Synthesis of (Carbo)nucleoside analogues by [3+2] annulation of aminocyclopropanes

Article abstract of DOI:10.1002/anie.201404832

(Carbo)nucleoside derivatives constitute an important class of pharmaceuticals, yet there are only few convergent methods to access new analogues. Here, we report the first synthesis of thymine-, uracil-, and 5-fluorouracil-substituted diester donor-acceptor cyclopropanes and their use in the indium- and tin-catalyzed [3+2] annulations with aldehydes, ketones, and enol ethers. The obtained diester products could be easily decarboxylated and reduced to the corresponding alcohols. The method gives access to a broad range of new (carbo)nucleoside analogues in only four or five steps and will be highly useful for the synthesis of libraries of bioactive compounds.

Full text of DOI:10.1002/anie.201404832

Angewandte
Chemie
DOI: 10.1002/anie.201404832
Synthetic Methods
Hot Paper
Synthesis of (Carbo)nucleoside Analogues by [3+2] Annulation of
Aminocyclopropanes**
Sophie Racine, Florian de Nanteuil, Eloisa Serrano, and Jꢀrꢁme Waser*
Abstract: (Carbo)nucleoside derivatives constitute an impor-
tant class of pharmaceuticals, yet there are only few convergent
methods to access new analogues. Here, we report the first
synthesis of thymine-, uracil-, and 5-fluorouracil-substituted
diester donor–acceptor cyclopropanes and their use in the
indium- and tin-catalyzed [3+2] annulations with aldehydes,
ketones, and enol ethers. The obtained diester products could
be easily decarboxylated and reduced to the corresponding
alcohols. The method gives access to a broad range of new
(carbo)nucleoside analogues in only four or five steps and will
be highly useful for the synthesis of libraries of bioactive
compounds.
T
he natural nucleosides constitute the building blocks of
DNA and RNA. The interaction of enzymes and other
biomolecules with nucleosides is essential for the regulation
of genetic expression and cell replication. Therefore, the
nucleoside scaffold constitutes a privileged structure in
medicinal chemistry (Figure 1).[1] In addition to bioactive
natural products, such as the antiviral and antibiotic aristero-
mycin (1), more than 45 FDA-approved drugs are nucleoside
analogues. Besides only slightly modified analogues, such as
cytarabine (2) and telbivudine (3), more elaborated com-
pounds derived from thymine have been successful, such as
the carbonucleoside stavudine (4), the anti-HIV front drug
azidothymidine (5), and the fluorinated floxuridine (6).
Nevertheless, resistances are emerging in viral infections,
and less toxic anti-cancer agents would be highly desirable,
calling for the development of new bioactive nucleoside
analogues.
Figure 1. Natural and synthetic bioactive nucleoside analogues.
side II[2a] (Scheme 1A). This approach is efficient if the
targeted analogue is similar to a natural ribose derivative, but
can involve a long multi-step sequence if a more elaborate
scaffold is desired.[3] This is particularly true for carbonucleo-
side analogues, for which elegant synthetic approaches
involving ring-closing metathesis,[3a] Pauson–Khand[3b] or
desymmetrization starting from cyclopentadiene and pro-
ceeding via diols,[3c–e] Vince lactam,[3f,g] or nitroso cycloaddi-
tion reactions[3h] have been developed.
Our group has introduced the use of imide-substituted
diester cyclopropanes in [3+2] annulation reactions.[4] With
this new class of donor–acceptor cyclopropanes,[5] access to
intermediates of type II became possible (Scheme 2B).
Nevertheless, the efficiency of the annulation process was
mitigated by the necessary removal of the phthalimide group
followed by DNA-base construction, which would add several
steps to the synthetic sequence. Furthermore, the deprotec-
tion of the pththalimide group could not be achieved on the
tetrahydrofurylamines.
If a DNA-base could be used as amino substituent on the
cyclopropane, a more efficient synthesis would become
possible (Scheme 1C). Herein, we report the successful
implementation of this strategy, including: 1) the first efficient
three-step synthesis of thymine/uracil donor–acceptor cyclo-
propanes, 2) their successful [3+2] cycloaddition with enol
ethers, aldehydes and ketones, and 3) their further derivati-
zation to access hydroxylated analogues.
The synthesis of nucleoside analogues has been the focus
of intensive effort since several decades.[2] Nevertheless, most
methods are based on a linear approach involving first the
synthesis of a ribose analogue followed by introduction of the
À
nucleobase, either by formation of the C N bond using
a substitution reaction from an acetate I (Vorbrꢀggen
reaction)[2b] or a condensation reaction from an aminoglyco-
[*] S. Racine, F. de Nanteuil, E. Serrano, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne, EPFL SB ISIC LCSO
BCH 4306, 1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
[**] EPFL, F. Hoffmann-La Roche Ltd, SNF (grant number
200021_129874) and the NCCR chemical biology (funded by the
Swiss National Science Foundation) are acknowledged for financial
support. Dr. Rosario Scopelliti (EPFL) is acknowledged for the X-ray
studies.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404832.
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In our work with phthalimide-substituted cyclopropanes,
modulating the electronic density on the nitrogen was
essential for a successful annulation reaction. Based on the
fact that thymine and phthalimide have similar pKa values
(8.3 and 9.9, respectively), we started our investigations with
thymine-substituted cyclopropanes (Scheme 2A). Cyclopro-
pane 7a was easily accessed by selective mono-benzoylation
of thymine (10),[6] followed by Pd-catalyzed vinylation under
slightly modified reported conditions[7] and cyclopropanation
using Du Boisꢁ Rhodium–espino complex.[8] As N3-selective
tert-butylbenzylation was not possible, a longer sequence
involving temporary Boc protection of the N1 nitrogen was
necessary in the case of cyclopropane 7b.[9]
With aminocyclopropanes 7a and 7b in hand, we first
examined the iron-catalyzed [3+2] annulation reaction with
benzaldehyde (14) (Scheme 2B).[4c] The reaction was suc-
cessful for both substrates 7a and 7b. Nevertheless, we were
never able to remove either of the protecting groups on the
nitrogen of thymine. We decided consequently to turn to the
easily removable tert-butoxy carbonyl (Boc) protecting group.
Due to the incompatibility of the Boc group with the
vinylation conditions, a method to access selectively N1-vinyl
thymine prior to introduction of the Boc group was required.
All the reported methods to access this substrate proceeded
with low yield and reproducibility in our hands.[10] Never-
theless, we discovered that N1-selective Pd-catalyzed vinyl-
ation was possible in 45% yield from thymine itself in
presence of trimethylsilyltriflate (TMSOTf) as additive
(Scheme 3A). Boc-protection[11] and cyclopropanation then
proceeded in good yields, giving access to 7c in only three
steps.
First attempts towards the annulation of 7c with benz-
aldehyde (14) using an iron catalyst gave the desired product
only in low yield (< 27%). This was due to loss of the Boc
protecting group during both reaction and purification.
Changing to In(OTf)3 as catalyst[12] and direct Boc depro-
tection of the crude product by heating in ethanol at 708C
afforded the desired NH-free product 8c in 87% yield
(Scheme 3B). Aminocyclopropane 7c could also be used in
other [3+2] annulation processes involving either ketones[4b]
Scheme 1. A) Traditional approach, B) our previous work, and C) new
strategy to access (carbo)nucleoside analogues. Phth=Phthamoyl,
Pg=protecting group, LA=Lewis acid.
Scheme 2. A) Synthesis of aminocyclopropanes 7a and 7b and B) first
attempts of [3+2] annulation. Reaction conditions: a) BzCl, pyridine,
CH3CN, 69%. b) 4 mol% Na2PdCl4, vinylacetate, 808C, 65%.
c) 0.2 mol% [Rh2(esp)2], diazodimethylmalonate, CH2Cl2. d) Boc2O,
DMAP, CH3CN. e) tBuBnBr, NaH, DMF, 08C, quant. f) K2CO3, MeOH,
81%. g) 4 mol% Na2PdCl4, vinylacetate, 808C, 23%, h) 5 mol%
Fe2O3·Al2O3, CH2Cl2.
Scheme 3. A) Synthesis of aminocyclopropanes 7c and B) optimized
conditions for [3+2] annulation reactions. Reaction conditions:
a) 4 mol% Pd(OAc)2, vinylacetate, TMSOTf, 708C, DMF, 45%.
b) Boc2O, DMAP, CH2Cl2, 75%. c) 0.02 mol% [Rh2(esp)2], diazodime-
thylmalonate, CH2Cl2. d) 20 mol% In(OTf)3, CH2Cl2; then EtOH, 708C.
e) 10 mol% SnCl4, CH2Cl2, À208C; then EtOH, 708C.
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Figure 2. Scope of the [3+2] annulation reaction. The reactions were run on 0.40 mmol scale using the conditions of Scheme 3 and isolated yields
after column chromatography are given. See Supporting Information for full experimental details. Thy=thymine, Ur=uracil, 5F-Ur=
5-fluorouracil.
or silyl enol ethers[4a] to give tetrahydrofuryl amine 8d and
cyclopentyl amine 9a in 94% and 84% yield, respectively. In
this case, the lower reactivity of 7c compared with phthal-
imide-substituted cyclopropanes required the use of a higher
temperature (À20 instead of À788C) in the tin-catalyzed
process.
We then turned to the investigation of the scope of the
[3+2] annulation (Figure 2).[13] The reaction was successful in
the case of aromatic (products 8c and 8e), aliphatic (products
8 f) and vinylic aldehydes (product 8g). Excellent diastereo-
selectivity (> 20:1) was observed, except for product 8g (5:1).
The same was also true for ketones (products 8d and 8h–k),
Scheme 4. Modification of A) the tetrahydrofuran and B) the cyclo-
although the diastereoselectivity was lower for vinylic ketones
(product 8k). With enol ethers, more substituted derivatives,
such as tetrasubstituted cyclopentane 9c, could also be
accessed. The [3+2] annulation product was obtained in
55% yield with a dienol ether as partner (product 9d). Finally,
modification of the thymine substituent was also examined.
Both cyclopropanes derived from uracil and 5-fluorouracil
could also be used in the annulation reaction with aldehydes,
ketones, and enol ethers (products 18–21).[14]
For most nucleoside drugs enzymatic phosphorylation of
a hydroxy group is an important step in the mode of action.[1]
Modification of the obtained products to include hydroxy
group(s) would be consequently highly rewarding in the quest
of new bioactive compounds. To reach this goal, saponifica-
tion followed by decarboxylation of diester 8c gave access to
a single isomer of the corresponding carboxylic acid,[15] which
could be reduced to primary alcohol 22 in 71% overall yield
(Scheme 4A). The same sequence was also successful for
styrene derivative 8g, giving the corresponding alcohol 24 in
59% yield. Products 8d and 8h could also be converted into
the desired alcohols 23 and 25 in 62 and 64% yield
respectively. In the case of the carbonucleoside analogues,
dibenzylester cyclopentylamine 26 could be converted into
pentane products. Reaction conditions: a) KOH, MeOH. b) BH3·SMe2,
THF. c) 10% Pd/C, 1 atm H2, EtOH, 578C, then neat, 808C. d) 5% Pd/
C, 1 atm H2, EtOH, 85%. e) iPr3SiCl, DMF, imidazole, 55% over two
steps.
the corresponding diacid by hydrogenation.[16] Heating the
neat crude diacid to 808C led then to decarboxylation and
silyl ether elimination to give acid 27 (Scheme 4B). Pd-
catalyzed hydrogenation followed by acid reduction gave the
corresponding unstable saturated alcohol, which was isolated
as silyl ether 28.
In conclusion, we have reported the first synthesis of
nucleobase-substituted diester cyclopropanes and their use in
cycloaddition with aldehydes, ketones, and enol ethers. This
new transformation gave access in a few steps to important
nucleoside analogues, which were easily modified to give
hydroxylated derivatives. Future work will focus on the
synthesis of a broader range of analogues to build up
a chemical library for biological testing and extending the
scope of the reaction to the purine class of nucleobases.
Received: April 30, 2014
Published online: && &&, &&&&
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Keywords: annulation · catalysis · cyclopropanes · nucleosides ·
stereoselective synthesis
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[13] The stereochemistry of compounds 8e, 8i, and 9a has been
determined by X-ray crystallography. CCDC 995573, 994735,
and 994948 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif. The stereochemistry of the other com-
pounds has been assigned by analogy or NMR experiments.
See Supporting Information for further details.
[14] The uracil- and 5-fluorouracil-substituted cyclopropanes were
obtained using a similar synthetic sequence. In the case of the 5-
fluorouracil derivatives, it was necessary to use a more stable
benzoyl protecting group. See Supporting Information for
further details.
[15] The diastereoselectivity in the decarboxylation step was usually
high (> 5:1, > 20:1 for 8c). The products are obtained under
kinetic control, but the rationalization of the high selectivity will
require further investigations.
[16] Cyclopentylamine 26 was obtained in 94% yield from the [3+2]
annulation of the corresponding dibenzylester-substituted cyclo-
propane with enol ether 17.
4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Communications
Synthetic Methods
S. Racine, F. de Nanteuil, E. Serrano,
J. Waser*
&&&& — &&&&
Synthesis of (Carbo)nucleoside
Analogues by [3+2] Annulation of
Aminocyclopropanes
(Carbo)nucleoside derivatives constitute
an important class of pharmaceuticals.
The first synthesis of thymine-, uracil-,
and 5-fluorouracil-substituted diester
donor–acceptor cyclopropanes and their
use in indium- and tin-catalyzed [3+2]
annulations with aldehydes, ketones, and
enol ethers is described. The method
gave access to (carbo)nucleoside ana-
logues in only few steps and will be highly
useful for the synthesis of libraries of
bioactive compounds.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!