Synthesis of Benzene and Pyridine 2′-C-Methyl-C-ribonucleosides and -nucleotides

FULL PAPER

DOI: 10.1002/ejoc.201501219

Synthesis of Benzene and Pyridine 2Ј-C-Methyl-C-ribonucleosides and

-nucleotides

[a]

ˇ

Anna Tokarenko, Lenka Postová Slavetínská, Blanka Klepetárová, and

Michal Hocek*^[a,b]

Keywords: Nucleosides / Nucleotides / Glycosides / Antiviral agents / Cross-coupling

A general and modular synthesis of substituted benzene and

pyridine 2Ј-C-methyl-C-ribonucleosides was developed.

Benzyl-protected haloaryl-C-nucleoside intermediates were

prepared by the addition of bromo(het)aryllithium reagents

to a protected lactone, followed by acetylation and reduction.

These halogenated intermediates were further transformed

by Pd-catalysed cross-couplings, aminations, or hydroxyl-

ations. The final deprotection was rather troublesome, and

different procedures involving catalytic hydrogenation on Pd/

C, or treatment with BCl₃, were optimized for each deriva-

tive. The final C-nucleosides were also all converted into the

corresponding NTPs. None of the C-nucleosides showed any

activity in the HCV replicon assay, and none of the NTPs

showed any significant inhibition of the HCV polymerase.

Introduction

Hepatitis C virus (HCV) is an RNA virus. It is a cause

of chronic hepatitis, which often leads to cirrhosis and car-

cinoma. Nucleoside inhibitors of the RNA-dependent

RNA polymerase of HCV show a broad spectrum of ac-

tivity across different serotypes.^[1]The attachment of a

methyl group at the 2Ј-position of ribose to generate modi-

fied ribonucleoside triphosphates is now an established ap-

proach to achieving specific inhibition of the viral RNA

polymerase (without affecting the eukaryotic RNA poly-

merases).^[2]On the other hand, it is known that most sugar-

modified nucleosides are not efficiently phosphorylated by

nucleoside kinases, and therefore they are often delivered

as phosphate prodrugs.^[3]Figure 1 shows the structures of

Sofosbuvir (1),^[4]a phosphate prodrug of a 2Ј-Me-2Ј-fluoro-

ribonucleoside which is now used clinically to treat HCV,

and Valopicitabine (2),^[5]a related unsuccessful clinical can-

didate. Although Sofosbuvir seems to be a very efficient

drug, there is always the threat of the development of resis-

tance, and other related RNA viruses (e.g., Dengue) are

emerging. Therefore, the search for new nucleoside antivi-

rals is still worthwhile.

Figure 1. Structures of anti-HCV nucleosides, and the design of C-

nucleoside analogues.

C-Nucleosides are characterized by replacement of the

enzymatically cleavable C–N nucleosidic bond by a more

stable C–C bond.^[6]There have been several reported exam-

ples of the synthesis of C-nucleoside analogues of 2Ј-Me-

ribonucleosides, mostly of purine analogues. Some of the

[a] Institute of Organic Chemistry and Biochemistry, Academy of triphosphate derivatives of these compounds showed good

inhibition of the HCV RNA polymerase.^[7,8]In most cases,

Sciences of the Czech Republic, Gilead & IOCB Research

Center,

the corresponding nucleosides were inactive or less active

due to inefficient activation, and were tested as diverse

phosphate prodrugs.^[7,8]The syntheses of those C-nucleo-

sides were laborious linear multistep sequences.^[7,8]Each

was aimed at a particular derivative of interest, so this did

not allow the synthesis of larger series of derivatives. In our

laboratory, we have recently developed a general modular

Flemingovo nám. 2, 16610 Prague-6, Czech Republic

E-mail: hocek@uochb.cas.cz

http://ww w .uochb.cas.cz/hocekgroup/

[b] Department of Organic Chemistry, Faculty of Science, Charles

University in Prague,

Hlavova 8, 12843 Prague-2, Czech Republic

Supporting information and ORCID(s) from the author(s) for

this article are available on the WWW under http://dx.doi.org/

10.1002/ejoc.201501219.

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2Ј-C-Methyl-C-ribonucleosides and -nucleotides

approach to C-nucleosides based on the synthesis of haloge- the configuration at C-1, the α and β anomers in hemiketals

nated (het)aryl-C-nucleoside intermediates, and their diver- (and their acetates) refer to the relative configuration of the

gent functionalization by cross-coupling or nucleophilic OH (OAc) at C-1 and O at C-4, whereas in C-nucleosides,

substitution.^[9–13]This approach is advantageous for the the α and β isomers refer to the relative configuration of

synthesis of larger series of C-nucleosides, including benz- the aryl group at C-1 and O at C-4 in analogy to the assign-

ene and pyridine C-ribonucleosides 3^[10–12](Figure 1) bear- ment of α and β anomers in natural N-linked nucleosides

ing different substituents. Therefore, we planned to apply (Figure 2).

this approach to the synthesis of three types of new benzene

and pyridine C-2Ј-Me-ribonucleosides that are carba- and

dicarba-analogues of parent pyrimidine nucleosides related

to Sofosbuvir. The choice of nucleobase surrogates included

phenyl and two isomeric pyridyl moieties substituted either

by hydrophobic (CH₃, OCH₃, NMe₂) or hydrophilic (NH₂,

OH) substituents. It has repeatedly been shown that even

hydrophobic analogues of nucleotides (lacking hydrogen-

bond donors or acceptors) can be substrates of polymer-

ases.^[14]Moreover, the lack of a minor groove hydrogen-

bond acceptor (i.e., the oxo group of cytosine or uracil)

might prevent extension^[15]of the growing DNA or RNA

strand, which would be an advantage for chain terminators.

Results and Discussion

Scheme 2.

The key intermediates for the synthesis of the target C-

nucleosides were the corresponding suitably protected 4-

bromophenyl, 2-bromopyridin-5-yl, and 5-bromopyridin-2-

yl 2Ј-C-methyl C-ribonucleosides. Initially, we attempted to

work with silyl-protected sugar building blocks (similarly to

our previous work^[10–12]), but this gave mixtures of products

that were difficult to separate. Therefore, we chose benzyl

ether protection for the sugars. The starting material, 2-C-

methyl-d-ribonolactone (4), is available in two steps from

d-glucose.^[16]Reaction of the lactone 4 with BnBr and NaH

in DMF at –10 °C gave key perbenzylated building block 5

in very good yield (89%) on a multigram scale (Scheme 1).

Figure 2. Assignment of the relative configuration at C-1 in hemi-

ketals and C-nucleosides.

4-Bromophenyl C-nucleoside intermediate 9 was pre-

pared in a similar way. 4-Bromophenyllithium, generated

by treatment of 1,4-dibromobenzene with nBuLi in THF at

–78 °C, was added to lactone 5 to give hemiketal 8 in excel-

Scheme 1.

lent yield (97%; Scheme 2). As in the previous case, an in-

To attach the aromatic nucleobase surrogate to lactone separable mixture of anomers (α/β = 44:56) was formed,

5, we ran a series of addition reactions using aryllithium and similar epimerization occurred when a solution of 8 in

compounds. Treatment of bromobenzene with nBuLi in [D₆]DMSO was stored at 4 °C (after 2 weeks, the ratio of

THF at –78 °C gave phenyllithium, which subsequently re- anomers became α/β = 8:92). Reduction of 8 (α/β = 44:56)

acted with the lactone to give hemiketal 6 in excellent yield under the standard conditions^[10]using a mixture of Et₃SiH

(99%) as an inseparable mixture of anomers (α/β = 51:49; and BF₃·Et₂O in CH₂Cl₂gave the desired Bn-protected C-

Scheme 2). Interestingly, when a solution of 6 in [D₆]DMSO nucleoside (i.e., 9) in 92% yield as a single β isomer. This

was kept at 4 °C, epimerization occurred, and after 2 weeks, stereoselectivity (which is similar to that seen in our pre-

the ratio of anomers had changed to α/β = 31:69 (in favour vious work^[12]on ribonucleosides) probably results from the

of the thermodynamically more stable β-hemiketal). Re- formation of a planar oxocarbenium cation intermediate

duction of 6 (the originally obtained mixture of anomers α/ (after treatment with Lewis acid), which is then reduced by

β = 51:49) was carried out using Et₃SiH and BF₃·Et₂O in Et₃SiH.

CH₂Cl₂in analogy to a previously developed procedure^[10]

The preparation of isomeric benzyl-protected 2-bromo-

to obtain the desired protected C-nucleoside (i.e., 7) in ex- pyridin-5-yl and 5-bromopyridin-2-yl 2Ј-C-methyl-C-ribo-

cellent yield (94%) as a pure β isomer. For assignment of nucleosides was based on the known dichotomy^[17]in the

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regioselective lithiation of 2,5-dibromopyridine using nBuLi an unwanted α-isomeric side-product 17. The two isomers

in different solvents at –78 °C, in analogy to our previous were easily separable by flash chromatography. Interest-

paper on ribonucleosides.^[12]In Et₂O, a coordinating sol- ingly, the stereoselectivity (the ratio of β isomer 16 to α

vent, 2-bromo-5-lithiopyridine is the dominant species, and isomer 17) of the reduction using Et₃SiH and BF₃·Et₂O was

this reacts with lactone 5 to give the desired hemiketal (i.e., always the same, irrespective of whether we started from

10) in very good yield (89%; Scheme 3). Again, an insepa- pure 14, pure 15, or from a mixture of the two anomers.

rable mixture of two anomers was obtained (α/β = 23:77). However, the ratio could be slightly influenced by the

All our attempts to reduce 10 under the conditions used for choice of solvent. The best results [89% of the desired β

the two previous hemiketals (i.e., 6 and 8; treatment with isomer (i.e., 16)] were achieved when reduction was carried

Et₃SiH and BF₃·Et₂O in CH₂Cl₂) were unsuccessful: no re- out in toluene. Therefore, in preparative experiments, mix-

action was observed, and only starting material was iso- tures of anomers of intermediate 13 and mixtures of 14 and

lated. In analogy to our previous work,^[12]we converted 15 were used directly, and the desired protected bromopyr-

hemiketal 10 into its acetate 11, which should be more reac- idyl C-nucleoside (i.e., 16) was obtained in 53% overall

tive towards reduction. Treatment of 10 with LiHMDS yield (starting from 5) on a multigram scale.

(lithium hexamethyldisilazide) in toluene at 0 °C and subse-

quent quenching with Ac₂O gave hemiketal acetate 11 in

91% yield as an inseparable mixture of anomers (α/β =

44:56). Reduction of 11 by treatment with Et₃SiH and

BF₃·Et₂O in CH₂Cl₂yielded the desired C-nucleoside (i.e.,

12) in good yield (80%) as a single β isomer.

Scheme 4.

Scheme 3.

In a noncoordinating solvent, such as toluene, the lithi-

ation gives^[17]another regioisomer, 5-bromo-2-lithiopyrid-

ine. The addition of this organolithium reagent to lactone

5 gave hemiketal 13 in 72% yield as an inseparable mixture

of anomers (α/β = 9:91; Scheme 4). An attempted direct

reduction of 13 using Et₃SiH and BF₃·Et₂O failed, as had

been seen for 10. To facilitate the reduction, we again tried

to convert 13 into its acetate by treatment with LiHMDS

and Ac₂O in toluene. In this case, the yield was higher when

Figure 3. Chemical and X-ray structures (ORTEP^[18]drawing) of

the deprotonation was carried out at room temperature. As

14 with the atom numbering scheme. Thermal ellipsoids are drawn

a result, we got a mixture of two anomers 14 (59%) and 15

at the 50% probability level.

(23%), which were separated by flash chromatography. The

structure of compound 14 was also confirmed by X-ray

With all three key intermediates 9, 12, and 16 in hand in

structural analysis (Figure 3). Then, we turned our atten- sufficient quantities, we carried out a series of Pd-catalysed

tion to the reduction of hemiketal acetates 14 and 15. Re- cross-coupling, amination and hydroxylation reactions

duction of a mixture of 14 and 15 using the standard pro- (Table 1) in analogy to our previous papers on ribonucleo-

cedure (Et₃SiH and BF₃·Et₂O in CH₂Cl₂) resulted in the sides.^[10–12]Cross-coupling of 9, 12, and 16 with trimethyl-

formation of the desired β isomer (i.e., 16) accompanied by aluminium in the presence of Pd(PPh₃)₄was used to intro-

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2Ј-C-Methyl-C-ribonucleosides and -nucleotides

Table 1. Cross-coupling, amination, and hydroxylation reactions of intermediates 9, 12, and 16.

[a] Then HCl (2 m). [b] Starting from 18d. [c] Starting from 19d. [d] Starting from 20d.

duce a methyl group. Reactions were carried out in THF at CH₃I in the presence of KOH and TBAB (tetrabutylammo-

66 °C, and gave compounds 18a, 19a, and 20a in very good nium bromide) at 80 °C to give methoxy compounds 18e

to excellent yields (91, 95, and 77% respectively).

and 20e in 81 and 66% yields (over two steps), respectively.

Pd-catalysed Hartwig–Buchwald amination reactions^[19]Since compound 19d exists mainly in a pyridone form, its

were used to introduce primary and tertiary amino groups. alkylation could yield products of N- as well as O-methyl-

Reaction with LiHMDS in the presence of Pd₂(dba)₃and ation. Under the conditions described above for the prepa-

Cy-JohnPhos^[20,21]as a ligand yielded aniline and amino- ration of compounds 18e and 20e (treatment with CH₃I and

pyridine C-nucleosides 18b and 19b in 85 and 94% yields, KOH in 1,4-dioxane/water), compound 19d was methylated

respectively. For the synthesis of 20b, P(tBu)₃·HBF₄was mainly at the N-site to give 92% of 21, and only 5% of

used as a ligand to get an acceptable yield of 73%. The the desired O-methylated product (i.e., 19e; Scheme 5). By

dimethylamino group was introduced by reaction with di- changing the base to Ag₂CO₃and the solvent to CH₂Cl₂,

methylamine in toluene in the presence of Pd₂(dba)₃, with

JohnPhos as a ligand and tBuONa as a base. Under these

conditions, compounds 18c, 19c, and 20c were obtained in

good yields of 83–87%.

Palladium-catalysed hydroxylation reactions using KOH,

Pd₂(dba)₃, and tetramethyl-di-tBuXPhos were used for the

preparation of hydroxy derivatives.^[22]Reactions were car-

ried out in a mixture of 1,4-dioxane and water (3:1) at

80 °C, and after heating for 2–4 h gave compounds 18d,

19d, and 20d in excellent yields (93–98%).

Since direct nucleophilic methoxylation of halogenated

intermediates 9, 12, and 16 gave low yields and complex

mixtures, the desired methoxy derivatives were prepared by

methylation of the corresponding hydroxy compounds.^[23]

The crude reaction mixtures after the synthesis of com-

pounds 18d and 20d were directly heated for 30 min with Scheme 5.

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we were able to obtain the desired methoxypyridine C-nu- desired deprotected β isomer (i.e., 22) was obtained in an

cleoside (i.e., 19e) in 68% yield.

excellent 94% yield (Table 2).

With all three series of benzyl-protected 2Ј-C-methyl-C-

The deprotection of dimethylaniline derivative 18c was

ribonucleosides complete, we proceeded to the final depro- the most difficult. Both methods of debenzylation led to the

tection step. The challenge here was the fact that the aryl-C- formation of mixtures of the desired β-C-nucleoside and

nucleosides inherently contain a cyclic benzylic ether group, other side-products (Scheme 7). Treatment with BCl₃at

which might be cleaved by common methods of debenz- –78 °C gave three compounds: β isomer 28c (21%), α iso-

ylation. We tested two different methods for the debenz- mer 24 (37%), and a pyranose derivative 25 (35%). On the

ylation: catalytic hydrogenation, and treatment with a other hand, catalytic hydrogenation of 18c gave a mixture

Lewis acid. For some compounds, the use of either one or of the desired β sugar (i.e., 28c; 43%) and an unexpected

both of these methods resulted in the formation of the de-

sired β-isomeric C-nucleosides. However, in many cases we

observed the formation of different undesired side-products,

and therefore the deprotection procedure had to be selected

and optimized for each particular derivative. For example,

catalytic hydrogenation of compound 7 with H₂and Pd on

charcoal (10%) in acetic acid gave the desired β-C-nucleo-

side (i.e., 22) in 40% yield, accompanied by an acyclic side-

product 23 (53%) containing an overreduced sugar ring

(Scheme 6). Better results were obtained when 7 was treated

with BCl₃at –78 °C for 2 h. Under these conditions, the

Scheme 6.

Scheme 7.

Table 2. Deprotection of benzylated C-nucleosides.

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2Ј-C-Methyl-C-ribonucleosides and -nucleotides

cyclohexanone side-product 26 (48%), which was appar- then be suitable for direct testing for HCV RNA polymer-

ently formed by partial reduction of the aromatic ring and ase inhibition. The NTPs were prepared similarly to a pub-

hydrolysis of an enamine intermediate. In both cases, HPLC lished procedure.^[25]First, the corresponding C-nucleoside

was required to separate the mixtures of products. The lat- was dissolved in P(O)(OMe)₃, and treated with POCl₃for

ter method was used for preparative purposes.

2 h at 0 °C. Then, a precooled solution of tributylammon-

Treatment of compound 19a with BCl₃at –78 °C resulted ium pyrophosphate in DMF and Bu₃N was added, and the

in partial deprotection, and gave C-nucleoside 27 with one reaction mixture was stirred for an additional 2 h. Quench-

benzyl group remaining at the 5Ј-position in 84% yield ing with TEAB (triethylammonium bicarbonate), and sepa-

(Scheme 8). Full deprotection of this C-nucleoside was ration using Sephadex and HPLC gave sodium or trieth-

achieved by gradual warming of the reaction mixture to ylammonium salts of the triphosphates in good to excellent

room temperature, or by catalytic hydrogenation of 19a. yields (51–96%) as hygroscopic white solids after lyophiliza-

(Table 2).

tion (Table 3).

Table 3. Synthesis of NTPs.

Scheme 8.

The optimized preparative procedures and conditions for

the deprotection of each of the C-nucleosides are summa-

rized in the Table 2. In general, catalytic hydrogenation pro-

ceeded better when a special type of palladium catalyst was

used.^[24]Unlike the usual Pd on charcoal (10%), this cata-

lyst contained an unreduced form of Pd distributed as an

“eggshell” on the charcoal particles. Reduction using this

catalyst usually proceeded more quickly, and gave better

yields of the desired β-C-nucleosides.

The structures of all the intermediates and all the final

C-nucleosides were confirmed by NMR spectroscopy. The

assignment of the C-1 configuration was based on two-di-

mensional ROESY experiments. The structure of free

phenol C-nucleoside 28d was confirmed by X-ray structural

analysis; this showed that the sugar ring had a 3Ј-endo con-

formation, which is typical for N-linked 2Ј-methylribo-

nucleosides (Figure 4). In contrast to the hemiketal inter-

mediates, which spontaneously epimerized, the final

C-nucleosides were sufficiently stable for testing and further

transformations.

All 16 final free C-nucleosides 22, 28a–28e, 29a–29e, and

30a–30e were tested for antiviral activity in Huh-7 cells har-

bouring sub-genomic reporter replicons derived from HCV

subtypes 1B and 2A.^[26]No inhibitory activity was observed

at a 10 μm concentration. All the NTPs (i.e., 31, 32a–32e,

33a–33e, and 34a–34e) were tested for inhibition of HCV

polymerase (NS5B),^[8]and no significant activity was ob-

served at a 10 μm concentration. Neither was any of the

NTPs found to be a substrate for T7 RNA polymerase.

Figure 4. Chemical and X-ray structures (ORTEP) of 28d with the

atom numbering scheme. Thermal ellipsoids are drawn at the 50%

probability level.

Since it was previously reported that sugar-modified nu-

cleosides might be poor substrates for nucleoside kinases,

and may not be activated by phosphorylation,^[3]we finally

Conclusions

We have developed a general and modular synthesis of

needed to convert all of the C-nucleosides to the corre- various substituted benzene and pyridine 2Ј-C-methyl-C-ri-

sponding nucleoside triphosphates (NTPs), which would bonucleosides. Although the overall approach is similar to

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2,3,5-Tri-O-benzyl-2-C-methyl- -ribono-1,4-lactone (5): A suspen-

FULL PAPER

our previous papers on the related C-ribonucleosides,^[10–12]

the presence of the additional methyl group at the 2Ј-posi-

tion of the sugar brought several synthetic challenges. There

was increased steric hindrance at C-1, it was necessary to

use more stable benzyl ether protection, and each step had

to be optimized. The synthesis of the key protected

haloaryl-C-nucleoside intermediates was based on additions

of bromo(het)aryllithium species to protected lactone 5, fol-

lowed by acetylation and reduction, which, in most cases,

D

sion of NaH (60% in mineral oil; 6.42 g, 160 mmol) in dry DMF

(30 mL) was added to a stirred solution of 2-C-methyl-d-ribono-

1,4-lactone (4; 20 g, 123 mmol) in dry DMF (400 mL) at –10 °C.

After 1 h, BnBr (22 mL, 185 mmol) was added, and the reaction

mixture was stirred at –10 °C for 30 min. The addition of a suspen-

sion of NaH [NaH (6.42 g) in dry DMF (30 mL)] followed by BnBr

(22 mL) was repeated two more times. The mixture was stirred at

–10 °C for 2 d, then it was poured onto ice, and extracted with

ethyl acetate. The organic phase was dried with anhydrous MgSO₄,

gave the desired β-configured C-nucleosides stereoselec- and concentrated under reduced pressure. The crude product was

purified by flash chromatography on silica gel (14 to 50% of ethyl

acetate in hexane) to give protected lactone 5 (47.5 g, 110 mmol,

89%) as a yellowish oil. HRMS (ESI): calcd. for C₂₇H₂₈O₅Na [M

+ Na]⁺455.18290; found 455.18281. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 1.51 (s, 3 H, CH₃-2), 3.63 (dd, 1 H, J_gem= 11.6, J_5a,4

= 5.0 Hz, 5a-H), 3.75 (dd, 1 H, J_gem= 11.6, J_5b,4= 2.5 Hz, 5b-H),

4.09 (d, 1 H, J_3,4= 7.5 Hz, 3-H), 4.50 (br. d, 1 H, J_gem= 12.1 Hz,

CH₂Bn-5), 4.55 (br. d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5), 4.57 (ddd,

1 H, J_4,3= 7.5, J_4,5a= 5.0, J_4,5b= 2.5 Hz, 4-H), 4.55–4.59 (m, 2 H,

CH₂Bn-2), 4.61 (br. d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3), 4.75 (br. d,

tively. These halogenated intermediates 9, 12, and 16 under-

went a series of Pd-catalysed cross-couplings, aminations,

and hydroxylations to introduce methyl, amino, dimeth-

ylamino, and hydroxy groups. The hydroxy groups were

also further methylated to give methoxy derivatives. The fi-

nal deprotection was the most difficult. Unwanted side-

products were often seen, and either catalytic hydrogenation

on Pd/C or treatment with BCl₃had to be chosen and opti-

mized for each particular derivative. The final C-nucleosides

were also all converted into the corresponding NTPs. Un- 1 H, J_gem= 11.7 Hz, CH₂Bn-3), 7.25–7.39 (m, 15 H, H-o,m,p-Bn)

ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 19.8 (CH₃-2), 67.0

fortunately, none of the C-nucleosides showed any activity

(CH₂Bn-2), 68.6 (CH₂-5), 72.7 (CH₂Bn-3), 72.9 (CH₂Bn-5), 77.3

in the HCV replicon assay, and none of the NTPs showed

(C-2), 80.3 and 80.5 (CH-3,4), 127.9 (CH-o-Bn), 128.0 and 128.1

any significant inhibition of the HCV polymerase, which

demonstrates the relatively narrow specificity of this en-

(CH-p-Bn), 128.1 (CH-o-Bn), 128.3 (CH-p-Bn), 128.4 (CH-o-Bn),

128.7, 128.7, and 128.8 (CH-m-Bn), 138.1, 138.3, and 138.4 (C-i-

zyme. On the other hand, we have shown that our pre-

Bn), 173.8 (C-1) ppm. IR (CCl₄): 3034, 2943, 2868, 1787, 1732,

viously developed modular approach^[9–13]can be extended

1603, 1497, 1454, 1277, 1111, 1028 cm^–1.

to sugar-modified C-nucleosides, which are very rare in the

literature and have much potential in medicinal chemistry.

2,3,5-Tri-O-benzyl-2-C-methyl-1-C-phenyl-α,β-D-ribofuranose (6):

nBuLi (1.6 m in hexanes; 8 mL, 12.71 mmol) was added to a cooled

(–78 °C) stirred solution of PhBr (1.21 mL, 11.55 mmol) in dry

THF (27 mL). After 20 min,

a solution of lactone 5 (1 g,

2.31 mmol) in dry THF (10 mL) was added, and reaction mixture

was stirred for a further 10 min. Subsequently, MeOH (2.8 mL,

69.3 mmol) was added, and the resulting solution was warmed to

room temp., and neutralized with HCl (2 m). The mixture was

washed with satd. aq. NaHCO₃(50 mL), and the aqueous phase

was extracted with ethyl acetate. The combined organic layers were

dried with anhydrous MgSO₄, and concentrated under reduced

pressure. The residue was purified by flash chromatography on sil-

ica gel (0 to 6% of ethyl acetate in hexane) to give hemiketal 6

(1.17 g, 2.29 mmol, 99%; α/β = 51:49) as a colourless oil. HRMS

(ESI): calcd. for C₃₃H₃₄O₅Na [M + Na]⁺533.22985; found

533.22972. ¹H NMR (500 MHz, [D₆]DMSO) α anomer: δ = 0.89

Experimental Section

General Information: All reactions were carried out in dried glass-

ware with magnetic stirring under an argon atmosphere, unless

otherwise specified. THF, toluene, and Et₂O were dried and dis-

tilled from sodium and benzophenone. Other reagents were pur-

chased from commercial suppliers, and were used directly without

further purification. NMR spectra were recorded with Bruker

Avance II 400 (¹H at 400 MHz, and ¹³C at 100.6 MHz), Bruker

Avance II 500 (¹H at 500 MHz, and ¹³C at 125.7 MHz) and Bruker

Avance II 600 (¹H at 600 MHz, and ¹³C at 150.9 MHz) spectrome-

ters. Samples were measured in CDCl₃(referenced to the solvent

signal ¹H NMR δ = 7.26 ppm, ¹³C NMR δ = 77.0 ppm), [D₆]- (s, 3 H, CH₃-2), 3.70–3.75 (m, 2 H, 5-H), 3.88 (d, 1 H, J_3,4= 4.2 Hz,

DMSO (referenced to the solvent signal ¹H NMR δ = 2.50 ppm,

¹³C NMR δ = 39.7 ppm), or D₂O (referenced to dioxane as an

internal standard ¹H NMR δ = 3.75 ppm, ¹³C NMR δ =

67.19 ppm). Chemical shifts are given in ppm (δ scale), and cou-

pling constants (J) in Hertz. Complete assignment of all NMR

signals was carried out using a combination of 2D NMR (H,H-

COSY, H,C-HSQC, and H,C-HMBC) experiments, and configura-

3-H), 4.39 (td, 1 H, J_4,5a= J_4,5b= 4.7, J_4,3= 4.2 Hz, 4-H), 4.52–

4.66 (m, 6 H, CH₂Bn-2,3,5), 5.58 (s, 1 H, OH-1), 7.23–7.41 (m, 18

H, H-o,m,p-Bn, H-m,p-Ph), 7.53 (m, 2 H, H-o-Ph); β anomer: δ =

1.36 (s, 3 H, CH₃-2), 3.65 (dd, 1 H, J_gem= 10.4, J_5a,4= 6.4 Hz, 5a-

H), 3.68 (dd, 1 H, J_gem= 10.4, J_5b,4= 4.0 Hz, 5b-H), 4.07 (d, 1 H,

J_gem= 12.5 Hz, CH₂Bn-2), 4.19 (d, 1 H, J_3,4= 8.0 Hz, 3-H), 4.30

(ddd, 1 H, J_4,3= 8.0, J_4,5a= 6.4, J_4,5b= 4.0 Hz, 4-H), 4.54–4.57

tions were established using two-dimensional ROESY spectra. (m, 2 H, CH₂Bn-5), 4.59 (d, 1 H, J_gem= 12.5 Hz, CH₂Bn-2), 4.67

High-resolution mass spectrometry (HRMS) was carried out with

an LTQ Orbitrap XL mass spectrometer (Thermo Fisher Scientific)

using the electrospray ionization (ESI) technique. Melting points

were measured with a Stuart SMP3 apparatus. IR spectra were

measured with Nicolet 6700 (in CCl₄) and Bruker Alpha (ATR)

FTIR spectrometers. X-ray diffraction experiments of single crys-

tals were carried out with an X-ray diffractometer using Cu_Kαradi-

ation (λ = 1.54180 Å). The purity of all final free C-nucleosides

was determined by analytical HPLC.

and 4.71 (2 d, 2ϫ 1 H, J_gem= 11.8 Hz, CH₂Bn-3), 6.65 (s, 1 H,

OH-1), 6.89 (m, 2 H, H-o-Bn), 7.09–7.16 and 7.23–7.42 (m, 16 H,

H-o,m,p-Bn, H-m,p-Ph), 7.52 (m, 2 H, H-o-Ph) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO) α anomer: δ = 20.7 (CH₃-2), 66.2

(CH₂Bn-2), 70.2 (CH₂-5), 71.9 and 72.7 (CH₂Bn-3,5), 80.1 (CH-4),

82.5 (CH-3), 82.0 (C-2), 105.2 (C-1), 127.0 (CH-o-Ph), 127.3 (CH-

p-Bn), 127.7 (CH-o-Bn), 127.8 (CH-p-Bn), 127.9 (CH-o-Bn), 128.2

and 128.3 (CH-o-Bn), 128.2, 128.4, and 128.5 (CH-m-Bn), 136.2,

138.5, and 139.5 (C-i-Bn), 141.1 (C-i-Ph); β anomer: δ = 15.0 (CH₃-

7968

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Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

2), 65.6 (CH₂Bn-2), 72.6 (CH₂Bn-5), 73.2 (CH₂-5 and CH₂Bn-3),

127.7 (CH-o-Bn), 127.7 (CH-p-Bn), 128.2 and 127.3 (CH-o,m-Bn),

79.4 (CH-4), 83.8 (C-2), 86.9 (CH-3), 106.7 (C-1), 126.3 (CH-o- 128.4 and 128.5 (CH-m-Bn), 129.3 and 130.6 (CH-o,m-Ph), 138.1,

Bn), 126.7 (CH-3), 126.9 and 127.7 (CH-p-Bn), 127.9 (CH-o-Bn), 138.5, and 139.4 (C-i-Bn), 140.5 (C-i-Ph); β anomer: δ = 14.8 (CH₃-

127.9 (CH-p-Bn), 127.8, 127.9, and 128.0 (CH-o,m-Bn, CH-m-Ph), 2), 65.8 (CH₂Bn-2), 72.6 (CH₂Bn-5), 73.0 (CH₂-5), 73.3 (CH₂Bn-

128.2 (CH-o-Ph), 128.4 and 128.5 (CH-m-Bn), 138.6, 138.7, and 3), 79.5 (CH-4), 83.7 (C-2), 86.7 (CH-3), 106.4 (C-1), 121.4 (C-p-

140.4 (C-i-Bn), 140.9 (C-i-Ph) ppm. IR (CCl₄): 3592, 3534, 3032,

Ph), 126.3 (CH-o-Bn), 126.8 and 127.6 (CH-p-Bn), 127.8 (CH-o,p-

Bn), 128.0 (CH-o,m-Bn), 128.4 and 128.5 (CH-m-Bn), 130.0 (CH-

m-Ph), 130.5 (CH-o-Ph), 138.6, 138.6, and 140.3 (C-i-Bn), 140.4

(C-i-Ph) ppm. IR (ATR): 3427, 3040, 2874, 1598, 1501, 1458, 1366,

1211, 1072, 1030, 1012 cm^–1.

2866, 1497, 1454, 1362, 1208, 1097, 1068, 1029 cm^–1.

(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)benzene

(7):

Et₃SiH (1.5 mL, 9.2 mmol) was added to a stirred solution of hemi-

ketal 6 (1.17 g, 2.29 mmol) in dry CH₂Cl₂(12 mL) at 0 °C. After

5 min, BF₃·Et₂O (0.6 mL, 4.6 mmol) was slowly added, and the

resulting mixture was warmed to room temp. over 5 min. Sub-

sequently, Et₃N (3.2 mL, 23 mmol) was added, and the reaction

mixture was concentrated under reduced pressure. The crude prod-

uct was purified by flash chromatography on silica gel (0 to 5% of

ethyl acetate in hexane) to give 7 (1.07 g, 2.16 mmol, 94%) as a

colourless oil. HRMS (ESI): calcd. for C₃₃H₃₄O₄Na [M + Na]⁺

517.23493; found 517.23486. ¹H NMR (500 MHz, CDCl₃): δ = 0.92

(s, 3 H, CH₃), 3.73 (dd, 1 H, J_gem= 10.3, J_5Јa,4Ј= 5.2 Hz, 5Јa-H),

1-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-4-bromo-

benzene (9): Et₃SiH (4.2 mL, 26.48 mmol) was added to a stirred

solution of hemiketal 8 (3.9 g, 6.62 mmol) in dry CH₂Cl₂(39 mL)

at 0 °C. After 5 min, BF₃·Et₂O (1.63 mL, 13.24 mmol) was slowly

added, and the resulting mixture was warmed to room temp. over

5 min. Subsequently, Et₃N (9.2 mL, 66.2 mmol) was added, and the

reaction mixture was concentrated under reduced pressure. The

crude product was purified by flash chromatography on silica gel

(0 to 5% of ethyl acetate in hexane) to give 9 (3.49 g, 6.09 mmol,

3.76 (dd, 1 H, J_gem= 10.3, J_5Јb,4Ј= 4.6 Hz, 5Јb-H), 3.81 (d, 1 H, 92%) as a colourless oil. HRMS (ESI): calcd. for C₃₃H₃₃O₄⁷⁹BrNa

J_3Ј,4Ј= 4.6 Hz, 3Ј-H), 4.36 (br. q, 1 H, J_4Ј,5Јa= J_4Ј,5Јb= J_4Ј,3Ј

=

[M + Na]⁺595.14544; found 595.14553. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.87 (s, 3 H, CH₃-2Ј), 3.69 (dd, 1 H, J_gem= 10.6,

J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 3.72 (dd, 1 H, J_gem= 10.6, J_5Јb,4Ј= 4.6 Hz,

4.8 Hz, 4Ј-H), 4.55, 4.58, 4.62, 4.65, 4.68, and 4.69 (6 d, 6ϫ 1 H,

J_gem= 11.5, 11.8, 11.6, 11.9, 12.0, and 11.8 Hz, CH₂-Bn), 5.09 (s,

1 H, 1Ј-H), 7.21–7.39 (m, 20 H, H-o,m,p-Ph,Bn) ppm. ¹³C NMR 5Јb-H), 3.84 (d, 1 H, J_3Ј,4Ј= 4.5 Hz, 3Ј-H), 4.23 (q, 1 H, J_4Ј,3Ј

=

(125.7 MHz, CDCl₃): δ = 19.2 (CH₃), 66.0 (CH₂Bn), 70.3 (CH₂- J_4Ј,5Јa= J_4Ј,5Јb= 4.6 Hz, 4Ј-H), 4.52 (d, 1 H, J_gem= 11.5 Hz,

5Ј), 71.9 and 73.5 (CH₂Bn), 81.7 (CH-4Ј), 83.1 (CH-3Ј), 83.2 (C-

2Ј), 84.5 (CH-1Ј), 126.5 (CH-o-Ph), 127.1 (CH-p-Bn), 127.2 (CH-

CH₂Bn-3Ј), 4.54 and 4.58 (2 d, 2ϫ 1 H, J_gem= 11.6 Hz, CH₂Bn-

2Ј), 4.60 (d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.62 (d, 1 H, J_gem

=

o-Bn), 127.3 and 127.7 (CH-p-Bn), 127.7, 127.8, and 128.2 (CH-o- 11.5 Hz, CH₂Bn-3Ј), 4.62 (d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.88

Bn, CH-m-Ph, CH-p-Ph), 128.3, 128.4, and 128.4 (CH-m-Bn),

137.8 and 138.1 (C-i-Bn), 138.3 (C-i-Ph), 139.3 (C-i-Bn) ppm. IR

(CCl₄): 3033, 2866, 1607, 1497, 1454, 1382, 1362, 1187, 1097,

1029 cm^–1.

(s, 1 H, 1Ј-H), 7.22–7.35 and 7.36–7.41 (2 m, 17 H, H-o,m,p-Bn, 2-

H, 6-H), 7.48–7.52 (m, 2 H, 3-H, 5-H) ppm. ^{1 3}C NMR

(125.7 MHz, [D₆]DMSO): δ = 18.8 (CH₃-2Ј), 65.6 (CH₂Bn-2Ј), 70.2

(CH₂-5Ј), 71.5 (CH₂Bn-3Ј), 72.7 (CH₂Bn-5Ј), 81.8 (CH-4Ј), 82.8

(C-2Ј, CH-3Ј), 83.3 (CH-1Ј), 120.7 (C-4), 127.3 (CH-p-Bn), 127.4

(CH-o-Bn), 127.7 (CH-p-Bn), 127.8 (CH-o-Bn), 127.8 (CH-p-Bn),

128.2 (CH-o-Bn), 128.3, 128.4, and 128.5 (CH-m-Bn), 128.6 (CH-

2, CH-6), 130.9 (CH-3, CH-5), 138.0 (C-1), 138.2, 138.5, and 139.5

(C-i-Bn) ppm. IR (CCl₄): 3032, 2866, 1608, 1595, 1489, 1454, 1362,

1187, 1093, 1073, 1029, 1013 cm^–1.

2,3,5-Tri-O-benzyl-1-C-(4-bromophenyl)-2-C-methyl-α,β-D-ribo-

furanose (8): nBuLi (1.6 m in hexanes; 11.9 mL, 19.07 mmol) was

added dropwise to a cooled (–78 °C) solution of 1,4-dibromobenz-

ene (4.09 g, 17.34 mmol) in dry THF (105 mL). After 30 min, a

solution of lactone 5 (2.5 g, 5.78 mmol) in dry THF (25 mL) was

added, and the reaction mixture was stirred for a further 10 min.

Subsequently, MeOH (7 mL, 173.4 mmol) was added, and the re-

sulting solution was warmed to room temp., and neutralized with

HCl (2 m). The mixture was washed with satd. aq. NaHCO₃

(130 mL), and the aqueous phase was extracted with ethyl acetate.

The combined organic layers were dried with anhydrous MgSO₄,

and concentrated under reduced pressure. The residue was purified

by flash chromatography on silica gel (0 to 10% of ethyl acetate in

hexane) to give hemiketal 8 (3.3 g, 5.6 mmol, 97%; α/β = 44:56) as

a colourless oil. HRMS (ESI): calcd. for C₃₃H₃₃O₅⁷⁹BrNa [M +

Na]⁺611.14036; found 611.14042. ¹H NMR (500 MHz, [D₆]-

DMSO) α anomer: δ = 0.89 (s, 3 H, CH₃-2), 3.67–3.74 (m, 2 H, 5-

2,3,5-Tri-O-benzyl-1-C-(2-bromopyridin-5-yl)-2-C-methyl-α,β-D-

ribofuranose (10): nBuLi (1.6 m in hexanes; 8 mL, 12.72 mmol) was

added dropwise to a cooled (–78 °C) solution of 2,5-dibromopyrid-

ine (2.74 g, 11.56 mmol) in dry Et₂O (140 mL). After 30 min, a

solution of lactone 5 (1 g, 2.31 mmol) in dry Et₂O (10 mL) was

added, and the reaction mixture was stirred for a further 10 min.

Subsequently, MeOH (2.8 mL, 69.3 mmol) was added, and the re-

sulting yellow solution was warmed to room temp., and neutralized

with HCl (2 m). The mixture was washed with satd. aq. NaHCO₃

(150 mL), and extracted with Et₂O. The combined organic layers

were dried with anhydrous MgSO₄, and concentrated under re-

duced pressure. The residue was purified by flash chromatography

H), 3.87 (d, 1 H, J_3,4= 4.1 Hz, 3-H), 4.39 (td, 1 H, J_4,5a= J_4,5b

=

4.8, J_4,3= 3.1 Hz, 4-H), 4.51–4.69 (m, 6 H, CH₂Bn-2,3,5), 5.68 (s, on silica gel (9 to 16% of ethyl acetate in hexane) to give hemiketal

1 H, OH), 7.22–7.56 (m, 19 H, H-o,m,p-Bn, H-o,m-Ph); β anomer:

δ = 1.35 (s, 3 H, CH₃-2), 3.64 (dd, 1 H, J_gem= 10.5, J_5a,4= 6.5 Hz,

5a-H), 3.68 (dd, 1 H, J_gem= 10.5, J_5b,4= 3.8 Hz, 5b-H), 4.18 (d, 1

10 (1.21 g, 2.06 mmol, 89%; α/β = 23:77) as a white foam. HRMS

(ESI): calcd. for C₃₂H₃₂O₅N⁷⁹BrNa [M + Na]⁺612.13561; found

612.13574. ¹H NMR (500 MHz, [D₆]DMSO) α anomer: δ = 0.93

H, J_gem= 12.6 Hz, CH₂Bn-2), 4.18 (d, 1 H, J_3,4= 8.1 Hz, 3-H), (s, 3 H, CH₃-2), 3.70 (dd, 1 H, J_gem= 10.7, J_5a,4= 4.8 Hz, 5a-H),

4.30 (ddd, 1 H, J_4,3= 8.1, J_4,5a= 6.5, J_4,5b= 3.8 Hz, 4-H), 4.50– 3.72 (dd, 1 H, J_gem= 10.7, J_5b,4= 4.7 Hz, 5b-H), 3.89 (d, 1 H, J_3,4

4.67 (m, 3 H, CH₂Bn-2,5), 4.67 (d, 1 H, J_gem= 11.8 Hz, CH₂Bn- = 4.2 Hz, 3-H), 4.40 (td, 1 H, J_4,5a= J_4,5b= 4.7, J_4,3= 4.2 Hz, 4-

3), 4.70 (d, 1 H, J_gem= 11.8 Hz, CH₂Bn-3), 6.79 (m, 2 H, OH),

6.87–6.92 (m, 2 H, H-o-Bn), 7.11–7.19 and 7.22–7.55 (2 m, 17 H,

H), 4.54–4.65 (m, 6 H, CH₂Bn-2,3,5), 5.97 (br. s, 1 H, OH-1), 7.23–

7.41 (m, 15 H, H-o,m,p-Bn), 7.62 (dd, 1 H, J_3Ј,4Ј= 8.3, J_3Ј,6Ј

=

H-o,m,p-Bn, H-o,m-Ph) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO) 0.8 Hz, 3Ј-H), 7.79 (dd, 1 H, J_4Ј,3Ј= 8.3, J_4Ј,6Ј= 2.5 Hz, 4Ј-H), 8.46

α anomer: δ = 20.7 (CH₃-2), 66.3 (CH₂Bn-2), 70.1 (CH₂-5), 71.9

(CH₂Bn-3), 72.7 (CH₂Bn-5), 80.3 (CH-4), 82.4 (CH-3), 83.0 (C-2), 3 H, CH₃-2), 3.63 (dd, 1 H, J_gem= 10.5, J_5a,4= 6.5 Hz, 5a-H), 3.68

104.9 (C-1), 121.4 (C-p-Ph), 127.3 and 127.3 (CH-p-Bn), 127.4 and (dd, 1 H, J_gem= 10.5, J_5b,4= 3.6 Hz, 5b-H), 4.20 (d, 1 H, J_3,4

(dd, 1 H, J_6Ј,4Ј= 2.5, J_6Ј,3Ј= 0.8 Hz, 6Ј-H); β anomer: δ = 1.34 (s,

=

Eur. J. Org. Chem. 2015, 7962–7983

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7969

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

8.1 Hz, 3-H), 4.27 (d, 1 H, J_gem= 12.4 Hz, CH₂Bn-2), 4.31 (ddd,

1 H, J_4,3= 8.1, J_4,5a= 6.5, J_4,5b= 3.6 Hz, 4-H), 4.52 and 4.55 (2

(CH₂Bn-2), 68.9 (CH₂-5), 72.6 (CH₂Bn-5), 73.5 (CH₂Bn-3), 81.2

(CH-4), 83.3 (CH-3), 84.2 (C-2), 108.0 (C-1), 126.4 (CH-o-Bn),

d, 2ϫ 1 H, J_gem= 12.0 Hz, CH₂Bn-5), 4.67 and 4.72 (2 d, 2ϫ 1 H, 127.0 and 127.1 (CH-p-Bn, CH-3Ј), 127.8 (CH-p-Bn), 128.0 (CH-

J_gem= 11.8 Hz, CH₂Bn-3), 4.76 (d, 1 H, J_gem= 12.4 Hz, CH₂Bn-2), o-Bn), 128.0 (CH-p-Bn), 128.1 and 128.1 (CH-o,m-Bn), 128.5 and

6.89–6.93 (m, 2 H, H-o-Bn), 7.06 (br. s, 1 H, OH-1), 7.13–7.22 and

7.27–7.38 (2 m, 13 H, H-o,m,p-Bn), 7.57 (dd, 1 H, J_3Ј,4Ј= 8.3, J_3Ј,6Ј

128.5 (CH-m-Bn), 133.1 (C-5Ј), 137.9 (CH-4Ј), 138.3, 138.4, and

139.5 (C-i-Bn), 140.9 (C-2Ј), 148.6 (CH-6Ј), 167.6 (CH₃CO) ppm.

= 0.8 Hz, 3Ј-H), 7.72 (dd, 1 H, J_4Ј,3Ј= 8.3, J_4Ј,6Ј= 2.5 Hz, 4Ј-H), IR (ATR): 3040, 2934, 2868, 1755, 1589, 1457, 1368, 1221,

8.38 (dd, 1 H, J_6Ј,4Ј= 2.5, J_6Ј,3Ј= 0.8 Hz, 6Ј-H) ppm. ¹³C NMR 1087 cm^–1.

(125.7 MHz, [D₆]DMSO) α anomer: δ = 20.8 (CH₃-2), 66.3

5-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-2-bromo-

(CH₂Bn-2), 69.9 (CH₂-5), 72.0 and 72.7 (CH₂Bn-3,5), 80.7 (CH-4),

82.2 (CH-3), 83.0 (C-2), 104.0 (C-1), 127.3 (CH-p-Bn), 127.4 (CH-

3Ј), 127.7 (CH-o-Bn), 127.8 (CH-p-Bn), 127.9 (CH-o-Bn), 128.2

and 128.3 (CH-o,m-Bn), 128.4 and 128.5 (CH-m-Bn), 136.6 (C-i-

Bn), 138.2 (C-5Ј), 138.2 (CH-4Ј), 138.4 and 139.3 (C-i-Bn), 141.2

(C-2Ј), 149.0 (CH-6Ј); β anomer: δ = 14.7 (CH₃-2), 66.1 (CH₂Bn-

2), 72.6 (CH₂Bn-5), 72.7 (CH₂-5), 73.4 (CH₂Bn-3), 79.8 (CH-4),

83.6 (C-2), 86.4 (CH-3), 105.6 (C-1), 126.4 (CH-o-Bn), 126.7 (CH-

3Ј), 126.9 and 127.7 (CH-p-Bn), 127.9 (CH-o-Bn), 127.9 (CH-p-

Bn), 128.1 (CH-o,m-Bn), 128.5 (CH-m-Bn), 136.3 (C-5Ј), 138.5 (C-

i-Bn), 139.4 (CH-4Ј), 140.0 (C-i-Bn), 141.0 (C-2Ј), 150.0 (CH-6Ј)

ppm. IR (CCl₄): 3033, 2927, 2867, 1583, 1497, 1454, 1361, 1208,

1087, 1029 cm^–1.

pyridine (12): Et₃SiH (2 mL, 12.6 mmol) was added to a stirred

solution of hemiketal acetate 11 (2.64 g, 4.2 mmol) in dry CH₂Cl₂

(27 mL) at 0 °C. After 5 min, BF₃·Et₂O (0.8 mL, 6.3 mmol) was

slowly added, and the resulting mixture was warmed to room temp.

over 5 min. Subsequently, Et₃N (5.85 mL, 42 mmol) was added,

and the reaction mixture was concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (6

to 13% of ethyl acetate in hexane) to give 12 (1.93 g, 3.36 mmol,

8 0 % ) a s a y e l l o w i s h o i l . H R M S ( E S I ) : c a l c d . f o r

C

₃₂H₃₂O₄N⁷⁹BrNa [M + Na]⁺596.14069; found 596.14079. ¹H

NMR (500 MHz, [D₆]DMSO): δ = 0.91 (s, 3 H, CH₃-2Ј), 3.70 (dd,

1 H, J_gem= 10.7, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 3.73 (dd, 1 H, J_gem

=

10.7, J_5Јb,4Ј= 4.7 Hz, 5Јb-H), 3.88 (d, 1 H, J_3Ј,4Ј= 4.4 Hz, 3Ј-H),

4.25 (br. q, 1 H, J_4Ј,3Ј= J_4Ј,5Јa= J_4Ј,5Јb= 4.6 Hz, 4Ј-H), 4.53 (d, 1

H, J_gem= 11.4 Hz, CH₂Bn-3Ј), 4.54–4.65 (m, 5 H, CH₂Bn-2Ј,3Ј,5Ј),

4.95 (br. s, 1 H, 1Ј-H), 7.23–7.35 and 7.36–7.41 (2 m, 15 H, H-

o,m,p-Bn), 7.60 (dd, 1 H, J_3,4= 8.3, J_3,6= 0.8 Hz, 3-H), 7.70 (dd,

1 H, J_4,3= 8.3, J_4,6= 2.5 Hz, 4-H), 8.34 (dd, 1 H, J_6,4= 2.5, J_6,3

= 0.8 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 18.7

(CH₃-2Ј), 65.7 (CH₂Bn-2Ј), 70.0 (CH₂-5Ј), 71.5 (CH₂Bn-3Ј), 72.7

(CH₂Bn-5Ј), 81.4 (CH-1Ј), 82.2 (CH-4Ј), 82.7 (CH-3Ј), 82.8 (C-2Ј),

127.3 (CH-p-Bn), 127.5 (CH-o-Bn), 127.6 (CH-3), 127.8 (CH-o,p-

Bn), 127.9 (CH-p-Bn), 128.3 (CH-o-Bn), 128.3, 128.4, and 128.5

(CH-m-Bn), 134.0 (C-5), 137.6 (CH-4), 138.2, 138.4, and 139.2 (C-

i-Bn), 140.6 (C-2), 148.5 (CH-6) ppm. IR (CCl₄): 3033, 2867, 1584,

1562, 1497, 1455, 1384, 1188, 1089, 1024 cm^–1.

1-O-Acetyl-2,3,5-tri-O-benzyl-1-C-(2-bromopyridin-5-yl)-2-C-

methyl-α,β-D-ribofuranose (11): LiHMDS (1 m in THF; 5.5 mL,

5.49 mmol) was added dropwise to a cooled (0 °C) solution of 10

(2.16 g, 3.66 mmol) in dry toluene (25 mL). After 10 min, Ac₂O

(0.53 mL, 5.49 mmol) was added, and the mixture was stirred for

a further 10 min. Then, the mixture was warmed to room temp.,

poured into satd. aq. NaHCO₃(50 mL), and extracted with tolu-

ene. The combined organic layers were dried with anhydrous

MgSO₄, and concentrated under reduced pressure. The residue was

purified by flash chromatography on silica gel (9 to 16% of ethyl

acetate in hexane) to give hemiketal acetate 11 (2.11 g, 3.33 mmol,

91 %; α/β = 44:56) as a yellowish oil. HRMS (ESI): calcd. for

C

₃₄H₃₄O₆N⁷⁹BrNa [M + Na]⁺654.14617; found 654.14623. ¹H

NMR (500 MHz, [D₆]DMSO) α anomer: δ = 0.90 (s, 3 H, CH₃-2),

1.99 (s, 3 H, CH₃CO), 3.68 (dd, 1 H, J_gem= 10.9, J_5a,4= 4.7 Hz, ribofuranose (13): nBuLi (1.6 m in hexanes; 3.4 mL, 5.5 mmol) was

2,3,5-Tri-O-benzyl-1-C-(5-bromopyridin-2-yl)-2-C-methyl-α,β-D-

5a-H), 3.71 (dd, 1 H, J_gem= 10.9, J_5b,4= 4.7 Hz, 5b-H), 3.94 (d, 1

H, J_3,4= 3.4 Hz, 3-H), 4.42 (td, 1 H, J_4,5a= J_4,5b= 4.7, J_4,3

3.4 Hz, 4-H), 4.53 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3), 4.56 (d, 1

added dropwise to a cooled (–78 °C) solution of 2,5-dibromopyrid-

ine (1.184 g, 5 mmol) in dry toluene (59 mL). The reaction mixture

was stirred at –78 °C for 7 h. Then, a solution of lactone 5 (0.433 g,

=

H, J_gem= 12.0 Hz, CH₂Bn-2), 4.57–4.64 (m, 2 H, CH₂Bn-5), 4.61 1 mmol) in dry toluene (5 mL) was added, and the mixture was

(d, 1 H, J_gem= 11.9 Hz, CH₂Bn-2), 4.63 (d, 1 H, J_gem= 11.7 Hz, stirred for a further 10 min. Subsequently, MeOH (1.2 mL,

CH₂Bn-3), 7.20–7.42 (m, 15 H, H-o,m,p-Bn), 7.65 (dd, 1 H, J_3Ј,4Ј30 mmol) was added, and the resulting brown-yellow solution was

= 8.3, J_3Ј,6Ј= 0.8 Hz, 3Ј-H), 7.70 (dd, 1 H, J_4Ј,3Ј= 8.3, J_4Ј,6Ј

=

warmed to room temp., and neutralized with HCl (2 m). The mix-

2.5 Hz, 4Ј-H), 8.38 (dd, 1 H, J_6Ј,4Ј= 2.5, J_6Ј,3Ј= 0.8 Hz, 6Ј-H); β

ture was washed with satd. aq. NaHCO₃(70 mL), and extracted

anomer: δ = 1.45 (s, 3 H, CH₃-2), 1.77 (s, 3 H, CH₃CO), 3.52 (dd, with toluene. The combined organic layers were dried with anhy-

1 H, J_gem= 11.3, J_5a,4= 3.3 Hz, 5a-H), 3.71 (dd, 1 H, J_gem= 11.3, drous MgSO₄, and concentrated under reduced pressure. The crude

J_5b,4= 2.5 Hz, 5b-H), 4.23 (d, 1 H, J_gem= 12.3 Hz, CH₂Bn-2), 4.38 product was purified by flash chromatography on silica gel (9 to

(br. ddd, 1 H, J_4,3= 8.4, J_4,5a= 3.3, J_4,5b= 2.4 Hz, 4-H), 4.41 (d,

1 H, J_3,4= 8.4 Hz, 3-H), 4.45 and 4.48 (2 d, 2 ϫ 1 H, J_gem

12.0 Hz, CH₂Bn-5), 4.67 (d, 1 H, J_gem= 11.8 Hz, CH₂Bn-3), 4.70

(d, 1 H, J_gem= 12.3 Hz, CH₂Bn-2), 4.75 (d, 1 H, J_gem= 11.8 Hz,

CH₂Bn-3), 6.86 (m, 2 H, H-o-Bn), 7.18–7.42 (m, 13 H, H-o,m,p-

16% of ethyl acetate in hexane) to give hemiketal 13 as a yellowish

oil (0.425 g, 0.72 mmol, 72%; α/β = 9:91). HRMS (ESI): calcd.

for C₃₂H₃₂O₅N⁷⁹BrNa [M + Na]⁺612.13561; found 612.13570. ¹H

NMR (500 MHz, [D₆]DMSO) α anomer: δ = 0.96 (s, 3 H, CH₃-2),

3.72 (dd, 1 H, J_gem= 10.7, J_5a,4= 4.2 Hz, 5a-H), 3.74 (dd, 1 H,

=

Bn), 7.58 (dd, 1 H, J_3Ј,4Ј= 8.3, J_3Ј,6Ј= 0.8 Hz, 3Ј-H), 7.65 (dd, 1 J_gem= 10.7, J_5b,4= 5.2 Hz, 5b-H), 4.00 (d, 1 H, J_3,4= 6.5 Hz, 3-

H, J_4Ј,3Ј= 8.3, J_4Ј,6Ј= 2.5 Hz, 4Ј-H), 8.31 (dd, 1 H, J_6Ј,4Ј= 2.5,

H), 4.35 (br. ddd, 1 H, J_4,3= 6.5, J_4,5b= 5.1, J_4,5a= 4.2 Hz, 4-H),

J_6Ј,3Ј= 0.8 Hz, 6Ј-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO) α 4.55 and 4.58 (2 br. d, 2ϫ 1 H, J_gem= 12.0 Hz, CH₂Bn-5), 4.58

anomer: δ = 20.9 (CH₃-2), 22.0 (CH₃CO), 66.2 (CH₂Bn-2), 69.6 and 4.65 (2 d, 2ϫ 1 H, J_gem= 11.5 Hz, CH₂Bn-3), 4.71 and 4.78

(CH₂-5), 71.5 (CH₂Bn-3), 72.8 (CH₂Bn-5), 80.9 (CH-3), 83.7 (CH- (2 d, 2ϫ 1 H, J_gem= 11.7 Hz, CH₂Bn-2), 6.01 (br. s, 1 H, OH-1),

4), 84.5 (C-2), 106.5 (C-1), 127.2 (CH-o-Bn), 127.2 (CH-p-Bn),

7.23–7.45 (m, 15 H, H-o,m,p-Bn), 7.62 (dd, 1 H, J_3Ј,4Ј= 8.5, J_3Ј,6Ј

127.6 (CH-3Ј), 127.7 (CH-p-Bn), 127.8 and 127.8 (CH-o-Bn), 128.2, = 0.8 Hz, 3Ј-H), 8.03 (dd, 1 H, J_4Ј,3Ј= 8.5, J_4Ј,6Ј= 2.4 Hz, 4Ј-H),

128.3, and 128.5 (CH-m-Bn), 133.8 (C-5Ј), 137.0 (CH-4Ј), 138.3, 8.69 (dd, 1 H, J_6Ј,4Ј= 2.4, J_6Ј,3Ј= 0.8 Hz, 6Ј-H); β anomer: δ = 1.53

138.5, and 139.5 (C-i-Bn), 141.1 (C-2Ј), 147.7 (CH-6Ј), 168.4

(CH₃CO); β anomer: δ = 14.2 (CH₃-2), 21.7 (CH₃CO), 66.1

(s, 3 H, CH₃-2), 3.65 (dd, 1 H, J_gem= 10.5, J_5a,4= 6.4 Hz, 5a-H),

3.69 (dd, 1 H, J_gem= 10.5, J_5b,4= 3.7 Hz, 5b-H), 4.14 (d, 1 H, J_3,4

7970

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Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

= 8.1 Hz, 3-H), 4.27 (d, 1 H, J_gem= 12.5 Hz, CH₂Bn-2), 4.29 (ddd, 1 H, J_4,3= 6.1, J_4,5a= 4.2, J_4,5b= 3.3 Hz, 4-H), 4.54 (d, 1 H, J_gem

1 H, J_4,3= 8.1, J_4,5a= 6.4, J_4,5b= 3.7 Hz, 4-H), 4.55 and 4.58 (2

d, 2ϫ 1 H, J_gem= 12.0 Hz, CH₂Bn-5), 4.68 (d, 1 H, J_gem= 11.8 Hz,

= 11.7 Hz, CH₂Bn-3), 4.57 (d, 1 H, J_gem= 12.0 Hz, CH₂Bn-5), 4.59

(br. d, 1 H, J_gem= 11.9 Hz, CH₂Bn-2), 4.61 (d, 1 H, J_gem= 12.1 Hz,

CH₂Bn-3), 4.69 (d, 1 H, J_gem= 12.5 Hz, CH₂Bn-2), 4.72 (d, 1 H, CH₂Bn-5), 4.64 (d, 1 H, J_gem= 11.8 Hz, CH₂Bn-3), 4.90 (d, 1 H,

J_gem= 11.8 Hz, CH₂Bn-3), 6.74 (s, 1 H, OH-1), 6.78–6.84 (m, 2 H, J_gem= 11.9 Hz, CH₂Bn-2), 7.21–7.46 (m, 15 H, H-o,m,p-Bn), 7.58

H-o-Bn), 7.11–7.16 and 7.26–7.39 (2 m, 13 H, H-o,m,p-Bn), 7.58 (dd, 1 H, J_3Ј,4Ј= 8.5, J_3Ј,6Ј= 0.8 Hz, 3Ј-H), 7.99 (dd, 1 H, J_4Ј,3Ј

(dd, 1 H, J_3Ј,4Ј= 8.5, J_3Ј,6Ј= 0.8 Hz, 3Ј-H), 7.95(dd, 1 H, J_4Ј,3Ј8.5, J_4Ј,6Ј= 2.4 Hz, 4Ј-H), 8.67 (dd, 1 H, J_6Ј,4Ј= 2.4, J_6Ј,3Ј= 0.8 Hz,

8.5, J_4Ј,6Ј= 2.4 Hz, 4Ј-H), 8.68 (dd, 1 H, J_6Ј,4Ј= 2.4, J_6Ј,3Ј= 0.8 Hz, 6Ј-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 20.7 (CH₃-2),

6Ј-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO) α anomer: δ = 19.4

21.8 (CH₃CO), 66.0 (CH₂Bn-2), 69.0 (CH₂-5), 72.2 (CH₂Bn-3),

(CH₃-2), 66.4 (CH₂Bn-2), 70.6 (CH₂-5), 72.6 and 72.6 (CH₂Bn- 72.7 (CH₂Bn-5), 81.4 (CH-4), 82.1 (CH-3), 84.0 (C-2), 107.7 (C-1),

=

3,5), 79.6 (CH-4), 82.7 (C-2), 83.9 (CH-3), 105.5 (C-1), 119.8 (C-

5Ј), 123.7 (CH-3Ј), 127.2 (CH-p-Bn), 127.5 and 127.7 (CH-o-Bn),

127.8 and 127.9 (CH-p-Bn), 127.9 (CH-o-Bn), 128.2, 128.2, and

128.4 (CH-m-Bn), 138.4 and 138.5 (C-i-Bn), 139.1 (CH-4Ј), 139.8

(C-i-Bn), 149.2 (CH-6Ј), 159.0 (C-2Ј); β anomer: δ = 15.6 (CH₃-2),

65.9 (CH₂Bn-2), 72.6 (CH₂Bn-5), 72.7 (CH₂-5), 73.3 (CH₂Bn-3),

79.5 (CH-4), 84.6 (C-2), 86.5 (CH-3), 105.7 (C-1), 119.6 (C-5Ј),

125.0 (CH-3Ј), 126.3 (CH-o-Bn), 126.8 and 127.6 (CH-p-Bn), 127.9

(CH-o,p-Bn), 128.9 (CH-o-Bn), 128.0, 128.4, and 128.5 (CH-m-Bn),

138.3 (CH-4Ј), 138.6 and 140.2 (C-i-Bn), 148.7 (CH-6Ј), 158.7 (C-

2Ј) ppm. IR (ATR): 3039, 2945, 2867, 1581, 1562, 1500, 1457, 1366,

1261, 1211, 1181, 1094, 1030 cm^–1.

119.5 (C-5Ј), 123.9 (CH-3Ј), 127.1 (CH-p-Bn), 127.3 (CH-o-Bn),

127.8 and 127.8 (CH-p-Bn), 127.9 and 128.0 (CH-o-Bn), 128.2,

128.3, and 128.6 (CH-m-Bn), 138.3 and 138.5 (C-i-Bn), 139.1 (CH-

4Ј), 140.0 (C-i-Bn), 149.2 (CH-6Ј), 156.5 (C-2Ј), 168.2 (CH₃CO)

ppm. IR (CCl₄): 3032, 2917, 2865, 1756, 1574, 1497, 1454, 1365,

1232, 1094, 1029 cm^–1.

2-(2,3,5-Tri-O-benzyl-2-C-methyl-β-

pyridine (16) and 2-(2,3,5-Tri-O-benzyl-2-C-methyl-α-

D

-ribofuranosyl)-5-bromo-

-ribofurano-

D

syl)-5-bromopyridine (17): Et₃SiH (3.77 mL, 23.61 mmol) was

added to a stirred solution of a mixture of hemiketal acetates 14

and 15 (4.98 g, 7.87 mmol) in dry toluene (50 mL) at 0 °C. After

5 min, BF₃·Et₂O (1.46 mL, 11.81 mmol) was slowly added, and the

resulting mixture was warmed to room temp. over 5 min. Sub-

sequently, Et₃N (11 mL, 78.7 mmol) was added, and the reaction

mixture was concentrated under reduced pressure. The crude prod-

uct was purified by flash chromatography on silica gel (6 to 13%

of ethyl acetate in hexane) to give 16 (4.02 g, 7 mmol, 89%) as a

yellowish oil, and as a side-product, α isomer 17 (0.41 g,

0.71 mmol, 9%) as a yellowish oil.

1-O-Acetyl-2,3,5-tri-O-benzyl-1-C-(5-bromopyridin-2-yl)-2-C-

methyl-β-

D

-ribofuranose (14) and 1-O-Acetyl-2,3,5-tri-O-benzyl-1-

-ribofuranose (15):

C-(5-bromopyridin-2-yl)-2-C-methyl-α-

D

LiHMDS (1 m in THF; 13 mL, 12.98 mmol) was added dropwise

to solution of 13 (5.11 g, 8.65 mmol) in dry toluene (70 mL) at

room temp. After 10 min, Ac₂O (1.23 mL, 12.98 mmol) was added,

and the mixture was stirred for a further 10 min. Then, the mixture

was poured into satd. aq. NaHCO₃(100 mL), and extracted with

toluene. The combined organic layers were dried with anhydrous

MgSO₄, and concentrated under reduced pressure. The residue was

purified by flash chromatography on silica gel (9 to 16% of ethyl

acetate in hexane) to give hemiketal acetates 14 (3.23 g, 5.1 mmol,

59%) as a white solid, and 15 (1.26 g, 1.99 mmol, 23%) as a yellow-

ish oil, which were used as a mixture for the next step.

Data for 16: HRMS (ESI): calcd. for C₃₂H₃₂O₄N⁷⁹BrNa [M +

Na]⁺596.14069; found 596.14080. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.94 (s, 3 H, CH₃-2Ј), 3.72 (dd, 1 H, J_gem= 11.0,

J_5Јa,4Ј= 4.5 Hz, 5Јa-H), 3.81 (dd, 1 H, J_gem= 11.0, J_5Јb,4Ј= 3.1 Hz,

5Јb-H), 3.88 (d, 1 H, J_3Ј,4Ј= 7.6 Hz, 3Ј-H), 4.21 (ddd, 1 H, J_4Ј,3Ј

7.6, J_4Ј,5Јa= 4.5, J_4Ј,5Јb= 3.1 Hz, 4Ј-H), 4.57 (d, 1 H, J_gem

=

11.9 Hz, CH₂Bn-5Ј), 4.59 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.61

(d, 1 H, J_gem= 11.9 Hz, CH₂Bn-5Ј), 4.63 (d, 1 H, J_gem= 11.7 Hz,

CH₂Bn-3Ј), 4.69 (m, 2 H, CH₂Bn-2Ј), 5.02 (s, 1 H, 1Ј-H), 7.23–7.41

Data for 14: m.p. 112–113 °C. HRMS (ESI): calcd. for

C

₃₄H₃₄O₆N⁷⁹BrNa [M + Na]⁺654.14617; found 654.14626. ¹H

NMR (500 MHz, [D₆]DMSO): δ = 1.58 (s, 3 H, CH₃-2), 1.72 (s, 3 (m, 15 H, H-o,m,p-Bn), 7.59 (dt, 1 H, J_3,4= 8.4, J_3,6= J_3,1Ј

=

H, CH₃CO), 3.55 (dd, 1 H, J_gem= 11.1, J_5a,4= 3.4 Hz, 5a-H), 3.73

(dd, 1 H, J_gem= 11.1, J_5b,4= 2.3 Hz, 5b-H), 4.16 (br. d, 1 H, J_gem

= 12.5 Hz, CH₂Bn-2), 4.36 (d, 1 H, J_3,4= 8.4 Hz, 3-H), 4.38 (ddd,

1 H, J_4,3= 8.4, J_4,5a= 3.4, J_4,5b= 2.4 Hz, 4-H), 4.47 and 4.50 (2

0.8 Hz, 3-H), 7.94 (dd, 1 H, J_4,3= 8.4, J_4,6= 2.4 Hz, 4-H), 8.67

(dd, 1 H, J_{6 ,4}= 2.4, J_{6, 3}= 0.8 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 19.1 (CH₃-2Ј), 65.2 (CH₂Bn-2Ј), 69.7

(CH₂-5Ј), 72.5 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 80.1 (CH-4Ј), 83.1

(CH-3Ј), 83.3 (C-2Ј), 85.7 (CH-1Ј), 119.2 (C-5), 123.4 (CH-3), 127.3

(CH-p-Bn), 127.4 (CH-o-Bn), 127.7 and 127.8 (CH-p-Bn), 127.9

and 128.1 (CH-o-Bn), 128.3, 128.4, and 128.5 (CH-m-Bn), 138.4

d, 2ϫ 1 H, J_gem= 12.0 Hz, CH₂Bn-5), 4.63 (br. d, 1 H, J_gem

=

12.5 Hz, CH₂Bn-2), 4.68 and 4.76 (2 d, 2ϫ 1 H, J_gem= 11.8 Hz,

CH₂Bn-3), 6.78 (m, 2 H, H-o-Bn-2), 7.12–7.17 (m, 3 H, H-m,p-Bn-

2), 7.26–7.40 (m, 10 H, H-o,m,p-Bn-3,5), 7.55 (dd, 1 H, J_3Ј,4Ј= 8.5, and 138.5 (C-i-Bn), 139.3 (CH-4), 139.5 (C-i-Bn), 149.5 (CH-6),

J_3Ј,6Ј= 0.8 Hz, 3Ј-H), 7.97 (dd, 1 H, J_4Ј,3Ј= 8.5, J_4Ј,6Ј= 2.4 Hz, 4Ј- 158.3 (C-2) ppm. IR (CCl₄): 3033, 2894, 2864, 1575, 1497, 1465,

H), 8.62 (dd, 1 H, J_6Ј,4Ј= 2.4, J_6Ј,3Ј= 0.8 Hz, 6Ј-H) ppm. 13C

NMR (125.7 MHz, [D₆]DMSO): δ = 14.9 (CH₃-2), 21.5 (CH₃CO),

65.9 (CH₂Bn-2), 69.3 (CH₂-5), 72.6 (CH₂Bn-5), 73.5 (CH₂Bn-3),

81.1 (CH-4), 83.8 (CH-3), 84.8 (C-2), 107.4 (C-1), 119.5 (C-5Ј),

125.3 (CH-3Ј), 126.3 (CH-o-Bn), 127.0 and 127.7 (CH-p-Bn), 127.9

(CH-o-Bn), 128.0 (CH-p-Bn), 128.0 (CH-o,m-Bn), 128.5 and 128.5

(CH-m-Bn), 138.4 and 138.4 (C-i-Bn), 138.4 (CH-4Ј), 139.6 (C-i-

Bn), 148.5 (CH-6Ј), 155.8 (C-2Ј), 167.5 (CH₃CO) ppm. IR (ATR):

3042, 2946, 2880, 1747, 1501, 1460, 1369, 1239, 1080, 1031 cm^–1.

1454, 1367, 1206, 1091, 1029 cm^–1.

Data for 17: HRMS (ESI): calcd. for C₃₂H₃₃O₄N⁷⁹Br [M + H]⁺

1

574.15875; found 574.15905. H NMR (500 MHz, [D₆]DMSO): δ

= 1.52 (s, 3 H, CH₃-2Ј), 3.61 (dd, 1 H, J_gem= 10.9, J_5Јa,4Ј= 5.0 Hz,

5Јa-H), 3.71 (dd, 1 H, J_gem= 10.9, J_5Јb,4Ј= 2.7 Hz, 5Јb-H), 4.13 (d,

1 H, J_3Ј,4Ј= 8.6 Hz, 3Ј-H), 4.27 (d, 1 H, J_gem= 12.4 Hz, CH₂Bn-

2Ј), 4.30 (ddd, 1 H, J_4Ј,3Ј= 8.6, J_4Ј,5Јa= 5.0, J_4Ј,5Јb= 2.7 Hz, 4Ј-H),

4.51 and 4.56 (2 d, 2ϫ 1 H, J_gem= 12.2 Hz, CH₂Bn-5Ј), 4.65 (d, 1

H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.70 (d, 1 H, J_gem= 12.4 Hz,

CH₂Bn-2Ј), 4.74 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.84 (s, 1 H,

1Ј-H), 6.85 (m, 2 H, H-o-Bn-2Ј), 7.12–7.18 (m, 3 H, H-m,p-Bn-2Ј),

7.27–7.40 (m, 10 H, H-o,m,p-Bn-3Ј,5Ј), 7.46 (dt, 1 H, J_3,4= 8.4,

Data for 15: HRMS (ESI): calcd. for C₃₄H₃₄O₆N⁷⁹BrNa [M +

Na]⁺654.14617; found 654.14652. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.92 (s, 3 H, CH₃-2), 1.96 (s, 3 H, CH₃CO), 3.70 (dd,

1 H, J_gem= 11.1, J_5a,4= 4.2 Hz, 5a-H), 3.79 (dd, 1 H, J_gem= 11.1, J_3,6= J_3,1Ј= 0.7 Hz, 3-H), 7.98 (dd, 1 H, J_4,3= 8.4, J_4,6= 2.4 Hz,

J_5b,4= 3.3 Hz, 5b-H), 3.83 (d, 1 H, J_3,4= 6.1 Hz, 3-H), 4.37 (ddd,

4-H), 8.63 (dd, 1 H, J_6,4= 2.4, J_6,3= 0.7 Hz, 6-H) ppm. ¹³C NMR

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7971

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

(125.7 MHz, [D₆]DMSO): δ = 17.9 (CH₃-2Ј), 65.8 (CH₂Bn-2Ј), 70.5

125.6 (C-4), 127.2 (CH-p-Bn), 127.3 (CH-3, CH-5, CH-o-Bn), 127.4

(CH₂-5Ј), 72.6 (CH₂Bn-5Ј), 73.3 (CH₂Bn-3Ј), 79.7 (CH-4Ј), 81.8 (CH-p-Bn), 127.7 (CH-o-Bn), 127.8 (CH-p-Bn), 128.2 and 128.3

(C-2Ј), 86.0 (CH-3Ј), 86.5 (CH-1Ј), 118.9 (C-5), 124.4 (CH-3), 126.3 (CH-o,m-Bn), 128.3 and 128.5 (CH-m-Bn), 138.4, 138.6, and 138.7

(CH-o-Bn-2Ј), 126.9 (CH-p-Bn-2Ј), 127.7, 127.8, 129.9, and 128.0 (C-i-Bn), 148.1 (C-1) ppm. IR (CCl₄): 3479, 3394, 3032, 2866, 1623,

(CH-o,p-Bn-3Ј,5Ј and CH-m-Bn-2Ј), 128.5 and 128.5 (CH-m-Bn-

3Ј,5Ј), 138.5 (C-i-Bn-3Ј,5Ј), 138.6 (CH-4), 140.1 (C-i-Bn-2Ј), 148.7

(CH-6), 157.7 (C-2) ppm. IR (CCl₄): 3032, 2876, 1578, 1497, 1467,

1454, 1367, 1209, 1090, 1029 cm^–1.

1519, 1497, 1454, 1382, 1362, 1275, 1177, 1096, 1029 cm^–1.

4-(2,3,5-Tri-O-benzyl-2-C-methyl-β- -ribofuranosyl)-N,N-di-

D

methylaniline (18c): Me₂NH (2 m in THF; 9 mL, 17.95 mmol) was

added to a stirred suspension of 9 (2 g, 3.49 mmol), Pd₂(dba)₃

(80 mg, 0.087 mmol), JohnPhos [(2-biphenyl)-di-tert-butylphos-

phine; 107 mg, 0.349 mmol], and tBuONa (2.012 g, 20.94 mmol)

in dry toluene (10 mL) in a flame-dried septum-sealed flask. The

resulting mixture was stirred at 70 °C for 24 h, then it was

quenched by pouring into satd. aq. NaHCO₃(30 mL). The mixture

was extracted with toluene. The combined organic layers were dried

with anhydrous MgSO₄, and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (5

to 15% of ethyl acetate in hexane) to give 18c (1.56 g, 2.9 mmol,

83%) as a yellowish solid, m.p. 65–66 °C. HRMS (ESI): calcd. for

C₃₅H₄₀O₄N [M + H]⁺538.29519; found 538.29510. ¹H NMR

(500 MHz, [D₆]DMSO): δ = 0.90 (s, 3 H, CH₃-2Ј), 2.86 [s, 6 H,

1-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-4-methyl-

benzene (18a): Me₃Al (2 m in toluene; 3.15 mL, 6.3 mmol) was

added to a stirred solution of 9 (1.2 g, 2.1 mmol) and Pd(PPh₃)₄

(127 mg, 0.11 mmol) in dry THF (12 mL) in a flame-dried septum-

sealed flask. The resulting mixture was stirred at 66 °C for 1 h, then

it was quenched by pouring into saturated NaH₂PO₄(50 mL). The

mixture was extracted with ethyl acetate. The combined organic

layers were dried with anhydrous MgSO₄, and concentrated under

reduced pressure. The residue was purified by flash chromatog-

raphy on silica gel (0 to 5% of ethyl acetate in hexane) to give 18a

(971 mg, 1.91 mmol, 91%) as a white solid, m.p. 57–58 °C. HRMS

(ESI): calcd. for C₃₄H₃₆O₄Na [M + Na]⁺531.25058; found

531.25072. ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.88 (s, 3 H, (CH₃)₂N], 3.69 (dd, 1 H, J_gem= 10.6, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 3.72

CH₃-2Ј), 2.28 (s, 3 H, CH₃-4), 3.70 (dd, 1 H, J_gem= 10.7, J_5Јa,4Ј(dd, 1 H, J_gem= 10.6, J_5Јb,4Ј= 4.5 Hz, 5Јb-H), 3.81 (d, 1 H, J_3Ј,4Ј

4.9 Hz, 5Јa-H), 3.73 (dd, 1 H, J_gem= 10.7, J_5Јb,4Ј= 4.6 Hz, 5Јb-H), = 4.9 Hz, 3Ј-H), 4.16 (q, 1 H, J_4Ј,3Ј= J_4Ј,5Јa= J_4Ј,5Јb= 4.8 Hz, 4Ј-

=

3.82 (d, 1 H, J_3Ј,4Ј= 4.8 Hz, 3Ј-H), 4.20 (q, 1 H, J_4Ј,3Ј= J_4Ј,5Јa

J_4Ј,5Јb= 4.7 Hz, 4Ј-H), 4.51–4.65 (m, 6 H, CH₂Bn), 4.86 (s, 1 H,

=

H), 4.53 (br. d, 1 H, J_gem= 11.5 Hz, CH₂Bn-2Ј), 4.54 (d, 1 H, J_gem

= 11.5 Hz, CH₂Bn-3Ј), 4.58 (br. d, 1 H, J_gem= 11.5 Hz, CH₂Bn-

1Ј-H), 7.11 (m, 2 H, 3-H, 5-H), 7.24 (m, 2 H, 2-H, 6-H), 7.25–7.42 2Ј), 4.60 (d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.61 (d, 1 H, J_gem

(m, 15 H, H-o,m,p-Bn) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO):

11.5 Hz, CH₂Bn-3Ј), 4.62 (d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.80

δ = 18.9 (CH₃-2Ј), 20.9 (CH₃-4), 65.5 (CH₂Bn-2Ј), 70.3 (CH₂-5Ј), (s, 1 H, 1Ј-H), 6.65 (m, 2 H, 2-H, 6-H), 7.16 (m, 2 H, 3-H, 5-H),

=

71.5 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 81.5 (CH-4Ј), 82.8 (C-2Ј), 83.1

(CH-3Ј), 84.0 (CH-1Ј), 126.4 (CH-2, CH-6), 127.2 (CH-p-Bn),

127.3 (CH-o-Bn), 127.7 (CH-o,p-Bn), 127.8 (CH-p-Bn), 128.2 and

7.22–7.36 (m, 11 H, H-o,m,p-Bn), 7.36–7.42 (m, 4 H, H-o,m-Bn)

ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 18.9 (CH₃-2Ј), 40.3

[(CH₃)₂N], 65.4 (CH₂Bn-2Ј), 70.4 (CH₂-5Ј), 71.6 (CH₂Bn-3Ј), 72.6

128.2 (CH-o,m-Bn), 128.3 and 128.5 (CH-m-Bn), 128.6 (CH-3, CH- (CH₂Bn-5Ј), 81.2 (CH-4Ј), 82.9 (C-2Ј), 83.2 (CH-3Ј), 84.4 (CH-1Ј),

5), 135.6 (C-1), 136.5 (C-4), 138.3, 138.5, and 138.6 (C-i-Bn) ppm.

IR (CCl₄): 3032, 2866, 1608, 1497, 1454, 1382, 1362, 1180, 1095,

1029 cm^–1.

111.9 (CH-2, CH-6), 125.9 (C-4), 128.2 (CH-p-Bn), 127.3 (CH-3,

CH-5, CH-o-Bn), 127.7 (CH-p-Bn), 127.7 (CH-o-Bn), 127.8 (CH-

p-Bn), 128.2 and 128.2 (CH-o,m-Bn), 128.3 and 128.5 (CH-m-Bn),

138.4, 138.6, and 138.7 (C-i-Bn), 149.9 (C-1) ppm. IR (ATR): 3072,

3040, 2876, 1621, 1528, 1457, 1359, 1190, 1092, 1065, 1030 cm^–1.

4-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)aniline (18b):

LiHMDS (1 m in THF; 4.2 mL, 4.18 mmol) was added to a flame-

dried septum-sealed flask containing 9 (1.2 g, 2.09 mmol), Pd₂-

(dba)₃(48 mg, 0.05 mmol), and Cy-JohnPhos [(2-biphenyl)dicyclo-

hexylphosphine; 73 mg, 0.21 mmol] in dry THF (15 mL). The re-

sulting solution was stirred at 66 °C for 30 min. The mixture was

then cooled to room temp., and stirred with HCl (2 m aq.; 10 mL)

for 10 min. The mixture was then washed with satd. aq. NaHCO₃

(20 mL), and the aqueous phase was extracted with ethyl acetate.

The combined organic layers were dried with anhydrous MgSO₄,

and concentrated under reduced pressure. The crude product was

purified by flash chromatography on silica gel (10 to 60% of ethyl

acetate in hexane) to (0.91 g, 1.78 mmol, 85%) give 18b as a yellow-

ish solid, m.p. 89–91 °C. HRMS (ESI): calcd. for C₃₃H₃₅O₄NNa

[M + Na]⁺532.24583; found 532.24566. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.89 (s, 3 H, CH₃-2Ј), 3.68 (dd, 1 H, J_gem= 10.6,

J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 3.71 (dd, 1 H, J_gem= 10.6, J_5Јb,4Ј= 4.5 Hz,

4-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)phenol (18d): A

suspension of 9 (1.15 g, 2 mmol), Pd₂(dba)₃(46 mg, 0.05 mmol),

Me₄(tBu)₂XPhos (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-

2Ј,4Ј,6Ј-triisopropylbiphenyl; 96 mg, 0.2 mmol), and KOH (337 mg,

6 mmol) in a mixture of 1,4-dioxane (9 mL) and water (3 mL) was

stirred at 80 °C for 2 h. The mixture was cooled to room temp.,

diluted with ethyl acetate, filtered through Celite, and concentrated

under reduced pressure. The crude product was purified by flash

chromatography on silica gel (9 to 14% of ethyl acetate in hexane)

to give 18d (0.972 g, 1.9 mmol, 95%) as a colourless oil. HRMS

(ESI): calcd. for C₃₃H₃₄O₅Na [M + Na]⁺533.22985; found

533.22966. ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.88 (s, 3 H,

CH₃-2Ј), 3.69 (dd, 1 H, J_gem= 10.6, J_5Јa,4Ј= 4.8 Hz, 5Јa-H), 3.72

(dd, 1 H, J_gem= 10.6, J_5Јb,4Ј= 4.5 Hz, 5Јb-H), 3.81 (d, 1 H, J_3Ј,4Ј

= 4.9 Hz, 3Ј-H), 4.17 (q, 1 H, J_4Ј,3Ј= J_4Ј,5Јa= J_4Ј,5Јb= 4.8 Hz, 4Ј-

5Јb-H), 3.78 (d, 1 H, J_3Ј,4Ј= 5.2 Hz, 3Ј-H), 4.13 (br. q, 1 H, J_4Ј,3ЈH), 4.53 (d, 1 H, J_gem= 11.5 Hz, CH₂Bn-3Ј), 4.53 (d, 1 H, J_gem

=

= J_4Ј,5Јa= J_4Ј,5Јb= 4.9 Hz, 4Ј-H), 4.53 (br. d, 1 H, J_gem= 11.6 Hz, 11.6 Hz, CH₂Bn-2Ј), 4.58 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-2Ј), 4.60

CH₂Bn-2Ј), 4.54 (d, 1 H, J_gem= 11.5 Hz, CH₂Bn-3Ј), 4.58 (br. d, 1

H, J_gem= 11.5 Hz, CH₂Bn-2Ј), 4.59 (d, 1 H, J_gem= 12.1 Hz,

CH₂Bn-5Ј), 4.61 (d, 1 H, J_gem= 11.5 Hz, CH₂Bn-3Ј), 4.62 (d, 1 H,

(d, 1 H, J_gem= 12.0 Hz, CH₂Bn-5Ј), 4.61 (d, 1 H, J_gem= 11.5 Hz,

CH₂Bn-3Ј), 4.62 (d, 1 H, J_gem= 12.0 Hz, CH₂Bn-5Ј), 4.80 (s, 1 H,

1Ј-H), 6.68 (m, 2 H, 2-H, 6-H), 7.14 (m, 2 H, 3-H, 5-H), 7.22–7.34

J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.73 (s, 1 H, 1Ј-H), 4.98 (br. s, 2 H, and 7.36–7.42 (2 m, 15 H, H-o,m,p-Bn), 9.32 (s, 1 H, OH-Ph) ppm.

NH₂), 6.48 (m, 2 H, 2-H, 6-H), 6.99 (m, 2 H, 3-H, 5-H), 7.21–7.35 ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 18.9 (CH₃-2Ј), 65.4

(m, 11 H, H-o,m,p-Bn), 7.36–7.42 (m, 4 H, H-o,m-Bn) ppm. ¹³C

(CH₂Bn-2Ј), 70.3 (CH₂-5Ј), 71.6 (CH₂Bn-3Ј), 72.7 (CH₂Bn-5Ј), 81.2

NMR (125.7 MHz, [D₆]DMSO): δ = 19.0 (CH₃-2Ј), 65.4 (CH₂Bn- (CH-4Ј), 82.8 (C-2Ј), 83.1 (CH-3Ј), 84.3 (CH-1Ј), 114.8 (CH-2, CH-

2Ј), 70.4 (CH₂-5Ј), 71.6 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 80.9 (CH- 6), 127.2 (CH-p-Bn), 127.3 (CH-o-Bn), 127.7 (CH-o-Bn, CH-3,

4Ј), 82.8 (C-2Ј), 83.2 (CH-3Ј), 84.8 (CH-1Ј), 113.4 (CH-2, CH-6),

CH-5), 127.7 (CH-p-Bn), 127.8 (CH-p-Bn), 128.2 (CH-o-Bn),

7972

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

128.3, 128.3, and 128.5 (CH-m-Bn), 128.8 (C-4), 138.3, 138.6, and 136.3 (CH-4), 137.5, 137.9, and 138.8 (C-i-Bn), 145.7 (CH-6), 156.5

139.7 (C-i-Bn), 156.8 (C-1) ppm. IR (ATR): 3368, 3039, 2875, 1620, (C-2) ppm. IR (CCl₄): 3067, 3032, 2866, 1604, 1571, 1496, 1454,

1521, 1457, 1366, 1268, 1172, 1078, 1029 cm^–1.

1382, 1188, 1095, 1029 cm^–1.

4-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)anisole (18e): A

2-Amino-5-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-

suspension of 9 (140 mg, 0.244 mmol), Pd₂(dba)₃(6 mg,

0.006 mmol), Me₄(tBu)₂XPhos (2-di-tert-butylphosphino-3,4,5,6-

tetramethyl-2Ј,4Ј,6Ј-triisopropylbiphenyl; 12 mg, 0.024 mmol), and

KOH (41 mg, 0.732 mmol) in a mixture of 1,4-dioxane (0.9 mL)

and water (0.3 mL) was stirred at 80 °C for 2 h. Then, the reaction

mixture was cooled to room temp., and TBAB (8 mg, 0.024 mmol),

additional KOH (27 mg, 0.488 mmol), and CH₃I (0.03 mL,

0.488 mmol) were added. The resulting suspension was stirred for

a further 30 min at 80 °C. The mixture was cooled to room temp.,

diluted with ethyl acetate, filtered through Celite, and concentrated

under reduced pressure. The residue was purified by flash

chromatography on silica gel (5 to 11% of ethyl acetate in hexane)

pyridine (19b): LiHMDS (1 m in THF; 1.4 mL, 1.4 mmol) was

added to a flame-dried septum-sealed flask containing 12 (400 mg,

0.7 mmol), Pd₂(dba)₃(16 mg, 0.018 mmol), and Cy-JohnPhos [(2-

biphenyl)dicyclohexylphosphine; 25 mg, 0.07 mmol] in dry THF

(7.5 mL). The resulting solution was stirred at 70 °C for 30 min.

The mixture was cooled to room temp., and stirred with HCl (2 m

aq.; 4 mL) for 10 min. The mixture was then washed with satd. aq.

NaHCO₃(10 mL), and the aqueous phase was extracted with ethyl

acetate. The combined organic layers were dried with anhydrous

MgSO₄, and concentrated under reduced pressure. The residue was

purified by flash chromatography on silica gel (33 to 67% of ethyl

acetate in hexane) to give 19b (335 mg, 0.66 mmol, 94%) as a yel-

to give 18e (0.972 g, 1.9 mmol, 95%) as a white solid, m.p. 67– lowish oil. HRMS (ESI): calcd. for C₃₂H₃₅O₄N₂[M + H]⁺

68 °C. HRMS (ESI): calcd. for C₃₄H₃₆O₅Na [M + Na]⁺547.24550;

511.25913; found 511.25905. H NMR (500 MHz, [D₆]DMSO): δ

= 0.94 (s, 3 H, CH₃-2Ј), 3.67 (dd, 1 H, J_gem= 10.6, J_5Јa,4Ј= 4.8 Hz,

1

found 547.24537. H NMR (500 MHz, [D₆]DMSO): δ = 0.88 (s, 3

H, CH₃-2Ј), 3.70 (dd, 1 H, J_gem= 10.6, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 5Јa-H), 3.70 (dd, 1 H, J_gem= 10.6, J_5Јb,4Ј= 4.6 Hz, 5Јb-H), 3.81 (d,

3.73 (dd, 1 H, J_gem= 10.6, J_5Јb,4Ј= 4.6 Hz, 5Јb-H), 3.73 (s, 3 H,

CH₃O), 3.82 (d, 1 H, J_3Ј,4Ј= 4.8 Hz, 3Ј-H), 4.19 (q, 1 H, J_4Ј,3Ј

1 H, J_3Ј,4Ј= 4.8 Hz, 3Ј-H), 4.16 (td, 1 H, J_4Ј,5Јa= J_4Ј,3Ј= 4.8, J_4Ј,5Јb

= 4.6 Hz, 4Ј-H), 4.51–4.63 (m, 6 H, CH₂Bn-2Ј,3Ј,5Ј), 4.75 (s, 1 H,

=

J_4Ј,5Јa= J_4Ј,5Јb= 4.8 Hz, 4Ј-H), 4.54 (d, 1 H, J_gem= 11.5 Hz, 1Ј-H), 5.86 (br. s, 2 H, NH₂), 6.37 (dd, 1 H, J_3,4= 8.5, J_3,6= 0.8 Hz,

CH₂Bn-3Ј), 4.54 and 4.59 (2 br. d, 2ϫ 1 H, J_gem= 11.6 Hz, CH₂Bn-

2Ј), 4.61 (d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.62 (d, 1 H, J_gem

11.5 Hz, CH₂Bn-3Ј), 4.63 (d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.85

(s, 1 H, 1Ј-H), 6.86 (m, 2 H, 2-H, 6-H), 7.22–7.42 (m, 17 H, H-

3-H), 7.22–7.34 and 7.35–7.40 (2 m, 16 H, H-o,m,p-Bn, 4-H), 8.01

(dt, 1 H, J_6,4= 2.4, J_6,3= J_6,1Ј= 0.8 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 18.9 (CH₃-2Ј), 65.4 (CH₂Bn-2Ј), 70.9

(CH₂-5Ј), 71.5 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 81.3 (CH-4Ј), 82.7

=

o,m,p-Bn, CH-3, CH-5) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): (C-2Ј), 82.9 (CH-1Ј), 83.0 (CH-3Ј), 107.3 (CH-3), 121.4 (C-5), 127.2

δ = 18.8 (CH₃-2Ј), 55.1 (CH₃O), 65.5 (CH₂Bn-2Ј), 70.3 (CH₂-5Ј), (CH-p-Bn), 127.3 (CH-o-Bn), 127.7 (CH-o,p-Bn), 127.8 (CH-p-Bn),

71.5 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 81.4 (CH-4Ј), 82.8 (C-2Ј), 83.1

(CH-3Ј), 83.9 (CH-1Ј), 113.3 (CH-2, CH-6), 127.2 (CH-p-Bn),

128.2 (CH-o-Bn), 128.3, 128.3, and 128.5 (CH-m-Bn), 135.7 (CH-

4), 138.3 (C-i-Bn-3Ј), 138.5 (C-i-Bn-5Ј), 139.6 (C-i-Bn-2Ј), 146.2

127.3 (CH-o-Bn), 127.7 (CH-o,p-Bn, CH-3, CH-5, CH-p-Bn), (CH-6), 159.5 (C-2) ppm. IR (ATR): 3477, 3374, 3186, 3039, 2875,

128.2, 128.3, and 128.5 (CH-o-Bn, CH-m-Bn), 130.5 (C-4), 138.3, 1623, 1504, 1412, 1364, 1088 cm^–1.

138.5, and 139.6 (C-i-Bn), 158.7 (C-1) ppm. IR (CCl₄): 2900, 2865,

5-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-2-(dimethyl-

1615, 1514, 1454, 1382, 1362, 1248, 1172, 1094, 1041, 1029 cm^–1.

amino)pyridine (19c): Me₂NH (2 m in THF; 4.9 mL, 9.85 mmol)

was added to a stirred suspension of 12 (1.13 g, 1.97 mmol),

Pd₂(dba)₃(45 mg, 0.049 mmol), JohnPhos [(2-biphenyl)-di-tert-but-

ylphosphine; 59 mg, 0.197 mmol], and tBuONa (1.136 g,

11.82 mmol) in dry toluene (4 mL) in a flame-dried septum-sealed

flask. The resulting mixture was stirred at 70 °C for 4 h, then it

was quenched by pouring into satd. aq. NaHCO₃(15 mL), and the

mixture was extracted with toluene. The combined organic layers

were dried with anhydrous MgSO₄, and concentrated under re-

duced pressure. The crude product was purified by flash

chromatography on silica gel (5 to 30% of ethyl acetate in hexane)

to give 19c (923 mg, 1.72 mmol, 87%) as a yellowish solid, m.p.

76–78 °C. HRMS (ESI): calcd. for C₃₄H₃₉O₄N₂[M + H]⁺

5-(2,3,5-Tri-O-benzyl-2-C-methyl-β- -ribofuranosyl)-2-methyl-

D

pyridine (19a): Me₃Al (2 m in toluene; 1 mL, 2.1 mmol) was added

to a stirred solution of 12 (400 mg, 0.7 mmol) and Pd(PPh₃)₄

(41 mg, 0.035 mmol) in dry THF (8 mL) in a flame-dried septum-

sealed flask. The resulting mixture was stirred at 66 °C for 1 h, then

it was quenched by pouring into saturated NaH₂PO₄(50 mL). The

mixture was extracted with ethyl acetate. The combined organic

layers were dried with anhydrous MgSO₄, and concentrated under

reduced pressure. The crude product was purified by flash

chromatography on silica gel (17 to 25% of ethyl acetate in hexane)

to give 19a (340 mg, 0.67 mmol, 95%) as a yellowish oil. HRMS

(ESI): calcd. for C₃₃H₃₆O₄N [M + H]⁺510.26389; found 510.26395.

¹H NMR (500 MHz, CDCl₃): δ = 0.91 (s, 3 H, CH₃-2Ј), 2.62 (s, 3

1

539.29043; found 539.29035. H NMR (500 MHz, [D₆]DMSO): δ

H, CH₃-2), 3.66 (dd, 1 H, J_gem= 10.2, J_5Јa,4Ј= 5.6 Hz, 5Јa-H), 3.71 = 0.94 (s, 3 H, CH₃-2Ј), 2.99 [s, 6 H, (CH₃)₂N], 3.68 (dd, 1 H, J_gem

(dd, 1 H, J_gem= 10.2, J_5Јb,4Ј= 4.7 Hz, 5Јb-H), 3.78 (d, 1 H, J_3Ј,4Ј

= 3.8 Hz, 3Ј-H), 4.36 (ddd, 1 H, J_4Ј,5Јa= 5.6, J_4Ј,5Јb= 4.7, J_4Ј,3Ј

= 10.6, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 3.71 (dd, 1 H, J_gem= 10.6, J_5Јb,4Ј

= 4.6 Hz, 5Јb-H), 3.83 (d, 1 H, J_3Ј,4Ј= 4.7 Hz, 3Ј-H), 4.17 (ddd, 1

H, J_4Ј,5Јa= 4.9, J_4Ј,3Ј= 4.7, J_4Ј,5Јb= 4.6 Hz, 4Ј-H), 4.53 (d, 1 H,

J_gem= 11.4 Hz, CH₂Bn-3Ј), 4.53 and 4.57 (2 br. d, 2ϫ 1 H, J_gem

=

3.8 Hz, 4Ј-H), 4.49 (d, 1 H, J_gem= 11.1 Hz, CH₂Bn-2Ј), 4.53 (d, 1

H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.56 (d, 1 H, J_gem= 11.1 Hz,

CH₂Bn-2Ј), 4.63 and 4.65 (2 d, 2ϫ 1 H, J_gem= 11.9 Hz, CH₂Bn-

5Ј), 4.68 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 5.05 (s, 1 H, 1Ј-H),

7.15 (br. d, 1 H, J_3,4= 8.1 Hz, 3-H), 7.23–7.41 (m, 15 H, H-o,m,p-

= 11.6 Hz, CH₂Bn-2Ј), 4.60 and 4.62 (2 br. d, 2ϫ 1 H, J_gem

=

12.1 Hz, CH₂Bn-5Ј), 4.61 (d, 1 H, J_gem= 11.5 Hz, CH₂Bn-3Ј), 4.79

(s, 1 H, 1Ј-H), 6.56 (dd, 1 H, J_3,4= 8.8, J_3,6= 0.8 Hz, 3-H), 7.21–

7.33 and 7.36–7.41 (2 m, 15 H, H-o,m,p-Bn), 7.46 (ddd, 1 H, J_4,3

= 8.8, J_4,6= 2.5, J_4,1Ј= 0.6 Hz, 4-H), 8.01 (dt, 1 H, J_6,4= 2.5, J_6,3

Bn), 7.75 (br. d, 1 H, J_4,3= 8.1 Hz, 4-H), 8.56 (br. dt, 1 H, J_6,4

=

2.2, J_6,3= J_6,1Ј= 0.8 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = 19.04 (CH₃-2Ј), 23.2 (CH₃-2), 66.3 (CH₂Bn-2Ј), 70.1 = J_6,1Ј= 0.8 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO):

(CH₂-5Ј), 71.7 (CH₂Bn-3Ј), 73.6 (CH₂Bn-5Ј), 82.0 (CH-1Ј), 82.6 δ = 18.9 (CH₃-2Ј), 37.9 [(CH₃)₂N], 65.5 (CH₂Bn-2Ј), 70.3 (CH₂-5Ј),

(CH-4Ј), 82.7 (CH-3Ј), 83.0 (C-2Ј), 123.2 (CH-3), 127.3 (CH-o-Bn), 71.5 (CH₂Bn-3Ј), 72.7 (CH₂Bn-5Ј), 81.5 (CH-4Ј), 82.7 (C-2Ј), 82.8

127.3 (CH-p-Bn), 127.8 (CH-o-Bn), 127.8 and 127.9 (CH-p-Bn), (CH-1Ј), 83.1 (CH-3Ј), 105.1 (CH-3), 120.9 (C-5), 127.2 (CH-p-Bn),

128.2 (CH-o-Bn), 128.3, 128.4, and 128.5 (CH-m-Bn), 131.7 (C-5),

127.4 (CH-o-Bn), 127.7 (CH-o,p-Bn), 127.8 (CH-p-Bn), 128.2 (CH-

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7973

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

o-Bn), 128.3, 128.4, and 128.5 (CH-m-Bn), 135.9 (CH-4), 138.3 (C-

p-Bn), 128.2 (CH-o-Bn), 128.2, 128.3, and 128.4 (CH-m-Bn), 137.5

i-Bn-3Ј), 138.5 (C-i-Bn-5Ј), 139.5 (C-i-Bn-2Ј), 146.1 (CH-6), 158.9 (CH-4), 138.2, 138.4, and 139.4 (C-i-Bn), 144.9 (CH-6), 163.3 (C-

(C-2) ppm. IR (ATR): 3071, 3039, 2884, 1702, 1613, 1522, 1458, 2) ppm. IR (ATR): 3039, 2874, 1613, 1579, 1498, 1458, 1287, 1093,

1381, 1200, 1108, 1030 cm^–1.

1028 cm^–1.

5-(2,3,5-Tri-O-benzyl-2-C-methyl-β-

D

-ribofuranosyl)-2-pyridone

Data for 21: HRMS (ESI): calcd. for C₃₃H₃₆O₅N [M + H]⁺

526.25880; found 526.25874. H NMR (500 MHz, [D₆]DMSO): δ

= 1.03 (s, 3 H, CH₃-2Ј), 3.32 (s, 3 H, CH₃N), 3.68 (dd, 1 H, J_gem

= 10.7, J_5Јa,4Ј= 4.6 Hz, 5Јa-H), 3.72 (dd, 1 H, J_gem= 10.7, J_5Јb,4Ј

1

(19d): A suspension of 12 (1.344 g, 2.34 mmol), Pd₂(dba)₃(54 mg,

0.059 mmol), Me₄(tBu)₂XPhos (2-di-tert-butylphosphino-3,4,5,6-

tetramethyl-2Ј,4Ј,6Ј-triisopropylbiphenyl; 112 mg, 0.234 mmol),

and KOH (394 mg, 7.02 mmol) in a mixture of 1,4-dioxane = 4.3 Hz, 5Јb-H), 3.85 (d, 1 H, J_3Ј,4Ј= 5.4 Hz, 3Ј-H), 4.16 (dt, 1 H,

(9.6 mL) and water (3.2 mL) was stirred at 80 °C for 2 h. The mix-

ture was cooled to room temp., then it was diluted with ethyl acet-

ate, filtered through Celite, and concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

gel (0 to 5 % of MeOH in ethyl acetate) to give 19d (1.115 g,

J_4Ј,3Ј= 5.4, J_4Ј,5Јa= J_4Ј,5Јb= 4.4 Hz, 4Ј-H), 4.56 (d, 1 H, J_gem=

11.5 Hz, CH₂Bn-3Ј), 4.62–4.56 (m, 4 H, CH₂Bn-2Ј,5Ј), 4.62 (d, 1

H, J_gem= 11.5 Hz, CH₂Bn-3Ј), 4.69 (s, 1 H, 1Ј-H), 6.31 (br. dd, 1

H, J_3,4= 9.4, J_3,6= 0.5 Hz, 3-H), 7.22–7.39 (m, 15 H, H-o,m,p-

Bn), 7.39 (dd, 1 H, J_4,3= 9.5, J_4,6= 2.5 Hz, 4-H), 7.60 (dt, 1 H,

J_6,4= 2.5, J_6,3= J_6,1Ј= 0.7 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz,

2.18 mmol, 93 %) as a yellowish oil. HRMS (ESI): calcd. for

1

C₃₂H₃₃O₅NNa [M + Na]⁺534.22509; found 534.22498. H NMR [D₆]DMSO): δ = 18.7 (CH₃-2Ј), 37.0 (CH₃N), 65.5 (CH₂Bn-2Ј),

(500 MHz, [D₆]DMSO): δ = 1.00 (s, 3 H, CH₃-2Ј), 3.65 (dd, 1 H, 69.9 (CH₂-5Ј), 71.7 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 81.0 (CH-4Ј),

J_gem= 10.7, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 3.69 (dd, 1 H, J_gem= 10.7,

J_5Јb,4Ј= 4.4 Hz, 5Јb-H), 3.82 (d, 1 H, J_3Ј,4Ј= 4.9 Hz, 3Ј-H), 4.15

(br. q, 1 H, J_4Ј,3Ј= J_4Ј,5Јa= J_4Ј,5Јb= 4.6 Hz, 4Ј-H), 4.53 (d, 1 H,

J_gem= 11.5 Hz, CH₂Bn-3Ј), 4.57 (m, 2 H, CH₂Bn-2Ј), 4.57 and

82.0 (CH-1Ј), 82.7 (CH-3Ј), 82.8 (C-2Ј), 115.6 (C-5), 118.6 (CH-3),

127.2 (CH-p-Bn), 127.4 (CH-o-Bn), 127.7 (CH-p-Bn), 127.8 (CH-

o,p-Bn), 127.2 (CH-o,m-Bn), 128.3 and 128.5 (CH-m-Bn), 137.4

(CH-6), 138.3 and 138.4 (C-i-Bn), 138.9 (CH-4), 139.5 (C-i-Bn),

4.60 (2 d, 2ϫ 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.60 (d, 1 H, J_gem161.7 (C-2) ppm. IR (CCl₄), 3032, 2866, 1673, 1614, 1541, 1497,

= 11.5 Hz, CH₂Bn-3Ј), 4.69 (br. d, 1 H, J_1Ј,LR= 0.9 Hz, 1Ј-H), 6.26

(dd, 1 H, J_3,4= 9.5, J_3,6= 0.8 Hz, 3-H), 7.21–7.41 (m, 16 H, H-

o,m,p-Bn, 6-H), 7.40 (br. dd, 1 H, J_4,3= 9.5, J_4,6= 2.6 Hz, 4-H),

11.53 (br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO):

δ = 18.7 (CH₃-2Ј), 65.5 (CH₂Bn-2Ј), 70.0 (CH₂-5Ј), 71.6 (CH₂Bn-

3Ј), 72.6 (CH₂Bn-5Ј), 81.4 (CH-4Ј), 81.7 (CH-1Ј), 82.7 (C-2Ј), 82.8

(CH-3Ј), 115.3 (C-5), 119.5 (CH-3), 127.2 (CH-p-Bn), 127.4 (CH-

o-Bn), 127.7 (CH-p-Bn, CH-o-Bn), 127.8 (CH-p-Bn), 128.2 (CH-o-

Bn), 128.2, 128.3, and 128.5 (CH-m-Bn), 132.9 (CH-4 or CH-6),

138.2, 138.4, and 139.4 (C-i-Bn), 139.9 (CH-4 or CH-6), 162.3 (C-

2) ppm. IR (CCl₄): 3067, 2976, 2901, 1665, 1627, 1552, 1454, 1364,

1207, 1187, 1095, 1029 cm^–1.

1454, 1362, 1188, 1096, 1029.

2-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-5-methyl-

pyridine (20a): Me₃Al (2 m in toluene; 2.61 mL, 5.22 mmol) was

added to a stirred solution of 16 (1 g, 1.74 mmol) and Pd(PPh₃)₄

(101 mg, 0.087 mmol) in dry THF (11 mL) in a flame-dried sep-

tum-sealed flask. The resulting mixture was stirred at 66 °C for 1 h,

then it was quenched by pouring into saturated NaH₂PO₄(70 mL).

The mixture was extracted with ethyl acetate. The combined or-

ganic layers were dried with anhydrous MgSO₄, and concentrated

under reduced pressure. The crude product was purified by flash

chromatography on silica gel (5 to 30% of ethyl acetate in hexane)

to give 20a (685 mg, 1.344 mmol, 77%) as a yellowish oil. HRMS

(ESI): calcd. for C₃₃H₃₆O₄N [M + H]⁺510.26389; found 510.26378.

¹H NMR (500 MHz, [D₆]DMSO): δ = 0.92 (s, 3 H, CH₃-2Ј), 2.28

(s, 3 H, CH₃-5), 3.74 (dd, 1 H, J_gem= 10.9, J_5Јa,4Ј= 4.6 Hz, 5Јa-

5-(2,3,5-Tri-O-benzyl-2-C-methyl-β-

pyridine (19e) and 5-(2,3,5-Tri-O-benzyl-2-C-methyl-β-

osyl)-1-methyl-2-pyridone (21): A suspension of 19d (240 mg,

D

-ribofuranosyl)-2-methoxy-

D-ribofuran-

0.47 mmol), CH₃I (0.09 mL, 1.41 mmol), and Ag₂(CO)₃(196 mg, H), 3.82 (dd, 1 H, J_gem= 10.9, J_5Јb,4Ј= 3.0 Hz, 5Јb-H), 3.89 (d, 1

0.71 mmol) in CH₂Cl₂(4 mL) was heated at 80 °C for 2 h. The

mixture was cooled to room temp., then it was filtered through

Celite, and concentrated under reduced pressure. The residue was

purified by flash chromatography on silica gel (0 to 50% of ethyl

H, J_3Ј,4Ј= 7.8 Hz, 3Ј-H), 4.20 (ddd, 1 H, J_4Ј,3Ј= 7.8, J_4Ј,5Јa= 4.5,

J_4Ј,5Јb= 3.0 Hz, 4Ј-H), 4.57 (d, 1 H, J_gem= 11.9 Hz, CH₂Bn-5Ј),

4.59 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.62 (d, 1 H, J_gem

=

11.9 Hz, CH₂Bn-5Ј), 4.64 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.69

acetate in hexane) to give 19e (165 mg, 0.32 mmol, 68 %) as a and 4.72 (2 d, 2ϫ 1 H, J_gem= 11.9 Hz, CH₂Bn-2Ј), 5.01 (s, 1 H,

colourless oil, and as a side-product, 21 (58 mg, 0.11 mmol, 23%)

as a yellowish oil.

1Ј-H), 7.23–7.41 (m, 15 H, H-o,m,p-Bn), 7.49 (dd, 1 H, J_3,4= 8.4,

J_3,6= 1.1 Hz, 3-H), 7.51 (ddq, 1 H, J_4,3= 8.0, J_4,6= 2.1, J_4,CH3

=

0.7 Hz, 4-H), 8.37 (dpent, 1 H, J_6,4= 2.1, J_6,3= J_6,CH3= 0.9 Hz,

6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 17.8 (CH₃-5),

19.1 (CH₃-2Ј), 65.1 (CH₂Bn-2Ј), 69.8 (CH₂-5Ј), 72.5 (CH₂Bn-3Ј),

72.6 (CH₂Bn-5Ј), 79.8 (CH-4Ј), 83.3 (CH-3Ј), 83.3 (C-2Ј), 86.3

(CH-1Ј), 121.0 (CH-3), 127.3 (CH-p-Bn), 127.4 (CH-o-Bn), 127.7

(CH-p-Bn), 127.8 (CH-o-Bn), 127.8 (CH-p-Bn), 128.1 (CH-o-Bn),

128.3, 128.4, and 128.5 (CH-m-Bn), 131.9 (C-5), 136.9 (CH-4),

138.5, 138.5, and 139.7 (C-i-Bn), 149.0 (CH-6), 156.6 (C-2) ppm.

IR (ATR): 3072, 3039, 2875, 1607, 1578, 1500, 1458, 1385, 1079,

1030 cm^–1.

Data for 19e: HRMS (ESI): calcd. for C₃₃H₃₆O₅N [M + H]⁺

526.25880; found 526.25881. H NMR (500 MHz, [D₆]DMSO): δ

1

= 0.92 (s, 3 H, CH₃-2Ј), 3.70 (dd, 1 H, J_gem= 10.7, J_5Јa,4Ј= 4.6 Hz,

5Јa-H), 3.73 (dd, 1 H, J_gem= 10.7, J_5Јb,4Ј= 4.6 Hz, 5Јb-H), 3.83 (s,

3 H, CH₃O), 3.86 (d, 1 H, J_3Ј,4Ј= 4.6 Hz, 3Ј-H), 4.22 (q, 1 H, J_4Ј,3Ј

= J_4Ј,5Јa= J_4Ј,5Јb= 4.7 Hz, 4Ј-H), 4.54 (d, 1 H, J_gem= 11.5 Hz,

CH₂Bn-3Ј), 4.55 and 4.59 (2 d, 2ϫ 1 H, J_gem= 11.5 Hz, CH₂Bn-

2Ј), 4.60 (br. d, 1 H, J_gem= 12.1 Hz, CH₂Bn-5Ј), 4.62 (d, 1 H, J_gem

= 11.5 Hz, CH₂Bn-3Ј), 4.63 (br. d, 1 H, J_gem= 12.1 Hz, CH₂Bn-

5Ј), 4.90 (s, 1 H, 1Ј-H), 6.76 (dd, 1 H, J_3,4= 8.6, J_3,6= 0.8 Hz, 3-

H), 7.22–7.41 (m, 15 H, H-o,m,p-Bn), 7.66 (ddd, 1 H, J_4,3= 8.6,

5-Amino-2-(2,3,5-tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-

J_4,6= 2.4, J_4,1= 0.7 Hz, 4-H), 8.11 (dpent, 1 H, J_6,4= 2.4, J_6,3

=

pyridine (20b): LiHMDS (1 m in THF; 0.52 mL, 0.52 mmol) was

added to a flame-dried septum-sealed flask containing 16 (150 mg,

J_6,1Ј= 0.8 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ =

18.7 (CH₃-2Ј), 53.2 (CH₃O), 65.5 (CH₂Bn-2Ј), 70.2 (CH₂-5Ј), 71.5 0.26 mmol), Pd₂(dba)₃(6 mg, 0.0065 mmol), and P(tBu)₃·HBF₄

(CH₂Bn-3Ј), 72.7 (CH₂Bn-5Ј), 81.7 (CH-4Ј), 82.1 (CH-1Ј), 82.7 (C- (15 mg, 0.052 mmol) in dry THF (3 mL). The resulting solution

2Ј), 82.9 (CH-3Ј), 109.9 (CH-3), 127.0 (C-5), 127.2 (CH-p-Bn), was stirred at 66 °C for 3 h. The mixture was cooled to room temp.,

127.3 (CH-o-Bn), 127.6 (CH-p-Bn), 127.7 (CH-o-Bn), 127.7 (CH- and stirred with HCl (2 m aq.; 3 mL) for 10 min. The mixture was

7974

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Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

then washed with satd. aq. NaHCO₃(8 mL), and the aqueous

phase was extracted with ethyl acetate. The combined organic lay-

ers were dried with anhydrous MgSO₄, and concentrated under re-

duced pressure. The residue was purified by flash chromatography

on silica gel (25 to 75% of ethyl acetate in hexane) to give 20b

(97 mg, 0.19 mmol, 73%) as a yellowish oil. HRMS (ESI): calcd.

for C₃₂H₃₄O₄N₂Na [M + Na]⁺533.24108; found 533.24098. ¹H

filtered through Celite, and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (10

to 50% of ethyl acetate in hexane) to give 20d (700 mg, 1.37 mmol,

98%) as a yellowish oil. HRMS (ESI): calcd. for C₃₂H₃₄O₅N [M +

H]⁺512.24315; found 512.24315. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.93 (s, 3 H, CH₃-2Ј), 3.73 (dd, 1 H, J_gem= 10.9,

J_5Јa,4Ј= 4.6 Hz, 5Јa-H), 3.81 (dd, 1 H, J_gem= 10.9, J_5Јb,4Ј= 3.0 Hz,

NMR (500 MHz, [D₆]DMSO): δ = 0.93 (s, 3 H, CH₃-2Ј), 3.71 (dd, 5Јb-H), 3.88 (d, 1 H, J_3Ј,4Ј= 7.8 Hz, 3Ј-H), 4.14 (ddd, 1 H, J_4Ј,3Ј

1 H, J_gem= 10.9, J_5Јa,4Ј= 4.7 Hz, 5Јa-H), 3.79 (dd, 1 H, J_gem7.8, J_4Ј,5Јa= 4.6, J_4Ј,5Јb= 3.0 Hz, 4Ј-H), 4.57 (d, 1 H, J_gem

=

10.9, J_5Јb,4Ј= 3.0 Hz, 5Јb-H), 3.87 (d, 1 H, J_3Ј,4Ј= 7.9 Hz, 3Ј-H), 11.9 Hz, CH₂Bn-5Ј), 4.59 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.60

4.14 (ddd, 1 H, J_4Ј,3Ј= 7.9, J_4Ј,5Јa= 4.7, J_4Ј,5Јb= 3.0 Hz, 4Ј-H), (d, 1 H, J_gem= 11.9 Hz, CH₂Bn-5Ј), 4.69 (d, 1 H, J_gem= 11.7 Hz,

4.56, 4.59, 4.60, and 4.64 (4 d, 4ϫ 1 H, J_gem= 11.9, 11.7, 12.0,

and 11.7 Hz, CH₂Bn-3Ј,5Ј), 4.67 (br. s, 2 H, CH₂Bn-2Ј), 4.87 (s, 1

CH₂Bn-3Ј), 4.68 (s, 2 H, CH₂Bn-2Ј), 4.95 (s, 1 H, 1Ј-H), 7.05 (dd,

1 H, J_4,3= 8.5, J_4,6= 2.9 Hz, 4-H), 7.23–7.39 (m, 15 H, H-o,m,p-

Bn), 7.41 (br. d, 1 H, J_3,4= 8.5 Hz, 3-H), 8.08 (dd, 1 H, J_6,4= 2.9,

J_6,3= 0.6 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ =

19.0 (CH₃-2Ј), 65.1 (CH₂Bn-2Ј), 69.9 (CH₂-5Ј), 72.5 and 72.6

(CH₂Bn-3Ј,5Ј), 79.6 (CH-4Ј), 83.3 (C-2Ј, CH-3Ј), 86.3 (CH-1Ј),

H, 1Ј-H), 6.28 (br. s, 2 H, NH₂), 6.83 (dd, 1 H, J_4,3= 8.4, J_4,6

=

2.7 Hz, 4-H), 7.21 (d, 1 H, J_3,4= 8.4 Hz, 3-H), 7.22–7.40 (m, 15 H,

H-o,m,p-Bn), 7.87 (br. d, 1 H, J_6,4= 2.7 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 19.0 (CH₃-2Ј), 65.0 (CH₂Bn-2Ј), 70.1

(CH₂-5Ј), 72.5 and 72.6 (CH₂Bn-3Ј,5Ј), 79.4 (CH-4Ј), 83.3 (C-2Ј), 122.0 (CH-3), 122.4 (CH-4), 127.2 (CH-p-Bn), 127.3 (CH-o-Bn),

83.5 (CH-3Ј), 86.6 (CH-1Ј), 120.2 (CH-4), 121.6 (CH-3), 127.2 127.7 (CH-p-Bn), 127.8 (CH-o,p-Bn), 128.1 (CH-o-Bn), 128.3,

(CH-p-Bn), 127.4 (CH-o-Bn), 127.6 (CH-p-Bn), 127.7 (CH-o-Bn), 128.3, and 128.4 (CH-m-Bn), 136.9 (CH-6), 138.5, 138.5, and 139.7

127.8 (CH-p-Bn), 128.1 (CH-o-Bn), 128.3 and 128.4 (CH-m-Bn),

135.2 (CH-6), 138.5, 138.6, and 139.8 (C-i-Bn), 144.0 (C-5), 146.3

(C-2) ppm. IR (ATR): 3470, 3365, 3222, 3040, 2869, 1631, 1577,

1498, 1456, 1306, 1078, 1026 cm^–1.

(C-i-Bn), 149.8 (C-2), 152.9 (C-5) ppm. IR (CCl₄): 3600, 3032,

2864, 1600, 1577, 1497, 1454, 1361, 1283, 1097, 1029 cm^–1.

2-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-5-methoxy-

pyridine (20e): A suspension of 16 (140 mg, 0.244 mmol), Pd₂-

(dba)₃(6 mg, 0.006 mmol), Me₄(tBu)₂XPhos (2-di-tert-butylphos-

phino-3,4,5,6-tetramethyl-2Ј,4Ј,6Ј-triisopropylbiphenyl; 12 mg,

0.024 mmol), and KOH (41 mg, 0.732 mmol) in a mixture of 1,4-

dioxane (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 4 h.

Then, the reaction mixture was cooled to room temp., and TBAB

(8 mg, 0.024 mmol), additional KOH (27 mg, 0.488 mmol), and

CH₃I (0.03 mL, 0.488 mmol) were added. The resulting suspension

was stirred for a further 30 min at 80 °C. The mixture was cooled

to room temp., diluted with ethyl acetate, filtered through Celite,

and concentrated under reduced pressure. The residue was purified

by flash chromatography on silica gel (6 to 13% of ethyl acetate in

hexane) to give 20e (84 mg, 0.16 mmol, 66%) as a yellowish oil.

HRMS (ESI): calcd. for C₃₃H₃₅O₅NNa [M + Na]⁺548.24074;

2-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-5-(dimethyl-

amino)pyridine (20c): Me₂NH (2 m in THF; 3.7 mL, 7.4 mmol) was

added to a stirred suspension of 16 (850 mg, 1.48 mmol), Pd₂-

(dba)₃(34 mg, 0.037 mmol), JohnPhos [(2-biphenyl)-di-tert-butyl-

phosphine; 44 mg, 0.148 mmol], and tBuONa (855 mg, 8.88 mmol)

in dry toluene (5 mL) in a flame-dried septum-sealed flask. The

resulting mixture was stirred at 70 °C for 2 h, then it was quenched

by pouring into satd. aq. NaHCO₃(12 mL). The mixture was ex-

tracted with toluene. The combined organic layers were dried with

anhydrous MgSO₄, and concentrated under reduced pressure. The

crude product was purified by flash chromatography on silica gel

(5 to 40 % of ethyl acetate in hexane) to give 20c (672 mg,

1.25 mmol, 84 %) as a yellowish oil. HRMS (ESI): calcd. for

₃₄H₃₉O₄N₂[M + H]⁺539.29043; found 539.29030. ¹H NMR

1

C

found 548.24013. H NMR (500 MHz, [D₆]DMSO): δ = 0.94 (s, 3

(500 MHz, [D₆]DMSO): δ = 0.95 (s, 3 H, CH₃-2Ј), 2.91 [s, 6 H,

(CH₃)₂N], 3.72 (dd, 1 H, J_gem= 10.9, J_5Јa,4Ј= 4.8 Hz, 5Јa-H), 3.80

(dd, 1 H, J_gem= 10.9, J_5Јb,4Ј= 3.1 Hz, 5Јb-H), 3.90 (d, 1 H, J_3Ј,4Ј

H, CH₃-2Ј), 3.73 (dd, 1 H, J_gem= 10.9, J_{5Јa 4Ј}

3.81 (dd, 1 H, J_gem= 10.9, J_{5Јb 4Ј}= 3.0 Hz, 5Јb-H), 3.81 (s, 3 H,

CH₃O), 3.90 (d, 1 H, J_3Ј,_4Ј= 7.7 Hz, 3Ј-H), 4.19 (ddd, 1 H, J_4Ј,3Ј

7.7, J_{4Ј 5Јa}= 4.7, J_{4Ј 5Јb}= 3.0 Hz, 4Ј-H), 4.58 (d, 1 H, J_gem

,

= 4.7 Hz, 5Јa-H),

,

=

= 7.8 Hz, 3Ј-H), 4.16 (ddd, 1 H, J_4Ј,3Ј= 7.8, J_4Ј,5Јa= 4.8, J_4Ј,5Јb

=

,

3.1 Hz, 4Ј-H), 4.57 (d, 1 H, J_gem= 12.0 Hz, CH₂Bn-5Ј), 4.59 (d, 1

H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.61 (d, 1 H, J_gem= 12.0 Hz,

CH₂Bn-5Ј), 4.64 (d, 1 H, J_gem= 11.7 Hz, CH₂Bn-3Ј), 4.68 and 4.70

(2 d, 2ϫ 1 H, J_gem= 11.7 Hz, CH₂Bn-2Ј), 4.94 (s, 1 H, 1Ј-H), 6.99

(dd, 1 H, J_4,3= 8.8, J_4,6= 3.1 Hz, 4-H), 7.23–7.39 (m, 16 H, H-

o,m,p-Bn, 3-H), 8.05 (dd, 1 H, J_6,4= 3.1, J_6,3= 0.7 Hz, 6-H) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 19.1 (CH₃-2Ј), 39.8

[(CH₃)₂N], 65.1 (CH₂Bn-2Ј), 70.1 (CH₂-5Ј), 72.4 (CH₂Bn-3Ј), 72.6

(CH₂Bn-5Ј), 79.6 (CH-4Ј), 83.3 (C-2Ј), 83.7 (CH-3Ј), 86.5 (CH-1Ј),

118.8 (CH-4), 121.4 (CH-3), 127.2 (CH-p-Bn), 127.3 (CH-o-Bn),

127.6 (CH-p-Bn), 127.7 (CH-o,p-Bn), 128.0 (CH-o-Bn), 128.2,

128.3, and 128.4 (CH-m-Bn), 133.6 (CH-6), 138.5, 138.5, and 139.8

(C-i-Bn), 145.3 (C-5), 146.4 (C-2) ppm. IR (CCl₄): 3032, 2876,

2807, 1596, 1561, 1498, 1454, 1356, 1207, 1098, 1029 cm^–1.

11.9 Hz, CH₂Bn-5Ј), 4.59 (br. d, 1 H, J_gem= 11.6 Hz, CH₂Bn-3Ј),

4.62 (br. d, 1 H, J_gem= 11.8 Hz, CH₂Bn-5Ј), 4.64 (d, 1 H, J_gem

=

11.7 Hz, CH₂Bn-3Ј), 4.70 (s, 2 H, CH₂Bn-2Ј), 5.01 (s, 1 H, 1Ј-H),

7.23–7.40 (m, 16 H, H-o,m,p-Bn, 4-H), 7.52 (dm, 1 H, J_3,4= 8.6 Hz,

3-H), 8.25 (dd, 1 H, J_6,4= 3.0, J_6,3= 0.7 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 19.1 (CH₃-2Ј), 55.7 (CH₃O), 65.1

(CH₂Bn-2Ј), 69.9 (CH₂-5Ј), 72.4 (CH₂Bn-3Ј), 72.6 (CH₂Bn-5Ј), 79.8

(CH-4Ј), 83.3 (C-2Ј), 83.4 (CH-3Ј), 86.1 (CH-1Ј), 120.8 (CH-4),

122.0 (CH-3), 127.2 (CH-p-Bn), 127.3 (CH-o-Bn), 127.6 (CH-p-

Bn), 127.7 (CH-o,p-Bn), 128.0 (CH-o-Bn), 128.2, 128.3, and 128.4

(CH-m-Bn), 136.3 (CH-6), 138.5 and 139.7 (C-i-Bn), 151.2 (C-2),

154.7 (C-5) ppm. IR (CCl₄): 3032, 2897, 2864, 1575, 1496, 1454,

1384, 1294, 1269, 1245, 1098, 1029 cm^–1.

(2-C-Methyl-β-D-ribofuranosyl)benzene (22) and 1-Deoxy-2-C-

methyl-1-C-phenylribitol (23)

2-(2,3,5-Tri-O-benzyl-2-C-methyl-β-D-ribofuranosyl)-5-hydroxy-

pyridine (20d): A suspension of 16 (800 mg, 1.39 mmol), Pd₂(dba)₃

(32 mg, 0.035 mmol), Me₄(tBu)₂XPhos (2-di-tert-butylphosphino-

3,4,5,6-tetramethyl-2Ј,4Ј,6Ј-triisopropylbiphenyl; 67 mg,

Method 1: Catalytic Hydrogenation: A suspension of 7 (100 mg,

0.2 mmol) and Pd/C (10%; 21 mg, 0.02 mmol) in acetic acid (1 mL)

0.139 mmol), and KOH (234 mg, 4.17 mmol) in a mixture of 1,4- was vigorously stirred under a hydrogen atmosphere at room temp.

dioxane (3.6 mL) and water (1.2 mL) was stirred at 80 °C for 4 h.

The mixture was cooled to room temp., diluted with ethyl acetate,

for 3 h. Then, the reaction mixture was filtered through a paper

filter, and the filtrate was concentrated under reduced pressure. The

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7975

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

residue was purified by flash chromatography on silica gel (0 to 5%

(C-5), 134.3 (CH-4), 138.6 (C-i-Bn), 147.0 (CH-6), 156.9 (C-2)

of MeOH in CH₂Cl₂) to give 22 (18 mg, 0.08 mmol, 40%) as a ppm. IR (ATR): 3420, 3071, 2805, 1505, 1454, 1305, 1151, 1090,

white foam, and as a side-product, 23 (24 mg, 0.11 mmol, 53%) as

1018 cm^–1.

a white foam.

4-Methyl-1-(2-C-methyl-β-D-ribofuranosyl)benzene (28a): A suspen-

Method 2: Treatment with BCl₃: BCl₃(1 m in CH₂Cl₂; 1.3 mL,

1.28 mmol) was added dropwise to a cooled (–78 °C) solution of 7

(210 mg, 0.425 mmol) in dry CH₂Cl₂(2 mL). The resulting solution

was stirred at –78 °C for 2 h. Subsequently, MeOH (1 mL) was

added, the reaction mixture was warmed to room temp., and con-

centrated under reduced pressure. The crude product was purified

sion of 18a (300 mg, 0.59 mmol) and Pd/C (5%; “eggshell”, unre-

duced form, 50% wet; 251 mg, 0.059 mmol) in acetic acid (3 mL)

was vigorously stirred under a hydrogen atmosphere at room temp.

After stirring for 6 h, the reaction mixture was filtered through a

paper filter, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

by flash chromatography on silica gel (0 to 5 % of MeOH in gel (0 to 5% of MeOH in CH₂Cl₂) to give 28a (131 mg, 0.55 mmol,

CH₂Cl₂) to give 22 (90 mg, 0.4 mmol, 94%) as a white foam.

93%) as a white foam. HRMS (ESI): calcd. for C₁₃H₁₈O₄Na [M +

Na]⁺261.10973; found 261.10975. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.63 (s, 3 H, CH₃-2Ј), 2.28 (s, 3 H, CH₃-Ph), 3.47 (t,

1 H, J_3Ј,4Ј= J_3Ј,OH= 5.8 Hz, 3Ј-H), 3.57 (dt, 1 H, J_gem= 11.7, J_5Јa,4Ј

Data for 22: HRMS (ESI): calcd. for C₁₂H₁₆O₄Na [M + Na]⁺

1

247.09408; found 247.09402. H NMR (500 MHz, [D₆]DMSO): δ

= 0.64 (s, 3 H, CH₃), 3.49 (t, 1 H, J_3Ј,4Ј= J_3Ј,OH= 5.8 Hz, 3Ј-H),

3.59 (dt, 1 H, J_gem= 11.8, J_5Јa,4Ј= J_5Ј,OH= 5.4 Hz, 5Јa-H), 3.68

(ddd, 1 H, J_gem= 11.8, J_5Јb,OH= 5.6, J_5Јb,4Ј= 3.7 Hz, 5Јb-H), 3.73

(ddd, 1 H, J_4Ј,3Ј= 5.9, J_4Ј,5Јa= 5.2, J_4Ј,5Јb= 3.7 Hz, 4Ј-H), 4.63 (s,

= J_5Јa,OH= 5.4 Hz, 5Јa-H), 3.66 (ddd, 1 H, J_gem= 11.7, J_5Јb,OH

=

5.6, J_5Јb,4Ј= 3.7 Hz, 5Јb-H), 3.70 (br. td, 1 H, J_4Ј,5Јa= J_4Ј,3Ј= 5.5,

J_4Ј,5Јb= 3.7 Hz, 4Ј-H), 4.58 (s, 1 H, 1Ј-H), 4.62 (s, 1 H, OH-2Ј),

4.80 (t, 1 H, J_OH,5Јa= J_OH,5Јb= 5.7 Hz, OH-5Ј), 5.09 (d, 1 H, J_3Ј,OH

= 5.8 Hz, OH-3Ј), 7.11 (m, 2 H, 3-H, 5-H), 7.22 (m, 2 H, 2-H, 6-

H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 21.2 (CH₃-Ph),

22.6 (CH₃-2Ј), 62.1 (CH₂-5Ј), 76.0 (CH-3Ј), 77.9 (C-2Ј), 84.2 (CH-

4Ј), 86.6 (CH-1Ј), 126.6 (CH-2, CH-6), 128.7 (CH-3, CH-5), 136.4

(C-4), 137.2 (C-1) ppm. IR (ATR): 3369, 2932, 1521, 1455, 1381,

1 H, 1Ј-H), 4.66 (s, 1 H, OH-2Ј), 4.81 (t, 1 H, J_OH,5Јa= J_OH,5Јb

=

5.6 Hz, OH-5Ј), 5.11 (d, 1 H, J_OH,3Ј= 5.8 Hz, OH-3Ј), 7.24 (m, 1

H, H-p-Ph), 7.30 (m, 2 H, H-m-Ph), 7.35 (m, 2 H, H-o-Ph) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 22.3 (CH₃), 61.8 (CH₂-

5Ј), 75.7 (CH-3Ј), 77.6 (C-2Ј), 84.0 (CH-4Ј), 86.3 (CH-1Ј), 126.4

(CH-o-Ph), 127.2 (CH-p-Ph), 127.8 (CH-m-Ph), 139.9 (C-i-Ph)

ppm. IR (ATR): 3363, 2937, 1500, 1458, 1380, 1295, 1220, 1177,

1180, 1039, 1024 cm^–1. [α]²_D⁰

C₁₃H₁₈O₄·0.3H₂O: calcd. C 64.07,; H 7.69; found C 64.12, H 7.68.

=

–7.7 (c 0.222, MeOH).

1071, 1044, 1030 cm^–1. [α]²_D⁰

=

–9.2 (c 0.250, MeOH).

C₁₂H₁₆O₄·0.1H₂O: calcd. C 63.76, H 7.22; found C 63.75, H 7.43.

4-(2-C-Methyl-β- -ribofuranosyl)aniline (28b): A suspension of 18b

D

(400 mg, 0.785 mmol) and Pd/C (5%; “eggshell”, unreduced form,

50% wet; 176 mg, 0.039 mmol) in acetic acid (4 mL) was vigorously

stirred under a hydrogen atmosphere at room temp. After stirring

for 3 d, the reaction mixture was filtered through a paper filter, and

the filtrate was concentrated under reduced pressure. The residue

was purified by flash chromatography on silica gel (0 to 3% of

MeOH in ethyl acetate) to give 28b (140 mg, 0.585 mmol, 75%) as

a yellowish foam. HRMS (ESI): calcd. for C₁₂H₁₇O₄NNa [M +

Na]⁺262.10498; found 262.10504. ¹H NMR (500 MHz, [D₆]-

Data for 23: HRMS (ESI): calcd. for C₁₂H₁₈O₄Na [M + Na]⁺

249.10973; found 249.10972. H NMR (500 MHz, [D₆]DMSO): δ

= 1.06 (s, 3 H, CH₃-2), 2.67 (d, 1 H, J_gem= 13.3 Hz, 1a-H), 2.78

1

(d, 1 H, J_gem= 13.3 Hz, 1b-H), 3.11 (dd, 1 H, J_3,4= 8.3, J_3,OH

6.5 Hz, 3-H), 3.39 (br. dt, 1 H, J_gem= 11.7, J_5a,4= J_5a,OH= 6.2 Hz,

5a-H), 3.56–3.62 (m, 2 H, 4-H, 5b-H), 4.43 (br. dd, 1 H, J_OH,5a

=

6.0, J_OH,5b= 5.4 Hz, OH-5), 4.82 (d, 1 H, J_OH,3= 6.5 Hz, OH-3),

4.89 (s, 1 H, OH-2), 5.22 (d, 1 H, J_OH,4= 3.6 Hz, OH-4), 7.16

(m, 1 H, H-p-Ph), 7.20–7.27 (m, 4 H, H-o,m-Ph) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 22.0 (CH₃-2), 45.1 (CH₂-1), 64.2

(CH₂-5), 72.7 (CH-3), 73.5 (CH-4), 75.0 (C-2), 125.7 (CH-p-Ph),

127.5 (CH-m-Ph), 131.2 (CH-o-Ph), 138.4 (C-i-Ph) ppm.

DMSO): δ = 0.65 (s, 3 H, CH₃-2Ј), 3.43 (t, 1 H, J_3Ј,4Ј= J_3Ј,OH

6.0 Hz, 3Ј-H), 3.55 (br. dt, 1 H, J_gem= 12.3, J_5Јa,4Ј= J_5Јa,OH

=

6.0 Hz, 5Јa-H), 3.63–3.70 (m, 2 H, 4Ј-H, 5Јb-H), 4.46 (s, 1 H, 1Ј-

H), 4.46 (s, 1 H, OH-2Ј), 4.74 (t, 1 H, J_OH,5Јa= J_OH,5Јb= 5.5 Hz,

OH-5Ј), 4.92 (br. s, 2 H, NH₂), 4.98 (d, 1 H, J_OH,3Ј= 6.0 Hz, OH-

3Ј), 6.49 (m, 2 H, 2-H, 6-H), 6.96 (m, 2 H, 3-H, 5-H) ppm. ¹³C

NMR (125.7 MHz, [D₆]DMSO): δ = 22.5 (CH₃-2Ј), 62.0 (CH₂-5Ј),

75.6 (CH-3Ј), 77.6 (C-2Ј), 83.4 (CH-4Ј), 87.2 (CH-1Ј), 113.4 (CH-

2, CH-6), 127.1 (C-4), 127.2 (CH-3, CH-5), 148.0 (C-1) ppm. IR

(ATR): 3404, 3331, 3255, 2896, 1619, 1521, 1451, 1384, 1275, 1162,

5-(5-O-Benzyl-2-C-methyl-β-D-ribofuranosyl)-2-methylpyridine (27):

BCl₃(1 m in CH₂Cl₂; 1.8 mL, 1.77 mmol) was added dropwise to

a cooled (–78 °C) solution of 19a (300 mg, 0.589 mmol) in dry

CH₂Cl₂(3 mL). The resulting solution was stirred at –78 °C for

4 h. Subsequently, MeOH (1.5 mL) was added, and the reaction

mixture was warmed to room temp., and concentrated under re-

duced pressure. The crude product was purified by flash

chromatography on silica gel (0 to 10% of MeOH in CH₂Cl₂) to

give 27 (162 mg, 0.492 mmol, 84 %) as a white solid, m.p. 101–

102 °C. HRMS (ESI): calcd. for C₁₉H₂₄O₄N [M + H]⁺330.16998;

1076, 1024 cm^–1. [α]²_D⁰

=

–4.2 (c 0.283,

MeOH).

C₁₂H₁₇O₄N·0.15H₂O: calcd. C 59.57, H 7.21, N 5.79; found C

59.75, H 7.2, N 5.47.

N,N-Dimethyl-4-(2-C-methyl-β-

Dimethyl-4-(2-C-methyl-α- -ribofuranosyl)aniline (24), N,N-Di-

methyl-4-(2-C-methyl-α- -ribopyranosyl)aniline (25), and 4-(2-C-

Methyl-β- -ribofuranosyl)cyclohexanone (26)

D-ribofuranosyl)aniline (28c), N,N-

1

found 330.16986. H NMR (500 MHz, [D₆]DMSO): δ = 0.66 (s, 3

D

H, CH₃-2Ј), 2.44 (s, 3 H, CH₃-2), 3.53 (t, 1 H, J_3Ј,4Ј= J_3Ј,OH

=

D

6.1 Hz, 3Ј-H), 3.67 (dd, 1 H, J_gem= 10.9, J_5Јa,4Ј= 3.2 Hz, 5Јa-H),

3.74 (dd, 1 H, J_gem= 10.9, J_5Јb,4Ј= 3.2 Hz, 5Јb-H), 3.91 (ddd, 1 H,

J_4Ј,3Ј= 6.4, J_4Ј,5Јa= 5.5, J_4Ј,5Јb= 3.2 Hz, 4Ј-H), 4.59 (s, 2 H,

D

Method 1: Catalytic Hydrogenation: A suspension of 18c (1.56 g,

CH₂Bn), 4.68 (s, 1 H, 1Ј-H), 4.81 (m, 1 H, OH-2Ј), 5.25 (dm, 1 H, 2.9 mmol) and Pd/C (10 %; 309 mg, 0.29 mmol) in acetic acid

J_OH,3Ј= 5.9 Hz, OH-3Ј), 7.17 (dm, 1 H, J_3,4= 7.9 Hz, 3-H), 7.30 (16 mL) was vigorously stirred under a hydrogen atmosphere at

(m, 1 H, H-p-Bn), 7.34–7.40 (m, 4 H, H-o,m-Bn), 7.60 (ddd, 1 H,

J_4,3= 7.9, J_4,6= 2.3, J_4,1Ј= 0.8 Hz, 4-H), 8.36 (dt, 1 H, J_6,4= 2.3,

room temp. for 20 h. Then, the reaction mixture was filtered

through a paper filter, and the filtrate was concentrated under re-

J_6,3= J_6,1Ј= 0.8 Hz, 6-H) ppm. 13C NMR (125.7 MHz, [D₆]- duced pressure. The residue was purified by HPLC (0 to 100% of

DMSO): δ = 22.3 (CH₃-2Ј), 23.9 (CH₃-2), 70.3 (CH₂-5Ј), 72.5 MeOH in water) to give 28c (333 mg, 1.25 mmol, 43%) as a white

(CH₂-Bn), 75.7 (CH-3Ј), 77.6 (C-2Ј), 82.2 (CH-4Ј), 84.8 (CH-1Ј), solid, and as an undesired side-product, 26 (340 mg, 1.39 mmol,

122.5 (CH-3), 127.6 (CH-o-Bn, CH-p-Bn), 128.5 (CH-m-Bn), 132.2 48%) as a colourless oil.

7976

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

Method 2: Treatment with BCl₃: BCl₃(1 m in CH₂Cl₂; 1.92 mL,

1.92 mmol) was added dropwise to a cooled (–78 °C) solution of

18c (341 mg, 0.64 mmol) in dry CH₂Cl₂(4 mL). The resulting solu-

tion was stirred at –78 °C for 1 h. Subsequently, MeOH (2 mL)

was added, and reaction mixture was warmed to room temp., and

concentrated under reduced pressure. The crude product was puri-

fied by HPLC (0 to 100% of MeOH in water) to give 28c (36 mg,

0.134 mmol, 21%) as a white solid, and as undesired side-products,

24 (63 mg, 0.237 mmol, 37 %) as a white foam, and 25 (60 mg,

0.224 mmol, 35%) as a white foam.

85.5 (CH-1Ј), 211.2 (C-1) ppm. IR (ATR): 3390, 2941, 2874, 1708,

1455, 1339, 1176, 1133, 1035 cm^–1.

4-(2-C-Methyl-β-D-ribofuranosyl)phenol (28d): A suspension of 18d

(570 mg, 1.12 mmol) and Pd/C (5%; “eggshell”, unreduced form,

50% wet; 477 mg, 0.112 mmol) in acetic acid (6 mL) was vigorously

stirred under a hydrogen atmosphere at room temp. After stirring

for 2 h, the reaction mixture was filtered through a paper filter, and

the filtrate was concentrated under reduced pressure. The residue

was purified by flash chromatography on silica gel (0 to 10% of

MeOH in CH₂Cl₂) to give 28d (244 mg, 1.02 mmol, 91 %) as a

white solid, m.p. 179–181 °C. HRMS (ESI): calcd. for C₁₂H₁₅O₅

Data for 28c: m.p. 126–127 °C. HRMS (ESI): calcd. for

1

[M – H]^–239.09250; found 239.09258. H NMR (500 MHz, [D₆]-

1

C₁₄H₂₁O₄NNa [M + Na]⁺290.13628; found 290.13635. H NMR

DMSO): δ = 0.64 (s, 3 H, CH₃-2Ј), 3.45 (t, 1 H, J_3Ј,4Ј= J_3Ј,OH

=

(500 MHz, [D₆]DMSO): δ = 0.65 (s, 3 H, CH₃-2Ј), 2.86 [s, 6 H,

(CH₃)₂N], 3.46 (m, 1 H, 3Ј-H), 3.57 (m, 1 H, 5Јa-H), 3.63–3.70 (m,

2 H, 4Ј-H, 5Јb-H), 4.50 (br. s, 1 H, OH-2Ј), 4.52 (s, 1 H, 1Ј-H),

4.75 (t, 1 H, J_OH,5Јa= J_OH,5Јb= 5.6 Hz, OH-5Ј), 5.00 (br. s, 1 H,

OH-3Ј), 6.66 (m, 2 H, 2-H, 6-H), 7.13 (m, 2 H, 3-H, 5-H) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 22.5 (CH₃-2Ј), 40.4

[(CH₃)₂N], 61.9 (CH₂-5Ј), 75.7 (CH-3Ј), 77.6 (C-2Ј), 83.5 (CH-4Ј),

86.8 (CH-1Ј), 111.9 (CH-2, CH-6), 127.2 (C-4), 127.5 (CH-3, CH-

5), 149.7 (C-1) ppm. IR (ATR): 3503, 3340, 2894, 2810, 1621, 1530,

1452, 1357, 1233, 1118, 1074, 1049 cm^–1. [α]²_D⁰= –9.6 (c 0.198,

MeOH). C₁₄H₂₁O₄N·0.25H₂O: calcd. C 61.86, H 7.97, N 5.15;

found C 61.99, H 7.87, N 5.03.

5.9 Hz, 3Ј-H), 3.56 (m, 1 H, 5Јa-H), 3.63–3.70 (m, 2 H, 4Ј-H, 5Јb-

H), 4.52 (s, 1 H, 1Ј-H), 5.55 (s, 1 H, OH-2Ј), 4.78 (t, 1 H, J_OH,5Јa

= J_OH,5Јb= 5.6 Hz, OH-5Ј), 5.03 (d, 1 H, J_3Ј,OH= 5.9 Hz, OH-3Ј),

6.68 (m, 2 H, 2-H, 6-H), 7.11 (m, 2 H, 3-H, 5-H), 9.24 (s, 1 H,

OH-1) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 22.4 (CH₃-

2Ј), 61.9 (CH₂-5Ј), 75.6 (CH-3Ј), 77.6 (C-2Ј), 83.6 (CH-4Ј), 86.6

(CH-1Ј), 114.6 (CH-2, CH-6), 127.6 (CH-3, CH-5), 130.2 (C-4),

156.5 (C-1) ppm. IR (ATR): 3279, 3166, 2940, 2886, 1620, 1523,

1474, 1387, 1272, 1229, 1117, 1075, 1043 cm^–1. [α]²_D⁰= –6.6 (c 0.288,

MeOH). C₁₂H₁₆O₅: calcd. C 59.99, H 6.71; found C 59.69, H 6.89.

4-(2-C-Methyl-β-D-ribofuranosyl)anisole (28e): A suspension of 18e

Data for 24: HRMS (ESI): calcd. for C₁₃H₁₆O₅N [M – H]^–

266.10340; found 266.10351. H NMR (500 MHz, [D₆]DMSO): δ

= 1.00 (s, 3 H, CH₃-2Ј), 2.87 [s, 6 H, (CH₃)₂N], 3.44 (ddd, 1 H,

J_gem= 11.8, J_5Јa,OH= 6.3, J_5Јa,4Ј= 4.6 Hz, 5Јa-H), 3.61 (ddd, 1 H,

J_gem= 11.8, J_5Јb,OH= 5.2, J_5Јb,4Ј= 2.4 Hz, 5Јb-H), 3.76 (dd, 1 H,

J_3Ј,4Ј= 8.4, J_3Ј,OH= 7.0 Hz, 3Ј-H), 3.80 (ddd, 1 H, J_4Ј,3Ј= 8.4,

J_4Ј,5Јa= 4.6, J_4Ј,5Јb= 2.4 Hz, 4Ј-H), 3.91 (d, 1 H, J_OH,LR= 0.7 Hz,

(220 mg, 0.42 mmol) and Pd/C (5%; “eggshell”, unreduced form,

50% wet; 89 mg, 0.021 mmol) in acetic acid (2 mL) was vigorously

stirred under a hydrogen atmosphere at room temp. After stirring

for 6 h, the reaction mixture was filtered through a paper filter, and

the filtrate was concentrated under reduced pressure. The residue

was purified by flash chromatography on silica gel (0 to 10% of

MeOH in ethyl acetate) to give 28e (97 mg, 0.38 mmol, 91%) as a

white solid, m.p. 79–80 °C. HRMS (ESI): calcd. for C₁₃H₁₈O₅Na

[M + Na]⁺277.10464; found 277.10462. ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 0.64 (s, 3 H, CH₃-2Ј), 3.47 (d, 1 H, J_3Ј,4Ј= 5.9 Hz, 3Ј-

H), 3.47 (dd, 1 H, J_gem= 11.5, J_5Јa,4Ј= 5.0 Hz, 5Јa-H), 3.67 (dd, 1

H, J_gem= 11.5, J_5Јb,4Ј= 3.6 Hz, 5Јb-H), 3.70 (ddd, 1 H, J_4Ј,3Ј= 5.9,

J_4Ј,5Јa= 5.0, J_4Ј,5Јb= 3.6 Hz, 4Ј-H), 3.73 (s, 3 H, CH₃O), 4.57 (s, 1

H, 1Ј-H), 6.87 (m, 2 H, 2-H, 6-H), 7.25 (m, 2 H, 3-H, 5-H) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 22.4 (CH₃-2Ј), 55.1 (CH₃-

O), 61.8 (CH₂-5Ј), 75.6 (CH-3Ј), 77.6 (C-2Ј), 83.8 (CH-4Ј), 86.3

(CH-1Ј), 113.2 (CH-2, CH-6), 127.5 (CH-3, CH-5), 131.9 (C-4),

158.5 (C-1) ppm. IR (ATR): 3379, 2975, 1619, 1519, 1464, 1295,

1260, 1164, 1120, 1057 cm^–1. [α]²_D⁰= –5.2 (c 0.317, MeOH).

C₁₃H₁₈O₅·0.3H₂O: calcd. C 60.13, H 7.22; found C 60.14, H 7.15.

1

OH-2Ј), 4.48 (s, 1 H, 1Ј-H), 4.65 (dd, 1 H, J_OH,5Јa= 6.3, J_OH,5Јb

=

5.2 Hz, OH-5Ј), 4.82 (d, 1 H, J_OH,3Ј= 7.1 Hz, OH-3Ј), 6.66 (m, 2

H, 2-H, 6-H), 7.13 (m, 2 H, 3-H, 5-H) ppm. ¹³C NMR (125.7 MHz,

[D₆]DMSO): δ = 21.1 (CH₃-2Ј), 40.5 [(CH₃)₂N], 62.5 (CH₂-5Ј), 76.5

(C-2Ј), 76.6 (CH-3Ј), 81.9 (CH-4Ј), 85.8 (CH-1Ј), 111.6 (CH-2, CH-

6), 126.0 (C-4), 128.9 (CH-3, CH-5), 150.1 (C-1) ppm.

Data for 25: HRMS (ESI): calcd. for C₁₃H₁₆O₅N [M – H]^–

1

266.10340; found 266.10349. H NMR (500 MHz, [D₆]DMSO): δ

= 0.77 (s, 3 H, CH₃-2Ј), 2.86 [s, 6 H, (CH₃)₂N], 3.34 (dd, 1 H,

J_3Ј,OH= 8.1, J_3Ј,4Ј= 3.2 Hz, 3Ј-H), 3.58 (dd, 1 H, J_gem= 12.1, J_5Јa,4Ј

= 1.3 Hz, 5Јa-H), 3.73 (dddd, 1 H, J_4Ј,OH= 5.2, J_4Ј,3Ј= 3.2, J_4Ј,5Јb

= 1.9, J_4Ј,5Јa= 1.3 Hz, 4Ј-H), 3.88 (dd, 1 H, J_gem= 12.1, J_5Јb,4Ј

=

2.0 Hz, 5Јa-H), 3.96 (s, 1 H, 1Ј-H), 4.39 (br. s, 1 H, OH-2Ј), 4.52

(d, 1 H, J_OH,3Ј= 8.1 Hz, OH-3Ј), 5.39 (d, 1 H, J_OH,4Ј= 5.2 Hz,

OH-4Ј), 6.63 (m, 2 H, 2-H, 6-H), 7.17 (m, 2 H, 3-H, 5-H) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 20.9 (CH₃-2Ј), 40.4

[(CH₃)₂N], 70.0 (CH-4Ј), 71.3 (CH₂-5Ј), 71.9 (CH-3Ј), 74.5 (C-2Ј),

85.1 (CH-1Ј), 111.4 (CH-2, CH-6), 126.3 (C-4), 129.6 (CH-3, CH-

5), 149.9 (C-1) ppm.

2-Methyl-5-(2-C-methyl-β-D-ribofuranosyl)pyridine (29a): A suspen-

sion of 19a (420 mg, 0.85 mmol) and Pd/C (5%; “eggshell”, unre-

duced form, 50% wet; 362 mg, 0.085 mmol) in acetic acid (5 mL)

was vigorously stirred under a hydrogen atmosphere at room temp.

After stirring for 2 d, the reaction mixture was filtered through a

paper filter, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

gel (0 to 15 % of MeOH in ethyl acetate) to give 29a (162 mg,

Data for 26: HRMS (ESI): calcd. for C₁₂H₁₉O₅[M – H]^–

1

243.12380; found 243.12350. H NMR (500 MHz, [D₆]DMSO): δ 0.68 mmol, 80%) as a yellowish solid, m.p. 155–158 °C. HRMS

= 1.10 (s, 3 H, CH₃-2Ј), 1.32–1.48 (m, 2 H, 3b-H, 5b-H), 1.83 (tdt,

1 H, J_4,3= J_4,3= 10.7, J_4,1Ј= 9.2, J_4,3= J_4,3= 3.4 Hz, 4-H), 2.08– ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.66 (s, 3 H, CH₃-2Ј), 2.44

2.23 (m, 4 H, 3a-H, 5a-H, 2b-H, 6b-H), 2.30–2.41 (m, 2 H, 2a-H, (s, 3 H, CH₃-2), 3.52 (t, 1 H, J_3Ј,4Ј= J_3Ј,OH= 5.7 Hz, 3Ј-H), 3.58

6a-H), 3.19 (d, 1 H, J_1Ј,4= 9.2 Hz, 1Ј-H), 3.31 (m, 1 H, 3Ј-H), 3.40– (ddd, 1 H, J_gem= 11.8, J_5Јa,4Ј= 5.8, J_5Јa,OH= 5.0 Hz, 5Јa-H), 3.67

(ESI): calcd. for C₁₂H₁₈O₄N [M + H]⁺240.12303; found 240.12297.

3.53 (m, 3 H, 4Ј-H, 5Ј-H), 4.29 (br. s, 1 H, OH-2Ј), 4.71 (br. t, 1

(ddd, 1 H, J_gem= 11.8, J_5Јb,OH= 5.5, J_5Јb,4Ј= 3.7 Hz, 5Јb-H), 3.73

(ddd, 1 H, J_4Ј,3Ј= 5.8, J_4Ј,5Јa= 5.0, J_4Ј,5Јb= 3.7 Hz, 4Ј-H), 4.63 (s,

H, J_OH,5Јa= J_OH,5Јb= 5.4 Hz, OH-5Ј), 5.17 (br. d, 1 H, J_3Ј,OH

=

4.3 Hz, OH-3Ј) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 21.1

(CH₃-2Ј), 28.0 and 30.2 (CH₂-3,5), 35.9 (CH-4), 40.0 and 40.1

1 H, 1Ј-H), 4.74 (s, 1 H, OH-2Ј), 4.85 (t, 1 H, J_OH,5Јa= J_OH,5Јb

=

5.7 Hz, OH-5Ј), 5.17 (d, 1 H, J_OH,3Ј= 5.7 Hz, OH-3Ј), 7.20 (dm, 1

(CH₂-2,6), 62.2 (CH₂-5Ј), 76.1 (C-2Ј), 77.4 (CH-3Ј), 85.0 (CH-4Ј), H, J_3,4= 7.9 Hz, 3-H), 7.62 (ddd, 1 H, J_4,3= 7.9, J_4,6= 2.3, J_4,1Ј

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7977

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

= 0.8 Hz, 4-H), 8.39 (dt, 1 H, J_6,4= 2.3, J_6,3= J_6,1Ј= 0.8 Hz, 6-H)

ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 22.2 (CH₃-2Ј), 23.9

0.721 mmol, 92%) as a white solid, m.p. 79–81 °C. HRMS (ESI):

calcd. for C₁₁H₁₅O₅NNa [M + Na]⁺264.08424; found 264.08432.

(CH₃-2), 61.6 (CH₂-5Ј), 75.5 (CH-3Ј), 77.7 (C-2Ј), 84.3 and 84.3 ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.77 (s, 3 H, CH₃-2Ј), 3.48

(CH-1Ј, CH-4Ј), 122.4 (CH-3), 132.2 (C-5), 134.4 (CH-4), 147.1 (br. d, 1 H, J_3Ј,4Ј= 5.9 Hz, 3Ј-H), 3.52 (m, 1 H, 5Јa-H), 3.61–3.68

(CH-6), 156.8 (C-2) ppm. IR (ATR): 3464, 3350, 2943, 2886, 1610, (m, 2 H, 5Јb-H, 4Ј-H), 4.40 (s, 1 H, 1Ј-H), 4.61 (s, 1 H, OH-2Ј),

1501, 1451, 1308, 1246, 1132, 1028 cm^–1. [α]²_D⁰= –11.5 (c 0.253,

MeOH). C₁₂H₁₇O₄N: calcd. C 60.24, H 7.16, N 5.85; found C

59.93, H 7.2, N 5.56.

4.81 (m, 1 H, OH-5Ј), 5.08 (br. s, 1 H, OH-3Ј), 6.29 (dd, 1 H, J_3,4

= 9.4, J_3,6= 0.6 Hz, 3-H), 7.27 (dt, 1 H, J_6,4= 2.6, J_6,3= J_6,1Ј

=

0.8 Hz, 6-H), 7.40 (dd, 1 H, J_4,3= 9.4, J_4,6= 2.6 Hz, 4-H), 11.49

(br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ =

22.1 (CH₃-2Ј), 61.3 (CH₂-5Ј), 75.1 (CH-3Ј), 77.6 (C-2Ј), 83.8 (CH-

1Ј, 4Ј-H), 116.6 (C-5), 119.3 (CH-3), 132.4 (CH-6), 140.2 (CH-4),

162.4 (C-2) ppm. IR (ATR): 3266, 3154, 2885, 1662, 1614, 1551,

2-Amino-5-(2-C-methyl-β-D-ribofuranosyl)pyridine (29b): BCl₃(1 m

in CH₂Cl₂; 3.9 mL, 3.9 mmol) was added dropwise to a cooled

(0 °C) solution of 19b (200 mg, 0.39 mmol) in dry CH₂Cl₂(2 mL).

The mixture was stirred for 1 h at 0 °C, then it was warmed to

room temp., and stirred for a further 1 h. Subsequently, MeOH

(1 mL) was added, and the resulting solution was concentrated un-

der reduced pressure. The crude product was purified by flash

chromatography on silica gel (0 to 30% of MeOH in ethyl acetate)

to give 29b (89 mg, 0.37 mmol, 95%) as a yellowish foam. HRMS

(ESI): calcd. for C₁₁H₁₇O₄N₂[M + H]⁺241.11828; found

241.11829. ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.70 (s, 3 H,

CH₃-2Ј), 3.47 (t, 1 H, J_3Ј,4Ј= J_3Ј,OH= 5.7 Hz, 3Ј-H), 3.54 (m, 1 H,

5Јa-H), 3.62–3.68 (m, 2 H, 5Јb-H, 4Ј-H), 4.46 (s, 1 H, 1Ј-H), 4.57

(s, 1 H, OH-2Ј), 4.78 (br. t, 1 H, J_OH,5Јa= J_OH,5Јb= 5.5 Hz, OH-

5Ј), 5.06 (d, 1 H, J_OH,3Ј= 5.7 Hz, OH-3Ј), 5.79 (br. s, 2 H, NH₂),

1460, 1425, 1073 cm^–1. [α]²_D⁰

= –29.1 (c 0.234, MeOH).

C₁₁H₁₅O₅N·0.2H₂O: calcd. C 53.96, H 6.34, N 5.72; found C 54.01,

H 6.27, N 5.53.

2-Methoxy-5-(2-C-methyl-β-D-ribofuranosyl)pyridine (29e): A sus-

pension of 19e (500 mg, 0.95 mmol) and Pd/C (5%; “eggshell”, un-

reduced form, 50% wet; 404 mg, 0.095 mmol) in acetic acid (5 mL)

was vigorously stirred under a hydrogen atmosphere at room temp.

After stirring for 1 d, the reaction mixture was filtered through a

paper filter, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

gel (0 to 3 % of MeOH in ethyl acetate) to give 29e (215 mg,

0.84 mmol, 89 %) as a white foam. HRMS (ESI): calcd. for

6.38 (d, 1 H, J_3,4= 8.5 Hz, 3-H), 7.32 (dd, 1 H, J_4,3= 8.5, J_4,6

=

C

₁₂H₁₈O₅N [M + H]⁺256.11795; found 256.11797. ¹H NMR

2.4 Hz, 4-H), 7.81 (d, 1 H, J_6,4= 2.4 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 22.4 (CH₃-2Ј), 61.7 (CH₂-5Ј), 75.5

(CH-3Ј), 77.6 (C-2Ј), 83.7 (CH-4Ј), 85.2 (CH-1Ј), 107.3 (CH-3),

122.9 (C-5), 135.7 (CH-4), 146.0 (CH-6), 159.3 (C-2) ppm. IR

(ATR): 3353, 3232, 2936, 1628, 1574, 1510, 1457, 1416, 1026 cm^–1.

[α]²_D⁰= –6.2 (c 0.273, MeOH). C₁₁H₁₆O₄N₂·0.65H₂O: calcd. C

52.44, H 6.92, N 11.12; found C 52.66, H 6.54, N 10.73.

(500 MHz, [D₆]DMSO): δ = 0.68 (s, 3 H, CH₃-2Ј), 3.53 (t, 1 H,

J_3Ј,4Ј= J_3ЈOHЈ= 5.8 Hz, 3Ј-H), 3.57 (ddd, 1 H, J_gem= 11.8, J_5Јa,OH

= 5.8, J_5Јa,4Ј= 4.8 Hz, 5Јa-H), 3.67 (ddd, 1 H, J_gem= 11.8, J_5Јb,OH

= 5.5, J_5Јb,4Ј= 3.6 Hz, 5Јb-H), 3.72 (ddd, 1 H, J_4Ј,3Ј= 5.9, J_4Ј,5Јa

=

4.8, J_4Ј,5Јb= 3.6 Hz, 4Ј-H), 3.83 (s, 3 H, CH₃O), 4.62 (s, 1 H, 1Ј-

H), 4.69 (s, 1 H, OH-2Ј), 4.82 (t, 1 H, J_OH,5Јa= J_OH,5Јb= 5.6 Hz,

OH-5Ј), 5.11 (d, 1 H, J_OH,3Ј= 5.8 Hz, OH-3Ј), 6.77 (dd, 1 H, J_3,4

= 8.5, J_3,6= 0.9 Hz, 3-H), 7.67 (ddd, 1 H, J_4,3= 8.5, J_4,6= 2.4,

J_4,1Ј= 0.6 Hz, 4-H), 8.10 (dt, 1 H, J_6,4= 2.4, J_6,3= J_6,1Ј= 0.8 Hz,

6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 22.2 (CH₃-2Ј),

53.2 (CH₃O), 61.5 (CH₂-5Ј), 75.3 (CH-3Ј), 77.7 (C-2Ј), 84.1 (CH-

4Ј), 84.3 (CH-1Ј), 109.8 (CH-3), 128.4 (C-5), 137.6 (CH-4), 144.8

(CH-6), 163.1 (C-2) ppm. IR (ATR): 3359, 2935, 1614, 1579, 1499,

1457, 1399, 1288, 1259, 1068, 1024 cm^–1. [α]²_D⁰= –6.7 (c 0.255,

MeOH). C₁₂H₁₇O₅N: calcd. C 56.46, H 6.71, N 5.49; found C

56.24, H 6.8, N 5.21.

2-(Dimethylamino)-5-(2-C-methyl-β-D-ribofuranosyl)pyridine (29c):

A suspension of 19c (850 mg, 1.58 mmol) and Pd/C (5%; “egg-

shell”, unreduced form, 50% wet; 337 mg, 0.08 mmol) in acetic acid

(9 mL) was vigorously stirred under a hydrogen atmosphere at

room temp. After stirring for 3 d, the reaction mixture was filtered

through a paper filter, and the filtrate was concentrated under re-

duced pressure. The residue was purified by flash chromatography

on silica gel (0 to 10% of MeOH in CH₂Cl₂) to give 29c (233 mg,

0.87 mmol, 55%) as a white solid, m.p. 163–165 °C. HRMS (ESI):

1

calcd. for C₁₃H₂₁O₄N₂[M + H]⁺269.14958; found 269.14957. H

5-Methyl-2-(2-C-methyl-β-D-ribofuranosyl)pyridine (30a): A suspen-

NMR (500 MHz, [D₆]DMSO): δ = 0.69 (s, 3 H, CH₃-2Ј), 2.99 [s, 6

H, (CH₃)₂N], 3.46 (d, 1 H, J_3Ј,4Ј= 6.1 Hz, 3Ј-H), 3.55 (m, 1 H, 5Јa-

sion of 20a (430 mg, 0.844 mmol) and Pd/C (5%; “eggshell”, unre-

duced form, 50% wet; 360 mg, 0.0844 mmol) in acetic acid (5 mL)

was vigorously stirred under a hydrogen atmosphere at room temp.

After stirring for 1 d, the reaction mixture was filtered through a

paper filter, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

gel (0 to 5 % of MeOH in CH₂Cl₂) to give 30a (175 mg,

0.731 mmol, 87%) as a yellowish foam. HRMS (ESI): calcd. for

C₁₂H₁₈O₄N [M + H]⁺240.12303; found 240.12296. ¹H NMR

(500 MHz, [D₆]DMSO): δ = 0.68 (s, 3 H, CH₃-2Ј), 2.27 (s, 3 H,

H), 3.66 (m, 1 H, 5Јb-H), 3.68 (br. ddd, 1 H, J_4Ј,3Ј= 6.1, J_4Ј,5Ј

=

4.8 and 3.5 Hz, 4Ј-H), 4.52 (s, 1 H, 1Ј-H), 4.60 (s, 1 H, OH-2Ј),

4.80 (m, 1 H, OH-5Ј), 5.07 (br. s, 1 H, OH-3Ј), 6.58 (br. d, 1 H,

J_3,4= 8.8 Hz, 3-H), 7.46 (dd, 1 H, J_4,3= 8.8, J_4,6= 2.4 Hz, 4-H),

8.00 (d, 1 H, J_6,4= 2.4 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 22.5 (CH₃-2Ј), 37.9 [(CH₃)₂N], 61.7 (CH₂-5Ј), 75.4

(CH-3Ј), 77.7 (C-2Ј), 83.7 (CH-4Ј), 85.1 (CH-1Ј), 105.1 (CH-3),

122.6 (C-5), 135.9 (CH-4), 145.9 (CH-6), 158.8 (C-2) ppm. IR

(ATR): 3339, 3192, 2929, 1623, 1534, 1444, 1414, 1331, 1266,

1081 cm^–1. [α]²_D⁰= –4.5 (c 0.246, MeOH). C₁₃H₂₀O₄N₂·0.35H₂O:

calcd. C 56.86, H 7.6, N 10.2; found C 57.13, H 7.45, N 9.78.

CH₃-5), 3.60 (m, 1 H, 5Јa-H), 3.69 (dd, 1 H, J_3Ј,4Ј= 8.2, J_3Ј,OH

6.9 Hz, 3-H), 3.77 (ddd, 1 H, J_gem= 11.7, J_5Јb,OH= 4.1, J_5Јb,4Ј

2.6 Hz, 5Јb-H), 3.80 (ddd, 1 H, J_4Ј,3Ј= 8.2, J_4Ј,5Јa= 3.8, J_4Ј,5Јb

=

5-(2-C-Methyl-β-

D

-ribofuranosyl)-2-pyridone (29d): BCl₃(1 m in

2.6 Hz, 4Ј-H), 4.70 (s, 1 H, OH-2Ј), 4.75 (s, 1 H, 1Ј-H), 4.93 (d, 1

H, J_OH,3Ј= 6.9 Hz, OH-3Ј), 5.20 (dd, 1 H, J_OH,5Јa= 6.5, J_OH,5Јb

CH₂Cl₂; 7.82 mL, 7.82 mmol) was added dropwise to a cooled

(–78 °C) solution of 19d (400 mg, 0.782 mmol) in dry CH₂Cl₂

(2 mL). The resulting solution was stirred at –78 °C for 1 h. Sub-

sequently, MeOH (2 mL) was added, and the reaction mixture was

warmed to room temp., and concentrated under reduced pressure.

The crude product was purified by flash chromatography on silica

gel (0 to 20 % of MeOH in ethyl acetate) to give 29d (174 mg,

=

4.1 Hz, OH-5Ј), 7.41 (dd, 1 H, J_3,4= 8.0, J_3,6= 0.8 Hz, 3-H), 7.58

(ddq, 1 H, J_4,3= 8.0, J_4,6= 2.3, J_4,CH3= 0.8 Hz, 4-H), 8.37 (dpent,

1 H, J_6,4= 2.3, J_6,3= J_6,CH3= 0.8 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 17.8 (CH₃-5), 22.2 (CH₃-2Ј), 61.1

(CH₂-5Ј), 73.9 (CH-3Ј), 78.6 (C-2Ј), 82.4 (CH-4Ј), 88.7 (CH-1Ј),

121.3 (CH-3), 131.8 (C-5), 137.1 (CH-4), 148.7 (CH-6), 157.8 (C-

7978

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Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

2) ppm. IR (ATR): 3330, 2933, 1610, 1579, 1497, 1456, 1382, 1294,

1 H, 5Јb-H), 3.78 (ddd, 1 H, J_4Ј,3Ј= 8.3, J_4Ј,5Јa= 3.8, J_4Ј,5Јb=

1073, 1048, 1021 cm^–1. [α]²_D⁰

=

–22 (c 0.286, MeOH).

2.5 Hz, 3Ј-H), 4.61 (s, 1 H, OH-2Ј), 4.69 (s, 1 H, 1Ј-H), 4.88 (d, 1

H, J_OH,3Ј= 6.8 Hz, OH-3Ј), 5.14 (br. dd, 1 H, J_OH,5Јa= 6.6, J_OH,5Јb

= 4.1 Hz, OH-5Ј), 7.13 (dd, 1 H, J_4,3= 8.5, J_4,6= 2.8 Hz, 4-H),

C₁₂H₁₇O₄N·0.35H₂O: calcd. C 58.69, H 7.26, N 5.7; found C 58.95,

H 7.42, N 5.4.

7.31 (d, 1 H, J_3,4= 8.5 Hz, 3-H), 8.03 (dd, 1 H, J_6,4= 2.8, J_6,3

=

5-Amino-2-(2-C-methyl-β-D-ribofuranosyl)pyridine (30b): BCl₃(1 m

0.7 Hz, 6-H), 9.84 (br. s, 1 H, OH) ppm. ¹³C NMR (125.7 MHz,

[D₆]DMSO): δ = 22.1 (CH₃-2Ј), 61.2 (CH₂-5Ј), 73.9 (CH-3Ј), 78.5

(C-2Ј), 82.3 (CH-4Ј), 88.6 (CH-1Ј), 122.4 (CH-3), 122.7 (CH-4),

136.5 (CH-6), 151.1 (C-2), 152.8 (C-5) ppm. IR (ATR): 3354, 2882,

1583, 1501, 1454, 1277, 1123, 1073 cm^–1. [α]²_D⁰= –22.3 (c 0.292,

MeOH). C₁₁H₁₅O₅N·0.4H₂O: calcd. C 53.18, H 6.41, N 5.64; found

C 53.4, H 6.41, N 5.4.

in CH₂Cl₂; 1.96 mL, 1.96 mmol) was added dropwise to a cooled

(–78 °C) solution of 20b (100 mg, 0.196 mmol) in dry CH₂Cl₂

(1 mL). The resulting solution was stirred at –78 °C for 1 h. Sub-

sequently, MeOH (1 mL) was added, and the reaction mixture was

warmed to room temp., and concentrated under reduced pressure.

The crude product was purified by flash chromatography on silica

gel (0 to 25 % of MeOH in ethyl acetate) to give 30b (46 mg,

0.191 mmol, 98 %) as a white foam. HRMS (ESI): calcd. for 5-Methoxy-2-(2-C-methyl-β-D-ribofuranosyl)pyridine (30e): A sus-

C₁₁H₁₇O₄N₂[M + H]⁺241.11828; found 241.11811. ¹H NMR

(500 MHz, [D₆]DMSO): δ = 0.69 (s, 3 H, CH₃-2Ј), 3.56 (m, 1 H,

5Јa-H), 3.72–3.79 (m, 3 H, 5Јb-H, 4Ј-H, 3Ј-H), 4.56 (s, 1 H, OH-

2Ј), 4.61 (s, 1 H, 1Ј-H), 4.86 (d, 1 H, J_OH,3Ј= 6.3 Hz, OH-3Ј), 5.27

pension of 20e (194 mg, 0.37 mmol) and Pd/C (5%; “eggshell”, un-

reduced form, 50% wet; 78 mg, 0.019 mmol) in acetic acid (2 mL)

was vigorously stirred under a hydrogen atmosphere at room temp.

After stirring for 1 d, the reaction mixture was filtered through a

paper filter, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

gel (0 to 10 % of MeOH in ethyl acetate) to give 30e (72 mg,

(br. s, 2 H, NH₂), 5.43 (br. s, 1 H, OH-5Ј), 6.89 (dd, 1 H, J_4,3

=

8.3, J_4,6= 2.7 Hz, 4-H), 7.08 (br. d, 1 H, J_3,4= 8.3 Hz, 3-H), 7.82

(dd, 1 H, J_{6 ,4}= 2.7, J_{6, 3}= 0.7 Hz, 6-H) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 22.1 (CH₃-2Ј), 61.2 (CH₂-5Ј), 73.7 0.28 mmol, 76 %) as a white foam. HRMS (ESI): calcd. for

(CH-3Ј), 78.7 (C-2Ј), 82.1 (CH-4Ј), 88.6 (CH-1Ј), 120.5 (CH-4),

C₁₂H₁₇O₅NNa [M + H]⁺278.09989; found 278.09993. ¹H NMR

122.1 (CH-3), 134.9 (CH-6), 144.1 (C-5), 147.6 (C-2) ppm. IR (500 MHz, [D₆]DMSO): δ = 0.68 (s, 3 H, CH₃-2Ј), 3.60 (m, 1 H,

(ATR): 3352, 3238, 2918, 1634, 1606, 1501, 1305, 1073, 1048,

1013 cm^–1. [α]²_D⁰= –18 (c 0.316, MeOH). C₁₁H₁₆O₄N₂·0.3H₂O:

calcd. C 53.78, H 6.81, N 11.4; found C 54.02, H 6.76, N 11.08.

5Јa-H), 3.68 (dd, 1 H, J_3Ј,4Ј= 8.3, J_3Ј,OH= 6.9 Hz, 3Ј-H), 3.76 (m,

1 H, 5Јb-H), 3.79 (ddd, 1 H, J_4Ј,3Ј= 8.3, J_4Ј,5Јa= 3.9, J_4Ј,5Јb

=

2.5 Hz, 4Ј-H), 3.81 (s, 3 H, CH₃O), 4.67 (s, 1 H, OH-2Ј), 4.74 (s, 1

H, 1Ј-H), 4.92 (d, 1 H, J_OH,3Ј= 6.9 Hz, OH-3Ј), 5.09 (dd, 1 H,

J_OH,5Јa= 6.3, J_OH,5Јb= 4.3 Hz, OH-5Ј), 7.36 (dd, 1 H, J_4,3= 8.6,

J_4,6= 3.0 Hz, 4-H), 7.47 (br. d, 1 H, J_3,4= 8.6 Hz, 3-H), 8.20 (dd,

1 H, J_6,4= 3.0, J_6,3= 0.7 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz,

[D₆]DMSO): δ = 22.2 (CH₃-2Ј), 55.7 (CH₃O), 61.1 (CH₂-5Ј), 73.9

(CH-3Ј), 78.5 (C-2Ј), 82.3 (CH-4Ј), 88.6 (CH-1Ј), 121.1 (CH-4),

122.2 (CH-3), 135.9 (CH-6), 152.7 (C-2), 154.6 (C-5) ppm. IR

(ATR): 3334, 2939, 1580, 1495, 1461, 1403, 1275, 1122, 1073,

1018 cm^–1. [α]²_D⁰= –18.9 (c 0.312, MeOH). C₁₂H₁₇O₅N·1.05H₂O:

calcd. C 52.57, H 7.02, N 5.11; found C 52.89, H 6.93, N 4.79.

5-(Dimethylamino)-2-(2-C-methyl-β-D-ribofuranosyl)pyridine (30c):

BCl₃(1 m in CH₂Cl₂; 9.28 mL, 9.28 mmol) was added dropwise to

a cooled (–78 °C) solution of 20c (500 mg, 0.928 mmol) in dry

CH₂Cl₂(5 mL). The resulting solution was stirred at –78 °C for

1 h. Subsequently, MeOH (1 mL) was added, and the reaction mix-

ture was warmed to room temp., and concentrated under reduced

pressure. The crude product was purified by flash chromatography

on silica gel (0 to 40 % of MeOH in ethyl acetate) to give 30c

(226 mg, 0.842 mmol, 91 %) as a white solid, m.p. 143–144 °C.

HRMS (ESI): calcd. for C₁₃H₂₁O₄N₂[M + H]⁺269.14958; found

269.14969. ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.69 (s, 3 H, General Procedure for the Synthesis of Triphosphates 31, 32a–32e,

CH₃-2Ј), 2.91 [s, 6 H, (CH₃)₂N], 3.58 (ddd, 1 H, J_gem= 11.7, J_5Јa,OH

= 6.7, J_5Ј,4Ј= 3.4 Hz, 5Јa-H), 3.73–3.81 (m, 3 H, 5Јb-H, 4Ј-H, 3Ј-

33a–33e, and 34a–34e: A solution of C-nucleoside (0.2 mmol) in

P(O)(OMe)₃(0.47 mL, 4 mmol) was treated with POCl₃(22 μL,

0.24 mmol) at 0 °C for 2 h. Then, an ice-cold solution of (Bu₃NH)

₂H₂P₂O₇(548 mg, 1 mmol) and Bu₃N (0.19 mL, 0.8 mmol) in dry

DMF (1.5 mL) was added, and the resulting solution was stirred

at 0 °C for an additional 2 h. The reaction mixture was quenched

with TEAB (2 m aq.; 1.5 mL), then it was warmed to room temp.,

H), 4.60 (s, 1 H, OH-2Ј), 4.69 (s, 1 H, 1Ј-H), 4.88 (d, 1 H, J_OH,3Ј

=

6.3 Hz, OH-3Ј), 5.35 (br. dd, 1 H, J_OH,5Јa= 6.7, J_OH,5Јb= 3.4 Hz,

OH-5Ј), 7.08 (dd, 1 H, J_4,3= 8.7, J_4,6= 3.1 Hz, 4-H), 7.26 (br. dt,

1 H, J_3,4= 8.7, J_3,6= J_3,1Ј= 0.6 Hz, 3-H), 7.99 (dd, 1 H, J_6,4

=

3.1, J_6,3= 0.7 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO):

δ = 22.1 (CH₃-2Ј), 39.9 [(CH₃)₂N], 61.3 (CH₂-5Ј), 73.8 (CH-3Ј), and concentrated under reduced pressure. The residue was coevap-

78.7 (C-2Ј), 82.2 (CH-4Ј), 88.6 (CH-1Ј), 119.2 (CH-4), 121.9 (CH- orated several times with water. The crude product was purified on

3), 133.2 (CH-6), 145.4 (C-5), 147.8 (C-2) ppm. IR (ATR): 3410, Sephadex [0 to 60 % of TEAB (2 m aq.) in water] and then by

2887, 1603, 1562, 1508, 1452, 1365, 1311, 1218, 1104, 1060 cm^–1.

[α]²_D⁰= –21.5 (c 0.256, MeOH). C₁₃H₂₀O₄N₂: calcd. C 58.19, H

7.51, N 10.44; found C 57.93, H 7.17, N 10.23.

HPLC {C18 column; TEAB (0.1 m aq.) to TEAB [0.1 m in water/

MeOH (1:1)]} to give the desired triphosphates.

(2-C-Methyl-β-

Compound 31 was prepared from compound 22 (45 mg, 0.2 mmol)

pension of 20d (170 mg, 0.33 mmol) and Pd/C (5%; “eggshell”, un- following the general procedure for the synthesis of triphosphates.

D-ribofuranosyl)benzene 5Ј-O-Triphosphate (31):

5-Hydroxy-2-(2-C-methyl-β-D-ribofuranosyl)pyridine (30d): A sus-

reduced form, 50% wet; 72 mg, 0.017 mmol) in acetic acid (2 mL)

was vigorously stirred under a hydrogen atmosphere at room temp.

After stirring for 1 d, the reaction mixture was filtered through a

paper filter, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by flash chromatography on silica

gel (0 to 10 % of MeOH in ethyl acetate) to give 30d (77 mg,

Before lyophilization, 31 was converted to its sodium salt form

(Dowex 50WX8 in Na⁺cycle). Lyophilization from water gave tri-

phosphate 31 (99 mg, 0.186 mmol, 93%; trisodium salt) as a white

powder. HRMS (ESI): calcd. for C₁₂H₁₆O₁₃Na₂P₃[M·3Na – Na]^–

506.95937; found 506.95962. H NMR (500 MHz, D₂O): δ = 0.87

(s, 3 H, CH₃-2Ј), 3.99 (d, 1 H, J_3Ј,4Ј= 7.3 Hz, 3Ј-H), 4.14 (dddd, 1

H, J_4Ј,3Ј= 7.3, J_4Ј,5Јa= 4.9, J_4Ј,5Јb= 3.1, J_4Ј,P= 1.2 Hz, 4Ј-H), 4.28

1

0.32 mmol, 97 %) as a white foam. HRMS (ESI): calcd. for

1

C₁₁H₁₅O₅NNa [M + Na]⁺264.08424; found 264.08431. H NMR (ddd, 1 H, J_gem= 11.7, J_5Јa,P= 6.5, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 4.36

(500 MHz, [D₆]DMSO): δ = 0.68 (s, 3 H, CH₃-2Ј), 3.58 (m, 1 H,

(ddd, 1 H, J_gem= 11.7, J_5Јb,P= 5.6, J_5Јb,4Ј= 3.1 Hz, 5Јb-H), 4.91

5Јa-H), 3.69 (dd, 1 H, J_3Ј,4Ј= 8.3, J_3Ј,OH= 6.7 Hz, 3Ј-H), 3.75 (m, (s, 1 H, 1Ј-H), 7.36–7.50 (m, 5 H, H-o,m,p-Ph) ppm. ¹³C NMR

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7979

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

(125.7 MHz, D₂O): δ = 21.72 (CH₃-2Ј), 65.9 [d, J_C,P= 5.6 Hz, CH₂-

5Ј], 75.1 (CH-3Ј), 79.4 (C-2Ј), 81.4 (d, J_C,P= 8.8 Hz, CH-4Ј), 88.7

2Ј), 43.2 [(CH₃)₂N], 47.3 [(CH₃CH₂)₃NH⁺], 65.7 (d, J_C,P= 5.6 Hz,

CH₂-5Ј), 74.8 (CH-3Ј), 79.6 (C-2Ј), 81.1 (d, J_C,P= 8.8 Hz, CH-4Ј),

(CH-1Ј), 127.4 (CH-o-Ph), 128.8 (CH-p-Ph), 129.0 (CH-m-Ph), 88.5 (CH-1Ј), 117.3 (CH-2, CH-6), 128.7 (CH-3, CH-5), 132.9 (C-

138.7 (C-i-Ph) ppm. ³¹P NMR (202.4 MHz, D₂O): δ = –22.59 (t, 1 4), 149.2 (C-1) ppm. ³¹P NMR (202.4 MHz, D₂O): δ = –22.54 (t,

P, J_β,α= J_β,γ= 19.6 Hz, P_β), –10.94 (d, 1 P, J_α,β= 19.5 Hz, P_α), 1 P, J_β,α= J_β,γ= 19.8 Hz, P_β), –10.48 (d, 1 P, J_α,β= 19.9 Hz, P_α),

–9.45 (d, 1 P, J_γ,β= 19.7 Hz, P_γ) ppm.

–9.95 (d, 1 P, J_γ,β= 19.8 Hz, P_γ) ppm.

4-Methyl-1-(2-C-methyl-β- -ribofuranosyl)benzene 5Ј-O-Triphos-

D

4-(2-C-Methyl-β- -ribofuranosyl)phenol 5Ј-O-Triphosphate (32d):

D

phate (32a): Compound 32a was prepared from compound 28a

(48 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 32a

(94 mg, 0.12 mmol, 60%; triethylammonium salt) as a white foam.

Compound 32d was prepared from compound 28d (48 mg,

0.2 mmol) following the general procedure for the synthesis of tri-

phosphates. Lyophilization from water gave triphosphate 32d

(110 mg, 0.14 mmol, 70%; triethylammonium salt) as a white foam.

HRMS (ESI): calcd. for C₁₃H₂₀O₁₃P₃[M – H]^–477.01222; found

HRMS (ESI): calcd. for C₁₂H₁₈O₁₄P₃[M – H]^–478.99149; found

1

477.01166. H NMR (500 MHz, D₂O): δ = 0.86 (s, 3 H, CH₃-2Ј), 478.99063. H NMR (500 MHz, D₂O): δ = 0.88 (s, 3 H, CH₃-2Ј),

1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃NH⁺], 2.34 (s, 3 H,

1.27 [t, 27 H, J_CH3,CH2= 7.4 Hz, (CH₃CH₂)₃NH⁺], 3.19 [q, 18 H,

CH₃-Ph), 3.19 [q, 18 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃NH⁺], 3.98 J_CH2,CH3= 7.4 Hz, (CH₃CH₂)₃NH⁺], 3.99 (d, 1 H, J_3Ј,4Ј= 7.4 Hz,

(d, 1 H, J_3Ј,4Ј= 7.3 Hz, 3Ј-H), 4.12 (dddd, 1 H, J_4Ј,3Ј= 7.3, J_4Ј,5Јa3Ј-H), 4.10 (dddd, 1 H, J_4Ј,3Ј= 7.4, J_4Ј,5Јa= 4.6, J_4Ј,5Јb= 3.0, J_4Ј,P

= 4.9, J_4Ј,5Јb= 3.1, J_4Ј,P= 1.3 Hz, 4Ј-H), 4.27 (ddd, 1 H, J_gem

11.6, J_5Јa,P= 6.4, J_5Јa,4Ј= 4.9 Hz, 5Јa-H), 4.34 (ddd, 1 H, J_gem

=

= 1.3 Hz, 4Ј-H), 4.26 (ddd, 1 H, J_gem= 11.6, J_5Јa,P= 6.4, J_5Јa,4Ј

4.7 Hz, 5Јa-H), 4.34 (ddd, 1 H, J_gem= 11.6, J_5Јb,P= 5.4, J_5Јb,4Ј

=

11.6, J_5Јb,P= 5.5, J_5Јb,4Ј= 3.1 Hz, 5Јb-H), 4.87 (s, 1 H, 1Ј-H), 7.29

3.0 Hz, 5Јb-H), 4.83 (s, 1 H, 1Ј-H), 6.92 (m, 2 H, 2-H, 6-H), 7.31

(m, 2 H, 3-H, 5-H), 7.33 (m, 2 H, 2-H, 6-H) ppm. ¹³C NMR (m, 2 H, 3-H, 5-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ = 8.8

(125.7 MHz, D₂O): δ = 8.8 [(CH₃CH₂)₃NH⁺], 20.8 (CH₃-Ph), 21.7 [(CH₃CH₂)₃NH⁺], 21.7 (CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 65.8 (d,

(CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 65.9 (d, J_C,P= 6.0 Hz, CH₂-5Ј), J_C,P= 5.6 Hz, CH₂-5Ј), 74.9 (CH-3Ј), 79.4 (C-2Ј), 81.1 (d, J_C,P

=

75.0 (CH-3Ј), 79.4 (C-2Ј), 81.2 (d, J_C,P= 9.0 Hz, CH-4Ј), 88.7 (CH-

8.9 Hz, CH-4Ј), 88.7 (CH-1Ј), 115.7 (CH-2, CH-6), 129.1 (CH-3,

1Ј), 127.5 (CH-2, CH-6), 129.6 (CH-3, CH-5), 135.8 (C-1), 139.0 CH-5), 130.9 (C-4), 155.9 (C-1) ppm. ³¹P NMR (202.4 MHz, D₂O):

(C-4) ppm. ³¹P NMR (202.4 MHz, D₂O): δ = –22.56 (t, 1 P, J_β,α

=

δ = –22.36 (t, 1 P, J_β,α= J_β,γ= 19.5 Hz, P_β), –10.44 (d, 1 P, J_α,β=

J_β,γ= 19.7 Hz, P_β), –10.49 (d, 1 P, J_α,β= 19.9 Hz, P_α), –10.23 (d,

1 P, J_γ,β= 19.6 Hz, P_γ) ppm.

19.7 Hz, P_α), –9.47 (br. s, 1 P, P_γ) ppm.

4-(2-C-Methyl-β-D-ribofuranosyl)anisole 5Ј-O-Triphosphate (32e):

4-(2-C-Methyl-β-D-ribofuranosyl)aniline 5Ј-O-Triphosphate (32b): Compound 32e was prepared from compound 28e (51 mg,

Compound 32b was prepared from compound 28b (48 mg,

0.2 mmol) following the general procedure for the synthesis of tri-

phosphates. Lyophilization from water gave triphosphate 32b

(87 mg, 0.128 mmol, 64%; diethylammonium salt) as a white foam.

0.2 mmol) following the general procedure for the synthesis of tri-

phosphates. Before lyophilization, 32e was converted to its sodium

salt form (Dowex 50WX8 in Na⁺cycle). Lyophilization from water

gave triphosphate 32e (86 mg, 0.154 mmol, 77%; trisodium salt) as

HRMS (ESI): calcd. for C₁₂H₁₉O₁₃NP₃[M – H]^–478.00747; found

a white powder. HRMS (ESI): calcd. for C₁₃H₁₈O₁₄Na₂P₃

1

478.00726. H NMR (500 MHz, D₂O): δ = 0.88 (s, 3 H, CH₃-2Ј), [M·3Na – Na]^–536.96993; found 536.96975. H NMR (500 MHz,

1.27 [t, 18 H, J_CH3,CH2= 7.4 Hz, (CH₃CH₂)₃NH⁺], 3.19 [q, 12 H, D₂O): δ = 0.87 (s, 3 H, CH₃-2Ј), 3.84 (s, 3 H, CH₃O), 4.00 (d, 1 H,

J_CH2,CH3= 7.4 Hz, (CH₃CH₂)₃NH⁺], 3.99 (d, 1 H, J_3Ј,4Ј= 7.4 Hz,

J_3Ј,4Ј= 7.5 Hz, 3Ј-H), 4.12 (dddd, 1 H, J_4Ј,3Ј= 7.5, J_4Ј,5Јa= 4.7,

3Ј-H), 4.10 (dddd, 1 H, J_4Ј,3Ј= 7.4, J_4Ј,5Јa= 4.7, J_4Ј,5Јb= 3.0, J_4Ј,PJ_4Ј,5Јb= 3.0, J_4Ј,P= 1.2 Hz, 4Ј-H), 4.28 (ddd, 1 H, J_gem= 11.7, J_5Јa,P

= 1.4 Hz, 4Ј-H), 4.26 (ddd, 1 H, J_gem= 11.7, J_5Јa,P= 6.4, J_5Јa,4Ј

4.7 Hz, 5Јa-H), 4.34 (ddd, 1 H, J_gem= 11.7, J_5Јb,P= 5.4, J_5Јb,4Ј

=

= 6.5, J_5Јa,4Ј= 4.8 Hz, 5Јa-H), 4.35 (ddd, 1 H, J_gem= 11.7, J_5Јb,P

5.5, J_5Јb,4Ј= 3.1 Hz, 5Јb-H), 4.87 (s, 1 H, 1Ј-H), 6.92 (m, 2 H, 2-

=

3.0 Hz, 5Јb-H), 4.83 (s, 1 H, 1Ј-H), 6.99 (m, 2 H, 2-H, 6-H), 7.31 H, 6-H), 7.27 (m, 2 H, 3-H, 5-H) ppm. ¹³C NMR (125.7 MHz,

(m, 2 H, 3-H, 5-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ = 8.9 D₂O): δ = 21.7 (CH₃-2Ј), 56.0 (CH₃O), 65.8 (d, J_C,P= 5.8 Hz, CH₂-

[(CH₃CH₂)₃NH⁺], 21.7 (CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 65.8 (d, 5Ј), 74.9 (CH-3Ј), 79.5 (C-2Ј), 81.2 (d, J_C,P= 8.7 Hz, CH-4Ј), 88.6

J_C,P= 5.6 Hz, CH₂-5Ј), 74.9 (CH-3Ј), 79.4 (C-2Ј), 81.1 (d, J_C,P

=

(CH-1Ј), 114.5 (CH-2, CH-6), 128.9 (CH-3, CH-5), 131.5 (C-4),

8.9 Hz, CH-4Ј), 88.7 (CH-1Ј), 118.3 (CH-2, CH-6), 128.8 (CH-3, 159.3 (C-1) ppm. ³¹P NMR (202.4 MHz, D₂O): δ = –20.08 (m, 1

CH-5), 132.0 (C-4), 142.9(C-1) ppm. ³¹P NMR (202.4 MHz, D₂O): P, P_β), –10.80 (br. d, 1 P, J_α,β= 19.5 Hz, P_α), –7.54 (m, 1 P, P_γ)

δ = –22.51 (t, 1 P, J_β,α= J_β,γ= 19.8 Hz, P_β), –10.44 (d, 1 P, J_α,β

19.9 Hz, P_α), –10.08 (d, 1 P, J_γ,β= 19.8 Hz, P_γ) ppm.

=

ppm.

2-Methyl-5-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

N,N-Dimethyl-4-(2-C-methyl-β-

D

-ribofuranosyl)aniline 5Ј-O-Tri-

phate (33a): Compound 33a was prepared from compound 29a

(48 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 33a

(139 mg, 0.178 mmol, 89%; triethylammonium salt) as a white

foam. HRMS (ESI): calcd. for C₁₂H₁₉O₁₃NP₃[M – H]^–478.00747;

found 478.00725. ¹H NMR (500 MHz, D₂O): δ = 0.93 (s, 3 H,

CH₃-2Ј), 2.65 (s, 3 H, CH₃-2), 1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz,

(CH₃CH₂)₃NH⁺], 3.19 [q, 18 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃-

phosphate (32c): Compound 32c was prepared from compound 28c

(53 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 32c

(133 mg, 0.164 mmol, 82%; triethylammonium salt) as a white

foam. HRMS (ESI): calcd. for C₁₄H₂₃O₁₃NP₃[M – H]^–506.03877;

found 506.03847. ¹H NMR (500 MHz, D₂O): δ = 0.87 (s, 3 H,

CH₃-2Ј), 1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃NH⁺], 2.97

[s, 6 H, (CH₃)₂N], 3.19 [q, 18 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃-

NH⁺], 4.07 (d, 1 H, J_3Ј,4Ј= 7.6 Hz, 3Ј-H), 4.16 (dddd, 1 H, J_4Ј,3Ј

7.6, J_4Ј,5Јa= 3.6, J_4Ј,5Јb= 2.6, J_4Ј,P= 2.0 Hz, 4Ј-H), 4.28 (ddd, 1 H,

=

NH⁺], 4.00 (d, 1 H, J_3Ј,4Ј= 7.5 Hz, 3Ј-H), 4.11 (dddd, 1 H, J_4Ј,3Ј

=

7.5, J_4Ј,5Јa= 4.5, J_4Ј,5Јb= 2.9, J_4Ј,P= 1.4 Hz, 4Ј-H), 4.27 (ddd, 1 H, J_gem= 11.8, J_5Јa,P= 6.0, J_5Јa,4Ј= 3.7 Hz, 5Јa-H), 4.38 (ddd, 1 H,

J_gem= 11.7, J_5Јa,P= 6.4, J_5Јa,4Ј= 4.6 Hz, 5Јa-H), 4.35 (ddd, 1 H, J_gem= 11.8, J_5Јb,P= 4.7, J_5Јb,4Ј= 2.6 Hz, 5Јb-H), 5.02 (s, 1 H, 1Ј-

J_gem= 11.7, J_5Јb,P= 5.3, J_5Јb,4Ј= 2.9 Hz, 5Јb-H), 4.87 (s, 1 H, 1Ј- H), 7.60 (d, 1 H, J_3,4= 8.3 Hz, 3-H), 8.08 (br. d, 1 H, J_4,3= 8.3 Hz,

H), 7.20 (m, 2 H, 2-H, 6-H), 7.43 (m, 2 H, 3-H, 5-H) ppm. ¹³C

4-H), 8.66 (br. s, 1 H, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ

NMR (125.7 MHz, D₂O): δ = 8.9 [(CH₃CH₂)₃NH⁺], 21.7 (CH₃- = 8.8 [(CH₃CH₂)₃NH⁺], 21.2 (CH₃-2), 21.5 (CH₃-2Ј), 47.3

7980

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Eur. J. Org. Chem. 2015, 7962–7983

2Ј-C-Methyl-C-ribonucleosides and -nucleotides

[(CH₃CH₂)₃NH⁺], 64.9 (d, J_C,P= 5.1 Hz, CH₂-5Ј), 73.9 (CH-3Ј),

79.6 (C-2Ј), 81.5 (d, J_C,P= 9.0 Hz, CH-4Ј), 85.8 (CH-1Ј), 126.2

(CH-3), 134.6 (C-5), 140.8 (CH-4), 142.9 (CH-6), 156.9 (C-2) ppm.

(m, 2 H, 4-H, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ = 8.9

[(CH₃CH₂)₃NH⁺], 21.4 (CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 65.1 (d,

J_C,P= 5.6 Hz, CH₂-5Ј), 74.0 (CH-3Ј), 79.4 (C-2Ј), 81.1 (d, J_C,P

=

³¹P NMR (202.4 MHz, D₂O): δ = –22.17 (t, 1 P, J_β,α= J_β,γ

=

9.0 Hz, CH-4Ј), 85.7 (CH-1Ј), 119.2 (CH-3), 120.7 (C-5), 133.7 and

143.3 (CH-4,6), 165.1 (C-2) ppm. ³¹P NMR (202.4 MHz, D₂O): δ

= –22.47 (br. s, 1 P, P_β), –10.48 (br. d, 1 P, J_α,β= 19.2 Hz, P_α),

–10.16 (br. s, 1 P, P_γ) ppm.

19.5 Hz, P_β), –10.18 (d, 1 P, J_α,β= 18.8 Hz, P_α), –8.58 (d, 1 P, J_γ,β

= 20.2 Hz, P_γ) ppm.

2-Amino-5-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

phate (33b): Compound 33b was prepared from compound 29b

(48 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 33b

2-Methoxy-5-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

phate (33e): Compound 33e was prepared from compound 29e

(51 mg, 0.2 mmol) following the general procedure for the synthesis

(120 mg, 0.176 mmol, 88 %; diethylammonium salt) as a white of triphosphates. Lyophilization from water gave triphosphate 33e

foam. HRMS (ESI): calcd. for C₁₁H₂₀O₁₃N₂P₃[M + H]⁺

481.01727; found 481.01746. H NMR (500 MHz, D₂O): δ = 1.01

(s, 3 H, CH₃-2Ј), 1.27 [t, 18 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃-

NH⁺], 3.19 [q, 12 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃NH⁺], 4.07 (d,

1 H, J_3Ј,4Ј= 8.2 Hz, 3Ј-H), 4.11 (dq, 1 H, J_4Ј,3Ј= 8.2, J_4Ј,5Јa= J_4Ј,5Јb

= J_4Ј,P= 2.5 Hz, 4Ј-H), 4.24 (ddd, 1 H, J_gem= 11.9, J_5Јa,P= 5.8,

(153 mg, 0.192 mmol, 96%; triethylammonium salt) as a white

foam. HRMS (ESI): calcd. for C₁₂H₁₉O₁₄NP₃[M – H]^–494.00239;

found 494.00244. ¹H NMR (500 MHz, D₂O): δ = 0.91 (s, 3 H,

CH₃-2Ј), 1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃NH⁺], 3.19

[q, 18 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃NH⁺], 3.92 (s, 3 H, CH₃O),

4.02 (d, 1 H, J_3Ј,4Ј= 7.3 Hz, 3Ј-H), 4.13 (dddd, 1 H, J_4Ј,3Ј= 7.3,

1

J_5Јa,4Ј= 2.8 Hz, 5Јa-H), 4.36 (ddd, 1 H, J_gem= 11.9, J_5Јb,P= 4.3, J_4Ј,5Јa= 4.4, J_4Ј,5Јb= 3.0, J_4Ј,P= 1.5 Hz, 4Ј-H), 4.27 (ddd, 1 H, J_gem

J_5Јb,4Ј= 2.2 Hz, 5Јb-H), 4.88 (s, 1 H, 1Ј-H), 6.79 (d, 1 H, J_3,4= 11.7, J_5Јa,P= 6.4, J_5Јa,4Ј= 4.4 Hz, 5Јa-H), 4.34 (ddd, 1 H, J_gem

=

9.2 Hz, 3-H), 7.83 (dd, 1 H, J_4,3= 9.2, J_4,6= 2.0 Hz, 4-H), 8.10

11.7, J_5Јb,P= 5.3, J_5Јb,4Ј= 3.0 Hz, 5Јb-H), 4.90 (s, 1 H, 1Ј-H), 6.96

(d, 1 H, J_3,4= 8.8 Hz, 3-H), 7.86 (dd, 1 H, J_4,3= 8.8, J_4,6= 2.4 Hz,

4-H), 8.10 (br. d, 1 H, J_6,4= 2.3 Hz, 6-H) ppm. ¹³C NMR

(br. s, 1 H, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ = 8.8 [(CH₃-

CH₂)₃NH⁺], 21.2 (CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 64.4 (d, J_C,P

=

5.0 Hz, CH₂-5Ј), 73.2 (CH-3Ј), 79.8 (C-2Ј), 80.8 (d, J_C,P= 9.1 Hz, (125.7 MHz, D₂O): δ = 8.8 [(CH₃CH₂)₃NH⁺], 21.6 (CH₃-2Ј), 47.3

CH-4Ј), 85.7 (CH-1Ј), 113.6 (CH-3), 125.1 (C-5), 134.7 (CH-6), [(CH₃CH₂)₃NH⁺], 54.8 (CH₃O), 65.5 (d, J_C,P= 5.5 Hz, CH₂-5Ј),

143.1 (CH-4), 154.5 (C-2) ppm. ³¹P NMR (202.4 MHz, D₂O): δ = 74.7 (CH-3Ј), 79.4 (C-2Ј), 81.5 (d, J_C,P= 8.9 Hz, CH-4Ј), 86.3 (CH-

–22.23 (br. t, 1 P, J_β,α= J_β,γ= 17.7 Hz, P_β), –10.09 (d, 1 P, J_α,β

18.6 Hz, P_α), –8.87 (br. d, 1 P, J_γ,β= 16.7 Hz, P_γ) ppm.

=

1Ј), 110.9 (CH-3), 128.1 (C-5), 139.7 (CH-4), 145.1 (CH-6), 164.5

(C-2) ppm. ³¹P NMR (202.4 MHz, D₂O): δ = –22.35 (t, 1 P, J_β,α

=

J_β,γ= 19.7 Hz, P_β), –10.48 (d, 1 P, J_α,β= 19.8 Hz, P_α), –9.76 (d, 1

P, J_γ,β= 19.7 Hz, P_γ) ppm.

2-(Dimethylamino)-5-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-

Triphosphate (33c): Compound 33c was prepared from compound

29c (54 mg, 0.2 mmol) following the general procedure for the syn-

thesis of triphosphates. Lyophilization from water gave triphos-

phate 33c (124 mg, 0.174 mmol, 87%; diethylammonium salt) as

a white foam. HRMS (ESI): calcd. for C₁₃H₂₂O₁₃N₂P₃[M – H]^–

5-Methyl-2-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

phate (34a): Compound 34a was prepared from compound 30a

(48 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 34a

(146 mg, 0.186 mmol, 93%; triethylammonium salt) as a white

foam. HRMS (ESI): calcd. for C₁₂H₁₉O₁₃NP₃[M – H]^–478.00747;

1

507.03402; found 507.03370. H NMR (500 MHz, D₂O): δ = 1.00

(s, 3 H, CH₃-2Ј), 1.27 [t, 18 H, J_CH3,CH2= 7.4 Hz, (CH₃-

CH₂)₃NH⁺], 3.19 [q, 12 H, J_CH2,CH3= 7.4 Hz, (CH₃CH₂)₃NH⁺], found 478.00737. ¹H NMR (500 MHz, D₂O): δ = 0.89 (s, 3 H,

3.22 [s, 6 H, (CH₃)₂N], 4.08 (d, 1 H, J_3Ј,4Ј= 8.2 Hz, 3Ј-H), 4.11

(dq, 1 H, J_4Ј,3Ј= 8.2, J_4Ј,5Јa= J_4Ј,5Јb= J_4Ј,P= 2.4 Hz, 4Ј-H), 4.27

CH₃-2Ј), 2.39 (s, 3 H, CH₃-5), 1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz,

(CH₃CH₂)₃NH⁺], 3.19 [q, 18 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃-

(ddd, 1 H, J_gem= 11.9, J_5Јa,P= 6.0, J_5Јa,4Ј= 2.7 Hz, 5Јa-H), 4.37 NH⁺], 4.00 (d, 1 H, J_3Ј,4Ј= 7.6 Hz, 3Ј-H), 4.18 (dddd, 1 H, J_4Ј,3Ј

=

(ddd, 1 H, J_gem= 11.9, J_5Јb,P= 4.2, J_5Јb,4Ј= 2.2 Hz, 5Јb-H), 4.87

(s, 1 H, 1Ј-H), 7.08 (dd, 1 H, J_3,4= 9.5, J_3,6= 0.7 Hz, 3-H), 7.84

7.6, J_4Ј,5Јa= 4.3, J_4Ј,5Јb= 2.7, J_4Ј,P= 1.6 Hz, 4Ј-H), 4.30 (ddd, 1 H,

J_gem= 11.8, J_5Јa,P= 6.4, J_5Јa,4Ј= 4.3 Hz, 5Јa-H), 4.40 (ddd, 1 H,

J_gem= 11.8, J_5Јb,P= 5.3, J_5Јb,4Ј= 2.7 Hz, 5Јb-H), 5.01 (s, 1 H, 1Ј-

(br. dd, 1 H, J_4,3= 9.5, J_4,6= 2.2 Hz, 4-H), 8.10 (dt, 1 H, J_6,4

=

2.2, J_6,3= J_6,1Ј= 0.8 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): H), 7.67 (d, 1 H, J_3,4= 8.2 Hz, 3-H), 7.92 (br. d, 1 H, J_4,3= 8.2 Hz,

δ = 8.8 [(CH₃CH₂)₃NH⁺], 21.3 (CH₃-2Ј), 39.4 [(CH₃)₂N], 47.3 4-H), 8.41 (br. s, 1 H, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ

[(CH₃CH₂)₃NH⁺], 64.6 (d, J_C,P= 5.2 Hz, CH₂-5Ј), 73.2 (CH-3Ј),

79.8 (C-2Ј), 80.8 (d, J_C,P= 9.1 Hz, CH-4Ј), 85.7 (CH-1Ј), 111.9

(CH-3), 123.6 (C-5), 135.4 (CH-6), 141.8 (CH-4), 153.6 (C-2) ppm.

= 8.8 [(CH₃CH₂)₃NH⁺], 17.9 (CH₃-5), 21.2 (CH₃-2Ј), 47.3

[(CH₃CH₂)₃NH⁺], 65.4 (d, J_C,P= 5.6 Hz, CH₂-5Ј), 74.4 (CH-3Ј),

79.9 (C-2Ј), 81.6 (d, J_C,P= 8.6 Hz, CH-4Ј), 87.8 (CH-1Ј), 122.8

³¹P NMR (202.4 MHz, D₂O): δ = –22.16 (br. m, 1 P, P_β), –10.27 (CH-3), 135.6 (C-5), 141.5 (CH-4), 147.0 (CH-6), 153.6 (C-2) ppm.

(d, 1 P, J_α,β= 19.3 Hz, P_α), –8.72 (br. s, 1 P, P_γ) ppm.

³¹P NMR (202.4 MHz, D₂O): δ = –22.25 (t, 1 P, J_β,α= J_β,γ

=

19.0 Hz, P_β), –10.40 (d, 1 P, J_α,β= 19.5 Hz, P_α), –9.49 (d, 1 P, J_γ,β

= 18.5 Hz, P_γ) ppm.

5-(2-C-Methyl-β- -ribofuranosyl)-2-pyridone 5Ј-O-Triphosphate

D

(33d): Compound 33d was prepared from compound 29d (48 mg,

0.2 mmol) following the general procedure for the synthesis of tri-

phosphates. Lyophilization from water gave triphosphate 33d

(118 mg, 0.15 mmol, 75%; triethylammonium salt) as a white foam.

5-Amino-2-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

phate (34b): Compound 34b was prepared from compound 30b

(48 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 34b

HRMS (ESI): calcd. for C₁₁H₁₇O₁₄NP₃[M – H]^–479.98674; found

1

479.98593. H NMR (500 MHz, D₂O): δ = 1.01 (s, 3 H, CH₃-2Ј), (70 mg, 0.102 mmol, 51%; diethylammonium salt) as a white foam.

1.27 [t, 27 H, J_CH3,CH2= 7.4 Hz, (CH₃CH₂)₃NH⁺], 3.19 [q, 18 H, HRMS (ESI): calcd. for C₁₁H₁₈O₁₃N₂P₃[M – H]^–479.00272; found

1

J_CH2,CH3= 7.4 Hz, (CH₃CH₂)₃NH⁺], 4.01 (d, 1 H, J_3Ј,4Ј= 7.7 Hz,

479.00163. H NMR (500 MHz, D₂O): δ = 0.95 (s, 3 H, CH₃-2Ј),

3Ј-H), 4.09 (br. dddd, 1 H, J_4Ј,3Ј= 7.7, J_4Ј,5Јa= 3.8, J_4Ј,5Јb= 2.7, 1.27 [t, 18 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃NH⁺], 3.19 [q, 12 H,

J_4Ј,P= 2.0 Hz, 4Ј-H), 4.24 (ddd, 1 H, J_gem= 11.8, J_5Јa,P= 6.1, J_5Јa,4ЈJ_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃NH⁺], 3.99 (d, 1 H, J_3Ј,4Ј= 7.3 Hz,

= 3.8 Hz, 5Јa-H), 4.33 (ddd, 1 H, J_gem= 11.8, J_5Јb,P= 4.8, J_5Јb,4Ј

2.7 Hz, 5Јb-H), 4.79 (s, 1 H, 1Ј-H), 6.66 (m, 1 H, 3-H), 7.70 –7.74

=

3Ј-H), 4.18 (dddd, 1 H, J_4Ј,3Ј= 7.3, J_4Ј,5Јa= 4.1, J_4Ј,5Јb= 2.6, J_4Ј,P

= 1.8 Hz, 4Ј-H), 4.28 (ddd, 1 H, J_gem= 11.9, J_5Јa,P= 6.4, J_5Јa,4Ј

=

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7981

A. Tokarenko, L. Posˇtová Slaveˇtínská, B. Klepetárˇová, M. Hocek

FULL PAPER

4.1 Hz, 5Јa-H), 4.40 (ddd, 1 H, J_gem= 11.9, J_5Јb,P= 5.2, J_5Јb,4Ј

2.6 Hz, 5Јb-H), 4.99 (s, 1 H, 1Ј-H), 7.57 (dd, 1 H, J_4,3= 8.7, J_4,6

=

CH₃-2Ј), 3.91 (s, 3 H, CH₃O), 1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz,

(CH₃CH₂)₃NH⁺], 3.19 [q, 18 H, J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃-

2.4 Hz, 4-H), 7.59 (dd, 1 H, J_3,4= 8.7, J_3,6= 0.9 Hz, 3-H), 8.07

NH⁺], 4.01 (d, 1 H, J_3Ј,4Ј= 8.0 Hz, 3Ј-H), 4.16 (dddd, 1 H, J_4Ј,3Ј

=

(br. dd, 1 H, J_6,4= 2.3, J_6,3= 0.9 Hz, 6-H) ppm. ¹³C NMR 8.0, J_4Ј,5Јa= 4.3, J_4Ј,5Јb= 2.7, J_4Ј,P= 1.6 Hz, 4Ј-H), 4.30 (ddd, 1 H,

(125.7 MHz, D₂O): δ = 8.9 [(CH₃CH₂)₃NH⁺], 21.1 (CH₃-2Ј), 47.3 J_gem= 11.8, J_5Јa,P= 6.3, J_5Јa,4Ј= 4.3 Hz, 5Јa-H), 4.39 (ddd, 1 H,

[(CH₃CH₂)₃NH⁺], 65.3 (d, J_C,P= 5.4 Hz, CH₂-5Ј), 74.4 (CH-3Ј),

79.9 (C-2Ј), 81.9 (d, J_C,P= 8.5 Hz, CH-4Ј), 86.1 (CH-1Ј), 124.6

(CH-3), 128.7 (CH-4), 131.3 (CH-6), 143.4 (C-2), 145.7 (C-5) ppm.

J_gem= 11.8, J_5Јb,P= 5.2, J_5Јb,4Ј= 2.7 Hz, 5Јb-H), 4.97 (s, 1 H, 1Ј-

H), 7.61 (dd, 1 H, J_4,3= 8.8, J_4,6= 2.9 Hz, 4-H), 7.70 (br. d, 1 H,

J_3,4= 8.8 Hz, 3-H), 8.23 (dd, 1 H, J_6,4= 2.9, J_6,3= 0.6 Hz, 6-H)

ppm. ¹³C NMR (125.7 MHz, D₂O): δ = 8.8 [(CH₃CH₂)₃NH⁺], 21.2

³¹P NMR (202.4 MHz, D₂O): δ = –22.49 (t, 1 P, J_β,α= J_β,γ

=

19.8 Hz, P_β), –10.42 (d, 1 P, J_α,β= 19.9 Hz, P_α), –9.94 (d, 1 P, J_γ,β

(CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 56.6 (CH₃O), 65.4 (d, J_C,P

=

= 19.8 Hz, P_γ) ppm.

5.6 Hz, CH₂-5Ј), 74.3 (CH-3Ј), 79.9 (C-2Ј), 81.2 (d, J_C,P= 8.8 Hz,

CH-4Ј), 88.4 (CH-1Ј), 123.6 (CH-3), 124.4 (CH-4), 135.5 (CH-6),

149.6 (C-2), 156.2 (C-5) ppm. ³¹P NMR (202.4 MHz, D₂O): δ =

5-(Dimethylamino)-2-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-

Triphosphate (34c): Compound 34c was prepared from compound

30c (54 mg, 0.2 mmol) following the general procedure for the syn-

thesis of triphosphates. Lyophilization from water gave triphos-

phate 34c (129 mg, 0.182 mmol, 91%; diethylammonium salt) as

a white foam. HRMS (ESI): calcd. for C₁₃H₂₂O₁₃N₂P₃[M – H]^–

–22.39 (t, 1 P, J_β,α= J_β,γ= 19.6 Hz, P_β), –10.43 (d, 1 P, J_α,β

19.9 Hz, P_α), –9.93 (d, 1 P, J_γ,β= 19.3 Hz, P_γ) ppm.

=

Single-Crystal X-Ray Structural Analysis: Single-crystal diffraction

data for 14 and 28d were collected with an Xcalibur X-ray dif-

fractometer with Cu-K_αradiation (λ = 1.54180 Å) at 180 K. Crys-

AlisProCCD^[27]was used for data collection, cell refinement, and

data reduction. The structures were solved by direct methods with

SIR92,^[28]and refined by the full-matrix least-squares method on

F with CRYSTALS.^[29]The hydrogen atoms were all located in a

difference Fourier map, but those attached to carbon atoms were

recalculated into idealized positions and refined with riding con-

straints. All non-hydrogen atoms were refined with anisotropic dis-

placement parameters.

1

507.03402; found 507.03323. H NMR (500 MHz, D₂O): δ = 0.95

(s, 3 H, CH₃-2Ј), 1.27 [t, 18 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃-

NH⁺], 3.02 [s, 6 H, (CH₃)₂N], 3.19 [q, 12 H, J_CH2,CH3= 7.3 Hz,

(CH₃CH₂)₃NH⁺], 4.00 (d, 1 H, J_3Ј,4Ј= 7.3 Hz, 3Ј-H), 4.18 (dddd,

1 H, J_4Ј,3Ј= 7.3, J_4Ј,5Јa= 4.0, J_4Ј,5Јb= 2.6, J_4Ј,P= 1.8 Hz, 4Ј-H),

4.30 (ddd, 1 H, J_gem= 11.9, J_5Јa,P= 6.5, J_5Јa,4Ј= 4.0 Hz, 5Јa-H),

4.42 (ddd, 1 H, J_gem= 11.9, J_5Јb,P= 5.2, J_5Јb,4Ј= 2.6 Hz, 5Јb-H),

5.02 (s, 1 H, 1Ј-H), 7.62 (dd, 1 H, J_4,3= 9.2, J_4,6= 2.7 Hz, 4-H),

7.65 (dd, 1 H, J_3,4= 9.2, J_3,6= 0.9 Hz, 3-H), 8.06 (dd, 1 H, J_6,4

=

2.7, J_6,3= 0.9 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ =

8.8 [(CH₃CH₂)₃NH⁺], 21.1 (CH₃-2Ј), 40.2 [(CH₃)₂N], 47.3 [(CH₃-

CH₂)₃NH⁺], 65.3 (d, J_C,P= 5.6 Hz, CH₂-5Ј), 74.3 (CH-3Ј), 80.0 (C-

2Ј), 82.0 (d, J_C,P= 8.4 Hz, CH-4Ј), 85.8 (CH-1Ј), 124.3 (CH-3),

126.1 (CH-4), 128.4 (CH-6), 140.7 (C-2), 148.1 (C-5) ppm. ³¹P

NMR (202.4 MHz, D₂O): δ = –22.44 (t, 1 P, J_β,α= J_β,γ= 20.0 Hz,

P_β), –10.44 (d, 1 P, J_α,β= 19.9 Hz, P_α), –9.70 (d, 1 P, J_γ,β= 20.0 Hz,

P_γ) ppm.

Crystal Data for 14: (colourless block, 0.19ϫ0.36ϫ0.74 mm):

C₃₄H₃₄Br₁N₁O₆, monoclinic, space group P2₁, a = 7.91533(7) Å, b

= 18.37168(13) Å, c = 10.53591(8) Å, β = 95.3841(7)°, V =

1525.35(2) Å³, Z = 2, M = 632.55, 19330 reflections measured,

6149 independent reflections. Final R = 0.032, wR = 0.039, GoF =

1.010 for 6078 reflections with IϾ2σ(I) and 381 parameters, Flack

parameter x = –0.026(10).

Crystal Data for 28d: (colourless block, 0.18ϫ0.37ϫ0.53 mm):

C₁₂H₁₆O₅, orthorhombic, space group P2₁2₁2₁, a = 6.90623(14) Å,

b = 9.06533(16) Å, c = 19.1665(3) Å, V = 1199.96(4) Å³, Z = 4, M

= 240.26, 6593 reflections measured, 2423 independent reflections.

Final R = 0.044, wR = 0.052, GoF = 1.063 for 2291 reflections with

IϾ2σ(I) and 155 parameters, Flack parameter x = 0.10(19).

5-Hydroxy-2-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

phate (34d): Compound 34d was prepared from compound 30d

(48 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 34d

(99 mg, 0.126 mmol, 63%; triethylammonium salt) as a white foam.

HRMS (ESI): calcd. for C₁₁H₁₇O₁₄NP₃[M – H]^–479.98674; found

1

CCDC-1415995 (for 14) and -1415996 (for 28d) contain the supple-

mentary crystallographic data for this paper. These data can be

obtained free of charge from The Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/data_request/cif

479.98593. H NMR (500 MHz, D₂O): δ = 0.92 (s, 3 H, CH₃-2Ј),

1.27 [t, 27 H, J_CH3,CH2= 7.3 Hz, (CH₃CH₂)₃NH⁺], 3.19 [q, 18 H,

J_CH2,CH3= 7.3 Hz, (CH₃CH₂)₃NH⁺], 4.00 (d, 1 H, J_3Ј,4Ј= 7.5 Hz,

3Ј-H), 4.17 (dddd, 1 H, J_4Ј,3Ј= 7.5, J_4Ј,5Јa= 4.1, J_4Ј,5Јb= 2.7, J_4Ј,P

= 1.7 Hz, 4Ј-H), 4.29 (ddd, 1 H, J_gem= 11.8, J_5Јa,P= 6.4, J_5Јa,4Ј

4.1 Hz, 5Јa-H), 4.39 (ddd, 1 H, J_gem= 11.8, J_5Јb,P= 5.2, J_5Јb,4Ј

2.7 Hz, 5Јb-H), 4.99 (s, 1 H, 1Ј-H), 7.58 (dd, 1 H, J_4,3= 8.8, J_4,6

2.8 Hz, 4-H), 7.65 (br. d, 1 H, J_3,4= 8.8 Hz, 3-H), 8.12 (dm, 1 H,

J_6,4= 2.8 Hz, 6-H) ppm. ¹³C NMR (125.7 MHz, D₂O): δ = 8.8

[(CH₃CH₂)₃NH⁺], 21.2 (CH₃-2Ј), 47.3 [(CH₃CH₂)₃NH⁺], 65.3 (d,

=

Supporting Information Available. Copies of ¹H, ¹³C, and ³¹P NMR

spectra of the products; HPLC purity of final unprotected C-nu-

cleosides; cif files for the crystal structures.

Acknowledgments

J_C,P= 5.5 Hz, CH₂-5Ј), 74.4 (CH-3Ј), 79.8 (C-2Ј), 81.7 (d, J_C,P

=

8.6 Hz, CH-4Ј), 87.0 (CH-1Ј), 124.5 (CH-3), 129.0 (CH-4), 134.3

(CH-6), 146.1 (C-2), 155.6 (C-5) ppm. ³¹P NMR (202.4 MHz,

D₂O): δ = –22.57 (t, 1 P, J_β,α= J_β,γ= 19.8 Hz, P_β), –10.46 (d, 1 P,

J_α,β= 19.8 Hz, P_α), –10.14 (d, 1 P, J_γ,β= 19.8 Hz, P_γ) ppm.

This work was supported by the Czech Science Foundation (P207/

11/0344 to A. T. and M. H.), and by Gilead Sciences, Inc. The au-

thors thank Drs. Joy Feng and Gina Bahador (Gilead Sciences,

Inc.) for anti-HCV testing, and Dr. Jaroslav Kozák (IOCB) for test-

ing the inhibition of RNA polymerase.

5-Methoxy-2-(2-C-methyl-β-D-ribofuranosyl)pyridine 5Ј-O-Triphos-

phate (34e): Compound 34e was prepared from compound 30e

(51 mg, 0.2 mmol) following the general procedure for the synthesis

of triphosphates. Lyophilization from water gave triphosphate 34e

(153 mg, 0.192 mmol, 96%; triethylammonium salt) as a white

foam. HRMS (ESI): calcd. for C₁₂H₁₉O₁₄NP₃[M – H]^–494.00239;

found 494.00168. ¹H NMR (500 MHz, D₂O): δ = 0.88 (s, 3 H,

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Published Online: November 17, 2015

Eur. J. Org. Chem. 2015, 7962–7983

www.eurjoc.org

7983

Article Doi

Synthesis of Benzene and Pyridine 2′-C-Methyl-C-ribonucleosides and -nucleotides

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