Cis-2,5-Disubstituted pyrrolidin

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). 

Two routes to the pyrrolidine system involving the generation of nitrogen-centred radicals have appeared. N-Methyl-cis-2,5-disubstituted pyrrolidines (232) may be obtained in moderate yields... 

Merck scientists reported a practical enantioselective synthesis of cis-2,5-disubstituted pyrrolidines where the key chiral step 3 is a dynamic kinetic bioreduction as shown in Scheme 6.29. The bioreduction is performed at pH 7 and 30 °C using GDH as the cofactor recycle system yielding 99% ee and more than 90% assayed yield [43]. 

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

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. 

Disubstituted pyrrolidines from ants have insecticidal activity and, as venom constituents, presumably serve the ants in a defensive repellant function (149). Some also may have trail pheromone activity. Synthetic cis/rra/ij-pyrrolidine 197B acted as a noncompetitive blocker of nicotinic... 

A 2,5-disubstituted pyrrolidine was obtained by this method as a 1 1 mixture of cis- and tran.r-isomers. However, since diastereomeric or enantiomeric boronic esters can be easily prepared via asymmetric hydroboration, the control of the relative and absolute stereochemistry at C-2 and C-3 (ring numbering) should easily be achieved. Diisopinocampheylborane was employed in the first step, but exclusively with allyl bromide. 

The silver-catalyzed cyclization of A -substituted, 1-substitnted l-amino-4,5-dienes gave the corresponding 2,5-disubstituted pyrrolidine derivatives 6 in good yield. The intramolecular reaction was performed using silver tetrafluoroborate in dichloromethane at 20 °C. High 1,3-asymmetric induction was observed with the .s-2,5-disubstituted pyrrolidine derivative essentially the only product observed86,87- 216 218. -Substitution proved necessary for asymmetric induction. In fact, when the free amine underwent cyclization, only an equimolar mixture of cis- and franx-diastereomers was recovered. 

Scheme 8-24 Stereocontrolled synthesis of cis and trans 2,5-disubstituted pyrrolidines.

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 reduction of pyrroles by zinc in acetic acid or hydrochloric acid gives, initially, as the major product, A-pyrroline, together with A1- and A2-pyrrolines, all of which are further reduced to pyrrolidine (Scheme 54) (B-77MI30507). Reduction of 2,5-disubstituted pyrroles produces both the cis- and the trans- A3-pyrrolines, (206) and (207). 

The catalytic hydrogenation of pyrroles to pyrrolidines (2,3,4,5-tetrahydropyrroles), although an old transformation (equation has not been heavily exploited as a preparative route to pyrrolidines. Nevertheless, sufficient examples exist so as to illustrate the importance of this method. As would be expected, the hydrogenation of 2,5-disubstituted pyrroles proceeds with cis stereoselectivity (equation 2). - ... 

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