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.     

Enantioselective inclusion of methyl phenyl sulfoxides and benzyl methyl sulfoxides by (R)-phenylglycyl-(R)-phenylglycine and the crystal structures of the inclusion cavities

Crystalline (R)-phenylglycyl-(R)-phenylglycine [(R,R)-1] includes methyl phenyl sulfoxides (2 and 3) and benzyl methyl sulfoxides (4) with high enantioselectivity. The dipeptide exhibited different stereoselectivity depending on four structural isomers of methyl tolyl sulfoxide (C(8)H(10)OS): R for methyl 2-tolyl sulfoxide, S for methyl 3-tolyl sulfoxide, and racemic for methyl 4-tolyl sulfoxide. A structural isomer, benzyl methyl sulfoxide, was included in racemic form. Chlorophenyl methyl sulfoxides 3 (C(7)H(7)ClOS) with a similar volume showed the same enantioselectivity for their recognition. By single-crystal X-ray analyses of these inclusion compounds, it was elucidated that (R,R)-1 molecules self-assembled to form layer structures and included the sulfoxides between these layers and that the origin of the enantioselectivity based on chiral cavities was induced by conformation of the C-terminal phenyl group of the dipeptide. The relative position between the ammonio proton and the C-terminal phenyl group in one molecule of the dipeptide determined the stereochemistry of the methyl sulfinyl groups to be recognized. Various positional isomers of methyl xylyl sulfoxide having the formula of C(9)H(12)OS were subjected to the enantioselective inclusion by (R,R)-1 crystals and these results are also discussed.     

The deoxygenation of sulfoxide mediated by the Ph3P/Lewis acid combination and the application to the kinetic resolution of racemic phosphines using optically active sulfoxide

It was found that the combination of Ph₃P/TiCl₄ was an effective promoter for the deoxygenation of sulfoxides and gave the corresponding sulfides in good yield (up to 97%) under mild conditions. This method was applied to the reaction between racemic phosphines and (R)-methyl p-tolyl sulfoxide, and it was found that the kinetic resolution was achieved in moderate selectivities.     

Palladium‐Catalyzed Enantioselective C−H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization

The first example of Pd^II‐catalyzed enantioselective C?H olefination with non‐chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity (up to 99 %) through both desymmetrization and parallel kinetic resolution (PKR). This is the first report of Pd^II‐catalyzed enantioselective C(sp²)?H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers.     

Reaction of magnesium alkylidene carbenoids with lithium alpha-sulfonyl carbanions: a novel synthesis of tri- and tetra-substituted allenes from 1-chlorovinyl p-tolyl sulfoxides and sulfones

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from ketones and chloromethyl p-tolyl sulfoxide, with ethylmagnesium chloride or isopropylmagnesium chloride at below -78 degrees C gave magnesium alkylidene carbenoids in about 90% yields. The reaction of the generated carbenoids with lithium alpha-sulfonyl carbanions was found to afford tri- and tetra-substituted allenes. Both cyclic ketones and acyclic ketones were useful in this procedure. However, the 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes gave only rearranged products, acetylenes, under the reaction conditions. The magnesium alkylidene carbenoid derived from an optically active 1-chlorovinyl p-tolyl sulfoxide was treated with lithium alpha-carbanion of 1-naphthyl phenyl sulfone; however, the obtained allene was found to be racemic. The mechanism of this reaction is also discussed.     

Resolution of racemic aryl dichloromethyl sulfoxides with (−)-menthone

The addition reaction of the sodium α-sulfinyl carbanion of a racemic aryl dichloromethyl sulfoxide to (?)-menthone in the presence of boron trifluoride diethyl etherate gave an adduct as a mixture of two easily separable diastereomers. After separation of the diastereomers, they were each treated with sodium hydride to afford enantiomerically pure aryl dichloromethyl sulfoxides and (?)-menthone both in high yields. This procedure provides a simple and efficient method for the resolution of racemic aryl dichloromethyl sulfoxides.     

Diaryl Sulfoxides from Aryl Benzyl Sulfoxides: A Single Palladium‐Catalyzed Triple Relay Process

A novel approach to produce diaryl sulfoxides from aryl benzyl sulfoxides is reported. Optimization of the reaction conditions was performed using high‐throughput experimentation techniques. The [Pd(dba)₂]/NiXantPhos catalyst system successfully promotes a triple relay process involving sulfoxide α‐arylation, C? S bond cleavage, and C? S bond formation. The byproduct benzophenone is formed by an additional palladium‐catalyzed process. It is noteworthy that palladium‐catalyzed benzylative C? S bond cleavage of sulfoxides is unprecedented. A wide range of aryl benzyl sulfoxides, as well as alkyl benzyl sulfoxides with various (hetero)aryl bromides were employed in the triple relay process in good to excellent yields (85–99 %). Moreover, aryl methyl sulfoxides, dibenzyl sulfoxides, and dimethylsulfoxide could be utilized to generate diaryl sulfoxides involving multiple catalytic cycles by a single catalyst.     

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.     

Stereoselective reductase-catalysed deoxygenation of sulfoxides in aerobic and anaerobic bacteria

Direct and indirect evidence, of unexpected stereoselective reductase-catalysed deoxygenations of sulfoxides, was found. The deoxygenations proceeded simultaneously, with the expected dioxygenase-catalysed asymmetric sulfoxidation of sulfides, during some biotransformations with the aerobic bacterium Pseudomonas putida UV4. Stereoselective reductase-catalysed asymmetric deoxygenation of racemic alkylaryl, dialkyl and phenolic sulfoxides was observed, without evidence of the reverse sulfoxidation reaction, using anaerobic bacterial strains. A purified dimethyl sulfoxide reductase, obtained from the intact cells of the anaerobic bacterium Citrobacter braakii DMSO 11, yielded, from the corresponding racemates, enantiopure alkylaryl sulfoxide and thiosulfinate samples.     

Efficient asymmetric oxidation of sulfides and kinetic resolution of sulfoxides catalyzed by a vanadium-salan system

The asymmetric oxidation of sulfides to chiral sulfoxides with hydrogen peroxide in good yield and high enantioselectivity has been catalyzed very effectively by chiral vanadium-salan [N,N'-alkyl bis(salicylamine)] complex. The salan ligand shows results superior in terms of reactivity and enantioselectivity to those of salen [N,N'-alkylene bis(salicylideneimine)] analogue, and provides the sulfoxide with opposite configuration. The high enantioselectivity of this reaction is the direct result of the asymmetric oxidation. The efficient kinetic resolution of racemic sulfoxides catalyzed by the vanadium-salan system is also described.     

Synergistic extraction of uranyl ion with 1-phenyl-3-methyl-4-benzoyl-pyrazolone-5 (HPMBP) and some long chain aliphatic sulfoxides

Synergistic extraction of uranyl ion with 1-phenyl-3-methyl-4-benzoyl pyrazolone-5 (HPMBP) and aliphatic sulfoxides of varying basicities, viz di-isoamyl (DIASO), di-n-hexyl (DHSO), di-n-septyl (DSSO), di-n-octyl (DOSO), di-n-nonyl (DNSO), di-n-decyl (DDSO) or di-n-undecyl (DuDSO) sulfoxide has been studied at 30±0.1°C. Extraction with some of these sulfoxides has been studied at various fixed temperatures also. The organic phase equilibrium constant (log Ks) has been found to increase with the basicity of the sulfoxide up to DOSO beyond which there is a gradual decreasing trend which has been attributed to the effect of possible steric hindrance (spatial) involved in the bonding of the higher sulfoxides (greater than 8 carbon atoms) with UO₂ (PMBP)₂ chelate. This has been supported by thermodynamic data involved in these systems. The entropy values for sulfoxides with eight or more carbon atoms are much more negative as compared to the lower sulfoxides and are also in contrast to HTTA and BTFA systems with these sulfoxides studied earlier.     

C−H Coupling Reactions Directed by Sulfoxides: Teaching an Old Functional Group New Tricks

Sulfoxides are classical functional groups for directing the stoichiometric metalation and functionalization of C?H bonds. In recent times, sulfoxides have been given a new lease on life owing to the development of modern synthetic methods that have arisen because of their unique reactivity. They have recently been used in catalytic C?H activation proceeding via coordination of an internal sulfoxide to a metal or through the action of an external sulfoxide ligand. Furthermore, sulfoxides are able to capture nucleophiles and electrophiles to give sulfonium salts, which subsequently enable the formation of C?C bonds at the expense of C?H bonds. This Review summarizes a renaissance period in the application of sulfoxides arising from their versatility in directing C?H functionalization.     

Kinetic resolution of phenyl methyl sulfoxides by mammalian methionine sulfoxide reductase A

Chiral sulfoxides are widely used in organic synthesis as chiral auxiliaries. There are numerous strategies for the preparation of enantiomerically pure sulfoxides, based either on the enantioselective oxidation of sulphides or the enantiospecific reduction of sulfoxides. For both cases, bioconversion techniques have been developed and proposed for large-scale synthesis. Methionine sulfoxide reductase enzymes (MsrA and MsrB) catalyse the stereoselective conversion of methionine sulfoxide to methionine. MsrA can also catalyse the reduction of other exogenous sulfoxides, including p-tolyl methyl sulfoxide. However, the stereoselectivity towards this type of substrate is not yet well characterized. The activity and enantioselectivity of MsrA toward several aryl methyl sulfoxides is presented in this paper.     

Ruthenium‐Catalyzed Oxidative Kinetic Resolution of Unactivated and Activated Secondary Alcohols with Air as the Hydrogen Acceptor at Room Temperature

Enantiopure alcohols are versatile building blocks for asymmetric synthesis and the kinetic resolution (KR) of racemic alcohols is a reliable method for preparing them. Although many KR methods have been developed, oxidative kinetic resolution (OKR), in which dioxygen is used as the hydrogen acceptor, is the most atom‐efficient. Dioxygen is ubiquitous in air, which is abundant and safe to handle. Therefore, OKR with air has been intensively investigated and the OKR of benzylic alcohols was recently achieved by using an Ir catalyst without any adjuvant. However, the OKR of unactivated alcohols remains a challenge. An [(aqua)Ru(salen)] catalyzed OKR with air as the hydrogen acceptor was developed, in which the aqua ligand is exchanged with alcohol and the Ru complex undergoes single electron transfer to dioxygen and subsequent alcohol oxidation. This OKR can be applied without any adjuvant to activated and unactivated alcohols with good to high enantioselectivity. The unique influence of substrate inhibition on the enantioselectivity of the OKR is also described.     

Chemical activation of cytochrome c proteins via crown ether complexation: cold-active synzymes for enantiomer-selective sulfoxide oxidation in methanol

Supramolecular complexation with 18-crown-6 significantly converted catalytically inactive cytochrome c (biological form) to catalytically active synzyme (artificial form). Although a family of cytochrome c proteins does not work as enzymes in nature, crown ether complexation modified their heme coordination structures and functionally activated them to promote the asymmetric oxidation of racemic sulfoxides at low temperature. Horse heart, pigeon breast, and yeast cytochrome c proteins were demonstrated to form supramolecular complexes with 18-crown-6 in methanol, which effectively oxidized (S)-isomers of naphthyl methyl sulfoxide, methyl tolyl sulfoxide, isopropyl phenyl sulfoxide, benzyl methyl sulfoxide, and 4-methylsulfenyl acetophenone at -40 degrees C. Because horse heart and pigeon breast cytochromes c exhibited more efficient and higher enantiomer-selective activities than yeast cytochrome c, a proper combination of cytochrome c and crown ether offers a new class of cold-active synzymes promoting nonbiological asymmetric oxidation.     

Efficient synthesis of racemic and chiral alkenyl sulfoxides by palladium-catalyzed Suzuki coupling

Alkenyl sulfoxide derivatives are obtained in high yields through a palladium-catalyzed Suzuki/Miyaura cross-coupling reaction of racemic and chiral 1-halo sulfoxides with aryl and alkenyl boronic acids. Chiral substrates react with no loss of optical purity and high optical yields. The reaction takes place with different palladium catalysts, such as Pd(PPh₃)₄ or Pd(OAc)₂/DABCO. Although nitrogen ligands like DABCO lead to an active palladium catalyst, they are less effective than the phosphine ones.     

Molecular recognition of l-leucyl-l-alanine: enantioselective inclusion of alkyl methyl sulfoxides

A simple aliphatic dipeptide, l-leucyl-l-alanine (Leu-Ala), includes several alkyl methyl sulfoxides enantioselectively to form inclusion crystals. From single-crystal X-ray analyses of three inclusion compounds of dimethyl sulfoxide (DMSO), isobutyl methyl sulfoxide, and benzyl methyl sulfoxide, it was elucidated that Leu-Ala molecules self-assemble to form layer structures and the sulfoxides are included via hydrogen bonding in a cavity between these layers. The inclusion cavity has methyl group and isobutyl group at its each side, and the guest sulfoxide is placed in such a manner that its methyl group faces toward the methyl of the Leu-Ala cavity. When the alkyl group of the sulfoxide is comparably large, it is located in the residual space of the cavity to attain effective crystal packing. Thus, the sulfoxides having a comparably large group such as isobutyl, butyl, and benzyl are included with a high (R)-enantioselectivity in Leu-Ala crystals.     

Gas chromatographic determination of S-alk(en)ylcysteine sulfoxides

A new GC method for determination of S-alk(en)ylcysteine sulfoxides, important secondary metabolites occurring in many plant genera, has been developed. The method is based on isolation of the amino acid fraction by ion-exchange chromatography followed by derivatization with ethyl chloroformate at ambient temperature and reduction of derivatized S-alk(en)ylcysteine sulfoxides by sodium iodide. The main advantages of the new method are its high sensitivity, excellent resolution capability, accuracy and reliability, as well as the possibility to identify unknown compounds by means of GC-MS. The content of alliin and other S-alk(en)ylcysteine sulfoxides was determined in nine different samples of garlic (Allium sativum L.) originating from the Czech Republic, France, and China. The total content of S-alk(en)ylcysteine sulfoxide pool ranged between 0.53 and 1.3% fresh weight, with S-allylcysteine sulfoxide (alliin) being predominant. A novel S-alkylcysteine derivative, S-ethylcysteine sulfoxide (ethiin), not previously reported to occur in Allium species, was found in some of the samples examined.     

Extraction behaviour of uranium,zirconium and ruthenium with gamma-irradiated sulfoxides and tri-n-butyl phosphate

The extraction, scrubbing and stripping behaviour of uranium, zirconium and ruthenium with di-n-hexyl and di-n-octyl sulfoxides in Solvesso-100 and tri-n-butyl phosphate (TBP) in shell Sol-T irradiated by various gamma doses (0–169 Mrads) have been investigated. 2M HNO₃ was used for extraction and scrubbing and 0.01M HNO₃ for stripping purposes. Results indicate that the extraction of uranium with TBP increases and that with sulfoxide decreases with dose. This is reflected in their corresponding scrubbing percentages too. The stripping percentage of uranium with TBP decreases with dose while the reverse is the case with sulfoxide. The extraction of zirconium with TBP increases sharply with dose as compared to sulfoxides. The extraction scrubbing and stripping of ruthenium remain almost unaffected by dose both in the case of TBP and sulfoxides. These results lead to much higher overall decontamination factors for uranium with respect to zirconium as well as ruthenium with irradiated sulfoxides as compared to those with irradiated TBP.     

Bacterial dioxygenase- and monooxygenase-catalysed sulfoxidation of benzo[b]thiophenes

Asymmetric heteroatom oxidation of benzo[b]thiophenes to yield the corresponding sulfoxides was catalysed by toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and styrene monooxygenase (SMO) enzymes present in P. putida mutant and E. coli recombinant whole cells. TDO-catalysed oxidation yielded the relatively unstable benzo[b]thiophene sulfoxide; its dimerization, followed by dehydrogenation, resulted in the isolation of stable tetracyclic sulfoxides as minor products with cis-dihydrodiols being the dominant metabolites. SMO mainly catalysed the formation of enantioenriched benzo[b]thiophene sulfoxide and 2-methyl benzo[b]thiophene sulfoxides which racemized at ambient temperature. The barriers to pyramidal sulfur inversion of 2- and 3-methyl benzo[b]thiophene sulfoxide metabolites, obtained using TDO and NDO as biocatalysts, were found to be ca.: 25-27 kcal mol(-1). The absolute configurations of the benzo[b]thiophene sulfoxides were determined by ECD spectroscopy, X-ray crystallography and stereochemical correlation. A site-directed mutant E. coli strain containing an engineered form of NDO, was found to change the regioselectivity toward preferential oxidation of the thiophene ring rather than the benzene ring.