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The first asymmetric synthesis of oxisuran and various related bioisosteres in optically pure form, where the pyridine ring has been replaced by another aromatic ring, is described. The synthesis of the sulfoxides proceeded using DAG methodology, a powerful approach for the synthesis of dialkyl chiral sulfoxides. Epimerization at sulfur was circumvented with the use of N,N-dimethylhydrazones, resulting in the complete inversion of chirality.

The reaction of diacetone-D-glucose (DAG) with sulfinyl chlorides were observed at -78 degrees Celsius using the bases i-Pr2NEt in toluene and Py in THF. The sulfinates were formed in high yields and purification was generally accomplished by column chromatography. The stereochemistry of the final sulfinate esters depends on the base used. Enantiomerically pure sulfoxides were obtained by reaction with several Grignard reagents.

Reports on the general method for synthesis of alpha-methylsulfinyl ketones. Application to the synthesis of oxisuran and bioisosteres; Diacetone D-glucose methodology; Reaction mechanisms; Configurational assignment; Determination of the optical purities of the beta-keto sulfoxides.

Reports on a highly convergent synthesis of the tetragalactose moiety of the glycosyl phosphatidyl inositol anchor of the variant surface glycoprotein of trypanosoma brucei. Reaction pathway; Vicinal proton-proton coupling constants; Reaction conditions.

The application of acyclic C2-symmetric chelating bis-sulfoxide ligands in the Rh(I)-catalyzed enantioselective 1,4-addition of boronic acids to electron-deficient alkenes is reported. Among the acyclic ethane-bridged bis-sulfoxides tested, the ligand Ferbisox (11), bearing ferrocenyl moieties as substituents at the sulfinyl sulfurs, has exhibited the best results in terms of chemical yield (up to 96%) and enantioselectivity (up to 97% ee). The conjugate addition takes place smoothly in toluene at room temperature in short reaction times (typically 2 h). The reaction scope, including the use of different boronic acids, five-, six-, and seven-membered cyclic enones, an unsaturated lactone, and the most challenging acyclic ketones, is reported. An X-ray diffraction study of the [Ferbisox·RhCl]2 precatalyst clearly exhibits a dimeric structure with an S coordination of the sulfoxide to rhodium. On the basis of the X-ray data and on structural studies conducted in solution by (1)H NMR, a model explaining the high enantioselection observed is proposed.

A convergent and high-yielding approach for the asymmetric synthesis of sulforaphane 2 and four analogues differently substituted at the sulfinyl sulfur has been developed. The key step of the synthesis is the diastereoselective synthesis of sulfinate ester 23-S(S), using the DAG (diacetone-D-glucofuranose)-methodology. The biological activity of these compounds as inductors of phase II detoxifying enzyme has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2.

An efficient and high-yielding approach for the asymmetric synthesis of calcimimetic (+)-NPS R-568 (1) has been developed. The key step of the synthesis is the highly diastereoselective addition of methyl Grignard to the (SS,E)-N-(3-methoxybenzylidene)-2-propanesulfinamide [5(S)], which afforded a single diastereoisomer in high yield in short reaction time.

A computational study with density functional theory (DFT) is carried out on the reaction between methyl sulfinyl chloride (MSC) and methanol in the presence of trimethylamine, a process which is a general model for two different methods used in practice for the obtention of chiral sulfoxides through dynamic kinetic resolution. Two mechanistic options are considered: in one of them, chloride is initially displaced by the base (ion pair mechanism), whereas in the other, chloride stays bound to sulfur until its final displacement by methoxy (neutral mechanism). In both cases, the approach of the alcohol to sulfur is coupled with a hydrogen transfer from methanol to the oxo group of MSC in a single concerted transition state. The presence of a trimethylamine molecule facilitates substantially the reaction by reducing the nucleophilic substitution barrier by more than 10 kcal/mol through the formation of a N-H bond with the hydrogen atom being transferred. The neutral mechanism presents a free energy barrier lower than the ion pair alternative and is thus preferred.

A synthetic route to imino thioglycosides and to imino sulfinylglycosides has been developed. A detailed study on the diastereoselective oxidation of 2-amino-2-deoxy-1-thio-beta-D-glucopyranosides is reported. It has been shown that the stereochemical outcome of the oxidation is highly dependent on the protective group of the amine function. While the oxidation of iminothioglycosides is slightly diastereoselective (up to 30% de in favor of the R(S) sulfoxide), a single isomer is obtained in the case of tetrachlorophthalimido derivatives. The absolute configuration of the sulfinyl glycoside was ascertained by NMR analysis using our recent model on the basis of the exo-anomeric effect corroborated by X-ray crystallography.

Two modular and highly convergent approaches for the synthesis of both isomers of a large number of optically pure C(2)-symmetric bis-sulfoxides have been developed, and their scope and limitations have been assessed. The first one uses as intermediate diastereomerically pure C(2)-symmetric bis-sulfinate esters 6(S(S),S(S)) and 6(R(S),R(S)), obtained by dynamic kinetic resolution of ethane-1,2-bis-sulfinyl chloride 5. A single inducer of chirality, the glucose-derived DAG (diacetone-D-glucose) 1 is used for the enantioselective synthesis of both diastereomerically pure C(2)-symmetric bis-sulfinate esters, thanks to the opposite stereodirecting effect of pyridine and (i)Pr(2)NEt used to catalyze the reaction. The second approach is based on the copper-catalyzed oxidative coupling of optically pure lithiomethyl sulfoxides. Both isomers of a large number of methyl sulfoxides can be obtained in a convergent manner using (R(S))- and (S(S))-DAG methanesulfinate esters 8R(S) and 8S(S). Methanesulfinates 8R(S) and 8S(S) are also obtained in an enantioselective way by a dynamic kinetic resolution of methane sulfinyl chloride 24. The final bis-sulfoxides are obtained with enhanced enantioselectivities compared to the corresponding monomers, as a result of the Horeau effect which is operating in both approaches. A model based on the formation of pentacoordinated sulfur intermediate is proposed. This model can explain the dynamic kinetic resolution observed via Berry pseudorotations, without the commonly accepted in situ racemization of the starting material. The usefulness of the approaches is demonstrated by the preparation of complexes of Pd(II) and Ru(II) bearing bidentated chiral sulfoxides as ligands.

The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers delta- or epsilon-functionalized with bromide, alpha,beta-unsaturated ester, aldehyde, or ketone groups is reported. The cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates derived from carbohydrates, this approach provides a selective entry to enantiomerically pure aminocyclitols of varying regio- and stereochemistry. In particular, the reductive coupling reaction of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered oxime ethers into the corresponding aminocyclitols. Moreover, the resultant O-benzylhydroxylamine products of these cyclizations can be further reduced in situ with excess samarium diiodide, in the presence of water, to the corresponding amino alcohols in excellent yields. Some transformations of these compounds are discussed.