1.3- Oxathiolane ring

For 1,3-dithiolanes the ring is flexible and only small energy differences are observed between the diastereoisomeric 2,4-dialkyl derivatives. The 1,3-oxathiolane ring is less mobile and pseudoaxial 2- or 5-alkyl groups possess conformational energy differences (cf. 113 114) see also the discussion of conformational behavior in Section 4.01.4.3. 

Most of the methods describing the preparation of Emtricitabine (and Racivir) rely on the construction of 1,3-oxathiolane ring by reaction of glycoMdehyde or glyoxalic acid derivatives with mercaptoacetic add or mercaptoacetic aldehyde (which exists as 1,4-ditiane 154). For example, one of the first of syntheses of this type commenced from allyl alcohol which was silylated and then subjected to ozon-olysis to give glycoMdehyde derivative 155 (Schane 36) [142], Reaction of 155 with mercaptoacetic add afforded 1,3-oxathiolane 156, which was reduced with LiAlH(OtBu)3 or DIBAL and then acetylated to form 157. Finally, reaction of 157 with silylated fluorocytosine derivative 158 followed by deprotection led to the formation of racemic 8 (Racivir). 

The axial equatorial ratio for oxygen in 1,3-oxathian 3-oxide in [ He]acetone is greater than 8 1 at -95 C however, in CDCI3 at 38 °C, no preference exists. In 1,4-oxathian 4-oxide the conformation with oxygen axial is preferred by 0.68 kcal mol at - 80 °C. Equilibrations and 220 MHz n.m.r. studies of various 2-alkyl-4-methyl- and 2-alkyl-4,4-dimethyl-l,3-oxathiolans confirmed earlier conclusions that the 1,3-oxathiolan ring is less flexible than the 1,3-dioxan ring, and somewhat more puckered. The data indicated a preferred envelope structure, in which either the oxygen or C-5 was the flap atom. 

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