Pyrrolidine, structure

G. M. Wall, J. M. Baker, Metabolism of 3-(/>-Chlorophenyl)pyrrolidine. Structural Effects in a Prototype y-Aminobutyric Acid Prodrug to Lactam and y-Aminobutyric Acid Type Metabolites , J. Med. Chem. 1989, 32, 1340-1348. 

Additions of Dialkylzinc Reagents. (lR,2S)-A/-Pyrrolidinyl-norephedrine (1) is an effective catalyst for the enantioselective addition of dialkylzinc reagents to aromatic aldehydes (eq 1). Optimized conditions involve reaction in toluene at 0°C with 10 mol % of the ligand and 2.2 equiv of the dialkylzinc reagent. Normal work-up after 20 h affords the product from addition to the Si face of the aldehyde. Product yields for a variety of alkylzinc reagents (1° and 2°) and an array of aromatic aldehydes are normally 80-100% with ee being nearly 90%. While similar results can be obtained for pyrazole-4-carbaldehydes, aliphatic aldehydes, and 1,2-phthalic dicarbaldehydes, the optimal ligand structure may involve variation of the amine substitution pattern (aliphatic tertiary amine rather than pyrrolidine structure). 

Shihunine, C12H13O2N (mp 79° picrate, mp 163°-164°) (I) was obtained from Dendrobium lohohense Tang et Wang (4) its phthalide-pyrrolidine structure was established by reduction and decarboxylation to 1-methyl-2-phenylpyrrolidine, by oxidation to phthalic acid, and with the help of IR-spectral data. 

Similarly, employing 2-azidoaldehydes as RAMA substrates allowed the preparation of polyhydroxylated pyrrolidines (Fig. 14.1-5)[38, 52> 53]. l,4-Dideoxy-l,4-imino-D-arabinitol1521 was synthesized from azidoacetaldehyde, and both (2R.5R)-1491 and (2S,5R)-bis(hydroxymethyl)-(3R,4R)-dihydroxypyrrolidine1531 were synthesized from racemic 2-azido-3-hydroxypropanal, respectively. In the latter case, the kinetic product of the aldol addition was transformed into the (2R,5R)-stereoisomer of the pyrrolidine, while the thermodynamic product gave the (2S,5R)-stereoisomer. Furthermore, pyrrolidines structurally related to GlcNAc have been prepared ster-eoselectively by a similar transformation from lipase-resolved aldehyde precursors [541. 

The alkaloid physostigmin (1) and its analogues bearing pyrrolo[2.3-b]pyrrolidine structural units have attracted attention because of their activity as cholinesterase inhibitors. A short synthesis of compound 2 possessing a pyrrolopyrrolidine skeleton includes the following reactions, in which 4-hydroxycoumarine (X, cf problem 76) is used as starting material ... 

The stereoselective vinylogous Michael addition-cyclization cascade of alkylidene malononitriles and 3-alkylideneoxindoles was effectively catalyzed by rosin-derived thiourea 36 to give spirocyclic oxindoles with excellent stereoselectivity (Scheme 35) [61]. Although simple thiourea 20 (see Scheme 16) provided low stereoselectivity (dr = 3 1, 29% ee), introduction of the rosin unit into the thiourea core significantly improved the diastereoselectivity to >20 1 the pyrrolidine structure was essential for high enantioselectivity. The effect of the chirality of the rosin component on the absolute stereocontrol was negligible and, thus, the major proposed role of this structural unit was to increase the steric hindrance of the catalyst. One of the salient features of this protocol is the... 

Analysis of presented copolymer spectra shows DAAH to copolymerize with VM and SO2, both double bonds participating, with formation of cis-, trans-stereoisomeric pyrrolidine structures in cyclolinear polymer chain in the proportion 4 1. 

The most useful catalysts are based on the pyrrolidine structure. The pyrrolidine may possess a large hydrophobic substituent at C2 or may be capable of establishing a H-bond with the acceptor molecule. Such a H-bond may be formed because of the presence of an acid hydrogen atom in the structure, or because of the... 

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

Kuehne and Foley (29) have found that the reaction of the pyrrolidine enamine of butyraldehyde with 2 equivalents of (8-nitrostyrene also led to a bis adduct with the structure as shown in 48. 

The reaction between the pyrrolidine enamine of butyraldehyde (52) and )3-nitrostyrene (53) provides cyclobutane adduct 54 quantitatively in either petroleum ether or acetonitrile solvent, but in the more polar ethanol solvent a 2 1 condensation product occurred. The structure of the product was shown to be 55 (57). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

The addition of ethyl acrylate to 1,2-dimethyl- -piperideine 163), l-methyl-2-ethyl-zJ -piperideine 164), and 1,2-dimethyl- -pyrrolidine 216,217) occurs, yielding both possible enamine structures (138 and 139, n=I,2). 

Enamines formed in this way may be distilled or used in situ. The ease of formation of the enamine depends on the structure of the secondary amine as well as the structure of the ketone. Thus pyrrolidine reacts faster than morpholine or piperidine, as expected from a rate-controlling transition state with imonium character. Six-membered ring ketones without a substituents form pyrrolidine enamines even at room temperature in methanol (20), and morpholine enamines are generated in cold acetic acid (21), but a-alkylcyclohexanones, cycloheptanone, and linear ketones react less readily. In such examples acid catalysis with p-toluenesulfonic acid or... 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

The relative stability of 2,5-diaminopyrrole- (95) and 2,5-diimino-pyrrolidine-type (96) structures for succimidines has not yet been clarified, although ultraviolet -spectral data indicate that forms of type 97 are probably unimportant. Banfield has discussed... 

Substituted TMMs also participate smoothly in imine cycloaddition to generate more structurally elaborate pyrrolidines. The regioselectivity of these reactions is similar to that of olefin addition, although subsequent isomerization of the initial adduct is often observed. For example, the cyano system produced the thermody-... 

I liickel 4/r + 2 rule and. 528-529 industrial synthesis of, 946 Pyrrolidine, electrostatic potential map of. 947 structure of, 918 Pyrrolysine, structure of, 1020 Pyruvate, acetyl CoA from. 

Menashi et al.153) could confirm the results of Privalov and Tiktopulo152 and inter-prete the described effects as follows In the case of native tropocollagen, the pyrrolidine residues are probably directed away from the fibrillar axis and are mostly coated by water which is structured in the immediate neighbourhood to the pyrrolidine residues. During the denaturation these pyrrolidine residues form hydrophobic bonds with each other or with other apolar residues within the same chain (endothermic interaction) while the structure of water breaks down (increase of entropy). 

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