Organocatalytic asymmetric deoxygenation of sulfones to access chiral sulfinyl compounds.

Over the past decades, many efficient methodologies have been developed that allow for the enantioselective synthesis of chiral sulfinyl compounds. However, the enantioselective deoxygenation of hexavalent sulfones for the formation of chiral sulfinyl compounds still remains one of the major challenges in the fields of asymmetric synthesis and organosulfur chemistry. Here we have demonstrated that a synergistic combination of organocatalysis and the incorporation of a cyano group into the sulfone generates a chiral sulfinic species as an active intermediate. A wide range of chiral sulfinates with high enantioselectivities could then be acquired using alcohols as nucleophiles, and the subsequent transformations allowed the collective preparation of a variety of chiral sulfinyl compounds. Density functional theory calculations revealed that the catalytic cycle involves a quinuclidine-assisted stepwise 1,2-cyano group transfer, base-assisted intermolecular substitution with alcohol and regeneration of the active catalyst. The enantioselectivity was determined by the cyano migration step.

Tunable Reaction Mode of Bifunctional Peroxides with Ketones to Access α-Oxacyclic Ketones and Enals.

A new annulation reaction between allylic/benzylic peroxides and ketones has been developed to provide the α-oxacyclic ketones in moderate yields under the KOtBu basic conditions. Mechanistic studies reveal that these peroxides undergo the Kornblum-DeLaMare rearrangement to release the aldehyde intermediates and subsequently initiate the aldol/etherification tandem process to deliver the final products. Accordingly, these peroxides serving as "masked" enals have also been utilized to prepare the previously hard-to-achieve α-enal-tethered ketones in one step.

Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs).

Atropisomers, arising from conformational restriction, are inherently chiral due to the intersecting dissymmetric planes. Since there are numerous applications of enantiopure atropisomers in catalyst design, drug discovery, and material science, the asymmetric preparation of these highly prized molecules has become a flourishing field in synthetic chemistry. A number of catalysts, synthetic procedures, and novel concepts have been developed for the manufacture of the atropisomeric molecules. However, due to the intrinsic properties of different types of atropisomers featuring biaryl, hetero-biaryl, or non-biaryl architectures, only very few methods pass the rigorous inspection and are considered generally applicable. The development of a broadly applicable synthetic strategy for various atropisomers is a challenge. In this Account, we summarize our recent studies on the enantioselective synthesis of atropisomers using the vinylidene ortho-quinone methides (VQMs) as pluripotent intermediates.The most appealing features of VQMs are the disturbed aromaticity and axial chirality of the allene fragment. At the outset, the applications of VQMs in organic synthesis have been neglected due to their principal liabilities: ephemeral nature, extraordinary reactivity, and multireaction sites. The domestication of this transient intermediate was demonstrated by in situ catalytic asymmetric generation of VQMs, and the reactivity and selectivity were fully explored by judiciously modifying precursors and tuning catalytic systems. A variety of axially chiral heterocycles were achieved through five-, six-, seven- and nine-membered ring formation of VQM intermediates with different kinds of branched nucleophilic functional groups. The axially chiral C-N axis could be constructed from VQM intermediates via N-annulation or desymmetrization of preformed C-N scaffolds. We take advantage of the high electrophilicity of VQMs toward a series of sulfur and carbon based nucleophiles leading to atropisomeric vinyl arenes. Furthermore, chiral helical compounds were realized by cycloaddition or consecutive annulation of VQM intermediates. These achievements demonstrated that the VQMs could work as a nuclear parent for the collective synthesis of distinct and complex optically active atropisomers. Recently, we have realized the isolation and structural characterization of the elusive VQMs, which were questioned as putative intermediates for decades. The successful isolation of VQMs provided direct evidence for their existence and an unprecedented opportunity to directly investigate their reactivity. The good thermal stability and reserved reactivity of the isolated VQMs demonstrated their great potential as synthetic reagents and expanded the border of VQM chemistry.

Organocatalytic Asymmetric Construction of Tetrasubstituted Carbon Stereocenters Bearing Three Heteroatoms via Intramolecular Cyclization of Vinylidene ortho-Quinone Methide with Imidates.

We report herein an organocatalytic asymmetric protocol for the construction of tetrasubstituted carbon stereocenters bearing three heteroatoms. The reaction proceeded via the enantioselective intramolecular cyclization reaction of vinylidene ortho-quinone methide (VQM) with imidates to form pentacyclic heterocycles. The formed tetrasubstituted carbon center was stable under a high temperature and the conditions for further transformations.

Organocatalytic atroposelective construction of axially chiral N, N- and N, S-1,2-azoles through novel ring formation approach.

1,2-Azoles are privileged structures in ligand/catalyst design and widely exist in many important natural products and drugs. In this report, two types of axially chiral 1,2-azoles (naphthyl-isothiazole S-oxides with a stereogenic sulfur center and atropoisomeric naphthyl pyrazoles) are synthesized via modified vinylidene ortho-quinone methide intermediates. Diverse products are acquired in satisfying yields and good to excellent enantioselectivities. The vinylidene ortho-quinone methide intermediates bearing two hetero atoms at 5-position have been demonstrated as a platform molecule for the atroposelective synthesis of axially chiral 1,2-azoles. This finding not only enrich our knowledge of vinylidene ortho-quinone methide chemistry but also provide the easy preparation method for diverse atropisomeric heterobiaryls that were inaccessible by existing methodologies. The obtained chiral naphthyl-isothiazole S-oxides and naphthyl-pyrazoles have demonstrated their potential application in further synthetic transformations and therapeutic agents.

Organocatalytic cascade reactions for multi-functionalized chiral cyclic ethers through vinylidene ortho-quinone methides.

An organocatalytic approach to installing various alcohols into the carbonyl of α,ß-unsaturated ketones mediated by VQM intermediates was achieved, followed by dearomatization to provide the stereo-defined cyclic ethers via a cascade process. Along with the transformations, this strategy affords efficient access to the underexplored chiral cyclic ether chemospace.

Organocatalytic Enantioselective Construction of Chiral Azepine Skeleton Bearing Multiple-Stereogenic Elements.

Enantioselective construction of molecules bearing multiple stereogenic elements is increasingly related to the synthesis of enantiopure natural products, pharmaceuticals, and functional materials. However, atom-economical and enantioselective approaches to install multiple stereogenic elements in a small molecular template by limited chemical transformation remain challenging. We describe an organocatalytic enantioselective method for the preparation of polychiral molecules bearing four types of stereogenic elements in fused azepines via vinylidene ortho-quinone methide (VQM)-mediated intramolecular electrophilic aromatic substitution. This method was proved robust with a wide range of substrate scope (46-92 % yield), with excellent diastereoselectivity (>20:1 dr) and enantioselectivity achieved (up to 97 % ee). Optical properties and Ru3+ -induced fluorescence responses of these compounds suggest their potential applications in optoelectronic materials and heavy metal ion detection.

Chiral Naphthyl-C2-Indole as Scaffold for Phosphine Organocatalysis: Application in Asymmetric Formal [4 + 2] Cycloaddition Reactions.

The applications of a newly designed chiral naphthyl-C2-indole bifunctional phosphine organocatalyst in stereoselective formal [4 + 2] cycloaddition reactions were reported. The chiral naphthyl-C2-indole skeleton was introduced to bifunctional phosphine organocatalysis for the first time, and excellent stereocontrol was achieved in two types of formal [4 + 2] cycloaddition reactions. With the optimal catalyst, a series of chiral spirooxindole and hydrodibenzofuran architectures were produced in moderate to good yields with excellent stereoselectivities (up to >99% ee, >20:1 dr).

N-Iodosuccinimide-Mediated Dimerization of 2-Alkynylnaphthols: A Highly Diastereoselective Construction of Bridged Polycyclic Compounds via Vinylidene ortho-Quinone Methide Intermediate.

An unprecedented highly diastereoselective dimerization of 2-alkynylnaphthols is presented to furnish bridged polycyclic compounds containing a bicyclo[3.2.1]octane moiety with good to excellent yields. The reaction proceeded under mild conditions using N-iodosuccinimide as a promoter, simultaneously constructing one new C-O bond and two new C-C bonds. A tetra-substituted vinylidene ortho-quinone methide intermediate was likely involved, and the steric hindrance of substituents played a critical role in this transformation.

Organocatalytic Enantioselective γ-Elimination: Applications in the Preparation of Chiral Peroxides and Epoxides.

An organocatalyzed enantioselective γ-elimination process has been achieved and applied in the kinetic resolution of peroxides to access chiral peroxides and epoxides. The reaction provided a pathway for the preparation of two useful synthetic and biologically important structural motifs through a single-step reaction. A range of substrates has been resolved with a selectivity factor up to 63. The obtained enantioenriched peroxides and epoxides allowed a series of transformations with retained optical purities.

Enantioselective Control of Both Helical and Axial Stereogenic Elements though an Organocatalytic Approach.

A highly diastereo- and enantio-selective method for the asymmetric synthesis of molecules containing helicenes and stereogenic axes was developed based on organocatalysis. Various compounds bearing both helical and axial stereogenic elements were obtained in excellent enantioselectivities. The mechanism study revealed that the reaction proceeded through two stages: 1) The first cyclization produces a reaction intermediate containing a stereogenic axis. 2) The dynamic kinetic resolution of helix reaction intermediate following with cyclization generates a helix and another stereogenic axis.

Organocatalytic Asymmetric Annulation of ortho-Alkynylanilines: Synthesis of Axially Chiral Naphthyl-C2-indoles.

A chiral Brønsted base catalyzed asymmetric annulation of ortho-alkynylanilines has been developed to access axially chiral naphthyl-C2-indoles via vinylidene ortho-quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl-C2-indole skeletons with excellent enantioselectivity and functional-group tolerance. This transformation was applicable to decagram-scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl-C2-indoles for a series of carbon-heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl-C2-indoles were applied as a chiral skeleton for organocatalytic aza-Baylis-Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.

Organocatalytic Enantioselective Selenosulfonylation of a C-C Double Bond To Form Two Stereogenic Centers in an Aqueous Medium.

Organocatalytic selenosulfonylation of the C-C double bond of α,ß-unsaturated ketones to construct two contiguous stereogenic centers in an aqueous medium was described. A series of α-selenyl and ß-sulfonyl ketones with various functional groups were synthesized in good yields and enantioselectivities with saturated NaCl solution as the solvent. In addition, this protocol had been successfully scaled up to a decagram scale via a simple workup procedure.

Metal-free difunctionalization of alkynes to access tetrasubstituted olefins through spontaneous selenosulfonylation of vinylidene ortho-quinone methide (VQM).

A metal-free difunctionalization of alkynes to access tetrasubstituted olefins through spontaneous selenosulfonylation of vinylidene ortho-quinone methide (VQM) was described herein. The reaction was conducted under mild conditions without any catalysts or additives. Preliminary mechanism studies revealed that the formation of VQM was the key for this alkyne di-functionalization reaction. The reaction could be applied in the enantioselective asymmetric synthesis of axially chiral styrene. Furthermore, the selenosulfonylation adducts can be transformed into useful naphtho[2,1-b]furan and benzofuran scaffolds.

Organocatalytic Asymmetric Atroposelective Construction of Axially Chiral 1,4-Distyrene 2,3-Naphthalene Diols.

An efficient organocatalytic construction of enantioenriched axially chiral 1,4-distyrene 2,3-naphthalene diols through the nucleophilic addition of α-amido sulfone to in situ generated vinylidene o-quinone methide is described. The reaction pathway was investigated by isolating reaction intermediates and performing a kinetic resolution process. Axially chiral 1,4-distyrene 2,3-naphthalene diol was used as the chiral ligand for the enantioselective addition of diethylzinc to naphthalene formaldehyde. The preliminary results revealed that these adducts could be potentially used as ligands in asymmetric synthesis.

Enantioselective Synthesis of anti-syn-Trihalides and anti-syn-anti-Tetrahalides via Asymmetric ß-Elimination.

Structural motifs containing contiguous halide-bearing stereocenters are common in natural products as well as bioactive molecules. A few successful examples have been reported in the area of asymmetric vicinal dihalogenation of alkenes for accessing dihalogenated products; in this report, an alternative generation method of contiguous halide-bearing stereocenters α,ß,γ,δ relative to carbonyl group in excellent enantioselectivity is proposed by utilizing a Song's oligoEG catalyst-catalyzed asymmetric ß-elimination. According to this methodology, a wide range of anti-syn-trihalides and anti-syn-anti-tetrahalides with high levels of enantioselectivity were synthesized. The synthetic utility of the contiguous halide-bearing stereocenters was demonstrated by several transformations. The results of high-resolution mass spectrometry indicated that the favorable interaction between catalyst and one of the enantiomers of racemic contiguously multihalogenated ketone contributed to the original enantioselectivity of dehydrohalogenation. A deuterium kinetic isotope effect experiment revealed that this ß-elimination reaction proceeds by the E2 mechanism. This strategy opens a new pathway for the asymmetric synthesis of contiguous halide-bearing stereocenters of great complexity.

Asymmetric Synthesis of Trisubstituted Tetrahydrothiophenes via in Situ Generated Chiral Fluoride-Catalyzed Cascade Sulfa-Michael/Aldol Reaction of 1,4-Dithiane-2,5-diol and α,ß-Unsaturated Ketones.

A chiral fluoride-catalyzed asymmetric cascade sulfa-Michael/aldol condensation reaction of 1,4-dithiane-2,5-diol and a series of α,ß-unsaturated ketones is described to access chiral trisubstituted tetrahydrothiophene derivatives. The target products, including the spiro tetrahydrothiophene derivatives bearing a five-, six-, and seven-membered ring, were highly functionalized and showed high ee value. This established protocol realized a highly enantioselective reaction with a catalytic amount of KF and Song's chiral oligoEG via in situ generated chiral fluoride to construct useful heterocyclic skeletons with great complexity.

Neurophysiological and Neuropsychological Correlates of Subconscious Auditory Processing During Anesthesia and Their Implications in Anesthesia Awareness.

Like any other unusual state of consciousness, the condition of anesthesia remains a mystery, especially regarding the information processing events of the brain. Evoked potentials are the only known way to understand the neurophysiological events of brain in this condition. Auditory evoked potentials (AEPs) have been used as a measure of the depth of anesthesia during the intra-operative process. AEPs have been classically divided, on the basis of their latency, into first, fast, middle, slow, and late components. Auditory evoked potential has been advocated for the assessment of intra-operative awareness (IOA) but has not been considered seriously enough to be universalized. It is because we have not explored enough the impact of auditory perception and auditory information processing on the IOA phenomena as well as on the subsequent psychological impact of IOA on the patient. This limitation is because we have poor understanding of the subconscious auditory processing itself. This perspective is especially important because more of the IOA phenomena exist in the subconscious domain than they do in the conscious domain of explicit recall. Two important forms of these subconscious manifestations of IOA are the implicit recall phenomena and post-operative dreams related to the operation. Here we present a review of the neurophysiological and neuropsychological correlates of auditory processing during anesthesia. We start with a brief description of auditory awareness and the factors affecting it. Further, we proceed to the evaluation of conscious and subconscious information processing by auditory modality and how they interact during and after intra-operative period. Further, we show that both conscious and subconscious auditory processing affect the IOA experience and both have serious psychological implications on the patient subsequently. These effects could be prevented using auditory evoked potential during monitoring of anesthesia, especially the midlatency auditory evoked potentials. To conclude, we propose that the use of Auditory evoked potential should be universal with general anesthesia use in order to prevent the occurrences of distressing outcomes resulting from both conscious and subconscious auditory processing during anesthesia.

ß-Lactam Antibiotics Renaissance.

Since the 1940s ß-lactam antibiotics have been used to treat bacterial infections. However, emergence and dissemination of ß-lactam resistance has reached the point where many marketed ß-lactams no longer are clinically effective. The increasing prevalence of multidrug-resistant bacteria and the progressive withdrawal of pharmaceutical companies from antibiotic research have evoked a strong reaction from health authorities, who have implemented initiatives to encourage the discovery of new antibacterials. Despite this gloomy scenario, several novel ß-lactam antibiotics and ß-lactamase inhibitors have recently progressed into clinical trials, and many more such compounds are being investigated. Here we seek to provide highlights of recent developments relating to the discovery of novel ß-lactam antibiotics and ß-lactamase inhibitors.

Schiff bases: a short survey on an evergreen chemistry tool.

The review reports a short biography of the Italian naturalized chemist Hugo Schiff and an outline on the synthesis and use of his most popular discovery: the imines, very well known and popular as Schiff Bases. Recent developments on their "metallo-imines" variants have been described. The applications of Schiff bases in organic synthesis as partner in Staudinger and hetero Diels-Alder reactions, as "privileged" ligands in the organometallic complexes and as biological active Schiff intermediates/targets have been reported as well.