Highly diastereoselective synthesis of modified nucleosides via an asymmetric multicomponent reaction

Article abstract of DOI:10.1039/b924807b

We have developed a practical synthesis of unique nucleoside derivatives via TiCl₄ promoted multicomponent reaction of optically active dihydrofuran, ethyl pyruvate/glyoxylate, and a TMS protected nucleobase in a single-pot operation.

Full text of DOI:10.1039/b924807b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly diastereoselective synthesis of modified nucleosides
via an asymmetric multicomponent reactionw
Arun K. Ghosh* and Jorden Kass
Received (in College Park, MD, USA) 25th November 2009, Accepted 11th January 2010
First published as an Advance Article on the web 25th January 2010
DOI: 10.1039/b924807b
We have developed a practical synthesis of unique nucleoside
derivatives via TiCl4 promoted multicomponent reaction of
optically active dihydrofuran, ethyl pyruvate/glyoxylate, and a
TMS protected nucleobase in a single-pot operation.
nucleosides in a single one-pot operation. Herein, we report
TiCl4 promoted multicomponent reactions of protected
(2,3-dihydrofuran-2-yl)methanol with a-keto esters in the
presence of silylated pyrimidines and purines provided rapid
access to functionalized nucleosides containing three contiguous
chiral centers in excellent diastereoselectivity and good to
excellent isolated yields.
The design and synthesis of modified nucleosides are of
significant interest because of their widespread applications
as antiviral, antitumor, and antibacterial agents.1 A variety of
synthetic nucleosides are also utilized in gene-therapy, duplex
stability and molecular probes for biological recognition.
Acyclic, carbocyclic, c-nucleosides and other modified nucleo-
sides have been used for treatment of AIDS, herpes, hepatitis,
and cancers.2 The well known modified nucleosides, AZT3 and
floxuridine4 (Fig. 1), are used for HIV/AIDS and cancer
respectively. Since the discovery of AZT, a number of more
effective modified nucleosides that lack specific components
inherent to natural counterparts have emerged for the treatment
of HIV/AIDS.5 When these modified nucleosides enter into
the cell, they are phosphorylated at the 50-position by kinases.
Their subsequent incorporation into the DNA as triphosphate
leads to the termination of synthesis of new strands of DNA or
RNA. There is a considerable interest in the development of
effective methods for the synthesis of modified nucleosides
because of their significance in medicinal and nucleic acid
research.6,7
As shown in Scheme 1, (S)-5-hydroxymethyl-2,3-dihydro-
furan (3) readily prepared11 from glutamic acid was converted
to its silyl ether 4. Dibal-H reduction of 4 afforded the
corresponding lactol. Treatment of the resulting lactol with
mesyl chloride and Et3N at 0 1C followed by heating the
resulting mixture at 42 1C provided dihydrofuran 5 in 56%
yield in two steps.z Our multicomponent strategy involved a
Lewis acid activation of pyruvate followed by attack with the
dihydrofuran derivative to form oxocarbenium ion (6), which
can be attacked by an appropriate purine or pyrimidine base
as a nucleophile to furnish the modified nucleoside. Accordingly,
ethyl pyruvate (1 equiv.) and TiCl4 (1.2 equiv.) in CH2Cl2 were
reacted with optically active dihydrofuran 5 (1 equiv.) at
ꢀ78 1C for 1 h. Bis(trimethylsilyl)thymine 7 (3 equiv.) was
then added, and the resulting reaction mixture was kept at
ꢀ78 1C for 1 h. The reaction was allowed to warm to 23 1C for
1 h. After this period, the mixture was quenched with NaHCO3
followed by standard workup and flash chromatography over
silica gel to provide nucleoside derivative 9 as a single
The pioneering work of Niedballa and Vorbruggen showed
¨
the utility of addition of trimethylsilyl protected purine and
pyrimidine bases to oxocarbenium ions to form nucleosides
and nucleoside analogs.8 In these reactions, an appropriately
protected sugar, usually ribose, is reacted with a strong Lewis
acid to form an oxocarbenium ion, to which a silated nucleo-
side is added.9 This reaction generally gives functionalized
Fig. 1 Structure of AZT and floxuridine.
Department of Chemistry, Purdue University, 560 Oval Drive,
West Lafayette, IN 47907, USA. E-mail: akghosh@purdue.edu;
Fax: +1 765-496-1612; Tel: +1 765-494-5323
w Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra for all new compounds and
X-ray crystallographic data for 9. CCDC 757621. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b924807b
Scheme 1 Multicomponent nucleoside synthesis.
ꢁc
This journal is The Royal Society of Chemistry 2010
1218 | Chem. Commun., 2010, 46, 1218–1220

View Article Online
diastereomer (by 1H NMR and HPLC analysis) in 70% yield.
This multicomponent reaction with 5-fluorobis(trimethylsilyl)-
pyrimidine 8 afforded functionalized nucleoside 10 in 65%
yield. Desilylation with HFꢂpyridine furnished modified
nucleosides 11 and 12.12 Stereochemical assignment of the
newly generated asymmetric centers is based upon our
previous observations,10 extensive 1H NMR studies, and
X-ray structural analysis of 10 (Fig. 2, see ESIw for details).
As shown in Table 1, the corresponding multicomponent
reaction with ethyl glyoxylate provided a 50 : 50 mixture of
diastereomers at the stereocenter bearing the hydroxyl group
(entry 3). We have also examined the synthesis of modified
nucleosides with a host of functionalized purine and pyrimidine
bases. Reactions with N6-benzoylcytosine and benzoyladenine
provided nucleosides 14 and 15 respectively (entries 4 and 5).
While, the reaction with N2-acetylguanine at ꢀ78 1C for 1 h
and then at 23 1C for 4 h resulted in a mixture (55 : 45) of
natural (17a) and unnatural (17b) isomers (entry 6). The
isomers were separated by HPLC and diastereoselectivity
was determined by analytical HPLC.13 Similar selectivity
problems were reported in the literature.14 The lack of regio-
selectivity is due to the fact that the steric differentiation
between the corresponding THM-derivative of N2-acetylguanine,
tautomers 16a and 16b, is marginal as shown in Scheme 2. To
overcome the regioselectivity issue, we have converted guanine
18 to bulky N2-acetyl-O6-diphenylcarbamoylguanine 19 as
shown.15 Presumably, tautomer 19b (R = TMS) is more
stable over 19a (R = TMS) because of the developing non-
bonding interactions. Thus, multicomponent reaction with the
corresponding in situ generated silyl derivative afforded the
natural N9 nucleoside 20 (entry 7) as a single product in
42% yield.
Table 1 Synthesis of modified nucleosides
Entry Nucleoside structure
dra (Yield (%))b
1
99 : 1 (70)
2
99 : 1 (65)
3
4
50 : 50 (45)
99 : 1 (53)
5
99 : 1 (60)
In conclusion, we have developed an effective multi-
component reaction for the synthesis of modified nucleosides
in a single step operation. The reaction formed three new
stereogenic centers in excellent diastereoselectivity. The
methodology provided convenient access to a variety of novel
6
99 : 1 (44)c
99 : 1
7
99 : 1 (42)
a
b
Ratio was determined by 1H NMR and HPLC analysis. Isolated
c
yield after chromatography. Ratio of 17a : 17b = 55 : 45.
modified nucleosides. Design and synthesis of modified
nucleosides for biological evaluation are in progress.
Financial support of this work was provided by the
National Institutes of Health (GM 53386). We also thank Sarang
Kulkarni (Purdue University) for his preliminary investigation.
Fig. 2 X-Ray structure of compound 10.
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 1218–1220 | 1219

View Article Online
(d, J = 5.7 Hz, 1H), 7.67–7.64 (m, 4H), 7.45–7.39 (m, 6H), 6.32
(dd, J = 3.9, 1.4 Hz, 1H), 4.40–4.23 (m, 3H), 4.00 (dd, J = 9.8, 2.0 Hz,
1H), 3.63 (s, 1H), 3.62 (dd, J = 9.1, 2.5 Hz, 1H), 2.74–2.68 (m, 1H),
2.24–2.16 (m, 1H), 1.91–1.85 (m, 1H), 1.48 (s, 3H), 1.32 (t, J = 7.1, 3H),
1.11 (s, 9H). 13C NMR (CDCl3, 100 MHz) d 175.7, 157.2, 156.9, 148.9,
141.9, 139.5, 135.5, 135.4, 132.6, 132.5, 130.0, 129.9, 127.8, 127.6,
124.5, 124.2, 86.0, 79.9, 74.5, 64.8, 62.5, 60.4, 52.3, 28.0, 26.9, 26.8,
25.0, 19.2, 14.1. 19F NMR (CDCl3, 376 MHz) d ꢀ164. FTIR (NaCl)
nmax = 3446, 3197, 3027, 2931, 2858, 1720, 1708, 1669, 1471, 1428,
1393, 1363, 1252, 1113, 1068, 758, 702. ESI (+) LRMS m/z (relative
intensity): 606.99 (100%), 607.99 (35%). ESI (+) HRMS (m/z):
[M + Na]+ calcd for C30H37N2O7FSi 607.2252; found, 607.2262.
1 P. Herdewijn, Modified Nucleosides, Biochemistry Biotechnology
and Medicine, Wiley-VCH Verlag Gmbh & Co, Weinheim, 2008.
2 (a) C. K. Chu, Antiviral Nucleosides: Chiral Synthesis and
Chemotherapy, Elsevier, New York, 2003; (b) C. K. Chu and
D. C. Baker, Nucleosides and Nucleotides as Antitumor and
Antiviral Agents, Plenum Press, New York, 1993.
3 M. A. Richman Fischl, D. D. Grieco, M. H. Gottlieb,
M. S. Volberding, P. A. Laskin, O. L. Leedom,
J. M. Groopman, J. E. Mildvan, D. Schooley, R. T. Jackson,
G. G. Durack and D. T. King, New Engl. J. Med., 1987, 317,
185–191.
Scheme 2 Nucleoside synthesis with N2-acetylguanine.
Notes and references
4 D. B. Longley, D. P. Harkin and P. G. Johnston, Nat. Rev. Cancer,
2003, 3, 330–338.
z General experimental procedure for multicomponent nucleoside
synthesis: dihydrofuran 5 (85 mg, 0.25 mmol) and ethyl pyruvate
(34 mL, 0.3 mmol, 1.2 equiv.) were dissolved in DCM (3 mL) under
argon. This was then cooled to ꢀ78 1C followed by the addition of
TiCl4 (0.3 mL, 1 M, 0.3 mmol, 1.2 equiv.). This was allowed to stir for
1 h. The TMS protected nucleoside (prepared according to either
method A or B) was then added. The reaction was then stirred at 1 h at
ꢀ78 1C followed by warming to 23 1C and stirring for 1 h. The
reaction was then cooled back to ꢀ78 1C and quenched with aq.
NaHCO3. The reaction mixture was then allowed to warm to 23 1C
then filtered through celite. The filtrate was then extracted with DCM
(3 ꢃ 10 mL). The organics were then washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The crude material was
then purified via flash chromatography. Method A: commercially
5 S. Broder, H. Mitsuya and R. Yarochoan, Science, 1990, 249,
1533–1544.
6 Handbook of Nucleoside Synthesis, ed. H. Vorbruggen and
C. Ruh-Pohlenz, Wiley Inter Science, New York, 2001.
7 For recent synthetic methods, see: (a) S. Son and G. C. Fu, J. Am.
Chem. Soc., 2007, 129, 1046–1047; (b) M. K. Lakshman,
J. C. Keeler, F. N. Ngassa, J. H. Hilmer, P. Pradhan, B. Zajc
and K. A. Thomasson, J. Am. Chem. Soc., 2007, 129, 68–76;
(c) A. K. Ogawa, Y. Q. Wu, D. L. McMinn, J. Q. Liu,
P. G. Schultz and F. E. Romesberg, J. Am. Chem. Soc., 2000,
122, 3274–3287; (d) B. M. Trost and Z. Shi, J. Am. Chem. Soc.,
1996, 118, 3037–3038; (e) W.-B. Choi, L. J. Wilson, S. Yeola and
D. C. Liotta, J. Am. Chem. Soc., 1991, 113, 9377–9379;
(f) L. J. Wilson and D. Liotta, Tetrahedron Lett., 1990, 31,
1815–1818; (g) L. J. Wilson and D. Liotta, J. Org. Chem., 1992,
57, 1948–1952 and references cited therein.
available, O,O0-bis(trimethylsilyl)thymine
Sigma-Aldrich) was added as solid to the reaction mixture.
7 (405 mg, 1.5 mmol,
a
Method B: silylated nucleoside was prepared as follows. To a suspension
of nucleoside (0.75 mmol, 3 equiv.) in dichloromethane (4 mL) were
added triethylamine (209 mL, 1.5 mmol, 6 equiv.), followed by
trimethylsilyl triflate (271 mL, 6 equiv.). The resulting reaction mixture
was stirred until clear, for about 30 min. The mixture was typically
transferred via cannula to the multicomponent reaction. Ethyl
2-((2R,3S,5S)-5-((tert-butyldiphenylsilyloxy)methyl)-2-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)-2-hydroxy-
propanoate (9): prepared via method A, purified with 60% EtOAc in
8 (a) U. Niedballa and H. Vorbruggen, J. Org. Chem., 1974, 39,
¨
1974, 39, 3672–3674 and references cited therein.
¨
3654–3660; (b) U. Niedballa and H. Vorbruggen, J. Org. Chem.,
9 H. Vorbruggen, K. Krolikiewicz and B. Bennua, Chem. Ber., 1981,
¨
114, 1234–1255.
10 (a) A. K. Ghosh, S. S. Kulkarni, C.-X. Xu and P. E. Fanwich, Org.
Lett., 2006, 8, 4509–4511; (b) A. K. Ghosh, C.-X. Xu,
S. S. Kulkarni and D. Wink, Org. Lett., 2005, 7, 7–10;
(c) A. K. Ghosh, R. Kawahama and D. Wink, Tetrahedron Lett.,
2000, 41, 8425–8429; (d) A. K. Ghosh and R. Kawahama, Tetra-
hedron Lett., 1999, 40, 1083–1086.
11 (a) C. Herdeis, Synthesis, 1986, 232–233; (b) J. A. Walker,
J. J. Chen, D. S. Wise and L. B. Townsend, J. Org. Chem., 1996,
61, 2219–2221.
hexanes. (70%) [a]D +37.7 (c 1.12, CHCl3). 1H NMR (CDCl3,
23
400 MHz) d 9.08 (s, 1H), 7.66 (d, J = 6.5 Hz, 4H), 7.43–7.35 (m, 7H),
6.33 (d, J = 6.5 Hz, 1H), 4.38–4.18 (m, 4H), 3.98 (dd, J = 9.1, 2.4 Hz,
1H), 3.68 (dd, J = 8.6, 2.9 Hz, 1H), 2.76–2.70 (m, 1H), 2.25–2.18 (m,
1H), 2.20–1.86 (m, 1H), 1.58 (s, 3H), 1.42 (s, 3H), 1.32 (t, J = 7.1, 3H),
1.11 (s, 9H). 13C NMR (CDCl3, 100 MHz) d 175.7, 163.7, 150.2, 135.8,
135.4, 135.2, 133.2, 132.6, 129.9, 129.8, 127.8, 127.7, 111.7, 85.1, 78.7,
77.2, 74.1, 65.1, 62.4, 51.3, 28.3, 27.0, 24.7, 19.4, 14.1, 11.9. FTIR
(NaCl) nmax = 2955, 2929, 1698, 1684, 1472, 1457, 1258, 1112, 703.
ESI (+) LRMS m/z (relative intensity): [M + Na]+ 603.14 (100%).
ESI (+) HRMS (m/z): [M]+ calcd for C31H40N2O7Si 603.2503; found,
603.2506. Ethyl 2-((2R,3S,5S)-5-((tert-butyldiphenylsilyloxy)methyl)-
2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-
3-yl)-2-hydroxypropanoate (10): prepared via method B, purified
12 Preliminary antiviral evaluation of compounds 11 and 12 was
carried out by Dr Hiroaki Mitsuya and Dr Kenji Maeda (National
Cancer Institute). These two compounds did not exhibit any
appreciable antiviral activity. Evaluation of other analogs is
ongoing.
13 Analytical HPLC conditions: column, Sunfire C18, 30 ꢃ 100 mm,
5 micron, flow rate = 40 mL minꢀ1, l = 215 nm,isocratic 75 : 25
MeOH–H2O; Rt 17a, 14.6 min; Rt 17b, 14.3 min.
23
with 60% EtOAc in hexanes. (65%) [a]D +50.3 (c 0.72, CHCl3).
14 P. Garner and S. Ramakanth, J. Org. Chem., 1988, 53, 1294–1298.
15 R. Zou and M. J. Robins, Can. J. Chem., 1987, 65, 1436–1437.
1H NMR (CDCl3, 400 MHz) d 9.79 (d, JH–F = 4.2 Hz, 1H), 7.91
ꢁc
This journal is The Royal Society of Chemistry 2010
1220 | Chem. Commun., 2010, 46, 1218–1220