Christopher S. Jeffrey

Generation and Reactivity of Aza-Oxyallyl Cationic Intermediates: Aza-[4 + 3] Cycloaddition Reactions for Heterocycle Synthesis

Aza-[4 + 3] cycloadditions of putative aza-oxyallyl cationic intermediates and cyclic dienes are reported. The intermediate is generated by the dehydrohalogenation of α-haloamides. The reaction is general to a variety of α-haloamides and is diastereoselective. Computational and experimental data suggest that an N-alkoxy substituent stabilizes the aza-oxyallyl cationic intermediate.

A Hypervalent Iodine-Induced Double Annulation Enables a Concise Synthesis of the Pentacyclic Core Structure of the Cortistatins

A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved from the (+)-Hajos-Parrish ketone. The cornerstone of our approach is a hypervalent iodine induced tandem intramolecular oxidative dearomatization and nitrile oxide cycloaddition. The manner in which these ring formations were orchestrated has yielded a rather concise strategy for synthesis.

Dearomative Indole Cycloaddition Reactions of Aza-Oxyallyl Cationic Intermediates: Modular Access to Pyrroloindolines

A regioselective dearomative aza-(3 + 2) cycloaddition reaction of substituted indoles with α-halohydroxamates has been developed. This transformation provides rapid access to highly functionalized pyrroloindolines that are represented in large number of bioactive compounds. The natural product, physostigmine, has been concisely synthesized utilizing this method.

Phytochemical diversity drives plant–insect community diversity

Significance Phytochemical diversity is a key component of functional diversity. Challenges in quantifying phytochemical diversity have limited our understanding of the causes and consequences of variation in phytochemical diversity across plant species and families. Here we show that phytochemical diversity across dozens of plant species predicts herbivore diversity, herbivore specialization, phototoxicity, herbivory, and attack by natural enemies. Our approach and findings provide a framework for future investigations focused on uncovering chemical underpinnings of trophic interactions at realistic ecological, geographic, and taxonomic scales, and have implications for the conservation of functional and taxonomic diversity. What are the ecological causes and consequences of variation in phytochemical diversity within and between plant taxa? Despite decades of natural products discovery by organic chemists and research by chemical ecologists, our understanding of phytochemically mediated ecological processes in natural communities has been restricted to studies of either broad classes of compounds or a small number of well-characterized molecules. Until now, no studies have assessed the ecological causes or consequences of rigorously quantified phytochemical diversity across taxa in natural systems. Consequently, hypotheses that attempt to explain variation in phytochemical diversity among plants remain largely untested. We use spectral data from crude plant extracts to characterize phytochemical diversity in a suite of co-occurring plants in the tropical genus Piper (Piperaceae). In combination with 20 years of data focused on Piper-associated insects, we find that phytochemical diversity has a direct and positive effect on the diversity of herbivores but also reduces overall herbivore damage. Elevated chemical diversity is associated with more specialized assemblages of herbivores, and the cascading positive effect of phytochemistry on herbivore enemies is stronger as herbivore diet breadth narrows. These results are consistent with traditional hypotheses that predict positive associations between plant chemical diversity, insect herbivore diversity, and trophic specialization. It is clear from these results that high phytochemical diversity not only enhances the diversity of plant-associated insects but also contributes to the ecological predominance of specialized insect herbivores.

Oxidative 1,4-Diamination of Dienes Using Simple Urea Derivatives

Diamination of alkenes and dienes has found widespread use in the synthesis of biologically active target molecules. Although the 1,2-diamination of alkenes has been comprehensively explored, versatile methods that install higher order 1,n-diamine moieties (e.g., n = 3-5) are not broadly developed. Herein, we report the development of an oxidative 1,4-diamination of dienes. This method represents one of the scarce examples of exclusive regioselectivity for 1,4-diamination. The reaction is easy to perform, uses simple reagents, works with a variety of functionalized dienes, and provides unique heterocyclic products.

1,4-Diamination of cyclic dienes via a (4 + 3) cycloaddition of diaza-allyl cationic intermediates.

Diaza-(4 + 3) cycloadditions of putative diaza-oxyallyl cationic intermediates and cyclic dienes are reported as a method for the 1,4-diamination of cyclic dienes. This reaction was entirely selective for diamination and provided cycloadducts in good to excellent yield.

Intraspecific phytochemical variation shapes community and population structure for specialist caterpillars

Summary Chemically mediated plant–herbivore interactions contribute to the diversity of terrestrial communities and the diversification of plants and insects. While our understanding of the processes affecting community structure and evolutionary diversification has grown, few studies have investigated how trait variation shapes genetic and species diversity simultaneously in a tropical ecosystem. We investigated secondary metabolite variation among subpopulations of a single plant species, Piper kelleyi (Piperaceae), using high‐performance liquid chromatography (HPLC), to understand associations between plant phytochemistry and host‐specialized caterpillars in the genus Eois (Geometridae: Larentiinae) and associated parasitoid wasps and flies. In addition, we used a genotyping‐by‐sequencing approach to examine the genetic structure of one abundant caterpillar species, Eois encina, in relation to host phytochemical variation. We found substantive concentration differences among three major secondary metabolites, and these differences in chemistry predicted caterpillar and parasitoid community structure among host plant populations. Furthermore, E. encina populations located at high elevations were genetically different from other populations. They fed on plants containing high concentrations of prenylated benzoic acid. Thus, phytochemistry potentially shapes caterpillar and wasp community composition and geographic variation in species interactions, both of which can contribute to diversification of plants and insects.

exo-Brevicomin biosynthetic pathway enzymes from the Mountain Pine Beetle, Dendroctonus ponderosae

exoBrevicomin (exo-7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane) is an important semiochemical for a number of beetle species, including the highly destructive Mountain Pine Beetle (Dendroctonus ponderosae). It is also found in other insects and the African elephant. Despite its significance, very little is known about its biosynthesis. A recent microarray analysis implicated a small cluster of three D. ponderosae genes in exo-brevicomin biosynthesis, two of which had identifiable open reading frames (Aw et al., 2010; BMC Genomics 11:215). Here we report further expression profiling of two genes in that cluster and functional analysis of their recombinantly-produced enzymes. One encodes a short-chain dehydrogenase that used NAD(P)(+) as a co-factor to catalyze the oxidation of (Z)-6-nonen-2-ol to (Z)-6-nonen-2-one. We therefore named the enzyme (Z)-6-nonen-2-ol dehydrogenase (ZnoDH). The other encodes the cytochrome P450, CYP6CR1, which epoxidized (Z)-6-nonen-2-one to 6,7-epoxynonan-2-one with very high specificity and substrate selectivity. Both the substrates and products of the two enzymes are intermediates in the exo-brevicomin biosynthetic pathway. Thus, ZnoDH and CYP6CR1 are enzymes that apparently catalyze the antepenultimate and penultimate steps in the exo-brevicomin biosynthetic pathway, respectively.

Access to bicyclic hydroxamate macrocycles via intramolecular aza-(4 + 3) cyloaddition reactions of aza-oxyallylic cation intermediates

The intramolecular aza-(4 + 3) cycloaddition reactions of in situ generated aza-oxyallylic cations and furans have been reported for the construction of medium sized hydroxamate macrocycles. This method provides direct access to 12–18 membered bicyclic macrocycles. The highly functionalized macrocycles have been transformed easily in to a wide range of highly functionalized heterocyclic scaffolds including lactones and lactams that could serve the synthesis of complex macrocyclic natural products and pharmaceuticals.

Oxidative (3 + 2) Cycloaddition Reactions of Diaza-Oxyallyl Cationic Intermediates and Indoles for the Synthesis of Imidazoloindolines

An oxidative diaza-(3 + 2) cycloaddition reaction of simple urea derivatives with substituted indoles has been developed. This transformation provides rapid access to highly functionalized imidazoloindolines that are represented in bioactive compounds. The reported method is compatible with a wide variety of functional groups and directly provides unique heterocyclic scaffolds from indoles and a simple urea derivative.