Synthesis of [2.2.1]bicyclo nucleosides

Details Synthesis of [2.2.1]bicyclo nucleosides Synthesis of [2.2.1]bicyclo nucleosides

2000-03-24

2003-10-28

Richter, Johann (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018600

Reexamination Certificate

active

06639059

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a new strategy for the synthesis of [2.2.1]bicyclo nucleosides which is shorter, provides higher overall yields, and thus more cost efficient than previously known methods for synthesis of [2.2.1]bicyclo nucleosides.
BACKGROUND OF THE INVENTION
Synthesis of the LNA (Locked Nucleic Acid) monomer (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane uracil was first reported by Obika. (Satashi Obika et al.,
Tetrahedron Lett.;
1997; 8735-8738) who used a linear strategy based on uridine as starting material for the synthesis of the intermediate 1-(3-O-benzyl-4-C-tosyloxymethyl-&bgr;
D
-ribofuranosyl)uridine. Treatment of the tosylated nucleoside intermediate with sodium hexamethyidisilazide in THF afforded the 2′-O,4′-C-methylene bicyclonucleoside which upon final debenzylation afforded (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane uracil in 36% yield from the tosylated nucleoside intermediate.
Wengel et al. (Singh, S. K.; Nielsen, P., Koshkin, A. A. and Wengel, J.,
Chem. Commun.,
1998, 455; Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.; Melgaard, M.; Olsen, C. E. and Wengel, J.,
Tetrahedron,
1998, 54, 3607) subsequently reported on a convergent strategy for the synthesis of the thymine analogue (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane. Starting from 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-&agr;-
D
-ribofuranose, the key intermediate for coupling with silylated thymine (or other silylated nucleobases), 4-C-acetoxymethyl-1,2-di-O-acetyl-3,5-di-O-benzyl-
D
-ribofuranose, was obtained by successive regioselective 5-O-benzylation, acetylation, acetolysis, and another acetylation. Coupling of the key intermediate with silylated thymine afforded the 4′-C-acetoxymethyl nucleoside which upon deacetylation and monotosylation followed by base-induced ring closure, afforded the 2′-O,4′-C-methylene bicyclonucleoside. Final debenzylation gives (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane in 40% yield (calculated from the key intermediate). Analogous synthetic procedure were applied for the synthesis of the uracil, 2-N-isobutyrylguanine, 4-N-benzoylcytosine and 6-N-benzoylcytosine LNA nucleoside analogues. The corresponding 2′-amino-LNA pyrimidine nucleosides were obtained by performing the ring closure in benzylamine. Debenzylation and subsequently silylation using 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane afforded a bicyclic intermediate which was easily converted into the 2′-thio-LNA analogue upon reaction with potassium thioacetate in DMF and final desilylation (Singh, S. K.; Kumar, R. and Wengel, J.,
J. Org. Chem.,
1998, 63, 6078).
An analogous convergent synthesis of the (1S, 3R, 4R, 7S) -7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane thymine using 4-C-tosyloxymethyl-1,2-di-O-acetyl-3,5-di-O-benzyl-
D
-ribofuranose as the key intermediate for coupling with silylated nucleobases has been reported by the same group (Koshkin, A. A., Rajwanshi, V. K., and Wengel J.,
Tetrahedron Lett.,
1998, 39, 4381).
The use of a 4-C-tosyloxymethyl ribofuranose intermediate has also been suggested by Obika, S. et al (WO 98/39352). In this strategy the 5-O-benzyl protecting group is exchanged for a tert-butyidimethylsilyl protecting group thereby extending the total synthesis of (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane nucleosides with one step.
Characteristic properties of the previously known strategies discussed above are relatively low overall yields and many synthetic steps. Thus, there is a great need for development of a more efficient synthesis strategy which will result in an improvement of the overall yield and a reduction in the production costs of [2.2.1]bicyclo nucleosides.
SUMMARY OF THE INVENTION
The present invention provides a novel strategy for the synthesis of [2.2.1]bicyclic nucleosides comprising the synthesis of a novel key intermediate. The novel strategy is demonstrated by the synthesis of (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane and has easily been extended to the synthesis of [2.2.1]bicyclo nucleosides containing other nucleobases and can be further extended to other heteroatoms than oxygen in the bicycle, such as amino and thio.
The present invention relates to a method for the synthesis of a novel intermediate of the general formula II:
wherein
R
1
is selected from optionally substituted aryl(C
1-6
-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;
each of the substituents R
2
and R
3
is independently selected from hydrogen, optionally substituted C
1-6
-alkyl, optionally substituted aryl, and optionally substituted aryl(C
1-6
-alkyl), with the proviso that R
2
and R
3
are not both hydrogen, or R
2
and R
3
together designate C
3-7
-alkylene; and
each of the substituents R
4
and R
5
independently is R′SO
2
O— wherein R′ is selected from optionally substituted alkyl and optionally substituted aryl;
said method comprising the following step:
treatment of a compound (hereinafter termed “starting material”) of the general formula I:
wherein
R
1
is selected from optionally substituted aryl(C
1-6
-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;
each of the substituents R
2
and R
3
is independently selected from hydrogen, optionally substituted C
1-6
-alkyl, optionally substituted aryl, and optionally substituted aryl(C
1-6
-alkyl), with the proviso that R
2
and R
3
are not both hydrogen, or R
2
and R
3
together designate C
3-7
-alkylene; and
with R′SO
2
X wherein R′ is selected from optionally substituted C
1-6
-alkyl and optionally substituted aryl, and X designates halogen.
The present invention also relates to the compound of the general formula II as defined above.
The present invention furthermore relates to the compound (hereinafter termed “key intermediate”) of the general formula III:
wherein
R
1
is selected from optionally substituted aryl(C
1-6
alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;
each of the substituents R
4
and R
5
independently is R′SO
2
O— wherein R′ is selected from optionally substituted alkyl and optionally substituted aryl;
R
6
is selected from hydrogen, optionally substituted (C
1-6
-alkyl)carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl(C
1-6
-alkyl), optionally substituted C
1-6
-alkyl, and tri(alkyl/aryl)silyl; and
R
7
is selected from optionally substituted (C
1-6
-alkyl)carbonyloxy, optionally substituted C
1-6
-alkoxy, halogen, optionally substituted arylthio, optionally substituted C
1-6
-alkylthio, and optionally substituted aryloxy.
The main advantages of the present invention comprise the following:
Obtaining the key intermediate of the general formula II ready for coupling with silylated nucleobases in very few steps from 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-&agr;-
D
-ribofuranose.
One-pot base-induced ring-closure and desulfonation of the formed [2.2.1]bicyclo nucleoside.
The possibility of using the 5′-sulfonated ring-closed intermediate (compound 5a in example 4) for synthesis of 5′-amino- and thio-LNA.
DETAILED DESCRIPTION OF THE INVENTION
In an attempt to improve the synthesis of [2.2.1]bicyclo nucleosides, a novel key intermediate for coupling with different nucleobases was synthesised. Using this novel synthesis strategy comprising the novel key intermediate of the general formula III, (1S, 3R, 4R, 7S)-7-hydroxy-1-hydroxymethyl-(thymin-1-yl)-2,5-dioxabicyclo [2.2.1]heptane was synthesised in only fiv

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