C4'-spiroalkylated nucleosides having sulfur incorporated at the apex position.

Article abstract of DOI:10.1021/jo030196w

Methodology based on the concept of thionium ion-initiated pinacolic ring expansion has been developed for accessing C4'-spirocyclic thionucleosides. The readily available racemic ketones 6 and 37 are conveniently resolved via their acetals with (R)-mandelic acid. Subsequent reactions beginning with utilization of the Pummerer rearrangement lend themselves to functionalization of the spirocyclic core and ultimately incorporation of the nucleosidic bases. Limitations to this strategy are pointed out. Acquisition of the alpha- and beta-isomers at C4' is equally facile. Absolute configurational assignments have been made possible by X-ray crystallography.

Full text of DOI:10.1021/jo030196w

C4′-Sp ir oa lk yla ted Nu cleosid es Ha vin g Su lfu r In cor p or a ted a t th e
Ap ex P osition
Leo A. Paquette,* Fabrizio Fabris, Fabrice Gallou, and Shuzhi Dong
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received J une 16, 2003
Methodology based on the concept of thionium ion-initiated pinacolic ring expansion has been
developed for accessing C4′-spirocyclic thionucleosides. The readily available racemic ketones 6
and 37 are conveniently resolved via their acetals with (R)-mandelic acid. Subsequent reactions
beginning with utilization of the Pummerer rearrangement lend themselves to functionalization
of the spirocyclic core and ultimately incorporation of the nucleosidic bases. Limitations to this
strategy are pointed out. Acquisition of the R- and â-isomers at C4′ is equally facile. Absolute
configurational assignments have been made possible by X-ray crystallography.
Since the earliest pioneering reports of the successful
synthesis of thionucleosides,1 it has come to be recognized
that hetero substitution of the furanose ring in this
fashion can have a profound effect on biological activity.
The rapidity with which 2′,3′-dideoxy-3′-thiacytidine was
adopted for clinical use in the treatment of AIDS,2 and
the high-level antiviral and anticancer potency of several
sulfur mimics having the heteroatom at the apex posi-
tion3,4 has ignited research in this area from several
directions. Included among the many modifications are
the original 4′-thionucleosides, thiatenose derivatives
exemplified by 1,5 1,3-oxathiolane analogues of type 2,6
as well as networks such as 3 that incorporate two sulfur
atoms.7 The heightened activity of L-3-TC and L-5-F-ddC
against HIV RT8 has likewise called attention to exciting
prospects in the enantiomeric L-series (e.g., 4).9 A notable
feature of this family of biosteres is their reduced toxicity
nonan-6-ones,11,12 the ready availability of 6 in this
manner was expected to open the door to a wide variety
of sulfur-containing spirocyclic nucleosides. Herein, we
detail our initial efforts that have culminated in the
production of several unique, conformationally restricted
nucleosides of the D enantiomeric series.
and improved therapeutic index relative to their D-forms.
Several years ago, we reported the ready conversion
of 2,3-dihydrothiophene (5) into 6 in a two-step overall
yield of 62-93%.10 In parallel with the 1-oxaspiro[4.4]-
(1) For example: (a) Secrist, J . A., III; Tiwari, K. N.; Riordan, J .
M.; Montgomery, J . A. J . Med. Chem. 1991, 34, 2361. (b) Dyson, M.
R.; Coe, P. L.; Walker, R. T. J . Med. Chem. 1991, 34, 2782. (c) Ewing,
D. F.; Mackenzie, G. Nucleosides Nucleotides 1996, 15, 809. (d) Van
Draanen, N. A.; Freeman, G. A.; Short, S. A.; Harvey, R.; J ansen, R.;
Szczech, G.; Koszalka, G. W. J . Med. Chem. 1996, 39, 538. (e) Rahim,
S. G.; Trivedi, N.; Bogunovic-Batchelor, M. V.; Hardy, G. W.; Mills,
G.; Selway, J . W. T.; Snowden, W.; Littler, E.; Coe, P. L.; Basnak, I.;
Whale, R. F.; Walker, R. T. J . Med. Chem. 1996, 39, 789. (f) Review:
Yokoyama, M. Synthesis 2000, 1637.
(2) Chao, Q.; Nair, V. Tetrahedron 1997, 53, 1957 and relevant
references therein.
(3) (a) Dyson, M. R.; Coe, P. L.; Walker, R. T. J . Chem. Soc., Chem.
Resu lts a n d Discu ssion
Commun. 1991, 741. (b) Tiwari, K. N.; Secrist, J . A., III; Montgomery,
J . A. Nucleosides Nucleotides 1994, 13, 1819. (c) Young, R. J .; Shaw-
by the absolute stereochemistry of the projected end
Ponter, S.; Thomson, J . B.; Miller, J . A.; Cumming, J . G.; Pugh, A. W.;
Resolu tion of Sp ir ok eton e 6. The critical role played
products demanded, of course, that proper attention be
accorded early to the resolution of 6 and the associated
definitive assignment of configuration to its antipodes.
The point of departure involved coupling of the enan-
tiopure lithiated N,S-dimethyl-(S)-(+)-phenylsulfoximine
713 to racemic 6 at low temperature14 (Scheme 1). This
choice of chiral auxiliary led to the formation of a 3:1:1
Rider, P. Bioorg. Med. Chem. Lett. 1995, 5, 2599.
(4) (a) Yoshimura, Y.; Watanabe, M.; Satoh, H.; Ashida, N.; Ijichi,
K.; Sakata, S.; Machida, H.; Matsuda, A. J . Med. Chem. 1997, 40, 2177
(b) Satoh, H.; Yoshimura, Y.; Watanabe, M.; Ashida, N.; Ijichi, K.;
Sakata, S.; Machida, H.; Matsuda, A. Nucleosides Nucleotides 1998,
17, 65.
(5) (a) Nishizono, N.; Koike, N.; Yamagata, Y.; Fujii, S.; Matsuda,
A. Tetrahedron Lett. 1996, 37, 7569. (b) Ichikawa, E.; Yamamura, S.;
Kato, K. Tetrahedron Lett. 1999, 40, 7385.
10.1021/jo030196w CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003
J . Org. Chem. 2003, 68, 8625-8634
8625

Paquette et al.
SCHEME 1
SCHEME 2
The three-dimensional stereostructure of 8 was de-
duced by single-crystal X-ray analysis (Figure 1, Sup-
porting Information), thereby confirming the expectation
that the absolute configurations and optical rotations of
(+)-6 and (-)-6 would parallel those established for their
oxygen counterparts.11 These structural elucidations also
reveal that 6 displays a kinetic preference for nucleophilic
attack anti to the sulfur atom in conformance to the
established pattern.15
The wide variability in yield with which 8-10 could
be generated on a useful scale prompted consideration
of an alternative resolution strategy. Once again, re-
course to acetalization with (R)-(-)-mandelic acid (11)
under catalysis by scandium triflate was found to be
particularly advantageous (Scheme 2).11,16 Significantly,
two of the four possible dioxolanones were formed in large
excess and chromatographically separated without com-
plication. At this point, the considerable difference in
polarity of these compounds was made yet more appar-
ent. Thus, 12 was readily recrystallized from hexanes,
whereas for 13 methanol was the solvent of choice.
Acetals 12 and 13 are characterized by the presence
of three stereogenic centers. The configuration of the
benzylic carbon is defined by the specific enantiomer of
mandelic acid in use. The absolute stereochemistry of the
spirocyclic carbon in 13 was elucidated following its
alkaline hydrolysis to give (+)-6. An X-ray determination
(Figure 2, Supporting Information) established that the
sterically demanding phenyl group occupies the exo
position with R-orientation of the lactonic oxygen. The
benzylic proton is consequently projected above the
carbocyclic chain of the tetrahydrothiophene ring and
exhibits an upfield chemical shift (δ 5.68 in CDCl3). For
12, the same proton is necessarily projected into the
deshielding region induced by the sulfur atom and
consequently appears at lower field (δ 5.84 in CDCl3).
mixture of diastereomers in a maximized 62% combined
yield at 68% conversion. More advanced consumption of
the spiro ketone appeared to be thwarted by competitive
enolization, although the co-addition of cerium trichloride
was to no avail. The three crystalline adducts 8, 9, and
10 proved amenable to chromatographic separation, thus
allowing for individual thermal fragmentation to be
performed. Heating a neat sample of 8 under vacuum at
150 °C in a Kugelrohr apparatus resulted in the isolation
of (-)-6 in 90% yield alongside recovered sulfoximine.
Comparable treatment of 9 and 10 gave rise to (+)-6
somewhat less efficiently although reproducibly (71% and
68%, respectively).
(6) (a) Beach, J . W.; J eong, L. S.; Alves, A. J .; Pohl, D.; Kim, H. O.;
Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K.
J . Org Chem. 1992, 57, 2217. (b) J eong, L. S.; Schinazi, R. F.; Beach,
J . W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A. J .;
McMillan, A.; Chu, C. K.; Mathis, R. J . Med. Chem. 1993, 36, 181. (c)
J eong, L. S.; Schinazi, R. F.; Beach, J . W.; Kim, H. O.; Shanmuga-
nathan, K.; Nampalli, S.; Chun, M. W.; Chung, W. K.; Choi, B. G.;
Chu, C. K. J . Med. Chem. 1993, 36, 2627. (d) J in, H.; Siddiqui, M. A.;
Evans, C. A.; Tse, H. L. A.; Mansour, T. S.; Goodyear, M. D.;
Ravenscroft, P.; Beels, C. D. J . Org. Chem. 1995, 60, 2621. (e) Brånalt,
J .; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J . Org. Chem. 1996,
61, 3604.
(7) (a) Brånalt, J .; Kvarnstro¨m, I.; Classon, B.; Samuelson, B. J . Org.
Chem. 1996, 61, 3611. (b) Nguyen-Ba, N.; Brown, W. L.; Chan, L.; Lee,
N.; Brasili, L.; Lafleur, D.; Zacharie, B. Chem. Commun. 1999, 1245.
(8) (a) Chang, C.-N.; Doong, S.-L.; Zhou, J . H.; Beach, J . W.; J eong,
L. S.; Chu, C. K.; Tsai, C.-h.; Cheng, Y.-c. J . Biol. Chem. 1992, 267,
13938. (b) Chang, C.-N.; Skalski, V.; Zhou, J . H.; Cheng, Y-.c. J . Biol.
Chem 1992, 267, 22414. (c) Coates, J . A. V.; Cammack, N.; J enkinson,
H. J .; Mutton, I. M.; Pearson, B. A.; Storer, R.; Cameron, J . M.; Penn,
C. R. Antimicrob. Agents Chemother. 1992, 36, 202. (d) Schinazi, R.
F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.; J eong,
L.-S.; Beach, J . W.; Choi, W.-B.; Yeola, S.; Liotta, D. C. Antimicrob.
Agents Chemother. 1992, 36, 672. (e) Hoong, L. K.; Strange, L. E.;
Liotta, D. C.; Koszalka, G. W.; Burns, C. L.; Schinazi, R. F. J . Org.
Chem. 1992, 57, 5563. (f) Furman, P. A.; Davis, M.; Liotta, D. C.; Paff,
M.; Frick, L. W.; Nelson, D. J .; Dornsife, R. E.; Wurster, J . A.; Wilson,
L. J .; Fyfe, J . A.; Tuttle, J . V.; Miller, W. H.; Condreay, L.; Averett, D.
R.; Schinazi, R.. F.; Painter, G. R. Antimicrob. Agents Chemother. 1992,
36, 2686. (g) Mansuri, M. M.; Farina, V.; Starrett, J . E., J r.; Benigni,
D. A.; Brankovan, V.; Martin, J . C. Bioorg. Med. Chem. Lett. 1991, 1,
65. (h) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Pai, S. B.; Dutschman, G. E.;
Cheng, Y.-C. J . Med. Chem. 1994, 37, 798. (i) Gosselin, G.; Schinazi,
R. F.; Sommadossi, J .-P.; Mathe´, C.; Bergogne, M.-C.; Aubertin, A.-
M.; Kirn, A.; Imbach, J .-L. Antimicrob. Agents Chemother. 1994, 38,
1292.
(9) J ung, M. E.; Kretschik, O. J . Org. Chem. 1998, 63, 2975.
(10) Paquette, L. A.; Dullweber, U.; Branan, B. M. Heterocycles 1994,
37, 187.
(11) Paquette, L. A.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K.;
Kahane, A. L.; Lanter, J . C.; Corral, M. A. J . Org. Chem. 2001, 66,
2828.
(12) (a) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A.
L. Org. Lett. 2001, 3, 4039. (b) Paquette, L. A.; Owen, D. R.; Bibart, R.
T.; Seekamp, C. K. Org. Lett. 2001, 3, 4043. (c) Paquette, L. A.;
Seekamp, C. K.; Kahane, A. L. submitted for publication.
(13) (a) J ohnson, C. R. Aldrichim. Acta 1985, 18, 3. (b) J ohnson, C.
R.; Zeller, J . R. J . Am. Chem. Soc. 1982, 104, 4021.
(14) For a preliminary report of the sulfoximine results, consult:
Paquette, L. A.; Lanter, J . C.; Owen, D. R.; Fabris, F.; Bibart, R. T.;
Alvarez, M. Heterocycles 2001, 54, 49.
(15) Dimitroff, M.; Fallis, A. G. Tetrahedron Lett. 1998, 39, 2527.
(16) Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett
1996, 839.
8626 J . Org. Chem., Vol. 68, No. 22, 2003

C4′-Spiroalkylated Nucleosides
SCHEME 3
SCHEME 4
SCHEME 5
F u n ction a liza tion of th e Sp ir ocyclic Cor e. Reduc-
tion of dextrorotatory 6 of 100% ee with lithium alumi-
num hydride in ether at 20 °C was met with the
formation of alcohols 14 and 15 in significantly less
stereoselective fashion than previously reported15 (Scheme
3). The observed 2:3 partitioning was in fact welcomed
since our goal was to access both diastereomeric series.
In addition, 14 and 15 differ sufficiently in polarity that
their chromatographic separation is routine. The subse-
quent formation of the tert-butyldimethylsilyl ethers 16
and 17 provided substrates ideally suited to examination
of the sulfoxidation reaction.
Quite unexpectedly, both tetrahydrothiophenes proved
to be unreactive toward m-chloroperbenzoic acid in CH2-
Cl2 at room temperature even when three equivalents of
the oxidant was present.17 Sodium periodate in aqueous
methanol, a reagent recognized to give very good selectiv-
ity in this type of oxidation,18 proved reasonably effective
only in the â series. Where (+)-16 is concerned, sulfoxide
18 was formed in 86% yield as a 6:1 mixture of isomers
alongside 8% of the sulfone. The sluggishness of (-)-17
under these circumstances can be attributed to the
consequences of steric shielding. In light of this ensemble
of facts, we were delighted to find that sodium periodate
supported on silica gel19a was notably effective in oxidiz-
ing both (+)-16 and (-)-17 to 18 and 19, respectively, at
the 10% level of loading.20 Longer reaction times were
required for the R-siloxy isomer, a kinetic feature that
was accompanied by an increase in stereoselectivity from
4:1 to 9:1. The use of ammonium molybdate19b provided
yet another convenient way to oxidize these sulfides
selectively to the sulfoxides (diastereomer ratios of 3:2)
without evidence of sulfone production.
acetate for the purpose of generating their R-acetoxy
sulfides by Pummerer rearrangement.21 In both in-
stances, TLC analysis of the unpurified reaction mixtures
showed the presence of several compounds, the separa-
tion of which proved difficult. At this point it was
observed that standing solutions of these mixtures in
CHCl3 underwent convergence largely to two end-
products after several hours. These findings prompted
the implementation of a second-stage protocol that
involved heating in benzene containing p-toluenesulfonic
acid in the presence of 4 Å molecular sieves.22 These
The diastereomeric mixtures represented by 18 and 19
were heated in acetic anhydride containing sodium
(17) (a) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J . Am. Chem. Soc.
1976, 98, 4887. (b) Madesclaire, M. Tetrahedron 1986, 42, 5459.
(18) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.
(19) (a) Gupta, D. N.; Hodge, P.; Davies, J . E. J . Chem. Soc., Perkin
Trans. 1 1981, 2970. (b) Bellingham, R.; J arowicki, K.; Kocienski, P.;
Martin, V. Synthesis 1996, 285.
(20) For these experiments, the solid reagents were not completely
dried because total dryness gave evidence of prolonging reaction times
and lowering reaction efficiency. This phenomenon has been seen in
other contexts: Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; LeGoffic,
F. Synthesis 1989, 64.
(21) De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157.
J . Org. Chem, Vol. 68, No. 22, 2003 8627

Paquette et al.
SCHEME 6
SCHEME 7
conditions were met with generation of the elimination
products (+)-20 and (+)-22 alongside acetates (+)-21 and
(-)-23. Each was formed in a yield approximating 30%
(Scheme 4). The stereochemical features of the acetates
were elucidated by NOE measurements. The rate of
rearrangement of 19 was noted to be somewhat slower
than that of 18.
The availability of (+)-20 and (+)-22 led us to explore
more advanced tetrahydrothiophene ring functionaliza-
tion from this direction. Although (+)-20 proved unre-
active to 9-BBN and catecholborane, hydroboration did
occur in the presence of the borane‚THF complex. Al-
though high regioselectivity could be realized in this
manner, alcohol 24 was produced in a 3:2 diastereomeric
ratio (Scheme 5). The less sterically congested nature of
(+)-22 proved sufficient to allow reaction with 9-BBN to
materialize. This more bulky reagent furnished 29 as a
9:1 mixture of epimers. In both cases, separation could
be best implemented following conversion to the ben-
zoates. Sulfoxidation as illustrated by the transformation
of 25 into 26 and 27 also proved beneficial in this
direction.
Sulfides (+)-20 and (+)-22 were also converted to their
sulfoxide isomer pairs 28 and 31, respectively, for the
purpose of assessing whether their double bond could be
migrated into the â,γ-environment.23,24 This goal was
never realized. Nor was allylic oxidation with reagents
such as selenium dioxide found to deliver characterizable
products. When Pummerer conditions were revisited, its
uncommon additive variant25,26 was found to operate
exclusively with formation of 32 and 33.27
chemoselective oxidation of 36 at selenium with concomi-
tant elimination was best effected under basic conditions
at high dilution.28
Spiroketone (()-37 was resolved by ketalization with
(R)-mandelic acid in the manner developed earlier. In the
present instance, all four possible dioxolanones were
found, with (-)-38 and (-)-39 predominating. Although
chromatographic separation of these diastereomers was
somewhat more involved (the two minor products (-)-
40 and (-)-41 were isolated by MPLC), the desired (-)-
39 was readily recrystallized from hot methanol. The
assignment of absolute configuration in all four diaster-
eomers was then achieved by the controlled catalytic
hydrogenation29 of (-)-38 and (-)-39 to (-)-12 and (+)-
13, respectively, alongside the four companion hydrolyses
summarized in Scheme 7.
Did eoxysp ir oth ion u cleosid e Syn th esis. The ready
availability of 18 and 19 led to their selection as ap-
(23) (a) O’Connor, D. E.; Broaddus, C. D. J . Am. Chem. Soc. 1964,
86, 2267. (b) Kimmelma, R. Acta Chem. Scand. 1993, 47, 706. (c)
O’Connor, D. E.; Lyness, W. I. J . Am. Chem. Soc. 1964, 86, 3840.
(24) (a) Guittet, E.; J ulia, S. Synth. Commun. 1981, 11, 709. (b)
Crumbie, R. L.; Ridley, D. D.; Steel, P. J . Aust. J . Chem. 1985, 38,
119. (c) Hoffmann, R. W.; Goldmann, S.; Maak, N.; Gerlach, R.; Frickel,
F.; Steinbach, G. Chem. Ber. 1980, 113, 819.
(25) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993, 48,
11263.
(26) Yamagiwa, S.; Sato, H.; Hoshi, N.; Kosugi, H.; Uda, H. J . Chem.
Soc., Perkin Trans. 1 1979, 570.
An effective means for arriving at this desired struc-
tural motif involved phenylselenenyl chloride-initiated
ring expansion/rearrangement of carbinol 34 (Scheme 6).
When performed in the presence of a large excess of
propylene oxide as acid scavenger, the conversion to
racemic 36 proceeded cleanly and in a highly selective
manner, presumably via the selenonium ion 35. The
(27) Fabris, F. Unpublished findings.
(28) Houllemare, D.; Ponthieux, S.; Outurquin, F.; Paulmier, C.
Synthesis 1997, 101.
(29) Mozingo, R.; Harris, S. A.; Wolf, D. E.; Hoffhine, C. E., J r.;
Easton, N. R.; Folkers, K. J . Am. Chem. Soc. 1945, 67, 2092.
(22) Calinaud, P.; Gelas, J . Can. J . Chem. 1983, 61, 2103.
8628 J . Org. Chem., Vol. 68, No. 22, 2003

C4′-Spiroalkylated Nucleosides
SCHEME 8
use of the protected derivative 44. In our hands, this
protocol was found to deliver (+)-45 in modest yield
alongside its epimer and other unidentified byproducts.
However, the ease with which (+)-45 could be purified
chromatographically made feasible its conversion to the
target (+)-46 under standard conditions.33
These accomplishments were matched in the stereo-
isomeric series defined by an R-hydroxyl on the cyclo-
pentane ring. Sulfoxide 19 proved to be an equally
serviceable precursor to 47-49 under closely comparable
experimental conditions. In the examples defined by this
subset of dideoxynucleosides, the glycosylations pro-
ceeded smoothly to give anomeric mixtures, the separa-
tion of which was accomplished after desilylation (or
deacyclation in the case of (-)-49). As before, the stere-
ochemical assignments are founded on NOE measure-
ments, in particular those shown on the structural
formulas.
propriate precursors to the dideoxyspirothio-nucleosides
of interest. This conclusion was reinforced when, in an
attempt to gain a stereoselective advantage and capital-
ize on the stereochemical configuration already defined
at C-1, (+)-21 was reacted directly with thymine in the
presence of hexamethyldisilazane and chlorotrimethyl-
silane.1a,30 Complex mixtures resulted. Instead, glycosy-
lation reactions were performed on 18 and 19 by means
of silylated bases (generated in situ) and trimethylsilyl
triflate, with zinc(II) iodide in catalytic quantities serving
as the promoter.31,32 Of the five examples studied, gua-
nine proved to be the only base that did not result in the
formation of dideoxynucleoside epimers (Scheme 8).
In light of the anticipated difficult separation of the
resulting pairs of anomers, the silyl groups were removed
with TBAF. With the â-hydroxyl group now unmasked,
it proved possible to isolate 42 and 43 in pure form and
to identify them on the strength of NOE studies. For the
cytosine and adenine examples, separation of the ano-
mers was yet not achieved.
The possible synthesis of unsaturated spirocyclic thio-
nucleosides was also briefly explored. As a consequence
of difficulties experienced with potential precursors 20,
22, 28, and 31, attention was turned to the possibilities
recognized to be offered by organoselenium chemistry.
This option held out the prospect of introducing the
double bond at a late stage, while simultaneously provid-
ing desirable stereoselectivity during incorporation of the
nucleobases.34 To this end, the Pummerer product (-)-
23 was saponified with lithium hydroxide and subse-
quently subjected to Swern oxidation under high dilution
conditions. This protocol led with good efficiency to 51
via 50 (Scheme 9).
Conversion of 51 to the O-silylated thioketene acetal
set the stage for R-phenylselenenylation as in 52. Al-
though a modest 3:1 level of diastereocontrol resulted, it
was an easy matter to separate the major R-isomer
cleanly by column chromatography. The ensuing tandem
Dibal-H reduction/acetylation of 52 gave rise to 53
without complication. Despite existing precedence,34 at-
tempts to engage 53 in various Vorbru¨ggen coupling
reactions35 involving silylated uracil and thymine proved
unrewarding. Facile cleavage of the OTBS group was
The difficulty experienced with the glycosylation of
guanine was considered to stem from its well recognized
proclivity for the competitive generation of N7 and N9
products. A solution to this problem, which has been
developed largely by Robins and co-workers,33 involves
(33) (a) Zou, R.; Robins, M. J . Can. J . Chem. 1987, 65, 1436. (b)
Robins, M. J .; Zou, R.; Hanske, F.; Madej, D.; Tyrrell, D. L. J .
Nucleosides Nucleotides 1989, 8, 725. (c) Robins, M. J .; Zou, R.; Guo,
Z.; Wnuk, S. F.; J . Org. Chem. 1996, 61, 9207.
(30) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.
(31) O’Neil, I. A.; Hamilton, K. M. Synlett 1992, 791.
(32) Ichikawa, E.; Yamamura, S.; Kato, K. Tetrahedron Lett. 1999,
40, 7385.
(34) J eong, L. S.; Kim, H. O.; Moon, H. R.; Hong, J . H.; Yoo, S. Y.;
Choi, W. J .; Chun, M. W.; Lee, C. K. J . Med. Chem. 2001, 44, 806.
(35) Vorbru¨ggen, H.; Ruh-Pohlenz, C. Org. React. 2000, 55, 1-630.
J . Org. Chem, Vol. 68, No. 22, 2003 8629

Paquette et al.
This diastereomer was subjected to X-ray crystallographic
analysis (Figure 1).
SCHEME 9
10: colorless crystals (from CH2Cl2/hexanes); mp 151-154
1
°C (250 mg, 12%); IR (film, cm-1) 3420, 1260; H NMR (300
MHz, CDCl3) δ 7.94-7.87 (m, 2 H), 7.68-7.54 (m, 3 H), 5.98
(br s, 1 H), 3.84 (d, J ) 14.1 Hz, 1 H), 3.30 (d, J ) 14.1 Hz, 1
H), 2.88-2.78 (m, 1 H), 2.76-2.66 (m, 1 H), 2.75 (s, 3 H), 2.32-
2.19 (m, 1 H), 2.12-1.89 (m, 3 H), 1.88-1.72 (m, 2 H), 1.60-
1.36 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 139.1, 133.1, 129.4,
129.3, 80.5, 72.3, 61.2, 39.3, 37.3, 35.8, 31.9, 30.7, 29.2, 19.5;
EI MS m/z (M+) calcd 325.1170, obsd 325.1192; [R]22 -23.6
D
(c 1.3, acetone).
Anal. Calcd for C16H23NO2S2: C, 59.04; H, 7.12. Found: C,
59.14; H, 7.12.
Th er m olysis of 8. A crystalline sample of 8 (930 mg, 2.86
mmol) was placed in a Kugelrohr apparatus, evacuated to 0.05
Torr, and heated to 150 °C where melting occurred. The
distillate accumulated in the collector bulb, which was cooled
in dry ice. Final purification of the spiroketone was ac-
complished by filtration through a pad of silica gel and elution
particularly vexatious. Recourse to less frangible alcohol-
protecting substituents might well rectify this matter, but
has not been investigated at this time.
In conclusion, we have developed a convenient strategy
for the synthesis of C4′-spiroalkylated thionucleosides.
Racemic universal precursors have been resolved and the
absolute configuration of their antipodal forms rigorously
established by crystallographic means. The corresponding
R- and â-carbinols are easily generated and separated,
thus demonstrating the feasibility of developing both
stereoisomeric series. This work represents the first
synthesis of these novel ribonucleoside analogues and
could ultimately serve to expand the repertoire of modi-
fied nucleic acids for use as biochemical probes.
with ether/CH2Cl2; colorless oil (400 mg, 95%); [R]22 -107.9
D
(c 1.5, acetone). Further elution with methanol returned 460
mg (95%) of the sulfoximine.
Comparable handling of 9 and 10 gave the dextrorotatory
enantiomer of 6 in yields of 71% and 68%, respectively; [R]22
+105 (c 1.5, acetone).
D
F or m a tion of Ma n d ela te Aceta ls 12 a n d 13. A solution
of (()-6 (20.0 g, 126 mmol), (R)-mandelic acid (24.0 g, 158
mmol), and scandium triflate (1.94 g, 3.94 mmol) in CH2Cl2
(500 mL) and acetonitrile (75 mL) was refluxed for 48 h in a
Soxhlet apparatus filled with 4 Å molecular sieves. Additional
(R)-mandelic acid (2.40 g, 15.8 mmol) and scandium triflate
(1.30 g, 2.64 mmol) were introduced, and heating was contin-
ued for another 24 h. The cooled, dark reaction mixture was
poured into saturated NaHCO3 solution (400 mL) and ex-
tracted with CH2Cl2. The combined extracts were washed with
water, dried, and concentrated to leave an oil that was
chromatographed on silica gel. Elution with 1:1 CH2Cl2/
hexanes led to the isolation of two diastereomers in the
following order:
Exp er im en ta l Section
Gen er a l In for m a tion . Consult ref 11.
Su lfoxim in e Resolu tion of 6. A solution of N,S-dimethyl-
(S)-(+)-phenylsulfoximine (1.19 g, 7.00 mmol) in dry THF (15
mL) was cooled to 0 °C under N2 and treated with a solution
of n-butyllithum in pentane (6.0 mL of 1.9 M, 7.7 mmol),
stirred for 20 min at this temperature, cooled to -78 °C, and
transferred via cannula to a solution of (()-6 (1.0 g, 6.4 mmol)
in dry THF (7 mL) at -78 °C. After 2 h, saturated NH4Cl
solution was introduced and the mixture was allowed to warm
to 20 °C prior to extraction with ether. The combined organic
layers were dried, and the volatile materials were removed to
afford an oil that was subjected to flash chromatography on
silica gel. Elution with 20% ethyl acetate in hexanes first
returned 320 mg (68% conversion) of the sulfoximine. Three
adducts were then eluted in the following order:
12: colorless needles; mp 65-66 °C (from hexanes) (15.8 g,
43%); IR (film, cm-1) 1795; 1H NMR (300 MHz, CDCl3) δ 7.50-
7.33 (m, 5 H), 5.84 (s, 1 H), 2.93-2.83 (m, 2 H), 2.43-1.67
(series of m, 10 H); 13C NMR (75 MHz, CDCl3) δ 171.8, 135.4,
128.8, 128.7, 126.3, 118.7, 77.2, 69.4, 38.3, 38.1, 34.0, 32.6, 30.8,
17.7; EI MS m/z (M+) calcd 290.0977, obsd 290.0971; [R]22
-167.4 (c 1.7, acetone).
D
Anal. Calcd for C16H18O3S: C, 66.18; H, 6.25. Found: C,
66.26; H, 6.24.
13: colorless platelets; mp 114-117 °C (from methanol) (14.0
g, 38%); IR (film, cm-1) 1790; 1H NMR (300 MHz, CDCl3) δ
7.47-7.34 (m, 5 H), 5.68 (s, 1 H), 2.89-2.80 (m, 2 H), 2.33-
2.03 (series of m, 6 H), 2.02-1.67 (series of m, 4 H); 13C NMR
(75 MHz, CDCl3) δ 170.8, 134.7, 128.5, 128.3, 125.8, 118.9,
76.6, 67.5, 38.1, 37.7, 33.4, 32.4, 30.6, 17.4; EI MS m/z (M+)
9: colorless crystals; mp 94-96 °C (300 mg, 15%); IR (film,
1
cm-1) 3200, 1450, 1250, 1150; H NMR (300 MHz, CDCl3) δ
7.94-7.88 (m, 2 H), 7.68-7.56 (m, 3 H), 6.81 (br s, 1 H), 3.76
(d, J ) 13.6 Hz, 1 H), 3.40 (d, J ) 13.6 Hz, 1 H), 2.92-2.83
(m, 1 H), 2.79-2.69 (m, 1 H), 2.61 (s, 3 H), 2.39-2.14 (series
of m, 3 H), 2.10-1.67 (series of m, 7 H); 13C NMR (75 MHz,
CDCl3) δ 138.9, 133.1, 129.6, 129.1, 82.7, 72.5, 61.1, 39.8, 36.6,
36.5, 33.5, 30.9, 28.8, 19.7; EI MS m/z (M+) calcd 325.1170,
calcd 290.0977, obsd 290.0982; [R]22 +16.8 (c 1.4, acetone).
D
Anal. Calcd for C16H18O3S: C, 66.18; H, 6.25. Found: C,
66.13; H, 6.26.
This diastereomer was subjected to X-ray crystallographic
analysis (Figure 2).
obsd 325.1162; [R]22 -4.9 (c 1.0, acetone).
D
Anal. Calcd for C16H23NO2S2: C, 59.04; H, 7.12. Found: C,
59.18; H, 7.13.
Hyd r olysis of (+)-13. A homogeneous solution of lithium
hydroxide dihydrate (7.0 g, 167 mmol) and (+)-13 (15.8 g, 54.5
mmol) in a 2:1 mixture of THF and water (1 L) was stirred for
4 h and extracted with ether. The combined organic extracts
were washed with water, dried, and concentrated to afford 8.5
g (100%) of (+)-6 as a colorless oil; [R]22D +108.4 (c 1.4, acetone).
Hyd r id e Red u ction of (+)-6. A N2-blanketed solution of
(()-6 (8.5 g, 54.4 mmol) in dry ether (50 mL) was transferred
via cannula into a solution of lithium aluminum hydride in
ether (30 mL of 1 M, 30 mmol). The reaction mixture was
stirred for 4 h, treated slowly with 1 M hydrochloric acid (100
mL), and extracted with ether. The combined organic phases
8: colorless crystals (from ether/hexanes); mp 132-133 °C
(728 mg, 35%); IR (film, cm-1) 3200, 1450, 1250, 1150; 1H NMR
(300 MHz, CDCl3) δ 7.90-7.79 (m, 2 H), 7.69-7.57 (m, 3 H),
7.06 (br s, 1 H), 3.78 (d, J ) 13.2 Hz, 1 H), 3.00 (d, J ) 13.2
Hz, 1 H), 2.84-2.75 (m, 1 H), 2.68-2.57 (m, 1 H), 2.60 (s, 3
H), 2.55-2.45 (m, 1 H), 2.38-2.26 (m, 1 H), 2.13-1.78 (series
of m, 5 H), 1.74-1.36 (series of m, 3 H);13C NMR (75 MHz,
CDCl3) δ 138.8, 133.2, 129.6, 129.1, 82.0, 71.6, 60.1, 39.5, 37.5,
35.2, 31.6, 30.5, 28.9, 19.6; EI MS m/z (M+) calcd 325.1170,
obsd 325.1180; [R]22 +3.5 (c 1.5, acetone).
D
Anal. Calcd for C16H23NO2S2: C, 59.04; H, 7.12. Found: C,
59.27; H, 7.13.
8630 J . Org. Chem., Vol. 68, No. 22, 2003

C4′-Spiroalkylated Nucleosides
were dried and concentrated to leave an oil that was subjected
to flash chromatography on silica gel (elution with 9:1 hexanes/
ethyl acetate). There was isolated 2.96 g (34%) of (+)-14 and
4.39 g (51%) of (-)-15, both as colorless oils.
and the residue was dissolved in dry benzene (50 mL), treated
with p-toluenesulfonic acid (10 mg), and refluxed over 4 Å
molecular sieves for 12 h. After solvent evaporation, the
residue was purified by flash chromatography on silica gel
(elution with 9:1 hexanes/ether). There was isolated 100 mg
(34%) of (+)-20 and 100 mg (31%) of (+)-21.
1
(+)-14: IR (film, cm-1) 3485; H NMR (300 MHz, CDCl3) δ
3.70-3.64 (m, 1 H), 2.95-2.77 (m, 2 H), 2.37 (br s, 1 H), 2.18-
1.66 (series of m, 8 H), 1.63-1.45 (m, 2 H); 13C NMR (75 MHz,
20: colorless oil; IR (film, cm-1) 1255; H NMR (300 MHz,
1
CDCl3) δ 78.2, 70.3, 41.0, 38.0, 32.8, 32.5, 30.5, 20.5; [R]22
CDCl3) δ 6.14-6.09 (m, 1 H), 5.42-5.37 (m, 1 H), 3.95-3.90
D
-27.9 (c 1.6, acetone). The racemic form of this alcohol has
(m, 1 H), 2.50-2.33 (m, 2 H), 2.16-2.03 (m, 1 H), 1.98-1.55
been reported.15
(series of m, 5 H), 0.89 (s, 9 H), 0.10 (s, 3 H), 0.06 (s, 3 H); 13
C
1
(-)-15: IR (film, cm-1) 3445; H NMR (300 MHz, CDCl3) δ
NMR (75 MHz, CDCl3) δ 126.4, 119.5, 80.4, 70.7, 44.8, 37.3,
32.7, 25.8, 19.9, 18.1, -4.5, -4.8; EI MS m/z (M+ - CH3) calcd
4.06 (t, J ) 5.1 Hz, 1 H), 2.89-2.81 (m, 2 H), 2.17-1.93 (m, 5
255.1222, obsd 255.1239; [R]22 +31.1 (c 0.4, acetone).
H), 1.93-1.47 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 79.0, 67.2,
D
37.9, 35.2, 33.0, 31.3, 30.4, 19.8; [R]22 -76.6 (c 1.1, actone).
Anal. Calcd for C14H26OSSi: C, 62.12; H, 9.69. Found: C,
62.01; H, 9.65.
D
The racemic form of this alcohol has been reported.15
1
21: colorless oil; IR (film, cm-1) 1745, 1250; H NMR (300
Com p ou n d 16. To a cold (0 °C), nitrogen-blanketed solution
of (+)-14 (2.90 g, 18.7 mmol) and 2,6-lutidine (4.40 mL, 37.4
mmol) in dry CH2Cl2 (80 mL) was added tert-butyldimethylsilyl
triflate (6.50 mL, 28.0 mmol). The reaction mixture was
allowed to rise slowly to room temperature overnight, filtered
through a pad of silica gel (elution with CH2Cl2), and evapo-
rated to give 4.8 g (95%) of (+)-16 as a colorless oil. The
analytical sample was obtained by flash chromatography on
MHz, CDCl3) δ 5.20-5.13 (m, 1 H), 4.13-4.07 (m, 1 H), 2.96-
2.81 (m, 2 H), 2.26-1.84 (series of m, 6 H), 2.04 (s, 3 H), 1.77-
1.58 (m, 2 H), 0.90 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 170.6, 80.4, 79.0, 69.3, 33.5, 31.7,
31.1, 30.8, 28.8, 25.7, 21.1, 18.0, -4.6, -4.9; EI MS m/z (M+)
calcd 330.1685, obsd 330.1639; [R]22 +29.9 (c 1.0, acetone).
D
Anal. Calcd for C16H30O3SSi: C, 58.14; H, 9.15. Found: C,
58.43; H, 9.17.
silica gel (elution with 9:1 hexanes/CH2Cl2): IR (film, cm-1
)
1115, 1065; 1H NMR (300 MHz, CDCl3) δ 3.78-3.74 (m, 1 H),
2.89-2.72 (m, 2 H), 2.14-1.92 (m, 3 H), 1.88-1.49 (series of
m, 7 H), 0.90 (s, 9 H), 0.11 (s, 3 H), 0.06 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 81.1, 68.5, 40.3, 38.4, 33.2, 32.0, 30.3, 25.9,
20.6, 18.2, -4.4, -4.6; EI MS m/z (M+) calcd 272.1630, obsd
P u m m er er Rea r r a n gem en t of 19. Analogous processing
of 19 (310 mg, 1.08 mmol) but for 4 h gave 88 mg (30%) of
(+)-22 and 90 mg (28%) of (-)-23.
1
22: colorless oil; IR (film, cm-1) 1260, 1080; H NMR (300
MHz, CDCl3) δ 6.07 (dt, J ) 6.1, 2.0 Hz, 1 H), 5.50 (dt, J )
6.1, 6.1 Hz, 1 H), 4.08 (dd, J ) 4.9, 2.4 Hz, 1 H), 3.04 (ddd, J
) 16.9, 3.0, 2.0 Hz, 1 H), 2.49 (dt, J ) 16.9, 2.5 Hz, 1 H), 3.04
(ddd, J ) 16.9, 3.0, 2.0 Hz, 1 H), 2.49 (dt, J ) 16.9, 2.5 Hz, 1
H), 2.09-1.93 (m, 2 H), 1.91-1.56 (m, 2 H), 0.88 (s, 9 H), 0.05
(s, 6 H); 13C NMR (75 MHz, CDCl3) δ 124.7, 121.8, 79.4, 70.9,
40.3, 36.7, 33.3, 25.8, 20.9, 18.0, -4.6, -4.9; EI MS m/z (M+)
272.1639; [R]22 +54.0 (c 1.5, acetone).
D
Anal. Calcd for C14H28OSSi: C, 61.70; H, 10.36. Found: C,
62.02; H, 10.56.
Com p ou n d 17. Entirely comparable silylation of (-)-15
(4.30 g, 27.1 mmol) furnished 6.6 g (90%) of (-)-17 as a
colorless oil. The analytical sample was comparably pre-
pared: IR (film, cm-1) 1260; 1H NMR (300 MHz, CDCl3) δ
4.04-3.99 (m, 1 H), 2.96-2.82 (m, 2 H), 2.24-2.13 (m, 1 H),
2.09-1.44 (series of m, 9 H), 0.88 (s, 9 H), 0.05 (s, 3 H), 0.04
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 80.3, 68.3, 37.8, 36.3,
33.2, 33.1, 30.2, 25.8, 20.6, 18.0, -4.5, -4,8; EI MS m/z (M+)
calcd 270.1474, obsd 270.1476; [R]22 +40.0 (c 0.7, acetone).
D
Anal. Calcd for C14H26OSSi: C, 62.16; H, 9.69. Found: C,
62.29; H, 9.78.
1
23: colorless oil; IR (film, cm-1) 1740, 1250; H NMR (300
MHz, CDCl3) δ 5.17 (dd, J ) 7.3, 4.4 Hz, 1 H), 4.10 (dd, J )
5.7, 4.3 Hz, 1 H), 2.96-2.82 (m, 2 H), 2.26-1.85 (series of m,
6 H), 3.03 (s, 3 H), 1.76-1.57 (m, 2 H), 0.90 (s, 9 H), 0.07 (s, 3
H), 0.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.7, 80.4, 79.0,
69.3, 33.5, 31.7, 31.2, 30.8, 28.8, 25.7, 21.2, 18.0, -4.6, -4.9;
calcd 272.1630, obsd 272.1653; [R]22 -15.7 (c 1.1, acetone).
D
Anal. Calcd for C14H28OSSi: C, 61.70; H, 10.36. Found: C,
61.46; H, 10.27.
Com p ou n d 18. A slurry of (+)-16 (4.50 g, 16.5 mmol) and
10% sodium periodate on silica gel (38 g) in a 1:1 mixture of
CH2Cl2 and hexanes (200 mL) was vigorously stirred for 12 h,
freed of solvent, and placed atop a short pad of silica gel.
Elution with 10% methanol in ether afforded 4.5 g (95%) of
18 as a colorless, oily 4:1 diastereomeric mixture. For the major
diastereomer: 1H NMR (300 MHz, CDCl3) δ 4.08 (t, J ) 7.1
Hz, 1 H), 3.09-2.94 (m, 2 H), 2.85-2.72 (m,1 H), 2.62-2.50
(m, 1 H), 2.41-2.26 (m, 1 H), 2.24-1.48 (series of m, 7 H),
0.86 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 81.0, 80.3, 54.2, 36.8, 34.4, 28.1, 25.8, 25.4, 20.1, 17.9,
-4.3, -5.0; EI MS m/z (M+) calcd 288.1578, obsd 288.1588.
Anal. Calcd for C14H28O2SSi: C, 58.28; H, 9.78. Found: C,
58.53; H, 9.77.
Com p ou n d 19. Comparable treatment of (-)-17 (6.0 g, 22.0
mmol), but for a reaction time of 24 h led to the isolation of
5.7 g (90%) of 19 as a colorless, oily 9:1 diastereomeric mixture.
For the major diastereomer: 1H NMR (300 MHz, CDCl3) δ 3.88
(dd, J ) 4.6, 4.4 Hz, 1 H), 3.17-3.03 (m, 1 H), 2.82-2.69 (m,
1 H), 2.25-2.24 (m, 2 H), 2.08-1.60 (series of m, 8 H), 0.88 (s,
9 H), 0.06 (s, 3 H), 0.03 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
84.8, 75.2, 53.4, 35.3, 31.5, 28.2, 25.7, 24.3, 21.3, 17.9, -4.3,
-5.1; EI MS m/z (M+) calcd 288.1578, obsd 288.1577.
Anal. Calcd for C14H28O2SSi: C, 58.28; H, 9.78. Found: C,
58.37; H, 9.84.
EI MS m/z (M+) calcd 330.1685, obsd 330.1695; [R]22 -21.0
D
(c 0.5, acetone).
Hyd r obor a tion -Oxid a tion of (+)-20. To a solution of (+)-
20 (230 mg, 0.85 mmol) in dry THF (4 mL) under N2 was added
a solution of the borane‚THF complex (1 mL of 1.0 M in THF,
1.0 mmol). The reaction mixture was stirred overnight, at
which point ethanol (2 mL), 3 M NaOH solution (2 mL), and
30% hydrogen peroxide (1 mL) were added consecutively at 0
°C. The resulting slurry was stirred in the cold for 3 h and
extracted with ether. The combined organic layers were
washed with water, dried, and concentrated to leave a residue
that was subjected to flash chromatography on silica gel
(elution with 25% ethyl acetate in hexanes). There was isolated
70 mg (29%) of 24 (3:2 isomeric ratio) as a colorless oil: IR
1
(film, cm-1) 3400, 1250; H NMR (300 MHz, CDCl3) δ 4.57-
4.50 (m, 0.6 H), 4.45-4.41 (m, 0.4 H), 3.94 (dd, J ) 7.0, 6.9
Hz, 0.6 H), 3.74 (t, J ) 5.2 Hz, 0.4 H), 3.16-2.97 (series of m,
0.6 H), 2.91-2.76 (series of m, 0.4 H), 2.15-1.50 (series of m,
8 H), 0.93 (s, 5.4 H), 0.90 (s, 3.6 H), 0.13 (s, 1.8 H), 0.12 (s, 1.2
H), 0.09 (s, 1.8 H), 0.06 (s, 1.2 H); EI MS m/z (M+) calcd
288.1579, obsd 288.1602.
Com p ou n d 25. A solution of 24 (150 mg, 0.52 mmol) and
DMAP (5 mg) in dry pyridine (0.8 mL) was cooled to 0 °C under
N2 and treated dropwise with benzoyl chloride (1.2 mL, 10
mmol). After 4 h of stirring at rt, methanol (1 mL) was
introduced and the volatiles were removed under vacuum. The
residue was purified by flash chromatography (silica gel,
elution with 9:1 hexanes/ethyl acetate) to furnish 200 mg (98%)
P u m m er er Rea r r a n gem en t of 18. A magnetically stirred
mixture of 18 (310 mg, 1.08 mmol), sodium acetate (290 mg,
3.60 mmol), and acetic anhydride (3 mL) was heated at 110
°C for 3 h. The volatile materials were removed in a vacuum,
J . Org. Chem, Vol. 68, No. 22, 2003 8631

Paquette et al.
of 25 as a 3.2 isomeric mixture: IR (film, cm-1) 1720, 1270;
1H NMR (300 MHz, CDCl3) δ 8.10-7.95 (m, 2 H), 7.62-7.53
(m, 1 H), 7.50-7.40 (m, 2 H), 5.75-5.67 (m, 0.4 H), 5.56-5.55
(m, 0.6 H), 3.96-3.92 (m, 0.4 H), 3.85 (t, J ) 5.3 Hz, 0.6 H),
3.33-3.24 (series of m, 1 H), 3.09 (dd, J ) 11.7, 3.9 Hz, 0.4
H), 2.95 (dd, J ) 11.0, 6.8 Hz, 0.6 H), 2.26-1.50 (series of m,
8 H), 0.93 (s, 3.6 H), 0.92 (s, 5.4 H), 0.14 (s, 3 H), 0.10 (s, 1.2
H), 0.08 (s, 1.8 H); 13C NMR (75 MHz, CDCl3) δ 166.0 (2C),
133.0 (2C), 130.2, 130.0, 129.6 (2C), 128.3 (2C), 80.6, 80.5, 78.0,
76.8, 66.6, 64.3, 44.4, 44.0, 39.0, 38.3, 37.0, 35.1, 32.6, 32.4,
25.8 (2C), 20.4, 20.1, 18.1(2C), -4.3, -4.4, -4.6, -4.7; EI MS
m/z (M+) calcd 392.1841, obsd 392.1868.
Su lfoxid a tion of 25. A slurry of 25 (140 mg, 0.35 mmol)
and 10% sodium periodate adsorbed on silica gel (1 g) in a 1:1
mixture of CH2Cl2 and hexanes (20 mL) was vigorously stirred
for 48 h. The volatiles were removed, and the dried sample
was placed directly atop a column of silica gel. Elution with
8:2 ether/hexanes gave 30 mg (21%) of pure 26 and 45 mg
(32%) of pure 27 in addition to a mixture of two lesser
sulfoxides. The two diastereomers were not specifically dis-
tinguished.
26: pale yellow oil; IR (film, cm-1) 1720, 1270; 1H NMR (300
MHz, CDCl3) δ 8.09-8.00 (m, 2 H), 7.60-7.52 (m, 1 H), 7.49-
7.38 (m, 2 H), 5.85-5.72 (m, 1 H), 4.19 (t, J ) 7.4 Hz, 1 H),
3.75 (dd, J ) 14.4, 7.6 Hz, 1 H), 2.89 (dd, J ) 14.4, 4.4 Hz, 1
H), 2.81-2.58 (series of m, 2 H), 2.45 (dd, J ) 13.7, 5.9 Hz, 1
H), 2.16-1.58 (series of m, 5 H), 0.92 (s, 9 H), 0.14 (s, 3 H),
0.11 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 166.0, 133.2, 129.8,
129.6, 128.4, 80.7, 78.1, 74.7, 58.9, 41.3, 34.0, 27.6, 25.8, 19.8,
17.9, -4.3, -4.9; EI MS m/z (M+) calcd 408.1790, obsd
408.1801.
25.8, 19.2, 18.1, -4.5, -4.7; EI MS m/z (M+) calcd 288.1579,
obsd 288.1576.
Com p ou n d 30. Reaction of 29 (80 mg, 0.30 mmol) with
benzoyl chloride (1.2 mL) and DMAP (5 mg) in dry pyridine
(0.8 mL) at 0 °C for 4 h as described above, gave 106 mg (98%)
of 30 as a 9:1 diastereomeric mixture: IR (film, cm-1) 1720,
1270; 1H NMR (300 MHz, CDCl3) δ 8.10-8.00 (m, 2 H), 7.62-
7.51 (m, 1 H), 7.49-7.39 (m, 2 H), 4.20 (dd, J ) 4.4, 4.3 Hz, 1
H), 3.86-3.75 (m, 1 H), 3.17 (dd, J ) 12.3, 8.6 Hz, 1 H), 2.44
(dd, J ) 12.3, 6.5 Hz, 1 H), 2.17-1.40 (series of m, 8 H), 0.93
(s, 9H), 0.16 (s, 3 H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 166.3, 133.0, 130.0, 129.6, 128.3, 81.1, 69.9, 54.9, 39.6, 35.0,
32.1, 31.2, 25.8, 19.4, 18.1, -4.5, -4.7; EI MS m/z (M+) calcd
392.1841, obsd 392.1814.
Com p ou n d 31. A mixture of (+)-22 (200 mg, 0.74 mmol)
and 10% sodium periodate adsorbed on silica gel (1.5 g) in 1:1
CH2Cl2/hexanes (20 mL) was vigorously stirred for 48 h.
Following the removal of volatiles, the residue was placed atop
a silica gel column and product was eluted with 5% methanol
in ether. There was isolated 120 mg (98%) of 31 as a 9:1
mixture of diastereomers: colorless oil; IR (film, cm-1) 1250,
1040; 1H NMR (300 MHz, CDCl3) δ 6.75-6.69 (m, 1 H), 6.64-
6.59 (m, 1 H), 3.96 (dd, J ) 4.5, 4.4 Hz, 1 H), 3.21 (ddd, J )
18.0, 3.2, 1.7 Hz, 1 H), 2.75 (dt, J ) 18.0, 2.4 Hz, 1 H), 2.55-
1.61 (series of m, 6 H), 0.86 (s, 9 H), 0.03 (s, 3 H), -0.03 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 145.0, 132.5, 77.2, 74.8, 38.3,
35.4, 28.3, 25.7, 21.6, 17.9, -4.6, -5.1; EI MS m/z (M+) calcd
286.1423, obsd 286.1432.
Com p ou n d 36. To a solution of 2,3-dihydrothiophene (2.2
g, 26 mmol) in dry THF (30 mL) cooled to -78 °C under N2
was added a solution of tert-butyllithium in pentane (20 mL
of 1.6 M, 32 mmol). The mixture was stirred at this temper-
ature for 30 min, maintained at 0 °C for 30 min, and returned
to -78 °C. Cyclobutanone (1.9 mL, 26 mmol) was introduced
via syringe and the mixture was allowed to warm to rt
overnight. Following the addition of 1 M hydrochloric acid (30
mL), the mixture was extracted with ether, and the combined
organic phases were washed with water and brine prior to
drying and solvent evaporation. The residue was taken up in
isopropyl alcohol (60 mL) and propylene oxide (40 mL), the
solution was cooled to -78 °C, and phenylselenenyl chloride
(5.0 g, 26 mmol) was added in one portion. The reaction
mixture was allowed to warm to rt during 5 h, the volatile
materials were removed, and the residue was purified by flash
chromatography on silica gel. Elution with 98:2 hexanes/ethyl
acetate furnished 5.7 g (70%) of 36 as a yellow oil: IR (film,
cm-1) 1730; 1H NMR (300 MHz, CDCl3) δ 7.60-7.52 (m, 2 H),
7.32-7.24 (m, 3 H), 3.48-3.39 (m, 1 H), 3.07-2.84 (m, 3 H)
2.77-2.68 (m, 1 H), 2.55-2.49 (m, 2 H), 2.26-1.97 (m, 3 H),
1.93-1.75 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 213.5, 133.8,
131.0, 129.2 (2 C), 127.5 (2 C), 65.2, 50.8, 37.2, 36.3, 34.5, 29.5,
20.6; EI MS m/z calcd 312.0087, obsd 312.0075.
1-Th ia sp ir o[4.4]n on -3-en -6-on e (37). To a solution of (()-
36 (8.8 g, 28.3 mmol) in 450 mL of CH2Cl2 was added a solution
of m-CPBA (4.88 g, 28.3 mmol, 1 eq) in 450 mL of CH2Cl2 at
-78 °C, and the mixture was stirred at this temperature for
40 min. Pyridine (6.92 mL, 84.9 mmol) was introduced via
syringe, and the resulting mixture was stirred at rt for 2 h,
washed with 200 mL of water, and quenched with 200 mL of
NaHCO3 solution. The separated aqueous layer was extracted
with CH2Cl2 (2 × 200 mL), and the combined organic extracts
were washed with H2O (50 mL) and brine (50 mL), dried, and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel (gradient elution: 1-5% ethyl acetate in
hexanes) to give 3.97 (91%) of (()-37 as a faint yellow oil: IR
(film, cm-1) 1745, 1150; 1H NMR (300 MHz, CDCl3) δ 6.10 (dt,
J ) 6.2, 2.6 Hz, 1 H), 5.52 (dt, J ) 6.2, 2.3 Hz, 1 H), 3.92 (dt,
J ) 14.8, 2.4 Hz, 1 H), 3.82 (dt, J ) 14.8, 2.4 Hz, 1 H), 2.56-
2.44 (m, 1 H), 2.35-2.14 (series of m, 3 H), 2.12-1.81 (series
of m, 2 H); 13C NMR (75 MHz, CDCl3) δ 214.7, 131.9, 131.0,
70.8, 39.2, 38.5, 35.2, 20.2; EI MS m/z (M+) calcd 154.0452,
obsd 154.0458.
Anal. Calcd for C21H32O4SSi: C, 61.73; H, 7.89. Found: C,
61.93; H, 7.97.
27: pale yellow oil; IR (film, cm-1) 1720, 1270; 1H NMR (300
MHz, CDCl3) δ 8.05-7.97 (m, 2 H), 7.64-7.55 (m, 1 H), 7.51-
7.40 (m, 2 H), 5.97-5.85 (m, 1 H), 4.21 (t, J ) 6.6 Hz, 1 H),
3.43 (dd, J ) 13.5, 6.2 Hz, 1 H), 3.09 (dd, J ) 13.5, 8.4 Hz, 1
H), 2.77-2.64 (m, 2 H), 2.22 (dd, J ) 13.6, 7.3 Hz, 1 H), 2.10-
1.55 (series of m, 5 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 165.6, 133.2, 129.8 (2C), 129.6,
128.4 (2C), 80.0, 78.0, 74.9, 55.9, 41.0, 33.7, 28.6, 25.7 (3C),
20.2, 18.0, -4.3, -4.9; EI MS m/z (M+) calcd 408.1790, obsd
408.1782.
Com p ou n d 28. A cold (-78 °C), magnetically stirred
solution of (+)-20 (445 mg, 1.65 mmol) in dry CH2Cl2 (10 mL)
was blanketed with N2 and treated slowly with a solution of
m-chloroperbenzoic acid (285 mg, 1.65 mmol) in dry CH2Cl2
(10 mL). The reaction mixture was allowed to warm to rt
overnight, poured into saturated NaHCO3 solution, and ex-
tracted with CH2Cl2. The combined organic phases were dried
and concentrated prior to flash chromatography on silica gel.
Elution with 2% methanol in ether afforded 140 mg (49%) of
28 as a 2:1 mixture of isomers; colorless oil: IR (film, cm-1
)
1
1120, 1000; H NMR (300 MHz, CDCl3) δ 6.84-6.72 (m, 2 H,
major), 6.64-6.59 (m, 2 H, minor), 4.43 (d, J ) 2.6 Hz, 1 H,
major), 4.14 (t, J ) 7.0 Hz, 1 H, minor), 3.07-2.95 (m, 1 H
from each isomer), 2.73-2.62 (m, 1 H, minor), 2.33-2.23 (m,
1 H, major), 2.22-1.60 (series of m, 6 H), 0.92 (s, 9 H, major),
0.82 (s, 9 H, minor), 0.16 (s, 3 H, major), 0.09 (s, 3 H, major),
0.02 (s, 3 H, minor), -0.01 (s, 3 H, minor); 13C NMR (75 MHz,
CDCl3) δ 144.4, 142.4, 135.7, 133.4, 104.1, 81.5, 77.4, 76.4, 43.6,
41.5, 33.5, 33.1, 31.6, 27.4, 25.7, 25.6, 21.2, 19.9, 18.0, 15.3,
-4.4, -4.5, -5.2 (2C); EI MS m/z (M+ - H) calcd 285.1344,
obsd 285.1310.
Hyd r obor a tion -Oxid a tion of (+)-22. Treatment of (+)-
22 (410 mg, 1.5 mmol) with 9-BBN (4.0 mL of 0.5 M in THF,
2.0 mmol) gave 130 mg (62%) of 29 (9:1 diastereomeric ratio)
1
as a colorless oil: IR (neat, cm-1) 3390, 1460; H NMR (300
MHz, CDCl3) δ 4.18 (dd, J ) 4.7, 4.6 Hz, 1 H), 3.03 (dd, J )
12.5, 8.2 Hz, 1 H), 2.48 (dd, J ) 12.5, 6.5 Hz, 1 H), 2.22-1.34
(series of m, 9 H), 0.92 (s, 9 H), 0.15 (s, 3 H), 0.10 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 81.1, 66.0, 54.2, 39.3, 37.0, 33.8, 31.2,
8632 J . Org. Chem., Vol. 68, No. 22, 2003

C4′-Spiroalkylated Nucleosides
F or m a tion of Ma n d ela te Aceta ls 38-41. A solution
consisting of (()-37 (1.22 g, 7.9 mmol), (R)-mandelic acid (24.2
g, 15.9 mmol), and scandium triflate (122 g, 0.24 mmol) in CH2-
Cl2 (33 mL) and CH3CN (4.1 mL) was refluxed for 2 days over
a dropping funnel filled with 4 Å molecular sieves. Additional
(R)-mandelic acid and Sc(OTf)3 were both added in the process,
and fresh sieves were also used. To the resulting dark solution
was added saturated NaHCO3 solution (30 mL) and the
mixture was extracted with CH2Cl2 (3 × 30 mL). The combined
organic extracts were washed with H2O (30 mL) and brine (30
mL), dried, and concentrated to afford an oil that was subjected
to flash chromatography on silica gel (gradient elution: 1% to
5% ethyl acetate/hexanes). The overall yield was 94% (2.14
g). Several fractions were further subjected to MPLC on silica
gel (5% ethyl acetate in hexanes) to afford the four diastere-
omers in the following order of elution. (-)-38: 33% yield;
(0.46 mL or 3.3 mmol for thymine and uracil; 0.61 mL or 4.4
mmol for adenine and cytosine) and trimethylsilyl triflate (0.59
mL or 3.3 mmol for thymine and uracil; 0.79 mL or 4.4 mmol
for ademine and cytosine). After the mixture had stirred for
15 min, 18 (0.20 mL, 0.60 mmol) was introduced via syringe
and zinc iodide (60 mg, 0.2 mmol) was rapidly added. The
resulting bilayer was vigorously stirred at rt for 48 h, at which
point saturated NaHCO3 solution was added and the resulting
slurry was extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried, and concentrated. The
residue was purified by flash chromatography on silica gel.
Uridines: elution with ether; 100 mg (43%), 6:4 mixture of
epimers.
Thymidines: elution with ether; 110 mg (46%); 6:4 mixture
of epimers.
Cytidines: elution with 15% methanol in ether; 110 mg
(68%); 1:1 mixture of epimers.
Adenosines: elution with 15% methanol in ether; 110 mg
(47%); 6:4 mixture of epimers.
colorless needles; mp 110 °C (from hexanes); IR (film, cm-1
)
1
1790; H NMR (300 MHz, CDCl3) δ 7.43-7.37 (m, 5 H), 5.96
(dt, J ) 8.8, 2.6 Hz, 1 H), 5.77 (dt, J ) 6.3, 2.2 Hz, 1 H), 5.68
(s, 1 H), 3.81 (dt, J ) 15.0, 2.4 Hz, 1 H), 3.78 (dt, J ) 15.2, 2.4
Hz, 1 H), 2.35-2.22 (m, 4 H), 1.93-1.88 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 171.3, 135.0, 131.5, 130.6, 128.9, 128.7 (2
C), 126.2 (2 C), 119.2, 77.4, 76.1, 38.4, 37.4, 33.9, 18.0; EI MS
The nucleoside epimers (100 mg, 0.26 mmol) in dry THF (1
mL) were cooled to 0 °C under N2, treated with TBAF (0.5 mL
of 1.0 M in THF, 0.5 mmol), and stirred at rt for 18 h. The
volatile materials were carefully removed, and the residue was
purified by flash chromatography on silica gel followed by
recrystallization.
m/z (M+ + H) calcd 290.0976, obsd 290.0911; [R]18 -92.4 (c
D
0.55, acetone).
(-)-39: 37% yield; colorless platelets; mp 119 °C (from
methanol); IR (film, cm-1) 1790; 1H NMR (300 MHz, CDCl3) δ
7.43-7.33 (m, 5 H), 5.97 (dt, J ) 6.4, 2.5 Hz, 1 H), 5.77 (dt, J
) 6.7, 2.2 Hz, 1 H), 5.56 (s, 1 H), 3.77 (t, J ) 2.4 Hz, 2 H),
2.42-2.16 (m, 4 H), 1.96-1.85 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 171.4, 134.9, 131.9, 130.0, 129.0, 128.7 (2 C), 126.2
(2 C), 118.5, 78.0, 75.5, 38.3, 37.7, 33.7, 18.0; EI MS m/z (M+
(-)-42: elution with 10% acetone in ether; 21 mg (30%);
colorless needles; mp 180-182 °C (from CH2Cl2); IR (film,
cm-1) 3400, 1695, 1375; 1H NMR (300 MHz, CDCl3) δ 9.34 (br
s, 1 H), 8.07 (d, J ) 8.1 Hz, 1 H), 6.33 (t, J ) 6.2 Hz, 1 H),
5.77 (d, J ) 8.1 Hz, 1 H), 3.98 (t, J ) 6.2 Hz, 1 H), 2.58-1.53
(series of m, 10 H); 13C NMR (75 MHz, CDCl3) δ 163.3, 150.7,
141.5, 102.5, 78.7, 71.4, 63.9, 38.4, 37.8, 36.8, 32.9, 19.8; EI
+ H) calcd 290.0976, obsd 290.0859; [R]18 -108 (c 1.28,
MS m/z (M+) calcd 268.0882, obsd 268.0888; [R]22 -13.8 (c
D
D
acetone).
0.60, acetone).
(-)-40: 10% yield; colorless oil; IR (film, cm-1) 1798; 1H NMR
(300 MHz, CDCl3) δ 7.53-7.49 (m, 2 H), 7.41-7.34 (m, 3 H),
5.94 (dt, J ) 6.4, 2.4 Hz, 1 H), 4.71 (dt, J ) 6.3, 2.2 Hz, 1 H),
5.36 (s, 1 H), 3.77 (dd, J ) 2.2, 1.1 Hz, 2 H), 2.37-2.11 (m, 4
H), 2.11-1.87 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 170.8,
133.7, 131.3, 131.2, 129.0, 128.4 (2 C), 127.0 (2 C), 118.7, 76.1,
73.7, 39.0, 37.5, 33.1, 18.1; ES MS m/z (C16H16O3SNa+) calcd
Anal. Calcd for C12H16N2O3S: C, 53.71; H, 6.01. Found: C,
53.44; H, 5.95.
(-)-43: elution with ether; 40% yield; colorless solid; mp 92
1
°C; IR (film, cm-1) 3400, 1675; H NMR (300 MHz, CDCl3) δ
8.75 (br s, 1 H), 7.77 (d, J ) 1.2 Hz, 1 H), 6.35 (t,J ) 6.5 Hz,
1 H), 3.99 (t, J ) 6.3 Hz, 1 H), 2.50-2.37 (m, 1 H), 2.28-1.55
(series of m, 10 H), 1.94 (d, J ) 1.2 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 163.5, 150.7, 136.9, 111.1, 78.7, 71.3, 63.5, 38.6,
37.9, 36.4, 32.9, 19.9, 12.7; EI MS m/z (M+) calcd 282.1038,
311.0712, obsd 311.0732; [R]18 -77.3 (c 0.74, acetone).
D
(-)-41: 14% yield; white solid; 103-104 °C; IR (film, cm-1
)
1796; 1H NMR (300 MHz, CDCl3) δ 7.55-7.52 (m, 2 H), 7.41-
7.34 (m, 3 H), 5.92 (dt, J ) 6.3, 2.5 Hz, 1 H), 5.74 (dt, J ) 6.3,
2.2 Hz, 1 H), 5.40 (s, 1 H), 3.66 (dt, J ) 15.0, 2.0 Hz, 1 H),
3.48 (dt, J ) 15.0, 2.4 Hz, 1 H), 2.33-2.15 (m, 4 H), 1.93-1.86
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 170.5, 134.1, 131.4,
130.0, 128.7, 128.3 (2 C), 126.7 (2 C), 117.9, 76.4, 74.1, 38.4,
37.6, 33.0, 17.6; ES MS m/z (C16H16O3SNa+) calcd 311.0712,
obsd 282.1038; [R]22 -1.6 (c 0.60, acetone).
D
Anal. Calcd for C13H18N2O3S: C, 55.30; H, 6.43. Found: C,
55.52; H, 6.56.
Com p ou n d 45. A solution of 44 (370 mg, 1.0 mmol) in dry
toluene (2 mL) under N2 was treated sequentially and in
dropwise fashion with triethylamine (0.46 mL, 3.3 mmol) and
trimethylsilyl triflate (0.59 mL, 3.3 mmol). After 20 min of
stirring, 18 (0.2 mL, 0.6 mmol) was introduced via syringe
followed by zinc iodide (60 mg, 0.2 mmol) under a stream of
N2. The resulting bilayer was vigorously stirred for 48 h,
quenched with saturated NaHCO3 solution, and extracted with
ethyl acetate. After the combined organic layers were washed
with brine, dried, and concentrated, the residue was purified
by flash chromatography on silica gel (elution with ethyl
acetate) to give 54 mg (13%) of 45: IR (film, cm-1) 1700, 1490,
1290; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1 H), 8.17 (s, 1 H),
7.47-7.20 (series of m, 10 H), 5.83-5.79 (m, 1 H), 4.00 (t, J )
4.8 Hz, 1 H), 2.62 (s, 3 H), 2.29-1.55 (series of m, 10 H), 0.93
(s, 9 H), 0.17 (s, 3 H), 0.13 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 171.7, 165.8, 152.1, 151.7, 149.0, 147.8, 141.3, 129.4, 129.1,
127.0, 110.6, 80.1, 71.4, 65.3, 38.4, 37.6, 35.3, 32.9, 25.9, 25.2,
19.7, 18.2, -4.3, -4.4; EI MS m/z (M+) calcd 307.1102, obsd
obsd 311.0716; [R]18 -69.8 (c 1.25, acetone).
D
Gen er a l P r oced u r e for Hyd r ogen a tion of 38 a n d 39.
A solution of (-)-38 (50.0 mg, 0.17 mmol) and 3 mL of ethyl
acetate was hydrogenated (1 atm, rt) over 6 mg of 5%
palladium on carbon for 48 h, filtered through a short plug of
silica gel, and evaporated to afford (-)-12 (45 mg, 90%).
Hydrogenation of (-)-39 gave (+)-13. Spectral data are
identical to those of authentic samples.
Gen er a l P r oced u r e for Hyd r olysis of 38-41. A hetero-
geneous solution of lithium hydroxide dihydrate (25.5 mg, 0.6
mmol) and (-)-38 (58.4 mg, 0.2 mmol) in a 2:1 mixture of THF
and water (3 mL) was stirred for 4 h and extracted with ether.
The combined organic extracts were washed with water and
brine, dried, and concentrated to afford 23.1 mg (73%) of (+)-
37 as a colorless oil.
Hydrolysis of (-)-38 and (-)-41 gave (+)-37: [R]17 +84.0
D
307.1111; [R]22 +8.8 (c 0.70, acetone).
D
(c 2.09, acetone).
Com p ou n d 46. A solution of 45 (50 mg, 0.076 mmol) and
TBAF (0.5 mL of 1.0 M in THF, 0.5 mmol) in dry THF (1 mL)
was prepared at 0 °C, stirred at rt for 24 h, and freed of
volatiles. The resulting viscous oil was subjected to flash
chromatography on silica gel (elution with 15% methanol in
ethyl acetate), and the collected concentrated fractions were
Hydrolysis of (-)-39 and (-)-40 gave (-)-37: [R]17 -76.0
D
(c 1.08, acetone).
Gen er a l P r oced u r e for Nu cleosid e F or m a tion . To a
nitrogen-blanketed slurry of the purine or pyrimidine base (1.0
mmol) in dry toluene (1 mL) were added in turn triethylamine
J . Org. Chem, Vol. 68, No. 22, 2003 8633

Paquette et al.
dissolved in methanol saturated with NH3 at 0 °C and stirred
overnight. The resulting solution was concentrated, and CH2-
Cl2 was introduced, causing the precipitation of a powder that
was washed with CH2Cl2 and dried to give 19 mg (80%) of 46:
mp 295-297 °C dec; IR (film, cm-1) 3320, 1670; 1H NMR (300
MHz, DMSO-d6) δ 10.81 (br s, 1 H), 8.42 (s, 1 H), 6.27 (dd, J
) 5.1, 2.4 Hz, 1 H), 4.27 (dd, J ) 9.3, 5.6 Hz, 1 H), 2.52-2.23
(series of m, 4 H), 2.01-1.40 (series of m, 6 H); 13C NMR (75
MHz, DMSO-d6) δ 163.5, 159.9, 157.9, 134.1, 132.3, 82.8, 76.0,
69.1, 43.3, 42.5, 41.0, 37.2, 24.6; EI MS m/z (M+ + H) calcd
and extraction with CH2Cl2. The combined organic phases were
dried and concentrated. Purification of the residue by chro-
matography on silica gel (elution with 5% ethyl acetate in
hexanes) furnished 69 mg (70%) of 51 as a colorless oil; IR
1
(film, cm-1) 1742; H NMR (300 MHz, CDCl3) δ 4.09 (t, J )
4.9 Hz, 1 H), 2.99-2.81 (m, 2 H), 2.62-2.50 (m, 1 H), 2.27-
1.71 (m, 1 H), 1.62-1.36 (m, 3 H), 0.89 (s, 9 H), 0.11 (s, 3 H),
0.09 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 215.3, 77.3, 71.4,
33.2, 32.7, 31.2, 30.4, 29.6, 25.7 (3C), 18.0, -4.4, -4.8; ES MS
m/z (M + Na)+ calcd 309.1315, obsd 309.1305; [R]22 -5.8 (c
D
307.1102, obsd 307.1099; [R]22 +10.0 (c 0.20, DMSO).
0.50, CHCl3).
D
Syn th esis of 47-49. Nucleoside formation in the R-hy-
droxyl series was performed in an entirely analogous fashion
to the â-hydroxyl series.
Uridines: elution with ether; 110 mg (47%); 6:4 mixture of
epimers.
Thymidines: elution with ether; 160 mg (66%); 6:4 mixture
of epimers.
Cytidines: elution with 15% methanol in ether; 150 mg
(54%); 1:1 mixture of epimers.
Com p ou n d 52. A solution of 51 (280 mg, 0.9 mmol) in dry
THF (10 mL) was treated at -78 °C with a solution of lithium
hexamethyldisilazide (1.08 mL of 1 M in THF, 1.08 mmol) and
stirred in the cold for 1 h prior to the addition of chlorotrim-
ethylsilane (0.18 mL, 1.44 mmol). The reaction mixture was
allowed to warm to room temperature during 30 min, returned
to -78 °C, and treated dropwise with a solution of phenylse-
lenenyl bromide (335 mg, 1.44 mmol) in THF (5 mL). After 1
h at -78 °C, water was introduced and the product was
extracted into ethyl acetate. The combined organic phases were
dried and the concentrated filtrate was chromatographed on
silica gel (elution with 5% ethyl acetate in hexanes) to give
151 mg of the pure R-isomer. The original R/â ratio was
Adenosines: elution with 15% methanol in ether; 90 mg
(38%); 6:4 mixture of epimers.
(-)-47: elution with 10% acetone in ether; 30% yield;
colorless needles; mp 187-188 °C; IR (film, cm-1) 3400, 1675;
1H NMR (300 MHz, CDCl3) δ 8.29 (br s, 2 H), 8.20 (d, J ) 8.0
Hz, 1 H), 6.29 (dd, J ) 6.1, 3.8 Hz, 1 H), 5.75 (dd, J ) 8.0, 2.3
Hz, 1 H), 4.31 (t, J ) 6.5 Hz, 1 H), 2.56-1.53 (series of m, 10
H); 13C NMR (75 MHz, CDCl3) δ 162.8, 150.4, 141.7, 101.9,
78.7, 68.3, 64.6, 37.5, 37.4, 32.4, 32.2, 19.4; EI MS m/z (M+)
1
determined to be 3:1 on the basis of the H NMR spectrum of
the unpurified product mixture.
For the pure R-isomer: IR (film, cm-1) 1734; 1H NMR (300
MHz, CDCl3) δ 7.64-7.59 (m, 2 H), 7.36-7.33 (m, 1 H), 7.30-
7.27 (m, 2 H), 4.05 (t, J ) 8.3 Hz, 1 H), 3.93 (t, J ) 4.5 Hz, 1
H), 2.96-2.91 (m, 2 H), 2.85-2.80 (m, 1 H), 2.36-2.30 (m, 1
H), 2.13-2.04 (m, 2 H), 1.94-1.89 (m, 1 H), 1.56-1.46 (m, 2
H), 0.86 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 211.8, 136.2 (2C), 129.0, 128.7, 127.2, 76.2, 71.2, 42.3,
38.1, 35.9, 32.6, 30.1, 25.6 (3C), 18.0, -4.6, -4.9; ES MS m/z
(M + Na)+ calcd 465.0799, obsd 465.0797; [R]22D -30.6 (c 0.60,
CHCl3).
calcd 268.0882, obsd 268.0883; [R]22 -41.8 (c 0.30, acetone).
D
Anal. Calcd for C12H16N2O3S: C, 53.71; H, 6.01. Found: C,
53.47; H, 5.96.
(-)-48: elution with ether; 46% yield; colorless solid, mp
1
146-147 °C; IR (film, cm-1) 3400, 1700, 1250; H NMR (300
MHz, CDCl3) δ 8.92 (br s, 2 H), 7.94 (d, J ) 1.0 Hz, 1 H), 6.29
(dd, J ) 4.8, 4.7 Hz, 1 H), 4.32 (t, J ) 6.2 Hz, 1 H), 2.54-1.54
(series of m, 10 H), 1.94 (d, J ) 1.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 163.6, 150.6, 137.4, 110.5, 78.8, 68.3, 64.2, 37.6,
37.2, 32.6, 32.2, 19.5, 12.6; EI MS m/z (M+) calcd 282.1038,
Com p ou n d 53. A solution of 52 (145 mg, 0.33 mmol) in
toluene (5 mL) at -78 °C was treated with a solution of
diisobutylaluminum hydride (0.49 mL of 1 M in toluene, 0.49
mmol), stirred in the cold for 2 h, quenched with methanol,
and stirred for another 10 min prior to the introduction of
brine. The products were extracted into ethyl acetate, and the
combined organic phases were dried and concentrated. Puri-
fication by chromatography over silica gel (elution with 5%
ethyl acetate in hexanes) afforded 115 mg of the anomeric
acetates 53: IR (film, cm-1) 1741; 1H NMR (300 MHz, CDCl3)
δ 7.62-7.48 (m, 4 H), 7.38-7.32 (m, 2 H), 7.30-7.20 (m, 4 H),
5.54-5.45 (m, 1 H), 5.04 (d, J ) 5.1 Hz, 1 H), 4.14-4.11 (m, 1
H), 3.81-3.79 (m, 1 H), 2.67 (dd, J ) 5.6, 7.4 Hz, 1 H), 2.26-
1.82 (m, 12 H), 1.79-1.77 (m, 1 H), 1.51 (dd, J ) 3.0, 5.0 Hz,
1 H), 0.89 (s, 4.5 H), 0.87 (s, 4.5 H), 0.09 (s, 1.5 H), 0.06 (s, 1.5
H), 0.05 (s, 1.5 H), 0.04 (s, 1.5 H); 13C NMR (75 MHz, CDCl3)
δ 170.4, 170.1, 135.4, 133.3, 131.5, 129.2, 129.1, 128.0, 127.7,
127.2, 84.4, 80.8, 80.6, 72.6, 71.1, 42.7, 41.7, 41.3, 40.4, 39.8,
35.1, 32.9, 32.1, 30.7, 29.8, 25.8, 25.6, 21.1 (3C), 20.9 (3C), 18.1,
18.0, -4.4, -4.5, -4.8, -4.9; ES MS m/z (M + Na)+ calcd
obsd 282.1045; [R]22 -13.8 (c 0.60, acetone).
D
(-)-49: 80% yield; white powder; mp 273-275 °C dec; IR
(neat, cm-1) 3340, 1650; 1H NMR (300 MHz, C6D6) δ 11.11 (br
s, 1 H), 8.81 (s, 1 H), 6.40 (dd, J ) 5.2, 2.3 Hz, 1 H), 4.27 (t, J
) 6.8 Hz, 1 H), 2.58-2.16 (series of m, 4 H), 2.06-1.45 (series
of m, 6 H); 13C NMR (75 MHz, DMSO-d6) δ 165.5, 159.8, 157.9,
146.7, 113.1, 82.0, 73.9, 69.5, 42.8, 42.4, 36.8, 36.5, 24.6; EI
MS m/z (M+ + H) calcd 307.1099, obsd 307.1101; [R]22D -34 (c
0.2, methanol).
Com p ou n d 50. To a solution of (-)-23 (120 mg, 0.36 mmol)
in a mixture of THF/methanol/water (3:1:1, 15 mL) was added
an excess of lithium hydroxide. The reaction mixture was
stirred until the disappearance of starting material (TLC
analysis), diluted with water, and extracted with ethyl acetate.
The combined organic phases were dried and evaporated to
leave a residue that was purified by flash chromatography on
silica gel. Gradient elution with 50-5% hexanes in ethyl
acetate gave 84 mg (80%) of 50 as a colorless oil: IR (film,
509.1061, obsd 509.1079; [R]22 -3.0 (c 0.40, CHCl3).
D
1
cm-1) 3416, 1252; H NMR (300 MHz, CDCl3) δ 4.27 (dd, J )
7.7, 7.7 Hz, 1 H), 3.82 (dd, J ) 5.3, 2.1 Hz, 1 H), 2.85-2.70
(m, 2 H), 2.26 (br s, 1 H), 2.21-2.00 (m, 5 H), 1.62-1.36 (m, 3
H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 78.9, 76.9, 72.2, 32.7, 32.5, 31.2, 30.4, 27.8, 25.8 (3C),
Ack n ow led gm en t. We thank the Eli Lilly Co. and
Aventis Pharmaceuticals for their financial support of
this investigation and Prof. Robin Rogers (University
of Alabama, Birmingham) for the X-ray crystallographic
measurements.
18.1, -4.6, -4.7; [R]22 -11.3 (c 0.20, CHCl3).
D
Com p ou n d 51. To a solution of oxalyl chloride (0.03 mL,
0.4 mmol) in CH2Cl2 (3 mL) was added a solution of DMSO
(0.05 mL, 0.9 mmol) in CH2Cl2 (3 mL) cooled to -78 °C. This
mixture was stirred for 20 min and treated with a solution of
50 (110 mg, 0.35 mmol) in CH2Cl2 (10 mL) via syringe at low
temperature. After 45 min, triethylamine (0.5 mL, 1.8 mmol)
was introduced, and warming to room temperature was
allowed to proceed for 30 min prior to quenching with water
Su p p or tin g In for m a tion Ava ila ble: Copies of high-field
1H NMR spectra of all compounds, together with tables giving
the crystallographic details and structure refinement for 8 and
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O030196W
8634 J . Org. Chem., Vol. 68, No. 22, 2003