Acyl Nitroso Research Articles

ChemInform Abstract: Diastereoselective [4 + 2]Cycloadditions of Acyl Nitroso Compounds.

Abstract A highly diastereoselective route to unsaturated amino alcohol derivatives has been developed that features the [4+2] cycloaddition of chiral acyl nitroso compounds to a variety of conjugated dienes; a useful oxidative method for generating acyl nitroso compounds from the corresponding hydroxamic acids under very mild conditions was also discovered.

Corrigendum to “Syntheses of structurally diverse amino acids, including δ-hydroxylysine, using the acyl nitroso Diels–Alder reaction” [Tetrahedron Lett. 51 (2010) 2160

Corrigendum to “Syntheses of structurally diverse amino acids, including δ-hydroxylysine, using the acyl nitroso Diels–Alder reaction” [Tetrahedron Lett. 51 (2010) 2160

Synthesis of 1,2- and 1,4-amino alcohols from 1,3-dienes via oxazines. Rearrangements of 1,4-amino alcohol derivatives to oxazolines

Conjugated dienes were converted to 1,2-oxazines by reaction with an acyl nitroso dienophile. The oxazines were reduced to 1,4- N-acetylamino alcohols, which were rearranged to the corresponding oxazolines upon treatment with methanesulfonyl chloride or anhydride. The oxazolines yielded 1,2- N-acetylamino alcohols upon hydrolysis. Thus either 1,4- or 1,2- N-acetylamino alcohols are available from 1,3-dienes via this methodology. Experimental and spectral data are provided for all new compounds.

Syntheses of structurally diverse amino acids, including δ-hydroxylysine, using the acyl nitroso Diels–Alder reaction

Abstract By virtue of its ability to introduce amino and hydroxy functionalities in a 1,4-relationship with fully controlled relative stereochemistry, the acyl nitroso Diels–Alder (ANDA) reaction is ideally suited to the synthesis of structurally diverse, including hydroxylated, amino acids. The major issue to be tackled is that of regiochemistry in the ANDA addition to unsymmetrical dienes. The transformation of three diverse types of ANDA adducts into amino acids is described, in particular, the synthesis of δ-hydroxylysine, an important constituent of collagen, as a single (2SR, 5SR) diastereoisomer in protected form.

Alternative photoinduced release of HNO or NO from an acyl nitroso compound, depending on environmental polarity

A hydrophilic hetero-Diels-Alder cycloadduct was synthesized as a novel photocontrollable donor of reactive nitrogen species. Production of either nitric oxide (NO) or nitroxyl (HNO) was photoinduced from this compound, depending on the environmental polarity.

The acyl nitroso Diels–Alder (ANDA) reaction of sorbate derivatives: an X-ray and 15N NMR study with an application to amino-acid synthesis

We present a study of the acyl nitroso Diels-Alder (ANDA) reaction of sorbate esters and sorbic alcohol derivatives, using alkoxycarbonyl nitroso dienophiles. An optimisation of the reaction conditions for ethyl sorbate is first presented, and the product is used in an efficient synthesis of 5-methylornithine. Structure-reactivity trends in sorbic alcohol (E,E-2,4-hexadien-1-ol) and its acylated analogues are then discussed. We present single-crystal X-ray structural proof for key adducts in both series and present in detail a novel HMBC/HSQC ((1)H-(15)N) criterion for ready distinction of regioisomers arising from such ANDA reactions.

Investigation of steric and functionality limits in the enzymatic dihydroxylation of benzoate esters. Versatile intermediates for the synthesis of pseudo-sugars, amino cyclitols, and bicyclic ring systems

A series of benzoate esters (methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl) were subjected to enzymatic dihydroxylation by E. coli JM 109(pDTG 601) strain in a whole-cell fermentation. The cis-cyclohexadienediols were obtained in yields of approximately 1g/L except for n-propyl- and i-propyl benzoate which were found to be poor substrates. n-Butyl and t-butyl benzoates were not oxidized at all. The absolute stereochemistry for all metabolites was determined by comparison with a standard prepared from (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol, whose absolute configuration is well established. The free diols were found to be quite stable compared to other cis-dihydrodiols of this type, however, their acetonides underwent a dimerization via a regio- and stereoselective Diels-Alder cycloaddition. The diol derived from ethyl benzoate was subjected to a stereo- and regioselective inverse electron demand Diels-Alder cycloadditions with several dienophiles. The new adducts were completely characterized. The hetero-Diels-Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols. The diol was also converted to carba-alpha-L-galactopyranose to demonstrate its potential utility as a source of pseudo sugars. Experimental and spectral data are provided for all new compounds.

Mechanistic Insights into Transition Metal‐Catalysed Oxidation of a Hydroxamic Acid with in situ Diels–Alder Trapping of the Acyl Nitroso Derivative

AbstractNew insights into the mechanism for the transition metal‐mediated oxidation of hydroxamic acids to give intermediate acyl nitroso species, with subsequent hetero‐Diels–Alder trapping are presented. The activation of triphenylphosphine‐ligated ruthenium‐salen complexes is examined, and evidence is presented for the ruthenium‐oxo species which are involved in the oxidative process of the hydroxamic acid. The observation of the lack of asymmetric induction involved in the intermolecular cycloaddition process involving the intermediate acyl nitrsoso species is explained, with the aid of comparing the ruthenium‐salen‐based systems with nitrosotoluene, and copper(I)/copper(II) BINAP‐based catalysis of nitrosopyridine complexes. This study demonstrates the importance of secondary coordination to achieve asymmetric induction in nitroso‐Diels–Alder reactions.

Photoactivatable HNO-releasing compounds using the retro-Diels–Alder reaction

We synthesized hetero-Diels-Alder cycloadducts from acyl nitroso derivatives and 9,10-dimethylanthracene, to be photo-inducible HNO-releasing agents and found that introduction of conjugated nitroaromatic groups effectively enhanced the responsiveness of HNO release to UV-A irradiation; we confirmed photoinduced HNO formation by EPR and GCMS analysis.

Development of new transition metal catalysts for the oxidation of a hydroxamic acid with in situ Diels–Alder trapping of the acyl nitroso derivative

New transition metal catalysts have been prepared and applied for in situ formation of acyl nitroso dienophiles.

Grignard Reagent-Mediated Conversion of an Acyl Nitroso-anthracene Cycloadduct to a Nitrone

An intramolecular hetero-Diels-Alder cycloadduct of an acyl nitroso compound and a 9,10-dimethyl anthracene derivative was prepared as a potential nitroxyl (HNO) donor. This compound did not release HNO under any of the conditions tested. Treatment of this cycloadduct with excess MeMgCl resulted in the formation of a nitrone, whose structure was confirmed by X-ray crystallography. A mechanism where MeMgCl acts as a nucleophile, strong base, and Lewis acid possibly explains the formation of this product.

Selective Opening of Ring C in the Morphine Skeleton by an Unexpected Cleavage of the C5−C6 Bond in Cycloadducts of Thebaine and Acyl Nitroso Compounds

[reaction: see text] Acyl nitroso cycloadducts of the alkaloid thebaine undergo an unexpected cleavage of the C5-C6 bond when treated with 2 equiv of samarium(II) iodide in THF to give novel hexahydrobenzazocine products. A proposed mechanism for the transformation involves rearrangement of the initial radical anion.

N-Hydroxyurea and Acyl Nitroso Compounds as Nitroxyl (HNO) and Nitric Oxide (NO) Donors

Hydroxyurea has emerged as a new therapy for sickle cell disease but a complete mechanistic description of its beneficial actions does not exist. Patients taking hydroxyurea show evidence for the in vivo conversion of hydroxyurea to nitric oxide (NO), which also has drawn interest as a sickle cell disease treatment. While the chemical oxidation of hydroxyurea produces NO or NO-related products, NO formation from the reactions of hydroxyurea and hemoglobin do not occur fast enough to account for the observed increases in patients taking hydroxyurea. Both horseradish peroxidase and catalase catalyze the rapid formation of nitric oxide and nitroxyl (HNO) from hydroxyurea. In these reactions, hydroxyurea is converted to an acyl nitroso species that hydrolyzes to form HNO. The ferric heme protein then oxidizes HNO to NO that combines with the heme iron to form a ferrous-NO complex that may act as an NO donor. In general, acyl nitroso compounds, regardless of the method of their preparation, hydrolyze to form HNO and the corresponding carboxylic acid derivative. Similarly, the incubation of blood and hydroxyurea with urease rapidly form NO-related species suggesting the initial urease-mediated hydrolysis of hydroxyurea to hydroxylamine, which then reacts quickly with hemoglobin to form these products. These studies present two NO releasing mechanisms from hydroxyurea that are kinetically competent with clinical observations.

Ene Reactions of Acyl Nitroso Intermediates with Alkenes and Their Halocyclization.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Nitroxyl (HNO) Release from New Functionalized N‐Hydroxyurea‐Derived Acyl Nitroso‐9,10‐dimethylanthracene Cycloadducts.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dual Function Catalysts. Dehydrogenation and Asymmetric Intramolecular Diels−Alder Cycloaddition of N-Hydroxy Formate Esters and Hydroxamic Acids: Evidence for a Ruthenium−Acylnitroso Intermediate

The chiral ruthenium salen complex, 13b, functions as an efficient catalyst for the sequential oxidation and asymmetric Diels-Alder cycloaddition of hydroxamic acids and N-hydroxy formate esters. This result provides evidence for the formation of a ruthenium-nitroso formate (acyl nitroso) intermediate. The Diels-Alder precursors are prepared from simple building blocks, and the cycloadducts, bridged oxazinolactams, can serve as useful intermediates in organic synthesis.

Ene reactions of acyl nitroso intermediates with alkenes and their halocyclization

Highly reactive acyl nitroso intermediates were formed in situ by transition metals-catalyzed hydrogen peroxide oxidation of hydroxamic acids 1a– b and these transient species trapped with alkenes 2a– c to afford the corresponding ene products 3a– d and 4b up to 91% yield, and halocyclization of 3d gave substituted oxazolidinone 5a in 77% yield.

Nitroxyl (HNO) release from new functionalized N-hydroxyurea-derived acyl nitroso-9,10-dimethylanthracene cycloadducts

A thermal retro-Diels–Alder decomposition of N-hydroxyurea-derived acyl nitroso compounds and 9,10-dimethylanthracene cycloadducts followed by acyl nitroso compound hydrolysis produces nitrous oxide, evidence for the formation of nitroxyl, the one-electron reduced form of nitric oxide that has drawn considerable attention for its potential roles in biological systems. EPR and NMR spectroscopy provide further evidence for nitroxyl formation and kinetic information, respectively. Such compounds may prove to be useful alternative nitroxyl donors.

The Development and Application of Ruthenium Catalyzed Oxidations of a Hydroxamic Acid and in situ Diels—Alder Trapping of the Acyl Nitroso Derivative.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Direct observation of an acyl nitroso species in solution by time-resolved IR spectrocopy.

Benzoyl nitroside (5) was generated in solution by laser photolysis of 3,5-diphenyl-1,2,4-oxadiazole-4-oxide (4) and studied by time-resolved infrared spectroscopy. The second-order rate constants for reaction of 5 with diethylamine and 1,3-cyclohexadiene were determined to be (1.3 +/- 0.5) x 10(5) M(-1) s(-1) and (6.0 +/- 0.5) x 10(3) M(-1) s(-1), respectively. The formation of nitroxyl (HNO), a product of the reaction of 5 with diethylamine, was also observed.