Enantioselective total synthesis of antiangeogenic pentaketide dimers, epoxyquinols A and B, through an asymmetric aldol approach to their common monomeric precursor

Article abstract of DOI:10.1016/j.tetlet.2004.12.001

A new enantioselective total synthesis of epoxyquinols A and B possessing unique pentaketide dimeric structures and potent antiangeogenic activity was achieved by oxidative dimerization of a monomeric pentaketide precursor obtained by the Evans asymmetric

Full text of DOI:10.1016/j.tetlet.2004.12.001

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 547–549
Enantioselective total synthesis of antiangeogenic
pentaketide dimers, epoxyquinols A and B, through an
asymmetric aldol approach to their common monomeric precursor
Shigefumi Kuwahara* and Sunao Imada
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received 2 November 2004; revised 26 November 2004; accepted 1 December 2004
Abstract—A new enantioselective total synthesis of epoxyquinols A and B possessing unique pentaketide dimeric structures and
potent antiangeogenic activity was achieved by oxidative dimerization of a monomeric pentaketide precursor obtained by the Evans
asymmetric aldol reaction and a series of operationally simple transformations.
Ó 2004 Elsevier Ltd. All rights reserved.
Angiogenesis, the formation of new blood capillaries
from preexisting ones, is strictly controlled in the
healthy human body by various endogenous angiogenic
and angiostatic factors, and plays essential roles in many
physiological processes such as wound heeling, embryo-
genesis, and the formation of the corpus luteum.1 It also
occurs in many pathological conditions like cancer, dia-
betic retinopathy, rheumatoid arthritis, and other
chronic inflammatory diseases, among which the rela-
tionship between cancer and angiogenesis have, in
ported to date. All the syntheses reported so far were
based on the proposal by Osada co-workers4,5 that
epoxyquinols A and B are both biosynthesized from
monomeric pentaketide precursor 4, which actually ex-
ists in the same fermentation broth as 1 and 2,14 via oxi-
dation to 3 followed by 6p-electrocyclic ring closure into
two diastereomeric 2H-pyrans (a and b), and their inter-
molecular Diels–Alder dimerization in the combinations
shown in Scheme 1. Indeed, Hayashi and co-workers
accomplished the first total synthesis of 1 and 2 by
employing, as the final step, MnO2-oxidation of 4, which
in turn were prepared by using a HfCl4-mediated asym-
metric Diels–Alder reaction and a series of efficient
transformations.6,15 Their synthesis was immediately
followed by Porcoꢀs elegant synthesis using an asymmet-
ric nucleophilic epoxidation7 and Mehtaꢀs practical syn-
thesis through an enzymatic desymmetrization,10 both
of which were, again, achieved by oxidative dimerization
of 4. Herein, we describe a new approach to the dimer-
ization precursor (4) through the Evans asymmetric
aldol reaction, and its conversion into epoxyquinols
A and B.
particular, attracted
a great deal of interest to
physiologists.2 At present, angiogenesis is considered
to be an absolute requirement for tumor growth and
metastasis, and, therefore, its inhibitors are drawing
increasing attention as new drugs in cancer therapy.1–3
In 2002, Osada and co-workers reported the identifica-
tion of two novel angiogenesis inhibitors, epoxyquinols
A and B (1 and 2, respectively), from a fermentation
broth of an uncharacterized fungus of soil origin
(Scheme 1).4,5 The complicated unique structures of 1
and 2 coupled with their potent antiangiogenic activity
immediately prompted synthetic chemists to their total
synthesis, and several successful total syntheses6–10 as
well as some related synthetic studies11–13 have been re-
Our synthesis began with the Evans asymmetric aldol
reaction16 between a known N-acyl-2-oxazolidinone
derivative (5)17 and senecialdehyde to give stereoselec-
tively syn-aldol 6 in 87% isolated yield (Scheme 2).
Reductive removal of the chiral auxiliary of 6 with lith-
ium borohydride afforded diol 7a, the hydroxyl groups
of which were then protected by reaction with TBSCl
Keywords: Epoxyquinol; Angeogenesis; Polyketide; Asymmetric aldol
reaction.
*
Corresponding author. Tel./fax: +81 22 717 8783; e-mail: skuwahar@
biochem.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.001

548
S. Kuwahara, S. Imada / Tetrahedron Letters 46 (2005) 547–549
O
HO
O
HO
OH
O
O
O
OH
O
O
O
O
O
b
O
H
OH
H
OH
O
OH
O
a
O
epoxyquinol A (1)
hetero-endo
OH
O
O
O
O
O
HO
OH
OH
O
3
4
O
O
O
O
O
O
O
a
H
a
O
O
epoxyquinol B (2)
homo-exo
Scheme 1. Structures of epoxyquinols A and B, and their proposed biosynthetic pathway.
O
O
OR OR
TBSO
OTBS
O
OH
O
X
b, c
f, g
d, e
a
O
N
O
N
Bn
6
Bn
O
5
7a: R = H
7b: R = TBS
8a: X = C(CH3)2
8b: X = O
TBSO
OTBS
4
TBSO
OTBS
TBSO
OTBS
OR OR
5
i, j, k
l, m
h
n
1
2
+
O
O
O
Y
O
O
O
O
9
10
11a: Y = H
11b: Y = Br
12: R = TBS
4: R = H
Scheme 2. Reagents and conditions: (a) (n-Bu)2BOTf, (i-Pr)2NEt, Me2C@CHCHO, CH2Cl2, ꢀ78 °C (87%); (b) LiBH4, THF–MeOH, 0 °C to rt; (c)
TBSCl, imidazole, DMF, 0 °C to rt; (d) PdCl2, Cu(OAc)2ÆH2O, O2, rt (93%, three steps); (e) O3, MeOH–CH2Cl2, ꢀ78 °C, Me2S (86%); (f) 6 M NaOH
aq, ether, rt (70%); (g) MsCl, Et3N, CH2Cl2, 0 °C to rt (93%); (h) TBHP, DBU, toluene, 0 °C to rt (quant); (i) LDA, PhSeCl, THF, ꢀ78 °C; (j) 30%
H2O2, CH2Cl2, rt (63%, two steps); (k) Br2, Et3N, CH2Cl2, rt (93%); (l) (E)-MeCH@CHSn(n-Bu)3, Pd2(dba)3, Ph3As, toluene, reflux (96%); (m)
HFÆPy, THF, 0 °C to rt (88%); (n) TEMPO, CuCl, O2, DMF,rt; neat, rt (46% for 1 and 20% for 2).
to provide 7b almost quantitatively. Preferential Wacker
oxidation of the terminal double bond of 7b proceeded
smoothly to give ketone 8a in 93% overall yield from
6. The remaining trisubstituted double bond of 8a was
oxidatively cleaved with ozone to deliver, in 86% yield,
keto aldehyde 8b, which was then subjected to various
basic or acidic intramolecular aldol condensation condi-
tions to obtain six-membered enone derivative 9.
Among several reaction conditions employed (PPTS/tol-
uene, AcOH/pyrrolidine/MeOH, K2CO3/t-BuOH, (n-
Bu)4NOH/THF/H2O, KOH/18-crown-6/toluene, etc.),
the best result was obtained by a two-step sequence con-
sisting of conversion of 8b into the corresponding cyclic
aldol intermediate (NaOH, H2O–ether two-phase sys-
tem,18 70% yield) and subsequent exposure of the aldol
intermediate to dehydration conditions (MsCl/Et3N/
CH2Cl2) to give the desired product 9 in 93% yield.
The stereochemical homogeneity of the cyclohexenone
derivative (9) possessing two cis-oriented substituents
in good accordance with data for analogous cis-
disubstituted cyclohexenones19 and no signal due to
the corresponding trans-diastereomer20 with more
thermodynamic stability was observed. Stereoselective
epoxidation of 9 was performed by treating the enone
with t-BuOOH and DBU in toluene to afford quantita-
tively 10 as a single stereoisomer. Two-step conversion
of 10 into 11a was performed by a-selenylation and oxi-
dative elimination in a moderate yield of 63%. Introduc-
tion of an iodine atom to the double bond of 11a was
troublesome as in the case of an analogous conversion
in the first total synthesis of 1 and 2 by Hayashi and
co-workers.6 Although various iodination conditions
including those investigated by Hayashi and co-workers
(I2/DMAP, I2/TMSN3, and I2/PhI(OCOCF3)/Py) were
attempted to convert 11a into 11b (Y = I),6 we failed to
obtain any satisfactory outcome. Quite gratifyingly, how-
ever, the corresponding bromination proceeded smoo-
thly by using a conventional method (Br2/Et3N/CH2Cl2)
to give 11b in 93% yield. The Stille coupling of the bro-
mide (11b) with (E)-tributyl(1-propenyl)stannane was
1
was confirmed by its H NMR spectrum, in which the
coupling constant between 4-H and 5-H was 3.5 Hz

S. Kuwahara, S. Imada / Tetrahedron Letters 46 (2005) 547–549
549
6. Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.;
Hayashi, Y. Angew. Chem., Int. Ed. 2002, 41, 3192–
3194.
7. Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore, T.
D., Jr.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267–3270.
8. Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada,
H.; Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155–9158.
9. Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569–
3572.
10. Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 3611–
3615.
11. Shoji, M.; Kishida, S.; Kodera, Y.; Shiina, I.; Kakeya, H.;
Osada, H.; Hayashi, Y. Tetrahedron Lett. 2003, 44, 7205–
7207.
12. Kakeya, H.; Miyake, Y.; Shoji, M.; Kishida, S.; Hayashi,
Y.; Kataoka, T.; Osada, H. Bioorg. Med. Chem. Lett.
2003, 13, 3743–3746.
13. Shoji, M.; Imai, H.; Shiina, I.; Kakeya, H.; Osada, H.;
Hayashi, Y. J. Org. Chem. 2004, 69, 1548–1556.
14. For the biological activity of 4, see: Miyake, Y.; Kakeya,
H.; Kataoka, T.; Osada, H. J. Biol. Chem. 2003, 278,
11213–11220, See also Refs. 7,12.
accomplished in 96% yield by adding a solution of
Pd2(dba)3 and Ph3As in toluene to a refluxing mixture
of 11b and the tin reagent in toluene over a period of
1 h according to Porcoꢀs procedure.7,21 Deprotection
of the TBS-protecting groups of the resulting coupling
product (12) with HFÆPy in THF proceeded without
event to give the oxidative dimerization precursor 4
24
D
½aꢁ +260 (c 0.785, CHCl3)] in 88% yield. The 1H
NMR spectrum of 4 was exactly the same as that of
an authentic sample.6 The final conversion of the diol
(4) into epoxyquinols A and B (1 and 2, respectively),
was conducted by chemoselective oxidation of the pri-
mary hydroxyl group of 4 (TEMPO/CuCl/O2/DMF)22
followed by leaving the resulting neat reaction
product at room temperature for 10 h to furnish 1
24
D
[46%, ½aꢁ +61 (c 0.075, MeOH), mp 184–185 °C; lit.4
21
½aꢁ +61.0 (c 0.146, MeOH), mp 186 °C] and 2
D
24
D
[20%, ½aꢁ +150 (c 0.22, MeOH), mp 208–210 °C; lit.5
21
½aꢁ +153.0 (c 0.315, MeOH); lit.7 mp 210–212 °C].23
D
1
The H and 13C NMR spectra of our synthetic epoxy-
quinols A and B were identical with those of the natural
material.
15. For a more practical synthesis of 1 and 2 via lipase-
mediated kinetic resolution of a cyclohexenol intermedi-
ate, see Ref. 8.
16. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
17. Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61,
4192–4193.
18. Bo¨rner, C.; Dennis, M. R.; Sinn, E.; Woodward, S. Eur. J.
Org. Chem. 2001, 2435–2446.
19. See, for example: (a) Weyerstahl, P.; Marschall, H.;
Weirauch, M.; Thefeld, K.; Surburg, H. Flavour Fragr.
J. 1998, 13, 295–318; (b) McNally, M.; Capon, R. J. J.
Nat. Prod. 2001, 64, 645–647.
In summary, a new enantioselective total synthesis of
epoxyquinols A [(+)-1] and B [(+)-2] was accomplished
by oxidative dimerization of the monomeric pentaketide
precursor (4), which in turn was prepared from known
oxazolidinone 5 in 22% overall yield by an operationally
simple 13-step sequence including the Evans asymmetric
aldol reaction as the source of chirality.
20. See, for example: Barros, M. T.; Maycock, C. D.; Ventura,
M. R. J. Org. Chem. 1997, 62, 3984–3988.
Acknowledgements
21. When a solution of 11b in toluene and a solution of the
tin reagent in toluene were successively added to a
solution of Pd2(dba)3 and Ph3As in toluene at room
temperature and the resulting mixture was heated at
reflux, the reaction was very sluggish, resulting in only
21% yield of 12.
We are grateful to Drs. Osada and Kakeya (RIKEN) for
providing the copies of the spectra of natural epoxyqui-
nols A and B. We also thank Drs. Hayashi and Shoji
(The Tokyo University of Science) for sending the copy
1
of the H NMR spectrum of intermediate 4. This work
22. Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou,
C. S. J. Am. Chem. Soc. 1984, 106, 3374–3376.
23. Besides 1 and 2, the oxidative dimerization generated trace
amounts of two other minor products. The 1H NMR
spectrum of one of the minor products, obtained in ca. 5%
yield, was identical with that of another diastereomer of 1
produced by microwave irradiation of 1,7 which was also
reported to be produced in 1% yield by dimerization of 3
in toluene at room temperature. For the formation of this
minor diastereomer (epoxyquinol C) in toluene, see: Shoji,
M.; Imai, H.; Hayashi, Y; Shiina, I.; Kakeya, H.; Osada,
H. Abstracts. The 46th Symposium on the Chemistry of
Natural Products, Hiroshima, Japan, October 6–8, 2004;
pp 305–310. The other product, formed in this oxidative
dimerization in less than 5% yield, could not be fully
purified, and its scarcity precluded us from determining
the structure, although its 1H NMR spectrum suggested
that the product might be another diastereomer of 1.
was supported, in part, by a Grant-in-Aid for Scientific
Research (B) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (No.
16380075).
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