Enantioselective synthesis of (+)-α-allokainic acid by asymmetric lewis acid-mediated intramolecular ene reaction

An enantiospecific total synthesis of (–)-α-kainic acid

“…[We anticipated a requirement for relatively robust protecting groups as these would have to survive a number of transformations including a lactonisation procedure during which N-t-butoxycarbonyl (Boc) groups are removed;13 hence also the use of an ethoxycarbonyl function to block the nitrogen in acid (S).] The required (2)-geometry of the allylic chloride ( 5 ) (Scheme 1) was realised by conjugate addition15 of lithium dimethylcuprate to the butynoate (9) (Scheme 2), which gave only the (2)-butenoate (10); subsequent reduction and chlorination then provided the desired chloride (11). The two fragments [(S) and ( l l ) ] were coupled together using a previously developed procedure13 (Scheme 3)t leading to the homologue (12).…”

Steric acceleration of activated ene reactions

“…4 For such routes, a high degree of control of the relative stereochemistry about the pyrrolidine positions 3 and 4 is required in order to produce the normal cis-kainic acid stereochemistry or the isomeric trans-allokainic acid stereochemistry. Use of Lewis acid catalysts to promote the ene cyclisation under milder conditions generally affords mainly the cyclic 3,4-trans isomers, 5 although, using the pyrrolidone precursor 5, Xia and Ganem showed that magnesium perchlorate catalysed the ene cyclisation to give mainly the cis-product 6. 6 Ene-routes to kainic acid and its congeners have been described by Oppolzer 7 , Kennewell et al 2 , Kirihata et al, 8 and Ogasawara and co-workers.…”

“…A similar thermal equilibration of the initial kinetic 3,4-cis-product 6 into the corresponding 3, 4-trans-isomer has been reported by Xia and Ganem. 5 In conclusion, nitrogen buttressing groups have been studied for their ability to effect the ene cyclisation on a model system related to the natural product, kainic acid. The results obtained demonstrate that steric factors outweigh any electronic considerations, at least in terms of promoting cyclisation and controlling stereoselectivity.…”