Total synthesis of epoxyquinols A, B, and C and epoxytwinol A and the reactivity of a 2H-pyran derivative as the diene component in the Diels-Alder reaction

Article abstract of DOI:10.1021/jo048425h

(Chemical Equation Presented). Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A (RKB-3564D) are described. In the first-generation synthesis, the HfCL₄-mediated diastereoselective Diels-Alder rea

Full text of DOI:10.1021/jo048425h

Total Synthesis of Epoxyquinols A, B, and C and Epoxytwinol A
and the Reactivity of a 2H-Pyran Derivative as the Diene
Component in the Diels-Alder Reaction
Mitsuru Shoji,† Hiroki Imai,† Makoto Mukaida,† Ken Sakai,‡ Hideaki Kakeya,§
Hiroyuki Osada,§ and Yujiro Hayashi*,†
Department of Industrial Chemistry, Faculty of Engineering, Department of Applied Chemistry,
Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and
Antibiotics Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako,
Saitama 351-0198, Japan
hayashi@ci.kagu.tus.ac.jp
Received September 7, 2004
Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A
(RKB-3564D) are described. In the first-generation synthesis, the HfCl4-mediated diastereoselective
Diels-Alder reaction of furan with Corey’s chiral auxiliary has been developed. In the second-
generation synthesis, a chromatography-free preparation of an iodolactone, by using acryloyl chloride
as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution
of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for
large-scale preparation. A biomimetic cascade reaction involving oxidation, 6π-electrocyclization,
and then Diels-Alder dimerization is the key reaction in the formation of the complex heptacyclic
structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction
composed of oxidation, 6π-electrocyclization, and formal [4 + 4] cycloaddition reactions. A 2H-
pyran, generated by oxidation/6π-electrocyclization, acts as a good diene, reacting with several
dienophiles to afford polycyclic compounds in one step. An azapentacyclic compound is synthesized
by a similar cascade reaction composed of the four successive steps: oxidation, imine formation,
6π-azaelectrocyclization, and Diels-Alder dimerization.
Introduction
8057 from the fungus Neosartorya sp. With the exception
of RK-805, these small natural products have structures
quite distinct from those of known angiogenesis inhibi-
tors, making their mechanism of action a matter of
considerable interest. A sufficient quantity of the natural
products is needed for biological investigations, and the
study of structure-reactivity relationships requires de-
rivatives. For these purposes an efficient and flexible
total synthesis is highly desirable, and recently we have
accomplished the first total synthesis of epoxyquinols A
and B8 and azaspirene.9
The inhibition of angiogenesis is a promising method
for treating angiogenesis-related diseases such as cancer
and rheumatoid arthritis.1 We have recently isolated and
determined the structures of epoxyquinols A (1)2, B (2),3
and C (3)4 and epoxytwinol A (RKB-3564D) (4)5 (Figure
1) from an unknown soil fungus and azaspirene6 and RK-
* Phone: (+81)3-5228-8318, Fax: (+81)3-5261-4631.
† Department of Industrial Chemistry, Tokyo University of Science.
‡ Department of Applied Chemistry, Tokyo University of Science.
§ RIKEN.
(1) (a) Folkman, J. J. Natl. Cancer Inst. 1990, 82, 4. (b) Risau, W.
Nature 1997, 386, 671. (c) Klagsbrum, M.; Moses, M. A. Chem. Biol.
1999, 6, R217. (d) Gasparini, G. Drugs 1998, 58, 17.
(2) Kakeya, H.; Onose, R.; Koshino, H.; Yoshida, A.; Kobayashi, K.;
Kageyama, S.-I.; Osada, H. J. Am. Chem. Soc. 2002, 124, 3496.
(3) Kakeya, H.; Onose, R.; Yoshida, A.; Koshino, H.; Osada, H. J.
Antibiot. 2002, 55, 829.
(5) (a) Osada, H.; Kakeya, H.; Konno, H.; Kanazawa, S. PCT Int.
Appl. 2002, WO 02088137. (b) Kakeya, H., Onose, R. Koshino, H.
Osada, H. A manuscript is in preparation.
(6) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.;
Osada, H. Org. Lett. 2002, 4, 2845.
(7) Asami, Y.; Kakeya, H.; Onose, R.; Chang, Y.-H.; Toi, M.; Osada,
H. Tetrahedron 2004, 60, 7085.
(4) Kakeya, H.; Osada, H. Unpublished work.
10.1021/jo048425h CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/08/2004
J. Org. Chem. 2005, 70, 79-91
79

Shoji et al.
FIGURE 1. Epoxyquinols A, B, and C, epoxytwinol A, azaspirene, and RK-805.
SCHEME 1. Retrosynthetic Analysis of
Epoxyquinols A, B, and C and Epoxytwinol A
those of epoxyquinols A, B, and C. It is postulated that
epoxytwinol A is biosynthetically generated by a formal
[4 + 4] cycloaddition reaction as used in the construction
of the same key 2H-pyran intermediate 5 of epoxyquinols
A, B, and C. Because of these compounds’ important
biological properties and synthetically challenging struc-
tures, several research groups, including ours,8 have
investigated these compounds total synthesis: Porco et
al. have published an elegant total synthesis of epoxy-
quinols A and B11 and just recently completed the first
total synthesis of epoxytwinol A using alkoxysilanol
methodology to promote formal [4 + 4] dimerization.12
Mehta et al.13 and Kuwahara et al.14 have also succeeded
in the total synthesis of epoxyquinols A and B. The
related epoxyquinoid Diels-Alder dimer, Torreyanic acid,
with selective cytotoxicity against human cancer cell
lines,15 was isolated by Lee and co-workers from the
fungus Pestalotiopsis and has been synthesized by Porco
and co-workers.16
Our group has completed the first asymmetric total
synthesis of epoxyquinols A and B,8a thus determining
their absolute stereochemistry. An HfCl4-mediated
Diels-Alder reaction of furan with Corey’s chiral auxil-
iary17 and a biomimetic, oxidative dimerization were
developed as key reactions. We have uncovered the
importance of hydrogen-bonding in the Diels-Alder
reaction forming epoxyquinol B using the combined use
of synthetic organic chemistry and theoretical chemis-
try.18 We have also developed a practical total synthesis
with a kinetic resolution using lipase as a key step.8b In
a study on the large-scale preparation of epoxyquinols A
and B, we carefully investigated the minor isomers of the
key oxidative dimerization and have isolated and identi-
Epoxyquinols A, B, and C are novel pentaketides, with
complex, highly oxygenated, heptacyclic structures con-
taining 12 chiral centers, which are biosynthetically
generated from the epoxyquinol monomer 7 by a cascade
reaction sequence of oxidation, 6π-electrocyclization,10
and Diels-Alder reaction. That is, diol monomer 7 is
oxidized to aldehyde 6, from which 6π-electrocyclization
proceeds, affording 2H-pyran derivative 5 (Scheme 1).
Diels-Alder dimerization of 2H-pyran 5 proceeds to
provide epoxyquinols A, B, and C. Several other diaster-
eomers have also been isolated along with epoxyquinols
A, B, and C from the same soil fungus, the structure
determination of which will be the subject of future
studies. We have isolated not only Diels-Alder dimers
but also epoxytwinol A from the same fungus. Epoxy-
twinol A possesses the 3,8-dioxatricyclo[4.2.2.22,5]dodeca-
9,11-diene skeleton, a completely different structure from
(11) Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore, T. D.;
Porco, J. A., Jr. Org. Lett. 2002, 4, 3267.
(12) Li, C.; Porco, J. A., Jr. J. Am. Chem. Soc. 2004, 126, 1310.
(13) (a) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569. (b)
Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 3611.
(14) Imada, S.; Kuwahara, S. Abstracts of Annual Meeting of Japan
Society for Bioscience, Biotechnology, and Agrochemistry, Hiroshima,
Japan, March 30th, 2004, p 274.
(15) (a) Lee, J. C.; Yang, X.; Schwartz, M.; Strobel, G.; Clardy, J.
Chem. Biol. 1995, 2, 721. (b) Lee, J. C.; Strobel, G. A.; Lobkovsky, E.;
Clardy, J. J. Org. Chem. 1996, 61, 3232. (c) Jarvis, B. B. Chemtracts:
Org. Chem. 1997, 10, 10.
(16) (a) Li, C.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc.
2000, 122, 10484. (b) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2003, 125, 5095.
(17) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741.
(18) (a) Shoji, M.; Kishida, S.; Kodera, Y.; Shiina, I.; Kakeya, H.;
Osada, H.; Hayashi, Y. Tetrahedron Lett. 2003, 44, 7205. (b) Shoji,
M.; Imai, H.; Shiina, I.; Kakeya, H.; Osada, H.; Hayashi, Y. J. Org.
Chem. 2004, 69, 1548.
(8) (a) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi,
Y. Angew. Chem., Int. Ed. 2002, 41, 3192. (b) Shoji, M.; Kishida, S.;
Takeda, M.; Kakeya, H.; Osada, H.; Hayashi, Y. Tetrahedron Lett.
2002, 43, 9155.
(9) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am.
Chem. Soc. 2002, 124, 12078.
(10) See: Fleming, I. Frontier Orbitals and Organic Chemical
Reactions; John Wiley & Sons: Chichester, UK, 1976; p 103.
80 J. Org. Chem., Vol. 70, No. 1, 2005

Total Synthesis of Epoxyquinols A-C and Epoxytwinol A
fied epoxyquinol C and epoxytwinol A from the crude
reaction mixture. These results are disclosed in this paper
along with the full details of the total synthesis of
epoxyquinols A and B.
Results and Discussion
First-Generation Monomer Synthesis. On the basis
of the above retrosynthetic analysis, the Diels-Alder
reaction of furan,20 which is a difficult cycloaddition due
to the facile retro-Diels-Alder reaction and low reactivity
of furan as a diene due to its aromatic character, is the
first step of our total synthesis. Although there are a
number of methods for the diastereoselective Diels-Alder
reaction of a chiral acrylate ester with furan,21 few of
these are synthetically useful with high endo/exo- and/
or diastereoselectivities. Recently, we have found that
HfCl4 is a highly efficient Lewis acid in the Diels-Alder
reaction of furan, and enables the reaction to proceed at
low temperature.22 The HfCl4-mediated Diels-Alder
reaction of furan was applied to chiral acrylate esters,
and the choice of the chiral auxiliary was found to be
important. While a chiral Evans’ acrylate derivative,
3-acryloyl-4-benzyl-1,3-oxazolidin-2-one,23 gave poor dia-
stereoselectivity, high selectivity was obtained with the
acrylate ester derived from Corey’s chiral auxiliary
((-)-(1R,2R)-2-(naphthalene-2-sulfonyl)cyclohexanol).17
That is, in the presence of 1.1 equiv of HfCl4, the acrylate
ester (-)-13 reacted with furan in toluene at low tem-
perature (-45 °C) for 34 h, giving the cycloadducts (+)-
14 in good yield with moderate endo/exo- and high
diastereoselectivities.
In the key oxidative Diels-Alder reaction, oxidation
of dienol 7 and subsequent 6π-electrocyclization affords
2H-pyran derivative 5, which dimerizes to afford epoxy-
quinols A and B. 2H-Pyran derivatives are seldom
employed in organic synthesis, and their reactivity has
not been systematically investigated because of difficulty
in generating them due to their easy isomerization into
dienals.19 As we found a simple method for generation
of 2H-pyran intermediates by oxidation and 6π-electro-
cyclization during the synthesis of epoxyquinols A and
B, we have investigated their reactivity as the diene
component in the Diels-Alder reaction, and these results
will also be presented here.
Encouraged by the facile generation of a 2H-pyran
intermediate by oxidation and 6π-oxaelectrocyclization,
the dimerization of 1,2-dihydropyridine, a nitrogen ana-
logue of 2H-pyran, generated by the cascade reaction of
oxidation, imine formation, and 6π-azaelectrocyclization
has been investigated for the synthesis of azapentacycles
and will also be described here.
In summary, in this paper we disclose the full
details of our total synthesis of epoxyquinols A, B,
and C and epoxytwinol A, as well as the results of
our work on the reactivity of a 2H-pyran derivative as
a diene in the Diels-Alder reaction with several dieno-
philes, and the formation of an azapentacycle via a
cascade reaction.
SCHEME 2. Synthesis of (+)-11
Retrosynthesis. Our retrosynthetic analysis of epoxy-
quinols A, B, and C and epoxytwinol A is summarized in
Scheme 1. Epoxyquinols A, B, and C and epoxytwinol A
would be synthesized from the same monomer 7 by the
postulated biosynthetic pathway involving an oxidation/
6π-electrocyclization/Diels-Alder reaction cascade for
epoxyquinols A, B, and C or an oxidation/6π-electro-
cyclization/[4 + 4] cycloaddition cascade for epoxytwinol
A. The monomer 7 could be synthesized from iodocyclo-
hexenone 8 by the Suzuki coupling reaction. Iodocyclo-
hexenone 8 was to be prepared by the R-iodination of
cyclohexenone 9, which should be available from bis-
epoxy cyclohexenol 10. Chiral cyclohexenol 10 would be
formed from the Diels-Alder reaction between furan and
a chiral acrylate derivative, followed by functional group
transformations.
In this retrosynthetic analysis, there are several
noteworthy features that should be pointed out: Syn-
thesis of derivatives with different side-chains should be
accessible because the side-chain is introduced at a late
stage of the monomer synthesis by a Suzuki coupling
reaction. All the carbon atoms except the side-chain are
introduced in the first Diels-Alder reaction, and the
remainder of the reactions are functional group trans-
formations except for the Suzuki coupling reaction.
Chirality is introduced at the stage of the initial Diels-
Alder reaction, and highly diastereoselective synthesis
of the monomer is possible by exploiting neighboring-
group participation.
Direct epoxidation of (+)-14 with MCPBA gave stereo-
selectively the exo-epoxide,24 which when reacted with
(20) Recent review of asymmetric Diels-Alder reactions: Hayashi,
Y. Catalytic Asymmetric Diels-Alder Reactions in Cycloaddition
Reactions in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.;
Wiley-VCH: Weinheim, 2001, pp 5-56. Review of Diels-Alder reaction
of furan: Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997,
53, 14179. Review of optically pure 7-oxabicyclo[2.2.1]hept-5-en-2-yl
derivatives: Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett
1990, 173.
(21) Catalytic asymmetric reaction by the use of a chiral Lewis acid;
(a) Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979. (b)
Yamamoto, I.; Narasaka, K. Chem. Lett. 1995, 1129. (c) Evans, D. A.;
Barnes, D. M. Tetrahedron Lett. 1997, 38, 57. Diastereoselective
reaction by the use of chiral dienophile; (d) Takayama, H.; Iyobe, A.;
Koizumi, T. J. Chem. Soc., Chem. Commun. 1986, 771. (e) Fraile, J.
M.; Garcia, J. I.; Gracia, D.; Mayoral, J. A.; Pires, E. J. Org. Chem.
1996, 61, 9479. (f) Adrio, J.; Carretero, J. C.; Ruano, J. L. G.; Cabrejas,
L. M. M. Tetrahedron: Asymmetry 1997, 8, 1623. (g) Arjona, O.; Iradier,
F.; Medel, R.; Plumet, J. Tetrahedron: Asymmetry 1999, 10, 2237. (h)
Burke, M. J.; Allan, M. M.; Parvez, M.; Keay, B. A. Tetrahedron:
Asymmetry 2000, 11, 2733 and references therein.
(22) Hayashi, Y.; Nakamura, M.; Nakao, S.; Inoue, T.; Shoji, M.
Angew. Chem., Int. Ed. 2002, 41, 4079.
(23) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238.
(19) Marvell, E. N. Thermal Electrocyclic Reactions; Academic
Press: New York, 1980.
J. Org. Chem, Vol. 70, No. 1, 2005 81

Shoji et al.
SCHEME 3. Synthesis of (()-11
KHMDS affords an undesired cyclopropane derivative (eq
1).25 As a result, it was necessary to find an alternative
route that would result in the preparation of the endo
epoxide isomer. After some experimentation, selective
formation of the endo epoxide was accomplished via
iodolactone (-)-15. Though the usual two-step procedure
(hydrolysis and iodolactonization) afforded iodolactone
(-)-15 in good yield, the chiral auxiliary was recovered
in only 40% yield along with 55% yield of 1-(naphthalene-
2-sulfonyl)cyclohexene. On the other hand, direct treat-
ment of endo Diels-Alder adduct (+)-14 with I2 in
aqueous CH3CN afforded iodolactone (-)-15 in 81% yield
with recovery of the chiral auxiliary in 94% yield. After
recrystallization, optically pure lactone (-)-15 was ob-
tained, and its absolute stereochemistry was determined
by comparing its optical rotation with that reported in
the literature.26 Though the direct transformation of
iodolactone (-)-15 to epoxy methyl ester (-)-12 in MeOH
under a variety of basic conditions was unsuccessful, a
two-step conversion (hydrolysis and esterification) worked
well: Hydrolysis and epoxide formation occurred on
treatment of (-)-15 with KOH in DMF at 60 °C for 10 h,
followed by esterification with MeI under sonication
conditions for 1 h, furnished epoxyester (-)-12 in one pot
and high yield (94%).
to be difficult, because while the Diels-Alder reaction of
furan and acrylate derivatives is a powerful means of
synthesizing this class of compounds,20,28 no method
suitable for large-scale preparation of the endo-isomer
has yet been described. Establishing such a route was
our first goal. Instead of using a Lewis acid to promote
the Diels-Alder reaction, we focused on the use of
acryloyl chloride as a reactive dienophile, which is
reported to react with furan in the presence of a hydrogen
chloride scavenger, propylene oxide, over 48 h, providing
the Diels-Alder adducts in 76.5% overall yield after
conversion of the adduct to the corresponding ester.
Under these conditions, the thermodynamically stable
exo-isomer predominates (endo:exo ) 3:7).28a After careful
experimentation, it was found that the kinetically favored
endo-isomer was generated predominately in the early
stages of the reaction. The Diels-Alder reaction of
acryloyl chloride and furan (8 equiv) proceeds in 5 h at
room temperature, providing the endo- and exo-cyclo-
adducts in 54 and 22% yields, respectively (1H NMR
yield). Though at this stage the starting material, acryloyl
chloride, still remained, the yield of the endo-isomer did
not increase further due to its conversion into the
thermodynamically stable exo-isomer after longer reac-
tion times. Hydrolysis of the acid chloride to the sodium
salt of the acid was carried out by treatment with
aqueous 1.5 M NaOH. On addition of I2 and CH2Cl2 to
the aqueous phase, iodolactonization proceeded effi-
ciently, providing (()-15 in 42% yield as a white solid,
which is pure enough to be used in the next experiment.
Unreacted acryloyl chloride and the exo-Diels-Alder
adduct could be easily separated from iodolactone (()-
15, as they both remained in the aqueous phase as the
sodium salts of the corresponding acids. Though the yield
was moderate, an efficient, chromatography-free proce-
Exposure of (-)-12 to LDA at -90 °C for 30 min led to
â-elimination, affording hydroxyester (+)-11. Low tem-
perature and an exact equivalent of LDA are both
essential for high yield in this step; otherwise, Michael
addition of diisopropylamine to (+)-11 occurs, generating
a â-aminoester as a side product.
The first total synthesis of epoxyquinols A and B was
accomplished using (+)-11 (vide infra). Though our HfCl4-
mediated, highly diastereoselective Diels-Alder reaction
using a chiral auxiliary is suitable for the construction
of optically active cyclohexanol derivatives, at least
equimolar amounts of the auxiliary and HfCl4 are neces-
sary. To circumvent this problem, we have developed a
more efficient and practical synthetic route to this key
intermediate (+)-11 for epoxyquinols A, B, and C and
epoxytwinol A.
Second-Generation Monomer Synthesis. We chose
as the key reaction of our new strategy the kinetic
resolution of racemic cyclohexenol (()-11 using lipase,27
as such reactions are known to be readily scalable.
However, preparation of this intermediate itself proved
(28) Diels-Alder reaction of methyl acrylate and furan: (a) Kotsuki,
H.; Asao, K.; Ohnishi, H. Bull. Chem. Soc. Jpn. 1984, 57, 3339. (b)
Moore, J. A.; Partain, E. M., III. J. Org. Chem. 1983, 48, 1105. (c) Brion,
F. Tetrahedron Lett. 1982, 23, 5299. (d) Fraile, J. M.; Garcia, J. I.;
Massam, J.; Mayoral, J. A.; Pires, E. J. Mol. Catal. A: Chem. 1997,
123, 43. (e) Ager, D. J.; East, M. B. Heterocycles 1994, 37, 1789. The
Diels-Alder reaction under high pressure: (f) Kotsuki, H.; Nishizawa,
H.; Ochi, M.; Matsuoka, K. Bull. Chem. Soc. Jpn. 1982, 55, 496. (g)
Dauben, W. G.; Krabbenhoft, H. O. J. Am. Chem. Soc. 1976, 98, 1992.
The Diels-Alder reaction of acrylic acid and furan: (h) Suami, T.;
Ogawa, S.; Nakamoto, K.; Kasahara, I. Carbohydr. Res. 1977, 58, 240
and references therein.
(24) (a) Campbell, M. M.; Kaye, A. D.; Sainsbury, M.; Yavarzadeh,
R. Tetrahedron Lett. 1984, 25, 1629. (b) Campbell, M. M.; Kaye, A. D.;
Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 2461. (c) Raja-
paksa, D.; Keay, B. A.; Rodrigo, R. Can. J. Chem. 1984, 62, 826.
(25) Rajapaksa, D.; Keay, B. A.; Rodrigo, R. Can. J. Chem. 1984,
62, 826.
(26) Literature data: [R]25 -113 (c 1.04, CHCl3). Ogawa, S.;
D
Yoshikawa, M.; Taki, T. J. Chem. Soc., Chem. Commun. 1992, 406.
Synthetic 15: [R]23 -114 (c 0.906, CHCl3).
(27) (a) Sugai, T.DCurr. Org. Chem. 1999, 3, 373. (b) Fuhshuku, K.;
Oda, S.; Sugai, T. Recent Res. Devel. Org. Chem. 2002, 6, 57.
82 J. Org. Chem., Vol. 70, No. 1, 2005

Total Synthesis of Epoxyquinols A-C and Epoxytwinol A
SCHEME 4. Synthesis (+)-19
TABLE 1. Kinetic Resolution of Cyclohexenol (()-11
Using Various Lipasesa
ratio of
11
16
entry
lipase
wt % 11:16b (% ee)c (% ee)c kfast/kslow
1
2
3
4
5
6
7
lipase TL
40
50
50:50
53:47
47:53
55:45
83:17
82:18
42:58
96
85
99
75
19
19
70
97
98
95
94
97
98
60
215
128
80
lipase QL
lipase QLM
lipase PL
50
90
50
100
40
52
lipase PS
32
17
6.1
lipase SL
chirazyme L-2
a Reaction was performed using 0.12 mmol of (()-11 for 18 h at
room temperature. b Ratio was determined by 1H NMR. c Enan-
tiomeric excess was determined by chiral HPLC analysis using a
Chiralcel OD-H column.
TABLE 2. Large-Scale Kinetic Resolution Using
Recovered Lipase TLa
scale time ratio of
11
16
method.30 As acetate (-)-16 was easily converted to
alcohol (-)-11 on treatment with K2CO3 in MeOH,
providing (-)-11 in 97% yield, both enantiomers of alcohol
11 could be synthesized in large quantities and with high
optical purity. This kinetic resolution is suitable for
producing both optically active cyclohexenols (+)-11 and
(-)-11 on a gram-scale, not only because high selectivity
is achieved but also because only a catalytic amount of
lipase is necessary and can be recycled.
entry
(g)
(h)
11:16b
(% ee)c (% ee)c kfast/kslow
1
8
14
21
36
40
36
49:51
49:51
49:51
99
99
99
96
93
94
211
201
195
2d
3e
a Reaction was performed with 10 wt % lipase TL. b Determined
by 1H NMR. c Enantiomeric excess was determined by chiral
HPLC analysis using a Chiralcel OD-H column. d Once-recycled
lipase TL was employed. e Twice-recycled lipase TL was employed.
Hydroxyl-directed epoxidation of homoallylic alcohol
(+)-11 using a catalytic amount of VO(acac)2 and excess
dure for the synthesis of iodolactone (()-15 has been
developed,29 and the reaction could easily be scaled up
to 90 g.
31
tert-butylhydroperoxide (TBHP) under reflux in CH2Cl2
proceeded to give diepoxide (+)-17 as a single isomer in
high yield. Although reduction of ester (+)-17 with
DIBAL proceeded smoothly, the recovered yield of the
diol (+)-18 was quite low due to its water solubility. A
nonaqueous workup was examined: Reduction with
NaBH4 in MeOH at room temperature for 15 min,
removal of solvent, and flash column chromatography
afforded the diol (+)-18. The primary alcohol of diol (+)-
18 was selectively protected with TBSCl, affording (+)-
10 in 81% yield over two steps. Though the oxidation of
(+)-10 with SO3‚pyridine32 afforded 2-(tert-butyldimeth-
ylsilyloxymethyl)-5,6-epoxy-2-cyclohexene-1,4-dione from
over-oxidation of (+)-9, TEMPO-oxidation33 gave the
desired â,γ-epoxyketone without formation of this byprod-
uct. Isomerization occurred on treatment of the â,γ-
epoxyketone with silica gel at 60 °C in toluene for 4 h,34
affording R,â-unsaturated ketone (+)-9 in 89% yield over
two steps. The R-iodination of cyclohexenone (+)-9 was
problematic, and the choice of diol protecting group and
After conversion of iodolactone (()-15 to cyclohexenol
(()-11 by the same procedure described in Scheme 2, the
kinetic resolution of (()-11 was examined (eq 2) with the
results summarized in Table 1. The reaction was per-
formed at room temperature in the presence of several
lipases (40-100 wt/%) using vinyl acetate as a solvent.
Among the lipases examined, the Pseudomonas stutzeri
lipase (Meito TL) was found to be most efficient: When
(()-11 was treated with a catalytic amount of lipase TL
(40 wt %) in vinyl acetate at room temperature for 18 h,
acetate (-)-16 was obtained in 50% yield with 97% ee,
while the desired alcohol (+)-11 was recovered in 50%
yield with 96% ee, indicating a very high selectivity (kfast
/
kslow ) 215).
Next, the large-scale kinetic resolution was examined
using recovered lipase TL, the results being summarized
in Table 2. The reaction proceeded efficiently even with
10 wt % of the lipase TL, with a very high value of kfast
/
kslow, though a longer reaction time was necessary. The
activity of recovered lipase did not decrease, and it
worked as efficiently as fresh batches. The absolute
configuration of (+)-11 was determined by comparison
of its optical rotation with that of previously synthesized
(+)-11, as well as by using the advanced Mosher’s MTPA
(30) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
(31) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136. (b) Meier, R.-M.; Tamm, C. Helv. Chim. Acta 1991, 74, 807.
(32) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505.
(33) In our previous paper,8a the Dess-Martin periodinane was
employed as the oxidant, which gave the desired product in good yield.
TEMPO oxidation is suitable for large-scale preparation. Anelli, P. L.;
Montanari, F.; Quici, S. Organic Syntheses; Wiley: New York, 1993;
Collect. Vol. VIII, p 367.
(29) Holmes and Jennings-White et al. elegantly synthesized cis-
maneonene A using a similar sequence involving the Diels-Alder
reaction of furan and fumaryl chloride, followed by hydrolysis and
bromo-lactonization; see: Jennings-White, C. L. D.; Holmes, A. B.;
Raithby, P. R. J. Chem. Soc., Chem. Commun. 1979, 542.
(34) Yadagiri, P.; Lumin, S.; Mosset, P.; Capdevila, J.; Falck, J. R.
Tetrahedron Lett. 1986, 27, 6039.
J. Org. Chem, Vol. 70, No. 1, 2005 83

Shoji et al.
TABLE 3. r-Iodonation of (+)-19 under Various
Reaction Conditions
temp
(°C)
time yield
entry
reagent
(h)
(%)a
1
2
3
4
I2, PhI(OCOCF3)2, pyridine
I2, PhI(OCOCF3)2, pyridine
I2, PhI(OCOCF3)2, pyridine
I2, PhI(OCOCF3)2, pyridine, 23
cat BHT
I2, DMAP, pyridine
NaN3, ICl
I2, CH3CO2Ag, pyridine
23
23
23
4
10
52
6
6.5
20
<5b
86
Biomimetic, Oxidative Dimerization of Monomer
(+)-7. With the monomer (+)-7 in hand, we examined
its dimerization. In our previous paper, we reported the
first total synthesis of epoxyquinols A and B, which
resulted from the biomimetic transformation involving
a cascade of reactions composed of oxidation, 6π-electro-
cyclization, and Diels-Alder reaction.8a This reaction was
carried out on a 0.03 mmol scale. To search for other
diastereomers in the crude reaction mixture, we exam-
ined the reaction on a 0.4 mmol scale. As there is a large
solvent effect in this oxidative Diels-Alder reaction as
reported in a previous paper,18b the present investigation
was performed in toluene-2H-pyran 5, which was ob-
tained by the following three steps: (1) oxidation of
alcohol (+)-7 with MnO2 in CH2Cl2, (2) filtration of the
inorganic materials, and (3) removal of the volatile
materials under reduced pressure, followed by dissolving
the resulting mixture in toluene. Dimerization proceeded
in 10 h at room temperature, and the crude material was
carefully purified by column chromatography, affording
epoxyquinols A and B in 24 and 33% yields, respectively,
along with epoxyquinol C in 1% yield and epoxytwinol A
in 8% yield. Epoxyquinol C, which is known to be formed
from epoxyquinol A by microwave irradiation,11 is a
Diels-Alder reaction product of 2H-pyran 5 via the exo-
syn(epoxide)-anti(Me)-homo reaction mode.41 Theoretical
calculations indicate that the energy for the transition
state leading to epoxyquinol C is the lowest except for
those leading to epoxyquinols A and B,18b which is in
accord with the experimental results. As for epoxytwinol
A, it is a formal [4 + 4] cycloaddition product of 2H-pyran
5 that gradually converted into epoxyquinol B. In addi-
tion to the total synthesis of these four compounds, we
isolated all of them from the same soil fungus. The fact
that the monomer (+)-6 spontaneously dimerized to
afford epoxyquinols A, B, and C and epoxytwinol A clearly
indicates that an enzyme such as Diels-Alderase is not
involved in this transformation.
5
6
7
23-70
-23-23
0-23
30
22
20
0c
0b
0b
a Isolated yield. b Complex mixture. c No reaction.
iodination reagent was found to be important for the
success of this reaction: None of the desired product was
obtained on treatment of hydroxy ketone (+)-9 with I2/
DMAP,35 I2/TMSN3,36 or NaN3/ICl,37 while the secondary
alcohol was oxidized, affording epoxyquinone in the
reaction using I2/PhI(OCOCF3)2/pyridine.38
The low reactivity and side reaction of (+)-9 can be
attributed to steric hindrance caused by the tert-butyl-
dimethylsiloxymethyl group at the C3 position and
nonprotected hydroxy group at the C4 position, respec-
tively, and so the sterically smaller protecting group had
to be employed. Acetonide derivative (+)-19 was prepared
in 64% yield from (+)-9 over two steps by TBS group
deprotection with Amberlyst in MeOH and protection of
the resulting 1,3-diol with 2,2-dimethoxypropane. Unlike
the result obtained with (+)-9, the reaction of (+)-19
proceeded in the presence of I2/PhI(OCOCF3)2/pyridine,
affording (+)-8, but unreproducibly. After careful exami-
nation, it was found that the iodination proceeded only
after a certain induction period and that, once generated,
(+)-8 began to decompose after a further induction period
as shown in entries 1-3 of Table 3. On the basis of our
speculation that the side reaction was radical in nature,
we carried out the reaction in the dark in the presence
of 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical
scavenger, conditions that gave reproducible results,
providing (+)-8 in 86% yield, though a longer reaction
time was required (entry 4).
As iodinated cyclohexenone (+)-8 was labile, it was
immediately subjected to the Suzuki coupling reaction
with (E)-1-propenyl borate39 under C. R. Johnson’s condi-
tions,40 affording dienone (+)-20 in 77% yield. Cleavage
of the acetonide under acidic conditions provided mono-
mer (+)-7 in 84% yield.
Isomerization Reaction of a Monomethyl Ether
of Epoxyquinol B. As we had observed the facile
transformation of epoxytwinol A into epoxyquinol B
during isolation of the former from the unidentified
fungus, we investigated whether the reverse, conversion
of epoxyquinol B into epoxytwinol A, could be realized,
but with disappointing results. Porco and co-workers
have also failed to achieve this transformation.12 During
these studies, we have encountered an interesting phe-
nomenon: When epoxyquinol B was treated with MeI
(35) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Chem. Eur. J.
2000, 6, 3991.
(36) Sha, C.-K.; Huang, S.-J. Tetrahedron Lett. 1995, 36, 6927.
(37) McIntosh, J. M. Can. J. Chem. 1971, 49, 3045.
(38) Benhida, R.; Blanchard, P.; Fourrey, J.-L. Tetrahedron Lett.
1998, 39, 6849.
(39) (a) Lee, A. S.-Y.; Dai, W.-C. Tetrahedron 1997, 53, 859. (b)
Matteson, D. S.; Jesthi, P. K. J. Organomet. Chem. 1976, 110, 25.
(40) Ruel, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1997, 75,
69.
(41) As for the classifications of the reaction modes, see ref 18b.
84 J. Org. Chem., Vol. 70, No. 1, 2005

Total Synthesis of Epoxyquinols A-C and Epoxytwinol A
SCHEME 5. Synthesis of Epoxyquinols A, B, and C and Epoxytwinol A
in a 7:1 ratio, with 3-methyl ether 21 predominating.
When this 7:1 mixture was refluxed in i-PrOH for 36 h,
the diastereomeric ratio changed from 7:1 to 1:3.5, this
time with the 13-methyl ether 22 as the major isomer.
This isomerization is thought to proceed as follows: The
C1-C17 bond of 21 was cleaved by the participation of
an oxygen lone pair to afford intermediate 23 containing
an oxonium ion and a vinylogous enolate, from which the
C11-C7 bond was formed, affording 22. Though this
isomerization may also proceed in the case of epoxyquinol
B itself, no reaction would be apparent as the starting
material and transformed product are the same.
Reactivity of a 2H-Pyran Derivative. In the bio-
mimetic oxidative dimerization of monomer (+)-7, the
reactive intermediate, 2H-pyran (+)-5, is generated,
which acts both as a diene and a dienophile. The cascade
reaction of oxidation/6π-electrocyclyzation is a useful
synthetic method for the formation of 2H-pyran deriva-
tives, but no systematic study has been made of the
reactivity of this reactive intermediate. Moreover, were
the 2H-pyran derivative to react with another diene or
dienophile instead of dimerizing, an efficient method
for the synthesis of polycyclic compounds would be
realized.
With this in mind, we examined the Diels-Alder
reaction of a 2H-pyran derivative with several dieno-
philes and dienes. We choose epoxycyclohexenone (+)-7
and cyclohexenone 25, with and without the epoxide and
a secondary hydroxy group as the monomers with which
to investigate the reactivity of 2H-pyrans. The reactions
using (+)-7 and 25 were performed as follows: Alcohols
(+)-7 and 25 were oxidized with MnO2 in CH2Cl2 at 0 °C
and room temperature, respectively, for 1 h. After
removal of inorganic materials by filtration, the solvent
was carefully removed under reduced pressure at 0 °C
and Ag2O in CH3CN, an inseparable mixture of mono-
methyl ethers of epoxyquinol B 21 and 22 was obtained
J. Org. Chem, Vol. 70, No. 1, 2005 85

Shoji et al.
SCHEME 6. Synthesis of Various Polycyclic Compounds 24 and 28
TABLE 4. Cascade Reaction of (+)-7 and 25 with Several Dienophiles
a Isolated yield. b 28f was isolated after hydrogenolysis of the Diels-Alder adduct.
86 J. Org. Chem., Vol. 70, No. 1, 2005

Total Synthesis of Epoxyquinols A-C and Epoxytwinol A
SCHEME 7. Synthesis of Azapentacycle 32
to suppress the self-dimerization. Immediately after
removal of the solvent, an excess of dienophile or diene
was added to the reaction mixture, which was then
stirred at room temperature.
The 2H-pyrans 5 and 27, acting as a diene, reacted
with reactive dienophiles such as methyl vinyl ketone,
ethyl vinyl ketone, acrolein, methacrolein, methyl acry-
late, and benzoquinone, affording polycyclic compounds
in moderate to good yield (52-76%) along with the self-
dimerized product in 10-20% yield, the results of which
are summarized in Table 4. In the case of benzoquinone,
isolation and characterization were performed after hy-
drogenolysis of the Diels-Alder adduct due to the latter’s
instability. Only the endo Diels-Alder adducts were
obtained stereoselectively in every reaction examined,
and only anti(epoxide)-anti(Me) reaction was observed in
the reaction of (+)-7. Though 2H-pyrans 5 and 27 also
reacted with maleic anhydride, acryloyl chloride, and
fumaryl chloride to provide Diels-Alder adducts quan-
titatively as single isomers as judged from 1H NMR,
attempts to isolate and characterize the products after
conversion into the corresponding methyl esters were not
successful. Less reactive dienophiles such as 2-cyclo-
hexen-1-one and 2-cyclopenten-1-one did not react with
2H-pyran 27, which instead generated the self-dimer-
ization product 29.18b
azaelectrocyclization, and finally Diels-Alder dimeriza-
tion, proceeded under mild conditions at room tempera-
ture. Though the yield was moderate, this is the first
example of the Diels-Alder dimerization of a 1,2-dihy-
dropyridine derivative. Azapentacycle 32 is the exo-
Diels-Alder product, which is in marked contrast to the
self-dimerization product 29 of 2H-pyran 27, which is the
endo-Diels-Alder product. In the dimerization of this 1,2-
dihydropyridine, steric repulsion caused by the two
phenyl groups makes the endo-Diels-Alder reaction
unfavorable, and as a result, the exo-isomer was selec-
tively obtained.
Next, the reaction with dienes was examined. Cyclo-
pentadiene, known to be a reactive diene, reacted with
2H-pyrans 5 and 27 as a dienophile, affording a tetra-
cyclic compound in moderate yield. Other dienes such as
isoprene gave complex mixtures. The fact that cyclo-
pentadiene reacted as a dienophile instead of a diene
demonstrates the high reactivity of 2H-pyrans 5 and 27
as diene components.
Conclusion
The total synthesis of epoxyquinols A, B, and C and
epoxytwinol A has been accomplished by a biomimetic
cascade reaction. Epoxyquinols A, B, and C were syn-
thesized by the cascade reaction consisting of oxidation/
6π-electrocyclization/Diels-Alder dimerization of the
monomer 7 as a key step, while epoxytwinol A was gen-
erated by the cascade reaction of oxidation/6π-electro-
cyclization/formal [4 + 4] cycloaddition reaction of the
monomer 7. The monomer 7 has been synthesized by two
different routes. In the first, the HfCl4-mediated dia-
stereoselective Diels-Alder reaction of furan with Corey’s
chiral auxiliary was developed, while chromatography-
free preparation of an iodolactone and lipase-mediated
kinetic resolution were key reactions in the second route.
The present method is practical not only for synthesizing
epoxyquinols in a large quantity but also preparing
various derivatives with different side chains via Suzuki
coupling of (+)-8 and alkenyl borates. In fact, we syn-
thesized several monomers, the biological activity of
which is under investigation.46 Another noteworthy
feature described in the present paper is the high
reactivity of 2H-pyrans 5 and 27 as dienes, used to
prepare several polycyclic compounds by the Diels-Alder
reaction. Azapentacycle 32 was also synthesized by the
cascade reaction oxidation/imine formation/6π-azaelec-
trocyclization/Diels-Alder dimerization.
Formation of an Azapentacycle via the Cascade
Reaction. 1,2-Dihydropyridine 31, a nitrogen analogue
of 2H-pyran 27, would be a useful synthetic intermediate
for the formation of azacyclic compounds, should the
same dimerization proceed. Though the 6π-azaelectro-
cyclization of a 1-azatriene to a 1,2-dihydropyridine is
known, it usually requires harsh reaction conditions.19,42
Recently, several 6π-azaelectrocyclizations that proceed
at room temperature have been reported43 and the
asymmetric version has been elegantly applied to a
formal total synthesis of 20-epiuleine.44 Considering the
facile 6π-oxaelectrocyclization of 6 to 5 and of 26 to 27,
the corresponding 6π-azaelectrocyclization of 30 to 31
was also expected to proceed under mild conditions.
Aldehyde 26, generated by the MnO2-mediated oxida-
tion of monomer 25, was treated with aniline, and the
reaction mixture was stirred at room temperature for 30
h, affording azapentacyclic compound 32 in 30% yield
along with the self-dimerization product 29 (15% yield)
of 2H-pyran 27. The structure of 32 was unambiguously
determined by X-ray crystallographic analysis.45 Aza-
pentacycle 32 was thought to be generated by the self-
dimerization of 1,2-dihydropyridine 31, which is formed
by the expected 6π-azaelectrocyclization. That is, the four
successive reactions, oxidation, imine formation, 6π-
(45) A CIF file for the structure of 32 has been deposited at the
Cambridge Crystallographic Data Centre with the deposition number
CCDC 243000. Copies of the data can be obtained free of charge via
the Internet at http://www.ccdc.cam.ac.uk or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ,
UK; fax: +44(1223)336033; email: deposit@ccdccam.ac.uk.
(46) Preliminary results have been published. Kakeya, H.; Miyake,
Y.; Shoji, M.; Kishida, S.; Hayashi, Y.; Kataoka, T.; Osada, H. Bioorg.
Med. Chem. Lett. 2003, 13, 3743.
(42) Rodriguez-Otero, J. J. Org. Chem. 1999, 64, 6842.
(43) (a) de Lera, A. R.; Reischl, W.; Okamura, W. H. J. Am. Chem.
Soc. 1989, 111, 4051. (b) Tanaka, K.; Mori, H.; Yamamoto, M.;
Katsumura, S. J. Org. Chem. 2001, 66, 3099 and references therein.
(44) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660.
J. Org. Chem, Vol. 70, No. 1, 2005 87

Shoji et al.
was concentrated in vacuo. The residue was filtered and
washed with water and then dried to afford iodolactone 15 (109
g, 42%) as a colorless solid. The crude product was used for
next reaction without further purification.
Experimental Section
(1R,2R,4R)-7-Oxa-bicyclo[2.2.1]hept-5-ene-2-carbox-
ylic Acid (1R,2R)-2-(Naphthalene-2-sulfonyl)-cyclohexyl
Ester (endo-14) and (1R,2S,4R)-7-Oxa-bicyclo[2.2.1]hept-
5-ene-2-carboxylic Acid (1R,2R)-2-(Naphthalene-2-sulfon-
yl)-cyclohexyl Ester (exo-14). To a solution of HfCl4 (70.0
mg, 0.219 mmol) in toluene (0.7 mL) was added (-)-13 (70.1
mg, 0.203 mmol) at 0 °C, and the mixture was cooled to -45
°C. To the mixture was added furan (0.32 mL, 4.4 mmol), and
the mixture was stirred for 34 h at that temperature. The
reaction mixture was quenched with saturated NaHCO3 (aq)
and filtered through a pad of Celite. The organic materials
were extracted with AcOEt three times and dried over Na2SO4.
The organic phase was concentrated in vacuo, and the residue
was purified by preparative thin-layer chromatography (AcOEt/
hexane ) 1) to endo-14 (47.7 mg, 56%, 87% de) as a colorless
solid and exo-14 (22.4 mg, 27%, 91% de, inseparable mixture)
as a colorless solid. endo-14: 1H NMR (400 MHz, CDCl3) δ
1.18-1.35 (4H, m), 1.49 (1H, qd, J ) 12.1, 3.8 Hz), 1.66-1.80
(3H, m), 1.98-2.10 (2H, m), 2.77 (1H, ddd, J ) 9.0, 4.8, 4.1
Hz), 3.36 (1H, ddd, J ) 12.1, 10.1, 4.1 Hz), 4.91 (1H, br-d, J )
4.9 Hz), 5.12 (1H, td, J ) 10.1, 4.9 Hz), 5.14 (1H, br-d, J ) 4.9
Hz), 6.37 (2H, s), 7.62-7.72 (2H, m), 7.83 (1H, dd, J ) 8.6, 1.7
Hz), 7.95 (1H, br-d, J ) 7.8 Hz), 8.01 (2H, d, J ) 8.3 Hz), 8.43
(1H, d, J ) 1.1 Hz); 13C NMR (100 MHz, CDCl3) δ 23.2, 24.1,
25.8, 28.5, 31.6, 42.8, 65.5, 70.5, 79.1, 79.2, 123.4, 127.8, 128.0,
129.3, 129.40, 129.41, 130.4, 132.1, 133.1, 135.3, 135.5, 136.4,
170.9; FT-IR (KBr) ν 3014, 2945, 2864, 1732, 1452, 1311, 1178,
1146, 1126, 1072, 1018, 756 cm-1. Anal. Calcd for C23H24O5S:
C 66.97, H 5.86. Found: C 66.73, H 5.78. [R]25D +2.62 (c 1.00,
CHCl3). exo-14: 1H NMR (400 MHz, CDCl3) δ 1.20-1.36 (4H,
m), 1.49-1.60 (1H, m), 1.65-1.78 (3H, m), 1.79-1.88 (2H, m),
2.07-2.13 (1H, m), 2.26-2.34 (1H, m), 3.39 (1H, ddd, J ) 12.1,
10.0, 4.1 Hz), 4.94 (1H, br-d, J ) 4.1 Hz), 5.09 (1H, td, J )
10.0, 5.0 Hz), 5.12 (1H, br-s), 6.00 (1H, dd, J ) 5.8, 1.3 Hz),
6.23 (1H, dd, J ) 5.8, 1.5 Hz), 7.61-7.70 (2H, m), 7.84 (1H,
dd, J ) 8.6, 1.7 Hz), 7.92 (1H, br-d, J ) 7.9 Hz), 7.98 (1H, d,
J ) 8.6 Hz), 8.01 (1H, d, J ) 7.9 Hz), 8.44 (1H, br-s); 13C NMR
(100 MHz, CDCl3) δ 23.2, 24.1, 25.1, 29.2, 31.5, 42.2, 65.7, 70.5,
77.6, 80.2, 123.5, 127.7, 127.9, 129.2, 129.3, 129.5, 130.4, 132.1,
134.6, 135.2, 135.6, 136.7, 172.5; FT-IR (KBr) ν 3012, 2943,
rel-(1R,2S,4R,5S,6R)-6-Methoxycarbonyl-3,8-dioxa-
tricyclo[3.2.1.02,4]octane (12). To a solution of iodolactone
15 (30.3 g, 0.114 mol) in DMF (450 mL) was added KOH (16.0
g, 0.285 mol) and stirred for 17 h at 60 °C. To the reaction
mixture was added CH3I (21.3 mL, 0.342 mol) at room
temperature, and the mixture was sonicated for 2 h. After
removal of volatile materials in vacuo, 1 N HCl (aq) (18 mL)
and saturated NH4Cl (aq) (150 mL) were added. The organic
materials were extracted with AcOEt (3 × 300 mL), and the
combined organic phases were washed with brine and then
dried over Na2SO4. The organic phase was concentrated in
vacuo, and the residue was purified by silica gel column
chromatography (AcOEt/hexane ) 1) to afford methyl ester
12 (17.5 g, 90%) as a colorless solid: 1H NMR (400 MHz,
CDCl3) δ 1.97 (1H, td, J ) 11.6, 5.1 Hz), 2.08 (1H, dd, J )
11.6, 4.2 Hz), 2.91 (1H, dt, J ) 11.6, 4.6 Hz), 3.74 (3H, s), 4.01
(1H, dd, J ) 4.5, 2.5 Hz), 4.10 (1H, dd, J ) 4.5, 2.3 Hz), 4.51
(1H, dt, J ) 5.0, 2.5 Hz), 4.69 (1H, dt, J ) 5.1, 2.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 29.2, 44.6, 51.5, 66.2, 66.4, 77.4,
78.0, 171.8; FT-IR (KBr) ν 3039, 2921, 1731, 1444, 1342, 1305,
1097, 956, 609 cm-1; HRMS (FAB) [M + H]+ calcd for C8H11O4
171.0657, found 171.0663. Anal. Calcd for C8H10O4: C 56.47,
H 5.92. Found: C 56.55, H 5.88.
rel-(1R,5R,6S)-3-Methoxycarbonyl-7-oxabicyclo[4.1.0]-
hept-2-en-5-ol (11). To a solution of diisopropylamine (1.17
mL, 8.32 mmol) in THF (6.3 mL) was added nBuLi solution
(1.58 M in hexane, 4.21 mL, 6.66 mmol) dropwise at 0 °C, and
the mixture was stirred for 10 min at that temperature. To a
solution of methyl ester 12 (944 mg, 5.55 mmol) in THF (8.4
mL) was added the LDA solution prepared above dropwise at
-90 °C, and the mixture was stirred for 10 min at that
temperature. The reaction was quenched with pH 7 phosphate
buffer, and organic materials were extracted with AcOEt (3
× 50 mL). The combined organic phases were washed with
brine and dried over Na2SO4. The organic phase was concen-
trated in vacuo, and the residue was purified by silica gel
column chromatography (AcOEt/hexane ) 1/3∼1/1) to afford
alcohol 11 (869 mg, 92%) as a colorless solid: 1H NMR (400
MHz, CDCl3) δ 1.83 (1H, bs), 2.33 (1H, ddd, J ) 17.6, 5.1, 3.4
Hz), 2.80 (1H, dt, J ) 17.6, 1.8 Hz), 3.48 (1H, t, J ) 4.8 Hz),
3.55-3.59 (1H, m), 3.75 (3H, s), 4.53-4.59 (1H, m), 7.13 (1H,
t, J ) 3.4 Hz); 13C NMR (100 MHz, CDCl3) δ 29.2, 46.2, 52.1,
56.0, 63.3, 130.7, 133.4, 166.6; FT-IR (neat) ν 3444, 2954, 1716,
1438, 1207, 819, 609, 509 cm-1; HRMS (EI) [M]+ calcd for
C8H10O4 170.0579, found 170.0619.
2864, 1736, 1308, 1144, 1126, 870, 758, 661 cm-1
.
(1R,2R,3R,6R,7S)-2-Iodo-4,8-dioxatricyclo[4.2.1.03,7]-
nonan-5-one (15). To a solution of endo-14 (64.6 mg, 0.156
mmol) in CH3CN (1.5 mL) and water (0.06 mL) was added I2
(194 mg, 0.764 mmol) at room temperature, and the mixture
was stirred for 5.5 h. To the reaction mixture was added
saturated Na2S2O3 (aq), and organic materials were extracted
with CHCl3 (3 × 15 mL). The combined organic phases were
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by thin-layer chromatography to afford 15 (33.7 mg,
81%) as a colorless solid along with the recovery of the chiral
auxiliary (42.4 mg, 94%). Iodolactone 15 was recrystallized
from benzene-hexane twice to give optically pure 15: 1H NMR
(400 MHz, CDCl3) δ 2.15 (1H, dd, J ) 13.5, 3.2 Hz), 2.20 (1H,
dd, J ) 13.5, 10.4, 4.7 Hz), 2.77 (1H, ddd, J ) 10.4, 4.7, 3.2
Hz), 3.94 (1H, s), 4.80 (1H, d, J ) 4.7 Hz), 5.12 (1H, d, J ) 4.9
Hz), 5.38 (1H, t, J ) 4.9 Hz); 13C NMR (100 MHz, CDCl3) δ
25.0, 36.1, 38.0, 81.9, 84.2, 87.5, 175.8; FT-IR (KBr) ν 2995,
1787, 1324, 1189, 1022, 661, 433 cm-1; HRMS (FAB) [M + H]+
Kinetic Resolution of Racemic Alcohol 11. To a solution
of racemic alcohol 11 (2.80 g, 16.5 mmol) in vinyl acetate (30
mL) was added Pseudomonas stutzeri lipase (Meito TL, 0.28
g), and the mixture was stirred at room temperature for 40 h.
The lipase was filtered off, and the filtrate was condensed in
vacuo. The residue was purified by silica gel column chroma-
tography (AcOEt/hexane ) 1/3∼1/1) to afford epoxy alcohol (+)-
11 (1.35 g, 49%, 99% ee) and acetate (-)-16 (1.65 g, 48%, 96%
ee) as a colorless oil. (1R,5R,6S)-3-Methoxycarbonyl-7-
oxabicyclo[4.1.0]hept-2-en-5-ol ((+)-11): [R]26D +213 (c 0.56,
MeOH). HPLC analysis conditions: CHIRALCEL OD-H col-
umn, 2-PrOH/hexane ) 1/20, 1.5 mL/min; retention times 28.7
min (major), 11.1 min (minor). (1S,5S,6S)-5-Acetoxy-3-meth-
oxycarbonyl-7-oxabicyclo[4.1.0]hept-2-ene ((-)-16): 1H
NMR (400 MHz, CDCl3) δ 2.04 (3H, s), 2.36 (1H, ddd, J ) 18.1,
5.3, 3.3 Hz), 2.82 (1H, dt, J ) 18.1, 1.8 Hz), 3.49 (1H, t, J )
3.9 Hz), 3.60-3.63 (1H, m), 3.77 (3H, s), 5.62 (1H, dt, J ) 5.4,
2.7 Hz), 7.14 (1H, t, J ) 3.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 20.9, 26.4, 46.5, 52.1, 53.9, 65.6, 131.0, 133.0, 166.1, 170.3;
FT-IR (neat) ν 2954, 2850, 1739, 1714, 1649, 1265, 1028, 818,
600 cm-1; HRMS (FAB) [M + H]+ calcd for C10H13O5 213.0763,
calcd for C7H8O3I 266.9518, found 266.9514; [R]23 -114 (c
D
0.906, CHCl3); lit.26) [R]25 -113 (c 1.04, CHCl3).
D
Synthesis of rac-15. To furan (580 mL, 8 mol) was added
acryloyl chloride (80 mL, 0.98 mol) at room temperature under
an argon atmosphere, and the ratio of the endo adduct was
1
monitored by H NMR. After 3.5 h, the reaction mixture was
quenched with 2 N NaOH (aq) (445 mL, 0.89 mol) and
saturated NaHCO3 (aq) (700 mL) and then stirred vigorously
for 1.5 h. To the separated aqueous phase was added CH2Cl2
(900 mL) and I2 (125 g, 0.49 mol) at 0 °C, and the mixture
was stirred vigorously for 2 h. The reaction mixture was
quenched with saturated Na2S2O3 (aq), and the organic phase
found 213.0772; [R]22 -226 (c 0.46, MeOH). HPLC analysis
D
88 J. Org. Chem., Vol. 70, No. 1, 2005

Total Synthesis of Epoxyquinols A-C and Epoxytwinol A
conditions: CHIRALCEL OD-H column, 2-PrOH/hexane )
1/20, 1.5 mL/min; retention times 5.6 min (major), 6.0 min
(minor).
869, 688 cm-1; HRMS (FAB) [M + H]+ calcd for C13H25O4Si
273.1522, found 273.1491; [R]26 +14.0 (c 0.89, MeOH).
D
(1R,5S,6R)-4-(tert-Butyl-dimethylsiloxymethyl)-5-hy-
droxy-7-oxabicyclo[4.1.0]hept-3-en-2-one ((+)-9). To a so-
lution of alcohol (+)-10 (95.9 mg, 0.352 mmol), TEMPO (0.6
mg, 0.004 mmol), and KBr (4.2 mg, 0.035 mmol) in CH2Cl2-
H2O (10:3, 1.3 mL) was added NaOCl-NaHCO3 (aq) (1.3 M,
pH 9.5, 0.27 mL, 0.36 mmol) at -10 °C, and the mixture was
stirred for 40 min at that temperature. The reaction was
quenched with saturated Na2S2O3 (aq), and organic materials
were extracted with CH2Cl2 (3 × 5 mL). The combined organic
phases were washed with brine and dried over Na2SO4. The
organic phase was concentrated in vacuo. To the residue was
added toluene (1.5 mL) and silica gel (0.5 g), and the mixture
was stirred at 70 °C for 4.5 h. The reaction mixture was cooled
to room temperature and condensed in vacuo. The residue was
purified by silica gel column chromatography (AcOEt/hexane
) 1/3∼1/1) to afford enone (+)-9 (84.7 mg, 89%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.10 (6H, s), 0.91 (9H, s),
3.29 (1H, bs), 3.43 (1H, s), 3.78 (1H, dd, J ) 3.4, 0.9 Hz), 4.28
(1H, d, J ) 15.6 Hz), 4.51 (1H, dd, J ) 15.6, 1.6 Hz), 4.63 (1H,
bs), 5.96 (1H, d, J ) 1.4 Hz); 13C NMR (100 MHz, CDCl3) δ
-5.5, 18.2, 25.7, 52.7, 56.4, 64.1, 65.0, 121.1, 156.9, 193.6; FT-
IR (neat) ν 3419, 2954, 2931, 2884, 1687, 1344, 1226, 1049,
879, 781 cm-1; HRMS (FAB) [M + H]+ calcd for C13H23O4Si
(1S,5S,6R)-3-Methoxycarbonyl-7-oxabicyclo[4.1.0]hept-
2-en-5-ol ((-)-11). To a solution of acetate (-)-16 (198 mg,
0.93 mmol) in MeOH (1.0 mL) was added K2CO3 (13 mg, 0.093
mmol) at 0 °C, and the mixture was stirred for 1 h at that
temperature. The reaction mixture was quenched with satu-
rated NH4Cl (aq) and concentrated in vacuo. The organic
materials were extracted with AcOEt (3 × 10 mL), and the
combined organic phases were washed with brine and dried
over Na2SO4. The organic phase was concentrated in vacuo,
and the residue was purified by silica gel column chromatog-
raphy (AcOEt/hexane ) 1/3∼1/1) to afford alcohol (-)-11 (154
mg, 97%) as a colorless oil.
(1S,2R,4S,6R,7S)-4-Methoxycarbonyl-3,8-dioxatricyclo-
[5.1.0.02,4]octan-6-ol ((+)-17). To a solution of alcohol (+)-11
(282 mg, 1.65 mmol) in CH2Cl2 (15 mL) was added VO(acac)2
(22.0 mg, 0.083 mmol), and the mixture was stirred for 5 min
at room temperature. To the reaction mixture was added
tBuOOH (4.2 M in toluene, 2.0 mL), and the mixture was
vigorously refluxed for 12 h. The reaction mixture was cooled
to room temperature and quenched with saturated Na2S2O3
(aq). Organic materials were extracted with AcOEt (3 × 30
mL), and the combined organic phases were washed with brine
and dried over Na2SO4. The organic phase was concentrated
in vacuo, and the residue was purified by silica gel column
chromatography (AcOEt/hexane ) 1/3∼1/1) to afford diepoxide
(+)-17 (297 mg, 96%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 2.33 (1H, bd, J ) 16.0 Hz), 2.41 (1H, dd, J ) 16.0,
4.4 Hz), 2.55 (1H, d, J ) 12.0 Hz), 3.27 (1H, t, J ) 3.4 Hz),
3.51 (1H, dd, J ) 3.9, 2.8 Hz), 3.71 (3H, s), 3.80 (1H, d, J )
2.5 Hz), 4.13-4.21 (1H, m); 13C NMR (100 MHz, CDCl3) δ 27.1,
50.3, 52.8, 53.7, 55.9, 57.5, 64.2, 168.5; FT-IR (neat) ν 3521,
271.1366, found 271.1368; [R]25 +149 (c 0.56, MeOH).
D
(4R,6R,7S)-9,9-Dimethyl-5,8,10-trioxatricyclo[5.4.0.04,6]-
undec-1-en-3-one ((+)-19). To a solution of TBS ether (+)-9
(38.7 mg, 0.143 mmol) in MeOH (1 mL) was added Amberlyst
15 (11.3 mg), and the mixture was stirred for 5 h at room
temperature. The reaction mixture was filtered, and the
filtrate was condensed in vacuo. The residue was dissolved in
CH2Cl2 (0.5 mL), and then 2,2-dimethoxypropane (0.35 mL,
2.85 mmol) and pyridinium p-toluenesulfonate (3.6 mg, 0.014
mmol) were added. After stirring for 4 h, the reaction mixture
was poured into saturated NaHCO3 (aq) and organic materials
were extracted with AcOEt (3 × 10 mL). The combined organic
phases were washed with brine and dried over Na2SO4. The
organic phase was concentrated in vacuo, and the residue was
purified by neutral silica gel column chromatography (AcOEt/
hexane ) 1/10-1/3) to afford acetonide (+)-19 (18.0 mg, 64%)
as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 1.43 (3H,
s), 1.60 (3H, s), 3.42-3.44 (1H, m), 3.67 (1H, d, J ) 3.2 Hz),
4.26 (1H, d, J ) 14.6 Hz), 4.58 (1H, dt, J ) 14.6, 1.3 Hz), 4.81
(1H, s), 5.83 (1H, t, J ) 1.1 Hz); 13C NMR (100 MHz, CDCl3)
δ 21.4, 27.1, 52.4, 57.3, 63.8, 64.0, 101.2, 120.1, 154.0, 190.9;
FT-IR (neat) ν 1674, 1269, 1201, 1159, 1078, 881, 856, 779,
540 cm-1; HRMS (FAB) [M + H]+ calcd for C10H13O4 197.0814,
found 197.0818. Anal. Calcd for C10H12O4: C 61.22, H 6.16.
Found: C 61.38, H 6.23; [R]25D +348 (c 0.10, CHCl3); mp 93.0-
94.0 °C.
2956, 1743, 1444, 1363, 1294, 1257, 1068, 863, 784 cm-1
;
HRMS (FAB) [M + H]+ calcd for C8H11O5 187.0606, found
187.0622; [R]26 +60.9 (c 0.54, MeOH).
D
(1R,2S,4S,5R,7R)-7-Hydroxymethyl-3,8-dioxatricyclo-
[5.1.0.02,4]octan-5-ol ((+)-18). To a solution of ester (+)-18
(367 mg, 1.97 mmol) in MeOH (3 mL) was added NaBH4 (223
mg, 5.91 mmol) at 0 °C, and the mixture was stirred for 30
min at room temperature. The volatile materials were evapo-
rated in vacuo, and the residue was purified by silica gel
column chromatography (MeOH/CHCl3 ) 1/10) to afford diol
1
(+)-18 (300 mg, 96%) as a colorless oil. H NMR (400 MHz,
CD3OD) δ 2.05 (1H, dd, J ) 15.6, 2.6 Hz), 2.08 (1H, dd, J )
15.6, 4.4 Hz), 3.22 (1H, bt, J ) 3.5 Hz), 3.43 (1H, d, J ) 12.4
Hz), 3.49 (1H, d, J ) 2.5 Hz), 3.53 (1H, t, J ) 3.2 Hz), 3.55
(1H, d, J ) 12.4 Hz), 4.14 (1H, dt, J ) 4.4, 3.0 Hz); 13C NMR
(100 MHz, CD3OD) δ 29.3, 52.2, 55.2, 55.4, 62.1, 65.4, 65.5;
FT-IR (neat) ν 3399, 3369, 2927, 1423, 1074, 1047, 809, 619
cm-1; HRMS (FAB) [M + H]+ Calcd for C7H11O4: 159.0657,
(4R,6R,7S)-2-Iodo-9,9-dimethyl-5,8,10-trioxatricyclo-
[5.4.0.04,6]undec-1-en-3-one ((+)-8). To a solution of iodine
(23.4 mg, 0.092 mmol) and pyridine (11.2 µL, 0.14 mmol) in
CH2Cl2 (0.3 mL) was added PhI(OCOCF3)2 (39.7 mg, 0.092
mmol), and the mixture was stirred at room temperature for
15 min in the dark. To the reaction mixture were added 2,6-
di-tert-butyl-4-methylphenol (1.0 mg, 0.0045 mmol) and enone
(+)-19 (18.1 mg, 0.092 mmol), and the mixture was stirred for
22 h at that temperature. The reaction was quenched with
saturated Na2S2O3 (aq), and organic materials were extracted
with AcOEt (3 × 10 mL). The combined organic phases were
washed with brine and dried over Na2SO4. The organic phase
was concentrated in vacuo, but not completely, and the residue
was purified by neutral silica gel column chromatography
(AcOEt/hexane ) 1/30-1/10) to afford iodoenone (+)-8 (25.5
mg, 86%) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ
1.40 (3H, s), 1.54 (3H, s), 3.63 (1H, dd, J ) 3.4, 1.4 Hz), 3.76
(1H, d, J ) 3.2 Hz), 4.35 (1H, dd, J ) 18.3, 1.4 Hz), 4.40 (1H,
dd, J ) 18.3, 1.4 Hz), 4.72 (1H, d, J ) 0.8 Hz); 13C NMR (100
MHz, CDCl3) δ 23.9, 25.7, 51.3, 57.4, 65.3, 69.6, 98.0, 102.8,
162.2, 184.3; FT-IR (neat) ν 2989, 2858, 1683, 1384, 1228, 1097,
found: 159.0650; [R]26 +11.1 (c 0.77, MeOH).
D
(1R,2S,4S,5R,7R)-7-(tert-Butyl-dimethyl-silanyloxy-
methyl)-3,8-dioxatricyclo[5.1.0.02,4]octan-5-ol ((+)-10). To
a solution of alcohol (+)-18 (134 mg, 0.85 mmol), Et3N (0.19
mL, 1.38 mmol), and 4-(dimethylamino)pyridine (10.3 mg,
0.085 mmol) in CH2Cl2 (2 mL) was added TBSCl (183 mg, 1.21
mmol) at 0 °C, and the mixture was stirred for 15 h at room
temperature. The reaction was quenched with pH 7.0 phos-
phate buffer, and organic materials were extracted with AcOEt
(3 × 10 mL). The combined organic phases were washed with
brine and dried over Na2SO4. The organic phase was concen-
trated in vacuo, and the residue was purified by silica gel
column chromatography (AcOEt/hexane ) 1/10∼1/1) to afford
TBS ether (+)-10 (339 mg, 84%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 0.03 (6H, s), 0.87 (9H, s), 2.02 (1H, dd, J
) 15.4, 4.2 Hz), 2.10 (1H, d, J ) 15.4 Hz), 2.82 (1H, d, J )
12.0 Hz), 3.29 (1H, bs), 3.47 (1H, d, J ) 11.8 Hz), 3.48 (2H, s),
3.66 (1H, d, J ) 11.8 Hz), 4.16 (1H, bd, J ) 12.0 Hz); 13C NMR
(100 MHz, CDCl3) δ -5.5, 18.2, 25.7, 27.8, 50.9, 54.3, 54.5,
62.2, 94.9, 65.0; FT-IR (neat) ν 3517, 2954, 2929, 2857, 1116,
J. Org. Chem, Vol. 70, No. 1, 2005 89

Shoji et al.
848, 518 cm-1; HRMS (FAB) [M + H]+ calcd for C10H12O4I
(1S,2S,4R,6R,7S,11R,12S,13S,16R,18R,19S,22R)-7,19-Di-
hydroxy-11,22-dimethyl-5,10,17,21-tetraoxaheptacyclo-
[11.7.2.02,8.02,12.04,6.014,20.016,18]docosa-8,14(20)-diene-3,15-
dione (Epoxyquinol B (2)):3 1H NMR (400 MHz, acetone-
d6) δ 0.73 (3H, d, J ) 6.4 Hz), 1.27 (3H, d, J ) 6.4 Hz), 2.79
(1H, dd, J ) 8.6, 3.0 Hz), 3.12 (1H, dd, J ) 3.0, 1.0 Hz), 3.31
(1H, dq, J ) 8.6, 6.4 Hz), 3.48 (1H, dd, J ) 3.1, 0.7 Hz), 3.50
(1H, dd, J ) 3.9, 0.8 Hz), 3.66 (1H, dd, J ) 3.1, 1.8 Hz), 3.85
(1H, dd, J ) 3.6, 1.6 Hz), 4.04 (1H, qd, J ) 6.4, 1.0 Hz), 4.60
(1H, bs), 4.81 (1H, bs), 5.18 (1H, s), 5.78 (1H, bs), 5.84 (1H,
bs), 6.61 (1H, s); 13C NMR (100 MHz, acetone-d6) δ 19.6, 20.5,
36.9, 42.2, 53.0, 53.3, 53.3, 55.4, 57.0, 64.4, 68.6, 70.5, 73.7,
322.9780, found 322.9791; [R]27 +206 (c 1.35, MeOH).
D
(4R,6R,7S)-9,9-Dimethyl-2-(E)-propenyl-5,8,10-trioxa-
tricyclo[5.4.0.04,6]undec-1-en-3-one ((+)-20). To a solution
of iodoenone (+)-8 (8.0 mg, 0.025 mmol), (E)-prppenyl borate
(6.6 mg, 0.077 mmol), Ag2O (18.4 mg, 0.079 mmol) and Ph3As
(1.5 mg, 0.0050 mmol) in THF-H2O (10:1, 0.5 mL) was added
Pd(PhCN)2Cl2 (1.0 mg, 0.0025 mmol) and stirred at room
temperature for 11 h in the dark. To the reaction mixture was
added saturated NH4Cl (aq) (2 mL) and stirred for 1 h at that
temperature. The reaction mixture was filtered through a pad
of Celite and organic materials were extracted with AcOEt (3
× 10 mL). The combined organic phases were washed with
brine and dried over Na2SO4. The organic phase was concen-
trated in vacuo and the residue was purified by preparative
thin-layer chromatography (Et2O/benzne ) 1/6) to afford
74.9, 107.0, 133.0, 150.9, 151.9, 191.9, 200.0; [R]23 +151 (c
D
0.710, MeOH); lit.3) [R]21 +153 (c 0.315, MeOH).
D
(1R,2R,4R,6R,7S,11S,12R,13R,16R,18R,19S,22S)-7,19-
Dihydroxy-11,22-dimethyl-5,10,17,21-tetraoxaheptacyclo-
[11.7.2.02,8.02,12.04,6.014,20.016,18]docosa-8,14(20)-diene-3,15-
dione (Epoxyquinol C (3)):11 1H NMR (400 MHz, acetone-
d6) δ 0.72 (3H, d, J ) 6.4 Hz), 1.14 (3H, d, J ) 6.4 Hz), 3.06
(1H, dd, J ) 8.0, 3.0 Hz), 3.12 (1H, dd, J ) 2.9, 1.2 Hz), 3.31
(1H, dq, J ) 7.9, 6.4 Hz), 3.47 (1H, dd, J ) 3.5, 1.0 Hz), 3.49
(1H, bd, J ) 3.6 Hz), 3.80 (1H, d, J ) 3.6 Hz), 3.83 (1H, dd, J
) 3.5, 1.0 Hz), 3.97 (1H, qd, J ) 6.4, 1.2 Hz), 4.57 (1H, bs),
5.00 (2H, bs), 5.27 (1H, s), 5.59 (1H, s), 6.64 (1H, d, J ) 1.9
Hz).
(1S,2S,4S,5R,7R,10S,11S,14R,16R,17S,20R,22R)-4,17-Di-
hydroxy-20,22-dimethyl-6,15,19,21-tetraoxaheptacyclo-
[9.7.2.22,10.03,9.05,7.012,18.014,16]docosa-3(9),12(18)-diene-8,13-
dione (Epoxytwinol A (4)):5a 1H NMR (270 MHz, acetone-
d6) δ 0.77 (6H, d, J ) 6.2 Hz), 3.21 (2H, bs), 3.53 (2H, dd, J )
3.7, 1.0 Hz), 3.85 (2H, dd, J ) 3.7, 1.0 Hz), 4.20 (2H, q, J )
6.4 Hz), 4.38 (2H, d, J ) 9.7 Hz), 4.60 (2H, bd, J ) 9.7 Hz),
4.80 (2H, s).
(1S,2S,4R,6R,7S,11R,12S,13S,16R,18R,19S,22R)-7-Hy-
droxy-19-methoxy-11,22-dimethyl-5,10,17,21-tetraoxa-
heptacyclo[11.7.2.02,8.02,12.04,6.014,20.016,18]docosa-8,14(20)-diene-
3,15-dione (21). To a solution of epoxyquinol B (3.0 mg, 0.0077
mmol) and iodomethane (48 µL, 0.77 mmol) in CH3CN (0.5
mL) was added Ag2O (90 mg, 0.39 mmol), and the mixture
was stirred at room temperature for 5 h in the dark. The
reaction mixture was filtered through a pad of Celite and
washed with AcOEt. The filtrate was concentrated in vacuo,
and the residue was purified by preparative thin-layer chro-
matography (AcOEt) to afford a 7:1 mixture of 3-methoxy
epoxyquinol B (21) and 13-methoxy epoxyquinol B (22) (3.1
mg, 100%, colorless solid): 1H NMR (400 MHz, CDCl3) δ 0.78
(3H, d, J ) 6.4 Hz), 1.27 (3H, d, J ) 6.4 Hz), 2.76 (1H, dd, J
) 6.1, 2.7 Hz), 3.12 (1H, br-d, J ) 2.5 Hz), 3.46 (1H, d, J ) 3.2
Hz), 3.54 (3H, s), 3.55-3.60 (2H, m), 3.66 (1H, br-t, J ) 2.6
Hz), 3.88 (1H, d, J ) 3.5 Hz), 4.18 (1H, br-q, J ) 6.4 Hz), 4.25
(1H, s), 4.53 (1H, br-d, J ) 1.8 Hz), 4.68 (1H, s), 5.13 (1H, s)
6.43 (1H, s); 13C NMR (100 MHz, CDCl3) δ 19.5, 19.9, 37.3,
42.0, 52.5, 52.7, 54.1, 54.7, 55.9, 67.6, 70.6, 72.4, 73.0, 74.2,
78.3, 107.1, 135.2, 146.3, 148.6, 189.9, 199.3; HRMS (FAB) [M
+ H]+ calcd for C21H23O8 403.1393, found 403.1399.
(1S,2S,4R,6R,7S,11R,12S,13S,16R,18R,19S,22R)-19-Hy-
droxy-7-methoxy-11,22-dimethyl-5,10,17,21-tetraoxa-
heptacyclo[11.7.2.02,8.02,12.04,6.014,20.016,18]docosa-8,14(20)-
diene-3,15-dione (22). A solution of 3-methoxy epoxyquinol
B and 13-methoxy epoxyquinol B (7:1 mxture, 1.5 mg) in
2-propanol (0.5 mL) was refluxed for 36 h. The reaction
mixture was concentrated in vacuo to afford 3.5:1 mixture of
22 and 21: 1H NMR (400 MHz, CDCl3) δ 0.79 (3H, d, J ) 6.4
Hz), 1.33 (3H, d, J ) 6.3 Hz), 2.86 (1H, dd, J ) 8.9, 3.1 Hz),
3.11 (1H, br-d, J ) 3.0 Hz), 3.29 (1H, dq, J ) 8.9, 6.3 Hz),
3.48-3.53 (2H, m), 3.71 (3H, s), 3.73 (1H, dd, J ) 2.9, 1.3 Hz),
3.82 (1H, dd, J ) 3.6, 1.3 Hz), 4.10 (1H, br-q, J ) 6.4 Hz),
4.11 (1H, s), 4.76 (1H, s), 4.88 (1H, s), 5.06 (1H, d, J ) 1.3 Hz)
6.60 (1H, s); 13C NMR (100 MHz, CDCl3) δ 19.2, 20.2, 35.9,
41.0, 51.0, 52.4, 52.6, 56.1, 58.0, 63.4, 63.8, 69.7, 72.8, 74.6,
78.3, 103.5, 132.3, 150.6, 152.4, 190.9, 197.9.
1
dienone (+)-20 (4.5 mg, 77%) as a colorless oil. H NMR (400
MHz, CDCl3) δ 1.34 (3H, s), 1.51 (3H, s), 1.82 (3H, dd, J )
6.5, 1.1 Hz), 3.48 (1H, d, J ) 3.5 Hz), 3.69 (1H, d, J ) 3.5 Hz),
4.59 (1H, d, J ) 16.8 Hz), 4.64 (1H, d, J ) 16.8 Hz), 4.88 (1H,
s), 5.89 (1H, qd, J ) 16.0, 6.5 Hz), 6.06 (1H, d, J ) 16.0 Hz);
13C NMR (100 MHz, CDCl3) δ 19.2, 24.8, 25.5, 53.1, 57.1, 63.0,
63.8, 101.5, 121.0, 127.9, 134.8, 148.7, 190.9; FT-IR (neat) ν
2989, 2931, 2854, 1682, 1385, 1373, 1238, 1082, 1038, 858
cm-1; HRMS (FAB) [M + H]+ calcd for C13H17O4 236.1049,
found 236.1053; [R]25 +231 (c 0.73, MeOH).
D
(1R,5S,6R)-5-Hydroxy-4-hydroxymethyl-3-(E)-propenyl-
7-oxabicyclo[4.1.0]hept-3-en-2-one ((+)-7). To a solution of
acetonide (+)-20 (9.0 mg, 0.038 mmol) in MeOH (0.8 mL) was
added Amberlyst 15 (9 mg), and the mixture was stirred at
room temperature for 40 min. The reaction mixture was
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by preparative thin-layer chromatography
(AcOEt) to afford epoxycyclohexenol ((+)-7) (6.2 mg, 84%) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.84 (3H, dd, J )
6.2, 1.0 Hz), 2.10 (1H, bs), 3.13 (1H, bd, J ) 3.9 Hz), 3.56 (1H,
dd, J ) 3.9, 0.7 Hz), 3.82 (1H, dd, J ) 3.9, 1.5 Hz), 4.49 (1H,
d, J ) 14.2 Hz), 4.77 (1H, d, J ) 14.2 Hz), 5.00 (1H, bs), 5.96
(1H, qd, J ) 16.0, 6.2 Hz), 6.06 (1H, d, J ) 16.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 19.2, 53.4, 55.6, 63.0, 65.2, 121.6, 131.0,
135.3, 146.3, 194.3; FT-IR (neat) ν 3371, 2916, 1676, 1444,
1373, 1051, 968, 868 cm-1; HRMS (FAB) [M + H]+ calcd for
C10H12O4 196.0736, found 196.0732; [R]25 +285 (c 0.41,
D
MeOH).
Epoxyquinols A (1), B (2), and C (3) and Epoxytwinol
A (4). To a solution of (+)-7 (78.9 mg, 0.402 mmol) in dry
CH2Cl2 (8 mL) was added MnO2 (700 mg, 75%, 6.03 mmol) at
0 °C under an argon atmosphere, and the mixture was stirred
for 1 h at that temperature. The reaction mixture was filtered
through a pad of Celite, washed with AcOEt, and then
concentrated in vacuo. The residue was diluted with toluene
(8 mL) and allowed to stand at room temperature for 10 h and
purified by silica gel column and preparative thin-layer
chromatography (MeOH/CHCl3 ) 1/10) to afford epoxyquinol
A (1) (18.9 mg, 24%, colorless solid), epoxyquinol B (2) (25.0
mg, 33%, colorless oil), epoxyquinol C (3) (0.8 mg, 1%, colorless
oil), and epoxytwinol A (4) (6.0 mg, 8%, colorless oil).
(1S,2R,4R,6R,7S,11S,12R,13S,16R,18R,19S,22R)-7,19-Di-
hydroxy-11,22-dimethyl-5,10,17,21-tetraoxaheptacyclo-
[11.7.2.02,8.02,12.04,6.014,20.016,18]docosa-8,14(20)-diene-3,15-
dione (Epoxyquinol A (1)):2 1H NMR (400 MHz, acetone-
d6) δ 0.71 (3H, d, J ) 6.2 Hz), 1.00 (3H, d, J ) 6.7 Hz), 2.44
(1H, bd, J ) 1.3 Hz), 3.10 (1H, bd, J ) 1.4 Hz), 3.38 (1H, d, J
) 3.6 Hz), 3.43 (1H, bd, J ) 4.5 Hz), 3.70-3.76 (2H, m), 4.30
(1H, qd, J ) 6.2, 1.2 Hz), 4.42 (1H, qd, J ) 6.7, 1.0 Hz), 4.63
(1H, bd, J ) 8.8 Hz), 4.69 (1H, bd, J ) 8.8 Hz), 4.89-4.97
(2H, m), 5.23 (1H, s), 6.73 (1H, d, J ) 1.7 Hz); 13C NMR (100
MHz, acetone-d6) δ 20.3, 20.9, 38.1, 39.3, 50.7, 53.6, 56.3, 58.8,
63.9, 64.2, 66.7, 67.0, 72.4, 74.8, 115.1, 134.4, 142.5, 153.5,
190.2, 200.7; [R]23 +63.1 (c 0.945, MeOH), lit.2) [R]21 +61.0
D
D
(c 0.146, MeOH).
90 J. Org. Chem., Vol. 70, No. 1, 2005

Total Synthesis of Epoxyquinols A-C and Epoxytwinol A
General Procedure of Table 4. To a solution of alcohol
25 (5.0 mg, 0.030 mmol) in dry CH2Cl2 (0.3 mL) was added
MnO2 (209 mg, 75%, 1.80 mmol) at 0 °C under an argon
atmosphere, and the mixture was stirred for 1 h at that
temperature. The reaction mixture was filtered through a pad
of Celite, washed with AcOEt, and then concentrated at 0 °C
in vacuo. To the residue was added methyl vinyl ketone (0.25
mL, 3.0 mmol), and the mixture was allowed to stand at room
temperature for 10 h. The mixture was concentrated in vacuo
and purified by preparative thin-layer chromatography (AcOEt/
hexane ) 1/1) to afford 28a (5.2 mg, 76%, colorless oil).
rel-(1S,8R,10R,12S)-12-Acetyl-10-methyl-9-oxatricyclo-
[6.2.2.02,7]dodec-2(7)-en-3-one (28a): 1H NMR (400 MHz,
CDCl3) δ 0.84 (3H, d, J ) 6.1 Hz), 1.26 (1H, ddd, J ) 12.3,
6.5, 2.6 Hz), 1.97-2.20 (6H, m), 2.44 (2H, t, J ) 6.6 Hz), 2.57
(2H, t, J ) 6.0 Hz), 3.19 (1H, bs), 3.29-3.39 (1H, m), 3.95 (1H,
q, J ) 6.1 Hz), 4.46 (1H, d, J ) 3.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.1, 23.1, 27.3, 28.4, 29.7, 31.4, 37.4, 51.7, 70.2, 72.1,
134.7, 161.2, 195.8, 207.7; FT-IR (neat) ν 2966, 2925, 2864,
1712, 1664, 1456, 1194, 1173, 1014, 876 cm-1; HRMS (FAB)
[M + H]+ calcd for C14H19O3 235.1334, found 235.1327.
rel-(1S,2S,10R,11S,12S,20R)-10,20-Dimethyl-9,19-diphen-
yl-9,19-diazapentacyclo[10.6.2.02,7.02,11.013,18]icosa-7,13-
(18)-diene-3,14-dione (32). To a solution of alcohol 25 (42.0
mg, 0.253 mmol) in dry CH2Cl2 (1.0 mL) was added MnO2 (1.17
g, 75%, 10.1 mmol) at 0 °C under an argon atmosphere, and
the mixture was stirred for 1 h at that temperature. The
reaction mixture was filtered through a pad of Celite, washed
with AcOEt, and then concentrated at 0 °C in vacuo. To the
residue was added aniline (0.47 mL, 5.1 mmol), and the
mixture was allowed to stand at room temperature for 12 h.
The mixture was concentrated in vacuo and purified by
alumina column chromatography (AcOEt/hexane ) 1/10) and
further recrystallization from AcOEt to afford azapentacycle
32 (18.1 mg, 30%, yellow prisms): mp 197.0-198.0 °C (dec);
1H NMR (400 MHz, CDCl3) δ 0.79 (3H, d, J ) 6.0 Hz), 1.00
(3H, d, J ) 6.7 Hz), 1.68 (1H, qt, J ) 13.6, 4.0 Hz), 1.93-2.27
(5H, m), 2.33-2.42 (2H, m), 2.56 (1H, ddd, J ) 18.0, 7.9, 5.0
Hz), 2.63-2.80 (3H, m), 3.27 (1H, s), 3.40 (1H, s), 3.94 (1H,
qd, J ) 6.0, 2.1 Hz), 3.99 (1H, q, J ) 6.7 Hz), 5.20 (1H, s), 6.18
(1H, s), 6.64 (1H, t, J ) 7.2 Hz), 6.72 (4H, d, J ) 7.2 Hz), 6.82
(1H, t, J ) 7.2 Hz), 7.15 (2H, t, J ) 7.5 Hz), 7.21 (2H, t, J )
7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 16.6, 16.8, 22.9, 27.6,
29.2, 29.4, 37.0, 39.4, 40.5, 43.9, 52.7, 53.8, 58.9, 59.2, 113.8,
113.8, 114.1, 117.1, 119.7, 125.1, 129.3, 129.3, 133.6, 144.7,
145.4, 156.5, 195.2, 206.0; FT-IR (film) ν 3058, 2968, 2929,
2864, 1705, 1668, 1595, 1504, 1404, 1246, 1030, 748, 694 cm-1
;
HRMS (FAB) [M + H]+ calcd for C32H35N2O2 479.2699, found
479.2693.
Acknowledgment. The authors thank Meito Sangyo
Co. for the generous gift of several lipases. The authors
are indebted to Professor Takeshi Sugai of Keio Uni-
versity for his invaluable suggestions concerning the
kinetic resolution by lipase. The authors are grateful
to Shinetsu-Kagaku Corporation for the gift of TBSCl.
This work was supported by a Grand-in-Aid for Scien-
tific Research on Priority Areas (A) “Creation of Biologi-
cally Functional Molecules” from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Full characteriza-
tion of compound 24 and 28, ORTEP drawing of compound
32, and copies of 1H and 13C NMR and IR of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO048425H
J. Org. Chem, Vol. 70, No. 1, 2005 91