Synthesis of spiro-pyridones and spiro-quinolones by sequential palladium on carbon-catalyzed allylation and ring closing metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2008.11.026

A rapid and efficient strategy for the preparation of spiro-pyridones and spiro-quinolones using sequential Pd(0)/C-catalyzed allylation and ring closing metathesis reactions is described. The developed protocol features a fully regioselective allylation

Full text of DOI:10.1016/j.tetlet.2008.11.026

Tetrahedron Letters 50 (2009) 506–508
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of spiro-pyridones and spiro-quinolones by sequential palladium
on carbon-catalyzed allylation and ring closing metathesis reactions
*
Laura Kersten, Rachel H. Taylor, François-Xavier Felpin
Université de Bordeaux, CNRS, Institut des Sciences Moléculaires, 351 Cours de la Libération, Talence 33405, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid and efficient strategy for the preparation of spiro-pyridones and spiro-quinolones using sequen-
tial Pd(0)/C-catalyzed allylation and ring closing metathesis reactions is described. The developed proto-
col features a fully regioselective allylation at C3 taking advantage of the unusual reactivity of Pd(0)/C
catalyst. Application of the present methodology in nucleoside chemistry has also been investigated.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 October 2008
Revised 4 November 2008
Accepted 7 November 2008
Available online 13 November 2008
The development of rapid and practical synthetic strategies di-
rected at the preparation of structurally original frameworks and
scaffolds is of great importance in the context of drug discovery.1
As part of a program focusing on the chemistry and biology of 4-
hydroxy-2-pyridones and 4-hydroxy-2-quinolones, we were inter-
ested in the transformation of such skeletons into spiro-pyridone A
and spiro-quinolone B whose structures are related to natural
product sesbanine 3 (Scheme 1). Although sesbanine 3 is only
weakly cytotoxic,2 we considered that its unusual structure could
serve as an interesting lead for the discovery of new antitumor
agents. Such a strategy has been successfully applied during a total
synthesis campaign of migrastatin in Danishefsky laboratories.3
This Letter describes the expedient synthesis of spiro com-
pounds making efficient use of our recently reported Pd(0)/C-med-
OH
O
O
[Ru]
OAc
Pd/C
N
R
O
N
R
O
N
R
O
E
D
C
Scheme 2. Sequential Pd(0)/C-catalyzed allylation-RCM reactions.
Our strategy required first the preparation of diallylic com-
pounds. Although trivial in appearance, it is well documented that
the C3,C3-dialkylation of 4-hydroxy-2-quinones and 4-hydroxy-2-
pyridones under basic condition is mostly accompanied by impor-
tant formation of O-alkylated and O,C3-dialkylated by-products.6
As a consequence, we regarded these substrates as b-dicarbonyl
compounds which should react as nucleophiles under palladium-
catalyzed allylation. Actually, a single report makes efficient use
of a 4-hydroxy-2-pyridone system for palladium-mediated selec-
tive mono-alkylation at C3.7 However, to the best of our knowl-
edge, there is no described method for an efficient and selective
C3,C3-diallylation. We recently, reported that Pd(0)/C (or Pd(II)/C)
could be used as practical and efficient heterogenous catalyst for
allylic alkylation of various nucleophiles.4 We noticed that cyclic
diketones such as Meldrum’s acid 4 gave only the product 5 result-
ing from a double alkylation with good yield even when the nucle-
ophile was used in excess. The same reactivity was not observed
under homogeneous conditions where the mono-alkylated product
6 was the major isolable compound (Scheme 3).8
With theaimof exploiting theinterestingreactivityof Pd(0)/C, we
selected the 4-hydroxy-2-pyridones 7a and 7b as model substrates
for reaction with allyl acetate under Pd(0)/C catalysis (Table 1).
When Ph3P was omitted, only trace amount of the desired prod-
uct was observed along with a number of unidentified by-products
(entry 1). The phosphine acts as a stabilizing agent for palladium,
generating in situ a more reactive Pd(0)–Ph3P complex. It is likely
that palladium nanoparticles, leached from the support, are the
iated allylic alkylation4 in combination with
a ring-closing
metathesis5 (Scheme 2). In addition, we demonstrated that the
present methodology could be extended to the preparation of no-
vel nucleosides related to the 3-deazauridine.
O
OH
OH
N
O
N
R
O
N
H
O
O
1
Spiro-pyridone A
OH
O
N
H
O
Sesbanine 3
N
H
O
N
R
2
Spiro-quinolone B
Scheme 1. Overall strategy.
* Corresponding author. Tel.: +33 4000 6285; fax: +33 4000 6286.
E-mail address: fx.felpin@ism.u-bordeaux1.fr (F.-X. Felpin).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.026

L. Kersten et al. / Tetrahedron Letters 50 (2009) 506–508
507
measured by ICP-MS in the solvent indicating a dissolution–repre-
cipitation process also called the boomerang effect. Although palla-
dium-free allylic alkylation has recently been reported,10 in our
case no reaction occurred in the absence of Pd(0)/C, where starting
material was quantitatively recovered (entry 2). This result indi-
cates a genuine Pd(0)/C-catalyzed reaction. As expected, a double
allylation occurred regioselectively at C3 with good yield (78%)
when an excess of allyl acetate was used (entry 4). Interestingly,
unprotected pyridone 7b was not only diallylated at C3 but also
selectively at the nitrogen atom, with no detectable O-allylated
by-product, with an exploitable yield (69%). It should be noted that
even when an excess of pyridone 7b was used, the tri-allylated
compound was isolated as the major compound. From these preli-
minary results, it should be noted that O-allylation compounds
were never observed from the crude reaction mixtures.
O
O
Pd(OAc)2
Ph3P
Pd(0)/C
O
O
H
O
O
O
O
O
OAc
4
AcO
O
O
O
79% - ref 8
94% - ref 4
6
5
Scheme 3. Dual reactivities of heterogeneous versus homogeneous Pd catalysts.
Table 1
Optimizations studies
O
OH
OAc
To further explore the scope of this transformation, we selected
a variety of pyridone- or quinolone-based nucleophiles 7a–d for
reaction with allyl acetate under Pd(0)/C-mediated catalysis. The
results compiled in Scheme 4 clearly highlight the efficiency of this
two-step transformation. As expected, O-allylation compounds
were never observed from the crude reaction mixtures, and the
targeted compounds 8a–d were, in all cases, the only isolable prod-
ucts. The subsequent RCM reaction on compounds 8a–d proceeded
smoothly with high yield to give spiro-compounds 9a–d. It should
be pointed out that the first-generation Grubbs catalyst was inef-
fective for this transformation leaving the diallylic compounds
8a–d unaltered.
Pd(0)/C, Ph3P
THF, K2CO3
60 ºC, 12 h
N
R
O
N
R
O
7a : R = Bn
7b : R = H
8a : R = Bn
8b : R = Allyl
Entry
Pyridone
Ph3P
(equiv)
Pd(0)/C
(equiv)
Allyl acetate
(equiv)
Product
Yielda (%)
1
2
3
4
5
6
7a
7a
7a
7a
7b
7b
—
0.05
—
0.05
0.05
0.05
0.05
2.2
2.2
2.2
4
2.2
6
—
—
8a
8a
8b
8b
—
—
50
78
50
69
0.2
0.2
0.2
0.2
0.2
In order to further illustrate the synthetic utility of the sequen-
tial allylation-RCM reactions for the rapid elaboration of spiro het-
erocycles of potential biological importance, we prepared a spiro
analogue of the 3-deazauridine 10 (DU), (Scheme 5).
a
Isolated yields.
true catalytic active species that required Ph3P as stabilizing ligand
as already observed for other Pd-catalyzed cross-couplings.9 How-
ever, at the end of the reaction, low palladium level (<10 ppm) was
It has been shown that DU 10 inhibits cytidine trophosphate
synthase, thereby reducing intracellular levels of cytidine triphos-
phate and disrupting DNA and RNA syntheses.11 Although DU 10
O
O
N
OH
N
OAc
[Ru], CH2Cl2, 50 ºC
(eq. 1)
93% yield
Pd(0)/C, K2CO3
THF, 60 ºC
80% yield
N
O
O
O
8a
8b
8c
8d
7a
7b
7c
7d
9a
9b
9c
9d
O
N
O
N
OH
OAc
[Ru], CH2Cl2, 50 ºC
77% yield
(eq. 2)
(eq. 3)
(eq. 4)
Pd(0)/C, K2CO3
THF, 60 ºC
69% yield
O
O
N
H
O
O
O
N
N
[Ru] =
Cl
Cl
Ru
P(Cy)3
Ph
O
N
O
N
OH
N
OAc
[Ru], CH2Cl2, 50 ºC
87% yield
Pd(0)/C, K2CO3
THF, 60 ºC
75% yield
O
O
O
O
O
N
O
N
OH
N
OAc
[Ru], CH2Cl2, 50 ºC
97% yield
Pd(0)/C, K2CO3
THF, 60 ºC
78% yield
Scheme 4. Scope of the protocol.

508
L. Kersten et al. / Tetrahedron Letters 50 (2009) 506–508
Zanese (University of Bordeaux) is gratefully acknowledged for
fruitful discussions.
O
N
OH
N
AcO
AcO
O
O
Supplementary data
OAc
O
O
Pd(0)/C, K2CO3
THF, 60 ºC
85% yield
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.026.
OAc OAc
12
11 OAc OAc
OH
O
References and notes
HO
N
O
AcO
N
O
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Scheme 5. Preparation of a spiro nucleoside.
used as a single agent exerts negligible clinical efficiency resulting
in a lack of interest in clinical investigation,12 it has been recently
disclosed that DU in combination with retinoic acid or dibutyryl
cyclic adenosine monophosphate (dbcAMP) induces cell death by
apoptosis in myeloid HL-60 cells.13 Moreover, our own investiga-
tions on the preparation of novel nucleosides derived from DU
10 indicated that such a skeleton has potent antiviral activities.14
We were pleased to find that our methodology proceeded in good
yield (68% over two steps) to furnish the new spiro analogue 13 of
DU 10. The mild conditions of the two steps seem particularly rel-
evant for sensitive substrates such as nucleosides.
In summary, we have disclosed along these lines a rapid and
efficient method for the construction of new spiro heterocycles.
The method features an unusual Pd(0)/C-mediated highly regiose-
lective diallylation at C3, which allows minimal contamination of
the products by palladium residues, followed by a ring closing
metathesis. We are currently exploring other applications of this
strategy in the chemistry of nucleosides. Detailed biological activ-
ities of various libraries of compounds will be disclosed in due
time.
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Acknowledgments
This work was supported by the ‘Université de Bordeaux’, the
‘Centre National de la Recherche Scientifique (CNRS)’ and the ‘Li-
gue Nationale contre le Cancer, Comité de la Gironde’. Mrs Marion
13. Savickiene, J.; Gineitis, A. Int. J. Biochem. Cell B 2003, 35, 1482–1494.
14. Results to be patented.