A Short Synthesis of Partially Protected l- and d-β-Hydroxyenduracididines and a Structurally Simplified Dipeptide Analogue

Abstract

A short synthesis of the C2-epimeric amino acids l- and d-β-hydroxyenduracididine (βhEnd) was developed. Both amino acids are part of the cyclopeptide portion of the mannopeptimycin antibiotics. The synthetic route comprises eight steps starting from Garner’s aldehyde and provides partially protected derivatives in good overall yields. Key steps are a stereodivergent olefination–bishydroxylation sequence and a regioselective guanidine cyclization reaction. In addition, precursor amino acids that contain a protected amino alcohol instead of the cyclic guanidine could be efficiently coupled to provide a structurally simplified analogue of the l-βhEnd-d-βhEnd dipeptide portion of the mannopeptimycin aglycone.

Key words

amino acids - cyclic guanidine - natural products - peptide coupling - stereoselective synthesis

• References

• 1 New address: Deutsches Textilforschungszentrum Nord-West, Adlerstraße 1, 47798 Krefeld, Germany; E-mail: [e-mail].
• 2 He H, Williamson RT, Shen B, Graziani EI, Yang HY, Sakya SM, Petersen PJ, Carter GT. J. Am. Chem. Soc. 2002; 124: 9729
• 3 Singh MP, Petersen PJ, Weiss WJ, Janso JE, Luckman SW, Lenoy EB, Bradford PA, Testa RT, Greenstein M. Antimicrob. Agents Chemother. 2003; 47: 62
• 4 Haltli B, Tan Y, Magarvey NA, Wagenaar M, Yin X, Greenstein M, Hucul JA, Zabriskie TM. Chem. Biol. 2005; 12: 1163
• 5 Wang T, Wheless KL, Sutherland AG, Dushin RG. Heterocycles 2004; 62: 131
• 6 Schwörer CJ, Oberthür M. Eur. J. Org. Chem. 2009; 6129
• 7 Olivier KS, vanNieuwenhze MS. Org. Lett. 2010; 12: 1680
• 8 Devel L, Vidal-Cros A, Thellend A. Tetrahedron Lett. 2000; 41: 299
• 9 Ribes C, Falomir E, Carda M, Marco JA. J. Org. Chem. 2008; 73: 7779
• 10 Koskinen AM. P, Chen J. Tetrahedron Lett. 1991; 32: 6977
• 11 Passiniemi M, Koskinen AM. P. Synthesis 2010; 2816
• 12a Ko SY. J. Org. Chem. 1995; 60: 6250
• 12b Shinada T, Ikebe E, Oe K, Namba K, Kawasaki M, Ohfune Y. Org. Lett. 2007; 9: 1765
• 13 Kuboki A, Tajimi T, Tokuda Y, Kato D, Sugai T, Ohira S. Tetrahedron Lett. 2004; 45: 4545
• 14 Schüler P, Fischer SN, Marsch M, Oberthür M. Synthesis 2013; 45: 27
• 15 At this stage, the correct stereoconfiguration of compound 11 was verified by cyclization of the obtained amino alcohol to the corresponding γ-lactam. Analysis of the NMR data showed that the ¹H coupling constants are in good agreement with the expected l-ribo-configuration.
• 16 A similar result was observed when the TBS group was used instead.
• 17 Mitsunobu O. Synthesis 1981; 1
• 18 In addition to pseudourea 12, a series of alternative guanylation reagents (Goodman’s reagent, pyrazole carboxamidines, benzotriazol-1-carboxamidines) as well as different activation reagents (Mukaiyama’s reagent, AgNO₃) were surveyed, none of which gave superior results. The low yield of the guanylation reaction compared to other substrates is a result of different side reactions, for example, a competing γ-lactam formation. Additional side products were not characterized any further. Nevertheless, linear guanidine 15 could be easily purified in gram quantities.
• 19 Tsuchiya S, Sunazuka T, Hirose T, Mori R, Tanaka T, Iwatsuki M, Omura S. Org. Lett. 2006; 8: 5577
• 20 Other sulfonyl chlorides were either too reactive (MsCl) or not reactive enough (TsCl) to achieve an acceptable regioselectivity for the sulfonate ester formation.
• 21 When the reaction was conducted in CH₂Cl₂ with Et₃N as the base, a lower selectivity for the esterification of the primary hydroxyl group was observed, which resulted in a more difficult chromatographic purification and slightly lowered yields of guanidine 14 (61%)
• 22 In this case, nosylation in CH₂Cl₂ in the presence of Et₃N instead of pyridine gave better results.