Collect. Czech. Chem. Commun.
2008, 73, 44-58
https://doi.org/10.1135/cccc20080044
Synthesis of Novel Carbocyclic Nucleoside Analogues Containing Bicyclo[2.2.1]hept-2-ene-2-methanol
Hubert Hřebabecký*, Martin Dračínský and Antonín Holý
Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic
Abstract
Starting ethyl (1R*,2R*,3R*,4S*)-3-bromobicyclo[2.2.1]hept-5-ene-2-carboxylate (9) was reduced with LiAlH4 and benzoylated giving [(1R*,2R*,3R*,4S*)-3-bromobicyclo[2.2.1]hept-5-en-2-yl]methyl benzoate (11). Treatment of 11 with NaN3 and CrO3 in acetic acid afforded [(1R*,2S*,3R*,4R*,5S*,6R*)-6-azido-3-bromo-5-hydroxybicyclo[2.2.1]hept-2-yl]methyl benzoate (12a) and [(1R*,2S*,3S*,4R*,5S*,6R*)-5-azido-3-bromo-6-hydroxybicyclo[2.2.1]heptan-2-yl]-methyl benzoate (12b). These key intermediates were separated and converted in five reaction steps to (1R*,2R*,3S*,4S*)-3-[(5-amino-6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)- bicyclo[2.2.1]hept-5-en-2-ol (17a) and (1R*,2R*,3S*,4S*)-3-[(5-amino-6-chloropyrimidin-4-yl)- amino]-6-(hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-ol (17b). Ring closure with triethyl orthoformate led to (1R*,2R*,3S*,4S*)-5-(chloromethyl)-3-(6-chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-ol (18a) and (1R*,2R*,3S*,4S*)-6-(chloromethyl)-3-(6-chloro-9H-purin-9-yl)- bicyclo[2.2.1]hept-5-en-2-ol (18b) using hydrochloric acid as a catalyst or (1R*,2R*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-ol (19a) and (1R*,2R*,3S*,4S*)- 3-(6-chloro-9H-purin-9-yl)-6-(hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-ol (19b) using trifluoro- acetic acid as a catalyst. From 19a and 19b, 6-amino- and 6-(cyclopropylamino)purine derivatives 20 and 21 were prepared.
Keywords: Nucleosides; Carbocyclic nucleosides; Norbornanes; Norbornenes; Purines; 6-Chloropurine; Adenine; 6-(Cyclopropylamino)purine; Antivirals.
References: 21 live references.
