Dioxygenase-catalysed oxidation of alkylaryl sulfides: sulfoxidation versus cis-dihydrodiol formation

Toluene- and naphthalene-dioxygenase-catalysed sulfoxidation of nine disubstituted methylphenyl sulfides, using whole cells of Pseudomonas putida, consistently gave the corresponding enantioenriched sulfoxides. Using the P. putida UV4 mutant strain, and these substrates, differing proportions of the corresponding cis-dihydrodiol sulfides were also isolated. Evidence was found for the concomitant dioxygenase-catalysed cis-dihydroxylation and sulfoxidation of methyl para-tolyl sulfide. A simultaneous stereoselective reductase-catalysed deoxygenation of (S)-methyl para-tolyl sulfoxide, led to an increase in the proportion of the corresponding cis-dihydrodiol sulfide. The enantiopurity values and absolute configurations of the corresponding cis-dihydrodiol metabolites from methyl ortho- and para-substituted phenyl sulfides were determined by different methods, including chemoenzymatic syntheses from the cis-dihydrodiol metabolites of para-substituted iodobenzenes. Further evidence was provided to support the validity of an empirical model to predict, (i) the stereochemistry of cis-dihydroxylation of para-substituted benzene substrates, and (ii) the regiochemistry of cis-dihydroxylation reactions of ortho-substituted benzenes, each using toluene dioxygenase as biocatalyst.     

Investigation of steric and electronic effects in the copper-catalysed asymmetric oxidation of sulfides

Steric and electronic effects in the copper-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and alkyl benzyl sulfides have been investigated. The presence of an aryl group directly attached to the sulfur is essential to afford sulfoxides with high enantioselectivities, with up to 97% ee for 2-naphthyl benzyl sulfoxide, the highest enantioselectivity achieved to date for copper-catalysed asymmetric sulfoxidation. In contrast, the benzyl substituent can be replaced by sterically comparable groups with no effect on enantioselectivity. Copper-mediated oxidation of substituted aryl benzyl sulfides display modest steric and electronic effects resulting in comparable or lower enantioselectivities to those obtained with the unsubstituted benzyl phenyl sulfide.     

A gentle and efficient route for the deoxygenation of sulfoxides using catecholborane (HBcat; cat = 1,2-O2C6H4)

The addition of catecholborane (HBcat; cat = 1,2-O₂C₆H₄) to a wide range of sulfoxides affords the corresponding sulfides, dihydrogen, and catBOBcat. The diboron compound catBOBcat acts like a Lewis acid and will coordinate one molecule of the starting sulfoxide. Although deoxygenations with bulky or electron withdrawing sulfoxides are slow, these reactions can be greatly accelerated with the use of excess HBcat or by employing a rhodium catalyst.     

Copper-catalyzed asymmetric oxidation of sulfides

Copper-catalyzed asymmetric sulfoxidation of aryl benzyl and aryl alkyl sulfides, using aqueous hydrogen peroxide as the oxidant, has been investigated. A relationship between the steric effects of the sulfide substituents and the enantioselectivity of the oxidation has been observed, with up to 93% ee for 2-naphthylmethyl phenyl sulfoxide, in modest yield in this instance (up to 30%). The influence of variation of solvent and ligand structure was examined, and the optimized conditions were then used to oxidize a number of aryl alkyl and aryl benzyl sulfides, producing sulfoxides in excellent yields in most cases (up to 92%), and good enantiopurities in certain cases (up to 84% ee).     

Hammett correlations in the photosensitized oxidation of 4-substituted thioanisoles

Singlet oxygen is quenched by a series of 4-substituted thioanisoles (methoxy to nitro), with rate constant k(t) = 7 x 10(4) to 7 x 10(6) M(-)(1) s(-)(1), close to the value observed for the myoglobin-catalyzed sulfoxidation of the same sulfides. Correlations with sigma (rho = -1.97) and with E(ox) (slope -3.9 V(-)(1)) are evidence for an electrophilic mechanism. In methanol sulfoxides are formed (85%) via an intermediate quenched by diphenyl sulfoxide; competing minor paths lead to arylthiols, arylsulfenic acid, and aryl sulfoxides. In aprotic solvents, the sulfoxidation is quite sluggish, but carboxylic acids (mostly 100. The protonated persulfoxide is formed in this case and acts as an electrophile with sulfides, again with a rate constant correlating with sigma (rho = -1.78).     

Structural changes by sulfoxidation of phenothiazine drugs

Summary The side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests.     

Novel catalytic asymmetric sulfoxidation in water using the hypervalent iodine reagent iodoxybenzene

A new catalytic asymmetric oxidation of sulfides to sulfoxides in water using the hypervalent iodine(V) reagent iodoxybenzene (PhIO2) has been developed. This methodology is distinctly different from the previously reported use of cyclodextrins or biological catalysts and provides a new route to asymmetric sulfoxidation in water.     

Chemo- and diastereoselectivity in the dimethyldioxirane oxidation of 2,3-dihydro-4H-1-benzothiopyran-4-ones and 4H-1-benzothiopyran-4-ones. Unusual reactivity of 4H-1-benzothiopyran-4-one 1-oxides

The oxidation of the 1-thiochromanones 1-3 by dimethyldioxirane (DMD) produced the corresponding sulfoxides 4-6 or sulfones 7-9; their relative amounts depended on the amount of oxidant used. A low diastereoselectivity was observed in the sulfoxidation of the 2-substituted 1-thiochromanones 2 and 3, due to the small steric differentiation during the DMD attack. An unusual reactivity pattern was found in the DMD oxidation of the 1-thiochromones 10-12, in that the sulfoxides 13-15 were more reactive toward the electrophilic oxidizing agent than the corresponding sulfides. The observed anomaly may be explained in terms of transannular stabilization of the transition structure (TS) for the sulfone formation, promoted through favorable conformational effects in the sulfoxide. Higher sulfoxide/sulfone ratios were found in solvents of greater hydrogen bond donor capacity, which is in accordance with the postulated stabilizing effect.     

Development of new synthetic methods with aryl 1-chlorovinyl sulfoxides

Aryl 1-chlorovinyl sulfoxides were easily synthesized from ketones and aldehydes with aryl chloromethyl sulfoxide in three-steps with high overall yields. Low-temperature treatment of the aryl 1-chlorovinyl sulfoxides with alkyllithium or a Grignard reagent gave alkylidene carbenoids via a sulfoxide-metal exchange reaction. From the alkylidene carbenoids, acetylenic compounds, tetra-substituted olefins, and allenes were synthesized. Enolization of alpha-chloro alpha-sulfinyl ketones, which were synthesized from methyl esters and chloromethyl phenyl sulfoxide, is another method for the generation of aryl 1-chloroalkyl sulfoxides. Treatment of 1-chlorovinyl phenyl sulfoxides so generated with t-BuLi followed by some nucleophiles having an acidic hydrogen gave one-carbon elongated carboxylic acids and their derivatives. Conjugate addition of some carbanions with 1-chlorovinyl p-tolyl sulfoxides was found to have taken place. For example, reaction of 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium gave high yields of cyclic enaminonitriles. Acidic treatment of the enaminonitriles afforded good yields of 4,4-disubstituted 2-cyclopentenones. By using unsymmetrical ketones and optically pure chloromethyl p-tolyl sulfoxide, this procedure suggests a good method for an asymmetric synthesis of optically pure 4,4-disubstituted 2-cyclopentenones. This method achieved an asymmetric total synthesis of (+)-alpha-cuparenone starting from methyl 4-methylphenyl ketone and (R)-(-)-chloromethyl p-tolyl sulfoxide. A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones is also successful using cyanomethyllithium and its homologues. Conjugate addition of the lithium enolate of tert-butyl acetate and its homologues gave high yields of the adduct, 3,3-disubstituted esters. Synthesis of various kinds of carboxylic acids and their derivatives and lactones was realized from the adducts.     

Highly enantioselective oxidation of sulfides to sulfoxides by a new oxaziridinium salt

The new oxaziridinium salt 5 (R2 = TBDPS) is an effective reagent for the highly enantioselective oxidation of sulfides to sulfoxides with up to >99% ee and good yields. As such, it represents a new valuable nonmetallic alternative to the existing methods for asymmetric sulfoxidation.     

Synthesis of Enantioenriched Sulfoxides by an Oxidation-Reduction Enzymatic Cascade

Chiral sulfoxides are versatile synthons and have gained a particular interest in asymmetric synthesis of active pharmaceutical and agrochemical ingredients. Herein, a linear oxidation–reduction bienzymatic cascade to synthesize chiral sulfoxides is reported. The extraordinarily stable and active vanadium-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) was used to oxidize sulfides into racemic sulfoxides, which were then converted to chiral sulfoxides by highly enantioselective methionine sulfoxide reductase A (MsrA) and B (MsrB) by kinetic resolution, respectively. The combinatorial cascade gave a broad range of structurally diverse sulfoxides with excellent optical purity (>99 % ee) with complementary chirality. The enzymatic cascade requires no NAD(P)H recycling, representing a facile method for chiral sulfoxide synthesis. Particularly, the envisioned enzymatic cascade not only allows CiVCPO to gain relevance in chiral sulfoxide synthesis, but also provides a powerful approach for (S)-sulfoxide synthesis; the latter case is significantly unexplored for heme-dependent peroxidases and peroxygenases.     

A new synthesis, including asymmetric synthesis, of spiro[4.n]alkenones from three components: cyclic ketones, chloromethyl p-tolyl sulfoxide, and acetonitrile; and a formal total synthesis of racemic acorone

1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of cyclic ketones and chloromethyl p-tolyl sulfoxide in good yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium at −78°C to room temperature gave spirocyclic enaminonitriles in high yields. Acidic treatment of the enaminonitriles afforded spiro[4.n]alkenones in good yields. By using an unsymmetrical cyclic ketone, α-tetralone, and optically active chloromethyl p-tolyl sulfoxide, this procedure afforded enantiomerically pure spiro[4.5]decenone in good yield with excellent asymmetric induction from the sulfoxide chiral center. By using this method a formal total synthesis of a racemic spirocyclic sesquiterpene, acorone, was realized.     

A new synthesis, including asymmetric synthesis, of alkylidenecyclopropanes by 1,2-CC insertion of cyclobutylmagnesium carbenoides as the key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters gave adducts in high yields. The adducts were converted to 1-chlorocyclobutyl p-tolyl sulfoxides in four steps in high overall yields. Treatment of the 1-chlorocyclobutyl p-tolyl sulfoxides with cyclopentylmagnesium chloride in THF at −40 °C resulted in the formation of cyclobutylmagnesium carbenoids. The magnesium carbenoid 1,2-CC insertion reaction took place smoothly from the cyclobutylmagnesium carbenoids to afford alkylidenecyclopropanes in good to high yields. An asymmetric synthesis of optically active alkylidenecyclopropane was successfully achieved starting from optically active 1-chlorovinyl p-tolyl sulfoxide.     

The first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis with enantiopure cyclopropylmagnesium carbenoids

The reaction of lithium α-sulfinyl carbanion of enantiopure dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave optically active 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group with high asymmetric induction from the sulfur chiral center. Reduction of the carbonyl group followed by treatment with Grignard reagent, the 1-chlorocyclopropyl p-tolyl sulfoxides resulted in the formation of enantiopure allenic alcohols via the Doering-LaFlamme-type rearrangement of enantiopure cyclopropylmagnesium carbenoid intermediates. This is the first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis.     

Sulfoxides in the allylation of aldehydes in the presence of silicon tetrachloride and allyltributylstannane

SiCl₄ can be conveniently activated by catalytic amounts of dimethyl sulfoxide or other readily-available sulfoxides for the allylation of aromatic, hetero-aromatic and unsaturated aldehydes in the presence of allyltributyl stannane. Chiral aryl methyl sulfoxides have been used to develop asymmetric allylation methods, as well as probe the aldehyde substrate scope.     

手性亚砜的合成及其在不对称合成中的应用

本文综述了手性亚砜的合成。由于亚砜结构上的特征以及与金属离子的络合能力,使手性亚砜在不对称合成中具有强烈的诱导作用,使它成为进行不对称合成的一个手段。本文列举了它在不对称合成中的应用情况。     

Asymmetric synthesis of 4,4-disubstituted 2-cyclopentenones from optically active 1-chlorovinyl p-tolyl sulfoxides and cyanomethyllithium with formation of a quaternary chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position, which were synthesized from unsymmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with cyanomethyllithium gave optically active 2-amino-1-cyano-5,5-disubstituted-1,3-cyclopentadienes with very high asymmetric induction from the sulfoxide chiral center. The products were converted to the enantiomerically pure 4,4-disubstituted 2-cyclopentenones by heating with phosphoric acid in acetic acid.     

Enzyme-catalysed oxygenation and deoxygenation routes to chiral thiosulfinates

Enantioenriched thiosulfinates have been obtained by dioxygenase- and chloroperoxidase-catalysed oxidation of 1,2-disulfides and dimethyl sulfoxide reductase-catalysed deoxygenation.     

Safe oxidation of sulfides into sulfoxides using SIBX

SIBX is a stabilized (i.e., nonexplosive) formulation of the λ⁵-iodane 2-iodoxybenzoic acid IBX that can be used as a suspension in various organic solvents to oxidize safely sulfides into sulfoxides. Most yields are comparable to those obtained using IBX or other iodanes such as PhIO and PhIO₂. An asymmetric version of this SIBX-mediated sulfoxidation was performed in high chemical yield and moderate enantioselectivity by simple addition of an external chiral source.