Synthesis of Pyrrolidine Derivatives

Similar to the synthesis of tetrahydrofuranols by the irradiation of [i-alkoxy ketones, Henning s group was the first to show that the photolysis of N-( 3-benzoylethyl)-N- 

The rate of photocyclization of 63 was greatly enhanced when irradiation was carried out by absorbing it on silica gel surface, possibly due to a higher content of the keto tautomer. 

The obvious extension of the above concept was made by Wessig etal. [23] to obtain optically active cis-3-hydroxyproline derivatives 66 in moderate to good yields by irradiating chiral N-(2-benzoylethyl)-N-tosy] glycinamide (65) in cyclohexane/ benzene (4 1) mixture. The diastereomeric excess (de) of the photocyclization was 

Giese et al. [25] have compared the steric course of the reaction ofTj (triplet) and S, (singlet) by studying the photocydization reaction of alanine derivatives 69, which led to the formation of proline derivatives 71a and 71b (Table 8.3) 

It was observed that photoreaction from Tj was almost nonselective as it gave all of the possible isomers, whereas S underwent stereoselective cyclization. This difference in selectivity was attributed to the faster rate of cyclization of the singlet diradical compared to the triplet. 

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Diastereoselective synthesis of pyrrolidine derivatives using chiral and non-racemic A-cyanomethyloxazolidines 99CSR383. 

Ma and co-workers have reported the selective synthesis of pyrrolidine derivatives through a three-component reaction based on a conceptually related strategy (Scheme 8.29) [72], Beginning with the catalytic intermolecular carbopalladation of y-allenic malonate 57 in the presence of a base, they succeeded in intercepting the internal carbonucleophile 58 with an imine such as the N-benzylidene p-toluenesulfonamide 59. The attack of the newly formed heteronucleophile on the 7r-allyl palladium intermediate affords the functionalized pyrrolidine 60 with high... 

Ma and co-workers [63] have developed a tandem procedure for the synthesis of pyrrolidine derivatives based on the three component coupling of... 

Synthesis of pyrrolidine derivatives and lactones based on conjugate addition of nitroalkanes to electron-poor alkenes 05CRV933. 

Scheme 8.4 Diastereoselective synthesis of pyrrolidine-derived arylgtycine methylester 6...

M. Komatsu, H. Okada, T. AkaM, Y. Oderaotoshi, S. Minakata, Generation and cycloaddition of polymer-supported azomethine yhde via a 1,2-silatropic shift of a-silylimines traceless synthesis of pyrrolidine derivatives. Org. Lett. 2002, 4, 3505-3508. 

The ring-closing metathesis (RCM) approach is useful for the synthesis of indolizidinone derivatives. The procedures published are based on the use of compound 103, an amide of a pyrrolidine derivative bearing on C-l the second unsaturated branch ready for the cyclization. The reaction proceeded smoothly with high yields in both examples (Scheme 27) <2001JOC9056, 2004JOC3968>. 

Rapid advances in the synthesis of naturally occurring pyrrolizidine bases can be expected, and the most promising method for this purpose is the Dieckmann cyclization of pyrrolidine derivatives. 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

Another synthesis of pyrrolidines, in this case with high enantioselectivity, has seen several enones with a chiral alkoxy or amino substituent in the y-position react with azome-thine yields (derived from glycine imine derivatives) upon treatment with DBU/AgOAc (equation 171)612-614. This reaction may also be done using other alkene-containing substrates615,616. 

Polymer-supported azomethine ylids generated from a-silylimines through a 1,2-silatropic shift, are shown to be versatile reagents suitable for the synthesis of libraries of pyrrolidine derivatives after 1,3-dipolar cycloaddition with a series of dipolarophiles. Effectively substituents R1, R2 and dipolarophiles A=B and A=B can be chosen to get the desired adduct.146... 

With adiponitrile, an open-chain dinitrile, however, such cyclization leading to a seven-membered cyclic imine occurs to a much lesser extent (see, e.g., eq. 7.25). The hydrogenative cyclizations have been utilized for the synthesis of pyrrolidine and piperidine derivatives from 1,2- and 1,3-dicyano compounds.118,119... 

Lithiated cyclic enamines 691 " 5 996 and amidines 692989,997 have been prepared by deprotonation of the corresponding heterocycles with f-BuLi in THF at — 78 °C, being allowed to react with several electrophiles. This methodology has been applied to the synthesis of pyrrolidine and piperidine derived compounds, intermediates 691 and 692 acting in these cases not as acyllithium equivalents. 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

Several examples have appeared in the literature in which this linker has been employed in combinatorial chemistry strategies. Thus, it has been used in a Pd-mediated three-component coupling strategy for the solid-phase synthesis of tropane derivatives [46], in the solid-phase synthesis of aspartic acid protease inhibitors [47], in the attachment of cholic acid as a template for a combinatorial approach [48] and, more recently, in the solid-phase synthesis of pyrrolidines via 2-aza allyl anion cycloadditions with alkenes [49]. 

ATi receptor ligands virtual-screening-based design with TOPP descriptors, synthesis, and biological evaluation of pyrrolidine derivatives. ChemMedChem, 2, 1298-1310. 

A short, convenient, stereoselective synthesis of pepper-derived alkaloids has been carried out by condensing piperonal with the ylide from methyl (E)-4-(diethylphosphono)-2-butenoate to give methyl (E,E)-5-(1,3-benzodioxol-5-yl)-2,4-pentadienoate, which on methoxide-catalysed aminolysis (piperidine, pyrrolidine, etc.) gave the required alkaloid. 

Coleman and Goheen409 found it better to use iV-chloro amines rather than the A-bromo compounds for synthesis of pyrrolidines and in this way achieved yields of around 75% of substituted pyrrolidines. The method has also proved valuable for synthesis of bicyclic tertiary amines.410"412 Schmitz413 applied it to N,N-dibromo derivatives of primary amines from iV,JV-dibromo-l-propylbutylamine he obtained pyrrolizidine in 35% yield,414 the best yields being obtained here, as in other cases,412 415 416 when the reaction is carried out with irradiation in ultraviolet light. Recently ring closure was also achieved with JV-monochloro derivatives of primary amines 417 pyrrolidine (70%) was obtained from butylamine, 2-methylpyrrolidine (80%) from pentylamine, and 2-propylpyrrolidine (50% and 70%, respectively) from heptylamine or 1-pro-pylbutylamine.417 The mechanism of the Hofmann-Loffler reaction has been discussed by Wawzonek and Culbertson.416... 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

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