Disubstituted Pyrrolidines

Intramolecular Reactions 7.2.6.2.I. Preparation of Pyrrolidines 2,5-Disubstituted Pyrrolidines... 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

Chiral N,N-disubstituted 2-(aminomethyl)pyrrolidines as catalysts for asymmetric acylation of alcohols 99YGK598. 

Kaiser and Muchowski (41) reduced A -(r-butoxycarbonyl) pyrroles to the corresponding pyrrolidines over 5% Pt-on-C at room temperature and atmospheric pressure. Under these conditions 0-benzyl groups are retained and 2,5-disubstituted pyrroles are reduced mainly or exclusively to thecis-2,5-disubstituted pyrrolidines. In some cases Pt-on-C proved superior to either Rh-on-C or PtO,. 

As well as the disubstituted C2-symmelrie pyrrolidines E and F, the monosubstituted (f> )-2-(mcthoxymethyl)pyrrolidine G can be used as chiral auxiliary for the diastereoselecti ve addition of organomctallic reagents to a-oxo amides16. As with the phenylglyoxylic acid derivatives derived from amines E and F. methyllithium or methylmagnesium bromide in diethyl ether preferentially attack the (,S)-mms-conformer 11 (R = ( 6H5), leading to predominant formation of the (2 S)-diastercomer by Re-side attack. 

Finally, it should be mentioned that the allylation of 2,4-disubstituted pyrrolidine derivatives proceeds with reasonable diastereosclectivity for the trans-compound 2,4-rra .v-l, but with low selectivity for the m-isomer 2,4-m-l131. 

The addition of (Z)-3-(alkylamino)-2-butenoic acid esters to nitroalkenes derived from open-chain sugars gave a 50 50 mixture of diastereomeric products 32. The reaction of chiral 2-sub-stituted l-(2-nitroethenyl)pyrrolidines with zinc enolates of 3-substituted tetrahydro-2//-pyran-2-oncs in 1,2-dimethoxyethane at — 78 °C afforded the corresponding 3,3-disubstituted products in 82-96% ee via an addition-elimination process33. The stereochemical course of the reaction was determined by chemical correlation of (S)-( )-3-ethyltetrahydro-3-(2-ni-troethenyl)-2//-pyran-2-one with ( + )-quebrachamine. 

The utility of strained disubstituted cycloheptenes in alkaloid syntheses is highlighted by Blechert s total syntheses of the bis-pyrrolidine alkaloid (+)-dihydrocuscohydrine (390) [161],thebis-piperidine alkaloid (-)-anaferin (in the form of its dihydrochloride 393) [162], and indolizine 167B (397) [163] (Scheme 77). 

Interestingly, in the case of enantiomerically pure internal allenes, a diastereose-lective IH is observed (e.g.. Scheme 4-17), as shown by the catalytic hydrogenation of the Z/E mixture to give the trans-2,5-disubstituted pyrrolidine as a single compound. 

The transformation proceeds with excellent stereoselectivity by kinetic formation of the 2,5-trans-disubstituted pyrrolidine 2-328 [182]. The tertiary amine can now initiate a nucleophilic backside displacement of the vicinal iodide in 2-328, leading to an aziridinium salt 2-329 [183]. This event ensures a net retention of the stereochemistry at C-13 in the following attack of the ester carbonyl in the butyrolactone ring closure to give 2-330. 

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. 

Denmark and coworkers have found that methylaluminum bis (2,6-di-tert-butyl-4-methyl-phenoxide) (MAD) or methylaluminum bis(2,6-diphenylphenoxide) (MAPh) is effective as the Lewis acid promoter for cycloaddition of 2,2-disubstituted 1-nitroalkenes (Eq. 8.100).158 Other Lewis acids such as SnCl4, TiCl4, and TiCl2(Oi-Pr)2 fail to promote the cycloaddition of 2,2-disubstituted 1-nitroalkenes. The products are converted into 3,3-disubstituted pyrrolidines via hydrogenolysis.158 Reductive cleavage of N-0 bonds produces oxime hemiacetals, which are further reduced to amido aldehydes and finally to pyrrolidines. This reaction provides a useful synthetic method for pyrrolidines, which is discussed later. 

Hydrogenolysis of the individual nitronate diastereomers presented in Scheme 8.30 provides the corresponding Irons- and cw-3,4-disubstituted pyrrolidines in good yields (Eq. 8.101).158... 

P-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiAlhL is a powerful method for the synthesis of stereodefined aziridines and azetidines <06OL1101>. However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cw-disubstituted pyrrolidines and piperidines 32 <060L1105>. During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of a peptide-... 

The reaction of nitrones with 3-butenylmagnesium bromide was used in the diastereoselective synthesis of cis -2,5-disubstituted pyrrolidines, arising from a Cope retro-elimination (Scheme 2.145) (Table 2.11) (201, 572). 

Significant decomposition prevented calculation of d.r. cNo 2,5-disubstituted pyrrolidine W-oxides were detected. 

Dipolar cycloaddition reactions between three A-benzyl-C-glycosyl nitrones and methyl acrylate afforded key intermediates for the synthesis of glyco-syl pyrrolidines. It was found that furanosyl nitrones (574) and (575) reacted with methyl acrylate to give mixtures of all possible 3,5-disubstituted isoxazolidines (577) and (578). On the other hand, the reaction with pyranosyl nitrone (576) was much more selective and cycloaddition at ambient temperatures afforded only one of the possible Re-endo adducts (579a). The obtained isoxazolidines were transformed into the corresponding (V-benzyl-3-hydroxy-2-pyrrolidinones (580—582) on treatment with Zn in acetic acid (Scheme 2.264) (773). 

Fig. 1 Schematic drawing showing the structure of tris(A/,AT-disubstituted-dithiocarbam-ato)iron(III). Substituents R1 and R2 represent various types of alkyl groups including those being part of the ring systems morpholine, pyrrolidine or pyrrole (Table 1)... 

Racemic 2,5-disubstituted 1-pyrrolines were kinetically resolved effectively by hydrogenation with a chiral titanocene catalyst 26 at 50% conversion, which indicates a large difference in the reaction rate of the enantiomers (Table 21.19, entries 4 and 5), while 2,3- or 2,4-disubstituted 1-pyrrolines showed moderate selectivity in the kinetic resolution (entries 6 and 7) [118]. The enantioselectivity of the major product with cis-configuration was very high for all disubstituted pyrrolidines. The high selectivity obtained with 2,5-disubstituted pyrrolines can be explained by the interaction of the substituent at C5 with the tetrahydroinde-nyl moieties of the catalyst [Eq. (17)]. 

The reductive animation of 1,4-diketones in the presence of an equivalent of ammonia opens an avenue to 2,4-disubstituted pyrrolidines. Since Stetter s thiazolium salt chemistry allows the preparation of 1,4-diketones from a, 3 unsaturated enones and aldehydes, a large variety of pyrrolidines may be prepared. Two examples of such syntheses have recently been published by the T. H. Jones group (Scheme 27) (132, 170). 

The ene reaction offers great possibilities in the synthesis of 3,4 disubstituted pyrrolidines or piperidines (775). An illustration of this reaction is a short and selective synthesis of allokainic acid by Oppolzer and Andres (176) (Scheme 31). In subsequent work, the influence of the double-bond geometry in the... 

The presence of a pyrrolidine unit in complex systems such as the azabicy-clo[2.1.1]hexane unit of 2,4-methanoproline (56) lends itself to synthesis pertaining to the 1,3-disubstituted cyclobutane part of the molecule. Thus two syntheses of 56 have been published, relying on the [2 + 2] photochemical synthesis of cyclobutanes. A nontrivial problem of the synthesis of these compounds is liberation of the target molecule from its protective groups (Scheme... 

Several diverse classes of potent CCR5 antagonists, Figure 7 have recently been reported [2], Scaffolds reported to support high potency against CCR5 in antiviral cellular assays included the aminocyclohexyl (compound 13) [45], 4,4-disubstituted piperidine (compound 14, GSK163929) [46,47], tetrahydro-2/T-1,3-oxazine (compound 15) [48], pyrrolidine (compound 16) [49], cyclopropyl (compound 17) [50] and 2,3-dihydro-lH-indene (compound 18) [51]. 

Pyrrolines. This diene undergoes a [4 + ljannelation with primary amines to form a pyrrolidine 2 that can be converted to a 3-(3-phenylsulfonyl)pyrroline (3) in high yield. These pyrrolines are oxidized by DDQ to pyrroles (4), which can be converted readily to 2,3-disubstituted pyrroles (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... 

Neutral aminyl radicals generated by anodic oxidation of lithium alkenyl amides undergo a stereoselective cyclization to cis-l-methyl-2,5-disubstituted pyrrolidines [249]. 

Claisen rearrangement presumably was the boat-like form 156 (bj0) with minimized 1,3 repulsive interactions resulting in the lactams 157. However, the 2,4-as disubstituted pyrrolidine 159 (R =OTBS, R, R =H) gave the expected lactam diastereomer 158 via a chair-like transition state conformation 160 (entry 16, Table 8) (Scheme 31). 

The cyclization of the lithium amide 29a to 2,5-disubstituted pyrrolidine shown in Scheme 17 is clearly a one-electron oxidation process. This suggests that the radical 29c is not an oxidizable species at the applied potential and thus... 

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