1.2- Oxathiolanes

5-(5-fluorocytosin-1 -yl)-1,3-Oxathiolane D.C. Liotta etal, US Patent 6,642,245 (November 4, 2003) Assignee Emory University Utility Antiviral Agent for Treatment of HIV 

A round bottom flask was charged with 2-butene-1,4-diol (1.135 mol), 1,4-dimethylaminopyridine (15 g) and 800 ml pyridine and cooled to 0°C. Thereafter, 260 ml butyryl chloride was added and the mixture stirred 1 hour. The reaction was quenched with a small amount of wafer, fhe organic layer washed once wifh a saturafed solufion of CUSO4, fwice with a saturated solution of NaHCOj, and filfered through a celite plug. The concentrated solution was dissolved in diethyl ether and the product isolated under vacuum in almost quantitative yield. 

The product from Sfep 1 (1.365 mol) was dissolved in 4L CH2CI2, cooled fo -78 °C, and purged wifh oxygen for 20 minufes. Thereafter, ozone was bubbled info fhe mixture at 8.5 psi, and upon completion, oxygen was re-bubbled into the solution. The mixture was treated with dimethylsulfide and then stirred at ambient temperature 2 days. The solvent was evaporated, the residue kept under vacuum several days, and the product isolated in 95% yield as a clear yellow liquid. 

The product from Step 2 (1 eq) was dissolved in toluene to provide a 0.80 M to 0.85 M solution in a flask equipped with a Dean-Stark trap. Thioglycolic acid (1.1 eq) was added and the mixture refluxed 3 hours and then cooled. The organic phase was washed with equal volumes of saturated solution of NaHC03, water, dried, and filtered through celite. The solution was evaporated under vacuum and the product isolated in 90% yield. 

The product from Step 3 (1.0 eq) was dissolved in THF to give a 0.23 M solution, cooled to 0°C, lithium tri(t-butoxide) aluminum hydride (1 eq) in THF added by canula, and the mixture stirred 3 hours. Thereafter, acetic anhydride (10 eq) was added and the mixture stirred 2 days. The reaction was quenched using a saturated solution of NaHC03 and the product isolated as an oily liquid in 70% purity. 

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The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

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. 

Dithiolanes are not affected by these conditions, but a 1,3-oxathiolane is cleaved (100% yield). 

Me2CH(CH2)20NO, CH2CI2, 25°, 15 min H2O, 63-93% yield." Isoamyl nitrite cleaves aromatic dithioacetals in preference to aliphatic dithioace-tals, and dithioacetals in preference to dithioketals. It also cleaves 1,3-oxathiolanes (1 h, 65-90% yield). 

O2, hv, hexane, Ph2CO, 2-5 h, 60-80% yield. 1,3-Oxathiolanes and dithiolanes are also cleaved by these conditions. 

For(n = 3) Me2CH(CH2)20N0, CH2CI2, reflux, 2.5 h, 65% yield. 1,3-Oxathiolanes are also cleaved by isoamyl nitrite. 

Cyclohexane-1,2-dione reacts with ethylene glycol (TsOH, benzene, 6 h) to form the diprotected compound. Monoprotected 1,3-oxathiolanes and 1,3-dithiolanes are isolated on reaction under similar conditions with 2-mercaptoethanol and eth-anedithiol, respectively. ... 

A somewhat similar method to that mentioned above involves alkylation of 4,4-dimethyl-1,3-oxathiolane 5,5-dioxide 32 at the 2 position followed by FVP at 400°C, which results in fragmentation with loss of SO2 and isobutene to give the aldehydes 33. Other electrophiles that may be used include aldehydes, ketones, and McsSiCl, making this a convenient formyl anion equivalent (79TL3375). 

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