Designed folding of pseudopeptides: the transformation of a configurationally driven preorganization into a stereoselective multicomponent macrocyclization reaction.
The efficient synthesis of large-ring pseudopeptidic macrocycles through a multicomponent [2+2] reductive amination reaction is described. The reaction was entirely governed by the structural information contained in the corresponding open-chain pseudopeptidic bis(amidoamine) precursors, which have a rigid (R,R)-cyclohexane-1,2-diamine moiety. A remarkable match/mismatch relationship between the configurations of the chiral centers of the cyclic diamine and those of the peptidic frame was observed. The macrocyclic tetraimine intermediates have been studied in detail by NMR spectroscopy, circular dichroism (CD), and molecular modeling, and the results support the appropriate preorganization induced by the match combination of the chiral centers. We have also synthesized the corresponding open-chain bis(imine) model compounds. The structural studies (NMR spectroscopy, CD, modeling) of these systems showed an intrinsically lower reactivity of the mismatch combination, even when the product of the reaction was acyclic. In addition, a synergistic effect between the two chiral substructures for the correct folding of the molecules was observed. Finally, X-ray analysis of the HCl salt of one of the macrocycles showed an interesting pattern; the macrocyclic rings stack in columnar aggregates leaving large interstitial channels filled with water-solvated chloride anions.
Alfonso
Ignacio
I
Departamento de Química Orgánica Biológica, Instituto de Investigaciones Químicas y Ambientales de Barcelona, Consejo Superior de Investigaciones Científicas (IIQAB-CSIC), Jordi Girona, 18-26, E-08034, Barcelona (Spain), Fax: (+34) 932-045-904.
Bolte
Michael
M
Institut für Anorganische Chemie, J. W. Goethe-Universität Frankfurt, Max-von-Laue-Str. 7, 60438, Frankfurt/Main (Germany).
Bru
Miriam
M
Departamento de Química Inorgánica y Orgánica, UAMOA, Universidad Jaume I/CSIC, Campus del Riu Sec, Avenida Sos Baynat, s/n, E-12071, Castellón (Spain), Fax: (+34) 964-728-214.
Burguete
M Isabel
MI
Departamento de Química Inorgánica y Orgánica, UAMOA, Universidad Jaume I/CSIC, Campus del Riu Sec, Avenida Sos Baynat, s/n, E-12071, Castellón (Spain), Fax: (+34) 964-728-214.
Luis
Santiago V
SV
Departamento de Química Inorgánica y Orgánica, UAMOA, Universidad Jaume I/CSIC, Campus del Riu Sec, Avenida Sos Baynat, s/n, E-12071, Castellón (Spain), Fax: (+34) 964-728-214.
D002942:Circular Dichroism; D003460:Crystallization; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D013237:Stereoisomerism
D010455:Peptides