Cyclic N-acyliminium Research Articles

Total Synthesis of the Tetracyclic Lupin Alkaloid (+)-Allomatrine

(+)-Allomatrine (1) has been synthesized using an imino-aldol reaction and N-acyliminium cyclization as key steps. Strategically, use of the tert-butylsulfinimine derivative of (E)-4-(trimethylsilyl)but-2-enal enabled the staged formation of three C-C bonds, a C-N bond, and the four stereogenic centers within the target.

A concise approach to the spiroiminal fragment of marineosins

A concise approach to the spiroiminal fragment of marineosins A and B is described. The key steps involve an acid-catalyzed N-acyliminium ion cyclization and a Vilsmeier-Haack type reaction with Tf2O.

A cascade approach to fused indolizinones through Lewis acid–copper(i) relay catalysis

A relay catalytic cascade process involving Lewis acid triggered ring-opening of cyclopropyl ketones with nitriles, the copper(I)-catalyzed Ritter process, and acid-promoted N-acyliminium ion cyclization is described, which efficiently provides thieno-, furano-, and benzo-indolizinones in moderate to good yields.

Solid‐Phase Synthesis of Structurally Diverse Heterocycles by an Amide–Ketone Condensation/N‐Acyliminium Pictet–Spengler Sequence

An efficient approach for the solid-phase synthesis of structurally diverse heterocyclic compounds is presented. Under acidic reaction conditions, peptidic levulinamides undergo intramolecular ketone-amide condensation reactions to form cyclic N-acyliminium intermediates. In the presence of a tethered nucleophile, a second cyclization reaction results in the formation of a fused bicyclic ring system. The scope of the methodology was demonstrated by several combinations of substituted ketones and nucleophiles, the latter conveniently originating from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. The cyclization sequence provides diastereomerically pure products in high yields. In one extension of the methodology, the resulting relative stereochemistry of the products enables the formation of bridged ring systems by a unique cyclative release mechanism.

Highly diastereoselective N-acyliminium ion cyclization reactions of a tethered furan

The acid catalysed cyclization reactions of tethered furan−4,5-dihydroxypyrrolid-2-ones and furan–4,5-diacetoxypyrrolid-2-ones, via their corresponding N-acyliminium ion intermediates, have been studied. In the case of the tethered furan–3,4-dihydroxypyrrolid-2-one 16, having a two carbon tether, the linearly fused tricyclic compound 18 was formed with high cis selectivity (cis/trans=84:16) when BF3·OEt2 was used as a catalyst. However, when the cyclization reaction was carried out on the related tethered furan–4,5-diacetoxypyrrolid-2-one 17, the linearly fused tricyclic compound 20 was formed as a single diastereoisomer with trans selectivity. In contrast, the attempted cyclization of the tethered furan–4,5-dihydroxypyrrolid-2-one 26, having a one carbon tether, did not result in formation of the corresponding linearly fused tricyclic system, instead it formed the dimer 29 as a single diastereoisomer. Cyclization reactions of the related tethered furan–4,5-diacetoxypyrrolid-2-one 27 also failed to give the corresponding linearly fused tricyclic system or macrocycle.

Dual Hard/Soft Gold Catalysis: Intermolecular Friedel–Crafts‐Type α‐Amidoalkylation/Alkyne Hydroarylation Sequences by N‐Acyliminium Ion Chemistry

Gold catalysts have been applied in cascade-type reactions for the synthesis of different nitrogen-based compounds. The reactions likely proceed by a new gold-catalyzed cascade intermolecular α-amidoalkylation/intramolecular carbocyclization cascade process by unifying both the σ- and π-Lewis acid properties of the gold salts. In the first part of this report we show that the σ-Lewis acidity of gold(I) and gold(III) could be exploited to efficiently catalyze the nucleophilic substitution of various alkoxy- and acetoxylactams. The reaction was found to be applicable to a wide range of cyclic N-acyliminium ion precursors and various nucleophiles, including allyltrimethylsilane, silyl enol ethers, arenes, and active methylene derivatives. As a logical progression of this study, a combined hard/soft binary catalytic gold system was then used to implement an unprecedented tandem intermolecular Friedel-Crafts amidoalkylation/intramolecular hydroarylation sequence allowing an expedient access to new, complex, fused polyheterocyclic structures from trivial materials.

ChemInform Abstract: Exploiting a Novel Size Exclusion Phenomenon for Enantioselective Acid/Base Cascade Catalysis.

AbstractA size exclusion phenomenon between PS‐BEMP and bulky BINOL phosphoric acid BPA allows for one‐pot base‐catalyzed Michael addition/acid‐catalyzed enantioselective N‐acyliminium cyclization cascade reactions [→(III); 10 examples].

ChemInform Abstract: N‐Acyliminium Cyclization as an Approach for an Asymmetric Synthesis of the Pyrrolo[2,1‐a]benzazepine Ring System.

AbstractThe key step is a stereoselective N‐acyliminium cyclization.

Polymer-Supported Stereoselective Synthesis of Benzimidazolinopiperazinones

We describe the efficient synthesis of 4,7,8,10-tetrasubstituted-(((4S,10aS)-3-oxo-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)alkyl)amides on solid phase via tandem N-acyliminium ion cyclization-nucleophilic addition reactions. The synthesis proceeded with complete stereocontrol of a newly formed stereogenic center, provided crude material of high purity, and used commercially available building blocks under mild reaction conditions.

ChemInform Abstract: Synthesis of Thiazolidine‐Fused Heterocycles via exo‐Mode Cyclizations of Vinylogous N‐Acyliminium Ions.

AbstractThe 6‐exo cyclization of vinylogous N‐acyliminium ions with tethered O‐, S‐, and N‐nucleophiles proceeds smoothly to afford fused thiazolidines (II) in good yields.

N-Acyliminium Cyclization as an Approach for an Asymmetric Synthesis of the Pyrrolo[2,1-a]benzazepine Ring System

In this article, we report a facile asymmetric synthesis of the pyrrolo[2,1-a]benzazepine ring system based around a stereoselective N-acyliminium cyclization of a novel chiral lactam template.

A convenient procedure for the solid-phase synthesis of hydroxamic acids on PEGA resins

An efficient method for the solid-phase synthesis of hydroxamic acids is described. The method comprises the nucleophilic displacement of esters immobilized on PEGA resins with hydroxylamine/sodium hydroxide in isopropanol. The hydroxyaminolysis protocol is compatible with a broad range of PEGA-supported peptide and peptidomimetic esters. The methodology was found to be compatible with two new strategies for the synthesis of solid-supported lactams and diketopiperazines, respectively, both relying on the high inter- and intramolecular reactivity of cyclic N-acyliminium ions with electron-rich aromatics and heteroaromatics, ultimately affording hydroxamic acid derivatives in high purities.

Formal synthesis of schulzeines B and C

A formal synthesis of schulzeines B and C, marine natural products with inhibitory effect against α-glucosidase, has been achieved. The key reactions of the synthesis are N-acyliminium ion cyclization, Sharpless asymmetric dihydroxylation, olefin cross metathesis, and asymmetric allylboration.

Enantioselective N–H Functionalization of Indoles with α,β‐Unsaturated γ‐Lactams Catalyzed by Chiral Brønsted Acids

Nitrogen revives: Cyclic N-acyliminium ions were generated from α,β-unsaturated γ-lactams (1) and underwent intermolecular addition by indole nucleophiles (2) under the catalysis of a chiral Brønsted acid (3). A variety of N-functionalized indole derivatives containing a pyrrolidinone moiety (4) were assembled with high enantioselectivity. Bn=benzyl.

Direct Enantioselective Brønsted Acid Catalyzed N-Acyliminium Cyclization Cascades of Tryptamines and Ketoacids

A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines with γ- and δ-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reaction is technically simple to perform, atom-efficient, and broad in scope. Employing 10 mol % of (R)-BINOL derived chiral phosphoric acids in refluxing toluene allowed the polycyclic product materials to be generated in good yields (53-99%) and moderate to high enantioselectivities (68-98% ee).

ChemInform Abstract: Synthesis of Angular-Substituted Tetracyclic Azepino-Indole Derivatives via N-Acyliminium Ion Cyclization.

Abstract A concise and efficient synthesis of tetracyclic azepino-indole derivatives 2 having a substituent at the angular position has been accomplished through an N-acyliminium ion cyclization. The coupling reaction of indol-3-yl-ethylamine 3 with 4-or 5-keto-acid 4 followed by cyclization reaction of the resulting tautomeric mixtures of keto-amide 5 and hydroxylactam 6 in refluxing formic acid provided 2.

ChemInform Abstract: Creation of Quaternary Stereocenters by the Addition of Allyltributyltin to Chiral Cyclic N-Acyliminium Ions.

Abstract 5,5-Disubstituted pyrrolidinones and 5-substituted pyrrolidinones were obtained with moderate to good diastereoisomeric excess through the cis addition of allyltributyltin and triethylsilane, respectively, to the 4-OTBS group in the N-acyliminium ion prepared from the corresponding 5-hydroxy lactams. Cyclization of an N-allyl-5-propargyl pyrrolidinone and N-allyl-5-allyl-5-substituted pyrrolidinones using Grubbs’ catalyst led to the preparation of a dehydropyrrolizinone and dehydroindolizinones containing a quaternary stereocenter.

Use of the cascade α-oxo-amidoalkylation/transposition/ p-cationic cyclization of N-acyliminium ions in the synthesis of novel fused heterocyclic N,O-acetals

Use of the cascade α-oxo-amidoalkylation/transposition/ p-cationic cyclization of N-acyliminium ions in the synthesis of novel fused heterocyclic N,O-acetals

Intermolecular Addition of Indoles to Cyclic N-Acyliminium Ions

A highly enantioselective intermolecular addition of indoles to cyclic N-acyliminium ions catalyzed by thiourea Schiff base 1 is presented. Electron-rich and electron-deficient indole nucleophiles are suitable substrates for this transformation. For electron-rich indoles TMSCl is used as an additive, whereas for the addition of electron-deficient indoles BCl3 turned out to be a more efficient additive. A catalytic cycle is proposed, where chlorolactam 2 is anticipated as the actual substrate in the alkylation.

Synthetic Study on Tetrapetalones: Stereoselective Cyclization of N-Acyliminium Ion To Construct Substituted 1-Benzazepines

The synthesis of the tetracyclic core of complex antibiotic tetrapetalones has been achieved in three steps starting from the simple intermediate gamma-hydroxy amide, which can be accessed through a high-yielding six-step sequence. The successful synthesis relies on a novel strategy based on the N-acyliminium ion cyclization.