Publications by authors named "James D Sunderhaus"

Prenylated indole alkaloids such as the calmodulin-inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution to provide access to the natural antipode (+)-malbrancheamide.

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The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (-)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers.

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A novel approach to the family of alkaloids was developed and applied to a concise total synthesis of (±)-pseudotabersonine that was accomplished in 11 steps. Key transformations include a stepwise variant of a Mannich-like multicomponent assembly process, a double ring-closing metathesis sequence, and a one-pot deprotection/cyclization reaction.

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We previously described the bioconversion of Notoamide T into (+)-Stephacidin A and (-)-Notoamide B, which suggested that Versicolamide B () is biosynthesized from 6--Notoamide T () via 6--Stephacidin A. Here we report that [C]- was incorporated into isotopically enriched and seven new metabolites, which were not produced under normal culture conditions. The results suggest that the addition of excess precursor activated the expression of dormant tailoring genes giving rise to these structurally unprecedented metabolites.

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In an effort to further elucidate the biogenesis of the stephacidin and notoamide families of natural products, notoamide T has been identified as the likely precursor to stephacidin A. The total synthesis of notoamide T is described along with it is C-6-epimer, 6-epi-notoamide T. The chemical conversion of stephacidin A to notoamide T by reductive ring opening is described as well as the oxidative conversion of notoamide T to stephacidin A.

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The stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a bicyclo[2.2.2]diazaoctane core.

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A concise synthesis of (+/-)-pseudotabersonine from commercially available 1-(phenylsulfonyl)-3-indolecarboxaldehyde has been accomplished. This synthesis features the convergent assembly of a key intermediate via a stepwise variant of a Mannich-type multicomponent coupling process, a double ring-closing metathesis, and a one-pot deprotection/cyclization reaction.

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A novel strategy has been developed for the efficient syntheses of diverse arrays of heterocyclic compounds. The key elements of the approach comprise a Mannich-type, multicomponent coupling reaction in which functionalized amines, aromatic aldehydes, acylating agents, and π- and organometallic nucleophiles are combined to generate intermediates that are then further transformed into diverse heterocyclic scaffolds via a variety of cyclization manifolds. Significantly, many of these scaffolds bear functionality that may be exploited by further manipulation to create diverse collections of compounds having substructures found in biologically active natural products and clinically useful drugs.

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The sequencing of multicomponent reactions (MCRs) and subsequent cyclization reactions is a powerful stratagem for the rapid synthesis of diverse heterocyclic scaffolds. The optimal MCR is sufficiently flexible that it can be employed to generate adducts bearing a variety of functional groups that may then be selectively paired to enable different cyclization manifolds, thereby leading to a diverse collection of products. The growing interest in diversity-oriented synthesis has led to increased attention to this paradigm for library synthesis, which has inspired many advances in the design and implementation of MCRs for the construction of diverse heterocyclic scaffolds.

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A four-component coupling process involving sequential reactions of aldehydes, primary amines, acid chlorides, and nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate a diverse array of functionalized heterocyclic scaffolds. This new approach to diversity-oriented synthesis was then applied to the first total synthesis of the isopavine alkaloid (+/-)-roelactamine.

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[reaction: see text] Herein we report on the use of siletanes as substrates for the oxidation of carbon-silicon bonds. These tetraalkylsilanes are easy to handle yet susceptible to rapid ring opening and oxidation upon exposure to aqueous fluoride and peroxide. This combination of stability and reactivity presents many practical benefits, including compatibility with silicon protecting groups and electron-rich aromatic rings.

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