Stereoselective Synthesis of 4′-Benzophenone-Substituted Nucleoside Analogs: Photoactive Models for Ribonucleotide Reductases

Article abstract of DOI:10.1021/jo961372m

Ribonucleotide reductases (RNRs) catalyze the 2′-reduction of ribonucleotides, thus providing 2′-deoxyribonucleotides, the monomers for DNA biosynthesis. The current mechanistic hypothesis for the catalysis effected by this class of enzymes involves a sequence of radical reactions. A reversible 3′-hydrogen abstraction, effected by a radical at the enzyme's active site, is believed to initiate the catalytic cycle. For the study of this substrate - enzyme interaction, a series of 4′-benzophenone-substituted model compounds was designed and synthesized. In these models, the benzophenone carbonyl group is oriented such that irradiation is expected to result in an enzyme-like, reversible 3′-hydrogen abstraction. The key step of our synthetic approach is the highly diastereoselective (dr > 95:5) Grignard-addition of carbonyl-protected o-benzophenone magnesium bromide to 2,3-O-isopropylidene-β-L-erythrofuranose. The configuration of the newly established chiral center was unambiguously proven by X-ray crystallography. The erythritol derivative thus obtained was dehydrated to a base-free, 4′-benzophenone-substituted nucleoside analog. This first model system was further modified by transforming the free 2′,3′-hydroxyl groups into the mono- and bis-methyl ethers, into the cyclic carbonate, and into the mono- and bis-mesylates. Alternatively, the primary hydroxyl group of the erythritol intermediate was selectively oxidized to the aldehyde. In the furanose thus obtained, the stage is set for the additional introduction of a nucleobase at the 1′-position.

Full text of DOI:10.1021/jo961372m

302
J . Org. Chem. 1997, 62, 302-309
Ster eoselective Syn th esis of 4′-Ben zop h en on e-Su bstitu ted
Nu cleosid e An a logs: P h otoa ctive Mod els for Ribon u cleotid e
Red u cta ses†
Thomas E. Lehmann and Albrecht Berkessel*
Organisch-Chemisches Institut der Universita¨t Heidelberg, Im Neuenheimer Feld 270,
D-69120 Heidelberg, Germany
Received J uly 22, 1996X
Ribonucleotide reductases (RNRs) catalyze the 2′-reduction of ribonucleotides, thus providing 2′-
deoxyribonucleotides, the monomers for DNA biosynthesis. The current mechanistic hypothesis
for the catalysis effected by this class of enzymes involves a sequence of radical reactions. A
reversible 3′-hydrogen abstraction, effected by a radical at the enzyme’s active site, is believed to
initiate the catalytic cycle. For the study of this substrate-enzyme interaction, a series of 4′-
benzophenone-substituted model compounds was designed and synthesized. In these models, the
benzophenone carbonyl group is oriented such that irradiation is expected to result in an enzyme-
like, reversible 3′-hydrogen abstraction. The key step of our synthetic approach is the highly
diastereoselective (dr > 95:5) Grignard-addition of carbonyl-protected o-benzophenone magnesium
bromide to 2,3-O-isopropylidene-â-L-erythrofuranose. The configuration of the newly established
chiral center was unambiguously proven by X-ray crystallography. The erythritol derivative thus
obtained was dehydrated to a base-free, 4′-benzophenone-substituted nucleoside analog. This first
model system was further modified by transforming the free 2′,3′-hydroxyl groups into the mono-
and bis-methyl ethers, into the cyclic carbonate, and into the mono- and bis-mesylates. Alterna-
tively, the primary hydroxyl group of the erythritol intermediate was selectively oxidized to the
aldehyde. In the furanose thus obtained, the stage is set for the additional introduction of a
nucleobase at the 1′-position.
In tr od u ction
f II, Scheme 1) is generated. Protonation of the 2′-
hydroxyl group and elimination of water gives rise to the
radical cation B (II f III f IV, Scheme 1). The formal
transfer of a hydride anion from the cysteine/cysteinate
ensemble present in the active site leads to the radical
species C (IV f V, Scheme 1). The radical C is again a
“3′-radical”. However, it is now the precursor to the 2′-
deoxygenated product. The reduction of the ribonucle-
otide is completed by the back-transfer of the hydrogen
atom Ha to the 3′-position of the ribose moiety (V f VI,
Scheme 1). After reduction of the cystine disulfide bond
in the active site to two cysteine thiol groups, the enzyme
is ready for the next turnover. This proposed mechanism
of catalysis is based on studies with isotopically labeled
substrates4 and substrate analogs,5 as well as on the
investigation of enzymes modified by site-directed mu-
tagenesis.6 Most importantly, at least one of the three
classes of RNRs is known to harbor a stable tyrosyl
radical.7 In fact, the so-called “aerobic” RNR from E. coli
was the first radical enzyme found.1 Finally, the X-ray
In all known organisms, 2′-deoxyribonucleotides are
synthesized by 2′-reduction of ribonucleotides. This
deoxygenation (eq 1) is effected by ribonucleotide reduc-
tases (RNRs).1 Therefore, RNRs play a central role in
(1)
DNA biosynthesis and in cell division, and they are
potential drug targets for tumor and viral diseases.2
A
mechanism involving the radicals A-C has been pro-
posed for the action of ribonucleotide reductases (Scheme
1).3 In this proposal, the catalytic cycle is initiated by
the regioselective attack of a radical species X• in the
enzyme’s active site on the 3′-position of the substrate
nucleotide. As a result, the hydrogen atom Ha is ho-
molytically removed and the so-called “3′-radical” A (I
(4) (a) Stubbe, J .; Ackles, D. J . Biol. Chem. 1980, 255, 8027 and ref
3d. For reviews of earlier work, see: (b) Thelander, L.; Reichard, P.
Ann. Rev. Biochem. 1979, 48, 133. (c) Follmann, H. Angew. Chem.,
Int. Ed. Engl. 1974, 13, 569. (d) Hogenkamp, H. P. C.; Sando, G. N.
Struct. Bonding (Berlin) 1974, 20, 23.
* To whom correspondence should be addressed. Tel.: int + 49-
6221-54-8407. Fax: int + 49-6221-54-4205. E-mail: gz7@ix.urz.uni-
heidelberg.de.
† Dedicated to Professor Waldemar Adam on the occasion of his 60th
birthday.
(5) (a) Salowe, S.; Bollinger, J . M.; Ator, M.; Stubbe, J .; McCracken,
J .; Peisach, J .; Samano, M. C.; Robins, M. J . Biochemistry 1993, 32,
12749. (b) Salowe, S. P.; Ator, M. A.; Stubbe, J . Biochemisty 1987, 26,
3408. (c) Ator, M. A.; Stubbe, J . Biochemistry 1985, 24, 7214. (d) Ator,
M; Salowe, S. P.; Stubbe, J .; Emptage, M. H.; Robins, M. J . J . Am.
Chem. Soc. 1984, 106, 1886. (e) Sjo¨berg, B.-M.; Gra¨slund, A.; Eckstein,
F. J . Biol. Chem. 1983, 258, 8060. (f) Thelander, L.; Larsson, B.; Hobbs,
J .; Eckstein, F. J . Biol. Chem. 1976, 251, 1398 and ref 1b.
(6) (a) Rova, U.; Goodtzova, K.; Ingemarson, R.; Behravan, G.;
Gra¨slund, A.; Thelander, L. Biochemistry 1995, 34, 4267. (b) Mao, S.
S.; Holler, T. P.; Yu, G. X.; Bollinger, J . M.; Booker, S.; J ohnston, M.
I.; Stubbe, J . Biochemistry 1992, 31, 9733. (c) Larsson, A.; Sjo¨berg,
B.-M. EMBO J . 1986, 5, 2037 and ref 1b.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) For reviews see: (a) Reichard, P. Science 1993, 260, 1773. (b)
Stubbe, J . Adv. Enzymol. Relat. Areas Mol. Biol. 1990, 63, 349. (c)
Lammers, M.; Follmann, H. Struct. Bonding (Berlin) 1983, 54, 27.
(2) (a) Stubbe, J .; van der Donk, W. A. Chem. Biol. 1995, 2, 793. (b)
Inhibitors of Ribonucleoside Diphosphate Reductase Activity. In
International Encyclopedia of Pharmacology and Therapeutics; Cory,
J . G., Cory, A. H.; Eds.; Pergamon Press: New York, 1989; Section
128.
(3) (a) Licht, S.; Gerfen, G. J .; Stubbe, J . Science 1996, 271, 477. (b)
Stubbe, J . J . Biol. Chem. 1990, 265, 5329. (c) Reichard, P.; Ehrenberg,
A. Science 1983, 221, 514. (d) Stubbe, J .; Ator, M., Krenitsky, T. J .
Biol. Chem. 1983, 258, 1625 and ref 1b.
(7) See refs 1a and 6a.
S0022-3263(96)01372-2 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Substituted Nucleoside Derivatives
J . Org. Chem., Vol. 62, No. 2, 1997 303
Sch em e 1. P ostu la ted Mech a n ism of
Ribon u cleotid e Red u cta ses
Sch em e 2. Design of Mod el Com p ou n d s
radical X•. In the long run, our mechanistic studies are
hoped to lead to new selective, mechanism-based inhibi-
tors of ribonucleotide reductases and to biomimetic
catalysts9 for RNR-type regioselective deoxygenations of
polyols/carbohydrates.
Carbonyl compounds, and in particular benzophenones,
are able to initiate reversible homolytic hydrogen ab-
stractions upon photochemical excitation into their triplet
states.10 Therefore, nucleoside derivatives were designed
that incorporate a benzophenone substituent into the
sugar moiety (Scheme 2). With the carbonyl oxygen atom
of the benzophenone moiety being fixed near the 3′-
hydrogen atom, these model compounds are expected to
reversibly generate “3′-radicals” upon irradiation. Mo-
lecular models suggest the attachment of the benzophe-
none substructure to the 4′-position of the ribose ring11
(for the sake of clarity, the conventional numbering of
the ribose unit in nucleosides is maintained throughout
the text). In this arrangement, the carbonyl oxygen atom
should be at a favorable distance to the 3′-hydrogen atom.
In this paper, the synthesis of nine 4′-benzophenone-
substituted model compounds is described.12 Eight are
simplified nucleoside analogs in that the nucleobase is
replaced by a hydrogen atom. The ninth one possesses
crystal structures of the two protein subunits (R1 and
R2) of this enzyme, which have become available only
recently,8 support the idea of a radical deoxygenation
sequence involving three cysteine residues: Two cys-
teines act as the formal hydride donor/redox shuttle,
while the third one most likely represents the radical X•
in the enzyme’s active site. The oxidation of the third
cysteine to the catalytically competent thiyl radical is
believed to take place by electron transfer to the remote
tyrosyl radical.8
As plausible as this mechanism may seem, it is so far
not supported by direct observation of the intermediate
substrate-derived radicals A-C (Scheme 1). Further-
more, there is no close analogy in the radical chemistry
of carbohydrates. With this in mind, we found it worth-
while to design and synthesize model compounds that
would allow for the selective generation of the 3′-radical
A (Scheme 1) proposed for the catalytic cycle of RNRs.
Of special interest are model compounds that are able
to imitate the proposed reversible hydrogen abstraction
from the 3′-carbon atom of the nucleotide by the protein
(9) Breslow, R. Chem. Soc. Rev. 1972, 1, 553.
(10) (a) Wagner, P.; Park, B.-S. In Organic Photochemistry; Pawda,
A., Ed.; Dekker: New York, 1991; Vol. 11; p 227. (b) Wagner, P. J .
Top. Curr. Chem. 1976, 66, 1. (c) Wagner, P. J . Acc. Chem. Res. 1971,
4, 168.
(11) A 4′-hydrogen abstraction might occur as well. However, the
photoenol formed by 4′-hydrogen abstraction can rapidly tautomerize
back to the starting material, thus making this reversible abstraction
process unproductive.
(8) (a) Uhlin, U.; Eklund, H. Nature 1994, 370, 533. (b) Nordlund,
P.; Sjo¨berg, B.-M.; Eklund, H. Nature 1990, 345, 593.
(12) Lehmann, T. E. Dissertation, Universita¨t Heidelberg, 1995.

304 J . Org. Chem., Vol. 62, No. 2, 1997
Lehmann and Berkessel
Sch em e 3. Syn th esis of 4′-Ben zop h en on e-Su bstitu ted Nu cleosid e Der iva tives
the intact anomeric hemiacetal center and may thus
serve as a precursor for the construction of nucleotide
analogs carrying both a nucleobase and the benzophe-
none chromophore. The mechanistic investigation of the
photochemical reactivity of these models will be described
in a subsequent paper.13
results (57% chemical yield) were obtained at room
temperature. At -78 °C, no reaction occurred. Warming
of the reaction mixture to ambient temperature before
quenching gave the diol 3 in 13% yield. Running the
coupling reaction in refluxing THF gave a 52% yield of
the addition product 3. According to NMR analyses, the
diastereoselectivity of the reaction did not change with
temperature. The configuration of the newly formed
stereogenic center (R) was unambiguously established by
the X-ray crystal structure of the silylated derivative 8
(Scheme 3, inset). Of course, the vicinal H-C-C-H
coupling constants18 measured for the bicycle 4 (Scheme
3) also supported this configurational assignment (vide
infra).
For the synthesis of the model compounds lacking the
nucleobase, the diol 3 was treated with tosyl chloride in
pyridine at -30 °C. After the mixture was warmed to
room temperature and stirred for several days, tetrahy-
drofuran derivative 4 was obtained in quantitative yield.
The primary tosylate that should be formed as an
intermediate could not be isolated. Nevertheless, the
intramolecular cyclization 3 f 4 is most reasonably
Resu lts
Our synthetic sequence is summarized in Scheme 3.
The ethylene glycol-protected o-bromobenzophenone 1
and the enantiomerically pure 2,3-O-isopropylidene-â-L-
erythrofuranose (2) served as starting materials.14,15
They were synthesized by modified literature proce-
dures14,15 in three steps each from 2-bromobenzoic acid
(65%) and from L-(+)-rhamnose (67%), respectively.
In the first step of our sequence, the Grignard com-
pound was prepared by treatment of the benzophenone
derivative 1 with Rieke magnesium.16 The protected
erythrofuranose 2 was treated with 3 equiv of the
organomagnesium reagent in THF. The addition pro-
ceeded with excellent anti-(like-)selectivity;17 only one
diastereomer was detected by NMR analysis of the crude
product (i.e., diastereomeric ratio > 95:5). The best
(17) For definitions see: (a) Masamune, S.; Kaiho, T.; Garvey, D.
S. J . Am. Chem. Soc. 1982, 104, 5521. (b) Seebach, D.; Prelog, V.
Angew. Chem. 1982, 94, 696; Angew. Chem., Int. Ed. Engl. 1982, 21,
654. For a recent review see: Helmchen, G. In Stereoselective Synthesis,
Methods of Organic Chemistry (Houben-Weyl); Helmchen, G., Hoff-
mann, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart,
1995; Vol. E 21a; p 1.
(18) (a) Saenger, W. Principles of Nucleic Acid Structure, 2nd ed.;
Springer: Heidelberg, 1988; p 48. (b) Davies, D. B., Prog. NMR
Spectrosc. 1978, 12, 135.
(13) Lehmann, T. E.; Zimmermann, G.; Griesinger, C.; Berkessel,
A. Manuscript in preparation.
(14) Lohner, W.; Praefcke, K. J . Organomet. Chem. 1981, 205, 167.
(15) Baxter, J . N.; Perlin, A. S. Can. J . Chem. 1960, 38, 2217.
(16) (a) Rieke, R. D. Acc. Chem. Res. 1977, 10, 301. (b) Rieke, R. D.;
Bales, S. E. J . Am. Chem. Soc. 1974, 96, 1175. Nonactivated magne-
sium failed to react with 1. Activating agents such as I2 or CCl4 had
no effect.

Synthesis of Substituted Nucleoside Derivatives
J . Org. Chem., Vol. 62, No. 2, 1997 305
Sch em e 4. Syn th esis of Di-O-su bstitu ted
Der iva tives of 5
In order to provide access to model compounds carrying
a nucleobase in the 1′-position, the primary hydroxyl
group of the diol 3 must be selectively oxidized to an
aldehyde. Due to the higher inherent reactivity of the
secondary, benzylic hydroxyl group, common oxidizing
agents like PCC or activated derivatives of DMSO
afforded the corresponding ketone instead of the desired
aldehyde. Nevertheless, the selective oxidation of the
primary alcohol was achieved either by using the protect-
ing group strategy outlined in Scheme 3 or by using PCC
adsorbed on neutral alumina. In the former approach,
the furanose 9 was synthesized from the diol 3 in five
steps and 52% overall yield. In the first step, the primary
hydroxyl group of 3 was selectively benzoylated, and the
ester 6 was obtained quantitatively. Treatment with
TBDMSOTf20 afforded the doubly protected compound 7
in 92% yield. Basic hydrolysis yielded the primary
alcohol 8. This material readily crystallized from diethyl
ether, thus affording single crystals suitable for X-ray
structural analysis (Scheme 3, inset). The crystal struc-
ture of the silyl ether 8, together with the known absolute
configuration of the two stereogenic centers derived from
2,3-O-isopropylidene-â-L-erythrofuranose (2), allowed for
the unambiguous assignment of the (R)-configuration to
the newly formed benzylic stereocenter. The oxidation
of 8 with PCC and the removal of the silyl group with
Bu4NF afforded the benzophenone-substituted furanose
9 in 57% yield. The latter approach (one-step oxidation
of the diol 3) gave the desired furanose 9 in 34% yield.
The furanose 9 is in the oxidation state required for the
nucleophilic introduction of a nucleobase by the Vor-
bru¨ggen method.21 It may thus serve as a precursor for
the model system of type 10 (Scheme 3), carrying both a
benzophenone moiety and a nucleobase.
interpreted by nucleophilic displacement of the primary
tosylate by the secondary (benzylic) hydroxyl group.
Consequently, the configuration at the benzylic position
should remain unchanged. In fact, only one diastereomer
was formed. As mentioned above, the (R)-configuration
of the benzylic stereogenic center could clearly be deduced
from the vicinal H-C-C-H coupling constant18 3J 4′H-3′H
) 2.2 Hz measured for the bicycle 4. 3J values below 3
Hz strongly indicate a trans-relationship for the corre-
sponding protons, whereas a cis-configuration should
result in 3J values larger than 3.5 Hz.18 The model
compound 5 was finally obtained in 76% yield by depro-
tection of the bis-dioxolane 4. Thus, the final product 5
was synthesized in a stereospecific manner, starting from
commercially available L-(+)-rhamnose in 29% overall
yield.
The proposed mechanism of RNR action involves the
acid-catalyzed elimination of the 2′-hydroxyl group from
the 3′-radical (Scheme 1, II f III f IV). For the
successful modeling of this reaction step, it may well be
necessary to “tune” the nucleofugal properties of the 2′-
hydroxyl group by derivatization. For example, treat-
ment of the diol 5 with 1,1′-carbonyldiimidazole/DMAP
gave the bicyclic carbonate 11 in 99% yield (Scheme 4).
The dimethyl ether 12 was obtained from 5 by alkylation
using the methyl Meerwein salt in the presence of the
proton sponge 1,8-bis(dimethylamino)naphthalene19 (55%).
Finally, the bismesylate 13 was synthesized from 5 and
mesyl chloride/triethyl amine in 95% yield.
Discu ssion
The key step of our synthetic sequence is the highly
diastereoselective addition of the Grignard reagent de-
rived from the bromoarene 1 to the erythrose 2. The
mechanism accounting for the observed extreme selectiv-
ity merits further consideration. The presence of Lewis-
acidic magnesium salts suggests a chelate-controlled22
addition of the nucleophile to the ring-opened form of the
erythrose 2. Besides the carbonyl oxygen atom, the
molecule contains three further oxygen atoms that may
participate in chelating a magnesium ion (formulas
I-III). Since the re-face of the aldehyde is attacked, a
Numerous attempts were made to selectively prepare
the 2′- or 3′-monomethylated or monomesylated deriva-
tives of 5. Under a variety of reaction conditions,
mixtures of both monoderivatized products and the
dimethyl ether 12 or the bismesylate 13, respectively,
were obtained. Although their separationseven by
preparative HPLCsproved difficult, we were able to
isolate the compounds 14-17 in pure form, albeit in
small (mg) quantities. Nevertheless, the structural as-
(20) TBDMSCl failed to react with the sterically hindered secondary
hydroxyl goup.
(21) Vorbru¨ggen, H.; Bennua, B. Chem. Ber. 1981, 114, 1279.
(22) (a) Reetz, M. T. Angew. Chem. 1984, 96, 542; Angew. Chem.,
Int. Ed. Engl. 1984, 23, 556. (b) Devant, R. M.; Radunz, H.-E.
Formation of C-C Bonds by Addition To Carbonyl Groups, Addition
of s-Type Organometallic Compounds. In Stereoselective Synthesis,
Methods of Organic Chemistry (Houben-Weyl); Helmchen, G., Hoff-
mann, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart,
1995; Vol. E 21 b; p 1151.
(23) (a) Mekki, Singh, G., Wightman, R. H. Tetrahedron Lett. 1991,
32, 5143. (b) There is a single report of syn-diastereoselectivity in the
addition of methyl magnesium chloride to the erythrofuranose 2 (see
ref 24). However, the authors of ref 24 do not state how the
configurational assignment was done.
signment, i.e., the distinction of 2′- vs 3′-derivatization,
3
could be unambiguously done on the basis of J OH-CH
couplings in the H-NMR spectra.
-
1
(19) Procedure according to Diem, M. J .; Burow, D. F.; Fry, J . L. J .
Org. Chem. 1977, 42, 1801. The attempted methylation of 5 using
methyl iodide failed under a variety of reaction conditions.
(24) Williams, D. R.; Klingler, F. D. J . Org. Chem. 1988, 53, 2134.

306 J . Org. Chem., Vol. 62, No. 2, 1997
Lehmann and Berkessel
Research Chromatotron Model 8924 with E. Merck silica gel
60 PF254 (with gypsum). Preparative HPLC was performed
on an E. Merck-Septech NovaPrep 5000 System using an E.
Merck LiChrosorb 100 RP-18, 10 µm, 250 × 50 mm column at
a flow rate of 78 mL/min. Analytical HPLC was performed
on an E. Merck-Hitachi L-6200 A/L-4500 DAD system using
a Hewlett-Packard Lichrospher 100 RP-18, 5 µm, 250 × 4 mm
column at a flow rate of 0.7 mL/min. For the other analytical
instrumentation used, see ref 28.
1,4-chelation involving the primary alcoholate anion
appears most likely (I). In fact, a similar re-selectivity
has also been observed in the additions of other organo-
magnesium compounds to the L-erythrosefuranose 2.23,24
2-(2-Br om op h en yl)-2-p h en yl-1,3-d ioxola n e (1) was pre-
pared in 3 steps from 2-bromobenzoic acid by the method of
Praefcke et al.14 in 65% yield as a colorless, crystalline solid:
1H-NMR (300 MHz, CDCl3) δ 3.99-4.06 (m, 2H), 4.10-4.24
(m, 2H), 7.19 (ddd, J ) 7.7, 7.7, 1.8 Hz, 1H), 7.30-7.34 (m,
3H), 7.37 (ddd, J ) 7.7, 7.7, 1.1 Hz, 1H), 7.42-7.47 (m, 2H),
7.58 (dd, J ) 7.7, 1.1 Hz, 1H), 7.86 (dd, J ) 7.7, 1.8 Hz, 1H);
13C-NMR (75 MHz, CDCl3) δ 65.1 (t), 109.5 (s), 121.9 (s), 126.6
(d), 126.7 (d), 127.8 (d), 128.2 (d), 128.7 (d), 129.8 (d), 135.0
(d), 140.1 (s), 140.4 (s); IR (KBr, pellet) 3058, 2887, 1585, 1447,
1206, 1092, 1074, 1026, 765, 703 cm-1; TLC (EtOAc/hexane
1:1) Rf 0.56; mp 137 °C (lit.14 mp 137 °C). Anal. Calcd for
C15H13BrO2: C, 59.04; H, 4.29. Found: C, 59.14; H, 4.38.
[3a S-(3a r,4r,6a r)]-Tet r a h yd r o-2,2-d im et h yl-fu r o[3,4-
d ]-1,3-d ioxol-4-ol (2,3-O-isop r op ylid en e-â-L-er yth r ofu r a -
n ose) (2) was prepared in three steps from L-(+)-rhamnose
by the method of Perlin et al.15 in 67% yield as a colorless,
crystalline solid: 1H-NMR (300 MHz, DMSO-d6) δ 1.22 (s, 3
H), 1.33 (s, 3 H), 3.76 (d, J ) 10.3 Hz, 1 H), 3.84 (dd, J ) 10.3,
3.5 Hz, 1 H), 4.38 (d, J ) 5.9 Hz, 1 H), 4.77 (dd, J ) 5.9, 3.5
Hz, 1 H), 5.14 (d, J ) 4.1 Hz, 1 H), 6.23 (d, J ) 4.1 Hz, 1 H,
exchangeable with D2O); 13C-NMR (75 MHz, DMSO-d6) δ 24.8
(q), 26.3 (q), 70.9 (t), 79.9 (d), 85.4 (d), 101.1 (d), 111.3 (s); IR
(NaCl, film) 3428, 2987, 1459, 1375, 1101, 1069 cm-1; TLC
(EtOAc/hexane 1:1) Rf 0.29; mp 29.5-30 °C (lit.15 mp 29-31
°C); [R]20 +74.8° (c 2.51, MeOH) [lit.15 [R]20 +72° (c 2.4,
Con clu sion
A convenient, convergent, and stereospecific synthetic
access to 4′-benzophenone-substituted nucleoside analogs
has been developed. Starting from commercially avail-
able L-(+)-rhamnose, nine model systems were synthe-
sized. With the exception of the monomethylated and
monomesylated compounds 14-17, quite reasonable
overall yields were achieved (16-29%). In our approach,
2,3-O-isopropylidene-â-L-erythrofuranose 2 served as a
central intermediate. It was shown that Grignard re-
agents can be added to this furanose with extremely high
anti-/ like-selectivity. Most likely, efficient chelate con-
trol accounts for the selectivity of this process. It is
expected that the model systems described in this paper
will for the first time allow for the selective, photochemi-
cal generation and study of the radicals postulated as
intermediates in the catalytic cycle of the ribonucleotide
reductases (RNRs).13 Furthermore, the modular char-
acter of our synthetic sequence [Grignard addition to the
erythrofuranose 2, elaboration to furanoses of the type
9/10 or simpler, “base-free” structures of the type 5
(Scheme 3)] may provide a wide variety of other nucleo-
side analogsspotentially even by combinatorial meth-
ods.25
D
D
MeOH)]. Anal. Calcd for C7H12O4: C, 52.49; H, 7.55.
Found: C, 52.72; H, 7.63.
[4R-[4r{R*},5r]]-2,2-Dim eth yl-r4-[2-(2-p h en yl-1,3-d iox-
olan -2-yl)ph en yl]-1,3-dioxolan e-4,5-dim eth an ol (3). A mix-
ture of 1.78 g (18.7 mmol) of anhydrous MgCl2, 1.57 g (9.45
mmol) of KI, and 1.32 g (33.7 mmol) of potassium in 35 mL of
anhydrous THF was refluxed under argon for 2 h with vigorous
stirring. The oil bath was removed, and stirring was continued
for another 1.5 h. A solution of 2.86 g (9.37 mmol) of 1 in 30
mL of anhydrous THF was added in a dropwise manner to
the resulting black suspension with stirring at room temper-
ature. Stirring at ambient temperature was continued for
another 3 h, and a solution of 0.50 g (3.12 mmol) of 2 in 15
mL of anhydrous THF was added. The reaction mixture was
stirred at room temperature for another 18 h, and 100 mL of
10% aqueous NH4Cl was added (CAUTION: In some cases,
especially during scale-up (20-30 g K), traces of unreacted
potassium remained. In this case, 2-propanol was added
dropwise prior to quenching with aqueous NH4Cl.) The layers
were separated, and the aqueous layer was extracted with 2
× 100 mL of EtOAc and 100 mL of Et2O. The combined
organic phases were washed with 4 × 50 mL of water and dried
over MgSO4. Evaporation afforded 2.54 g of the crude product
as a clear, pale yellow oil. Flash chromatography (EtOAc/
hexane 1:1) of 2.16 g of the crude product afforded 0.58 g (57%)
of 3 as a colorless, solid foam. An analytically pure sample
was obtained by preparative HPLC (MeOH/H2O 6:4, tR 15.5
min) as a colorless, solid foam: 1H-NMR (300 MHz, DMSO-
d6) δ 1.00 (s, 3H), 1.10 (s, 3H), 3.27-3.37 (m, 1H), 3.65 (ddd,
J ) 10.7, 8.2, 5.5 Hz, 1H), 3.81-4.19 (m, 5H), 4.38 (dd, J )
9.2, 6.3 Hz, 1H), 4.76 (d, J ) 4.8 Hz, 1H, exchangeable with
D2O), 4.78 (d, J ) 5.5 Hz, 1H, exchangeable with D2O), 5.23
(dd, J ) 9.2, 4.8 Hz, 1H), 7.23-7.42 (m, 7H), 7.59 (d, J ) 7.3
Hz, 1H), 7.65 (d, J ) 7.4 Hz, 1H); 13C-NMR (75 MHz, DMSO-
d6) δ 25.0 (q), 27.6 (q), 60.6 (t), 64.2 (t), 64.7 (t), 65.0 (d), 78.0
(d), 79.2 (d), 107.1 (s), 109.1 (s), 126.1 (d), 126.4 (d), 126.7 (d),
127.7 (d), 127.9 (d), 128.1 (d), 128.4 (d), 139.3 (s), 140.9 (s),
142.1 (s); IR (NaCl, film) 3442, 3063, 2036, 1473, 1371, 1217,
1071, 1048, 757, 700 cm-1; MS (CI) m/ z 387 [(M + H)+], 386
[M+], 371, 368, 353, 352, 308, 295; TLC (EtOAc/hexane 1:1)
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reagents
were purchased from commercial suppliers and were used as
received. L-(+)-Rhamnose monohydrate (high purity grade)
was purchased from E. Merck. Pyridinium chlorochromate
(PCC) and PCC/Al2O3 were prepared according to Corey et al.26
and Tietze et al.27 respectively. All solvents were distilled.
Methylene chloride was stirred for 2 d with concd sulfuric acid,
decanted, washed with water and aqueous NaHCO3, dried over
MgSO4, distilled from P4O10, and stored over 4 Å molecular
sieves. THF was distilled from sodium benzophenone ketyl
prior to use. Triethylamine and pyridine were distilled from
CaH2 and stored over 3.3 Å molecular sieves. Methanol was
distilled from magnesium. Flash chromatography was carried
out on E. Merck or Macherey-Nagel silica gel 60 (230-400
mesh). Radial chromatography was performed on a Harrison
(25) (a) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555.
(b) Lowe, G. Chem. Soc. Rev. 1995, 24, 309.
(26) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 16, 2647.
(27) Tietze, L.-F.; Eicher, T. Reaktionen und Synthesen im organisch-
chemischen Praktikum; Thieme: Stuttgart, 1981; p 85.
(28) Berkessel, A.; Bolte, M.; Frauenkron, M.; Nowak, T.; Schwen-
kreis, T.; Seidel, L.; Steinmetz, A. Chem. Ber. 1996, 129, 59.
Rf 0.28; mp 42-47 °C; [R]22 -74.7° (c 1.35, MeOH). Anal.
D

Synthesis of Substituted Nucleoside Derivatives
J . Org. Chem., Vol. 62, No. 2, 1997 307
Calcd for C22H26O6: C, 68.38; H, 6.78. Found: C, 68.20; H,
6.86.
1381, 1275, 1217, 1098, 1070, 1027, 756, 713, 702 cm-1; MS
(EI) m/ z 490 (M+), 475, 428, 255, 235, 211, 177, 149, 105; TLC
(EtOAc/hexane 3:7) Rf 0.33; mp 50-62 °C; [R]20D -40.5° (c 2.00,
MeOH). Anal. Calcd for C29H30O7: C, 71.01; H, 6.16.
Found: C, 71.17; H, 6.33.
[3a R-(3a r,4r,6a r)]-Te t r a h yd r o-2,2-d im e t h yl-4-[2-(2-
ph en yl-1,3-dioxolan -2-yl)ph en yl]fu r o[3,4-d]-1,3-dioxole (4).
Tosyl chloride [0.74 g (3.88 mmol)] was added to a solution of
1.50 g (3.88 mmol) of the diol 3 in 30 mL of anhydrous pyridine
at -30 °C in small portions. The solution was allowed to warm
to room temperature. After the solution was stirred for 2 d,
an additional equivalent of TsCl was added with cooling as
described above. After being stirred for 4 d at room temper-
ature, the reaction mixture was taken up in a mixture of 50
mL of Et2O and 50 mL of water. The organic layer was
separated and washed with 50 mL of water. The combined
aqueous layers were extracted with 2 × 25 mL of Et2O. The
combined organic phases were dried over MgSO4 and rota-
evaporated. Purification by flash chromatography (EtOAc/
hexane 3:7) afforded 1.44 g (quantitative) of 4 as a clear,
colorless oil. An analytically pure sample was obtained by
radial chromatography (EtOAc/hexane 3:7): 1H-NMR (300
MHz, DMSO-d6) δ 1.20 (s, 3H), 1.40 (s, 3H), 3.72 (dd, J ) 10.3,
2.9 Hz, 1H), 3.86-4.08 (m, 4 H), 4.13 (dd, J ) 10.3, 5.5 Hz,
1H), 4.53 (dd, J ) 6.3, 2.2 Hz, 1H), 4.88 (ddd, J ) 6.3, 5.5, 2.9
Hz, 1H), 5.41 (d, J ) 2.2 Hz, 1H), 7.27-7.38 (m, 8H), 7.58-
7.62 (m, 1H); 13C-NMR (75 MHz, DMSO-d6) δ 25.1 (q), 27.0
(q), 64.5 (t), 64.6 (t), 73.4 (t), 80.3 (d), 82.3 (d), 86.9 (d), 109.3
(s), 111.8 (s), 126.4 (d), 127.3 (d), 127.5 (d), 128.1 (d), 128.3
(d), 128.7 (d), 138.6 (s), 138.7 (s), 141.7 (s); IR (NaCl, film) 3062,
2937, 1601, 1474, 1380, 1207, 1088, 1070, 759, 700 cm-1; MS
(EI) m/ z 368 (M+), 353, 323, 222, 177, 149, 105; TLC (EtOAc/
hexane 1:1) Rf 0.76; [R]20D +18.4° (c 1.01, MeOH). Anal. Calcd
for C22H24O5: C, 71.72; H, 6.57. Found: C, 71.81; H, 6.63.
[2R-(2r,3â,4â)]-P h en yl[2-(tetr a h yd r o-3,4-d ih yd r oxy-2-
fu r a n yl)p h en yl]m eth a n on e (5). A suspension of 128 mg
(348 µmol) of 4 in 0.6 mL of AcOH/H2O 4:1 was stirred under
argon at room temperature for 7 d. It was then neutralized
by the addition of 0.79 g of K2CO3 and 5 mL of water. The
mixture was extracted with 3 × 5 mL of CH2Cl2. The
combined organic phases were dried over MgSO4 and rota-
evaporated. Purification by flash chromatography (Et2O/
hexane 8:2) afforded 75 mg (76%) of 5 as colorless crystals.
1H-NMR (200 MHz, DMSO-d6) δ 3.43 (dd, J ) 9.3, 1.7 Hz, 1H),
3.66 (dd, J ) 9.3, 3.7 Hz, 1H), 3.87-4.00 (m, 2H), 4.65 (d, J )
7.3 Hz, 1H), 4.89 (d, J ) 3.4 Hz, 1H, exchangeable with D2O),
5.00 (d, J ) 6.6 Hz, 1H, exchangeable with D2O), 7.20 (d, J )
7.3 Hz, 1H), 7.34-7.53 (m, 5H), 7.58-7.69 (m, 3H); 13C-NMR
(75 MHz, CDCl3) δ 71.6 (d), 73.7 (t), 79.6 (d), 80.5 (d), 126.6
(d), 126.8 (d), 128.5 (d), 129.8 (d), 131.0 (d), 132.0 (d), 133.8
(d), 136.6 (s), 137.1 (s), 141.7 (s), 199.0 (s); IR (NaCl, film) 3397,
[4S-[4r,5r(S*)]]-4-[(Ben zoyloxy)m et h yl]-5-[[[(1,1-d i-
m eth yleth yl)d im eth ylsilyl]oxy][2-(2-ph en yl-1,3-d ioxola n -
2-yl)p h en yl]m eth yl]-2,2-d im eth yl-1,3-d ioxola n e (7). To a
solution of 861 mg (1.76 mmol) of 6 in 1.8 mL of anhydrous
CH2Cl2 were added at room temperature 0.51 mL (3.86 mmol)
of 2,4,6-trimethylpyridine and 0.61 mL (2.64 mmol) of TBDM-
SOTf. After being stirred for 19 h at room temperature, the
reaction mixture was poured into 10 mL of water. The layers
were separated, and the aqueous layer was extracted with 3
× 20 mL of CH2Cl2. The combined organic layers were washed
with 3 × 20 mL of water, dried over MgSO4, and rota-
evaporated. Purification of the crude product by flash chro-
matography (EtOAc/hexane 1:9) afforded 978 mg (92%) of 7
as a colorless foam: 1H-NMR (300 MHz, DMSO-d6) δ -0.64
(s, 3 H), -0.21 (s, 3 H), 0.77 (s, 9 H), 1.11 (s, 3 H), 1.25 (s, 3
H), 3.91-4.08 (m, 4 H), 4.18-4.24 (m, 2 H), 4.38-4.45 (m, 1H),
4.60-4.65 (m, 1H), 5.57 (d, J ) 4.0 Hz, 1H), 7.28-7.75 (m, 12
H), 7.98-8.02 (m, 2H); 13C-NMR (75 MHz, DMSO-d6) δ -5.3
(q), -5.2 (q), 17.8 (s), 25.5 (q), 25.6 (q), 27.9 (q), 64.7 (t), 65.1
(t), 68.2 (d), 74.6 (d), 80.7 (d), 107.5 (s), 109.1 (s), 126.1 (d),
126.8 (d), 127.4 (d), 127.9 (d), 128.3 (d), 128.4 (d), 128.6 (d),
128.8 (d), 129.4 (d), 129.8 (s), 133.4 (d), 138.6 (s), 139.8 (s),
141.8 (s), 161.9 (s); IR (KBr, pellet) 3964, 2931, 1721, 1602,
1472, 1380, 1273, 1253, 1085, 1069, 838, 779, 712 cm-1; TLC
(EtOAc/hexane 1:9) Rf 0.26; mp 43-51 °C; [R]20D -90.2° (c 1.55,
CHCl3); HRMS m/ z 604.2909 (M+, 604.2856 calcd for C35H44O7-
Si). Anal. Calcd for C35H44O7Si: C, 69.51; H, 7.33. Found:
C, 69.48; H, 7.39.
[4S-[4r,5r(S*)]]-5-[[[(1,1-Dim eth yleth yl)d im eth ylsilyl]-
oxy][2-(2-p h en yl-1,3-d ioxola n -2-yl)p h en yl]m et h yl]-2,2-
d im eth yl-4-(h yd r oxym eth yl)-1,3-d ioxola n e (8). To a so-
lution of 771 mg (1.27 mmol) of 7 in 40 mL of anhydrous MeOH
was added 254 mg (6.35 mmol) of powdered NaOH. The
suspension was stirred at room temperature for 23 h. The
reaction mixture was then partitioned between 50 mL of water
and 50 mL of Et2O. The layers were separated, and the
aqueous layer was extracted with 2 × 50 mL of Et2O. The
combined organic phases were washed with 2 × 40 mL of
water, dried over MgSO4, and rota-evaporated. The crude
product was purified by flash chromatography (EtOAc/hexane
3:7), affording 626 mg (99%) of 8 as colorless, crystals. 1H-
NMR (300 MHz, DMSO-d6) δ -0.74 (s, 3H), -0.29 (s, 3H), 0.74
(s, 9H), 1.07 (s, 3H), 1.17 (s, 3H), 3.46 (ddd, J ) 11.0, 9.2, 4.8
Hz, 1H), 3.67 (ddd, J ) 11.0, 6.3, 2.9 Hz, 1H), 3.88-4.05 (m,
5H), 4.10 (dd, J ) 6.6, 5.9 Hz, 1H), 4.39 (dd, J ) 6.3, 4.8 Hz,
1H, exchangeable with D2O), 5.41 (d, J ) 6.6 Hz, 1H), 7.26-
7.43 (m, 7H), 7.57 (dd, J ) 7.6, 1.3 Hz, 1H), 7.70 (dd, J ) 7.6,
1.6 Hz, 1H); 13C-NMR (75 MHz, DMSO-d6) δ -5.3 (q), -5.1
(q), 17.8 (s), 25.6 (q), 25.7 (q), 28.2 (q), 61.3 (t), 64.6 (t), 64.7
(t), 67.7 (d), 78.5 (d), 80.9 (d), 106.9 (s), 109.1 (s), 126.2 (d),
126.7 (d), 127.2 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.4 (d),
138.7 (s), 140.5 (s), 141.9 (s); IR (KBr, pellet) 3562, 1089, 1029,
840, 778 cm-1; MS (CI) m/ z 500 (M+), 499 [(M - H)+], 485,
443, 439, 368, 325, 293, 249, 207, 149, 133, 115, 101; TLC
(EtOAc/hexane 3:7) Rf 0.48; mp 144.5-145.5 °C; [R]20D -66.7°
(c 0.68, MeOH). Anal. Calcd for C28H40O6Si: C, 67.17; H, 8.05.
Found: C, 67.21; H, 8.05.
3062, 2945, 1664, 1597, 1449, 1316, 1059, 936, 758, 703 cm-1
;
MS (EI) m/ z 284 (M+), 266, 222, 211, 194, 133, 105; TLC (Et2O/
hexane 8:2) Rf 0.22; mp 90.5-91.5 °C; [R]20 -23.7° (c 0.38,
D
EtOH). Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found:
C, 71.54; H, 5.68.
[4S-[4r,5r(S*)]]-4-[(Ben zoyloxy)m eth yl]-2,2-d im eth yl-
5-[[2-(2-ph en yl-1,3-dioxolan -2-yl)ph en yl]h ydr oxym eth yl]-
1,3-d ioxola n e (6). To a solution of 1.00 g (2.59 mmol) of 3 in
40 mL of anhydrous CH2Cl2 were added 2.16 mL (15.5 mmol)
of Et3N and 0.90 mL (7.76 mmol) of benzoyl chloride at -45
°C. After being stirred for 7 h at ca. -40 °C, the reaction
mixture was poured into 40 mL of cold water. The layers were
separated, and the organic layer was washed with 40 mL of
water. The combined aqueous layers were extracted with 3
× 20 mL of Et2O. The combined organic phases were washed
with 20 mL of water, dried over MgSO4, and rota-evaporated.
Purification by flash chromatography (EtOAc/hexane 3:7)
afforded 1.28 g (quantitative) of 6 as a colorless foam: 1H-
NMR (300 MHz, DMSO-d6) δ 1.05 (s, 3 H), 1.13 (s, 3 H), 3.85-
4.08 (m, 4H), 4.25 (dd, J ) 11.0, 7.0 Hz, 1H), 4.40-4.49 (m, 3
H), 4.94 (d, J ) 5.2 Hz, 1 H, exchangeable with D2O), 5.30
(dd, J ) 8.5, 5.2 Hz, 1 H), 7.23-7.43 (m, 7 H), 7.50-7.55 (m,
2 H), 7.62-7.69 (m, 3 H), 7.99-8.02 (m, 2 H); 13C-NMR (75
MHz, DMSO-d6) δ 25.1 (q), 27.5 (q), 63.9 (t), 64.2 (t), 64.7 (t),
64.9 (d), 74.6 (d), 79.2 (d), 107.8 (s), 109.1 (s), 126.1 (d), 126.3
(d), 126.8 (d), 127.7 (d), 127.9 (d), 128.0 (d), 128.4 (d), 128.6
(d), 129.3 (d), 129.7 (s), 133.2 (d), 139.3 (s), 141.1 (s), 142.0 (s),
165.7 (s); IR (NaCl, film) 3516, 3063, 2936, 1720, 1602, 1451,
X-r a y Str u ctu r a l An a lysis of 8. Single crystals suitable
for X-ray structural analysis were obtained by slow evapora-
tion of a solution of 8 in Et2O at room temperature. Crystal
dimensions: 0.40 × 0.30 × 0.40 mm. Crystal data: monoclinic
P21; a ) 1143(1) pm, b ) 1016.5(6) pm, c ) 1250(1) pm, â )
106.00(8)°, V ) 1395.50 × 106 pm3; Z ) 2; Dc ) 1.192 g cm-3
(200 K), number of reflections used for unit cell parameter
refinement ) 24. Data were collected at 200 K on a Siemens
Nicolet Syntex R3m/V diffractometer using a graphite mono-
chromator and Mo KR radiation; scan range 3.4° < 2θ < 45.1°;
ω-scan with ∆ω ) 0.75°, scan rate 6.0-29.3°/min, number of
reflections collected: 2035, independent reflections: 1929,
number of unique data with I > 2σ: 1843. Applied correc-
tions: Lorentz and polarization correction; exp. absorption

308 J . Org. Chem., Vol. 62, No. 2, 1997
Lehmann and Berkessel
correction, Ψ-scan (∆Ψ ) 10°). The structure was solved by
direct methods using SHELXTL and SHELX93 and refined
by least squares procedures.29 Refined parameters: 326,
maximum residual electron density: 0.29 × 10-6 e/pm3, R1 )
0.0311, Rw ) 0.082 (F2 refinement).30
(MeOH/H2O 6:4, tR 16.3 min) as a colorless, solid foam: 1H-
NMR (300 MHz, CDCl3) δ 4.02-4.04 (m, 2H), 5.22 (ddd, J )
7.4, 4.0, 3.3 Hz, 1H), 5.28 (dd, J ) 7.4, 2.6 Hz, 1H), 5.38 (d, J
) 2.6 Hz, 1H), 7.35-7.61 (m, 7H), 7.73-7.77 (m, 2H); 13C-NMR
(75 MHz, CDCl3) δ 72.7 (t), 79.8 (d), 85.3 (d), 85.4 (d), 127.1
(d), 128.0 (d), 128.5 (d), 129.7 (d), 130.0 (d), 130.6 (d), 133.4
(d), 136.4 (s), 137.0 (s), 137.1 (s), 153.9 (s), 197.9 (s); IR (NaCl,
film) 3062, 2928, 1819, 1659, 1597, 1473, 1290, 1270, 1159,
1079, 1057, 769, 735, 705 cm-1; TLC (Et2O/hexane 8:2) Rf 0.28;
[3a R-(3a r,4r,6r,6a r)]-Tetr a h yd r o-2,2-d im eth yl-6-[2-(2-
p h en yl-1,3-d ioxola n -2-yl)p h en yl]fu r o[3,4-d ]-1,3-d ioxol-4-
ol (9). (a ) F r om 8. A solution of 100 mg (200 µmol) of 8 in
0.4 mL of anhydrous CH2Cl2 was added to a suspension of 4.6
mg (56 µmol) of NaOAc and 67.1 mg (311 µmol) of PCC in 0.5
mL of anhydrous CH2Cl2 in a dropwise manner at room
temperature. After the mixture was stirred for 2.5 h, another
68.2 mg (316 µmol) of PCC was added, and stirring was
continued for 16 h. The reaction mixture was filtered through
Celite. The filtrate was washed with 2 × 1 mL of water, and
the aqueous phase was extracted with 1 mL of CH2Cl2. The
combined organic phases were dried over MgSO4, filtered
through Celite and silica gel, and evaporated. The resulting
clear, colorless oil (83 mg) was dissolved in 0.9 mL of
anhydrous THF and 157 mg (498 µmol) of Bu4NF‚3 H2O were
added at 0 °C. After stirring for 10 min at 0 °C and 50 min at
room temperature, the reaction mixture was partitioned
between 10 mL of 10% aqueous NH4Cl and 10 mL of Et2O.
The layers were separated, and the aqueous layer was
extracted with 2 × 10 mL of Et2O. The combined organic
phases were washed with 2 × 5 mL of water, dried over
MgSO4, and concentrated. Purification by flash chromatog-
raphy (EtOAc/hexane 3:7) afforded 44 mg (57%) of 9 as a clear,
colorless oil.
(b) F r om 3. A solution of 200 mg (518 µmol) of 3 in 0.5
mL of anhydrous CH2Cl2 was added to a stirred suspension of
8.5 mg (104 µmol) of NaOAc and 520 mg (520 µmol) of PCC/
Al2O3 (1 mmol PCC/g) in 0.5 mL of anhydrous CH2Cl2 at room
temperature. After the mixture was stirred for 20 h, 10 mL
of Et2O was added. The suspension was filtered, and the
filtrate was washed with 2 × 5 mL of water. The combined
aqueous layers were extracted with 10 mL of Et2O. The
combined organic phases were dried over MgSO4 and rota-
evaporated. The resulting crude mixture of 3 and 9 was
separated by flash chromatography (EtOAc/hexane 3:7), af-
fording 68 mg (34%) of 9 and 80 mg (40%) of 3 as clear, pale
yellow oils.
mp 48-55 °C; [R]22D -2.9°, [R]22578 -4.6°, [R]22546 -10.9°, [R]22
436
-120.2° (c 1.10, CH2Cl2); HRMS m/ z 310.0853 (M+, 310.0841
calcd for C18H14O5). Anal. Calcd for C18H14O5: C, 69.67; H,
4.55. Found: C, 69.40; H, 4.60.
[2R-(2r,3â,4â)]-P h en yl[2-[tetr a h yd r o-3,4-d im eth oxy-2-
fu r a n yl]p h en yl]m eth a n on e (12). Under argon, a solution
of 500 mg (1.76 mmol) of 5 in 15 mL of anhydrous CH2Cl2 was
added to a suspension of 1.35 g (9.13 mmol) of trimethyloxo-
nium tetrafluoroborate and 2.33 g (10.8 mmol) of 1,8-bis-
(dimethylamino)naphthalene in 60 mL of anhydrous CH2Cl2
at room temperature. The mixture was stirred for 3 d, and
another 530 mg (3.58 mmol) of trimethyloxonium tetrafluo-
roborate and 823 g (3.88 mmol) of 1,8-bis(dimethylamino)-
naphthalene were added. Stirring was continued for 1 d, and
50 mL of CH2Cl2 and 50 mL of water were added. The layers
were separated, and the aqueous layer was extracted with 2
× 50 mL of CH2Cl2. The combined organic phases were
washed with 2 × 50 mL of 5% K2CO3 and 10 mL of water,
dried over MgSO4, filtered through silica gel, and rota-
evaporated. Purification of the crude product by radial chro-
matography (Et2O/hexane 2:8, two runs) and preparative
HPLC (MeOH/H2O 65:35, tR 14.7 min) afforded 301 mg (55%)
of 12 as colorless crystals: 1H-NMR (300 MHz, CDCl3) δ 3.37
(s, 3H), 3.38 (s, 3H), 3.76 (dd, J ) 9.9, 4.1 Hz, 1H), 3.81 (dd, J
) 9.9, 2.6 Hz, 1H), 3.92-3.98 (m, 2H), 4.99 (d, J ) 6.6 Hz,
1H), 7.21 (d, J ) 7.4 Hz, 1H), 7.34 (ddd, J ) 7.5, 6.3, 2.2 Hz,
1H), 7.38-7.47 (m, 4H), 7.51-7.57 (m, 1H), 7.76-7.79 (m, 2H);
13C-NMR (75 MHz, CDCl3) δ 57.4 (q), 58.2 (q), 69.5 (t), 78.9
(d), 81.4 (d), 86.5 (d), 126.9 (d), 127.4 (d), 127.6 (d), 128.3 (d),
129.2 (d), 129.8 (d), 132.9 (d), 137.5 (s), 137.6 (s), 139.7 (s),
197.9 (s); IR (KBr, pellet) 3056, 2894, 1657, 1595, 1450, 1135,
1074, 935, 720, 703 cm-1; TLC (Et2O/hexane 8:2) Rf 0.34; mp
58-61 °C; [R]20D -13.8° (c 1.53, CHCl3); HRMS m/ z 312.1346
(M+, 312.1362 calcd for C19H20O4). Anal. Calcd for C19H20O4:
C, 73.06; H, 6.45. Found: C, 72.88; H, 6.34.
9: 1H-NMR (300 MHz, DMSO-d6) δ 1.18 (s, 3H), 1.40 (s,
3H), 3.87-4.09 (m, 4H), 3.39-4.44 (m, 2H), 5.24 (dd, J ) 4.8,
1.5 Hz, 1H), 5.50 (s, 1H), 6.93 (d, J ) 4.8 Hz, 1H, exchangeable
with D2O), 7.28-7.42 (m, 7H), 7.57 (dd, J ) 7.4, 1.5 Hz, 1H),
7.86 (dd, J ) 7.7, 1.1 Hz, 1H); 13C-NMR (75 MHz, DMSO-d6)
δ 25.4 (q), 27.2 (q), 64.6 (t), 64.7 (t), 83.0 (d), 85.8 (d), 86.4 (d),
103.6 (d), 109.2 (s), 111.7 (s), 126.4 (d), 126.6 (d), 127.2 (d),
128.2 (d), 128.4 (d), 128.7 (d), 129.3 (d), 138.3 (s), 139.6 (s),
141.7 (s); IR (NaCl, film) 3426, 3058, 2891, 1481, 1375, 1208,
1077, 982, 875, 762, 702 cm-1; MS (EI) m/ z 384 (M+), 369,
322, 307, 255, 211, 149, 133; HRMS m/ z 384.1605 (M+,
384.1573 calcd for C22H24O6); TLC (EtOAc/hexane 3:7) Rf 0.22.
[3aR-(3ar,4r,6ar)]-4-(2-Ben zoylph en yl)tetr ah ydr ofu r o-
[3,4-d ]-1,3-d ioxol-2-on e (11). A solution of 500 mg (1.76
mmol) of 5 in 6 mL of anhydrous CH2Cl2 was added to a
suspension of 898 mg (5.54 mmol) of 1,1′-carbonyldiimidazole
and 43 mg (0.35 mmol) of DMAP in 3 mL of anhydrous CH2-
Cl2 at room temperature under argon. The mixture was
stirred for 7 d in the dark, and 10 mL of CH2Cl2 and 5 mL of
water were added. The layers were separated, and the
aqueous layer was extracted with 5 mL of CH2Cl2. The
combined organic phases were dried over MgSO4, filtered
through silica gel and rota-evaporated. Purification of the
crude product by radial chromatography (EtOAc/hexane 2:8,
4:6) afforded 543 mg (99%) of 11 as a clear, colorless oil. An
analytically pure sample was obtained by preparative HPLC
[2R-(2r,3â,4â)]-P h en yl[2-[t et r a h yd r o-3,4-b is[(m et h yl-
su lfon yl)oxy]-2-fu r a n yl]p h en yl]m eth a n on e (13). To a
solution of 417 mg (1.47 mmol) of 5 in 15 mL of anhydrous
CH2Cl2 were added 1.22 mL (8.80 mmol) of Et3N and 0.57 mL
(7.33 mmol) of MsCl at room temperature under argon. After
the mixture was stirred for 17 h, 10 mL of saturated aqueous
NaHCO3 was added. The layers were separated, and the
aqueous layer was extracted with 2 × 10 mL of CH2Cl2. The
combined organic phases were dried over MgSO4, filtered
through silica gel, and rota-evaporated. Purification of the
crude product by radial chromatography (EtOAc/hexane 1:9,
2:8, two runs) and preparative HPLC (MeOH/H2O 6:4, tR 16.0
min) afforded 612 mg (95%) of 13 as a colorless, solid foam:
1H-NMR (300 MHz, CDCl3) δ 2.90 (s, 3H), 3.13 (s, 3H), 4.02
(dd, J ) 10.7, 3.3 Hz, 1H), 4.13 (dd, J ) 10.7, 4.7 Hz, 1H),
5.12 (d, J ) 7.0 Hz, 1H), 5.27 (pseudo dd, J ≈ 8, 5 Hz, 1H),
5.36 (dd, J ) 7.4, 4.8 Hz, 1H), 7.31 (d, J ) 7.7 Hz, 1H), 7.38-
7.61 (m, 6H), 7.74-7.77 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ
38.1 (q), 38.6 (q), 71.2 (t), 76.8 (d), 80.7 (d), 82.0 (d), 128.1 (d),
128.2 (d), 128.5 (d), 128.8 (d), 130.1 (d), 130.2 (d), 133.5 (d),
136.6 (s), 137.1 (s), 137.6 (s), 198.0 (s); IR (KBr, pellet) 3059,
2983, 1663, 1596, 1449, 1363, 1178, 935, 766, 704 cm-1; MS
(CI) m/ z 441 ((M + H)+), 345, 249; TLC (Et2O/hexane 2:1) Rf
0.15; mp 55-62 °C; [R]20 +1.5°, [R]20 +0.7°, [R]20 -2.6°,
D
578
546
[R]20 -58.3° (c 1.22, CHCl3). Anal. Calcd for C19H20O8S2:
436
C, 51.81; H, 4.58; S, 14.56. Found: C, 52.00; H, 4.57; S, 14.47.
[2R-(2r,3â,4â)]-P h en yl[2-(tetr ah ydr o-3-h ydr oxy-4-m eth -
oxy-2-fu r an yl)ph en yl]m eth an on e (14) an d [2R-(2r,3â,4â)]-
P h en yl[2-(t et r a h yd r o-4-h yd r oxy-3-m et h oxy-2-fu r a n yl)-
p h en yl]m eth a n on e (15). Under argon, a solution of 50 mg
(176 µmol) of 5 in 0.35 mL of anhydrous CH2Cl2 was added to
a suspension of 45 mg (211 µmol) of 1,8-bis(dimethylamino)-
(29) (a) Sheldrick, G. M. SHELX93, Universita¨t Go¨ttingen, 1993.
(b) Sheldrick, G. M. SHELXTL PLUS, Universita¨t Go¨ttingen, 1988.
(c) International Tables for X-ray Crystallography; Kynoch-Press:
Birmingham, 1974; Vol. 4.
(30) The author has deposited atomic coordinates for 8 with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Synthesis of Substituted Nucleoside Derivatives
J . Org. Chem., Vol. 62, No. 2, 1997 309
naphthalene and 26 mg (176 µmol) of trimethyloxonium
tetrafluoroborate in 0.2 mL of anhydrous CH2Cl2 at room
temperature. The mixture was stirred for 7 d at room
temperature, and 1.5 mL of CH2Cl2 and 1.5 mL of water were
added. The layers were separated, and the aqueous layer was
extracted with 2 × 0.7 mL of CH2Cl2. The combined organic
phases were washed with 2 × 1.0 mL of 5% K2CO3 and 1.0
mL of water, dried over MgSO4, filtered through silica gel, and
rota-evaporated. Purification of the crude product (74 mg) by
radial chromatography (gradient: EtOAc/hexane 1:9, 2:8, 3:7,
6:4) afforded a mixture of the two isomers: 5.2 mg (10%) 14
and 9.7 mg (19%) 15 (determined by NMR). The isomers 14
and 15 were separated by preparative HPLC (MeCN/H2O 4:6).
14: 1H-NMR (300 MHz, DMSO-d6) δ 3.30 (s, 3H), 3.57 (dd,
J ) 9.6, 2.3 Hz, 1H), 3.63 (dd, J ) 9.6, 3.7 Hz, 1H), 3.69 (ddd,
J ) 4.4, 3.7, 2.3 Hz, 1H), 4.05 (ddd, J ) 7.9, 7.4, 4.4 Hz, 1H),
4.67 (d, J ) 7.9 Hz, 1H), 5.08 (d, J ) 7.4 Hz, 1H, exchangeable
with D2O), 7.21 (d, J ) 7.4 Hz, 1H), 7.35-7.40 (m, 1H), 7.46-
7.52 (m, 4H), 7.60-7.67 (m, 3H); TLC (EtOAc/hexane 8:2) Rf
0.53; preparative HPLC tR 19.4 min.
hexane 2:1) afforded (1) 30 mg pure 13 as a colorless, viscous
oil; (2) 51 mg of a mixture of 13, 16, and 17 (13:16:17 1.0:6.1:
1.6, determined by NMR) as a colorless, viscous oil, and (3) 16
mg of a mixture of 16 and 17 (16:17 1.0:1.2, determined by
NMR) as a colorless oil (yields: 13, 24%, 16, 33%, 17, 14%).
The isomers 16 and 17 were separated by preparative HPLC
(MeCN/H2O 4:6).
16: 1H-NMR (300 MHz, CDCl3) δ 3.21 (s, 3H), 4.13 (ddd, J
) 8.5, 4.4, 3.7 Hz, 1H), 4.16 (dd, J ) 11.0, 1.8 Hz, 1H), 4.43
(dd, J ) 11.0, 4.1 Hz, 1H), 4.99 (d, J ) 8.5 Hz, 1H), 5.19 (d, J
) 3.7, 1H, exchangeable with D2O), 5.26 (ddd, J ) 4.4, 4.1,
1.8 Hz, 1H), 7.33-7.41 (m, 2H), 7.44-7.49 (m, 2H), 7.57-7.65
(m, 2H), 7.71-7.80 (m, 3H); 13C-NMR (75 MHz, CDCl3) δ 39.1
(q), 71.7 (t), 76.9 (d), 80.1 (d), 81.1 (d), 126.8 (d), 127.1 (d), 128.5
(d), 130.0 (d), 131.0 (d), 132.0 (d), 133.8 (d), 137.0 (s), 137.2
(s), 140.4 (s), 198.8 (s); TLC (Et2O/hexane 2:1) Rf 0.10;
analytical HPLC (MeCN/H2O 4:6) tR 17.7 min.
17: 1H-NMR (300 MHz, CDCl3) δ 2.97 (s, 3H), 3.79 (dd, J
) 9.6, 4.4 Hz, 1H), 4.10 (dd, J ) 9.6, 5.1 Hz, 1H), 4.55 (pseudo
dd, J ) 4.8, 4.4 Hz, 1H), 5.08 (dd, J ) 6.2, 4.8 Hz, 1H), 5.16
(d, J ) 6.2 Hz, 1H), 7.29-7.60 (m, 7H), 7.74-7.77 (m, 2H);
13C-NMR (75 MHz, CDCl3) δ 38.1 (q), 70.2 (t), 72.5 (d), 80.2
(d), 85.4 (d), 127.6 (d), 127.8 (d), 128.5 (d), 128.7 (d), 130.1 (d),
130.3 (d), 133.3 (d), 137.3 (s), 137.6 (s), 137.8 (s), 197.7 (s);
TLC (Et2O/hexane 2:1) Rf 0.10; analytical HPLC (MeCN/H2O
4:6) tR 15.7 min.
15: 1H-NMR (300 MHz, DMSO-d6) δ 3.15 (s, 3H), 3.52 (dd,
J ) 9.6, 2.2 Hz, 1H), 3.61 (dd, J ) 7.9, 4.3 Hz, 1H), 3.77 (dd,
J ) 9.6, 4.1 Hz, 1H), 4.22 (dddd, J ) 4.4, 4.3, 4.1, 2.2 Hz, 1H),
4.81 (d, J ) 7.9 Hz, 1H), 4.90 (d, J ) 4.4 Hz, 1H, exchangeable
with D2O), 7.20-7.23 (m, 1H), 7.36-7.42 (m, 1H), 7.47-7.54
(m, 4H), 7.60-7.69 (m, 3H); TLC (EtOAc/hexane 8:2) Rf 0.53;
preparative HPLC tR 17.3 min.
[2R -(2r,3â,4â)]-P h e n yl[2-[t e t r a h yd r o-3-h yd r oxy-4-
[(m eth ylsu lfon yl)oxy]-2-fu r a n yl]p h en yl]m eth a n on e (16)
a n d [2R-(2r,3â,4â)]-P h en yl[2-[t et r a h yd r o-4-h yd r oxy-3-
[(m eth ylsu lfon yl)oxy]-2-fu r a n yl]p h en yl]m eth a n on e (17).
To a solution of 100 mg (352 µmol) of 5 and 73 µL (528 µmol)
of Et3N in 2 mL of anhydrous CH2Cl2 were added 30 µL (387
µmol) of MsCl at -40 °C under argon. After the solution was
stirred for 2 h at -40 °C and 45 h at room temperature, 10
mL of CH2Cl2 and 20 mL of saturated aqueous NaHCO3 were
added. The layers were separated, and the aqueous layer was
extracted with 2 × 10 mL of CH2Cl2. The combined organic
phases were dried over MgSO4 and rota-evaporated. Purifica-
tion of the crude product by flash chromatography (Et2O/
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (priority program:
“Novel reactions and mechanisms of catalysis in anaero-
bic microorganisms” Grant Nos. Be-998/4-1,2) and by
the Fonds der Chemischen Industrie. T.E.L. thanks the
Fonds der Chemischen Industrie for a Kekule´ fellow-
ship. The authors thank Dr. B. Schiemenz and Prof.
Dr. G. Huttner, Anorganisch-Chemisches Institut der
Universita¨t Heidelberg, for poviding the X-ray struc-
tural analysis of the silyl ether 8.
J O961372M