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

• Published in: Journal of organic chemistry 2002-03, Vol.67 (5), p.1669-1677
• Main Authors: Kazuta, Yuji, Matsuda, Akira, Shuto, Satoshi
• Format: Article
• Language: English
• Subjects: Chemistry; Chromatography; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Histamine - analogs & derivatives; Histamine - chemical synthesis; Histamine - chemistry; Imidazoles - chemical synthesis; Imidazoles - chemistry; Magnetic Resonance Spectroscopy; Molecular Structure; Organic chemistry; Preparations and properties; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo010852x

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.