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.     

Site-selective catalysis: toward a regiodivergent resolution of 1,2-diols

This paper demonstrates that the secondary hydroxyl can be functionalized in preference to the primary hydroxyl of a 1,2-diol. The site selectivity is achieved by using an enantioselective organic catalyst that is able to bond to the diol reversibly and covalently. The reaction has been parlayed into a divergent kinetic resolution on a racemic mixture, providing access to highly enantioenriched secondary-protected 1,2-diols in a single synthetic step.     

Asymmetric Synthesis of Chiral Sulfoximines through the S‐Alkylation of Sulfinamides

Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult‐to‐access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur‐selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S‐alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.     

Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols

The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.     

Role of sulfur chirality in the chemical processes of biology

Chiral structures profoundly influence chemical and biological processes. While chiral carbon biomolecules have received much attention, chirality is also possible in certain sulfur compounds; just as with carbon, there can be differences in the physiological behavior of chiral sulfur compounds. For instance, one drug enantiomer, Nexium (esomeprazole, a chiral sulfoxide), is used for its superior clinical properties as a proton pump inhibitor over the racemic mixture, Prilosec (Losec, omeprazole). This critical review introduces sulfur stereochemistry and nomenclature, and provides a comprehensive approach to chiral sulfur compounds and their enzymatic reactions in general and secondary metabolism. The major structural types of biological interest are sulfonium salts, sulfoxides, and sulfoximines. (103 references).     

Alternative approach to the synthesis of optically active β-keto sulfoxides by furylhydroperoxides enantioselective oxidations

Enantiomerically enriched β-keto sulfoxides are obtainable by an alternative method to the classical reaction of the enantiomerically pure α-sulfinyl anion with esters or by Andersen's synthesis, through Sharpless modified kinetic resolution of racemic β-keto sulfoxides. High e.e.s are achieved by combining asymmetric oxidation and kinetic resolution using furylhydroperoxides as oxidants.     

Novel catalytic kinetic resolution of racemic epoxides to allylic alcohols

[formula: see text] The kinetic resolution of racemic epoxides via catalytic enantioselective rearrangement to allylic alcohols was investigated. Using the Li-salt of (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo [2.2.1] heptane 1 as catalyst allowed both epoxides and allylic alcohols to be obtained in an enantioenriched form.     

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.     

A convenient approach to chiral sulfoxides by enantioselective oxidation with a steroidal furylhydroperoxide

The introduction of a steroidal residue into a position distant from the reaction center shows a beneficial effect on the reactivity of secondary furylhydroperoxides: chiral sulfoxides are obtained by asymmetric oxidation of sulfides and/or kinetic resolution of racemic sulfoxides with reduced reaction times and high enantiomeric excesses.     

Efficient synthesis of highly enantiopure β-lactam derivatives from biocatalytic transformations of amides and nitriles

Catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase and amidase containing microbial strain, under mild conditions, kinetic resolution of racemic amides provides an efficient and scalable route to highly enantioenriched R-4-carboxymethyl-β-lactams and S-4-carbamoylmethyl-β-lactams despite the substrates contain a stereogenic center that is β-positioned to amide functionality. Synthetic potential of the method was demonstrated by the constructions of novel β-lactam-fused heterocyclic compounds through convenient and practical chemical transformations.     

Electrochemical imination of sulfoxides using N-aminophthalimide

[reaction: see text] A novel electrochemical sulfoxide imination process is described. Our approach starts with a highly selective nitrene transfer from N-aminophthalimide to a variety of sulfoxides. This oxidative treatment is followed by reductive N-N bond cleavage under the controlled current conditions, which leads to a range of parent NH sulfoximines. In addition to solving the challenging problem of removing the N-phthalimido group, the overall process avoids the use of toxic oxidants and metal additives.     

Nickel-Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio-, Diastereo-, and Regioselective Hydroamination

Kinetic resolution is a powerful strategy for the isolation of enantioenriched compounds from racemic mixtures, and the development of selective catalytic processes is an active area of research. Here, we present a nickel-catalyzed kinetic resolution of racemic α-substituted unconjugated carbonyl alkenes via the enantio-, diastereo-, and regioselective hydroamination. This protocol affords both chiral α-substituted butenamides and syn-β^2,3-amino acid derivatives with high enantiomeric purity (up to 99 % ee) and selectivity factor up to >684. The key to the excellent kinetic resolution efficiency is the distinctive architecture of the chiral nickel complex, which enables successful resolution and enantioselective C−N bond construction. Mechanistic investigations reveal that the unique structure of the chiral ligand facilitates a rapid migratory insertion step with one enantiomer. This strategy provides a practical and versatile approach to prepare a wide range of chiral compounds.     

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.     

Divergent reactions on racemic mixtures

Methods that furnish enantioenriched products are crucial in modern organic synthesis. An underutilized strategy to arrive at enantioenriched products is to perform divergent reactions on racemic mixtures, where each enantiomer of the starting material reacts with a single chiral reagent to furnish two separable, non-enantiomeric products that are enantioenriched. Stereodivergent, regiodivergent and structurally divergent reactions on racemic mixtures are discussed in this tutorial review.     

Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides

A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for metal catalysts. Mixing ammonium salts with diacetoxyiodobenzene directly converts sulfoxides into sulfoximines. This report describes the first example of using of ammonia sources with diacetoxyiodobenzene to generate an electrophilic nitrogen center. Control and mechanistic studies suggest a short‐lived electrophilic intermediate, which is likely to be PhINH or PhIN⁺.     

Kinetic resolution of racemic tertiary allylic alcohols through SN2′ reaction using a chiral bisphosphoric acid/silver(i) salt co-catalyst system

A highly efficient kinetic resolution (KR) of racemic tertiary allylic alcohols was achieved through an intramolecular allylic substitution reaction using a co-catalyst system composed of chiral bisphosphoric acid and silver carbonate. This reaction afforded enantioenriched diene monoepoxides along with the recovery of tertiary allylic alcohols in a highly enantioselective manner, realizing an extremely high s-factor in most cases. The present method provides a new access to enantioenriched tertiary allylic alcohols, multifunctional compounds that are applicable for further synthetic manipulations.

A highly efficient KR of racemic tertiary allylic alcohols was developed through the intramolecular S_N2′ reaction using the chiral bisphosphoric acid/silver carbonate co-catalyst system, affording cis-epoxides and recovered alcohols in a high s-factor.     

Oxidative kinetic resolution of heterocyclic sulfoxides with a porphyrin-inspired manganese complex by hydrogen peroxide

We have successfully reported here the low loading porphyrin-inspired high-valent manganese (IV)-oxo complex was applied in oxidative kinetic resolution (OKR) of racemic heterocyclic sulfoxides using the environmentally benign hydrogen peroxide for the first time. This approach allows for rapid OKR (0.5?h) of a variety of racemic sulfoxides (including pyridine, pyrimidine, pyrazine, thiazole, benzothiazole, thiophene) in excellent enantioselectivity (up to?>?99%?ee), simultaneously generating the corresponding sulfones in high yield (up to 80%). The catalytic system also showed an unexceptionable chemoselectivity for the sulfoxide substrates with hydroxyl groups in which only the sulfoxide group was oxidized. The practical utility of the method has been demonstrated in the OKR of gram-scale sulfoxides.     

Kinetic resolutions of azomethine imines via copper-catalyzed [3 + 2] cycloadditions

An effective method has been developed for the kinetic resolution of racemic azomethine imines via [3 + 2] cycloadditions with alkynes catalyzed by a chiral copper complex. Efficient kinetic resolution is observed for a variety of N1 and C5 substituents on the dipole, thereby furnishing a wide array of useful enantioenriched azomethine imines, which can readily be transformed into monocyclic and bicyclic pyrazolidinones.     

Chiral Brønsted Acid Catalyzed Dynamic Kinetic Asymmetric Hydroamination of Racemic Allenes and Asymmetric Hydroamination of Dienes

The first highly efficient and practical chiral Brønsted acid catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes and asymmetric hydroamination of unactivated dienes with both high E/Z selectivity and enantioselectivity are described herein. The transformation proceeds through a new catalytic asymmetric model involving a highly reactive π‐allylic carbocationic intermediate, generated from racemic allenes or dienes through a proton transfer mediated by an activating/directing thiourea group. This method affords expedient access to structurally diverse enantioenriched, potentially bioactive alkenyl‐containing aza‐heterocycles and bicyclic aza‐heterocycles.     

Iron(II)‐Catalyzed Direct Synthesis of NH Sulfoximines from Sulfoxides

Free NH‐sulfoximines were directly prepared from sulfoxides through iron catalysis by applying a readily available, shelf‐stable hydroxylamine triflic acid salt. No additional oxidant is needed, and the substrate scope is broad, including a range of heterocyclic compounds.