Palladium(II)-catalyzed enyne cyclization strategies toward the podophyllotoxin ring system

Article abstract of DOI:10.1016/j.tet.2011.11.002

A functionally enriched ABCD ring system of podophyllotoxin was generated through Pd(II)-templated cyclization of an alkynoic alkene, prepared in five steps from commercially available 6-bromopiperonal. This research expands upon the recent carboesterification methodology of Dong et al. (Angew. Chem., Int. Ed. 2009, 48, 9690-9692) by the application of PdCl₂(MeCN) ₂, LiCl, and CuCl₂ conditions, which yielded the desired podophyllotoxin scaffold with an embedded vinyl chloride moiety. Likewise, these conditions were successfully applied to a propargylic alkene prepared in three steps from 6-bromopiperonal. The resulting product contains the ABCD ring system of podophyllotoxin, but substitutes a D-ring furan for the D-ring lactone. Application of the recent methodology of Lu et al. (J. Org. Chem. 1995, 60, 1160-1169) on a related 1,6-enyne substrate led to functionalized α-methylene γ-butyrolactones instead (Pd₂(dba) ₃·CHCl₃, LiBr, and CuBr₂). The latter conditions applied to an alkynoic alkene afforded the ABCD ring system of podophyllotoxin with a vinyl bromide group. These vinyl halides allow for derivatization at a critical juncture in order to access novel podophyllotoxin analogs.

Full text of DOI:10.1016/j.tet.2011.11.002

Tetrahedron 68 (2012) 423e428
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium(II)-catalyzed enyne cyclization strategies toward the podophyllotoxin
ring system
,
b
c
a
Jason N. Abrams a , Qi Zhao , Ion Ghiviriga , Minaruzzaman
*
a Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive; New Orleans, LA 70125, USA
b Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
c Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A functionally enriched ABCD ring system of podophyllotoxin was generated through Pd(II)-templated
cyclization of an alkynoic alkene, prepared in five steps from commercially available 6-bromopiperonal.
This research expands upon the recent carboesterification methodology of Dong et al. (Angew. Chem., Int.
Ed. 2009, 48, 9690e9692) by the application of PdCl2(MeCN)2, LiCl, and CuCl2 conditions, whichyielded the
desired podophyllotoxin scaffold with an embedded vinyl chloride moiety. Likewise, these conditions were
successfully applied to a propargylic alkene prepared in three steps from 6-bromopiperonal. The resulting
product contains the ABCD ring system of podophyllotoxin, but substitutes a D-ring furan for the D-ring
lactone. Application of the recent methodology of Lu et al. (J. Org. Chem. 1995, 60, 1160e1169) on a related
Received 5 September 2011
Received in revised form 2 November 2011
Accepted 2 November 2011
Available online 10 November 2011
Dedicated to Professor Lu Xiyan on the oc-
casion of his pioneering work on Pd(II)-
catalyzed enyne cyclizations
1,6-enyne substrate led to functionalized a-methylene g-butyrolactones instead (Pd2(dba)3$CHCl3, LiBr,
and CuBr2). The latter conditions applied to an alkynoic alkene afforded the ABCD ring system of podo-
phyllotoxin with a vinyl bromide group. These vinyl halides allow for derivatization at a critical juncture in
order to access novel podophyllotoxin analogs.
Keywords:
Palladium-catalyzed
Enyne cyclization
Carboesterification
Podophyllotoxin
Etoposide
Ó 2011 Elsevier Ltd. All rights reserved.
Anticancer
1. Introduction
utility of the molecule as an anticancer therapy agent. The toxicity
manifests as nausea, diarrhea, vomiting, and injury to healthy tis-
The aryltetralin lactone podophyllotoxin is a member of a group
of lignans for which coniferyl alcohol is a key biosynthetic pre-
cursor via oxidative dimerization.1 Podophyllotoxin is a major
constituent of species of the genus Podophyllum (Berberidaceae). It
is contained in the resin of the roots and rhizomes of two pre-
dominant species: Indian Podophyllum (Podophyllum hexandrum
Royle) and the American Mayapple (Podophyllum peltatum L.).2 In
these plants, it is produced as a secondary metabolite and has been
used as a component of traditional folk medicine in various cul-
tures.3 As illustrated in Fig. 1, podophyllotoxin4 exhibits an in-
triguing architecture with four contiguous chiral centers, a rigid
trans-lactone, and a pseudoaxial E-ring.
sues, including peripheral and autonomic neuropathy. Neverthe-
less, efforts to reduce these side effects led to the discovery of
etoposide (VP-16) 2 as well as teniposide 3, a related thiophene
derivative. Etoposide is an epimeric glucopyranoside analog of
podophyllotoxin in which 40-O-demethyl-4-epipodophyllotoxin
serves as the aglycone (Fig. 2).
In addition to its unique and synthetically challenging structure,
podophyllotoxin exhibits high antimitotic and apoptotic activity
because of its high affinity for tubulin and mitotic spindles of di-
viding cells at metaphase.5 It is this high toxicity that limits the
* Corresponding author. Tel.: þ1 504 520 5075; fax: þ1 504 520 7942; e-mail
address: jabrams@xula.edu (J.N. Abrams).
Fig. 1. Numbering and ring lettering systems of podophyllotoxin.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.002

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J.N. Abrams et al. / Tetrahedron 68 (2012) 423e428
2. Results and discussion
2.1. Initial synthetic route
-Methylene -butyrolactones were selected as simple podo-
a
g
phyllotoxin synthons from which to create novel analogs. Our
initial retrosynthetic strategy toward this goal is outlined below
(Scheme 1). Deoxypodophyllotoxin scaffold
4 is envisioned
coming from methylene lactone Z-5, which can arise through
a pivotal Pd(II)-catalyzed cyclization of allylic alkynoate 6, itself
readily accessible in three steps starting from 5-bromo-1,3-
benzodioxole (7).
Fig. 2. Structure of etoposide (VP-16) and teniposide.
Preliminary work toward this target resulted from the single-
step conversion of p-tolyl acetylene into lithium acetylide using
n-butyllithium, followed by reaction with allyl chloroformate
to give the corresponding enyne 9 (Scheme 2). The newly gen-
erated enyne alkynoate 9 was then treated under conditions
developed by Lu et al.:13 enyne 9 was exposed to tris(dibenzy-
lideneacetone)dipalladium(0) (Pd2(dba)3$CHCl3) in the presence
Etoposide’s mechanism of action represents a good example of
how a simple structural modification can dramatically affect bi-
ologically activity. Due to the bulky glucopyranoside moiety, eto-
poside does not bind to tubulin and does not act as a microtubule
inhibitor, but instead forms a ternary complex with DNA and
topoisomerase II.6 The stability of this complex inhibits topoisom-
erase II from unwinding or untangling DNA, leading to DNA strand
scission and, ultimately, apoptosis. Etoposide has been found clin-
ically effective in the treatment of several cancers, including small-
cell lung carcinoma, testicular cancer, and Kaposi’s sarcoma.
The clinical promise of etoposide as an anticancer agent has,
however, been subject to drug resistance,7 possibly through alter-
ations in apoptotic pathways or decreases in expression of top-
oisomerases,8 poor oral bioavailability,9 and myelosuppression (an
especially high risk in cytotoxic chemotherapy for leukemia).10
Therefore, developing clinically useful analogs of etoposide with
improved selectivity requires a robust and versatile methodology
for their synthesis.
of HOAc, CuBr2, and LiBr to generate
g-lactone 10 with two
bromine atoms that could be further elaborated in an orthogonal
fashion. Unfortunately, the reaction produced two diastereomers
in a roughly 1.5:1 Z/E ratio according to isolated yields and NMR
analysis of the crude reaction mixture. This result contrasts
with Lu’s substituted enyne substrates, which underwent cycli-
zation to provide almost exclusively the Z-exocyclic methylene
diastereomer.
The configurations of the exocyclic methylenes of both Z-10 and
E-10 diastereomers were determined using NOESY analysis.14
2.2. Synthesis of target system
Podophyllotoxin finds limited use as a synthetic precursor to
potent analogs firstly because of its inherent chemical inflexibility
to extensive structural modification. Secondly, the plant source
with the highest podophyllotoxin content, P. hexandrum Royle, is
overharvested and is considered an endangered species.11
Our group is interested in exploiting the unique reactivity of
alkynes by incorporating recently developed methods into novel
reaction sequences. Alkynes not only undergo a variety of func-
tional group transformations but also often participate in tandem/
cascade reaction processes in which several bonds are produced in
a single operation. By exploiting the latter feature for step econ-
omy,12 our group has focused on the pursuit of a synthetic strategy
leading toward the ABCD ring scaffold of podophyllotoxin, which
should allow for the preparation of novel analogs in a rapid and
efficient manner.
5-Bromo-1,3-benzodioxole 7 was treated with TMS-acetylene
under Sonogashira conditions to form aryl acetylene 11 (Scheme
3). The alkyne moiety of this intermediate was subsequently
deprotected under standard conditions to form terminal alkyne 12,
which was then transformed into the desired enyne 6 through
lithium acetylide formation, followed by coupling with allyl
chloroformate. Upon exposure to in situ generated Pd(II)-templated
cyclization conditions according to Lu’s protocol, a-methylene g-
butyrolactones were formed cleanly and were isolated chromato-
graphically in a 1.5:1 Z/E stereoisomeric ratio, as before in the
simpler model system.14
Z-configured methylene lactones (Z-5 and Z-10) contain two
orthogonally reactive halides providing a concise route toward
the target tetralin scaffold of podophyllotoxin. Accordingly, in an
Scheme 1. Retrosynthetic strategy toward ABCD rings of deoxypodophyllotoxin.
Scheme 2. Synthesis of model a-methylene g-butyrolactone.

J.N. Abrams et al. / Tetrahedron 68 (2012) 423e428
425
Scheme 3. Formation of target enyne system followed by Pd(II)-catalyzed cyclization.
initial elaboration study, the vinyl bromide of the more readily
2.3. Second-generation retrosynthetic strategy
accessible Z-10 was successfully reacted with trimethoxyphenyl
boronic acid under typical Suzuki conditions to form diaryl
methylene lactone 13, albeit on an unoptimized small scale
(Scheme 4), while 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-in-
duced alkyl dehydrohalogenation appeared to provide exo-
methylene product 14, according to 1H NMR analysis of the crude
reaction mixture. Nevertheless, subsequent attempts at purifi-
cation proved unfruitful.
Therefore, another strategy was required, one that utilized an
alternative Pd(II)-catalyzed enyne cyclization involving intra-
molecular carboesterification of an alkynoic alkene15 and occurring
via a formal [3þ2] cycloaddition pathway. With the ABCD ring
scaffold in hand, the vinyl halide moiety might be transformed into
a variety of E-rings under Suzuki16 conditions with arylboronic
acids serving as the coupling partner (Fig. 3).
Retrosynthetically, as shown in Scheme 5, functionally enriched
scaffold 15 was envisioned coming from alkynoic alkene 16 via
Pd(II)-catalyzed intramolecular carboesterification. In turn, sub-
strate 16 could be arrived at expeditiously by protection of the al-
lylic alcohol of substrate 17, coupling of terminal alkyne with
a chloroformate, and then saponification of the resulting alkynoate
ester. And alkyne 17 could arise via vinyl Grignard addition to 6-
bromopiperonal (18), followed by a Sonogashira reaction17 be-
tween an aryl bromide and TMS-acetylene.
Scheme 4. Elaboration of model a-methylene g-butyrolactone Z-10.
2.4. Synthesis of target system
We envisioned the possibility of convergence of our
a-methy-
lene -butyrolactone advanced substrate with end-game strategies
g
According to the retrosynthetic path depicted, synthesis began
with inexpensive, commercially available 6-bromopiperonal 18
(Scheme 6). Vinyl Grignard addition to 18 cleanly provided allylic
alcohol 19 in high yield. Substrate 19 was next subjected to Sono-
gashira reaction conditions with TMS-acetylene to provide phenyl
acetylene 20, which was smoothly converted into terminal alkyne
that have recently been employed. However, as discussed, a tech-
nical hurdle surfaced: a lack of diastereocontrol during the trans-
formation of our allylic alkynoate substrates. This was evidenced by
the resulting product mixtures, with both E and Z double bond
geometry on the exocyclic alkene.
Fig. 3. Formal [3þ2] cycloaddition of alkynoic alkene and subsequent elaboration.
Scheme 5. Alternative Pd(II)-catalyzed enyne cyclization retrosynthetic strategy.

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J.N. Abrams et al. / Tetrahedron 68 (2012) 423e428
Scheme 6. Construction of cyclization precursor alkynoic alkene 16.
17. The alcohol moiety of 17 was next protected with TBS chloride to
furnish silyl ether 21.18 In this regard, substrate 21 was first con-
verted into the requisite lithium acetylide before addition of allyl
chloroformate to form alkynoate 22.19 Finally, alkynoate 22 was
transformed into alkynoic alkene 16, the Pd(II)-catalyzed cyclization
precursor, under typical saponification conditions. Interestingly, the
in situ generated lithium acetylide of terminal alkyne 21 can be
exposed to dry ice, rather than a chloroformate source, to form
substrate 16 directly, thereby eliminating one step.20
which supports a cis configuration. In addition, a smaller coupling
constant (J¼3.8 Hz) between HD and HC in the 1H NMR spectrum is
also consistent with this finding.
2.5. Synthesis of target system part II
We were also interested in subjecting alkynoic alkene 16 to the
Pd(II)-catalyzed cyclization conditions originally used for the
preparation of our
a-methylene g-butyrolactones. To this end,
Synthesis of scaffold 15 from alkynoic acid 16 was carried out
under conditions recently identified by Dong et al. regarding
palladium-catalyzed intramolecular carboesterification of olefins.15
Accordingly, a stock solution of PdCl2(MeCN)2 in acetonitrile
was added to alkynoic acid 16, LiCl, and CuCl2 in acetonitrile
(Scheme 7). Complete consumption of the starting material was
effected by stirring at 50 ꢀC for 24e48 h to afford 15. The proposed
mechanism for this palladium-catalyzed intramolecular carboes-
terification is virtually analogous to that reported originally by Lu
et al. for allylic alkynoates.13
alkynoic alkene 16 was treated with 5 mol % Pd2(dba)3$CHCl3, along
with 6 equiv of lithium bromide and 3 equiv of copper(II) bromide,
while stirring at room temperature in glacial acetic acid (Scheme 8).
The reaction was monitored by TLC for disappearance of the
starting material. Cyclized product 23 has the same relative ste-
reochemistry in comparison to cyclized product 15.
Scheme 8. Cyclization of alkynoic alkene 16 to tetralin scaffold 23.
2.6. Synthesis of simpler system
Scheme 7. Cyclization of alkynoic alkene 16 to tetralin scaffold 15.
Podophyllotoxin-related compounds containing a trans-fused
delactonized ring-D were prepared by Gensler et al.22 The non-
enolizable nature of these analogs allowed them to have enhanced
physiological lifetimes as a consequence of minimized metabolic C-2
epimerization. Most retained activity as tubulin polymerization in-
hibitors, although with less pronounced cytotoxicity.
We only discerned and isolated a single diastereomer, with a cis-
relative configuration of hydrogens on C3eC4 of the ring junction
D/C and ring-C, respectively. The structure of 15 was definitively
established by NMR studies.21
In the 1D selective nuclear Overhauser effect (NOE) spectra,
with selective irradiation at
d
3.51 ppm (HC), a very strong doublet
With this in mind, and to further explore the opportunity of
preparing podophyllotoxin scaffolds in a step-economical fash-
ion,12 we investigated the cyclization of propargylic species 25,
which is readily accessible in only three steps starting from 6-
bromopiperonal (Scheme 9).
at 4.56 ppm (HD) was observed (Fig. 4). This strong NOE effect
d
between HD and HC shows that both protons are close in space,
The previously described method for the preparation of allyl
alcohol 19 was followed by protection of the resulting free alcohol
with TBS chloride to form silyl ether 24. This species was then
subjected to Sonogashira reaction conditions with propargyl alco-
hol to form the desired cyclization precursor 25. Sonogashira cross-
coupling occurred in modest yield via
a recently described
procedure.23
These atypical conditions employed Pd2(dba)3$CHCl3, copper
iodide, n-butylamine, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
Fig. 4. Conformational analysis of product 15.

J.N. Abrams et al. / Tetrahedron 68 (2012) 423e428
427
Scheme 9. Cyclization of propargyl alcohol substrate 25 to tetralin scaffold 26.
pyrimidinone (DMPU) as the reaction solvent. The reaction mixture
was heated at 80 ꢀC in a sealed tube for 24 h to provide substrate 25
in moderate yield. Subsequent conversion of 25 into product 26
employed the same conditions as the cyclization of carboxylic acid
substrate 16. The relative configuration of product 26 was assigned
by comparison of its NMR spectra with that of products 15 and 23.
As an aside, our initial efforts to utilize traditional Sonogashira
reaction conditions (PdCl2(PPh3)2, triethylamine, copper iodide,
and DMF) (Scheme 9) between substrate 24 and propargyl alcohol
led to poor yield. We therefore attempted conversion of 24 into an
iodinated species, envisioning its enhanced cross-coupling ability.
In this manner, lithiumehalogen exchange was promoted with the
addition of n-butyllithium followed by the addition of iodine.
However, the intended iodinated product was not produced, as
most of the reaction formed silane species 27, via a retro-Brook
rearrangement (Scheme 10).24 This result led us to investigate our
currently employed Sonogashira conditions.23
variation at a late stage. This should facilitate the continual dis-
covery of biologically active podophyllotoxin derivatives.29
Future work will entail tuning the reaction conditions to im-
prove the yield of desired scaffolds.30 Such optimization will en-
hance this strategy’s potential for use in the development of
therapeutic leads through function-oriented synthesis (FOS)12 in an
atom-economic fashion.31 This could be particularly applicable to
the simpler sequence leading to substrate 26. In addition to im-
proving the yield of desired products, future work will also explore
other relevant transformations of ABCD ring scaffolds.32
Acknowledgements
We gratefully acknowledge the Louisiana Cancer Research
Consortium (LCRC), the Research Centers for Minority Institutes
(RCMI) (NIH 1G12RR026260), and Center for Undergraduate Re-
search (CUR) for funding for this project. We are especially thankful
for the time afforded on the 500-MHz Bruker NMR spectrometer at
Tulane University’s Coordinated Instrument Facility as well as the
NMR instrument facility at the University of New Orleans. We thank
the University of Florida Mass Spec Services, and in particular, Dr.
David H. Powell, Dr. Maria C. Dancel, Dr. Jodie Johnson, and Noelle
Elliott for all the mass spectral data. We are also thankful to Dr. Neil
R. McIntyre of Xavier University for his editing suggestions. Finally,
we acknowledge the RCMI core at Xavier University.
Scheme 10. Formation of retro-Brook rearrangement product.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.11.002.
3. Conclusions
This paper reports the preparation of
a-methylene g-butyr-
References and notes
olactones from alkenyl propynoates. The inability to transform
these products into the desired ABCD ring scaffold of podophyllo-
toxin led our group to focus on cyclization studies of alkynoic al-
kene substrate 16. To this end, we employed two similar catalytic
systems, which yielded tetralin products 15 and 23. Cyclization
studies on a simpler substrate 25 also led to tetralin product 26.
Therefore, this study demonstrates the feasibility of exploiting the
properly embedded vinyl halide functionality to elaborate sub-
strates 15 or 23 or 26 toward podophyllotoxin and etoposide de-
rivatization via cross-coupling protocols.
Our racemic approach toward the podophyllotoxin ABCD ring
system is unique in several respects.25 Some previous syntheses
utilize more labile intermediates26 or a large number of steps,27
thus thwarting the economical feasibility of large-scale pro-
duction. The E-ring is considered a crucial moiety for podophyllo-
toxin’s biological activity. Contemporary strategies introduce the
pendent E-ring at an early stage,28 hampering the ability to prepare
analogs at this position. By contrast, this study developed a modu-
lar synthetic route that allows for the introduction of E-ring
1. (a) Yousefzadi, M.; Sharifi, M.; Behmanesh, M.; Moyano, E.; Bonfill, M.; Cusido,
R. M.; Palazon, J. Eng. Life Sci. 2010, 10, 281e292; (b) Canel, C.; Moraes, R. M.;
Dayan, F. E.; Ferreira, D. Phytochemistry 2000, 54, 115e120.
2. (a) Ayres, D. C.; Loike, J. D. In Lignans: Chemical, Biological and Clinical Properties
(Chemistry and Pharmacology of Natural Products); Phillipson, J. D., Ayres, D. C.,
Baxter, H., Eds.; Cambridge University: Cambridge, UK, 1990; (b) Gordaliza, M.;
ꢀ
García, P. A.; Miguel del Corral, J. M.; Castro, M. A.; Gomez-Zurita, M. A. Toxicon
2004, 44, 441e459.
3. Fukuda, Y.; Osawa, T.; Namiki, M.; Ozaki, T. Agric. Biol. Chem. 1985, 49, 301e306.
4. Liu, Y. Q.; Yang, L.; Tian, X. Curr. Bioact. Compd. 2007, 3, 37e66.
5. (a) Loike, J. D.; Horwitz, S. B. Biochemistry 1976, 15, 5435e5443; (b) Loike, J. D.;
Brewer, C. F.; Sternlicht, H.; Gensler, W. J.; Horwitz, S. B. Cancer Res. 1978, 38,
2688e2693.
6. (a) Meresse, P.; Dechaux, E.; Monneret, C.; Bertounesque, E. Curr. Med. Chem.
2004, 11, 2443e2466; (b) Issell, B. F.; Tihon, C.; Curry, M. E. Cancer Chemother.
Pharmacol. 1982, 7, 113e115; (c) Minocha, A.; Long, B. H. Biochem. Biophys. Res.
Commun. 1984, 122, 165e170.
7. Helmbach, H.; Kern, M. A.; Rossmann, E.; Renz, K.; Kissel, C.; Gschwendt, B.;
Schadendorf, D. J. Invest. Dermatol. 2002, 118, 923e932.
8. Asano, T.; An, T.; Mayes, J.; Zwelling, L. A.; Kleinerman, E. S. Biochem. J. 1996,
319, 307e317.
9. Etoposide phosphate was designed by BristoleMyers Squibb as a pro-drug with
greater water solubility than etoposide, it can be administered intravenously at

428
J.N. Abrams et al. / Tetrahedron 68 (2012) 423e428
higher doses and is rapidly converted by phosphatases in the plasma to eto-
24. For spectral data of the silane compound, see Supporting Information, p 10. For
an original reference, see: (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77e84; (b) For
a review relating to [1,4] and [1,5] Brook and retro-Brook rearrangements, see
Lautens, M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H. J. Org. Chem. 1995, 60,
4213e4227.
25. Below are representative examples of entry to podophyllotoxin and related
compounds. For routes involving intramolecular cycloaddition/DielseAlder
reactions of substituted o-quinodimethanes, see: (a) Jung, M. E.; Yuk-Sun Lam,
P.; Mansuri, M. M.; Speltz, L. M. J. Org. Chem. 1985, 50, 1087e1105; (b) Mac-
donald, D. I.; Durst, T. J. Org. Chem. 1986, 51, 4749e4750; (c) Kraus, G. A.; Wu, Y.
J. Org. Chem. 1992, 57, 2922e2925. For other DielseAlder approaches, see: (d)
Bush, E. J.; Jones, D. W. C. S. J. Chem. Soc., Chem. Commun. 1993, 1200e1201. For
tandem-conjugate addition routes, see: (e) Wu, Y.; Zhao, J.; Chen, J.; Pan, C.; Li,
L.; Zhang, H. Org. Lett. 2009, 11, 597e600; (f) Hadimani, S. B.; Tanpure, R. P.;
Bhat, S. V. Tetrahedron Lett. 1996, 37, 4791e4794; (g) Harrowven, D. C. Tetra-
hedron 1993, 49, 9039e9048; (h) Stadler, D.; Bach, T. Angew. Chem., Int. Ed.
poside. For another analog with twice the water solubility of etoposide, see
Yoshida, M.; Kobunai, T.; Aoyagi, K.; Saito, H.; Utsugi, T.; Wierzba, K.; Yamada, Y.
Clin. Cancer Res. 2000, 6, 4396e4401.
10. Kobayashi, K.; Ratain, M. J. Cancer Chemother. Pharmacol. 1994, 34, S64eS68.
11. Alam, M. A.; Gulati, P.; Gulati, A. K.; Mishra, G. P.; Naik, P. K. Indian J. Biotechnol.
2009, 8, 391e399.
12. Wender, P. A.;Verma, V.A.;Paxton, T. J.;Pillow, T. H.Acc. Chem. Res. 2008, 41, 40e49.
13. Ji, J.; Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 1160e1169.
14. NOESY and gHMBC NMR analyses were performed on all a-methylene g-bu-
tyrolactones. See Supplementary data, Chemical Shift Assignments, Com-
pounds E-5, E-10, Z-5, Z-10, pp 12e13.
15. Li, Y.; Jardine, K. J.; Tan, R.; Song, D.; Dong, V. M. Angew. Chem., Int. Ed. 2009, 48,
9690e9692.
16. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437e3440;
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2483. For recent studies,
see: (c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020e4028; (d)
Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685e4696.
2008, 47, 7557e7559;
ˇ (i) For a palladium-catalyzed approach, see Charruault,
L.; Michelet, V.; Genet, J.-P. Tetrahedron Lett. 2002, 43, 4757e4760; (j) For an
aryl radical cyclization approach, see Ishibashi, H.; Ito, K.; Hirano, T.; Tabuchi,
M.; Ikeda, M. Tetrahedron 1993, 49, 4173e4182.
17. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467e4470.
18. Initially, substrate 17 was treated with 2.1 equiv of n-butyllithium, followed by
26. For example, see Ref. 25b.
1
equiv of allyl chloroformate, yet produced exclusively the undesired
27. Many syntheses employ at least 13 steps or more from commercially available
starting materials: see citations in Ref. 25. For a review of synthetic approaches
to the Podophyllum lignans, see: (a) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75e96;
(b) Ward, R. S. Phytochem. Rev. 2003, 2, 391e400.
28. The majority of studies cited in Ref. 25. install the E-ring at an early stage.
29. For brief reviews of E-ring modifications to podophyllotoxin, see: (a) Ref. 2b.
For studies validating the functional importance of the E-ring of etoposide, see:
(b) Wilstermann, A. M.; Bender, R. P.; Godfrey, M.; Choi, S.; Anklin, C.; Berko-
witz, D. B.; Osheroff, N.; Graves, D. E. Biochemistry 2007, 46, 8217e8225.
30. The major byproduct from transformation of 16 into 15 has been isolated.
Extensive spectral analysis has lead to its tentative assignment as a tetralone
cyclopropane. See Supplementary data, pp 15e16.
carbonate.
19. Ethyl chloroformate was also employed to form the corresponding ethyl enyne
alkynoate. However, the subsequent saponification appeared to proceed more
smoothly with the analogous allyl enyne alkynoate.
20. Ganolix Lifescience recently prepared substrate 16 for our group using this
route. These materials are allocated for future analog development with the
Louisiana Cancer Research Consortium (LCRC) Molecular Biology Core. See
Supplementary data, p 4.
21. These structural elucidations were performed through a combination of HMBC
and NOESY NMR techniques. See Supplementary data, Chemical Shift Assign-
ments Compounds 15, pp 11e12.
22. Walter, J.; Gensler, W. J.; Murthy, C. D.; Trammell, M. H. J. Med. Chem. 1977, 20,
31. Trost, B. M. Science 1991, 254, 1471e1477.
635e644.
32. For example, spectral evidence for the conversion of the D-ring lactone moiety
of substrate 15 into a lactam derivative has been found. See Supplementary
data, p 16.
23. Houpis, I. N.; Shilds, D.; Nettekoven, U.; Schnyder, A.; Bappert, E.; Weerts, K.;
Canters, M.; Vermuelen, W. Org. Process Res. Dev. 2009, 13, 598e606.