This study describes a general method for the preparation of 1,4-oxazin-2-one intermediates from acetylene dicarboxylate and β-amino alcohol precursors. Oxazinones prepared in this manner were employed in a tandem cycloaddition/cycloreversion reaction sequence with a model alkyne (phenyl acetylene) to give substituted pyridine products. Fundamental reactivity and selectivity studies are complemented by the synthesis of the polycyclic ergot alkaloid natural product xylanigripone A.

This study explores the merged cycloaddition/cycloreversion of a 1,4-oxazinone substrate and conjugated bisalkyne precursors. Good regioselectivity in the Diels-Alder operation is observed and pyridines bearing 3-alkynyl functionality are afforded following cycloreversion and extrusion of CO2. Examples with both symmetric and nonsymmetric bisalkyne substrates are included.

This study describes the synthesis of the 4-azafluorenone core in a single operation using readily available starting materials. Condensation of an amidrazone with ninhydrin intercepts an intermediate 1,2,4-triazine derivative, which engages norbornadiene in a merged [4 + 2]/bis-retro[4 + 2] sequence to deliver the azafluorenone core. The tricyclic core established in this manner was elaborated to onychine, the simplest natural product in the 4-azafluorenone alkaloid family.

A new method to prepare 1,4-oxazinone intermediates was developed based on aza-conjugate addition of β-amino alcohols to electron-deficient alkyne precursors. A tandem intramolecular cycloaddition/cycloreversion reaction sequence was evaluated, leading to the synthesis of the guaipyridine alkaloid natural products rupestine M and L. Starting from (-)-citronellal and thus a known configuration of the C5 stereocenter, a revised absolute configuration of natural rupestine L is suggested based on optical rotation.

This study investigates a synthetic sequence for the preparation of 1,2-diketone products. The sequence avoids oxidative conditions and instead employs reliable transformations including the Horner-Wadsworth-Emmons and addition of Grignard reagents to N-methyl-N-methoxy (Weinreb) amide intermediates. The reaction sequence is suitable for the synthesis of nonsymmetric aliphatic and aryl substituted derivatives.

This study reveals a new method for the preparation of 1,4-oxazinone derivatives by Staudinger reductive cyclization of functionalized vinyl azide precursors. The resulting oxazinone derivatives prepared in this manner were intercepted with terminal alkyne substrates through an intermolecular cycloaddition/cycloreversion sequence to afford polysubstituted pyridine products. Alkyne substrates bearing propargyl oxygen substitution showed good regioselectivity in the cycloaddition operation selectively affording 2,4,6-substituted pyridines. Application of this chemistry to the synthesis of an ErbB4 receptor inhibitor is also described.

This study reveals an alternative sequence for the synthesis of compounds that contain the pyrrolodiketopiperazine structural motif. Starting with a diketopiperazine precursor, a mild aldol condensation precedes pyrrole annulation and bicyclic ring fusion. The derived intermediate aldol condensation products, which bear either a protected carbonyl or a functionalized alkyne, can be cyclized to the pyrrolodiketopiperazine by protic or gold Lewis acid catalysis.

A new extension for the ‘one pot’ construction of diverse 1-azafluorene derivatives featuring a Diels–Alder/retro-Diels–Alder cycloaddition is reported. Conditions were also determined for oxidation to the derived azafluorenones. The spectrophotometric analysis of five different azafluorenones were performed. Moderate fluorescence was observed with azafluorenone derivatives that bear an imbedded pyridone motif; whereas those bearing substituted pyridines do not fluoresce.

Infrared multiple photon dissociation action spectroscopy was performed on the AlaOrn b 2 + and AlaAlaOrn b 3 + fragment ions from ornithine-containing tetrapeptides. Infrared spectra were obtained in the fingerprint region (1000–2000 cm −1 ) using the infrared free electron lasers at the Centre Laser Infrarouge d’Orsay (CLIO) facility in Orsay, France, and the free electron lasers for infrared experiments (FELIX) facility in Nijmegen, the Netherlands. A novel terminal ornithine lactam AO + b 2 + structure was synthesized for experimental comparison and spectroscopy confirms that the b 2 + fragment ion from AOAA forms a lactam structure. Comparison of experimental spectra with scaled harmonic frequencies at the B3LYP/6-31+G(d,p) level of theory shows that AO + b 2 + forms a terminal lactam protonated either on the lactam carbonyl oxygen or the N-terminal nitrogen atom. Several low-lying conformers of these isomers are likely populated following IRMPD dissociation. Similarly, a comparison of the experimental IRMPD spectrum with calculated spectra shows that AAO + b 3 + -ions also adopt a lactam structure, again with multiple different protonation sites, during fragmentation. This study provides spectroscopic confirmation for the lactam cyclization proposed for the “ornithine effect” and represents an alternative b n + structure to the oxazolone and diketopiperazine/macrocycle structures most often formed.

A new domino reaction sequence for the construction of 2-pyridone structures is reported. The reaction sequence begins with diacetyldiketopiperazine and proceeds via aldol condensation, alkene isomerization, and intramolecular Diels-Alder cycloaddition. The intermediate [2.2.2]diazabicycloalkene cycloadducts can be isolated or can engage in a base-accelerated extrusion of one lactam bridge to provide the 2-pyridone cycloreversion products. The operation leading to pyridone products can occur in one reaction vessel and proceeds at convenient temperatures.

The convergent synthesis of bicyclo[2.2.2]diazaoctane structures using an intermolecular Diels-Alder cycloaddition between a pyrazinone and commercially available fumarate or maleate precursors is reported. High reactivity and stereoselection is observed with both dienophile substrates. Structure validation was achieved by conversion of cycloadducts into known [2.2.2]diazabicyclic compounds or into crystalline derivatives suitable for X-ray analysis. The cycloadduct derived from reaction of pyrazinone and maleic anhydride underwent selective anhydride ring opening and intersected an established precursor in the synthesis of brevianamide B.

A domino reaction sequence has been evaluated that begins with union of novel dihydrooxazinone precursors with 2-alkynyl-substituted benzaldehyde components through aldol condensation. Ensuing operations, including alkene isomerization, Diels-Alder, and retrograde Diels-Alder with loss of CO2 occurs in the same reaction vessel to provide polysubstituted tricyclic pyridine products.

The synthesis of barettin, a selective serotonin receptor inhibitor and potent antibiofouling natural product, is described. The synthesis starts with the diketopiperazine nucleus intact and the side chains are installed using iterative aldol condensations. The route represents a general strategy for synthesis of a wide array of mono-alkylidene diketopiperazine structures, including those derived from non-canonical amino acid residues.

A stereoselective intermolecular Diels-Alder cycloaddition of an intermediate pyrazinone with both achiral and chiral acrylate-derived dienophiles provides rapid access to the bicyclo[2.2.2]diazaoctane core shared among several prenylated indole alkaloids. The product derived from cycloaddition with 2-nitroacrylate required an additional five to six synthetic operations to intercept established precursors to premalbrancheamide and brevianamide B. The chemistry detailed in this manuscript constitutes a formal total synthesis (12 steps each) of these [2.2.2]diazabicyclic natural products from proline methyl ester.

A seven-step synthesis of peramine, which required three chromatographic separations, is described. Key to the synthesis is an enolate alkylation of a pyrrole-fused diketopiperazine, reduction of the acyl pyrrole, and dehydration of the intermediate pyrrolyl carbinol to establish the pyrrolopyrazine core of peramine.

The intermolecular cycloaddition of pyrazinone precursors with alkyne substrates was evaluated. The resulting regioisomeric [2.2.2]-diketopiperazine alkene cycloadducts were diverted into 2-pyridone products through cycloreversion of the [2.2.2]-bicyclic intermediates. New insights into the regioselectivity of pyrazinone azadiene Diels–Alder reactions as well as cycloreversion reactivity were revealed in this study. Synthetic sequences using this [4+2]/r[4+2] strategy were determined that can produce predominantly the 3,5-disubstituted 2-pyridone alkaloid structures; pyridones featuring the 3,4-substitution pattern are observed as the minor regioisomeric products.

The loline alkaloids present a compact polycyclic pyrrolizidine skeleton and contain a strained five-membered ethereal bridge, structural features that have proven challenging for synthetic chemists to incorporate since the discovery of this natural product family more than 100 years ago. These alkaloids are produced by mutualistic fungal symbionts (endophytes) living on certain species of pasture grasses and protect the host plant from insect herbivory. The asymmetric total synthesis of loline alkaloids is reported and extends our first-generation (racemic) synthesis of this alkaloid family. Key to the synthesis is a diastereoselective tethered aminohydroxylation of a homoallylic carbamate function and a Petasis Borono-Mannich addition.

A general strategy for the conversion of [2.2.2]-diazabicyclic alkene structures to 2-pyridone aromatic heterocyclic products is reported. The reaction sequence starts from 2,5-diketopiperazine (DKP) derivatives, is compatible with both aromatic and aliphatic aldehyde components, and can intercept either intra- or intermolecular cycloaddition manifolds. Priming of one aza-bridging function in the intermediate [2.2.2]-DKP scaffold permits cycloreversion (microwave heating) and selective extrusion of cyanate derivatives leading to the formation of 2-pyridone structures. Progress toward the synthesis of louisianin A and B, antiproliferative 2-pyridone naturalproducts, is also disclosed.

The asymmetric total synthesis of the chlorinated [2.2.2]-diazabicyclic indole alkaloid (+)-malbrancheamide B is reported. Key to the synthesis is a domino reaction sequence that employs an aldol condensation, alkene isomerization, and intramolecular Diels-Alder cycloaddition. Diastereofacial selection between the azadiene stereofaces is enforced with a chiral aminal auxiliary. A formal 7-step (longest linear route) synthesis of (±)-malbrancheamide B is also reported.

The diastereoselective aminoconjugate addition of benzylamine and lithiobenzylamine to both E and Z-configured vinylogous proline derivatives has been investigated. The results from this study have enabled the stereoselective synthesis of the 1-aminopyrrolizidine alkaloid (−)-absouline.