Enantioselective Allylboration of Acetylene: A Versatile Tool for the Stereodivergent Synthesis of Natural Products.

Efficient catalytic methods that allow the use of simple and abundant chemical feedstocks for the preparation of synthetically versatile compounds are central to modern synthetic chemistry. Acetylene is a basic feedstock with a remarkable production over one million tons per year, although it is underutilized in the stereoselective synthesis of fine chemicals. Here we report a facile catalytic multicomponent reaction that allows for the enantio- and diastereoselective allylboration of acetylene gas. This process is catalyzed by a chiral copper catalyst, operates without specialized equipment or pressurization, and provides chiral skipped dienes bearing stereodefined and orthogonally functionalized olefins with excellent levels of chemo-, regio-, enantio- and diastereoselectivity. The combined stereochemical features and orthogonal functionalization make the products privileged structural scaffolds to access the complete set of stereoisomers of the chiral skipped diene core through simple enantio- and diastereodivergent pathways. The utility of the method is demonstrated with the enantioselective synthesis of three bioactive natural skipped diene products, namely (+)-Nyasol, (+)-Hinokiresinol and Phorbasin C, and other related synthetically relevant chiral molecules.

Enantioselective Synthesis of α-Chiral Bicyclo[1.1.1]pentanes via Multicomponent Asymmetric Allylic Alkylation.

Bicyclo[1.1.1]pentanes (BCPs) have emerged as important structural motifs in drug design. However, asymmetric transformations that provide chiral BCPs bearing an adjacent stereocenter are still scarce. Here, we report a catalytic methodology for the enantioselective synthesis of α-chiral 1,3-difunctionalized BCPs from a three-component coupling of [1.1.1]propellane, a Grignard reagent, and an allylic phosphate. The reaction proceeds via the addition of the Grignard reagent to [1.1.1]propellane followed by an asymmetric N-heterocyclic carbene (NHC)-catalyzed allylic substitution of the resulting BCP-Grignard, providing a broad range of α-chiral BCPs with excellent levels of regioselectivity and enantioselectivity.

Enantioselective synthesis of chiral BCPs.

Bicyclo[1.1.1]pentanes (BCPs) have emerged as an interesting scaffold in drug design. These strained molecules can act as bioisosteres of para-substituted phenyl rings, tert-butyl groups or internal alkynes, leading to drug analogues with enhanced pharmacokinetic and physicochemical properties. Thus, catalytic methodologies for the synthesis of BCPs represent a major goal in modern organic synthesis. In particular, asymmetric transformations that provide chiral BCPs bearing an adjacent stereocenter are particularly valuable to expand the chemical space of this important scaffold. In this article, we discuss the available methodologies for the asymmetric synthesis of α-chiral BCPs, their key mechanistic features and their application in bioisosteric replacements in drug design.

Catalytic Alkyne Allylboration: A Quest for Selectivity.

Catalytic methodologies that enable the synthesis of complex organic molecules from simple and readily available starting materials represent a goal in modern synthetic chemistry. In particular, multicomponent carboboration reactions that provide stereoselective access to densely functionalized building blocks are particularly valuable to achieve molecular diversity. This Perspective covers the developments in the area of catalytic allylboration of alkynes and highlights the key features that have allowed for the control of the regio-, diastereo-, and enantioselectivity in these transformations.

C-C bond formation via photocatalytic direct functionalization of simple alkanes.

The direct functionalization of alkanes represents a very important challenge in the goal to develop more atom-efficient and clean C-C bond forming reactions. These processes, however, are hampered by the low reactivity of the aliphatic C-H bonds. Photocatalytic processes based on hydrogen atom transfer C-H bond activation strategies have become a useful tool to activate and functionalize these inert compounds. In this article, we summarize the main achievements in this field applied to the development of C-C bond forming reactions, and we discuss the key mechanistic features that enable these transformations.

Copper-Catalyzed Enantioselective Borylative Allyl-Allyl Coupling of Allenes and Allylic gem-Dichlorides.

A catalytic asymmetric reaction between allenes, bis(pinacolato)diboron, and allylic gem-dichlorides is reported. The method involves the coupling of a catalytically generated allyl copper species with the allylic gem-dichloride and provides chiral internal 1,5-dienes featuring (Z)-configured alkenyl boronate and alkenyl chloride units with high levels of chemo-, regio-, enantio-, and diastereoselectivity. The synthetic utility of the products is demonstrated with the synthesis of a range of optically active compounds. DFT calculations reveal key noncovalent substrate-ligand interactions that account for the enantioselectivity outcome and the diastereoselective formation of the (Z)-alkenyl chloride.

Bifunctional Skipped Dienes through Cu/Pd-Catalyzed Allylboration of Alkynes with B2pin2 and Vinyl Epoxides.

A method for the use of vinyl epoxides in catalytic allylboration of alkynes is described. This transformation allows for the synthesis of bifunctional skipped dienes bearing both an allylic alcohol and an alkenylboronate from simple starting materials with high regio- and stereoselectivity. These two functionalities provide these products with highly versatile reactivity, as shown by their stereocontrolled conversion into cyclic boron compounds and polyenes.

Direct C-H Allylation of Unactivated Alkanes by Cooperative W/Cu Photocatalysis.

Here we report a photocatalytic methodology that enables the direct allylation of strong aliphatic C-H bonds with simple allylic chlorides. The method relies on a cooperative interaction of two metal catalysts in which the decatungstate anion acts as a hydrogen-atom abstractor generating a nucleophilic carbon-centered radical that engages in an SH2' reaction with an activated allylic π-olefin-copper complex. Because of this dual catalysis, the protocol allows for the functionalization of a range of chemical feedstocks and natural products under mild conditions in short reaction times.

Catalytic Lewis Base Additive Enables Selective Copper-Catalyzed Borylative α-C-H Allylation of Alicyclic Amines.

Functionalized alicyclic amines are important building blocks for the synthesis of bioactive natural compounds and drugs. Existing methods of functionalization are typically limited to the synthesis of protected amines or the use of highly basic organometallic reagents that can compromise functional group tolerance. Here, we report a novel approach that enables the transformation of O-benzoyl hydroxylamines into α-functionalized cyclic secondary amines by means of a copper-catalyzed regio-, stereo-, and chemoselective coupling with allenes and bis(pinacolato)diboron. A key feature of the present transformation is the use of a catalytic Lewis base additive which inhibits the competing C-N bond forming reaction between the catalytically generated boron-substituted allylcopper intermediate with the O-benzoyl hydroxylamine, thus enabling in situ transformation of the latter into an alicyclic imine which undergoes selective C-C bond formation with the allylcopper species.

Enantio- and Diastereoselective Copper-Catalyzed Allylboration of Alkynes with Allylic gem-Dichlorides.

Allylic gem-dichlorides are shown to be efficient substrates for catalytic asymmetric allylboration of alkynes. The method employs a chiral NHC-Cu catalyst capable of generating in a single step chiral skipped dienes bearing a Z-alkenyl chloride, a trisubstituted E-alkenyl boronate and a bis-allylic stereocenter with excellent levels of chemo-, regio- enantio- and diastereoselectivity. This high degree of functionalization makes these products versatile building blocks as illustrated with the synthesis of several optically active compounds. DFT calculations support the key presence of a metal cation bridge ligand-substrate interaction and account for the stereoselectivity outcome.

Heterometallic palladium-iron metal-organic framework as a highly active catalyst for cross-coupling reactions.

Palladium-based metal-organic frameworks (Pd-MOFs) are an emerging class of heterogeneous catalysts extremely challenging to achieve due to the facile leaching of palladium and its tendency to be reduced. Herein, Pd(ii) was successfully incorporated in the framework of a MOF denoted as MUV-22 using a solvent assisted reaction. This stable MOF, with square-octahedron (soc) topology as MIL-127, and a porosity of 710 m2 g-1, is highly active, selective, and recyclable for the Suzuki-Miyaura allylation of aryl and alkyl boronates as exemplified with the coupling between cinnamyl bromide and Me-Bpin, a typically reluctant reagent in cross-coupling reactions.

Stereoselective Synthesis of Highly Substituted 1,3-Dienes via "à la carte" Multifunctionalization of Borylated Dendralenes.

Despite the high relevance of 1,3-dienes, stereoselective methods to access tetrasubstituted conjugated dienes are still scarce. We here report an efficient and modular approach that provides access to multifunctional tetrasubstituted 1,3-dienes with excellent levels of regio- and stereoselectivity. This methodology is based on a tetracomponent reaction between a borylated dendralene, an organolithium reagent and two different electrophiles. Mechanistic studies reveal that this transformation proceeds through a regio- and stereoselective carbolithiation/electrophilic trapping of an in situ formed dendralenic boron-ate complex, followed by a stereoretentive halodeborylation. The ease in which complex structural dienes can be accessed and their synthetic versatility highlight the importance and utility of this method.

Copper-catalyzed protoboration of borylated dendralenes: a regio- and stereoselective access to functionalized 1,3-dienes.

A copper-catalyzed protoboration of borylated dendralenes is reported. The method employs an NHC-Cu catalyst and provides access to 1,4-addition products with excellent levels of chemo-, regio- and stereoselectivity. The resulting diene bis(boronates) are oxidized to the corresponding diene diols which are synthetically versatile building blocks.

Copper-catalyzed O-alkenylation of phosphonates.

Copper catalysis allows the direct oxygen alkenylation of dialkyl phosphonates with alkenyl(aryl)iodonium salts with selective transfer of the alkenyl group. This novel methodology proceeds with a wide range of phosphonates under mild conditions and gives straightforward access to valuable enol phosphonates in very good yields.

Copper-Catalyzed Enantioselective Allylboration of Alkynes: Synthesis of Highly Versatile Multifunctional Building Blocks.

The first copper-catalyzed enantioselective allylboration of alkynes is reported. The method employs a multitasking chiral NHC-Cu catalyst and provides access to densely functionalized molecules from simple starting materials with excellent levels of chemo-, regio-, and enantioselectivity. These multifunctional products display highly versatile reactivity as shown by the synthesis of a variety of non-racemic molecular scaffolds. DFT calculations were conducted to gain insight into the high selectivity levels of this catalytic process.

Synthesis of Stereodefined Borylated Dendralenes through Copper-Catalyzed Allylboration of Alkynes.

An efficient method to access diversely substituted borylated dendralenes from simple and readily available materials is reported. This method is based on a multicomponent copper-catalyzed allylboration of alkynes with diboron and a 1,4-dibromo-2-butene which provides bromo- and boron-substituted skipped dienes with a remarkable chemo-, stereo-, and regioselectivity. These products can be easily transformed into dendralenic organoboronates, which display an extremely versatile reactivity as demonstrated by novel selective transformations.

Catalytic Asymmetric Synthesis of Butenolides and Butyrolactones.

γ-Butenolides, γ-butyrolactones, and derivatives, especially in enantiomerically pure form, constitute the structural core of numerous natural products which display an impressive range of biological activities which are important for the development of novel physiological and therapeutic agents. Furthermore, optically active γ-butenolides and γ-butyrolactones serve also as a prominent class of chiral building blocks for the synthesis of diverse biological active compounds and complex molecules. Taking into account the varying biological activity profiles and wide-ranging structural diversity of the optically active γ-butenolide or γ-butyrolactone structure, the development of asymmetric synthetic strategies for assembling such challenging scaffolds has attracted major attention from synthetic chemists in the past decade. This review offers an overview of the different enantioselective synthesis of γ-butenolides and γ-butyrolactones which employ catalytic amounts of metal complexes or organocatalysts, with emphasis focused on the mechanistic issues that account for the observed stereocontrol of the representative reactions, as well as practical applications and synthetic potentials.

Cu-catalyzed enantioselective allylic alkylation with organolithium reagents.

This protocol describes a method for the catalytic enantioselective synthesis of tertiary and quaternary carbon stereogenic centers, which are widely present in pharmaceutical and natural products. The method is based on the direct reaction between organolithium compounds, which are cheap, readily available and broadly used in chemical synthesis, and allylic electrophiles, using chiral copper catalysts. The methodology involves the asymmetric allylic alkylation (AAA) of allyl bromides, chlorides and ethers with organolithium compounds using catalyst systems based on Cu-Taniaphos and Cu-phosphoramidites. The protocol contains a complete description of the reaction setup, a method based on 1H-NMR, gas chromatography-mass spectrometry (GC-MS) and chiral HPLC for assaying the regioselectivity and enantioselectivity of the product, and isolation, purification and characterization procedures. Six Cu-catalyzed AAA reactions between different organolithium reagents and allylic systems are detailed in the text as representative examples of these procedures. These reactions proceed within 1-10 h, depending on the nature of the allylic substrate (bromide, chloride, or ether and disubstituted or trisubstituted) or the chiral ligand used (Taniaphos or phosphoramidite). However, the entire protocol, including workup and purification, generally requires an additional 4-7 h to complete.

Tandem Long Distance Chain-Walking/Cyclization via RuH2(CO)(PPh3)3/Brønsted Acid Catalysis: Entry to Aromatic Oxazaheterocycles.

A novel route to 1,3-oxazaheterocycles based on cooperative Ru-H/Brønsted acid catalysis is reported. The use of the commercially available RuH2(CO)(PPh3)3 complex allows for an efficient long distance chain-walking process while the Brønsted acid is responsible for generation of an electrophilic iminium ion which is trapped intramolecularly by an alcohol moiety. The alcohol, besides its nucleophilic function, also plays an important role in the stabilization of the Ru catalyst.

Chiral Diarylmethanes via Copper-Catalyzed Asymmetric Allylic Arylation with Organolithium Compounds.

A highly enantioselective copper/N-heterocyclic carbene catalyzed allylic arylation with organolithium compounds is presented. The use of commercial or readily prepared aryllithium reagents in the reaction with allyl bromides affords a variety of chiral diarylvinylmethanes, comprising a privileged structural motif in pharmaceuticals, in high yields with good to excellent regio- and enantioselectivities. The versatility of this new transformation is illustrated in the formal synthesis of the marketed drug tolterodine (Detrol).