γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C-H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)-H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

The APJ receptor and its endogenous peptidic ligand apelin have been implicated as important modulators of cardiovascular function, and APJ receptor agonists may be beneficial in the treatment of heart failure. In this article, we describe the discovery of a series of biphenyl acid derivatives as potent APJ receptor agonists. Following the identification of initial high-throughput screen lead 2, successive optimization led to the discovery of lead compound 15a. Compound 15a demonstrated comparable in vitro potency to apelin-13, the endogenous peptidic ligand for the APJ receptor. In vivo, compound 15a demonstrated a dose-dependent improvement in the cardiac output in male Sprague Dawley rats with no significant changes in either mean arterial blood pressure or heart rate, consistent with the hemodynamic profile of apelin-13 in an acute pressure volume loop model.

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Antibiotic-resistant bacteria present an ongoing challenge to both chemists and biologists as they seek novel compounds and modes of action to out-maneuver continually evolving resistance pathways, especially against Gram-negative strains. The dimeric pyrrole-imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture. This full account traces the strategy used to develop a second-generation route to key spirocycle 9, culminating in a practical synthesis of the axinellamines and enabling their discovery as broad-spectrum antibacterial agents, with promising activity against both Gram-positive and Gram-negative bacteria. While their detailed mode of antibacterial action remains unclear, the axinellamines appear to cause secondary membrane destabilization and impart an aberrant cellular morphology consistent with the inhibition of normal septum formation. This study serves as a rare example of a natural product initially reported to be devoid of biological activity surfacing as an active antibacterial agent with an intriguing mode of action.

A protocol for the Pd(II)-catalyzed ortho-C-H alkylation of phenylacetic and benzoic acids using alkylboron reagents is disclosed. Monoprotected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was also investigated.

We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and dibromophakellstatin (3) inhibit the proteolytic activity of the human 20S proteasome as well as the (i)20S immunoproteasome catalytic core. Palau'amine is found to prevent the degradation of ubiquitinylated proteins, including IκBα, in cell culture, which may be indicative of the potential mechanism by which these agents exhibit their exciting cytotoxic and immunosuppressive properties.

Sequential cycloisomerizations of diynyl o-benzaldehyde substrates to access novel polycyclic cyclopropanes are reported. The reaction sequence involves initial Cu(I)-mediated cycloisomerization/nucleophilic addition to an isochromene followed by diastereoselective Pt(II)-catalyzed enyne cycloisomerization.

The development of a simple, efficient, scalable, and stereocontrolled synthesis of a common intermediate en route to the axinellamines, massaclines, and palau'amine is reported. This completely new route was utilized to prepare the axinellamines on a gram scale. In a more general sense, three distinct and enabling methodological advances were made during these studies: (1) an ethylene glycol-assisted Pauson-Khand cycloaddition reaction, (2) a Zn/In-mediated Barbier-type reaction, and (3) a TfNH2-assisted chlorination-spirocyclization.

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau'amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels-Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments, are described.

Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF 3 I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.

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The direct coupling of arylboronic acids to electron-deficient N-heterocycles is described. The reaction is catalyzed by silver nitrate in the presence of a persulfate co-oxidant under ambient conditions. It does not require prefunctionalization of the heterocycle and shows a high functional group tolerance.

Worth the wait: The long anticipated total synthesis of palau'amine has been accomplished by a route featuring highly chemoselective transformations, cascade reactions, and a remarkable transannular cyclization to secure the unprecedented trans-5,5 ring junction (shown in red). Polycyclic dimeric pyrrole–imidazole alkaloids such as palau'amine (1, Scheme 1),1 axinellamine A (2),2 and massadine chloride (3)3 possess daunting structural and physical attributes, including nine or more nitrogen atoms, eight contiguous stereogenic centers, reactive (hemi)aminal moieties, oxidation-prone pyrroles, and highly polar, non-crystalline morphologies. Their unique structures have been the focus of numerous publications from many groups worldwide, and have led to notable advances in synthetic methodology.4 Among the more complex members of this class, only the axinellamines (e.g. 2)5 and the massadines (e.g. 3)6 have succumbed to total synthesis, aided by the invention of a highly chemoselective and controllable late-stage oxidation reaction. Compared to its congeners (2 and 3), palau'amine (1) possesses a unique chemical challenge: one of the pyrrole-amide sidechains is embedded in an exquisite, hexacyclic core architecture which contains a highly strained trans-azabicyclo[3.3.0]octane substructure (unprecedented among natural products). This is undoubtedly a central reason why the synthesis of palau'amine (1) has thus far eluded organic chemists despite the dozens of Ph.D. theses7 and studies towards publications8 that have appeared since its isolation in 1993 and structural reassignment in 2007.1 Many well-founded and logical plans to secure the peculiar trans-5,5 core of 1 in our laboratory resulted in unfortunate outcomes. Presumably, the high degree of strain implicit in the hexacyclic architecture thwarted all attempts at a biomimetic closure (N14-C10 and N1-C6 simultaneously)4 or a stepwise closure (N14-C10 followed by N1-C6).9 The lessons learned during those initial attempts inspired an alternative strategy that ultimately led to the total synthesis of 1 presented herein. As depicted in Scheme 1, our retrosynthetic analysis relied upon a speculation that hypothetical macrocycle 4, dubbed "macro-palau'amine", would be a kinetically stable isomer of 1. It was predicted that an irreversible transannular ring–chain tautomerization would convert 4 into its consitutional isomer 1 through a dynamic equilibrium involving amidine tautomer 4′. Handheld molecular models suggested that 4 might adopt a folded conformation wherein N14 and C10 would be in close proximity to facilitate such a ring closure. A conceptually related late-stage shift of topology between constitutional isomers through dynamic equilibration was a key design element of our recent synthesis of the kapakahines.10 As with 1, "macro palau'amine" (4) exhibits a high level of strain and was believed to be accessible through macrolactamization of the diamine derived from diazide 5. This intermediate was envisioned to arise from the SNAr of a pyrrole (or surrogate thereof) to the bromo-aminoimidazole 6. Selected pyrrole–imidazole alkaloids, and retrosynthetic analysis of palau'amine (1). Ar=2-(4,5-dibromopyrrole). The total synthesis of 1, outlined in Scheme 2, commences with the readily available cyclopentane core 7, an intermediate enlisted in the synthesis of the massadines and available in 19 steps from commercially available materials in 1 % overall yield.6 Treatment of 7 with aqueous TFA unveiled aminoguanidine 8, which was directly converted in unprotected form to the hemiaminal 10 in 64 % isolated yield (along with 17 % recovered 8, 130 mg scale)11 using silver(II)-picolinate (9). It is notable that this oxidation reaction takes place with precise position selectivity—no oxidation of the primary amine is observed under these acidic reaction conditions. Construction of the remaining 2-aminoimidazole took place in 65 % yield (251 mg scale)11 to afford 11 using cyanamide in brine (sat. aq. NaCl), a solvent that minimizes displacement of the highly labile chlorine atom.3, 6 Subsequent bromination using Br2 in a 1:1 mixture of TFA/TFAA delivered the desired 2-amino-4-bromoimidazole 6 in 54 % yield (150 mg scale).11 The introduction of the pyrrole moiety proved challenging, as standard conditions to couple amines to aryl halides using transition metal catalysis failed to produce any detectable amounts of product (even on the Boc-shielded 2-amino-4-bromoimidazole derivatives). In principle, the inherent ambiphilicity of the 2-aminoimidazole could lend itself to a unique reactivity pattern, one that would allow for uncatalyzed nucleophilic attack on the 2-amino-4-bromoimidazole as a possible direct route to the pyrrole-acid intermediate 5. Total synthesis of palau'amine (1). Counterions are CF3CO2− and are omitted for clarity. Reagents and conditions: a) TFA/H2O (1:1), 50 °C, 12 h, then silver(II)-picolinate (2.4 equiv), TFA/H2O (1:9), 23 °C, 5 min, 64 % + 17 % recovered 8; b) H2NCN (40 equiv), pH 5, brine, 70 °C, 4 h, 65 %; c) TFAA/TFA (1:1), 1 h, then Br2 (2.0 equiv), 1 h, then TFA/H2O (1:1) 1 h, 38 °C, 54 %; d) AcOH (3.0 equiv), 12 (3.0 equiv), THF, 38 °C, 6 h, then TFA/DCM (1:30 to 1:1), 23 °C, 12 h, 44 %; e) Pd(OAc)2 (1.6 equiv), H2 (bubbled through solution) TFA/H2O (1:9), 23 °C, then EDC (2.8 equiv), HOBt (2.8 equiv), DMF, 23 °C, 3 h, then TFA, 70 °C, 38 h, 17 % from 5. TFA=trifluoroacetic acid, TFAA=trifluoroacetic anhydride, THF=tetrahydrofuran, HOBt=N-hydroxybenzotriazole, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMF=N,N-dimethylformamide. In the event, the nucleophilic pyrrole surrogate 1212 was reacted with 2-amino-4-bromoimidazole 6 buffered with AcOH, followed by treatment with TFA, to deliver the desired N-coupled pyrrole-2-carboxylic acid 5 in a one-pot operation in 44 % yield (91 mg scale).11 Presumably, facile NC bond formation is observed due to the high reactivity of its tautomeric amidine form (6′). This reaction appears to be general and its scope will be reported in the full account of this work. The pyrrole-forming step, mediated by TFA and traversing through oxonium 14, involves no less than five chemical transformations occurring in tandem to deliver 5. In preparation for the key macrolactamization step, the azide groups of 5 were reduced to afford highly polar diamine 15 (4.0 mg scale). The synthesis of "macro-palau'amine" 4 was effected using EDC and HOBt. Heating of the crude reaction mixture in TFA (70 °C) elicited the crucial transannular cyclization (presumably proceeding through amidine tautomer 4′) that fastened the remaining two stereocenters and cemented the hallmark trans-5,5 ring system to deliver palau'amine (1) in 17 % overall yield from 5 (one-pot, average of 55 % per operation) after repeated purification with reverse phase HPLC (spectroscopically identical to that reported for 1 with the exception of optical rotation).13 Optimization and mechanistic investigation of this final sequence (5→1) is currently underway.9 The journey to 1 (25 steps from commercial material, 0.015 % overall yield with current procedures)9 has led not only to useful strategies and methods, but also to an empirical demonstration of numerous guiding principles for synthesis design at the frontiers of chemical complexity.14 Over six years ago our group embarked on the synthesis of dimeric pyrrole–imidazole alkaloids by methodically applying the logic of biosynthesis where appropriate during the syntheses of sceptrin, oxysceptrin, nakamuric acid, ageliferin, nagelamide, the axinellamines (e.g. 2), and the massadines (e.g. 3).5, 6, 15 The synthesis of 1 benefited from a tremendous amount of chemical reactivity learned during those endeavours. Our 2004 biosynthetic hypothesis15b led us to pursue the true structure of 1 prior to the realization of its revised structure.1 In an effort to apply redox economic principles16 to this chemical synthesis program, a late-stage, chemoselective, silver-mediated oxidation was invented to circumvent laborious routes to the key hemiaminal unit expressed in 1–3 (C-20, Scheme 1). Cascade reactions were incorporated to rapidly assemble complexity (e.g. 6→5→1). Finally, innate reactivity was utilized so as to minimize the use of redundant and orthogonal protecting group operations,17 and instead maximize the discovery of interesting chemical reactivity such as the direct coupling of nucleophiles to unprotected 2-amino-4-bromoimidazoles. An enantioselective, scalable variant of the current synthesis, as well as a full account of this work will be forthcoming. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

A direct arylation of a variety of electron-deficient heterocycles with arylboronic acids has been developed. This new reaction proceeds readily at room temperature using inexpensive reagents: catalytic silver(I) nitrate in the presence of persulfate co-oxidant. The scope with respect to heterocycle and boronic acid coupling partner is broad, and sensitive functional groups are tolerated. This method allows for rapid access to a variety of arylated heterocycles that would be more difficult to access with traditional methods.

Die pazifischen Palau-Inseln bieten eine außergewöhnliche Artenvielfalt, und von ebensolcher Exotik ist auch die Struktur des Naturstoffs Palau'amin, das zum meistgejagten Alkaloid in der Synthesechemie des 21. Jahrhunderts wurde. Die erste Totalsynthese von Palau'amin wird nun von P. S. Baran und Mitarbeitern in der Zuschrift auf S. 1113 ff. beschrieben. Die erfolgreiche Syntheseroute umfasst Transformationen ungeschützter Zwischenstufen, Kaskadenreaktionen und einen bemerkenswerten Abschluss mit einer transannularen Cyclisierung zum Aufbau der entscheidenden Bindung. Bildentwurf Paul Krawczuk; Copyright iStockphoto.com/clumpner.

The total syntheses of the complex pyrrole-imidazole alkaloids (+/-)-massadine and (+/-)-massadine chloride is described using a carefully orchestrated sequence of manipulations on highly polar and structurally complex intermediates. Key to the completion of this synthetic endeavor was the exploration of a unique and chemoselective method to oxidize unprotected guanidines under aqueous conditions in air, This oxidation has been optimized and applied to a selection of spirocyclic guanidines of varying complexity. Additionally, the 3,7-epi analogues of these interesting natural products have been synthesized and fully characterized.

The synthesis of isoquinoline alkaloid frameworks has been achieved via a series of cascade reactions identified through reaction discovery utilizing 1,2-dihydroisoquinoline scaffolds.

Multidimensional reaction screening of ortho-alkynyl benzaldehydes with a variety of catalysts and reaction partners was conducted in an effort to identify new chemical reactions. Reactions affording unique products were selected for investigation of preliminary scope and limitations.