N-substituted tetronamides as ambident nucleophilic building blocks for the synthesis of new 4-aza-2,3-didehydropodophyllotoxins

Article abstract of DOI:10.1055/s-2008-1078429

Aza-analogues of podophyllotoxin were synthesized in two steps from N-substituted tetronamides. The acid-mediated benzhydrylation of N-substituted tetronamides with a suitably func-tionalized benzhydrol quantitatively afforded the cyclization precursors.

Full text of DOI:10.1055/s-2008-1078429

LETTER
1475
N-Substituted Tetronamides as Ambident Nucleophilic Building Blocks for the
Synthesis of New 4-Aza-2,3-didehydropodophyllotoxins
Synthesis of
N
ew 4
a
-Aza-2,3-d
v
idehydropod
i
ophyll
d
otoxins Madec,* Francesco Mingoia,1 Guillaume Prestat, Giovanni Poli*
Laboratoire de Chimie Organique, FR2769 Institut de Chimie Moléculaire, UPMC Univ Paris 06, UMR CNRS 7611, Case 183, 75005 Pa-
ris, France
Fax +33(1)44277567; E-mail: giovanni.poli@upmc.fr; E-mail: david.madec@upmc.fr
Received 13 March 2008
Dedicated to Professor Jean-Pierre Genêt in honor of his 65th birthday
O
R
O
Abstract: Aza-analogues of podophyllotoxin were synthesized in
two steps from N-substituted tetronamides. The acid-mediated
benzhydrylation of N-substituted tetronamides with a suitably func-
tionalized benzhydrol quantitatively afforded the cyclization pre-
cursors. The target pentacyclic 4-aza-2,3-didehydropodo-
phyllotoxins were next obtained via an intramolecular copper-me-
diated Ullmann-type N-arylation.
O
O
HO
OH
C
OH
O
A
O
O
B
D
O
O
O
O
O
E
Key words: podophyllotoxin, benzhydrylation, copper, N-aryla-
tion, tetronamide
MeO
OMe
MeO
OMe
OMe
OH
etoposide (R = Me)
teniposide (R = 2-thienyl)
(–)-podophyllotoxin
OH
Podophyllotoxin (Figure 1), the parent member of arylte-
tralin lignan lactone family,2 was first isolated in 1880
from podophyllin,3 a resinous powder obtained by precip-
itating an alcoholic tincture of American Mayapple rhi-
zome (Podophyllum peltatum). Although the medicinal
properties of podophyllotoxin have been known for thou-
sands of years, particular attention toward this molecule
arose since the discovery of its antimitotic activity,4 due to
its high affinity for tubulin.5 Indeed, podophyllotoxin,
while altering cellular division during mitosis, triggers
cellular death.6 However, the use of this molecule as anti-
cancer agent is hampered due to its high toxicity associat-
ed with numerous secondary effects such as nausea,
diarrhea, vomiting and injury of healthy tissues.7 As a
consequence, several hemisynthetic derivatives, such as
etoposide8 or teniposide9 have been developed and suc-
cessfully used for the clinical treatment of several cancers,
including small cell lung carcinoma, testicular cancer, or
Kaposi’s sarcoma.10 Interestingly and in contrast to podo-
phyllotoxin, these analogues do not target tubulin, but in-
hibit topoisomerase II, a nuclear enzyme involved in
transitional breaks of DNA double-strand and compulsory
for transcription.11 More recently, it was reported that pi-
cropodophyllin and various aza-analogues of podophyllo-
toxin (Figure 1) are potent selective inhibitors of the
insulin-like growth factor 1 receptor (IGF-1R).12 These
compounds blocking tyrosine phosphorylation, can be
considered as interesting drugs for the treatment of IGF-
1R dependent diseases, such as cancer, psoriasis, arterio-
sclerosis and others endocrine or metabolic disorders. In-
H
N
O
O
O
O
O
O
O
O
MeO
OMe
MeO
OMe
OMe
OMe
picropodophyllin
4-aza-2,3-didehydropodophyllotoxin
Figure 1 Structures of podophyllotoxin and related aryltetralin li-
gnan lactones
transformation, growth and survival of malignant cells.13
As a consequence, the development of new aza-analogues
of the podophyllotoxin family is a crucial area of re-
search.14 The synthesis15 and biological evaluation of 4-
aza-2,3-didehydropodophyllotoxins by Takeya et al.16
and the development of an efficient multicomponent one-
step procedure toward similar structures by Husson et al.17
represent two relevant examples in this field.
In 2002, we described the acid-mediated reaction between
active methylenes such as ethyl acetoacetate, acetylace-
tone and N,N-dibenzylmalonamic acid methyl ester with
benzhydrols or their derivatives, to afford the correspond-
ing alkylated products in quantitative yields (Scheme 1).18
This new reaction could later be exploited for the prepara-
tion of an advanced intermediate of podophyllotoxin19
and of an aza-analogue of it.20
deed, the IGF-1R plays
a central role in the
From these results and following our ongoing interest in
the synthesis of aza-analogues of podophyllotoxin, we
next envisaged to exploit N-substituted tetronamides,21
vinylogous carbamates easily available from tetronic acid,
SYNLETT 2008, No. 10, pp 1475–1478
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078429; Art ID: G09508ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1476
D. Madec et al.
LETTER
O
O
O
O
OH
equimolar mixture of 1 and 2 with BF3⋅OEt2 (1.5 equiv) in
CH2Cl2 at room temperature gave the desired alkylated
tetronic acid 3 in quantitative yield. Encouraged by this
result, N-benzyl tetronamide (4a), easily obtained from
tetronic acid and benzylamine,22 was then engaged in the
same procedure. Again, the expected corresponding ad-
duct 5 was quantitatively obtained.
BF3⋅OEt2
+
Ar1
Ar2
Me
X
>98% yield
Me
X
Ar1
Ar2
X = OEt, Me, NBn2
Scheme 1 Acid-mediated benzhydrylation of active methylenes
as ambident nucleophilic building blocks to generate the
D-ring of 4-aza-2,3-didehydropodophyllotoxins. We de-
scribe herein the synthesis of such analogues following
the retrosynthetic strategy depicted in Scheme 2.
Properly functionalized benzhydrylic alcohol 6, required
for the synthesis of aza-analogues of podophyllotoxin,
was obtained from piperonal and 1-bromo-3,4,5-tri-
methoxybenzene, according to the two-step procedure de-
scribed by Jung et al.23 Then, its reaction with tetronic
acid (1) and three other N-alkyl tetronamides 4a–c was
studied (Scheme 4).
O
O
O
O
R
MeO
MeO
MeO
MeO
MeO
MeO
X
N-arylation
O
O
N
R
HN
O
O
MeO
MeO
MeO
Br
MeO
MeO
MeO
Br
O
O
O
O
X
A
B
OH
(a)
benzhydrylation
O
6
O
O
+
X
HN
R
7, X = OH, 70%
O
MeO
MeO
MeO
X
8a, X = NHBn, 80%
8b, X = NHPh, 95%
8c, X = NHPMB, 35%
O
O
+
O
O
OH
1, 4a–c
C
D
Scheme 4 Reagents and conditions: (a) BF3⋅OEt2 (3 equiv),
CH2Cl2, r.t., 2 h.
Scheme 2 Retrosynthetic approach to 4-aza-2,3-didehydropodo-
phyllotoxins
Tetronic acid (1) reacted with benzhydrol 6 to afford the
corresponding adduct 7 in 70% yield. In this case, and not
unexpectedly, the use of an excess of Lewis acid (3 equiv)
was required for satisfactory kinetics. Indeed, the several
Lewis basic sites present in the benzhydrylic substrate 6
are likely to interact with the Lewis acid, thereby inhibit-
ing the ionization process, necessary for the alkylation to
take place. Reaction between N-benzyl tetronamide (4a)
or N-phenyl tetronamide (4b)22 and 6, using the above op-
timized reaction conditions, gave rise to the correspond-
ing alkylated products 8a and 8b in 80% or 95% yields,
respectively.24 Disappointingly enough, tetronamide 4c,
derived from p-methoxybenzylamine, afforded the de-
sired product 8c in a moderate 35% yield.
The targeted 4-aza-2,3-didehydropodophyllotoxins A
would result from the intramolecular N-arylation of benz-
hydryltetronamides B. The latter intermediates could in
turn arise from alkylation of N-substituted tetronamides D
with the functionalized benzhydrol C, according to our
acid-catalyzed methodology.18
The feasibility of this type of benzhydrylation was first
studied in the direct reaction of tetronic acid (1) with
benzhydrol (2; Scheme 3). In this event, treatment of an
Ph
OH
OH
Ph
Ph
Ph
(a)
(a)
+
O
OH
O
O
O
O
O
O
1
2
3
O
MeO
MeO
MeO
MeO
MeO
MeO
Br
(b)
Ph
(a)
NHBn
+
N
R
NHR
NHBn
Ph
2
O
O
O
O
O
O
O
O
4a
5
8a–c
9a, R = Bn, 100%
9b, R = Ph, 82%
9c, R = PMB, 84%
Scheme 3 Reagents and conditions: (a) BF3⋅OEt2 (1.5 equiv),
CH2Cl2, r.t., 2 h, quantitative; (b) BnNH2 (5 equiv), AcOH, reflux,
3 h, 53%.
Scheme 5 Reagents and conditions: (a) CuI (1.2 equiv), Cs2CO3
(2.5 equiv), DMF, 90 °C, 16 h.
Synlett 2008, No. 10, 1475–1478 © Thieme Stuttgart · New York

LETTER
Synthesis of New 4-Aza-2,3-didehydropodophyllotoxins
1477
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With the desired intermediates 8a–c in hand, we next
studied the intramolecular C–N bond-forming reaction.
Buchwald–Hartwig palladium-catalyzed N-arylation25
was first tested using precursor 8a as the model substrate.
Unfortunately, the use of Pd2dba3 or Pd(OAc)2 as palladi-
um sources, 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl
(BINAP), P(o-Tol)3 or P(t-Bu)3 as ligands, and t-BuONa
as base at reflux of toluene did not afford the desired pen-
tacyclic product, the starting material being totally recov-
ered. A copper-mediated Ullmann-type N-arylation was
thus envisioned as an alternative.26 Much to our satisfac-
tion, treatment of the benzhydrylated N-benzyl tetrona-
mide 8a with CuI (1.2 equiv) and Cs2CO3 (2.5 equiv) in
DMF gave, after 16 hours at 90 °C, according to Fukuya-
ma’s protocol,27 the expected 4-aza-2,3-didehydropodo-
phyllotoxin 9a in quantitative yield (Scheme 5).
Analogously, starting from the N-substituted tetronamide
precursors 8b and 8c, the corresponding aza-analogues 9b
and 9c were obtained in 82% and 84% yields, respective-
ly.28,29
Feliciano, A. Curr. Pharm. Des. 2000, 6, 1811.
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see: (a) Magedov, I. G.; Manpadi, M.; Rozhkova, E.;
Przheval’skii, N. M.; Rogelj, S.; Shors, S. T.; Steelant, W. F.
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Przheval’skii, N. M.; Rogelj, S.; Kornienko, A. J. Med.
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Monneret, C.; Rager, M. N.; Bertounesque, E. Synlett 2006,
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Giorgi-Renault, S. J. Org. Chem 2008, 73, 3642.
(15) Hitotsuyanagi, Y.; Kobayashi, M.; Fukuyo, M.; Takeya, K.;
Itokawa, H. Tetrahedron Lett. 1997, 38, 8295.
In summary, three aza-analogues of podophyllotoxin have
been synthesized in two steps using N-alkyl tetronamides
as suitable ambident D-ring generating building blocks.
The cyclization precursors were formed through the
Lewis acid mediated benzhydrylation of N-alkyl tetrona-
mides with a suitably functionalized benzhydrol. The de-
sired pentacyclic structure of the 4-aza-2,3-
didehydropodophyllotoxins was next obtained via an in-
tramolecular copper-mediated Ullmann-type N-arylation.
The elaboration of the cyclization precursors by a multi-
component reaction and the development of a copper-cat-
alyzed N-arylation of these enamines are currently under
investigation.
(16) Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.; Kobayashi, M.;
Ozeki, A.; Itokawa, H.; Takeya, K. Bioorg. Med. Chem. Lett.
2000, 10, 315.
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2002, 4, 3187. (b) Giorgi-Renault, S. Ann. Pharm. Fr. 2005,
63, 63. (c) Husson, H.-P.; Giorgi-Renault, S.; Tratrat, C.;
Atassi, G.; Pierre, A.; Renard, P.; Pfeiffer, B. Eur. Patent,
EP1103554, 2000.
Acknowledgment
CNRS, CNR and UPMC are acknowledged for financial support.
The sponsorship of COST Action D40 ‘Innovative Catalysis: New
Processes and Selectivities’ is kindly acknowledged.
(18) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002,
1823.
(19) Mingoia, F.; Vitale, M.; Madec, D.; Prestat, G.; Poli, G.
Tetrahedron Lett. 2008, 49, 760.
(20) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456.
(21) For previous use of N-benzyl tetronamides as building block,
see: (a) Sydorenko, N.; Hsung, R. P.; Darwish, O. S.; Hahn,
J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732.
References and Notes
(1) Present address: Istituto per lo Studio dei Materiali
Nanostrutturati, CNR, Via Ugo La Malfa 153, 90146
Palermo, Italy
(b) McLaughlin, M. J.; Hsung, R. P.; Cole, K. C.; Hahn, J.
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10, 1.
(22) Momose, T.; Toyooka, N.; Nishi, T.; Takeuchi, Y.
Heterocycles 1988, 27, 1907.
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J. Org. Chem. 1985, 50, 1087.
(3) Podwyssotzki, V. Arch. Exp. Pathol. Pharmakol. 1880, 13,
29.
(24) Representative Experimental Procedure for
Benzhydrylation Reaction: To a stirred solution of
benzhydrol 6 (437 mg, 1.1 mmol, 1.1 equiv) and enamine 4a
(189 mg, 1 mmol) in anhyd CH2Cl2 (10 mL) under a N2
atmosphere at r.t. was added BF3⋅OEt2 (0.380 mL, 3 equiv).
The mixture was stirred for 2 h before a sat. aq NaHCO3
solution (10 mL) was added. The aqueous layer was
extracted with Et2O (3 × 10 mL). The organic layers were
washed with brine (5 mL), dried over MgSO4 and
(4) King, L.; Sullivan, M. Science 1946, 104, 244.
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Synlett 2008, No. 10, 1475–1478 © Thieme Stuttgart · New York

1478
D. Madec et al.
LETTER
concentrated under reduced pressure. The crude material
was purified by flash chromatography (cyclohexane–
EtOAc, 7:3) to afford the alkylated product 8a as a white
foam (455 mg, 80% yield). 1H NMR (400 MHz, CDCl3): d =
3.74 (s, 6 H), 3.80 (s, 3 H), 4.05–4.16 (m, 2 H), 4.64–4.79 (d,
AB system, J = 15.4 Hz, 2 H), 5.38 (s, 1 H), 5.93 (d, J = 1.3
Hz, 1 H), 6.00 (d, J = 1.3 Hz, 1 H), 6.35 (s, 2 H), 6.65 (s, 1
H), 6.95 (d, J = 7.6 Hz, 2 H), 7.07 (s, 1 H), 7.32–7.28 (m, 3
H). 13C NMR (100 MHz, CDCl3): d = 46.0, 47.8, 56.3, 61.0,
65.3, 95.8, 101.9, 105.7, 109.6, 113.5, 115.8, 126.6, 128.3,
129.1, 133.3, 136.0, 136.7, 137.1, 147.4, 147.5, 153.7,
163.3, 174.5. IR (neat): 3375, 2930, 2870, 1730, 1625, 1585,
1500, 1475, 1415, 1230, 1120, 1035 cm–1. HRMS (CI): m/z
calcd for C28H26O7N79BrNa: 590.07849 and
(28) Representative Experimental Procedure for
Intramolecular Copper-Mediated N-Arylation Reaction:
To a solution of cyclization precursor 8a (217 mg, 0.38
mmol) in anhyd DMF (4 mL) at r.t. were added CuI (87 mg,
0.46 mmol, 1.2 equiv) and Cs2CO3 (311 mg, 0.96 mmol, 2.5
equiv). The resulting mixture was stirred at 90 °C for 16 h.
A sat. aq NH4Cl solution (5 mL) was added and the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The collected
organic phases were washed with aq NH3–NH4Cl solution
(1:1, 10 mL), brine (3 × 5 mL), and dried over MgSO4. The
solvent was removed under reduced pressure. The crude
product was purified by flash chromatography
(cyclohexane–EtOAc, 7:3) to afford aza-analogue 9a as a
yellow foam (185 mg, quantitative yield). 1H NMR (400
MHz, CDCl3): d = 3.82 (s, 9 H), 4.75–4.89 (m, 4 H), 5.08 (s,
1 H), 5.89 (d, J = 1.2 Hz, 1 H), 5.91 (d, J = 1.2 Hz, 1 H), 6.45
(s, 1 H), 6.46 (s, 2 H), 6.59 (s, 1 H), 7.24–7.38 (m, 5 H). 1H
NMR (400 MHz, DMSO-d6): d = 3.61 (s, 3 H), 3.73 (s, 6 H),
4.94 (s, 1 H), 4.96 (d, AB system, J = 17.4 Hz, 2 H), 5.13 (d,
AB system, J = 15.9 Hz, 2 H), 5.87 (d, J = 0.8 Hz, 1 H), 5.95
(d, J = 0.8 Hz, 1 H), 6.53 (s, 2 H), 6.72 (s, 1 H), 6.77 (s, 1 H),
7.29–7.40 (m, 5 H). 13C NMR (100 MHz, DMSO-d6): d =
39.8, 48.9, 55.8, 59.9, 65.6, 95.5, 96.7, 101.4, 104.6, 110.0,
119.1, 126.5, 127.6, 128.9, 131.1, 136.0, 136.5, 142.6,
143.5, 146.7, 152.9, 159.9, 172.2. IR (neat): 2935, 2845,
1730, 1645, 1615, 1590, 1505, 1475, 1240, 1190, 1125, 1040
cm–1. HRMS (CI): m/z calcd for C28H25O7NNa: 510.15232;
found: 510.15154.
C28H26O7N81BrNa: 592.07692; found: 590.07755 and
592.07560.
(25) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (c) Hartwig, J. F. Acc.
Chem. Res. 1998, 31, 852. (d) Yang, B. H.; Buchwald, S. L.
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(29) The cyclization of enolic precursors such as 7 to give 4-oxa-
2,3-didehydropodophyllotoxin analogues will be the object
of a separate study and will be reported elsewhere.
(27) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5,
4987.
Synlett 2008, No. 10, 1475–1478 © Thieme Stuttgart · New York

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