Stereoselective synthesis of β-anomeric 4′-thiaspirocyclic ribonucleosides carrying the full complement of RNA-level hydroxyl substitution

Article abstract of DOI:10.1021/jo0506985

Stereoselective syntheses of a group of 4′-thiaspirocyclic ribonucleosides featuring both pyrimidine and purine classes and both possible configurations at C-5′ are described. Use is made of the Pummerer reaction of substrates carrying an α-oriented 2,4-dimethoxybenzoyloxy substituent at C-2 in order to gain reliable stereocontrol via neighboring group participation. Irrespective of the S or R configuration of the pivotal sulfoxide intermediates, the nucleobase is captured from the β-face. The competing process is formation of unsaturated sulfoxides, presumably via competing E2-type elimination. Although differences in reactivity between the two stereoisomeric series were noted, the common route has successfully given rise for the first time to desirable β-anomeric sulfur-containing spiroribonucleosides with minimum formation of the a-anomers.

Full text of DOI:10.1021/jo0506985

Stereoselective Synthesis of â-Anomeric 4′-Thiaspirocyclic
Ribonucleosides Carrying the Full Complement of RNA-Level
Hydroxyl Substitution
Leo A. Paquette* and Shuzhi Dong
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received April 7, 2005
Stereoselective syntheses of a group of 4′-thiaspirocyclic ribonucleosides featuring both pyrimidine
and purine classes and both possible configurations at C-5′ are described. Use is made of the
Pummerer reaction of substrates carrying an R-oriented 2,4-dimethoxybenzoyloxy substituent at
C-2 in order to gain reliable stereocontrol via neighboring group participation. Irrespective of the
S or R configuration of the pivotal sulfoxide intermediates, the nucleobase is captured from the
â-face. The competing process is formation of unsaturated sulfoxides, presumably via competing
E2-type elimination. Although differences in reactivity between the two stereoisomeric series were
noted, the common route has successfully given rise for the first time to desirable â-anomeric sulfur-
containing spiroribonucleosides with minimum formation of the R-anomers.
Pyrimidine and purine nucleosides where conforma-
tional rotation about the 5′-hydroxymethyl substituent
is structurally inhibited by spirocyclic annulation con-
stitute a novel class of mimics.1 Under such circum-
stances, the possibility exists to define new stereoisomeric
series not otherwise available as a consequence of the
necessary presence of two additional stereogenic centers.
Beyond that, the broad group of spirocyclic nucleosides
may be classified as to the presence of an oxygen, sulfur,
or carbon center at the apical position. The extent of
hydroxyl functionalization about the nucleobase-sub-
stituted ring as in 1-4 is an important added consider-
ation.
Synthetic approaches to the syn and anti epimers
defined by 1-4 have been successfully devised in this
laboratory for most members.2-4 A notable exception is
the series represented by 4a,b (X ) S),5 interest in which
has remained high because of the obvious relationship
to systems based on natural D-ribose and the biological
activity/chemotherapeutic value of thianucleosides in
general.6 These considerations have prompted us to
develop a convenient synthetic approach to such sulfur-
containing spirocyclic agents. The outcome described
(1) Review: Paquette, L. A. Austr. J. Chem. 2004, 57, 7.
(2) Examples featuring X ) O: (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.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K.;
Kahane, A. L.; Lanter, J. C.; Corral, M. A. J. Org. Chem. 2001, 66,
2828. (d) Paquette, L. A.; Seekamp, C. K.; Kahane, A. L. J. Org. Chem.
2003, 68, 8614. (e) Paquette, L. A.; Kahane, A. L.; Seekamp, C. K. J.
Org. Chem. 2004, 69, 5555. (f) Paquette, L. A.; Seekamp, C. K.; Kahane,
A. L.; Hilmey, D. G.; Gallucci, J. J. Org. Chem. 2004, 69, 7442. (g) See
also: Wendeborn, S.; Binot, G.; Nina, M.; Winkler, T. Synlett 2002,
1683.
(3) Examples featuring X ) S: (a) Paquette, L. A.; Fabris, F.; Gallou,
F.; Dong, S. J. Org. Chem. 2003, 68, 8625. (b) Dong, S.; Paquette, L.
A. J. Org. Chem. 2005, 70, 1580.
(4) Examples featuring X ) CH2: (a) Paquette, L. A.; Hartung, R.
E.; France, D. J. Org. Lett. 2003, 5, 869. (b) Hartung, R. E.; Paquette,
L. A. J. Org. Chem. 2005, 70, 1597. (c) Hartung, R. E.; Paquette, L. A.
Synthesis 2005, in press.
(5) Review: Yokoyama, M. Synthesis 2000, 1637.
10.1021/jo0506985 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/14/2005
J. Org. Chem. 2005, 70, 5655-5664
5655

Paquette and Dong
SCHEME 1
below is a route that proceeds readily with high â-ste-
reoselectivity.
Results and Discussion
Adjacent acyloxy groups at C-2 and C-3 have come to
be recognized as reasonably effective neighboring groups
in Vorbru¨ggen-type glycosylation reactions involving a
ribofuranose derivative and a nucleobase to deliver
â-ribonucleosides.7 However, unsatisfactory levels of ste-
reocontrol and overall yield are often encountered during
the synthesis of 4′-thiaribonucleosides even when a 2-O-
acetal substituent is present to offer directive assistance.8
An explanation for this appreciable difference has been
advanced on the basis of computational analysis.9 In
essence, R-thiacarbocation intermediates carry less net
atom charge at the R-position and consequently are less
susceptible to neighboring group effects relative to struc-
turally related oxocarbocations. These unsatisfactory
stereochemical features are particularly evident when
recourse is made to application of the Pummerer reaction
for condensing a nucleobase with a sulfoxide.10 In the
absence of any neighboring group assistance, this process
gives rise to the R-anomer as the major product. The
presence of a 2-O-acyl substituent serves to lead to the
â-anomer only in slight excess in many cases.
Several years ago, this problem was addressed sys-
tematically by Matsuda and co-workers, and a satisfac-
tory solution was identified in the form of the 2,4-di-
methoxybenzoyl group (DMBz).11 The present investiga-
tion details the conversion of the previously described
enantiopure acetonides 5 and 63b to RNA-configured
spirocyclic thianucleosides and in so doing explores the
extent to which Matsuda activation can be relied upon
to guide â-anomer production.
anhydro-4-thio-D-ribitol is that silylation occurs most
readily at 5-OH and 3-OH. For steric reasons, the
expectation with spirocyclic analogues such as 7 is that
initial reaction should occur regioselectively at the less
hindered 2-OH site since the other two hydroxyls are now
attached to neopentyl carbon atoms. The merger of these
effects was manifested in a slow rate of reaction of 7 with
2,4-dimethoxybenzoyl chloride13 in CH2Cl2 solution. Ac-
companying quantities of both DABCO14 and DMAP were
required to bring about acylation to the 84% level in 9 h
at room temperature.15 1H NMR analysis of unpurified
reaction mixtures revealed a 4.5:1 ratio of 8 and 9 to be
The syn series represented by 5 was first examined.
Its hydrolysis with 6% hydrochloric acid in THF12 gave
the polar triol 7 in good yield (Scheme 1). Proper
incorporation of the 2,4-DMBz group into the C-2 position
now had to be addressed. The situation with the more
commonplace 4-thiaribofuranose systems such as 1,4-
(6) For recent selected reports, consult: (a) Yoshimura, Y.; Wa-
tanabe, M.; Satoh, H.; Ashida, N.; Ijichi, K.; Sakata, S.; Machida, H.;
Matsuda, A. J. Med. Chem. 1997, 40, 2177. (b) Haraguchi, K.;
Nishikawa, A.; Sasakura, E.; Tanaka, H.; Nakamura, K. T.; Miyasaka,
T. Tetrahedron Lett. 1998, 39, 3713. (c) Yoshimura, Y.; Endo, M.;
Miura, S.; Sakata, S. J. Org. Chem. 1999, 64, 7912. (d) Miller, J. A.;
Pugh, A. W.; Ullah, G. M. Tetrahedron Lett. 2000, 41, 3265. (e)
Minakawa, N.; Kaga, D.; Kato, Y.; Endo, K.; Tanaka, M.; Sasaki, T.;
Matsuda, A. J. Chem. Soc., Perkin Trans. 1 2002, 2182. (f) Haraguchi,
K.; Takahashi, H.; Tanaka, H. Tetrahedron Lett. 2002, 43, 5657. (g)
Haraguchi, K.; Takahashi, H.; Shiina, N. Horii, C.; Yoshimura, Y.;
Nishikawa, A.; Sasakura, E.; Nakamura, K. T.; Tanaka, H. J. Org.
Chem. 2002, 67, 5919. (h) Haraguchi, K.; Shiina, N.; Yoshimura, Y.;
Shimada, H.; Hashimoto, K.; Tanaka H. Org. Lett. 2004, 6, 2645.
(7) Vorbru¨ggen, H.; Ruh-Pohlenz, C. Org. React. 2000, 55, 1.
(8) (a) Bobek, M.; Bloch, A.; Parthasarathy, R.; Whistler, R. L. J.
Med. Chem. 1975, 18, 784. (b) Tiwari, K. N.; Secrist, J. A., III;
Montgomery, J. A. Nucleosides Nucleotides 1994, 13, 1819.
(10) (a) O’Neil, I. A.; Hamilton, K. M. Synlett 1992, 791. (b)
Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata,
S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822. (c) Nishizono,
N.; Koike, N.; Yamagata, Y.; Matsuda, A. Tetrahedron Lett. 1996, 37,
7569. (d) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe,
M.; Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997,
62, 3140. (e) Jeong, L. S.; Moon, H. R.; Choi, Y. J.; Chun, M. W.; Kim.
H. O. J. Org. Chem. 1998, 63, 4821. (f) Lim, M. H.; Kim, H. O.; Moon,
H. R.; Chun, M. W.; Jeong, L. S. Org. Lett. 2002, 4, 529. (g) Zhang, X.;
Xia, H.; Dong, X.; Jin, J.; Meng, W.-D.; Qing, F.-L. J. Org. Chem. 2003,
68, 9026.
(11) Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am.
Chem. Soc. 2000, 122, 7233.
(12) Varela, O.; Zunszain, P. A. J. Org. Chem. 1993, 58, 7860.
(13) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978,
43, 1372.
(14) Hartung, J.; Hu¨nig, S.; Kneuer, R.; Schwarz, M.; Wenner, H.
Synthesis 1997, 1433.
(15) Triethylamine proved to be a less efficient base than DABCO.
Use of pyridine as the base gave rise to only trace amounts of products.
(9) Naka, T.; Nishizono, N.; Minakawa, N.; Matsuda, A. Tetrahedron
Lett. 1999, 40, 6297.
5656 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Anomeric 4′-Thiaspirocyclic Ribonucleosides
TABLE 1. Spectroscopic Comparison of Sulfoxides 11
and 12
in hand. After chromatographic purification on silica gel,
the ratio had changed to 3:1, thereby implicating possible
acyl migration. The signals due to H-2 in 8 and H-3 in 9
were used to estimate these ratios. Comparable behavior
was noted when crude samples were stored during 2 days
or more on the shelf. At first glance, the conversion of 8
into 9 would appear unlikely. However, conformations
of the tetrahydrothiophene ring can be adopted that
project the 3-carboxylate ester into a quasiequatorial
conformation, thereby avoiding nonbonded interaction
with the adjacent methylene group.
The position of the ODMBz group in 8 and in 9 is quite
apparent by 1H NMR spectroscopy. The 2-derivative dis-
plays a characteristic downfield shift for H-2 (5.57-5.51
ppm) relative to the H-3 (4.15 ppm) and H-5 (3.89-3.81
ppm) signals.16 For 9, the reverse is true. In this case,
H-3 (5.37 ppm) appears downfield of the absorptions
attributable to H-2 (4.65-4.58 ppm) and H-5 (3.92-3.85
ppm). Additional evidence was secured on the basis of
the 3-OH and 5-OH peaks in 8 whose identity was
corroborated by 2D NMR correlations and D2O exchange
experiments.
11
12
proton
CDCl3
C6D6
∆δ
CDCl3
C6D6
∆δ
H-1â
H-1R
3.84
2.61
3.14
2.54
-0.70
-0.07
3.28
3.43
2.88
2.88
-0.40
-0.55
SCHEME 2
The critical disilylation of 8 to generate 10 could be
performed directly on the 8/9 mixture provided that
reaction was performed under dilute conditions (0.02 mol/
L). Upon adoption of otherwise standard guidelines, 8
reacts with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane17
while 9 is inert. The fully protected sulfide 10 produced
in this manner was subsequently oxidized with the Davis
oxaziridine18 to furnish the pair of diastereomeric sul-
foxides 11 and 12 in isolated yields of 75% and 2.5%,
respectively. On the basis of our earlier efforts3b and
supportive MM3 calculations,19 it is known that the
disiloxane belt is positioned on the â-surface of the
spirocyclic core. As a consequence, the R-face of the
tetrahydrothiophene ring is left open for delivery of the
oxygen atom. On this basis, major product 11 should be
the R-sulfoxide as shown.
level of shielding is expected for the proton more remote
from the sulfinyl oxygen atom. The relevant data for
sulfoxides 11 and 12, with assignments based on NOESY
and COSY data, are listed in Table 1. This analysis
conforms fully with the observations made by Rayner
who noted that a sulfoxide group has a strong deshielding
effect on the 1,3-protons that lie parallel to the S f O
bond.22 When comparison is made between the chemical
shifts of H-2 and H-3 in 11 (5.57 and 3.87-3.81 ppm,
respectively, in CDCl3) to those of 12 (6.02 and 5.27 ppm,
respectively, in the same solvent), it is again evident that
the minor sulfoxide must be S-configured.
The coupling of sulfoxide 11 to silylated thymine was
conducted under the optimized Pummerer conditions
(such as adding 8 equiv of Et3N in two portions) described
by Matsuda et al.11 (Scheme 2). Reaction proceeded im-
mediately to deliver the desired thiaspiroribonucleoside
14 in 35% yield, alongside the unsaturated sulfoxide 13
(65%). The â configuration assigned to 14 was suggested
by two key NOESY correlations involving H-6/H-2′ and
H-6/H-3′. Additional corroboration was gained on the
basis of a simple 1D NMR analysis that takes advantage
of the fact that ribonucleosides possessing a 1,1,3,3-
Over the years, several spectroscopic methods have
been advanced for establishing proper sulfoxide configu-
rational assignments. Recourse to Eu(dpm)3- and solvent-
1
induced H NMR shifts is one of these.20 The europium
reagent coordinates to the sulfinyl oxygen atom, thereby
inducing via a pseudo-contact mechanism the downfield
shifting of signals stemming from nearby methylene
groups. The benzene- or TFA-induced shifts of the
resonances of the nonequivalent diastereotopic methylene
protons R to the sulfinyl group has been rationalized on
the basis of specific interactions of the solvent molecules
with the positive end of the S+-O- dipole.21 This diag-
nostic tool is particularly reliable and convenient when
the molecules under consideration are conformationally
restricted as in the present setting. As a consequence,
by simply going from CDCl3 to C6D6 solutions, a greater
(16) Fromageot, H. P. M.; Griffin, B. E.; Reese, C. B.; Sulston, J. E.;
Trentham, D. R. Tetrahedron 1966, 22, 705.
(17) (a) Hutchinson, J. H.; Daynard, T. S.; Gillard, J. W. Tetrahedron
Lett. 1991, 32, 573. (b) Bradford, C. L.; Fleming, S. A.; Ward, S. C.
Tetrahedron Lett. 1995, 36, 4189.
(18) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(b) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (c) Davis, F.
A.; Jenkins, R., Jr.; Yocklovich, S. G. Tetrahedron Lett. 1978, 5171.
(19) Dong, S. Unpublished results.
(20) (a) Folli, U.; Iarossi, D.; Taddei, F. J. Chem. Soc., Perkin Trans.
2 1974, 933. (b) Fraser, R. R.; Durst, T.; McClory, M. R.; Viau, R.;
Wigfield, Y. Y. Int. J. Sulfur Chem. A 1971, 1, 133. (c) Barbarella, G.;
Garbesi, A.; Fava, A. J. Am. Chem. Soc. 1975, 97, 5883.
(21) Ledaal, T. Tetrahedron Lett. 1968, 1683.
(22) Westwell, A. D.; Thornton-Pett, M.; Rayner, C. M. J. Chem.
Soc., Perkin Trans. 1 1995, 847.
J. Org. Chem, Vol. 70, No. 14, 2005 5657

Paquette and Dong
SCHEME 3
tetraisopropyldisiloxane-1,3-diyl group to mask their 3′-
and 5′-hydroxyl groups are locked into a 2′-exo/3′-endo
conformation. As a direct consequence, H-1′ in the â
anomer appears as a doublet with a small J value, while
the same proton in the R isomer emerges as a doublet
with a large coupling constant.11 These features are
maintained in the spirocyclic analogues, the anomeric
proton signal in 14 appearing as a doublet at 6.16 ppm
with a J value of 1.2 Hz.
ties of acetic acid to skirt potential complications arising
from displacement of the chlorine substituent by fluoride
ion. After this maneuver, 24 and 27 were transformed
by conventional means into the spiro 4′-â-thiaadenosine
25 and guanosine 28.
The anomeric configuration was assigned as â for 24,
26, and 27 on the strength of the appearance of the
anomeric protons as doublets featuring small J values
(0-1.1 Hz). The associated splitting constant in 23 is 5.5
Hz, implicating its R configuration, which was confirmed
by NOESY analysis (H-1′/H-3′ correlation observed).
Attempts to confirm the regiochemistry of 23 by HMBC
analysis gave rise to inconclusive results. Recourse was
then made to the reliable 1D NMR analysis of the purine
base.23 According to Kjellberg and Johansson, the most
pronounced difference in N-9 and N-7 isomers resides in
the C-5 signal. Thus, the C-5 signal in the N-7 system
23 is shifted upfield (122.9 ppm) relative to the corre-
sponding shift (132.7 ppm) in the N-9 derivative 24.
Furthermore, all of the carbon signals of the purine
skeleton in 24 compare very closely with those of 6-chlo-
ropurine riboside, which is most compatible with the N-9
feature. The regiochemical assignments to 26 and 27
relied on the characteristic downfield shift displayed by
H-8 (8.68 ppm) in the N-7 isomer 26 relative to that (8.04
ppm) of N-9-substituted molecule 27. In all cases, the
regiochemistry of the final products was further con-
firmed by comparing the 13C NMR chemical shifts of C-5
and C-8 with those of natural ribopurine nucleosides
(Table 2).
The efficient conversion of 11 to 13 and 14 implicates
the competing operation of two reaction pathways. Fol-
lowing initial activation by O-silylation with trimethyl-
silyl triflate, the proton trans to the sulfinyl oxygen atom
is presumably rendered more acidic11 and most prone to
abstraction. This would be cause for electron flow to
operate in two directions, which are labeled as path a
and path b in Scheme 2. The E2 elimination of Me3SiOH
leads to sulfonium intermediates 16 and 17, with sub-
sequent nucleophilic attack operating to deliver 14 ste-
reoselectively. With regard to path b, the elimination of
2,4-dimethoxybenzoic acid results in dead-end generation
of the unsaturated sulfoxide. Attempts to alter the prod-
uct distribution, such as to involve different silylating
agents (e.g., TESCl) of the 3- and 5-hydroxyls, and to use
ZnCl2 as the Lewis acid, did not improve matters. When
12 was subjected to comparable Pummerer conditions,
the unsaturated (S)-sulfoxide was formed exclusively.
Unmasking of the hydroxyl groups in 14 was achieved
in a one-flask operation by sequential desilylation and
aminolysis to deliver 18 quantitatively (Scheme 3). The
two other pyrimidine ribonucleosides 20 and 22 were pre-
pared under similar conditions and in comparable yield.
The introduction of a pair of purine bases was ac-
complished by coupling 11 to the 6-chloro- and 2-amino-
6-chloropurines (Scheme 4). Both reactions were con-
ducted in refluxing dichloroethane-acetonitrile solvent
systems and N-9-â isomers were generated preferably
over the other stereo- and regioisomers by rearrange-
ment. The N-9 isomers 24 and 27 were subsequently
desilylated with TBAF admixed with equimolar quanti-
As progress was being realized in the syn series,
expectations grew that reasonably parallel chemical
behavior would be manifested during elaboration of the
anti analogues. This was not the case. When acetonide 6
(23) (a) Kjellberg, J.; Johansson, N. G. Tetrahedron 1986, 42, 6541.
(b) Kjellberg, J.; Johansson, N. G. Nucleosides Nucleotides 1989, 8,
225. (c) Chenon, M.-T.; Pugmire, R. J.; Grant, D. M.; Panzica, R. P.;
Townsend, L. B. J. Am. Chem. Soc. 1975, 97, 4627. (d) Chenon, M.-T.;
Pugmire, R. J.; Grant, D. M.; Panzica, R. P.; Townsend, L. B. J. Am.
Chem. Soc. 1975, 97, 4636.
5658 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Anomeric 4′-Thiaspirocyclic Ribonucleosides
SCHEME 4
TABLE 2. Comparison of 13C NMR Shifts for
SCHEME 5
Ribopurine Nucleosides (DMSO-d6)
carbon
adenosine
25
guanosine
28
C-5
C-8
119.6
140.2
119.6
140.7
117.5
136.9
116.3
136.0
was treated with 6% HCl in THF as before, a large
amount of unidentified side product, which proved dif-
ficult to separate from desired triol 29 was generated.
Alternative recourse to hydrolysis with p-toluenesulfonic
acid in methanol led to formation of a complex reaction
mixture. Ultimately it was discovered that 80% acetic
acid in methanol at the reflux temperature24 was well
suited to generating 29 in good yield (Scheme 5). When
29 was subjected to the benzoylating conditions that
proved so effective with its diastereomer 7, complex
product mixtures were generated. From among the
alternative options that exist, that involving the transient
generation of an O-stannylene acetal was pursued.25
Masking of the 1,2-diol functionality in this manner was
accomplished by heating 29 with an equivalent of dibu-
tyltin oxide suspended in benzene with removal of
water.26 Subsequent exposure to 2,4-dimethoxybenzoyl
chloride gave the 2-acylated product 30 in 71% yield. As
before, the location of the acyl functionality was deduced
on the basis of the downfield shift experienced by H-2
(5.61-5.56 ppm) relative to the signals arising from H-3
(24) Nishizono, N.; Baba, R.; Nakamura, C.; Oda, K.; Machida, M.
Org. Biomol. Chem. 2003, 1, 3692.
(25) Wagner, D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem.
1974, 39, 24.
(26) David, S.; Thieffrey, A. J. Chem. Soc., Perkin Trans. 1 1979,
1568.
J. Org. Chem, Vol. 70, No. 14, 2005 5659

Paquette and Dong
SCHEME 6
(4.56 ppm) and H-5 (4.18 ppm). Also diagnostic was the
presence of the 3-OH and 5-OH signals. The ensuing
TIPDS protection of 30 as in 31 and oxidation to the
sulfoxide level with the Davis sulfonyloxaziridine pro-
ceeded uneventfully. The configuration of the major
sulfoxide 32 was identified as S by virtue of the charac-
teristic downfield shifts of H-2/H-3 (5.96/5.29 ppm) rela-
tive to those of minor sulfoxide 33 (5.71/4.45 ppm).
Consequently, unlike the effects operating in sulfide 10
which contribute to favored attack from the R-face, the
TIPDS protecting group in 31 does not shield the â-face
in comparable fashion. In actuality, the R-face in 31 is
more congested, thus causing sulfoxidation to occur more
readily on the â-face.
Despite the fact that 11 and 32 are differently config-
ured at sulfur, these two substrates undergo the Pum-
merer reaction in comparable fashion (Scheme 6). Three
examples were studied with incorporation of thymine, N4-
acetylcytosine, and 6-chloropurine; unsaturated sulfoxide
34 was concomitantly formed as a byproduct. In the case
of purine base incorporation, it should be noted that the
isomeric rearrangement was finished in 9 h (shown by
TLC analysis) and N-9-â isomer 39 was the only stereo-
and regioisomer isolated in 31% yield.
the 5′-position has been realized via a route involving the
Pummerer rearrangement as the key step. The successful
approach, which began by acidic deprotection of aceto-
nides 5 and 6, involved subsequent regioselective intro-
duction of a 2,4-dimethoxybenzoyl substituent at C-2
followed by TIPDS protection to arrive at sulfides 10 and
31. After oxidation of these advanced intermediates to
their sulfoxides with the Davis reagent, reaction with
several nucleobases was effected with trimethylsilyl
triflate and triethylamine. Under these conditions, neigh-
boring group participation was effective in delivering
â-configured ribonucleosides alongside the corresponding
unsaturated sulfoxides. Arrival at the targeted nucleo-
sides was then achieved conventionally. The difference
in configuration at C-5 was sufficient to induce reactivity
differences in the early phases of the synthetic scheme.
Finally, all of the many thiaspirocyclicnucleosides syn-
thesized in the course of this investigation have been
submitted to the NIH for evaluation in as many antiviral
screens as possible.
Experimental Section
General Procedure. Consult ref 2c.
Triol 7. Acetonide 5 (304 mg, 1.32 mmol) was dissolved in
a mixture of THF (8 mL) and 6% aqueous HCl (4 mL), and
the solution was stirred for 8 h at rt. Evaporation afforded a
dark oil, which was submitted to silica gel chromatography
with 85% EtOAc/hexanes as eluent to afford triol 7 (228 mg,
91%) as a colorless syrup: IR (neat, cm-1) 3371 (br), 1447,
1
1078; H NMR (300 MHz, DMSO-d6) δ 4.79 (d, J ) 6.0 Hz, 1
H), 4.75 (d, J ) 5.2 Hz, 1 H), 4.26 (d, J ) 6.3 Hz, 1 H), 4.18-
4.12 (m, 1 H), 3.61-3.51 (m, 2 H), 2.67 (d, J ) 7.0 Hz, 2 H),
2.18-2.09 (m, 1 H), 1.81-1.31 (series of m, 5 H); 13C NMR (75
MHz, DMSO-d6) δ 76.9, 76.1, 74.4, 68.1, 32.8, 32.4, 32.3, 19.4;
Summary
The stereoselective synthesis of spirocyclic 4′-thia-â-
ribonucleosides featuring syn or anti stereochemistry at
5660 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Anomeric 4′-Thiaspirocyclic Ribonucleosides
EI HRMS m/z (M+) calcd 190.0658, obsd 190.0679; [R]20D +37.9
(c 0.29, CHCl3).
For 12: IR (CHCl3, cm-1) 1731, 1608, 1249, 1138, 1037; 1H
NMR (300 MHz, CDCl3) δ 7.76 (d, J ) 9.3 Hz, 1 H), 6.49-6.45
(m, 2 H), 6.02 (t, J ) 5.4 Hz, 1 H), 5.27 (d, J ) 5.4 Hz, 1 H),
4.39 (dd, J ) 11.7, 7.3 Hz, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H),
3.42 (dd, J ) 15.7, 1.6 Hz, 1 H), 3.28 (dd, J ) 15.7, 7.0 Hz, 1
H), 2.34-1.61 (series of m, 6 H), 1.12-0.97 (m, 28 H); 13C NMR
(75 MHz, CDCl3) δ 164.4, 164.2, 161.5, 133.5, 112.0, 104.5,
98.9, 77.2, 74.3, 70.8, 69.9, 57.9, 55.8, 55.5, 30.0, 29.7, 22.7,
17.4, 17.3, 17.28, 17.25, 17.22, 17.1, 17.0, 16.9, 13.4, 13.3, 12.9,
12.5; ES HRMS m/z (M+Na+) calcd 635.2501, obsd 635.2505;
2,4-Dimethoxybenzoylation of Triol 7. A CH2Cl2 solution
(100 mL) of triol 7 (1.84 mg, 9.66 mmol), DABCO (3.36 g,
30 mmol), and DMAP (1.83 g, 15 mmol) was charged with N2
and cooled to 0 °C. 2,4-Dimethoxybenzoyl chloride (3.00 g, 15
mmol) was added in small portions, and the mixture was
stirred for 9 h at rt, quenched with saturated NaHCO3 solution
(50 mL), and washed three times with CH2Cl2 (50 mL). The
combined organic layers were dried and concentrated in vacuo,
and the residue was purified by silica gel chromatography
(elution with 40-80% EtOAc/hexanes) to give 2,4-dimethoxy-
benzoates 8 and 9 as colorless syrups (2.57 g total, 84% yield,
3:1 ratio).
[R]19 +59.5 (c 1.11, CHCl3).
D
Pummerer Reaction of Sulfoxide 11 with Thymine. A
suspension of thymine (9 mg, 0.071 mmol) in toluene (1 mL)
was treated with triethylamine (20 µL, 0.14 mmol) and
TMSOTf (50 µL, 0.29 mmol), and the resulting mixture was
stirred at rt for 1 h before the addition of dichloromethane
(0.5 mL). The clear solution of silylated thymine was added to
a solution of 11 (22 mg, 0.036 mmol) in dichloromethane (0.5
mL) slowly over 15 min. An additional amount of triethylamine
(20 µL, 0.14 mmol) in toluene (0.5 mL) was added dropwise to
the reaction mixture to initiate the Pummerer reaction. After
5 min of stirring at rt, cold water (2 mL) was added, and the
aqueous layer was extracted with dichloromethane (3 × 4 mL).
The combined organic phases were washed with saturated
NaHCO3 solution (4 mL) and brine, dried, and concentrated
in a vacuum. The residue was purified by chromatography on
silica gel with 25-33% AcOEt/hexanes as eluent to give 13
(10 mg, 65%) and 14 (9 mg, 35%).
For 8: IR (neat, cm-1) 3475 (br), 1706, 1609, 1252; 1H NMR
(300 MHz, CDCl3) δ 7.85 (d, J ) 8.6 Hz, 1 H), 6.65-6.48 (m,
2 H), 5.57-5.51 (m, 1 H), 4.15 (br s, 1 H), 3.89-3.81 (m, 1 H),
3.89 (s, 3 H), 3.86 (s, 3 H), 3.21 (dd, J ) 11.2, 6.1 Hz, 1 H),
3.07 (dd, J ) 11.2, 6.0 Hz, 1 H), 2.94 (br d, J ) 4.8 Hz, 1 H),
2.44 (br d, J ) 8.5 Hz, 1 H), 2.34-2.26 (m, 1 H), 2.05-1.94
(m, 2 H), 1.73-1.42 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ
165.3, 164.8, 161.0, 134.4, 111.6, 105.0, 99.0, 77.5, 77.1, 76.3,
69.2, 55.6 (2 C), 32.6, 31.9, 30.9, 19.7; ES HRMS m/z (M +
Na+) calcd 377.1029, obsd 377.1020; [R]21 +72.1 (c 0.99,
D
CHCl3).
For 9: IR (neat, cm-1) 3467 (br), 1706, 1609, 1251; 1H NMR
(300 MHz, CDCl3) δ 7.85 (d, J ) 8.6 Hz, 1 H), 6.58-6.50 (m,
2 H), 5.37 (d, J ) 3.6 Hz, 1 H), 4.65-4.58 (m, 1 H), 3.92-3.85
(m, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.13-2.95 (series of m, 2
H), 2.22-1.95 (series of m, 3 H), 1.67-1.48 (series of m, 3 H);
13C NMR (75 MHz, CDCl3) δ 166.1, 164.7, 160.6, 134.2, 112.0,
105.1, 99.1, 81.1, 76.4, 74.8, 68.6, 56.0, 55.6, 34.1, 33.6, 32.6,
19.6; ES HRMS m/z (M + Na+) calcd 377.1029, obsd 377.1020;
For 13: white solid; mp 83-84 °C; IR (CHCl3, cm-1) 1464,
1
1131, 1054, 1030; H NMR (300 MHz, CDCl3) δ 6.45 (dd, J )
6.5, 1.5 Hz, 1 H), 6.34 (dd, J ) 6.5, 2.5 Hz, 1 H), 4.73 (br s, 1
H), 4.27 (dd, J ) 11.4, 7.7 Hz, 1 H), 2.37-2.28 (m, 1 H), 2.08-
1.95 (m, 2 H), 1.89-1.83 (m, 1 H), 1.64-1.56 (m, 2 H), 1.09-
0.96 (m, 28 H); 13C NMR (75 MHz, CDCl3) δ 138.4, 133.8, 93.5,
72.2, 68.4, 30.1, 18.4, 17.6, 17.3 (2 C), 17.2 (2 C), 17.1 (2 C),
17.0 (2 C), 13.5, 13.4, 12.8, 12.7; ES HRMS m/z (M + Na+)
[R]21 +48.1 (c 0.48, CHCl3).
D
TIPDS Protection of 8. A solution of 8 (1050 mg, 2.97
mmol) in THF (150 mL) was admixed with pyridine (1.15 mL,
14.24 mmol). Silver nitrate (1.21 g, 7.12 mmol) was introduced,
and stirring was maintained for 1 h at rt prior to the addition
of TIPDSCl2 (1.14 mL, 3.56 mmol). After vigorous stirring in
the dark for 6 h, the cloudy white reaction mixture was filtered
into saturated NaHCO3 solution (50 mL). The product was
extracted into CH2Cl2 (3 × 50 mL) and purified by flash
chromatography on silica gel (10% EtOAc/hexanes) to furnish
calcd 453.1922, obsd 453.1938; [R]19 -111 (c 1.50, CHCl3).
D
For 14: colorless oil; UV (MeOH) λmax 286 nm (ꢀ 8900), λmax
1
262 nm (ꢀ 15 700); H NMR (300 MHz, CDCl3) δ 8.18 (br s, 1
H), 7.80 (d, J ) 8.3 Hz, 1 H), 7.35 (d, J ) 1.0 Hz, 1 H), 6.50-
6.47 (m, 2 H), 6.16 (d, J ) 1.2 Hz, 1 H), 5.64 (dd, J ) 5.7, 1.2
Hz, 1 H), 4.56 (d, J ) 5.7 Hz, 1 H), 4.06 (dd, J ) 11.5, 7.1 Hz,
1 H), 3.85 (s, 6 H), 2.18-1.52 (series of m, 6 H), 1.91 (d, J )
1.0 Hz, 3 H), 1.25-1.01 (m, 28 H); 13C NMR (75 MHz, CDCl3)
δ 164.5, 163.8, 161.7, 149.8 (2 C), 136.4, 133.7, 112.3, 111.6,
104.5, 98.9, 76.8, 72.8, 72.6, 70.8, 62.3, 55.8, 55.5, 30.0, 29.8,
29.7, 17.6, 17.24 (2 C), 17.19, 17.13 (2 C), 17.11 (2 C), 17.06,
13.6, 13.5, 13.0, 12.6; ES HRMS m/z (M + Na+) calcd 743.2824,
sulfide 10 (1288 mg, 97%) as a colorless oil: IR (neat, cm-1
)
1
1720, 1609, 1465, 1265, 1130; H NMR (300 MHz, CDCl3) δ
7.85 (d, J ) 8.7 Hz, 1 H), 6.51-6.48 (m, 2 H), 5.72 (t, J ) 5.2
Hz, 1 H), 4.26 (d, J ) 4.7 Hz, 1 H), 3.99 (dd, J ) 11.4, 7.0 Hz,
1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.28 (dd, J ) 12.9, 6.5 Hz, 1
H), 2.95 (d, J ) 12.9 Hz, 1 H), 2.15-2.09 (m, 2 H), 1.92-1.85
(m, 2 H), 1.70-1.50 (m, 2 H), 1.14-0.98 (m, 28 H); 13C NMR
(75 MHz, CDCl3) δ 164.6, 164.3, 161.6, 133.7, 112.4, 104.4,
98.9, 73.8, 73.1, 72.6, 67.0, 55.9, 55.5, 31.3, 29.9, 29.7, 17.5 (2
C), 17.4 (2 C), 17.3, 17.2 (2 C), 17.1 (2 C), 13.6, 13.1, 13.0, 12.6;
obsd 743.2835; [R]19 -10.2 (c 2.19, CH3OH).
D
Spirocyclic 4′-â-Thiaribonucleoside 18. A solution of 14
(64 mg, 0.089 mmol) in THF (3 mL) was treated with tetra-
butylammonium fluoride (1 M THF solution, 0.20 mL, 0.20
mmol) under Ar at 0 °C. After being stirred for 30 min, the
reaction mixture was evaporated to dryness and placed un-
der high vacuum for 30 min. Methanolic ammonia (5 mL)
was added, and the mixture was kept at rt for 24 h prior to
chromatography on silica gel (10% EtOH/toluene) to afford 18
(28 mg, 100%) as a white solid: mp 134-136 °C; UV (MeOH)
λmax 272 nm (ꢀ 8500); 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1
H), 6.19 (d, J ) 8.0 Hz, 1 H), 4.47 (dd, J ) 8.0, 3.4 Hz, 1 H),
3.98 (t, J ) 7.2 Hz, 1 H), 3.88 (d, J ) 3.4 Hz, 1 H), 2.32-2.18
ES HRMS m/z (M + Na+) calcd 619.2554, obsd 619.2567; [R]18
+44.5 (c 0.91, CHCl3).
D
Sulfoxides 11 and 12. To a solution of sulfide 10 (430 mg,
0.72 mmol) in 75 mL of CHCl3 was added the Davis oxaziridine
reagent (226 mg, 0.86 mmol). The reaction mixture was stirred
at 0 °C for 4 h. The solvent was removed, and the residue was
subjected to flash chromatography (25-50% AcOEt/hexanes).
Sulfoxides 11 (333 mg, 75%) and 12 (11 mg, 2.5%) are both
white foams.
(m, 1 H), 2.07-1.85 (series of m, 6 H), 1.67-1.60 (m, 2 H); 13
C
For 11: IR (CHCl3, cm-1) 1729, 1600, 1249, 1128, 1043; 1H
NMR (300 MHz, CDCl3) δ 7.87 (d, J ) 8.6 Hz, 1 H), 6.53-6.48
(m, 2 H), 5.57 (t, J ) 5.5 Hz, 1 H), 4.29 (t, J ) 9.3 Hz, 1 H),
3.88 (s, 3 H), 3.86 (s, 3 H), 3.87-3.81 (m, 2 H), 2.64-2.48 (m,
2 H), 2.22-1.57 (series of m, 5 H), 1.08-0.90 (m, 28 H); 13C
NMR (75 MHz, CDCl3) δ 164.6, 164.3, 161.8, 133.8, 111.6,
104.5, 98.9, 76.2, 73.1, 71.3, 67.0, 55.8, 55.5 (2 C), 29.7, 19.5,
18.2, 17.3, 17.2 (2 C), 17.13 (2 C), 17.10 (2 C), 16.9, 13.5 (2 C),
12.8, 12.6; ES HRMS m/z (M + Na+) calcd 635.2501, obsd
NMR (75 MHz, CD3OD) δ 166.3, 153.2, 139.6, 112.0, 80.0, 79.2,
78.6, 69.9, 64.4, 34.5, 33.1, 19.6, 12.5; ES HRMS m/z (M +
Na+) calcd 337.0829, obsd 337.0823; [R]18D -35.7 (c 1.19, CH3-
OH).
Pummerer Reaction of 11 with Uracil. The Pummerer
reaction was carried out according to the procedure described
for the preparation of 14 starting from 11 (120 mg, 0.20 mmol),
uracil (44 mg, 0.40 mmol), triethylamine (109 µL, 0.80 mmol,
and additional 109 µL, 0.80 mmol), and TMSOTf (0.27 mL,
1.6 mmol). The usual workup followed by silica gel chroma-
635.2505; [R]19 +3.2 (c 0.94, CHCl3).
D
J. Org. Chem, Vol. 70, No. 14, 2005 5661

Paquette and Dong
tography (50% AcOEt/hexanes) of the crude product gave 13
(53.8 mg, 69%) and 19 (40 mg, 30%).
dichloroethane (0.8 mL) was added dropwise to the reaction
mixture to initiate the Pummerer reaction. After being stirred
for 5 min at rt, the reaction mixture was heated at reflux for
24 h. Cold water (5 mL) was added for quenching purposes,
and the aqueous layer was extracted with dichloromethane
(3 × 5 mL). After being washed with saturated NaHCO3
solution (5 mL) and brine, the combined organic layers were
dried and concentrated in a vacuum. The residue was purified
by chromatography on silica gel with 25-50% AcOEt/hexanes
as eluent to give 13 (24.3 mg, 33%), 23 (13.4 mg, 10%), and 24
(39.3 mg, 29%).
For 19: white foam; UV (MeOH) λmax 294 nm (ꢀ 5800), λmax
1
262 nm (ꢀ 15 900); H NMR (300 MHz, CDCl3) δ 8.51 (br s, 1
H), 7.81 (d, J ) 8.3 Hz, 1 H), 7.68 (d, J ) 8.1 Hz, 1 H), 6.51-
6.44 (m, 2 H), 6.09 (d, J ) 1.1 Hz, 1 H), 5.74 (dd, J ) 8.1, 2.2
Hz, 1 H), 5.64 (dd, J ) 5.4, 1.1 Hz, 1 H), 4.48 (d, J ) 5.4 Hz,
1 H), 4.09 (dd, J ) 15.2, 7.1 Hz, 1 H), 3.85 (s, 6 H), 2.18-1.52
(series of m, 6 H), 1.18-0.95 (m, 28 H); 13C NMR (75 MHz,
CDCl3) δ 164.5, 163.7, 162.4, 161.7, 149.7, 140.9, 133.7, 111.6,
104.6, 103.2, 98.9, 76.9, 72.8, 72.2, 70.6, 62.8, 55.8, 55.5, 30.1,
29.6, 17.5, 17. 4, 17.3, 17.2, 17.1, 17.09, 16.9, 13.6, 13.4, 13.1,
12.9; ES HRMS m/z (M + Na+) calcd 729.2668, obsd 729.2698;
For 23: white foam; UV (MeOH) λmax 288 nm (ꢀ 7000), λmax
262 nm (ꢀ 13 400); 1H NMR (500 MHz, CDCl3) δ 8.87 (s, 1 H),
8.84 (s, 1 H), 7.49 (d, J ) 8.7 Hz, 1 H), 6.88 (d, J ) 5.4 Hz, 1
H), 6.41 (dd, J ) 8.7, 2.3 Hz, 1 H), 6.35 (d, J ) 2.3 Hz, 1 H),
6.16 (dd, J ) 5.4, 3.8 Hz, 1 H), 4.48 (d, J ) 3.8 Hz, 1 H), 4.05
(dd, J ) 11.7, 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.72 (s, 3 H), 2.39-
1.52 (series of m, 6 H), 1.29-0.95 (m, 28 H); 13C NMR (125
MHz, CDCl3) δ 164.7, 163.6, 162.2, 161.1, 152.4, 149.4, 142.9,
133.3, 122.9, 110.6, 104.8, 98.8, 73.9, 72.5, 72.1, 70.8, 59.1, 55.7,
55.5, 30.9, 29.7, 29.5, 17.31, 17.26 (2 C), 17.16, 17.14 (2 C),
17.06, 16.9, 13.7, 13.6, 12.9, 12.7; ES HRMS m/z (M + Na+)
[R]18 -0.3 (c 1.63, CH3OH).
D
Spirocyclic 4′-â-Thiauridine 20. Compound 19 (40 mg,
0.057 mmol) was deprotected in a similar manner as described
for 14 by sequential treatment with TBAF (1 M THF solution,
0.12 mL, 0.12 mmol) in THF (3 mL) and methanolic ammonia
(5 mL). After purification on silica gel (10% EtOH/toluene),
20 (16 mg, 94%) was obtained as a syrup: UV (MeOH) λmax
1
266 nm (ꢀ 7900); H NMR (300 MHz, CD3OD) δ 8.43 (d, J )
8.1 Hz, 1 H), 6.20 (d, J ) 7.9 Hz, 1 H), 5.75 (d, J ) 8.1 Hz, 1
H), 4.47 (dd, J ) 7.9, 3.3 Hz, 1 H), 3.97 (t, J ) 7.2 Hz, 1 H),
3.88 (d, J ) 3.3 Hz, 1 H), 2.28-2.17 (m, 1 H), 2.02-1.87 (m, 2
H), 1.64-1.58 (m, 3 H); 13C NMR (75 MHz, CD3OD) δ 166.1,
153.1, 144.1, 103.2, 80.0, 79.4, 78.5, 70.0, 64.6, 34.4, 33.1, 19.6;
calcd 771.2441, obsd 771.2464; [R]19 -48.9 (c 0.90, CH3OH).
D
For 24: white foam; UV (MeOH) λmax 292 nm (ꢀ 5600), λmax
262 nm (ꢀ 17 700); 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1 H),
8.33 (s, 1 H), 7.87 (d, J ) 8.6 Hz, 1 H), 6.53-6.48 (m, 2 H),
6.12 (d, J ) 1.1 Hz, 1 H), 5.97 (dd, J ) 5.4, 1.1 Hz, 1 H), 5.09
(d, J ) 5.4 Hz, 1 H), 4.13 (dd, J ) 11.6, 7.2 Hz, 1 H), 3.86 (s,
3 H), 3.85 (s, 3 H), 2.29-1.52 (series of m, 6 H), 1.19-0.85 (m,
28 H); 13C NMR (75 MHz, CDCl3) δ 164.8, 163.9, 161.9, 152.0
(2 C), 151.3, 144.3, 133.9, 132.7, 111.2, 104.7, 98.9, 77.2, 72.8,
72.0, 71.2, 61.7, 55.8, 55.6, 30.1, 29.8, 17.8, 17.4, 17.3 (2 C),
17.23, 17.17, 17.14, 17.07, 16.96, 13.6, 13.4, 13.0, 12.9; ES
ES HRMS m/z (M + Na+) calcd 323.0672, obsd 323.0673; [R]21
-37.2 (c 0.90, CH3OH).
D
Pummerer Reaction of 11 with N4-Acetylcytosine. The
Pummerer reaction was carried out according to the procedure
described for the preparation of 14 starting from 11 (120 mg,
0.20 mmol), N4-acetylcytosine (92 mg, 0.60 mmol), triethyl-
amine (82 µL, 0.60 mmol, and additional 136 µL, 1.0 mmol),
and TMSOTf (0.27 mL, 1.6 mmol). The usual workup followed
by silica gel chromatography (75% AcOEt/hexanes) of the crude
product gave 13 (50 mg, 69%) and 21 (40 mg, 30%).
HRMS m/z (M + Na+) calcd 771.2441, obsd 771.2435; [R]18
-10.8 (c 1.32, CH3OH).
D
Spirocyclic 4′-â-Thiaadenosine 25. A solution of 24 (33
mg, 0.044 mmol) in THF (3 mL) was treated with AcOH (6.6
µL, 0.11 mmol) and TBAF (1 M THF solution, 0.11 mL, 0.11
mmol). After being stirred at rt for 10 min, the reaction
mixture was evaporated to dryness, and the residue was
purified by silica gel chromatography (elution with 10% EtOH/
toluene). The resulting desilylation product was treated with
ethanolic ammonia (5 mL), and the reaction mixture was
heated at 100 °C for 24 h in a sealed thick-wall tube. The
solvent was removed, and the residue was purified by chro-
matography on silica gel. Elution with 20% EtOH/toluene gave
25 (12 mg, 85%) as a white solid: mp 134-136 °C; UV (MeOH)
λmax 262 nm (ꢀ 7100); 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s,
1 H), 8.13 (s, 1 H), 7.30 (br s, 2 H), 5.91 (d, J ) 5.7 Hz, 1 H),
5.43 (br s, 3 H), 4.74 (br d, J ) 4.2 Hz, 1 H), 3.91 (br s, 1 H),
3.80 (br s, 1 H), 2.24-2.17 (m, 1 H), 1.95-1.91 (m, 1 H), 1.76-
1.69 (m, 1 H), 1.49-1.48 (m, 3 H); 13C NMR (125 MHz, DMSO-
d6) δ 156.5, 152.7, 150.0, 140.7, 119.6, 78.7, 77.8, 76.7, 69.7,
62.3, 33.4, 32.9, 19.4; ES HRMS m/z (M + Na+) calcd 346.0944,
For 21: white solid, mp 253-254 °C; UV (MeOH) λmax 296
nm (ꢀ 15 700), λmax 256 nm (ꢀ 30 500); 1H NMR (300 MHz,
CDCl3) δ (br s, 1 H), 8.14 (d, J ) 7.4 Hz, 1 H), 7.81 (d, J ) 8.4
Hz, 1 H), 7.43 (d, J ) 7.4 Hz, 1 H), 6.50-6.45 (m, 2 H), 6.24
(s, 1 H), 5.68 (d, J ) 5.2 Hz, 1 H), 4.50 (d, J ) 5.2 Hz, 1 H),
4.05 (dd, J ) 11.7, 7.2 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H),
2.27 (s, 3 H), 2.17-2.12 (m, 2 H), 1.98-1.89 (m, 2 H), 1.75-
1.53 (m, 2 H), 1.17-0.85 (m, 28 H); 13C NMR (75 MHz, CDCl3)
δ 171.1, 164.4, 163.5, 162.4, 161.6, 154.7, 145.9, 133.7, 111.8,
104.5, 98.9, 97.4, 77.0, 72.8, 72.1, 70.5, 64.0, 55.8, 55.5, 30.2,
29.6, 25.0, 17. 4 (2 C), 17.3, 17.23 (2 C), 17.19 (2 C), 17.09 (2
C), 13.6, 13.5, 13.0, 12.9; ES HRMS m/z (M + Na+) calcd
770.2933, obsd 770.2908; [R]20 -10.0 (c 0.29, CH3OH).
D
Spirocyclic 4′-â-Thiacytidine 22. Compound 21 (40 mg,
0.053 mmol) was deprotected in a similar manner as described
for 14 by sequential treatment with TBAF (1 M THF solution,
0.12 mL, 0.12 mmol) in THF (3 mL) and methanolic ammonia
(5 mL). After purification on silica gel (30% EtOH/toluene)
22 (16 mg, 100%) was obtained as a glass: UV (MeOH) λmax
278 nm (ꢀ 6400), λmax 226 nm (ꢀ 7700); 1H NMR (300 MHz,
CD3OD) δ 8.39 (d, J ) 7.3 Hz, 1 H), 6.21 (d, J ) 7.3 Hz, 1 H),
5.95 (d, J ) 7.3 Hz, 1 H), 4.46 (dd, J ) 7.3, 3.1 Hz, 1 H), 3.97
(t, J ) 6.9 Hz, 1 H), 3.88 (d, J ) 3.1 Hz, 1 H), 2.29-2.19 (m,
1 H), 2.02-1.87 (m, 2 H), 1.66-1.56 (m, 3 H); 13C NMR (75
MHz, CD3OD) δ 168.2, 160.1, 145.7, 97.8, 80.8, 80.5, 79.3, 70.9,
66.8, 35.4, 34.1, 20.7; ES HRMS m/z (M + Na+) calcd 322.0832,
obsd 346.0935; [R]21 -16.7 (c 0.18, CH3OH).
D
Pummerer Reaction of 11 with 2-Amino-6-chloropu-
rine. The Pummerer reaction was carried out according to the
procedure described for the preparation of 24 starting from
11 (120 mg, 0.20 mmol), 2-amino-6-chloropurine (84 mg, 0.50
mmol), triethylamine (136 µL, 1.0 mmol with an additional
109 µL, 0.80 mmol), and TMSOTf (0.30 mL, 1.8 mmol). The
usual workup followed by silica gel chromatography (25-50%
AcOEt/hexanes) of the crude product gave 13 (33.8 mg, 46%),
26 (6.2 mg, 7%), and 27 (30.6 mg, 22%).
For 26: white solid; mp 89-90 °C; UV (MeOH) λmax 326 nm
(ꢀ 2800), λmax 298 nm (ꢀ 5300), λmax 258 nm (ꢀ 13 800), λmax
224 nm (ꢀ 38 500); 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1 H),
7.80 (d, J ) 8.5 Hz, 1 H), 6.54-6.49 (m, 2 H), 6.40 (s, 1 H),
5.78 (d, J ) 4.9 Hz, 1 H), 5.27 (br s, 2 H), 4.57 (d, J ) 4.9 Hz,
1 H), 4.11-4.04 (m, 1 H), 3.87 (s, 6 H), 2.22-2.17 (m, 2 H),
2.04-1.94 (m, 2 H), 1.79-1.74 (m, 1 H), 1.62-1.55 (m, 1 H),
1.20-0.91 (m, 28 H); 13C NMR (100 MHz, CDCl3) δ 164.6,
21
obsd 322.0839; [R]D -42.1 (c 1.43, CH3OH).
Pummerer Reaction of Sulfoxide 11 with 6-Chloro-
purine. A suspension of 6-chloropurine (121 mg, 0.80 mmol)
in a mixture of acetonitrile (3.2 mL) and 1,2-dichloroethane
(1.6 mL) was treated with triethylamine (109 µL, 0.80 mmol)
and TMSOTf (0.27 mL, 1.6 mmol), and the resulting mixture
was stirred at rt for 1 h. The clear solution of silylated
6-chloropurine was added to a solution of 11 (120 mg, 0.20
mmol) in 1,2-dichloroethane (1.6 mL) slowly over 15 min. An
additional amount of triethylamine (109 µL, 0.80 mmol) in 1,2-
5662 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of â-Anomeric 4′-Thiaspirocyclic Ribonucleosides
163.6, 161.5, 159.4, 156.3, 147.0, 143.9, 133.4, 116.4, 111.8,
104.7, 99.0, 77.7, 72.8, 71.6, 70.4, 62.6, 55.8, 55.6, 30.5, 29.6,
17.5, 17.3, 17.2 (2 C), 17.12, 17.08, 16.98 (2 C), 16.91, 13.6,
13.5, 13.2, 12.8; ES HRMS m/z (M + Na+) calcd 786.2550, obsd
TIPDS Protection of 30. The conversion was carried out
according to the procedure described for the preparation of 10
starting from 30 (178 mg, 0.50 mmol), TIPDSCl2 (0.19 mL,
0.60 mmol), pyridine (0.19 mL, 2.41 mmol), and silver nitrate
(205 mg, 1.21 mmol) in THF (25 mL). The predescribed workup
followed by silica gel chromatography (5-10% AcOEt/hexanes)
of the crude product gave 31 (183 mg, 79%) as a colorless oil:
786.2565; [R]19 +68.4 (c 0.70, CH3OH).
D
For 27: white foam; UV (MeOH) λmax 320 nm (ꢀ 5100), λmax
300 nm (ꢀ 8800), λmax 256 nm (ꢀ 14 100), λmax 222 nm (ꢀ 27 800);
1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1 H), 7.83 (d, J ) 8.4
Hz, 1 H), 6.52-6.48 (m, 2 H), 5.95 (d, J ) 1.1 Hz, 1 H), 5.91
(dd, J ) 5.3, 1.1 Hz, 1 H), 5.24 (br s, 2 H), 4.79 (d, J ) 5.3 Hz,
1 H), 4.09 (dd, J ) 11.7, 7.2 Hz, 1 H), 3.86 (s, 6 H), 2.22-1.52
(series of m, 6 H), 1.18-0.85 (m, 28 H); 13C NMR (75 MHz,
CDCl3) δ 164.7, 163.6, 161.7, 159.1, 153.3, 151.5, 140.7, 133.7,
125.4, 111.4, 104.7, 98.9, 77.2, 72.8, 72.2, 70.6, 60.4, 55.9, 55.5,
30.2, 29.7, 17.6, 17.4 (2 C), 17.3 (2 C), 17.2 (2 C), 17.1, 17.07,
13.5, 13.2, 13.0, 12.9; ES HRMS m/z (M + Na+) calcd 786.2550,
1
IR (neat, cm-1) 1732, 1608, 1464, 1251; H NMR (300 MHz,
CDCl3) δ 7.95 (d, J ) 8.5 Hz, 1 H), 6.53-6.46 (m, 2 H), 5.74 (t,
J ) 4.0 Hz, 1 H), 4.61 (d, J ) 4.0 Hz, 1 H), 4.36 (br s, 1 H),
3.88 (s, 3 H), 3.86 (s, 3 H), 3.19 (dd, J ) 12.5, 4.6 Hz, 1 H),
2.88 (d, J ) 12.5 Hz, 1 H), 2.72-2.64 (m, 1 H), 2.09-2.04 (m,
1 H), 1.87-1.58 (m, 4 H), 1.16-0.86 (m, 28 H); 13C NMR (75
MHz, CDCl3) δ 164.6, 164.3, 161.6, 133.8, 112.4, 104.3, 98.9,
84.2, 77.7, 76.3, 66.1, 55.8, 55.5, 34.5, 30.6, 29.7, 20.4, 17.7,
17.6, 17.5, 17.4, 17.3, 17.25, 17.22, 17.0, 13.5, 13.4, 13.1, 12.8;
ES HRMS m/z (M + Na+) calcd 619.2554, obsd 619.2567; [R]20
+41.5 (c 0.68, CHCl3).
obsd 786.2562; [R]18 +23.2 (c 1.71, CH3OH).
D
D
Spirocyclic 4′-â-Thiaguanosine 28. Compound 27 (31 mg,
0.041 mmol) was desilylated in a similar manner as described
for 24 by treatment with AcOH (5.1 µL, 0.089 mmol) and TBAF
(1 M THF solution, 89 µL, 0.089 mmol) in THF (3 mL) at rt.
After purification by silica gel chromatography (10% EtOH/
toluene), the resulting product was treated with 2-mercapto-
ethanol (28 µL, 0.41 mmol) and NaOMe (28% solution, 75 µL,
0.41 mmol) in refluxing methanol (5 mL) for 24 h. After
neutralization with 1 N HCl, the solution was concentrated
in vacuo. The residue was purified by silica gel chromatogra-
phy (elution with 30% EtOH/toluene) to give 28 (8 mg, 62%)
as a white solid: mp 185-186 °C; UV (MeOH) λmax 276 nm (ꢀ
Sulfoxides 32 and 33. The oxidation was effected according
to the procedure described for the preparation of 11 and 12
starting from 31 (382 mg, 0.64 mmol) and the Davis oxaziri-
dine reagent (200 mg, 0.77 mmol) in CHCl3 (50 mL). Silica
gel chromatography (25-50% AcOEt/hexanes) of the crude
product gave 32 (314 mg, 80%) and 33 (43 mg, 11%) as white
foams.
For 32: IR (CHCl3, cm-1) 1731, 1608, 1464, 1249, 1134,
1
1021; H NMR (300 MHz, CDCl3) δ 7.83 (d, J ) 8.6 Hz, 1 H),
6.51-6.48 (m, 2 H), 5.96 (t, J ) 5.0 Hz, 1 H), 5.29 (d, J ) 5.0
Hz, 1 H), 5.15 (br s, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.61 (d,
J ) 15.5 Hz, 1 H), 3.10 (dd, J ) 15.5, 6.4 Hz, 1 H), 2.62-2.52
(m, 1 H), 2.10-2.00 (m, 2 H), 1.86-1.79 (m, 2 H), 1.51-1.42
(m, 1 H), 1.16-0.86 (m, 28 H); 13C NMR (75 MHz, CDCl3) δ
164.6, 164.0, 161.7, 133.7, 111.6, 104.5, 98.9, 77.5, 76.6, 73.8
(2 C), 56.1, 55.8, 55.5, 35.0, 29.7, 22.1, 17.6, 17.5, 17.46, 17.40
(2 C), 17.3, 17.1, 16.9, 13.8, 13.2, 12.9, 12.6; ES HRMS m/z (M
1
4000), λmax 258 nm (ꢀ 5600); H NMR (400 MHz, DMSO-d6) δ
10.70 (br s, 1 H), 8.08 (s, 1 H), 6.63 (br s, 2 H), 5.72 (d, J ) 5.7
Hz, 1 H), 5.44 (br s, 3 H), 4.61 (br d, J ) 4.2 Hz, 1 H), 3.87 (br
s, 1 H), 3.78 (br s, 1 H), 2.18-2.14 (m, 1 H), 1.91-1.87 (m, 1
H), 1.73-1.68 (m, 1 H), 1.49-1.46 (m, 3 H); 13C NMR (125
MHz, DMSO-d6) δ 156.7, 153.7, 151.6, 136.0, 116.3, 78.3, 77.3,
76.2, 68.7, 60.4, 32.8, 32.2, 18.7; ES HRMS m/z (M + Na+)
+ Na+) calcd 635.2501, obsd 635.2500; [R]20 +68.6 (c 0.56,
D
calcd 362.0893, obsd 362.0895; [R]21 +7.1 (c 0.07, CH3OH).
CHCl3).
D
For 33: IR (CHCl3, cm-1) 1728, 1608, 1464, 1248, 1136,
Triol 29. To a solution of 6 (460 mg, 2.0 mmol) in methanol
(16 mL) was added 80% AcOH (16 mL), and the mixture was
refluxed for 8 h. The reaction mixture was quenched with
saturated K2CO3 solution and filtered. The solvent was
removed under reduced pressure, and the residue was purified
by chromatography on silica gel (elution with 50-90% AcOEt/
hexanes) to give 29 (320 mg, 85%) as a colorless syrup: IR
(neat, cm-1) 3407 (br), 1638; 1H NMR (300 MHz, DMSO-d6) δ
4.92 (d, J ) 4.7 Hz, 1 H), 4.82 (d, J ) 6.9 Hz, 1 H), 4.67 (d, J
) 4.7 Hz, 1 H), 4.23-4.15 (m, 1 H), 4.02 (t, J ) 4.0 Hz, 1 H),
2.80-2.69 (m, 2 H), 2.30-2.20 (m, 1 H), 1.90-1.83 (m, 1 H),
1.68-1.55 (m, 2 H), 1.50-1.37 (m, 2 H); 13C NMR (75 MHz,
DMSO-d6) δ 79.7, 74.9, 74.4, 67.7, 33.1, 32.9, 32.5, 19.7; EI
HRMS m/z (M+) calcd 213.0556, obsd 213.0567; [R]20D -4.5 (c
0.22, CHCl3).
1
1023; H NMR (300 MHz, CDCl3) δ 7.96 (d, J ) 8.7 Hz, 1 H),
6.54-6.46 (m, 2 H), 5.71 (t, J ) 4.0 Hz, 1 H), 4.61 (br s, 1 H),
4.45 (d, J ) 4.0 Hz, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.33 (dd,
J ) 15.4, 4.8 Hz, 1 H), 2.83 (d, J ) 15.4 Hz, 1 H), 2.54-2.47
(m, 2 H), 2.04-1.64 (m, 4 H), 1.13-0.85 (m, 28 H); 13C NMR
(75 MHz, CDCl3) δ 164.5, 164.1, 161.9, 134.2, 111.6, 104.5,
98.9, 81.3, 78.8, 75.4, 72.7, 55.8, 55.5, 52.8, 34.8, 29.7, 22.0,
17.7, 17.6, 17.5, 17.4, 17.3 (2 C), 17.1, 16.9, 13.9, 13.4, 13.0,
12.9; ES HRMS m/z (M + Na+) calcd 635.2501, obsd 635.2500;
[R]21 +28.2 (c 0.44, CHCl3).
D
Pummerer Reaction of 32 with Thymine. The Pum-
merer reaction was carried out according to the procedure
described for the preparation of 14 starting from 32 (58 mg,
0.095 mmol), thymine (35.8 mg, 0.28 mmol), triethylamine (79
µL, 0.57 mmol with an additional 26 µL, 0.19 mmol), and
TMSOTf (0.14 mL, 0.76 mmol). The usual workup followed
by silica gel chromatography (20-30% AcOEt/hexanes) of the
crude product gave 34 (25.6 mg, 68%) and 35 (21 mg, 31%).
2,4-Dimethoxybenzoylation of Triol 29. A mixture of
triol 29 (301 mg, 1.58 mmol) and dibutyltin oxide (394 mg,
1.58 mmol) in benzene (150 mL) was refluxed overnight with
azeotropic removal of water in a Dean-Stark apparatus. After
evaporation of excess benzene (120 mL), the mixture was
cooled to rt and treated with 4 Å molecular sieves (1.5 g)
followed by benzoyl chloride (380 mg, 1.90 mmol). After 5 min,
the solution was filtered and evaporated to dryness. The
residue was purified by silica gel chromatography (elution with
25-75% AcOEt/hexanes) to give 30 (395 mg, 71%) as a
colorless syrup: IR (neat, cm-1) 3481 (br), 1702, 1610, 1254;
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J ) 8.7 Hz, 1 H), 6.54-
6.46 (m, 2 H), 5.61-5.56 (m, 1 H), 4.56 (t, J ) 4.8 Hz, 1 H),
4.18 (t, J ) 3.8 Hz, 1 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.32 (dd,
J ) 11.8, 6.2 Hz, 1 H), 3.23 (d, J ) 6.0 Hz, 1 H), 3.08 (dd, J )
For 34: white solid; mp 73-75 °C; IR (CHCl3, cm-1) 1609,
1464, 1116, 1021; 1H NMR (300 MHz, CDCl3) δ 6.73-6.67 (m,
2 H), 5.91 (br s, 1 H), 4.87 (d, J ) 3.1 Hz, 1 H), 2.44-2.36 (m,
1 H), 2.08-1.81 (m, 5 H), 1.34-0.94 (m, 28 H); 13C NMR (75
MHz, CDCl3) δ 150.6, 130.9, 77.1, 77.0 (2 C), 34.5, 23.1, 21.1,
17.64, 17.59, 17.44, 17.33 (2 C), 17.27, 17.06, 16.9, 13.7, 13.3,
12.8, 12.7; ES HRMS m/z (M + Na+) calcd 453.1922, obsd
453.1902; [R]21 +61.3 (c 0.98, CHCl3).
D
For 35: white foam; UV (MeOH) λmax 282 nm (ꢀ 10 500),
1
λmax 262 nm (ꢀ 18 300), λmax 222 nm (ꢀ 21 400); H NMR (300
MHz, CDCl3) δ 8.32 (s, 1 H), 7.90 (d, J ) 8.6 Hz, 1 H), 7.47 (s,
1 H), 6.52-6.48 (m, 2 H), 5.88 (s, 1 H), 5.69 (d, J ) 4.6 Hz, 1
H), 4.91 (d, J ) 4.6 Hz, 1 H), 4.52 (br s, 1 H), 3.86 (s, 6 H),
2.74-2.69 (m, 1 H), 2.12-1.67 (series of m, 5 H), 1.94 (s, 3 H),
1.18-0.88 (m, 28 H); 13C NMR (75 MHz, CDCl3) δ 164.6, 163.4,
163.1, 161.8, 149.7, 136.6, 133.9, 111.5, 111.3, 104.5, 98.9, 82.8,
11.8, 4.6 Hz, 1 H), 2.56-2.49 (m, 2 H), 2.02-1.64 (m, 5 H); 13
C
NMR (75 MHz, CDCl3) δ 165.4, 164.8, 161.1, 134.4, 111.6,
105.0, 99.0, 81.8, 77.2, 75.9, 65.4, 55.9, 55.6, 33.3, 32.9, 31.5,
20.5; ES HRMS m/z (M + Na+) calcd 377.1029, obsd 377.1039;
[R]20 +28.1 (c 0.69, CHCl3).
D
J. Org. Chem, Vol. 70, No. 14, 2005 5663

Paquette and Dong
80.4, 73.8, 68.8, 63.3, 55.8, 55.5, 34.7, 31.6, 20.4, 17.74, 17.69
(2 C), 17.5, 17.3 (3 C), 17.0, 16.9, 13.7, 13.2, 13.1, 12.5; ES
H), 6.29 (d, J ) 8.6 Hz, 1 H), 5.98 (d, J ) 7.4 Hz, 1 H), 4.51
(dd, J ) 8.6, 3.6 Hz, 1 H), 4.26-4.21 (m, 2 H), 2.42-2.38 (m,
1 H), 2.13-2.07 (m, 1 H), 1.83-1.52 (series of m, 4 H); 13C
NMR (75 MHz, CD3OD) δ 167.2, 159.1, 143.8, 97.0, 81.9, 80.1,
75.7,67.8, 65.6, 33.9, 33.2, 20.4; ES HRMS m/z (M + Na+) calcd
HRMS m/z (M + Na+) calcd 743.2824, obsd 743.2820; [R]21
D
-11.7 (c 0.84, CH3OH).
Spirocyclic 4′-â-Thiaribonucleoside 36. Compound 35
(44 mg, 0.061 mmol) was deprotected in a manner similar to
that described for 14 by sequential treatment with TBAF (1
M THF, 0.13 mL, 0.13 mmol) in THF (3 mL) and methanolic
ammonia (5 mL). After purification on silica gel (10% EtOH/
toluene) 36 (17.5 mg, 92%) was obtained as a white solid: mp
125-126 °C; UV (MeOH) λmax 272 nm (ꢀ 6800); 1H NMR (300
MHz, CD3OD) δ 7.84 (d, J ) 1.0 Hz, 1 H), 6.22 (d, J ) 8.8 Hz,
1 H), 4.55 (dd, J ) 8.8, 3.6 Hz, 1 H), 4.26-4.22 (m, 2 H), 2.42-
2.35 (m, 1 H), 2.13-2.08 (m, 1 H), 1.93 (d, J ) 1.0 Hz, 3 H),
1.80-1.55 (m, 4 H); 13C NMR (75 MHz, CD3OD) δ 166.1, 153.2,
138.6, 112.4, 81.9, 79.4, 75.3, 67.8, 64.5, 33.9, 33.1, 20.3, 12.5;
322.0832, obsd 322.0830; [R]21 -82.0 (c 0.05, CH3OH).
D
Pummerer Reaction of 32 with 6-Chloropurine. The
Pummerer reaction was carried out according to the procedure
described for the preparation of 24 starting from 32 (100 mg,
0.16 mmol), 6-chloropurine (101 mg, 0.65 mmol), triethylamine
(91 µL, 0.65 mmol with an additional 91 µL, 0.65 mmol), and
TMSOTf (0.24 mL, 1.3 mmol). The usual workup followed by
silica gel chromatography (20-40% AcOEt/hexanes) of the
crude product gave 34 (20 mg, 31%) and 39 (38 mg, 31%).
For 39: white foam; UV (MeOH) λmax 294 nm (ꢀ 3200), λmax
262 nm (ꢀ 13 500); 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1 H),
8.30 (s, 1 H), 8.00 (d, J ) 8.7 Hz, 1 H), 6.56-6.50 (m, 2 H),
5.96 (s, 1 H), 5.87 (d, J ) 4.5 Hz, 1 H), 5.72 (d, J ) 4.5 Hz, 1
H), 4.63 (br s, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 2.88-2.77 (m,
1 H), 2.21-2.14 (m, 1 H), 1.98-1.71 (series of m, 4 H), 1.20-
0.84 (m, 28 H); 13C NMR (75 MHz, CDCl3) δ 164.9, 163.9, 162.0,
151.7, 151.6, 150.9, 144.8, 134.2, 132.7, 111.0, 104.7, 98.9, 82.8,
81.3, 73.7, 69.7, 61.5, 55.9, 55.6, 34.7, 31.4, 20.3, 17.7, 17.6,
17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 13.5, 13.2, 13.0, 12.8; ES
ES HRMS m/z (M + Na+) calcd 337.0829, obsd 337.0822; [R]21
-86.6 (c 0.29, CH3OH).
D
Pummerer Reaction of 32 with N4-Acetylcytosine. The
Pummerer reaction was carried out according to the procedure
described for the preparation of 14 starting from 32 (101 mg,
0.16 mmol), N4-acetylcytosine (76 mg, 0.49 mmol), triethyl-
amine (69 µL, 0.49 mmol with an additional 115 µL, 0.82
mmol), and TMSOTf (0.24 mL, 1.3 mmol). The usual workup
followed by silica gel chromatography (50-75% AcOEt/hex-
anes) of the crude product gave 34 (36 mg, 56%) and 37 (35.7
mg, 29%).
HRMS m/z (M + Na+) calcd 771.2441, obsd 771.2435; [R]21
-32.7 (c 0.81, CH3OH).
D
Spirocyclic 4′-â-Thiaadenosine 40. Compound 39 (36.5
mg, 0.049 mmol) was treated in a similar manner as described
for 24 by sequential treatment with AcOH (6.1 µL, 0.11 mmol),
TBAF (1 M THF solution, 0.11 mL, 0.11 mmol) in THF (3 mL)
at rt, and ethanolic ammonia (5 mL) at 100 °C. After purifica-
tion on silica gel (30% EtOH/toluene) 40 (15.2 mg, 97%) was
obtained as a white solid: mp 134-136 °C; UV (MeOH) λmax
For 37: white foam; UV (MeOH) λmax 296 nm (ꢀ 6200), λmax
256 nm (ꢀ 14 300), λmax 218 nm (ꢀ 20 000); 1H NMR (300 MHz,
CDCl3) δ 9.75 (br s, 1 H), 8.19 (d, J ) 7.4 Hz, 1 H), 7.90 (d, J
) 8.6 Hz, 1 H), 7.48 (d, J ) 7.4 Hz, 1 H), 6.52-6.47 (m, 2 H),
5.95 (s, 1 H), 5.75 (d, J ) 4.1 Hz, 1 H), 4.88 (d, J ) 4.1 Hz, 1
H), 4.53 (br s, 1 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.74-2.68 (m,
1 H), 2.34-1.62 (series of m, 5 H), 2.27 (s, 3 H), 1.16-0.85 (m,
28 H); 13C NMR (75 MHz, CDCl3) δ 170.9, 164.5, 163.4, 162.3,
161.7, 154.7, 145.9, 133.9, 111.7, 104.5, 98.9, 96.9, 83.0, 80.2,
73.3, 68.6, 65.3, 55.8, 55.5, 34.7, 31.8, 25.0, 20.4, 17.72, 17.67,
17.51, 17.37, 17.30, 17.2, 17.1, 16.9, 13.7, 13.3, 13.2, 13.0; ES
1
262 nm (ꢀ 12100); H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1
H), 8.14 (s, 1 H), 7.26 (s, 2 H), 5.97 (d, J ) 8.8 Hz, 1 H), 5.41-
5.33 (m, 3 H), 5.07 (br d, J ) 6.4 Hz, 1 H), 4.37 (br s, 1 H),
4.22 (br s, 1 H), 2.33-2.28 (m, 1 H), 1.98-1.92 (m, 1 H), 1.69-
1.41 (series of m, 4 H); 13C NMR (75 MHz, DMSO-d6) δ 156.1,
152.3, 149.6, 140.2, 119.3, 79.5, 77.4, 73.9, 67.9, 62.2, 32.8, 32.2,
19.4; ES HRMS m/z (M + Na+) calcd 346.0944, obsd 346.0952;
HRMS m/z (M + Na+) calcd 770.2933, obsd 770.2948; [R]21
-1.6 (c 0.37, CH3OH).
D
[R]21 -75.0 (c 0.16, CH3OH).
Spirocyclic 4′-â-Thiacytidine 38. Compound 37 (37.5 mg,
0.050 mmol) was deprotected in a manner similar to that
described for 14 by sequential treatment with TBAF (1 M THF
solution, 0.16 mL, 0.16 mmol) in THF (3 mL) and methanolic
ammonia (5 mL). After purification on silica gel (30% EtOH/
toluene) 38 (15 mg, 100%) was obtained as a white solid: mp
176-177 °C; UV (MeOH) λmax 278 nm (ꢀ 5100), λmax 234 nm (ꢀ
D
1
Supporting Information Available: High-field H and
13C NMR spectra for all compounds described herein. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
5400); H NMR (300 MHz, CD3OD) δ 8.04 (d, J ) 7.4 Hz, 1
JO0506985
5664 J. Org. Chem., Vol. 70, No. 14, 2005