Alder Reaction Sequence Research Articles

Design, Synthesis and Late-Stage Modification of Indane-Based Peptides via [2+2+2] Cyclotrimerization.

Here, we prepared several dipeptides containing 2-aminoindane-2-carboxylic acid (Aic) and carried out further synthetic transformations. Synthesis and purification of modified peptides by using [2+2+2] cyclotrimerization is a challenging task. We are able to modify the unusual amino acids and peptide derivatives by late-stage incorporation of benzylhalo functionality. To incorporate benzylhalo moiety we used [2+2+2] cyclotrimerization in the presence of Mo(CO)6 . These halo derivatives are potential substrates for further modification by Sonogashira reaction, Suzuki-Miyaura cross-coupling, sultine formation, and the Diels-Alder reaction sequence.

Mono‐Gold(I)‐Catalyzed Enantioselective Intermolecular Reaction of Ynones with Styrenes: Tandem Diels–Alder and Ene Sequence

AbstractGold‐catalyzed intermolecular reaction leading to dihydronaphthalene derivatives in one pot from two equivalents of ynones with respect to styrene is uncovered. The [4+2] Diels–Alder cycloaddition of ynones and styrenes is catalyzed by a mono‐gold(I) complex and the conjugated acid to provide an unstable 3,8a‐dihydronaphthalene to subsequently undergo an intermolecular ene‐type reaction with the π‐activated ynone to afford multi‐component coupling dihydronaphthalene products. Linear relationships between chiral ligand‐gold complexes and chiral dihydronaphthalene products proves mono‐gold catalysis that triggers an asymmetric tandem Diels–Alder and ene reaction sequence.

Total Synthesis of Talatisamine

AbstractTalatisamine (1) is a member of the C19‐diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5‐membered‐ring structure (ABCDEF‐ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6‐membered AE‐ring 7 and aromatic 6‐membered D‐ring 6. AE‐ring 7 was constructed from 2‐cyclohexenone (8) through fusing an N‐ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels–Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6‐membered ring system was then stereospecifically reorganized into the 7/5‐membered BC‐ring of 3 via a Wagner–Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza‐Prins cyclization of 2, thereby forging the remaining 5‐membered F‐ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8.

Synthesis of the Bicyclic Lactone Core of Leonuketal, Enabled by a Telescoped Diels-Alder Reaction Sequence.

The Diels-Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels-Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]-bicyclic lactone ring system and its [3.2.1] isomer. Our four-step, protecting-group-free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels-Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.

Homodimerization of 2H-chromenes catalyzed by Brønsted-acid derived UiO-66 MOFs

Brønsted acid UiO-66 MOFs were prepared for the efficient homo-dimerization of 2H-chromenes, which involves a tandem rearrangement/hetero-Diels–Alder reaction sequence.

ChemInform Abstract: A New Synthetic Strategy to 2,3‐Diallyl‐1,4‐quinones via One‐Pot Double Claisen Rearrangement and Retro Diels—Alder Reaction.

AbstractA simple alternative method to 2,3‐diallyl‐1,4‐quinone derivatives via a one‐pot double claisen rearrangement and retro Diels—Alder reaction sequence involving readily available starting materials is reported.

One-Pot Cascade Synthesis of Fused Nitrogen-Containing Heterocycles in Aqueous Media – Utility of N-Protective Groups in Intramolecular Diels–Alder Reaction of Furan

A metal-free, thermal, intramolecular Diels–Alder (IMDA) reaction of furan in aqueous media without the use of microwave irradiation was investigated. Protection of the amine functionality and the cycloaddition reaction were performed as a one-pot, two-component process. Various nitrogen-protecting groups and their electronic and steric effects on the cycloaddition reaction were studied. The protection–intramolecular Diels–Alder reaction sequence proceeds under environmentally benign aqueous conditions, which are tolerated by substrates with a broad range of nitrogen-protecting groups such as benzyloxycarbonyl (Cbz), trityl, tert-butoxycarbonyl (Boc), trifluoroacetyl, tosyl, mesyl, and p-nosyl [(4-nitrophenyl)sulfonyl]. This study allowed the development of a stereoselective, tandem allylamine isomerization–Diels–Alder cycloaddition sequence leading to the rapid assembly of complex nitrogen-containing heterocycles in a simple one-pot process.

Illustrating the Utility of X-ray Crystallography for Structure Elucidation through a Tandem Aldol Condensation/Diels–Alder Reaction Sequence

Two introductory organic chemistry laboratory experiments are described based on the Diels–Alder reaction of 2,3,4,5-tetraphenylcyclopentadienone, which is synthesized prior to or in a one-pot reaction, with styrene. Students are presented with three possible products, the endo and exo diastereomers and the decarbonylated product, for the beautiful crystalline compound isolated. Analysis by IR and 1H NMR spectroscopy aid investigators in proposing an initial structure for the product, but the solved X-ray crystal structure provides unequivocal evidence of its stereochemistry. Both versions of the synthesis introduce two important and atom economical reactions, employ the Karplus relationship for 1H NMR interpretation, and illustrate the power of X-ray crystallography for molecular structure determination.

ChemInform Abstract: Tandem inverse‐Electron‐Demand hetero‐/retro‐Diels—Alder Reactions for Aromatic Nitrogen Heterocycle Synthesis

AbstractReview: 85 refs.

The synthesis of 3-hydroxymethylfuro[3,2- b]naphtho[2,3- d]furan-5,10-dione, a novel metabolite isolated from Crescentia cujete

The title natural product 1, which possesses a new ring skeleton, has been synthesised by a sequence in which the key steps involve a tandem intramolecular Diels–Alder/reverse Diels–Alder reaction sequence. Thus 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol was treated with ethyl 3-bromopropiolate, and without isolation, the resulting acetylenic ether was heated in the presence of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine. Intramolecular addition of the pendant acetylenic chain to the furan ring followed by cycloaddition of the electron-deficient tetrazine and subsequent cycloreversion delivered ethyl 5,10-dimethoxyfuro[3,2- b]naphtho[2,3- d]furan-3-carboxylate, which has the ring system of the natural product. Functional group manipulation then provided 1.

Facile synthesis of benzo-fused 2,8-dioxabicyclo[3.3.1]nonane derivatives via a domino Knoevenagel condensation/hetero-Diels–Alder reaction sequence

A facile two-step synthesis of a series of benzo-fused 2,8-dioxabicyclo[3.3.1]nonane derivatives is described, featuring a domino Knoevenagel condensation/intramolecular hetero-Diels–Alder reaction sequence.

An enyne metathesis/Diels–Alder reaction sequence towards the synthesis of cup-shaped 5/5/6-tricyclic architectures

A strategy to synthesize the 5/5/6-tricyclic framework of presilphiperfolane natural products is described, involving a model dienyne compound ( I). The key steps are an enyne metathesis reaction to introduce the diene part and a Diels–Alder cycloaddition to reveal the tricyclic architecture.

Synthesis of 2,3‐Di‐ and 2,3,4‐Trisubstituted Furans from 1,2‐Dioxines Generated by an Enyne‐RCM/Diels—Alder Reaction Sequence.

An efficient method for the synthesis of 2,3- and 2,3,4-substituted furans starting from acyclic enynes was developed using an enyne-RCM/Diels-Alder reaction sequence. The reaction conditions for the transformation of 1,2-dioxines having an adjacent 1,2-oxazine ring into furans and the cleavage of N-O bonds are discussed.

Consecutive Rh(I)‐Catalyzed Alder‐ene/Diels—Alder/Diels—Alder Reaction Sequence Affording Rapid Entry to Polycyclic Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 2,3-Di- and 2,3,4-Trisubstituted Furans from 1,2-Dioxines Generated by an Enyne-RCM/Diels−Alder Reaction Sequence

An efficient method for the synthesis of 2,3- and 2,3,4-substituted furans starting from acyclic enynes was developed using an enyne-RCM/Diels-Alder reaction sequence. The reaction conditions for the transformation of 1,2-dioxines having an adjacent 1,2-oxazine ring into furans and the cleavage of N-O bonds are discussed.

Consecutive Rh(I)-catalyzed Alder-ene/Diels–Alder/Diels–Alder reaction sequence affording rapid entry to polycyclic compounds

Conversion of acyclic allenynes to polycyclic compounds using consecutive transition metal catalyzed carbon–carbon bond forming reactions in a single chemical operation is described. Reaction of an allenyne with a Rh(I) catalyst affords a cross-conjugated triene via a formal Alder-ene reaction. The triene then participates in a Rh(I)-catalyzed intramolecular [4+2] cycloaddition reaction to generate a new conjugated diene. An external dienophile is added to this diene which then undergoes a second [4+2] cycloaddition reaction to afford a complex polycyclic ring system. This reaction sequence demonstrates the synthetic potential of allenynes and cross conjugated trienes and highlights the rapid increases in molecular complexity that are possible by one-pot sequential transition metal catalyzed carbon–carbon bond forming reactions.

Synthesis of Cyclic Peroxides via Enyne‐RCM/Diels—Alder Reaction Sequence.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of polycyclic polyfunctionalized carbocycles by a cobalt(I)‐initiated tandem diels–alder reaction sequence

AbstractThe cobalt(I)‐catalyzed neutral Diels–Alder reaction of acyclic 1,3‐dienes with conjugated enynes can be used to generate secondary dihydroaromatic 1,4,8‐trienes containing a 1,3‐diene substructure, in good yields under mild reaction conditions. These 1,3‐dienes can be converted, with reactive dienophiles in a tandem normal Diels–Alder reaction, into polycyclic compounds. In a similar tandem Diels–Alder sequence, the cobalt‐catalyzed neutral homo Diels–Alder reaction of 2,5‐norbornadiene can be used to generate polycyclic cycloaddition adducts. A sequential triple Diels–Alder reaction sequence can be realized when norbornadiene is reacted with the excess of the conjugated enynes under cobalt(I) catalysis. In a homo Diels–Alder, neutral Diels–Alder, normal Diels–Alder reaction sequence, the intermediately formed adducts are reacted with activated dienophiles to yield polycyclic compounds in a short sequence. The structures of several products were established by X‐ray analysis. This showed that predominantly endo‐products are formed in the tandem reaction sequences, while the exo‐product becomes predominant in the triple Diels–Alder reaction sequence.

New Phosphorus−Carbon Cage Compounds by Diels−Alder and Homo Diels−Alder Reactions of 1,3,5-Triphosphabenzenes with Alkenes

Ethylene, various monosubstituted alkenes (acrylic acid derivatives, styrene), as well as some selected disubstituted alkenes (maleic acid derivatives, fumaric acid derivatives, norbornene, cyclopentadiene) undergo Diels−Alder reactions with the 1,3,5-triphosphabenzenes 1 under mild conditions to furnish the dihydrotriphosphabarrelenes 9, 11a−c, 13a−e, 15a−d, 17a,b, and 24. The monoadduct 26 as well as the diadducts 27 and 28 are isolated following the reaction with norbornadiene. Cyclopropene is the only alkene to undergo a Diels−Alder/homo Diels−Alder reaction sequence to afford the hexacyclic system 20.

A Novel Approach to Bicyclic Alkaloids Using a Tandem Diastereoselective Acyliminocyclization and Retro Diels–Alder Reaction Sequence. Synthesis of (+)-Indolizidine and (+)-Laburnine

Abstract A new approach to a diastereoselective cationic cyclization by stereocontrol due to the bicyclo[2.2.1]heptene moiety in a chiral γ-hydroxy lactam is described. The diastereoselective reaction followed by Diels–Alder cycloreversion has been successfully applied to a chiral synthesis of (+)-indolizidine and (+)-laburnine (=trachelanthamidine).