Endocyclic Enecarbamates Research Articles

Palladium‐Catalyzed Decarboxylative Benzylation and Allylation of Six‐Membered Endocyclic Enecarbamates

AbstractSix‐membered endocyclic benzyl/allyl enecarbamates undergo a Pd‐catalyzed decarboxylation process to generate endocyclic 1‐azaallyl anions and Pd–benzyl/allyl cations. The ion pair then react with each other followed by reduction to ultimately give unprotected 2‐(hetero)aryl‐3‐benzylpiperidines and 2‐(hetero)aryl‐3‐allylpiperidines in 31–91% yields as single cis‐diastereomers. These reactions represent a strategy to form unprotected β‐substituted piperidines, which generates elusive endocyclic 1‐azaallyl anion intermediates by introducing the negative charge from the N‐terminal.

Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N-Heterocycles.

Two catalytic systems have been developed for the arylboration of endocyclic enecarbamates to deliver synthetically versatile borylated saturated N-heterocycles in good regio- and diastereoselectivities. A Cu/Pd dual catalytic reaction enables the synthesis of borylated, α-arylated azetidines, while a Ni-catalysed arylboration reaction efficiently functionalizes 5-, 6-, and 7-membered enecarbamates. In the case of the Cu/Pd-system, a remarkable additive effect was identified that allowed for broader scope. The products are synthetically useful, as demonstrated by manipulations of the boronic ester to access biologically active compounds.

Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N‐Heterocycles

AbstractTwo catalytic systems have been developed for the arylboration of endocyclic enecarbamates to deliver synthetically versatile borylated saturated N‐heterocycles in good regio‐ and diastereoselectivities. A Cu/Pd dual catalytic reaction enables the synthesis of borylated, α‐arylated azetidines, while a Ni‐catalysed arylboration reaction efficiently functionalizes 5‐, 6‐, and 7‐membered enecarbamates. In the case of the Cu/Pd‐system, a remarkable additive effect was identified that allowed for broader scope. The products are synthetically useful, as demonstrated by manipulations of the boronic ester to access biologically active compounds.

Trans‐Selective Aryldifluoroalkylation of Endocyclic Enecarbamates and Enamides by Nickel Catalysis

AbstractEfficient methods for the dicarbofuntionalization of the cyclic alkenes 2‐pyrroline and 2‐azetine are limited. Particularly, the dicarbofunctionalization of endocyclic enecarbamates to achieve fluorinated compounds remains an unsolved issue. Reported here is a nickel‐catalyzed trans‐selective dicarbofunctionalization of N‐Boc‐2‐pyrroline and N‐Boc‐2‐azetine, a class of endocyclic enecarbamates previously unexplored for transition metal catalyzed dicarbofunctionalization. The reaction can be extended to six‐ and seven‐membered endocyclic enamides. A variety of arylzinc reagents and bromodifluoroacetate, and its derivatives, undergo the reaction, providing straightforward and efficient access to an array of pyrrolidine‐ and azetidine‐containing fluorinated amino acids and oligopeptides, which may have applications in the life sciences.

Trans-Selective Aryldifluoroalkylation of Endocyclic Enecarbamates and Enamides by Nickel Catalysis.

Efficient methods for the dicarbofuntionalization of the cyclic alkenes 2-pyrroline and 2-azetine are limited. Particularly, the dicarbofunctionalization of endocyclic enecarbamates to achieve fluorinated compounds remains an unsolved issue. Reported here is a nickel-catalyzed trans-selective dicarbofunctionalization of N-Boc-2-pyrroline and N-Boc-2-azetine, a class of endocyclic enecarbamates previously unexplored for transition metal catalyzed dicarbofunctionalization. The reaction can be extended to six- and seven-membered endocyclic enamides. A variety of arylzinc reagents and bromodifluoroacetate, and its derivatives, undergo the reaction, providing straightforward and efficient access to an array of pyrrolidine- and azetidine-containing fluorinated amino acids and oligopeptides, which may have applications in the life sciences.

A new asymmetric synthesis of 2,6-cis-diarylated piperidines

A new synthetic approach to a variety of enantioenriched 2,6-cis-diarylated piperidines has been developed. This new methodology hinges upon the diastereoselective reduction of enantioenriched endocyclic enecarbamates obtained through a two step sequence involving a Suzuki–Miyaura cross coupling reaction between an aminovinyl phosphate and a variety of (hetero)aromatic boronic acids.

Synthesis and Conformational Analysis of Fluorinated Pipecolic Acids

A short sequence to methyl cis- and trans-5-fluoro pipecolate is described via electrophilic fluorination of a pipecolate-based endocyclic enecarbamate by using Selectfluor® as a fluorinating agent. Methyl 5,5-difluoro pipecolate was also obtained by difluorodeoxygenation of the corresponding ketone, which was obtained in two steps from the same enecarbamate. The conformational profile of both methyl 5-fluoropipecolate isomers was investigated by NMR spectroscopy in solution and X-ray crystallography of the corresponding piperidinium picrates.

Synthesis of pentabromopseudilin and other arylpyrrole derivatives via Heck arylations

Pentrabromopseudilin and other 2 and 3-arylpyrrole derivatives were synthesized through the Heck–Matsuda reaction involving endocyclic enecarbamates and N-protected 3-pyrrolines, respectively. The overall processes permitted an easy and efficient access to these structural motifs present in several bioactive compounds. Attempts to synthesize the compound isopentabromopseudilin led to a tribromo aryl maleimide. We hypothesize that this latter compound is the putative product arising from the unusual thermal instability of isopentabromopseudilin.

Stereoselective Synthesis of Aza Analogues of Isoaltholactone and Goniothalesdiol – New Applications of the Heck–Matsuda Reaction (Eur. J. Org. Chem. 36/2011)

AbstractThe cover picture shows the Heck–Matsuda reaction as the key step in the total synthesis of the aza analogue of the natural product isoaltholactone, which was isolated from several species of Goniothalamus. The stereoselective synthesis of this aza analogue was accomplished by Heck–Matsuda arylation between a chiral endocyclic enecarbamate and benzenediazonium tetrafluoroborate. This transformation not only forged the key carbon–carbon bond between the aryl group and the pyrrolidine moiety, but also placed the olefin functional group at the appropriate position for the construction of aza‐isoaltholactone. Moreover, the synthesis of a new nitrogen analogue of the natural compound goniothalesdiol was also accomplished by using an intermediate produced in the synthesis of aza‐altholactone, making the overall process more divergent. Details are discussed in the article by C. R. D. Correia et. al. on p. 7259 ff. magnified image

Stereoselective Synthesis of Aza Analogues of Isoaltholactone and Goniothalesdiol – New Applications of the Heck–Matsuda Reaction

AbstractThe stereoselective synthesis of nitrogen analogues of biologically active isoaltholactone and goniothalesdiol are described. The successful strategy employed a Heck–Matsuda reaction between a chiral endocyclic enecarbamate bearing an ester functionality and arenediazonium tetrafluoroborates in a divergent approach at an early stage of the synthesis. Several aspects related to this critical arylation reaction are discussed to highlight structural features that affect the outcome of the arylation process. The synthesis of (–)‐aza‐isoaltholactone 6 was successfully accomplished in nine steps from the starting enecarbamate. We also performed the synthesis of the new fully substituted pyrrolidine (–)‐(2R,3R,4S,5S)‐1‐(tert‐butoxycarbonyl)‐3,4‐dihydroxy‐5‐phenylpyrrolidin‐2‐ylacrylic acid 28, which is a potential advanced intermediate in the route to aza‐altholactone. Moreover, the synthesis of a new nitrogen analogue of goniothalesdiol (+)‐33 was accomplished from the protected dihydroxypyrrolidine (–)‐27, obtained from an attempted synthesis of aza‐altholactone.

Síntese e avaliação preliminar da atividade antinociceptiva de novas isoxazolil-aril-hidrazonas

New 2-isoxazoline aldehydes were synthesized, in good yields, from cycloadduct of the 1,3-dipolar cycloaddition reaction between endocyclic enecarbamate and carboethoxyformonitrile oxide (CEFNO). Condensation of these 2-isoxazoline aldehydes with several phenyl-hydrazines produced new isoxazolyl-aryl-hydrazones, which showed low toxicity and excellent antinociceptive activity, when compared to dipyrone. The antinociceptive activity of isoxazolyl-aryl-hydrazones was performed using the acetic acid-induced mice abdominal constrictions test.

Studies on the Lithiation of Hydroxypyrrolidines: Synthesis of Polyhydroxy­lated Pyrrolidines via Chiral Enecarbamates

The chiral endocyclic enecarbamate 14 has been obtained by deprotonation-elimination from the N-Boc pyrrolidine 5 (or its racemic counterpart from 15). Efficiently stereocontrolled epoxidation-methanolysis of 14 afforded α-alkoxy carbamates, which undergo completely stereoselective nucleophilic substitutions to give trisubstituted dihydroxypyrrolidines.

ChemInform Abstract: Efficient and Expeditious Protocols for the Synthesis of Racemic and Enantiomerically Pure Endocyclic Enecarbamates from N-Acyl Lactams and N-Acyl Pyrrolidines.

A mild, practical, and straightforward protocol for the construction of endocyclic enecarbamates starting from N-acyl lactams and N-acyl pyrrolidines is presented. Lactams were reduced to the corresponding α-hydroxycarbamates in good to excellent yields using DIBAL-H, SuperHydride, or NaBH4 followed by β-elimination (dehydration) promoted by trifluoroacetic anhydride in the presence of hindered nitrogenated bases such as 2,6-lutidine, diisopropylethylamine, or triethylamine. Small variations of this protocol permitted the preparation of several endocyclic enecarbamates (12 examples) in good to excellent overall yields (56−96%). The protocol was demonstrated to be applicable to several ring sizes, compatible with different protecting groups, and to be mild enough to prevent racemization of racemization-prone stereocenters. The efficacy of the procedure in the preparation of enantiomerically pure endocyclic enecarbamates was also demonstrated and compared to the commonly used Shono's protocol, which in our ...

ChemInform Abstract: Synthesis of New Aza‐Bicyclic 2‐Isoxazolines by 1,3‐Dipolar Cycloaddition of Endocyclic Enecarbamates and Enamides with Nitrile Oxides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of new aza-bicyclic 2-isoxazolines by 1,3-dipolar cycloaddition of endocyclic enecarbamates and enamides with nitrile oxides

Novel aza-bicyclic 2-isoxazolines, 4,5-dihydroisoxazole[5,4- b]pyrrolidines, and 4,5-dihydroisoxazole[5,4- b]piperidines were synthesized in a highly regioselective manner through a 1,3-dipolar cycloaddition reaction of 5- and 6-membered endocyclic enecarbamates and enamides with several nitrile oxides in good to excellent yields. Hydrogenolysis of 5- and 6-membered Cbz-cycloadducts led to secondary amines, which presented distinctive stabilities. 2-Isoxazoline bisamides were obtained in good yields through a N-benzoylation, followed by ammonolysis of the secondary amine, or directly from ammonolysis of the cycloadducts.

Synthesis of alexine-like compounds from chiral five-membered endocyclic enecarbamates

Stereoselective syntheses of enantiomerically enriched trihydroxy pyrrolizidine and indolizidines were accomplished from a common chiral endocyclic enecarbamate. The synthetic strategy features an efficient [2+2] cycloaddition of ketenes to the endocyclic enecarbamate and a highly regioselective Baeyer–Villiger oxidation of the intermediate azabicyclic-cyclobutanones. These new heterocycles are compounds structurally related to the alexines.

Diastereoselective functionalizations of enecarbamates derived from pipecolic acid towards 5-guanidinopipecolates as arginine mimetics

Various substituents could be diastereoselectively introduced into the 5-position of pipecolic acid via electrophilic or free-radical-initiated addition to the carbon-carbon double bond of endocyclic enecarbamates derived from pipecolic acid. This study allowed the diastereoselective synthesis of both cis- and trans-5-guanidino pipecolates, which were designed as constrained arginine mimetics and whose potential inhibition of nitric oxide synthase (NOS) was evaluated with three NOS isoforms.

Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-pyrrolidine: A New Conformationally Constrained Mescaline Analogue

The total synthesis of the 3‐(3,4,5-trimethoxyphenyl)-pyrrolidine, a new and conformationally constrained mescaline analogue, was accomplished in a concise and efficient manner. The synthetic route encompassed only 4 steps from the starting N-Cbz-3-pyrrolidine, in 46% overall yield. The route features a highly effective Heck arylation of the non-activated olefin N-Cbz-3-pyrrolidine with the 3,4,5-trimethoxybenzene diazonium tetrafluoroborate. The hemiaminal (lactamol) Heck adduct was converted to the mescaline analogue in a sequence of reactions: (a) dehydration of the intermediate hemiaminal 3 with trifluoroacetic acid anhydride, (b) hydrogenation/hydrogenolysis of the endocyclic enecarbamate 6 with H2-Pd/C, and (c) formation of the rather stable mescaline analogue in the form of a hydrochloride salt. The target molecule constitutes a new mescaline analogue with potential activity towards 5‐HT2 dopamine receptors.

Synthesis of conformationally restricted acetylcholine analogues. Comparing lipase-mediated resolution with simulated moving bed chromatography of arylated β-hydroxy-pyrrolidines

The enantiodivergent synthesis of new, conformationally restricted acetylcholine analogues was accomplished using arylated endocyclic enecarbamates as key intermediates. Stereoselective hydroboration of the aryl enecarbamates provided the corresponding aryl-β-hydroxy-pyrrolidines. Acetylation, deprotection, followed by N-bismethylation, led to the desired betaine products. The kinetic resolution of the intermediate alcohols was performed by lipase-mediated hydrolysis of its acetate derivatives, resulting in excellent enantioselectivities ( E > 100). An enzymatic enantiopreference predicted by the Kazlauskas’s model was confirmed following Riguera’s protocol. Finally, chromatographic resolution of racemic alcohol 5a was evaluated by semi-preparative scale chiral simulated moving bed chromatography and its performance compared with biocatalysis.

Montmorillonite KSF Catalyzed One‐Pot Synthesis of Hexahydro‐1H‐pyrrolo[3,2‐c]quinoline Derivatives.

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