DOI: 10.1002/adsc.201100333 Stereoselective Synthesis of syn-b-Amino Propargylic Ethers: Application to the Asymmetric Syntheses of (+)-b-Conhydrine and ()-Balanol Julien Louvel, a Fabrice Chemla, a, * Emmanuel Demont, b Franck Ferreira, a, * Alejandro PØrez-Luna, a, * and Arnaud Voituriez a a UPMC-Univ Paris 6, UMR CNRS 7201, Institut Parisien de Chimie MolØculaire, Institut de Chimie MolØculaire ACHTUNGTRENNUNG(FR 2769), case 183, 4 Place Jussieu, 75005 Paris, France Fax: (+ 33)-1-4427-7567; phone: (+ 33)-1-442755-71; e-mail: fabrice.chemla@upmc.fr, franck.ferreira@upmc.fralejandro.perez_luna@upmc.fr b Immuno-Inflammation CEDD Medicinal Chemistry, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, SG1 2NY, Hertfordshire, U.K. Received: April 28, 2011; Published online: August 10, 2011 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adcs.201100333. Abstract: The stereoselective synthesis of syn-b- amino propargylic ethers by the addition of racemic lithio 3-(methoxymethoxy)allenylcuprates, and more particularly (cyano) and (mesityl)cuprates, to enan- tiopure chiral N-tert-butylsulfinylimines is reported. The scope and limitations of the reaction is studied. The usefulness of the methodology for the synthesis of compounds having a syn-1,2-amino alcohol unit is shown through the development of the asymmetric syntheses of (+)-b-conhydrine and of an advanced intermediate of ()-balanol. Keywords: amino alcohols; asymmetric synthesis; chiral resolution; copper; nitrogen heterocycles Introduction b-Amino propargylic ethers of type 1 (Scheme 1) have proven to be valuable building blocks for the synthesis of number of bioactive natural products. [1] Owing to their great synthetic potential, numerous efforts for the stereoselective preparation of b-amino propargylic ethers 1 have been undertaken. [2] The syn- thesis of anti-b-amino propargylic ethers 1 has been the subject of frequent publications. [1b,c,i,k,3] By con- trast, access to their syn counterparts has been report- ed only in a few special cases. These include the regio- and stereoselective attack of oxygen nucleo- philes at the propargylic position of cis-ethynylaziridi- nes, [3f–j,4] the addition of several alkynylmetals to a- amino aldehydes, [1b,c,5] the reduction of a-amino acety- lenic ketones with LiAlH 4 [3a] or chiral oxazaborolidi- nes, [3h] and the diastereoselective addition of racemic 3-(methoxymethoxy)allenylzinc bromide to iminium ions. [6] Thus, a general stereoselective entry to syn-b- amino propargylic ethers 1 is still lacking. In this paper we report our recent efforts towards this goal. Results and Discussion Reactions of Zinc Reagents with Racemic Imines As part of our ongoing research on the preparation and the use of 3-heterosubstituted allyl- and allenyl- metals, [7] we have recently demonstrated that the re- action of 4 equivalents of racemic 3-(meth- ACHTUNGTRENNUNGoxymethoxy)allenylzinc bromide ()-3-ZnBr with (S S )-N-tert-butylsulfinylimines 4, [8] in Et 2 O and in the presence of TMEDA (0.1 equivalent relative to the zinc species), leads to the formation of anti- (S S ,1R,2S)-b-amino propargylic ethers 5 within 1 h at 80 8C (Scheme 2). In all cases, adducts 5 were ob- tained in high yields (up to 94%) with a high level of stereoselectivity as only one anti isomer of the four Scheme 1. b-Amino propargylic ethers 1. Adv. Synth. Catal. 2011, 353, 2137 – 2151  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2137 FULL PAPERS