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New Pyrimidine Cyclonucleosides with Hydrogenated Aglycones: Synthesis and Structure

Anatoly D. Shutalev*a and Galina V. Gurskayab

aDepartment of Organic Chemistry, State Academy of Fine Chemical Technology, Vernadsky Avenue 86, Moscow 117571, Russian Federation; bInstitute of Molecular Biology RAS, Vavilova Street 32, Moscow 117984, Russian Federation


Introduction
Results and Discussion
  Synthesis of Ribosides
  Synthesis of Xylosides
Conclusion
References


Introduction

Base-modified nucleoside analogues received significant interest as potential biologically active substances. However, only few investigations were concerned with the syntheses of nucleoside analogues containing hydrogenated aglycones. Some of these compounds possess antiviral and antitumor activities, enzymatic inhibitory properties, etc. In continuation of our studies on hydrogenated heterocycles with two heteroatoms at the 1,3 positions [1] we interested in synthesis of nucleoside analogues containing these heterocycles as aglycones. In result of our interest we developed two methods for the synthesis of N-glycosides of 4-hydroxyhexahydropyrimidine-2-thiones [2, 3] as outlined in Scheme 1.
 
 
The first method of the nucleoside synthesis is based on the reaction of readily available glycosylamines with b-isothiocyanatoaldehydes or b-isothiocyanatoketones [2]. For example, b-D-glucopyranosylamine 1 easily reacted with 3-isothiocyanatopropanal in pyridine to give 3-(b-D-glucopyranosyl)-4-hydroxyhexahydropyrimidine-2-thione 2 in 79 % yield (Scheme 2).
 
 
The second method includes the reaction of peracetylglycosylisothiocyanates with b-aminoaldehydes or b-aminoketones as well as their derivatives [3]. The synthesis of N-glucoside 2 starting from readily available 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylisothiocyanate 3 can serve as an illustration of this approach (Scheme 3). Thus the reaction of 3 with 3,3-diethoxypropane-1-amine gave the glucosylthiourea 4 which after deprotection was transformed into the target nucleoside 2 in 63 % overall yield.
 
 
The described methods were also applied to the syntheses of 3-(b-D-galactopyranosyl)-4-hydroxy- and 4-hydroxy-3-(D-ribosyl)hexahydropyrimidine-2-thiones [2, 3].

One of the structural peculiarities of the obtained nucleoside analogues lies in the presence of semiacetal hydroxyl group at the pyrimidine ring as well as several hydroxyl groups in sugar moiety. Earlier we demonstrated that 4-hydroxyhexahydropyrimidine-2-thiones easily react with a large variety of nucleofiles (alcohols, amines, etc.) to give the products of substitution of the hydroxyl group [4]. We proposed that intramolecular nucleophilic substitution of the hydroxyl group of pyrimidine moiety could take place in the case of some 3-glycosyl-4-hydroxyhexahydropyrimidine-2-thiones to produce the corresponding cyclonucleosides (Scheme 4).
 

 
Here we report the synthesis of some new types of pyrimidine cyclonucleosides with hydrogenated  aglycones starting from partly protected ribo- and xylofuranosylamines.
 

Results and Discussion

  Synthesis of Ribosides

We found that 2,3-O-isopropylidene-D-ribofuranosylammonium p-toluenesulfonate 5 reacts readily with the b-isothiocyanatoaldehydes 6a-c in the presence of bases (triethylamine or pyridine) to produce 4,5'-anhydro-4-hydroxy-3-(2,3-O-isopropylidene-b-D-ribofuranosyl)hexahydropyrimidine-2-thiones 7a-c in 66-79 % isolated yields (Scheme 5). Evidently, the 4,5'-anhydroribosides 7a-c are formed in result of spontaneous intramolecular nucleophilic replacement of the hydroxyl group at the pyrimidine ring in b-anomers of the intermediate 4-hydroxy-3-(D-ribofuranosyl)hexahydropyrimidine-2-thiones 8a-c.
 
 
It should be noted that the reaction of 5 with 6a,b proceeds with complete diastereoselectivity to give (S)-configuration of the chiral center C(4) of the nucleosides 7a,b. The structures of these compounds were assigned on the bases of their NMR spectra as well as NOE measurements on the nucleoside 7a. In addition the structure of 7a was unambiguously established by a single crystal X-ray diffraction study.
 
  
 
The reaction of ribosylamine 5 with 6c also gives exclusively (4S)-4,5'-anhydroriboside 7c. However, as we used racemic 3-isothiocyanatobutanal 6c, the nucleoside 7c are obtained as a mixture of two diastereomers (1:1) which differ by configuration at the C(6). These diastereomers were separated by column chromatography.

The next step of our investigation included removal of the isopropylidene protective group from 7a-c. However, to our surprise, heating of 7a in 25 % aqueous AcOH at 95 oC during 5 h failed to give the expected (4S)-4,5'-anhydro-4-hydroxy-3-(b-D-ribofuranosyl)hexahydropyrimidine-2-thione 10a. Instead of 10a, 4,2'-anhydro-4-hydroxy-3-(a-ribofuranosyl)hexahydropyrimidine-2-thione 9a was obtained as the main product (57 % isolated yield) of the reaction (Scheme 6). Besides 9a, the products of cleavage of the glycosidic bond namely 4-hydroxyhexahydropyrimidine-2-thione (12 %) and D-ribose were also isolated from the reaction mixture.
 

 
We found that this unusual conversion of the 4,5'-anhydroriboside 7a into the 4,2'-anhydroriboside 9a involves initial deprotection of the compound 7a to yield the b-riboside 10a. Subsequent cleavage of the oxygen-bridge of the nucleoside 10a leads to 4-hydroxy-3-(D-ribosyl)hexahydropyrimidine-2-thione 11a which is an equilibrium mixture of a- and b-ribopyranosides and a- and b-ribofuranosides [3]. At last the a-ribofuranose form of 11a gives the final product 9a in result of intramolekular cyclization (Scheme 6).

Use of shorter reaction time (less than 4.5-5 h) showed that the reaction mixtures consist of the starting material 7a, the final product 9a as well as two other nucleosides namely the 4,5'-anhydro-b-riboside 10a and the riboside 11a. All the components of the reaction mixtures (7a, 9a, 10a, 11a, D-ribose and 4-hydroxyhexahydropyrimidine-2-thione) were isolated by column chromatography. Ratio of all these components depends on reaction time. For example, isolated yields of 7a, 9a, 10a, 11a and 4-hydroxyhexahydropyrimidine-2-thione were 25, 43, 16, 4 and 3 % (reaction time 1.17 h) or 20, 47, 13, 8 and 6 % (reaction time 1.58 h). Ratios of 7a, 9a and 10a determined by NMR spectroscopy were 31:46:23 (reaction time 1.17 h), 17:65:18 (reaction time 1.58 h), 7:85:8 (reaction time 2.75 h) or ~0:100:~0 (reaction time 5 h).

The proposed route of transformation of 7a into 9a was also confirmed by preparation of the 4,2'-anhydroriboside 9a starting from the ribosides 10a or 11a (25 % AcOH, 95 oC).

The similar reactions proceed by heating of the 4,5'-anhydroribosides 7b,c in 25 % aqueous acetic acid to afford the 4,2'-anhydroribosides 9b,c as the final products. However, stability of the oxygen-bridge to the hydrolytic cleavage is increased in the sequence of the compounds 10a>10c>10b. Actually, the heating of 7c for 1.17 h in 25 % AcOH gave 29, 18, 33, 14 and 5 % isolated yields for 7c, 9c, 10c, 11c and trans-4-hydroxy-6-methylhexahydropyrimidine-2-thione correspondingly. Transformation of 7b into 9b proceeds in 25 % AcOH at 95 oC very slowly. For example, after 4.5 h we were able to isolate the 4,2'-anhydroriboside 9b only in 14 % yield whereas 10b in 54 % yield.

It is essential to note that in all the studied cases the 4,2'-anhydroribosides 9a-c are formed exclusively as one of two possible diastereomers. We showed that the obtained ribosides 9a-c have (R)-configuration at the C(4). The structures of these compounds were assigned on the bases of their NMR spectra as well as NOE measurements on the nucleoside 12 synthesized in 88 % yield by treatment of 9a with acetic anhydride in pyridine.
 

 

  Synthesis of Xylosides

We showed that 3,5-O-isopropylidenexylofuranosylammonium p-toluenesulfonate 13 reacts readily with the b-isothiocyanatoaldehydes 6a-c in the presence of triethylamine in chloroform to afford 4,2'-anhydro-4-hydroxy-3-(3,5-O-isopropylidene-a-D-xylofuranosyl)hexahydropyrimidine-2-thiones 14a-c in 43-59 % isolated yields (Scheme 8). These compounds are formed in result of spontaneous intramolecular nucleophilic replacement of the hydroxyl group at the pyrimidine ring in a-anomers of the intermediate 4-hydroxy-3-(D-xylofuranosyl)hexahydropyrimidine-2-thiones 15a-c. The reactions of 13 with 6a-c proceed with complete diastereoselectivity to give (R)-configuration of the chiral center C(4) of the nucleosides 14a-c.
 
 
Deprotection of the 4,2'-anhydroxylosides 14a-c proceeds very readily by heating of these compounds in 25 % aqueous acetic acid (95 oC, 5 min) or in ethanol in the presence of HCl (reflux, 5 min) to produce (4R)-4,2'-anhydro-4-hydroxy-3-(a-D-xylofuranosyl)hexahydropyrimidine-2-thiones 16a-c in 82-100 % isolated yields.
 

Conclusion

Thus reaction of partly protected ribo- and xylofuranosylamines with  b-isothiocyanatoaldehydes gives convenient stereoselective access to new types of cyclonucleosides containing hydrogenated pyrimidine aglycone. Synthesized cyclonucleosides are of great interests as starting compounds for syntheses of new nucleoside analogues as well as potential biologically active substances.
 

References

1. Shutalev, A.D.; Kishko, E.A.; Sivova, N.V.; Kuznetsov, A.Yu. Molecules 1998, 3, 100-106; Shutalev, A.D.; Kuksa, V.A. Khim. Geterotsikl. Soedin. 1997, 105-109; Shutalev, A.D.; Sivova, N.V. Khim. Geterotsikl. Soedin. 1996, 1337-1342; Shutalev, A.D.; Kuksa, V.A. Khim. Geterotsikl. Soedin. 1995, 97-103; Shutalev, A.D.; Pagaev, M.T.; Ignatova, L.A. Khim. Geterotsikl. Soedin. 1994, 1093-1104;
Shutalev, A.D. Chemistry of Heterocyclic Compounds, 1993, 29, 1192-1199. Engl. transl. from Khim. Geterotsikl. Soedin. 1993, 1389-1397; Shutalev, A.D. Chemistry of Heterocyclic Compounds, 1993, 29, 1421-1425. Engl. transl. from Khim. Geterotsikl. Soedin. 1993, 1645-1649; Shutalev, A.D.; Pagaev, M.T.; Ignatova, L.A. Zh. Org. Khim. 1991, 27, 1274-1285.

2. Shutalev, A.D.; Ignatova, L.A.; Unkovsky, B.V. USSR 1392864 (Cl C 07 H 19/06), 15 Sept 1987;
Shutalev, A.D. unpublished data.

3. Ignatova, L.A.; Shutalev, A.D.; Unkovsky, B.V.; Sinilova, N.G.; Duplischeva, A.P.  Khimiko- farmatsevtich. zhurnal, 1985, 1447-1453; Shutalev, A.D.; Ignatova, L.A.; Unkovsky, B.V. Khim. geterotsicl. soedin. 1984, 548-551; Shutalev, A.D.; Ignatova, L.A.; Unkovsky, B.V. Khim. geterotsicl. soedin. 1982, 825-829; Shutalev, A.D.; Ignatova, L.A.; Unkovsky, B.V. Khim. geterotsicl. soedin. 1982, 269.

4. Shutalev, A.D.; Alekseeva, S.G. Khim. Geterotsikl. Soedin. 1995, 377-380; Shutalev, A.D.;  Komarova, E.N.; Ignatova, L.A. Chemistry of Heterocyclic Compounds 1993, 29, 1182-1191. Engl. transl. from Khim. Geterotsikl. Soedin. 1993, 1378-1388; Shutalev, A.D.; Komarova, E.N.; Pagaev, M.T.; Ignatova, L.A. Chemistry of Heterocyclic Compounds 1993, 29, 1077-1086. Engl. transl. from Khim. Geterotsikl. Soedin. 1993, 1259-1270; Shutalev, A.D.; Ignatova, L.A. Khim. Geterotsikl. Soedin. 1991, 228-236; Ignatova, L.A.; Shutalev, A.D.; Shingareeva, A.G.; Dymova, S.F.; Unkovsky, B.V. Khim. Geterotsikl. Soedin. 1985, 260-266.