Copper-Catalyzed [1,3]-Dipolar Cycloaddition for the Synthesis of Macrocycles Containing Acyclic, Aromatic and Steroidal Moieties

Abstract

Copper-catalyzed 1,3-dipolar cycloaddition reactions are used for the synthesis of a series of bis(1,2,3-triazole)-containing macrocycles possessing acyclic, aromatic and steroidal fragments. The influence of the nature of the substituents on the diazides, and the length of the dialkyne-linking chain, in the substrates, on the product yields is studied. Macrocycles containing steroidal fragments are prepared via reactions of bis(cholane)-24,24¢-diazides with aliphatic dipropargyl esters, or bis(cholane)-24,24¢-dipropargyl esters with aromatic diazides, or by cyclization-dimerization of bile acid derivatives possessing both azide and acetylene groups in the same molecule.Macrocycles containing bile acid fragments are of substantial interest because such compounds can be used for modeling biological systems and for molecular recognition. 1 The rigid lipophilic skeleton of the steroid molecule, together with the presence of several endocyclic hydroxy groups, imparts macrocycles derived from bile acids with high selectivity towards cations, anions and neutral molecules. 2 Chola-crown ethers produced from bile acids readily form complexes with alkali metal ions. 3 Ester, amide and ether fragments have been used as linkers to bind two bile acid units. We have reported previously that palladium-catalyzed amination reactions can be employed for the synthesis of macrocyclic derivatives of bile acids in unexpectedly high yields. 4 This was explained by the fact that the final macrocyclization step proceeds within the coordination sphere of the transition metal, which enables favorable orientation of the two reacting fragments of the intermediate during macrocycle formation. In addition, metathesis has been proposed for the synthesis of steroid-containing macrocycles. 5Following reports of the catalytic effect of copper(I) in the Huisgen reaction, interest in the synthesis of complexing agents possessing a 1,2,3-triazole moiety has increased significantly. 6 This approach has several attractive features including a simple synthetic procedure, the stability of triazoles towards many reagents, and the ability of the triazole group to act both as an inert linker and a complexant for cations 7 and anions. 8 The synthesis of macrocycles possessing triazole groups is of interest because, in addition to above-mentioned properties, the formation of triazole rings is substantially exothermic 9 which can lead to increased product yields. To date, triazole units have been introduced into macrocycles via peptides and glycopeptides, 10 sugars 11 and steroids. 8 Copper-catalyzed syntheses of compounds containing several triazole rings conjugated to an aromatic ring is limited to only a few examples. 7b,12 No reports of aromatic diazides as easily available precursors to such conjugated systems were found in the literature.Herein we report a new approach to triazole-containing macrocycles which employs a copper-catalyzed 1,3-dipolar cycloaddition. We used aromatic 1a-e, aliphatic 1f-h, and cholane-containing 1i diazides in reactions wit...

Steroidal Conjugates: Synthesis, Spectroscopic, and Biological Studies

“…The synthesis of (54) was started with 29-deoxyuridine ( Fig. SCHEME 6.5 Regio-and chemoselective synthesis of steroid-thiopyrimidine (49)(50)(51)(52)(53) conjugates [46]. Derivative of this compound 59-O-DMT-5-amino-29-deoxyuridine was synthesized in four steps.…”

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

“…Though this method is often preferable for the macrocyclization in comparison to classical nucleophilic substitution [28,31], it is limited to bile acid derivatives bearing groups with C(sp 2 )–Hal bonds. In addition, the use of bile acid moieties saturated with hydroxy groups was inconvenient for the syntheses of bis(polyoxamino) derivatives by Pd-catalyzed amination [34–35].…”

Synthesis of Macrocycles Containing Endocyclic Chiral BINAM Moieties

“…[4,5] Also we elaborated a new type of macrocycles with endocyclic chiral cholane fragments. [6][7][8][9] Macrocyclic compounds containing fragments with C2 chirality are known for quite a long time, and the majority Macrocycles Containing Endocyclic Chiral BINAM Moieties of them possess 2,2'-binaphthol (BINOL) moiety. Some of them were reported before 1991 when a comprehensive review on all types of known macrocycles emerged.…”

“…Obtained from compound 7 (0.13 mmol, 82 mg), dioxadiamine 2b (0.13 mmol, 26 mg), in the presence of Pd(dba) 2 1, 2,8,9,10,11,13,14,16,17,19,20,21,22,28,7:27, [1,4,7,11,18,23, (13). A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with (S)-BI-NAM (2.4 mmol, 674mg), 1,3-dibromo-5-(bromomethyl)benzene (4.8 mmol, 1551 mg), acetonitrile (24 ml) and potassium carbonate (9.6 mmol, 1325 mg).…”