Conformational Restriction of Nucleosides by Spirocyclic Annulation at C4′ Including Synthesis of the Complementary Dideoxy and Didehydrodideoxy Analogues

Article abstract of DOI:10.1021/jo0301954

The concept of spirocyclic restriction, when generically applied to nucleoside mimics, allows for the preparation of diastereomeric pairs carrying either a syn- or anti-oriented hydroxyl at C-5′. Reported herein are convenient synthetic routes to enantiomerically pure 1-oxaspiro[4.4]nonanes featuring fully dihydroxylated end products as well as congeners having dideoxy and didehydrodideoxy substitution patterns. Notable use is made of the capacity for introducing unsaturation in the furanose sector via phenylsulfenylation and the incorporation of uracil and thymine by way of their silylated derivatives under catalysis with stannic chloride.

Full text of DOI:10.1021/jo0301954

Con for m a tion a l Restr iction of Nu cleosid es by Sp ir ocyclic
An n u la tion a t C4′ In clu d in g Syn th esis of th e Com p lem en ta r y
Did eoxy a n d Did eh yd r od id eoxy An a logu es
Leo A. Paquette,* Christopher K. Seekamp, and Alexandra L. Kahane
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received J une 16, 2003
The concept of spirocyclic restriction, when generically applied to nucleoside mimics, allows for
the preparation of diastereomeric pairs carrying either a syn- or anti-oriented hydroxyl at C-5′.
Reported herein are convenient synthetic routes to enantiomerically pure 1-oxaspiro[4.4]nonanes
featuring fully dihydroxylated end products as well as congeners having dideoxy and didehy-
drodideoxy substitution patterns. Notable use is made of the capacity for introducing unsaturation
in the furanose sector via phenylsulfenylation and the incorporation of uracil and thymine by way
of their silylated derivatives under catalysis with stannic chloride.
In recent years, attention has been increasingly focused
on those structural modifications of nucleosides that
feature restrictions in their conformational flexibility.
These analogues include, but are not restricted to, the
bicyclo[3.1.0]hexane-derived carbocyclic pseudosugars 1
and 2 devised by the Altmann1 and Marquez groups,2
Leumann’s bi- and tricyclic networks 3 and 4,3 and
Wengel’s locked systems.4 Eschenmoser’s thorough in-
vestigation of homo-DNA oligonucleotides (constructed
of hexose units rather than pentose)5 is also exemplary.
Our own thrust in this area involves detailed scrutiny of
the level of structural preorganization attainable by
spirocyclization at C4′ as featured in 5-8. This choice
has been motivated by several factors. Immediately
adoption of rather different spatial orientations. Beyond
this, extensive crystal structure data, most notably those
for DNA and RNA fragments, reveal the existence of
considerable void space in the region below C4′ of each
nucleoside building block. The “empty space” (presumably
occupied by water molecules) being referred to is suf-
ficiently voluminous to accommodate more than the
string of three methylene groups under consideration
apparent is the fact that the glycosyl torsion angle about
the C4′-C5′ bond is now fixed, such that positioning of
the hydroxyl functionality at R1 or R2 results in the
(1) (a) Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G.
Tetrahedron Lett. 1994, 35, 2331. (b) Altmann, K.-H.; Imwinkelried,
R.; Kesselring, R.; Rihs, G. Tetrahedron Lett. 1994, 35, 7625.
(2) (a) Rodriguez, J . B.; Marquez, V. E.; Nicklaus, M. C.; Barchi, J .
J ., J r. Tetrahedron Lett. 1993, 34, 6233. (b) Rodriguez, J . B.; Marquez,
V. E.; Nicklaus, M. C.; Mitsuya, H.; Barchi, J . J ., J r. J . Med. Chem.
1994, 37, 3389. (c) J eong, L. S.; Marquez, V. E.; Yuan, C.-S.; Borchardt,
R. T. Heterocycles 1995, 41, 2651. (d) Ezzitouni, A.; Barchi, J . J ., J r.;
Marquez, V. E. J . Chem. Soc., Chem. Commun. 1995, 1345. (e)
Siddiqui, M. A.; Ford, H., J r.; George, C.; Marquez, V. E. Nucleosides
Nucleotides 1996, 15, 235. (f) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni,
A.; Russ, P.; Wang, J .; Wagner, R. W.; Matteucci, M. D. J . Med. Chem.
1996, 39, 3739. (g) Ezzitouni, A.; Marquez, V. E. J . Chem. Soc., Perkin
Trans. 1 1997, 1073. (h) Marquez, V. E.; Ezzitouni, A.; Russ, P.;
Siddiqui, M. A.; Ford, H., J r.; Feldman, R. J .; Mitsuya, H.; George, C.;
Barchi, J . J ., J r. J . Am. Chem. Soc. 1998, 120, 2780. (i) Marquez, V.
E.; Russ, P.; Alonso, R.; Siddiqui, M. A.; Hernandez, S.; George, C.;
Nicklaus, M. C.; Dai, F.; Ford, H., J r. Helv. Chim. Acta 1999, 82, 2119.
(j) Shin, K. J .; Moon, H. R.; George, C.; Marquez, V. E. J . Org. Chem.
2000, 65, 2172.
(4) (a) Singh, S. K.; Nielsen, P.; Koshkin, A. A.; Wengel, J . Chem.
Commun. 1998, 455. (b) Koshkin, A. A.; Singh, S. K.; Nielsen, P.;
Rajwanshi, V. K.; Kumar, R.; Meldgaard, M.; Olsen, C. E.; Wengel, J .
Tetrahedron 1998, 54, 3607. (c) Koshkin, A. A.; Rajwanshi, V. K.;
Wengel, J . Tetrahedron Lett. 1998, 39, 4381. (d) Singh, S. K.; Wengel,
J . Chem. Commun. 1998, 1247. (e) Singh, S. K.; Kumar, R.; Wengel,
J . J . Org. Chem. 1998, 63, 10035. (f) Koshkin, A. A.; Nielsen, P.;
Meldgaard, M.; Rajwanshi, V. K.; Singh, S. K.; Wengel, J . J . Am. Chem.
Soc. 1998, 120, 13252. (g) Rajwanshi, V. K.; Håkansson. A. E.;
Sørensen, M. D.; Pitsch, S.; Singh, S. K.; Kumar, R.; Nielsen, P.;
Wengel, J . Angew. Chem., Int. Ed. 2000, 39, 1656. (h) Bryld, T.;
Sørensen, M. H.; Nielsen, P.; Koch, T.; Nielsen, C.; Wengel, J . J . Chem.
Soc., Perkin Trans. 1 2002, 1655.
(3) (a) Tarkoy, M.; Bolli, M.; Leumann, C.; Helv. Chim. Acta 1994,
77, 716. (b) Bolli, M.; Trafelet, H. U.; Leumann, C. Nucleic Acids Res.
1996, 24, 4660. (c) Hildbrand, S.; Leumann, C. J . Angew. Chem., Int.
Ed. Engl. 1996, 35, 1968. (d) Steffens, R.; Leumann, C. J . J . Am. Chem.
Soc. 1997, 119, 11548. (e) Steffens, R.; Leumann, C. J . Am. Chem. Soc.
1999, 121, 3249. (f) Meier, R.; Gru¨schow, S.; Leumann, C. Helv. Chim.
Acta 1999, 82, 1813.
(5) (a) Eschenmoser, A.; Dobler, M. Helv. Chim. Acta 1992, 75, 218.
(b) Bo¨hringer, M.; Roth, H.-J .; Hunziker, J .; Go¨bel, M.; Krishnan, R.;
Giger, A.; Schwetzer, B.; Schreiber, J .; Leumann, C.; Eschenmoser, A.
Helv. Chim. Acta 1992, 75, 1416. (c) Hunziker, J .; Roth, H.-J .;
Bo¨hringer, M.; Giger, A.; Diderichsen, U.; Go¨bel, M.; Krishnan, R.;
J aun, B.; Leumann, C.; Eschenmoser. A. Helv. Chim. Acta 1993, 76,
259.
10.1021/jo0301954 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003
8614
J . Org. Chem. 2003, 68, 8614-8624

Conformational Restriction of Nucleosides by Spirocyclic Annulation
here. Accordingly, there are no pertinent concerns dealing
with nonbonded steric superimposition. In this context,
it is rather surprising that no C4′ R-homologated nucleo-
sides were reported prior to 1992.6 At the present time,
molecules of this class are of high interest.7
A final point to be mentioned here is the anticipated
Resu lts a n d Discu ssion
enhanced stability of 5, 7, and 8 to radical attack. DNA
strand cleavage has been shown to occur because of the
transient intervention of C4′ radicals resulting from
hydrogen atom abstraction at that site.8 Visual inspection
of the spirocyclic systems reveals that the 4′-hydrogen
is no longer present, being replaced by a carbon center
that forms part of the cyclopentane ring. At the same
time, the C5′ site is made neopentylic in nature, a feature
that should certainly curtail competitive attack at that
position as well for the usual steric reasons. Similar
considerations lead to the added conclusion that phos-
phodiester linkages in nucleotides containing spirocyclic
components such as 7 and 8 may not be as susceptible
to degradation by cellular nucleases. Customarily, re-
duced hydrolysis rates translate into reduced levels of
catabolic degradation.
The synthetic approach takes advantage of the feasi-
bility of generating the phenylthio-substituted lactone 11
by the bis-R-functionalization of 9 (R ) TBS) with phenyl
benzenethiosulfonate and subsequent monoreduction
with ethylmagensium bromide.9a,10 As shown in Scheme
1, submission of 11 to diisobutylaluminum hydride
reduction followed directly by acetylation gave in 94%
yield an anomeric mixture of 12. The coupling reactions
between 12 and persilylated uracil or thymine were
performed at -78 °C to room temperature in CH2Cl2
solutions containing SnCl4.11,12 Our expectation was that
reliance could be placed on the transient intervention of
an episulfonium ion intermediate13 and/or complexation
of the sulfur atom to the tin Lewis acid in advance of
oxonium ion formation14 to foster selective formation of
(10) The configuration of the carbinol center in 11 is well established
from several perspectives. Thus, 11 is chemically derived from the
known alcohol i (Dimitroff, M.; Fallis, A. G. Tetrahedron Lett. 1998,
39, 2531),
which was prepared by stereocontrolled reduction of the spiro ketone.
The favored direction of hydride attack parallels the reaction course
followed by other nucleophiles, for which X-ray crystallographic
structural confirmation is available.9a The chemical conversion of i to
ii earlier reported by us9a disturbs no resident stereocenters and
provides confirmation that the prior assignment of stereochemistry
made by Trost and co-workers (Trost, B. M.; Mao, M. K.-T.; Balkovec,
J . M.; Buhlmayer, P. J . Am. Chem. Soc. 1986, 108, 4965) is in error.
Direct spectral comparisons of samples of ii from both research groups
provided convincing demonstration of their common anti arrangement.
The configuration of the phenylthio substituent in 11 is likewise
unambiguously based. As in less constrained nucleosides such as iii
and iv, equilibration in the presence of a base such as DBU allows
the ready interconversion of the C2â isomer with its thermodynamically
more favored R diastereomer (Beach, J . W.; Kim, H. O.; J eong, L. S.;
Nampali, S.; Islam, Q.; Ahn, S. K.; Babu, J . R.; Chu, C. K. J . Org.
Chem. 1992, 57, 3887).
In previous papers,9 our long-standing interest in
designing strategies for the synthesis of spirotetrahydro-
furanyl networks has led us to develop expedient routes
to γ-butyrolactones of general formula 9 and 10. Key
issues such as their production in enantiomerically pure
form and with defined absolute configuration have equally
been solved. Here, we report the conversion of these and
related central building blocks into the broad range of
spironucleosides defined by 5, 6, and 7. Our ultimate
expectation is that future work will establish that
analogues of this type hold attraction as tools in molec-
ular biology and as possible therapeutic agents. The
synthesis of 2′-deoxy congeners 8 and designed assembly
of the latter into spirocyclo-DNA oligomers are presently
under active investigation.
This useful protocol, which was utilized to prepare large amounts of
11, is illustrated in more detail for the interconversion of 21 with 22
in Scheme 3. The spatial proximity of the three protons illustrated in
v for 21 and the more direct interaction shown in vi for its analogues
25 and 27 are readily apparent from NOE analysis.
(6) Lipshutz, B. H.; Sharma, S.; Dimock, S. H.; Behling, J . R.
Synthesis 1992, 191.
(7) Crich, D.; Hao, X. J . Org. Chem. 1999, 64, 4016 and relevant
references therein.
(8) Strittmatter, H.; Dussy, A.; Schwitter, U.; Giese, B. Angew.
Chem., Int. Ed. 1999, 38, 135.
(9) (a) 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. (b) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.
Org. Lett. 2001, 3, 4039. (c) Paquette, L. A.; Owen, D. R.; Bibart, R.
T.; Seekamp, C. K. Org. Lett. 2001, 3, 4043.
(11) Kawakami, H.; Ebata, T.; Koseki, K.; Matsumoto, K.; Mat-
sushita, H.; Naoi, Y.; Itoh, K. Heterocyles 1991, 32, 2451.
(12) (a) Niedballa, U.; Vorbru¨ggen, H. J . Org. Chem. 1974, 39, 3654.
(b) Vorbru¨ggen, H.; Huh-Polenz, C. Org. React. 2000, 55, 1.
(13) Nicolaou, K. C.; Laaduwahetty, T.; Randall, T. L.; Chu-
cholowski, A. J . Am. Chem. Soc. 1986, 108, 2466.
(14) Wilson, L. J .; Hager, M. W.; El-Kattan, Y. A.; Liotta, D. L.
Synthesis 1995, 1465.
J . Org. Chem, Vol. 68, No. 22, 2003 8615

Paquette et al.
SCHEME 1
SCHEME 2
reflects its exceptional stability under these conditions.
In contrast, epimerization was encountered in both
examples when recourse was made to TBAF for desily-
lation.
Saturation of the double bond in these systems was
most efficaciously performed while the TBS group re-
mained installed. The conversions of 14 to 16 proceeded
in yields exceeding 90% (Scheme 2). Both dihydro prod-
ucts were deprotected with KF as previously described.
Attempts were also made to generate 16 by the Raney
nickel desulfurization of 13a and 13b. However, this
reaction proved to be unserviceable due to its nonrepro-
duciblity and degradative tendencies. Its utilization is not
advised. In contrast, the OsO4-promoted dihydroxylation
of 14 proceeded very satisfactorily in the presence of
NMO, thereby making possible targeted arrival at 19a
and 19b.
The attractive features of the global approach detailed
above prompted a companion investigation of the intrin-
sic reactivity resident in the epimeric R-C5′ series.
Matters began well when 10 (R ) TBS) was found to be
responsive to bissulfenation and that product 20 under-
went efficient reduction with ethylmagnesium bromide
to give 21 and 22 (Scheme 3). Of comparable attractive-
ness were the discoveries that this lactone pair was
chromatographically separable and that unwanted 22
could be equilibrated with 21 in THF solution containing
DBU. The 21/22 equilibrium ratio of 7:1 played nicely
into our hands and made feasible the acquisition of
reasonable quantities of this key intermediate.
In view of existing precedent,11 we envisioned that the
reductive acetylation of 21, as effected with diisobutyla-
luminum hydride/acetic anhydride, would be not at all
problematic. However, experiments carried out at both
-78 and -100 °C produced unacceptable amounts (up
to 39%) of the overreduction product 24. To prevent this
undesired side reaction, the conversion to 23 was at-
tempted with disiamylborane at room temperature.20
Although these conditions are well-known to produce
lactols without evidence of over-reduction, the problem
persisted in this instance. Finally, it was uncovered that
the co-addition of chlorotrimethylsilane to the Dibal-H
reaction mixtures was reproducibly effective in suppress-
a 1,2-trans glycosyl bond.15-18 In actuality, the â stere-
oisomer 13a was isolated as a 9:1 mixture of anomers.
With the somewhat more bulky thymine example, 13b
was the only product observed, in line with customary
steric effects. The yield in both cases was approximately
60%.
Elimination of the 2-phenylthio substituent in 13 was
next accomplished by controlled oxidation with the Davis
oxaziridine reagent19 and subsequent heating in xylene11
to bring about the thermal elimination of phenylsulfenic
acid. The first step generated diastereomeric pairs of
sulfoxides (NMR analysis), which underwent conversion
to 14 at different rates. The less reactive stereoisomer is
presumed to be the one that necessarily projects its
phenyl group under the furanoside ring during the Ei
process. The transformations to 14 were therefore moni-
tored by TLC until conversion to 15 was complete. In
addition, pyridine was present to deter any possible
deleterious side reactions capable of being brought on by
the PhSOH byproduct. This step was notably efficient
in both series (88-90%). The unprotected didehy-
drodideoxy nucleosides 15a and 15b were generated by
reaction with potassium fluoride and 18-crown-6 in THF
solution. The excellent yield of the thymidine example
(15) Wilson, L. J .; Liotta, D. Tetrahedron Lett. 1990, 31, 1815.
(16) Montgomery, J . A.; Thomas, H. J . J . Heterocycl. Chem. 1979,
16, 353.
(17) Horton, D.; Sakata, M. Carbohydr. Res. 1976, 48, 41.
(18) Ryan, K. J .; Acton, E. M.; Goodman, L. J . Org. Chem. 1971,
36, 2646.
(19) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, R. T.;
Chen, B.-C. J . Org. Chem. 1992, 57, 7274.
(20) Pedersen, C.; J enson, H. S. Acta Chem. Scand. 1994, 48, 222.
8616 J . Org. Chem., Vol. 68, No. 22, 2003

Conformational Restriction of Nucleosides by Spirocyclic Annulation
SCHEME 3
SCHEME 4
SCHEME 5
ing the generation of 24 to less than 5%. In situ silylation
of the intermediate lactol aluminate in this fashion may
prove to be a generally useful protocol.
Matters were considerably improved when the glyco-
sylation step was performed in acetonitrile solution at
-50 °C to room temperature. This change in solvent was
met with unexpected removal of the tert-butyldimethyl-
silyl protecting group. Although stereoselectivity was
lowered, the isolated yields of 27a and 27b proved
sufficiently elevated to be attractive. The advantages
offered by this pathway were further reinforced by the
finding that thermal elimination of the derived sulfoxides
gave rise to 28a and 28b in an efficient manner. Satura-
tion of the double bond in these substrates required an
increase in pressure to 50 psi (Scheme 5).
The next targeted area of investigation, the dihydroxy-
lation of 28a and 28b, quickly revealed that a significant
reactivity difference exists when comparison is made with
14a and 14b. To facilitate handling, conversion to the
dibenzoyl derivatives 32a and 32b was initially under-
In an attempt to achieve high-level â-selectivity in the
glycosylation of 23, combined use was again made of
silylated bases and SnCl4 in CH2Cl2 solution. The disap-
pointing results were the same for both the uracil and
the thymine examples. The yields of 25a and 25b were
below the 25% level because of a competing fragmenta-
tion of the furanoside ring that delivered aldehyde 26.
In this stereoisomeric series, the stereoelectronic features
resident in 29 are evidently conducive to operation of an
E2 elimination (Scheme 4). Once this irreversible step
operates, the resulting silyl enol ether functionality in
30 becomes subject to hydrolysis during the aqueous
workup with liberation of the cyclopentanone carbonyl
group.
J . Org. Chem, Vol. 68, No. 22, 2003 8617

Paquette et al.
SCHEME 6
SCHEME 7
taken. In the presence of catalytic quantities of osmium
tetraoxide and various co-oxidants, no evidence of reac-
tion was uncovered in either case. The application of
forcing conditions simply induced hydrolysis of the ben-
zoate ester. These problems were resolved in part by the
use of stoichiometric amounts of the osmium reagent in
4:1 THF-pyridine as the reaction medium.21 Early
attempts to realize purification by chromatography of the
osmate esters were soon abandoned as this operation did
not resolve the considerable difficulty experienced in
bringing about their hydrolytic degradation. However,
exposure to gaseous hydrogen sulfide22 proved to be
serviceable and provided the opportunity for convenient
product purification and characterization. When the base
was uracil, the diol distribution favored 33a over 34a by
a factor of 3:1. The electron-donating properties of the
added methyl group in thymine proved sufficient to invert
this ratio.23 Although the yields are not elevated, it was
possible to establish that dihydroxylation at either the
dihydrofuran double bond or the nucleobase site gave rise
to single diastereomers.
In an effort to realize more efficient access to these
dihydroxylated products, an alternative approach via 25b
was explored as illustrated in Scheme 6. Following
thermolysis of the sulfoxide and quantitative conversion
to 36, dihydroxylation to generate 37 could be achieved
in 36% yield. Deprotection of the silyl ether under acidic
conditions completed the crossing to 38. In an unexpected
development, 38 proved to be a diastereomer of 35b.
Although both members of this pair were in hand, we
could not distinguish between the R,R- and â,â-isomers.
As a result, the illustrated structures are not intended
to force a distinction.
glycosylation conditions with persilylated cytosine 39 in
CH2Cl2 as solvent. These conditions led to the generation
of the targeted nucleoside in 67% yield and highly
diastereoselective fashion (â/R > 97:3) (Scheme 7). Acety-
lation with acetic anhydride made available enantiomeri-
cally pure 40a for further processing. The desired ster-
eochemistry was also introduced upon coupling of 23 with
41 in acetonitrile in the presence of SnCl4. This synthetic
approach led directly to 40b, the â isomer of which
predominated by a factor of 5:1.
The glycosidation of 12 with persilylated benzoylad-
enine 42 proved to be particularly sensitive to the choice
of solvent utilized in conjunction with SnCl4. In several
instances (e.g., ether, dichloromethane), mixtures of
anomers were produced in addition to N7 and N9 adducts.
Chromatographic separation under these circumstances
was not feasible. When the use of acetonitrile was probed,
43 was found to be produced in 50% yield with ap-
preciable â-selectivity (>97%). Although this conversion
was found to proceed with loss of the tert-butyldimeth-
ylsilyl group, no N9 isomer was detected. The practicality
of these reaction conditions is obvious.
With 40a , 40b, and 43 in hand, oxidative elimination
was the next requisite transformation. In line with our
earlier studies, exposure of each of these nucleosides
resulted in efficient formation of the epimeric sulfoxides.
However, the thermolysis of these intermediates proved
to be problematic, giving rise invariably to total degrada-
tion. This is not the first occasion where the removal of
sulfide or sulfoxide proved unworkable when other cyti-
dine and adenosine congeners were subjected to related
chemical transformations.24
In conclusion, syntheses of the first spirocyclic nucleo-
sides featuring both R- and â-hydroxyl substituents at
C-5′ have been achieved for the nucleobases uracil and
thymine. The chemical routing is concise for those
nucleoside derivatives featuring three different substitu-
With these objectives met, our focus turned to intro-
duction of the remaining nucleosidic bases. To this end,
the acetate derivative 12 was subjected to the standard
(21) Paquette, L. A.; Brand, S.; Behrens, C. J . Org. Chem. 1999,
64, 2010.
(22) Zhang, W.; Wang, C.; J imenez, L. S. Synth. Commun. 2000,
30, 351.
(23) (a) Barvian, M. R.; Greenberg, M. M. J . Org. Chem. 1993, 58,
6151. (b) Iwai, S. Angew. Chem., Int. Ed. Engl. 2000, 39, 3874. (c)
Deubel, D. V. Angew. Chem., Int. Ed. Engl. 2003, 42, 1974.
8618 J . Org. Chem., Vol. 68, No. 22, 2003

Conformational Restriction of Nucleosides by Spirocyclic Annulation
(s, 3 H), 0.10 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.2, 150.3,
tion plans at C-2′ and C-3′. The combination of these
features makes possible ready assessment of the biologi-
cal activity of the several end products. Such studies are
in progress, as are efforts to develop a viable entry to
the purine analogues.
134.6, 133.5 (2C), 132.2, 129.0 (2C), 128.1, 111.2, 91.0, 88.3,
78.5, 49.6, 36.8, 36.1, 31.7, 25.9 (3C), 18.5, 18.0, 12.2, -3.9,
-4.6; ES HRMS m/z (M + Na)+ calcd 511.2057, obsd 511.2009;
[R]18 -6.7 (c 0.6, C2H5OH).
D
Gen er a l P r oced u r e for Su lfoxid a tion a n d Th er m oly-
sis. The glycosidated sulfide (1.0 equiv) was dissolved in CHCl3
(50 mL) and treated with the Davis oxaziridine (1.1 equiv).
After 16-24 h of stirring, the solvent was evaporated to leave
a residue that was taken up in xylenes (125 mL) containing
2-3 equiv of pyridine. The solution was refluxed for 4 h, cooled,
and freed of solvent under reduced pressure. The residue was
dissolved in ethyl acetate, washed with sodium thiosulfate
solution, dried, and evaporated.
Exp er im en ta l Section
Gen er a l In for m a tion . Consult ref 9a.
Red u ction a n d Acetyla tion of 11. Lactone 119a,10 (0.47
g, 1.20 mmol) was dissolved in CH2Cl2 (25 mL), cooled to -78
°C, and treated with Dibal-H (2.40 mL of 1.0 M, 2.40 mmol).
After 30 min of stirring, a saturated solution of Rochelle’s salt
(40 mL) was introduced, the reaction mixture was allowed to
warm to rt, and the separated aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The organic phases were combined,
dried, and evaporated to leave an oil that was dissolved in CH2-
Cl2 (20 mL) and treated sequentially with pyridine (4.05 mL,
49.5 mmol), acetic anhydride (1.55 mL, 16.5 mmol), and a
catalytic quantity of DMAP. After 30 min, the reaction mixture
was poured into saturated NaHCO3 solution (30 mL), and the
separated aqueous phase was extracted with CH2Cl2 (2 × 20
mL). The combined organic phases were washed with water
(15 mL) and brine (15 mL) prior to drying and solvent
evaporation. There was obtained 0.48 g (94%) of 12 as an
anomeric mixture that was used without further purification.
Gen er a l Glycosid a tion P r oced u r e for 12. For the gly-
cosidations of pyrimidine bases, CH2Cl2 is the solvent of choice.
When purine bases are involved, CH3CN is the preferred
reaction medium. The sample of 12 and the heterocyclic base
must be dissolved in the same solvent in order to realize good
stereoselectivity. The persilylated base (1.5 equiv) was placed
in the appropriate solvent (0.06 mmol/mL) and SnCl4 (2.0
equiv) was added, at which time the base dissolved. The SnCl4
used was 1 M in CH2Cl2 for thymine, cytosine, and uracil, and
neat for adenine. The solution was stirred at rt for 1.5 h,
cannulated into a cold (-78 °C) solution of 12 (0.03 mmol/mL),
maintained at -78 °C for 30 min, warmed to rt, and stirred
for 30 min prior to quenching with saturated NaHCO3 solution.
The separated aqueous layer was extracted with ethyl acetate,
and the combined organic phases were dried and evaporated.
P r od u ct 13a . From 0.30 g (0.71 mmol) of 12 and 0.28 g
(1.1 mmol) of persilylated uracil was obtained 0.22 g (61%) of
13a as a 9:1 â/R anomeric mixture after chromatography on
silica gel (elution with 3:2 hexane-ether): colorless syrup; 1H
NMR (300 MHz, CDCl3) δ 9.06 (s, 1 H), 7.47-7.43 (m, 2 H),
7.28-7.22 (m, 4 H), 6.09 (d, J ) 8.2 Hz, 1 H), 5.58 (dd, J )
8.1, 2.0 Hz, 1 H), 4.05 (t, J ) 7.2 Hz, 1 H), 3.65 (dt, J ) 10.6,
8.1 Hz, 1 H), 2.81 (dd, J ) 12.9, 8.0 Hz, 1 H), 2.00-1.60 (m, 7
H), 0.93 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 163.0, 150.3, 139.2, 133.4 (2C), 131.9, 129.0 (2C),
128.1, 102.8, 91.5, 88.5, 78.5, 50.3, 36.9, 35.6, 31.3, 25.8 (3C),
18.0, 17.9, -4.0, -4.7; ES HRMS m/z (M + Na)+ calcd
P r od u ct 14a . From 0.22 g (0.46 mmol) of 13a was isolated
0.16 g (94%) of 14a as a colorless syrup following chromatog-
raphy on silica gel (elution with 3:2 hexane-ether): 1H NMR
(300 MHz, CDCl3) δ 8.95 (br s, 1 H), 7.35 (d, J ) 8.1 Hz, 1 H),
6.98 (t, J ) 1.4 Hz, 1 H), 6.41 (dd, J ) 5.9, 4.8 Hz, 1 H), 5.74-
5.69 (m, 2 H), 3.99 (t, J ) 5.3 Hz, 1 H), 2.09-1.54 (series of m,
6 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 163.4, 150.8, 140.0, 138.9, 123.7, 102.7, 101.1,
89.2, 80.1, 35.2, 33.6, 25.7 (3C), 20.4, 17.9, -4.2, -4.7; ES
HRMS m/z (M + Na)+ calcd 387.1701, obsd 387.1745; [R]18
-39 (c 1.2, CHCl3).
D
P r od u ct 14b. From 0.22 g (0.46 mmol) of 13b was isolated
0.15 g (88%) of 14b as a colorless syrup following chromatog-
raphy on silica gel (elution with 3:2 hexane-ether): 1H NMR
(300 MHz, CDCl3) δ 8.55 (br s, 1 H), 7.26 (s, 1 H), 7.03 (s, 1
H), 6.43 (dd, J ) 5.9, 1.6 Hz, 1 H), 5.72 (dd, J ) 5.9, 0.9 Hz,
1 H), 3.93 (dd, J ) 4.8, 2.7 Hz, 1 H), 2.12-1.58 (series of m, 9
H), 0.91 (s, 9 H), 0.07 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ
163.4, 150.6, 139.2, 135.3, 124.0, 111.1, 101.2, 89.3, 80.6, 35.4,
34.1, 25.8 (3C), 21.3, 18.0, 17.5, -4.3, -4.8; ES HRMS m/z (M
+ Na)+ calcd 401.1873, obsd 401.1852; [R]18 -34 (c 0.4,
D
CHCl3).
Desilyla tion of 14a . A solution of 14a (0.07 g, 0.19 mmol)
in THF (3 mL) was treated with the 18-crown-6-CH3CN
complex (0.18 g, 0.58 mmol) and potassium fluoride (0.03 g,
0.58 mmol), stirred at rt for 3 days, quenched with water (10
mL), and extracted with ethyl acetate (3 × 10 mL). The
combined organic phases were dried and evaporated to leave
a residue that was chromatographed on silica gel. Elution with
ether gave 0.04 g (57%) of 15a as a white foam; 1H NMR (300
MHz, CDCl3) δ 8.64 (br s, 1 H), 7.57 (d, J ) 8.1 Hz, 1 H), 6.96
(t, J ) 1.4 Hz, 1 H), 6.45 (dd, J ) 5.9, 1.8 Hz, 1 H), 5.78 (dd,
J ) 5.9, 1.2 Hz, 1 H), 5.71 (dd, J ) 8.1, 1.8 Hz, 1 H), 4.14-
4.10 (m, 1 H), 2.27-1.59 (series of m, 6 H) (OH not observed);
13C NMR (75 MHz, CDCl3) δ 163.1, 150.7, 140.6, 137.3, 124.4,
102.5, 100.4, 89.7, 79.1, 34.9, 32.9, 19.6; ES HRMS m/z (M +
Na)+ calcd 273.0846, obsd 273.0866; [R]18 -13 (c 0.10, C2H5-
D
OH).
Desilyla tion of 14b. A solution of 14b (0.13 g, 0.34 mmol)
in THF (30 mL) was treated with the 18-crown-6-CH3CN
complex (1.05 g, 3.4 mmol) and potassium fluoride (0.20 g, 3.4
mmol), stirred at rot for 7 days, quenched with water (20 mL),
and extracted with ethyl acetate (3 × 20 mL). The combined
organic phases were dried and evaporated to leave a residue
that was chromatographed on silica gel. Elution with ether
furnished 0.03 g (33%) of 15b as a white foam and returned
0.09 g (68%) of unreacted 14b.
497.1901, obsd 497.1913; [R]18 +8.8 (c 1.5, C2H5OH).
D
Anal. Calcd for C24H34N2O4SSi: C, 60.73; H, 7.22. Found:
C, 60.83; H, 7.17.
P r od u ct 13b. From 0.30 g (0.71 mmol) of 12 and 0.29 g
(1.1 mmol) of persilylated thymine (0.29 g, 1.1 mmol) was
isolated 0.22 g (59%) of 13b with a diastereomeric purity in
excess of 97:3 after chromatography on silica gel (elution with
3:2 hexane-ether): colorless syrup; 1H NMR (300 MHz,
CDCl3) δ 7.94 (s, 1 H), 7.44-7.40 (m, 2 H), 7.27-7.21 (m, 3
H), 6.88 (d, J ) 1.2 Hz, 1 H), 5.99 (d, J ) 8.6 Hz, 1 H), 4.03 (t,
J ) 7.3 Hz, 1 H), 3.62 (dt, J ) 10.8, 8.3 Hz, 1 H), 2.82 (dd, J
) 12.8, 8.1 Hz, 1 H), 2.00-1.57 (m, 10 H), 0.94 (s, 9 H), 0.12
For 15b: 1H NMR (500 MHz, CDCl3) δ 8.44 (br s, 1 H), 7.40
(d, J ) 1.0 Hz, 1 H), 7.00 (s, 1 H), 6.49 (dd, J ) 5.9, 1.7 Hz, 1
H), 5.83 (d, J ) 5.9 Hz, 1 H), 4.19-4.16 (m, 1 H), 2.40-1.47
(series of m, 9 H) (OH not observed); 13C NMR (125 MHz,
CDCl3) δ 163.7, 150.6, 137.8, 136.7, 125.2, 100.7, 90.0, 79.7,
35.4, 33.3, 30.8, 20.1, 12.9; ES HRMS m/z (M + Na)+ calcd
287.1002, obsd 287.1011; [R]18 -3.0 (c 0.10, C2H5OH).
(24) (a) Kawakami, H.; Ebata, T.; Koseki, K.; Matsushita, H.; Naoi,
Y.; Itoh, K. Chem. Lett. 1990, 1459. (b) Kawakami, H.; Ebata, T.;
Koseki, K.; Matsumoto, K.; Matsushita, H.; Naoi, Y.; Itoh, K. Hetero-
cycles 1991, 32, 2451. (c) Kawakami, H.; Ebata, T.; Koseki, K.;
Matsumoto, K.; Okano, K.; Matsushita, H. Nucleosides Nucleotides
1992, 11, 1673.
D
Hyd r ogen a tion of 14a . A 0.17 g (0.47 mmol) sample of
14a was dissolved in ethanol (15 mL) and admixed with 5%
palladium on charcoal (0.042 g). H2 was bubbled through the
suspension for 5 min, after which time a balloon of H2 was
J . Org. Chem, Vol. 68, No. 22, 2003 8619

Paquette et al.
attached to the flask. The mixture was stirred for 24 h, filtered
through a pad of Celite, and evaporated to give 0.13 g (90%)
of 16a as a white foam: 1H NMR (500 MHz, CDCl3) δ 8.18 (br
s, 1 H), 7.68 (d, J ) 8.1 Hz, 1 H), 6.08-6.06 (m, 1 H), 5.68 (d,
J ) 8.1 Hz, 1 H), 4.17 (t, J ) 7.3 Hz, 1 H), 2.48-2.42 (m, 1 H),
2.27-2.20 (m, 1 H), 2.02-1.85 (m, 3 H), 1.76-1.45 (m, 5 H),
0.91 (s, 9 H), 0.09 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 162.9,
144.3, 140.0, 101.7, 94.9, 85.4, 77.9, 34.3, 32.5, 31.7, 27.7, 25.8
(3C), 18.3, 18.0, -4.0, -4.6; ES HRMS m/z (M + Na)+ calcd
H) (OH and NH not observed); 13C NMR (125 MHz, CD3OD) δ
165.3, 151.9, 136.9, 110.9, 95.5, 88.1, 79.1, 74.0, 70.7, 32.7, 30.0,
25.6 (3C), 18.7, 18.0, 11.6, -4.7, -5.3; ES HRMS m/z (M +
Na)+ calcd 435.1928, obsd 435.1882; [R]18 -20 (c 0.20, C2H5-
D
OH).
Desilyla tion of 18a . A solution of 18a (0.10 g, 0.25 mmol)
in THF (20 mL) was treated with TBAF (1.25 mL of 1 M in
THF, 1.25 mmol), stirred for 1 h, admixed with silica gel (0.05
g), and freed of solvent. The residue was placed atop a column
of silica gel, and the product was eluted with ethyl acetate to
give 0.02 g (50%) of 19a as a white solid: mp 198-200 °C dec;
1H NMR (300 MHz, CD3OD) δ 7.82 (d, J ) 8.1 Hz, 1 H), 5.93
(d, J ) 7.0 Hz, 1 H),5.72 (d, J ) 8.1 Hz, 1 H) 4.39 (dd, J ) 7.0,
5.1 Hz, 1 H), 4.23 (d, J ) 5.1 Hz, 1 H), 4.04 (t, J ) 7.3 Hz, 1
H), 2.28-1.40 (series of m, 6 H) (3 OH and 1 NH not observed);
13C NMR (125 MHz, CD3OD) δ 166.1, 152.8, 142.6, 103.1, 96.6,
89.2, 78.9, 75.9, 71.7, 32.3, 30.7, 19.2; ES HRMS m/z (M +
389.1867, obsd 389.1872; [R]18 -12 (c 0.2, CHCl3).
D
Hyd r ogen a tion of 14b. Hydrogenation of 14b (0.13 g, 0.34
mmol) in the predescribed manner for 24 h provided 0.13 g
(100%) of 16b as a white foam: 1H NMR (300 MHz, CDCl3) δ
8.10 (br s, 1 H), 7.25 (s, 1 H), 6.07 (t, J ) 5.9 Hz, 1 H), 4.10 (t,
J ) 6.4 Hz, 1 H), 2.47-2.24 (m, 2 H), 2.06-1.61 (series of m,
11 H), 0.91 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 163.8, 150.4, 135.2, 110.6, 94.3, 84.7, 77.9, 35.1,
32.0, 32.4, 29.2, 25.8 (3C), 19.1, 18.0, 12.6, -4.1, -4.7; ES
Na)+ calcd 307.0901, obsd 307.0898; [R]18 -31 (c 0.5, C2H5-
D
HRMS m/z (M + Na)+ calcd 403.2023, obsd 403.2044; [R]18
+17 (c 0.3, CHCl3).
OH).
D
Desilyla tion of 18b. Diol 18b (60 mg, 0.15 mmol) was
dissolved in THF (20 mL), treated with TBAF (1.25 mL of 1
M in THF, 1.25 mmol), stirred for 1 h, and processed in the
predescribed manner to furnish 21 mg (50%) of 19b as a white
solid: mp 205-207 °C dec; 1H NMR (500 MHz, CD3OD) δ 7.88
(br s, 1 H), 7.65 (d, J ) 1.1 Hz, 1 H), 5.91 (d, J ) 7.1 Hz, 1 H),
4.40 (dd, J ) 7.1, 5.2 Hz, 1 H), 4.22 (d, J ) 5.2 Hz, 1 H), 4.05
(t, J ) 7.4 Hz, 1 H), 2.40-2.30 (m, 1 H), 2.11-2.03 (m, 1 H),
1.89 (d, J ) 1.1 Hz, 3 H), 1.75-1.65 (m, 3 H), 1.60-1.52 (m, 1
H) (3 OH not observed); 13C NMR (125 MHz, CD3OD) δ 166.3,
153.0, 138.3, 112.0, 96.3, 89.0, 78.9, 75.6, 71.6, 32.4, 30.7, 19.2,
12.4; ES HRMS m/z (M + Na)+ calcd 321.1057, obsd 321.1061;
Desilyla tion of 16a . A solution of 16a (0.09 g, 0.25 mmol)
in THF (20 mL) was treated with the 18-crown-6-CH3CN
complex (0.77 g, 2.5 mmol) and potassium fluoride (0.15 g, 2.5
mmol), stirred at rt for 7 days, and worked up as described
earlier. Elution with ether afforded 0.05 g (83%) of 17a : 1H
NMR (500 MHz, CD3OD) δ 7.95 (d, J ) 8.1 Hz, 1 H), 6.03 (dd,
J ) 6.4, 4.1 Hz, 1 H), 5.66 (d, J ) 8.1 Hz, 1 H), 4.11 (t, J ) 7.1
Hz, 1 H), 2.51-2.42 (m, 1 H), 2.35-2.25 (m, 1 H), 2.12-2.00
(m, 2 H), 1.85-1.64 (m, 5 H), 1.58-1.50 (m, 1 H), (NH and
OH not observed); 13C NMR (125 MHz, CD3OD) δ 166.4, 152.3,
142.4, 102.0, 96.2, 87.1, 77.6, 35.8, 33.1, 32.2, 28.7, 19.5; ES
[R]18 -11 (c 0.10, C2H5OH).
HRMS m/z (M + Na)+ calcd 275.1002, obsd 275.1017; [R]18
+3.5 (c 0.4, C2H5OH).
D
D
Bisu lfid e La cton e 20. Spirolactone 10 (5.00 g, 18.4 mmol)
dissolved in dry THF (60 mL) was cooled to -78 °C, treated
with lithium hexamethyldisilazide (45.0 mL of 1.0 M in THF,
45.0 mmol), and stirred for 1 h in the cold. After the introduc-
tion of phenyl benzenethiosulfonate (11.58 g, 47.2 mmol) as a
solution in dry THF (40 mL), the reaction mixture was held
at -78 °C for 3 h, allowed to warm to rt overnight, and
quenched with saturated NH4Cl solution (50 mL) prior to
extraction with ether (3 × 100 mL). The combined organic
phases were dried and concentrated to leave a residue that
was purified by chromatography on silica gel (elution with 6%
ether in hexane) to give 20 (7.74 g, 86%) as a colorless solid:
Desilyla tion of 16b. A solution of 16b (0.10 g, 0.26 mmol)
in THF (30 mL) was treated with the 18-crown-6-CH3CN
complex (0.79 g, 2.6 mmol) and potassium fluoride (0.15 g, 2.6
mmol), stirred at rt for 7 days, and worked up as described
earlier. Elution with ether gave 17b (0.06 g, 83%): 1H NMR
(500 MHz, CD3OD) δ 7.81 (d, J ) 1.1 Hz, 1 H), 6.05 (dd, J )
6.5, 4.2 Hz, 1 H), 4.12 (t, J ) 7.3 Hz, 1 H), 2.50-2.38 (m, 1 H),
2.33-2.25 (m, 1 H), 2.10-1.98 (m, 2 H), 1.87 (d, J ) 1.1 Hz, 3
H), 1.80-1.62 (m, 5 H), 1.58-1.50 (m, 1 H) (NH and OH not
observed); 13C NMR (125 MHz, CD3OD) δ 166.5, 152.4, 138.2,
111.0, 95.8, 86.7, 77.6, 35.8, 32.9, 32.1, 28.7, 19.4, 12.4; ES
1
mp 115.0-115.8 °C; H NMR (300 MHz, CDCl3) δ 7.73-7.64
HRMS m/z (M + Na)+ calcd 289.1159, obsd 289.1164; [R]18
-1.5 (c 0.8, C2H5OH).
D
(m, 4 H), 7.43-7.33 (m, 6 H), 3.61 (t, J ) 7.1 Hz, 1 H), 2.64 (d,
J ) 14.3 Hz, 1 H), 2.17 (d, J ) 14.3 Hz, 1 H), 2.09 (t, J ) 9.3
Hz, 1 H), 1.83-1.69 (m, 3 H), 1.51-1.43 (m, 2 H), 0.86 (s, 9
H), 0.06 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 172.1, 136.4
(2C), 135.8 (2C), 131.1, 130.6, 130.0 (2C), 129.5 (2C), 129.0 (2C),
90.0, 77.4, 63.0, 42.8, 33.9, 30.2, 25.8 (3C), 18.2, 18.1, -4.4,
-4.6; ES HRMS m/z (M + Na)+ calcd 509.1616, obsd 509.1612;
Gen er a l P r oced u r e for Dih yd r oxyla tion . Either 14a or
14b (1 equiv) was dissolved in a 5:1 acetone-water mixture
(15 mL), treated with osmium tetraoxide (30 mol %) and
N-methylmorpholine-N-oxide (2.5 equiv), stirred for 48 h,
quenched with a saturated solution of Na2S2O3 (15 mL), and
stirred for 30 min. The black mixture was extracted with ethyl
acetate (3×), and the combined organic layers were dried and
evaporated. Chromatography of the residue on silica gel
(elution with hexane-ether 3:2) gave the desired diol.
[R]20 -47.9 (c 1.09, CHCl3).
D
Mon op h en ylth io La cton es 21 a n d 22. To a solution of
20 (7.74 g, 15.8 mmol) in dry THF (100 mL) was added
ethylmagnesium bromide (9.5 mL of 3.0 M in ether, 28.5 mmol)
at -10 °C. After 2 h of stirring in the cold, the reaction mixture
was quenched by the dropwise addition of saturated NH4Cl
solution (50 mL) and extracted with ether (3 × 100 mL). The
combined organic layers were dried and concentrated to leave
a residue that was purified by chromatography on silica gel.
Elution with 4% ether in hexane provided 21 (3.75 g) and 22
(1.24 g) as colorless oils in a combined 83% yield.
18a . From a 0.14 g (0.40 mmol) of 14a was isolated 0.13 g
(87%) of 18a as a colorless syrup: 1H NMR (300 MHz, CDCl3)
δ 9.96 (br s, 1 H), 7.57 (d, J ) 8.2 Hz, 1 H), 5.75 (d, J ) 8.4
Hz, 1 H), 5.71 (d, J ) 4.5 Hz, 1 H), 4.39 (br s, 1 H), 4.34-4.31
(m, 2 H), 4.06 (t, J ) 6.9 Hz, 1 H), 3.03 (br s, 1 H), 2.05-1.96
(m, 1 H), 1.82-1.55 (m, 5 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.05
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.1, 151.5, 139.7, 102.3,
97.2, 91.1, 79.0, 77.2, 71.1, 32.3, 29.0, 25.8 (3C), 18.7, 17.9,
-4.0, -4.8; ES HRMS m/z (M + Na)+ calcd 421.1765, obsd
For 21: 1H NMR (300 MHz, CDCl3) δ 7.53-7.50 (m, 2 H),
7.33-7.28 (m, 3 H), 4.18 (dd, J ) 10.6, 9.3 Hz, 1 H), 3.83 (dd,
J ) 9.0, 7.4 Hz, 1 H), 2.53 (dd, J ) 9.3, 9.0 Hz, 1 H), 2.20 (dd,
J ) 10.7, 12.0 Hz, 1 H), 1.86-1.78 (m, 4 H), 1.65-1.60 (m, 2
H), 0.83 (s, 9 H), 0.04 (s, 3 H), 0.02 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 175.0, 132.9, 132.7 (2C), 129.1 (2C), 128.0, 90.7, 79.6,
46.4, 37.0, 33.1, 30.5, 25.7 (3C), 18.5, 17.8, -4.2, -5.1; ES
421.1754; [R]18 -45 (c 1.4, CHCl3).
D
18b. Reaction of 0.17 g (0.45 mmol) of 14b afforded 0.14 g
(85%) of 18b as a colorless syrup: 1H NMR (500 MHz, CD3-
OD) δ 7.40 (s, 1 H), 5.80 (d, J ) 7.4 Hz, 1 H), 4.27-4.25 (m, 1
H), 4.21 (d, J ) 5.3 Hz, 1 H), 4.15-4.10 (m, 1 H), 2.29-2.24
(m, 1 H), 2.01-1.92 (m, 1 H), 1.84 (s, 3 H), 1.65-1.56 (m, 3
H), 1.55-1.45 (m, 1 H), 0.89 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3
HRMS m/z (M + Na)+ calcd 401.1583, obsd 401.1588; [R]20
+26.2 (c 1.05, CHCl3).
D
8620 J . Org. Chem., Vol. 68, No. 22, 2003

Conformational Restriction of Nucleosides by Spirocyclic Annulation
1
For 22: 1H NMR (300 MHz, CDCl3) δ 7.56-7.53 (m, 2 H),
7.35-7.29 (m, 3 H), 4.03 (t, J ) 9.9 Hz, 1 H), 3.75 (t, J ) 7.4
Hz, 1 H), 2.39 (dd, J ) 13.0, 9.6 Hz, 1 H), 2.24 (dd, J ) 13.0,
10.2 Hz, 1 H), 2.02-1.58 (series of m, 6 H), 0.86 (s, 9 H), 0.03
(s, 6 H); 13C NMR (75 MHz, CDCl3) δ 174.5, 133.0, 132.9 (2C),
129.4 (2C), 128.3, 91.1, 77.4, 46.4, 36.6, 33.8, 30.6, 26.1 (3C),
18.4, 18.3, -4.2, -4.4; ES HRMS m/z (M + Na)+ calcd
25a : colorless needles; mp 165.9-169.3 °C; H NMR (300
MHz, CDCl3) δ 8.10 (d, J ) 8.2 Hz, 1 H), 8.02 (br s, 1 H), 7.44-
7.41 (m, 2 H), 7.28-7.23 (m, 3 H), 6.11 (d, J ) 8.2 Hz, 1 H),
5.30 (dd, J ) 2.1, 6.0 Hz, 1 H), 3.84 (dd, J ) 2.3, 7.7 Hz, 1 H),
3.74 (dt, J ) 7.5, 11.6 Hz, 1 H), 2.39-2.22 (m, 1 H), 2.17-2.08
(m, 1 H), 1.87-1.57 (series of m, 6 H), 0.93 (s, 9 H), 0.12 (s, 3
H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 164.8, 150.2,
140.8, 133.7 (2C), 132.2, 129.3 (2C), 128.4, 102.7, 89.8, 88.3,
80.3, 51.2, 38.1, 34.8, 30.7, 26.2 (3C), 18.4, 15.5, -4.2, -4.5;
401.1583, obsd 401.1595; [R]20 +19 (c 0.57, CHCl3).
D
Equ ilibr a tion of 22 w ith 21. A solution of 22 (1.34 g, 3.5
mmol) in THF (15 mL) was treated with DBU (0.05 mL, 0.3
mmol), stirred overnight at rt, diluted with 10% HCl (2 mL),
and extracted with ethyl acetate (2 × 15 mL). The combined
organic phases were washed with brine (3 mL), dried, and
concentrated. Chromatography of the residue on silica gel
(elution with 3% ether in hexanes) afforded 21 (1.10 g, 83%)
in addition to unreacted 22 (0.15 g, 12%).
Red u ction a n d Acetyla tion of 21. A solution of 21 (100
mg, 0.26 mmol) in dry CH2Cl2 (16 mL) was treated with
Dibal-H (0.3 mL of 1 M, 0.30 mmol) at -78 °C, stirred at this
temperature for 2 h, quenched with saturated Rochelle’s salt
solution (16 mL), and stirred overnight. The separated aqueous
phase was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic layers were dried and evaporated to provide
the crude lactol that was immediately acetylated.
The above material was dissolved in pyridine (2 mL), treated
with acetic anhydride (0.5 mL) at rt, stirred overnight, and
evaporated to dryness under high vacuum. The residue was
dissolved in ethyl acetate (10 mL), washed sequentially with
saturated CuSO4 solution (5 mL), water (5 mL), and brine (5
mL), dried, and concentrated. Purification of the residue by
chromatography on silica gel (elution with 95:5 petroleum
ether-ether) gave 38.7 mg (34%) of 23 and 43.7 mg (39%) of
24, both as colorless oils.
ES HRMS m/z (M + Na)+ calcd 497.1901, obsd 497.1879; [R]19
D
+36 (c 0.71, CHCl3).
1
25b: white solid; mp 167.2-168.4 °C; H NMR (300 MHz,
CDCl3) δ 7.85 (br s, 1 H), 7.55 (d, J ) 1.2 Hz, 1 H) 7.43-7.40
(m, 2 H), 7.24-7.22 (m, 3 H), 6.08 (d, J ) 8.8 Hz, 1 H), 3.82 (t,
J ) 7.4 Hz, 1 H), 3.74-3.65 (m, 1 H), 2.35 (dd, J ) 12.9, 7.4
Hz, 1 H), 2.09 (t, J ) 12.9 Hz, 1 H), 1.85-1.53 (series of m, 6
H), 1.81 (d, J ) 1.2 Hz, 3 H), 0.96 (s, 9 H), 0.14 (s, 3 H), 0.13
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.1, 150.2, 135.3, 133.5
(2C), 132.2, 129.0 (2C), 128.1, 111.0, 88.7, 87.3, 79.9, 50.2, 37.7,
34.3, 30.2, 29.7, 26.0 (3C), 18.2, 12.2, -4.2, -4.7; ES HRMS
m/z (M + Na)+ calcd 511.2057, obsd 511.2055; [R]20 +44 (c
D
0.50, CHCl3).
26: colorless oil; inseparable 4:3 mixture of diastereomers;
1H NMR (300 MHz, CDCl3) δ 9.48-9.47 (m,1 H), 7.42-7.38
(m, 2 H), 7.31-7.24 (m, 3 H), 3.95 (td, J ) 7.4, 3.0 Hz, 0.5 H),
3.76 (td, J ) 7.5, 3.1 Hz, 0.5 H), 2.43-1.99 (series of m, 4 H),
1.86-1.73 (series of m, 2 H), 1.71-1.47 (series of m, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 219.9, 219.7, 194.7, 194.4, 133.4 (2C),
133.3 (2C), 131.8, 131.4, 129.2 (4C), 128.5, 128.4, 55.1, 55.0,
46.4, 45.8, 37.8 (2C), 30.1, 29.9, 28.1, 27.7, 20.6, 20.5; HRMS
m/z (M + Na)+ calcd 271.0763, obsd 271.0762.
Gen er a l Glycosid a tion of 23 in Aceton itr ile Solu tion .
The silylated base (1.4 mmol) and anomeric acetate 23 (300
mg, 0.71 mmol) were dissolved in dry acetonitrile (3.0 mL),
cooled to -78 °C, treated with tin(IV) chloride (2.8 mL of 1 M
in CH2Cl2, 2.8 mmol), allowed to warm to rt over the course of
4 h, and stirred overnight. The reaction mixture was quenched
with saturated NaHCO3 solution (6 mL), the aqueous phase
was extracted with ethyl acetate (3 × 20 mL), and the
combined organic layers were dried and freed of solvent. The
residue was chromatographed on silica gel (elution with 4:3
ethyl acetate-hexane) to give 144 mg (56%) of 27a or 179 mg
(69%) of 27b.
For 23 (predominant anomer): 1H NMR (300 MHz, CDCl3)
δ 7.41-7.38 (m, 2 H), 7.31-7.23 (m, 3 H), 6.22 (d, J ) 1.7 Hz,
1 H), 3.90-3.85 (m, 1 H), 3.74-3.70 (m, 1 H), 2.37 (dd, J )
13.3, 7.6 Hz, 1 H), 2.25-1.50 (series of m, 10 H), 0.90 (s, 9 H),
0.08 (s, 3 H), 0.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.0,
134.3, 131.5 (2C), 128.9 (2C), 127.2, 102.4, 93.9, 78.1, 51.5, 37.3,
34.6, 30.8, 25.7 (3C), 21.3, 18.4, 18.1, -4.5, -4.7; ES HRMS
m/z (M + Na)+ calcd 445.1839, obsd 445.1814; [R]20 +28 (c
D
2.0, CHCl3) (for the diastereomeric mixture).
For 24: 1H NMR (300 MHz, CDCl3) δ 7.48-7.44 (m, 2 H),
7.31-7.20 (m, 3 H), 4.24 (dd, J ) 5.7, 1.1 Hz, 2 H), 3.76 (t, J
) 6.9 Hz, 1 H), 3.68 (pent, J ) 5.6 Hz, 1 H), 2.67 (s, 1 H), 2.02
(s, 3 H), 1.98-1.45 (series of m, 8 H), 0.88 (s, 9 H), 0.06 (s, 3
H), 0.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.8, 134.5,
132.1 (2C), 128.9 (2C), 127.1, 79.4, 78.6, 66.7, 43.1, 40.4, 35.3,
31.3, 25.8 (3C), 20.8, 19.4, 17.9, -4.3, -4.9; ES HRMS m/z (M
For 27a : white solid; mp 187.2-190.0 °C; 1H NMR (300
MHz, CDCl3) δ 8.51 (br s, 1 H), 7.44-7.41 (m, 2 H), 7.33 (d, J
) 8.1 Hz, 1 H), 7.27-7.24 (m, 3 H), 5.73 (d, J ) 8.0 Hz, 1 H),
5.53 (dd, J ) 8.1, 1.5 Hz, 1 H), 4.21-4.09 (m, 1 H), 3.90 (q, J
) 7.3 Hz, 1 H), 2.55 (dd, J ) 13.1, 7.9 Hz, 1 H), 2.09-1.92 (m,
3 H), 1.86-1.52 (series of m, 4 H)(OH not observed); 13C NMR
(75 MHz, CDCl3) δ 162.3, 150.0, 141.7, 133.0 (2C), 131.9, 129.3
(2C), 128.3, 102.7, 93.8, 90.3, 78.1, 47.8, 38.7, 35.6, 31.4, 18.8;
+ Na)+ calcd 447.1996, obsd 447.1981; [R]19 +6.4 (c 2.9,
D
CHCl3).
ES HRMS m/z (M + Na)+ calcd 383.1036, obsd 383.1016; [R]19
D
Red u ction of 21 w ith Min im ized Over r ed u ction . Treat-
ment of a solution of 21 (50 mg, 0.13 mmol) and trimethylsilyl
chloride (0.10 mL) in dry CH2Cl2 (8 mL) with Dibal-H (1.5 mL
of 1 M in hexane, 0.15 mmol) at -78 °C was followed by
application of the preceding procedure. There were isolated
32.1 mg (66%) of 23 and 2.2 mg (4%) of 24.
Gen er a l Glycosid a tion of 23 in CH2Cl2 Solu tion . The
silylated base (1.0 mmol) and 23 (202 mg, 0.48 mmol) were
dissolved in CH2Cl2 (2.5 mL), cooled to -78 °C, and treated
with tin tetrachloride (1.9 mL of 1 M in CH2Cl2, 2 equiv). The
reaction mixture was maintained at -78 °C for 15 min, allowed
to warm to rt, quenched with saturated NaHCO3 solution (3
mL), and extracted with CH2Cl2. The combined organic layers
were dried and concentrated to leave a residue that was
chromatographed on silica gel (elution with 3:1 hexane-ether)
to give the nucleoside.
+65 (c 0.53, CHCl3-CH3OH 1:1).
For 27b: white solid; mp 201.1-202.8 °C; 1H NMR (300
MHz, CDCl3) δ 8.18 (br s, 1 H), 7.44-7.39 (m, 2 H), 7.26-7.22
(m, 3 H), 6.92 (d, J ) 1.2 Hz, 1 H), 5.60 (d, J ) 8.1 Hz, 1 H),
4.27 (dt, J ) 10.6, 8.3 Hz, 1 H), 3.89 (q, J ) 7.1 Hz, 1 H), 3.04
(d, J ) 7.1 Hz, 1 H), 2.56 (dd, J ) 13.0, 8.0 Hz, 1 H), 2.04-
1.93 (m, 3 H), 1.75 (d, J ) 1.2 Hz, 3 H), 1.74-1.52 (m, 3 H)
(OH not observed); 13C NMR (75 MHz, CDCl3) δ 162.9, 150.1,
137.7, 132.9 (2C), 132.1, 129.1 (2C), 128.1, 110.9, 94.9, 90.2,
78.1, 47.1, 38.7, 35.7, 31.4, 18.9, 12.3; ES HRMS m/z (M +
Na)+ calcd 397.1192, obsd 397.1163; [R]20 +12 (c 0.95, CH3-
D
OH-CHCl3 9:1).
For the diastereomer of 27b: white solid; mp 117.4-119.9
°C; 1H NMR (300 MHz, CDCl3) δ 7.95 (br s, 1 H), 7.35 (d, J )
1.1 Hz, 1 H), 7.29-7.16 (m, 5 H), 6.33 (d, J ) 5.1 Hz, 1 H),
4.42 (dt, J ) 7.9, 5.0 Hz, 1 H), 3.77 (dd, J ) 13.4, 6.6 Hz, 1 H),
2.69 (dd, J ) 13.9, 7.9 Hz, 1 H), 2.28-2.22 (m, 1 H), 2.20-
2.05 (m, 2 H), 1.96 (d, J ) 1.1 Hz, 3 H), 2.02-1.56 (series of
m, 4 H) (OH not observed); 13C NMR (75 MHz, CDCl3) δ 163.1,
149.8, 135.9, 133.5, 129.9 (2C), 128.9 (2C), 127.3, 109.4, 90.7,
For 25a : 62.9 mg (22%) of the uridine and 36.2 mg (26%)
of aldehyde 26.
For 25b: 30.1 mg (17%) of the thymidine and 66 mg (48%)
of aldehyde 26.
J . Org. Chem, Vol. 68, No. 22, 2003 8621

Paquette et al.
86.9, 78.2, 49.3, 39.4, 35.5, 31.3, 19.0, 12.7; ES HRMS m/z (M
+ Na)+ calcd 397.1192, obsd 397.1202.
) 8.2 Hz, 1 H), 2.21-1.42 (series of m, 6 H); 13C NMR (125
MHz, CDCl3) δ 169.2, 166.5, 162.9, 150.1, 140.3, 138.5, 135.5,
134.2, 133.1, 130.9 (2C), 130.2 (2C), 130.1, 129.5 (2C), 129.1
(2C), 126.2, 102.8, 98.1, 89.4, 77.7, 35.6, 28.7, 19.1; ES HRMS
Oxid a tive Elim in a tion of 27a . A solution of 27a (122 mg,
0.34 mmol) in CHCl3 (10.0 mL) was treated at rt with the
Davis oxaziridine (98 mg, 0.37 mmol), stirred for 4 h, concen-
trated under reduced pressure, and redissolved in pyridine (1
mL), diluted with xylene (4 mL), refluxed for 4 h, and freed of
solvent. The residue was chromatographed on silica gel (elu-
tion with 1:1 hexane-ethyl acetate) to give 28a (79.1 mg, 85%)
as a white solid: mp 84.7-86.1 °C; 1H NMR (300 MHz, CDCl3)
δ 8.93 (br s, 1 H), 7.68 (d, J ) 8.1 Hz, 1 H), 7.09 (t, J ) 1.5 Hz,
1 H), 6.26 (dd, J ) 5.9, 1.9 Hz, 1 H), 5.75 (dd, J ) 5.9, 1.3 Hz,
1 H), 5.69 (dd, J ) 8.1, 1.4 Hz, 1 H), 4.03 (q, J ) 7.2 Hz, 1 H),
2.32 (d, J ) 9.4 Hz, 1 H), 2.12-2.05 (m, 1 H), 1.95-1.82 (m, 2
H), 1.76-1.58 (series of m, 2 H) (OH not observed); 13C NMR
(75 MHz, CDCl3) δ 163.2, 151.0, 140.9, 139.1, 124.6, 102.4,
m/z (M + Na)+ calcd 481.1370, obsd 481.1371; [R]20 -25 (c
D
0.96, CHCl3).
For 32b: white solid; mp 161.2-162.7 °C; 1H NMR (300
MHz, CDCl3) δ 8.04 (dd, J ) 8.2, 1.3 Hz, 2 H), 7.90 (dd, J )
8.3, 1.2 Hz, 2 H), 7.68-7.53 (m, 2 H), 7.51-7.42 (m, 4 H), 7.03
(d, J ) 1.2 Hz, 1 H), 6.97-6.91 (m, 1 H), 6.39 (dd, J ) 5.9, 2.0
Hz, 1 H), 5.80 (dd, J ) 5.9, 1.3 Hz, 1 H), 5.45 (t, J ) 7.9 Hz,
1 H), 2.22-1.93 (m, 5 H), 1.77-1.69 (m 1 H), 1.28 (d, J ) 1.1
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 169.0, 166.4, 162.8,
138.3, 135.5, 134.9, 133.5, 131.7, 130.6 (2C), 129.7 (2C), 129.6,
129.1 (2C), 128.5 (2C), 125.4, 111.4, 97.2, 88.9, 76.8, 35.4, 28.8,
18.9, 11.7; ES HRMS m/z (M + Na)+ calcd 495.1527, obsd
495.1517; [R]20 -17 (c 0.92, CHCl3).
98.6, 89.1, 76.8, 34.9, 32.4, 19.0; [R]19 +24 (c 0.60, CH3OH).
D
D
Dih yd r oxyla tion of 32a . A 96.0 mg (0.209 mmol) sample
of 32a was dissolved in THF (12 mL) containing pyridine (3
mL) and treated with a solution of osmium tetraoxide (53.6
mg, 0.211 mmol) in pyridine (1 mL). After 18 h of stirring, the
volatiles were removed under reduced pressure. This material
was used directly. An analytical sample was purified by
chromatography on silica gel (elution with hexane-ethyl
acetate 1:1 to 100% ethyl acetate) to furnish the osmate ester
vii as a brown oil: 1H NMR (500 MHz, CDCl3) δ 8.86 (s, 4 H),
8.11 (t, J ) 8.0 Hz, 3 H), 7.95 (d, J ) 7.5 Hz, 4 H), 7.61 (q, J
) 7.2 Hz, 2 H), 7.56 (s, 4 H), 7.50 (t, J ) 7.9 Hz, 2 H), 7.45-
7.42 (m, 2 H), 6.45 (d, J ) 4.9 Hz, 1 H), 6.05 (t, J ) 2.8 Hz, 1
H), 5.65 (d, J ) 8.2 Hz, 1 H), 5.23 (t, J ) 5.4 Hz, 1 H), 4.89 (d,
J ) 6.0 Hz, 1 H), 2.21-1.50 (series of m, 6 H); ES HRMS m/z
(M - py + Na)+ calcd 816.1203, obsd 816.1218.
Oxid a tive Elim in a tion of 27b. Entirely comparable treat-
ment of 27b (127 mg, 0.34 mmol) afforded 70 mg (78%) of 28b
as a white solid: mp 228.1-229.0 °C dec; 1H NMR (300 MHz,
CDCl3) δ 8.53 (br s, 1 H), 7.46 (d, J ) 1.2 Hz, 1 H), 7.10 (t, J
) 1.5 Hz, 1 H), 6.26 (dd, J ) 5.9, 1.9 Hz, 1 H), 5.74 (dd, J )
5.9, 1.2 Hz, 1 H), 4.08-4.00 (m, 1 H), 2.26 (d, J ) 9.6 Hz, 1
H), 2.13-2.04 (m, 1 H), 1.95-1.72 (m, 2 H), 1.87 (s, 3 H), 1.70-
1.57 (m, 2 H) (OH not observed); 13C NMR (75 MHz, CDCl3) δ
163.6, 150.9, 138.9, 136.4, 124.8, 110.9, 98.3, 88.9, 76.9, 34.9,
32.4, 19.1, 12.3; ES HRMS m/z (M + Na)+ calcd 287.1002, obsd
287.1014; [R]20 +76 (c 0.92, CHCl3).
D
Hyd r ogen a tion of 28a . A solution of 28a (13.9 mg, 0.054
mmol) in ethanol (3 mL) was treated with 10% palladium on
carbon (2.6 mg), stirred overnight under 50 psi of H2 in a
pressure reactor, and filtered through a pad of Celite (rinsed
with 3 × 5 mL of methanol). Since reaction was incomplete,
the sample was submitted two more times to the above
protocol. The solvent was evaporated, and the residue was
purified by chromatography on silica gel (elution with 3:2 ethyl
acetate-hexane) to give 12.1 mg (89%) of 31a as a white
1
solid: mp 272.1-273.5 °C dec; H NMR (300 MHz, CDCl3) δ
8.74 (br s, 1 H), 7.82 (d, J ) 7.5 Hz, 1 H), 6.17 (dd, J ) 3.4, 2.1
Hz, 1 H), 5.74 (d, J ) 7.2 Hz, 1 H), 3.94 (t, J ) 7.0 Hz, 1 H),
2.52-1.57 (series of m, 10 H); 13C NMR (75 MHz, CDCl3) δ
163.2, 150.4, 140.6, 102.3, 92.7, 85.7, 77.1, 34.8, 32.2, 31.8, 31.7,
18.7; ES HRMS m/z (M + Na)+ calcd 275.1002, obsd 275.0994;
The osmate ester was dissolved in THF (12 mL), and H2S
was bubbled through the solution for 15 min, during which
time a black precipitate formed and TLC indicated the
consumption of starting material. This mixture was purged
with N2 for 5 min, filtered through a pad of Celite, rinsed with
ether, and concentrated. The residue was chromatographed
on silica gel (elution with hexane-ethyl acetate 1:1) to give
21.7 mg (21%) of 33a and 7.2 mg (7%) of 34a .
[R]20 +17 (c 0.82, CH3OH).
D
Hyd r ogen a tion of 28b. A solution of 28b (15.8 mg, 0.060
mmol) in ethanol (3 mL) was hydrogenated similarly over 10%
palladium on carbon (2.9 mg). Only one pass was necessary
to deliver 31b (14.6 mg, 92%) as a white solid: mp 172.3 °C
dec; 1H NMR (300 MHz, CDCl3) δ 8.05 (dd, J ) 8.5, 1.4 Hz, 2
H), 7.91 (dd, J ) 8.5, 1.3 Hz, 2 H), 7.63 (t, J ) 1.1 Hz, 1 H),
6.98 (t, J ) 1.4 Hz, 1 H), 6.40 (dd, J ) 5.9, 1.9 Hz, 1 H), 5.79
(dd, J ) 5.9, 1.2 Hz, 1 H), 5.46 (t, J ) 7.9 Hz, 1 H), 2.22-1.93
(m, 5 H), 1.77-1.74 (m, 1 H), 1.27 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 169.2, 166.3, 150.1, 138.5, 135.7, 135.2, 133.8, 131.8,
130.7 (2C), 129.9 (2C), 129.8 (2C), 129.3 (2C), 128.9, 125.5,
111.2, 97.4, 89.1, 76.9, 35.6, 29.0, 19.0, 11.9; ES HRMS m/z
For 33a : white solid; mp 102.4-103.5 °C; 1H NMR (300
MHz, CDCl3) δ 8.05 (d, J ) 1.4 Hz, 2 H), 7.94 (d, J ) 4.3 Hz,
1 H), 7.88 (dd, J ) 7.2, 1.1 Hz, 2 H), 7.65-7.60 (m, 2 H), 7.47
(q, J ) 8.2 Hz, 4 H), 6.03 (d, J ) 4.3 Hz, 1 H), 5.71 (t, J ) 6.9
Hz, 1 H), 5.52 (d, J ) 8.3 Hz, 1 H), 4.49-4.44 (m, 1 H), 3.66
(d, J ) 8.1 Hz, 1 H), 2.38-1.64 (series of m, 6 H) (neither OH
observed); 13C NMR (75 MHz, CDCl3) δ 168.6, 167.2, 163.0,
149.9, 141.6, 135.1, 131.5, 130.5 (2C), 127.8 (2C), 129.1 (2C),
128.7, 128.6 (2C), 100.8, 91.8, 84.8, 77.2, 74.5, 71.6, 35.2, 29.7,
29.2, 19.1; ES HRMS m/z (M + Na)+ calcd 515.1424, obsd
(M + Na)+ calcd 495.1527, obsd 495.1517; [R]20 -44 (c 0.87,
D
CHCl3).
Ben zoyla tion of 28a a n d 28b. The spironucleoside (0.11
mmol) was dissolved in dry pyridine (4 mL), treated with
benzoyl chloride (0.5 mL), and stirred overnight. The volatiles
were removed, and the residue was dissolved in CH2Cl2 (30
mL) and washed with brine. The combined organic phases
were dried and evaporated to leave a residue that was purified
by chromatography on silica gel. Elution with 2:1 hexane-
ethyl acetate gave 32a (39 mg, 78%) as well as 32b (47.2 mg,
91%).
For 32a : pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 8.04
(dd, J ) 6.1, 1.1 Hz, 2 H), 7.91 (dd, J ) 8.2, 1.2 Hz, 2 H), 7.66-
7.61 (m, 2 H), 7.59-7.50 (m, 4 H), 7.45 (d, J ) 1.9 Hz, 1 H),
6.97 (t, J ) 1.5 Hz, 1 H), 6.34 (dd, J ) 5.9, 1.9 Hz, 1 H), 5.78
(dd, J ) 5.8, 1.3 Hz, 1 H), 5.49 (t, J ) 8.0 Hz, 1 H), 5.22 (d, J
515.1458; [R]20 +41 (c 0.53, CHCl3).
D
For 34a : 1H NMR (300 MHz, CDCl3) δ 8.06 (dd, J ) 8.4,
1.4 Hz, 2 H), 7.92 (dd, J ) 8.4, 1.3 Hz, 2 H), 7.64-7.56 (m, 2
H), 7.50-7.43 (m, 4 H), 6.82 (t, J ) 1.6 Hz, 1 H), 6.24 (dd, J
) 5.9, 2.0, 1 H), 5.94 (dd, J ) 5.9, 1.2 Hz, 1 H), 5.45-5.38 (m,
2 H), 4.45 (d, J ) 3.2 Hz, 1 H), 3.45 (br s, 1 H), 2.87 (br s, 1
H), 2.19-2.02 (m, 4 H), 1.85-1.75 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 169.5, 167.2, 163.0, 149.7, 136.7, 134.9, 133.4, 130.5
(2C), 129.8, 129.7 (2C), 129.1 (2C), 128.7 (2C), 127.4, 126.0,
96.5, 88.9, 77.3, 73.3, 69.5, 34.6, 28.8, 9.1; ES HRMS m/z (M
+ Na)+ calcd 515.1424, obsd 515.1417; [R]17 +78 (c 0.52,
D
CHCl3).
8622 J . Org. Chem., Vol. 68, No. 22, 2003

Conformational Restriction of Nucleosides by Spirocyclic Annulation
Dih yd r oxyla tion of 32b. A 94 mg (0.199 mmol) sample of
32b was dissolved in THF (12 mL) containing pyridine (3 mL)
and treated with a solution of osmium tetraoxide (51.1 mg,
0.201 mmol) in pyridine (1 mL). After 18 h of stirring, the
volatiles were removed under reduced pressure. This osmate
ester was dissolved in THF (12 mL), and H2S was bubbled
through the solution for 15 min, during which time a black
precipitate formed and TLC indicated the consumption of
starting material. This mixture was purged with N2 for 5 min,
filtered through a pad of Celite, rinsed with ether, and
concentrated. The residue was chromatographed on silica gel
(elution with hexane-ethyl acetate 1:1) to give 5.7 mg (6%) of
33b and 25.1 mg (25%) of 34b.
rated to leave a residue that was chromatographed on silica
gel. Elution with 3:1 hexanes-ethyl acetate furnished 0.09 g
(100%) of 36 as a white foam: 1H NMR (300 MHz, CDCl3) δ
8.21 (br s, 1 H), 7.70 (d, J ) 1.1 Hz, 1 H), 6.83 (t, J ) 1.4 Hz,
1 H), 6.05 (dd, J ) 5.9, 1.9 Hz, 1 H), 5.91 (dd, J ) 5.9, 1.1 Hz,
1 H), 4.06 (t, J ) 7.1 Hz, 1 H), 2.07-1.70 (m, 9 H), 0.88 (s, 9
H), 0.07 (s, 3 H), 0.05 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
163.7, 153.5, 136.6 (2 C), 127.1, 109.9, 98.8, 89.4, 77.2, 36.4,
33.7, 25.8 (3 C), 18.6, 18.3, 12.7, -4.3, -4.5; ES HRMS m/z
(M + Na)+ calcd 401.1867, obsd 401.1886.
Dih yd r oxyla tion of 36. To a solution of 36 (0.10 g, 0.26
mmol) in 8:1 acetone-water (6 mL) were added osmium
tetraoxide (0.008 g, 0.032 mmol) and NMO (0.092 g, 0.80
mmol). The yellow reaction mixture was stirred for 24 h,
quenched with saturated Na2S2O4 solution, and agitated for a
final 30 min. After extraction with ethyl acetate (3 × 5 mL),
the combined organic layers were dried and evaporated. The
residue was purified by chromatography on silica gel (elution
with 1.5 hexanes-ethyl acetate) to give 37 (0.04 g, 36%) as a
For 33b: colorless gum; 1H NMR (300 MHz, CDCl3) δ 8.09
(d, J ) 7.1 Hz, 2 H), 7.87 (d, J ) 7.3 Hz, 2 H), 7.66-7.59 (m,
3 H), 7.46 (q, J ) 7.7 Hz, 4 H), 6.00 (d, J ) 5.0 Hz, 1 H), 5.75
(t, J ) 6.3 Hz, 1 H), 4.51-4.49 (m, 1 H), 4.13-4.12 (m, 1 H),
3.76 (br d, J ) 5.5 Hz, 1 H), 2.24 (br s, 1H), 2.23-2.01 (m, 3
H), 1.84-1.80 (m, 1H), 1.74 (s, 3H), 1.60-1.48 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ 168.9, 162.8, 150.0, 137.7, 134.9,
133.6, 131.6, 130.4 (2C), 129.8 (2C), 129.1 (2C), 128.6 (2C),
109.5, 91.7, 84.8, 77.2, 74.7, 71.6, 35.1, 29.7, 19.4, 12.2; ES
1
white solid: mp 122-123.5 °C; H NMR (300 MHz, CDCl3) δ
9.10 (br s, 1 H), 7.80 (d, J ) 1.2 Hz, 1 H), 5.76 (d, J ) 5.7 Hz,
1 H), 4.90 (br s, 1 H), 4.34 (t, J ) 5.3 Hz, 1 H), 4.08 (d, J ) 5.1
Hz, 1H), 3.96 (dd, J ) 10.3, 7.2 Hz, 1 H), 3.24 (br s, 1 H), 2.08-
1.61 (m, 9 H), 0.84 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 163.8, 152.0, 136.6, 109.8, 96.6, 91.3,
77.6, 77.2, 74.8, 313, 29.2, 25.7 (3 C), 18.0, 17.9, 12.7, -4.5,
-4.9; ES HRMS m/z (M + Na)+ calcd 435.1922, obsd 435.1936.
HRMS m/z (M + Na)+ calcd 529.1581, obsd 529.1566; [R]19
+27 (c 0.65, CHCl3).
D
For 34b: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J ) 7.3 Hz,
2 H), 7.93 (d, J ) 7.3 Hz, 2 H), 7.61-7.54 (m, 2 H), 7.45 (t, J
) 7.7 Hz, 4 H), 6.83 (s, 1 H), 6.20 (dd, J ) 5.9, 1.9 Hz, 1 H),
5.92 (d, J ) 5.9 Hz, 1 H), 5.37 (t, J ) 6.5 Hz, 1H), 5.13 (s, 1
H), 2.19-1.76 (series of m, 6 H), 2,03 (s, 3H) (2 OH not
observed); 13C NMR (75 MHz, CDCl3) δ 172.8, 167.9, 166.5,
149.8, 135.7, 134.9, 133.3, 131.9, 130.4 (2C), 130.1 (2C), 129.1
(2C), 128.5 (2C), 128.4, 126.9, 96.2, 88.3, 77.6, 77.2, 72.7, 34.0,
28.2, 21.9, 18.5; ES HRMS m/z (M + Na)+ calcd 529.1581, obsd
Desilyla tion of 37. A solution of 37 (0.02 g, 0.05 mmol) in
absolute ethanol (4 mL) was treated with pyridinium p-
toluenesulfonate (0.02 g, 0.084 mmol) followed by one drop of
concentrated HCl. The reaction mixture was heated overnight
at 60 °C, cooled, admixed with silica gel (0.3 g), and freed of
solvent under reduced pressure. The residue was loaded atop
a column of silica gel. Elution with 9:1 ethyl acetate-methanol
afforded 6 mg (60%) of 38 as a white solid: mp 254.5-257.5
°C dec; IR (CH3CN, cm-1) 3628, 3537, 1695, 1634; 1H NMR
(300 MHz, CD3OD) δ 8.11 (d, ) 1.2 Hz, 1H), 5.92 (d, J ) 6.1
Hz, 1 H), 4.33 (dd, J ) 5.8, 5.3 Hz, 1 H), 4.01 (d, J ) 5.1 Hz,1
H), 3.91 (t, J ) 8.0 Hz, 1 H) 2.09-1.54 (m, 9 H) (3 OH and
NH protons not observed); 13C NMR (75 MHz, CD3OD) δ 166.6,
153.1, 139.5, 111.5, 94.8, 89.8, 77.2, 75.6, 74.5, 32.3, 31.1, 19.4,
12.6; ES HRMS m/z (M + Na)+ calcd 321.1057, obsd 321.1037;
529.1600; [R]19 +44 (c 0.78, CHCl3).
D
Sa p on ifica tion of 33a . A solution of 33a (21.7 mg, 0.044
mmol) in methanol (10 mL) was saturated with NH3 by
bubbling ammonia gas into the solution for 1 h at rt. The
reaction vessel was sealed with a rubber septum and allowed
to stir for 12 h. The solvent was removed under reduced
pressure, and the residue was chromatographed on silica gel
(elution with ethyl acetate) to give 12.0 mg (96%) of 35a as a
colorless gum: 1H NMR (300 MHz, CD3OD) δ 8.25 (d, J ) 8.1
Hz, 1 H), 6.02 (d, J ) 4.1 Hz, 1 H), 5.63 (d, J ) 8.1 Hz, 1 H),
4.29 (t, J ) 4.3 Hz, 1 H), 4.24-4.20 (m, 2 H), 2.17-1.56 (series
of m, 6 H) (1 NH and 3 OH not observed); 13C NMR (75 MHz,
CD3OD) δ 166.6, 152.3, 144.5, 100.6, 89.9, 86.2, 74.9, 73.1, 72.7,
35.3, 31.7, 19.8; ES HRMS m/z (M + Na)+ calcd 307.0900, obsd
[R]18 +12 (c 1.0, C2H5OH).
D
Gen er a tion of 40a fr om 12. The general glycosylation
procedure for 12 was followed. From 0.30 g (0.71 mmol) of 12,
0.28 g (1.1 mmol) of persilylated cytosine 39, and 1.40 mL of
1 M SnCl4 in CH2Cl2 was produced 0.23 g (67%) of 40a (>97:3
â/R isomeric purity) after chromatography on silica gel (elution
with benzene-ethyl acetate 1:1): colorless gum; 1H NMR (300
MHz, CDCl3) δ 7.42-7.38 (m, 2 H), 7.26 (d, J ) 7.4 Hz, 1 H),
7.22-7.15 (m, 3 H), 6.18 (d, J ) 7.6 Hz, 1 H), 5.79 (d, J ) 7.4
Hz, 1 H), 4.01 (t, J ) 6.4 Hz, 1 H), 3.61 (q, J ) 8.0 Hz, 1 H),
2.75 (dd, J ) 13.0, 7.9 Hz, 1 H), 1.98-1.25 (series of m, 7 H),
0.87 (s, 9 H), 0.06 (s, 6 H) (NH2 protons not seen); 13C NMR
(75 MHz, CDCl3) δ 165.4, 155.9, 140.0, 133.0, 132.9 (2C), 129.0
(2C), 127.6, 95.6, 91.8, 88.8, 78.4, 51.1, 37.2, 35.8, 31.7, 25.8
(3C), 18.6, 17.9, -4.0, -4.7; ES HRMS m/z (M + Na)+ calcd
307.0913; [R]19 +39 (c 0.70, CH3OH).
D
Sa p on ifica tion of 33b. A solution of 33b (5.7 mg, 0.011
mmol) in methanol (5 mL) was saturated with NH3 by bubbling
ammonia gas into the solution for 1 h at rt. The reaction vessel
was sealed with a rubber septum and allowed to stir for 12 h.
The solvent was removed under reduced pressure, and the
residue was chromatographed on silica gel (elution with ethyl
acetate) to give 3.3 mg (97%) of 35b: 1H NMR (300 MHz, CD3-
OD) δ 8.14 (d, J ) 1.1 Hz, 1 H), 6.04 (d, J ) 4.0 Hz, 1 H), 4.30
(t, J ) 4.3 Hz, 1 H), 4.26-4.23 (m, 2 H), 2.03-2.00 (m, 1 H),
1.90 (d, J ) 1.1 Hz, 3 H), 1.88-1.85 (m, 4 H), 1.68-1.61 (m, 1
H) (1 NH and 3 OH not observed); 13C NMR (125 MHz, CD3-
OD) δ 165.7, 151.5, 139.4, 108.2, 92.1, 85.0, 74.0, 72.2, 71.7,
34.3, 30.8, 18.8. 11.5; ES HRMS m/z (M + Na)+ calcd 321.1057,
496.2061, obsd 496.2046; [R]18 +20 (c 1.9, C2H5OH).
D
The above nucleoside (0.16 g, 0.34 mmol) was dissolved in
CH2Cl2 (20 mL), treated with acetic anhydride (0.13 mL, 1.4
mmol), pyridine (0.28 mL, 3.4 mmol), and DMAP (8 mg -
catalytic), and stirred for 1 h prior to quenching with saturated
NaHCO3 solution (30 mL). The product was extracted with
ethyl acetate (3 × 15 mL), the combined organic phases were
dried and evaporated, and the residue was chromatographed
on silica gel. Elution with hexane-ether 1:2 furnished 0.16 g
obsd 321.1068; [R]17 +31 (c 0.43, CH3OH).
D
Oxid a tive Elim in a tion of 25b. A solution of 25b (0.12 g,
0.25 mmol) in CHCl3 (10 mL) was treated with Davis oxaziri-
dine (0.07 g, 0.27 mmol), stirred for 16 h, and quenched with
water (5 mL). The aqueous layer was extracted with CH2Cl2
(3 × 5 mL), and the combined organic phases were washed
with 1 M HCl (10 mL), dried, and evaporated to leave the
sulfoxide that was dissolved in toluene (100 mL) containing
calcium carbonate (100 mg). The suspension was heated
overnight at reflux, cooled, and filtered. The filtrate was
washed with saturated Na2S2O4 solution, dried, and evapo-
1
(89%) of 40a as a white solid: mp 190-192 °C dec; H NMR
(500 MHz, CDCl3) δ 10.33 (br s, 1 H), 7.72 (d, J ) 7.6 Hz, 1
H), 7.43-7.22 (m, 6 H), 6.19 (d, J ) 7.2 Hz, 1 H), 4.10 (t, J )
6.9 Hz, 1 H), 3.70 (q, J ) 7.9 Hz, 1 H), 2.78 (dd, J ) 13.1, 7.9
Hz, 1 H), 2.28 (s, 3 H), 2.05-1.40 (series of m, 7 H), 0.89 (s, 9
H), 0.10 (s, 3 H), 0.09 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ
J . Org. Chem, Vol. 68, No. 22, 2003 8623

Paquette et al.
171.5, 162.9, 155.0, 144.0, 133.0 (2C), 132.9, 129.1 (2C), 127.9,
97.2, 93.1, 89.9, 78.4, 52.0, 37.3, 35.8, 31.6, 25.9 (3C), 24.9,
18.5, 17.9, -4.0, -4.6; ES HRMS m/z (M + Na)+ calcd
aqueous layer was extracted with ethyl acetate (3 × 15 mL),
and the combined organic solutions were dried and evaporated.
Chromatography of the residue on silica gel (elution with 1:1
benzene-ethyl acetate) furnished 60 mg (50%) of 43 as a
colorless syrup: 1H NMR (500 MHz, C6D6) δ 8.53 (br s, 1 H),
7.70-7.68 (m, 2 H), 7.27 (s, 1 H), 7.05-7.02 (m, 3 H), 6.95-
6.92 (m, 3 H), 6.73-6.69 (m, 3 H), 5.54 (d, J ) 8.0 Hz, 1 H),
5.04-5.00 (m, 1 H), 4.27 (t, J ) 8.7 Hz, 1 H), 3.04 (dd, J )
12.6, 7.5 Hz, 1 H), 2.03-1.89 (m, 3 H), 1.59-1.51 (m, 1 H),
1.41-1.32 (m, 3 H) (OH not observed); 13C NMR (125 MHz,
CDCl3) δ 164.2, 152.0, 150.2, 143.0, 139.5, 133.0, 132.2 (2C),
131.8, 129.0 (2C), 128.9 (2C), 128.3, 128.0, 127.8 (2C), 94.1,
93.1, 78.0, 48.5, 38.5, 36.0, 28.6, 17.4 (C4 of adenine not
observed); ES HRMS m/z (M + Na)+ calcd 510.1577, obsd
538.2166, obsd 538.2165; [R]18 +45 (c 2.8, CHCl3).
D
Gen er a tion of 40b fr om 23. The general glycosidation
procedure in acetonitrile was utilized to give 40b in 70% yield
as a white solid: mp 79.8-81.7 °C following chromatographic
purification (elution with 2% CH3OH in CH2Cl2): 1H NMR (300
MHz, CDCl3) δ 10.31 (br s, 1 H), 8.67 (d, J ) 7.5 Hz, 1 H),
7.46-7.43 (m, 2 H), 7.30 (d, J ) 7.5 Hz, 1 H), 7.27-7.21 (m, 3
H), 6.28 (d, J ) 6.9 Hz, 1 H), 3.84 (t, J ) 7.5 Hz, 1 H), 3.71
(dt, J ) 7.1, 7.0 Hz, 1 H), 2.35 (dd, J ) 13.1, 7.3 Hz, 1 H), 2.29
(s, 3 H), 2.10 (dd, J ) 13.1, 9.4 Hz, 1 H), 1.99-1.57 (series of
m, 6 H), 0.93 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 171.4, 162.9, 155.2, 145.3, 133.3 (2C), 132.9,
129.0 (2C), 127.9, 97.0, 91.1, 88.7, 79.3, 53.0, 38.3, 34.7, 30.5,
25.9 (3C), 24.9, 18.2, 18.1, -4.5, -4.7; ES HRMS m/z (M+Na)+
510.1626; [R]19 -14 (c 0.30, CHCl3).
D
Ack n ow led gm en t. We thank the Eli Lilly Co. and
Aventis Pharmaceuticals for their financial support of
this investigation.
calcd 538.2166, obsd 538.2138; [R]20 +89.6 (c 1.32, CHCl3).
D
Gen er a tion of 43 fr om 12. Into a solution of persilylated
benzoyladenine 42 (0.11 g, 0.36 mmol) in dry acetonitrile (10
mL) was introduced neat SnCl4 (0.11 mL, 0.96 mmol), and this
mixture was stirred for 1 h before being slowly added to a -40
°C solution of 12 (0.10 g, 0.24 mmol) in the same solvent (15
mL). After 30 min, warming to rt was allowed to occur slowly
and stirring was maintained for another 6 h prior to quenching
with saturated NaHCO3 solution (20 mL). The separated
Su p p or tin g In for m a tion Ava ila ble: Copies of the high-
field 1H NMR spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0301954
8624 J . Org. Chem., Vol. 68, No. 22, 2003