Total Synthesis of the Leucosceptroid Family of Natural Products

A highly efficient strategy enabled the asymmetric total synthesis of 15 antifeedant leucosceptroid natural products. The advanced tricyclic core, available in gram quantity, served as the pivotal intermediate for the preparation of norleucosceptroids B, C, F, and G and leucosceptroids A, B, G, I, J, L, and M. Additionally, the bioinspired oxidative transformation of leucosceptroid A to leucosceptroids C, K, O, and P using singlet oxygen supports the hypothesis that leucosceptroids A and B are most likely the biogenetic precursors of all other members of this natural product family

A Bioinspired Cyclization Sequence Enables the Asymmetric Total Synthesis of Dictyoxetane

We have developed the first synthesis of the unique oxetane containing diterpene (+)-dictyoxetane. Our retrosynthetic planning was guided by the putative biosynthesis of the unprecedented 2,7-dioxatricyclo­[4.2.1.0^3,8]­nonane ring system. A bioinspired 4-<i>exo</i>-tet, 5-<i>exo</i>-trig cyclization sequence enabled the construction of the synthetically challenging dioxatricyclic framework. The overall synthesis proceeds in 15 linear steps from a known and readily available <i>trans</i>-hydrindane fragment. In addition, we were able to realize the first dyotropic rearrangement of an epoxide–oxetane substrate

Short, Divergent, and Enantioselective Total Synthesis of Bioactive <i>ent</i>-Pimaranes

We present the first total synthesis of eight ent-pimaranes via a short and enantioselective route (11–16 steps). Key features of the divergent synthesis are a Sharpless asymmetric dihydroxylation, a Brønsted acid catalyzed cationic bicyclization, and a mild Rh-catalyzed arene hydrogenation for rapid access to a late synthetic branching point. From there on, selective functional group manipulations enable the synthesis of ent-pimaranes bearing different modifications in the A- and C-rings

Experimental Studies on the Selective β‑C–H Halogenation of Enones

Here we describe the realization of a one-pot protocol for the β-C–H halogenation of cyclic enones via umpolung of the β-carbon. The developed method includes hydrazone formation and selective β-halogenation (bromination, chlorination) with <i>N</i>-bromosuccinimide and Palau’chlor (2-chloro-1,3-bis­(methoxycarbonyl)­guanidine) followed by hydrolysis of the hydrazone moiety. Using the optimized conditions, we were able to effectively β-brominate and β-chlorinate for the first time cyclic enones with different substitution patterns and various functional groups in one flask, whereas previous methods for this transformation required several steps. Additionally, the utility of the method was demonstrated in a short synthesis of the core structure of the <i>Aspidosperma</i> alkaloid jerantinine E

Total Synthesis of Salimabromide: A Tetracyclic Polyketide from a Marine Myxobacterium

Salimabromide is an antibiotic polyketide that was previously isolated from the obligate marine myxobacterium Enhygromyxa salina, and its densely functionalized and conformationally rigid tetracyclic framework is unprecedented in nature. Herein we report the first chemical synthesis of the target structure by employing a series of well-orchestrated, robust transformations, highlighted by an acid-promoted, powerful Wagner–Meerwein rearrangement/Friedel–Crafts cyclization sequence to forge the two adjacent quaternary carbon centers embedded in the tetrahydronaphthalene. A high-yielding ketiminium mediated [2+2]-cycloaddition was also utilized for the simultaneous construction of the remaining three stereocenters

Total Synthesis of Salimabromide: A Tetracyclic Polyketide from a Marine Myxobacterium

Salimabromide is an antibiotic polyketide that was previously isolated from the obligate marine myxobacterium Enhygromyxa salina, and its densely functionalized and conformationally rigid tetracyclic framework is unprecedented in nature. Herein we report the first chemical synthesis of the target structure by employing a series of well-orchestrated, robust transformations, highlighted by an acid-promoted, powerful Wagner–Meerwein rearrangement/Friedel–Crafts cyclization sequence to forge the two adjacent quaternary carbon centers embedded in the tetrahydronaphthalene. A high-yielding ketiminium mediated [2+2]-cycloaddition was also utilized for the simultaneous construction of the remaining three stereocenters

Development of a β‑C–H Bromination Approach toward the Synthesis of Jerantinine E

The development of an asymmetric and highly convergent three-component synthesis of the functionalized ABC ring system of the <i>Aspidosperma</i> alkaloid jerantinine E is reported. The presented synthetic strategy relies on our recently developed method for the one-pot β-C–H bromination of enones, which allows for rapid construction of the tricyclic tetrahydro­carbazolone core via a palladium-catalyzed amination and oxidative indole formation. Moreover, a secondary amine building block that contains all carbon atoms of the D and E ring of the natural product could be installed in three additional steps

Unraveling the Metabolic Pathway in <i>Leucosceptrum canum</i> by Isolation of New Defensive Leucosceptroid Degradation Products and Biomimetic Model Synthesis

Seven new leucosceptroid degradation products possessing a C₂₀, C₂₁, or C₂₅ framework, norleucosceptroids D–H (<b>1</b>–<b>5</b>), leucosceptroids P (<b>6</b>), and Q (<b>7</b>), have been isolated from <i>Leucosceptrum canum</i>. Their structures were determined by comprehensive NMR, MS, and single-crystal X-ray diffraction analyses. Discovery of these key intermediates, together with the biomimetic oxidation of a model system, supports the hypothesis that two biosynthetic pathways are operative. Antifeedant activity was observed for compounds <b>1</b>–<b>3</b>