Intramolecular Hetero Diels-Alder Reaction Research Articles

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Method for the synthesis of chromenopyrimidine-fused azoles by copper-catalyzed intramolecular hetero-Diels–Alder reaction

Method for the synthesis of chromenopyrimidine-fused azoles by copper-catalyzed intramolecular hetero-Diels–Alder reaction

Multifaceted Domino Knoevenagel‐Cyclization Reactions; Four Movements for 2H‐Chromenes and Chromans

AbstractDomino Knoevenagel‐cyclization reactions of 2H‐chromene and chroman derivatives containing o‐formylaryl amine or ether side‐chain was carried out to produce four series of chiral condensed heterocycles representing four novel skeletons and exhibiting antiproliferative activity. The cyclization step occurred with four different mechanisms: a concerted intramolecular hetero Diels‐Alder reaction (IMHDA), a stepwise polar [2+2] cycloaddition, a [1,5]‐hydride shift‐6‐endo cyclization or a multi‐step nitro hetero Diels‐Alder‐ring‐opening‐Cadogan‐type cyclization sequence. The latter reaction provided a new route to hydroxyindoles by an inverse Cadogan‐type cyclization, in which the nitro group is deoxygenated by a nitro IMHDA‐ring‐opening sequence. The cyclization mechanisms and their stereoselectivity were studied by DFT calculations, based on which we proposed a mechanism for the multi‐step cyclization to hydroxyindoles and explained the observed diastereoselectivity.

Tandem vinylogous Mannich and hetero Diels-Alder reactions: Concise total synthesis of (±)-Alstoscholarisine E

The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in 15.2% overall yield requiring only seven linear steps from commercially available reagents. The approach features a tandem vinylogous Mannich reaction and an intramolecular hetero Diels-Alder reaction to access the cis -oxahydroisoquinolone core. Following the coupling of this cis- oxahydroisoquinolone subunit with a 3-methylindole derivative via a Suzuki reaction, a novel tactic to induce the challenging diastereoselective reduction of the cyclic vinyl ether moiety was discovered. Completion of the synthesis was achieved using a new procedure we developed for iridium-catalyzed, reductive formation of aminals from tertiary lactams, thereby expanding the utility of tertiary amides and lactams as surrogates for iminium ions.

Divergent Total Syntheses of Six Ganoderma Meroterpenoids: A Bioinspired Two-Phase Strategy

We briefly highlight our recent work on the total synthesis of six Ganoderma phenolic meroterpenoids: ganocins A–C, ganocochlearins A–D, and cochlearol T. Critical to this success was a bioinspired two-phase strategy that featured an early-stage rapid construction of a common planar tricyclic intermediate and late-stage highly selective transformations of this intermediate into various Ganoderma meroterpenoids. Key steps of the synthesis include a biomimetic ortho-quinone methide intramolecular hetero-Diels–Alder reaction, a Stahl-type oxidative aromatization, a nucleophilic dearomatization of a phenol, a regioselective 1,4-reduction of a dienone, a site-selective Mukaiyama hydration, and an intramolecular oxa-Michael addition/triflation cascade.

Divergent Biomimetic Total Syntheses of Ganocins A–C, Ganocochlearins C and D, and Cochlearol T

A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A-C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two-phase strategy which includes early-stage rapid construction of a common planar tricyclic intermediate followed by highly selective late-stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero-Diels-Alder reaction and Stahl-type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4-reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site-selective Mukaiyama hydration, followed by an intramolecular oxa-Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A.

Efficient synthesis of pentacyclic benzosultam-annulated thiopyranoindoles via domino Knoevenagel / intramolecular hetero-Diels–Alder reactions in water

A convenient catalyst-free synthesis of hitherto unknown pentacyclic benzosultam-annulated thiopyranoindole derivatives is reported which proceeds via domino Knoevenagel / intramolecular hetero-Diels–Alder reactions of (E)-N-alkyl-2-aryl-N-(2-formylphenyl)ethene-1-sulfonamides with indoline-2-thiones in water. The products were obtained regioselectively in high yields.

Accessing Tricyclic Imines Comprising a 2-Azabicyclo[2.2.2]octane Scaffold by Intramolecular Hetero-Diels–Alder Reaction of 4-Alkenyl-Substituted N-Silyl-1,4-dihydropyridines

Tricyclic imines inheriting a 2-azabicyclo[2.2.2]octane (isoquinuclidine) scaffold were provided with high regioselectivity in moderate to very good yields by a smooth, broadly applicable intramolecular hetero-Diels–Alder reaction of various 4-ω-alkenyl-substituted 1,4-dihydropyridines (DHPs) under trifluoroacetic acid catalysis. The required­ 4,4-disubstituted 1,4-DHPs were obtained by introduction of ω-alkenyl moieties of varying chain length via diorganomagnesium reagents into the 4-position of diversely 4-substituted pyridines after prior N-activation with triisopropylsilyltriflate.

Total Syntheses and Determination of Absolute Configurations of Cep-212 and Cep-210, Predicted Biosynthetic Intermediates of Tetrodotoxin Isolated from Toxic Newt.

Total syntheses of Cep-212 and Cep-210, predicted biosynthetic intermediates of tetrodotoxin isolated from the Japanese toxic newt, have been accomplished from geraniol by an intramolecular hetero Diels-Alder reaction as a key step in a highly stereoselective manner. The success of these syntheses enabled us to determine their absolute configurations by using a chiral normal-phase HPLC/MS analysis of the bis-dinitrobenzene derivative of natural Cep-212 and reference derivatives prepared from chemically synthesized enantiomers.

Double-Diels-Alder Approach to Maoecrystal V. Unexpected C-C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core.

Synthetic studies toward maoecrystal V are reported. An oxidative dearomatization/Diels-Alder cascade to assemble the natural product carbocyclic core in one step is proposed. A facile electrocyclization is shown to suppress the intramolecular allene Diels-Alder pathway. This obstacle is alleviated via a stepwise approach with an allene equivalent to access the key cyclopentadiene-fused [2.2.2]-bicyclic core. Upon treatment with Lewis acid, the proposed intramolecular hetero-Diels-Alder reaction is cleanly and unexpectedly diverted either via C-C bond-forming fragmentation to the spiro-indene product (when R = OMe) or via elimination (when R = H).

ZnCl2-Promoted Intramolecular Hetero-Diels-Alder Reaction of o-Alkynylphenylcarbodiimides for Synthesis of Dihydrodibenzo[b,g][1,8]naphthyridines.

The ZnCl2-promoted intramolecular hetero-Diels-Alder reaction of N-(ortho-propargylphenyl)-N'-arylcarbodiimides, in which the aryl-N=C moiety functioned as a 2-azabuta-1,3-diene, 4π component, has been achieved. By this method, very rare 5,12-dihydrodibenzo[b,g][1,8]naphthyridines and fully aromatized dibenzo[b,g][1,8]naphthyridines were successfully synthesized.

Taichunamides: Prenylated Indole Alkaloids from Aspergillus taichungensis (IBT 19404)

AbstractSeven new prenylated indole alkaloids, taichunamides A–G, were isolated from the fungus Aspergillus taichungensis (IBT 19404). Taichunamides A and B contained an azetidine and 4‐pyridone units, respectively, and are likely biosynthesized from notoamide S via (+)‐6‐epi‐stephacidin A. Taichunamides C and D contain endoperoxide and methylsulfonyl units, respectively. This fungus produced indole alkaloids containing an anti‐bicyclo[2.2.2]diazaoctane core, whereas A. protuberus and A. amoenus produced congeners with a syn‐bicyclo[2.2.2]diazaoctane core. Plausible biosynthetic pathways to access these cores within the three species likely arise from an intramolecular hetero Diels–Alder reaction.

Synthesis of triterpenoid triazine derivatives from allobetulone and betulonic acid with biological activities

The synthetic transformation and modification of natural products with the aim to improve the biological properties is an area of current interest. The triterpenoids betulin and betulinic acid are very abundant in nature and now are commercially available. In our study, starting from betulin and betulinic acid, we obtained allobetulone and betulonic acid in a few synthetic steps. The ketone function at the A-ring was used as the starting point for the synthesis of a series of 1,2,4-triazine-fused triterpenoids. The alkylation and Liebeskind–Srogl coupling were used for further substitution of 1,2,4-triazines, and the intramolecular hetero Diels–Alder reaction leads to interesting fused thienopyridine derivatives. All new compounds were tested for their cytostatic activities against murine leukemia L1210, human cervix carcinoma HeLa and human lymphoblast CEM tumor cells. The results show that some triterpenoid triazine betulonic acid derivatives have a promising cytostatic activity in vitro and could be used as potential leads for the development of new type of anti-cancer agents. Several compounds were also endowed with anti-HCMV activity in the low micromolar range.

A facile stereoselective synthesis of julolidine hybrid analogs via domino knoevenagel intramolecular hetero Diels–Alder reaction

We have reported here a facile stereoselective synthesis of julolidine hybrid analogs by employing domino Knoevenagel intramolecular hetero Diels–Alder reaction on symmetrical 1,3-diones and unsymmetrical 1,3-diones It was found that the cycloaddition proceeded efficiently under microwave irradiation to afford highly stereoselective cycloadducts in good yields

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

AbstractA new type of terpenoid cyclization by manganese(III)‐initiated oxidation of β‐ketoester, followed by an intramolecular hetero Diels—Alder reaction with the terpenoid chain is investigated.

ChemInform Abstract: Synthetic Studies Toward Communesins

AbstractReview: 31 refs.

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.

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.