Rational synthesis of all the four stereoisomers of 3-(trans-2-aminocyclopropyl)alanine Oleg V. Larionov, Sergei I. Kozhushkov, Melanie Brandl and Armin de Meijere* Institut für Organische Chemie der Georg-August-Universität Göttingen, D-37077 Göttingen, Germany. Fax: + 49 0 551 39 9475; e-mail: Armin.deMeijere@chemie.uni-goettingen.de 10.1070/MC2003v013n05ABEH001817 All the four stereoisomers of 3-(trans-2-aminocyclopropyl)alanine – a key constituent of the potential antitumor agent belactosin A – were prepared by simple catalytic hydrogenation of (2S,1'S,2'S)-, (2S,1'R,2'R)-, (2R,1'R,2'R)-, and (2R,1'S,2'S)-3-(trans-2-nitro- cyclopropyl)alanines in 95, 93, 91 and 92% yields, respectively. Most of the over two dozen known naturally occurring amino acids containing a cyclopropyl group, as well as most of the cyclopropyl analogues of natural amino acids, are responsible for interesting biological activities of compounds containing them as constituents. 1 Among such natural products, peptido- lactone hormaomycin 1, which influences the secondary metabolite production of certain bacteria, 2 and recently isolated belactosin A 2, which is interesting as a potential antitumor agent and effects proteasome inhibition, 3 are especially intriguing as they contain previously unknown 3-(trans-2-nitrocyclo- propyl)alanines [(NcP)ala] (2S,1'R,2'R)-3 and (2R,1'R,2'R)-3, and 3-(trans-2-aminocyclopropyl)alanine [(AcP)ala] (2S,1'R,2'S)-4 as key constituents (Scheme 1). Recently, Armstrong and Scutt 4 reported an elegant multistep synthesis of an epimer of naturally occurring (AcP)ala 4 starting from commercially available, yet expensive, glycidol benzyl ether with a key step like the one in our previously published synthesis of 3,3-dideuterio-3-(trans-2-aminocyclopropyl)alanine 3,3-D 2 -rac-4. 5 It is obvious that our recently developed asym- metric synthesis of all the four diastereomers of (NcP)ala 3 (Scheme 1), 6 which in terms of ease and productivity estab- lished a big leap forward in comparison with the previously reported multistep procedure, 7 also offered itself as a rational access to all the four stereoisomers of (AcP)ala 4 in multi- gramme quantities simply by chemoselective reduction of the nitro group in enantiomerically pure (NcP)ala 3. However, an attempted catalytic hydrogenation of the hydro- chloride of racemic (NcP)ala rac-3·HCl in water, analogously to the preparation of 2-(trans-2-aminocyclopropyl)glycine, 7(b),(d) furnished a non-separable mixture of starting rac-3·HCl, target rac-4·HCl and the hydrochloride of racemic lysine rac-7·HCl in different ratios (Scheme 2, Table 1). No improvement was observed upon either varying the solvent, the catalyst or the hydrogen pressure or by applying other reducing agents recom- mended for the chemoselective reduction of aliphatic nitro into amino derivatives, 8 such as ammonium formate under palladium catalysis or sodium borohydride under nickel catalysis (Table 1). Most probably, protonation of the amino group on the three- membered ring in the target molecule creates a kind of donor– acceptor-substituted cyclopropane, 9 which is particularly prone to undergo ring opening under hydrogenation conditions. However, catalytic hydrogenation of free rac-3 under neutral Table 1 Attempted chemoselective reduction of the nitro group in the hydrochloride of racemic 2-(trans-2-nitrocyclopropyl)alanine (rac-3·HCl) under various conditions at ambient temperature (see Scheme 2). Entry Reducing agent (catalyst) Pressure of H 2 /bar (Reaction time/h) Solvent Yield (%) rac-3·HCl rac-4·HCl rac-7·HCl 1 H 2 (Pd/C) 1 (24) H 2 O 55 40 0 2 H 2 (Pd/C) 2 (60) H 2 O 0 60 35 3 H 2 (Pd/C) 2 (20) H 2 O 0 53 41 4 H 2 (PdCl 2 ) 1 (96) MeOH 0 0 94 5 NaBH 4 (NiCl 2 ·6H 2 O) 1 (20) MeOH 15 0 80 6 HCO 2 NH 4 (Pd/C) 1 (20) MeOH 10 0 83 O NH NH O H HN O HN NO 2 O HN O N O O N N O N H H O O O H N H 2 N CO 2 H H N O O O CO 2 H H 2 N NO 2 H 2 N CO 2 H NH 2 3 4 2 H 2 N CO 2 H NO 2 (2S,1'S,2'S)-3 (24%, ee 96%) H 2 N CO 2 H NO 2 (2S,1'R,2'R)-3 (32%, ee 99%) H 2 N CO 2 H NO 2 (2R,1'R,2'R)-3 (22%, ee 96%) H 2 N CO 2 H NO 2 (2R,1'S,2'S)-3 (18%, ee 99%) NO 2 I rac-5 (S)-6 or (R)-6 i, NaH (1.2 equiv.) DMF/MeCN ii, 60% aq. AcOH iii, 6 N aq. HCl, MeOH reflux 7 min iv, DOWEX O HN H NO 2 O N Cl HO * Ni 1 Scheme 1 , 2003, 13(5), 199–200 – 199 –