2-Amido pyrrolidines

Carretero s group further developed a highly exo-diastereoselective and enantioselective catalytic asymmetric protocol for the [3-h2] cycloaddition of a-iminoamides by using Cu(l)/DTBM-SEGPHOS complexes as catalyst system, providing a variety of 2-amido pyrrolidines, including Weinreb-type amides, with excellent levels of enantiocontrol (Scheme 10) [22]. Other activated alkenes, such... 

The intermolecular addition on the phenyl vinyl sulfone 73 was not described but it was demonstrated that an intramolecular version of this reaction was possible [67]. Amido-pyrrolidine 76 could promote the enantioselective cyclization of precursor 77 with a moderate level of selectivity (Scheme 34.27). 

Cagnoli R, Ghelfi F, Pagnoni UM, Parsons AF, Schenetti L. Hydro-de-halogenation and consecutive deprotection of chlorinated Al-amido-pyrrolidin-2-ones with Raney-Ni an effective approach to gahapentin. Tetrahedron 2003 59 (50) 9951 9960. 

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. 

Reincorporation of the tin can be avoided by using a tri wry/stannane precursor.156 This means that the product organolithium can be trapped with other electrophiles, provided that the solvent is 10 1 hexane-ether, and not THF, which otherwise protonates the product organolithium.157 The hexane-ether mixture slows down the tin-lithium exchange reaction dramatically, and it proceeds only at room temperature. Cyclisation of 323 thus leads to the synthesis of a simple GABA uptake inhibitor 324. A-acyl pyrrolidines cannot be made directly from a-amido organolithiums, as these fail to cyclise, possibly because they are too well stabilised by O-Li coordination.138... 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

Group 4 bis(amidate)bis(amido) complexes have also been identified as precatalysts for the more challenging hydroamination of alkenes. The majority of investigations in this field focus on the intramolecular cychzation of aminoalkenes with zirconium-based catalysts. [64e] Neutral group 4 bis(amidate) zirconium amido or imido complexes are efficient precatalysts for the intramolecular cychzation of primary amines to form pyrrolidine and piperidine products (Scheme 12). The monomeric imido complex can be generated by reaction of the bis(amido) complex with 2,6-dimethylaniline and trapped with triphenylphosphine oxide. [64e] The bis(amido) and imido complexes... 

Evidence of an undesired P-elimination pathway can be demonstrated when enantioenriched a-phenyl pyrrolidine is subjected to the standard reaction conditions. Although this amine couples in 60% yield with bromobenzene, the resulting product is racemic. This indicates that the palladium-amido intermediate is in equilibrium with an imine. 

Ytrium amido complexes generated in situ from chiral iV-benzyl-like-substituted binaphthyldiamines and [(THF)4Li][Y(CH2SiMe3]4 (both at 6-12 mol% loading) have been shown to catalyse the enantioselective intramolecular hydroamination of primary amines tethered to an alkene moiety (e.g. H2NCH2C(Me)2CH2CR=CR ) at 40-110 °C. Aminoalkenes bearing 1,2-dialkyl-substituted C=C bonds (R = H, R = Me) afforded the corresponding pyrrolidines with <77% ee, whereas trisubstituted alkenes (R = R = Me) were cyclized with only <55% eeP ... 

The pyrrolidine, profadol, (17) had one-quarter the activity of morphine in clinical trial.3 its capacity to precipitate the morphine abstinence syndrome was demonstrated35 along with its failure to substitute for morphine in dependent subjects. Chronic parenteral administration to post-addicts, however, led to an abstinence syndrome of its own on withdrawal. A detailed account of the compound has appeared.3° Tne amido-... 

Anisic acid was used with benzoxazole, whereas /i-toluic acid was more suited for benzothiazole derivatives. Formamides bearing pyrrolidine, piperidine, and morpholine derivatives were viable coupling partners however, amido- and ester-substituted substrates were unreactive. Notably, an optically active formamide could function as a coupling partner without racemization, suggesting that optically active amino groups could be incorporated onto heterocyclic systems via this process (eq 19). 

The catalytic cycle of this reaction has been shown in Scheme 40.5. At first, the Pd(0) catalyst reacts with the aryl bromide to generate the Pd(Ar)Br complex 19 via a simple oxidative addition. Complex 19 reacts with the amino alkene in the presence of NaO Bu base to generate the Pd (Ar)amido complex 21, which after subsequent alkene insertion into the Pd N bond followed by C C bondforming reductive elimination leads to the formation of substimted pyrrolidine derivative 23 along with the regeneration of the Pd(0). 

---