A concise route to the key intermediate of (+)-vernolepin using a bicyclo[3.2.1]octane Chiral building block

Article abstract of DOI:10.1055/s-2002-32603

An enantioselective route to the key intermediate leading to (+)-vernolepin, an antitumor sesquiterpene, isolated from Vernonia hymenolepis, has been developed starting from the chiral building block having a bicyclo[3.2.1]octane framework accessible by either enzymatic or catalytic kinetic resolution.

Full text of DOI:10.1055/s-2002-32603

LETTER
1065
A Concise Route to the Key Intermediate of (+)-Vernolepin Using
A Bicyclo[3.2.1]octane Chiral Building Block
Concise Route to
t
o
he
K
eyInter
r
m
ediate
i
of (+)-V
o
ernolepin Miyazawa, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 26 April 2002
diastereocontrolled construction of the diterpene (+)-fer-
ruginol,6 the A-ring8 and the C/D-ring7 moieties of vita-
min D, and the analgesic alkaloid (-)-morphine.9 Utilizing
this chiral building block (–)-2, we attempted the enanti-
oselective construction of the bicyclic orthoester 1,4d the
racemate of which has been transformed into racemic ver-
nolepin,3,4d to develop a more efficient enantioselective
route to enantiopure (+)-vernolepin as well as to demon-
strate the versatility of our chiral building block 2. We
wish to report here the successful enantioselective con-
struction of the key intermediate 1 starting from the enan-
tiopure enone (–)-2 (Scheme 1).
Abstract: An enantioselective route to the key intermediate leading
to (+)-vernolepin, an antitumor sesquiterpene, isolated from Ver-
nonia hymenolepis, has been developed starting from the chiral
building block having a bicyclo[3.2.1]octane framework accessible
by either enzymatic or catalytic kinetic resolution.
Key words: chiral building block, convex-face stereoselection,
(+)-vernolepin precursor, antitumor sesquiterpene, bicyc-
lo[3.2.1]octenone
(+)-Vernolepin, a sesquiterpene isolated from the Ethiopi-
an plant Vernonia hymenolepis,1 has been the subject of
intense synthetic investigation owing to its potent antitu-
mor activity and unique structure. Since the total synthe-
ses by Grieco’s group2 and Danishefsky’s group3 in 1976,
several syntheses of vernolepin have been reported.4,5
However, included among them was only one synthesis,
by Shibasaki’s group,5 which allowed the enantioselective
construction of the natural product by employing an
asymmetric Heck reaction as the key step. We have re-
cently developed an efficient method for the preparation
the enantiopure enone 2 having a bicyclo[3.2.1]octane
framework in both enantiomeric forms by employing ei-
ther the enzymatic6 or the catalytic7 kinetic resolution
method. The enone 2 exhibits inherent convex-face selec-
tivity owing to its sterically biased framework to allow di-
astereocontrolled modification which led to enantio- and
The synthesis began with the reaction of the enone (–)-2
with the carbanion generated in situ from benzyloxymeth-
yltributylstannane and butyllithium.10,11 The reaction pro-
ceeded diastereoselectively from the convex-face to give
23
the tertiary allyl alcohol 3, [ ]D –161.2 (c 1.1, CHCl3),
which was oxidized with pyridinium chlorochromate
(PCC)11 to afford the -substituted enone 4, [ ]D22 +54.8
(c 1.0, CHCl3). On 1,4-addition with the vinyl cuprate
reagent, prepared in situ, in THF containing hexame-
thylphosphoric triamide (HMPA),12 the enone 4 furnished
24
selectively the ketone 5, [ ]D +105.0 (c 1.0, CHCl3),
having a quaternary stereogenic center. The overall yield
of the ketone 5 from the chiral building block (–)-1 was
66% in three steps (Scheme 2).
OH
OH
O
known
present study
O
O
O
O
H
OMOM
O
O
H
(–)-2
O
(+)-vernolepin
key intermediate 1
Scheme 1
OBn
iii
ii
i
O
O
(–)-2
OBn
OMOM
OBn
OMOM
OH
OMOM
(+)-5
3
4
Scheme 2 Reagents and conditions: i) Bu3SnCH2OBn, BuLi, THF, –78 °C (95%). ii) PCC, CH2Cl2 (75%). iii) vinyl-MgCl, CuBr Me2S,
HMPA, TMS-Cl, THF, –78 °C, then TBAF (92%).
Synlett 2002, No. 7, Print: 01 07 2002.
Art Id.1437-2096,E;2002,0,07,1065,1068,ftx,en;Y04802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1066
N. Miyazawa, K. Ogasawara
LETTER
Utilizing the ketone 5 thus obtained we first attempted to ketone 5 was treated with hydrochloric acid in THF to re-
transform it into the bicyclic keto-lactone 10 the racemate move the MOM-protecting group to give the secondary
of which has been prepared by Heathcock’s group13 em- alcohol 12, [ ]D24+110.9 (c 1.0, CHCl3), leaving the ben-
ploying a completely different approach. Although the zyl protecting group intact. Oxidation of the alcohol 12
Heathcock group did not report its conversion into racem- with PCC gave the 1,3-diketone 13, [ ]D27+279.7 (c 1.2,
ic vernolepin,14 it seemed to us the most suitable precursor CHCl3). When the diketone 13 was exposed to sodium
for the key intermediate 1 since there is very little differ- methoxide in methanol a facile and clean reaction took
27
ence between the keto-lactone 10 and our target molecule place immediately to furnish the cyclohexanone 15, [ ]D
1: namely, introduction of a double bond and stereoselec- –4.9 (c 1.0, CHCl3), in nearly quantitative yield as the sin-
tive reduction of the ketone functionality.
gle product. The observed remarkable regioselective ret-
ro-Dieckmann cleavage may be due to the steric
congestion of the cyclohexanone moiety compared to the
cyclopentanone moiety, which forced the methoxide at-
tack on the cyclopentanone carbonyl to form a single tran-
sient intermediate 14, which collapsed to give the
cyclohexanone 15 exclusively. We have observed the op-
posite situation in which exclusive cleavage occurred with
the cyclohexanone moiety to furnish the cyclopentanone
derivative in the synthesis of the C/D-ring system of the
vitamin D derivative.6 Upon exposure to iodoxybenzoic
acid (IBX)19 in toluene containing DMSO and a catalytic
amount of p-TsOH at 65 °C, the cyclohexanone 15 afford-
Thus, the ketone 5 was first exposed to boron tribromide
to give the crystalline keto-diol 6, mp 141–143 °C, [ ]D
23
+131.5 (c 0.9, CHCl3), by concurrent removal of the ben-
zyl and MOM-protecting groups. Refluxing the keto-diol
6 with a catalytic amount of p-toluenesulfonic acid (p-
TsOH) in 50% aqueous dioxane initiated the retro-al-
dolization, followed by hemiacetalization to give rise to
the bicyclic keto-hemiacetal mixture 9 presumably
through the transient intermediates 7 and 8. On Fetizon
oxidation,15 the hemiacetal mixture 9 afforded the optical-
ly active Heathcock lactone 10, mp 104–106 °C,
[ ]D23+11.3 (c 0.8, CHCl3), as a single crystalline product.
The overall yield of the lactone 10 from the ketone 5 was
64%.
28
ed the cyclohexenone 16, [ ]D –97.8 (c 1.1, CHCl3),
cleanly in satisfactory yield. Although we could not
find the optimal conditions to induce diastereoselective
reduction, reduction of the enone16 with sodium borohy-
dride-cerium (III) chloride at –78 °C afforded a readily
However, we were unable to introduce the double bond at
the requisite position of the keto-lactone 10 even using a
variety of conditions including the selenide,16 the sul-
fide,17 the Saegusa,18 and the IBX19 methods, respectively.
Discrimination of the two carbonyl functionalities of the
lactone 10 was also found to be difficult since both be-
haved as ketone functionalities under borohydride reduc-
tion and ketalization conditions. We now understand why
the Heathcock group did not report the synthesis of race-
mic vernolepin from the racemic keto-lactone ( )-10 even
though they had obtained it in a hundred-gram quantity
and referred13 to it as ‘an attractive intermediate’
(Scheme 3).
24
separable 3.8:1 mixture of the desired -alcohol 17, [ ]D
–97.8 (c 1.0, CHCl3), and the undesired -epimer 18,
[ ]D24 –47.5 (c 1.0, CHCl3), the latter of which reverted to
the enone 16 in 85% yield upon oxidation and could be
recycled. Having installed the requisite cyclohexenol
moiety, the benzyl protecting group was next removed us-
ing 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).20
Since direct treatment induced oxidation of the allylic al-
cohol moiety, the major alcohol 17 was first transformed
25
into the trifluoroacetate 19, [ ]D –88.8 (c 1.2, CHCl3),
under standard conditions. On stirring with DDQ in 1,2-
ethylene dichloride containing a small amount of water at
50 °C, the monocyclic ester 19 furnished the lactone 20,
[ ]D25 –102.9 (c 1.0, CHCl3), by spontaneous debenzyla-
tion and lactonization under these conditions presumably
We, therefore, turned our attention to the introduction of
the requisite double bond at an earlier stage before form-
ing the cis-decalin framework which, we believed, was
hindering the introduction of the double bond. Thus, the
OH
i
ii
O+H
O
HO
(+)-5
OH
OH
H+O
OH
OH
H
6
8
7
O
O
O
O
O
O
iii
HO
O
O
H
H
H
9
10
11
Scheme 3 Reagents and conditions: i) BBr3, CH2Cl2, –78 °C (92%). ii) p-TsOH (cat.), 50% aq Dioxane, reflux (79%). iii) Fetizon oxidation
(88%).
Synlett 2002, No. 7, 1065–1068 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Concise Route to the Key Intermediate of (+)-Vernolepin
1067
via the hydroxy-ester. Transformation of the lactone 20
into the orthoester 21 was readily carried out under the
same conditions as those reported in the Danishefsky syn-
thesis.3,4d Finally, the ester 21 was treated with potassium
carbonate to give the target molecule, the key intermedi-
References
(1) (a) Kupchan, S. M.; Hemingway, R.; Karin, A. J. Am. Chem.
Soc. 1968, 90, 3596. (b) Kupchan, S. M.; Hemingway, R.;
Werner, D.; Karin, A. J. Org. Chem. Soc. 1969, 34, 3903.
(2) (a) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.;
Marinovic, N. J. Am. Chem. Soc. 1976, 98, 1612.
(b) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.;
Marinovic, N. J. Am. Chem. Soc. 1977, 99, 5773.
(3) (a) Danishefsky, S.; Kitahara, T.; Schuda, P. F.; Etheredge,
S. J. J. Am. Chem. Soc. 1976, 98, 3028. (b) Danishefsky, S.;
Kitahara, T.; Schuda, P. F.; Etheredge, S. J. J. Am. Chem.
Soc. 1977, 99, 6066. (c) Danishefsky, S.; Kitahara, T.;
Schuda, P. F.; Etheredge, S. J. J. Am. Chem. Soc. 1977, 99,
6066.
(4) For racemic syntheses, see: (a) Kieczykowski, G. R.;
Quesada, M. L.; Schlessinger, R. H. J. Am. Chem. Soc. 1978,
100, 1938. (b) Kieczykowski, G. R.; Quesada, M. L.;
Schlessinger, R. H. J. Am. Chem. Soc. 1980, 102, 782.
(c) Isobe, M.; Iio, M.; Kawai, T.; Goto, T. J. Am. Chem. Soc.
1978, 100, 1940. (d) Iio, M.; Isobe, M.; Kawai, T.; Goto, T.
J. Am. Chem. Soc. 1979, 101, 6076. (e) Zutterman, F.; De
Wilde, H.; Mijngheer, R.; De Clercq, P.; Vandewalle, M.
Tetrahedron 1979, 35, 2389. (f) Wakamatsu, T.; Hara, H.;
Ban, Y. J. Org. Chem. 1985, 50, 10.
27
ate 1, [ ]D –157.6 (c 1.1, CHCl3), of (+)-vernolepin by
removal of the trifluoroacetyl moiety. The overall yield of
the key intermediate (-)-1 from the ketone (+)-5 was 22%
in nine steps, and, thus, 15% in twelve steps from the
chiral building block (–)-2. Since the route to racemic ver-
nolepin from the racemic 1 employing the Danishefsky
synthesis3 has been established,4d the present acquisition
of the optically active key intermediate (–)-1 constitutes a
formal synthesis of (+)-vernolepin (Scheme 4).
In summary, we have found a new utilization for the chiral
building block we developed by converting it enantiose-
lectively into the key intermediate of the sesquiterpene
(+)-vernolepin. The present example demonstrates not
only the potential of the chiral building block owing to its
inherent stereochemical and chemical nature, but also
shows a facile entry into the physiologically and structur-
ally interesting natural product.
(5) For a enantiocontrolled synthesis, see: (a) Kondo, K.;
Sodeoka, M.; Mori, M.; Shibasaki, M. Tetrahedron Lett.
1993, 34, 4219. (b) Ohrai, K.; Kondo, K.; Sodeoka, M.;
Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737.
(6) Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001,
3, 1737.
Acknowledgement
We are grateful to the Ministry of Education, Culture, Sports,
Science and Technology, Japan for support of this research.
(7) Hanada, K.; Miyazawa, N.; Naagata, H.; Ogasawara, K.
Synlett 2002, 125.
(8) Miyazawa, N.; Tosaka, A.; Hanada, K.; Ogasawara, K. to be
published.
O
O
O
BnO
O
iii
ii
i
(+)-5
MeO
OBn
OBn
OBn
MeO2C
O–
14
O
OH
H
13
12
15
OCOCF3
R1
R2
O
BnO
MeO2C
vi
BnO
iv
BnO
v
MeO2C
MeO2C
H
H
H
17:R1= OH, R2= H
18:R1= H, R2= OH
19
16
OCOCF3
OCOCF3
OH
O
O
O
ix
viii
O
O
vii
O
O
O
H
H
H
(–)-1
21
20
Scheme 4 Reagents and conditions: i) concd HCl–THF (1:4) (90%). ii) PCC, CH2Cl2 (84%). iii) NaOMe, MeOH, 0 °C (99%). iv) IBX,
p-TsOH (cat.), DMSO, toluene, 65 °C (78%). v) NaBH4–CeCl3–7H2O, –78 °C (17: 65% and 18: 17%). vi) (CF3CO)2O, pyridine, THF (100%).
vii) DDQ, (CH2Cl)2, H2O (cat.) (77%). viii) (CH2OH)2, p-TsOH (cat.), Dowex-50W-X8, MgSO4, benzene, reflux. ix) K2CO3, MeOH (75%,
2 steps).
Synlett 2002, No. 7, 1065–1068 ISSN 0936-5214 © Thieme Stuttgart · New York

1068
N. Miyazawa, K. Ogasawara
LETTER
(9) Nagata, H.; Miyazawa, N.; Ogasawara, K. Chem. Commun.
2001, 1094.
(10) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(11) Nagata, H.; Kawamura, M.; Ogasawara, K. Synthesis 2000,
1825.
(14) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. The Total Synthesis of Natural Products, Vol.
5; ApSimon, J., Ed.; Wiley-Interscience: New York, 1993,
93–107.
(15) Fetizon, M.; Golfier, M. Compt. Rend. (C) 1968, 267, 900.
(16) Sharpless, K. B.; Lauer, R. F.; Terenishi, Y. J. Am. Chem.
Soc. 1973, 95, 6137.
(12) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4025.
(13) Wege, P. M.; Clark, R. D.; Heathcock, C. H. J. Org. Chem.
1976, 41, 3144.
(17) Trost, B. M.; Salzmann, T. N. J. Am. Chem. Soc. 1973, 95,
6840.
(18) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(19) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem.
Soc. 2000, 122, 7596.
(20) Matsumura, R.; Suzuki, T.; Hagiwara, H.; Hashi, T.; Ando,
M. Tetrahedron Lett. 2001, 42, 1543.
Synlett 2002, No. 7, 1065–1068 ISSN 0936-5214 © Thieme Stuttgart · New York