Enantioselective total synthesis of (-)-epoxyquinols a and B. Novel, convenient access to chiral epoxyquinone building blocks through enzymatic desymmetrization

Article abstract of DOI:10.1016/j.tetlet.2004.03.057

Following our recent total synthesis of the biologically potent natural products epoxyquinols A and B in racemic form, we have now accomplished the total synthesis of the (-)-epoxyquinols A and B, anti-podes of the angiogenesis inhibiting natural products, through a protocol that involves enzymatic desymmetrization of a versatile epoxyquinone derivative, readily available from the Diels-Alder adduct of cyclopentadiene and p-benzoquinone.

Full text of DOI:10.1016/j.tetlet.2004.03.057

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3611–3615
Enantioselective total synthesis of ())-epoxyquinols A and B.
Novel, convenient access to chiral epoxyquinone building
blocks through enzymatic desymmetrization
*
Goverdhan Mehta and Kabirul Islam
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 15 January 2004; revised 1 March 2004; accepted 10 March 2004
Abstract—Following our recent total synthesis of the biologically potent natural products epoxyquinols A and B in racemic form,
we have now accomplished the total synthesis of the ())-epoxyquinols A and B, anti-podes of the angiogenesis inhibiting natural
products, through a protocol that involves enzymatic desymmetrization of a versatile epoxyquinone derivative, readily available
from the Diels–Alder adduct of cyclopentadiene and p-benzoquinone.
Ó 2004 Elsevier Ltd. All rights reserved.
Several polyketide derived natural products, bearing the
epoxyquinone moiety 1 as the core structure, have been
encountered in nature from diverse sources in recent
recently disclosed a convenient three step access to the
3
epoxyquinone building block 5 (cf. 1) from the readily
available Diels–Alder adduct 6 of cyclopentadiene and
p-benzoquinone, Scheme 1. Recognizing the inherent
versatility of 5 in the synthesis of epoxyquinone natural
products, it was considered imperative to access its
derivatives in enantiomerically pure form to harness
fully its potential. The symmetrical nature of 5 lends
itself amenable to the enzyme mediated ‘meso trick’.
Indeed, the enzymatic desymmetrization of 5 has now
been achieved and in this letter, we demonstrate the
preparation of enantiomerically enriched derivatives of
5 and their utility in the total synthesis of ())-epoxy-
1
years. Typical examples of such natural products are
1a
1b
1c
eupenoxide 2, cycloepoxydon 3 and ECH 4 among
others, and many of them exhibit promising, wide
ranging biological activity profiles. Quite naturally,
epoxyquinone natural products have evoked consider-
able attention from the synthetic community over the
2
past few years. In our view, central to the synthetic
approach to these natural products is a short, viable
access route to the core structure 1 with adequately
functionalized side arms. In this context, we have
4
quinols A and B.
O
OH
C
C
O
O
HO
O
O
HO
HO
OH
OH
O
O
O
O
R
OH
O
O
O
O
1
. R= OH, =O
2
CH3
H
CH3
CH3
H
CH3
O
O
O
OH
(
+) - Epoxyquinol A
(+) - Epoxyquinol B
O
HO
O
O
OH
OH
O
4
After considerable experimentation with several lipases
and reaction conditions, we were able to devise a simple,
reproducible protocol for the enzymatic desymmetriza-
tion of 5 through transesterification, in a biphasic
medium employing lipase PS 30 (Amano) immobilized
on Celite, to furnish monoacetate (+)-7 (ꢀ99% ee),
3
*
0
Corresponding author. Tel.: +91802932850; fax: +91803600936;
e-mail: gm@orgchem.iisc.ernet.in
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.057

3612
G. Mehta, K. Islam / Tetrahedron Letters 45 (2004) 3611–3615
O
OH
H
H
O
a
O
O
O
c
HO
HO
b
O
H
H
HO
O
O
O
O
O
6
5
Scheme 1. Reagents and conditions: (a) 30% H
0%.
2
O
2
, 10% Na
2
CO , acetone, 0 °C, 95%; (b) DBU, 40% formalin, THF, 92%; (c) diphenylether, 240 °C,
3
9
3
;8
O
O
appeared in the literature. Two of these synthetic
accomplishments by the groups of Hayashi and
8a
HO
HO
a
AcO
HO
8b
O
O
Porco are enantioselective and have led to the natural
enantiomers (+)-epoxyquinol A and (+)-epoxyquinol B.
On the other hand, our group has reported a synthesis of
O
O
3
5
(
+) - 7
racemic epoxyquinols A and B. In addition, Hayashi
and co-workers have delineated a practical approach to
both the enantiomers of epoxyquinols A and B and also
disclosed the preparation of some related model com-
b
O
O
1c;9
pounds.
AcO
AcO
c
HO
O
O
Our synthesis of ())-9 and ())-10, patterned along a
biomimetic route, emanated from (+)-7 and a modified
and improved variant of our previously described syn-
AcO
O
O
3
8
(-) - 7
thesis of racemic 9 and 10 was executed. DIBAL-H
10
reduction of (+)-7 was regio- and stereoselective and
directed by the primary hydroxyl group and epoxide
oxygen and furnished diol ())-12 through the interme-
Scheme 2. Reagents and conditions: (a) Lipase PS 30 (Amano), vinyl
acetate, t-butylmethylether, 0 °C, 6 h, 82%; (b) Ac O, pyridine, DMAP,
DCM, 0 °C, 75%; (c) C. rugosa lipase, distd water, phosphate buffer, rt
6%.
2
11
diacy of the aluminium chelate 11, Scheme 3. The diol
moiety in 12 was protected as the acetonide ())-13.
Reduction of the carbonyl group in 13 with Luche
8
12
reagent
was moderately stereoselective, directed
5
Scheme 2. The absolute configuration of (+)-7 followed
from its conversion to the natural products ())-cyclo-
epoxydon and ())-epoxyquinols A and B (vide infra).
Concurrently, meso-diol 5 was converted to the diacetate
through the coordination of the ceric ion with the epoxy
oxygen, to furnish a 7:1 diastereomeric mixture, which
on further acetate hydrolysis led to ())-14 and ())-15.
The relative stereochemical issue was settled through the
2i
13
8
and desymmetrization employing enzymatic hydroly-
X-ray crystal structure determination of the minor
diastereomer ())-14, Scheme 3. The primary hydroxyl
group in the major epimer ())-15 was chemoselectively
11
sis with the same lipase PS 30 (Amano) gave ())-7
(
ꢀ86% ee) with modest enantioselectivity, Scheme 2.
14
However, with the lipase from Candida rugosa ())-7 was
oxidized with TEMPO to furnish the aldehyde ())-
16.
5
11
obtained from 8 in high enantiomeric purity (ꢀ99% ee).
The versatile building block 7 thus became readily
accessible in both its enantiomerically enriched forms
through enantiodivergency based protocols. We dem-
onstrate here the utility of one of the enantiomers (+)-7
towards the enantioselective synthesis of epoxyquinone
natural products ())-epoxyquinol A 9 and ())-epoxy-
quinol B 10.
Although hydroxy-aldehyde ())-16 was ready for the
installation of the requisite side chain, we found that
without the protection of the hydroxyl group, Wittig
olefination was capricious. Protection of the hydroxyl
group as acetate 17a and Wittig olefination furnished a
1:1 mixture of E and Z isomers 18a in moderate yield.
Protection of the hydroxyl group in 16 as TES ether 17b
and Wittig olefination gave 18b in improved yield and
an altered E:Z ratio of 1:3, Scheme 4. For further efforts,
both 18a and 18b were serviceable and after hydroxyl
group deprotection and oxidation, diastereomeric (E)-
dienone ())-19 and (Z)-dienone ())-20 were readily
Angiogenesis inhibition is emerging as a very promising
protocol with therapeutic potential for a variety of dis-
orders ranging from rheumatoid arthritis to cancer and
several natural products are being explored as leads for
6
7
clinical development. In this context, the report of the
11
isolation of two pentaketide derived dimers (+)-epoxy-
quinol A and (+)-epoxyquinol B from a soil based
unknown fungus in 2002, by Japanese scientists, has
drawn the immediate attention of synthetic chemists as
these unusual natural products exhibited impressive
separated and fully characterized, Scheme 4.
The acetonide deprotection in ())-19 and ())-20 led to
1
1
the diols ())-21 and ())-22, respectively, Scheme 5.
14
TEMPO mediated chemoselective oxidation of ())-21
and ())-22 furnished aldehydes 23 and 24, respectively,
to set up the pericyclic cascade of 6p electrocyclization
4
inhibition of angiogenesis. In a short span of one year,
three total syntheses of these natural products have

G. Mehta, K. Islam / Tetrahedron Letters 45 (2004) 3611–3615
3613
O
O
O
O
AcO
iBu
O
b
AcO
AcO
HO
AcO
HO
a
O
Al
O
O
H
iBu
O
O
Al iBu
O
OH
O
O
Bui
(+) - 7
11
(-) - 12
(-) - 13
c
OH
OH
OH
OH
O
HO
HO
d
AcO
e
O
O
O
O
+
O
O
O
O
O
O
O
O
(
-) - 16
(-) - 15
(-) - 14
α : β = 7 : 1
, CeCl Æ7H O, MeOH, 0 °C,
Scheme 3. Reagents and conditions: (a) DIBAL-H, THF, )78 °C, 74%; (b) DMP, PPTS, acetone, rt 89%; (c) NaBH
4
3
2
8
6%; (d) K
2
CO
3
, MeOH, 0 °C, ())-14 (11%) and ())-15 (74%); (e) TEMPO, O
2
, CuCl, DMF, 76%.
OH
OR
OR
O
O
a or b O
c
O
O
O
O
O
O
O
O
(
-) - 16
(-)-17a : R= Ac
18a : R= Ac, E:Z (1:1)
18b : R= TES, E:Z (1:3)
(
-)-17b : R= TES
d or e
O
O
O
OH
f
O
O
O
+
O
O
O
O
O
(
-) - 19
(-) - 20
Scheme 4. Reagents and conditions: (a) Ac
C
2
O, pyridine, DMAP, DCM, 0 °C, 87%; (b) TESCl, imidazole, DMAP, DCM, 0 °C, 70%; (c)
2
H
5
PPh
3
Br, n-BuLi, THF, 0 °C (52% for 18a, 76% for 18b); (d) K
2
CO
3
, MeOH, 0 °C, 90%; (e) HFÆpy, THF, 0 °C, 78%; (f) PDC, DCM, 0 °C, 81%.
and [4+2]-cycloaddition as depicted in Scheme 5. When
aldehydes 23 and 24 were left aside neat at ambient
temperature, the desired cyclization–cycloaddition
occurred readily. In the (E)-series ())-epoxyquinols ())-
that both the diastereomers ())-21 and ())-22 are ser-
viceable and undergo the projected electrocyclization–
cycloaddition cascade process with equal felicity
and efficiency to furnish the epoxyquinol natural prod-
ucts.
9
and ())-10 were obtained in a ratio of 3.5:1 from 21,
Scheme 5. On the other hand, in the (Z)-series ())-
epoxyquinols ())-9 and ())-10 were realized in a ratio of
In short, we have outlined a simple, convenient access to
enantiomerically enriched, versatile building blocks
(+)-7 and ())-7 from the readily available Diels–Alder
adduct of cyclopentadiene and p-benzoquinone. The
former has been elaborated to ())-epoxyquinols A 9 and
B 10, following a biomimetic pathway.
15
4
:1 in comparable yield. While an hetero-[4+2]cyclo-
addition through an endo-transition state 25 accounts
for the formation of ())-9, an analogous homo-[4+2]
cycloaddition through an exo-transition state would
result in the formation of ())-10. It is interesting to note

3614
G. Mehta, K. Islam / Tetrahedron Letters 45 (2004) 3611–3615
O
O
O
O
a
b
c
O
O
O
O
O
6π-e-
O
cyclisation
O
O
OH
OH
OH
OH
(-) - 19
(-) - 21
23
[4 + 2]
O
CH3
O
CH3
O
H
H
H3C
CH3
CH3
CH3
O
O
O
O
+
O
O
O
O
O
O
O
O
OH
OH
OH
HO
HO
O
O
HO
O
(
-) - 9
(-) - 10
25
[4 + 2]
O
O
O
O
a
b
c
O
O
O
O
6
π-e-
cyclisation
O
O
O
O
OH
OH
OH
OH
(-) - 20
(-) - 22
24
Scheme 5. Reagents and conditions: (a) Amberlyst 15, MeOH, rt (79% for 21, 73% for 22); (b) TEMPO, O
))-9 (48%) and ())-10 (18%).
2
, CuCl, DMF, rt; (c) neat, ꢀ30 °C, 8 h,
(
Acknowledgements
Lett. 2002, 43, 3573; (g) Lei, X.; Johnson, R. P.; Porco, J.
A., Jr. Angew. Chem., Int. Ed. 2003, 42, 3913; (h) Mehta,
G.; Ramesh, S. S. Tetrahedron Lett. 2004, 45, 1985; (i)
Mehta, G.; Islam, K. Org. Lett. 2004, 6, 807.
. Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569.
. (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,
K.I. thanks CSIR, India for the award of a research
fellowship. This work was supported by the Chemical
Biology Unit of JNCASR at the Indian Institute of
Science, Bangalore. The lipase used in this study was a
gift from Dr. Y. Hirose of Amano Pharmaceutical Co.
Ltd, Japan.
3
4
A.; Koshino, H.; Osada, H. J. Antibiot. 2002, 55, 829.
. Enantiomeric excess (ee) was determined through
1
5
H
NMR analyses (integration of the acetate methyl groups)
after the addition of chiral shift reagent tris[3-(tri-
fluoromethylhydroxymethylene)-(+)-camphorato]europium
References and notes
(
ture of meso-diol (2 g, 10.9 mmol), vinyl acetate
III). Procedure for enzymatic transesterification: A mix-
5
1
. (a) Eupenoxide: Duke, R. K.; Rickards, R. W. J. Org.
Chem. 1984, 49, 1898; Liu, Z.; Jensen, P. R.; Fenical, W.
Phytochemistry 2003, 64, 571; (b) Cycloepoxydon: Gehrt,
A.; Erkel, G.; Anke, H.; Anke, T.; Sterner, O. Nat. Prod.
Lett. 1997, 9, 259; Gehrt, A.; Erkel, G.; Anke, T.; Sterner,
O. J. Antibiot. 1998, 51, 455; (c) ECH: Kakeya, H.;
Miyake, Y.; Shoji, M.; Kishida, S.; Hayashi, Y.; Kataoka,
T.; Osada, H. Bioorg. Med. Chem. Lett. 2003, 13, 3743.
. Selected references: (a) Kamikubo, T.; Ogaswara, K.
Chem. Commun. 1996, 1679; (b) Kamikubo, T.; Hiroya,
K.; Ogaswara, K. Tetrahedron Lett. 1996, 37, 499; (c)
Taylor, R. J. K.; Alkaraz, L.; Kapfer-Eyer, I.; Macdonald,
G.; Wei, X.; Lewis, N. Synthesis 1998, 775; (d) Li, C.;
Lobskovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc. 2000,
(4.09 mL, 43.6 mmol) and Amano lipase PS-30 immobi-
lized on Celite (2 g) in t-butylmethylether was stirred for
6 h at 0 °C. The reaction mixture was filtered through a
pad of Celite and the filtrate was concentrated. The crude
product was subjected to column chromatography on
silica gel and elution with hexane/ethyl acetate (2:1)
furnished (+)-7 (2.0 g, 82%) adjudged pure spectroscopi-
2
D
4
2
cally, as a colourless oil; ½aꢁ +11.5 (c 3.2, CHCl
3
).
Procedure for enzymatic hydrolysis: A mixture of meso-
diacetate 8 (50 mg, 0.187 mmol) and lipase from C. rugosa
(Sigma-Aldrich) in distilled water (1.5 mL) was stirred at
room temperature for 40 h. The reaction mixture was kept
neutral by occasional addition of phosphate buffer (pH 7).
After the usual work-up involving extraction with ethyl
acetate, the crude product was subjected to column
chromatography on silica gel to furnish ())-7 (28 mg,
1
22, 10484; (e) Wood, J. L.; Thompson, B. D.; Yusuff, N.;
Pflum, D. A.; Matthaus, S. P. J. Am. Chem. Soc. 2001,
23, 2097; (f) Genski, T.; Taylor, R. J. K. Tetrahedron
1

G. Mehta, K. Islam / Tetrahedron Letters 45 (2004) 3611–3615
3615
ꢀ
ꢀ
8
6% based on recovered starting material) as a colourless
).
b ¼ 6:415 (2) A, c ¼ 9:288 (2) A, b ¼ 92:690 (5),
2
D
4
3
ꢂ3
ꢀ
oil; ½aꢁ )11.6 (c 1.5, CHCl
3
V ¼ 2245:2 A , Z ¼ 8, D
c
¼ 1:35 g cm , F ð000Þ ¼ 976:0,
ꢂ1
6
. (a) Ryan, C. J.; Wilding, G. Drugs Aging 2000, 17, 249; (b)
Folkman, J.; Browder, T.; Palmblad, J. Thromb. Haemo-
stasis 2001, 86, 23.
l ¼ 0:11 mm . Total number of l.s. parameters ¼ 209,
R1 ¼ 0:0436 for 2028 Fo > 4rðFoÞ and 0.0534 for all 2452
data. wR2 ¼ 0:1090, GOF ¼ 1:011, restrained GOF ¼
1:011 for all data (CCDC 234194). ORTEP diagram is
shown below
7
8
. Paper, D. H. Planta Med. 1998, 64, 686.
. (a) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.;
Hayashi, Y. Angew. Chem., Int. Ed. 2002, 41, 3192; (b) Li,
C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore,
T. D.; Porco, J. A. Org. Lett. 2002, 4, 3267.
9
. (a) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada,
H.; Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155; (b) Shoji,
M.; Kishida, S.; Kodera, U.; Shiina, I.; Kakeya, H.; Osada,
H.; Hayashi, Y. Tetrahedron Lett. 2003, 44, 7205.
1
1
1
1
0. Kiyooka, S.-I.; Kuroda, H.; Shimasaki, Y. Tetrahedron
Lett. 1986, 27, 3009.
1. All new compounds were characterized on the basis of
spectral (IR, H and C NMR and mass spectral) data.
2. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
1
13
5
454.
3. X-ray data for ())-14: X-ray data were collected at 293 K
on a BRUKER SMART APEX CCD diffractometer with
graphite monochromated Mo Ka radiation (k ¼
ꢀ
:7107 A). Structure was solved by direct methods
0
(
SIR92). Refinement was done by full-matrix least-squares
2
14. Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou,
C. S. J. Am. Chem. Soc. 1984, 106, 3374.
procedures on F using SHELXL-97. The nonhydrogen
atoms were refined anisotropically whereas hydrogen
atoms were refined isotropically.
2
space group: C2=c, cell parameters: a ¼ 37:508 (11) A,
15. Specific rotation for epoxyquinol A: ½aꢁ ())-58° (c 0.43,
D
4
a
C
11
H
16
O
5
,
28:24, colourless crystal, crystal system: monoclinic,
MW ¼
MeOH), [lit. ½aꢁ (+)-61° (c 0.15, MeOH)] and for
4b
D
epoxyquinol B: ½aꢁ ())-146° (c 0.52, MeOH), [lit. ½aꢁD (+)-
D
ꢀ
153° (c 0.32, MeOH)].