Dihydrothiazine oxide

Solvolysis of Diels-Alder adducts provides a useful means of preparing a variety of nitrogen-containing compounds. For instance, the hydrolysis of A Cbz or A -Ts bicylic sulfonamides 44 and 112 with NaOH affords the homoallylic carbamate 113 and sulfonamide 114, respectively (Scheme 12) <2000TL3743, 2002TA2407>. Related hydrolysis reactions have also been reported with monocyclic 1,2-dihydrothiazine oxides <2004JOC7198>. 

Until recently, dihydrothiazine oxides had not found much use in synthesis. Recently, Weinreb and coworkers have exploited some of the known reactions of these adducts, along with some new transformations, in stereoselective preparation of some complex nitrogen-containing molecules. One useful transformation of these adducts is the hydrolysis/retro-ene elimination of sulfur dioxide shown in equation (53). Thus dihydrothiazine oxide (120), prepared from ( , )-tetramethylbutadiene, underwent hydrolysis to allylic sulfinic acid (121) which suffered a retro-ene reaction via the chair-like conformation... 

Another useful reaction of these Diels-Alder adducts is shown in equation (54). Dihydrothiazine oxide (123) from ( . )-2,4-hexadiene can be opened with a Grignard reagent to allylic sulfoxide (124) which undergoes a stereoselective 2,3-sigmatropic rearrangement via the envelope-like transition state conformation shown, having a quasi-equatorial methyl group to afford sulfenate ester (125). Desulfurization of (125) provides E)-threo smino alcohol derivative (126) in excellent overall yield. If ( ,Z)-2,4-hexadiene is used, the E)-erythro epimer of (126) is formed cleanly. 

The Weinreb group has reported the only examples of intramolecular [4 + 2] cycloadditions of iV-sulfi-nyl compounds. - For example, diene carbamate (127) could be converted to an -sulfmyl compound which cyclized intramolecularly to dihydrothiazine oxide (128) (Scheme 16). Using the chemistry outlined in equation (54), (128) was transformed stereoselectively to tAreo-sphingosine (129). Similarly, ( ,Z)-diene carbamate (130) was transformed via adduct (131) to erytAro-sphingosine (132). 

An intramolecular version of this methodology was further applied to construction of amino sugars, such as the unnatural C-5 epimer of desosamine (399) (84JOC3243) and deoxyaminopentose (406) (85T1143). When ( , )-diene carbamate 393 was treated with thionyl chloride/pyridine between 0°C and room temperature, a single Diels-Alder adduct (395) was formed in 80% yield. The structure and stereochemistry of this dihydrothiazine oxide were... 

Dihydrothiazine oxides have been much less studied then dihydrothiazines. The available syntheses may be divided into two types, which reflect the nature of the immediate precursor of the dihydrothiazine oxide ring. 

The most widely used method for the preparation of dihydrothiazine oxides involves the oxidation of the parent dihydrothiazines with sodium periodate or w-chloroperbenzoic In certain in-... 

The only example in which a dihydrothiazine oxide is formed in a direct manner from an acyclic precursor involves the ammonia-induced cyclization of the acetylene 214 to the sulfoxide 215. Although both isomers of the... 

The conversion of dihydrothiazine oxides into dihydrothiazine dioxides is discussed later (Section VII,B,1). Treatment of the sulfoxide 208a with triethyloxonium tetrafluoroborate yielded the salt 216, which was converted into the (S)-oxide 217 by sodium hydroxide. The formation of the same sulfoxonium salt 218, of unestablished configuration at sulfur, was observed by NMR spectroscopy when the sulfoxides 212 and 213 were treated with acetyl chloride in [ Hs] methyl cyanide at — 35°C. ° ... 

The hydrogen atoms at position 2 of 2-unsubstituted dihydrothiazine oxides are expected to possess acidic properties. Thus, when treated with sodium deuterioxide in deuterium oxide, the compound 208b underwent deuterium exchange of the hydrogen atoms adjacent to the sulfinyl group ... 

An unusual Pummerer-Iike reaction has been reported to occur when certain 3-hydroxymethyl dihydrothiazine oxides are treated with acetyl chloride. For example, the compounds 212 and 213 were convert into the bicyclic derivative 180b, which was isolated as a 4 1 mixture of diastereoisomers. The reaction probably occurs by a pathway similar to that depicted in Scheme 9. 

There are two examples in which dihydrothiazine oxides are converted into other heterocycles ring contractions are involved in each case. 

Only two reactions leading to the formation of ring-opened products have been reported for dihydrothiazine oxides. Thus when treated with acetyl chloride, the sulfoxide 221 was converted into the oxazolinone 235, probably by way of the intermediate 234. Raney nickel has been shown to effect the desulfurization of the compound 236, to give the oxazolidine 237. ... 

The conformational properties of dihydrothiazine oxides of types 239 and 242 have been examined by NMR spectroscopy. In the case of the (R)-oxides 239, there is a dramatic preference for the conformer 241 by contrast, the (S)-oxides 242 exist overwhelmingly as the conformer 243. These results illustrate that the conformer that possesses an axial 5-oxide is favored. The eonformer 243 possesses an imfavorable 1,3-diaxial interaction between the oxide group and R, and the conformer 241 is destabilized by an allylic interaction between R and R. Evidently, these interactions are less severe than the allylic interaction between the oxide and methoxy-carbonyl groups which would be present in the conformers 244 and 240. 

The most widely used method for the preparation of dihydrothiazine oxides involves the oxidation of the parent dihydrothiazines with sodium periodate or w-chloroperbenzoic acid.79,95,98,100-102,113.114 jn certajn jn stances, oxygen will act as the oxidant for example, the sulfoxide 187 was formed when a cyclohexane solution of the compound 117 was exposed to the air.44,46,86 The mechanism of this reaction, in which the thiazolidine 186 was a co-product, has already been discussed (Section V,C,2,b). 

The application of theoretical methods to 1,2-thiazines has been nonexistent. However, FMO theory has been used to explain the stereochemical outcome of [4 - - 2] cycloaddition reactions of N-sulfinylamine dienophiles leading to 3,6-dihydrothiazine oxides <85JCS(P2)589>. 

The noteworthy feature of this transformation is that the C-3 substituent of the dihydrothiazine oxide acts as an equatorial anchor and, hence, the retro-ene proton transfer occurs onto a single diastereotopic face of the double bond. 

The dihydrothiazine oxide (73) can be effectively converted into the ( )-tAreo-hydroxy carbamate... 

The dihydrothiazine oxide (73) gives the (Z)-allylic sulfoxide (77), which (/,/2 = 90 min) is slowly converted to a mixture of ( )-allylic sulfoxides (78) that are epimeric at the sulfur atom. This well-precedented transformation of (77) to the thermodynamically more stable (78) involves conformational inversion of the sulfenate ester (79a) to (79b). At any stage of this equilibrium, treatment with a thiophile such as trimethyl phosphite can stereospecifically lead to the (F -hydroxy carbamate (74) (Scheme 13) <84JA7861>. This versatile transformation has been applied to stereospecific vicinal amino alcohol synthesis. 

Dihydrothiazine oxides with aryl groups on the ring nitrogen do not undergo clean deprotonation, and a mixture of products derived from ring cleavage are formed. The 2-phenyl-substituted heterocycle (99) leads to products derived from attack of the methyllithium on the sulfur (Equation... 

---