Stereoselective formation of fused tricyclic amines from acyclic aldehydes by a cascade process involving condensation, cyclization, and dipolar cycloaddition

The preparation of tricyclic amines from acyclic precursors is described using a cascade of tandem reactions involving condensation of an aldehyde with a primary amine, cyclization (with displacement of a halide), and then in situ deprotonation or decarboxylation to give an azomethine ylide or nitrone followed by intramolecular dipolar cycloaddition. The methodology is straightforward, and the aldehyde precursors are prepared easily and quickly in high yield using nitrile alkylations followed by DIBAL-H reduction. The relative ease of reaction of various substrates with different tether lengths between the aldehyde and the halide or dipolarophile has been studied. Several primary amines including simple amino acids such as glycine, alanine, and phenylalanine and derivatives such as glycine ethyl ester and also hydroxylamine have been investigated. High yields are obtained in the formation of different tricyclic ring sizes; the dipolar cycloaddition necessarily creates a five-membered ring, and we have investigated the formation of five- and six-membered rings for the other two new ring sizes. In all cases, yields are high (except when using glycine when the tether to the terminal alkene dipolarophile leads to a six-membered ring), and most efficient is the formation of the tricyclic product in which all five-membered rings are formed. Examples with an alkyne as the dipolarophile were also successful. In all the reactions studied, the products are formed with complete regioselectivity and remarkably with complete stereoselectivity. The key step involves the formation of three new rings and potentially up to four new stereocenters in a single transformation. The power of the chemistry was demonstrated by the synthesis of the core ring systems of the alkaloids (+/-)-scandine and (+/-)-myrioneurinol and the total syntheses of the alkaloids (+/-)-aspidospermine, (+/-)-quebrachamine, and (+/-)-aspidospermidine.     

Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids

A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.     

Stereoselective synthesis of novel glyco-pyrano pyrrolidines/pyrrolizidines/indolizidines through intramolecular [3+2] cycloaddition approach

An efficient and stereoselective synthesis of novel furo-pyrano pyrrolidine/pyrrolizidine/indolizidine derivatives has been achieved by intramolecular [3+2] cycloaddition reaction of azomethine ylide generated in situ from O-allyl sugar-derived aldehyde and different secondary amino acids.     

Synthesis of decahydropyrrolo[2,1,5-cd]indolizine through consecutive [2 + 3] cycloadditions and 6-exo-trig cyclization

Azomethine ylide formed from glycine methyl ester and cinnamaldehyde adds to N-phenylmaleimide to form pyrrolidine derivative, further treatment of which with cinnamaldehyde and N-phenylmaleimide affords the second [2 + 3] cycloaddition adduct, a pyrrolizine derivative with two styrenyl groups at the 3,5-positions. Addition of ICl to the pyrrolizine derivative results in the 6-exo-trig cyclization of the styrenyl groups to form a cycl[3.2.2]azine derivative. The reactions are highly stereoselective affording 11 chiral carbons in three steps. The structure of the cycl[3.2.2]azine derivative was determined by single-crystal X-ray analysis.     

Intramolecular cycloaddition of azomethine ylides, from imines of O-acylsalicylic aldehyde and ethyl diazoacetate, to ester carbonyl--experimental and DFT computational study

Intramolecular 1,3-dipolar cycloaddition of alkoxycarbonyl-substituted azomethine ylides to ester carbonyl was realized for the first time in the reaction of imines of O-acylsalicylic aldehyde with ethyl diazoacetate in the presence of Cu(tfacac)(2). The stereoselectivity of the cycloaddition is explained using DFT calculations.     

Bifunctional AgOAc/ThioClickFerrophos complex-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with aryl- and alkylidene malonates

AgOAc/ThioClickFerrophos complex-catalyzed 1,3-dipolar cycloaddition of glycine imino ester, the precursor of azomethine ylide, with aryl- and alkylidene malonates afforded the corresponding exo-cycloadducts, that is, proline ester derivatives in high yields with high enantiomeric excess (up to 99% ee). The reactions proceeded smoothly under base-free conditions demonstrating the bifunctional catalysis of the silver complex.     

Hetero [6+3] cycloaddition of fulvenes with N-alkylidene glycine esters: a facile synthesis of the delavayine and incarvillateine framework

[reaction: see text] In contrast to the [3+2] or [4+3] cycloaddition of N-metalated azomethine ylides and various alkenes, N-benzylidene glycine ethyl ester reacts with fulvenes to give the hetero [6+3] cycloaddition adducts with high stereoselectivity, constituting an efficient and novel route to [2]pyrindines.     

Porphyrins in 1,3-dipolar cycloaddition reactions. Synthesis of new porphyrin-chlorin and porphyrin-tetraazachlorin dyads

N-(Porphyrin-2-ylmethyl)glycine was synthesized and used as precursor of azomethine ylide, which was trapped with several dipolarophiles. The reaction of that azomethine ylide with dimethyl fumarate afforded the expected adduct. However, with 1,4-benzo- and 1,4-naphthoquinones only dehydrogenated adducts were isolated. Also, the reaction of that ylide with meso-tetrakis(pentafluorophenyl)porphyrin and tetraazaporphine allowed access to novel porphyrin-chlorin and porphyrin-tetraazachlorin dyads.     

Synthesis of pyrrolo[3,4-b]pyrroles and perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles

The 1,3-dipolar cycloaddition reactions of various N-tethered alkenyl aldehydes with some cyclic and acyclic amino acids have been studied. Some key sulfonamides having strategically positioned aldehyde and olefinic tether have been synthesized and effectively subjected to intramolecular azomethine ylide cycloaddition reaction resulting in a series of pyrrolo[3,4-b]pyrrole and its N-1-C-2 derivatives, and a series of novel heterotricyclic compounds, perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles, in good yields. The intramolecular cycloaddition reaction was found to be highly stereoselective to form only cis-fused cycloadducts in all cases.     

Efficiency in isotetronic acid synthesis via a diamine-acid couple catalyzed ethyl pyruvate homoaldol reaction

[reaction: see text] L-proline failed to act as an organocatalyst in the homoaldol reaction of ethyl pyruvate; however, it reacted with the ester to give an azomethine ylide that in turn underwent 1,3-dipolar cycloaddition with a second molecule of pyruvate. Direct catalytic homoaldol reaction of ethyl pyruvate was performed using an (S)-(+)-1-(2-pyrrodinylmethyl)pyrrolidine/trifluoroacetic acid combination as organocatalyst. The use of polymer-supported reagents allowed for the lactonization of the aldol and isolation of the isotetronic acid derivative in hydroxy-free form.     

Cascade cyclization intermolecular dipolar cycloaddition by multi-component couplings—synthesis of indolizidines and pyrrolizidines

A three-component coupling reaction of a primary amine (an amino-acid or amino-ester or hydroxylamine), an alkene or alkyne dipolarophile and an aldehyde bearing a halide as a leaving group has been developed. Condensation of the amine with the aldehyde and cyclization (intramolecular N-alkylation) provides, after decarboxylation or deprotonation, a cyclic azomethine ylide (or nitrone) that undergoes intermolecular dipolar cycloaddition with the dipolarophile. This sets up, in a single step, the bicyclic indolizidine or pyrrolizidine ring system, depending on the length of the tether between the aldehyde and the halide. The reaction is successful with stabilized and non-stabilized azomethine ylides that result from using primary amino-esters or amino-acids, respectively.     

Total Synthesis of (−)‐Daphenylline

Total synthesis of (?)‐daphenylline, a hexacyclic Daphniphyllum alkaloid, was achieved. Construction of the tricyclic DEF ring system was initiated by asymmetric Negishi coupling followed by an intramolecular Friedel–Crafts reaction. Installation of a side chain onto the tricyclic core was carried out through Sonogashira coupling, stereocontrolled Claisen rearrangement by taking advantage of the characteristic conformation of the tricyclic DEF core, and the stereoselective alkylation of a lactone. After the introduction of a glycine unit, the ABC ring system was stereoselectively constructed through intramolecular cycloaddition of the cyclic azomethine ylide.     

Unexpected formation of novel pyrrole derivatives by the reaction of thioamide with dimethyl acetylenedicarboxylate

The reaction of thioamides with DMAD gave the pyrrole derivatives in good yield and the thiophene derivatives as a byproduct. These were formed by 1,3-dipolar cycloaddition of themodynamicaly stable azomethine ylide or less stable thiocarbonyl ylide with DMAD, followed by elimination of thioaldehyde or imine derivatives.     

Intramolecular 1,3-Dipolar Cycloaddition of Azomethine Ylides Generated from Ethoxycarbonylcarbenoids and Schiff Bases

Decomposition of ethyl diazoacetate in the presence of copper, copper acetylacetonate, or copper trifluoroacetylacetonate and ethyl 4-[2-(R-imino)phenoxymethyl]-2-butenoate leads to formation of chromeno-[4,3-b]pyrrole-2,3-dicarboxylic acid derivatives. The reactions involve intermediate formation of azomethine ylides which undergo regio- and stereoselective intramolecular cycloaddition at the C=C bond to afford chromeno[4,3-b]pyrroles. The steric structure of the product depends on the configuration of intermediate ylide and nature of the substituent at the ylide nitrogen atom.     

3 + 2]-cycloaddition of nonstabilized azomethine ylides. 10. An efficient strategy for the construction of x-Azatricyclo[m.n.0. 0

Various new structural entities related to x-azatricyclo[m.n.0. 0(a)()(,)(b)()]alkanes are constructed by the intramolecular [3 + 2] dipolar cycloaddition of nonstabilized cyclic azomethine ylides. The ylide is generated by the sequential double desilylation of N-alkyl alpha,alpha'-bis(trimethylsilyl)cyclic amines using Ag(I)F as a one-electron oxidant.     

Three-component synthesis of polysubstituted pyrroles from α-diazoketones, nitroalkenes, and amines

Polysubstituted pyrroles are regiospecifically synthesized via the copper-catalyzed three-component reaction of α-diazoketones, nitroalkenes, and amines under aerobic conditions. The cascade process involves an N-H insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3 + 2] cycloaddition of azomethine ylide.     

Regio‐ and stereoselective synthesis of 1‐benzopyrano[2,3‐b]pyrrolo[2,3‐d]pyridines: A microwave‐accelerated intramolecular [3+2] cycloaddition reaction of azomethine ylide

Regio‐ and stereoselective syntheses of tetracyclic compounds having chromone, pyrrolidine, and piperidine rings have been accomplished by an intramolecular [3+2] cycloaddition reaction involving azomethine ylide. The reactions were carried out thermally as well as by irradiation with microwave. The latter process accelerates the reaction. The selectivities were investigated by density functional theory computation. J. Heterocyclic Chem., (2011).     

A novel entry into 1-methyl- and 1-aryl-octahydropyrrolo[3,4-b]pyrroles and their N-1-C-2 fused derivatives: stereoselective synthesis via an intramolecular azomethine ylide cycloaddition reaction

Synthesis of some novel pyrrolo[3,4-b]pyrrole derivatives has been accomplished in good yields by the intramolecular azomethine ylide cycloaddition reaction of a strategically situated unactivated alkenyl aldehyde with various secondary amino acids. A cis fused cycloadduct was formed in all cases.     

Transannular dipolar cycloaddition as an approach towards the synthesis of the core ring system of the sarain alkaloids

Intramolecular transannular dipolar cycloaddition was investigated as a key step in a synthetic approach to the core of the sarain alkaloids; although the use of an azomethine ylide was unsuccessful with the chosen aldehyde substrate, cycloaddition with a nitrone did give the alternative regioisomeric bridged cycloadduct.     

A new, one-step synthesis of 1-heteroaryl-2-alkylaminoethanols

Refluxing a mixture of a heteroarylcarboxaldehyde and an N-alkylamino acid in dry toluene, in the presence of 4 Å molecular sieves, results in the formation of β-hydroxyamines through the 1,3-electrocyclisation of an azomethine ylide and the subsequent ring-opening hydrolysis of an aziridine. The intermediacy of an azomethine ylide in this process is suggested by the isolation of oxazolidines from the cycloaddition of the azomethine ylides to their aldehyde precursors.