The Asymmetric Aza-silyl-Prins Reaction: Synthesis of Enantiopure Piperidines

Abstract

The design and development of the first asymmetric aza-silyl-Prins reaction is reported, giving rise to valuable and diverse piperidines and pipecolic acid derivatives in both high yields and as single enantiomers. The creation of a novel chiral auxiliary-homoallylic amine for the aza-silyl-Prins reaction is essential to its success.

A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

“…17,20,29 Further, we have recently reported that chiral auxiliaries on nitrogen, for example -methylbenzyl, in place of the tosyl group, were inefficient for promoting asymmetric aza-silyl-Prins-type reactions. 27 Therefore we have instead focused on developing a novel, easy to prepare and use chiral-auxilliary-containing a homoallylic amine. We have previously shown that the aza-Prins and aza-silyl-Prins reactions are 2,6-trans selective across the nitrogen 17,23,27,[30][31] and reasoned that this trans relationship would be maintained when employing a chiral centre adjacent to nitrogen in the homoallylic amine starting material and thus generating a new chiral centre across the nitrogen after cyclisation.…”

“…27 Therefore we have instead focused on developing a novel, easy to prepare and use chiral-auxilliary-containing a homoallylic amine. We have previously shown that the aza-Prins and aza-silyl-Prins reactions are 2,6-trans selective across the nitrogen 17,23,27,[30][31] and reasoned that this trans relationship would be maintained when employing a chiral centre adjacent to nitrogen in the homoallylic amine starting material and thus generating a new chiral centre across the nitrogen after cyclisation. In order to test this hypothesis, starting from (R)-allyl glycine, it was possible to prepare (R)-allylmorpholin-2-one (3) in a single step.…”

“…While methods for the asymmetric synthesis of heterocycles via chiral iminium ion cyclisations have been extensively reviewed 26 , there are only isolated examples of attempts at simple asymmetric aza-Prins reactions and there remains no general catalytic and asymmetric aza-Prins cyclisation reaction and interest in developing enantioselective aza-Prins processes is high and very challenging. Recently we have reported a related asymmetric aza-silyl-Prins reaction 27 and Maruoka has described an aza-Prins endo-type cyclisation of 2-(1-phenylvinyl)benzaldehyde and BocNH2 catalysed by a BINOL-derived N-triflyl phosphoramide to form 1-aminoindenes. 28 SCHEME 1: 1.…”

Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications

“…Substrates bearing a pendent amine functionalized with a newly developed chiral auxiliary undergo cyclization to achieve the diastereoselective synthesis of substituted piperidines and pipecolic acids. 45 Notably, chiral Lewis acid complexes did not affect enantioinduction, either through condensation of the amine and aldehyde partner or with a preformed imine. Consequently, it was proposed that the Lewis acid is only involved in imine formation and does not provide a chiral environment for the cyclization event.…”

Synthesis of Six-Membered Spiro Azacyclic Oxindole Derivatives via a One-Pot Process of Umpolung Allylation/Aza-Prins Cyclization

“…The well-established aza-Prins cyclization , is a stereoselective strategy for the synthesis of piperidines. Generally, the aza-Prins cyclization involves the condensation of homoallylic amines with aldehydes in the presence of a Lewis acid to generate iminium ions, which cyclize spontaneously through intramolecular nucleophilic attack from the olefin (Scheme a).…”