N-acyliminium Ion Research Articles

Stereodivergent Synthesis of the Four Stereoisomers of Diethyl 4-Hydroxyphosphopipecolate from Ethyl (R)-4-Cyano-3-hydroxybutanoate

AbstractThe stereodivergent synthesis of all four stereoisomers of diethyl 4-hydroxyphosphopipecolate from the commercial chiral building block ethyl (R)-4-cyano-3-hydroxybutanoate is described. Key steps in the synthesis of the target compounds involve the triethyl phosphite nucleophilic addition to chiral N-acyliminium ion easily obtained from (R)-4-hydroxypiperidin-2-one, giving diethyl (2R,4R)- and (2S,4R)-4-hydroxyphosphopipecolate diastereoisomers, easily separable by column chromatography followed by the 4-hydroxy epimerization through a sequential oxidation and highly diastereoselective reduction strategy, affording the diethyl (2R,4S)- and (2S,4S)-4-hydroxyphosphopipecolate, respectively, consistent with our recently found results. All synthesized compounds were thoroughly characterized.

Industrial Grade Resin as Reusable Catalyst for Amidoalkylation of γ-Hydroxy Lactams.

Herein, we disclose a selective, versatile, accessible, cost-effective and highly efficient cation-exchange industrial grade INDION 130 resin as a reusable catalyst for the synthesis of 3-substituted isoindolinones from various γ-hydroxy lactams and a variety of C, N, O, and S nucleophiles involving N-acyliminium ion intermediates under mild reaction conditions. Mechanistic studies suggested the generation of a different kind of kinetically and thermodynamically controlled intermediates/eliminated products, which further converted to their corresponding products depending upon the nucleophile, reaction parameter and nitrogen substitution (benzyl vs. aryl) of the substrate (succinamidals vs. phthalimidals). The easy synthesis, efficient reactivity and selectivity, broad substrate scope with verities of C, N, O, and S nucleophiles, and efficient recycling make the catalyst and the protocol economical and sustainable.

Mannich-type addition of cyclic 1,3-diketones to N-acyliminium ions: Access to aza-sugars

A novel three-component strategy has been developed for the synthesis of iminosugars in good to excellent yields. This is the first report on the Mannich type addition of cyclic 1,3-diketones to aza-acetal derived from hydroxy-γ-lactone and arylamine to produce a novel series of aza-sugars with high selectivity.

Synthesis of 1,2,3-triazole-fused N-heterocycles from N-alkynyl hydroxyisoindolinones and sodium azide via the Huisgen reaction.

An efficient methodology for the synthesis of dihydro[1,2,3]triazolo-pyrimidoisoindolones and dihydro[1,2,3]triazolo-diazepinoisoindolones has been developed using the Huisgen reaction from sodium azide and alkyne substituted amido alcohols in moderate to good yields. The reaction involves the in situ generation of the N-acyliminium ion intermediate, which undergoes a nucleophilic attack by the azide ion, followed by a [3 + 2]-intramolecular azide-alkyne cycloaddition reaction. Importantly, the reaction proceeds without the involvement of any transition metal catalyst. This methodology can be further utilized for the synthesis of dihydro[1,2,3]triazolo-pyrimidoisoindolthiones via thionation of amides.

Stereoselective synthesis of 1,6-diazecanes by a tandem aza-Prins type dimerization and cyclization process.

We report the stereocontrolled synthesis of 1,6-diazecanes via a tandem aza-Prins type reaction of N-acyliminium ions with allylsilanes. It involves an aza-Prins type dimerization and cyclization in a single-step operation. This reaction represents the first example of 10-membered N-heterocycle synthesis using an aza-Prins reaction. Also, the interesting formation of an unusual tetracyclic compound through further cyclization of 1,6-diazecane and bicyclic compounds by the intramolecular cyclization of linear allylsilane are described. This tandem aza-Prins protocol provides a new synthetic strategy for the direct synthesis of medium-sized nitrogen heterocycles.

Asymmetric Synthesis of 3,3-Disubstituted Isoindolinones Enabled by Organocatalytic Functionalization of Tertiary Alcohols

AbstractAn enantioselective intramolecular heterocyclization with in situ generated 3-hydroxyisoindolinone-derived N-acyliminium ions has been successfully accomplished. In the presence of a catalytic amount of a chiral phosphoric acid, functionalized 3,3-disubstituted isoindolinones bearing N-acyl-N,O-acetal moieties were obtained with good yields and a high level of stereocontrol (up to 98:2 er). This efficient method proceeds under mild conditions and exhibits broad scope with respect to both 3-hydroxyisoindolinones and hydroxyl partners.

Electrochemical Friedel–Crafts-type amidomethylation of arenes by a novel electrochemical oxidation system using a quasi-divided cell and trialkylammonium tetrafluoroborate

Electrochemical Friedel–Crafts-type amidomethylation was successfully carried out by a novel electrochemical oxidation system using a quasi-divided cell and trialkylammonium tetrafluoroborates, such as iPr2NHEtBF4. Constant current electrolysis of 1,3,5-trimethoxybenzene or indoles in DMA containing 0.1 M iPr2NHEtBF4 using an undivided cell equipped with a Pt plate cathode and a Pt wire anode (a quasi-divided cell) resulted in selective formation of N-acyliminium ions of DMA at the anode, which reacted with arenes to give the corresponding amidomethylated products in good to high yields.

Synthesis of Spiro[furan-2,1'-isoindolin]-3'-ones from 2-(4-Hydroxybut-1-yn-1-yl)benzonitriles and Aryl Aldehydes under the Action of Triflic Acid.

The synthesis of spiro[furan-2,1'-isoindolin]-3'-ones from 2-(4-hydroxybut-1-yn-1-yl)benzonitriles and aryl aldehydes is demonstrated. It involves the initial formation of dihydrofuranylideneisoindolinone via intramolecular sequential Prins and Ritter reactions, followed by the ring opening of the furanyl moiety to generate N-acyliminium ions and alcohols for the final cyclization reaction, and the spiro-cyclic compounds are produced in moderate to good yields. It is a one-pot, three-component reaction in which one new quaternary carbon, two five-membered rings, one C-N bond, two C-O bonds, and one C-C bond are formed. The reaction is carried out with a Brønsted acid from 0 °C to room temperature within a short period of time.

α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies.

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1.

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.

Enantioselective Annulation of α,β-Unsaturated N-Acyliminium Ions with β-Keto Ester Enolates via Cooperative Palladium and Brønsted Acid Catalysis.

We herein report a cooperative palladium- and Brønsted acid-catalyzed strategy toward the first enantioselective annulation of in situ generated α,β-unsaturated N-acyliminium ions with chiral metal enolates. Novel polycyclic oxoisoindoles featuring three contiguous stereogenic centers have been obtained with typically good yields, outstanding enantiocontrol, and moderate to good diastereoselectivity. The utility of the process was further demonstrated by their conversion to synthetically valuable scaffolds.

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.

Hidden Heptacyclic Chiral N-Acyl Iminium Ions: A New Entry to Enantioenriched Polycyclic Azepanes and Azocanes by Superacid-Promoted Intramolecular Pictet-Spengler Reaction.

Enantioenriched complex fused-tricyclic azepanes or bridged-polycyclic azocanes were constructed via a two-step sequence involving an enantioselective organocascade followed by superacid activation of the domino adduct. The activated oxa-bridged azepane acts as a key hidden heptacyclic chiral N-acyl iminium ion triggering a chemo- and diastereoselective intramolecular mono- or di-arylation.

Asymmetric Addition of Enol Silanes to In Situ Generated N-Acyliminium Ions

Key words confined acids - enol silanes - acyliminium ions - asymmetric catalysis - pyrrolidinyl ketones

Flash Electrochemical Approach to Carbocations.

A novel flow electrochemical reactor that accomplishes electrolysis within a few seconds in a single passage was developed. By using the flow reactor system, the flash electrochemical generation of short-lived carbocations, including oxocarbenium ions, N-acyliminium ions, glycosyl cations, and Ferrier cations was achieved within a few seconds, enabling the subsequent reaction with nucleophiles before their decomposition. Moreover, continuous operation based on the present system enabled the rapid synthesis of pharmaceutical precursors on demand.

Catalytic Asymmetric Additions of Enol Silanes to In Situ Generated Cyclic, Aliphatic N-Acyliminium Ions.

Strong and confined imidodiphosphorimidate (IDPi) catalysts enable highly enantioselective substitutions of cyclic, aliphatic hemiaminal ethers with enol silanes. 2‐Substituted pyrrolidines, piperidines, and azepanes are obtained with high enantioselectivities, and the method displays a broad tolerance of various enol silane nucleophiles. Several natural products can be accessed using this methodology. Mechanistic studies support the intermediacy of non‐stabilized, cyclic N‐(exo‐acyl)iminium ions, paired with the confined chiral counteranion. Computational studies suggest transition states that explain the observed enantioselectivity.

Divergent Electrochemical Carboamidation of Cyclic Amines.

We developed an electrochemical carboamidation sequence that affords either cyclic β-amidoamine products via direct functionalization or linear hydroxybisamide products via a ring opening pathway. The reaction pathway was dependent on the nature of the N-acyl activating group, with carbamate groups favoring direct isocyanide addition to the N-acyliminium ion intermediate and the benzoyl activating group favoring the ring opening-functionalization pathway. Both protocols are one-pot reaction sequences, have general applicability, and lead to peptide-like products of greatly increased molecular complexity.

AgNTf2 catalyzed cycloaddition of N-acyliminium ions with alkynes for the synthesis of the 3,4-dihydro-1,3-oxazin-2-one skeleton.

A catalyzed process for the synthesis of the 4,6-substituted 3,4-dihydro-1,3-oxazin-2-one skeleton has been developed through cycloaddition of in situ generated acyliminium intermediates with alkynes. A range of chain N,O-acetals and terminal alkynes were amenable for this mild transformation. As a result, a series of desired cycloaddition products were obtained in moderate to good yields.

Aza-[4 + 2] cycloadditions employing catalytically derived N-acyliminium ions.

Herein, we report the development of a novel route to tricyclic lactam products via a facile aza-[4 + 2] cycloaddition of catalytically generated acyliminium ions. Employing a Ca(NTf2)2/nBu4NPF6 catalyst system in low loadings, a range of diverse fused ring systems can be synthesised in predominantly good yields.

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.