Oxathiolanes, hydrolysis

Treatment of the oxathiolan 1 with two equivalents of sulfuryl chloride in carbon tetrachloride at 0°C gives the 1,4-oxathian 2 which, on treatment with two equivalents of triethylamine followed by hydrolysis with wet silica gel, is converted into the oxathiolan 3 in 95% yield. The latter is unstable to acid, and when heated in benzene with p-toluenesulfonic acid is slowly converted into 4 in 83% yield. 

Since 1,3-dioxolanes are cyclic acetals it follows that they are readily hydrolyzed by acids. The kinetics of this hydrolysis have been extensively reviewed (57MI43000). The acidic hydrolysis of 1,3-oxathiolanes is of theoretical importance in that there are conflicting reports as to whether the C—O or the C—S bond is ruptured first. It is known that protonation of 2,2-dimethyl-l,3-oxathiolane in fluorosulfonic acid leads to the exclusive formation of dication (68) (71BSF541). Based on deuterium labelling studies, however, the present data suggest that the C—O bond is broken first in aqueous systems (72TL2569). 

The oxygen derivatives are stable to most oxidants the sulfur derivatives are cleaved by a wide range of oxidants. The oxygen, but not the sulfur, analogs are readily cleaved by acidic hydrolysis. Sulfur derivatives are cleaved under neutral conditions by mercury(II), silver(I), or copper(II) salts oxygen analogs are stable to those conditions. The properties of oxygen and sulfur derivatives are combined in the cyclic 1,3-oxathianes and 1,3-oxathiolanes. 

In the hydrolysis of 1,3-dioxolane, kH is increased by 3.5 powers of ten with the introduction of the first methyl group at the 2-position, but by 1 power of ten only with the introduction of the second methyl group [161]. Furthermore, introduction of a 2-methyl group causes kH to increase by a factor of 2 in the case of 2-phenyl-l,3-oxathiolane [168], but causes kH to decrease by a factor of 5 in the case of 2-phenyl-l,3-dioxolane [165]. 

As shown in Scheme 12.54, oxathiolane nucleoside 230, has been prepared by the method of Schinazi and Liotta." Thus, the coupling of sUylated flucytosine 231 preparing from 217 with lactol 232 gave racemic compound, 2-hydroxymethyl-5-(5-fluorocytosin-l-yl)-l,3-oxathiolane [( )-FTC], which afforded the title compound 230 after an enantioseiective enzymic resolution and hydrolysis. 

Secondary isotope effects (15) and nmr evidence (16) clearly show that a C—O bond scission occurs during the acid hydrolysis of oxathiolanes. Proton-transfer rates for acidic alcohols are several orders of magnitude higher than those for the corresponding thiols (17). These species-specific interactions are in good agreement with the HSAB dictum. 

The hydrolysis of 1,3-oxathiolanes with acid or mercuric ion also provides a suitable procedure for regenerating the ketone. The mechanism involved appears similar to that with Raney nickel, but with a proton or mercuric ion taking the place of the nickel. 

Due to our earlier work with the carbocyclic nucletsides (+) 5 and (+) 8 (Figure 2), we also investigated enzymatic methods to effect resolution prior to the addition of the cytosine base. One such route considered was the enantir elective hydrolysis of racemic trnns 5 propionyloxy l,3-oxathiolane 2-methanol benzoate, 14, to obtain the key intermediate (—)-14 (69) (Figure 3). The tnms xathiolane benzoate, 14, synthesized from benzoyloxyacetaldehyde, 9 (three steps), was an attractive sidistrate because it could... 

In the oxathiolane area, a paper from Wellcome Laboratories describes work done there on the preparation of 3-thiacytosine and related compounds, whilst a synthesis of 3TC involving an enantioselective enzymic hydrolysis has been reported. The difluorophosphonate analogue 200 of FTC has been made as a racemate with other diastereomers, and 1,2,6-thiadiazine dioxide analogues of 3TC have been reported. A full account has appeared concerning the synthesis of regioisomeric systems such as 201 (see Vol.28, p.297). ... 

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