Dehydrative Cyclization Reactions Research Articles

Tf2O-Promoted Morgan–Walls Reaction: From a Flexible Approach to Functionalized Phenanthridines and Quinazolines to the Short and Divergent Total Syntheses of Alkaloids

AbstractA new protocol for the direct transformation of secondary amides (N-acyl-o-xenylamines) to phenanthridines under mild conditions is reported. The method features trifluoromethanesulfonic anhydride (Tf2O)/2-fluoropyridine as the efficient amide activation system and MeCN or CH2Cl2 as the solvent. For some substrates, MeCN participated in the reaction, which affords a mild access to polysubstituted quinazolines. By employing a Tf2O/2,4,6-tri-tert-butylpyrimidine (TTBP) combination, the method was extended to an N-formyl-o-xenylamine, which represents a recalcitrant amide substrate type for the dehydrative cyclization reaction. More importantly, a one-pot method was established for the direct and divergent synthesis of four types of phenanthridinoids from o-xenylamines, which features both a tert-N-formyl-o-xenylamine and phenanthridinium salt as key and versatile intermediates. The investigation has resulted in one of the shortest and the most efficient total syntheses of the three natural products trisphaeridine, 5,6-dihydrobicolorine, and N-methylcrinasiadine, and in the formal total syntheses of three other ones: 3-hydroxytrisphaeridine, bicolorine, and zephycandidine A.

Synthesis of Nitrogen-Containing Heterocycles through Catalytic Dehydrative Cyclization Reactions.

Re2O7 in hexafluoroisopropyl alcohol provides access to cationic intermediates from alcohols through the intermediacy of perrhenate esters. This manuscript describes the application of the system to the formation of a number of weakly basic heterocyclic systems through dehydration reactions and intramolecular nucleophilic addition. The influence of the substrate structure on the reaction rates and stereocontrol is discussed with respect to intermediate ion pairs.

Re2O7‐Mediated Dehydrative Cyclization Reactions: Total Synthesis of Herboxidiene and Its 12‐Desmethyl Analogue

Re2 O7 catalysis effects efficient and stereoselective dehydrative cyclization reactions from monoallylic diols, with stereocontrol arising from thermodynamic equilibration. This method was applied to a rapid synthesis of the spliceosome inhibitor herboxidiene. The route was also utilized for the synthesis of an analogue that highlights the importance of a single methyl group in biasing the conformation in the acyclic region of the molecule.

Re2O7‐Mediated Dehydrative Cyclization Reactions: Total Synthesis of Herboxidiene and Its 12‐Desmethyl Analogue

AbstractRe2O7 catalysis effects efficient and stereoselective dehydrative cyclization reactions from monoallylic diols, with stereocontrol arising from thermodynamic equilibration. This method was applied to a rapid synthesis of the spliceosome inhibitor herboxidiene. The route was also utilized for the synthesis of an analogue that highlights the importance of a single methyl group in biasing the conformation in the acyclic region of the molecule.

Supramolecular Wiring of Benzo-1,3-chalcogenazoles through Programmed Chalcogen Bonding Interactions.

The high-yielding synthesis of 2-substituted benzo-1,3-tellurazoles and benzo-1,3-selenazoles through a dehydrative cyclization reaction has been reported, giving access to a large variety of benzo-1,3-chalcogenazoles. Exceptionally, these aromatic heterocycles proved to be very stable and thus very handy to form controlled solid-state organizations in which wire-like polymeric structures are formed through secondary N⋅⋅⋅Y bonding interactions (SBIs) engaging the chalcogen (Y=Se or Te) and nitrogen atoms. In particular, it has been shown that the recognition properties of the chalcogen centre at the solid state could be programmed by selectively barring one of its σ-holes through a combination of electronic and steric effects exerted by the substituent at the 2-position. As predicted by the electrostatic potential surfaces calculated by quantum chemical modelling, the pyridyl groups revealed to be the stronger chalcogen bonding acceptors, and thus the best ligand candidate for programming the molecular organization at the solid state. In contrast, the thiophenyl group is an unsuitable substituent for establishing SBIs in this molecular system as it gives rise to chalcogen-chalcogen repulsion. The weaker chalcogen donor properties of the Se analogues trigger the formation of feeble N⋅⋅⋅Se contacts, which are manifested in similar solid-state polymers featuring longer nitrogen-chalcogen distances.

Stereoselective Total Synthesis of the Marine Macrolide Sanctolide A

AbstractThe stereoselective total synthesis of sanctolide A, a 14‐membered polyketide‐nonribosomal peptide (PK‐NRP) hybrid macrolide, was accomplished. Sanctolide A contains a rare N‐methyl enamide and 2‐hydroxyisovaleric acid functionality embedded into the macrocycle. The synthesis relied on Yamaguchi esterification and intramolecular dehydrative cyclization reactions to construct the core skeleton of the macrolide. The two key chiral centers were generated by Maruoka's allylation and Noyori's asymmetric ketone reduction reactions. Commercially available, inexpensive 2‐hydroxyisovaleric acid and hexanaldehyde were utilized as the raw materials for the total synthesis.

Tandem Gold-Catalyzed Dehydrative Cyclization/Diels–Alder Reactions: Facile Access to Indolocarbazole Alkaloids

A gold-catalyzed synthesis of cyclic 2-oxodienes from readily prepared propargyl alcohols and the subsequent Diels-Alder reaction are reported. The dehydrative cyclization reactions proceeded smoothly, and the dienes formed in situ were demonstrated to undergo cycloaddition with a variety of dienophiles. This method offers a new strategy for the synthesis of indolocarbazole alkaloids, whereby the convergent synthetic design allows for differentiation between the indole nitrogens.

PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives

New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4-triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1-acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 ± 1.09 μM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P ≥ 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.

Nitrogen Nucleophiles in Au‐Catalyzed Dehydrative Cyclization Reactions

AbstractMild conditions for the gold‐catalyzed dehydrative cyclization of carbamate‐protected azaallylic alcohols to form saturated nitrogen heterocycles are reported. The cyclization reactions are high‐yielding, operationally easy to perform, and provide heterocycles with a synthetically useful vinyl group, strategically located on the ring system, which can facilitate further transformations for target oriented synthesis. It is also demonstrated through chirality transfer experiments that the mechanism can be either cationic in nature or a Au‐catalyzed addition/elimination sequence. The diverging mechanistic scenario is dependent on the nature of the substituents on the allylic alcohol and necessitates judicious substrate design.

PdII‐Catalyzed Spiroketalization of Ketoallylic Diols

A high-yielding stereoselective method for forming spiroketals from simple ketoallylic diols is reported. Employing catalytic [PdCl2(MeCN)2] in THF at 0 °C, these dehydrative cyclization reactions require only mild conditions to produce vinyl-substituted spiroketals in high yields after brief reaction times with water as the only byproduct. Using this method, the stereochemical information embedded at the nucleophile is transmitted "down-the-chain" and efficiently sets the stereochemistry at both the anomeric carbon atom and the newly formed allylic stereocenter.

Collective synthesis of several 2,7′-cyclolignans and their correlation by chemical transformations

Collective synthesis of anti-malarial 2,7'-cyclolignans has been stereoselectively achieved employing (±)-cyclogalgravin (2) as a linchpin through a series of functional group conversions, including redox reactions. Interestingly, 2 can be correlated with the neolignan (±)-kadangustin J (1) isolated from a different plant source, through a highly efficient dehydrative cyclization reaction with excellent diastereotopic differentiation of the veratryl group and concomitant construction of the C1–C7 bond. It is noteworthy that the first total synthesis of stereodivergent (±)-8,8'-epi-aristoligone (5), (±)-8'-epi-aristoligone (7), (±)-8'-epi-8-OH-aristoligone (8) and (±)-8'-epi-aristoligol (9) was demonstrated.

Synthesis of (E)-3′-Phosphonoalkenyl Modified Nucleoside Phosphonates via a Highly Stereoselective Olefin Cross-Metathesis Reaction

The synthesis of (E)-3'-phosphonoalkenyl and 3'-phosphonoalkyl modified nucleoside analogues with a β-D-erythrofuranose moiety is reported. The highly stereoselective olefin cross-metathesis reaction was applied to introduce the phosphonoalkenyl group at the 3'-position of the sugar moiety with absolute (E)-selectivity. The 3',6'-cyclomonophosphonic acids of 3'-phosphonoethyl-β-D-erythrofuranosyl nucleosides were synthesized via a dehydrative intramolecular cyclization reaction. None of the synthesized compounds shows significant in vitro activity against HIV, HCV, and RSV.

Copper‐Catalyzed Transformation of Carbonyl‐ene‐nitrile Compounds: Vinylation, Imino Ene Reaction, and Alkynylation of 2‐Aza‐2,4‐cyclopentadienone Intermediates Generated via Ritte‐Type Hydration and Dehydrative Cyclization Reactions.

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Copper-catalyzed transformation of carbonyl-ene-nitrile compounds: Vinylation, imino ene reaction, and alkynylation of 2-aza-2,4-cyclopentadienone intermediates generated via Ritter-type hydration and dehydrative cyclization reactions

1 H-pyrrolin-2(5 H)-one derivatives are easily obtained from carbonyl-ene-nitrile compounds and alkenes or alkynes by copper(II)-catalyzed tandem sequence involving vinylation or allylation as well as Ritter-type hydration and dehydrative cyclization.

1,3,4-Oxadiazole formation as traceless release in solid phase organic synthesis

Oxadiazoles were generated upon a dehydrative cyclization reaction with 2-acyl hydrazides bound to the polymeric support via one of their N atoms using TFAA as a dehydration agent.

Conformational effects on the mechanism of acid-catalyzed dehydration of hexitols

The Monte Carlo search of the low-energy regions of D-mannitol (4) and D-glucitol (5) conformational space was undertaken in order to investigate conformational effects on the stereochemistry of the acid-catalyzed dehydrative cyclization reaction of 4 and 5 to the corresponding 1,4:3,6-dianhydrohexitols. It was found that although dominant conformations in water resemble closely the crystal state conformations of 4 and 5, the same is not true in solvents of low polarity. The magnitudes of the calculated energies of the reactive conformations for the dehydrative cyclization reaction suggest an SN2 mechanism with a late transition state. Copyright © 1998 John Wiley & Sons, Ltd.

Access to the 2,3‐dihydropyridazin‐3‐one and as‐triazino[3,4‐a]phthalazine ring systems from 4‐aryl‐2‐oxo‐butanoic acids

AbstractA novel series of 2,3‐dihydropyridazin‐3‐ones 15 were synthesized via condensation between hydrazines and 4‐(p‐chlorophenyl)‐2‐hydroxy‐2‐(2‐oxo‐2‐substituted ethyl)butanoic acids 8 which in turn were prepared by the reaction of substituted benzylpyruvic acids 6 with methyl alkyl(aryl) ketones 7. Dehydration of 8b‐d by a mixture of glacial acetic acid and hydrochloric acid afforded 4‐(p‐chorophenyl)‐2‐(substituted phenacyl)‐2‐butenoic acids 10. Condensation reaction of 10 with hydrazines gave type 15 compounds in good yields. Also, a new series of as‐triazino[3,4‐a]phthalazines 20 was obtained from the reaction of substituted benzylpyruvic acids 6 with hydralazine to give the hydralazones 19 which underwent dehydrative cyclization reaction with PPA to afford 20. Structure assignments are based on 1H, 13C nmr and ir spectra.