Column asymmetric catalysis for beta-lactam synthesis

[structure] A catalytic asymmetric reaction process was designed involving the use of solid-phase reagents and catalysts that constitute the packing of a series of "reaction columns". This process was applied to the catalytic asymmetric synthesis of beta-lactams, yielding pure product after crystallization with exceptional enantio- and diastereoselectivity.     

Pyran annulation: asymmetric synthesis of 2,6-disubstituted-4-methylene tetrahydropyrans

[reaction: see text] A reaction process for the asymmetric construction of a variety of cis or trans disubstituted pyrans is described. This sequences allows for the asymmetric convergent union of two aldehydes with silyl-stannane reagent 1 in a two-step process: catalytic asymmetric allylation of the first aldehyde using 1 with a BITIP catalyst, followed by reaction of the alcohol so obtained with a second aldehyde and TMSOTf.     

A new entry to Pd-H chemistry: catalytic asymmetric conjugate reduction of enones with EtOH and a highly enantioselective synthesis of warfarin

[reaction: see text] We report here the catalytic asymmetric conjugate reduction of enones using ethanol as a hydride source. The reaction was carried out in the presence of a chiral Pd complex at ambient temperature in ethanol, and the desired products were obtained in high chemical yield and high enantioselectivity. We applied this novel reaction to the catalytic asymmetric synthesis of warfarin (96% ee), and on the basis of d-labeling experiments, the reaction mechanism is proposed.     

Generation of ketenes from acid chlorides using NaH/crown ether shuttle-deprotonation for use in asymmetric catalysis

[reaction: see text] We describe methodology for the in situ generation of reactive monosubstituted ketenes from acid chlorides through a shuttle deprotonation process using NaH as an inexpensive stoichiometric base and a crown ether cocatalyst. We have successfully applied this new procedure to the catalytic, asymmetric synthesis of beta-lactams and alpha-haloesters.     

Catalytic Asymmetric [ 2,3 ] -Sigmatropic Rearrangement of Sulfur Ylides Generated from Carbenoids

The catalytic asymmetric reactions of oxygen or sulfur ylides generated from carbenoids have attracted consider able attention in recent years. High enantioselectivities have been achieved in the 1,3-dipolar cycloaddition reactions and [ 2,3 ]-sigmatropic rearrangement of oxygen ylides. In contrast to the oxygen ylide, the corresponding catalytic asymmetric reaction of sulfur ylide is less developed. Compared to oxygen ylides, the sulfur ylides are more stable and experimental evidence supports a free ylide rather than a metal-bound ylide as reaction intermediate. That means the enantio-control must be in the step of the ylide formation. If the subsequent reaction such as [ 2,3 ]-sigmatropic rearrangement or 1,3-dipolar cycloaddition is a concerted process and is faster than the racemization of the chiral ylide intermediate, then the catalytic asymmetric sulfur ylide reaction will be possible.     

An anionic nucleophilic catalyst system for the diastereoselective synthesis of trans-beta-lactams

Trans-disubstituted beta-lactams show increasing utility and prominence in numerous pharmaceutical applications, making their asymmetric synthesis an attractive goal for chemists. We introduce an anionic, nucleophilic catalyst system that provides an efficient, diastereoselective route to trans-disubstituted beta-lactams, a complement to our previously described catalytic methodology for generating the corresponding cis diastereomers. This catalytic, "switch mechanism" process allows for flexibility in the stereoselective synthesis of beta-lactams, producing either cis or trans products as desired from the same substrates. [reaction: see text]     

Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones

We describe the development of a highly efficient catalytic asymmetric conjugate addition to α,β-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to α,β-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.     

Rhodium-catalyzed enantioselective diboration of simple alkenes

Enantioselective catalytic reactions that operate directly on inexpensive unactivated alkenes are extraordinarily useful for the preparation of chiral organic building blocks and new materials. While a number of such processes have been developed, our ability to meet the intensifying demand for inexpensive stereochemically complex materials will require a significant expansion of practical catalytic asymmetric reaction methodology. In this regard, the rhodium-catalyzed enantioselective diboration reaction has been developed in order to address a number of extant problems in catalytic alkene transformation simultaneously. This process provides an enantiomerically enriched reactive dimetalated intermediate which can be converted to a variety of difunctional reaction products.     

Enantioselective syntheses of aeruginosin 298-A and its analogues using a catalytic asymmetric phase-transfer reaction and epoxidation

We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogues, in which all stereocenters were controlled by a catalytic asymmetric phase-transfer reaction and epoxidation. Furthermore, drastic counteranion effects in phase-transfer catalysis were observed for the first time, making it possible to three-dimensionally fine-tune the catalyst (ketal part, aromatic part, and counteranion).     

Catalytic asymmetric epoxidation of alpha,beta-unsaturated amides: efficient synthesis of beta-aryl alpha-hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process

The catalytic asymmetric epoxidation of alpha,beta-unsaturated amides using Sm-BINOL-Ph3As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst, a variety of amides were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process, was developed. This method was successfully utilized for the efficient synthesis of beta-aryl alpha-hydroxy amides, including beta-aryllactyl-leucine methyl esters. Interestingly, it was found that beneficial modifications on the Pd catalyst were achieved by the constituents of the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed epoxide opening reaction in terms of chemoselectivity.     

Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient

The continuous flow, enantioselective, organophotoredox catalytic asymmetric alkylation of aldehydes was studied, by using a homemade, custom-designed photoreactor for reactions under cryogenic conditions. Going from microfluidic conditions up to a 10 mL mesofluidic reactor, an increase of productivity by almost 18000 % compared to the batch reaction was demonstrated. Finally, for the first time, a stereoselective photoredox organocatalytic continuous flow reaction in a fully telescoped process for an active pharmaceutical ingredient (API)synthesis was successfully achieved. The final process consists of four units of operation: visible light-driven asymmetric catalytic benzylation under continuous flow, inline continuous work-up, neutralisation and a final oxidative amidation step afforded the pharmaceutically active molecule in 95 % e.e.     

A new method for translating the asymmetric Ni/Cr-mediated coupling reactions from stoichiometric to catalytic

[reaction: see text] A new method has been developed for effectively translating the degree of asymmetric induction and the chemical yield achieved in the stoichiometric asymmetric Ni/Cr-mediated coupling to a catalytic asymmetric process via a chiral sulfonamide ligand. It has also been shown that the Ni catalyst plays a central role. Among a number of the Ni catalysts, the 2,9-dimethylphenanthroline/NiCl(2) complex (7) has been found to be the most effective.     

The state of the art in asymmetric induction: the aldol reaction as a case study

This review highlights the achievements in asymmetric induction in the context of the aldol reaction during the years 2003–2007. While chiral auxiliary-mediated methods are the best understood and developed, catalytic methods based on chiral metal–ligand complexes and more recently organocatalysts promise to improve the efficacy and economics of asymmetric induction. This review provides a brief summary of work prior to 2003 on chiral auxiliaries, metal catalysts and organocatalysts, and then delineates the state of the art in each process. It appears that no one method of achieving asymmetric induction in the aldol reaction is universally superior.     

Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis

Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels–Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid–Cu²⁺ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities.     

Catalytic, asymmetric transannular aldolizations: total synthesis of (+)-hirsutene

We report an asymmetric, catalytic transannular aldolization that provides polycyclic products useful for natural product synthesis. We found that a proline-derivative catalyzes the transannular aldol reaction of 1,4-cyclooctanediones to the corresponding cyclic beta-hydroxy ketones in good yields and with high enantioselectivities. The utility of our reaction has been demonstrated in a total synthesis of (+)-hirustene.     

An Asymmetric Hydrogenation/N-Alkylation Sequence for a Step-Economical Route to Indolizidines and Quinolizidines

The direct catalytic asymmetric hydrogenation of pyridines for the synthesis of piperidines remains a challenge. Herein, we report a one-pot asymmetric hydrogenation of pyridines with subsequent N-alkylation using a traceless Brønsted acid activation strategy. Catalyzed by an iridium-BINAP complex, the substrates undergo ketone reduction, cyclization and pyridine hydrogenation in sequence to form indolizidines and quinolizidines. The absolute configuration of the stereocenter of the alcohol is retained and influences the formation of the second stereocenter. Experimental and theoretical mechanistic studies reveal that the chloride anion and certain noncovalent interactions govern the stereoselectivity of the cascade reaction throughout the catalytic process.     

Merging Aerobic Oxidation and Enamine Catalysis in the Asymmetric α‐Amination of β‐Ketocarbonyls Using N‐Hydroxycarbamates as Nitrogen Sources

We describe herein an unprecedented asymmetric α‐amination of β‐ketocarbonyls under aerobic conditions. The process is enabled by a simple chiral primary amine through the coupling of a catalytic enamine ester intermediate and a nitrosocarbonyl (generated in situ) derived from N‐hydroxycarbamate. The reaction features high chemoselectivity and excellent enantioselectivity for a broad range of substrates.     

手性炔丙醇的不对称催化合成研究进展

手性炔丙醇是一种重要中间体化合物,作为合成多种光学活性化合物的重要合成前体受到学者们广泛关注。目前通过酮的不对称催化反应合成手性炔丙醇的研究开发具有极大发展前景,因此本文围绕酮类化合物的不对称催化反应来进行综述,结合相关反应最新研究进展,全面总结并分类了不对称催化还原、催化不对称加成等反应类型,介绍了合成不同结构手性炔丙醇的新思路,并对酮的不对称催化反应在未来能成为工业化重要生产途径作出展望。     

Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of Fluorinated Olefins

The development of new general methods for the synthesis of chiral fluorine‐containing molecules is important for several scientific disciplines. We herein disclose a straightforward method for the preparation of chiral organofluorine molecules that is based on the iridium‐catalyzed asymmetric hydrogenation of trisubstituted alkenyl fluorides. This catalytic asymmetric process enables the synthesis of chiral fluorine molecules with or without carbonyl substitution. Owing to the tunable steric and electronic properties of the azabicyclo thiazole‐phosphine iridium catalyst, this stereoselective reaction could be optimized and was found to be compatible with various aromatic, aliphatic, and heterocyclic systems with a variety of functional groups, providing the highly desirable products in excellent yields and enantioselectivities.     

A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH₃CN)₄]PF₆/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Brønsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor^®: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol.