Pyrrolidine derivatives, synthesis

Synthesis of the densely functionalized heterocyclic system of antitumor antibiotics azinomycins AandB, azirino [l,2-<2]pyrrolidine derivatives 98SL1031. 

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

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

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>. 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

The key step is the construction of a bicyclo[4.2.1] system. To this end, pyrrolidine derivative 95 having fif-substituents is synthesized from (+)-pyroglutamic acid and subjected to enyne metathesis using Ig to result in formation of 96 in 84% yield. From 96, synthesis of (+)-anatoxin-a is straightforward and successfully achieved. 

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. 

Trianthine. Central to Oppolzer s synthesis [70] of (+)-trianthine (278) [71] (Scheme 43) was the observation that appropriately substituted N-pentenylhydroxylamines undergo thermal suprafacial cyclisations to 2-substituted pyrrolidine derivatives, wherein the stereochemistry of the newly created asymmetric centres is found to be determined exclusively by the geometry of the starting olefins. Thus the E-olefin A, on thermolysis, yielded only B. None of its stereoisomer C was formed in the reaction (Figure 5). 

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... 

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... 

A similar result occurs in the synthesis of the stereochemically defined (35,4R) isomer of a pyrrolidine derivative which was transformed into the desired boropeptide thrombin inhibitor showing a binding affinity seven times greater than that of its non-pyrrolidinic... 

Azomethine ylides are organic 1,3-dipoles possessing a carbanion next to an im-monium ion [ 12]. Cycloadditions to dipolarophiles provide access to pyrrolidine derivatives, useful intermediates in organic synthesis with stereo- and regiochem-ical control. Azomethine ylides can be readily produced upon decarboxylation of immonium salts derived from the condensation of a-amino acids with aldehydes or ketones. When they are added to C60, a fulleropyrrolidine monoadduct is formed in which a pyrrolidine ring is fused to the junction between two six-memberedrings of afullerene [13-15].Very importantly,functionalized aldehydes lead to the formation of 2-substituted fulleropyrrolidines, whereas reaction with AT-substituted glycines leads to AT-substituted fulleropyrrolidines (Scheme 1). 

For the analogous synthesis of acromelic acid A 5, a more complex precursor 30 was prepared for cobaloxime-mediated cyclization.35 This yielded pyrrolidine derivative 31 in a 64% yield as a 1 1 mixture of the two side-chain double bond diastereoisomers (Scheme 7). The C-4 epimer was obtained in an 11% yield (i.e., a 6 1 ratio of C-4 epimers),... 

Recently, Kraus and Maeda have reported an elegant synthesis of the important C-4 o-anisyl derivative 26 in racemic form.85 This route involves pyrrolidine ring synthesis with key steps being Michael addition of the enolate of dimethyl a-ketoglutarate 174 to nitrostyrene derivative 175 followed by cyclization of the adduct 176 under reductive conditions to hemiaminal 177 (Scheme 63). 

Beilina, F. and Rossi, R. (2006) Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions. Tetrahedron, 62, 7213-7256. 

Chiral amides, pyrrolidine derivatives, in asymmetric synthesis 92 PAC1849. 

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