An epiisopicropodophyllin aza analogue via palladium-catalyzed pseudo-domino cyclization

Article abstract of DOI:10.1021/jo026068+

A new aza analogue of epiisopicropodophyllin (the C-3 epimer of podophyllotoxin) has been synthesized exploiting two original strategic steps. Rings A/B and E are entered at an early stage via a cationic benzhydrylation process. A palladium-catalyzed pseudo-domino (Pd-PDOM) intramolecular process generates rings C/D in a single synthetic operation.

Full text of DOI:10.1021/jo026068+

An Ep iisop icr op od op h yllin Aza An a logu e
via P a lla d iu m -Ca ta lyzed P seu d o-Dom in o
Cycliza tion
Giovanni Poli* and Giuliano Giambastiani†
UMR 7611 CNRS, Universite´ Pierre et Marie Curie,
4 Place J ussieu, Tour 44-45, Boˆıte 183,
F-75252, Paris, Cedex 05, France
poli@ccr.jussieu.fr
Received J une 17, 2002
F IGUR E 1. Structures of podophyllotoxin 1 and etoposide
(VP 16-213) 2.
Abst r a ct : A new aza analogue of epiisopicropodophyllin
(the C-3 epimer of podophyllotoxin) has been synthesized
exploiting two original strategic steps. Rings A/B and E are
entered at an early stage via a cationic benzhydrylation
process. A palladium-catalyzed pseudo-domino (Pd-PDOM)
intramolecular process generates rings C/D in a single
synthetic operation.
structures. Following a similar concept, Kadow and co-
workers converted the lactone moiety of etoposide into a
number of N-substituted lactam derivatives.7 Although
the synthetic protocol suffers from C-2 epimerization and
the biological tests against P388 leukemia indicate
inferior activity of these derivatives with respect to
etoposide, podophyllotoxin- and etoposide-lactam deriva-
tives may be regarded as interesting candidates.
The synthesis of analogues of the well-known natural
product podophyllotoxin 1 (Figure 1) and of the related
etoposide 2 has attracted organic chemists since the
antimitotic activity of the former compound and the
antitumor properties of the latter were discovered.1 In
this context, a great deal of studies have been so far
addressed to the synthesis of 2-azapodophyllotoxin ana-
logues.2 In fact, the presence of the amidic-type nitrogen
atom at position 2 has been shown to remove the
undesired trans-to-cis C/D-ring fusion epimerization,
while enhancing D-ring stability. Indeed, hydrolytic
D-ring opening is another major cause of concern since
it also leads to drug inactivation.3 To solve this problem,
several D-ring modifications have been studied so as to
take advantage of a nonhydrolyzable (and nonepimeriz-
able) D-ring. Transformation of the podophyllotoxin or
etoposide lactone D-ring into a trans-fused cyclopentane,4
cyclopentanone,3 tetrahydrofuran,4,5 tetrahydrothiophene,4
or δ-lactone6 gave compounds less active than the parent
The field of one-pot multistep processes is witnessing
everincreasing attention and a consequent rapid evolu-
tion. Despite this evidence, a satisfactory conceptual
picture covering transition metal-catalyzed domino reac-
tions has, to the best of our knowledge, not been put
forward yet. According to the commonly accepted defini-
tion by Tietze:8 “a domino reaction is a process involving
two or more bond-forming transformations which take
place under the same reaction conditions without ad-
ditional reagents and catalysts, and in which the subse-
quent reactions result as a consequence of the functionality
formed in the previous step”. On the other hand, when
the above domino process is transition metal-catalyzed,
three conceptually distinct categories may be further
discriminated.9 Thus, the process may either involve a
single catalytic cycle, driven by a single catalytic system
(“M”) and featuring several distinct transition metal-
catalyzed transformations, or be composed of sequential
and mechanistically independent catalytic cycles, each
one involving a simple catalytic transformation. Accord-
† Present address: Institute of Chemistry of Organometallic Com-
pounds ICCOM-CNR, Firenze, Italy.
(1) 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.
(2) (a) Katritzky, A. R.; Cobo-Domingo, J .; Yang, B.; Steel, P. J .
Tetrahedron: Asymmetry 1999, 10, 255-263. (b) Hitotsuyanagi, Y.;
Yamagami, K.; Fujii, A.; Naka, Y.; Ito, Y.; Tahara, T. Biorg. Med. Chem.
Lett. 1995, 5, 1039-1042. (c) Hitotsuyanagi, Y.; Kobayashi, M.; Takeya,
K.; Itokawa, H. J . Chem. Soc., Perkin Trans. 1 1995, 1387-1390. (d)
Hitotsuyanagi, Y.; Naka, Y.; Yamagami, K.; Fujii, A.; Tahara, T. Chem.
Commun. 1995, 49-50. (e) Hitotsuyanagi, Y.; Ichihara, Y.; Takeya,
K. Itokawa, H. Tetrahedron Lett. 1994, 35, 9401-9402. (f) Tomioka,
K.; Kubota, Y.; Koga, K. Tetrahedron 1993, 49, 1891-1900. (g) Lienard,
P.; Quirion, J .-C.; Husson, H.-P. Tetrahedron 1993, 49, 3995-4006.
(h) Tomioka, K.; Kubota, Y.; Koga, K. Chem. Commun. 1989, 1622-
1624. (i) Van der Eycken, J .; Bosmans, J .-P.; Van Haver, D.; Vande-
walle, M. Tetrahedron Lett. 1989, 30, 3873-3876. (j) Bosmans, J .-P.;
Van der Eycken, J .; Vandewalle, M.; Hulkenberg, A.; Van Hes, R.;
Veerman, W. Tetrahedron Lett. 1989, 30, 3877-3880. (k) Pearce, H.
L.; Bach, N. J . Cramer, T. L. Tetrahedron Lett. 1989, 30, 907-910. (l)
Tomioka, K.; Kubota, Y.; Koga, K. Tetrahedron Lett. 1989, 30, 2953-
2954.
(5) (a) J ardine, I.; Strife, R. J .; Kozlowski, J . J . Med. Chem. 1982,
25, 1077-1081. (b) Zhou, X. M.; Lee, K. J .-H.; Cheng, J .; Wu, S.-S.;
ChenH.-X.; Guo, X.; Cheng, Y.-C.; Lee, K.-H. J . Med. Chem. 1994, 37,
287-292. (c) Subrahmanyam, D.; Renuka, B.; Kumar, G. S.; Vandana,
V.; Deevi, D. S. Bioorg. Med. Chem. Lett. 1999, 9, 2131-2134.
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1989, 30, 3299-3302. (b) Kadow, J . F.; Vyas, D. M. Eur. Pat. Appl.
EP 329,108, 1990; Chem. Abstr. 1990, 112, 56571k.
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reviews see: (b) Tietze, L. F.; Haunert, F. In Stimulating Concepts in
Chemistry; Shibasaki, M., Stoddart, J . F., Vo¨gtle, F., Eds.; Wiley-
VCH: Weinheim, 2000; pp 39-64. (c) Tietze, L. F. Chem. Ind. 1995,
453-457. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131-163. (e) Ho, T. L. Tandem Organic Reactions; Wiley:
New York, 1992. (f) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl.
1992, 31, 1332-1334. (g) Tietze, L. F. J . Heterocycl. Chem. 1990, 27,
47-69. (h) Ziegler, F. E. Chem. Rev. 1988, 88, 1423-1452. (i) Posner,
G. H. Chem. Rev. 1986, 86, 831-844.
(3) Clark, P. I.; Slevin, M. L. Clin. Pharmacokinet. 1987, 12, 223-
252.
(4) Gensler, W. J .; Murthy, C. D.; Trammel, M. H. J . Med. Chem.
1977, 20, 635-644.
(9) We warmly thank a referee for having provided us with the
fundamental concepts enabling articulation of the principles underlying
Figure 2.
10.1021/jo026068+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/21/2002
9456
J . Org. Chem. 2002, 67, 9456-9459

SCHEME 2
F IGUR E 2. Classification of domino transition metal-
catalyzed processes.
egy, from an “intra-inter” to an “intra-intra” type of
process could offer an original access to lactam analogues
of the podophyllotoxin family.17
SCHEME 1
The retrosynthetic disconnection of the podophyllotoxin
lactam skeleton 5 leads first to the terminal alkene
derivative 6 (Scheme 2). Such an intermediate may in
turn be related to the open precursor 7 according to a
5-exo intramolecular allylic alkylation process followed
by an intramolecular 6-exo-trig Heck reaction. Then,
dissection at C-1/C-2 in 7 divides the molecule into the
well-known unsaturated amide 818 and the diarylmetha-
nol derivative 9.
The synthesis commenced with the preparation of the
benzhydryl moiety. The required aromatic bromoalde-
hyde 10 (Scheme 3) was first secured in two steps via
MnO2 oxidation of piperonyl alcohol19 followed by regio-
selective bromination of the resulting carbonyl deriva-
tive.20 Addition of phenylmagnesium bromide to 10 in
Et2O gave the o-bromobenzhydrol 11 in 97% yield.21
Treatment of this alcohol with PBr3 in CHCl3 afforded
the benzhydrylbromide 12 in 94% yield.22
The reaction between the sodium enolate of 3 and the
above dibromide 12 proved to be exceptionally inefficient,
with only tiny amounts of the expected alkylated product
13 being isolated after 5 h at 60 °C in DMF.23 An
alternative approach was thus undertaken. Despite the
virtual absence of similar examples in the literature,24
direct addition of 3 to benzhydrol 11 in the presence of
BF3‚OEt2 gave the desired adduct 13 in quantitative yield
as a mixture of the two possible diastereoisomers.25,26
ing to the above consideration, we propose to distinguish
and classify the two transition metal-catalyzed transfor-
mations as pure-domino (TM-DOM)10 and pseudo-domino
(TM-PDOM)10 processes, respectively. Furthermore, the
latter type of process may either involve a single “mul-
tipurpose” catalytic system (“M”) sharing the sequential
cycles (type I)11 or call for mutually compatible catalytic
systems of different nature (“M1, M2, ...”) (type II). Figure
2 illustrates the above concept.
Although, according to the above notation, most of the
known multistep transition metal-catalyzed reactions are
TM-DOM processes,12 examples of TM-PDOM type I13,14
or TM-PDOM type II15 transformations have been re-
ported and are likely to receive increasing interest in the
future.
We have recently developed a new Pd-PDOM type I
process in which a single Pd-based catalytic system
promotes two Pd-catalyzed processes in a one-pot proce-
dure and in chronologically distinct order.13 The first step
consists of an intramolecular 5-exo cyclization of a
stabilized acetamide anion onto an allylic acetate, whereas
the latter one is an intermolecular regio- and stereoslec-
tive Heck arylation of the newly generated vinylpyrro-
lidinone (Scheme 1).16
(17) For a recent total synthesis of (-)-podophyllotoxin see: (a)
Berkowitz, D. B.; Choi, S.; Maeng, J .-H. J . Org. Chem. 2000, 65, 847-
860. For a recent B-ring modification see: (b) Ramos, A. C.; Pela´ez,
R.; Lo´pez, J . L.; Caballero, E.; Medarde, M.; san Feliciano, A.
Tetrahedron 2001, 57, 3963-3977. For approaches to related structures
via palladium chemistry see: (c) Ishibashi, H.; Ito, K.; Hirano, T.;
Tabuchi, M.; Ikeda, M. Tetrahedron 1993, 49, 4173-4182. (d) Galland,
J .-C.; Dias, S.; Savignac, M.; Geneˆt, J .-P. Tetrahedron 2001, 57, 5137-
5148. (e) Charruault, L.; Michelet, V.; Geneˆt, J .-P. Tetrahedron Lett.
2002, 43, 4757-4760.
Given the feasibility of such a sequence, we speculated
that modification of the molecularity of the above strat-
(10) For the sake of straightforwardness we propose the intuitive
acronyms TM-DOM and TM-PDOM to designate the transition metal-
catalyzed domino and pseudo-domino processes, respectively, TM
indicating the generic transition metal(s) involved in the catalysis.
(11) Of course, the real active catalysts driving each of the two
sequential transformations may differ from one another, although
deriving from the same catalytic system.
(18) Giambastiani, G.; Pacini, B.; Porcelloni, M.; Poli, G. J . Org.
Chem. 1998, 63, 804-807.
(19) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai,
M.; Ando, A.; Shioiri, T. Synlett 1998, 35-36.
(12) For a review see: Poli, G.; Giambastiani, G.; Heumann, A.
Tetrahedron 2000, 56, 5959-5989.
(20) Conrad, P. C.; Kwiatkowski, P. L.; Fuchs, P. L. J . Org. Chem.
1987, 52, 586-591.
(13) Poli, G.; Giambastiani, G.; Pacini, B. Tetrahedron Lett. 2001,
42, 5179-5182.
(21) Brown, E.; Le´se´, A.; Touet, J . Tetrahedron: Asymmetry 1992,
3, 841-844.
(14) Tietze, L. F.; Nordmann, G. Eur. J . Org. Chem. 2001, 3247-
(22) Bream, J . B.; Schmutz, J . Helv. Chim. Acta 1977, 60, 2872-
3253.
2880.
(15) J eong, N.; Seo, D.; Shin, J .-Y. J . Am. Chem. Soc. 2000, 122,
10220-10221.
(16) For two recently published palladium-catalyzed pure-domino
processes involving carbopalladation/allylation see: (a) Shimizu, I.; Lee,
Y.; Fujiwara, Y. Synlett 2000, 1285-1286. (b) Flubacher, D.; Helmchen,
G. Tetrahedron Lett. 1999, 40, 3867-3868.
(23) The presence of the methylenedioxy bridge on the electrophile
had a detrimental effect on the SN2 substitution process. In fact, an
analogous transformation using o-bromobenzhydryl bromide instead
of 12 gave the desired alkylated product in high yield.
(24) Adams, J . T.; Levine, R.; Hauser, C. R. Organic Syntheses;
Wiley: New York, 1955; Collect. Vol. III, pp 405-407.
J . Org. Chem, Vol. 67, No. 26, 2002 9457

SCHEME 3 a
F IGURE 3. Selected NOE interactions observed in 16 and
17.
obtained in 77:23 ratio and could be easily separated by
column chromatography. The relevant coupling constants
in both the isomers of 16, as well as NOE experiments,
suggest that the two epimers possess a cis C/D-ring
junction and they differ by the relative stereochemistry
between C-1 and C-2 (Figure 3).31,32
Finally, treatment of the major epimeric ketone 16a
with NaBH4 in methanol afforded the crystalline carbinol
17 as a single diastereoisomer in quantitative yield.31
A
1
a
strong NOE value between H1 and H4 in the H NMR
spectrum clearly indicated a cis relationship between the
phenyl ring and the hydroxyl group as well as their
equatorial disposition. Furthermore, the coupling con-
stant between H2 and H3 was suggestive of a cis ring
junction.32,33 Definitive stereochemical assignment came
from the X-ray diffraction analysis of a single crystal of
17. Inspection of the crystal structure28 reveals also some
remarkable conformational features. Owing to the cis
fusion between the pyrrolidinone ring and the boat-
shaped cyclohexane, the fused tetracyclic fragment ap-
pears as a bent ribbon. The boatlike shape of the
cyclohexane is due to equatorial disposition of the hy-
droxyl and the phenyl ring. The E-ring is orthogonally
disposed with respect to the cyclohexane ring, so as to
minimize interaction with the neighboring atoms. Last,
but not least, the N-benzyl group lies in the concave site
of the tetracyclic moiety, in a “scorpion tail” disposition,
with its phenyl ring almost bisecting the A/B/C/D scaffold.
Concerning the configurational assignment, the spec-
troscopic and crystallographic analyses unambiguously
indicate that the newly synthesized aza-analogue 17
possesses the epiisopicropodopyllin stereochemistry (i.e.,
it is epimeric at C-3 with respect to podophyllotoxin).
Although cis ring junction in the podophyllolactone
series is normally associated with low pharmacological
activity, it should be pointed out that investigation on
epiisopicropodophyllin has been so far hampered by its
instability. In fact, this epimer is known to spontaneously
rearrange to the more stable bridged isomeric form.34
This is not the case for the aza-analogue 17 owing to the
lower electrophilicity of the lactam with respect to the
lactone function. Thus, the above synthesis represents
the first entry to the epiisopicropodohyllin stereochem-
istry.
Reagents and conditions: (a) PhMgBr, Et2O, 0 °C f reflux,
10 min, 97%; (b) PBr3, CHCl3, rt, 22 h, 94%; (c) 3, BF3‚OEt2, rt,
15 min, quant.; (d) 10% Pd(OAc)2, dppe, AcOK, DMF, 145 °C, 25
min, dr 75:25, 55%; (e) wet DMSO, NaCl, 160 °C, 5 h, 57%; (f)
NMO, 5% OsCl3, THF/H2O, then NaIO4, MeCOMe/H2O, 91%; (g)
NaBH4, MeOH, rt, 30 min, quant.
Having successfully installed rings A/B and E, the
crucial generation of C/D-rings was then tackled. Quite
gratifyingly, treatment of 13 with a catalytic amount of
Pd(OAc)2 in the presence of dppe and AcOK,27 in DMF
at 145 °C, gave the desired tetracyclic structure 14 in
55% yield as a 75:25 mixture of two (out of four possible)
diastereoisomers. Corollary cyclization experiments in-
dicated that after 20 min at 85 °C the intermediate allylic
alkylation product 13′ (not shown)28 could be isolated in
79% yield, and its resubmission to the original reaction
conditions gave again the final Heck product 14. Careful
NMR analysis suggested that both the isomers possessed
a cis ring junction.29 Heating 14 at 160 °C in the presence
of NaCl in wet DMSO30 gave three isomeric demethoxy-
carbonylated products in a 71:21:8 ratio. Chromato-
graphic purification of the crude product allowed an easy
removal of the third minor isomer 15′ (not shown) and
isolation of the two major cis-fused diastereoisomers 15
as an inseparable 77:23 mixture. Given the reaction
conditions of the decarboxylation reaction, preferential
formation of the thermodynamically more stable cis-fused
products was expected. Indeed, further transformations
(see below) confirmed this expectation.
Unmasking of the C-4 carbonyl function was ac-
complished via osmium-catalyzed alkene cis-dihydroxyl-
ation followed by periodic oxidation of the generated diols.
The resulting diastereomeric ketones 16a and 16b were
(25) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823-
1826.
(26) The diastereoisomeric ratio was not detectable by 1H NMR
owing to amide bond effect.
(31) Brewer, C. F.; Loike, J . D.; Horwitz, S. B.; Sternlicht, H.;
Gensler, W. J . J . Med. Chem. 1979, 22, 215-221.
(27) Molar ratio Pd(OAc)2:dppe:AcOK:13 ) 0.1:0.2:2.0:1.0.
(28) See Supporting Information.
(32) 16a (major): J 1,2 ) 6.64 Hz, J 2,3 ) 9.92 Hz; 16b (minor): J 1,2
1.44 Hz, J 2,3 ) 7.32 Hz. 17: J 1,2 ) 4.56 Hz; J 2,3 ) 9.16 Hz.
)
(29) The value of the allylic coupling constants in both the diaste-
reoisomers 14 was essentially zero. Previous studies in the laboratory
indicated that such a feature is associated to cis junction.
(30) For reviews see: (a) Krapcho, A. P. Synthesis 1982, 805-822.
(b) Krapcho, A. P. Synthesis 1982, 893-914.
(33) Analogously, NaBH4 reduction of the minor diastereoisomer 16b
gave quantitatively alcohol 17b (structure not shown in the publication)
as the only detectable epimer.
(34) Forsey, S. P.; Rajapaksa, D.; Taylor, N. J .; Rodrigo, R. J . Org.
Chem. 1989, 54, 4280-4290.
9458 J . Org. Chem., Vol. 67, No. 26, 2002

147.87, 148.44, 149.01, 149.85, 169.34, 169.98, 171.47, 173.51.
IR (CDCl3): 3090, 3020, 2950, 2900, 1735, 1695 cm-1. MS (CI -
NH3) m/z (%): 468 (M+ + H+), 485 (M+ + NH4+). Anal. Calcd
for C29H25NO5: C, 74.50; H, 5.39; N, 3.00. Found: C, 74.36; H,
5.20; N, 2.88.
In conclusion, the present study has allowed the
synthesis of (()-demethoxy epiisopicropodophyllin N-
benzyl lactam. The crucial step consists of a Pd-PDOM
type I doubly intramolecular process (allylic alkylation/
Heck), which generates rings C/D in a single synthetic
operation. Rings A/B and E are separately assembled and
entered at an early stage via a new and efficient cationic
benzhydrylation process. The synthesis is convergent and
straightforward, entailing 10 sequential synthetic opera-
tions starting from 1,4-dihydroxy-2-butene with a 15%
global yield. Future investigations will address the
installation of the methoxylated E-ring and access to the
different stereochemical manifolds, possibly in enantio-
selective versions. Biological activity tests for 17 and
related derivatives will also be addressed.
(()-(1R,2R,3R)-12-Ben zyl-6,7-m eth ylen ed ioxy-4-m eth yl-
en e-1-p h en yl-2,3-d ih yd r oben zo[f]isoin d ol-13-on e a n d (()-
(1R,2S,3S)-12-Ben zyl-6,7-m et h ylen ed ioxy-4-m et h ylen e-1-
p h en yl-2,3-d ih yd r oben zo[f]isoin d ol-13-on e (15), a n d (()-
(6,7-Meth ylen ed ioxy-4-m eth ylen e-1-p h en yl-12-ben zyl-2,3-
d ih yd r oben zo[f]isoin d ol-1-on e (15′) (unknown relative con-
figuration, structure not shown in the publication). To a solution
of the fused lactams 14 (0.226 g, 0.483 mmol), in DMSO (4 mL)
and H2O (20 µL), was added NaCl (56 mg, 0.966 mmol), and the
resulting mixture was stirred at 160 °C for 5 h. After the mixture
was cooled to ambient temperature, water was added (40 mL)
and the solution was extracted with AcOEt (3 × 15 mL). The
collected organic phases were dried, and the solvent was removed
in a vacuum. 1H NMR analysis of the crude product showed the
presence of three diastereomeric decarboxylated lactams in a
71:21:8 ratio. Flash-chromatography (hexanes/AcOEt, 80:20)
allowed isolation of the two major, inseparable, cis-fused dia-
stereisomers 15 (49%, 74% considering the recovered unreacted
starting material) and of the minor one 15′, whose relative
stereochemistry could not be assigned. 15: 1H NMR (CDCl3, 400
MHz): δ 7.28-7.10 and 6.90-6.66 (12H), 5.99 (AB system, 2H,
23%), 5.97 (AB system, 2H, 77%), 5.52 (d, 1H, 77%, J ) 3.08
Hz), 5.24 (s, 1H, 23%), 4.89 (s, 1H, 23%), 4.86 (d, 1H, 77%, J )
2.56 Hz), 4.70 (d, 1H, 23%, J ) 1.52 Hz), 4.62 (part of AB system,
1H, 23%), 4.54 (d, 1H, 77%, J ) 6.08 Hz), 4.27 (part of AB
system, 1H, 77%), 4.14 (part of AB system, 1H, 23%), 4.11 (part
of AB system, 1H, 77%), 3.65 (dd, 1H, 23%, J ) 9.64 Hz, J )
7.64 Hz), 3.55 (m, 1H, 77%), 3.38 (part of ABX system, 1H, 77%),
3.39-3.30 (1H, 77%, part of ABX system, 2H, 23%), 3.18 (dd,
1H, 77%, J ) 10.16 Hz, J ) 6.08 Hz), 2.99 (dd, 1H, 23%, J )
10.16 Hz, J ) 2.04 Hz), 2.66 (part of AB system, 1H, 77%). 13C
NMR (CDCl3, 100 MHz, selected data): δ 35.46, 36.07, 45.63,
46.34, 47.76, 48.63, 52.71, 54.35, 101.12, 101.26, 105.31, 105.75,
108.89, 111.31, 126.34, 126.94, 127.31, 127.41, 127.61, 127.83,
127.92, 128.20, 128.42, 128.56, 129.59, 130.16, 130.87, 131.07,
132.52, 135.72, 135.98, 139.97, 142.96, 144.01, 146.13, 147.49,
147.59, 148.20, 174.10, 174.18. IR (CDCl3): 3075, 3010, 2960,
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were conducted under dried
nitrogen or argon atmosphere using oven-dried glassware. For
air- and/or water-sensitive reactions, glassware was flame-dried
and then allowed to cool under argon or dried nitrogen atmo-
sphere before use. All solvents were purified and distilled
according to standard methods. Chromatographic purifications
were conducted using 40-63 µm or 15-40 µm silica gel. All NMR
spectra were recorded in CDCl3 or DMSO-d6 (D2O). Elemental
analyses were carried out with accepted tolerance of (0.3 units
on carbon (C), hydrogen (H), and nitrogen (N). All compounds
were isolated as oils unless otherwise specified, and their purities
were determined to be >95% by NMR analysis. Compounds 14-
17 are named according to podophyllotoxin numbering.
(()-(1R,2R,3S)-12-Ben zyl-2-m eth oxyca r bon yl-4-m eth yl-
en e-6,7-m eth ylen edioxy-1-ph en yl-3-h ydr oben zo[f]isoin dol-
13-on e a n d (()-(1S,2R,3S)-12-Ben zyl-2-m eth oxyca r bon yl-
4-m eth ylen e-6,7-m eth ylen ed ioxy-1-p h en yl-3-h yd r oben zo-
[f]isoin d ol-13-on e (14). To a solution of the acyclic precursor
13 (180 mg, 0.298 mmol) in dry DMF (2 mL), at 0 °C, under
argon atmosphere was added NaH (60% dispersion in mineral
oil) (13 mg, 0.328 mmol), and the solution was stirred at ambient
temperature for 20 min. In a separate flask, Pd(OAc)2 (6.6 mg,
0.0298 mmol) and dppe (24 mg, 0.0596 mmol) were dissolved in
dry DMF (1 mL). After 20 min stirring at ambient temperature
solid AcOK (58 mg, 0.596 mmol) was added to the thus formed
Pd(0) complex. The previously generated enolate was then
cannulated into the Pd(0) solution, and the resulting mixture
was stirred at 145-147 °C for 25 min. A 25 wt % aqueous NH4-
Cl solution (2 mL) was then added, and the aqueous phase was
extracted with Et2O (3 × 6 mL). The collected organic phases
were dried, and the solvent was removed in a vacuum. Flash
chromatography (hexanes/AcOEt, 75:25) gave the desired hy-
drobenzoisoindolone derivative 14 as an inseparable mixture of
1685 cm-1. MS (CI - NH3) m/z (%): 410 (M+ + H+), 427 (M+
+
NH4+). Anal. Calcd for C27H23NO3: C, 79.20; H, 5.66; N, 3.42.
Found: C, 79.44; H, 5.73; N, 3.58. 15′: 1H NMR (CDCl3, 400
MHz): δ 7.37-7.07 (11H), 6.30 (s, 1H), 5.91 (AB system, 2H),
5.39 (d, 1H, J ) 1.88 Hz), 4.72 (d, 1H, J ) 2 Hz), 4.46 (AB
system, 2H), 4.25 (d, 1H, J ) 11.4 Hz), 3.41 (AB system, 2H),
2.94-2.89 (m, 1H), 2.69 (dd, 1H, J ) 13.64 Hz, J ) 11.4 Hz).
MS (CI - NH3) m/z (%): 410 (M+ + H+), 427 (M+ + NH4+).
Ack n ow led gm en t. This work was supported by the
Comite´ National de la Recherche Scientifique and by a
COST action of the European Community. We thank
Dr. Cristina Faggi (University of Florence) for the X-ray
analysis and Dr. Emmanuel Bertounesque (Institut
Curie) for fruitful discussions.
1
two diastereoisomers (75:25): pale yellow gum (55%). H NMR
(CDCl3, 400 MHz): δ 7.36-7.13 and 6.87-6.84 (11H), 6.56 (s,
1H, 25%), 6.37 (m, 1H, 75%), 5.95 (AB system, 2H, 25%), 5.93
(AB system, 2H, 75%), 5.51 (s, 1H, 75% and s, 1H, 25%), 4.82
(part of AB system, 1H, 75%), 4.74 (d, 1H, J ) 2.55 Hz, 25%),
4.68 (s, 1H, 75% and s, 1H, 25%), 4.66 (d, 1H, J ) 1.53 Hz, 75%),
4.49 (part of AB system, 1H, 25%), 4.33 (part of AB system, 1H,
75%), 4.28 (part of AB system, 1H, 25%), 3.58 (s, 3H, 25%), 3.40-
3.25 (3H, 75% and 2H, 25%), 3.37 (s, 3H, 75%), 3.23-3.19 (m,
1H, 25%). 13C NMR (CDCl3, 100 MHz, selected data): δ 46.45,
47.39, 47.63, 49.16, 49.79, 53.43, 52.84, 60.98, 62.10, 102.24,
102.36, 104.27, 104.56, 105.21, 105.86, 111.01, 111.48, 128.18,
128.59, 128.83, 128.91, 129.01, 129.52, 129.70, 129.82, 130.64,
132.65, 133.85, 134.08, 137.17, 137.37, 140.79, 141.10, 142.06,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for the following com-
pounds: piperonal, 10, 11, 12, 13, 13′, 16a , 16b, 17, and 17′.
X-ray ORTEP structure and crystallographic data for com-
pound 17. 1H and 13C NMR spectra for all previously unre-
ported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O026068+
J . Org. Chem, Vol. 67, No. 26, 2002 9459