Total synthesis of (+)-epoxyquinols A and B

Article abstract of DOI:10.1002/1521-3773(20020902)41:17<3192::AID-ANIE3192>3.0.CO;2-E

A highly stereoselective HfCl₄-mediated Diels-Alder reaction of furan and the chiral acrylate ester of Corey's auxiliary to subsequently give 1, and the realization of the postulated biosynthetic pathway for the construction of epoxyquinols A a

Full text of DOI:10.1002/1521-3773(20020902)41:17<3192::AID-ANIE3192>3.0.CO;2-E

COMMUNICATIONS
introduce all the carbon atoms except those in the side chain.
Though there are a number of methods for the diastereose-
lective Diels Alder reaction of a chiral acrylate ester with
furan,[5] few of these are synthetically useful with high endo/
exo selectivities and diastereoselectivities. The low selectiv-
ities can be attributed to rapid endo/exo isomerization and/or
to a retro-Diels Alder reaction, which occurs at around
À208C.[5c] 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.[6] Thus,
the HfCl4-mediated Diels Alder reaction of furan was
applied to the chiral acrylate ester derived from Corey©s
chiralauxiialry (( À)-(1R,2R)-2-(naphthalene-2-sulfonyl)cy-
clohexanol),[7] in the expectation of high selectivity. In fact,
in the presence of HfCl4, the chiralacryalte ester 5 reacted
with furan in toluene at low temperature (À458C) over 48 h to
give the cycloadducts 4 in good yield with moderate endo/exo
selectivities and high diastereoselectivities (Scheme 2).
Total Synthesis of (þ)-Epoxyquinols A and B**
Mitsuru Shoji, Junichiro Yamaguchi,
Hideaki Kakeya, Hiroyuki Osada, and
Yujiro Hayashi*
Angiogenesis inhibitors are promising drugs for the treat-
ment of angiogenesis-related diseases such as cancer.[1] We
have recently reported the isolation and structural determi-
nation of unique pentaketide dimers, epoxyquinols A (1)[2]
and B (2; Scheme 1),[3] which show anti-angiogenic activity,
but have different structuralproperties from the known
O
O
OH
OH
HO
HO
O
O
O
O
O
O
O
O
CH3
CH3
H
H
The next stage was the preparation of endo-epoxide 7. As an
exo-epoxide was obtained by the direct epoxidation reaction
of 4,[8] a novelmethod was deveolped for the seelctive
formation of the endo-epoxide via the iodolactone 6. Though
the usual two-step procedure (hydrolysis and iodolactoniza-
tion) afforded iodolactone 6 in good yield, the chiral auxiliary
was recovered in only 40% yield along with 55% of 1-
(naphthalene-2-sulfonyl)cyclohexene. On the other hand,
direct treatment of the endo isomer with I2 in aqueous
CH3CN afforded iodolactone 6 in 81% yield with recovery of
the chiral auxiliary in 94% yield. After recrystallization,
optically pure lactone 6 was obtained, and its absolute
stereochemistry was determined by comparing its optical
rotation with that in the literature.[9] Though the direct
transformation of iodolactone 6 to epoxy methylester 7 in
MeOH under a variety of basic conditions was unsuccessful, a
two-step conversion (hydrolysis and esterification) worked
well: Treatment of 6 with KOH in DMF at 608C for 10 h,
followed by esterification with MeI under sonication con-
ditions for 1 h, furnished 7 in one pot, in high yield (94%).
Exposure of 7 to lithium diisopropylamide (LDA) at À908C
for 30 min led to b-elimination, affording hydroxy ester 8. An
excess of LDA should be avoided owing to Michael addition
of diisopropylamine to 8, which provides a b-amino ester as a
side product. Hydroxyl-directed epoxidation of homoallylic
alcohol 8 using a catalytic amount of [VO(acac)2] (acac ¼
acetylacetonate) and excess tert-butylhydroperoxide (TBHP)
O
O
CH3
CH3
epoxyquinol A (1)
epoxyquinol B (2)
O
O
CH3
OH
O
OR*
O
OH
4
3
Scheme 1. Retrosynthesis of epoxyquinols A(1) and B (2).
angiogenesis inhibitors. To facilitate elucidation of the
mechanism of action of epoxyquinols A and B, the develop-
ment of a method for their totalsynthesis and derivatization is
highly desirable. Though structurally epoxyquinols A and B
have a highly functionalized and complicated heptacyclic ring
system containing 12 stereocenters, biosynthetically it is
proposed they are formed by an unusualoxidative dimeriza-
tion of the much simpler epoxycyclohexenone
3
(Scheme 1).[2,3] Herein we report the first totalsynthesis of
the naturally occurring enantiomers of (þ)-epoxyquinols A
and B using the postulated biomimetic oxidative dimeriza-
tion, along with determination of their absolute stereochem-
istry.
The monomer 3 of epoxyquinols A and B was the initial
target. The synthesis starts from the Diels Alder reaction
between furan and a chiraldienophiel,
such a way to establish the correct stereochemistry and
[4]
which is planned in
[10]
under reflux in CH2Cl2 proceeded to give diepoxide 9 as a
single isomer in high yield. Although reduction of ester 9 with
diisobutylaluminum hydride (DIBAL) proceeded smoothly,
the yield of the diol 10 was quite low owing to its water
solubility. Thus, a nonaqueous workup was examined: Re-
duction with NaBH4 in MeOH at room temperature for
15 min, removal of solvent, and flash column chromatography
afforded the diol 10. The primary alcohol of the diol 10 was
selectively protected with tert-butyldimethylsilyl chloride
(TBSCl), affording 11 in 81% yield over two steps. Though
the oxidation of 11 with SO3¥pyridine[11] afforded an epoxy-
quinone,[12] the over-oxidation product of 12, the use of the
Dess Martin periodinane[13] gave the desired b,g-epoxyke-
tone without formation of this by-product. Isomerization
[*] Prof. Dr. Y. Hayashi, Dr. M. Shoji, J. Yamaguchi
Department of IndustrialChemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax : (þ 81)3-5261-4631
E-mail: hayashi@ci.kagu.sut.ac.jp
Dr. H. Kakeya, Prof. Dr. H. Osada
Antibiotics Laboratory, RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
[**] This work was supported by the Sumitomo Foundation and a Grant-
in-Aid for Scientific Research on Priority Areas (A) ™Exploitation of
Multi-Element Cyclic Molecules∫ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
3192
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3192 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 17

COMMUNICATIONS
O
O
O
KOH, DMF
60 °C
SO2Np
O
I2
O
HfCl4
I
+
CH3CN
RT
then
MeI, RT
toluene
-45 °C
CO2Me
O
O
O
OR*
O
O
6
7
4
94%
81%
83%
5
endo:exo=68:32
87% de (endo)
91% de (exo)
>99% ee after
recrystallization
LDA, THF
-90 °C
92%
OH
O
OH
OH
1) NaBH4, MeOH
0 °C~RT
cat. [VO(acac)2]
excess TBHP
1) DMP, CH2Cl2
0 °C~RT
O
O
O
O
OTBS
OR
CH2Cl2
reflux
2) TBSCl, Et3N
DMAP, CH2Cl2
RT
2) silica gel
toluene, 60 °C
CO2Me
O
CO2Me
O
OH
96%
quant.
9
8
10: R=H
11: R=TBS
81%
12
1) Amberlyst 15, MeOH, RT
2) (MeO)2CMe2, PPTS, CH2Cl2, 40 °C
64%
O
O
O
O
O
O
(E)-1-Propenylborate
[Pd(PhCN)2Cl2], Ph3As
Ag2O
I2, PhI(OCOCF3)2
pyridine
CH3
I
CH3
Amberlyst 15
MeOH, RT
84%
O
O
O
O
THF, H2O, RT
77%
OH
CH2Cl2, RT
52%
O
O
OH
O
O
3
13
14
15
of epoxyquinols A (1) and
Scheme 2. Synthesis of the monomeric precursor
toluenesulfonate; for other abbreviations see text.
3
B
(2). DMAP ¼ 4-dimethylaminopyridine; PPTS ¼ pyridinium
occurred on treatment of b,g-epoxyketone with silica gel at
608C in toluene for 4 h,[14] affording a,b-unsaturated ketone
12 quantitatively over two steps.
Amberlyst in MeOH, and 2) protection of the resulting 1,3-
diolwith 2,2-dimethoxypropane) gave the iodinated cycol-
hexenone 14 in moderate yield. As 14 is labile, it was
immediately subjected to the Suzuki coupling reaction with
trans-1-propenylborate[18] under Johnson©s conditions,[19] af-
fording dienone 15 in 77% yield. Cleavage of the acetonide
group under acidic conditions provided monomer 3 in 84%
yield.
The a-iodonation of cyclohexenone 12 was problematic,
and the choice of diolprotecting group and 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 12 with I2/DMAP[15] or I2/trimethylsilylazide
(TMSN3)[16] and only a low yield was observed in the reaction
using I2/PhI(OCOCF3)2/pyridine.[17] On the other hand, the
reaction of I2/PhI(OCOCF3)2/pyridine with the corresponding
acetonide 13 (prepared in 64% yield from 12 over two steps:
1) deprotection of the tert-butyldimethylsilyl group with
Next the biomimetic oxidative dimerization was examined.
After severalexperiments, it was found that the monomer 3
could be directly oxidized without protection of the secondary
hydroxy group. That is, the oxidation proceeded on treatment
[20]
of epoxycyclohexenol 3 with excess MnO2 in CH2Cl2 for
Scheme 3. Biomimetic dimerization approach towards epoxyquinols A (1) and B (2).
Angew. Chem. Int. Ed. 2002, 41, No. 17 ¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3193 $ 20.00+.50/0
3193

COMMUNICATIONS
[5] Catalytic asymmetric reaction by the use of a chiral Lewis acid; a) E. J.
Corey, T. P. Loh, Tetrahedron Lett. 1993, 34, 3979; b) I. Yamamoto, K.
Narasaka, Chem. Lett. 1995, 1129; c) D. A. Evans, D. M. Barnes,
Tetrahedron Lett. 1997, 38, 57. Diastereoselective reaction by the use of
chiraldienophiel ; d) H. Takayama, A. Iyobe, T. Koizumi, J. Chem.
Soc. Chem. Commun. 1986, 771; e) J. M. Fraile, J. I. Garcia, D. Gracia,
J. A. Mayoral, E. Pires, J. Org. Chem. 1996, 61, 9479; f) J. Adrio, J. C.
Carretero, J. L. G. Ruano, L. M. M. Cabrejas, Tetrahedron: Asymme-
try 1997, 8, 1623; g) O. Arjona, F. Iradier, R. Medel, J. Plumet,
Tetrahedron: Asymmetry 1999, 10, 2237; h) M. J. Burke, M. M. Allan,
M. Parvez, B. A. Keay, Tetrahedron: Asymmetry 2000, 11, 2733, and
references therein.
40 min at 08C (Scheme 3), affording hydroxyaldehyde 16 and
2H-pyran derivatives 17a and 17b which would be formed by
6p-electrocyclization reaction of the former. The dimerization
reaction proceeded when the crude oxidized mixture was
allowed to stand at room temperature without solvent. After
4 h, epoxyquinols A (1) and B (2) were isolated in 40 and 25%
yields, respectively. Epoxyquinol A (1) is a heterodimer of
17a and 17b, which would be generated by an exo intermo-
lecular Diels Alder reaction with the anti stereochemistry at
the C9 and C19 methylpositions to reduce the steric hindrance
at these positions.[2] On the other hand, epoxyquinolB ( 2) is a
homodimer of 17a, which would be generated by an endo
intermolecular Diels Alder reaction, also with the sterically
favored anti stereochemistry at the C9 and C19 methyl
[6] Y. Hayashi, M. Nakamura, S. Nakao, T. Inoue, M. Shoji, unpublished
results.
[7] G. Sarakinos, E. J. Corey, Org. Lett. 1999, 1, 1741.
[8] a) M. M. Campbell, A. D. Kaye, M. Sainsbury, R. Yavarzadeh,
Tetrahedron Lett. 1984, 25, 1629; b) M. M. Campbell, A. D. Kaye,
M. Sainsbury, R. Yavarzadeh, Tetrahedron 1984, 40, 2461; c) D.
Rajapaksa, B. A. Keay, R. Rodrigo, Can. J. Chem. 1984, 62, 826.
[9] Literature data; [a]2D5 ¼ À113 (c ¼ 1.04, CHCl3). S. Ogawa, M. Yoshi-
kawa, T. Taki, J. Chem. Soc. Chem. Commun. 1992, 406. Synthetic 6;
[a]2D3 ¼ À114 (c ¼ 0.906, CHCl3).
positions.[3] In their recent elegant total synthesis of torreyanic
[22]
acid[21] and jesterone dimer (unnaturalproduct),
Porco, Jr.
et al. have demonstrated the oxidative dimerization of
epoxyquinones, in which only heterodimers were formed.
As shown by the dimerization of 3, not only epoxyquinones,
but also epoxycyclohexenones can be oxidatively dimerized to
form highly functionalized heptacyclic ring systems, in which
both hetero- and homodimerizations occur.
[10] a) K. B. Sharpless, R. C. Michaelson, J. Am. Chem. Soc. 1973, 95, 6136;
b) R.-M. Meier, C. Tamm, Helv. Chim. Acta 1991, 74, 807.
[11] J. R. Parikh, W. van E. Doering, J. Am. Chem. Soc. 1967, 89,
5505.
[12] 2-(tert-Butyldimethylsilyloxymethyl)-5,6-epoxy-2-cyclohexene-1,4-di-
one was obtained as a major by-product.
[13] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4115; b) D. B. Dess,
J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277; c) R. E. Ireland, L.
Liu, J. Org. Chem. 1993, 58, 2899.
[14] P. Yadagiri, S. Lumin, P. Mosset, J. Capdevila, J. R. Falck, Tetrahedron
Lett. 1986, 27, 6039.
[15] M. T. Barros, C. D. Maycock, M. R. Ventura, Chem. Eur. J. 2000, 6,
3991.
[16] C.-K. Sha, S.-J. Huang, Tetrahedron Lett. 1995, 36, 6927.
[17] R. Benhida, P. Blanchard, J.-L. Fourrey, Tetrahedron Lett. 1998, 39,
6849.
[18] a) A. S.-Y. Lee, W.-C. Dai, Tetrahedron 1997, 53, 859; b) D. S.
Matteson, P. K. Jesthi, J. Organometal. Chem. 1976, 110, 25.
[19] F. S. Ruel, M. P. Braun, C. R. Johnson, Org. Synth. 1997, 75, 69.
[20] T. Aoyama, N. Sonoda, M. Yamauchi, K. Toriyama, M. Anzai, A.
Ando, T. Shioiri, Synlett 1998, 35.
Synthetic epoxyquinols A (1) and B (2) exhibited identical
1
properties to those of the naturalsubstances ( H NMR, 13C
NMR, IR). Comparison of the opticalrotation (synthetic
epoxyquinolA; [ a]2D2 ¼ þ 60 (c ¼ 0.17, MeOH), naturalepoxy-
quinolA; [2] [a]2D1 ¼ þ 61.0 (c¼ 0.146, MeOH), synthetic epoxy-
quinolB; [ a]2D1 ¼ þ 150 (c ¼ 0.060, MeOH), naturalepoxy-
[3]
quinolB;
[a]2D1 ¼ þ 153.0 (c ¼ 0.315, MeOH)) determined
the absolute stereochemistry to be as shown in 1 and 2.
In summary, the first totalsynthesis of epoxyquinosl A ( 1)
and B (2) has been achieved, and their absolute stereo-
chemistry has been determined. The combination of HfCl4
and the chiral acrylate ester of Corey©s auxiliary enables the
highly diastereoselective Diels Alder reaction of furan, which
estabilshed the correct stereochemistry. Al12 chiralcenters
of epoxyquinols A and B are controlled by the highly
diastereoselective reactions in the route from the initial
Diels Alder product. A diastereoselective synthesis of endo-
epoxide 7 via iodolactone 6, and a biomimetic oxidative 6p-
electrocyclization, followed by Diels Alder reaction of the
nonprotected diolmonomer 3 are other noteworthy features
of the synthesis.
[21] C. Li, E. Lobkovsky, J. A. Porco, Jr.,J. Am. Chem. Soc. 2000, 122,
10484.
[22] Y. Hu, C. Li, B. A. Kulkarni, G. Strobel, E. Lobkovsky, R. M.
Torcznski, J. A. Porco, Jr.,Org. Lett. 2001, 3, 1649.
Received: May 23, 2002 [Z19362]
[1] a) J. Folkman, J. Natl. Cancer Inst. 1990, 82, 4; b) W. Risau, Nature,
1997, 386, 671; c) M. Klagsbrum, M. A. Moses, Chem. Biol. 1999, 6,
R217; d) G. Gasparini, Drugs 1998, 58, 17.
[2] H. Kakeya, R. Onose, H. Koshino, A. Yoshida, K. Kobayashi, S.-I.
Kageyama, H. Osada, J. Am. Chem. Soc. 2002, 124, 3496.
[3] H. Kakeya, R. Onose, A. Yoshida, H. Koshino, H. Osada, J. Antibiot.
submitted.
[4] Recent review of asymmetric Diels Alder reactions: Y. Hayashi,
Catalytic Asymmetric Diels Alder Reactions in Cycloaddition Re-
actions in Organic Synthesis (Eds.: S. Kobayashi, K. A. Jorgensen),
Wiley-VCH, Weinheim, 2001, pp. 5 56; Review of Diels Alder
reaction of furan; C. O. Kappe, S. S. Murphree, A. Padwa, Tetrahedron
1997, 53, 14179; Review of optically pure 7-oxabicyclo[2.2.1]hept-5-
en-2-ylderivatives; P. Voge,l D. Fattori, F. Gasparini, C. L. Drian,
Synlett 1990, 173.
3194
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3194 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 17