The selective synthesis of metallanucleosides and metallanucleotides: A new tool for the functionalization of nucleic acids

Article abstract of DOI:10.1002/chem.201202327

Nucleobases team up: The efficient and selective preparation of purine-derived metallanucleosides, metallanucleotides, and metalladinucleotides having M-C bonds (M=Ir^III, Rh^III) is reported for the first time (see scheme). The results presented may be applied to the synthesis of functionalized nucleic acids, or DNA/RNA-modified segments. Copyright

Full text of DOI:10.1002/chem.201202327

COMMUNICATION
DOI: 10.1002/chem.201202327
The Selective Synthesis of Metallanucleosides and Metallanucleotides:
A New Tool for the Functionalization of Nucleic Acids
Mamen Martꢀn-Ortꢀz,[a] Mar Gꢁmez-Gallego,*[a] Carmen Ramꢀrez de Arellano,[b] and
Miguel A. Sierra*[a]
The combination of nucleobases with transition metals[1,2]
is an attractive area of research due to the key role of metal
complexes in cancer chemotherapy.[3,4] In this context, many
efforts in the field have been devoted to nucleobase-Pt coor-
dination complexes with the aim to study the mechanisms of
interaction of cis-platinum (and its analogues) with DNA.[3]
Other modified nucleosides are also known to possess a
broad spectrum of biological activities,[5] although to date,
the studies have been mostly limited to 6-aryl(heteroaryl)
purines and their nucleosides, which have shown to display
significant noticeable cytostatic and antibacterial activity
avoid the hydrolysis of the labile glycosidic bond.[12] The re-
sults presented in this work provide new pathways to the
functionalization of nucleic acids, to the synthesis and study
of new unusual nucleosides[13] or to metal-containing un-
natural DNA fragments, and could be applied to the prepa-
ration of other metal-derived molecules of biological inter-
est.
and are potent hepatitis C virus (HCV) antivirals.[6–8]
À
Nucleosides and nucleotides having M C bonds (in which
C is part of the nucleobase skeleton) are essentially differ-
ent from the known metal-coordination complexes. Their
synthesis and properties have not been studied, and the
À
presence of M C bonds in their structures would also make
them interesting building blocks for the construction of new
metalla-macrocyclic or supramolecular molecules.[9,10] We
now report the successful application of an N-directed cyclo-
metallation reaction to the synthesis of metal-arylpurine nu-
cleosides 1 and nucleotides (or dinucleotides) 2 (M=IrIII,
RhIII) and explore their reactivity in the formation of new
To determine the suitability of our strategy to selectively
functionalize the purine ring, we chose the N9-tetrahydro-
pyranyl (THP)-protected compound 3 as a purine nucleo-
side model.[14] The reaction of 3 with [{IrCl2Cp*}2 (Cp*=h-
C5Me5)] and NaOAc, in CH2Cl2 at RT[15] cleanly afforded
cyclometallated complex 4 as a diastereomeric (1:0.7) mix-
ture in 75% yield of the isolated product (Scheme 1). The
1H NMR spectrum of 4 clearly indicated that the coordina-
À
À
M C and M N bonds. Initially the idea of using an N-di-
[11]
À
rected C H activation reaction
to prepare these purine
À
derivatives was somewhat challenging. First, the presence of
tion of the metal to N1 and the C H activation of the aro-
several nitrogen atoms in the 6-phenylpurine skeleton could
matic phenyl ring had occurred. Further confirmation of the
structure was gained by X-ray diffraction analysis of a crys-
tal of one of the diasteroisomers of 4 (slow diffusion in
CHCl3/hexane) showing the expected pseudo-tetrahedral
three-legged piano-stool structure (iridium bite angle
77.51(14)8 (N1-Ir1-C12). As far as we are aware, this is the
first structure of a metal C,N-bonded purine derivative re-
ported in the literature.[16] The corresponding Rh complex 5
À
lead to selectivity problems as well as to mixtures of C H
activation/coordination products.[1,2] On the other hand, the
incorporation of a sugar unit and a phosphate group in the
nucleobase skeleton worsens the scenario, making the
choice of the reaction conditions and reagents important to
[a] M. Martꢀn-Ortꢀz, Prof. Dr. M. Gꢁmez-Gallego, Prof. Dr. M. A. Sierra
Departamento de Quꢀmica Orgꢂnica I
Facultad de Ciencias Quꢀmicas
was quantitatively obtained by reaction of
[{RhCl2Cp*}2] under similar conditions (Scheme 1).
The effect of the free (basic) N9 position was studied with
6-phenylpurine 6 (prepared by removal of the THP group in
3).[14] Whereas treatment of 6 with [{RhCl2Cp*}2]/NaOAc in
3
and
Universidad Complutense
28040 Madrid (Spain)
E-mail: margg@quim.ucm.es
sierraor@quim.ucm.es
À
the conditions above led to the C H insertion product 8
[b] Prof. Dr. C. Ramꢀrez de Arellano
Departamento de Quꢀmica Orgꢂnica
Universidad de Valencia
(58%), the reaction with [{IrCl2Cp*}2]/NaOAc only afforded
the N9-[IrClCp*]2 coordinated dimeric product 7 in 71%
yield of the isolated product (Scheme 1).[17] Further treat-
ment of 7 with either [{IrCl2Cp*}2]/NaOAc or [{RhCl2Cp*}2]/
46100 Valencia (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202327.
À
NaOAc did not afford any of the C H activation products.
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acetyl derivative 9, which was prepared in three steps from
commercially available inosine.[14] Treatment of 9 with
[{MCl2Cp*}2]/NaOAc (M=Ir, Rh) afforded the correspond-
ing Ir- and Rh-cyclometallated derivatives 13 and 14 in 73
and 98% yields, respectively. The presence of a free (5’) pri-
mary OH group in the sugar moiety did not substantially
change the reaction outcome. Thus, isopropylidene deriva-
tive 10 (prepared from nucleoside 11 and acetone/pTsOH)
afforded the corresponding metal-aryl purine derivatives 15
and 16 in 97 and 93% yields, respectively. Finally, the meth-
odology was tested with free ribose and deoxyribose nucleo-
sides 11 (obtained by removal of the acetate groups in 9
with NaOMe/MeOH) and 12 (prepared in a four-step se-
quence from 2’-deoxyadenosine).[14] In both cases the ex-
pected cyclometallated nucleosides 17–20 were obtained in
nearly quantitative yields (Scheme 2). These results show
the complete selectivity of the process and the full compati-
bility of the reaction conditions with the labile glycosidic
bond and also with the free OH groups in the ribose and de-
oxyribose moieties. Both facts are very important for the
use of this methodology in DNA chemistry.
Phosphorylation of isopropylidene derivative 10 afforded
phosphate 21 as the ammonium salt (two steps, 42% aver-
age yield) (Scheme 3).[14] Unfortunately, the reaction of this
compound with [{IrCl2Cp*}2]/NaOAc failed to yield the ex-
Scheme 1. Synthesis of metal-arylpurines. Yields are for the pure prod-
ucts. Compounds 4 and 5 were obtained as (1:0.7) diastereomeric mix-
tures.
À
pected C H activation product. Instead, in all the conditions
tested (increase of the temperature, use of NEt3 or NHiPr2
These results show the higher preference of the iridium
À
complex for the N H activation process in 6 compared with
as base), the reaction crudes afforded complex mixtures of
À
the C H activation reaction.
Cyclometallation of the more sensitive and densely func-
tionalized 6-penylpurine nucleosides 9–12 was next studied
(Scheme 2). The compatibility of the reaction conditions
with the labile glycosidic bond was first tested with tri-O-
Scheme 3. Synthesis of metal-arylpurine nucleotides. Yields are for the
pure isolated products. [a]=Compounds obtained as diastereomeric mix-
tures.
Scheme 2. Synthesis of metal-arylpurine nucleosides. Yields are for the
pure products. Compounds obtained as (1:1) diastereomeric mixtures.
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Functionalization of Nucleic Acids
COMMUNICATION
products compatible with the involvement of the phosphate
group in metal coordination and/or ligand displacement
processes.[18] To avoid these undesirable competitive reac-
tions, we tested the reaction conditions with allyl phosphate
22, obtained by reaction of 10 with POCl3 and allyl alcohol
(Scheme 3).[14] Reaction of 22 with [{IrCl2Cp*}2]/NaOAc,
however, only yielded complex mixtures of products. Re-
placement of the allyl with a methyl group in the phosphate
proved essential for the reaction success. Phosphorylation of
isopropylidene derivative 10 with N,N-diisopropyl-dimethyl-
phosphoramidite afforded methyl phosphate 23, which after
cyclometallation in the conditions described above, smooth-
ly yielded metal-arylpurine nucleotides 25 and 26 in 96 and
94% yields, respectively (Scheme 3). Removal of the isopro-
pylidene group in 23 followed
was prepared from deoxyribose phosphate 32 and monopro-
tected nucleoside 33.[14] Treatment of this compound with
[{MCl2Cp*}2]/NaOAc afforded the metallated Ir- and Rh-
DNA segments 35 and 36 in 81 and 57% yields, respectively
(diastereomeric mixtures). These results are a promising
start for the synthesis of unusual homo- and heterometalla-
DNA fragments.
The efficient preparation of cyclometallated IrIII or RhIII
complexes derived from purine nucleobases opens new and
interesting possibilities for the further functionalization of
the nucleosides and nucleotides.[19] In this context, Ir and Rh
cyclometallated intermediates structurally related to the
metal-arylpurines reported in this work have been proposed
[20,21]
À
to be involved in C C coupling reactions.
Also, iridium
by reaction with [{MCp*Cl2}2]/
NaOAc yielded the correspond-
ing IrIII and RhIII ribose nucleo-
tides 27 and 28 (in 90 and 84%
yields, respectively). These
compounds are, to the best of
our knowledge, the first exam-
ples of cyclometallated nucleo-
tides reported in the literature.
Being aware of the additional
stereochemical complexity de-
rived from the presence of the
phosphate groups, the synthesis
of metal-arylpurine dinucleoti-
des was our final goal. First at-
tempts were made with dimeric
ribose derivative 29 (prepared
from 10 and bis-N,N-diisoprop-
yl-methylphosphoramidite using
phosphate nucleotide bonding
methodology)
(Scheme 4).[14]
Although the reaction required
an excess of NaOAc (three
times
the
stoichiometric
amount) and longer reaction
times, the IrIII insertion product
30 could be obtained in 64%
yield of the isolated product
(diastereomeric mixture). In
turn, the formation of the cor-
responding RhIII product was
less efficient, and
a
larger
excess of base and two days at
room temperature were re-
quired to obtain 31 in 34%
yield. These optimized reaction
conditions were finally used to
the preparation of metal-aryl-
purine dinucleotides 35 and 36,
resembling the structure of a
DNA fragment (Scheme 4).
The starting dinucleotide 34 Scheme 4. Synthesis of metal-arylpurine dinucleotides.
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M. Gꢁmez-Gallego, M. A. Sierra et al.
half-sandwich complexes of the type [Ir
(N-C)ClCp*] have
photochemical or electrochemical markers. Furthermore,
the cyclometallated nucleosides and nucleotides prepared
are susceptible of selective post-functionalization, either by
shown ability as catalyst precursors for oxidation reac-
tions.[22,23] In a first trial, {IrClCp*}purine 15 was reacted
with dimethylacetylenedicarboxylate (DMAD) at room tem-
perature in MeOH.[20] Under these conditions, a cyclometal-
lated complex 37, derived from the insertion of one mole-
À
À
means of C C insertion reactions into the M C bonds or as
building blocks for macrocyclic chiral polymetallic struc-
tures. Development of the full potential of this chemistry to
the study of new metal-derived molecules of biological inter-
est is currently underway in our laboratories.
À
cule of DMAD in the M C bond, was obtained in 81%
yield (Scheme 5). Apart from the interest of the reactivity
Experimental Section
The representative experimental procedures followed for the preparation
of compounds 4, 5, 30, 36 and 37 are as follows:
Synthesis of 4: NaOAc (12 mg, 0.15 mmol) and 3 (35 mg, 0.12 mmol)
were added to a solution of [IrCl2Cp*]2 (50 mg, 0.06 mmol) in dichloro-
methane (5 mL). The mixture was stirred at room temperature for 12 h
and filtered through celite. The solvent was removed under reduced pres-
sure. The crude was purified by flash SiO2 chromatography (hexane/ethyl
acetate 3:2 to ethyl acetate) to yield an orange solid 4 (30 mg, 75%) as a
mixture of isomers (1:07).
Synthesis of 5: NaOAc (16 mg, 0.20 mmol) and 3 (56 mg, 0.20 mmol)
were added to a solution of [RhCl2Cp*]2 (50 mg, 0.08 mmol) in dichloro-
methane (5 mL). The mixture was stirred at room temperature for 24 h
and filtered through celite. The solvent was removed under reduced pres-
sure. The crude was purified by flash SiO2 chromatography (dichlorome-
thane to dichloromethane/ethyl acetate, 10:1) to yield an orange solid 5
(44 mg, 98%) as a mixture of isomers (1:0.7).
Synthesis of 30: NaOAc (12 mg, 0.14 mmol) and 29 (50 mg, 0.06 mmol)
were added to a solution of [IrCl2Cp*]2 (49 mg, 0.06 mmol) in dichloro-
methane (5 mL). The mixture was stirred at room temperature for 18 h
and filtered through celite. The solvent was removed under reduced pres-
sure. The crude was purified by flash SiO2 chromatography (hexane/ethyl
acetate, 1:1 to ethyl acetate) to yield an orange solid 30 (59 mg, 64%) as
a mixture of isomers.
Scheme 5. Reactivity examples.
studies, the selective involvement of the N1 position of the
purine skeleton in the formation of the metallacycles offers
the possibility of exploring the ability of other free nitrogen
atoms in the nucleobase for the coordination with metals. In
this regard, the basic N9 position could be ideal to make
Synthesis of 36: NaOAc (7 mg, 0.09 mmol) and 34 (20 mg, 0.02 mmol)
were added to a solution of [RhCl2Cp*]2 (15 mg, 0.02 mmol) in dichloro-
methane (5 mL). The mixture was stirred at room temperature for 12 h
and filtered through celite. The solvent was removed under reduced pres-
sure. The crude was purified by flash SiO2 chromatography (ethyl acetate
to ethyl acetate/methanol, 10:1) to yield an orange solid 36 (19 mg, 57%)
as a mixture of isomers.
À
À
structures that combine C M and N M coordination bonds.
Thus, removal of the THP-group (Dowex 50ꢄ8, H+) in Ir-
metal-arylpurine 4, followed by treatment with saturated
ammonia solution in methanol, smoothly afforded the trinu-
clear metallacycle 38 (in 86% yield), which was character-
ized by NMR and MS analysis (Scheme 5). Amazingly, this
compound was obtained as a single C3 diastereoisomer, as
Synthesis of 37: Dimethylacetylenedicarboxylate (12 mL, 0.09 mmol) was
added to a solution of 15 (70 mg, 0.09 mmol) in dry methanol (28 mL)
and the reaction was stirred for 5 h (during this time the reaction turned
from orange to yellow). The solvent was evaporated under reduced pres-
sure and the yellow solid was washed with hexane several times to yield
a yellow solid 37 (67 mg, 81%) as a mixture of isomers (1:0.85).
Additional details for the preparation of iridium and rhodium complexes,
crystallographic details for the structure of 4, and full characterization
data of all new compounds are provided in the Supporting Information.
1
shown in the H- and 13C NMR spectra.[14] The total selectiv-
ity in the formation of 38 can be explained by chiral self-rec-
ognition between the metal fragments during the triangle
formation, a process that has very few precedents with re-
spect to metallacycles based on metal-coordination
bonds.[10e]
Acknowledgements
In summary, this paper reports for the first time the effi-
cient preparation of purine derived metal-arylpurine nucleo-
sides, metal-arylpurine nucleotides, and metal-arylpurine di-
Financial support from the Spanish MICINN: Projects CTQ-2010–20414-
C02–01/BQU, and Consolider Ingenio 2010 (CSD2007–00006) and from
the Comunidad de Madrid: (CCG07-UCM/PPQ-2596 is acknowledged.
A generous loan of MCl3 (M=Ir, Rh) from Johnson-Matthey PLC is
gratefully acknowledged. M.M.O thanks the MEC for a FPI fellowship.
III
III
À
nucleotides having M C bonds (M=Ir , Rh ). The meth-
odology has been also applied to the preparation of a metal-
la-DNA segment. The results reported in this work could be
applied to the design and synthesis of functionalized nucleic
acids, or of DNA/RNA-modified segments, to be used as
Keywords: cancer
·
iridium
·
metalation
·
metallanucleotides · nucleobases · rhodium
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Functionalization of Nucleic Acids
COMMUNICATION
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À
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[14] See the Supporting Information for full experimental details.
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[16] Cambridge Structural Database, February 2012 update version
(5.33), 603297 entries).
[17] The structure of 7 was established by NMR and ESI-MS. Although
the molecular peak (m/z=1116 [M+H]+) was not detected, the
highest peak in the ESI-MS spectra was m/z 885, in which the mass
and isotopic pattern correspond to the fragment [(C31H37N4Ir2Cl)]+.
See the Supporting Information for details.
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[7] 6-Arylalkynyl and 6-arylalkenyl purine derivatives have also anti-
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a) A. Brathe, G. Andresen, L.-L. Gundersen, K. E. Malterud, F.
Rise, Bioorg. Med. Chem. 2002, 10, 1581; b) A. Brathe, G. Andre-
sen, L.-L. Gundersen, F. Rise, A. B. Eriksen, A. V. Vollsness, L.
Wang, Tetrahedron 1999, 55, 211.
À
ing group in metal-catalyzed C C arylations: H.-M. Guo, l.-L.
Jiang, H.-Y. Niu, W.-H. Rao, L. Liang, R.-Z. Mao, D.-Y. Li, G.-R.
Qu, Org. Lett. 2011, 13, 2008.
[20] L. Li, W. W. Brennessel, W. D. Jones, J. Am. Chem. Soc. 2008, 130,
12414.
[21] Ru-cyclometallated intermediates structurally related to the metal-
nucleobases reported in this work were proposed to be involved as
À
key intermediates in the catalytic cycles of C C arylations, see:
[8] 6-Heteroaryl purines: a) M. Hocek, P. Naus, R. Pohl, I. Votruba,
P. A. Furman, P. M. Tharnish, M. J. Otto, J. Med. Chem. 2005, 48,
5869; b) A. K. Bakkestuen, L. L. Gundersen, B. T. Utenova, J. Med.
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11400.
Chem. Eur. J. 2012, 00, 0 – 0
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M. Gꢁmez-Gallego, M. A. Sierra et al.
[22] J. D. Blakemore, N. D. Schley, D. Balcells, J. F. Hull, G. W. Olack,
C. D. Incarvito, O. Eisenstein, G. W. Brudvig, R. H. Crabtree, J. Am.
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bles were almost immediately observed. Further experimentation in
this aspect of the chemistry of metallanucleosides has not yet been
pursued.
[23] In a preliminary experiment, compound 15 was treated with an
excess of cerium(IV) ammonium nitrate in water/MeOH. Gas bub-
Received: June 29, 2012
Published online: && &&, 2012
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Functionalization of Nucleic Acids
COMMUNICATION
Metallanucleobases
M. Martꢀn-Ortꢀz, M. Gꢁmez-Gallego,*
C. Ramꢀrez de Arellano,
M. A. Sierra* .................. &&&& — &&&&
The Selective Synthesis of Metallanu-
cleosides and Metallanucleotides: A
New Tool for the Functionalization of
Nucleic Acids
Nucleobases team up: The efficient
and selective preparation of purine-
derived metallanucleosides, metallanu-
cleotides, and metalladinucleotides
reported for the first time (see
scheme). The results presented may be
applied to the synthesis of functional-
ized nucleic acids, or DNA/RNA-
modified segments.
III
III
À
having M C bonds (M=Ir , Rh ) is
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!