5-Endo-dig electrophilic cyclization of α-alkynyl carbonyl compounds: Synthesis of novel bicyclic 5-iodo- and 5-bromofuranopyrimidine nucleosides

Article abstract of DOI:10.1021/jo0345648

5-Endo-dig electrophilic cyclization of 5-alkynyl-2′-deoxyuridines with N-iodosuccinimide or N-bromosuccinimide in acetone at room temperature gives 3-(2′-deoxy-β-D-ribofuranosyl)-5-halo-2,3-dihydrofuro[2,3-d] pyrimidin-2-ones that usually precipitate fro

Full text of DOI:10.1021/jo0345648

5
-En d o-Dig Electr op h ilic Cycliza tion of
r-Alk yn yl Ca r bon yl Com p ou n d s: Syn th esis
of Novel Bicyclic 5-Iod o- a n d
-Br om ofu r a n op yr im id in e Nu cleosid es
5
Meneni Srinivasa Rao, Noor Esho, Craig Sergeant, and
Roman Dembinski*
Department of Chemistry, Oakland University,
200 N. Squirrel Road, Rochester, Michigan 48309-4477
2
dembinsk@oakland.edu
Received April 30, 2003
F IGURE 1. Structure of furanopyrimidine nucleoside 2.
nism involving a cationic intermediate.8
,11
Although
7
reactions of o-alkynyl phenols, acetoxy- or benzyloxypy-
Abstr a ct: 5-Endo-dig electrophilic cyclization of 5-alkynyl-
′-deoxyuridines with N-iodosuccinimide or N-bromosuccin-
imide in acetone at room temperature gives 3-(2′-deoxy-â-
D-ribofuranosyl)-5-halo-2,3-dihydrofuro[2,3-d]pyrimidin-2-
ones that usually precipitate from the reaction mixture (86-
8
12
ridines, and thiophenols have been investigated, the
electrophilic halocyclization of R-alkynyl carbonyl com-
pounds has not been synthetically explored.6
2
,13
Elucidation of biological properties for 5-alkynyl uridines
1
4,15
7
4%).
(1) has resulted in detailed synthetic studies.
When
synthesis of 1 via palladium-catalyzed coupling is carried
out at a higher temperature in the presence of a base,
Construction of the furan ring, which is found in many
1
-3
formation of bicyclic furanopyrimidine (2, Figure 1) is
natural and biologically important molecules,
is at-
observed.1
4c,d,16
The recent discovery of selective inhibi-
4
tracting considerable attention. Heteroannulation proc-
esses for the synthesis of substituted furans have been
vigorously applied, in particular palladium-catalyzed
1
7,18
tion of varicella-zoster virus (VZV) replication
has
revitalized interest in bicyclic structure 2. In particular,
5
,6
the activity of furanopyrimidines substituted at C-6 with
annulation of alkynes, which is also suited for com-
4
3
the 4-(n-alkyl)phenyl group surpasses ca. 10 times the
binatorial synthesis. Electrophilic cyclization of unsat-
activity of acyclovir or (E)-5-(2-bromovinyl)-2′-deoxy-
urated compounds has also proven to be an efficient
method for one-step construction and functionalization
of the furan unit.7
-10
This reaction is generally believed
(10) Anionic process (n-BuLi/I
Buckle, D. R.; Rockell, C. J . M. J . Chem. Soc., Perkin Trans. 1 1985,
443-2446.
11) Ren, X.-F.; Turos, E. Tetrahedron Lett. 1993, 34, 1575-1578.
2
) leads also to iodofuran derivatives:
to proceed through an intramolecular, stepwise mecha-
2
(
(
1) (a) K o¨ nig, B. Furan. In Hetarenes and Related Ring Systems;
Science of Synthesis; Maas, G., Ed.; George Thieme Verlag: Stuttgart,
001; Category 2, Vol. 9, pp 183-285. (b) Dell, C. P. Benzo[b]furans.
In Hetarenes and Related Ring Systems; Science of Synthesis; Thomas,
(12) (a) Yue, D.; Larock, R. C. J . Org. Chem. 2002, 67, 1905-1909.
(b) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011-6013.
(13) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.; Tseng, J .-C.;
Luh, T.-Y. J . Am. Chem. Soc. 2000, 122, 4992-4993.
(14) (a) Robins, M. J .; Vinayak, R. S.; Wood, S. G. Tetrahedron Lett.
1990, 31, 3731-3734. (b) Cruickshank, K. A.; Stockwell, D. L.
Tetrahedron Lett. 1988, 29, 5221-5224. (c) Robins, M. J .; Barr, P. J .
J . Org. Chem. 1983, 48, 1854-1862. (d) Robins, M. J .; Barr, P. J .
Tetrahedron Lett. 1981, 22, 421-424. (e) Crisp, G. T.; Flynn, B. L. J .
Org. Chem. 1993, 58, 6614-6619.
(15) Review: Korshun, V. A.; Manasova, E. V.; Berlin, Yu. A.
Bioorganicheskaya Khimia 1997, 23, 324-387 (in Russian).
(16) Yu, C. J .; Yowanto, H.; Wan, Y.; Meade, T. J .; Chong, Y.; Strong,
M.; Donilon, L. H.; Kayyem, J . F.; Gozin, M.; Blackburn, G. F. J . Am.
Chem. Soc. 2000, 122, 6767-6768.
(17) Reviews: (a) De Clercq, E. D. Med. Res. Rev. 2003, 23, 253-
274. (b) Balzarini, J .; McGuigan, C. Biochim. Biophys. Acta 2002, 1587,
287-295. (c) Balzarini, J .; McGuigan, C. J . Antimicrob. Chemother.
2002, 50, 5-9. (d) McGuigan, C.; Brancale, A.; Barucki, H.; Srinivasan,
S.; J ones, G.; Pathirana, R.; Carangio, A.; Blewett, S.; Luoni, G.; Bidet,
O.; J ukes, A.; J arvis, C.; Andrei, G.; Snoeck, R.; De Clercq. E.;
Balzarini, J. Antiviral Chem. Chemother. 2001, 12, 77-89. (e) McGuigan,
C.; Brancale, A.; Barucki, H.; Srinivasan, S.; J ones, G.; Pathirana, R.;
Blewett, S.; Alvarez, R.; Yarnold, C. J .; Carangio, A.; Vel a´ zquez, S.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J . Drugs Future 2000,
25, 1151-1161.
2
E. J ., Ed.; George Thieme Verlag: Stuttgart, 2000; Category 2, Vol.
1
0, pp 11-86. (c) Eberbach, W. Furan. In Houben-Weyl; George Thieme
Verlag: Stuttgart, 1994; E6a, Teil I, pp 16-185d. (d) Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955-2020.
(
2) Mendez-Andino, J .; Paquette, L. A. Org. Lett. 2000, 2, 4095-
4
097 and references therein.
3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
03, 893-930.
4) (a) Gilchrist, T. L. J . Perkin 1 2001, 2491-2515. (b) Gilchrist,
T. L. J . Chem. Soc., Perkin Trans. 1 1999, 2849-2866.
5) (a) Larock, R. C. Palladium-Catalyzed Annulation. In Perspec-
(
1
(
(
tives in Organopalladium Chemistry for the XXI Century; Tsuji, J ., Ed.;
Elsevier Press: Lausanne, Switzerland, 1999; pp 111-124. (b) Larock,
R. C. Pure Appl. Chem. 1999, 71, 1435-1442. (c) Larock, R. C. J .
Organomet. Chem. 1999, 576, 111-124. (d) Larock, R. C.; Yum, E. K.;
Doty, M. J .; Sham, K. K. C. J . Org. Chem. 1995, 60, 3270-3271.
6) Kel’in, A. V.; Gevorgyan, V. J . Org. Chem. 2002, 67, 95-98.
7) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
999, 1432-1434.
8) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F.
Org. Lett. 2002, 4, 2409-2412.
9) (a) El-Taeb, G. M. M.; Evans, A. B.; J ones, S.; Knight, D. W.
(
(
1
(
(
(18) (a) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.;
Erichsen, J . T.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J . J .
Med. Chem. 2000, 43, 4993-4997. (b) Brancale, A.; McGuigan, C.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J . Bioorg. Med. Chem.
Lett. 2000, 10, 1215-1217. (c) McGuigan, C.; Yarnold, C. J .; J ones,
G.; Vel a´ zquez, S.; Barucki, H.; Brancale, A.; Andrei, G.; Snoeck, R.;
De Clercq, E.; Balzarini, J . J . Med. Chem. 1999, 42, 4479-4484.
Tetrahedron Lett. 2001, 42, 5945-5948. (b) Bew, S. P.; Barks, J . M.;
Knight, D. W.; Middleton, R. J . Tetrahedron Lett. 2000, 41, 4447-
4
(
3
2
451. (c) Bew, S. P.; Knight, D. W. Chem. Commun. 1996, 1007-1008.
d) Nichols, C. J .; Parks, J . J . J . Undergrad. Chem. Res. 2002, 1, 27-
2. (e) See also: Knight, D. W.; Redfern, A. L.; Gilmore, J . J . Perkin 1
002, 622-628.
1
0.1021/jo0345648 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/18/2003
6
788
J . Org. Chem. 2003, 68, 6788-6790

SCHEME 1. Syn th esis of Bicyclic Ha lofu r a n op yr im id in e Nu cleosid es 3 a n d 4
uridine (BVDU).18a It is likely that 2 will be further
pursued for clinical development.1
propargylic alcohols have led to vinyl diiodides.9e How-
ever, a cyclization reaction was observed when cyclo-
propyl-substituted ethynyluridine (1c, R ) c-C ) was
treated with I in CH Cl . Two products were isolated in
7a,b
The synthetic methodology leading to bicyclic furano-
pyrimidine nucleosides 2 includes palladium- or copper-
catalyzed 5-endo-dig cyclization of alkynyluridines 1,1
involving the C-4 pyrimidine oxygen and acetylenic bond.
This approach introduces hydrogen at C-5 of the furano
pyrimidine (IUPAC nomenclature numbering of the
bicyclic ring, Figure 1), limiting access to nucleoside
analogues with different substitutents at this position.19
Here we report a type of new chemistry that opens a
valuable route to a new series of iodo- and bromofurano-
pyrimidine nucleosides (3, 4), with a potential for biologi-
cal activity.20 We have synthesized the halo-functional-
ized bicyclic structures for the following reasons: (i) vinyl
halides 3 and 4 are key synthons; palladium-catalyzed
reactions will allow for introduction of a variety of
substituents at C-5 of the furanopyrimidine, thus provid-
3 5
H
2
2
2
4c,18
poor yield; the structures were assigned as the iodo-
cyclized nucleoside 3c and its base. Therefore, we have
turned our attention to N-halosuccinimides, which have
precedence in the synthesis of bromobenzo[b]thio-
phene.1
1,25,26
5-Alkynyluridines 1b,c were prepared by Sonogashira
coupling at room temperature,1
4c,27
similar to 1a . 5-Iodo-
2′-deoxyuridine (5) (1.0 equiv) was combined with ter-
minal alkyne HCtCR (R ) C -p-C(CH , c-C ) (1.8-
2.0 equiv) in the presence of Pd(PPh (0.11 equiv), CuI
(0.3-1.0 equiv), Ph P (1.0 equiv), n-Bu NI (1.0 equiv), and
Et N (2.0 equiv) in DMF (Scheme 1). Alkynyl nucleosides
28
6
H
4
3
)
3
3 5
H
3 4
)
3
4
3
1b/c were obtained in 84/76% yield. The isolated nucleo-
sides 1a -c were treated with N-iodosuccinimide (NIS)
(1.5 equiv) in acetone at room temperature, as visualized
in Scheme 1. Formation of precipitate was observed after
2 h or more for aryl-substituted compounds 1a ,b. The
solid was isolated by filtration, giving usually analytically
pure bicyclic 5-iodofuranopyrimidines 3a /b in 86/74%
yield. Short column silica gel chromatography was ap-
plied as needed. The cyclopropyl derivative 3c is more
soluble in acetone; therefore, it was isolated by column
chromatography in 80% yield. The results are sum-
marized in Table 1.
A p-tolyl derivative 1a was treated with N-bromo-
succinimide (NBS) (1.9 equiv) in a similar manner to
access a bromoderivative 4 and compare reactivity of an
analogous reagent. Reaction time was prolonged com-
pared to iodination; full conversion and precipitation
occurred after 5 h. Although it is known that substituted
furans undergo oxidative ring opening with NBS in
acetone,29 bicyclic 5-bromofuranopyrimidine 4a was iso-
lated, after workup, in 79% yield. However, the bromo-
cyclization is sensitive to the quality of the reagents.
ing access to a wide range of functionalized 5,6-disubsti-
tuted furano nucleosides;7
,21
(ii) nucleosides 3 or 4
2
2
combine halovinyl- and furanopyrimidine fragments,
both with well-documented high activity.17,18,23
Halogens were introduced via electrophilic 5-endo-dig
1
7,18a
cyclization of 5-alkynyluridines. 4-Alkylphenyls
and
cyclopropyl24 were selected as model R substituents.
Iodination using elemental iodine was approached; a base
was not included as it may affect the N-glycosidic bond.
Although successful I
2
electrophilic cyclizations have been
described,7 attempts to effect iodocyclization of homo-
-9
(19) Conversion of alkynyl uridines to 5-aryl substituted furano
pyrimidines has been reported: Carangio, A.; McGuigan, C.; Andrei,
G.; Snoeck, R.; De Clercq, E.; Balzarini, J . Antiviral Chem. Chemother.
2
001, 12, 187-197. Also carbonylative annulation allows for function-
alization of benzofurans at analogous position: Liao, Y.; Reitman, M.;
Zhang, Y.; Fathi, R.; Yang, Z. Org. Lett. 2002, 4, 2607-2609. Chaplin,
J . H.; Flynn, B. L. Chem. Commun. 2001, 1594-1595.
(20) In a preliminary studies, the iodonucleoside 3a was tested using
cytotoxicity assay and exhibited activity comparable to 5-fluorouracil.
We are indebt to Prof. Rasul Chaudry for this experiment.
(
21) 3a was successfully coupled with p-(CH
gashira conditions. We thank Ms. Bo Bezeau for this observation.
22) Synthesis of 6-bromofurano pyrimidine (2, R ) Br): Eger, K.;
J alalian, M.; Schmidt, M. J . Heterocycl. Chem. 1995, 32, 211-218.
23) (a) De Clercq, E. Antiviral activity of nucleoside analogues: the
3 3 6 4
) CC H CtCH in Sono-
(
(25) For application of NBS in relevant nucleoside chemistry see:
Kumar, R.; Nath, M.; Tyrrell, D. L. J . J . Med. Chem. 2002, 45, 2032-
2040.
(
BVDU connection. In Recent Advances in Nucleosides: Chemistry and
Chemotherapy; Chu, C. K., Ed.; Elsevier Science: New York, 2002; pp
(26) For NBS bromination of furan ring, see: (a) Grubenmann, W.;
Erlenmeyer, H. Helv. Chim. Acta 1948, 31, 78-83. (b) Lukevics, E.;
Ignatovich, L.; Goldberg, Yu.; Polyak, F.; Gaukhman, A.; Rozite, S.;
Popelis, J . J . Organomet. Chem. 1988, 348, 11-23.
4
1
33-454. (b) Walker, R. T.; De Clercq, E. Pharmacol. Ther. 1984, 26,
-44. (c) De Clercq, E.; Descamps, J .; De Sommer, P.; Barr, P. J .;
J ones, A. S.; Walker, R. T. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2947-
(27) (a) Sonogashira, K. Cross-coupling Reactions to sp Carbon
Atoms. In Metal catalyzed Cross-coupling Reactions; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998; pp 203-230. (b)
Nakamura, K.; Okubo, H.; Yamaguchi, M. Synlett 1999, 549-550.
(28) Esho, N.; Davies, B.; Lee, J .; Dembinski, R. Chem. Commun.
2002, 332-333.
2
951. (d) See also: Guenther, S.; Balzarini, J .; De Clercq, E.; Nair, V.
J . Med. Chem. 2002, 45, 5426-5429.
24) (a) Zemlicka, J . Unusual analogues of nucleosides: chemistry
(
and biological activity. In Recent Advances in Nucleosides: Chemistry
and Chemotherapy; Chu, C. K., Ed.; Elsevier Science: New York, 2002;
pp 327-357. (b) De Clercq E. Biochim. Biophys. Acta 2002, 1587, 258-
(29) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J . Org.
Chem. 1998, 63, 7505-7515.
2
75. (c) Pietruszka, J . Chem. Rev. 2003, 103, 1051-1070.
J . Org. Chem, Vol. 68, No. 17, 2003 6789

TABLE 1. P r ep a r a tion of Ha lofu r a n op yr im id in es 3 a n d
via Cycliza tion of 1
4
Sometimes cleavage of the N-glycosidic bond was ob-
served in repeated experiments, especially when acetone
was not of high purity. In that case the bromocyclized
F IGURE 2. UV-vis (s) and fluorescence (λex ) 340) (- - -)
spectra for 3a (methanol).
1
nucleoside base was isolated, as determined by H and
1
3
C NMR.
tion was also undertaken as fluorescent nucleosides find
1
The bicyclic nucleosides were characterized by H and
30
practical applications. We found optimal excitations
1
3
C NMR, IR, MS, UV-vis, and fluorescence spectros-
between 320 and 350 nm. Wavelengths of the observed
emissions do not vary much, and are between 430 and
1
13
copy. The H and C NMR spectra supported the struc-
tural assignment for 3a -c and 4a . First, the furano-
pyrimidine H-4 signal exhibited a downfield shift by
comparison to its alkynyl precursor (9.00-8.63 vs 8.35-
4
50 nm, slightly shifted to the red by comparison to the
28
alkynyl precursor 1a . A representative emission curve
for 3a is shown in Figure 2. All iodobicyclic nucleosides
8
.11 (H-6) ppm, DMSO-d
signals showed a chemical shift (157.8-154.2 and 59.0-
8.4 (I), 90.3 (Br) ppm, DMSO-d ) characteristic for
6
). Second, the furan CdC
3
gave the correct elemental analyses.
In summary, we have demonstrated that electrophilic
5
6
cyclization of R-alkynyl carbonyl compounds leads to
halofurans in mild conditions, and we have synthesized
a new class of modified nucleosides containing biologically
active substructures. The resulting bicyclic nucleoside
iodides or bromides should be particularly useful as
substrates in a variety of palladium-catalyzed reactions
such as Heck, Suzuki, Sonogashira, or amination, and
should thus provide material for a broad range of
modified nucleosides for drug discovery. Corresponding
synthetic studies are currently underway in our labora-
tory. Our protocol also offers a potential for iodine isotope
labeling.
8
O-vinyl and I/Br-vinyl carbons. Distinctive changes occur
as compared to the parent alkynes 1a -c (96.9-91.8 and
8
6
2.1-68.6 ppm, DMSO-d ) or nonhalogenated bicyclic
furano pyrimidines 2 (100.2-99.5 (C-5) ppm, DMSO-
d
1
8a
13
6
).
Third, the C NMR coupled (gated decoupling)
experiment showed an absence of hydrogen at C-5 for 3a .
In addition, this experiment allowed assignment of the
1
3
C signals based upon the 1
J C-H coupling constants
pattern, which was extrapolated for other analogues.
Mass spectra of 3a -c and 4a exhibited intense molec-
ular ions. The IR νCO values clustered in a narrow range
-1
(
1663-1670 cm ). The representative UV-vis spectrum
for 3a is shown in Figure 2. As expected, absorptions shift
to longer wavelengths for the fused cyclic system, as
compared to the parent alkynyl uridines 1a -c. The first
two bands usually appear at 248-257 and 282-285 nm
for aryl-substituted compounds, but a single band was
observed at 248 nm for the cyclopropyl derivative 3c. The
position of the last well-pronounced band (longest wave-
length), shifts slightly from cyclopropyl substituted 3c
Ack n ow led gm en t. We thank the Oakland Univer-
sity, Research Excellence Program in Biotechnology, for
support of this research, and Profs. J . A. Gladysz, M.
A. Ubeda, and J . Zemlicka for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and analytical and spectral characterization data for all
1
13
new compounds, and H and C NMR and MS spectra for 1b,c,
a -c, and 4a . This material is available free of charge via
3
(341 nm) to the aryl derivatives 3a ,b and 4a (357/356/
the Internet at http://pubs.acs.org.
3
56 nm) and does not depend on the halogen. The molar
-
1
-1
absorptivities reach nearly to 18 000 M cm
.
J O0345648
Both iodo- and bromofurano pyrimidines 3 and 4
exhibited a strong purple luminescence on TLC plates
under a UV lamp (254 nm); more detailed characteriza-
(30) See, for example: Okamoto, A.; Tainaka, K.; Saito, I. J . Am.
Chem. Soc. 2003, 125, 4972-4973.
6
790 J . Org. Chem., Vol. 68, No. 17, 2003