z 428 (M+), 403, 387, 289; EI-HRMS m/z calcd for C17H31-
OSn 371.1397, found 371.1412. trans-14: IR (neat) 2956, 2926, 1734,
486.2542. 9a: IR (neat) 2956, 2928, 1726, 1696 cm-1 1H NMR
;
1
1638 cm-1; H NMR (CDCl3) δ 0.89-0.94 (m, 15 H), 1.02 (s, 3 H),
(CDCl3) δ 0.90 (s, 3 H), 1.05 (s, 3 H), 1.22 (s, 3 H), 2.47 (d, J ) 6.2
Hz, 2 H), 2.49 (d, J ) 14.6 Hz, 2 H), 2.63 (d, J ) 14.6 Hz, 2 H),
5.05-5.09 (m, 2 H), 5.54-5.62 (m, 1 H); 13C NMR (CDCl3) δ 27.43,
27.94, 29.24, 30.62, 41.51, 51.66, 64.25, 119.29, 132.02, 209.45; MS
m/z 194 (M+), 149, 110, 83; EI-HRMS m/z calcd for C12H18O2
194.1307, found 194.1300.
1.30-1.37 (m, 6 H), 1.47-1.53 (m, 6 H), 1.66 (dd, J ) 7.7, 12.1 Hz,
1 H), 1.85 (dd, J ) 7.7, 13.8 Hz, 1 H), 1.91-2.07 (m, 2 H), 2.14-
2.22 (m, 1 H), 2.30 (dd, J ) 6.9, 14.0 Hz, 1 H), 2.35 (ddd, J ) 2.8,
7.7, 19.1 Hz, 1 H), 4.96-5.05 (m, 2 H), 5.67-5.75 (m, 1 H); 13C NMR
(CDCl3) δ 9.43, 13.64, 21.43, 23.25, 27.51, 29.28, 37.71, 37.88, 41.97,
51.90, 117.60, 133.98, 221.76; 119Sn NMR (CDCl3) δ -21.204; MS
m/z 371 (M+ - Bu), 177, 84; EI-HRMS m/z calcd for C18H35OSn
(M+- allyl) 387.1710, found 387.1708.
4-Methyl-2-methylidene-1,5-cyclooctanedione (7b), 4-Methyl-2-
(tributylstannyl)methyl-1,5-cyclooctanedione (8b), and 2-Methyl-
2-(2-propenyl)-1,3-cyclohexanedione (9b). 7b: 39% yield; IR (neat)
2928, 1698 cm-1; 1H NMR (CDCl3) δ 1.09 (d, J ) 6.8 Hz, 3 H), 1.91-
2.11 (m, 3 H), 2.42-2.77 (m, 5 H), 3.00 (ddd, J ) 0.8, 4.3, 14.0 Hz,
1 H), 5.33 (br s, 1 H), 6.02 (d, J ) 1.6 Hz, 1 H); MS m/z 166 (M+),
127; EI-HRMS m/z calcd for C10H14O2 166.2188, found 166.2190.
(2S*,3S*)-2-Methyl-2-(2-propenyl)-3-(tributylstannyl)methylcy-
clopentanone (cis-14). Following the general procedure for the ring
expansion, 119 mg (0.33 mmol) of the trans-12, upon reaction with
0.46 mL (1.33 mmol) of Me3SiSnBu3 and 202 mg (1.33 mmol) of CsF
in 2.4 mL of DMF, afforded, after 2 h of reaction at room temperature,
72.2 mg (51%) of cis-14. This compound was purified by flash column
chromatography (hexane/EtOAc 30:1, 10:1, 3:1 as gradient elution):
1
8b: 3% yield; IR (neat) 2956, 2926, 1706 cm-1; H NMR (CDCl3) δ
0.75-1.05 (m, 18 H), 1.07 (d, J ) 6.8 Hz, 3 H), 1.25-1.58 (m, 13 H),
1.90-2.10 (m, 2 H), 2.15-2.28 (m, 1 H), 2.32-2.50 (m, 2 H), 2.55-
2.75 (m, 3 H); 13C NMR (CDCl3) δ 9.54, 11.71, 13.65, 14.97, 25.41,
27.57, 29.12, 36.97, 38.24, 39.14, 45.06, 47.89, 214.62, 215.56; MS
m/z 458 (M+), 401, 251, 235, 177; EI-HRMS m/z calcd for C22H42O2-
Sn 458.2187, found 458.2197. 9b: 33% yield; IR (neat) 3734, 2964,
1726, 1696 cm-1; 1H NMR (CDCl3) δ 1.24 (s, 3 H), 1.79-2.08 (m, 2
H), 2.52 (br d, 2 H), 2.62-2.67 (m, 4 H), 5.06 (br d, 2 H), 5.49-5.65
(m, 1 H); 13C NMR (CDCl3) δ 17.44, 19.49, 38.12, 41.22, 65.12, 119.09,
132.20, 209.75; MS m/z 166 (M+), 127; EI-HRMS m/z calcd for
C10H14O2 166.2188, found 166.2180.
1
IR (neat) 2956, 2926, 1736, 1638 cm-1; H NMR (CDCl3) δ 0.87-
0.92 (m, 15 H), 0.96 (s, 3 H), 1.29-1.37 (m, 6 H), 1.46-1.52 (m, 6
H), 1.86-1.95 (m, 2 H), 2.01 (dd, J ) 8.7, 13.9 Hz, 1 H), 2.03-2.09
(m, 2 H), 2.35 (dd, J ) 6.9, 13.8 Hz, 1 H), 2.45 (dd, J ) 6.1, 13.7 Hz,
1 H), 4.98-5.04 (m, 2 H), 5.56-5.64 (m, 1 H); 13C NMR (CDCl3) δ
9.37, 13.62, 23.96, 24.08, 27.52, 29.29, 32.63, 39.48, 41.61, 51.95,
117.84, 134.73, 222.93; 119Sn NMR (CDCl3) δ -21.352; MS m/z 371
(M+ - Bu), 291, 235, 177, 121; EI-HRMS m/z calcd for C18H35OSn
(M+ - allyl) 387.1710, found 387.1682.
Ring Expansion to Cyclooctenone. (Z)-1,1,6-Trimethyl-4-meth-
ylidene-6-cyclooten-3-one (cis-18a): IR (neat) 2958, 2930, 2866, 1688
cm-1; 1H NMR (CDCl3, 400 MHz) (-50 °C) δ 0.95 (s, 3 H), 1.04 (s,
3 H), 1.70 (s, 3 H), 1.79 (dd, J ) 8.3, 13.7 Hz, 1 H), 2.34 (d, J ) 11.2
Hz, 1 H), 2.43 (dd, J ) 7.8, 13.7 Hz, 1 H), 2.68 (d, J ) 12.7 Hz, 1 H),
3.58 (d, J ) 14.7 Hz, 2 H), 5.16 (s, 1 H), 5.42 (t, J ) 8.1 Hz, 1 H),
5.69 (d, J ) 1.0 Hz, 1 H); 13C NMR (CDCl3, 100 MHz ) δ 205.78,
148.26, 136.43, 123.41, 120.17, 53.24, 39.80, 38.95, 37.35, 32.17, 25.07,
23.36; MS m/z 178 (M+), 163, 122, 94, 79; EI-HRMS m/z calcd for
C12H18O 178.1358, found 178.1372.
(Z)-1,1,6-Trimethyl-4-acetoxyethylidene-3,5-cyclooctanedione (7c):
1
38% yield; IR (neat) 2962, 2936, 1738, 1702, 1678 cm-1; H NMR
(CDCl3) δ 1.04 (s, 3 H), 1.08 (d, J ) 6.7 Hz, 3 H), 1.13 (s, 3 H), 2.07
(s, 3 H), 2.27 (d, J ) 12.1 Hz, 1 H), 2.34 (d, J ) 11.7 Hz, 1H), 2.41
(dd, J ) 9.4, 14.4 Hz, 1 H), 2.52 (d, J ) 11.7 Hz, 1 H), 2.55 (d, J )
12.1 Hz, 1 H), 2.61-2.67 (m, 1 H), 2.78 (dd, J ) 4.2, 14.4 Hz, 1 H),
4.93 (dd, J ) 4.6, 17.3 Hz, 1 H), 4.95 (dd, J ) 5.6, 17.3 Hz, 1 H),
5.93 (br t, J ) 5.2 Hz, 1 H); 13C NMR (CDCl3) δ 15.61, 20.93, 29.41,
29.92, 34.97, 37.83, 50.83, 50.86, 51.89, 63.94, 137.76, 141.29, 170.85,
202.11, 212.42; FAB-MS m/z 267 (M+ + 1), 207, 154, 136; FAB-
HRMS m/z calcd for C15H23O4 (M+ + 1) 267.1596, found 267.1567.
(Z)-4-Methyl-2-acetoxyethylidene-1,5-cyclooctanedione (7d) and
(E)-2-Methyl-2-[(4-acetoxy)-2-butenyl]-1,3-cyclohexanedione (9d).
7d: 58% yield; IR (neat) 2968, 2934, 2872, 1740, 1704, 1680, 1232
(Z)-1,1,6-Trimethyl-4-(tributylstannyl)methyl-6-cyclooten-3-
one (cis-19a). IR (neat) 2954, 2924, 2870, 2852, 1698 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 0.80-0.91 (m, 16 H), 0.94 (s, 3 H), 0.97 (dd, J
) 5.9, 12.8 Hz, 1 H), 1.03 (s, 3 H), 1.27-1.32 (m, 6 H), 1.43-1.48
(m, 6 H), 1.74 (dd, J ) 9.1, 13.1 Hz, 1 H), 1.74 (s, 3 H), 1.83 (br d,
J ) 12.1 Hz, 1 H), 1.92 (d, J ) 13.4 Hz, 1 H), 2.13 (dd, J ) 9.1, 13.1
1
cm-1; H NMR (CDCl3) δ 1.06 (d, J ) 6.6 Hz, 3 H), 1.95-2.02 (m,

1224 J. Am. Chem. Soc., Vol. 121, No. 6, 1999
Imai et al.
Hz, 1 H), 2.54 (d, J ) 12.1 Hz, 1 H), 2.58 (d, J ) 13.4 Hz, 1 H),
2.65-2.71 (m, 1 H), 5.34 (br t, J ) 8.1 Hz, 1 H); 13C NMR (CDCl3,
125 MHz) δ 8.26, 9.49, 10.77, 12.62, 13.62, 24.00, 27.56, 28.99, 36.52,
37.05, 40.76, 49.68, 53.76, 123.56, 137.79, 214.42; 119Sn NMR (CDCl3,
100.55 MHz) δ -9.3; MS m/z 470 (M+), 413, 251, 235, 177, 161;
EI-HRMS m/z calcd for C24H46OSn 470.2571, found 470.2562.
(E)-1,1,6-Trimethyl-4-methylidene-6-cyclooten-3-one (trans-18a):
mixture and purification by preparative thin-layer chromatography
(hexane/Et2O 50:1), 6.2 mg (17%) of the trans-19a was isolated,
together with 19.0 mg (51%) of the isomerized cis-19a. trans-19a: IR
1
(neat) 2932, 1738, 1684, 1232 cm-1; H NMR (CDCl3, 500 MHz) δ
0.78 (t, J ) 8.2 Hz, 6 H), 0.82 (dd, J ) 6.8, 13.1 Hz, 1 H), 0.89 (t, J
) 7.3 Hz, 9 H), 0.99 (s, 3 H), 1.02 (dd, J ) 8.0, 13.1 Hz, 1 H), 1.13
(s, 3 H), 1.25-1.33 (m, 6 H), 1.42-1.47 (m, 6 H), 1.60 (d, J ) 12.6
Hz, 1 H), 1.85 (dd, J ) 3.4, 12.5 Hz, 1 H), 1.97 (d, J ) 1.0 Hz, 3 H),
2.18 (dd, J ) 12.5, 12.5 Hz, 1 H), 2.23 (d, J ) 12.6 Hz, 1 H), 2.33
(dd, J ) 5.0, 11.8 Hz, 1 H), 2.48 (dd, J ) 11.8 Hz, 1 H), 3.14-3.21
(m, 1 H), 5.19 (br d, J ) 11.3 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 1.02, 9.41, 10.97, 13.74, 18.11, 26.37, 27.43, 29.20, 33.35, 40.78,
41.81, 51.91, 54.29, 125.85, 137.18, 217.34; 119Sn NMR (CDCl3, 100.55
MHz) δ -12.0; MS m/z 413 (M+ - Bu), 235, 177, 161; EI-HRMS
m/z calcd for C20H37OSn (M+ - Bu) 413.1867, found 413.1888.
The isolated Michael adduct trans-19a (100 mg, 0.21 mmol) reacted
further with 0.22 mL (0.64 mmol) of Me3SiSnBu3 and 97 mg of CsF
(0.64 mmol) in 1.9 mL of DMF. After 7 h of reaction time at room
temperature, 95 mg of a mixture of trans-19a and cis-19a was obtained,
1
IR (neat) 2956, 2932, 2870, 1722, 1684 cm-1; H NMR (CDCl3, 500
MHz) δ 1.02 (s, 3 H), 1.11 (s, 3 H), 1.74 (d, J ) 12.1 Hz, 1 H), 1.88
(s, 3 H), 1.86-1.89 (m, 1 H), 2.23 (dd, J ) 12.6 Hz, 1 H), 2.30 (dd,
J ) 12.6, 12.6 Hz, 1 H), 2.81 (d, J ) 12.7 Hz, 1 H), 3.48 (br d, J )
12.7 Hz, 1 H), 4.69 (d, J ) 2.3 Hz, 1 H), 4.79 (d, J ) 2.3 Hz, 1 H),
5.39 (ddd, J ) 1.5, 1.5, 12.6 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 211.66, 156.91, 135.04, 128.02, 110.36, 53.50, 48.76, 43.83, 42.17,
33.21, 26.09, 17.49; MS m/z 178 (M+), 163, 149, 122, 94, 79; EI-
HRMS m/z calcd for C12H18O 178.1358, found 178.1353.
(Z)-4-Methyl-2-methylidene-4-cycloocten-1-one (cis-18b): IR (neat)
2932, 2856, 1690, 1616 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.63 (br
s, 3 H), 1.69-1.78 (m, 2 H), 2.21-2.25 (m, 2 H), 2.60-2.62 (m, 2
H), 3.12 (s, 2 H), 5.06 (d, J ) 1.5 Hz, 1 H), 5.46 (ddd, J ) 1.0, 8.0,
8.0 Hz, 1 H), 5.58 (d, J ) 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 207.29, 149.42, 136.00, 125.79, 118.51, 42.44, 36.82, 28.63, 27.93,
22.47; MS m/z 150 (M+), 135; EI-HRMS m/z calcd for C10H14O
150.1044, found 150.1040.
1
in the ratio of 1:3.16, determined by H NMR, which corresponds to
76% of isomerization.
Ring Expansion of Chiral (+)-trans-17c. The chiral substrate (+)-
trans-17c (200 mg, 0.42 mmol) reacted with 0.30 mL (0.85 mmol) of
Me3SiSnBu3 and 129 mg (0.85 mmol) of CsF in 3.0 mL of DMF at
room temperature for 2 h and 50 min, resulting in 24.5 mg (31%) of
the cyclooctenone (+)-trans-18c ([R]27D +292.7 (c 0.980, CHCl3), other
spectral data consistent with the racemic cyclooctenone).
(Z)-4-Methyl-2-(tributylstannyl)methyl-4-cycloocten-1-one (cis-
1
19b): IR (neat) 2954, 2926, 2854, 1704 cm-1; H NMR (CDCl3, 500
MHz) δ 0.84-0.92 (m, 16 H), 1.01 (dd, J ) 5.7, 12.9 Hz, 1 H), 1.26-
1.34 (m, 6 H), 1.44-1.55 (m, 7 H), 1.71 (s, 3 H), 1.72-1.78 (m, 1 H),
1.88 (dd, J ) 3.9, 12.9 Hz, 1 H), 2.03-2.11 (m, 2 H), 2.17 (ddd, J )
2.9, 7.4, 11.6 Hz, 1 H), 2.56 (t, J ) 12.9 Hz, 1 H), 2.68-2.74 (m, 1
H), 2.69 (ddd, J ) 3.3, 11.6, 11.6 Hz, 1 H), 5.37 (t, J ) 8.0 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ 216.86, 137.13, 125.32, 53.80, 37.60,
36.99, 29.14, 27.54, 27.37, 26.38, 23.73, 13.64, 11.76, 9.51; 119Sn NMR
(CDCl3, 100.55 MHz) δ -9.3; MS m/z 413 (M+ - Bu), 235, 177,
161; EI-HRMS m/z calcd for C24H46OSn 470.2571, found 470.2562.
(E)-4-Methyl-2-methylidene-4-cycloocten-1-one (trans-18b): IR
Ring Expansion of Chiral (-)-trans-17c. The chiral substrate (-)-
trans-17c (252 mg, 0.53 mmol) reacted with 0.37 mL (1.07 mmol) of
Me3SiSnBu3 and 162 mg (1.07 mmol) of CsF in 3.8 mL of DMF at
room temperature for 2 h and 50 min, resulting in 40 mg (30%) of the
cyclooctenone (-)-trans-18c ([R]28 -285.8 (c 1.170, CHCl3), other
D
spectral data consistent with the racemic cyclooctenone).
(R)-MTPA Ester 28. To a solution of 31.5 mg (71.87 mmol) of the
secondary alcohol 26 in 1 mL of dichloromethane were added 4.4 mg
(35.93 mmol) of DMAP and 24.4 mg (118.58 mmol) of DCC. The
solution was cooled to 0 °C, and 25.2 mg (107.80 mmol) of (+)-MTPA
was added. The mixture was stirred at room temperature for 3 days,
quenched with ammonium chloride, and extracted with ethyl acetate.
The crude product was purified by silica gel column chromatography
(hexane/EtOAc 5:1), and 31 mg (67%) of the (R)-MTPA ester was
1
(neat) 2934, 1690, 1632, 1438 cm-1; H NMR (CDCl3, 500 MHz) δ
1.90 (s, 3 H), 2.09-2.25 (m, 3 H), 2.27-2.36 (m, 2 H), 2.31 (ddd, J
) 5.4, 12.2, 12.2 Hz, 1 H), 2.89 (d, J ) 12.7 Hz, 1 H), 3.52 (br d, J
) 12.7 Hz, 1 H), 4.73 (d, J ) 2.4 Hz, 1 H), 4.85 (d, J ) 2.4 Hz, 1 H),
5.18 (br d, J ) 2.2 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 17.67,
28.77, 31.42, 41.40, 48.94, 108.96, 129.08, 133.74, 156.59, 214.71;
MS m/z 150 (M+), 124, 109, 43; EI-HRMS m/z calcd for C10H14O
150.1044, found 150.1030.
1
isolated: IR (neat) 2988, 1742, 1738 cm-1; H NMR (CDCl3) δ 0.97
(s, 3 H), 1.12 (s, 3 H), 1.25 (s, 3 H), 1.45 (s, 2 H), 1.60 (dd, J ) 11.6,
12.9 Hz, 1 H), 1.75 (dd, J ) 4.6, 12.9 Hz, 1 H), 2.06 (s, 3 H), 2.38 (d,
J ) 14.8 Hz, 1 H), 2.97 (d, J ) 14.8 Hz, 1 H), 3.58 (s, 3 H), 3.79
(ddd, J ) 7.9, 7.9 Hz, 1 H), 3.83 (ddd, J ) 5.4, 7.9, 7.9 Hz, 1 H), 3.92
(ddd, J ) 7.9, 7.9 Hz, 1 H), 4.02 (ddd, J ) 5.4, 7.9, 7.9 Hz, 1 H), 4.54
(dd, J ) 5.8, 13.8 Hz, 1 H), 4.56 (dd, J ) 5.8, 13.8 Hz, 1 H), 5.26 (dd,
J ) 4.6, 11.6 Hz, 1 H), 5.53 (t, J ) 5.8 Hz, 1 H), 7.39-7.41 (m, 3 H),
7.54-7.55 (m, 2 H); 13C NMR (CDCl3) δ 15.71, 20.90, 26.79, 30.20,
33.30, 38.51, 40.69, 46.82, 48.02, 55.56, 62.50, 63.92, 69.27, 78.57,
83.94 (q, J ) 28 Hz), 104.97, 111.95, 123.32 (q, J ) 288 Hz), 127.07,
128.33, 129.52, 132.28, 132.40, 165.56, 170.56; MS m/z 654 (M+),
527, 421, 189; EI-HRMS m/z calcd for C27H34IO7F3 654.1302, found
654.1304.
(4Z,6Z)-1,1,6-Trimethyl-4-acetoxyethylidene-6-cyclooctene-3-
one (cis-18c): IR (neat) 2958, 2932, 1742, 1684, 1232 cm-1; 1H NMR
(CDCl3, 500 MHz) (-50 °C) δ 0.94 (s, 3 H), 1.05 (s, 3 H), 1.68 (s, 3
H), 1.80 (dd, J ) 8.3, 13.7 Hz, 1 H), 2.12 (s, 3 H), 2.30 (d, J ) 11.2
Hz, 1 H), 2.42 (dd, J ) 8.3, 13.7 Hz, 1 H), 2.56 (d, J ) 14.3 Hz, 1 H),
2.65 (d, J ) 11.2 Hz, 1 H), 3.60 (d, J ) 14.3 Hz, 1 H), 4.80 (d, J )
5.4 Hz, 2 H), 5.42 (t, J ) 8.3 Hz, 1 H), 5.66 (t, J ) 5.4 Hz, 1 H); 13
C
NMR (CDCl3, 125 MHz) (-50 °C) δ 205.78, 171.16, 142.26, 136.41,
131.55, 123.65, 62.69, 53.67, 39.85, 39.01, 37.88, 32.33, 25.02, 23.30,
21.16; MS m/z 235 (M+ - Me), 208, 190, 43; HRMS (FAB) m/z calcd
for C15H22O3 (M+ + 1) 251.1647, found 251.1666.
(4Z,6E)-1,1,6-Trimethyl-4-acetoxyethylidene-6-cyclooctene-3-
(S)-MTPA 28. To a solution of 35.3 mg (80.5 mmol) of the
secondary alcohol 26 in 1.2 mL of dichloromethane was added 13.0
mL (35.93 mmol) of pyridine. The solution was cooled to 0 °C, and
22.6 mL (120.80 mmol) of (-)-MTPA-Cl was added. The mixture was
stirred at room temperature for 3 days, quenched with brine, washed
with 10% HCl solution, and extracted with ethyl acetate. The crude
product was purified by silica gel column chromatography (hexane/
EtOAc 5:1), and 25 mg (48%) of the (S)-MTPA ester was isolated:
IR (neat) 2954, 1742 cm-1; 1H NMR (CDCl3) δ 0.94 (s, 3 H), 1.11 (s,
3 H), 1.25 (s, 3 H), 1.44 (s, 2 H), 1.49 (dd, J ) 11.5, 13.0 Hz, 1 H),
1.69 (dd, J ) 4.5, 13.0 Hz, 1 H), 2.04 (s, 3 H), 2.54 (dd, J ) 0.6, 14.8
Hz, 1 H), 3.06 (d, J ) 14.8 Hz, 1 H), 3.50 (s, 3 H), 3.80 (ddd, J ) 7.9
Hz, 1 H), 3.84 (ddd, J ) 5.4, 7.9, 7.9 Hz, 1 H), 3.92 (ddd, J ) 7.9 Hz,
1 H), 4.02 (ddd, J ) 5.4, 7.9, 7.9 Hz, 1 H), 4.57 (dd, J ) 5.8, 13.7 Hz,
1 H), 4.59 (dd, J ) 5.8, 13.7 Hz, 1 H), 5.27 (dd, J ) 4.5, 11.5 Hz, 1
H), 5.66 (t, J ) 5.8 Hz, 1 H), 7.42-7.43 (m, 3 H), 7.52-7.54 (m, 2
1
one (trans-18c): IR (neat) 2956, 2934, 1742, 1684, 1232 cm-1; H
NMR (CDCl3, 500 MHz) δ 1.03 (s, 3 H), 1.12 (s, 3 H), 1.78 (d, J )
12.3 Hz, 1 H), 1.86 (s, 3 H), 1.87 (dd, J ) 3.5, 12.6 Hz, 1 H), 2.02 (s,
3 H), 2.21 (dd, J ) 12.6 Hz, 1 H), 2.34 (d, J ) 12.3 Hz, 1 H), 2.76 (d,
J ) 12.4 Hz, 1 H), 3.46 (br d, J ) 12.4 Hz, 1 H), 4.31 (ddd, J ) 2.1,
6.0, 13.1 Hz, 1 H), 4.37 (ddd, J ) 0.9, 8.1, 13.1 Hz, 1 H), 5.28 (ddd,
J ) 2.1, 6.0, 8.0 Hz, 1 H), 5.36 (br d, J ) 12.6 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 211.12, 170.55, 151.37, 134.39, 127.88, 118.49,
61.24, 53.74, 49.10, 43.25, 41.63, 32.92, 25.95, 20.80, 17.11; MS m/z
250 (M+), 235, 208, 190, 152, 137, 107, 91, 43; EI-HRMS m/z calcd
for C15H22O3 250.1569, found 250.1586.
Isomerization of trans-Cyclooctenone to cis-Cyclooctenone. The
trans-cyclooctenone 18a (14.5 mg, 0.08 mmol) reacted with 80 mL
(0.24 mmol) of silylstannane and 36.5 mg (0.24 mmol) of CsF in 0.5
mL of DMF at room temperature for 6.5 h. After workup of the reaction

Stereospecific Synthesis of (+)- and (-)-Cyclooctenones
J. Am. Chem. Soc., Vol. 121, No. 6, 1999 1225
H); 13C NMR (CDCl3) δ 15.87, 20.89, 26.93, 30.13, 33.19, 38.15, 40.69,
46.75, 48.40, 55.31, 62.57, 63.91, 69.28, 78.82, 84.75 (q, J ) 27 Hz),
104.92, 112.04, 120.43 (q, J ) 288 Hz), 127.56, 128.44, 129.57, 131.65,
132.54, 165.78, 170.59; MS m/z 654 (M+), 527, 421, 189; EI-HRMS
m/z calcd for C27H34IO7F3 654.1302, found 654.1282.
cis- and trans-16a-e, 17a-c, (2R,3S)- and (2S,3R)-20-27 and
(+)- and (-)-17c; 1H NMR spectra for cis-18a and trans-18a,
and cis-18a at -50 °C. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental proce-
dures for the synthesis of 6a-d, 10, cis- and trans-11 and -12,
JA983168H