Synthesis of Carbocyclic 4'-C-Hydroxymethyl Analogues of Azidodeoxythymidine, Deoxythymidine, Deoxydidehydrothymidine and Thymidine Carba Analogue with Fused Oxetane Ring

Abstract

Tosylation of (±)-1-[trans-4-hydroxy-3,3-bis(hydroxymethyl)cyclopentyl]-5-methylpyrimidine-2(1H),4(3H)-dione (1) and (±)-1-[cis-4-hydroxy-3,3-bis(hydroxymethyl)cyclopentyl]-5-methylpyrimidine-2(1H),4(3H)-dione (2) and treatment of the obtained 1-{(1R*,3R*,4S*)- 4-hydroxy-3-(hydroxymethyl)-3-[(tosyloxy)methyl]cyclopentyl}-5-methylpyrimidine- 2(1H),4(3H)-dione (6) and 1-{(1R*,3S*,4R*)-4-hydroxy-3-(hydroxymethyl)-3-[(tosyloxy)- methyl]cyclopentyl}-5-methylpyrimidine-2(1H),4(3H)-dione (9) with methanolic sodium methoxide gave 1-[(1R*,4S*,6S*)-4-hydroxymethyl-2-oxabicyclo[3.2.0]hept-6-yl]-5-methylpyrimidine-2(1H),4(3H)-dione (7) and 1-[(1R*,4S*,6R*)-4-hydroxymethyl-2-oxabicyclo[3.2.0]hept-6-yl]-5-methylpyrimidine-2(1H),4(3H)-dione (10), respectively. Treatment of (±)-1-{cis-4-mesyloxy-3,3-bis[(trityloxy)methyl]cyclopentyl}-5-methylpyrimidine-2(1H),4(3H)-dione (11), which was prepared from 2 by tritylation and mesylation, with 1,8-diazabicyclo[5.4.0]undec-7-ene in dimethylformamide afforded after deprotection (±)-1-[4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl]-5-methylpyrimidine-2(1H),4(3H)-dione (14). Hydrogen- ation of 14 led to (±)-1-[3,3-bis(hydroxymethyl)cyclopentyl]-5-methylpyrimidine-2(1H),4(3H)- dione (15). (±)-1-{trans-4-Mesyloxy-3,3-bis[(trityloxy)methyl]cyclopentyl}-5-methylpyrimidine- 2(1H),4(3H)-dione (17), which was prepared from 1, was converted to (1R*,9R*)-6-methyl-5-oxo-11,11-bis(trityloxymethyl)-2-oxa-4,8-diazatricyclo[7.2.1.03,8]dodec-3,6-diene (18). The compound 18 was deprotected and heated with lithium azide in dimethylformamide to give (±)-1-[trans-4-azido-3,3-bis(hydroxymethyl)cyclopentyl]-5-methylpyrimidine-2(1H),4(3H)-dione (21).