Other 2,4-Substituted Pyrrolidines

The asymmetric electrophilic a-fluorination of aldehydes with 2,5-disub-stituted pyrrolidines was tested independently by Jorgensen and Barbas III, but in these reactions MacMillan s imidazolidinones (Chapter 18) or diatylprolinol silyl ethers (Chapter 8) afforded much better yields and higher enantioselectivities. 

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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]. 

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]. 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

Other radical cyclization methodologies have been used to generate the kainoid substituted pyrrolidine skeleton.1... 

Biradicais other than 1,4-biradirals do not break down to give electron-paired cleavage products, and so photocyclization is an efficient reaction for carbonyl compouds where the y-position does not carry a hydrogen atom. Hence N-methyl P-ketoamides react to give substituted pyrrolidin-2-ones (4.51), and p-allyloxyketones lead... 

The TLSER methodology has been successfully applied to develop correlation equations for a wide variety of solvent-dependent properties and processes [350, 364-369]. Some examples are the characterization of other solvent polarity, acidity, and basicity scales [364], the acidities of substituted acetic acids in various solvents [365], the basicities of substituted dimethylamines in various solvents [366], the decarboxylation kinetics of 3-carboxybenzisoxazole [367], the C=0 stretching frequencies of substituted pyrrolidin-2-ones [368], and gas-water distribution coefficients [369]. 

Eeduction with sodium and ethanol has been used in the synthesis of hexahydropyridazine which is obtained together with 1,4-diaminobutane. Similarly, reduction of 3-(p-tolyl)-pyridazine gave besides the corresponding hexahydropyridazine also a substituted pyrrolidine. 3,6-Dimethylpyridazine, when reduced in this way, can give its dihydro or hexahydro analog.In all other cases of pyridazine reductions, no dihydro- and tetrahydropyridazines have been isolated, probably on account of their more ready reduc-ibility compared to aromatic pyridazines. 

Visible light irradiation of l,2-dihydro-2-thioxo-l-pyridinyl jV-(4-alkenyl)-A-alkylcarbamates (PTOC carbamates) produces substituted pyrrolidines by a radical chain reaction (see Section 7.2.5.1). In the absence of hydrogen donors, the intermediate pyrrolidinylmethyl radical reacts with the PTOC carbamate itself to afford 2-[(2-pyridinylthio)methyl]pyrrolidines, e.g., 1, 2, 4 and 521,22. On the other hand, in the presence of a good transfer reagent, another functionality can be introduced. In the presence of diphenyl diselenide, the phenylseleno-sub-stituted products were obtained in good yield, e.g., 3 and 622. In every case, however, a low degree of diastereoselectivity of the cyclization products is observed. 

Chiral azomethine ylides were prepared and used for the preparation of ferrocenyl-substituted pyrrolidines <2002TA2099>. Other enantiopure azomethine ylides were produced from aziridines by thermolysis <2001T71> and an enantiopure nitrile oxide was trapped by alkenes <2001GH629>. 

TV-Substituted pyrrolidines (and piperidines) are, similarly to other tertiary aliphatic amines, anodically cyanated a to the nitrogen in aqueous methanolic solution containing sodium cyanide [216]. 

Other CCR3-specific antagonists are characterized by the piperidine ureas (31-33), and the di-substituted pyrrolidine (34) (158). Again, a basic nitrogen, capable of protonation at physiologic pH, appears to be a common feature. It is important to note that the quaternary ammonium salt (32)demonstrates enhanced potency, relative to that of its parent (31) in binding, chemotaxis, and a whole-blood GAFS assay (Table 4.8) (159). 

The Eschenmoser reaction was applied a second time as one of the methods to introduce the -butyl appendage. The alkylated a-amino ester (97) was oxidized to the monosubstituted thiolactam (98), and introduction of the butyl side chain, via sulfide contraction as described above, yielded a mixture of vinylogous carbamates (99). Treatment of the carbamates (99) under transfer hydrogenolysis conditions yielded the optically pure dialkylpyrroline (100), another component of the ant trail pheromone. Subsequent reduction of the pyrroline with platinum afforded the optically pure ds-2,5-dialkyl-substituted pyrrolidine (101). Other pyrrolidine-containing alkaloids have been prepared by similar approaches involving the Eschenmoser reaction. ... 

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