Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes

Article abstract of DOI:10.1021/jm960400q

A series of individual sugar-modified pyrimidine nucleosides including enantiomerically enriched 2',3'-dideoxynucleosides 14a-c (α and β anomers of L- and D-series), 2',3'-dideoxy-4'-thionucleosides 21a-c (α and β anomers of L- and D-series), and 2',3'-dideoxy-4'-azanucleosides 28a-c (β anomers of L- and D-series) were synthesized, with uniform chemistry and high stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert- butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-butoxycarbonyl)-2-(tert- butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advantageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-member ensemble of chiral analogues (L-L), along with some related sublibraries.

Full text of DOI:10.1021/jm960400q

168
J . Med. Chem. 1997, 40, 168-180
Exp ed itiou s Syn th eses of Su ga r -Mod ified Nu cleosid es a n d Collection s Th er eof
Exp loitin g F u r a n -, P yr r ole-, a n d Th iop h en e-Ba sed Siloxy Dien es
Gloria Rassu,*,† Franca Zanardi,‡ Lucia Battistini,‡ Enrico Gaetani,‡ and Giovanni Casiraghi*,‡
Istituto per l’Applicazione delle Tecniche Chimiche Avanzate del CNR, I-07100 Sassari, Italy, and Dipartimento Farmaceutico,
Universita` di Parma, I-43100 Parma, Italy
Received J une 4, 1996
A series of individual sugar-modified pyrimidine nucleosides including enantiomerically
enriched 2′,3′-dideoxynucleosides 14a -c (R and â anomers of L- and D-series), 2′,3′-dideoxy-
4′-thionucleosides 21a -c (R and â anomers of L- and D-series), and 2′,3′-dideoxy-4′-azanucleo-
sides 28a -c (â anomers of L- and D-series) were synthesized, with uniform chemistry and high
stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-
butyldimethylsiloxy)furan (TBSOF), 2-(tert-butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-
butoxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advan-
tageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality
and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the
rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-
member ensemble of chiral analogues (L-L), along with some related sublibraries.
Sch em e 1. Retrosynthetic Analysis of Oxygen, Sulfur,
and Nitrogen Nucleosides A
In tr od u ction
Planning and synthetic exploitation of chemically
uniform, modular procedures amenable to construction
of ensembles of structurally related small organic
molecules with specific functions represent centrally
important issues of both life and material sciences.
Parallel and repetitive execution of common synthetic
protocols employing sets of equally reacting reagents or
precursors ensures the production of collections of
individual structures to be used as the basis for discov-
ery of lead candidates. On the other hand, for a given
class of potentially active molecules, adaptation of
similar uniform protocols according to a combinatorial
tactic allows for a more rapid access to mixtures of vast
numbers of compounds with a higher level of molecular
and stereochemical diversity.1 Along this line of thought,
since 1990 we have embarked upon a research program
focused on the development of a modular, flexible
strategy addressing the synthesis of a structurally
diverse series of bioactive molecules by exploiting
oxygen-, sulfur-, and nitrogen-containing heterocyclic
siloxy diene nucleophiles and employing a limited set
of simple, unified reactions.2
As part of these studies, herein we report on the
diastereoselective synthesis of a collection of 30 indi-
vidual enantiopure pyrimidine 2′,3′-dideoxynucleosides
comprising D- and L-furanoses 14a -c, 4′-thiofuranoses
21a -c, and 4′-azafuranoses 28a -c by starting with
2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert-bu-
tyldimethylsiloxy)thiophene (TBSOT), and N-(tert-bu-
toxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole (TB-
SOP), respectively.
have gained much attention by virtue of their significant
biological profiles, including use in antisense and anti-
viral therapies.3
Resu lts a n d Discu ssion
Str a tegy. At the planning stage of our syntheses,
we recognized that there were two stringent require-
ments that an ideal chemically uniform protocol has to
meet: (1) availability of a number of structural variants
of equally-reacting precursors and (2) viability of a
common synthetic path accommodating all the chosen
precursors. The starting point for this work (Scheme
1) was the observation that the suitable five-carbon
sugar cores B of the target nucleosides A could be
produced, by following strictly related transformations,
by removal of two carbon atoms from the seven-carbon
intermediates C, which can be, in turn, obtainable by
four-carbon homologation of D- and L-glyceraldehyde
acetonides, D-1 or L-1, with the siloxy diene reagents
TBSOF, TBSOT, and TBSOP. According to this simple
plan, glyceraldehyde enantiomers D-1 and L-1 can be
envisioned as “chiral” hydroxymethyl cation equivalents,
whereas the three siloxy dienes act as surrogates of the
five-membered oxygen, sulfur, and nitrogen heterocycles
within A and B.
We also describe the assemblage of a model 30-
compound combinatorial library of the same nucleosides
in racemic form as well as one 15-component sublibrary
of homochiral representatives of the L- series.
As assessed by recent studies, sugar-altered nucleo-
side building blocks and oligonucleotides there from
† Istituto CNR, Sassari.
Syn th esis of P r ecu r sor s. The preparation of the
siloxy diene reagents TBSOF, TBSOT, and TBSOP took
advantage of some previously described procedures.
‡ Dipartimento Farmaceutico, Universita` di Parma. E-mail: casirag@
ipruniv.cce.unipr.it.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
S0022-2623(96)00400-1 CCC: $14.00 © 1997 American Chemical Society

Expeditious Syntheses of Sugar-Modified Nucleosides
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 169
Sch em e 2.a Syn th esis of Siloxy Dien e P r ecu r sor s
Sch em e 3.a Syn th esis of 2′,3′-Did eoxyn u cleosid es
of th e L-Ser ies
a
(a) 2 to 3, HCO2Na, 30% H2O2 (50%, ref 4); 4 to 5, n-BuLi,
methyl borate, 30% H2O2 (70%, ref 5); 6 to 7, 30% H2O2; then
Boc2O, DMAP, CH2Cl2 (30%, ref 6); (b) 3 to TBSOF, TBSOTf, Et3N,
CH2Cl2 (70%); 5 to TBSOT and 7 to TBSOP, TBSOTf, 2,6-lutidine,
CH2Cl2 (91% and 90%, respectively).
Essentially according to literature (Scheme 2),4 furan-
2(5H)-one (3) was prepared by treatment of 2-furalde-
hyde (2), in sodium formate buffered solution, with 30%
hydrogen peroxide (∼50% yield). Unsaturated thiolac-
tone 5 (70% yield) derived from thiophene (4) via
oxidation with n-butyllithium/methyl borate/30% H2O2
system.5 Lactam 7 (30% yield) resulted from direct
H2O2 oxidation of pyrrole (6),6 followed by nitrogen
protection (Boc2O, DMAP, CH2Cl2).
Parallel execution of optimized enolization-silylation
protocols (TBSOTf, 2,6-lutidine or Et3N, CH2Cl2) rapidly
ensured preparation of the requisite triad of reagents,
TBSOF, TBSOT, and TBSOP, by starting from the
respective heterocycles individually, 3, 5, and 7, in
excellent isolated yields ranging from 70 to 90%. Sub-
stantial amounts of (R)- and (S)-glyceraldehyde ac-
etonides D-1 and L-1 were obtained from inexpensive
D-mannitol7 and L-ascorbic acid,8 respectively, by fol-
lowing exactly the known procedures.
a
(a) BF3‚OEt2, CH2Cl2, -90 °C (75%); (b) H2, Pd/C, THF (95%);
(c) 80% aqueous AcOH, 50 °C; then 0.65 M aqueous NaIO4, SiO2,
CH2Cl2; then NaBH4, MeOH, -30 to -15 °C (88%); (d) TBSCl,
imidazole, CH2Cl2 (92%); (e) DIBAL-H, CH2Cl2, -90 °C; then
CH(OMe)3, BF3‚OEt2, Et2O, 4 Å molecular sieves (95%); (f) 13 to
L-14a , silylated uracil, SnCl4/TMSOTf (1:1), 1,2-dichloroethane;
then TBAF, THF (60%); 13 to L-14b, silylated thymine, SnCl4/
TMSOTf (1:1), 1,2-dichloroethane; then TBAF, THF (65%); 13 to
L-14c, silylated 4-N-acetylcytosine, SnCl4/TMSOTf (1:1), 1,2-
dichloroethane; then TBAF, THF; then K2CO3, MeOH (70%).
Syn th esis of 2′,3′-Did eoxyn u cleosid es. The syn-
thesis of enantiomerically enriched L-pyrimidine nucleo-
sides R-L-14 and â-L-14 (Scheme 3) commenced with the
preparation of 4,5-threo-5,6-erythro (D-arabino) config-
ured R,â-unsaturated lactone 8,9 which was readily
available via BF3‚OEt2-promoted condensation of TB-
SOF to glyceraldehyde D-1. The event proved highly
diastereoselective (75% yield, de >90%), forming lactone
8 contaminated by only a minor amount of its unwanted
4,5-erythro diastereoisomer. Hydrogenation of 8 (H2,
THF, Pd on carbon) led to saturated heptonolactone 9
(95%), which was then subjected to acidic deacetonida-
tion to afford a triol intermediate (not isolated). Sub-
sequent oxidative cleavage of the C(5)-C(6) linkage
(NaIO4) producing aldehyde 1010 was followed by NaBH4
reduction of the formyl function, giving rise to hy-
droxymethyl-substituted lactone 11 in 88% overall yield
from 9. After silylation of the primary OH function
within 11 to 12 (92%), the key sugar 13 was easily
generated in 95% yield by a two-step protocol, consisting
of DIBAL-H reduction of the carbonyl moiety and
O-methyl glycosylation of the formed lactol [CH(OMe)3,
BF3‚OEt2].
Reaction of 13 with activated pyrimidine bases,
namely uracil, thymine, and 4-N-acetylcytosine, was
conveniently conducted employing the mixed Lewis acid
promoter SnCl4/TMSOTf (1:1) in 1,2-dichloroethane at
ambient temperature, essentially according to a Vor-
bru¨ggen-type protocol.11,12 There was obtained a 1:1 R/â
mixture of protected nucleosides, which were finally
deprotected by conventional chemistry (TBAF or TBAF/
K2CO3) to free compounds R-L-14a -c and â-L-14a -c in
acceptable combined yields ranging from 60 to 70%. The
separation of the anomers in the mixture was ac-
complished by silica gel flash chromatography and/or
preparative TLC (see the Experimental Section), thus
allowing individual nucleosides to be obtained in a pure
state.
The identity of R- and â-L-14a -c was mainly estab-
1
lished by H NOE-difference spectroscopy and/or NOE-
SY experiments. While diagnostic contacts were ob-
served between H(5′) and H(6), and between H(1′) and
H(4′) within â-L-14a -c, no such effects were detectable
in the R anomeric counterparts. In addition, an NOE
between H(4′) and H(6) in R-L-14a -c clearly indicated
a syn relationship for these protons. Support for the
assignment of the components as R or â anomers came
from the observation of a large downfield chemical shift
(0.3-0.8 ppm) for the protons at C(4′) in the R anomers,
possibly arising from the interaction between the syn-
located nucleobase, which is clearly forbidden in the â
counterparts (anti-location). Conversely, the H-5′ pro-
tons of the â anomers appear at a lower field than that
of the R anomers.13
The optical purity of the nucleosides 14 could be
approximately judged based on comparison with the
reported chiroptical data for known compounds in both
the D- and L-series. Our measurements satisfactorily
matched the literature data14 with small deviations in
the range (5%. A more precise estimation of the
enantiomeric purity of the synthesized nucleosides came
from our synthetic protocol, showing an extremely high
level of enantioconservation. By starting with virtually
pure 8, our optimized protocol ensured clean prepara-
tion of (R)-(-)-dihydro-5-(hydroxymethyl)-2(3H)-fura-
none (11) ([R]20D -54.5 (c 2.0, CHCl3), lit.15a [R]30D -53.5
(c 3.17, CHCl3)), whose enantiomeric excess was evalu-

170 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Rassu et al.
Sch em e 4.a Syn th esis of 2′,3′-Did eoxyn u cleosid es
Sch em e 5.a Syn th esis of
of th e D-Ser ies
2′,3′-Did eoxy-4′-th ion u cleosid es of th e L-Ser ies
a
Reagents and conditions, see Scheme 3. The formulas referring
to compounds ent-8-ent-13 are the enantiomeric counterparts of
those in Scheme 3.
ated to be 96 ( 2% by conversion to the corresponding
Mosher ester and NMR analysis.16 Owing to the
conservative character of the final stages of the synthe-
sis, the enantiomeric excess of the nucleosides in our
hands could be estimated at the same level (96 ( 2%)
as that of their common precursor 11.
a
(a) BF3‚OEt2, CH2Cl2, -78 °C (78%); (b) H2, Pd/C, THF (90%);
The above disclosed synthetic protocol was next
adopted with complete parallelism to preparation of the
same set of nucleosides in the enantiomeric D-series
(Scheme 4). By starting with TBSOF and L-glyceral-
dehyde L-1, through the various synthetic intermediates
ent-8-ent-13 (not shown), the D-nucleosides R-D-14a -c
and â-D-14a -c were rapidly synthesized without inci-
dents. The yields for pure isolated anomers ranged from
29 to 35%, based on their common precursor ent-13.
(c) 80% aqueous AcOH, 50 °C; then 0.65 M aqueous NaIO4, SiO2,
CH2Cl2 (75%); (d) NaBH4, MeOH, -30 to -15 °C (65%); (e) TBSCl,
imidazole, CH2Cl2; then Ac2O, pyridine, DMAP, CH2Cl2 (70%); (f)
20 to L-21a , silylated uracil, SnCl4/TMSOTf (1:1), 1,2-dichloroeth-
ane; then TBAF, THF (61%); 20 to L-21b, silylated thymine, SnCl4/
TMSOTf (1:1), 1,2-dichloroethane; then TBAF, THF (70%); 20 to
L-21c, silylated 4-N-acetylcytosine, SnCl4/TMSOTf (1:1), 1,2-
dichloroethane; then TBAF, THF; then K2CO3, MeOH (61%).
Sch em e 6.a Syn th esis of
2′,3′-Did eoxy-4′-th ion u cleosid es of th e D-Ser ies
Having both the D- and L-enantiomeric series strongly
facilitated the assessment of the constitutional and
enantiomeric purity of the materials by direct compari-
son of the spectroscopic and chiroptical data of the
various enantiocouples. In all cases, good correspon-
dence was observed, indicative of the high performance
of the overall synthetic strategy.
Syn th esis of 2′,3′-Dideoxy-4′-th ion u cleosides. The
assembly of the related 12-compound collection of less
common, but clinically promising 2′,3′-dideoxy-4′-thio-
nucleosides,3d,17 R-21 and â-21, was accomplished by
paralleling the entire strategy developed with the
furanose “cousins”, using TBSOT instead of TBSOF.18
Thus, as shown in Scheme 5, starting with D-arabino-
configured unsaturated thiolactone 15, obtained in 78%
yield and with high stereochemical efficiency (91% de
by HPLC analysis) by coupling of TBSOT to D-glycer-
aldehyde D-1 (BF3‚OEt2 as catalyst), saturated lactone
16 was easily synthesized (90%), whose relative and
absolute configuration was firmly ascertained by single-
crystal X-ray analysis.19 Deprotection of 16 and sub-
sequent oxidative two-carbon excision gave rather un-
stable aldehyde 17 (75%),10 whose NaBH4 reduction
directly furnished the five-carbon thiolactol 19 (65%
yield) with no appreciable formation of the correspond-
ing pyranose form, through the temporary intermediacy
of thiolactone 18. The reductive step differed from the
protocol employed in the above oxygenated series due
to competitive reduction of the thiolactone carbonyl
function. Under carefully controlled conditions and
stopping the reduction prior to complete consumption
of aldehyde 17, it was possible to prepare a sufficient
amount of intermediate 18, suitable for ee measure-
ments. Mosher ester analysis,16 as described for 11
a
Reagents and conditions, see Scheme 5 legend. The formulas
referring to compounds ent-15-ent-20 are the enantiomeric coun-
terparts of those in Scheme 5.
(vide supra), revealed an enantiomeric purity of the
carbinol 18 as high as 90+%. Conventional protection
of the terminal hydroxyl function as TBS ether (TBSCl,
imidazole) and acetylation of the anomeric OH (Ac2O,
pyridine, DMAP) converted 19 into activated thiosugar
20 in 70% yield, which was finally used in the subse-
quent coupling reaction with the usual three persily-
lated pyrimidine bases.20 These reactions afforded high
yields of the protected nucleoside mixtures, from which
individual free nucleosides R-L-21a -c and â-L-21a -c
were isolated in 61-70% combined yields by deprotec-
tive workup (TBAF or TBAF/K2CO3) followed by TLC
preparative chromatography.
In an analogous manner and with comparable ef-
ficiency, condensation of TBSOT with L-glyceraldehyde
L-1 (Scheme 6) gave rise to the six thionucleosides of
the D-series R-D-21a -c and â-D-21a -c through the
intermediacy of the pertinent precursors ent-15-ent-
20. The R vs â assignment for the sulfur-containing

Expeditious Syntheses of Sugar-Modified Nucleosides
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 171
Sch em e 7.a Syn th esis of N-Boc-P r otected
2′,3′-Did eoxy-4′-a za n u cleosid es of th e L-Ser ies
Sch em e 8.a Syn th esis of N-Boc-P r otected
2′,3′-Did eoxy-4′-a za n u cleosid es of th e D-Ser ies
a
Reagents and conditions, see Scheme 7 legend. The formulas
referring to compounds ent-22-ent-27 are the enantiomeric coun-
terparts of those in Scheme 7.
silylated pyrimidine bases, was accomplished as usual,
using the mixed catalyst system SnCl4/TMSOTf. Quite
unexpectedly, the coupling behavior proved highly ste-
reoselective, providing, in all instances, the â anomeric
nucleosides as the main products accompanied by only
minor amounts (<5%) of the respective R anomers (not
characterized). After deprotective workup and flash
chromatographic purification, free azanucleosides â-L-
28a -c were isolated in good yields (62-70%). Confir-
mation of the â anomeric configuration for nucleosides
28 essentially followed from 1D and 2D NOE measure-
ments, showing unequivocal contacts between syn-
disposed H(5′) and H(6) and between H(1′) and H(4′).
Remarkably, the highly stereoselective and efficient
formation of the â anomeric compounds during the
Lewis acid catalyzed coupling of silylated bases with
N-Boc protected methyl glycoside 27 is in strong con-
trast with the few existing studies dealing with similar
syntheses of 4′-acetamido- and 4′-(tert-butylcarbamyl)-
pyrimidine nucleoside analogues which exhibit unse-
lective nucleobase coupling behaviors.21 The exact
reason for the stereoselective formation of the â nucleo-
sides in this report remains unclear, and further studies
will be necessary in order for these results to be
elucidated and rationalized. However, one can specu-
late that nitrogen pyramidalization within the hetero-
cyclic iminium intermediate with preferential trans-
disposition of the N-Boc moiety may play a role in
hindering the R-face of the pyrrolidine nucleus favoring
the attack of the nucleobase on the less demanding
â-face.24 As with the oxygen and sulfur counterparts,
adaptation of this chemistry to L-1 made D-enantiomers
â-D-28a -c available with equal parallelism and ef-
ficiency (Scheme 8).
P r ep a r a tion of Mod el Nu cleosid e Libr a r ies. Be-
cause of the inadequate pharmaceutical profiles of
oligomeric and polymeric biosubstances, including nu-
cleotides, intense effort has been focused on the genera-
tion of small monomeric compound libraries.1 The
experiments in the previous sections furnish the basis
for easy extension of our chemistry to expeditious
assembly of collections of oxygen, sulfur, and nitrogen
nucleosides. In particular, the above investigations
have highlighted the versatility of TBSOF, TBSOT, and
TBSOP as a triad of chemically homogeneous building
blocks, associated with a general and reliable strategy
compatible with the diverse heteroatoms within the
three siloxy dienes.
a
(a) SnCl4, Et2O, -90 °C (80%); (b) H2, Pd/C, THF (92%); (c)
80% aqueous AcOH, 50 °C; then 0.65 M aqueous NaIO4, SiO2,
CH2Cl2 (63%); (d) NaBH4, MeOH, -30 to 0 °C; (e) TBSCl,
imidazole, CH2Cl2 (72%); (f) LiEt3BH, THF, -78 °C; then CH(OMe)3,
BF3‚OEt2, Et2O, 4 Å molecular sieves (78%); (g) 27 to L-28a ,
silylated uracil, SnCl4/TMSOTf (1:1), 1,2-dichloroethane; then
TBAF, THF (65%); 27 to L-28b, silylated thymine, SnCl4/TMSOTf
(1:1), 1,2-dichloroethane; then TBAF, THF (70%); 27 to L-28c,
silylated 4-N-acetylcytosine, SnCl4/TMSOTf (1:1), 1,2-dichloroeth-
ane; then TBAF, THF; then K2CO3, MeOH (62%).
nucleosides of this section was as straightforward as
that of the oxygenated relatives, based on 1H NMR
analyses and NOE measurements (vide supra).
Syn th esis of 2′,3′-Dideoxy-4′-azan u cleosides. With
a uniform protocol to assemble oxygen- and sulfur-
containing 2′,3′-dideoxynucleosides at hand, we next
turned to preparation of the analogous pyrrolidine-based
congeners, which represent a quite novel progeny of
sugar-modified nucleosides.21 Again, a parallel path
was undertaken employing our third siloxy diene,
namely, the pyrrole-based reagent TBSOP.22 As de-
picted in Scheme 7, SnCl4-catalyzed (instead of BF3‚
OEt2) condensation of TBSOP with D-1 proved success-
ful, allowing the preparation of crystalline D-arabino
lactam 22 in excellent yield (80%),23 which was the
template used to create the key azasugar precursor 27.
As described earlier, the three-carbon C(5)-C(7) ap-
pendage in 22 was utilized to generate the requisite
hydroxymethyl group at C(4) by the sequence 22 f 23
(H2, Pd/C, 92%), 23 f 24 (AcOH, then NaIO4, 63%), and
24 f 26 (NaBH4, then TBSCl, imidazole, 72%). As for
the corresponding carbynols 11 and 18, the enantio-
meric purity of 25 was checked by NMR analysis of its
Mosher ester16 and was found to be quite high.
The subsequent stage, the reductive conversion of the
protected lactam 26 to azasugar 27, called for a different
reducing agent, since neither DIBAL-H nor NaBH4 gave
the expected transformation. However, the use of
superhydride (LiEt3BH) proved fruitful, giving, after
methylation [CH(OMe)3, BF3‚OEt2], a 78% yield of the
requisite azafuranose 27 as a R/â anomeric mixture. The
final task, the coupling of the aminol 27 with the three
The first step in an expeditious synthesis of a model
30-component library of racemic nucleosides was the
preliminary synthesis of racemic sugar precursors, (()-
13, (()-20, and (()-27. This was accomplished, in a

172 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Rassu et al.
Sch em e 10.a Sch em a tic Descr ip tion of th e
Sch em e 9.a Syn th esis of Ra cem ic P r ecu r sor s
(()-13, (()-20, a n d (()-27
Con str u ction of a F u ll Libr a r y, D,L-L, a n d Th r ee
Rela ted Su blibr a r ies, D,L-SLUr , D,L-SLTh , a n d
D,L-SLCy of Ra cem ic P yr im id in e Nu cleosid es
a
(a) BF3‚OEt2, Et2O, -80 °C (95-98%); (b) H2, Pd/C, THF; then
10% aqueous HCl, THF (76-82%, two steps); (c) for (()-13, NaBH4,
MeOH, -30 to -15 °C; then TBSCl, imidazole; then DIBAL-H,
CH2Cl2, -90 °C; then CH(OMe)3, BF3‚OEt2 (75%, four steps); for
(()-20, NaBH4, MeOH, -30 to -15 °C; then TBSCl, imidazole;
then Ac2O, pyridine, DMAP (50%, three steps); (d) SnCl4, Et2O,
-80 °C (60%); (e) H2, Pd/C, THF (93%); (f) LiEt3BH, THF, -78
°C; then CH(OMe)3 BF3‚OEt2, 4 Å molecular sieves (75%, two
steps).
a
Key: OUr ) (()-14a ; STh ) (()-21b; NCy ) (()-28c; and so on.
mmol each) by dissolving them in anhydrous dichloro-
ethane, and the resulting solution was subdivided into
three equal portions. Each portion was then indepen-
dently reacted with one individual base, Ur, Th, and
Cy (4.0 equiv), under SnCl4/TMSOTf catalysis to give,
after complete deprotection and separation of the nu-
cleoside fractions, three diverse sublibraries of three
straightforward manner (Scheme 9), by formylation or
hydroxymethylation of the individual siloxy dienes with
either orthoformate or gaseous formaldehyde. For (()-
13 and (()-20 (not for (()-27), a direct formylation
procedure with ethyl orthoformate was advantageously
employed. Thus, BF3-catalyzed condensation of TBSOF
and TBSOT with ethyl orthoformate gave rise to the
expected acetals (()-29a,b (95-98%), which were cleanly
transformed to free saturated aldehydes (()-10 and (()-
17 by double bond saturation followed by acidic hy-
drolysis.
Reduction of both the formyl and carbonyl moieties
within (()-10 and (()-17 followed by methylation or
acetylation then allowed sugars (()-13 and (()-20 to be
prepared in good overall yields from the respective siloxy
diene precursors. Unfortunately, this high-yielding
reaction sequence failed with (()-27, the acetal hydroly-
sis stage being incompatible with the acid-sensitive
N-Boc protection of the aminated counterparts. For (()-
27, an alternative procedure was planned employing
gaseous formaldehyde as hydroxymethylation agent.
Thus, SnCl4-catalyzed reaction of TBSOP with CH2O-
(g) directly gave rise to protected unsaturated lactam
(()-30 in 60% isolated yield which was hydrogenated
to (()-26 and then transformed to (()-27 by employing
the same protocol as that utilized in the analogous
homochiral series (vide supra).
racemates (D,L-SLUr , D,L-SLTh , and D,L-SLCy) which
were finally combined to furnish a full library of
nucleosides (D,L-L) comprising the expected 15 race-
mates with a 64% combined yield based on the average
molecular weight of the nucleoside mixture.25 In prin-
ciple, a truly random synthesis would furnish an
ensemble of 36 different nucleosides (18 racemates), i.e.
32 × 2i, where i ) 2 is the number of stereocenters in
the resulting nucleosides. In practice, however, due to
(here unwanted) stereoselective character of the cou-
pling reaction involving the azafuranose template
strongly favoring the â anomeric compounds (vide
supra), the total number of parents in the full library
was reduced to 15 major racemates (out of 18).
The three nucleoside mixtures were analyzed by
reverse-phase HPLC, and typical profiles are shown in
Figures 1-3. Having individual pure components
strongly facilitated the analysis of the mixtures by
simply comparing the experimental HPLC traces with
standard profiles of artificial mixtures of pure nucleo-
sides. In the uridine-related trace (Figure 1) six peaks
were detected, peak 5 being tentatively attributed to a
minor amount of R anomeric azauridine derivative. The
corresponding trace of thymidine ensemble (Figure 2)
reveals four major peaks which were attributed to the
expected nucleoside products with the peaks of sulfur-
containing R and â anomers (peak 3) overlapped. As
previously observed for uridine compounds, a minor
amount of an additional compound was detected (peak
4), which was tentatively assigned to R-azathymidine.
Next, a “combine-split” in-solution technical ap-
proach was adopted (Scheme 10) using the three racemic
sugars (()-13 (indicated as O), (()-20 (S), and (()-27
(N), and the three pyrimidine bases, uracil (Ur), thymine
(Th), and cytosine (Cy). Thus, the carbohydrate precur-
sors O, S, and N were mixed in equimolar quantity (0.2

Expeditious Syntheses of Sugar-Modified Nucleosides
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 173
a 58% averaged yield. The HPLC trace of the chiral
collection was almost superimposable with the profile
of the above racemic counterpart, indicative of good
reproducibility of the overall methodology.
Biologica l Su r vey
This work should be intended as a successful attempt
to establish a novel methodological approach toward a
relevant and representative class of biomolecules whose
use in medicinal chemistry is well documented.14,17,21
The majority of nucleoside compounds in this study,
comprising some sulfur and nitrogen congeners, has
been previously subjected to biological evaluation against
HIV and HVB replication in vitro. Selected examples
include: cytidine â-D-14c, highly HIV and HBV active;14c
cytidine â-L-14c, highly HBV active and moderately HIV
active;14c cytidine R-L-14c, HBV active and HIV inac-
tive;14c thiocytidine â-D-21c, HIV active and HBV
inactive.17a,c
F igu r e 1. HPLC trace of racemic uridine-related sublibrary
D,L-SLUr . Each peak was assigned as 1, 2, 3, 4, 5, and 6, which
correspond to uridine nucleosides R-OUr (4.61 min), â-OUr (4.79
min), R-SUr (9.80 min), â-SUr (10.38 min), R-NUr (tentative,
14.90 min), and â-NUr (16.86 min), respectively. Ratio of (1 +
2)/(3 + 4)/(5 + 6) was measured as 1.0:1.5:0.9.
Uridine and thymidine derivatives of both the D- and
L-series showed moderate to poor antiviral activity,
while similar inefficacy was observed for thiouridines
R- and â-L- and -D-21a ,17e azauridine â-D-28a ,21d thio-
thymidines R- and â-L- and -D-21b,17e and azathymidine
â-D-28b.21d,26
F igu r e 2. HPLC trace of racemic thymidine-related subli-
brary D,L-SLTh . Each peak was assigned as 1, 2, 3, 4, and 5,
which correspond to thymidine nucleosides R-OTh (8.47 min),
â-OTh (8.73 min), R,â-STh (overlapped, 13.2 min), R-NTh (tenta-
tive, 19.20 min), and â-NTh (20.00 min), respectively. Ratio of
(1 + 2)/3/(4 + 5) was measured as 1.0:0.7:0.8.
Con clu sion s
We have described a flexible synthetic procedure to
access pharmacologically important 2′,3′-dideoxypyrim-
idine nucleosides27 and their thio- and azasugar vari-
ants. The strategy is highlighted by (1) easy availability
of the key building blocks (i.e. glyceraldehyde acetonides
and the siloxy dienes triad) from common and inexpen-
sive raw materials; (2) clean reactions, with (usually)
only the product and unreacted starting material de-
tected; (3) convenient use of both enantiomers of glyc-
eraldehyde as synthetic equivalents of “chiral” formyl
(and hydroxymethyl) cation units; (4) uniform protocols
compatible with the diverse nature of the matrices
employed; and (5) concrete possibility to enlarge the
synthetic scope of the reaction to 2′- and 3′-substituted
(and to 2′,3′-disubstituted) congeners by functionaliza-
tion of the appropriate R,â-unsaturated intermediates.
This work has resulted in the development of a
uniform protocol which allows for (1) linear stereose-
lective syntheses of individual enantiomerically en-
riched (>90% ee) nucleosides of both L- and D-series; (2)
divergent and/or parallel execution to access many
structural variants within a given class of nucleoside
compounds; (3) adaptation, without significant changes,
to combinatorial assembly of collections and/or subcol-
lections of nucleoside mixtures with rather uniform
component dispersion, useful for both racemic and
homochiral synthesis.
F igu r e 3. HPLC trace of racemic cytidine-related sublibrary
D,L-SLCy. Each peak was assigned as 1, 2, 3, and 4, which
correspond to cytidine nucleosides R-OCy (4.27 min) â-OCy (4.54
min), R,â-SCy (overlapped 7.52 min), and â-NCy (15.31 min),
respectively. Ratio of (1 + 2)/3/4 was measured as 1.0:1.1:1.1.
For the cytidine-related sublibrary (Figure 3) only four
peaks were evident, the sulfur derivative peaks being
overlapped. For a given series, uridine derivatives move
faster than the corresponding thymidine congeners, but
slower than the cytidine counterparts, and, as a rule,
sulfur-bearing compounds move faster than nitrogen
products, but slower than oxygenated nucleosides.
Remarkably, the HPLC analyses indicated the presence
of the expected nucleosides with no detectable byprod-
ucts. Furthermore, though it is difficult to quantitate
the relative amounts of each product due to differences
in extinction coefficients, the mixtures appear to be close
to equimolar.
Exp er im en ta l Section
Gen er a l. Flash chromatography was performed on 32-
63 µm silica gel ICN Biomedicals, using the indicated solvent
mixtures. Analytical thin-layer chromatography was per-
formed on Merck silica gel 60 F254 plates (0.25 mm). The
compounds were visualized by dipping the plates in an aqueous
H2SO4 solution of cerium sulfate/ammonium molybdate or in
an ethanolic solution of ninhydrin, followed by charring with
a heat gun.
The final task of this study was the construction of
one analogous 15-component homochiral library, L-L,
employing the pure sugar substrates of the L-series 13,
20, and 27 and adopting a strictly parallel chemistry.
After completion of the procedure, there was obtained
a product mixture comprising the expected chiral oxy-
gen, sulfur, and nitrogen L-nucleosides, accounting for
1H NMR spectra were obtained on a Bruker AC-300 or
Varian XL-300 and are reported in parts per million (δ)
relative to tetramethylsilane (0.0 ppm) as an internal refer-

174 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Rassu et al.
ence, with coupling constants in hertz (Hz). Rotations were
measured on a Perkin-Elmer 241 polarimeter and are given
(MgSO4), and concentrated in vacuum. The residue was flash
chromatographed on silica gel (4:6 hexanes/ethyl acetate) to
in units of 10-1 deg cm2 g-1
.
Elemental analyses were
furnish 16.1 g (75%) of 8 as white crystals: mp 125 °C; [R]20
D
performed by the Microanalytical Laboratory of University of
Sassari.
+69.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.37 (s,
3H), 1.42 (s, 3H), 2.94 (d, J ) 6.6 Hz, 1H), 3.67 (m, 1H), 4.05
(m, 1H), 4.18 (m, 2H), 5.27 (m, 1H), 6.17 (dd, J ) 5.8, 1.9 Hz,
1H), 7.59 (dd, J ) 5.8, 1.7 Hz, 1H). Anal. (C10H14O5) C, H.
6,7-O-Isop r op ylid en e-2,3-d id eoxy-D-a r a bin o-h ep ton o-
1,4-la cton e (9). A solution of the R,â-unsaturated lactone 8
(16.1 g, 75 mmol) in anhydrous THF (500 mL) in the presence
of AcONa (750 mg) was subjected to catalytic hydrogenation
with 10% Pd on carbon (1.6 g) at room temperature for 24 h.
The catalyst was then filtered off and the filtrate evaporated
to give saturated lactone 9 (15.4 g, 95%) as a colorless oil:
The HPLC analyses were performed using a system consist-
ing of a Varian 9010 pump, a Philips PU 4021 spectrophoto-
metric detector operating at 265 nm, a Rheodyne 10 µL loop
injector, and a Kontron computing integrator. The analyses
were performed on a Merck LiChroCART 250-4 Purospher RP-
18 (5 µm) column thermostated at 32 °C. The mobile phase
was (A) 0.01 M ammonium phosphate, pH 5.0, and 10%
methanol; (B) methanol. Gradient: 0-2 min, 5% B; 2-22 min,
5-45% B. Flow: 1.0 mL/min.
Ma ter ia ls. 2-Furaldehyde (2), thiophene (4), and pyrrole
(6) were purchased from Aldrich and vacuum-distilled prior
to use. D-(R)-Glyceraldehyde acetonide (D-1) was prepared
from D-mannitol (Aldrich) according to literature.7 L-(S)-
Glyceraldehyde acetonide (L-1) was obtained from 5,6-O-
isopropylidene-L-gulonic acid 1,4-lactone (Fluka) following a
known protocol.8 Furan-2(5H)-one (3) was synthesized from
2 by a known procedure.4 3-Thiolen-2-one (5) was obtained
from 4 following a literature preparation.5 N-Boc-pyrrolinone
(7) was prepared from 6, via pyrrol-2(5H)-one, as previously
described.6
2-(ter t-Bu tyld im eth ylsiloxy)fu r a n (TBSOF ). To a solu-
tion of 2(5H)-furanone 3 (10.0 g, 119 mmol) in anhydrous CH2-
Cl2 (80 mL) were added Et3N (23.2 mL, 166 mmol) and TBSOTf
(30 mL, 131 mmol) under argon at 0 °C. After ambient
temperature was reached, the reaction mixture was stirred
for 2 h, the solvent was removed under vacuum, and the oily
residue was subjected to flash chromatographic purification
on silica gel (9:1 hexanes/ethyl acetate) to furnish 16.5 g (70%)
of TBSOF as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.24
(s, 6H), 0.97 (s, 9H), 5.10 (dd, J ) 3.0, 1.0 Hz, 1H), 6.20 (dd, J
) 3.0, 2.1 Hz, 1H), 6.81 (dd, J ) 2.1, 1.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ -4.8 (2 C), 18.0, 25.5 (3 C), 83.5, 111.0,
132.2, 156.9. Anal. (C10H18O2Si) C, H.
2-(ter t-Bu tyld im eth ylsiloxy)th iop h en e (TBSOT). To a
solution of 3-thiolen-2-one (5) (12.4 g, 124 mmol) in anhydrous
CH2Cl2 (200 mL) were added 2,6-lutidine (43 mL, 371 mmol)
and TBSOTf (36.9 mL, 161 mmol) under argon at room
temperature. After the reaction mixture was stirred for 30
min, the solvent was evaporated and the residue purified by
flash chromatography on silica gel (7:3 hexanes/ethyl acetate)
to furnish 24.0 g (91%) of TBSOT as a pale yellow oil: 1H NMR
(300 MHz, CDCl3) δ 0.21 (s, 6H), 0.96 (s, 9H), 6.11 (dd, J )
3.6, 1.2 Hz, 1H), 6.46 (dd, J ) 6.0, 1.2 Hz, 1H), 6.62 (dd, J )
6.0, 3.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -5.0 (2 C), 18.2,
25.6 (3 C), 109.0, 112.7, 124.4, 150.8. Anal. (C10H18OSSi) C,
H.
N-(ter t-Bu toxyca r bon yl)-2-(ter t-bu tyld im eth ylsiloxy)-
p yr r ole (TBSOP ). To a solution of N-Boc-pyrrolinone (7) (6.1
g, 33 mmol) in anhydrous CH2Cl2 (50 mL) were added 2,6-
lutidine (11.6 mL, 99 mmol) and TBSOTf (7.6 mL, 33 mmol)
under argon at room temperature. After being stirred for 45
min, the solvent was evaporated and the residue flash chro-
matographed over silica gel (1:1 hexanes/ethyl acetate) to give
8.8 g (90%) of pure TBSOP as a pale yellow oil: 1H NMR (300
MHz, CDCl3) δ 0.20 (s, 6H), 0.97 (s, 9H), 1.54 (s, 9H), 5.20
(dd, J ) 3.6, 2.1 Hz, 1H), 5.86 (t, J ) 3.7 Hz, 1H), 6.66 (dd, J
) 3.9, 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -4.9 (2 C),
18.3, 25.7 (3 C), 28.1 (3 C), 82.7, 92.4, 108.0, 113.0, 145.5, 148.2.
Anal. (C15H27NO3Si) C, H, N.
6,7-O-Isop r op ylid en e-2,3-d id eoxy-D-a r a bin o-h ep t -2-
en on o-1,4-la cton e (8). 2,3-O-Isopropylidene-D-glyceralde-
hyde (D-1) (13.0 g, 100 mmol) and TBSOF (20.9 mL, 100 mmol)
were dissolved in dry CH2Cl2 (250 mL) under nitrogen, and
the mixture was cooled to -90 °C. With stirring, BF3‚OEt2
(12.3 mL, 100 mmol) cooled at the same temperature was
added, and the solution was allowed to stir for 6 h. The
reaction was then quenched at -90 °C by addition of an
aqueous saturated NaHCO3 solution, and after ambient tem-
perature was reached, the mixture was extracted with CH2-
Cl2 (3 × 50 mL) and the organic layer washed with brine, dried
[R]20 -38.2 (c 1.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.35
D
(s, 3H), 1.41 (s, 3H), 2.31 (m, 2H), 2.45-2.70 (m, 2H), 3.35 (bs,
1H), 3.53 (bs, 1H), 4.01 (m, 1H), 4.14 (m, 2H), 4.77 (td, J )
7.5, 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.6, 25.1, 26.6,
28.5, 66.8, 73.7, 75.6, 79.9, 109.3, 178.0. Anal. (C10H16O5) C,
H.
(R)-Dih yd r o-5-(h yd r oxym et h yl)-2(3H )-fu r a n on e (11).
Lactone 9 (5.0 g, 23 mmol) was dissolved with 50 mL of 80%
aqueous acetic acid, and the resulting solution was allowed to
react at 50 °C. The reaction was monitored by TLC and was
judged complete after 8 h. The solution was concentrated to
give a crude triol intermediate which was used as such in the
subsequent step. The triol (3.9 g, 22 mmol) was then dissolved
in CH2Cl2 (150 mL) and treated with a 0.65 M aqueous NaIO4
solution (75 mL) and chromatography grade SiO2 (15 g). The
resulting slurry was vigorously stirred for 15 min at what time
TLC showed complete consumption of the starting material.
The slurry was filtered under suction and the silica thoroughly
washed with CH2Cl2 and ethyl acetate. The filtrates were
evaporated to leave the crude aldehyde 10, which was directly
subjected to reductive workup. Thus, crude 10 (2.3 g, 20 mmol)
was dissolved in methanol (100 mL) and the solution treated
with NaBH4 (1.5 g, 40 mmol) at -30 °C. After 30 min, the
temperature was allowed to rise to -15 °C, while stirring was
continued until the starting aldehyde was consumed (1 h). The
slurry was quenched by adding acetone and a saturated
aqueous citric acid solution. The mixture was concentrated
to leave an oily residue, which was subjected to flash chro-
matographic purification on silica gel (ethyl acetate as an
eluant) to furnish furanone 11 (2.1 g, 88%) as a colorless oil:
[R]20D -54.5 (c 2.0, CHCl3) (lit.15a [R]30D -53.5 (c 3.17, CHCl3));
1H NMR (300 MHz, CDCl3) δ 2.0-2.4 (m, 2H), 2.4-2.7 (m,
2H), 3.66 (dd, J ) 12.6, 4.8 Hz, 1H), 3.69 (s, 1H), 3.92 (dd, J
) 12.6, 2.7 Hz, 1H), 4.65 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 23.1, 28.7, 64.1, 80.7, 178.3.
Using the standard protocol,16 alcohol 11 was quantitatively
transformed to the corresponding Mosher ester. Quantitative
NMR measurements established a g96% ee for this material.
(R)-5-O-(ter t-Bu t yld im et h ylsilyl)d ih yd r o-5-(h yd r oxy-
m eth yl)-2(3H)-fu r a n on e (12). To a solution of alcohol 11
(1.7 g, 14.4 mmol) in anhydrous CH2Cl2 (34 mL) at room
temperature were added TBSCl (2.6 g, 17.5 mmol) and
imidazole (1.2 g, 17.5 mmol), with stirring. After 3 h, the
reaction was quenched with saturated aqueous citric acid
solution, extracted with ethyl acetate, dried over MgSO4, and
concentrated to give a yellow oil. Purification by flash chro-
matography (1:1 hexanes/ethyl acetate) gave pure protected
lactone 12 (3.0 g, 92%) as a clear oil: [R]20 -11.3 (c 0.5,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ -0.03 (s, 3H), -0.02 (s,
3H), 0.79 (s, 9H), 2.00-2.25 (m, 2H), 2.30-2.55 (m, 2H), 3.59
(dd, J ) 11.2, 1.5 Hz, 1H), 3.76 (dd, J ) 11.2, 1.8 Hz, 1H),
4.49 (m, 1H); 13C NMR (75 MHz, CDCl3) δ -5.8, -5.7, 18.0,
23.3, 25.5 (3 C), 28.3, 64.7, 79.9, 177.3. Anal. (C11H22O3Si) C,
H.
Meth yl 5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-d id eoxy-r,â-
L-r ibofu r a n o-sid e (13). To a solution of furanone 12 (2.0 g,
8.6 mmol) in anhydrous CH2Cl2 (100 mL) at -90 °C was slowly
added via cannula DIBAL-H (17.2 mL, 1.5 M in toluene, 25.8
mmol) with stirring. After 2 h, the reaction was quenched with
methanol and an aqueous sodium tartrate solution at -90 °C.
After ambient temperature was reached, the slurry was stirred
for 40 min, extracted with ethyl actetate, dried (Na2SO4), and

Expeditious Syntheses of Sugar-Modified Nucleosides
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 175
concentrated to give a crude lactol, which was directly sub-
jected to methylation. Thus, crude lactol (1.9 g, 8.2 mmol) was
dissolved in anhydrous diethyl ether (25 mL), and powdered
anhydrous molecular sieves (4 Å, 0.2 g) were added. With
stirring, methyl orthoformate (1.8 mL, 16 mmol) and BF3‚O-
Et2 (250 µL) were added, and the mixture was allowed to react
for 30 min. The reaction was quenched with Et3N and brine
until neutral, extracted with diethyl ether, dried (MgSO4), and
concentrated to give crude 13, which was purified by flash
column chromatography (8:2 hexanes/ethyl acetate) to give R,â-
methyl glycoside 13 (2.0 g, 95%) as a colorless oil: [R]20D -17.2
(c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 3H), 0.03
(s, 3H), 0.86 (s, 5.4H), 0.87 (s, 3.6H), 1.6-2.1 (m, 4H), 3.28 (s,
1.2H), 3.30 (s, 1.8H), 3.5-3.7 (m, 2H), 4.11 (m, 1H), 4.93 (d, J
) 3.9 Hz, 0.4H), 4.98 (d, J ) 4.8 Hz, 0.6H); 13C NMR (75 MHz,
CDCl3) δ -5.5, -5.4, 18.2, 25.8 (3 C), 25.3 and 26.2, 31.6 and
32.6, 54.1 and 54.2, 65.4 and 67.2, 78.5 and 80.8, 105.0 and
105.3. Anal. (C12H26O3Si) C, H.
1H), 3.79 (dd, J ) 12.4, 5.0 Hz, 1H), 3.94 (dd, J ) 12.4, 3.0
Hz, 1H), 4.29 (m, 1H), 6.18 (dd, J ) 7.0, 3.5 Hz, 1H), 7.76 (s,
1H); 13C NMR (75 MHz, D2O) δ 12.9, 26.0, 32.1, 63.7, 82.8,
87.1, 111.7, 138.6, 152.8, 163.6.
2′,3′-Did eoxy-r-L-cytid in e (r-L-14c) a n d 2′,3′-Did eoxy-
â-L-cytid in e (â-L-14c). Compounds R-L-14c and â-L-14c were
synthesized from 13 (0.5 g, 2.0 mmol) and 4-N-acetylcytosine
(0.6 g, 4.0 mmol) essentially according to the procedure
described for R- and â-L-14a except for the deprotection stage
which, in addition to the TBAF-promoted desilylation, included
deacetylation (K2CO3, MeOH).
Compound R-L-14c (70 mg, 33%) was isolated as a glass:
[R]20 +45.9 (c 0.2, MeOH) (lit.14c [R]D +46.6 (c 0.1, MeOH));
D
1H NMR (300 MHz, D2O) δ 1.8-2.5 (m, 4H), 3.5-3.9 (m, 2H),
4.69 (m, 1H), 6.11 (d, J ) 7.6 Hz, 1H), 6.15 (m, 1H), 7.75 (d, J
) 7.6 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 26.5, 30.7, 65.2,
83.5, 86.9, 95.0, 141.9, 157.5, 166.8.
Compound â-L-14c (78 mg, 37%) was isolated as a white
solid: mp 190-193 °C (lit.14c mp 194-196 °C); [R]20 -88.6 (c
2′,3′-Did eoxy-r-L-u r id in e (r-L-14a ) a n d 2′,3′-Did eoxy-
â-L-u r id in e (â-L-14a ). A mixture of uracil (0.45 g, 4.0 mmol),
1,1,1,3,3,3-hexamethyldisilazane (25 mL), and ammonium
sulfate (20 mg) was refluxed for 2 h and then cooled to room
temperature. The clear mixture was concentrated in vacuo
to give a residue, to which a solution of compound 13 (0.5 g,
2.0 mmol) in anhydrous 1,2-dichloroethane (25 mL) was added,
followed by the addition of SnCl4 (234 µL, 2.0 mmol) and
TMSOTf (462 µL, 2.0 mmol) at 0 °C. The reaction mixture
was stirred for 2 h at room temperature and then quenched
with a saturated aqueous NaHCO3 solution until neutral pH
was reached. The mixture was extracted thoroughly with
ethyl acetate, dried (MgSO4), and concentrated to give a
residue, which was subjected to flash chromatography in order
to isolate the protected nucleoside fraction. The 1H NMR
analysis of this material revealed the presence of a mixture
of â and R anomers in the ratio of 1:1, estimated by integration
of the signals at 8.07 and 7.35 ppm, respectively. To a stirred
solution of protected nucleoside mixture (0.45 g) in THF (20
mL) was added tetra-n-butylammonium fluoride (1.6 g, 5
mmol) at ambient temperature. After 8 h, the mixture was
evaporated in vacuo to dryness, leaving a residue from which
individual pure R and â anomers were separated by silica gel
preparative TLC (9:1:0.5 ethyl acetate/methanol/aqueous am-
monia). This afforded R-L-14a (64 mg, 30%) and â-L-14a (63
mg, 30%).
D
1
0.1, MeOH) (lit.14c [R]D -90.3 (c 0.14, MeOH)); H NMR (300
MHz, D2O) δ 1.7-2.5 (m, 4H), 3.5-4.0 (m, 2H), 4.40 (m, 1H),
6.09 (d, J ) 7.3 Hz, 1H), 6.15 (dd, J ) 7.4, 3.7 Hz, 1H), 7.96
(d, J ) 7.3 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 25.6, 34.2,
63.6, 83.6, 88.5, 95.3, 142.7, 158.0, 167.7.
The enantiomeric intermediates ent-8-ent-13 and enantio-
meric nucleosides R-D-14a -c and â-D-14a -c were prepared
by starting with L-glyceraldehyde L-1 adopting the procedures
above described for their respective counterparts 8-13 and
R- and â-L-14a -c. Diagnostic data are as follows:
ent-8: yield 72%, colorless crystals; mp 123 °C; [R]20D -68.9
(c 1.0, CHCl3). Anal. (C10H14O5) C, H.
ent-9: yield 92%, an oil; [R]20 +39.6 (c 2.0, CHCl3). Anal.
D
(C10H16O5) C, H.
ent-11: yield 89%, an oil; [R]20 +55.1 (c 2.1, CHCl3) (lit.15b
D
[R]20 +31.3 (c 2.92, EtOH)).
D
ent-12: yield 90%, an oil; [R]20 +11.0 (c 0.5, CHCl3) (lit.13a
D
[R]D +11.11 (c 0.92, CHCl3)).
ent-13: yield 92%, an oil; [R]20D +16.9 (c 0.5, CHCl3). Anal.
(C12H26O3Si) C, H.
R-D-14a : yield 32%, a foam; [R]20 -13.1 (c 0.5, MeOH).
D
Anal. (C9H12N2O4) C, H, N.
â-D-14a : yield 29%, a white solid; mp 129-131 °C (lit.14d
mp 117.5-118.5 °C); [R]20D +32.5 (c 0.5, H2O) (lit.14d [R]25D +31
(c 0.43, H2O)).
Compound R-L-14a was isolated as a foam: [R]20 +12.7 (c
D
0.5, MeOH); 1H NMR (300 MHz, D2O) δ 1.90 (m, 1H), 2.15 (m,
2H), 2.50 (m, 1H), 3.60 (dd, J ) 11.7, 5.3 Hz, 1H), 3.73 (dd, J
) 11.7, 4.1 Hz, 1H), 4.56 (m, 1H), 5.85 (d, J ) 7.9 Hz, 1H),
6.14 (t, J ) 5.4 Hz, 1H), 7.67 (d, J ) 7.9 Hz, 1H); 13C NMR (75
MHz, D2O) δ 28.4, 38.8, 66.8, 85.1, 91.0, 105.2, 144.4, 158.9,
175.2. Anal. (C9H12N2O4) C, H, N.
R-D-14b: yield 32%, a white solid; mp 105-107 °C; [R]20
D
-17.2 (c 0.1, MeOH). Anal. (C10H14N2O4) C, H, N.
â-D-14b: yield 33%, white crystals; mp 154-155 °C (lit.14e
mp 155-156 °C); [R]20 +24.0 (c 0.5, H2O) (lit.14e [R]19 +20.0
D
D
(c 0.6, H2O)).
R-D-14c: yield 35%, a solid; mp 165-166 °C (lit.13a mp 169-
Compound â-L-14a was isolated as a foam: [R]20 -30.0 (c
172 °C); [R]20 -80.4 (c 0.5, MeOH) (lit.13a [R]D -83.39 (c 0.56,
D
D
0.2, MeOH) (lit.14c [R]D -28.0 (c 0.1, MeOH)); 1H NMR (300
MHz, D2O) δ 1.60 (m, 2H), 1.99 (m, 2H), 3.52 (dd, J ) 11.6,
6.7 Hz, 1H), 3.62 (dd, J ) 11.6, 4.5 Hz, 1H), 3.75 (m, 1H), 5.71
(dd, J ) 11.7, 6.2 Hz, 1H), 5.99 (d, J ) 7.8 Hz, 1H), 7.70 (d, J
) 7.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 30.6, 33.6, 68.7, 74.4,
90.5, 106.5, 143.9, 164.6, 177.5.
MeOH)).
â-D-14c: yield 35%, a white solid; mp 215-217 °C (lit.13a
mp 214-217 °C); [R]20 +102.5 (c 0.5, MeOH) (lit.13a [R]D
D
+105.9 (c 0.53, MeOH)).
6,7-O-Isopr opyliden e-2,3-dideoxy-4-th io-D-a r a bin o-h ept-
2-en on o-1,4-la ct on e (15). The above procedure for 8 was
employed with TBSOT (8.5 g, 39.6 mmol), D-glyceraldehyde
D-1 (5.1 g, 39.6 mmol), and BF3‚OEt2 (4.8 mL, 39.6 mmol) in
CH2Cl2 (200 mL) at -78 °C for 3 h to afford, after flash
3′-Deoxy-r-L-th ym id in e (r-L-14b) a n d 3′-Deoxy-â-L-th y-
m id in e (â-L-14b). Compounds R-L-14b and â-L-14b were
synthesized from 13 (0.5 g, 2.0 mmol) and thymine (0.5 g, 4.0
mmol) by the same methodology described for the synthesis
of R- and â-L-14a .
chromatographic purification (1:1 hexanes/ethyl acetate), 7.1
1
g (78%) of 15 as an oil: [R]20 +67.0 (c 2.5, CHCl3); H NMR
D
Compound R-L-14b (70 mg, 31%) was isolated as a white
(300 MHz, CDCl3) δ 1.32 (s, 3H), 1.41 (s, 3H), 2.74 (bs, 1H),
3.8-4.2 (m, 4H), 4.91 (m, 1H), 6.31 (dd, J ) 6.1, 1.9 Hz, 1H),
7.54 (dd, J ) 6.1, 2.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
24.9, 26.7, 58.4, 67.1, 72.9, 78.1, 110.0, 133.4, 156.7, 199.6.
Anal. (C10H14O4S) C, H.
solid: mp 110-113 °C (lit.14c mp 109-111 °C); [R]20 +16.3 (c
D
0.5, MeOH) (lit.14c [R]D +17.7 (c 0.1, MeOH)); 1H NMR (300
MHz, D2O) δ 1.95 (s, 3H), 1.96 (m, 1H), 2.21 (m, 2H), 2.53 (m,
1H), 3.65 (dd, J ) 12.0, 5.7 Hz, 1H), 3.78 (dd, J ) 12.0, 3.2
Hz, 1H), 4.61 (m, 1H), 6.19 (t, J ) 5.5 Hz, 1H), 7.57 (s, 1H);
13C NMR (75 MHz, D2O) δ 12.8, 26.4, 32.3, 64.5, 82.9, 88.4,
111.4, 135.5, 153.5, 163.0.
6,7-O-Isopr opyliden e-2,3-dideoxy-4-th io-D-a r a bin o-h ep-
ton o-1,4-la cton e (16). The above procedure for 9 was em-
ployed with 6.5 g (28.2 mmol) of unsaturated thiolactone 15,
0.8 g of 10% Pd on carbon, and 250 mg of AcONa in 150 mL of
THF to afford 5.9 g (90%) of saturated thiolactone 16 as white
crystals: mp 128-130 °C; [R]20D -52.9 (c 2.0, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.34 (s, 3H), 1.42 (s, 3H), 2.1-2.5 (m, 2H),
Compound â-L-14b (77 mg, 34%) was isolated as colorless
crystals: mp 148-150 °C (lit.14c mp 148-149 °C); [R]20D -30.9
(c 0.4, MeOH) (lit.14c [R]D -31.2 (c 0.1, MeOH)); 1H NMR (300
MHz, D2O) δ 1.92 (m, 1H), 1.96 (s, 3H), 2.17 (m, 2H), 2.51 (m,

176 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Rassu et al.
2.5-2.8 (m, 2H), 2.91 (d, J ) 3.6 Hz, 1H), 3.77 (dd, J ) 7.2,
3.9 Hz, 1H), 3.95 (m, 2H), 4.09 (m, 1H), 4.25 (ddd, J ) 7.5,
7.0, 3.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 25.0, 26.6, 28.4,
41.7, 53.3, 66.5, 74.6, 77.5, 109.6, 208.2. Anal. (C10H16O4S)
C, H.
vidual components were isolated by preparative TLC (98:2:
0.5 ethyl acetate/methanol/aqueous ammonia).
Compound R-L-21a (59 mg, 30%) was isolated as a foam:
1
[R]20 -11.5 (c 0.3, MeOH); H NMR (300 MHz, D2O) δ 1.8-
D
2.7 (m, 4H), 3.6-4.1 (m, 3H), 5.83 (d, J ) 7.5 Hz, 1H), 6.19
(dd, J ) 6.1, 3.9 Hz, 1H), 7.48 (d, J ) 7.5 Hz, 1H); 13C NMR
(75 MHz, D2O) δ 33.8, 39.4, 55.3, 63.0, 68.2, 105.1, 146.6, 155.3,
169.4. Anal. (C9H12N2O3S) C, H, N.
(R)-5-F or m ylth iola n -2-on e (17). The above procedure for
10 was employed with 5.0 g (21.5 mmol) of 16 to afford 2.1 g
(75%) of aldehyde 17, which was isolated in a pure state as a
1
colorless oil: [R]20 -43.6 (c 1.1, CHCl3); H NMR (300 MHz,
Compound â-L-21a (61 mg, 31%) was isolated as a foam:
[R]20D -8.0 (c 0.2, MeOH); 1H NMR (300 MHz, D2O) δ 1.8-2.7
(m, 4H), 3.6-4.1 (m, 3H), 5.85 (d, J ) 7.5 Hz, 1H), 6.66 (t, J
) 7.5 Hz, 1H), 7.50 (d, J 7.5 Hz, 1H); 13C NMR (75 MHz, D2O)
δ 33.6, 39.2, 55.6, 65.0, 67.7, 104.8, 146.7, 155.1, 169.2. Anal.
(C9H12N2O3S) C, H, N.
3′-Deoxy-4′-th io-r-L-th ym id in e (r-L-21b) a n d 3′-Deoxy-
4′-th io-â-L-th ym id in e (â-L-21b). The above procedure for R-
and â-L-14b was employed with 0.5 g (1.72 mmol) of 20 and
651 mg (5.16 mmol) of thymine to afford a 1:1 R,â anomeric
mixture of nucleosides, from which pure individual compounds
were isolated by preparative TLC (99:1:0.3 ethyl acetate/
methanol/aqueous ammonia).
D
CDCl3) δ 2.37 (m, 1H), 2.63 (m, 3H), 4.35 (m, 1H), 9.63 (d, J )
1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 24.3, 39.8, 56.1,
194.2, 205.5. Anal. (C5H6O2S) C, H.
2,3-Did eoxy-4-th io-r,â-L-r ibofu r a n ose (19). To a solu-
tion of aldehyde 17 (1.5 g, 11.5 mmol) in methanol (50 mL),
was added NaBH4 (435 mg, 11.5 mmol) with stirring at -30
°C during a period of 1 h. The temperature was allowed to
rise to -15 °C while a further portion of NaBH4 (435 mg, 11.5
mmol) was added and the mixture was stirred at -15 °C for
3 h. Acetone (10 mL) was then added, and the resulting
mixture was allowed to stir at room temperature for 1 h. The
mixture was concentrated under vacuum and the residue
subjected to flash chromatography (3:7 hexanes/ethyl acetate)
to afford 1.0 g (65%) of pure 19 as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 2.0-2.3 (m, 4H), 2.6 (bs, 2H), 3.53 (qd, J
) 11.1, 6.1 Hz, 1H), 3.75 (m, 2H), 5.52 (dd, J ) 3.7, 1.3 Hz,
0.7H), 5.56 (dd, J ) 4.2, 1.7 Hz, 0.3H); 13C NMR (75 MHz,
CDCl3) δ 29.3 and 29.8, 38.9 and 41.2, 50.9 and 52.4, 65.0 and
65.6, 82.2 and 82.4. Anal. (C5H10O2S) C, H.
Compound R-L-21b (71 mg, 34%) was isolated as a powder:
[R]20D -19.8 (c 0.3, MeOH); 1H NMR (300 MHz, CD3OD) δ 1.89
(s, 3H), 1.9-2.4 (m, 4H), 3.4-3.9 (m, 2H), 3.96 (m, 1H), 6.19
(dd, J ) 6.2, 4.7 Hz, 1H), 8.08 (s, 1H). Anal. (C10H14N2O3S)
C, H, N.
Compound â-L-21b (150 mg, 36%) was isolated as a pow-
der: [R]20
-10.5 (c 0.45, MeOH); 1H NMR (300 MHz, CD3-
D
OD) δ 1.90 (s, 3H), 1.8-2.5 (m, 4H), 3.4-3.7 (m, 3H), 6.25 (t,
J ) 7.8 Hz, 1H), 7.76 (s, 1H). Anal. (C10H14N2O3S) C, H, N.
2′,3′-Did eoxy-4′-th io-r-L-cytid in e (r-L-21c) a n d 2′,3′-
Did eoxy-4′-th io-â-L-cytid in e (â-L-21c). The above procedure
described for R- and â-L-14c, employing 0.5 g (1.72 mmol) of
20 and 790 mg (5.16 mmol) of 4-N-acetylcytosine gave a 1:1
R,â anomeric mixture of the title nucleosides, which were
separated, as individual components, by preparative TLC (90:
10:0.5 ethyl acetate/methanol/aqueous ammonia).
Compound R-L-21c (61 mg, 31%) was isolated as a foam:
[R]20D -30.0 (c 0.3, MeOH); 1H NMR (300 MHz, CD3OD) δ 1.9-
2.2 (m, 3H), 2.42 (m, 1H), 3.51 (dd, J ) 11.1, 6.9 Hz, 1H), 3.60
(dd, J ) 11.1, 6.6 Hz, 1H), 3.84 (quint, J ) 6.0 Hz, 1H), 5.92
(d, J ) 7.2 Hz, 1H), 6.27 (dd, J ) 6.6, 4.2 Hz, 1H), 8.05 (d, J
) 7.2 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 31.7, 37.7, 53.0,
60.0, 66.6, 96.1, 143.7, 158.7, 167.4. Anal. (C9H13N3O2S) C,
H, N.
(R)-5-(Hyd r oxym eth yl)th iola n -2-on e (18). To a solution
of aldehyde 17 (0.5 g, 3.8 mmol) in methanol (16 mL) was
carefully added NaBH4 (145 mg, 3.8 mmol) in small portions
during a period of 1 h at -30 °C. The mixture was slowly
warmed to -20 °C, while the progress of the reduction is
monitored by TLC. When starting aldehyde was almost
entirely consumed, the reaction was rapidly quenched with a
chilled saturated aqueous NH4Cl solution and then extracted
with ethyl acetate. The extracts were dried (MgSO4) and
concentrated, and the residue was chromatographed on silica
gel (3:7 hexanes/ethyl acetate) to afford 261 mg (52%) of alcohol
18 as an oil: 1H NMR (300 MHz, CDCl3) δ 2.15 (m, 1H), 2.35
(m, 1H), 2.64 (m, 2H), 3.69 (s, 1H), 3.86 (m, 2H), 4.05 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 27.5, 41.1, 52.0, 65.4, 210.5. Anal.
(C5H8O2S) C, H.
Using the standard protocol,16 as for 11, an ee of g90% was
measured for 18.
Compound â-L-21c (58 mg, 30%) was isolated as colorless
1-O-Acetyl-5-O-(ter t-bu tyld im eth ylsilyl)-2,3-d id eoxy-4-
th io-r,â-L-r ibofu r a n ose (20). To a solution of thiolactol 19
(1.0 g, 7.5 mmol) in anhydrous CH2Cl2 (50 mL) were added
TBSCl (1.5 g, 10.0 mmol) and imidazole (680 mg, 10.0 mmol)
with stirring at ambient temperature. After 10 h, the reaction
was quenched by adding a 5% aqueous citric acid solution and
the mixture extracted thoroughly with ethyl acetate. After
drying (MgSO4), the solvent was removed and the residue
purified by flash chromatography (7:3 hexanes/ethyl acetate)
to afford a 5-O-protected intermediate (not characterized)
which was employed in the successive acetylation reaction.
Thus, the product was dissolved in anhydrous CH2Cl2 (25 mL),
and pyridine (2.0 mL), Ac2O (1.4 mL), and a catalytic amount
of DMAP were sequentially added. After being stirred at room
temperature for 30 min, the reaction was quenched with
aqueous NaHCO3 and then extracted with CH2Cl2. The
extracts were dried (Na2SO4), and the solvent was removed
under vacuum. Flash chromatographic purification of the
crude product (8:2 hexanes/ethyl acetate) afforded pure thio-
furanose 20 (1.5 g, 70%) as a colorless oil which solidified on
1
crystals: mp 86-87 °C; [R]20 -15.0 (c 0.3, MeOH); H NMR
D
(300 MHz, CD3OD) δ 1.88 (m, 1H), 2.15 (m, 2H), 2.31 (m, 1H),
3.63 (m, 1H), 3.72 (dd, J ) 11.1, 5.4 Hz, 1H), 3.81 (dd, J )
11.1, 5.7 Hz, 1H), 5.90 (d, J ) 7.5 Hz, 1H), 6.24 (dd, J ) 6.0,
4.2 Hz, 1H), 8.30 (d, J ) 7.5 Hz, 1H); 13C NMR (75 MHz, CD3-
OD) δ 31.3, 38.4, 53.9, 65.6, 66.6, 95.7, 144.0, 158.7, 167.5.
Anal. (C9H13N3O2S) C, H, N.
The enantiomeric intermediates ent-15-ent-20 and enan-
tiomeric nucleosides R-D-21a -c and â-D-21a -c were prepared
by starting with L-glyceraldehyde L-1, adopting the procedures
above described for their respective counterparts 15-20 and
R- and â-L-21a -c. Diagnostic data are as follows:
ent-15: yield 71%, an oil; [R]20D -65.9 (c 2.4, CHCl3). Anal.
(C10H14O4S) C, H.
ent-16: yield 90%, colorless crystals; mp 130-131 °C; [R]20
D
+53.7 (c 2.4, CHCl3). Anal. (C10H16O4S) C, H.
ent-17: yield 76%, an oil; [R]20D +42.5 (c 0.6, CHCl3). Anal.
(C5H6O2S) C, H.
ent-19: yield 67%, colorless oil. Anal. (C5H10O2S) C, H.
ent-18: yield 52%, an oil. Anal. (C5H8O2S) C, H.
standing: [R]20 -30.0 (c 0.5, CHCl3); 1H NMR δ 0.05 (s, 6H),
D
0.88 (s, 4.5H), 0.89 (s, 4.5H), 2.03 (s, 1.5H), 2.04 (s, 1.5H), 1.8-
2.3 (m, 4H), 3.4-3.8 (m, 3H), 6.13 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ -5.3 (2 C), 18.3, 21.3, 25.9 (3 C), 29.5 and 31.0, 34.7
and 37.0, 49.7 and 51.9, 65.8 and 67.5, 82.8, 170.4. Anal.
(C13H26O3SSi) C, H.
2′,3′-Did eoxy-4′-t h io-r-L-u r id in e (r-L-21a ) a n d 2′,3′-
Did eoxy-4′-th io-â-L-u r id in e (â-L-21a ). The above procedure
described for R- and â-L-14a was followed with 0.5 g (1.72
mmol) of 20 and 0.58 g of uracil (5.16 mmol) to afford a 1:1
R,â anomeric mixture of nucleosides from which pure indi-
ent-20: yield 70%, glassy solid; [R]20 +28.5 (c 0.6, CHCl3).
D
Anal. (C13H26O3SSi) C, H.
R-D-21a : yield 28%, a foam; [R]20 +12.2 (c 0.2, MeOH).
D
Anal. (C9H12N2O3S) C, H, N.
â-D-21a : yield 34%, a foam; [R]20D +8.7 (c 0.2, MeOH). Anal.
(C9H12N2O3S) C, H, N.
R-D-21b: yield 31%, a foam; [R]20 +18.5 (c 0.3, MeOH).
D
Anal. (C10H14N2O3S) C, H, N.
â-D-21b: yield 39%, a powder; [R]20 +11.4 (c 0.3, MeOH).
D
Anal. (C10H14N2O3S) C, H, N.

Expeditious Syntheses of Sugar-Modified Nucleosides
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 177
R-D-21c: yield 29%, white foam; [R]20D +28.7 (c 0.15, MeOH).
Anal. (C9H13N3O2S) C, H, N.
under argon. After being stirred for 2 h, additional hydride
(3.35 mL, 3.35 mmol) was added and the reaction was allowed
to stir at the same temperature. After 3 h, the reaction was
quenched with methanol and water, and after ambient tem-
perature was reached, the resulting slurry was extracted with
CH2Cl2. The extracts were dried (MgSO4), and the solvent was
removed under vacuum to give a crude aminol, which was used
in the subsequent step. Thus, the crude product was dissolved
in anhydrous ethyl ether (25 mL), and trimethyl orthoformate
(1.4 mL, 12.4 mmol), BF3‚OEt2 (250 µL), and powdered 4 Å
molecular sieves (200 mg) were sequentially added at ambient
temperature. After 30 min, the reaction was quenched with
brine and few drops of Et3N. The mixture was extracted with
diethyl ether and, after drying, the solvent evaporated to give
crude O-methyl derivative 27, which was purified by silica gel
flash chromatography (8:2 hexanes/ethyl acetate). There were
â-D-21c: yield 30%, colorless crystals; mp 86-89 °C (lit.17a
mp 83-85 °C); [R]20 +16.6 (c 0.25, MeOH).
D
N-(ter t-Bu t oxyca r b on yl)-6,7-O-isop r op ylid en e-2,3-d i-
d eoxy-D-a r a bin o-h ep t-2-en on o-1,4-la cta m (22). To a solu-
tion of 2,3-O-isopropylidene-D-glyceraldehyde (D-1) (6.0 g, 46
mmol) in anhydrous Et2O (300 mL) were added TBSOP (13.6
g, 46 mmol) and SnCl4 (8.1 mL, 69 mmol) under argon at -85
°C. The mixture was stirred at this temperature for 3 h, a
saturated aqueous NaHCO3 solution was added at -85 °C, and
after ambient temperature was reached, the resulting mixture
was extracted with Et2O (3 × 60 mL). After drying (MgSO4),
the solution was evaporated under reduced pressure and the
crude product was crystallized from CH2Cl2/hexane to give 11.5
g (80%) of 22 as a white solid: mp 138-140 °C; [R]20D +197.59
1
obtained 1.8 g (78%) of 27 (mixture of R and â anomers) as a
(c 0.83, CHCl3); H NMR (300 MHz, CDCl3) δ 1.32 and 1.37
1
colorless oil: [R]20 +54.6 (c 1.3, CHCl3); H NMR (300 MHz,
(2s, each 3H), 1.57 (s, 9H), 3.63 (d, J ) 3.9 Hz, 1H), 3.86 (dd,
J ) 8.1, 6.0 Hz, 1H), 3.94 (dd, J ) 8.1, 6.0 Hz, 1H), 4.01 (q, J
) 6.0 Hz, 1H), 4.09 (ddd, J ) 6.0, 5.7, 3.9 Hz, 1H), 4.81 (dt, J
) 5.7, 2.4 Hz, 1H), 6.13 (dd, J ) 6.3, 1.5 Hz, 1H), 7.43 (dd, J
) 6.3, 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 25.1, 26.4,
28.0 (3 C), 65.6, 66.4, 72.6, 75.6, 83.8, 109.2, 126.9, 148.2, 150.9,
168.9. Anal. (C15H23NO6) C, H, N.
D
CDCl3) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.48 (s, 9H), 1.75 (m, 1H),
1.85 (m, 1H), 2.01 (m, 2H), 3.28 (s, 3H), 3.3-4.0 (m, 3H), 5.17
(m, 1H); 13C NMR (75 MHz, CDCl3) (major isomer) δ -5.4 (2
C), 18.2, 25.8 (3 C), 27.3, 28.4 (3 C), 29.6, 55.5, 59.2, 64.9, 79.8,
89.5, 154.2. Anal. (C17H35NO4Si) C, H, N.
4′-[(ter t-Bu tyloxyca r bon yl)a m in o]-2′,3′,4′-tr id eoxy-â-L-
u r id in e (â-L-28a ). The above procedure described for R- and
â-L-14a was followed with 0.5 g (1.45 mmol) of 27 and 0.33 g
(2.9 mmol) of uracil to afford a crude nucleoside product from
which pure â-L-28a (293 mg, 65%) was obtained by preparative
TLC purification (95:5:0.5 ethyl acetate/methanol/aqueous
N-(ter t-Bu t oxyca r b on yl)-6,7-O-isop r op ylid en e-2,3-d i-
d eoxy-D-a r a bin o-h ep ton o-1,4-la cta m (23). The above pro-
cedure for 9 was employed with 5.7 g (18.2 mmol) of unsat-
urated lactam 22, 600 mg of 10% Pd on carbon, and 250 mg of
AcONa in 200 mL of THF to afford 5.2 g (92%) of saturated
ammonia) as the sole anomer, as a powder: [R]20 +58.8 (c
lactam 23 as a white solid: mp 99-103 °C; [R]20 +59.24 (c
D
D
0.3, MeOH); 1H NMR (300 MHz, D2O) δ 1.40 (s, 9H), 2.10 (m,
3H), 2.39 (m, 1H), 3.81 (m, 1H), 3.99 (m, 2H), 5.89 (d, J ) 7.9
Hz, 1H), 6.12 (m, 1H), 8.03 (d, J ) 7.9 Hz, 1H); 13C NMR (75
MHz, D2O) δ 28.2, 30.7 (3 C), 33.5, 63.1, 74.6, 75.2, 81.0, 105.2,
145.3, 151.0, 157.8, 174.2. Anal. (C14H21N3O5) C, H, N.
4′-[(ter t-Bu tyloxycar bon yl)am in o]-3′,4′-dideoxy-â-L-th y-
m id in e (â-L-28b). The above procedure described for R- and
â-L-14b was followed with 0.5 g (1.45 mmol) of 27 and 0.45 g
(3.6 mmol) of thymine to afford a crude nucleoside product
from which pure â-L-28b (330 mg, 70%) was obtained by
preparative TLC purification (95:5:0.5 ethyl acetate/methanol/
1.26, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.30 and 1.36 (2s,
each 3H), 1.48 (s, 9H), 2.10 (m, 2H), 2.32 (ddd, J ) 17.7, 6.0,
4.8 Hz, 1H), 2.71 (dt, J ) 17.1, 10.5 Hz, 1H), 3.54 (d, J ) 6.3
Hz, 1H), 3.69 (q, J ) 5.7 Hz, 1H), 3.97 (ddd, J ) 5.5, 4.8, 1.2
Hz, 1H), 4.05 (m, 2H), 4.31 (ddd, J ) 5.7, 5.4, 3.9 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) δ 21.7, 25.1, 26.6, 28.0 (3 C), 32.0, 60.4,
66.8, 74.5, 77.7, 83.6, 109.4, 151.7, 174.5. Anal. (C15H25NO6)
C, H, N.
(R )-N -(t er t -Bu t oxyca r b on yl)-5-for m ylp yr r olid in -2-
on e (24). The above procedure for 10 was employed with 5.0
g (15.9 mmol) of 23 to afford 2.2 g (63%) of aldehyde 24, which
was isolated in a pure state as an oil: 1H NMR (300 MHz,
CDCl3) δ 1.50 (s, 9H), 2.05 (m, 1H), 2.25 (m, 1H), 2.54 (m, 2H),
4.58 (ddd, J ) 7.2, 4.8, 2.2 Hz, 1H), 9.60 (d, J ) 2.2 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 18.3, 27.8 (3 C), 31.2, 64.2, 84.3,
141.4, 173.0, 196.9. Anal. (C10H15NO4) C, H, N.
aqueous ammonia) as the sole anomer, as a waxy solid: [R]20
D
+35.9 (c 2.0, CHCl3); 1H NMR (300 MHz, CD3OD, 50 °C) δ
1.39 (s, 9H), 1.87 (d, J ) 0.9 Hz, 3H), 2.07 (m, 3H), 2.29 (m,
1H), 3.69 (dd, J ) 11.1, 2.7 Hz, 1H), 3.92 (m, 1H), 4.11 (dd, J
) 11.1, 4.6 Hz, 1H), 6.09 (dd, J ) 7.4, 5.1 Hz, 1H), 8.11 (d, J
) 0.9 Hz, 1H); 13C NMR (75 MHz, CD3OD, 50 °C) δ 12.3, 25.5,
28.1 (3 C), 31.2, 60.7, 64.5, 71.5, 81.8, 110.2, 136.4, 150.6, 154.9,
164.0. Anal. (C15H23N3O5) C, H, N.
(R)-N-(ter t-Bu toxyca r bon yl)-5-O-(ter t-bu tyld im eth yl-
silyl)-5-(h yd r oxym eth yl)-2-p yr r olid in on e (26). To a solu-
tion of pyrrolinone 24 (2.0 g, 9.4 mmol) in methanol (30 mL),
was added NaBH4 (356 mg, 9.4 mmol) in small portions at
-30 °C. The mixture was allowed to warm to 0 °C; the
progress of the reaction was monitored by TLC. After the
reduction was complete (2 h), a saturated aqueous NH4Cl
solution was added, and the mixture was thoroughly extracted
with ethyl acetate to give 1.8 g of essentially pure 25 (g98%
ee) which was used as such in the subsequent step. Thus,
alcohol 25 was dissolved in CH2Cl2 (40 mL), and TBSCl (1.25
g, 10.0 mmol) and imidazole (562 mg, 10.0 mmol) were
sequentially added at room temperature. After being stirred
for 18 h, the mixture was quenched by a 5% aqueous citric
acid solution and extracted with ethyl acetate. The extracts
were dried and evaporated under vacuum to give an oily
residue, from which pure protected lactam 26 (2.23 g, 72%)
was isolated as an oil by silica gel flash chromatography (7:3
4′-[(ter t-Bu tyloxyca r bon yl)a m in o]-2′,3′,4′-tr id eoxy-â-L-
cytid in e (â-L-28c). The above procedure described for R- and
â-L-14c was followed with 0.5 g (1.45 mmol) of 27 and 0.67 g
(4.4 mmol) of 4-N-acetylcytosine to afford a crude nucleoside
product from which pure â-L-28c (278 mg, 62%) was obtained
by preparative TLC purification (70:30:0.5 ethyl acetate/
methanol/aqueous ammonia) as the sole anomer, as a colorless
glass which solidified on standing: [R]20D +38.5 (c 0.4, MeOH);
1H NMR (300 MHz, D2O) δ 1.34 (s, 9H), 1.98 (m, 2H), 2.10 (m,
1H), 2.38 (m, 1H), 3.82 (m, 1H), 3.97 (m, 2H), 6.06 (m, 2H),
7.97 (d, J ) 7.4 Hz, 1H); 13C NMR (75 MHz, D2O) δ 28.2, 30.7
(3 C), 34.0, 63.1, 65.4, 75.2, 81.1, 99.1, 144.9, 150.9, 161.1,
169.4. Anal. (C14H22N4O4) C, H, N.
The enantiomeric intermediates ent-22-ent-27 and enan-
tiomeric nucleosides â-D-28a -c were prepared by utilizing
L-glyceraldehyde L-1, adopting the procedures above described
for their respective counterparts 22-27 and â-L-28a -c. Di-
agnostic data are as follows:
hexanes/ethyl acetate): [R]20 +55.6 (c 1.12, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H),
1.53 (s, 9H), 2.05 (m, 2H), 2.37 (ddd, J ) 17.4, 9.6, 2.4 Hz,
1H), 2.71 (dt, J ) 17.4, 9.6 Hz, 1H), 3.69 (dd, J ) 10.3, 2.1 Hz,
1H), 3.92 (dd, J ) 10.3, 3.9 Hz, 1H), 4.17 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ -5.7, -5.6, 18.1, 21.0, 25.7 (3 C), 27.9 (3
C), 32.3, 58.8, 64.2, 82.5, 149.9, 174.8. Anal. (C16H31NO4Si)
C, H, N.
ent-22: yield 78%, white solid; mp 135-136 °C; [R]20
D
-195.66 (c 0.4, CHCl3). Anal. (C15H23NO6) C, H, N.
ent-23: yield 90%, colorless solid; mp 101-102 °C; [R]20
D
-60.14 (c 1.0, CHCl3). Anal. (C15H25NO6) C, H, N.
ent-24: yield 60%, an oil. Anal. (C10H15NO4) C, H, N.
ent-26: yield 72%, a colorless oil; [R]20D -53.4 (c 0.8, CHCl3).
Anal. (C16H31NO4Si) C, H, N.
(R)-N-(ter t-Bu toxyca r bon yl)-5-O-(ter t-bu tyld im eth yl-
silyl)-2-m eth oxyp yr r olid in e (27). To a solution of pyrroli-
dinone 26 (2.2 g, 6.7 mmol) in THF (100 mL) was added a 1.0
M THF solution of LiEt3BH (3.35 mL, 3.35 mmol) at -78 °C,
ent-27: yield 81%, an oil; [R]20D -52.3 (c 1.5, CHCl3). Anal.
(C17H35NO4Si) C, H, N.

178 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Rassu et al.
1
â-D-28a : yield 63%, a waxy solid; [R]20D -59.2 (c 0.3, MeOH).
Anal. (C14H21N3O5) C, H, N.
(()-30 as a white solid (6.7 g, 60%): mp 44-48 °C; H NMR
(300 MHz, CDCl3) δ -0.19 (s, 3H), -0.01 (s, 3H), 0.81 (s, 9H),
1.50 (s, 9H), 3.67 (dd, J ) 9.7, 6.7 Hz, 1H), 4.09 (dd, J ) 9.7,
3.6 Hz, 1H), 4.55 (dddd, J ) 6.7, 3.6, 1.9, 1.7 Hz, 1H), 6.07
(dd, J ) 6.1, 1.7 Hz, 1H), 7.21 (dd, J ) 6.1, 1.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ -5.6, -5.5, 18.0, 25.6 (3 C), 28.1 (3
â-D-28b: yield 72%, a waxy solid; [R]20D -36.0 (c 2.8, CHCl3).
Anal. (C15H23N3O5) C, H, N.
â-D-28c: yield 65%, a glass; [R]20 -37.5 (c 0.5, MeOH).
D
Anal. (C14H22N4O4) C, H, N.
(R,S)-5-(Dieth oxym eth yl)-2(5H)-fu r a n on e [(()-29a ]. To
a stirred solution of TBSOF (9.86 g, 49.8 mmol) in Et2O (160
mL) cooled at -80 °C were added ethyl orthoformate (9.9 mL,
59.7 mmol) and BF3‚OEt2 (9.2 mL, 74.7 mmol) under nitrogen.
After being stirred at this temperature for 30 min, the reaction
was quenched with a saturated aqueous NaHCO3 solution and
extracted three times with diethyl ether. After drying (Mg-
SO4), the solvent was evaporated to give virtually pure acetal
(()-29a (9.0 g, 98%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 0.84 (t, J ) 7.0 Hz, 3H), 0.90 (t, J ) 7.0 Hz, 3H),
3.23 (m, 1H), 3.32 (m, 1H), 3.43 (m, 2H), 4.23 (d, J ) 4.9 Hz,
1H), 4.71 (ddd, J ) 4.9, 2.0, 1.5 Hz, 1H), 5.84 (dd, J ) 5.7, 2.0
Hz, 1H), 7.23 (dd, J ) 5.7, 1.5 Hz, 1H). Anal. (C9H14O4) C,
H.
C), 62.4, 63.5, 82.8, 127.0, 149.6, 153.1, 169.2. Anal. (C16H29
NO4Si) C, H, N.
-
(R,S)-N-(ter t-Bu toxyca r bon yl)-5-O-(ter t-bu tyld im eth -
ylsilyl)-5-(h yd r oxym eth yl)-2-p yr r olid in on e [(()-26].
A
solution of unsaturated lactam (()-30 (6.7 g, 20.5 mmol) in
300 mL of THF was hydrogenated in the presence of 580 mg
of 10% Pd on carbon and 650 mg of NaOAc. After the mixture
was stirred for 20 h at ambient temperature, the catalyst was
removed by passing the slurry through a short SiO2 column
eluting with hexanes/ethyl acetate (70:30). The solvents were
evaporated to give essentially pure saturated lactam (()-26
(6.3 g, 93%) as an oil, whose spectral characteristics match
those reported above for enantiopure 26. Anal. (C16H31NO4-
Si) C, H, N.
(R,S)-5-(Dieth oxym eth yl)th iolen -2-on e [(()-29b]. The
above procedure described for (()-29a , but with a reaction time
of 2 h at -80 °C and 2 h at -15 °C, was followed by starting
with 10.0 g (46.6 mmol) of TBSOT to afford (()-29b as an oil
(8.95 g, 95%): 1H NMR (300 MHz, CDCl3) δ 1.13 (t, J ) 7.1
Hz, 3H), 1.16 (t, J ) 7.1 Hz, 3H), 3.53 (m, 2H), 3.67 (m, 2H),
4.35 (d, J ) 7.6 Hz, 1H), 4.56 (ddd, J ) 7.6, 2.8, 1.9 Hz, 1H),
6.24 (dd, J ) 6.2, 1.9 Hz, 1H), 7.42 (dd, J ) 6.2, 2.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 15.0 (2 C), 57.4, 63.3, 63.5, 103.6,
133.6, 154.4, 199.3. Anal. (C9H14O3S) C, H.
(R,S)-5-F or m yld ih yd r o-2(3H)-fu r a n on e [(()-10]. A so-
lution of unsaturated lactone (()-29a (9.0 g, 48.4 mmol) in 400
mL of THF was hydrogenated in the presence of 0.9 g of 10%
Pd on carbon and 1.5 g of NaOAc. After being stirred for 24
h at room temperature, the catalyst was removed by filtration
on a pad of silica gel, and the solution was concentrated to
give a residue (8.2 g) which was directly treated with a solution
of 10% aqueous HCl (70 mL) in THF (220 mL). The solution
was stirred at room temperature for 2 h and then evaporated
under vacuum to give crude aldehyde (()-10, which was
purified by flash chromatography (ethyl acetate). There was
obtained pure (()-10 (4.5 g, 82%) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 2.24 (m, 1H), 2.50 (m, 3H), 4.54 (m, 1H),
9.74 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 21.7, 27.7, 80.5,
171.1, 197.8. Anal. (C5H6O3) C, H.
(R,S)-5-F or m ylth iola n -2-on e [(()-17]. The above proce-
dure described for (()-10 was employed with 8.0 g (39.6 mmol)
of (()-29b to afford 3.9 g (76%) of (()-17 as an oil, whose
spectral characteristics coincide with those for 17. Anal.
(C5H6O2S) C, H.
Meth yl 5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-d id eoxy-r,â-
D,L-r ibo-fu r a n osid e [(()-13]. The above transformations 10
to 13 were followed with 4.0 g (35 mmol) of (()-10, to obtain
6.5 g (75%) of (()-13 as a colorless oil, whose spectral data
coincide with those of homochiral compound 13. Anal.
(C12H26O3Si) C, H.
1-O-Acetyl-5-O-(ter t-bu tyld im eth ylsilyl)-2,3-d id eoxy-4-
th io-r,â-D,L-r ibofu r a n ose [(()-20]. The above protocol to
transform 17 into 20 was adopted with 3.9 g (30 mmol) of (()-
17 to give 4.35 g (50%) of thiosugar (()-20 as a glassy material,
whose spectral data exactly coincide with those of homochiral
compound 20. Anal. (C13H26O3SSi) C, H.
(R,S)-N-(ter t-Bu toxyca r bon yl)-5-[(ter t-bu tyld im eth yl-
siloxy)m eth yl]-2,5-d ih yd r op yr r ol-2-on e [(()-30]. To a
stirred solution of TBSOP (10.0 g, 34 mmol) in Et2O (200 mL)
cooled at -80 °C was added SnCl4 (8 mL, 67 mmol) under
nitrogen. A stream of gaseous formaldehyde, obtained by
thermal depolymerization of solid paraformaldehyde (4.0 g, 135
mmol), was passed throughout the resulting slurry using
nitrogen as a carrier, the temperature being maintained at
-80 °C for 2 h. After this, the reaction was quenched by
addition of saturated aqueous NaHCO3 to the reaction mixture
which was then extracted with ethyl acetate (3 × 100 mL).
The combined extracts were evaporated and the crude product
was purified by flash chromatography on silica gel, eluting
with hexanes/ethyl acetate (70:30) to afford the pyrrolidinone
5(R,S)-N-(ter t-Bu toxyca r bon yl)-5-[(ter t-bu tyld im eth yl-
siloxy)m eth yl]-2-m eth oxyp yr r olid in e [(()-27]. The above
described procedure for 27 was followed starting with 6.0 g
(18.2 mmol) of (()-26 to afford (()-27 (4.7 g, 75%) as a colorless
oil, whose spectral data coincide with those of compound 27.
Anal. (C17H35NO4Si) C, H, N.
Ra cem ic Nu cleosid e Libr a r y (D,L-L). Gen er a l P r oce-
d u r e. A solution of (()-13 (50 mg, 0.2 mmol), (()-20 (58 mg,
0.2 mmol), and (()-27 (69 mg, 0.2 mmol) in 1,2-dichloroethane
(9.0 mL) was subdivided into three equal parts of 3.0 mL, and
each portion was added via cannula to three different vessels
containing the appropriate silylated uracil, thymine, and
cytosine bases (0.8 mmol each). After cooling to 0 °C, each
solution was then treated with a mixture of SnCl4 (0.2 mmol)
and TMSOTf (0.2 mmol) under an argon atmosphere with
stirring. After 10 min, the temperature was allowed to rise
to 20 °C, while stirring was continued for an additional 2 h.
The mixtures were quenched by a saturated aqueous NaHCO3
solution and extracted five times with ethyl acetate (5 × 10
mL). After drying (MgSO4), the organic layers were evapo-
rated under vacuum to leave three gummy solids which were
separately dissolved in 10 mL of THF. Solid TBAF was then
added with stirring at room temperature, and the resulting
mixtures were allowed to react for 8 h. The solvent was
removed, and the three residues were redissolved in 9:1 MeOH/
H2O solvent mixtures. Solid K2CO3 (30 mg) was added at room
temperature, and after 3 h, the solvent was removed. The
three residues, dissolved in 4 mL of 92:8 ethyl acetate/MeOH
mixtures, were independently passed through short silica gel
columns eluting with a 92:8:0.5 ethyl acetate/MeOH/30%
aqueous NH4OH solvent mixture to remove unreacted nucleo-
base materials. The collected fractions were evaporated to
afford three collections of different nucleosides, D,L-SLUr (33
mg, 65% based on a average MW ) 250.6); D,L-SLTh (35 mg,
66% based on a average MW ) 264.6); and D,L-SLCy (30 mg,
60% based on a average MW ) 249.6).
The above individual sublibraries were dissolved in HPLC-
grade water and subjected without any further purification
to reverse-phase HPLC analyses according to the described
standard conditions (vide supra), the results being displayed
in Figures 1-3 (see text for details). Mixing the three
mixtures finally resulted in formation of a complete collection
of nucleosides, D,L-L (98 mg, 64% based on an average MW )
254.9, assuming equimolar product distribution), comprising
the expected 15 racemic compounds.
Hom och ir a l Nu cleosid e Libr a r y (L-L). The above de-
tailed protocol for racemic library was adopted here by starting
with the carbohydrate precursors of the L-series 13, 20, and
27 (0.1 mmol each). There was obtained the title full-library
of fifteen chiral L-nucleosides (40 mg, 58%). The HPLC
analyses, performed on the pertinent three uridine, thymidine,
and cytosine sublibraries, revealed profiles which, apart from
few negligible discrepancies, corresponded to those of the
racemic counterparts in Figures 1-3.

Expeditious Syntheses of Sugar-Modified Nucleosides
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 179
(4) Na¨sman, J . H. 3-Methyl-2(5H)-Furanone. Org. Synth. 1990, 68,
162-174.
Ack n ow led gm en t. The authors acknowledge Drs.
Sabrina Cassinari, Rosella Massitti, and Lara Montruc-
chio Toppia for their precious technical assistance. We
also thank Professors Giovanna Gasparri Fava and
Marisa Belicchi Ferrari and Dr. Giorgio Pelosi for single-
crystal X-ray analyses of compounds 8, 15, and 22.
Financial support of this work received from Consiglio
Nazionale delle Ricerche (Grant no. 95.00986.CT03) and
Centro Interdipartimentale di Misure “Giuseppe Cas-
nati” dell’Universita` di Parma for the use of NMR
instrumentation are gratefully acknowledged.
(5) Hawkins, R. T. Thienyl Methacrylates. J . Heterocycl. Chem.
1974, 11, 291-294.
(6) Bocchi, V.; Chierici, L.; Gardini, G. P.; Mondelli, R. On Pyrrole
Oxidation with Hydrogen Peroxide. Tetrahedron 1970, 26, 4073-
4082.
(7) Schmid, C. R.; Bryant, J . D. D-(R)-Glyceraldehyde Acetonide.
Org. Synth. 1995, 72, 6-13.
(8) Hubschwerlen, C.; Specklin, J .-L.; Higelin, J . L-(S)-Glyceralde-
hyde Acetonide. Org. Synth. 1995, 72, 1-5.
(9) The absolute configuration of 8 derived from a X-ray analysis
of its deprotected derivative: Casiraghi, G.; Colombo, L.; Rassu,
G.; Spanu, P.; Gasparri Fava, G.; Ferrari Belicchi, M. The Four-
Carbon Elongation of Three-Carbon Chiral Synthons using
2-(Trimethylsiloxy)furan: Highly Stereocontrolled Entry to
Enantiomerically Pure Seven-Carbon R,â-Unsaturated 2,3-
Dideoxy-Aldonolactones. Tetrahedron 1990, 46, 5807-5824.
(10) R-Substituted aldehydes such as 10, and its relatives 17 and
24, are readily subjected to epimerization. However, the mild,
neutral conditions adopted during the oxidation maneuver
accompanied by prompt reduction of the aldehyde products to
the corresponding carbinols 11, 18, and 25 almost completely
obviated this inconvenience. The enantiomeric integrity of the
aldehyde products was judged by checking the enantiomeric
purity of 11, 18, and 25 (vide infra).
Refer en ces
(1) For recent reviews and general articles on the use of combina-
torial technology for drug discovery, see: Madden, D.; Krchna´k,
V.; Lebl, M. Synthetic Combinatorial Libraries: Views on
Techniques and their Application. Perspect. Drug Disc. Des.
1995, 2, 269-285. Ellman, J . A. Combinatorial Organic Librar-
ies. ChemtractssOrg. Chem. 1995, 8, 1-4. Pirrung, M. C.
Combinatorial Libraries: Chemistry Meets Darwin. Ibid. 1995,
8, 5-12. Czarnik, A. W. Why Combinatorial Chemistry, Why
Now (and Why You Should Care). Ibid. 1995, 8, 13-18. Mitscher,
L. A. Some Ruminations on the Present and Future Roles of
Combinatorial and Multiplex Syntheses in Medicinal Chemistry.
Ibid. 1995, 8, 19-25. Cabri, W. Combinatorial Chemistry:
Status and Perspectives. Chim. Ind. (Milan) 1995, 77, 406-410.
Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gordon, E. M. Applications of Combinatorial Technologies to
Drug Discovery. 1. Background and Peptide Combinatorial
Libraries. J . Med. Chem. 1994, 37, 1233-1251. Gordon, E. M.;
Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.; Gallop, M. A.
Applications of Combinatorial Technologies to Drug Discovery.
2. Combinatorial Organic Synthesis, Library Screening Strate-
gies, and Future Directions. J . Med. Chem. 1994, 37, 1385-1401.
Moos, W. H.; Green, G. D.; Pavia, M. R. Recent Advances in the
Generation of Molecular Diversity. Annu. Rep. Med. Chem. 1993,
28, 315-324.
(2) Casiraghi, G.; Rassu, G. Furan-, Pyrrole-, and Thiophene-Based
Siloxydienes for Syntheses of Densely Functionalized Homo-
chiral Compounds. Synthesis 1995, 607-626. Casiraghi, G.;
Zanardi, F.; Rassu, G.; Spanu, P. Stereoselective Approaches to
Bioactive Carbohydrates and Alkaloids-With a Focus on Recent
Syntheses Drawing from the Chiral Pool. Chem. Rev. 1995, 95,
1677-1716. Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P.
Ascent of the Aldose Series by Four Carbon Atoms: Total
Synthesis of D-glygero-D-talo-L-talo-Undecose Pentaacetonide. J .
Org. Chem. 1991, 56, 2135-2139. Casiraghi, G.; Colombo, L.
Rassu, G.; Spanu, P. Total Synthesis of 6-Deoxy-6-aminohepto-
pyranuronic Acid Derivatives. J . Org. Chem. 1991, 56, 6523-
6527. Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L.; Ulgheri F.
Total Syntheses of (+)-2,8,8a-Tri-epi-swainsonine and (-)-1-epi-
Swainsonine. J . Org. Chem. 1993, 58, 3397-3400. Casiraghi,
G.; Spanu, P.; Rassu, G.; Pinna, L.; Ulgheri, F. Total Syntheses
of All Four Isomers of cis-1,2-Dihydroxypyrrolizidine. J . Org.
Chem. 1994, 59, 2906-2909. Rassu, G.; Zanardi, F.; Cornia, M.;
Casiraghi, G. General Approach to Hydroxylated R-Amino Acids
Exploiting N-(tert-Butoxycarbonyl)-2-(tert-butyldimethylsiloxy)-
pyrrole. J . Chem. Soc., Perkin Trans. 1 1994, 2431-2437.
Zanardi, F.; Battistini, L.; Rassu, G.; Cornia, M.; Casiraghi, G.
γ-Substituted Pyrrole-Based Silyl Dienol Ethers as R-Amino Acid
Enolate Equivalents: a Versatile Entry to Racemic R-Substi-
tuted R-Amino Acids. J . Chem. Soc., Perkin Trans. 1 1995, 2471-
2475.
(3) (a) Uhlmann, E.; Peyman, A. Antisense Oligonucleotides: A New
Therapeutic Principle. Chem. Rev. 1990, 90, 543-584. (b)
Milligan, J . F.; Matteucci, M. D.; Martin, J . C. Current Concepts
in Antisense Drug Design. J . Med. Chem. 1993, 36, 1923-1937.
(c) De Clercq, E. Toward Improved Anti-HIV Chemotherapy:
Therapeutic Strategies for Intervention with HIV Infections. J .
Med. Chem. 1995, 38, 2491-2517. (d) Wnuk, S. F. Sulfur- and
Seleno-Sugar Modified Nucleosides. Synthesis, Chemical Trans-
formations and Biological Properties. Tetrahedron 1993, 49,
9877-9936. (e) Stein, C. A.; Cheng, Y.-C. Antisense Oligonu-
cleotides as Therapeutic Agents-Is the Bullet Really Magical?
Science 1993, 261, 1004-1012. (f) J eong, L. S.; Schinazi, R. F.;
Beach, J . W.; Kim, H. O. Nampalli, S.; Shanmuganathan, K.;
Alves, A. J .; McMillan, A.; Chu, C. K.; Mathis, R. Asymmetric
Synthesis and Biological Evaluation of â-L-(2R,5S)- and R-L-
(2R,5R)-1,3-Oxathiolane-Pyrimidine and -Purine Nucleosides as
Potential Anti-HIV Agents. J . Med. Chem. 1993, 36, 181-195.
(g) De Mesmaeker, A.; Ha¨ner, R.; Martin, P.; Moser, H. E.
Antisense Oligonucleotides. Acc. Chem. Res. 1995, 28, 366-374.
(h) Morvan, F.; Sanghvi, Y. S.; Perbost, M.; Vasseur, J .-J .; Bellon,
L. Oligonucleotide Mimics for Antisense Therapeutics: Solution
Phase and Automated Solid-Support Synthesis of MMI Linked
Oligomers. J . Am. Chem. Soc. 1996, 118, 255-256.
(11) Vorbru¨ggen, H.; Bennua, B. A New Simplified Nucleoside
Synthesis. Chem. Ber. 1981, 114, 1279-1286.
(12) The use of a 1:1 SnCl4/TMSOTf promoter mixture in 1,2-
dichloroethane came from an extensive optimization of the
coupling reactions between sugar 13 and a given nucleobase vis-
a-vis the sulfur and nitrogen relatives 20 and 27. In our hands,
the synthetic efficiency of this promoter mix overrode by far the
other Lewis acidic systems tested. More importantly, irrespective
of the heteroatom involved, the three sugar components dis-
played comparable reaction rates with this promoter system,
allowing easy adaptation of the chemistry to parallel and
combinatorial executions (vide infra).
(13) (a) Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J .; Coffen,
D. L. Synthesis of the Dideoxynucleosides ddC and CNT from
Glutamic Acid, Ribonolactone, and Pyrimidine Bases. J . Org.
Chem. 1988, 53, 4780-4786. (b) Lin, T.-S.; Luo, M.-Z.; Liu, M.-
C. Synthesis of Several Pyrimidine L-Nucleoside Analogues as
Potential Antiviral Agents. Tetrahedron 1995, 51, 1055-1068.
(14) (a) Farina, V.; Benigni, D. A. A New Synthesis of 2′,3′-Dideoxy-
nucleosides for AIDS Chemotherapy. Tetrahedron Lett. 1988, 29,
1239-1242. (b) Farina, V.; Martin, J . C.; Benigni, D. A. Process
for Preparation of 2′,3′-Dideoxynucleosides from 5-Carboxy-γ-
butyrolactone. Eur. Patent EP 285884, 1988; Chem. Abstr. 1989,
111, 23911. (c) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Pai, S. B.;
Dutschman, G. E.; Cheng, Y.-C. Synthesis and Biological Evalu-
ation of 2′,3′-Dideoxy-L-pyrimidine Nucleosides as Potential
Antiviral Agents against Human Immunodeficiency Virus (HIV)
and Hepatitis B Virus (HBV). J . Med. Chem. 1994, 37, 798-
803. (d) Horwitz, J . P.; Chua, J .; Da Rooge, M. A.; Noel, M.;
Klundt, I. L. Nucleosides. IX. The Formation of 2′,3′-Unsaturated
Pyrimidine Nucleosides via a Novel â-Elimination Reaction. J .
Org. Chem. 1966, 31, 205-211. (e) Michelson, A. M.; Todd, A.
R. Deoxyribonucleosides and Related Compounds. Part V. cyclo
Thymidines and other Thymidine Derivatives. The Configura-
tion at the Glycosidic Centre in Thymidine. J . Chem. Soc. 1955,
816-823.
(15) (a) Eguchi, C.; Kakuta, A. The Novel Synthesis of L-Hydroxy-
proline from D-Glutamic Acid. Bull. Chem. Soc. J pn 1974, 47,
1704-1708. (b) Taniguchi, M.; Koga, K.; Yamada, S. Stereo-
chemical Studies-XXX. Stereoselective Synthesis of D-Ribose
from L-Glutamic Acid. Tetrahedron 1974, 30, 3547-3552.
(16) Dale, J . A.; Dull, D. L.; Mosher, H. S. R-Methoxy-R-trifluoro-
methylphenylacetic Acid, a Versatile Reagent for the Determi-
nation of Enantiomeric Composition of Alcohols and Amines. J .
Org. Chem. 1969, 34, 2543-2549.
(17) (a) Secrist, J . A., III; Riggs, R. M.; Tiwari, K. N.; Montgomery,
J . A. Synthesis and Anti-HIV Activity of 4′-Thio-2′,3′-dideoxy-
nucleosides. J . Med. Chem. 1992, 35, 533-538. (b) Tiwari, K.
N.; Secrist, J . A. III; Montgomery, J . A. Synthesis and Biological
Activity of 4′-Thionucleosides of 2-Chloroadenine. Nucleosides
Nucleotides 1994, 13, 1819-1828. (c) Brånalt, J .; Kvarnstro¨m,
I.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. A New
Synthesis of 4-Thiofuranosides via Regioselective Opening of an
Episulfide with Allylmagnesium Bromide. J . Org. Chem. 1994,
59, 4430-4432. (d) Mann, J .; Tench, A. J .; Weymouth-Wilson,
A. C.; Shaw-Ponter, S.; Young, R. J . Two Synthetic Routes to
2′,3′-Dideoxy-3′-C-(hydroxymethyl)-4′-thionucleosides. J . Chem.
Soc., Perkin Trans. 1 1995, 677-681. (e) Young, R. J .; Shaw-
Ponter, S.; Thomson, J . B.; Miller, J . A.; Cumming, J . G.; Pugh,
A. W.; Rider, P. Synthesis and Antiviral Evaluation of Enan-
tiomeric 2′,3′-Dideoxy- and 2′,3′-Didehydro-2′,3′-dideoxy-4′-thio-
nucleosides. Bioorg. Med. Chem. Lett. 1995, 5, 2599-2604. (f)

180 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Rassu et al.
Van Draanen, N. A.; Freeman, G. A.; Short, S. A.; Harvey, R.;
J ansen, R.; Szczech, G.; Koszalka, G. W. Synthesis and Antiviral
Activity of 2′-Deoxy-4′-thio Purine Nucleosides. J . Med. Chem.
1996, 39, 538-542.
(f) Reist, E. J .; Fisher, L. V.; Goodman, L. Pyrrolidine Sugars.
Synthesis of 9-(4-Acetamido-4-deoxy-â-D-xylofuranosyl)adenine
and Other Derivatives of 4-Amino-4-deoxy-D-xylose. J . Org.
Chem. 1967, 32, 2541-2544. (g) Reist, E. J .; Gueffroy, D. E.;
Blackford, R. W.; Goodman, L. Pyrrolidine Sugars. Synthesis of
4′-Acetamidoadenosine and Other Dervatives of 4-Amino-4-
deoxy-D-ribose. J . Org. Chem. 1966, 31, 4025-4030.
(18) Rassu, G.; Spanu, P.; Pinna, L.; Zanardi, F.; Casiraghi, G. 2-(tert-
Butyldimethylsiloxy)thiophene: Application to Total Syntheses
of Both Enantiomers of 2′,3′-Dideoxy-4′-thiocytidine. Tetrahedron
Lett. 1995, 36, 1941-1944.
(19) Gasparri Fava, G.; Belicchi Ferrari, M.; Pelosi, G., Zanardi, F.;
Casiraghi, G.; Rassu, G. X-Ray Crystal and Molecular Structure
of 2,3-Dideoxy-4-thio-D-arabino-heptonic Acid 1,4-Lactone: a Key
Intermediate for Syntheses of 2′,3′-Dideoxy-4′-thio-L-nucleosides.
J . Chem. Crystallogr. 1996, 26, 509-513.
(20) Initial attempts to carry out the coupling reaction on the
corresponding O-methyl derivative using a variety of Lewis acid
catalysts met with failure.
(21) (a) Huang, B.; Chen, B.; Hui, Y. First Synthesis of 4′-Acetamido-
2′-deoxythymidine. Synthesis 1993, 769-771. (b) Altmann, K.-
H. Pyrrolidine Based Analogs of 3′-Deoxythymidine. Tetrahedron
Lett. 1993, 34, 7721-7724. (c) Altmann, K.-H.; Freier, S. M.;
Pieles, U.; Winkler, T. Synthesis of an Azathymidine and Its
Incorporation into Oligonucleotides. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1654-1657. (d) Pickering, L.; Malhi, B. S.; Coe,
P. L.; Walker, R. T. The Synthesis of 4′-t-Butylcarbamyl- and
4′-p-Toluenesulphonamidyl-2′,3′-dideoxy Pyrimidine Nucleoside
Analogues. Nucleosides Nucleotides 1994, 13, 1493-1506. (e)
Pickering, L.; Malhi, B. S.; Coe, P. L.; Walker, R. T. 4′-
Methyloxycarbamyl-3′-deoxy-5-methyluridine; Synthesis of a
Novel Nucleoside Analogue. Tetrahedron 1995, 51, 2719-2728.
(22) Rassu, G.; Pinna, L.; Spanu, P.; Ulgheri, F.; Casiraghi, G. Total
Synthesis of N-Boc-Protected 3′-Deoxy-4′-azathymidine and 4′-
Azauridine. Tetrahedron Lett. 1994, 35, 4019-4022.
(23) The absolute configuration of 22 was ascertained by single-
crystal X-ray analysis: Rassu, G.; Casiraghi, G.; Spanu, P.;
Pinna, L.; Gasparri Fava, G.; Belicchi Ferrari, M.; Pelosi, G.
Homochiral R,â-Unsaturated γ-Lactams: Versatile Templates.
Tetrahedron Asymmetry 1992, 3, 1035-1048.
(24) Thanks are due to Prof. J ean-Claude Depezay (Universite´ de
Paris V) for a useful discussion about this topic.
(25) To ensure uniform product dispersion within the nucleoside pools
by minimizing any kinetic discrepancies, a 4 equiv excess of each
silylated base was employed throughout.
(26) To complement the available data, a scrutiny of the L-cytidine
sublibrary L-SLCy in this study is under way, and the results
should be published in due course.
(27) In the oxygen series, the majority of the compounds prepared
are known substances. Their preparation should be intended as
unavoidable complement of the whole synthetic procedure.
J M960400Q