N-acyliminium Ion Research Articles

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.

Expedient Pyrrolizidine Synthesis by Propargylsilane Addition toN-Acyliminium Ions followed by Gold-Catalyzed α-Allenyl Amide Cyclization

A reaction sequence, involving the addition of (substituted) propargylsilanes to lactam-derived N-acyliminium ions followed by gold-catalyzed cyclization of the resulting alpha-allenyl amide, is applied in expedient syntheses of pyrrolizidine alkaloids heliotridine and ent-retronecine in five steps from (S)-malic acid.

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.

Enantioselective, Thiourea‐Catalyzed Intermolecular Addition of Indoles to Cyclic N‐Acyl Iminium Ions

Enantioselective, Thiourea‐Catalyzed Intermolecular Addition of Indoles to Cyclic <i>N</i>‐Acyl Iminium Ions

A Straightforward Total Synthesis of (−)‐Chaetominine

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available D-tryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (first step) of the quinazolinone moiety and the late stage introduction (penultimate step) of the hydroxy group allowed a synthetic strategy devoid of protective groups. The key step of the process is the a-c tricyclic ring construction via an unprecedented NCS-mediated N-acyl cyclization on an indole ring to give tetrahydro-1H-pyrido[2,3-b]indole 11. In the penultimate step, oxidation of the tetracyclic intermediate 14 with oxaziridine 15 gave only one of the four possible diastereoisomers, the cis-diastereoisomer 16 resulting from the attack of the oxaziridine to the double bond face opposite to the c-d ring substituents. In the last step, the complete stereocontrol of the Et(3)SiH/TFA reduction of compound 16, probably involving a N-acyliminium ion, can be attributed to ring constrain, which forces the b-c ring junction in the more stable cis-orientation. (-)-Chaetominine (1) showed a negligible inhibitory activity on several cancer cell lines.

Stereoselective synthesis of N,N-acetals by cyclization of an N-acyliminium ion through interaction with an N-sulfonyl group

A new method for the stereoselective synthesis of five- and six-membered bicyclic N,N-acetals with trans configuration was developed using N-acyliminium ion cyclization. The N-sulfonyl substituted compounds were effectively cyclized to give the corresponding acetals in high yields and stereoselectivities, suggesting that the intramolecular interaction between the iminium and the sulfonyl group plays a key role in the cyclization.

Synthetic Chemistry with N-Acyliminium Ions Derived from Piperazine-2,5-Diones and Related Compounds

Synthetic Chemistry with N-Acyliminium Ions Derived from Piperazine-2,5-Diones and Related Compounds

Intramolecular N-acyliminium ion versus Friedel–Crafts cyclization onto 3-indoles: synthesis of the novel rings pyrrolizino[2,1- b]indole and homologues

Acid treatment of indole-2-carboxylic acid β- and γ-oxoamides causes Friedel–Crafts intramolecular cyclization to β-carbolinones and dihydro-2 H-azepino[3,4- b]indol-1-ones, in contrast to secondary δ-,ɛ-, and ζ-oxoamides, which cyclize to the novel heterocyclic rings pyrrolizino[2,1- b]indole, indolizino[2,1- b]indole, and 9a,11-diaza-indeno[1,2- a]azulene, via an intermediate N-acyliminium ion. Tertiary amides lead only the Friedel–Crafts ring closure, thus allowing the synthesis of larger fused rings.

Intermolecular Addition Reactions of N-Acyliminium Ions (Part II)¹

This review highlights the advances in the literature up to July2008 on the intermolecular reactions of acyclic and cyclic N-acyliminium ions. This is an updateof an earlier review in 2000 on this topic and does not includeintramolecular addition reactions to N-acyliminiumions which was recently reviewed. This review is presented in twoparts, with the first part having dealt with acyclic and pyrrolidinone-based N-acyliminium ions. Part II continueswith other five-membered heterocyclic derivatives and higher systems. Part I 1 Introduction 2 Acyclic N-Acyliminium Ions 2.1 Synthesis of Acyclic N-AcyliminiumIon Precursors 2.2 Reactions of Acyclic N-AcyliminiumIons 2.2.1 Reactions with Nucleophiles 2.2.2 Cycloaddition Reactions 2.2.3 Cationic Carbohydroxylation Reactions 3 Cyclic N-Acyliminium Ions 3.1 Synthesis of Cyclic N-AcyliminiumIon Precursors 3.1.1 Preparation of Iminium Ions in situ by Anodic Oxidation 3.2 Five-Membered-Ring N-AcyliminiumIons 3.2.1 Reactions of Pyrrolidinone-Based N-AcyliminiumIons Part II 3.2.2 Reactions of N-Acylpyrrolidine-Based N-Acyliminium Ions with Nucleophiles 3.2.2.1 Silicon-Based Nucleophiles 3.2.2.2 Aromatic Nucleophiles 3.2.2.3 Organostannanes 3.2.2.4 Organometallic Reagents 3.2.2.5 Carbonyl Compounds 3.2.2.6 Alkyl Radicals 3.2.2.7 Thiols 3.2.2.8 Active Methylene Compounds 3.2.3 Reactions of Oxazolidinone-Based N-AcyliminiumIons with Nucleophiles 3.2.3.1 Silicon-Based Nucleophiles 3.2.3.2 Organometallic Reagents 3.2.3.3 Active Methylene Compounds 3.2.4 Cyclocondensation Reaction of N-AminidinylIminium Ions 3.3 Reactions of Six-Membered-Ring N-AcyliminiumIons 3.3.1 Reactions of Piperidinone-Based N-AcyliminiumIons with Nucleophiles 3.3.1.1 Silicon-Based Nucleophiles 3.3.1.2 Organostannanes 3.3.1.3 Organometallic Reagents 3.3.2 Reactions of N-Acylpiperidine-Based N-Acyliminium Ions 3.3.2.1 Reactions with Nucleophiles 3.3.2.2 Cycloaddition Reactions 3.3.3 Reactions of Piperazine-Based N-AcyliminiumIons with Nucleophiles 3.3.3.1 Silicon-Based Nucleophiles 3.3.3.2 Aromatic Nucleophiles 3.3.4 Reactions of Pyridine-Based N-AcyliminiumIons with Nucleophiles- 3.3.4.1 Organometallic Reagents 3.3.5 Reactions of N, O-Acetal Oxathiazinane N-Sulfonyl-iminiumIons with Nucleophiles 3.3.5.1 Organometallic Reagents 3.4 Reactions of Seven-Membered-Ring N-AcyliminiumIons 3.4.1 Reactions with Silicon-Based Nucleophiles 3.4.2 Cycloaddition Reactions 3.5 Reactions of Bicyclic N-AcyliminiumIons 3.5.1 Reactions with Nucleophiles 3.5.1.1 Silicon-Based Nucleophiles 3.5.1.2 Organometallic Reagents 3.5.1.3 Enamines 3.5.2 Cycloaddition Reactions 3.6 Other Systems 3.6.1 Silicon-Based Nucleophiles 4 Stereochemical Outcomes 5 Conclusions

Intermolecular Addition Reactions of N-Acyliminium Ions (Part I)

This review highlights the advances in the literature up to July 2008 on the intermolecular reactions of acyclic and cyclic N-acyliminium ions. This is an update of an earlier review in 2000 on this topic and does not include intramolecular addition reactions to N-acyliminium ions which was recently reviewed. This review is presented in two parts, with the first part dealing with acyclic and pyrrolidinone-based N-acyliminium ions. Part II continues with other five-membered heterocyclic derivatives and higher systems.

Diastereoselective Synthesis of Bicyclic γ-Lactams via Ring Expansion of Monocyclic β-Lactams

cis-4-(1-Chloro-1-methylethyl)-1-(omega-hydroxyalkyl)azetidin-2-ones were diastereoselectively transformed into novel trans-1-aza-4-oxabicyclo[3.3.0]octan-8-ones and trans-1-aza-5-oxabicyclo[4.3.0]nonan-9-ones upon treatment with 1 equiv of AgBF4 and pyridine in toluene via intramolecular nucleophilic trapping of N-acyliminium intermediates by the hydroxyl moiety. Additionally, the corresponding aza-analogues of the aforementioned bicyclic gamma-lactams (i.e., trans-1,4-diazabicyclo[3.3.0]octan-8-ones and trans-1,5-diazabicyclo[4.3.0]nonan-9-ones) were prepared in a convenient way starting from cis-4-(1-chloro-1-methylethyl)-1-{omega-[(tert-butoxycarbonyl)amino]alkyl}azetidin-2-ones applying the same reaction conditions. The intermediate N-acyliminium ions were formed by ring expansion of the starting beta-lactams through generation of a transient silver(I)-induced carbenium ion.

Parallel Electrosynthesis of N-Acyliminium Ion Equivalents Using Silica Gel-supported Piperidine

Abstract Parallel anodic methoxylation of carbamates was successfully carried out to provide the corresponding α-methoxylated products as N-acyliminium ion equivalents in high to excellent yields using silica gel-supported piperidine (Si–piperidine).

Spirocyclization of Six-Membered Cyclic N-Acyliminium Ions with a Conjugated Diene

Intramolecular spirocyclization of six-membered cyclic N-acyliminium ions with a tethered conjugated diene has been studied. The reaction of an N-acyliminium ion bearing an endocyclic amide carbonyl group led to spirocyclization to give a l-azaspiro[5.5]undecane compound.

A facile synthesis of pyrrolo-(di)-benzazocinones via an intramolecular N-acyliminium ion cyclisation

A facile, moderate to high yielding synthesis of hexahydro-(di)-benzazocinones is described via an intramolecular N-acyliminium ion cyclisation. The iminium ion intermediates are formed from the readily available 4,4-diethoxybutyl amides with an excess of triflic acid. For electron-withdrawing substituents, better yields were obtained from the pre-formed 2-hydroxypyrrolidine amides. From NMR studies, at ambient temperatures the pyrrolo-benzazocin-3-ones exist as a slowly equilibrating mixture of two conformations.

Stereoselective Synthesis of a 4a,9-Disubstituted Octahydroacridine from Isatin

An efficient method for stereoselective synthesis of a 4a,9-disubstituted octahydroacridine derivative from isatin (2,3-indolinedione) was developed; the method is based on an intramolecular reaction of an N-acyliminium ion with a conjugated diene system.

Stereoselective Nucleophilic Addition of Potassium Alkyltrifluoroborates to Cyclic N-Acyliminium Ions: a Simple and Mild Approach to Chiral 5-Alkyl-pyrrolidin-2-ones

The stereoselective nucleophilic addition of potassium alkyltrifluoroborates to cyclic N-acyliminium ions derived from N-benzyl-3,4,5-triacetoxy-pyrrolidin-2-one, which affords 5-substituted-pyrrolidin-2-ones, is described. The products are obtained in moderate to good yields and are produced predominantly as the anti diastereomer.

New approaches for the synthesis of erythrinan alkaloids

A concise asymmetric total synthesis of (+)-erysotramidine is described, using chiral base desymmetrisation of a meso-imide, N-acyliminium addition, retro-Diels-Alder cycloaddition and radical cyclisation as the key steps. A related route, starting from a cyclobutene-fused imide, was explored, and established a novel construction of the Erythrina alkaloid skeleton using a key ring-opening/ring-closing metathesis step. Completion of this synthesis was thwarted by problems with the removal of an unwanted vinylic side-chain. Complementary enantiospecific routes to Erythrina systems were explored, starting from (L)-malic acid. Some unexpected observations were made concerning the diastereocontrol in malic acid-derived N-acyliminium ion cyclisations, where changing the protecting group of the alcohol function from acetate to OTIPS resulted in a dramatic change in diastereocontrol. Products from these reactions could be transformed into known intermediates for natural alkaloids, and into (+)-demethoxyerythratidinone itself, by means of radical cyclisations or intramolecular aldol reactions as the key steps.

Enantioselective total synthesis of pyrroloquinolone as a potent PDE5 inhibitor

A concise enantioselective strategy for the synthesis of key PDE5 inhibitor 2 was developed in 5 and 6 steps using asymmetric hydrogenation and one-pot chiral auxiliary approaches, respectively. The synthesis features the use of imine 6 obtained through Bischler–Napieralsky reaction from amide 5. Absolute R configuration was introduced in (+)- 7 by asymmetric transfer-hydrogenation reaction with Ru(II) catalyst followed by establishing the tricyclic pyrroloquinalone core using the Winterfeldt oxidation. Another alternative synthetic approach for the introduction of chirality in the molecule employed imine 6 and chloroformates of different chiral auxiliaries, which achieved N-acyliminium ion intermediates that were reduced in situ using PdCl 2/Et 3SiH protocol. These synthetic routes were applied in the total synthesis of promising male erectile dysfunction (MED) PDE5 inhibitor 1.

Electro-initiated Coupling Reactions of N-Acyliminium Ion Pools with Arylthiomethylsilanes and Aryloxymethylsilanes

Abstract Electro-initiated coupling reactions of N-acyliminium ion with arylthiomethylsilanes and aryloxymethylsilanes were developed. Pulse electrolyses with intervals were found to be quite effective for the initiation. A chain mechanism involving cation, radical cation, and radical intermediates has been proposed.

N,N-Acetals as N-Acyliminium Ion Precursors: Synthesis and Absolute Stereochemistry of Epiquinamide

A stereoselective synthesis of (+)-epiquinamide is presented in combination with determination of the absolute configuration of the natural product. Key steps in the sequence involved chemoenzymatic formation of an enantiomerically pure cyanohydrin, reductive cyclization to the corresponding cyclic N,N-acetal, and subsequent conversion into a suitable N-acyliminium ion precursor to enable construction of the second ring.