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.

Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R)

“…Compound 27 was converted to intermediate 28 in the presence of O -benzylhydroxylamine HCl as a mixture of the cis and trans isomers of the resulting oxime (~1:1) in 59% yield. 41 The benzyloxime 28 was reduced in the presence of LiAlH 4 to the amine 29 and coupled with 12a to give the amide 30a . The tetrahydropyranyl group was removed under acidic conditions to give the alcohol 31a , which was oxidized to 32a , and reductively aminated to give the target compound 25a , as described in the previous scheme.…”

The conversion of alkynes into substituted cyclopropanes effected by CH2I2-R3Al (R = Me, Et, i-Bu)

“…Among the cyclopropane-containing natural compounds, methyl-substituted cyclopropanes occupy a special place [23]. Therefore the transformation of alkynes into substituted methylcyclopropanes is of particular interest.…”

“…Calcd. for C 12 14)), 17.88 (C(4)), 19.38 (C(6)), 22.67 (C(13)), 23.48 (C(3)), 26.81 (C(8)), 29.46 (C (7) …”

“…13 C NMR d 11.31 (t, 1 J CD ¼ 19.04 Hz, C(9)), 11.34 (C(1)) 11.37 (C (6)), 22.79 (C(12)), 23.61 (C(8)), 23.73 (C(13)), 24.17 (C(2)), 24.99 (C (7)), 25.09 (C(5)), 26.19 (C(11)), 28. …”

Conformationally Restricted GABA with Bicyclo[3.1.0]hexane Backbone as the First Highly Selective BGT-1 Inhibitor

“…Therefore, we previously developed the four types of chiral cyclopropane units bearing two adjacent substituents in a trans or a cis relationship, namely, 1 and 2, and their enantiomers ent-1 and ent-2 ( Figure 2). 17 These units are effectively used for three-dimensionally diverse conformational restriction of biologically active compounds, 18 and therefore ,we previously designed a series of cyclopropane-based conformationally restricted GABA analogues with stereochemical diversity to develop useful GABA transporter inhibitors. 19 Although some of these cyclopropane-based conformationally restricted GABA analogues have been synthesized by other groups, 20−27 we systematically synthesized all of the 2,3-methano-and 3,4-methano stereoisomers of GABA from the chiral cyclopropane units 1 and 2, and their enantiomers ent-1 and ent-2.…”