Nitroso Diels-Alder Research Articles

Synthesis of the Cyclopentane Core Skeleton of Cranomycin and Jogyamycin.

Cranomycin and jogyamycin, two aminocyclopentitol natural products, possess complex structures and potential medicinal properties. This review describes synthetic studies about the process of making an advanced intermediate of cranomycin and jogyamycin. This highly functionalized intermediate, featuring three contiguous amine-substituted stereocenters, was constructed from cyclopentadiene through a series of reactions including the nitroso Diels-Alder reaction, nitrogen radical cyclization reaction, 1,2-nitrogen migration, and stereoselective nitrogen addition.

Diastereoselective acyl nitroso Diels-Alder reactions using 1,3-dienes derived from (R)-4-tert-butyldimethylsilyloxy-2-cyclohexen-1-one

1,3-Dienes derived from (R)-4-t-butyldimethylsilyloxy-2-cyclohexen-1-one react with acyl nitroso dienophiles to form exclusively anti [4 + 2] cycloaddition products. These regio and diastereoselective acyl nitroso Diels-Alder reactions increase the asymmetric complexity from one chiral center in the starting material to three chiral centers in the products in a single step and provide a powerful approach for the asymmetric synthesis of compounds containing 3,6-dihydro-1,2-oxazine structural feature.

Synthesis and biological evaluation of 10-benzyloxy-Narciclasine

A chemoenzymatic convergent synthesis of 10-benzyloxy narciclasine from bromobenzene was accomplished in 16 steps. The key transformations included toluene dioxygenase-mediated hydroxylation, nitroso Diels-Alder reaction and intramolecular Heck cyclization. The unnatural derivative of narciclasine was subjected to biological evaluation and its activity was compared to other C-10 and C-7 compounds prepared previously.

Alternating Current Electrolysis as Efficient Tool for the Direct Electrochemical Oxidation of Hydroxamic Acids for Acyl Nitroso Diels-Alder Reactions.

The acyl nitroso Diels–Alder reaction of 1,3‐dienes with electrochemically oxidised hydroxamic acids is described. By using alternating current electrolysis, their typical electro‐induced decomposition could be suppressed in favour of the 1,2‐oxazine cycloaddition products. The reaction was optimised using Design of Experiments (DoE) and a sensitivity test was conducted. A mixture of triethylamine/hexafluoroisopropanol served as supporting electrolyte in dichloromethane, thus giving products of high purity after evaporation of the volatiles without further purification. The optimised reaction conditions were applied to various 1,3‐dienes and hydroxamic acids, giving up to 96 % isolated yield.

Ring Opening Metathesis Polymerization of a New Monomer Derived from a Nitroso Diels–Alder Reaction

AbstractA nitroso Diels–Alder (NDA) reaction between cyclopentadiene and an in situ generated nitroso compound leads to a new heterocyclic monomer for ring opening metathesis polymerization (ROMP) reactions. This monomer could be polymerized in the presence of Grubbs‐third generation initiator with good control over Mn and decent Ð values. The resulting isoxazolidine‐containing material could undergo further hydrogenation, deprotection, and modification with Dansyl chloride as well as ring opening to provide an amino‐and hydroxyl‐decorated “polyolefin.”

Synthetic Studies on Pactamycin: A Synthesis of Johnson's Intermediate.

A formal total synthesis of pactamycin (1) has been accomplished by face-selective and regioselective nitroso Diels-Alder (NDA) reaction of acyl nitroso compound 14, which contains a camphorsultam chiral auxiliary, and chiral cyclopentadiene 12. Construction of the chiral secondary alcohol of 12 was performed by (S,S)-Ts-DENEB catalyst-mediated reduction, and the NDA adduct 15a was readily converted to Johnson's intermediate 21.

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity.

This review focuses upon the use of nitroso Diels–Alder reactions as a structural complexity generating reaction that has been so far a quite scarcely treated topic, despite its potential. In particular, the use of N-acyl-1,2-dihydropyridines as a non-symmetrical diene component in nitroso Diels–Alder reactions encompasses an initial diversification of pathways giving rise to different cycloadducts (direct and inverse). Selective elaborations of these cycloadducts, basically using a reagent-based approach, deliver a discrete number of structurally diverse compounds, including some original heterobicyclic scaffolds and functionalized heterocycles. This forward synthetic planning allowed the individuation of a new biologically active compound based on a novel oxadiaza-bicyclic-[3.3.1]-nonene scaffold which is still under preclinical evaluation.

Aerobic Tetrazine‐Catalyzed Oxidative Nitroso‐Diels‐Alder Reaction of N‐Arylhydroxylamines with Dienecarbamates: Access to Functionalized 1,6‐Dihydro‐1,2‐oxazines

AbstractA new organocatalytic and environmentally friendly aerobic oxidative‐catalyzed nitroso‐Diels‐Alder (NDA) reaction of N‐arylhydroxylamines with dienecarbamates has been developed. 3,6‐Bis(2,2,2‐trifluoroethoxy)‐s‐tetrazine was found to be an effective catalyst to selectively oxidize various N‐arylhydroxylamines in the presence of molecular oxygen, but in the absence of photostimulation, as a terminal oxidant. In addition, active catalytic species can be generated in situ from commercially available 3,6‐dichlorotetrazine.

Erratum to: Recent Advances in Asymmetric Nitroso Diels-Alder Reactions

Erratum to: Recent Advances in Asymmetric Nitroso Diels-Alder Reactions

Recent Advances in Asymmetric Nitroso Diels—Alder Reactions

The nitroso Diels—Alder (NDA) reaction has occupied an important place in organic synthesis, and numbers of important compounds and bioactive skeletons have been synthesized by this method during the past decade. Good regiocontrol and enantioselectivity of the NDA reaction allow it to have wider application. This microreview discusses the latest advances in the area of asymmetric NDA reactions and their synthetic applications since Yamamoto’s detailed summary made in 2006.

Base-Mediated Fragmentation of Bicyclic Dihydro-3,6-oxazines: Transformation of Nitroso Diels-Alder Cycloadducts.

Nitroso Diels-Alder cycloadditions of benzene oxide with various acyl-nitroso derivatives are described. Treatment of these cycloadducts with methyllithium results in a fast fragmentation reaction, leading to highly functionalized cyclic amino alcohols. The mechanism of the reaction and the role of the epoxide in the fragmentation process are investigated. The reaction proceeds via the formation of an unsaturated imine, which tautomerizes to an enamine if no neighboring epoxide is present.

Highly Regio‐ and Enantioselective Nitroso Diels−Alder Reaction of 1,3‐Diene‐1‐carbamates Catalyzed by Chiral N,N′‐Dioxide/Copper(II) Complex

AbstractA chiral N,N′‐dioxide/Copper(II) complex‐catalyzed highly regio‐ and enantioselective nitroso Diels−Alder (NDA) reaction of 2‐nitrosopyridines with 1,3‐diene‐1‐carbamates was described. A series of 3,6‐dihydro‐1,2‐oxazines were obtained in good to excellent yields and ee values. On the basis of the control experiments, ESI‐MS analysis and the absolute configuration of the product, a possible transition state model was proposed to explain the stereocontrol.magnified image

Study of Enantioselective Catalysis of Nitroso-Diels-Alder Reaction on Solid Support

Nitroso-Diels-Alder (NDA) reaction is used as a tool for the synthesis of 3,6-dihydro-1,2-oxazine derivatives, which are important intermediates in the synthesis of natural products and biologically active compounds. In this work, we investigated the enantioselective version of this reaction on a solid support. We studied various catalysts, concentrations, temperatures and solvents and compared them with the best conditions reported for solution-phase chemistry. The best conditions were also applied to other 1,2-oxazine derivatives.

Copper(i)/TF-BiphamPhos catalyzed asymmetric nitroso Diels-Alder reaction.

A highly efficient enantioselective nitroso Diels-Alder reaction of 6-methyl-2-nitroso pyridine with various 1,3-dienes was successfully developed using a Cu(i)/(S)-TF-BiphamPhos complex as the catalyst. For most of the cyclic dienes, synthetically important heterocyclic 3,6-dihydro-1,2-oxazines were obtained in high yields with excellent regio-, diastereo- and enantioselectivities. Acyclic 2-silyloxy-1,3-diene also worked well in the reaction.

Catalytic Enantioselective Nitroso Diels-Alder Reaction.

The nitroso Diels-Alder (NDA) reaction is an attractive strategy for the synthesis of 3,6-dihydro-1,2-oxazines and 1-amino-4-hydroxy-2-ene derivatives. Herein we report the Cu(I)-DTBM-Segphos catalyzed asymmetric intermolecular NDA reaction of variously substituted cyclic 1,3-dienes using highly reactive nitroso compounds derived from pyrimidine and pyridazine derivatives. In most of the cases studied, the cycloadducts were obtained in high yields (up to 99%) with very high regio-, diastereo-, and enantioselectivities (up to regioselectivity > 99:1, d.r. > 99:1, and >99% ee). As an application of this methodology, formal syntheses of conduramine A-1 and narciclasine were accomplished.

An Experimental and Computational Approach to Understanding the Reactions of Acyl Nitroso Compounds in [4 + 2] Cycloadditions.

Catalytic aerobic oxidation of phenyl hydroxycarbamate 1 and 1-hydroxy-3-phenylurea 2 using CuCl2 and 2-ethyl-2-oxazoline in methanol gave acyl nitroso species in situ, which were trapped in nitroso-Diels-Alder (NDA) reactions with various dienes to afford the corresponding cycloadducts in high yields (90-98%). Competing ene products were also present for dienes containing both alkene π-bonds and allylic σ-bonds, and the ene yields are higher with 1 than with 2. The use of the chiral hydroxamic acid, (R)-1-hydroxy-3-(1-phenylethylurea) 3 (same conditions) gave NDA cycloadducts in high yields (97-99%) with no ene product from 2,3-dimethyl-1,3-butadiene. NDA cycloadducts were not obtained from other hydroxamic acid analogues [RCONHOH (R = PhCH2 4; Ph(CH2)2 5; Ph(CH2)3 6; Ph(CH2)4 7; Ph 8; 2-pyridyl 9; 3-pyridyl 10] with various dienes using copper-oxidation but rather were obtained using sodium periodate, resulting in variable NDA yields (13-51%) from hydroxamic acids 1-10 with cyclohexa-1,3-diene and 2,3-dimethyl-1,3-butadiene (several cycloadducts characterized by X-ray crystallography). The NDA and nitroso-ene reaction pathways of nitroso intermediates with dienes were mapped by DFT computations (B3LYP/6-31G*), which showed that the acyl nitroso species are super-reactive and that activation energies in the NDA processes are lower than the isomerization barriers between some cis- and trans-butadienes.

ChemInform Abstract: Nitroso Diels—Alder (NDA) Reaction as an Efficient Tool for the Functionalization of Diene‐Containing Natural Products

AbstractReview: [170 refs.

Nitroso Diels-Alder (NDA) reaction as an efficient tool for the functionalization of diene-containing natural products.

This review describes the use of nitroso Diels-Alder reactions for the functionalization of complex diene-containing natural products in order to generate libraries of compounds with potential biological activity. The application of this methodology to the structural modification of a series of natural products (thebaine, steroidal dienes, rapamycin, leucomycin, colchicine, isocolchicine and piperine) is discussed using relevant examples from the literature from 1973 onwards. The biological activity of the resulting compounds is also discussed. Additional comments are provided that evaluate the methodology as a useful tool in organic, bioorganic and medicinal chemistry.

A new life for nitrosocarbonyls in pericyclic reactions

Cu(I/II) salts or Rose Bengal, used in a catalytic amounts, allow for the mild and easy oxidation of hydroxamic acids to nitrosocarbonyls, using air as final oxidant. These new mild oxidative protocols open new vistas in the field of nitroso Diels-Alder (NDA) and ene reactions (ER) of these fugitive intermediates.

Stereodivergent Synthesis of Piperidine Alkaloids by Ring‐Rearrangement Metathesis/Reductive Lactam Alkylation of Nitroso Diels–Alder Cycloadducts

A general methodology for the stereoselective synthesis of 2-(2-hydroxyalkyl)piperidine alkaloids by ring-rearrangement metathesis of nitroso Diels-Alder cycloadducts is reported. The approach is illustrated by the formal synthesis of porantheridine and the total synthesis of andrachcinidine through a diastereodivergent allylation of an N-alkoxy bicyclic lactam. The asymmetric synthesis of the latter alkaloid provides new insights into the configurational stability of cycloadducts between chloronitroso reagents and cyclopentadiene.