Synthetic studies on the taxane skeleton: Construction of eight-membered carbocyclic rings by the intramolecular B-alkyl Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1021/ol0481939

(Chemical equation presented) Construction of eight-membered carbocyclic rings via the intramolecular B-alkyl Suzuki-Miyaura cross-coupling reaction has been studied. This protocol proved its potency through the formation of the eight-membered ring posses

Full text of DOI:10.1021/ol0481939

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4491-4494
Synthetic Studies on the Taxane
Skeleton: Construction of
Eight-Membered Carbocyclic Rings by
the Intramolecular B-Alkyl
Suzuki−Miyaura Cross-Coupling
Reaction
Hatsuo Kawada, Mitsuhiro Iwamoto, Masayuki Utsugi, Masayuki Miyano, and
Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda UniVersity,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
mnakada@waseda.jp
Received September 7, 2004
ABSTRACT
Construction of eight-membered carbocyclic rings via the intramolecular B-alkyl Suzuki−Miyaura cross-coupling reaction has been studied.
This protocol proved its potency through the formation of the eight-membered ring possessing a quaternary carbon on its ring in high yield,
affording promise of a new access to the eight-membered ring of Taxol.
Palladium-mediated cross-coupling reactions have been
utilized in organic synthesis because of their high efficiency
and mild conditions. Among these reactions, the most utilized
C-C bond-forming cross-coupling reactions are Mizoroki-
Heck,1 Stille,2 and Suzuki-Miyaura reactions.3 Because the
Suzuki-Miyaura cross-coupling reaction is a powerful C-C
bond-forming reaction under mild conditions, an increasing
number of its variants have been reported.4
The B-alkyl Suzuki-Miyaura reaction, first reported by
Suzuki and Miyaura in 1986, is an important variant,
occurring between an alkyl borane and an aryl or vinyl halide,
triflate, or enol phosphate.5 The formation of five- and six-
membered rings by the intramolecular B-alkyl Suzuki-
Miyaura reaction has been reported to occur in a facile
manner;6 however, the closing of larger ring sizes by this
(4) (a) Liu, S.-Y.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 23,
2408-2409. (b) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 1945-1947. (c) Kirchhoff, J. H.; Netherton, M. R.; Hills, I.
D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662-13663. (d) Netherton,
M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-3912. (e) Zhou,
J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727. (f) Zhou, J.; Fu,
G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.
(1) (a) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Hegedus, L. S. Transition
Metals in the Synthesis of Complex Organic Molecules, 2nd ed.; University
Science Books, Sausalito, 1999.
(2) (a) Still, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524. (b)
Mitchell, T. N. Synthesis 1992, 803-815.
(3) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c) Chemler, S. R.;
Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-
4568.
(5) (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369-6372. (b) Sato, M.; Miyaura, N.; Suzuki, A. Chem.
Lett. 1989, 1405-1408. (c) Oh-e, T.; Miyayra, N.; Suzuki, A. J. Org. Chem.
1993, 58, 2201-2208.
10.1021/ol0481939 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/03/2004

Table 1. Intramolecular B-Alkyl Suzuki-Miyaura Cross-Coupling Reaction of 1
entry
Pd (mol %)
ligand (mol %)
base (equiv)
solvent
yield (%)a
1
2
3
4
5
6
7
PdCl2(dppf) (50)
PdCl2(dppf) (50)
PdCl2(dppf) (50)
PdCl2(dppf) (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
AsPh3 (100)
AsPh3 (100)
AsPh3 (100)
Cs2CO3 (2.0)
Tl2CO3 (2.0)
Tl2CO3 (2.0)
Tl2CO3 (2.0)
Tl2CO3 (2.0)
NaOH (4.0)
CsF (4.0)
THF/DMF/H2O (6:3:1)
THF/DMF/H2O (6:3:1)
CH3CN/H2O (10:1)
CH3CN/H2O (10:1)
CH3CN/H2O (10:1)
CH3CN/H2O (10:1)
CH3CN/H2O (10:1)
32
37
41
18
8
33
51
a Isolated yields.
palladium-mediated reaction has been reported in either very
poor yield or not at all.7
gave lower yields (entries 4 and 5, 18% and 8%, respec-
tively). We found that the conditions in entry 6, which
afforded 2 in 33% yield, were comparable to Johnson’s
conditions; furthermore, the use of CsF11 gratifyingly in-
creased the yield to 51% (entry 7). Encouraged by these
preliminary studies that disclosed the first synthesis of the
eight-membered carbocyclic ring by the intramolecular
B-alkyl Suzuki-Miyaura cross-coupling reaction, we next
examined the reactions of more complex substrates. Thus,
substrate 3, prepared according to Danishefsky’s procedure,12
was subjected to the intramolecular B-alkyl Suzuki-Miyaura
reaction (Table 2).
As shown in Table 2, the reaction of 3 under Johnson’s
conditions produced the deprotected product 5 in only 9%
yield (entry 1). Hence, the reaction condition was optimized
considering the results obtained in Table 1. Thus, Pd(PPh3)4
in aqueous acetonitrile gave a better yield (31%, entry 2),
but Tl2CO3 did not improve the yield (22%, entry 3). Use
of NaOH in aqueous acetonitrile did not improve the yield
of 5 (14%, entry 4); furthermore, use of Cs2CO3, Tl2CO3, or
NaOH in aqueous acetonitrile merely produced the depro-
tected product 5 (entries 1-5). Fortunately, when the reaction
was carried out using less basic CsF, the desired 4 was
obtained without formation of 5 (entries 6 and 7). In the use
of CsF, aqueous acetonitrile as solvent was crucial for high
yield again, affording 4 in 62% yield (entry 6). To our
knowledge, the conditions for the intramolecular B-alkyl
Suzuki-Miyaura reaction affording the eight-membered ring
in good yield shown in Tables 1 and 2 have never been
reported.
Eight-membered carbocyclic rings are difficult to construct
because of entropy reasons, ring strain, the transannular
interaction, and competing oligomerization processes; hence,
their synthesis has been a challenging problem. Although
the macrocyclization by the intramolecular B-alkyl Suzuki-
Miyaura reaction has been reported, no examples of its
application to the synthesis of eight-membered rings have
been reported as far as we know.8 We report herein our
studies on the synthesis of eight-membered carbocyclic rings
by the intramolecular B-alkyl Suzuki-Miyaura cross-
coupling reaction and the promising result toward construc-
tion of a taxane skeleton.
First, we investigated the intramolecular B-alkyl Suzuki-
Miyaura reaction of a simple substrate 19 (Table 1). As
shown in Table 1, the reaction of 1 under Johnson’s
conditions10 produced the cyclized product 2 but in 32% yield
(entry 1). Hence, the reaction conditions were optimized by
changing the base, solvent, and catalyst. By the use of Tl2-
8e
CO3 instead of Cs2CO3 under Johnson’s conditions, the
yield slightly increased (entry 2, 37%). When the solvent
was changed to aqueous acetonitrile, the yield was further
increased (entry 3, 41%); however, the reactions in the
absence of AsPh3 or with the use of Pd(PPh3)4 as catalyst
(6) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321. (b) Miyaura, N.;
Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1992, 33, 2571-2574. (c)
Soderquist, J. A.; Leon, G.; Colberg, J. C.; Martinez, I. Tetrahedron Lett.
1995, 36, 3119-3122.
(7) (a) Kwochka, W. R.; Damrauer, R.; Schmidt, M. W.; Gordon, M. S.
Organometallics 1994, 13, 3728-3732. (b) Smith, B. B.; Kwochka, W. R.
J. Org. Chem. 1997, 62, 8589-8590. (c) Bracher, F.; Schulte, B. J. Chem.
Soc., Perkin Trans. 1 1996, 2619.
(8) (a) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000, 2, 2687-2690.
(b) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695-2698. (c)
Gagnon, A.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 1581-
1584. (d) Bauer, M.; Maier, M. E. Org. Lett. 2002, 4, 2205-2208. (e) Mohr,
P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125, 1712-1713. (f)
Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313-10318.
(9) 2-Iodobenzaldehyde was reacted with the Grignard reagent prepared
from 5-bromo-1-pentene, and the resulting alcohol was protected with
MOMCl (82%, 2 steps).
These optimization studies in Table 2 indicate the impor-
tance of the base and solvent in this reaction. Moreover, the
yield was surmised to be reduced by hydrolysis of the cyclic
carbonate group under the rather basic conditions because
some unidentified byproducts formed in entries 1-5. Hence,
other protective groups for the C1 and C2 hydroxyls stable
(11) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095-6097.
(12) Young, W. B.; Masters, J. J.; Danishefsky, S. J. J. Am. Chem. Soc.
1995, 117, 5228-5234.
(10) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014-
11015.
4492
Org. Lett., Vol. 6, No. 24, 2004

Table 2. Intramolecular B-Alkyl Suzuki-Miyaura Cross-Coupling Reaction of 3
entry
Pd (mol %)
ligand (mol %)
AsPh3 (100)
base (equiv)
solvent
product/yield (%)a
1
2b
3
4
5
PdCl2(dppf) (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
Pd(PPh3)4 (50)
Cs2CO3 (2.0)
Cs2CO3 (4.0)
Tl2CO3 (2.0)
NaOH (4.0)
NaOH (4.0)
CsF (4.0)
THF/DMF/H2O (6:3:1)
CH3CN//H2O (5:1)
CH3CN/H2O (10:1)
CH3CN/H2O (10:1)
THF/H2O (10:1)
5/9
5/31
5/22
5/14
5/36
4/62
4/28
6
7c
CH3CN/H2O (10:1)
DMF/H2O (5:1)
CsF (4.0)
a Isolated yields. b Reaction time was 74 h. c Reaction temperature was 85 °C.
under the reaction conditions were examined. That is,
acetonide 10 was prepared according to the literature,13 and
the substrate 9 having an MOM group at the C1 hydroxyl
group and a benzyl group at the C2 hydroxyl group was
prepared as shown in Scheme 1. Reduction of the known
mol %; CsF, 4.0 equiv; CH3CN/H2O, 10:1; reflux; 72 h) gave
11 and 12 in 58% and 59% yields, respectively. These results
indicate that conditions A are the better conditions for these
substrates. The protective groups were also shown to be
important to increase the yield. Thus, the protective groups
of the hydroxyls on the forming eight-membered ring should
be stable under the basic conditions, and the acyclic
protective groups such as in 9 are better than the cyclic ones
such as carbonate or acetonide. The cyclic protective groups
were surmised to restrict free rotation of the C1-C2 bond
to enhance the ring closure; however, the transition state of
the substrate possessing the cyclic protective group would
be energetically unfavored as a result of the increasing
strain.14
Scheme 1a
Scheme 2a
nonchiral aldehyde 612 (79%) and removal of TMS gave 7
(quant). Selective acetylation (96%), protection of the tertiary
alcohol with methoxymethyl ether (97%), removal of the
acetyl group (97%), and Dess-Martin oxidation generated
aldehyde 8 (97%). Treatment of 2-iodostylene with n-BuLi
and then with 8 produced an inseparable mixture of diaster-
eomers (quant, R/â ) 10/1), which was converted to
separable benzyl ether 9 (88%).
The intramolecular B-alkyl Suzuki-Miyaura cross-
coupling reactions of 10 and 9 were carried out under the
optimized conditions in Table 2. As shown in Scheme 2,
the reactions of 10 and 9 under the conditions A (Pd(PPh3)4,
50 mol %; NaOH, 4.0 equiv; CH3CN/H2O, 10:1; reflux; 72
h) gave 11 and 12 in dramatically improved yields (70%
and 82% yields, respectively). On the other hand, the
reactions of 10 and 9 under the conditions B (Pd(PPh3)4, 50
Finally, we examined the reaction of the more complex
substrate 17 possessing a quaternary carbon on the forming
eight-membered ring (Scheme 3). Previously reported chiral
alcohol 13 (>99% ee)15 was converted to 14 by hydro-
(14) For the similar results obtained, see: Miyamoto, S.; Doi, T.;
Takahashi, T. Synlett 2002, 97-99.
(15) Iwamoto, M.; Kawada, H.; Tanaka, T.; Nakada, M. Tetrahedron
Lett. 2003, 44, 7239-7243.
(13) Masters, J. J.; Jung, D. K.; Bornmann, W. G.; Danishefsky, S. J.
Tetrahedron Lett. 1993, 34, 7253-7256.
Org. Lett., Vol. 6, No. 24, 2004
4493

Scheme 3a
Scheme 4a
producing the cyclized product 18 in 85% yield under the
conditions A. Because the product 18 possesses a 6-8-6
carbon skeleton required for the synthesis of Taxol, the
intramolecular B-alkyl Suzuki-Miyaura reaction was found
to be a promising method to construct the eight-membered
ring of Taxol.
In summary, we have succeeded in constructing eight-
membered rings via the intramolecular B-alkyl Suzuki-
Miyaura cross-coupling reaction under new conditions. This
protocol proved its potency through the formation of the
eight-membered ring possessing a quaternary carbon on its
ring in high yield. We are now developing this protocol to
synthesize the more advanced synthetic intermediate pos-
sessing the tricyclic 6-8-6 carbon skeleton of Taxol. The
further studies will be reported in due course.
genolysis and the following benzylidene formation (88%, 2
steps). Ketone 14 was transformed to hydrazone, which was
then treated with I2 and DBU16 to afford iodide 15 (85%, 2
steps). The selective reduction of the benzylidene group of
15 (97%), Dess-Martin oxidation (91%), and olefination by
Takai’s reagent17 afforded 16 (93%). Coupling of the
alkenyllithium derived from 16 with aldehyde (+)-818
afforded the desired product as a single diastereomer (99%),
which was protected as a benzyl ether 17 (88%).
Acknowledgment. This work was financially supported
in part by Uehara Memorial Foundation and Waseda
University Grant for Special Research Projects. We are also
indebted to 21COE “Practical Nano-Chemistry”.
With 17 in hand, the intramolecular B-alkyl Suzuki-
Miyaura cross-coupling reaction was executed under condi-
tions A and B (Scheme 4). Gratifyingly, we succeeded in
(16) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron
1988, 44, 147-162. (b) Grandi, M. J. D.; Jung, D. K.; Krol, W. J.;
Danishefsky, S. J. J. Org. Chem. 1993, 58, 4989-4992.
Supporting Information Available: Spectral data for all
new compounds and experimental procedures for the reaction
of 17. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) (a) Okazoe, T.; Hibino, J.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 5581-5584. (b) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto,
K. J. Org. Chem. 1994, 59, 2668-2670.
(18) Iwamoto, M.; Miyano, M.; Utsugi, M.; Kawada, H.; Nakada, M.
Tetrahedron Lett. 2004, 45, 8647-8651.
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Org. Lett., Vol. 6, No. 24, 2004