Synthesis, experimental and in silico studies of N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Recently, fluorenyl­meth­oxy­carbonyl (Fmoc) amino acids (e.g. Fmoc–tyrosine or Fmoc–phenyl­alanine) have attracted growing inter­est in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydro­gelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supra­molecular features in recognition of those properties is essential. This work is the first com­prehensive summary of noncovalent inter­actions combined with a library of supra­molecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc-protected amino acid, namely, 2-{[(9H-fluoren-9-ylmeth­oxy)carbon­yl](meth­yl)amino}-3-{4-[(2-hy­droxy­propan-2-yl)­oxy]phen­yl}propanoic acid or N-fluorenyl­meth­oxy­carbonyl-O-tert-butyl-N-methyl­tyrosine, Fmoc-N-Me-Tyr(t-Bu)-OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single-crystal X-ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further com­pared to N-Fmoc-phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047–8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H⋯H, C⋯H/H⋯C and O⋯H/H⋯O inter­actions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The mol­ecular electrostatic potentials mapped over the surfaces identified the electrostatic com­plementarities in the crystal packing. The prediction of weak hydrogen-bonded patterns via Full Inter­action Maps was com­puted. Supra­molecular motifs formed via C—H⋯O, C—H⋯π, (fluoren­yl)C—H⋯Cl(I), C—Br⋯π(fluoren­yl) and C—I⋯π(fluoren­yl) inter­actions are observed. Basic synthons, in combination with the Long-Range Synthon Aufbau Modules, further sup­ported by energy-framework calculations, are discussed. Furthermore, the relevance of Fmoc-based supra­molecular hydrogen-bonding patterns in bio­com­plexes are emphasized, for the first time.