Table 2 Acid-alkyne cyclization reaction with catalyst 1c to afford
different lactonesa
mixture of isomers (eqn (1), Scheme 1). A g-double bond
relative to the acid group was also reacted, obtaining mainly a
5 : 2 : 1 mixture of the internal double bond 7b : 7b0 and also the
conjugated acid 7b0 0 as the minor product (eqn (2)). With these
results in mind we decided to carry out the experiment with a
longer alkyl chain as (Z)-icos-5-enoic acid 6c (eqn (3)). After
four days at the same reaction conditions we detected a
mixture of different alkene-acids (see ESIw). Therefore, the
nature and the properties of these unsaturated-acids could be
changed with these platinum complexes which transform the
original fatty acid to different ones.14
In conclusion, we have shown an efficient cyclization of
alkyne-acids to enol-lactones catalyzed by anticancer Pt(II)
and Pt(IV) compounds. This is a significant unprecedented fact
which proves that these compounds are not only DNA-binding
complexes; they can also modify biological molecules such as
unsaturated fatty acids in aqueous media.
a
All reactions were performed on a 0.2 mmol scale in 0.2 mL of
b
solvent and stopped after 12 h. This reaction was carried out with
This work was made possible by the Ministerio de Educacio
y Ciencia (grant SAF2006-03296 and SAF2009-09431) and is
gratefully acknowledged. Ministerio de Ciencia e Innovacio
´
n
catalyst 1b in CH2Cl2 and the yield is based on recovered material.
c
d
No reaction. This reaction was carried out with catalyst 1b.
´
n
is thanked for a Juan de la Cierva contract (J. A.) and a
pre-doctoral fellowship (V. S.).
Notes and references
1 For recent reviews in the use of metal compounds in medicinal
chemistry, see: (a) M. A. Jakupec, M. Galanski, V. B. Arion,
C. G. Hartinger and B. K. Keppler, Dalton Trans., 2008, 183;
(b) T. W. Hambley, Dalton Trans., 2007, 4929; (c) R. W.-Y. Sun,
D.-L. Ma, E. L.-M. Wong and C. M. Che, Dalton Trans., 2007,
4884; (d) S. P. Fricker, Dalton Trans., 2007, 4903.
2 B. Rosenberg, Interdiscip. Sci. Rev., 1978, 3, 134.
3 P. J. O’Dwyer, J. P. Stevenson and S. W. Johnson, Drugs, 2000,
59, 19.
4 For recent reviews in platinum anticancer complexes, see:
(a) M. Bruyninx and P. J. Sadler, Curr. Opin. Chem. Biol., 2008,
12, 197; (b) L. Kelland, Expert Opin. Invest. Drugs, 2007, 16, 1009.
5 For a review in Pt(IV) complexes, see: M. D. Hall, H. R. Mellor,
R. Callaghan and T. W. Hambley, J. Med. Chem., 2007, 50, 3403.
6 M. A. Jakupec, M. Galanski and B. K. Keppler, Rev. Physiol.,
Biochem., Pharmacol., 2003, 146, 1.
7 (a) M. D. Hall and T. W. Hambley, Coord. Chem. Rev., 2002, 232,
49; (b) M. D. Hall, R. C. Dolman and T. W. Hambley, Met. Ions
Biol. Syst., 2004, 42, 297; (c) For a review in the Photoactivatable
Platinum Complexes, see: P. J. Bednarski, F. S. Mackay and
P. J. Sadler, Anti-Cancer Agents Med. Chem., 2007, 7, 75.
Scheme 1 Transformation of some alkene-acids 6a–c.
cannot be carried out, obtaining only starting material after
24 h, at room temperature and also at higher temperatures
(37 1C). Other substitutions in the a position of the acid
moiety was tolerated, such as esters (2d), allyl groups (2e)
and propargyl groups (2f), obtaining in all cases the expected
products (3d–f) in moderate to good yields. Interestingly, a
tandem reaction could be performed using the double acid-
double alkyne 2g, thus leading to the double spiro-lactone
compound 3g. In the final entries of Table 2, we showed the
influence of a substitution at the triple bond. When a methyl
group was present in the alkyne (2h), a mixture of five and six
member rings in a 3 : 1 ratio (3h/3h0) was obtained. We
confirmed this fact also for the triple bond 2i, obtaining a
mixture of 3i/3i0. From a mechanistic point of view we carried
out the reaction with D2O, observing a 95% incorporation of
deuterium into the double bond and longer reaction times,
from 4 h (H2O) to 10 h (D2O) which was followed by NMR.
This slightly kinetic primary isotopic effect indicates that the
rate limiting step is related to the cleavage of the platinum
complex from the recently formed double bond via deuterolysis
(see ESIw).
8 For a review in gold and platinum catalysis, see e.g.: A. Furstner
¨
and P. W. Davies, Angew. Chem., Int. Ed., 2007, 46, 3410.
9 For palladium complexes, e.g. N. Yanagihara, C. Lambert,
K. Iritani, K. Utimoto and H. Nozaki, J. Am. Chem. Soc., 1986,
108, 2753.
10 For gold, see e.g. E. Genin, P. Y. Toullec, S. Antoniotti,
C. Brancour, J.-P. Genet and V. Michelet, J. Am. Chem. Soc.,
´
2006, 128, 3112.
11 For ruthenium complexes, see: (a) T. Mitsudo, Y. Hori,
Y. Yamakawa and Y. Watanabe, J. Org. Chem., 1987, 52, 2230;
(b) For copper, see: T. L. Mindt and R. Schibli, J. Org. Chem.,
2007, 72, 10247; (c) The use of PtCl2 for this reaction has been
reported for one example in an organic solvent (DCE) in the
screening table. See: K. Komeyama, K. Takahashi and
K. Takaki, Chem. Lett., 2008, 37, 602.
12 D. E. Sok, C. Q. Han, J.-K. Pai and C. J. Sih, Biochem. Biophys.
Res. Commun., 1982, 107, 101.
13 Although the conversion was 499%, the isolated yield is lower due
to the low boiling point of the product 3a.
14 We are currently studying the mechanism of the isomerization with
other complexes and other double bonds. Also, further studies
oriented towards reactions with other different organic molecules,
are in progress and will be reported at a later date.
Acids containing double bonds were also tested with these
platinum complexes. Thus, the but-3-enoic acid 6a at 37 1C
was transformed into the conjugated 7a : 7a0 in a 3 : 2 Z/E
ꢀc
This journal is The Royal Society of Chemistry 2010
456 | Chem. Commun., 2010, 46, 454–456