1.3- Dithianes 1-oxide

Dithiane 1-oxide derivatives as chiral auxiliaries and asymmetric building blocks for organic synthesis 980PP145. 

Besides 1,3-oxathianes, the 1,3-dithiane 1-oxide moiety can be used for directing the nucleophilic addition of an organometallic reagent to a carbonyl group in a diastereoselective manner. The addition of methylmagnesium iodide to the 2-acyl-l,3-dithiane 1-oxide 23A leads exclusively to the diastereomer which is formed by Re-side attack. On the other hand, addition... 

For the 1,3-dithiane-1-oxide (R=H) case molecular dynamics simulations at the experimental temperature revealed that the R-hydroxysulfoniiun cation was considerably more stable than the more weakly adsorbed 1,3-dithiane molecule We consider that the hydroxydithiane cation may act as a proton transfer agent and this may account for the enhanced reactivity of this system. 

The stereospecific base-cleavage of the trimethylsilyl group in 1,3-dithiane 1-oxides 499 enables to obtain the specifically deuteriated products 500 (equation 303), A nitro group in y-nitroalkyl sulphoxides 501 (obtained by the Michael addition of nitroalkanes to a, j8-unsaturated sulphoxides) is replaced by hydrogen by means of tributyltin hydride (equation 304). This reagent does not affect the sulphinyl function. The overall procedure provides an efficient method for the conjugate addition of alkyl groups to a, -unsaturated sulphoxides . ... 

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

The conformational equilibrium of 1,3-dithiane 1-oxide (the sulfoxide) was studied by low-temperature H and NMR spectroscopy <1999RJC5> at —80 to —90°C the two chair conformers could be detected (the one with the equatorial S —> O bond preferred by ca. 90%). Besides discussing the influence of the sulfoxide conformation on both NMR spectra, the enthalpy and entropy differences AH° = 0.55 0.1 kcal mol AS° = 1.88 e.u.) between the two conformers were detected in CDCl3 CS2= 1 2. 

Oxidation of 1,3-dithianes to 1,3-dithiane 1-oxides has been carried out by various methods using H2O2 or /-butyl hydroperoxide (TBHP) as oxidant. In the presence of chiral co-oxidants, optically active 1,3-dithiane 1-oxides have been prepared (Scheme 66). A compilation of some currently used methods is given in Table 13. The oxidation to 1,3-dithiane 1,3-dioxides was conducted similarly. Sharpless conditions were found to be highly effective with 2-alkyl- or alkylidenyl-substituted substrates. The parent 1,3-dithiane 1,3-dioxide was obtained by basic removal of a 2-carboxyl group in 83% yield and 99% ee <1998JOC7306>. 

Tabie 13 Oxidation of 1,3-dithianes to 1,3-dithiane 1 -oxides or 1, 3-dithiane 1,3-dioxides under various (asymmetric) reaction ... 

As expected, 2-halo-l,3-dithianes react with nucleophiles under Sn conditions. Suitable nucleophiles are enamines <2002TL9517, 2004T6931> and phenols <1997MOL7>. The reaction with EtOC(S)S K, followed by oxidation, provided a xanthate which generated a 1,3-dithiane 1-oxide radical upon treatment with Bu3SnH (Scheme 69) <2004T7781>. An efficient one-carbon radical precursor has also been obtained by addition of 2,2,6,6-tetramethyl-piperidine-l-oxyl (TEMPO) to 2-lithio-l,3-dithiane. The reactivity of this compound has been demonstrated <2005S1389>. 

The chemistry of chiral 1,3-dithiane 1-oxides, in particular their use as chiral auxiliaries, has been reviewed <19980PP145>. Some further developments in this field are the stereoselective a-alkylation with alkyl halides <1997T13149> or a-hydrazination with di-fert-butyl azodicarboxylate (DBAD) <2000T9683>. The carbonyl group of 2-acyl-l,3-dithiane 1-oxides was also used as an electrophile (Scheme 82). Interestingly, acyclic enolates react with these substrates to give a 95 5 mixture of anti- and ry -adduct, whereas cyclic enolates produce a mixture of anti- and ry -adduct in 8 92 ratio <2000JOC6027>. 

Oxygen at the heterocyclic sulfur atom has been functionalized in two ways (1) by a TMSOTf-catalyzed Pummerer reaction in the presence of a silyl enol ether (Scheme 95) <1998TL9131> or (2) by reductive removal of the oxygen using Ac20/Zn/cat. 4-dimethylaminopyridine (DMAP) <1996SL885>. The formation of 1,3-dithiane from 1,3-dithiane 1-oxide proceeds efficiently in 95% yield (Equation 70). 

Calculations have also been performed for the monosulfoxides of 1,4-dithiane, 1,3-dithiane and 1,3,5-trithiane, the cis and trans disulfoxides of 1,4-dithiane and 1,3,5-trithiane and the cis and trans trisulfoxides of 1,3,5-trithiane (76T529). For all the compounds mentioned, a chair conformer is calculated to be most stable and the results are consistent with experimental findings which reveal that the S—O- bond exhibits an axial preference within 1,4-dithiane 1-oxide but an equatorial preference within 1,3-dithiane 1-oxide and 1,3,5-trithiane 1-oxide (Section 2.26.2.5). 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

A Pummerer reaction may feature in the epimerisation of syn-2-acy 1-2-alkyl-1,3-dithiane 1-oxides by TFAA (95S73). 

Table 1. Addition of Methylmagnesium Iodide to syn and anti 2-Propionyl-2-methyl-1,3-dithiane 1-Oxide Substrates...

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

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