Development of a concise synthesis of (-)-oseltamivir (Tamiflu)

We report a full account of our work towards the development of an eight‐step synthesis of anti‐influenza drug (?)‐oseltamivir (Tamiflu) from commercially available starting materials. The final synthetic route proceeds with an overall yield of 30 %. Key transformations include a novel palladium‐catalyzed asymmetric allylic alkylation reaction (Pd‐AAA) as well as a rhodium‐catalyzed chemo‐, regio‐, and stereoselective aziridination reaction.     

Stereoconvergent,Redox‐Neutral Access to Tetrahydroquinoxalines through Relay Epoxide Opening/Amination of Alcohols

We present an economical catalytic procedure to convert readily available 1,2‐diaminobenzenes and terminal epoxides into valuable 1,2,3,4‐tetrahydroquinoxalines in a highly enantioselective fashion. This procedure operates through relay zinc and iridium catalysis, and achieves redox‐neutral and stereoconvergent production of valuable chiral heterocycles from racemic starting materials with water as the only side product. The use of commercially available reagents and catalysts and a convenient procedure also make this catalytic method attractive for practical application.     

Enantioselective Preparation of Arenes with β‐Stereogenic Centers: Confronting the 1,1‐Disubstituted Olefin Problem Using CuH/Pd Cooperative Catalysis

Arenes with β‐stereogenic centers are important substructures in pharmaceuticals and natural products. We have developed an asymmetric anti‐Markovnikov hydroarylation of 1,1‐disubstituted olefins by dual palladium and copper hydride catalysis as a convenient and general approach to access these substructures. This efficient one‐step process addresses several limitations of the traditional stepwise approaches. The use of cesium benzoate as a base and a common phosphine ligand for both the Cu‐ and Pd‐catalyzed processes were important discoveries that allow these challenging olefin substrates to be efficiently transformed. A variety of aryl bromide coupling partners, including numerous heterocycles, were coupled with 1,1‐disubstituted alkenes to generate arenes with β‐stereogenic centers.     

Pd‐Catalyzed Asymmetric Intramolecular Arylative Dearomatization of para‐Aminophenols†

Asymmetric arylative dearomatization reactions of para‐aminophenols are realized by a Pd‐catalyst consisting of a TADDOL (α,α,α',α'‐tetraaryl‐2,2‐disubstituted 1,3‐dioxolane‐4,5‐dimethanol)‐derived chiral phosphoramidite ligand. The tetracyclic products bearing the key skeleton of Erythrina alkaloids are afforded in reasonable yields (up to 73%) with good to excellent enantioselectivity (up to 97% ee). Concise total synthesis of (–)‐3‐demethoxyerythratidinone is achieved by employing this method as the key step.     

Asymmetric Wacker‐Type Oxyallenylation and Azaallenylation of Cyclic Alkenes

Palladium‐catalyzed three‐component carboetherification of cyclic alkenes proceeded to give trans adducts exclusively with excellent enantioselectivity through a Wacker‐type pathway. The reaction is also applicable to other oxygen nucleophiles, such as water, phenols, and carboxylic acids, as well as some electron‐poor aryl amines.     

Lewis碱协助的 Lewis酸催化醇脱水合成烯烃及二氢吡喃开环合成2-肉桂基取代1,3-二羰基化合物

醇脱水是合成烯烃的重要方法之一。全球每年约有15%的苯乙烯是通过1-苯乙醇在酸性条件下脱水反应生产。虽然人们对该反应进行了较为深入的研究,但是当使用活性较高的1-苯乙醇衍生物为底物时,由于得到的取代苯乙烯产物具有较高的反应性,在脱水过程中会发生聚合而导致反应选择性降低,因此有必要探索适宜在高活性1-苯基乙醇脱水反应中应用的催化剂体系。
　　本文借助酸碱协同催化方法考察了1-(4-甲氧基苯基)乙醇制备4-甲氧基苯乙烯的反应。发现三苯基磷与 AlCl3构建的 Lewis碱/Lewis酸协同催化体系在硝基甲烷中可以接近定量的收率得到4-甲氧基苯乙烯。 Lewis碱/Lewis酸协同催化体系有效避免了4-甲氧基苯乙烯的二聚现象。底物拓展研究显示该方法具有很好的底物普适性,对多种取代苯乙烯的收率均超过80%。机理研究表明,1-(4-甲氧基苯基)乙醇在酸作用下先生成碳正离子,三苯基磷作为偶极性的电子给体不但能在一定程度上稳定该苄基碳正离子,而且抑制了其与4-甲氧基苯乙烯之间的亲电反应,进而最大化了脱质子生成4-甲氧基苯乙烯的选择性。
　　将Lewis碱协助的 Lewis酸催化提高反应选择性策略用于2-苯基-3,4-二氢吡喃衍生物合成2-肉桂基-1,3-二羰基化合物的开环反应。该类取代二氢吡喃在酸催化剂作用下也可生成苄基碳正离子,但是该中间体易受分子间和分子内亲电反应影响,反应选择性不高。而当使用单质碘/三苯基磷协同催化体系时,2-苯基-3,4-二氢吡喃衍生物能高选择性地实现开环反应,得到反式2-肉桂基-1,3-二羰基化合物。该类1,3-二羰基化合物具有丰富的反应性,是一类重要的合成子。     

Cooperative Dehydrogenation of N‐Heterocycles Using a Carbon Nanotube–Rhodium Nanohybrid

Rhodium nanoparticles were anchored on carbon nanotubes and the resulting nanohybrid was studied as co‐catalyst, along with tert‐butylcatechol, for the dehydrogenation of various N‐heterocycles. The co‐catalytic system operates in high yields, under the mildest conditions reported so far, and can be applied to a wide variety of secondary amine‐containing scaffolds.     

Phosphoramidites: Privileged Ligands in Asymmetric Catalysis

Asymmetric catalysis with transition‐metal complexes is the basis for a vast array of stereoselective transformations and has changed the face of modern synthetic chemistry. Key to this success has been the design of chiral ligands to control the regio‐, diastereo‐, and enantioselectivity. Phosphoramidites have emerged as a highly versatile and readily accessible class of chiral ligands. Their modular structure enables the formation of ligand libraries and easy fine‐tuning for a specific catalytic reaction. Phosphoramidites frequently show exceptional levels of stereocontrol, and their monodentate nature is essential in combinatorial catalysis, where a ligand‐mixture approach is used. In this Review, recent developments in asymmetric catalysis with phosphoramidites used as ligands are discussed, with a focus on the formation of carbon–carbon and carbon–heteroatom bonds.     

Polymer‐Supported Enantioselective Bifunctional Catalysts for Nitro‐Michael Addition of Ketones and Aldehydes

Introduction of an L ‐amino acid as a spacer and a urea‐forming moiety in a polymer‐supported bifunctional urea–primary amine catalyst, based on (1R, 2R)‐(+)‐1,2‐diphenylethylenediamine, significantly improves the catalyst’s activity and stereoselectivity in the asymmetric addition of ketones and aldehydes to nitroolefins. Yields and enantioselectivities, unprecedented for immobilized catalysts, were obtained with such challenging donors as acetone, cyclopentanone, and α,α‐disubstituted aldehydes, which usually perform inadequately in this reaction (particularly when a secondary‐amine‐based catalyst is used). Remarkably, though in the examined catalysts the D ‐amino acids as spacers were significantly inferior to the L isomers, for the chosen configuration of the diamine (match–mismatch pairs) the size of the side chain of the amino acid hardly influenced the enantioselectivity of the catalyst. These results, combined with the reactivity profile of the catalysts with substrates bearing two electron‐withdrawing groups and the behavior of the catalysts’ analogues based on tertiary (rather than primary) amine, suggest an enamine‐involving addition mechanism and a particular ordered C? C bond‐forming transition state as being responsible for the catalytic reactions with high enantioselectivity.     

Asymmetric Radical–Radical Cross‐Coupling through Visible‐Light‐Activated Iridium Catalysis

Combining single electron transfer between a donor substrate and a catalyst‐activated acceptor substrate with a stereocontrolled radical–radical recombination enables the visible‐light‐driven catalytic enantio‐ and diastereoselective synthesis of 1,2‐amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99 % ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C? C bond formation mediated by single electron transfer.     

Highly Enantioselective Iron‐Catalyzed cis‐Dihydroxylation of Alkenes with Hydrogen Peroxide Oxidant via an FeIII‐OOH Reactive Intermediate

The development of environmentally benign catalysts for highly enantioselective asymmetric cis‐dihydroxylation (AD) of alkenes with broad substrate scope remains a challenge. By employing [Fe^II(L)(OTf)₂] (L=N,N′‐dimethyl‐N,N′‐bis(2‐methyl‐8‐quinolyl)‐cyclohexane‐1,2‐diamine) as a catalyst, cis‐diols in up to 99.8 % ee with 85 % isolated yield have been achieved in AD of alkenes with H₂O₂ as an oxidant and alkenes in a limiting amount. This “[Fe^II(L)(OTf)₂]+H₂O₂” method is applicable to both (E)‐alkenes and terminal alkenes (24 examples >80 % ee, up to 1 g scale). Mechanistic studies, including ¹⁸O‐labeling, UV/Vis, EPR, ESI‐MS analyses, and DFT calculations lend evidence for the involvement of chiral Fe^III‐OOH active species in enantioselective formation of the two C?O bonds.     

Asymmetric Phase‐Transfer‐Catalyzed Intramolecular N‐Alkylation of Indoles and Pyrroles: A Combined Experimental and Theoretical Investigation

Asymmetric phase‐transfer catalysis (PTC) has risen to prominence over the last decade as a straightforward synthetic methodology for the preparation of pharmacologically active compounds in enantiomerically pure form. However, the complex interplay of weak nonbonded interactions (between catalyst and substrate) that could account for the stereoselection in these processes is still unclear, with tentative pictorial mechanistic representations usually proposed. Here we present a full account dealing with the enantioselective phase‐transfer‐catalyzed intramolecular aza‐Michael reaction (IMAMR) of indolyl esters, as a valuable synthetic tool to obtain added‐value compounds, such as dihydro‐pyrazinoindolinones. A combined computational and experimental investigation has been carried out to elucidate the key mechanistic aspects of this process.     

Direct Regiospecific and Highly Enantioselective Intermolecular α‐Allylic Alkylation of Aldehydes by a Combination of Transition‐Metal and Chiral Amine Catalysts

The first direct intermolecular regiospecific and highly enantioselective α‐allylic alkylation of linear aldehydes by a combination of achiral bench‐stable Pd⁰ complexes and simple chiral amines as co‐catalysts is disclosed. The co‐catalytic asymmetric chemoselective and regiospecific α‐allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2‐alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2‐alkyl substituted hemiacetals, 2‐alkyl‐butane‐1,4‐diols, and amines. The concise co‐catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

From Waste Biomass to Solid Support: Lignosulfonate as a Cost‐Effective and Renewable Supporting Material for Catalysis

Lignosulfonate (LS) is an organic waste generated as a byproduct of the cooking process in sulfite pulping in the manufacture of paper. In this paper, LS was used as an anionic supporting material for immobilizing cationic species, which can then be used as heterogeneous catalysts in some organic transformations. With this strategy, three lignin‐supported catalysts were prepared including 1) lignin‐SO₃Sc(OTf)₂, 2) lignin‐SO₃Cu(OTf), and 3) lignin‐IL@NH₂ (IL=ionic liquid). These solid materials were then examined in many organic transformations. It was finally found that, compared with its homogeneous counterpart as well as some other solid catalysts that are prepared by using different supports with the same metal or catalytically active species, the lignin‐supported catalysts showed better performance in these reactions not only in terms of activity but also with regard to recyclability.     

Using Soluble Polymers to Enforce Catalyst‐Phase‐Selective Solubility and as Antileaching Agents to Facilitate Homogeneous Catalysis

The enforced phase‐selective solubility of polyisobutylene (PIB)‐bound Rh^II catalysts in biphasic heptane/acetonitrile mixtures can be used not only to recycle these catalysts but also to minimize bimolecular reactions with ethyl diazoacetate. When cyclopropanation and O? H insertion reactions are carried out with PIB‐bound Rh^II catalysts either with or without addition of an unfunctionalized hydrocarbon polymer cosolvent, dimer by‐product formation is suppressed even without slow syringe pump addition of the ethyl diazoacetate. This suppression of by‐product formation is shown to be due to increased phase segregation of the soluble polymer‐bound catalyst and the ethyl diazoacetate reactant. These studies also reveal that added hydrocarbon polymer cosolvents can function as antileaching agents, decreasing the already small amount of a soluble polymer‐bound species that leaches into a polar phase in a biphasic mixture during a liquid/liquid separation step.     

Asymmetric Allylation of Ketones and Subsequent Tandem Reactions Catalyzed by a Novel Polymer‐Supported Titanium–BINOLate Complex

By using a novel, simple, and convenient synthetic route, enantiopure 6‐ethynyl‐BINOL (BINOL=1,1‐binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper‐catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The polystyrene (PS)‐supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert‐butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson–Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co₂(CO)₈/N‐methyl morpholine N‐oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.     

Asymmetric Gold‐Catalyzed Lactonizations in Water at Room Temperature

Asymmetric gold‐catalyzed hydrocarboxylations are reported that show broad substrate scope. The hydrophobic effect associated with in situ‐formed aqueous nanomicelles gives good to excellent ee’s of product lactones. In‐flask product isolation, along with the recycling of the catalyst and the reaction medium, are combined to arrive at an especially environmentally friendly process.     

Catalytic Asymmetric Phase‐Transfer Michael Reaction and Mannich‐Type Reaction of Glycine Schiff Bases with Tartrate‐Derived Diammonium Salts

Catalytic asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with chiral two‐center organocatalysts, tartrate‐derived diammonium salts (TaDiASs), are described. On the basis of conformational studies, optimized TaDiASs with a 2,6‐disubstituted cyclohexane spiroacetal were newly designed. These TaDiASs catalyzed the asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with higher enantioselectivity than previous catalysts. In the Mannich‐type reaction, aromatic N‐Boc‐protected imines (Boc=tert‐butoxycarbonyl) as well as enolizable alkyl imines were applicable. As a synthetic application of the catalytic asymmetric Mannich‐type reaction with the optimized TaDiASs, we developed a catalytic asymmetric total synthesis of (+)‐nemonapride, which is an antipsychotic agent.     

Amide Synthesis by Nickel/Photoredox‐Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides

Herein, we report a one‐electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross‐coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive‐functional‐group‐containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron‐poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.