Cyclic Precursors Research Articles

Synthesis of γ-Butyrolactams by Photoinduced PhSe Group Transfer Radical Cyclization and Formal Synthesis of (±)-Isocynometrine with Diphenyldiselenide as Promoter

We have developed a strategy for constructing nitrogen heterocycles by photoinduced PhSe group transfer radical cyclization. trans-Alpha,beta-disubstituted gamma-butyrolactams (2-pyrrolidinones) were prepared in good yields (38-73%) with high regioselectivity and stereoselectivity from N-alkenyl alpha-PhSe beta-keto amides. Reaction outcomes were modulated by the steric effect of the substituents on the nitrogen atom of the cyclization precursors and the stereoelectronic effect of the substrates. Diphenyldiselenide, as an additive, was found to promote ring closure. The advantage of this strategy in natural product synthesis is demonstrated by a formal synthesis of (+/-)-isocynometrine.

A new approach to indolo[2,3- a]quinolizidines through radical cyclization of 2-acyl-1-phenylthiotetrahydro-β-carbolines bearing pendent α,β-unsaturated esters

A new method is reported for the preparation of indolo[2,3- a]quinolizidines based on radical cyclization of a 2-acyl-1-phenylthiotetrahydro-β-carboline bearing a pendent α,β-unsaturated ester. The required radical cyclization precursor is efficiently assembled from E-5-ethoxycarbonyl-4-pentenoic acid and 3,4-dihydro-β-carboline through a DCC/HOBt-activation/N-acylation and BF 3·Et 2O/PhSH iminium-ion trapping sequence. Tin-mediated radical cyclization of the radical cyclization precursor affords stereoselectively a cis-lactam (dr = 7:1) in good yield (81%), bearing the correct D/E ring fusion stereochemistry for the Tacaman alkaloids. The methodology has been applied to formal syntheses of the indoloquinolizidine alkaloids, (±)-eburnaminol and (±)-larutensine.

The Synthesis of Functionalised Bicyclo[3.3.1]nonanes Related to Huperzine A

Radical cyclisation-based synthetic routes to the core structure of huperzine A, are described. Cyclisation of (2-pyridyl)methyl radicals derived from two model [(2-phenylseleno­methyl)-3-pyridyl]cyclohexenones, proceeds in 6-exo-trig mode to give bicyclo[3.3.1]nonanes. Cyclisation yields are related to the substitution pattern and relative stereochemistry about the enone ring. Cyclisation precursors were accessed by either conjugate addition of a (3-pyridyl)cuprate onto an enone or by Diels-Alder cycloaddition of a (3-pyridyl)-substituted alkene with Rawal’s diene.

Ultrafast time‐resolved studies of the photochemistry of diazo carbonyl compounds

AbstractThe rich photochemistry of diazo carbonyl compounds in solution has been extensively studied by ultrafast transient absorption spectroscopy with UV–Vis and mid‐IR detection. Both, stepwise (carbene mediated) and concerted Wolff rearrangement (WR) mechanisms have been confirmed for cyclic and acyclic diazo carbonyl precursors. Cyclic diazo‐carbonyl compounds are structurally locked in a syn conformation and mainly follow the concerted mechanism, however, a stepwise pathway does slightly contribute to the overall WR process, contrary to Kaplan's rule. With acyclic diazo ester carbonyl compounds, the WR process is dominated by the stepwise mechanism. A carbene–carbene interconversion process and singlet to triplet carbene intersystem crossing (ISC) processes are discussed in this review. The growth of secondary species (cations, ylides, OH insertion product) emerging from an interaction between a singlet carbene and solvent molecules has been characterized by picosecond time‐resolved UV–Vis transient absorption spectroscopy. Carbene reactivity results in shortening of the singlet carbene lifetime relative to more inert solvents. The quantum yield of diazo decomposition can be deduced from partial ground state bleach recovery using ultrafast time‐resolved IR spectroscopy. Copyright © 2009 John Wiley & Sons, Ltd.

Total Synthesis of the Aspercyclides

Two different approaches to the eleven-membered biaryl ether lactones of the aspercyclide family are disclosed. The core regions of these highly strained targets, which are able to interfere with the binding of immunoglobulin E to its high affinity receptor, can either be forged by ring-closing olefin metathesis (RCM) or by a highly diastereoselective chromium-mediated Nozaki-Hiyama-Kishi (NHK) reaction. Whereas the RCM approach turned out to be responsive to minor changes in the substitution pattern of the substrate, the NHK route is more generally applicable. The preparation of the required cyclization precursor 43 hinged on a palladium-catalyzed ortho-iodination reaction of 2-methylbenzoic acid, an efficient copper-catalyzed Ullmann coupling, and a Takai-Utimoto olefination as the key steps. Moreover, the esterification of the 2,6-disubstituted benzoic acid 34 with the sterically hindered secondary alcohol 37 was far from trivial. However, this and related transformations were accomplished by recourse to the corresponding acid fluorides, which provided excellent yields in cases in which the more commonly used acid chlorides or mixed anhydrides failed to afford any of the desired products.

Mechanistic Analysis of Intramolecular Free Radical Reactions toward Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives

The mechanisms for the formation of conformationally constrained epibatidine analogues by intramolecular free radical processes have been computationally addressed by means of DFT methods. The mechanism and the critical effect of the 7-nitrogen protecting group on the outcome of these radical-mediated cyclizations are discussed. Theoretical findings account for unexpected experimental results and can assist in the selection of proper precursors for a successful cyclization.

Synthesis of new 7-azabicyclo[2.2.1]heptane derivatives

The synthesis of new 7-azabicyclo[2.2.1]heptane derivatives has been achieved in a four-step synthetic sequence, starting from readily available cyclohex-3-enecarboxylic acid, Curtius reaction, stereoselective bromination leading to major benzyl(cis-3,trans-4-dibromocyclohex-1yl)carbamates (amides or sulfonamides), followed by NaH-mediated intramolecular cyclization. The synthesis and free radical cyclization of precursors 4-7, as well as the synthesis of a conformationally constrained epibatidine analogue 3 exploiting the reactivity of the 7azabicyclo[2.2.1]hept-2-yl radical in intramolecular reactions, are described. The N-sulfonyl functional motif is the only one to afford a cyclized product when incorporated in the radical precursor.

Cluster self-organization of Na-TR-Ge-O-H (TR = La-Lu, Y, and Sc) germanate systems: Suprapolyhedral precursor clusters and self-assembly of Na2Pr6Ge8O26, Na4Sc2Ge4O13, and Na5ScGe4O12 crystal structures

In an M-T-O model system (M is a polyvalent metal; T = Ge or Si), we consider initial stages of formation of cyclic MT clusters and the mechanism of their modification by T tetrahedra. The polyhedron ratio T/M in clusters increases progressively during modeling from one in M2T2 to two (M2T2 + 2T = M2T4), three (M2T2 + 2T2 = M2T6), and four (M2T2 + 2T + 2T2 = M2T8). These types of clusters were used to find precursor clusters for T-condensed structures of Na2Pr6Ge8O26, Na4Sc2Ge4O13, and Na5ScGe4O12. The TOPOS program package was used to carry out the complete 3D reconstruction of the self-assembly of Na,TR germanates: precursor cluster → primary chain → microlayer → microframework (supraprecursor) → ... framework. In all structures, as previously in six orthotetrahedral Na,TR germanate structures, the basic invariant type of four-polyhedral cyclic precursor cluster M2T2 was identified; this cluster is built of TR polyhedra, with CN = 6 or 7, linked via orthotetrahedra. The features of the generation of a Ge radical were considered in the form of a Ge2O7 chain and a Ge4O12 ring in various layers of the Na2Pr6Ge8O26 composite structure, a Ge4O13 chain in Na4Sc2Ge4O13, and a Ge12O36 ring in the Na5ScGe4O12 superionic conductor.

Total Synthesis of (−)‐Norzoanthamine

No bones about it: (-)-Norzoanthamine, a promising candidate for an anti-osteoporotic drug, was the target of a total synthesis (see scheme). The final bisaminal formation with AcOH/H(2)O gave the DEFG ring, while the cyclization precursor was prepared by installing the remaining bisaminal unit after oxidative cleavage of the cyclopentanol moiety.

Mechanistic study of 7-endo selective radical cyclization of the aryl radical

Mechanistic studies on the novel 7-endo selective radical cyclization were carried out. The reaction afforded three products, 7-endo product, 6-exo product, and reduced product. The distribution of these products was estimated by GC analyses. The 7-endo/6-exo selectivity was almost constant against variation in the concentration of Bu 3SnH, while the reduction/cyclization ratio was sensitive to the concentration of Bu 3SnH. The reduction/cyclization ratio was mainly affected by the rotational isomeric ratio of the cyclization precursor. Kinetic analyses indicated that the cyclization process should be irreversible, and the rate constant of 7-endo/6-exo radical cyclization was estimated to be about 3.3 × 10 8 s −1 at 80 °C.

Unexpected decarbonylation during an acid-mediated cyclization to access the carbocyclic core of zoanthenol

An unusual loss of CO was observed during a key cyclization event in efforts toward the total synthesis of zoanthenol. The synthesis of the cyclization precursor and a proposed mechanism for decarbonylation are detailed.

Direct synthesis of sulfonated azacalixarenes in water

Successive treatment of cyanuric chloride with two aromatic diamines, at least one of them sulfonated, yields water-soluble sulfonated azacalix[4]arenes which may be isolated by crystallisation. Functionalised azacalixarenes may be made by first displacing two chloro substituents from the cyclisation precursor. Attempted formation of an azacalix[6]arene led to a dimeric species for which two structures may be proposed, one of them an azacalixarene catenane.

Topological Polymer Chemistry in Pursuit of Elusive Polymer Ring Constructions

Current challenges and future perspectives of topological polymer chemistry have been reviewed. A variety of novel cyclic and multicyclic macromolecular topologies has now been realized by intriguing synthetic protocols. In particular, the electrostatic polymer self-assembly of telechelic precursors having cyclic ammonium salt groups accompanying polyfunctional carboxylate counteranions has been exploited in dilution to produce topologically significant, non–covalent constructions of a dynamic nature. The subsequent covalent conversion through the ring–opening or through the ring–emitting reaction of cyclic ammonium salt groups by carboxylate counteranions provides cyclic and multicyclic polymer products effectively. Furthermore, the metathesis condensation process with functional cyclic polymer precursors has been demonstrated as a promising synthetic means to construct a variety of complex polymer topologies.

Interrupting the Nazarov reaction: domino and cascade processes utilizing cyclopentenyl cations

The Nazarov reaction entails the electrocyclic closure of a conjugated pentadienyl cation to furnish a cyclopentenyl cation. In its conventional protocol, this intermediate is allowed to undergo elimination through loss of an adjacent proton, providing cyclopentenone products. This feature article describes a relatively new class of domino and cascade processes in which the mechanistic course of the Nazarov reaction is diverted at the point of the cyclopentenyl cation intermediate, collectively referred to as "interrupted Nazarov reactions." A variety of intra- or intermolecular nucleophiles, including silyl hydrides, alkenes, arenes, amines, halides, oxygen nucleophiles and azides, can capture the cation at one terminus, resulting in interesting polycyclic structures. 1,3-Dienes also trap the cyclopentenyl cation, but in this case via concerted [4 + 3]-cycloaddition to give keto-bridged cyclooctenes. An alternative method for generating the pentadienyl cyclization precursor from dichlorocyclopropanes rather than cross-conjugated dienones is also discussed, along with some novel trapping processes.

Rapid synthesis of macrocycles from diol precursors

A method for the formation of synthetic macrocycles with different ring sizes from diols is presented. Reacting a simple diol precursor with electrophilic reagents leads to a cyclic carbonate, sulfite, or phosphate in a single step in 25–60% yield. Converting the cyclization precursor to a bis-electrophilic iodide or aldehyde enables preparation of a cyclic sulfide and amine, respectively, the latter using a double-reductive amination to induce ring closure.

ChemInform Abstract: Novel Synthesis of Cinnolines and 1‐Aminoindolines via Cu‐Catalyzed Intramolecular N‐Arylation of Hydrazines and Hydrazones Prepared from 3‐Haloaryl‐3‐hydroxy‐2‐diazopropanoates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Second Generation Formal Synthesis of (−)-Cephalotaxine

A second generation formal synthesis of the alkaloid (-)-cephalotaxine has been achieved using an alkylidene carbene 1,5-CH insertion reaction to establish a key quaternary stereocenter. The carbene precursor was readily derived from L-proline, and the 1,5-CH insertion reaction was performed under Ohira's conditions using lithiotrimethylsilyldiazomethane (LTDM), which gave the desired spirocyclic product in 74% yield. The hydroxymethyl group was then oxidized and then decarbonylated (93%), and this material was easily transformed into the desired Friedel-Crafts cyclization precursor. Exposure of this material to SnCl4 then gave the desired pentacyclic product, which was identical to that previously prepared by Mori and thus represents a formal total synthesis of (-)-cephalotaxine.

A practical approach to the synthesis of enantiomerically pure 2,6-disubstituted morpholines under phase transfer catalysis conditions

A novel, straightforward and high yielding synthesis of enantiomerically pure 2,6-disubstituted morpholines has been developed through the regioselective cyclization of diols. Cyclization precursors have been obtained by the ring opening of commercially available chiral epoxides under solid–liquid phase transfer catalysis conditions (SL-PTC).

Durable and rechargeable biocidal polypropylene polymers and fibers prepared by using reactive extrusion

Incorporation of N-halamine precursor onto polypropylene was explored by using a reactive extrusion process. Several cyclic and acyclic halamine precursors were grafted onto polypropylene backbone through a melt free radical graft copolymerization. The structures and morphology of the grafted polymer were characterized with FTIR, and scanning electron microscope. Thermal properties of the polymers were evaluated by differential scanning calorimetry. The halogenated products of the corresponding grafted samples exhibited potent antimicrobial properties against Escherichia coli, and the antimicrobial properties were durable and regenerable. The relationship between effective surface contact and biocidal efficacy are further discussed.

Total Synthesis of Largazole and Its Biological Evaluation

We achieved a total synthesis of largazole. The optically active β-hydroxycarbonyl unit was prepared from a modified Nagao’s N-acetylthiazolidinethione. A 4-methylthiazoline-thiazole amino ester was prepared by both a step-by-step method and tandem cyclization from Cys-2-MeCys-containing tripeptide. Amidation of the activated β-hydroxycarbonyl unit and 4-methyl-thiazoline-thiazole-containing amino ester, followed by esterification with N-Fmoc valine afforded cyclization precursor after selective removal of the methyl ester at the C-terminus and the Fmoc group at the N-terminus. Macrolactamization, deprotection of thiol, and S-acylation provided largazole. Biological evaluation of its S-modified derivatives as well as the synthetic largazole exhibited strong inhibitory activity against histone deacetylases (HDAC).