Amino Pyrrolidine Derivatives

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

An auxiliary controlled enantioselective route to generate seven-membered ring lactams 75 used the a-alkylation of cyclic hydrazide derivatives 74. Initially, 6-chloro hydrazides 73,bearing the chiral information in the M-amino-pyrrolidine function underwent amidocyclization in the presence of a base. A subse-... 

A wide variety of other photocyclizations have been reported, but only a few of these have any general application. The unsaturated amine 366 undergoes cyclization in cyclohexane to give the 7-azabicyclo[4.3.0]nonan-2-one 367.303 The formation of pyrrolidine derivatives by photocyclization has also been observed in JV-alkyl-2-allylanilines,304 and imidazoles have been obtained by irradiation of 2-amino-1-dialkylaminoanthraquinones.30 5... 

Figure 15.17 An amino-PEG-pyrrolidine derivative of carbon nanotubes can be used to couple metal chelating groups, such as DTPA. Subsequent coordination of mIn results in an indium chelate that can be used for imaging applications.

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

Barriers to rotation of nitrosamines in which the amino part is embedded in a cyclic system seem generally to be smaller. However, Harris and associates (82) reported that the barrier of /V-nitroso-2,2,5,5-tetramethylpyrrolidine (43) was over 22.6 kcal/mol. This must be higher than the barrier required for isolation of rotamers at room temperature, and is even higher than that in /V-nitroso-2,2,6,6-tetramethylpiperidine (44). Harris and Pryce-Jones attribute the high barrier of 43 relative to 44 to the more stable ground state of the former. If the pyrrolidine derivative is properly substituted, the atropisomers are expected to be isolable at room temperature. 

The metabolism of most five-membered azaheterocycles such as pyrrolidines can be described by the scheme given in Fig. 5.23. Thus, nicotine (5.86, Fig. 5.24), tremorine (5.89, Fig. 5.24), a pharmacological reagent used to produce experimental parkinsonism, and the antidepressant prolintane (5.90, Fig. 5.24) are metabolized to both lactam and co-amino acid derivatives [185-187]. 

One may, therefore, assume that the lactam metabolites formed are rather resistant to hydrolytic degradation and do not contribute significantly to the formation of the co-amino acid derivatives. This is in line with the observation that substituted pyrrolidin-2-ones are generally resistant to metabolic hydrolysis (see Sect. 5.3). 

Azomethine ylides can be generated in situ from various readily accessible starting materials. One of the easiest approaches to produce 1,3-dipoles involves the decarboxylation of immonium salts derived from condensation of a-amino acids with aldehydes or ketones [3, 204—206]. For example, the azomethine ylide 203, obtained by decarboxylating the condensation product of N-methylglycine and paraformaldehyde in refluxing toluene, reacts with Cjq to give the N-methyl-pyrrolidine derivative 204 in 41% yield (Scheme 4.32) [204]. 

By surveying 72 catalysts from the proline family, including piperidine- and pyrrolidine-derived catalysts, amino acids and diamines investigated over the past decade (Appendices 7.B-D), we may better understand both the structural features that are compatible with a successful catalyst and those which are detrimental and preferably avoided. 

Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201... 

Chiral pyrrolidine derivatives, proline, and amino acid-derived imidazolidinones mediate the asymmetric epoxidation of ,/i-unsalurated aldehydes. Protected a,a-diphenyl-2-prolinol catalyses the asymmetric formation of 2-epoxyaldehydes, with hydrogen peroxide or sodium percarbonate as the oxygen sources, with 81-95% conversion with up to 96 4 dr and 98% ee.204... 

Norephedrine 9 is alkylated with dibromide 26 to give pyrrolidine derivative 10.2 The hydroxy group of 9 is not alkylated under the conditions applied because of its lower basicity and nucleophilicity. First, the amino group of 9 is monoalkylated and the resulting ammonium salt 27 is deprotonated with NaHC03 as base. This yields secondary amine 28, which then undergoes intramolecular nucleophilic attack to furnish the desired A-pyrrolidinyl norephedrine 10 after deprotonation. Intermolecular nucleophilic substitution was not observed under these conditions. 

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). 

The scope of the silver-catalyzed [3+2] cycloaddition is not limited to amino acid-derived iminoesters. Grigg has reported the use of aminophosphane-derived azomethine ylides in the cycloaddition to afford the corresponding phosphonate-substituted pyrrolidines (Scheme 2.36).62 The diastereoselectivity of these cycloadditions is not inferior to those of standard amino acid-derived imines. 

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

The generation of an 1,2-oxazine 4-1 by hetero Diels-Alder reaction is a transformation which opens a versatile array of highly functionalised acyclic and cyclic structures. Thus, pyrrolidine derivatives 4-2, amino alcohols 4-3 and aza sugars 4-4 are easily available from these cycloadducts. Cyclic dienes, e.g. 4-5 are converted into bicyclic adducts 4-6 representing straightforward intermediates for aminocyclitols 4-7 (Fig. 4-1). 

Surprisingly, the photocyclization is enantioselective with amino acid derivatives 180 of phthalimide. For example, an inversion of the starting stereogenic center on the pyrrolidine ring was observed from the corresponding proline derivatives 182 (Scheme 47) [110]. 

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