Synthesis of 3′,3′-difluoro-2′-hydroxymethyl-4′, 5′-unsaturated carbocyclic nucleosides

Article abstract of DOI:10.1021/ol7023955

3′,3′-Difluoro-2′-hydroxymethyl-4′, 5′-unsaturated carbocyclic nucleosides 1-3 have been stereoselectively synthesized from ester 10, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 7 in five steps. The whole synthesis highligh

Full text of DOI:10.1021/ol7023955

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5437-5440
Synthesis of 3
hydroxymethyl-4
Carbocyclic Nucleosides
′
,3
′
-Difluoro-2
′-
′
,5 -Unsaturated
′
Yan-Yan Yang,§ Jun Xu,§ Zheng-Wei You,§ Xiu-hua Xu,§ Xiao-Long Qiu,§ and
Feng-Ling Qing*,†,§
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China,
and College of Chemistry, Chemical Engineering and Biotechnology, Donghua
UniVersity, 2999 North Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received October 1, 2007
ABSTRACT
3
′
,3
can be conveniently prepared from 2,3-isopropylidene-
Reformatskii Claisen rearrangement, ring-closing metathesis (RCM), and palladium-catalyzed allylic alkylation, in which the regioselectivity
′
-Difluoro-2
′
-hydroxymethyl-4
′
,5
′
-unsaturated carbocyclic nucleosides 1
−3 have been stereoselectively synthesized from ester 10, which
D-glyceraldehyde 7 in five steps. The whole synthesis highlighted the stereoselective
−
was reversed from that of nonfluorinated substrates.
Carbocyclic nucleosides (CNAs) have received considerable
attention because they possess greater metabolic stability
toward the nucleoside phosphorylases and higher lipophi-
licity, two properties that are potentially beneficial in terms
of increased in vivo half-life, oral efficiency, and cell-wall
penetration.1 In the past two decades, a large number of
CNAs have been synthesized and biologically evaluated.2,3
The best known CNAs are the anti-HIV (-)-carbovir,4
abacavir,5 and entecarvir6 (Figure 1); all of them are already
in clinical use. Now modifications to some bioactive CNAs
(3) For reviews, see: (a) Marquez, V. E.; Lim, M.-U. Med. Res. ReV.
1986, 6, 1. (b) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48,
571. (c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R. S.; Challand,
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (d) Crimmins, M.
T. Tetrahedron 1998, 54, 9229. (e) Ferrero, M.; Gotor, V. Chem. ReV. 2000,
100, 4319. (f) Schneller, S. W. Curr. Top. Med. Chem. 2002, 2, 1087. (g)
Ishikura, M.; Katagiri, N. Trends Heterocycl. Chem. 2003, 9, 83. (h)
Rodriguez, J. B.; Comin, M. J. Mini-ReV. Med. Chem. 2003, 3, 95. (i) Wu,
Q.; Simons, C. Synthesis 2004, 1533. (j) Wang, J.; Froeyen, M.; Herdewijn,
P. AdVances in AntiViral Drug Design 2004, 4, 119. (k) Jeong, J. S.; Lee,
J. A. AntiViral Chem. Chemother. 2004, 15, 235. (l) Casu, F.; Chiacchio,
M. A.; Romeo, R.; Gumina, G. Curr. Org. Chem. 2007, 11, 999.
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McDowell, J. A.; LaFon, S. W.; Symonds, W. T. AntiViral Res. 1995, 26,
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§ Shanghai Institute of Organic Chemistry.
† Donghua University.
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X.-F. Nucleosides Nucleotides Nucleic Acids 2000, 19, 651.
(2) For recent example, see: (a) Comin, M. J.; Agbaria, R.; Ben-Kasus,
T.; Huleihel, M.; Liao, C.; Sun, G.; Nicklaus, M. C.; Deschamps, J. R.;
Parrish, D. A.; Marquez, V. E. J. Am. Chem. Soc. 2007, 129, 6216. (b)
Huang, W.; Miller, M. J.; De Clercq, E.; Balzarini, J. Org. Biomol. Chem.
2007, 5, 1164. (c) Aubin, Y.; Audran, G.; Vanthuyne, N.; Monti, H.
Tetrahedron 2007, 63, 5050. (d) Comin, M. J.; Parrish, D. A.; Deschamps,
J. R.; Marquez, V. E. Org. Lett. 2006, 8, 705. (e) Jiang, M. X.; Jin, B.;
Gage, J. L.; Priour, A.; Savela, G.; Miller, M. J. J. Org. Chem. 2006, 71,
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10.1021/ol7023955 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

fluorination of carbonyl groups with DAST, which has been
limited to wide use not only for its frequently low yield but
also for its invalidity to stereo-hindered cyclopentones. To
break through this limitation and continue our ongoing efforts
to develop new antiviral and anticancer agents, we would
like to explore an efficient synthetic route to optically pure
gem-difluorinated CNAs utilizing commercially available
fluorinated building blocks. Herein we describe the stereo-
selective synthesis of 3′,3′-difluoro-4′,5′-unsaturated OTCs
1-3.
Our retrosynthetic analysis of target molecules 1-2
highlighted three key steps, as outlined in Scheme 1.
Figure 1. Some highly bioactive CNAs and rational design of 3′,3′-
difluoro-4′,5′-unsaturated OTCs 1-3.
Scheme 1. Retrosynthetic Analysis of 1-2
represent an important active area in search for compounds
with improved biological property. Based on CNAs skel-
etons, 1,2-disubstituted carbocyclic nucleosides (OTCs),
recently attracted more and more attention,7 especially after
De Clercq et al. found that some OTCs showed moderate to
good activity against murine leukemia cells L1210/0, human
T-lymphocyte cells Molt4/C8, and CEM/0 via topological
substructural approach to molecular design (TOSS-MODE).8
On the other hand, it is well-known that the introduction of
fluorine atom(s), especially gem-difluoromethylene (CF2)
group, into an organic compound can bring about remarkable
changes in the physical, chemical, and biological properties.9
However, to the best of our knowledge, only a few gem-
difluorinated CNAs have been developed,10 which was
attributed to the limitation of fluorination method.11 In the
reported syntheses of gem-difluorinated CNAs, all the gem-
difluoromethylene groups (CF2) were introduced via direct
As for regio- and stereoselective installation of the base
moiety of carbocyclic nucleosides, one of the most conve-
nient methods was palladium-catalyzed allylic substitution.12
Konno and Okano have reported that the nucleophile would
attack at the carbon remote from the electro-withdrawing
fluoroalkyl groups,13 so compound 1-2 may be prepared
from allylic carbonate 4 through palladium-catalyzed allylic
alkylation. The special backbone of 4 could be built from
diene 5 via ring-closing metathesis (RCM), which was
considered as a potential tool to build five-membered
carbasugar.14 Compound 5 could be derived from chlorodi-
fluoroacetic ester 6 through silicon-induced Reformatskii-
Claisen rearrangement. According to Lewis’s report,15 the
(6) (a) Innaimo, S. F.; Seifer, M.; Bisacchi, G. S.; Standring, D. N.;
Zahler, R.; Colonno, R. J. Antimicrob. Agents Chemother. 1997, 41, 1444.
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Ferro, B.; Santana, L.; Teijeira, M.; Uriarte, E. Nucleosides Nucleotides
1997, 16, 1453. (c) Besada, P.; Tera´n, C.; Teijeira, M.; Uriarte, E.
Nucleosides Nucleotides 1999, 18, 725. (d) Tera´n, C.; Gonza´lez-Moa, M.
J.; Mosquera, R.; Santana, L. Nucleosides Nucleotides Nucleic Acids 2001,
20, 999. (e) Santana, L.; Teijeira, M.; Tera´n, C.; Uriarte, E.; Vin˜a, D.
Synthesis 2001, 1532. (f) Besada, P.; Gonza´lez-Moa, M. J.; Tera´n, C.;
Santana, L.; Uriarte, E. Synthesis 2002, 2445. (g) Gonza´lez-Moa, M. J.;
Besada, P.; Teijeira, M.; Tera´n, C.; Uriarte, E. Synthesis 2004, 543.
(8) Estrada, E.; Uriarte, E.; Montero, A.; Teijeira, M.; Santana, L.; De
Clercq, E. J. Med. Chem. 2000, 43, 1975.
(9) For recent reviews, see: (a) Thayer, A. M. Chem. Eng. News 2006,
June 5, 15-24. (b) Begue, J. P.; Bonnet-Delpon, D. J. Fluorine Chem.
2006, 127, 992. (c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (d)
Ojima, I. ChemBioChem 2004, 5, 628. For recent excellent overviews, see:
(e) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford,
2004. (f) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, 2004. (g) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, 2006.
(10) (a) Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.; Kirk,
B. E.; Robberts, S. M.; Stephenson, L.; Youds, P.; Slawin, A. M. Z.;
Williams, D. J. J. Chem. Soc., Chem. Commun. 1987, 251. (b) Borthwick,
A. D.; Evans, D. N.; Kirk, B. E.; Biggadike, K.; Exall, A. M.; Youds, P.;
Roberts, S. M.; Knight, D. J.; Coatesf, J. A. V. J. Med. Chem. 1990, 33,
179. (c) Atanu, R.; Stewart, W. S.; Kathy, A. K.; Caroll, B. H.; Earl, R. K.
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S. T. Bioorg. Med. Chem. 2006, 14, 4980.
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R. E.; Hunt, A. H. Synthesis 1992, 565. (b) Xiang, Y.; Kotra, L. P.; Chu,
C. K.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 1995, 5, 743. (c) Fernandez,
R.; Mathea, M. I.; Echarri, R.; Castillon, S. Tetrahedron 1998, 54, 3523.
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1988, 53, 2406.
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in nucleoside chemistry, see: (a) Hegedus, L. S.; Cross, J. J. Org. Chem.
2004, 69, 8492. (b) Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J.
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dron: Asymmetry 2001, 12, 2743. (c) Konno, T.; Nagata, K.; Ishihara, T.;
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5438
Org. Lett., Vol. 9, No. 26, 2007

chiral auxiliary of 6 may induce the rearrangement and
resulted in the desired product. The target molecule 3 could
also be prepared by the same synthetic route.
Scheme 3
The required gem-difluorinated ester was synthesized in
a straightforward manner (Scheme 2). Aldehyde 7 was
Scheme 2
the carbonyl group into hydroxyl group should alleviate the
electron-deficient status. Thus, reduction of the ketones 14
and 15 with NaBH4/CeCl3 provided the alcohols 16 and 17,
respectively. As expected, subjecting of the alcohols 16 and
17 to RCM reaction using 2.5 mol % Grubbs II catalyst
smoothly caused the complete conversion of the starting
materials, and the cyclic alcohols 18-19 and 20-21 were
provided, respectively. The diastereoisomers 18 and 19, 20
and 21 were readily separated by column chromatography.
To determine the configuration of compounds 18-19 and
12-13, the alcohol 18, at this stage, was converted to the
ester 22 in 56% yield over three steps (Scheme 4).
subjected to Wadsworth-Emmons condensation with ethyl
diethylphosphonoacetate to provide the corresponding ester,
of which the protecting group was changed to give ester 8.
Reduction of the ester 8 with DIBAL-H gave the allyl alcohol
9 in good yield. Upon treatment of 9 with the excess
chlorodifluoroacetic acid in refluxing CHCl3, the esterifica-
tion took place to deliver the chlorodifluoroacetic ester 10
in 87% yield. Then, ester 10 underwent a silicon-induced
Reformatskii-Claisen reaction.16 A mixture of ester 10,
chlorotrimethylsilane and freshly activated zinc dust was
heated in dry acetonitrile at 105 °C for 24 h. The resulting
crude product was further esterified with ethanol catalyzed
by H2SO4 to give our desired gem-difluorinated ester 11 (syn/
anti ) 3:1, determined by 19F NMR) in 72% yield.
Scheme 4
After the access to the optically active ester 11 was
accomplished, the ring-closing metathesis (RCM) reaction
was implemented to establish the cyclopentene ring (Scheme
3). Ester 11 was converted to the Weinreb amides 12 and
13 by treatment with HN(Me)OMe‚HCl/n-BuLi in 87%
yield. Gratifyingly, diastereoisomers 12 and 13 could be
readily separated by flash chromatography. Subjecting the
isomers 12 and 13 to 2 equiv allylmagnesium chloride at
-78 °C in THF followed by Et3N-mediated double bond
migration gave the R,â-unsaturated ketone 14 (94%) and 15
(90%), respectively. When the diene 14 was treated with the
Grubbs II catalyst (5 mol %) in toluene at 100 °C, 40%
starting material was recovered. In our opinion, the low
conversion of the RCM reaction of compound 14 was mainly
ascribed to the strong electron-withdrawing effect of gem-
difluoromethylene group and carbonyl group. Reduction of
The structure of compound 22 was then confirmed by
X-ray crystal analysis (see Supporting Information). Fur-
thermore, on the basis of the X-ray structure of compound
22, the configuration of compounds 20 and 21 was estab-
lished by COSY and NOESY experiments (Figure 2). The
obvious correlations between H1 and H3 was observed in
NOESY of compound 21, whereas there was no considerable
correlation between H1 and H3 in NOESY of compound
20.
With the chiral difluorinated cyclic alcohols in hand, we
embarked on installation of base moieties into them (Scheme
5). The intermediate 18 was treated with methyl chlorofor-
mate in the presence of pyridine to give the corresponding
(16) (a) Yang, Y. Y.; Meng, W. D.; Qing, F. L. Org. Lett. 2004, 6, 4257.
(b) Greuter, H.; Lang, R. W.; Romann, A. J. Tetrahedron Lett. 1988, 29,
3291.
Org. Lett., Vol. 9, No. 26, 2007
5439

Scheme 5
benzoyl groups and benzyl groups in compounds 23 and 24
the allylic carbonate, which reacted with suitably protected
nucleobases 3-benzoyl uracil and 3-benzoyl thymine in the
afforded diols 25 and 26, which were directly converted to
the target molecules 1 and 2 by oxidation with NaIO4 and
subsequent reduction with NaBH4. The structure of com-
pound 2 was confirmed by X-ray crystal analysis.
In addition, utilizing the identical reaction conditions as
described for 2, the nucleoside analogue 3 was prepared
1
starting from the alcohol 21. The H NMR, 19F NMR and
13C NMR spectra of product 3 were identical to those of
compound 2, and the optical rotation of compound 3 was
opposite to that of compound 2. Therefore compound 3 was
demonstrated as the enantiomer of compound 2. The stere-
ochemistry of compound 3 and 21 were further confirmed.
In conclusion, we have completed the synthesis of 3′,3′-
difluoro-4′,5′-unsaturated OTCs 1-3. The key steps included
the Reformatskii-Claisen rearrangement, ring-closing me-
tathesis (RCM), and palladium-catalyzed allylic substitution.
Figure 2. NOESY correlations of compounds 20 and 21.
presence of catalytic amount of Pd(PPh3)4 at 60 °C in THF.
Just as we predicted in the retrosynthetic analysis, the
regioselectivity of these Pd-catalyzed allylic substitution was
very high and only γ-substituted compounds 23 and 24 were
obtained in good yields, respectively. The outcome of the
exclusive regioselectivity was totally different from those
of nonfluorinated substrates.17 The structures of compounds
23 and 24 were elucidated from their NMR spectra and later
were further confirmed by the X-ray structure of compound
2 (see Supporting Information). Finally, removal of the
Acknowledgment. The National Natural Science Foun-
dation of China and the Shanghai Municipal Scientific
Committee are greatly acknowledged for funding this work.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds, copies
1
of H NMR and 13C NMR spectra of all compounds, and
crystallographic data for compounds 2 and 22 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Nokami, J.; Matsuura, H.; Nakasima, K.; Shibata, S. Chem. Lett.
1994, 23, 1071.
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