Asymmetric synthesis of C4'α-carboxylated 2'-deoxynucleosides. Preparation of oxetanone derivatives and influence of solvent on the stereochemistry of base introduction

Article abstract of DOI:10.1021/jo990046e

A synthesis of methyl 5-O-benzyl-3-O-tert-butyldimethylsilyl-4α- methoxycarbonyl-2-deoxyribofuranoside from dimethyl L-tartrate is presented. Coupling of this substance with standard purine and pyrimidine bases, promoted by tin tetrachloride, provides the corresponding 4'α- methoxycarbonyl-nucleosides with moderate yield and selectivity. A series of related bicyclic donors, derived by forming a β-lactone between the 3-OH and the 4α-carboxy group, were prepared and assayed in coupling reactions. In nonpolar solvents good endo-selectivity is observed whereas in acetonitrile the exo-anomers are preferentially obtained. Methods for the removal of the 5'-O-benzyl ethers of the nucleosides are presented.

Full text of DOI:10.1021/jo990046e

4016
J . Org. Chem. 1999, 64, 4016-4024
Asym m etr ic Syn th esis of C4′r-Ca r boxyla ted 2′-Deoxyn u cleosid es.
P r ep a r a tion of Oxeta n on e Der iva tives a n d In flu en ce of Solven t on
th e Ster eoch em istr y of Ba se In tr od u ction
David Crich* and Xiaolin Hao
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, ILinois 60607-7061
Received J anuary 11, 1999
A synthesis of methyl 5-O-benzyl-3-O-tert-butyldimethylsilyl-4R-methoxycarbonyl-2-deoxyribofura-
noside from dimethyl L-tartrate is presented. Coupling of this substance with standard purine and
pyrimidine bases, promoted by tin tetrachloride, provides the corresponding 4′R-methoxycarbonyl-
nucleosides with moderate yield and selectivity. A series of related bicyclic donors, derived by forming
a â-lactone between the 3-OH and the 4R-carboxy group, were prepared and assayed in coupling
reactions. In nonpolar solvents good endo-selectivity is observed whereas in acetonitrile the exo-
anomers are preferentially obtained. Methods for the removal of the 5′-O-benzyl ethers of the
nucleosides are presented.
In tr od u ction
thymidine series. Almost without fail, the synthesis3,6,16,17
of these ramified thymidines can be traced back to
original work by J ones on the Cannizzaro reaction of
aldehyde 1 with formaldehyde giving the diol 2.18 The
C4′R-Homologated nucleotides, especially esters and
ketones, are molecules of considerable current interest.
One reason for this prominence arises from the ability
of certain C4′R-ketones to block DNA polymerase and
reverse transcriptase enzymes, such as the HIV-1 RT,
and so their potential as antiviral agents.1-4 Alterna-
tively, the C4′R-selenol5 and thiol esters6 and the C4′R-
tert-butylcarbonyl derivative1 serve as convenient and
unambiguous precursors to nucleotide C4′ radicals,7
which are central to the degradation of oligonucleotides
by bleomycin,8,9 the enediyne antitumor antibiotics,10,11
and ionizing radiation.12 Nucleotide C4′ radicals are also
key intermediates in DNA footprinting13,14 and are
convenient precursors to guanine radical cations.15 The
vast majority of work with these 2-deoxy-4′R-carbonyl-
substituted nucleotides has been conducted with the
(1) Hess, M. T.; Schwitter, U.; Petretta, M.; Giese, B. Biochemistry
1997, 36, 2332-2337.
(2) Marx, A.; MacWilliams, M. P.; Bickle, T. A.; Schwitter, U.; Giese,
B. J . Am. Chem. Soc. 1997, 119, 1131-1132.
(3) Hrebabecky, H.; Holy, A. Collect. Czech. Chem. Commun. 1997,
62, 1128-1135.
(4) Prisbe, E. J .; Maag, H.; Verheyden, J . P. H.; Rydzewski, R. M.
In Nucleosides and Nucleotides as Antitumor and Antiviral Agents;
Chu, C. K., Baker, D. C., Eds.; Pergamon: New York, 1993; pp 101-
113.
(5) Giese, B.; Erdmann, P.; Giraud, L.; Gobel, T.; Petretta, M.;
Schafer, T.; von Raumer, M. Tetrahedron Lett. 1994, 35, 2683-2686.
(6) Crich, D.; Yao, Q. Tetrahedron 1998, 54, 305-318.
(7) Beckwith, A. L. J .; Crich, D.; Duggan, P. J .; Yao, Q. Chem. Rev.
1997, 97, 3273-3312.
(8) Stubbe, J .; Kozarich, J . W.; Wu, W.; Vanderwall, D. E. Acc. Chem.
Res. 1996, 29, 322-330.
(9) Burger, R. M. Chem. Rev. 1998, 98, 1153-1169.
(10) Christner, D. F.; Frank, B. L.; Kozarich, J . W.; Stubbe, J .; Golik,
J .; Doyle, T. W.; Rosenberg, I. E.; Krishnan, B. J . Am. Chem. Soc. 1992,
114, 8763-8767.
(11) Hangeland, J . J .; De Voss, J . J .; Heath, J . A.; Townsend, C. A.
J . Am. Chem. Soc. 1992, 114, 9200-9202.
(12) von Sonntag, C. The Chemical Basis of Radiation Biology;
Taylor and Francis: London, 1987.
reactivity profile of 2 is such that the R-OH is more
readily protected than the â-OH,19,20 which means that
selective oxidation of the R-hydroxymethyl nucleoside 3
to the desired aldehyde or acid is typically preceded by a
laborious three-step selective double-protection and mon-
odeprotection sequence.3,6,16 This lengthy sequence, in-
volving a minimum of nine steps from thymidine to a
fully 3′,5′-protected 4′R-tert-butyloxycarbonylated system
(4), is not readily applicable to the more sensitive purine
nucleosides because of the necessary chromate oxidation
step. This has the unfortunate consequence of limiting
nucleoside and nucleotide C4′ chemistry and biochemis
(16) Marx, A.; Erdmann, P.; Senn, M.; Ko¨rner, S.; J ungo, T.;
Petretta, M.; Imwinkelreid, P.; Dussy, A.; Kulicke, K. J .; Macko, L.;
Zehnder, M.; Giese, B. Helv. Chim. Acta 1996, 79, 1980-1994.
(17) Thrane, H.; Fensholt, J .; Regner, M.; Wengel, J . Tetrahedron
1995, 51, 10389-10402.
(13) Pogozelski, W. K.; McNeese, T. J .; Tullius, T. D. J . Am. Chem.
Soc. 1995, 117, 6428-6433.
(14) Pogozelski, W. K.; Tullius, T. D. Chem. Rev. 1998, 98, 1089-
1107.
(15) Meggers, E.; Michel-Beyerle, M. E.; Giese, B. J . Am. Chem. Soc.
1998, 120, 12950-12955.
(18) J ones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt, J . G. J . Org.
Chem. 1979, 44, 1309-1317.
(19) O-Yang, C.; Wu, Y. H.; Fraser-Smith, E. B.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 37-40.
(20) However for an exception see: Maag, H.; Schmidt, B.; Rose, S.
J . Tetrahedron Lett. 1994, 35, 6449-6452.
10.1021/jo990046e CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/01/1999

Asymmetric Synthesis of C4′R-Carboxylated Nucleosides
J . Org. Chem., Vol. 64, No. 11, 1999 4017
Sch em e 1
Sch em e 2
try to the pyrimidine series. For a variety of reasons,21
we are interested in studying C4′ homologues of the
complete set of natural purine and pyrimidine nucleo-
sides. Faced with the unattractive option of running
through a greater than ten step sequence for each of the
four DNA bases and with the need to develop much
milder oxidizing conditions for the purine series, we opted
instead to design and implement a de novo asymmetric
synthesis. Ideally, this would have the flexibility to
permit the incorporation of all bases, natural or un-
natural, at an advanced stage, so providing a consider-
able economy of time and effort. Here, we describe in full
the successful implementation of this design philosophy.22
Additionally, we describe our attempts at using a â-lac-
tone, formed by condensing the 3′-OH group with the 4′-
acid, as a means of stereocontrol in the glycosidation step
together with some interesting solvent effects in this
coupling reaction.
Sch em e 3
Sch em e 4
Resu lts a n d Discu ssion
Retrosynthetic analysis pointed to L-tartaric acid as a
cheap, readily available starting material, possessing the
correct absolute stereochemistry, for the proposed syn-
thesis. The dimethyl ester 5 was converted to the
cyclopentylidene acetal 6, on exposure to cyclopentanone
dimethyl acetal and catalytic toluenesulfonic acid, in 90%
yield. Taking advantage of Seebach’s earlier demonstra-
tion that the alkylation of tartrate acetals takes place
with retention of the configuration,23 6 was deprotonated
with LDA in a mixture of THF and HMPA and the
enolate quenched with freshly distilled benzyloxymethyl
chloride (BOM-Cl). In this manner the monoalkylation
product 7 could be isolated in 60% yield, as a single
isomer (Scheme 1).
Hoffmann had earlier reported that the enolate derived
from the related ester 8 was unreactive toward BOM-Cl
but underwent alkylation with benzyloxymethyl iodide
(BOM-I) to give a 3:2 mixture of diastereomers 9 and 10.
In contrast, he found that alkylation of 8 with methyl
iodide gave a 95:5 mixture of diastereomers 11 and 12
(Scheme 2).24 Evidently, the diastereoselectivity of such
alkylations is a function of the alkylating agent with the
more reactive ones being less selective. The stereochem-
istry of 7 was initially assigned by simple analogy with
alkylations of diethyl tartrate acetonide conducted by the
Seebach group; it was confirmed by subsequent steps in
the synthesis as described below.
afforded aldehyde 14 which was homologated using
standard Wittig chemistry to give the enol ether 15, a
separable 1:1 mixture of E:Z isomers (Scheme 3).
Mild acid hydrolysis was expected to release the
aldehyde and diol functions latent in 15, followed by
spontaneous cyclization to the furanose 18. In the event,
all such direct conversions assayed were marred by
elimination and resulted in the formation of the R,â-
unsaturated aldehyde 16. After some experimentation we
discovered, however, that 15 could be converted in
excellent yield to the diacetal 17 by treatment with
methanolic mercuric acetate followed by borohydride
reduction. This species was then readily hydrolyzed to
the desired ribofuranose 18 on exposure to 3 N HCl in
THF. Crude 18 was converted to the methyl glycosides
19, isolated in 85% overall yield from 17, with methanolic
TsOH (Scheme 4).
Silylation of 19 with TBDMSOTf gave 20, which
proved to be a suitable donor for coupling to the various
bases. Thus, treatment of a room-temperature acetoni-
trile solution 20 with suitably protected forms of the four
standard DNA bases and SnCl4 as the promoter25 pro-
vided the nucleosides in moderate-to-good yield as R:â
mixtures (Scheme 5, Table 1). In each case the pairs of
anomers were readily separated by chromatography over
silica gel. In the guanosine series we also isolated minor
amounts of both the R- and â-anomers of the N-7-
Controlled reduction of 7 with Dibal gave the alcohol
13 in 75% yield. This 4-hydroxy ester showed no tendency
toward lactonization, which would have been the case for
the stereoisomer, so providing strong support for the
stereochemistry assigned to 7. Swern oxidation then
(21) Crich, D.; Mo, X.-S. Tetrahedron Lett. 1997, 38, 8169-8172.
(22) Crich, D.; Hao, X. J . Org. Chem. 1998, 63, 3796-3797.
(23) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708-2748.
(25) J anardhanam, S.; Nambiar, K. P. Tetrahedron Lett. 1994, 35,
3657-3660.
(24) Ditrich, K.; Hoffmann, R. W. Liebigs 1990, 15-21.

4018 J . Org. Chem., Vol. 64, No. 11, 1999
Crich and Hao
Sch em e 5
quent introduction of both purine and pyrimidine bases,
it was marred by the lack of selectivity in the final
couplings. This is a very common problem in the area
and is not seen as a major drawback coming as it does
at the very end of the synthesis and giving readily
separable anomers. However, the mixture of stereoiso-
mers offended our sense of aesthetics and we resolved to
search for a more selective coupling system. Premixing
of the donor 20 with SnCl4 prior to addition of the
silylated heterocycle has been found to provide an ele-
ment of stereocontrol in some systems,29 but made little
or no difference in the present instance. TMS iodide
mediated coupling30,31 of 20 with persilylated N-acetyl-
cytosine in acetonitrile, followed by desilylation with the
triethylamine-HF complex, was selective but in the
wrong sense, giving the R-nucleoside 36R in 45% overall
yield. Replacement of TMSI as a mediator in this reaction
by TMSOTf32,33 gave a better yield (75%) but no selectiv-
ity (∼1:1). It was felt that more control would be gained
by incorporating the glycosyl donor temporarily into a
bicyclic system with stereodifferentiated concave and
convex faces. Furthermore, it was felt that this might be
achieved through the condensation of the 3′-OH with the
4′R-carboxylate group giving a â-lactone. 2-Oxetanones
have a rich and interesting chemistry,34-37 occur in
natural products,38 and have begun to be employed as
intermediates in asymmetric synthesis.39-41 However, we
are not aware of any instances of their use as temporary
control elements in the manner envisaged here. Of
course, there is considerable literature covering the
chemistry of the 3′,5′-anhydronucleosides,42-45 but the
oxetane is typically closed on a preformed nucleoside and
does not appear to have been used as a stereocontrolling
element in a coupling reaction. The anticipated use of
the â-lactone function in turn required milder conditions
for the actual glycosylation. To this end we elected to
investigate Fraser-Reid’s pentenyl glycosides,46,47 thiogly-
cosides, and Kahne’s sulfoxide method.48,49
Ta ble 1. Syn th esis of Nu cleosid es fr om 20
product
(% yield)
base
â:Ra
T
21 (70)
22 (90)
23 (83)
24 (40)
1:1
5:7
1:3
1:1
4-N-Ac-C
2-N-Ac-G
6-N-Bz-A
Anomeric ratios were determined by integrationof the 1H NMR
spectra of the crude reaction mixtures.
a
Sch em e 6
glycosylated isomers.26 These were readily distinguished
from the desired N-9 isomers by well-established spec-
troscopic methods.26b,c,27
NOE studies were largely inconclusive and ultimately
the configuration of 21â was confirmed by removal of the
benzyl ether by hydrogenolysis over Pd/C, giving 25
(Scheme 6). This substance was found to be identical in
every respect to an authentic sample obtained by deben-
zoylation and transesterification of 26, which itself had
been previously obtained from 2 via 3.6 This experiment,
aside from establishing anomeric configuration, also
nicely served to further confirm the stereochemical
outcome of the initial alkylation (6 f 7). The anomeric
configurations of 22-24Râ were assigned following close
parallels in their 1H NMR spectra with those of 21Râ.
Further supporting evidence for the configurational
assignments in 22-24 was gleaned from specific rota-
tions: at the sodium D line the â-anomers of the two
pyrimidines (21â and 22â) were found to be more
dextrorotatory than their R-epimers, whereas the op-
posite was true for the two purines (23â and 24â). This
is exactly the pattern seen with the four natural DNA
bases and their R-anomers.28 It was also noted that all
four â-anomers were eluting faster from silica gel than
their R-isomers.
Three bicyclic glycosyl donors were prepared as out-
lined in Scheme 7. Thus, furanose 18 was condensed with
4-pentenol to give the pentenyl glycoside 27, saponfica-
tion of which gave the acid 28. Dehydration of this acid
(29) Choi, W.-B.; Wilson, L. W.; Yeola, S.; Liotta, D. C. J . Am. Chem.
Soc. 1991, 113, 9377-9379.
(30) Tse, A.; Mansour, T. S. Tetrahedron Lett. 1995, 36, 7807-7810.
(31) J in, H.; Siddiqui, M. A.; Evans, C. A.; Tse, H. L. A.; Mansour,
T. S. J . Org. Chem. 1995, 60, 2621-2623.
(32) Abdel-Rahman, A. A.-H.; Zahran, M. A.; Abdel-Megied, A. E.-
S.; Pedersen, E. B.; Nielsen, C. Synthesis 1996, 237-241.
(33) Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234-1255.
(34) Zaugg, H. E. Org. React. 1954, 8, 305-363.
(35) Pommier, A.; Pons, J .-M. Synthesis 1993, 441-449.
(36) Lowe, C.; Vederas, J . C. Org. Prep. Proc. Int. 1995, 27, 305-
346.
(37) Crich, D.; Mo, X.-S. J . Am. Chem. Soc. 1998, 120, 8298-8304.
(38) Pommier, A.; Pons, J .-M. Synthesis 1995, 729-744.
(39) Schmitz, W. D.; Messerschmidt, N. B.; Romo, D. J . Org. Chem.
1998, 63, 2058-2059.
(40) White, J . D.; J ohnson, A. T. J . Org. Chem. 1994, 59, 3347-
3358.
Although the above chemistry was satisfactory and met
with our original objectives insofar as it provided a rapid
asymmetric entry into the glycosyl donor 20 and subse-
(26) For solutions to this problem see: (a) Zou, R.; Robins, M. J .
Can. J . Chem. 1987, 65, 1436-1437; (b) Garner, P.; Ramakanth, S. J .
Org. Chem. 1988, 53, 1294-1298; (c) Robins, M. J .; Zou, R.; Guo, Z.;
Wnuk, S. F. J . Org. Chem. 1996, 61, 9207-9212.
(27) Kjellberg, J .; J ohansson, N. G. Tetrahedron 1986, 42, 6541-
6544; Chenon, M.-T.; Pugmire, R. J .; Grant, D. M.; Panzica, R. P.;
Townsend, L. B. J . Am. Chem. Soc. 1975, 97, 4627-4635.
(28) R-T: Lemieux, R. U.; Hoffer, M. Can. J . Chem. 1961, 39, 110-
115; â-T: Hoffer, M.; Duschinsky, R.; Fox, J . J .; Yung, N. J . Am. Chem.
Soc. 1959, 81, 4112-4113; R-C: Yamaguchi, T.; Saneyoshi, M. Chem.
Pharm. Bull. 1984, 32, 1441-1450; â-C: Pathak, T.; Chattopadhyaya,
J . Tetrahedron 1987, 43, 4227-4234; R- and â-G: Robins, M. J .; Robins,
R. K. J . Org. Chem. 1969, 34, 2160-2163; R- and â-A: Ness, R. K.;
Fletcher, H. G. J . Am. Chem. Soc. 1959, 81, 4752-4753.
(41) Corey, E. J .; Reichard, G. A.; Kania, R. Tetrahedron Lett. 1993,
34, 6977-6980.
(42) Horwitz, J . P.; Chua, J .; Noel, M.; Donatti, J . T. J . Org. Chem.
1967, 32, 817-818.
(43) Moffat, J . G. In Nucleoside Analogues: Chemistry, Biology and
Medical Applications; Walker, R. T., De Clercq, E., Eckstein, F., Eds.;
Plenum: New York, 1979; pp 71-164.
(44) Hrebabecky, H.; Holy, A. Collect. Czech. Chem. Commun. 1997,
62, 1114-1127.
(45) O.-Yang, C.; Kurz, W.; Eugui, E.; McRoberts, M. J .; Verheyden,
J . P. H.; Kurz, L. J .; Walker, K. A. M. Tetrahedron Lett. 1992, 33, 41-
44.

Asymmetric Synthesis of C4′R-Carboxylated Nucleosides
J . Org. Chem., Vol. 64, No. 11, 1999 4019
Sch em e 7
ties ranging from 5:1 â:R to almost exclusively R, depend-
ing on the solvent (Table 2, entries 3-5). Activation of
sulfoxide 32R with Tf2O at -78 °C in propionitrile
followed by coupling with thymine again afforded a 5:1
mixture of â:R-anomers of 33 (Table 2, entry 6). Unfor-
tunately, attempted coupling of 32 to thymine in dichlo-
romethane or toluene solution resulted in complex reac-
tion mixtures. The configurations of the two anomers of
33 were assigned by opening of the â-lactone with
methanol, giving 34 and subsequent comparison to
authentic samples obtained by desilylation of 21. Less
experiments were conducted with persilylated N-acetyl
cytosine as the glycosyl acceptor but the results were
similar to those obtained with thymine; the yields were
moderate and the selectivities solvent dependent with
acetonitrile favoring the â-anomer and dichloromethane
the R-anomer (Table 2, entries 9-11). The stereochem-
istry of 35 was assigned similarly to that of 33 by
conversion to 36, which was independently accessible
from 22. All attempts at coupling any of the donors 29-
32 with N-benzoyladenine or with N-acetylguanine un-
fortunately resulted in complex mixtures from which pure
coupled products were not isolated.
Ta ble 2. Syn th esis of Bicyclic Nu cleosid es
temp
%
â:R
entry substrate base activator
solvent
(°C) product yield ratio
1
2
3
4
5
6
7
8
9
29
29
30
30
T
T
T
T
T
T
T
T
NIS/TfOH MeCN
NIS/TfOH CH2Cl2
rt
rt
rt
rt
rt
33
33
33
33
33
33
33
33
35
35
35
47
50
40
40
5:1
1:1
5:1
1:1
AgOTf
AgOTf
AgOTf
Tf2O
MeCN
CH2Cl2
benzene
MeCH2CN -78
CH2Cl2
toluene
30
45 <1:10
32r
32r
32r
29
30
31
38
<5
<5
40
5:1
Tf2O
Tf2O
-78
-78
rt
rt
rt
CAc NIS/TfOH MeCN
3:1
3:1
10
11
CAc AgOTf
CAc NBS
MeCN
CH2Cl2
30
50 <1:10
with BOP-Cl50 gave the â-lactone 29 in 85% yield. The
formation of â-lactone 29, as a stable entity enshrined
within a bicyclo[3.2.0]heptane framework, provides the
final and incontrovertible proof of the relative configu-
ration of 7 (Scheme 1). Activation of 29 with bromine in
dichloromethane provided the unstable bromide 30 which
was converted to the thioglycosides 31 in 50% overall
yield. We note in passing that the â-lactone moiety was
stable to these Lewis-acid-promoted coupling reactions
but that any exposure to thiophenol in the presence of a
base inevitably resulted in opening to the thioester.
Finally, oxidation of 31R with oxone provided sulfoxide
32R in 60% yield as a single diastereomer, which we
tentatively assign SR on the basis of related oxidations
of R-thioglycosides in the pyranose series.51
The solvent effects on stereoselectivity observed with
donors 29-32 suggest that, contrary to our initial
expectation, an intermediate oxacarbenium ion 37 is
attacked preferentially from the endo- (or R-) face in
dichloromethane or benzene. The reversal of selectivity
Coupling of 29 with persilylated thymine in acetonitrile
solution with activation by the NIS/TfOH couple resulted
in a 47% isolated yield of a 5:1 â:R-anomers of 33 (Table
2, entry 1). Changing the solvent to dichloromethane
afforded a similar yield of 33 but with only 1:1 selectivity
(Table 2, entry 2). In situ generation of bromide 30
followed by AgOTf mediated coupling to persilylated
thymine gave yields in the range 40-45% with selectivi-
in acetonitrile, or propionitrile, is then explained by a
parallel endo-attack by the solvent to form the nitrilium
2
ion 38, which serves as an electrophile in a final SN
-
like displacement. Whatever the reason for the change
in selectivity, it is clear that the fused â-lactone does not
have the strong exo-biasing effect on stereochemistry that
we had anticipated. It is evidently oversimplistic to make
predictions on the stereoselectivity of reactions of fused
bicyclic systems based uniquely on the concept of exo-
and endo-surfaces as we,52,53 and others,23,54,55 have
previously found in bicyclo[3.3.0]octane-type skeletons.
At the very least the 5′-carbon, on the exo-surface, needs
to be taken into consideration in the present system.
Whatever the reason, the â-selectivities observed in
(46) Mootoo, D. R.; Date, V.; Fraser-Reid, B. J . Am. Chem. Soc. 1988,
110, 2662-2663.
(47) Chapeau, M.-C.; Marnett, L. J . J . Org. Chem. 1993, 58, 7258-
7262.
(48) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J . Am. Chem.
Soc. 1989, 111, 6881-6882.
(49) Chanteloup, L.; Beau, J .-M. Tetrahedron Lett. 1992, 33, 5347-
5350.
(50) Tung, R. D.; Rich, D. H. J . Am. Chem. Soc. 1985, 107, 4342-
4343.
(51) Crich, D.; Mataka, J .; Sun, S.; Lam, K.-C.; Rheingold, A. R.;
Wink, D. J . J . Chem. Soc., Chem. Commun. 1998, 2763-2764.

4020 J . Org. Chem., Vol. 64, No. 11, 1999
Crich and Hao
3.81 (s, 6 H), 4.76 (s, 2 H). 13C NMR δ: 23.1, 36.2, 52.4, 76.5,
123.0, 169.7. Anal. Calcd. for C11H16O6: C, 54.09; H, 6.60.
Found: C, 53.97; H, 6.71.
Sch em e 8
2R,3R-2-Ben zyloxym et h yl-2,3-b is(m et h oxyca r b on yl)-
1,4-d ioxa sp ir o[4.4]n on a n e (7). To a stirred solution of 6
(24.4 g, 0.10 mol) and benzyl chloromethyl ether (37.5 g, 0.23
mol) in THF (0.5 L) and HMPA (100 mL) at -78 °C under Ar
was added lithium diisopropylamide via cannula in THF (500
mL) for 1 h. [The LDA was generated from diisopropylamine
(18.4 mL, 0.13 mol) and 2.5 M n-butyllithium (42 mL, 0.11
mol) at -78 °C for 30 min.] The mixture was stirred at -78
°C under Ar overnight and then warmed slowly to -5 °C.
EtOAc (1.5 L) was added and the organic layer was washed
with water and brine and then dried. Evaporation of the
solvent followed by distillation (80-100 °C/1 mmHg) removed
most of the starting materials and benzyl alcohol. The residue
was purified by column chromatography on silica gel (eluent:
EtOAc/Hexane, 1/7-1/5). 7 was obtained as a colorless oil (16.4
20
g, 60% based on recovered starting material 6.1 g). [R]D
1
-34.0° (c 2.8). H NMR δ: 1.68-1.89 (m, 6 H), 1.96-2.06 (m,
6 H), 2.10-2.17 (m, 1 H), 3.63 (s, 3 H), 3.72 (s, 2 H), 3.85 (s, 3
H), 4.50 (s, 2 H), 5.01 (s, 1 H), 7.25-7.34 (m, 5 H). 13C NMR δ:
22.9, 23.8, 36.7 (2 × C), 52.2, 52.9, 69.7, 73.6, 77.3, 84.8, 122.1,
127.4 (2 × C), 137.4, 168.6, 170.6. Anal. Calcd. for C19H24O7:
C, 62.63, H, 6.64. Found: C, 62.96, H, 6.66.
2R,3S-2-Ben zyloxym et h yl-3-h yd r oxym et h yl-2-m et h -
oxyca r bon yl-1,4-d ioxa sp ir o[4.4]n on a n e (13). To a stirred
solution of 7 (10 g, 27.5 mmol) in THF (250 mL) at -78 °C
was added dropwise 1.5 M DIBAL-H in toluene (27.5 mL, 41.3
mmol) and then the reaction was warmed to 0 °C slowly and
stirred at this temperature for 1 h. The reaction was quenched
with 2 M HCl and diluted with EtOAc (0.5 L). The organic
extracts were separated, washed, and dried. Removal of the
solvent followed by column chromatography (eluent: EtOAc/
Hexane, 3/1) gave 13 as a colorless oil (5 g, 75% based on 2.8
g of recovered starting material.). [R]D20 -11.3 (c, 0.9). 1H NMR
δ: 1.65-1.94 (m, 8 H), 3.68 (dd, J ) 22.1, 9.5 Hz, 2 H), 3.82
(s, 3 H), 3.82-3.92 (m, 2 H), 4.40 (t, J ) 5.4 Hz, 1 H), 4.55
(dd, J ) 15.2, 12.2 Hz, 2 H), 7.26-7.35 (m, 5 H). 13C NMR δ:
23.0, 24.0, 36.4, 37.0, 52.6, 60.3, 70.1, 73.6, 79.4, 83.3, 119.8,
127.6 (2 × C), 127.8, 128.3 (2 × C), 137.1, 171.7. Anal. Calcd.
for C18H24O6: C, 64.27; H, 7.19. Found: C, 63.97; H, 7.25.
2R,3R-2-Ben zyloxym et h yl-2-m et h oxyca r bon yl-1,4-d i-
oxa sp ir o[4.4]n on a n e-3-ca r boxa ld eh yd e (14). To a well-
stirred solution of anhydrous dichloromethane (580 mL) at -78
°C was added oxalyl chloride (16.1 mL, 0.18 mol). After 15 min,
anhydrous DMSO (24.1 mL, 0.34 mol) was added dropwise.
After the mixture stirred for 15 min, 13 (21.74 g, 64.7 mmol)
in anhydrous dichloromethane (72 mL) was added followed by
diisopropylethylamine (57 mL, 0.33 mol, after additional 30
min). The reaction mixture was allowed to warm to room
temperature, water (300 mL) was added, and the organic layer
was washed and dried. Removal of solvent followed by column
coupling the pyrimidine bases to the various â-lactone
donors in acetonitrile (Table 2) are superior to those
obtained with the monocyclic donor 20 in the same
solvent (Table 1).
Finally, we turned our attention to the removal of the
5′-O-benzyl ether, a somewhat unorthodox protecting
group in nucleoside and nucleotide chemistry. As already
noted in Scheme 6 standard hydrogenolytic cleavage is
affected cleanly in the thymidine series. This was also
the case with the â-guanosine (23â) and R-adenosine
(24R) systems inspected (Scheme 8). However, attempted
hydrogenolysis of the various cytidine derivatives re-
sulted in competing reduction of the base, whether using
hydrogen gas or cyclohexadiene in a transfer system.56
Eventually conditions were discovered (Scheme 8) for
satisfactory removal of the 5′-O-benzyl ether in the
cytidine series involving initial saponification of the labile
N-acetyl group followed by treatment with BCl3.
Exp er im en ta l Section
Gen er a l. Unless otherwise stated NMR spectra were taken
at 300 MHz (1H) or 75 MHz (13C) for CDCl3 solutions. Chemical
shifts are in ppm downfield from tetramethylsilane as the
internal standard. Specific rotations were measured for chlo-
roform solutions. All solvents were dried and degassed accord-
ing to standard procedures. Microanalyses were conducted by
Midwest Microlabs, Indianapolis, IN.
20
chromatography gave 14 as a colorless oil (16 g, 80%). [R]D
-15.5° (c, 3.1). 1H NMR δ: 1.69-1.86 (m, 6 H), 2.01-2.06 (m,
2 H), 3.66 (dd, J ) 9.2, 5.7 Hz, 2 H), 3.82 (s, 3 H), 4.46 (dd, J
) 16.3, 12.0 Hz, 2 H), 4.79 (s, 1 H), 7.24-7.36 (m, 5 H), 9.68
(s, 1 H). 13C NMR δ: 23.1, 24.1, 36.8, 36.9, 53.3, 69.2, 73.6,
83.0, 85.9, 122.3, 127.8 (2 × C), 128.0, 128.6 (2 × C), 137.3,
170.7, 197.0. Anal. Calcd. for C18H22O6‚H2O: C, 61.35; H, 6.86.
Found: C, 61.62; H, 6.49.
Dim eth yl 2,3-O-Cyclop en tylid en e-L-ta r tr a te (6). A mix-
ture of dimethyl L-tartrate (5) (50 g, 0.28 mol), 1,1-dimethoxy-
cyclopentane (60 g, 0.46 mol), and p-toluenesulfonic acid
monohydrate (0.84 g, 4.4 mmol) was dissolved in benzene (500
mL) and refluxed for 12 h. After the resulting solution was
cooled to room temperature, EtOAc (1 L) was added. The
resulting solution was washed with saturated NaHCO3, brine,
and dried. Removal of the solvent followed by distillation (95
°C/2 mmHg) gave 6 as a colorless oil (57.8 g, 90%). [R]D20 -38.4°
2R,3S-2-Ben zyloxym et h yl-3-(E/Z-2-m et h oxyvin yl)-2-
m eth oxyca r bon yl-1,4-d ioxa sp ir o[4.4]n on a n e (15). To a
stirred suspension of methoxymethyltriphenylphosphonium
chloride (4.31 g, 12.6 mmol) in THF (150 mL) at 0 °C was
added lithium diisopropylamide via cannula in THF (150 mL)
[LDA was generated from diisopropylethylamine (2.15 mL,
15.3 mmol) and 2.5 M n-butyllithium in hexane (5 mL, 12.5
mmol) at -78 °C for 30 min]. The mixture was stirred at 0 °C
for 30 min before 14 (2.0 g, 6.0 mmol) in THF (150 mL) was
added via cannula. After stirring at 0 °C for 30 min, the
reaction mixture was poured into water (0.5 L) and extracted
with EtOAc. The combined organic layers were dried, and
removal of the solvent, followed by column chromatography
(eluent: EtOAc/hexane, 1/3), gave two isomeric vinyl ethers
1
(c, 4.2). H NMR δ: 1.68-1.74 (m, 4 H), 1.81-1.91 (m, 4 H),
(52) Crich, D.; Bruncko, M.; Natarajan, S.; Teo, B. K.; Tocher, D. A.
Tetrahedron 1995, 51, 2215-2228.
(53) Crich, D.; Natarajan, S. J . Org. Chem. 1995, 60, 6237-6241.
(54) Meyers, A. I.; Brengel, G. P. J . Chem. Soc., Chem. Commun.
1997, 1-8.
(55) Renaud, P.; Giraud, L. Synthesis 1996, 913-926.
(56) Watkins, B. E.; Kiely, J . S.; Rapoport, H. J . Am. Chem. Soc.
1982, 104, 5702-5708.

Asymmetric Synthesis of C4′R-Carboxylated Nucleosides
15-E (0.7 g) and 15-Z (0.65 g) as colorless oils (overall yield
J . Org. Chem., Vol. 64, No. 11, 1999 4021
1
+107.3° (c, 1.6). H NMR δ: 2.04-2.09 (m, 1 H), 2.24 (dt, J )
62%). For 15-E: [R]D -9.7° (c, 3.3). 1H NMR δ: 1.68-2.05
13.5, 4.9 Hz, 1 H), 3.22 (d, J ) 11.4 Hz, 1 H), 3.54 (s, 3 H),
3.64 (d, J ) 9.9 Hz, 1 H), 3.71-3.77 (m, 4 H), 4.19 (dd, J )
11.3, 5.3 Hz, 1 H), 4.56 (dd, J ) 14.8, 12.3 Hz, 2 H), 5.25 (d, J
) 4.4 Hz, 1 H), 7.26-7.36 (m, 5 H). 13C NMR δ: 41.0, 52.1,
55.2, 72.5, 73.5, 75.0, 93.3, 106.6, 127.5 (2 × C), 127.6, 128.3
(2 × C), 137.6, 170.5. Anal. Calcd. for C15H20O6: C, 60.80; H,
6.80. Found: C, 60.70; H, 6.76.
20
(m, 8 H), 3.54 (s, 3 H), 3.64 (dd, J ) 47.3, 9.7 Hz, 2 H), 3.77 (s,
3 H), 4.53-4.57 (m, 3 H), 4.75 (dd, J ) 12.6. 9.1 Hz, 1 H), 6.63
(d, J ) 12.5 Hz, 1 H), 7.26-7.35 (m, 5 H). 13C NMR δ: 23.0,
23.9, 36.4, 37.3, 52.1, 56.1, 71.3, 73.4, 79.4, 84.6, 95.9, 119.6,
127.5 (3 × C ), 128.2 (2 × C ), 137.8, 152.6, 172.0. Anal. Calcd.
for C20H26O6: C, 66.28; H, 7.23; Found: C, 65.83; H, 7.17. For
20
1
15-Z: [R]D +13.4° (c 2.4, CHCl3). H NMR δ: 1.67-2.02 (m,
8 H), 3.54 (d, J ) 9.7 Hz, 1 H), 3.62 (s, 3 H), 3.75-3.78 (m, 4
H), 4.43 (dd, J ) 9.5, 6.3 Hz, 1 H), 4.58 (dd, J ) 16.7, 12.7 Hz,
2 H), 5.15 (d, J ) 9.5 Hz, 1 H), 6.13 (d, J ) 6.3 Hz, 1 H), 7.30
(s, 5 H). 13C NMR δ: 23.1, 23.9, 36.5, 37.4, 52.3, 60.1, 71.2,
73.4, 73.9, 84.7, 99.0, 119.9, 127.4 (3 × C ), 128.1 (2 × C ),
138.0, 151.0, 172.0. Anal. Calcd. for C20H26O6: C, 66.28; H,
7.23. Found: C, 66.41; H, 7.24.
Meth yl 5-O-Ben zyl-3-O-(ter t-bu tyld im eth ylsilyl)-2-d e-
oxy-4r-m eth oxycar bon yl-r,â-D-r ibo-pen tofu r an oside (20r).
To a stirred solution of 19R (633 mg, 2.1 mmol), and 2,6-
lutidine (0.54 mL, 4.6 mmol) in dichloromethane (5 mL) at
room temperature was added TBDMSOTf (0.61 mL, 2.7 mmol)
dropwise. After 1 h, the reaction mixture was poured into brine
and diluted with dichloromethane. The organic layer was
separated, washed, and dried. Removal of the solvent followed
by column chromatography (eluent: EtOAc/Hexane, 1/7) gave
20R as a colorless oil (840 mg, 96%). [R]D -25.9° (c, 2.7). H
NMR δ: 0.015 (s, 3 H), 0.021 (s, 3 H), 0.83 (s, 9 H), 2.13-2.19
(m, 2 H), 3.38 (s, 3 H), 3.63 (d, J ) 10.2 Hz, 1 H), 3.72 (s, 3 H),
3.92 (d, J ) 10.2 Hz, 1 H), 4.45 (t, J ) 71. Hz, 1 H), 4.63 (s, 2
H), 5.28-5.30 (m, 1 H), 7.28-7.34 (m, 5 H). 13C NMR δ: -5.1,
-4.8, 17.9, 25.7 (3 × C), 41.2, 52.1, 55.4, 72.3, 73.8, 73.9, 90.3,
105.4, 127.6, 127.8 (2 × C), 128.4 (2 × C), 138.4, 170.6. Anal.
Calcd for C21H34O6Si: C, 61.43; H, 8.35. Found: C, 61.50; H,
8.42.
Gen er a l Meth od for th e Cou p lin g Rea ction betw een
20 a n d Ba ses. Properly protected base (2.2 equiv) in freshly
distilled acetonitrile under Ar was stirred with N,O-bis-
(trimethylsilyl)-acetamide at 80 °C for 30 min. The reaction
mixture was cooled to 0 °C and 20 (1.0 equiv) and SnCl4 (10
equiv) were added. The reaction mixture was then stirred at
room temperature until the disappearance of 20. The reaction
was diluted with EtOAc, washed, and dried. Removal of the
solvent followed by gradient elution from silica gel (EtOAc/
hexane, 1/4-6/1) gave the R- and â-anomers of the nucleosides,
respectively.
2S-Met h yl 2-Ben zyloxym et h yl-2-h yd r oxy-5-oxa -3-E-
p en ten oa te (16). To a stirred solution of 15 (36 mg, 0.1 mmol)
in dichloromethane (1 mL) were added trifluoroacetic acid (0.5
mL) and water (0.05 mL). The reaction mixture was stirred
at room temperature for 1 h and then the reaction quenched
with saturated NaHCO3 solution. The organic layer was
separated, washed, and dried. Removal of the solvent followed
by column chromatography (eluent: EtOAc/Hexane, 2/1) gave
20
1
20
16 as a white crystalline solid (21 mg, 80%). [R]D -18.1° (c,
1.9). 1H NMR δ: 3.50 (d, J ) 9.5 Hz, 1 H), 3.76 (s, 1 H), 3.84-
3.89 (m, 4 H), 4.60 (dd, J ) 31.8, 12.2 Hz, 2 H), 6.55 (dd, J )
15.6, 7.7 Hz, 1 H), 6.80 (d, J ) 15.6 Hz, 1 H), 7.26-7.39 (m, 5
H), 9.59 (d, J ) 7.7 Hz, 1 H). 13C NMR δ: 53.6, 73.6, 74.1,
78.3, 127.2 (2 × C), 127.9, 128.4 (2 × C), 132.9, 137.1, 150.9,
171.6, 192.5. Anal. Calcd. for C14H16O5: C, 63.63; H, 6.10.
Found: C, 63.27; H, 6.14.
2R,3S-2-Ben zyloxym eth yl-3-[2,2-d i(m eth oxy)eth yl]-2-
m eth oxyca r bon yl-1,4-d ioxa sp ir o[4.4]n on a n e (17). To a
stirred solution of 15 (3.62 g, 10 mmol) in methanol (50 mL)
was added mercuric acetate (3.50 g, 11 mmol). Stirring was
continued at room temperature until no more starting material
was detectable by TLC, then the reaction mixture was cooled
to 0 °C, and NaBH4 (0.42 g, 11 mmol) was added in portions.
After addition, the suspension was stirred at 0 °C for 30 min
and at room temperature for 30 min. The reaction mixture
was decanted and the residue was washed with additional
solvent. The combined organic solutions were concentrated and
the residue was partitioned between dichloromethane and
water. The organic layer was separated, washed, and dried.
Removal of the solvent followed by column chromatography
(eluent: EtOAc/Hexane, 1/1) gave 17 as a colorless oil (3.23 g,
5′-O-Ben zyl-3′-O-(ter t-bu tyld im eth ylsilyl)-2′-d eoxy-4′r-
m eth oxyca r bon yl-D-th ym id in e (21â) a n d th e An om er
(21r). These were prepared from thymine and 20 according
to the general method. Chromatography eluent: EtOAc/
hexane, from 1/4 to 3/1. The R- and â-anomers were both
obtained as foams (R/â, 1/1, yield 70%). For 21â: [R]D20 +27.2°
1
(c, 2.2). H NMR δ: 0.05 (s, 3 H), 0.07 (s, 3 H), 0.85 (s, 9 H),
1.57 (s, 3 H), 2.16-2.25 (m, 1 H), 2.39-2.47 (m, 1 H), 3.74 (s,
3 H), 3.84 (d, J ) 10.5 Hz, 1 H), 4.04 (d, J ) 10.5 Hz, 1 H),
4.57 (dd, J ) 11.8, 5.1 Hz, 2 H), 4.69 (dd, J ) 6.8, 4.8 Hz, 1
H), 6.57 (t, J ) 6.4 Hz, 1 H), 7.26-7.38 (m, 5 H), 7.56 (s, 1 H),
8.77 (br, 1 H). 13C NMR δ: -7.0, -6.7, 10.3, 15.9, 23.7, 39.1,
50.4, 68.4, 71.4, 72.0, 83.9, 89.0, 109.1, 125.9, 126.4, 126.9,
134.1, 135.3, 148.1, 161.5, 168.0. Anal. Calcd for C25H36N2O7-
20
1
85%). [R]D -13.9° (c, 2.6). H NMR δ: 1.63-2.11 (m, 10 H),
3.32 (s, 3 H), 3.33 (s, 3 H), 3.52 (d, J ) 9.3 Hz, 1 H), 3.72 (d,
J ) 10.6 Hz, 1 H), 3.76 (s, 3 H), 4.22 (dd, J ) 10.6, 2.7 Hz, 1
H), 4.50-4.61 (m, 3 H), 7.26-7.35 (m, 5 H). 13C NMR δ: 23.4,
24.2, 32.2, 36.8, 37.5, 52.7, 53.6, 70.7, 73.7, 78.3, 84.0, 102.0,
119.8, 127.8 (3 × C), 128.5 (2 × C), 137.9, 171.9. HRMS Calcd
for C21H30O7: 394.1992. Found: 394.1996 (M+.).
20
Si: C, 59.50; H, 7.19. Found: C, 59.68; H, 7.30. For 21R: [R]D
1
+3.2° (c, 1.8). H NMR δ: 0.00 (s, 3 H), 0.03 (s, 3 H), 0.78 (s,
9 H), 1.93 (d, J ) 1.1 Hz, 3 H), 2.04-2.10 (m, 1 H), 2.71-2.77
(m, 1 H), 3.71 (dd, J ) 13.4, 10.2 Hz, 2 H), 3.75 (s, 3 H), 4 45
(dd, J ) 5.5, 2.5 Hz, 1 H), 4.58 (s, 2 H), 6.31 (dd, J ) 7.0, 3.2
Hz, 1 H), 7.26-7.38 (m, 5 H), 8.19 (s, 1 H), 8.80 (br, 1 H). 13C
NMR δ: -5.3, -4.8, 12.9, 17.8, 25.5, 42.2, 52.6, 72.0, 74.1, 74.7,
87.3, 94.1, 110.0, 127.9, 128.2 (2 × C), 128.8 (2 × C), 137.5,
137.6, 150.6, 164.2, 169.5. Anal. Calcd for C25H36N2O7Si: C,
59.50; H, 7.19. Found: C, 59.33; H, 7.15.
Meth yl 5-O-Ben zyl-2-d eoxy-4r-m eth oxyca r bon yl-r,â-
D-r ibo-p en tofu r a n osid e (19r,â). To a solution of 17 (0.9 g,
2.4 mmol) in THF (50 mL) was added 3 M HCl (50 mL). The
mixture was stirred at room temperature for 6 h and then
extracted with EtOAc. The combined organic layers were
washed and dried. Removal of the solvent gave a colorless oil,
which was placed in a 100 mL flask with methanol (50 mL)
and p-toluenesulfonic acid (0.1 g). This reaction mixture was
stirred at room temperature for 3 h, before it was poured into
saturated NaHCO3 solution (50 mL), and extracted with
dichloromethane (3 × 60 mL). The combined organic layers
were dried and concentrated in vacuo to leave an oil. Column
chromatography gave 19R (0.43 g) and 19â (0.15 g) as colorless
4-N-Acet yl-5′-O-b en zyl-3′-O-(ter t-b u t yld im et h ylsilyl)-
2′-d eoxy-4′r-m eth oxyca r bon yl-D-cytid in e (22â) a n d th e
An om er (22r). These were prepared from N4-acetylcytosine
and 20 according to the general procedure. Chromatography
eluent: EtOAc/hexane, from 3/1 to 6/1. The R-anomer was
obtained as a foam and the â-anomer as a crystal (R/â, 7/5,
20
20
1
yield 90%). For 22â: mp 169-172 °C; [R]D +99.7° (c, 3.8).
oils (yield: 85%). For 19R: [R]D -42.0° (c, 2.7). H NMR δ:
2.14-2.28 (m, 2 H), 2.62 (d, J ) 4.6 Hz, 1 H), 3.38 (s, 3 H),
3.63 (d, J ) 9.8 Hz, 1 H), 3.80 (s, 3 H), 3.83 (d, J ) 9.9 Hz, 1
H), 4.47 (dd, J ) 11.1, 6.4 Hz, 1 H), 4.60 (dd, J ) 15.3, 12.4
Hz, 2 H), 5.27 (dd, J ) 5.0, 2.8 Hz, 1 H), 72.8-7.36 (m, 5 H).
13C NMR δ: 40.5, 52.8, 55.7, 73.2, 73.8, 74.2, 90.2, 105.6, 127.9
(3 × C), 128.4 (2 × C), 138.0, 171.5. Anal. Calcd. for C15H20O6:
1H NMR δ: 0.02 (s, 6 H), 0.84 (s, 9 H), 2.12-2.20 (m, 1 H),
2.23 (s, 3 H), 2.65-2.75 (m, 1 H), 3.75 (s, 3 H), 3.95 (dd, J )
34.8, 10.6 Hz, 2 H), 4.95 (s, 2 H), 4.62 (t, J ) 6.8 Hz, 1 H),
6.48 (dd, J ) 7.0, 4.4 Hz, 1 H), 7.10 (d, J ) 7.5 Hz, 1 H), 7.31-
7.42 (m, 5 H), 8.37 (d, J ) 7.6 Hz, 1 H), 8.66 (br, 1 H). 13C
NMR δ: -5.4, -5.0, 17.6, 24.7, 25.4 (3 × C), 41.3, 52.1, 69.1,
71.9, 73.8, 87.5, 90.7, 96.7, 128.0 (2 × C), 128.3, 128.6 (2 × C),
20
C, 60.80; H, 6.80. Found: C, 60.53; H, 6.76. For 19â: [R]D

4022 J . Org. Chem., Vol. 64, No. 11, 1999
Crich and Hao
136.8, 144.7, 154.8, 163.1, 169.7, 171.4. Anal. Calcd. for C26H37
-
39.8, 52.4, 63.7, 73.3, 90.0, 91.8, 111.4, 138.3, 150.3, 163.6,
170.8. Anal. Calcd. for C18H30N2O7Si: C, 52.15; H, 7.29.
Found: C, 52.19; H, 7.27.
N3O7Si: C, 58.74; H, 7.01. Found: C, 58.69; H, 7.01. For 22R:
[R]D -36.2° (c, 2.5). 1H NMR δ: -0.11 (s, 3 H), -0.03 (s, 1
20
H), 0.70 (s, 9 H), 2.15-2.25 (m, 4 H), 2.80-2.90 (m, 1 H), 3.71
(dd, J ) 15.0, 10.1 Hz, 2 H), 3.79 (s, 3 H), 4.40 (d, J ) 3.5 Hz,
1 H), 4.57 (s, 2 H), 6.26 (d, J ) 5.2 Hz, 1 H), 72.6-7.42 (m, 6
H), 8.84 (d, J ) 7.5 Hz, 1 H), 8.93 (br, 1 H). 13C NMR δ: -5.5,
-4.9, 17.6, 24.8, 25.3 (3 × C), 42.2, 52.5, 72.0, 73.8, 74.8, 89.4,
95.2, 96.3, 127.7 (2 × C), 128.0, 128.5 (2 × C), 137.2, 146.3,
155.2, 163.2, 169.2, 171.3. Anal. Calcd. for C26H37N3O7Si: C,
58.74; H, 7.01. Found: C, 58.62; H, 6.94.
P r ep a r a tion of Au th en tic 25 fr om 26. To a solution of
26 (11 mg, 0.02 mmol) in dichloromethane (0.5 mL) was added
trifluoroacetic acid (64 µL) at 0 °C. The reaction mixture was
stirred at room temperature for 1 h. The solvent and volatiles
were coevaporated with benzene. The crude acid was then
taken up with benzene (0.5 mL) and treated with 1,1-
dichloromethyl methyl ether (36 µL). The reaction mixture was
heated to gentle reflux for 1 h. After cooling to room temper-
ature, the solvent was removed under vacuum. The resulting
acid chloride was taken up with dry dichloromethane (0.3 mL)
and treated with MeOH (8.1 µL, 0.2 mmol), followed by DMAP
(3 mg, 0.025 mmol). After the mixture was stirred at room
temperature for 12 h, the solvent was removed and the crude
reaction mixture was dissolved in MeOH (0.5 mL) and K2CO3
(5 mg, 0.022 mmol) was added. After 30 min, the solvent was
removed and column chromatography on silica gel (eluent,
EtOAc/Hexane, 2/1) gave 25 (7 mg, 90%) as a white foam,
whose spectral data were identical in every aspect to those of
the sample obtained above.
Cou p lin g of 20 w ith N-Acetylcytosin e Med ia ted by
TMS Iod id e: 4-N-Acetyl-1-(2S,3S,5S-2-ben zyloxym eth yl-
3-h yd r oxy-2-m eth oxyca r bon yl-5-tetr a h yd r ofu r a n yl)cy-
tosin e. (36r). To a solution of 20 (50 mg, 0.12 mmol) in
acetonitrile (1 mL) at 0 °C was added TMSI (21 µL, 0.14 mmol)
dropwise. After 5 min a solution of persilylated N-acetylcy-
tosine (0.24 mmol) in acetonitrile (0.5 mL) was added. The
reaction mixture was allowed to warm to room temperature
and was then stirred for 5 h before the reaction was quenched
with 3 N HCl and the solution extracted with EtOAc. The
extracts were washed with saturated NaHCO3, and brine, and
dried. Removal of the solvent and filtration on silica gel
(eluent: EtOAc) gave a mixture of 22R and a trimethylsilylated
derivative (30 mg). This mixture (27 mg) was dissolved in THF
(1 mL), treated with Et3N‚3HF (81 µL, 0.5 mmol), and then
heated to reflux under Ar for 3 h. Removal of the solvent
followed by chromatography on silica gel (eluent: EtOAc/
MeOH 40/1) gave anomerically pure 36R (19 mg, 45% overall)
which was identical to the sample described below.
2-N-Acetyl-5′-O-Ben zyl-3′-O-(ter t-bu tyld im eth ylsilyl)-
2′-d eoxy-4′r-m eth oxyca r bon yl-D-gu a n osin e (23â) a n d th e
An om er (23r). These were prepared from 2-acetylamino-6-
hydroxy-purine and 20 according to the general method.
Chromatography eluent: CHCl3/CH3OH, from 20/1 to 10/1.
Both anomers were obtained crystalline. (R/â, 3/1, yield 83%).
For 23â: mp 229-232 °C; [R]D +12.2° (c, 0.8). 1H NMR δ:
20
0.05 (s, 3 H), 0.06 (s, 3 H), 0.83 (s, 9 H), 2.24 (s, 3 H), 2.45-
2.53 (m, 1 H), 2.55-2.64 (m, 1 H), 3.74-3.80 (m, 4 H), 3.98 (d,
J ) 10.6 Hz, 1 H), 4.55 (dd, J ) 18.8, 11.9 Hz, 2 H), 4.81 (t, J
) 5.5 Hz, 1 H), 6.47 (t, J ) 6.2 Hz, 1 H), 7.24-7.34 (m, 5 H),
7.95 (s, 1 H). 13C NMR δ: -5.0, -4.7, 18.0, 24.7, 25.7, 41.2,
52.4, 70.1, 73.6, 74.1, 84.4, 91.5, 121.6, 128.1 (2 × C), 128.3,
128.8 (2 × C), 137.4, 137.6, 147.2, 148.0, 156.1, 170.3, 171.4.
Anal. Calcd. for C27H37N5O7Si: C, 56.72; H, 6.52. Found: C,
57.14; H, 6.70. For 23R: mp 156-158 °C; [R]D20 +31.3° (c, 1.4).
1H NMR δ: -0.08 (s, 3 H), -0.01 (s, 3 H), 0.81 (s, 9 H), 2.14 (s,
3 H), 2.28-2.35 (m, 1 H), 2.81-2.90 (m, 1 H), 3.71 (s, 3 H),
3.83 (dd, J ) 19.8, 10.2 Hz, 2 H), 4.53-4.57 (m, 3 H), 3.20 (dd,
J ) 7.4, 4.2 Hz, 1 H), 7.26-7.35 (m, 5 H), 8.37 (s, 1 H), 9.55
(br, 1 H). 13C NMR δ: -5.2, -4.8, 18.0, 24.4, 25.7 (3 × C), 29.9,
41.8, 52.6, 72.3, 74.2, 75.1, 84.7, 93.7, 120.9, 128.1 (2 × C),
128.4, 128.8 (2 × C), 137.3, 138.9, 156.3, 169.5, 172.6. Anal.
Calcd. for C27H37N5O7Si: C, 56.72; H, 6.52. Found: C, 56.68;
H, 6.61.
5′-O-Ben zyl-6-N-ben zoyl-3′-O-(ter t-bu tyld im eth ylsilyl)-
2′-d eoxy-4′r-m eth oxyca r bon yl-D-a d en osin e (24â) a n d th e
An om er (24r). These were prepared from N6-benzoyladenine
and 20 according to the general method. The chromatography
eluent was EtOAc/hexane, from 1/1 to 6/1. Two anomers were
20
obtained as foams (R/â, 1/1, yield 40%). For 24â: [R]D +6.2°
4-P en ten yl 5-O-Ben zyl-2-d eoxy-4r-m eth oxyca r bon yl-
r,â-D-r ibo-p en tofu r a n osid e (27r a n d 27â). To a solution of
18, obtained by hydrolysis of 17 as described in the preparation
of 19 above (1.82 g, 6.5 mmol) in 4-pentenol (8 mL) was added
camphor 10-sulfonic acid (89 mg, 0.4 mmol) followed by stirring
at room temperature for 4 h. The excess 4-pentenol was then
recovered by distillation and the residue was partitioned
between saturated sodium bicarbonate solution and EtOAc.
The organic layer was washed with brine and dried over
sodium sulfate. Removal of the solvent followed by column
chromatography (eluent: EtOAc/hexane, 1/1) gave 27R (0.72
g) and 27â (1.44 g) as colorless oils (combined yield: 95%).
1
(c, 3.3). H NMR δ: 0.05 (s, 3 H), 0.08 (s, 3 H), 0.86 (s, 9 H),
2.57-2.67 (m, 1 H), 2.75-2.84 (m, 1 H), 3.76 (s, 3 H), 4.03
(dd, J ) 40.5, 7.1 Hz, 2 H), 4.56 (s, 2 H), 4.90 (t, J ) 6.1 Hz,
1 H), 6.73 (t, J ) 6.7 Hz, 1 H), 7.23-7.34 (m, 5 H), 7.50 (t, J
) 7.0 Hz, 2 H), 7.59 (t, J ) 7.3 Hz, 1 H), 8.02 (d, J ) 7.1 Hz,
1 H), 8.37 (s, 1 H), 8.74 (s, 1 H), 9.10 (br, 1 H). 13C NMR δ:
-5.3, -5.0, 14.1, 17.7, 25.4 (3 × C), 40.6, 52.1, 69.8, 73.3, 85.0,
91.1, 123.3, 127.8 (3 × C), 127.9, 128.4 (2 × C), 128.8 (2 × C),
132.7, 133.6, 137.1, 142.0, 149.3, 151.2, 152.4, 164.5, 170.0.
Anal. Calcd. for C32H39N5O6Si: C, 62.22; H, 6.36. Found: C,
62.25; H, 6.47. For 24R: [R]D20 +28.7° (c, 2.5). 1H NMR δ: -0.13
(s, 3 H), -0.01 (s, 3 H), 0.70 (s, 9 H), 2.48 (d, J ) 13.9 Hz, 1
H), 2.92-3.00 (m, 1 H), 3.74-3.76 (m, 4 H), 3.87 (d, J ) 10.2
Hz, 1 H), 4.56-4.61 (m, 3 H), 6.68 (dd, J ) 7.0, 2.6 Hz, 1 H),
7.30-7.40 (m, 5 H), 7.51 (t, J ) 7.0 Hz, 2 H), 7.56 (t, J ) 7.2
Hz, 1 H), 8.02 (d, J ) 7.4 Hz, 2 H), 8.80 (s, 1 H), 8.86 (s, 1 H),
9.1 (br, 1 H). 13C NMR δ: -5.6, -5.2, 17.5, 25.2 (3 × C), 25.4,
42.2, 52.3, 71.8, 73.9, 75.0, 86.1, 94.1, 122.8, 127.6 (2 × C),
127.7 (2 × C), 127.9, 128.5 (2 × C), 128.7 (2 × C), 132.6, 133.8,
137.2, 142.7, 149.1, 151.0, 151.3, 164.5, 169.2. Anal. Calcd. for
For 27R: [R]D -35.3° (c, 2.7). 1H NMR δ: 1.56-1.65 (m, 2
20
H), 2.02-2.09 (m, 2 H), 2.18-2.22 (m, 2 H), 2.95 (d, J ) 4.6
Hz, 1 H), 3.37-3.45 (m, 1H), 3.62 (d, J ) 9.8 Hz, 1 H), 3.71-
3.82 (m, 1 H), 3.79 (s, 3 H), 3.84 (d, J ) 9.8 Hz, 1 H), 4.42-
4.48 (m, 1 H), 4.58 (dd, J ) 17.8, 12.3 Hz, 2 H), 4.92-5.02 (m,
2 H), 5.36 (dd, J ) 5.1, 3.0 Hz, 1 H), 5.73-5.83 (m, 1 H), 7.24-
7.35 (m, 5 H). 13C NMR δ: 28.9, 30.4, 40.5, 52.4, 52.7, 67.8,
73.3, 73.8, 74.3, 90.1, 104.5, 114.9, 127.8, 138.0, 171.5. Anal.
Calcd. For C19H26O6: C, 65.13; H, 7.48. Found: C, 64.98; H,
20
C
32H39N5O6Si: C, 62.22; H, 6.36. Found: C, 62.43; H, 6.56.
7.45. For 27â: [R]D +93.7° (c, 1.3). 1H NMR δ: 1.66-1.73
3′-O-(ter t-Bu t yld im et h ylsilyl)-2′-d eoxy-4′r-m et h oxy-
(m, 2 H), 2.04-2.14 (m, 3 H), 2.20-2.26 (m, 1 H), 3.30 (d, J )
11.7 Hz, 1 H), 3.42-3.49 (m, 1 H), 3.64 (d, J ) 9.9 Hz, 1 H),
3.74 (d, J ) 9.9 Hz, 1 H), 3.76 (s, 3 H), 4.10-4.22 (m, 2 H),
4.54 (d, J ) 1.6 Hz, 2 H), 4.94-5.05 (m, 2 H), 7.25-7.35 (m, 5
H). 13C NMR δ: 28.9, 30.5, 41.3, 52.3, 67.6, 72.8, 73.9, 75.5,
93.5, 105.6, 114.9, 127.8, 137.9, 138.3, 170.7. Anal. Calcd. for
ca r bon yl-D-th ym id in e (25) fr om 21â. To a solution of 21â
(20 mg, 0.04 mmol) in methanol (0.5 mL) was added Pd/C
(10%, 2 mg). The reaction mixture was stirred at room
temperature under H2 until TLC showed the disappearance
of the starting material. The reaction mixture was filtered and
washed with MeOH. Removal of the solvent gave 25 (16 mg,
C
19H26O6: C, 65.13; H, 7.48. Found: C, 64.88; H, 7.48.
20
1
98%) as a white foam. [R]D +28.0° (c, 0.5). H NMR δ: 0.08
(s, 6 H), 0.86 (s, 9 H), 1.91 (s, 3 H), 2.35-2.38 (m, 1 H), 2.54-
2.61 (m, 1 H), 3.76 (s, 3 H), 3.89-3.94 (m, 1 H), 4.00-4.07 (m,
1 H), 4.78 (dd, J ) 7.1, 4.5 Hz, 1 H), 6.20 (t, J ) 6.7 Hz, 1 H),
7.21 (s, 1 H). 13C NMR δ: -5.0, -4.7, 12.6, 18.0, 25.7 (3 × C),
1R,3R,5S-1-(Ben zyloxym eth yl)-2,6-dioxa-7-oxo-3-(4-pen -
ten yloxy)bicyclo[3.2.0]h ep ta n e (29r). To a solution of 27R
(700 mg, 2 mmol) in THF (10 mL) was added 1 M aqueous
LiOH (10 mL, 10 mmol) and the mixture was stirred at room
temperature for 6 h before it was neutralized with 2 N HCl to

Asymmetric Synthesis of C4′R-Carboxylated Nucleosides
J . Org. Chem., Vol. 64, No. 11, 1999 4023
pH 7. The THF was removed under reduced pressure and the
residue re-acidified to pH 2 with 2 N HCl. The mixture was
extracted with EtOAc and the organic layer was washed with
brine and dried over sodium sulfate. Removal of the solvent
gave 28R as a colorless oil (630 mg, 99%). To a solution of this
crude acid (480 mg, 1.4 mmol) in dichloromethane (20 mL) at
room temperature were added Et3N (0.64 mL, 4.6 mmol) and
BOP-Cl (550 mg, 2.2 mmol). The resulting mixture was stirred
at room temperature for 3 h before the solvent was removed
under reduced pressure. Column chromatography of the
residue on silica gel (eleunt: EtOAc/hexane, 1/9) gave the title
136.9, 141.8, 168.4. υ (CHCl3): 1831 cm-1. Anal. Calcd. for
C
19H18O5S: C, 63.67; H, 5.06. Found: C, 63.88; H, 5.29.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of P er silyl-
a ted Ba ses.33 A mixture of base (0.2 mmol) and ammonium
sulfate (1 crystal) in hexamethyldisilazide (1 mL) was refluxed
under Ar for 8 h before the solvent was removed under
vacuum. After the mixture was dried under high vacuum for
a further 2 h, the crude preparation was used directly in the
coupling reaction.
Gen er a l P r oced u r e for Cou p lin g w ith Don or s 29râ
P r om oted by NIS a n d TfOH. Pentenyl glycoside 29R or 29â
(32 mg, 0.1 mmol), silylated base (0.2 mmol), NIS (24 mg, 0.11
mmol), and activated powdered 4Α molecular sieves (100 mg)
in anhydrous solvent (2 mL) were stirred under Ar for 5 min
before TfOH (11 µL, 0.12 mmol) was added. The reaction
mixture was then stirred at room temperature for 2 h after
which it was diluted with EtOAc (5 mL). The organic layer
was washed with Na2S2O3, NaHCO3, and brine and dried over
sodium sulfate. Removal of the solvent followed by column
chromatography gave the desired nucleosides, as Râ mixtures,
which were converted immediately to the methyl esters as set
out in the general protocol.
Gen er a l P r oced u r e for Cou p lin g w ith Br om id e 30. To
a solution of 29R or 29â (32 mg, 0.1 mmol) in dichloromethane
(1 mL), bromine solution in dichloromethane was added
dropwise at 0 °C under Ar until a brown color persisted. The
solvent was then removed under reduced pressure and the
residue dried under high vacuum for 20 min before it was
dissolved in the dry reaction solvent (1 mL). This solution was
then added dropwise to a mixture of silylated base (0.2 mmol)
and AgOTf (31 mg, 0.12 mmol) in dichloromethane (1 mL)
containing 100 mg of powered activated 4Α molecular sieves
at room temperature (Table 2). The reaction mixture was
stirred at room temperature for 2 h and then diluted with
EtOAc (10 mL). The resulting mixture was washed with
saturated aqueous NaHCO3 and brine and dried over sodium
sulfate. Removal of the solvent followed by column chroma-
tography gave the desired nucleosides, as Râ mixtures of
isomers, which were converted immediately to the methyl
esters as set out in the general protocol.
Gen er a l P r oced u r e for Cou p lin g w ith Th ioglycosid es
31r a n d 31â. To a solution of 31R or 31â (34 mg, 0.1 mmol)
and powdered 4Α molecular sieves (50 mg) in dichloromethane
(1 mL) at room temperature under Ar was added silylated
N-acetyl cytosine (31 mg, 0.2 mmol) in dichloromethane (1 mL).
After the mixture was stirred for 20 min, NBS (24 mg, 0.13
mmol) in dichloromethane (0.5 mL) was added and the reaction
mixture allowed to stand overnight before the reaction was
quenched with sodium bicarbonate solution and the solvent
extracted with dichloromethane. It was then worked up as
above to give the crude nucleoside â-lactones, which were
converted immediately to the methyl esters as set out below.
Gen er a l P r oced u r e for Cou p lin g w ith Su lfoxid e 32r.
To a solution of sulfoxide 32R (36 mg, 0.1 mmol) and 2,6-di-
tert-butyl-4-methylpyridine (41 mg, 0.2 mmol) in the anhy-
drous reaction solvent (1 mL) at -78 °C under Ar was added
Tf2O (21 µL, 0.12 mmol), followed by stirring for 5 min.
Silylated thymine (0.2 mmol) in the same solvent (1 mL) was
then added and the mixture was allowed to warm to room
temperature. After standing overnight, the reaction was
quenched with NaHCO3 and worked up as above for coupling
with bromide 30 to give the crude nucleoside â-lactones which
were immediately converted to the methyl esters as set out in
the general protocol.
Gen er a l P r oced u r e for th e Con ver sion of th e â-La c-
ton e Nu cleosid es in to Meth yl Ester s. The Râ mixtures of
isomers obtained from the coupling reactions were treated with
triethylamine (1 equiv) in MeOH for 30 min at room temper-
ature. Removal of the volatiles under reduced pressure and
column chromatography then gave 34R and 34â, or 36R and
36â, which were identical to authentic samples obtained by
desilylation of 21R and 21â, or 22R and 22â, respectively.
Gen er a l P r oced u r e for Desilyla tion of 21r, 21â a n d
22r, 22â. The nucleoside (1 mmol) in THF (1 mL) was treated
with triethylamine trihydrofluoride (10 equiv) at room tem-
20
compound as a colorless oil (320 mg, 85%). [R]D -78.5° (c,
2.5). 1H NMR δ: 1.57-1.71 (m, 2 H), 2.00-2.13 (m, 3 H), 2.48
(d, J ) 15.2 Hz, 1H), 3.38-3.45 (m, 1 H), 3.71-3.82 (m, 2 H),
3.90 (d, J ) 10.7 Hz, 1 H), 4.69 (s, 2 H), 4.94-5.04 (m, 2 H),
5.05 (d, J ) 5.2 Hz, 1 H), 5.50 (d, J ) 5.2 Hz, 1 H), 5.73-5.87
(m, 1 H), 7.28-7.38 (m, 1 H). 13C NMR δ: 28.6, 30.3, 37.3,
52.4, 65.6, 68.2, 74.1, 77.0, 79.1, 97.0, 107.2, 115.0, 127.9, 128.7,
137.4, 138.3, 170.7. υ (CHCl3): 1843 cm-1. Anal. Calcd. for
C18H22O5: C, 67.91; H, 6.96. Found: C, 68.01; H, 7.01.
1R,3S,5S-1-(Ben zyloxym eth yl)-2,6-dioxa-7-oxo-3-(4-pen -
ten yloxy)bicyclo[3.2.0]h ep ta n e (29â). 29â was prepared
20
from 27â analogously to the R-anomer above. [R]D +76.8° (c,
1.4). 1H NMR δ: 1.63-1.72 (m, 2 H), 1.95-2.13 (m, 3 H), 2.60
(dd, J ) 15.2, 4.8 Hz, 1 H), 3.49-3.56 (m, 1 H), 3.71 (d, J )
10.4 Hz, 1 H), 3.76-3.83 (m, 1 H), 3.89 (d, J ) 10.4 Hz, 1 H),
4.62 (dd, J ) 15.5, 12.1 Hz, 2 H), 4.96-5.04 (m, 2 H), 5.09 (d,
J ) 5.3 Hz, 1 H), 5.38 (dd, J ) 6.3, 4.7 Hz, 1 H), 5.74-5.83
(m, 1 H), 7.27-7.38 (m, 5 H). 13C NMR δ: 28.9, 30.2, 37.3,
65.9, 69.9, 74.0, 58.5, 96.4, 107.3, 115.3, 127.9, 128.2, 128.7,
137.4, 138.0, 169.5. υ (CHCl3): 1837 cm-1. Anal. Calcd. for
C
18H22O5:C, 67.91; H, 6.96. Found: C, 67.70; H, 6.98.
1R,3R,5S-1-(Ben zyloxym eth yl)-2,6-d ioxa -7-oxo-3-p h en -
ylth iobicyclo[3.2.0]h ep ta n e (31r) a n d th e 3S Dia ster e-
om er (31â). To a solution of 29R (115 mg, 0.36 mmol) in
dichloromethane (5 mL) was added a solution of bromine in
dichloromethane dropwise at 0 °C under Ar until a brown color
persisted. The solvent was then removed under reduced
pressure and the resulting solid dried for 20 min under vacuum
and then redissolved in dichloromethane (2 mL). This solution
and PhSH (41 µL, 0.4 mmol) were added at the same time to
a stirred solution of AgOTf (111 mg, 0.43 mmol) in dichlo-
romethane (2 mL) at -78 °C under Ar. The reaction mixture
was allowed to warm to 0 °C, then diluted with aqueous
NaHCO3, and extracted with EtOAc. The combined organic
layers were washed and dried. Removal of the solvent followed
by column chromatography on silica gel (eluent: EtOAc/
hexane, 1/7) gave pure 31â (30 mg) and 31R mixed with an
inseparable impurity (60 mg, 50% purity) (overall yield: 50%).
For 31â: mp 64-66 °C. [R]D20 -84.4° (c, 1.0). 1H NMR δ: 1.86-
1.96 (m, 1 H), 2.67 (d, J ) 14.9, 5.0 Hz, 1 H), 3.76 (d, J ) 10.6
Hz, 1 H), 3.95 (d, J ) 10.6 Hz, 1 H), 4.62 (s, 2 H), 5.07 (d, J )
4.7 Hz, 1 H), 5.50 (dd, J ) 10.7, 5.0 Hz, 1 H), 7.25-7.39 (m, 8
H), 7.48-7.51 (m, 2 H). 13C NMR δ: 36.7, 65.4, 74.2, 79.4, 86.4,
98.9, 128.0, 128.7, 129.3, 132.3, 137.2, 169.0. υ (CHCl3): 1833
cm-1. Anal. Calcd. for C19H18O4S: C, 66.65; H, 5.30. Found:
C, 66.64; H, 5.40. 31R was characterized by an anomeric signal
at δ 6.01 in the 1H spectrum. It was used as obtained in the
next step because of the difficulties with purification.
1R,3R,5S-1-(Ben zyloxym eth yl)-2,6-d ioxa -7-oxo-3-p h en -
ylth iobicyclo[3.2.0]h ep ta n e S-Oxid e (32r). To the solution
of the impure 31R (60 mg, 0.09 mmol) in THF (1 mL) at 0 °C
was added dropwise Oxone (54 mg, 0.09 mmol) in water (0.2
mL) after which the reaction mixture was stirred at 0 °C for
30 min and then diluted with EtOAc (5 mL). The organic layer
was washed and dried. Removal of the solvent followed by
column chromatography on silica gel (eluent: EtOAc/hexane,
3/1) gave 32R (19 mg, 60%) as a single diastereomer at S. mp
20
1
103-105 °C. [R]D +67.7° (c, 0.7). H NMR δ: 2.42-2.52 (m,
1 H), 3.32 (d, J ) 16.7 Hz, 1 H), 3.67 (d, J ) 10.8 Hz, 1 H),
3.87 (d, J ) 10.8 Hz, 1 H), 4.57 (s, 2 H), 4.92 (d, J ) 7.4 Hz,
1 H), 5.28 (d, J ) 5.0 Hz, 1 H), 7.26-7.37 (m, 5 H), 7.52-7.57
(m, 3 H), 7.68-7.72 (m, 2 H). 13C NMR δ: 32.1, 64.8, 74.3,
80.1, 100.8, 101.1, 125.3, 128.1, 128.4, 128.8, 129.4, 132.0,

4024 J . Org. Chem., Vol. 64, No. 11, 1999
Crich and Hao
1
perature for 12 h. Removal of the volatiles and chromatogra-
phy over silica gel then gave the desilylated compound.
5′-Ben zyl-2′-d eoxy-4′r-m eth oxyca r bon yl-D-th ym id in e
) +15.3° (c, 1.1, MeOH). H NMR δ: 0.08 (s, 3 H), 0.13 (s, 3
H), 0.85 (s, 9 H), 2.27 (s, 3 H), 2.27-2.36 (m, 1 H), 2.85-2.95-
(m, 1 H), 3.73 (s, 3 H), 3.90-4.10 (m, 2 H), 4.79 (br s, 1 H),
5.14(br s, 1 H), 6.37 (t, J ) 6.9 Hz, 1 H), 7.90 (s, 1 H). 13C
NMR δ: -5.0, -4.7, 18.0, 24.6, 25.7 (3 × C), 40.9, 52.3, 63.9,
74.1, 86.4, 93.0, 122.1, 139.2, 147.7, 155.5, 170.4, 172.8. Anal.
Calcd. for C20H31N5O7Si‚0.5H2O: C, 48.96; H, 6.57. Found: C,
48.96; H, 6.57.
(34â). [R]D +6.4° (c, 2.4). 1H NMR δ: 1.60 (s, 3 H), 2.24-
20
2.33 (m, 1 H), 2.42-2.50 (m, 1 H), 3.49 (br s, 1 H), 3.79 (s, 3
H), 4.01 (d, J ) 10.3 Hz, 1 H), 4.06 (d, J ) 10.3 Hz, 1 H), 4.60
(dd, J ) 16.8, 11.7 Hz, 2 H), 4.68-4.74 (m, 1 H), 6.60 (t, J )
7.4 Hz, 1 H), 7.27-7.37 (m, 5 H), 7.54 (s, 1 H), 9.26 (br s, 1 H).
13C NMR δ: 12.3, 40.2, 52.9, 71.6, 74.1, 86.0, 91.5, 111.4, 127.8
(2 × C), 128.4, 128.8 (2 × C), 136.1, 137.2, 150.6, 164.1, 170.7.
Anal. Calcd. for C19H22N2O7‚0.25H2O: C, 57.79; H, 5.74.
Found: C, 57.55; H, 5.72.
6-N-Ben zoyl-1-[2S,3S,5S-2-ben zyloxym eth yl-3-(ter t-bu -
tyldim eth ylsiloxy)-2-m eth oxycar bon yl-5-tetr ah ydr ofu r a-
n yl]a d en in e (40). Prepared from 24R by hydrogenolysis as
described for 39 above with the difference that removal of the
solvent was followed by chromatography on silica gel (eluent:
MeOH/CHCl3, 1/10) which gave 39 as a white foam (yield:
50%). [R]D +39.8° (c, 0.8). H NMR δ: -0.01 (s, 3 H), 0.05 (s,
3 H), 0.74 (s, 9 H), 2.56-2.63 (m, 1 H), 2.85-2.94 (m, 1 H),
3.75 (s, 3 H), 3.88 (s, 2 H), 4.71 (dd, J ) 5.7, 3.7 Hz, 1 H), 6.65
(dd, J ) 6.8, 3.7 Hz, 1 H), 7.41-7.62 (m, 3 H), 8.04 (d, J ) 7.1
Hz, 2 H), 8.78 (s, 1 H), 8.86 (s, 1 H), 9.29 (br s, 1 H). 13C NMR
δ: -5.1, -4.8, 17.9, 25.6 (3 × C), 41.5, 52.7, 64.6, 74.4, 85.3,
93.6, 123.0, 128.2, 128.5, 129.0, 130.2, 132.9, 134.0, 142.8,
149.6, 151.5, 152.7, 165.5, 170.4. Anal. Calcd. for C25H33N5O6-
Si: C, 56.91; H, 6.30. Found: C, 56.74; H, 6.36.
1-(2S,3S,5S-2-Ben zyloxym eth yl-3-h yd r oxy-2-m eth oxy-
car bon yl-5-tetr ah ydr ofu r an yl)th ym in e (34r). [R]D20 +11.1°
1
20
1
(c, 1.2). H NMR δ: 1.77 (s, 3 H), 2.47-2.52 (m, 1 H), 2.64-
2.73 (m, 1 H), 3.68 (dd, J ) 20.6, 10.1 Hz, 1 H), 3.81 (s, 3 H),
4.37-4.46 (m, 2 H), 4.55 (s, 2 H), 6.19-6.22 (m, 1 H), 7.26-
7.36 (m, 5 H), 8.14 (s, 1 H). 13C NMR δ: 12.6, 41.4, 52.7, 72.4,
73.7, 88.3, 94.8, 109.2, 127.8 (2 × C), 128.1, 128.7 (2 × C),
137.5, 138.6, 151.2, 165.0, 169.8. Anal. Calcd. for C19H22N2O7‚
0.75H2O: C, 56.50; H, 5.86. Found: C, 56.56; H, 5.58.
4-N-Acetyl-5′-O-ben zyl-2′-d eoxy-4′r-m eth oxyca r bon yl-
D-cytid in e. (36â). [R]D +64.1° (c, 1.9). 1H NMR δ: 2.13-
20
2.20 (m, 1 H), 2.24 (s, 3 H), 2.79-2.88 (m, 1 H), 3.78 (s, 3 H),
3.88 (d, J ) 10.3 Hz, 1 H), 3.96 (d, J ) 10.3 Hz, 1 H), 4.60 (s,
2 H), 4.67 (t, J ) 4.4 Hz, 1 H), 6.53 (t, J ) 6.2 Hz, 1 H), 7.22
(d, J ) 7.5 Hz, 1 H), 7.26-7.40 (m, 5 H), 8.24 (d, J ) 7.5 Hz,
1 H). 13C NMR δ: 25.0, 41.4, 52.8, 71.0, 73.4, 74.1, 88.3, 91.9,
96.8, 128.2 (2 × C), 128.5, 128.9 (2 × C), 137.0, 145.1, 15.5,
162.7, 170.5, 171.0. Anal. Calcd. for C20H23N3O7‚0.75H2O: C,
57.74; H, 5.73. Found: C, 55.86; H, 5.60.
3′-O-(ter t-Bu t yld im et h ylsilyl)-2′-d eoxy-4′r-m et h oxy-
ca r bon yl-D-cytid in e (42). A solution of 22â (54 mg, 0.1 mmol)
in MeOH (2 mL) and 0.1 N NaOH (2 mL, 0.2 mmol) was stirred
at room temperature for 1 h and then the MeOH was removed
under vacuum. The remaining aqueous phase was acidified
to pH 2 and the solvent extracted with EtOAc. The combined
organic layers were washed with brine, dried (Na2SO4), and
evaporated down to give a white foam (49 mg, 100%) which
was dissolved in dichloromethane (1 mL) at -78 °C under Ar
amd treated dropwise with 1 M boron trichloride (0.4 mL, 0.4
mmol) in dichloromethane. The reaction mixture was allowed
to warm to 0 °C gradually and then MeOH (2 mL) was added
to quench the reaction. The volatiles were removed under
reduced pressure and the residue triturated with dry ether to
4-N-Acetyl-1-(2S,3S,5S-2-ben zyloxym eth yl-3-h yd r oxy-
2-m eth oxyca r bon yl-5-tetr a h yd r ofu r a n yl)cytosin e. (36r).
20
1
[R]D -86.0° (c, 2.5). H NMR δ: 2.15 (s, 3 H), 2.02-2.09 (m,
1 H), 2.73-2.78 (m, 1 H), 3.63 (d, J ) 10.0 Hz, 1 H), 3.74 (d,
J ) 10.0 Hz, 1 H), 3.76 (s, 3H), 4.43 (d, J ) 4.1 Hz, 1 H), 4.54
(dd, J ) 16.5, 12.6 Hz, 2 H), 4.70 (br s, 1 H), 6.11 (d, J ) 6.7
Hz, 1 H), 7.20-7.34 (m, 5 H), 7.42 (d, J ) 7.5 Hz, 1 H), 8.79
(d, J ) 7.5 Hz, 1 H), 9.58 (br s, 1 H). 13C NMR δ: 24.9, 41.7,
52.8, 72.4, 73.8, 73.9, 90.3, 95.7, 96.2, 127.8 (2 × C), 128.1,
128.7 (2 × C), 137.4, 146.8, 155.7, 162.6, 169.9, 171.0. Anal.
Calcd. for C20H23N3O7‚H2O: C, 55.16; H, 5.79. Found: C, 55.20;
H, 5.79.
20
give 42 as a white solid (32 mg, 80%). mp 164-166 °C. [R]D
1
+74.5° (c, 0.6). H NMR (CD3OD) δ: 0.09 (s, 3 H), 0.10 (s, 3
H), 0.88 (s, 9 H), 2.21-2.29 (m, 1 H), 2.39-2.47 (m, 1 H), 3.73
(s, 3 H), 3.89 (s, 2 H), 4.67 (dd, J ) 6.5, 4.4 Hz, 1 H), 5.90 (d,
J ) 7.5 Hz, 1 H), 6.45 (t, J ) 6.5 Hz, 1 H), 7.96 (d, J ) 7.5 Hz,
1 H). 13C NMR δ: -4.6, -4.3, 19.1, 26.6, 42.7, 53.0, 64.5, 75.2,
89.5, 94.0, 96.6, 143.7, 158.5, 168.1, 172.6. Anal. Calcd. for:
2-N-Acetyl-3′-O-(ter t-bu tyld im eth ylsilyl)-2′-d eoxy-4′r-
m eth oxyca r bon yl-D-gu a n osin e (39). To a solution of 23â
(50 mg, 0.09 mmol) in a mixture of EtOAc (2 mL) and MeOH
(2 mL) was added Pd-C (10%, 50 mg) and then hydrogen was
bubbled through the solution until TLC showed the disap-
pearance of the starting material. After filtration and removal
of the solvent, the residue was triturated with dry ether to
C
7.40.
17H29N3O6Si‚0.5H2O: C, 49.98; H, 7.40. Found: C, 49.96; H,
Ack n ow led gm en t. We thank the National Cancer
Institute for support of this work (CA 60500).
give 39 as a white solid (40 mg, 95%). mp 242-244 °C. [R]20
J O990046E
D