Jean-Philip Lumb

An Atom-Economic Synthesis of Nitrogen Heterocycles from Alkynes

A robust route to 2,4-disubstituted pyrrole heterocycles relying upon a cascade reaction is reported. The reaction benefits from operational simplicity: it is air and moisture tolerant and is performed at ambient temperature. Control over the reaction conditions provides ready access to isopyrroles, 2,3,4-trisubstituted pyrroles, and 3-substituted pyrollidin-2-ones.

Controlling the catalytic aerobic oxidation of phenols.

The oxidation of phenols is the subject of extensive investigation, but there are few catalytic aerobic examples that are chemo- and regioselective. Here we describe conditions for the ortho-oxygenation or oxidative coupling of phenols under copper (Cu)-catalyzed aerobic conditions that give rise to ortho-quinones, biphenols or benzoxepines. We demonstrate that each product class can be accessed selectively by the appropriate choice of Cu(I) salt, amine ligand, desiccant and reaction temperature. In addition, we evaluate the effects of substituents on the phenol and demonstrate their influence on selectivity between ortho-oxygenation and oxidative coupling pathways. These results create an important precedent of catalyst control in the catalytic aerobic oxidation of phenols and set the stage for future development of catalytic systems and mechanistic investigations.

Ortho-Quinone Methides from para-Quinones : Total Synthesis of Rubioncolin B

A concise synthesis of rubioncolin B is described, which features an unprecedented intramolecular Diels-Alder reaction involving an ortho-quinone methide and a naphthofuran moiety. The ortho-quinone methide is generated through a surprisingly facile tautomerization of a para-quinone.

A Biomimetic Catalytic Aerobic Functionalization of Phenols

The importance of aromatic C-O, C-N, and C-S bonds necessitates increasingly efficient strategies for their formation. Herein, we report a biomimetic approach that converts phenolic C-H bonds into C-O, C-N, and C-S bonds at the sole expense of reducing dioxygen (O2) to water (H2O). Our method hinges on a regio- and chemoselective copper-catalyzed aerobic oxygenation to provide ortho-quinones. ortho-Quinones are versatile intermediates, whose direct catalytic aerobic synthesis from phenols enables a mild and efficient means of synthesizing polyfunctional aromatic rings.

A TEMPO-free copper-catalyzed aerobic oxidation of alcohols.

The copper-catalyzed aerobic oxidation of primary and secondary alcohols without an external N-oxide co-oxidant is described. The catalyst system is composed of a Cu/diamine complex inspired by the enzyme tyrosinase, along with dimethylaminopyridine (DMAP) or N-methylimidazole (NMI). The Cu catalyst system works without 2,2,6,6-tetramethyl-l-piperidinoxyl (TEMPO) at ambient pressure and temperature, and displays activity for un-activated secondary alcohols, which remain a challenging substrate for catalytic aerobic systems. Our work underscores the importance of finding alternative mechanistic pathways for alcohol oxidation, which complement Cu/TEMPO systems, and demonstrate, in this case, a preference for the oxidation of activated secondary over primary alcohols.

Biomimetic synthesis of the IDO inhibitors exiguamine A and B

Biomimetic synthesis is an attempt to assemble natural products along biosynthetic lines without recourse to the full enzymatic machinery of nature. We exemplify this with a total synthesis of exiguamine A and the newly isolated natural product exiguamine B. The most noteworthy feature of this work is an oxidative endgame drawing from the complex chemistry of catecholamines, which allows for ready access to a new class of nanomolar indoleamine-2,3-dioxygenase inhibitors.

A New Strategy for the Synthesis of Chiral β-Alkynyl Esters via Sequential Palladium and Copper Catalysis

A new strategy for the synthesis of chiral β-alkynyl esters which relies on sequential Pd and Cu catalysis is reported. Terminal alkynes bearing aryl, alkyl, and silyl groups can be employed without prior activation yielding a wide range of important chiral building blocks. The reaction sequence utilizes a robust Pd(II)-catalyzed hydroalkynylation of ynoates with terminal alkynes providing geometrically pure ynenoates which are readily reduced by CuH. In contrast to previous reports, where additions to ynenoates proceed with marginal preference for the 1,6-pathway, this conjugate reduction occurs with high 1,4-selectivity yielding β-alkynyl esters with excellent levels of enantioselectivity. Importantly, the method tolerates a wide range of functionality, including allylic carbonates and carbamates, and thus allows for rapid elaboration of the β-alkynyl esters into a variety of chiral, substituted heterocycles.

A Biomimetic Mechanism for the Copper-Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol

Controlling product selectivity during the catalytic aerobic oxidation of phenols remains a significant challenge that hinders reaction development. This work provides a mechanistic picture of a Cu-catalyzed, aerobic functionalization of phenols that is selective for phenoxy-coupled ortho-quinones. We show that the immediate product of the reaction is a Cu(II)-semiquinone radical complex and reveal that ortho-oxygenation precedes oxidative coupling. This complex is the resting state of the Cu catalyst during turnover at room temperature. A mechanistic study of the formation of this complex at low temperatures demonstrates that the oxygenation pathway mimics the dinuclear Cu enzyme tyrosinase by involving a dinuclear side-on peroxodicopper(II) oxidant. Unlike the enzyme, however, the rate-limiting step of the ortho-oxygenation reaction is the self-assembly of the oxidant from Cu(I) and O2. We provide details for all steps in the cycle and demonstrate that turnover is contingent upon proton-transfer events that are mediated by a slight excess of ligand. Finally, our knowledge of the reaction mechanism can be leveraged to diversify the reaction outcome. Thus, uncoupled ortho-quinones are favored in polar, coordinating media, highlighting unusually high levels of chemoselectivity for a catalytic aerobic oxidation of a phenol.

A bio-inspired total synthesis of tetrahydrofuran lignans.

Lignan natural products comprise a broad spectrum of biologically active secondary metabolites. Their structural diversity belies a common biosynthesis, which involves regio- and chemoselective oxidative coupling of propenyl phenols. Attempts to replicate this oxidative coupling have revealed significant challenges for controlling selectivity, and these challenges have thus far prevented the development of a unified biomimetic route to compounds of the lignan family. A practical solution is presented that hinges on oxidative ring opening of a diarylcyclobutane to intercept a putative biosynthetic intermediate. The effectiveness of this approach is demonstrated by the first total synthesis of tanegool in 4 steps starting from ferulic acid, as well as a concise synthesis of the prototypical furanolignan pinoresinol.

Total Synthesis of Exiguamines A and B Inspired by Catecholamine Chemistry

The evolution of a total synthesis of the exiguamines, two structurally unusual natural products that are highly active inhibitors of indolamine-2,3-dioxygenase (IDO), is described. The ultimately successful strategy involves advanced cross-coupling methodology and features a potentially biosynthetic tautomerization/electrocyclization cascade reaction that forms two heterocycles and installs a quaternary ammonium ion in a single synthetic operation.