Diastereoselective sulfur oxidation

Oakes RS, Clilford AA, Bartle KD, Petti MT, Rayner CM. Sulfur oxidation in supercritical carbon dioxide dramatic pressure dependant enhancement of diastereoselectivity for sulfoxidation of cysteine derivatives. Chem Commun 1999 247-248. 

Since allyl sulfoxides may quite easily undergo racemization at the sulfur atom via a reversible [2,3] sigmatropic process, the configurationally more stable chiral allylic phosphine oxides were also investigated.201 Compounds (184) and (185), prepared as a 1 1 mixture from allylphosphonyl dichloride and (-)-ephedrine, were shown to add to cycloalkenones with reasonably high diastereoselectivities. Ozono-lysis of the initially formed 1,4-adducts affords the respective optically active ketoaldehydes (Scheme 67). With a / /-isopropyl-substituted derivative even higher selectivities (88-98% ee) could be obtained. 

The fact that these adducts were diastereoisomerically pure (deduced from the reported melting points and NMR spectra) suggests that these reactions took place with a complete control of the diastereoselectivity. Bearing this in mind, in 1989 Waldner [64] synthesized optically pure sulfoxide 55 (by MCPBA oxidation of the corresponding chiral thioether and further separation from the epimeric mixture so obtained) and studied its reactions with dienes and aza-dienes (Scheme 29). A high 7r-facial selectivity (almost complete with cyclopen-tadiene and azadienes) was observed in all cases, the approach of the diene from the dienophilic face supporting the lone pair of electrons at sulfur being favored. In the case of the reaction with cyclopentadiene, the endo-selectivity was complete as well. 

Major interest has been expressed in the synthesis of chiral sulfoxides since the early 1980s, when it was discovered that chiral sulfoxides are efficient chiral auxiliaries that are able to bring about important asymmetric transformations [22]. Sulfoxides are also constituents of important drugs (e.g., omeprazole (Losec , Priso-lec )) [23]. There is a plethora of routes of access to enantioenriched sulfoxides, and many involve metal-catalyzed asymmetric oxidations [24]. Examples of ruthenium metal-based syntheses of sulfoxides are scarce, presumably due to the tendency of sulfur atoms to bind irreversibly to a ruthenium center. Schenk et al. reported a dia-stereoselective oxidation of Lewis acidic Ru-coordinated thioethers with dimethyl-dioxirane (DMD) (Scheme 10.16) [25[. Coordination of the prochiral thioether to the metal is followed by diastereoselective oxygen transfer from DMD in high yield. The... 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

A remarkable effect of the reaction medium has been observed in the heterogeneously catalyzed diastereoselective oxidation of sulfur compounds as shown in Scheme 14 [82]. The reaction, which was completely non-selective in conventional solvents, could be optimized up to 95% de in SCCO2 whereby a dramatic dependence on pressure (and hence bulk density) was observed. Although no fully satisfactory explanation is yet available for these results, they seem to support again the potential to use the density of SCCO2 as an additional parameter for the optimization of organic syntheses. 

Chiral sulfoxides with a pyridine substituent 16 are useful chiral dienophiles (Section D. 1.6.1.1.1.1.2.2.). The synthesis starts with the (—)-menthyl ester of propynoic acid which undergoes addition of 2-pyridinethiol to the triple bond. The oxidation of the sulfur occurs with some diastereoselectivity and the isomers are separated by crystallization from hexane16. 

Asymmetric ene reaction of N-sulfinylcarbamatesf The ability of Lewis acids to promote ene reactions (11,413,414 12,389) is useful for asymmetric reactions. Thus the SnCU-promoted reaction of chiral N-sulfinylcarbamates (1) with alkenes results in thermally unstable adducts (2) in 65-91% yield. Use of trans-2-phenylcyclohexanol (13,244) or 8-phenylmenthol as the source of chirality results in high diastereoselective induction in generation of the new carbon to sulfur bond (usually >95 5). This reaction is applicable to both (E)- and (Z)-alkenes, but the former react more readily. These ene adducts can be transformed into optically active allylic alcohols (4) by N-alkylation and conversion to an aryl allylic sulfoxide (3), which undergoes rearrangement in the presence of a thiophile (piperidine) to 4, with retention of configuration at carbon imparted in the ene reaction. The overall process effects enantioselective allylic oxidation of an alkene with retention of the original position of the double bond. 

The fully diastereoselective Michael addition of selected sulfur and nitrogen nucleophiles (NuH) to a chiral non-racemic 2-phosphono-2,3-didehydrothiolane S -oxide (466) has been described by Kielbasinski and co-workers (Scheme 118). " The enantiomeric excesses of the obtained adducts (467) could be determined by P NMR spectroscopy using (R)-( + )-t-butyl(phenyl)phosphinothioic acid as a chiral solvating agent. 

Only recently, the diastereoselective synthesis and preparative separation of the enantiomers of galaxolide (Givaudan) have been described. [169] The titanium tetrachloride-catalysed Friedel-Crafts alkylation of 1,1,2,3,3-pentamethylin-dane with (S)-propylene oxide produces two epimeric alcohols (whereby no racemisation is observed) with paraformaldehyde and catalytic amounts of sulfuric acid, these are converted into the desired isochroman diastereomers. The separation of the epimers is accomplished by means of the corresponding chro-... 

---