Bicyclic Framework Research Articles

Synthesis of bicyclic diphosphine having a P−P bond doubly clamped with two 1,8-naphthalenediyl groups

A synthetic route was developed for a novel bicyclic diphosphine 5 in which two structurally robust 1,8-naphthalenediyl groups clamp the P–P bond of the diphosphine to form a butterfly structure. The bicyclic framework was synthesized by a ring-opening dimerization of a strained four-membered phosphacycle of iPr2NP-peri-bridged naphthalene 8. A toluene solution of 8 was heated for 2days in the presence of O2 and one equivalent of H2O to give a mixture of oxides of the target diphosphine 5, then the mixture of oxides was reduced with HSiCl3 to afford 5 in a moderate yield. The crystal structure of 5 confirmed that the P–P bond and the two naphthalene groups form a butterfly molecular structure, and the two lone pairs on the respective phosphorus centers are disposed in a synperiplanar configuration. These two phosphorus donor atoms bind two AuCl fragments to form a unique “U-shape” binuclear complex (μ-5)-[AuCl]2 in which the two Au(I) centers are separated by ca. 4.4Å that indicates the negligible intramolecular Au–Au interaction. In the crystal, the two binuclear complexes interlocked with each other through multiple intermolecular Au–Au interactions between the two U-shape units.

A versatile, RCM based approach to eudesmane and dihydroagarofuran sesquiterpenoids from (−)-carvone: a formal synthesis of (−)-isocelorbicol

An enantiospecific and diversity oriented approach to a range of functionalized eudesmane, nor-, iso-, and dihydroagarofuran frameworks from (−)-carvone is delineated. The cornerstone of this approach is the installation of the quaternary carbon center through reductive opening of the carvone epoxide and setting-up of RCM reaction to generate the bicyclic eudesmane framework. Various options like carbocation mediated oxycyclization and intramolecular hydroxy directed epoxide opening have been explored for the construction of the bridged tetrahydrofuran moiety. Among the several eudesmane and dihydroagarofurans accessed during the present study, one has been previously elaborated to isocelorbicol, thus constituting its formal synthesis.

Diastereoselective tandem reactions of substituted 3-sulfolenes with bis-vinyl ketones leading to highly functionalized bicyclic and tricyclic frameworks.

The base-promoted reaction of 3-sulfolene with bis-vinyl ketones was shown in earlier work to proceed through a γ-1,2 addition/anionic oxy-Cope cascade; a subsequent treatment with base induced a second γ-1,2 addition to provide a [3.3.0] bicyclic framework that our group then exploited in the design of rigidified enzyme inhibitors for influenza neuraminidase. Out of a desire to expand the range of structural archetypes accessible through these couplings (and hopefully access additional conformationally-constrained inhibitor platforms) we have revisited this methodology, this time using substituted starting reagents. We show that judicious choice of the newly added substituent can control the exclusive formation of one of four new structural types, each formed as a single diastereomer. These include bicyclo[3.2.1] sulfones and spiro[5.4] sulfones, as well as an expanded collection of our original bicyclo[3.3.0] sulfone scaffolds, this time incorporating adjacent quaternary centres or additional rings.

Convergent synthesis of fully functionalized decalin skeleton of (+)-fusarisetin A

Fully functionalized decalin skeleton of (+)-fusarisetin A is stereoselectively synthesized from (+)-citronellal and methyl (S)-(+)-3-hydroxybutyrate. The bicyclic framework has been constructed using intramolecular Diels–Alder reaction.

Hydroarylations of heterobicyclic alkenes through rhodium-catalyzed directed C-H functionalizations of S-aryl sulfoximines.

Rhodium-catalyzed directed CH-functionalizations have been used in hydroarylations of heterobicyclic alkenes with NH-sulfoximines. Unexpectedly, the bicyclic framework is retained, resulting in the formation of addition products being attractive intermediates for functionalized molecules that are difficult to prepare by other means.

Chiral sulfinamidourea and strong Brønsted acid-cocatalyzed enantioselective Povarov reaction to access tetrahydroquinolines.

This protocol describes a method for the laboratory synthesis of enantiomerically enriched, chiral tetrahydroisoquinolines through the application of a chiral sulfinamido urea catalyst for the Povarov reaction. Tetrahydroisoquinolines are bicyclic organic frameworks present in a wide assortment of natural and synthetic biologically important compounds including martinelline, scoulerine and tubocurarine. The methodology involves the [4+2] cycloaddition of a N-arylimines with electron-rich olefins such as vinyl lactams and dihydropyrroles in the presence of a two-catalyst system consisting of an achiral strong Brønsted acid (o-nitrobenzenesulfonic acid), together with the chiral sulfinamido urea derivative 1. The anion-binding properties of the urea lead to the association of the ion pair that results from protonation of the imine substrate. Cycloaddition is followed by spontaneous proton loss with re-aromatization to provide the tetrahydroisoquinoline products in highly enantio-enriched form.

1,3-Dipolar cycloadditions of nitrile oxides with 7-oxa- and 7-azabenzonorbornadienes

Dipolar cycloaddition reactions allow for the efficient construction of five-membered heterocycles, often with diverse medicinal applications. We examined the 1,3-dipolar cycloaddition of 7-oxabenzonorbornadienes and 7-azabenzonorbornadienes with acetonitrile oxide and benzonitrile oxide, achieving an assortment of heterobicycle-fused isoxazolines with good to excellent yields. All isoxazolines were consistently directed to the exo face of the bicyclic framework with complete stereoselectivity. Preliminary biological testing of the adducts also showed positive anti-cancer activity, suggesting their potential pharmaceutical utility.

Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-castanospermine

Abstract A novel gem-difluoromethylenated castanospermine analogue B was designed and synthesized, starting from 3-bromo-3,3-difluoropropene and l -(−)-malic acid. The key steps involve substitution cyclization reaction and RCM reaction to construct the aza fused bicyclic framework.

A biomimetic approach for bicyclic alkaloids using acetal pro-nucleophile: total synthesis of (±)-epilupinine and formal syntheses of (±)-laburnine, (±)-isoretronecanol, (±)-tashiromine

A direct Mannich type diastereoselective biomimetic cyclization using acetal as a pro-nucleophile leading to the hydroxymethyl substituted bicyclic framework of various bicyclic alkaloids is presented. Following this protocol, total synthesis of (±)-epilupinine and formal syntheses of (±)-laburnine, (±)-isoretronecanol and (±)-tashiromine are described.

Molecular Rearrangements of Highly Functionalized Terpenes. An Unique Reactivity of Bicyclic Framework and Polienic Chain Inhibition under Superacidic Treatment

Molecular Rearrangements of Highly Functionalized Terpenes. An Unique Reactivity of Bicyclic Framework and Polienic Chain Inhibition under Superacidic Treatment

Synthesis of Polyhydroxylated Quinolizidines and Azaspiro[4.5]decanes from d-Xylose

The synthesis of novel polyhydroxylated quinolizidines and azaspiro[4.5]decanes is reported. A key step of this transformation involved an addition of allylmagnesium bromide to an ω-bromonitrile derived from D-xylose followed by an intramolecular displacement of a bromide. The resulting cyclic imine was treated either with allylmagnesium bromide or with NaBH4, to provide 2,2-diallyl- or 2-allylpiperidine, respectively. The desired bicyclic framework was constructed via a ring-closing metathesis reaction. The Ru catalysts were reused in the following syn-dihydroxylation step.

ChemInform Abstract: Enantioselective Synthesis of Hindered Cyclic Dialkyl Ethers via Catalytic Oxa‐Michael/Michael Desymmetrization.

An asymmetric oxa-Michael/Michael cascade reaction of p-quinols and α,β-unsaturated aldehydes provides access to hindered dialkyl ethers. A highly enantioselective oxa-Michael addition of a tertiary alcohol precedes an intramolecular cyclohexadienone desymmetrization, which allows for the concomitant formation of four contiguous stereocenters in a single step. The highly functionalized bicyclic frameworks are rapidly obtained from simple starting materials with good diastereoselection and serve as valuable precursors for further manipulation.

An Approach to 2,4‐Substituted Pyrazolo[1,5‐a]pyridines and Pyrazolo[1,5‐a]azepines by Ring‐Closing Metathesis

AbstractThe ring‐closing metathesis (RCM) reactions of dienylpyrazoles have been employed in the synthesis of pyrazolo[1,5‐a]pyridine and pyrazolo[1,5‐a]azepine derivatives. Based on this approach, the diastereoselective synthesis of potential peptidomimetics containing four amino acid residues with the second (i+1) and third (i+2) fragments having been substituted by bicyclic frameworks is described.

Formal Homoiodo Allylsilane Annulations: Dual Total Syntheses of (±)-Hirsutene and (±)-Capnellene

Dual total syntheses of (±)-hirsutene and (±)-capnellene, two typical linear triquinane sesquiterpenes, were achieved via a formal [3 + 2] annulation strategy, as illustrated schematically. Cyclic homoiodo allylsilanes were employed as key bifunctional synthons in the synthesis, which were readily prepared from the corresponding cyclopropanated cyclopentenones. A formal [3 + 3] annulation approach for the elaboration of the bicyclic framework of the Eudesmane sesquiterpenoids based on this type of synthon was also developed.

Radical copolymerization of alkyl cyclobutenecarboxylates fused with cycloaliphatic framework with alkyl (meth)acrylates

ABSTRACTRadical copolymerization behavior of alkyl cyclobutenecarboxylate‐derivatives 4‐6 and related norbornene‐derived compounds 7–9 is described. A variety of alkyl cyclobutenecarboxylates fused with cycloaliphatic framework (4–6) were prepared by [2 + 2] cycloaddition of five, six, and eight‐membered cycloolefins with alkyl propiolates [alkyl = Me, 2‐hydroxyethyl, and 3‐γ‐butyrolactonyl (γ‐BL)]. The fused cyclobutenecarboxylates 4–6 were radically copolymerized with n‐butyl acrylate (nBA) to afford random copolymers, and terpolymerized with alkyl methacrylates with bulky ester groups [alkyl = γ‐BL and 3‐(3‐methyladamantyl)]. The cyclobutane‐containing bicyclic framework incorporated in the resulting polymer backbone contributes to raising Tg of resulting copolymers. Similar results were obtained when a mixture of related norbornene‐derived compounds were used as monomers with an apparently enhanced Tg‐raising effect in the copolymerization with nBA. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2716–2724

The fluorine-NHC gauche effect: a structural and computational study

Herein, we report the synthesis and X-ray structural analysis of a collection of fluorinated metal N-heterocyclic carbenes (Ag, Au, Pd, Rh, Ir) and their precursor salts. The common structural feature of these species is a flanking fluoroethyl group, which is either freely rotating or embedded within a bicyclic framework. Solid state analysis confirmed a gauche conformational preference in all cases with the fluorine adopting a syn clinal arrangement (ϕ[NCCF]∼60°) with respect to the triazolium nitrogen at the vicinal position of the NHC. A density functional theory analysis was employed to quantify these effects and evaluate the influence of electronic modulation of the carbenic carbon [(CN+); neutral carbene (C:); metal-bound carbene (CM)], on the relative gauche/anti preference, thus highlighting the potential of this conformational phenomenon as a useful molecular design strategy for controlling the topology of organometallic complexes.

Synthesis and Coordination Chemistry of an Enantiomerically Pure Pentadienyl Ligand

The coordination chemistry of the enantiomerically pure dimethylnopadienyl ligand (Pdl*) with early to late transition metals is presented. Dimethylnopadiene is prepared by a Wittig reaction from (1R)-(−)-myrtenal, which is readily available from the chiral pool. Deprotonation of dimethylnopadiene with a Schlosser base gives K(Pdl*), which is a good starting material for the preparation of the early- to late-transition-metal open metallocenes [M(η5-Pdl*)2] (M = Ti, V, Cr, Fe) and mono(pentadienyl) complexes [(η5-Cp′)Fe(η5-Pdl*)] (Cp′ = 1,2,4-(Me3C)3C5H2), [(η7-C7H7)Zr(η5-Pdl*)], and [(η4-COD)Ir(η5-Pdl*)]. These complexes have been fully characterized by several spectroscopic techniques, elemental analysis, and X-ray crystallography. In all of these cases the Pdl* ligand exhibits excellent face selectivity upon metal coordination, because it coordinates exclusively from the sterically less hindered site of the bicyclic ligand framework. Within the series of open metallocenes [M(η5-Pdl*)2] (M = Ti, V, Cr, F...

Visible light photoredox atom transfer Ueno–Stork reaction

A visible light-promoted atom transfer Ueno-Stork reaction was developed using Ir(ppy)2(dtb-bpy)PF6 as the sensitizer. 2-Iodoethyl propargyl ethers or 2-iodoethyl allyl ethers were used as the radical precursors to construct tetrahydrofuran-containing fused [6,5] and [5,5] bicyclic frameworks.

Enantioselective synthesis of hindered cyclic dialkyl ethers via catalytic oxa-Michael/Michael desymmetrization.

An asymmetric oxa-Michael/Michael cascade reaction of p-quinols and α,β-unsaturated aldehydes provides access to hindered dialkyl ethers. A highly enantioselective oxa-Michael addition of a tertiary alcohol precedes an intramolecular cyclohexadienone desymmetrization, which allows for the concomitant formation of four contiguous stereocenters in a single step. The highly functionalized bicyclic frameworks are rapidly obtained from simple starting materials with good diastereoselection and serve as valuable precursors for further manipulation.

Analysis of Optical Activity in Terms of Bonds and Lone-Pairs: The Exceptionally Large Optical Rotation of Norbornenone.

Norbornenone, which has both a C═O and a C═C chromophore in a rigid bicyclic hydrocarbon framework, exhibits optical rotation (OR) an order of magnitude larger than that of similar molecules with only one of these chromophores (e.g., α-pinene). Its OR is also very sensitive to approximations in electronic structure calculations. The present study demonstrates a novel approach to interpret optical rotation using familiar concepts of chemical bonding, aided by first-principles calculations. A theoretical procedure is developed for analyzing the OR tensor components of a molecule in terms of individual bonds and lone pairs. The link between the chemist's bond and quantum mechanics is provided by localized molecular orbitals obtained from density functional theory (DFT) calculations. Delocalization of π orbitals is shown to play a crucial role in the large OR of norbornenone, as hinted by the DFT delocalization error inherent in many standard functionals and confirmed by detailed analysis. The OR contributions generated by the double bond in α-pinene are even stronger than that of norbornenone. The isotropic average, observed in solution or in gas phase, is small as a result of cancellation of tensor components with opposite signs. The electronic coupling and delocalization of the C═C π bond and the C═O oxygen π lone pair in norbornenone selectively enhance one of the OR tensor components, resulting in the exceptionally large negative isotropic OR.