Planar‐Chiral [7]Orthocyclophanes

Abstract

Medium-sized bridged cyclophanes have attracted considerable interest because of their unusual conformational, chemical, and spectroscopic properties caused by deformation and strain in the aromatic ring and in the bridging ansa chain. [1] Among cyclophanes, meta-or paracyclophanes having dynamic planar chirality have generated much theoretical and synthetic interest as unique chiral molecules. In contrast, their regioisomer, that is, orthocyclophane (A) does not attract much attention owing to its less interesting topology and lack of planar chirality. [2] However, the introduction of a properly designed ansa chain, which can be on the outside of the plane of the benzene ring and decrease the flexibility of the molecule, may create stable planar chirality, even in simple orthocyclophanes. Herein we report the design and synthesis of the planar-chiral [7]orthocyclophanes 1 having an E alkene in the ansa chain, as well as a detailed stereochemical analysis and a demonstration of their utility in synthesis.Recently, we discovered a novel class of planar-chiral heterocycles (2) which consist of a bis(allylic) skeleton and the heteroatom X (X = O, NTs, SO n ; Ts= 4-toluenesulfonyl). [3] The chirality of these compounds originates from the presence of suitably located E and Z alkenes in the ninemembered ring. [4] On the basis of this stereochemical phenomenon, we anticipated that the orthocyclophane 1, in which the Z alkene of 2 is replaced by a benzene ring, may display planar chirality. It is also expected that 1 can achieve thermal stability, which 2 does not exhibit (see below). The details of the study are provided below.At the outset, we examined the synthesis of the nitrogencontaining orthocyclophane 1 aa (X = NTs, R = H) from the known diol 3 (Scheme 1). The Mitsunobu reaction of 3 and TsNHCO 2 Me proceeded with high group selectivity and provided the amide alcohol 4 as the only product in 78 % yield. [5] The Dess-Martin oxidation of the alcohol moiety of 4 followed by the Horner-Wadsworth-Emmons reaction and treatment with DIBAL provided the key intermediate (E)-5 in 71 % yield (three steps). The intramolecular Mitsunobu reaction of (E)-5 under a high dilution conditions (ca. 0.01m) provided the desired cyclic amide 1 aa in excellent yield (90 %). It should be noted that only a negligible amount of dimerized product (< 1 %) was formed in this reaction. The orthocyclophane 1 aa afforded a crystal suitable for X-ray analysis. The analysis reveals that the ansa chain is located on the outside of the plane of the benzene ring and both the benzene ring and alkene moieties of the ansa chain form chiral planes in the solid state (Scheme 1). [6] The existence of isolable enantiomers of 1 aa in solution was revealed by HPLC analysis using a chiral stationary column equipped with a CD spectropolarimeter. As shown in Figure 1, both enantiomers of 1 aa were successfully separated on an analytical as well as a semi-preparative scale. [7] The Scheme 1. Synthesis and X-ray analysis of 1 aa: a) TsNHCO 2 Me, PPh 3 , DEAD, TH...

Medium‐Sized‐Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion

“…[19] 1 HNMR analyses of 4a-l showed diastereotopic signals for the methylene groups within the ring, thus indicating that these heterocycles adopt chiral ground states whose enantio-meric conformations interconvert slowly on the NMR time scale. [20,21] We determined the rate constants for interconversion of the enantiomers (k enant )o f4a-d and 4l by variabletemperature exchange spectroscopy (VT-EXSY), as summarized in Table 3( see the Supporting Information for details).…”

Stereochemical study on planar‐chiral cyclic molecules using polysaccharide‐based column chromatography

“…As an example, data of 2bb were shown in Figure 6. 24 Furthermore, we have also developed an asymmetric synthetic approach for planar-chiral heterocycles: asymmetric cyclization of the achiral precursor 13 promoted by chiral alkoxide 14 and 15, or Pd catalyst in the presence of chiral ligand 16, leading to the formation of cyclic amides 1b and 2b in high enantiopurity, as shown in Scheme 1. 39,40 Thus, the obtained enantioenriched cyclic molecules are useful as chiral building blocks because their planar chirality can be converted into a variety of central chiralities via intermolecular or intramolecular reactions.…”

“…42 The stereochemical stability, or in other words, the energy of the rotation barrier, was strongly dependent on the ring size, difference of the heteroatom X embedded in the ring, and the substituents R R 0 on the alkene moiety. [18][19][20][21][22][23][24][25] The representative example of half-lives of the optical activity of diallylic amide 1b and o-cyclophene 2 at 25 C in hexane is shown in Figure 9. The rate constants for racemization were obtained by HPLC measurements of enantiopurity at proper time intervals under constant temperature.…”