Synthesis of Enantiopure 1‐Aryl‐1‐butylamines and 1‐Aryl‐3‐butenylamines by Diastereoselective Addition of Allylzinc Bromide to Imines Derived from (R)‐Phenylglycine Amide.

Abstract

Synthesis of enantiopure 1-aryl-1-butylamines and 1-aryl-3-butenylamines by diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide Dalmolen, Jan; Sluis, Marcel van der; Nieuwenhuijzen, José W.; Meetsma, Auke; Lange, Ben de; Kaptein, Bernard; Kellogg, Richard M.; Broxterman, Quirinus B. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Keywords: Allylation / Asymmetric synthesis / Chiral auxiliaries / DiastereoselectivityThe synthesis of enantiopure 1-aryl-1-butylamines via a highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. These are synthesised by a three-step procedure, which involves: (a) formation of the chiral imines; (b) asymmetric addition of the allylzinc reagent; (c) removal of the chiral auxiliary by IntroductionEnantiomerically pure amines with a chiral centre at the α-position are valuable synthons in the synthesis of biologically active natural products and compounds of pharmaceutical interest.[1] One of the strategies used to obtain chiral amines is an asymmetric 1,2-addition of nucleophiles to the electrophilic CϭN imino group of chiral aldimines (Scheme 1). Other methods include e.g. catalytic asymmetric addition of dialkylzinc to imines, [2] diastereoselective reduction of chiral imines, [3] enantioselective reduction of prochiral imines [4] and oximes, [5] or use of a transaminase. [6] Scheme 1. Synthesis of enantiomerically enriched primary amines by asymmetric 1,2-addition Enantiomerically pure imines can be generated, in most cases fairly easily, by condensation of an enantiopure amine R 2 ϪNH 2 used as a (readily available) chiral auxiliary, with the corresponding carbonyl compound. High asymmetric [a] University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands [b] Syncom B.V., Kadijk 3, 9747 AT Groningen, The Netherlands E-mail: R.M.Kellogg@syncom.nl [c] means of a reductive or non-reductive method. The reductive method provides 1-aryl-1-butylamines whereas the non-reductive method preserves the double bond to afford 1-aryl-3-butenylamines.( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) induction during the addition can be achieved by using imines derived from chiral auxiliaries such as α-arylethylamines, [7] β-amino alcohols, β-alkoxy amines, and α-amino acid esters. [8] A common feature of the latter three auxiliaries is the presence of a second heteroatom, which is capable of rigidifying the transition state of the 1,2-addition through chelation. [7] This effect is also referred to as ''chelation control''. [9] Drawbacks are the availability, in some cases, of only one enantiomer, high costs, low re...