Pyrrolidines, 2-substituted, synthesis

A number of highly potent DHP-I stable lP-methylcarbapenems having a variety of C-2 substiments have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C17H2BN3ObS. An acylamino compound (66) and a lP-methoxy analogue (70) provide other variations. The pyrrolidine substituted lP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectrum parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

Peixoto S, Ngueyen TM, Crich D, Delpech B, Marazano C. One-pot formation of piperidine- and pyrrolidine-substituted pyridinum salts via addition of 5-alkylamino-penta-2,4-dienals to N-acyliminium ions Applications to the synthesis of (+/-)-nicotine and analogs. Org Lett 2010 12(21) 4760-3. 

Scheme 4.30 Pyrrolidine-catalyzed synthesis of highly substituted 1,2,3-triazoles.

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). ... 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

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). 

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]. 

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. 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

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 highly diastereoselective exchange reaction between a variety of bis(dimethy-lamino)arylphosphines and (S)-2-(anilinomethyl)pyrrolidine (197a) and its SV-aryl analogues constituted a key step in the synthesis of a series of substituted monodonor diazaphospholidine ligands, 213-220 [90, 91] (Figure 1). 

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... 

Two transformations should be discussed in more detail (1) presence of the amino group in 275 was utilized for the synthesis of the fused isoquinolinium salt 276 bearing the bicyclic heterocycle as an A-substituent <2003JHC1041> (2) selective nucleophilic substitution of 277 with pyrrolidine was reported <2001ZOR604> to yield only substitution on the phenyl substituent without formation of an amide from the ester group 278. 

Shimizu and Tsuji [4] reported the first highly regioselective synthesis of 1,2-di-substituted allylic amines through capture of a Jt-allylpalladium complex by pyrrolidine (Scheme 16.2). This methodology has since been extended to a wide range of amines and allenes [5]. 

This method for preparing 2-phenyl-1-pyrroline, and assorted 2-substituted 1-pyrrolines, is one of the best currently available, particularly because it reproducibly affords clean materials. Generally, the procedure is amenable to various aromatic esters 2 it has also been applied successfully to aliphatic esters (Table I).3 An advantage of this method is the use of readily available, inexpensive N-vinyl-pyrrolidin-2-one as a key starting material. This compound serves effectively as a 3-aminopropyl carbanion equivalent. The method illustrated in this procedure has been extended to include the synthesis of 2,3-disubstituted pyrrolines. Thus, alkylation of the enolate of the intermediate keto lactam, followed by hydrolysis, leads to various disubstituted pyrrolines in good yields (see Table II).3... 

Some A -enecarboxylic acids undergo a rapid intramolecular cyclization reaction of the 5-exo-trig type prior to the radical coupling step. Substituted tetrahydro-furans [95] and pyrrolidines [96] can be prepared by this Kolbe route. It is preferable to protect the amine function in the pyrrolidine synthesis by N-formy ation in... 

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). ... 

During synthesis of the hormone rf-aldosterone, 20,21-dihydroxy-lip,18-epoxy-5a-pregnan-3-one diacetate was oxidised to the 3-oxo acid by stoich. RuOy CCl [78, 79], Oxidation of a substituted pyrrolidine to a pyroglutamate, part of the total synthesis of the antibiotic biphenomycin B, was effected by RuO /aq. Na(lO )/ EtOAc [102], Oxidation of a number of A-5 steroids to enones was effected by RuClj/TBHP/cyclohexane [391] safety aspects of these large-scale reactions were examined, as in the preparation of the antibacterial squalamine [186],... 

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