James D. Cuthbertson

The direct arylation of allylic sp 3 C–H bonds via organic and photoredox catalysis

The direct functionalization of unactivated sp3 C–H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp3 C–H bonds in C–C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C–H bonds (that is, C–H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C–C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug’s action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C–H arylation. This C–C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C–H bonds.

Switching on elusive organometallic mechanisms with photoredox catalysis

Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon–carbon and carbon–heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C−C bond-forming reactions, most notably Negishi, Suzuki–Miyaura, Stille, Kumada and Hiyama couplings. Despite the tremendous advances in C−C fragment couplings, the ability to forge C−O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C–O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(iii) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(iii) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon–oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to ‘switch on’ important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.

Silver(I)- or copper(II)-mediated dearomatization of aromatic ynones: direct access to spirocyclic scaffolds.

A high-yielding silver(I)- or copper(II)-catalyzed dearomatizing spirocyclization strategy allows the conversion of simple aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, into functionalized spirocyclic scaffolds. A high-yielding asymmetric variant furnishes spirocyclic indolenines in up to 89:11 e.r.

Total Synthesis of Spirobacillene A

The first total synthesis of spirobacillene A, an indole alkaloid isolated from Lysinibacillus fusiformis, is reported. A Lewis acid mediated spirocyclization of an anisole derivative onto a tethered ynone was used as a key step, drawing inspiration from a potential biosynthesis of the natural product.

Palladium-Catalyzed Enantioselective C–H Activation of Aliphatic Amines Using Chiral Anionic BINOL-Phosphoric Acid Ligands

The design of an enantioselective Pd(II)-catalyzed C-H amination reaction is described. The use of a chiral BINOL phosphoric acid ligand enables the conversion of readily available amines into synthetically valuable aziridines in high enantiomeric ratios. The aziridines can be derivatized to afford a range of chiral amine building blocks incorporating motifs readily encountered in pharmaceutically relevant molecules.

A Telescoped Route to 2,6‐Disubstituted 2,3,4,5‐Tetrahydropyridines and 2,6‐syn‐Disubstituted Piperidines: Total Synthesis of (−)‐Grandisine G

Nitrogen heterocycles constitute one of the most important classes of lead compounds in the pharmaceutical and agrochemical industries, with pyridines and their reduced analogues occupying a prominent position, particularly in the case of piperidines. New and efficient routes to such compounds are always valuable and herein we describe a remarkable one-pot rearrangement for the conversion of readily available 6-acyl cyclohexenones 1 into 2,6-disubstituted 2,3,4,5-tetrahydropyridines 2 and then into 2,6-syndisubstituted piperidines 3 after diastereoselective reduction (Scheme 1). The conceptual novelty of such a telescoped

The preparation of (-)-grandisine B from (+)-grandisine D; a biomimetic total synthesis or formation of an isolation artefact?

An efficient new alkyne-acetal cyclization procedure has been developed to prepare enantiopure indolizidine building blocks from l-proline and then applied to prepare the Elaeocarpus-derived alkaloids grandisine B and grandisine D in an efficient manner. However, evidence is presented which indicates that grandisine B does not occur naturally but is formed by reaction of grandisine D with ammonia during the extraction/purification process.

Dearomatisation approaches to spirocyclic dienones via the electrophilic activation of alkynes

Two complementary dearomatising spirocyclisation protocols to generate spirocyclic dienones from anisole and phenol-tethered ynones are described, each proceeding via electrophilic alkyne activation. The first approach focuses on the spirocyclisation of para-substituted anisoles using either SnCl2·2H2O or Cu(OTf)2. The second approach, which enables the spirocyclisation of both ortho- and para-substituted phenols, uses silica-supported AgNO3 to generate similar scaffolds with much greater efficiency. Initial asymmetric studies are also outlined.