Using decision analysis to support proactive management of emerging infectious wildlife diseases

Despite calls for improved responses to emerging infectious diseases in wildlife, management is seldom considered until a disease has been detected in affected populations. Reactive approaches may limit the potential for control and increase total response costs. An alternative, proactive management framework can identify immediate actions that reduce future impacts even before a disease is detected, and plan subsequent actions that are conditional on disease emergence. We identify four main obstacles to developing proactive management strategies for the newly discovered salamander pathogen Batrachochytrium salamandrivorans (Bsal). Given that uncertainty is a hallmark of wildlife disease management and that associated decisions are often complicated by multiple competing objectives, we advocate using decision analysis to create and evaluate trade-offs between proactive (pre-emergence) and reactive (post-emergence) management options. Policy makers and natural resource agency personnel can apply principles from decision analysis to improve strategies for countering emerging infectious diseases

Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives

We report the first total syntheses of (+)-haplocidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide-directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (E = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine.National Institute of General Medical Sciences (U.S.) (GM089732)Amgen Inc

Concise Total Syntheses of (+)-Haplo­cidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendler­idine Derivatives

We report the first total syntheses of (+)-haplo­cidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C–H oxidation of complex aspido­sperma alkaloid derivatives. A versatile, amide-directed <i>ortho</i>-acet­oxyl­ation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemi­aminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemi­aminal ether alkaloids (+)-fendler­idine, (+)-acetyl­aspido­albidine, and (+)-propionyl­aspido­albidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (<i>E</i> = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspido­sperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspido­sperma derivatives, including the anti­proliferative alkaloid (+)-haplo­cidine

Directed Palladium-Catalyzed Acetoxylation of Indolines. Total Synthesis of <i>N</i>-Benzoylcylindrocarine

We describe a palladium-catalyzed C7-acetoxylation of indolines with a range of amide directing groups. While a variety of substituents are tolerated on the indoline-core and the N1-acyl group, the acetoxylation is most sensitive to the C2- and C6-indoline substituents. The practicality of this indoline C7-acetoxylation is demonstrated using a cinnamamide substrate on a mmol scale. Several N1-acyl groups, including those present in natural alkaloids, guide C7-acetoxylation of indoline substrates over a competitive C5-oxidation. The application of this chemistry allowed for the first synthesis of N-benzoylcylindrocarine by late-stage C17-acetoxylation of N-benzoylfendleridine

Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction

The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, ¹H, ¹³C, and ¹⁹F NMR in our interrupted Bischler–Napieralski-based synthetic strategy to the aspidosperma alkaloids, including a complex tetracyclic diiminium ion, is discussed. The reactivity of a wide range of pyridines with trifluoromethanesulfonic anhydride was systematically examined, and characteristic IR absorption bands for the corresponding <i>N</i>-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates were assigned. The reversible formation of diiminium ether intermediates was studied, providing insight into divergent mechanistic pathways as a function of the steric environment of the amide substrate and stoichiometry of reagents. Importantly, when considering base additives during electrophilic amide activation, more hindered α-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation

Enantioselective synthesis of (-)-vallesine: late-stage C17-oxidation via complex indole boronation

The first enantioselective total synthesis of (-)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (-)-vallesine, from a common intermediate.NIH-NIGMS (grant no. GM074825

Enantioselective total synthesis of (-)-deoxoapodine

The first enantioselective total synthesis of (−)-deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum-catalyzed enantioselective ring-closing metathesis reaction for the desymmetrization of an advanced intermediate that introduces the C5-quaternary stereocenter. After C21-oxygenation, the pentacyclic core was accessed by electrophilic C19-amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6-etherification reaction proved highly effective to secure the F-ring and the fourth contiguous stereocenter of (−)-deoxoapodine with complete stereochemical control.NIH-NIGMS (grant no. GM074825

Enantioselective Synthesis of (−)-Vallesine: Late-Stage C17-Oxidation via Complex Indole Boronation

The first enantioselective total synthesis of (−)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (−)-vallesine, from a common intermediate