Bile Acid-Piperazine Diamides: Novel Steroidal Templates in Syntheses of Supramolecular Hosts: Isomeric Pyridine-n-carboxy Containing Dimers and a Cholaphane

Abstract

Novel steroidal dimers: 3a,3'a-dihydroxy-5b-cholan-24-oic acid piperazine diamide 3, its 3a,3'a-bis(trifluoroacetoxy) protected derivative 2, and 3a,3'a-bis(pyridine-n-carboxy, n = 2-4) derivatives 4-6 and their Ag + -complexes have been prepared. A novel cholaphane 7 has also been synthesized from 3 by cyclization with terephthalic acid by Yamaguchi method. Products were characterized by 13 C and 15 N NMR chemical shifts and MALDI-TOF MS. In addition, MO-calculations (PM3) for 3 and 7 were performed.The design of novel molecular architectures is one of the most exciting fields in the supramolecular chemistry. 1 Macrocyclic and cleft type supramolecular structures are especially interesting because they could bind substrates on their cavity or trap around a substrate molecule, respectively. Bile acids are very appropriate compounds from the molecular engineering point of view. Their chiral, rigid framework and chemically different hydroxyl groups make them attractive building blocks in tailoring supramolecular hosts. 2-8 Bile acid based macrocycles consists of two to four bile acid units joined together by various spacer groups, called cholaphanes. A cholaphane, reported previously by us, 9 consists of two lithocholic acid moieties, an ethylene glycol joint, and terephthalic acid spacer. Pandey and Singh have synthesized a cholic acid based cholaphane including an ethylenediamine bridge and a terephthalate spacer group. 10 One example of the bile acid based cleft type structures is a host molecule which Kohmoto et al. have synthesized from 3a-aminocholanoate derivative and naphthalene-1,4,5,8-tetracarboxylic acid dianhydride. 11 We have also prepared some molecular clefts 12,13 and investigated their Ag + -cation binding properties. 13 In this study we have chosen piperazine as a bridging group for our lithocholic acid derivatives because piperazine has metal complexing capabilities and it is a good hydrogen-bond acceptor, which makes its derivatives interesting for supramolecular complexation chemistry. 14 In addition, Zhang et al. have demonstrated 15 that some N,N'-disubstituted piperazine compounds are high-affinity ligands for s-1 and s-2 type receptors, which have potential functional role in several important physiological and biochemical processes.The entire synthetic route leading to 3a,3'a-bis(pyridinen-carboxy)lithocholic acid piperazine diamides 4-6 (n = 2-4) and cholaphane 7 is described in the Scheme.3a-Trifluoroacetoxy-5b-cholan-24-oyl chloride (1) was synthesized from lithocholic acid (3a-hydroxy-5b-cholan-24-oic acid), whose 3a-hydroxy was first protected with trifluoroacetic acid anhydride leading to 3a-trifluoroacetoxy-5b-cholan-24-oic acid. The latter was then refluxed with thionyl chloride giving 1 in ~ 100% yield. Detailed synthetic description, 13 C NMR, MS, and elemental analysis data of 3a-trifluoroacetoxy-5b-cholan-24-oic acid and 1 has been described before. 9 Our first aim was to synthesize a piperazine monoamide from 1 using starting compounds in a molar ratio 1:1. However, NMR and MA...

Multinuclear magnetic resonance, electrospray ionization time‐of‐flight mass spectral and molecular modelling characterization of lithocholic acid amide esters with various nitrogen heterocycles

“…This indicates that the conformational preferences of the tail are changed when the cyclic structure is formed, as also happened in the cases of terephthalic-and thiophene-2,5-dicarboxylates of lithocholic acid piperazine diamides. 23,25 Furthermore, the cyclization caused broadening of some of the 13 C NMR signals of the bile acid moieties in 5, implying that the At 303 K, the 1 H NMR resonances of piperazine in 5 appeared unsymmetrical, resembling the piperazine pattern of 4 at lower temperatures (223 K; see Fig. 1).…”

“…23 The most remarkable changes were detected for the shifts of the carbons C-17 and C-20, which were shielded ca 2 ppm, and for the resonance of C-23, which was shifted from 30.27 ppm in 3 to 26.69 ppm in 5. This indicates that the conformational preferences of the tail are changed when the cyclic structure is formed, as also happened in the cases of terephthalic-and thiophene-2,5-dicarboxylates of lithocholic acid piperazine diamides.…”

“…Alternatively, the synthesis could be performed in the presence of a guest acting as a template. A PM3 energetically optimized terephthalate-closed cholaphane 23 from allo-lithocholic acid (with trans-A/B ring fusion) shows a better cavity for molecular recognition purposes. These syntheses are in progress.…”

“…21 We have previously reported syntheses and spectral characterizations of several bile acid-based open dimers and cholaphanes. 22 -28 We have also investigated their alkali metal 24 and Ag(I) cation 23,25,27 binding properties. Recently, Dukh et al 29 reported studies on novel deep cavity calix [4]pyrroles derived from steroidal ketones (prepared from cholic acid), which have enantiomeric recognition potency towards some carboxylate anions.…”

Synthesis of Nitrogen‐ and Oxygen‐Containing Macrocycles—Derivatives of Lithocholic Acid

“…[15,17,18] To improve the flexibility of the macrocycle, ester groups were used for the cyclization. [19][20][21][22][23] Cholaphanes containing amide and ester groups are susceptible to acidic and basic conditions, and to the reduction by metal or hydrogen. Ra, Cho, and Choi developed the synthesis of the cholaphane in which steroidal fragments are linked through ethyleneglycol moieties.…”