Substituted pyrrolidine

The 1,2-, 1,2,5-, 1,3,4-, and 1,2,5-substituted pyrrolidines afford the corresponding pyrrolines very readily by oxidation with mercuric acetate. In the case of 1,2,2-trimethylpyrrolidine (35), the formation of a double bond... 

Both the infrared and ultraviolet spectra of pyrrolidine-2,3,5-triones (75) have been interpreted to support their existence as hydroxy-maleimides (76), and the occurrence of a strong OH stretching band in the infrared spectrum of 4-phenylpyrrolidine-2,3,5-trione has been taken as evidence that it too exists in a hydroxy form, probably 76 (R CeHg). However, the trioxo formulation is suggested by t/j the infrared spectra of jV-substituted pyrrolidine-2,3,5-triones, although an equilibrium apparently occurs depending upon the substituents and conditions. The zwitterion formulation 77 has been advanced for 4-aminopyrrolidine-2,3,5-trione. For chemical evidence... 

Fluoro atom of 2-amino-8,9-difluoro-5-methyl-6,7-dihydro-5//-pyr-ido[3,2,l-y]quinazoline-l,3-dione was replaced by 3-substituted pyrrolidines in the presence of NEt3 in DMSO at 110°C for 18h (01MIP23). 

The acetate (1) and its mosylate analog (79) have been shown to undergo cydoad-dition with the CN double bond of alkyl imines to generate substituted pyrrolidines in the presence of nickel or palladium catalyst [35]. For example, both the phenyl imine (80) and the diazene (81) gave reasonable yields of adducts (82) and (83) respectively (Scheme 2.23). 

Reduction to the corresponding ] -substituted pyrrolidine (23) (lakes place with sodium borohydride/boron trifluoride. Saponification completes the synthesis of the diuretic agent piret-.inide (24). ... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Corma et al. [55] have prepared chiral Cu(I) complexes with substituted pyrrolidine ligands bearing a triethoxysilyl group (Scheme 24). 

In addition, (Z,Z)-3,4-diethylene-substituted pyrrolidines and cyclopentane are obtained when 2,7-diynes were used as a starting material in Scheme 39. 

Other patent reports covering PDF inhibitors from structural classes different from those discussed above include hydrazides (43) [118], aryl-substituted pyrrolidines (44) [119], benzimidazoles (45, 46) [120-121], hydantoins (47) [122] and oxo-pyrrolidines (48) [123], A prodrug approach utilising PDF has been published by Pei, and patents have been published by NewBiotics, but in this case the compounds of interest are used as substrates rather than inhibitors (49) [124-126]. 

Analogous rearrangement occurs under much milder conditions when the reactant is a zwitterion generated by deprotonation of an acylammonium ion. Substituted pyrrolidines were used as the chiral auxiliary, with the highest enantioselectivity being achieved with a 2-TBDMS derivative.267... 

N-Substituted pyrrolidines were subjected to catalytic transfer hydrogenolysis affording pyrrolidines, but the yields were low. However, when di-tert-butyl dicarbonate was added to the N-substituted pyrrolidines before catalytic hydrogenolysis, the N-Boc derivatives were all formed in good yield (Scheme... 

Domino processes involving Homer-Wadsworth-Emmons (HWE) reactions constitute another important approach. Among others, HWE/Michael sequences have been employed by the group of Rapoport for the synthesis of all-cis-substituted pyrrolidines [143], and by Davis and coworkers to access new specific gly-coamidase inhibitors [144]. Likewise, arylnaphthalene lignans, namely justicidin B (2-281) and retrojusticidin B (2-282) [145], have been synthesized utilizing a domino HWE/aldol condensation protocol developed by Harrowven s group (Scheme 2.65) [146]. 

Another domino cuprate 1,4-addition-initiated threefold anionic domino sequence was developed by Chemla and coworkers (Scheme 2.93) [214]. Michael addition of the a, 3-unsaturated ester 2-387 with PhCu(CN)ZnBr was followed by a carbocyclization to give the zinc species 2-388 which can be intercepted by iodine or an allyl bromide affording substituted pyrrolidines 2-389 and 2-390, respectively. 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

Baker s yeast reduction of y-nitroketones offers the corresponding chiral nitro alcohols, which are useful building blocks for the synthesis of chiral natural compounds.120 For example, optically active 2-substituted pyrrolidine can be prepared using the chiral nitro alcohol (Eq. 10.75).121... 

A very simple and straightforward access to enantiopure substituted pyrrolidines and piperidines was obtained by reaction of phenylglycinol 178 with co-chloroketones 179. The intermediate oxazolidines 180 were then easily converted into the desired compounds <00EJO1719>. Compound 182 was obtained by reaction of the correspondent oxazolidine with a complex alkyllithium derivatives and was the intermediate for the synthesis of... 

The reaction can be extended to more elaborate systems as shown in the reactions of the substituted pyrrolidines (Equations (25) and (26)).85,86 Even though the 2-substituted pyrrolidine 8 has three electronically activated sites, two are sterically crowded. Furthermore, the Rh2(5-DOSP)4-catalyzed C-H insertion exhibited extreme stereodifferentiation, such that only one enantiomer of 8 was reactive under the reaction conditions. Consequently, a high level of kinetic resolution was observed, and the C-H insertion product was produced with 98% ee (Equation (25)).85 Similar reactivity was seen in the reaction of the 3-substituted pyrrolidine 9. In some regards, this reaction is even more impressive, because there was selective insertion into one of the two available methylene groups adjacent to nitrogen (Equation (26)).85... 

Increasing the steric hindrance of the ester was found to suppress completely the undesired lactamization. Thus, C-5-/-butoxycarbonyl cycloadducts 54a-e were reduced in near quantitative yield (NaBH3CN, 2M HC1, THF) to the A-substituted pyrrolidines 55a-e with, in some cases, the formation of the C-4 epimers 56c and 56d in low yield (Equation 6) <1996TL1711>. 

Oxazines are prone to hydrogenolysis since the relatively weak N-O bond is easily cleaved. This reaction has often been employed for the transformation of this cycle (generally obtained from nitrones) into amino alcohols in a stereocontrolled manner. For example, reaction of 57 with hydrogen and palladium on charcoal as catalyst (Equation 1) furnished the expected substituted pyrrolidine 58 in moderate yields <2003EJ01153>. 

This cyclization can also be used to obtain substituted pyrrolidines, as in the conversion of 7 to 8.3... 

Table 6.15. STRUCTURES AND ANTIBACTERIAL ACTIVITY OF (45)-7-(4-AMINO-2-SUBSTITUTED-PYRROLIDIN-l-YL)QUINOLONES [85]...

Similar to the results observed with 3-substituted pyrrolidine derivatives, it has also been found that the enantiomers of temafloxacin (a 3-substituted piperazine analogue) do not show significantly different antibacterial properties [92],... 

Substituted pyrrolidin-2-ones are generally resistant to metabolic hydrolysis as seen in the cases of rolipram and doxapram. Metabolic studies of the antidepressant rolipram (5.64) in several mammalian species, including humans, did not reveal any cleavage of the pyrrolidinone ring [174], Similarly, no metabolite with an opened pyrrolidin-2-one ring was found for doxapram (5.65), a respiratory stimulant [174],... 

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). 

Type iii-c reaction leads to the formation of (68). In the case of 6-alkenoic acids an intramolecular addition takes place. The Kolbe electrolysis of f)- N-allylamino)alkanoate (83) in the presence of a co-acid (84) gave 3-alkyl-substituted pyrrolidine (85) through an intramolecular... 

A nucleophilic attack of methanol in the a-position to a nitrogen atom can take place through an electrochem-ically generated iminium cation from substituted pyrrolidine [171,172], piperidine [173-180] or oxazolidinone [181,182] derivatives, as illustrated in Scheme 99 for A-carbomethoxypyrrolidine [163] and N-carbomethoxypiperidine [174]. 

Lithium ( )- or (Z)-5-alkenylamides are converted regio- and stereoselectively in a 5-exo-fng-cyclization of an intermediate amide radical to substituted pyrrolidines [84]. 

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

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