A practical total synthesis of both enantiomers of epoxyquinols A and B

Article abstract of DOI:10.1016/S0040-4039(02)02271-2

A practical total synthesis of both enantiomers of epoxyquinols A and B has been developed. Key reactions are the chromatography-free preparation of an iodolactone by using acryloyl chloride as dienophile in the Diels-Alder reaction of furan, the lipase-mediated kinetic resolution of a cyclohexenol derivative, and a modified procedure for α-iodonation of a cyclohexenone.

Full text of DOI:10.1016/S0040-4039(02)02271-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9155–9158
A practical total synthesis of both enantiomers of epoxyquinols
A and B
Mitsuru Shoji,a Satoshi Kishida,a Mitsuhiro Takeda,a Hideaki Kakeya,b Hiroyuki Osadab and
Yujiro Hayashia,*
aDepartment of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
bAntibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Received 4 September 2002; revised 2 October 2002; accepted 4 October 2002
Abstract—A practical total synthesis of both enantiomers of epoxyquinols A and B has been developed. Key reactions are the
chromatography-free preparation of an iodolactone by using acryloyl chloride as dienophile in the Diels–Alder reaction of furan,
the lipase-mediated kinetic resolution of a cyclohexenol derivative, and a modified procedure for a-iodonation of a cyclohexenone.
© 2002 Elsevier Science Ltd. All rights reserved.
Epoxyquinols A (1) and B (2), recently discovered
anti-angiogenic natural products, have complex, highly-
oxygenated, heptacyclic structures.1 These structures
are quite distinct from those of known angiogenesis
inhibitors,2 making their mechanism of action a matter
of considerable interest. To facilitate elucidation of this
mechanism, methods for the multi-gram synthesis, and
derivatization of epoxyquinols A (1) and B (2) are
highly desirable. We have completed the first asymmet-
ric total synthesis of these molecules,3 determining their
absolute stereochemistry, in which an HfCl4-mediated
Diels–Alder reaction of furan with Corey’s chiral auxil-
iary,4 and a biomimetic, oxidative dimerization were
developed as key reactions (Scheme 1). Porco et al. also
have accomplished the total synthesis of epoxyquinols
A (1) and B (2) just recently.5 Though our HfCl4-medi-
ated, highly diastereoselective Diels–Alder reaction of a
chiral auxiliary is suitable for the construction of opti-
Scheme 1. Total synthesis of epoxyquinols (+)-A (1) and (+)-B (2) via diastereoselective Diels–Alder reaction.
Keywords: Diels–Alder reaction; resolution; lipase; epoxyquinols A and B.
* Corresponding author. Tel.: (+81)3-5228-8318; fax: (+81)3-5261-4631; e-mail: hayashi@ci.kagu.tus.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02271-2

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respectively (1H NMR yield). Hydrolysis of the acid
chloride to the sodium salt of the acid was carried out
by treatment with aq. 1.5 M NaOH. On addition of I2
and CH2Cl2 to the aqueous phase, iodolactonization
proceeded efficiently, providing ( )-5 in 42% yield as a
white solid,9 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 ( )-5 because the former two remain in the
aqueous phase as the sodium salt of the corresponding
acid. Though the yield is moderate, the reaction could
easily be scaled up to 60 g.10
cally-active, cyclohexanol derivatives, an equimolar
amount of the auxiliary is necessary. To circumvent this
problem, we have developed a more efficient and prac-
tical synthetic route to epoxyquinols A (1) and B (2),
which is disclosed in this letter.
We chose as the key reaction of our new strategy
kinetic resolution of racemic cyclohexenol ( )-6 using
lipase,6 as such reactions are known to be easily
scaleable. However preparation of this intermediate
itself proved to be difficult, as while the Diels–Alder
reaction of furan and acrylate derivatives is a powerful
means of synthesizing this class of compounds,7 no
method suitable for large-scale applications has yet
been described. Establishing such a route was our first
goal. Acryloyl chloride, a reactive dienophile, is known
to react with furan in the presence of a hydrogen
chloride scavenger, propylene oxide, over 48 h provid-
ing 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).7b After some
experimentation, we developed an efficient, chromato-
graphy-free procedure for the synthesis of iodolactone
( )-5 via hydrolysis and iodolactonization of the kineti-
cally-favored, endo-Diels–Alder adduct (Scheme 2).8
Thus, the Diels–Alder reaction of acryloyl chloride and
furan (8 equiv.) proceeds in 5 h at 23°C, providing the
endo- and exo-cycloadducts in 54% and 25% yield,
After conversion of the iodolactone ( )-5 to the substi-
tuted cyclohexenol ( )-6 using the previously reported
procedures,3 the kinetic resolution by lipase was exam-
ined. After screening various lipases, it was found that
the Pseudomonas stutzeri lipase (Meito TL) was most
efficient. When racemic ( )-6 was treated with a cata-
lytic amount of this lipase (10 wt%) in vinyl acetate at
room temperature for 40 h,11 acetate (−)-7 was obtained
in 48% yield with 96% ee,12 while the desired alcohol
(+)-6 was recovered in 49% yield with 99% ee,13 indicat-
ing a very high selectivity (kfast/kslow=211). Activity of
recovered lipase dose not decrease, and it works as
efficiently as fresh batches. The absolute configuration
of (+)-6 was determined by comparison of its optical
rotation with that of previously synthesized (+)-6,3 as
well as by using the advanced Mosher’s MTPA
Scheme 2. Synthetic route for both enantiomers of monomer 4.

M. Shoji et al. / Tetrahedron Letters 43 (2002) 9155–9158
9157
method.14 As acetate (−)-7 was easily converted to
References
alcohol (−)-6 on treatment with K2CO3 in MeOH,
providing (−)-6 in 97% yield, both enantiomers of
alcohol 6 could be synthesized in large quantity and
with high optical purity. This kinetic resolution is
suitable for producing chiral cyclohexenol 6 on a
gram-scale, not only because high selectivity is
achieved, but also because only a catalytic amount of
lipase is necessary and this can be recycled.
1. (a) Kakeya, H.; Onose, R.; Koshino, H.; Yoshida, A.;
Kobayashi, K.; Kageyama, S.-I.; Osada, H. J. Am. Chem.
Soc. 2002, 124, 3496; (b) Kakeya, H.; Onose, R.;
Yoshida, A.; Koshino, H.; Osada, H. J. Antibiot. 2002,
55, 829.
2. (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.
We went on to prepare monomer (+)-4 using the pro-
cedures developed during our previous synthesis, with
the exception of the conversion of cyclohexenone (+)-
8 to 2-iodocyclohexenone (+)-9. There was a problem
with the reproducibility of this step, in which I2,
PhI(OCOCF3)2 and pyridine were used.15 We
observed that iodonation proceeded only after a cer-
tain induction period, and that once generated (+)-9
began to decompose after a further induction period.
Based on 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-methylphe-
nol (BHT) as a radical scavenger, conditions which
gave reproducible results, providing (+)-9 in 67%
yield.
3. Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.;
Hayashi, Y. Angew. Chem., Int. Ed. 2002, 41, 3192.
4. Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741.
5. Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore,
T. D.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267.
6. (a) Sugai, T. Curr. Org. Chem. 1999, 3, 373; (b)
Fuhshuku, K.; Oda, S.; Sugai, T. Recent Res. Devel. Org.
Chem. 2002, 6, 57.
7. For the Diels–Alder reaction of benzyl acrylate and
furan, see: (a) Hayashi, Y.; Nakamura, M.; Nakao, S.;
Inoue, T.; Shoji, M. Angew. Chem., Int. Ed., in press. For
the Diels–Alder reaction of methyl acrylate and furan,
see: (b) Kotsuki, H.; Asao, K.; Ohnishi, H. Bull. Chem.
Soc. Jpn. 1984, 57, 3339; (c) Moore, J. A.; Partain, E. M.,
III. J. Org. Chem. 1983, 48, 1105; (d) Brion, F. Tetra-
hedron Lett. 1982, 23, 5299; (e) Fraile, J. M.; Garcia, J. I.;
Massam, J.; Mayoral, J. A.; Pires, E. J. Mol. Catal. A:
Chem. 1997, 123, 43; (f) Ager, D. J.; East, M. B. Hetero-
cycles 1994, 37, 1789. For the Diels–Alder reaction under
high pressure, see: (g) Kotsuki, H.; Nishizawa, H.; Ochi,
M.; Matsuoka, K. Bull. Chem. Soc. Jpn. 1982, 55, 496;
(h) Dauben, W. G.; Krabbenfoft, H. O. J. Am. Chem.
Soc. 1976, 98, 1992. For the Diels–Alder reaction of
acrylic acid and furan, see: (i) Suami, T.; Ogawa, S.;
Nakamoto, K.; Kasahara, I. Carbohydr. Res. 1977, 58,
240 and references cited therein.
We also synthesized the enantiomer, monomer (−)-4,
by the same route from resolved monomer (−)-6.
Epoxyquinols A (1) and B (2), were synthesized from
(+)-4, and their enantiomers from (−)-4, by the
biomimetic oxidative 6p-electrocyclization, followed
by Diels–Alder reaction procedure we have previously
established.3
In summary we have developed a practical synthetic
route to epoxyquinols A (1) and B (2), which is suit-
able for their multi-gram synthesis. Key reactions are
the chromatography-free preparation of iodolactone
( )-5 by using acryloyl chloride as a dienophile, the
P. stutzeri lipase-mediated kinetic resolution of a key
intermediate ( )-6, and a modified procedure for a-
iodonation of cyclohexenone 8. The efficiency of the
present method was successfully demonstrated by the
simple synthesis of both enantiomers of epoxyquinols
A (1) and B (2).16
8. Holmes and co-workers elegantly synthesized cis-
maneonene A using a similar sequence involving the
Diels–Alder reaction of furan and fumaryl chloride, fol-
lowed by hydrolysis and bromo-lactonization. See: Jen-
nings-White, C. L. D.; Holmes, A. B.; Raithby, P. R. J.
Chem. Soc., Chem. Commun. 1979, 542.
9. Mp 153.8–155.8°C (( )-5: recrystallized from MeOH).
Mp 153.8–156.2°C (unpurified ( )-5).
10. Experimental procedure for the synthesis of ( )-5: A mix-
ture of acryloyl chloride (45 mL, 0.56 mol) and furan
(338 mL, 4.62 mol) was stirred at room temperature,
1
while the progress of the reaction was monitored by H
NMR. After 5 h, a 1.5 M NaOH solution (336 mL, 0.51
mol) was added and the reaction mixture was stirred for
a further 2 h. The water phase was separated and CH2Cl2
(520 mL) and I2 (70.2 g, 0.27 mol) were added to it. The
mixture was stirred vigorously for 2 h. Sat. Na2S2O3
solution was added until the color of iodine disappeared.
After the organic solvent had been removed under
reduced pressure, a white solid precipitated which was
collected and dried to afford 62 g (0.23 mol) of iodolac-
tone ( )-5 (42%).
Acknowledgements
The authors thank Meito Sangyo Co. for the gener-
ous gift of several lipases. We are indebted to Profes-
sor Takeshi Sugai of Keio University for his
invaluable suggestions concerning the kinetic resolu-
tion by lipase. This work was supported by the
Sumitomo Foundation and a Grant-in-Aid for Scien-
tific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
11. To a solution of vinyl acetate (150 mL) of racemic
cyclohexenol derivative ( )-6 (14.0 g, 82.5 mmol) was
added P. stutzeri lipase (Meito TL) (1.40 g), and the
reaction mixture was stirred vigorously for 40 h at room
temperature. After filtration of the lipase, the volatile

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M. Shoji et al. / Tetrahedron Letters 43 (2002) 9155–9158
organic compounds were removed under reduced pres-
sure and the remaining materials were purified by flash
column chromatography (ethyl acetate:hexane=1:3–1:1)
to afford (+)-6 (6.75 g, 49%, 99% ee) and (−)-7 (8.25 g,
48%, 96% ee).
Chemical Ind.), 2-propanol:hexane=1:20, 1.5 mL/min,
retention times, 28.7 min (major), 11.1 min (minor).
14. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092.
15. Benhida, R.; Blanchard, P.; Fourrey, J.-L. Tetrahedron
Lett. 1998, 39, 6849.
12. HPLC conditions: Chiralcel OD-H column (Daicel
Chemical Ind.), 2-propanol:hexane=1:20, 1.5 mL/min,
retention times, 5.6 min (major), 6.0 min (minor).
16. Detailed biological study of both enantiomers of
epoxyquinols A (1) and B (2) is underway, the results of
which will be reported in due course.
13. HPLC conditions: Chiralcel OD-H column (Daicel