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9 páginas, 4 figuras, 5 esquemas., 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., Financial support from the DGICyT (grant nos. CTQ2006-15515-CO2-01 and CTQ2007-61185) and the Junta de Andalucía (grants P06-FQM-01852 and P07-FQM-2774) is gratefully acknowledged. A.A. thanks the Ministerio de Ciencia e Innovación for a Ramón y Cajal contract. F.L. is supported by a predoctoral fellowship of the “Studienstiftung des Deutschen Volkes”.

The Diels–Alder reaction of enantiomerically pure (E)-γ-keto-α,β-unsaturated p-tolylsulphoxides 3 with cyclopentadiene give four easily separable diastereomers. The effect of several Lewis acids on the reaction was studied, finding a high endo selectivity with respect to the carbonyl group and moderate π-diastereoselectivity using BF3·Et2O as catalyst. The reactivity of compounds 3 as well as their endo selectivity are both higher than those observed for the corresponding (E)-3-sulfinylacrylates.

Chlorambucilamide derivatives involving chiral glycosyl glycerols derived from D-glucosamine were synthesized in good yield by coupling the chlorambucil moiety to the amino group of ω-amino-(ω-1)-hydroxyalkyl 2-acylamino-4,6-O-benzylidene-2-deoxy-β-D-glucopyranosides, and subsequent hydrolysis of the benzylidene group. The starting material was easily available from 2-acetamido-2-deoxy-D-glucose. The bonding of 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosylamine to chlorambucil by formation of an amide function is also described. Chirality Chirality 14:199–203, 2002. © 2002 Wiley-Liss, Inc.

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 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.

Chiral tert -butylsulfinyl group has been shown to be the chiral auxiliary of choice for the asymmetric aziridination of N-sulfinyliminas. Moreover, the sense of the asymmetric induction can be tuned in two ways: the chirality at the tert -butylsulfinyl Sulfur, or the nature of the methylene transfer reagent used. Thus, both aziridines 10( S s , S ) and 10( R s , R ), epimeric at C-2, were obtained in enantiomerically pure form by a single crystallisation (75% yield).

The electron impact ionization mass spectra of new alkyl (and phenyl) 4,6-benzylidene-2-amino-N-alkyl- and N,N-dialkyl-2-deoxy-D-hexopyranosides and benzyl (and phenyl) 4,6-O-benzylidene-2,3-di-O-alkyl-D- hexopyranosides were examined. Three general pathways of fragmentation were encountered. The competition the two most important pathways of fragmentation ([M - R 1 O→]# and H routes) depends primarily on the nature of the aglycone and secondarily on the nature of nitrogen substituents. In addition, relationships between the different peak intensities in each pathways of fragmentation depend exclusively on the nature of nitrogen substituents. Definitive chemical evidence for different pathways of fragmentation was found.

Diacetone- D -glucose (DAG) reacts with t -BuSOCl in the presence of NEt 3 and Py to give (−)-( S )- and (+)-( R )- tert -butanesulfinate respectively, in high diastereomeric excess. These sulfinates were transformed into various enantiomerically pure tert -butyl sulfoxides by reaction with different Grignard reagents. Additionally, the reaction of tert-butylmagnesium chloride with (+)-( R )- and (−)-( S )-methanesulfinates of DAG has been found to occur with complete inversion of configuration and not with retention as previously reported.

Homochiral D - and L -hexose precursors have been prepared in good overall yield from ( R )-methyl- p -tolylsulfoxide as the sole asymmetric inductor. The process involves sequential condensation of the sulfoxide with ethyl 2-furancarboxylate, stereoselective sulfoxide-monitored carbonyl reduction, Pummerer rearrangement of the sulfinyl group, reduction of the resulting aldehydes and ring-oxidation of the corresponding furfuryl alcohols.

The syntheses of eight conformationally restricted analogues of N -acetylmuramyl- l -alanyl d -isoglutamine (MDP) based on the d -glucopyrano[2,3- d ]oxazolidine ring system are described.

Title compounds can be synthesised by an easy two-step method from the readily available benzyl 2-acylamino-4,6-O-benzylidene-2-deoxy-D-glucopyranosides (1–5), by nucleophilic cleavage of the oxazolidine ring previously formed between the positions 2 and 3 of the aminosugars.

Optically pure [4-(3′-oxazoline)]methyl methyl- and p-tolylsulfoxides ( 5R, 5S, 6R and 6S ) were prepared from the enolate of the 3-oxazoline 4 and the corresponding o.p. diacetone-D-glucofuranosyl methanesulfinate and menthyl p-toluenesulfinate. The highly diastereoselective reduction of these substrates was successfully achieved using DIBAL/ZnCl 2 at −78°C. In this way, four o.p. N-cyclohexyl-β-amino-γ-hydroxysulfoxides, chiral key intermediates in the asymmetric synthesis of various biologically active molecules, were obtained.

A novel enantiodivergent approach to 5-hydroxy-5,6-dihydro-2(1H)-pyridones using a ring closing metathesis and a lipase-mediated kinetic resolution as key steps is described and applied to the first synthesis of both enantiomers of pipermethystine.

The asymmetric synthesis of (R C,SS) and (S C,R S), important intermediates in the synthesis of optically pure Sparsomycin analogs, is discussed. The enantioselective synthesis of both isomers, R and S, of Oxisuran and three of their bioisosters is also described. In both strategies o.p. methanesulfinate esters of DAG were used as starting material.

The synthesis and conformational analysis of the title compounds are reported. The conformational properties of the 2-thienyl derivatives, deduced from 1H-nmr and ir data, are compared with those for 2-furyl analogs and the results have been interpreted taking into account the stronger (OH…Ring) intramolecular association in the 2-furyl derivatives.

A novel series of cis-fused 2-N,N-dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo[b,f]furo[2,3-d]oxepin derivatives modified at position C-11 was prepared and evaluated for its potential antidepressant/anxiolytic properties. In vitro affinities for the norepinephrine transporter and for 5-HT(2A) and 5-HT(2C) receptors, as well as the ED(50) values obtained in some in vivo assays predictive for antidepressant and anxiolytic potential are reported.

4 páginas, 2 tablas, 3 esquemas., A comparative study shows that the isopropylsulfinyl group for which an enantiodivergent and highly diastereoselective approach is reported behaves better than the tert-butylsulfinyl and p-tolylsulfinyl groups, both in terms of reactivity and stereoselectivity in the Corey-Chaykovsky reaction of chiral sulfinylimines and the organocatalytic allylation of acyl hydrazones, We thank the Dirección General de Investigación Científica y Técnica for financial support (Grants PB BQU2003-00937 and CTQ2004-01057).

The syntheses are described of four conformationally restricted derivatives of muramic acid based on the α- d -glucopyrano[2,3- d ]oxazolidine ring system.

The asymmetric synthesis of (R C,SS) and (S C,R S), important intermediates in the synthesis of optically pure Sparsomycin analogs, is discussed. The enantioselective synthesis of both isomers, R and S, of Oxisuran and three of their bioisosters is also described. In both strategies o.p. methanesulfinate esters of DAG were used as starting material.

Synthesis and conformational analysis of 1-phenyl-2-methylsulfinyl-(and -sulfonyl-) ethylamine (and its N -methyl and N , N -dimethylderivatives) are reported. Conformational preferences have been determined by carefully observing the changes of the vicinal coupling constants with protonation in the 1H-nmr spectra. The strongly configuration dependent conformational behavior displayed by sulfoxides is explained in terms of a previously proposed donor-acceptor interaction between nitrogen and sulfur. Conformational equilibria of sulfones are controlled by steric interactions except when nitrogen is protonated in which case a relatively weak electrostatic attraction takes place between the heteroatomic functions.

The synthesis and conformational analysis of the title compounds are reported. The conformational equilibria have been established from 1 H-NMR data and the role of hydrogen bonding in the hydroxylated compounds has been studied by high dilution IR spectroscopy. In all of these derivatives, the bulky Bu t group blocks rotation around the C-S bond. The results for these compounds are compared with those reported for their analogous 2-methylthioderivatives. For sulphones and RR/SS sulphoxides, the possible dihedral angle deformations have also been evaluated.

In this paper, the conformational and configurational analyses of cyclic and acyclic β-oxygenated sulphoxides are reviewed. In addition, the conformational behaviour of pairs of diastereomeric 2-(alkylsulphinyl)-1-arylethanols, Ar-CH(OH)-CH 2 -SOR (R = Me, Bu τ ; Ar = phenyl, furyl, thienyl) and their O -methyl derivatives has been studied. From the 1 H-NMR and IR data obtained, together with the published results for other analogous β-oxygenated sulphoxides, the role played by stereoelectronic interactions, hydrogen bonding and steric factors on conformational equilibria has been established. Finally, the relative configurations of these pairs of diastereomers have been correlated with 13 C-NMR data. We thus establish an easy and efficient method for the configurational assignment of β-hydroxysulphoxides, based on 13 C-NMR spectroscopy.

The conformational analysis of the diastereomeric 2-methylsulphinyl-1-phenylethanol and its O-methyl and O-acetyl derivatives has been performed by 1H NMR spectroscopy. The study of the influence of dilution and solvent polarity changes on the coupling constants has permitted the configurational assignment of each diastereoisomer. The role played by hydrogen bonding in the hydroxysulphoxides has also been studied by IR spectroscopy.

The synthesis and conformational analysis of 2-fluoro, 2-hydroxy and 2-methoxy thioderivatives (thioethers, sulphoxides, sulphones and sulphonium salts) of 1,2-dimethyl and 1,2-diphenylethanes ( erythro and threo ) are reported. Steric effects in thioethers and electrostatic interactions in sulphonium salts are the main factors determining the stability rotamers. A balance of these factors controls the conformational equilibria in sulphoxides and sulphones. Electronic interactions between the π -aromatic electrons or the unshared β-heteroatomic electrons and the sulphur atom are suggested to explain large differences in rotamer populations induced by changes in the carbon sketelon or in the relative configuration of the sulphinylic sulphur.

The synthesis and conformational analysis of cis- and trans-2-methoxy-5-X-oxane, by 13C n.m.r. at low temperature in several solvents, are reported. ΔG° Values in CD2Cl2 of trans-isomers are –0.61 (X, SMe), +1.65 (X, SOMe more polar isomer), +0.57 (X, SOMe less polar isomer), –0.50 (X, SO2Me), and +1.4 (X, +SMe2) kcal mol–1, negative values indicating a preference for the diequatorial conformer. In all cis-compounds only one conformation is present. By comparison of these values with those calculated from 2-methoxyoxane and 3-methylthio derivatives of oxane the role played by the anomeric effect on the (oxygen–sulphur)1,2-g interaction can be inferred.

The synthesis and conformational analysis of some thioderivatives But-CHX-CH2Y (X = OH and OAc: Y = SH, SMe, SO2Me and SMe2) are reported. The conformational equilibra have been established from IH-NMR data and high dilution ir studies. All the compounds exhibited almost monoconformational behaviour around the C(1)-C(2) bond, due to strong steric factors. The observed vicinal coupling constants were used to check the different parameterizations of Altona's equation for our compounds with sulphur in distinct oxidation states. The possible dihedral angle deformations were also evaluated.

The synthesis, isolation and conformational analysis of the diastereomeric 2-methylsulphinyl-1,2-diphenylethanol and of its O -methyl and O -acetyl derivatives are reported. Chemical correlations and the study of the influence of solvent polarity changes on the coupling constants have permitted the configurational assignment. Lanthanide shift reagents have been used also. to this effect. The role of hydrogen bonding in the hydroxysulphoxides has been evaluated in diluted solutions by IR and NMR spectroscopy. A donor-acceptor interaction between oxygen and sulphur has been invoked to explain the differences in conformational behaviour between epimeric sulphoxides at sulphur atom.

A conformational study of erythro-1,2-diphenyl-2-X-ethanol [X = SH, SCH3, SOCH3, SO2, CH3, and +S(CH3)2] and its O-acetyl derivatives is reported. The electrostatic interactions between the heteroatoms, when the sulphur atom supports a positive charge determine a preference for gauche conformations in spite of the fact that they are destabilized by steric factors. The synthesis of new compounds is described.

Syntheses and conformational study of 1-X-2-phenylethyl methyl sulfide (X=NH 2 , NHMe, NMe 2 , and + NMe 3 are reported. Conformational populations have been inferred mainly from the variations in vicinal coupling constants induced by protonation and solvent polarity changes. Steric factors are in general dominant. The dimethylami no group additionally showed a strong repulsive gauche effect. However, when the nitrogen bore positive charge, the attractive + N/SMe interaction dominated the equilibria except in the trimethylammonium derivative. Solvent polarity effects were very significant.

The synthesis and conformational analysis of some β-thioderivatives of 1-(2'-furyl)ethanol and their O -methyl derivatives, Ar-CHX-CH2-Y (X: OH and OMe; Y: SMe, SOMe and SO2Me), are reported. The conformational equilibria have been established from 1H-nmr data and high dilution ir studies. Immunosuppressive properties of (methylsulphinyl)methyl 2-furyl ketone and 2-(methylsulphinyl)-1-(2'-furyl)ethanol, (RR/SS) and (RS/SR), have been tested.

The synthesis and conformational analysis, by 1H-NMR in several solvents, of 2-X-1,1-dimethoxyethane (X: MeS, EtS, tPrS, tBuS, BnS, SOMe, SOEt, SOiPr, SOiBu, SOBn) are reported. The results are concordant with a high, unexpected, solvent independent preference (∼30%) of the sterically most hindered conformation. A stereoelectronic interaction between orbitals has been invoked to explain the obtained results. MM2 method was used to calculate the energy of the conformations resulting from CH[sbnd]CH2 bond rotation.

A conformational study of 1-X-2-propanol (X = SH, SMe, SOMe, SO2Me, +SMe2) and their O-acetyl derivatives (X = SMe, SOMe, SO2Me, and +SMe2) is reported. From the relative values of the vicinal coupling constants in 1H nmr spectra it has been possible to establish the conformational preference. When a density of opposite charge is supported by heteratoms, polar factors determined a great predominance of that conformation in which the sulphur function has an anti-relationship with respect to the methyl group. In thiol and thioethers the conformational preference is not so marked.