Total synthesis of (-)-coriolin

Article abstract of DOI:10.1021/jo981478c

An efficient synthetic method for (-)-coriolin has been developed on the basis of a [3+2] cycloaddition reaction of a 1-(methylthio)-2-siloxyallyl cationic species and vinylsulfides. An enantiomerically pure C-ring unit was prepared through optical resolution of five-membered allyl ester 6b using a lipase. The first [3+2] cycloaddition reaction of C-ring unit (S)-7 gave bicyclic ketones 8 and 9, which were easily converted into vinyl sulfide 11. Stereoselective construction of the A-ring was achieved by the second [3+2] cycloaddition reaction of the BC-ring unit. New methods for introduction of the oxygen functional groups to the triquinane skeleton were also developed for the last stages of the total synthesis. Thus, the C7 hydroxyl group was introduced by epoxidation of dienol silyl ether 17, and stereocontrolled construction of the spiro epoxide moiety was accomplished on the basis of a Darzens-type reaction.

Full text of DOI:10.1021/jo981478c

2648
J . Org. Chem. 1999, 64, 2648-2656
Tota l Syn th esis of (-)-Cor iolin
Hajime Mizuno, Kei Domon, Keiichi Masuya, Keiji Tanino,* and Isao Kuwajima*,†
Department of Chemistry, Tokyo Institute of Technology, Meguro, Tokyo 152-8551, J apan
Received J uly 27, 1998
An efficient synthetic method for (-)-coriolin has been developed on the basis of a [3+2] cycloaddition
reaction of a 1-(methylthio)-2-siloxyallyl cationic species and vinylsulfides. An enantiomerically
pure C-ring unit was prepared through optical resolution of five-membered allyl ester 6b using a
lipase. The first [3+2] cycloaddition reaction of C-ring unit (S)-7 gave bicyclic ketones 8 and 9,
which were easily converted into vinyl sulfide 11. Stereoselective construction of the A-ring was
achieved by the second [3+2] cycloaddition reaction of the BC-ring unit. New methods for
introduction of the oxygen functional groups to the triquinane skeleton were also developed for the
last stages of the total synthesis. Thus, the C7 hydroxyl group was introduced by epoxidation of
dienol silyl ether 17, and stereocontrolled construction of the spiro epoxide moiety was accomplished
on the basis of a Darzens-type reaction.
In tr od u ction
Cyclopentanoid compounds are found in a wide range
of natural products,1 and various kinds of synthetic
methods have been explored.2 While intramolecular ring
closure of an acyclic compound is generally applicable to
cyclopentane synthesis, a [3+2] cycloaddition approach
which produces two C-C bonds in one stage is advanta-
geous from the viewpoint of efficiency.3 We recently
reported a new synthetic method for functionalized
cyclopentanones on the basis of a [3+2] cycloaddition
reaction of a 1-(methylthio)-2-siloxyallyl cationic species
and olefins (eq 1).4 The wide range of applicability as
well as the high selectivities of this transformation led
us to develop a straightforward methodology for con-
structing triquinane skeletons. To this end coriolin,5
which has attracted much attention due to its highly
functionalized, unique carbon framework as well as
F igu r e 1. Straightforward methodology for constructing a
triquinane skeleton via sequential [3+2] cycloaddition reac-
tions.
important biological activities, was chosen as the syn-
thetic target (Figure 1).6-8
† Present address: The Kitasato Institute, 5-9-1 Shirokane, Minato-
ku, Tokyo 108-8642, J apan.
(1) For reviews, see: (a) Cyclopentanoid Terpene Derivatives; Taylor,
W. I., Battersby, A. R., Eds.; M. Dekker: New York, 1969. (b) Paquette,
L. A. Top. Curr. Chem. 1984, 119, 1. (c) Paquette, L. A.; Doherty, A.
M. Polyquinane Chemistry: Synthesis and Reactions; Springer-Ver-
lag: Berlin, 1987. (d) Hudlicky, T.; Rulin, F.; Lovelace, T. C.; Reed, J .
W. In Studies in Natural Products Chemistry; Atta-ur Rahman, Ed.;
Elsevier: Oxford, 1989; Vol. 3, Part B, pp 3-72. (e) Mehta, G.;
Srikrishna, A. Chem. Rev. 1997, 97, 671.
The synthetic plan of coriolin was made up of two
stages, that is, (I) stereocontrolled synthesis of the known
intermediate E via sequential [3+2] cycloaddition reac-
tions, and (II) stereoselective introduction of the oxygen
functionalities. For stage I, a synthetic route starting
(2) For reviews of cyclopentane synthesis, see: (a) Ramaiah, M.
Synthesis 1984, 529. (b) Hudlicky, T.; Price, J . D. Chem. Rev. 1989,
89, 1467.
(3) For reviews of [3+2] cycloaddition reactions, see: (a) Little, R.
D. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, Chapter 3.1, pp 239-270. (b) Chan,
D. M. T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 5, Chapter 3.2, pp 271-314.
(4) (a) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. Synlett
1996, 157. (b) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J . Am.
Chem. Soc. 1998, 120, 1724. Similar methylenecyclopentane annulation
could also be effected by using the substrate having a TMS-methyl
group in place of the siloxy group of 1b. Takahashi, Y.; Tanino, K.;
Kuwajima, I. Tetrahedron Lett. 1996, 37, 5943.
(5) Isolation and characterization of coriolin: (a) Takeuchi, T.;
Iinuma, H.; Iwanaga, J .; Takahashi, S.; Takita, T.; Umezawa, H. J .
Antibiot. 1969, 22, 215. (b) Nakamura, H.; Takita, T.; Umezawa, H.;
Kunishima, M.; Nakayama, Y. J . Antibiot. 1974, 27, 301. (c) Nishimura,
Y.; Koyama, Y.; Umezawa, S.; Takeuchi, T.; Ishizuka, M.; Umezawa,
H. J . Antibiot. 1980, 33, 404 and references therein.
(6) For a review of total synthesis of coriolin: Mulzer, J . In Organic
Synthesis Highlights; Mulzer, J ., Altenbach, H.-J ., Braun, M., Krohn,
K., Reissig, H.-U., Eds.; VCH: Weinheim, 1991; pp 323-334.
(7) Fomal total synthesis of (()-coriolin which were not covered in
ref 6: (a) Hijfte, L. V.; Little, R. D. J . Org. Chem. 1985, 50, 3940. (b)
Funk, R. L.; Bolton, G. L.; Daggett, J . U.; Hansen, M. M.; Horcher, L.
H. M. Tetrahedron 1985, 41, 3479. (c) Magnus, P.; Exon, C.; Albaugh-
Robertson, P. Tetrahedron 1985, 41, 5861. (d) Mehta, G.; Murthy, A.
N.; Reddy, D. S.; Reddy, A. V. J . Am. Chem. Soc. 1986, 108, 3443. (e)
Wender, P. A.; Correia, C. R. D. J . Am. Chem. Soc. 1987, 109, 2523.
(f) Hijfte, L. V.; Little, R. D.; Petersen, J . L.; Moeller, K. D. J . Org.
Chem. 1987, 52, 4647. (g) Singh, V.; Samanta, B. Tetrahedron Lett.
1999, 40, 383.
(8) Total synthesis of (-)-coriolin which was not covered in ref 6:
Weinges, K.; Braun, R.; Huber-Patz, U.; Irngartinger, H. Liebigs Ann.
Chem. 1993, 1133.
10.1021/jo981478c CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999

Total Synthesis of (-)-Coriolin
J . Org. Chem., Vol. 64, No. 8, 1999 2649
Sch em e 1. Design of a Ster eocon tr olled
Tr iqu in a n e Syn th esis
Sch em e 3. P r ep a r a tion of th e C-Rin g Un it
cant amounts of the parent R,â-unsaturated ketone F
(Scheme 2). On the other hand, steps ii and iii have
usually been performed in one pot through epoxidation
of the corresponding dienone J (eq 2).8,9a,c,11 While com-
plete stereoselection has been achieved for step ii, ste-
reocontrol in step iii has been notoriously difficult.9c
Therefore, we also explored new methods for introduction
of the oxygen functional groups with improved chemical
yields as well as high stereoselectivities.12
Sch em e 2. Con ven tion a l Meth od s for
In tr od u cin g 7-OH Gr ou p
Resu lts a n d Discu ssion
A. P r ep a r a tion of th e Op tica lly P u r e C-Rin g Un it.
The cyclopentene framework of the C-ring unit was
constructed as shown in Scheme 3. The reaction of nitrile
2, which was prepared by alkylation of isobutyronitrile,13
with (methylthio)methyllithium followed by acetic acid
yielded ketone 3. Successive treatment of ketone 3 with
sulfuric acid and an aqueous NaOH solution gave cyclo-
pentenone 4 via intramolecular aldol condensation of the
corresponding keto aldehyde. Since initial attempts for
asymmetric reduction of enone 4 by using several chiral
borane reagents were fruitless,14 we explored enzymatic
optical resolution15 of racemic alcohol 5.
Although the reaction of acetate 6a with Lipase PS in
a buffer solution was found to be extremely sluggish,
chloroacetate 6b underwent smooth hydrolysis to give
alcohol (S)-5 (95% ee) in 46% yield along with 51%
recovery of (R)-6b. Finally, (S)-5 was obtained in enan-
tiomerically pure form after repetition of a similar
procedure starting from (S)-5 in 95% ee (Scheme 4). The
enantiomeric purity of (S)-5 was determined by Mosher’s
method,16 and the absolute configuration was confirmed
by X-ray crystallographic analysis.17
from optically active cyclopentene derivative A was
designed as shown in Scheme 1. Since the re-face of A is
shielded by the alkoxy group, the [3+2] cycloaddition
reaction with 1a gives bicyclic ketone B stereoselectively.
In the second [3+2] cycloaddition step, three-carbon unit
1b is introduced to bicyclic olefin C from the convex face
to yield D, which has the triquinane skeleton with the
correct configuration.
For stage II, the following transformations are re-
quired: (i) stereoselective introduction of the C7 hydroxyl
group, (ii) epoxidation of the C5-C6 double bond, and
(iii) stereoselective construction of the spiro epoxide
moiety. Although several groups have already finished
total synthesis of coriolin through these transformations,
there still remain problems from the viewpoint of ef-
ficiency. Thus, epoxidation of either â,γ-unsaturated
ketone G7c,9 or dienol acetate H10 has always been
adopted for step i, despite the fact that preparation of
these intermediates suffers from the recovery of signifi-
(9) (a) Danishefsky, S.; Zamboni, R.; Kahn, M.; Etheredge, S. J . J .
Am. Chem. Soc. 1980, 102, 2097. (b) Shibasaki, M.; Iseki, K.; Ikegami,
S. Tetrahedron Lett. 1980, 21, 3587. (c) Danishefsky, S.; Zamboni, R.;
Kahn, M.; Etheredge, S. J . J . Am. Chem. Soc. 1981, 103, 3460. (d)
Trost, B. M.; Curran, D. P. J . Am. Chem. Soc. 1981, 103, 7380. (e)
Iseki, K.; Yamazaki, M.; Shibasaki, M.; Ikegami, S. Tetrahedron 1981,
37, 4411. (f) Exon, C.; Magnus, P. J . Am. Chem. Soc. 1983, 105, 2477.
(g) Schuda, P. F.; Heimann, P. R. Tetrahedron 1984, 40, 2365.
(10) (a) Ito, T.; Tomiyoshi, N.; Nakamura, K.; Azuma, S.; Izawa, M.;
Maruyama, F.; Yanagiya, M.; Shirahama, H.; Matsumoto, T. Tetra-
hedron Lett. 1982, 23, 1721. (b) Ito, T.; Tomiyoshi, N.; Nakamura, K.;
Azuma, S.; Izawa, M.; Maruyama, F.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. Tetrahedron 1984, 40, 241. (c) Demuth, M.; Ritter-
skamp, P.; Schaffner, K. Helv. Chim. Acta 1984, 67, 2023. (d) Demuth,
M.; Ritterskamp, P.; Weigt, E.; Schaffner, K. J . Am. Chem. Soc. 1986,
108, 4149.
B. Con str u ction of th e Tr iqu in a n e Sk eleton via
[3+2] Cycloa d d ition Rea ction s. Next, the triquinane
(11) (a) Tatsuta, K.; Akimoto, K.; Kinoshita, M. J . Antibiotics 1980,
33, 100. (b) Tatsuta, K.; Akimoto, K.; Kinoshita, M. Tetrahedron 1981,
37, 4365.
(12) For a preliminary report of a part of this work, see: Domon,
K.; Masuya, K.; Tanino, K.; Kuwajima, I. Tetrahedron Lett. 1997, 38,
465.
(13) Larcheveˆque, M.; Cuvigny, T. Tetrahedron Lett. 1975, 3851.
(14) Singh, V. K. Synthesis 1992, 605.
(15) For a recent review, see: Santaniello, E.; Ferraboschi, P. In
Advances in Asymmetric Synthesis; Hassner, A., Ed.; J AI Press:
Greenwich, 1997; Vol. 2, pp 237-283, and references therein.

2650 J . Org. Chem., Vol. 64, No. 8, 1999
Mizuno et al.
Sch em e 4. Op tica l Resolu tion of Ester 6 by Usin g
Lip a se
Sch em e 6
Sch em e 5. Con str u ction of th e A- a n d B-Rin g by
[3+2] Cycloa d d ition Rea ction s
To set the stage for the second [3+2] annulation
reaction, it was required to convert ketone 10 into vinyl
sulfide 11 having a fully substituted carbon-carbon
double bond. Fortunately, combined use of ethanethiol
and chlorotrimethylsilane, which was reported to be
useful for dithioacetal synthesis,21 afforded the desired
vinyl sulfide 11 directly. The absence of the corresponding
regioisomer of the double bond suggests that the reaction
proceeded under thermodynamic control. In the presence
of 1b and EtAlCl2, vinyl sulfide 11 underwent [3+2]
annulation reaction to give ketone 12 along with enone
13. Treatment of the crude mixture with tetrabutylam-
monium fluoride (TBAF) promoted â-elimination of
ethanethiol from 12, and enone 13 was isolated as a
single diastereomer.
Although reductive desulfurization of an R-(alkylthio)-
ketone is generally easy, it is not the case for enone 13,
having the C-S bond which is perpendicular to the
π-orbital of the carbonyl group. For example, the reaction
of 13 with Raney-Ni failed to give the desired enone 14.
On the other hand, it has been reported that a thiolate
ion effects desulfurization of an R-(alkylthio)ketone via
nucleophilic attack on the alkylthio group.22 We envi-
sioned that Michael addition of a thiol to enone 13 would
give a ketone analogous to 12, which may undergo one-
pot desulfurization promoted by a thiolate ion. Indeed,
enone 14 was obtained in good yield by successive
treatment of enone 13 with a mixture of thiophenol and
the corresponding lithium salt followed by an aqueous
NaOH solution (Scheme 6). Removal of the benzyl group
by boron tribromide23 afforded the known alcohol 15;24,25
accordingly, the stereochemistry of the tricyclic system
carbon framework was constructed via successive [3+2]
cycloaddition reactions (Scheme 5). Benzyl ether (S)-7
derived from (S)-5 was subjected to a [3+2] cycloaddition
reaction with 1a , and two annulation products 8 and 9
were obtained in diastereomerically pure form, respec-
tively.18 It was proved that these products have a common
configuration at the benzyloxy group and the angular
methyne proton, because ketone 8 was transformed into
enone 9 by treating with Raney-Ni. Although direct
assignment of the configuration of 8 and 9 was difficult,19
the cis relationship between the benzyloxy group and the
angular methyne proton was confirmed at a later stage
(vide infra). This stereochemical feature of the cycload-
dition reaction indicates that the re-face of (S)-7 was
effectively shielded by the benzyloxy group from the
attack of the allyl cationic intermediate. The crude
mixture of 8 and 9 was eventually transformed into
ketone 10 through desulfurization using tributyltin hy-
dride20 followed by hydrogenation (73% from (S)-7).
(21) Ong, B. S.; Chan, T. H. Synth. Commun. 1977, 7, 283.
(22) Oki, M.; Funakoshi, W.; Nakamura, A. Bull. Chem. Soc. J pn.
1971, 44, 828-832.
(23) (a) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.;
Marinovic, N. J . Am. Chem. Soc. 1977, 99, 5773. (b) Demuynck, M.;
De Clercq, P.; Vandewalle, M. J . Org. Chem. 1979, 44, 4863.
(24) Enone 15 in racemic form: Koreeda, M.; Mislankar, S. G. J .
Am. Chem. Soc. 1983, 105, 7203, and refs 7a,b,f, 9d, 10a-c.
(25) Enone 15 in optically active form: Weinges, K.; Dietz, U.; Oeser,
T.; Irngartinger, H. Angew. Chem., Int. Ed. Engl. 1990, 29, 680, and
ref 10d.26
(16) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(17) Treatment of (S)-5 with N-p-toluenesulfonyl-L-phenylalaninyl
chloride and pyridine afforded the corresponding ester, which was then
converted into a sulfone derivative. See the Suporting Information.
(18) The reaction mechanism of formation of enone 9 is not clear.
We confirmed that the ratio between 8 and 9 is not affected by a
prolonged reaction period. Treatment of ketone 8 with EtAlCl2 also
failed to give enone 9, while 8 was slowly converted into 9 by heating
at 180 °C.
(19) The stereochemistry of ketone 8 could be determined after
conversion into the corresponding enol silyl ether.4b See the Suporting
information.
(20) (a) Haskell, T. H.; Woo, P. W. K.; Watson, D. R. J . Org. Chem.
1977, 42, 1302. (b) Gutierrez, C. G.; Stringham, R. A.; Nitasaka, T.;
Glasscock, K. G. J . Org. Chem. 1980, 45, 3393. (c) Gutierrez, C. G.;
Summerhays, L. R. J . Org. Chem. 1984, 49, 5206, and references
therein.
(26) The different rotation values for the same compound 15 have
been reported by Demuth (-115.4°),10d by Weinges (+34°),25 and now
by us (+42.5°). Furthermore, compound 18 was reported to have a
rotation of -105.2° by Demuth,10d which is quite different from our
observation (+90.4°). Weinges determined the stereochemistry of 15
by X-ray crystallographic analysis, and the 13C NMR spectrum of our
compound 15 matches that reported by Weinges. In our study, the
absolute configuration at the C(11) position was established by X-ray
crystallographic analysis17 in the early stage of the total synthesis,
and the rotation of (-)-coriolin was again confirmed at the last stage.
We have also confirmed that compound 15 was obtained in optically
pure form by our method (Suporting Information). Therefore, it seems
that there are some errors in structual assignment made by Demuth,
not only for 15 but also for 18.

Total Synthesis of (-)-Coriolin
Sch em e 7
J . Org. Chem., Vol. 64, No. 8, 1999 2651
F igu r e 2. Stereoselective construction of the spiro epoxide
moiety.
Sch em e 8
was confirmed at this stage.26 The (S)-configuration at
the C2 position (coriolin numbering) indicates that the
second [3+2] annulation reaction occurred at the convex
face of vinyl sulfide 11.
C. In tr odu ction of th e Oxygen Fu n ction al Gr ou ps.
As was mentioned before, introduction of the C7 hydroxyl
group was accomplished by several groups through
epoxidation of either a â,γ-unsaturated ketone or a dienol
acetate, which were prepared in fairly low yields as a
mixture with the parent R,â-unsaturated ketone (Scheme
2). To achieve a complete conversion of the R,â-unsatur-
ated ketone, we chose the corresponding dienol silyl ether
as an epoxidation precursor. Successive treatment of
enone 16 with potassium hydride and triisopropylsilyl
chloride effected selective formation of linear dienol silyl
ether 17. Since 17 was sensitive to silica gel column
chromatography, the crude product was directly subjected
to oxidation reactions. Although use of m-CPBA resulted
in rather complex results, OXONE in acetone-water10d,27
was found to give the desired labile epoxide which was
converted into diol 1828 by exposure to acetic acid
(Scheme 7). It should be noted that no product arising
from Baeyer-Billiger reaction or epoxidation at the A
ring was detected, probably because the highly strained
C6-C7 double bond is much more reactive than the C4-
C5 double bond.29
While an efficient method for introducing the C7
hydroxyl group has been established, stereocontrolled
construction of the spiro epoxide moiety remained as the
final problem in coriolin synthesis. To this end, we
designed a new approach for epoxide K by a Darzens-
type30 reaction of R-haloketone M (Figure 2). We envi-
sioned that formaldehyde would react with the enolate
of M at the convex face of the BC-ring to give halohydrin
L selectively.
bromoketones 20 and ep i-20 as a 4:1 mixture (Scheme
8). The configuration of the major isomer 20 was con-
firmed by observation of NOE between the angular
methyl group and the C3 methyne proton. Successive
treatment of the bromoketones with lithium hexameth-
yldisilazide (LHMDS) and paraformaldehyde afforded
bromohydrin 21 as a single diastereomer. While the
stereochemistry at the C3 position could not be deter-
mined at this stage, 21 was subjected to a cyclization
reaction under the influence of several bases. Although
use of potassium tert-butoxide led to bromoketones 20
and ep i-20 via a retro-aldol reaction, heating with DBU
in DMF induced smooth cyclization to give epoxide 22.
Surprisingly, removal of the silyl groups followed by
epoxidation of the C5-C6 double bond afforded 3-epi-
coriolin, which was reported by Danishefsky9a,c as a minor
product in the final step of coriolin synthesis. Therefore,
the stereochemistry at the C3 position of bromohydrin
21 was assigned as S, which indicates that formaldehyde
reacted with the enolate of the R-bromoketone at the
concave face. It is noteworthy that a similar stereoselec-
tivity was observed in bromination of enone 19, in which
bromoketone 20 was obtained as a major isomer (vide
supra). These stereochemical features suggest that the
convex face of the enolates exhibits unexpectedly low
reactivity, presumably because of the blocking effect of
the angular methyl group as shown in Figure 3.
The reaction of the lithium enolate of enone 19 with
5,5-dibromo-2,2-dimethyl-1,3-dioxane-4,6-dione31 yielded
(27) Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J . O.; Pater, R.
H. J . Org. Chem. 1980, 45, 4758.
These results allowed us to control the stereochemistry
at the C3 position by introducing the substituents in a
reversed manner. Indeed, treatment of hydroxyketone 24,
which was prepared from enone 19 and paraformalde-
(28) Diol 18 in racemic form: ref 7c, 9d,f, 10a-c. Diol 18 in optically
active form: ref 10d.26
(29) Suryawanshi, S. N.; Fuchs, P. L. Tetrahedron Lett. 1981, 22,
4201.
(30) Rosen, T. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, Chapter 1.13, pp
409-440.
(31) Bloch, R. Synthesis 1978, 140.

2652 J . Org. Chem., Vol. 64, No. 8, 1999
Mizuno et al.
Sch em e 10
F igu r e 3.
Sch em e 9
cationic species and vinylsulfides. An enantiomerically
pure C-ring unit was prepared through optical resolution
of a five-membered allyl ester using a lipase. The
triquinane skeleton was constructed stereoselectively
through successive [3+2] cycloaddition reactions. New
methods for introduction of the oxygen functional groups
to the triquinane skeleton were also developed for the
later stages of the total synthesis. The C7 hydroxyl group
was introduced by epoxidation of a dienol silyl ether, and
stereocontrolled construction of the spiro epoxide moiety
was accomplished on the basis of a Darzens-type reaction.
The high overall yield of (-)-coriolin (4.4% from isobu-
tyronitrile) indicates the efficiency of this straightforward
methodology based on a [3+2] cycloaddition reaction, and
synthetic studies on other natural products are now in
progress.
hyde, with an excess amount of LDA followed by NBS
afforded the desired bromohydrin ep i-21 as a single
diastereomer (Scheme 9). On heating with DBU in DMF,
however, ep i-21 underwent a retro-aldol reaction rather
than cyclization to epoxide 25. Since several attempts
using other bases were also fruitless, we employed the
corresponding iodide in place of the bromide.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
positive pressure of dry nitrogen or argon. Diethyl ether and
tetrahydrofuran were distilled from sodium and benzophenone
immediately before use. CH2Cl2 was distilled successively from
P2O5 and K2CO3 under nitrogen and stored over molecular
sieves. Hexane was distilled from LiAlH4 under nitrogen and
stored over potassium mirror. HMPA and diisopropylamine
were distilled from CaH2 under nitrogen and stored over
molecular sieves. Flash chromatography was performed using
40-100 µm mesh KANTO (silica gel 60N, spherical, neutral)
or 100 µm mesh Fuji Silysia (FL100DX, spherical, basic) silica
gel. Analytical TLC was carried out on 250 µm Merck (Kiesegel
60F-254) silica gel plates. Melting points are corrected. 1H and
13C NMR spectra were recorded at 270 or 300 MHz (1H) using
CDCl3 with tetramethylsilane as the internal standard.
(Z)-1-Acetoxy-3-(m eth ylth io)-2-(tr iisop r op ylsiloxy)-2-
bu ten e (1a ) a n d (Z)-3-Acetoxy-1-(m eth ylth io)-2-(tr iiso-
p r op ylsiloxy)-1-p r op en e (1b). These compounds were pre-
pared according to a previously described procedure.4b
4,4-Dieth oxy-2,2-d im eth ylbu tyr on itr ile (2). Preparation
of this compound was previously described.13 A solution of
lithium diisopropylamide (LDA) was prepared from diisopro-
pylamine (25.4 mL, 180 mmol) and a 1.6 M hexane solution of
butyllithium (103 mL, 165 mmol) in THF (300 mL) at 0 °C.
The solution was cooled to -78 °C, and isobutyronitrile (13.6
mL, 150 mmol) was added. After being stirred for 2 h, a
mixture of HMPA (39 mL, 225 mmol) and THF (20 mL)
followed by bromoacetaldehyde diethyl acetal (22.6 mL, 150
mmol) was added. The reaction mixture was allowed to warm
to 0 °C over 1 h, and then a saturated aqueous NH4Cl solution
was added. The mixture was separated, and the aqueous layer
was extracted with ether. The combined organic layer was
washed with brine and dried over MgSO4. Concentration
followed by distillation under reduced pressure (bp 74-77 °C/
2.5 mmHg) afforded nitrile 2 (24.3 g, 132 mmol, 88%) as a
Unfortunately, the reactions of the dianion of 24 with
NIS, iodine, or iodine monochloride resulted in recovery
of 24 or dehydration to give an R-methylene ketone.
While addition of HMPA or TMEDA was entirely inef-
fective, potassium pinacolate was found to enhance the
reactivity of the lithium enolate dramatically. Thus,
epoxide 25 was directly obtained by successive treatment
of the dianion of 24 with NIS and potassium pinacolate32
(Scheme 10). Although the results suggest that the
reactive intermediate is the corresponding potassium
enolate, treatment of 24 with KHMDS resulted in rapid
decomposition even at -78 °C. Therefore, combined use
of the lithium enolate and potassium pinacolate seems
to be essential because the labile potassium enolate can
be generated in the presence of NIS. Finally, epoxide 25
was converted into (-)-coriolin (mp 175-176 °C; lit.5a mp
175-176 °C; [R]26.0D ) -19.4 (c ) 0.44, CHCl3); lit.5c [R]20
D
) -21 (c ) 1.0, CHCl3)) through removal of the silyl
groups followed by epoxidation of the C5-C6 double
bond.
Con clu sion
In conclusion, an efficient synthetic method for (-)-
coriolin has been developed on the basis of a [3+2]
cycloaddition reaction of a 1-(methylthio)-2-siloxyallyl
(32) Use of potassium tert-butoxide resulted in a much more sluggish
transformation.

Total Synthesis of (-)-Coriolin
J . Org. Chem., Vol. 64, No. 8, 1999 2653
colorless oil: 1H NMR (CDCl3, 270 MHz) δ 1.23 (t, J ) 7.1 Hz,
6 H), 1.41 (s, 6 H), 1.86 (d, J ) 5.5 Hz, 2 H), 3.56 (dq, J ) 9.4,
7.1 Hz, 2 H), 3.70 (dq, J ) 9.4, 7.1 Hz, 2 H), 4.74 (t, J ) 5.5
Hz, 1 H); 13C NMR (CDCl3, 67.5 MHz) δ 15.13, 27.42, 29.91,
43.77, 61.74, 100.58, 124.63.
Op tica l Resolu tion of Ester 6b Med ia ted by Lip a se. A
mixture of ester 6b (9.78 g, 41.7 mmol), lipase Amano PS (4.9
g), KH2PO4 (0.17 g), and Na2HPO4 (0.53 g) in water (300 mL)
was vigorously stirred for 65 h at room temperature. The pH
of the mixture was maintained between 7 and 7.5 by adding
an adequate amount of a 5% NaOH solution during the period.
The mixture was filtered through a pad of Celite, and the
residue was washed with ether. The filtrate was separated,
and the aqueous layer was extracted with ether. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica gel
column chromatography afforded (S)-5 (3.00 g, 19.0 mmol,
46%) and (R)-6b (5.02 g, 21.4 mmol, 51%). The enantiomeric
purity of (S)-5 (95% ee) was determined by converting into
the corresponding Mosher ester (see the Supporting Informa-
tion). The resulting (S)-5 (3.0 g, 19.0 mmol) was converted into
chloroacetate (S)-6b (4.30 g, 18.3 mmol, 97%), which was again
subjected to optical resolution using lipase Amano PS (2.15 g)
to yield (S)-5 (2.46 g, 15.5 mmol, 85%) in enantiomerically pure
form. The enantiomeric purity was confirmed by the Mosher
method (see the Supporting Information): [R]26D ) -81.9 (c )
1.35, EtOH).
5,5-Dim eth yl-2-(m eth ylth io)-2-cyclop en ten -1-on e (4). A
mixture of dimethyl sulfide (25.0 mL, 340 mmol), N,N,N′,N′-
tetramethylethylenediamine (38.5 mL, 255 mmol), and a 1.56
M hexane solution of BuLi (164 mL, 255 mmol) was stirred at
18 °C for 4 h. The solution was cooled to -45 °C, and to this
was added a THF (150 mL) solution of nitrile 2 (32.9 mL, 170
mmol). After being stirred at -45 °C for 1 h and at 0 °C for 1
h, 20% aqueous acetic acid (150 mL) was slowly added. The
mixture was separated, and the aqueous layer was extracted
with ether. The combined organic layer was washed with
saturated aqueous NaHCO3 solution and concentrated under
reduced pressure to afford ketone 3 as a colorless oil: IR (ether)
1
1700, 1440, 1350 cm-1; H NMR (CDCl3, 300 MHz) δ 1.12 (t,
J ) 7.1 Hz, 6 H), 1.17 (s, 6 H), 1.89 (d, J ) 5.6 Hz, 2 H), 2.08
(s, 3 H), 3.39 (dq, J ) 9.3, 7.1 Hz, 2 H), 3.45 (s, 2 H), 3.59 (dq,
J ) 9.3, 7.1 Hz, 2 H), 4.44 (t, J ) 5.6 Hz, 1 H); 13C NMR
(CDCl3, 75.5 MHz) δ 15.07, 15.96, 25.34, 39.05, 44.56, 45.36,
62.16, 100.76, 208.71; HRMS (FAB+, glycerol/NaI) calcd for
(S)-3-(Ben zyloxy)-4,4-d im eth yl-2-(m eth ylth io)-1-cyclo-
p en ten e ((S)-7). To a suspension of NaH (1.36 g, 56.5 mmol)
in DMF (50 mL) was successively added a THF (50 mL)
solution of alcohol (S)-5 (5.66 g, 35.8 mmol) and benzyl
bromide (4.68 mL, 39.4 mmol) at 0 °C. After being stirred for
2 h at room temperature, a saturated aqueous NaHCO3
solution was added. The mixture was separated, and the
aqueous layer was extracted with ether. The combined organic
layer was washed with brine and dried over MgSO4. Concen-
tration under reduced pressure followed by silica gel column
chromatography afforded ether (S)-7 (8.67 g, 35.1 mmol,
C
12H24O3SNa (M + Na+) 2271.1344, found 271.1358.
The crude product was treated with a mixture of THF (100
mL) and 10% H2SO4 (200 mL) at room temperature for 1 h,
and then aqueous 15% NaOH solution was slowly added until
the solution was pH 13-14 to a pH test paper. After being
stirred for 30 min at room temperature, the mixture was
separated, and the aqueous layer was extracted with ether.
The combined organic layer was washed with brine and dried
over MgSO4. Concentration followed by distillation under
reduced pressure (bp 77-81 °C/1.0 mmHg) afforded enone 4
(22.0 g, 141 mmol, 83%) as a pale yellow oil: IR (neat) 1695,
1570 cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.16 (s, 6 H), 2.37 (s,
3 H), 2.54 (d, J ) 3.1 Hz, 2 H), 6.93 (t, J ) 3.1 Hz, 1 H); 13C
NMR (CDCl3, 75 MHz) δ 13.55, 24.94, 43.68, 44.21, 140.64,
147.54, 209.66. Anal. Calcd for C8H12OS: C, 61.50; H, 7.74; S,
20.52. Found: C, 61.65; H, 7.96; S, 20.73.
5,5-Dim eth yl-2-(m eth ylth io)-2-cyclop en ten -1-ol (5). A
solution of enone 4 (6.4 g, 41 mmol) in CH2Cl2 (81 mL) was
treated with a 0.96 M hexane solution of DIBAL (47 mL, 45
mmol) at -78 °C for 1 h. A saturated aqueous sodium
potassium tartarate solution was slowly added, and the
mixture was stirred at room temperature. The mixture was
separated, and the aqueous layer was extracted with ether.
The combined organic layer was washed with brine and dried
over MgSO4. Concentration under reduced pressure followed
by silica gel column chromatography afforded alcohol 5 (5.8 g,
36.7 mmol, 89%) as a colorless oil: IR (neat) 3400, 1600, 1060
cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.08 (s, 3 H), 1.11 (s, 3 H),
1.57 (d, J ) 7.3 Hz, 1 H), 2.23 (ddd, J ) 16.0, 2.4, 0.9 Hz, 1
H), 2.26 (ddd, J ) 16.0, 2.4, 1.7 Hz, 1 H), 2.31 (s, 3 H), 4.12
(bd, J ) 7.3 Hz, 1 H), 5.37 (t, J ) 2.4 Hz, 1 H); 13C NMR
(CDCl3, 67.5 MHz) δ 14.61, 22.30, 27.98, 42.62, 45.59, 85.37,
122.50, 140.63. Anal. Calcd for C8H14OS: C, 60.72; H, 8.92; S,
20.26. Found: C, 61.00; H, 9.22; S, 19.96.
98%): [R]26 ) -96.8 (c ) 1.21, EtOH); IR (neat) 1600, 1455,
D
735, 700 cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.12 (s, 3 H), 1.15
(s, 3 H), 2.10 (dd, J ) 15.9, 2.2 Hz, 1 H), 2.21-2.36 (m,
involving a singlet at 2.29, 4 H), 3.97 (s, 1 H), 4.68 (s, 2 H),
5.32 (t, J ) 2.2 Hz, 1 H), 7.24-7.43 (m, 5 H); 13C NMR (CDCl3,
67.5 MHz) δ 14.06, 23.08, 28.97, 43.15, 46.36, 73.26, 92.56,
121.82, 127.48, 127.87, 128.23, 138.69, 139.73. Anal. Calcd for
C
15H20OS: C, 72.53; H, 8.12; S, 12.91. Found: C, 73.23; H,
8.18; S, 12.96.
Con str u ction of th e B-Rin g via a [3+2] Cycloa d d ition
Reaction : 6-Ben zyloxy-4,7,7-tr im eth yl-4,5-bis(m eth ylth io)-
bicyclo[3.3.0]octa n -3-on e (8) a n d (5R,8S)-8-Ben zyloxy-
2,7,7-tr im eth ylbicyclo-[3.3.0]oct-1-en -3-on e (9). To a mix-
ture of (S)-7 (1.5 g, 6.1 mmol) and 1a (2.1 g, 6.3 mmol) in
CH2Cl2 (14 mL) was added a 0.96 M hexane solution of EtAlCl2
(7.2 mL, 6.9 mmol) at -45 °C. After being stirred at -45 °C
for 1 h, -23 °C for 1 h, and 0 °C for 1 h, a saturated aqueous
NaHCO3 solution was added. The mixture was separated, and
the aqueous layer was extracted with ether. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica gel
column chromatography afforded ketone 8 (0.93 g, 2.6 mmol,
42%) and enone 9 (0.68 g, 2.5 mmol, 41%). 8: [R]22.7D ) -121.1
(c ) 1.23, CH2Cl2); IR (ether) 1730, 1440, 1350, 1170 cm-1; 1H
NMR (CDCl3, 270 MHz) δ 0.99 (s, 3 H), 1.20 (s, 3 H), 1.64 (s,
3 H), 1.75 (t, J ) 12.4 Hz, 1 H), 1.83 (s, 3 H), 1.91 (dd, J )
12.4, 8.0 Hz, 1 H), 1.97 (s, 3 H), 2.43 (dd, J ) 19.0, 10.0 Hz, 1
H), 2.74 (dd, J ) 19.0, 5.0 Hz, 1 H), 3.00-3.18 (m, 1 H), 4.30
(s, 1 H), 4.41 (d, J ) 11.4 Hz, 1 H), 4.84 (d, J ) 11.4 Hz, 1 H),
7.30-7.45 (m, 5 H); 13C NMR (CDCl3, 75.5 MHz) δ 11.59, 12.56,
17.30, 22.30, 27.10, 39.63, 43.11, 43.96, 47.15, 60.30, 68.22,
73.81, 88.15, 127.47, 127.75, 128.16, 138.42, 208.57. Anal.
Calcd for C20H28O2S2: C, 65.89; H, 7.74; S, 17.59. Found: C,
5,5-Dim eth yl-2-(m eth ylth io)-2-cyclop en ten -1-yl ch lo-
r oa ceta te (6b). To a solution of alcohol 5 (5.8 g, 36.7 mmol)
and pyridine (5.0 mL, 62 mmol) in CH2Cl2 (44 mL) was added
a CH2Cl2 (27 mL) solution of chloroacetic anhydride (8.0 g, 47
mmol) at 0 °C. After being stirred for 2 h, a saturated aqueous
NaHCO3 solution was added. The mixture was separated, and
the aqueous layer was extracted with ether. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica gel
column chromatography afforded ester 6b (8.50 g, 36.2 mmol,
65.70; H, 7.63; S, 17.30. 9: [R]25 ) +68.4 (c ) 1.29, EtOH);
1
99%) as a colorless oil: IR (neat) 1745, 1600 cm-1; H NMR
D
1
IR (neat) 1710, 1675, 1455 cm-1; H NMR (CDCl3, 270 MHz)
(CDCl3, 270 MHz) δ 1.06 (s, 3 H), 1.17 (s, 3 H), 2.19 (dd, J )
16.4, 3.0 Hz, 1 H), 2.29 (s, 3 H), 2.39 (ddd, J ) 16.4, 3.0, 1.8
Hz, 1 H), 4.51 (s, 2 H), 5.41 (d, J ) 1.8 Hz, 1 H), 5.57 (t, J )
3.0 Hz, 1 H); 13C NMR (CDCl3, 67.5 MHz) δ 14.75, 22.53, 28.10,
40.76, 42.02, 46.17, 87.59, 126.54, 136.19, 166.97. Anal. Calcd
for C10H15ClO2S: C, 51.17; H, 6.44; S, 13.66. Found: C, 50.87;
H, 6.56; S, 13.78.
δ 0.91 (s, 3 H), 1.08 (dd, J ) 12.5, 8.0 Hz, 1 H), 1.25 (s, 3 H),
1.76 (s, 3 H), 2.03 (dd, J ) 18.0, 2.6 Hz, 1 H), 2.07 (dd, J )
12.5, 9.9 Hz, 1 H), 2.74 (dd, J ) 18.0, 6.4 Hz, 1 H), 3.16-3.31
(m, 1 H), 3.99 (s, 1 H), 4.46 (d, J ) 12.0 Hz, 1 H), 4.56 (d, J )
12.0 Hz, 1 H), 7.25-7.40 (m, 5 H); 13C NMR (CDCl3, 67.5 MHz)
δ 8.70, 23.57, 29.82, 39.50, 43.63, 43.68, 44.33, 71.22, 81.89,

2654 J . Org. Chem., Vol. 64, No. 8, 1999
Mizuno et al.
127.16, 127.49, 128.22, 135.22, 138.14, 178.86, 211.07. Anal.
Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 79.73; H,
8.50.
solution was added. The mixture was separated, and the
aqueous layer was extracted with ether. Concentration of the
combined organic layer gave the crude product, which was
treated with a 1 M THF solution of tetrabutylammonium
fluoride (50 mL, 50 mmol) at room temperature. After being
stirred for 1.5 h, a saturated aqueous NH4Cl was added. The
mixture was separated, and the aqueous layer was extracted
with ether. The combined organic layer was washed with brine
and dried over MgSO4. Concentration under reduced pressure
followed by silica gel column chromatography afforded enone
13 (6.26 g, 17.6 mmol, 87%); [R]23D ) -166.9 (c ) 0.95, EtOH);
(1R,2R,5R,8R)- a n d (1R,2S,5R,8R)-8-Ben zyloxy-2,7,7-
tr im eth ylbicyclo[3.3.0]octa n -3-on e (10). To a mixture of
(S)-7 (6.87 g, 27.8 mmol) and 1a (10.2 g, 31.6 mmol) in CH2-
Cl2 (75 mL) was added a 0.98 M hexane solution of EtAlCl2
(34 mL, 33 mmol) at -45 °C. After being stirred at -45 °C for
1 h, -23 °C for 1 h, and 0 °C for 1 h, a saturated aqueous
NaHCO3 solution was added. The mixture was separated, and
the aqueous layer was extracted with ether. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure gave the crude product
containing ketone 8 and enone 9, which was used for the next
step without purification.
IR (CH2Cl2) 1705, 1620 cm-1 1H NMR (CDCl3, 270 MHz) δ
;
1.02 (s, 3 H), 1.03 (s, 3 H), 1.16 (s, 3 H), 1.20-1.35 (m, 1 H),
1.86 (dd, J ) 12.2, 6.8 Hz, 1 H), 2.10-2.33 (m, 2 H), 2.34 (s, 3
H), 2.38 (d, J ) 17.4 Hz, 1 H), 2.45 (d, J ) 17.4 Hz, 1 H), 2.77-
2.99 (m, 2 H), 3.64 (d, J ) 6.8 Hz, 1 H), 4.52 (d, J ) 11.9 Hz,
1 H), 4.59 (d, J ) 11.9 Hz, 1 H), 7.20-7.40 (m, 5 H); 13C NMR
(CDCl3, 67.5 MHz) δ 14.86, 21.19, 25.68, 27.60, 31.97, 41.17,
46.10, 47.50, 47.72, 52.46, 56.36, 71.97, 87.07, 127.12, 127.55,
128.04, 128.37, 138.81, 189.26, 206.15. Anal. Calcd for
A mixture of the crude product, Bu3SnH (7.5 mL, 27.8
mmol), and AIBN (0.46 g, 2.8 mmol) in benzene (63 mL) was
refluxed for 1.5 h. After cooling, water was added. The organic
phase was separated, and the aqueous phase was extracted
with ether. The combined organic layer was successively
treated with DBU (4.2 mL, 28 mmol) and MgSO4. The
insoluble material was removed by filtration through a pad of
Celite, and the filtrate was passed through a short column of
silica gel to remove polar impurities. Hydrogenation (1 atm)
of the crude product catalyzed by 10% Pd-C (0.9 g) in ethanol
(80 mL) followed by purification by silica gel column chroma-
tography gave 10 (5.49 g, 20.3 mmol, 73% from (S)-7) as a
63:37 mixture of C2 epimers; [R]26D ) +34.2 (c ) 0.91, EtOH).
C
22H28O2S: C, 74.11; H, 7.92; S, 8.99. Found: C, 73.92; H, 8.22;
S, 9.13.
(3aS,3bR,4R,6aS)-4-Ben zyloxy-3,3a,3b,4,5,6,6a,7-octah y-
d r o-3a ,5,5-tr im eth ylcyclop en ta [a ]p en ta len -2-on e (14). A
mixture of enone 13 (164 mg, 0.46 mmol), thiophenol (0.24 mL,
2.3 mmol), and a 1.67 M hexane solution of butyllithium (0.28
mL, 0.46 mmol) in DME (0.5 mL) was heated under reflux for
4 h. After cooling to room temperature, 10% aqueous NaOH
solution was added, and the mixture was stirred for 1 h. The
mixture was separated, and the aqueous layer was extracted
with ether. The combined organic layer was washed with brine
and dried over MgSO4. Concentration under reduced pressure
followed by silica gel column chromatography afforded enone
14 (130 mg, 0.42 mmol, 91%): [R]27D ) -54.5 (c ) 0.74, EtOH);
1
Major isomer of 10: IR (neat) 1740, 1455, 535, 500 cm-1; H
NMR (CDCl3, 270 MHz) δ 1.06 (s, 3 H), 1.12 (s, 3 H), 1.17 (d,
J ) 7.8 Hz, 3 H), 1.17-1.36 (m, 1 H), 1.89 (dd, J ) 12.9, 8.0
Hz, 1 H), 2.06 (dd, J ) 18.2, 1.9 Hz, 1 H), 2.12 (quintet, J )
7.8 Hz, 1 H), 2.30 (ddd, J ) 9.9, 7.8, 6.0 Hz, 1 H), 2.52 (dd, J
) 18.2, 9.8 Hz, 1 H), 2.72-2.88 (m, 1 H), 3.38 (d, J ) 6.0 Hz,
1 H), 4.56 (d, J ) 11.6 Hz, 1 H), 4.62 (d, J ) 11.6 Hz, 1 H),
7.25-7.40 (m, 5 H); 13C NMR (CDCl3, 67.5 MHz) δ 15.87, 21.64,
28.12, 32.66, 43.35, 43.69, 47.40, 48.66, 53.10, 72.69, 94.97,
127.23, 127.52, 128.33, 138.78, 221.82. Anal. Calcd for
IR (CH2Cl2) 1700, 1630 cm-1 1H NMR (CDCl3, 270 MHz) δ
;
1.04 (s, 3 H), 1.07 (s, 3 H), 1.18 (s, 3 H), 1.18-1.40 (m, 1 H),
1.86 (dd, J ) 13.3, 6.6 Hz, 1 H), 2.16-2.32 (m, 2 H), 2.38 (s, 2
H), 2.71-2.94 (m, 2 H), 3.63 (d, J ) 6.8 Hz, 1 H), 4.52 (d, J )
12.0 Hz, 1 H), 4.59 (d, J ) 12.0 Hz, 1 H), 5.69 (d, J ) 2.0 Hz,
1 H), 7.22-7.42 (m, 5 H); 13C NMR (CDCl3, 67.5 MHz) δ 21.17,
25.30, 27.53, 32.47, 41.04, 45.97, 47.71, 48.84, 52.83, 56.19,
71.95, 86.97, 122.12, 127.12, 127.49, 128.34, 138.81, 194.72,
210.22. Anal. Calcd for C21H26O2: C, 81.25; H, 8.44. Found:
C, 81.43; H, 8.56.
C
18H24O2: C, 79.37; H, 8.88. Found: C, 79.24; H, 9.03. Minor
isomer of 10: 1H NMR (CDCl3, 270 MHz) δ 1.05 (s, 3 H), 1.17
(s, 3 H), 1.17 (d, J ) 9.8 Hz, 3 H), 1.17-1.36 (m, 1 H), 1.87
(dd, J ) 17.0, 3.0 Hz, 1 H), 1.96 (dd, J ) 13.4, 8.2 Hz, 1 H),
2.88 (q, J ) 9.8 Hz, 1 H), 2.56-2.70 (m, 1 H), 2.61 (dd, J )
17.9, 9.8 Hz, 1 H), 2.70-2.78 (m, 1 H), 3.29 (d, J ) 9.0 Hz, 1
H), 4.46 (d, J ) 10.4 Hz, 1 H), 4.71 (d, J ) 10.4 Hz, 1 H), 7.25-
7.40 (m, 5 H).
(3a S ,3b R ,4R ,6a S )-3,3a ,3b ,4,5,6,6a ,7-O c t a h y d r o -4-
h ydr oxy-3a,5,5-tr im eth ylcyclopen ta[a ]pen talen -2-on e (15).
To a solution of enone 14 (3.92 g, 12.7 mmol) in CH2Cl2 (46
mL) was added a 1 M CH2Cl2 solution of boron tribromide (25
mL, 25 mmol) at -78 °C. After being stirred for 2 h, 15%
aqueous NaOH solution (60 mL) was added. The mixture was
stirred at room temperature for 1 h. The mixture was
separated, and the aqueous layer was extracted with ether.
The combined organic layer was washed with brine and dried
over MgSO4. Concentration under reduced pressure followed
by silica gel column chromatography afforded alcohol 15 (2.75
(1R,5R,8R)-8-Ben zyloxy-3-(et h ylt h io)-2,7,7-t r im et h yl-
bicyclo[3.3.0]oct-2-en e (11). A mixture of ketone 10 (5.73 g,
21.2 mmol), ethanethiol (6.3 mL, 85 mmol), and chlorotrim-
ethylsilane (7.9 mL, 63 mmol) in CH2Cl2 (70 mL) was stirred
at room temperature for 3 h. The reaction mixture was
carefully poured into a saturated aqueous NaHCO3 solution.
The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was washed
with brine and dried over MgSO4. Concentration under
reduced pressure followed by silica gel column chromatography
g, 12.5 mmol, 98%): [R]26 ) +37.1 (c ) 2.25, EtOH); [R]25
)
D
D
afforded vinyl sulfide 11 (6.40 g, 20.3 mmol, 96%): [R]23
)
+42.5 (c ) 0.20, CHCl3); IR (CH2Cl2) 3600, 1700, 1630 cm-1
;
D
+91.6 (c ) 0.99, EtOH); IR (neat) 1500, 1450, 735, 700 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 0.94 (s, 3 H), 1.07 (s, 3 H), 1.20-
1.32 (m, 4 H, involving a singlet at 1.22), 1.67 (bs, 1 H), 1.90
(dd, J ) 11.8, 7.6 Hz, 1 H), 2.10-2.30 (m, 2 H), 2.34 (d, J )
16.8 Hz, 1 H), 2.46 (d, J ) 16.8 Hz, 1 H), 2.62-2.84 (m, 2 H),
3.80 (d, J ) 8.0 Hz, 1 H), 5.70 (d, J ) 1.8 Hz, 1 H); 13C NMR
(CDCl3, 67.5 MHz) δ 19.85, 24.88, 26.53, 33.30, 40.15, 45.45,
46.50, 48.12, 53.36, 56.80, 80.91, 122.31, 194.20, 210.70. Anal.
Calcd for C14H20O2: C, 76.32; H, 9.15. Found: C, 76.36; H,
9.43.
1H NMR (CDCl3, 270 MHz) δ 1.01 (s, 3 H), 1.10 (s, 3 H), 1.13-
1.24 (m, 4 H, involving a triplet at 1.20, J ) 7.2 Hz), 1.72-
1.82 (m, 4 H, involving a singlet at 1.80), 2.15 (bd, J ) 14 Hz,
1 H), 2.58-2.82 (m, 4 H, involving a quartet at 2.64, J ) 7.2
Hz), 2.98-3.10 (m, 1 H), 3.28 (d, J ) 5.8 Hz, 1 H), 4.60 (d, J
) 11.6 Hz, 1 H), 4.63 (d, J ) 11.6 Hz, 1 H), 7.23-7.46 (m, 5
H); 13C NMR (CDCl3, 67.5 MHz) δ 13.93, 15.55, 21.53, 25.36,
28.05, 35.44, 42.27, 43.25, 47.62, 61.51, 72.98, 92.81, 126.00,
127.39, 127.46, 128.27, 139.03, 139.80. Anal. Calcd for C20H28
OS: C, 75.90; H, 8.92; S, 10.13. Found: C, 76.09; H, 8.81; S,
9.86.
(3aS,3bR,4R,6aR)-4-Ben zyloxy-3,3a,3b,4,5,6,6a,7-octah y-
dr o-3a,5,5-tr im eth yl-1-(m eth ylth io)cyclopen ta[a ]pen talen -
2-on e (13). To a solution of vinyl sulfide 11 (6.40 g, 20.3 mmol)
and 1b (8.3 g, 26.5 mmol) in CH2Cl2 (83 mL) was added a 0.96
M hexane solution of EtAlCl2 (30 mL, 29 mmol) at -23 °C.
After being stirred for 3 h, a saturated aqueous NaHCO3
-
(3a S,3b R,4R,6a S)-3,3a ,3b ,4,5,6,6a ,7-Oct a h yd r o-3a ,5,5-
t r im et h yl-4-(t r im et h ylsiloxy)cyclop en t a [a ]p en t a len -2-
on e (16). To a solution of alcohol 15 (1.52 g, 6.9 mmol) and
imidazole (1.1 g, 16.7 mmol) in DMF (15 mL) was added
chlorotrimethylsilane (1.0 mL, 8.4 mmol) at 0 °C. After being
stirred for 1 h, a saturated aqueous NaHCO3 solution was
added. The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was washed
with brine and dried over MgSO4. Concentration under

Total Synthesis of (-)-Coriolin
J . Org. Chem., Vol. 64, No. 8, 1999 2655
reduced pressure followed by silica gel column chromatography
0.86, 21.12, 25.14, 27.08, 35.78, 44.62, 45.70, 47.97, 55.31,
57.15, 68.63, 81.48, 122.71, 191.44, 211.01. Anal. Calcd for
C20H36O3Si2: C, 63.10; H, 9.53. Found: C, 63.07; H, 9.83.
afforded silyl ether 16 (1.89 g, 6.49 mmol, 94%): [R]26.5
)
D
+12.5 (c ) 0.87, EtOH); IR (ether) 3050, 2970, 1700, 1630 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 0.11 (s, 9 H), 0.89 (s, 3 H), 0.99
(s, 3 H), 1.16-1.28 (m, 4 H, involving a singlet at 1.21), 1.85
(dd, J ) 12.5, 7.2 Hz, 1 H), 2.18-2.24 (m, 2 H), 2.35 (s, 2 H),
(3S,3a S,3bR,4R,6a S,7S)-3-Br om o-3,3a ,3b,4,5,6,6a ,7-oc-
t a h yd r o-3a ,5,5-t r im et h yl-4,7-b is(t r im et h ylsiloxy)cyclo-
p en ta [a ]p en ta len -2-on e (20) a n d (3R,3a S,3bR,4R,6a S,7S)-
3-Br om o-3,3a ,3b ,4,5,6,6a ,7-oct a h yd r o-3a ,5,5-t r im et h yl-
4,7-bis(tr im eth ylsiloxy)cyclopen ta[a ]pen talen -2-on e (epi-
20). To a solution of enone 19 (54 mg, 0.14 mmol) in THF (0.71
mL) was added a 1 M THF solution of LHMDS (0.17 mL, 0.17
mmol) at -45 °C. After being stirred for 1.5 h, 5,5-dibromo-
2,2-dimethyl-1,3-dioxane-4,6-dione (64 mg, 0.21 mmol) was
added. After being stirred for 1 h, a saturated aqueous
NaHCO3 solution was added. The mixture was separated, and
the aqueous layer was extracted with ether. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica gel
column chromatography afforded bromoketone 20 (51 mg,
0.111 mmol, 78%) and ep i-20 (13 mg, 0.028 mmol, 20%). 20:
[R]26.3D ) -47.7 (c ) 1.37, CH2Cl2); IR (ether) 2980, 1960, 1730,
2.71-2.82 (m, 2 H), 3.81 (d, J ) 7.5 Hz, 1 H), 5.69 (s, 1 H); 13
C
NMR (CDCl3, 75.5 MHz) δ 0.63, 20.47, 24.85, 26.79, 32.62,
40.40, 45.79, 46.52, 48.16, 52.87, 57.41, 80.85, 122.01, 194.36,
210.30. Anal. Calcd for C17H28O2Si: C, 69.81; H, 9.65. Found:
C, 70.10; H, 9.79.
(3a S,3b R,4R,6a S,7S)-3,3a ,3b ,4,5,6,6a ,7-Oct a h yd r o-4,7-
d ih yd r oxy-3a ,5,5-t r im e t h ylcyclop e n t a [a ]p e n t a le n -2-
on e (18). To a suspension of KH (0.19 g, 4.73 mmol) in DME
(2.2 mL) was added a solution of enone 16 (461 mg, 1.58 mmol)
in DME (3 mL) at 0 °C. After being stirred for 1 h at room
temperature, the mixture was cooled to 0 °C, and chlorotri-
isopropylsilane (0.50 mL, 2.4 mmol) was added. After being
stirred for 30 min, the mixture was poured into a saturated
aqueous NaHCO3 solution containing a small amount of
triethylamine. The mixture was separated, and the aqueous
layer was extracted with ether. The combined organic layer
was washed with brine and dried over MgSO4. Concentration
under reduced pressure afforded dienol silyl ether 17, which
was used for the next step without purification. 17: 1H NMR
(CDCl3, 300 MHz) δ 0.08 (s, 9 H), 0.1 (s, 9 H), 0.92 (s, 3 H),
0.98 (s, 3 H), 1.10 (d, J ) 8.0 Hz, 18 H), 1.15-1.32 (m, 7 H,
involving a singlet at 1.2), 1.55 (dd, J ) 12.1, 6.0 Hz, 1 H),
1.98 (d, J ) 14.9 Hz, 1 H), 2.36 (d, J ) 14.9 Hz, 1 H), 2.50 (dd,
J ) 10.1, 5.0 Hz, 1 H), 3.34-3.50 (m, 1 H), 3.96 (d, J ) 5.0
Hz, 1 H), 4.80 (d, J ) 4.0 Hz, 1 H), 5.20 (s, 1 H).
1
1380, 1120 cm-1; H NMR (CDCl3, 300 MHz) δ 0.12 (s, 9 H),
0.15 (s, 9 H), 0.95 (s, 3 H), 1.03 (s, 3 H), 1.37 (dd, J ) 12.9, 9.0
Hz, 1 H), 1.46 (s, 3 H), 1.75 (dd, J ) 12.9, 9.3 Hz, 1 H), 2.54-
2.66 (m, 1 H), 2.97 (dd, J ) 12.2, 9.0 Hz, 1 H), 3.80 (d, J ) 8.8
Hz, 1 H), 4.15 (s, 1 H), 4.48 (d, J ) 5.9 Hz, 1 H), 5.78 (s, 1 H);
13C NMR (CDCl3, 75.5 MHz) δ -0.11, 0.99, 21.60, 25.78, 27.31,
35.37, 44.59, 45.35, 51.63, 53.21, 59.89, 69.10, 81.61, 119.09,
188.57, 204.54. Anal. Calcd for C20H35BrO3Si2: C, 52.27; H,
7.86. Found: C, 52.30; H, 7.93. ep i-20: 1H NMR (CDCl3, 300
MHz) δ 0.12 (s, 9 H), 0.19 (s, 9 H), 0.91 (s, 3 H), 1.05 (s, 3 H),
1.37 (dd, J ) 12.9, 9.3 Hz, 1 H), 1.42 (s, 3 H), 1.77 (dd, J )
11.7, 9.0 Hz, 1 H), 2.36 (dd, J ) 12.2, 9.0 Hz, 1 H), 2.56-2.66
(m, 1 H), 3.79 (d, J ) 9.0 Hz, 1 H), 4.43 (s, 1 H), 4.48 (d, J )
5.6 Hz, 1 H), 5.93 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ -0.10,
1.17, 21.43, 24.05, 27.31, 34.98, 44.12, 44.50, 52.19, 57.06,
67.25, 69.16, 81.77, 120.54, 189.48, 201.68.
To a mixture of crude 17, KHCO3 (1.6 g, 16 mmol), acetone
(11.5 mL), and water (11.5 mL) was added OXONE (0.97 g,
1.6 mmol) at 0 °C. After being stirred for 30 min at room
temperature, a saturated aqueous Na2S2O3 solution was added.
The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was concen-
trated under reduced pressure. The crude mixture was dis-
solved in a mixture of acetic acid (9.5 mL), THF (3.2 mL), and
water (3.2 mL). After being stirred for 30 min at room
temperature, the mixture was poured into a saturated aqueous
NaHCO3 solution. The mixture was separated, and the aque-
ous layer was extracted with ethyl acetate. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by recrystal-
ization from ethyl acetate/hexane afforded diol 18 (168 mg,
0.71 mmol). The residue was purified by silica gel column
chromatography to give additional 18 (131 mg, 0.55 mmol).
(3S ,3a S ,3b R ,4R ,6a S ,7S )-3-Br om o-3,3a ,3b ,4,5,6,6a ,7-
oct a h yd r o-3-h yd r oxym e t h yl-3a ,5,5-t r im e t h yl-4,7-b is-
(tr im eth ylsiloxy)cyclop en ta [a ]p en ta len -2-on e (21). To a
solution of bromoketone 20 (38 mg, 0.083 mmol) in THF (0.41
mL) was added a 1 M THF solution of LHMDS (0.10 mL, 0.10
mmol) at -45 °C. After being stirred for 1.5 h, paraformalde-
hyde (10 mg, 0.33 mmol) was added. After being stirred for
30 min at 0 °C, a saturated aqueous NaHCO3 solution was
added. The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was washed
with brine and dried over MgSO4. Concentration under
reduced pressure followed by silica gel column chromatography
The yield of 18 based on 16 was 80%: mp 165-169 °C; [R]29
D
afforded bromohydrin 21 (36 mg, 0.073 mmol, 88%): [R]25.7
D
) +90.4 (c ) 0.27, CH2Cl2); IR (CH2Cl2) 3600, 3400, 3060, 2960,
1710, 1640, 1410, 1270, 1260 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.95 (s, 3 H), 1.10 (s, 3 H), 1.45 (s, 3 H), 1.48 (dd, J ) 13.2,
8.0 Hz, 1 H), 1.84 (dd, J ) 13.2, 9.5 Hz, 1 H), 2.05 (dd, J )
12.4, 9.1 Hz, 1 H), 2.38 (d, J ) 18.4 Hz, 1 H), 2.52 (d, J ) 18.4
Hz, 1 H), 2.67-2.78 (m, 1 H), 3.81 (d, J ) 9.1 Hz, 1 H), 4.65
(d, J ) 5.4 Hz, 1 H), 5.84 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz)
δ 20.37, 24.94, 26.57, 35.05, 44.31, 44.93, 47.72, 56.04,
56.50, 68.64, 81.15, 123.83, 190.32, 211.18. Anal. Calcd for
) +50.8 (c ) 0.6, CH2Cl2); IR (ether) 3000, 2990, 1720, 1440,
1
1380, 1350, 1160 cm-1; H NMR (CDCl3, 300 MHz) δ 0.12 (s,
9 H), 0.19 (s, 9 H), 0.93 (s, 3 H), 1.06 (s, 3 H), 1.34-1.42 (m, 1
H), 1.52 (s, 3 H), 1.75-1.82 (m, 1 H), 2.54 (dd, J ) 9.3, 4.4 Hz,
1 H), 2.60-2.70 (m, 2 H), 3.70 (dd, J ) 12.1, 9.3 Hz, 1 H), 3.87
(brd, 1 H), 3.92 (dd, J ) 12.1, 4.4 Hz, 1 H), 4.52 (brd, 1 H),
5.92 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ -0.11, 1.09, 21.30,
27.41, 28.49, 35.55, 44.18, 44.54, 50.52, 54.90, 68.32, 68.50,
81.49, 81.94, 120.44, 190.41, 203.75. Anal. Calcd for C21H37
BrO4Si2: C, 51.52; H, 7.62. Found: C, 51.82; H, 7.69.
-
C
14H20O3: C, 71.16; H, 8.53. Found: C, 71.12; H, 8.57.
(3aS,3bR,4R,6aS,7S)-3,3a,3b,4,5,6,6a,7-Octah ydr o-3a,5,5-
Ep oxid e 22. A solution of bromohydrin 21 (34 mg, 0.069
mmol) and DBU (32 µL, 0.21 mmol) in DMF (0.69 mL) was
heated at 50 °C for 2.5 h. After cooling to room temperature,
a saturated aqueous NaHCO3 solution was added. The mixture
was separated, and the aqueous layer was extracted with
ether. The combined organic layer was washed with brine and
dried over MgSO4. Concentration under reduced pressure
followed by silica gel column chromatography afforded epoxide
22 (23 mg, 0.055 mmol, 80%) along with bromoketone 20 (2.5
tr im eth yl-4,7-bis(tr im eth ylsiloxy)cyclopen ta[a ]pen talen -
2-on e (19). To a solution of diol 18 (168 mg, 0.71 mmol) and
imidazole (0.34 g, 5.0 mmol) in DMF (3.5 mL) was added
chlorotrimethylsilane (0.32 mL, 2.5 mmol) at 0 °C. After being
stirred for 10 min, a saturated aqueous NaHCO3 solution was
added. The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was washed
with brine and dried over MgSO4. Concentration under
reduced pressure followed by silica gel column chromatography
mg, 0.006 mmol, 16%): [R]25.6 ) -9.88 (c ) 0.27, CH2Cl2); IR
afforded silyl ether 19 (249 mg, 0.65 mmol, 92%): [R]24.5
)
D
D
(ether) 2980, 2880, 1730, 1440, 1380, 1360, 1110 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.14 (s, 9 H), 0.14 (s, 9 H), 0.90 (s, 3 H),
1.03 (s, 3 H), 1.32-1.41 (m, 4 H, involving a singlet at 1.41),
1.72-1.80 (m, 1 H), 2.51-2.60 (m, 2 H), 2.84 (d, J ) 5.7 Hz, 1
H), 3.34 (d, J ) 5.7 Hz, 1 H), 3.73 (d, J ) 8.3 Hz, 1 H), 4.50 (d,
J ) 4.7 Hz, 1 H) 5.98 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ
-0.08, 1.13, 21.30, 22.93, 27.40, 35.09, 44.31, 44.86, 47.98,
+34.9 (c ) 0.51, EtOH); IR (ether) 3050, 2980, 1250, 1100 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.08 (s, 9 H), 0.11 (s, 9 H), 0.86
(s, 3 H), 0.99 (s, 3 H), 1.27 (dd, J ) 12.7, 8.3 Hz, 1 H), 1.34 (s,
3 H), 1.71 (dd, J ) 12.7, 10.1 Hz, 1 H), 2.14 (dd, J ) 12.3, 8.3
Hz, 1 H), 2.31 (d, J ) 18.0 Hz, 1 H), 2.38 (d, J ) 18.0 Hz, 1 H),
2.61-2.73 (m, 1 H), 3.77 (d, J ) 8.3 Hz, 1 H), 4.50 (d, J ) 6.3
Hz, 1 H), 5.72 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ -0.13,

2656 J . Org. Chem., Vol. 64, No. 8, 1999
Mizuno et al.
48.63, 49.30, 68.11, 70.26, 81.49, 122.27, 191.89, 204.58. Anal.
Calcd for C21H36O4Si2: C, 61.72; H, 8.88. Found: C, 61.47; H,
9.09.
added. The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was washed
with brine and dried over MgSO4. Concentration under
reduced pressure followed by silica gel column chromatography
afforded epoxide 25 (11 mg, 0.026 mmol, 72%) along with
Ep oxid e 23. To a solution of epoxide 22 (19 mg, 0.046
mmol) in THF (0.3 mL) was added a few drops of hydrogen
fluoride-pyridine at 0 °C. After being stirred for 5 min, a
saturated aqueous NaHCO3 solution was added, and the
mixture was extracted with ethyl acetate. Drying over MgSO4
and concentration under reduced pressure followed by silica
gel column chromatography afforded epoxide 23 (12 mg, 0.045
hydroxyketone 24 (1 mg, 0.0024 mmol, 7%): [R]25.1 ) +25.5
D
(c ) 1.1, CH2Cl2); IR (ether) 3057, 2980, 2720, 1280, 1260 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.13 (s, 9 H), 0.14 (s, 9 H), 0.87
(s, 3 H), 1.03 (s, 3 H), 1.28-1.35 (m, 4 H involving a singlet at
1.32), 1.76 (t, J ) 12.7 Hz, 1 H), 2.24 (dd, J ) 12.4, 8.6 Hz, 1
H), 2.56-2.69 (m, 1 H), 3.02 (d, J ) 6.8 Hz, 1 H), 3.11 (d, J )
6.8 Hz, 1 H), 3.72 (d, J ) 8.6 Hz, 1 H) 4.57 (d, J ) 6.1 Hz, 1
H), 6.05 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ -0.08, 0.90,
20.54, 20.92, 27.15, 35.70, 44.55, 44.60, 48.27, 52.78, 54.69,
69.36, 69.43, 81.29, 123.22, 190.15, 204.58. Anal. Calcd for
C21H36O4Si2: C, 61.72; H, 8.88. Found: C, 62.01; H, 9.04.
mmol, 98%): mp 152-155 °C (dec); [R]25 ) +27.1 (c ) 0.14,
D
1
CH2Cl2); IR (CH2Cl2) 3700, 3600, 2930, 1720, 1420 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.94 (s, 3 H), 1.10 (s, 3 H), 1.43-
1.53 (m, 4 H, involving a singlet at 1.49), 1.84 (dd, J ) 12.7,
10.7 Hz, 1 H), 2.43 (dd, J ) 12.0, 9.5 Hz, 1 H) 2.63-2.75 (m,
1 H), 2.98 (d, J ) 5.5 Hz, 1 H), 3.37 (d, J ) 5.5 Hz, 1 H),
3.37 (d, J ) 5.5 Hz, 1 H), 3.65 (d, J ) 9.5 Hz, 1 H), 4.73 (d, J
) 5.6 Hz, 1 H), 6.10 (s, 1 H); 13C NMR (CDCl3, 75.5 MHz) δ
20.24, 22.42, 26.61, 35.00, 44.26, 44.51, 47.63, 49.37, 49.97,
67.93, 69.83, 80.34, 123.68, 190.14, 204.24. Anal. Calcd for
Ep oxid e 26. To a solution of epoxide 25 (33 mg, 0.081
mmol) in THF (0.4 mL) was added a few drops of hydrogen
fluoride-pyridine at 0 °C. After being stirred for 10 min, a
saturated aqueous NaHCO3 solution was added, and the
mixture was extracted with ethyl acetate. Drying over MgSO4
and concentration under reduced pressure followed by silica
gel column chromatography afforded epoxide 26 (21 mg, 0.080
mmol, 99%): mp 155-156 °C; [R]25.7D ) +125.7 (c ) 0.20, CH2-
Cl2); IR (CH2Cl2) 3690, 3600, 3050, 2980, 1720, 1600, 1420
cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.94 (s, 3 H), 1.09 (s, 3 H),
1.40 (s, 3 H), 1.49 (dd, J ) 12.7, 8.5 Hz, 1 H), 1.85 (t, J ) 12.7
Hz, 1 H), 2.25 (dd, J ) 12.2, 8.9 Hz, 1 H), 2.68-2.81 (m, 1 H),
3.09 (d, J ) 6.6 Hz, 1 H), 3.23 (d, J ) 6.6 Hz, 1 H), 3.74 (d, J
) 8.9 Hz, 1 H), 4.76 (d, J ) 6.1 Hz, 1 H), 6.16 (s, 1 H); 13C
NMR (CDCl3, 75.5 MHz) δ 20.21, 20.34, 26.56, 35.51, 44.23,
44.45, 48.00, 52.89, 53.94, 69.19, 69.37, 80.08, 124.40, 188.97,
204.35. Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found:
C, 67.90; H, 7.83.
C
15H20O4: C, 68.16; H, 7.63. Found: C, 68.20; H, 7.93.
3-Ep i-cor iolin . To a mixture of epoxide 23 (14 mg, 0.053
mmol), NaHCO3 (70 mg, 0.83 mmol), THF (2.1 mL), and water
(2.1 mL) was added 35% aqueous H2O2 (42 µL, 0.43 mmol) at
0 °C. After being stirred for 45 min, a saturated aqueous NH4-
Cl solution was added. The mixture was separated, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica gel
column chromatography afforded 3-epi-coriolin (12 mg, 0.042
mmol, 80%): mp 206-209 °C (dec); [R]25.5 ) -95.8 (c ) 0.16,
D
acetone); IR (CH2Cl2) 3600, 3400, 1760 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.94 (s, 3 H), 1.10 (s, 3 H), 1.37 (s, 3 H), 1.49 (dd,
J ) 12.7, 8.8 Hz, 1 H), 1.81 (dd, J ) 12.7, 10.7 Hz, 1 H) 2.04
(brs, 1 H), 2.43 (dd, J ) 11.9, 9.0 Hz, 1 H), 2.76-2.89 (m, 1
H), 2.96 (d, J ) 6.0 Hz, 1 H), 2.99 (d, J ) 6.0 Hz, 1 H), 3.51 (s,
1 H), 3.66 (d, J ) 9.0 Hz, 1 H), 4.06 (d, J ) 6.1 Hz, 1 H); 13C
NMR (CDCl3, 75.5 MHz) δ 16.42, 20.16, 26.53, 35.22, 40.88,
41.71, 43.09, 52.31, 53.31, 58.68, 67.71, 71.19, 78.85, 79.85,
204.91.
(-)-Cor iolin . To a mixture of monoepoxide 26 (20 mg, 0.076
mmol), NaHCO3 (0.10 g, 1.2 mmol), THF (3 mL), and water (3
mL) was added 35% aqueous H2O2 (60 µL, 0.57 mmol) at 0
°C. After being stirred for 1.5 h, a saturated aqueous NH4Cl
solution was added. The mixture was separated, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica gel
column chromatography afforded (-)-coriolin (20 mg, 0.072
(3R,3a S,3bR,4R,6a S,7S)-3,3a ,3b,4,5,6,6a ,7-Octa h yd r o-3-
h yd r oxym eth yl-3a ,5,5-tr im eth yl-4,7-bis(tr im eth ylsiloxy)-
cyclop en ta [a ]p en ta len -2-on e (24). To a solution of enone
19 (21 mg, 0.055 mmol) in ether (0.28 mL) was added a 1 M
etherial solution of LDA (0.14 mL, 0.14 mmol) at -23 °C. After
being stirred for 2 h, paraformaldehyde (5.0 mg, 0.16 mmol)
was added. After being stirred for 1 h at 0 °C, a saturated
aqueous NaHCO3 solution was added. The mixture was
separated, and the aqueous layer was extracted with ether.
The combined organic layer was washed with brine and dried
over MgSO4. Concentration under reduced pressure followed
by silica gel column chromatography afforded hydroxyketone
24 (16 mg, 0.040 mmol, 72%): [R]24.4D ) +25.36 (c ) 1.08, CH2-
mmol, 95%): mp 175-176 °C; [R]26.0 ) -19.4 (c ) 0.44,
D
CHCl3); IR (CH2Cl2) 3600, 3400, 3000, 1750, 1090 cm-1
;
1H
NMR (CDCl3, 300 MHz) δ 0.92 (s, 3 H), 1.08 (s, 3 H), 1.22 (s,
3 H), 1.49 (dd, J ) 12.9, 8.8 Hz, 1 H), 2.04 (s, 1 H), 2.32 (dd,
J ) 12.2, 9.3 Hz, 1 H), 2.74-2.86 (m, 1 H), 2.99 (d, J ) 6.8
Hz, 1 H), 3.13 (d, J ) 6.8 Hz, 1 H), 3.57 (s, 1 H), 3.76 (d, J )
9.3 Hz, 1 H), 4.04 (d, J ) 6.1 Hz, 1 H); 13C NMR (CDCl3, 75.5
MHz) δ 13.92, 20.22, 26.34, 34.92, 40.12, 42.80, 42.98, 51.54,
54.67, 59.70, 65.74, 70.23, 78.00, 80.33, 204.62.
Cl2); IR (ether) 2900, 1710, 1440, 1370, 1250, 1180, 1070 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.11 (s, 9 H), 0.19 (s, 9 H), 0.94
(s, 3 H), 1.10, (s, 3 H), 1.35 (dd, J ) 12.7, 8.7 Hz, 1 H), 1.42 (s,
3 H), 1.80 (dd, J ) 12.8, 11.0 Hz, 1 H), 2.37 (dd, J ) 12.2, 8.8
Hz, 1 H), 2.54-2.70 (m, 2 H, involving a doublet-doublet at
2.56, J ) 9.3, 5.9 Hz), 3.21 (dd, J ) 9.8, 3.9 Hz, 1 H), 3.56-
3.75 (m, 2 H), 3.90 (d, J ) 8.8 Hz, 1 H), 4.51 (d, J ) 6.3 Hz, 1
H), 5.73 (s, 1 H), with peaks due to the minor epimer at 1.05
(s), 1.30 (s), 4.45 (d, J ) 5.3 Hz), 5.79 (s); 13C NMR (CDCl3,
75.5 MHz) δ -0.12, 1.06, 20.81, 27.23, 27.41, 36.21, 44.51,
44.87, 49.76, 50.21, 61.65, 62.95, 68.57, 82.09, 122.32, 191.03,
Ack n ow led gm en t. We are grateful to Professor
Takeshi Sugai, Department of Chemistry, Keio Univer-
sity, for helpful discussions on optical resolution using
enzymes. We express our thanks to Amano Pharma-
ceutical Co. Ltd. for the kind donation of “Amano Lipase
PS”. This work was financially supported by the Min-
istry of Education, Science, Sports, and Culture of the
J apanese Government. K.M. thanks J SPS for a predoc-
tral fellowship.
210.56. Anal. Calcd for
Found: C, 61.22; H, 9.48.
C21H38O4Si2: C, 61.41; H, 9.33.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 6a , ep i-21, and MTPA
esters of (S)-5 and 15. Preparation of a N-p-toluenesulfonyl-
L-phenylalaninyl derivative from (S)-5 for X-ray crystal-
lographic analysis. The experimental procedures for determi-
nation of the stereochemistry of ketone 8. The normal and
Ep oxid e 25. A solution of pinacol (59 mg, 0.5 mmol) in THF
(0.5 mL) was slowly added to a suspension of KH (44 mg, 1.1
mmol) in THF (0.5 mL) to afford a 0.5 M suspension of
potassium pinacolate. To a solution of hydroxyketone 24 (15
mg, 0.036 mmol) in THF (0.12 mL) was added a 1 M THF
solution of LDA (0.12 mL, 0.12 mmol) at -23 °C. After being
stirred for 4 h, the mixture was cooled to -78 °C. To this was
successively added N-iodosuccinimide (40 mg, 0.18 mmol) and
a 0.5 M THF suspension of potassium pinacolate (0.24 mL,
0.12 mmol). After being stirred for 1 h, an aqueous Na2SO3
solution containing a small amount of triethylamine was
1
NOE spectra of 20 and ep i-20. The H and 13C NMR spectra
of (-)-coriolin and epi-coriolin. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O981478C