Study On Synthesis Of New Clitocine Analogues

Clitocine, 6-amino-5-nitro-4-(?-D-ribofuranosylamino)-pyrimidine, is a naturally occurring amino exocyclic nucleoside isolated from the mushroom Clitocybe inversa. The study shows that Clitocine and its analogues have good anti-tumor biological activity. In this paper, further modification and transformation of Clitocine's structure is studied. We successfully synthesized 2-deoxy Clitocine and its derivatives by using the linear and convergence synthesis method. It will provide reasonable strategies and methods for the synthesis of new Clitocine analogues.Firstly, we studied the synthesis method of 2, 3-dideoxy-3-azido-ribose, compared three ways to synthesize 1-azido-2-deoxy-ribose. Then, after protecting 5-hydroxyl group, 1-azido-2-deoxy-3?-O-Methylsulfonyl-5-O-p-chlorobenzoylribofuranose was achieved by Mitsunobu reaction. Followed by selective hydrogenation of 1-azido, 1-amino-2-deoxy-3?-O-Methylsulfonyl-5-O-p- Chlorobenzoyl-ribofuranose was afforded in a yield of 5.1%, which is an important intermediate to produce the final product 1-amino-2-deoxy-3-azide-5-O-p-chlorobenzoyl-ribofuranose.Then we started with 2-deoxy-D- ribofuranose, after methylation, hydroxyl protection, Mitsunobu reaction and azide substitution, we got 3-azido-5-O-tert-butyldiphenylsily-2,3-dideoxy-D- ribofuranose in a yield of 19.7%.Secondly, we used 1-chloro-2-deoxy--3,5-O-di-p- chlorobenzoyl ribose as starting material, after 1- azidation, selective hydrogenation of l-azido, to give 1-amino-2-deoxy--3,5-O- di-p-chlorobenzoyl-ribose, followed by coupling with 4,6-dichloro-5-nitro-pyrimidin and deprotection to give the final product 2-deoxy Clitocine, the anomeric carbon mixture ?: ? = 4: 1.Finally, we applied convergence synthesis method to get 2-deoxy Clitocine and its derivatives with their bases substituted. Started with 1-methoxy-3,5-p-chlorobenzoyl-2-deoxy-D- ribose, after 1-acetoxylation and 1-chlorination to give 1-acetyl-3,5-p-chlorobenzoyl-2-deoxy-D- ribose and 1-chloro3,5-p-chlorobenzoyl-2-deoxy-D- ribose, with highest yield of 79 % and 76%. Then they coupled with 4,6-diamino-5-nitro-pyrimidin respectively, after deprotection we got 2-deoxy Clitocine, almost all of the product was ?-configuration. Using the same method, we got 2-deoxy Clitocine derivatives with their bases substituted through ribose above coupling with 4-amino-5-nitro-6-methylamino pyrimidin and 4-amino-5-nitro-6-N-methyl-phenylamino pyrimidine respectively, the yield was 24% and 3%.