A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

Article abstract of DOI:10.1039/c3sc50424g

(-)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization strategy toward the enantioselective total synthesis of deguelin, which allows access to either stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural (+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells when compared to the natural product.

Full text of DOI:10.1039/c3sc50424g

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A concise enantioselective synthesis and cytotoxic
evaluation of the anticancer rotenoid deguelin enabled
by a tandem Knoevenagel/conjugate addition/
decarboxylation sequence†
Cite this: DOI: 10.1039/c3sc50424g
Rebecca L. Farmer and Karl A. Scheidt*
(ꢀ)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and
chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal
evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We
describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization
strategy toward the enantioselective total synthesis of deguelin, which allows access to either
stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no
protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent
inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural
Received 12th February 2013
Accepted 6th June 2013
DOI: 10.1039/c3sc50424g
(
+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells
www.rsc.org/chemicalscience
when compared to the natural product.
normal HBE cells, indicating that it could act as a specic
chemopreventive agent. In addition, deguelin has demon-
Introduction
2
(

ꢀ)-Deguelin (1) is a compact natural product isolated from the strated chemopreventive activity in skin and mammary carci-
1
3
owering plants Lonchocarpus utilis and urucu that is related to nogenesis models, and also inhibits the metastatic spread of
4
the pesticide rotenone (2) (Fig. 1). This rotenoid has demon- lung cancer cells in a murine model. Like rotenone, deguelin
strated signicant anticancer activity in a number of in vitro and
in vivo studies and is a compelling target for further therapeutic
lead optimization and development. Deguelin has been shown
derives its cytotoxicity from inhibition of ornithine decarboxy-
lase, an enzyme associated with tumor progression, and
5,6
NADH:ubiquinone oxidoreductase, the rst protein in the
7
to induce apoptosis in premalignant and malignant human electron-transport chain (ETC) for oxidative phosphorylation.
bronchial epithelial (HBE) cells without affecting the growth of This interaction was further conrmed by a recent report by
Winssinger, which demonstrated that uorescently-labeled
deguelin conjugates bind selectively to mitochondria, the site of
8
the ETC in human cells. These in vitro and in vivo results
suggest that deguelin has signicant potential as a chemo-
therapeutic agent, since it is able to inhibit relevant anticancer
cellular targets, thereby reducing tumor growth and metastasis
in several models.
Despite this promising biological activity, there remains a
need for the development of a concise and enantioselective
synthesis of (ꢀ)-deguelin and related structures. While racemic
Fig. 1 The natural product (ꢀ)-deguelin (1) and related compound rotenone (2). syntheses of deguelin and a formal synthesis from rotenone
9–13
have been reported,
there is only one asymmetric synthesis
of this compound reported by Winssinger, who relied on a
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, chiral epoxide opening/Mitsunobu sequence to set the key C13a
Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road,
14
stereocenter. Furthermore, much like the abyssinone family of
Evanston, IL 60208, USA. E-mail: scheidt@northwestern.edu; Fax: +1-847-467-2184
15
natural products previously studied by our group, the effect
†
Electronic supplementary information (ESI) available: Experimental procedures
of the absolute stereochemistry on the anticancer activity of
deguelin has not been formally studied/reported to the best of our
knowledge. Given the power of enantioselective catalysis to
and spectroscopic data for all new compounds. CCDC 924171. For ESI and
crystallographic data in CIF or other electronic format see DOI:
1
0.1039/c3sc50424g
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address this type of question, we saw the opportunity to apply a deguelin for biological testing. Similar to our approach with the
thiourea-catalyzed asymmetric cyclization strategy to the abyssinones, the alkylidene precursor 4 would be obtained
construction of (ꢀ)-deguelin based on our program in asym- through a Knoevenagel condensation between the b-ketoester 5
1
5–19
metric pyran methodology.
nantiomeric thiourea catalysts
Furthermore, since pseudoe- and aldehyde 6. These starting materials would be easily
15,16,20
could be utilized in the key obtained from 2,4-dihydroxyacetophenone and 3,4-dimethoxy-
cyclization step to set the C13a stereocenter, this approach phenol, two achiral and readily available starting materials.
would facilitate efficient access to either enantiomer of the The synthesis of the natural product deguelin commenced
natural product and analogs for biological evaluation. Herein with the construction of the requisite b-ketoester starting
we report the use of this synthetic strategy to obtain the rst material, which followed a similar route to that which was used
15
catalytic, enantioselective total synthesis of the natural product to construct the b-ketoester substrate for the abyssinones.
ꢀ)-deguelin, and the biological evaluation of this important Using the same copper-catalyzed etherication strategy, we
anticancer natural product and its unnatural enantiomer in alkylated 2,4-dihydroxyacetophenone (7) selectively at the C4
(
relevant cytotoxicity assays.
phenol to yield alkyne 8 in 80% yield on multi-gram scale
23
(
Scheme 2). This alkyne 8 was then subjected to microwave
ꢁ
conditions at 180 C to yield the cyclized material 9. Although
Results and discussion
there have been reports supporting the regiochemical outcome
24–28
of this type of thermal cyclization reaction,
it does appear to
To construct the natural product (ꢀ)-deguelin, we wanted to
capitalize on our chiral thiourea-catalyzed intramolecular
cyclization strategy to control the stereochemistry of the center
go against conventionally held steric arguments which would
21
22
at C13a. We envisioned a late-stage oxidative alpha-arylation
to generate (ꢀ)-deguelin, which would be obtained from the
unsubstituted chromanone precursor 3 (Scheme 1). The enan-
tioenriched chromanone material 3 could be synthesized
through the thiourea-catalyzed intramolecular cyclization of
alkylidene 4, similar to the strategy that was used for the
15
construction of the abyssinone natural products by our group.
Using both Hiemstra's and “epi”-Hiemstra's thiourea cata-
16,20
lysts,
both the (R) and (S) congurations at the C13a
stereocenter could be obtained, which would allow for the
generation of the natural and unnatural enantiomers of
Scheme 2 Synthesis of the b-ketoester starting materials 10 and 13. Reagents
and conditions: (a) 3-chloro-3-methylbutyne (1.8 equiv.), K
2
CO
3
(2 equiv.), KI
ꢁ
ꢁ
(
1.7 equiv.), CuI (5 mol%), DMF, 65 C, 15 h, 80%; (b) mwave, PhMe, 180 C, 30
ꢁ
min, >99%; (c) hexamethyldisilazane (4 equiv.), nBuLi (4 equiv.), THF, ꢀ78 C, then
ꢁ
ꢁ
ꢁ
9
(1 equiv.), ꢀ20 C, 2 h, then diallyl carbonate (4 equiv.), ꢀ78 C / 23 C, 16 h,
ꢁ
7
2%; (d) mwave, PhMe, 180 C, 30 min, >99%; (e) hexamethyldisilazane (6 equiv.),
ꢁ
ꢁ
Scheme
1
Retrosynthetic analysis of (ꢀ)-deguelin, featuring
a
late-stage
nBuLi (6 equiv.), THF, ꢀ78 C, then tert-butyl acetate (3.5 equiv.), ꢀ78 C, 2 h, then
12 (1 equiv.), ꢀ78 ꢁC / 23 C, 15 h, 70%.
ꢁ
oxidative alpha-arylation and a thiourea-catalyzed intramolecular cyclization.
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16
dictate that the cyclization occur in the opposite direction. conditions (piperidine, acetic acid, benzene, Dean–Stark) to
Therefore, the structure of 9 was conrmed by X-ray diffraction yield the desired alkylidene 17, but the reaction gave extremely
before moving onto the next step of the synthesis, with the poor conversion and resulted in the generation of the racemic
results supporting the formation of the desired product cyclized material. Other conditions utilizing the dimethyl acetal
(Scheme 2).
15 as the coupling partner were also attempted, but none of the
With the correct crystal structure conrmed, the substituted reactions yielded the desired material. Finally, switching to the
acetophenone 9 was then deprotonated with excess LiHMDS to bis-morpholine aminal substrate 16 (actually a 3 : 1 : 1 mixture
form the dianion, which was trapped with diallyl carbonate to of the two possible enamine isomers) led to the generation of
give the desired allyl b-ketoester 10 in 72% yield. The allyl the desired alkylidene substrate 17, although it was only iso-
b-ketoester was chosen for this synthesis since it had worked lated in a 26% yield due to spontaneous cyclization when the
well in the synthesis of the abyssinones, allowing for the material was exposed to silica gel (Scheme 4). While the
deprotection and decarboxylation of the ester in one pot using majority of the product that was obtained from this reaction
29
previously reported Pd(0) conditions. However, since cycliza- was the racemic cyclized material, the alkylidene product was
tions with thiourea catalysts in our laboratory have typically isolated and tested in cyclization reactions with pseudoe-
given higher enantioselectivity when the ester substituent is nantiomeric thiourea catalysts 18 and 19. As expected, the
30,31
bulky,
the t-butyl b-ketoester 13 was also synthesized. This cyclization with the thiourea catalysts proceeded smoothly
t-butyl b-ketoester was synthesized through a similar method to under standard conditions, and the desired enriched chroma-
32
the allyl b-ketoester 10, except 2,4-dihydroxymethyl benzoate nones 3 were obtained in 85 : 15 er (with 18) and 84 : 16 er (with
was used as the initial substrate. The lithium anion of t-butyl 19) aer deprotection/decarboxylation with Pd(0). A second
acetate was then used in the last step to displace the methyl repeat of each experiment conrmed the results of this rst
ester of intermediate 12 to generate the required b-ketoester in attempt, giving the cyclized material 3 with the same levels of
16
70% yield.
stereoinduction.
Once the desired b-ketoester substrates were in hand, it was
Although we were encouraged by this initial success, there
necessary to synthesize the requisite aldehyde coupling partner was a need to devise another strategy that avoided purication
for the desired Knoevenagel cyclization (Scheme 3). Several of the alkylidene precursor 17. This intermediate was exqui-
6
approaches toward this aldehyde were attempted, including sitely sensitive to silica gel and would readily cyclize upon
3
3
34,35
reduction of the ethyl ester and Weinreb amide
with DIBAL-H,
substrates purication to give the racemic cyclized products. In our 2007
36,37
38
16
cleavage of the allyl ether with OsO /NaIO ,
report on the thiourea-catalyzed synthesis of avanones,
a
4
4
and oxidation of the alcohol precursor with TPAP$NMO or similar problem had been encountered with the synthesis of the
17
Dess–Martin periodinane. However, the desired product could chromanone natural product indersiachromanone, which also
not be obtained using any of these routes. Ultimately, we were has an aliphatic substituent at C2. Since both the Knoevenagel
able to obtain the desired material in 88% yield through the reaction to form the alkylidene and the thiourea-catalyzed
mildly acidic deprotection of dimethyl acetal 15 with Amberlyst- cyclization were run in toluene, these two steps could be
3
9,40
ꢁ
1
5 resin,
although the material had to be stored at ꢀ20 C at combined successfully in a one-pot procedure, thereby avoiding
all times to prevent decomposition.
purication of the sensitive alkylidene intermediate. Hence,
Aer developing the routes to construct the desired combining allyl b-ketoester 10 and bis-morpholine aminal 16
b-ketoester and aldehyde starting materials, our attention with 20 mol % thiourea catalyst 18 under these one-pot condi-
turned to the asymmetric synthesis of the chromanone tions led to the formation of the desired chromanone product 3
precursor 3. Initially, we attempted to directly couple the allyl in 34% yield (over 3 steps) and 79 : 21 er (Table 1, entry 1) aer
b-ketoester 10 with the aldehyde 6 under standard Knoevenagel deprotection/decarboxylation. While this one-pot yield was a
slight improvement when compared to the original two-step
procedure described in Scheme 4, the enantioselectivity was
still unacceptably low for this process. Several attempts at
optimization of this reaction were made by decreasing the
ꢁ
temperature to ꢀ30 C (Table 1, entry 2) or changing the catalyst
loading (Table 1, entries 3 and 4). However, none of these
optimization attempts led to the formation of the desired
chromanone 3 in acceptable yield and enantioselectivity.
At this point, other modications that might increase the
enantioselectivity of the one-pot process were considered. As
mentioned earlier, it has been shown that bulkier b-ketoesters
are more reactive and provide high enantioselectivity in this
30,31
type of intramolecular cyclization reaction.
Therefore, we
attempted the one-pot process using the t-butyl b-ketoester 13
instead of the allyl b-ketoester 10. With this modication, both
the yield and enantioselectivity of the one-pot reaction
increased signicantly, to 67% and 90 : 10 er, respectively
Scheme 3 Synthesis of the aldehyde 6. Reagents and conditions: (a) bromoa-
ꢁ
cetaldehyde dimethyl acetal (1.4 equiv.), K
2
CO
3
(6 equiv.), DMF, 150 C, 16 h,
ꢁ
9
7%; (b) Amberlyst-15 resin (10 mol%), MeCN–water (5 : 1), 85 C, 20 h, 88%.
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ꢁ
Scheme 4 Initial synthesis of enantioenriched chromanone 3. Reagents and conditions: (a) morpholine (2 equiv.), benzene, Dean–Stark, 110 C, 1 h, 93%; (b) AcOH
4 equiv.), 16 (2 equiv.), PhMe, 23 ꢁC, 2 h, 26%; (c) 10 mol% 18 or 19, PhMe, ꢀ25 ꢁC, 2 days; (d) Pd(PPh
)
4
(5 mol%), morpholine (25 equiv.), THF, 23 C, 1 h, 82% over
ꢁ
(
3
two steps (with 18) and 80% (with 19).
Table 1 Optimization of one-pot synthesis of chromanone 3
Hiemstra and “epi”-Hiemstra catalysts 18 and 19 were utilized
to complete the synthesis of both enantiomers of the chroma-
none precursor 3 (Table 1, entries 6 and 7).
With the enantioenriched chromanone product 3 con-
structed via the one-pot sequence described above, the last
steps of the synthesis were accomplished through an oxidative
22
arylation based upon a report by Snider. The requisite TBS silyl
enol ether 20 was rst synthesized through treatment of enan-
41
tioenriched chromanone 3 with triethylamine, TBSCl and NaI.
2
The resulting TBS ether (20) was then exposed to Cu(OTf) /Cu O
2
ꢁ
b
Entry
R
Catalyst
mol%
Temp. ( C)
% yield
er
in the presence of 2,6-di-t-butylpyridine (DTBP). These oxidative
conditions directly yielded the natural product (ꢀ)-deguelin in
1
2
3
4
5
6
7
Allyl
Allyl
Allyl
Allyl
t-Bu
t-Bu
t-Bu
18
18
18
18
18
18
19
20
20
5
50
50
20
20
23
ꢀ30
23
34 c
NR
25
79 : 21
NR
60 : 40
78 : 22
25% yield, with the remainder of the mass balance identied as
over-oxidized decomposition products. Interestingly, there was
no evidence of the trans-fused product in this reaction, despite
23
42
23
23
23
67
46
33
90 : 10 the fact that the report by Snider demonstrated formation of
87 : 13
84 : 16
22
both cis- and trans-fused [5,6] systems. However, calculations
of energy differences between the cis- and trans-fused systems in
a
Reagents and conditions: 10 or 13 (1 equiv.), 16 (2 equiv.), catalyst 18 or this reaction demonstrated that the natural conguration was
9, AcOH (4 equiv.), 0.1 M in PhMe, 23 C, 3 days; then Pd(PPh
), morpholine (25 equiv.), THF, 23 C, 1 h (with 10) or TsOH (50 mol
), 0.1 M in PhMe, 80 C, 16 h (with 13). Yield over three steps
ꢁ
1
3
)
4
(5 mol
energetically preferred, which likely explains the lack of trans-
fused product. Therefore, the efficiency of this particular bond
ꢁ
%
%
ꢁ
b
c
(Knoevenagel, conjugate addition, and decarboxylation). NR ¼ no disconnection made it an attractive route to access the natural
reaction.
product in an efficient and convergent manner (Scheme 5).
Although a number of in vitro cell-based toxicity studies have
been performed on deguelin, there are no investigations into
(Table 1, entry 5). These results demonstrated that we could the effect of stereochemistry on its anticancer potential. Since
efficiently access the desired chromanone material 3 in very the successful thiourea-catalyzed cyclization strategy described
high enantioselectivity by utilizing this one-pot procedure. above provides both enantiomers of deguelin, we were able to
42
Furthermore, reducing the catalyst loading to 20 mol % (Table evaluate each pure stereoisomer in cytotoxicity assays against
, entry 6) provided the desired material 3 with minimal loss of a panel of cancer cell lines. Selected IC50 data from this
1
yield (46%) and enantioselectivity (87 : 13), and allowed us to preliminary biological screen is shown in Fig. 2. As shown in the
advance material through the end of the synthesis with minimal gure, both enantiomers of deguelin inhibited the growth of
use of catalyst. Therefore, these conditions with 20 mol% of the PC-3 (prostate), MCF-7 (breast), HepG2 (liver) and Jurkat
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this unnatural antipode and reiterate the importance of a
modular synthetic approach which can be used to access both
enantiomers of this chemotherapeutic target.
Conclusions
(
ꢀ)-Deguelin is a rotenoid natural product that has demon-
strated signicant chemotherapeutic and chemopreventive
potential in a number of in vitro and in vivo cancer models.
Motivated by this potential, we have established a stereo-
selective synthesis employing
a thiourea-catalyzed intra-
molecular cyclization to successfully access the unnatural and
natural enantiomers of deguelin. When coupling this asym-
Scheme 5 Completion of the synthesis of the anticancer natural product
metric approach with
ꢀ)-deguelin was accessed in the shortest asymmetric synthesis
to date (six linear steps with no protecting groups) from
,4-dihydroxymethyl benzoate with good levels of enantiose-
a
copper-promoted arylation,
(
(
(
ꢀ)-deguelin (1). Reagents and conditions: (a) NEt
3
(2 equiv.), TBSCl (2 equiv.), NaI
(
ꢁ
2 equiv.), MeCN, 23 C, 16 h, 58%; (b) Cu(OTf)
2
(2 equiv.), Cu O (3.5 equiv.), DTBP
2
4 equiv.), MeCN, ꢀ30 ꢁC, 5 min, 25%.
2
lectivity. Additionally, our ability to access either enantiomer of
this rotenoid with our tandem cyclization/arylation strategy
allowed us to demonstrate for the rst time that (+)-deguelin
and (ꢀ)-deguelin have differential cytotoxicity proles when
evaluated against a panel of relevant cancer cell lines. These
results not only conrm the importance of a general catalytic,
enantioselective approach, but also present new possibilities
for the therapeutic development of deguelin and related
rotenoids.
Acknowledgements
The authors thank Dr Andrew Mazar, Dr Irawati Kandela, and
the Developmental Therapeutics Core of the Chemistry of Life
Processes Institute for their help with the biological screening
assays. This work has been supported by the American Cancer
Society (Research Scholar award 09-016-01 CDD). R. L. F. thanks
the NIH for a predoctoral fellowship (F31CA138097), as well as
the Malkin Scholars Program for a cancer research grant. We
thank John Roberts and Michael Wang (NU) for assistance with
X-ray crystallography. Purication support was provided by
the Center for Molecular Innovation and Drug Discovery
ChemCore (supported in part by an NIH instrumentation grant,
S10RR025690) and the Chicago Biomedical Consortium with
support from The Searle Funds at The Chicago Community
Trust (Lever Award). Funding for the NU Integrated Molecular
Structure and Education Research Center (IMSERC) has been
furnished in part by the NSF (CHE-9871268).
Fig. 2 IC50 studies for (ꢀ)-deguelin and (+)-deguelin against a panel of cancer
cell lines. The average IC50 values for each enantiomer are shown in the graph as
well as the table, along with the unpaired t-test values for comparison between
enantiomers.
(leukemia) cells at low micromolar IC50 values, conrming that
this natural product does possess promising anticancer poten-
tial. However, the most interesting nding was that the unnat-
ural enantiomer (+)-deguelin inhibited the growth of both the
MCF-7 and HepG2 cell lines more effectively than the natural
enantiomer (ꢀ)-deguelin (p ¼ 0.006 and p ¼ 0.04, respectively,
by unpaired t-test). In fact, (+)-deguelin was 2-fold more effective
than the natural product against the MCF-7 breast cancer line,
and demonstrated nanomolar activity against the HepG2 cell
Notes and references
1 N. Fang and J. E. Casida, J. Agric. Food Chem., 1999, 47, 2130–
2136.
15
line. Similar to our studies on the abyssinone natural products
which also demonstrated variable biological activity depending
on the conguration of the C2 stereocenter, these initial results
conrm the importance of stereochemical control during the
synthesis of deguelin. Furthermore, since (+)-deguelin has
never been previously tested in biological assays, these
preliminary results demonstrate the therapeutic potential of
2 K.-H. Chun, J. W. Kosmeder, S. Sun, J. M. Pezzuto, R. Lotan,
W. K. Hong and H.-Y. Lee, J. Natl. Cancer Inst., 2003, 95, 291–
302.
3 G. O. Udeani, C. Gerhauser, C. F. Thomas, R. C. Moon,
J. W. Kosmeder, A. D. Kinghorn, R. M. Moriarty and
J. M. Pezzuto, Cancer Res., 1997, 57, 3424–3428.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
Chemical Science
Edge Article
4
5
6
J. Hu, H. Y. Ye, A. Fu, X. A. Chen, Y. S. Wang, X. C. Chen, 24 S. C. Joshi and K. N. Trivedi, Tetrahedron, 1992, 48, 563–570.
X. Ye, W. J. Xiao, X. M. Duan, Y. Q. Wei and L. J. Chen, Int. 25 A. J. Quillinan and F. J. Scheinmann, J. Chem. Soc., Perkin
J. Cancer, 2010, 127, 2455–2466.
Trans. 1, 1972, 1382–1387.
C. Gerhauser, S. K. Lee, J. W. Kosmeder, R. M. Moriarty, 26 R. S. Subramanian and K. K. Balasubramanian, Tetrahedron
E. Hamel, R. G. Mehta, R. C. Moon and J. M. Pezzuto,
Cancer Res., 1997, 57, 3429–3435.
C. Gerhauser, W. Mar, S. K. Lee, N. Suh, Y. Luo, J. Kosmeder,
Lett., 1988, 29, 6797–6800.
27 P. Thomas and D. A. Whiting, Tetrahedron Lett., 1984, 25,
1099–1102.
L. Luyengi, H. H. Fong, A. D. Kinghorn, R. M. Moriarty, et al., 28 S. Yamaguchi, M. Ishibashi, K. Akasaka, H. Yokoyama,
Nat. Med., 1995, 1, 260–266.
N. Fang and J. E. Casida, Proc. Nat. Acad. Sci. U. S. A., 1998,
M. Miyazawa and Y. Hirai, Tetrahedron Lett., 2001, 42,
1091–1093.
7
8
9
9
5, 3380–3384.
29 J. Tsuji, I. Shimizu, I. Minami, Y. Ohashi, T. Sugiura and
K. Takahashi, J. Org. Chem., 1985, 50, 1523–1529.
30 S. J. Connon, Chem. Commun., 2008, 2499–2510.
31 S. J. Connon, Synlett, 2009, 354–376.
J. Garcia, S. Barluenga, K. Gorska, F. Sasse and
N. Winssinger, Bioorg. Med. Chem., 2012, 20, 672–680.
P. B. Anzeveno, J. Org. Chem., 1979, 44, 2578–2580.
1
1
1
0 H. Fukami, J. Oda, M. Nakajima and G. Sakata, Agric. Biol. 32 D. M. X. Donnelly, B. M. Fitzpatrick and J. P. Finet, J. Chem.
Chem., 1961, 25, 252–253. Soc., Perkin Trans. 1, 1994, 1791–1795.
1 H. Fukami, J. Oda, G. Sakata and M. Nakajima, Bull. Agric. 33 B. J. Gwag et al., Salicylic Acid Derivative Compounds and
Chem. Soc. Jpn., 1960, 24, 327–328.
Pharmaceutical Compositions Containing Them, Korea Pat.,
WO2007119984, 2007.
2 H. Omokawa and K. Yamashita, Agric. Biol. Chem., 1974, 38,
1
731–1734.
34 Z. M. Shen, P. K. Dornan, H. A. Khan, T. K. Woo and
V. M. Dong, J. Am. Chem. Soc., 2009, 131, 1077–1091.
1
1
3 S. J. Pastine and D. Sames, Org. Lett., 2003, 5, 4053–4055.
4 J. Garcia, S. Barluenga, K. Beebe, L. Neckers and 35 H. Takikawa and K. Suzuki, Org. Lett., 2007, 9, 2713–
N. Winssinger, Chem.–Eur. J., 2010, 16, 9767–9771. 2716.
5 R. L. Farmer, M. M. Biddle, A. E. Nibbs, X. K. Huang, 36 A. Ahmed, E. K. Hoegenauer, V. A. S. Enev, M. Hanbauer,
1
R. C. Bergan and K. A. Scheidt, ACS Med. Chem. Lett., 2010,
, 400–405.
H. Kaehlig, E. Ohler and J. Mulzer, J. Org. Chem., 2003, 68,
3026–3042.
1
1
1
1
1
2
2
6 M. M. Biddle, M. Lin and K. A. Scheidt, J. Am. Chem. Soc., 37 C. Alemparte-Gallardo, D. Barros-Aguirre, M. Cacho-
2
007, 129, 3830–3831.
Izquierdo, J. M. Flandor-Romanand M. J. Remuinan-
Blanco, Tricyclic Nitrogen Containing Compounds and Their
Use as Antibacterials, US Pat., WO2009141399, 2009.
7 E. A. Crane, T. P. Zabawa, R. L. Farmer and K. A. Scheidt,
Angew. Chem., Int. Ed., 2011, 50, 9112–9115.
8 D. W. Custar, T. P. Zabawa and K. A. Scheidt, J. Am. Chem. 38 H. C. Arndt and S. A. Carroll, Synthesis, 1979, 202–204.
Soc., 2008, 130, 804–805.
9 W. J. Morris, D. W. Custar and K. A. Scheidt, Org. Lett., 2005,
39 E. M. Phillips, M. Wadamoto, H. S. Roth, A. W. Ott and
K. A. Scheidt, Org. Lett., 2009, 11, 105–108.
7
, 1113–1116.
40 G. Speranza, B. Mueller, M. Orlandi, C. F. Morelli, P. Manitto
and B. Schink, Helv. Chim. Acta, 2003, 86, 2629–2636.
41 S. Dratch, T. Charnikhova, F. C. E. Saraber, B. J. M. Jansen
and A. de Groot, Tetrahedron, 2003, 59, 4287–4295.
42 The samples of (ꢀ)-deguelin and (+)-deguelin used in the
cytotoxicity assay were rst puried by preparatory-scale
chiral-phase HPLC to ensure optically pure material for
biological evaluation.
0 T. Marcelli, R. N. S. van der Haas, J. H. van Maarseveen and
H. Hiemstra, Angew. Chem., Int. Ed., 2006, 45, 929–931.
1 L. Luyengi, I. S. Lee, W. Mar, H. H. S. Fong, J. M. Pezzuto and
A. D. Kinghorn, Phytochemistry, 1994, 36, 1523–1526.
22 B. B. Snider and T. Kwon, J. Org. Chem., 1992, 57, 2399–2410.
3 D. Bell, M. R. Davies, G. R. Geen and I. S. Mann, Synthesis,
2
1995, 707–712.
Chem. Sci.
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