title: Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine.
abstract: The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kazuta
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D002845:Chromatography; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D006632:Histamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D003521:Cyclopropanes; D007093:Imidazoles; D006632:Histamine