Synthesis of novel C2-C3′N-linked macrocyclic taxoids by means of highly regioselective heck macrocyclization

Article abstract of DOI:10.1021/ol0354627

(Matrix presented) Novel C2-C3′N-linked macrocyclic taxoids are synthesized using intramolecular Heck reaction in the key step. Macrocyclization proceeds with high regioselectivity in good yield. Taxoids bearing an olefin moiety at C2 and an iodide at C3′

Full text of DOI:10.1021/ol0354627

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3733-3736
Synthesis of Novel C2−C3′N-Linked
Macrocyclic Taxoids by Means of Highly
Regioselective Heck Macrocyclization
Xudong Geng, Michael L. Miller, Songnian Lin, and Iwao Ojima*
Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
iojima@notes.cc.sunysb.edu
Received August 2, 2003
ABSTRACT
Novel C2
−
C3
′
N-linked macrocyclic taxoids are synthesized using intramolecular Heck reaction in the key step. Macrocyclization proceeds with
N give exo-products exclusively. However, the
high regioselectivity in good yield. Taxoids bearing an olefin moiety at C2 and an iodide at C3
′
endo-products are formed with up to 100% regioselectivity just by switching the positions of the olefin and the iodide moieties. Some of these
macrocyclic taxoids are significantly cytotoxic.
The Heck reaction was introduced to organic chemists in
the late 1960s,1 but only the past decade or so has witnessed
the rapid development and wide applications of this powerful
and flexible C-C bond-forming reaction.2 Now, the Heck
reaction has become one of the most useful synthetic tools
with its excellent functional group tolerance and highly
successful stereoselective processes. The asymmetric in-
tramolecular Heck reaction has recently been extensively
studied because of its ability to efficiently construct congested
quaternary carbon centers.2a,3 Such capability has led to its
various applications in the key steps in the assembly of many
complex molecules.2a-d,3b,4
In the course of our study on the bioactive conformation
of paclitaxel and its congeners,5 we became interested in
constructing C2-C3′N-linked macrocyclic taxoids to mimic
the tubulin-bound docetaxel conformation proposed by
Nogales et al.,6 which is close to that found in its X-ray
crystallographic analysis.7 Accordingly, we reported previ-
ously the synthesis of a series of such macrocyclic taxoids
using ring-closing metathesis (RCM) as the key reaction.8
However, we found that RCM reactions using the Grubbs
(4) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53,
7371.
(5) (a) Ojima, I.; Kuduk, S. D.; Chakravarty, S.; Ourevitch, M.; Be´gue´,
J.-P. J. Am. Chem. Soc. 1997, 119, 5519. (b) Ojima, I.; Chakravarty, S.;
Inoue, T.; Lin, S.; He, L.; Horwitz, S. B.; Kuduk, S. D.; Danishefsky, S. J.
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 4256. (c) Rao, S.; He, L.;
Chakravarty, S.; Ojima, I.; Orr, G. A.; Horwitz, S. B. J. Biol. Chem. 1999,
274, 37990. (d) Ojima, I.; Lin, S.; Inoue, T.; Miller, M. L.; Borella, C. P.;
Geng, X.; Walsh, J. J. J. Am. Chem. Soc. 2000, 122, 5343.
(6) Nogales, E.; Wolf, S. G.; Downing, K. H. Nature 1998, 391, 199.
(7) Gue´ritte-Voegelein, F.; Mangatal, L.; Gue´nard, D.; Potier, P.;
Guilhem, J.; Cesario, M.; Pascard, C. Acta Crystallogr. 1990, C46, 781.
(8) Ojima, I.; Geng, X.; Lin, S.; Pera, P.; Bernacki, R. J. Bioorg. Med.
Chem. Lett. 2002, 12, 349.
(1) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518.
(2) For reviews, see: (a) Overman, L. E. Pure Appl. Chem. 1994, 66,
1423. (b) de Meijere, A.; Meyer, F. E. Angew. Chem. 1994, 106, 2473. (c)
Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427. (d) Loiseleur, O.; Hayashi,
M.; Keenan, M.; Schmees, N.; Pfaltz, A. J. Organomet. Chem. 1999, 576,
16. (e) Shibasaki, M.; Vogl, E. M. J. Organomet. Chem. 1999, 576, 1. (f)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(3) For reviews, see: (a) Gibson, S. E.; Middleton, R. J. Contemp. Org.
Synth. 1996, 3, 447. (b) de Meijere, A.; Brase, S. J. Organomet. Chem.
1999, 576, 88. (c) Ikeda, M.; El Bialy, S. A. A.; Yakura, T. Heterocycles
1999, 51, 1957.
10.1021/ol0354627 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/06/2003

catalyst9 were rather sensitive to the substitution pattern in
the proximity of the terminal olefin, e.g., certain allylic
substitutions substantially slowed or inhibited ring closing
to form macrocyclic taxoids.5d Consequently, we decided to
explore an alternative approach, i.e., intramolecular Heck
reaction.
Scheme 1. Preparation of Taxoid Substrates 1a and 2aa
The intramolecular Heck reaction has two modes of ring-
closing, i.e., exo- and endo-cyclization. Small size ring (5,
6, 7) formation usually favors exo-cyclization2a,b,f,4,10 since
the corresponding endo-cyclization is sterically very de-
manding. endo-Cyclization requires that the olefin bond
moves into the loop of the substrate and generates an
energetically favorable substituted alkene product. Thus, a
large size ring (∼20) formation with a flexible tether
generally favors endo-cyclization.2c,10a,11,12 To the best of our
knowledge, only a limited number of examples of macro-
cyclization by intramolecular Heck reaction have appeared
in the literature.11-14 We report here efficient and highly
regioselective intramolecular Heck macrocyclizations to
construct novel C2-C3′N-linked macrocyclic taxoids that
have shown significant cytotoxicity.
a (i) LiHMDS (1.5 equiv), 4 or 5 (1.5-2.0 equiv), THF, -40
°C, 0.5 h. 1a 81%; 2a 88%.
tam 4 was prepared by acylation of the corresponding N-H-
â-lactam.8,17 Modified baccatin 38 was coupled with â-lactam
4 in the presence of LiHMDS to afford 1a in high yield.
For the synthesis of 2a, 3-TESO-â-lactam 5, prepared fol-
lowing the procedure we reported previously,18 was em-
ployed since we19 and others14 had found that N-benzoyl-
4-phenyl â-lactams bearing a large silyl group (TIPS or TBS)
at C3 were difficult to couple with baccatins. The coupling
of â-lactam 5 with baccatin 3 proceeded smoothly to afford
2a in excellent yield.
We first designed taxoid substrates 1a and 2a, bearing
2-methylprop-1-enyl or phenyl at the C3′ position as shown
in Figure 1A. exo-Cyclization or endo-cyclization of these
As Scheme 2 shows, the reaction of 1a was carried out in
acetonitrile with a catalytic amount of Pd(PPh3)4 and excess
triethylamine at 55 °C overnight. The reaction gave only exo-
cyclization product 6 in 65% isolated yield, which is
substantially higher than those achieved in most of the
reported macrocyclic intramolecular Heck reactions.11-13
Then, the deprotection of 6 with HF-pyridine afforded
macrocyclic taxoid 7-exo in 74% yield. Taxoid 2a was
subjected to the same conditions but failed to give any
cyclized product. However, the use of triphenylarsine, a
weaker σ-donor ligand,20 in place of triphenyphosphine
solved the problem. Thus, the reaction of 2a using Pd2(dba)3
as the Pd source and AsPh3 as the ligand afforded exo-
Figure 1. Taxoid substrates 1 and 2.
substrates would give the corresponding 19- or 20-membered
macrocyclic taxoids.
The taxoids 1a and 2a were synthesized through the
Ojima-Holton â-lactam ring-opening coupling reaction with
properly modified baccatins (Scheme 1).15
(15) (a) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.
M.; Brigaud, T. Tetrahedron 1992, 48, 6985. (b) Holton, R. A.; Biediger,
R. J.; Boatman, P. D. In Taxol: Science and Applications; Suffness, M.,
Ed.; CRC Press: New York, 1995; p 97. (c) Ojima, I.; Kuduk, S. D.;
Chakravarty, S. In AdVances in Medicinal Chemistry; Maryanoff, B. E.,
Reitz, A. B., Eds.; JAI Press: Greenwich, CT, 1998; Vol. 4, p 69. (d) Ojima,
I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927.
(16) Ojima, I.; Wang, T.; Miller, M. L.; Lin, S.; Borella, C. P.; Geng,
X.; Pera, P.; Bernacki, R. J. Bioorg. Med. Chem. Lett. 1999, 9, 3423.
(17) Ojima, I.; Slater, J. S.; Kuduk, S. D.; Takeuchi, C. S.; Gimi, R. H.;
Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J. M.; Bernacki, R. J. J. Med.
Chem. 1997, 40, 267.
Enantiopure â-lactams were prepared through a highly
efficient chiral enolate-imine cyclocondensation.5d,15,16 â-Lac-
(9) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(10) (a) Negishi, E.; Coperet, C.; Ma, S. M.; Liou, S. Y.; Liu, F. Chem.
ReV. 1996, 96, 365. (b) Ha, H. J.; Ahn, Y. G.; Woo, J. S. Bull. Korean
Chem. Soc. 1998, 19, 818. (c) Denieul, M. P.; Laursen, B.; Hazell, R.;
Skrydstrup, T. J. Org. Chem. 2000, 65, 6052.
(11) Ma, S.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 6345.
(12) Stocks, M. J.; Harrison, R. P.; Teague, S. J. Tetrahedron Lett. 1995,
36, 6555.
(18) (a) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk,
S. D. Tetrahedron Lett. 1993, 34, 4149. (b) Ojima, I.; Zucco, M.; Duclos,
O.; Kuduk, S. D.; Sun, C.-M.; Park, Y. H. Bioorg. Med. Chem. Lett. 1993,
3, 2479.
(13) (a) Hiroshige, M.; Hauske, J. R.; Zhou, P. J. Am. Chem. Soc. 1995,
117, 11590. (b) Akaji, K.; Teruya, K.; Akaji, M.; Aimoto, S. Tetrahedron
2001, 57, 2293.
(14) An intramolecular Heck reaction to construct C2-C3′ linked
macrocyclic taxoid using stoichiometric amount of Pd was reported to yield
inactive taxoids: Boge, T. C.; Wu, Z.-J.; Himes, R. H.; Vander, D. G.;
Georg, G. I. Bioorg. Med. Chem. Lett. 1999, 9, 3047.
(19) Ojima, I.; Kuduk, S. D.; Slater, J. C.; Gimi, R. H.; Sun, C. M.
Tetrahedron 1996, 52, 209.
(20) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(b) Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595.
3734
Org. Lett., Vol. 5, No. 20, 2003

Macrocyclization of 1b was carried out using the same
conditions as those employed for 1a (cat. ) Pd(PPh3)4),
which gave a mixture of exo- and endo-products (exo:endo
) 3:1) in 68% isolated yield (Scheme 4). Thus, the formation
Scheme 2. Heck Macrocyclization of Taxoids 1a and 2aa
Scheme 4. Heck Macrocyclization of Taxoid 1ba
a (i) Pd(PPh3)4 (0.07 equiv), Et3N, CH3CN, 55 °C, overnight,
65%; (ii) HF-pyridine, pyridine, CH3CN, overnight, 74%, (iii)
Pd2(dba)3 (0.05 equiv), AsPh3 (0.2 equiv), Et3N, CH3CN, 55 °C, 1
d, then (ii). 56% for two steps.
a (i) Pd(PPh3)4 (0.07 equiv), Et3N, CH3CN, 50 °C, overnight,
68% (exo:endo ) 3:1); (ii) HF-pyridine, pyridine, CH3CN, over-
night. 7-exo 56%; 7-endo 19%. (iii) Pd/C, H2, EtOAc, 18 h, 83%.
product 8 exclusively (Scheme 2). Removal of silyl protect-
ing groups by HF-pyridine gave 9-exo in 56% yield for two
steps.
of the endo-product was observed. Deprotection with
HF-pyridine and HPLC separation afforded macrocyclic
taxoids 7-exo (56%) and 7-endo (19%). For 7-endo, only
the Z-isomer was formed on the basis of NMR analysis
(JHaHb ) 9.0 Hz). Taxoid 7-exo was hydrogenated over
Pd/C to afford 7-exo(H) (3.5:1 diastereomer mixture)
(Scheme 4).
Next, the Heck macrocyclization of 2b was examined.
Unlike its regioisomer 2a, this taxoid underwent macrocy-
clization smoothly under the “standard conditions”, i.e., using
Pd(PPh3)4 as the catalyst, to afford the corresponding endo-
product exclusively. Deprotection with HF-pyridine gave
macrocylic taxoid 9-endo in 87% yield for two steps (Scheme
5). Again, only the Z-isomer was formed on the basis of
Since the observed exclusive exo-cyclization was unex-
pected, we switched the positions of iodide and olefin
moieties in 1a and 2a to examine a possible effect of this
change on the regioselectivity. Thus, taxoid substrates 1b
and 2b (Figure 1B) were synthesized in a manner similar to
that for 1a and 2b (Scheme 3). Baccatin 10 was prepared
using the same protocol as that for 38,16 and coupled with
â-lactams 11 and 12 to give 1b and 2b, respectively, in good
yields.
Scheme 3. Preparation of Taxoids 1b and 2ba
NMR analysis (J
) 10.2 Hz).
HcHd
Scheme 5. Heck Macrocyclization of Taxoid 2ba
a (i) LiHMDS (1.5 equiv), 11 or 12 (1.5-1.8 equiv), THF, -40
°C, 35 min. 1b 78%; 2b 77%.
a (i) Pd(PPh3)4 (0.07 equiv), Et3N, CH3CN, 50 °C, 11 h; (ii)
HF-pyridine, pyridine, CH3CN, overnight. 87% for two steps.
Org. Lett., Vol. 5, No. 20, 2003
3735

transition state/intermediate of this process have been
performed using the Spartan program (sybyl and PM3),
which are found to be able to accommodate the observed
switching between exo-cyclization and endo-cyclization,
depending on the relative positions of the iodide and ethenyl
moieties. However, the geometry of Pd needs optimization
in some cases. Thus, further studies are currently underway
in these laboratories, and the results will be reported in due
course.
Scheme 6. Heck Macrocyclization of Taxoid 13a
Biological Activity of Macrocyclic Taxoids. Some of
these macrocyclic taxoids, especially the exo-isomers, were
found to be significantly cytotoxic against the LCC6-WT
human breast cancer cell line, with IC50 values of 0.071 µM
for 7-exo and 0.067 µM for 9-exo (paclitaxel 0.004 µM),
despite their rigidity. Interestingly, 7-exo(H) (IC50 0.060 µM)
exhibited potency even higher than that of 7-exo. These
macrocyclic taxoids are considerably more potent than most
of the previously reported macrocyclic taxoids synthesized
using RCM.5d,8,14,21 The cytotoxicity of 9-endo (IC50 0.530
µM) was substantially weaker than that of 9-exo. Also,
14-endo (IC50 4.5 µM) was less potent than 14-exo (IC50
0.79 µM). Obviously, taxoids 14 are much less potent than
taxoids 7 and 9, which can be ascribed to the increased
flexibility of the molecule as a result of the lack of a benzene
moiety. Further SAR studies on macrocyclic taxoids are
actively underway in these laboratories.
a (i) Pd(PPh3)4 (0.1 equiv), Et3N, CH3CN, 70 °C, 1 d; (ii)
HF-pyridine, pyridine, CH3CN, overnight. 67% for two steps:
14-endo:14-exo ) 3:1 (HPLC).
We have also found that the Heck macrocyclization can
be applied to unactivated olefin systems. As Scheme 6 shows,
the reaction of taxoid 13, prepared in a manner similar to
those of taxoids 1 and 2, proceeded under the standard
conditions to give macrocyclic taxoids 14 (exo:endo ) 1:3)
in 67% yield after deprotection. Two regioisomers were
separated by HPLC. It should be noted that the cinnamyl
group at C3′ was intact during the reaction. To the best of
our knowledge, only a few examples have been reported of
the macrocyclization by intramolecular Heck reactions
involving unactivated olefin.11,12 However, we have dem-
onstrated here that the intramolecular Heck reaction serves
as a highly efficient method for constructing macrocyclic
compounds.
The observed regioselectivity in these intramolecular Heck
reactions may well be predictable by estimating the relative
energies of the endo- or exo-ring-closing transition states or
the Pd(II)I-olefin intermediate complexes, which should be
influenced by the unique tetracyclic taxane skeleton. Ac-
cordingly, extensive molecular modeling studies on the
Acknowledgment. This work has been supported by a
grant from the National Institutes of Health (NIGMS).
Generous support from the Indena SpA is gratefully ac-
knoweldged. The authors thank Dr. Ralph J. Bernacki and
Ms. Paula Pera at the Roswell Park Cancer Institute for the
cytotoxicity assays.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0354627
(21) Metaferia, B. B.; Hoch, J.; Glass, T. E.; Bane, S. L.; Chatterjee, S.
K.; Snyder, J. P.; Lakdawala, A.; Cornett, B.; David G. I. Kingston, D. G.
I. Org. Lett. 2001, 3, 2461.
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