Tricyclic Adducts Research Articles

Quantum chemical studies on the mechanistic aspects of tandem sequential cycloaddition reactions of cyclooctatetraene with ester and nitrones

The mechanisms of the tandem sequential [4 + 2]/[3 + 2] and [3 + 2]/[4 + 2] cycloaddition sequences involving an ester, cyclooctatetraene (COTE), and cyclic and acyclic nitrones for the formation of a diverse range of isoxazolidine derivatives and other synthetic precursors are reported. A thorough exploration of the PES has characterized several regio-, stereo- and enantio-selective mechanistic channels involved in these reactions. A perturbation molecular orbital (PMO) analysis been employed to rationalize the results. It has also been found that the initial electrocyclic ring closure of the COTE is the rate-determining step in the tandem sequential [4 + 2]/[3 + 2] addition sequence. The thermolytic breakdown of the tandem adducts to subsequent monocyclic, bicyclic and tricyclic adducts occurs generally with very high activation barriers making it an inconvenient synthetic approach. The different reactivity of all the three double bonds present in the dipolarophile is reported. Finally, the mechanistic possibilities of [3 + 2]/[4 + 2] addition sequences involving the same reaction components in the case of cyclic and acyclic nitrones are explored extensively. The results suggest a novel and convenient routes for obtaining products of high selectivity with less energetic requirements. In some instances, new cycloadducts hitherto unreported are obtained.

Access to 3-Oxindoles from Allylic Alcohols and Indoles.

The site-selective and regioselective allylation of 2-substituted indoles was performed by using a ruthenium(IV) precatalyst containing a phosphine-sulfonate chelate. Mono-, di-, and triallylated indoles were selectively obtained depending on the reaction conditions with the formation of water as the only byproduct. The preparation of 3-oxindole derivatives was then successfully performed owing to air oxidation of the corresponding allylated indoles. Diallylated pseudoindoxyls were proven to be good synthons to perform cyclization through a ring-closing metathesis reaction to afford the corresponding tricyclic adducts. The photophysical properties of the 3-oxindoles were measured, and some of the compounds showed strong fluorescence in water.

Short Approach toward the Nonracemic A,B,E Tricyclic Core of Calyciphylline B-Type Alkaloids.

A suitably functionalized tricyclic adduct containing the common A,B,E rings found in calyciphylline B-type alkaloids was obtained in nine linear steps. The key transformation features an efficient one-pot sequence of intramolecular Vilsmeier-Haack cyclization and azomethine ylide 1,3-dipolar cycloaddition in which three cycles, three new carbon-carbon bonds, and three stereocenters are formed, one being fully substituted. This work also demonstrates the first use of a chiral, nonracemic cyclic enol ether as an internal carbon nucleophile.

Gold(I)-catalyzed intramolecular cycloisomerization of propargylic esters with furan rings.

A gold-catalyzed intramolecular cycloisomerization of α-yne-furans 1 is described in this contribution. A variety of cyclic α,β-unsaturated aldehyde or ketone derivatives and nitrogen-containing tricyclic adducts were obtained selectively in moderate to excellent yields under mild conditions by varying the substituents on the standard substrates.

Thio-Michael–Aldol–Cyclization Cascade of N-Enoyl Thiazolidinethiones with Aliphatic Aldehydes and Cyclic Ketones

A thio-Michael–aldol–cyclization cascade reaction of N-enoyl thiazolidinethiones with aliphatic aldehydes and cyclic ­ketones was promoted by Ti(IV) chloride to deliver highly complex tricyclic adducts possessing a carbon atom tetrasubstituted with ­heteroatoms and up to four stereogenic centers in good to very good yields.

Homoallenyl azines in criss-cross cycloaddition reactions

Thermally initiated combined intra-intermolecular criss-cross cycloadditions of substituted nonsymmetrical allenyl azines with isocyanate or isothiocyanate dipolarophiles were investigated. Substituted 1,3,10-triazatricyclo[ 5.2.1.04,10]dec-6-en-2-ones or -dec-6-ene-2-thiones were obtained as the main products in moderate to very good yields. The thermal stabilities of the tricyclic adducts in reactions with the competing reactive dipolarophile dimethyl acetylenedicarboxylate were studied and are discussed. In some cases, substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles were found as side products. This reaction showed high atomeconomy and in all caseswe observed the presence of one diastereoisomer and regioisomer only, which was clearly revealed by crystallographic analysis.

ChemInform Abstract: An Easy Route Toward Enantio‐Enriched Polycyclic Derivatives via an Asymmetric Domino Conjugate Reduction—Aldol Cyclization Catalyzed by a Chiral Cu(I) Complex.

AbstractThe intramolecular reductive aldol cyclization of diketo esters in the presence of a silane as reducing agent and a copper/chiral diphosphane complex allows the synthesis of manifold bi‐ and tricyclic adducts with high levels of diastereo‐ and enantiocontrol.

Intramolecular Diels–Alder Reactions of Cycloalkenones: Translation of High Endo Selectivity to Trans Junctions

Intramolecular Diels-Alder reactions of cyclobutenone and larger cycloalkenones are described. High levels of endo addition attained from Lewis acid catalysis translate to trans hydrindene junctions upon fragmentation of the tricyclic adducts.

Concise Enantiospecific, Stereoselective Syntheses of (+)-Crispine A and Its (−)-Antipode

An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.

Tyrosine−Lipid Peroxide Adducts from Radical Termination: Para Coupling and Intramolecular Diels−Alder Cyclization

Free radical co-oxidation of polyunsaturated lipids with tyrosine or phenolic analogues of tyrosine gave rise to lipid peroxide-tyrosine (phenol) adducts in both aqueous micellar and organic solutions. The novel adducts were isolated and characterized by 1D and 2D NMR spectroscopy as well as by mass spectrometry (MS). The spectral data suggest that the polyunsaturated lipid peroxyl radicals give stable peroxide coupling products exclusively at the para position of the tyrosyl (phenoxy) radicals. These adducts have characteristic (13)C chemical shifts at 185 ppm due to the cross-conjugated carbonyl of the phenol-derived cyclohexadienone. The primary peroxide adducts subsequently undergo intramolecular Diels-Alder (IMDA) cyclization, affording a number of diastereomeric tricyclic adducts that have characteristic carbonyl (13)C chemical shifts at ~198 ppm. All of the NMR HMBC and HSQC correlations support the structure assignments of the primary and Diels-Alder adducts, as does MS collision-induced dissociation data. Kinetic rate constants and activation parameters for the IMDA reaction were determined, and the primary adducts were reduced with cuprous ion to give a phenol-derived 4-hydroxycyclohexa-2,5-dienone. No products from adduction of peroxyls at the phenolic ortho position were found in either the primary or cuprous reduction product mixtures. These studies provide a framework for understanding the nature of lipid-protein adducts formed by peroxyl-tyrosyl radical-radical termination processes. Coupling of lipid peroxyl radicals with tyrosyl radicals leads to cyclohexenone and cyclohexadienone adducts, which are of interest in and of themselves since, as electrophiles, they are likely targets for protein nucleophiles. One consequence of lipid peroxyl reactions with tyrosyls may therefore be protein-protein cross-links via interprotein Michael adducts.

ChemInform Abstract: “Bicyclobenzodiazepinones” from 3-Oxo-1,2-diazetidinium Hydroxide, Inner Salts.

Abstract 1,3-Dipolar cycloaddition of benzyne with 3-oxo-l,2-diazetidinium hydroxide, inner salts leads to tricyclic adducts which have been termed “bicyclobenzodiazepinones” because of their structural relationship to 1,4-benzodiazepinones. In analogous fashion, cycloaddition of benzyne with 3-oxopyrazolidinium hydroxide, inner salts, leads to homologous tricyclic adducts. Efforts to convert these readily accessible condensed aza-β-lactams and aza-γ-lactams to benzodiazepinones and benzodiazocinones are described. Several novel ring cleavage reactions leading from the above “bicyclobenzodiazepinones” to indazoles are reported.

Intramolecular cycloaddition in 6,6-spiroepoxycyclohexa-2,4-dienone: simple aromatics to (±)-Platencin

A formal total synthesis of platencin from a simple aromatic precursor is described. Transformation of the aromatic compound into reactive spiroepoxycyclohexa-2,4-dienone and intramolecular cycloaddition are the key features of our methodology. 2-Hydroxymethyl-6-(3-hydroxy-hex-5-enyl)-phenol was oxidized with NaIO(4) to give a dimer that, upon a retro-Diels-Alder reaction, generated the spiroepoxycyclohexa-2,4-dienone that underwent intramolecular Diels-Alder reaction to give a tricyclic adduct having a core structure of platencin and appropriately disposed functional groups in a single step. Reduction of the double bond present in the ethano-bridge, manipulation of the oxirane ring and introduction of a double bond in the six-membered ring furnished a tricyclic intermediate which has already been converted into platencin.

Electronic and Steric Effects on the Mechanism of the Inverse Electron Demand Diels−Alder Reaction of 2-Aminopyrroles with 1,3,5-Triazines: Identification of Five Intermediates by 1H, 13C, 15N, and 19F NMR Spectroscopy

The inverse electron demand Diels-Alder (IEDDA) reaction of 1-tert-butyl-2-aminopyrrole with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine in THF-d(8) to give a pyrrolo[2,3-d]pyrimidine was studied by (1)H, (13)C, (15)N, and (19)F NMR spectroscopy, and five intermediates were identified. A zwitterion was the first intermediate detected, and it cyclized to a tricyclic adduct and its conjugate acid. It also gave a neutral imine via a proton switch. The tricyclic adduct underwent a retro-Diels-Alder reaction, but the expected CF(3)CN was not detected. NMR indicated that the amino group of the 2-aminopyrrole was bonded to the CF(3)CN to form a trifluoroacetoamidinium ion. The products of the retro-Diels-Alder reaction reacted rapidly with each other to give the final intermediate observed. Acid-catalyzed loss of an amidine gave the final aromatic product. This is the first study in which direct experimental evidence for the order of the steps in the IEDDA cascade reaction of 1,3,5-triazines with amino-containing dienophiles has been obtained. This study and analogous 1,3-dipolar cycloaddition reactions, in which zwitterions have been detected or proposed, have two factors in common: electronic effects that stabilize the zwitterions and steric effects that inhibit their cyclization.

A Versatile Cascade of Intramolecular Vilsmeier−Haack and Azomethine Ylide 1,3-Dipolar Cycloaddition toward Tricyclic Cores of Alkaloids

In the pursuit of synthetic efficiency, we developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using a cascade of amide activation, nucleophilic cyclization, azomethine ylide generation, and subsequent inter- or intramolecular 1,3-dipolar cycloaddition. Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good to excellent yields.

Molecular Complexity from Aromatics: A Novel, Stereoselective Route to Tricyclo[5.2.2.01,5]undecenones, Tricyclo[6.2.2.01,6]Dodecenones, and [n.3.3]Propellanes

A general stereoselective route to functionalized and substituted tricyclo [5.2.2.0(1,5)]undecenones, tricyclo[6.2.2.0(1,6)]dodecenones, and [3.3.3]- and [4.3.3]propellanes from simple aromatic precursors is reported. The methodology involves generation and cycloaddition of annulated cyclohexa-2,4-dienones with various acrylates followed by manipulation of the resulting tricyclic adducts, leading to functionalized tricyclo[5.2.2.0(1,5)]undecenones and tricyclo[6.2.2.0(1,6)]dodecenones endowed with a beta,gamma-enone chromophore. Photochemical reaction of the tricyclic chromophoric systems followed by reductive cleavage provided an efficient entry into propellanes.

Efficient synthesis of 3-hydroxymethylated cis- and trans-cyclobutane β-amino acids using an intramolecular photocycloaddition strategy

Uracil bearing a tethered allyl alcohol appendage at N1 undergoes a [2+2] photocycloaddition reaction to provide a single tricyclic adduct in high yield. This compound is transformed in one step into a cis-cyclobutane β-amino acid bearing a 3-hydroxymethyl group. Through appropriate functionalization and epimerization, the trans isomer is obtained therefrom in only three further steps.

Interrupted Nazarov Reactions Using Dichlorocyclopropanes: A Novel Mode of Arene Trapping

2-Siloxy-2-alkenyl-1,1-dichlorocyclopropanes with aryl-terminated side chains undergo silver-assisted electrocyclic opening/Nazarov cyclization. The resulting 2-siloxycyclopentenyl cations are intercepted by the pendant arenes to furnish tricyclic adducts in moderate to good yields. In cases where the arene trap was tethered through the cyclopropane unit, a new mode of trapping occurred to generate unique bridged carbon frameworks.

Preparation of Highly Alkoxy‐Substituted Naphthaldehyde Derivatives – A Regioselective Approach to Building Blocks for the Synthesis of Rubromycins

AbstractAn efficient synthesis of highly substituted naphthaldehyde derivatives 8 was required for the planned synthesis of compounds of the rubromycin family. Three different routes towards this goal were attempted. Route I started with 1,5‐dihydroxynaphthalene (10), and the pentaalkoxy‐substituted naphthaldehyde 17 was obtained in a straightforward sequence in moderate overall yield. Route II employed an aryne cycloaddition to generate the functionalized naphthalene skeleton. This sequence smoothly provided the bromonaphthalene derivative 19, which served as a very suitable precursor of aldehyde 24, boronic acid 25, and finally the unsymmetrically substituted hexaalkoxynaphthalene derivative 18. Unfortunately, though, the regioselective formylation of 18 to provide the desired aldehyde 8a was not possible, this key compound being obtained only in low yield. Whereas an attempted Claisen rearrangement of O‐allylated derivative 30 furnished the wrong regioisomer 33, the ortho‐Fries rearrangement of the easily available carbamate 34 smoothly afforded the expected amide 35, which turned out to be essentially inert and could not be converted into the corresponding naphthaldeyde 8b. We therefore developed Route III, involving an alternative aryne cycloaddition and a subsequent regioselective ring‐opening of the tricyclic adduct 41. This sequence enabled us to efficiently prepare acetal 44, which was transformed into the desired highly substituted and regioselectively protected naphthaldehyde derivative 8b. The synthesis of this key compound could be achieved in a 12‐step sequence in an overall yield of 9 %. Our planned rubromycin synthesis was successfully verified by the conversion of 8b into the protected α‐hydroxy enone 7b by addition of lithiated methoxyallene followed by hydrolysis and subsequent silylation of intermediate 7a. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis of (±)‐Deoxysymbioimine Using an Intramolecular Diels–Alder Reaction with an N‐Alkoxycarbonyl 2,3‐Dihydropyridinium Cation as the Dienophile

Three rings: Treatment of an N-2,2,2-trichloroethoxycarbonyl (Troc)-substituted tetrahydropyridinol (1) with BF3⋅Et2O in CH2Cl2 gave a tricyclic adduct 2 (31 % yield) through an intramolecular Diels–Alder reaction. Reduction with zinc gave deoxysymbioimine (3), a potential antiresorptive and anti-inflammatory drug.

Access to Tri‐ and Tetracyclic Structures by Thermally Promoted and High‐Pressure‐Promoted [4+2] Cycloadditions of 2‐, 3‐ or 4‐Vinyl‐Substituted Binuclear Heterocycles

AbstractA set of 3‐(2‐alkoxyvinyl)benzofurans, ‐furopyridines and‐indoles 5–8 have been tested in [4+2] cycloaddition reactions. The results indicate that they all behave as good dienes, even with only moderately activated dienophiles such as acrylates or MVK. The endo/exo selectivity observed in the adducts depends on the activation conditions: in general, thermal conditions tend to favour the exo isomers, while high pressures preferentially provide the endo isomers. Only the (E) isomers of these dienes proved reactive, the (Z) isomers generally being recovered unaltered. The [4.4.0] binuclear heterocycles such as the isochromene compound 13 and the isoquinolinones 14–16 tested here proved to be significantly less reactive. Finally, the resulting tricyclic adducts 19 were engaged in ene reactions with NPM. Additions involving solely the endo isomers of these adducts took place, stereoselectively affording the succinimide derivatives 29, although in low yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)