Justin M. Lopchuk

New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress.

We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress.

Strain-release amination

Opening one ring to tack on another Curious chemists have long sought to learn just how tightly carbon atoms can be bound together. For instance, its possible to form a bond between two opposite corners of an already strained four-membered ring to make an edge-sharing pair of triangles. Gianatassio et al. have now devised a general use for these and related molecular curiosities. They show that appropriately modified nitrogen centers can pop open the most highly strained bond, leaving the more modestly strained ring motif intact. In this way, small rings can emerge as a convenient diversifying element in compounds, including new pharmaceutical candidates. Science, this issue p. 241 Strained rings are appended to compounds of pharmaceutical interest through the use of even more highly strained precursors. To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C–C and C–N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.

A Unified Approach to ent-Atisane Diterpenes and Related Alkaloids: Synthesis of (−)-Methyl Atisenoate, (−)-Isoatisine, and the Hetidine Skeleton

A unified approach to ent-atisane diterpenes and related atisine and hetidine alkaloids has been developed from ent-kaurane (−)-steviol (1). The conversion of the ent-kaurane skeleton to the ent-atisane skeleton features a Mukaiyama peroxygenation with concomitant cleavage of the C13–C16 bond. Conversion to the atisine skeleton (9) features a C20-selective C–H activation using a Suárez modification of the Hofmann–Löffler–Freytag (HLF) reaction. A cascade sequence involving azomethine ylide isomerization followed by Mannich cyclization forms the C14–C20 bond in the hetidine skeleton (8). Finally, attempts to form the N–C6 bond of the hetisine skeleton (7) with a late-stage HLF reaction are discussed. The synthesis of these skeletons has enabled the completion of (−)-methyl atisenoate (3) and (−)-isoatisine (4).

What controls regiochemistry in 1,3-dipolar cycloadditions of münchnones with nitrostyrenes?

The distinct experimentally observed regiochemistries of the reactions between mesoionic münchnones and β-nitrostyrenes or phenylacetylene are shown by DFT/BDA/ETS-NOCV analyses of the transition states to be dominated by steric and reactant reorganization factors, rather than the orbital overlap considerations predicted by Frontier Molecular Orbital (FMO) Theory.

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

A short, protecting group-free total synthesis of bruceollines D, E, and J.

A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with β-chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities. Reduction with bakers yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee.

Chapter 1 - Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids

Aspidosperma alkaloids are complex indole-containing natural products that historically have generated a considerable amount of interest from the synthetic community. Many members of this class are biologically active and replete with functional groups and chiral centers which provide a challenging proving ground for new methodology. This review will highlight recent advances in the total synthesis of molecules such as aspidospermidine, the subincanadines, vinblastine, and haplophytine in the past decade.

Bruceolline D: 3,3-dimethyl-1H,4H-cyclo­penta­[b]indol-2(3H)-one

The title compound, C13H13NO, crystallizes with four independent molecules in the asymmetric unit. The 12-membered penta[b]indole rings are essentially planar, with maximum deviations ranging from 0.034 (4) to 0.036 (4) Å in the four unique molecules. In the crystal, weak C—H⋯O interactions are observed, which link the molecules into chains along [010].

Chapter 5.2 - Five-Membered Ring Systems: Pyrroles and Benzo Analogs

Abstract The reactions and syntheses of pyrroles, indoles, isatins, carbazoles, and related fused heterocyclic ring systems from the year 2014 are reviewed. Pyrroles and indoles are treated in separate sections with the ring-forming reactions discussed by intramolecular or intermolecular bond disconnection. Other sections include nucleophilic, electrophilic, or radical reactivity of the parent rings, C H functionalization/organometallic reactions, reactions of side chains, and examples in total synthesis.

Azoles with 3-4 Heteroatoms

Direct metalation of various 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, and 1,3,4-oxadiazoles is reviewed through early 2012. The monograph is divided into sections by heterocycle; the most attention is paid to lithiation chemistry, however, transmetalation, directed ortho-lithiation, and other applications are noted where applicable.