Photo‐Organocatalytic Enantioselective Radical Cascade Reactions of Unactivated Olefins

Radical cascade processes are invaluable for their ability to rapidly construct complex chiral molecules from simple substrates. However, implementing catalytic asymmetric variants is difficult. Reported herein is a visible‐light‐mediated organocatalytic strategy that exploits the excited‐state reactivity of chiral iminium ions to trigger radical cascade reactions with high enantioselectivity. By combining two sequential radical‐based bond‐forming events, the method converts unactivated olefins and α,β‐unsaturated aldehydes into chiral adducts in a single step. The implementation of an asymmetric three‐component radical cascade further demonstrates the complexity‐generating power of this photochemical strategy.     

The homo‐PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α‐Oxo‐ or α‐Hydroxy‐γ‐acylaminoamides and Chromanes

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α‐oxo‐γ‐acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection–acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo‐Passerini–amine deprotection–acyl migration (PADAM) strategy. Highly stereoselective reduction of the α‐oxo‐γ‐acylaminoamides afforded α‐hydroxy‐γ‐acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.     

钯配合物催化烯烃氧化合成酮类物质的研究进展

本文系统地评述了钯配合物催化烯烃氧化合成酮类物质的研究进展。综述了改进Wacker 类催化剂催化活性的几种方法。总结了烯烃氧化合成酮类物质反应的几种典型催化体系及其作用机理。着重介绍了Pd (Ⅱ) HPA (杂多酸)、Pd (Ⅱ) FePc (酞菁铁)、Pd (Ⅱ) HQ (氢醌) FePc、Pd (Ⅱ) HQHPA、Pd (Ⅱ) CuSO₄ HPA 等Wacker 类催化体系在烯烃氧化合成酮类物质中的应用; 对Pd (Ⅱ) LCoNO₂、PdCl₂(MeCN)₂ CuCl、Pd (OAc)₂ 吡啶、氟两相等非Wacker 类催化体系在烯烃氧化合成酮类物质中的应用也作了讨论。     

Radical Cyclization of Alkene‐Tethered Ketones Initiated by Hydrogen‐Atom Transfer

An unprecedented C?C coupling reaction between alkenes and ketones by hydrogen‐atom transfer, using Fe(acac)₃ and PhSiH₃ in EtOH, is described. This mild protocol features high site selectivity and allows the construction of sterically congested structures containing tertiary alcohols and quaternary centers. The overall process introduces a novel strategic bond disconnection for ring‐closing reactions.     

Radical Acylfluoroalkylation of Olefins through N‐Heterocyclic Carbene Organocatalysis

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N‐heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late‐stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.     

Peptide‐Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide

The tripeptide H‐d Pro‐Pro‐Asn‐NH₂ is presented as a catalyst for asymmetric conjugate addition reactions of aldehydes to maleimide. The peptidic catalyst promotes the reaction between various aldehydes and unprotected maleimide with high stereoselectivities and yields. The obtained products were readily derivatized to the corresponding pyrrolidines, lactams, lactones, and peptide‐like compounds. ¹H NMR spectroscopic, crystallographic, and computational investigations provided insight into the conformational properties of H‐d Pro‐Pro‐Asn‐NH₂ and revealed the importance of hydrogen bonding between the peptide and maleimide for catalyzing the stereoselective C?C bond formation.     

Me2Zn‐Mediated Catalytic Enantio‐ and Diastereoselective Addition of TosMIC to Ketones

The first catalytic asymmetric addition of TosMIC to unactivated ketones is presented. A combination of Me₂Zn and aminoalcohol catalyst promoted the aldol addition/cyclization reaction to render oxazolines possessing a fully substituted stereocenter with excellent yields (up to 92 %), high enantioselectivities (up to 96 %), and complete diastereoselectivity. The chiral oxazolines were then used to give, after a straightforward acid hydrolysis, enantioenriched building blocks bearing tertiary alcohol motifs such as hydroxylaldehydes, hydroxylacids, and hydroxylesters without racemization.     

Copper‐Catalyzed Aerobic Oxidative CC Bond Cleavage for CN Bond Formation: From Ketones to Amides

A novel copper‐catalyzed aerobic oxidative C(CO)? C(alkyl) bond cleavage reaction of aryl alkyl ketones for C? N bond formation is described. A series of acetophenone derivatives as well as more challenging aryl ketones with long‐chain alkyl substituents could be selectively cleaved and converted into the corresponding amides, which are frequently found in biologically active compounds and pharmaceuticals.     

Rhodium‐Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

We describe the synthetically useful enantioselective addition of Br−CX₃ (X=Cl or Br) to terminal olefins to introduce a trihalomethyl group and generate optically active secondary bromides. Computational and experimental evidence supports an asymmetric atom‐transfer radical addition (ATRA) mechanism in which the stereodetermining step involves outer‐sphere bromine abstraction from a [(bisphosphine)Rh^IIBrCl] complex by a benzylic radical intermediate. This mechanism appears unprecedented in asymmetric catalysis.     

Microwave‐Assisted Copper‐Catalyzed Oxidative Cyclization of Acrylamides with Non‐Activated Ketones

An operationally simple and efficient microwave‐assisted protocol for the oxidative cyclization of acrylamide derivatives with non‐activated ketones to generate 3,3‐disubstituted oxindoles is described. The reaction proceeds by a copper‐catalyzed tandem radical addition/cyclization strategy and tolerates a series of functional groups with moderate to excellent yields.     

Brønsted Acid‐Catalyzed,Highly Enantioselective Addition of Enamides to In Situ‐Generated ortho‐Quinone Methides: A Domino Approach to Complex Acetamidotetrahydroxanthenes

The highly enantioselective conjugate addition of enamides and enecarbamates to in situ‐generated ortho‐quinone methides, upon subsequent N,O‐acetalization, gives rise to acetamido‐substituted tetrahydroxanthenes with generally excellent enantio‐ and diastereoselectivities. A chiral BINOL‐based phosphoric acid catalyst controls the enantioselectivity of the carbon–carbon bond‐forming event. The products are readily converted into other xanthene‐based heterocycles.     

Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes

β,γ‐Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β‐γ‐unsaturated ketones through 1,2‐addition of α‐carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)‐trichostatin A, a histone deacetylase inhibitor.     

Photoinduced Radical Borylation of Alkyl Bromides Catalyzed by 4‐Phenylpyridine

Utilizing pyridine catalysis, we developed a visible‐light‐induced transition‐metal‐free radical borylation reaction of unactivated alkyl bromides that features a broad substrate scope and mild reaction conditions. Mechanistic studies revealed a novel nucleophilic substitution/photoinduced radical formation pathway, which could be utilized to trigger a variety of radical processes.     

Titanocene(III)‐Catalyzed Three‐Component Reaction of Secondary Amides,Aldehydes, and Electrophilic Alkenes

An umpolung Mannich‐type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one‐pot formation of C? N and C? C bonds by a titanocene‐catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N‐substituted γ‐amido‐acid derivatives and γ‐amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α‐amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.