Photochemistry on Soluble Polymer Supports: Synthesis of Nucleosides

Article abstract of DOI:10.1021/ol026881r

(Matrix Presented) A new soluble polymer support synthesis of nucleosides is described. The photochemical ring expansion of cyclobutanones in the presence of poly(ethylene glycol) (PEG) results in polymer-supported ribosides. These photoadducts can be cle

Full text of DOI:10.1021/ol026881r

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4415-4417
Photochemistry on Soluble Polymer
Supports: Synthesis of Nucleosides
Jian-Hua Zhong, Alex Fishman, and Edward Lee-Ruff*
Department of Chemistry, York UniVersity, 4700 Keele Street,
Toronto, Ontario M3J 1P3, Canada
leeruff@yorku.ca
Received September 10, 2002
ABSTRACT
A new soluble polymer support synthesis of nucleosides is described. The photochemical ring expansion of cyclobutanones in the presence
of poly(ethylene glycol) (PEG) results in polymer-supported ribosides. These photoadducts can be cleaved from the polymer under Vorbru1ggen
coupling conditions with TMS-protected purines and pyrimidines to give ribonucleosides. The method has been extended to include modified
PEGs with dendritic end-groups in order to improve the loading levels for these coupling reactions.
The use of polymer supports has been the backbone of
combinatorial chemistry and the production of chemical
libraries for the identification of lead compounds of medicinal
interest.1 The development of a new nucleoside synthesis
based on the photochemical ring expansion of cyclo-
butanones2 has prompted us to adapt such methodology to a
polymer support approach. Whereas cross-linked polystyrene
beads have been used in solid-phase synthesis,3 our earlier
attempts to use these as supports for cyclobutanone photo-
chemistry were not encouraging after observation of the low
efficiency for photoconversion. This is largely due to light
scattering and competing chromophore absorption associated
with the resin. Furthermore, photodegradation of the polymer
backbone was also observed. To circumvent these problems,
we investigated the use of soluble polymer supports4 for the
key photochemical step in order to reinstate the advantages
of homogeneity used in synthetic photochemistry. We chose
poly(ethylene glycol) (PEG) as the support since these
polymers do not possess interfering chromophores that could
mask the cyclobutanone carbonyl group. These polymers are
photostable and commercially available as polydispersed
mixtures with a range of molecular weights. Furthermore,
these polymers are recyclable and inexpensive. We have also
prepared a class of modified PEGs containing dendritic end
groups based on glycerol and pentaerythritol in order to
improve loading capacities of these resins and yet maintain
the attractive solubility properties of commercial PEG.5
A general method for preparation of nucleosides involves
the use of the Vorbru¨ggen coupling of O-glycosides with
TMS-protected purines or pyrimidines in the presence of a
Lewis acid.6 In the current investigation, we report the
preparation of O-ribosides attached to both commercial and
modified PEG by photochemical ring-expansion of cyclo-
butanones and the coupling of these ribosides with silylated
purines and pyrimidines under Vorbru¨ggen coupling condi-
tions. The photochemistry of cyclobutanones in the presence
of alcohols gives O-ribosides as one of two principal
pathways.7 This is accompanied by moderate amounts (up
* Corresponding author. Phone: 416-736-5443. Fax: 416-736-5936.
(1) DeWitt, S. H.; Czarnik, A. W. Acc. Chem. Res. 1996, 29, 114.
(2) (a) Lee-Ruff, E.; Jandrisits, L.; Hayes, I. E. E. Can. J. Chem. 1989,
67, 2057. (b) Lee-Ruff, E.; Jiang, J.-L.; Wan, W.-Q. Tetrahedron Lett. 1993,
34, 261. (c) Lee-Ruff, E.; Wan, W.-Q. J. Org. Chem. 1994, 59, 2114. (d)
Lee-Ruff, E.; Xi, F.-D.; Qie, J.-H. J. Org. Chem. 1996, 61, 1547. (e) Lee-
Ruff, E.; Ostrowski, M.; Ladha, A.; Stynes, D. V.; Vernik, I.; Jiang, J.-L.;
Wan, W.-Q.; Ding, S. F.; Joshi, S. J. Med. Chem. 1996, 39, 5276. (f) Lee-
Ruff, E.; Margau, R. Nucleosides, Nucleotides Nucleic Acids 2001, 20, 185-
196.
(5) Fishman, A.; Farrah, M. E.; Zhong, J.-H.; Lee-Ruff, E. Manuscript
in preparation.
(6) Vorbru¨ggen, H.; Ruh-Pohlenz, C. Org. React. 2000, 55, 1.
(7) Lee-Ruff, E. In New Synthetic Pathways from Cyclobutanones in
AdVances in Strain in Organic Chemistry; Halton, B., Ed.; JAI Press:
London, 1991; Vol. 1, p 167.
(3) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555.
(4) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489.
10.1021/ol026881r CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/21/2002

to 30%) of cycloelimination products. The use of a polymer
support such as PEG would enable the facile separation of
the ring-expanded ribosides from these cycloelimination
byproducts by precipitation of the polymer upon dilution with
diethyl ether.4 Furthermore, the Vorbru¨ggen coupling of the
polymer-supported riboside enables both the cleavage and
base substitution steps to occur by the same process.
Reaction of photoadducts 3 and 4 with bis(trimethyl-
silylated) uracil or N-trimethylsily-6-chloropurine in the
presence of trimethylsilyl triflate in 1,2-dichloroethane
(typical Vorbru¨ggen coupling conditions6) gave the corre-
sponding uracils 7 and 8, respectively, or purines 9 and 10,
respectively, in yields ranging from 42 to 70%.10 These
conversions were comparable in efficiency to the transforma-
tions of methoxy acetals 5 and 6 to the same nucleosides
under the Vorbru¨ggen conditions. Anomeric mixtures were
obtained that showed some stereoselectivity. This selctivity
differed slightly from that observed in the nucleosides derived
from methoxy acetals 5 and 6 (see Table 1). The R- and
Irradiation of cyclobutanones 1 and 2 (2-3 equiv per OH
group in PEG) in acetonitrile or methylene chloride solutions
containing PEG diol (MW 3400) resulted in photoadducts 3
and 4, respectively.8 Loading levels were determined by two
independent methods: (1) methanol cleavage and recovery
of methyl acetals 59 and 6 or (2) NMR integration of the
signals associated with the acetal or benzyl protons with those
of the backbone methylene protons of PEG. The former
method gives loading levels of 0.12-0.21 mmol/g for 3 (21-
36% of theoretical) and 0.06-0.15 mmol/g for 4 (10-26%).
The NMR integration method gives loading levels of 0.48
mmol/g (83% of theoretical) for 3 and 0.416 mmol/g (72%
of theoretical) for 4. Loading levels as determined by the
chemical method represent lower limits since aromatic
signals associated with the benzoate ester groups were
observed for the residual PEG, indicating that cleavage of
the tetrahydrofuranosides of polymer-supported substrates 3
and 4 under the methanolysis conditions was not complete
and that other acid-catalyzed transformations of these acetals
(e.g., ring-opening) were taking place competitively.
Table 1. Yieldsa and Stereoselectivity of Vorbru¨ggen Coupling
Products
deprotection
compd
% yields (R:â)b
products
% yieldsc
7 (from 3)
7 (from 5)
8 (from 4)
8 (from 6)
9 (from 3)
9 (from 5)
10 (from 4)
10 (from 6)
42 (1.4:1)
83 (1.4:1)
66 (1:1)
73 (1:1)
61 (1:2)
25 (1:2.4)
52 (1:1)
27.6 (3.7:1)
13r
13â
14r
14â
11r
11â
12r
12â
86
94
91
80
76
85
65
67
a Isolated yields. b Obtained from integration of 1H NMR spectra of the
anomeric mixture. c Yields for the deprotection step.
(8) Typical reaction conditions for the preparation of 3 and 4: 10.0 g
(2.9 mmol) of HO-PEG3400-OH (dried at 80° C under high vacuum for
30 min, 5.88 mmol of free OH groups) was dissolved in 500 mL of CH3CN
followed by addition of 6 mmol of cyclobutanone 1 or 2. The solution was
purged with argon and irradiated in nine Pyrex tubes using a medium-
pressure Hg lamp (Hannovia, 450 W) for 20 h. After the solution was
concentrated to 40-60 mL, cold anhydrous ether was added and diluted to
800 mL whereupon the polymer precipitated and was filtered off and
â-anomers (trans and cis, respectively) were separated at this
stage by silica gel chromatography, and the stereochemistry
assigned for 7-10 was based on the splitting patterns
associated with the anomeric N-acetal proton.11 Furthermore,
the known benzoate-protected derivatives 7r and 7â showed
1H NMR spectra that were similar to those reported in the
literature.9 Deprotection of the benzoate groups in anomeri-
1
subjected to H NMR analysis.
(9) Bamford, M. J.; Humber, D. C.; Storer, R. Tetrahedron Lett. 1991,
32, 271.
4416
Org. Lett., Vol. 4, No. 25, 2002

cally pure 7 and 8 was accomplished with methanolic
hydroxide ion solutions, whereas deprotection and amination
of 9 and 10 proceeded efficiently in 7 M methanolic
ammonia solutions at 100 °C. The resultant deprotected
nucleosides 11-14 were obtained anomerically pure.12
Loading levels could be increased to about 85% of theoretical
by the use of excess (3 equiv) cyclobutanone substrate.
Nevertheless, the inherently limiting loading capacity of
commercial PEG with only two terminal OH groups does
not rival that for the functionalized cross-linked polystyrene
resins or poly(vinyl alcohol) (PVA).4 Our substrates are not
suitable for coupling to PVA or alcohol dendrimers13 because
of the inefficient coupling of the photochemically generated
oxacarbenes to secondary or tertiary alcohols. We have
recently investigated the use of modified PEGs with den-
drimeric end units based on glycerol or pentaerythritol14 as
soluble polymer supports in order to improve the low loading
capacities of commercial PEG.5 PEG hexitol 16 was prepared
by coupling of pentaerythritol with PEG dimesylate, whereas
polyols 15 and 17 were obtained from coupling of 1,3-
dibenzyloxyglycerol and 1,3-bis(1,3-dibenzyloxyglyceroxy)-
glycerol, respectively, with PEG dimesylate followed by
deprotection of benzyl using hydrogenolysis.5 The loading
levels for modified PEGs 15-175 were measured for the
coupling of the photochemically derived carbene from ketone
2. Although some improvement in loading levels is observed
for 16 and 17 (see Table 2), these are not reflected with
limits this approach. Thus, the use of modified PEGs with
high loading levels (increased density of attached substrates)
would represent a more efficacious method for anhydrous
polymer support reactions.
In summary, it has been shown that cyclobutanones can
photoinsert into PEG (MW 3400) forming photoadducts that
can act as polymer-supported glycosyl donors in Vorbru¨ggen
coupling reactions to give ribonucleosides. This method has
the advantage of by-passing the separation of the cyclo-
elimination products associated with the photochemical step,
thus eliminating time-consuming chromatography methods
and the use of costly and environmentally unfriendly
solvents. The inherently low loading levels for this coupling
with commercial PEG can be improved with the use of
modified PEGs with dendritic end-groups based on glycerol
and pentaerythritol. The low cost and recyclable properties
of PEG make these attractive candidates as supports for
automated combinatorial synthesis of nucleosides. We are
presently looking at other chemically modified PEGs in order
to improve loading levels for the key photochemical coupling
step.
Acknowledgment. We thank the Ontario HIV Treatment
Network (OHTN) and the Natural Sciences and Engineering
Research Council of Canada (NSERC) for financial support.
OL026881R
(10) Typical procedure: a suspension consisting of 6-chloropurine (0.67
g, 4.32 mmol), a few crystals of ammonium sulfate, hexamethyldisalazane
(11.1 mL), and trichloromethylsilane (1.1 mL) was heated to reflux under
argon until a clear solution was obtained. The volatile compounds were
evaporated off, and the residue was coevaporated twice with 8 mL of dry
toluene. The resulting mixture was cooled to room temperature and dissolved
in 15 mL of 1,2-dichloromethane to which was added PEG-acetal 3 (3.48
g, 1.02 mmol, dried by coevaporation with 30-40 mL of toluene) and
trimethylchlorosilane (0.14 mL, 1.0 mmol) in 20 mL of 1,2-dichloroethane
under argon. To this mixture was added trimethylsilyl triflate (0.66 mL,
2.88 mmol), and the mixture was heated to reflux for 2 h. After cooling to
room temperature, the solution was diluted with acetonitrile (30 mL) and
the reaction quenched with 10 mL of saturated NaHCO3. After stirring for
30 min, the organic layer was separated and dried over Na2SO4. After the
solution was concentrated, cold anhydrous ether was added whereupon the
polymer precipitated out and was filtered off. The filtrated was evaporated,
and the residue was chromatographed on preparative TLC plates (repeated
elution with 1:1 hexane/ethyl acetate) to give 0.088 g (0.24 mmol) of 9R
and 0.171 g (0.48 mmol) of 9â.
Table 2. Loading Levels for Photochemical Coupling of
Ketone 2 with Resins 15-17
theoretical capacity
(mmol/g)
measured loading
(mmol/g)a
polymer
PEG3200(OH)2
PEG(OH)4 (15)
PEG(OH)6 (16)
PEG(OH)8 (17)
0.59
1.12
1.64
2.07
0.42
0.48
0.88
1.12
a Loading levels were determined by 1H NMR integration using the
polymer backbone signal as an internal standard.
(11) Se´quin, E.; Tamm, C. HelV. Chim. Acta 1972, 55, 1196.
(12) All compounds exhibited 1H and 13C NMR and mass spectra
consistent with their structures. The elemental analysis for all new
compounds were satisfactory. Known nucleosides 13R and 13â exhibited
similar 1H NMR and UV spectra to those previously reported; cf.: Sells, T.
B.; Nair, V. Tetrahedron 1994, 50, 117.
(13) Sunder, A.; Hanselmann, R.; Frey, H.; Mu¨lhaupt, R. Macromolecules
1999, 32, 4240.
(14) Lubineau, A.; Malleron, A.; Le Narvor, C. Tetrahedron Lett. 2000,
41, 8887.
respect to their theoretical loading capacities. This observa-
tion, which has been observed for other coupling reactions,5
is attributed to intramolecular hydrogen bonding and steric
effects. Although conversion efficiencies can be improved
in principle by using a stoichiometric excess of PEG, the
hygroscopic nature of these polyethers along with the
competing coupling reaction of the oxacarbene with water
Org. Lett., Vol. 4, No. 25, 2002
4417