Novel synthesis of isoquinolines using isobenzofuran-nitrile Diels-Alder reactions

[reaction: see text] The synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with beta-cyanocarbene complexes has been examined. The reaction involves formation of an isobenzofuran followed by intramolecular Diels-Alder reaction with the nitrile, a process with limited precedent. The unique success of this process in this system has been attributed to deoxygenation of the initial adduct to form the isoquinoline ring system.     

A convenient synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-diones

The synthesis of 5-heteroaryl-substituted uracil derivatives is presented. The 1,3-dipolar cycloaddition reaction was applied for the construction of a heterocyclic ring. The nitrile oxides were obtained from the appropriate 4-substituted benzaldoximes using N-chlorosuccinimide (NCS) under basic conditions. [2+3] Cycloaddition of nitrile oxides with 5-cyanouracil as a dipolarophile gave the corresponding 5-(3-substituited-1,2,4-oxadiazol-5-yl)uracils in satisfactory yields under mild conditions. 5-Substituted uracils having an additional heterocyclic ring were obtained as a result of the [2+3] cycloaddition of 5-cyanouracil to nitrile oxides generated from thiophene-2-carbaldehyde and 5-formyluracil derivatives.     

Intramolecular 1,3-dipolar cycloaddition strategy for enantioselective synthesis of FR-900482 analogues

[reaction: see text] Enantioselective synthesis of FR-900482 analogues is described. The key reaction of the synthesis is intramolecular 1,3-dipolar cycloaddition of a highly functionalized nitrile oxide with complete stereo- and regioselectivities to construct the eight-membered benzazocine ring.     

Synthesis of a novel class of steroidal tetrazolo[1,5-a]pyridines via intramolecular 1,3-dipolar cycloadditions

A facile synthesis of a novel class of steroidal A/B/D-ring annulated tetrazolo[1,5-a]pyridine derivatives has been accomplished via intramolecular 1,3-dipolar cycloaddition reaction of azide with nitrile in aprotic solvent. The synthesis of D-ring annulated tetrazolo[1,5-a]pyridine in alcohol showed incorporation of an alcohol molecule into the heterocyclic system.     

Total synthesis of the sesquiterpene (+/-)-illudin C via an intramolecular nitrile oxide cycloaddition

[reaction: see text] A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition.     

A new route to C-aryl glycosides

[reaction: see text] A six-step route for de novo synthesis of C-aryl glycosides based on cycloaddition of an aryl nitrile oxide with 4-pentyn-2-ol has been developed.     

Catalytic asymmetric synthesis of glutamate analogues

Utilizing our lateral metalation coupled with Jacobsen's catalytic asymmetric amino nitrile synthesis, we have demonstrated the ability to synthesize isoxazole-containing amino acid glutamate analogues in high yield and high enantiomeric excesses. Chiral centers alpha or beta at the C-5 position do not detract from diastereoselectivity of the Jacobsen-Strecker reaction. [reaction: see text]     

Divergent cycloaddition and ring-closing metathesis approaches to indolizidine and pyrrolo[1,2-a]azepine skeletons from a chiral precursor: an expeditious route to (-)-8-epi-swainsonine triacetate

[reaction: see text] A divergent strategy for the synthesis of diverse azabicyclic ring systems has been developed in which a chiral N-allylpyrrolidine derivative, obtained from a carbohydrate precursor was converted to (-)-8-epi-swainsonine triacetate by RCM and to a pyrrolo[1,2-a]azepine derivative and a 3-hydroxymethyl-substituted indolizidine by N-allylcarbohydrate nitrone and nitrile oxide cycloadditions.     

Synthetic studies on altemicidin: stereocontrolled construction of the core framework

The stereoselective synthesis of the key intermediate for altemicidin has been accomplished. The synthesis commenced with a bicyclo[3.3.0] framework, which was readily obtained via an intramolecular C-H insertion reaction. A Curtius rearrangement was employed as a key step to stereoselectively construct the beta-hydroxyl alpha-disubstituted-alpha-amino acid structure. Synthesis of vinylogous urea was achieved using hydrolysis of nitrile intermediate.     

Novel stereoselective synthesis of all four diastereomers of 3a-methyl-pyrrolo[3,4-c]piperidine from glycine ethyl ester

Asymmetric synthesis of all four diastereomers of 3a-methyl-pyrrolo[3,4-c]piperidine is described herein. The key steps in this synthesis are the highly diastereoselective hydrogenation of an alkenyl nitrile through a hydroxyl-directed or sterically controlled hydrogenation, and the resolution of enantiomers using a chiral auxiliary.     

Enantioselective cycloadditions with alpha,beta-disubstituted acrylimides

[reaction: see text] The use of N-H imide templates provides a solution to the problem of rotamer control in Lewis acid catalyzed reactions of alpha,beta-disubstituted acryloyl imides. Reactions proceed through the s-cis rotamer and with improved reactivity because A(1,3) strain is avoided. Enantioselective nitrone, nitrile oxide, and Diels-Alder cycloadditions demonstrate the principle.     

Synthesis of L-carbafuranomycin, an unnatural analogue of the antibiotic amino acid furanomycin

[reaction: see text] L-(+)-carbafuranomycin is a novel analogue of L-(+)-furanomycin, an unusual antibiotic alpha-amino acid that attracted great interest due to its activity as an isoleucine antagonist. We present here a concise and efficient asymmetric synthesis of this carba-analogue starting with the 1,3-dipolar cycloaddition of a chiral nitrile oxide with cyclopentadiene. Notably, the methyl group was introduced by an S(N)2' cuprate substitution with high stereo- and regioselectivity.     

Enantioselective Palladium‐Catalyzed [3+2] Cycloaddition of Trimethylenemethane and Fluorinated Ketones

A nitrile‐substituted trimethylenemethane (TMM) donor undergoes palladium‐catalyzed [3+2] cycloadditions with fluorinated ketones to generate tetrasubstituted trifluoromethylated centers in high enantioselectivity under mild conditions. The generation of the palladium–TMM complex was achieved by a self‐deprotonation strategy, which shows remarkable improvements in regiocontrol, efficiency, and atom economy of asymmetric [3+2] cycloadditions. Moreover, the versatility of the nitrile group provides direct access to a variety of synthetically useful intermediates, including amides, aldehydes, and esters. The developed reaction conditions allow for the synthesis of a wide variety of aromatic, heteroaromatic, and aliphatic fluorinated dihydrofurans in excellent regio‐ and enantioselectivities.     

Polyamide synthesis from 6-aminocapronitrile, part 1: N-alkyl amide formation by amine amidation of a hydrolyzed nitrile

The synthesis of N-hexylpentanamide from a stoichiometric amount of pentanenitrile and hexylamine has been studied as a model reaction for the synthesis of nylon-6 from 6-aminocapronitrile. The reaction was carried out under mild hydrothermal conditions and in the presence of a homogeneous ruthenium catalyst. For the mild hydrothermal conditions the presence of hexylamine distinctively increases the nitrile hydrolysis compared to the nitrile hydrolysis in the absence of hexylamine. Amine-catalyzed nitrile hydrolysis mainly produces the N-substituted amide. A clear product development is observed, consisting of first the terminal amide formation and second the accumulation of N-hexylpentanamide. With a maximum conversion of only 80 % after 18 h, the nitrile hydrolysis rate at 230 degrees C is still much too low for nylon-6 synthesis. Ruthenium dihydride phosphine was therefore used as a homogeneous catalyst, which significantly increases the nitrile hydrolysis rate. At a temperature of 140 degrees C and with only 0.5 mol % [RuH(2)(PPh(3))(4)] a 60 % nitrile conversion is already reached within 2 h. Initially the terminal amide is the sole product, which is gradually converted into N-hexylpentanamide. The reaction has a high initial rate, however, for higher conversions a strong decrease in hydrolysis rate is observed. This is ascribed to product inhibition, which results from the equilibrium nature of the reaction.     

Saponification Kinetics of Acrylonitrile Terpolymer and Polyacrylonitrile

Saponification kinetics of acrylic terpolymer and polyacrylonitrile were studied. The influence of alkali concentration and the time of hydrolysis on the degree of saponification were determined by the residual nitrogen content. The order of reaction was graphically determined and the rate of saponification was found to be faster in the terpolymer than in the homopolymer. Chemical and infrared spectroscopy methods reveal that the reaction is initiated through cyclization of nitrile groups, followed by hydrolysis to amide and carboxylic groups of the [sbnd](C[dbnd]N)_n[sbnd] segments produced.

The saponification of nitrile groups in the terpolymer initially yields amide groups, then slows down to yield carboxylic groups.     

Molecular diversity via amino acid derived alpha-amino nitriles: synthesis of spirocyclic 2,6-dioxopiperazine derivatives

[reaction: see text] Chiral spirocyclic 2,6-dioxopiperazines were synthesized from amino acid derived alpha-quaternary alpha-amino nitriles via H(2)SO(4)-promoted cyano hydration, followed by base-mediated cyclization and N-alkylation. This methodology, requiring the previous preparation of the amino nitrile by a modified Strecker reaction, was applied to Phe, Trp, Pro, Asp, Glu, and Ser derivatives. In the case of the Trp-derived amino nitrile the major product of the treatment with H(2)SO(4) was not the expected carboxamide, but a new tetracyclic indoline derivative containing the novel heterocyclic system hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indole, as a result of a domino tautomerization. The treatment of this indoline derivative with refluxing 1 N HCl led to a Trp-derived 2,6-dioxopiperazine. The 2,6-dioxopiperazine ring opened under the reaction conditions of methyl ester saponification, giving N-(carboxyalkyl)amino acid derivatives. Therefore, the synthesis of 2,6-dioxopiperazines containing free carboxylic acids from the respective methyl esters required transesterification to benzyl esters, followed by hydrogenolysis.     

An easy two step synthesis of macrocyclic peptidotriazoles via a four-component reaction and copper catalyzed intramolecular azide–alkyne [3+2] click cycloaddition

A two-step macrocyclization strategy for the synthesis of 12- and 14-membered cyclic peptidotriazoles by combining a one pot four-component reaction and an intramolecular [3+2] azide–alkyne click cycloaddition reaction is described. Macrocycles are obtained in good to excellent yield from the aqueous work-up of the reaction mixture and it is possible to expand or contract the ring size by adjusting the length of the nitrile moiety used in the MCR stage.     

Synthesis of the pyridine core of cyclothiazomycin

A highly convergent synthesis of the pyridine core of the thiopeptide antibiotic cyclothiazomycin has been developed based on a [2+2+2] cyclotrimerization key step. The regioselective assembly of the heterocyclic center of this important class of antibiotics takes advantage of a temporary silicon tether and the ruthenium-catalyzed cyclotrimerization reaction of a diyne and an electron-poor thiazole nitrile.     

Unprecedented stereospecific synthesis of a novel tetracyclic ring system, a hybrid of tetrahydropyrrolo[2,3-b]indole and tetrahydroimidazo[1,2-a]indole, via a domino reaction upon a tryptophan-derived amino nitrile

Compounds containing a novel tetracyclic ring system, a hybrid of tetrahydropyrrolo[2,3-b]indole and tetrahydroimidazo[1,2-a]indole, are synthesized via an acid-mediated stereospecific domino tautomerization of a tryptophan-derived alpha-amino nitrile. Characterization of these new compounds and preliminary studies on the reactivity of the tetracyclic heterocyclic system are reported. [reaction: see text]     

Stereochemically rich pentaketides from bis(isoxazolines): a general strategy for efficient polyketide synthesis

[reaction: see text] A strategy based on diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates has been applied to the synthesis of bis(isoxazolines) that are precursors to polyketide fragments. These intermediates can be elaborated into protected polyols by chemoselective reductive opening of each isoxazoline sequentially or, alternatively, both simultaneously, potentially providing access to all stereoisomers of this carbon skeleton.