Steroid-derived macrocycles

Fig. 21 Concept towards steroid-derived macrocycles via Mibs.

The first macrocyclic steroid derivative intended for use in molecular recognition chemistry has been synthesized by direct cyclodimerization of amide 99, which in turn was prepared from acid 97 and amine 98 using DEPC.38... 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

In principle, the synthesis can be realized as a one-pot process treatment of ketones with hydroxylamine in KOH-DMSO following interaction of the formed ketoximes with acetylene. Various pyrroles with alkyl, cycloalkyl, aryl and hetaryl substituents, as well as pyrroles condensed with aliphatic macrocycles, terpenic and steroid structures, together with their vinyl derivatives now become available. 

Using steroid as supporting scaffold, the reaction of diamine 67, diisocyanide 68 (both being derived from lithocholic acid), acetic acid and formaldehyde afforded the macrocycle 69a in 58% yield as a mixture of head-to-tail and head-to head cyclic dimers ((1), Scheme 20 for the sake of clarity, only the head-to-tail regioi-somer was shown) [96-98]. On the other hand, the reaction of diacid 70, diisocyanide 68, isopropylamine and formaldehyde afforded the steroid-peptoid conjugate... 

The macrocycle l,4,7,10-tetraazacyclododecane-N,N, N",N" -tetraacetic acid (DOTA) is known to form stable complexes with lanthanides. A steroid conjugate (Fig. 8.16) was prepared via coupling of 6a-amino-17p-estradiol with a C functionalized DOTA derivative, namely, p-thiocyanatobenzyl DOTA, as a BFCA. The synthesis of 6a-amino-17p-estradiol was carried out by a four step reaction sequence. The intermediate and target compounds were characterized using high resolution H-NMR spectroscopy. 

Synthesis and characterization of lithocholic acid derived dipyrromethanes. Koivukorpi et aO in early 2004 reported the synthesis of a series of steroidal dipyrromethane analogues that can be exploited for the synthesis of pyrrole-steroidal macrocycles. The authors used long-range HMBC data to confirm the structure. 

A number of mammalian pheromones are combinations of low-molecular-weight carboxylic acids. In other mammals, steroids, sulfur-containing compounds, amines, and alcohols play pheromonal roles some of these compounds also are derived from carboxylic acids (Albone, 1984 Harbome, 1982). Macrocyclic lactones such as civetone (77) and mus-cone (78) are the active odor compounds of the civet cat and the musk deer, respectively. 

Baurle S, Blume T, Mengel A, Parchman C, SkubaUa W, Easier S, Schafer M, Siilzle D, Wrona-Metzinger H-P. Erom rigidity to conformational flexibility macrocyclic templates derived from ansa-steroids. Angew. Chem. Int. Ed. 2003 21 3961-3964. 

---