New picropodophyllin analogs via palladium-catalyzed allylic alkylation-Hiyama cross-coupling sequences

Article abstract of DOI:10.1021/jo800707q

(Chemical Equation Presented) Unsaturated malonyl esters underwent Pd-catalyzed intramolecular allylic alkylation to give 4-vinyl-substituted γ-lactones. In contrast to the formerly studied cyclization of malonamides, this reaction could be achieved only

Full text of DOI:10.1021/jo800707q

New Picropodophyllin Analogs via Palladium-Catalyzed Allylic
Alkylation-Hiyama Cross-Coupling Sequences
Maxime Vitale,† Guillaume Prestat,*,† David Lopes,† David Madec,† Claire Kammerer,†
Giovanni Poli,*,† and Leonard Girnita‡
UPMC UniV Paris 06, UMR CNRS 7611 Laboratoire de Chimie Organique, FR2769 Institut de Chimie
Mole´culaire, case 183, F-75005 Paris, France, Department of Oncology-Pathology, Cellular and
Molecular Tumor Pathology, Cancer Center Karolinska R8:04, Karolinska UniVersity Hospital and
Karolinska Institutet, Stockholm, Sweden
gioVanni.poli@upmc.fr; guillaume.prestat@upmc.fr
ReceiVed April 2, 2008
Unsaturated malonyl esters underwent Pd-catalyzed intramolecular allylic alkylation to give 4-vinyl-
substituted γ-lactones. In contrast to the formerly studied cyclization of malonamides, this reaction could
be achieved only with a substrate incorporating a suitably positioned silicon moiety, which directs the
ionization toward the desired η3-allylpalladium complex. The resulting 4-[dimethyl-(2-thienyl)silylvi-
nyl]lactone could be subsequently engaged into Hiyama couplings with various iodoarenes, to give the
corresponding 4-(R-styryl)-γ-lactones. The use of a specifically substituted iodoarene generated an advanced
tetracyclic lactone intermediate incorporating rings A-D of lignans belonging to the podophyllotoxin
family. Subsequent electrophilic aromatic substitution with a variety of electron-rich arenes afforded the
target picropodophyllin analogs.
Introduction
A few years later, the concatenation of such cyclization with
a suitably conceived intramolecular Mizoroki-Heck coupling
set the stage for the synthesis of a lactam analog of the
podophyllotoxin family.4
In 1998 we reported a stereoselective approach toward 3,4-
disubstituted γ-lactams based on the intramolecular palladium-
catalyzed allylic alkylation of unsaturated amides (eq 1).1
Interestingly, such cyclizations took place exclusively via a
5-exo process. This result is in contrast with what was observed
by Tsuji2 and Pfalz3 with analogous ꢀ-ketoesters precursors,
which led competitively to 5-exo and 7-endo products. Such a
method was revealed to be very effective for the synthesis of a
variety of substituted γ-lactams and totally stereoselective in
favor of the trans diastereomer.
(1)
Podophyllotoxin (Figure 1, left) is a well-known natural
product showing high affinity for tubulin.5 Its action halts
cellular division during mitosis, which in turn triggers cellular
death.6 However, the use of this molecule as a anticancer agent
† UPMC Univ Paris 6.
‡ Karolinski Institutet.
(1) Giambastiani, G.; Pacini, B.; Porcelloni, M.; Poli, G. J. Org. Chem. 1998,
63, 804–807.
(2) Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron Lett.
1980, 21, 1475–1478.
(3) Koch, G.; Pfaltz, A. Tetrahedron: Asymmetry 1996, 7, 2213–2216.
(4) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456–9459.
J. Org. Chem. 2008, 73, 5795–5805 5795
10.1021/jo800707q CCC: $40.75
Published on Web 06/25/2008
2008 American Chemical Society

Vitale et al.
SCHEME 1. Synthesis of
(()-Demethoxyepiisopicropodophyllin
FIGURE 1. Structure of podophyllotoxin and picropodophyllin.
is hampered as a result of its high toxicity and secondary effects
such as nausea, diarrhea, vomiting, and injury of healthy tissues.7
As a consequence, several modifications of podophyllotoxin
structure have been accomplished with the aim of reducing its
toxicity. Structure-activity relationship (SAR) studies8 estab-
lished that the 2,3-trans junction of the lactone is necessary,
whereas the presence of methoxy groups on the E aromatic cycle
appears not to be compulsory for antimitotic activity.9
A few years ago we disclosed the synthesis of an original
aza-analog of podophyllotoxin exploiting the above cited method
as the key step.4 The synthesis started with the benzhydrylation10
of a suitable unsaturated amide, according to a protocol
previouslydevelopedinourlaboratory.Subsequentpseudo-domino4,11
Pd-catalyzed intramolecular allylic alkylation/Mizoroki-Heck
sequence gave the desired pentacyclic structure. Finally, Krapcho
decarboxylation followed by double bond oxidative cleavage
and reduction of the resulting keto function afforded the final
aza-analog (Scheme 1).
SCHEME 2. Possible Paths for the Ester Precursor under
Pd(0) Catalysis
As a logical continuation of this project, we next envisaged
to replace the amide function with an ester, so as to target
γ-lactones instead of γ-lactams.12 In particular, we were
interested in the synthesis of 4-(R-styryl)-γ-lactones13 as
potential precursors of new podophyllotoxin analogs as well as
biologically interesting lignan derivatives.14
Although such a modification is seemingly trivial, a number
of challenges become apparent: (a) The new substrate incor-
porates two allylically disposed leaving groups. As a conse-
quence, oxidative addition of the substrate to Pd(0) may take
an alternative path that cleaves the precursor (Scheme 2, path
a). (b) A switch from a tertiary amide to an ester precursor may
(5) Reviews: (a) Damayanthi, Y.; Lown, J. W. Curr. Med. Chem. 1998, 5,
205–252. (b) Zhang, Y.; Lee, K.-H. Chin. Pharm. J. 1994, 46, 319–369. (c)
Ramos, A. C.; Pelae´z-Lamamie´ de Clairac, R.; Medarde, M. Heterocycles 1999,
51, 1443–1470. (d) Ward, R. S. Chem. Soc. ReV. 1982, 75–125. (e) Ward, R. S.
Synthesis 1992, 719–730. (f) Sellars, J. D.; Steel, P. G. Eur. J. Org. Chem. 2007,
3815–3828. (g) Gordaliza, M.; Garc´ıa, P. A.; Miguel del Corral, J. M.; Castro,
M. A.; Go´mez-Zurita, M. A. Toxicon 2004, 44, 441–459.
(6) (a) Cortese, F.; Bhattacharyya, B.; Wolff, J. J. Biol. Chem. 1977, 252,
1134–1140. (b) Andreu, J. M.; Timasheff, S. N. Biochemistry 1982, 21, 6465–
6476. (c) Sackett, D. L. Pharm. Ther. 1993, 59, 163–228.
dramatically lower the proportion of the conformer(s) having a
suitable geometry for cyclization (Scheme 2, path b).15 (c)
Although with the lactam precursor the caprolactam correspond-
ing to a 7-endo mode of cyclization was not observed, a
corresponding lactone precursor may not be as regioselective,
giving a mixture of the desired 5-exo and undesired 7-endo
product (Scheme 2, path c).16 As a consequence, the success of
such a deceptively simple variant could not be taken for granted
at the outset.
(7) Kelly, M. G.; Hartwell, J. L. J. Nat. Cancer Inst. 1954, 14, 967–1010.
(8) (a) Zhang, Y.; Lee, K.-H. Chin. Pharm. J. 1994, 46, 319–369. (b)
Damayanthi, Y.; Lown, J. W. Curr. Med. Chem. 1998, 5, 205–252. (c) Xiao,
Z.; Xiao, Y.-D.; Feng, J.; Golbraikh, A.; Tropsha, A.; Lee, K.-H. J. Med. Chem.
2002, 45, 2294–2309.
(9) Berkowitz, D. B.; Maeng, J.-H.; Dantzig, A. H.; Shepard, R. L.; Norman,
B. H. J. Am. Chem. Soc. 1996, 118, 9426–9427.
(10) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823–1826.
(11) (a) Lemaire, S.; Prestat, G.; Giambastiani, G.; Madec, D.; Pacini, B.;
Poli, G. J. Organomet. Chem. 2003, 687, 291–300. (b) Prestat, G.; Poli, G.
Chemtracts: Org. Chem. 2004, 17, 97–103. (c) Kammerer, C.; Prestat, G.;
Gaillard, T.; Madec, D.; Poli, G. Org. Lett. 2008, 10, 405–408.
(12) Mingoia, F.; Vitale, V.; Madec, D.; Prestat, G.; Poli, G. Tetrahedron
Lett. 2008, 49, 760–763.
(15) Esters are known to prefer the s-trans conformation, which does not
possess the correct geometry for cyclization. (a) Deslongchamps, P. Stereoelec-
tronic Effects in Organic Chemistry; Pergamon Press: Oxford, 1984. (b) Jung,
M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224–232. For a radical cyclization
concerning an ester precursor see, for example: (c) Yorimitsu, H.; Nakamura,
T.; Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J. Am. Chem. Soc.
2000, 122, 11041–1047.
(13) See, for example: Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J.
Org. Chem. 2002, 67, 1738–1745.
(14) For a preliminary account on this work, see:(a) Vitale, M.; Prestat, G.;
Lopes, D.; Madec, D.; Poli, G. Synlett 2006, 2231–2234.
5796 J. Org. Chem. Vol. 73, No. 15, 2008

Picropodophyllin Analogs Via Palladium-Catalyzed Sequences
TABLE 1. Preliminary Essays of Cyclizationa
SCHEME 3. Control of Regioselectivity in the Ionization
rather low yield (Table 1, entry 5). This result suggested that
the released malonate moiety may participate in other undesired
intramolecular processes.
entry
1
R1
R2
prod (%)
methodb
1
2
3
4
5
1a
1b
1b
1c
1d
H
H
H
H
Y
CH2OAc
CH2OCO2Me
CH2OCO2Me
A
B
C
B
A
We speculated that the failure of 1a and 1b to cyclize could
be mainly due to the regioselective generation of the undesired
η3-allylic complex. Accordingly, we decided to bias such
substrates toward the desired pathway. Malacria and Thorimbert
have reported that the ionization of 1,4-diallyl systems carrying
a triethylsilyl group on one of the vinylic carbon atoms takes
place with complete chemoselectivity, so as to expel the acetoxy
group vicinal to the silicon atom (Scheme 3).21
3c (25)
2 (25)
Y
H
a Y ) CH2OCOCH2CO2Me. b Method A: NaH (1.0 equiv), Pd(OAc)2
(5 mol %), dppe (10 mol %), 1.5 h, DMF, 80 °C. Method B: as method
A, at 60 °C. Method C: Pd(OAc)2 (5 mol %), dppe (10 mol %), 1.5 h,
DMF, 60 °C. c 1:1 diastereomeric mixture.
We thus decided to test the above silicon effect in the hope
to direct ionization of our precursor toward the desired site.22
Accordingly, starting from the commercially available butyn-
1,4-diol, the silicon-substituted precursors 8a-c were synthe-
sized for subsequent cyclization tests. Platinum-catalyzed syn-
hydrosilylation23 of butyn-1,4-diol followed by regioselective
silylation and acetylation gave the fully protected intermediate
6. Desilylation followed by standard malonylation afforded the
first precursor 8a. A three-step sequence entailing generation
of the monomethylcarbonate 9, regioselective hydrosilylation
to give the allylic alcohol 10, and malonylation gave carbonate
8b. Finally, 8c was prepared via dimalonylation of the starting
diol, followed by syn-hydrosilylation of the corresponding
tetraester 11 (Scheme 4).
From a synthetic point of view, we were particularly
interested in the development of new analogs possessing the
picropodophyllin cis configuration (Figure 1, right).17 Indeed,
this podophyllotoxin epimer, although having no activity against
tubuline,18 showed inhibitory activity against insulin-like growth
factor 1 receptor (IGF-1R),19 which plays a crucial role in the
transformation, growth, and survival of malignant cells. As a
consequence, the development of more potent IGF-1R inhibitors
appears a new challenge in the fight against cancer.
Results and Discussion
Unsaturated esters 1a-d were first prepared according to
known procedures. Treatment of the acetate precursor 1a or the
carbonate 1b under reaction conditions analogous to those used
to cyclize the lactam precursors gave only degradation products
(Table 1, entries 1 and 2). On the other hand, in the absence of
base, 1b gave the undesired rearranged lactone 3 as the only
isolated product (Table 1, entry 3).20
To circumvent the above-mentioned regioselectivity problem,
we first tested the corresponding dimalonyl derivatives as the
precursors. In the event, the Z-configured 1c precursor gave a
complicated mixture devoid of 2 (Table 1, entry 4), whereas
the E-configured isomer 1d afforded the desired lactone 2 in a
To our delight, our first cyclization attempt using substrate
8a gave diastereoselectively the trans diastereomer of lactone
12 in a satisfactory yield (Table 2, entry 1).
The desired lactone 12 was also obtained using carbonate
8b in the presence (Table 2, entry 2) as well as in the absence
(Table 2, entry 3) of base. The readily available dimalonyl
derivative 8c was also easily cyclized. This result confirms the
good leaving group ability of the malonyl moiety and suggests
that the silicon moiety not only assists the η3-allylpalladium
complex formation but also inhibits the side reactions mentioned
above (compare Table 1, entry 4 with Table 2, entry 4). Finally,
a test with substrate 8c indicated that the amount of catalyst
could be decreased without any loss of efficiency (Table 2, entry
5).24
(16) (a) Norrby, P.-O.; Mader, M. M.; Vitale, M.; Prestat, G.; Poli, G.
Organometallics 2003, 22, 1849–1855. Erratum: 2006, 25, 4234. (b) Madec,
D.; Prestat, G.; Martini, E.; Fristrup, P.; Poli, G.; Norrby, P.-O. Org. Lett. 2005,
7, 995–998.
(17) For recent synthetic approaches, see: (a) Berkowitz, D. B.; Choi, S.;
Maeng, J.-H. J. Org. Chem. 2000, 65, 847–860. (b) Meresse, P.; Monneret, C.;
Bertounesque, E. Tetrahedron 2004, 60, 2657–2671. (c) Dorbec, M.; Florent,
J. C.; Monneret, C.; Rager, M.-N.; Bertounesque, E. Tetrahedron 2006, 62,
11766–11781. See also: (d) Pullin, R. D. C.; Sellars, J. D.; Steel, P. G. Org.
Biomol. Chem. 2007, 5, 3201–3206.
(21) (a) Thorimbert, S.; Malacria, M. Tetrahedron Lett. 1996, 37, 8483–
8486. (b) Commandeur, C.; Thorimbert, S.; Malacria, M. J. Org. Chem. 2003,
68, 5588–5592. (c) Branchadell, V.; Moreno-Man˜as, M.; Pleixats, R.; Thorimbert,
S.; Commandeur, C.; Boglio, C.; Malacria, M. J. Organomet. Chem. 2003, 687,
337–345. (d) Thorimbert, S.; Tailler, C.; Bareyt, S.; Humilie`re, D.; Malacria,
M. Tetrahedron Lett. 2004, 45, 9123–9126. (e) Boglio, C.; Stahike, S.;
Thorimbert, S.; Malacria, M. Org. Lett. 2005, 7, 4851–4854.
(18) Seidlova-Masinova, V.; Malinsky, J.; Santavy, F. J. Natl. Cancer Inst.
1957, 18, 359–371.
(19) See, for example: (a) Girnita, A.; Girnita, L.; del Prete, F.; Bartolazzi,
A.; Larsson, O.; Axelson, M. Cancer Res. 2004, 64, 236–242. (b) Girnita, A.;
All-Ericsson, C.; Economou, M. A.; Åstro¨m, K.; Axelson, M.; Seregard, S.;
Larsson, O.; Girnita, L. Clin. Cancer Res. 2006, 12, 1383–1391. (c) Colo´n, E.;
Zaman, F.; Axelson, M.; Larsson, O.; Carlsson-Skwirut, C.; Svechnikov, K. V.;
So¨der, O. Endocrinology 2007, 148, 128–139. (d) Karolinska Innovations AB;
Larsson, O.; Axelson, M. PCT Int. Appl. WO 02/102804, 2002. (e) Echeverria,
C. G. In Topics in Medicinal Chemistry; Bradbury, R. H., Ed.; Springer-Verlag:
Berlin, Heidelberg Germany, 2007; pp 169-206.
(22) Inspection of molecular models of the silylated substrate 8 suggests that
the allylic C-O bond vicinal to silicon is likely to be forced by the bulky Et3Si
group to be almost orthogonal to the CdC, whereas the distal allylic C-O bond
is not expected to suffer such a restriction. Since the oxidative addition of allylic
acetates to Pd(0) is known to be operative only if the substrate can adopt an
orthogonal CdC/C-O disposition, ( Fiaud, J. C.; Aribi-Aouioueche, L. J. Chem.
Soc., Chem. Commun. 1986, 390–391) it appears that the silylated substrates 8
might be intrinsically biased to expel the vicinal rather than the distal allylic
leaving group.
(20) Formation of the lactone 3 may derive from addition of the malonyl
carbon acid to the distal terminus of the η3-allylpalladium complex, followed
by lactonization via carboxylate addition to a newly generated η3-allyl complex.
In this case, the Pd-catalyzed cleavage of the malonyl moiety from the substrate
might take place either before or after the C-C bond formation. See also: (a)
Silvestri, M. A.; He, C.; Khoram, A.; Lepore, S. D. Tetrahedron Lett. 2006, 47,
1625–1626.
(23) Speier, J. L.; Webster, J. A.; Barnes, G. H. J. Am. Chem. Soc. 1957,
79, 974–979.
(24) Although the yields are only moderate, 1H NMR of the crude products
as well as TLC analysis indicate complete disappearance of the starting material
and the absence of other possible regio- or stereoisomers of 8. Partial
decomposition of the starting material as polymeric material is thus likely.
J. Org. Chem. Vol. 73, No. 15, 2008 5797

Vitale et al.
TABLE 2. Intramolecular Allylic Alkylation of the Triethylsilyl
Precursors 8a-c
SCHEME 4. Synthesis of Silylated Cyclization Precursors
8a-c
entry
8
OR
methoda
yieldb (%)
1
2
3
4
5
8a
8b
8b
8c
8c
OAc
OCO2Me
OCO2Me
OCOCH2CO2Me
OCOCH2CO2Me
A
A
B
A
C
53
48
61
57
59
a Method A: NaH (1.1 equiv), Pd(OAc)2 (5 mol %), dppe (10 mol
%), 1.5 h, DMF, 60 °C. Method B: Pd(OAc)2 (5 mol %), dppe (10
mol %), 1.5 h, DMF, 60 °C. Method C: NaH (1.1 equiv), Pd(OAc)2
(1 mol %), dppe (2 mol %), 1.5 h, DMF, 60 °C. b Only one
diastereoisomer was detected in each experiment (1H NMR of the crude
product) whose trans configuration was assigned via NOE experiments.
SCHEME 5. Intramolecular Allylic Alkylation To Give
Silylated Lactone 14
specific nontransferable groups. For our purpose, such groups
should also be compatible with the allylic alkylation step. With
this constraint, the dimethyl-2-thienylsilyl moiety emerged as
a suitable candidate, due to its recognized stability.27
Silane 13 was easily obtained via standard dimalonylation
of butyn-1,4-diol followed by platinum-catalyzed syn-hydrosi-
lylation of the resulting tetraester with (2-thienyl)Me2SiH.
Cyclization of 13 under the conditions previously described gave
the corresponding lactone 14 (59% yield) as the only isomer
(Scheme 5).28
Hiyama coupling of some representative aryl halides with
lactone 14 was then undertaken (Table 3). Following a brief
optimization study, the reactions were conducted in the presence
of n-Bu4NF and catalytic Pd2(dba)3, in THF at room temperature.
The efficiency of the coupling was found to be strongly
dependent on the nature of the aryl halide. Indeed and not
unexpectedly, iodobenzene cross-coupled with 14 in a more
satisfactory yield (Table 3, entry 2, 70% yield) than bromoben-
zene (Table 3, entry 1, 25% yield). The nature of the substituents
on the aryl iodides was also found to be crucial. In particular,
electron-donating methoxy groups in the para or ortho position
Having succeeded in transposing the catalytic cyclization
strategy from γ-lactams to γ-lactones, we planned to take
advantage of the newly generated vinylsilane moiety to incor-
porate the desired aryl moieties.
Hiyama coupling25 is a powerful transformation attracting
ever-increasing interest. However, in contrast to the related
Stille26 coupling, vinyl trialkyl derivatives are not suitable
substrates for such transformations. Indeed, in the case of
fluoride-activated Hiyama couplings, the silicon atom requires
(25) For reviews, see: (a) Denmark, S. E.; Ober, M. H. Aldrichimica Acta
2003, 36, 75–85. (b) Hiyama, T. J. Organomet. Chem. 2002, 653, 58–61. (c)
Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835–846. (d) Hiyama,
T., ; Shirakawa, E. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed., Wiley-Interscience: New York, 2002, pp 285-301.
(26) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524. (b)
Mitchell, T. N. In Metal-Catalysed Cross-Coupling Reactions; Dietrich, F., ;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 4.
(27) Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett. 2002, 2, 138–139.
(28) The trans configuration of 14 was assigned on the basis of the well
known stereochemical outcome of this type of cyclizations as well as the relative
stereochemistry of the intermediates deriving from it (see later).
5798 J. Org. Chem. Vol. 73, No. 15, 2008

Picropodophyllin Analogs Via Palladium-Catalyzed Sequences
TABLE 3. Cross-Coupling of Lactone 14 with Aryl Halidesa
SCHEME 7. First Attempts toward Podophyllotoxin and/or
Picropodophyllin Analogs
entry
X
R
product
yield (%)
1
2
3
4
5
6
7
8
Br
I
I
I
I
I
I
I
H
H
15a
15a
15b
15c
15d
15e
15f
25
70
95
38
79
45
20
26
4-MeO
3-MeO
2-MeO
4-MeCO
4-NO2
4-CF3
15g
a Conditions: TBAF (2.4 equiv, 1.0 M solution in THF), Pd2(dba)3
(2.5 mol %), THF, rt, 16 h.
SCHEME 6. First Retrosynthetic Plan of Podophyllotoxin
and/or Picropodopyllin Analogs
according to the protocol described by Jung et al.,31 gave
benzhydrol 16 (70% yield), which was quantitatively converted
into the corresponding acetate 17 (Scheme 7).
Lewis acid promoted benzhydrylation of the model ester 8b
with 17 was then attempted. However, neither BF3 ·OEt2 nor
TiCl4 were successful in promoting the desired alkylation, the
starting ester being recovered in both cases. Therefore, an
alternative route to access precursor 21 was envisioned. After
a brief survey of reaction conditions, we found that treatment
of benzhydryl acetate 17 with dimethyl malonate in the presence
of TiCl4 in toluene at room temperature gave the coupling
product 18 in 86% yield. Exposure of the latter diester to NaOH
in H2O/THF triggered a clean monosaponification32 affording
the corresponding monoacid 19 as an equimolar mixture of the
two possible diastereoisomers in 72% yield. Esterification of
the corresponding acid chloride with silylalcohol 20, previously
obtained in 44% yield via regioselective hydrosilylation of
butyn-1,4-diol monomethylcarbonate, gave uneventfully the
desired ester 21. Much to our disappointment, treatment of either
diastereomer of 21 with Pd(OAc)2 (5 mol%) and dppe (10
mol%) in DMF did not afford the expected cyclized lactone,
gave good coupling yields (Table 3, entries 3 and 5). On the
other hand, a methoxy substituent in the meta position or an
acetyl group in the para position was less satisfactory (Table
3, entries 4 and 6). Such behavior suggests that, in the case of
the aryl iodides tested, transmetalation rather than oxidative
addition is likely to be the rate determining step.29
After validation of the “allylic alkylation/Hiyama” sequence,
we next tackled the synthesis of podophyllotoxin analogs. The
retrosynthetic plan first conceived is depicted in Scheme 6. Its
first part, involving the terminal alkene II as the precursor,
strictly follows the same logic as the previously mentioned
lactam synthesis (Scheme 1).4 The C ring is generated by an
intramolecular Hiyama coupling of vinylsilane III, whereas the
D ring comes from the intramolecular allylic alkylation of
precursor IV. The latter intermediate may be in turn derived
from benzhydrylation of the known silyl precursor 13.
Bromine-lithium exchange on 3,4,5-trimethoxybromoben-
zene30 and subsequent treatment with 2-bromo-piperonaldehyde,
(30) Koza´d, I.; Konra´d, L.; Procha´zka, M. J. Labelled Compd. Radiopharm.
1978, XV, 401–405.
(31) Jung, M. E.; Lam, P. Y. S.; Mansuri, M. M.; Speltz, L. M. J. Org.
Chem. 1985, 50, 1087–1105.
(29) Hiyama couplings involving 1,2-disubstituted vinylsilanes do not show
the same trend.
(32) Niwayama, S. J. Org. Chem. 2000, 65, 5834–5836.
J. Org. Chem. Vol. 73, No. 15, 2008 5799

Vitale et al.
SCHEME 8. Mechanistic Hypothesis for the Generation of
Ester 22
SCHEME 10. Attempted Hiyama Couplings between 14 and
Benzhydrol Derivatives
SCHEME 11. Successful Hiyama Coupling and Generation
of the C Ring
SCHEME 9. Variations of the Retrosynthetic Plan
second variant of the synthetic plan (Scheme 9, path b), which
involves a less advanced (and less bulky) aryl halide building
block for the Hiyama coupling. Such a strategy derives I from
an aromatic electrophilic substitution of an appropriate electron-
rich derivative33 on the tricyclic intermediate VII. This latter
is expected to derive from an intermolecular Hiyama coupling
involving lactone 14 and an aromatic haloaldehyde IX, followed
by an intramolecular aldol condensation. This new strategy is
more modular than the former one and is well suited for the
synthesis of a family of podophyllotoxin analogs having
different E rings. Indeed, such diversification may be obtained
just by varying the aromatic partner in a late stage of the
synthetic sequence.
the bromoester 22 being the only isolated product. This
undesired cleavage product is very likely generated via the
departure of the malonate moiety during η3-allyl formation,
followed by decarboxylation and final reprotonation (Scheme
8).
In view of the above failure, two alternative retrosynthetic
plans were next considered (Scheme 9). The first one (path a)
entails the same key steps as the original plan but with different
chronological order and molecularity. Thus, the advanced
intermediate I was thought to derive from an intramolecular
benzhydrylation of V, this latter in turn stemming from an
intermolecular Hiyama coupling of the already known vinyl
silane 14.
Unfortunately, attempted Hiyama coupling between vinylsi-
lane 14 and bromobenzhydrol 16 using the reaction conditions
previously optimized degraded the lactone moiety without
producing the desired coupling product (Scheme 10). The same
negative result was obtained using the bromoacetate 17, the
bromomethyl ether 23, and the iodomethyl ether 24 as the
benzhydryl counterpart.
The known aldehyde 2534 was first submitted to Hiyama
coupling with lactone 14. Although this coupling was again
unsuccessful, submission to the same coupling with 14 of the
dioxolane derivative 26, immediate precursor of 25, finally gave
the desired adduct 27 (Scheme 11). A single crystal X-ray
diffraction structure of 27 revealed the trans stereochemistry
of the substituted lactone and, assuming that the coupling took
place under nonepimerizing conditions, that of its silane
precursor also. Treatment of the dioxolane 27 with formic acid
in THF at 0 °C with the aim of demasking the aldehyde function
took place with concomitant intramolecular aldolization, af-
Judging that the failure of the coupling was likely due to the
excessive bulk of the aryl halide, we turned our attention to the
(33) Stadler, D.; Bach, T. Chem. Asian J. 2008, 3, 272–284.
(34) Bogucki, D. E.; Charlton, J. L. J. Org. Chem. 1995, 60, 588–593.
5800 J. Org. Chem. Vol. 73, No. 15, 2008

Picropodophyllin Analogs Via Palladium-Catalyzed Sequences
SCHEME 12. Introduction of the E Ring and Double Bond
Oxidative Cleavage for Three Analogs
SCHEME 13. Oxidative Cleavage for a Fourth Analog
TABLE 4. Reduction of Ketones 32a,ba
entry
method
ketone
33:34
yield (%)
1
2
3
A
B
B
32a
32a
32b
89:11
92:8
95: 5
86
89
82
a (i) Method A: NaBH4, MeOH, rt. Method B: NaBH4, CeCl3, MeOH,
-78°C, rt.
Two of the three advanced intermediates were then submitted
to the protocol previously reported for the synthesis of the aza-
analog.4 Decarboxylation of 30a and 30b under classical
Krapcho35 conditions gave lactones 31a and 31b in 90% and
70% yield, respectively. Subsequent cis-dihydroxylation36 fol-
lowed by periodate cleavage of the crude diols37 gave ketones
32a and 32b in 76% and 85% yield. Single crystal X-ray
analysis of 32a disclosed the relative configuration between the
benzhydrylic center and the carbon R to the lactone. This
analysis confirmed unambiguously our previous assignment of
cis C/D ring junction for this structure as well as for the
precursors 30a38 and 31a. The relative configuration of 30b,38
30c,38 31b, and 32b are deduced by analogy with that of 32a.
In order to make a further analog, nonepimerizable at the R
position relative to the lactone function, the nondecarboxylated
tetracycle 30a was also submitted to the above-described
oxidative cleavage to give ketone 32a′ (Scheme 13).
Having in hand the three ketones 32a,b and 32a′, we tackled
the final reduction step. Treatment of ketone 32a with NaBH4
in MeOH at room temperature gave the expected alcohols 33a
and 34a as an 89/11 diastereomeric mixture in 86% yield (Table
4, entry 1). A NOESY experiment showing a spatial proximity
between the hydrogen atoms in positions 1 and 4 unequivocally
indicated the picropodophyllin relative configuration of the
major isomer. In a second experiment, reduction of the same
fording the tetracyclic lactone 28 as an equimolar mixture of
two diastereomers in quantitative yield. Inspection of molecular
models indicated that a cis C/D ring junction was reasonably
the only possible issue. This in turn revealed, as will be later
confirmed, that the mixture was due to the presence of the two
possible epimers at the carbinol center.
With the desired carbinol 28 in our hands, our next plan was
to introduce various electron-rich aromatic rings via aromatic
substitution. Our first choice went to 1,2,3-trimethoxybenzene.
Because of the well-known selectivity rules of the aromatic
electrophilic substitution, we were aware that use of such a
nucleophile could not generate an adduct bearing an E ring
trimethoxylated at the same positions as picropodophyllin.
Although this may be viewed as a limitation, this strategy
appeared attractive in that it could open the way to the synthesis
of picropodophyllin analogs bearing diverse E rings substitution
patterns with a late stage diversification.
After some experimentations, the desired aromatic substitution
could be satisfactorily accomplished (77% yield) by reacting
excess 1,2,3-trimethoxybenzene in the presence of BF3 ·OEt2
and the acetate 29, in turn obtained via standard acetylation of
carbinol 28 (Scheme 12). Worthy of note, the epimeric mixture
of 29 converged into the single diastereoisomer 30a. 1,3,5-
Trimethoxybenzene and pyrrole behaved analogously, giving
the corresponding arylated products in 84% and 50% yield,
respectively, as single diastereomers. The stereoconvergence of
these electrophilic couplings can be easily accounted for
according to approach mode X deriving from exclusive addition
of the aromatic partner on the more accessible convex face of
the transient cationic intermediate.
(35) For reviews, see: (a) Krapcho, A. P. Synthesis 1982, 805–822. (b)
Krapcho, A. P. Synthesis 1982, 893–914. (c) Krapcho, A. P. ArkiVoc 2007, 54–
120.
(36) Poli, G., Scolastico, C. In Houben Weyl Methods of Organic Chemistry;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds; Georg Thieme
Verlag: Stuttgart, New York, 1995; Chapter 4.4, Vol. E21, pp 4547-4598.
(37) (a) Manzoni, L.; Pilati, T.; Poli, G.; Scolastico, C. J. Chem. Soc., Chem.
Commun. 1992, 1027–1029. (b) Fatiadi, A. J. Synthesis 1976, 133–167.
(38) Assuming that the Krapcho decarboxylation took place with retention
of configuration.
J. Org. Chem. Vol. 73, No. 15, 2008 5801

Vitale et al.
SCHEME 14. Reduction of Ketone 32a′a
Experimental Section
(()-Methyl (3S,4S)-4-{1-[6-(1,3-Dioxolan-2-yl)-1,3-benzodioxol-
5-yl]vinyl}-2-oxotetrahydrofuran-3-carboxylate (27). At room tem-
perature, a freshly prepared 1.0 M solution of tetra-n-butylammo-
nium fluoride (7.85 mL, 7.85 mmol, 2.4 equiv) in THF was added
to a solution of vinylsilyl-lactone 14 (1.22 g, 3.92 mmol, 1.2 equiv).
The reaction mixture was then stirred for 10 min and 5-[1,3]diox-
olan-2-yl-6-iodo-benzo[1,3]dioxole 26 (1.05 g, 3.27 mmol, 1 equiv)
and Pd2(dba)3 (75 mg, 0.082 mmol, 0.025 equiv) were added
successively. After being stirred overnight, the resulting mixture
was quenched with a saturated solution of ammonium chloride.
The aqueous layer was extracted with CH2Cl2 and the combined
organic layer was washed with brine. Solvents were removed under
reduced pressure, and the crude material was purified by silica gel
flash column chromatography (cyclohexane/ethyl acetate 70/30).
Precipitation in Et2O and filtration afforded 27 (818 mg, 69% yield)
as a white solid. Recrystallization from cyclohexane/ethyle acetate
gave a suitable single crystal for X-ray analysis (data available in
Supporting Information); mp 132-133 °C; IR (neat) 2906, 1787,
1743, 1500, 1478 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.65 (d, J
) 10.4 Hz, 1H), 3.78 (s, 3H), 3.92-3.98 (m, 2H), 3.98-4.08 (m,
2H), 4.08-4.15 (m, 2H), 4.42 (m, 1H), 5.18 (s,1H), 5.33 (s, 1H),
5.66 (s, 1H), 5.96 (s, 2H), 6.51 (s, 1H), 7.06 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 46.9, 50.7, 53.2, 65.5, 70.4, 100.9, 101.6,
107.1, 108.3, 118.0, 128.9, 133.4, 142.8, 147.7, 148.3, 167.7, 171.4;
MS (CI, NH3) m/z 363 (M + H)+, 380 (M + NH4)+, Anal. Calcd
for C18H18O8: C, 59.67; H, 5.01, found: C, 59.89; H, 5.29.
a NaBH4, MeOH, rt, d.r. 72:28 (60%). b NaBH4, CeCl3, MeOH, 78 °C-->
rt, d.r. 18:82 (quant).
ketone under Luche conditions39 (NaBH4, CeCl3, MeOH, -78
°C) (Table 4, entry 2) gave the same alcohols as a 92/8
diastereomeric ratio and 89% yield. Reduction of ketone 32b
under Luche conditions gave the alcohol 33b as the sole
observable diastereoisomer (Table 4, entry 3). In this case too,
a NOE experiment (12%) showed the spatial proximity between
the hydrogen atoms at positions 1 and 4, confirming again a
picropodophyllin stereochemistry.
It is worthy to note that the hydride attacks on the carbonyl
functionality of compounds 32a,b takes place with a strong or
total preference for the face opposite to the E ring, independently
of the reaction conditions used. Such a behavior can be
accounted for by the strong steric bulk of the axial40 E ring
that disfavors attack from that side.
Ketone 32a′ was also reduced with NaBH4 alone or in the
presence of CeCl3. In this case, the former method provided
the expected diastereomeric alcohols 35a′ in a 72/28 ratio and
60% yield, whereas the Luche conditions gave quantitatively a
reversed ratio of 18/82. The relative configuration of the two
diastereomeric alcohols has not been assigned (Scheme 14).41
(()-Methyl (5aR,8aR)-5-Hydroxy-9-methylene-6-oxo-5,8,8a,9-
tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-5a(6H)-carbox-
ylate (28). To a solution of dioxolane 27 (1.00 g, 2.76 mmol, 1
equiv) in THF (30 mL) was added at 0 °C a solution of formic
acid in water (80%, 10 mL). After 2.5 h of stirring at 0 °C, a
saturated solution of sodium bicarbonate was added until a basic
pH was reached. The aqueous layer was extracted with CH2Cl2 (3
× 50 mL) and the combined organic layer was dried over Na2SO4.
Solvents were removed under reduced pressure to afford 28 (880
mg, quantitative yield) as a 1/1 mixture of 2 diastereomers and as
a white foam. This crude material was pure enough to be used in
the next step without further purification. First distereomer: 1H NMR
(400 MHz, CDCl3) δ 3.83 (s, 3H), 3.94 (dd, J ) 8.4, 4.3 Hz, 1H),
4.20 (dd, J ) 8.4, 4.3 Hz, 1H), 4.71 (t, J ) 8.4 Hz, 1H), 5.04 (s,
1H), 5.17 (s, 1H), 5.39 (s, 1H), 5.97 (m, 2H), 6.90 (s, 1H), 7.03 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 45.1, 53.7, 59.2, 70.3, 74.4,
101.6, 105.7, 106.3, 113.0, 127.6, 130.7, 141.0, 148.4, 148.8, 169.0,
Conclusion
In summary, we have been able to transpose the Pd-catalyzed
cyclization of unsaturated malonyl amides previously reported
by us, to the corresponding malonyl esters, so as to obtain
γ-lactones instead of γ-lactams. Such cyclization is less
straightforward than the previously studied nitrogen-based one
and can only be achieved in the presence of a juxtaposed silicon
atom in the substrate, which directs the palladium-catalyzed
ionization to the desired transient η3-allylpalladium complex.
The resulting silylvinyl-lactone 14 could be subsequently
engaged into Hiyama cross-couplings to give the corresponding
4-styryl-lactones 15a-g. Exploitation of this methodology
allowed the successful synthesis of the podophyllotoxin analogs
33a/34a, 33b, and 35a′ featuring picropodophyllin configuration
and a modified E ring substitution pattern. Key steps to achieve
these analogs, after the palladium-catalyzed cyclization and the
Hiyama coupling, are an intramolecular aldol condensation and
a stereoconvergent electrophilic aromatic substitution.
1
174.5. Second diastereomer: H NMR (400 MHz, CDCl3) δ 3.88
(s, 3H), 4.07-4.16 (m, 2H), 4.76 (dd, J ) 8.5, 7.4 Hz, 1H), 5.14
(s, 1H), 5.26 (s, 1H), 5.41 (s, 1H), 5.97 (m, 2H), 6.85 (s, 1H), 6.93
(s, 1H); 13C NMR (100 MHz; CDCl3,) δ 43.1, 53.9, 60.1, 70.9,
74.9, 101.6, 106.4, 108.8, 113.0, 128.9, 129.0, 142.9, 148.5, 149.2,
169.0, 171.6.
(()-Methyl (5aR,8aR)-5-(Acetyloxy)-9-methylene-6-oxo-5,8,8a,9-
tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-5a(6H)-carbox-
ylate (29). To a solution of diastereomeric alcohols 28 (880 mg,
2.76 mmol, 1 equiv) in CH2Cl2 (30 mL) were added successively
at 0 °C triethylamine (580 µL, 4.14 mmol, 1.5 equiv), acetic
anhydride (390 µL, 4.14 mmol, 1.5 equiv), and DMAP (17 mg,
0.14 mmol, 0.05 equiv). The mixture was then allowed to reach
room temperature and was stirred for 2 h. A saturated solution of
ammonium chloride (10 mL) was added, the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL) and the combined organic layer
was washed with a saturated sodium bicarbonate (10 mL) and brine
(10 mL). The resulting organic layer was dried over MgSO4 and
concentrated under reduced pressure, and the crude material was
purified by silica gel flash column chromatography (cyclohexane/
ethyl acetate 70/30) to afford a 1/1 diastereoisomeric mixture of
The present work has established an original method to build
up vinyl-lactones and aryltetralin lignan derivatives belonging
to picropodophyllin configuration.42
(39) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(40) It is supposed that the same conformation as observable in the X-ray
crystal structure of 32a is maintained in solution.
(41) Although a serious stereochemical analysis is not possible at this stage,
we suspect that in the absence of Ce(III) addition of the hydride takes place
preferentially from the same side as cycle E under assistance of the neighboring
methyl ester oxygen atom. On the other hand, Ce ions may forbid such assistance
via competitive coordination, thereby favoring attack from the side opposite to
E ring.
(42) The results of the biological tests of the synthesized picropodophyllotoxin
analogs will be reported elsewhere.
5802 J. Org. Chem. Vol. 73, No. 15, 2008

Picropodophyllin Analogs Via Palladium-Catalyzed Sequences
acetates 29 (930 mg, 93% yield from 27) as a white foam. IR (neat)
carboxylate (30c). To a solution of acetates 29 (50 mg, 0.139 mmol,
1 equiv) in CH2Cl2 (1 mL) at -30 °C were added freshly distilled
pyrrole (50 µL, 0.694 mmol, 5 equiv) and, dropwise, BF3 ·Et2O
(53 µL, 0.416 mmol, 3 equiv). The mixture was then allowed to
warm up slowly to room temperature over 1 h before a saturated
solution of sodium bicarbonate (1 mL) was added. The aqueous
layer was extracted with CH2Cl2 (2 × 2 mL), the combined organic
layer was dried over MgSO4 and concentrated under reduced
pressure, and the crude material was purified by silica gel flash
column chromatography (cyclohexane/ethyl acetate 85/15) to afford
1
2921, 1779, 1740, 1608, 1505, 1483 cm-1. First diastereomer: H
NMR (400 MHz, CDCl3) δ 1.91 (s, 3H), 3.67 (s, 3H), 4.25-4.40
(m, 2H), 4.85 (dd, J ) 8.4, 6.6 Hz, 1H), 4.98 (d, J ) 1.8 Hz, 1H),
5.53 (d, J ) 1.8 Hz, 1H), 5.93 (d, J ) 1.3 Hz, 1H), 5.95 (d, J )
1.3 Hz, 1H), 6.46 (s, 1H), 6.95 (s, 1H), 7.00 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.9, 41.4, 53.7, 58.1, 71.4, 72.7, 101.7, 105.0,
110.5, 111.3, 125.4, 129.0, 139.2, 148.0, 149.4, 167.6, 168.9, 172.0.
Second diastereomer: 1H NMR (CDCl3, 400 MHz) δ 1.89 (s, 3H),
3.82 (s, 3H), 4.14 (dd, J ) 8.8, 1.5 Hz, 1H), 4.19 (bd, J ) 7.4 Hz,
1H), 4.75 (dd, J ) 8.8, 7.4 Hz, 1H), 5.16 (s, 1H), 5.37 (s, 1H),
5.91 (d, J ) 1.3 Hz, 1H), 5.92 (d, J ) 1.3 Hz, 1H), 6.41 (s, 1H),
6.87 (s, 1H), 6.98 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.7,
42.4, 53.8, 59.4, 71.7, 75.9, 101.6, 105.8, 110.8, 113.2, 125.3, 130.1,
143.2, 148.0, 149.4, 166.6, 169.5, 170.4; HRMS (CI) m/z calcd
for C18H16O8Na (M + Na+) 383.0737, found 383.0738.
1
30c (25 mg, 50% yield) as a yellow foam. H NMR (400 MHz,
CDCl3) δ 3.80 (s, 3H), 4.17 (bd, J ) 6.6 Hz, 1H), 4.22 (dd, J )
8.8, 1.0 Hz, 1H), 4.68 (dd, J ) 8.8, 6.6 Hz, 1H), 4.95 (s, 1H), 5.23
(s, 1H), 5.50 (s, 1H), 5.87 (m, 1H), 5.92 (d, J ) 1.4 Hz, 1H), 5.95
(d, J ) 1.4 Hz, 1H), 6.01 (m, 1H), 6.71 (s, 1H), 6.95 (s, 1H), 8.02
(bs, 1H); 13C NMR (100 MHz, CDCl3) δ 43.4, 43.6, 53.7, 60.5,
75.8, 101.5, 108.5, 105.8, 107.7, 109.1, 113.2, 118.1, 128.1, 128.7,
130.0, 144.9, 148.3, 148.9, 167.4, 172.4; HRMS (CI) m/z calcd
for C20H17O6NNa (M + Na+) 390.0948, found 390.0949.
(()-(5S,5aS,8aS)-9-Methylene-5-(2,3,4-trimethoxyphenyl)-5,8,8a,9-
tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one (31a).
To a solution of 30a (120 mg, 0.256 mmol, 1 equiv) in DMSO (2
mL) were added NaCl (30 mg, 0.512 mmol, 2 equiv) and H2O (11
µL, 0.611 mmol, 2.4 equiv). The resulting mixture was stirred at
155 °C and completion of the reaction was monitored by TLC.
After cooling down to room temperature, H2O (30 mL) and AcOEt
(10 mL) were added. The aqueous layer was extracted with AcOEt
(3 × 10 mL), the combined organic layer was dried over MgSO4
and concentrated under reduced pressure, and the crude material
was purified by silica gel flash column chromatography (cyclohex-
ane/ethyl acetate 65/35) to afford 31a (95 mg, 90% yield) as a white
foam. IR (neat) 2904, 2254, 1766, 1600, 1480 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.38 (dd, J ) 9.0, 2.7 Hz, 1H), 3.47 (m, 1H),
3.79, (s, 3H), 3.88 (s, 3H), 4.01 (s, 3H), 4.18 (dd, J ) 9.0, 2.3 Hz,
1H), 4.50 (dd, J ) 9.0, 6.9 Hz, 1H), 4.72 (d, J ) 2.7 Hz, 1H), 5.01
(s, 1H), 5.44 (s, 1H), 5.93 (d, J ) 1.3 Hz, 1H), 5.94 (d, J ) 1.3
Hz, 1H), 6.27 (d, J ) 8.7 Hz, 1H), 6.44 (d, J ) 8.7 Hz, 1H), 6.62
(s, 1H), 7.00 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 39.5, 39.6,
44.7, 56.0, 60.9, 61.2, 74.8, 101.3, 105.3, 106.7, 109.5, 111.8, 123.3,
127.7, 129.6, 130.9, 142.2, 143.9, 147.8, 148.5, 151.5, 152.9, 177.5;
HRMS (CI) m/z calcd for C23H22O7Na (M + Na+) 433.1258, found
433.1256.
(()-(5S,5aS,8aS)-9-Methylene-5-(2,4,6-trimethoxyphenyl)-5,8,8a,9-
tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one (31b).
To a solution of 30b (200 mg, 0.427 mmol, 1 equiv) in DMSO
(3.5 mL) were added NaCl (50 mg, 0.854 mmol, 2 equiv) and H2O
(18 µL, 1.025 mmol, 2.4 equiv). After cooling down to room
temperature, H2O (30 mL) and AcOEt (10 mL) were added. The
aqueous layer was extracted with AcOEt (3 × 10 mL), the
combined organic layer was dried over MgSO4 and concentrated
under reduced pressure, and the crude material was purified by silica
gel flash column chromatography (cyclohexane/ethyl acetate 7/3)
to afford 31b (123 mg, 70% yield) as a white foam. IR (neat) 2902,
2253, 1769, 1591, 1478 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.31
(t, J ) 8.6 Hz, 1H), 3.65-3.75 (m, 1H), 3.69 (s, 6H), 3.81 (s, 3H),
4.28 (t, J ) 8.6 Hz, 1H), 4.53 (t, J ) 8.6 Hz, 1H), 4.76 (d, J ) 8.6
Hz, 1H), 5.00 (s, 1H), 5.49 (s, 1H), 5.84 (s, 1H), 5.87 (s, 1H), 6.17
(s, 2H), 6.33 (s, 1H), 7.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
26.9, 41.1, 42.5, 55.3, 55.8, 71.2, 91.2, 100.9, 104.1, 107.1, 109.7,
109.7, 127.6, 132.8, 140.6, 146.3, 148.0, 159.2, 160.5, 178.0; HRMS
(CI) m/z calcd for C23H22O7Na (M + Na+) 433.1258, found
433.1259.
(()-Methyl (5S,5aS,8aR)-9-Methylene-6-oxo-5-(2,3,4-trimethox-
yphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-
5a(6H)-carboxylate (30a). To a solution of acetates 29 (50 mg, 0.139
mmol, 1 equiv) in CH2Cl2 (1.5 mL) were added, at -20 °C under
argon atmosphere, 1,2,3-trimethoxybenzene (70 mg, 0.416 mmol,
3 equiv) and, dropwise, BF3 ·Et2O (90 µL, 0.694 mmol, 5 equiv).
The mixture was then allowed to warm up slowly to room
temperature over 1 h before a saturated solution of sodium
bicarbonate (1 mL) was added. The aqueous layer was extracted
with CH2Cl2 (2 × 2 mL), the combined organic layer was dried
over MgSO4 and concentrated under reduced pressure, and the crude
material was purified by silica gel flash column chromatography
(cyclohexane/ethyl acetate 70/30) to afford 30a (50 mg, 77% yield)
as a white solid. Mp 181-183 °C; IR (neat) 2909, 1770, 1736,
1
1598, 1476 cm-1; H NMR (400 MHz, CDCl3) δ 3.61 (s, 3H),
3.77 (s, 3H), 3.83 (s, 3H), 4.00 (s, 3H), 4.27 (dd, J ) 8.8, 1.0 Hz,
1H), 4.35 (m, 1H), 4.64 (dd, J ) 8.8, 6.6 Hz, 1H), 5.22 (d, J ) 1.0
Hz, 1H), 5.30 (s, 1H), 5.49 (s, 1H), 5.87 (d, J ) 1.4 Hz, 1H), 5.92
(d, J ) 1.4 Hz, 1H), 6.47 (d, J ) 8.8 Hz, 1H), 6.77 (d, J ) 8.8 Hz,
1H), 6.83 (s, 1H), 6.91 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
42.1, 43.8, 53.27, 55.7, 59.3, 60.6, 61.0, 75.4, 101.2, 105.1, 107.0,
109.1, 112.0, 122.3, 126.3, 127.6, 131.5, 142.1, 144.6, 147.7, 148.5,
151.5, 152.7, 167.6, 173.1; HRMS (CI) m/z calcd for C25H24O9Na
(M + Na+) 491.1313, found 491.1310.
(()-Methyl (5S,5aS,8aR)-9-Methylene-6-oxo-5-(2,4,6-trimethox-
yphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-
5a(6H)-carboxylate (30b). To a solution of acetates 29 (500 mg,
1.39 mmol, 1 equiv) in CH2Cl2 (15 mL) at -20 °C were added
1,3,5-trimethoxybenzene (700 mg, 4.16 mmol, 3 equiv) and,
dropwise, BF3 ·Et2O (900 µL, 6.94 mmol, 5 equiv). The mixture
was then allowed to warm up slowly to room temperature over 1 h
before a saturated solution of sodium bicarbonate (10 mL) was
added. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL),
the combined organic layer was dried over MgSO4 and concentrated
under reduced pressure, and the crude material was purified by silica
gel flash column chromatography (cyclohexane/ethyl acetate 70/
30) to afford 30b (550 mg, 84% yield) as a white foam. IR (neat)
2951, 1779, 1735, 1605, 1482 cm-1; 1H NMR (400 MHz, CDCl3)
δ 3.10-4.10 (bs, 6H), 3.44 (s, 3H), 3.75 (s, 3H), 4.28 (bd ) 5.6
Hz, 1H), 4.34 (d, J ) 8.7 Hz, 1H), 4.54 (dd, J ) 8.7, 5.6 Hz, 1H),
5.09 (d, J ) 1.5 Hz, 1H), 5.56 (d, J ) 1.5 Hz, 1H), 5.74 (s, 1H),
5.82 (d, J ) 1.4 Hz, 1H), 5.87 (d, J ) 1.4 Hz, 1H), 6.05 (bs, 2H),
6.65 (s, 1H), 7.00 (s, 1H); 1H NMR (400 MHz, DMSO-d6, 80 °C)
δ 3.41 (s, 3H), 3.71(s, 6H), 3.76 (s, 3H), 4.20 (m, 1H), 4.29 (d, J
) 9.0 Hz, 1H), 4.50 (dd, J ) 9.0, 5.8 Hz, 1H), 5.23 (d, J ) 1.5
Hz, 1H), 5.57 (s, 1H), 5.65 (d, J ) 1.5 Hz, 1H), 5.88 (s, 1H), 5.93
(s, 1H), 6.18 (s, 2H), 6.52 (s, 1H), 7.11 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 37.2, 44.0, 52.8, 55.3, 58.0, 75.8, 90.6, 101.1, 103.3,
108.6, 109.1, 109.6, 127.6, 130.3, 144.9, 147.1, 148.0, 159.2, 160.5,
167.9, 174.0; HRMS (CI) m/z calcd for C25H24O9Na (M + Na+)
491.1313, found 491.1311.
(()-(5aR,8aS,9S)-9-(2,3,4-Trimethoxyphenyl)-5a,6,8a,9-tetrahy-
drofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-5,8-dione (32a). To a
solution of alkene 31a (220 mg, 0.536 mmol, 1 equiv) in a mixture
of THF/H2O (11 mL/1.4 mL) were added successively 4-methyl-
morpholine-N-oxide (126 mg, 1.07 mmol, 2 equiv) and OsCl3 ·xH2O
(8 mg). The resulting dark suspension was stirred at room
temperature until no starting alkene was detected by TLC. A 50%
(()-Methyl (5R,5aS,8aR)-9-Methylene-6-oxo-5-(1H-pyrrol-2-yl)-
5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-5a(6H)-
J. Org. Chem. Vol. 73, No. 15, 2008 5803

Vitale et al.
sodium bisulfite solution (10 mL) was then added and the resulting
solution was stirred for 15 min. The aqueous layer was extracted
with AcOEt (3 × 10 mL), the combined organic layer was dried
over MgSO4 and concentrated under reduced pressure, and the crude
material was filtered on a pad of silica gel (cyclohexane/ethyl acetate
6/4). The filtrate was concentrated under reduced pressure, the
residue was dissolved in a mixture of acetone/H2O (30 mL/20 mL)
and NaIO4 (345 mg, 1.61 mmol, 3 equiv) was added in one portion.
The reaction mixture was stirred at room temperature until no diol
was detected by TLC. Acetone was removed under reduced
pressure, brine was added (25 mL), and the resulting aqueous layer
was extracted with AcOEt (3 × 25 mL). The combined organic
layer was dried over Na2SO4 and concentrated under reduced
pressure, and the crude material was purified by silica gel flash
column chromatography (cyclohexane/ethyl acetate 7/3) to afford
32a (169 mg, 76% yield) as a white foam. IR (neat) 2910, 2254,
1772, 1667, 1614, 1478 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.25
(dd, J ) 8.0, 6.0 Hz, 1H), 3.33 (dd, J ) 8.0, 1.5 Hz, 1H), 3.79 (s,
3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.30 (dd, J ) 9.1, 6.0 Hz, 1H),
4.72 (d, J ) 9.1 Hz, 1H), 4.91 (bd, J ) 1.5 Hz, 1H), 6.00 (s, 2H),
6.32 (d, J ) 8.6 Hz, 1H), 6.48 (d, J ) 8.6 Hz, 1H), 6.63 (s, 1H),
7.47 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 37.7, 43.7, 45.0, 55.9,
60.7, 61.0, 70.3, 102.1, 105.9, 106.9, 109.3, 123.1, 127.7, 128.1,
140.2, 142.4, 148.1, 151.1, 153.3, 153.5, 175.9, 194.0; HRMS (CI)
m/z calcd for C22H20O8Na (M + Na+) 435.1050, found 435.1049.
(()-(5aR,8aS,9S)-9-(2,4,6-Trimethoxyphenyl)-5a,6,8a,9-tetrahy-
drofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-5,8-dione (32b). To a
solution of alkene 31b (139 mg, 0.339 mmol, 1 equiv) in a mixture
of THF/H2O (7 mL/0.9 mL) were added successively 4-methyl-
morpholine-N-oxide (80 mg, 0.677 mmol, 2 equiv) and OsCl3 ·xH2O
(5 mg). The resulting dark suspension was stirred at room
temperature until no starting alkene was detected by TLC. A 50%
sodium bisulfite solution (10 mL) was then added and the resulting
solution was stirred for 15 min. The aqueous layer was extracted
with AcOEt (3 × 10 mL), the combined organic layer was dried
over MgSO4 and concentrated under reduced pressure, and the crude
material was filtered on a pad of silica gel (cyclohexane/ethyl acetate
6/4). The filtrate was concentrated under reduced pressure, the
residue was dissolved in a mixture of acetone/H2O (15 mL/10 mL)
and NaIO4 (217 mg, 1.02 mmol, 3 equiv) was added in one portion.
The reaction mixture was stirred at room temperature until no diol
was detected by TLC. Acetone was removed under reduced
pressure, brine was added (25 mL) and the resulting aqueous layer
extracted with AcOEt (3 × 25 mL). The combined organic layer
was dried over Na2SO4 and concentrated under reduced pressure,
and the crude material was purified by silica gel flash column
chromatography (cyclohexane/ethyl acetate 7/3) to afford 32b (119
mg, 85% yield) as a white foam. IR (neat) 2911, 2841, 1769, 1665,
(cyclohexane /ethyl acetate 6/4). The filtrate was concentrated under
reduced pressure, the residue was dissolved in a mixture of acetone/
H2O (18 mL/12 mL), and NaIO4 (255 mg, 1.19 mmol, 3 equiv)
was added in one portion. The reaction mixture was stirred at room
temperature until no diol was detected by TLC. Acetone was
removed under reduced pressure, brine was added (25 mL), and
the resulting aqueous layer was extracted with AcOEt (3 × 25 mL).
The combined organic layer was dried over Na2SO4 and concen-
trated under reduced pressure, and the crude material was purified
by silica gel flash column chromatography (cyclohexane/ethyl
acetate 7/3) to afford 32a′ (149 mg, 80% yield) as a white foam.
IR (neat) 2943, 2255, 1785, 1737, 1668, 1478 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.46 (s, 3H), 3.50 (s, 3H), 3.73 (s, 3H), 3.77 (s,
3H), 4.08 (d, J ) 5.8 Hz, 1H), 4.38 (dd, J ) 9.1, 5.8 Hz, 1H), 4.68
(d, J ) 9.1 Hz, 1H), 5.07 (bs, 1H), 5.91 (m, 1H), 5.94 (m, 1H),
6.53 (d, J ) 8.5 Hz, 1H), 6.66 (s, 1H), 6.79 (bd, J ) 8.5 Hz, 1H),
7.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 43.8, 47.8, 53.2, 55.9,
58.7, 60.1, 60.6, 70.9, 102.1, 105.7, 106.9, 108.9, 124.0, 124.9,
126.3, 139.3, 142.3, 147.9, 152.0, 153.3, 153.8, 166.1, 172.3, 193.6;
HRMS (CI) m/z calcd for C24H22O10Na (M + Na+) 493.1105, found
493.1103.
(()-(5S,5aS,8aR)-9-Hydroxy-5-(2,3,4-trimethoxyphenyl)-5,8,8a,9-
tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one (33a
(9R) and 34a (9S)). Procedure A. To a solution of ketone 32a (42
mg, 0.102 mmol, 1 equiv) in dry MeOH (10 mL) was added NaBH4
(11.5 mg, 0.305 mmol, 3 equiv) in one portion at room temperature.
After 1.5 h of stirring, a saturated solution of ammonium chloride
(20 mL) and Et2O (10 mL) was added. The aqueous layer was
extracted with Et2O (2 × 10 mL) and the combined organic layer
was concentrated under reduced pressure. The residue was treated
with CH2Cl2 (20 mL) and filtered to remove residual boron salts.
The filtrate was concentrated under reduced pressure, and the crude
material was purified by silica gel flash column chromatography
(cyclohexane/ethyl acetate 6/4) to afford the mixture of epimers
33a and 34a (36 mg, 86% yield) in a 89/11 ratio and as a white
foam. Procedure B. To a solution of ketone 32a (19 mg, 0.046
mmol, 1 equiv) and CeCl3 ·7H2O (26 mg, 0.069 mmol, 1.5 equiv)
in a 1/1 mixture of dry MeOH and CH2Cl2 (2 mL) was added
NaBH4 (2.6 mg, 0.069 mmol, 1.5 equiv) in one portion at -78 °C.
The solution was allowed to warm up slowly to room temperature
before a saturated solution of ammonium chloride (10 mL) and
CH2Cl2 (5 mL) were added. The aqueous layer was extracted with
CH2Cl2 (2 × 5 mL), the combined organic layer was dried over
MgSO4 and concentrated under reduced pressure, and the crude
material was purified by silica gel flash column chromatography
(cyclohexane/ethyl acetate 6/4) to afford the mixture of epimers
33a and 34a (17 mg, 89% yield) in a 92/8 ratio and as a white
foam. Major diastereomer (33a): IR (neat) 3442, 2941, 1769, 1664,
1
1
1606, 1477 cm-1; H NMR (400 MHz, CDCl3) δ 3.14 (dd, J )
1661, 1479 cm-1; H NMR (400 MHz, CDCl3) δ 2.59-2.68 (m,
8.7, 1.9 Hz, 1H), 3.56 (ddd, J ) 8.7, 6.9, 1.4 Hz, 1H), 3.66 (bs,
6H), 3.76 (s, 3H), 4.35 (dd, J ) 9.1, 6.9 Hz, 1H), 4.68 (dd, J )
9.1, 1.4 Hz, 1H), 5.42 (d, J ) 1.9 Hz, 1H), 5.89 (s, 1H), 5.91 (s,
1H), 6.09 (s, 2H), 6.55 (s, 1H), 7.36 (s, 1H); 13C NMR (100 MHz,
CDCl3,) δ 31.3, 43.9, 45.2, 55.3, 55.5, 69.8, 91.1, 101.7, 105.2,
108.5, 111.8, 127.2, 141.5, 147.1, 152.7, 158.7, 160.6, 177.2, 194.6;
HRMS (CI) m/z calcd for C22H20O8Na (M + Na+) 435.1050, found
435.1049.
(()-Methyl (5S,5aS,8aR)-6,9-Dioxo-5-(2,3,4-trimethoxyphenyl)-
5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-5a(6H)-
carboxylate (32a′). To a solution of alkene 30a (186 mg, 0.397
mmol, 1 equiv) in a mixture of THF/H2O (8 mL/1 mL) were added
successively 4-methylmorpholine-N-oxide (93 mg, 0.794 mmol, 2
equiv) and OsCl3 ·xH2O (6 mg). The resulting dark suspension was
stirred at 50 °C until no starting alkene was detected by TLC. A
50% sodium bisulfite solution (10 mL) was then added and the
resulting solution was stirred for 15 min. The aqueous layer was
extracted with AcOEt (3 × 20 mL), the combined organic layer
was dried over MgSO4 and concentrated under reduced pressure,
and the crude material was filtered on a pad of silica gel
1H), 3.23 (dd, J ) 9.1, 6.0 Hz, 1H), 3.67 (s, 3H), 3.86 (s, 3H),
3.87 (s, 3H), 4.18 (d, J ) 6.0 Hz, 1H), 4.38 (dd, J ) 9.6, 6.0 Hz,
1H), 4.43 (d, J ) 9.5 Hz, 1H), 4.58 (dd, J ) 9.6, 1.5 Hz, 1H), 5.84
(d, J ) 1.4 Hz, 1H), 5.87 (d, J ) 1.4 Hz, 1H), 6.18 (s, 1H), 6.66
(d, J ) 8.6 Hz, 1H), 6.85 (d, J ) 8.6 Hz, 1H), 7.07 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 38.8, 43.1, 44.5, 56.1, 60.7, 60.8, 68.7,
69.7, 101.1, 104.8, 107.3, 108.0, 124.5, 129.2, 131.5, 132.4, 142.7,
146.5, 146.9, 151.9, 153.3, 178.8; HRMS (CI) m/z calcd for
C22H22O8Na (M + Na+) 437.1207, found 437.1206.
(()-(5S,5aS,8aR,9R)-9-Hydroxy-5-(2,4,6-trimethoxyphenyl)-
5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-
one (33b). To a solution of ketone 32b (28 mg, 0.068 mmol, 1
equiv) and CeCl3 ·7H2O (38 mg, 0.102 mmol, 1.5 equiv) in dry
MeOH (2 mL) was added NaBH4 (3.8 mg, 0.102 mmol, 1.5 equiv)
in one portion at -78 °C. The solution was allowed to warm up
slowly to room temperature before a saturated solution of am-
monium chloride (10 mL) and CH2Cl2 (5 mL) was added. The
aqueous layer was extracted with CH2Cl2 (2 × 5 mL), the combined
organic layer was dried over MgSO4 and concentrated under
reduced pressure, and the crude material was purified by silica gel
5804 J. Org. Chem. Vol. 73, No. 15, 2008

Picropodophyllin Analogs Via Palladium-Catalyzed Sequences
flash column chromatography (cyclohexane/ethyl acetate 6/4) to
chromatography (cyclohexane/ethyl acetate 6/4) to afford 35a′ as
afford 33b (23 mg, 82% yield) as a white foam. IR (neat) 3442,
a 18/82 mixture of epimers and as a white foam (20 mg, quantitative
yield). First diastereomer: H NMR (400 MHz, CDCl3) δ 3.45 (s,
1
2940, 1754, 1591, 1476 cm-1; H NMR (400 MHz, CDCl3) δ
1
2.50-2.60 (m, 1H), 3.42 (dd, J ) 9.4, 7.6 Hz, 1H), 3.72 (s, 6H),
3.84 (s, 3H), 4.39 (dd, J ) 9.6, 6.3 Hz, 1H), 4.46 (bdd, J ) 10.0,
6.7 Hz, 1H), 4.59 (d, J ) 7.6 Hz, 1H), 4.63 (dd, J ) 9.6, 1.9 Hz,
1H), 5.83 (d, J ) 1.4 Hz, 1H), 5.88 (d, J ) 1.4 Hz, 1H), 6.19 (d,
3H), 3.54 (td, J ) 5.2, 0.8 Hz, 1H), 3.71(s, 3H), 3.81 (s, 3H), 3.83
(s, 3H), 4.41 (dd, J ) 9.1, 0.8 Hz, 1H), 4.47 (dd, J ) 9.1, 5.2 Hz,
1H), 4.66 (bd, J ) 5.2 Hz, 1H), 5.07 (s, 1H), 5.87 (d, J ) 1.3 Hz,
1H), 5.89 (d, J ) 1.3 Hz, 1H), 6.57 (d, J ) 8.8 Hz, 1H), 6.66 (s,
1H), 6.89 (s, 1H), 7.01 (d, J ) 8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3,) δ 41.8, 45.5, 53.1, 56.0, 59.1, 60.6, 60.8, 71.6, 72.3, 101.3,
106.9, 107.1, 109.5, 124.7, 126.4, 129.4, 130.5, 142.3, 147.2, 147.8,
1
J ) 1.0 Hz, 1H), 6.21 (s, 2H), 7.07 (s, 1H); H NMR (400 MHz,
C6D6) δ 2.20 (dddd, J ) 10.6, 9.5, 6.2, 1.4 Hz, 1H), 1.68 (d, J )
6.2 Hz, 1H), 3.23-3.28 (m, 1H), 3.26 (bs, 6H), 3.42 (s, 3H), 3.68
(dd, J ) 9.4, 6.2 Hz, 1H), 3.90 (bdd, J ) 10.6, 6.2 Hz, 1H), 4.18
(dd, J ) 9.4, 1.4 Hz, 1H), 5.00 (d, J ) 7.3 Hz, 1H), 5.26 (d, J )
1.4 Hz, 1H), 5.28 (d, J ) 1.4 Hz, 1H), 6.15 (s, 2H), 6.63 (d, J )
1.0 Hz, 1H), 7.17 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 32.4,
42.1, 44.0, 55.5, 56.1, 68.9, 69.1, 91.6, 100.9, 104.0, 106.8, 110.5,
131.7, 132.4, 146.0, 146.9, 159.2, 160.7, 179.1; HRMS (CI) m/z
calcd for C22H22O8Na (M + Na+) 437.1207, found 437.1205.
(()-Methyl (5S,5aS,8aR)-9-Hydroxy-6-oxo-5-(2,3,4-trimethox-
yphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxole-
5a(6H)-carboxylate (35a′). Procedure A. To a solution of ketone
32a′ (30 mg, 0.064 mmol, 1 equiv) in dry MeOH (5 mL), NaBH4
(5 mg, 0.127 mmol, 2 equiv) was added in one portion at room
temperature. The resulting reaction mixture was stirred 2 h at room
temperature before a saturated solution of ammonium chloride (10
mL) and Et2O (10 mL) were added. The aqueous layer was extracted
with Et2O (2 × 10 mL) and the combined organic layer was
concentrated under reduced pressure. The residue was treated with
CH2Cl2 (20 mL) and filtered to remove residual boron salts. The
filtrate was concentrated under reduced pressure, and the crude
material was purified by silica gel flash column chromatography
(cyclohexane/ethyl acetate 7/3 to 1/1) to afford 35a′ as a 72/28
mixture of epimers and as a white foam (18 mg, 60% yield).
(Starting material 32a′ was also recovered (10 mg, 33%). Procedure
B. To a solution of ketone 32a′ (20 mg, 0.042 mmol, 1 equiv) and
CeCl3 ·7H2O (24 mg, 0.064 mmol, 1.5 equiv) in dry MeOH (1 mL)
was added NaBH4 (2.4 mg, 0.064 mmol, 1.5 equiv) in one portion
at -78 °C. The solution was allowed to warm up slowly to room
temperature before a saturated solution of ammonium chloride (10
mL) and CH2Cl2 (5 mL) was added. The aqueous layer was
extracted with CH2Cl2 (2 × 5 mL), the combined organic layer
was dried over MgSO4 and concentrated under reduced pressure,
and the crude material was purified by silica gel flash column
1
152.3, 153.3, 167.7, 173.4. Second diastereomer: H NMR (400
MHz, CDCl3) δ 3.59 (s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 3.88 (s,
3H), 4.10 (m, 1H), 4.36 (dd, J ) 9.1, 8.5 Hz, 1H), 4.52 (dd, J )
9.1, 2.5 Hz, 1H), 5.17 (s, 1H), 5.20 (m, 1H), 5.90 (m, 2H), 6.50 (d,
J ) 8.7 Hz, 1H), 6.71 (d, J ) 8.7 Hz, 1H), 6.96 (s, 1H), 6.99 (s,
1H); 13C NMR (100 MHz; CDCl3) δ 43.9, 45.2, 53.6, 56.0, 59.6,
60.5, 60.8, 65.7, 66.6, 101.1, 104.7, 106.1, 111.0, 121.3, 125.3,
129.2, 130.8, 142.7, 147.0, 147.3, 152.5, 153.0, 168.8, 173.9; IR
(neat) 3412, 2919, 2850, 1775, 1735, 1599, 1482 cm-1; HRMS
(CI) m/z calcd for C24H24O10Na (M + Na+) 495.1262, found
495.1260.
Acknowledgment. The support and sponsorship concerted
by MENRT, CNRS, and COST Action D40 “Innovative
Catalysis: New Processes and Selectivities” are kindly acknowl-
edged. We sincerely thank Professor Professor Olle Larsson at
Cancer Center Karolinska, Karolinska Hospital, Stockholm, for
fruitful discussions.
Supporting Information Available: Experimental details
concerning the preparations and cyclizations of precursors 1a-d,
8a-c, and 13; general procedure for the Hiyama cross-coupling
of 14 to give 15a-g; preparation and cyclization attempt of
1
precursor 21; preparation of compounds 23-26; copies of H
and 13C NMR spectra; and X-ray diffraction analysis data of
compounds 27 and 32a and their checkCIF validated cif files.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800707Q
J. Org. Chem. Vol. 73, No. 15, 2008 5805