Cyclic N-acyliminium Research Articles

Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding Proteins.

Access to small, rigid, and sp3-rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506-binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate-mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14-step gram-scale synthesis featuring anodic oxidation, stereospecific vinylation, and N-acyl iminium cyclization. Structure-based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.

A modular and divergent approach for the total synthesis of Elaeocarpus alkaloids

Modular and divergent synthesis of six Elaeocarpus alkaloids in 6–10 steps utilizing NbCl5 mediated N-acyliminium cyclization as the key strategy.

Enantioselective Construction of Tetrasubstituted Carbon Stereocenters via Chiral Phosphoric Acid-Catalyzed Friedel-Craft Alkylation of Indoles with 5-Substituted Hydroxybutyrolactams.

The first intermolecular organocatalytic enantioselective addition of indoles to prochiral 5-membered cyclic N-acyliminium ions, generated from 5-hydroxy-α,β-unsaturated pyrrolidin-2-ones, is reported hereinafter. The reaction proceeds smoothly with a range of 5-hydroxy-5-substituted-α,β-unsaturated pyrrolidin-2-ones and indoles using BINOL-derived phosphoric acid catalyst to afford α,β-unsaturated lactams embedding a tetrasubstituted stereogenic center in high yields and enantioselectivities.

Diastereoselective Synthesis of Tetrahydrofurano[2,3-g]indolizidines and 8-Aminoindolizidines from l-Asparagine

Abstract8-Aminoindolizidines were synthesized from l-asparagine as the chiral starting material. The key dibenzylamino succinimide intermediate was synthesized in two steps. Three homologs of chiral hydroxy lactams tethered with hydroxyalkenes were synthesized from the succinimide through a sequence involving N-alkylation, cross-olefin metathesis, and hydride reduction. The dibenzylamino group gave stereocontrol of the key N-acyliminium ion cyclization of these hydroxy lactams. 5-Substituted aminoindolizidines were synthesized with high diastereoselectivity at C6. A tandem cyclization of an N-(6-hydroxyhex-3-en-1-yl) γ-hydroxy lactam resulted in the formation of a tetrahydrofurano[2,3-g]indolizidine system.

Catalytic asymmetric addition to cyclic N-acyl-iminium: access to sulfone-bearing contiguous quaternary stereocenters.

Herein, we report the first chiral phosphoric acid (CPA)-catalyzed asymmetric addition of α-fluoro(phenylsulfonyl)methane (FSM) derivatives to in situ generated cyclic N-acyliminium. This process enables metal-free expeditious access to sulfone and fluorine incorporating contiguous all substituted quaternary stereocenters ingrained in biorelevant isoindolinones in excellent stereoselectivities (up to 99% ee and up to 50 : 1 dr).

Enantiodivergent Synthesis of Benzoquinolizidinones from L-Glutamic Acid.

Benzoquinolizidinone systems were synthesized in both enantiomeric forms from L-glutamic acid. The key chiral arylethylglutarimide intermediate was synthesized from dibenzylamino-glutamate and homoveratrylamine. Aldol reaction of the glutarimide afforded a mixture of syn and anti-aldol adducts. Subsequent regioselective hydride reduction of the glutarimide carbonyl followed by N-acyliminium ion cyclization afforded a product with opposite absolute configurations at C3 and C11b. Cope elimination of the dibenzylamino group then converted the two diastereomers into enantiomers.

De Novo Approach to Izidines via A Gold-Catalyzed Hydroamination–N-acyliminium Ion Cyclization of Acyclic Ynamides

De Novo Approach to Izidines via A Gold-Catalyzed Hydroamination–N-acyliminium Ion Cyclization of Acyclic Ynamides

Synthesis of aminal-type Lilium candidum alkaloids and lilaline; determination of their relative configuration by the concerted use of NMR spectroscopy and DFT conformational analysis

Abstract We hereby report the synthesis of six racemic alkaloids isolated from Lilium candidum L. Their common structural feature is a five-membered lactam ring which is, in the case of the flavonoid alkaloid lilaline, attached to the molecule’s aromatic core, while in the case of the other five compounds, it is connected to the nitrogen atom of a pyrrolinone ring by an aminal function. The syntheses of these natural products were achieved via Mannich-type alkylations through cyclic N-acyliminium ions as intermediates. Besides the synthesis, the so far unexplored stereochemistry of these natural products was determined by a combination of NMR-based proton–proton distance measurements and theoretical conformational analyses carried out at the DFT level.

Synthesis and X-ray diffraction structure of a novel steroid-pyrrolidinoisoquinoline alkaloid hybrid

A novel steroid – pyrrolidinoisoquinoline alkaloid hybrid has been successfully synthesized by Diels-Alder reaction N-acyliminium ion cyclization sequence.

Experimental and Computational Studies Unraveling the Peculiarity of Enolizable Oxoesters in the Organocatalyzed Mannich-Type Addition to Cyclic N-Acyl Iminium Ions.

γ− and δ-Oxoesters are easily available starting materials that have been sparingly used in some organocatalyzed reactions proceeding with a high enantioselectivity. In our experimentation we found that the use of these compounds as the enolizable (nucleophilic) component in organocatalyzed Mannich-type reactions using in situ-generated cyclic N-acyl iminium ions gave low diastereoselectivity and low to moderate values of enantioselectivity. This significant drop of facial selectivity with respect to simple aliphatic aldehydes has been rationalized by means of density functional theory (DFT) calculations.

The Pictet-Spengler Reaction Updates Its Habits.

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

Synthesis of 5-Substituted 2-Pyrrolidinones by Coupling of Organozinc Reagents with Cyclic N-Acyliminium Ions

A coupling reaction between cyclic N-acyliminium ions with organozinc reagents is described. The cyclic N-acyliminium ions, generated in situ from N-substituted-5-hydroxy-2-pyrrolidinones by treatment with boron trifluoride–diethyl ether complex or titanium tetrachloride, are trapped by the organozinc reagent, which is formed from an alkyl bromide in the presence of zinc in the same reaction medium. The N-substituted-5-allyl-2-pyrrolidinones generated using this method serve as versatile intermediates for the synthesis of azabicyclic systems with indolizidine and pyrroloazepinolizidine cores.

Exocyclic N-Acyliminium Ion (NAI) Cyclization: Access to Fully Substituted Oxazoles and Furocoumarins.

A concise, one-pot route to oxazoles and furocoumarins has been reported. The key step in this transformation involves in situ generation of N-acyliminium ion (NAI) precursor under catalyst and solvent-free conditions and their further transformations promoted by superacid in the same pot. We have also presented the experimental evidence for the involvement of proto-solvated novel exocyclic N-acyliminium ion. Further, the UV-visible and fluorescence studies revealed that few of the compounds reported here exhibited emission of blue light upon irradiation in EtOH in the region of 404-422 nm.

Unified Total Synthesis of Madangamine Alkaloids

Abstract The full details of a unified total synthesis of madangamine alkaloids are disclosed. Our central strategy is based on the construction of a common ABCE-tetracyclic system, followed by the late-stage installation of various D-rings. The common intermediate is assembled through N-acyliminium cyclization of a propargylsilane, and formation of the (Z,Z)-skipped diene. Stereoselective synthesis of the (Z,Z)-skipped diene is especially challenging, and is accomplished by the combination of Z-selective hydroboration of the 1,1-disubstituted allene and subsequent Migita-Kosugi-Stille coupling. Macrocyclic alkylation enables the late-stage variation of the D-rings on the common tetracyclic intermediate, resulting in the collective total syntheses of madangamines A–E. The synthetic madangamine alkaloids exhibited inhibitory activities against a variety of human cancer cell lines.

Configuration-Dependent Medium-Sized Ring Formation: Chiral Molecular Framework with Three-Dimensional Architecture.

This report describes a configuration-dependent [6 + 8 + 5] fused ring formation via a tandem cyclic N-acyliminium nucleophilic addition reaction. Cyclization of the acyclic precursor prepared on a solid phase using l-Ser and a racemic mixture of Fmoc- trans-2-aminocyclohexanecarboxylic acid predominantly yielded the cyclic diastereomer with the (1 R,2 R)-2-aminocyclohexane moiety rather than the tricyclic diastereomer from the (1 S,2 S)-enantiomer. In contrast, the model compound prepared with d-Ser predominantly cyclized with the (1 S,2 S)-2-aminocyclohexanecarboxylic acid substrate. The outcome of the cyclization was not influenced by the type of resin, the spacer, or the N-substituent. The analogous synthesis of the [6 + 7 + 5] fused ring system yielded inseparable diastereomers in a 1:0.6 ratio.

Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations.

In this study, six-membered N-acyliminium ions were generated by the “indirect cation pool” method and reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be consistent with the Steven’s hypothesis.

Stereoselective Synthesis of Pyrroloisoindolone and Pyridoisoindolone via aza-Prins Cyclization of Endocyclic N-Acyliminium Ions.

A simple methodology has been developed for the synthesis of substituted pyrroloisoindolone and pyridoisoindolone via aza-Prins cyclization of endocyclic N-acyliminium ions, which are derived from the triflic acid treatment of regioselectively reduced N-homopropargyl imides in excellent yields. The reaction is highly diastereoselective, and only one diastereoisomer is formed during the reaction. The methodology can be utilized for the synthesis of pyrimidoisoindole.

Synthesis of a tetracyclic core of Erythrina alkaloids and analogs of crispine A

Both enantiomers of C10b methyl analogs of crispine A and a tetracyclic core of Erythrina alkaloids were synthesized starting from l-aspartic acid via a common chiral N-arylethyl succinimide intermediate. The pivotal C10a-C10b bond formation and construction of the C10b stereogenic center were achieved via diastereoselective N-acyliminium ion cyclization. The dibenzylamino group gave stereochemical control where 1,2- and 1,3-stereoinductions led to the cyclized products with opposite configurations at the newly generated stereogenic center. Cope elimination of the dibenzylamino group gave a cyclic enamide which underwent Michael addition and ring closing metathesis of the resulting bis-allyl intermediate in the synthesis of a tetracyclic core of Erythrina alkaloids.

Scaffold Diversity from N-Acyliminium Ions.

N-Acyliminium ions are powerful reactive species for the formation of carbon-carbon and carbon-heteroatom bonds. Strategies relying on intramolecular reactions of N-acyliminium intermediates, also referred to as N-acyliminium ion cyclization reactions, have been employed for the construction of structurally diverse scaffolds, ranging from simple bicyclic skeletons to complex polycyclic systems and natural-product-like compounds. This review aims to provide an overview of cyclization reactions of N-acyliminium ions derived from various precursors for the assembly of structurally diverse scaffolds, covering the literature over the past 12 years (from 2004 to 2015).

Triflic Acid Mediated Cyclization of Unsymmetrical N-Phenethyl- and N-(3-Indolylethyl)succinimides: Regio- and Diastereoselective Synthesis of Substituted Pyrroloisoquinolinones and Indolizino­indolones

The regio and diastereoselective synthesis of 1 or 2 alkyl-substituted pyrroloisoquinolinones and indolizinoindolones by triflic acid mediated cyclization via an electrophilic activation of unsymmetrical succinimide carbonyl groups followed by the reduction of fused cyclic N-acyliminium ion is reported. This strategy successfully furnished the pyrroloisoquinolinone and indolizinoindolone derivatives in regio- and diastereoselective manner. The steric factor dictates the regioselectivity in N-phenethyl unsymmetrical succinimides and electronic factor seems to dictate the regioselectivity in N-(3-indolylethyl) unsymmetrical succinimides.