New approach to 1′C-modified riboside scaffold via stereoselective functionalization of D-(+)-ribonic-γ-lactone [1]

Article abstract of DOI:10.1002/jhet.5570400218

We describe the preparation and spectroscopic properties of a novel class of nucleoside analogues in which a phenyl sulfonyl methylene group is attached to the 1′-carbon atom of β-D-ribofuranose. The glycosylation of 5.0.(tert-butyldiphenylsilyl)-2,3-O-is

Full text of DOI:10.1002/jhet.5570400218

317
New Approach to 1'C-Modified Riboside Scaffold
Via Stereoselective Functionalization of D-(+)-Ribonic-γ-lactone [1]
Arnaldo Alzérreca
Mar-Apr 2003
Department of Chemistry, Metropolitan Campus, Inter American University of Puerto Rico,
P.O. Box 19-1293, San Juan, Puerto Rico 00919
Received September 24, 2002
We describe the preparation and spectroscopic properties of a novel class of nucleoside analogues in
which a phenyl sulfonyl methylene group is attached to the 1'-carbon atom of β-D-ribofuranose. The glyco-
sylation of 5-O-(tert-butyldiphenylsilyl)-2,3-O-isopropylidene-D-ribofuranolactone 1b with phenyl methyl-
lithium sulfone in THF at -60° C afforded 5-O-(tert-butyldiphenylsilyl)-1'-(benzenesulfonylmethylene)-
2',3'-O-isopropylidene-α-D-ribofuranose 2b. When subjected to deoxydative reaction conditions with boron
trifluoride etherate in the presence of triethylsilane at -45° C, lactol 2b was converted into 2',3'-O-isopro-
pylidene-1'-deoxy-1'-(benzenesulfonylmethylene)-β-D-ribofuranose 4b with excellent stereocontrol over
the anomeric carbon in moderate yield. This method has the potential for the development of a wider array
of useful probes derived from 1'-deoxy-β-D-ribofuranose for nucleic acid research and for antisense thera-
peutic agents through further functionalization of the coupled sulfonyl group.
J. Heterocyclic Chem., 40, 317 (2003).
Synthetic methods for the preparation of base-modified
stereocontrol of the anomeric atom and its subsequent
Lewis-acid catalyzed dehydration to the corresponding
2-benzenesulfonylmethylene derivatives. We also
reported that when a similar procedure was applied to the
5-O-(tert-butyldimethylsilyl)-2',3'-O-isopropylidene-D-
ribofuranolactone 1a, lactol 2a was obtained in good
yields and high stereoselection [Scheme1]. However,
under Lewis-acid promoted dehydration conditions lactol
2a was converted into its 1',5'-anhydro derivative 3 via
competing intramolecular substitution after cleavage of
the tert-butyldimethylsilyl (TBDMS) protecting group
[8]. On the basis of our previous experience, changing
the protecting devise at the 5'-hydroxyl group and
modifying reaction conditions were necessary to avoid
exclusive formation of the 1',5'-anhydro derivative 3.
Therefore, we examined the potential of other protecting
devises under similar reaction conditions for allowing
both a stereoselective nucleophilic attack by the
organometallic species to D-ribofuranolactone 1b from
the β-face, and the Lewis acid-promoted deoxydation of
2b with retention of the β-stereochemistry of the 1'-C-
coupled methyl phenyl sulfone functionality. To our
knowledge, there were no reports on the synthesis of this
glycosides are of current interest primarily because of their
application in antisense technology of therapeutic oligonu-
cleotides with improved properties such as enzymatic sta-
bility, binding specificity or cellular uptake [2], and for the
study of aromatic stacking as a contributing factor with
respect to the thermodynamic stability of nucleic acids in
protic media [3]. Glycosylation reactions starting from pro-
tected sugar lactones or from 1-chloro derivatives of pro-
tected sugars as the glycosyl donors have not been an easy
task mainly because of problems related with α/β-anomer
stereoselectivity, glycosyl donor activation, and the often-
dual role of the protecting functionalities. For example,
mono-and polycyclic aromatic hydrocarbons as the DNA
"base analogue", such as phenyl, naphthalene- or phenan-
threne-residues were successfully incorporated at the α-1'-
C-position of D-ribose and 2-deoxy-D-ribose via coupling
reactions of organometallic derivatives of these aromatic
compounds with Hoffer's chlorosugar [4]. Although the
coupling was reported to work efficiently, the α-anomers
were obtained as the major products, and the β-anomers
were prepared by acid-catalyzed isomerization of the
α-compounds [5]. Also, earlier attempts for the glycosyla-
tion of benzyl-protected sugar lactones with phenyllithium,
and deoxydation with boron trifluoride etherate and
triethylsilane were successful in the pyrano series but failed
to afford the corresponding D-ribose derivatives since
debenzylation was found to proceed with opening of the
tetrahydrofuran ring [6]. Subsequently, it was also reported
that glycosylation of protected D-(+)-ribonic-γ-lactone with
phenyllithium afforded a 1:3 α /β mixture of the
corresponding lactols, which were then reduced to yield the
anomeric mixture of protected phenyl ribosides [7].
1
class of C-riboside derivatives.
In a previous paper, we described the phenylsulfonyl
methylenation of 2,3-isopropylidene-D-erythronolactone
to give the corresponding lactols of type 2 with good

318
A. Alzérreca
Vol. 40
In this paper, we describe the highly stereoselective
phenylsulfonyl methylenation of 5-O-(tert-butyl-
diphenylsilyl)-2',3'-O-isopropylidene-D-ribofuranolactone
1b and the subsequent deoxydation to afford the β-1'-C-
coupled riboside analogue 4b [Scheme 2]. The addition of
lithiated methyl phenyl sulfone to 5-O-(tert-butyl-
diphenylsilyl)-2',3'-O-isopropylidene-D-ribofuranolactone
1b [9,10] in tetrahydrofuran at –60 °C leads exclusively to
α-lactol 2b, which can be isolated as a white foam in 84%
8.2 Hz between H and its vicinal H proton. The same
2'
3'
approximation predicts a very weak coupling of less than
1.0 Hz for the near orthogonal relationships between
H H and H H
By comparison, although smaller
2', 1'α
3', 4'α
than expected coupling constants are expected between
protons on vicinal oxygenated carbon atoms in rigid ring
yield after silica gel column chromatography. Structure
1
13
1
1
assignments are based on infrared, H nmr, C nmr, H- H
COSY, mass spectral and elemental analysis. When lactol
2b is subsequently treated with boron trifluoride etherate in
the presence of 2.5 equivalents of triethylsilane in acetonitril
at -45 °C, the major diastereomer β-D-ribofuranose deriva-
tive 4b is isolated as a crystalline and colorless solid after
column chromatographic separation on silica gel using
EtOAc-petroleum ether mixtures as eluent in 48% yield.
The β-stereochemistry of the 1'carbon atom of 4b is
tentatively assigned on the basis of its proton nmr
spectrum. It shows two doublets at 4.87 and 4.49 ppm for
systems [8], the H resonance of the α-anomer 5 should
2'
appear as a doublet of doublets with coupling constants
larger than 1 Hz. The β-stereochemistry assignment is
1
1
confirmed by 2D H- H correlation analysis, which
shows only three sets of cross peaks between H -H ,
2' 3'
H
-H - H , and H -H - H . In contrast, the pres-
4'α
5'a 5'b 1'α 1a 1b
ence of only very small amounts of the 1'-deoxy-1'-
(benzenesulfonylmethylene)-α-D-ribofuranose anomer 5
could be detected in the proton nmr spectrum of the crude
reaction mixture for which the integration of nmr signals
shows a α/β ratio of 4/96, thus establishing the highly
stereoselective course of this two step C-glycosylation
sequence.
The combined steric demands of the phenyl sulfonyl
methylene group and the appropriately selected protecting
tert-butyldiphenylsilyl group imposed on the intermediate
oxocarbenium ion 6b may strongly limit the approach of
triethyl silane to the 1'C-atom from the β-face and thus
determine the stereochemical outcome of the reaction.
H and H , respectively, with a coupling constant of 5.7
3'
2'
Hz for both vicinal protons. Protons H and H appear
4'α
1'α
as multiplets centered at 4.23 and 3.33 ppm due to vicinal
coupling to both of their respective vicinal proton pairs
H
-H , and H -H . Karplus-Conroy approximation
5'a 5'b
1a 1b
for vicinal coupling with dihedral angles of 102.9°,
106.0° and 2.6° for H H , H H and H H , esti-
2', 1'α
3', 4'α
2', 3'
mated by conformational optimization with MM2 Force
Field Method [11] for 4b suggests a coupling constant of

New Approach to 1'C-Modefied Riboside Scaffold
Mar-Apr 2003
319
hydrogen. The 7.26 ppm resonance of residual chloroform and
77.0 ppm of deuterochloroform were used as internal references
for H and C nmr spectra, respectively. Mass spectral analysis
and combustion analysis were performed by Oneida Research
Services, Whitesboro, NY 13492. For thin layer chromatography
Alternatively, the intermediate oxocarbenium ion 6c may
be formed via Lewis-acid assisted cleavage of the TBDPS
protecting group prior to the reaction with triethyl silane.
According to preliminary geometry optimization of molec-
ular models [11] 6c may adopt a conformation in which the
5'-hydroxyl group and the sulfonyl group are close enough
to undergo hydrogen-bonding, and prevent formation of
anomer 5 to a greater extent.
1
13
(TLC) Riedel-de-Haen plates with fluorescence indicator (SiO -
2
60, F-254), and for flash column chromatography purifications E.
Merck silica gel grade 9385 (230-400 mesh) were used.
5-O-(tert-Butyldiphenylsilyl)-1'-(benzenesulfonylmethylene)-
2',3'-O-isopropylidene-α-D-ribofuranose (2b).
In addition to the desired 4b riboside, the 1',5'-anhydro
derivative 3 was obtained after column chromatographic
separation on silica gel with EtOAc-Petroleum ether
mixtures as eluent in 29% yield. Thus, the competitive
intramolecular substitution of the 5'-hydroxyl group in 6c
could not be completely suppressed under these reaction
conditions. However, these results contrast with the exclu-
sive formation of compound 3 under similar reaction
conditions when the 5'-hydroxyl group carries a TBDM
protecting devise, instead. On the other hand, the infrared
spectrum of the crude reaction mixture of 4b shows two
Commercially available 2',3'-O-isopropylidene-D-ribofura-
nolactone 1 (2.5 g, 0.013 mol), tert-butyldiphenylsilyl chloride
(5.47 g, 0.019 mol), and imidazole (2.21 g, 0.032 mol) were
dissolved in dimethylformamide (5.0 ml) and stirred at room
temperature for 24 hours to afford 5-O-(tert-butyldiphenylsilyl)-
2',3'-O-isopropylidene-D-ribofuranolactone [10]. The crude prod-
uct was recrystallized from isopropyl alcohol to give a colorless
solid, 5.4 g (95%), mp 99-100°. To a magnetically stirred solution
of methyl phenyl sulfone (1.09 g, 0.007 mol) in dry tetrahydrofu-
ran (60 ml) under argon n-butyllithium (3.2 ml of a 2.5 M solution
in hexanes, 0.008 mol) was added at -60°, warmed up to -10° and
stirred for 1 hour. The solution was then cooled again to -60°, and a
solution of 5-O-(tert-butyldiphenylsilyl)-2',3'-O-isopropylidene-
D-ribofuranolactone 1b (3.0 g, 0.007 mol) was added over a period
of 10 minutes. After addition, the solution was warmed up to -35°
and stirred for three hours, warmed up again to room temperature
and stirred for 3 more hours. The reaction mixture was then
quenched with a saturated solution of ammonium chloride (20 ml).
After extraction with ethyl acetate the organic layer was dried with
magnesium sulfate, filtered and concentrated under reduced pres-
sure. Purification of the remaining crude reaction mixture using
silica gel column chromatography with EtOAc/petroleum ether
mixtures as eluent afforded 2b (3.4 g, 84%), as a white foam; ir
-1
very small absorption bands at 1646 and 1636 cm ,
which are preliminarily assigned to the geometric isomers
7Z and 7E, formed only in trace amounts via elimination
of the methylen hydrogen atoms 1a and 1b from the
intermediate oxocarbenium ion 6b. Isomers of this type
were the major products when the α-lactol derived from
1'-(benzenesulfonylmethylene)-2',3'-O-isopropylidene-D-
erythronolactone was dehydrated with BF ·Et O at low
3
2
temperatures [8].
In conclusion, we have developed a convenient protocol
for the synthesis of novel β–1'-C-coupled riboside
analogues with excellent stereoselectivity in moderate yield.
The synthetic approach involves low temperature coupling
of phenyl methyllithium sulfone to 5-O-(tert-butyldiphenyl-
silyl)-2',3'-O-isopropylidene-D-ribofuranolactone 1b, and
Lewis-acid catalyzed deoxydation of the intermediate lactol
2b. Current work to increase the overall yield of 4b, and
further functionalization of the attached phenylmethylene
sulfonyl functional group to provide access to a wider
variety of synthetic derivatives is now in progress.
(CHCl ): 3461 (-OH), 3068 (=C-H), 2940 (aliphatic C-H), 1380
3
-1
(tert-butyl), 1320 (ν -SO -), 1141 and 1108 (ν
H nmr: δ 7.98-7.26 (m, 15H, ArH), 5.10 (s, 1H, OH), 4.70
(dd, 1H, J = 5.9 Hz, J = 1.5 Hz, H ), 4.45 (d, 1H, J = 5.9
-SO -) cm ;
as
2
sym
2
1
3',2'
3',4'
3'
2',3'
Hz, H ), 4.13 (m, 1H, H ), 3.70 (m, 4H, H ,H ,H ,H ), 1.38
2'
4'α
5'a 5'b 1a 1b
13
(s, 3H), 1.26 (s, 3H), 1.05 (s, 9H); C nmr: δ 140.8, 135.5, 133.4,
132.3, 130.0, 128.6, 127.8 (ArC), 112.8 (C ), 104.4 (O-C-O), 86.8
1'
(C ), 86.6 (C ), 81.8 (C ), 64.9 (C ), 59.9 (C-SO Ph), 27.0
2'
5'
3'
4'
2
+
(CH ) , 26.6 (CH ), 25.2 (CH ), 19.3 (CMe ). Ms: m/z 565 (M -
3 3
3
3
3
OH, 100% relative intensity).
Anal. Calcd. for C O SSi: C, 63.89; H, 6.57; S, 5.50.
Found: C, 63.50; H, 6.46; S, 5.15.
H
31 38
7
EXPERIMENTAL
General.
2',3'-O-Isopropylidene-1'-deoxy-1'-(benzenesulfonylmethylene)-
β-D-ribofuranose (4b).
Melting points were determined on an Electrothermal
apparatus and are uncorrected. Commercially available reagents
and solvents were used without further purification. N,N-
Dimethylformamide was purified by fractional distillation in
vacuo. Tetrahydrofuran was distilled from sodium metal in the
presence of benzophenone under dry argon; acetonitrile was
refluxed over phosphorus pentoxide and distilled with a Vigreaux
column. 2',3'-O-Isopropylidene-D-ribofuranolactone was
purchased from Aldrich and used without further purification.
Infrared spectra were recorded on a Perkin-Elmer 1620 FT-IR
spectrophotometer in carbon chloride and methylene chloride
5-O-(tert-Butyldiphenylsilyl)-1'-(benzenesulfonylmethylene)-
2',3'-O-isopropylidene-α-D-ribofuranose 2b (2.0 g, 0.003 mol)
was dissolved in dry acetonitrile (45 ml) and cooled down to
-45° under argon. Then, triethylsilane (0.87 g, 0.007 mol) was
added followed by the dropwise addition of boron trifluoride-
diethyl etherate (0.46 g, 0.003 mol) and the reaction mixture was
stirred at -40° for 1.5 hour. After warming up to room tempera-
ture, the solution was quenched with saturated aqueous potas-
sium carbonate (40 ml). The reaction mixture was extracted with
ethyl acetate and the organic layer dried with magnesium sulfate
and concentrated under reduced pressure. Purification of the
crude reaction mixture using silica gel column chromatography
1
13
solutions. H and C nmr spectra were recorded on a 200 MHz
Varian spectrometer at the nominal frequency of 199.97 MHz for

320
A. Alzérreca
Vol. 40
with EtOAc/petroleum ether mixtures afforded first 3 (0.32 g,
29%) [8], and then 4b (0.53 g, 48%), as colorless crystals, mp
[2] H. An, T. Wang, M. A. Maier, M. Manoharan, Bruce S.
Ross, and P. D. Cook, J. Org. Chem., 66, 2789 (2001); C. A. Stein and
th
Y.-C. Cheng, in "Cancer: Principles & Practice of Oncology", 5
161-162° (isopropyl alcohol); ir (CHCl ): 3436 (-OH), 3083 (=C-
3
Edition, V. T. DeVita, Jr., S. Hellman, S. A. Rosenberg, Editors.
Lippincott-Raven Publishers, Philadelphia, Chapter 63,1997; A. De
Mesmaeker, R. Häner, P. Martin and H. E. Moser, Acc. Chem. Res., 28,
366 (1995).
[3] K. M. Guckian, B. A. Schweitzer, R. X.-F. Ren, C. J. Sheils,
D. C. Tahmassebi, and E. T. Kool, J. Am. Chem. Soc., 122, 2213 (2000);
E. T. Kool, J. C. Morales, and K. M. Guckian, Angew. Chem. Int. Ed., 39,
990 (2000).
[4] M. Hoffer, Chem. Ber., 93, 2777 (1960).
[5] C. Strässler, N. E. Davis, and E. T. Kool, Helv. Chim. Acta, 82,
2160 (1999).
[6] S. Czernecki and G. Ville, J. Org. Chem., 54, 610 (1989).
[7] J. Matulic-Adamic, L. Beigelman, S. Portman, M. Egli and N.
Usman, J. Org. Chem., 3909, 61 (1996).
H), 2954 (aliphatic C-H), 1384 (gem-dimethyl), 1319 (ν -SO -),
as
2
-1
1
1161 and 1084 (ν
-SO -) cm ; H nmr: δ 7.98-7.93 (m, 2H,
sym
2
ArH), 7.69-7.50 (m, 3H, ArH), 5.95 (s, 1H, OH), 4.87 (d, 1H,
= 5.7 Hz, H ), 4.49 (d, 1H, J = 5.7 Hz, H ), 4.23 (m, 1H,
J
3',2'
3'
2',3'
2'
H
), 3.68 (m, 4H, H ,H ,H ,H ), 3.33 (m, 1H, H ), 1.37
4'α
5'a 5'b 1a 1b
13
1'α
(s, 3H), 1.24 (s, 3H); C nmr: δ 140.2 (ArCSO ), 133.9 (ArC ),
2
p
128.9 (ArC ), 128.1 (ArC ), 112.7 (O-C-O), 104.4 (C ), 87.7
o
m
1'
(C ), 87.3 (C ), 81.4 (C ), 63.7 (C ), 59.6 (C ), 26.2 (CH ),
2'
4'
3'
5'
1
3
+
24.5 (CH ); Ms: m/z 327 (100%), 328 (M , 17 % relative inten-
3
sity).
Anal. Calcd. for C
H O S: C, 54.86; H, 6.14; S, 9.76.
15 20 6
Found: C, 54.23; H, 6.06; S, 9.31.
Acknowledgement.
[8] A. Alzérreca, E. Hernández, E. Mangual and J. A. Prieto,
J. Heterocyclic Chem., 36, 555 (1999).
[9] M. G. B. Drew, J. Mann and A. Thomas, J. Chem. Soc. Perkin
Trans. 1, 2279 (1986).
NIGMS-MBRS-SCORE Grant S06 RR08159 from the
National Institutes of Health supported this work.
REFERENCES AND NOTES
[10] E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 94,
6190 (1972).
[11] N. L. Allinger and U. Burkert, Molecular Mechanics, ACS
Monograph 177, American Chemical Society, Washington DC, 1982.
[12] Yields are given after column chromatographic purification.
[*] Author email: aalzerre@inter.edu.
[1] Presented in part at the American Chemical Society Meeting,
Puerto Rico Section, San Juan, Puerto Rico, August 6, 2002.