Pyrrolidine Products Research Articles

Alkene hydroamination with a chiral zirconium catalyst. Connecting ligand design, precatalyst structure and reactivity trends

A set of chiral bis(amidate) proligands were synthesized based on a 3,3′-substituted biphenyldiamine backbone. Zirconium precatalysts were synthesized using these proligands in situ and used for catalytic testing for intramolecular alkene hydroamination, achieving moderate enantiomeric excesses. Ligands containing electron-withdrawing substituents were found to be exceptionally reactive, in some cases catalyzing formation of pyrrolidine products at room temperature. Substitution at the 3,3′-position of the biphenyldiamine backbone was observed to significantly impact N,O-chelate binding modes, which in turn affect observed enantioselectivities.

One‐Pot Tandem Strecker Reaction and Iminocyclisations: Syntheses of Trihydroxypiperidine α‐Iminonitriles

AbstractUnbranched, and α‐ and β‐methyl‐branched, trihydroxypiperidine α‐iminonitriles have been obtained in a single step from protected 5‐O‐tosylate pentoses. This reaction comprises a one‐pot tandem Strecker reaction and iminocyclisation. These trihydroxypiperidine α‐iminonitriles are precursors to trihydroxypipecolic acids. No formation of pyrrolidine products was observed.

Silver-catalyzed dynamic systemic resolution of α-iminonitriles in a 1,3-dipolar cycloaddition process

A dynamic azomethine ylide system was established using Sc(OTf)3 and Ag/Taniaphos as catalysts. The system was subsequently kinetically resolved in a tandem 1,3-dipolar cycloaddition process where the silver complex acted as both a reaction catalyst and an external selector, resulting in the formation of an exclusive pyrrolidine product in good yield and enantiopurity.

Enantioselective thiourea-catalyzed intramolecular cope-type hydroamination.

Catalysis of Cope-type rearrangements of bis-homoallylic hydroxylamines is demonstrated using chiral thiourea derivatives. This formal intramolecular hydroamination reaction provides access to highly enantioenriched α-substituted pyrrolidine products and represents a complementary approach to metal-catalyzed methods.

C2-Symmetric Cyclic Selenium-Catalyzed Enantioselective Bromoaminocyclization

A catalytic asymmetric bromocyclization of trisubstituted olefinic amides that uses a C(2)-symmetric mannitol-derived cyclic selenium catalyst and a stoichiometric amount of N-bromophthalimide is reported. The resulting enantioenriched pyrrolidine products, which contain two stereogenic centers, can undergo rearrangement to yield 2,3-disubstituted piperidines with excellent diastereoselectivity and enantiospecificity.

Diastereoselective synthesis of pyrrolidine derivatives via a one-pot nitro-Mannich/hydroamination cascade using base and gold catalysis

An efficient one-pot nitro-Mannich/hydroamination cascade reaction for the synthesis of substituted pyrrolidines bearing three stereocentres is reported. Proceeding under the control of a combination of base and gold(I) catalysts, the cascade reaction affords the pyrrolidine products in high yields with good to excellent diastereoselectivities.

Fluorine as a Regiocontrol Element in the Ring Opening of Bicyclic Aziridiniums

The origin of the variation in the regioselectivity of the nucleophilic ring-opening of a series of bicyclic aziridinium ions derived from N-alkylprolinols was investigated by quantum chemical computations (M06-2X/6-31+G(d,p)-SMD). These aziridiniums differ only in the degree and the stereochemistry of fluoro substitution at C(4). With the azide ion as nucleophile, the ratio of the piperidine to the pyrrolidine product was computed. An electrostatic gauche effect influences the conformation of the adjoining five-membered ring in the fluorinated bicyclic aziridinium. This controls the regioselectivity of the aziridinium ring-opening.

Enantioselective organo-SOMO cycloadditions: a catalytic approach to complex pyrrolidines from olefins and aldehydes.

A new method to rapidly generate pyrrolidines via a SOMO-activated enantioselective (3 + 2) coupling of aldehydes and conjugated olefins has been accomplished. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine radical cation and oxidation of the resulting radical furnish a cationic intermediate which is vulnerable to nucleophilic addition of a tethered amine group. A range of olefins, including styrenes and dienes, are shown to provide stereochemically complex pyrrolidine products with high chemical efficiency and enantiocontrol.

A highly enantioselective approach towards 2-substituted 3-bromopyrrolidines

A facile and highly enantioselective approach towards 2-substituted 3-bromopyrrolidines has been developed. The process involves an amino-thiocarbamate catalyzed bromoaminocyclization of 1,2-disubstituted olefinic amides. The pyrrolidine products could readily be converted into other useful building blocks including a dihydropyrrole and a 2-substituted pyrrolidine.

A smooth rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenylsilylmethyl-substituted azetidines into N-p-toluenesulfonyl 3-tert-butyldiphenylsilyl-substituted pyrrolidines

The rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenylsilylmethyl-substituted azetidines into 3-tert-butyldiphenylsilyl-substituted pyrrolidines under Lewis acid conditions in dichloromethane involves 1,2-migration of silicon through a siliranium ion. The formation of siliranium ion was discovered not to be in concert with σ(C-N) cleavage from stereochemical analysis of the pyrrolidine products formed from 3- and 4-substituted-2-tert-butyldiphenylsilylmethyl azetidines and also from the optical rotation data and chiral HPLC analysis of the pyrrolidine product formed from N-p-toluenesulfonyl 2(R)-tert-butyldiphenylsilylmethyl azetidine. The formation of sterically less hindered siliranium ion is followed by its S(N)2 opening by the internal nitrogen nucleophile. Oxidative cleavage of σ(C-Si) bond leads to the formation of 3-hydroxypyrrolidines.

Design and synthesis of pyrrolidine-containing sphingomimetics

Based on the structures of natural sphingolipids, we designed heterocyclic sphingoid base mimetics in which the conformational restriction is introduced by incorporation of a pyrrolidine moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a regioselective nucleophilic ring opening of a cyclic sulfate with cyanide and subsequent manipulation of the cyanide group. During the course of synthesis, Staudinger-type reductive cyclization of 1,3-azido carboxylic acid and 1,4-azido alcohol offers a direct route to the five-membered pyrrolidone and pyrrolidine products. The preliminary biological evaluation indicates that the designed pyrrolidine analog is biologically active and its cytotoxic effect is associated with the induction of apoptosis.

Corrigendum: Chiral Neutral Zirconium Amidate Complexes for the Asymmetric Hydroamination of Alkenes

The authors would like to thank Prof. Kai Hultzsch of Rutgers University for alerting them to their erroneous illustration of the tetrasubstituted stereogenic center in the Mosher amide derivatives as S in the Supporting Information. The authors have verified, with the assistance of Prof. Hultzsch, that the method and NMR data presented in the Supporting Information gives the correct configuration of 2-methyl-4,4-diphenylpyrrolidine as indicated.1 While the illustrated and assigned configuration of the pyrrolidine products in both the manuscript and Supporting Information are correct,1 because of the Cahn–Ingold–Prelog priorities in assigning configuration there is a change from S to R upon amide synthesis. Thus, the use of (S)-Mosher acid chloride gives the (R)-Mosher amide products. To ensure that this error is not propagated in the literature, a revised version of the Supporting Information has been filed with all of the corrected illustrations included on the spectra. The sentence at the bottom of the first column on page 356 should be corrected to read “Reported ee values were determined by integration of 1H and/or 19F NMR spectra of the (S)-Mosher acid chloride derivatives of at least two independent experiments.” The authors regret any confusion that may have arisen from their erroneous illustration. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Stereoselective cyclo-addition reactions of azomethine ylides catalysed by in situ generated Ag(I)/bisphosphine complexes

Stereoselective cyclo-addition reactions of azomethine ylides promoted by in situ generated Ag(I)/bisphosphine complexes were studied. Under the optimized conditions, the pyrrolidine products were isolated in up to 84 % yield and with up to 71% e.e. The effects of various reaction variables on the stereoselectivity were also investigated.

Gold(I)-catalyzed enantioselective [4 + 2]-cycloaddition of allene-dienes.

An enantioselective gold(I)-catalyzed intramolecular [4 + 2]-cycloaddition of allenes and dienes is reported. The reactions allow for the asymmetric synthesis of trans-hexahydroindenes and pyrrolidine products using C(3)-symmetric phosphitegold(I) and ortho-arylphosphoramiditegold(I) complexes as catalysts, respectively.

Chiral Neutral Zirconium Amidate Complexes for the Asymmetric Hydroamination of Alkenes

The authors would like to thank Prof. Guofu Zi and Li Xiang of Beijing Normal University for alerting us to our erroneous assignment of 2,2′-diamino-6,6′-dimethylbiphenyl ([α]D=−35° in 10 % HCl) as the S absolute configuration in our communication. In fact, (S)-(−)-2,2′-diamino-6,6′-dimethylbiphenyl has negative specific rotation in non-acidic solvents ([α]D=−51.7°±2.4 in EtOH,1 [α]D=+34° in 10% HCl2).3 Thus, the resolution of racemic 2,2′-diamino-6,6′-dimethylbiphenyl in the Supporting Information should be corrected to read L-(+)-tartaric acid (sometimes given as d-tartaric acid in the literature3) gives (R)-(+)-2,2′-diamino-6,6′-dimethylbiphenyl. Then (S)-(−)-2,2′-diamino-6,6′-dimethylbiphenyl enriched materials can be resolved with D-(−)-tartaric acid. These resolved axially chiral diamines can then be used to make all the proligands, precatalysts, and pyrrolidine products as described in the communication. Notably, owing to the fact that proligands and precatalysts are reported using specific rotation (not absolute configuration) the misassignment of the naming of the ligand does not change any of the data presented regarding the absolute configurations of the products (i.e. in Table 2, entry 2 precatalyst (−)-4 a does give the (S)-pyrrolidine product). Figure 1, which shows the solution of a racemic crystal, is corrected to read “Two views of an ORTEP diagram (ellipsoids shown at the 50 % probably level) of the dimethylamine adduct of (±)-4 a …︁ ”. The initial erroneous absolute configuration assignment of the diamine means that in Figure 2 we in fact illustrated (−)-4 a. Thus, based upon the suggestion of Prof. Zi, we modify our working hypothesis for selectivity in setting the stereocenter as presented in the corrected Figure 2. Suggested intermediates in the enantioselective aminoalkene hydroamination using precatalyst (+)-4 a in which the alkene can approach from the Re face or the Si face. While the misassignment of the absolute configuration of the chiral diamine ligand backbone was erroneous and unfortunate, the stereochemistry of the products, and the enantiomeric excesses reported remain unchanged.

Copper-Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides

A novel N,P-ligand is employed in the copper-catalyzed 1,3-dipolar cycloaddition of azomethine ylides giving the substituted pyrrolidine products in high yields and excellent enantio­selectivity. Significant improvement of substrate scope over previous studies is realized in this work.

Gold‐ and Silver‐Catalyzed Tandem Amination/Ring Expansion of Cyclopropyl Methanols with Sulfonamides as an Expedient Route to Pyrrolidines

An efficient synthetic route to pyrrolidines that relies on AuCl/AgOTf-catalyzed tandem amination/ring expansion of substituted cyclopropyl methanols with sulfonamides is reported herein. The reactions proceed rapidly at 100 degrees C with catalyst loadings as low as 2 mol % and produce the pyrrolidine products in yields of 30-95 %. The method was shown to be applicable to a broad range of cyclopropyl methanols, including unactivated ones, and sulfonamide substrates containing electron-withdrawing, electron-donating, and sterically-demanding substituents. The mechanism is suggested to involve activation of the alcohol substrate by the AuCl/AgOTf catalyst, followed by ionization of the starting material, which causes ring opening of the cyclopropane moiety and trapping by the sulfonamide nucleophile. The resultant aminated acyclic intermediate undergoes subsequent intramolecular hydroamination to give the pyrrolidine.

Mild conditions for Pd-catalyzed carboamination of N-protected hex-4-enylamines and 1-, 3-, and 4-substituted pent-4-enylamines. Scope, limitations, and mechanism of pyrrolidine formation.

The use of the weak base Cs2CO3 in Pd-catalyzed carboamination reactions of N-protected gamma-aminoalkenes with aryl bromides leads to greatly increased tolerance of functional groups and alkene substitution. Substrates derived from (E)- or (Z)-hex-4-enylamines are stereospecifically converted to 2,1'-disubstituted pyrrolidine products that result from suprafacial addition of the nitrogen atom and the aryl group across the alkene. Transformations of 4-substituted pent-4-enylamine derivatives proceed in high yield to afford 2,2-disubstituted products, and cis-2,5- or trans-2,3-disubstituted pyrrolidines are generated in good yield with excellent diastereoselectivity from N-protected pent-4-enylamines bearing substituents at C1 or C3. The reactions tolerate a broad array of functional groups, including esters, nitro groups, and enolizable ketones. The scope and limitations of these transformations are described in detail, along with models that account for the observed product stereochemistry. In addition, deuterium labeling experiments, which indicate these reactions proceed via syn-aminopalladation of intermediate palladium(aryl)(amido)complexes regardless of degree of alkene substitution or reaction conditions, are also discussed.

Development of Highly Regioselective Amidyl Radical Cyclization Based on Lone Pair−Lone Pair Repulsion

The substituent effect on the reactivity and regioselectivity of N-(4-pentenyl)amidyl radical cyclization was investigated. Exclusive 6- endo cyclization was observed for N-(4-pentenyl)amidyl radicals with internal vinylic heteroatom substitution (Cl, Br, I, OMe, SEt). The substituent on the carbonyl group also showed a significant influence on the reactivity of amidyl radicals, which increases in the order of Ph < Me < OEt. As a result, the photostimulated reactions of N-(4-halopent-4-enyl)amides and carbamates (X = Cl, Br, I) with DIB/I 2 or Pb(OAc) 4/I 2 led to the efficient and exclusive formation of the corresponding piperidines while those of N-(5-halopent-4-enyl)amides afforded the pyrrolidine products only. The halogen-substitution effect also allowed the 6- exo and 7- endo amidyl radical cyclization to proceed in a highly regioselective manner. The above experimental results, in combination with theoretical analyses, revealed that the lone pair-lone pair repulsion between the nitrogen radical and the vinylic heteroatom played an important role in controlling the regioselectivity of cyclization.

Ruthenium-Catalyzed Enantioselective Hydrogenation of Pyrroles

Enantioselective hydrogenation of pyrroles would provide direct access to chiral ­pyrrolidine rings. The current work succeeded in ­using 2,3,5-trisubstituted pyrroles as substrate to give all-cis pyrrolidine products with three chiral centers, or chiral 4,5-dihydropyrroles. Basically, this method is a powerful entry to chiral pyrrolidine, very useful for pharmaceutical applications as well as organocatalysis.