Pyrrolidines, 2,5-disubstituted, amides

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. 

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

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... 

Aminyl radicals also can be generated via electrochemical oxidation of amide bases or O-substituted hydroxylamines. Suginome has studied radical cyclizations involving oxidations of lithium alkenylamides as a route to ccs-l-methyl-2,5-disubstituted pyrrolidines (85TL6085). Electrolysis of lithium alkenylamide 17a, generated from the amine and butyllithium at - 78°C, led to the formation of 18a, exclusively cis, in 52% yield (Scheme 4). The reactions require 0.25 M UC104 in THF HMPA (30 1) as the supporting electrolyte. A variety of 2-substituted amines were studied. 

Asymmetric rearrangement of cyclohexene oxide Cyclohexene oxide is rearranged to (S)-2-cyclohexene-l-ol in 92% ee by the chiral lithium amide (2) prepared from n-butyllithium and 1. Several related (S)-2-(disubstituted aminomethyl)pyrrolidines prepared from (S)-proline are almost as stereoselective.3... 

The iodolactonization of amides containing (2/ ,5/ )-bis(methoxymethyl)pyrrolidine as a chiral auxiliary38 gives high enantiomeric excesses through diastereotopic alkene differentiation, as well as face differentiation. Thus, treatment of amide 5 with iodine in tetrahydrofuran under kinetic conditions affords the 2,4-tra/w-disubstituted lactone in 54% yield and 91%ee, as determined by H NMR with Eu(hfc)3. 

The mercuration of 1,5-hexadiene in the presence of aromatic amines, amides or carbamates is a suitable method for the preparation of 2,5-disubstituted pyrrolidines. The stereochemical outcome of this cyclization is strongly determined by the reaction conditions, 1,3-asymmetric induction depends on whether kinetic or thermodynamic control takes place. When mercury(II) acetate was allowed to react at — 20 °C in tetrahydrofuran with 1,5-hexadiene in the presence of an excess of arylamine (kinetic control), tra s-.V-substituted 2,5-dimethylpyrro-lidines 7 were the major product after reductive cleavage of the C —Hg bond88,89. 

Disubstituted pyrrolidinones are formed when the bicyclic lactam is tieaiedvjith AllyltrimethylsilanelJitaniumilV) Chloride. The remaining phenylglycinol moiety is cleaved with Li/NHs (see Lithium Amide) (eq 12). Further reduction with lAthium Aluminum Hydride affords 2,2-disubstituted pyrrolidines. 

Lithium 1,2-dialkyl-1-(4-pentenyl)amide ions obtained from secondary pentenyla-mines may be anodically oxidized to form aminyl radicals which undergo cyclization to give regio- and stereoselectively c/5 -A/ -alkyl-2,5-disubstituted pyrrolidines [26] ... 

Perhydrobenzoxazine 73 was reported as being a chiral auxiliary used to control the stereoselectivity of a thermally induced Alder-Ene reaction. In this instance, both endo- or exo-transition states seemed plausible to provide the observed products. Both TS minimize non-bonding steric interactions and were used to explain the selectivity observed. Ultimately, 74 was used to prepare cw-3,4-disubstituted pyrrolidines. For the conversion of 73 into 74, it should be noted that the enophile was the a,P-unsaturated amide and that the new C-C bond formed was alpha to the carbonyl. This appeared counter-intuitive for a LUMO enophile controlled reaction. 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

Higher enantioselectivities of up to 93% ee were achieved using the chiral bis(amidate) zirconium complex (5)-77 (Mes = 2,4,6-Me3CgH2), [250-253, 256], but again the high selectivities are limited to the formation of pyrrolidines, and unlike 75 and 76, only gcw-disubstituted substrates were reactive. 

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