TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 5905–5907 Pergamon Diastereoselective synthesis of syn -aminoalcohols via contributing CH- interaction: simple synthesis of (-)-bestatin Byong Won Lee, a Jin Hwan Lee, a Ki Chang Jang, a Jae Eun Kang, a Jin Hyo Kim, a Ki-Min Park b and Ki Hun Park a, * a Division of Applied Life Science (BK21 program), Department of Agricultural Chemistry, Gyeongsang National University, Chinju 660 -701, South Korea b The Research Institute of Natural Science, Gyeongsang National University, Chinju 660 -701, South Korea Received 16 April 2003; revised 29 May 2003; accepted 30 May 2003 Abstract— 1 H NMR and X-ray crystallography studies revealed that a CH- and chelation control in aromatic aminoaldehydes (1–6) effects a highly diastereoselective addition to afford optically active syn -aminoalcohols (1a–6a). This methodology was applied to the synthesis of (-)-bestatin. © 2003 Elsevier Ltd. All rights reserved. The stereoselective transformation of aromatic - aminoaldehydes to syn -aminoalcohols is attractive syn- thetic strategy, since aromatic syn --hydroxy--amino acid is a key unit of small peptides (e.g. bestatin, phebestin and probestin) which function as aminopepti- dase inhibitor. 1 In the stereoselective transformation of -aminoaldehydes to aminoalcohols using organometal- lic reagent, the most frequently used protecting group is benzyl (Bn) group. The benzyl group allowed a high degree of diastereoselectivity in nucleophilic addition of -aminoaldehydes, but produced an anti -aminoalcohols with non-chelating control. 2 Thus, aromatic -amino acids have been modified by a number of methods 3 such as asymmetric dihydroxylation, 4 Ojimas’ ring opening procedure, 5 etc. Our previous work has demonstrated that a diastereoselective addition utilizing the 9-phenylfluoren-9-yl (Pf) group affords syn - aminoalcohol. 6 The extension and application of this methodology for the asymmetric synthesis of a syn -- hydroxy--amino acid is described herein. We also described the first evidence for a CH- interaction to contribute a highly diastereoselective addition using NMR technique and X-ray study. The requisite substrates (1–10) were prepared easily by the usual method from commercially available phenyl- alanine, p -nitrophenylalanine, tyrosine, valine, leucine, alanine, and serine. We chose the 9-phenylfluoren-9-yl (Pf) group for protection of amine since this protecting group has been shown to inhibit deprotonation at the -position of -aminoaldehyde. 7 -Aminoaldehydes having the Pf group are stable to Grignard reaction condition. 8 (R )-Phenylalaninal 1 was treated with ethynylmagne- sium bromide at -40°C for 10 min to give syn -aminoal- cohol 1a as a 9.5:1 ratio in 96% yield via a diastereoselective addition (vida infra). As shown in Table 1, other aromatic -aminoaldehydes (2–6) were also exposed to the same reaction conditions to give syn products (2a–6a) in high selectivity and quantitative yields. While, treatments of aliphatic -aminoaldehydes (7–10) under same condition afforded a less than 3:1 ratio of the syn and anti isomers. The above results show that aromatic aminoaldehydes (1–6) provide much higher selectivity than aliphatic aminoaldehydes (7–10). Each diastereomeric aminoalcohol given by the Grignard reaction could easily be isolated in pure form by column chromatography. The structures of all aminoalcohols (1a/b–10a/b) were confirmed by their characteristic spectroscopic data. The relative stereo- chemistries of the products 1a and 1b were determined Keywords : bestatin; AHPBA; syn -aminoalcohol; CH- interaction; -hydroxy--amino acid. * Corresponding author. Tel: +82-55-7515472; fax: +82-55-7570178; e-mail: khpark@gshp.gsnu.ac.kr 0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0040-4039(03)01394-7