Stereocontrolled Syntheses of Deoxyribonucleosides via Photoinduced Electron-Transfer Deoxygenation of Benzoyl-Protected Ribo- and Arabinonucleosides

J . Org. Chem. 2000, 65, 5969-5985

5969

Ster eocon tr olled Syn th eses of Deoxyr ibon u cleosid es via

P h otoin d u ced Electr on -Tr a n sfer Deoxygen a tion of

Ben zoyl-P r otected Ribo- a n d Ar a bin on u cleosid es

Zhiwei Wang, Daniel R. Prudhomme, J ason R. Buck, Minnie Park, and Carmelo J . Rizzo*

Department of Chemistry, Box 1822, Station B, Vanderbilt University, Nashville, Tennessee 37235

c.j.rizzo@vanderbilt.edu

Received March 14, 2000

The stereocontrolled, de novo syntheses of â-2′-deoxy-, R-2′-deoxy-, â-3′-deoxy-, and â-2′,3′-

dideoxyribonucleosides are described. Strategically protected ribose, arabinose, and xylose glyco-

sylation precursors were synthesized bearing C2-esters capable of directing Vorbru¨ggen glycosyl-

ation. The key step is the regioselective deoxygenation of the desired hydroxyl group as either the

benzoyl- or 3-(trifluoromethyl)benzoyl derivative. This deoxygenation is accomplished via a

photoinduced electron-transfer (PET) mechanism using carbazole derivatives as the photosensitizer.

The syntheses of the desired deoxynucleoside generally proceed in three steps from a common,

readily available precursor.

In tr od u ction

specific genes, thus inhibiting the biosynthesis of disease

related proteins. Thus, general and convenient methods

for the synthesis of nucleosides are of obvious importance

and widespread interest.¹

Nucleosides and nucleoside analogues have long been

an important class of medicinal agents, possessing an-

ticancer and antiviral activity.^1,25-Fluoro-2′-deoxyuridine

is an inhibitor of thymidylate synthase and has been used

clinically for the treatment of leukemia and colorectal

cancer.²Recent interest in antiviral nucleosides has

centered on the development of reverse transcriptase

inhibitors as potential AIDS therapies.^1aThe nucleoside

analogues 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-

cytidine (ddC), 2′,3′-dideoxyinosine (ddI), and 2′,3′-dideoxy-

3′-thiacytidine (3TC) are currently approved for the

treatment of AIDS and are believed to work by termina-

tion of the replicating DNA chain since these compounds

do not possess a 3′-hydroxyl group. In addition to these

compounds, a number of nucleoside analogues have been

synthesized and undergone preliminary clinical testing;

this subject has been extensively reviewed in recent

years.¹Modified nucleosides play a central role in the

development of genetic therapies such as triplex (anti-

gene) and antisense strategies.³In these approaches, 2′-

deoxyoligonucleotides can prevent the expression of

The most widely used strategy for the chemical syn-

thesis of nucleosides involves Vorbru¨ggen glycosylation

of ribose tetraesters (1) with a silylated nucleoside base

under strong Lewis acid conditions (Scheme 1).⁴In this

approach, the presence of a C2-directing group on the

ribose glycosylation precursor is necessary to control the

anomeric stereochemistry; glycosylation of 2-deoxyribose

derivatives generally leads to a mixture of anomers which

can be difficult to separate.⁵If 2′-deoxyribonucleosides

are desired, the 3′ and 5′-hydroxyls are selectively

protected with a bifunctional silylating agent (3)⁶followed

by radical deoxygenation of the 2′-hydroxyl as developed

by Robins (Scheme 1).⁷

We are interested in developing more efficient methods

for the deoxygenation of ribonucleosides to deoxynucleo-

sides. For example, our strategy for the synthesis of â-2′-

deoxynucleosides involved the preparation of a ribose

glycosylation precursor in which the C2-hydroxyl was

derivatized with a group capable of directing the glyco-

sylation and serving as a deoxygenation precursor (Scheme

2). Since our initial report,⁸we have extended this

strategy to the stereocontrolled syntheses of R-2′-deoxy-

ribonucleosides,⁹â-3′-deoxyribonucleosides, and â-2′,3′-

dideoxyribonucleosides. The key step in this work was

the use of a photoinduced electron-transfer (PET) deoxy-

(1) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745. (b)

Wilson, L. W.; Hager, M. W.; El-Kattan, Y. A.; Liotta, D. C. Synthesis

1995, 1465. (c) Hunziker, J .; Leumann, C. In Modern Synthetic

Methods 1995; Ernst, B., Leumann, C., Eds.; VCH: Basel, 1995; pp

333-417.

(2) (a) Heidelberger, C. Prog. Nucleic Acid Res. Mol. Biol. 1965, 4,

1. (b) Perigaud, C.; Gosselin, G.; Imbach, J .-L. Nucleosides Nucleotides

1992, 11, 903. (c) De Clercq, E. In Targets for the Design of Antiviral

Agents; De Clercq, E., Walker, R. T., Eds.; Plenum Press: New York,

1984, pp 203-230. (d) Nucleosides and Nucleotides as Antitumor and

Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New

York, 1993.

(4) (a) Vorbru¨ggen, H. F.; Ruh-Pohlenz, C. Org. React. 2000, 55, 1.

(b) Vorbru¨ggen, H. F. Acc. Chem. Res. 1995, 28, 509. (c) Vorbru¨ggen,

H. Acta Biochim. Pol. 1996, 43, 25.

(3) (a) Antisense Research and Applications; Crooke, S. T., Lebleu,

B., Eds.; CRC Press: Boca Raton, 1993. (b) Milligan, J . F.; Matteucci,

M. D.; Martin, J . C. J . Med. Chem. 1993, 36, 1923. (c) Uhlmann, E.;

Peyman, A. Chem. Rev. 1990, 90, 543. (d) Bischofberger, N.; Shea, R.

G. In Nucleic Acid Targeted Drug Design; Propst, C. L., Perun, T. J .,

Eds.; Marcel Dekker: New York, 1992; pp 579-612. (e) Varma, R. S.

Synlett 1993, 713. (f) Cohen, J . S.; Hogan, M. E. Sci. Am. 1994

(December issue), p 76. (g) De Mesmaeker, A.; Haner, R.; Martin, P.;

Moser, H. E. Acc. Chem. Res. 1995, 28, 366. (h) De Mesmaeker, A.;

Altmann, K.-H.; Waldner, A.; Wendeborn, S. Curr. Opin. Struct. Biol.

1995, 5, 343.

(5) Dueholm, K. L.; Pedersen, E. B. Synthesis 1992, 1.

(6) (a) Markiewicz, W. T. J . Chem. Res., Synop. 1979, 24. (b) Wada,

T.; Tobe, M.; Nagayama, T.; Furusawa, K.; Sekine, M. Tetrahedron

Lett. 1995, 36, 1683.

(7) (a) Robins, M. J .; Wilson, J . S. J . Am. Chem. Soc. 1981, 103,

932. (b) Robins, M. J .; Wilson, J . S.; Hansske, F. J . Am. Chem. Soc.

1983, 105, 4059.

(8) (a) Park, M.; Rizzo, C. J . J . Org. Chem. 1996, 61, 6092. (b)

Prudhomme, D. R.; Park, M.; Wang, Z.; Buck, J . R.; Rizzo, C. J . Org.

Synth. 1999, 77, 162.

(9) Wang, Z.; Rizzo, C. J . Tetrahedron Lett. 1997, 38, 8177.

Published on Web 08/25/2000

5970 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

Sch em e 1

Sch em e 3

Sch em e 2

Sch em e 4

genation of 3-(trifluoromethyl)benzoates and benzoates

using carbazoles as the photosensitizer.¹⁰This method

has been used rather sparingly for the deoxygenation of

alcohols.¹¹Greenberg and co-workers have made excel-

lent use of this PET deoxygenation to study the fate of

nucleoside radicals as mechanistic models for oxidative

damage to DNA.¹²

â-2′-Deoxyr ibon u cleosid es. Prior to our work, Ben-

ner and co-workers reported an identical strategy for the

synthesis of potential antisense nucleosides with modified

backbones (Scheme 3).¹³In this work, a glycosylation

precursor 5 was prepared in about 10 steps from diac-

etone glucose in which a 3-(trifluoromethyl)benzoyl group

was used to direct the Vorbru¨ggen glycosylation. PET

deoxygenation under the conditions originally reported

by Saito^10ausing stoichiometric 9-methylcarbazole (MCZ)

as the photosensitizer gave the 2′-deoxynucleoside ana-

logues (7). It was also reported that PET deoxygenation

of the corresponding cytidine derivative proceeded in

lower yield and the N-benzoyladenosine derivative failed

to give the desired 2′-deoxynucleoside analogue.^13a

We generalized this approach for the synthesis of

natural â-2′-deoxyribonucleosides according to Scheme

4.⁸The glycosylation precursor was easily prepared by

esterification of commercially available R-^D-1,3,5-triben-

zoylribofuranose (8) with m-(trifluoromethyl)benzoyl chlo-

ride to give 9. Vorbru¨ggen glycosylation of 9 with

silylated nucleoside bases (10-17) gave the protected

â-ribonucleosides (18) in high yield; in no case did we

detect any of the R-anomer. PET deoxygenation of 18

provided the corresponding protected â-2′-deoxyribo-

nucleoside (19). Our results are shown in Table 1. Our

original report was limited to the synthesis of â-2′-

deoxypyrimidines (entries a-e) and the PET deoxygen-

ation was accomplished as previously described by Saito,^10a

Benner,^13aand others,^11,12using stoichiometric 9-meth-

ylcarbazole (20, MCZ). We have since extended this

strategy to the synthesis of â-2′-deoxypurines and have

developed a more efficient photosensitizer, 3,6-dimethyl-

9-ethylcarbazole (21, DMECZ, Figure 1).^10bWe proposed

that the methyl groups of DMECZ block or slow potential

degradation pathways of the carbazole radical cation, an

intermediate in the PET deoxygenation, allowing for the

photosensitizer to turnover. Deoxygenations are typically

accomplished with 10-15 mol % of DMECZ. In addition,

we found this photosensitizer to be significantly more

reactive, deoxygenating both 3-(trifluoromethyl)benzoates

and benzoates faster than stoichiometric MCZ.^10bFor the

ribothymidine example 18b (Scheme 5), deoxygenation

with DMECZ gave protected thymidine (19b) in 52%

yield along with 12% of the dideoxynucleoside 22.^8bThe

PET deoxygenations of examples f-h in Table 1, as well

as all subsequent work, were accomplished using DMECZ

and the 2′,3′-dideoxynucleosides were often minor prod-

ucts.

(10) (a) Saito, I.; Ikehira, H.; Kasatani, R.; Watanabe, M.; Matsuura,

T. J . Am. Chem. Soc. 1986, 108, 3115. (b) Prudhomme, D. R.; Wang,

Z.; Rizzo, C. J . J . Org. Chem. 1997, 62, 8257.

(11) (a) Riedel, S.; Donnerstag, A.; Hennig, L.; Welzel, P.; Richter,

J .; Hobert, K.; Muller, D.; van Heijenoort, J . Tetrahedron 1999, 55,

1921. (b) J ung, P. M. J .; Burger, A.; Biellmann, J .-F. J . Org. Chem.

1997, 62, 8309. (c) Ireland, R. E.; Armstrong, J . D.; Lebreton, J .;

Meissner, R. S.; Rizzacasa, M. A. J . Am. Chem. Soc. 1993, 115, 7152.

(d) Myers, A. G.; Condroski, K. R. J . Am. Chem. Soc. 1995, 117, 7926.

(e) Clive, D. L. J .; Daigneault, S. J . Org. Chem. 1991, 56, 3801. (f)

Almond, M. R.; Collins, J . L.; Reitter, B. E.; Rideout, J . L.; Freeman,

G. A.; St Clar, M. H. Tetrahedron Lett. 1991, 32, 5745. (g) Suzuki, M.;

Koyano, H.; Noyori, R. J . Org. Chem. 1987, 52, 5583.

(12) (a) Barvian, M. R.; Barkley, R. M.; Greenberg, M. M. J . Am.

Chem. Soc. 1995, 117, 4894. (b) Barvian, M. R.; Greenberg, M. M. J .

Org. Chem. 1993, 58, 6151. (c) Barvian, M. R.; Greenberg, M. M.

Tetrahedron Lett. 1992, 33, 6057.

(13) (a) Huang, Z.; Schneider, K. C.; Benner, S. A. J . Org. Chem.

1991, 56, 3869. (b) This strategy was also proposed by Chapeau and

Marnett: Chapeau, M.-C.; Marnett, L. J . J . Org. Chem. 1993, 58, 7258

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5971

Ta ble 1. Yield s for th e Gycosyla tion of 9 a n d Deoxygen a tion of 18

Sch em e 6

F igu r e 1.

Sch em e 5

In all of our work, the PET deoxygenation reaction was

carried out using a Hanovia medium-pressure Hg lamp

through Pyrex, which has a UV cutoff of approximately

280 nm. The carbazole photosensitizers have UV absor-

bances at 290 (ꢀ ) 18 000), 330 (ꢀ ) 4400) and 340 (ꢀ )

5400) for 20 and 300 (ꢀ)18 000), 340 (ꢀ ) 4000) and 360

(ꢀ ) 4400) for 21. When the deoxygenation was attempted

through a uranium glass filter (340 nm cutoff), very little

reaction was observed. This indicates that the absorbance

at 290 and 300 for 20 and 21, respectively, are probably

responsible for the PET chemistry.

A second disadvantage to using MCZ as the photosen-

sitizer is that the rate of PET deoxygenation is optimal

at a substrate concentration of 1.4 mM. For ribonucleo-

side examples 18, this translated to about 1 mg of

substrate per mL of solution; increasing the substrate

concentration resulted in sharp decreases in the rate of

deoxygenation. We found using 15 mol % of DMECZ, the

concentration of 18b could be increased to nearly 10 mM

with only a modest increase in reaction times.^8b

Glycosylation of 9 with per-silylated N⁶-benzoyladenine

gave the corresponding protected ribonucleoside (18g, R

) Bz) in 80% yield as a single regio- and stereoisomer.

PET deoxygenation, however only gave a trace of the

desired product, consistent with the results previously

reported by Benner.^13aSaito demonstrated that adenosine

derivative 23 could be successfully deoxygenated with

stoichiometric MCZ (Scheme 6).^10aThe principle differ-

ence between 23 and our substrate (18g) is that N⁶is

5972 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

F igu r e 2.

Sch em e 7

F igu r e 3.

9, giving instead a complex mixture of products that were

difficult to purify by flash chromatography. J enny and

Benner reported that glycosylation with O⁶-2-(4-nitro-

phenyl)ethyl-protected guanine gave exclusively the N9

glycosylated nucleoside; however, we did not feel that the

4-nitrophenyl group would be compatible with the PET

deoxygenation reaction.¹⁷

Nucleosides with chloropurine bases such as 6-chloro-,

2,6-dichloro-, and 2-amino-6-chloropurine are important

intermediates for the preparation of biologically active

nucleosides. It has been shown that glycosylation of

ribose tetraester with 6-chloropurine is regioselective,

giving the N7-product exclusively.^18aPreviously, we at-

tempted the PET deoxygenation of R-6-bromouridine

derivative of 34 (Scheme 8) and observed a variety of

decomposition products which we attributed to reduction

of the 6-bromo group. We therefore had reservation as

to whether the chloro group of chloropurines would

survive the PET deoxygenation reaction. To test this, we

prepared protected nucleoside 28a (X ) Cl) from com-

mercially available 6-chloropurine ribonucleoside (Figure

3). Using DMECZ as the photosensitizer, attempted

photodeoxygenation of 28a resulted in clean dechlorina-

tion to give 28b.^18bThe structure of 28b was confirmed

by independent synthesis from commercially available

purine ribonucleoside

unprotected in the Saito example. Glycosylation with per-

silylated adenine without an N⁶-protecting group gave

the desired glycosylation product (18h , R ) H), however,

as a mixture of N9 and N7 regioisomers. It had been

previously reported that selective N-deacylation of nu-

cleoside bases could be achieved with zinc bromide.¹⁴We

therefore elected to selectively deprotect the N⁶-benzoyl

group of 18g (R ) Bz) which was accomplished in 86%

yield to give 18h (R ) H); PET deoxygenation now

proceeded smoothly to give the corresponding 2′-deoxy-

adenosine derivatives (19h , R ) H) in 58% yield.

The regiochemistry for the glycosylation of guanine is

a long-standing problem in the synthesis of nucleosides

giving a mixture of N9 (18j) and N7 (18i) products

(Figure 2). Under kinetic conditions (Lewis acid, dichloro-

ethane, -20 °C), Vorbru¨ggen glycosylation gave exclu-

sively the unnatural N7-isomer (18i). When the reaction

was heated at reflux for 8 h, the N9-isomer (18j) was

isolated in 65% yield, along with 7% of the N7-isomer;

importantly, these products were separable by flash

chromatography on silica. These results are in accord

with previous observations.^4a,15The PET deoxygenation

of both regioisomers proceeded smoothly.

r-2′-Deoxyr ibon u cleosid es. R-Nucleosides have of-

ten been regarded as unwanted side products of nonste-

reoselective glycosylation reactions and there has been

relatively little interest in their biological activity. In-

spired by predictions made by Sequin based on Dreiding

stereomodels,¹⁹Imbach prepared oligo-R-2′-deoxynucle-

otides in order to study their hybridization properties.

In accord with Sequin’s predictions, oligo-R-2′-deoxy-

nucleotides hybridized with a complimentary oligo-â-2′-

deoxynucleotides to form a B-like parallel duplex. The

parallel nature of the hybridization was confirmed by 2D-

NMR and molecular modeling²⁰and the stability of the

duplexes were studied by melting temperature (T_m)

Recently, solutions to the regiochemical problem of

guanine glycosylation have been reported, most notably

by Robins and co-workers (Scheme 7), who showed that

glycosylation with the O⁶-diphenylcarbamoyl derivative

of N²-acetylguanine (26, after in situ silylation) gave

exclusively the N9-regioisomer (27).¹⁶While we were able

to repeat the regioselective glycosylation of 25, less

optimistic results were obtained for the glycosylation of

(17) (a) J enny, T. F.; Benner, S. A.; Tetrahedron Lett. 1992, 33, 6619.

(b) For an enzymatic solution to the regiochemical problem of guanine

glycosylation see: Mu¨ller, M.; Hutchinson, L. K.; Guengerich, F. P.

Chem. Res. Toxicol. 1996, 9, 1140 and references therein.

(18) (a) Saneyoshi, M.; Satoh, E. Chem. Pharm. Bull. 1979, 27, 2518.

(b) We are grateful to a reviewer of this manuscript for suggesting

this experiments.

(14) Kierzek, R.; Ito, H.; Bhatt, R.; Itakura, K. Tetrahedron Lett.

1981, 22, 3761.

(19) Sequin, U. Experientia 1973, 29, 1059.

(15) (a) Dudycz, L. W.; Wright, G. E. Nucleosides Nucleotides 1984,

3, 33. (b) Wright, G. E.; Dudycz, L. W. J . Med. Chem. 1984, 27, 175.

(c) Garner, P.; Ramakanth, S. J . Org. Chem. 1988, 53, 1294.

(16) (a) Robins, M. J .; Zou, R.; Guo, Z.; Wnuk, S. F. J . Org. Chem.

1996, 61, 9207. (b) Zou, R.; Robins, M. J . Can. J . Chem. 1987, 65, 1436.

(c) Robins, M. J .; Zou, R.; Hansske, F.; Madej, D.; Tyrrell, D. L. J .

Nucleosides Nucleotides 1989, 8, 725.

(20) (a) Morvan, F.; Rayner, B.; Imbach, J . L. Anticancer Drug Des.

1991, 6, 521. (b) Morvan, F.; Rayner, B.; Imbach, J .-L.; Chang, D.-K.;

Lown, J . W. Nucleosides Nucleotides 1987, 6, 471. (c) Debart, F.;

Rayner, B.; Degols, G.; Imbach, J .-L. Nucleic Acids Res. 1992, 20, 1193.

(d) Gmeiner, W. H.; Rao, K. E.; Rayner, B.; Vasseur, J .-J .; Morvan, F.;

Imbach, J .-L.; Lown, J . W. Biochemistry 1990, 29, 10329. (e) Also see

ref 1c and references therein.

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5973

Ta ble 2. Syn th esis of r-2′-Deoxyn u cleosid es. Yield s for

Sch em e 8

th e Glycosyla tion of 33 a n d Deoxygen a tion of 34

measurements.²¹The stability of the parallel R-â hybrid

was dependent upon the sequence but was generally in

the range of the corresponding antiparallel â-â duplex.

Of note, the unnatural oligo-R-2′-deoxynucleotides were

resistant to enzymatic degradation making them of

interest as potential antisense agents.^1c,20,21

R-Nucleosides are prepared by nonstereoselective gly-

cosylation from a 2-deoxyribose precursor or anomeriza-

tion of natural 2′-deoxynucleosides with Lewis acids;²²

both methods require separation of the anomers. We set

out to extend our strategy for the stereocontrolled

synthesis of â-2′-deoxyribonucleosides to the R-anomers.

It is documented that Vorbru¨ggen glycosylation of ara-

binose tetraesters selectively gives the R-anomeric ster-

eochemistry.²³Our initial plan was to invert the C-2

stereochemistry of 8 to give the desired arabinose deriva-

tive, however Mitsunobu reaction of 8 with 3-(trifluo-

romethyl)benzoic acid failed to give the desired inverted

product under a variety of conditions.^9,24Instead, we

obtained compound 29 (Figure 4) which we believe arises

from an S_N1 type mechanism with suprafacial migration

of the anomeric benzoate.⁹Glycosylation of 29 with bis-

trimethylsilylthymidine gave 30, the structure of which

was confirmed by independent synthesis providing fur-

ther support for the structure of 29. Concurrent with our

work, Perez-Perez reported that under different condi-

tions, Mitsonobu reaction of 8 gave retention of the C2-

configuration, providing 9 in up to 70% yield.²⁴

of methyl arabinoside 2,3,5-tribenzoate (31) could be

selectively hydrolyzed,²⁵however in our hands this was

only a minor product with the major product being the

C3-deprotected compound 32. The ability of 3,6-dimethyl-

9-ethylcarbazole to efficiently deoxygenate benzoates is

now a key observation in that the C2-benzoyl group could

be used instead of the more expensive 3-(trifluoromethyl)-

benzoate as the directing group and deoxygenation

precursor. Acetylation of 32 and Vorbru¨ggen glycosyla-

tion of 33 gave arabinonucleoside 34 exclusively as the

R-anomer. PET deoxygenation of the 2′-benzoate provided

the protected R-2′-deoxynucleoside 35. The sequence

required seven steps from arabinose, but only three steps

from common intermediate 33. The results of our effort

toward R-2′-deoxynucleosides are summarized in Table

2.⁹

F igu r e 4.

The synthesis of a suitable glycosylation precursor (33)

is shown in Scheme 8. It is reported that the C2-benzoate

In most cases, the glycosylation proceeded smoothly

to give the desired protected R-arabinonucleoside 34. The

(21) (a) Morvan, F.; Rayner, B.; Imbach, J .-L.; Thenet, S.; Bertrand,

J .-R.; Paoletti, J .; Malvy, C.; Paoletti, C. Nucleic Acids Res. 1987, 15,

3421. (b) Cazenave, C.; Chevrier, M.; Thuong, N. T.; Helene, C. Nucleic

Acids Res. 1987, 15, 10507.

(22) (a) Yamaguchi, T.; Saneyoshi, M. Chem. Pharm. Bull. 1984,

32, 1441. (b) Ward, D. I.; J effs, S. M.; Coe, P. L.; Walker, R. T.

Tetrahedron Lett. 1993, 34, 6779. (c) Morvan, F.; Rayner, B.; Imbach,

J .-L. In Protocols for Oligonucleotides and Analogs; Synthesis and

Properties; Agrawal, S., Ed.; Humana Press: Totowa, NJ , 1993; pp

261-283.

(23) Adams, A. D.; Petrie, C. R.; Meyer, R. B. Nucleic Acids Res.

1991, 19, 3647.

(24) (a) Rubira, M.-J .; Perez-Perez, M.-J .; Balzarini, J .; Camarasa,

M.-J . Synlett 1998, 177. (b) Hughes, D. L. Org. React. 1992, 42, 335.

(25) (a) Ishido, Y.; Sakairi, N.; Sekiya, M.; Nakazaki, N. Carbohydr.

Res. 1981, 97, 51. (b) Kawabata, Y.; Kaneko, S.; Kusakabe, I.; Gama,

Y. Carbohydr. Res. 1995, 267, 39.

5974 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

Sch em e 9

F igu r e 5.

deoxygenation of the 2′-O-benzoyl group using 3,6-di-

methyl-9-ethylcarbazole as the photosensitizer worked

with varying success. We found that the attempted

deoxygenation of protected R-arabinocytosine and ad-

enine (34c and 34e) gave decomposition. Based on the

Saito result discussed earlier,^10awe suspected that the

protecting group on the exocyclic amino group might be

responsible for the photodecomposition. In analogy to the

â-nucleoside series, selective deprotection of the N⁶-

benzoyl group of 34e with ZnBr₂gave 34f, which under-

goes PET deoxygenation to afford R-2′-deoxyadenosine

in 76% yield. However, deoxygenation with N⁶-unpro-

tected cytosine (34d ) proceeded in only 33% yield with

35% recovery of starting material (entry d, Table 2).

Prolonged irradiation gave lower yields of the desired

product.

Glycosylation of N²-acetylguanine at -20 °C gave

exclusively the N7-glycosylated R-guanosine derivative

(entry g) in analogy with the â-series discussed earlier.

When the glycosylation was carried out in acetonitrile

at reflux, the R-N9-guanosine derivative was isolated in

53% yield along with 8% of the R-N7 isomer. Both the

N7- and N9-regioisomers were deoxygenated in excellent

yield.

In the â-series, the structure of the N9 regioisomer was

confirmed by chemical correlation to natural guanosine.

The N7 and N9 regioisomers of simple methylated

purines have been distinguished by selective INEPT

spectra where the N-methyl protons were irradiated and

either the C4 or C5 carbon resonance was enhanced.²⁶

For the R-nucleosides and other unnatural nucleoside

analogues, we relied on long-range ¹H-¹³C heteronuclear

correlation spectroscopy (HMBC) to unambiguously as-

sign the structures.²⁷We were able to correlate three-

bond coupling from the anomeric proton (H1′) to key

carbon resonances of the base (Figure 5). In general, upon

2′-deoxygenation, the key ¹H-¹³C three-bond coupling

constant were on the order of 1-2 Hz and were regarded

as unreliable; these coupling constants were significantly

larger (∼10 Hz) at the ribo- or arabinonucleoside stage.

For the N7-isomer, we observed three bond coupling from

H1′ (δ ) 6.64 ppm) to C5 (δ ) 111.4 ppm) of the base,

but not to C4 (δ ) 157.5 ppm). For N9-guanosine, three

bond coupling was observed from H1′ (δ ) 6.24 ppm) to

C4 (δ ) 155 ppm). The carbon resonances of guanosine

have been previously assigned.²⁸Our assignments are

also in accord with the empirical observation that the

C8 proton of the N-7-isomer is downfield from that of the

N9-isomer.²⁹

in this class of compounds has centered on cordycepin

(3′-deoxyadenosine), which was the first reported nucleo-

side antibiotic.³⁰More recently, 3′-deoxynucleosides were

shown to possess antiviral, antifungal and antitumor

activities as well.³¹Oligomers of 3′-deoxynucleosides

possessing the unnatural 2′,5′-phosphodiester linkage

have also attracted some interest.^32,33

We have extended our strategy to include â-3′-deoxy-

nucleosides (Scheme 9), which also rely on the ability of

DMECZ to deoxygenate simple benzoyl groups. Acylation

of R-1,3,5-tribenzoylribose (8) gave glycosylation precur-

sor 36. Glycosylation of 36 is directed by the C2-acetyl

group to give exclusively the â-ribonucleoside 37. Deoxy-

genation using 3,6-dimethyl-9-ethylcarbazole provided

the protected â-3′-deoxyribonucleoside (38) in variable

yield (Table 3). We found that deoxygenation of the 3′-

position of 37 is much slower than the 2′-position of 18

or 34, used in the synthesis of â- and R-2′-deoxyribo-

nucleosides, and required significantly longer reaction

times. Unfortunately, the longer reaction times allow for

unwanted side reactions or decomposition to take place.

For instance, PET deoxygenation of 37b (base ) T) gave

only 33% of the desired product with the major product

arising from reduction of the 5,6-double bond of the base.

When the deoxygenation was carried out in 2-propanol-

d1 (ⁱPr-OD), we observed no deuterium incorporation in

the 5,6-dihydroribothymidine products. When per-deu-

terated 2-propanol-d₈was used, the rate of this undesired

reaction was significantly slowed so that 3′-deoxygenation

was the only observed product (61% yield). NMR analysis

of the 3′-deoxy-5-methyluridine (38b) indicated that

deuterium was incorporated exclusively into the 3′-R-

position. 5-Fluorouridine derivative 37c, gave decomposi-

tion upon attempted PET deoxygenation, presumably

through the 5,6-dihydro derivative. Attempted PET

(30) Murray, D. H.; Prokop, J . J . Pharm. Sci. 1965, 54, 1468.

(31) (a) Kumar, A.; Khan, S. I.; Manglani, A.; Khan, A. K.; Katti, S.

B. Nucleosides Nucleotides 1994, 13, 1049. (b) Ge, G.-X.; Bischofberger,

N. Tetrahedron Lett. 1995, 36, 6991. (c) J agger, D. V.; Kredich, N. M.;

Guarino, A. J . Cancer Res. 1961, 21, 216. (d) Nakatsugawa, S.; Dewey,

W. C. Int. J . Radiat. Oncol., Biol., Phys. 1984, 10, 1425. (e) Widell, A.;

Hansson, B. G.; Oberg, B.; Nordenfelt, E. Antiviral Res. 1986, 6, 103.

(f) Volpini, R.; Camaioni, E.; Costanzi, S.; Vittori, S.; Cristalli, G. Helv.

Chim. Acta 1998, 81, 2326. (g) Volpini, R.; Costanzi, S.; Vittori, S.;

Cristalli, G.; Lupidi, G. Helv. Chim. Acta 1999, 82, 2112. (h) Ghosal,

S.; KrishnaPrasad, B. N.; Khanna, M.; Dwivedi, A. K.; Singh, S.;

Kumar, A.; Katti, S. B. Int. J . Pharm. 2000, 194, 15. (i) Gosselin, G.;

Boudou, V.; Griffon, J .-F.; Pavia, G.; Pierra, C.; Imbach, J .-L.; Faraj,

A.; Sommadossi, J .-P. Nucleosides Nucleotides 1998, 17, 1731.

(32) (a) Dougherty, J . P.; Rizzo, C. J .; Breslow, R. J . Am. Chem. Soc.

1992, 114, 6254. (b) Rizzo, C. J .; Dougherty, J . P.; Breslow, R.

Tetrahedron Lett. 1992, 33, 4129. (c) J in, R.; Chapman, W. H.;

Srinivasan, A. R.; Olson, W. K.; Breslow, R.; Breslauer, K. J . Proc.

Natl. Acad. Sci. U.S.A. 1993, 90, 10568. (d) Sheppard, T. L.; Rosenblatt,

A. T.; Breslow, R. J . Org. Chem. 1994, 59, 7243. (e) Sheppard, T. L.;

Breslow, R. C. J . Am. Chem. Soc. 1996, 118, 9810. (f) Breslow, R.;

Sheppard, T. L. Pure Appl. Chem. 1996, 68, 2037.

â-3′-Deoxyr ib on u cleosid es. â-3′-Deoxynucleosides

have been known for over 40 years. Much of the interest

(26) Osterman, P. M.; McKittrick, B. A.; Chan, T.-M. Tetrahedron

Lett. 1992, 33, 4867.

(27) Wang, Z.; Rizzo, C. J . Org. Lett. 2000, 2, 227.

(28) Kalinowski, H.-O.; Berger, S.; Braun, S. Carbon-13 NMR

Spectroscopy; J . Wiley & Sons: New York, 1988; p 440.

(29) Kjellberg, J .; J ohansson, N.; G. Tetrahedron 1986, 42, 6541.

(33) (a) Hashimoto, H.; Switzer, C. J . Am. Chem. Soc. 1992, 114,

6255. (b) Kung, K.-E.; Switzer, C. J . Am. Chem. Soc. 1994, 116, 6059.

(c) Robinson, H.; J ung, K.-E.; Switzer, C.; Wang, A. H.-J . J . Am. Chem.

Soc. 1995, 117, 837.

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5975

Ta ble 3. Syn th esis of â-3′-Deoxyn u cleosid es. Yield s for

Sch em e 11

th e Glycosyla tion of 36 a n d Deoxygen a tion of 37

We have previously shown that 40, the immediate

precursor to 41, can be conveniently prepared by ben-

zoylation of 1,2-O-isopropylidene-^D-xylose to give 39,

followed by PET deoxygenation.^10bGiven some of the

difficulties we experienced in the deoxygenation of 37

such as long reactions times and unwanted side reactions,

the synthesis of â-3′-deoxynucleosides from 41 (Scheme

10) may be superior in some cases.

2′,3′-Did eoxyr ibon u cleosid es. In addition to being

an important class of antiviral agents,³⁴2′,3′-dideoxy-

nucleosides are an established class of anticancer nucleo-

sides, particularly for virally transmitted leukemias.³⁵

They are also key reagents used in the Sanger method

of DNA sequencing. Of particular interest is the incor-

poration of fluorescent tags on dideoxynucleosides so that

detection is spectrophotometric rather than requiring a

radioactive ³²P label. As such, there is still some interest

in efficient methods for the de novo synthesis of this class

of compounds. Approaches involving tin hydride reduc-

tion of 2′,3′-bis-xanthates produce the 2′,3′-olefin since

the radical that results from reduction of one xanthate

disproportionates to give the double bond.^1aSince R-ben-

zoyl radicals do not undergo disproportionation, each

benzoate is reduced independently to give the saturated

product directly.

Sch em e 10

With the example shown in Scheme 6, Saito demon-

strated that the PET deoxygenation is a viable route to

â-2′,3′-dideoxyribonucleosides.^10aWe have generalized

this approach for the synthesis of â-2′,3′-dideoxyribo-

nucleosides (Scheme 11). Glycosylation precursor 45 was

synthesized in three steps from ribose (Ar ) 3-(trifluo-

romethyl)benzoyl-). For entries a and b (Table 4), glyco-

sylation gave the â-ribonucleosides 46a and b as a single

regioisomer. In the case of per-silylated hypoxanthine

(entry c), we obtained an inseparable 1:1 mixture of N7-

and N9-regioisomers. To explore the deoxygenation of

46c, the desired N9 regioisomer was prepared by esteri-

fication of inosine with 3-(trifluoromethyl)benzoyl chlo-

deoxygenation of the N4-protected or unprotected cyti-

dine (entries d and e) gave no reaction. The corresponding

uridine and N7 and N9 guanosine derivatives of 37

undergo PET deoxygenation in 66-80% yield.

Stereocontrolled syntheses of 3′-deoxynucleosides have

been previously reported from the glycosylation of 41

(Scheme 10). In this work, 41 was prepared from com-

mercially available 1,2-O-isopropylidene-^D-xylose by se-

lective benzoylation of the C5-hydroxyl followed by

Barton deoxygenation of the C3-position to give 40.^31a,f,32b

(34) Herdewijn, P.; Balzarini, J .; De Clercq, E. In Advances in

Antiviral Drug Design; De Clercq, E., Ed.; J AI Press: Greenwich, 1993;

Vol. 1, pp 233-318.

(35) (a) Lin, T.-S.; Liu, M.-C. In Nucleosides and Nucleotides as

Antitumor and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum

Press: New York, 1993; 177-202. (b) Lin, T.-S.; Chen, M. S.; McLaren,

C.; Gao, Y.-S.; Ghazzouli, I.; Prusoff, W. H. J . Med. Chem. 1987, 30,

440.

5976 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

Ta ble 4. Syn th esis of â-2′,3′-Deoxyn u cleosid es. Yield s for

th e Gycosyla tion of 45 a n d Deoxygen a tion of 46 (Ar )

3-CF ₃C₆H₄-)

Sch em e 13

in 94% yield.³⁶PET deoxygenation of 49 was somewhat

improved over 46b or 48, giving the desired 2′,3′-

dideoxynucleoside 50, in 50% unoptimized yield along

with an inseparable mixture of 2′-deoxy- and 3′-deoxy-

nucleoside.

Syn th esis of Deoxycytid in es. Although we reported

that N⁴-protected cytidine 18e (R ) -CH(CH₃)₂) in the

â-series undergoes PET deoxygenation (Table 1), we have

subsequently found the deoxygenation of this and other

cytidine derivatives to be capricious and in some cases

not work at all, which is consistent with previous studies

by Benner.^13aIt is well established that uridine can be

converted into cytidines by conversion of the C4-carbonyl

to a thionocarbonyl (Lawesson’s reagents) or the 4-tria-

Sch em e 12

zolo group (triazole, POCl₃) followed by aminolysis.³⁷

A

general solution for the synthesis of cytidines via the PET

deoxygenation route was developed and is shown in

Scheme 13 for R-2′-deoxycytidine. Vorbru¨ggen glycosy-

lation was accomplished with silylated 4-methoxypyrimi-

done (51) and the intermediate R-arabinonucleoside 52a

was deoxygenation in good yield. Treatment of the

deoxynucleoside 53a with methanolic ammonia in a

sealed tube at 100 °C, deprotects the 3′- and 5′-esters as

well as displaces the C4-methoxy group to give R-2′-

deoxycytidine (54a ) in 68% yield.³⁸We successfully

extended this sequence to the â-2′-deoxy and â-3′-deoxy

series as well (Table 5).

We attempted to further extend this strategy to the

synthesis of the anticancer nucleoside 5-aza-2′-deoxycy-

tidine (58, Scheme 14).³⁹Glycosylation of 9 with silylated

4-methoxy-5-azapyrimidone⁴⁰(55) gave ribonucleoside 56

in 85% yield. Unfortunately, PET deoxygenation of 56

proceeded poorly, giving a number of unidentified prod-

ucts, from which 57 was isolated in less than 10% yield.

The PET deoxygenation substrate (56) was stable to the

irradiation conditions without DMECZ, however, when

the photosenstizer was added, it was quickly consumed.

A ribonucleoside similar to intermediate 57 with 2′,3′,5′-

acetyl groups has been previously converted to 5-aza-2′-

deoxycytidine (58) by displacement of a 4-methoxy group

with ammonia.^38b

ride in pyridine. The PET deoxygenation to the corre-

sponding â-2′,3′-dideoxyribonucleosides (47) proceeded in

good yield.

Since we have shown that 3,6-dimethyl-9-ethylcarba-

zole is capable of deoxygenating benzoates, we examined

the dideoxygenation of benzoyl-protected ribonucleoside

48 (Scheme 12). An advantage to this sequence is that

the glycosylation precursor, 1-acetyl-2,3,5-tribenzoylri-

bose (1), is commercially available and the de novo

synthesis of 2′,3′-dideoxynucleoside would require only

three steps from this starting material. The Vorbru¨ggen

glycosylation of 1 is well established.^1,4When the deoxy-

genation of 2′,3′,5′-tri-O-benzoyluridine (48) was at-

tempted with DMECZ (21) as the photosensitizer, we

found that the reaction could be stopped at the 2′-deoxy

stage (Scheme 12). Upon prolonged irradiation, the 2′,3′-

dideoxynucleoside was obtained, although the reaction

time was significantly longer than for 46a .

Su m m a r y. In summary, we have developed a unified

synthetic strategy for the synthesis of â-2′-deoxyribo-

(36) Gosselin, G.; Bergogne, M. C.; de Rudder, J .; De Clercq, E.;

Imbach, J . L. J . Med. Chem. 1986, 29, 203.

(37) (a) Kaneko, K.; Katayama, H.; Wakabayashi, T.; Kumonaka,

T. Synthesis 1988, 152. (b) Sung, W. L. J . Org. Chem. 1982, 47, 3623.

(38) (a) Acedo, M.; Fabrega, C.; Avino, A.; Goodman, M.; Fagan, P.;

Wemmer, D.; Eritja, R. Nucleic Acid. Res. 1994, 22, 2982. (b) Pikala,

A.; Sorm, F. Collect. Czech. Chem. Commun. 1964, 29, 2060.

(39) (a) Momparler, R. L. Pharmac. Ther. 1985, 30, 287. (b) Driscoll,

J . S.; J ohns, D. A.; Plowman, J . Invest. New Drugs 1985, 3, 331.

(40) Piskala, A.; Gut, J . Collect. Czech. Chem. Commun. 1963, 28,

1681.

Since the 3′-R-position seems to be inherently more

difficult to deoxygenate, we also examined the deoxygen-

ation of the corresponding xylonucleoside which possesses

the 3′-â-stereochemistry (Scheme 12). â-Xylonucleoside

49 was prepared via Vorbru¨ggen glycosylation of com-

mercially available 1,2,3,5-tetra-O-benzoylxylofuranose

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5977

Ta ble 5. Syn th esis of Deoxycytid in es (Ar )

3-CF ₃C₆H₄CO-)

strategy possible and this method of deoxygenation much

more useful. By studying the radical cation chemistry of

carbazoles, an intermediate in the PET deoxygenation

reaction, we were able to design new, more reactive

carbazole photosensitizers (DMECZ) that showed turn-

over and is typically used in 10 mol %.^10bThese improve-

ments will make the PET deoxygenation of benzoyl

derivatives more useful to synthetic chemists as an

alternative to the Barton and related deoxygenation

reactions.

Exp er im en ta l Section

All commercially obtained chemicals were used as received.

Acetonitrile and 2,6-lutidine were purchased from Aldrich in

Sure Seal bottles and used as received. Methylene chloride was

freshly distilled from calcium hydride. All reactions were

performed under an argon atmosphere. Melting points are

uncorrected. Proton and carbon-13 NMR data were recorded

at 300 and 75 MHz, respectively in CDCl₃unless otherwise

noted. Coupling constants are reported as absolute values in

Hz. Elemental analyses were performed by Atlantic Microlabs

(Norcross, GA). High resolution FAB mass spectra were

obtained from the University of Illinois or the University of

Notre Dame Mass Spectrometry Centers using either “magic

bullet” (MB) or nitrobenzyl alcohol (NBA) as the matrix.

9-Methylcarbazole (MCZ) was purchased from Aldrich and

recrystallized from ethanol; 3,6-dimethyl-9-ethylcarbazole was

prepared as previously described.⁴¹Silylated pyrimidine bases

were prepared and distilled as previously reported;⁴²purine

bases were silylated in situ.¹⁵

Sch em e 14

r-D-1,3,5-Tr i-O-ben zoyl-2-O-[3-(tr iflu or om eth yl)ben zoyl]-

r ibofu r a n ose (9). A stirred solution of 1,3,5-tri-O-benzoyl-R-

D-ribofuranose (8, 436 mg, 1.0 mmol) and 2,6-lutidine (0.14

mL, 1.2 mmol) in dry CH₂Cl₂(10 mL) was cooled to 0 °C, and

then 3-(trifluoromethyl)benzoyl chloride (0.23 mL, 1.5 mmol)

was added dropwise. The solution was stirred for 2.5 h at room

temperature and then quenched with saturated aqueous

bicarbonate, and the aqueous layer was extracted with ethyl

acetate. The combined organic layers were dried over anhy-

drous magnesium sulfate, filtered, and concentrated. The

residue was purified by flash chromatography eluting with

25% ethyl acetate in hexanes. The resulting solid was recrys-

tallized from ethyl acetate/hexane to give 615 mg (97%) of 9

as white prisms: mp 109-111 °C (lit.⁴³mp 102 °C); [R]²³

D

1

+89.5° (c 0.1, CHCl₃); H NMR (CDCl₃) δ 8.11-8.0 (m, 8H),

7.72 (d, J ) 4.3, 1H), 7.61-7.31 (m, 10H), 6.91 (d, J ) 4.3,

1H), 5.88 (dd, J ) 2.1, 6.5, 1H), 5.79 (dd, J ) 4.4, 6.5, 1H),

4.93 (m, 1H), 4.71 (ABX, J _AB) 12.1, J _AX) 3.5, J _BX) 3.1, ∆ν_AB

) 32.6, 2H); ¹³C NMR δ 166.0, 165.6, 165.1, 163.5, 133.7, 133.6,

133.4, 133.0, 130.0, 129.8, 129.7, 129.5, 129.3, 129.2, 128.9,

128.6, 128.5, 128.4, 126.4, 126.3, 94.9, 82.8, 71.5, 70.7, 64.0.

Anal. Calcd for C₃₄H₂₅F₃O₉: C, 64.36; H, 3. 97. Found: C,

64.36; H, 3.99.

nucleosides, R-2′-deoxyribonucleosides, â-3′-deoxyribo-

nucleosides, and â-2′,3′-dideoxy-nucleosides. The overall

strategy is shown in Scheme 15 and involved the prepa-

ration of strategically protected furanose tetra-ester

glycosylation precursors. The stereochemistry of the

Vorbru¨ggen glycosylation is directed by a C2-ester of the

glycosylation precursor. The key step in the sequences

is the selective deoxygenation of a benzoyl or 3-(trifluo-

romethyl)benzoyl group of the ribo-, arabino- or xylo-

nucleoside via a photoinduced electron-transfer (PET)

mechanism using carbazoles as the photosensitizer to

give the desired deoxynucleoside. In each case, the

glycosylation precursor is readily available and the

deoxynucleosides are obtained in three steps from a

common intermediate. While the developmental work

described here was typically performed on less than 0.1

mmol scale, we have recently showed that the sequence

can carried out to provide one gram of the protected

deoxygenated nucleoside using a 500 mL photochemical

immersion well.^8bThus, our work should make modified

deoxynucleosides available in gram quantities by an

operationally simple procedure. Of note, we have made

significant practical improvements of the PET deoxygen-

ation of benzoyl groups that made this unified synthetic

Gen er a l P r oced u r e for th e Glycosyla tion Rea ction .

3′,5′-Di-O-b en zoyl-2′-O-[3-(t r iflu or om et h yl)b en zoyl]u r i-

d in e (18a ). A stirred solution of 9 (1.0 g, 1.6 mmol) and 2,4-

42

bis-trimethylsilyluracil (10)

(0.577 g, 2.4 mmol) in dry

CH₃CN (16 mL) was cooled to 0 °C, and then SnCl₄(2.08 g,

8.0 mmol) was added dropwise with vigorous stirring. The

reaction was warmed to room temperature and stirred for 4

h, after which time the reaction was quenched with saturated

aqueous bicarbonate. The mixture was filtered through a pad

of Celite and extracted with ethyl acetate. The organic extracts

were washed with brine, dried over anhydrous sodium sulfate,

(41) (a) Park, M.; Buck, J . R.; Rizzo, C. J . Tetrahedron 1998, 54,

12707. (b) Buck, J . R.; Park, M.; Wang, Z.; Prudhomme, D. R.; Rizzo,

C. J . Org. Synth. 1999, 77, 153.

(42) (a) Nishimura, T.; Iwai, I. Chem. Pharm. Bull. 1964, 12, 352.

(b) Nishimura, T.; Shimizu, B.; Iwai, I. Chem. Pharm. Bull. 1964, 12,

1471.

(43) Koch, A.; Lamberth, C.; Wetterich, F.; Giese, B. J . Org. Chem.

1993, 58, 1083.

5978 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

Sch em e 15

and concentrated. The residue was purified by flash chroma-

tography on silica eluted with 25% ethyl acetate in hexanes

to afford 18a (932 mg, 95% yield) as a viscous oil which

crystallized on standing: mp 134-135 °C; [R]²³_D-55.5° (c 0.1,

7.90 (m, 3H), 7.80 (d, J ) 7.8, 1H), 7.64-7.37 (m, 8H), 7.47 (d,

J ) 7.5, 1H), 6.41 (d, J ) 4.2, 1H), 5.93-5.85 (m, 2H), 4.88-

4.70 (m, 3H), 2.65-2.55 (m, 1H), 1.22 (d, J ) 6.9, 6H); ¹³C

NMR δ 177.4, 166.0, 165.1, 163.8, 163.2, 154.9, 144.3, 133.7,

133.5, 133.0, 129.6, 129.5, 129.1, 128.6, 128.3. 97.4, 89.9, 80.4,

75.0, 70.9, 63.5, 36.4, 18.9; HRMS (FAB, MB) m/z for

1

CHCl₃); IR (thin film) 1726, 1697, 1453, 1264, 1216 cm^-1; H

NMR (CDCl₃) δ 9.27 (br s, 1H), 8.16-8.08 (m, 4H), 7.99 (d, J

) 7.6, 2H),7.79 (d, J ) 7.8, 1H), 7.63-7.39 (m, 8H), 6.30 (d, J

) 5.3, 1H), 5.90 (pseudo t, J _app) 5.8, 1H), 5.81 (t, J ) 5.7, 1H),

C

₃₅H₃₁F₃N₃O₉(M + H) 694.2012, found 694.2012.

Anal. Calcd for C₃₅H₃₁F₃N₃O₉: C, 60.61; H, 4.36; N, 6.09.

5.63 (d, J ) 8.0, 1H), 4.77 (ABX, J _AB) 12.0, J _AX) 2.6, J _BX

)

Found: C, 60.56; H, 4.39; N, 6.12.

3.7, ∆ν_AB) 49.9, 2H), 4.75 (m, 1H); ¹³C NMR δ 166.0, 165.3,

164.1, 162.8, 150.1, 139.5, 133.9, 133.7, 1334., 133.1, 133.0,

130.3, 129.8, 129.7, 129.3, 129.2, 129.1, 128.7, 128.6, 128.3,

103.4, 88.2, 80.4, 74.1, 71.1, 63.7; HRMS (FAB, MB) m/z calcd

for C₃₁H₂₄F₃N₂O₉(M + H) 615.1435, found 615.1435.

3′,5′-Di-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)ben zoyl]-â-

D-r ibofu r a n osylcya n u r ic Acid (18f). Obtained in 85% yield

as a white solid: mp 252.2-252.7 °C; [R]²³-23.2° (c 0.5_,

D

DMSO); IR (KBr) 1703, 1463, 1244 cm^-1; ¹H NMR (methanol-

d₄) δ 11.78 (s, 1H), 8.24 (d, J ) 7.9, 1H), 8.14 (s, 1H), 8.04 (d,

J ) 7.9, 1H), 8.0-7.95 (m, 2H), 7.80-7.72 (m, 3H), 7.66-7.56

(m, 2H), 7.47 (t, J ) 7.7, 2H), 7.34 (t, J ) 7.7, 2H), 6.44 (d, J

) 2.3, 1H), 6.15-6.03 (m, 2H), 4.75-4.48 (m, 3H); ¹³C NMR

(methanol-d₄) δ 165.8, 164.8, 163.9, 149.4, 148.6, 134.1, 133.8,

130.7, 130.2, 130.1, 129.8, 129.7, 129.6, 129.4, 129.0, 128.8,

128.7, 126.0, 126.0, 124.9 (1, J _C-F) 272), 85.8, 78.1, 74.5, 70.1,

63.6; HRMS (FAB, NBA) m/z calcd for C₃₀H₂₃F₃N₃O₁₀(M +

H) 642.1336, found 642.1342.

3′,5′-Di-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)ben zoyl]-5-

m eth ylu r id in e (18b). Obtained in 98% yield as a white

powder: mp 92-95 °C; [R]²³-78.0° (c 0.1, CHCl₃); ΙR (KBr)

D

1725, 1619, 1452, 1267 cm^-1

;

¹H NMR (CDCl₃) δ 8.78 (br s,

1H), 8.17-7.99 (m,4H), 7.93 (d, J ) 7.3, 2H), 7.63-7.33 (m,

8H), 6.33 (d, J ) 6.1, 1H), 5.84 (dd, J ) 3.8, 6.0, 1H), 5.75 (t,

J ) 6.1, 1H), 4.70 (ABX, J _AB) 12.3, J _AX) 2.6, J _BX) 3.5, ∆ν_AB

) 69.5, 2H), 4.65 (m, 1H), 1.54 (s, 3H); ¹³C NMR δ 166.2, 165.7,

164.4, 163.7, 150.6, 135.1, 134.0, 133.4, 130.6, 130.0, 129.9,

129.6, 129.4, 129.1, 128.9, 128.7, 127.0, 112.5, 87.3, 80.8, 74.0,

71.6, 64.2, 12.4; HRMS (FAB) m/z calcd for C₃₂H₂₆F₃N₂O₉(M

+ H) 639.1599, found 639.1598.

N⁶-Ben zoyl-3′,5′-d i-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)-

ben zoyl]a d en osin e (18g, R ) Bz). Obtained in 80% yield

as a pale yellow solid: mp 80-82 °C; [R]²³-74.6° (c 0.55,

D

CHCl₃); IR (thin film) 1726, 1585, 1270 cm^-1; ¹H NMR (CDCl₃)

δ 8.96 (s, 1H), 8.65 (s, 1H), 8.15-8.10 (m, 2H), 8.08 (d, J )

7.24, 4H), 8.01-7.97 (m, 4H), 7.78 (d, J ) 7.9, 1H), 7.61-7.35

(m, 9H), 6.49-6.43 (m, 2H), 6.22 (t, J ) 4.7, 1H), 4.91 (dd, J

) 3.3, 12.1, 1H), 4.86-4.82 (m, 1H), 4.68 (dd, J ) 4.0, 12.1,

1H), 1.61 (s, 3H); ¹³C NMR (CDCl₃) δ 166.1, 165.3, 164.4, 163.9,

153.0, 141.5, 133.9, 133.5, 133.1, 132.8, 130.3, 129.7, 129.3,

128.9, 128.7, 127.8, 126.7, 86.9, 81.0, 74.3, 71.5, 63.5; HRMS

(FAB, NBA) m/z calcd for C₃₉H₂₉F₃N₅O₈(M + H) 752.1968,

found 752.1981.

Anal. Calcd for C₃₂H₂₆F₃N₂O₉: C, 60.19; H, 3.95; N, 4.39.

Found: C, 60.13; H, 4.03; N, 4.26.

3′,5′-Di-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)ben zoyl]-5-

flu or ou r id in e (18c). Obtained in 91% yield as a white

powder: mp 187-188 °C; [R]²³-21.8° (c 0.1_,CH₃CN); IR

D

1

(KBr) 1726, 1675, 1452, 1267 cm^-1; H NMR (CD₃CN) δ 9.38

(br s, 1H), 8.16 (d, J ) 6.4, 2H), 8.05 (d, J ) 8.0, 2H), 7.91 (d,

J ) 8.0, 3H), 7.70-7.37 (m, 8H), 6.19 (d, J ) 4.5, 1H), 5.91-

5.82 (m, 2H), 4.79-4.61 (m, 3H); ¹³C NMR δ 166.9, 166.0,

164.8, 157.9, 157.6, 149.8, 143.4, 140.3, 134.7, 134.5, 134.2,

131.7, 131.2, 130.9, 130.7, 130.4, 129.9, 129.7, 129.6, 127.1,

126.0, 125.6, 89.7, 80.9, 75.2, 71.5, 64.5; HRMS (FAB, MB)

m/z for C₃₁H₂₃F₄N₂O₉(M + H) 643.1316, found 643.1316.

Anal. Calcd for C₃₁H₂₃F₄N₂O₉: C, 57.95; H 3.45, N, 4.36.

Found: C, 57.85; H, 3.54; N, 4.25.

3′,5′-Di-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)ben zoyl]a d -

en osin e (18h , R ) H). Obtained in 86% yield from 18g, as a

white powder: mp 80-81 °C; [R]²³-43.7° (c 2.7, CHCl₃); IR

D

(thin film) 1729, 1633, 1218 cm^-1; ¹H NMR (CDCl₃) δ 8.25 (s,

1H), 8.18 (s, 1H), 8.12-8.07 (m, 3H), 8.00 (d, J ) 7.4, 2H),

7.96 (s, 1H), 7.80 (d, J ) 7.9, 1H), 7.62-7.26 (m, 7H), 6.43 (m,

2H), 6.28-6.25 (m, 1H), 5.86 (s, 1H), 4.91 (dd, J ) 3.3, 11.9,

1H), 4.84 (m, 1H), 4.71 (dd, J ) 11.9, 4.0, 1H); ¹³C NMR

(CDCl₃) δ 164.7, 163.8, 162.5, 154.2, 152.0, 148.4, 137.6, 132.4,

132.0, 131.6, 130.1, 128.8, 128.3, 128.0, 127.9, 127.8, 127.7,

127.2, 127.1, 125.3, 125.2, 85.4, 79.3, 76.0, 72.9, 70.1, 62.2, 58.9,

28.3; HRMS (FAB, NBA) m/z calcd for C₃₂H₂₅F₃N₅O₇(M + H)

648.1706, found 648.1720.

3′,5′-Di-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)ben zoyl]-5-

tr iflu or om eth ylu r id in e (18d ). Obtained in 97% yield as a

white powder: mp 115-117 °C; [R]²³-76.0° (c 0.1, CHCl₃);

D

IR (KBr) 1727, 1461, 1336, 1267 cm^-1; ¹H NMR (CDCl₃) δ 9.75

(br s, 1H), 8.15-8.02 (m, 8H), 7.78 (d, J ) 7.8, 1H), 7.62-7.40

(m, 6H), 6.29 (d, J ) 5.5, 1H), 5.93-5.90 (m, 1H), 5.84 (t, J )

5.7, 1H), 4.82-4.71 (m, 3H); ¹³C NMR δ 170.9, 165.8, 165.1,

164.0, 158.2, 148.9, 140.6, 133.8, 133.5, 132.9, 129.5, 129.3,

128.4, 128.2, 88.6, 80.9, 74.2, 71.0, 63.4.

N²-Acetyl-N7-(3′,5′-d i-O-ben zoyl-2′-O-[(3-tr iflu or om eth -

yl)ben zoyl]-â-D-r ibofu r a n osyl)gu a n in e (18i). Obtained in

Anal. Calcd for C₃₂H₂₃F₆N₂O₉: C, 55.50; H, 3.20; N, 4.05.

Found: C, 55.27, H, 3.20, N, 3.97.

85% yield as a white solid: mp 117-125 °C; [R]²³+15.04° (c

D

0.25, CHCl₃); IR (thin film) 1715, 1363, 1266, 1223 cm^-1; H

1

3′,5′-Di-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)ben zoyl]-4-

isobu tyr oylcytosin e (18e, R ) -COCH(CH₃)₂). Obtained

in 91% yield as a white powder: mp 146-148 °C; [R]²³_D-36.4°

NMR (CDCl₃) δ 11.18 (s, 1H), 8.17-8.01 (m, 5H), 7.96 (d, J )

7.4, 2H), 7.75 (d, J ) 7.8, 1H), 7.60-7.36 (m, 8H), 6.61 (d, J )

5.0, 1H), 6.17 (t, J ) 5.6, 1H), 6.02 (t, J ) 5.6, 1H), 4.92-4.73

(m, 3H), 2.35 (s, 3H); ¹³C NMR (CDCl₃) 173.2, 166.1, 165.2,

163.8, 157.6, 152.7, 148.4, 141.9, 133.8, 133.5, 133.1, 132 (q,

(c 0.1_,CHCl₃); IR (KBr) 1728, 1692, 1627, 1494, 1266 cm^-1

;

¹H NMR (CDCl₃) δ 8.58 (br s, 1H), 8.18-8.07 (m, 4H), 7.97-

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5979

1

J _C-F) 33), 130.2, 129.7, 129.4, 129.3, 128.6, 128.4, 127.0,

126.7, 126.6, 125.2 (q, J _C-F) 272), 111.6, 89.0, 80.6, 75.6, 71.0,

63.6, 25.1, 24.5; HRMS (FAB, NBA) m/z calcd for C₃₄H₂₇F₃N₅O₉

(M + H) 706.1761, found 706.1746.

74 °C (lit.⁴⁵mp 57-9 °C); H NMR (CDCl₃) δ 8.98 (br s, 1H),

8.03 (d, J ) 7.1, 2H), 7.60 (t, J ) 7.4, 1H), 7.45 (t, J ) 7.5,

2H), 7.35 (s, 1H), 6.1 (dd, J ) 6.4, 4.2, 1H), 4.65 (dd, J ) 12.2,

2.8, 1H), 4.53 (dd, J ) 12.2, 4.6, 1H), 4.40-4.50 (m, 1H), 2.44-

2.51 (m, 1H), 1.76-2.21 (m, 3H), 1.70 (d, J ) 0.9, 3H); ¹³C

NMR δ 166.0, 163.8, 150.3, 135.1, 133.5, 133.4, 129.6, 128.7,

110.7, 86.1, 78.4, 65.3, 32.3, 26.0, 12.4.

N²-Acetyl-3′,5′-d i-O-ben zoyl-2′-O-[3-(tr iflu or om eth yl)-

ben zoyl]gu a n osin e (18j). Obtained in 72% yield as a white

powder: mp 130-132 °C; [R]²³_D-44.6° (c 1.42, CHCl₃); IR (thin

film) 1702, 1527, 1216 cm^-1; ¹H NMR (CDCl₃) δ 11.89 (s, 1H),

9.36 (s, 1H), 8.15 (s, 1H), 8.11 (d, J ) 7.7, 1H), 7.94-7.90 (m,

4H), 7.84 (d, J ) 7.4, 1H), 7.76 (s, 1H), 7.61-7.54 (m, 3H),

7.41-7.35 (m, 4H), 6.42 (t, J ) 5.4, 1H), 6.35 (t, J ) 4.6, 1H),

6.20 (d, J ) 3.6, 1H), 5.09 (dd, J ) 11.5, 5.1, 1H), 4.90-4.86

(m, 1H), 4.81 (dd, J ) 11.5, 5.0, 1H), 2.32 (s, 1H); ¹³C NMR

(CDCl₃) 173.4, 171.7, 166.9, 166.2, 165.5, 163.9, 155.3, 147.4,

147.2, 138.6, 133.9, 133.8, 133.1, 131.1, (q, J _C-F) 30) 130.4,

129.7, 129.6, 129.4, 129.3, 128.9, 128.6, 128.4, 126.5, 122.7,

(q, J _C-F) 270), 88.2, 80.0, 74.6, 71.4, 62.8, 29.7, 24.3; HRMS

(FAB, NBA) m/z calcd for C₃₄H₂₇F₃N₅O₉(M + H) 706.1761,

found 706.1762.

3′,5′-Di-O-ben zoyl-5-flu or o-2′-d eoxyu r id in e (19c). Ob-

tained in 53% yield. Recrystallized from chloroform: mp 246

°C dec (lit.⁴⁶mp >250 °C dec); H NMR (CDCl₃) δ 8.07-8.02

1

(m, 4H), 7.65-7.60 (m, 3H), 7.51-7.46 (m, 4H), 6.40-6.38 (m,

1H), 5.62 (d, J ) 6.6, 1H), 4.78-4.74 (m, 2H), 4.57 (d, J ) 2.6,

1H), 2.79-2.72 (m, 1H), 2.32-2.25 (m, 1H); ¹³C NMR (DMSO-

d₆) δ 165.5, 165.2, 157.0 (J _C-F) 104), 149.0, 140.2 (J _C-F

920), 133.7, 133.6, 129.4, 129.2, 128.8, 128.4, 124.8 (J _C-F

137) 85.0, 81.2, 74.5, 64.3, 35.9.

)

3′,5′-Di-O-b en zoyl-5-t r iflu or om et h yl-2′-d eoxyu r id in e

(19d ). Obtained in 44% yield (71% yield based on recovered

starting material). Recrystallized from ethyl acetate/hex-

anes: mp 152-155 °C; [R]²³-28.3° (c 0.1_,CHCl₃); IR (KBr)

D

Gen er a l P r oced u r e for th e P ET Deoxygen a tion Rea c-

t ion w it h N-Met h ylca r b a zole.^8a3′,5′-Di-O-b en zoyl-2′-

d eoxyu r id in e (19a ). A solution of 18a (20 mg, 0.03 mmol),

9-methylcarbazole (20, 6 mg, 0.03 mmol), and magnesium

perchlorate hexahydrate (10 mg, 0.03 mmol) in 9:1 2-pro-

panol-water (21 mL) was degassed with argon. The reaction

mixture was irradiated in a water-jacketed Pyrex reaction

vessel (UV cutoff is ∼280 nm) with a Hanovia 450 W medium-

pressure mercury lamp for 10-15 h under an argon atmo-

sphere at 25 °C. The temperature was maintained by a

circulating temperature bath. After the reaction was complete,

the reaction mixture was diluted with saturated aqueous

bicarbonate and extracted with ethyl acetate. The combined

organic layers were washed with brine, dried over anhydrous

sodium sulfate and concentrated. The residue was purified by

preparative TLC to afford 18a (9.8 mg, 70% yield). Recrystal-

lized from ethyl acetate/hexanes: mp 221-223 °C (lit.⁴⁴mp

1723, 1465, 1269 cm^-1; H NMR (CDCl₃) δ 8.68 (br s, 1H), 8.12-

7.97 (m, 5H), 7.66-7.58 (m, 2H), 7.51-7.43 (m, 4H), 6.33 (dd,

J ) 5.5, 8.5, 1H), 5.64 (d, J ) 6.4, 1^H), 4.77-4.75 (m, 2H), 4.64

(d, J ) 2.25, 1H), 2.90 (dd, J ) 5.5, 14.2, 1H), 2.36-2.26 (m,

1H); 13C NMR δ 171.2, 166.0, 165.9, 158.6, 149.1, 140.1, 140.0,

133.8, 133.7, 130.2, 129.8, 128.9, 128.8, 86.6, 83.8, 74.9, 64.1,

39.0; HRMS (FAB, MB) m/z calcd for C₂₄H₂₀F₃N₂O₇(M + H)

505.1222, found 505.1223.

3′,5′-Di-O-ben zoyl-4-isobu tyr oyl-2′-d eoxycytid in e (19e,

R ) -COCH(CH₃)₂). Obtained in 62% yield. Recrystallized

from ethyl acetate/hexanes: mp 182-183 °C; [R]²³-24.0° (c

D

0.1_,CHCl₃); IR (KBr) 1722, 1668, 1626, 1493, 1316, 1271 cm^-1

;

¹H NMR (CDCl₃) δ 8.62 (br s, 1H), 8.17-7.97 (m, 5H), 7.64-

7.32 (m, 7H), 6.38 (dd, J ) 5.7, 7.8, 1H), 5.62 (d, J ) 6.36,

1H), 4.76-4.65 (m, 3H), 3.12-3.05 (m, 1H), 2.62-2.57 (m, 1H),

2.32-2.22 (m, 1H), 1.23 (d, J ) 6.8, 6H); ¹³C NMR δ 176.9,

166.0, 165.9, 162.5, 154.9, 143.3, 133.6, 133.5, 129.7, 129.4,

128.6, 128.5, 96.6, 87.4, 83.4, 75.0, 64.1, 39.3, 36.6, 19.0, 18.9;

HRMS (FAB, MB) m/z calcd for C₂₇H₂₈N₃O₇(M + H) 506.1927,

found 506.1925.

1

225-6 °C); H NMR(CDCl₃) δ 8.30 (br s, 1H), 8.04-8.00 (m,

4H), 7.63-7.58 (m, 2H), 7.52-7.44 (m, 5H), 6.39 (dd, J ) 5.6,

8.3, 1H), 5.63-5.56 (m, 2H), 4.73-4.66 (m, 2H), 4.56-4.54 (m,

1H), 2.78-2.72 (m, 1H), 2.36-2.27 (m, 1H); ¹³C NMR δ 166.0,

162.3, 150.0, 138.8, 133.8, 129.8, 129.5, 128.8, 128.2, 102.9,

85.4, 82.9, 74.8, 64.2, 38.3.

3,5-Di-O-ben zoyl-2-d eoxy-â-^D-er yth r o-p en tofu r a n osyl-

cya n u r ic Acid (19f). Obtained in 75% yield as a white solid:

mp ) 171.2-172.0 °C; [R]²³-14.0° (c 1.17, MeOH); IR (KBr)

D

1721, 1450, 1275 cm^-1

;

¹H NMR (methanol-d₄) δ 8.02-7.98

Gen er a l P r oced u r e for th e P ET Deoxygen a tion Rea c-

tion w ith 3,6-Dim eth yl-9-Eth ylca r ba zole. 3′,5′-Di-O-ben -

zoylth ym id in e (19b).^8b,10bA solution of 18b (1.0, 1.57 mmol),

3,6-dimethyl-9-ethylcarbazole (21, 35 mg, 0.28 mmol), and

magnesium perchlorate (130 mg, 0.39 mmol) in 2-propanol

(m, 4H), 7.60-7.35 (m, 6H), 6.65 (m, 1H), 5.87-5.80 (m, 1H),

4.68-4.61 (m, 2H), 3.23-3.14 (m, 1H), 2.55-2.45 (m, 1H); ¹³

C

NMR (methanol-d₄) δ 168.2, 167.8, 151.2, 134.9, 134.7, 131.5,

131.3, 131.1, 131.0, 130.0, 129.8, 84.3, 83.5, 77.0, 66.3, 36.6.

3′,5′-Di-O-ben zoyl-2′-d eoxya d en osin e (19h , R ) H).

Obtained in 55% yield as a pale yellow foam: mp 105-107 °C

(lit.⁴⁷140-141 °C); [R]²³_D-23.5° (c 0.65, CHCl₃); IR (KBr) 1710,

(270 mL) and water (30 mL) was placed in

a 500 mL

photochemical immersion well and degassed with an argon for

20 min (sonication may be necessary to fully dissolve 21). The

solution was placed in a water jacketed, Pyrex reaction vessel

(UV cutoff is ∼280 nm) and degassed for an additional 10 min

with argon. The reaction was photolyzed with a Hanovia 450W

medium-pressure mercury lamp under an argon atmosphere;

the reaction temperature was maintained below 23 °C with

an ice bath. After 1.5 h the reaction was judged complete by

TLC analysis and neutralized with saturated sodium bicar-

bonate. The reaction mixture was transferred to a round-

bottomed flask and concentrated with a rotary evaporated. The

residue was taken up in ethyl acetate and washed with brine.

Purification by flash chromatography on silica, eluting with

25% ethyl acetate in hexanes gave 19b (367 mg, 52% yield)

1

1690, 1600, 1290 cm^-1; H NMR (CDCl₃) δ 8.32 (s, 1H), 8.08

(d, J ) 7.4, 2H), 8.03-7.98 (m, 3H), 7.65-7.40 (m, 6H), 6.54

(dd J ) 5.8, 8.2, 1H), 5.85-5.82 (m, 3H), 4.81-4.63 (m, 3H),

3.21-3.12 (m, 1H), 2.87-2.80 (m, 1H); ¹³C NMR (CDCl₃) δ

166.1, 165.9, 155.4, 153.1, 138.7, 133.7, 133.4, 129.8, 129.6,

129.4, 129.1, 128.6, 84.8, 82.8, 75.3, 64.2, 37.7, 29.7; HRMS

(FAB, NBA) m/z calcd for C₂₄H₂₁N₅O₅(M⁺) 459.1543, found

459.1525.

N²-Acet yl-N7-(3,5-d i-O-b en zoyl-2-d eoxy-â-D-er yth r o-

p en tofu r a n osyl)gu a n in e (19i). Obtained in 75% yield as a

pale yellow syrup which solidified upon standing: mp 79-81

°C; [R]²³_D-6.5° (c 2.6, CHCl₃); IR (thin film) 1720, 1460, 1216,

1253 cm^-1; ¹H NMR (CDCl₃) δ 12.31 (s, 1H), 10.61 (s, 1H), 8.14

(s, 1H), 8.07 (d, J ) 7.2, 2H), 7.98 (d, J ) 7.1, 2H), 7.65-7.37

(m, 6H), 6.73 (t, J ) 7.5, 1H), 5.72-5.69 (m 1H), 4.81-4.63

(m, 1H), 3.04-2.96 (m, 1H), 2.83-2.73 (m, 1H), 2.37 (s, 3H);

¹³C NMR (CDCl₃) δ 172.8, 166.1, 165.9, 157.5, 152.8, 147.9,

1

as a white powder [mp 193-195 °C (lit.⁴⁴mp 194-5 °C); H

NMR (CDCl₃) δ 8.50 (br s, 1H), 8.09-8.03 (m, 4H), 7.65-7.60

(m, 2H), 7.51-7.46 (m, 5H), 6.47 (dd, J ) 5.6, 8.7, 1H), 5.66

(d, J ) 4.5, 1H), 4.75 (ABX, J

) 12.3, J _AX)3.0, J _BX) 2.9,

AB

∆ν_AB) 36.7, 2H), 4.54 (d, J ) 2.0 H, 1H), 2.73-2.67 (m, 1H),

2.37-2.35 (m, 1H), 1.62 (s, 3H); ¹³C NMR δ 166.0, 163.2, 150.1,

134.4, 133.7, 129.8, 129.5, 129.3, 129.0, 128.8, 128.6, 111.7,

84.9, 82.7, 75.0, 64.3, 38.0, 12.7] and 5′-O-ben zoyl-3′-d eoxy-

th ym id in e (22, 62 mg, 12% yield) as a white powder: mp 71-

(45) Palomino, E.; Meltsner, B. R.; Kessel, D.; Horwitz, J . P. J . Med.

Chem. 1990, 33, 258.

(46) Holy, A.; Cech, D. Collect. Czech. Chem. Commun. 1974, 39,

3157.

(47) Stawinski, J .; Hozumi, T.; Narang, S. A. J . Chem. Soc. Chem.

Commun. 1976, 243.

(44) Holy, A.; Soucek, M. Tetrahedron Lett. 1971, 185.

5980 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

140.7, 133.7, 133.4, 129.8, 129.6, 129.1, 128.6, 87.3, 83.3, 74.8,

64.2, 49.8, 40.3, 24.6; HRMS (FAB, NBA) calcd for C₂₆H₂₄N₅O₇

(M + H) 518.1676, found 518.1699.

removed by suction filtration. The filtrate was evaporated and

the residue purified by a flash chromatography on silica eluted

with 10% ethyl acetate in hexanes. The resulting syrup was

recrystallized from ethyl acetate/hexanes (1:10) to give 30 (19

g, 30%) as colorless needles: mp 92-94 °C (lit.^25bmp 92-93

N²-acetyl-3′,5′-di-O-ben zoyl-2′-deoxygu an osin e (19j). Ob-

tained in 70% yield as a white powder: mp 96-98 °C; [R]²³

D

-45.2° (c 1.55, CHCl₃); IR (KBr) 1683, 1613, 1270 cm^-1

;

¹H

°C); [R]²³+46.3° (c 0.86, CHCl₃); IR (thin film) 1721, 1601,

D

NMR (CDCl₃) δ 9.65 (s, 1H), 8.05-7.98 (m, 4H), 7.76 (s, 1H),

7.64-7.55 (m, 2H), 7.50-7.26 (m, 4H), 6.30 (t, J ) 7.0, 1H),

5.83-5.81 (m, 1H), 5.21-5.14 (m, 1H), 4.75-4.67 (m, 2H),

3.21-3.12 (m, 1H), 2.72-2.65 (m, 1H), 2.36 (s, 1H); ¹³C NMR

(CDCl₃) δ 175.1, 172.0, 167.4, 165.8, 155.3, 147.3, 138.3, 133.7,

129.7, 129.2, 128.7, 122.8, 86.2, 82.5, 75.3, 63.9, 36.9, 24.3;

HRMS (FAB, NBA) calcd for C₂₆H₂₄N₅O₇(M + H) 518.1676,

found 518.1685.

1452, 1273 cm^-1; ¹H NMR(CDCl₃) δ 8.04-8.00 (m, 4H), 7.63-

7.57 (m, 1H), 7.55-7.49 (m, 1H), 7.47-7.42 (m, 2H), 7.37-

7.32 (m, 2H), 5.20 (s, 1H), 5.12 (d, J ) 2.2, 1H), 4.64 (dd, J )

11.9, 3.8,1H), 4.52 (dd, J ) 11.9, 5.4, 1H), 4.46-4.41 (m, 1H),

4.26-4.21 (m, 1H), 3.48 (s, 3H), 3.28 (d, J ) 5.6, 1H); ¹³C NMR

δ 166.6, 166.3, 133.7, 133.1, 129.8, 129.7, 129.0, 128.6, 128.3,

106.5, 85.5, 81.9, 77.3, 63.8, 55.1. Anal. Calcd for C₂₀H₂₀O₇:

C, 64.51; H, 5.41. Found: C, 64.26; H, 5.53.

N 9-[3′,5′-O-(1,1,3,3-t e t r a k is(isop r o p y l)-1,3-d isilox -

a n ed iyl)-2′-O-(3-t r iflu or om et h yl)b en zoyl-â-^D-r ib osyl]-6-

ch lor op u r in e (28a ). To a stirred solution of 6-chloropurine

ribonucleoside (57 mg, 0.2 mmol) and pyridine (1 mL) was

added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (69 mg, 0.22

mmol). The reaction was stirred at room temperature for 12

h, then quenched with saturated sodium bicarbonate. The

aqueous was extracted with ethyl acetates, and the organic

extracts were dried over magnesium sulfate, filtered, and

evaporated to give red syrup. The residue was taken up in

methylene chloride (5 mL), cooled to 0 °C then 2,6-lutidine (33

µL, 0.28 mmol) and 3-(trifluoromethyl)benzoyl chloride (29 µL,

0.21 mmol) were added successively. The reaction mixture was

allowed to warm to room temperature and stirred for 12 h after

which time it was quenched with saturated sodium bicarbon-

ate, and the aqueous was extracted with ethyl acetate. The

organic extracts were dried over magnesium sulfate, filtered

and evaporated. Purification by flash chromatography on silica

1,3-Di-O-acetyl-2,5-di-O-ben zoyl-^D-ar abin ofu r an ose (33).

To a solution of 32 (1.0 g, 2.7 mmol) and 2,6-lutidine (0.63 mL,

5.4 mmol) in dry methylene chloride (25 mL) at 0 °C was added

acetyl chloride (0.24 mL, 3.4 mmol) dropwise over 5 min. The

reaction mixture was stirred for 6 h at 25 °C and then diluted

with CH₂Cl₂and washed with brine, 10% HCl, saturated

bicarbonate, and brine. The organic layer was dried over Na₂-

SO₄, filtered, and evaporated to give 1.15 g of colorless oil,

which was dissolved in a solution of acetic anhydride (2.7 mL)

and acetic acid (13.5 mL). The solution was cooled to 0 °C then

sulfuric acid (0.78 mL) was added dropwise. The reaction

mixture was stirred at 5-10 °C for 12 h and then poured into

ice-water and extracted with chloroform. The combined

organic layers were washed with saturated bicarbonate until

then pH was 8 (pH paper) and then washed with brine, dried

over Na₂SO₄and evaporated to give 33 (1.17 g, 99% yield) as

a mixture of two anomers which could be used in the next step

without further purification. The two anomers can be sepa-

rated by flash chromatography on silica, eluted with 5% ethyl

acetate in hexanes. 1,3-Di-O-acetyl-2,5-O-dibenzoyl-R-^D-ara-

gave 28a (99 mg, 75% yield) as clear syrup: [R]²³-27.3° (c

D

2.0, CHCl₃);¹H NMR (CDCl₃) δ 8.74 (s, 1H), 8.37 (s, 1H), 8.35

(s, 1H), 8.28 (d, J ) 7.8, 1H), 7.88 (d, J ) 7.8, 1H), 7.64 (t, J

) 7.8, 1H),), 6.26 (s, 1H), 6.02 (d, J ) 5.6, 1H), 5.20-5.16 (m,

1H), 4.26-4.20 (m, 1H), 4.10 dd, J ) 13.3, 3.1, 1H), 1.13-

0.90 (m, 28 H); ¹³C NMR (CDCl₃) δ 164.4, 152.6, 144.2, 133.4,

130.6, 130.4, 129.7, 129.5, 127.1, 88.3, 82.9, 69.9, 60.7, 17.8,

17.7, 17.6, 17.5, 17.3, 17.2, 17.1, 13.8, 13.3, 13.2, 13.0; HRMS

(FAB, NBA) calcd for C₃₀H₄₁ClF₃N₄O₆Si₂(M + H) 701.2205,

found 701.2206.

binofuranose was obtained as a colorless oil: [R]²³+14.4 ° (c

D

4.25, CHCl₃); IR (thin film) 1726, 1452, 1370, 1275 cm^-1; H

1

NMR(CDCl₃) δ 8.01-7.96 (m, 4H), 7.59-7.46 (m, 2H), 7.38 (t,

J ) 7.7, 2H), 7.27 (t, J ) 7.7, 2H), 6.39 (s, 1H), 5.47 (s, 1H),

5.37 (d, J ) 3.8, 1H), 4.72-4.54 (m, 3H), 2.14 (s, 3H), 2.13 (s,

3H); ¹³C NMR δ170.0, 169.2, 166.1, 165.2, 133.7, 133.1, 129.9,

129.7, 129.6, 128.7, 128.6, 128.3, 99.4, 82.8, 81.5, 77.1, 63.4,

21.0, 20.7. 1,3-Di-O-acetyl-2,5-O-dibenzoyl-â-^D-arabinofuranose

N 9-[3′,5′-O-(1,1,3,3-t e t r a k is(isop r o p y l)-1,3-d isilox -

a n ed iyl)-2′-O-(3-tr iflu or om eth yl)ben zoyl-â-^D-r ibosyl]-p u -

was obtained as a colorless oil; [R]²³-36° (c 1.25, CHCl₃); IR

D

(thin film) 1751, 1725, 1602, 1452, 1371, 1315, 1271 cm^-1; ¹H

NMR(CDCl₃) δ 8.11-8.02 (m, 4H), 7.61-7.54 (m, 2H), 7.49-

7.41 (m, 4H), 6.57 (d, J ) 4.7, 1H), 5.74 (dd, J ) 6.8, 5.7, 1H),

5.60 (dd, J ) 6.8, 4.7, 1H), 4.69 (dd, J ) 11.9, 4.2H, 1H), 4.56

(dd, J ) 11.9, 6.1, 1H), 4.45-4.41 (m, 1H), 2.11 (s, 3H), 1.92

(s, 3H); ¹³C NMR δ170.2, 169.2, 166.0, 165.4, 133.7, 133.2,

129.9, 129.8, 129.7, 128.7, 128.6, 128.4, 93.7, 79.7, 76.0, 74.8,

64.6, 20.9, 20.7.

r in e (28b). Obtained as a pale yellow syrup: [R]²³-14.6° (c

D

0.33, CHCl₃); ¹H NMR (CDCl₃) δ 9.12 (s, 1H), 8.90 (s, 1H),

8.28-8.15 (m,3H), 7.81 (d, J ) 7.8, 1H), 7.57 (t, J ) 7.8, 1H),

6.20 (s, 1H), 6.01 (d, J ) 5.0, 1H), 5.22-5.17 (m, 1H), 4.19-

4.12 (m, 2H), 4.04 (dd, J ) 13.2, 3.0, 1H), 1.06-0.70 (m, 28

H); ¹³C NMR (CDCl₃) δ 164.5, 153.2, 149.5, 144.4, 133.4, 130.7,

130.4, 129.7, 127.1, 87.9, 82.8, 69.6, 60.9, 17.8, 17.7, 17.6, 17.3,

17.3, 17.1, 13.7, 13.4, 13.2, 13.0; HRMS (FAB, NBA) calcd for

N1-(3-O-Acetyl-2,5-d i-O-ben zoyl-r-^D-a r a bin ofu r a n osy-

l)u r a cil (34a ). Obtained in 94% yield as a white powder: mp

C

₃₀H₄₂F₃N₄O₆Si₂(M + H) 667.2595, found 667.2578.

1-[3-(Tr iflu or om eth yl)ben zoyl]-2,3,5-tr iben zoyl-â-^D-r i-

96-98 °C; [R]²³+24.6° (c 0.57, CHCl₃); IR (KBr) 1724, 1693,

D

bofu r a n ose (29). Obtained as a syrup: [R]²³+8.7°(c 0.76,

D

1453, 1266, 1110 cm^-1; ¹H NMR (CDCl₃) δ 8.60 (br s, 1H), 8.07

(d, J ) 7.2, 2H), 8.01 (d, J ) 7.2, 2H), 7.63-7.53 (m, 2H), 7.47-

7.37 (m, 5H), 6.15 (d, J ) 3.3,1H), 5.80 (dd, J ) 8.1, 2.1, 1H),

5.77 (t, J ) 3.3,1H), 5.52 (t, J ) 3.3, 1H), 4.83-4.78 (m, 1H),

4.69-4.56 (m, 2H), 2.13 (s, 3H); ¹³C NMR δ 169.7, 166.1, 165.3,

162.9, 150.0, 140.2, 134.0, 133.4, 130.0, 129.8, 129.3, 128.7,

128.5, 128.3, 102.8, 91.4, 83.4, 80.5, 76.8, 63.7, 20.7.

CHCl₃); ¹H NMR (CDCl₃) δ 8.29 (s, 1H), 8.14 (d, J ) 7.9, 1H),

8.03 (d, J ) 7.9, 2H), 7.93 (m, 4H), 7.83 (d, J ) 7.8, 1H), 7.62-

7.41(m, 6H), 7.38 (t, J ) 7.8, 2H), 7.23 (t, J ) 7.8, 2H), 6.68 (s,

1H), 6.00 (m, 2H), 4.89 (m, 1H), 4.82 (dd, J ) 12.1, 3.9, 1H),

4.57 (dd, J ) 12.1, 4,4, 1H); ¹³C NMR δ 165.9, 165.4, 165.0,

163.6, 133.7, 133.6, 133.1, 132.9, 131.3(q, J _C-F) 33), 130.0,

129.8, 129.7, 129.5, 129.3, 129.2, 129.0, 128.7, 128.6, 128.5,

128.4, 128.2, 126.9, 123.4(q, J _C-F) 273), 99.6, 80.3, 75.0, 71.3,

63.5; HRMS (FAB, NBA) m/z calcd for C₃₄H₂₅F₃O₉Na (M+ Na)

657.1348, found 657.1342.

Anal. Calcd for C₂₅H₂₂N₂O₉: C, 60.73; H, 4.48; N, 5.67.

Found: C, 60.49; H, 4.53; N, 5.53.

N1-(3-O-Acetyl-2,5-di-O-ben zoyl-r-^D-ar abin ofu r an osyl)-

5-m eth ylu r a cil (34b). Obtained in 97% yield. Recrystallized

from CH₂Cl₂/pentane to give white prisms: mp 110-112 °C;

[R]²³_D+48.6° (c 0.35, CHCl₃); IR (KBr) 1724, 1693, 1452, 1268

cm^-1; ¹H NMR (CDCl₃) δ 8.52 (br s, 1H), 8.08 (d, J ) 7.2, 2H),

7.99 (d, J ) 7.2, 2H), 7.63-7.53 (m, 2H), 7.47-7.38 (m, 4H),

7.20 (d, J ) 1.5, 1H), 6.18 (d, J ) 3.6, 1H), 5.77 (t, J ) 3.6,

1H), 5.54 (t, J ) 3.6, 1H), 4.82-4.77 (m, 1H), 4.68-4.56 (m,

2H), 2.14 (s, 3H), 1.96 (d, J ) 1.5, 3H); ¹³C NMR δ 169.7, 166.1,

165.4, 163.3, 150.0, 135.9, 133.9, 133.4, 130.0, 129.8, 129.4,

128.7, 128.5, 128.3, 111.4, 90.8, 82.8, 80.3, 63.8, 20.7, 12.6.

Meth yl 2,5-Di-O-ben zoyl-^D-a r a bin ofu r a n osid e (32). To

a solution of methyl 2,3,5-tribenzoylarabinofuranoside²⁵(31,

80 g, 0.168 mol) in dry pyridine (800 mL) was added hydrazine

monohydrate (16.8 g, 0.336 mol) at 0 °C. The reaction mixture

was stirred at room temperature for 12 h and then quenched

by the additional of acetone and the mixture stirred for an

additional 2 h. The solvents were evaporated under reduced

pressure while keeping the temperature below 40 °C. The

residue was dissolved hot ethyl acetate/hexanes (1:4, 500 mL);

after cooling to room temperature the precipitates were

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5981

Anal. Calcd for C₂₆H₂₄N₂O₉: C, 61.41; H, 4.76; N, 5.51.

Found: C, 61.14; H, 4.84; N, 5.37.

N²-Acetyl-N9-(3-O-a cetyl-2,5-d i-O-ben zoyl-r-D-a r a bin o-

fu r a n osyl)gu a n in e (34h ). Obtained in 53% yield as a white

powder: mp 127-129 °C; [R]²³+37.4° (c 0.54, CHCl₃); IR

N⁴-Acetyl-N1-(3-O-a cetyl-2,5-d i-O-ben zoyl-r-D-a r a bin o-

fu r a n osyl)cytosin e (34c). Obtained in 95% yield as a white

D

(KBr) 1723, 1681, 1612, 1560, 1269 cm^-1; H NMR (CDCl₃) δ

1

powder: mp 170-171 °C; [R]²³-18.7° (c 0.76, CHCl₃); ¹H

12.1 (br s, 1H), 9.5 (br s, 1H), 8.04-7.96 (m, 4H), 7.98 (s, 1H),

7.62-7.51 (m, 2H), 7.44-7.34 (m, 4H), 6.24 (d, J ) 2.1, 1H),

6.08 (t, J ) 2.2, 1H), 5.54 (dd, J ) 2.5, 3.8,1H), 4.88-4.83 (m,

1H), 4.66-4.65 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H); ¹³C NMR δ

172.1, 169.7, 166.2, 165.2, 155.4, 147.9, 147.7, 137.0, 134.1,

133.4, 129.9, 129.8, 129.3, 128.7, 128.5, 128.2, 121.3, 88.5, 83.2,

80.3, 77.0, 63.4, 24.4, 20.7; HRMS (FAB, MB) m/z calcd for

D

NMR(CDCl₃) δ 9.12 (br s, 1H), 8.08-8.02 (m, 4H), 7.80 (d, J

) 7.2, 1H). 7.63-7.53 (m, 2H), 7.50-7.37 (m, 5H), 6.20 (d, J

) 2.0, 1H), 5.82 (t, J ) 2.0, 1H), 5.44 (t, J ) 2.5, 1H), 4.93-

4.88 (m, 1H), 4.67 (dd, J ) 11.8, 6.3, 1H), 4.58 (dd, J ) 11.8,

5.0, 1H), 2.25 (s, 3H), 2.07 (s, 3H); ¹³C NMR δ 171.0, 169.5,

166.1, 164.9, 163.3, 155.0, 144.4, 133.9, 133.4, 130.0, 129.8,

129.4, 128.7, 128.5, 96.6, 93.0, 84.9, 80.4, 80.3, 63.6, 25.0, 20.7;

C

₂₈H₂₆N₅O₉(M + H) 576.1731, found 576.1733.

N1-(3-O-Acetyl-5-O-ben zoyl-2-d eoxy-r-^D-er yth r o-p en to-

HRMS (FAB, NBA) m/z calcd for

536.1669, found 536.1691.

C₂₇H₂₆N₃O₉(M + H)

fu r a n osyl)u r id in e (35a ). Obtained in 69% yield as a white

powder: mp 168-170 °C; [R]²³_D-38.4° (c 0.5, CHCl₃); IR (thin

N1-(3-O-Acetyl-2,5-di-O-ben zoyl-r-^D-ar abin ofu r an osyl)-

cytosin e (34d ). Obtained in 93% yield as a white powder: mp

114-117 °C; [R]²³_D+17.8° (c 0.93, CHCl₃); IR (thin film) 1726,

1644, 1489, 1271 cm^-1; ¹H NMR(CDCl₃) δ 8.20 (br s, 1H), 8.07-

8.00 (m, 4H), 7.59-7.51 (m, 2H), 7.45-7.36 (m, 5H), 6.43 (br

s, 1H), 6.11 (d, J ) 2.1,1H), 5.90 (d, J ) 7.5, 1H), 5.82 (t, J )

2.1,1H), 5.40 (t, J ) 2.6, 1H), 4.85-4.80 (m, 1H), 4.66-4.54

(m, 2H), 2.06 (s, 3H); ¹³C NMR δ 169.7, 166.1, 166.0, 165.1,

155.5, 140.9, 133.8, 133.3, 130.0, 129.8, 129.4, 128.6, 128.5,

95.1, 92.5, 84.1, 80.5, 76.8, 63.8, 20.7;

film) 1719, 1701, 1688, 1460, 1377, 1269 cm^-^{1 1}H NMR

;

(CDCl₃) δ 9.41 (br s, 1H), 8.00 (d, J ) 7.3, 2H), 7.57 (t, J )

7.3, 1H), 7.48-7.43 (m, 3H), 6.24 (dd, J ) 6.9, 1.6, 1H), 5.74

(d, J ) 8.1, 1H), 5.33 (d, J ) 6.3, 1H), 4.70 (t, J ) 4.3,1H),

4.49-4.40 (m, 2H), 2.83 (dt, J ) 15.4, 6.7, 1H), 2.30 (br d, J )

15.4, 1H), 2.03 (s, 3H); ¹³C NMR δ 170.0, 166.1, 163.6, 150.3,

139.4, 133.6, 129.7, 129.2, 128.7, 101.6, 87.6, 85.1, 74.3, 64.0,

38.7, 20.9; HRMS (FAB, MB) m/z calcd for C₁₈H₁₉N₂O₇(M +

H) 375.1192, found 375.1194.

N1-(3-O-Acetyl-5-O-ben zoyl-2-d eoxy-r-^D-er yth r o-p en to-

Anal. Calcd for C₂₅H₂₃N₃O₈: C, 60.85; H, 4.70; N, 8.52.

Found: C, 60.56 H, 4.81; N, 8.31.

fu r a n osyl)th ym in e (35b). Obtained in 73% yield as a white

powder: mp 60-62 °C; [R]²³-18 °(c 0.75, CHCl₃); IR (thin

D

N⁶-Ben zoyl-N9-(3-O-a cet yl-2,5-d i-O-b en zoyl-r-D-a r a -

bin ofu r a n osyl)a d en in e (34e, R ) Bz). Obtained in 87%

film) 1721, 1702, 1476, 1451, 1379, 1272 cm^-1; ¹H NMR δ 8.74

(br s, 1H), 8.01 (d, J ) 7.3, 2H), 7.65-7.57 (m, 1H), 7.47 (t, J

) 7.7, 2H), 7.33 (d, J ) 0.9, 1H), 6.32 (dd, J ) 7.2, 2.3, 1H),

5.35 (d, J ) 6.4, 1H), 4.73 (t, J ) 4.1, 1H), 4.52-4.40 (m, 2H),

2.87 (dt, J ) 15.4, 7.0, 1H), 2.30 (br d, J ) 15.4, 1H), 2.05 (s,

3H), 1.96 (d, J ) 0.9, 3H). ¹³C NMR δ 169.9, 166.1, 164.0, 150.3,

135.3, 133.5, 129.7, 129.3, 128.7, 110.3, 86.9, 84.6, 74.4, 64.1,

38.5, 20.9, 12.7; HRMS (FAB, MB) m/z calcd for C₁₉H₂₁N₂O₇

(M + H) 389.1349, found 389.1349.

yield as a white powder: mp 83-85 °C; [R]²³+55° (c, 2.25,

D

CHCl₃); IR (thin film) 1725, 1609, 1583, 1510, 1488, 1452, 1273

1

cm^-1; H NMR(CDCl₃) δ 9.30 (br s, 1H), 8.77 (s, 1H), 8.26 (s,

1H), 8.07-7.98 (m, 6H), 7.61-7.29 (m, 9H), 6.51 (d, J ) 2.7,

1H), 6.29 (t, J ) 2.8, 1H), 5.67 (dd, J ) 2.8, 4.7, 1H), 4.98-

4.93 (m, 1H), 4.74-4.63 (m, 2H), 2.10 (s, 3H); ¹³C NMR δ 169.8,

166.1, 165.3, 164.9, 152.8, 151.8, 149.8, 141.5, 134.0, 133.5,

133.4, 132.8, 130.0, 129.8, 129.4, 128.8, 128.7, 128.5, 128.2,

128.0, 123.4, 88.7, 82.9, 80.4, 76.6, 63.4, 20.7.

N1-(3-O-Acetyl-5-O-ben zoyl-2-d eoxy-r-^D-er yth r o-p en to-

fu r a n osyl)cytid in e (35d ). Obtained in 33% yield as a white

Anal. Calcd for C₃₃H₂₇N₅O₈: C, 63.76,; H, 4.38; N, 11.27.

Found: C, 63.79 H, 4.55; N, 11.08.

powder: mp 86-88 °C; [R]²³-41° (c, 0.42, CHCl₃); IR (thin

D

film) 1721, 1643, 1525, 1486, 1452, 1272, 1247 cm^-1; ¹H NMR

(CDCl₃) δ 8.02 (d, J ) 7.2, 2H), 7.62-7.56 (m, 2H), 7.47 (t, J

) 7.6, 2H), 6.24 (dd, J ) 6.7, 1.2, 1H), 5.74 (d, J ) 7.5, 1H),

5.33 (d, J ) 6.1, 1H), 4.72 (t, J ) 4.2,1H), 4.52-4.42 (m, 2H),

2.85 (dt, J ) 15.4, 6.6, 1H), 2.46 (br d, J ) 15.4, 1H), 1.97 (s,

3H); ¹³C NMR δ 170.0, 166.1, 165.6, 155.6, 140.8, 133.5, 129.7,

129.3, 128.7, 93.0, 88.7, 85.1, 74.6, 64.2, 38.9, 20.9; HRMS

(FAB, MB) m/z calcd for C₁₈H₂₀N₃O₆(M + H) 374.1352, found

374.1352.

Gen er a l P r oced u r e for th e Selective N⁶-Deben zoyla -

tion of P r otected Ad en osin e. N9-(3-O-Acetyl-2,5-d i-O-

ben zoyl-r-^D-a r a bin ofu r a n osyl)a d en in e (34f, R ) H). N⁶-

Ben zoyl-(R-^D-3′-O-a cet yl-2′,5′-di-O-ben zoyla r a bin osyl)-

adenine (34e, 30 mg, 0.048 mmol) was dissolved in 3 mL of 1

M solution of dry ZnBr₂in methanol/chloroform (4:1). The

mixture was stirred at room temperature for 12 h and then

diluted with chloroform and washed with brine. The organic

layer was dried over Na₂SO₄, filtered, and evaporated. The

residue was purified by a flash chromatography on silica,

eluted with chloroform/methanol (80:1) to give 32f (22 mg, 88%

yield) as a white powder: mp 116-119 °C; [R]²³_D+58.1° (c 1.06,

N9-(3-O-Acetyl-5-O-ben zoyl-2-d eoxy-r-^D-er yth r o-p en to-

fu r a n osyl)a d en in e (35f, R ) H). Obtained in 76% yield as

a white powder: mp 177-179 °C; [R]²³22.5° (c 0.55, CHCl₃);

D

IR (thin film) 1723, 1644, 1600, 1473, 1274 cm^-1

;

¹H NMR

1

CHCl₃); IR (thin film) 1725, 1643, 1600, 1273 cm^-1; H NMR

(CDCl₃) δ 8.35 (s, 1H), 8.11 (s, 1H), 8.03 (d, J ) 7.0, 2H), 7.59

(t, J ) 7.6, 1H), 7.46 (t, J ) 7.6, 2H), 6.57 (dd, J ) 7.1, 1.9,

1H), 6.11 (br s, 2H), 5.45 (dt, J ) 6.8, 1.7, 1H), 4.77 (m, 1H),

4.60-4.50 (m, 2H), 2.99 (dt, J ) 15.2, 6.9, 1H), 2.82 (dt, J )

15.2, 1.7, 1H), 1.99 (s, 3H); ¹³C NMR δ 170.2, 166.1, 155.3,

152.7, 149.4, 138.5, 133.5, 129.6, 129.4, 128.6, 119.9, 85.4, 84.3,

74.6, 64.1, 38.3, 20.9; HRMS (FAB, MB) m/z calcd for

(CDCl₃) δ 8.39 (s, 1H), 8.04 (s, 1H), 8.09-8.01 (m, 4H), 7.63-

7.53 (m, 2H), 7.47-7.37 (m, 4H), 6.43 (d, J ) 3.0, 1H), 6.31 (t,

J ) 3.0, 1H), 5.90 (br s, 2H), 5.65 (dd, J ) 3.0, 4.8, 1H), 4.97-

4.92 (m, 1H), 4.74-4.62 (m, 2H), 2.12 (s, 3H); ¹³C NMR δ 169.8,

166.1, 165.3, 155.4, 153.2, 149.8, 139.0, 134.0, 133.3, 130.0,

129.8, 129.4, 128.7, 128.5, 128.3, 120.0, 88.4, 82.5, 80.3, 76.7,

63.4, 20.7.

C

₁₉H₂₀N₅O₅(M + H) 398.1464, found 398.1463.

N²-Acetyl-N7-(3-O-acetyl-5-O-ben zoyl-2-deoxy-r-D-er yth -

Anal. Calcd for C₂₆H₂₃N₅O₇: C, 60.35; H, 4.48; N, 13.53.

Found: C, 60.12; H, 4.58; N, 13.36.

r o-p en tofu r a n osyl)gu a n in e (35g). Obtained in 78% yield.

N²-Acetyl-N7-(3-O-a cetyl-2,5-d i-O-ben zoyl-r-D-a r a bin o-

fu r a n osyl)gu a n in e (34 g). Obtained in 92% yield as a white

powder: mp 134-136 °C; [R]²³_D+18.2° (c 1.06, CHCl₃); IR (thin

film) 1727, 1681, 1613, 1548, 1451, 1371, 1264 cm^-1; ¹H NMR

(CDCl₃) δ 12.4 (br s, 1H), 11.0 (br s, 1H), 8.07 (s, 1H), 8.09-

8.00 (m, 4H), 7.62-7.53 (m, 2H), 7.47-7.37 (m, 4H), 6.64 (d,

J ) 3.3, 1H), 6.13 (t, J ) 3.3, 1H), 5.61 (t, J ) 3.3, 1H), 5.00-

Recrystallized from chloroform to give colorless needles: mp

108-110 °C; [R]²³-19° (c 0.7, CH₂Cl₂); IR (thin film) 1681,

D

1613, 1547, 1529, 1451, 1369, 1270 cm^-1; H NMR (acetone-

1

d₆) δ 12.2 (br s, 1H), 10.6 (br s, 1H), 8.33 (s, 1H), 8.07 (d, J )

7.6, 2H), 7.60 (t, J ) 7.4, 1H), 7.47 (t, J ) 7.6, 2H), 6.76 (dd,

J ) 6.7, 1.8, 1H), 5.47 (m, 1H), 4.96 (m, 1H), 4.60-4.40 (m,

2H), 3.08 (dt, J ) 15.2, 6.7 1H), 2.65 (br d, J ) 15.2, 1H), 2.29

(s, 3H), 1.92 (s, 3H); ¹³C NMR δ 174.1, 170.7, 166.5, 159.1,

153.7, 148.1, 142.3, 134.2, 130.7, 130.3, 129.5, 111.8, 88.8, 85.3,

75.3, 65.1, 45.4, 40.3, 24.1, 20.8; HRMS (FAB, MB) m/z calcd

for C₂₁H₂₂N₅O₇(M + H) 456.1519, found 456.1519.

4.95 (m, 1H), 4.67-4.66 (m, 2H), 2.37 (s, 3H), 2.09 (s, 3H); ¹³

C

NMR δ 173.3, 169.8, 166.1, 165.0, 157.5, 153.1, 148.4, 141.7,

133.9, 133.4, 130.0, 129.8, 129.4, 128.7, 128.5, 128.3, 111.4,

90.5, 82.9, 81.2, 76.4, 63.7, 24.6, 20.7.

Anal. Calcd for C₂₈H₂₅N₅O₉: C, 58.43; H, 4.38; N, 12.17.

Found: C, 58.19; H, 4.44; N, 11.92.

N²-acetyl-N9-(3-O-Acetyl-5-O-ben zoyl-2-deoxy-r-D-er yth -

r o-p en tofu r a n osyl)gu a n in e (35h ). Obtained in 81% yield.

5982 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

Recrystallized from chloroform to give colorless needles: mp

4.80-4.63 (m, 3H), 2.27 (s, 3H), 2.04 (s, 3H); ¹³C NMR (CDCl₃)

δ 171.0, 169.4, 166.0, 165.2, 163.2, 154.8, 144.0, 133.8, 133.7,

129.8, 129.6, 129.1, 128.7, 128.6, 97.5, 89.2, 80.4, 74.0, 70.7,

63.4, 49.6, 24.9, 20.4.

Anal. Calcd for C₂₇H₂₅N₃O₉: C, 60.56; H, 4.71; N, 7.85.

Found: C, 60.59; H, 4.70; N, 7.74.

131-133 °C; [R]²³+11° (c 0.75, CHCl₃); IR (thin film) 1714,

D

1680, 1611, 1555, 1475, 1400, 1270 cm^-1; H NMR (CDCl₃) δ

1

12.1 (br s, 1H), 9.3 (br s, 1H), 8.11 (s, 1H), 8.02 (d, J ) 7.3,

2H), 7.60 (t, J ) 7.4, 1H), 7.47 (t, J ) 7.6, 2H), 6.27 (d, J )

6.8, 1H), 5.42 (d, J ) 6.7, 1H), 4.68 (m, 1H), 4.57-4.46 (m,

2H), 2.90 (m, 1H), 2.60 (br d, J ) 15.4, 1H), 2.32 (s, 1H), 2.06

(s, 3H); ¹³C NMR (CDCl₃) δ 172.0, 170.3, 166.2, 155.3, 147.8,

147.6, 136.9, 133.6, 129.7, 129.3, 128.7, 120.6, 84.8, 84.2, 74.2,

64.0, 38.0, 24.5, 20.9; HRMS (FAB, MB) m/z calcd for

2′-O-Acetyl-3′,5′-O-d iben zoylcytid in e (37e, R ) H). Ob-

tained in 66% yield. Recrystallized from chloroform/hexanes

to give a white powder: mp 225-227 °C; [R]²³-11° (c 1.8,

D

CH₂Cl₂); IR (thin film) 1723, 1649, 1603, 1492, 1451, 1373,

1268 cm^-1; ¹H NMR (DMSO-d₆) δ 7.97 (d, J ) 7.4, 4H), 7.71-

7.61 (m, 3H), 7.57-7.44 (m, 4H), 7.37 (br s, 2H), 5.92 (d, J )

4.1, 1H), 5.81 (t, J ) 6.0, 1H), 5.70 (d, J ) 7.4, 1H), 5.64 (dd,

J ) 6.0, 4.1, 1H), 4.67-4.52 (m, 3H), 1.97 (s, 3H); ¹³C NMR

(DMSO-d₆) δ 169.4, 165.9, 165.5, 164.6, 154.7, 142.9, 133.8,

133.5, 129.4, 129.3, 129.2, 128.9, 128.7, 94.7, 90.5, 78.5, 72.9,

70.6, 63.9, 20.3; HRMS (FAB, MB) m/z calcd for C₂₅H₂₄N₃O₈

(M + H) 494.1563, found 494.1561.

C

₂₁H₂₂N₅O₇(M + H) 456.1519, found 456.1519.

r-^D-2-O-Acetyl-1,3,5-tr i-O-ben zoylr ibofu r a n ose (36). To

a stirred solution of 8 (3.0 g, 6.5 mmol) and 2,6-lutidine (3 mL,

25.7 mmol) in dry methylene chloride (50 mL) at -20 °C was

added acetyl chloride (0.7 mL, 9.8 mmol) dropwise over 10 min.

The reaction was stirred at room temperature for 10 h then

diluted with methylene chloride (100 mL) and washed with

brine (3 × 50 mL). The organic layer was dried over Na₂SO₄,

filtered and evaporated. Purification by flash chromatography

on silica eluting with 25% ethyl acetate in hexanes gave 36

2′-O-Acetyl-3′,5′-di-O-ben zoyl-N⁶-ben zoyladen osin e (37f,

R ) Bz). Obtained in 91% as a white powder: mp 85-87 °C;

(3.0 g, 92% yield) as a colorless oil: [R]²³+67.2° (c 0.96,

[R]²³-62.9° (c 1.95, CHCl₃); IR (thin film) 1725, 1611, 1584,

D

CHCl₃); IR (thin film) 1726, 1602, 1452, 1268 cm^-1; H NMR

1511, 1453, 1268 cm^-1; ¹H NMR (CDCl₃) δ 9.20 (br s, 1H), 8.63

(s, 1H), 8.15 (s, 1H), 8.12-8.01 (m, 6H), 7.65-7.43 (m, 9H),

6.37 (d, J ) 6.1, 1H), 6.27 (dd, J ) 6.1, 5.5, 1H), 6.10 (dd, J )

5.5, 3.8, 1H), 4.89 (dd, J ) 12.2, 3.1, 1H), 4.80-4.73 (m, 1H),

4.65 (dd, J ) 12.2, 4.0, 1H), 2.04 (s, 3H); ¹³C NMR δ 169.4,

166.1, 165.3, 152.9, 151.8, 149.8, 141.7, 133.8, 133.4, 132.8,

129.8, 129.7, 129.3, 128.8, 128.7, 128.6, 127.9, 123.7, 86.4, 81.0,

73.0, 71.5. 63.6, 20.3.

1

(CDCl₃) δ 8.14-8.08 (m, 6H), 7.66-7.57 (m, 3H), 7.50-7.37

(m, 6H), 6.80 (d, J ) 4.4, 1H), 5.80 (dd, J ) 6.4, 1.8, 1H), 5.56

(dd, J ) 6.4, 4.4, 1H), 4.85 (m, 1H), 4.73 (dd, J ) 12.2, 3.0,

1H), 4.61 (dd, J ) 12.2, 3.5, 1H), 2.02 (s, 3H); ¹³C NMR δ 169.6,

166.1, 165.7, 165.2, 133.7, 133.5, 133.4, 130.0, 129.9, 129.7,

129.6, 129.4, 129.3, 128.6, 128.5, 128.4, 94.7, 82.8, 70.9, 70.7,

64.0, 20.3; HRMS (FAB, NBA) m/z calcd for C₂₁H₁₉O₇(M -

C₆H₅CO₂) 383.1131, found 383.1125.

Anal. Calcd for C₃₃H₂₇N₅O₈: C, 63.76; H, 4.38; N, 11.27.

Found: C, 63.46 H, 4.50; N, 11.12.

2′-O-Acetyl-3′,5′-O-ben zoylu r id in e (37a ). Obtained in

99% yield as a white powder: mp 100-103 °C; [R]²³-35° (c

2′-O-Acetyl-3′,5′-d i-O-ben zoyla d en osin e (37g, R ) H).

D

1.0, CHCl₃); IR (KBr) 1722, 1695, 1633, 1602, 1453, 1379, 1268

Obtained in 75% yield from 37f, as a white powder: mp 86-

1

cm^-1; H NMR (CDCl₃) δ 9.00 (br s, 1H), 8.08-8.04 (m, 4H),

89 °C; [R]²³-64° (c 1.0, CHCl₃); IR (thin film) 1723, 1642,

D

1

7.66-7.57 (m, 2H), 7.51-7.45 (m, 4H), 7.35 (d, J ) 8.2, 1H),

6.21 (d, J ) 5.9, 1H), 5.75 (dd, J ) 5.9, 4.1, 1H), 5.60-5.52

(m, 2H), 4.81-4.75 (m, 1H), 4.66-4.58 (m, 2H), 2.05 (s, 3H);

¹³C NMR δ 169.7, 166.0, 165.3, 162.6, 150.1, 139.2, 133.9,

133.7, 129.8, 129.6, 129.1, 128.8, 128.7, 128.6, 103.5, 87.3, 80.4,

73.0, 71.0, 63.7, 20.4;

1599, 1451, 1266 cm^-1; H NMR (CDCl₃) δ 8.23 (s, 1H), 8.08

(d, J ) 8.0, 4H), 7.91 (s, 1H), 7.65-7.53 (m, 2H), 7.51-7.40

(m, 4H), 6.29 (d, J ) 5.6, 1H), 6.22 (t, J ) 5.6, 1H), 6.17 (br s,

2H), 6.11 (t, J ) 4.8,1H), 4.84 (dd, J ) 12.0, 3.1, 1H), 4.75-

4.71 (m, 1H), 4.65 (dd, J ) 12.0, 4.1, 1H), 2.02 (s, 3H); ¹³C

NMR δ 169.5, 166.1, 165.3, 155.6, 153.2, 149.8, 139.1, 133.8,

133.4, 129.8, 129.7, 129.4, 128.8, 128.6, 128.5, 120.1, 86.3, 80.7,

73.2, 71.5, 63.7, 20.4.

Anal. Calcd for C₂₅H₂₂N₂O₉: C, 60.73; H, 4.48; N, 5.67.

Found: C, 60.48; H, 4.60; N, 5.54.

2′-O-Acetyl-3′,5′-O-ben zoyl-5-m eth ylu r id in e (37b). Ob-

Anal. Calcd for C₂₆H₂₃N₅O₇: C, 60.35; H, 4.48; N, 13.53.

Found: C, 60.16; H, 4.57; N, 13.28.

tained in 94% yield as a white powder: mp 163-165 °C; [R]²³

D

-70.7° (c 1.01, CHCl₃); IR (KBr,) 1724, 1694, 1452, 1375, 1267

N²-Acetyl-2′-O-acetyl-3′,5′-di-O-ben zoylgu an osin e (37h ).

Obtained in 78% yield as a white powder: mp 135-138 °C;

[R]²³_D-77° (c 0.935, CHCl₃); IR (KBr) 1725, 1682, 1612, 1561,

1

cm^-1; H NMR (CDCl₃) δ 9.05 (br s, 1H), 8.12-8.05 (m, 4H),

7.64-7.59 (m, 2H), 7.51-7.46 (m, 4H), 7.10 (d, J ) 1.0, 1H),

6.31 (d, J ) 6.7, 1H), 5.78 (dd, J ) 5.9, 3.1, 1H), 5.56 (t, J )

6.3, 1H), 4.83 (dd, J ) 11.7, 2.1, 1H), 4.63-4.56 (m, 2H), 2.05

(s, 3H), 1.54 (d, J ) 1.0, 3H); ¹³C NMR δ 169.8, 165.9, 165.4,

163.2, 150.4, 134.5, 133.9, 133.8, 129.9, 129.6, 129.1, 128.9,

128.7, 112.3, 86.2, 80.4, 72.6, 71.3, 63.9, 20.4, 12.1. Anal. Calcd

for C₂₆H₂₄N₂O₉: C, 61.41; H, 4.76; N, 5.51. Found: C, 61.30;

H, 4.86; N, 5.44.

1

1538, 1405, 1374, 1268 cm^-1; H NMR (CDCl₃) δ 12.10 (br s,

1H), 10.40 (br s, 1H), 7.98 (d, J ) 7.7, 2H), 7.90 (s, 1H), 7.84

(d, J ) 7.6, 2H), 7.59 (t, J ) 7.4, 1H), 7.49-7.40 (m, 3H), 7.28

(t, J ) 7.6, 2H), 6.20 (t, J ) 5.2, 1H), 6.12 (d, J ) 5.2, 1H),

6.07 (t, J ) 4.1, 1H), 4.74-4.65 (m, 2H), 4.59-4.53 (m, 1H),

2.31 (s, 3H), 1.99 (s, 3H); ¹³C NMR δ 172.8, 169.7, 166.4, 165.3,

155.5, 148.0, 147.8, 139.1, 133.8, 133.5, 129.7, 129.5, 128.9,

128.7, 128.6, 128.4, 122.3, 87.6, 80.2, 72.7, 71.6, 63.4, 24.3, 20.5.

Anal. Calcd for C₂₈H₂₅N₅O₉: C, 58.43; H, 4.38; N, 12.17.

Found: C, 58.19; H, 4.33; N, 11.91.

2′-O-Acetyl-3′,5′-O-d iben zoyl-5-flu or ou r id in e (37c). Ob-

tained in 89% yield. Recrystallization from ethyl acetate/

hexanes gave colorless needles: mp 183-84 °C; [R]²³_D-24° (c

0.495, CH₂Cl₂); IR (KBr) 1719, 1672, 1638, 1601, 1452, 1378,

1266 cm^-1; ¹H NMR (DMSO-d₆) δ 12.0 (br s, 1H), 8.15 (d, J )

6.8, 1H), 8.00-7.95 (m, 4H), 7.72-7.62 (m, 2H), 7.58-7.45 (m,

4H), 5.99 (d, J ) 4.6, 1H), 5.77 (dd, J ) 5.9, 5.0, 1H), 5.66 (dd,

J ) 5.9, 5.0, 2H), 4.67-4.59 (m, 3H), 1.98 (s, 3H); ¹³C NMR δ

169.3, 165.5, 164.6, 157.0 (d, J _C-F) 26), 149.0, 140.2 (d, J _C-F

) 230), 133.9, 133.6, 129.4, 129.3, 129.2, 128.9, 128.8, 128.6,

125.8 (d, J _C-F) 35), 88.3, 78.9, 72.2, 70.0, 63.7, 20.2; HRMS

(FAB, MB) m/z calcd for C₂₅H₂₂N₂O₉F (M + H) 513.1309, found

513.1307.

N²-Acetyl-N7-(â-D-2′-O-a cetyl-3′,5′-d i-O-ben zoyl-â-D-r i-

bofu r a n osyl)gu a n in e (37i). Obtained in 96% yield as a white

powder: mp 148-150 °C; [R]²³_D-6.2° (c 1.1, CHCl₃); IR (KBr)

3148, 3071, 2960, 1725, 1687, 1614, 1549, 1452, 1377, 1267

cm^-1; ¹H NMR (CDCl₃) δ 12.4 (br s, 1H), 11.1 (br s, 1H), 8.09-

8.04 (m, 4H), 7.65-7.54 (m, 2H), 7.50-7.40 (m, 3H), 6.47 (d,

J ) 5.0, 1H), 5.98 (t, J ) 5.1, 1H), 5.91 (t, J ) 5.0, 1H), 4.86-

4.67 (m, 3H), 2.39 (s, 3H), 2.05 (s, 3H); ¹³C NMR δ 173.4, 169.4,

166.1, 165.2, 157.5, 152.7, 148.4, 141.7, 133.8, 133.5, 129.8.

129.7. 129.3. 128.7, 128.6, 111.6, 88.8, 80.4, 74.6, 70.7, 63.6,

24.7, 20.4.

N4-Acetyl-2′-O-a cetyl-3′,5′-O-d iben zoylcytid in e (37d , R

) Ac). Obtained in 86% yield. Recrystallized from ethyl

acetate/hexanes to give colorless needles: mp 217-218 °C;

Anal. Calcd for C₂₈H₂₅N₅O₉: C, 58.43; H, 4.38; N, 12.17.

Found: C, 58.16; H, 4.45; N, 11.99.

[R]²³-15° (c 1.0, CHCl₃); IR (thin film) 1725, 1671, 1628,

2′-O-Acet yl-5′-O-b en zoyl-3′-d eoxyu r id in e (38a ). Ob-

D

1561, 1492, 1451, 1373, 1316, 1267 cm^-1; H NMR (CDCl₃) δ

tained in 60% yield as a white powder: mp 64-66 °C; [R]²³

1

D

10.00 (br s, 1H), 8.06-7.99 (m, 4H), 7.90 (d, J ) 7.6, 1H), 7.63-

7.57 (m, 2H), 7.49-7.42 (m, 4H), 7.34 (d, J ) 7.6, 1H), 6.25 (d,

J ) 4.5, 1H), 5.74 (t, J ) 5.4, 1H), 5.64 (dd, J ) 5.4, 4.5, 1H),

+5.0° (c 1.0, CHCl₃); IR (thin film) 1714, 1692, 1601, 1453,

1377, 1274 cm^-1; ¹H NMR(CDCl₃) δ 8.55 (br s, 1H), 8.03-8.00

(m, 2H), 7.61-7.57 (m, 1H), 7.46 (t, J ) 8.1, 3H), 5.80 (d, J )

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5983

1.6, 1H), 5.53 (dd, J ) 8.1, 2.2, 1H), 5.34 (m, 1H), 4.69 (dd, J

) 12.2, 2.7, 1H), 4.66-4.62 (m, 1H), 4.51 (dd, J ) 12.2, 4.2,

1H), 2.35-2.27 (m, 1H), 2.17 (ddd, J ) 14.0, 5.6, 1.7, 1H), 2.11

(s, 3H); ¹³C NMR δ 170.0, 166.2, 162.9, 149.8, 139.9, 133.7,

129.6, 129.4, 128.7, 102.5, 91.6, 78.3, 77.7, 64.3, 32.5, 20.9;

HRMS (FAB, MB) m/z calcd for C₁₈H₁₉N₂O₇(M + H) 375.1192,

found 375.1191.

5.44 and 5.24 (diastereomers, d, s, J ) 4 0.4, 1H), 4.82-4.60

(m, 3H), 3.53 and 3.48 (diasteromers, s, s, 3H).

1-O-Acet yl-2,3,5-t r i-O-[3-(t r iflu or om et h yl)b en zoyl]-^D-

r ibofu r a n ose (45). To a stirred solution of 44 (1.30 g, 2.0

mmol) in acetic acid (10.1 mL) cooled to 4 °C, was added acetic

anhydride (7.3 mL) and concentrated sulfuric acid (0.6 mL).

The reaction was stirred at 4 °C for 5 h, then at room-

temperature overnight. The reaction was then cooled to 4 °C

and quenched with an ice cold, saturated bicarbonate. The

layers were separated and the aqueous phase extracted with

chloroform water and brine, then dried over sodium sulfate,

filtered and evaporated under reduced pressure. Flash chro-

matography on silica eluted with 5% ethyl acetate/hexanes,

gave 45 as a 3:2 (â:R) mixture of anomers as a syrup (1.30 g,

92% yield): [R]²³_{D 17.7}(c 2.53, CHCl₃); ¹H NMR (CDCl₃) δ 8.21-

8.16 (m, 4H), 8.00-7.94 (m, 2H), 7.76-7.66 (m, 3H), 7.52-

7.39 (m, 3H), 6.63 and 6.41 (diastereomers, d, s, J ) 4.5, 1H),

5.90-5.80 (m, 1H), 5.75-5.70 and 5.65-5.55 (diastereomers,

m, m, 1H), 4.70-4.50 (m, 3H), 2.07 and 1.98 (diastereomers,

s, s, 3H).

2′-O-Acetyl-5′-O-ben zoyl-3′-deoxy-5-m eth ylu r idin e (38b).

Obtained in 33% yield as a white powder: mp 60-62 °C; [R]²³

D

-18°(c 0.45, CHCl₃); IR (thin film) 1712, 1693, 1601, 1452,

1373, 1273 cm^-1; ¹H NMR (CDCl₃) δ 8.32 (br s, 1H), 8.05 (d, J

) 7.2, 2H), (m, 2H), 7.63-7.57 (m,1H), 7.46 (t, J ) 7.6, 2H),

7.14 (d, J ) 1.0, 1H), 5.83 (d, J ) 2.4, 1H), 5.37 (dt, J ) 6.7,

2.4, 1H), 4.71 (dd, J ) 12.2, 2.6, 1H), 4.63 (m, 1H), 4.47 (dd, J

) 12.2, 4.4, 1H), 2.46-2.36 (m, 1H), 2.20 (ddd, J ) 14.0, 5.9,

2.4, 1H), 2.13 (s, 3H), 1.70 (d, J ) 1.0, 3H); ¹³C NMR δ 170.1,

166.2, 163.3, 149.8, 135.6, 133.6, 129.6, 129.4, 128.7, 111.2,

91.2, 77.6, 77.4, 64.6, 32.8, 20.9, 12.3; HRMS (FAB, MB) m/z

calcd for C₁₉H₂₁N₂O₇(M + H) 389.1349, found 389.1349.

2′-O-Acetyl-5′-O-ben zoyl-3′-d eoxya d en osin e (38 g). Ob-

tained in 78% yield as a white powder: mp 73-76 °C; [R]²³

2′,3′,5′-Tr i-O-[3-(tr iflu or om eth yl)ben zoyl]u r id in e (46a ).

Obtained in 91% yield as a white powder. Recrystallized from

D

-9.6° (c 0.5, CHCl₃); IR (thin film) 1744, 1721, 1643, 1600,

1

1476, 1373, 1274 cm^-1; H NMR (CDCl₃) δ 8.27 (s, 1H), 7.97

ethanol to give white needles: mp 179-180 °C; [R]²³-28.40

D

(d, J ) 7.8, 2H), 7.94 (s, 1H), 7.56 (t, J ) 7.4, 1H), 7.41 (dd, J

) 7.8, 7.4, 2H), 6.06 (d, J ) 1.0, 1H), 5.99 (br s, 1H), 5.83 (d,

J ) 5.8, 1H), 4.78-4.71 (m, 1H), 4.68 (dd, J ) 12.1, 3.0, 1H),

4.53 (dd, J ) 12.1, 5.3, 1H), 2.85 (m, 1H), 2.30 (ddd, J ) 14.0,

5.6, 0.8, 1H), 2.15 (s, 3H); ¹³C NMR δ 170.1, 166.3, 155.0, 152.1,

149.2, 139.7, 133.3, 129.6, 129.5, 128.4, 120.2, 90.2, 78.8, 77.9,

64.9, 33.1, 20.9; HRMS (FAB, MB) m/z calcd for C₁₉H₂₀N₅O₅

(M + H) 398.1464, found 398.1465.

(c 1.0, CHCl₃); IR (thin film) 1727, 1700, 1336, 1250, 1130 cm^-1

;

¹H NMR (CDCl₃) δ 9.24 (br s, 1H), 8.24 (s, 1H), 8.19 (s, 1H)

8.17 (s, 1H), 8.10-8.00 (m, 4H), 7.80-7.70 (m, 3H), 7.53-7.42

(m, 3H), 7.28 (d, J ) 8.1, 1H), 5.96 (d, J ) 4.0, 1H), 5.92-5.89

(m, 1H), 5.85-5.81 (m, 1H), 5.69 (dd, J ) 8.1, 2.0, 1H), 4.78-

4.67 (m, 3H); ¹³C NMR (CDCl₃) δ 167.5, 166.8, 166.6, 165.7,

152.6, 143.5, 135.6, 135.5, 134.1 (q, J _C-F) 33), 133.9 (q, J _C-F

) 33), 133.1, 133.0, 132.8, 132.7, 132.1, 132.0, 131.9, 131.8,

131.7, 126.1 (q, J _C-F) 272), 125.9 (q, J _C-F) 273), 125.7 (q,

J _C-F) 272), 106.0, 93.6, 82.5, 77.0, 73.9, 66.7; HRMS (FAB,

NBA) m/z calcd for C₃₃H₂₂F₉N₂O₉(M + H) 761.1182, found

761.1157.

N ²-Ac e t y l-2′-O -a c e t y l-5′-O -b e n z o y l-3′-d e o x y g u a -

n osin e (38h ). Obtained in 71% yield as a white powder: mp

108-110 °C; [R]²³_D-52.3° (c 0.83, CHCl₃); IR (thin film) 1719,

1

1680, 1612, 1560,1482, 1374, 1253 cm^-1; H NMR (CDCl₃) δ

12.0 (br s, 1H), 9.81 (br s, 1H), 7.97 (d, J ) 7.3, 2H), 7.78 (s,

1H), 7.59 (t, J ) 7.4, 1H), 7.44 (t, J ) 7.5, 2H), 5.91 (d, J )

1.0, 1H), 5.55 (m, 1H), 5.05 (dd, J ) 11.3, 5.7, 1H), 4.80-4.74

(m, 1H), 4.52 (dd, J ) 11.3, 5.5, 1H), 2.84 (ddd, J ) 14.0, 9.5,

6.2, 1H), 2.34 (s, 1H), 2.18 (ddd, J ) 14.0, 6.1, 1.4, 1H), 2.11

(s, 3H); ¹³C NMR δ 172.4, 170.2, 166.9, 155.5, 147.6, 147.4,

138.4, 133.7, 129.6, 129.2, 128.6, 121.9, 91.0, 78.9, 78.2, 64.7,

33.2, 24.3, 20.9; HRMS (FAB, MB) m/z calcd for C₂₁H₂₂N₅O₇

(M + H) 456.1519, found 456.1517.

2′,3′,5′-Tr i-O-[3-(tr iflu or om eth yl)ben zoyl]-5-m eth ylu r i-

d in e (46b). Obtained in 95% yield as a white powder: mp,

99-100 °C; [R]²³_D-39.70° (c 1.25, CHCl₃); IR (thin film) 1727,

1

1336, 1255, 1174 cm^-1; H NMR (CDCl₃) δ 8.44 (s, 1H), 8.37

(s, 1H), 8.30 (d, J ) 7.9, 1H), 8.18-8.12 (m, 4H), 7.88-7.81

(m, 3H), 7.66-7.55 (m, 3H), 7.12 (d, J ) 1.0, 1H), 6.10 (d, J )

4.7, 1H), 5.98 (t, J ) 5.8, 1H), 5.90-5.86 (m, 1H), 4.87-4.84

(m, 1H), 4.76-4.73 (m, 2H), 1.8 (d, J ) 1.0, 3H); ¹³C NMR

(CDCl₃) δ 167.5, 166.7, 166.6, 166.1, 152.7, 138.7, 135.6, 135.5,

134.0 (q, J _C-F) 33), 133.1, 132.1, 132.0, 131.9, 131.8, 129.3,

129.1, 129.0, 125.9 (q, J _C-F) 270), 114.7, 92.6, 82.4, 76.7, 74.0,

66.7; HRMS (FAB, NBA) m/z calcd for C₃₄H₂₃F₉N₂O₉(M + H)

775.1338, found 775.1357.

N²-Acetyl-N7-(2-O-acetyl-5-O-ben zoyl-3-deoxy-â-D-er yth -

r o-p en tofu r a n osyl)gu a n in e (38i). Obtained in 80% yield as

a white powder: mp 114-116 °C; [R]²³_D+82.4° (c 1.0, CHCl₃);

IR (thin film) 1746, 1720, 1685, 1614, 1548, 1451, 1372 cm^-1

;

¹H NMR (CDCl₃) δ 12.3 (br s, 1H), 10.9 (br s, 1H), 8.06 (d, J )

7.5, 2H), 8.04 (s, 1H), 7.59 (t, J ) 7.5, 1H), 7.46 (t, J ) 7.5,

2H), 6.32 (s, 1H), 5.79 (d, J ) 5.4, 1H), 4.80-4.76 (m, 1H),

4.71 (dd, J ) 12.3, 2.8, 2H), 4.62 (dd, J ) 12.3, 5.4, 2H), 2.50

(m, 1H), 2.36 (s, 3H), 2.25-2.18 (m, 1H), 2.18 (s, 3H); ¹³C NMR

δ 173.3, 170.0, 166.3, 157.4, 152.8, 148.0, 140.8, 133.5, 129.7,

129.4, 128.6, 111.1, 91.8, 79.1, 79.0, 64.9, 32.3, 24.5, 21.0;

HRMS (FAB, MB) m/z calcd for C₂₁H₂₂N₅O₇(M + H) 456.1519,

found 456.1517.

2′,3′,5′-Tr i-O-[3-(tr iflu or om eth yl)ben zoyl]in osin e (46c).

Inosine was dried overnight at 100 °C under vacuum over

P₂O₅. To a solution of inosine (0.320 g, 1.2 mmol) and DMAP

(20 mg) in pyridine (20 mL) was added 3-(trifluoromethyl)-

benzoyl chloride (1.00 g, 4.8 mmols), dropwise over 10 min.

The reaction was stirred for 27 h, and then the pyridine

removed in vacuo. The residue was then taken up in ethyl

acetate and quenched with saturated bicarbonate. The organic

layer was then washed with brine and water and then dried

over magnesium sulfate, filtered and evaporated. Purification

by flash chromatography, eluting with 1% methanol in chlo-

roform gave 46c (0.600 g, 86% yield) as a white solid: mp 110-

112 °C; [R]²³_D-45.0 (c 0.80, CHCl₃); IR (thin film) 1731, 1705,

1336, 1250, 1127 cm^-1; ¹H NMR (CDCl₃) δ 8.38-8.24 (m, 3H),

8.19-8.15 (m, 3H), 8.05 (d, J ) 4.0, 2H), 7.84-7.82 (m, 3H),

7.65-7.54 (m, 3H), 6.44-6.37 (m, 2H), 6.25 (t, J ) 5.4, 1H),

4.95-4.87 (m, 2H), 4.86-4.77 (m, 1H); ¹³C NMR (CDCl₃) δ

169.3, 165.2, 164.3, 164.2, 159.2, 149.0, 146.2, 140.2, 133.6,

133.4, 133.3, 132.0, 131.5, 131.4, 130.8, 130.6, 129.8, 129.5,

129.7, 129.4, 127.1, 127.0, 126.9, 126.8, 121.7, 88.1, 80.7, 74.8,

72.1, 64.4; HRMS (FAB, NBA) m/z calcd for C₃₄H₂₁F₃N₄O₈(M

+ H) 785.1294, found 785.1298.

Meth yl 2,3,5-Tr i-O-[3-(tr iflu or om eth yl)ben zoyl]-^D-r i-

bofu r a n osid e (44). To a stirred solution of the 43 (2.6 g, 15.8

mmol) and 2, 6-lutidine (5.36 g, 50 mmol) in dry methylene

chloride (54 mL) at 0 °C, was added 3-(trifluoromethyl)benzoyl

chloride (9.91 g, 47.5 mmol) dropwise over 15 min. The reaction

was allowed to warm to room temperature and stirred for 14

h at room temperature after which time saturated bicarbonate

solution was added. The layers were separated and the

aqueous phase extracted with ethyl acetate. The organic

extracts were dried over sodium sulfate, filtered and concen-

trated under reduced pressure. Purification by flash chroma-

tography on silica, eluted with 5% ethyl acetate/hexanes, gave

44 as a 3:1 (â:R) mixture of anomers and as a waxy white solid

(7.8 g, 73% yield): mp 63-65 °C; [R]²³25.6 (c 1.75, CHCl₃);

5′-O-[3-(Tr iflu or om e t h yl)b e n zoyl]-2′,3′-d id e oxyu r i-

D

¹H NMR (CDCl₃) δ 8.36-8.30 (m, 1H), 8.26-8.22 (m, 3H),

8.11-8.08 (m, 2H), 7.87-7.76 (m, 3H), 7.60-7.50 (m, 3H), 5.95

and 5.76 (diastereomers, dd, J ) 6.4, 5.0 J ) 6.9, 2.9, 1H),

5.72 and 5.38 (diastereomers. d, dd, J ) 5.0, J ) 6.9, 4.4, 1H),

d in e. (47a ). Obtained in 68% yield as a clear syrup: [R]²³

D

+24.9° (c 0.65, CHCl₃); IR (thin film) 1690, 1254, 1128 cm^-1

;

¹H NMR (CDCl₃) δ 8.23-8.15 (m, 3H), 7.80 (d, J ) 6.8, 1H),

7.55 (t, J ) 8.0, 1H), 7.50 (d, J ) 8.1, 1H), 6.01-5.98 (m, 1H),

5984 J . Org. Chem., Vol. 65, No. 19, 2000

Wang et al.

5.55 (dd, J ) 8.1, 1.8, 1H), 4.54 (s, 2H), 4.43-4.38 (m, 1H),

129.8, 129.6, 129.5, 129.2, 128.7, 128.6, 128.4, 126.7, 123.4 (q,

J _C-F) 272), 96.7, 89.2, 80.6, 75.0, 71.2, 63.8, 54.6.

Anal. Calcd for C₃₂H₂₅F₃N₂O₉: C, 60.19; H, 3.95; N, 4.39.

Found: C, 60.27; H, 3.89; N, 4.41.

2.55-2.41 (m, 1H), 2.15-2.01 (m, 2H), 1.87-1.80 (m, 1H); ¹³

C

NMR (CDCl₃) δ 165.4, 163.5, 150.6, 139.7, 133.2, 131.6 (J _C-F

) 33), 130.6 (J _C-F) 28), 129.7, 127.0, 121 (J _C-F) 275), 102.5,

87.1, 79.2, 66.1, 32.9, 26.3; HRMS (FAB, NBA) m/z calcd for

1-(2-O-Acetyl-3,5-O-diben zoyl-â-^D-r ibofu r an osyl)-4-m eth -

oxy-2-p yr im id on e (52c). Obtained in 83% yield from 36, as

a white powder: mp 170-171 °C; [R]²³_D+10.8° (c 1.15, CHCl₃);

IR (thin film) 1725, 1676, 1637, 1601, 1543, 1482, 1452, 1316

C

₁₇H₁₆F₃N₂O₅(M + H) 385.1011, found 385.1010.

5′-O-[3-(Tr iflu or om eth yl)ben zoyl]-3′-d eoxyth ym id in e

(47b). Obtained in 85% yield as a clear syrup: [R]²³+11.0°

D

1

cm^-1; H NMR (CDCl₃) δ 8.07-8.03 (m, 4H), 7.64 (d, J ) 7.5,

(c 0.41, CHCl₃); IR (thin film) 1692, 1470, 1335, 1254, 1130

cm^-1; H NMR (CDCl₃) δ 8.69 (s, 1H), 8.25 (s, 1H), 8.17 (d, J

1

1H), 7.64-7.57 (m, 2H), 7.50-7.43 (m, 4H), 6.35 (d, J ) 5.4,

1H), 5.76 (d, J ) 7.5, 1H), 5.73 (t, J ) 4.7, 1H), 5.57 (t, J )

5.4, 1H), 4.79 (dd, J ) 11.5, 1.9, 1H), 4.69-4.60 (m, 2H), 3.94

(s, 3H), 2.06 (s, 3H); ¹³C NMR δ 171.8, 169.6, 166.0, 165.3,

155.6, 141.8, 133.8, 133.6, 129.8, 129.6, 129.2, 128.7, 128.6,

96.7, 88.4, 80.4, 73.8, 71.0, 63.7, 54.6, 20.5.

) 7.8, 1H), 7.80-7.70 (m, 1H), 7.57-7.50 (m, 1H), 7.22 (d, J

) 1.1, 1H), 6.02 (dd, J ) 6.6, 4.5, 1H), 4.59-4.20 (m, 3H), 2.47-

2.38 (m, 1H), 2.24-1.82 (m, 3H), 1.71 (d, J ) 1.1, 3H); ¹³C

NMR (CDCl₃) δ 165.4, 164.0, 150.6, 135.4, 133.2, 130.6 (J _C-F

)

38), 129.7, 127.0, 111.2, 86.7, 78.5, 66.5, 32.4, 26.6, 12.8; HRMS

(FAB, NBA) m/z calcd for C₁₈H₁₈F₃N₂O₅(M + H) 399.1168,

found 399.1174.

Anal. Calcd for C₂₆H₂₄N₂O₉: C, 61.41; H, 4.76; N, 5.51.

Found: C, 61.31; H, 4.88; N, 5.58.

5′-O -[3-(T r iflu o r o m e t h y l)b e n zo y l]-2′,3′-d id e o x y i-

n osin e (47c). Obtained in 65% yield as a white powder: mp

197 °C dec; [R]²³_D+18.35 (c 0.85, DMSO); IR (KBr) 1728, 1676,

1340, 1255, 1130 cm^-1; ¹H NMR (methanol-d4) 8.12 (br s, 1H),

8.09 (s, 1H), 8.02 (d, J ) 7.9, 1H), 7.88 (s, 1H), 7.79 (d, J )

7.9, 1H), 7.56 (t, J ) 7.9, 1H), 6.20 (dd, J ) 6.7, 3.4, 1H), 4.55-

4.44 (m, 3H), 2.59-2.55 (m, 2H), 2.22-2.17 (m, 2H); ¹³C NMR

(CDCl₃) 164.7, 157.5, 148.1, 146.4, 138.4, 133.5, 130.7, 130.6,

130.3, 130.2, 130.1, 129.7, 125.8, 125.6, 124.8, 122.2, 105.2,

84.3, 78.8, 66.8, 31.5, 26.7; HRMS (FAB) m/z calcd for

1-(3-O-Acet yl-5-O-b en zoyl-2-d eoxy-r-^D-er yth r o-p en t o-

fu r a n osyl)-4-m eth oxy-2-p yr im id on e (53a ). Obtained in

80% yield as a white powder: mp 135-137 °C; [R]²³-74.7°

D

(c 0.9, CHCl₃); IR (thin film) 1734, 1661, 1621, 1603, 1584,

1

1538, 1476, 1380, 1316, 1273 cm^-1; H NMR (CDCl₃) δ 8.01

(d, J ) 7.4, 2H), 7.71 (d, J ) 7.4, 1H), 7.59 (t, J ) 7.4, 1H),

7.46 (t, J ) 7.4, 2H), 6.25 (d, J ) 6.0, 1H), 5.92 (d, J ) 7.4,

1H), 5.34 (d, J ) 6.0, 1H), 4.74 (m, 1H), 4.52-4.42 (m, 2H),

3.96 (s, 3H), 2.87 (dt, J ) 15.5, 6.5, 1H), 2.48 (br d, J ) 15.5,

1H), 1.94 (s, 3H); ¹³C NMR δ 172.1, 169.9, 166.0, 155.8, 141.8,

133.5, 129.6, 129.3, 128.6, 94.6, 89.0, 85.4, 74.5, 64.1, 54.5, 38.8,

20.8; HRMS (FAB, MB) m/z calcd for C₁₉H₂₁N₂O₇(M + H)

389.1349, found 389.1349.

C

₁₈H₁₆F₃N₄O₄(M + H) 409.1124, found 409.1108.

1-(2′,3′,5′-Tr i-O-ben zoyl-â-^D-xylofu r a n osyl)u r a cil (49).

A solution of R-^D-1,2,3,4-tetra-O-benzoylxylofuranose (0.5 g,

0.882 mmol) and 2,4-bis-trimethylsilyluracil (0.45 g, 1.75

mmol) in dry dichloroethane (10 mL) was cooled to -20 °C.

To the vigorously stirred solution was added dropwise SnCl₄

(0.52 mL, 4.4 mmol). The reaction was allowed to warm to

room temperature and stirred overnight, after which time it

was quenched with saturated aqueous bicarbonate. The layers

were separated and the aqueous phase extracted with ethyl

acetate. The combined organic extracts were washed with

brine, dried over anhydrous sodium sulfate, filtered and

evaporated Purification by flash chromatography on silica,

eluting with 1% methanol in chloroform, gave 49 (430 mg, 87%)

1-(3,5-O-Diben zoyl-2-deoxy-â-^D-er yth r o-pen tofu r an osyl)-

4-m eth oxy-2-p yr im id on e (53b). Obtained in 63% yield as a

white powder: mp 72-75 °C; [R]²³+5.0° (c 2.0, CHCl₃); IR

D

(thin film) 1721, 1668, 1633, 1544, 1314, 1269 cm^-1; ¹H NMR

(CDCl₃) δ 8.06 (d, J ) 7.0, 2H), 7.97 (d, J ) 7.0, 2H), 7.83 (d,

J ) 7.5, 1H), 7.64-7.57 (m, 2H), 7.51-7.42 (m, 4H), 6.42 (dd,

J ) 8.0, 5.6, 1H), 5.79 (d, J ) 7.5, 1H), 5.61 (dt, J ) 6.5, 2.0,

1H), 4.76 (dd, J ) 12.2, 3.4, 1H), 4.69 (dd, J ) 12.2, 3.6, 1H),

4.63-4.60 (m, 1H), 3.94 (s, 3H), 3.03 (ddd, J ) 14.5, 5.6, 2.0,

1H), 2.26 (ddd, J ) 14.5, 8.0, 6.5, 1H); ¹³C NMR δ 171.8, 166.1,

155.7, 141.4, 133.7, 133.6, 129.9, 129.5, 129.2, 129.0, 128.7,

128.6, 95.9, 87.2, 83.3, 75.1, 64.4, 54.5, 39.2; HRMS (FAB,

NBA) m/z calcd for C₂₄H₂₃N₂O₇(M + H) 451.1505, found

451.1497.

as a white solid: mp 106-108 °C; [R]²³+67° (c 2.0, CHCl₃);

D

¹H NMR (CDCl₃) δ 9.37 (br, s, 1H), 8.06 (d, J ) 7.8, 2H), 7.95

(d, J ) 8.2, 4H), 7.74 (d, J ) 8.2, 1H), 7.62-7.51 (m, 3H), 7.48-

7.35 (m, 6H), 6.26 (d, J ) 2.0, 1H), 5.85 (1H, dd, J ) 3.9, 1.5,

1H), 5.71 (dd, J ) 8.2, 1.2, 1H), 5.67 (t, J ) 2.0, 1H), 4.90-

4.85 (m, 1H), 4.80-4.69 (m, 2H); ¹³C NMR δ 166.0, 164.7,

164.6, 162.9, 150.0, 139.2, 134.1, 133.9, 133.4, 130.0, 129.7,

129.6, 129.1, 128.7, 128.5, 128.4, 128.3, 128.2, 102.7, 88.8, 80.2,

79.5, 75.1, 61.4; HRMS (FAB, NBA) m/z calcd for C₃₀H₂₅N₂O₉

(M + H) 557.1560, found 557.1541.

1-(2-O-Acet yl-5-O-b en zoyl-3-d eoxy-â-^D-er yth r o-p en t o-

fu r a n osyl)-4-m eth oxy-2-p yr im id on e (53c). Obtained in

55% yield as a white powder: mp 62-64 °C; [R]²³+53° (c

D

0.45, CHCl₃); IR (thin film) 1744, 1722, 1669, 1632, 1602, 1543,

1

1481, 1371, 1313, 1275 cm^-1; H NMR (CDCl₃) δ 8.03 (d, J )

7.4, 2H), 7.82 (d, J ) 7.4, 1H), 7.61 (t, J ) 7.4, 2H), 7.47 (t, J

) 7.4, 2H), 5.95 (d, J ) 0.7, 1H), 5.72 (d, J ) 7.4, 1H), 5.40-

5.35 (m, 1H), 4.74-4.65 (m, 2H), 4.56 (dd, J ) 12.8, 5.0, 1H),

3.94 (s, 3H), 2.20-2.15 (m, 2H), 2.14 (s, 3H); ¹³C NMR δ 171.9,

169.8, 166.1, 155.4, 142.2, 133.5, 129.6, 129.4, 128.6, 95.6, 92.1,

78.6, 78.0, 64.5, 54.5, 32.3, 21.0.; HRMS (FAB, MB) m/z calcd

for C₁₉H₂₁N₂O₇(M + H) 389.1349, found 389.1349.

1-(2′,5′-O-Diben zoyl-3′-O-a cetyl-R-^D-a r a bin ofu r a n osyl)-

4-m eth oxy-2-p yr im id on e (52a ). Obtained in 96% yield from

33, as a white powder: mp 70-72 °C; [R]²³-19° (c 2.0,

D

CHCl₃); IR (thin film) 1725, 1664, 1631, 1601, 1585, 1542,

1

1481, 1316, 1266 cm^-1; H NMR (CDCl₃) δ 8.08 (d, J ) 7.2,

2H), 8.03 (d, J ) 7.2, 2H), 7.61-7.50, (m, 2H), 7.46-7.35 (m,

4H), 6.18 (d, J ) 2.4, 1H), 5.94 (d, J ) 7.4, 1H), 5.82 (t, J )

2.4, 1H), 5.46 (t, J ) 2.9, 1H), 4.90-4.85 (m, 1H), 4.67-4.54

(m, 2H), 3.96 (s, 3H), 2.07 (s, 3H); ¹³C NMR δ 172.2, 169.6,

166.1, 165.2, 155.6, 142.9, 133.8, 133.3, 130.0, 129.8, 129.4,

128.6, 128.5, 95.7, 93.0, 84.2, 80.7, 76.9, 63.8, 54.6, 20.7.

Anal. Calcd for C₂₆H₂₄N₂O₉: C, 61.41; H, 4.76; N, 5.51.

Found: C, 61.32; H, 4.88; N, 5.52.

r-2′-Deoxycytid in e (54a ). A solution of 53a (40 mg, 0.103

mmol) in 2.0 M methanolic ammonia (5 mL) was heated at

100 °C for 15 h in a sealed tube. The reaction mixture was

then cooled to room temperature and evaporated to dryness.

Purification by flash chromatography on silica, eluted with

33% methanol in chloroform, gave R-2′-deoxycytidine (54a , 16

mg, 68% yield) as a white powder: mp 201-203 °C (lit.^22amp

203-4 °C); [R]²³-47° (c 0.65, H₂O); IR (KBr) 1658, 1642,

D

1-(3,5-O-Diben zoyl-2-O-[3-(tr iflu or om eth yl)ben zoyl])-

â-^D-r ibofu r a n osyl]-4-m eth oxy-2-p yr im id on e (52b). Ob-

tained in 92% yield from 9, as a white powder: mp 181-182

°C; [R]²³_D-3.9°(c 1.14, CHCl₃); IR (thin film) 1727, 1675, 1638,

1544, 1483, 1315, 1269 cm^-1; ¹H NMR (CDCl₃) δ 8.19 (s, 1H),

8.14 (d, J ) 7.9, 1H), 8.10-8.07 (m, 2H), 7.98-7.95 (m, 2H),

7.79 (d, J ) 7.9, 1H), 7.69 (d, J ) 7.5, 1H), 7.63-7.36 (m, 7H),

6.45 (d, J ) 4.9, 1H), 5.90 (t, J ) 5.4, 1H), 5.82 (m, 2H), 4.85

(dd, J ) 12.0, 2.8, 1H), 4.79-4.75 (m, 1H), 4.69 (dd, J ) 12.0,

3.9, 1H), 3.94 (s, 3H); ¹³C NMR δ 171.9, 166.0, 165.3, 164.1,

155.5, 142.1, 133.8, 133.6, 133.2, 131.2 (q, J _C-F) 33), 130.1,

1605, 1530, 1492, 1289 cm^-1

;

¹H NMR (D₂O) δ 7.80 (d, J )

7.5, 1H), 6.07 (dd, J ) 7.0, 2.4, 1H), 5.96 (d, J ) 7.5, 1H), 4.38-

4.34 (m, 2H), 3.66 (dd, J ) 12.4, 3.7, 1H), 3.57 (dd, J ) 12.4,

5.3, 1H), 2.65 (dt, J ) 14.7, 6.5, 1H), 2.09 (br d, J ) 14.7, 1H);

¹³C NMR δ 166.6, 157.8, 142.2, 95.6, 89.2, 88.3, 71.1, 61.9, 40.3.

2′-Deoxycytid in e (54b). Obtained in 50% as white pow-

der: mp 206-209 °C (lit.⁴⁸mp 200-201 °C); [R]²³_D+54°(c, 0.5,

H₂O) (lit. [R]²⁵D +54° (c 2.0, H₂O); IR (KBr) 1661, 1618, 1486

1

cm^-1; H NMR (D₂O) δ 7.78 (d, J ) 7.5, 1H), 6.23 (t, J ) 6.6,

1H), 6.00 (d, J ) 7.5, 1H), 4.41-4.36 (m, 1H), 4.03-3.99 (m,

Stereocontrolled Syntheses of Deoxyribonucleosides

J . Org. Chem., Vol. 65, No. 19, 2000 5985

1H), 3.80 (dd, J ) 12.5, 3.6, 1H), 3.71 (dd, J ) 12.5, 5.2, 1H),

2.39 (m, 1H), 2.25 (m, 1H). ¹H NMR data are identical with

those of authentic sample.

HRMS (FAB, NBA) m/z calcd for C₃₁H₂₅F₃N₃O₉(M + H)

640.1543 found 640.1547.

1-(3,5-O-Diben zoyl-2-deoxy-â-^D-er yth r o-pen tofu r an osyl)-

4-m eth oxy-1,3,5-tr ia zin -2-on e (57). Obtained as a white

3′-Deoxycytid in e (54c). Obtained in 80% yield as a white

powder: mp 217-219 °C (lit.^31amp 220 °C); [R]²³_D+50° (c 0.8,

solid: mp 196-198 °C; [R]²³6.8° (c 0.32, CHCl₃); ¹H NMR

D

1

H₂O); IR (KBr) 1649, 1605, 1529, 1492, 1403, 1288 cm^-1; H

(CDCl₃) δ 8.54 (s, 1H), 8.04 (d, J ) 8.1, 2H), 7.93 (d, J ) 8.1,

2H), 7.62-7.54 (m, 2H), 7.49-7.40 (m, 4H), 6.26 (dd, J ) 7.8,

5.7, 1H), 5.61 (dt, J ) 6.5, 1.8, 1H), 4.73-4.66 (m, 3H), 3.97

(s, 3H), 3.10 (ddd, J ) 14.5, 5.7, 1.8, 1H), 2.32 (ddd, J ) 14.5,

7.8, 6.5, 1H); ¹³C NMR δ 170.4, 166.0, 165.9, 156.4, 154.1,

133.8, 133.7, 129.8, 129.5, 129.0, 128.9, 128.7, 128.6, 87.7, 84.1,

75.0, 64.2, 56.1, 39.7; HRMS (FAB, NBA) m/z calcd for

NMR (D₂O) δ 7.83 (d, J ) 7.5, 1H), 5.93 (d, J ) 7.5, 1H), 5.75

(s, 1H), 4.51-4.43 (m, 1H), 4.40-4.37 (m, 1H), 3.90 (dd, J )

12.7, 2.8, 1H), 3.71 (dd, J ) 12.7, 5.0, 1H), 1.95-1.90 (m, 2H);

¹³C NMR δ 166.5, 157.8, 141.5, 95.8, 93.3, 81.9, 76.0, 62.4, 32.8.

1-(3,5-O-Diben zoyl-2-[3-(tr iflu or om eth yl)ben zoyl]-â-^D-

r ib ofu r a n osyl)-4-m et h oxy-1,3,5-t r ia zin -2-on e (56). Ob-

tained as a white solid: mp 188-190 °C; [R]²³_D-11.0 ° (c 0.95,

CHCl₃); ¹H NMR (CDCl₃) δ 8.40 (s, 1H), 8.15 (s, 1H), 8.11 (d,

J ) 8.0, 1H), 8.06 (d, J ) 7.9, 2H), 8.00 (d, J ) 7.9, 2H), 7.79

(d, J ) 7.8, 1H), 7.61-7.38 (m, 7H), 6.16 (d, J ) 4.0, 1H), 5.99-

5.90 (m, 2H), 4.86-4.70 (m, 3H), 4.02 (s, 1H); ¹³C NMR δ 170.2,

166.0, 165.2, 164.2, 157.6, 153.6, 133.9, 133.6, 133.2, 131.3 (q,

J _C-F) 33), 130.4, 129.8, 129.7, 129.3, 129.1, 128.7, 128.6, 128.3,

126.7, 123.3 (q, J _C-F) 274), 90.4, 81.1, 75.2, 71.3, 63.7, 56.3;

C

₂₃H₂₂N₃O₇(M + H) 452.1458, found 452.1487.

Ack n ow led gm en t. This work was supported by

Grant No. RPG-96-061-04-CDD from the American

Cancer Society.

Su p p or tin g In for m a tion Ava ila ble: UV spectra of 20

and 21. This material is available free of charge via the

Internet at http://pubs.acs.org.

(48) Fox, J . J .; Yung, N. C.; Wempen, I.; Hoffer, M. J . Am. Chem.

Soc. 1961, 83, 4066.

J O0003652

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Stereocontrolled Syntheses of Deoxyribonucleosides via Photoinduced Electron-Transfer Deoxygenation of Benzoyl-Protected Ribo- and Arabinonucleosides

DOI: 10.1021/jo0003652

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