Synthesis of yomogin using a telescoped α-methylene-γ- butyrolactone annelation procedure

Article abstract of DOI:10.1016/j.tetlet.2010.11.143

A novel and efficient synthetic route to the anti-cancer natural product yomogin has been developed using a Telescoped Intramolecular Michael-Olefination (TIMO) sequence as the key step. Two variants of the TIMO sequence have been used successfully: a two

Full text of DOI:10.1016/j.tetlet.2010.11.143

Tetrahedron Letters 52 (2011) 561–564
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Tetrahedron Letters
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Synthesis of yomogin using a telescoped
annelation procedure
a
-methylene-c-butyrolactone
⇑
Russell R. A. Kitson, Graeme D. McAllister, Richard J. K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient synthetic route to the anti-cancer natural product yomogin has been developed
using a Telescoped Intramolecular Michael-Olefination (TIMO) sequence as the key step. Two variants
of the TIMO sequence have been used successfully: a two-step acylation approach using diethyl phospho-
noacetic acid and a base-free variant using triphenylphosphoranylideneketene (Bestmann’s ylide). The
natural product, 3-oxodiplophyllin, was also prepared en route to yomogin.
Received 25 October 2010
Revised 17 November 2010
Accepted 26 November 2010
Available online 2 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The eudesmane sesquiterpene lactone yomogin (1) was first
isolated from Artemisia princeps Pamp., a common perennial plant
found in Japan, by Geissman in 1966.1 A. princeps (also known as
Japanese mugwort or yomogi) has long been used in traditional or-
iental medicine for treating infections, asthma and circulatory
problems,2 but interest in this compound has heightened recently
with the discovery of its anti-cancer properties2,3 (yomogin can in-
duce apoptosis in human leukaemia cells via caspase-8 activa-
tion3), as well as its anti-inflammatory,4 anti-allergy4 and anti-
TB5 properties.
ylene unit (Scheme 1). Thus, in 1975, Caine and Hasenhuettl re-
ported a total synthesis of racemic yomogin, which started from
the readily-available diketone 26 and proceeded by way of 3-oxo-
diplophyllin (3) (3-oxoalloalantolactone), which is itself a natural
product.7 Subsequently, chiral pool syntheses of (À)-yomogin were
reported by Yamakawa’s group using a-santonin (4) as the starting
material,8 and by Marco et al. commencing from (À)-artemisin
(5).9 The biological potential of yomogin has also stimulated re-
search to prepare and screen novel yomogin analogues.10
We have recently become interested in a-methylene-c-butyro-
Yomogin (1) has been the subject of three total syntheses, with
all of the synthetic routes proceeding via lactonisation to generate
lactone natural products,11–13 and have developed novel tele-
scoped annelation procedures for preparing such compounds
an intermediate
c-lactone, followed by installation of the
a
-meth-
from
c-hydroxy-enones (e.g., 6?11, Scheme 2). Thus, acylation
i. LDA
then HCHO
ii. MsCl, Py
Me
O
Me
Me
O
O
O
O
O
DDQ
iii. pTSA
acetone
O
O
O
Me
Me
Me
Me
O
3-oxodiplophyllin (3)
2
O
O
Me
yomogin (1)
Me
Me
O
Me
OH
Me
or
O
i. LDA then
PhSeSePh
ii. H2O2
O
O
Me
O
Me
Me
O
Me
O
Me
O
O
α-santonin (4)
(-)-artemisin (5)
Scheme 1.
⇑
Corresponding author.
E-mail addresses: rjkt1@york.ac.uk, tet@york.ac.uk (R.J.K. Taylor).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.143

562
R. R. A. Kitson et al. / Tetrahedron Letters 52 (2011) 561–564
(EtO)2P(O)CH2CO2H
O
OH
O
7
O
O
O
O
O
or
Ph3P C C O
8
P*
P*
6
9
10
P* = PPh3 or
P(O)(OEt)2
Tandem Intramolecular Michael-Olefination
O
HCHO
O
O
Me
OH
O
Me
O
OH
O
O
O
O
O
O
11
oleocanthal
(+)-paeonilactone B
Scheme 2.
of
c
-hydroxy-enones with diethyl phosphonoacetic acid (7) and
mediated rearrangement. TMS protection followed by methylation
and deprotection afforded the key -hydroxy-cyclohexenone 21 in
74% yield over the three steps. The methylation occurred without
then treatment with base12 or, in the base-free variant,13 direct
use of triphenylphosphoranylideneketene (8) (Bestmann’s ylide)
gave intermediates 9. Michael addition in situ then generated the
organophosphorus intermediates 10, which produced the required
c
stereocontrol generating 21 as
a
statistical mixture of
diastereoisomers.
a
-methylene-
c-butyrolactones 11 on trapping with formalde-
Having prepared the key cyclisation precursor, we were now in
a position to apply the TIMO annelation chemistry (Scheme 5,
21?22). We were delighted to observe that both variants of the
methodology were successful; the original two-step acylation ap-
proach using diethyl phosphonoacetic acid (7) and then treatment
hyde.12,13 The diethyl phosphonoacetic acid variant of the Tele-
scoped Intramolecular Michael-olefination (TIMO) sequence was
employed by our group to prepare (+)-paeonilactone B,12 and more
recently by English and Williams in a synthesis of racemic
oleocanthal.14
12
with base/(CH2O)n gave an overall yield of 60%, whereas the
We were intrigued by the idea of employing a TIMO-type pro-
base-free variant using triphenylphosphoranylideneketene (8)
cess to prepare yomogin (1) using a protected version of
c
-hydro-
(Bestmann’s ylide)13 gave a 78% yield of
a-methylene-c-butyrolac-
xy-cyclohexenone 14 to give an -methylene- -butyrolactone
a
c
tone 22.
such as 12 (via intermediate 13), which could be subjected to intra-
molecular aldol cyclisation and dehydrogenation to give yomogin
(1) (Scheme 3).
In order to complete the synthesis, deprotection of the TBS
group was achieved using HF (TBAF gave no reaction) and DMP
oxidation afforded the ketone 23 in excellent yield. On attempting
the intramolecular aldol condensation of compound 23 with p-TSA
under Dean-Stark conditions, only the required syn,syn-diastereo-
mer underwent cyclisation, giving 3-oxodiplophyllin (3) in 54%
Thus, devising a synthetic route to a c-hydroxy-cyclohexenone
of type 15 became the first objective. Several slightly different vari-
ants were explored and the most reliable is shown in Scheme 4.
Hence, conjugate addition of the cuprate 16, derived from com-
mercially available 2-iodoanisole, to ethyl vinyl ketone gave ad-
duct 1715 in 72% yield. Reduction and TBS-protection proceeded
efficiently to produce silyl ether 18. Birch reduction of compound
18 proceeded in quantitative yield, although NMR analysis
indicated that cyclohexadiene 19 was accompanied by ca. 2% of a
regioisomeric diene. Using the procedure reported by Danishefsky
yield (accompanied by the unreacted
a-methylated diastereomer
24; stereochemistry confirmed by NOE analysis). To complete the
total synthesis, 3-oxodiplophyllin (3) was treated with DDQ in
1,4-dioxane exactly as described by Caine and Hasenhuettl6 to give
racemic yomogin (1) in 81% yield (published6 yield 65%; mp 208.5–
210 °C; lit.1 mp 210–211 °C).
In summary, we have developed a concise synthesis of the anti-
cancer natural product yomogin in racemic form (14 steps, 12%
overall yield) from known ketone 17. This overall yield compares
and Simoneau,16 enol ether 19 was converted into
c-hydroxy-
cyclohexenone 20 by acid hydrolysis/epoxidation/alumina-
Me
Me
Me
TIMO
O
O
O
O
O
O
O
O
O
O
O
P*
Me
12
13
yomogin (1)
OP
Me
Me
OH
OH
O
O
O
15
14
Scheme 3.

R. R. A. Kitson et al. / Tetrahedron Letters 52 (2011) 561–564
563
LiCu(CN)
i. NaBH4
Na, NH3
EtOH, THF
-78 °C to -33 °C
O
CH2Cl2/MeOH
-78 °C to 0 °C
98%
TBSO
16
MeO
O
98%
ii. TBSCl, imid.
DMF, rt
94%
THF, -78 °C to rt
72%
MeO
MeO
18
17
i. (CO2H)2.2H2O
MeOH, 0 °C to rt
ii. m-CPBA,
i. TMSCl, Et3N,
CH2Cl2, rt
ii. LDA, THF, MeI
-78 °C to -40 °C
TBSO
TBSO
H
CH2Cl2, 0 °C
OH
TBSO
Me
OH
iii. Al2O3, Et2O, rt
74% (3 steps)
d.r. ca. 9:9:1:1
iii. (CO2H)2.2H2O
MeOH, rt
74% (3 steps)
MeO
O
O
19
20
d.r. ca. 1:1:1:1
21
Scheme 4.
(T3P = propane
phosphonic acid anhydride)
i. (EtO)2P(O)CH2CO2H 7
T3P, DIPEA, PhMe, rt, 81%
ii. KOt-Bu, THF, -78 °C, rt
then (CH2O)n
a) HF,
MeCN,
72%
TBSO
TBSO
Me
Me
O
74%, d.r. ca. 1:1:1:1
OH
O
Or
b) DMP,
CH2Cl2,
quant.
O
O
Ph3P
C C O 8
21
22
1,4-dioxane, Δ
78%, d.r. ca. 1:1:1:1
O
Me
Me
Me
O
DDQ
O
O
p-TSA
O
O
O
1,4-dioxane, Δ
O
PhMe, Δ
Dean-Stark
54%
O
O
81%
Me
rac-yomogin (1)
Me
23
rac-3-oxodiplophyllin (3)
(+ 43% 24)
+
O
Me
O
O
O
24
Scheme 5.
well with the three published approaches.6,8,9 The cornerstone of
the route involved the use of the Telescoped Intramolecular
References and notes
1. Geissman, T. A. J. Org. Chem. 1966, 31, 2523.
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2004, 27, 1106.
Michael-Olefination (TIMO) sequence to construct the
a-alkyl-
idene- -butyrolactone moiety. We are currently optimising the
c
methodology described herein and are investigating an asymmet-
3. Kim, S. H.; Kim, T. S. Planta Med. 2002, 68, 886.
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Acknowledgements
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We thank the EPSRC for studentship support (R.R.A.K.). We are
also grateful to Dr. T. Dransfield (MS) for technical assistance.

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R. R. A. Kitson et al. / Tetrahedron Letters 52 (2011) 561–564
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