Synthesis of N,O-nucleosides

 

The scheme 2 shows a facile entry to N,O-nucleosides, according to the pericyclic reaction of substituted nitrones with vinyl acetate.

 
Nitrone 
R1 
R2 
R3 
Yield %a 
Epimeric ratio
cis/trans 
4b 
Me 
Me 
CO2Et 
90 
8:12 (1:1) 
5b 
PhCH2 
CH3-(CH2)4
CO2Et 
81 
9:13 (1:1) 
6b 
PhCH2 
CO2Et 
87 
10:14 (1:4)d 
7c 
PhCH2 
PhCO 
92 
11:15 (1:3) 
aTotal yield. bReaction at 70 °C in sealed tube. cReaction at room temperature. dUnseparable mixture. 
Scheme 2

The designed reaction scheme develops in only three steps with an overall high yields and allows for the insertion of different functionalizable groups on the N,O-nucleoside system.
Nitrones 4-7 have been reacted with vinyl acetate in the absence of solvent using a 1:10 relative ratio of dipole to dipolarophile until tlc showed the disappearance of the starting nitrones. As reported in Table 1 the investigate reactions was found to be regiospecific to afford mixture of epimeric 5-substituted isoxazolidines 8-15 (81-95% yields) as exclusive adducts. As expected, the reaction of C-disubstituted nitrones 4 and 5 resulted in the observation of a poor stereoselectivity leading to the formation of a nearly equimolar mixture of epimeric isoxazolidines; on the contrary, nitrones 6 and 7 showed a good stereoselectivity with the trans isomers 14 and 15 as the major products. The relative configurational assignments of compounds 8-11 were attributed by NOE experiments.
Isoxazolidine 8-15, as epimeric mixtures, were coupled with silylated adenine, thymine or 5-fluorouracil, in CH2Cl2 at 0° C, in the presence of SnCl4 as catalyst: nucleosidation proceeded with a moderate stereoselectivity in good yields to give 16-19 (a) and 20-23 (b) in 60:40 ratio respectively, as determined by 1H NMR of the crude reaction mixture (Scheme 3).

Isoxazolidine 
R1 
R2 
R3 
Yield %a 
Nucleoside 
8, 12 
Me 
Me 
CO2Et 
Thymine 
91 
16, 20 
9, 13 
PhCH2 
CH3-(CH2)4
CO2Et 
5-Fluorouracil 
89 
17, 21 
10, 14 
PhCH2 
CO2Et 
5-Fluorouracil 
82 
18, 22b 
11, 15 
PhCH2 
PhCO 
Thymine 
90 
19, 23b 
aYield of a + b mixture. bSeparated by silica gel flash-chromatography. 

Scheme 3

Our initial goal, directed towards the design of a new synthetic approach to suitably substituted N,O-nucleosides containing a hydroxymethyl group at C3, necessary for phosphorylation reactions, has been then reached by NaBH4 reduction. Treatment of nucleosides 16, 17, 20 and 21 with NaBH4 in a 1:2 ratio (dioxane/water 1:1), at room temperature, afforded, in high yields to corresponding nucleosides 24-27 (Scheme 4).

Scheme 4

The introduction of a chiral auxiliary, as L-menthol, in the starting nitrone can afford a route for an enantioselective synthesis of the above reported N,O-nucleosides. Thus nitrone 28 prepared from 6 through a transesterification reaction with L-menthol (1:1.5 ratio) in the presence of TiCl4 as catalyst and molecular sieves, reacts with vinyl acetate to give three stereoisomeric compounds (29 and 30) two trans and one cis in a 8:1 ratio trans:cis and in a 5:1 ratio trans:trans (Scheme 5).

Scheme 5

The major isomer, whose stereochemistry was tentatively assigned as 29a according to PM3 calculations which show that the E-exo transition state of this compound is about 1.1 Kcal/mol more stable than its stereoisomer 29b, was subjected to coupling reaction with nucleoside bases, to give after NaBH4 reduction the N,O-nucleosides 33 and 34 in an enantiomerically pure forms. The assessment of the absolute configuration is actually in progress (Scheme 6).

Scheme 6

An alternative route directed to the synthesis of homochiral N,O-nucleosides, based on the introduction of a stereocenter in a with respect to the nitrone functionality, is described in scheme 7.

Scheme 7

Nitrones 37 have been prepared from the corresponding a -hydroxyesters which have been silylated with tert-butildiphenylsilylchloride, reduced with DIBALH to the corresponding aldehydes and finally converted in nitrones by reaction with MeNHOH. The obtained nitrones, all in a Z-configuration as confirmed by NOE experiments, have been reacted with vinyl acetate to give the isoxazolidines 38 and 39, epimeric only at C5, in a 1:1 ratio. Thus the cycloaddition occurs with complete diastereofacial selectivity, but with no preference for an endo or exo TS. Compounds 38 and 39 have been then separated by flash chromatography and coupled with silylated bases to give, after deprotection, the a - and b -nucleosides 40 and 41 in a 3:2 ratio respectively.


Introduction

Synthesis of N,O-nucleosides

Synthesis of 2-dimethylamino-2,3-dideoxynucleosides

Synthesis of d4T and its methyl analogue

References