ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2 -/- Mice.

Intracellular Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1; "ent-B1") in RyR2 single channel and [3H]ryanodine binding assays, and in Casq2 -/- cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca2+ release in Casq2 -/- cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity - ent-B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. SIGNIFICANCE STATEMENT: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.

Generality-Driven Catalyst Development: A Universal Catalyst for Enantioselective Nitroalkene Reduction.

Cracking the selectivity-generality paradox is among the most pressing challenges in asymmetric catalysis. This obstacle prevents the immediate and successful translation of new methods to diverse small molecules. This is particularly rate-limiting for therapeutic development, where availability and structural diversity are often critical components of successful campaigns. Here we describe the union of generality-driven enantioselective catalysis and the preparation of diverse peptidomimetics. A single new organocatalyst provides high selectivity and substrate generality that is matched only by a combination of metal and organocatalysts. Within organocatalysis, this discovery breaks a 16-year monolithic paradigm, uncovering a powerful new scaffold for enantioselective reduction with behavior that suggests the recognition of a nitroethylene minimal catalaphile.

The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and morbidity. The strongest genetic risk factors for AF in humans are variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene PITX2. Although mice deficient in Pitx2 (Pitx2+/-) have increased AF susceptibility, the mechanism remains controversial. Recent evidence has implicated hyperactivation of the cardiac ryanodine receptor (RyR2) in Pitx2 deficiency, which may be associated with AF susceptibility. We investigated pacing-induced AF susceptibility and spontaneous Ca2+ release events in Pitx2 haploinsufficient (+/-) mice and isolated atrial myocytes to test the hypothesis that hyperactivity of RyR2 increases susceptibility to AF, which can be prevented by a potent and selective RyR2 channel inhibitor, ent-verticilide. Compared with littermate wild-type Pitx2+/+, the frequency of Ca2+ sparks and spontaneous Ca2+ release events increased in permeabilized and intact atrial myocytes from Pitx2+/- mice. Atrial burst pacing consistently increased the incidence and duration of AF in Pitx2+/- mice. The RyR2 inhibitor ent-verticilide significantly reduced the frequency of spontaneous Ca2+ release in intact atrial myocytes and attenuated AF susceptibility with reduced AF incidence and duration. Our data demonstrate that RyR2 hyperactivity enhances SR Ca2+ leak and AF inducibility in Pitx2+/- mice via abnormal Ca2+ handling. Therapeutic targeting of hyperactive RyR2 in AF using ent-verticilide may be a viable mechanism-based approach to treat atrial arrhythmias caused by Pitx2 deficiency.

Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts.

BACKGROUND: Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy correlated with plakophilin-2 (PKP2) mutations. Separate data show that reduced abundance of PKP2 leads to dysregulation of intracellular Ca2+ (Ca2+i) homeostasis. Here, we study the relation between excercise, catecholaminergic stimulation, Ca2+i homeostasis, and arrhythmogenesis in PKP2-deficient murine hearts. METHODS: Experiments were performed in myocytes from a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2cKO). For training, mice underwent 75 minutes of treadmill running once per day, 5 days each week for 6 weeks. We used multiple approaches including imaging, high-resolution mass spectrometry, electrocardiography, and pharmacological challenges to study the functional properties of cells/hearts in vitro and in vivo. RESULTS: In myocytes from PKP2cKO animals, training increased sarcoplasmic reticulum Ca2+ load, increased the frequency and amplitude of spontaneous ryanodine receptor (ryanodine receptor 2)-mediated Ca2+ release events (sparks), and changed the time course of sarcomeric shortening. Phosphoproteomics analysis revealed that training led to hyperphosphorylation of phospholamban in residues 16 and 17, suggesting a catecholaminergic component. Isoproterenol-induced increase in Ca2+i transient amplitude showed a differential response to ß-adrenergic blockade that depended on the purported ability of the blockers to reach intracellular receptors. Additional experiments showed significant reduction of isoproterenol-induced Ca2+i sparks and ventricular arrhythmias in PKP2cKO hearts exposed to an experimental blocker of ryanodine receptor 2 channels. CONCLUSIONS: Exercise disproportionately affects Ca2+i homeostasis in PKP2-deficient hearts in a manner facilitated by stimulation of intracellular ß-adrenergic receptors and hyperphosphorylation of phospholamban. These cellular changes create a proarrhythmogenic state that can be mitigated by ryanodine receptor 2 blockade. Our data unveil an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of PKP2 deficit. We suggest that membrane-permeable ß-blockers are potentially more efficient for patients with arrhythmogenic right ventricular cardiomyopathy, highlight the potential for ryanodine receptor 2 channel blockers as treatment for the control of heart rhythm in the population at risk, and propose that PKP2-dependent and phospholamban-dependent arrhythmogenic right ventricular cardiomyopathy-related arrhythmias have a common mechanism.

In Vivo Pharmacokinetic and Pharmacodynamic Properties of the Antiarrhythmic Molecule ent-Verticilide.

The unnatural verticilide enantiomer (ent-verticilide) is a selective and potent inhibitor of cardiac ryanodine receptor (RyR2) calcium release channels and exhibits antiarrhythmic activity in a murine model of catecholaminergic polymorphic ventricular tachycardia (CPVT). To determine verticilide's pharmacokinetic and pharmacodynamic properties in vivo, we developed a bioassay to measure nat- and ent-verticilide in murine plasma and correlated plasma concentrations with antiarrhythmic efficacy in a mouse model of CPVT. nat-Verticilide rapidly degraded in plasma in vitro, showing >95% degradation within 5 minutes, whereas ent-verticilide showed <1% degradation over 6 hours. Plasma was collected from mice following intraperitoneal administration of ent-verticilide at two doses (3 mg/kg, 30 mg/kg). Peak C max and area under the plasma-concentration time curve (AUC) scaled proportionally to dose, and the half-life was 6.9 hours for the 3-mg/kg dose and 6.4 hours for the 30-mg/kg dose. Antiarrhythmic efficacy was examined using a catecholamine challenge protocol at time points ranging from 5 to 1440 minutes after intraperitoneal dosing. ent-Verticilide inhibited ventricular arrhythmias as early as 7 minutes after administration in a concentration-dependent manner, with an estimated potency (IC50) of 266 ng/ml (312 nM) and an estimated maximum inhibitory effect of 93.5%. Unlike the US Food and Drug Administration-approved pan-RyR blocker dantrolene, the RyR2-selective blocker ent-verticilide (30 mg/kg) did not reduce skeletal muscle strength in vivo. We conclude that ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development. SIGNIFICANCE STATEMENT: ent-Verticilide has therapeutic potential to treat cardiac arrhythmias, but little is known about its pharmacological profile in vivo. The primary purpose of this study is to determine the systemic exposure and pharmacokinetics of ent-verticilide in mice and estimate its efficacy and potency in vivo. The current work suggests ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development.

Secondary Orbital Effect Involving Fluorine is Responsible for Substrate-Controlled Diastereodivergence in the Catalyzed syn-aza-Henry Reaction of α-Fluoronitroalkanes.

The fluorine atom is a powerful, yet enigmatic influence on chemical reactions. True to form, fluorine was recently discovered to effect diastereodivergence in an enantioselective aza-Henry reaction, resulting in a very rare case of syn-ß-amino nitroalkane products. More bewildering was the observation of an apparent hierarchy of substituents within this substrate-controlled behavior: Ph>F>alkyl. These cases have now been examined comprehensively by computational methods, including both non-fluorinated and α-fluoro nitronate additions to aldimines catalyzed by a chiral bis(amidine) [BAM] proton complex. This study revealed the network of non-covalent interactions that dictate anti- (α-aryl) versus syn-selectivity (α-alkyl) using α-fluoronitronate nucleophiles, and an underlying secondary orbital interaction between fluorine and the activated azomethine.

RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.

RATIONALE: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide's efficacy in CPVT. OBJECTIVE: To determine whether RyR2 block independently contributes to flecainide's efficacy for suppressing spontaneous sarcoplasmic reticulum Ca release and for preventing ventricular tachycardia in vivo. METHODS AND RESULTS: We synthesized N-methylated flecainide analogues (QX-flecainide and N-methyl flecainide) and showed that N-methylation reduces flecainide's inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N-methylation did not alter flecainide's inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes-lacking intact sarcolemma and devoid of sodium channel contribution-flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and N-methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas N-methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block. CONCLUSIONS: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis.

Amide synthesis is one of the most widely practiced chemical reactions, owing to its use in drug development and peptide synthesis. Despite the importance of these applications, the attendant effort to eliminate waste associated with these protocols has met with limited success, and pernicious α-epimerization is most often minimized but not eliminated when targeting challenging amides (e.g., N-aryl amides). This effort has focused on what is essentially a single paradigm in amide formation wherein an electrophilic acyl donor reacts with a nucleophilic amine. Umpolung amide synthesis (UmAS) emerged from α-halo nitroalkane reactions with amines and has since been developed into a method for the synthesis of enantiopure amides using entirely catalytic, enantioselective synthesis. However, its inability to forge N-aryl amides has been a longstanding problem, one limiting its application more broadly in drug development where α-chiral N-aryl amides are increasingly common. We report here the reaction of α-fluoronitroalkanes and N-aryl hydroxyl amines for the direct synthesis of N-aryl amides using a simple Brønsted base as the promoter. No other activating agents are required, and experiments guided by mechanistic hypotheses outline a mechanism based on the UmAS paradigm and confirm that the N-aryl amide, not the N-aryl hydroxamic acid, is the direct product. Ultimately, select chiral α-amino-N-aryl amides were prepared with complete conservation of enantioenrichment, in contrast to a parallel demonstration of their ability to epimerize using the conventional amide synthesis alternative.

Resolving Bromonitromethane Sourcing by Synthesis: Preparation at the Decagram Scale.

The accessibility of bromonitromethane has declined in recent years, limiting its viability as a reagent for chemical synthesis. The reinvestigation and optimization of a variety of preparations, and the development of safe operating principles, are described. The reproducible protocol described here leverages the effectiveness of hydroxide for nitromethane bromination while respecting its incompatibility with the product it forms. This careful balance was achieved at scales up to 56 g, resulting in a reproducible procedure that provides straightforward, sustainable, and affordable access to this critical reagent.

Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic.

Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (-)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (-)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2-/-). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2-/- mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.

The Formation of Impossible Rings in Macrocyclooligomerizations for Cyclodepsipeptide Synthesis: The 18-from-12 Paradox.

A reinvestigation into the macrocyclooligomerization (MCO) of a tetradepsipeptide is reported, uncovering a paradox in which the MCO of depsipeptide monomers can produce "impossible" ring sizes: a 12-atom chain produced the expected 24-membered ring, alongside unexpected 18- and 30-membered cyclic oligomeric depsipeptides (CODs). We report an alternative preparation of authentic 18- and 36-membered macrocycles for this case using a stepwise synthesis that provides definitive analytical characterization for each ring size. Our investigation yields a recharacterization and reassignment of two macrocycles originally reported in this MCO series, along with updated yields and isothermal titration calorimetry data after implementation of new critical protocols for purification and subsequent analysis. Initial studies to probe this mechanistic conundrum are described.

DFT-Based Stereochemical Rationales for the Bifunctional Brønsted Acid/Base-Catalyzed Diastereodivergent and Enantioselective aza-Henry Reactions of α-Nitro Esters.

A pair of chiral bis(amidine) [BAM] proton complexes provide reagent (catalyst)-controlled, highly diastereo- and enantioselective direct aza-Henry reactions leading to α-alkyl-substituted α,ß-diamino esters. A C2-symmetric ligand provides high anti-selectivity, while a nonsymmetric congener exhibits syn-selectivity in this example of diastereodivergent, enantioselective catalysis. A detailed computational analysis is reported for the first time, one that supports distinct models for selectivity resulting from the more hindered binding cavity of the C1-symmetric ligand. Binding in this congested pocket accommodates four hydrogen bond contacts among ligands and substrates, ultimately favoring a pre-syn arrangement highlighted by pyridinium-azomethine activation and quinolinium-nitronate activation. The complementary transition states reveal a wide range of alternatives. Comparing the C1- and C2-symmetric catalysts highlights distinct electrophile binding orientations despite their common hydrogen bond donor-acceptor features. Among the factors driving unusual high syn-diastereoselection are favorable dispersion forces that leverage the anthracenyl substituent of the C1-symmetric ligand.

Catalytic, Enantioselective Synthesis of Cyclic Carbamates from Dialkyl Amines by CO2-Capture: Discovery, Development, and Mechanism.

Cyclic carbamates are a common feature of small-molecule therapeutics, offering a constrained hydrogen bond acceptor that is both polar and sterically small. Methods for their preparation most often focus first on amino alcohol synthesis and then reaction with phosgene or its equivalent. This report describes an enantioselective synthesis of cyclic carbamates in which carbon dioxide engages an unsaturated basic amine, facilitated by a bifunctional organocatalyst designed to stabilize a carbamic acid intermediate while activating it toward subsequent enantioselective carbon-oxygen bond formation. Six-membered cyclic carbamates are prepared in good yield with high levels of enantioselection, as constrained 1,3-amino alcohols featuring a chiral tertiary alcohol carbon. Spectroscopic analysis (NMR, DOSY) of various substrate-reagent combinations provides insight into the dominant species under the reaction conditions. Two peculiar requirements were identified to achieve highest consistency: a "Goldilocks" amount of water and the use of a noncrystalline form of the ligand. These atypical features of the final protocol notwithstanding, a diverse range of products could be prepared. Their functionalizations illustrate the versatility of the carbamates as precursors to enantioenriched small molecules.

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control.

Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes.

Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides.

The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle-metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity ( Ka), enthalpy of binding (Δ H), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides.

Biomimetic Desymmetrization of a Carboxylic Acid.

The enantioselective desymmetrization of carboxylic acids by chiral Brønsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Brønsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter and can be derivatized to functionalized cyclopentanes.

On-Demand Complex Peptide Synthesis: An Aspirational (and Elusive?) Goal for Peptide Synthesis.

Peptide synthesis is a truly interdisciplinary tool, familiar to a broad group of scientists who do not otherwise overlap scientifically. For this reason, some may perceive even complex peptide synthesis to be a "solved problem", while others might argue that immense opportunity remains untapped or simply inaccessible. At the extreme of complexity, what might a concise assessment of the state-of-the-art in peptide synthesis look like? As one of the most practiced forms of synthetic chemistry by chemists and non-chemists alike, what restrictions remain that constrain access to chemical space? Using popular terminology, what forms of peptide synthesis are appropriately termed "on-demand"? The purpose of this Perspective is to appraise synthetic access to complex peptides, particularly those containing unnatural α-amino amides. Several case studies in complex peptide synthesis are summarized here, each selected to characterize the challenges attendant to unnatural α-amino amide synthesis. As peptidic molecules find increasing value in therapeutic development, especially in clinical applications, their impact will ultimately be determined by efficient preparative methods.

Enantioselective Synthesis of ß-Fluoro Amines via ß-Amino α-Fluoro Nitroalkanes and a Traceless Activating Group Strategy.

Preparation of a range of enantioenriched ß-fluoro amines (α,ß-disubstituted) is described in which the nitrogen and fluorine atoms are attached to sp3-hybridized carbons. The key finding is a chiral bifunctional Brønsted acid/base catalyst that can deliver ß-amino-α-fluoro nitroalkanes with high enantio- and diastereoselection. A denitration step renders the nitro group "traceless" and delivers secondary, tertiary, or vinyl alkyl fluorides embedded within a vicinal fluoro amine functional group. A synthesis of each possible stereoisomer of a ß-fluoro lanicemine illustrates the potential ease with which fluorinated small molecules relevant to neuroscience drug development can be prepared in a stereochemically comprehensive manner.

Umpolung reactivity in amide and peptide synthesis.

The amide bond is one of nature's most common functional and structural elements, as the backbones of all natural peptides and proteins are composed of amide bonds. Amides are also present in many therapeutic small molecules. The construction of amide bonds using available methods relies principally on dehydrative approaches, although oxidative and radical-based methods are representative alternatives. In nearly every example, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon-nitrogen bond-forming step. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products. Preliminary observations support a mechanism in which the polarities of the two reactants are reversed (German, umpolung) during carbon-nitrogen bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods.