Hetero Diels Research Articles

Manganese(III)‐Promoted Tandem Oxidation and Cyclization of β‐Keto Ester Derivatives of Terpenoids

AbstractA new type of terpenoid cyclization directed by a β‐keto ester moiety has been developed, which proceeded by manganese(III)‐initiated oxidation of the β‐keto ester, followed by an intramolecular hetero Diels–Alder reaction with the terpenoid chain. This reaction produces polycyclic dihydropyrans in high yields and stereoselectivities under mild conditions.

ChemInform Abstract: Hetero Diels—Alder Reactions of Acyl Phosphonates: Synthesis of Glycosyl Type Phosphonates.

AbstractThe hetero Diels—Alder reaction of acyl phosphonates with activated dienes is presented.

ChemInform Abstract: Cobalt(I) Catalysis in the Diastereoselective Two‐Step Synthesis of Tricyclic Systems.

AbstractThe cobalt‐catalyzed cycloaddition reaction of dienes (I) with alkynes (II) and (VII) followed by a Knoevenagel—hetero—Diels—Alder multicomponent reaction of resulting cyclooctatrienes (III) and cyclohexa‐1,4‐dienes (VIII) with diones (IV) and formaldehyde leads to desired tricyclic pyran derivatives (VI) and (VIII), respectively.

ChemInform Abstract: Cycloaddition Reactions in Aqueous Systems: A Two‐Decade Trend Endeavor

AbstractReview: 154 refs.

Total Synthesis of Indoline Alkaloids: A Cyclopropanation Strategy

Indoline alkaloids constitute a large class of natural products; their diverse and complex structures contribute to potent biological activities in a range of molecules. Designing an appropriate strategy for the total synthesis of indoline alkaloids is a difficult task that depends on being able to efficiently assemble the core architectures. The best strategies allow access to a variety of different indoline alkaloid structures in a minimum of steps. The cyclopropanation of simple olefins and the subsequent synthetic transformation of the resulting cyclopropyl intermediates has been intensively studied in recent decades. In contrast, the cyclopropanation of enamines, especially for the construction of complex nitrogen-containing ring systems, remained relatively unexplored. Previous success with the cyclopropanation of simple indoles to form stable indolylcyclopropanocarboxylates encouraged us to explore the assembly of indoline alkaloid skeletons with cyclopropanation as a key reaction. Theoretically, indolylcyclopropanocarboxylates are doubly activated by a vicinally substituted amino group and carboxyl group; that is, they are typical donor-acceptor cyclopropanes. Accordingly, they tend to yield an active iminium intermediate, which can undergo inter- and intramolecular nucleophilic reactions to form the core structure of indoline alkaloids with an expanded ring system. In this Account, we summarize our efforts to develop a cascade or stepwise reaction of cyclopropanation/ring-opening/iminium cyclization (the CRI reaction) on tryptamine derivatives for assembling indoline alkaloid skeletons. With the CRI approach, three types of indoline alkaloid skeletons have been efficiently constructed: (i) hexahydropyrrolo[2,3-b]indoline (type I), (ii) tetrahydro-9a,4a-iminoethano-9H-carbazole (type II), and (iii) tetrahydroquinolino[2,3-b]indoline (type III). The effects of substituents on tryptamine derivatives were carefully investigated for inter- and intramolecular CRI reactions during construction of type I and type II skeletons. These results provided a basis for the further design and synthesis of complex natural products containing nitrogen. The usefulness of the CRI reaction is well demonstrated by our total synthesis of structurally intriguing indoline alkaloids such as N-acetylardeemin, minfiensine, vincorine, and communesin F. In addition, we highlight advances by other groups in construction of the three types of skeletons as well as their total syntheses of these indoline alkaloids. Discussion of the total syntheses of these indoline alkaloids focuses on comparing the individual synthetic strategies for forming the ring systems embedded in the final products. We also describe the total synthesis of perophoramidine, which has the same type III skeleton as communesin F. The observation of a retro Diels-Alder reaction during our synthesis of communesin F inspired the hetero Diels-Alder reaction on which our total synthesis of perophoramidine was based.

Synthetic Studies toward Communesins

AbstractCommunesins A–H are a growing family of natural products isolated from a marine fungal strain of Penicillium species. Preliminary biological evaluation has revealed that these compounds possess insecticidal activity and cytotoxicity against several tumor cell lines. Their interesting biological activities and unique structures have attracted considerable attention of synthetic chemists worldwide. To date, several elegant protocols for assembling the core structure of these indole alkaloids have been described, including intermolecular Diels–Alder reaction of methylated aurantioclavine with quinine methide imine and intramolecular hetero Diels–Alder reaction of the azaortho‐xylylene intermediates. Recently, three completed total syntheses for communesin F have been disclosed, in which the crucial vicinal quaternary stereogenic centers were constructed by employing an intramolecular cyclopropanation; an intramolecular Heck reaction of a tetrasubstituted alkene, or an oxidative coupling of a 3‐substituted indole, as the key step. Accompanying the total synthesis, the absolute configuration of natural communesin F was established as 6R,7R,8R,9S,11R. However, total syntheses of other members of communesin family that contain an epoxide moiety have not been achieved, which will stimulate more synthetic studies.

Synthesis of hexahydro[2]benzopyrano[3,4- c]pyrroles as serotonin 5-HT 2C receptor agonists via intramolecular hetero Diels–Alder reactions

[2]Benzopyrano[3,4- c]pyrroles were synthesized via an intramolecular hetero Diels–Alder reaction. The reaction was applicable to a wide range of substrates and the products could be easily converted into serotonin 5-HT 2C receptor agonists.

Synthesis of hexahydro[2]benzopyrano[4,3- c]pyridines as serotonin 5-HT 2C receptor agonists via intramolecular hetero Diels–Alder reactions

Hexahydro[2]benzopyrano[4,3- c]pyridines were synthesized by an intramolecular hetero Diels–Alder reaction. The reaction was applicable to a range of substrates and the products could be easily converted into serotonin 5-HT 2C receptor agonists.

Towards Total Synthesis of Communesins and Perophoramidine: Unexpected Cascade Reaction of Michael-Mannich-Mannich Additions

A new type of chiral amidinobenzodiene 5 was prepared from isatin in ten steps. While attempting to prepare the core structure from 5 and tryptamine derivative 17 via a hetero Diels–Alder reaction for the total synthesis of communesin and perophoramidine,we observed an unexpected three-step, one-pot cascade reaction of Michael–Manich–Manich additions. The cascade reaction between 5 and 17 yielded diasteromers 21a and 21b with a complex polycyclic skeleton of 2,3,4,5-diindolinohexahydropyrrole in 76%yield and a ratio of 3:1. The stereochemistry of 21a was confirmed by X-ray crystal-structural analysis.

Preparation of a chiral azadiene for the synthesis of 5-aza analogues of angucyclinones

We have developed an efficient synthesis of both enantiomers of a key azadiene for the preparation of 5-aza analogues of angucyclinones through a hetero Diels–Alder reaction. These dienes were efficiently prepared via a 4-step procedure from known and readily available chiral diketoesters.

Hetero Diels–Alder reactions of acyl phosphonates: synthesis of glycosyl type phosphonates

We have prepared glycosyl type phosphonates via hetero Diels–Alder (HDA) reactions of acyl phosphonates with electron rich dienes. HDA reactions of acyl phosphonates with Danishefsky’s diene required thermal activation to yield the desired dihydropyranones in good yield (70–91%). The reactions with Brassard’s diene involved Lewis acid promotion to yield the corresponding lactones, though in moderate yield (33–69%).

ChemInform Abstract: Concise Synthesis of (.+‐.)‐Perrottetinene with Bibenzyl Cannabinoid.

AbstractThe title compound (.+‐.)‐(VI) is structurally related to cannabinoids and is synthesized via hetero Diels—Alder reaction of a quinine methide intermediate, derived from citral addition product (III).

Mechanisms of the Knoevenagel hetero Diels–Alder sequence in multicomponent reactions to dihydropyrans: experimental and theoretical investigations into the role of water

The role of water in a multicomponent domino reaction (MCR) involving styrene, 2,4-pentanedione, and formaldehyde was studied. Whereas anhydrous conditions produced no reaction, the MCR successfully proceeded in the presence of water, affording the targeted dihydropyran derivatives with good yield. The mechanism of this MCR (Knoevenagel hetero Diels-Alder sequence) was studied with and without explicit water molecules using the SMD continuum solvation model in combination with the B3LYP density functional and the 6-311++G** basis set to compute the water and acetone (aprotic organic solvent) solution Gibbs free energies. In the Knoevenagel step, we found that water acted as a proton relay to favor the formation of more flexible six-membered ring transition state structures both in concerted (direct H(2)O elimination) and stepwise (keto-enol tautomerization and dehydration) pathways. The inclusion of a water molecule in our model resulted in a significant decrease (-8.5 kcal mol(-1)ΔG(water)(‡)) of the direct water elimination activation barrier. Owing to the presence of water, all chemical steps involved in the MCR mechanism had activation free energies barriers lower than 39 kcal mol(-1) at 25 °C in aqueous solvent (<21 kcal mol(-1) ZPE corrected electronic energies barriers). Consequently, the MCR proceeded without the assistance of any catalyst.

Enantioselective syntheses of carbocyclic nucleosides 5′-homocarbovir, epi-4′-homocarbovir, and their cyclopropylamine analogs using facially selective Pd-mediated allylations

Carbocyclic nucleosides (−)-5′-homocarbovir and (+)- epi-4′-homocarbovir were prepared from an acylnitroso-derived hetero Diels–Alder cycloadduct. A kinetic enzymatic resolution generated an enantiopure aminocyclopentenol and Pd(0)-mediated decarboxylative allylations of allyl 2,2,2-trifluoroethyl malonates were used to install the 4′-hydroxyethyl groups. Late stage derivatization gave access to the cyclopropylamine analogs, (−)-5′-homoabacavir, and (+)- epi-4′-homoabacavir. All carbonucleoside target molecules were evaluated for antiviral activity.

Diastereoselective synthesis of cis-fused pyrano[4,5- c]pyrrole derivatives via microwave-accelerated intramolecular Knoevenagal hetero Diels–Alder reaction

The synthesis of enantiomerically pure pyrano[4,5- c]pyrroles has been accomplished by the intramolecular hetero Diels–Alder reaction of enantiomerically pure N-allyltetheredalkenyl aldehydes with various 1,3-diones. The reaction led to the formation of cis-fused enantiomerically pure pyrano[4,5- c]pyrroles in excellent yield under mild conditions and the products were characterized by spectroscopic data.

ChemInform Abstract: Synthesis and Theoretical Studies of Gallium Complexes Back‐Shielded by a Cage‐Shaped Framework of Tris(m‐oxybenzyl)arene.

AbstractFour novel cage‐shaped gallium complexes (I) are prepared and evaluated for their catalytic activity in a hetero Diels—Alder reaction of Danishefsky′s diene (II) with benzaldehyde.

Straightforward hetero Diels–Alder reactions of nitroso dienophiles by microreactor technology

The hetero Diels–Alder reactions of 2-nitrosotoluene and some representative acylnitrosodienophiles with a selected set of 1,3-dienes were studied under microflow conditions. The main assets of the technology, that is, an accurate control of the reaction parameters and continuous operating, led to an increased efficiency of this reaction.

Cycloaddition reactions in aqueous systems: A two-decade trend endeavor

Abstract Cycloaddition reactions are an integral and weighty part of organic chemistry in pedagogy and research as well. The wealthy literature on cycloaddition reactions from their birth up to now, unequivocally witnesses to their leading chemistry. The so-called “conventional solvents” are organic solvents that have indubitably promoted their success. Yet, the toxicity facet of these solvents impedes their use freely and with no fear. Not only is the operating chemist uncomfortable while experimenting, but also the environment is equally threatened. Working out the cycloaddition reactions and other organic ones in aqueous systems would certainly bring some relief to the chemist and to the environment as well. Unusual outcomes in terms of yield, reactivity and selectivity compared to those performed in organic solvents were commonly observed, and have overwhelmed the chemists with surprise indeed. In this review, homo Diels–Alder reactions in aqueous media include those involving the following dienophiles: maleimides, α,β-unsaturated esters, p-benzoquinones, vinyl ketones, phenyl-1-(2-pyridyl)-2-propen-1-one, α,β-unsaturated esters. A special case is the organocatalysis of Diels–Alder cycloaddition of α,β-unsaturated ketones (aldehydes). Of no less importance, some hetero Diels–Alder cycloaddition reactions in water systems are delineated. The impact of additives (salts, organic and inorganic chemicals), micellar catalysis and Lewis/Bronsted acid catalysis on outcomes of such cycloaddition reactions is discussed. The 1,3-dipolar cycloaddition methodology applied to aqueous media has brought forth a number of heterocyclic compounds, usually with a regio- and stereoselectivity pecularity. These heterocycles include triazoles, tetrazoles, pyrazoles, isoxazoles, isoxazolidines, pyrroles and pyrrolidines. The superiority of copper(I) catalysis in the azide-alkyne cycloaddition (Huisgen cycloaddition) in water is endorsed by a number of examples.

ChemInform Abstract: Cooperativity of Chirality in Homogeneous Catalysis: The Gold(I)- Catalyzed Aldol Reaction and the Vanadium(IV)-Catalyzed Hetero-Diels- Alder Cycloaddition

The notion of internal (or intramolecular) cooperativity of chirality is reviewed on the basis of various examples of diastereoisomeric ferrocenylphosphine ligands used in the gold(I)-catalyzed aldol reaction. It was found that the stereochemical outcome of this reaction strongly depends on the specific combination of the absolute configuration of the different stereogenic centers present in the ligand. Thus, individual chirotopic segments in these ligand molecules can act either in a cooperative or noncooperative manner in determining both diastereo-and enantioselectivity. Furthermore, several examples of application of the strategy of double stereodifferentiation (external, or intermolecular cooperativity of chirality) in the gold(I)-catalyzed aldol reaction and the vanadium(IV)-catalyzed hetero Diels–Alder condensation are presented. Based on our work it is apparent that, whether the diastereoselectivity of these two reactions is controlled by the catalyst or by a chiral substrate, cannot be predicted and very much depends on the nature of every individual reactant. Thus, it was found that in both reactions the chiral aldehyde substrate usually has a strong impact on the diastereoselectivity, leading to interesting patterns of double asymmetric induction. On the other hand, chiral isocyanoacetate and chiral-activated dienes, respectively, showed little or no effect on the stereochemical outcome of the reactions.

ChemInform Abstract: Enhanced Stereoselectivity in Aqueous Intramolecular Hetero Diels- Alder Cycloaddition of Chiral Acylnitroso Compounds.

Abstract In an aqueous medium, intramolecular hetero Diels-Alder cycloadditions of the chiral acylnitroso compounds, generated from the chiral hydroxamic acids by in situ periodate oxidation, shows a pronounced enhancement of the trans selectivity compared with the results obtained by employing nonaqueous conditions.