Selective amidation of 2,6-dihalogenopurines: Application to the synthesis of new 2,6,9-trisubstituted purines

Article abstract of DOI:10.1021/jo071196p

(Chemical Equation Presented) We report herein the palladium(0)/Xantphos- catalyzed cross-coupling of various amides with 2,6-dihalogenopurines, with substituent-dependent regioselectivity. Furthermore, subjecting the same 2,6-dihalogenopurines to S_N

Full text of DOI:10.1021/jo071196p

SCHEME 1. Structure of the Purine Ring
Selective Amidation of 2,6-Dihalogenopurines:
Application to the Synthesis of New
2,6,9-Trisubstituted Purines
Sandrine Piguel†,‡ and Michel Legraverend*,‡
UniV Paris-Sud, Orsay F-91405, France, and UMR 176, Institut
Curie, Baˆt. 110-112, Centre UniVersitaire, 91405 Orsay, France
6-amido-2-aminopurines have not yet been explored and,
therefore, could find new applications in biology.
michel.legraVerend@curie.u-psud.fr
ReceiVed June 6, 2007
Following our previous efforts to synthesize 2-amidopurines
from 6-amino-2-iodopurines,4 the goal of the present work was
to synthesize purine derivatives bearing the alternative combina-
tion of an amide at the 6-position and an amine at position 2
from a readily available 2,6-dihalogenopurine such as 11
(Schemes 1 and 2). However, according to the literature (Scheme
1), an initial amination step (SNAr) of 1 would occur at position
6.5-8 Thus, to prepare a 6-amidopurine from 1, the amidation
step must be carried out first. While 6-amidopurines can be
synthesized in two steps from 2,6-dihalogenopurine (amination
followed by acylation9-11), a more straightforward method
would be a direct amidation of 2,6-dihalogenopurine 1. Although
Pd(0)-catalyzed amidations of 6-bromo-12 and 6-chloropurine13
have been described during the progress of our work, the
regioselectivity in amidations of 2,6-dihalogenopurines has not
yet been studied. Therefore, this paper reports the first examples
of regioselective amidation of 2,6-dihalogenopurines via an
efficient Pd(0)-catalyzed reaction using Buchwald conditions.14
Palladium-catalyzed reactions on purines can be performed
by taking advantage of the well-known regioselectivity between
the 6 and 2 positions in Suzuki,15 Sonogashira,16,17 and Stille18
reactions. For example, Pd(0)-catalyzed alkyne cross-coupling
with 1, at room temperature, provides the 2-alkynyl derivative
We report herein the palladium(0)/Xantphos-catalyzed cross-
coupling of various amides with 2,6-dihalogenopurines, with
substituent-dependent regioselectivity. Furthermore, subject-
ing the same 2,6-dihalogenopurines to SNAr conditions with
amide/NaH in DMF leads to inverted regioselectivity albeit
in lower yield. These methodologies allow the two-step
synthesis of new 2,6,9-trisubstituted purines from readily
available 2,6-dihalogenopurines.
(4) Vandromme, L.; Legraverend, M.; Kreimerman, S.; Lozach, O.;
Meijer, L.; Grierson, D. S. Bioorg. Med. Chem. 2007, 15, 130.
(5) Chang, Y.-T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon,
S.; Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. G. Chem.
Biol. 1999, 6, 361.
(6) Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L.;
Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg. Med. Chem. 1999, 7, 1281.
(7) (a) Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma,
A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang,
X.; Wick, M. M.; Zhang, X.; Lum, R. T. Bioorg. Med. Chem. Lett. 1997,
7, 2697. (b) Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1998, 39, 1827.
(8) Liu J.; Robins, M. J. J. Am. Chem. Soc. 2007, 129, 5962 and
references cited therein.
(9) Jagtap, P. G.; Chen, Z.; Szabo, C.; Klotz, K.-N. Bioorg. Med. Chem.
Lett. 2004, 14, 1495.
(10) Buck, I. M.; Eleuteri, A.; Reese, C. B. Tetrahedron 1994, 50, 9195.
(11) Aritomo, K.; Wada, T.; Sekine, M. J. Chem. Soc., Perkin Trans. 1
1995, 1837.
(12) Terrazas, M.; Ariza, X.; Farras, J.; Guisado-Yang, J. M.; Vilarrasa,
J. J. Org. Chem. 2004, 69, 5473.
A great variety of di-, tri-, or tetrasubstituted purines so far
described in the literature have been found to be potent inhibitors
of chaperone HSP90, protein kinases (MAP, Src, and Cdk),
sulfotransferases, phosphodiesterases, and microtubule assembly,
inducers of interferon and (de)differenciation, antagonists of
adenosine receptors, and corticotropin-releasing hormone recep-
tors.1 This wide range of biological activities displayed by
purines is confered by the diversity of the substituents that can
be combined on the C-2, C-6, C-8, and N-9 centers (Scheme
1). It is therefore of great interest to explore new types of
substituents on the purine ring of which introduction of an amide
function at positions 2 and/or 6 is particularly pertinent since
known inhibitors of various protein kinases have been improved
in this way.2,3 Whereas many 2,6-diaminopurine derivatives
(roscovitine, purvalanol)1 exhibit potent biological activities,
(13) Terrazas, M.; Ariza, X.; Vilarrasa, J. Org. Lett. 2005, 7, 2477.
(14) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(15) Havelkova, M.; Dvorak, D.; Hocek, M. Synthesis 2001, 1704.
(16) Abiru, T.; Miyashita, T.; Watanabe, Y.; Yamaguchi, T.; Machida,
H.; Matsuda, A. J. Med. Chem. 1992, 35, 2253.
(17) Harada, H.; Asano, O.; Hoshino, Y.; Yoshikawa, S.; Matsukura,
M.; Kabasawa, Y.; Niijima, J.; Kotake, Y.; Watanabe, N.; Kawata, T.; Inoue,
T.; Horizoe, T.; Yasuda, N.; Minami, H.; Nagata, K.; Murakami, M.;
Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S. J. Med. Chem. 2001, 44,
170.
* To whom correspondance should be addressed. Tel: +33(0)169863085.
Fax: +33(0)169075381.
† Univ Paris-Sud.
‡ Institut Curie.
(1) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987.
(2) Furet, P.; Bold, G.; Hofmann, F.; Manley, P.; Meyer, T.; Altmann,
K.-H. Bioorg. Med. Chem. Lett. 2003, 13, 2967.
(3) Yue, E. W.; DiMeo, S. V.; Higley, C. A.; Markwalder, J. A.; Burton,
C. R.; Benfield, P. A.; Grafstrom, R. H.; Cox, S.; Muckelbauer, J. K.;
Smallwood, A. M. Bioorg. Med. Chem. Lett. 2004, 14, 343.
(18) Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52, 5625.
10.1021/jo071196p CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/08/2007
7026
J. Org. Chem. 2007, 72, 7026-7029

SCHEME 2. Palladium-Catalyzed Amidation of 2,6-Dihalogenopurines
SCHEME 3. Synthesis of 2-Amido- or 6-Amidopurines Using Amide/NaH
in high yield. In this context, we first investigated the cross-
coupling of 1.05 equiv of different amides (aryl or alkyl) and
6-chloro-2-iodopurine 1, in the presence of 2 mol % of
Pd2dba3, 6 mol % of Xantphos, and 1.4 equiv of Cs2CO3 in
anhydrous dioxane at 100 °C, according to the conditions
described by Buchwald.14 These conditions led to the regiose-
lective formation of 2-amidopurines 2a-d in 67-80% yield
(Scheme 2). As proof of the regioselectivity, 13C NMR
experiments revealed the disappearence of the characteristic
signal of the C-2-I of 1 (δ ) 116.4 ppm) and appearance of a
new signal for C-2-NHCOR (δ ) 151-153 ppm). In addition,
the structure of compounds 2a-d was also confirmed by their
mass spectra, which showed the presence of the two isotopes
of the chlorine atom in a 3/1 ratio. This regioselectivity is
comparable to that observed in Sonogashira or Suzuki coupling
when applied to the same dihalogenopurine 1. Interestingly,
Buchwald amidation of 1 was significantly faster than the
previously reported amidation of various aryl halides (2 h vs
18-24 h).14 We found that reaction of more than 1 equiv of
amide led to trace amounts of 2,6-diamidopurines, while no
reaction occurred in the absence of palladium catalyst.
coupling with the adjacent fluorine atom. No reaction occurred
at room temperature, and incomplete conversion was observed
below 100 °C.
As an alternative to the Pd(0)-catalyzed cross-coupling of
amides to 2,6-dihalogenopurines, a mixture of amide and NaH20
was reacted with 1 in anhydrous DMF to give the 6-substituted
purines 5 as the sole products in moderate yield (35-56%)
(Scheme 3). Lower yields were observed with less than 3 equiv
of amide/NaH. Interestingly, the regioselectivity of this typical
SNAr-type reaction was inverted as compared to the palladium-
catalyzed amidation of 1 (Scheme 2). When the 6-chloro-2-
fluoropurine 3 was subjected to the same reaction conditions,
2-substituted purines (2a,b,d) were obtained as the main
products as well as a small amount of 6-substituted purine (4a,b)
(Scheme 3). This substrate-dependent regioselectivity, although
incomplete, is particularly noteworthy as it allows access to
2-amido-6-aminopurines of biological interest.4
With the goal in mind of synthesizing 6-amido-2-aminopu-
rines, we focused our attention on 6-amido-2-fluoropurines 4a-d
(Scheme 4). Substitution at position 2 of 6-amido-2-iodopurine
5 with various amines would involve prolonged reaction time
(>24 h) and high temperature (>120 °C), which may be
deleterious to the amide at 6. However, a palladium-catalyzed
amination21-24 may be used to overcome the low reactivity of
the iodine atom at position 2 in 5 toward SNAr. Therefore, since
When Buchwald amidation conditions where applied to
6-chloro-2-fluoropurine19 3 (Scheme 2), a different regioselec-
tivity was observed giving exclusively the 6-amido substituted
purines 4a-e in good yield (69-85%). The structure of these
compounds (4a-e) was unambiguously confirmed by 13C NMR
experiments showing the characteristic splitting of C-2 (d, JC-F
) 200 Hz) and C-4 and C-6 (d, JC-F ≈ 18 Hz) due to the large
(20) Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.; Dutia,
M.; Powell, D. W.; Wissner, A.; Arndt, K.; Weber, J. M.; Boschelli, F. J.
Med. Chem. 2001, 44, 822.
(19) Compound 3 was prepared from commercially available 2-amino-
6-chloropurine and sodium nitrite in aqueous tetrafluoroboric acid as
described by: Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett. 1997,
38, 1161. This was followed by a Mitsunobu reaction with isopropyl alcohol,
according to a modification of ref 5. See the Supporting Information for
the preparation of 3.
(21) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.
(22) Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560.
(23) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003,
68, 2861.
(24) Lakshman, M. K. J. Organomet. Chem. 2002, 653, 234.
J. Org. Chem, Vol. 72, No. 18, 2007 7027

SCHEME 4. Synthesis of 2-Amino-6-amidopurines
the fluorine atom is more reactive than iodine toward SNAr
conditions, 6-amido-2-fluoropurines 4 (Scheme 2) are valuable
intermediates that can be subjected to an additional SNAr with
various amines to provide interesting analogues of known
inhibitors of biological targets such as Cdk’s.
Experimental Section
General Procedure for Pd-Catalyzed Couplings of 2,6-
Dihalogenopurines and Amides As Illustrated by the Synthesis
of N-(6-Chloro-9-isopropyl-9H-purin-2-yl)-3-methylbutyramide
(2d). A Schlenk tube was charged with 6-chloro-2-iodo-9-isopropyl-
9H-purine 16 (198 mg, 0.61 mmol), isovaleramide (66 mg, 0.65
mmol), cesium carbonate (280 mg, 0.86 mmol), Pd2dba3 (12.4 mg,
0.013 mmol), and Xantphos (21.2 mg, 0.036 mmol). The Schlenk
tube was fitted with a condenser, capped with a rubber septum,
evacuated, and backfilled with argon. This evacuation/backfill was
repeated twice. Then 1,4-dioxane (4 mL) was added through the
septum. The mixture was stirred for 1 h at 100 °C. The reaction
mixture was then cooled to room temperature and partitioned
between H2O/CH2Cl2. The aqueous phase was extracted with CH2-
Cl2. The combined organic layers were dried over Na2SO4 and
filtered, and the solvent was removed in vacuo. The yellow solid
was purified by flash chromatography on silica gel (0-3% EtOH/
CH2Cl2) to afford the title compound 2d (140 mg, 77%) as a pale
yellow amorphous solid: mp 175-177 °C. An analytical sample
was obtained by trituration with Et2O as a white solid (72%): 1H
NMR (300 MHz, CDCl3) δ 1.05, (d, J ) 6.7 Hz, 6H),1.64 (d, J )
6.8 Hz, 6H), 2.27 (sept, J ) 6.7 Hz, 1H), 2.65 (bd, J ) 6.7 Hz,
2H), 4.85 (sept, J ) 6.8 Hz, 1H), 8.05 (bs, 1H); 13C NMR (75
MHz, CDCl3) δ 22.4, 22.5, 25.5, 46.3, 47.9, 128.3, 142.3, 150.9,
151.5, 152.2, 171.9; MS (electrospray) m/z 296.1 (45) [M + H]+,
298.1 (10) [M + H]+, 318.1 (100) [M + Na]+, 320.1 (30) [M +
Na]+. Anal. Calcd for C13H18ClN5O: C, 52.79; H, 6.13; N, 23.68.
Found: C, 52.69; H, 6.33; N, 23.59.
Thus, substitution of the fluorine atom in 4a-d (Scheme 4)
with (R)-(-)-2-pyrrolidine methanol in DMF was achieved at
room temperature and gave the corresponding trisubstituted
purines 6a-d in good yield, whereas substitution of the fluorine
atom using a stoichiometric amount of primary amine ((R)-
(-)-2-aminobutanol) required heating to 100 °C and led to 7a-c
in moderate yield.
Fluorine substitution with excess amine and prolonged
reaction times led to decreased yields of the desired products
and the formation of significant amounts of 6-aminopurine 8
(Scheme 4) and N-(1-hydroxymethylpropyl)benzamide (not
shown). In each case, these products were isolated by chroma-
tography and could be rationalized by attack by the amine at
the amide carbonyl of 4a-c.
In conclusion, the regioselectivity of the amidation of 2,6-
dihalogenopurines strongly depends on the reaction conditions
(Pd(0) versus SNAr) and opens an easy access to 2- or
6-amidopurines from the same precursor. Overall, the methods
of amidation reported in the present paper are straightforward
using readily available starting materials. We have shown that
Buchwald amidation (Pd2dba3, Xantphos, and Cs2CO3 in diox-
ane at 100 °C) of 6-chloro-2-fluoropurine 3 is regioselective at
position 6. In contrast, when an iodine atom is present at position
2 (as in 1), the 2-amido-6-chloropurine derivative 2 is obtained
regioselectively. An alternative method using RCONH2/NaH
in DMF (SNAr) allowed us to achieve the inverted regioselective
amidation at position 6 in the presence of an iodine atom at
position 2. Interestingly, this reaction was performed at 0 °C,
but in lower yield as compared to the Pd(0) cross-coupling
amidation. This SNAr-type reaction of 6-chloro-2-fluoropurine
derivative 3 gave selectively the 2-amido-substituted purine 2
and a small amount of the 6-amido-substituted purine 4. In
addition, in order to obtain the desired 6-amido-2-aminopurines,
the 6-chloro-2-fluoropurine 3 is the molecule of choice to
perform Pd(0)-catalyzed amidation at position 6, followed by
SNAr at position 2 with various amines.
N-(2-Fluoro-9-isopropyl-9H-purin-6-yl)-3-methylbutyra-
mide (4e). The same procedure as above was followed with
6-chloro-2-fluoro-9-isopropyl-9H-purine 319 (198 mg, 0.920 mmol),
isovaleramide (101 mg, 1 mmol), cesium carbonate (421 mg, 1.29
mmol), Pd2dba3 (17.5 mg, 0.019 mmol), Xantphos (32.1 mg, 0.055
mmol), and dioxane (5.5 mL). The residue was purified by flash
chromatography on silica gel (1% EtOH/CH2Cl2) to afford the title
compound 4e (181 mg, 70%) as a yellow solid. An analytical
sample was obtained by recrystallization from hot heptane as off-
1
white crystals: mp 156-158 °C; H NMR (300 MHz, CDCl3) δ
1.05, (d, J ) 6.7 Hz, 6H), 1.62 (d, J ) 6.8 Hz, 6H), 2.28 (m, 1H),
2.83 (bd, J ) 6.7 Hz, 2H), 4.81 (sept, J ) 6.8 Hz, 1H), 8.07 (s,
1H), 8.97 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 22.4, 22.5, 25.5,
46.6, 47.89, 120.2, 141.1, 150.7 (d, J ) 19 Hz), 152.6 (d, J ) 18
Hz), 157.8 (d, J ) 212 Hz), 172.9; MS (electrospray) m/z 302 (100)
[M + Na]+, 280 (30) [M + H]+. Anal. Calcd for C13H18FN5O: C,
55.90; H, 6.50; N, 25.07. Found: C, 55.53; H, 6.35; N, 25.06.
General Procedure for Amidation of 2,6-Dihalogenopurines
with Amides Using NaH As Illustrated by the Synthesis of N-(2-
Iodo-9-isopropyl-9H-purin-6-yl)benzamide (5a). To a suspension
of NaH (60% in mineral oil, 42 mg, 1 mmol) in anhydrous DMF
(2.5 mL) was added at once benzamide (115 mg, 0.95 mmol), and
the mixture was stirred at room temperature for 1.5 h. To the
resultant thick white suspension cooled to 0 °C was added dropwise
The synthesis of several new trisubstituted purines (6a-d,
7a-c) bearing an amine at position 2 and an amide at position
6 highlights the potential of our strategy from intermediate 3.
The biological activity of these new purine derivatives is under
investigation and will be reported in a separate article.
7028 J. Org. Chem., Vol. 72, No. 18, 2007

a solution of 6-chloro-2-iodo-9-isopropyl-9H-purine 1 (102 mg, 0.32
mmol) in anhydrous DMF (1.1 mL). The reaction mixture was
allowed to warm to room temperature overnight. The DMF was
evaporated off after quenching with a few drops of water. The
resulting crude mixture was partitioned between H2O/CH2Cl2. The
aqueous phase was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4, and filtered,
and the solvent was removed in vacuo. The yellow solid was
purified by flash chromatography on silica gel (0-1% EtOH/CH2-
Cl2) to afford the title compound 5 (69 mg, 50%) as a yellow
amorphous solid. An analytical sample was obtained by trituration
with Et2O as a white solid (53%): mp 181-184 °C; 1H NMR (300
MHz, CDCl3) δ 1.63 (d, J ) 6.6 Hz, 6H), 4.93 (sept, J ) 6.6 Hz,
1H), 7.52 (m, 2H), 7.60 (m, 1H), 8 (m, 3H), 8.74 (bs, 1H); 13C
NMR (75 MHz, CDCl3) δ 23, 47.9, 118, 124.1, 128.4, 129.2, 133.3,
133.4, 141.1, 149.5, 153.6, 164.8; MS (electrospray) m/z 408.3 (70)
[M + H]+, 430.3 (100) [M + Na]+. Anal. Calcd for C15H14IN5O,
H2O: C, 42.37; H, 3.79; N, 16.47. Found: C, 42.77; H, 3.56; N,
16.61.
General Procedure for Couplings of Compounds 4a-d and
(R)-(-)-2-pyrrolidinemethanol As Illustrated by the Synthesis
of 2-Hydroxy-N-[2-((R)-(-)-2-hydroxymethylpyrrolidin-1-yl)-
9-isopropyl-9H-purin-6-yl]benzamide (6d). To a solution of
compound 4d (129.5 mg, 0.41 mmol) in anhydrous DMF (2 mL)
were successively added N,N-diisopropylethylamine (210 µL, 1.2
mmol) and (R)-(-)-2-pyrrolidinemethanol (85 µL, 0.92 mmol). The
mixture was stirred overnight at room temperature. The DMF was
then evaporated off, and the residue was purified by flash
chromatography on silica gel (1-2% MeOH/CH2Cl2) to give a
white solid which was further triturated with Et2O to afford the
title compound 6d (114 mg, 70%) as a yellow solid: mp 178-180
°C; 1H NMR (300 MHz, CDCl3) δ 1.58 (d, J ) 6.7 Hz, 6H), 1.81
(m, 1H), 1.99-2.19 (m, 3H), 3.68-3.90 (m, 4H), 4.41 (m, 1H),
4.68 (sept, J ) 6.7 Hz, 1H), 6.89 (t, J ) 7.5 Hz, 1H), 6.98 (d, J )
8 Hz, 1H), 7.41 (t, J ) 7.2 Hz, 1H), 7.74 (s, 1H), 7.86
(d, J ) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.1, 22.2, 24,
29.4, 47, 48.5, 61, 69, 116.1, 117, 117.9, 118.9, 128.9, 134.6, 137.9,
150, 152.9, 160.8; MS (electrospray) m/z 397.2 (45) [M + H]+,
419.2 (100) [M + Na]+. Anal. Calcd for C20H24N6O3: C, 60.59;
H, 6.10; N, 21.20. Found: C, 60.36; H, 6.07; N, 21.25.
General Procedure for Couplings of Compounds 4a-c and
(R)-(-)-2-aminobutan-1-ol As Illustrated by the Synthesis of
N-[2-((R)-(-)-1-Hydroxymethylpropylamino)-9-isopropyl-9H-
purin-6-yl]benzamide (7a). To a solution of compound 4a (70
mg, 0.234 mmol) in anhydrous DMF (1.5 mL) were successively
added N,N-diisopropylethylamine (110 µL, 0.631 mmol) and (R)-
(-)-2-aminobutan-1-ol (25 µL, 0.264 mmol). The mixture was
stirred for 6 h at 110 °C. The DMF was then evaporated off, and
the residue was purified by flash chromatography on silica gel (1-
3% EtOH/CH2Cl2) to give the title compound 7a (38 mg, 44%) as
a yellow pale oil: 1H NMR (300 MHz, CDCl3) δ 1 (t, J ) 7.5 Hz,
3H), 1.53-1.67 (m, 8H), 3.64-3.89 (m, 2H), 4 (m, 1H), 4.65 (sept,
J ) 6.7 Hz, 1H), 5.59 (bs, 1H), 7.46 (m, 2H), 7.55 (m, 1H), 7.70
(s, 1H), 7.99 (d, J ) 7.3 Hz, 2H), 9.3 (bs, 1H); 13C NMR (75 MHz,
CDCl3) δ 10.7, 22.1, 22.2, 24.7, 46.8, 55.4, 66, 116.4, 127.8, 128.5,
132.3, 134, 137.2, 149.6, 153, 159.3, 165.2; HRMS (ESI) calcd
for C19H24N6O2Na [(M + Na)+] 391.1853, found 391.1859.
Acknowledgment. We thank Dr David S. Grierson for
supporting this work. We thank Dr. Jason Martin for proofread-
ing the manuscript. We thank ARC (Association pour la
Recherche sur le Cancer, France) (Contract No. 4660 to M.L.)
for financial support.
Supporting Information Available: 1H and 13C NMR and
MS data for compounds 2a-d, 4a-e, 5a-c, 6a-d, 7a-c, and 8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO071196P
J. Org. Chem, Vol. 72, No. 18, 2007 7029