Asymmetric total syntheses of (+)-cheimonophyllon E and (+)-cheimonophyllal

Article abstract of DOI:10.1021/jo0203140

The highly enantiocontrolled total syntheses of natural (+)-cheimonophyllon E (5) and (+)-cheimonophyllal (6), biologically intriguing oxygenated bisabolane-type sesquiterpenoids, have been completed. The present synthetic strategy featured the use of an asymmetric aldol-type reaction for preparing in the first synthetic step an optically active 6-C-substituted 3-methyl-2-cyclohexenone derivative. Thus, a Mukaiyama aldol reaction of 1-methyl-3-silyloxy-1,3-cyclohexadiene 31 with α,β-unsaturated aldehyde 11 in the presence of a chiral (acyloxy)borane (CAB)-type Yamamoto catalyst 33 proceeded with high levels of both diastereo- and enantioselectivities. The predominant aldol adduct, syn-9, was transformed into γ,δ-epoxy allylic alcohol 8 by a nine-step sequence, including the substrate-controlled 1,2-reduction of enone, syn-12, also the epoxidation of allylic alcohol 15. Epoxy-alcohol 8 underwent 5-exo-cyclization in a high regioselective manner under acidic conditions to produce a bicyclic key intermediate (+)-7, which was eventually efficiently converted to (+)-cheimonophyllon E (5) or (+)-cheimonophyllal (6).

Full text of DOI:10.1021/jo0203140

Asym m etr ic Tota l Syn th eses of (+)-Ch eim on op h yllon E a n d
(+)-Ch eim on op h ylla l
Ken-ichi Takao, Tomohiro Tsujita, Manabu Hara, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, J apan
tadano@applc.keio.ac.jp
Received May 2, 2002
The highly enantiocontrolled total syntheses of natural (+)-cheimonophyllon E (5) and (+)-
cheimonophyllal (6), biologically intriguing oxygenated bisabolane-type sesquiterpenoids, have been
completed. The present synthetic strategy featured the use of an asymmetric aldol-type reaction
for preparing in the first synthetic step an optically active 6-C-substituted 3-methyl-2-cyclohexenone
derivative. Thus, a Mukaiyama aldol reaction of 1-methyl-3-silyloxy-1,3-cyclohexadiene 31 with
R,â-unsaturated aldehyde 11 in the presence of a chiral (acyloxy)borane (CAB)-type Yamamoto
catalyst 33 proceeded with high levels of both diastereo- and enantioselectivities. The predominant
aldol adduct, syn-9, was transformed into γ,δ-epoxy allylic alcohol 8 by a nine-step sequence,
including the substrate-controlled 1,2-reduction of enone, syn-12, also the epoxidation of allylic
alcohol 15. Epoxy-alcohol 8 underwent 5-exo-cyclization in a high regioselective manner under acidic
conditions to produce a bicyclic key intermediate (+)-7, which was eventually efficiently converted
to (+)-cheimonophyllon E (5) or (+)-cheimonophyllal (6).
In tr od u ction
the chiral Lewis acid catalyzed asymmetric aldol meth-
odology, and the introduction of all remaining stereogenic
centers at C-1, -2, -3, and -8 by internal asymmetric
inductions.
During a screening of the higher fungal metabolites
for nematicidal activities, six new bisabolane-type ses-
quiterpenoids, cheimonophyllons A-E and cheimono-
phyllal (1-6), were isolated from the submerged cultures
of basidiomycete Cheimonophyllum candidissimum.1These
compounds were found to exhibit not only nematicidal
but also antifungal, antibacterial, and cytotoxic activi-
ties.1 Their relative structures have been determined by
extensive 1H and 13C NMR spectroscopic analysis.2 Their
absolute stereochemistries have not been established.
Among these cheimonophyllons, 5 and 6 possess five or
four stereogenic carbons, respectively, in a highly oxy-
genated 7-oxabicyclo[4.3.0]nonane core skeleton. We have
recently reported preliminarily the first total syntheses
of (+)- and (-)-cheimonophyllon E (5) using an optical
resolution strategy; thereby, the previously unknown
absolute stereochemistry of 5 has been established.3 As
a result of our continuous interest in synthetic studies
on biologically active sesquiterpenoides,4 we have com-
pleted the highly enantioselective syntheses of (+)-
cheimonophyllon E (5) and (+)-cheimonophyllal (6),
employing a catalytic asymmetric aldol reaction in the
initial stage of their total synthesis. Herein, we describe
the complete details of the asymmetric total syntheses
of 5 and 6. The present asymmetric approach relies on
the enantioselective construction of the absolute stereo-
chemistry of C-6 (cheimonophyllons numbering), using
Resu lts a n d Discu ssion
Syn th etic P la n . Our retrosynthesis for cheimono-
phyllon E (5) and cheimonophyllal (6) is outlined in
(4) For our previous results on this subject, see: (a) A formal
synthesis of enantiomeric paniculide B. Tadano, K.; Miyake, A.; Ogawa,
S. Tetrahedron 1991, 47, 7259-7270. (b) A total synthesis of (+)-
eremantholide A. Takao, K.; Ochiai, H.; Yoshida, K.; Hashizuka, T.;
Koshimura H.; Tadano, K.; Ogawa, S. J . Org. Chem. 1995, 60, 8179-
8193. (c) Total synthesis of (-)-verrucarol. Ishihara, J .; Nonaka, R.;
Terasawa, Y.; Shiraki, R.; Yabu, K.; Kataoka, H.; Ochiai, Y.; Tadano,
K. J . Org. Chem. 1998, 63, 2679-2688. (d) Total synthesis of (-)-
mniopetal E. Suzuki, Y.; Nishimaki, R.; Ishikawa, M.; Murata, T.;
Takao, K.; Tadano, K. J . Org. Chem. 2000, 65, 8595-8607. (e) Total
synthesis of (-)-mniopetal F. Suzuki, Y.; Ohara, A.; Sugaya K.; Takao,
K.; Tadano, K. Tetrahedron 2001, 57, 7291-7301.
(1) (a) Stadler, M.; Anke, H.; Sterner, O. J . Antibiot. 1994, 47, 1284-
1289. (b) Stadler, M.; Fouron, J .-Y.; Sterner O.; Anke, H. Z. Naturfor-
sch. 1995, 50c, 473-475.
(2) Stadler, M.; Anke, H.; Sterner, O. Tetrahedron 1994, 50, 12649-
12654.
(3) Preliminary communication on part of the results described
here: Takao, K.; Hara, M.; Tsujita, T.; Yoshida, K.; Tadano, K.
Tetrahedron Lett. 2001, 42, 4665-4668.
10.1021/jo0203140 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
6690
J . Org. Chem. 2002, 67, 6690-6698

(+)-Cheimonophyllon E and (+)-Cheimonophyllal
SCHEME 1
SCHEME 3
SCHEME 2
Scheme 1. We considered a 7-oxabicyclo[4.3.0]non-4-ene
derivative 7, which possesses the cheimonophyllons
skeleton as well as modifiable carbon-carbon double
bonds, to be an advanced synthetic intermediate. For the
construction of the bicyclic core in 7, the cyclization of
6-[(R-methylene-â,γ-epoxy]cyclohexen-1-ol 8 was expected
to proceed via 5-exo-tet mode,5 forming a tetrahydrofuran
ring exclusively. The three stereogenic centers (C-1, -8,
and -9) in 8 could be introduced via stereoselective 1,2-
reduction and epoxidation of the cyclohexenone syn-9,
which has a 5-methyl-2-hexen-1-ol as a side chain. The
intermediate, syn-9, in turn could be prepared by the
aldol reaction of commercially available 3-methyl-2-
cyclohexenone 10 and known (E)-5-methyl-2-hexenal 11.6
As no information on the absolute stereochemistries of
cheimonophyllons was available for us, we first explored
the syntheses and establishment of the absolute stere-
ochemistries of both enantiomers (+)- and (-)-5 through
the optical resolution of the key intermediate 7.
Con str u ction of th e Com m on Bicyclic Cor e Sk el-
eton of 5 a n d 6. At the outset, the aldol reaction of 10
and 11 was performed in a racemic manner (Scheme 2).
The kinetic enolate derived from 10, using LDA as a base
at -78 °C, reacted with 11 at the same temperature to
afford an inseparable mixture of syn-9 and anti-9 in a
combined yield of 63%. The ratio of the desired syn-9 to
the anti-97 was disappointingly determined to be 1:4.5
(1H NMR analysis). It has been reported that diastereo-
selectivity in the aldol reaction of cyclohexanone lithium
enolate with benzaldehyde depends strongly on the
reaction temperaure.8 In fact, when the aldol reaction
mixture was allowed to warm to -18 °C, the ratio of syn-9
and anti-9 was improved to 1.2:1 without a loss of the
combined yield (66%). This fact indicated that a warming
reaction temperature occurs with the equilibration of the
two diastereomers resulting in the preferred formation
of syn-9. Benzoylation of the aldol mixture provided syn-
12 and anti-12, which were cleanly separated by chro-
matography on silica gel.
The 1,2-reduction of the enone syn-12 was conducted
using Luche’s conditions9 to afford allylic alcohol 13 with
a high level of diastereoselectivity (dr ) 20:1) (Scheme
3). Protection of 13 as the triethylsilyl (TES) ether
followed by reductive cleavage of the benzoyl group in
the resulting 14 gave 15 (90%) along with a trace amount
(4%) of the diastereomer 16, which could be removed by
chromatography on silica gel. The stereochemistries of
C-1 in 15 and 16 were determined by the 1H NMR
analysis. A large coupling constant between H-1 and H-6
(J 1,6 ) 8.1 Hz) was observed for 16, whereas that of 15
was J 1,6 ) 4.0 Hz. This stereochemical outcome of the
(5) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-736.
(6) Compound 11 was prepared from isovaleraldehyde by a modified
literature procedure: (i) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C; (ii)
Dibal-H, CH2Cl2, -78 °C; (iii) MnO2, CH2Cl2. Vig, O. P.; Bari, S. S.;
Puri, S. K.; Dua, D. M. Indian J . Chem. 1981, 20B, 342-343.
(7) The relative configurations (syn or anti) in the aldol products
were determined by 1H NMR analysis: Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: Orlando, 1984; Vol.
3, pp 111-212.
(8) Hirama, M.; Noda, T.; Takeishi, S.; Itoˆ, S. Bull. Chem. Soc. J pn.
1988, 61, 2645-2646.
(9) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
J . Org. Chem, Vol. 67, No. 19, 2002 6691

Takao et al.
SCHEME 4
1,2-reduction indicated that the hydride attack occurred
preferentially from the less-hindered R-face of the enone
face. As expected, the vanadium-catalyzed epoxidation10
of 15 preferentially provided R,â anti-epoxy alcohol 17
(anti-isomer 17:syn-isomer 18 ) 5.6:1). These allylic
alcohols 17 and 18 were readily separated by chroma-
tography on silica gel. The introduction of an exo-
methylene group into 19, which was prepared by the
oxidation of 17 with Dess-Martin periodinane,11 was
achieved efficiently using a Peterson olefination strat-
egy.12,13 Thus, ketone 19 was reacted with (trimethylsi-
lylmethyl)magnesium chloride to provide 20 as a single
diastereomer,14 which was subjected to â-elimination with
potassium hexamethyldisilazide (KHMDS) to give exo-
methylene-epoxide 21. Desilylation of the TES group in
21 provided γ,δ-epoxy allylic alcohol 8. As we anticipated,
exposure of 8 to a catalytic amount of camphorsulfonic
acid (CSA) in CH2Cl2 underwent intramolecular epoxy-
ring-opening cyclization in an exclusive 5-exo-tet mode,
resulting in the formation of rac-7 almost quantita-
tively.15
Op tica l Resolu tion of Ra cem ic 7. We then investi-
gated the optical resolution of the bicyclic alcohol rac-7.
When rac-7 was acylated with (S)-O-acetylmandelic
acid,16 diastereomers 22 and 23 were obtained, which
were readily separated by chromatography on silica gel
(Scheme 4). With the diisobutylaluminum hydride (Dibal-
H) reduction of 22 and 23, optically pure (+)-7 and (-)-
7, respectively, were obtained. The assignment of the
absolute stereochemistries for both enantiomers was
conducted by the following two methods. The esterifica-
tion of (+)- and (-)-7 with (R)-R-methoxy-R-(trifluoro-
methyl)phenylacetic acid (MTPA)17 afforded the MTPA
esters 24 and 25, respectively. As shown, positive ∆δ
values [δ(25) - δ(24)] were observed for the protons on
the right side of the MTPA plane, whereas negative
values were observed for those on the left side, indicating
that the absolute configuration of 24 was that depicted
in Scheme 4.18,19 In addition, the diastereomer 22 was
subjected to the Sharpless asymmetric dihydroxylation
conditions using AD-mix-â.20 As a result, R-vicinal diol
26 was obtained as the sole product with excellent
stereoselectivity. In contrast, the treatment of another
diastereomer 23 under the same dihydroxylation condi-
tions led to an inseparable mixture of â- and R-vicinal
diols 27 and 28, respectively, with a complete loss of
stereoselectivity (1.2:1) in a low combined yield of 40%.21
The latter case is considered to be mismatched, resulting
from the fact that the substrate and the chiral oxidizing
reagent have opposite stereofacial preferences. Conse-
quently, based on the Sharpless mnemonic device,20,22 the
structures of 22 and 23 were established as those
depicted. These results also were consistent with the
result obtained from the above modified Mosher’s ester
method.
(10) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron
Lett. 1979, 4733-4736.
(11) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287. (c) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(12) Anger, D. J . Org. React. 1990, 38, 1-223.
(13) When ketone 19 was subjected to Wittig methylenation (Ph3Pd
CH2), the undesired â-elimination of TESOH occurred to produce R,â:
γ,δ-unsaturated ketone. When the Takai reagent (CH2Br2-Zn-TiCl4;
Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. J pn.
1980, 53, 1698-1702) was employed, the epoxide in 19 was reduced
to an olefin.
(14) We did not determined the configuration of the newly intro-
duced stereogenic center in 20.
(15) The following alternative route to 7 from 17 was investigated.
Namely, the benzoate of 17 was desilylated, and the resulting allylic
alcohol derivative was subjected to the epoxy ring opening intramo-
(18) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096.
(19) (a) Kusumi, T. J . Synth. Org. Chem. J pn. 1993, 51, 462-470.
(b) Mori, M.; Saitoh, F.; Uesaka, N.; Shibasaki, M. Chem. Lett. 1993,
213-216.
lecular cyclization (CSA in CH2Cl2). As
a
result, two cyclization
(20) For a leading review on this subject, see: Kolb, H. C.; Van-
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547.
(21) On the other hand, dihydroxylation of 22 and 23 using a
standard achiral reagent system (OsO4-NMO) exclusively provided
26 (84%) and 27 (91%), respectively. Under these conditions as well
as the Sharpless asymmetric dihydroxylation conditions, dihydroxyl-
ation of the exo-methylene group in 22 or 23 was not observed. We
concluded that the use of 26 or 27 for the aimed total synthesis was
unacceptable as a result of longer reaction steps and more manipula-
tion steps for protection-deprotection.
products were obtained with incomplete regioselectivity (5-exo:6-endo
) 6:1). Furthermore, the introduction of an exo-methylene group into
the 5-exo-cyclization product under several conditions did not gave
fruitful results.
(16) (a) Whitesell, J . K.; Reynolds, D. J . Org. Chem. 1983, 48, 3548-
3551. (b) Garegg, P. J .; Lindberg, B.; Kvarnstro¨m, I.; Svensson, S. C.
T. Carbohydr. Res. 1985, 139, 209-215.
(17) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519.
6692 J . Org. Chem., Vol. 67, No. 19, 2002

(+)-Cheimonophyllon E and (+)-Cheimonophyllal
SCHEME 5
SCHEME 6
TABLE 1. Mu k a iya m a Ald ol Rea ction of 31 w ith 11
entry
conditionsa
yield (%)b syn:antic
1
2
3
4
TiCl4, CH2Cl2, -78 °C
53
57
76
31
68
52
1:5.8
1:4.0
1:2.3
1:2.5
1:3.0
1:1.6
Cl2Ti(O-i-Pr)2, CH2Cl2, -18 °C
EtAlCl2, CH2Cl2, -78 °C
Et2AlCl, CH2Cl2, -78 °C
BF3‚OEt2, CH2Cl2, -78 °C
TMSOTf, CH2Cl2, -78 °C
5
6d
a
Unless otherwise noted, 1.1 equiv of Lewis acid was used.
Isolated yield. c Determined by 1H NMR analysis. 0.2 equiv of
b
d
Lewis acid was used.
Tota l Syn th eses of (+)- a n d (-)-Ch eim on op h yllon
E (5). The remaining tasks for the total synthesis of 5
were the oxidation of the hydroxy group at the side chain
in 7 and the stereoselective introduction of the vicinal
dihydroxy group to the endocyclic double bond. These
were achieved as follows (Scheme 5). Dess-Martin
oxidation of the stereochemically defined (+)-7 gave 29,
been devised, and their usefulness has been demon-
strated through the asymmetric total syntheses of natu-
ral products.26 We were concerned with the catalytic
asymmetric Mukaiyama aldol reaction of the trimethyl-
silyl enol ether 31, kinetically derived from 10,27 with
aldehyde 11 (Scheme 6). In some cases, 2-silyloxy-1,3-
dienes, such as 31 are known to serve as dienes for [4 +
2] cycloadditions28 or as substrates for sequential Michael
reactions29 with R,â-unsaturated carbonyl compounds. To
confirm the feasibility of the aldol addition of 31 to R,â-
unsaturated aldehyde 11, the mixture was treated with
a variety of achiral Lewis acids. The results are sum-
marized in Table 1. In every case, a mixture of syn-9 and
anti-9 was obtained in moderate yields. Neither the
cycloaddition product(s) nor the Michael adduct(s) was
found in the reaction mixture. The ratio of syn/ anti
depended on the Lewis acid used, whereas the anti-
adduct was preferentially formed in all cases.
1
of which the structure was again confirmed by H NMR
analysis, including NOE experiments, as shown in Scheme
5. Finally, 29 was subjected to standard dihydroxylation
conditions using the OsO4-NMO system. The vicinal diol
was introduced exclusively from the convex face of the
bicyclic system to provide a 42% yield of (+)-cheimono-
phyllon E (5).23 A small amount of the regioisomeric
R-diol 30 was also obtained (14%).24 Analogously, (-)-7
was converted into (-)-cheimonophyllon E (5). The
spectroscopic data (IR, 1H, and 13C NMR; HRMS) of
synthetic (+)- and (-)-5 matched well those reported for
natural 5.2 In addition, the synthetic sample (+)-5
derived from (+)-7 had the same specific rotation (sign
and magnitude) as that of the natural product. Therefore,
the absolute stereochemistry of the natural product was
established as (+)-5, depicted in Scheme 5.
Ca ta lytic Asym m etr ic Mu k a iya m a Ald ol Rea c-
tion for Dia ster eoselective P r ep a r a tion of En a n -
tioen r ich ed syn -9. Having assigned the absolute ster-
eochemistry of (+)- and (-)-5, our interest was next
focused on the enantioselective synthesis of cheimono-
phyllons by an asymmetric aldol reaction approach. The
asymmetric aldol reaction is one of the most promising
methods for the enantioselective construction of carbon-
carbon bonds.25 As one of the representative approaches
to this subject, the chiral auxiliary-based aldol reactions
have been explored extensively, resulting in numerous
successes in the synthesis of complex chiral compounds.25a
On the other hand, catalytic versions of the asymmetric
aldol reaction have become major topics in synthetic
organic chemistry.25b,c,e A number of chiral catalysts have
Since the Mukaiyama aldol reaction of 31 with 11
approved successful, the use of chiral Lewis acid for the
enantioselective reaction was next investigated. Yama-
moto and co-workers reported the use of a chiral (acyl-
oxy)borane (CAB) complex 32 as the Lewis acid catalyst
(25) For recent reviews on the asymmetric aldol reaction, see: (a)
Cowden, C. J .; Paterson, I. Org. React. 1997, 51, 1-200. (b) Nelson, S.
G. Tetrahedron: Asymmetry 1998, 9, 357-389. (c) Gro¨ger, H.; Vogl,
E. M.; Shibasaki, M. Chem. Eur. J . 1998, 4, 1137-1141. (d) Arya, P.;
Qin, H. Tetrahedron 2000, 56, 917-947. (e) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int Ed. 2000, 39, 1352-1374.
(26) For some recent examples for this subject, see: (a) Kobayashi,
S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J . Am. Chem.
Soc. 1998, 120, 908-919. (b) Kim, Y.; Singer, R. A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 1261-1263. (c) Kobayashi, S.; Furuta,
T. Tetrahedron 1998, 54, 10275-10294. (d) Kobayashi, S.; Ueno, M.;
Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y. J . Org. Chem. 1999,
64, 6833-6841. (e) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J .
J . Am. Chem. Soc. 2000, 122, 10033-10046. (f) Sawada, D.; Kanai,
M.; Shibasaki, M. J . Am. Chem. Soc. 2000, 122, 10521-10532. (g)-
Wakabayashi, T.; Mori, K.; Kobayashi, S. J . Am. Chem. Soc. 2001, 123,
1372-1375. (h) Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.;
Hanada, K. J . Org. Chem. 2001, 66, 5580-5584.
(22) A publication on the Sharpless asymmetric dihydroxylation of
2-methylcyclohexene derivatives: Becker, H.; Soler, M. A.; Sharpless,
K. B. Tetrahedron 1995, 51, 1345-1376. In the present case, the
methyl group is pointing to the southwest quadrant in the mnemonic
device.
(27) Rubottom, G. M.; Gruber, J . M. J . Org. Chem. 1977, 42, 1051-
1056.
(28) (a) J ung, M. E.; McCombs, C. A. Tetrahedron Lett. 1976, 2935-
2938. (b) Rubottom, G. M.; Krueger, D. S. Tetrahedron Lett. 1977, 611-
614.
(23) We noticed that compound 5 decomposed slowly upon storage
at an ambient temperature.
(24) We made an effort to improve the yield of 5 in the final
dihydroxylation step. AD-mix reagents and the addition of tertiary
amine (diisopropylethylamine or 1,4-diazabicyclo[2.2.2]octane; DABCO)
to the OsO4-NMO conditions were both ineffective.
(29) (a) Mukaiyama, T.; Sagawa, Y.; Kobayashi, S. Chem. Lett. 1986,
1821-1824. (b) Asaoka, M.; Ishibashi, K.; Takahashi, W.; Takei, H.
Bull. Chem. Soc. J pn. 1987, 60, 2259-2260. (c) Spitzner, D.; Wagner,
P.; Simon, A.; Peters, K. Tetrahedron Lett. 1989, 30, 547-550. (d)
Hagiwara, H.; Okano, A.; Uda, H. J . Chem. Soc., Perkin Trans. 1 1990,
2109-2113.
J . Org. Chem, Vol. 67, No. 19, 2002 6693

Takao et al.
TABLE 2. Asym m etr ic Mu k a iya m a Ald ol Rea ction of 31
w ith 11
SCHEME 7
ee (%)
yield
of synd
entry
conditionsa
(%)b syn:antic (config)e
1
2
3
4
5
32 (20 mol %), EtCN, -78 °C
32 (50 mol %), EtCN,-78 °C
33 (20 mol %), EtCN, -78 °C
51
37
94f
1:1.4
1:1.4
10:1
10:1
1:1.2
24 (R)
18 (R)
99 (R)g
97 (S)g
75 (S)
ent-33 (20 mol %), EtCN, -78 °C 85f
34 (10 mol %), Et2O, -20 °C
15
a
b
Quenched with diluted hydrochloric acid. Isolated yield.
c Determined by H NMR analysis. Determined by HPLC analy-
sis using a chiral column. e Absolute configuration of C-6 is
indicated in parentheses. f Combined isolated yields of syn- and
1
d
confirmed after being transformed into the aforemen-
tioned advanced intermediate (+)-7 (Scheme 7). Interest-
ingly, the minor anti-9 was obtained as an almost racemic
form. The observed syn-selectivity and re-face attack of
the nucleophile to the aldehyde carbonyl are well con-
sistent with Yamamoto’s explanation in previous re-
ports.30 The acyclic extended transition state model has
been proposed for the high syn-selectivity.30 As for
enantioselectivity, it has been pointed out that the
benzene ring of the CAB catalyst shields the si-face of
the coordinating aldehyde, which is fixed by π-stacking
and formyl CH-O hydrogen bonds.31h,34 The use of ent-
33, derived from unnatural D-tartaric acid, as a chiral
source afforded the opposite enantiomeric adduct in a
similar yield and stereoselectivity (entry 4).33 On the
other hand, the aldol reaction using the Ti(IV) complex
34 gave the adducts in a poor yield along with less
satisfactory diastereo- and enantioselectivites (entry 5),
precluding further investigation of this catalyst.
g
anti-12 for two steps. ee of syn-12.
for the highly diastereo- and enantioselective Mukaiyama
aldol reaction of silyl enol ethers or ketene silyl acetals
with various aldehydes.30 In addition, a modified CAB
complex 33 was also found to increase the enantioselec-
tivity without reducing the chemical yield.30c The CAB
complexes 32 and 33 were easily prepared from a natural
tartaric acid derivative.31 On the other hand, Keck and
co-workers reported that the chiral Ti(IV) complex 34,
derived from Ti(O-i-Pr)4 and BINOL (1:2), catalyzed the
enantioselective addition of Danishefsky’s diene to alde-
hydes with good to excellent asymmetric induction.32
These chiral Lewis acids 32-34 were examined as the
catalyst for our aldol reaction of 31 with 11. The results
are shown in Table 2. In the presence of 20 mol % CAB
complex 32, a mixture of the aldol products and the
corresponding trimethylsilyl ether was observed. After
a workup with diluted hydrochloric acid, the desilylated
aldol products syn-9 and anti-9 were obtained (entry 1).
Disappointingly, the ratio was 1:1.4 and the enantiomeric
excess of the syn-adduct was determined to be 24% by
chiral HPLC analysis. Despite using 50 mol % 32, neither
the syn/ anti selectivity nor the ee of syn-9 improved
(entry 2). Gratifyingly, another CAB complex 33 realized
high levels of diastereo- and enantioselectivities for syn-9
(entry 3).33 It should be emphasized that both excellent
enantioselectivity and high syn selectivity were observed
in this case. The absolute stereochemistry in the pre-
dominant enantiomer syn-9 was assigned to be R and was
E n a n t ioselect ive Tot a l Syn t h eses of (+)-Ch ei-
m on op h yllon E (5) a n d (+)-Ch eim on op h ylla l (6). As
shown in Table 2 (entry 3), practical syn-selectivity and
exceptionally high enantioselectivity were realized with
the CAB catalyst 33. The conversion of the highly
enantioenriched aldol adduct into (+)-cheimonophyllon
E (5) was then pursued. After benzoylation of the aldol
mixture, (-)-syn-12 was isolated in an 86% yield in two
steps along with an 8% yield of anti-12 (Scheme 7). The
ee of (-)-syn-12 was determined to be 99%, indicating
that no racemization occurred during the benzoylation
and purification. From (-)-syn-12, the aforementioned
reaction sequence used for the conversion of syn-12 into
(+)-5 via rac- and (+)-7 was repeated to complete the
asymmetric total synthesis of (+)-cheimonophyllon E (5).
The optical rotation of the synthetic sample was con-
firmed to be well matched again with the natural one.
We also achieved the total synthesis of (+)-cheimono-
phyllal (6). The synthesis of (+)-6 began with the bicyclic
intermediate (+)-7 (Scheme 8). The vanadium-catalyzed
epoxidation of (+)-7 and the Dess-Martin oxidation of
the resulting 35 gave keto-epoxide 36 as a single isomer.
(30) (a) Furuta, K.; Maruyama, T.; Yamamoto, H. J . Am. Chem. Soc.
1991, 113, 1041-1042. (b) Furuta, K.; Maruyama, T.; Yamamoto, H.
Synlett 1991, 439-440. (c) Ishihara, K.; Maruyama, T.; Mouri, M.; Gao,
Q.; Furuta, K.; Yamamoto, H. Bull. Chem. Soc. J pn. 1993, 66, 3483-
3491.
(31) The CAB-type complexes have been widely used as Lewis acids
in the asymmetric Diels-Alder, hetero-Diels-Alder, allylation, and
Baylis-Hillman reactions; see: (a) Furuta, K.; Miwa, Y.; Iwanaga, K.;
Yamamoto, H. J . Am. Chem. Soc. 1988, 110, 6254-6255. (b) Furuta,
K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. J . Org. Chem. 1989, 54,
1481-1483. (c) Furuta, K.; Kanematsu, A.; Yamamoto, H.; Takaoka,
S. Tetrahedron Lett. 1989, 30, 7231-7232. (d) Furuta, K.; Mouri, M.;
Yamamoto, H. Synlett 1991, 561-562. (e) Gao, Q.; Maruyama, T.;
Mouri, M.; Yamamoto, H. J . Org. Chem. 1992, 57, 1951-1952. (f)
Marshall, J . A.; Tang, Y. Synlett 1992, 653-654. (g) Ishihara, K.; Gao,
Q.; Yamamoto, H. J . Org. Chem. 1993, 58, 6917-6919. (h) Ishihara,
K.; Gao, Q.; Yamamoto, H. J . Am. Chem. Soc. 1993, 115, 10412-10413.
(i) Gao, Q.; Ishihara, K.; Maruyama, T.; Mouri, M.; Yamamoto, H.
Tetrahedron 1994, 50, 979-988. (j) Barrett, A. G. M.; Kamimura A. J .
Chem. Soc., Chem. Commun. 1995, 1755-1756.
(32) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J . Org. Chem. 1995,
60, 5998-5999. The exact structure of the catalyst 34 has not yet been
clarified in detail.
(33) In this case, the desired adduct 9 was inseparable from 33-
derived o-phenoxyphenyl-boronic acid. The yield and ee of the product
were determined after the conversion of 9 into the benzoates syn-12
and anti-12, which were isolated in their pure forms.
(34) Corey, E. J .; Rohde, J . J . Tetrahedron Lett. 1997, 38, 37-40.
6694 J . Org. Chem., Vol. 67, No. 19, 2002

(+)-Cheimonophyllon E and (+)-Cheimonophyllal
internal standard. 13C NMR spectra were recorded at 75 MHz
in CDCl3 solution. Thin-layer chromatography (TLC) was
performed on Kieselgel 60 F254 plates (Merck). The crude
reaction mixtures and extractive materials were purified by
chromatography on Daisogel IR-60 (Daiso) or Wakogel C-300
(Wako). Unless otherwise described, reactions were carried out
at ambient temperature. Combined organic extracts were dried
over anhydrous Na2SO4. Solvents were removed from the
reaction mixture or combined organic extracts by concentration
under reduced pressure using an evaporator with a water bath
at 35-45 °C.
SCHEME 8
Mixt u r e of r el-(6R)-6-[(1S a n d R,2E)-1-H yd r oxy-5-
m eth yl-2-h exen yl]-3- m eth yl-2-cycloh exen -1-on e (syn -9
a n d a n ti-9). The following reaction was carried out under Ar.
To a cooled (0 °C) stirred solution of i-Pr2NH (2.8 mL, 20 mmol)
in THF (20 mL) was added n-BuLi (1.54 M solution in hexane,
11.5 mL, 18.4 mmol). After being stirred at 0 °C for 30 min,
the mixture was cooled to -78 °C, and 10 (2.10 mL, 18.1 mmol)
was added. The mixture was stirred at -78 °C for 30 min and
then warmed to -18 °C, and a solution of 11 (2.03 g, 18.1
mmol) in THF (20 mL) was added. After being stirred at -18
°C for 15 min, the mixture was quenched with saturated
aqueous NH4Cl (3 mL), diluted with EtOAc (200 mL), and
washed with saturated aqueous NH4Cl (200 mL × 3). The
organic layer was dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:8) to provide 2.64 g (66%) of an inseparable mixture
(1.2:1) of syn-9 and anti-9 as a colorless oil: TLC Rf 0.35
(EtOAc/hexane, 1:3); IR 3450, 1670, 1650 cm-1; 1H NMR δ 0.86
(d, 3 H, J ) 6.6 Hz), 0.88 (d, 3 H, J ) 6.6 Hz), 1.62 (m, 1 H),
1.81-2.51 (m, 7 H), 1.96 (s, 3 H), 4.24 (t, 1 H × 5/11, J ) 8.3
Hz, H-1 of the side chain at C-6 in anti-9), 4.43 (dd, 1 H ×
6/11, J ) 3.5, 7.0 Hz, H-1 of the side chain at C-6 in syn-9),
5.41 (m, 1 H × 5/11), 5.49 (m, 1 H × 6/11), 5.67 (m, 1 H), 5.89
(s, 1 H); 13C NMR signals attributable to syn-9 δ 22.2, 22.3,
23.7, 24.2, 28.1, 30.9, 41.6, 50.2, 72.8, 126.9, 130.3, 132.1,163.5,
201.7; signals attributable to anti-9 δ 22.2, 22.4, 24.1, 25.3,
28.1, 30.8, 41.6, 50.2, 74.2, 126.7, 130.5, 133.4, 163.9, 203.3;
HRMS calcd for C14H22O2 (M+) m/z 222.1620, found 222.1619.
Under the analogous conditions (OsO4-NMO) used for
the synthesis of 5, vicinal dihydroxylation of 36 afforded
an inseparable mixture of diol 37 and its diastereomer
at a ratio of 10:1. The addition of 1,4-diazabicyclo[2.2.2]-
octane (DABCO)35 to these oxidation conditions improved
the diastereoselectivity (more than 20:1), and the desired
37 was obtained as an almost single isomer. Finally,
compound 37 was subjected to the â-elimination ac-
companying the epoxy ring opening mediated by sodium
ethoxide, followed by the chemoselective oxidation of the
resulting allylic alcohol with RuCl3-NMO reagents,36
eventually providing (+)-cheimonophyllal (6).37 Our syn-
thetic (+)-6 was identical in all respects to a natural
1
sample ([R]D, IR, H and 13C NMR, HRMS).2
Con clu sion s
The highly enantiocontrolled total syntheses of (+)-
cheimonophyllon E (5) and (+)-cheimonophyllal (6) have
been accomplished. Highlights of these synthetic ven-
tures include the CAB (33)-catalyzed asymmetric Mu-
kaiyama aldol reaction of the 2-silyloxy-1,3-cyclohexadi-
ene derivative 31 and the R,â-unsaturated aldehyde 11
for the enantioselective preparation of the enantioen-
riched cyclohexenone building block syn-9; the substrate-
induced diastereoselective 1,2-reduction of the enone syn-
12 and epoxidation of the allylic alcohol 15; and the
assembly of the bicyclic core skeleton by the highly
selective 5-exo-tet cyclization of the γ,δ-epoxy allylic
alcohol 8. Our asymmetric synthesis of (+)-cheimono-
phyllon E (5) was accomplished in 13 steps with a 16%
overall yield from the known achiral R,â-unsaturated
aldehyde 11 and the synthesis of (+)-cheimonophyllal (6)
in 16 steps with a 14% overall yield.
r el-(6R)-6-[(1S,2E)- (syn -12) a n d r el-(6R)-6-[(1R,2E)-1-
Ben zoyloxy-5-m eth yl- 2-h exen yl]-3-m eth yl-2-cycloh exen -
1-on e (a n ti-12). To a cooled (0 °C) stirred solution of the 1.2:1
mixture of syn-9 and anti-9 (2.64 g, 11.9 mmol) in pyridine
(50 mL) was added benzoyl chloride (2.8 mL, 24 mmol). The
mixture was stirred for 2.5 h and diluted with EtOAc (200 mL).
The resulting mixture was washed with 1 M aqueous HCl (200
mL), saturated aqueous NaHCO3 (200 mL), and saturated
brine (200 mL), successively. The organic layer was dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:16) to provide
1.93 g (50%) of syn-12 and 1.67 g (43%) of anti-12. Compound
syn-12 was obtained as a colorless oil: TLC Rf 0.55 (EtOAc/
hexane, 1:3); IR 1720, 1670 cm-1; 1H NMR δ 0.86 (d, 6 H, J )
6.6 Hz), 1.62 (m, 1 H), 1.91-1.96 (m, 2 H), 1.96 (s, 3 H), 2.10-
2.26 (m, 2 H), 2.37-2.44 (m, 2 H), 2.54 (dt, 1 H, J ) 10.7, 4.5
Hz), 5.56 (ddt, 1 H, J ) 15.4, 6.1, 1.0 Hz), 5.74 (ddt, 1 H, J )
15.4, 0.7, 7.1 Hz), 5.89 (d, 1 H, J ) 1.2 Hz), 6.07 (br dd, 1 H,
J ) 6.1, 4.5 Hz), 7.38-7.55 (m, 3 H), 7.98-8.02 (m, 2 H); 13C
NMR δ 22.21, 22.24, 22.9, 24.2, 28.1, 30.2, 41.5, 49.7, 72.4,
126.7, 127.1, 128.2 × 2, 129.5 × 2, 130.5, 132.7, 133.6, 162.0,
165.3, 197.2; HRMS calcd for C21H26O3 (M+) m/z 326.1882,
found 326.1883. Compound anti-12 was obtained as a colorless
oil: TLC Rf 0.61 (EtOAc/hexane, 1:3); IR 1720, 1670 cm-1; 1H
NMR δ 0.85 (d, 3 H, J ) 6.6 Hz), 0.86 (d, 3 H, J ) 6.6 Hz),
1.63 (m, 1 H), 1.91-1.97 (m, 3 H), 1.95 (s, 3 H), 2.19 (m, 1 H),
2.32-2.36 (m, 2 H), 2.76 (dt, 1 H, J ) 11.2, 5.1 Hz), 5.53 (ddt,
1 H, J ) 15.4, 6.4,1.2 Hz), 5.82 (ddt, 1 H, J ) 15.4,1.0, 7.3
Hz), 5.87 (brd, 1 H, J ) 1.5 Hz), 6.06 (brdd, 1 H, J ) 6.4, 5.1
Hz), 7.41-7.58 (m, 3 H), 8.03-8.07 (m, 2 H); 13C NMR δ 22.21,
22.24, 23.5, 24.2, 28.1, 30.0, 41.6, 49.2, 73.9, 126.1, 126.6, 128.3
× 2, 129.5 × 2, 130.5, 132.8, 134.2, 161.7, 165.3, 197.6; HRMS
calcd for C21H26O3 (M+) m/z 326.1882, found 326.1874.
Exp er im en ta l Section 38
Melting points are uncorrected. Specific rotations were
1
measured in a 10-mm cell. H NMR spectra were recorded at
300 MHz in CDCl3 solution with tetramethylsilane as an
(35) Erdik, E.; Kaˆhya, D.; Daskapan, T. Synth. Commun. 1998, 28,
1-7.
(36) Sharpless, K. B.; Akashi, K.; Oshima, K. Tetrahedron Lett. 1976,
2503-2506.
(37) As compared to 5, compound 6 was much more unstable and
decomposed slowly upon storage even in a freezer.
(38) The numbering adopted for the nomenclatures of the com-
pounds described in the Experimental Section is in accord with the
IUPAC rules and is not in accord with that used in the text.
J . Org. Chem, Vol. 67, No. 19, 2002 6695

Takao et al.
Mixtu r e of r el-(1R a n d S,6S)-6-[(1S,2E)-1-Ben zoyloxy-
5-m eth yl-2-h exen yl]- 3-m eth yl-2-cycloh exen -1-ol (13). To
a cooled (-78 °C) stirred solution of syn-12 (1.93 g, 5.91 mmol)
in MeOH (40 mL) was added CeCl3‚7H2O (6.71 g, 18.0 mmol).
After the mixture stirred at -78 °C for 15 min, NaBH4 (340
mg, 8.99 mmol) was added to the solution. The mixture was
stirred at -18 °C for 1 h, diluted with EtOAc (200 mL), and
washed with H2O (200 mL × 3). The organic layer was dried
and concentrated in vacuo to provide crude 13 (1.94 g) as an
inseparable diastereomeric mixture (20:1), which was used
directly in the next step. In a small scale experiment, crude
13 was purified by column chromatography on silica gel
(EtOAc/hexane, 1:10) and obtained as a colorless oil: TLC Rf
0.56 (EtOAc/hexane, 1:3); IR 3500, 1720 cm-1; 1H NMR for the
major isomer δ 0.86 (d, 3 H, J ) 6.6 Hz), 0.88 (d, 3 H, J ) 6.6
Hz), 1.55-1.86 (m, 4 H), 1.69 (s, 3 H), 1.88-2.03 (m, 4 H),
4.15 (m, 1 H), 5.57-5.65 (m, 3 H), 5.92 (m, 1 H), 7.41-7.56
(m, 3 H), 8.05-8.08 (m, 2 H); 13C NMR for the major isomer δ
19.4, 22.3 × 2, 23.4, 28.1, 30.6, 41.7, 43.8, 64.4, 77.0, 123.0,
128.2, 128.3 × 2, 129.5 × 2, 130.8, 132.7, 134.8, 140.0, 165.9;
HRMS calcd for C21H28O3 (M+) m/z 328.2039, found 328.2036.
130.7, 132.0, 136.7; HRMS calcd for C20H38O2Si (M+) m/z
338.2641, found 338.2640.
r el-(3R,4R)-4-[(1R,2R,3R)- (17) an d r el-(3R,4R)-4-[(1R,2S,
3S)-2,3-Ep oxy-1- h yd r oxy-5-m eth ylh exa n yl]-1-m eth yl-3-
tr ieth ylsilyloxy-1-cycloh exen e (18). The following reaction
was carried out under Ar. To a cooled (0 °C) stirred solution
of 15 (1.51 g, 4.46 mmol) in CH2Cl2 (30 mL) were added VO-
(acac)2 (60.1 mg, 0.23 mmol) and t-BuOOH (5.13 M solution
in toluene, 2.65 mL, 13.6 mmol). The mixture was stirred at 0
°C for 2.5 h, quenched with saturated aqueous NaHSO3 (2 mL),
and diluted with EtOAc (150 mL). The resulting mixture was
washed with saturated aqueous NaHSO3 (150 mL), saturated
aqueous NaHCO3 (150 mL), and saturated brine (150 mL),
successively. The organic layer was dried and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:40) to provide 1.24 g (78%) of
17 and 217 mg (14%) of 18. Compound 17 was obtained as a
colorless oil: TLC Rf 0.47 (EtOAc/hexane, 1:10); IR 3500 cm-1
;
1H NMR δ 0.62 (q, 6 H, J ) 7.8 Hz), 0.95 (t, 9 H, J ) 7.8 Hz),
0.99 (d, 6 H, J ) 6.8 Hz), 1.39 (m, 1 H), 1.49-1.58 (m, 2 H),
1.65-2.11 (m, 5 H), 1.69 (s, 3 H), 2.81 (dd, 1 H, J ) 6.1, 2.2
Hz), 3.02 (ddd, 1 H, J ) 7.1, 4.7, 2.2 Hz), 3.70 (dd, 1 H, J )
6.1, 1.8 Hz), 3.80 (s, 1 H, OH), 4.28 (t, 1 H, J ) 3.7 Hz), 5.48
(br d, 1 H, J ) 3.7 Hz); 13C NMR δ 5.4 × 3, 6.8 × 3, 16.5, 22.5,
22.9, 23.5, 26.5, 30.6, 41.0, 41.2, 56.9, 58.7, 70.4, 74.1, 122.7,
139.8; HRMS calcd for C20H38O3Si (M+) m/z 354.2590, found
354.2590. Compound 18 was obtained as a colorless oil: TLC
Mixtu r e of r el-(3R a n d S,4R)-4-[(1S,2E)-1-Ben zoyloxy-
5-m eth yl-2-h exen yl]- 1-m eth yl-3-tr ieth ylsilyloxy-1-cyclo-
h exen e (14). To a cooled (0 °C) stirred solution of crude 13
obtained above (20:1 mixture, 1.94 g) in DMF (40 mL) were
added imidazole (2.42 g, 35.5 mmol) and TESCl (3.0 mL, 18
mmol). The mixture was stirred at 0 °C for 2 h, diluted with
EtOAc (200 mL), and washed with saturated aqueous NH4Cl
(200 mL). The organic layer was dried and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:45) to provide 2.37 g (91% from
syn-12) of an inseparable mixture (20:1) of 14 as a colorless
oil: TLC Rf 0.78 (EtOAc/hexane, 1:6); IR 1720 cm-1; 1H NMR
for the major isomer δ 0.59 (q, 6 H, J ) 8.1 Hz), 0.86 (d, 3 H,
J ) 6.4 Hz), 0.88 (d, 3 H, J ) 6.4 Hz), 0.96 (t, 9 H, J ) 8.1
Hz), 1.58-1.78 (m, 4 H), 1.68 (s, 3 H), 1.90-2.04 (m, 4 H),
4.19 (m, 1 H), 5.48-5.73 (m, 3 H), 5.82 (dt, 1 H, J ) 14.0, 7.0
Hz), 7.40-7.56 (m, 3 H), 8.02-8.07 (m, 2 H); 13C NMR for the
major isomer δ 5.9 × 3, 7.0 × 3, 19.3, 22.3, 22.4, 23.3, 28.1,
30.7, 41.9, 44.7, 65.0, 77.1, 123.7, 128.2 × 2, 128.6, 129.5 × 2,
131.1, 132.6, 134.1, 138.7, 165.9; HRMS calcd for C27H42O3Si
(M+) m/z 442.2903, found 442.2894.
1
Rf 0.32 (EtOAc/hexane, 1:10); IR 3450 cm-1; H NMR δ 0.61
(q, 6 H, J ) 7.9 Hz), 0.95 (t, 9 H, J ) 7.9 Hz), 0.97 (d, 3 H, J
) 6.7 Hz), 0.98 (d, 3 H, J ) 6.7 Hz), 1.41-1.46 (m, 2 H), 1.61
(m, 1 H), 1.69 (s, 3 H), 1.78-2.05 (m, 5 H), 2.85 (dd, 1 H, J )
3.9, 2.2 Hz), 2.98 (dt, 1 H, J ) 2.2, 5.9 Hz), 3.38 (br, 1 H, OH),
3.82 (m, 1 H), 4.30 (t, 1 H, J ) 3.9 Hz), 5.50 (br d, 1 H, J ) 3.9
Hz); 13C NMR δ 5.4 × 3, 6.7 × 3, 17.5, 22.4, 22.9, 23.7, 26.4,
30.6, 40.9, 43.0, 53.9, 60.7, 69.2, 72.7, 122.7, 139.7; HRMS calcd
for C20H38O3Si (M+) m/z 354.2590, found 354.2586.
r el-(3R,4S)-4-[(2S,3R)-2,3-Ep oxy-5-m eth ylh exa n oyl]-1-
m eth yl-3-tr ieth ylsilyloxy-1-cycloh exen e (19). To a cooled
(0 °C) stirred solution of 17 (1.24 g, 3.50 mmol) in CH2Cl2 (14
mL) was added Dess-Martin periodinane (1.65 g, 3.89 mmol).
The mixture was stirred for 1 h and diluted with EtOAc (100
mL). The resulting mixture was washed with saturated
aqueous Na2S2O3 (100 mL), saturated aqueous NaHCO3 (100
mL), and saturated brine (100 mL), successively. The organic
layer was dried and concentrated in vacuo to provide crude
19 (1.17 g), which was used directly in the next step. In a small
scale experiment, crude 19 was purified by column chroma-
tography on silica gel (EtOAc/hexane, 1:40) and obtained as a
r el-(3R,4R)-(15) a n d r el-(3S,4R)-4-[(1S,2E)-1-Hyd r oxy-
5-m eth yl-2-h exen yl]-1-m eth yl-3-tr ieth ylsilyloxy-1-cyclo-
h exen e (16). The following reaction was carried out under
Ar. To a cooled (-78 °C) stirred solution of 14 (20:1 mixture,
2.20 g, 4.97 mmol) in CH2Cl2 (40 mL) was added Dibal-H (1.0
M solution in toluene, 11 mL, 11 mmol). The mixture was
stirred at -78 °C for 1.5 h and quenched with H2O (2 mL).
The precipitated solids were removed by filtration through a
Celite pad and washed well with CH2Cl2. The combined filtrate
and washings were concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:40) to provide 1.51 g (90%) of 15 and 63.7 mg (4%)
of 16. Compound 15 was obtained as a colorless oil: TLC Rf
colorless oil: TLC Rf O.27 (EtOAc/hexane, 1:20); IR 1720 cm-1
;
1 H NMR δ 0.56 (q, 6 H, J ) 7.9 Hz), 0.92 (t, 9 H, J ) 7.9 Hz),
0.98 (d, 3 H, J ) 6.6 Hz), 0.99 (d, 3 H, J ) 6.6 Hz), 1.42-1.56
(m, 3 H), 1.71 (s, 3 H), 1.78-2.08 (m, 4 H), 2.63 (ddd, 1 H, J
) 11.1, 4.6, 2.8 Hz), 3.07 (ddd, 1 H, J ) 6.7, 4.9, 2.2 Hz), 3.48
(d, 1 H, J ) 2.2 Hz), 4.64 (t, 1 H, J ) 4.6 Hz), 5.53 (dt, 1 H, J
) 4.6,1.5 Hz); 13C NMR δ 5.5 × 3, 7.0 × 3, 18.7, 22.5, 23.0,
23.5, 26.5, 29.5, 41.2, 51.1, 58.1,58.6, 66.0, 123.0, 138.9, 206.2;
HRMS calcd for C20H36O3Si (M+) m/z 352.2434, found 352.2427.
1
0.59 (EtOAc/hexane, 1:8); IR 3500 cm-1; H NMR δ 0.63 (q, 6
H, J ) 7.9 Hz), 0.89 (d, 6 H, J ) 6.6 Hz), 0.96 (t, 9 H, J ) 7.9
Hz), 1.44 (m, 1 H), 1.59-1.66 (m, 3 H), 1.68 (s, 3 H), 1.72-
2.09 (m, 4 H), 3.87 (br s, 1 H, OH), 4.30 (t, 1 H, J ) 4.0 Hz),
4.45 (brd, 1 H, J ) 4.8 Hz), 5.44 (ddt, 1 H, J ) 15.4,4.8, 1.2
Hz), 5.49 (brd, 1 H, J ) 4.0 Hz), 5.69 (ddt, 1 H, J ) 15.4,1.0,
7.1 Hz); 13C NMR δ 5.5 × 3, 6.8 × 3, 15.8, 22.3 × 2, 23.4, 28.3,
30.9, 41.9, 44.4, 70.4, 74.4, 123.0, 129.6, 132.2, 139.8; HRMS
calcd for C20H38O2Si (M+) m/z 338.2641, found 338.2657.
Compound 16 was obtained as a colorless oil: TLC Rf 0.54
(EtOAc/hexane, 1:8); IR 3450 cm-1; 1H NMR δ 0.66 (q, 6 H, J
) 8.1 Hz), 0.90 (d, 6 H, J ) 6.6 Hz), 0.99 (t, 9 H, J ) 8.1 Hz),
1.40 (m, 1 H), 1.55-1.75 (m, 3 H), 1.67 (s, 3 H), 1.80-2.10 (m,
4 H), 2.48 (br s, 1 H, OH), 4.25 (m, 1 H), 4.33 (br d, 1 H, J )
8.1 Hz), 5.31 (br s, 1 H), 5.51 (dd, 1 H, J ) 15.4, 5.9 Hz), 5.66
(ddt, 1 H, J ) 15.4, 1.1, 7.0 Hz); 13C NMR δ 5.3 × 3, 6.9 × 3,
21.4, 22.3, 22.4, 23.2, 28.3, 29.8, 41.8, 46.8, 69.6, 72.9, 125.4,
r el-(3R,4S)-4-[(2S,3R)-2,3-Ep oxy-1-h yd r oxy-5-m eth yl-1-
(tr im eth ylsilylm eth yl)h exa n yl]-1-m eth yl-3-tr ieth ylsilyl-
oxy-1-cycloh exen e (20). The following reaction was carried
out under Ar. To a cooled (0 °C) stirred solution of crude 19
obtained above (1.17 g) in THF (25 mL) was added TMSCH2-
MgCl (1.0 M solution in Et2O, 7.0 mL, 7.0 mmol). The mixture
was stirred at 0 °C for 1 h, quenched with H2O (2 mL), and
diluted with EtOAc (100 mL). The resulting mixture was
washed with saturated aqueous NH4Cl (100 mL × 3). The
organic layer was dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:50) to provide 1.34 g (87% from 17) of 20 as a
colorless oil: TLC Rf 0.47 (EtOAc/hexane, 1:20); IR 3500 cm-1
;
1H NMR δ 0.08 (s, 9 H), 0.62 (q, 6 H, J ) 7.8 Hz), 0.95 (t, 9 H,
J ) 7.8 Hz), 0.98 (d, 6 H, J ) 6.1 Hz), 1.17-1.65 (m, 5 H),
6696 J . Org. Chem., Vol. 67, No. 19, 2002

(+)-Cheimonophyllon E and (+)-Cheimonophyllal
1.19 (d, 1 H, J ) 14.6 Hz), 1.36 (d, 1 H, J ) 14.6 Hz), 1.70 (s,
3 H), 1.80-2.10 (m, 3 H), 2.52 (d, J ) 2.4 Hz, 1 H), 3.21 (ddd,
1 H, J ) 7.6, 2.8, 2.4 Hz), 4.08 (s, 1 H, OH), 4.52 (m, 1 H),
5.54 (br d, 1 H, J ) 4.4 Hz); 13C NMR δ 0.02 × 3, 5.2 × 3, 6.3
× 3, 17.7, 22.1, 22.5, 22.8, 25.0, 27.4, 30.7, 40.8, 44.3, 54.9,
63.7, 66.9, 73.7, 122.1, 139.5; HRMS calcd for C24H48O3Si2 (M+)
m/z 440.3142, found 440.3126.
1.80 mmol) and o-phenoxyphenylboronic acid (382 mg, 1.79
mmol) in propionitrile (24 mL) was stirred for 30 min to
prepare 33. The solution was cooled to -78 °C, and 11 (1.00
g, 8.92 mmol) and 31 (2.46 g, 13.4 mmol) were added. After
being stirred at -78 °C for 2.5 h, the mixture was quenched
with 0.2 M aqueous HCl (10 mL), warmed to room tempera-
ture, and stirred for an additional 1 h. The resulting mixture
was diluted with EtOAc (100 mL) and washed with H2O (50
mL × 3). The organic layer was dried and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:5) to provide 2.61 g of crude
mixture (10:1) of syn-9 and anti-9 as a pale yellow oil, which
was contaminated with o-phenoxyphenylboronic acid but used
to the next step without further purification: HPLC analysis
(column, Daicel Chiralcel OD+OD-H, EtOH/hexane ) 1:60,
flow rate ) 0.7 mL/min); tR (min) ) 22.5 for (6R)-syn-9, 23.2
for (6S)-syn-9, 24.2 and 25.8 for anti-9.
r el-(3R,4R)-4-[(2R,3R)-2,3-E p oxy-5-m et h yl-1-m et h yl-
en eh exa n yl]-1-m et h yl-3-t r iet h ylsilyloxy-1-cycloh exen e
(21). The following reaction was carried out under Ar. To a
cooled (0 °C) stirred solution of 20 (1.34 g, 3.04 mmol) in THF
(25 mL) was added KHMDS (0.5 M solution in toluene, 16 mL,
8.0 mmol). The mixture was stirred at 0 °C for 1.5 h, quenched
with saturated aqueous NH4Cl (2 mL), and diluted with EtOAc
(150 mL). The resulting mixture was washed with saturated
aqueous NH4Cl (100 mL × 3). The organic layer was dried
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:50) to provide
0.988 g (93%) of 21 as a colorless oil: TLC Rf 0.58 (EtOAc/
As described for the preparation of (()-12, the crude mixture
of syn-9 and anti-9 obtained above (2.61 g) was treated with
benzoyl chloride (2.6 mL, 22 mmol) in pyridine (40 mL) to
provide 2.50 g (86% from 11) of (-)-syn-12 and 247 mg (8%
from 11) of anti-12: HPLC analysis (column, Daicel Chiralcel
OD+OD-H, EtOH/hexane ) 1:30, flow rate ) 0.7 mL/min); tR
(min) ) 21.3 for (-)-syn-12, 25.3 for (+)-syn-12. Compound (-)-
1
hexane, 1:20); H NMR δ 0.55 (q, 6 H, J ) 7.9 Hz), 0.92 (t, 9
H, J ) 7.9 Hz), 0.97 (d, 3 H, J ) 6.6 Hz), 0.99 (d, 3 H, J ) 6.6
Hz), 1.43-1.51 (m, 3 H), 1.68 (s, 3 H), 1.83 (m, 1 H), 1.94-
2.08 (m, 4 H), 2.79 (dt, 1 H, J ) 2.1, 5.8 Hz), 3.09 (d, 1 H, J )
2.1 Hz), 4.06 (m, 1 H), 5.00 (s, 1 H), 5.21 (s, 1 H), 5.52 (br d,
J ) 3.9 Hz, 1 H); 13C NMR δ 5.2 × 3, 6.9 × 3, 22.1, 22.5, 23.0,
23.4, 26.4, 31.0, 41.4, 41.5, 58.9, 60.0, 66.1, 113.9, 124.3, 137.6,
145.9; HRMS calcd for C21H38O2Si (M+) m/z 350.2641, found
350.2637.
syn-12 was determined to be 99% ee: [R]25 -139 (c 1.94,
D
CHCl3).
P r ep a r a tion of (+)-7 fr om (-)-syn -12. Compound (-)-syn-
12 was converted into (+)-7 by the same reaction sequence
r el-(1R,6R)-6-[(2R,3R)-2,3-E p oxy-5-m et h yl-1-m et h yl-
en eh exa n yl]-3-m eth yl-2-cycloh exen -1 -ol (8). To a cooled
(0 °C) stirred solution of 21 (0.988 g, 2.82 mmol) in THF (15
mL) was added n-Bu4NF (1.0 M solution in THF, 4.5 mL, 4.5
mmol). The mixture was stirred at 0 °C for 3 h, quenched with
saturated aqueous NaHCO3 (2 mL), and diluted with Et2O (150
mL). The resulting mixture was washed with saturated
aqueous NaHCO3 (100 mL) and saturated brine (100 mL ×
2), successively. The organic layer was dried and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:8) to provide 0.652 g (98%) of 8
as a colorless oil: TLC Rf 0.21 (EtOAc/hexane, 1:10); IR 3450
used for the preparation of rac-7: (-)-13 [R]25 -81.8 (c 2.04,
D
CHCl3), (-)-14 [R]24D -89.1 (c 3.34, CHCl3), (-)-15 [R]24D -138
(c 2.11, CHCl3), (+)-16 [R]24D +6.6 (c 1.60, CHCl3), (-)-17 [R]24
D
-107 (c 2.93, CHCl3), (-)-18 [R]24 -139 (c 2.04, CHCl3), (-)-
D
19 [R]26 -131 (c 1.53, CHCl3), (-)-20 [R]24 -84.1 (c 3.12,
D
D
CHCl3), (-)-21 [R]25 -120 (c 2.30, CHCl3), (-)-8 [R]24 -153
D
D
(c 1.54, CHCl3), (+)-7 [R]24 +147 (c 4.64, CHCl3).
D
(1R,6R,8S)-3-Meth yl-8-(3-m eth ylbu tan oyl)-7-m eth ylen e-
9-oxa bicyclo-[4.3.0]n on -2-en e (29). To a cooled (0 °C) stirred
solution of (+)-7 (26.9 mg, 0.114 mmol) in CH2Cl2 (2 mL) was
added Dess-Martin periodinane (97.7 mg, 0.230 mmol). The
mixture was stirred at 0 °C for 15 h and diluted with EtOAc
(20 mL). The resulting mixture was washed with saturated
aqueous Na2S2O3 (10 mL), saturated aqueous NaHCO3 (10
mL), and saturated brine (10 mL), successively. The organic
layer was dried and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:35) to provide 24.2 mg (91%) of 29 as a colorless oil:
TLC Rf 0.81 (EtOAc/hexane, 1:3); [R]23D +67.4 (c 3.27, CHCl3);
IR 1720, 1670 cm-1; 1H NMR δ 0.89 (d, 3 H, J ) 6.7 Hz), 0.93
(d, 3 H, J ) 6.7 Hz), 1.71 (s, 3 H), 1.75-1.86 (m, 3 H), 2.02 (m,
1 H), 2.15 (m, 1 H), 2.35 (dd, 1 H, J ) 17.3, 7.1 Hz), 2.55 (dd,
1 H, J ) 17.3, 6.3 Hz), 2.75 (m, 1 H), 4.66 (m, 1 H), 4.70 (m,
1 H), 5.08 (t, 1 H, J ) 2.3 Hz), 5.15 (t, 1 H, J ) 2.3 Hz), 5.50
(m, 1 H); 13C NMR δ 22.5, 22.6, 23.4, 23.7, 24.0, 26.8, 40.7,
46.6, 76.5, 84.5, 107.0, 120.2, 140.4, 148.6, 209.6; HRMS calcd
for C15H22O2 (M+) m/z 234.1620, found 234.1618.
1
cm-1; H NMR δ 0.97 (d, 3 H, J ) 6.7 Hz), 0.99 (d, 3 H, J )
6.7 Hz), 1.33 (m, 1 H), 1.40-1.60 (m, 2 H), 1.73 (s, 3 H), 1.77-
1.93 (m, 3 H), 2.04-2.08 (m, 2 H), 2.22 (br, 1 H, OH), 2.89 (dt,
1 H, J ) 2.0, 6.1 Hz), 3.10 (d, 1 H, J ) 2.0 Hz), 4.13 (m, 1 H),
5.05 (s, 1 H), 5.30 (s, 1 H), 5.66 (m, 1 H); 13C NMR δ 21.2,
22.5, 22.9, 23.4, 26.3, 30.9, 41.2, 42.3, 59.0, 59.6, 64.5, 113.7,
122.2, 139.7, 146.4; HRMS calcd for
236.1776, found 236.1783.
C
15H24O2 (M+) m/z
r el-(1R,6R,8S)-8-[(1R)-1-Hydr oxy-3-m eth ylbu tyl]-3-m eth -
yl-7-m eth ylen e-9-oxa bicyclo[4.3.0]n on -2-en e (r a c-7). To a
cooled (-18 °C) stirred solution of 8 (0.538 g, 2.28 mmol) in
CH2Cl2 (10 mL) was added CSA (52.9 mg, 0.23 mmol). The
mixture was stirred at -18 °C for 1 h, quenched with saturated
aqueous NaHCO3 (1 mL), and diluted with EtOAc (50 mL).
The resulting mixture was washed with saturated aqueous
NaHCO3 (50 mL × 2) and saturated brine (50 mL), succes-
sively. The organic layer was dried and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:10) to provide 0.529 g (98%) of rac-7 as
a colorless oil: TLC Rf 0.42 (EtOAc/hexane, 1:3); IR 3450, 1670
(1S,2R,3S,6R,8S)-2,3-Dih yd r oxy-3-m et h yl-8-(3-m et h -
ylbu ta n oyl)-7-m eth ylen e-9-oxa bicyclo[4.3.0]n on a n e ((+)-
ch eim on oph yllon E) ((+)-5) an d (1R,6S,7S,8S)-7-Hydr oxy-
m e t h yl-3-m e t h yl-8-(3-m e t h ylb u t a n oyl)-9-oxa b icyclo-
[4.3.0]n on -2-en -7-ol (30). To a cooled (0 °C) stirred solution
of 29 (96.3 mg, 0.411 mmol) in acetone and H2O (2:1, v/v, 2
mL) were added OsO4 (0.05 M solution in t-BuOH, 0.82 mL,
0.041 mmol) and NMO (96.1 mg, 0.823 mmol). The mixture
was stirred at 0 °C for 2.5 h, quenched with 10 wt % aqueous
NaHSO3 (1 mL), and diluted with EtOAc (20 mL). The
resulting mixture was washed with 10 wt % aqueous NaHSO3
(10 mL × 2) and saturated brine (10 mL), successively. The
organic layer was dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:2) to provide 45.7 mg (42%) of (+)-5 and 15.4 mg
(14%) of 30. Compound (+)-5 was obtained as a colorless oil:
1
cm-1; H NMR δ 0.90 (d, 3 H, J ) 6.6 Hz), 0.95 (d, 3 H, J )
6.6 Hz), 1.28 (ddd, 1 H, J ) 13.9, 9.5, 3.1 Hz), 1.49 (ddd, 1 H,
J ) 13.9, 10.2, 4.4 Hz), 1.67 (s, 3 H), 1.72-1.85 (m, 4 H), 2.03
(m, 1 H), 2.20 (m, 1 H), 2.78 (m, 1 H), 3.72 (dt, 1 H, J ) 10.2,
3.1 Hz), 4.38 (m, 1 H), 4.57 (m, 1 H), 5.01 (t, 1 H, J ) 2.2 Hz),
5.04 (t, 1 H, J ) 2.2 Hz), 5.42 (br, 1 H); 13C NMR δ 21.6, 22.9,
23.7, 23.8, 24.5, 25.9. 40.7, 41.1, 72.0, 75.9, 82.9, 105.5, 121.5,
139.0, 150.4; HRMS calcd for C15H24O2 (M+) m/z 236.1776,
found 236.1777.
Asym m etr ic Mu k a iya m a Ald ol Rea ction of 31 w ith 11.
The following reaction was carried out under Ar. A solution
of (2R,3R)-2-O-(2,6-diisopropoxybenzoyl)tartaric acid (666 mg,
TLC Rf 0.08 (EtOAc/hexane, 1:3); [R]22 +129 (c 1.46, CHCl3);
D
J . Org. Chem, Vol. 67, No. 19, 2002 6697

Takao et al.
1
IR 3460, 3380,1720, 1670 cm-1; H NMR δ 0.88 (d, 3 H, J )
mixture was stirred for 4 h, quenched with 10 wt % aqueous
NaHSO3 (1 mL), and diluted with EtOAc (20 mL). The
resulting mixture was washed with 10 wt % aqueous NaHSO3
(10 mL × 2) and saturated brine (10 mL), successively. The
organic layer was dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (acetone/
hexane, 1:2) to provide 33.9 mg (97%) of 37 as a colorless oil:
TLC Rf 0.08 (EtOAc/hexane, 1:1); [R]21D +10.0 (c 1.78, CHCl3);
IR 3450, 1720 cm-1; 1H NMR δ 0.92 (d, 3 H, J ) 6.6 Hz), 0.93
(d, 3 H, J ) 6.6 Hz), 1.32 (s, 3 H), 1.26-1.43 (m, 2 H), 1.69-
1.90 (m, 2 H), 2.15 (m, 1 H), 2.23 (br, 1 H, OH), 2.33 (dd, 1 H,
J ) 18.0, 7.3 Hz), 2.42 (m, 1 H), 2.57 (dd, 1 H, J ) 18.0, 6.6
Hz), 2.86 (d, 1 H, J ) 4.2 Hz), 2.90 (br, 1 H, OH), 2.95 (d, 1 H,
J ) 4.2 Hz), 3.56 (d, 1 H, J ) 5.9 Hz), 4.37 (s, 1 H), 4.55 (t, 1
H, J ) 5.9 Hz); 13C NMR δ 19.5, 22.5, 22.6, 23.2, 25.7, 32.5,
39.5, 47.6, 48.1, 65.2, 71.4, 73.4, 80.8, 82.7, 207.2; HRMS calcd
for C15H24O5 (M+) m/z 284.1624, found 284.1627.
6.7 Hz), 0.91 (d, 3 H, J ) 6.7 Hz), 1.25 (s, 3 H), 1.45 (m, 1 H),
1.56-1.80 (m 2 H), 2.12 (m, 2 H), 2.35 (dd, 1 H, J ) 17.3, 7.0
Hz), 2.52 (dd, 1 H, J ) 17.3, 6.6 Hz), 2.93 (m, 1 H), 3.16 (d, 1
H, J ) 8.0 Hz), 4.36 (t, 1 H, J ) 8.0 Hz), 4.71 (q, 1 H, J ) 2.2
Hz), 5.04 (dd, 1 H, J ) 2.8, 2.2 Hz), 5.24 (dd, 1 H, J ) 2.8, 2.2
Hz); 13C NMR δ 18.6, 22.4, 22.6, 23.4, 26.7, 31.8, 41.4, 46.6,
72.3, 74.8, 83.8, 85.2, 106.9, 145.9, 208.4; HRMS calcd for
C
15H24O4 (M+) m/z 268.1675, found 268.1675. Compound 30
was obtained as white crystals, mp 153-155 °C; TLC Rf 0.17
(EtOAc/hexane, 1:3); [R]19 -119 (c 0.515, CHCl3); IR (CHCl3)
D
3450, 1700 cm-1; 1H NMR δ 0.93 (d, 6 H, J ) 6.6 Hz), 1.27 (m,
1 H), 1.67 (m, 1 H), 1.77 (s, 3 H), 1.96-2.10 (m, 3 H), 2.17 (m,
1 H), 2.55 (dd, 1 H, J ) 18.1, 6.8 Hz), 2.71 (dd, 1 H, J ) 18.1,
6.6 Hz), 3.73 (d, 1 H, J ) 11.6 Hz), 3.94 (d, 1 H, J ) 11.6 Hz),
4.24 (s, 1 H),4.76 (m, 1 H), 5.72 (m, 1 H); 13C NMR δ 19.7,
22.6, 22.7, 23.2, 23.7, 29.2, 47.2, 49.2, 64.5, 75.4, 83.8, 88.2,
118.7, 141.2, 216.4; HRMS calcd for C14H21O3 (M+ - CH2OH)
m/z 237.1491, found 237.1489.
(1S,2R,3S,6R)-2,3-Dih yd r oxy-7-for m yl-3-m et h yl-8-[3-
m eth ylbu ta n oyl]-9-oxa bicyclo[4.3.0]n on -7-en e ((+)-Ch ei-
m on op h ylla l) ((+)-6). To a cooled (0 °C) stirred solution of
37 (33.9 mg, 0.119 mmol) in EtOH (2 mL) was added NaOEt
(1.0 M solution in EtOH, 0.18 mL, 0.18 mmol). The mixture
was stirred for 15 min, diluted with saturated aqueous
NaHCO3 (15 mL), and extracted with CH2Cl2 (15 mL × 3).
The combined extracts were dried and concentrated in vacuo
to provide crude allylic alcohol (33.9 mg), which was used
immediately to the next step. To a cooled (0 °C) stirred solution
of crude allylic alcohol obtained above (33.9 mg) in DMF (2
mL) were added NMO (27.9 mg, 0.238 mmol) and RuCl3‚nH2O
(4.9 mg). The mixture was stirred at 0 °C for 4 h, diluted with
EtOAc (20 mL), and washed with saturated brine (10 mL ×
3). The organic layer was dried and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 2:3) to provide 13.2 mg (39%) of (+)-6 as a
(1R,6S,7S,8R)-8-[(1R)-1-Hydr oxy-3-m eth ylbu tyl]-3-m eth -
yl-9-oxa sp ir o[bicyclo[4.3.0]n on -2-en e-7,3′-oxir a n e] (35).
As described for the preparation of 17 and 18 from 15, (+)-7
(35.9 mg, 0.152 mmol) was treated with VO(acac)2 (2.0 mg,
7.5,mol) and t-BuOOH (6.63 M solution in isooctane, 46 µL,
0.31 mmol) in CH2Cl2 (2 mL) to provide 35.2 mg (92%) of 35
as a colorless oil: TLC Rf 0.62 (EtOAc/hexane, 1:2); [R]22
D
+33.2 (c 1.11, CHCl3); IR 3480 cm-1; H NMR δ 0.92 (d, 3 H,
1
J ) 5.9 Hz), 0.94 (d, 3 H, J ) 5.9 Hz), 1.74 (s, 3 H), 1.25-1.38
(m, 2 H), 1.42-1.72 (m, 3 H), 1.82-1.99 (m, 2 H), 2.05 (m, 1
H), 2.95 (d, 1 H, J ) 4.4 Hz), 3.01 (d, 1 H, J ) 4.4 Hz), 3.82-
3.89 (m, 2 H), 4.51 (t, 1 H, J ) 4.3 Hz), 5.57 (m, 1 H); 13C
NMR δ 21.3, 21.5, 23.7, 23.8, 24.2, 28.4, 41.7, 42.8, 48.8, 69.3,
70.0, 73.3, 77.6, 119.5, 140.7; HRMS calcd for C15H24O3 (M+)
m/z 252.1726, found 252.1724.
yellow oil: TLC Rf 0.68 (acetone/hexane, 1:1); [R]21 +106 (c
(1R,6S,7S,8S)-3-Meth yl-8-[3-m eth ylbu tan oyl]-9-oxaspir o-
[bicyclo[4.3.0]n on -2-en e-7,3′-oxir a n e] (36). As described for
the preparation of 29, 35 (53.7 mg, 0.213 mmol) was treated
with Dess-Martin periodinane (182 mg, 0.429 mmol) in CH2-
Cl2 (4 mL) to provide 48.3 mg (91%) of 36 as a colorless oil:
TLC Rf 0.68 (EtOAc/hexane, 1:3); [R]23D -66.4 (c 2.42, CHCl3);
IR 1720 cm-1; 1H NMR δ 0.921 (d, 3 H, J ) 6.7 Hz), 0.924 (d,
3 H, J ) 6.7 Hz), 1.78 (s, 3 H), 1.47-1.75 (m, 2 H), 1.93-2.01
(m, 3 H), 2.14 (m, 1 H), 2.37 (dd, 1 H, J ) 17.8, 6.7 Hz), 2.62
(dd,1 H, J ) 17.8, 6.5 Hz), 2.86 (d,1 H, J ) 4.1 Hz), 2.99 (d, 1
H, J ) 4.1 Hz), 4.45 (s, 1 H), 4.77 (t, 1 H, J ) 4.7 Hz), 5.67 (m,
1 H); 13C NMR δ 21.5, 22.5, 22.7, 23.2, 23.7, 28.5, 41.4, 46.2,
47.6, 66.9, 75.4, 81.2, 118.8, 141.3, 208.5; HRMS calcd for
D
0.565, CHCl3); IR 3420, 1700, 1650 cm-1; 1H NMR δ 0.98 (d, 6
H, J ) 6.6 Hz), 1.32 (s, 3 H), 1.55 (ddd, 1 H, J ) 13.7, 8.6, 4.9
Hz), 1.74 (ddd, 1 H, J ) 13.7, 8.5, 4.5 Hz), 1.85 (m, 1 H), 2.10
(m, 1 H), 2.22 (m, 1 H), 2.62 (dd, 1 H, J ) 17.0, 6.7 Hz), 2.68
(dd, 1 H, J ) 17.0, 7.0 Hz), 3.53 (dt, 1 H, J ) 9.6, 6.7 Hz), 3.58
(d, 1 H, J ) 6.8 Hz), 4.76 (dd, 1 H, J ) 9.6, 6.8 Hz), 10.22 (s,
1 H); 13C NMR δ 20.8, 22.5 × 2, 24.1, 26.8, 33.7, 40.1, 49.3,
70.9, 74.8, 88.0, 125.4, 161.8, 189.0, 195.2; HRMS calcd for
C
15H22O5 (M+) m/z 282.1467, found 282.1464.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 22, 23, (+)-7, (-)-7, 24-28; 1H
and 13C NMR spectra of syn-9 + anti-9, syn-12, anti-12, 13-
23, 8, 7, 29, 30, synthetic 5, 35-37, synthetic 6; 1H NMR
spectra of 24-28 including COSY (1H-1H) of 24 and 25. This
material is available free of charge via the Internet at
http://pubs.acs.org.
C
15H22O3 (M+) m/z 250.1569, found 250.1572.
(1S,2R,3S,6S,7S,8S)-2,3-Dih yd r oxy-3-m eth yl-8-[3-m eth -
ylbu tan oyl]-9- oxaspir o[bicyclo[4.3.0]n on an e-7,3′-oxir an e]
(37). To a cooled (0 °C) stirred solution of 36 (30.6 mg, 0.122
mmol) in acetone and H2O (2:1, v/v, 2 mL) were added OsO4
(0.05 M solution in t-BuOH, 0.13 mL, 6.5 µmol), NMO (42.9
mg, 0.366 mmol), and DABCO (42.0 mg, 0.374 mmol). The
J O0203140
6698 J . Org. Chem., Vol. 67, No. 19, 2002