Studies on the generation of unnatural C-nucleosides with 1-alkynyl-2-deoxy-D-riboses

Article abstract of DOI:10.1021/ol701794u

(Chemical Equation Presented) 1-Alkynyl-2-deoxy-D-riboses 7 and 8 were independently synthesized and subsequently used to generate several novel C-nucleosides.

Full text of DOI:10.1021/ol701794u

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4443-4446
Studies on the Generation of Unnatural
C-Nucleosides with
1-Alkynyl-2-deoxy- -riboses
D
Mauro F. A. Adamo* and Roberto Pergoli
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical
and Medicinal Chemistry, The Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Dublin, Ireland
madamo@rcsi.ie
Received July 26, 2007
ABSTRACT
1-Alkynyl-2-deoxy-D-riboses 7 and 8 were independently synthesized and subsequently used to generate several novel C-nucleosides.
The discovery of new chemotherapeutic treatments for
controlling microbial infections is an important topic in
medicinal chemistry. Nucleosides and nucleoside biochem-
istry lie at the heart of life and life propagation, and therefore
nucleoside analogues have attracted much attention as
potential antimicrobial and antitumor agents. Many nucleo-
sides of natural origin have been found to be bioactive.
Bredinine1 (Mizoribine) is an imidazole nucleoside antibiotic
clinically used as an immunosuppressant;2 Toyocamycin,3
Mycalisin A,4 and Thiosangivamycin3 are three naturally
occurring nucleosides exerting potent antiviral and antine-
oplastic activity; Pseudouridine,5 Showdomycin,6 Pyrazofu-
rin,7 and Tiazofurin8 have been shown to possess a wide
range of medicinal properties, including antibiotic, antiviral,
and antitumor activity. C-Nucleosides belonging to the
2-deoxy-D-ribose series have been scarcely explored and at
present no data are available on the biological activity of
nucleosides of the R-anomeric series.9 In recent times interest
increased on the medicinal chemistry of alkynyl-substituted
(4) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K. Tetrahedron
Lett. 1985, 29, 3483.
(5) Buchanan, J. G.; Wightman, R. H. Top. Antibiot. Chem. 1982, 6,
229.
(6) Mubarak, A. M.; Brown, D. M. Tetrahedron Lett. 1981, 22, 683.
(7) Shaban, M. A. E.; Nasr, A. Z. AdV. Heterocycl. Chem. 1997, 68,
223.
(8) Sallam, M. A. E.; Luis, F. F.; Cassady, J. M. Nucleosides Nucleotides
1998, 17, 769.
(1) Mizuno, K.; Tsujino, M.; Takada, M.; Hayashi, K.; Atsumi, K.;
Asano, K.; Matsuda, T. J. Antibiot. 1974, 27, 775.
(2) Amenmiya, H.; Itoh, H. In ImmunosuppressiVe Drugs: DeVelopments
in Anti-rejection Therapy; Thompson, A. W., Starzt, T. E., Eds.; Edward
Arnord: London, UK, 1993; p 161. Giruber, S. A. Immunol. ReV. 1992,
129, 5. Turka, L. A.; Dayton, J.; Sinclair, G.; Thomson, C. B.; Mitchell, B.
S. J. Clin. InVest. 1991, 87, 940.
(3) Krawczyc, S. H.; Nassiri, M. R.; Kucera, L. S.; Kern, E. R.; Ptak, R.
G.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1995, 38,
4106.
(9) Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Day, A. L.
Tetrahedron 2004, 60, 841.
10.1021/ol701794u CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/02/2007

nucleosides.10,11 For instance, Matzuda described the syn-
thesis of 3′-alkynyl cytosine and 3′-alkynyl uridine.10 The
presence of an additional electrophilic element (alkyne)
imparted to these molecules a high antitumor activity.
Additionally, 4′-alkynyl nucleosides have been prepared and
found to be remarkably active against HIV.11 The high
activity displayed by 3′- and 4′-alkynyl nucleosides poses
questions about the activity of other alkynyl nucleosides
including 1-alkynyl nucleoside analogues. With this in mind,
we set out to develop a synthetic route to families of
C-nucleosides 1 and 2 (Figure 1) that (a) allows the inclusion
Scheme 1. Inouye’s Synthesis of Scaffolds 7 and 812
The stereochemistry at the anomeric position was assigned
by NOE experiments: in the â anomer, positive NOE was
observed between the anomeric H-5 and H-2; in the R
anomer, positive NOE was observed between the anomeric
H-5 and H-3 and between the anomeric H-5 and H-6.
Scheme 2. Stereospecific Synthesis of 7 and 8
Figure 1. A family of 2-deoxyribose-based C-nucleosides.
of a wide variety of heterocyclic moieties, (b) allows the
introduction of an alkynyl moiety at C-1′, and (c) allows
the preparation of R and â C-nucleosides independently. We
now report a preliminary account of the studies we have
undertaken.
A retrosynthetic analysis of C-nucleosides 1 and 2 identi-
fied 1-alkynyl-2-deoxy-D-ribose 3 as a key synthon for their
preparation. For example, several compounds of general
structure 1 could potentially be prepared from 3 by reacting
the alkyne moiety in a cycloaddition reaction with various
1,3-dipoles. Alternatively, 1-alkynyl C-nucleosides of struc-
ture 2 could be obtained from 3 through a Sonogashira
coupling or through a reaction with a suitable electrophile.
A literature survey revealed that the preparation of 1-alkynyl-
2-deoxy-D-riboses 7 and 8 has been reported.12 In this report,
4 (Scheme 1) was converted to 7 and 8 by treatment with
alkynylmagnesium bromide followed by intramolecular
Nicholas reaction.
This route offered the advantage of avoiding the use of
highly sensitive Co2(CO)8 and rendered the preparation of 7
and 8 operationally simpler. Additionally, the chromato-
graphic separation of 5 and 6 was easier compared to the
separation of 7 from 8. With compounds 7 and 8 in hand,
we explored their potential for the preparation of C-
nucleosides of structures 1 and 2.
We began our studies by generating the lithium alkynoates
of 7 and 8 (Scheme 3 and Table 1) and then reacting them
On the basis of this report, we have developed a more
practical synthesis of compounds 7 and 8 that allowed their
selective preparation independently (Scheme 2). In our
synthesis, 3,5-di-O-benzyl-2-deoxy-D-ribofuranose 4 was
reacted with ethynylmagnesium bromide and the resulting
diastereoisomeric diols 5 and 6 were subsequently separated
by SiO2 column chromatography. Diols 5 and 6 were then
independently reacted with p-toluenesulfonyl chloride and
base to obtain 7 and 8, respectively, in stereospecific fashion.
Scheme 3. Preparation of Propargyl Alcohols 9-12
(10) Hattori, H.; Nozawa, E.; Iino, T.; Yoshimura, Y.; Shuto, S.;
Shimamoto, Y.; Nomura, M.; Fukushima, M.; Tanaka, M.; Sasaki, T.;
Matzuda, A. J. Med. Chem. 1998, 41, 2892.
(11) Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.;
Yoshimura, K.; Matsuoka, M.; Shigeta, S.; Mitzuya, H. J. Med. Chem. 2000,
43, 4516.
with aromatic or aliphatic aldehydes. 2-Furaldehyde and
cyclohexylcarboxaldehyde were selected as examples of an
aromatic and an aliphatic aldehyde. We were delighted to
observe that, in these experiments, propargylic alcohols 9-12
were obtained in high isolated yields (Scheme 3 and Table
(12) Masayoshi, T.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003,
5, 625.
4444
Org. Lett., Vol. 9, No. 22, 2007

Scheme 5. Reaction of 1-Alkynyl Ester 13 with Nitrones
Table 1. Isolated Yields of Propargyl Alcohols 9-12 (Scheme
3)
regioisomer 16.16 Despite the poor yields, compounds 14-
16 remain interesting for their potential medicinal properties.
The reactivity of 7 and 8 as alkyne components in the
Sonogashira reaction was also studied. 2-Bromopyridine was
selected as the arylbromide component and was reacted with
7 and 8 under standard Pd0/CuI catalysis.17 In these experi-
ments, 17 and 18 were obtained in only 16-17% yields
(Scheme 6).
a Isolated yields after flash chromatography.
1). Remarkably, in these reactions only one diastereoisomer
was obtained.13
Lithiated 7 was also used as a starting material for the
preparation of alkynyl ester 13 (Scheme 4). We were
Scheme 6. Preparation of 1-Alkynyl-C-nucleosides 17-20
Scheme 4. Preparation of 1-Alkynyl Ester Deoxyribose 13
interested in attaching an electron-withdrawing group to the
alkyne since, usually, electronic dissymmetry favors the
reactivity of alkynes in 1,3-dipolar cycloadditions.14
Compound 13 was obtained in 37% isolated yield by
reaction of 7 with lithium bis(trimethylsilyl)amide (LiTMSA)
followed by treatment with ethyl chloroformate15 (Scheme
4). To explore the potential of 13 for the generation of
C-nucleosides, we have reacted 13 with phenyl N-tert-
butylbenzyl nitrone (Scheme 5). Several reports described
the 1,3-dipolar cycloaddition of nitrones to propargylic esters
as proceeding with high levels of regio- and diastereoselec-
tivity.
Compounds 19 and 20, arising from an alkyne homocou-
pling process, were isolated as the principal products of the
reaction.18
Several attempts were made to reduce the extent of
formation of 19 and 20. This included carrying out the
reaction under nonoxidative atmosphere (hydrogen atmo-
sphere),18 or in the absence of copper cocatalyst,18 or by using
different ratios of Pd0/CuI catalysts. To optimize the yield
of 17 and 18 and reduce the long reaction time required, we
However, the reaction of 13 with N-tert-butylbenzyl
nitrone yielded two diastereoisomeric isoxazolidines 14 and
1516 in a 1:1 ratio, together with a minor amount of
(13) Compounds 9-12 were obtained as colorless liquid. NOE were run
in order to assign the absolute stereochemistry of 9-12, but unfortunately
these experiments were inconclusive.
(14) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, 1984; Chapter 9, p 83. (b) Torssell,
K. B. G. Nitrile Oxides, Nitrones, and Nitronates; VCH Publishers Inc.:
New York, 1988.
(15) Uenishi, J.; Matsui, K.; Ohmiya, H. J. Organomet. Chem. 2002,
653, 141.
(16) Compounds 14-16 were obtained as colorless liquid. NOE experi-
ments were run in order to assign the absolute stereochemistry of 14-16,
but unfortunately these experiments were inconclusive.
(17) Elangovan, A.; Wang, Y. H.; Ho, T. I. Org. Lett. 2003, 5 (11), 1841.
(18) Lou, Y.; Gao, H.; Li, Y.; Huang, W.; Lu, W.; Zhang, Z. Tetrahedron
2006, 62, 2465.
Org. Lett., Vol. 9, No. 22, 2007
4445

have studied the effect of temperature, ratio of reagents,
concentration of reactants, solvent, and aryl halide. In no
case was an improvement of the yields of 17 and 18 noted.
It was lately found that a more efficient Sonogashira coupling
occurred by reaction of 1-alkynylsugars 21 and 22 and
2-iodopyridine (Scheme 7). Additionally, in these experi-
Scheme 8. Preparation of C-Nucleosides 27 and 28
Scheme 7. Preparation of 1-Alkynyl-C-nucleosides 23 and 24
ments no evidence for the formation of homocoupled
compound was observed. Acetyl-protected alkynyl sugars 21
and 22 were opportunely prepared from 7 and 8 by means
of debenzylation and subsequent acetylation.19
Alkynyl sugars 7 and 8 were also reacted with Co2(CO)6
to obtain the corresponding cobalt complexes 25 and 26 that
are intermediates required for the Pauson-Khand reaction
(Scheme 8).20
In this experiment, cobalt complexes 25 and 26 were
obtained in high isolated yields. Compounds 25 and 26 were
subsequently used to prepare cyclopentenones 27 and 28 by
treatment with excess vinyl benzoate and N-methylmorpho-
line (NMO) (Scheme 8).
Considering the modular nature of this reaction, it is easy
to envisage that several analogues could be prepared by
means of variation of the alkene component.
In conclusion we have developed a practical synthesis of
1-alkynyl-2-deoxy-D-riboses 7 and 8 and we have studied
their reactivity as starting materials for the generation of
novel unnatural C-nucleosides. These studies identified the
potential and limitation of 7 and 8 in synthesis and furnished
several classes of novel C-nucleosides. Studies aimed at
developing diversity orientated synthesis from 7 and 8 are
in progress.
Acknowledgment. We would like to acknowledge the
Irish Research Council for Science, Engineering and Tech-
nology (IRCSET) for a grant to R.P. and PTRLI cycle III
for a grant to M.F.A.A.
Supporting Information Available: Procedures for the
preparation and spectroscopic data of compounds 5-28 and
1
NOE and H-1H cosy spectra of compounds 7 and 8. This
(19) A full account for the preparation of 21-24 is reported in the
Supporting Information together with their spectroscopic and analytical data.
(20) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc.
2003, 125, 14992. Kerr, W. J.; McLaughlin, M.; Pauson, P. L.; Robertson,
S. M. J. Organomet. Chem. 2001, 630, 104.
material is available free of charge via the Internet at
http://pubs.acs.org.
OL701794U
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Org. Lett., Vol. 9, No. 22, 2007